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PENDING
Wireless Power Receiver and Control Method Thereof
A wireless power receiver according to an embodiment wirelessly receives power from a wireless power transmitter. The wireless power receiver includes a printed circuit board having a reception space in a predetermined area, a receiving coil disposed in the reception space of the printed circuit board for receiving power from the wireless power transmitter, and a short-range communication antenna disposed on the printed circuit board while surrounding the receiving coil.
1. A wireless power receiver that wirelessly receives power from a wireless power transmitter, the wireless power receiver comprising: a board comprising a plurality of layers; a wireless receiving coil disposed in the board; a short-range communication coil disposed in the board; and a shielding unit disposed in the board, wherein the shielding unit is disposed on the wireless receiving coil and the short range communication coil, and wherein the wireless receiving coil, the short-range communication coil, and the shielding unit are disposed between the plurality of layers. 2. A wireless power receiver of claim 1, wherein the plurality of players comprises a first layer, a second layer under the first layer, and a third layer under the second layer. 3. A wireless power receiver of claim 2, wherein the shielding unit is disposed between the first layer and the second layer. 4. A wireless power receiver of claim 3, wherein the short-range communication coil is disposed between the second layer and the third layer. 5. A wireless power receiver of claim 4, further comprising a separation distance between the second layer and the third layer. 6. A wireless power receiver of claim 5, wherein the separation distance is smaller than a thickness of the short-range communication coil. 7. A wireless power receiver of claim 3, wherein the wireless receiving coil is disposed between the second layer and the third layer. 8. A wireless power receiver of claim 7, further comprising a separation distance between the second layer and the third layer. 9. A wireless power receiver of claim 8, wherein the separation distance is smaller than a thickness of the wireless receiving coil. 10. A wireless power receiver of claim 1, wherein the plurality of layers comprises a first layer, a second layer under the first layer, a third layer under the second layer, and a fourth layer under the third layer. 11. A wireless power receiver of claim 10, wherein the shielding unit is disposed between the first layer and the second layer. 12. A wireless power receiver of claim 11, wherein the wireless receiving coil comprises a plurality of layers. 13. A wireless power receiver of claim 12, wherein the wireless receiving coil is disposed between the second layer and the third layer and between the third layer and the fourth layer. 14. A wireless power receiver of claim 13, further comprising a separation distance between the second layer and the third layer and between the third layer and the fourth layer. 15. A wireless power receiver of claim 14, wherein the separation distance is smaller than a thickness of at least one of the plurality of layers of the wireless receiving coil. 16. A wireless power receiver of claim 11, wherein the short-range communication coil comprises a plurality of layers. 17. A wireless power receiver of claim 16, wherein the short-range communication coil is disposed between the second layer and the third layer and between the third layer and the fourth layer. 18. A wireless power receiver of claim 17, further comprising a separation distance between the second layer and the third layer and between the third layer and the fourth layer. 19. A wireless power receiver of claim 18, wherein the separation distance is smaller than a thickness of at least one of the plurality of layers of the short-range communication coil. 20. A wireless power receiver of claim 1, wherein the wireless receiving coil comprises a first wireless receiving coil and a second wireless receiving coil, wherein at least one of the plurality of layers is disposed between the first wireless receiving coil and the second wireless receiving coil. 21. A wireless power receiver of claim 1, wherein the short-range communication coil comprises a first short-range communication coil and a second short-range communication coil, wherein at least one of the plurality of layers is disposed between the first short-range communication coil and the second short-range communication coil. 22. A wireless power receiver of claim 1, wherein the wireless receiving coil is surrounded by the short-range communication coil. 23. A wireless power receiver of claim 1, wherein the shielding unit is arranged to correspond to an area occupied by the wireless power receiving coil and the short-range communication coil. 24. A wireless power receiver of claim 1, wherein the shielding unit comprises a ferrite. 25. A wireless power receiver of claim 1, wherein the board comprises a reception space. 26. A wireless power receiver of claim 20, wherein a thickness of the first wireless receiving coil is thinner than a thickness of the shielding unit. 27. A wireless power receiver of claim 26, wherein a thickness of the first wireless receiving coil is thicker than a thickness of at least one of the plurality of layers. 28. A wireless power receiver of claim 21, wherein a thickness of the first short-range communication coil is thinner than a thickness of the shielding unit. 29. A wireless power receiver of claim 28, wherein a thickness of the first short-range communication coil is thicker than a thickness of at least one of the plurality of layers.
CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 15/195,390, filed Jun. 28, 2016, entitled “Wireless Power Receiver and Control Method Thereof”, which is a continuation of U.S. application Ser. No. 13/658,116, filed Oct. 23, 2012, now U.S. Pat. No. 9,461,364, issued on Oct. 4, 2016, entitled “Wireless Power Receiver and Control Method Thereof”, which claims the benefit under 35 U.S.C. §119 of Korean Patent Application No. 10-2011-0114721, filed Nov. 4, 2011, entitled “Apparatus for Receiving Wireless Power and Method for Controlling Thereof”, all of which are incorporated herein by reference in their entirety. BACKGROUND The embodiment relates to a wireless power receiver and a control method thereof. A wireless power transmission or a wireless energy transfer refers to a technology of wirelessly transferring electric energy to desired devices. In the 1800's, an electric motor or a transformer employing the principle of electromagnetic induction has been extensively used and then a method for transmitting electrical energy by irradiating electromagnetic waves, such as radio waves or lasers, has been suggested. Actually, electrical toothbrushes or electrical razors, which are frequently used in daily life, are charged based on the principle of electromagnetic induction. Until now, the long-distance transmission using the magnetic induction, the resonance and the short-wavelength radio frequency has been used as the wireless energy transfer scheme. Recently, among wireless power transmitting technologies, an energy transmitting scheme employing resonance has been widely used. Since an electric signal generated between the wireless power transmitter and the wireless power receiver is wirelessly transferred through coils in a wireless power transmitting system using electromagnetic induction, a user may easily charge electronic appliances such as a portable device. However, due to the thickness of each of a receiving coil, a short-range communication antenna and a printed circuit board constituting a receiving side, a size of an electronic appliance becomes larger and it is not easy to embed them in the electronic appliance. Specifically, the size of the electronic appliance is increased corresponding to the thickness of the receiving coil, the short-range communication antenna and the printed circuit board. Further, when an overcurrent flows through the short-range communication module, it is difficult to effectively cope with the overcurrent. Further, a magnetic field generated from the receiving coil exerts an influence on an inside of an electronic appliance, so that the electronic appliance malfunctions. SUMMARY The embodiment provides a wireless power receiver with a minimized thickness by suitably arranging a receiving coil, a short-range communication antenna and a printed circuit board. The embodiment provides a wireless power receiver with a reduced thickness by allowing a short-range communication antenna to be included in a printed circuit board. The embodiment provides a wireless power receiver which prevents an electronic appliance from malfunctioning using a shielding unit. The embodiment provides a wireless power receiver which breaks an overcurrent by using a protecting unit to protect a short-range communication module. A wireless power receiver according to the embodiment wirelessly receives power from a wireless power transmitter. The wireless power receiver includes: a printed circuit board having a reception space in a predetermined area; a receiving coil disposed in the reception space of the printed circuit board for receiving power from the wireless power transmitter; and a short-range communication antenna disposed on the printed circuit board while surrounding the receiving coil. A wireless power receiver according to the embodiment wirelessly receives power from a wireless power transmitter. The wireless power receiver includes: a short-range communication antenna for performing short-range communication; a receiving coil for wirelessly receiving power from the wireless power transmitter; and a switch for changing a conducting state of the short-range communication antenna according to a reception of the power, wherein the wireless power receiver opens or shorts the switch according to the reception of the power. A method of controlling a wireless power receiver, which includes a short-range communication antenna for communicating with an outside, according to the embodiment includes determining whether power is received from a transmitting coil through electromagnetic induction; opening a switch which changes a conducting state of the short-range communication antenna when the power is received; identifying whether an amount of received power is equal to or greater than a threshold value; and shorting the switch when the amount of the received power is equal to or greater than the threshold value. According to the embodiments, the thickness of the wireless power receiver can be minimized by suitably arranging the receiving coil, the short-range communication antenna and the printed circuit board. According to the embodiments, the wireless power receiver can be prevented from being broken by preventing an overcurrent from flowing in the wireless power receiver and malfunction of the wireless power receiver can be prevented by shielding a magnetic field. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a view showing a wireless power transmission system according to the embodiment; FIG. 2 is an equivalent circuit diagram of a transmitting coil according to the embodiment; FIG. 3 is an equivalent circuit diagram of the wireless power transmission system according to the embodiment; FIG. 4 is a block diagram of a wireless power receiver according to the embodiment; FIG. 5 is a view showing an example of a configuration of the wireless power receiver according to the embodiment; FIG. 6 is a exploded perspective and sectional view illustrating the wireless power receiver according to the embodiment; FIG. 7 is a sectional view showing an arrangement of elements of the wireless power receiver according to the embodiment; FIG. 8 is a view illustrating a top surface and a bottom surface of the wireless power receiver according to the embodiment; FIG. 9 is a view illustrating one example of attaching a shielding unit onto the wireless power receiver according to the embodiment; FIG. 10 is a view illustrating one example of inserting the shielding unit into the wireless power receiver according to the embodiment; and FIG. 11 is a flowchart illustrating a control method of the wireless power receiver according to the embodiment. DETAILED DESCRIPTION OF THE EMBODIMENTS Hereinafter, exemplary embodiments of the disclosure will be described in detail so that those skilled in the art can easily comprehend the disclosure. FIG. 1 illustrates a wireless power transmission system according to an embodiment. The power generated from a power source 100 is provided to a wireless power transmitter 200, such that the power is transferred by electromagnetic induction to a wireless power receiver 300. In detail, the power source 100 is an AC power source for supplying AC power of a predetermined frequency. The wireless power transmitter 200 includes a transmitting coil 210. The transmitting coil 210 is connected to the power source 100, such that an AC current flows through the transmitting coil 210. When the AC current flows through the transmitting coil 210, an AC current is induced to the receiving coil 310 physically apart from the transmitting coil 210 due to electromagnetic induction, so that the AC power is transferred to the wireless power receiver 300. Power may be transferred by electromagnetic induction between two LC circuits which are impedance-matched with each other. The power transmission through electromagnetic induction may enable high efficiency power transmission. The wireless power receiver 300 may include a receiving coil 310, a rectifier circuit 320 and a load 330. In the embodiment, the load 330 may be not included in the wireless power receiver 300, but may be provided separately. The power transmitted through the transmitting coil 210 is received at the receiving coil 310 by electromagnetic induction. The power transferred to the receiving coil 310 is transferred through the rectifier circuit 320 to the load 330. FIG. 2 is an equivalent circuit diagram of the transmitting coil 210 according to the embodiment. As shown in FIG. 2, the transmitting coil 210 may include an inductor L1 and a capacitor C1, and form a circuit having a suitable inductance value and a suitable capacitance value. The capacitor C1 may be a variable capacitor. By controlling the variable capacitor, an impedance matching may be performed. Meanwhile, an equivalent circuit of the receiving coil 320 may be equal to that depicted in FIG. 2. FIG. 3 is an equivalent circuit diagram of the wireless power transmitting system according to the embodiment. As shown in FIG. 3, the transmitting coil 210 may include an inductor L1 having a predetermined inductance value and a capacitor C1 having a predetermined capacitance value. Further, as shown in FIG. 3, the receiving coil 310 may include an inductor L2 having a predetermined inductance value and a capacitor C2 having a predetermined capacitance value. The rectifier circuit 320 may include a diode D1 and a rectifying capacitor C3 such that the rectifier circuit 320 converts AC power into DC power and outputs the DC power. Although the load 330 is denoted as a DC power source, the load 330 may be a battery or other devices requiring DC power. Next, a wireless power receiver according to the embodiment will be described with reference to FIGS. 4 to 10. FIG. 4 is a block diagram of a wireless power receiver according to the embodiment, FIG. 5 is a view showing an example of a configuration of the wireless power receiver according to the embodiment, FIG. 6 is a exploded perspective and sectional view illustrating the wireless power receiver according to the embodiment, FIG. 7 is a sectional view showing an arrangement of elements of the wireless power receiver according to the embodiment, FIG. 8 is a view illustrating a top surface and a bottom surface of the wireless power receiver according to the embodiment, FIG. 9 is a view illustrating one example of attaching a shielding unit onto the wireless power receiver according to the embodiment, and FIG. 10 is a view illustrating one example of inserting the shielding unit into the wireless power receiver according to the embodiment. First, referring to FIG. 4, the wireless power receiver 300 may include a receiving coil 310, a short-range communication antenna 340, a switch 350, a protecting unit 360, a short-range communication module 370, a shielding unit 380, and a controller 390. The wireless power receiver 300 according to the embodiment may be installed in a terminal or an electronic appliance requiring power, such as a portable terminal, a laptop computer, and a mouse. The receiving coil 310 receives power from the transmitting coil 210 of the wireless power transmitter 200 through electromagnetic induction. That is, if a magnetic field is generated as an AC current flows through the transmitting coil 210, a current is induced to the receiving coil 310 by the generated magnetic field so that an AC current flows therethrough. In the embodiment, the receiving coil 310 may be disposed in a reception space of a printed circuit board 301. The receiving coil 310 may be provided by winding a conducting wire server times. In the embodiment, the receiving coil 310 may have a spiral shape, but the embodiment is not limited thereto. The short-range communication antenna 340 may communicate with a reader capable of performing a short-range communication. The short-range communication antenna 340 may perform a function of an antenna which transmits and receives information to and from the reader. In the embodiment, the short-range communication antenna 340 may be disposed at an outside of the receiving coil 310. In the embodiment, the receiving coil 310 may be disposed in the reception space inside the printed circuit board 301, and the short-range communication antenna 340 may be disposed to surround the receiving coil 310 on the printed circuit board 301. The above configuration will be described in more detail with reference to FIG. 6. Referring to the exploded perspective view of the wireless power receiver 300 shown in FIG. 6(a), the wireless power receiver 300 may include a case 302, the printed circuit board 301, the receiving coil 310, the short-range communication antenna 340 and the shielding unit 380. Here, the case 302 refers to a case of a portable terminal, but the embodiment is not limited thereto. The shielding unit 380 will be described later. Referring to FIG. 6(a), it may be identified that the receiving coil 310 is disposed in the reception space A of the printed circuit board 301 and the short-range communication antenna 340 is disposed on the printed circuit board 301. That is, the receiving coil 310 may be disposed in the reception space A provided inside the printed circuit board 301, and the short-range communication antenna 340 may be disposed at an upper side of the printed circuit board 301 while surrounding the reception space A. FIG. 6 (b) is a sectional view showing the arrangement of the elements of the wireless power receiver 300 illustrated in FIG. 6(a). In the embodiment, the printed circuit board 301, the receiving coil 310 and the short-range communication antenna 340 may be inserted into the case 302 through the injection molding. Further, as described above, the short-range communication antenna 340 may be disposed at an outer periphery on the printed circuit board 301 while surrounding the receiving coil 310 placed in the reception space A. Hereinafter, the arrangement among the receiving coil 310, the short-range communication antenna 340 and the printed circuit board 301 will be described in more detail with reference to FIGS. 7 and 8. First, referring to FIG. 7, the printed circuit board 301 has the reception space A in a predetermined area thereof. In the embodiment, the predetermined area may include the central portion of the printed circuit board 301. In the embodiment, the central portion of the printed circuit board 301 may have the reception space having a polygonal shape, such as a rectangular shape and a circular shape. The receiving coil 310 is disposed in the reception space A of the printed circuit board 301, and receives power from the transmission induction coil 210 through electromagnetic induction. In the embodiment, the receiving coil 310 and the printed circuit board 301 may be manufactured such that the thickness of the receiving coil 310 may be equal to that of the printed circuit board 301 or the thickness of the receiving coil 310 may be less than that of the printed circuit board 301. In this case, the increase of the thickness of the wireless power receiver 300 due to the thicknesses of the receiving coil 310 and the short-range communication antenna 340 is prevented, so that the wireless power receiver 300 can be easily embedded in the case of the portable terminal. In the embodiment, the receiving coil 310 may be manufactured to have a shape in match with a shape of the reception space A of the printed circuit board 310. For example, when the shape of the reception space A of the printed circuit board 310 is rectangular, the receiving coil 310 or the conducting wire may be wound in a rectangular shape. When the shape of the reception space A of the printed circuit board 310 is circular, the receiving coil 310 or the conducting wire may be wound in a circular shape. Thus, the receiving coil 310 or the conducting wire may have various shapes. The short-range communication antenna 340 may be included in the printed circuit board 301 and may be configured to surround the receiving coil 310. In the embodiment, the short-range communication antenna 340 may be manufactured such that the short-range communication antenna 340 may be embedded in the printed circuit board 301, and may be configured to surround the outer periphery of the receiving coil 310 having various shapes such as a rectangular shape or a circular shape. In this case, the increase of the thickness of the wireless power receiver 300 due to the thickness of the printed circuit board 301 and the short-range communication antenna 340 can be prevented so that the wireless power receiver 300 can be easily installed in the case of the portable terminal. The wireless power receiver 300 may further include a shielding unit 380 for shielding a magnetic field generated by the receiving coil 310. In the embodiment, the shielding unit 380 may be disposed to cover an area occupied by the receiving coil 310. In the embodiment, the shielding unit 380 may be disposed on the receiving coil 310 and the short-range communication antenna 340 such that the shielding unit 380 may include the area occupied by the receiving coil 310 and the short-range communication antenna 340. In the embodiment, the shielding unit 380 may have a reception space in a predetermined area thereof. A wireless charging circuit 375, which is place on the top surface of the printed circuit board 301, may be disposed in the reception space of the shielding unit 380. The wireless charging circuit 375 may include a rectifier circuit for converting AC power into DC power, a capacitor for removing a noise signal, and a main IC chip for performing the operation for the wireless power reception. In the embodiment, the shielding unit 380 and the wireless charging circuit 375 may be manufactured such that the thickness of the shielding unit 380 may be equal to that of the wireless charging circuit 375 or the thickness of the shielding unit 380 may be less than that of the wireless charging circuit 375. In this case, the increase of the thickness of the wireless power receiver 300 due to the thicknesses of the shielding unit 380 and the wireless charging circuit 375 can be prevented, so that the wireless power receiver 300 can be easily installed in the case of the portable terminal. FIG. 8(a) is a view showing a bottom surface of the wireless power receiver according to the embodiment and FIG. 8(b) is a view showing a top surface of the wireless power receiver according to the embodiment. FIG. 8(a) illustrates the arrangement of the printed circuit board 310, the receiving coil 310 and the short-range communication antenna 340 according to the embodiment. The printed circuit board 301 has a reception space A in the central area, and the receiving coil 310 having a rectangular shape is disposed in the reception space A. The short-range communication antenna 340 is embedded in the printed circuit board 301. In this case, the increase of the thickness of the wireless power receiver 300 due to the thickness of the printed circuit board 301 and the short-range communication antenna 340 can be prevented, so that the wireless power receiver 300 can be easily installed in the case of the portable terminal. Further, the receiving coil 310 and the printed circuit board 301 may be manufactured such that the thickness of the receiving coil 310 may be equal to that of the printed circuit board 301 or the thickness of the receiving coil 310 may be less than that of the printed circuit board 301. In this case, the increase of the thickness of the wireless power receiver 300 due to the thickness of the receiving coil 310 and the printed circuit board 301 can be prevented, so that the wireless power receiver 300 can be easily installed in the case of the portable terminal. FIG. 8 (b) illustrates the arrangement of the wireless charging circuit 375 and the shielding unit 380 according to the embodiment. The shielding unit 380 may have a reception space in a predetermined area thereof, and the wireless charging circuit 375 may be disposed in the reception space of the shielding unit 380. In the embodiment, the shielding unit 380 and the wireless charging circuit 375 may be manufactured such that the thickness of the wireless charging circuit 375 may be equal to that of the wireless charging circuit 375 or the thickness of the shielding unit 380 may be less than that of the wireless charging circuit 375. In this case, the increase of the thickness of the wireless power receiver 300 due to the thickness of the shielding unit 380 and the wireless charging circuit 375 can be prevented, so that the wireless power receiver 300 can be easily installed in the case of the portable terminal. Referring again to FIG. 4, although various technologies can be applied to a short-range communication protocol used in the wireless communication antenna 340 and a short-range are communication module 370 which will be described below, NFC (Near Field Communication) may be preferably used for the wireless communication antenna 340 and the short-range communication module 370. The NFC is a technology for performing wireless communication in a short-range through the bandwidth of 13.56 MHz. The switch 350 is connected to the short-range communication antenna 340 and receives an open or short signal from the controller 390 to be described below such that the switch 350 may change a conducting state of the short-range communication antenna. If it is determined that the power is received from the transmitting coil 320, the switch 350 may receive the open signal from the controller 390 such that the switch 350 may break the current from flowing through the short-range communication antenna 340. If the wireless power receiver 300 is charged with an amount of power equal to or higher than a threshold value, the switch 350 may receive the short signal from the controller 390 such that the switch 350 may conduct the current through the short-range communication antenna 340, so the switch 350 may allow the short-range communication antenna 340 to be operated. The protecting unit 360 is operated when a current equal to or higher than a threshold current value flows through the protecting unit 360, such that the protecting unit 360 may break the current equal to or higher than the threshold current value from being transferred to the short-range communication module 370. In the embodiment, as shown in FIG. 5, the protecting unit 360 may include at least one zener diode. The zener diode may allow only a current having a value equal to or less than a threshold current value to flow through a circuit. The threshold current value may be variably set and may be a limit value at which the short-range communication module 370 may be normally operated. When a current transferred to the short-range communication antenna 340 has the threshold current value or above, the protecting unit 360 changes the flowing direction or the flow of the current to prevent an overcurrent from flowing through the short-range communication module 370. Referring to FIG. 5, if the current flowing through the short-range communication antenna 340 has the threshold current value or above, the protecting unit 350 is operated. Referring to FIG. 5, when the current flowing in the A-direction has the threshold current value or above, the current having the threshold current value or above flows into the zener diode placed at an upper side of the protecting unit 350. In a case that the current flowing in the B-direction has the threshold current value or above, the same procedure is performed. An overcurrent having the threshold current value or above flows through the zener diode and is discharged as thermal energy. That is, the protecting unit 360 may prevent the overcurrent from flowing through the short-range communication module 370, so that damage of the communication module 370 may be prevented. Referring again to FIG. 4, the short-range communication module 370 may receive a current through the short-range communication antenna 340. Although various types of communication technologies can be applied to the short-range communication module 370, the NFC (Near Field Communication) protocol may be preferably used. The shielding unit 380 may change a direction of the magnetic field generated from the receiving coil 310. The shielding unit 380 may absorb the magnetic field generated from the receiving coil 310 and may discharge the absorbed magnetic field as thermal energy. That is, as the shielding unit 380 may change the direction of the magnetic field generated from the coil 310 or absorb and discharge the magnetic field as thermal energy, it is possible to prevent the magnetic field from exerting bad influence upon any other elements inside an electronic appliance to which the wireless power receiver 300 is installed. That is, the shielding unit 380 can prevent the malfunction caused by the magnetic field applied to other elements. The shielding unit 380 may include ferrite, but the embodiment is not limited thereto. The shielding unit 380 may be disposed at one side of the wireless power receiver 300. Hereinafter, the arrangement of the shielding unit 380 on the wireless power receiver 300 will be described with reference to FIGS. 9 and 10. First, referring to FIG. 9, after the short-range communication antenna 340 has been disposed on the printed circuit board 301, the shielding unit 380 may be attached to one side of the printed circuit board 301 with an adhesive. Referring to FIG. 10, while the procedure of disposing the short-range communication antenna 340 or receiving coil (310)(not shown in the FIG. 10) in the printed circuit board 301 is being performed, the shielding unit 380 may be inserted into the printed circuit board 301. That is, unlike FIG. 9, since the shielding unit 380 is disposed in the printed circuit board 301, the procedure of disposing the shielding unit 380 may be included in the procedure of disposing the short-range communication antenna 340 without performing the procedure of disposing the shielding unit 380 at one side of the printed circuit board 301. That is, as described above, according to the embodiment shown in FIG. 8, when the shielding unit 380 is inserted into the printed circuit board 301, the entire thickness of the wireless power receiver 300 may be reduced corresponding to the thickness of the adhesive 303. Thus, a separate procedure of attaching the shielding unit 380 is not necessary, so the manufacturing process may be simplified. Referring again to FIG. 4, the controller 390 may control an entire operation of the wireless power receiver 300. The controller 390 may change an operating mode of the wireless power receiver 300 into a charging mode or a communication mode according to a reception of the power. In the embodiment, the charging mode may be that the wireless power receiver 300 does not communicate with an outside through the short-range communication module 370, but receives power from the transmitting coil 210. The communication mode may be that the wireless power receiver 300 does not receive power from the transmitting coil 210, but communicate with an outside through the short-range communication module 370. The controller 390 may change the conducting state of the short-range communication antenna 340 by opening or shorting the switch 350. If a current is induced to the receiving coil 310 in the state that the switch 350 is shorted, the controller 390 may open the switch 350 to change the operating mode of the wireless power receiver 300 into the charging mode. That is, if the controller 390 receives power from the transmitting coil 210, the controller 390 opens the switch 350 to prevent the current from flowing through the short-range communication antenna 340. In the state that the switch 350 is opened, if a current is not induced to the receiving coil 310, the controller 390 may short the switch 350 to change the operating mode of the wireless power receiver 300 into the communication mode. That is, if the controller does not receive power from the transmitting coil 210, the controller 390 may short the switch 350 to allow a current to conduct the short-range communication antenna 340. The controller 390 may sense the current flowing through the receiving coil 310 for changing the conductive state of the short-range communication antenna 340. In another embodiment, the wireless power receiver 300 may further include a separate current sensing unit (not shown) which can sense the current induced to the receiving coil 310 to sense the current flowing through the receiving coil 310. The controller 390 may open or short the switch 350 according to an amount of power received at the wireless power receiver 300. This will be described below with reference to FIG. 11. FIG. 11 is a flowchart illustrating a control method of the wireless power receiver according to the embodiment. Hereinafter, the control method of the wireless power receiver according to the embodiment will be described with reference to FIGS. 1 to 10. In step S101, the controller 390 may determine whether the receiving coil 310 receives power from the transmitting coil 210 through electromagnetic induction. In the embodiment, the wireless power receiver 300 may further include a detecting unit (not shown) to determine whether power is received. A detecting coil may be used as the detecting unit. In step S103, if it is determined that the receiving coil 310 receives power from the transmitting coil 210 through electromagnetic induction, the switch 350, which changes the conductive state of the short-range communication antenna 340, may be opened. That is, the controller 390 may transmit an open signal to the switch 350 to prevent the current from flowing through the short-range communication antenna 340. In the embodiment, when it is determined that the receiving coil 310 receives power from the transmitting coil 210 through electromagnetic induction, the wireless power receiver 300 may be in the charging mode. When the wireless power receiver 200 is operated in the charging mode to receive power from the transmitting coil 310, the current flowing through the short-range communication antenna must be shut off because the magnetic field generated during the charging mode may interfere with the communication between the short-range communication module 370 and the outside. Then, in step S105, the controller 390 may determine whether the amount of power received at the wireless power receiver 300 is more than the threshold value. In the embodiment, although the threshold value corresponds to the state that the wireless power receiver 300 is charged at 100%, the threshold value is not limited thereto and may be variously set by a user. Then, in step S107, when the amount of power has the threshold value or above, the controller 390 allows the switch to be shorted. In this case, the wireless power receiver 300 terminates the charging mode and operates in the communication mode. Then, in step S109, the controller 390 determines whether the current flowing through the short-range communication antenna 340 is equal to or greater than the threshold current value. In step S111, when the current flowing through the short-range communication antenna 340 is equal to or greater than the threshold current value, the current flowing direction may be changed. In the embodiment, the threshold current value may mean a limit value allowing the short-range communication to be operated normally. In the embodiment, the threshold current value may be variously set by a user. In the embodiment, the change of the current flowing direction may be performed through the protecting unit 360. In the embodiment, the protecting unit 360 may be a zener diode. If the current having the threshold current value or above flows, the zener diode performs the function of discharging the current as thermal energy. In this case, the zener diode may prevent an overcurrent from flowing through the short-range communication module 370, such that damage of the short-range communication module 370 may be prevented. Although embodiments have been described with reference to a number of illustrative embodiments thereof, it should be understood that numerous other modifications and embodiments can be devised by those skilled in the art that will fall within the spirit and scope of the principles of this disclosure. More particularly, various variations and modifications are possible in the component parts and/or arrangements of the subject combination arrangement within the scope of the disclosure, the drawings and the appended claims. In addition to variations and modifications in the component parts and/or arrangements, alternative uses will also be apparent to those skilled in the art.
<SOH> BACKGROUND <EOH>The embodiment relates to a wireless power receiver and a control method thereof. A wireless power transmission or a wireless energy transfer refers to a technology of wirelessly transferring electric energy to desired devices. In the 1800's, an electric motor or a transformer employing the principle of electromagnetic induction has been extensively used and then a method for transmitting electrical energy by irradiating electromagnetic waves, such as radio waves or lasers, has been suggested. Actually, electrical toothbrushes or electrical razors, which are frequently used in daily life, are charged based on the principle of electromagnetic induction. Until now, the long-distance transmission using the magnetic induction, the resonance and the short-wavelength radio frequency has been used as the wireless energy transfer scheme. Recently, among wireless power transmitting technologies, an energy transmitting scheme employing resonance has been widely used. Since an electric signal generated between the wireless power transmitter and the wireless power receiver is wirelessly transferred through coils in a wireless power transmitting system using electromagnetic induction, a user may easily charge electronic appliances such as a portable device. However, due to the thickness of each of a receiving coil, a short-range communication antenna and a printed circuit board constituting a receiving side, a size of an electronic appliance becomes larger and it is not easy to embed them in the electronic appliance. Specifically, the size of the electronic appliance is increased corresponding to the thickness of the receiving coil, the short-range communication antenna and the printed circuit board. Further, when an overcurrent flows through the short-range communication module, it is difficult to effectively cope with the overcurrent. Further, a magnetic field generated from the receiving coil exerts an influence on an inside of an electronic appliance, so that the electronic appliance malfunctions.
<SOH> SUMMARY <EOH>The embodiment provides a wireless power receiver with a minimized thickness by suitably arranging a receiving coil, a short-range communication antenna and a printed circuit board. The embodiment provides a wireless power receiver with a reduced thickness by allowing a short-range communication antenna to be included in a printed circuit board. The embodiment provides a wireless power receiver which prevents an electronic appliance from malfunctioning using a shielding unit. The embodiment provides a wireless power receiver which breaks an overcurrent by using a protecting unit to protect a short-range communication module. A wireless power receiver according to the embodiment wirelessly receives power from a wireless power transmitter. The wireless power receiver includes: a printed circuit board having a reception space in a predetermined area; a receiving coil disposed in the reception space of the printed circuit board for receiving power from the wireless power transmitter; and a short-range communication antenna disposed on the printed circuit board while surrounding the receiving coil. A wireless power receiver according to the embodiment wirelessly receives power from a wireless power transmitter. The wireless power receiver includes: a short-range communication antenna for performing short-range communication; a receiving coil for wirelessly receiving power from the wireless power transmitter; and a switch for changing a conducting state of the short-range communication antenna according to a reception of the power, wherein the wireless power receiver opens or shorts the switch according to the reception of the power. A method of controlling a wireless power receiver, which includes a short-range communication antenna for communicating with an outside, according to the embodiment includes determining whether power is received from a transmitting coil through electromagnetic induction; opening a switch which changes a conducting state of the short-range communication antenna when the power is received; identifying whether an amount of received power is equal to or greater than a threshold value; and shorting the switch when the amount of the received power is equal to or greater than the threshold value. According to the embodiments, the thickness of the wireless power receiver can be minimized by suitably arranging the receiving coil, the short-range communication antenna and the printed circuit board. According to the embodiments, the wireless power receiver can be prevented from being broken by preventing an overcurrent from flowing in the wireless power receiver and malfunction of the wireless power receiver can be prevented by shielding a magnetic field.
H02J5012
20170810
20171123
97085.0
H02J5012
1
FLEMING, FRITZ M
Wireless Power Receiver and Control Method Thereof
UNDISCOUNTED
1
CONT-ACCEPTED
H02J
2,017
15,674,043
ACCEPTED
1-[2-(2,4-DIMETHYLPHENYLSULFANYL)-PHENYL]PIPERAZINE AS A COMPOUND With COMBINED SEROTONIN REUPTAKE, 5-HT3 AND 5-HT1A ACTIVITY FOR THE TREATMENT OF COGNITIVE IMPAIRMENT
1-[2-(2,4-dimethylphenylsulphanyl)phenyl)]piperazine exhibits potent activity on SERT, 5-HT3 and 5-HT1A and may as such be useful for the treatment of cognitive impairment, especially in depressed patients.
1. A method of alleviating a symptom or complication of depression or major depressive disorder, or delaying progression of depression or major depressive disorder, comprising: administering to a patient in need thereof a pharmaceutical composition comprising a hydrobromide salt of a 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine selected from the group consisting of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt alpha form, 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt beta form, 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt gamma form, 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt hemihydrate, 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt ethyl acetate solvate, and mixtures thereof, wherein said method alleviates a symptom or complication of depression or major depressive disorder, or delays the progression of depression or major depressive disorder, in said patient. 2. The method of claim 1, wherein said hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt alpha form. 3. The method of claim 2, wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt alpha form characterized by an XRPD pattern as shown in FIG. 2. 4. The method of claim 2, wherein the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt alpha form is characterized by XRPD peaks at 5.85, 9.30, 17.49, and 18.58+/−0.10° 2θ. 5. The method of claim 1, wherein said hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt beta form. 6. The method of claim 5, wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt beta form characterized by an XRPD pattern as shown in FIG. 3. 7. The method of claim 5, wherein the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt beta form is characterized by XRPD peaks at 6.89, 9.73, 13.78, and 14.62 +/−0.10° 2θ. 8. The method of claim 1, wherein said hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt gamma form. 9. The method of claim 8, wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt gamma form characterized by an XRPD pattern as shown in FIG. 4. 10. The method of claim 8, wherein the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt gamma form is characterized by XRPD peaks at 11.82, 16.01, 17.22, and 18.84 +/−0.10° 2θ. 11. The method of claim 1, wherein said hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt hemihydrate. 12. The method of claim 11, wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt hemihydrate characterized by an XRPD pattern as shown in FIG. 5. 13. The method of claim 11, wherein the 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine hydrobromide salt hemihydrate is characterized by XRPD peaks at 10.69, 11.66, 15.40, and 17.86 +/−0.10° 2θ. 14. The method of claim 1, wherein said hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt ethyl acetate solvate. 15. The method of claim 14, wherein the 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine hydrobromide ethyl acetate solvate is characterized by XRPD peaks at 8.29, 13.01, 13.39, and 16.62 +/−0.10° 2θ. 16. The method of claim 1, wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is a mixture of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt ethyl acetate solvate and 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt alpha form characterized by an XRPD pattern as shown in FIG. 6.
CROSS REFERENCE TO PRIOR APPLICATIONS This is a continuation application of U.S. application Ser. No. 14/948,775, filed Nov. 23, 2015, which is a continuation application of U.S. application Ser. No. 14/242,337, filed Apr. 1, 2014, which is a divisional application of U.S. application Ser. No. 12/301,061, filed Nov. 17, 2008, which is a U.S. National Phase application under 35 U.S.C. §371 of International Patent Application No. PCT/DK2007/050075, filed Jun. 15, 2007, and claims the benefit of Danish Patent Application No. PA 2006 00824, filed Jun. 16, 2006; U.S. Provisional Application No. 60/805,014, filed Jun. 16, 2006; Danish Patent Application No. PA 2006 01223, filed Sep. 22, 2006; U.S. Provisional Application No. 60/826,666, filed Sep. 22, 2006; Danish Patent Application No. PA 2006 01384, filed Oct. 25, 2006; U.S. Provisional Application No. 60/862,826, filed Oct. 25, 2006; and Danish Patent Application No. PA 2007 00427, filed Mar. 20, 2007, all of which are incorporated by reference herein. The International Application published in English on Dec. 21, 2007 as WO 2007/144005 under PCT Article 21(2). FIELD OF THE INVENTION The present invention relates to compounds, which exhibit serotonin reuptake inhibition activity combined with an activity on the serotonin receptor 1A (5-HT1A) and the serotonin receptor 3 (5-HT3), and which as such are useful in treatment of CNS related diseases. BACKGROUND OF THE INVENTION Selective serotonin reuptake inhibitors (SSRI) have for years been the first choice therapeutics for the treatment of certain CNS related diseases, in particular depression, anxiety and social phobias because they are effective, well tolerated and have a favourable safety profile as compared to previously used compounds, i.e. the classical tri-cyclic compounds. Nonetheless, therapeutic treatment using SSRI is hampered by a significant fraction of non-responders, i.e. patients who do not respond or only respond to a limited extent to the SSRI treatment. Moreover, typically an SSRI treatment does not begin to show an effect until after several weeks of treatment. In order to circumvent some of these shortcomings of SSRI treatment, psychiatrists sometimes make use of augmentation strategies. Augmentation of antidepressants may be achieved e.g. by combination with mood stabilisers, such as lithium carbonate or triiodothyronin, or by the parallel use of electroshock. It is known that a combination of inhibition of the serotonin transporter (SERT) with an activity on one or more serotonin receptors may be beneficial. It has previously been found that the combination of a serotonin reuptake inhibitor with a compound having 5-HT2C antagonistic or inverse agonistic effect (compounds having a negative efficacy at the 5-HT2C receptor) provides a considerable increase in the level of 5-HT (serotonin) in terminal areas, as measured in microdialysis experiments (WO 01/41701). This would imply a shorter onset of antidepressant effect in the clinic and an augmentation or potentiation of the therapeutic effect of the serotonin reuptake inhibitor (SRI). Similarly, it has been reported that the combination of pindolol, which is a 5-HT1A partial agonist, with a serotonin reuptake inhibitor gives rise to fast onset of effect [Psych. Res., 125, 81-86, 2004]. CNS related diseases, such as e.g. depression, anxiety and schizophrenia are often co-morbid with other disorders or dysfuntionalities, such as cognitive deficits or impairment [Scand. J. Psych., 43, 239-251, 2002; Am. J. Psych., 158, 1722-1725, 2001]. Several neurotransmitters are presumed to be involved in the neuronal events regulating cognition. In particular, the cholinergic system plays a prominent role in cognition, and compounds affecting the cholinergic system are thus potentially useful for the treatment of cognitive impairment. Compounds affecting the 5-HT1A receptor and/or the 5-HT3 receptor are known to affect the cholinergic system, and they may as such be useful in the treatment of cognitive impairment. Hence, a compound exerting 5-HT1A and/or 5-HT3 receptor activity would be expected to be useful in the treatment of cognitive impairment. A compound which moreover also exerts SERT activity would be particular useful for the treatment of cognitive impairment in depressed patients as such compound would also provide a fast onset of the treatment of the depression. WO 03/029232 discloses e.g. the compound 1-[2-(2,4-dimethylphenyl-sulfanyl)phenyl]piperazine (example 1e) as a compound having SERT activity. SUMMARY OF THE INVENTION The present inventors have surprisingly found that 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine exerts a combination of SERT inhibition, 5-HT3 antagonism and 5-HT1A partial agonism. Accordingly, in one embodiment the present invention provides compound I which is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine and pharmaceutically acceptable salts thereof, provided said compound is not the free base in a non-crystalline form. In one embodiment, the invention provides the use of compound I in therapy. In one embodiment, the invention provides a pharmaceutical composition comprising compound I. In one embodiment, the invention provides therapeutic methods comprising the administration of an effective amount of compound I to a patient in need thereof. In one embodiment, the invention provides the use of compound I in the manufacture of a medicament. FIGURES FIG. 1: XRPD of crystalline base FIG. 2: XRPD of alpha form of hydrobromide salt FIG. 3: XRPD of beta form of hydrobromide salt FIG. 4: XRPD of gamma form of hydrobromide salt FIG. 5: XRPD of hemi hydrate of hydrobromide salt FIG. 6: XRPD of the mixture of the ethyl acetate solvate and the alpha form of the hydrobromide salt FIG. 7: XRPD of hydrochloride salt FIG. 8: XRPD of monohydrate of hydrochloride salt FIG. 9: XRPD of mesylate salt FIG. 10: XRPD of fumarate salt FIG. 11: XRPD of maleate salt FIG. 12: XRPD of meso-tartrate salt FIG. 13: XRPD of L-(+)-tartrate salt FIG. 14: XRPD of D-(−)-tartrate salt FIG. 15: XRPD of sulphate salt FIG. 16: XRPD of phosphate salt FIG. 17: XRPD of nitrate salt FIGS. 18a and 18b: Effect of compounds of the present invention in the intradermal formalin test. X-axis shows the amount of compound administered; Y-axis shows the amount of time (sec) spent licking the paw. FIG. 18a: Response in the 0-5 minutes period; FIG. 18b: Response in the 20-30 minutes period FIG. 19a: Extra-cellular acetylcholine levels in prefrontal cortex in freely moving rats upon administration of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine HBr salt. FIG. 19b: Extra-cellular acetylcholine levels in ventral hippocampus in freely moving rats upon administration of 1-[2-(2,4-dimethylphenyl-sulfanyl)phenyl]piperazine HBr salt. FIG. 20: Effect of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine HBr salt on contextual fear conditioning in Sprague-Dawley rats when given 60 minutes before acquisition. Freezing behaviour was scored during 58-s habituation period prior to the foot shock US (pre-shock acquisition) (white bars). Freezing behaviour was measured 24 h after the training (retention test) (black bars). FIG. 21: Effect of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine HBr salt on contextual fear conditioning in Sprague-Dawley rats when given 1 h prior to the retention test. Freezing behaviour was scored during 58-s, prior to the foot shock US (acquisition) (white bars). Freezing behaviour was measured 24 h after the training (retention test) (black bars). FIG. 22: Effect of AA21004 on contextual fear conditioning in Sprague-Dawley rats when given immediately after the acquisition. Freezing behaviour was scored during 58-s, prior to the foot shock US (pre-sock acquisition) (white bars). Freezing behaviour was measured 24 h after the training (retention test) (black bars). DETAILED DESCRIPTION OF THE INVENTION The invention relates to compound I, 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine, the structure of which is and pharmaceutically acceptable salts thereof provided compound I is not the free base in a non-crystalline form. In one embodiment, said pharmaceutically acceptable salts are acid addition salts of acids that are non-toxic. Said salts include salts made from organic acids, such as maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Said salts may also be made from inorganic salts, such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Particular mentioning is made of salts made from methanesulfonic acid, maleic acid, fumaric acid, meso-tartaric acid, (+)-tartaric acid, (−)-tartaric acid, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphorous acid and nitric acid. Distinct mentioning is made of the hydrobromide salt. Oral dosage forms, and in particular tablets, are often preferred by the patients and the medical practitioner due to the ease of administration and the consequent better compliance. For tablets, it is preferable that the active ingredients are crystalline. In one embodiment, the compounds of the present invention are crystalline. In one embodiment the crystals of the present invention are solvates, i.e. crystals wherein solvent molecules from part of the crystal structure. The solvate may be formed from water, in which case the solvates are often referred to as hydrates. Alternatively, the solvates may be formed from other solvents, such as e.g. ethanol, acetone, or ethyl acetate. The exact amount of solvate often depends on the conditions. For instance, hydrates will typically loose water as the temperature is increased or as the relative humidity is decreased. In one embodiment, the compounds of the present invention are unsolvated crystals. Some compounds are hygroscopic, i.e. the absorb water when exposed to humidity. Hygroscopicity is generally regarded as an undesired property for compounds that are to be presented in a pharmaceutical formulation, in particular in a dry formulation, such as tablets. In one embodiment, the invention provides crystals with low hygroscopicity. For oral dosage forms using crystalline active ingredients it is also beneficial if said crystals are well-defined. In the present context, the term “well-defined” in particular means that the stoichiometry is well-defined, i.e. that the ratio between the ions forming the salt is the ratio between small integers, such as 1:1, 1:2, 2:1, 1:1:1, etc. In one embodiment, the compounds of the present invention are well-defined crystals. The crystalline compounds of the present invention may exist in more than one form, i.e. they may exist in polymorphic forms. Polymorphic forms exist if a compound can crystallize in more than one form. The present invention is intended to encompass all such polymorphic forms, either as pure compounds or as mixtures thereof. In one embodiment, the compounds of the present invention are in a purified form. The term “purified form” is intended to indicate that the compound is essentially free of other compounds or other forms of the same compound, as the case may be. In one embodiment, the invention provides crystalline salts of compounds of the present invention with XRPD as shown in FIGS. 1-17, and in particular FIGS. 2, 3, 4 and 5. The table below shows the major XRPD reflections for compounds of the present invention. Selected X-ray peak positions (° 2θ), All values +−0.1° Crystalline base 11.10 16.88 17.42 22.23 hydrobromide (α) 5.85 9.30 17.49 18.58 hydrobromide (β) 6.89 9.73 13.78 14.62 hydrobromide (γ) 11.82 16.01 17.22 18.84 hydrobromide (hydrate) 10.69 11.66 15.40 17.86 hydrobromide (ethylacetate solvate) 8.29 13.01 13.39 16.62 hydrochloride 9.41 12.37 19.66 22.55 hydrochloride (monohydrate) 7.72 13.45 15.39 17.10 mesylate 8.93 13.39 15.22 17.09 hydrogenfumarate 5.08 11.32 17.12 18.04 hydrogenmaleate 9.72 13.19 14.72 17.88 mesohydrogentartrate 9.51 10.17 16.10 25.58 L-(+)-hydrogentartrate 13.32 13.65 14.41 15.80 D-(−)-hydrogentartrate 13.32 13.65 14.41 15.80 hydrogen sulphate 11.82 17.22 17.72 20.13 dihydrogenphosphate 7.91 11.83 15.69 17.24 nitrate 12.50 17.41 18.12 18.47 As evidenced, e.g., by FIGS. 2-5, compounds of the present invention, in casu the hydrobromide salt, may exist in several forms, i.e. be polymorphic. The polymorphic forms have different properties, and as shown in example 4d. The beta form of the hydrobromide salt is the more stable as demonstrated by the higher DSC melting point and the lower solubility. Moreover, the beta form has an attractive combination of low hygroscopicity and solubility, which makes this compound particular suited for making tablets. Hence, in one embodiment, the invention provides the hydrobromide salt of 1-[2-(2,4-dimethylphenylsulphanyl)-phenyl]piperazine with XRPD reflections at approximately 6.89, 9.73, 13,78 and 14.62 (° 2θ), and in particular with an XRPD as shown in FIG. 3. The solubility of an active ingredient is also of significance for the choice of dosage form as it may have a direct impact on bio-availability. For oral dosage forms, a higher solubility of the active ingredient is generally believed to be beneficial as it increases the bio-availability. Cortical and hippocampal cholinergic neurotransmission are of great importance for cognition, and a number of preclinical observations point to the importance of the serotonin receptor 1A (5-HT1A) for this system. T. Koyama in Neurosci. Lett, 265, 33-36, 1999 reports that the 5-HT1A agonists BAYX3702 increases the acetylcholin efflux from the cortex and hippocampus in rats. Interestingly, the 5-HT1A antagonist WAY-100635 is capable of eliminating the effect of BAYX3702 showing that the effect of BAYX3702 is 5-HT1A mediated. A number of studies have reported an effect of modulators of 5-HT1A on cognitive impairment. A. Meneses in Neurobiol. Learn. Memory, 71, 207-218, 1999 reports that the partial 5-HT1A agonist (±)-8-hydroxy-2-(di-n-propylamino)-tetralin, HCl (8-OH-DPAT) facilitates the consolidation of learning in normal rats and normalises cognitive functions in cognitively impaired rats. These pre-clinical observations seem to be reflected in the clinic, too. T Sumiyoshi in Am. J. Psych., 158, 1722-1725, 2001 reports a study wherein patients received typical anti-psychotics, such as haloperidol, sulpride and pimozide, which all lack 5-HT1A activity in combination with placebo or tandospirone, which is a 5-HT1A agonist. Patients receiving tandospirone on top of the anti-psychotic showed an improvement in their cognitive performance whereas patients receiving placebo did not. Similarly, atypical anti-psychotics, such as clozapine, which are also 5-HT1A agonists enhance cognition in schizophrenic patients, whereas typical anti-psychotics, such as haloperidol which have no 5-HT1A activity, do not, Y. Chung, Brain Res., 1023, 54-63, 2004. As mentioned above, the cholinergic system is believed to be involved in the neuronal events regulating cognition, and the cholinergic system may be subject to an inhibitory control by the serotonin receptor 3 (5-HT3) [(Giovannini et al, J Pharmacol Exp Ther 1998, 285:1219-1225; Costall and Naylor, Current Drug Targets—CNS & Neurobiol Disord 2004, 3: 27-37)]. In a habituation test in mice, in a T-maze reinforced alternation task in rats, and in an object discrimination and reversal learning task in the marmoset, ondansetron reduced the impairment caused by the muscarinic antagonist, scopolamine or lesions of the cholinergic pathways emerging from the nucleus basalis (Barnes et al, Pharamcol Biochem Behav 1990, 35: 955-962; Carey et al, Pharamcol Biochem Behav 1992, 42: 75-83). Boast et al (Neurobiol Learn Mem 1999, 71: 259-271) used MK-801, a noncompetitive antagonist of the NMDA receptor, to disrupt the cognitive performance of rats trained on a delayed non-matching to sample radial maze task. Ondansetron was shown to block the cognitive impairment. Moreover, in a study on the amnesic effect of ethanol in a passive avoidance task in mice, this amnesic effect of ethanol was partially restored to normal by ondansetron (Napiorkowska-Pawlak et al, Fundam Clin pharmacol 2000, 14: 125-131). Thus, facilitation of the cholinergic transmission by 5-HT3 antagonism after impairment of the cholinergic system in preclinical models (Diez-Ariza et al, Psychopharmacology 2003, 169: 35-41; Gil-Bea et al, Neuropharmcol 2004, 47: 225-232), suggests a basis for using this treatment in the therapy of cognitive disorders. In a randomised double blind crossover study in healthy male subjects, assessments of verbal and spatial memory and sustained attention demonstrated that the 5-HT3 antagonist, alosetron attenuated scopolamine induced deficits in verbal and spatial memory (Preston, Recent Advances in the treatment of Neurodegenerative disorders and cognitive function, 1994, (eds.) Racagni and Langer, Basel Karger, p. 89-93). In conclusion, compounds exerting 5-HT1A partial agonistic activity in combination with 5-HT3 antagonistic activity are believed to be particular useful for the treatment of cognitive impairment. Compounds which moreover exert serotonin reuptake inhibition would be particular useful for the treatment of cognitive impairment in association with depression as the serotonin reuptake inhibition in combination with the 5-HT1A partial agonism will lead to a faster onset of the effect of the treatment of the depression. As shown in example 1, the compounds of the present invention are potent inhibitors of the human serotonin transporter, i.e. they inhibit serotonin reuptake. Moreover, the compounds are potent antagonists at the mouse, rat, guinea pig and canine 5-HT3 receptor. At the human 5-HT3 receptor, cloned into oocytes, the compounds were found to be antagonists at low concentrations (IC50 approx. 30 nM), whilst at higher concentrations the compounds display agonistic properties (ED50=2.1 μM). A subsequent application of compounds of the present invention at high concentration did not show any agonistic response, which could be due to rapid desenitisation or direct antagonism in vitro. Thus, at low concentrations compounds of the present invention display a marked antagonism at the human 5-HT3 receptor as observed on the 5-HT3 receptor from other species. Compounds of the present invention bind with very low affinity to the 5-HT1A receptor in brain homogenate of both rats and mice. However, the compounds of the present invention bind to the human 5-HT1A receptor with a Ki of 40 nM. Moreover, functional data show that the compounds of the present invention are partial agonists at the human 5-HT1A receptor, displaying an efficacy of 85%. It is anticipated that the activity of the present invention at SERT, 5-HT3−, and 5-HT1A receptors contribute to the in vivo profile of the compound in humans. As shown in example 26 the compounds of the present invention give rise to an increase in the extra-cellular level of acetylcholine in the prefrontal cortex and the ventral hippocampus in rats. These pre-clinical findings are expected to translate into a clinical effect in the treatment of cognitive impairments, cf. the use of acetylcholine esterase inhibitors in the treatment of cognitive impairments, e.g. in Alzheimer's disease. Further support to this position can be found in example 27, wherein data show that compounds of the present invention enhances contextual memory in rats. All in all, the pharmacological profile of the compounds of the present invention combined with the effects on acetylcholine levels and memory in rats strongly suggest that the compounds of the present invention are useful in the treatment of cognitive impairment. In one embodiment, the present invention relates to a method for the treatment of cognitive deficits or cognitive impairment, said method comprising the administration of a therapeutically effective amount of a compound of the present invention to a patient in need thereof. Cognitive deficits or cognitive impairment include a decline in cognitive functions or cognitive domains, e.g. working memory, attention and vigilance, verbal learning and memory, visual learning and memory, reasoning and problem solving e.g. executive function, speed of processing and/or social cognition. In particular, cognitive deficits or cognitive impairment may indicate deficits in attention, disorganized thinking, slow thinking, difficulty in understanding, poor concentration, impairment of problem solving, poor memory, difficulties in expressing thoughts and/or difficulties in integrating thoughts, feelings and behaviour, or difficulties in extinction of irrelevant thoughts. The terms “cognitive deficits” and “cognitive impairment” are intended to indicate the same and are used interchangeably. In one embodiment, said patient is also diagnosed with another CNS disorder, such as affective disorders, such as depression; generalised depression; major depressive disorder; anxiety disorders including general anxiety disorder and panic disorder; obsessive compulsive disorder; schizophrenia; Parkinson's; dementia; AIDS dementia; ADHD; age associated memory impairment; or Alzheimer's. Cognitive impairment is among the classic features of depression, such as e.g. major depressive disorder. Cognitive disorders may to some extent be secondary to depression in the sense that an improvement in the depressive state will also lead to an improvement of the cognitive impairment. However, there is also clear evidence that cognitive disorders are, indeed, independent from depression. For instance, studies have shown persistent cognitive impairment upon recovery from depression [J Nervous Mental Disease, 185, 748-754, 197]. Moreover, the differential effect of antidepressants on depression and cognitive impairments lends further support to the notion that depression and cognitive impairment are independent, albeit often co-morbid conditions. While serotonin and noradrenalin medicaments provide comparable improvements in depressive symptoms, several studies have shown that modulation of the noradrenergic system does not improve the cognitive functions as much as serotonin modulation [Brain Res. Bull., 58, 345-350, 2002; Hum Psychpharmacol., 8, 41-47, 1993]. The treatment of cognitive impairment in depressed patients by the administration of the compounds of the present invention is believed to be particular advantageous. The multifaceted pharmacology of the compounds of the present invention, in particular the SERT, 5-HT3 and 5-HT1A activity is expected to lead to improvement in cognitive functioning in combination with a fast onset treatment of the depressed state. Cognitive impairment is a particularly important consideration in the elderly. Cognitive impairment normally increases with age, and further with depression. Hence, in one embodiment, the patient to be treated for cognitive impairment is elderly, and in particular elderly with depression. Cognitive functions are, as mentioned above, often impaired in schizophrenic patients. Studies have also concluded that cognitive functioning is associated with vocational functioning in schizophrenia [Scizophrenia Res., 45, 175-184, 2000]. In one embodiment, the patient to be treated for cognitive impairment is schizophrenic. 5-HT3 receptor antagonists have additionally been suggested for the treatment of diseases such as emesis, chemotherapy-induced emesis, craving, substance abuse, pain, irritable bowel syndrome (IBS), schizophrenia, and eating disorders, [Eur. J. Pharmacol., 560, 1-8, 2007; Pharmacol. Therapeut., 111, 855-876, 2006; Alimentary Pharmacol. Ther., 24, 183-205, 2006] Clinical studies show that a combination of mirtazipine and an SSRI are superior to SSRIs alone for the treatment of depressed patients with an inadequate clinical response (treatment resistant depression, TRD, or refractory depression) [Psychother. Psychosom., 75, 139-153, 2006]. Mirtazapine is a 5-HT2 and a 5-HT3 antagonist, which lends support to the notion that compounds of the present invention are useful for the treatment of TRD. Hot flushes are a symptom associated with the menopausal transition. Some women may suffer from this to an extent where it interferes with sleep or activities in general, and where treatment is necessary. Hormone replacement therapy with oestrogen has been established practice for decades, however, recently concerns have been voiced on side effects, such as breast cancer and cardiac events. Clinical trials with SSRIs have shown that these compounds have an effect on hot flushes, albeit less than for oestrogen [J. Am. Med. Ass., 295, 2057-2071, 2006]. Treatment of hot flushes with compounds inhibiting serotonin reuptake, e.g. compounds of the present invention could, however, be an alternative treatment for women who can not or will not accept oestrogen. Sleep apnoea or obstructive sleep apnoea-hyponea syndrome or obstructive sleep-disordered breathing is a disorder for which an effective pharmacotherapy remains to be identified. Several studies in animals, however, suggest that 5-HT3 antagonists, e.g. compounds of the present invention may be effective in the treatment of these diseases [Sleep, 21, 131-136, 1998; Sleep, 8, 871, 878, 2001]. In one embodiment, the invention relates to a method of treating a disease selected from affective disorders, depression, major depressive disorder, postnatal depression, depression associated with bipolar disorder, Alzheimer's disease, psychosis, cancer, age or Parkinson's disease, anxiety, general anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, panic attacks, phobia, social phobia, agoraphobia, stress urinary incontinence, emesis, IBS, eating disorders, chronic pain, partial responders, treatment resistant depression, Alzheimer's disease, cognitive impairment, ADHD, melancholia, PTSD, hot flushes, sleep apnoea, alcohol, nicotine or carbohydrate craving, substance abuse and alcohol or drug abuse, the method comprising the administration of a therapeutically effective amount of a compound of the present invention to a patient in need thereof. In one embodiment, said patient being treated for any of the above listed diseases has initially been diagnosed with said disease. It is well know that treatment with anti-depressants in general and SSRI's in particular may be associated with sexual dysfunction and which frequently leads to discontinuation of the treatment. As much as 30-70% of patients on SSRIs report deficits in sexual function [J. Clin. Psych., 66, 844-848, 2005], which deficits include decreased libido, delayed, reduced or absent orgasms, diminished arousal, and erectile dysfunction. A total of 114 subjects have been exposed to compounds of the present invention in clinical trials; of these 114 subjects, only one subject reported sexual dysfunction. These data suggest that clinical intervention using compounds of the present invention is associated with surprisingly few deficits in sexual functioning. As mentioned above, compounds of the present invention are particularly well suited for the treatment of chronic pain. Chronic pain includes indications such as phantom limb pain, neuropathic pain, diabetic neuropathy, post-herpetic neuralgia (PHN), carpal tunnel syndrome (CTS), HIV neuropathy, complex regional pain syndrome (CPRS), trigeminal neuralgia/trigeminus neuralgia/tic douloureux, surgical intervention (e.g. post-operative analgesics), diabetic vasculopathy, capillary resistance or diabetic symptoms associated with insulitis, pain associated with angina, pain associated with menstruation, pain associated with cancer, dental pain, headache, migraine, tension-type headache, trigeminal neuralgia, temporomandibular joint syndrome, myofascial pain muscular injury, fibromyalgia syndrome, bone and joint pain (osteoarthritis), rheumatoid arthritis, rheumatoid arthritis and edema resulting from trauma associated with burns, sprains or fracture bone pain due to osteoarthritis, osteoporosis, bone metastases or unknown reasons, gout, fibrositis, myofascial pain, thoracic outlet syndromes, upper back pain or lower back pain (wherein the back pain results from systematic, regional, or primary spine disease (radiculopathy), pelvic pain, cardiac chest pain, non-cardiac chest pain, spinal cord injury (SCI)-associated pain, central post-stroke pain, cancer neuropathy, AIDS pain, sickle cell pain or geriatric pain. Data presented in example 16 shows that compounds of the present invention are useful in the treatment of pain, and that they may even have an analgesic effect, additionally studies in an animal model of neuropathic pain confirm this observation. A “therapeutically effective amount” of a compound as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of said compound. An amount adequate to accomplish this is defined as “a therapeutically effective amount”. Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician. The term “treatment” and “treating” as used herein means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder. The term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. Nonetheless, prophylactic (preventive) and therapeutic (curative) treatment are two separate aspects of the invention. The patient to be treated is preferably a mammal, in particular a human being. Typically, the treatment of the present invention will involve daily administration of the compounds of the present invention. This may involve once daily administration, or administration twice a day or even more frequently. In one embodiment, the invention relates to the use of a compound of the present invention for the manufacture of a medicament for the treatment of affective disorders, depression, major depressive disorder, postnatal depression, depression associated with bipolar disorder, Alzheimer's disease, psychosis, cancer, age or Parkinson's disease, anxiety, general anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, panic attacks, phobia, social phobia, agoraphobia, stress urinary incontinence, emesis, IBS, eating disorders, chronic pain, partial responders, treatment resistant depression, Alzheimer's disease, cognitive impairment, ADHD, melancholia, PTSD, hot flushes, sleep apnoea, alcohol, nicotine or carbohydrate craving substance abuse, or alcohol or drug abuse. In one embodiment, the invention relates to compounds of the present inventions for use in the treatment of a disease selected from affective disorders, depression, major depressive disorder, postnatal depression, depression associated with bipolar disorder, Alzheimer's disease, psychosis, cancer, age or Parkinson's disease, anxiety, general anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, panic attacks, phobia, social phobia, agoraphobia, stress urinary incontinence, emesis, IBS, eating disorders, chronic pain, partial responders, treatment resistant depression, Alzheimer's disease, cognitive impairment, ADHD, melancholia, PTSD, hot flushes, sleep apnea, alcohol, nicotine or carbohydrate craving, substance abuse, and alcohol and drug abuse. The effect of the compounds of the present invention on cognition in humans may be evaluated in a number of ways. The effect may be evaluated in tests wherein healthy volunteers are administered the compound followed by a measurement of the cognitive performance in recognised tests, such as e.g. Auditory Verbal Learning Test (AVLT), Wisconsin Card Sorting Test (WCST), or sustained attention, [Psycopharmacol, 163, 106-110, 2002; Psychiatry Clin. Neurosci., 60, 70-76, 2006]. The effect may of course also be assessed in patients suffering from cognitive impairment using the same sort of tests. Alternatively, cognitive models may be used wherein cognitive impairment is induced in healthy volunteers and wherein a restorative effect of the compounds of the present invention is measured. Cognitive impairment may be induced by e.g. scopolamine, sleep deprivation, alcohol, and tryptophane depletion. The pharmaceutical formulations of the invention may be prepared by conventional methods in the art. Particular mentioning is made of tablets, which may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents comprise: anhydrous calcium hydrogen phosphate, PVP, PVP-VA co-polymers, microcrystalline cellulose, sodium starch glycolate, corn starch, mannitol, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients. Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to desired volume, sterilising the solution and filling it in suitable ampules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc. The pharmaceutical compositions of this invention or those which are manufactured in accordance with this invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection. For preparing such compositions, methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients or other additives normally used in the art may be used. Conveniently, the compounds of the invention are administered in unit dosage form containing said compounds in an amount of about 1 to 50 mg. An upper limit is believed to be set by the concentration dependency of the 5-HT3 activity. The total daily dose is usually in the range of about 1-20 mg, such as about 1 to 10 mg, about 5-10 mg, about 10-20 mg, or about 10-15 mg of the compound of the invention. Particular mentioning is made of daily doses of 5, 10, 15 or 20 mg. Tablets comprising a compound of the present invention may conveniently be prepared by wet granulation. Using this method, the dry solids (active ingredients, filler, binder etc.) are blended and moistened with water or another wetting agent (e.g. an alcohol) and agglomerates or granules are built up of the moistened solids. Wet massing is continued until a desired homogenous particle size has been achieved whereupon the granulated product is dried. The compounds of the present invention are typically mixed with lactose monohydrate, corn starch and copovidone in a high shear mixer together with water. Following formation of granulates, these granulates may be sieved in a sieve with a suitable sieve size, and dried. The resulting, dried granulates are then mixed with microcrystalline cellulose, croscarmellose sodium and magnesium stearate, following which the tablets are pressed. Alternatively, wet granulation of the compounds of the present invention may be achieved using mannitol, corn starch and copovidone, which granulates are mixed with microcrystalline cellulose, sodium starch glycolate and magnesium stearate before tablets are pressed. Alternatively, wet granulation of the compounds of the present invention may be achieved by using anhydrous calcium hydrogen phosphate, corn starch and copovidone, which granulates are mixed with microcrystalline cellulose, sodium starch glycolate (type A), talc and magnesium stearate before tablets are pressed. Copovidone is a PVP-VA copolymer. In one embodiment, the compound of the present invention is the hydrobromide acid salt, e.g. in the beta form, and suitable tablets may be composed as follows—percentages indicated are w/w-% HBr salt 2-20% Lactose monohydrate 30-50% Starch 15-30% Copovidone 3-5% Microcrystalline cellulose 15-25% Croscarmellose sodium 2-5% Mg stearate 0.5-5% In particular, the tablets may be composed as follows HBr salt 3-4% Lactose monohydrate 44-46% Starch 22-23% Copovidone 3-4% Microcrystalline cellulose 20-22% Croscarmellose sodium 3-3.5% Mg stearate 0.5-1% or HBr salt 15-16% Lactose monohydrate 35-38% Starch 18-20% Copovidone 3-4% Microcrystalline cellulose 20-22% Croscarmellose sodium 3-3.5% Mg stearate 0.5-1% or HBr salt 1-2% Lactose monohydrate 44-46% Starch 20-24% Copovidone 3-4% Microcrystalline cellulose 22-24% Croscarmellose sodium 3-4% Mg stearate 0.5-1% In one embodiment, the compound of the present invention is the hydrobromide salt, e.g. in the beta form, and suitable tablets may be composed as follows HBr salt 2-30% Mannitol 25-45% Corn starch 10-20% Copovidone 2-4% Microcrystalline cellulose 22-27% Sodium starch glycolate 4-5% Mg stearate 0.25-5%, such as 0.25-2% In particular, the tablets may be composed as follows HBr salt 20-22% Mannitol 35-36% Corn starch 10-12% Copovidone 2.5-3% Microcrystalline cellulose 24-25% Sodium starch glycolate 3-4% Mg stearate 0.25-1% or HBr salt 12-13% Mannitol 36-37% Corn starch 18-19% Copovidone 3-4% Microcrystalline cellulose 24-25% Sodium starch glycolate 3-4% Mg stearate 0.25-1% or HBr salt 25-27% Mannitol 27-29% Corn starch 13-15% Copovidone 3-4% Microcrystalline cellulose 24-25% Sodium starch glycolate 3-5% Mg stearate 0.25-1% or HBr salt 3-4% Mannitol 40-42% Corn starch 20-22% Copovidone 3-4% Microcrystalline cellulose 26-28% Sodium starch glycolate 3-5% Mg stearate 0.5% In one embodiment, the compound of the present invention is the hydrobromide salt and suitable tablets may be composed as follows HBr salt 3-8% Anhydrous calcium hydrogen phosphate 35-45% Corn starch 15-25% Copovidone 2-6% Microcrystalline cellulose 20-30% Sodium starch glycolate 1-3% Talc 2-6% Magnesium stearate 0.5-2% In particular, the tablets may be composed as follows HBr salt approximately 5% Anhydrous calcium hydrogen phosphate approximately 39% Corn starch approximately 20% Copovidone approximately 3% Microcrystalline cellulose approximately 25% Sodium starch glycolate approximately 3% Talc approximately 4% Magnesium stearate approximately 1% Tablets with different amounts of active compound, such as corresponding to e.g. 2.5, 5, 10, 20, 25, 30, 40, 50, 60 or 80 mg of the free base may be obtained by choosing the right amount of the compound of the present invention in combination with a tablet of an appropriate size. The size of the crystals used for preparing tablets comprising compounds of the present invention are of significance. If the crystals are too small they may stick to the plunger in the tablet machines. On the other hand, they cannot be too large either. The dissolution rate in the intestines decrease when crystal size increases. Hence, if the crystals are too large it may compromise the bioavailability of the compounds. Particle size distribution may be described using quantiles, e.g. D5%, D10%, D50%, D90%, D95% and D98%. As used herein, “particle size distribution” means the cumulative volume size distribution of equivalent spherical diameters as determined by laser diffraction at 1 bar dispersive pressure in a Sympatec Helos equipment. In one embodiment, the crystals of the compound of the present invention, and in particular the beta from of the hydrobromide salt have a particle size distribution corresponding to D98%: 650-680 μm; D50%: 230-250 μm; and D5%: 40-60 μm. In a further embodiment, the particle size distribution corresponds to D98%: 370-390; d50%: 100-120 μm; D5%: 5-15 μm. In a still further embodiment, the particle size distribution corresponds to D98%: 100-125 μm; D50%: 15-25 μm; and D5%: 1-3 μm. In an even further embodiment, the particle size distribution corresponds to D98%: 50-70 μm; D50%: 3-7 μm; and D5%: 0.5-2. The free base of the present invention may be prepared as disclosed in WO 2003/029232. Salts of the present invention may be prepared by dissolving the free base in an appropriate solvent, adding the relevant acid, followed by precipitation. Precipitation may be accomplished either by the addition of a second solvent, and/or evaporation, and/or cooling. Alternatively, the free base of the present invention and ultimately the compounds of the present invention may be synthesised in a palladium catalysed reaction as described below. Formation of aromatic carbon-heteroatom bonds may be achieved by nucleophilic aromatic substitution or copper-mediated Ullman reactions. More recently, palladium has been shown to be a powerful catalyst for the formation of such bonds, and in particular the formation of C—N and C—S bonds, see e.g. U.S. Pat. No. 5,573,460. In one embodiment, the invention provides a process for the preparation of the process comprising reacting compound II wherein R′ represents hydrogen or a mono-valent metal ion, with a compound of formula III wherein X1 and X2 independently represent halogen, and a compound of formula IV wherein R represents hydrogen or a protecting group, in the presence of a solvent, a base and a palladium catalyst consisting of a palladium source and a phosphine ligand at a temperature between 60° C. and 130° C. In one embodiment, the process is divided in sub-processes wherein compound II and compound III are reacted in a first reaction to provide a compound of the formula This compound is then optionally purified to a suitable degree before being reacted with compound IV to provide 4-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine. One-pot syntheses, i.e. syntheses wherein all reactants are mixed together at the start of the reaction or process, are particularly useful due to their inherent simplicity. On the other hand, the number of possible unwanted side-reactions is dramatically increased, which again means that the number and/or the amount of unwanted side products may increase and the yield of the desired product decrease correspondingly. For the present process in particular, it may be observed that piperazine has two nitrogens each of which could potentially participate in the formation of a C—N bond. It has surprisingly been found that the present process may be run as a one-pot synthesis, i.e. a process wherein compound II, compound III and compound VI are mixed from the beginning, while maintaining a high yield of a pure compound. Compound II is a thiol or the corresponding thiolate. From a occupational health perspective is may be beneficial to use a thiolate, such as the Li+, Na+or K+thiolate to avoid the odour problems associated with thiols. Nonetheless, in one embodiment, R′ is hydrogen. Compound III is a 1,2-dihalogen activated benzene, and the halogens may be any of Cl, Br and I. In particular, compound II is 1-bromo-2-iodo-benzene or 1,2-dibromo-benzene. The solvent used in the process of the present invention may be selected from aprotic organic solvents or mixtures of such solvents with a boiling temperature within the reaction temperature range, i.e., 60-130° C. Typically, the solvent is selected from amongst toluene, xylene, triethyl amine, tributyl amine, dioxan, N-methylpyrrolidone, or from any mixture thereof. Particular mentioning is made of toluene as solvent. Central to the present process is the use of a palladium catalyst without which the reactions do not take place. The palladium catalyst consists of a palladium source and a phosphine ligand. Useful palladium sources include palladium in different oxidations states, such as e.g. 0 and II. Examples of palladium sources which may be used in the process of the present invention are Pd2dba3, Pddba2 and Pd(OAc)2. dba abbreviates dibenzylideneacetone. Particular mentioning is made of Pddba2 and Pd2dba3. The palladium source is typically applied in an amount of 0.1-10 mole-%, such as 1-10 mole-%, such as 1-5 mole-%. Throughout this application, mole-% is calculated with respect to the limiting reactant. Numerous phosphine ligands are known, both monodentate and bidentate. Useful phosphine ligands include racemic 2,2′-bis-diphenylphosphanyl-[1,1′]binaphtalenyl (rac-BINAP), 1,1′-bis(diphenylphosphino)ferrocene (DPPF), bis-(2-diphenylphosphinophenyl)ether (DPEphos), tri-t-butyl phosphine (Fu's salt), biphenyl-2-yl-di-t-butyl-phosphine, biphenyl-2-yl-dicyclohexyl-phosphine, (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine, [2′-(di-t-butyl-phosphanyl)-biphenyl-2-yl]-dimethyl-amine, and dicyclohexyl-(2′, 4′, 6′-tri-propyl-biphenyl-2-yl)-phosphane. Moreover, carbene ligands, such as 1,3-bis-(2,6-di-isopropyl-phenyl)-3H-imidazol-1-ium; chloride may be used in stead of phosphine ligands. In one embodiment, the phosphine ligand is rac-BINAP, DPPF or DPEphos, and in particular rac-BINAP. The phosphine ligand is usually applied in an amount between 0.1 and 10 mole-%, such as 1 and 5 mole-%, typically around 1-2 mole-%. Base is added to the reaction mixture to increase pH. In particular bases selected from NaOt-Bu, KOt-Bu and Cs2CO3 are useful. Organic bases, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO) may be applied as well. Particular mentioning is made of NaO(t-Bu) and KO(t-Bu). Typically, the base is added is an amount around 1-5 equivalents, such as 1-3 equivalents, such as 2-3 equivalents. Compound IV is a piperazine compound. Piperazine has two nitrogens, only one of which is to participate in the C—N bond formation. In one embodiment, formation of bonds to the second nitrogen is avoided by using a mono-protected piperazine, i.e. an embodiment wherein R is a protective group. Many protective groups are known in the art, and useful examples include boc, Bn, Cbz, C(═O)OEt and Me, and in particular boc. Bn abbreviates benzyl; boc abbreviates t-butyloxycarbonyl; and cbz abbreviates benzyloxycarbonyl. If a protected piperazine is used in the reactions, the protecting group has to be removed in a subsequent step, typically by the addition of aqueous acid. If methyl is used as the protecting group, the methyl may be removed in a reaction with carbamate and subsequent removal of this group. It has surprisingly been found that unprotected piperazine may be used as well without the formation of unwanted bonds to the second nitrogen. Protected and unprotected piperazine have different solubilities in different solvents; as an example, piperazine is practically insoluble in toluene whereas boc protected piperazine is highly soluble in toluene. Normally it would be expected that it is a requirement for a successful reaction that all reactants are readily soluble in the applied solvent. Nevertheless, it has been found that the process of the present invention runs with a high yield with toluene as solvent and with unprotected piperazine, i.e. in an embodiment wherein R is hydrogen. Hence, in one embodiment, the solvent is toluene and compound IV is piperazine. In a further embodiment, this combination of conditions is used in a one-pot synthesis. In one embodiment, the temperature under which to run to process is approximately 80° C.—approximately 120° C. In one embodiment, 1-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]-piperazine is prepared in a process comprising the following steps: a. dissolving or dispersing 1-1.5 equivalents of compounds II, III and IV in toluene to obtain mixture A; b. adding 1-2 mole-% of Pddba2 and 1-2 mole-% of rac-BINAP together with 2-3 equivalents of NaOt-Bu, optionally dispersed or dissolved or dispersed in toluene, to mixture A to obtain mixture B, which is heated to around 100° C. until compound II and III are fully converted, typically 5-10 hours; c. increasing the temperature of the mixture obtained in step b to around 120° C. until compound IV is fully converted, typically 16-32 hours; and d. optionally removing the protecting group by the addition of aqueous acid if compound III is a protected piperazine. Optionally, purifications steps may be included in the above sequence of reaction steps. In one embodiment, 1-1.5 equivalents of 2,4-dimethyl-thiol, 1-bromo-2-iodo benzene (or 1,2-dibromo-benzene) and piperazine is dispersed in toluene followed by the addition of 2-5, such as 3 equivalents NaOt-Bu and 1-2 Mole-% Pd2dba3 and rac-BINAP dispersed in toluene to obtain a mixture which is refluxed for 2-10 hours, typically 3-5 hours to obtain 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine. Optionally, this product may be further reacted with aqueous HBr to achieve the corresponding hydrobromic acid addition salt. In one embodiment, 2-5 equivalents of NaOt-Bu, 2-5 equivalents piperazine, 0.2-0.6 mole-% Pddba2, and 0.6-1 mole-% rac-BINAP is dispersed in toluene to obtain mixture A′, to which mixture approximately 1 equivalent 2-bromo-iodobezene is added to obtain mixture B′, to which mixture 1 equivalent 2,4-dimethylthiophenol is added and the resulting mixture is heated to reflux for 3-7 hours, such as 4-6 hours to obtain 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine. Optionally, this product may be further reacted with aqueous HBr to achieve the corresponding hydrobromic acid addition salt. In some situations it may be desirable to obtain an acid addition salt of 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine rather than the free base. Acid addition salts may be achieved in a further process step in which the free base obtained is reacted with a relevant acid, such as e.g. fumaric acid, sulphuric acid, hydrochloric acid or hydrobromic acid. The acid may be added directly to the reaction mixture or, alternatively, the free base may be purified to any suitable degree initially before such step. If the free base has been isolated as a dry compound, it may be necessary to use a solvent in order to bring the free base into solution prior to a reaction with the acid. In one embodiment, aqueous hydrobromic acid is added directly to the reaction mixture without any initial purification of the free base. In processes wherein a protected piperazine has been used, the protecting group has to be removed by the addition of an aqueous acid as explained above. In one embodiment, said aqueous acid may be selected to achieve two transformations, i.e. the de-protection of the protected piperazine and the formation of an acid addition salt. In particular, aqueous hydrobromic acid may be used to de-protect protected piperazine and to obtain the hydrobromic acid addition salt in one process step. It goes for all the reactions and reaction mixtures mentioned here that it may be an advantage to purge them with an inert gas or run them under a blanket of inert gas. Nitrogen is a cheap and readily available example of an inert gas All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent permitted by law), regardless of any separately provided incorporation of particular documents made elsewhere herein. The use of the terms “a” and “an” and “the” and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. For example, the phrase “the compound” is to be understood as referring to various compounds of the invention or particular described aspect, unless otherwise indicated. Unless otherwise indicated, all exact values provided herein are representative of corresponding approximate values (e.g., all exact exemplary values provided with respect to a particular factor or measurement can be considered to also provide a corresponding approximate measurement, modified by “about,” where appropriate). The description herein of any aspect or aspect of the invention using terms such as “comprising”, “having,” “including,” or “containing” with reference to an element or elements is intended to provide support for a similar aspect or aspect of the invention that “consists of”, “consists essentially of”, or “substantially comprises” that particular element or elements, unless otherwise stated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood as also describing a composition consisting of that element, unless otherwise stated or clearly contradicted by context). EXAMPLES Analytical Methods 1H NMR spectra are recorded at 500.13 MHz on a Bruker Avance DRX500 instrument. Dimethyl sulfoxide (99.8% D) is used as solvent, and tetramethylsilane (TMS) is used as internal reference standard. The melting points are measured using Differential Scanning Calorimetry (DSC). The equipment is a TA-Instruments DSC-Q1000 calibrated at 5°/min to give the melting point as onset value. About 2 mg of sample is heated 5°/min in a loosely closed pan under nitrogen flow. Thermo gravimetric analysis (TGA) used for estimation of solvent/water content of dried material is performed using a TA-instruments TGA-Q500. 1-10 mg sample is heated 10°/min in an open pan under nitrogen flow. X-Ray powder diffractograms were measured on a PANalytical X′Pert PRO X-Ray Diffractometer using CuKα1 radiation. The samples were measured in reflection mode in the 2θ-range 5-40° using an X′celerator detector. Example 1 In Vitro Receptor Pharmacology Rat serotonin transporter: IC50 5.3 nM (blockade of 5-HT uptake) Human serotonin transporter: IC50 40 nM (blockade of 5-HT uptake) Human 5-HT1A receptor: Ki 40 nM with partial agonism (efficacy 85%) Rat 5-HT3 receptor: IC50 0.2 nM (antagonism in functional assay) Human 5-HT3A receptor: IC50 around 20 nM (antagonism in functional assay). At higher concentration, the compound exhibits agonistic activity with an ED50 of 2.1 μM. The compound of the invention also showed high affinity for the human 5HT3 receptor in an in vitro binding assay (Ki 4.5 nM). Example 2 Cognitive Effects As discussed above, the compounds of the present invention interact with the cholinergic system, and it would be expected to see an effect in one or more of the following in vivo models. Five choice serial reaction time test (5-CSRT), which is useful for demonstrating an effect on continuous attention Spatial Y maze test, which is useful for demonstrating effects on short, long-term and working memory Attentional set shifting model, which is useful for demonstrating effects on executive functioning, i.e. reasoning and problem solving Example 3a Preparation of the Free Base of compound I 10 grams of 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide was treated with a stirred mixture of 100 ml 3 M NaOH and 100 ml ethyl acetate for 10 minutes. The organic phase was separated, washed with 100 ml 15%-wt NaCl (aq), dried over MgSO4, filtered and concentrated in vacuum producing 7.7 gram (98%) of compound I base as a clear colourless oil. NMR complies with structure. Example 3b Preparation of Crystalline Base of compound I 3.0 gram of 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine colourless oil was treated with 70 ml acetonitrile and heated to reflux. The almost clear solution was filtered and the clear filtrate was cooled spontaneously upon which precipitation began shortly after filtration. The mixture was stirred at room temperature (22° C.) for 2 hours and the product was isolated by filtration and dried in vacuum (40° C.) overnight. The crystalline base was isolated as a white solid in 2.7 gram (90%). NMR complies with structure. Elemental analysis: 72.40% C, 9.28% N, 7.58% H (theory: 72.26% C, 9.36% N, 7.42% H) Example 3c Characterisation of Crystalline Base of compound I The base, as prepared in example 3b, is crystalline (XRPD)—see FIG. 1. It has a melting point of ˜117° C. It is not hygroscopic and has a solubility of 0.1 mg/ml in water. Example 4a Preparation of the Alpha Form of the hydrobromide salt of compound I 2.0 gram of 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine was dissolved in hot 30 ml ethyl acetate and added 0.73 ml 48%-wt HBr (aq). This addition caused formation of a thick slurry and additional 10 ml ethyl acetate was added in order to have proper stirring. The slurry was stirred at room temperature for one hour. Filtration and drying in vacuum (20° C.) over night produced 2.0 gram of the product as a white solid (80%). NMR complies with structure. Elemental analysis: 57.05% C, 7.18% N, 6.16% H (Theory for 1:1 salt: 56.99% C, 7.39% N, 6.11% H) Example 4b Characterisation of the Alpha Form of the hydrobromide of compound I The alpha form of the hydrobromide, as prepared in example 4a, is crystalline (XRPD)—see FIG. 2. It has a melting point of ˜226° C. It absorbs about 0.3% of water when exposed to high relative humidity and has a solubility of 2 mg/ml in water. Example 4c Preparation of the Beta Form of the hydrobromide salt of compound I 49.5 gram of 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine colourless oil was dissolved in 500 ml ethyl acetate and added 18.5 ml 48%-wt HBr (aq). This addition caused formation of a thick slurry which was stirred over night at room temperature. Filtration and drying in vacuum (50° C.) over night produced the product in 29.6 gram as white solid (47%). NMR complies with structure. Elemental analysis: 56.86% C, 7.35% N, 6.24% H (Theory for 1:1 salt: 56.99% C, 7.39% N, 6.11% H) Example 4d Characterisation of the Beta Form of the hydrobromide of compound I The beta form of the hydrobromide, as prepared in example 4c, is crystalline (XRPD) see FIG. 3. It has a melting point of ˜231° C. It absorbs about 0.6% of water when exposed to high relative humidity and has a solubility of 1.2 mg/ml in water. Example 4e Preparation of the Gamma Form of the hydrobromide salt of compound I 1 g of 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide as prepared in example 4a was added 20 ml water and heated to 85° C. The solution was almost clear. Addition of 1 drop of HBr made it clear. HBr was added until cloud point was observed. The solution was cooled to room temperature and dried. NMR complies with structure. Elemental analysis: 56.63% C, 7.18% N, 6.21% H (Theory for 1:1 salt: 56.99% C, 7.39% N, 6.11% H). Example 4f Characterisation of the Gamma Form of the hydrobromide of compound I The hydrobromide, as prepared in example 6e, is crystalline (XRPD)—see FIG. 4. The DSC curve shows some thermal events at about 100° C.; probably change in crystal form. Then it melts at about 220° C. It absorbs about 4.5% of water when exposed to high relative humidity and at 30% RH at room temperature about 2% of water is absorbed. Example 4g Preparation of the hydrobromide hydrate of compound I 1.4 gram of 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine oil was added 20 ml water, and heated to 60° C. pH was adjusted to 1 using 48% HBr. The solution was cooled to room temperature and dried. NMR complies with structure. Elemental analysis: 55.21% C, 7.16% N, 6.34% H (Theory for 1:1 salt hemihydrate: 55.68% C, 7.21% N, 6.23% H) Example 4h Characterisation of the Hemi Hydrate of the hydrobromide of compound I The hydrate as prepared in Example 4g is crystalline (XRPD)—see FIG. 5. The water content depends strongly on the relative humidity. At room temperature and 95% RH the water content is about 3.7%. Dehydration occurs by heating to about 100° C. Example 4i Preparation of the ethyl acetate solvate of the hydrobromide salt of compound I 0.9 gram of 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine oil was dissolved in 35 ml ethyl acetate and added 0.5 ml 48%-wt HBr (aq). This addition caused formation of a thick slurry which was stirred over night at room temperature. Filtration and washing with 30 ml diethyl ether followed by drying in vacuum (50° C.) over night produced 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine HBr EtOAc solvate in 1.0 gram (65%). NMR complies with structure. Elemental analysis: 56.19% C, 6.60% N, 6.56% H (Theory for 1:1 salt when corrected for 8% of Ethyl acetate and 0.5% water as determined by TGA and KF: 56.51% C, 6.76% N, 6.38% H) Example 4j Characterisation of the ethyl acetate solvate of the hydrobromide of compound I The ethyl acetate solvate, as prepared in example 4i, is crystalline (XRPD)—see FIG. 6. The batch contains a mixture of the solvate and the alpha form of compound I, probably because the drying has caused partly desolvation. The desolvation starts at ˜75° C. when heated 10°/min. After desolvation the alpha form is formed. If exposed to high relative humidity, the ethyl acetate is replaced by water, which is released when the humidity subsequently is lowered. The resulting solid is hygroscopic and absorbs 3.2% of water at high relative humidity. Example 5a Preparation of hydrochloride salt of compound I 1.0 gram of 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine oil was dissolved in 20 ml ethyl acetate using gentle heating (30° C.). When a clear solution was obtained a solution of 2 M HCl in diethyl ether was added slowly until pH was approximately 1-2. During the addition spontaneous precipitation was observed. After final addition the suspension was stirred for 1 hour before the white precipitate was isolated by filtration and dried in vacuum (40° C.) overnight. 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine hydrochloride was isolated in 1.1 gram (99%). NMR complies with structure. Elemental analysis: 64.18% C, 8.25% N, 6.96% H (Theory for 1:1 salt when corrected for 0.66% of water as determined by TGA: 64.13% C, 8.31% N, 6.95% H) Example 5b Characterisation of the hydrochloride of compound I The hydrochloride, as prepared in example 5a, is crystalline (XRPD)—see FIG. 7. It has a melting point of ˜236° C. It absorbs about 1.5% of water when exposed to high relative humidity and has a solubility of 3 mg/ml in water. Example 5c Preparation of the hydrochloride monohydrate of compound I 11.9 gram of 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine oil was dissolved in 100 ml ethanol using heating. When a homogenous solution was obtained addition of 3.5 ml conc. HCl (aq) took place causing the immediately precipitation of a white solid. The suspension was stirred for 5 minutes at first and then on ice-bath another hour before filtration. The white solid was washed using 100 ml of fresh cool ethanol (placed in freezer at −18° C. for 2 hours), 50 ml acetone and finally 50 ml diethyl ether before dried in vacuum (50° C.) overnight. 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine HCl was isolated in 5.1 gram (38%). NMR complies with structure. Elemental analysis: 61.23% C, 7.91% N, 7.16% H (Theory for 1:1 salt monohydrate: 61.26% C, 7.94% N, 7.14% H) Example 5d Characterisation of the hydrochloride monohydrate of compound I The hydrochloride monohydrate, as prepared in example 5c, is crystalline (XRPD)—see FIG. 8. It dehydrates starting at about 50° C. Some thermal events, probably rearrangement, occur by further heating, and it melts at about 230° C. followed by recrystallisation and melting at about 236° C. It does not absorb further amount of water when exposed to high relative humidity and the hydrate bounded water is not released until the relative humidity is decreased to below 10% RH at room temperature. It has a solubility of about 2 mg/ml in water. Example 6a Preparation of mesylate salt of compound I 1.0 gram of 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine oil was dissolved in 20 ml ethyl acetate by heating (70° C.). When a clear solution was obtained 0.35 gram of methane sulphonic acid (1.1 eqv.) was added slowly. After final addition the solution was cooled on ice and diethyl ether was added slowly causing the precipitation of the product. The suspension was stirred for 2 hours on ice before the white precipitate was isolated by filtration and dried in vacuum (40° C.) overnight. 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine mesylate was isolated in 1.1 gram (85%). NMR complies with structure. Elemental analysis: 57.81% C, 6.81% N, 6.68% H (Theory for a 1:1 salt: 57.81% C, 7.10% N, 6.64% H) Example 6b Characterisation of the mesylate of compound I The mesylate, as prepared in example 7a, is crystalline (XRPD)—see FIG. 9. It has a melting point of ˜163° C. It is hygroscopic (absorbs about 8% of water when exposed to 80% relative humidity and is thereby transformed into a hydrated form. The last 6% of the absorbed water is not released until the relative humidity is below 10% RH. It has a very high solubility in water (>45 mg/ml). Example 7a Preparation of fumarate of compound I 5.5 gram 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine oil was heated to reflux in a mixture of 50 ml methanol and 50 ml ethyl acetate. The solution was left to cool slightly before addition of 2.1 gram fumaric acid took place causing an exothermic reaction and precipitation of a white solid. The suspension was stirred while being allowed to cool to room temperature followed by 2 hours in the freezer at −18° C. The white solid was collected by filtration and washed with 20 ml cold ethyl acetate before drying in vacuum (50° C.) over night. The product was isolated in 3.1 gram (44%). NMR complies with structure. Elemental analysis: 63.42% C, 6.64% N, 6.42% H (Theory for a 1:1 salt: 63.74% C, 6.76% N, 6.32% H) Example 7b Characterisation of the fumarate of compound I The fumarate, as prepared in example 7a, is crystalline (XRPD)—see FIG. 10. It has a melting point of ˜194° C. The solubility in water is 0.4 mg/ml. Example 8a Preparation of maleate of compound I 2.5 gram 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine oil was dissolved in 50 ml ethyl acetate and heated to 60° C. followed by addition of 1.1 gram maleic acid. The mixture was heated again to reflux for 5 minutes and left to cool to room temperature while stirring. During the cooling precipitation started and was finalized by 4 hours in the freezer (−18° C.). The white solid was collected by filtration and washed with 50 ml diethyl ether before drying in vacuum (50° C.) over night. This produced 1.3 gram of 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine Maleate (38%) that was recrystallised by treatment with 40 ml ethyl acetate and 5 ml methanol at reflux. The clear solution was cooled to room temperature followed by 2 hours in the freezer (−18° C.) before filtering and washed twice with 10 ml cold ethyl acetate followed by drying in vacuum (50° C.) for two days. 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine Maleate was isolated in 0.9 gram (69%). NMR complies with structure. Elemental analysis: 63.57% C, 6.79% N, 6.39% H (Theory for a 1:1 salt: 63.74% C, 6.76% N, 6.32% H) Example 8b Characterisation of the maleate of compound I The maleate, as prepared in example 8a, is crystalline (XRPD)—see FIG. 11. It has a melting point of ˜152° C. The solubility in water is ˜1 mg/ml. Example 9a Preparation of meso-tartrate of compound I 11.1 ml of a 0.30 M solution of 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine in acetone was treated with 0.5 gram meso-tartaric acid dissolved in 5 ml acetone. The mixture was stirred at room temperature for 30 minutes during which precipitation took place. Filtration and washing first with 5 ml acetone and then 3 ml diethyl ether produced the product as a white solid that was dried in vacuum (50° C.) over night. 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine meso-tartaric acid was isolated in 1.4 gram (93%). NMR complies with structure. Elemental analysis: 58.58% C, 6.29% N, 6.40% H (Theory for a 1:1 salt: 58.91% C, 6.25% N, 6.29% H) Example 9b Characterisation of the meso-tartrate of compound I The meso-tartrate, as prepared in example 9a, is crystalline (XRPD)—see FIG. 12. It has a melting point of ˜164° C. The solubility in water is ˜0.7 mg/ml. Example 10a Preparation of L-(+)-tartrate of compound I 11.1 ml of a 0.30 M solution of 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine in acetone was treated with 0.5 gram L-(+)-tartaric acid dissolved in 5 ml acetone. The mixture was stirred at room temperature for 30 minutes during which precipitation took place. Filtration and washing first with 5 ml acetone and then 3 ml diethyl ether achieved the product as a white solid that was dried in vacuum (50° C.) over night. 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine (+)-tartaric acid was isolated in 1.2 gram (81%). NMR complies with structure. Elemental analysis: 58.86% C, 6.30% N, 6.38% H (Theory for a 1:1 salt: 58.91% C, 6.25% N, 6.29% H) Example 10b Characterisation of the L-(+)-tartrate of compound I The L-(+)-tartrate, as prepared in example 10a, is crystalline (XRPD)—see FIG. 13. It has a melting point of ˜171° C. The solubility in water is ˜0.4 mg/ml. Example 11a Preparation of D-(−)-tartrate of compound I 11.1 ml of a 0.30 M solution of 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine in acetone was treated with 0.5 gram D-(−)-tartaric acid dissolved in 5 ml acetone. The mixture was stirred at room temperature for 30 minutes during which precipitation took place. Filtration and washing first with 5 ml acetone and then 3 ml diethyl ether produced the product as a white solid that was dried in vacuum (50° C.) over night. 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine D-(−)-tartaric acid was isolated in 1.0 gram (68%). NMR complies with structure. Elemental analysis: 58.90% C, 6.26% N, 6.35% H (Theory for a 1:1 salt: 58.91% C, 6.25% N, 6.29% H) Example 11b Characterisation of the D-(−)-tartrate of compound I The D-(+)-tartrate, as prepared in example 11a, is crystalline (XRPD)—see FIG. 14. It has a melting point of ˜175° C. The solubility in water is ˜0.4 mg/ml. Example 12a Preparation of sulphate of compound I 11.1 ml of a 0.30 M solution of 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine in acetone was treated with 2.2 ml of a 3 M solution of H2SO4 (aq). The mixture was stirred at room temperature for 30 minutes and then on ice-bath for another 4 hours before precipitation took place and was finalized. Filtration and washing first with 5 ml acetone and then 3 ml diethyl ether produced the product as a white solid that was dried in vacuum (50° C.) over night. 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine sulphate was isolated in 0.51 gram (39%). NMR complies with structure. Elemental analysis: 54.53% C, 7.22% N, 6.28% H (Theory for a 1:1 salt: 54.52% C, 7.07% N, 6.10% H) Example 12b Characterisation of the sulphate of compound I The sulphate, as prepared in example 12a, is crystalline (XRPD)—see FIG. 15. It has a melting point of ˜166° C. The solubility in water is ˜0.1 mg/ml. Example 13a Preparation of phosphate of compound I 11.1 ml of a 0.30 M solution of 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine in acetone was treated with 0.2 ml 65% H3PO4 (aq). The mixture was stirred at room temperature for 30 minutes during which precipitation took place. Filtration and washing first with 5 ml acetone and then 3 ml diethyl ether produced the product as a white solid that was dried in vacuum (50° C.) over night. 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine phosphate was isolated in 1.23 gram (94%). NMR complies with structure. Elemental analysis: 54.21% C, 7.15% N, 6.43% H (Theory for a 1:1 salt: 54.53% C, 7.07% N, 6.36% H) Example 13b Characterisation of the phosphate of compound I The phosphate, as prepared in example 13a, is crystalline (XRPD) see FIG. 16. It has a melting point of ˜224° C. The solubility in water is ˜1 mg/ml. Example 14a Preparation of nitrate of compound I 11.1 ml of a 0.30 M solution of 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine in acetone was treated with 0.2 ml of 16.5 M HNO3 (aq). The mixture was stirred at room temperature for 30 minutes during which precipitation took place. Filtration and washing first with 5 ml acetone and then 3 ml diethyl ether produced the product as a white solid that was dried in vacuum (50° C.) over night. 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine nitrate was isolated in 0.87 gram (73%). NMR complies with structure. Elemental analysis: 59.80% C, 11.67% N, 6.51% H (Theory for a 1:1 salt: 59.81% C, 11.63% N, 6.41% H) Example 14b Characterisation of the nitrate of compound I The nitrate, as prepared in example 14a, is crystalline (XRPD)—see FIG. 17. It does not melt but decomposes under an exothermic reaction at about 160° C. The solubility in water is ˜0.8 mg/ml. Example 15 Tablet The examples below show representative examples of how tablets comprising compounds of the present invention may be prepared. The beta form of the hydrobromide salt has been used in all examples. Example 15a 63.55 g of the hydrobromide salt, 923.65 g Lactosum 350M, 461.8 g corn starch and 76.0 g Kollidon VA64 were mixed for 2 minutes in a Diosna PP1 high shear mixer at an impeller speed of 1000 rpm. Next, the speed of the impeller was lowered to 800 rpm and 220 g water was added during the course of a minute. Massing was performed for 7 minutes and the resulting granules were passed through a sieve, size 4000 μm. The granules were dried and passed through a sieve, size 710 μm. 1383.5 g of the resulting granules were mixed with 400 g Avicel PH200 and 60 g Ac-Di-Sol. Following lubrication of the blend by mixing with 15 g magnesium stearate the powder blend was transferred to a tablet press. Tablets having a target core weight of 200 mg and a diameter of 8 mm were prepared to obtain tablets with a target content corresponding to 5 mg of the free base. Example 15b 317.75 g of the hydrobromide salt, 754.15 g Lactosum 350M, 377.1 g corn starch and 76.0 g Kollidon VA64 were mixed for 2 minutes in a Diosna PP1 high shear mixer at an impeller speed of 1000 rpm. Next, the speed of the impeller was lowered to 800 rpm and 210 g water was added during the course of a minute. Massing was performed for 7 minutes and the resulting granules were passed through a sieve, size 4000 μm. The granules were dried and passed through a sieve, size 710 μm. 1386.2 g of the resulting granules were mixed with 400 g Avicel PH200 and 60 g Ac-Di-Sol. Following lubrication of the blend by mixing with 15 g magnesium stearate the powder blend was transferred to a tablet press. Tablets having a target core weight of 200 mg and a diameter of 8 mm were prepared to obtain tablets with a target content corresponding to 25 mg of the free base. Example 15c 32.2 g of the hydrobromide salt, 944.82 g Lactosum 350M, 472.4 g corn starch and 76.0 g Kollidon VA64 were mixed for 2 minutes in a Diosna PP1 high shear mixer at an impeller speed of 1000 rpm. Next, the speed of the impeller was lowered to 800 rpm and 220 g water was added during the course of a minute. Massing was performed for 7 minutes and the resulting granules were passed through a sieve, size 4000 μm. The granules were dried and passed through a sieve, size 710 μm. 1317 g of the resulting granules were mixed with 400 g Avicel PH200 and 60 g Ac-Di-Sol. Following lubrication of the blend by mixing with 15 g magnesium stearate the powder blend was transferred to a tablet press. Tablets having a target core weight of 208 mg and a diameter of 8 mm were prepared to obtain tablets with a target content corresponding to 2.5 mg of the free base. Example 15d 540.85 g of the hydrobromide salt, 953.00 g Pearlitol 50 C, 296.22 g corn starch and 70.5 g Kollidon VA64 were mixed for 2 minutes in an Aeromatic-Fielder PMA1 high shear mixer at an impeller speed of 1000 rpm. Next, the speed of the impeller was lowered to 800 rpm and 241.87 g water was added during the course of a minute. Massing was performed for 7 minutes and the resulting granules were passed through a sieve, size 4000 μm. The granules were dried and passed through a sieve, size 710 μm. 1500 g of the resulting granules were mixed with 531.91 g Avicel PH200 and 85.11 g Primojel. Following lubrication of the blend by mixing with 10.64 g magnesium stearate the powder blend was transferred to a tablet press. Tablets having a target core weight of 125 mg and a diameter of 6 mm were prepared to obtain tablets with a target content corresponding to 25 mg of the free base. Example 15e 270.45 g of the hydrobromide salt, 772.0 g Pearlitol 50 C, 386.41 g corn starch and 70.5 g Kollidon VA64 were mixed for 2 minutes in an Aeromatic-Fielder PMA1 high shear mixer at an impeller speed of 1000 rpm. Next, the speed of the impeller was lowered to 800 rpm and 195 g water was added during the course of a minute. Massing was performed for 5.5 minutes and the resulting granules were passed through a sieve, size 4000 μm. The granules were dried and passed through a sieve, size 710 μm. 1200.3 g of the resulting granules were mixed with 425.5 g Avicel PH200 and 68.09 g Primojel. Following lubrication of the blend by mixing with 8.8 g magnesium stearate the powder blend was transferred to a tablet press. Tablets having a target core weight of 100 and a diameter of 6 mm were prepared to obtain tablets with a target content corresponding to 10 mg of the free base. Example 15f 504.85 g of the free base, 552.95 g Pearlitol 50 C, 276.53 g corn starch and 65.7 g Kollidon VA64 were mixed for 2 minutes in an Aeromatic-Fielder PMA1 high shear mixer at an impeller speed of 1000 rpm. Next, the speed of the impeller was lowered to 800 rpm and 182 g water was added during the course of a minute. Massing was performed for 5.5 minutes and the resulting granules were passed through a sieve, size 4000 μm. The granules were dried and passed through a sieve, size 710 μm. 1250.7 g of the resulting granules were mixed with 443.31 g Avicel PH200 and 70.8 g Primojel. Following lubrication of the blend by mixing with 8.92 g magnesium stearate the powder blend was transferred to a tablet press. Tablets having a target core weight of 250 mg and a diameter of 8 mm were prepared to obtain tablets with a target content corresponding to 50 mg of the free base. Example 15g 135.23 g of the hydrobromide salt, 863.2 g Pearlitol 50 C, 432.69 g corn starch and 70.66 g Kollidon VA64 were mixed for 2 minutes in an Aeromatic-Fielder PMA1 high shear mixer at an impeller speed of 1000 rpm. Next, the speed of the impeller was lowered to 800 rpm and 195 g water was added during the course of a minute. Massing was performed for 5.5 minutes and the resulting granules were passed through a sieve, size 4000 μm. The granules were dried and passed through a sieve, size 710 μm. 1200 g of the resulting granules were mixed with 425.28 g Avicel PH200 and 68.2 g Primojel. Following lubrication of the blend by mixing with 8.58 g magnesium stearate the powder blend was transferred to a tablet press. Tablets having a target core weight of 100 mg and a diameter of 6 mm were prepared to obtain tablets with a target content of corresponding to 5 mg of the free base. Example 15h 67.6 g of the hydrobromide salt, 908.0 g Pearlitol 50 C, 453.9 g corn starch and 70.51 g Kollidon VA64 were mixed for 2 minutes in a Diosna PP1 high shear mixer at an impeller speed of 1000 rpm. Next, the speed of the impeller was lowered to 800 rpm and 195 g water was added during the course of a minute. Massing was performed for 5.5 minutes and the resulting granules were passed through a sieve, size 4000 μm. The granules were dried and passed through a sieve, size 710 μm. 1325 g of the resulting granules were mixed with 531.91 g Avicel PH200 and 85.11 g Primojel. Following lubrication of the blend by mixing with 10.64 g magnesium stearate the powder blend was transferred to a tablet press. Tablets having a target core weight of 207.8 mg and a diameter of 7 mm were prepared to obtain tablets with a target content corresponding to 5 mg of the free base. Example 15i 2290.1 g of the hydrobromide salt, 17568 g anhydrous calcium hydrogen phosphate and 8783 g of corn starch and 1510 g copovidone were mixed for 3 minutes in an Aeromatic-Fielder PMA100 high-shear mixer at an impeller speed of 200 rpm. Next, 5130 g water was added during the course of 2 minutes at an impeller speed of 150 rpm. Massing was performed for 15 minutes and the resulting granules were passed through a cone mill operating at about 2700 rpm with a screen, size 9.525 mm. The granules were dried and passed through cone mill operating at about 1500 rpm with a screen, size 2.388 mm. 28747 g of the resulting granules were mixed with 11250 g microcrystalline cellulose, 1350 g sodium starch glycolate (type A) and 1800 g talc. Following lubrication of the blend by mixing with 450 g magnesium stearate the powder blend was transferred to a tablet press. Tablets having a target core weight of 125 mg and a diameter of 6 mm were prepared to obtain tablets with a target content of the hydrobromide salt corresponding to 5 mg of the free base. In addition, tablets having a target core weight of 250 mg and a diameter of 8 mm were prepared to obtain tablets with a target content of the hydrobromide salt corresponding to 10 mg of the free base. Example 16 Pain Effects in the Mouse Intradermal formalin Test In this model, mice receive an injection of formalin (4.5%, 20 μl) into the left hind paw. The irritation caused by the formalin injection elicits a characteristic biphasic behavioural response, as quantified by the amount of time spent licking the injured paw. The first phase (˜0-10 minutes) represents direct chemical irritation and nociception, whereas the second (˜20-30 minutes) is thought to represent pain of neuropathic origin. The two phases are separated by a quiescent period in which behaviour returns to normal. The effectiveness of test compounds to reduce the painful stimuli is assessed by counting the amount of time spent licking the injured paw in the two phases. Compounds of the present invention showed a significant reduction in second phase pain scores (FIG. 18b), indicating efficacy against pain of neuropathic origin. Furthermore, the compounds of the present invention showed a significant reduction in the first phase scores (FIG. 18a), indicating a more analgesic action at the highest dose. In summary, these results indicate that compounds of the present invention are likely to be effective in the treatment of pain disorders. Example 17 20 g 2-bromoiodobenzene (71 mmol) and 9.8 g 2,4-dimethylthiophenol (71 mmol) were dissolved in 100 ml toluene. The solution was purged with nitrogen before 324 mg Pd2dba3 (0.35 mmol; 1 mol-%) and 381 mg DPEPhos (0.71 mmol; 1 mol-%). The reaction mixture was stirred 5 min during which the colour changes from dark-red to orange. Addition of 8.7 g KOBut (78 mmol) took place and a heterogeneous mixture was formed instantly. The suspension was heated to 100° C. under nitrogen. After 1 hour the mixture was cooled to 0° C. and stirred for 2 hours before filtering the mixture though a pad of celite. The filter cake was washed with 2 ×50 ml toluene and the combined filtrates evaporated to 21 g of a orange-reddish oil (99% yield) that proved >96% pure on HPLC and GC-MS. Example 18 500 ml toluene was placed in a 1 L three necked round bottle with a mechanical stirrer and added 203 mg Pddba2 (0.35 mmol; 0.1 mol-%) and 760 mg DPEPhos (1.5 mmol; 0.4 mol-%). The dark-red solution was purged with nitrogen for 5 minutes before addition of 100 g 2-bromoiodobenzene (353 mmol) and 48.9 g 2,4-dimethylthiophenol (353 mmol) took place. Addition of 43.6 g KOBut (389 mmol) caused an exothermic reaction increasing the temperature from 20° C. to 36° C. simultaneously with the formation of heterogeneous mixture. The suspension was heated to 100° C. under nitrogen. After 7 hours the mixture was cooled to 0° C. and stirred for 2 hours before filtering the mixture though a pad of celite. The filter cake was washed with 2×200 ml toluene and the combined filtrates was evaporated to 104 g of an orange oil (105% yield) that proved 97% pure on HPLC and NMR conforms to desired structure. The oil solidified during standing at room temperature. Example 19 A solution of 10 gram 1-(2-Bromo-phenylsulfanyl)-2,4-dimethyl-benzene (34 mmol) in 50 ml dry toluene was added 7 gram boc-piperazine (38 mmol), degassed with nitrogen for 5 minutes, added 312 mg Pd2dba3 (2 mol-%) and 637 mg rac-BINAP (3 mol-%), degassed for another 5 minutes before adding 3.9 gram ButONa (41 mmol) and heated to 80° C. for 15 hours. The reaction mixture was cooled to RT and extracted twice with 20 ml 15% brine, dried over Na2SO4, added charcoal, refluxed for 15 minutes, filtered though celite and evaporated to 14.2 gram of brownish oil (4-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-BOC-piperazine) having a purity of 95% determined by NMR. The crude oil was dissolved in 200 ml MeOH and 20 ml 6M HCl (aq.) and refluxed for 1 hour after which HPLC showed full deprotection. After cooling to RT the methanol was removed by vacuum on a rotary-evaporator, 20 ml conc. NaOH (pH was measured to 13-14) was added after which the mixture was stirred 15 minutes with 100 ml EtOAc. The organic phase was collected and extracted twice with 30 ml 15% brine, dried over Na2SO4 and added 5.2 g fumaric acid (44 mmol) in 30 ml MeOH. During heating to reflux a homogenous solution forms from which a rapid precipitation takes place either during further heating or upon cooling. The precipitate was collected, washed with 20 ml EtOAc and 20 ml acetone, dried in vacuum giving 9.3 gram of 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine fumarate (22 mmol) as a white powder in 66% overall yield having a purity of 99.5% by LC-MS. Example 20 100 g 1,2-dibromobenzene (424 mmol) and 58.6 g 2,4-dimethylthiophenol (424 mmol) are dissolved in 800 ml toluene. The solution is purged with nitrogen before 4.6 g Pddba2 (8 mmol; 2 mol-%) and 13.1 g rac-BINAP (21 mmol; 5 mol-%). The reaction mixture is stirred 5 min during which the colour changes from dark-red to orange. Addition of 61 g NaOBut (636 mmol) and 200 ml toluene took place and a heterogeneous mixture was formed instantly. The suspension was heated to 80° C. under nitrogen. After 10 hours the mixture is cooled to 60° C. before adding a slurry of 102.6 g boc-piperazine (551 mmol) and another 61 g NaOBut (636 mmol) in 500 ml toluene. The reaction mixture was purged with nitrogen before adding another portion of 4.6 g Pddba2 (8 mmol; 2 mol-%) and 13.1 g rac-BINAP (21 mmol; 5 mol-%). The mixture was heated to reflux this time (110° C.) for another 6 hours or until HPLC shows full conversion. The reaction mixture was cooled on ice for 2 hours before filtering the mixture though a pad of celite. The filter cake is washed with 2×200 ml toluene and the combined filtrates evaporated to 242 g of red oil. The oil was dissolved in 1000 ml MeOH and slowly added 115 ml 48-wt % HBr (aq.) followed by heating to reflux for 2 hours after which full deprotection was detected by HPLC. The mixture was cooled, added 1000 ml EtOAc and the MeOH was removed by evaporation. Addition of 1000 ml Et2O caused a precipitation. Stirring was continued at room temperature for 2 hours before leaving the slurry in the freezer overnight (−18° C.). Filtration and washing twice with 200 ml Et2O produced 172 g brownish solid after drying in vacuum at 40° C. The brownish solid was treated with 1500 ml boiling H2O for 1 hour before cooled to room temperature for another 2 hours. Filtering and drying in vacuum at 40° C. overnight produced 98 g of 4-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (61%). Example 21 102 g 2-bromo-iodobenzene (362 mmol) and 50 g 2,4-dimethylthiophenol (362 mmol) are dissolved in 1000 ml toluene. To this solution was added 81 g BOC-piperazine (434 mmol) followed by 2.08 g Pddba2 (1 mol%) and 4.51 g rac-BINAP (2 mol%). The mixture was purged with nitrogen for 5 minutes before adding a slurry of 87 g NaOBut (905 mmol) in 300 ml toluene. The suspension was heated to 100° C. under nitrogen overnight. A GCMS analysis showed full conversion into the intermediate product (1-(2-Bromo-phenylsulfanyl)-2,4-dimethyl-benzene) and the temperature was increased to reflux (120° C.) for another 24 hours. A HPLC analysis showed full conversion into the intermediate (1-BOC-4-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine). The reaction mixture was cooled on ice for one hour before filtering the mixture. The filter cake is washed with 2×200 ml toluene and to the combined filtrates was added 80 ml 48-wt % HBr (aq.) followed by heating to reflux for 18 hours after which full deprotection was detected by HPLC. The mixture was cooled on ice for 2 hours and filtrated. The brownish solid was dissolved in 1000 ml boiling H2O for 1 hour together with activated charcoal (25 g), filtered while hot and left to cool. The precipitate was collected by filtration and drying in vacuum at 40° C. overnight produced 49 g of 4-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (36%) as a white solid. Example 22 500 ml toluene was placed in a 1 L three-necked round bottle with a mechanical stirrer and added 809 mg Pd2dba3 (0.88 mmol; 0.5 mol-%) and 952 mg DPEPhos (1.77 mmol; 0.5 mol-%). The dark-red solution was purged with nitrogen for 5 minutes before addition of 100 g 2-bromoiodobenzene (353 mmol) and 48.9 g 2,4-dimethylthiophenol (353 mmol) took place. Addition of 43.6 g KOBut (389 mmol) caused an exothermic reaction increasing the temperature from 20° C. to 42° C. simultaneously with the formation of a heterogeneous mixture and the colour changed from dark-red into orange/brownish. The suspension was heated to 100° C. under nitrogen. After only 20 minutes a HPLC showed full conversion into 1-(2-Bromo-phenylsulfanyl)-2,4-dimethyl-benzene. The mixture was cooled to 40° C., added 600 ml 15-wt %NaCl and stirred for 5 minutes. The organic phase was separated and the aqueous phase was washed with 2×100 ml toluene. The combined organic phases were washed with 100 ml 2M HCl (aq.), 100 ml 15-wt %NaCl, dried over Na2SO4, refluxed for 15 minutes with activated charcoal (10 g), filtered twice and evaporated to 107.3 g orange-red oil (103%) that was found to be 98% pure by HPLC. A solution of 90 gram of the orange-red oil (307 mmol) in 500 ml dry toluene was added 57 gram boc-piperazine (307 mmol), degassed with nitrogen for 5 minutes, added 1.4 g Pd2dba3 (1.53 mmol; 0.5 mol-%) and 2.9 g rac-BINAP (4.6 mmol; 1.5 mol-%), degassed for another 2 minutes before adding 35.4 gram ButONa (368 mmol) and heated to 80° C. for 18 hours. HPLC showed full conversion and the reaction mixture was cooled to RT, filtered and the filter cake was washed with 2×100 ml toluene. The combined filtrates was extracted twice with 2×150 ml 15-wt %NaCl, dried over Na2SO4, added charcoal, refluxed for 30 minutes, filtered twice and evaporated to 140.7 gram of brownish oil (4-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-BOC-piperazine). The crude oil was dissolved in 300 ml MeOH and 200 ml 6M HCl (aq.) and refluxed for 1 hour after which HPLC showed full deprotection. After cooling to RT the methanol was removed by vacuum on a rotary-evaporator, 200 ml conc. NaOH (pH was measured to 13-14) was added after which the mixture was stirred 15 minutes with 1000 ml EtOAc. The organic phase was collected and extracted with 300 ml 15-wt % brine, dried over Na2SO4 and added to a solution of 46.3 g fumaric acid (399 mmol) in 300 ml MeOH. The mixture was heated to reflux, cooled to room temperature and then left in the freezer overnight (−18° C.). The precipitate was collected, washed with 100 ml EtOAc and 100 ml acetone, dried in vacuum (50° C.) producing 103.2 g of 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine fumarate (249 mmol) as a white powder in 81% overall yield having a purity of 99% by LC-MS. The fumarate was transfer into the free base (1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine) using EtOAc/H2O/conc. NaOH, the organic phase was washed with brine, dried using Na2SO4, filtered and to the filtrate was added 34 ml 48-wt % HBr (aq.) causing a precipitation of a white solid. The solid was collected, treated with 1000 ml boiling H2O, which upon cooling to room temperature formed a slurry. The final product (1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide) was collected by filtration and dried in vacuum (50° C.) producing 83 g of white powder (71% yield overall), CHN (teo.) 56.99; 6.11; 7.39; CHN (found) 57.11; 6.15; 7.35. Example 23 815 g NaOBut (8.48 mol), 844 g Piperazine (9.8 mol), 6.6 g Pd(dba)2 (11.48 mmol) and 13.6 g rac-BINAP (21.84 mmol) were stirred with 4 L toluene for 50 minutes. 840 g 2-bromo-iodobenzene (2.97 mol) was then added along with 1.5 L Toluene and stirring continued for 30 min. 390.8 g 2,4-dimethylthiophenol (2.83 mol) was finally added with 1.5 L toluene. The suspension was heated to reflux and reflux continued for 5 hours. The reaction mixture was cooled down over night. 2 L water was added and stirred for 1 hour before the mixture was filtrated through filter aid. The filtrate was then washed with 3×1 L brine. The combined water phases were then extracted with 600 ml toluene. The combined toluene phases were then heated to 70° C. followed by addition of 329.2 ml 48-wt % HBr (aq.) and 164.6 ml water. The mixture was cooled to room temperature over night. The final product (1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide) was collected by filtration and dried in vacuum (60° C.) producing 895 g (84% yield). Example 24 40.76 g NaOBut (424.1mol), 0.33 g Pddba2 (0.57 mmol) and 0.68 g rac-BINAP (1.09 mmol) were stirred with 200 ml toluene. 42 g 2-bromo-iodobenzene (362 mmol) and 19.54 g 2,4-dimethylthiophenol (362 mmol) were added with 50 ml toluene. The suspension was heated to reflux and reflux continued over night. A HPLC analysis showed full conversion into the intermediate product (1-(2-Bromo-phenylsulfanyl)-2,4-dimethyl-benzene). The reaction mixture was cooled to RT and filtered through filter aid. The filtrate was added to a mixture of 40.76 g NaOBut (424.1 mmol), 42.2 g piperazine (489.9 mmol), 0.33 g Pddba2 (0.57 mmol) and 0.68 g rac-BINAP (1.09 mmol) and heated to reflux for 2 hours. The reaction mixture was cooled down over night. 100 ml water was added and the water phase separated off. The organic phase was filtered through filter aid and the filtrate was then washed with 3×80 ml brine. The combined water phases were then extracted with 50 ml toluene. The combined toluene phases were then heated to 70° C. and followed by addition of 16.5 ml 48-wt % HBr (aq.) and 8.25 ml water. The mixture was cooled to room temperature over night. The final product (1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide) was collected by filtration and dried in vacuum (60° C.) producing 40.18 g of off-white powder (75% yield) Example 25 40.76 g NaOBut (424.1 mmol), 0.33 g Pddba2 (0.57 mmol) and 0.68 g rac-BINAP (1.09 mmol) were stirred with 200 ml toluene. 42 g 2-bromo-iodobenzene (148.5 mmol) and 19.54 g 2,4-dimethylthiophenol (141.4 mmol) was added with 50 ml toluene. The suspension was heated to reflux and reflux continued over night. A HPLC analysis showed full conversion into the intermediate product (1-(2-Bromo-phenylsulfanyl)-2,4-dimethyl-benzene). Reaction cooled to 50° C. and 42.2 g piperazine (489.9 mmol) was added along with 100 ml toluene. The mixture was heated to reflux for 4 hours. The reaction mixture was cooled to RT over night. 100 ml water was added and the reaction mixture was filtered through filter aid. The filter cake was then washed with 50 ml toluene. The water phase was separated off and the organic phase was then washed with 3×25 ml brine and 25 ml water. The combined water phases was then extracted with 30 ml toluene. The combined toluene phases was then heated to 70° C. and followed by addition of 16.46 ml 48-wt % HBr (aq.) and 8.23 ml water. The mixture was cooled to room temperature over night. The final product (1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide) was collected by filtration and dried in vacuum (60° C.) producing 46.8 g (87% yield). Example 26 Effects on Extracellular Levels of Acetylcholine in the Brain of Freely Moving Rats Methods The animals were administered 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]-piparazine, HBr salt. Animals Male Sprague-Dawley rats, initially weighing 275-300 g, were used. The animals were housed under a 12-hr light/dark cycle under controlled conditions for regular in-door temperature (21±2° C.) and humidity (55±5%) with food and tap water available ad libitum. Surgery and Microdialysis Experiments Rats were anaesthetised with hypnorm/dormicum (2 ml/kg) and intracerebral guide cannulas (CMA/12) were stereotaxically implanted into the brain, aiming at positioning the dialysis probe tip in the ventral hippocampus (co-ordinates: 5.6 mm posterior to bregma, lateral—5.0 mm, 7.0 mm ventral to dura) or in the prefrontal cortex (co-ordinates: 3.2 mm anterior to bregma; lateral, 0.8 mm; 4.0 mm ventral to dura). Anchor screws and acrylic cement were used for fixation of the guide cannulas. The body temperature of the animals was monitored by rectal probe and maintained at 37° C. The rats were allowed to recover from surgery for 2 days, housed singly in cages. On the day of the experiment a microdialysis probe (CMA/12, 0.5 mm diameter, 3 mm length) was inserted through the guide cannula. The probes were connected via a dual channel swivel to a microinjection pump. Perfusion of the microdialysis probe with filtered Ringer solution (145 mm NaCl, 3 mM KCl, 1 mM MgCl2, 1.2 mM CaCl2 containing 0.5 μM neostigmine) was begun shortly before insertion of the probe into the brain and continued for the duration of the experiment at a constant flow rate of 1 μl/min. After 180 min of stabilisation, the experiments were initiated. Dialysates were collected every 20 min. After the experiments the animals were sacrificed, their brains removed, frozen and sliced for probe placement verification. The compound dissolved in 10% HPbetaCD and injected subcutaneously (2.5-10 mg/kg). Doses are expressed as mg salt/kg body weight. The compound was administered in a volume of 2.5 ml/kg. Analysis of Dialysate Acetylcholine Concentration of acetylcholine (ACh) in the dialysates was analysed by means of HPLC with electrochemical detection using a mobile phase consisting of 100 mM disodium hydrogenphosphate, 2.0 mM octane sulfonic acid, 0.5 mM tetramethyl-ammonium chloride and 0.005% MB (ESA), pH 8.0. A pre-column enzyme reactor (ESA) containing immobilised choline oxidase eliminated choline from the injected sample (10 μl) prior to separation of ACh on the analytical column (ESA ACH-250); flow rate 0.35 ml/min, temperature: 35° C. After the analytical column the sample passed through a post-column solid phase reactor (ESA) containing immobilised acetylcholineesterase and choline oxidase. The latter reactor converted ACh to choline and subsequently choline to betaine and H2O2. The latter was detected electrochemical by using a platinum electrode (Analytical cell: ESA, model 5040). Data Presentation In single injection experiments the mean value of 3 consecutive ACh samples immediately preceding compound administration served as the basal level for each experiment and data were converted to percentage of basal (mean basal pre-injection values normalized to 100%). Results The compound significantly increased extra-cellular levels of ACh in the rat prefrontal cortex and the ventral hippocampus—see FIGS. 19a and 19b. Example 27 Contextual Fear Conditioning in Rats The compound administered in the present experiment was 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine HBr salt. We have studied the effect of the compound on acquisition, consolidation and recall of contextual fear conditioning in rats. In the fear conditioning paradigm animals learn to associate a neutral environment (context, the training chamber, CS) with an aversive experience (an electrical foot-shock, US). During re-exposure to the training chamber, animals express a freezing behaviour, which is taken as a direct measure of the fear-related memory [Pavlov J. Biol. Sci., 15, 177-182, 1980]. The neuroanatomy of contextual fear conditioning has been thoroughly investigated and several studies have demonstrated that the hippocampus and amygdala are necessary for the formation of this memory [Hippocampus, 11, 8-17, 2001; J. Neurosci., 19, 1106-1114, 1999; Behav. Neurosci., 106, 274-285, 1992]. Animals and Drugs Adult male Sprague-Dawley rats (weighing 250-300 g at time of training) from Charles River Laboratories, housed two per cage under a 12 h light/dark cycle, were used. Food and water were available ad libitum. Rats were used 1 week after arrival. The compound was dissolved in 10% HPbetaCD and injected subcutaneously. The drug was administered in a volume of 2.5 ml/kg. Apparatus Training and testing were conducted in a soundproof chamber (30×20×40 cm) housed in an isolated room and connected to a ventilation system. Illumination was provided by a white light (60 Watt). The floor of the chamber consisted of a metal grid attached to an electric shock generator. Prior to training and testing, the chamber was cleaned with a 70% ethanol solution. A video camera allowed for behavioral observations and recording of the training session for off-line analysis. Acquisition and Retention Test During the acquisition animals were allowed to freely explore the novel environment for a 1 min habituation period, which co-terminated with one inescapable foot-shock (unconditioned stimulus, US) through the electrifiable grid floor. The foot shock had a duration of 2 s and an intensity of 0.75 mA. Animals remained in the conditioning chamber for another 60 s after the US. Freezing behaviour was scored during the first 58 s (pre-shock acquisition; experimenter blinded to groups) to determine baseline-freezing responses to the context. At the end of the acquisition animals were gently removed and placed into their home cages. After 24 h the same animals were reintroduced into the training context (fear conditioning chamber) and a 2 min retention test was performed. During this period no foot shocks were applied. Freezing behaviour was scored during the whole test period with the experimenter blinded to groups and presented as percent of total test period. Results and Discussion Effect of the Compound on Contextual Fear Cognition in Rats The effect of the compound on contextual fear conditioning in rats was studied (i) on acquisition (drug applied before acquisition, FIG. 20), (ii) on memory recall (drug applied before test, FIG. 21) and (iii) on consolidation (drug applied immediately after the acquisition, FIG. 22). In the first set of experiments, the compound (1, 5 and 10 mg/kg) was administered 1 h prior to the acquisition session. FIG. 20 depicts the acquisition of freezing behavior during training (58 s prior to the food shock) and the retention test 24 after. The following findings were observed: The compound does not affect baseline freezing behaviour before the presentation of the foot shock at any dose tested. The compound at 5 mg/kg has a tendency to increase the time spent freezing during the retention test, 24 h after the acquisition (39.24±13.76%, n=6, versus 24.30±4.40%, n=16, in the vehicle-treated animals). The compound at 10 mg/kg significantly increases the time spent freezing during the retention test, 24 h after the acquisition (52.15±5.68%, n=10, versus 24.30±4.40%, n=16, in the vehicle-treated animals, p<0.01). The fear conditioning model, as described in FIG. 20, is a standard procedure described in the literature for the investigation of learning and memory. In order to further elucidate the acute effects of this drug on memory recall, the compound (5, 10 and 20 mg/kg) was applied 1 h prior to the retention test. It was observed that the compound inhibits the expression of freezing behaviour at 5 mg/kg during the memory test (12.86±3.57%, n=9, versus 33.61±4.29%, n=13, in the vehicle-treated animals, p<0.05) (FIG. 21). As described above, the compound by itself does not affect baseline freezing behaviour before the onset of US (FIG. 20), thus the most plausible hypothesis is that the observed effect in FIG. 21 is due to an anxiolytic effect. The conditioned memory is assessed via freezing behaviour, a response that is reduced by compounds with potential anxiolytic effects. This experiment demonstrates that the compound given acutely before memory recall has anxiolytic efficacy, it is therefore unlikely that increased freezing shown in FIG. 20 is due to an anxiogenic effect of the compound. In order to strengthen that the compound is not anxiogenic but bears pro-cognitive potential, the compound was administered at 5, 10 and 20 mg/kg after the acquisition session. Consequently, in this set of experiments, the compound was onboard neither during the acquisition nor throughout the retention test. Here, it was observed that the compound at 5 mg/kg significantly enhances the time spent freezing during the retention test, 24 h after the acquisition session (45.58±4.50%, n=8, versus 25.26±3.57%, n=19, in the vehicle-treated animals, p<0.05). The percentage of time spent freezing during the context re-exposure has been described as a measure of a fear-related memory [Pavlov J. Biol. Sci, 15, 177-182, 1980], which is enhanced in compound-treated rats when compared to vehicle-treated animals (FIGS. 20 and 21). Taken together, the data show that the compound enhances contextual memory.
<SOH> BACKGROUND OF THE INVENTION <EOH>Selective serotonin reuptake inhibitors (SSRI) have for years been the first choice therapeutics for the treatment of certain CNS related diseases, in particular depression, anxiety and social phobias because they are effective, well tolerated and have a favourable safety profile as compared to previously used compounds, i.e. the classical tri-cyclic compounds. Nonetheless, therapeutic treatment using SSRI is hampered by a significant fraction of non-responders, i.e. patients who do not respond or only respond to a limited extent to the SSRI treatment. Moreover, typically an SSRI treatment does not begin to show an effect until after several weeks of treatment. In order to circumvent some of these shortcomings of SSRI treatment, psychiatrists sometimes make use of augmentation strategies. Augmentation of antidepressants may be achieved e.g. by combination with mood stabilisers, such as lithium carbonate or triiodothyronin, or by the parallel use of electroshock. It is known that a combination of inhibition of the serotonin transporter (SERT) with an activity on one or more serotonin receptors may be beneficial. It has previously been found that the combination of a serotonin reuptake inhibitor with a compound having 5-HT 2C antagonistic or inverse agonistic effect (compounds having a negative efficacy at the 5-HT 2C receptor) provides a considerable increase in the level of 5-HT (serotonin) in terminal areas, as measured in microdialysis experiments (WO 01/41701). This would imply a shorter onset of antidepressant effect in the clinic and an augmentation or potentiation of the therapeutic effect of the serotonin reuptake inhibitor (SRI). Similarly, it has been reported that the combination of pindolol, which is a 5-HT 1A partial agonist, with a serotonin reuptake inhibitor gives rise to fast onset of effect [ Psych. Res., 125, 81-86, 2004]. CNS related diseases, such as e.g. depression, anxiety and schizophrenia are often co-morbid with other disorders or dysfuntionalities, such as cognitive deficits or impairment [ Scand. J. Psych., 43, 239-251, 2002; Am. J. Psych., 158, 1722-1725, 2001]. Several neurotransmitters are presumed to be involved in the neuronal events regulating cognition. In particular, the cholinergic system plays a prominent role in cognition, and compounds affecting the cholinergic system are thus potentially useful for the treatment of cognitive impairment. Compounds affecting the 5-HT 1A receptor and/or the 5-HT 3 receptor are known to affect the cholinergic system, and they may as such be useful in the treatment of cognitive impairment. Hence, a compound exerting 5-HT 1A and/or 5-HT 3 receptor activity would be expected to be useful in the treatment of cognitive impairment. A compound which moreover also exerts SERT activity would be particular useful for the treatment of cognitive impairment in depressed patients as such compound would also provide a fast onset of the treatment of the depression. WO 03/029232 discloses e.g. the compound 1-[2-(2,4-dimethylphenyl-sulfanyl)phenyl]piperazine (example 1e) as a compound having SERT activity.
<SOH> SUMMARY OF THE INVENTION <EOH>The present inventors have surprisingly found that 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine exerts a combination of SERT inhibition, 5-HT 3 antagonism and 5-HT 1A partial agonism. Accordingly, in one embodiment the present invention provides compound I which is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine and pharmaceutically acceptable salts thereof, provided said compound is not the free base in a non-crystalline form. In one embodiment, the invention provides the use of compound I in therapy. In one embodiment, the invention provides a pharmaceutical composition comprising compound I. In one embodiment, the invention provides therapeutic methods comprising the administration of an effective amount of compound I to a patient in need thereof. In one embodiment, the invention provides the use of compound I in the manufacture of a medicament.
A61K31495
20170810
20180109
20171221
84397.0
A61K31495
15
POLANSKY, GREGG
1-[2-(2,4-DIMETHYLPHENYLSULFANYL)-PHENYL]PIPERAZINE AS A COMPOUND With COMBINED SEROTONIN REUPTAKE, 5-HT3 AND 5-HT1A ACTIVITY FOR THE TREATMENT OF COGNITIVE IMPAIRMENT
UNDISCOUNTED
1
CONT-ACCEPTED
A61K
2,017
15,674,122
ACCEPTED
SEEDING MACHINE WITH SEED DELIVERY SYSTEM
A seed delivery system for use in a seeding or planting machine that removes the seed from a seed meter by capturing the seed therefrom. The delivery system then moves the seed down to a lower discharge point and accelerates the seed horizontally rearward to a speed approximately equal to the forward travel speed of the seeding machine such that the seed, when discharged has a low or zero horizontal velocity relative to the ground. Rolling of the seed in the trench is thus reduced. Furthermore, as the seed only has a short drop from the outlet to the bottom of the seed trench, the seed has little vertical speed to induce bounce. The delivery system uses a brush belt to capture, move and accelerate the seed. By capturing the seed and moving it from the meter to the discharge, the seed is held in place relative to other seeds and the planter row unit. As a result, the seeds are isolated from row unit dynamics thereby maintaining seed spacing.
1. A seeding machine, comprising: a seed metering system; a seed transfer device positioned adjacent to the seed metering system; a seed delivery system comprising a housing having a first opening and a second opening, the first opening located proximal to the seed transfer device through which seed is transferred from the seed metering system into the seed delivery system, and the second opening located distal of the seed transfer device through which seed is discharged from the seed delivery system; and an endless member of the seed delivery system movable within the housing to receive the seed at the first opening and transport the seed to the second opening. 2. The seeding machine of claim 1, wherein the housing comprises an elongated side wall that defines the first and second openings. 3. The seeding machine of claim 1, wherein the first opening is defined in an upper portion of the housing and the second opening is defined in a lower portion of the housing. 4. The seeding machine of claim 1, wherein the housing forms a ramp at the second opening along which the seed is discharged from the seed delivery system. 5. The seeding machine of claim 4, wherein the seed is transported by the endless member in a direction from the first opening to the second opening substantially perpendicular to the ramp formed at the second opening. 6. The seeding machine of claim 1, wherein the transfer device comprises a wheel. 7. The seeding machine of claim 1, wherein the transfer device is rotatable about a first axis and the seed metering system is rotatable about a second axis, the first and second axes being offset from but parallel to one another. 8. The seeding machine of claim 1, wherein the seed metering disk is rotatable about a first axis in a first rotational direction, the transfer device is rotatable about a second axis in a second rotational direction, and the endless member moves about at least one pulley which is rotatable about a third axis in a third rotational direction, wherein the first and second rotational directions are the same but opposite of the third rotational direction. 9. The seeding machine of claim 8, wherein the first axis, the second axis and the third axis are offset from but parallel to one another. 10. The seeding machine of claim 8, wherein the first axis and the third axis are not parallel to one another. 11. The seeding machine of claim 1, wherein the endless member comprises a belt that is rotatably driven by at least one pulley. 12. The seeding machine of claim 1, wherein the seed transfer device comprises a surface that contacts the seed and directs the seed through the first opening onto the endless member. 13. The seeding machine of claim 1, wherein the seed metering system comprises a plurality of apertures through which an air differential is applied for maintaining seed thereon, the seed metering system being movable to convey seed to the seed transfer device. 14. The seeding machine of claim 1, wherein the seed travels along a seed path defined between the seed metering system and the second opening of the seed delivery system, wherein the seed transfer device is located upstream of the first opening along the seed path. 15. The seeding machine of claim 14, wherein the seed transfer device is positioned along the seed path between the seed metering system and the endless member. 16. The seeding machine of claim 1, wherein the endless member travels about a first curved path at an upper portion of the housing and about a second curved path at a lower portion of the housing, wherein the first opening is positioned along the first curved path and the second opening is positioned along the second curved path. 17. A row unit of a planter configured to move in a travel direction while planting seed, comprising: a seed hopper for holding a plurality of seeds; a seed metering system including a seed metering device for receiving seed from the seed hopper; a seed delivery system comprising a housing defining a first opening and a second opening, the first opening located proximal to the seed metering system through which seed is transferred into the seed delivery system, and the second opening located distal of the seed metering system through which seed is discharged from the seed delivery system for planting in a furrow; an endless member of the seed delivery system movable within the housing to receive the seed at the first opening and transport the seed to the second opening; and a seed transfer device disposed adjacent to the first opening for transferring seed from the seed metering system to the seed delivery system. 18. The row unit of claim 17, wherein: the housing comprises an elongated side wall that defines the first opening in an upper portion of the housing and the second opening in a lower portion of the housing; and the housing forms a ramp at the second opening along which the seed is discharged from the seed delivery system in a direction substantially opposite of the travel direction. 19. The row unit of claim 17, wherein: the seed metering system comprises a disk having a plurality of apertures through which an air differential is applied for maintaining seed thereon, the disk being rotatable to transport seed to the seed transfer device; and the seed transfer device comprises a rotatable wheel for transferring seed from one of the plurality of apertures through the first opening to the endless member. 20. The row unit of claim 17, wherein: the transfer device comprises a wheel rotatable about a first axis; and the seed metering system is rotatable about a second axis, the first and second axes being offset from but parallel to one another.
RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 14/616,877, filed Feb. 9, 2015, which is a continuation of U.S. patent application Ser. No. 14/504,801, filed Oct. 2, 2014 and issued as U.S. Pat. No. 9,686,905 on Jun. 27, 2017, which is a continuation of U.S. patent application Ser. No. 12/364,010, filed Feb. 2, 2009 and issued as U.S. Pat. No. 8,850,995 on Oct. 7, 2014, the disclosures of which are hereby incorporated by reference in their entirety. FIELD OF THE INVENTION The invention relates to a seeding machine having a seed metering system and a seed delivery system for delivering seed from the meter to the ground. BACKGROUND OF THE INVENTION An agricultural seeding machine such as a row crop planter or grain drill places seeds at a desired depth within a plurality of parallel seed trenches formed in soil. In the case of a row crop planter, a plurality of row crop units is typically ground driven using wheels, shafts, sprockets, transfer cases, chains and the like or powered by electric or hydraulic motors. Each row crop unit has a frame which is movably coupled with a tool bar. The frame may carry a main seed hopper, herbicide hopper and insecticide hopper. If a herbicide and insecticide are used, the metering mechanisms associated with dispensing the granular product into the seed trench are relatively simple. On the other hand, the mechanisms necessary to properly meter the seeds, and dispense the seeds at predetermined relative locations within the seed trench are relatively complicated. The mechanisms associated with metering and placing the seeds generally can be divided into a seed metering system and a seed placement system which are in series communication with each other. The seed metering system receives the seeds in a bulk manner from the seed hopper carried by the planter frame or by the row unit. Different types of seed metering systems may be used, such as seed plates, finger plates, seed disks, etc. In the case of a seed disk metering system a seed disk is formed with a plurality of seed cells spaced about the periphery of the disk. Seeds are moved into the seed cells with one or more seeds in each seed cell depending upon the size and configuration of the seed cell. A vacuum or positive air pressure differential may be used in conjunction with the seed disk to assist in movement of the seeds into the seed cell. The seeds are singulated and discharged at a predetermined rate to the seed placement or delivery system. The most common seed delivery system may be categorized as a gravity drop system. In the case of the gravity drop system, a seed tube has an inlet end which is positioned below the seed metering system. The singulated seeds from the seed metering system merely drop into the seed tube and fall via gravitational force from a discharge end thereof into the seed trench. The seed tube may have a rearward curvature to reduce bouncing of the seed as it strikes the bottom of the seed trench and to impart a horizontal velocity to the seed in order to reduce the relative velocity between the seed and the ground. Undesirable variation in resultant in-ground seed spacing can be attributed to differences in how individual seeds exit the metering system and drop through the seed tube. The spacing variation is exacerbated by higher travel speeds through the field which amplifies the dynamic field conditions. Further seed spacing variations are caused by the inherent relative velocity difference between the seeds and the soil as the seeding machine travels through a field. This relative velocity difference causes individual seeds to bounce and tumble in somewhat random patterns as each seed comes to rest in the trench. Various attempts have been made to reduce the variation in seed spacing resulting from the gravity drop. U.S. Pat. No. 6,681,706 shows two approaches. One approach uses a belt with flights to transport the seeds from the meter to the ground while the other approach uses two belts to grip the seed and transport it from the meter to the ground. While these approaches control the seed path and reduce variability due to dynamic events, neither approach seeks to deliver the seed with as small as possible horizontal velocity difference relative to the ground. U.S. Pat. Nos. 6,651,57, 7,185,596 and 7,343,868 show a seed delivery system using a brush wheel near the ground to regulate the horizontal velocity and direction of the seed as it exits the seeding machine. However, there is still a gravity drop between the seed meter and the brush wheel which produces variation in seed spacing. SUMMARY OF THE INVENTION The present invention provides a seed delivery system that removes the seed from the seed meter by capturing the seed. The delivery system then moves the seed down to a lower discharge point and accelerates the seed rearward to a horizontal velocity approximately equal to the forward travel speed of the seeding machine such that the seed, when discharged, has a low or zero horizontal velocity relative to the ground. Rolling of the seed in the trench is reduced as a result of the near zero horizontal velocity relative to the ground. Furthermore, as the seed experiences a controlled descent from the point at which it is removed from the meter to a point very near the bottom of the trench, the system becomes a nearly impervious to the field dynamics experienced by the row unit. The combination of controlled descent and discharge at a substantially zero horizontal speed relative to the ground reduces seed spacing variability. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a plan view of a planter having the seed delivery system of the present invention; FIG. 2 is a side view of a row unit of the planter of FIG. 1; FIG. 3 is an enlarged side view of the seed delivery system of the present invention; FIG. 4 is a top view of a planter row unit showing the metering system orientation in one alternative arrangement of the metering system and delivery system of the present invention; FIG. 5 is a top view similar to FIG. 4 illustrating the delivery system with the meter housing removed; FIG. 6 is a side view of the row unit of FIG. 4; FIG. 7 is a perspective view of the seed disk used in the seed meter shown in FIGS. 4-6; FIG. 8 is a sectional view along the line 8-8 of FIG. 7 illustrating the orientation of the seed disk and brush or the seed delivery system of the present invention; FIG. 9 is a side view of a row unit showing the orientation of the delivery system of the present invention and a vacuum belt seed meter; FIG. 10 is a side view of another orientation of the seed delivery system of the invention with a vacuum belt seed meter; and FIG. 11 is a side view illustrating the orientation of the seed delivery system of the invention with a finger pick-up meter. DESCRIPTION OF THE PREFERRED EMBODIMENT With reference to FIG. 1 an example planter or seeding machine 10 is shown containing the seed delivery system of the present invention. Planter 10 includes a tool bar 12 as part of a planter frame 14. Mounted to the tool bar are multiple planting row units 16. Row units 16 are typically identical for a given planter but there may be differences. A row unit 16 is shown in greater detail in FIG. 2. The row unit 16 is provided with a central frame member 20 having a pair of upwardly extending arms 21 (FIG. 4) at the forward end thereof. The arms 21 connect to a parallelogram linkage 22 for mounting the row unit 16 to the tool bar 12 for up and down relative movement between the unit 16 and toolbar 12 in a known manner. Seed is stored in seed hopper 24 and provided to a seed meter 26. Seed meter 26 is of the type that uses a vacuum disk as are well known to meter the seed. Other types of meters can be used as well. From the seed meter 26 the seed is carried by a delivery system 28 into a planting furrow, or trench, formed in the soil by furrow openers 30. Gauge wheels 32 control the depth of the furrow. Closing wheels 34 close the furrow over the seed. The gauge wheels 32 are mounted to the frame member 20 by arms 36. The toolbar and row unit are designed to be move over the ground in a forward working direction identified by the arrow 38. The row unit 16 further includes a chemical hopper 40, a row cleaner attachment 42 and a down force generator 44. The row unit 16 is shown as an example of the environment in which the delivery system of the present invention is used. The present invention can be used in any of a variety of planting machine types such as, but not limited to, row crop planters, grain drills, air seeders, etc. With reference to FIG. 3, the seed delivery system 28 is shown in greater detail. Delivery system 28 includes a housing 48 positioned adjacent the seed disk 50 of the seed meter. The seed disk 50 is a generally flat disk with a plurality of apertures 52 adjacent the periphery of the disk. Seeds 56 are collected on the apertures from a seed pool and adhere to the disk by air pressure differential on the opposite sides of the disk 50 in a known manner. The disk may have a flat surface at the apertures 52 or have seed cells surrounding the apertures 52. The disk rotates clockwise as viewed in FIG. 3 as shown by the arrow 54. At the top of FIG. 3, seeds 56 are shown adhered to the disk. The seed delivery system housing 48 has spaced apart front and rear walls 49 and 51 and a side wall 53 therebetween. An upper opening 58 in the housing side wall 53 admits the seed from the metering disk 50 into the housing. A pair of pulleys 60, 62 are mounted inside the housing 48. The pulleys support a belt 64 for rotation within the housing. One of the pulleys is a drive pulley while the other is an idler pulley. The belt has a base member 66 to engage the pulleys and elongated bristles 70 extending therefrom. The bristles are joined to the base member at proximal, or radially inner, ends of the bristles. Distal, or radially outer, ends 74 of the bristles touch, or are close to touching, the inner surface 76 of the housing side wall 53. A lower housing opening 78 is formed in the side wall 53 and is positioned as close to the bottom 80 of the seed trench as possible. As shown, the lower opening 78 is near or below the soil surface 82 adjacent the trench. The housing side wall forms an exit ramp 84 at the lower opening 78. Returning attention to the upper portion of FIG. 3, a loading wheel 86 is provided adjacent the upper opening 58. The loading wheel is positioned on the opposite side of the seeds 56 from the brush 64 such that the path of the seeds on the disk brings the seeds into a nip 88 formed between the loading wheel and the distal ends 74 of the bristles 70. At the location of the nip 88, the air pressure differential across the seed disk 50 is terminated, freeing the seed from the apertures 52 in the disk. The bottom surface of the loading wheel, facing the seed disk 50, has recesses 90 formed therein. The recesses 90 receive seed agitators 92 projecting from the seed disk 50. The moving agitators, by engagement with the recesses in the loading wheel, drive the loading wheel in a clockwise rotation. In operation, the belt 64 is rotated in a counterclockwise direction. As the belt curves around the pulleys, the bristles will naturally open, that is, separate from one another as the distal ends of the bristles travel a larger circumferential distance around the pulleys than the inner ends of the bristle at the belt base member. This produces two beneficial effects as described below. The seeds are transferred from the seed meter to the delivery system as the seeds are brought by the disk into the nip 88. There the seeds are pinched off the seed disk between the loading wheel and the bristles 70 to remove the seed from the seed disk and seed meter. The seeds are captured or entrapped in the bristles by insertion of the seed into the bristles in a radial direction, that is from the ends of the bristles in a direction parallel to the bristle length. This occurs just as the belt path around the pulley 60 ends, when the bristle ends are closing back together upon themselves, allowing the bristles to close upon, and capture the seeds therein. As the belt continues to move, the bristles move or convey the seeds downward to the housing lower opening. The side wall 53 of the housing cooperates with the bristles 70 to hold the seed in the brush bristles as the seed is moved to the lower opening. The lower opening 78 and the ramp 84 are positioned along the curved belt path around the pulley 62. The bristle distal ends thus cause the linear speed of the seeds to accelerate relative to the speed of the belt base member 66 and the housing as shown by the two arrows 94 and 96. The seeds are then propelled by the bristles over the ramp 84 and discharged through the lower opening 78 into the seed trench. The angle of the ramp 84 can be selected to produce the desired relationship between the seed vertical and horizontal speeds at discharge. The forward travel direction of the row unit is to the left in FIG. 3 as shown by the arrow 38. At the discharge, the horizontal speed of the seed relative to the ground is minimized to reduce roll of the seed in the trench. The belt shown in FIG. 3 has relatively long bristles. As a result of the long bristles and the seed loading point being at the end of the curved path of the brush around the pulley 60 results in the seeds being loaded into the belt while the bristles have slowed down in speed. The bristle speed at loading is thus slower than the bristle speed at the discharge opening as the belt travels around the pulley 62. This allows in the seed to be loaded into the belt at a relatively lower speed while the seed is discharged at the lower end at a desired higher speed. As described above, it is preferred that the horizontal velocity of the seed at the discharge be equal to the forward travel speed of the planter but in the rearward direction such that the horizontal velocity of the seed relative to the ground is close to or equal to zero. The long bristles can be used to increase the speed of the seed as it travels around the pulley. However, a short bristle brush can be used as well. With a short bristle brush, there will be little acceleration in the speed of the seed as the seed travels around the pulleys. The belt will have to be driven at a speed to produce the desired horizontal velocity of the seed at the discharge. Even with a short bristle brush, the seed is still accelerated in the horizontal direction. As the belt travels around the pulley, the direction of travel of the seed changes from the predominantly vertical direction, when the seed is moved downward from the seed meter, to a predominantly horizontal direction at the discharge. This produces an acceleration of the seed velocity in the horizontal direction. With the delivery system 28, the seed is captured by the delivery system to remove the seed from the seed meter. The seed is then moved by the delivery system to the seed discharge point where the seed is accelerated in a rearward horizontal direction relative to the housing. From the seed meter to the discharge, the seed travel is controlled by the delivery system, thus maintaining the seed spacing relative to one another. In the embodiment shown in FIG. 3, the seed disk and the front and rear walls 49, 51 of the housing 48 lie in planes that are generally parallel one another. As shown, the plane of the delivery system is generally parallel to the direction of travel of the row unit. Other relationships between the seed meter and delivery system are shown and described below. As shown in FIG. 3, the side wall 53 is divided by the upper and lower openings 58, 78 into two segments, 53a and 53b. Segment 53a is between the upper and lower openings in the direction of belt travel while the segment 53b is between the lower and upper openings in the direction of belt travel. It is the gaps in the side wall 53 that form the upper and lower openings. It should be understood, however, that the delivery system will function without the segment 53b of the side wall. It is only the segment 53a that functions together with the belt bristles to deliver the seed from the meter to the seed trench. Thus, the term “upper opening” shall be construed to mean an open area before the side wall segment 53a in the direction of belt travel and the term “lower opening” shall mean an open area after the side wall segment 53a in the direction of belt travel. With reference to FIGS. 4-7, the delivery system 28 is shown in combination with the seed meter and row unit structure in an alternative arrangement of the seed meter and delivery system 28. The seed meter 200 is shown mounted to the row unit with the seed disk 202 in a vertical orientation but at an angle to the forward travel direction shown by the arrow 38. FIG. 4 shows of the seed meter orientation in the row unit without the delivery system 28. The seed meter includes a housing having two halves 204 and 206 releasable joined together in a known manner. The seed meter is driven through a transmission 208 coupled to a drive cable, not shown. In FIG. 5 only the seed disk 202 of the meter is shown with the seed delivery system 28. As previously mentioned, the seed disk 202 is in a vertical orientation but it does not lie in a plane parallel to the forward direction 38. Instead, the meter is oriented such that the disk is at a 60° angle relative to the forward direction when viewed from above. The seed of delivery system 28 is generally identical to that shown in FIG. 3 and is driven by a motor 65. The delivery system, including of the brush belt 64, is generally vertical and aligned with the fore and aft direction of the planter such that the angle between the brush and the seed disk is approximately 60°. The angle between the delivery system and a seed disk produces a partial “cross feed” of the seed into the brush. That is, the seed is fed into the brush at an angle to the lengthwise direction of the bristles. This is in contrast to FIG. 3 where the seed enters the brush in a direction substantially parallel to the lengthwise direction of the brush bristles. If the brush and seed disk were oriented at 90° to one another, a total cross feed would be produced with seed entering the brush perpendicular to the bristles. The seed disk 202 is shown enlarged in FIGS. 7 and 8. The disk 202 has opposite sides, a vacuum side 216 and seed side 218. The seed side 218 has a surface 219 near the periphery that defines a reference plane. The reference plane will be used to describe the features of the disk near the disk periphery. An outer peripheral lip 220 is recessed from the reference plane. The peripheral lip 220 creates a radially outward edge face 222. A circumferential row of spaced apart apertures 224 is arranged around a circular path radially inward of the edge face 222. Each aperture extends through the disk between the vacuum side 216 and the seed side 218. Radially inward of each aperture 224, there is a radially elongated recess 226. The recess 226 is recessed axially into the disk from the reference plane. In operation, the disk rotates in a counterclockwise direction as indicated by the arrow 228. During rotation, the recesses 226 agitate the seed in the seed pool. Surrounding each aperture 224 is a tapered recess, or shallow seed cell, 232 that extends axially into the disk from the reference plane. Seed cell 232 begins at a leading edge 234 in the direction of rotation of the disk and is progressively deeper into the seed side 218 to a trailing edge formed by an axially projecting wall 236. The tapered recess or seed cell 232 reduces the vacuum needed to pick-up and retain seed in the apertures 224. The seed cell also enables the seed to sit lower relative to the seed side 218 of the disk, allowing the seed to be retained while the seed singulator removes doubles or multiples of seed from the apertures 224. In addition, the recess wall 236 agitates seed in the seed pool, further aiding in seed pick-up. The wall 236 extends lengthwise in a predominately radial direction as shown by the dashed line 238. The walls 236, while predominately radial, are inclined to the radial direction such that the inner end of the wall 236 is leading the outer end of the wall in the direction of rotation. Immediately following each wall 236, as the disk rotates, is a projection, or upstanding peg, 240 extending axially from the disk seed side. The pegs engage seed in the seed pool for agitation to aide in seed pick-up. The pegs 240 are located slightly radially inward of the circular path of apertures 224 to avoid interference with the seed singulator. With reference to FIG. 8, the disk 202 is shown in operation and in position relative to the belt 64 in the delivery system 28. As seeds 244 are carried by the disk 202 into the bristles of the brush 64, the wall 236 and the pegs 240 act to push the seed 244 into the bristles of the brush 64 and assist in keeping the seed from being knocked off the disk upon the seed's initial contact with the brush bristles. Once the seed is inserted into the brush bristles, the vacuum from the opposite side of the disk is cut-off, allowing the brush to sweep the seed off the disk in a predominately radial direction relative to the disk. An insert 246 overlies the lip 220 at the point of seed release to hold the seed in the brush bristles in the transition between the disk and the side wall 53 (FIG. 3) of the delivery system housing. The disk 202 is inclined to the length of the brush bristles at approximately a 60 degree angle. This produces the partial cross-feed of the seed into the brush bristles. FIG. 9 shows the brush belt seed delivery system 28 in combination with a vacuum belt metering system having a metering belt 302. The vacuum belt meter is fully described in co-pending U.S. patent application Ser. No. 12/363,968, now issued U.S. Pat. No. 7,918,168, and incorporated herein by reference. The belt 302 picks-up seed at a pick-up region 304 at a lower, front location of the belt's path and transports it to the delivery system at a release region 306 at an upper, rear location of the belt's path. In this arrangement of the belt meter and the brush delivery system, the delivery system is again partially cross fed with seeds from the meter. Another arrangement of the delivery system together with a vacuum meter belt is shown in FIG. 10. The delivery system 28 is in-line with the belt meter 124. This allows the distal ends of the brush bristles to sweep over the surface of the metering belt 126 to capture the seed therefrom. The meter belt 126 is wrapped around pulleys 128. The metering belt 124 is similar and functions as the belt 302 mentioned above. The delivery system of the present invention can also be used with seed meters other than air pressure differential meters. For example, with reference to FIG. 11, a finger pick-up meter 130 is shown, such as that described in U.S. Pat. No. 3,552,601 and incorporated herein by reference. Seed is ejected from the meter through an opening 132. The delivery system 134 has a brush belt 136 wrapped about pulleys 138 and 140. As shown, the belt pulley 138 shares a common drive shaft with finger pick-up meter 130. A hub transmission such as a spherical continuously variable transmission or a three speed hub can be used to drive the belt 136 at a different speed from the meter 130. The delivery system housing includes a side wall 142. A ramp 146 is formed at the lower end of the wall 142 adjacent the lower opening 148. At the upper end of the delivery system, the upper opening is formed in the housing rear wall adjacent the opening 132 through which seeds are ejected from the seed meter. The seeds are inserted laterally into the brush bristles in a complete cross-feed. As in the other embodiments, the seed is captured in the brush bristles, moved downward to the lower opening, accelerated rearward and discharged through the lower opening 148. The endless member of the delivery system has been described as being a brush belt with bristles. In a broad sense, the bristles form an outer periphery of contiguous disjoint surfaces that engage and grip the seed. While brush bristles are the preferred embodiment, and may be natural or synthetic, other material types can be used to grip the seed such as a foam pad, expanded foam pad, mesh pad or fiber pad. Having described the preferred embodiment, it will become apparent that various modifications can be made without departing from the scope of the invention as defined in the accompanying claims.
<SOH> BACKGROUND OF THE INVENTION <EOH>An agricultural seeding machine such as a row crop planter or grain drill places seeds at a desired depth within a plurality of parallel seed trenches formed in soil. In the case of a row crop planter, a plurality of row crop units is typically ground driven using wheels, shafts, sprockets, transfer cases, chains and the like or powered by electric or hydraulic motors. Each row crop unit has a frame which is movably coupled with a tool bar. The frame may carry a main seed hopper, herbicide hopper and insecticide hopper. If a herbicide and insecticide are used, the metering mechanisms associated with dispensing the granular product into the seed trench are relatively simple. On the other hand, the mechanisms necessary to properly meter the seeds, and dispense the seeds at predetermined relative locations within the seed trench are relatively complicated. The mechanisms associated with metering and placing the seeds generally can be divided into a seed metering system and a seed placement system which are in series communication with each other. The seed metering system receives the seeds in a bulk manner from the seed hopper carried by the planter frame or by the row unit. Different types of seed metering systems may be used, such as seed plates, finger plates, seed disks, etc. In the case of a seed disk metering system a seed disk is formed with a plurality of seed cells spaced about the periphery of the disk. Seeds are moved into the seed cells with one or more seeds in each seed cell depending upon the size and configuration of the seed cell. A vacuum or positive air pressure differential may be used in conjunction with the seed disk to assist in movement of the seeds into the seed cell. The seeds are singulated and discharged at a predetermined rate to the seed placement or delivery system. The most common seed delivery system may be categorized as a gravity drop system. In the case of the gravity drop system, a seed tube has an inlet end which is positioned below the seed metering system. The singulated seeds from the seed metering system merely drop into the seed tube and fall via gravitational force from a discharge end thereof into the seed trench. The seed tube may have a rearward curvature to reduce bouncing of the seed as it strikes the bottom of the seed trench and to impart a horizontal velocity to the seed in order to reduce the relative velocity between the seed and the ground. Undesirable variation in resultant in-ground seed spacing can be attributed to differences in how individual seeds exit the metering system and drop through the seed tube. The spacing variation is exacerbated by higher travel speeds through the field which amplifies the dynamic field conditions. Further seed spacing variations are caused by the inherent relative velocity difference between the seeds and the soil as the seeding machine travels through a field. This relative velocity difference causes individual seeds to bounce and tumble in somewhat random patterns as each seed comes to rest in the trench. Various attempts have been made to reduce the variation in seed spacing resulting from the gravity drop. U.S. Pat. No. 6,681,706 shows two approaches. One approach uses a belt with flights to transport the seeds from the meter to the ground while the other approach uses two belts to grip the seed and transport it from the meter to the ground. While these approaches control the seed path and reduce variability due to dynamic events, neither approach seeks to deliver the seed with as small as possible horizontal velocity difference relative to the ground. U.S. Pat. Nos. 6,651,57, 7,185,596 and 7,343,868 show a seed delivery system using a brush wheel near the ground to regulate the horizontal velocity and direction of the seed as it exits the seeding machine. However, there is still a gravity drop between the seed meter and the brush wheel which produces variation in seed spacing.
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides a seed delivery system that removes the seed from the seed meter by capturing the seed. The delivery system then moves the seed down to a lower discharge point and accelerates the seed rearward to a horizontal velocity approximately equal to the forward travel speed of the seeding machine such that the seed, when discharged, has a low or zero horizontal velocity relative to the ground. Rolling of the seed in the trench is reduced as a result of the near zero horizontal velocity relative to the ground. Furthermore, as the seed experiences a controlled descent from the point at which it is removed from the meter to a point very near the bottom of the trench, the system becomes a nearly impervious to the field dynamics experienced by the row unit. The combination of controlled descent and discharge at a substantially zero horizontal speed relative to the ground reduces seed spacing variability.
A01C716
20170810
20180626
20171123
99684.0
A01C716
1
NOVOSAD, CHRISTOPHER J
SEEDING MACHINE WITH SEED DELIVERY SYSTEM
UNDISCOUNTED
1
CONT-ACCEPTED
A01C
2,017
15,674,827
PENDING
APPARATUS FOR SEPARATING USABLE CROP FROM INTERMIXED DEBRIS
An apparatus for separating usable crop from intermixed debris, the apparatus having: a movable support; a conveying system on the movable support to convey usable crop in a processing path from an upstream input location to a downstream output location; at least a first separating system on the movable support to cause separation of debris intermixed with usable crop in a first manner as usable crop is conveyed; a vacuum system on the movable support downstream of the first separating system to generate a low pressure volume which causes additional debris intermixed with the usable crop to be drawn away from the usable crop; and a collection container on the movable support configured to accumulate debris drawn away from the conveying usable crop. The movable support, conveying system, at least first separating system, vacuum system, and collection container define a unit that can be moved to relocate the apparatus.
1. An apparatus for separating usable crop from intermixed debris, the apparatus comprising: a movable support; a conveying system on the movable support configured to convey usable crop in a processing path from an upstream input location to a downstream output location; at least a first separating system on the movable support configured to cause separation of debris intermixed with usable crop in a first manner as usable crop is conveyed in the processing path; a vacuum system on the movable support downstream of the first separating system and configured to generate a low pressure volume which causes additional debris intermixed with the usable crop to be drawn away from the usable crop by vacuum; and a collection container on the movable support configured to accumulate debris drawn away from the conveying usable crop, wherein the movable support, conveying system, at least first separating system, vacuum system, and collection container define a unit that can be moved to relocate the apparatus. 2. The apparatus for separating usable crop from intermixed debris according to claim 1 wherein the movable support comprises a frame with wheels that can be rolled against underlying terrain to relocate the apparatus. 3. The apparatus for separating usable crop from intermixed debris according to claim 2 wherein the movable support comprises a component that is configured to be hitched to a towing vehicle that is usable to move the apparatus. 4. The apparatus for separating usable crop from intermixed debris according to claim 1 wherein the apparatus further comprises an evacuating system on the movable support, the evacuating system configured to create a low pressure volume in a space in the collection container. 5. The apparatus for separating usable crop from intermixed debris according to claim 4 wherein the apparatus is configured so that the low pressure volume which causes additional debris intermixed with the usable crop to be drawn away from the usable crop is created by the evacuating system. 6. The apparatus for separating usable crop from intermixed debris according to claim 1 wherein the movable support has a length between upstream and downstream ends, the processing path has at least a portion that extends substantially in a line from the upstream end towards the downstream end, the apparatus comprises a housing with a chamber through which the processing path extends, the vacuum system generates the low pressure volume within the housing chamber, and the collection container is downstream of the housing. 7. The apparatus for separating usable crop from intermixed debris according to claim 6 wherein the apparatus further comprises an evacuating system on the movable support and the evacuating system is downstream of the collection container and configured to create a low pressure volume in a space in the collection container. 8. The apparatus for separating usable crop from intermixed debris according to claim 6 wherein the apparatus further comprises a funneling conduit that directs debris from the housing chamber in a downstream direction into the collection container. 9. The apparatus for separating usable crop from intermixed debris according to claim 1 wherein the apparatus further comprises a delivery unit on the movable support that is configured to continuously direct a supply of intermixed debris and usable crop to the upstream input location. 10. The apparatus for separating usable crop from intermixed debris according to claim 1 wherein the at least first separating system comprises a second separating system spaced along the processing path from the first separating system and configured to cause separation of debris intermixed with usable crop in a second manner that is different than the first manner. 11. The apparatus for separating usable crop from intermixed debris according to claim 1 wherein the conveying system comprises a plurality of cooperating, independently operating, conveying sections. 12. The apparatus for separating usable crop from intermixed debris according to claim 1 wherein the apparatus further comprises at least one auxiliary conveyor on the movable support configured to intercept downwardly traveling debris and convey intercepted downwardly traveling debris towards a collection location. 13. The apparatus for separating usable crop from intermixed debris according to claim 6 wherein the housing has a top opening and the vacuum system comprises an evacuating system that is in communication with the top opening. 14. The apparatus for separating usable crop from intermixed debris according to claim 6 wherein the conveying system comprises at least one discharge conveying section that receives advancing usable crop after debris is separated from the advancing usable crop by the at least first separating system, the at least one discharge conveying section directing received advancing usable crop transversely to the length of the movable support to a collection location. 15. The apparatus for separating usable crop from intermixed debris according to claim 6 wherein the movable support comprises first and second platforms at different heights, the collection container is supported on the first platform and the housing is supported on the second platform. 16. The apparatus for separating usable crop from intermixed debris according to claim 15 wherein the collection container has an outer perimeter and the first platform is configured to define an upwardly facing walking surface around at least a part of the outer perimeter of the collection container. 17. The apparatus for separating usable crop from intermixed debris according to claim 6 wherein the apparatus further comprises an evacuating system on the movable support, the evacuating system configured to create a low pressure volume in a space defined by the collection container and bounded by a floor, wherein the collection container has spaced first and second openings, the first opening receiving debris from the housing chamber, the second opening in communication with the evacuating system, wherein each of the first and second openings is spaced above the floor so that a substantial height of debris can be accumulated upon the floor without obstructing the first or second openings. 18. The apparatus for separating usable crop from intermixed debris according to claim 7 wherein the movable support comprises a frame with wheels that can be rolled against underlying terrain to relocate the apparatus, the movable support frame further comprising a component at the downstream end of the movable support that is configured to be hitched to a towing vehicle that is usable to move the apparatus. 19. The apparatus for separating usable crop from intermixed debris according to claim 1 wherein the apparatus is configured to cause the usable crop to move in opposite directions over different parts of the processing path. 20. The apparatus for separating usable crop from intermixed debris according to claim 3 wherein the apparatus has a length and width that allow the apparatus to be towed on a public right-of-way.
CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of U.S. patent application Ser. No. 14/630,723 filed Feb. 25, 2015. BACKGROUND OF THE INVENTION Field of the Invention This invention relates to crop harvesting and, more particularly, to an apparatus through which usable crop can be separated from debris such as dirt, rocks, vines, corn stalks, crowns, etc. Background Art Efficient and effective separation of a usable crop from field debris remains an ongoing challenge in the agricultural industry. Apparatus used for crop separation are generally developed with the following design objectives: a) maximum separation of debris from usable crop while minimizing crop damage; b) accommodating different types of debris that might be encountered in different geographical areas and with different field makeups—namely, dirt and clay, small and potentially large rocks, vines, corn stalks, crowns, etc.; c) accumulating separated debris in a controlled manner so that staged debris can be appropriately handled after a field operation is concluded, as by onsite disposal or relocation; d) providing an overall system that is affordable to users with a range of different volume requirements; e) providing an overall system that has components capable of being transported to different sites, as within a user's field and between fields using public right-of-ways; and f) providing an overall system that can be easily and efficiently operated by a limited number of personnel in a manner that is safe for the operators and so that there is a minimal impact on the environment around the system. Many existing systems have been designed that focus on one or more of the above objectives. However, after many decades of evolution, improvements remain necessary. This is particularly the case since competition challenges all in the agricultural industry to effect crop separation more effectively and efficiently while controlling overall operational costs. Some of the specific design challenges can be identified relative to the harvesting of potatoes. Mixed potatoes and debris that are delivered for separation may contain: a) dirt, sand, clay, etc., that may be in different forms with different consistencies and adhered to the potatoes with different tenacity; b) vines; and c) rocks of different size, shape, and composition, with sizes ranging from small pebbles to large boulders. Conventional systems generally are not capable of accommodating all different types of debris and, as a result, generally either the fully processed crop remains intermixed with a significant amount of debris and/or system operators must manually perform steps during the separation process to maximize results. The latter may necessitate interruption of the processing, which compromises efficiency. Systems not equipped to accommodate certain types of debris, such as large boulders, may become jammed or, in a worst case, damaged during normal operations. In either case, processing may be interrupted for potentially significant time periods to allow the problems to be alleviated. Undue progressive wear may lead to more regular maintenance and potentially extensive repairs. Certain prior systems have utilized pressurized fluid and vacuum to reposition crop and debris during a separation process. These systems create their own inherent challenges, particularly integrating the same with conventional separation components. Further, such systems entrain dust particles in the air around the system which must be controlled to create a safe environment for operators and also allow an appropriate accumulation and/or disposal. Another challenge to those designing this type of agricultural equipment is making the same transportable in a practical manner from one location to the next. This movement of equipment may involve relocation in the same field or relocation that requires the use of a public right-of-way. While having the system made up of multiple independent components may afford the ability to conveniently move these individual components, such an exercise introduces the problem of having to disconnect and reconnect components each time a relocation is undertaken. This may be labor intensive and time consuming, again requiring the use of valuable time in a limited harvesting window. Further, transporting of several components may necessitate multiple trips or use of multiple vehicles. Both options may be inefficient. The challenges to equipment designers in the agricultural industry continue to even a greater extent to this day. SUMMARY OF THE INVENTION In one form, the invention is directed to an apparatus for separating usable crop from intermixed debris. The apparatus includes: a movable support; a conveying system on the movable support configured to convey usable crop in a processing path from an upstream input location to a downstream output location; at least a first separating system on the movable support configured to cause separation of debris intermixed with usable crop in a first manner as usable crop is conveyed in the processing path; a vacuum system on the movable support downstream of the first separating system and configured to generate a low pressure volume which causes additional debris intermixed with the usable crop to be drawn away from the usable crop by vacuum; and a collection container on the movable support configured to accumulate debris drawn away from the conveying usable crop. The movable support, conveying system, at least first separating system, vacuum system, and collection container define a unit that can be moved to relocate the apparatus. In one form, the movable support has a frame with wheels that can be rolled against underlying terrain to relocate the apparatus. In one form, the movable support has a component that is configured to be hitched to a towing vehicle that is usable to move the apparatus. In one form, the apparatus further includes an evacuating system on the movable support. The evacuating system is configured to create a low pressure volume in a space in the collection container. In one form, the apparatus is configured so that the low pressure volume which causes additional debris intermixed with the usable crop to be drawn away from the usable crop is created by the evacuating system. In one form, the movable support has a length between upstream and downstream ends. The processing path has at least a portion that extends substantially in a line from the upstream end towards the downstream end. The apparatus has a housing with a chamber through which the processing path extends. The vacuum system generates the low pressure volume within the housing chamber. The collection container is downstream of the housing. In one form, the apparatus further includes an evacuating system on the movable support. The evacuating system is downstream of the collection container and configured to create a low pressure volume in a space in the collection container. In one form, the apparatus further includes a funneling conduit that directs debris from the housing chamber in a downstream direction into the collection container. In one form, the apparatus further includes a delivery unit on the movable support that is configured to continuously direct a supply of intermixed debris and usable crop to the upstream input location. In one form, the at least first separating system includes a second separating system spaced along the processing path from the first separating system and configured to cause separation of debris intermixed with usable crop in a second manner that is different than the first manner. In one form, the conveying system is made up of a plurality of cooperating, independently operating, conveying sections. In one form, the apparatus further includes at least one auxiliary conveyor on the movable support configured to intercept downwardly traveling debris and convey intercepted downwardly traveling debris towards a collection location. In one form, the housing has a top opening. The vacuum system has an evacuating system that is in communication with the top opening. In one form, the conveying system has at least one discharge conveying section that receives advancing usable crop after debris is separated from the advancing usable crop by the at least first separating system. The at least one discharge conveying section directs received advancing usable crop transversely to the length of the movable support to a collection location. In one form, the movable support has first and second platforms at different heights. The collection container is supported on the first platform. The housing is supported on the second platform. In one form, the collection container has an outer perimeter. The first platform is configured to define an upwardly facing walking surface around at least a part of the outer perimeter of the collection container. In one form, the apparatus further includes an evacuating system on the movable support. The evacuating system is configured to create a low pressure volume in a space defined by the collection container and bounded by a floor. The collection container has spaced first and second openings. The first opening receives debris from the housing chamber. The second opening is in communication with the evacuating system. Each of the first and second openings is spaced above the floor so that a substantial height of debris can be accumulated upon the floor without obstructing the first or second openings. In one form, the movable support has a frame with wheels that can be rolled against underlying terrain to relocate the apparatus. The movable support frame further includes a component at the downstream end of the movable support that is configured to be hitched to a towing vehicle that is usable to move the apparatus. In one form, the apparatus is configured to cause the usable crop to move in opposite directions over different parts of the processing path. In one form, the apparatus has a length and width that allow the apparatus to be towed on a public right-of-way. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic representation of a system/apparatus for separating usable crop from intermixed debris, according to the present invention; FIG. 2 is an exploded, perspective view of one specific form of system/apparatus, as shown in FIG. 1, and including a primary product and debris handling system, a delivery unit for inputting usable crop mixed with debris, a collection container for debris, and an evacuating system for generating a low pressure volume to control movement of crop and debris; FIG. 3 is an enlarged, perspective view of the apparatus/system in FIG. 2 with components therein in an assembled state; FIG. 4 is a side elevation view of the system/apparatus in FIG. 3; FIG. 5 is an enlarged, rear, perspective view of the delivery unit shown in the system/apparatus in FIGS. 2-4; FIG. 6 is an enlarged, side elevation view of a unit on the primary product and debris handling system in FIGS. 2-4 that makes up a conveying section/separating system for debris; FIG. 7 is an enlarged, exploded, perspective view of cooperating rollers on the unit in FIG. 6; FIG. 8 is an enlarged, fragmentary, rear perspective view of the unit in FIGS. 6 and 7 on the primary product and debris handling system; FIG. 9 is a view as in FIG. 8 and showing an additional conveying section/separating system on the primary product and debris handling system downstream of the unit shown in FIG. 8; FIG. 10 is an enlarged, fragmentary, perspective view of structure for controlling separate support roller assemblies on the conveying section/separating system shown in FIG. 9; FIG. 11 is a view similar to that in FIG. 10 and showing the controlling structure associated with one of the support roller assemblies; FIG. 12 is an enlarged, fragmentary, perspective view of the frame portion in FIGS. 10 and 11 and showing the support roller assemblies thereon; FIG. 13 is an enlarged, fragmentary, perspective view of an auxiliary conveyor for debris separated from the conveying section/separating system shown in FIG. 9; FIG. 14 is an enlarged, fragmentary, perspective view of the inside of a housing on the primary product and debris handling system within which the low pressure volume is generated to reposition crop and debris moving along the conveying section/separating system in FIG. 9; FIG. 15 is an enlarged, fragmentary, perspective view of an extension on the housing in FIG. 14 showing a shield associated with the underlying conveying section moving within the inside of the housing in FIG. 14; FIG. 16 is an enlarged, exploded, perspective view of the housing as shown in FIGS. 14 and 15; FIG. 17 is an enlarged, exploded, perspective view of the housing as shown in FIG. 16 and taken from a different perspective; FIG. 18 is an enlarged, exploded, perspective view of the housing in FIGS. 14-17 and in relationship to a conduit section that communicates with the collection container; FIG. 19 is a flow diagram representation of a method for separating usable crop from intermixed debris according to the invention; FIG. 20 is a schematic representation of a modified form of system/apparatus for separating usable crop from intermixed debris, according to the invention; FIG. 21 is a perspective view of one exemplary form of system/apparatus as shown schematically in FIG. 20; FIG. 22 is a side elevation view of the system/apparatus in FIG. 21; FIG. 23 is a reduced, plan view of the system/apparatus shown in FIGS. 21 and 22; and FIG. 24 is an enlarged, front elevation view of the system/apparatus in FIGS. 21-23. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT In FIG. 1, a system/apparatus for separating usable crop from intermixed debris, according to the present invention, is shown in schematic form at 10. The apparatus 10 consists of a primary product and debris handling system 12 on which a conveying system 14 is provided. The conveying system 14 is configured to convey usable crop in a processing path from an upstream input location 16 to a downstream output location 18. From the output location 18, the crop can be staged, packaged, or otherwise processed at a point of use 20. The conveying system 14 is made up of a plurality of cooperating conveying sections 22. The conveying system 14 further includes a plurality of separating systems 24 configured to cause separation of debris intermixed with usable crop as the usable crop is conveyed in the processing path. The separating systems 24 convey separated debris to auxiliary conveyors 26 that deliver the debris to one or more collection locations 28. The apparatus 10 further includes a vacuum system 30 that is shown to include components that are part of the primary product and debris handling system 12 and components separate therefrom. The entire vacuum system 30 might be incorporated into the primary product and debris handling system 12. The vacuum system 30 is preferably provided downstream of at least one separating system 24 and is configured to generate a low pressure volume within a chamber 32 bounded by a housing 34. The low pressure volume creates vacuum that draws debris away from the conveying, usable crop, and further assists in advancing the usable crop into the chamber 32 through which the processing path extends to the output location 18. In the depicted embodiment, the vacuum system 30 consists of an evacuating system 36 that produces low pressure in a space 38 within a container 40 that defines a debris collection location. The space 38 is in communication with the chamber 32 and the housing 34 through a conduit 42. A low pressure volume is created in the chamber 32 through the conduit 42. Separated debris in the housing chamber 32 is caused to move in an accelerated air volume, generated by the evacuating system 36, through the conduit 42 and accumulate in the space 38 in the collection container 40. As depicted, each of the conduit 42, collection container 40, and evacuating system 36 is separate from the system 12. As noted above, this is not a requirement. A delivery unit 44 is used to continuously direct a supply of intermixed debris and usable crop to the input location 16. The delivery unit 44 may be integrated into the system 12 or separately constructed. The depicted evacuating system 36 can be separated from the collection container 40 and is provided with a wheeled carriage 46 to facilitate its transportation to and from, and around, a site at which the apparatus 10 is used. The primary product and debris handling system 12 is likewise provided with a wheeled carriage 48 to facilitate its transportation to and from, and around, an operating site. The schematic representation of the apparatus 10 is intended to encompass the components in the exemplary apparatus described herein, as well as virtually an unlimited number of variations of those components and their interactions that would be obvious to one skilled in the art with the teachings of the present invention in hand. The embodiments described below are exemplary in nature only and should not be viewed as limiting. Before getting into the details of certain of the components making up the exemplary form of the specific system/apparatus 10 shown herein, the basic structure and overall operation of the apparatus/system 10 will be generally described with reference to FIGS. 2-4. In the depicted exemplary embodiment of the inventive apparatus 10, the primary product and debris handling system 12 is combined with the delivery unit 44. Together these components are supported on the wheeled carriage 48 which has a towing tongue 50 with a hitch component at 52 that can be engaged with a drawing vehicle (not shown). Ideally, the combined dimension of the components on the wheeled carriage 48, and the wheeled carriage 48 itself, is such that travel on public right-of-ways is permitted. Adjustable feet 54 are provided to selectively and separately elevate and lower the corners of a frame 56 upon which wheels 58 are provided. This allows on site levelling and stabilization of the frame 56 and the components supported thereon. The delivery unit 44 consists of a conveying component 60 that moves in an endless path around end rollers 62, 64 mounted on a main frame 66. The frame 66 is mounted to the frame 56 so as to pivot relative thereto selectively around a horizontal and laterally extending axis, as indicated by the double-headed arrow 68, to allow an inclination angle α of an upwardly facing surface 70 on the conveying component 60 to be selectively varied, as through an extendible, manually operated cylinder 72. Remote and automated adjustment are also contemplated. A mixture of usable crop and debris, shown at 74, is introduced in bulk at an upstream end 76 of the delivery unit 44. The mixture 74 travels progressively forwardly and upwardly to a downstream discharge end 78 of the delivery unit 44 at which the mixture 74 falls under its own weight to a lower unit at 80 that functions as both a conveying section 22a and a separating system 24a. The unit 80 is made up of a plurality of intermeshing, parallel, cleaning rollers 82, 84, and an intermediate control cylinder 88 which cooperatively function as a “cleaning table” that removes excess dirt, vines, and other trash. The rollers 82, 84 and cylinder 88 cooperate to create gaps between which small/flat rocks can drop through. By controlling the vertical relationship between the rollers 82, 84 and cylinder 88, a “stall point”, at which an accumulated flow is blocked, can be increased/decreased. As seen in FIG. 4, rocks 90 that pass between the rollers 82, 84 and cylinder 88 are intercepted by a debris conveyor 26a that consists of an endless conveying component 92 trained around end rollers 94, 96. An upwardly facing surface 98 on the conveying component 92 advances the rocks 90, and potentially other debris passing through the rollers 82, 84 and cylinder 88, rearwardly in the direction of the arrow 100. This debris is advanced over an end 102 of the auxiliary conveyor 26a and falls therefrom under its own weight to an additional auxiliary conveyor 26b, which advances the accumulated debris laterally to a desired collection location 28a. The usable crop 104 (shown as but not limited to potatoes), with at least some of the debris from the mixture 74 removed, continues to beyond the unit 80 to a further conveying section 22b, which also functions as a separating system 24b. The conveying section 22b is reconfigurable adjacent its downstream end 106. More specifically, the conveying section 22b consists of an endless conveying component 108 trained about a series of rollers including end rollers 110, 112, with the latter elevated above the former. The rollers 110, 112 turn around substantially parallel, horizontal axes. In addition to the end rollers 110, 112, there is a plurality of intermediate support rollers/roller assemblies, including separate support roller assemblies at 114, 114′ that function independently and are configured to locally change the inclination angle and height of an upwardly facing surface 116 on the conveying component 108 in the vicinity of where the conveying crop 104 is diverted progressively upwardly towards the end 106. The support roller assembly 114′ is configured so that a variable gap G is formed between the surface 116 overlying the support roller assembly 114′ and a lower edge 118 of the housing 34 bounding an inlet 120 to the chamber 32 bounded by the housing 34. The air velocity at the inlet 120 to the chamber 32 is adequate to draw the crop 104 off of the conveying surface in the direction of the arrow 122 into the chamber 32 towards and onto a further conveying section 22c. Rocks 90 can pass between the edge 118 and upwardly facing surface 116 to be directed past the end 106, whereupon they fall under their weight to an auxiliary conveyor 26c. Through the auxiliary conveyor 26c, this debris can be controllably directed to a separate collection location 28b. The support roller assembly 114′ is pivotable about a horizontally and laterally extending axis, as indicated by the double-headed arrow 123, to change an inclination angle α1 of the upwardly facing surface 116 under the inlet 120, thereby varying the angle at which the crop advances towards the inlet 120 and to a certain extent the suction applied to the crop at the inlet 120. The upstream support roller assembly 114 is configured so that in response to the application of a predetermined downward force, as by a large anticipated rock size, the downstream end of the support roller assembly 114 will pivot downwardly around a horizontally and laterally extending axis to locally increase the vertical spacing between the upwardly facing surface 116 and a horizontally extending frame component 124 so that such a large rock can pass thereby in the processing path to move eventually off of the conveying section 22b to the auxiliary conveyor 26c. Once the weight of the rock(s) is removed, the support roller assembly will be biased to its resting state as shown in FIG. 4. Once the crop 104 is drawn into the housing chamber 32, it is distributed across the width of the conveying section 22c. Additional loose debris is drawn upwardly by the airstream that creates the low pressure volume in the chamber 32 and guided by an inclined housing surface 126 through a top opening 127 in the housing 34 and into the conduit 42. The cleaned usable crop 104 conveys in the direction of the arrow 128 to the output location at 18 from where the crop 104 is delivered to the point of use 20, which as previously indicated, may be a staging location, one or more containers, etc. Through the various conveying sections 22a, 22b, 22c, and the vacuum system 30, the usable crop 104 is caused to travel in a series of discrete path portions that together make up the overall processing path between the input location 16 and output location 18. The conveying section 22a defined by the unit 80 conveys the crop 104 in a path portion P1 that is substantially horizontal in a forward direction. The conveying section 22b conveys the crop 104 in a path portion P2 that is substantially parallel to the path portion P1. From the conveying section 22b, the vacuum system 30 causes the crop 104 to travel rearwardly in the direction of the arrow 122 that identifies a path portion P3. Once on the conveying section 22c, the usable crop 104 travels laterally in the direction of the arrow 128, which identifies the path portion P4. The delivery unit 44 may also be considered to define part of the processing path, specifically causing the usable crop 104 to travel in a path portion P5 between the upstream end 76 and the input location 16 in a substantially straight line parallel to the path portions P1, P2. The auxiliary debris conveyor 26a can be extended, as depicted, to underlie substantially the entire length of the conveying sections 22a, 22b/separating systems 24a, 24b, thereby to intercept separated debris passing off/through these conveying sections 22a, 22b/separating systems 24a, 24b. The conveying components 60, 92, 108 are driven by motors 130 that allow for infinite speed control to maximize the processing capability based upon the nature of the crop and the encountered debris. The operation of all the motors 130 can be coordinated through a central control unit 131. As mentioned above, the last stage of debris separation produces debris pieces 132 that become entrained in the air flow in the housing chamber 32. This debris 132 is drawn into the conduit 42 through the top housing opening 127 and, through the conduit 42, the debris 132 is delivered to the space 38 defined by the collection container 40. In this embodiment, the collection container 40 has a generally square construction, though this is not a requirement. The depicted collection container 40 has a generally rectangular shape, as viewed in plan, with a pair of spaced side walls 134, 136 and shorter, spaced, end walls 138, 140. The end wall 140 is configured to gain access to the space 38. The end wall 140 may incorporate one or more movable doors D. The side wall 136 has a first opening 144 formed therethrough to accommodate an end 146 of the conduit 42. A second opening 148 is formed through the side wall 134 to allow communication between the evacuating system 36 and the space 38. Each of the openings 144, 148 is spaced a height H above a floor 150 of the collection container 40 upon which debris is progressively accumulated. The height H is selected so that a substantial quantity of debris can be accumulated upon the floor 150 without obstructing either of the openings 144, 148. The drop in air velocity generated by the evacuating system 36, below the openings 144, 148, allows the debris to settle into the space 38 below the openings 144, 148 while at the same time clean air is allowed to exhaust from the collection container space 38 through the opening 148 and discharge from an outlet conduit 152 to the atmosphere. As a result, substantially clean air is discharged to the surrounding environment while the majority of the debris is confined to within the space 38. In a preferred form, the conduit 42 has an inverted “U” shape. The debris 132 is caused to be funnelled by the inclined housing surface 126, and an overall converging housing shape, into one leg 154 of the U. From the leg 154, the debris 132 travels in a downward path through the other leg 156 of the “U” and discharges into the space 38 through the first opening 144. As noted above, the evacuating system 36 may be a self-contained unit separable from the collection container 40 and supported on the wheeled carriage 46. Levelling feet 158 are provided on a frame 160 that is supported by the wheeled carriage 46. The levelling feet 158 can be used on a particular site to elevate the frame 160 off of carriage wheels 162, to stably support the evacuating system 36 in a desired orientation relative to the collection container 40. The frame 160 has a towing tongue 164 with a hitch component 166 to engage a cooperating component on a drawing vehicle (not shown) used to transport the evacuating system 36. Additional detail of certain components of the apparatus 10 will now be described. It should be understood that this detail is not critical to the present invention, but helpful in fully understanding the preferred form thereof. In FIG. 5, details of the delivery unit 44 are shown. At the upstream end 76, a funnelling wall 168 is provided to control and confine the introduced mixture 74. The introduced mixture 74 is guided thereby towards the conveying component 60. The conveying component 60 has laterally extending slats 170 projecting upwardly therefrom at regular intervals along the length of the conveying component 60. The slats 170 positively grip the mixture 74 as the conveying component 60 is advanced. The frame 66 further comprises an inverted “U”-shaped height control bar 172 that defines, in conjunction with the upwardly facing conveying surface 70, a surrounded entry passage with a fixed area. This facilitates control of the volume of the mixture 74 being introduced to against the conveying surface 70. A laterally centered, and inverted, “V”-shaped divider 174 disperses introduced mixture 74 evenly across the width of the conveying surface 70. The mixture 74 is confined at the lateral ends of the surface 70 by flexible skirts 176. In FIGS. 6-8, additional detail regarding the unit 80 is shown. The unit 80 in this embodiment consists of three of the aforementioned rollers 82, two of the rollers 84, and the cylinder 88 between the rollers 82, 84 in the depicted combination. The rollers 82, 84 and cylinder 88 are rotatable about parallel axes X1, X2, X3, X4, X5 spaced so that the rollers 82, 84 are in mesh. The rollers 82, 84, 88 and cylinder 88 are simultaneously rotated by a drive 178. The rollers 82 each is made up of a shaft 180 with fingered wheels 182 keyed to rotate therewith and be slidable axially therealong. The roller 84 has the same general construction with a different configuration for the fingered wheels 184 that can be arranged to cooperatively produce the depicted spiral shape. The rotating and meshed rollers 82, 84 cooperate to break loose excess dirt, vines, and other trash accompanying the usable crop 104. The meshed arrangement creates gaps/openings for small rocks/debris to pass downwardly therethrough. The cylinder 88 can be moved vertically relative to the rollers 82, 84 to create a gap at the cylindrical roller 88 that allows small/flat rocks to drop therethrough. By adjusting the cylindrical roller 88 up or down, a “stall point” can also be adjusted for the incoming supply of crop 104 with intermingled debris. By changing the stall point, the residence time of the mixture 74 on the unit 80 can be selected to control the degree of cleaning and debris breakup performed by the unit 80. In FIG. 8 the transition from the unit 80 to the conveying section 22b can be clearly seen. FIG. 9 shows the upstream end of the conveying section 22b/separating system 24b. The conveying component 108 is made from a series of elongate, laterally extending tubes 188 that are in parallel relationship with gaps therebetween that allow passage of small debris downwardly therethrough to the solid surface 98 of the conveying component 92 that is traveling in an opposite direction. The tubes 188 may be coated with rubber and may be shaken by an appropriate actuator 189 to enhance debris separation and release to the underlying auxiliary conveyor 26b. In FIGS. 10-12, details for the support roller assemblies 114, 114′, as seen also in FIG. 4, are shown. It should be mentioned that the various conveying sections 22 may utilize roller components, support roller assemblies, etc. of like construction at laterally spaced locations. The description herein is limited to the roller components/support roller assemblies at one such location. The support roller assembly 114′ has separate rollers 190, 192 supported on a cantilevered arm 194. The arm 194 extends from a tube 196 that projects through a frame part 198. An actuating arm 200 is connected to the projecting part of the tube 196. The tube 196, together with the arms 194, 200, pivots as a unit relative to the frame part 198 about a laterally extending axis 202. The angular position of the actuating arm 200, and thus the arm 194 and associated rollers 190, 192, is controlled by a manually operated actuator at 204. The actuator 204 has an elongate configuration with one end 206 attached for pivoting relative to the frame part 198 through a bracket 208. The opposite end 210 is pivotably connected to the end of the arm 200, remote from the tube 196. The actuator 204 utilizes cooperating threaded components that are relatively turned to change the effective length thereof. As depicted, this relative turning is accomplished through a hand-operable tool 212 which may utilize a ratchet arrangement. Alternatively, automated adjustment can be effected. By operating the actuator 204, the angle α1 of the incline of the conveying component 108 can be locally changed, thereby changing the angle at which the crop is advanced towards and through the chamber inlet 120. The spacing between the inlet 120 and the location on the conveying component 108 at which crop separates can also be controlled through this adjustment. Upstream of the support roller assembly 14 is the aforementioned support roller assembly 114, which repositions under the weight of large rocks and the like. The roller assembly 114 has rollers 190′, 192′ carried on an arm 194′ at each side of the conveying section 22b. The arms 194′ have an associated tube 196′ that projects through the frame part 198 and connects to an actuating arm 200′. The arm 200′ is normally biased around a pivot axis 202′ in the direction of the arrow 214. As this occurs, the actuating arm 200′ abuts to a stop element 216 fixed on the frame part 198 to consistently place the arm 200′ and support roller assembly 114 in a relaxed/no load position, as shown in FIG. 4. A pair of tension coil springs 218 act between an end 220 of the arm 200′ and a bracket 222 on the frame part 198 to draw the roller assembly 114 to its no load position. When a predetermined weight is applied to the conveying component, the springs 218 will extend to locally lower the conveying component in the vicinity of the frame part 124, thereby to allow a greater clearance so that the heavy debris/rock may pass beyond the frame part 124 to move off of the end 106 of the conveying section 22b to the auxiliary conveyor 26b, as shown in FIGS. 10 and 13. In FIGS. 14-18, additional details of the housing 34 and chamber 32 defined thereby are shown, as well as the interaction of the housing 34 with the conveying section 22c. These components are shown assembled on the apparatus in FIGS. 2-4. The housing 34 has two main parts—a crop control component 224 and a transition component 226 that connects between the crop control component 224 and the conduit 42. The crop control component 224 is generally wedge-shaped so that the portion of the chamber 32 bounded thereby diverges towards the transition component 226, which in turn converges towards the top opening 127. Flexible flaps 228, 230 are provided on the housing 34 at the sides of the conveying section 22c. The flap 228 confines crop at one side of the conveying section 22c. Crop that is propelled to encounter the flexible flap 230 on the other side of the conveying section 22c is guided under its own weight downwardly by a convex surface thereon to the conveying surface 232 on the conveying section, which is shown with discrete slats 233 that enhance gripping and conveyance of crop. The flexible construction of the flaps 228, 230 allows them to absorb impact forces from the crop without inflicting damage thereon. A lateral extension housing 234 supports an additional flexible flap 236 which overlies and affords a partial seal where the conveying section 22c departs from the chamber 32, thereby to maximize low pressure maintenance on the chamber 32 and air flow velocity therethrough. To further reduce gaps that might compromise the low pressure maintenance in the chamber 32, a series of deflectable flaps 238 cooperatively span the width of the gap G and are normally biased to cooperatively block the gap G. Advancing heavy debris will pivot the flaps 238 against a biasing force to allow movement of such debris out of the processing path for delivery to the auxiliary conveyor 26c. Repositionable access doors 240, 242 are provided at the front of the housing 34 with a separate repositionable access door 244 provided on the extension 234. The evacuating system 36 in FIG. 3 is shown with a fan unit at 246 operated by a fuel powered engine 248, such as a diesel engine that may be operably connected to the fan unit 246 by conventional components such as an hydraulic clutch, sheaves, belts, etc. (not shown). An electric motor 250 might alternatively be used. An isolation sleeve 252 (FIG. 3) is used to connect to the collection container 40 to reduce any migrating vibration. In FIG. 19, there is a flow diagram representation of a method of separating usable crop from intermixed debris, using an apparatus as described above. As shown at block 254, an apparatus as described above is provided. As shown at block 256, usable crop intermixed with debris is placed at an input location on a conveying system to be conveyed in a processing path. As shown at block 258, through a first separating system, certain debris is separated from usable crop. As shown at block 260, through a vacuum system, additional debris is separated from usable crop. As shown at block 262, usable crop with removed debris is collected. In FIG. 20, a modified form of apparatus for separating usable crop from intermixed debris, according to the invention, is shown schematically at 300. The apparatus 300 has a movable support 302. The movable support has a frame 304 with at least one wheel 306 thereon that can be rolled against underlying terrain to relocate the apparatus 300. The movable support 302 has a component 308 on the frame 304 that is configured to be hitched to a component 310 on a towing vehicle 312 that is usable to move the apparatus 300. The apparatus 300 incorporates some or all of the systems/components in the earlier described embodiments into the movable support 302 to be movable as a unit therewith. The components/systems may have the same, or a similar, construction as those described above. The schematic showing is intended to encompass the earlier described components/systems in their depicted form and virtually an unlimited number of variations thereof and interactions therebetween. For purposes of simplicity, each of the components/systems on the apparatus 300 will be identified with the reference numerals used for corresponding components/systems described above and additionally include a “″” designation. Since the components/systems operate in substantially the same manner as those described above, there is no need to describe the structure or operation thereof in detail hereinbelow. A conveying system 14″ is provided on the frame 304 of the movable support 302 and is configured to convey usable crop in a processing path (P as described above) from an upstream input location to a downstream output location. One or more separating systems 24″ are mounted on the frame 304 of the movable support 302, with each configured to cause separation of debris intermixed with usable crop as usable crop is conveyed in the processing path. The different separating systems may separate debris from usable crop in the same manner or in different manners. A vacuum system 30″ is provided on the frame 304 on the movable support 302 and is located preferably downstream of at least the initial separating system 24″. The vacuum system 30″ is configured to generate a low pressure volume which causes additional debris intermixed with the usable crop to be drawn away from the usable crop by vacuum. A collection container 40″ is mounted on the frame 304 on the movable support 302 and is configured to accumulate debris drawn away from the usable crop during its conveyance in the path P. The movable support 302, conveying system 14″, at least a first separating system 24″, the vacuum system 30″, and the collection container 40″ together define a functioning unit 314 that can be moved as one piece to relocate the apparatus 300. An evacuating system 36″, that may be part of the vacuum system 30″ or an independent system, makes up part of the apparatus 300 and is mounted on the movable support 302. The evacuating system 36″ is configured to create a low pressure volume in a space 318 within the collection chamber 40″. The apparatus 300 further has a housing 34″ with a chamber 32″ through which the processing path P extends. The vacuum system 30″ and/or the evacuating system 36″ generate the low pressure volume within the housing chamber 32″. The collection container 40″ is preferably downstream of the housing 34″. This location is not required. The evacuating system 36″ is preferably downstream of the collection container 40″, though this again is not a requirement. The apparatus 300 may further have a delivery unit 44″ on the frame 304 of the movable support 302. The delivery unit 44″ is configured to continuously direct a supply of intermixed debris and usable crop to an upstream input location for the conveying system 14″. The apparatus 300 may further include at least one auxiliary conveyor 26″ on the frame 304 on the movable support 302. The at least one auxiliary conveyor 26″ is configured to intercept downwardly traveling debris separated from the advancing usable crop and convey the same towards a collection location 320. One exemplary form of the apparatus 300 will now be described with respect to FIGS. 21-24. As noted above, the basic components/systems can be essentially the same as those described above and thus there is no need to describe specific details thereof. What is significant is the basic arrangement of components as integrated into the movable support 302. The movable support 302 has a length, as indicated by the double-headed arrow 322, between upstream and downstream ends 324, 326, respectively. The aforementioned processing path P has at least a portion that extends substantially in a line from the upstream end 324 towards the downstream end 326. As described above, the conveying sections 22a″, 22b″ are independently operable and convey usable crop and attendant debris generally along this line. The delivery unit 44″ may be a permanent part of the apparatus 300 or may be separately attached thereto. The delivery unit 44″ continuously directs a supply of intermixed debris and usable crop to the upstream input location 324 to the conveying system 14″ made up in part by the conveying sections 22a″, 22b″. The housing 34″, bounding the chamber 32″, is downstream of the conveying sections 22a″, 22b″. The collection container 40″, bounding the space 318, is downstream of the housing 32″. The vacuum system 30″, including the evacuating system 36″, is located downstream of the collection container 40″. Through the evacuating system 36″, the vacuum system 30″ creates a low pressure volume within the space 318. The space 318 is in communication with the housing chamber 32″ to create a low pressure volume therein as well. This communication is effected through a funneling conduit 328 that has a cross-sectional shape that tapers progressively in a direction from the housing 34″ towards the collection container 40″. This low pressure volume may be responsible for redirecting the conveying usable crop in a different path portion, as described above, but at least draws debris from within the housing chamber 32″ into the collection container space 318 for accumulation. The movable support 302 has three different frame platforms 330a, 330b, 330c. The platforms 330a, 330b, 330c are at different heights. The lowest level platform 330b supports the collection container 40″, which is the highest profile component. The evacuating system 36″ is on the most downstream platform 330a, with the housing 34″ on the most upstream platform 330c. The platform 330b is configured to define an upwardly facing walking surface 332 around at least a part of the outer perimeter of the collection container 40″. The funneling conduit 328 spans between the platforms 330b, 330c and has an elbow 334 that connects to the housing 34″ to establish communication with the housing chamber 32″ through a top opening 336 on the housing 34″. As in the prior embodiment, the conveying system 14″ includes at least one discharge conveying section 22c″ that is operable independently of the conveying sections 22a″, 22b″ and receives advancing usable crop after debris is separated therefrom by the separating system(s) 24″. The at least one discharge conveying section 22c″ directs received advancing usable crop transversely to the length L of the movable support 302 to a collection location 338. The aforementioned auxiliary conveyor 26″ may be provided at any location where debris is separated along the conveying path to intercept downwardly traveling debris and convey the same towards the collection location 320. One or more auxiliary conveyors 26″ may be strategically situated. The collection container 40″ has the same configuration as the container 40 with openings 144″, 148″ located a substantial distance above a floor 150″ so that a substantial height of debris can be accumulated upon the floor 150″ without obstructing the openings 144″, 148″. Accordingly, processing may be carried out for relatively long periods without requiring emptying of the collection container 40″. The various components/systems are arranged on the movable support 302 so that the overall system length L1 and width W1 of the apparatus 300 allow the apparatus 300 to be towed on a public right-of-way. In the depicted exemplary form of the apparatus, wheels 304 are provided on the frame 304 at locations spaced in a fore-and-aft direction to facilitate over-the-road travel. The hitching component 308 is provided at the downstream region of the platform 330a so that the apparatus 300 is towed by the vehicle 312 from the downstream end of the movable support 302 in a direction indicated by the arrow 340. To minimize the width W1, the rectangular footprint of the collection container 40″ is arranged so that its longer dimension aligns with the length of the movable support 302. The components/systems are spaced serially lengthwise of the movable support 302 to provide a width dimension W1 that can be accommodated by public right-of-ways. The shape of the funneling conduit 328 allows a relatively compact structure to be used for communication of debris from the housing 34″ to the collection container 40″. As noted above, the systems/components may be formed substantially identically to those described above whereby the conveying usable crop with associated debris moves in substantially the same processing path P. However, it is not necessary that the components/systems have the same construction. For example, while the above-described system causes usable crop to be moved in opposite directions over different parts of the processing path, this is not a requirement. The equal pressure volume may be provided simply to control debris rather than redirect the usable crop in any significant manner. The foregoing disclosure of specific embodiments is intended to be illustrative of the broad concepts comprehended by the invention.
<SOH> BACKGROUND OF THE INVENTION <EOH>
<SOH> SUMMARY OF THE INVENTION <EOH>In one form, the invention is directed to an apparatus for separating usable crop from intermixed debris. The apparatus includes: a movable support; a conveying system on the movable support configured to convey usable crop in a processing path from an upstream input location to a downstream output location; at least a first separating system on the movable support configured to cause separation of debris intermixed with usable crop in a first manner as usable crop is conveyed in the processing path; a vacuum system on the movable support downstream of the first separating system and configured to generate a low pressure volume which causes additional debris intermixed with the usable crop to be drawn away from the usable crop by vacuum; and a collection container on the movable support configured to accumulate debris drawn away from the conveying usable crop. The movable support, conveying system, at least first separating system, vacuum system, and collection container define a unit that can be moved to relocate the apparatus. In one form, the movable support has a frame with wheels that can be rolled against underlying terrain to relocate the apparatus. In one form, the movable support has a component that is configured to be hitched to a towing vehicle that is usable to move the apparatus. In one form, the apparatus further includes an evacuating system on the movable support. The evacuating system is configured to create a low pressure volume in a space in the collection container. In one form, the apparatus is configured so that the low pressure volume which causes additional debris intermixed with the usable crop to be drawn away from the usable crop is created by the evacuating system. In one form, the movable support has a length between upstream and downstream ends. The processing path has at least a portion that extends substantially in a line from the upstream end towards the downstream end. The apparatus has a housing with a chamber through which the processing path extends. The vacuum system generates the low pressure volume within the housing chamber. The collection container is downstream of the housing. In one form, the apparatus further includes an evacuating system on the movable support. The evacuating system is downstream of the collection container and configured to create a low pressure volume in a space in the collection container. In one form, the apparatus further includes a funneling conduit that directs debris from the housing chamber in a downstream direction into the collection container. In one form, the apparatus further includes a delivery unit on the movable support that is configured to continuously direct a supply of intermixed debris and usable crop to the upstream input location. In one form, the at least first separating system includes a second separating system spaced along the processing path from the first separating system and configured to cause separation of debris intermixed with usable crop in a second manner that is different than the first manner. In one form, the conveying system is made up of a plurality of cooperating, independently operating, conveying sections. In one form, the apparatus further includes at least one auxiliary conveyor on the movable support configured to intercept downwardly traveling debris and convey intercepted downwardly traveling debris towards a collection location. In one form, the housing has a top opening. The vacuum system has an evacuating system that is in communication with the top opening. In one form, the conveying system has at least one discharge conveying section that receives advancing usable crop after debris is separated from the advancing usable crop by the at least first separating system. The at least one discharge conveying section directs received advancing usable crop transversely to the length of the movable support to a collection location. In one form, the movable support has first and second platforms at different heights. The collection container is supported on the first platform. The housing is supported on the second platform. In one form, the collection container has an outer perimeter. The first platform is configured to define an upwardly facing walking surface around at least a part of the outer perimeter of the collection container. In one form, the apparatus further includes an evacuating system on the movable support. The evacuating system is configured to create a low pressure volume in a space defined by the collection container and bounded by a floor. The collection container has spaced first and second openings. The first opening receives debris from the housing chamber. The second opening is in communication with the evacuating system. Each of the first and second openings is spaced above the floor so that a substantial height of debris can be accumulated upon the floor without obstructing the first or second openings. In one form, the movable support has a frame with wheels that can be rolled against underlying terrain to relocate the apparatus. The movable support frame further includes a component at the downstream end of the movable support that is configured to be hitched to a towing vehicle that is usable to move the apparatus. In one form, the apparatus is configured to cause the usable crop to move in opposite directions over different parts of the processing path. In one form, the apparatus has a length and width that allow the apparatus to be towed on a public right-of-way.
B07B902
20170811
20180201
71430.0
B07B902
0
FABIAN-KOVACS, ARPAD
APPARATUS FOR SEPARATING USABLE CROP FROM INTERMIXED DEBRIS
UNDISCOUNTED
1
CONT-ACCEPTED
B07B
2,017
15,675,361
PENDING
INHIBITORS OF INDUCED MMP-1 PRODUCTION
The present invention provides methods and compositions of prophylaxis for, or for treating, chronic obstructive pulmonary disease (COPD), cancer, arthritis, skin damage, or atherosclerotic plaque rupture in a subject in need thereof, which comprise i) a statin or ii) selective serotonin reuptake inhibitor (SSRI).
1. A method of prophylaxis for, or for treating, chronic obstructive pulmonary disease (COPD), cancer, arthritis, skin damage, or atherosclerotic plaque rupture in a subject in need thereof, which comprises administering to the subject i) a statin or ii) a selective serotonin reuptake inhibitor (SSRI) in an amount that is effective to treat the COPD, cancer, arthritis, skin damage, or atherosclerotic plaque rupture. 2. The method of claim 1, for treatment of a subject who has been diagnosed with COPD, cancer, arthritis, skin damage, or atherosclerotic plaque rupture. 3. The method of claim 2, for treating COPD. 4. The method of claim 1, for prophylactic treatment of a subject for COPD. 5. The method of any one of claims 1-4, wherein the amount of the statin or the SSRI is effective to improve pulmonary function in the subject compared to i) the subject before administration of the amount of the statin or the SSRI or ii) a corresponding subject who has not been administered the amount of the statin or the SSRI. 6. The method of any one of claims 1-4, wherein the amount of the statin or the SSRI is effective to reduce pulmonary inflammation in the subject compared to i) the subject before administration of the amount of the statin or the SSRI or ii) a corresponding subject who has not been administered the amount of the statin or the SSRI. 7. The method of claim 6, wherein reduced pulmonary inflammation in the subject comprises a) reduced expression of at least one cytokine or b) a reduced number of neutrophils in the lungs of the subject. 8. The method of claim 7, wherein reduced pulmonary inflammation in the subject comprises a reduced expression of interleukin 8 (IL-8) in the lungs of the subject. 9. The method of any one of claims 1-8, wherein treating the subject comprises reducing the expression of at least one protease in the lungs of the subject compared to i) the subject before administration of the amount of the statin or the SSRI or ii) a corresponding subject who has not been administered the amount of the statin or the SSRI. 10. The method of claim 9, wherein the at least one protease is at least one matrix metalloproteinase (MMP). 11. The method of claim 10, wherein the at least one MMP comprises at least MMP-1, MMP-2, MMP-9, MMP-12 or MMP-13. 12. The method of any one of claims 1-11, wherein the COPD comprises emphysema. 13. The method of claim 12, wherein the amount of the statin or the SSRI is effective to slow, halt, or reverse the progression of emphysema in the subject. 14. The method of any one of claims 1-13, wherein the statin or the SSRI is capable of reducing cigarette smoke-induced or cigarette smoke extract (CSE)-induced MMP-1 expression without causing cytotoxicity. 15. The method of any one of claims 1-14, wherein the statin or the SSRI is capable of reducing cigarette smoke-induced or CSE-induced MMP-1 expression with an IC50 equal to or less than 1 μM. 16. The method of any one of claims 1-15, wherein the statin or the SSRI is capable of reducing cigarette smoke-induced or CSE-induced MMP-1 expression by 80-120%, wherein the level of MMP-1 expression in the absence of cigarette smoke or CSE induction is 100%. 17. The method of any one of claims 1-16, wherein the statin or the SSRI is capable of reducing MMP-1 or IL-8 expression in small airway epithelial cells (SAECs) contacted with cigarette smoke or CSE. 18. The method of any one of claims 1-17, wherein the statin or the SSRI is capable of reducing expression of TLR-4 receptor, PRAS40, BAD or GSK-3b, or reducing IRAK phosphorylation in SAECs in the subject. 19. The method of claim 17 or 18, wherein the expression is reduced by 80-120%, wherein the baseline level of expression is 100%. 20. The method of any one of claims 1-19, wherein the statin or the SSRI is an organic compound having a molecular weight less than 1000 Daltons, a DNA aptamer, an RNA aptamer, or a polypeptide. 21. The method of claim 20, wherein the statin or the SSRI is an organic compound having a molecular weight less than 1000 Daltons. 22. The method of any one of claims 1-21, wherein a statin is administered to the subject. 23. The method of claim 22, wherein the statin is Simvastatin, Lovastatin, Itavastatin, Fluvastatin, Mevastatin, Cerivastatin or Ezetimibe, or a pharmaceutically acceptable salt or ester thereof. 24. The method of any one of claims 1-23, wherein the statin is a compound that a) is in a clinical trial; b) is approved for use in human subjects; or c) was previously approved for use in human subjects but whose approval was subsequently withdrawn. 25. The method of any one of claims 1-21, wherein an SSRI is administered to the subject. 26. The method of claim 25, wherein the SSRI is Duloxetine, Nefazodone, Fluoxetine or Sertraline, or a pharmaceutically acceptable salt or ester thereof. 27. The method of any one of claim 1-21, 25 or 26, wherein the SSRI is a compound that a) is in a clinical trial; b) is approved for use in human subjects; or c) was previously approved for use in human subjects but whose approval was subsequently withdrawn. 28. The method of any one of claims 1-27, wherein the subject is a mammalian subject. 29. The method of any one of claims 1-28, wherein the subject is a human subject. 30. The method of any one of claims 1-29, wherein the subject is or was a cigarette smoker. 31. The method of any one of claims 1-30, wherein the COPD is caused by chronic cigarette smoking. 32. The method of any one of claims 1-31, wherein the statin or the SSRI is administered to the subject as an aerosol. 33. The method of claim 32, wherein the statin or the SSRI is administered to the subject using an inhaler. 34. The method of any of claims 1-33, wherein the statin or the SSRI is administered to the subject in a dose of between 0.1 mg/kg to 2 mg/kg. 35. The method of any of claims 1-34, wherein the statin or the SSRI is administered to the subject in a dose of about 0.8 mg/kg. 36. The method of any one of claim 1, 2 or 19-29, for treating skin damage. 37. The method of any one of claim 1, 2, 20-30 or 36, wherein administering the statin or the SSRI to the subject comprises topically applying the statin or the SSRI to the subject's skin. 38. The method of any one of claims 1-37, wherein the amount of the statin or the SSRI is effective to reduce the expression of at least one cytokine or at least one protease in the subject compared to i) the subject before administration of the amount of the statin or the SSRI or ii) a corresponding subject who has not been administered the amount of the statin or the SSRI. 39. The method of any one of claims 1-38, wherein the subject is a) a COPD-drug, cancer-drug, arthritis-drug, skin damage-drug, or atherosclerotic plaque rupture-drug naïve subject; b) a statin naïve subject; or c) an SSRI naïve subject. 40. A composition for use in prophylaxis for, or in treating, chronic obstructive pulmonary disease (COPD), cancer, arthritis, skin damage, or atherosclerotic plaque rupture in a subject in need thereof which comprises i) a statin or ii) a selective serotonin reuptake inhibitor (SSRI). 41. The composition of claim 39, wherein the subject is a) a COPD-drug, cancer-drug, arthritis-drug, skin damage-drug, or atherosclerotic plaque rupture-drug naïve subject; b) a statin naïve subject; or c) an SSRI naïve subject. 42. Use of i) a statin or ii) a selective serotonin reuptake inhibitor (SSRI) for the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease (COPD), cancer, arthritis, skin damage, or atherosclerotic plaque rupture in a subject in need thereof. 43. The use of claim 42, wherein the treatment is prophylactic treatment. 44. The use of claim 42 or 43, wherein the subject is a) a COPD-drug, cancer-drug, arthritis-drug, skin damage-drug, or atherosclerotic plaque rupture-drug naïve subject; b) a statin naïve subject; or c) an SSRI naïve subject. 45. An inhaler containing a statin or an SSRI. 46. The inhaler of claim 45, for use in treating a subject afflicted with chronic obstructive pulmonary disease (COPD). 47. The inhaler of claim 45 or 46, wherein the subject is a) a COPD-drug, cancer-drug, arthritis-drug, skin damage-drug, or atherosclerotic plaque rupture-drug naïve subject; b) a statin naïve subject; or c) an SSRI naïve subject.
This application is a continuation-in-part of PCT International Application No. PCT/US2016/017562, filed Feb. 11, 2016, claiming the benefit of U.S. Provisional Application No. 62/115,021, filed Feb. 11, 2015, the contents of each of which are hereby incorporated by reference into the application. This invention was made with government support under grant number R01HL086936 awarded by the National Institutes of Health. The U.S. Government has certain rights in the invention. Throughout this application, various publications are referenced, including referenced in parentheses. Full citations for publications referenced in parentheses may be found listed at the end of the specification immediately preceding the claims. The disclosures of all referenced publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. BACKGROUND OF INVENTION Chronic obstructive pulmonary disease (COPD) is an enormous unmet medical need. Present therapies offer relief from its symptoms, but no drug treats the cause or slows progression of the disease. The most common cause of COPD is cigarette smoking, a behavior whose prevalence in the U.S. has remained fairly constant but continues to rise worldwide. In the U.S. alone, each year this disease results in more than 100,000 deaths, is responsible for over 600,000 hospitalizations and over 15 million physician office visits, causing approximately 150 million days of disability (CDC 2003). It is estimated that about 600 million adults have COPD, of which 24 million live in the U.S. (CDC, 2003). In 2010 the annual cost for COPD was $20.4 billion in direct health care expenditures, and $29.5 billion in indirect costs (COPD Fact Sheet, 2014). As of 2008 COPD became the third leading cause of death (Minino et al., 2011) and analysts estimate the worldwide market for COPD therapy at $15.6 billion in 2019 (GOLD, 2013). Spiriva® (tiotropium, Boehringer Ingelheim/Pfizer) was launched outside the U.S. in 2002 and is marketed exclusively for COPD. Its European sales are over 2.4 billion euros and US sales topping 1 billion (COPD Market to 2019, 2013). Recently, Roflumilast, a phosphodiesterase type 4 (PDE-4) inhibitor was approved as a new therapeutic for COPD exacerbations with sales progressively growing since release (Fabbri et al., 2010). The massive health cost burden of COPD is due to a combination of an increased incidence and sub-optimal treatment strategies. In the past, the desire to develop new pharmaceuticals has met with resistance because targets have been difficult to select and test and, furthermore, the disease has been treated as “self-inflicted” by the public and has not therefore received the attention warranted by its human and economic costs. The industry has recently witnessed high-profile attitude changes, and therefore, today the present barrier to the creation of effective drugs for COPD is the development of agents that act upon validated drug targets in this disease (COPD Market to 2019, 2013). More than 43.8 million, or 19%, of adults in the U.S were smokers in 2011 (CDC, 2011). While the prevalence of current smoking during 2005-2011 has been slightly declining overall (CDC, 2012), the worldwide prevalence of smoking continues to rise. Smokers are ten times more likely than non-smokers to die of COPD. Smoking cessation is the only intervention of proven value in early-stage COPD, however, even with cessation, the destructive process initiated by cigarette smoking continues (COPD Fact Sheet, 2014) emphasizing the need for therapies targeted towards smoke induced inflammation and lung destruction. Present interventions used for COPD serve to ameliorate the symptoms of the disease but do not address its overall course. The physiologic hallmark of COPD is fixed airway obstruction with a progressive decline in the forced expiratory volume in one second (FEV1). Bronchodilators, including anticholinergics (e.g., Atrovent®, Spiriva®) and β-adrenergic agonists (e.g., albuterol, Opened®), relax airway smooth muscle and appear to decrease dyspnea, increase FEV1, and decrease the frequency of reported exacerbations in certain populations (Hanania and Marciniuk, 2011). The effect of bronchodilators is short-lived, however, and these agents do not slow the progression of the disease as measured by a long-term decline in FEV1 (Hanania and Marciniuk, 2011). The regular use of inhaled corticosteroids (e.g., Flovent®) reduces symptoms, frequency of exacerbations, and numbers of outpatient physician visits in patients with moderate or severe COPD, but does not affect the rate of decline in post-bronchodilator FEV1 (Hanania and Marciniuk, 2011). However, chronic use of systemic corticosteroids does not improve the course of COPD, and may increase mortality (Hanania and Marciniuk, 2011). New methods and compositions for treating COPD are needed. SUMMARY OF THE INVENTION The present invention provides a method of prophylaxis for, or for treating, chronic obstructive pulmonary disease (COPD), cancer, arthritis, skin damage, or atherosclerotic plaque rupture in a subject in need thereof, which comprises administering to the subject i) a statin or ii) a selective serotonin reuptake inhibitor (SSRI) in an amount that is effective to treat the COPD, cancer, arthritis, skin damage, or atherosclerotic plaque rupture. The present invention also provides a composition for use in prophylaxis for, or in treating, chronic obstructive pulmonary disease (COPD), cancer, arthritis, skin damage, or atherosclerotic plaque rupture in a subject in need thereof which comprises i) a statin or ii) a selective serotonin reuptake inhibitor (SSRI). Aspects of the present invention relate to the use of i) a statin or ii) a selective serotonin reuptake inhibitor (SSRI) for the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease (COPD), cancer, arthritis, skin damage, or atherosclerotic plaque rupture in a subject in need thereof. The present invention further provides an inhaler containing a statin or an SSRI. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1. Cigarette smoke induces MMP-1 through a MAPKinase dependent pathway via a conserved cigarette smoke element (CRE) that induces the transcription of MMP-1 (Mercer et al., 2009). This CRE is conserved in several MMPs and cytokines. A library of compounds was screened for their ability to block the cigarette smoke induction of MMP-1. These compounds will then be tested for their ability to block the inflammatory cascade and induction of other MMPs. If successful these compounds will be further tested in vivo for their ability to protect from emphysema formation and further developed as a therapeutic in the disease. FIG. 2A. Intra-assay variability test. To test for reproducibility of the assay, cells were transfected with the MMP-1/pGL3 reporter plasmid. Cells were seeded in three 96-well plates using an interleaved format and treated with, 5% CSE media (H), 1% CSE (M), No CSE (L). After 1, 2 and 3 days incubation, the luciferase activity was measured in each well. FIG. 2B. Variability test with a known small inhibitor compound. To test for function of the assay, cells were transfected with the MMP-1/pGL3 reporter plasmid. Cells were seeded in three 96-well plates using an interleaved format and treated with, 5% CSE media with various concentrations of PD098059 (an ERK inhibitor) After 24 hr incubation, the luciferase activity was measured in each well. FIG. 3. Inhibitory effect of a collection of 727 small molecule compunds on CSE induced MMP-1 transcription activity. For the fifteen compounds identified as active during the primary screen, independent compound batches were obtained from the NIH Molecular Libraries Small Molecule Repository and 10 dilution points, of 1:3 serial dilutions starting from a nominal 10 mM solution prepared and tested in triplicate for inhibition of CSE/MMP-1 induction. IC50 values were calculated for each compound using a four-parameter equation describing a sigmoidal dose response curve. Lead compounds were selected if they possessed an IC50 value ≦1 μM (Data not shown). FIG. 4. Reduction of markers for inflammation after treatment of SAECs with CSE and Compound 1 (simvastatin, Class A-Statin). SAEC treatment with 5% CSE and 10 uM Compound 1 (simvastatin, a Statin), showing decreased IL-8 levels. Compound 1 (simvastatin, a Statin) decreases the induction of IL-8 after cigarette smoke treatment indicated by *). Data is presented as mean+standard error. There was no statistically significant difference in the expression of IL-8 between un-treated cells and those treated with compound 1 (simvastatin, a Statin) under non-smoke exposed conditions. FIG. 5. Blockade of MMP-1 induction after treatment of SAECs with CSE and Duloxetine. SAEC treatment with 5% CSE and 10 uM Duloxetine, demonstrating decreased MMP-1 expression. Duloxetine decreases the induction of MMP-1 after cigarette smoke treatment indicated by * p<0.05. Data is presented as mean+standard error. FIG. 6. The expression of MMP-1 protein in BAL from smoke rabbits. Duloxetine administrated to smoke exposed rabbits down regulated the expression of MMP-1 in BAL. SM-smoke without the duloxetine, SMD-smoke with duloxetine. FIG. 7A. Attenuation of smoke induced emphysema in a rabbit smoke exposure model. H&E representation of lungs from rabbits untreated, treated with duloxetine, smoke exposed, and smoke exposed with duloxetine. Duloxetine was administered 3 mg/day given once a day. The development of emphysema was blocked in the treated group. FIG. 7B. Morphometric analysis of rabbit study groups. SM group had statistically significant increased mean linear intercept (unit: μm) compared to the rest of the groups (p=0.0495). NS-non-smoke without the duloxetine, NS-D-non-smoke with duloxetine, SM-smoke without the duloxetine, SM-D-smoke with duloxetine. FIG. 8. Blockade of MMP-1 induction after treatment of SAECs with CSE and Fluoxetine. SAEC treatment with 5% CSE, 10 nM Fluoxitine, 10 uM Fluoxitine, and combinations of 5% CSE and Fluoxitine. CSE induces MMP1 expression and when treated with Fluoxetine and CSE MMP-1 induction was attenuated (p<0.05). Data is presented as mean+standard error. FIG. 9A. Cigarette Smoke induces TLR4 expression in SAE cells, which is blocked when cells are treated with Fluoxetine. SAEC treatment with 5% CSE and 10 uM fluoxetine (Fluo), exhibit down regulation of TLR-4 receptor expression. FIG. 9B. Western blot analysis demonstrates that the phosphorylation of IRAK (downstream target of TLR-4 signaling pathway) was suppressed by Fluoxetine. FIG. 10. Protein Array Analysis of Cells Treated with CSE compared to Cells Treated with CSE combined with Fluoxetine. Three transcription factors were found to increase with CSE treatment and when pretreated with Fluoxetine these factors return to baseline. PRAS40, BAD and GSK-3b are increased with cigarette smoke treatment and return to baseline upon Fluoxetine treatment. The lines representing these three transcription factors, along with ERK 1/2, are labeled. Additionally, the lines compressed at the bottom of the figure represent the following transcription factors that were also tested: PC, NC, Stat1, Stat2, Akt (Thr308), Akt (Ser473), AMPKa, S6 Ribosomal Protein, mTOR, HSP27, p70 S6 Kinase, p53, p38, SAPK/JNK, PARP and Caspase-3. FIG. 11A. Standard Fluoxetine Chromatographic Characteristics. The chromatogram of Fluoxetine displays a retention time of 17.69 mins. The peak corresponding to Fluoxetine is highlighted. FIG. 11B. Absorbance spectra for Fluoxetine. FIG. 12A. Chromatographic Characteristics of Control Samples. The standard chromatogram for no drug administration. FIG. 12B. The standard chromatogram for administration of PBS. FIG. 13A. Fluoxetine Quantification in Oral Gavage Method of Drug Administration. A study was conducted to determine whether fluoxetine is absorbed in the lung when delivered orally. Animals were given PBS and 10 mg/kg oral gavage of fluoxetine. Mice were sacrificed, lungs lyophilized and protein homogenate prepared for chromatographic analysis. Oral gavage of fluoxetine yielded two compounds showing chromatographic peaks at similar retention times. FIG. 13B. Absorbance spectra suggested the occurrence of a metabolite of fluoxetine, an isomer or enantiomer of the compound. FIG. 14A. Fluoxetine Quantification in Inhalation Method of Drug Administration. A study was conducted to determine whether fluoxetine is absorbed in the lung when delivered through inhalation. Animals were given PBS and 10 mg/kg of inhaled Fluoxetine. Mice were sacrificed, lungs lyophilized and protein homogenate prepared for chromatographic analysis. Inhalation of fluoxetine yielded three compounds that can be identified in lung samples. FIG. 14B. Absorbance spectra of the three peaks showed that two of the compounds have almost identical absorbance spectra; the third compound retained a more polar characteristic eluting at 14.7 mins. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method of prophylaxis for, or for treating, chronic obstructive pulmonary disease (COPD), cancer, arthritis, skin damage, or atherosclerotic plaque rupture in a subject in need thereof, which comprises administering to the subject i) a statin or ii) a selective serotonin reuptake inhibitor (SSRI) in an amount that is effective to treat the COPD, cancer, arthritis, skin damage, or atherosclerotic plaque rupture. In some embodiments, the method is for treatment of a subject who has been diagnosed with COPD, cancer, arthritis, skin damage, or atherosclerotic plaque rupture. In some embodiments, the method is for treating COPD. In some embodiments, the method is for prophylactic treatment of a subject for COPD. In some embodiments, the amount of the statin or the SSRI is effective to improve pulmonary function in the subject compared to i) the subject before administration of the amount of the statin or the SSRI or ii) a corresponding subject who has not been administered the amount of the statin or the SSRI. In some embodiments, the amount of the statin or the SSRI is effective to reduce pulmonary inflammation in the subject compared to i) the subject before administration of the amount of the statin or the SSRI or ii) a corresponding subject who has not been administered the amount of the statin or the SSRI. In some embodiments, reduced pulmonary inflammation in the subject comprises a) reduced expression of at least one cytokine or b) a reduced number of neutrophils in the lungs of the subject. In some embodiments, reduced pulmonary inflammation in the subject comprises a reduced expression of interleukin 8 (IL-8) in the lungs of the subject. In some embodiments, treating the subject comprises reducing the expression of at least one protease in the lungs of the subject compared to i) the subject before administration of the amount of the statin or the SSRI or ii) a corresponding subject who has not been administered the amount of the statin or the SSRI. In some embodiments, the at least one protease is at least one matrix metalloproteinase (MMP). In some embodiments, the at least one MMP comprises at least MMP-1, MMP-2, MMP-9, MMP-12 or MMP-13. In some embodiments, the COPD comprises emphysema. In some embodiments, the amount of the statin or the SSRI is effective to slow, halt, or reverse the progression of emphysema in the subject. In some embodiments, the statin or the SSRI is capable of reducing cigarette smoke-induced or cigarette smoke extract (CSE)-induced MMP-1 expression without causing cytotoxicity. In some embodiments, the statin or the SSRI is capable of reducing cigarette smoke-induced or CSE-induced MMP-1 expression with an IC50 equal to or less than 1 pM. In some embodiments, the statin or the SSRI is capable of reducing cigarette smoke-induced or CSE-induced MMP-1 expression by 80-120%, wherein the level of MMP-1 expression in the absence of cigarette smoke or CSE induction is 100%. In some embodiments, the statin or the SSRI is capable of reducing MMP-1 or IL-8 expression in small airway epithelial cells (SAECs) contacted with cigarette smoke or CSE. In some embodiments, the statin or the SSRI is capable of reducing expression of TLR-4 receptor, PRAS40, BAD or GSK-3b, or reducing IRAK phosphorylation in SAECs in the subject. In some embodiments, the expression is reduced by 80-120%, wherein the baseline level of expression is 100%. In some embodiments, the statin or the SSRI is an organic compound having a molecular weight less than 1000 Daltons, a DNA aptamer, an RNA aptamer, or a polypeptide. In some embodiments, the statin or the SSRI is an organic compound having a molecular weight less than 1000 Daltons. In some embodiments, a statin is administered to the subject. In some embodiments, the statin is Simvastatin, Lovastatin, Itavastatin, Fluvastatin, Mevastatin, Cerivastatin or Ezetimibe, or a pharmaceutically acceptable salt or ester thereof. In some embodiments, the statin is a compound that a) is in a clinical trial; b) is approved for use in human subjects; or c) was previously approved for use in human subjects but whose approval was subsequently withdrawn. In some embodiments, an SSRI is administered to the subject. In some embodiments, the SSRI is Duloxetine, Nefazodone, Fluoxetine or Sertraline, or a pharmaceutically acceptable salt or ester thereof. In some embodiments, the SSRI is a compound that a) is in a clinical trial; b) is approved for use in human subjects; or c) was previously approved for use in human subjects but whose approval was subsequently withdrawn. In some embodiments, the subject is a mammalian subject. In some embodiments, the subject is a human subject. In some embodiments, the subject is or was a cigarette smoker. In some embodiments, the COPD is caused by chronic cigarette smoking. In some embodiments, the statin or the SSRI is administered to the subject as an aerosol. In some embodiments, the statin or the SSRI is administered to the subject using an inhaler. In some embodiments, the statin or the SSRI is administered to the subject in a dose of between 0.1 mg/kg to 2 mg/kg. In some embodiments, the statin or the SSRI is administered to the subject in a dose of about 0.8 mg/kg. In some embodiments, the method is for treating skin damage. In some embodiments, administering the statin or the SSRI to the subject comprises topically applying the statin or the SSRI to the subject's skin. In some embodiments, the amount of the statin or the SSRI is effective to reduce the expression of at least one cytokine or at least one protease in the subject compared to i) the subject before administration of the amount of the statin or the SSRI or ii) a corresponding subject who has not been administered the amount of the statin or the SSRI. In some embodiments, the subject is a) a COPD-drug, cancer-drug, arthritis-drug, skin damage-drug, or atherosclerotic plaque rupture-drug naïve subject; b) a statin naïve subject; or c) an SSRI naïve subject. The present invention also provides a composition for use in prophylaxis for, or in treating, chronic obstructive pulmonary disease (COPD), cancer, arthritis, skin damage, or atherosclerotic plaque rupture in a subject in need thereof which comprises i) a statin or ii) a selective serotonin reuptake inhibitor (SSRI). In some embodiments, the subject is a) a COPD-drug, cancer-drug, arthritis-drug, skin damage-drug, or atherosclerotic plaque rupture-drug naïve subject; b) a statin naïve subject; or c) an SSRI naïve subject. Aspects of the present invention relate to the use of i) a statin or ii) a selective serotonin reuptake inhibitor (SSRI) for the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease (COPD), cancer, arthritis, skin damage, or atherosclerotic plaque rupture in a subject in need thereof. In some embodiments, the treatment is prophylactic treatment. In some embodiments, the subject is a) a COPD-drug, cancer-drug, arthritis-drug, skin damage-drug, or atherosclerotic plaque rupture-drug naïve subject; b) a statin naïve subject; or c) an SSRI naïve subject. The present invention further provides an inhaler containing a statin or an SSRI. In some embodiments, the inhaler is for use in treating a subject afflicted with chronic obstructive pulmonary disease (COPD). In some embodiments, the subject is a) a COPD-drug, cancer-drug, arthritis-drug, skin damage-drug, or atherosclerotic plaque rupture-drug naïve subject; b) a statin naïve subject; or c) an SSRI naïve subject. Each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. Thus, all combinations of the various elements described herein are within the scope of the invention. It is understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also provided by the invention. For example, “0.2-5 mg/kg/day” is a disclosure of 0.2 mg/kg/day, 0.3 mg/kg/day, 0.4 mg/kg/day, 0.5 mg/kg/day, 0.6 mg/kg/day etc. up to 5.0 mg/kg/day. Terms Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art to which this invention belongs. As used herein, and unless stated otherwise or required otherwise by context, each of the following terms shall have the definition set forth below. As used herein, “about” in the context of a numerical value or range means±10% of the numerical value or range recited or claimed, unless the context requires a more limited range. As used herein, a subject “in need” of treatment for a disease, e.g. COPD, cancer, arthritis, skin damage, or atherosclerotic plaque rupture, means a subject who was been affirmatively diagnosed to have the disease. As used herein, a subject who is “naïve” for a drug used to treat a disease is a subject who has not been administered any drug for that disease. Therefore, a COPD-drug naïve subject has not been administered any drug for COPD, a cancer-drug naïve subject has not been administered any drug for cancer, an arthritis-drug naïve subject has not been administered any drug for arthritis, a skin damage-drug naïve subject has not been administered any drug for skin damage, and an atherosclerotic plaque rupture-drug naïve subject has not been administered any drug for atherosclerotic plaque rupture. As used herein, a “statin naïve subject” is a subject that has not been administered any statin. As used herein, an “SSRI naïve subject” is a subject that has not been administered any SSRI. As used herein, “effective” when referring to an amount of a compound or compounds refers to the quantity of the compound or compounds that is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention. The specific effective amount will vary with such factors as the physical condition of the patient, the type of subject being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compound or its derivatives. As used herein, “approved for use in human subjects” means approved for any medicinal use in human subjects at any time by any government agency of any country. In some embodiments, a compound that has been approved for use in human subjects was approved by the Food and Drug Administration (FDA) of the United States. For example, a statin that is approved for use in human subjects may in some embodiments be a statin that is approved for use in treating human subjects afflicted with high cholesterol or cardiovascular disease. Similarly, an SSRI that is approved for use in human subjects may in some embodiments be an SSRI that is approved for use in treating depression by the FDA. Non-limiting examples of commercially available statins include: Simvastatin, Lovastatin, Itavastatin, Fluvastatin, Mevastatin, Cerivastatin and Ezetimibe. Simvastatin is a statin that is commercially available from Merck Sharp & Dohme Corp. (Cramlington, Northumberland, UK NE23 3JU). The CAS Registry number for Simvastatin is 79902-63-9. Simvastatin is also known as Zocor, Synvinolin, and MK-733. Simvastatin is described in Neuvonen et al. (2008). Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin. Clinical Pharmacokinetics 47 (7): 463-74; U.S. Pat. No. 5,393,893, issued Feb. 28, 1995; and U.S. Pat. No. 6,384,238, issued May 7, 2002, the entire contents of each of which are hereby incorporated herein in their entireties. Lovastatin is a statin that is commercially available from Merck Sharp & Dohme Corp. (Cramlington, Northumberland, UK NE23 3JU) and Mylan Pharmaceuticals Inc. (Morgantown, W. Va. 26505). The CAS Registry number for Lovastatin is 75330-75-5. Lovastatin is also known as Monacolin K, Mevinolin, Altoprev, and Mevacor. Lovastatin is described in U.S. Pat. No. 4,231,938, issued Nov. 4, 1980 and U.S. Pat. No. 5,712,130, issued Jan. 27, 1998, the entire contents of each of which are hereby incorporated herein in their entireties. Itavastatin is a statin that is commercially available from Kowa Pharmaceuticals America, Inc. (Montgomery, Ala. 36117). The CAS Registry number for Itavastatin is 147526-32-7. Itavastatin is also known as Pitavastatin. Itavastatin is described in U.S. Pat. No. 8,829,186, issued Sep. 9, 2014, and Kajinami et al. (2003). Pitavastatin: efficacy and safety profiles of a novel synthetic HMG-CoA reductase inhibitor. Cardiovascular drug reviews 21 (3): 199-215, the entire contents of each of which are hereby incorporated herein in their entireties. Fluvastatin is a statin that is commercially available from Novartis Pharmaceuticals Corporation (East Hanover, New Jersey 07936). The CAS Registry number for Fluvastatin is 93957-54-1. Fluvastatin is also known as Lescol, Canef, and Vastin. Fluvastatin is described in Neuvonen et al. (2008). Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin. Clinical Pharmacokinetics 47 (7): 463-74 and U.S. Pat. No. 8,115,013, issued Feb. 14, 2012, the entire contents of each of which are hereby incorporated herein in their entireties. Mevastatin is a statin that is commercially available from Sigma-Aldrich Co. LLC (St Louis, Mo.). The CAS Registry number for Mevastatin is 73573-88-3. Mevastatin is also known as compactin and ML-236B. Mevastatin is described in Endo et al. (1976) ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinium. Journal of Antibiotics (Tokyo) 29 (12): 1346-8 and U.S. Pat. No. 7,582,464, issued Sep. 1, 2009, the entire contents of each of which are hereby incorporated herein in their entireties. Cerivastatin is a statin. Cerivastatin sodium salt hydrate is commercially as available from Sigma-Aldrich Co. LLC (St Louis, Mo.). The ChemSpider identification number for Cerivastatin is 393588. Cerivastatin is also known as Baycol and Lipobay. Cerivastatin is described in Furberg and Pitt (2001) Withdrawal of cerivastatin from the world market. Curr Control Trials Cardiovasc Med 2:205-207 and U.S. Pat. No. 8,586,527, issued Nov. 19, 2013, the entire contents of each of which are hereby incorporated herein in their entireties. Ezetimibe is a statin that is commercially available from Merck Sharp & Dohme Corp. (Cramlington, Northumberland, UK NE23 3JU). The CAS Registry number for Ezetimibe is 163222-33-1. Ezetimibe is also known as SCH-58235, Zetia, and Ezetrol. Ezetimibe is described in Phan et al. (2012) Ezetimibe therapy: mechanism of action and clinical update. Vasc Health Risk Manag 8: 415-27 and U.S. Patent Application Publication No. 2011/0262497, published Oct. 27, 2011, the entire contents of each of which are hereby incorporated herein in their entireties. Numerous other statins are known in the art. Additional non-limiting examples of statins are described in U.S. Pat. No. 5,393,893, issued Feb. 28, 1995; U.S. Pat. No. 6,384,238, issued May 7, 2002; U.S. Pat. No. 6,541,511, issued Apr. 1, 2003; U.S. Pat. No. 7,166,638, issued Jan. 23, 2007; U.S. Pat. No. 6,933,292, issued Aug. 23, 2005; and U.S. Patent Application Publication No. 2008/0318920, published Dec. 25, 2008, the entire contents of each of which are hereby incorporated herein by reference. Non-limiting examples of commercially available SSRIs include: Duloxetine, Nefazodone, Fluoxetine, and Sertraline. Duloxetine is an SSRI that is commercially available from Eli Lilly and Company (Indianapolis, Ind. 46285). The ChemSpider identification number for Duloxetine is 54822. Duloxetine is also known as Cymbalta. Duloxetine is described in Perahia et al. (2006) Duloxetine 60 mg once daily in the treatment of milder major depressive disorder. Int. J. Clin. Pract. 60 (5): 613-20 and U.S. Pat. No. 8,269,023, the entire contents of each of which are hereby incorporated herein in their entireties. Nefazodone is an SSRI that is commercially available from Bristol-Myers Squibb Company (Princeton, N.J. 08543). The CAS Registry number for Nefazodone is 83366-66-9. Nefazodone is also known as Dutonin, Nefadar, and Serzone (Nefazodone Hydrochloride). Nefazodone is described in Saper et al. (2001) Nefazodone for chronic daily headache prophylaxis: an open-label study. Headache 41 (5): 465-74, and U.S. Pat. No. 6,034,085, issued Mar. 7, 2000, the entire contents of each of which are hereby incorporated herein in their entireties. Fluoxetine is an SSRI that is commercially available from Eli Lilly and Company (Indianapolis, Ind. 46285). The CAS Registry number for Fluoxetine is 54910-89-3. Fluoxetine is also known as Lilly-110140, Sarafem, and Prozac (fluoxetine hydrochloride). Fluoxetine is described in Altamura et al. (1994). Clinical Pharmacokinetics of Fluoxetine. Clinical Pharmacokinetics 26 (3): 201-214 and U.S. Pat. No. 5,166,437, issued Nov. 24, 1992, the entire contents of each of which are hereby incorporated herein in their entireties. Sertraline is an SSRI that is commercially available from Pfizer (New York, N.Y. 10017). The CAS Registry number for Sertraline is 79617-96-2. Sertraline is also known as Zoloft (sertraline hydrochloride), and Lustral (sertraline hydrochloride). Sertraline is described in Obach et al., (2005) Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study. Drug Metab. Dispos. 33 (2): 262-70 and U.S. Pat. No. 7,186,863, issued Mar. 6, 2007, the entire contents of each of which are hereby incorporated herein in their entireties. Numerous other SSRIs are known in the art. Additional non-limiting examples of SSRIs are described in U.S. Pat. No. 7,186,863, issued Mar. 6, 2007; U.S. Pat. No. 7,217,696, issued May 15, 2007; U.S. Pat. No. 5,104,899, issued Apr. 14, 1992; and U.S. Pat. No. 8,524,950, issued Sep. 3, 2013, the entire contents of each of which are hereby incorporated herein by reference. Aspects of the present invention relate to compounds that inhibit the induction of MMP-1 expression by cigarette smoke or cigarette smoke extract (CSE). In some embodiments, compounds that block more than 80% and no more than 120% of cigarette or CSE induced MMP-1 expression are selected for use in treating subjects (inhibition greater than 120% would indicate baseline inhibition of MMP-1 expression unrelated to CSE). Therefore, aspects of the present invention relate to statins and SSRIs that reduce the induction of MMP-1 by cigarette smoke or CSE without reducing baseline MMP-1 expression more than 5, 10, 15, or 20%. In come embodiments, and depending on the assay used, the percentage inhibition of the CSE/MMP-1 induction may be calculated for compounds on a per-plate basis, using the equation: % inhibition of compound=100×[1−(test well−median high-signal control)/(median high−signal control−median low-signal control)]. It will be understood by persons skilled in the art that the percent inhibition of MMP-1 induced expression may be assayed using the methods described in the Examples herein. It will also be understood that assays other than the methods exemplified herein, or variations thereof, may be used to determine the percent inhibition of the induced expression of MMP-1. Non-limiting examples of other methods for assaying the induced expression of MMP-1 (and the inhibition thereof) include quantitative real-time PCR (qPCR), Western Blot analysis, Northern Blot, and array analysis (such as microarray analysis). Dosage Forms and Administration Ester derivatives of compounds used in the subject invention may be generated from a carboxylic acid group in accordance with the present invention using standard esterification reactions and methods readily available and known to those having ordinary skill in the art of chemical synthesis. Ester derivatives may serve as pro-drugs that can be converted into compounds by serum esterases. Compounds used in the methods of the present invention may be prepared by techniques well know in organic synthesis and familiar to a practitioner ordinarily skilled in the art. However, these may not be the only means by which to synthesize or obtain the desired compounds. Compounds used in the methods of the present invention may be prepared by techniques described in Vogel's Textbook of Practical Organic Chemistry, A. I. Vogel, A. R. Tatchell, B. S. Furnis, A. J. Hannaford, P.W.G. Smith, (Prentice Hall) 5th Edition (1996), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, (Wiley-Interscience) 5th Edition (2007), and references therein, which are incorporated by reference herein. However, these may not be the only means by which to synthesize or obtain the desired compounds. In some embodiments, a compound may be in a salt form. As used herein, a “salt” is a salt of the instant compound which has been modified by making acid or base salts of the compounds. In the case of the use of compounds for treatment of a disease, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines. The term “pharmaceutically acceptable salt” in this respect, refers to the relatively non-toxic, inorganic and organic base addition salts of compounds. These salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting a purified compound in its free acid form with a suitable organic or inorganic base, and isolating the salt thus formed. The compounds used in some embodiments of the present invention can be administered in a pharmaceutically acceptable carrier. As used herein, a “pharmaceutically acceptable carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the compounds to the subject. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also a pharmaceutically acceptable carrier. The compounds used in the methods of the present invention can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, rectal, topical, intravenous or direct injection or parenteral administration. The compounds can be administered alone or mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. The active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorants and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen. “Administering” compounds in embodiments of the invention can be effected or performed using any of the various methods and delivery systems known to those skilled in the art. The administering can be, for example, intranasal, intravenous, oral, intramuscular, intravascular, intra-arterial, intracoronary, intramyocardial, intraperitoneal, and subcutaneous. Aspects of the present invention relate to the nasal or oral inhalation of a compound using an inhaler. Other non-limiting examples include topical administration, or coating of a device to be placed within the subject. In some embodiments, administration is effected by injection or via a catheter. Aspects of the present invention relate to the administration of a compound using an inhaler. In some embodiments, an amount of a compound-containing aerosol or powder is discharged into the nose or mouth of a subject using an inhaler. Non-limiting examples of inhalers are described in U.S. Pat. No. 7,900,625, issued Mar. 8, 2011; U.S. Pat. No. 5,891,419, issued Apr. 6, 1999; U.S. Pat. No. 3,456,644, issued Jul. 22, 1969; U.S. Pat. No. 6,684,879, issued Feb. 3, 2004; U.S. Pat. No. 7,448,385, issued Nov. 11, 2008; U.S. Pat. No. 8,555,878, issued Oct. 15, 2013; U.S. Pat. No. 7,073,499, issued Jul. 11, 2006; and PCT International Patent Application Publication No. 2014/137215, published Sep. 12, 2014. Injectable drug delivery systems may be employed in the methods described herein include solutions, suspensions, and gels. Oral delivery systems include tablets and capsules. These can contain excipients such as binders (e.g., hydroxypropylmethylcellulose, polyvinyl pyrilodone, other cellulosic materials and starch), diluents (e.g., lactose and other sugars, starch, dicalcium phosphate and cellulosic materials), disintegrating agents (e.g., starch polymers and cellulosic materials) and lubricating agents (e.g., stearates and talc). Solutions, suspensions and powders for reconstitutable delivery systems include vehicles such as suspending agents (e.g., gums, zanthans, cellulosics and sugars), humectants (e.g., sorbitol), solubilizers (e.g., ethanol, water, PEG and propylene glycol), surfactants (e.g., sodium lauryl sulfate, Spans, Tweens, and cetyl pyridine), preservatives and antioxidants (e.g., parabens, vitamins E and C, and ascorbic acid), anti-caking agents, coating agents, and chelating agents (e.g., EDTA). General techniques and compositions for making dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol. 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). These references in their entireties are hereby incorporated by reference into this application. The dosage of a compound administered in treatment will vary depending upon factors such as the pharmacodynamic characteristics of the compound and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect. A dosage unit of a compound may comprise a compound alone, or mixtures of a compound with additional compounds used to treat a disease, e.g. COPD. The compounds can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by injection or other methods, into the eye, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. A compound can be administered in a mixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, rectal, topical, intravenous or direct injection or parenteral administration. The compounds can be administered alone but are generally mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. In one embodiment the carrier can be a monoclonal antibody. The active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorants and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen. Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. A compound may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. The compounds may be administered as components of tissue-targeted emulsions. A compound may also be coupled to soluble polymers as targetable drug carriers or as a prodrug. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, a compound may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels. Gelatin capsules may contain a compound and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. For oral administration in liquid dosage form, a compound may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. A compound may also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen. The compounds and compositions thereof can be coated onto stents for temporary or permanent implantation into the cardiovascular system of a subject. All publications and other references mentioned herein are incorporated by reference in their entirety, as if each individual publication or reference were specifically and individually indicated to be incorporated by reference. Publications and references cited herein are not admitted to be prior art. This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as defined in the claims which follow thereafter. EXPERIMENTAL DETAILS Examples are provided below to facilitate a more complete understanding of the invention. The following examples illustrate the exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only. Example 1. Translational Approach to the Treatment of COPD Exposure to tobacco smoke is a major risk factor for chronic obstructive pulmonary disease (COPD) with the ultimate tissue destruction in emphysema resulting from an imbalance in protease/antiprotease activity. The D'Armiento laboratory has demonstrated that lung parenchymal cells in patients with emphysema express MMP-1 as opposed to smokers without the disease and through in vitro and in vivo studies we demonstrated that cigarette smoke can directly induce MMP production in epithelial cells in a MAP Kinase dependent fashion. Subsequent studies identified a novel cigarette smoke responsive (CSR) element within the promoter region of MMP-1. The upstream signaling pathway regulating MMP-1 induction by cigarette smoke was further delineated and TLR4 was identified as an important regulator of the induction of MMP-1. After the identification of the CSE in MMP-1 we used this knowledge to develop a novel mammalian cell-based assay to screen for inhibitors to the smoke induced MMP-1 pathway by transfecting a human cell line (HEK 293T) with a vector containing a luciferase reporter gene under the control of the MMP-1 promoter. Using this novel cell based system we screened an NIH library of compounds and identify novel compounds that exhibited strong activity in our assay. This screening has led to several candidate molecules we are pursuing for the treatment of emphysema. Studies are conducted to elucidate the role of these compounds in treating emphysema. Example 2. Inhibitors of Cigarette Smoke Induced MMP-1 Production (SSRI) Preliminary Studies The aim of this study is to develop molecules that can modulate both the transcriptional induction of MMPs and the inflammatory cascade induced by cigarette smoke. As a preliminary essential step in this proposed study, a mammalian cell-based assay was developed based on transfection of a human cell line (HEK 293T) with a vector containing a luciferase reporter gene under the control of the MMP-1 promoter. This method is based on the fact that the MMP-1 promoter contains a specific cigarette smoke responsive element (CRE) (Golovatch et al., 2009). Utilizing the MMP-1 promoter, an MMP-1/pGL3 luciferase reporter vector was prepared and transfected into cells. The assay was developed by treating transfected cells with cigarette smoke, tested for reproducibility and inhibition with MAPKinase inhibitors that were known to block smoke induced MMP-1 expression (FIGS. 2A and 2B) (Mercer et al., 2004). The assay was shown to be stable over several days in separate batches. The cigarette smoke induction is MAPKinase dependent therefore the dose dependency of the assay was demonstrated using a MAPKinase inhibitor. Pilot Screen of Small Molecules from the NIH Clinical Collection and their Validation Utilizing the developed assay above, the effect of a collection of 727 structurally diverse small molecules obtained from the NIH clinical collection was tested. The compounds in this clinical set have all been tested and utilized in humans for various indications. These molecules, dissolved in DMSO, were all tested at the concentration of 10 μM for their capacity to modulate MMP-1 smoke induced transcriptional activation. The percentage inhibition of the CSE/MMP-1 induction was calculated for each tested compound on a per-plate basis, using the equation: % inhibition of compound=100×[1−(test well−median high-signal control)/(median high-signal control−median low-signal control)]. Compounds that block more than 80% and no more than 120% of CSE induced MMP-1 expression are considered as initial hit compounds (Inhibition greater than 120% would indicate baseline inhibition of MMP-1 expression unrelated to CSE). As shown in FIG. 3, fifteen of the tested returned Luciferase activity to baseline. As expected, none of the compounds exhibited cytotoxic activity, as assayed by the CellTiter-Glo (Promega Corp.; data not shown). At this point 10 promising compounds were selected, and classified in two major categories as follows: A. Statins (Simvastatin, Lovastatin, Fluvastatin, Mevastatin, Cerivastatin, Ezetimibe), B. Selective Sertonin Reuptake Inhibitors (Duloxetine, Nefazodone, Fluoxetine, sertraline,) A purpose of these studies was to identify compounds that not only block transcription of MMP-1 but other MMPs and cytokines important in the pathogenesis of COPD (Decramer et al., 2012). Therefore, after completion of the above studies involving the primary screening campaign the activity and potency of validated hits was confirmed in secondary assays to assess their effect on the up regulation of IL-8 (CXCL8) in small airway epithelial cells (SAECs) treated with CSE (FIG. 4). IL-8 is a major chemokine increased in the sputum of COPD patients and correlates with the number of neutrophils present in the lung (Barnes et al., 2004). The neutrophil is a major inflammatory cell present as a result of smoke exposure (Stockley et al., 2009) and is thought to be recruited through the induction of IL-8 by cigarette smoke (Moon et al., 2013). Therefore, identifying mechanisms to block production of IL-8 will prevent the influx of neutrophils and limit inflammation secondary to cigarette smoke. These assays, based on established protocols for treatment of SAECs (Lonza, Walkersville, Md.) with cigarette smoke extract (Mercer et al., 2004), were performed in the same format optimized for the initial screen. The In Vivo Effect of these Compounds on an Animal Model of COPD After confirming the in vitro activity of the compounds within the two catagories described above, rabbits were then treated under smoke exposure conditions with Duloxetine and examined the effect on MMP-1 expression. Rabbits were stratified into one of four groups (Unexposed, treated with vehicle, Smoke exposed, treated with vehicle, Unexposed, treated with Duloxetine and smoke exposed treated with Duloxetine. Animals are maintained on room air or smoke exposed for 16 weeks and then sacrificed. Lung lavage is taken, lungs are fixed and sectioned and protein homogenate from lungs frozen. The lung lavage from the rabbits indicates that there in an increase in MMP-1 protein expression in rabbits exposed to cigarette smoke and the addition of Duloxetine blocked the increase in MMP-1 protein suggesting that the compound blocked the induction of MMP-1 caused by cigarette smoke (FIG. 5). Histological analysis of the lungs demonstrated that rabbits exposed to smoke developed emphysema and when treated with duloxetine emphysema was attenuated (FIGS. 7A, 7B). Conclusion These results indicate that the cells treated with SSRI (duloxetine) exposed to cigarette smoke inhibited MMP-1 expression. These data also demonstrate that the compound can modulate the expression of cigarette smoke induced MMP-1 expression and protect from the development of emphysema. Example 3 An experiment was performed to determine if Fluoxetine (an SSRI) could block transcription of MMP1 and cell signaling in cigarette smoke exposed SAE cells. Additionally, studies were undertaken to ensure that Fluoxetine was absorbed into the lung when delivered by gavage and inhalation. In the first experiment, SAE cells were treated with 5% CSE, 10 nM Fluoxitine, 10 uM Fluoxitine, and combinations of 5% CSE and Fluoxitine (FIG. 8). CSE induces MMP1 expression and when treated with Fluoxetine and CSE MMP-1 induction was attenuated (p<0.05). Data is presented as mean+standard error. SAE cells treated with 5% CSE and 10 uM fluoxetine (Fluo) were shown to exhibit down regulation of TLR-4 receptor expression (FIG. 9A). Further, Western blot analysis of the treated cells demonstrates that the phosphorylation of IRAK (downstream target of TLR-4 signaling pathway) was suppressed by Fluoxetine (FIG. 9B). Next, cells treated with CSE were compared to cells treated with CSE combined with fluoxetine using a protein array analysis (FIG. 10). Three transcription factors were found to increase with CSE treatment and when pretreated with Fluoxetine these factors return to baseline. PRAS40, BAD and GSK-3b are increased with cigarette smoke treatment and return to baseline upon Fluoxetine treatment. Studies were also undertaken to quantify fluoxetine in lung samples. FIGS. 11A and 11B demonstrate the standard chromatographic characteristics of Fluoxetine and FIGS. 12A and 12B demonstrate the standard chromatographic characteristics of a control (no drug administration) and PBS, respectively. In order to determine whether fluoxetine is absorbed in the lung, fluoxetine was delivered either through oral gavage or inhaled. Animals were given PBS, 10 mg/kg oral, gavage of fluoxetine (FIGS. 13A and 13B), and 10 mg/kg of inhaled Fluoxetine (FIGS. 14A and 14B). Mice were sacrificed, lungs lyophilized and protein homogenate prepared for chromatographic analysis. Both oral and inhaled delivery of Fluoxetine resulted in the detection of Fluoxetine in the lung of mice. Inhalation resulted in higher levels of Fluoxetine within the lung. Oral gavage of fluoxetine yielded two compounds showing chromatographic peaks at similar retention times and absorbance spectra that suggested the occurrence of a metabolite of fluoxetine, an isomer or enantiomer of the compound (FIGS. 13A and 13B). Oral gavage of fluoxetine yielded lower quantifiable concentrations than nebulized administration of the drug. Following drug inhalation, three compounds could be identified in lung samples, where two of the compounds had almost identical absorbance spectra; the third compound retained a more polar characteristic eluting at 14.7 mins (FIGS. 14A and 14B). Detailed quantification results for fluoxetine inhaled or orally administered are found in the tables below. TABLE 1 Administration of Fluoxetine through Oral Gavage Retention Time Area mM mg/ml ng/ml Replicate 1 17.08010655 12906.1476 0.003711878 0.001283493 1283.493254 16.6131189 27449.95881 0.005789566 0.002001916 2001.915974 Replicate 2 17.08063126 12631.40873 0.00367263 0.001269922 1269.921939 16.61380581 32793.07907 0.006552868 0.002265851 2265.850849 Replicate 3 17.08660679 14782.81571 0.003979974 0.001376195 1376.195297 16.61993572 33850.94473 0.006703992 0.002318106 2318.10639 Average (17.08) 0.003788161 0.00130987 1309.870163 SD (17.08) 0.00016727 5.78387E−05 57.83867771 Average (16.6) 0.006348809 0.002195291 2195.291071 SD (16.6) 0.000490178 0.000169494 169.4936767 TABLE 2 Administration of Fluoxetine Through Inhalation Injection # Retention Time Area mM mg/ml ng/ml Replicate 1 3 17.0888794 172094.4234 0.02645306 0.009146939 9146.939256 2 16.62415789 148723.6065 0.023114372 0.007992488 7992.487673 1 14.67573133 103467.6833 0.01664924 0.005756974 5756.974369 Replicate 2 1 14.67975811 94922.53266 0.015428505 0.005334868 5334.868343 2 16.63809468 146811.073 0.022841153 0.007898014 7898.013983 3 17.10260277 167626.8324 0.025814833 0.008926253 8926.253025 Replicate 2 3 17.10524028 170318.3142 0.026199331 0.009059205 9059.204534 2 16.64006528 151315.2219 0.023484603 0.008120506 8120.506072 1 14.67979678 104234.9551 0.016758851 0.005794875 5794.875404 Average (17.08) 0.026155741 0.009044132 9044.132272 SD (17.08) 0.000321339 0.000111112 111.1124791 Average (16.6) 0.02314671 0.008003669 8003.669243 SD (16.6) 0.000322941 0.000111667 111.6667051 Average (14.6) 0.016278865 0.005628906 5628.906039 SD (16.6) 0.00073847 0.000255348 255.3482855 Results The experiments demonstrated that MMP1 induction by cigarette smoke in SAEC cells could be attenuated by treatment with Fluoxetine (FIG. 8). These studies demonstrate that Fluoxetine behaves in a similar fashion as duloxetine in vitro. The ability of Fluoxetine to act on the TLR4 signaling pathway was then examined. FIGS. 9A and 9B demonstrate that while CSE increases TLR4 signaling this pathway is attenuated when cells are treated with Fluoxetine. Finally, studies were carried out in vivo to determine if Fluoxetine delivered both orally and through inhalation was present within the lung of mice. As seen in FIGS. 11A-14B Fluoxetine was present within the lung under both delivery methods with inhalation revealing higher levels. In conclusion these results indicate that cells treated with SSRI (Fluoxetine) exposed to cigarette smoke inhibited MMP-1 expression. Furthermore, Fluoxetine is absorbed in the lung when delivered through gavage or inhaled. Discussion Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States (Podowski et al. (2012); Mannino et al. (2007)) with tobacco smoke the key etiologic agent of this disease process; the inflammatory response to inhaled cigarette smoke and other noxious particles (Global Initiative for Chronic Obstructive Lung Disease, 2011; Global Initiative for chronic obstructive Lung Disease., 2007) is thought to be a primary initiator of the disease. COPD is characterized by progressive airflow limitation that is not fully reversible. A spectrum of pathological findings are observed in COPD ranging from inflammation of the larger airways (termed chronic bronchitis), remodeling of the small airways, and parenchymal tissue destruction with airspace enlargement (defined as emphysema) (Global Initiative for Chronic Obstructive Lung Disease, 2011; Global Initiative for chronic obstructive Lung disease., 2007). In addition, COPD contributes to systemic manifestations affecting skeletal muscles, bone and the cardiovascular system (Yoshida and Tuder (2007); Celli et al. (2006)). Despite the heterogeneity of COPD, the small airway walls in the emphysematous lung consistently demonstrate persistent inflammation with mononuclear phagocytes that play a major role in the inflammatory response (Shan et al. (2009); Shaykhiev et al. (2009)). Chronic obstructive pulmonary disease (COPD) is a progressively worsening lung disease that is characterized by disrupted airflow (Decramer et al. (2012)). Currently, approximately a third of a billion people suffer from COPD. COPD is one of the top 10 leading causes of death, according to the WHO (World Health Organization (2013)). COPD is most often caused by cigarette smoke (Decramer et al. (2012)). Constant exposure to cigarette smoke eventually causes COPD to develop into emphysema (Rabe et al. (2007)). Matrix metalloproteinase-1 (MMP-1) play an important role in the development of COPD (D'Armiento et al. 1992). MMP-1 contains a cigarette smoke response element in its promoter, indicating that cigarette smoke promotes COPD and emphysema via MMP-1 expression (Mercer et al. (2009)). This Technology Using a luciferase based reporter assay to look for compounds that bind to the MMP-1 promoter region, two classes of drugs were found to inhibit MMP-1. Selective serotonin reuptake inhibitors (SSRIs) and statins were both capable of inhibiting MMP-1 at low concentrations. In vitro data showed that MMP-1 expression decreased with one of the compounds (Duloxetine). Discussion Cigarette smoke intake results in a number of comorbidities, including chronic obstructive pulmonary disease (COPD)/emphysema, a debilitating lung disease that afflicts millions of smokers. A family of proteins known as matrix metalloproteinases, or MMPs, regulates the progression of COPD/emphysema. Without wishing to be bound by any scientific theory, since cigarette smoke can directly bind to the promoter region of MMP-1, one of the proteins in the MMP family, and induce expression, a therapeutic strategy is to inhibit MMP-1 transcription to potentially delay or halt the development of COPD/emphysema in smokers. Using an in vitro screening assay that targets the response element, this technology has identified two drug classes that decrease MMP-1 transcription. The classes, SSRIs and statins, inhibited MMP-1 mRNA at low concentrations, making them ideal therapeutic candidates. Identification of these small molecules may potentially provide a viable means of treating COPD, as well as other highly prevalent pathologies that respond to these molecules, such as arthritis and atherosclerosis. COPD/emphysema is a highly prevalent disease. While it is clearly established that cigarette smoke is the principal cause of COPD, the mechanism by which cigarette smoke exposure leads to destruction of the lung architecture as seen in emphysema is unknown. The D'Armiento laboratory was the first to demonstrate a direct role for MMPs in emphysema causation through the generation of several transgenic mouse lines that express human MMP-1 in lung epithelial cells. Recent studies in the D'Armiento laboratory have shown that cigarette smoke can induce expression of MMP-1 in resident lung cells in emphysema and have identified a cigarette smoke responsive element in the MMP-1 promoter region. In order to identify molecules that can modulate the transcriptional activity of MMP-1 induced by cigarette smoke, a mammalian cell line-based transfection assay in a 96-well format was developed that can easily be implemented for HTS. The method is based on transfection of a human cell line (HEK 293T) with a vector containing a luciferase reporter gene, which is under the control of the MMP-1 promoter. Then, the effect of a small collection of 727 structurally diverse small molecules was tested on the MMP-1 transcriptional activity. The molecules were obtained from NIH clinical collection. Through this pilot screening, two classes of drugs that can prevent the expression of MMP-1 induced by cigarette smoke were identified. The one is selective serotonin reuptake inhibitors (SSRIs) and the other is Statins. Both drugs could inhibit the MMP-1 expression less than 10 nM concentrations. In addition, one of the compounds, Duloxetine ((+)-(S)—N-Methyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl) propan-1-amine; Cymbalta®) was studied and it could block the MMP-1 expression at the concentration of 10 nM in cell culture system as well as rabbit cigarette smoke model by ELISA of lung homogenate (20 weeks of cigarette smoke and giving the compound in the last four weeks). Apart from its role in emphysema formation described above, MMP-1 has been implicated in several pathological processes, including tumor invasion, arthritis, skin repair and atherosclerotic plaque rupture. Therefore, the small molecules identified in this study will have wide applicability for the treatment of various diseases. The present invention provides compounds and methods for preventing the destruction of lung in emphysema. Additionally, compounds of the invention may be used prophylactically, to prevent the development of COPD/emphysema. Because MMP-1 is involved in arthritis, the compounds can also be used to treat arthritis. MMP-1 is also implicated in atherosclerosis, and therefore the compounds can also be used to treat arthritis. Emphysema is a debilitating lung condition that affects millions of smokers. Cigarette smoke may cause emphysema by directly activating MMP-1 expression, a matrix metalloproteinase protein involved in promoting the disease. This technology has identified two classes of drugs that inhibit MMP-1 expression. With the discovery of these inhibitors, the technology may prevent millions of smokers from developing emphysema. The present invention is unique since it relates to the identification of compounds directly targeting the pathogenic processes responsible for lung destruction in COPD and not simply treating the symptoms of disease. Initial studies have identified compounds that block smoke induced protease production and inflammation. Therefore, the use of such compounds will be exclusive in the field of COPD with the ability to actually target two processes known to be important in actively degrading and damaging the lung secondary to cigarette smoke (Barnes, 2003). These compounds would therefore benefit not only severely affected COPD patients but potentially target all patients with COPD to stabilize disease and protect the lung from further destruction. REFERENCES Barnes P J. Mediators of chronic obstructive pulmonary disease. Pharmacol Rev. 2004; 56(4):515-48. Barnes P. New concepts in chronic obstructive pulmonary disease. Annu Rev Med. 2003; 54, 113-29. Centers for Disease C, and Prevention. Current cigarette smoking among adults—United States, 2011. MMWR Morb Mortal Wkly Rep. 2012; 61(44):889-94 (“CDC, 2012”) Celli B R. Roger s. Mitchell lecture. Chronic obstructive pulmonary disease phenotypes and their clinical relevance. Proc Am Thorac Soc. 2006; 3(6):461-5. Chronic Obstructive Pulmonary Disease (COPD) Fact Sheet. (2014) www.lung.org/lung-disease/copd/resources/facts-figures/COPD-Fact-Sheet.html. Accessed Dec. 3, 2014 Chronic Obstructive Pulmonary Disease (COPD) Market to 2019. (2013) www.gbiresearch.com/report-store/market-reports/therapy-analysis/chronic-obstructive-pulmonary-disease-(copd)-market-to-2019-highly-priced-new-combination-products-forecast-to-capture-signif. Accessed Dec. 3, 2014 D'Armiento J, Dalal S S, Okada Y, Berg R A, Chada K. (1992). Collagenase expression in the lungs of transgenic mice causes pulmonary emphysema. Cell. 71:955-961. Decramer M, Janssens W, Miravitlles M. (2012) Chronic obstructive pulmonary disease. The Lancet 379:1341-1351. Fabbri L M, Beghe B, Yasothan U, and Kirkpatrick P. Roflumilast. Nature reviews Drug discovery. 2010; 9(10):761-2. From the Centers for Disease Control and Prevention. Prevalence of current cigarette smoking among adults and changes in prevalence of current and some day smoking—United States, 1996-2001. JAMA. 2003; 289(18):2355-6 (“CDC 2003”) Global Initiative for Chronic Obstructive Lung Disease (GOLD); 2013. Global Initiative for Chronic Obstructive Lung Disease, 2011. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Global Initiative for chronic obstructive Lung disease., 2007. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Golovatch P, Mercer B A, Lemaitre V, Wallace A, Foronjy R F, and D'Armiento J. Role for cathepsin K in emphysema in smoke-exposed guinea pigs. Exp Lung Res. 2009; 35(8):631-45. Hanania N A, and Marciniuk D D. A unified front against COPD: clinical practice guidelines from the American College of Physicians, the American College of Chest Physicians, the American Thoracic Society, and the European Respiratory Society. 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Proc Am Thorac Soc. 2009; 6(6):524-6. World Health Organization. (2013, July) The Top 10 Causes of Death. Retrieved from who.int/mediacentre/factsheets/fs310/en/. Yoshida T, Tuder R M. Pathobiology of cigarette smoke-induced chronic obstructive pulmonary disease. Physiol Rev. 2007; 87(3):1047-82.
<SOH> BACKGROUND OF INVENTION <EOH>Chronic obstructive pulmonary disease (COPD) is an enormous unmet medical need. Present therapies offer relief from its symptoms, but no drug treats the cause or slows progression of the disease. The most common cause of COPD is cigarette smoking, a behavior whose prevalence in the U.S. has remained fairly constant but continues to rise worldwide. In the U.S. alone, each year this disease results in more than 100,000 deaths, is responsible for over 600,000 hospitalizations and over 15 million physician office visits, causing approximately 150 million days of disability (CDC 2003). It is estimated that about 600 million adults have COPD, of which 24 million live in the U.S. (CDC, 2003). In 2010 the annual cost for COPD was $20.4 billion in direct health care expenditures, and $29.5 billion in indirect costs (COPD Fact Sheet, 2014). As of 2008 COPD became the third leading cause of death (Minino et al., 2011) and analysts estimate the worldwide market for COPD therapy at $15.6 billion in 2019 (GOLD, 2013). Spiriva® (tiotropium, Boehringer Ingelheim/Pfizer) was launched outside the U.S. in 2002 and is marketed exclusively for COPD. Its European sales are over 2.4 billion euros and US sales topping 1 billion (COPD Market to 2019, 2013). Recently, Roflumilast, a phosphodiesterase type 4 (PDE-4) inhibitor was approved as a new therapeutic for COPD exacerbations with sales progressively growing since release (Fabbri et al., 2010). The massive health cost burden of COPD is due to a combination of an increased incidence and sub-optimal treatment strategies. In the past, the desire to develop new pharmaceuticals has met with resistance because targets have been difficult to select and test and, furthermore, the disease has been treated as “self-inflicted” by the public and has not therefore received the attention warranted by its human and economic costs. The industry has recently witnessed high-profile attitude changes, and therefore, today the present barrier to the creation of effective drugs for COPD is the development of agents that act upon validated drug targets in this disease (COPD Market to 2019, 2013). More than 43.8 million, or 19%, of adults in the U.S were smokers in 2011 (CDC, 2011). While the prevalence of current smoking during 2005-2011 has been slightly declining overall (CDC, 2012), the worldwide prevalence of smoking continues to rise. Smokers are ten times more likely than non-smokers to die of COPD. Smoking cessation is the only intervention of proven value in early-stage COPD, however, even with cessation, the destructive process initiated by cigarette smoking continues (COPD Fact Sheet, 2014) emphasizing the need for therapies targeted towards smoke induced inflammation and lung destruction. Present interventions used for COPD serve to ameliorate the symptoms of the disease but do not address its overall course. The physiologic hallmark of COPD is fixed airway obstruction with a progressive decline in the forced expiratory volume in one second (FEV1). Bronchodilators, including anticholinergics (e.g., Atrovent®, Spiriva®) and β-adrenergic agonists (e.g., albuterol, Opened®), relax airway smooth muscle and appear to decrease dyspnea, increase FEV1, and decrease the frequency of reported exacerbations in certain populations (Hanania and Marciniuk, 2011). The effect of bronchodilators is short-lived, however, and these agents do not slow the progression of the disease as measured by a long-term decline in FEV1 (Hanania and Marciniuk, 2011). The regular use of inhaled corticosteroids (e.g., Flovent®) reduces symptoms, frequency of exacerbations, and numbers of outpatient physician visits in patients with moderate or severe COPD, but does not affect the rate of decline in post-bronchodilator FEV1 (Hanania and Marciniuk, 2011). However, chronic use of systemic corticosteroids does not improve the course of COPD, and may increase mortality (Hanania and Marciniuk, 2011). New methods and compositions for treating COPD are needed.
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides a method of prophylaxis for, or for treating, chronic obstructive pulmonary disease (COPD), cancer, arthritis, skin damage, or atherosclerotic plaque rupture in a subject in need thereof, which comprises administering to the subject i) a statin or ii) a selective serotonin reuptake inhibitor (SSRI) in an amount that is effective to treat the COPD, cancer, arthritis, skin damage, or atherosclerotic plaque rupture. The present invention also provides a composition for use in prophylaxis for, or in treating, chronic obstructive pulmonary disease (COPD), cancer, arthritis, skin damage, or atherosclerotic plaque rupture in a subject in need thereof which comprises i) a statin or ii) a selective serotonin reuptake inhibitor (SSRI). Aspects of the present invention relate to the use of i) a statin or ii) a selective serotonin reuptake inhibitor (SSRI) for the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease (COPD), cancer, arthritis, skin damage, or atherosclerotic plaque rupture in a subject in need thereof. The present invention further provides an inhaler containing a statin or an SSRI.
A61K31366
20170811
20180201
66987.0
A61K31366
0
THOMAS, TIMOTHY P
INHIBITORS OF INDUCED MMP-1 PRODUCTION
SMALL
1
CONT-REJECTED
A61K
2,017
15,675,368
ACCEPTED
SHELVING SYSTEM
A shelving system includes a plurality of horizontal support members, each horizontal support member having a length; a plurality of wall supports, each wall support including a first surface on which at least a portion of a horizontal support member rests; a plurality of brackets, each bracket attachable to the horizontal support members at different positions along the length of the horizontal support member; a plurality of vertical support members, each vertical support member coupled to at least one bracket; and a shelf attached to at least two of the plurality of vertical support members.
1. A shelving system comprising: a support assembly comprising first and second support posts, each support post having a pair of mounting surfaces that face away from each other and a first abutment surface that is orthogonal to and between the mounting surfaces, and a plurality of support pins fixed to each of the first and second support posts along a height of each post and extending away from at least one of the mounting surfaces on each support post; and a pair of bracket assemblies, each bracket assembly associated with one of the first and second support posts and comprising a first member comprising a pair of spaced-apart parallel planar surfaces each configured to be positioned adjacent one of the mounting surfaces of the associated support post, wherein each of the pair of planar surfaces includes apertures configured for releasable engagement with selected ones of the plurality of support pins on the associated support post, each aperture formed as a slot with an open end, and a second abutment surface orthogonal to and extending between the pair of spaced-apart parallel planar surfaces, wherein the second abutment surface is configured to be in contact with and extend across the first abutment surface of the support post when the shelving system is assembled, and at least one second member associated with the first member, the second member being separable from the associated first member, the at least one second member comprising a first portion for removably coupling to the associated support post and a second portion configured for supporting a shelf, wherein the second member prevents movement of the shelf in a direction orthogonal to a plane coincident with the first abutment surface of the associated support post when the shelving system is assembled. 2. The shelving system of claim 1, wherein the at least one second member comprises two second members, wherein when the shelving system is assembled one of the two second members is positioned proximate to a first of the mounting surfaces and the other of the two second members is positioned proximate to a second of the mounting surfaces. 3. The shelving system of claim 2, wherein when the shelving system is assembled the shelving system comprises two adjacent shelves supported at the same height on the associated support post by one of the pair of the bracket assemblies, and each of the two second members is positioned to support a different adjacent shelf 4. The shelving system of claim 1, wherein when the shelving system is assembled the first member of each of the pair of bracket assemblies is configured to couple the associated support post to a support surface. 5. The shelving system of claim 1, wherein the first portion and the second portion of the at least one second member is formed from a single piece of material. 6. The shelving system of claim 1, wherein when the shelving system is assembled the shelf is fixed to the second portion of the at least one second member. 7. The shelving system of claim 1, wherein when the shelving system is assembled a top side of the at least one second member does not extend above a top side of the associated first member. 8. The shelving system of claim 1, wherein when the shelving system is assembled a top side of the shelf does not extend above a top side of the first member. 9. The shelving system of claim 1, wherein when the shelving system is assembled the at least one second member is configured to support a bottom side of the shelf above at least one of the apertures engaged with one of the plurality of support pins. 10. The shelving system of claim 1, wherein the first portion of the at least one second member includes apertures, each aperture formed as a slot with an open end and configured for releasable engagement with selected ones of the plurality of support pins on the associated support post. 11. A shelving system comprising: a support assembly, wherein the support assembly has a plurality of support pins fixed to the support assembly along a height of the support assembly; and a support bracket assembly configured to be coupled to the support assembly, the support bracket assembly comprising a pair of first support brackets, each first support bracket comprising a pair of spaced-apart parallel planar surfaces and a third surface orthogonal to and between the spaced-apart pair of planar surfaces, each of the parallel planar surfaces including apertures configured for releasable engagement with selected ones of the plurality of support pins, each aperture formed as a slot with an open end, and at least one second support bracket associated with each of the first support brackets, wherein the at least one second support bracket is separable from the associated first support bracket, the at least one second support bracket comprising a first portion configured for removably coupling to the support assembly and a second portion configured for supporting a shelf, and wherein the second portion is configured to prevent movement of the shelf in a direction orthogonal to a plane coincident with the third surface of the associated first support bracket when the shelving system is assembled, and wherein when the shelving system is assembled the second portion is configured to support a bottom of the shelf above at least one of the selected ones of the plurality of support pins. 12. The shelving system of claim 11, wherein the support assembly comprises a pair of support posts and the plurality of support pins are fixed to and extend along a height of each of the support posts. 13. The shelving system of claim 11, wherein when the shelving system is assembled the shelf is fixed to the second portion of the at least one second support bracket of the pair of first support brackets. 14. The shelving system of claim 11, wherein when the shelving system is assembled a top side of each of the at least one second support bracket does not extend above a top side of each of the first support brackets. 15. The shelving system of claim 11, wherein when the shelving system is assembled a top side of the shelf does not extend above a top side of each of the first support brackets. 16. The shelving system of claim 11, wherein the support assembly comprises a pair of support posts, each post of the pair of support posts having a pair of mounting surfaces that face away from each other and an abutment surface orthogonal to and between the mounting surfaces, wherein when the shelving system is assembled each of the spaced- apart parallel planar surfaces of each first support bracket is configured to be positioned adjacent one of the mounting surfaces of an associated support post, and wherein when the shelving system is assembled the third surface of each of the first support brackets is configured to be in contact with and extend across the abutment surface of the associated support post. 17. The shelving system of claim 16, wherein the pair of first support brackets is configured to couple the pair of support posts to a support surface. 18. The shelving system of claim 11, wherein the first portion of the at least one second support bracket includes apertures, each aperture formed as a slot with an open end and configured for releasable engagement with selected ones of the plurality of support pins. 19. A support bracket assembly for a shelving system positionable on a support surface and having a support post with a mounting portion including a first mounting surface and a second mounting surface facing away from the first mounting surface, a third surface between and orthogonal to the first and second mounting surfaces, a plurality of support pins fixed to the support post and extending outward from each of the first and second mounting surfaces, and a shelf configured for coupling to the support post, the support bracket assembly comprising: a first portion including a first planar portion configured for attachment to the first mounting surface and a second planar portion configured for attachment to the second mounting surface when the shelving system is assembled, wherein each of the first and second planar portions includes at least one aperture to releasably engage selected support pins, each aperture formed as a slot with an open end; a second portion coupled to the first portion; and a third portion configured to support a portion of the shelf and extending from the second portion, wherein when the shelving system is assembled the third portion is configured to support a bottom side of the shelf above at least one of the apertures of the first and second planar portions engaged with the selected support pins, wherein when the shelving system is assembled the third portion is configured to prevent the shelf from moving in a direction orthogonal to a plane coincident with the third support post surface, and wherein the first planar portion and the second planar portion are configured to cooperate to transmit a loading force from the shelf to the support surface through the support post when the shelving system is assembled. 20. The support bracket assembly of claim 19, wherein one of the apertures of the first portion opens in a first direction away from the shelf and another of the apertures opens in a second direction different than the first direction. 21. The shelving system of claim 19, wherein the third portion includes apertures, each aperture formed as a slot with an open end and configured for releasable engagement with selected ones of the plurality of support pins. 22. A support bracket assembly for a shelving system positionable on a support surface and having a support post with a mounting portion including a first mounting surface and a second mounting surface facing away from the first mounting surface, a third surface between and orthogonal to the first and second mounting surfaces, a plurality of support pins fixed to the support post and extending outward from each of the first and second mounting surfaces, and a shelf configured for coupling to the support post, the support bracket assembly comprising: a first bracket including a first planar portion configured for attachment to the first mounting surface and a second planar portion configured for attachment to the second mounting surface when the shelving system is assembled, wherein each of the first and second planar portions includes apertures for releasable engagement with selected support pins, each aperture formed as a slot with an open end; and a second bracket associated with the first bracket and configured to support a portion of the shelf, the second bracket including an end portion configured for removably coupling to the support post, the end portion including apertures configured for releasable engagement with selected ones of the plurality of support pins on the support post, each aperture formed as a slot with an open end, wherein the second bracket is separable from the first bracket, wherein when the shelving system is assembled the second bracket is configured to support a bottom side of the shelf above at least one of the apertures of the end portion engaged with one of the selected ones of the plurality of support pins, and wherein when the shelving system is assembled the second bracket is configured to prevent the shelf from moving in a direction orthogonal to a plane coincident with the third support post surface.
CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 15/026,519 filed on Mar. 31, 2016, which is a U.S. National Phase entry of International Patent Application PCT/US14/58308 filed on Sep. 30, 2014, which claims priority to U.S. Provisional Patent Application No. 61/885,480 filed on Oct. 1, 2013, and to U.S. Provisional Patent Application No. 61/885,969 filed on Oct. 2, 2013, the entire contents of each of which are incorporated herein by reference. FIELD The present invention relates to shelves, racks, and workstations, and more particularly to shelves, racks, and workstations that are supported by a wall or ceiling and cantilevered for supporting items or for supporting work surfaces. SUMMARY An important function of most shelving and rack systems and workstations is the ability to increase storage and working space. Limitations exist in the design and assembly of many conventional shelving systems, racks and workstations. These limitations are most apparent in highly competitive industries in which space, assembly and adjustment time, and reliability are at a premium. One such industry is the food service industry, where each of these factors plays a significant role in the success and profitability of a business. Therefore, although the present invention (and the problems that exist in conventional shelving systems, racks, and workstations) is particularly well-adapted for use in the food service industry, it should be noted that the present invention is applicable to and solves similar problems in any industry employing shelving systems, racks, and workstations. Examples of such industries include retail stores in which merchandise is displayed and stored, laboratories and shops where storage and work space are needed, and warehouses in which any type of product is organized and stored. Increased utilization of floor and storage space are primary goals for most businesses, and can significantly impact profitability of such businesses. For example, work spaces and/or storage spaces are often important resources in the food service industry, retail businesses and warehouses, to name just a few different types of businesses where space may typically be limited for such purposes. Varying the sizes and layouts of work and storage spaces calls for varying types, kinds and sizes of shelves, racks, and workstations. These structures typically consist of vertical supports, horizontal storage and support structures, and connecting elements for connecting the horizontal storage and support structures to the vertical supports, which are supported on a floor or similar surface. It is normally desirable for shelving systems and workstations to be inexpensive, modular, adjustable, easy to assemble and disassemble, easy to clean and reliable. Conventional shelving systems and workstations do not always satisfy such criteria or provide the optimal features necessary to accomplish the goals desired. Specifically, many conventional shelving systems and workstations are often expensive, difficult to clean, assemble, disassemble, and adjust. Also, conventional systems often lack the modularity necessary to meet a wide variety of environments or prove to be unreliable. In many conventional shelving systems and workstations, shelves are welded or otherwise permanently attached to vertical support posts, making the shelving system or workstation a single integral structure (or defining large subassemblies in such shelving systems and workstations). This makes the shelving systems and workstations more difficult to move due to the size and weight of the integral assemblies or subassemblies. Also, by permanently attaching the shelves to support posts, the shelving systems and workstations can only be arranged in a single configuration. In other conventional shelving systems and workstations, assembly can be difficult and time consuming. In light of the problems and limitations of the prior art described above, a need exists for shelving systems and workstations that are easy to clean, are easy and quick to assemble, provide an adjustable and reliable connection between shelves and vertical support posts, can support a relatively large amount of weight, and can be supported by a wall or ceiling, thereby freeing up valuable floor space for other purposes. Each preferred embodiment of the present invention achieves one or more of these results. In one embodiment, a shelving system is provided which includes a plurality of horizontal support members, each horizontal support member having a length; a plurality of wall supports, each wall support including a first surface on which at least a portion of a horizontal support member rests; a plurality of brackets, each bracket attachable to the horizontal support members at different positions along the length of the horizontal support member; a plurality of vertical support members, each vertical support member coupled to at least one bracket; and a shelf attached to at least two of the plurality of vertical support members. In another embodiment, a shelving system is provided which includes a plurality of horizontal support members, each horizontal support member having a length; a plurality of wall supports, each wall support including a first surface on which at least a portion of a horizontal support member rests; a plurality of brackets, each bracket attachable to the horizontal support members at different positions along the length of the horizontal support member; a plurality of vertical support members, each vertical support member coupled to at least one bracket; a ceiling support including a second surface on which at least a portion of a horizontal support member rests, the ceiling support including an upper plate and a lower plate coupled by a least one pin, wherein the second surface is coupled to the lower plate; and a shelf attached to at least two of the plurality of vertical support members. Various aspects of the invention will become apparent by consideration of the detailed description and accompanying drawings BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a perspective view of a shelving system. FIG. 2 includes an enlarged perspective view of a portion of the shelving system of FIG. 1. FIG. 3 is a perspective view of a wall support, a portion of a horizontal support member, a portion of a vertical support member, and a bracket. FIG. 4 includes an enlarged perspective view of a portion of the shelving system of FIG. 1. FIG. 5 is a perspective view of a portion of the horizontal support member, a bracket, a portion of a vertical support member, and a portion of a shelf. FIG. 6 includes an enlarged perspective view of a portion of the shelving system of FIG. 1. FIG. 7 is a perspective view of a portion of a shelving system including a ceiling support. FIG. 8 includes an enlarged perspective view of a portion of the shelving system of FIG. 1. FIG. 9 illustrates a vertical support member according to one embodiments and a vertical support member according to another embodiment. DETAILED DESCRIPTION Before any embodiments of the invention are explained in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the following drawings. The invention is capable of other embodiments and of being practiced or of being carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. FIGS. 1 and 2 show a shelving system 10 for supporting multiple shelves. In certain embodiments, the shelving system 10 may be positioned, for example, within a walk-in cooler or other refrigerated compartment or other types of compartments, rooms, or areas. In the illustrated embodiment, the shelving system 10 includes wall supports 18, first or horizontal support members 22, second or vertical support members 26, brackets 30, a ceiling support 34, and shelves 38. As used herein, the term “shelf” or “shelves” refers to any storage or support surface used to support product or other types of articles or upon which work can be performed. As best shown in FIGS. 2 and 3, each of the wall supports 18 includes a plate 46 coupled to the surface of a wall (e.g., by a bolt or other fastener). Each wall support 18 includes a flange 50 extending outwardly from the plate 46. Plate 46 can be secured to a support surface such as a wall using, for example, fasteners 19 that extend through the plate and into the support surface (e.g. a wall). The flange 50 forms a surface or ledge 51 upon which the horizontal support members 22 rest. In the illustrated embodiment the ledge includes an optional lip 53 at the outer edge to securely hold the horizontal support members 22 in place on the ledge. In the illustrated embodiment, the horizontal support members 22 are fastened to the flange 50 (e.g., by a fastener such as a bolt or pin 54 extending through support member 22 and an aperture 23 that is provided in flange 50 and aligned apertures 25 that are provided in opposing upper and lower surfaces of the horizontal support member 22). In the illustrated embodiment, the horizontal support member 22 extends partially across the surface of flange 50, allowing an end of another horizontal support member 22 to be placed adjacent to the support member 22 shown in FIG. 3 and thereby to also be supported on the other portion of the surface of flange 50 as shown in FIGS. 4 and 5. Each horizontal support member 22 placed end-to-end on flange 50 is thus fastened to flange 50 by a bolt or pin 54 or other suitable fastener that extends through a flange aperture 23. Any number of horizontal support members 22 can be used to form shelving system 10 and provide a framework for vertical support members 26, as described below. In addition, each bracket 30 is coupled to one of the horizontal support members 22. As shown in FIGS. 3-5, each bracket 30 includes a clamp 58 extending substantially around the top, rear, and bottom surfaces of horizontal support member 22, and includes a first clamping plate 62 and a second clamping plate 66 (FIG. 5). The clamp 58 includes upper and lower flanged portions 59 for coupling of the clamp 58 to the first clamping plate 62 and the second clamping plate 66 (FIG. 5). The clamp 58 is movable to different attachment positions along the horizontal support member 22 in order to accommodate different spacings for vertical support members 26, as described below. In one embodiment, the horizontal support member 22 includes detents or other marking or alignment mechanisms positioned at regular intervals (e.g., every six inches, every twelve inches, etc.) to indicate the spacing between adjacent brackets 30 and assist in positioning the vertical support members 26 relative to one another. Also, each clamping plate 62, 66 is fastened to the clamp 58 (e.g., by a pair of fasteners 70) to secure the bracket 30 to the horizontal support member 22 in a desired position along the length of the horizontal support member 22. The fasteners 70 can be loosened so that the bracket 30 can slide along the horizontal support member 22 to a desired position, where the fasteners 70 are again tightened to secure the bracket 30. Thus, it is desirable that the dimensions of clamp 58 are made such that tightening of fasteners 70 to join the clamp 58 to the first clamping plate 62 and the second clamping plate 66 causes bracket 30 to be tightened around the horizontal support member 22 to securely hold the clamp 58 in a desired position on the horizontal support member 22, whereas loosening the fasteners 70 allows the bracket 30 to slide along the horizontal support member 22. The fasteners 70 may be bolts which have matching nuts that are integrated into clamp 58 or which are separate parts from clamp 58. The first clamping plate 62 and second clamping plate 66 may be two separate pieces, or the first clamping plate 62 and second clamping plate 66 may be part of a single piece (FIG. 9, left) which meets up with the clamp 58. The clamping plates 62, 66 are spaced apart from one another such that one of the vertical support members 26 may be positioned between the clamping plates 62, 66. When the first clamping plate 62 and second clamping plate 66 are part of a single piece, this may facilitate maintaining the correct size opening into which the vertical support member 26 fits between the first clamping plate 62 and second clamping plate 66. Each clamping plate 62, 66 includes an outwardly-extending flange 63, 67, respectively (see FIG. 9), each flange 63, 67 including multiple grooves 74 to receive pins 78 that extend outwardly from opposing sides of vertical support members 26. In the illustrated embodiment, each vertical support member 26 is formed as a closed or box channel frame having a rectangular cross-section. In other embodiments (FIGS. 8 and 9), the vertical support member 26b is formed as an open or U-shaped channel. Each vertical support member 26 includes multiple pins 78 extending outward from opposing sides of the vertical support member 26. The pins 78 may extend through the vertical support member 26 or may simply project from the outer surfaces of the vertical support member 26. The ends of the pins 78 are positioned within the grooves 74 to secure the vertical support member 26 relative to the bracket 30. Thus, the bracket 30 serves to join the horizontal support members 22 to the vertical support members 26 in an adjustable manner. In a preferred embodiment, the pins 78 are mounted incrementally along the vertical support members 26. The pins 78 can be mounted at any regular or irregular distance from one another along any length or lengths of the vertical support member 26. However, in some preferred embodiments, the pins 78 are mounted at regular intervals along the majority of the support member's length. The pins 78 preferably extend laterally through the vertical support members 26 as shown in FIGS. 8-9. Specifically, each pin 78 is preferably a single piece that extends laterally through the support member 26 and has a portion of the pin 26 protruding laterally from both opposing sides of the member 26 (i.e., protruding from the left and right side surfaces of the support member 26 with respect to a viewing position in front of and facing the shelving system). Preferably, each pin 78 is welded to the vertical support member 26 on the left side or the right side or, more preferably, on both the left and right side. Although the pins 78 are preferably welded to both lateral sides of the support member 26, it should be noted that pins 78 extending through and past both opposing sides of the vertical support member 26 can be secured to member 26 in a number of other manners, including without limitation, by being press-fit or by otherwise having an interference fit within apertures on both opposing sides of member 26 or by being fastened to member 26 with one or more fasteners. With reference to FIGS. 1, 2, 5, 6, and 8, the shelving system 10 preferably includes one or more shelves 38 having any size desired. In some preferred embodiments (including those shown in the figures), the shelves 38 are mounted to the vertical support members 26 by way of the support pins 78 as will be discussed below. A preferred embodiment of a shelf 38 used in shelving system 10 is illustrated in FIGS. 1, 2, 5, and 6. However, it should be noted that other shelves 38 having different sizes and shapes can employ the same features described hereafter, or shelves of different constructions may also be used in shelving system 10. In some preferred embodiments, the shelf 38 is a single integral piece having one or more cross members 39 and side braces 79. The cross members 39 preferably extend between the side braces 79 and provide a support surface for the shelf 38. Alternatively, the side braces 79 can be connected by a frame, sheet, series of bars or poles, mesh, screen, or any other element extending between the side braces 79 for purposes of supporting weight, for supporting surface covers upon which to work or store and display articles, and/or for securing the side braces 79 with respect to one another. In one embodiment, the side braces 79 may be attached to the vertical support members 26 by means of pins 78 to attach shelves 38 or like support structures or surfaces to the vertical support members 26, as described in U.S. Pat. No. 7,494,019, filed Apr. 16, 2003, the entire contents of which is incorporated herein by reference. Thus, shelves 38 may be mounted to vertical support members 26 at a desired height along the member. The side braces 79 may be separate components on which the shelves 38 are disposed, or the side braces 79 may be integrated with the shelves 38 as a single component. The side braces 79 may include multiple grooves, projections, or hooks (e.g. as shown and described in FIGS. 6-7 and col. 9:5-46 of U.S. Pat. No. 7,494, 019, the entire contents of which is incorporated herein by reference) which engage with the pins 78. As explained above, brackets 30 can be attached to horizontal support members 22 at different positions along the horizontal support member 22 to allow a user to change the spacing between adjacent vertical supports 26 and account for variations in the width of the shelves 38. Also, the pins 78 allow for conventional shelves to be used in conjunction with the shelving system 10. Examples of such a shelving system are described in U.S. Pat. No. 7,494,019, filed Apr. 16, 2003, and U.S. Pat. No. 5,592,886, filed Jan. 31, 1994, the entire contents of both of which are incorporated herein by reference. Of course, other means of attaching shelves 38 to vertical support members 26 can be employed as known by those having ordinary skill in the art. As shown in FIGS. 6 and 7, the ceiling support 34 is coupled to an end of one of the horizontal support members 22. The ceiling support 34 includes a pair of parallel, spaced apart horizontal plates 86a, 86b. A lower plate 86a is positioned adjacent an interior surface of a ceiling (not shown) of a room or compartment in which the shelving system 10 is located. An upper plate 86a is positioned above the ceiling of the room or compartment, adjacent an outer surface above the ceiling, thereby distributing force from the shelving system 10 over a wider area. One or multiple pins 90 extend through the space and ceiling between the plates 86a, 86b, coupling the plates 86a, 86b together. In addition, the lower plate 86a has attached thereto a ledge or channel 94 which is connected to the lower plate 86a by a pair of extensions 95. The ledge or channel 94 extends below the lower plate 86a and supports an end of at least one of the horizontal support members 22; one or more bolts or pins may be used to secure the horizontal support member 22 to the ledge or channel 94. The ledge or channel 94 may be located at various distances from the lower plate 86a, for example by providing extensions 95 of different lengths. The ceiling support 34 provides additional support and versatility for configuring shelving system 10. For example, the ceiling support 34 is useful when the shelving system 10 is mounted on a wall with a horizontal support member 22 being sufficiently close to the ceiling to allow use of the ceiling support 34, particularly in situations in which the walls of the compartment are not load-bearing, e.g. in a walk-in refrigerator or freezer. As used herein, a ceiling refers to any overhead or upper surface of a room, compartment, or area. The wall supports 18 may also help to stabilize and maintain alignment of the horizontal support members 22. To the extent that the vertical support members 26 are supported by a wall or a ceiling of a compartment, this permits the floor to remain generally unobstructed. The load on the shelves is supported by the wall and/or ceiling in a cantilevered configuration, and the shelves 38 can be positioned above the level of the floor to permit free access to the floor space. In some embodiments, the shelving system 10 can be used alone or in conjunction with a freestanding shelving system and may also include an attachment to transfer some or all of the load to the floor. The shelving system 10 may also incorporate features of a freestanding shelving system such as those shown in U.S. Pat. No. 7,494,019, the entire contents of which is incorporated herein by reference. By employing the wall and/or ceiling mounted horizontal members 22 to support vertical members 26, as described above, a number of embodiments of the present invention provide a workstation or a shelving or rack system that is highly adjustable, modular, and adaptable to a large number of applications, spaces, and environments, freeing up valuable floor space for other uses or purposes. In the various embodiments described above and illustrated in the figures, the use of vertical support members 26 that can be attached at a variety of desired positions along the length of horizontal support members 22, and having pins 78 extending from opposite sides thereof, enables a user to accommodate shelves 38 of different sizes and mount adjacent shelves 38 on both sides of the vertical support members 26 in a variety of configurations. Thus, once wall supports 18 and optional ceiling supports 34 have been installed, various arrangements of horizontal support members 22 and vertical support members 26 can be provided in order to accommodate a given arrangement of shelves 38. The arrangement of shelves 38 can readily be changed by rearranging the horizontal support members 22 and vertical support members 26 without having to mount any additional supports in the wall or ceiling. This versatility, coupled with the more reliable and simpler shelf mounting arrangement of the present invention, provides a number of advantages as discussed above. Thus, the invention may provide, among other things, a shelving system. Although the invention has been described in detail with reference to certain independent embodiments, variations and modifications exist within the scope and spirit of one or more independent aspects of the invention as described. Various features and advantages of the invention are set forth in the following claims.
<SOH> FIELD <EOH>The present invention relates to shelves, racks, and workstations, and more particularly to shelves, racks, and workstations that are supported by a wall or ceiling and cantilevered for supporting items or for supporting work surfaces.
<SOH> SUMMARY <EOH>An important function of most shelving and rack systems and workstations is the ability to increase storage and working space. Limitations exist in the design and assembly of many conventional shelving systems, racks and workstations. These limitations are most apparent in highly competitive industries in which space, assembly and adjustment time, and reliability are at a premium. One such industry is the food service industry, where each of these factors plays a significant role in the success and profitability of a business. Therefore, although the present invention (and the problems that exist in conventional shelving systems, racks, and workstations) is particularly well-adapted for use in the food service industry, it should be noted that the present invention is applicable to and solves similar problems in any industry employing shelving systems, racks, and workstations. Examples of such industries include retail stores in which merchandise is displayed and stored, laboratories and shops where storage and work space are needed, and warehouses in which any type of product is organized and stored. Increased utilization of floor and storage space are primary goals for most businesses, and can significantly impact profitability of such businesses. For example, work spaces and/or storage spaces are often important resources in the food service industry, retail businesses and warehouses, to name just a few different types of businesses where space may typically be limited for such purposes. Varying the sizes and layouts of work and storage spaces calls for varying types, kinds and sizes of shelves, racks, and workstations. These structures typically consist of vertical supports, horizontal storage and support structures, and connecting elements for connecting the horizontal storage and support structures to the vertical supports, which are supported on a floor or similar surface. It is normally desirable for shelving systems and workstations to be inexpensive, modular, adjustable, easy to assemble and disassemble, easy to clean and reliable. Conventional shelving systems and workstations do not always satisfy such criteria or provide the optimal features necessary to accomplish the goals desired. Specifically, many conventional shelving systems and workstations are often expensive, difficult to clean, assemble, disassemble, and adjust. Also, conventional systems often lack the modularity necessary to meet a wide variety of environments or prove to be unreliable. In many conventional shelving systems and workstations, shelves are welded or otherwise permanently attached to vertical support posts, making the shelving system or workstation a single integral structure (or defining large subassemblies in such shelving systems and workstations). This makes the shelving systems and workstations more difficult to move due to the size and weight of the integral assemblies or subassemblies. Also, by permanently attaching the shelves to support posts, the shelving systems and workstations can only be arranged in a single configuration. In other conventional shelving systems and workstations, assembly can be difficult and time consuming. In light of the problems and limitations of the prior art described above, a need exists for shelving systems and workstations that are easy to clean, are easy and quick to assemble, provide an adjustable and reliable connection between shelves and vertical support posts, can support a relatively large amount of weight, and can be supported by a wall or ceiling, thereby freeing up valuable floor space for other purposes. Each preferred embodiment of the present invention achieves one or more of these results. In one embodiment, a shelving system is provided which includes a plurality of horizontal support members, each horizontal support member having a length; a plurality of wall supports, each wall support including a first surface on which at least a portion of a horizontal support member rests; a plurality of brackets, each bracket attachable to the horizontal support members at different positions along the length of the horizontal support member; a plurality of vertical support members, each vertical support member coupled to at least one bracket; and a shelf attached to at least two of the plurality of vertical support members. In another embodiment, a shelving system is provided which includes a plurality of horizontal support members, each horizontal support member having a length; a plurality of wall supports, each wall support including a first surface on which at least a portion of a horizontal support member rests; a plurality of brackets, each bracket attachable to the horizontal support members at different positions along the length of the horizontal support member; a plurality of vertical support members, each vertical support member coupled to at least one bracket; a ceiling support including a second surface on which at least a portion of a horizontal support member rests, the ceiling support including an upper plate and a lower plate coupled by a least one pin, wherein the second surface is coupled to the lower plate; and a shelf attached to at least two of the plurality of vertical support members. Various aspects of the invention will become apparent by consideration of the detailed description and accompanying drawings
A47F508
20170811
20180206
20171130
73203.0
A47F508
1
NOVOSAD, JENNIFER ELEANORE
SHELVING SYSTEM
UNDISCOUNTED
1
CONT-ACCEPTED
A47F
2,017
15,675,492
PENDING
FRAUD PREVENTION BASED ON USER ACTIVITY DATA
A user conducts activities, such as researching a product online or visiting a store that sells the product. A user then utilizes a risk analysis system to receive and store user activity data for the user's activities. When a purchase attempt is made with the user's financial account, a merchant sends a transaction request to the risk analysis system. The risk analysis system locates a record for the user and determines whether the product is identified in the user activity data. If the product is identified, the risk analysis system provides a risk score to the merchant indicating that the transaction is unlikely fraudulent. Alternatively, identification of the product provides a positive factor among multiple factors considered in a transaction risk analysis. An absence of the product in the activity can be used as a neutral or negative factor among multiple factors considered in a risk analysis of the transaction.
1.-20. (canceled) 21. A computer-implemented method to reduce fraud in online transactions by correlating shopping behaviors of users in physical merchant locations with product identification information associated with products being purchased in the online transactions, comprising: logging, by one or more computing devices, a location history of a user computing device, the location history comprising physical merchant locations visited by the user computing device; associating, by the one or more computing devices, user activity data comprising the logged location history of the user computing device with a record for the user; receiving, by the one or more computing devices, a request from an online merchant computing system, wherein the request identifies a product for a transaction involving an account of the user and provides information sufficient to identify the record of the user; determining, by the one or more computing devices, one or more physical merchant locations at which the product may be purchased; comparing, by the one or more computing devices, the one or more physical merchant locations visited by the user in the logged location history of the user with the one or more physical merchant locations at which the product may be purchased; determining, by the one or more computing devices, based on the comparison, that one or more particular physical merchant locations logged in the location history of the user is a match of one or more physical merchant locations at which the product may be purchased; determining, by the one or more computing devices, a risk indicator for the transaction based on the match of the one or more particular locations logged in the location history of the user to the one or more locations at which the product may be purchased, wherein the determined risk indicator is lower based on the presence of one or more matches between the particular locations logged in the location history of the user and the one or more locations at which the product may be purchased, and wherein a lower risk indicator is associated with a transaction that has a lower risk of fraud and a higher risk indicator is associated with a transaction that has a higher risk of fraud. 22. The computer-implemented method of claim 21, further comprising: calculating, by the one or more computing devices, a risk score for the transaction based on the determined risk indicator, the risk score being indicative if the transaction is likely to be fraudulent; and communicating, by the one or more computing devices, the risk score to the merchant computing system. 23. The computer-implemented method of claim 1, wherein the presence of a greater number of matches results in a lower risk indicator for the purchase transaction. 24. The computer-implemented method of claim 1, wherein the risk indicator is a qualitative risk score. 25. The computer-implemented method of claim 1, wherein the risk indicator is a quantitative risk score. 26. The computer-implemented method of claim 1, wherein a greater number of matches correlates to an increased likelihood that the purchase transaction involving the financial account of the user is a valid transaction. 27. The computer-implemented method of claim 1, wherein the information sufficient to identify the record of the user comprises financial account information of the user. 28. A system to correlate location history with transaction information to reduce fraud in online transactions by correlating shopping behaviors of users in physical merchant locations with product identification information associated with products being purchased in the online transactions, comprising: a storage device; a processor communicatively coupled to the storage device, wherein the processor executes application code instructions that are stored in the storage device to cause the system to: receive user activity data associated with a user, wherein the user activity data comprises a location history of a user computing device associated with a user, the location history being obtained from a location determining function of the user computing device; associate the user activity data with a record for the user; receive a purchase transaction request from a computing system, wherein the purchase transaction request identifies a product for a purchase transaction involving a financial account of the user and provides information sufficient to identify the record of the user; determine one or more locations at which the product may be purchased; compare the one or more locations stored in the location history of the user with the one or more locations at which the product may be purchased; determine that one or more particular locations stored in the location history of the user matches one or more locations at which the product may be purchased; determine a risk indicator for the transaction based on the match of the one or more particular locations stored in the location history of the user to the one or more locations at which the product may be purchased, wherein the determined risk indicator is lower based on the presence of one or more matches between the particular locations stored in the location history of the user and the one or more locations at which the product may be purchased, and wherein a low risk indicator is associated with a transaction that has a low risk of fraud and a high risk indicator is associated with a transaction that has a high risk of fraud. 29. The system of claim 28, further comprising application code instructions to: calculate a risk score for the transaction based on the determined risk indicator, the risk score being indicative if the transaction is likely to be fraudulent; and communicate the risk score to a computing system. 30. The system of claim 28, wherein the computer system is a merchant computing system or a financial account issuer computing system. 31. The system of claim 28, wherein the presence of a greater number of matches results in a lower risk score for the purchase transaction. 32. The system of claim 28, wherein the risk indicator is a qualitative risk score or a quantitative risk score. 33. The system of claim 28, wherein a greater number of matches correlates to an increased likelihood that the purchase transaction involving the financial account of the user is a valid transaction. 34. The system of claim 28, wherein the information sufficient to identify the record of the user comprises financial account information of the user. 35. A computer program product, comprising: a non-transitory computer-readable storage device having computer-executable program instructions embodied thereon that when executed by a computer cause the computer to reduce fraud in online transactions by correlating shopping behaviors of users in physical merchant locations with product identification information associated with products being purchased in the online transactions, the computer-executable program instructions comprising: computer-executable program instructions to receive user activity data associated with a user, wherein the user activity data comprises a location history of a user computing device associated with a user, the location history being obtained from a location determining function of the user computing device; computer-executable program instructions to associate the user activity data with a record for the user; computer-executable program instructions to receive a purchase transaction request from a merchant computing system, wherein the purchase transaction request identifies a product for a purchase transaction involving a financial account of the user and provides information sufficient to identify the record of the user; computer-executable program instructions to determine one or more locations at which the product may be purchased; computer program instructions to identify information in the record of the user based on the purchase transaction request; computer-executable program instructions to identify one or more locations stored in the location history of the user; computer-executable program instructions to compare the one or more locations stored in the location history of the user with the one or more locations at which the product may be purchased; computer program instructions to determine that one or more particular locations stored in the location history of the user matches one or more locations at which the product may be purchased; computer-executable program instructions to determine a risk indicator for the purchase transaction based on the match of the one or more particular locations stored in the location history of the user to the one or more locations at which the product may be purchased, wherein the determined risk indicator is lower based on the presence of one or more matches between the particular locations stored in the location history of the user and the one or more locations at which the product may be purchased, and wherein a low risk indicator is associated with a transaction that has a low risk of fraud and a high risk indicator is associated with a transaction that has a high risk of fraud. 36. The computer program product of claim 35, further comprising computer-executable program instructions to: calculate a risk score for the transaction based on the determined risk indicator, the risk score being indicative if the transaction is likely to be fraudulent; and communicate the risk score to the merchant computing system. 37. The computer program product of claim 35, wherein the presence of a greater number of matches results in a lower risk score for the purchase transaction. 38. The computer program product of claim 35, wherein the risk indicator is a qualitative risk score or a quantitative risk score. 39. The computer program product of claim 35, wherein the presence of a greater number of matches results in a lower risk score for the purchase transaction. 40. The computer program product of claim 35, wherein the information sufficient to identify the record of the user comprises financial account information of the user.
TECHNICAL FIELD The present disclosure relates generally to fraud prevention, and more particularly to methods and systems that rely on user-provided activity data, such as user search history, to detect possible fraudulent activity for purchase transactions involving a financial account of the user. BACKGROUND Electronic commerce, such as online shopping, has been increasingly common since the advent of the Internet. Online shopping websites generally provide a user interface for customers to select products to purchase. After the customer has selected products for purchase, the customer typically may choose from multiple payment options to purchase the products. One conventional payment option generally supported by both merchant storefronts and online merchants is the use of a user financial account, such as a credit card account. To make an online purchase with a credit card, for example, a user will commonly enter necessary credit card information online. For example, a user wishing to purchase a product online will enter an account identifier (such as a credit card number, debit card number, etc.), shipping information, and the name, address, and contact information of the user. To make a purchase at a merchant storefront, the user will typically swipe the card or provide the card to a merchant storefront operator that manually enters the credit card information. Although the use of user financial accounts to conduct purchase transactions is convenient for both the user and the merchant, relying on user financial accounts to conduct purchase transactions is subject to fraudulent activity. For example, it is becoming increasingly difficult for online shoppers to keep their credit card information confidential and out of the possession of those who would use that information for fraudulent purposes. Likewise, users that keep a physical credit card must worry about theft of the physical card or the information contained thereon. Merchants themselves even present a potential risk to a user, whether through negligence or intentional fraud. For example, an employee of a merchant may submit erroneous transaction information to the financial institution issuing the financial account. Once a user's financial information is stolen, the user—and the financial institution issuing the financial account—has limited means of determining whether subsequent purchases are legitimate or fraudulent. And while fraud detection systems have been developed that rely on historical transaction data of the user in an attempt to predict subsequent user transactions, the narrow focus of these systems on user transaction history continues to leave users vulnerable to fraud. Such systems are thus inadequate at detecting fraud. SUMMARY In certain example aspects described herein, a computer-implemented method for transaction risk analysis is provided. A risk analysis system receives a registration from a user that desires to have their purchase transactions monitored for possible fraudulent activity. The risk analysis system, for example, receives user activity data associated with a user, such as online activity information that is generated by the user's online activity. The risk analysis system associates the user activity data with a record for the user. The risk analysis system then receives a purchase transaction request, such as from a merchant computing system. The purchase transaction request identifies a product for a purchase transaction involving a financial account of the user and provides information sufficient to identify the record of the user. Based on the information in the purchase transaction request, for example, the risk analysis system identifies the record of the user. The risk analysis system then compares the identity of the product with the online activity information for the user to determine a purchase transaction indicator for the product in the online activity information. The purchase transaction indicator, for example, provides an indication that the user may purchase the product. Based on the comparison of the identity of the product with the online activity information for the user, the risk analysis system determines a risk score or indicator for the purchase transaction and communicates the risk score or indicator to the merchant computing system. In certain other example aspects, a system for transaction risk analysis provided herein. Also provided in certain aspects is a computer program product to analyze transaction risk. These and other aspects, objects, features and advantages of the example embodiments will become apparent to those having ordinary skill in the art upon consideration of the following detailed description of illustrated example embodiments. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a block diagram depicting a system for determining transaction risk for a purchase transaction, in accordance with certain example embodiments. FIG. 2 is a block flow diagram depicting a method for transaction risk analysis for a purchase transaction, in accordance with certain example embodiments. FIG. 3 is a block flow diagram depicting a method for determining a risk score for a purchase transaction, in accordance with certain example embodiments. FIG. 4 is a block diagram depicting a computing machine and a module, in accordance with certain example embodiments. DETAILED DESCRIPTION OF THE EXAMPLE EMBODIMENTS Overview As disclosed herein, a risk analysis system allows a participating user to have their purchase transactions monitored for possible fraudulent transactions. A user conducts activities related to a particular product or service, such as conducting searches to purchase a product online. At the option of the user, a risk analysis system receives and stores user activity data about the product. For example, the user allows the risk analysis system to store the user's search history for the product. When a purchase attempt is made with the user's financial account at a merchant, for example, the merchant sends a purchase transaction request to the risk analysis system for evaluation of the purchase transaction. Based on the request, the risk analysis system locates the record for the user and determines whether the product is identified in the user activity data. If the product is identified, the risk analysis system provides a risk score to the merchant indicating that the purchase transaction is not likely to be fraudulent. Alternatively, the product being identified in the user activity can be used as a positive factor among multiple factors considered in a risk analysis of the transaction. An absence of the product being identified in the user activity can be used as a neutral or negative factor among multiple factors considered in a risk analysis of the transaction. More particularly, a user registers with the risk analysis system. As part of the registration, the user provides the user's name and other information so that the risk analysis system can create an account (or record) for the user. In certain examples, the user may also provide a user name and password so that the user can access a user account of the risk analysis system. The user may also provide one or more user financial accounts, such as a credit card account or a debit card account, that the user intends the risk analysis system to monitor. The risk analysis system also receives an authorization from the user to monitor the activities of the user. For example, in certain example embodiments the user may activate or otherwise authorize an application executing on the user device to monitor the user's activities, such as the user's online activities or the location of the user device. In order to obtain the benefits of the techniques herein and such monitoring, the user may have to select a setting or install an application. Following user registration, a user conducts activity related to a product or service. The activity can encompass any activity related to a product or service. For example, the user may conduct online activities, such as researching a product online to learn more about the product. A user interested in purchasing a television, for instance, may research product specifications online or conduct online price comparisons for particular televisions. A user may also email a friend about a television the user intends to purchase. The user may later post information about the purchased television in a social network of the user, or prior to purchase post information about a television the user is considering purchasing. In other examples, a user may research particular vacation destinations, airfare, or other products or services related to a destination online. The user may also email friends about a planned vacation or share vacation destination ideas on line. A user may also post information online about a trip the user has recently taken. In certain examples, the user may visit a merchant storefront to examine a product. For example, the user may visit several electronics stores while shopping for a television. Based on the user's authorization for the risk analysis system to determine the user's activities, the risk analysis system receives relevant user activity data. That is, at the option of the user, the risk analysis system receives information about the user's activities related to products and services. For example, the risk analysis system receives the user's search history regarding the television the user intends to purchase. The risk analysis system may also receive any other online user activity related to a product or service, such as the user's search history regarding a vacation destination or user emails. For example, the risk analysis system may receive emails pertaining to products and services, such as emails about a planned vacation or a vacation the user has recently taken. The risk analysis system may also receive information for products or services that the user shares online, such as in a social network. In addition to the user's online activities, the risk analysis system may receive authorized location data for the user device. That is, if the user includes their location information as part of the user activity to be monitored, the risk analysis system receives location data from the user device regarding locations pertinent to products and services. For example, if a user visits an electronics store, such as in the user's search for a television, the risk analysis system may receive location data for the electronics store. Likewise, if a user visits a travel agent, such as while planning a vacation, the risk analysis system may receive location data for the travel agent. The user device can obtain the location data by any suitable method, such as through a location service that relies on a global positioning system (“GPS”) or Wi-Fi hotspots and cellular communication towers available to the user device. The location data can comprise any information that establishes the location of the user's computing device, such as a street address, Ordnance Survey Grid Reference information, and/or latitude and longitude coordinates for points of interest. After receiving the activity data of the user and at the option of the user, the risk analysis system associates the activity data with a record for the user. That is, the risk analysis system stores the user activity data in an accessible account record associated with the user, so that the risk analysis system can later access the activity. For example, when the risk analysis system receives the name of the user or user account information, such as from a merchant as described herein, the risk analysis system can locate the record of the user, along with the stored user activity data associated with the user account. After the risk analysis system has received and stored user activity data for a particular user, the risk analysis system receives a purchase transaction request for a purchase transaction involving a financial account of the user. For example, a purchaser attempts to purchase a product with a financial account of the user at a point-of-sale terminal of a merchant, such as by swiping a credit card. Before completing the purchase transaction, the merchant sends a request to the risk analysis system to receive a risk score for the purchase transaction. The request includes, for example, information sufficient to identify the record for the user, as well as information about the product or service that was (or will be) purchased. For example, the purchase transaction request may identify a financial account of the user that a purchaser has presented to complete the purchase transaction. The purchaser may be the user, in which case the purchase transaction would likely not be fraudulent. If the purchaser is not the user, however, the transaction is likely fraudulent. In certain example embodiments, after a purchase transaction is complete, the merchant or a custodian of the financial account such as the account issuer, for example, may send a purchase transaction request regarding the purchase transaction. The risk analysis system then receives the request and provides a risk score to the financial account issuer. The risk analysis system determines a risk score or risk indicator for the purchase transaction based on the information received in the purchase transaction request and the information in the user activity data. The risk analysis system reads the content of the purchase transaction request to identify the product or service that is the subject of the purchase transaction. For example, the risk analysis system may determine that the purchase transaction concerns a television or an airline ticket, such as an airline ticket to a particular vacation destination. The risk analysis system also determines user-identity information from the request, such as by reading the account information used in the purchase transaction. The risk analysis system then uses the user identification information to locate the record of the user corresponding to the identification information. After identifying the user record based on the user information, the risk analysis system compares the identified product or service to the user activity record to determine purchase transaction indicators for the product. That is, the risk analysis system reads the stored user activity history for any sign or other indication that the user would purchase the product or service of the purchase transaction. The indicators can comprise any connection or correlation between the product or service identified in the purchase transaction request and the activity data associated with the record for the user. For example, a user search history for a television would constitute an indicator that the user may purchase the television. Likewise, location data showing that the user device (and hence the user) was recently at an electronics store may also serve as an indicator that the user would purchase a television. A user search history for a particular vacation destination—or an email or social network entry about the destination—may serve as an indicator that the user, for example, would purchase airfare (or other fare) to the vacation destination. Based on the purchase transaction indicators that the risk analysis system determines from the user activity data, the risk analysis system generates a risk score or risk indicator for the purchase transaction. The risk analysis system then communicates the risk score or risk indicator to the entity, such as a merchant, that sought the risk score. For example, if the risk analysis system is unable to determine any purchase transaction indicators for the purchase transaction, the risk analysis system generates a neutral or negative score or indicator for the purchase transaction. In certain examples, a neutral or negative score reflects the fact that nothing in the user activity data suggests that the user would purchase the product or service associated with the purchase transaction. A merchant providing a purchase transaction request for the purchase of a television, for example, may receive a neutral or negative score when nothing in the user activity indicates that the user would purchase the television. Based on the neutral or negative score, the merchant may thus conclude that the purchaser is fraudulently attempting to buy the television or may look for other indicators of fraudulent activity. Hence, the negative risk-score may also prompt the merchant to require additional identification from the purchaser to confirm the purchaser's identity and the validity of the purchase transaction. Additionally, an absence of the product being identified in the user activity can be used as a neutral or negative factor (or indicator) among multiple factors considered in a risk analysis of the transaction. In contrast, if the risk analysis system determines purchase transaction indicators in the user activity data, the risk analysis system generates a positive score in response to the purchase transaction request. As noted above, user activity data indicating that a user would purchase a television would operate as a purchase transaction indicator for a purchase transaction involving a television. Based on the identification of such an indicator, the risk analysis system would generate a positive score in response to the purchase transaction request for the purchase transaction involving the television. Likewise, if the risk analysis system identified a purchase transaction indicator for airfare to a vacation destination—such as a user search history concerning the vacation destination—the risk analysis system would generate a positive risk score for the airfare purchase. If the product is identified, the risk analysis system provides a risk score to the merchant indicating that the purchase transaction is not likely to be fraudulent. Alternatively, the product being identified in the user activity can be used as a positive factor (or indicator) among multiple factors considered in a risk analysis of the transaction. In certain examples, the risk score that the risk analysis system generates is qualitative. For example, the identification of one or more purchase transaction indicators may result in a “Yes” response from the risk analysis system indicating that the purchase transaction is likely valid. In the absence of any purchase transaction indicators, a “No” response from the risk analysis system indicates that the risk analysis system cannot conform whether the transaction is fraudulent, or that the transaction may be fraudulent, and that hence the entity receiving the “No” response should take precautions or request additional information prior to approving the transaction. In other examples, the determined risk score is quantitative. That is, the risk analysis system may configure the risk score to correspond to the number and/or weight of the identified indicators. For example, a single purchase transaction indicator for a particular purchase transaction may result in a low score, whereas the identification of multiple purchase transaction indicators for the purchase transaction results in a high score. A single purchase transaction indicator that a user would purchase a television, for example, may result in a risk score of “1.” The identification of two indicators, however—such as a search history for the television and location data placing the user device near an electronics store—may results in a risk score of “5” or “6.” If additional purchase transaction indicators are determined, such as user emails regarding a television purchase, then a higher score of “9” or “10” may be generated, thus indicating a very low likelihood that the purchase transaction is fraudulent. Additionally or alternatively, the risk analysis system may weight different purchase transaction indicators differently when generating a risk score. For example, when the purchase transaction involves a television, user emails about a television may receive more or less weight than location data placing the user device near an electronics score. In certain examples, a financial account of the user is associated with the risk analysis system. For example, the risk analysis system may be associated with a digital wallet account of the user. Thus, when the user utilizes the digital wallet account to process a purchase transaction, the risk analysis system receives a purchase transaction authorization request from a merchant. In such examples, the purchase transaction authorization request can operate as a purchase transaction request. In other words, the risk analysis system determines a risk score as described herein before authorizing the transaction. In other examples, the risk analysis system may determine negative risk score for a purchase transaction after the transaction is completed, in which case the risk analysis system may communicate a warning to the user, merchant, financial account issuer, or other entity that the transaction may be fraudulent. By using and relying on the methods and systems described herein, a user can increase the likelihood that fraudulent activity involving the user's purchase transactions is detected. In other words, by allowing the risk analysis system described herein determine and store user activity data—and provide purchase transaction risk-scores/indicators based on the user activity data—a user can increase the likelihood that fraudulent transactions involving the user's financial accounts will be detected. The methods and systems described herein not only benefit the user, but also merchants, financial account issuers, or any other entities seeking to reduce fraudulent purchase transactions. Example System Architectures Turning now to the drawings, in which like numerals indicate like (but not necessarily identical) elements throughout the figures, example embodiments are described in detail. FIG. 1 is a block diagram depicting a system for determining transaction risk for a purchase transaction, in accordance with certain example embodiments. As depicted in FIG. 1, the exemplary operating environment 100 includes a user network computing device 110, a merchant computing system 130, a risk analysis computing system 140, and a financial account computing system 170. Each network 105 includes a wired or wireless telecommunication means by which network devices (including devices 110, 130, 140, and 170) can exchange data. For example, each network 105 can include a local area network (“LAN”), a wide area network (“WAN”), an intranet, an Internet, a mobile telephone network, or any combination thereof. Throughout the discussion of example embodiments, it should be understood that the terms “data” and “information” are used interchangeably herein to refer to text, images, audio, video, or any other form of information that can exist in a computer-based environment. In some embodiments, a user 101 associated with a device must install an application and/or make a feature selection to obtain the benefits of the techniques described herein. Each network computing device 110, 130, 140, and 170 includes a device having a communication module capable of transmitting and receiving data over the network 105. For example, each network device 110, 130, 140, and 170 can include a server, desktop computer, laptop computer, tablet computer, a television with one or more processors embedded therein and/or coupled thereto, smart phone, handheld computer, personal digital assistant (“PDA”), or any other wired or wireless, processor-driven device. In the example embodiment depicted in FIG. 1, the network devices 110, 130, 140, and 170 are operated by end-users or consumers, merchant system operators, risk analysis system operators, and financial account issuer system operators, respectfully. The user 101 can use the communication application 113, such as a web browser application or a stand-alone application, to view, download, upload, or otherwise access documents or web pages via a distributed network 105. The network 105 includes a wired or wireless telecommunication system or device by which network devices (including devices 110, 120, 140, and 150) can exchange data. For example, the network 105 can include a local area network (“LAN”), a wide area network (“WAN”), an intranet, an Internet, storage area network (SAN), personal area network (PAN), a metropolitan area network (MAN), a wireless local area network (WLAN), a virtual private network (VPN), a cellular or other mobile communication network, Bluetooth, near field communication (NFC), or any combination thereof or any other appropriate architecture or system that facilitates the communication of signals, data, and/or messages. The communication application 113 can interact with web servers or other computing devices connected to the network 105. For example, the communication application 113 can interact with the user network computing device 110, the merchant system 130, the risk analysis system 140, and the financial account system 170. The communication application 113 may also comprise a web browser (not shown), which provides a user interface, for example, for accessing other devices associated with the network 105. The user computing device 110 may include a digital wallet application 111. The digital wallet application 111 may encompass any application, hardware, software, or process the user computing device 110 may employ to assist the user 101 in completing a purchase transaction. The digital wallet application 111 can interact with the communication application 113 or can be embodied as a companion application of the communication application 113. As a companion application, the digital wallet application 111 can execute within the communication application 113. That is, the digital wallet application 111 may be an application program embedded in the communication application 113. The user computing device 110 may also include a risk analysis application 112. The risk analysis application 112, for example, communicates and interacts with the risk analysis system 140, such as via that the communication application 113. In order to obtain the benefits of the risk analysis system 140 as described herein, for example, a user 101 may have to download and install the risk analysis application 112. The risk analysis application 112, for example, may be configured, based on user preferences, to obtain, receive, and communicate activity data of the user 101, such as online activity information pertaining to the user's online activities. For example, the risk analysis application 112 may be configured to receive content of the websites that a user visits. The risk analysis application 112 may also be configured to obtain, receive, and/or communicate location data for the user device 110. For example, the risk analysis application 112 may be configured to communicate and interact with a location service provider that, in conjunction with the user device 110, facilitates determination of the location of the user device 110. For example, the risk analysis application 112 may, along with a location service and/or hardware of the user device 110, rely on WiFi signals and cellular communication towers to determine the location of the user device 110. Additionally or alternatively, the risk analysis application 112 may rely on satellites, Global Positioning System (“GPS”) location technology, a Network Location Provider (“NLP”), a map application, or other location identifying technology of the user device 110 to determine location data for the user device 110. In certain example embodiments, the risk analysis application 112 can interact with the digital wallet application 111 or can be embodied as a companion application of the digital wallet application 111. As a companion application, the risk analysis application 112 can execute within the digital wallet application 111. That is, the risk analysis application 112 may be an application program embedded in the digital wallet application 111. In certain example embodiments, the risk analysis application 112 executes and operates independently of the digital wallet application 111. The user computing device 110 may also include a data storage unit 117. The example data storage unit 117 can include one or more tangible computer-readable storage devices. The data storage unit 117 can be a component of the user device 110 or be logically coupled to the user device 110. For example, the data storage unit 117 can include on-board flash memory and/or one or more removable memory cards or removable flash memory. In certain example embodiments, the data storage unit 117 may, at the option of the user, store activity data pertaining to the user 101. The merchant computing system 130 represents a system that offers products and/or services for the user 101 to purchase or use. In certain example embodiments, the merchant system 130 includes a point-of-sale (“POS”) terminal 134. The point-of-sale terminal 134 may be operated by a salesperson that enters purchase data into the point-of-sale terminal to complete a purchase transaction. The merchant system 130 may be a physical location or an online merchant or comprise both a physical location and an online merchant. Affiliated or associated with the merchant system 130 is a merchant system operator (not shown). The merchant computing system 130 comprises a merchant server 135, which in certain example embodiments may represent the computer-implemented system that the object provider system 120 employs to create and assemble a website 136 and content for the website 136. The risk analysis system 140 represents a system for analyzing and determining fraud risk associated with a purchase transaction. The risk analysis system 140 is configured to interact with and receive data and information from the user computing device 110 via the network 105. For example, at the option of the user 101 the risk analysis system 140 is configured to receive user activity data from the user computing device 110, such as from the risk analysis application 112. The risk analysis system 140 is also configured to communicate with the merchant system 130 and the financial account system 170, such as via the network 105. The risk analysis system 140 can include a web sever 141, which may represent the computer-implemented system that the risk analysis system 140 employs to determine fraud risk for a purchase transaction. For example, the risk analysis system 140 and associated web server 141 may be configured to obtain user activity data, associate the user activity data with a record for the user 101, read purchase transaction requests, identify purchase transaction indicators, and determine a risk score for a purchase transaction as described herein. The risk analysis system 140 may also include a website 142 and a user account 143. A user 101, for example, may utilize a user interface of the website 142 to register with the risk analysis system 140 and hence create a record with the risk analysis system 140, such as the user account 143. The risk analysis system 140 may also include an accessible data storage unit 147. In certain example embodiments, for example, the data storage unit 147 stores activity data of the user 101. For example, the data storage unit 147 may receive and store online activity information generated from the user's online activities associated with the user device 110. The data storage unit 147 may also receive and store location data for the user device 110, such as cellular communication towers and Wi-Fi signals that are or have been available to the user device 110. The exemplary data storage unit 147 can include one or more tangible computer-readable media. The data storage unit 147 can be stored on the user device 110 or can be logically coupled to the user device 110. For example, the data storage unit 147 can include on-board flash memory and/or one or more removable memory cards or removable flash memory. In certain example embodiments, the risk analysis functions of the risk analysis system 140 operate and execute fully and completely on the user device 110, such as within, or as a companion application to, the risk analysis application 112. Alternatively, the risk analysis functions of the risk analysis system 140 may operate and execute separately independently from the user device 110. For example, risk analysis system 140 may operate and execute within a separate computing system or other computing system that analyzes risk as described herein. Alternatively, in other example embodiments the risk analysis functions of the risk analysis system 140 may execute partially on the user device 110 and/or partially on a separate computing system. For example, the risk analysis functions of the risk analysis system 140 occur both via the risk analysis system 140 and the risk analysis application 112. The financial account issuer system 170 comprises a financial account web server 171, which may represent the computer-implemented system that the financial account issuer system 170 employs to host a web site (not shown) of the financial account issuer system 170. The financial account web server 171 and associated website of the financial account issuer system 170 can also represent the computer-implemented system that the financial account issuer system 170 uses to create, provide, maintain, and administer a user financial account 172 for a user 101. The financial account issuer system 170 also comprises a data storage unit 177, which can used to store financial account information associated with a user financial account 172. The financial account issuer system 170 is configured to receive and store financial account information from a user 101 and to create a user financial account 172. For example, financial account information from a user 101 can be received via the network 105 and stored in the data storage unit 177 of the financial account issuer system 170. The financial account issuer system 170 is also configured to communicate with the risk analysis system 140, the user device 110, and the merchant system 130, such as via the network. In other embodiments, the financial account issuer system 170 may communicate with the risk analysis system 140, the user device 110, and the merchant system 130 via convention credit card channels, such as through an acquirer associated card network (not shown). It will be appreciated that the network connections shown are example and other means of establishing a communications link between the computers and devices can be used. Moreover, those having ordinary skill in the art and having the benefit of the present disclosure will appreciate that the user device 110, merchant system 130, risk analysis system 140, and the financial account issuer system 170 illustrated in FIG. 1 can have any of several other suitable computer system configurations. For example a user computing device 110 embodied as a mobile phone or handheld computer may not include all the components described above. Example Processes The components of the example operating environment 100 are described hereinafter with reference to the example methods illustrated in FIGS. 2-4. FIG. 2 is a block flow diagram depicting a method for transaction risk analysis for a purchase transaction, in accordance with certain example embodiments. With reference to FIGS. 1 and 2, in block 205, a risk analysis system receives registration request of a user 101 and creates a record for the user 101. That is, a user 101 desiring to have one or more financial accounts 172 monitored for fraud risk establishes a record, such as a user account 143, with the risk analysis system 140. For example, the user 101 accesses a website 142 of the risk analysis system 140 to provide information about the user 101 to establish the account. The user information may comprise, for example, the name of the user 101 as well as contact information for the user 101 such as an email address, mailing address, or telephone number for the user 101. The user 101 may also provide or identify specific user financial accounts 172 that the user 101 intends the risk analysis system 140 to monitor. The user 101 may also provide or select configurable rules or preferences governing the user account 143, such as rules governing communications from the risk analysis system 140. For example, the user 101 may request to be notified every time the risk analysis system 140 provides a fraud risk score associated with a purchase transaction as described herein. When providing account information, the user 101 may also provide information regarding the user device 110, such as the Internet protocol address (IP address) for the user device 110. In some embodiments, as part of the registration process, the user 101 also authorizes the risk analysis system 140 to obtain user activity data for the user 101. That is, the user 101 provides consent for the risk analysis system 140 to obtain information about the user's digital activities so that the risk analysis system 140 can monitor the user-specified accounts for potentially fraudulent purchase transactions. For example, the user 101 may authorize the risk analysis system 140 to receive and obtain user activity data, such as user search history data and user location data (based on the location of the user device 110). The user 101 may also authorize the risk analysis system 140 to access email accounts of the user 101. The user 101 may also authorize the risk analysis system 140 to access user data associated with social network websites the user 101 visits, such as posts or emails the user 101 communicates through the social network website. The risk analysis system 140 may also place cookies on the user device 110, at the option and consent of the user 101, so that the risk analysis system 140 can identify the user device 110. In order to obtain the benefits of such monitoring, the user may have to select a setting or install an application, such as the risk analysis application 112. Based on the information that the user 101 provides when establishing an account, the risk analysis system 140 receives the information and establishes a record for the user 101, such as in the user account 143 of the risk analysis system 140. In certain example embodiments, the risk analysis system 140 provides the user 101 with online access to the user account 143. For example, the risk analysis system 140 establishes, with the user 101, a unique username and password that allow the user 101 to access the user account 143. By accessing the user account 143, the user 101 can change the user account rules and preferences, such as the rules regarding the communication of risk scores. The user 101 can also review and revoke any authorizations or consents that the user 101 granted to the risk analysis system 140 during the registration process, including those that permit the risk analysis system 140 to obtain and use user activity data for the user 101. In block 210, the user 101 conducts activity regarding a product. The activity can encompass any activity related to a product. As used herein, a “product” comprises any tangible or intangible product, including services. For example, the product may include merchandise offered for sale at a merchant point-of-sale terminal or at an online retailer. In certain example embodiments, the user 101 may conduct activity for classes of products, such as electronics. In other examples, the user 101 may conduct activities for more specific products, such televisions or even a particular model of television. In certain example embodiments, the user activity comprises online activity, such as searching or researching a product online. For example, a user 101 may conduct a product search via a web browser (not shown) on the user device 110. The user 101 may also visit product manufacturer websites to learn more about a particular product. For example, a user 101 interested in purchasing a television may research product specifications online or conduct online price comparisons for particular televisions. A user 101 may likewise visit a website 136 of a merchant system 130 that offers a particular product, such as a television, for sale. A user 101 looking for a particular service, for example, may visit websites that advertise the service or that provide references, reviews, or rankings for various providers of the service. For example, a user 101 looking for a television repair service may research available television repairmen. The user 101 may likewise research online reviews for a particular television repairman. In other examples, a user 101 may research particular vacation destinations, airfare, or other products or services related to vacation destinations online. A user may also search online for locations offering a product for sale. Additionally or alternatively, in certain example embodiments the user activity comprises communications about a product online, such as on a social network website. For example, user 101 may post information about a product that the user 101 intends to purchase or that the user 101 has recently purchased. The user 101 may also, for example, share photos of the product or solicit information about the product on the social network website. For example, the user 101 may share photos of a vacation destination that the user 101 has visited or intends to visit. A user 101 may likewise comment on products that other users have purchased. For example, a user 101 provide an indication that the user 101 likes a particular product or service that is discussed on the social network website. Additionally or alternatively, in certain example embodiments the user activity comprises electronic communications about a product, such as text messages or emails. For example, a user 101 may email a manufacturer seeking information about product specifications for a particular product. The user 101 may then receive a response email from the manufacturer regarding the product specifications for the product. The user 101 may likewise send or receive emails or texts regarding a product to other users 101. For example, a user 101 may email a contact about a particular television that the user 101 intends to purchase. A user 101 may also send email communicates to contacts or others, such as travel agents, regarding a vacation destination the user 101 intends to visit, for example. Additionally or alternatively, in certain example embodiments the user activity comprises the user 101 obtaining online digital offers for a product of class of products. For example, the user 101 may visit one or more websites to clip digital offers for a product such as a discount offer on a television or vacation package. In certain example embodiments, the user 101 may save the coupons in a digital wallet account of the user 101, such as via the digital wallet application 111. The offer can be any type of offer, such as a ticket, coupon, discount, rebate, voucher, special offer, prepaid offer, or any other type of promotion that can be exchanged for a financial discount or rebate when purchasing a product or service, for example. For online retailers or merchants, for example, the offer may be any type of coupon code, promotional or promo code, discount code, key code, reward code, or any other type code of exchanged for a financial discount on a product. In certain example embodiments, a user 101 may visit a merchant storefront, such as a merchant point-of-sale terminal, to research a product or to purchase a product. Thus, in addition to online activities such as searching for a product, the user activity may include the user 101 visiting a location pertaining to a product. For example, the user 101 may visit various electronics stores when researching a television. A user 101 planning a vacation may likewise visit a travel agent to make arrangements for the vacation. As one skilled in the art will appreciate, a user 101 may visit a variety of different locations in connection with researching and/or purchasing a product. A user 101 will henna generate a variety of activity data regarding a user's location. It will also be appreciated that a user 101 may additionally or alternatively conduct a variety of online activities in connection with researching and/or purchasing a product. The user thus will generate a variety of activity data that includes online activity information. In block 215, the risk analysis system 140 receives user activity data. That is, based on of the user's authorization for the risk analysis system 140 to receive data regarding the user's activities, the risk analysis system 140 receives content generated by the user's activities. For example, the risk analysis system 140 receives online activity information of the user 101 that is generated from the user's online activity, such as a search history of a registered user 101 when the user searches for or researches a product online. The risk analysis system 140 receives, for example, the user search history for televisions (or a particular television) of interest to the user 101. In another example, the risk analysis system 140 may receive a user search history, browser history, email, or text for airfare or other fare to a particular destination. The risk analysis system 140 may likewise receive a web browsing history (or any other online history) related to any online activity of the user 101, such as a history of all the websites the user 101 visits. For example, the risk analysis system 140 may receive a web browsing history for social network sites that the user 101 visits to discuss a product. The risk analysis system 140 will also receive—at the option of the user 101 and as part of the online user activity data—electronic correspondence, such as emails and text messages regarding a product. For example, the risk analysis system 140 may receive email content from the user 101 to a product manufacturer about a particular product. The risk analysis system 140 may also receive user activity data regarding the location of the user device 110 (and hence the user 101). For example, the user activity data may comprise locations, such as electronics stores, that the user 101 has visited when researching or purchasing a television. The risk analysis system 140 obtains the user activity data from any source associated with the user device 110 of the user 101. For example, the user activity data may come from search engine websites, web browsers, social network website accounts, contact list entries, email contacts, or other programs and applications running or operating on the user device 110. To obtain location data for the user device 110, the risk analysis application 112 may rely on a location provider service. For example, the location provider may rely on WiFi signals, cellular communication data, satellites, a Global Positioning System (“GPS”) location technology, a Network Location Provider (“NLP”), a map application, or other location identifying technology of the user device 110 to determine the user device location. The risk analysis application 112 may also rely on WiFi hotspots that are available to the user device 110 to determine the location of the user device 110. The location data can comprise any information that establishes the location of the user device 110, such as a street address, Ordnance Survey Grid Reference information, and/or latitude and longitude coordinates of the device. In certain example embodiments, a risk analysis application 112 on the user device 110 receives the activity data from the user device 110 and communicates the activity data to the risk analysis system 140. The risk analysis system then receives the user activity data. In block 220, the risk analysis system 140 associates user activity data with the user 101 in a record for the user. That is, after the risk analysis system 140 receives the user activity data for a particular user 101, the risk analysis system 140 identifies the record, such as the user account 143, corresponding to the user 101 the generated the activity data. For example, the risk analysis system 140 may identify the record of the user 101 based on cookies placed on the user device 110. The risk analysis system 140 may also determine the Internet protocol address (IP address) for the user device 110 from the user activity data. The risk analysis system 140 may also rely on other information provided by the user 101 to identify the record of the user 101, such as login credentials that the user 101 may provide when logging in to a search engine or social network website, for example. After identifying the record of the user 101, the risk analysis system 140 links the user activity data with the user account 143 so that the activity data is accessible to the risk analysis system 140. For example, the risk analysis system 140 stores the user activity data, along with information for the user account 143, in the data storage unit 147 of the risk analysis system. In certain example embodiments, such as when the risk analysis system 140 operates completely or partially on the user device 110, the risk analysis application 112 may store all or part of the user activity data in the data storage unit 117 of the user device 110. The risk analysis system 140 and/or the risk analysis application 112 then access the use activity data as described herein to determine a risk score for a particular purchase transaction associated a user financial account 172. In block 225, the risk analysis system 140 receives a purchase transaction request involving a user financial account 172. That is, once the risk analysis system 140 has associated user activity data with the record for a particular user 101, the risk analysis system receives receive a request to process a pending or completed purchase transaction involving the user's financial account 172. The purchase transaction comprises information identifying the user 101, such as an account number for the user's financial account 172, as well as information about the product being purchased (such as a television). For example, a purchaser attempts to purchase a product, such as a television, online or at a merchant point-of-sale terminal 134 using an account number associated with the user financial account 172. The purchaser, for example, may be the particular user 101 associated with the user financial account 172. But in other instances, such as when the information for the user's financial account 172 has been stolen, the purchaser may not be the user 101 and hence the purchase transaction is a fraudulent transaction. Based on the attempted purchase, a merchant operator (not shown) associated with the merchant system 130 sends a purchase transaction request to the risk analysis system 140, such as via the network 105. For example, the risk analysis system 140 and the merchant system 130 communicate via a Transmission Control Protocol (TCP)/Internet Protocol (IP). In other example embodiments, the merchant system 130 may rely on conventional credit card processing to indirectly communicate with the risk analysis system 140 over the conventional credit card channels. The risk analysis system 140 then receives the transaction request. Additionally or alternatively, in certain example embodiments a custodian of the financial account, such as the financial account issuer system 170, may send the purchase transaction request. For example, when the financial account issuer system 170 may receive an authorization request for an identified product from a merchant system 130, such as through an acquirer associated with the merchant system 130. The financial account issuer system 170 may then send a purchase transaction request to the risk analysis system 140. In other example embodiments, the financial account issuer system 170 may send the risk analysis system 140 a purchase transaction request for a completed purchase transaction in order to assess the likelihood of fraud associated with the completed transaction. In other embodiments, the risk analysis system 140 may administer or otherwise operate as the custodian of one or more financial accounts for the user 101, such as a digital wallet account for the user 101. In such embodiments, the risk analysis system 140 may evaluate the risk of fraud as described herein for purchase transactions involving the digital wallet account for the user 101. For example, the risk analysis system 140 may receive the purchase transaction request information from the digital wallet application 111 on the user device 110 when the user 101 makes a purchase with the digital wallet application 111. In block 230, the risk analysis system 140 determines a risk score for the purchase transaction. That is, the risk analysis system reads the purchase transaction request to identity both the product associated with the request and the user 101. For example, the risk analysis system 140 may determine that the product is a television. The risk analysis system 140 then locates the record for the identified user 101. The risk analysis system 140 then compares the identified product to the user activity data associated with the record for the user 101 to identify purchase transaction indicators for the product. For example, the risk analysis system 140 looks for a signal in the user activity data for the user 101 indicating that the user would purchase the identified product. If the product is a television, for example, the risk analysis system 140 may look for an indication regarding the particular television. Based on the identified purchase transaction indicators, the risk analysis system 140 determines a risk score for the purchase transaction. Example details of block 230 are described hereinafter with reference to FIG. 3. In block 235, the risk analysis system 140 communicates the risk score to the entity providing the purchase transaction request. That is, after determining a risk score for the purchase transaction request, the risk analysis system 140 transmits the determined risk score to the entity providing the purchase transaction request, such as via the network 105. For example, the risk analysis system 140 communicates the risk score to a merchant that has provided a purchase transaction request for a television. If a custodian of the user financial account 172, such as the financial account issuer system 170, provides the purchase transaction request, then the risk analysis system 140 communicates the risk score to the custodian. The risk score, for example, operates to inform the entity providing the purchase transaction request of the fraud risk associated with the purchase transaction. In certain example embodiments, the risk analysis system 140 may also communicate the risk score to the user 101. After receiving the risk score, the entity receiving the score can take whatever action is appropriate in view of the received risk score, such as asking for additional identity verification from the purchaser. If the product is identified in the user activity data, for example, the risk analysis system 140 provides a risk score to the merchant system 130, for example, indicating that the purchase transaction is not likely to be fraudulent. Alternatively, the product being identified in the user activity data can be used as a positive factor among multiple factors considered in a risk analysis of the transaction. If the product is not identified in the user activity data, for example, the risk analysis system 140 provides a risk score to the merchant system 130, for example, indicating that the purchase transaction is may be fraudulent or that the risk analysis system 140 does not have information to support a positive assessment of the transaction. Alternatively, the product not being identified in the user activity data can be used as a negative or neutral factor among multiple factors considered in a risk analysis of the transaction. FIG. 3 is a block flow diagram depicting a method 230 for determining a risk score for a purchase transaction, in accordance with certain example embodiments, as referenced in block 230 of FIG. 3. With reference to FIGS. 1 and 2, in block 305 of method 230, the risk analysis system 140 reads the purchase transaction request to identify the product associated with purchase transaction and the user information. For example, if the product associated with the purchase transaction is a television, the risk analysis system 140 determines from the content of the purchase transaction request that the product is a television. Likewise, if the product of the purchase transaction is airfare, the risk analysis system 140 determines from the content of the purchase transaction request that the product is airfare. If the product of the purchase transaction is a travel agent service fee, for example, the risk analysis system 140 determines from the content of the purchase transaction request that the product a travel agent service fee. In addition to identifying the product that is the subject of the purchase transaction, the risk analysis system 140 reads the purchase transaction request to identify information associated with the user 101. That is, the risk analysis system 140 reads the purchase transaction for information that allows the risk analysis system 140 to identify the record of the user, such as the user account 143, as described herein. For example, a purchaser may present an account number for a user financial account 172 to complete a transaction. If the account number is provided as part of the purchase transaction request, the risk analysis system 140 identifies the account number, for example. Additionally or alternatively, the risk analysis system 140 may determine other user-identifying information from the purchase transaction request. For example, the purchaser may provider the user's name when attempting to complete a purchase transaction. If the name of the user 101 is included as part of the purchase transaction request, then the risk analysis system 140 determines the name of the user 101 from the purchase transaction request. In certain example embodiments, if the purchase transaction request does not include sufficient information for the risk analysis system 140 to identify either the product or the record of the user 101, then the risk analysis system 140 may seek additional information regarding the purchase transaction request. For example, the risk analysis system 140 may contact the merchant providing the request. In block 310, the risk analysis system 140 locates the record for the user 101 based on information in the purchase transaction request. That is, based on the user-identifying information from the purchase transaction request, the risk analysis system 140 identifies the record of the user 101 associated with the user activity data. For example, the risk analysis system 140 identifies the user account 143 of the risk analysis system 140. To locate the record of the user 101, the risk analysis system 140, for example, compares the user-identifying information of the purchase transaction request with the information for the user account 143. For example, the risk analysis system 140 compares the financial account number received in the purchase transaction request with the financial account numbers that the user 101 provides to the risk analysis system 140 when establishing the user account 143. The risk analysis system 140 then locates the user account 143 based on a match of the financial account numbers. In certain example embodiments, the risk analysis system 140 may identify the record of the user, such as the user account 143, based on other information provided in the purchase transaction request. For example, as described herein the risk analysis system 140 may identify the name of the user from the purchase transaction request. In block 315, the risk analysis system 140 compares the identified product to the user activity data to determine purchase transaction indicators for the product. That is, based on the product identified from the purchase transaction request, the risk analysis system 140 scans the user activity data associated with the record of the user 101 for purchase transaction indicators. The purchase transaction indicators comprise any indication, such as an sign, signal, note, confirmation, corroboration, confirmation, or any other evidence, that user 101 might purchase the product that is the subject of the purchase transaction. As such, the purchase transaction indicators comprise any connection or correlation between the product identified in the purchase transaction request and the activity data associated with the record for the user 101. For example, a user search history for a television would constitute a purchase transaction indicator that the user may purchase the television. Likewise, a user search history for a particular vacation destination—or an email or social network entry about the vacation destination—may serve as an indicator that the user, for example, might purchase airfare (or other fare) to the vacation destination. Similarly, location data showing that the user device (and hence the user) was recently at an electronics store may also serve as an indicator that the user would purchase a television. In another example, location data placing the user 101 at a travel agent may serve as a purchase transaction indication that the user 101 may purchase airfare. As one skilled in the art will appreciate, numerous activities of a user 101 that are included in a user's activity data may service as a purchase transaction indicator of the user 101 for a product that is the subject of a user purchase transaction. For example, the online activity information generated by the online activity of the user 101 may provide one or more purchase transaction indicators for a purchase transaction. If the risk analysis system 140 identifies one or more purchase transaction indicators for a purchase transaction in the user activity data for a user 101, the method follows the “yes” branch of block 320 to block 325. If the risk analysis system 140 does not identify any purchase transaction indicators for a purchase transaction in the user activity data for a user 101, the method follows the “no” branch of block 320 to block 330. From blocks 325 and 330, the method 230 proceeds to block 235 of FIG. 2. In block 325, the risk management system 140 generates a positive risk score. That is, if the risk analysis system 140 identifies at least one purchase transaction indicator for a purchase transaction in the user activity data, the risk management system 140 generates a risk score—in response to the purchase transaction request—that informs the recipient of the risk score that the transaction is less likely to be fraudulent. For example, if the risk management system 140 identifies—based on a purchase transaction request for a television—a purchase transaction indicator for the television, such as a user search for the television, the risk management system 140 generates a positive risk score for the purchase transaction request for the television. If the product is identified in the user activity data, the risk analysis system provides a risk score to the merchant indicating that the purchase transaction is not likely to be fraudulent. Alternatively, the product being identified in the user activity can be used as a positive factor among multiple factors considered in a risk analysis of the transaction. In this case, the risk score is the positive factor provided for consideration by the entity receiving the risk score. In another example, if the purchase transaction concerns an airfare purchase and the user activity data includes a user search for airline tickets, then the risk management system 140 provides a positive risk score for the user's airfare purchase. Likewise, if recent location data places the user device 110 (and hence the user 101) at an electronics store, for example, then the risk management system 140 provides a positive risk score for a user television purchase. In other words, the location data placing the user 101 at the electronics store serves as a purchase transaction indicator for the television. Hence, the risk management system 140 relies on the location data to generate a positive risk score for the television purchase. In certain example embodiments, the positive risk score may be a qualitative risk score. That is, after identifying a purchase transaction indicator for a purchase transaction, the risk analysis system 140 generates a risk score that indicates a lower risk of fraud, but that does not attempt to quantitate the level of risk. For example, the risk analysis system 140 may generate a “yes” score, a “positive” score, a “low risk” score, or any other qualitative-type score that arises from the risk analysis system 140 identifying one or more purchase transaction indicators in the user activity data. The risk analysis system 140 can then communicate such qualitative risk scores to the entity requesting the score, thus informing the entity that the purchase transaction is (or was) less likely to be fraudulent. Additionally or alternatively, the risk analysis system 140 generates a quantitative risk score. That is, the risk analysis system 140 associates with the risk score a measure of likelihood that the purchase transaction is (or was) fraudulent. In certain example embodiments, the risk analysis system 140 provide a risk score that is a function of the number of purchase transaction indicators for a particular purchase transaction that the risk analysis system 140 identifies in the user activity data. For example, a single purchase transaction indicator for a particular purchase transaction may result in a low score, whereas the identification of multiple purchase transaction indicators for the purchase transaction results in a high score. A single purchase transaction indicator that a user would purchase a television, for example, may result in a risk score of “1.” The identification of two indicators, however—such as a search history for the television and location data placing the user device near an electronics store—may results in a risk score of “5” or “6.” The risk score may also be range, for example, such as 1-10, with “1” corresponding to the identification of a single or a few purchase transaction indicators and “10” corresponding to the identification of multiple transaction indicators. In certain example embodiments, the risk score may correspond to the number of purchase transaction indicators that the risk analysis system 140 identifies is in the user activity data. For example, if the risk analysis system 140 identifies 20 purchase transaction indicators, the risk analysis system 140 may generate a risk score of “20.” Additionally or alternatively, in certain example embodiments, the risk analysis system 140 may assign weights to various purchase transaction indicators identified in a user's activity data. That is, in addition or alternatively to being a function of the number of purchase transaction indicators, the risk score may be a function of weighted purchase transaction indicators. The risk analysis system 140, for example, may assign more weight to those purchase transaction indicators that the risk analysis system 140 deems to be more predicative of purchasing the product that is the subject o the purchase transaction. For example, if the purchase transaction involves a television, user emails about a specific television may receive more weight than location data placing the user device near an electronics score. In another example, a user search history for airfare may receive more weight than a user 101 posting non-specific vacation photographs on a social network page. In another example, a user search history for televisions generally may receive less weight than a user search history for a specific television. As those skilled in the art will appreciate, the risk analysis system 140 described herein may determine a number of quantitative risk scores that are a function of the number of purchase transaction indicators and/or the weight assigned to one or more of the purchase transactions. In block 330, the risk management system 140 generates negative or neutral risk score. That is, if the risk management system 140 does not identify any purchase transaction indicators for a particular purchase transaction in the user activity data, the risk management system 140 generates a risk score—in response to the purchase transaction request—that informs the recipient of the risk score that the transaction might be fraudulent or that the risk management system 140 does not have information to assess whether the transaction is fraudulent. In certain example embodiments, the risk management system 140 generates a negative score, for example, such as a “No” score or “likely fraudulent” score. In certain example embodiments, the risk management system 140 may generate a neutral score, such as a “no score available” or “no indicators identified” score. For example, because the absence of a purchase transaction indicator may not necessarily indicate that a transaction is fraudulent—while the existence of purchase transaction indicators may indicate lower likelihood of fraud—the risk management system 140 may generate a neutral score in the absence of an identified purchase transaction indicator for a purchase transaction. Additionally, an absence of the product being identified in the user activity data can be used as a neutral or negative factor among multiple factors considered in a risk analysis of the transaction. In this case, the risk score is the positive factor provided for consideration by the entity receiving the risk score. In certain example embodiments, in addition to receiving user activity data from a user 101, the risk analysis system 140 may independently obtain general information that may be useful to the risk analysis functions of the risk management system 140. For example, the risk analysis system 140 may obtain information for specific merchants, online merchants, retailers, online retailers, service providers, online service providers, restaurants, landmarks, buildings, parks, rail stations, airports, ports, sports arenas, or any other location or entities that might be useful to the risk analysis functions of the risk management system 140. The risk analysis system 140 may obtain the information from any source. For example, the risk analysis system 140 may obtain the information from online sources, such as merchant or retailer websites. The risk analysis system 140 may also categorize the information for use in determining a risk score. A restaurant called “John Doe's Steak House,” for example, may be hierarchically categorized from a specific category to a more general category. That is, beyond the specific name “John Doe's Steak House,” the risk analysis system 140 may categorize the restaurant as a “steak house,” a “fine-dining restaurant,” a “restaurant,” or “food,” with the latter category of “food” being the most generic (in this example). In certain example embodiments, the risk analysis system 140 determines a risk score for a particular user 101 that is a function of both the categorized information and purchase transaction indicators identified in the user activity data. That is, the risk analysis system 140 may weight a purchase transaction indicator based on the category of information to which the identified purchase transaction indicator corresponds. For example, if the risk analysis system 140 receives a purchase transaction request regarding “John Doe's Steak House,” an identified purchase transaction indicator—such as a user search for “John Doe's Steak House”—would receive significantly more weight than a user search for “food.” Continuing with this same example, a search by the user 101 for “steak house” would receive more weight than a user search for a “restaurant.” In another example, the risk analysis system 140 may categorize a television based first on the particular television, and thereafter the “brand name” of the television, “televisions” generally, and then “consumer electronics.” A purchase transaction for the particular television may receive the highest weight, with the categories of “brand name,” “televisions” generally, and “consumer electronics” respectively receiving less and less weight. In certain example embodiments, the risk analysis system 140 determines categorized information for use in a risk score determination in response to receiving a purchase transaction request. For example, the risk analysis system 140 may receive a purchase transaction request for “John Doe's Steak House.” In response to the purchase transaction request, the risk analysis system 140 may determine that the “John Doe's Steak House” is a steak house, and hence further determine categories of “steak house,” “fine-dining restaurant,” “restaurant,” and “food” for “John Doe's Steak House.” The risk analysis system 140 may then, when processing the purchase transaction request for “John Doe's Steak House,” correlate an identified purchase transaction indicator to the determined category as described herein. For example, a purchase transaction indicator, such as a user online search for “steak house,” may receive more weight than a user online search for the more general category of “food.” Likewise, the risk analysis system 140 may receive a purchase transaction request for a particular television. In response to the request, the risk analysis system 140 may determine “brand name,” “televisions,” and “consumer electronics” categories for the television. The risk analysis system 140 can then identify purchase transaction indicators in the user activity data as described herein, and also weight the identified purchase transaction indicators based on the more specific (or less specific) determined categories. For example, a purchase transaction indicator for the “brand name,” such as a search by the user 101 for the “brand name,” may receive more weight than a search by the user 101 for “consumer electronics.” Other Example Embodiments FIG. 4 depicts a computing machine 2000 and a module 2050 in accordance with certain example embodiments. The computing machine 2000 may correspond to any of the various computers, servers, mobile devices, embedded systems, or computing systems presented herein. The module 2050 may comprise one or more hardware or software elements configured to facilitate the computing machine 2000 in performing the various methods and processing functions presented herein. The computing machine 2000 may include various internal or attached components such as a processor 2010, system bus 2020, system memory 2030, storage media 2040, input/output interface 2060, and a network interface 2070 for communicating with a network 2080. The computing machine 2000 may be implemented as a conventional computer system, an embedded controller, a laptop, a server, a mobile device, a smartphone, a set-top box, a kiosk, a vehicular information system, one more processors associated with a television, a customized machine, any other hardware platform, or any combination or multiplicity thereof. The computing machine 2000 may be a distributed system configured to function using multiple computing machines interconnected via a data network or bus system. The processor 2010 may be configured to execute code or instructions to perform the operations and functionality described herein, manage request flow and address mappings, and to perform calculations and generate commands. The processor 2010 may be configured to monitor and control the operation of the components in the computing machine 2000. The processor 2010 may be a general purpose processor, a processor core, a multiprocessor, a reconfigurable processor, a microcontroller, a digital signal processor (“DSP”), an application specific integrated circuit (“ASIC”), a graphics processing unit (“GPU”), a field programmable gate array (“FPGA”), a programmable logic device (“PLD”), a controller, a state machine, gated logic, discrete hardware components, any other processing unit, or any combination or multiplicity thereof. The processor 2010 may be a single processing unit, multiple processing units, a single processing core, multiple processing cores, special purpose processing cores, co-processors, or any combination thereof. According to certain example embodiments, the processor 2010 along with other components of the computing machine 2000 may be a virtualized computing machine executing within one or more other computing machines. The system memory 2030 may include non-volatile memories such as read-only memory (“ROM”), programmable read-only memory (“PROM”), erasable programmable read-only memory (“EPROM”), flash memory, or any other device capable of storing program instructions or data with or without applied power. The system memory 2030 may also include volatile memories such as random access memory (“RAM”), static random access memory (“SRAM”), dynamic random access memory (“DRAM”), and synchronous dynamic random access memory (“SDRAM”). Other types of RAM also may be used to implement the system memory 2030. The system memory 2030 may be implemented using a single memory module or multiple memory modules. While the system memory 2030 is depicted as being part of the computing machine 2000, one skilled in the art will recognize that the system memory 2030 may be separate from the computing machine 2000 without departing from the scope of the subject technology. It should also be appreciated that the system memory 2030 may include, or operate in conjunction with, a non-volatile storage device such as the storage media 2040. The storage media 2040 may include a hard disk, a floppy disk, a compact disc read only memory (“CD-ROM”), a digital versatile disc (“DVD”), a Blu-ray disc, a magnetic tape, a flash memory, other non-volatile memory device, a solid sate drive (“SSD”), any magnetic storage device, any optical storage device, any electrical storage device, any semiconductor storage device, any physical-based storage device, any other data storage device, or any combination or multiplicity thereof. The storage media 2040 may store one or more operating systems, application programs and program modules such as module 2050, data, or any other information. The storage media 2040 may be part of, or connected to, the computing machine 2000. The storage media 2040 may also be part of one or more other computing machines that are in communication with the computing machine 2000 such as servers, database servers, cloud storage, network attached storage, and so forth. The module 2050 may comprise one or more hardware or software elements configured to facilitate the computing machine 2000 with performing the various methods and processing functions presented herein. The module 2050 may include one or more sequences of instructions stored as software or firmware in association with the system memory 2030, the storage media 2040, or both. The storage media 2040 may therefore represent examples of machine or computer readable media on which instructions or code may be stored for execution by the processor 2010. Machine or computer readable media may generally refer to any medium or media used to provide instructions to the processor 2010. Such machine or computer readable media associated with the module 2050 may comprise a computer software product. It should be appreciated that a computer software product comprising the module 2050 may also be associated with one or more processes or methods for delivering the module 2050 to the computing machine 2000 via the network 2080, any signal-bearing medium, or any other communication or delivery technology. The module 2050 may also comprise hardware circuits or information for configuring hardware circuits such as microcode or configuration information for an FPGA or other PLD. The input/output (“I/O”) interface 2060 may be configured to couple to one or more external devices, to receive data from the one or more external devices, and to send data to the one or more external devices. Such external devices along with the various internal devices may also be known as peripheral devices. The I/O interface 2060 may include both electrical and physical connections for operably coupling the various peripheral devices to the computing machine 2000 or the processor 2010. The I/O interface 2060 may be configured to communicate data, addresses, and control signals between the peripheral devices, the computing machine 2000, or the processor 2010. The I/O interface 2060 may be configured to implement any standard interface, such as small computer system interface (“SCSI”), serial-attached SCSI (“SAS”), fiber channel, peripheral component interconnect (“PCI”), PCI express (PCIe), serial bus, parallel bus, advanced technology attached (“ATA”), serial ATA (“SATA”), universal serial bus (“USB”), Thunderbolt, FireWire, various video buses, and the like. The I/O interface 2060 may be configured to implement only one interface or bus technology. Alternatively, the I/O interface 2060 may be configured to implement multiple interfaces or bus technologies. The I/O interface 2060 may be configured as part of, all of, or to operate in conjunction with, the system bus 2020. The I/O interface 2060 may include one or more buffers for buffering transmissions between one or more external devices, internal devices, the computing machine 2000, or the processor 2010. The I/O interface 2060 may couple the computing machine 2000 to various input devices including mice, touch-screens, scanners, electronic digitizers, sensors, receivers, touchpads, trackballs, cameras, microphones, keyboards, any other pointing devices, or any combinations thereof. The I/O interface 2060 may couple the computing machine 2000 to various output devices including video displays, speakers, printers, projectors, tactile feedback devices, automation control, robotic components, actuators, motors, fans, solenoids, valves, pumps, transmitters, signal emitters, lights, and so forth. The computing machine 2000 may operate in a networked environment using logical connections through the network interface 2070 to one or more other systems or computing machines across the network 2080. The network 2080 may include wide area networks (WAN), local area networks (LAN), intranets, the Internet, wireless access networks, wired networks, mobile networks, telephone networks, optical networks, or combinations thereof. The network 2080 may be packet switched, circuit switched, of any topology, and may use any communication protocol. Communication links within the network 2080 may involve various digital or an analog communication media such as fiber optic cables, free-space optics, waveguides, electrical conductors, wireless links, antennas, radio-frequency communications, and so forth. The processor 2010 may be connected to the other elements of the computing machine 2000 or the various peripherals discussed herein through the system bus 2020. It should be appreciated that the system bus 2020 may be within the processor 2010, outside the processor 2010, or both. According to some embodiments, any of the processor 2010, the other elements of the computing machine 2000, or the various peripherals discussed herein may be integrated into a single device such as a system on chip (“SOC”), system on package (“SOP”), or ASIC device. In situations in which the systems discussed here collect personal information about users, or may make use of personal information, the users may be provided with a opportunity or option to control whether programs or features collect user information (e.g., information about a user's social network, social actions or activities, profession, a user's preferences, or a user's current location), or to control whether and/or how to receive content from the content server that may be more relevant to the user. In addition, certain data may be treated in one or more ways before it is stored or used, so that personally identifiable information is removed. For example, a user's identity may be treated so that no personally identifiable information can be determined for the user, or a user's geographic location may be generalized where location information is obtained (such as to a city, ZIP code, or state level), so that a particular location of a user cannot be determined. Thus, the user may have control over how information is collected about the user and used by a content server. Embodiments may comprise a computer program that embodies the functions described and illustrated herein, wherein the computer program is implemented in a computer system that comprises instructions stored in a machine-readable medium and a processor that executes the instructions. However, it should be apparent that there could be many different ways of implementing embodiments in computer programming, and the embodiments should not be construed as limited to any one set of computer program instructions. Further, a skilled programmer would be able to write such a computer program to implement an embodiment of the disclosed embodiments based on the appended flow charts and associated description in the application text. Therefore, disclosure of a particular set of program code instructions is not considered necessary for an adequate understanding of how to make and use embodiments. Further, those skilled in the art will appreciate that one or more aspects of embodiments described herein may be performed by hardware, software, or a combination thereof, as may be embodied in one or more computing systems. Moreover, any reference to an act being performed by a computer should not be construed as being performed by a single computer as more than one computer may perform the act. The example embodiments described herein can be used with computer hardware and software that perform the methods and processing functions described previously. The systems, methods, and procedures described herein can be embodied in a programmable computer, computer-executable software, or digital circuitry. The software can be stored on computer-readable media. For example, computer-readable media can include a floppy disk, RAM, ROM, hard disk, removable media, flash memory, memory stick, optical media, magneto-optical media, CD-ROM, etc. Digital circuitry can include integrated circuits, gate arrays, building block logic, field programmable gate arrays (FPGA), etc. The example systems, methods, and acts described in the embodiments presented previously are illustrative, and, in alternative embodiments, certain acts can be performed in a different order, in parallel with one another, omitted entirely, and/or combined between different example embodiments, and/or certain additional acts can be performed, without departing from the scope and spirit of various embodiments. Accordingly, such alternative embodiments are included in the examples described herein. Although specific embodiments have been described above in detail, the description is merely for purposes of illustration. It should be appreciated, therefore, that many aspects described above are not intended as required or essential elements unless explicitly stated otherwise. Modifications of, and equivalent components or acts corresponding to, the disclosed aspects of the example embodiments, in addition to those described above, can be made by a person of ordinary skill in the art, having the benefit of the present disclosure, without departing from the spirit and scope of embodiments defined in the following claims, the scope of which is to be accorded the broadest interpretation so as to encompass such modifications and equivalent structures.
<SOH> BACKGROUND <EOH>Electronic commerce, such as online shopping, has been increasingly common since the advent of the Internet. Online shopping websites generally provide a user interface for customers to select products to purchase. After the customer has selected products for purchase, the customer typically may choose from multiple payment options to purchase the products. One conventional payment option generally supported by both merchant storefronts and online merchants is the use of a user financial account, such as a credit card account. To make an online purchase with a credit card, for example, a user will commonly enter necessary credit card information online. For example, a user wishing to purchase a product online will enter an account identifier (such as a credit card number, debit card number, etc.), shipping information, and the name, address, and contact information of the user. To make a purchase at a merchant storefront, the user will typically swipe the card or provide the card to a merchant storefront operator that manually enters the credit card information. Although the use of user financial accounts to conduct purchase transactions is convenient for both the user and the merchant, relying on user financial accounts to conduct purchase transactions is subject to fraudulent activity. For example, it is becoming increasingly difficult for online shoppers to keep their credit card information confidential and out of the possession of those who would use that information for fraudulent purposes. Likewise, users that keep a physical credit card must worry about theft of the physical card or the information contained thereon. Merchants themselves even present a potential risk to a user, whether through negligence or intentional fraud. For example, an employee of a merchant may submit erroneous transaction information to the financial institution issuing the financial account. Once a user's financial information is stolen, the user—and the financial institution issuing the financial account—has limited means of determining whether subsequent purchases are legitimate or fraudulent. And while fraud detection systems have been developed that rely on historical transaction data of the user in an attempt to predict subsequent user transactions, the narrow focus of these systems on user transaction history continues to leave users vulnerable to fraud. Such systems are thus inadequate at detecting fraud.
<SOH> SUMMARY <EOH>In certain example aspects described herein, a computer-implemented method for transaction risk analysis is provided. A risk analysis system receives a registration from a user that desires to have their purchase transactions monitored for possible fraudulent activity. The risk analysis system, for example, receives user activity data associated with a user, such as online activity information that is generated by the user's online activity. The risk analysis system associates the user activity data with a record for the user. The risk analysis system then receives a purchase transaction request, such as from a merchant computing system. The purchase transaction request identifies a product for a purchase transaction involving a financial account of the user and provides information sufficient to identify the record of the user. Based on the information in the purchase transaction request, for example, the risk analysis system identifies the record of the user. The risk analysis system then compares the identity of the product with the online activity information for the user to determine a purchase transaction indicator for the product in the online activity information. The purchase transaction indicator, for example, provides an indication that the user may purchase the product. Based on the comparison of the identity of the product with the online activity information for the user, the risk analysis system determines a risk score or indicator for the purchase transaction and communicates the risk score or indicator to the merchant computing system. In certain other example aspects, a system for transaction risk analysis provided herein. Also provided in certain aspects is a computer program product to analyze transaction risk. These and other aspects, objects, features and advantages of the example embodiments will become apparent to those having ordinary skill in the art upon consideration of the following detailed description of illustrated example embodiments.
G06Q204016
20170811
20171130
64483.0
G06Q2040
0
ZIMMERMAN, MATTHEW E
METHOD, MEDIUM, AND SYSTEM FOR ONLINE FRAUD PREVENTION
UNDISCOUNTED
1
CONT-ACCEPTED
G06Q
2,017
15,675,789
ACCEPTED
CONCEALABLE BODY ARMOR AND COMBINATION BAG/VEST
Described herein are combination bag/vests which, in a bag configuration, serve as a functional bag and which, in a vest configuration, include a system for attaching one or more modular accessories to the vest in a desired configuration. Also described herein are such combination bag/vests wherein the vest configuration operates as a tactical personal body armor vest and the bag configuration conceals the tactical vest portion while permitting the one or more modular accessories to remain in the desired configuration.
1. A combination bag/vest comprising: a vest comprising: a chest covering portion and a back covering portion the chest covering portion and back covering portion each portion having a vest surface; a pair of separable shoulder straps each connecting an upper portion of the chest covering portion with an upper portion of the back covering portion to form and defining a head opening; a modular accessory attachment system disposed on a vest surface of the chest and/or back covering portions for attaching one or more modular accessories to the chest and/or back covering elements in a desired configuration; and a bag comprising: at least one back bag layer attached to the back covering portion opposite the vest surface; at least one chest bag layer attached to the chest covering portion opposite the vest surface; a back fastener band extending from the at least one back bag layer and a chest fastener band extending from the at least one chest bag layer; and at least one fastener for fastening the back fastener band to the chest fastener band; wherein, in a vest configuration, the vest surface of the chest covering portion the vest surface of the back covering portion faces away from a wearer of the vest; wherein, in a bag configuration, the back fastener band and the chest fastener band are at least partially fastened such that the back bag layer and the chest bag layer are exposed and the vest surfaces of the chest covering portion and back covering portion are concealed; wherein the desired configuration of the one or more modular accessories attached to the modular accessory attachment system on the vest surface of the chest and/or back covering portions is maintained in both the vest configuration and the bag configuration; and wherein, in a bag configuration, the desired configuration of the one or more modular accessories attached to the modular accessory attachment system on the vest surface of the chest and/or back covering portions is concealed from view. 2. The combination bag/vest of claim 1, wherein the at least one fastener is a zipper. 3. The combination bag/vest of claim 1, wherein the vest further comprises at least one securing device for securing the vest to the wearer by securing a lower end of the back covering portion to a lower end of the chest covering portion. 4. The combination bag/vest of claim 1, wherein, in the bag configuration, the combination bag/vest is configured to appear to be one or more of a briefcase, a backpack, a duffel bag, a laptop case, a beach bag, a diaper bag, a satchel, and/or a purse. 5. The combination bag/vest of claim 4, wherein, in the bag configuration, the bag functions as the one or more of a briefcase, a backpack, a duffel bag, a laptop case, a beach bag, a diaper bag, a satchel, and/or a purse, the concealment portion including one or more compartments and/or pockets. 6. The combination bag/vest of claim 1, wherein the vest further comprises one or more PALS webbing elements disposed on a surface of the shoulder straps for routing at least one tube and/or wire between the chest covering portion and the back covering portion. 7. The combination bag/vest of claim 1, further comprising at least one closeable chest pouch defined in the chest covering portion between an outer chest textile layer and an interior chest textile layer for receiving one or more inserts and/or at least one closeable back pouch defined in the back covering portion between an outer back textile layer and an interior back textile layer for receiving one or more inserts. 8. The combination bag/vest of claim 7, wherein the at least one closeable back pouch and/or the at least one closeable chest pouch are configured to receive one or more armor plates. 9. The combination bag/vest of claim 7, wherein the at least one closeable back pouch and/or the at least one closeable chest pouch are configured to receive one or more floatation elements. 10. The combination bag/vest of claim 7, wherein the at least one closeable back pouch and/or the at least one closeable chest pouch are configured to receive one or more insulation elements. 11. The combination bag/vest of claim 1, wherein the chest covering portion and/or the back covering portion includes an insulating layer and at least one reflective element disposed on the vest surface. 12. The combination bag/vest of claim 1, wherein the modular accessory attachment system includes a plurality of Pouch Attachment Ladder System (PALS) webbing elements attaching one or more Modular Lightweight Load-carrying Equipment (MOLLE)-compatible accessories to the chest and/or back covering elements in a desired configuration.
CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation application claiming the benefit of U.S. patent application Ser. No. 14/153,687, filed Jan. 13, 2014, the disclosure of which is herein incorporated by reference. BACKGROUND 1. Field of the Invention The present invention relates generally to multifunction garments and personal body armor and more particularly to a combination bag/vest and concealable personal body armor. 2. Discussion of Background Information Police officers and military personnel generally wear tactical personal body armor vests such as bullet resistant vests into a situation with the potential for violence such as gun fire. Such tactical vests are generally tailored to provide maximal protection and maneuverability for the wearer. These vests also generally have systems for attaching, in any configuration desired by the wearer, tactical gear such as, for example, pouches for ammunition or first aid gear and holsters for radios, stun guns, knives, tear gas, or sidearms. Unfortunately, these personnel are often placed in mission scenarios where overtly wearing a bullet resistant vest and/or carrying weapons, ammunition, or other tactical gear is impossible. For example, an undercover police officer investigating a criminal organization may have arranged for a raid on a gathering of his subjects. However, as an attendee of the gathering, that officer would not be able to wear personal body armor such as a tactical bullet resistant vest without raising suspicion. Without armor and/or other tactical gear, this officer's life will be at increased risk in the likely event of violence. Unfortunately, other than carrying such tactical gear in a bag or overtly wearing it, there are few options available to such personnel. One known option is a foldable armor curtain which may be stored inconspicuously in a briefcase or other carrying device but provides only limited protection for the user, who must hold up and hide behind the curtain, similar to an oversized shield carried by a medieval knight. Furthermore, such devices obstruct the user's vision and maneuverability and provide no back protection. Another known option is a two piece armor “vest” where the two pieces zip together to form a rifle/gun bag. However, such devices are large and conspicuous, thereby providing minimal, if any concealment of the armor and/or other tactical gear. Furthermore, the two pieces lack any of the shaping or tailoring found in a true tactical vest. Additionally, these known options do not offer means for attaching or configuring other tactical gear such as ammunition, mace, radios, stun guns, etc. Therefore, a user of such options is provided with only limited protection while suffering from minimal concealment of the equipment, restricted movement, and a tactical disadvantage caused by having insufficient available gear arranged in an unfamiliar configuration. In other applications, various activities such as, for example, hunting, hiking, camping, boating, canoeing/kayaking, fishing, diving, etc. also require important gear and/or tools. This gear, e.g., fishing lures, fishing hooks, whistles, rations, ammunition, floatation, tools, knives, flashlights, axes, and/or any other suitable equipment can sometimes be kept in a carried bag or pack, but participation in the activities can, at times, dictate that some gear must be kept on the person of a participant in the activity. Garments such as hunting vests or fishing vests generally serve a specific purpose, e.g., increasing observability of the wearer or holding a small amount of fishing equipment, but overall provide minimal functionality for the user. No options exist to such participants for a means of rapidly transferring gear from a bag or pack onto the participant's person in the participant's preferred configuration. SUMMARY OF THE INVENTION It would be desirable to produce a combination bag/vest which, in a bag configuration, serves as a functional bag and which, in a vest configuration, includes a system for attaching one or more accessories in a desired configuration. It would also be desirable to produce such combination bag/vests wherein the vest configuration operates as a tactical personal body armor vest and the bag configuration conceals the tactical vest portion while permitting the one or more accessories to remain in the desired configuration. Described herein are devices and techniques for solving the problems, such as limited protection, restriction of movement, conspicuousness, and the inability to deploy tactical gear, associated with current body armors and for providing participants in various activities a means of rapidly transferring gear from a bag or pack onto the participant's person in the participant's preferred configuration. The combination bag/vest described herein includes a vest portion having a chest covering portion, shoulder straps, and a back covering portion and a system for attaching modular accessories to the chest and/or back covering portions. The combination bag/vest also includes a bag portion having a back bag layer and a chest bag layer attached to the back and chest portions, respectively, and a fastener for connecting the back bag layer to the chest bag layer. In a bag configuration the system for attaching modular accessories and any attached accessories face inward and the back and chest bag layers face outward. In a vest configuration the system for attaching modular accessories and any attached accessories face outward and the back and chest bag layers face a chest and a back of a wearer of the vest. In one aspect, at least one embodiment described herein provides a combination bag/vest. The combination bag/vest includes a vest. The vest includes a chest covering portion and a back covering portion. The vest also includes a central portion including shoulder straps, the shoulder straps connecting an upper end of the chest covering portion to an upper end of the back covering portion. The vest also includes a modular accessory attachment system disposed on a vest surface of the chest and/or back covering portions for attaching one or more modular accessories to the chest and/or back covering elements in a desired configuration. The combination bag/vest also includes a bag. The bag includes at least one back bag layer attached to the back covering portion opposite the vest surface. The bag also includes at least one chest bag layer attached to the chest covering portion opposite the vest surface. The bag also includes at least one fastener for fastening the back bag layer to the chest bag layer. The combination bag/vest wherein, in a vest configuration, the vest surface of the outer chest and/or back textile layers faces away from a wearer of the vest. The combination bag/vest wherein, in a bag configuration, the at least one back bag layer and the at least one chest bag layer are at least partially fastened and face outward and the vest surface of the chest and/or back covering portions faces inward. The combination bag/vest wherein the desired configuration of the one or more modular accessories attached to the modular accessory attachment system on the vest surface of the chest and/or back covering portions is maintained in both the vest configuration and the bag configuration. Any of the embodiments described herein can include one or more of the following embodiments. In some embodiments, the at least one fastener is a zipper. In some embodiments, the vest further comprises at least one securing device for securing the vest to the wearer by securing a lower end of the back covering portion to a lower end of the chest covering portion. In some embodiments, in the bag configuration, the combination bag/vest is configured to appear to be one or more of a briefcase, a backpack, a duffel bag, a laptop case, a beach bag, a diaper bag, a satchel, and/or a purse. In some embodiments, in the bag configuration, the bag functions as the one or more of a briefcase, a backpack, a duffel bag, a laptop case, a beach bag, a diaper bag, a satchel, and/or a purse, the concealment portion including one or more compartments and/or pockets. In some embodiments, the vest further comprises one or more PALS webbing elements disposed on a surface of the shoulder straps for routing at least one tube and/or wire between the chest covering portion and the back covering portion. In some embodiments, the combination bag/vest further comprises at least one closeable chest pouch defined in the chest covering portion between an outer chest textile layer and an interior chest textile layer for receiving one or more inserts and/or at least one closeable back pouch defined in the back covering portion between an outer back textile layer and an interior back textile layer for receiving one or more inserts. In some embodiments, the at least one closeable back pouch and/or the at least one closeable chest pouch are configured to receive one or more armor plates. In some embodiments, the at least one closeable back pouch and/or the at least one closeable chest pouch are configured to receive one or more floatation elements. In some embodiments, the at least one closeable back pouch and/or the at least one closeable chest pouch are configured to receive one or more insulation elements. In some embodiments, the chest covering portion and/or the back covering portion includes an insulating layer and at least one reflective element disposed on the vest surface. In some embodiments, the chest covering portion and/or the back covering portion includes one or more side covering portions. In some embodiments, the one or more side covering portions further comprise at least one closeable side pouch defined in the one or more side covering portions between an outer side textile layer and an interior side textile layer for receiving one or more inserts. In some embodiments, the modular accessory attachment system includes a plurality of Pouch Attachment Ladder System (PALS) webbing elements attaching one or more Modular Lightweight Load-carrying Equipment (MOLLE)-compatible accessories to the chest and/or back covering elements in a desired configuration. In one aspect, at least one embodiment described herein provides a concealable body armor. The concealable body armor includes an armor vest. The vest includes a chest covering portion and a back covering portion. The vest also includes a central portion including shoulder straps, the shoulder straps connecting an upper end of the chest covering portion to an upper end of the back covering portion. The vest also includes at least one closeable chest pouch defined in the chest covering portion between an outer chest textile layer and an interior chest textile layer for receiving one or more armor plates. The vest also includes at least one closeable back pouch defined in the back covering portion between an outer back textile layer and an interior back textile layer for receiving one or more armor plates. The vest also includes a plurality of Pouch Attachment Ladder System (PALS) webbing elements disposed on a surface of the outer chest and/or back textile layers for attaching one or more Modular Lightweight Load-carrying Equipment (MOLLE)-compatible accessories to the chest and/or back covering elements in a desired configuration. The concealable body armor also includes a concealment portion. The concealment portion includes at least one back concealment layer attached to the interior back textile layer opposite the outer back textile layer. The concealment portion also includes at least one chest concealment layer attached to the interior chest textile layer opposite the outer chest textile layer. The concealment portion also includes at least one fastener for connecting the back concealment layer to the chest concealment layer. The concealable body armor wherein, in a deployed state, the at least one back concealment layer and at least one chest concealment layer face a back and a chest, respectively, of a wearer of the armor vest. The concealable body armor wherein, in a concealed state, the at least one back concealment layer and at least one chest concealment layer are at least partially fastened and face outward and the outer chest and back textile layers face inward. The concealable body armor wherein the desired configuration of the one or more MOLLE-compatible accessories attached to the plurality of PALS webbing elements on the chest and back covering portions is maintained in both the deployed state and the concealed state. Any of the embodiments described herein can include one or more of the following embodiments. In some embodiments the at least one closeable back pouch and the at least one closeable chest pouch are configured to receive the one or more armor plates in any size up to 11 inches in width and 14 inches in height. In some embodiments, in the concealed state, the concealable body armor is configured to appear to be one or more of a briefcase, a backpack, a duffel bag, a laptop case, a beach bag, a diaper bag, a satchel, and/or a purse. In some embodiments, in the concealed state, the concealable body armor functions as the one or more of a briefcase, a backpack, a duffel bag, a laptop case, a beach bag, a diaper bag, a satchel, and/or a purse, the concealment portion including one or more compartments and/or pockets. In some embodiments, the chest covering portion and/or the back covering portion includes one or more side covering portions. In some embodiments, the one or more side covering portions further comprise at least one closeable side pouch defined in the one or more side covering portions between an outer side textile layer and an interior side textile layer for receiving one or more armor plates. In some embodiments, the vest further comprises one or more PALS webbing elements disposed on a surface of the shoulder straps for routing at least one tube and/or wire between the chest covering portion and the back covering portion. BRIEF DESCRIPTION OF THE DRAWINGS One will better understand these and other features, aspects, and advantages of the present invention following a review of the description, appended claims, and accompanying drawings: FIG. 1 is an isometric view of a combination bag/vest in a bag configuration in accordance with various embodiments. FIG. 2 is an isometric view of a combination bag/vest in a partially deployed configuration in accordance with various embodiments. FIG. 3 is a top view of a combination bag/vest in fully deployed, unworn vest configuration in accordance with various embodiments. FIG. 4 is a top view of a combination bag/vest in separated, unworn vest configuration in accordance with various embodiments. FIG. 5 is a front bottom view of a combination bag/vest in accordance with various embodiments. FIG. 6 is a side view of a combination bag/vest in a vest configuration and in accordance with various embodiments. FIG. 7 is a close up side view of a combination bag/vest in a vest configuration in accordance with various embodiments. FIG. 8 is a view of a chest portion of a combination bag/vest in a vest configuration in accordance with various embodiments. FIG. 9 is a close up view of a chest portion of a combination bag/vest showing PALS webbing in accordance with various embodiments. FIG. 10 is an isometric view of a partially deployed combination bag/vest having pre-configured modular accessories equipped thereon in accordance with various embodiments. FIG. 11 is a view of a chest portion of a combination bag/vest having modular accessories equipped thereon in a first configuration in accordance with various embodiments. FIG. 12 is a close up view of a chest portion of a combination bag/vest having modular accessories equipped thereon in a second configuration in accordance with various embodiments. FIG. 13 is a close up view of a closeable bag pocket of a combination bag/vest in a bag configuration in accordance with various embodiments. DETAILED DESCRIPTION Described herein are combination bag/vests which, in a bag configuration, serve as a functional bag and which, in a vest configuration, include a system for attaching one or more accessories in a desired configuration. Also described herein are such combination bag/vests wherein the vest configuration operates as a tactical personal body armor vest and the bag configuration conceals the tactical vest portion while permitting the one or more accessories to remain in the desired configuration. The combination bag/vests described herein include a vest portion having a chest covering portion, shoulder straps, and a back covering portion and a system for attaching modular accessories to the chest and/or back covering portions. The combination bag/vest also includes a bag portion having a back bag layer and a chest bag layer attached to the back and chest portions, respectively, and a fastener for connecting the back bag layer to the chest bag layer. In a bag configuration the system for attaching modular accessories and any attached accessories face inward and the back and chest bag layers face outward. In a vest configuration the system for attaching modular accessories and any attached accessories face outward and the back and chest bag layers face a chest and a back of a wearer of the vest. Although the combination bag/vest is illustrated herein to show an exemplary briefcase/body armor vest, it will be apparent in view of this disclosure that any number of bag and/or vest configurations can be used. For example, the bag configuration can appear to be and/or function as a briefcase, a backpack, a duffel bag, a laptop case, a beach bag, a diaper bag, a satchel, a purse, and/or any other suitable bag or luggage. The vest configuration can be a simple textile vest or can be configured to contain floatation elements, armor plates, insulation elements, and/or any other suitable features. Additionally, the configuration and appearance of the vest can be designed for various specific applications such as, for example, a hunting vest, a construction crew vest, a fishing vest, a diving or snorkeling vest, a canoeing or kayaking vest, a personal floatation device, and/or a vest for any other purpose. As shown in FIGS. 1-9, various embodiments of a combination bag/vest 100 include a bag 100a and a vest 100b. As best shown in FIGS. 3, 4, and 6 the vest 100b, in accordance with various embodiments, includes a chest covering portion 107 for being worn over a chest of a wearer of the vest 100b, a back covering portion 109 for being worn over a back of the wearer, and shoulder straps 111 defining a head opening 112 for being worn on shoulders of the wearer and for connecting an upper portion of the chest covering portion 107 with an upper portion of the back covering portion 109. As best shown in FIGS. 1 and 2, the bag 100a includes a chest bag layer 101 attached to the chest covering portion 107 of the vest 100b, a back bag layer 102 attached to the back covering portion 109 of the vest 100b, and a fastener 103, e.g., a zipper as shown, for connecting the chest bag layer 101 to the back bag layer 102. In a bag 100a configuration the chest covering portion 107 and the back covering portion 109 face inward and the chest 101 and back 102 bag layers face outward. In a vest 100b configuration the chest covering portion 107 and the back covering portion 109 face outward and the chest 101 and back 102 bag layers face a chest and a back of a wearer of the vest as shown, for example, in FIGS. 6 and 7. As best shown in FIGS. 1 and 2, the fastener 103 may be disposed along a chest fastener band 104 and a back fastener band 106. The chest 104 and back 106 fastener bands each connect to and extend from the appropriate bag layer, i.e., the chest fastener band 104 connects to and extends from the chest bag layer 101, and the back fastener band 106 connects to and extends from the back bag layer 102. When attached using the fastener 103, the chest fastener band 104 and the back fastener band 106 provide the bag 100a with sufficient depth to adequately conceal any equipment fastened to the chest covering portion 107 or the back covering portion 109. As depicted in FIG. 1, the back fastener band 106 may be wider than the chest fastener band 104 to ensure that the chest fastener band 104 does not interfere with the user during operation in the vest 100b configuration. However, in some embodiments the chest fastener band 104 may be wider than the back fastener band 106 or the chest 104 and back 106 fastener bands may be the same width. As shown in FIGS. 1-7, in accordance with various embodiments, when the combination bag/vest 100 is in the bag 100a configuration and the vest 100b is concealed by the bag 100a, e.g., as shown in FIG. 1, a wearer can convert the combination bag/vest 100 from a bag 100a configuration to a vest 100b configuration in three simple steps. First, the wearer uses the fastener 103 to unfasten the chest bag layer 101 of the bag 100a from the back bag layer 102 of the bag 100a, e.g., as shown in FIG. 2. Second, the wearer separates the chest and back bag layers 101, 102 to reveal the chest covering portion 107 of the vest 100b, the back covering portion 109 of the vest 100b, and the head opening 112 defined by the shoulder straps, e.g., as shown in FIG. 3. Third, the wearer then passes his or her head through the head opening 112 with the chest and back covering portions 107, 109 facing outward and secures one or more securing devices 117 around his or her torso, e.g., as shown in FIGS. 6 and 7, at which point the vest 100b is deployed and ready for use by the wearer. As shown in FIG. 10, in accordance with various embodiments, maximum efficiency in establishing tactical readiness can be achieved by configuring one or more modular accessories 201 on a modular accessory attachment system 113 on the chest and/or back covering portions 107, 109 prior to use so that the wearer's desired complement and configuration of equipment is available for use upon full deployment of the vest 100b. The shoulder straps 111 are configured for being worn on the shoulders of the wearer and for connecting an upper portion of the chest covering portion 107 with an upper portion of the back covering portion 109. The shoulder straps 111, in cooperation with the chest covering portion 107 and back covering portion 109 define a head opening 112 for passing the head and neck of the wearer, allowing the shoulder straps 111 to rest on the shoulders of the wearer. In accordance with various embodiments, the shoulder straps 111 can be adjustable (as shown) and/or fixed in length. In accordance with various embodiments, the shoulder straps 111 can be simple straight straps or can be shaped and/or padded for added ergonomic function and wearer comfort. As shown in FIG. 6, the shoulder straps 111 may be formed by overlapping a chest strap portion 111a and a back strap portion 111b. In this embodiment, the chest strap portion 111a and the back strap portion 111b may overlay each other, providing a degree of movement to ensure proper positioning of the shoulder straps 111 when resting on the shoulders of the wearer. One of skill in the art will appreciate that the chest strap portion 111a and the back strap portion 111b may be temporarily secured using hook and loop fasteners, buttons, snaps, laces, hook-and-eye, buckles, or a combination thereof. Removably securing the chest strap portion 111a and the back strap portion 111b provides the additional benefit of allowing the user to adjust the shoulder straps 111 to the correct size, without worrying that the shoulder straps 111 will shift as a result of putting the vest 100b on or taking the vest 100b off. In embodiments where the shoulder straps 111 are formed by overlaying chest 111a and back 111b strap portions, it is preferable that reinforcing straps 114, which connect to the chest covering portion 107 and the back covering portion 109 as best shown in FIG. 3, reinforce the shoulder straps 111. When included, the reinforcing straps 114 may be removably secured using a buckle or other fastener as known in the art. As best shown in FIG. 4, a pair of chest strap portions 111a extend from the chest covering portion 107, while a pair of back strap portions 111b extend from the back covering portion 109. As depicted in FIG. 6, each of the chest strap portions 111a overlaps the corresponding back strap portion 111b, to form a shoulder strap 111. As depicted in FIG. 4, the chest strap portions 111a and the back strap portions 111b are distinct sections. As will be readily apparent to one of skill in the art, the chest strap portion 111a and the back strap portion 111b may be overlapped such that either portion is on top without deviating from the scope of the present invention. The chest covering portion 107 and the back covering portion 109 may be separated completely by separating the chest strap portion 111a and the back strap portion 111b as shown in FIG. 4. In embodiments where a reinforcing strap 114 is present, complete separation further requires separating the reinforcing straps 114. Complete separation of the chest covering portion 107 and the back covering portion 109 is advantageous because it allows users to preconfigure one or more additional chest covering portions 107 and/or one or more back covering portions 109 with one or more modular accessories 201 on a modular accessory attachment system 113. These preconfigured chest covering portions 107 and/or back covering portions 109 may then be quickly and easily interchanged, so that the wearer's desired compliment and configuration of equipment is available for use upon full deployment of the vest 100b. The chest covering portion 107, the back covering portion 109 of the vest 100b include at least one textile layer, which can be constructed of any suitable material, including for example but not limited to, nylon, cotton, polyester, polypropylene, wool, leather, Kevlar, canvas, any woven textile, any non-woven textile, any tricot, any knit textile, and/or any other suitable material. In accordance with various embodiments, the chest covering portion 107 and/or the back covering portion 109 includes one or more closeable pouches 123 defined by an outer textile layer and an inner textile layer. As best shown in FIG. 5, the closeable pouches 123 can be configured for receiving one or more inserts 125. Inserts 125, in accordance with various embodiments, can include armor plates, trauma plates, floatation elements, insulation elements, padding elements, heating elements, cooling elements, hydration system bladders, and/or any other suitable insert 125. In accordance with various embodiments, armor and/or trauma plate inserts 125 can be of any type, protection rating, size, and/or shape e.g., conforming to one or more size and/or performance requirements prescribed by the U.S. National Institute of Justice (NIJ) standards, the UK Home Office Scientific development branch standards, U.S. Armed Forces Small Arms Protective Insert (SAPI) standards, U.S. Armed Forces Enhanced Small Arms Protective Insert (ESAPI) standards, and/or any other standard. As shown in FIG. 3, in accordance with various embodiments, the chest covering portion 107 and/or the back covering portion 109 can include one or more optional side covering portions 118. The side covering portions 118 shown in FIG. 3 are small extensions of the one or more textile layers to provide improved fit and a more stable securing of the vest to the wearer. However, it will be apparent in view of this disclosure that the side covering portions can also include more comprehensive side coverage. In such embodiments the side covering portions can include one or more closeable side pouches, defined by an outer textile layer and an inner textile layer, similar to the chest and/or back closeable pouches 123. The closeable side pouches can, in accordance with various embodiments, be configured to receive one or more side inserts, which, can be, but are not limited to, the inserts 125 described above with reference to the chest and/or back closeable pouches 123. As shown in FIGS. 3-7, the vest 100b can, in accordance with various embodiments, include one or more securing devices 117 for securing a lower end of the chest covering portion 107 with a lower end of the back covering portion 109. Securing devices 117 can be, for example, one or more of a belt, a strap, an adjustable strap, laces, a buckle, a clip, a ratchet strap, and/or any other suitable securing device. In accordance with various embodiments, the securing devices can be attached to the chest covering portion 107 and/or the back covering portion 109. In accordance with various embodiments having side covering portions 118, the securing devices 117 can be attached to the side covering portions 118. As best shown in FIGS. 3, 8, and 9, the chest covering portion 107 and/or the back covering portion 109 of the vest 100b includes a modular accessory attachment system 113. As shown, the modular accessory attachment system 113 includes a plurality of Pouch Attachment Ladder System (PALS) webbing elements disposed on a vest surface, i.e., the surface that faces outward when the vest 100b is being worn, of the chest covering portion 107 and/or the back covering portion 109 for attaching one or more modular accessories 201, e.g., Modular Lightweight Load-carrying Equipment (MOLLE)-compatible accessories 201a, 201b as shown in FIGS. 10-12. The modular accessory attachment system 113 advantageously allows a wearer of the vest 100b to attach one or more modular accessories to the vest 100b in any configuration desired by the user. It will be apparent in view of this disclosure that any other modular accessory attachment system 113 such as, for example, loop and/or hook fabric for mating with hook and/or loop fabric on one or more modular accessories, snaps for snapping on accessories, and/or any other suitable system can also be used in accordance with various embodiments. By way of example, as shown in FIG. 11, the wearer of the vest 100b has attached two modular accessories 201 to the chest covering portion 109 in a first configuration which includes two MOLLE-compatible pouch accessories 201a. As shown in FIG. 12, a different wearer of the vest 100b has attached four modular accessories 201 to the chest covering portion 109 in a second configuration which includes one MOLLE-compatible pouch accessory 201a and three MOLLE-compatible ammunition clip holder accessories 201b. It will be apparent in view of this disclosure that the first and second configurations are provided for example only and that any type and/or number of modular accessories 201 can be attached to the chest covering portion 107, the back covering portion 109, and/or the shoulder straps 111 in any configuration desired by the wearer. As best shown in FIG. 10, which shows a combination bag/vest 100 having been partially converted from the bag 100a configuration into the vest 100b configuration, the combination bag/vest 100 is advantageously designed to convert between the bag 100a configuration and the vest 100b configuration with the one or more modular accessories 201 attached to the modular accessory attachment system 113. This design allows the vest 100b to be deployed with all of the modular accessories 201 already attached and in the configuration preferred by the wearer. The time required to achieve full deployment is therefore advantageously reduced and the wearer suffers none of the tactical disadvantages associated with unfamiliar equipment configurations. As shown in FIGS. 3 and 11, the modular accessory attachment system 113 can also be disposed on one or more of the shoulder straps 111. In accordance with various embodiments, PALS webbing elements can be disposed on the shoulder straps 111 for attaching modular accessories 201 and/or for routing one or more wires and/or tubes 205 between the back covering portion 109 and the chest covering portion 107. Such wires and/or tubes 205 can include, for example but not limited to, radio wires, hydration tubes (as shown in FIG. 11), oxygen/breathing tubes, and/or electrical power cords. As best shown in FIGS. 3 and 11, the chest covering portion 107, back covering portion 109, and/or shoulder straps 111 of vest 100b can also include additional features such as, for example, a gear attachment member 115 and/or loop fabric for retaining an informational placard 203 and/or other additional gear. Gear attachment members 115, in accordance with various embodiments, can include any clip, buckle, and/or any other type of releasable attachment suitable for attaching a weapon, e.g., a gun as shown in FIG. 11, a whistle, an oar or paddle, an electronic device, and/or any other gear desired by the wearer. Placards 203, in accordance with various embodiments, can include any patches, nametags, or other devices mateable with loop fabric. Such placards 203, in accordance with various embodiments, can be configured to convey any desired information, e.g., displaying an American flag, identifying the wearer as “SHERRIF”, and/or providing medical information such as blood type as shown in FIG. 11. As best shown in FIGS. 1 and 2, the bag 100a includes a chest bag layer 101 attached to the chest covering portion 107 of the vest 100b, a back bag layer 102 attached to the back covering portion 109 of the vest 100b, and a fastener 103, e.g., a zipper as shown, for connecting the chest bag layer 101 to the back bag layer 102. In the bag 100a configuration, the chest covering portion 107 and the back covering portion 109 face inward and the chest 101 and back 102 bag layers face outward. As shown in FIG. 1, in accordance with various embodiments, when the combination bag/vest 100 is in the bag 100a configuration the vest 100b is concealed by the bag 100a. In accordance with some embodiments, this feature advantageously allows a wearer to inconspicuously maintain access to personal protection and/or tactical equipment. The chest and back bag layers 101, 102 can be constructed of one or more layers of any suitable material, including for example but not limited to, nylon, cotton, polyester, polypropylene, wool, leather, Kevlar, canvas, any woven textile, any non-woven textile, any tricot, any knit textile, and/or any other suitable material. In general, to provide inconspicuous concealment of the vest 100b, the chest and back bag layers 101, 102 should be constructed from materials and designed to have an appearance consistent with the desired bag 100a configuration, e.g., a briefcase as shown in FIG. 1. Although the bag 100a configuration as illustrated herein shows only a simple exemplary briefcase for clarity, it will be apparent in view of this disclosure that any number of bag 100a configurations can be used. For example, the bag 100a configuration can include chest and back bag layers 101, 102 that appear to be and/or function as a briefcase, a backpack, a duffel bag, a laptop case, a beach bag, a diaper bag, a satchel, a purse, and/or any other suitable bag or luggage. As shown in FIGS. 1 and 13, the bag 100a can include any number, size, shape, and style of bag pockets, e.g., zippable pocket 301 as shown in FIG. 13, storage compartments, and/or other additional features, e.g., handles 105 as shown in FIG. 1, buttons, snaps, flaps, embroidery, and/or patches. These additional features can, in accordance with various embodiments, be included to allow the bag 100a and the chest and back layers 101, 102 to achieve appropriate function and/or appearance consistent with the bag 100a configuration of the particular combination bag/vest 100. In accordance with some embodiments, the chest bag layer 101 and/or the back bag layer 102 are fixedly attached (e.g., glued, sewn, stitched, and/or heat pressed) to the chest covering portion 107 and/or back covering portion 109 of the vest 100b. In accordance with various embodiments, the chest bag layer and/or the back bag layer 102 are removably attached (e.g., zipped, snapped, fastened by hook and loop fastener, and/or pinned) to the chest covering portion 107 and/or back covering portion 109 of the vest 100b. Such removable chest and back bag layers 101, 102 can, in accordance with various embodiments, advantageously provide a means for altering the appearance of the bag 100a configuration as appropriate for various activities and/or missions. For example, a first set of chest and back bag layers 101, 102 could be configured to appear and function as a briefcase at the office. However, a briefcase is inappropriate for a day at the beach and would be conspicuous. Accordingly, rather than owning two combination bag/vests 100 (one appearing to be a briefcase and one appearing to be a beach bag), the wearer of a combination bag/vest 100 having removable chest and back bag layers 101, 102 could simply swap the first set of chest and back bag layers 101, 102 for a second set of chest and back bag layers 101, 102 configured to appear and function as a beach bag. Accordingly, combination bag/vests which, in a bag configuration, serve as a functional bag and which, in a vest configuration, include a system for attaching one or more modular accessories to the vest in a desired configuration are provided herein. Also described herein are such combination bag/vests wherein the vest configuration operates as a tactical personal body armor vest and the bag configuration conceals the tactical vest portion while permitting the one or more modular accessories to remain in the desired configuration. It is noted that the foregoing examples have been provided merely for the purpose of explanation and are in no way to be construed as limiting of the present invention. While the present invention has been described with reference to an exemplary embodiment, it is understood that the words, which have been used herein, are words of description and illustration, rather than words of limitation. Changes may be made, within the purview of the appended claims, as presently stated and as amended, without departing from the scope and spirit of the present invention in its aspects. Although the present invention has been described herein with reference to particular means, materials and embodiments, the present invention is not intended to be limited to the particulars disclosed herein; rather, the present invention extends to all functionally equivalent structures, methods and uses, such as are within the scope of the appended claims.
<SOH> BACKGROUND <EOH>
<SOH> SUMMARY OF THE INVENTION <EOH>It would be desirable to produce a combination bag/vest which, in a bag configuration, serves as a functional bag and which, in a vest configuration, includes a system for attaching one or more accessories in a desired configuration. It would also be desirable to produce such combination bag/vests wherein the vest configuration operates as a tactical personal body armor vest and the bag configuration conceals the tactical vest portion while permitting the one or more accessories to remain in the desired configuration. Described herein are devices and techniques for solving the problems, such as limited protection, restriction of movement, conspicuousness, and the inability to deploy tactical gear, associated with current body armors and for providing participants in various activities a means of rapidly transferring gear from a bag or pack onto the participant's person in the participant's preferred configuration. The combination bag/vest described herein includes a vest portion having a chest covering portion, shoulder straps, and a back covering portion and a system for attaching modular accessories to the chest and/or back covering portions. The combination bag/vest also includes a bag portion having a back bag layer and a chest bag layer attached to the back and chest portions, respectively, and a fastener for connecting the back bag layer to the chest bag layer. In a bag configuration the system for attaching modular accessories and any attached accessories face inward and the back and chest bag layers face outward. In a vest configuration the system for attaching modular accessories and any attached accessories face outward and the back and chest bag layers face a chest and a back of a wearer of the vest. In one aspect, at least one embodiment described herein provides a combination bag/vest. The combination bag/vest includes a vest. The vest includes a chest covering portion and a back covering portion. The vest also includes a central portion including shoulder straps, the shoulder straps connecting an upper end of the chest covering portion to an upper end of the back covering portion. The vest also includes a modular accessory attachment system disposed on a vest surface of the chest and/or back covering portions for attaching one or more modular accessories to the chest and/or back covering elements in a desired configuration. The combination bag/vest also includes a bag. The bag includes at least one back bag layer attached to the back covering portion opposite the vest surface. The bag also includes at least one chest bag layer attached to the chest covering portion opposite the vest surface. The bag also includes at least one fastener for fastening the back bag layer to the chest bag layer. The combination bag/vest wherein, in a vest configuration, the vest surface of the outer chest and/or back textile layers faces away from a wearer of the vest. The combination bag/vest wherein, in a bag configuration, the at least one back bag layer and the at least one chest bag layer are at least partially fastened and face outward and the vest surface of the chest and/or back covering portions faces inward. The combination bag/vest wherein the desired configuration of the one or more modular accessories attached to the modular accessory attachment system on the vest surface of the chest and/or back covering portions is maintained in both the vest configuration and the bag configuration. Any of the embodiments described herein can include one or more of the following embodiments. In some embodiments, the at least one fastener is a zipper. In some embodiments, the vest further comprises at least one securing device for securing the vest to the wearer by securing a lower end of the back covering portion to a lower end of the chest covering portion. In some embodiments, in the bag configuration, the combination bag/vest is configured to appear to be one or more of a briefcase, a backpack, a duffel bag, a laptop case, a beach bag, a diaper bag, a satchel, and/or a purse. In some embodiments, in the bag configuration, the bag functions as the one or more of a briefcase, a backpack, a duffel bag, a laptop case, a beach bag, a diaper bag, a satchel, and/or a purse, the concealment portion including one or more compartments and/or pockets. In some embodiments, the vest further comprises one or more PALS webbing elements disposed on a surface of the shoulder straps for routing at least one tube and/or wire between the chest covering portion and the back covering portion. In some embodiments, the combination bag/vest further comprises at least one closeable chest pouch defined in the chest covering portion between an outer chest textile layer and an interior chest textile layer for receiving one or more inserts and/or at least one closeable back pouch defined in the back covering portion between an outer back textile layer and an interior back textile layer for receiving one or more inserts. In some embodiments, the at least one closeable back pouch and/or the at least one closeable chest pouch are configured to receive one or more armor plates. In some embodiments, the at least one closeable back pouch and/or the at least one closeable chest pouch are configured to receive one or more floatation elements. In some embodiments, the at least one closeable back pouch and/or the at least one closeable chest pouch are configured to receive one or more insulation elements. In some embodiments, the chest covering portion and/or the back covering portion includes an insulating layer and at least one reflective element disposed on the vest surface. In some embodiments, the chest covering portion and/or the back covering portion includes one or more side covering portions. In some embodiments, the one or more side covering portions further comprise at least one closeable side pouch defined in the one or more side covering portions between an outer side textile layer and an interior side textile layer for receiving one or more inserts. In some embodiments, the modular accessory attachment system includes a plurality of Pouch Attachment Ladder System (PALS) webbing elements attaching one or more Modular Lightweight Load-carrying Equipment (MOLLE)-compatible accessories to the chest and/or back covering elements in a desired configuration. In one aspect, at least one embodiment described herein provides a concealable body armor. The concealable body armor includes an armor vest. The vest includes a chest covering portion and a back covering portion. The vest also includes a central portion including shoulder straps, the shoulder straps connecting an upper end of the chest covering portion to an upper end of the back covering portion. The vest also includes at least one closeable chest pouch defined in the chest covering portion between an outer chest textile layer and an interior chest textile layer for receiving one or more armor plates. The vest also includes at least one closeable back pouch defined in the back covering portion between an outer back textile layer and an interior back textile layer for receiving one or more armor plates. The vest also includes a plurality of Pouch Attachment Ladder System (PALS) webbing elements disposed on a surface of the outer chest and/or back textile layers for attaching one or more Modular Lightweight Load-carrying Equipment (MOLLE)-compatible accessories to the chest and/or back covering elements in a desired configuration. The concealable body armor also includes a concealment portion. The concealment portion includes at least one back concealment layer attached to the interior back textile layer opposite the outer back textile layer. The concealment portion also includes at least one chest concealment layer attached to the interior chest textile layer opposite the outer chest textile layer. The concealment portion also includes at least one fastener for connecting the back concealment layer to the chest concealment layer. The concealable body armor wherein, in a deployed state, the at least one back concealment layer and at least one chest concealment layer face a back and a chest, respectively, of a wearer of the armor vest. The concealable body armor wherein, in a concealed state, the at least one back concealment layer and at least one chest concealment layer are at least partially fastened and face outward and the outer chest and back textile layers face inward. The concealable body armor wherein the desired configuration of the one or more MOLLE-compatible accessories attached to the plurality of PALS webbing elements on the chest and back covering portions is maintained in both the deployed state and the concealed state. Any of the embodiments described herein can include one or more of the following embodiments. In some embodiments the at least one closeable back pouch and the at least one closeable chest pouch are configured to receive the one or more armor plates in any size up to 11 inches in width and 14 inches in height. In some embodiments, in the concealed state, the concealable body armor is configured to appear to be one or more of a briefcase, a backpack, a duffel bag, a laptop case, a beach bag, a diaper bag, a satchel, and/or a purse. In some embodiments, in the concealed state, the concealable body armor functions as the one or more of a briefcase, a backpack, a duffel bag, a laptop case, a beach bag, a diaper bag, a satchel, and/or a purse, the concealment portion including one or more compartments and/or pockets. In some embodiments, the chest covering portion and/or the back covering portion includes one or more side covering portions. In some embodiments, the one or more side covering portions further comprise at least one closeable side pouch defined in the one or more side covering portions between an outer side textile layer and an interior side textile layer for receiving one or more armor plates. In some embodiments, the vest further comprises one or more PALS webbing elements disposed on a surface of the shoulder straps for routing at least one tube and/or wire between the chest covering portion and the back covering portion.
A41D1504
20170814
20180109
20171130
97819.0
A41D1504
2
QUINN, RICHALE LEE
CONCEALABLE BODY ARMOR AND COMBINATION BAG/VEST
SMALL
1
CONT-ACCEPTED
A41D
2,017
15,675,895
PENDING
Combinatory Score Having a Fitness Sub-Score and an Athleticism Sub-Score
Example embodiments may relate to a system, method, apparatus, and computer readable media configured for monitoring a user performing an athletic movement and/or exercise and generating a combinatory fitness athleticism score. The score may comprise a fitness sub-score and a fitness sub-score. The athletic movement may comprise a plurality of drills configured to test a plurality of fitness attributes and/or a plurality of athleticism attributes of the user. At least one of the plurality of fitness attributes may be selected from the group consisting of: endurance, flexibility, strength and combinations thereof; and at least one of the plurality of athleticism attributes may be selected from the group consisting of: speed, agility, reaction, power, balance, and combinations thereof.
1. A computer-implemented method comprising: providing first instructions to a user to perform a first athletic movement; receiving, from a sensor, first activity data representing the first athletic movement; calculating with a processor, based on the first activity data, a first combinatory fitness-athleticism score; providing, in response to a triggering event, second instructions to the user to perform a second athletic movement,; receiving, from the sensor, second activity data representing the second athletic movement; calculating, with the processor, based on the second activity data, a second combinatory fitness-athleticism score, wherein the first and the second combinatory fitness-athleticism scores each comprise a fitness sub-score and a separate athleticism sub-score of the user, wherein the fitness sub-score is calculated, by the processor, using one or more of an endurance fitness attribute, a flexibility fitness attribute and a strength fitness attribute of the user, and wherein the athleticism sub-score is calculated, by the processor, using one or more of a speed athleticism attribute, an agility athleticism attribute, a reaction athleticism attribute, a power athleticism attribute and a balance athleticism attribute of the user. 2. The method of claim 1, wherein the triggering event is based on a detected heart rate of the user. 3. The method of claim 1, wherein the triggering event is based on a detected geographic location of the user. 4. The method of claim 1, further comprising: providing an indication of an activity that the user can perform that will not cause injury, based upon the first and second combinatory fitness-athleticism scores for the user. 5. The method of claim 1, wherein the first athletic movement comprises predefined criteria, the method further comprising: providing the first instructions to the user to perform, during a first time period, the first athletic movement. 6. The method of claim 1, wherein the first instructions and the second instructions include a plurality of drills configured to test a plurality of fitness attributes of the user and a plurality of athleticism attributes of the user. 7. The method of claim 1, wherein the first instructions and the second instructions include a predefined ordering of drills that are configured to be provided to the user during a single workout session. 8. The method of claim 1, wherein the fitness sub-score is based upon a percentile rank of the user within a population of users. 9. The method of claim 1, wherein the athleticism sub-score is based upon a percentile rank of the user within a population of users. 10. The method of claim 5, wherein at least one of the endurance fitness attribute, the flexibility fitness attribute and the strength fitness attribute and at least one of the speed athleticism attribute, the agility athleticism attribute, the reaction athleticism attribute, the power athleticism attribute and the balance athleticism attribute is determined by calculating an energy expenditure estimate during a performance by the user of at least a portion of the criteria. 11. The method of claim 10, wherein the energy expenditure estimate is determined utilizing a metabolic equivalent of task (MET) table for a type of an exercise that the user performs during an athletic performance by the user. 12. The method of claim 1, wherein the sensor comprises an accelerometer. 13. An apparatus configured to be worn by a user, comprising: a structure configured to be worn around an appendage of a user comprising a sensor configured to capture movement data from the appendage of the user; a processor; and a non-transitory computer-readable medium comprising computer-executable instructions that when executed by a processor cause the processor to perform at least: providing first instructions to the user to perform a first athletic movement; receiving first movement data captured from the sensor during the first athletic movement of the user; calculating, from the received first movement data, a first combinatory fitness-athleticism score; providing, in response to a triggering event, second instructions to the user to perform a second athletic movement; receiving second movement data captured from the sensor during the second athletic movement of the user; and calculating, from the received second movement data, a second combinatory fitness-athleticism score, wherein the first and second combinatory fitness-athleticism score each comprise a fitness sub-score and a separate athleticism sub-score of the user; wherein the fitness sub-score is calculated using one or more of an endurance fitness attribute, a flexibility fitness attribute and a strength fitness attribute of the user, and wherein the athleticism sub-score is calculated using one or more of a speed athleticism attribute, an agility athleticism attribute, a reaction athleticism attribute, a power athleticism attribute and a balance athleticism attribute of the user. 14. The apparatus of claim 13, wherein the triggering event is based on a detected heart rate of the user. 15. The apparatus of claim 13, wherein the triggering event is based on a detected geographic location of the user. 16. The apparatus of claim 13, wherein the sensor is a first sensor and the apparatus further comprises a second sensor configured to capture movement data and the computer-readable medium further comprises computer-executable instructions that when executed by the processor cause the processor to perform at least: utilizing movement data from the second sensor in the calculation of the first and second combinatory fitness-athletici sm scores. 17. The apparatus of claim 13, wherein the sensor is a first sensor and the computer-readable medium further comprises computer-executable instructions that when executed by the processor cause the processor to perform at least: utilizing movement data captured from a second sensor that is located externally from the apparatus in the calculation of the first and second combinatory fitness-athleticism scores. 18. The apparatus of claim 13, wherein the sensor is a first sensor and the computer-readable medium further comprises computer-executable instructions that when executed by the processor cause the processor to perform at least: receiving the movement data from a second sensor located externally from the apparatus; and based upon the movement data from the second sensor, instructing the user to perform an athletic movement with a predefined criterion. 19. The apparatus of claim 13, wherein the sensor is an accelerometer. 20. The apparatus of claim 13, wherein the computer-readable medium further comprises computer-executable instructions that when executed by the processor cause the processor to perform at least: providing an indication of an activity that the user can perform that will not cause injury, based upon the first and second combinatory fitness-athleticism scores for the user.
CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 15/074,682, filed Mar. 18, 2016, which is a continuation of U.S. application Ser. No. 13/909,832, filed Jun. 4, 2013, now U.S. Pat. No. 9,289,674, which claims the benefit of U.S. Provisional Patent Application No. 61/655,365, filed Jun. 4, 2012, which are each incorporated herein by reference in their entirety for any and all non-limiting purposes. BACKGROUND While most people appreciate the importance of physical fitness, many have difficulty finding the motivation required to maintain a regular exercise program. Some people find it particularly difficult to maintain an exercise regimen that involves continuously repetitive motions, such as running, walking and bicycling. Additionally, individuals may view exercise as work or a chore and thus, separate it from enjoyable aspects of their daily lives. Often, this clear separation between athletic activity and other activities reduces the amount of motivation that an individual might have toward exercising. Further, athletic activity services and systems directed toward encouraging individuals to engage in athletic activities might also be too focused on one or more particular activities while an individual's interest are ignored. This may further decrease a user's interest in participating in athletic activities or using the athletic activity services and systems. Therefore, improved systems and methods to address these and other shortcomings in the art are desired. SUMMARY The following presents a simplified summary of the present disclosure in order to provide a basic understanding of some aspects of the invention. This summary is not an extensive overview of the invention. It is not intended to identify key or critical elements of the invention or to delineate the scope of the invention. The following summary merely presents some concepts of the invention in a simplified form as a prelude to the more detailed description provided below. Aspects relate to systems and methods for estimating a combined or a combinatory fitness-athleticism score comprised of a fitness sub-score and an athleticism sub-score. The fitness-athleticism score may be estimated based on a user's athletic movements, wherein the user's athletic movements are monitored by a first sensor. Further aspects relate to an apparatus configured to be worn by a user. The apparatus may comprise a structure that is worn around an appendage of the user. The apparatus may include a sensor configured to capture data related to the movement of the appendage of the user. The apparatus also includes a processor, and a non-transitory computer-readable medium with computer-executable instructions. The computer-executable instructions may be executed by a processor, including the local processor, to receive movement data captured by the sensor, and/or to estimate a combined fitness-athleticism score from the received movement data. This combined athleticism score may comprise a fitness sub-score and an athleticism sub-score. In yet another aspect, this disclosure relates to a computer-implemented method for receiving data related to the physical movements of a user from a first sensor on a wrist-worn device. The received motion data may be utilized to estimate, using a processor, a combinatory fitness-athleticism score, wherein the combinatory fitness-athleticism score may comprise a fitness sub-score and an athleticism sub-score. The method further displays a combinatory fitness-athleticism score on a display device. This Summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. The Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter. BRIEF DESCRIPTION OF THE DRAWINGS The present disclosure is illustrated by way of example and not limited in the accompanying figures in which like reference numerals indicate similar elements and in which: FIGS. 1A-B illustrate an example of a system for providing personal training in accordance with example embodiments, wherein FIG. 1A illustrates an example network configured to monitor athletic activity, and FIG. 1B illustrates an example computing device in accordance with example embodiments. FIGS. 2A-B illustrate example sensor assemblies that may be worn by a user in accordance with example embodiments. FIG. 3 illustrates an example flow diagram of a method for calculating an energy expenditure estimate for a user that accounts for a user's form while exercising as part of the estimate, in accordance with example embodiments. FIG. 4 illustrates example points on a user's body for monitoring during exercising in accordance with example embodiments. FIG. 5 illustrates an example posture assessment in accordance with example embodiments. FIG. 6 illustrates example displays of a virtual avatar of a user performing an exercise in accordance with example embodiments. FIGS. 7A-B illustrate example displays of a virtual avatar of a user performing a squat in accordance with example embodiments. FIG. 8 illustrates an example flow diagram of a method for calculating an energy expenditure estimate for a user while performing an athletic activity based on monitoring changes in potential energy, in accordance with example embodiments. FIGS. 9, 10A-B, and 11 illustrate example locations of centers of mass for a virtual avatar of user, in accordance with example embodiments. FIG. 12 provides an example graphical user interface (GUI) showing an example combinatory score comprising a fitness sub-score and an athleticism sub-score. FIG. 13 shows an example listing of fitness attributes and athleticism attributes in accordance with one embodiment. FIG. 14 shows an example GUI having a user-selectable fitness sub-score in accordance with one embodiment. FIG. 15 shows an example GUI displaying a plurality of fitness attributes in accordance with one embodiment. FIG. 16 shows an example GUI displaying a plurality of results for an example fitness attribute in accordance with one embodiment of the invention. FIG. 17 shows an example GUI providing a plurality of selectable populations that a user may compare a combinatory score, sub-score, and/or values with as well as an indication of energy expenditure for the user. DETAILED DESCRIPTION In the following description of the various embodiments, reference is made to the accompanying drawings, which form a part hereof, and in which is shown by way of illustration various embodiments in which the disclosure may be practiced. It is to be understood that other embodiments may be utilized and structural and functional modifications may be made without departing from the scope and spirit of the present disclosure. Further, headings within this disclosure should not be considered as limiting aspects of the disclosure. Those skilled in the art with the benefit of this disclosure will appreciate that the example embodiments are not limited to the example headings. I. Example Personal Training System A. Illustrative Computing Devices FIG. 1A illustrates an example of a personal training system 100 in accordance with example embodiments. Example system 100 may include one or more electronic devices, such as computer 102. Computer 102 may comprise a mobile terminal, such as a telephone, music player, tablet, netbook or any portable device. In other embodiments, computer 102 may comprise a set-top box (STB), desktop computer, digital video recorder(s) (DVR), computer server(s), and/or any other desired computing device. In certain configurations, computer 102 may comprise a gaming console, such as for example, a Microsoft® XBOX, Sony® Playstation, and/or a Nintendo® Wii gaming consoles. Those skilled in the art will appreciate that these are merely example consoles for descriptive purposes and this disclosure is not limited to any console or device. Turning briefly to FIG. 1B, computer 102 may include computing unit 104, which may comprise at least one processing unit 106. Processing unit 106 may be any type of processing device for executing software instructions, such as for example, a microprocessor device. Computer 102 may include a variety of non-transitory computer readable media, such as memory 108. Memory 108 may include, but is not limited to, random access memory (RAM) such as RAM 110, and/or read only memory (ROM), such as ROM 112. Memory 108 may include any of: electronically erasable programmable read only memory (EEPROM), flash memory or other memory technology, CD-ROM, digital versatile disks (DVD) or other optical disk storage, magnetic storage devices, or any other medium that can be used to store the desired information and that can be accessed by computer 102. The processing unit 106 and the system memory 108 may be connected, either directly or indirectly, through a bus 114 or alternate communication structure to one or more peripheral devices. For example, the processing unit 106 or the system memory 108 may be directly or indirectly connected to additional memory storage, such as a hard disk drive 116, a removable magnetic disk drive, an optical disk drive 118, and a flash memory card. The processing unit 106 and the system memory 108 also may be directly or indirectly connected to one or more input devices 120 and one or more output devices 122. The output devices 122 may include, for example, a display device 136, television, printer, stereo, or speakers. In some embodiments one or more display devices may be incorporated into eyewear. The display devices incorporated into eyewear may provide feedback to users. Eyewear incorporating one or more display devices also provides for a portable display system. The input devices 120 may include, for example, a keyboard, touch screen, a remote control pad, a pointing device (such as a mouse, touchpad, stylus, trackball, or joystick), a scanner, a camera or a microphone. In this regard, input devices 120 may comprise one or more sensors configured to sense, detect, and/or measure athletic movement from a user, such as user 124, shown in FIG. 1A. As used herein, an “athletic movement” includes movements relating to fitness, exercise, flexibility, including movements that may be part of one or more single and multiple participant athletic competitions, exercise routines, and/or combinations thereof. Looking again to FIG. 1A, image-capturing device 126 and/or sensor 128 may be utilized in detecting and/or measuring athletic movements of user 124. In one embodiment, data obtained from image-capturing device 126 or sensor 128 may directly detect athletic movements, such that the data obtained from image-capturing device 126 or sensor 128 is directly correlated to a motion parameter. For example, and with reference to FIG. 4, image data from image-capturing device 126 may detect that the distance between sensor locations 402g and 402i has decreased and therefore, image-capturing device 126 alone may be configured to detect that user's 124 right arm has moved. Yet, in other embodiments, data from image-capturing device 126 and/or sensor 128 may be utilized in combination, either with each other or with other sensors to detect and/or measure movements. Thus, certain measurements may be determined from combining data obtained from two or more devices. Image-capturing device 126 and/or sensor 128 may include or be operatively connected to one or more sensors, including but not limited to: an accelerometer, a gyroscope, a location-determining device (e.g., GPS), light sensor, temperature sensor (including ambient temperature and/or body temperature), heart rate monitor, image-capturing sensor, moisture sensor and/or combinations thereof. Example uses of illustrative sensors 126, 128 are provided below in Section I.C, entitled “Illustrative Sensors.” Computer 102 may also use touch screens or image capturing device to determine where a user is pointing to make selections from a graphical user interface. One or more embodiments may utilize one or more wired and/or wireless technologies, alone or in combination, wherein examples of wireless technologies include Bluetooth® technologies, Bluetooth® low energy technologies, and/or ANT technologies. B. Illustrative Network Still further, computer 102, computing unit 104, and/or any other electronic devices may be directly or indirectly connected to one or more network interfaces, such as example interface 130 (shown in FIG. 1B) for communicating with a network, such as network 132. In the example of FIG. 1B, network interface 130, may comprise a network adapter or network interface card (NIC) configured to translate data and control signals from the computing unit 104 into network messages according to one or more communication protocols, such as the Transmission Control Protocol (TCP), the Internet Protocol (IP), and the User Datagram Protocol (UDP). These protocols are well known in the art, and thus will not be discussed here in more detail. An interface 130 may employ any suitable connection agent for connecting to a network, including, for example, a wireless transceiver, a power line adapter, a modem, or an Ethernet connection. Network 132, however, may be any one or more information distribution network(s), of any type(s) or topology(s), alone or in combination(s), such as internet(s), intranet(s), cloud(s), LAN(s). Network 132 may be any one or more of cable, fiber, satellite, telephone, cellular, wireless, etc. Networks are well known in the art, and thus will not be discussed here in more detail. Network 132 may be variously configured such as having one or more wired or wireless communication channels to connect one or more locations (e.g., schools, businesses, homes, consumer dwellings, network resources, etc.), to one or more remote servers 134, or to other computers, such as similar or identical to computer 102. Indeed, system 100 may include more than one instance of each component (e.g., more than one computer 102, more than one display 136, etc.). Regardless of whether computer 102 or other electronic device within network 132 is portable or at a fixed location, it should be appreciated that, in addition to the input, output and storage peripheral devices specifically listed above, the computing device may be connected, such as either directly, or through network 132 to a variety of other peripheral devices, including some that may perform input, output and storage functions, or some combination thereof. In certain embodiments, a single device may integrate one or more components shown in FIG. 1A. For example, a single device may include computer 102, image-capturing device 126, sensor 128, display 136 and/or additional components. In one embodiment, sensor device 138 may comprise a mobile terminal having a display 136, image-capturing device 126, and one or more sensors 128. Yet, in another embodiment, image-capturing device 126, and/or sensor 128 may be peripherals configured to be operatively connected to a media device, including for example, a gaming or media system. Thus, it goes from the foregoing that this disclosure is not limited to stationary systems and methods. Rather, certain embodiments may be carried out by a user 124 in almost any location. C. Illustrative Sensors Computer 102 and/or other devices may comprise one or more sensors 126, 128 configured to detect and/or monitor at least one fitness parameter of a user 124. Sensors 126 and/or 128 may include, but are not limited to: an accelerometer, a gyroscope, a location-determining device (e.g., GPS), light sensor, temperature sensor (including ambient temperature and/or body temperature), sleep pattern sensors, heart rate monitor, image-capturing sensor, moisture sensor and/or combinations thereof. Network 132 and/or computer 102 may be in communication with one or more electronic devices of system 100, including for example, display 136, an image capturing device 126 (e.g., one or more video cameras), and sensor 128, which may be an infrared (IR) device. In one embodiment sensor 128 may comprise an IR transceiver. For example, sensors 126, and/or 128 may transmit waveforms into the environment, including towards the direction of user 124 and receive a “reflection” or otherwise detect alterations of those released waveforms. In yet another embodiment, image-capturing device 126 and/or sensor 128 may be configured to transmit and/or receive other wireless signals, such as radar, sonar, and/or audible information. Those skilled in the art will readily appreciate that signals corresponding to a multitude of different data spectrums may be utilized in accordance with various embodiments. In this regard, sensors 126 and/or 128 may detect waveforms emitted from external sources (e.g., not system 100). For example, sensors 126 and/or 128 may detect heat being emitted from user 124 and/or the surrounding environment. Thus, image-capturing device 126 and/or sensor 128 may comprise one or more thermal imaging devices. In one embodiment, image-capturing device 126 and/or sensor 128 may comprise an IR device configured to perform range phenomenology. As a non-limited example, image-capturing devices configured to perform range phenomenology are commercially available from Flir Systems, Inc. of Portland, Oreg. Although image capturing device 126 and sensor 128 and display 136 are shown in direct (wirelessly or wired) communication with computer 102, those skilled in the art will appreciate that any may directly communicate (wirelessly or wired) with network 132. 1. Multi-Purpose Electronic Devices User 124 may possess, carry, and/or wear any number of electronic devices, including sensory devices 138, 140, 142, and/or 144. In certain embodiments, one or more devices 138, 140, 142, 144 may not be specially manufactured for fitness or athletic purposes. Indeed, aspects of this disclosure relate to utilizing data from a plurality of devices, some of which are not fitness devices, to collect, detect, and/or measure athletic data. In one embodiment, device 138 may comprise a portable electronic device, such as a telephone or digital music player, including an IPOD®, IPAD®, or iPhone®, brand devices available from Apple, Inc. of Cupertino, Calif. or Zune® or Microsoft® Windows devices available from Microsoft of Redmond, Wash. As known in the art, digital media players can serve as both an output device for a computer (e.g., outputting music from a sound file or pictures from an image file) and a storage device. In one embodiment, device 138 may be computer 102, yet in other embodiments, computer 102 may be entirely distinct from device 138. Regardless of whether device 138 is configured to provide certain output, it may serve as an input device for receiving sensory information. Devices 138, 140, 142, and/or 144 may include one or more sensors, including but not limited to: an accelerometer, a gyroscope, a location-determining device (e.g., GPS), light sensor, temperature sensor (including ambient temperature and/or body temperature), heart rate monitor, image-capturing sensor, moisture sensor and/or combinations thereof. In certain embodiments, sensors may be passive, such as reflective materials that may be detected by image-capturing device 126 and/or sensor 128 (among others). In certain embodiments, sensors 144 may be integrated into apparel, such as athletic clothing. For instance, the user 124 may wear one or more on-body sensors 144a-b. Sensors 144 may be incorporated into the clothing of user 124 and/or placed at any desired location of the body of user 124. Sensors 144 may communicate (e.g., wirelessly) with computer 102, sensors 128, 138, 140, and 142, and/or camera 126. Examples of interactive gaming apparel are described in U.S. patent application Ser. No. 10/286,396, filed Oct. 30, 2002, and published as U.S. Pat. Pub, No. 2004/0087366, the contents of which are incorporated herein by reference in its entirety for any and all non-limiting purposes. In certain embodiments, passive sensing surfaces may reflect waveforms, such as infrared light, emitted by image-capturing device 126 and/or sensor 128. In one embodiment, passive sensors located on user's 124 apparel may comprise generally spherical structures made of glass or other transparent or translucent surfaces which may reflect waveforms. Different classes of apparel may be utilized in which a given class of apparel has specific sensors configured to be located proximate to a specific portion of the user's 124 body when properly worn. For example, golf apparel may include one or more sensors positioned on the apparel in a first configuration and yet soccer apparel may include one or more sensors positioned on apparel in a second configuration. Devices 138-144 may communicate with each other, either directly or through a network, such as network 132. Communication between one or more of devices 138-144 may communicate through computer 102. For example, two or more of devices 138-144 may be peripherals operatively connected to bus 114 of computer 102. In yet another embodiment, a first device, such as device 138 may communicate with a first computer, such as computer 102 as well as another device, such as device 142, however, device 142 may not be configured to connect to computer 102 but may communicate with device 138. Those skilled in the art will appreciate that other configurations are possible. Some implementations of the example embodiments may alternately or additionally employ computing devices that are intended to be capable of a wide variety of functions, such as a desktop or laptop personal computer. These computing devices may have any combination of peripheral devices or additional components as desired. Also, the components shown in FIG. 1B may be included in the server 134, other computers, apparatuses, etc. 2. Illustrative Apparel/Accessory Sensors In certain embodiments, sensory devices 138, 140, 142 and/or 144 may be formed within or otherwise associated with user's 124 clothing or accessories, including a watch, armband, wristband, necklace, shirt, shoe, or the like. Examples of shoe-mounted and wrist-worn devices (devices 140 and 142, respectively) are described immediately below, however, these are merely example embodiments and this disclosure should not be limited to such. i. Shoe-Mounted Device In certain embodiments, sensory device 140 may comprise footwear which may include one or more sensors, including but not limited to: an accelerometer, location-sensing components, such as GPS, and/or a force sensor system. FIG. 2A illustrates one example embodiment of a sensor system 202. In certain embodiments, system 202 may include a sensor assembly 204. Assembly 204 may comprise one or more sensors, such as for example, an accelerometer, location-determining components, and/or force sensors. In the illustrated embodiment, assembly 204 incorporates a plurality of sensors, which may include force-sensitive resistor (FSR) sensors 206. In yet other embodiments, other sensor(s) may be utilized. Port 208 may be positioned within a sole structure 209 of a shoe. Port 208 may optionally be provided to be in communication with an electronic module 210 (which may be in a housing 211) and a plurality of leads 212 connecting the FSR sensors 206 to the port 208. Module 210 may be contained within a well or cavity in a sole structure of a shoe. The port 208 and the module 210 include complementary interfaces 214, 216 for connection and communication. In certain embodiments, at least one force-sensitive resistor 206 shown in FIG. 2A may contain first and second electrodes or electrical contacts 218, 220 and a force-sensitive resistive material 222 disposed between the electrodes 218, 220 to electrically connect the electrodes 218, 220 together. When pressure is applied to the force-sensitive material 222, the resistivity and/or conductivity of the force-sensitive material 222 changes, which changes the electrical potential between the electrodes 218, 220. The change in resistance can be detected by the sensor system 202 to detect the force applied on the sensor 216. The force-sensitive resistive material 222 may change its resistance under pressure in a variety of ways. For example, the force-sensitive material 222 may have an internal resistance that decreases when the material is compressed, similar to the quantum tunneling composites described in greater detail below. Further compression of this material may further decrease the resistance, allowing quantitative measurements, as well as binary (on/off) measurements. In some circumstances, this type of force-sensitive resistive behavior may be described as “volume-based resistance,” and materials exhibiting this behavior may be referred to as “smart materials.” As another example, the material 222 may change the resistance by changing the degree of surface-to-surface contact. This can be achieved in several ways, such as by using microprojections on the surface that raise the surface resistance in an uncompressed condition, where the surface resistance decreases when the microprojections are compressed, or by using a flexible electrode that can be deformed to create increased surface-to-surface contact with another electrode. This surface resistance may be the resistance between the material 222 and the electrode 218, 220 222 and/or the surface resistance between a conducting layer (e.g., carbon/graphite) and a force-sensitive layer (e.g., a semiconductor) of a multi-layer material 222. The greater the compression, the greater the surface-to-surface contact, resulting in lower resistance and enabling quantitative measurement. In some circumstances, this type of force-sensitive resistive behavior may be described as “contact-based resistance.” It is understood that the force-sensitive resistive material 222, as defined herein, may be or include a doped or non-doped semiconducting material. The electrodes 218, 220 of the FSR sensor 216 can be formed of any conductive material, including metals, carbon/graphite fibers or composites, other conductive composites, conductive polymers or polymers containing a conductive material, conductive ceramics, doped semiconductors, or any other conductive material. The leads 212 can be connected to the electrodes 218, 220 by any suitable method, including welding, soldering, brazing, adhesively joining, fasteners, or any other integral or non-integral joining method. Alternately, the electrode 218, 220 and associated lead 212 may be formed of a single piece of the same material. ii. Wrist-Worn Device As shown in FIG. 2B, device 226 (which may resemble or be sensory device 142 shown in FIG. 1A) may be configured to be worn by user 124, such as around a wrist, arm, ankle or the like. Device 226 may monitor athletic movements of a user, including all-day activity of user 124. In this regard, device assembly 226 may detect athletic movement during user's 124 interactions with computer 102 and/or operate independently of computer 102. For example, in one embodiment, device 226 may be an-all day activity monitor that measures activity regardless of the user's proximity or interactions with computer 102. Device 226 may communicate directly with network 132 and/or other devices, such as devices 138 and/or 140. In other embodiments, athletic data obtained from device 226 may be utilized in determinations conducted by computer 102, such as determinations relating to which exercise programs are presented to user 124. In one embodiment, device 226 may also wirelessly interact with a mobile device, such as device 138 associated with user 124 or a remote website such as a site dedicated to fitness or health related subject matter. At some predetermined time, the user may wish to transfer data from the device 226 to another location. As shown in FIG. 2B, device 226 may include an input mechanism, such as a depressible input button 228 assist in operation of the device 226. The input button 228 may be operably connected to a controller 230 and/or any other electronic components, such as one or more of the elements discussed in relation to computer 102 shown in FIG. 1B. Controller 230 may be embedded or otherwise part of housing 232. Housing 232 may be formed of one or more materials, including elastomeric components and comprise one or more displays, such as display 234. The display may be considered an illuminable portion of the device 226. The display 234 may include a series of individual lighting elements or light members such as LED lights 234 in an exemplary embodiment. The LED lights may be formed in an array and operably connected to the controller 230. Device 226 may include an indicator system 236, which may also be considered a portion or component of the overall display 234. It is understood that the indicator system 236 can operate and illuminate in conjunction with the display 234 (which may have pixel member 235) or completely separate from the display 234. The indicator system 236 may also include a plurality of additional lighting elements or light members 238, which may also take the form of LED lights in an exemplary embodiment. In certain embodiments, indicator system may provide a visual indication of goals, such as by illuminating a portion of lighting members 238 to represent accomplishment towards one or more goals. A fastening mechanism 240 can be unlatched wherein the device 226 can be positioned around a wrist of the user 124 and the fastening mechanism 240 can be subsequently placed in a latched position. The user can wear the device 226 at all times if desired. In one embodiment, fastening mechanism 240 may comprise an interface, including but not limited to a USB port, for operative interaction with computer 102 and/or devices 138, 140. In certain embodiments, device 226 may comprise a sensor assembly (not shown in FIG. 2B). The sensor assembly may comprise a plurality of different sensors. In an example embodiment, the sensor assembly may comprise or permit operative connection to an accelerometer (including in the form of a multi-axis accelerometer), a gyroscope, a heart rate sensor, location-determining device (e.g., GPS), light sensor, temperature sensor (including ambient temperature and/or body temperature), heart rate monitor, image-capturing, such as a GPS sensor, moisture sensor and/or combinations thereof other sensors. Detected movements or parameters from device's 142 sensor(s), may include (or be used to form) a variety of different parameters, metrics or physiological characteristics including but not limited to speed, distance, steps taken, and energy expenditure such as calories, heart rate and, sweat detection, effort, oxygen consumed, and/or oxygen kinetics. Such parameters may also be expressed in terms of activity points or currency earned by the user based on the activity of the user. Examples of wrist-worn sensors that may be utilized in accordance with various embodiments are disclosed in U.S. patent application Ser. No. 13/287,064, filed on Nov. 1, 2011, the contents of which are incorporated herein in their entirety for any and all non-limiting purposes. II. Illustrative Athletic Monitoring Methods System 100 may prompt a user to perform one or more exercises, monitor user movement while performing the exercises, and provide the user with an energy expenditure estimate based on their movement. System 100 may analyze a user's form to determine if the user is making an exercise more or less difficult, and adjust the energy expenditure estimate accordingly. Energy expenditure estimates may be, or comprise, an estimate of calories burned by the user. In certain embodiments, energy expenditure determinations may be based on, and/or conveyed as a point system. In one embodiment, calories may be converted to a point system, yet in other embodiments, measurements may be directly obtained in one or more point systems. In one implementation, activity points may be based upon: form, body movements, and/or completion of certain activities. In further embodiments, energy expenditure calculations may comprise determinations relating to: effort, oxygen consumed, and/or oxygen kinetics of the user. In one embodiment, computer 102, camera 126, sensor 128, and display 136 may be implemented within the confines of a user's residence, although other locations, including gyms and/or businesses are contemplated. Further, as discussed above, computer 102 may be a portable device, such as a cellular telephone, therefore, one or more aspects discussed herein may be conducted in almost any location. In this regard, the example embodiments of this disclosure are discussed in the context of being implemented with one or more of the example components of system 100. Those skilled in the art will appreciate that reference(s) to a particular component, such as computer 102, is not meant to be limiting, but rather to provide an illustrative example of one of many possible implementations. Thus, although certain components may be referenced, it is to be assumed that other components of system 100 may be utilized unless expressly disclaimed or physically impossible. Further, aspects disclosed herein are not limited to example system 100. A. Monitoring User Movements While exercising, the system 100 may use one or more techniques to monitor user movement. FIG. 3 illustrates an example flow diagram of a method for calculating an energy expenditure estimate for a user that accounts for a user's form while exercising as part of the estimate, in accordance with example embodiments. The method may be implemented by a computer, such as, for example, computer 102, device 138, 140 and/or 142, as well as or other apparatuses. The blocks shown in FIG. 3 may be rearranged, some blocks may be removed, additional blocks may be added, each block may be repeated one or more times, and the flow diagram may be repeated one or more times. The flow diagram may begin at block 302. 1. Perform User Assessment In block 302, the method may include performing an initial assessment of the user. A user, such as user 124, may be positioned in range of a sensor, such as in front of the image capturing device 126 and/or sensor 128, which may comprise an infrared transceiver. Display 136 may present a representation of user 124 that may be a “mirror-image” or depict a virtual avatar, such as a user avatar, that moves to correspond with user movement. Computer 102 may prompt the user to move into a certain region relative to the image capturing device 126 and/or relative to the infrared transceiver 128 so that the user is within frame and/or range. When properly positioned, system 100 may process movement of the user. Although the term “initial” has been utilized, this assessment may occur each time the user initiates system 100, performs certain movements, upon passage of time, or for any other reason. Thus, references to assessments herein are not limited to a single assessment. a. Identify Sensory Locations System 100 may process sensory data to identify user movement data. In one embodiment, sensory locations on a user's body may be identified. With reference to FIG. 4, sensory locations 402a-402o may correspond to locations of interest on the user's 124 body (e.g., ankles, elbows, shoulders, etc.). For example, images of recorded video, such as from camera 126, may be utilized in an identification of the sensory locations 402a-402o. For example, the user may stand a certain distance, which may or may not be predefined, from the camera 126, and system 100 may process the images to identify the user 124 within the video, for example, using disparity mapping techniques. In an example, image capturing device 126 may be a stereo camera having two or more lenses that are spatially offset from one another and that simultaneously capture two or more images of the user. System 100 may process the two or more images taken at a same time instant to generate a disparity map for determining a location of certain parts of the user's body in each image (or at least some of the images) in the video using a coordinate system (e.g., Cartesian coordinates). The disparity map may indicate a difference between an image taken by each of the offset lenses. In a second example, one or more sensors may be located on or proximate to the user's 124 body at the sensory locations 402a-402o or the user 124 may wear a suit having sensors situated at various locations. Yet, in other embodiments, sensor locations may be determined from other sensory devices, such as devices 138, 140 and/or 142. In this regard, sensors may be physical sensors located on a user's clothing, yet in other embodiments, sensor locations 402a-402o may be based upon identification of relationships between two moving body parts. For example, sensor location 402a may be determined by identifying motions of user 124. In this regard, the overall shape or portion of a user's body may permit identification of certain body parts. Regardless of whether a camera, such as camera 126, is utilized and/or a physical sensor located on the user 124, such as sensors within device(s) 138, 140, 142 are utilized, the sensors may sense a current location of a body part and/or track movement of the body part. In certain embodiments, a time stamp may be added to the data collected (such as collected part of block 302 in FIG. 3) indicating a specific time when a body part was at a certain location. Sensor data may be received at computer 102 (or other device) via wireless or wired transmission. A computer, such as computer 102 and/or devices 138, 140, 142, may process the time stamps to determine the locations of the body parts using a coordinate system (e.g., Cartesian coordinates) within each (or at least some) of the images in the video. Data received from camera 126 may be corrected, modified, and/or combined with data received from one or more other devices 138, 140, and 142. In a third example, system 100 may use infrared pattern recognition to detect user movement and locations of body parts of the user 124. For example, sensor 128 may include an infrared transceiver, which may be part of camera 126, or another device, that may emit an infrared signal to illuminate the user's 124 body using infrared signals. The infrared transceiver 128 may capture a reflection of the infrared signal from the body of user 124. Based on the reflection, the system 100 may identify a location of certain parts of the user's body using a coordinate system (e.g., Cartesian coordinates) at particular instances in time. Which and how body parts are identified may be predetermined based on a type or types of exercise a user is requested to perform. As part of a workout routine, system 100 may make an initial postural assessment of the user 124 as part of the initial user assessment in block 302 of FIG. 3. With reference to FIG. 5, system 100 may analyze front and side images of a user 124 to determine a location of one or more of a user's shoulders, upper back, lower back, hips, knees, and ankles. On-body sensors and/or infrared techniques may also be used, either alone or in conjunction with camera 126, to determine the locations of various body parts for the postural assessment. For example, system 100 may determine assessment lines 124a-g and/or regions 502-512 to determine the locations of a various points on a user's body, such as, for example, ankles, knees, hips, upper back, lower back, and shoulders. b. Identify Sensory Regions In further embodiments, system 100 may identify sensory regions (see, e.g., block 302). In one embodiment, assessments lines 124a-g may be utilized to divide the user's body into regions. For example, lines 124b-f may be horizontal axes. For example, a “shoulders” region 502 may correlate to a body portion having a lower boundary around the user's shoulders (see line 124b), region 504 may correlate to the body portion between the shoulders (line 124b) and about half the distance to the hips (see line 124c) and thus be an “upper back” region, and region 506 may span the area between line 124c to the hips (see line 124d) to comprise a “lower back region.” Similarly, region 508 may span the area between the “hips” (line 124d) and the “knees” (see line 124e), region 510 may span between lines 124e and 124f and region 512 (see “ankles”) may have an upper boundary around line 124f. Regions 502-512 may be further divided, such as into quadrants, such as by using axes 124a and 124g. To aid in the identification of one or more sensory regions, system 100 may prompt the user to make one or more specific movements. For example, system 100 may prompt a user to move a specific body part or region (e.g., waive their right arm, or waive the left arm in a specific pattern) to aid the system 100 (e.g., computer algorithm processing information received from the infrared transceiver 128) in determining which body part or region is in a specific location within a coordinate system. c. Categorize Locations or Regions In certain embodiments, body parts or regions that are not proximate to each other may nonetheless be categorized into the same movement category (see, e.g., block 302). For example, as shown in FIG. 5, the “upper back”, “hips”, and “ankles” regions 504, 508, 512 may be categorized as belonging to a “mobility” category. In another embodiment, the “lower back” and “knees” regions 506, 510 may be categorized as belonging to a “stability” category. The categorizations are merely examples, and in other embodiments, a location or region may belong to multiple categories. For example, a “center of gravity” region may be formed from regions 504 and 506. In one embodiment, a “center of gravity” may comprise portions of regions 504 and 506. In another embodiment, a “center of moment” category may be provided, either independently, or alternatively, as comprising a portion of at least another category. In one embodiment, a single location may be weighted in two or more categories, such as being 10% weighted in a “stability” category and 90% weighted in a “mobility” category. System 100 may also process the image to determine a color of clothing of the user or other distinguishing features to differentiate the user from their surroundings. After processing, system 100 may identify a location of multiple points on the user's body and track locations of those points, such as locations 402 in FIG. 4. System 100 may also prompt the user to answer questions to supplement the postural assessment, such as, for example, age, weight, etc. Again, block 302 is optional and is not required in accordance with various embodiments. 2. Providing Instructions With reference again to FIG. 3, in block 304, one or more embodiments may instruct a user to perform an athletic movement with predefined criteria. In certain embodiments, block 304 may include prompting a first user, such as user 124, to perform at least one exercise during a workout session. In an example, system 100 may prompt a user to perform one or more exercises during a workout session. A workout session may include a predetermined number of exercises (e.g., pushups, squats, lunges, etc.) where computer 102 prompts the user to perform a predetermined number of repetitions of each exercise. A workout session may also involve a single athletic activity (e.g., run 10 miles). Instructions to user 124 may be audible, visual, tactile or combinations thereof. With reference again to FIG. 3, various embodiments may include demonstrating proper form for an exercise and prompting the user to perform the exercise. For example, after or in addition to the initial postural assessment, the system 100 (such as with computer 102) may cause the display 136 to present a virtual trainer demonstrating an exercise to instruct the user on proper form and/or may present a depiction and/or an actual video of a real person demonstrating proper form for an exercise. System 100 may then prompt the user to begin performing the exercise. With reference to FIG. 3, in block 306, various embodiments may include monitoring form of a user performing the exercise. As seen in FIG. 6, system 100, such as through computer 102, may cause the display 136 to present a virtual avatar 602 of the user. The virtual avatar 602 may move in synchronism with the user 124. Also, the display 136 may present video of the actual user, rather than avatar 602. System 100 may process one or more frames in the video to determine at least some of the sensory locations 402, or may receive data from sensors worn on-body by the user. As shown in FIG. 6, sensory locations 402 may be displayed on the virtual avatar. In certain embodiments, at least a portion of the instructions may relate to a personalized workout program. In one embodiment, a personalized workout program may be formed, at least in part, from data collected as part of block 302. Further, data collected from one or more other devices, such as devices 138, 140 and, or 142, may be utilized in determining which instructions to provide and/or how to provide instructions to the user 124. For proper form during many exercise routines, a user may proceed through multiple positions during a repetition of an exercise. Certain aspects disclosed herein relate to defining one or more measurement positions and/or desired locations for one or more sensory locations 402. For example, a measurement position may refer to a particular relationship between various body parts during a repetition. For example, a measurement position may indicate a desired location for a user's body part (e.g., desired location of user's left elbow) and may indicate a desired relationship between multiple body parts (e.g., angle between a user's torso and thigh). For a movement or series of movements (such as an exercise routine), system 100 may define one or more measurement positions and/or desired locations for one or more of the sensory locations 402 for a measurement position. In various implementations, each repetition of an exercise can be broken down into one or more measurement positions. System 100, such as through computer 102, may process video or sensor data of a user performing an exercise to determine when a user's body has reached a measurement position. For each measurement position, system 100 may compare the measured sensory locations to desired sensory locations to monitor the user's form while performing the exercise. For example, frame 1 of FIG. 6 may correspond to a first measurement position and frame 2 may correspond to a second measurement position. System 100 may determine a distance between sensory locations 402c and 402d at each measurement position. Other relationships between sensory locations may be specified (e.g., certain angle, certain position, etc.) With reference again to FIG. 3, in block 308, various embodiments may include calculating an energy expenditure estimate for the user. Calculations may be based on a type of the exercise and/or on the form of the user. The energy expenditure estimate may be, or comprise, for example, an estimate of calories burned by the user. In certain embodiments, energy expenditure calculations comprise determinations relating to: effort, oxygen consumed, and/or oxygen kinetics of the user. During a workout session or upon its completion, the system 100 may inform the user of energy expended. In one embodiment, system 100 may provide an indication of a quantity of calories they have burned. To provide a more accurate calories burned estimate, system 100 may account for a user's form while performing an exercise as well as the type of exercise that was performed. Further embodiments may utilize user attributes to more accurately identify a number of calories burned by a user. Example user attributes may be height, weight, age, etc. One or more sensors may determine the user attributes, or the user may input the user attributes via an interface to a computer, such as computer 102. System 100 may use information from sensory locations 402 detected at measurement positions of an exercise in combination with one or more known values to obtain a more accurate determination of calories burned. In one embodiment, a known value may comprise or be part of a Metabolic Equivalent of Task (MET) table. A MET table, for example, may be defined for a particular exercise (e.g., squat, lunge, etc.) and used to determine how many calories a user burned during a workout. System 100 may store or have access to multiple MET tables corresponding to different exercises (e.g., squat, lunge, jumping rope, push up, running, etc.). System 100 may process data from the video and/or sensors to determine a number of repetitions of an exercise that a user has performed or duration of an exercise, and may estimate a number of calories burned by the user based on the repetitions and/or duration information and the one or more known values, such as may be obtained from MET tables. MET tables, however, are statistical averages and are not as accurate as they could be. Thus, conventional calorie measurement systems that rely on MET tables merely provide a user with a rough estimate of how many calories they burned during a workout. Although embodiments of this disclosure may utilize one or more values from a MET table, aspects of this disclosure are not limited by the deficiencies of prior measurements systems. For example, in one embodiment the user's form may be accounted for. System 100 may apply a scaling factor to a calories burned estimate based on detected sensory location information. The scaling factor may reflect how well a user has performed an exercise and in certain embodiments may consider attributes of the user. For example, the scaling factor may be a function of one or more of the sensory location information, a duration during which the user performed an exercise, information reported by the user (e.g., age, weight), a user's heart rate taken by a heart rate monitor, a pressure measurement, and/or other data. A pressure measurement may be obtained from pressure sensor 140 located in a shoe, for example, to determine how much force a user exerts during movement. For example, a user may be holding a weight in each hand and the pressure sensor 140 may monitor pressure at the shoe. The pressure sensor 140 may also indicate how quickly a user changes direction (e.g., how hard a user made a cut) or how much power was exerted when jumping. To determine the scaling factor, system 100 may monitor for relationships between one or more body parts at one or more measurement positions during a repetition of an exercise. Modifications to these relationships may make an exercise easier or harder to perform. The scaling factor may consider factors indicative of whether a user is making the exercise more or less difficult to complete, and may adjust a calories burned estimate accordingly. In a squat, for example, relationships may be defined for a first angle between a user's torso and thighs, and a second angle between a user's thighs and shin while performing the squat. System 100 may process sensory location information to measure the first and second angle of the user over time for comparison with the desired first and second angle. In an example, with reference to FIGS. 7A-B, a virtual avatar 702 of a user is displayed performing a squat. Virtual avatar 702 is depicted as a stick figure, and proper technique for an exercise is shown as a shaded region 704. At the lowest part of the squat (for example, as shown in FIG. 7A), the desired form may specify a relationship between a user's thigh and shin, between a user's back and arms, and/or any other two parts or locations the user. In one embodiment, the desired form may specify a first predetermined angle between a location or part. For example, a user's upper leg and lower leg, and/or a second predetermined angle between a user's back and arms. System 100 may process the sensory location information to compare the user's form to the desired form. For example, system 100 may process the sensory location information to determine an angle between the user's thigh and shin, and an angle between the user's back and arms when performing a squat. System 100 may define thresholds for the relationships between various body parts for adjusting the scaling factor. The thresholds may permit the user's form to differ by a certain amount from the desired form. For a preferred threshold, system 100 may determine that the user has good form that does not require any adjustment of the scaling factor (e.g., less than a 5% difference between angle between the user's upper leg and lower leg and desired angle). For an acceptable threshold, the system 100 may nominally adjust the scaling factor upward or downward to reflect increased or reduced effort by the user (e.g., 5-15% difference between angle between the user's upper leg and lower leg and desired angle). For an unacceptable threshold, the system 100 may determine that the user's form has reduced the amount of effort to perform the exercise and may downwardly adjust the scaling factor (e.g., greater than a 15% difference between angle between the user's upper leg and lower leg and desired angle). System 100 may also adjust the scaling factor based on omissions or additions a user makes when performing an exercise. For example, a user may not be doing an arm movement in an exercise that requires movement of both arms and legs. Also, if the user is performing an additional movement beyond what is specified for an exercise, the system 100 may adjust the scaling factor to increase the calorie estimate. Upon determining the scaling factor, the system 100 may determine an amount of calories burned as a function of the scaling factor(s) and the calorie estimate. The function may be a multiplication of the calorie estimate by the scaling factor, or via other relationships. For example, the scaling factor may be adjustments to a number of variables in a mathematical equation for adjusting calories burned by one or more of multiplication, addition, and subtraction. In further embodiments, system 100 may cease determinations relating to caloric expenditure if the user deviates from a threshold. For example, a user may be interrupted during a workout routine and either forget or be too distracted to “pause” the determination, thus, certain embodiments may cease determining caloric expenditure upon detecting that a user is not performing an exercise. Further embodiments may cease or otherwise alter determinations of caloric expenditure if one or more variation thresholds are exceeded, such as for example, if a user is over-extending or under-extending a body region or part. In certain embodiments, if a user's movements are prone to cause injury, measurements and/or determinations relating to caloric expenditure may be stopped. In one implementation, system 100 may provide cues and/or instructions to correct the user's deficiencies or incorrect movements. The following provides an example equation for calculating an amount of calories burned by a user during a workout. Calories burned=BMR*(Activity modifier)*(Completeness modifier). Equation (1) In equation (1), BMR is an acronym for Basal Metabolic Rate. The system 100 may calculate the BMR using the Mifflin-St. Jeor Equation, BMR=(10*w)+(6.25*h)−(5.0*a)+(5 for men, −161 for women), where “*” is the multiplication symbol, “w”=weight in kilograms, “h”=height in centimeters, “a”=age in years. The system 100 may also use the Harris-Benedict equation instead of or, in addition to, the Mifflin-St. Jeor Equation. The activity modifier may be an adjustment corresponding to a type of exercise being performed by a user. The activity modifier may be larger for more strenuous exercises, and smaller for less strenuous. System 100 may store a file containing activity modifiers, where each activity modifier may have a value for a particular exercise type. Two or more exercises may have activity modifiers with a same value, or certain exercise may have a unique value for the activity modifier. The activity modifier may have a default value. In one example embodiment, the default value may be 0.1. In a second embodiment, the default value may be 1.0. The default value may be any value, including 0.0. System 100 may update the default value to correspond to the activity modifier for an exercise currently being performed by the user. Over a duration of the workout, system 100 may use different ones of the activity modifiers to calculate calories burned using equation (1) corresponding to different exercises the user is prompted to perform. One or more factors may contribute to the activity modifier and/or adjustment of the modifier. Examples include, but are not limited to: pace, type of exercise, duration, and combinations thereof. Further, activity modifiers and/or variation of activity modifiers may be determined from predetermined values (such as a value assigned to an exercise or movement that a user is prompted to perform), the user's performance, information from a MET table on a particular exercise, and combinations thereof. The completeness modifier may be used for adjusting the BMR based on how well a user's form corresponds to a desired form when performing an exercise. In an example, the completeness modifier may indicate what percentage of full movement was achieved for each repetition when performing an exercise (e.g., determine a percentage of a measured angle between the user's torso and thighs for a particular repetition of an exercise relative to a desired angle), or may be an average of the percentage of full movement for a predetermined number of repetitions (e.g., last three exercises, last five exercises, all exercises, etc.). The completeness modifier may have a default value. In one example embodiment, the default value may be 0.1. In a second embodiment, the default value may be 1.0. The default value may be any value, including 0.0. System 100 may update the completeness modifier over time based on how well the user's form conforms to a desired form. One or more factors may contribute to the activity modifier and/or adjustment of the modifier. Examples include, but are not limited to: pace, type of exercise, duration, and combinations thereof. Further, activity modifiers and/or variation of activity modifiers may be determined from predetermined values (such as a value assigned to an exercise or movement that a user is prompted to perform), the user's performance, and combinations thereof. Equation (2), provided below, may be utilized in further embodiments. Calories burned=BMR*(Activity modifier)*(Completeness modifier)*(Multiply Modifier)+(Addition Modifier) Equation (2) Values for BMR, Activity Modifier, and/or Completeness Modifier of Equation (2) may be determined in accordance with one or more embodiments described above in reference to Equation (1). In one embodiment, the value of the Multiply Modifier may be defined for each type of exercise. In one example embodiment, the default value may be 0.1. In a second embodiment, the default value may be 1.0. The default value may be any value, including 0.0. System 100 may update the Multiply Modifier during a workout to correspond to a type of exercise the user is prompted to perform. In certain embodiments, the Activity Modifier may be obtained (either partially or entirely) from empirical data. In certain embodiments, the value of the Addition Modifier may be defined for each type of exercise. In one example embodiment, the default value may be 0.1. In a second embodiment, the default value may be 1.0. The default value may be any value, including 0.0. System 100 may update the Addition Modifier during a workout to correspond to a type of exercise the user is prompted to perform. In certain embodiments, the Activity Modifier may be obtained (either partially or entirely) from empirical data. System 100 may calculate the calories burned over a duration of a workout, which may incorporate the utilization of equations (1) or (2). System 100 may cause the display 136 to display a running total of calories burned. In certain embodiments, the total may be determined for one or more completed repetitions and one or more completed sets of each exercise. System 100 may also calculate and cause display of calories burned by type of exercise performed. Other information such as, for example, peak/minimum/average calorie burning rate by workout, by repetition, by set, or by exercise type may also be calculated and displayed. System 100 may periodically determine an amount of calories burned by the user while exercising using equation (1). System 100 may indicate a current amount of calories burned that is continually updated over a workout (e.g., a running total), or may update the calories burned amount at predetermined times (e.g., user completes a set of a first type of exercise and begins a set of second type of exercise, at the end of the workout session, etc.). System 100 may also inform the user how many calories were burned during each repetition as well as in each set of an exercise. One or more of the inputs and/or variables used in the determination of caloric expenditure (such as with equation (1)) may remain the same regardless of the type of exercise being performed by the user, yet others may vary. For example, the BMR may be the same over the entire workout as a user's weight, height, and age do not change appreciably over the course of a workout. Further, one or more of the Activity modifier, Completeness modifier, Multiply Modifier, and Addition Modifier may vary over the workout. The values (and/or variation) of the values may depend on the type exercise currently being performed by the user. The Completeness modifier may vary from repetition to repetition. As noted above, system 100 may generate the Completeness modifier based on monitoring a user's form while they perform an exercise. Generally, an exercise includes a sequence of motions to perform one repetition, and a user typically performs a set that includes two or more repetitions. A user's form may vary from repetition to repetition, and so may the Completeness modifier. System 100 may determine calories burned using equation (1) based on a Completeness modifier that varies from repetition to repetition, or based on a filtered version of the Completeness modifier. To filter the Completeness modifier, the system 100 may, for example, determine a Completeness modifier for one or more repetitions, may average some or all of the Completeness modifiers, and may use the average in equation (1). Also, system 100 may generate the Completeness modifier as a weighted average, where Completeness modifiers of some repetitions may be given greater weight than others. For example, system 100 may apply a decaying function where more recent Completeness modifiers are weighted more heavily than less recent when generating an average. System 100 may also allow a user to make desired movements, and calculate an amount of calories burned for such movement. In one embodiment, all detected movements may be utilized in calculations. Yet in other embodiments, only certain (e.g., system supported and/or those prompted to be performed) movements may be considered. System 100 may process data from image capturing device 126 and/or from various sensors to attempt to classify a user's movement. For example, system 100 may compare the user's movement to other known movements for which a MET table has been defined. If a user's movement corresponds to a known movement for which a MET table has been defined, then system 100 may use the identified MET table for calculating an amount of calories burned. If the user's movement does not match an exercise defined by a MET table, the system 100 may identify one or more exercises that include movements similar to the movement being performed by the user. For example, system 100 may determine that the user's lower body moves similar to a squat and upper body moves similar to a pushup. System 100 may calculate the number of calories the user would burn using the identified MET tables as if the users were doing a squat, and as if they were doing a pushup, as approximations for the amount of calories burned by the user. In further embodiments, a new entry may be created. In this regard, certain embodiments may permit the entry and later identification of new movements and/or exercises. In certain embodiments, the user may provide inputs regarding an approximate caloric expenditure for an unidentified movement/exercise. Yet in other embodiments, system 100 may calculate caloric expenditure, such as from one or more sensors as discussed herein. In still yet further embodiments, system 100 may utilize one or more sensor readings as well as an input from a user (and/or third-party) in determining attributes, such as caloric expenditure, for previously unknown movements or exercises. Examples of estimating caloric expenditure without MET tables, may include but are not limited to, determining changes in potential energy. Examples of using changes in potential energy are provided in the next section. System 100 may be configured to transmit calories burned estimates to a social networking website. The users may be ranked based on their total number of calories burned for a desired time interval (e.g., rank by day, week, month, year, etc.). With reference again to FIG. 3, the method may end or may return to any of the preceding blocks. i. Energy Expenditure Estimate Based on Changes in Potential Energy System 100 may also calculate an energy expenditure estimate of a user for physical activities not defined by a MET table. For example, system 100 may calculate an amount of calories burned by a user performing any desired combination of movements. During a workout, a user may be exposed to their own body weight and gravity. A location of a user's center of mass, or of a center of mass of a particular body part, may be utilized in estimating an amount of calories burned by the user performing an athletic activity. FIG. 8 illustrates an example flow diagram of a method for calculating an energy expenditure estimate for a user while performing an athletic activity based on monitoring changes in potential energy, in accordance with example embodiments. The method may be implemented by a computer, such as, for example, computer 102, device 138, 140 and/or 142 as well as other apparatuses. The blocks shown in FIG. 8 may be rearranged, some blocks may be removed, additional blocks may be added, each block may be repeated one or more times, and the flow diagram may be repeated one or more times. The flow diagram may begin at block 802. In block 802, various embodiments may involve processing data captured of a user performing an athletic activity over a time interval. In an example, system 100 may prompt a user to perform ten repetitions of a lunge and may process data captured of the user performing the lunge. The data may be video captured by the camera 126 or may be captured by the infrared transceiver 128, and/or by the other device sensors 138, 140, and 142. In block 804, various embodiments may involve determining a location of a center of mass of a body part, body region, or of an entire body of the user at a first time instant and at a second time instant within the time interval. Yet in other embodiments, a center of movement may be utilized. For simplicity purposes, however, a center of mass will be discussed. In an example, system 100 may instruct the user to place sensors at locations of corresponding to a center of mass for one or more body parts of the user. With reference to FIG. 9, one or more of center of mass locations may be at example locations 904A-D and 906, or at other locations on the user's body. Any number of locations may be monitored. At least one sensor may wirelessly transmit sensor data indicating a time and a location of the sensor (or location of a body part as detected by the sensor). A location may be coordinates in a coordinate system (e.g., Cartesian coordinate system) and may be associated with a time stamp indicating when the sensor was at a particular coordinate. In certain embodiments, system 100 may process the sensor data to periodically determine locations 904A-D and 906. For example, system 100 may receive sensor data, such as from device sensors 138, 140 and/or 142. Computer 102 (or another component of system 100) may process data as part of determining locations (such as locations 904A-D and 906). In one embodiment, data may be processed on a routine ongoing-basis, such as four times per second. In another example, computer 102 (or another component of system 100) may process data from image capturing device 126 to determine locations 904A-D and/or 906. In block 806, various embodiments may involve identifying a change in the location of the center of mass from the first time instant to a second time instant. As discussed above, system 100 may determine locations 904A-D and 906 at one time and at a subsequent time. For example and with reference to FIGS. 10A-B, a user is shown performing a lunge. FIG. 10A corresponds to a first time instant and FIG. 10B corresponds to a second time instant. In FIG. 10A, a location 906 of a user's center of mass is at a height “h1” (designated by 908A) off of the ground. In FIG. 10B, a location 906 of a user's center of mass is at a height “h2” (designated by 908A) off of the ground. One or more components of system 100 may determine a difference between height “h1” and “h2” to determine a change in a location 906 of the center of mass. System 100 may also calculate changes to locations 904A-D of centers of mass for other body parts, or changes to other locations of body parts or body regions of the user. System 100 may also process video of a user taken from different angles, as shown in FIG. 11, to determine locations 904A-D and 906. For example, system 100 may determine height “h1” for location 906 in a perspective view and height “h2” for location 906 in a front view of the user. System 100 may average the different height measurements, or may use one or the other. With reference again to FIG. 8, in block 808, various embodiments may calculate an energy expenditure estimate for the user due to the change. In an example, the physics concept of potential energy may be used to estimate the amount of work done by the user, and to calculate calories burned based on work. In an example, one or more components of system 100 may determine changes of a location 906 from one time instant to another to determine an amount of work performed by the user. Potential Energy (PE)=m*g*h, where m=mass of the user (or body part), g=the acceleration due to gravity, and h=height above ground. Work (W)=−ΔPE, where Δ is represents a change in potential energy. Substituting m*g*h, Work (W)=−m*g*Δh. Based on the above example in FIGS. 10A-B, W=−m*g*(h1−h2). System 100 may determine an amount of calories burned as a function of work multiplied by physiology of human efficiency. System 100 may determine the amount of calories burned based on the amount of work and a physiology of human efficiency (PHE) scaling factor. The system 100 may determine the PHE scaling factor as a function of one or more of the user's heart rate, pressure sensor data, and other information input by the user (e.g., age, weight, etc.) System 100 may keep and/or transmit a running total of calories burned between subsequent time instants and inform the user of a total amount of calories burned up to that point in an exercise session. For example, system 100 may determine a height h of location 906 at a certain frequency (e.g., 2 times per second), and may calculate calories burned based on a difference in calories burned between each determination of height h. The system 100 may also track a total number of calories burned over a predetermined time range covering one or more workouts. A time range may include a week, month, year, cumulative time since a user began working out, or other defined metrics. One or metrics may comprise default values, predefined values, user-selectable values, and/or user-defined values. For example, system 100 may inform the user of how many calories they have burned during a specified time period, such as a day, week, month, and/or year. System 100 may also maintain data on average number of calories burned per workout, average number of calories burned based on a type of workout, a greatest number of calories burned during a single workout or during a predetermined time interval (e.g., month where highest amount of calories were burned), or other types of data. In another example, system 100 may determine calories burned by movement of a particular body part or by a collection of body parts. For instance, a user may desire to know how many calories were burned by movement of their right leg. Using the above relationship between work and potential energy, and with reference again to FIG. 9, system 100 may monitor changes in the location 904A of the center of mass of the user's right leg (e.g., height 908B) from one time instant to a different time instant to calculate work. System 100 may estimate the mass of the user's right leg based on the user's weight and proportions. System 100 may then determine an amount of calories burned as a function of work multiplied by physiology of human efficiency, as described above. During an exercise session, system 100 may display, such as through display 136, a running total of calories burned attributable to movement of the user's right leg. System 100 may similarly determine calories burned based on locations 904B-D for the other limbs of the user. During an exercise session, system 100 may display a running total of calories burned by a user's entire body, as well by each limb. System 100 may also permit a user to review an exercise session to determine how many calories were burned at certain times. For example, an exercise may involve performing repetitive motions (e.g., pushups). System 100 may identify each repetition within a set (e.g., each pushup within a set of 10), as well as a number of calories burned during each repetition. Over a set, one or more components of system 100 may identify the repetition where the user burned a highest number of calories as well as a lowest number of calories. In further embodiments, system 100 may estimate an average number of calories. These are merely exemplary statistics and those skilled in the art will readily appreciate that other analysis may be conducted without departing from the scope of this disclosure. If an exercise session involves different types of exercises, system 100 may rank the exercise types based on the amount of calories burned by type. For example, an exercise session may involve 3 different types of exercises (e.g., pushups, sit-ups, squats). After completing the exercise session, system 100 may determine how many calories were burned by each exercise type (e.g., 10 calories for pushups, 13 calories for sit-ups, and 18 calories for squats), and rank the exercise types based on the number of calories burned (e.g., first squats, second sit-ups, third pushups). In further embodiments, energy expenditure (e.g., a quantity of calories burned) may be ranked as percentage over an ideal value or range for an exercise or routine. For example, if perfectly performing an exercise would burn about 100 calories, a first user who burned 90 calories may be assigned a better ranking than second user who only burned 85 for the same exercise. The users could have different ideal values or ranges, thus the determinations may utilize the percentage of the detected and/or estimated values as a percentage for that user's ideal value. In further embodiments, a user who is closer to 100% of their ideal value may be ranked higher than users who have over 100% of the ideal quantity of calories burned. In this regard, a user who expends more energy than estimated or calculated for an activity (e.g., exercise) may indicate improper movements, inefficiency, increased likelihood of injury, and/or combinations thereof. In certain implementations, the method of FIG. 8 may then end, or may return to any of the preceding blocks and/or other processes. System 100 may also determine calories expended from pre-recorded videos. For example, a user may upload video of a professional basketball player dunking a basketball to system 100. One or more components of system 100 may process the video to determine locations of a center of mass of the player, or of particular body parts, at various points in time, and determine the amount of calories expended during the physical activity (e.g., by the player during the dunk) using the work-based calorie determination, described above. In addition to using multiple independent sensors and sensor systems for calculating energy expenditure, some embodiments of the invention may utilize multiple display devices for displaying energy expenditure or energy expenditure point values. When one sensor or sensor system is used to calculate energy expenditure, the display device associated with the sensor or sensor system that is not used may be disabled. Alternative, the display device associated with the sensor or sensor system that is not used may be driven by the sensor or sensor system that is used. For example, a wrist worn sensor system and a camera based system may both include displays for displaying energy expenditure. When both systems are available and the camera based system is selected to calculate energy expenditure, the camera based system may provide data to the wrist worn sensor system so that the display associated with the wrist worn sensor system displays the same values as the display associated with the camera based system. III. Example Combinatory Scores Further aspects relate to calculating one or more values, such as a rating or score, indicative of a user's fitness level, athleticism, and/or combinations thereof. In certain embodiments, a fitness component and an athleticism component may be combined to create a combinatory score or rating. For example, a fitness sub-score and an athleticism sub-score may each be utilized in the calculation of a combinatory score that provides an indication of the user's fitness and athleticism. For example, FIG. 12 shows an example combinatory score of 76/65, in which 76 represents the user's fitness sub-score and 65 represents the user's athleticism sub-score. In certain embodiments, the combinatory score may be represented by the two individual sub-scores, such as shown in FIG. 12, however, in further embodiments, the combinatory score may be represented by a single score. In one embodiment, a plurality of sub-scores, such as including the athleticism sub-score and the athleticism sub-score may average, summed, or otherwise combined to form a single score. Additional methods for generating and displaying example combinatory scores are provided below. A combinatory score, a component sub-score, or values utilized in determining a score and/or sub-score may be determined based upon a user's physical activity. In one embodiment, values may be calculated or derived from the user's performance during of physical movements with predefined criteria, such as predefined drills or tests. In accordance with one embodiment, instructions may be provided to a user requesting that the user perform physical activity with predefined criteria. As one example, embodiments may include prompting a first user, such as user 124 shown in FIG. 1, to perform athletic movements, including completing at least one drill and/or exercise. In an example, system 100 may prompt user 124 to perform one or more exercises that are part of a drill. A drill may include a predetermined number of exercises (e.g., pushups, squats, lunges, etc.) where system 100 prompts the user to perform a number of repetitions of each exercise. Instructions to user 124 may be audible, visual, tactile or combinations thereof. Further, instructions may include demonstrating proper form for an exercise and prompting the user to perform the exercise, such as discussed throughout this disclosure, including requesting that the user perform a personalized workout program. Detection (and/or receipt of an indication of the presence) of one or more devices, such as devices 138, 140 and, or 142, may be utilized in determining which instructions to provide and/or how to provide instructions to the user 124. In accordance with certain implementations, system 100 may cause the display 136 to present a virtual trainer demonstrating an exercise to instruct the user on proper form, such as but not limited to the embodiments described in relation to FIG. 3, 6 and/or 7. Determinations of values, sub-scores, and the combinatory score may consider a plurality of parameters relating to the user's performance. For example, the user's form, tempo, estimated fatigue, oxygen kinetics, and/or other parameters may be utilized. For example, instructions embodiment may instruct a user to perform a 10 pushups followed by 5 burpees. In one embodiment, if the user performs the pushups and/or burpees too fast or too slow, they may be credited with fewer points or be penalized. In one embodiment, pushups falling outside a tempo range may not be counted. Further, if the user does not adequately rest between the pushups and burpees or takes too long to initiate the burpees following the pushups, then scaling of their points may occur. Likewise, if a user demonstrates bad form during the performance, certain activities may not be quantified or otherwise considered in the analysis, or alternatively, certain activities may be scored differently. A plurality of drills may be presented to the user during a single session. In one embodiment, a workout session or drill may consist of a single athletic activity (e.g., run 10 miles), and sub-scores may be calculated therefrom. Yet in another embodiment, at least a first exercise may be designed to specifically test attributes of athleticism and at least a second exercise may be utilized to specifically test attributes of fitness. In yet another embodiment, a single exercise may be utilized to measure at least one athleticism attribute and at least one fitness attribute. One or more attribute values may be detected, measured, and/or calculated and utilized as part of determining the fitness sub-score. As shown in FIG. 13, example fitness attributes may include, but are not limited to: endurance, flexibility, strength and combinations thereof. As further shown in FIG. 13, example athleticism attributes may include, but are not limited to: speed, agility, reaction, power, balance, and combinations thereof. In one embodiment, the calculation of the fitness sub-score consists of utilizing three fitness attributes, specifically endurance, flexibility, and strength. In certain embodiments, the calculation of the athleticism score consists of utilizing three athleticism attributes, namely: a value representing speed, agility, reaction, a second value representing power, and a third value representing balance. In one embodiment, the endurance attribute may be determined from drills comprising or consisting of vertical jumps. As one example, the quantity of vertical jumps the user conducts within a predetermined time period may be utilized. The flexibility attribute may be determined from reps of leg raises and/or reverse reaches. As one example, the range of flexibility of at least one body part or region. The strength attribute may be determined from the user's performance of reps of static lunges and/or push-ups. As one example, the user's ability to maintain their performance within a predetermined range of tempo during the activities may be utilized. The power attribute may be determined from drills comprising or consisting of vertical jumps. In one embodiment, the user's performance during the vertical jumps utilized as part of determining endurance may also be used to determine power. As one example, the user's vertical distance during the vertical jump(s) may be utilized in determining power. The balance attribute may be determined from drills comprising or consisting of hop and sticks, in which the user's stability may be measured. A value indicative of the user's speed, agility and reaction may be determined from drills comprising or consisting of cone sprints. As one example, the user's reaction and/or target return may be utilized in determining this value or sub-values. In accordance with certain embodiments, one or more sub-scores may be sport or activity specific. Accordingly, drills and/or activity utilized to measure attributes may be sport or activity specific. For example, a first drill or activity may be designed to measure athleticism attributes relating to football, whereas a second drill or activity may be designed to measure athleticism attributes relating to basketball. In further embodiments, at least one may measure fitness across two or more sports or activities, however, the execution of activities configured to measure that attribute may differ across different drills or exercises. Drills or tests may be presented to the user in a specific or predefined ordering. The ordering may be identical for each iteration (such as during the same workout session or across different workout sessions), or in further embodiments, may be adjusted based upon on or more factors. In one embodiment, the ordering, duration and/or any other parameters of the drill or test may be adjusted based upon on or more factors, including but not limited to: the user's selection, past performance, current performance, and combinations thereof. In certain embodiments, at least one parameter of a drill or test may be determined by a user assessment, such as for example, the user assessment described in relation to block 302 of FIG. 3. In further embodiments, the criteria of any drills or tests may be identical for each iteration, or alternatively, updated or otherwise altered over time. The drills or tests configured to measure one or more attributes may be administered on a routine basis, during a specific time frame, and/or upon occurrence of a triggering event. In one embodiment, the user may not be permitted to access the drills and/or not be able to utilize the performance of the drills to calculate one or more scores during a period of time following calculation of one or more scores, sub-scores and/or values. For example, in one embodiment, user 124 may be limited to being assessed under the combinatory fitness/athleticism score about once per month. In this regard, it may take several weeks for the human body to show certain improvements resulting from specific physical activity. Therefore, in certain embodiments, a user may only be evaluated every few weeks for the combinatory score. In certain embodiments, user 124 may be able to conduct the drills/activities set forth in the relevant testing criteria; however, a new score may not be displayed or calculated during this period. In this regard, certain embodiments may calculate the score, sub-score(s), and/or values; however, they may not be displayed or otherwise made available to the user. In one embodiment, a series of eight consecutive drills are presented to the user about once per month. The eight drills may be presented in a serial manner during a single session. The ordering of the eight drills may be static during subsequent administrations. Those skilled in the art will readily appreciate that these are merely example ranges, and that any aspects of the drills (e.g., duration, repetitions, ordering, etc.) may be adjusted. Further, utilizing a different duration of time between subsequent testing time may be suitable for a plurality of embodiments within the scope of this disclosure. Calculation of the combinatory score and/or the sub-scores may be based upon combining a plurality of drill scores. In one embodiment, a plurality of athletic drill scores may be summed, averaged or otherwise utilized to form the athleticism sub-score and a plurality of fitness drills scores may be summed, averaged, or otherwise utilized to form the fitness sub-score. In certain embodiments, a drill score may be provided for each drill. At least one fitness or athleticism drill score may be weighted more than another drill score. In certain embodiments, the calculation of at least one drill score may be based upon drill or sub-scores of other users. For example, in certain implementations drill score(s) and/or sub-score(s) may be based upon the user's performance as compared to a plurality of other users. As one example, a fitness sub-score of 52 may represent that the user's fitness level (as indicated by their performance) is at about the 52nd percentile of a comparative population of users. The population may be filtered or otherwise selectable. For example, a user may wish to compare their performance with their friends, colleagues, or others of a certain demographic range (such as including: age, weight, sex, and combinations thereof). Further embodiments may allow a user to review and/or compare their results. For example, FIG. 14 shows a screenshot showing a selection of the “FITNESS” sub-score in which the “ATHLETICISM” sub-score may also be selected. As further seen in FIG. 15, selection of the FITNESS sub-score may cause the display of values obtained or derived from the user's performance during one or more drills or tests. The illustrated example values (an endurance value, a flexibility value, and a strength value) may be utilized in the creation of the fitness sub-score (displayed as “76”). As shown in FIG. 16, a GUI may allow a user to select “ENDURANCE” and observe the result (shown as “80”). In one embodiment, an endurance score of 80 may designate that the user performed better than about 81 percent than other users within a population (and thus within the 82nd percentile. Yet in other embodiments, it may represent that the user completed about 82% of predefined criteria designated for a specific endurance test (or determinations of endurance from a plurality of endurance tests). As further seen in FIG. 16, individual scores may be provided for other fitness values, such as “flexibility” (value of “73”) and “strength” (value of “75”). In addition to being displayed numerically, results for endurance, flexibility, and strength are also shown graphically in FIG. 16 as percentage lines that form a semi-circle to the left of the score. In further embodiments, actual results from one or more drills may be provided and/or compared. For example, FIG. 17 shows example results utilized in the determination of the illustrated “endurance” value. Specifically, results from a “HIGH KNEE RUN” are provided in which the user completed 29, 27, and 27 reps for the first, second and third set, respectively. As further shown in FIG. 17, a community average, which may be user-selectable or filtered, may be provided. As seen in FIG. 17, the chosen community or population for which the results may be compared may be altered in accordance with certain embodiments. Further, as seen in FIG. 17, the combinatory score, sub-scores, attribute values, and/or actual results from the drills and/or tests may be correlated with and/or displayed with a user's energy expenditure value(s), including but not limited to one or more energy expenditure values described herein. CONCLUSION Providing an activity environment having one or more of the features described herein may provide a user with an immersive experience that will encourage and motivate the user to engage in athletic activities and improve his or her fitness. Users may further communicate through social communities and challenge one another to reach various levels of fitness, and to view their fitness level and activity. Aspects of the embodiments have been described in terms of illustrative embodiments thereof. Numerous other embodiments, modifications and variations within the scope and spirit of the appended claims will occur to persons of ordinary skill in the art from a review of this disclosure. For example, one of ordinary skill in the art will appreciate that the steps illustrated in the illustrative figures may be performed in other than the recited order, and that one or more steps illustrated may be optional in accordance with aspects of the embodiments.
<SOH> BACKGROUND <EOH>While most people appreciate the importance of physical fitness, many have difficulty finding the motivation required to maintain a regular exercise program. Some people find it particularly difficult to maintain an exercise regimen that involves continuously repetitive motions, such as running, walking and bicycling. Additionally, individuals may view exercise as work or a chore and thus, separate it from enjoyable aspects of their daily lives. Often, this clear separation between athletic activity and other activities reduces the amount of motivation that an individual might have toward exercising. Further, athletic activity services and systems directed toward encouraging individuals to engage in athletic activities might also be too focused on one or more particular activities while an individual's interest are ignored. This may further decrease a user's interest in participating in athletic activities or using the athletic activity services and systems. Therefore, improved systems and methods to address these and other shortcomings in the art are desired.
<SOH> SUMMARY <EOH>The following presents a simplified summary of the present disclosure in order to provide a basic understanding of some aspects of the invention. This summary is not an extensive overview of the invention. It is not intended to identify key or critical elements of the invention or to delineate the scope of the invention. The following summary merely presents some concepts of the invention in a simplified form as a prelude to the more detailed description provided below. Aspects relate to systems and methods for estimating a combined or a combinatory fitness-athleticism score comprised of a fitness sub-score and an athleticism sub-score. The fitness-athleticism score may be estimated based on a user's athletic movements, wherein the user's athletic movements are monitored by a first sensor. Further aspects relate to an apparatus configured to be worn by a user. The apparatus may comprise a structure that is worn around an appendage of the user. The apparatus may include a sensor configured to capture data related to the movement of the appendage of the user. The apparatus also includes a processor, and a non-transitory computer-readable medium with computer-executable instructions. The computer-executable instructions may be executed by a processor, including the local processor, to receive movement data captured by the sensor, and/or to estimate a combined fitness-athleticism score from the received movement data. This combined athleticism score may comprise a fitness sub-score and an athleticism sub-score. In yet another aspect, this disclosure relates to a computer-implemented method for receiving data related to the physical movements of a user from a first sensor on a wrist-worn device. The received motion data may be utilized to estimate, using a processor, a combinatory fitness-athleticism score, wherein the combinatory fitness-athleticism score may comprise a fitness sub-score and an athleticism sub-score. The method further displays a combinatory fitness-athleticism score on a display device. This Summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. The Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter.
A63B7106
20170814
20180111
76440.0
A63B7106
1
ROWLAND, STEVE
Combinatory Score Having a Fitness Sub-Score and an Athleticism Sub-Score
UNDISCOUNTED
1
CONT-ACCEPTED
A63B
2,017
15,675,930
PENDING
VIRTUAL 360-DEGREE VIEW OF A TELECOMMUNICATIONS SITE
Systems and method for creating and utilizing a virtual 360-degree view of a telecommunications site include capturing first data of a 360-degree view at multiple points around the telecommunications site; capturing second data of a 360-degree view at aerial points above the telecommunications site; capturing third data of a 360-degree view inside a shelter or cabinet at the telecommunications site, wherein each of the first data, second data, and third data comprise one or more of photos and video; stitching the first data, the second data, and the third data together with links to create a virtual 360-degree view environment of the telecommunications site, wherein the links enable virtual navigation about the telecommunications site; and displaying the virtual 360-degree view environment to a viewer over a network and adjusting the virtual 360-degree view environment based on commands received from the viewer.
1. A method for creating and utilizing a virtual 360-degree view of a telecommunications site, the method comprising: capturing first data of a 360-degree view at multiple points around the telecommunications site; capturing second data of a 360-degree view at aerial points above the telecommunications site; capturing third data of a 360-degree view inside a shelter or cabinet at the telecommunications site, wherein each of the first data, second data, and third data comprise one or more of photos and video; stitching the first data, the second data, and the third data together with links to create a virtual 360-degree view environment of the telecommunications site, wherein the links enable virtual navigation about the telecommunications site; and displaying the virtual 360-degree view environment to a viewer over a network and adjusting the virtual 360-degree view environment based on commands received from the viewer. 2. The method of claim 1, wherein the telecommunications site comprises a cell site and the second data is captured via an Unmanned Aerial Vehicle. 3. The method of claim 1, wherein each of the first data, second data, and third data is captured using a 360-degree camera. 4. The method of claim 1, wherein the commands comprise navigation to different locations about the telecommunications site and viewing details of specific objects at the telecommunications site. 5. The method of claim 4, wherein the navigation is based on location items and the viewing details of specific objects is based on information icons in the virtual 360-degree view environment. 6. The method of claim 1, wherein the commands comprise zooming into a specific object of interest at the telecommunications site. 7. The method of claim 1, wherein the capturing first data comprises taking photos or video at each corner of surrounding geography at the telecommunications site. 8. A server for creating and utilizing a virtual 360-degree view of a telecommunications site, the server comprising: a network interface and a processor communicatively coupled to one another; and memory storing instructions that, when executed, cause the processor to obtain first data of a 360-degree view at multiple points around the telecommunications site; obtain second data of a 360-degree view at aerial points above the telecommunications site; obtain third data of a 360-degree view inside a shelter or cabinet at the telecommunications site, wherein each of the first data, second data, and third data comprise one or more of photos and video; stitch the first data, the second data, and the third data together with links to create a virtual 360-degree view environment of the telecommunications site, wherein the links enable virtual navigation about the telecommunications site; and display the virtual 360-degree view environment to a viewer over a network and adjust the virtual 360-degree view environment based on commands received from the viewer. 9. The server of claim 8, wherein the telecommunications site comprises a cell site and the second data is captured via an Unmanned Aerial Vehicle. 10. The server of claim 8, wherein each of the first data, second data, and third data is captured using a 360-degree camera. 11. The server of claim 8, wherein the commands comprise navigation to different locations about the telecommunications site and viewing details of specific objects at the telecommunications site. 12. The server of claim 11, wherein the navigation is based on location items and the viewing details of specific objects is based on information icons in the virtual 360-degree view environment. 13. The server of claim 8, wherein the commands comprise zooming into a specific object of interest at the telecommunications site. 14. The server of claim 8, wherein the capturing first data comprises taking photos or video at each corner of surrounding geography at the telecommunications site. 15. A non-transitory computer readable medium includes instructions that, when executed, cause one or more processors to perform the steps of: obtaining first data of a 360-degree view at multiple points around the telecommunications site; obtaining second data of a 360-degree view at aerial points above the telecommunications site; obtaining third data of a 360-degree view inside a shelter or cabinet at the telecommunications site, wherein each of the first data, second data, and third data comprise one or more of photos and video; stitching the first data, the second data, and the third data together with links to create a virtual 360-degree view environment of the telecommunications site, wherein the links enable virtual navigation about the telecommunications site; and displaying the virtual 360-degree view environment to a viewer over a network and adjusting the virtual 360-degree view environment based on commands received from the viewer.
CROSS-REFERENCE TO RELATED APPLICATION(S) The present patent/application is continuation-in-part of and the content of each are incorporated by reference herein: Filing Date Ser. No. Title Jul. 7, 2017 15/644,144 DETECTING CHANGES AT CELL SITES AND SURROUNDING AREAS USING UNMANNED AERIAL VEHICLES May 17, 2017 15/597,320 MODELING FIBER CABLING ASSOCIATED WITH CELL SITES Apr. 6, 2017 15/480,792 SUBTERRANEAN 3D MODELING AT CELL SITES Mar. 27, 2017 15/469,841 CELL SITE AUDIT AND SURVEY VIA PHOTO STITCHING Jan. 25, 2017 15/415,040 SYSTEMS AND METHODS FOR OBTAINING ACCURATE 3D MODELING DATA USING MULTIPLE CAMERAS Oct. 31, 2016 15/338,700 SYSTEMS AND METHODS FOR OBTAINING ACCURATE 3D MODELING DATA USING UAVS FOR CELL SITES Oct. 3, 2016 15/283,699 OBTAINING 3D MODELING DATA USING UAVS FOR CELL SITES Aug. 19, 2016 15/241,239 3D MODELING OF CELL SITES TO DETECT CONFIGURATION AND SITE CHANGES Jul. 15, 2016 15/211,483 CLOSE-OUT AUDIT SYSTEMS AND METHODS FOR CELL SITE INSTALLATION AND MAINTENANCE May 31, 2016 15/168,503 VIRTUALIZED SITE SURVEY SYSTEMS AND METHODS FOR CELL SITES May 20, 2016 15/160,890 3D MODELING OF CELL SITES AND CELL TOWERS WITH UNMANNED AERIAL VEHICLES Apr. 14, 2015 14/685,720 UNMANNED AERIAL VEHICLE-BASED SYSTEMS AND METHODS ASSOCIATED WITH CELL SITES AND CELL TOWERS FIELD OF THE DISCLOSURE The present disclosure relates generally to telecommunication site monitoring systems and methods. More particularly, the present disclosure relates to systems and methods for a virtual 360-degree view of a telecommunications site, such as a cell site, for purposes of site surveys, site audits, and the like. BACKGROUND OF THE DISCLOSURE Due to the geographic coverage nature of wireless service, there are hundreds of thousands of cell towers in the United States. For example, in 2014, it was estimated that there were more than 310,000 cell towers in the United States. Cell towers can have heights up to 1,500 feet or more. There are various requirements for cell site workers (also referred to as tower climbers or transmission tower workers) to climb cell towers to perform maintenance, audit, and repair work for cellular phone and other wireless communications companies. This is both a dangerous and costly endeavor. For example, between 2003 and 2011, 50 tower climbers died working on cell sites (see, e.g., www.pbs.org/wgbh/pages/frontline/social-issues/cell-tower-deaths/in-race-for-better-cell-service-men-who-climb-towers-pay-with-their-lives/). Also, OSHA estimates that working on cell sites is 10 times more dangerous than construction work, generally (see, e.g., www.propublica.org/article/cell-tower-work-fatalities-methodology). Furthermore, the tower climbs also can lead to service disruptions caused by accidents. Thus, there is a strong desire, from both a cost and safety perspective, to reduce the number of tower climbs. Concurrently, the use of unmanned aerial vehicles (UAV), referred to as drones, is evolving. There are limitations associated with UAVs, including emerging FAA rules and guidelines associated with their commercial use. It would be advantageous to leverage the use of UAVs to reduce tower climbs of cell towers. US 20140298181 to Rezvan describes methods and systems for performing a cell site audit remotely. However, Rezvan does not contemplate performing any activity locally at the cell site, nor various aspects of UAV use. US20120250010 to Hannay describes aerial inspections of transmission lines using drones. However, Hannay does not contemplate performing any activity locally at the cell site, nor various aspects of constraining the UAV use. Specifically, Hannay contemplates a flight path in three dimensions along a transmission line. Of course, it would be advantageous to further utilize UAVs to actually perform operations on a cell tower. However, adding one or more robotic arms, carrying extra equipment, etc. presents a significantly complex problem in terms of UAV stabilization while in flight, i.e., counterbalancing the UAV to account for the weight and movement of the robotic arms. Research and development continues in this area, but current solutions are complex and costly, eliminating the drivers for using UAVs for performing cell tower work. 3D modeling is important for cell site operators, cell tower owners, engineers, etc. There exist current techniques to make 3D models of physical sites such as cell sites. One approach is to take hundreds or thousands of pictures and to use software techniques to combine these pictures to form a 3D model. Generally, conventional approaches for obtaining the pictures include fixed cameras at the ground with zoom capabilities or pictures via tower climbers. It would be advantageous to utilize a UAV to obtain the pictures, providing 360-degree photos from an aerial perspective. Use of aerial pictures is suggested in US 20100231687 to Armory. However, this approach generally assumes pictures taken from a fixed perspective relative to the cell site, such as via a fixed, mounted camera and a mounted camera in an aircraft. It has been determined that such an approach is moderately inaccurate during 3D modeling and combination with software due to slight variations in location tracking capabilities of systems such as Global Positioning Satellite (GPS). It would be advantageous to adapt a UAV to take pictures and provide systems and methods for accurate 3D modeling based thereon to again leverage the advantages of UAVs over tower climbers, i.e., safety, climbing speed and overall speed, cost, etc. In the process of planning, installing, maintaining, and operating cell sites and cell towers, site surveys are performed for testing, auditing, planning, diagnosing, inventorying, etc. Conventional site surveys involve physical site access including access to the top of the cell tower, the interior of any buildings, cabinets, shelters, huts, hardened structures, etc. at the cell site, and the like. With over 200,000 cell sites in the U.S., geographically distributed everywhere, site surveys can be expensive, time-consuming, and complex. The various parent applications associated herewith describe techniques to utilize UAVs to optimize and provide safer site surveys. It would also be advantageous to further optimize site surveys by minimizing travel through virtualization of the entire process. Again, with over 200,000 cell sites in the U.S., each time there is maintenance or installation activity at each cell site, operators and owners typically require a close-out audit which is done to document and verify the work performed. For example, the maintenance or installation activity can be performed by a third-party installation firm (separate from an operator or owner) and an objective of the close-out audit is to provide the operator or owner verification of the work as well as that the third-party installation firm did the work in a manner consistent with the operator or owner's expectations. Conventionally, close-out audits are performed by another firm, i.e., a third-party inspection firm, separate from the third-party installation firm, the owner, and the operator. Disadvantageously, this conventional approach with a separate third-party inspection firm is inefficient, expensive, etc. Also, with over 200,000 cell sites, it is difficult to monitor activity, namely configurations, physical structure, surroundings, etc., and associated changes. The typical arrangement includes a cell site owner, which is typically a real estate company, leasing space to cell site operators, i.e., wireless service providers. It is incumbent that the cell site owners maintain accurate records of the cell sites, including the configuration (i.e., are the operators deploying more equipment than agreements state?), physical structure (i.e., are there mechanical issues with the cell site?), surroundings (i.e., are there safety issues?), and the like. Conventional approaches require physical site surveys to obtain such information which with over 200,000 cells sites is expensive, time-consuming, slow, etc. The number of cell sites continues to grow and with the advent of 5G, to dramatically increase. For example, with 5G, small cell deployments are expected to increase to address capacity and coverage. All cell sites require so-called backhaul to provide network access to the cell site. One technique for backhaul includes fiber optic connections to the cell site. For site owners, it can be problematic to determine fiber optic cabling to a cell site, e.g., are there currently cables at the location, what are the possibilities of new cabling, etc. As the number of cell sites increases, it is important to get this data efficiently. BRIEF SUMMARY OF THE DISCLOSURE In an exemplary embodiment, a method for creating and utilizing a virtual 360-degree view of a telecommunications site includes capturing first data of a 360-degree view at multiple points around the telecommunications site; capturing second data of a 360-degree view at aerial points above the telecommunications site; capturing third data of a 360-degree view inside a shelter or cabinet at the telecommunications site, wherein each of the first data, second data, and third data comprise one or more of photos and video; stitching the first data, the second data, and the third data together with links to create a virtual 360-degree view environment of the telecommunications site, wherein the links enable virtual navigation about the telecommunications site; and displaying the virtual 360-degree view environment to a viewer over a network and adjusting the virtual 360-degree view environment based on commands received from the viewer. In another exemplary embodiment, a server for creating and utilizing a virtual 360-degree view of a telecommunications site includes a network interface and a processor communicatively coupled to one another; and memory storing instructions that, when executed, cause the processor to obtain first data of a 360-degree view at multiple points around the telecommunications site; obtain second data of a 360-degree view at aerial points above the telecommunications site; obtain third data of a 360-degree view inside a shelter or cabinet at the telecommunications site, wherein each of the first data, second data, and third data comprise one or more of photos and video; stitch the first data, the second data, and the third data together with links to create a virtual 360-degree view environment of the telecommunications site, wherein the links enable virtual navigation about the telecommunications site; and display the virtual 360-degree view environment to a viewer over a network and adjust the virtual 360-degree view environment based on commands received from the viewer. In a further exemplary embodiment, a non-transitory computer readable medium includes instructions that, when executed, cause one or more processors to perform the steps of obtaining first data of a 360-degree view at multiple points around the telecommunications site; obtaining second data of a 360-degree view at aerial points above the telecommunications site; obtaining third data of a 360-degree view inside a shelter or cabinet at the telecommunications site, wherein each of the first data, second data, and third data comprise one or more of photos and video; stitching the first data, the second data, and the third data together with links to create a virtual 360-degree view environment of the telecommunications site, wherein the links enable virtual navigation about the telecommunications site; and displaying the virtual 360-degree view environment to a viewer over a network and adjusting the virtual 360-degree view environment based on commands received from the viewer. BRIEF DESCRIPTION OF THE DRAWINGS The present disclosure is illustrated and described herein with reference to the various drawings, in which like reference numbers are used to denote like system components/method steps, as appropriate, and in which: FIG. 1 is a diagram of a side view of an exemplary cell site; FIG. 2 is a diagram of a cell site audit performed with a UAV; FIG. 3 is a screen diagram of a view of a graphical user interface (GUI) on a mobile device while piloting the UAV; FIG. 4 is a perspective view of an exemplary UAV; FIG. 5 is a block diagram of a mobile device; FIG. 6 is a flow chart of a cell site audit method utilizing the UAV and the mobile device; FIG. 7 is a network diagram of various cell sites deployed in a geographic region; FIG. 8 is a diagram of the cell site and an associated launch configuration and flight for the UAV to obtain photos for a 3D model of the cell site; FIG. 9 is a satellite view of an exemplary flight of the UAV at the cell site; FIG. 10 is a side view of an exemplary flight of the UAV at the cell site; FIG. 11 is a logical diagram of a portion of a cell tower along with associated photos taken by the UAV at different points relative thereto; FIG. 12 is a screen shot of a GUI associated with post processing photos from the UAV; FIG. 13 is a screen shot of a 3D model constructed from a plurality of 2D photos taken from the UAV as described herein; FIGS. 14-19 are various screen shots illustrate GUIs associated with a 3D model of a cell site based on photos taken from the UAV as described herein; FIG. 20 is a photo of the UAV in flight at the top of a cell tower; FIG. 21 is a flowchart of a process for modeling a cell site with an Unmanned Aerial Vehicle (UAV); FIG. 22 is a diagram of an exemplary interior of a building, such as a shelter or cabinet, at the cell site; FIG. 23 is a flowchart of a virtual site survey process for the cell site; FIG. 24 is a flowchart illustrates a close-out audit method performed at a cell site subsequent to maintenance or installation work; FIG. 25 is a flowchart of a 3D modeling method to detect configuration and site changes; FIG. 26 is a flow diagram of a 3D model creation process; FIG. 27 is a flowchart of a method using an Unmanned Aerial Vehicle (UAV) to obtain data capture at a cell site for developing a three dimensional (3D) thereof; FIG. 28 is a flowchart of a 3D modeling method for capturing data at the cell site, the cell tower, etc. using the UAV; FIGS. 29A and 29B are block diagrams of a UAV with multiple cameras (FIG. 29A) and a camera array (FIG. 29B); FIG. 30 is a flowchart of a method using multiple cameras to obtain accurate three-dimensional (3D) modeling data; FIGS. 31 and 32 are diagrams of a multiple camera apparatus and use of the multiple camera apparatus in a shelter or cabinet or the interior of a building; FIG. 33 is a flowchart of a data capture method in the interior of a building using the multiple camera apparatus; FIG. 34 is a flowchart of a method for verifying equipment and structures at the cell site using 3D modeling; FIG. 35 is a diagram of a photo stitching User Interface (UI) for cell site audits, surveys, inspections, etc. remotely; FIG. 36 is a flowchart illustrates a method for performing a cell site audit or survey remotely via a User Interface (UI); FIG. 37 is a perspective diagram of a 3D model of the cell site, the cell tower, the cell site components, and the shelter or cabinet along with surrounding geography and subterranean geography; FIG. 38 is a flowchart of a method for creating a three-dimensional (3D) model of a cell site for one or more of a cell site audit, a site survey, and cell site planning and engineering; FIG. 39 is a perspective diagram of the 3D model of FIG. 37 of the cell site, the cell tower, the cell site components, and the shelter or cabinet along with surrounding geography, subterranean geography, and including fiber connectivity; FIG. 40 is a flowchart of a method for creating a three-dimensional (3D) model of a cell site and associated fiber connectivity for one or more of a cell site audit, a site survey, and cell site planning and engineering; FIG. 41 is a perspective diagram of a cell site with the surrounding geography; FIG. 42 is a flowchart of a method for cell site inspection by a cell site operator using the UAV; FIG. 43 is a flowchart illustrates a virtual 360 view method 2700 for creating and using a virtual 360 environment; and FIGS. 44-55 are screen shots from an exemplary implementation of the virtual 360-degree view environment from FIG. 43. DETAILED DESCRIPTION OF THE DISCLOSURE Again, the present disclosure relates to systems and methods for a virtual 360-degree view of a telecommunications site, such as a cell site, for purposes of site surveys, site audits, and the like. The objective of the virtual 360 view is to provide an environment, viewable via a display, where personnel can be within the telecommunications site remotely. That is, the purpose of the virtual 360 view creation is to allow industry workers to be within the environment of the location captured (i.e. telecommunications cellular site). Within this environment, there is an additional augmented reality where a user can call information from locations of importance. This environment can serve as a bid walk, pre-construction verification, post installation verification, or simply as an inventory measurement for companies. The information captured with the virtual 360 view captures the necessary information to create action with respect to maintenance, upgrades, or the like. This actionable information creates an environment that can be passed from tower owner, carrier owner, construction company, and installation crews with the ease of an email with a Uniform Resource Locator (URL) link to the web. This link can be sent to a user's phone, Virtual Reality (VR) headset, computer, tablet, etc. This allows for a telecom engineer to be within the reality of the cell site or telecommunications site from their desk. For example, the engineer can click on an Air Conditioning (AC) panel and a photo is overlaid in the environment showing the engineer the spaces available for additional breakers or the sizes of breakers being used. Further, the present disclosure relates to systems and methods to detect changes cell sites and the surrounding area using Unmanned Aerial Vehicles (UAVs). Specifically, the systems and methods can be utilized by cell site operators (e.g., real estate companies) to quickly and efficiently determine the current state of a cell site including the surrounding geography. For example, the surrounding geography can include access roads, trees, physical structures, cell tower structure, etc. The systems and methods utilize a UAV to detect changes (deltas) between two different points in time in a quick and efficient manner. The changes can include changes to the cell tower, ground disturbances, potential hazards, loss of gravel on the access road, etc. Cell site operators can utilize the systems and methods for proactive monitoring and maintenance of their facilities. Note, a cell site operator may own or manage thousands or hundreds of thousands of sites, and the systems and methods are critical for efficiently handling the vast number of sites. Further, the present disclosure relates to systems and methods modeling fiber optic cabling associated with cell sites such as using Unmanned Aerial Vehicles (UAVs) or the like. Specifically, the systems and methods include building a three-dimensional (3D) model of the cell site including associated surroundings as well as focusing on fiber optic cables to/from the cell site. The 3D model can be used to remotely engineer backhaul access to the cell site. For example, the 3D model can be used to determine equipment placement for optimal connectivity to a fiber network. Also, the 3D model can be used to determine where to install fiber cabling if needed. As noted herein, next-gen small cells can be installed practically anywhere, and the 3D model can be used to aid in the planning, engineering, and installation. Further, in an exemplary embodiment, the present disclosure relates to systems and methods for cell site modeling including subterranean modeling of the area associated with the cell site. Specifically, the systems and methods include building a three-dimensional (3D) model of the cell site including the cell tower and associated cell site components, shelters/buildings and interiors, as well as a model of the surrounding geographic area including subterranean modeling. The 3D model can be used to perform cell site audits, planning, monitoring, etc. remotely. The subterranean modeling provides insight for site engineering such as to determine locations of underground utility cabling, pipes, etc., to determine structural aspects of site construction, to proactively determine problems, etc. Further, in an exemplary embodiment, the present disclosure relates to systems and methods for cell site audits and surveys using photo stitching based on photos taken at the cell site via various techniques including Unmanned Aerial Vehicles (UAVs). A remote user can use a photo stitched User Interface (UI) to perform a cell site audit, survey, inspection by navigating, zooming, etc. through a plurality of photos with links between one another. With the UI, the remote user can zoom in, virtually walk around, etc. and perform functions without a physical site visit. Further, in an exemplary embodiment, the present disclosure relates to systems and methods for verifying cell sites using accurate three-dimensional (3D) modeling data. In an exemplary embodiment, systems and method for verifying a cell site utilizing an Unmanned Aerial Vehicle (UAV) include providing an initial point cloud related to the cell site to the UAV; developing a second point cloud based on current conditions at the cell site, wherein the second point cloud is based on data acquisition using the UAV at the cell site; detecting variations between the initial point cloud and the second point cloud; and, responsive to detecting the variations, determining whether the variations are any of compliance related, load issues, and defects associated with any equipment or structures at the cell site. Further, in an exemplary embodiment, the present disclosure relates to systems and methods for obtaining accurate three-dimensional (3D) modeling data using a multiple camera apparatus. Specifically, the multiple camera apparatus contemplates use in a shelter or the like to simultaneously obtain multiple photos for purposes of developing a three-dimensional (3D) model of the shelter for use in a cell site audit or the like. The multiple camera apparatus can be portable or mounted within the shelter. The multiple camera apparatus includes a support beam with a plurality of cameras associated therewith. The plurality of cameras each face a different direction, angle, zoom, etc. and are coordinated to simultaneously obtain photos. Once obtained, the photos can be used to create a 3D model. Advantageously, the multiple camera apparatus streamlines data acquisition time as well as ensures the proper angles and photos are obtained. The multiple camera apparatus also is simply to use allowing untrained technicians the ability to easily perform data acquisition. Further, in an exemplary embodiment, the present disclosure relates to systems and methods for obtaining accurate three-dimensional (3D) modeling data using multiple cameras such as with Unmanned Aerial Vehicles (UAVs) (also referred to as “drones”) or the like at cell sites, cell towers, etc. The systems and methods utilize two or more cameras simultaneously to capture the modeling data and associated synchronization techniques to ensure the modeling data is accurately and timely captured. The multiple cameras can be part of a camera array. The camera array can be a single hardware entity or on different UAVs. Variously, the multiple cameras are communicatively coupled to one another and configured to take photos together, such as the same time, but different vantage points, angles, perspective, etc. Taking the photos together enables efficient data capture to create 3D models, such as at cell sites. Using the systems and methods described herein, the process of data capture can be at least twice as fast which is important for field operations where multiple cell sites need to be characterized. Further, in an exemplary embodiment, the present disclosure relates to systems and methods for obtaining three-dimensional (3D) modeling data using Unmanned Aerial Vehicles (UAVs) (also referred to as “drones”) or the like at cell sites, cell towers, etc. Variously, the systems and methods describe various techniques using UAVs or the like to obtain data, i.e., pictures and/or video, used to create a 3D model of a cell site subsequently. Various uses of the 3D model are also described including site surveys, site monitoring, engineering, etc. Further, in an exemplary embodiment, the present disclosure relates to three-dimensional (3D) modeling of cell sites to detect configuration and site changes. Again, the challenge for cell site owners is to manage thousands of cell sites which are geographically distributed. The 3D modeling systems and methods utilize various techniques to obtain data, to create 3D models, and to detect changes in configurations and surroundings. The 3D models can be created at two or more different points in time, and with the different 3D models, a comparison can be made to detect the changes. Advantageously, the 3D modeling systems and methods allow cell site operators to manage the cell sites without repeated physical site surveys efficiently. Further, in various exemplary embodiments, the present disclosure relates to close-out audit systems and methods for cell site installation and maintenance. Specifically, the systems and methods eliminate the separate third-party inspection firm for the close-out audit. The systems and methods include the installers (i.e., from the third-party installation firm, the owner, the operator, etc.) performing video capture subsequent to the installation and maintenance and using various techniques to obtain data from the video capture for the close-out audit. The close-out audit can be performed off-site with the data from the video capture thereby eliminating unnecessary tower climbs, site visits, and the like. Further, in various exemplary embodiments, the present disclosure relates to virtualized site survey systems and methods using three-dimensional (3D) modeling of cell sites and cell towers with and without unmanned aerial vehicles. The virtualized site survey systems and methods utilizing photo data capture along with location identifiers, points of interest, etc. to create three-dimensional (3D) modeling of all aspects of the cell sites, including interiors of buildings, cabinets, shelters, huts, hardened structures, etc. As described herein, a site survey can also include a site inspection, cell site audit, or anything performed based on the 3D model of the cell site including building interiors. With the data capture, 3D modeling can render a completely virtual representation of the cell sites. The data capture can be performed by on-site personnel, automatically with fixed, networked cameras, or a combination thereof. With the data capture and the associated 3D model, engineers and planners can perform site surveys, without visiting the sites leading to significant efficiency in cost and time. From the 3D model, any aspect of the site survey can be performed remotely including determinations of equipment location, accurate spatial rendering, planning through drag and drop placement of equipment, access to actual photos through a Graphical User Interface, indoor texture mapping, and equipment configuration visualization mapping the equipment in a 3D view of a rack. Further, in various exemplary embodiments, the present disclosure relates to three-dimensional (3D) modeling of cell sites and cell towers with unmanned aerial vehicles. The present disclosure includes UAV-based systems and methods for 3D modeling and representing of cell sites and cell towers. The systems and methods include obtaining various pictures via a UAV at the cell site, flying around the cell site to obtain various different angles of various locations, tracking the various pictures (i.e., enough pictures to produce an acceptable 3D model, usually hundreds, but could be more) with location identifiers, and processing the various pictures to develop a 3D model of the cell site and the cell tower. Additionally, the systems and methods focus on precision and accuracy ensuring the location identifiers are as accurate as possible for the processing by using multiple different location tracking techniques as well as ensuring the UAV is launched from the same location and/or orientation for each flight. The same location and/or orientation, as described herein, was shown to provide more accurate location identifiers versus arbitrary location launches and orientations for different flights. Additionally, once the 3D model is constructed, the systems and methods include an application which enables cell site owners and cell site operators to “click” on any location and obtain associated photos, something extremely useful in the ongoing maintenance and operation thereof. Also, once constructed, the 3D model is capable of various measurements including height, angles, thickness, elevation, even Radio Frequency (RF), and the like. Still further, in additional exemplary embodiments, UAV-based systems and methods are described associated with cell sites, such as for providing cell tower audits and the like, including a tethered configuration. Various aspects of UAVs are described herein to reduce tower climbs in conjunction with cell tower audits. Additional aspects are described utilizing UAVs for other functions, such as flying from cell tower to cell tower to provide audit services and the like. Advantageously, using UAVs for cell tower audits exponentially improves the safety of cell tower audits and has been shown by Applicants to reduce costs by over 40%, as well as drastically improving audit time. With the various aspects described herein, a UAV-based audit can provide superior information and quality of such information, including a 360-degree tower view. In one aspect, the systems and methods include a constrained flight zone for the UAV such as a three-dimensional rectangle (an “ice cube” shape) about the cell tower. This constrained flight zone allows the systems and methods to operate the UAV without extensive regulations such as including extra personnel for “spotting” and requiring private pilot's licenses. §1.0 Exemplary Cell Site Referring to FIG. 1, in an exemplary embodiment, a diagram illustrates a side view of an exemplary cell site 10. The cell site 10 includes a cell tower 12. The cell tower 12 can be any type of elevated structure, such as 100-200 feet/30-60 meters tall. Generally, the cell tower 12 is an elevated structure for holding cell site components 14. The cell tower 12 may also include a lighting rod 16 and a warning light 18. Of course, there may various additional components associated with the cell tower 12 and the cell site 10 which are omitted for illustration purposes. In this exemplary embodiment, there are four sets 20, 22, 24, 26 of cell site components 14, such as for four different wireless service providers. In this example, the sets 20, 22, 24 include various antennas 30 for cellular service. The sets 20, 22, 24 are deployed in sectors, e.g. there can be three sectors for the cell site components—alpha, beta, and gamma. The antennas 30 are used to both transmit a radio signal to a mobile device and receive the signal from the mobile device. The antennas 30 are usually deployed as a single, groups of two, three or even four per sector. The higher the frequency of spectrum supported by the antenna 30, the shorter the antenna 30. For example, the antennas 30 may operate around 850 MHz, 1.9 GHz, and the like. The set 26 includes a microwave dish 32 which can be used to provide other types of wireless connectivity, besides cellular service. There may be other embodiments where the cell tower 12 is omitted and replaced with other types of elevated structures such as roofs, water tanks, etc. §2.0 Cell Site Audits Via UAV Referring to FIG. 2, in an exemplary embodiment, a diagram illustrates a cell site audit 40 performed with an unmanned aerial vehicle (UAV) 50. As described herein, the cell site audit 40 is used by service providers, third party engineering companies, tower operators, etc. to check and ensure proper installation, maintenance, and operation of the cell site components 14 and shelter or cabinet 52 equipment as well as the various interconnections between them. From a physical accessibility perspective, the cell tower 12 includes a climbing mechanism 54 for tower climbers to access the cell site components 14. FIG. 2 includes a perspective view of the cell site 10 with the sets 20, 26 of the cell site components 14. The cell site components 14 for the set 20 include three sectors—alpha sector 54, beta sector 56, and gamma sector 58. In an exemplary embodiment, the UAV 50 is utilized to perform the cell site audit 40 in lieu of a tower climber access the cell site components 14 via the climbing mechanism 54. In the cell site audit 40, an engineer/technician is local to the cell site 10 to perform various tasks. The systems and methods described herein eliminate a need for the engineer/technician to climb the cell tower 12. Of note, it is still important for the engineer/technician to be local to the cell site 10 as various aspects of the cell site audit 40 cannot be done remotely as described herein. Furthermore, the systems and methods described herein provide an ability for a single engineer/technician to perform the cell site audit 40 without another person handling the UAV 50 or a person with a pilot's license operating the UAV 50 as described herein. §2.1 Cell Site Audit In general, the cell site audit 40 is performed to gather information and identify a state of the cell site 10. This is used to check the installation, maintenance, and/or operation of the cell site 10. Various aspects of the cell site audit 40 can include, without limitation: Verify the cell site 10 is built according to a current revision Verify Equipment Labeling Verify Coax Cable (“Coax”) Bend Radius Verify Coax Color Coding/Tagging Check for Coax External Kinks & Dents Verify Coax Ground Kits Verify Coax Hanger/Support Verify Coax Jumpers Verify Coax Size Check for Connector Stress & Distortion Check for Connector Weatherproofing Verify Correct Duplexers/Diplexers Installed Verify Duplexer/Diplexer Mounting Verify Duplexers/Diplexers Installed Correctly Verify Fiber Paper Verify Lacing & Tie Wraps Check for Loose or Cross-Threaded Coax Connectors Verify Return (“Ret”) Cables Verify Ret Connectors Verify Ret Grounding Verify Ret Installation Verify Ret Lightning Protection Unit (LPI) Check for Shelter/Cabinet Penetrations Verify Surge Arrestor Installation/Grounding Verify Site Cleanliness Verify LTE GPS Antenna Installation Of note, the cell site audit 40 includes gathering information at and inside the shelter or cabinet 52, on the cell tower 12, and at the cell site components 14. Note, it is not possible to perform all of the above items solely with the UAV 50 or remotely. §3.0 Piloting the UAV at the Cell Site It is important to note that the Federal Aviation Administration (FAA) is in the process of regulating commercial UAV (drone) operation. It is expected that these regulations would not be complete until 2016 or 2017. In terms of these regulations, commercial operation of the UAV 50, which would include the cell site audit 40, requires at least two people, one acting as a spotter and one with a pilot's license. These regulations, in the context of the cell site audit 40, would make use of the UAV 50 impractical. To that end, the systems and methods described herein propose operation of the UAV 50 under FAA exemptions which allow the cell site audit 40 to occur without requiring two people and without requiring a pilot's license. Here, the UAV 50 is constrained to fly up and down at the cell site 10 and within a three-dimensional (3D) rectangle at the cell site components. These limitations on the flight path of the UAV 50 make the use of the UAV 50 feasible at the cell site 10. Referring to FIG. 3, in an exemplary embodiment, a screen diagram illustrates a view of a graphical user interface (GUI) 60 on a mobile device 100 while piloting the UAV 50. The GUI 60 provides a real-time view to the engineer/technician piloting the UAV 50. That is, a screen 62 provides a view from a camera on the UAV 50. As shown in FIG. 3, the cell site 10 is shown with the cell site components 14 in the view of the screen 62. Also, the GUI 60 has various controls 64, 66. The controls 64 are used to pilot the UAV 50, and the controls 66 are used to perform functions in the cell site audit 40 and the like. §3.1 FAA Regulations The FAA is overwhelmed with applications from companies interested in flying drones, but the FAA is intent on keeping the skies safe. Currently, approved exemptions for flying drones include tight rules. Once approved, there is some level of certification for drone operators along with specific rules such as speed limit of 100 mph, height limitations such as 400 ft, no-fly zones, day only operation, documentation, and restrictions on aerial filming. Accordingly, flight at or around cell towers is constrained, and the systems and methods described herein fully comply with the relevant restrictions associated with drone flights from the FAA. §4.0 Exemplary Hardware Referring to FIG. 4, in an exemplary embodiment, a perspective view illustrates an exemplary UAV 50 for use with the systems and methods described herein. Again, the UAV 50 may be referred to as a drone or the like. The UAV 50 may be a commercially available UAV platform that has been modified to carry specific electronic components as described herein to implement the various systems and methods. The UAV 50 includes rotors 80 attached to a body 82. A lower frame 84 is located on a bottom portion of the body 82, for landing the UAV 50 to rest on a flat surface and absorb impact during landing. The UAV 50 also includes a camera 86 which is used to take still photographs, video, and the like. Specifically, the camera 86 is used to provide the real-time display on the screen 62. The UAV 50 includes various electronic components inside the body 82 and/or the camera 86 such as, without limitation, a processor, a data store, memory, a wireless interface, and the like. Also, the UAV 50 can include additional hardware, such as robotic arms or the like that allow the UAV 50 to attach/detach components for the cell site components 14. Specifically, it is expected that the UAV 50 will get bigger and more advanced, capable of carrying significant loads, and not just a wireless camera. The present disclosure contemplates using the UAV 50 for various aspects at the cell site 10, including participating in construction or deconstruction of the cell tower 12, the cell site components 14, etc. These various components are now described with reference to a mobile device 100. Those of ordinary skill in the art will recognize the UAV 50 can include similar components to the mobile device 100. Of note, the UAV 50 and the mobile device 100 can be used cooperatively to perform various aspects of the cell site audit 40 described herein. In other embodiments, the UAV 50 can be operated with a controller instead of the mobile device 100. The mobile device 100 may solely be used for real-time video from the camera 86 such as via a wireless connection (e.g., IEEE 802.11 or variants thereof). Some portions of the cell site audit 40 can be performed with the UAV 50, some with the mobile device 100, and others solely by the operator through visual inspection. In some embodiments, all of the aspects can be performed in the UAV 50. In other embodiments, the UAV 50 solely relays data to the mobile device 100 which performs all of the aspects. Other embodiments are also contemplated. Referring to FIG. 5, in an exemplary embodiment, a block diagram illustrates a mobile device 100, which may be used for the cell site audit 40 or the like. The mobile device 100 can be a digital device that, in terms of hardware architecture, generally includes a processor 102, input/output (I/O) interfaces 104, wireless interfaces 106, a data store 108, and memory 110. It should be appreciated by those of ordinary skill in the art that FIG. 5 depicts the mobile device 100 in an oversimplified manner, and a practical embodiment may include additional components and suitably configured processing logic to support known or conventional operating features that are not described in detail herein. The components (102, 104, 106, 108, and 102) are communicatively coupled via a local interface 112. The local interface 112 can be, for example, but not limited to, one or more buses or other wired or wireless connections, as is known in the art. The local interface 112 can have additional elements, which are omitted for simplicity, such as controllers, buffers (caches), drivers, repeaters, and receivers, among many others, to enable communications. Further, the local interface 112 may include address, control, and/or data connections to enable appropriate communications among the aforementioned components. The processor 102 is a hardware device for executing software instructions. The processor 102 can be any custom made or commercially available processor, a central processing unit (CPU), an auxiliary processor among several processors associated with the mobile device 100, a semiconductor-based microprocessor (in the form of a microchip or chip set), or generally any device for executing software instructions. When the mobile device 100 is in operation, the processor 102 is configured to execute software stored within the memory 110, to communicate data to and from the memory 110, and to generally control operations of the mobile device 100 pursuant to the software instructions. In an exemplary embodiment, the processor 102 may include a mobile optimized processor such as optimized for power consumption and mobile applications. The I/O interfaces 104 can be used to receive user input from and/or for providing system output. User input can be provided via, for example, a keypad, a touch screen, a scroll ball, a scroll bar, buttons, bar code scanner, and the like. System output can be provided via a display device such as a liquid crystal display (LCD), touch screen, and the like. The I/O interfaces 104 can also include, for example, a serial port, a parallel port, a small computer system interface (SCSI), an infrared (IR) interface, a radio frequency (RF) interface, a universal serial bus (USB) interface, and the like. The I/O interfaces 104 can include a graphical user interface (GUI) that enables a user to interact with the mobile device 100. Additionally, the I/O interfaces 104 may further include an imaging device, i.e. camera, video camera, etc. The wireless interfaces 106 enable wireless communication to an external access device or network. Any number of suitable wireless data communication protocols, techniques, or methodologies can be supported by the wireless interfaces 106, including, without limitation: RF; IrDA (infrared); Bluetooth; ZigBee (and other variants of the IEEE 802.15 protocol); IEEE 802.11 (any variation); IEEE 802.16 (WiMAX or any other variation); Direct Sequence Spread Spectrum; Frequency Hopping Spread Spectrum; Long Term Evolution (LTE); cellular/wireless/cordless telecommunication protocols (e.g. 3G/4G, etc.); wireless home network communication protocols; paging network protocols; magnetic induction; satellite data communication protocols; wireless hospital or health care facility network protocols such as those operating in the WMTS bands; GPRS; proprietary wireless data communication protocols such as variants of Wireless USB; and any other protocols for wireless communication. The wireless interfaces 106 can be used to communicate with the UAV 50 for command and control as well as to relay data therebetween. The data store 108 may be used to store data. The data store 108 may include any of volatile memory elements (e.g., random access memory (RAM, such as DRAM, SRAM, SDRAM, and the like)), nonvolatile memory elements (e.g., ROM, hard drive, tape, CDROM, and the like), and combinations thereof. Moreover, the data store 108 may incorporate electronic, magnetic, optical, and/or other types of storage media. The memory 110 may include any of volatile memory elements (e.g., random access memory (RAM, such as DRAM, SRAM, SDRAM, etc.)), nonvolatile memory elements (e.g., ROM, hard drive, etc.), and combinations thereof. Moreover, the memory 110 may incorporate electronic, magnetic, optical, and/or other types of storage media. Note that the memory 110 may have a distributed architecture, where various components are situated remotely from one another but can be accessed by the processor 102. The software in memory 110 can include one or more software programs, each of which includes an ordered listing of executable instructions for implementing logical functions. In the example of FIG. 5, the software in the memory 110 includes a suitable operating system (O/S) 114 and programs 116. The operating system 114 essentially controls the execution of other computer programs, and provides scheduling, input-output control, file and data management, memory management, and communication control and related services. The programs 116 may include various applications, add-ons, etc. configured to provide end user functionality with the mobile device 100, including performing various aspects of the systems and methods described herein. It will be appreciated that some exemplary embodiments described herein may include one or more generic or specialized processors (“one or more processors”) such as microprocessors, digital signal processors, customized processors, and field programmable gate arrays (FPGAs) and unique stored program instructions (including both software and firmware) that control the one or more processors to implement, in conjunction with certain non-processor circuits, some, most, or all of the functions of the methods and/or systems described herein. Alternatively, some or all functions may be implemented by a state machine that has no stored program instructions, or in one or more application specific integrated circuits (ASICs), in which each function or some combinations of certain of the functions are implemented as custom logic. Of course, a combination of the aforementioned approaches may be used. Moreover, some exemplary embodiments may be implemented as a non-transitory computer-readable storage medium having computer readable code stored thereon for programming a computer, server, appliance, device, etc. each of which may include a processor to perform methods as described and claimed herein. Examples of such computer-readable storage mediums include, but are not limited to, a hard disk, an optical storage device, a magnetic storage device, a ROM (Read Only Memory), a PROM (Programmable Read Only Memory), an EPROM (Erasable Programmable Read Only Memory), an EEPROM (Electrically Erasable Programmable Read Only Memory), Flash memory, and the like. When stored in the non-transitory computer readable medium, software can include instructions executable by a processor that, in response to such execution, cause a processor or any other circuitry to perform a set of operations, steps, methods, processes, algorithms, etc. §4.1 RF Sensors in the UAV In an exemplary embodiment, the UAV 50 can also include one or more RF sensors disposed therein. The RF sensors can be any device capable of making wireless measurements related to signals associated with the cell site components 14, i.e., the antennas. In an exemplary embodiment, the UAV 50 can be further configured to fly around a cell zone associated with the cell site 10 to identify wireless coverage through various measurements associated with the RF sensors. §5.0 Cell Site Audit with UAV and/or Mobile Device Referring to FIG. 6, in an exemplary embodiment, a flow chart illustrates a cell site audit method 200 utilizing the UAV 50 and the mobile device 100. Again, in various exemplary embodiments, the cell site audit 40 can be performed with the UAV 50 and the mobile device 100. In other exemplary embodiments, the cell site audit 40 can be performed with the UAV 50 and an associated controller. In other embodiments, the mobile device 100 is solely used to relay real-time video from the camera 86. While the steps of the cell site audit method 200 are listed sequentially, those of ordinary skill in the art will recognize some or all of the steps may be performed in a different order. The cell site audit method 200 includes an engineer/technician at a cell site with the UAV 50 and the mobile device 100 (step 202). Again, one aspect of the systems and methods described herein is the usage of the UAV 50, in a commercial setting, but with constraints such that only one operator is required and such that the operator does not have to hold a pilot's license. As described herein, the constraints can include a flight of the UAV 50 at or near the cell site 10 only, a flight pattern up and down in a 3D rectangle at the cell tower 12, a maximum height restriction (e.g., 500 feet or the like), and the like. For example, the cell site audit 40 is performed by one of i) a single operator flying the UAV 50 without a license or ii) two operators including one with a license and one to spot the UAV 50. The engineer/technician performs one or more aspects of the cell site audit 40 without the UAV 50 (step 204). Note, there are many aspects of the cell site audit 40 as described herein. It is not possible for the UAV 50 to perform all of these items such that the engineer/technician could be remote from the cell site 10. For example, access to the shelter or cabinet 52 for audit purposes requires the engineer/technician to be local. In this step, the engineer/technician can perform any audit functions as described herein that do not require climbing. The engineer/technician can cause the UAV 50 to fly up the cell tower 12 or the like to view cell site components 14 (step 206). Again, this flight can be based on the constraints, and the flight can be through a controller and/or the mobile device 100. The UAV 50 and/or the mobile device 100 can collect data associated with the cell site components 14 (step 208), and process the collected data to obtain information for the cell site audit 40 (step 210). As described herein, the UAV 50 and the mobile device 100 can be configured to collect data via video and/or photographs. The engineer/technician can use this collected data to perform various aspects of the cell site audit 40 with the UAV 50 and the mobile device 100 and without a tower climb. The foregoing descriptions detail specific aspects of the cell site audit 40 using the UAV 50 and the mobile device 100. In these aspects, data can be collected—generally, the data is video or photographs of the cell site components 14. The processing of the data can be automated through the UAV 50 and/or the mobile device 100 to compute certain items as described herein. Also, the processing of the data can be performed either at the cell site 10 or afterward by the engineer/technician. In an exemplary embodiment, the UAV 50 can be a commercial, “off-the-shelf” drone with a Wi-Fi enabled camera for the camera 86. Here, the UAV 50 is flown with a controller pad which can include a joystick or the like. Alternatively, the UAV 50 can be flown with the mobile device 100, such as with an app installed on the mobile device 100 configured to control the UAV 50. The Wi-Fi enable camera is configured to communicate with the mobile device 100—to both display real-time video and audio as well as to capture photos and/or video during the cell site audit 40 for immediate processing or for later processing to gather relevant information about the cell site components 14 for the cell site audit 40. In another exemplary embodiment, the UAV 50 can be a so-called “drone in a box” which is preprogrammed/configured to fly a certain route, such as based on the flight constraints described herein. The “drone in a box” can be physically transported to the cell site 10 or actually located there. The “drone in a box” can be remotely controlled as well. §5.1 Antenna Down Tilt Angle In an exemplary aspect of the cell site audit 40, the UAV 50 and/or the mobile device 100 can be used to determine a down tilt angle of individual antennas 30 of the cell site components 14. The down tilt angle can be determined for all of the antennas 30 in all of the sectors 54, 56, 58. The down tilt angle is the mechanical (external) down tilt of the antennas 30 relative to a support bar 200. In the cell site audit 40, the down tilt angle is compared against an expected value, such as from a Radio Frequency (RF) data sheet, and the comparison may check to ensure the mechanical (external) down tilt is within ±1.0° of specification on the RF data sheet. Using the UAV 50 and/or the mobile device 100, the down tilt angle is determined from a photo taken from the camera 86. In an exemplary embodiment, the UAV 50 and/or the mobile device 100 is configured to measure three points—two defined by the antenna 30 and one by the support bar 200 to determine the down tilt angle of the antenna 30. For example, the down tilt angle can be determined visually from the side of the antenna 30—measuring a triangle formed by a top of the antenna 30, a bottom of the antenna 30, and the support bar 200. §5.2 Antenna Plumb In an exemplary aspect of the cell site audit 40 and similar to determining the down tilt angle, the UAV 50 and/or the mobile device 100 can be used to visually inspect the antenna 30 including its mounting brackets and associated hardware. This can be done to verify appropriate hardware installation, to verify the hardware is not loose or missing, and to verify that antenna 30 is plumb relative to the support bar 200. §5.3 Antenna Azimuth In an exemplary aspect of the cell site audit 40, the UAV 50 and/or the mobile device 100 can be used to verify the antenna azimuth, such as verifying the antenna azimuth is oriented within ±5° as defined on the RF data sheet. The azimuth (AZ) angle is the compass bearing, relative to true (geographic) north, of a point on the horizon directly beneath an observed object. Here, the UAV 50 and/or the mobile device 100 can include a location determining device such as a Global Positioning Satellite (GPS) measurement device. The antenna azimuth can be determined with the UAV 50 and/or the mobile device 100 using an aerial photo or the GPS measurement device. §5.4 Photo Collections As part of the cell site audit 40 generally, the UAV 50 and/or the mobile device 100 can be used to document various aspects of the cell site 10 by taking photos or video. For example, the mobile device 100 can be used to take photos or video on the ground in or around the shelter or cabinet 52 and the UAV 500 can be used to take photos or video up the cell tower 12 and of the cell site components 14. The photos and video can be stored in any of the UAV 50, the mobile device 100, the cloud, etc. In an exemplary embodiment, the UAV can also hover at the cell site 10 and provide real-time video footage back to the mobile device 100 or another location (for example, a Network Operations Center (NOC) or the like). §5.5 Compound Length/Width The UAV 50 can be used to fly over the cell site 10 to measure the overall length and width of the cell site 10 compound from overhead photos. In one aspect, the UAV 50 can use GPS positioning to detect the length and width by flying over the cell site 10. In another aspect, the UAV 50 can take overhead photos which can be processed to determine the associated length and width of the cell site 10. §5.6 Data Capture—Cell Site Audit The UAV 50 can be used to capture various pieces of data via the camera 86. That is, with the UAV 50 and the mobile device 100, the camera 86 is equivalent to the engineer/technician's own eyes, thereby eliminating the need for the engineer/technician to physically climb the tower. One important aspect of the cell site audit 40 is physically collecting various pieces of information—either to check records for consistency or to establish a record. For example, the data capture can include determining equipment module types, locations, connectivity, serial numbers, etc. from photos. The data capture can include determining physical dimensions from photos or from GPS such as the cell tower 12 height, width, depth, etc. The data capture can also include visual inspection of any aspect of the cell site 10, cell tower 12, cell site components 14, etc. including, but not limited to, physical characteristics, mechanical connectivity, cable connectivity, and the like. The data capture can also include checking the lighting rod 16 and the warning light 18 on the cell tower 12. Also, with additional equipment on the UAV 50, the UAV 50 can be configured to perform maintenance such as replacing the warning light 18, etc. The data capture can also include checking maintenance status of the cell site components 14 visually as well as checking associated connection status. Another aspect of the cell site audit 40 can include checking the structural integrity of the cell tower 12 and the cell site components 14 via photos from the UAV 50. §5.7 Flying the UAV at the Cell Site In an exemplary embodiment, the UAV 50 can be programmed to automatically fly to a location and remain there without requiring the operator to control the UAV 50 in real-time, at the cell site 10. In this scenario, the UAV 50 can be stationary at a location in the air at the cell site 10. Here, various functionality can be incorporated in the UAV 50 as described herein. Note, this aspect leverages the ability to fly the UAV 50 commercially based on the constraints described herein. That is, the UAV 50 can be used to fly around the cell tower 12, to gather data associated with the cell site components 14 for the various sectors 54, 56, 58. Also, the UAV 50 can be used to hover around the cell tower 12, to provide additional functionality described as follows. §5.8 Video/Photo Capture—Cell Site With the UAV 50 available to operate at the cell site 10, the UAV 50 can also be used to capture video/photos while hovering. This application uses the UAV 50 as a mobile video camera to capture activity at or around the cell site 10 from the air. It can be used to document work at the cell site 10 or to investigate the cell site 10 responsive to problems, e.g. tower collapse. It can be used to take surveillance video of surrounding locations such as service roads leading to the cell site 10, etc. §5.9 Wireless Service Via the UAV Again, with the ability to fly at the cell site 10, subject to the constraints, the UAV 50 can be used to provide temporary or even permanent wireless service at the cell site. This is performed with the addition of wireless service-related components to the UAV 50. In the temporary mode, the UAV 50 can be used to provide services over a short time period, such as responding to an outage or other disaster affecting the cell site 10. Here, an operator can cause the UAV 50 to fly where the cell site components 14 are and provide such service. The UAV 50 can be equipped with wireless antennas to provide cell service, Wireless Local Area Network (WLAN) service, or the like. The UAV 50 can effectively operate as a temporary tower or small cell as needed. In the permanent mode, the UAV 50 (along with other UAVs 50) can constantly be in the air at the cell site 10 providing wireless service. This can be done similar to the temporary mode but over a longer time period. The UAV 50 can be replaced over a predetermined time to refuel or the like. The replacement can be another UAV 50. The UAV 50 can effectively operate as a permanent tower or small cell as needed. §6.0 Flying the UAV from Cell Site to Another Cell Site As described herein, the flight constraints include operating the UAV 50 vertically in a defined 3D rectangle at the cell site 10. In another exemplary embodiment, the flight constraints can be expanded to allow the 3D rectangle at the cell site 10 as well as horizontal operation between adjacent cell sites 10. Referring to FIG. 7, in an exemplary embodiment, a network diagram illustrates various cell sites 10a-10e deployed in a geographic region 300. In an exemplary embodiment, the UAV 50 is configured to operate as described herein, such as in FIG. 2, in the vertical 3D rectangular flight pattern, as well as in a horizontal flight pattern between adjacent cell sites 10. Here, the UAV 50 is cleared to fly, without the commercial regulations, between the adjacent cell sites 10. In this manner, the UAV 50 can be used to perform the cell site audits 40 at multiple locations—note, the UAV 50 does not need to land and physically be transported to the adjacent cell sites 10. Additionally, the fact that the FAA will allow exemptions to fly the UAV 50 at the cell site 10 and between adjacent cell sites 10 can create an interconnected mesh network of allowable flight paths for the UAV 50. Here, the UAV 50 can be used for other purposes besides those related to the cell site 10. That is, the UAV 50 can be flown in any application, independent of the cell sites 10, but without requiring FAA regulation. The applications can include, without limitation, a drone delivery network, a drone surveillance network, and the like. As shown in FIG. 7, the UAV 50, at the cell site 10a, can be flown to any of the other cell sites 10b-10e along flight paths 302. Due to the fact that cell sites 10 are numerous and diversely deployed in the geographic region 300, an ability to fly the UAV 50 at the cell sites 10 and between adjacent cell sites 10 creates an opportunity to fly the UAV 50 across the geographic region 300, for numerous applications. §7.0 UAV and Cell Towers Additionally, the systems and methods described herein contemplate practically any activity at the cell site 10 using the UAV 50 in lieu of a tower climb. This can include, without limitation, any tower audit work with the UAV 50, any tower warranty work with the UAV 50, any tower operational ready work with the UAV 50, any tower construction with the UAV 50, any tower decommissioning/deconstruction with the UAV 50, any tower modifications with the UAV 50, and the like. §8.0 Cell Site Operations There are generally two entities associated with cell sites—cell site owners and cell site operators. Generally, cell site owners can be viewed as real estate property owners and managers. Typical cell site owners may have a vast number of cell sites, such as tens of thousands, geographically dispersed. The cell site owners are generally responsible for the real estate, ingress and egress, structures on site, the cell tower itself, etc. Cell site operators generally include wireless service providers who generally lease space on the cell tower and in the structures for antennas and associated wireless backhaul equipment. There are other entities that may be associated with cell sites as well including engineering firms, installation contractors, and the like. All of these entities have a need for the various UAV-based systems and methods described herein. Specifically, cell site owners can use the systems and methods for real estate management functions, audit functions, etc. Cell site operators can use the systems and methods for equipment audits, troubleshooting, site engineering, etc. Of course, the systems and methods described herein can be provided by an engineering firm or the like contracted to any of the above entities or the like. The systems and methods described herein provide these entities time savings, increased safety, better accuracy, lower cost, and the like. §10.0 3D Modeling Systems and Methods with UAVs Referring to FIG. 8, in an exemplary embodiment, a diagram illustrates the cell site 10 and an associated launch configuration and flight for the UAV 50 to obtain photos for a 3D model of the cell site 10. Again, the cell site 10, the cell tower 12, the cell site components 14, etc. are as described herein. To develop a 3D model, the UAV 50 is configured to take various photos during flight, at different angles, orientations, heights, etc. to develop a 360-degree view. For post processing, it is important to differentiate between different photos accurately. In various exemplary embodiments, the systems and methods utilize accurate location tracking for each photo taken. It is important for accurate correlation between photos to enable construction of a 3D model from a plurality of 2D photos. The photos can all include multiple location identifiers (i.e., where the photo was taken from, height and exact location). In an exemplary embodiment, the photos can each include at least two distinct location identifiers, such as from GPS or GLONASS. GLONASS is a “GLObal NAvigation Satellite System” which is a space-based satellite navigation system operating in the radio navigation-satellite service and used by the Russian Aerospace Defence Forces. It provides an alternative to GPS and is the second alternative navigational system in operation with global coverage and of comparable precision. The location identifiers are tagged or embedded to each photo and indicative of the location of the UAV 50 where and when the photo was taken. These location identifiers are used with objects of interest identified in the photo during post processing to create the 3D model. In fact, it was determined that location identifier accuracy is very important in the post processing for creating the 3D model. One such determination was that there are slight inaccuracies in the location identifiers when the UAV 50 is launched from a different location and/or orientation. Thus, to provide further accuracy for the location identifiers, each flight of the UAV 50 is constrained to land and depart from a same location and orientation. For example, future flights of the same cell site 10 or additional flights at the same time when the UAV 50 lands and, e.g., has a battery change. To ensure the same location and/or orientation in subsequent flights at the cell site 10, a zone indicator 800 is set at the cell site 10, such as on the ground via some marking (e.g., chalk, rope, white powder, etc.). Each flight at the cell site 10 for purposes of obtaining photos for 3D modeling is done using the zone indicator 800 to land and launch the UAV 50. Based on operations, it was determined that using conventional UAVs 50; the zone indicator 800 provides significantly more accuracy in location identifier readings. Accordingly, the photos are accurately identified relative to one another and able to create an extremely accurate 3D model of all physical features of the cell site 10. Thus, in an exemplary embodiment, all UAV 50 flights are from the same launch point and orientation to avoid calibration issues with any location identifier technique. The zone indicator 800 can also be marked on the 3D model for future flights at the cell site 10. Thus, the use of the zone indicator 800 for the same launch location and orientation along with the multiple location indicators provide more precision in the coordinates for the UAV 50 to correlate the photos. Note, in other exemplary embodiments, the zone indicator 800 may be omitted, or the UAV 50 can launch from additional points, such that the data used for the 3D model is only based on a single flight. The zone indicator 800 is advantageous when data is collected over time or when there are landings in flight. Once the zone indicator 800 is established, the UAV 50 is placed therein in a specific orientation (orientation is arbitrary so long as the same orientation is continually maintained). The orientation refers to which way the UAV 50 is facing at launch and landing. Once the UAV 50 is in the zone indicator 800, the UAV 50 can be flown up (denoted by line 802) the cell tower 12. Note, the UAV 50 can use the aforementioned flight constraints to conform to FAA regulations or exemptions. Once at a certain height and certain distance from the cell tower 12 and the cell site components 14, the UAV 50 can take a circular or 360-degree flight pattern about the cell tower 12, including flying up as well as around the cell tower 12 (denoted by line 804). During the flight, the UAV 50 is configured to take various photos of different aspects of the cell site 10 including the cell tower 12, the cell site components 14, as well as surrounding area. These photos are each tagged or embedded with multiple location identifiers. It has also been determined that the UAV 50 should be flown at a certain distance based on its camera capabilities to obtain the optimal photos, i.e., not too close or too far from objects of interest. The UAV 50 in a given flight can take hundreds or even thousands of photos, each with the appropriate location identifiers. For an accurate 3D model, at least hundreds of photos are required. The UAV 50 can be configured to take pictures automatically are given intervals during the flight, and the flight can be a preprogrammed trajectory around the cell site 10. Alternatively, the photos can be manually taken based on operator commands. Of course, a combination is also contemplated. In another exemplary embodiment, the UAV 50 can include preprocessing capabilities which monitor photos taken to determine a threshold after which enough photos have been taken to construct the 3D model accurately. Referring to FIG. 9, in an exemplary embodiment, a satellite view illustrates an exemplary flight of the UAV 50 at the cell site 10. Note, photos are taken at locations marked with circles in the satellite view. Note, the flight of the UAV 50 can be solely to construct the 3D model, or as part of the cell site audit 40 described herein. Also note, the exemplary flight allows photos at different locations, angles, orientations, etc. such that the 3D model not only includes the cell tower 12, but also the surrounding geography. Referring to FIG. 10, in an exemplary embodiment, a side view illustrates an exemplary flight of the UAV 50 at the cell site 10. Similar to FIG. 9, FIG. 10 shows circles in the side view at locations where photos were taken. Note, photos are taken at different elevations, orientations, angles, and locations. The photos are stored locally in the UAV 50 and/or transmitted wirelessly to a mobile device, controller, server, etc. Once the flight is complete and the photos are provided to an external device from the UAV 50 (e.g., mobile device, controller, server, cloud service, or the like), post processing occurs to combine the photos or “stitch” them together to construct the 3D model. While described separately, the post processing could occur in the UAV 50 provided its computing power is capable. Referring to FIG. 11, in an exemplary embodiment, a logical diagram illustrates a portion of a cell tower 12 along with associated photos taken by the UAV 50 at different points relative thereto. Specifically, various 2D photos are logically shown at different locations relative to the cell tower 12 to illustrate the location identifiers and the stitching together of the photos. Referring to FIG. 12, in an exemplary embodiment, a screen shot illustrates a Graphic User Interface (GUI) associated with post processing photos from the UAV 50. Again, once the UAV 50 has completed taking photos of the cell site 10, the photos are post processed to form a 3D model. The systems and methods contemplate any software program capable of performing photogrammetry. In the example of FIG. 12, there are 128 total photos. The post processing includes identifying visible points across the multiple points, i.e., objects of interest. For example, the objects of interest can be any of the cell site components 14, such as antennas. The post processing identifies the same object of interest across different photos, with their corresponding location identifiers, and builds a 3D model based on multiple 2D photos. Referring to FIG. 13, in an exemplary embodiment, a screen shot illustrates a 3D model constructed from a plurality of 2D photos taken from the UAV 50 as described herein. Note, the 3D model can be displayed on a computer or another type of processing device, such as via an application, a Web browser, or the like. The 3D model supports zoom, pan, tilt, etc. Referring to FIGS. 14-19, in various exemplary embodiments, various screen shots illustrate GUIs associated with a 3D model of a cell site based on photos taken from the UAV 50 as described herein. FIG. 14 is a GUI illustrating an exemplary measurement of an object, i.e., the cell tower 12, in the 3D model. Specifically, using a point and click operation, one can click on two points such as the top and bottom of the cell tower and the 3D model can provide a measurement, e.g. 175′ in this example. FIG. 15 illustrates a close-up view of a cell site component 14 such as an antenna and a similar measurement made thereon using point and click, e.g. 4.55′ in this example. FIGS. 16 and 17 illustrate an aerial view in the 3D model showing surrounding geography around the cell site 10. From these views, the cell tower 12 is illustrated with the surrounding environment including the structures, access road, fall line, etc. Specifically, the 3D model can assist in determining a fall line which is anywhere in the surroundings of the cell site 10 where the cell tower 12 may fall. Appropriate considerations can be made based thereon. FIGS. 18 and 19 illustrate the 3D model and associated photos on the right side. One useful aspect of the 3D model GUI is an ability to click anywhere on the 3D model and bring up corresponding 2D photos. Here, an operator can click anywhere and bring up full sized photos of the area. Thus, with the systems and methods described herein, the 3D model can measure and map the cell site 10 and surrounding geography along with the cell tower 12, the cell site components 14, etc. to form a comprehensive 3D model. There are various uses of the 3D model to perform cell site audits including checking tower grounding; sizing and placement of antennas, piping, and other cell site components 14; providing engineering drawings; determining characteristics such as antenna azimuths; and the like. Referring to FIG. 2021, in an exemplary embodiment, a photo illustrates the UAV 50 in flight at the top of a cell tower 12. As described herein, it was determined that the optimum distance to photograph the cell site components 14 is about 10′ to 40′ distance. Referring to FIG. 21, in an exemplary embodiment, a flowchart illustrates a process 850 for modeling a cell site with an Unmanned Aerial Vehicle (UAV). The process 850 includes causing the UAV to fly a given flight path about a cell tower at the cell site, wherein a launch location and launch orientation is defined for the UAV to take off and land at the cell site such that each flight at the cell site has the same launch location and launch orientation (step 852); obtaining a plurality of photographs of the cell site during about the flight plane, wherein each of the plurality of photographs is associated with one or more location identifiers (step 854); and, subsequent to the obtaining, processing the plurality of photographs to define a three dimensional (3D) model of the cell site based on the associated with one or more location identifiers and one or more objects of interest in the plurality of photographs (step 856). The process 850 can further include landing the UAV at the launch location in the launch orientation; performing one or more operations on the UAV, such as changing a battery; and relaunching the UAV from the launch location in the launch orientation to obtain additional photographs. The one or more location identifiers can include at least two location identifiers including Global Positioning Satellite (GPS) and GLObal NAvigation Satellite System (GLONASS). The flight plan can be constrained to an optimum distance from the cell tower. The plurality of photographs can be obtained automatically during the flight plan while concurrently performing a cell site audit of the cell site. The process 850 can further include providing a graphical user interface (GUI) of the 3D model; and using the GUI to perform a cell site audit. The process 850 can further include providing a graphical user interface (GUI) of the 3D model; and using the GUI to measure various components at the cell site. The process 850 can further include providing a graphical user interface (GUI) of the 3D model; and using the GUI to obtain photographs of the various components at the cell site. §11.1 3D Modeling Systems and Methods without UAVs The above description explains 3D modeling and photo data capture using the UAV 50. Additionally, the photo data capture can be through other means, including portable cameras, fixed cameras, heads up displays (HUD), head mounted cameras, and the like. That is the systems and methods described herein contemplate the data capture through any available technique. The UAV 50 will be difficult to obtain photos inside the buildings, i.e., the shelter or cabinet 52. Referring to FIG. 22, in an exemplary embodiment, a diagram illustrates an exemplary interior 900 of a building 902, such as the shelter or cabinet 52, at the cell site 10. Generally, the building 902 houses equipment associated with the cell site 10 such as wireless RF terminals 910 (e.g., LTE terminals), wireless backhaul equipment 912, power distribution 914, and the like. Generally, wireless RF terminals 910 connect to the cell site components 14 for providing associated wireless service. The wireless backhaul equipment 912 includes networking equipment to bring the associated wireless service signals to a wireline network, such as via fiber optics or the like. The power distribution 914 provides power for all of the equipment such as from the grid as well as a battery backup to enable operation in the event of power failures. Of course, additional equipment and functionality are contemplated in the interior 900. The terminals 910, equipment 912, and the power distribution 914 can be realized as rack or frame mounted hardware with cabling 916 and with associated modules 918. The modules 918 can be pluggable modules which are selectively inserted in the hardware and each can include unique identifiers 920 such as barcodes, Quick Response (QR) codes, RF Identification (RFID), physical labeling, color coding, or the like. Each module 918 can be unique with a serial number, part number, and/or functional identifier. The modules 918 are configured as needed to provide the associated functionality of the cell site. The systems and methods include, in addition to the aforementioned photo capture via the UAV 50, photo data capture in the interior 900 for 3D modeling and for virtual site surveys. The photo data capture can be performed by a fixed, rotatable camera 930 located in the interior 900. The camera 930 can be communicatively coupled to a Data Communication Network (DCN), such as through the wireless backhaul equipment 912 or the like. The camera 930 can be remotely controlled, such as by an engineer performing a site survey from his or her office. Other techniques of photo data capture can include an on-site technician taking photos with a camera and uploading them to a cloud service or the like. Again, the systems and methods contemplate any type of data capture. Again, with a plurality of photos, e.g., hundreds, it is possible to utilize photogrammetry to create a 3D model of the interior 900 (as well as a 3D model of the exterior as described above). The 3D model is created using physical cues in the photos to identify objects of interest, such as the modules 918, the unique identifiers 920, or the like. Note, the location identifiers described relative to the UAV 50 are less effective in the interior 900 given the enclosed, interior space and the closer distances. §12.0 Virtual Site Survey Referring to FIG. 23, in an exemplary embodiment, a flowchart illustrates a virtual site survey process 950 for the cell site 10. The virtual site survey process 950 is associated with the cell site 10 and utilizes three-dimensional (3D) models for remote performance, i.e., at an office as opposed to in the field. The virtual site survey process 950 includes obtaining a plurality of photographs of a cell site including a cell tower and one or more buildings and interiors thereof (step 952); subsequent to the obtaining, processing the plurality of photographs to define a three dimensional (3D) model of the cell site based on one or more objects of interest in the plurality of photographs (step 954); and remotely performing a site survey of the cell site utilizing a Graphical User Interface (GUI) of the 3D model to collect and obtain information about the cell site, the cell tower, the one or more buildings, and the interiors thereof (step 956). The 3D model is a combination of an exterior of the cell site including the cell tower and associated cell site components thereon, geography local to the cell site, and the interiors of the one or more buildings at the cell site, and the 3D model can include detail at a module level in the interiors. The remotely performing the site survey can include determining equipment location on the cell tower and in the interiors; measuring distances between the equipment and within the equipment to determine actual spatial location; and determining connectivity between the equipment based on associated cabling. The remotely performing the site survey can include planning for one or more of new equipment and changes to existing equipment at the cell site through drag and drop operations in the GUI, wherein the GUI includes a library of equipment for the drag and drop operations; and, subsequent to the planning, providing a list of the one or more of the new equipment and the changes to the existing equipment based on the library, for implementation thereof. The remotely performing the site survey can include providing one or more of the photographs of an associated area of the 3D model responsive to an operation in the GUI. The virtual site survey process 950 can include rendering a texture map of the interiors responsive to an operation in the GUI. The virtual site survey process 950 can include performing an inventory of equipment at the cell site including cell site components on the cell tower and networking equipment in the interiors, wherein the inventory from the 3D model uniquely identifies each of the equipment based on associated unique identifiers. The remotely performing the site survey can include providing an equipment visual in the GUI of a rack and all associated modules therein. The obtaining can include the UAV 50 obtaining the photographs on the cell tower, and the obtaining includes one or more of a fixed and portable camera obtaining the photographs in the interior. The obtaining can be performed by an on-site technician at the cell site, and the site survey can be remotely performed. In another exemplary embodiment, an apparatus adapted to perform a virtual site survey of a cell site utilizing three-dimensional (3D) models for remote performance includes a network interface and a processor communicatively coupled to one another; and memory storing instructions that, when executed, cause the processor to receive, via the network interface, a plurality of photographs of a cell site including a cell tower and one or more buildings and interiors thereof process the plurality of photographs to define a three dimensional (3D) model of the cell site based on one or more objects of interest in the plurality of photographs, subsequent to receiving the photographs; and provide a Graphical User Interface of the 3D model for remote performance of a site survey of the cell site utilizing the 3D model to collect and obtain information about the cell site, the cell tower, the one or more buildings, and the interiors thereof. In a further exemplary embodiment, a non-transitory computer readable medium includes instructions that, when executed, cause one or more processors to perform the steps of: receiving a plurality of photographs of a cell site including a cell tower and one or more buildings and interiors thereof processing the plurality of photographs to define a three dimensional (3D) model of the cell site based on one or more objects of interest in the plurality of photographs, subsequent to receiving the photographs; and rendering a Graphical User Interface of the 3D model for remote performance of a site survey of the cell site utilizing the 3D model to collect and obtain information about the cell site, the cell tower, the one or more buildings, and the interiors thereof. The virtual site survey can perform anything remotely that traditionally would have required on-site presence, including the various aspects of the cell site audit 40 described herein. The GUI of the 3D model can be used to check plumbing of coaxial cabling, connectivity of all cabling, automatic identification of cabling endpoints such as through unique identifiers detected on the cabling, and the like. The GUI can further be used to check power plant and batteries, power panels, physical hardware, grounding, heating and air conditioning, generators, safety equipment, and the like. The 3D model can be utilized to automatically provide engineering drawings, such as responsive to the planning for new equipment or changes to existing equipment. Here, the GUI can have a library of equipment (e.g., approved equipment and vendor information can be periodically imported into the GUI). Normal drag and drop operations in the GUI can be used for equipment placement from the library. Also, the GUI system can include error checking, e.g., a particular piece of equipment is incompatible with placement or in violation of policies, and the like. §13.0 Close-Out Audit Systems and Methods Again, a close-out audit is done to document and verify the work performed at the cell site 10. The systems and methods eliminate the separate third-party inspection firm for the close-out audit. The systems and methods include the installers (i.e., from the third-party installation firm, the owner, the operator, etc.) performing video capture subsequent to the installation and maintenance and using various techniques to obtain data from the video capture for the close-out audit. The close-out audit can be performed off-site with the data from the video capture thereby eliminating unnecessary tower climbs, site visits, and the like. Referring to FIG. 24, in an exemplary embodiment, a flowchart illustrates a close-out audit method 1350 performed at a cell site subsequent to maintenance or installation work. The close-out audit method 1350 includes, subsequent to the maintenance or installation work, obtaining video capture of cell site components associated with the work (step 1352); subsequent to the video capture, processing the video capture to obtain data for the close-out audit, wherein the processing comprises identifying the cell site components associated with the work (step 1354); and creating a close-out audit package based on the processed video capture, wherein the close-out audit package provides verification of the maintenance or installation work and outlines that the maintenance or installation work was performed in a manner consistent with an operator or owner's guidelines (step 1356). The video capture can be performed by a mobile device and one or more of locally stored thereon and transmitted from the mobile device. The video capture can also be performed by a mobile device which wirelessly transmits a live video feed, and the video capture is remotely stored from the cell site. The video capture can also be performed by an Unmanned Aerial Vehicle (UAV) flown at the cell site. Further, the video capture can be a live video feed with two-way communication between an installer associated with the maintenance or installation work and personnel associated with the operator or owner to verify the maintenance or installation work. For example, the installer and the personnel can communicate to go through various items in the maintenance or installation work to check/audit the work. The close-out audit method 1350 can also include creating a three-dimensional (3D) model from the video capture; determining equipment location from the 3D model; measuring distances between the equipment and within the equipment to determine actual spatial location; and determining connectivity between the equipment based on associated cabling from the 3D model. The close-out audit method 1350 can also include uniquely identifying the cell site components from the video capture and distinguishing in the close-out audit package. The close-out audit method 1350 can also include determining antenna height, azimuth, and down tilt angles for antennas in the cell site components from the video capture; and checking the antenna height, azimuth, and down tilt angles against predetermined specifications. The close-out audit method 1350 can also include identifying cabling and connectivity between the cell site components from the video capture and distinguishing in the close-out audit package. The close-out audit method 1350 can also include checking a plurality of factors in the close-out audit from the video capture compared to the operator or owner's guidelines. The close-out audit method 1350 can also include checking the grounding of the cell site components from the video capture, comparing the checked grounding to the operator or owner's guidelines and distinguishing in the close-out audit package. The close-out audit method 1350 can also include checking mechanical connectivity of the cell site components to a cell tower based on the video capture and distinguishing in the close-out audit package. In another exemplary embodiment, a system adapted for a close-out audit of a cell site subsequent to maintenance or installation work includes a network interface and a processor communicatively coupled to one another; and memory storing instructions that, when executed, cause the processor to, subsequent to the maintenance or installation work, obtain video capture of cell site components associated with the work; subsequent to the video capture, process the video capture to obtain data for the close-out audit, wherein the processing comprises identifying the cell site components associated with the work; and create a close-out audit package based on the processed video capture, wherein the close-out audit package provides verification of the maintenance or installation work and outlines that the maintenance or installation work was performed in a manner consistent with an operator or owner's guidelines. In a further exemplary embodiment, a non-transitory computer readable medium includes instructions that, when executed, cause one or more processors to perform the steps of, subsequent to the maintenance or installation work, obtaining video capture of cell site components associated with the work; subsequent to the video capture, processing the video capture to obtain data for the close-out audit, wherein the processing comprises identifying the cell site components associated with the work; and creating a close-out audit package based on the processed video capture, wherein the close-out audit package provides verification of the maintenance or installation work and outlines that the maintenance or installation work was performed in a manner consistent with an operator or owner's guidelines. The close-out audit package can include, without limitation, drawings, cell site component settings, test results, equipment lists, pictures, commissioning data, GPS data, Antenna height, azimuth and down tilt data, equipment data, serial numbers, cabling, etc. §14.0 3D modeling systems and methods Referring to FIG. 25, in an exemplary embodiment, a flowchart illustrates a 3D modeling method 1400 to detect configuration and site changes. The 3D modeling method 1400 utilizes various techniques to obtain data, to create 3D models, and to detect changes in configurations and surroundings. The 3D models can be created at two or more different points in time, and with the different 3D models, a comparison can be made to detect the changes. Advantageously, the 3D modeling systems and methods allow cell site operators to manage the cell sites without repeated physical site surveys efficiently. The modeling method 1400 includes obtaining first data regarding the cell site from a first audit performed using one or more data acquisition techniques and obtaining second data regarding the cell site from a second audit performed using the one or more data acquisition techniques, wherein the second audit is performed at a different time than the first audit, and wherein the first data and the second data each comprise one or more location identifiers associated therewith (step 1402); processing the first data to define a first model of the cell site using the associated one or more location identifiers and processing the second data to define a second model of the cell site using the associated one or more location identifiers (step 1404); comparing the first model with the second model to identify the changes in or at the cell site (step 1406); and performing one or more actions based on the identified changes (step 1408). The one or more actions can include any remedial or corrective actions including maintenance, landscaping, mechanical repair, licensing from operators who install more cell site components 14 than agreed upon, and the like. The identified changes can be associated with cell site components installed on a cell tower at the cell site, and wherein the one or more actions comprises any of maintenance, licensing with operators, and removal. The identified changes can be associated with physical surroundings of the cell site, and wherein the one or more actions comprise maintenance to correct the identified changes. The identified changes can include any of degradation of gravel roads, trees obstructing a cell tower, physical hazards at the cell site, and mechanical issues with the cell tower or a shelter at the cell site. The first data and the second data can be obtained remotely, without a tower climb. The first model and the second model each can include a three-dimensional model of the cell site, displayed in a Graphical User Interface (GUI). The one or more data acquisition techniques can include using an Unmanned Aerial Vehicle (UAV) to capture the first data and the second data. The one or more data acquisition techniques can include using a fixed or portable camera to capture the first data and the second data. The one or more location identifiers can include at least two location identifiers comprising Global Positioning Satellite (GPS) and GLObal NAvigation Satellite System (GLONASS). The second model can be created using the first model as a template for expected objects at the cell site. In another exemplary embodiment, a modeling system adapted for detecting changes in or at a cell site includes a network interface and a processor communicatively coupled to one another; and memory storing instructions that, when executed, cause the processor to obtain first data regarding the cell site from a first audit performed using one or more data acquisition techniques and obtain second data regarding the cell site from a second audit performed using the one or more data acquisition techniques, wherein the second audit is performed at a different time than the first audit, and wherein the first data and the second data each comprise one or more location identifiers associated therewith; process the first data to define a first model of the cell site using the associated one or more location identifiers and process the second data to define a second model of the cell site using the associated one or more location identifiers; compare the first model with the second model to identify the changes in or at the cell site; and cause performance of one or more actions based on the identified changes. In a further exemplary embodiment, a non-transitory computer readable medium includes instructions that, when executed, cause one or more processors to perform the steps of: obtaining first data regarding the cell site from a first audit performed using one or more data acquisition techniques and obtaining second data regarding the cell site from a second audit performed using the one or more data acquisition techniques, wherein the second audit is performed at a different time than the first audit, and wherein the first data and the second data each comprise one or more location identifiers associated therewith; processing the first data to define a first model of the cell site using the associated one or more location identifiers and processing the second data to define a second model of the cell site using the associated one or more location identifiers; comparing the first model with the second model to identify the changes in or at the cell site; and performing one or more actions based on the identified changes. §15.0 3D Modeling Data Capture Systems and Methods Again, various exemplary embodiments herein describe applications and uses of 3D models of the cell site 10 and the cell tower 12. Further, it has been described using the UAV 50 to obtain data capture for creating the 3D model. The data capture systems and methods described herein provide various techniques and criteria for properly capturing images or video using the UAV 50. Referring to FIG. 26, in an exemplary embodiment, a flow diagram illustrates a 3D model creation process 1700. The 3D model creation process 1700 is implemented on a server or the like. The 3D model creation process 1700 includes receiving input data, i.e., pictures and/or video. The data capture systems and methods describe various techniques for obtaining the pictures and/or video using the UAV 50 at the cell site 10. In an exemplary embodiment, the pictures can be at least 10 megapixels, and the video can be at least 4 k high definition video. The 3D model creation process 1700 performs initial processing on the input data (step 1702). An output of the initial processing includes a sparse point cloud, a quality report, and an output file can be camera outputs. The sparse point cloud is processed into a point cloud and mesh (step 1704) providing a densified point cloud and 3D outputs. The 3D model is an output of the step 1704. Other models can be developed by further processing the densified point cloud (step 1706) to provide a Digital Surface Model (DSM), an orthomosaic, tiles, contour lines, etc. The data capture systems and methods include capturing thousands of images or video which can be used to provide images. Referring to FIG. 27, in an exemplary embodiment, a flowchart illustrates a method 1750 using an Unmanned Aerial Vehicle (UAV) to obtain data capture at a cell site for developing a three dimensional (3D) thereof. The method 1750 includes causing the UAV to fly a given flight path about a cell tower at the cell site (step 1752); obtaining data capture during the flight path about the cell tower, wherein the data capture comprises a plurality of photos or video, wherein the flight path is subjected to a plurality of constraints for the obtaining, and wherein the data capture comprises one or more location identifiers (step 1754); and, subsequent to the obtaining, processing the data capture to define a three dimensional (3D) model of the cell site based on one or more objects of interest in the data capture (step 1756). The method 1750 can further include remotely performing a site survey of the cell site utilizing a Graphical User Interface (GUI) of the 3D model to collect and obtain information about the cell site, the cell tower, one or more buildings, and interiors thereof (step 1758). As a launch location and launch orientation can be defined for the UAV to take off and land at the cell site such that each flight at the cell site has the same launch location and launch orientation. The one or more location identifiers can include at least two location identifiers including Global Positioning Satellite (GPS) and GLObal NAvigation Satellite System (GLONASS). The plurality of constraints can include each flight of the UAV having a similar lighting condition and at about a same time of day. Specifically, the data capture can be performed on different days or times to update the 3D model. Importantly, the method 1750 can require the data capture in the same lighting conditions, e.g., sunny, cloudy, etc., and at about the same time of day to account for shadows. The data capture can include a plurality of photographs each with at least 10 megapixels and wherein the plurality of constraints can include each photograph having at least 75% overlap with another photograph. Specifically, the significant overlap allows for ease in processing to create the 3D model. The data capture can include a video with at least 4 k high definition and wherein the plurality of constraints can include capturing a screen from the video as a photograph having at least 75% overlap with another photograph captured from the video. The plurality of constraints can include a plurality of flight paths around the cell tower with each of the plurality of flight paths at one or more of different elevations, different camera angles, and different focal lengths for a camera. The plurality of flight paths can be one of: a first flight path at a first height and a camera angle and a second flight path at a second height and the camera angle; and a first flight path at the first height and a first camera angle and a second flight path at the first height and a second camera angle. The plurality of flight paths can be substantially circular around the cell tower. In another exemplary embodiment, an apparatus adapted to obtain data capture at a cell site for developing a three dimensional (3D) thereof includes a network interface and a processor communicatively coupled to one another; and memory storing instructions that, when executed, cause the processor to cause the UAV to fly a given flight path about a cell tower at the cell site; cause data capture during the flight path about the cell tower, wherein the data capture comprises a plurality of photos or video, wherein the flight path is subjected to a plurality of constraints for the data capture, and wherein the data capture comprises one or more location identifiers; and, subsequent to the data capture, process the data capture to define a three dimensional (3D) model of the cell site based on one or more objects of interest in the data capture. §15.1 3D Methodology for Cell Sites Referring to FIG. 28, in an exemplary embodiment, a flowchart illustrates a 3D modeling method 1800 for capturing data at the cell site 10, the cell tower 12, etc. using the UAV 50. The method 1800, in addition to or in combination with the method 1750, provides various techniques for accurately capturing data for building a point cloud generated a 3D model of the cell site 10. First, the data acquisition, i.e., the performance of the method 1800, should be performed in the early morning or afternoon such that nothing is overexposed and there is a minimum reflection off of the cell tower 12. It is also important to have a low Kp Index level to minimize the disruption of geomagnetic activity on the UAV's GPS unit, sub level six is adequate for 3D modeling as described in this claim. Of course, it is also important to ensure the camera lenses on the UAV 50 are clean prior to launch. This can be done by cleaning the lenses with alcohol and a wipe. Thus, the method 1800 includes preparing the UAV 50 for flight and programming an autonomous flight path about the cell tower 12 (step 1802). The UAV 50 flight about the cell tower 12 at the cell site 10 can be autonomous, i.e., automatic without manual control of the actual flight plan in real-time. The advantage here with autonomous flight is the flight of the UAV 50 is circular as opposed to a manual flight which can be more elliptical, oblong, or have gaps in data collection, etc. In an exemplary embodiment, the autonomous flight of the UAV 50 can capture data equidistance around the planned circular flight path by using a Point of Interest (POI) flight mode. The POI flight mode is selected (either before or after takeoff), and once the UAV 50 is in flight, an operator can select a point of interest from a view of the UAV 50, such as but not limited to via the mobile device 100 which is in communication with the UAV 50. The view is provided by the camera 86, and the UAV 50 in conjunction with the device identified to be in communication with the UAV 50 can determine a flight plan about the point of interest. In the method 1800, the point of interest can be the cell tower 12. The point of interest can be selected at an appropriate altitude and once selected, the UAV 50 circles in flight about the point of interest. Further, the radius, altitude, direction, and speed can be set for the point of interest flight as well as a number of repetitions of the circle. Advantageously, the point of interest flight path in a circle provides an even distance about the cell tower 12 for obtaining photos and video thereof for the 3D model. In an exemplary embodiment of a tape drop model, the UAV 50 will perform four orbits about a monopole cell tower 12 and about five or six orbits about a self-support/guyed cell tower 12. In the exemplary embodiment of a structural analysis model, the number of orbits will be increased from 2 to 3 times to acquire the data needed to construct a more realistic graphic user interface model. Additionally, the preparation can also include focusing the camera 86 in its view of the cell tower 12 to set the proper exposure. Specifically, if the camera 86's view is too bright or too dark, the 3D modeling software will have issues in matching pictures or frames together to build the 3D model. Once the preparation is complete and the flight path is set (step 1802), the UAV 50 flies in a plurality of orbits about the cell tower 12 (step 1804). The UAV obtains photos and/or video of the cell tower 12 and the cell site components 14 during each of the plurality of orbits (step 1806). Note, each of the plurality of orbits has different characteristics for obtaining the photos and/or video. Finally, photos and/or video is used to define a 3D model of the cell site 10 (step 1808). For the plurality of orbits, a first orbit is around the entire cell site 10 to cover the entire cell tower 12 and associated surroundings. For monopole cell towers 12, the radius of the first orbit will typically range from 100 to 150 ft. For self-support cell towers 12, the radius can be up to 200 ft. The UAV 50's altitude should be slightly higher than that of the cell tower for the first orbit. The camera 86 should be tilted slightly down capturing more ground in the background than sky to provide more texture helping the software match the photos. The first orbit should be at a speed of about 4 ft/second (this provides a good speed for battery efficiency and photo spacing). A photo should be taken around every two seconds or at 80 percent overlap decreasing the amount that edges and textures move from each photo. This allows the software to relate those edge/texture points to each photo called tie points. A second orbit of the plurality of orbits should be closer to the radiation centers of the cell tower 12, typically 30 to 50 ft with an altitude still slightly above the cell tower 12 with the camera 86 pointing downward. The operator should make sure all the cell site components 12 and antennas are in the frame including those on the opposite side of the cell tower 12. This second orbit will allow the 3D model to create better detail on the structure and equipment in between the antennas and the cell site components 14. This will allow contractors to make measurements on equipment between those antennas. The orbit should be done at a speed around 2.6 ft/second and still take photos close to every 2 seconds or keeping an 80 percent overlap. A third orbit of the plurality of orbits has a lower altitude to around the mean distance between all of the cell site components 14 (e.g., Radio Access Devices (RADs)). With the lower altitude, the camera 86 is raised up such as 5 degrees or more because the ground will have moved up in the frame. This new angle and altitude will allow a full profile of all the antennas and the cell site components 14 to be captured. The orbit will still have a radius around 30 to 50 ft with a speed of about 2.6 ft/second. The next orbit should be for a self-support cell tower 12. Here, the orbit is expanded to around 50 to 60 ft, and the altitude decreased slightly below the cell site components 14 and the camera 86 angled slightly down more capturing all of the cross barring of the self-support structure. All of the structure to the ground does not need to be captured for this orbit but close to it. The portion close to the ground will be captured in the next orbit. However, there needs to be clear spacing in whatever camera angle is chosen. The cross members in the foreground should be spaced enough for the cross members on the other side of the cell tower 12 to be visible. This is done for self-support towers 12 because of the complexity of the structure and the need for better detail which is not needed for monopoles in this area. The first orbit for monopoles provides more detail because they are at a closer distance with the cell towers 12 lower height. The speed of the orbit can be increased to around 3 ft/second with the same spacing. The last orbit for all cell towers 12 should have an increased radius to around 60 to 80 ft with the camera 86 looking more downward at the cell site 10. The altitude should be decreased to get closer to the cell site 10 compound. The altitude should be around 60 to 80 ft but will change slightly depending on the size of the cell site 10 compound. The angle of the camera 86 with the altitude should be such to where the sides and tops of structures such as the shelters will be visible throughout the orbit. It is important to make sure the whole cell site 10 compound is in the frame for the entire orbit allowing the capture of every side of everything inside the compound including the fencing. The speed of the orbit should be around 3.5 ft/second with same photo time spacing and overlap. The total amount of photos that should be taken for a monopole cell tower 12 should be around 300-400 and the total amount of photos for self-support cell tower 12 should be between 400-500 photos. Too many photos can indicate that the photos were taken too close together. Photos taken in succession with more than 80 percent overlap can cause errors in the processing of the model and cause extra noise around the details of the tower and lower the distinguishable parts for the software. §16.0 3D Modeling Data Capture Systems and Methods Using Multiple Cameras Referring to FIGS. 29A and 29B, in an exemplary embodiment, block diagrams illustrate a UAV 50 with multiple cameras 86A, 86B, 86C (FIG. 29A) and a camera array 1900 (FIG. 29B). The UAV 50 can include the multiple cameras 86A, 86B, 86C which can be located physically apart on the UAV 50. In another exemplary embodiment, the multiple cameras 86A, 86B, 86C can be in a single housing. In all embodiments, each of the multiple cameras 86A, 86B, 86C can be configured to take a picture of a different location, different area, different focus, etc. That is, the cameras 86A, 86B, 86C can be angled differently, have a different focus, etc. The objective is for the cameras 86A, 86B, 86C together to cover a larger area than a single camera 86. In a conventional approach for 3D modeling, the camera 86 is configured to take hundreds of pictures for the 3D model. For example, as described with respect to the 3D modeling method 1800, 300-500 pictures are required for an accurate 3D model. In practice, using the limitations described in the 3D modeling method 1800, this process, such as with the UAV 50, can take hours. It is the objective of the systems and methods with multiple cameras to streamline this process such as reduce this time by half or more. The cameras 86A, 86B, 86C are coordinated and communicatively coupled to one another and the processor 102. In FIG. 29B, the camera array 1900 includes a plurality of cameras 1902. Each of the cameras 1902 can be individual cameras each with its own settings, i.e., angle, zoom, focus, etc. The camera array 1900 can be mounted on the UAV 50, such as the camera 86. The camera array 1900 can also be portable, mounted on or at the cell site 10, and the like. In the systems and methods herein, the cameras 86A, 86B, 86C and the camera array 1900 are configured to work cooperatively to obtain pictures to create a 3D model. In an exemplary embodiment, the 3D model is of a cell site 10. As described herein, the systems and methods utilize at least two cameras, e.g., the cameras 86A, 86B, or two cameras 1902 in the camera array 1900. Of course, there can be greater than two cameras. The multiple cameras are coordinated such that one event where pictures are taken produce at least two pictures. Thus, to capture 300-500 pictures, less than 150-250 pictures are actually taken. Referring to FIG. 30, in an exemplary embodiment, a flowchart illustrates a method 1950 using multiple cameras to obtain accurate three-dimensional (3D) modeling data. In the method 1950, the multiple cameras are used with the UAV 50, but other embodiments are also contemplated. The method 1950 includes causing the UAV to fly a given flight path about a cell tower at the cell site (step 1952); obtaining data capture during the flight path about the cell tower, wherein the data capture includes a plurality of photos or video subject to a plurality of constraints, wherein the plurality of photos are obtained by a plurality of cameras which are coordinated with one another (step 1954); and, subsequent to the obtaining, processing the data capture to define a three dimensional (3D) model of the cell site based on one or more objects of interest in the data capture (step 1956). The method 1950 can further include remotely performing a site survey of the cell site utilizing a Graphical User Interface (GUI) of the 3D model to collect and obtain information about the cell site, the cell tower, one or more buildings, and interiors thereof (step 1958). The flight path can include a plurality of orbits comprising at least four orbits around the cell tower each with a different set of characteristics of altitude, radius, and camera angle. A launch location and launch orientation can be defined for the UAV to take off and land at the cell site such that each flight at the cell site has the same launch location and launch orientation. The plurality of constraints can include each flight of the UAV having a similar lighting condition and at about a same time of day. A total number of photos can include around 300-400 for the monopole cell tower and 500-600 for the self-support cell tower, and the total number is taken concurrently by the plurality of cameras. The data capture can include a plurality of photographs each with at least 10 megapixels and wherein the plurality of constraints comprises each photograph having at least 75% overlap with another photograph. The data capture can include a video with at least 4 k high definition and wherein the plurality of constraints can include capturing a screen from the video as a photograph having at least 75% overlap with another photograph captured from the video. The plurality of constraints can include a plurality of flight paths around the cell tower with each of the plurality of flight paths at one or more of different elevations and each of the plurality of cameras with different camera angles and different focal lengths. In another exemplary embodiment, an apparatus adapted to obtain data capture at a cell site for developing a three dimensional (3D) thereof includes a network interface and a processor communicatively coupled to one another; and memory storing instructions that, when executed, cause the processor to cause the UAV to fly a given flight path about a cell tower at the cell site; obtain data capture during the flight path about the cell tower, wherein the data capture comprises a plurality of photos or video subject to a plurality of constraints, wherein the plurality of photos are obtained by a plurality of cameras which are coordinated with one another; and process the obtained data capture to define a three dimensional (3D) model of the cell site based on one or more objects of interest in the data capture. In a further exemplary embodiment, an Unmanned Aerial Vehicle (UAV) adapted to obtain data capture at a cell site for developing a three dimensional (3D) thereof includes one or more rotors disposed to a body; a plurality of cameras associated with the body; wireless interfaces; a processor coupled to the wireless interfaces and the camera; and memory storing instructions that, when executed, cause the processor to fly the UAV about a given flight path about a cell tower at the cell site; obtain data capture during the flight path about the cell tower, wherein the data capture comprises a plurality of photos or video, wherein the plurality of photos are obtained by a plurality of cameras which are coordinated with one another; and provide the obtained data for a server to process the obtained data capture to define a three dimensional (3D) model of the cell site based on one or more objects of interest in the data capture. §17.0 Multiple Camera Apparatus and Process Referring to FIGS. 31 and 32, in an exemplary embodiment, diagrams illustrate a multiple camera apparatus 2000 and use of the multiple camera apparatus 2000 in the shelter or cabinet 52 or the interior 900 of the building 902. As previously described herein, the camera 930 can be used in the interior 900 for obtaining photos for 3D modeling and for virtual site surveys. The multiple camera apparatus 2000 is an improvement to the camera 930, enabling multiple photos to be taken simultaneously of different views, angles, zoom, etc. In an exemplary embodiment, the multiple camera apparatus 2000 can be operated by a technician at the building 902 to quickly, efficiently, and properly obtain photos for a 3D model of the interior 900. In another exemplary embodiment, the multiple camera apparatus 2000 can be mounted in the interior 900 and remotely controlled by an operator. The multiple camera apparatus 2000 includes a post 2002 with a plurality of cameras 2004 disposed or attached to the post 2002. The plurality of cameras 2004 can be interconnected to one another and to a control unit 2006 on the post. The control unit 2006 can include user controls to cause the cameras 2004 to each take a photo and memory for storing the photos from the cameras 2004. The control unit 2006 can further include communication mechanisms to provide the captured photos to a system for 3D modeling (either via a wired and/or wireless connection). In an exemplary embodiment, the post 2002 can be about 6′ and the cameras 2004 can be positioned to enable data capture from the floor to the ceiling of the interior 900. The multiple camera apparatus 2000 can include other physical embodiments besides the post 2002. For example, the multiple camera apparatus 2000 can include a box with the multiple cameras 2004 disposed therein. In another example, the multiple camera apparatus 2000 can include a handheld device which includes the multiple cameras 2004. The objective of the multiple camera apparatus 2000 is to enable a technician (either on-site or remote) to quickly capture photos (through the use of the multiple cameras 2004) for a 3D model and to properly capture the photos (through the multiple cameras 2004 have different zooms, angles, etc.). That is, the multiple camera apparatus 2000 ensures the photo capture is sufficient to accurately develop the 3D model, avoiding potentially revisiting the building 902. Referring to FIG. 33, in an exemplary embodiment, a flowchart illustrates a data capture method 2050 in the interior 900 using the multiple camera apparatus 2000. The method 2050 includes obtaining or providing the multiple camera apparatus 2000 at the shelter or cabinet 52 or the interior 900 of the building 902 and positioning the multiple camera apparatus 2000 therein (step 2052). The method 2050 further includes causing the plurality of cameras 2004 to take photos based on the positioning (step 2054) and repositioning the multiple camera apparatus 2000 at a different location in the shelter or cabinet 52 or the interior 900 of the building 902 to take additional photos (step 2056). Finally, the photos taken by the cameras 2004 are provided to a 3D modeling system to develop a 3D model of the shelter or cabinet 52 or the interior 900 of the building 902, such as for a virtual site survey (step 2058). The repositioning step 2056 can include moving the multiple camera apparatus to each corner of the shelter, the cabinet, or the interior of the building. The repositioning step 2056 can include moving the multiple camera apparatus to each row of equipment in the shelter, the cabinet, or the interior of the building. The multiple camera apparatus can include a pole with the plurality of cameras disposed thereon, each of the plurality of cameras configured for a different view. The plurality of cameras are communicatively coupled to a control unit for the causing step 2054 and/or the providing step 2058. Each of the plurality of cameras can be configured on the multiple camera apparatus for a different view, zoom, and/or angle. The method 2050 can include analyzing the photos subsequent to the repositioning; and determining whether the photos are suitable for the 3D model, and responsive to the photos not being suitable for the 3D model, instructing a user to retake the photos which are not suitable. The method 2050 can include combing the photos of the shelter, the cabinet, or the interior of the building with photos of a cell tower at the cell site, to form a 3D model of the cell site. The method 2050 can include performing a virtual site survey of the cell site using the 3D model. The repositioning step 2056 can be based on a review of the photos taken in the causing. In a further exemplary embodiment, a method for obtaining data capture at a cell site for developing a three dimensional (3D) thereof includes obtaining or providing the multiple camera apparatus comprising a plurality of cameras at a shelter, a cabinet, or an interior of a building and positioning the multiple camera apparatus therein; causing the plurality of cameras to simultaneously take photos based on the positioning; repositioning the multiple camera apparatus at a different location in the shelter, the cabinet, or the interior of the building to take additional photos; obtaining exterior photos of a cell tower connect to the shelter, the cabinet, or the interior of the building; and providing the photos taken by the multiple camera apparatus and the exterior photos to a 3D modeling system to develop a 3D model of the cell site, for a virtual site survey thereof. §18.0 Cell Site Verification Using 3D Modeling Referring to FIG. 34, in an exemplary embodiment, a flowchart illustrates a method 2100 for verifying equipment and structures at the cell site 10 using 3D modeling. As described herein, an intermediate step in the creation of a 3D model includes a point cloud, e.g., a sparse or dense point cloud. A point cloud is a set of data points in some coordinate system, e.g., in a three-dimensional coordinate system, these points are usually defined by X, Y, and Z coordinates, and can be used to represent the external surface of an object. Here, the object can be anything associated with the cell site 10, e.g., the cell tower 12, the cell site components 14, etc. As part of the 3D model creation process, a large number of points on an object's surface are determined, and the output is a point cloud in a data file. The point cloud represents the set of points that the device has measured. Various descriptions were presented herein for site surveys, close-out audits, etc. In a similar manner, there is a need to continually monitor the state of the cell site 10. Specifically, as described herein, conventional site monitoring techniques typically include tower climbs. The UAV 50 and the various approaches described herein provide safe and more efficient alternatives to tower climbs. Additionally, the UAV 50 can be used to provide cell site 10 verification to monitor for site compliance, structural or load issues, defects, and the like. The cell site 10 verification can utilize point clouds to compare “before” and “after” data capture to detect differences. With respect to site compliance, the cell site 10 is typically owned and operated by a cell site operator (e.g., real estate company or the like) separate from cell service providers with their associated cell site components 14. The typical transaction includes leases between these parties with specific conditions, e.g., the number of antennas, the amount of equipment, the location of equipment, etc. It is advantageous for cell site operators to periodically audit/verify the state of the cell site 10 with respect to compliance, i.e., has cell service provider A added more cell site components 14 than authorized? Similarly, it is important for cell site operators to periodically check the cell site 10 to proactively detect load issues (too much equipment on the structure of the cell tower 12), defects (equipment detached from the structure), etc. One approach to verifying the cell site 10 is a site survey, including the various approaches to site surveys described herein, including the use of 3D models for remote site surveys. In various exemplary embodiments, the method 2100 provides a quick and automated mechanism to quickly detect concerns (i.e., compliance issues, defects, load issues, etc.) using point clouds. Specifically, the method 2100 includes creating an initial point cloud for a cell site 10 or obtaining the initial point cloud from a database (step 2102). The initial point cloud can represent a known good condition, i.e., with no compliance issues, load issues, defects, etc. For example, the initial point cloud could be developed as part of the close-out audit, etc. The initial point cloud can be created using the various data acquisition techniques described herein using the UAV 50. Also, a database can be used to store the initial point cloud. The initial point cloud is loaded in a device, such as the UAV 50 (step 2104). The point cloud data files can be stored in the memory in a processing device associated with the UAV 50. In an exemplary embodiment, multiple point cloud data files can be stored in the UAV 50, allowing the UAV 50 to be deployed to perform the method 2100 at a plurality of cell sites 10. The device (UAV 50) can be used to develop a second point cloud based on current conditions at the cell site 10 (step 2106). Again, the UAV 50 can use the techniques described herein relative to data acquisition to develop the second point cloud. Note, it is preferable to use a similar data acquisition for both the initial point cloud and the second point cloud, e.g., similar takeoff locations/orientations, similar paths about the cell tower 12, etc. This ensures similarity in the data capture. In an exemplary embodiment, the initial point cloud is loaded to the UAV 50 along with instructions on how to perform the data acquisition for the second point cloud. The second point cloud is developed at a current time, i.e., when it is desired to verify aspects associated with the cell site 10. Variations are detected between the initial point cloud and the second point cloud (step 2108). The variations could be detected by the UAV 50, in an external server, in a database, etc. The objective here is the initial point cloud and the second point cloud provides a quick and efficient comparison to detect differences, i.e., variations. The method 2100 includes determining if the variations are ant of compliance related, load issues, or defects (step 2110). Note, variations can be simply detected based on raw data differences between the point clouds. The step 2110 requires additional processing to determine what the underlying differences are. In an exemplary embodiment, the variations are detected in the UAV 50, and, if detected, additional processing is performed by a server to actually determine the differences based on creating a 3D model of each of the point clouds. Finally, the second point cloud can be stored in the database for future processing (step 2112). An operator of the cell site 10 can be notified via any technique of any determined variations or differences for remedial action based thereon (addressing non-compliance, performing maintenance to fix defects or load issues, etc.). §19.0 Cell Site Audit and Survey Via Photo Stitching Photo stitching or linking is a technique where multiple photos of either overlapping fields of view or adjacent fields of view are linked together to produce a virtual view or segmented panorama of an area. A common example of this approach is the so-called Street view offered by online map providers. In various exemplary embodiments, the systems and methods enable a remote user to perform a cell site audit, survey, site inspection, etc. using a User Interface (UI) with photo stitching/linking to view the cell site 10. The various activities can include any of the aforementioned activities described herein. Further, the photos can also be obtained using any of the aforementioned techniques. Of note, the photos required for a photo stitched UI are significantly less than those required by the 3D model. However, the photo stitched UI can be based on the photos captured for the 3D model, e.g., a subset of the photos. Alternatively, the photo capture for the photo stitched UI can be captured separately. Variously, the photos for the UI are captured, and a linkage is provided between photos. The linkage allows a user to navigate between photos to view up, down, left, or right, i.e., to navigate the cell site 10 via the UI. The linkage can be noted in a photo database with some adjacency indicator. The linkage can be manually entered via a user reviewing the photos or automatically based on location tags associated with the photos. Referring to FIG. 35, in an exemplary embodiment, a diagram illustrates a photo stitching UI 2200 for cell site audits, surveys, inspections, etc. remotely. The UI 2200 is viewed by a computer accessing a database of a plurality of photos with the linkage between each other based on adjacency. The photos are of the cell site 10 and can include the cell tower 12 and associated cell site components as well as interior photos of the shelter or cabinet 52 of the interior 900. The UI 2200 displays a photo of the cell site 12 and the user can navigate to the left to a photo 2202, to the right to a photo 2204, up to a photo 2206, or down to a photo 2208. The navigation between the photos 2202, 2204, 2206, 2208 is based on the links between the photos. In an exemplary embodiment, a navigation icon 2210 is shown in the UI 2200 from which the user can navigate the UI 2200. Also, the navigation can include opening and closing a door to the shelter or cabinet 52. In an exemplary embodiment, the UI 2200 can include one of the photos 2202, 2204, 2206, 2208 at a time with the navigation moving to a next photo. In another exemplary embodiment, the navigation can scroll between the photos 2202, 2204, 2206, 2208 seamlessly. In either approach, the UI 2200 allows virtual movement around the cell site 10 remotely. The photos 2202, 2204, 2206, 2208 can each be a high-resolution photo, e.g., 8 megapixels or more. From the photos 2202, 2204, 2206, 2208, the user can read labels on equipment, check cable runs, check equipment location and installation, check cabling, etc. Also, the user can virtually scale the cell tower 12 avoiding a tower climb. An engineer can use the UI 2200 to perform site expansion, e.g., where to install new equipment. Further, once the new equipment is installed, the associated photos can be updated to reflect the new equipment. It is not necessary to update all photos, but rather only the photos of new equipment locations. The photos 2202, 2204, 2206, 2208 can be obtained using the data capture techniques described herein. The camera used for capturing the photos can be a 180, 270, or 360-degree camera. These cameras typically include multiple sensors allowing a single photo capture to capture a large view with a wide lens, fish eye lens, etc. The cameras can be mounted on the UAV 50 for capturing the cell tower 12, the multiple camera apparatus 2000, etc. Also, the cameras can be the camera 930 in the interior 900. Referring to FIG. 36, in an exemplary embodiment, a flowchart illustrates a method 2300 for performing a cell site audit or survey remotely via a User Interface (UI). The method 2300 includes, subsequent to capturing a plurality of photos of a cell site and linking the plurality of photos to one another based on their adjacency at the cell site, displaying the UI to a user remote from the cell site, wherein the plurality of photos cover a cell tower with associated cell site components and an interior of a building at the cell site (step 2302); receiving navigation commands from the user performing the cell site audit or survey (step 2304); and updating the displaying based on the navigation commands, wherein the navigation commands comprise one or more of movement at the cell site and zoom of a current view (step 2306). The capturing the plurality of photos can be performed for a cell tower with an Unmanned Aerial Vehicle (UAV) flying about the cell tower. The linking the plurality of photos can be performed one of manually and automatically based on location identifiers associated with each photo. The user performing the cell site audit or survey can include determining a down tilt angle of one or more antennas of the cell site components based on measuring three points comprising two defined by each antenna and one by an associated support bar; determining plumb of the cell tower and/or the one or more antennas, azimuth of the one or more antennas using a location determination in the photos; determining dimensions of the cell site components; determining equipment type and serial number of the cell site components; and determining connections between the cell site components. The plurality of photos can be captured concurrently with developing a three-dimensional (3D) model of the cell site. The updating the displaying can include providing a new photo based on the navigation commands. The updating the displaying can include seamlessly panning between the plurality of photos based on the navigation commands. §20.0 Subterranean 3D Modeling The foregoing descriptions provide techniques for developing a 3D model of the cell site 10, the cell tower 12, the cell site components 14, the shelter or cabinet 52, the interior 900 of the building 902, etc. The 3D model can be used for a cell site audit, survey, site inspection, etc. In addition, the 3D model can also include a subterranean model of the surrounding area associated with the cell site 10. Referring to FIG. 37, in an exemplary embodiment, a perspective diagram illustrates a 3D model 2400 of the cell site 10, the cell tower 12, the cell site components 14, and the shelter or cabinet 52 along with surrounding geography 2402 and subterranean geography 2404. Again, the 3D model 2400 of the cell site 10, the cell tower 12, the cell site components 14, and the shelter or cabinet 52 along with a 3D model of the interior 900 can be constructed using the various techniques described herein. In various exemplary embodiments, the systems and methods extend the 3D model 2400 to include the surrounding geography 2402 and the subterranean geography 2404. The surrounding geography 2402 represents the physical location around the cell site 10. This can include the cell tower 12, the shelter or cabinet 52, access roads, etc. The subterranean geography 2404 includes the area underneath the surrounding geography 2402. The 3D model 2400 portion of the surrounding geography 2402 and the subterranean geography 2404 can be used by operators and cell site 10 owners for a variety of purposes. First, the subterranean geography 2404 can show locations of utility constructions including electrical lines, water/sewer lines, gas lines, etc. Knowledge of the utility constructions can be used in site planning and expansion, i.e., where to build new structures, where to run new underground utility constructions, etc. For example, it would make sense to avoid new above ground structures in the surrounding geography 2402 on top of gas lines or other utility constructions if possible. Second, the subterranean geography 2404 can provide insight into various aspects of the cell site 10 such as depth of support for the cell tower 12, the ability of the surrounding geography 2402 to support various structures, the health of the surrounding geography 2402, and the like. For example, for new cell site components 14 on the cell tower 12, the 3D model 2400 can be used to determine whether there will be support issues, i.e., a depth of the underground concrete supports of the cell tower 12. Data capture for the 3D model 2400 for the subterranean geography 2404 can use various known 3D subterranean modeling techniques such as sonar, ultrasound, LIDAR (Light Detection and Ranging), and the like. Also, the data capture for the 3D model 2400 can utilize external data sources such as utility databases which can include the location of the utility constructions noted by location coordinates (e.g., GPS). In an exemplary embodiment, the data capture can be verified with the external data sources, i.e., data from the external data sources can verify the data capture using the 3D subterranean modeling techniques. The 3D subterranean modeling techniques utilize a data capture device based on the associated technology. In an exemplary embodiment, the data capture device can be on the UAV 50. In addition to performing the data capture techniques described herein for the cell tower 12, the UAV 50 can perform data capture by flying around the surrounding geography 2402 with the data capture device aimed at the subterranean geography 2404. The UAV 50 can capture data for the 3D model 2400 for both the above ground components and the subterranean geography 2404. In another exemplary embodiment, the data capture device can be used separately from the UAV 50, such as via a human operator moving about the surrounding geography 2402 aiming the data capture device at the subterranean geography 2404, via a robot or the like with the data capture device connected thereto, and the like. Referring to FIG. 38, in an exemplary embodiment, a flowchart illustrates a method 2400 for creating a three-dimensional (3D) model of a cell site for one or more of a cell site audit, a site survey, and cell site planning and engineering. The method 2450 includes obtaining first data capture for above ground components including a cell tower, associated cell site components on the cell tower, one or more buildings, and surrounding geography around the cell site (step 2402); obtaining second data capture for subterranean geography associated with the surrounding geography (step 2404); utilizing the first data capture and the second data capture to develop the 3D model which includes both the above ground components and the subterranean geography (step 2406); and utilizing the 3D model to perform the one or more of the site audit, the site survey, and the cell site planning and engineering (step 2408). The method 2450 can further include obtaining third data capture of interiors of the one or more buildings; and utilizing the third data capture to develop the 3D model for the interiors. The obtaining second data capture can be performed with a data capture device using one of sonar, ultrasound, and LIDAR (Light Detection and Ranging). The obtaining first data capture can be performed with an Unmanned Aerial Vehicle (UAV) flying about the cell tower, and wherein the obtaining second data capture can be performed with the data capture device on the UAV. The obtaining first data capture can be performed with an Unmanned Aerial Vehicle (UAV) flying about the cell tower. The first data capture can include a plurality of photos or video subject to a plurality of constraints, wherein the plurality of photos are obtained by a plurality of cameras which are coordinated with one another. The 3D model can be presented in a Graphical User Interface (GUI) to perform the one or more of the site audit, the site survey, and the cell site planning and engineering. The subterranean geography in the 3D model can illustrate support structures of the cell tower and utility constructions in the surrounding geography. The method can further include utilizing an external data source to verify utility constructions in the second data capture for the subterranean geography. §21.0 3D Model of Cell Sites for Modeling Fiber Connectivity As described herein, various approaches are described for 3D models for cell sites for cell site audits, site surveys, close-out audits, etc. which can be performed remotely (virtual). In an exemplary embodiment, the 3D model is further extended to cover surrounding areas focusing on fiber optic cables near the cell site. Specifically, with the fiber connectivity in the 3D model, backhaul connectivity can be determined remotely. Referring to FIG. 39, in an exemplary embodiment, a perspective diagram illustrates the 3D model 2400 of the cell site 10, the cell tower 12, the cell site components 14, and the shelter or cabinet 52 along with surrounding geography 2402, subterranean geography 2404, and fiber connectivity 2500. Again, the 3D model 2400 of the cell site 10, the cell tower 12, the cell site components 14, and the shelter or cabinet 52 along with a 3D model of the interior 900 can be constructed using the various techniques described herein. Specifically, FIG. 39 extends the 3D model 2400 in FIG. 38 and in other areas described herein to further include fiber cabling. As previously described, the systems and methods extend the 3D model 2400 to include the surrounding geography 2402 and the subterranean geography 2404. The surrounding geography 2402 represents the physical location around the cell site 10. This can include the cell tower 12, the shelter or cabinet 52, access roads, etc. The subterranean geography 2404 includes the area underneath the surrounding geography 2402. Additionally, the 3D model 2400 also includes the fiber connectivity 2500 including components above ground in the surrounding geography 2402 and as well as the subterranean geography 2404. The fiber connectivity 2500 can include poles 2502 and cabling 2504 on the poles 2502. The 3D model 2400 can include the fiber connectivity 2500 at the surrounding geography 2402 and the subterranean geography 2404. Also, the 3D model can extend out from the surrounding geography 2402 on a path associated with the fiber connectivity 2500 away from the cell site 10. Here, this can give the operator the opportunity to see where the fiber connectivity 2500 extends. Thus, various 3D models 2400 can provide a local view of the cell sites 10 as well as fiber connectivity 2500 in a geographic region. With this information, the operator can determine how close fiber connectivity 2500 is to current or future cell sites 10, as well as perform site planning. A geographic region can include a plurality of 3D models 2400 along with the fiber connectivity 2500 across the region. A collection of these 3D models 2400 in the region enables operators to perform more efficient site acquisition and planning. Data capture of the fiber connectivity 2500 can be through the UAV 50 as described herein. Advantageously, the UAV 50 is efficient to capture photos or video of the fiber connectivity 2500 without requiring site access (on the ground) as the poles 2502 and the cabling 2504 may traverse private property, etc. Also, other forms of data capture are contemplated such as via a car with a camera, a handheld camera, etc. The UAV 50 can be manually flown at the cell site 10 and once the cabling 2504 is identified, an operator can trace the cabling 2504 to capture photos or video for creating the 3D model 2400 with the fiber connectivity 2500. For example, the operator can identify the fiber connectivity 2500 near the cell site 10 in the surrounding geography 2402 and then cause the UAV 50 to fly a path similar to the path taken by the fiber connectivity 2500 while performing data capture. Once the data is captured, the photos or video can be used to develop a 3D model of the fiber connectivity 2500 which can be incorporated in the 3D model 2400. Also, the data capture can use the techniques for the subterranean geography 2404 as well. Referring to FIG. 40, in an exemplary embodiment, a flowchart illustrates a method 2550 for creating a three-dimensional (3D) model of a cell site and associated fiber connectivity for one or more of a cell site audit, a site survey, and cell site planning and engineering. The method 2550 includes determining fiber connectivity at or near the cell site (step 2552); obtaining first data capture of the fiber connectivity at or near the cell site (step 2554); obtaining second data capture of one or more paths of the fiber connectivity from the cell site (step 2556); obtaining third data capture of the cell site including a cell tower, associated cell site components on the cell tower, one or more buildings, and surrounding geography around the cell site (step 2558); utilizing the first data capture, the second data capture, and the third data capture to develop the 3D model which comprises the cell site and the fiber connectivity (step 2560); and utilizing the 3D model to perform the one or more of the site audit, the site survey, and the cell site planning and engineering (step 2560). The method 2550 can further include obtaining fourth data capture for subterranean geography associated with the surrounding geography of the cell site; and utilizing the fourth data capture with the first data capture, the second data capture, and the third data capture to develop the 3D model. The fourth data capture can be performed with a data capture device using one of sonar, ultrasound, photogrammetry, and LIDAR (Light Detection and Ranging). The method 2550 can further include obtaining fifth data capture of interiors of one or more buildings at the cell site; and utilizing the fifth data capture with the first data capture, the second data capture, the third data capture, and the fourth data capture to develop the 3D model. The obtaining first data capture and the obtaining second data capture can be performed with an Unmanned Aerial Vehicle (UAV) flying about the cell tower with a data capture device on the UAV. An operator can cause the UAV to fly the one or more paths to obtain the second data capture. The obtaining first data capture, the obtaining second data capture, and the obtaining third data capture can be performed with an Unmanned Aerial Vehicle (UAV) flying about the cell tower with a data capture device on the UAV. The third data capture can include a plurality of photos or video subject to a plurality of constraints, wherein the plurality of photos are obtained by a plurality of cameras which are coordinated with one another. The 3D model can be presented in a Graphical User Interface (GUI) to perform the one or more of the site audit, the site survey, and the cell site planning and engineering. In a further exemplary embodiment, an apparatus adapted to create a three-dimensional (3D) model of a cell site and associated fiber connectivity for one or more of a cell site audit, a site survey, and cell site planning and engineering includes a network interface, a data capture device, and a processor communicatively coupled to one another; and memory storing instructions that, when executed, cause the processor to determine fiber connectivity at or near the cell site based on feedback from the data capture device; obtain first data capture of the fiber connectivity at or near the cell site; obtain second data capture of one or more paths of the fiber connectivity from the cell site; obtain third data capture of the cell site including a cell tower, associated cell site components on the cell tower, one or more buildings, and surrounding geography around the cell site; utilize the first data capture, the second data capture, and the third data capture to develop the 3D model which comprises the cell site and the fiber connectivity; and utilize the 3D model to perform the one or more of the site audit, the site survey, and the cell site planning and engineering. §22.0 Detecting Changes at the Cell Site and Surrounding Area Using UAVs Referring to FIG. 41, in an exemplary embodiment, a perspective diagram illustrates a cell site 10 with the surrounding geography 2402. FIG. 41 is an example of a typical cell site. The cell tower 12 can generally be classified as a self-support tower, a monopole tower, and a guyed tower. These three types of cell towers 12 have different support mechanisms. The self-support tower can also be referred to as a lattice tower, and it is free standing, with a triangular base with three or four sides. The monopole tower is a single tube tower, and it is also free standing, but typically at a lower height than the self-support tower. The guyed tower is a straight rod supported by wires attached to the ground. The guyed tower needs to be inspected every 3 years, or so, the self-support tower needs to be inspected every 5 years, and the monopole tower needs to be inspected every 7 years. Again, the owners (real estate companies generally) of the cell site 10 have to be able to inspect these sites efficiently and effectively, especially given the tremendous number of sites—hundreds of thousands. A typical cell site 10 can include the cell tower 12 and the associated cell site components 14 as described herein. The cell site 10 can also include the shelter or cabinet 52 and other physical structures—buildings, outside plant cabinets, etc. The cell site 10 can include aerial cabling, an access road 2600, trees, etc. The cell site operator is concerned generally about the integrity of all of the aspects of the cell site 10 including the cell tower 12 and the cell site components 14 as well as everything in the surrounding geography 2402. In general, the surrounding geography 2402 can be about an acre; although other sizes are also seen. Conventionally, the cell site operator had inspections performed manually with on-site personnel, with a tower climb, and with visual inspection around the surrounding geography 2402. The on-site personnel can capture data and observations and then return to the office to compare and contrast with engineering records. That is, the on-site personnel capture data, it is then compared later with existing site plans, close-out audits, etc. This process is time-consuming and manual. To address these concerns, the systems and methods propose a combination of the UAV 50 and 3D models of the cell site 10 and surrounding geography 2402 to quickly capture and compare data. This capture and compare can be done in one step on-site, using the UAV 50 and optionally the mobile device 100, quickly and accurately. First, an initial 3D model 2400 is developed. This can be as part of a close-out audit or part of another inspection. The 3D model 2400 can be captured using the 3D modeling systems and methods described herein. This initial 3D model 2400 can be referred to as a known good situation. The data from the 3D model 2400 can be provided to the UAV 50 or the mobile device 100, and a subsequent inspection can use this initial 3D model 2400 to simultaneously capture current data and compare the current data with the known good situation. Any deviations are flagged. The deviations can be changes to the physical infrastructure, structural problems, ground disturbances, potential hazards, loss of gravel on the access road 2600 such as through wash out, etc. Referring to FIG. 42, in an exemplary embodiment, a flowchart illustrates a method 2650 for cell site inspection by a cell site operator using the UAV 50 and a processing device, such as the mobile device 100 or a processor associated with the UAV 50. The method 2650 includes creating an initial computer model of a cell site and surrounding geography at a first point in time, wherein the initial computer model represents a known good state of the cell site and the surrounding geography (step 2652); providing the initial computer model to one or more of the UAV and the processing device (step 2654); capturing current data of the cell site and the surrounding geography at a second point in time using the UAV (step 2656); comparing the current data to the initial computer model by the processing device (step 2658); and identifying variances between the current data and the initial computer model, wherein the variances comprise differences at the cell site and the surrounding geography between the first point in time and the second point in time (step 2660). The method can further include specifically describing the variances based on comparing the current data and the initial computer model, wherein the variances comprise any of changes to a cell tower, changes to cell site components on the cell tower, ground hazards, state of an access road, and landscape changes in the surrounding geography. The initial computer model can be a three-dimensional (3D) model describing by a point cloud, and where the comparing comprises a comparison of the current data to the point cloud. The initial computer model can be determined as part of one of a close-out audit and a site inspection where it is determined the initial computer model represents the known good state. The UAV can be utilized to capture data for the initial computer model, and the UAV is utilized in the capturing the current data. A flight plan of the UAV around a cell tower can be based on a type of the cell tower including any of a self-support tower, a monopole tower, and a guyed tower. The initial computer model can be a three-dimensional (3D) model viewed in a Graphical User Interface, and wherein the method can further include creating a second 3D model based on the current data and utilizing the second 3D model if it is determined the cell site is in the known good state based on the current data. In another exemplary embodiment, a processing device for cell site inspection by a cell site operator using an Unmanned Aerial Vehicle (UAV) includes a network interface and a processor communicatively coupled to one another; and memory storing instructions that, when executed, cause the processor to, responsive to creation of an initial computer model of a cell site and surrounding geography at a first point in time, wherein the initial computer model represents a known good state of the cell site and the surrounding geography, receive the initial computer model; receive captured current data of the cell site and the surrounding geography at a second point in time using the UAV; compare the current data to the initial computer model; and identify variances between the current data and the initial computer model, wherein the variances comprise differences at the cell site and the surrounding geography between the first point in time and the second point in time. In a further exemplary embodiment, a non-transitory computer readable medium includes instructions that, when executed, cause one or more processors to perform the steps of: creating an initial computer model of a cell site and surrounding geography at a first point in time, wherein the initial computer model represents a known good state of the cell site and the surrounding geography; providing the initial computer model to one or more of an Unmanned Aerial Vehicle (UAV), and a processing device; capturing current data of the cell site and the surrounding geography at a second point in time using the UAV; comparing the current data to the initial computer model by the processing device; and identifying variances between the current data and the initial computer model, wherein the variances comprise differences at the cell site and the surrounding geography between the first point in time and the second point in time. §23.0 Virtual 360 View Systems and Methods Referring to FIG. 43, in an exemplary embodiment, a flowchart illustrates a virtual 360 view method 2700 for creating and using a virtual 360 environment. The method 2700 is described referencing the cell site 10 and using the UAV 50; those skilled in the art will recognize that other types of telecommunication sites are also contemplated such as data centers, central offices, regenerator huts, etc. The objective of the method 2700 is to create the virtual 360 environment and an example virtual 360 environment is illustrated in FIGS. 44-53. The method 2700 includes various data capture steps including capturing 360-degree photos at multiple points around the ground portion of the cell site 10 (step 2702), capturing 360-degree photos of the cell tower 12 and the surrounding geography 2402 with the UAV 50 (step 2704), and capturing photos inside the shelter or cabinet 52 (step 2706). Once all of the data is captured, the method 2700 includes stitching the various photos together with linking to create the virtual 360-degree view environment (step 2708). The virtual 360-degree view environment can be hosted on a server, in the cloud, etc. and accessible remotely such as via a URL or the like. The hosting device can enable display of the virtual 360-degree view environment for an operator to virtually visit the cell site 10 and perform associated functions (step 2710). For example, the operator can access the virtual 360-degree view environment via a tablet, computer, mobile device, etc. and perform a site survey, site audit, site inspection, etc. for various purposes such as maintenance, installation, upgrades, etc. An important aspect of the method 2700 is proper data capture of the various photos. For step 2702, the photos are preferably captured with a 360-degree camera or the like. The multiple points for the ground portion of the cell site 10 can include taking one or more photos at each corner of the cell site 10 to get all of the angles, e.g., at each point of a square or rectangle defining the surrounding geography 2402. Also, the multiple points can include photos at gates for a walking path, access road, etc. The multiple points can also include points around the cell tower 12 such as at the base of the cell tower, points between the cell tower 12 and the shelter or cabinet 52, points around the shelter or cabinet 52 including any ingress (doors) points. The photos can also include at the ingress points into the shelter or cabinet 52 and then systematically working down the rows of equipment in the shelter or cabinet 52 (which is covered in step 2706). For step 2704, the UAV 50 can employ the various techniques described herein. In particular, the UAV 50 is used to take photos at the top of the cell tower 12 including the surrounding geography 2402. Also, the UAV 50 is utilized to take detailed photos of the cell site components 14 on the cell tower 12, such as sector photos of the alpha, beta, and gamma sectors to show the front of the antennas and the direction each antenna is facing. Also, the UAV 50 or another device can take photos or video of the access road, of a tower climb (with the UAV 50 flying up the cell tower 12), at the top of the cell tower 12 including pointing down showing the entire cell site 10, etc. The photos for the sectors should capture all of the cell site equipment 14 including cabling, serial numbers, identifiers, etc. For step 2706, the objective is to obtain photos inside the shelter or cabinet 52 to enable virtual movement through the interior and to identify (zoom) items of interest. The photos capture all model numbers, labels, cables, etc. The model numbers and/or labels can be used to create hotspots in the virtual 360-degree view environment where the operator can click for additional details such as close up views. The data capture should include photos with the equipment doors both open and closed to show equipment, status identifiers, cabling, etc. In the same manner, the data capture should include any power plant, AC panels, batteries, etc. both with doors open and closed to show various details therein (breakers, labels, model numbers, etc.). Also, the data capture within the shelter or cabinet 52 can include coax ports and ground bars (inside/outside/tower), the telco board and equipment, all technology equipment and model numbers, all rack mounted equipment, all wall mounted equipment. For ground-based photo or video capture, the method 2700 can use the multiple camera apparatus 2000 (or a variant thereof with a single camera such as a 360-degree camera). For example, the ground-based data capture can use a tripod or pole about 4-7′ tall with a 360-degree camera attached thereto to replicate an eye-level view for an individual. A technician performing this data capture place the apparatus 2000 (or variant thereof) at all four corners of the cell site 10 to capture the photos while then placing and capturing in between the points to make sure every perspective and side of objects can be seen in a 360/VR environment of the virtual 360-degree view environment. Also, items needing additional detail for telecommunication audits can be captured using a traditional camera and embedded into the 360/VR environment for viewing. For example, this can include detailed close-up photos of equipment, cabling, breakers, etc. The individual taking the photos places themselves among the environment where the camera cannot view them in that perspective. For UAV-based data capture, the UAV 50 can include the 360-degree camera attached thereto or mounted. Importantly, the camera on the UAV 50 should be positioned so that the photos or video are free from the UAV, i.e., the camera's field of view should not include any portion of the UAV 50. The camera mount can attach below the UAV 50 making sure no landing gear or other parts of the UAV 50 are visible to the camera. The camera mounts can be attached to the landing gear or in place of or on the normal payload area best for the center of gravity. Using the UAV 50, data capture can be taken systematically around the cell tower 12 to create a 360 view on sides and above the cell tower 12. For step 2708, the 360-degree camera takes several photos of the surrounding environment. The photos need to be combined into one panoramic like photo by stitching the individual photos together. This can be performed at the job site to stitch the photos together to make it ready for the VR environment. Also, the various techniques described herein are also contemplated for virtual views. Once the virtual 360-degree view environment is created, it is hosted online for access by operators, installers, engineers, etc. The virtual 360-degree view environment can be accessed securely such as over HTTPS, over a Virtual Private Network (VPN), etc. The objective of the virtual 360-degree view environment is to provide navigation in a manner similar to as if the viewer was physically located at the cell site 10. In this manner, the display or Graphical User Interface (GUI) of the virtual 360-degree view environment supports navigation (e.g., via a mouse, scroll bar, touch screen, etc.) to allow the viewer to move about the cell site 10 and inspect/zoom in on various objects of interest. FIGS. 44-55 illustrate screen shots from an exemplary implementation of the virtual 360-degree view environment. FIG. 44 is a view entering the cell site 10 facing the cell tower 12 and the shelter or cabinet 52. Note, this is a 360-view, and the viewer can zoom, pan, scroll, etc. as if they were at the cell site 10 walking and/or moving their head/eyes. The display can include location items which denote a possible area the viewer can move to, such as the northwest corner or the back of shelter in FIG. 44. Further, the display can include information icons such as tower plate which denotes the possibility of zooming in to see additional detail. In FIG. 45, the viewer has moved to the back of the shelter, and there are now information icons for the GPS antenna and the exterior coax port. In FIG. 46, the viewer navigates to the top of the cell tower 12 showing a view of the entire cell site 10. In FIG. 47, the viewer zooms in, such as via an information icon, to get a closer view of one sector. In FIG. 48, the viewer navigates to the side of the shelter or cabinet 52, and there is an information icon for the propane tank. In FIG. 49, the viewer navigates to the front of the shelter or cabinet 52 showing doors to the generator room and to the shelter itself along with various information icons to display details on the door. In FIG. 49, the viewer navigates into the generator room, and this view shows information icons for the generator. In FIG. 50, the viewer navigates into the shelter or cabinet 52 and views the wall showing the power panel with associated information icons. In FIG. 51, the viewer looks around the interior of the shelter or cabinet 52 showing racks of equipment. In FIG. 52, the viewer looks at a rack with the equipment door closed, and this view shows various information icons. Finally, in FIG. 53, the viewer virtually opens the door for LTE equipment. FIGS. 54 and 55 illustrate the ability to “pop-up” or call an additional photo within the environment by clicking the information icons. Note, the viewer can also zoom within the environment and on the popped out photos. Although the present disclosure has been illustrated and described herein with reference to preferred embodiments and specific examples thereof, it will be readily apparent to those of ordinary skill in the art that other embodiments and examples may perform similar functions and/or achieve like results. All such equivalent embodiments and examples are within the spirit and scope of the present disclosure, are contemplated thereby, and are intended to be covered by the following claims.
<SOH> BACKGROUND OF THE DISCLOSURE <EOH>Due to the geographic coverage nature of wireless service, there are hundreds of thousands of cell towers in the United States. For example, in 2014, it was estimated that there were more than 310,000 cell towers in the United States. Cell towers can have heights up to 1,500 feet or more. There are various requirements for cell site workers (also referred to as tower climbers or transmission tower workers) to climb cell towers to perform maintenance, audit, and repair work for cellular phone and other wireless communications companies. This is both a dangerous and costly endeavor. For example, between 2003 and 2011, 50 tower climbers died working on cell sites (see, e.g., www.pbs.org/wgbh/pages/frontline/social-issues/cell-tower-deaths/in-race-for-better-cell-service-men-who-climb-towers-pay-with-their-lives/). Also, OSHA estimates that working on cell sites is 10 times more dangerous than construction work, generally (see, e.g., www.propublica.org/article/cell-tower-work-fatalities-methodology). Furthermore, the tower climbs also can lead to service disruptions caused by accidents. Thus, there is a strong desire, from both a cost and safety perspective, to reduce the number of tower climbs. Concurrently, the use of unmanned aerial vehicles (UAV), referred to as drones, is evolving. There are limitations associated with UAVs, including emerging FAA rules and guidelines associated with their commercial use. It would be advantageous to leverage the use of UAVs to reduce tower climbs of cell towers. US 20140298181 to Rezvan describes methods and systems for performing a cell site audit remotely. However, Rezvan does not contemplate performing any activity locally at the cell site, nor various aspects of UAV use. US20120250010 to Hannay describes aerial inspections of transmission lines using drones. However, Hannay does not contemplate performing any activity locally at the cell site, nor various aspects of constraining the UAV use. Specifically, Hannay contemplates a flight path in three dimensions along a transmission line. Of course, it would be advantageous to further utilize UAVs to actually perform operations on a cell tower. However, adding one or more robotic arms, carrying extra equipment, etc. presents a significantly complex problem in terms of UAV stabilization while in flight, i.e., counterbalancing the UAV to account for the weight and movement of the robotic arms. Research and development continues in this area, but current solutions are complex and costly, eliminating the drivers for using UAVs for performing cell tower work. 3D modeling is important for cell site operators, cell tower owners, engineers, etc. There exist current techniques to make 3D models of physical sites such as cell sites. One approach is to take hundreds or thousands of pictures and to use software techniques to combine these pictures to form a 3D model. Generally, conventional approaches for obtaining the pictures include fixed cameras at the ground with zoom capabilities or pictures via tower climbers. It would be advantageous to utilize a UAV to obtain the pictures, providing 360-degree photos from an aerial perspective. Use of aerial pictures is suggested in US 20100231687 to Armory. However, this approach generally assumes pictures taken from a fixed perspective relative to the cell site, such as via a fixed, mounted camera and a mounted camera in an aircraft. It has been determined that such an approach is moderately inaccurate during 3D modeling and combination with software due to slight variations in location tracking capabilities of systems such as Global Positioning Satellite (GPS). It would be advantageous to adapt a UAV to take pictures and provide systems and methods for accurate 3D modeling based thereon to again leverage the advantages of UAVs over tower climbers, i.e., safety, climbing speed and overall speed, cost, etc. In the process of planning, installing, maintaining, and operating cell sites and cell towers, site surveys are performed for testing, auditing, planning, diagnosing, inventorying, etc. Conventional site surveys involve physical site access including access to the top of the cell tower, the interior of any buildings, cabinets, shelters, huts, hardened structures, etc. at the cell site, and the like. With over 200,000 cell sites in the U.S., geographically distributed everywhere, site surveys can be expensive, time-consuming, and complex. The various parent applications associated herewith describe techniques to utilize UAVs to optimize and provide safer site surveys. It would also be advantageous to further optimize site surveys by minimizing travel through virtualization of the entire process. Again, with over 200,000 cell sites in the U.S., each time there is maintenance or installation activity at each cell site, operators and owners typically require a close-out audit which is done to document and verify the work performed. For example, the maintenance or installation activity can be performed by a third-party installation firm (separate from an operator or owner) and an objective of the close-out audit is to provide the operator or owner verification of the work as well as that the third-party installation firm did the work in a manner consistent with the operator or owner's expectations. Conventionally, close-out audits are performed by another firm, i.e., a third-party inspection firm, separate from the third-party installation firm, the owner, and the operator. Disadvantageously, this conventional approach with a separate third-party inspection firm is inefficient, expensive, etc. Also, with over 200,000 cell sites, it is difficult to monitor activity, namely configurations, physical structure, surroundings, etc., and associated changes. The typical arrangement includes a cell site owner, which is typically a real estate company, leasing space to cell site operators, i.e., wireless service providers. It is incumbent that the cell site owners maintain accurate records of the cell sites, including the configuration (i.e., are the operators deploying more equipment than agreements state?), physical structure (i.e., are there mechanical issues with the cell site?), surroundings (i.e., are there safety issues?), and the like. Conventional approaches require physical site surveys to obtain such information which with over 200,000 cells sites is expensive, time-consuming, slow, etc. The number of cell sites continues to grow and with the advent of 5G, to dramatically increase. For example, with 5G, small cell deployments are expected to increase to address capacity and coverage. All cell sites require so-called backhaul to provide network access to the cell site. One technique for backhaul includes fiber optic connections to the cell site. For site owners, it can be problematic to determine fiber optic cabling to a cell site, e.g., are there currently cables at the location, what are the possibilities of new cabling, etc. As the number of cell sites increases, it is important to get this data efficiently.
<SOH> BRIEF SUMMARY OF THE DISCLOSURE <EOH>In an exemplary embodiment, a method for creating and utilizing a virtual 360-degree view of a telecommunications site includes capturing first data of a 360-degree view at multiple points around the telecommunications site; capturing second data of a 360-degree view at aerial points above the telecommunications site; capturing third data of a 360-degree view inside a shelter or cabinet at the telecommunications site, wherein each of the first data, second data, and third data comprise one or more of photos and video; stitching the first data, the second data, and the third data together with links to create a virtual 360-degree view environment of the telecommunications site, wherein the links enable virtual navigation about the telecommunications site; and displaying the virtual 360-degree view environment to a viewer over a network and adjusting the virtual 360-degree view environment based on commands received from the viewer. In another exemplary embodiment, a server for creating and utilizing a virtual 360-degree view of a telecommunications site includes a network interface and a processor communicatively coupled to one another; and memory storing instructions that, when executed, cause the processor to obtain first data of a 360-degree view at multiple points around the telecommunications site; obtain second data of a 360-degree view at aerial points above the telecommunications site; obtain third data of a 360-degree view inside a shelter or cabinet at the telecommunications site, wherein each of the first data, second data, and third data comprise one or more of photos and video; stitch the first data, the second data, and the third data together with links to create a virtual 360-degree view environment of the telecommunications site, wherein the links enable virtual navigation about the telecommunications site; and display the virtual 360-degree view environment to a viewer over a network and adjust the virtual 360-degree view environment based on commands received from the viewer. In a further exemplary embodiment, a non-transitory computer readable medium includes instructions that, when executed, cause one or more processors to perform the steps of obtaining first data of a 360-degree view at multiple points around the telecommunications site; obtaining second data of a 360-degree view at aerial points above the telecommunications site; obtaining third data of a 360-degree view inside a shelter or cabinet at the telecommunications site, wherein each of the first data, second data, and third data comprise one or more of photos and video; stitching the first data, the second data, and the third data together with links to create a virtual 360-degree view environment of the telecommunications site, wherein the links enable virtual navigation about the telecommunications site; and displaying the virtual 360-degree view environment to a viewer over a network and adjusting the virtual 360-degree view environment based on commands received from the viewer.
H04N523238
20170814
20171221
99058.0
H04N5232
1
LETT, THOMAS J
VIRTUAL 360-DEGREE VIEW OF A TELECOMMUNICATIONS SITE
SMALL
1
CONT-ACCEPTED
H04N
2,017
15,676,631
PENDING
SELF-OPTIMIZING DISTRIBUTED ANTENNA SYSTEM USING SOFT FREQUENCY REUSE
A method of determining a carrier power in a communications system including a processor includes a) setting a power differential between a reference carrier and one or more carriers, b) measuring a number of satisfied users at the power differential, and c) measuring a capacity for the satisfied users at the power differential. The method also includes d) increasing the power differential by a predetermined amount and e) determining, using the processor, that the number of satisfied users at the increased power differential is greater than or equal to the number of satisfied users at the power differential. The method further includes f) repeating a)-c) and g) setting the carrier power at an iterated power level.
1. (canceled) 2. A method of determining a transmission power of a digital remote unit (DRU) in a distributed antenna system (DAS), the method comprising: a) setting a transmission power level for the DRU; b) determining a key performance indicator related to a number of satisfied users at the transmission power; c) iteratively adjusting a transmission power level for the DRU to increase the key performance indicator related to the number of satisfied users; and d) setting the transmission power level for the DRU at an iterated power level. 3. The method of claim 2 wherein the transmission power comprises a differential between a reference carrier and one or more carriers. 4. The method of claim 3 wherein the reference carrier comprises a first frequency carrier, and the one or more carriers comprise a second frequency carrier and a third frequency carrier. 5. The method of claim 3 wherein the reference carrier is utilized by multiple antennas of the DRU and the one or more carriers are utilized by a single antenna of the DRU. 6. The method of claim 5 wherein the single antenna is a center antenna of the DRU. 7. The method of claim 6 wherein a set of multiple antennas are edge antennas of the DRU. 8. The method of claim 7 wherein the set of multiple antennas comprise six antennas. 9. The method of claim 2 further comprising: a) determining a second key performance indicator related to a capacity for the number of satisfied users; b) iteratively adjusting the transmission power level for the DRU to increase the second key performance indicator related to the capacity for the number of satisfied users; and c) setting the transmission power level for the DRU at the iterated power level. 10. The method of claim 9 wherein the second key performance indicator related to the capacity for the number of satisfied users is a number of users having a capacity above a predetermined threshold capacity. 11. The method of claim 10 wherein the predetermined threshold capacity is defined by a predetermined threshold bit rate. 12. The method of claim 2 further comprising determining that the transmission power is outside a predetermined range; and terminating the method. 13. The method of claim 2 further comprising: determining that an oscillation indicator is equal to a predetermined value; and terminating the method. 14. A distributed antenna system comprising: a digital access unit (DAU) communicatively coupled to a signal source, wherein the DAU is operable to receive wireless resources associated with one or more signal source sectors; a central DRU coupled to the DAU and assigned to a specific sector of the one or more signal source sectors; and one or more DRUs communicatively coupled to the central DRU and assigned to the specific sector, and wherein, the central DRU is assigned a full-reused frequency associated with the specific sector, and wherein each of the one or more DRUs are assigned a particular frequency partition of the full-reused frequency. 15. The distributed antenna system of claim 14 wherein the signal source is assigned the full frequency spectrum and connected to a public switched telephone network or a mobile switching center. 16. The distributed antenna system of claim 14 wherein the specific sector is assigned a plurality of frequency partitions of the full-reused frequency; and a central antenna is assigned the plurality of frequency partitions. 17. The distributed antenna system of claim 14 wherein the one or more DRUs comprises at least six first-tier DRUs surrounding the central DRU and 12 second-tier DRUs surrounding the first tier DRUs. 18. The distributed antenna system of claim 14 wherein the central DRU and the one or more DRUs are adjacent to a second central DRU and a plurality of DRUs. 19. The distributed antenna system of claim 14 wherein the full-reused frequency comprises 3 frequency partitions. 20. The distributed antenna system of claim 14 wherein the central DRU and the one or more DRUs have multi-drop bus topology. 21. The distributed antenna system of claim 14 coupled by at least one of Ethernet cable, Optical Fiber, Microwave Line of Sight or Non Line of Sight Link, Wireless Link, or Satellite Link.
CROSS-REFERENCES TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 15/154,073, filed May 13, 2016, which is a continuation of U.S. patent application Ser. No. 13/935,157, filed on Jul. 3, 2013, now U.S. Pat. No. 9,363,768, which claims priority to U.S. Provisional Patent Application No. 61/669,572, filed on Jul. 9, 2012; the disclosures of which are hereby incorporated by reference in their entirety. SUMMARY OF THE INVENTION According to an embodiment of the present invention, a method of determining a carrier power in a communications system including a processor is provided. The method includes a) setting a power differential between a reference carrier and one or more carriers, b) measuring a number of satisfied users at the power differential, and c) measuring a capacity for the satisfied users at the power differential, which may be referred to as an initial power differential. The method also includes d) adjusting the power differential by a predetermined amount and e) determining, using the processor, that the number of satisfied users at the adjusted power differential is greater than or equal to the number of satisfied users at the initial power differential. The method further includes f) repeating a)-e) and g) setting the carrier power at an iterated power level. As described herein, unbalanced traffic distributions inside cellular networks are common occurrences. Embodiments of the present invention provide a throughput-balancing system that optimizes cellular performance according to the geographic traffic distribution in order to provide a high quality of service (QoS). The throughput of an Orthogonal Frequency Division Multiple Access (OFDMA) based architecture (DAS-SFR) that utilizes a combination Soft Frequency Reuse (SFR) technique and a Distributed Antenna System (DAS) is analyzed in light of embodiments of the present invention. A concept employed by this architecture is to distribute the antennas in a hexagonal cell in such a way that the central antenna is responsible for serving a special area, using all of the frequency bands, while the remaining antennas utilize only a subset of the frequency bands based on a frequency reuse factor. A DAS-SFR has the ability to distribute the cellular capacity (throughput) over a given geographic area. To enable throughput balancing among Distributed Antennas (DAs), embodiments of the present invention dynamically change the DA's carrier power to manage the inter-cell interference, as a function of the time-varying traffic. A Downlink Power Self-Optimization (PSO) algorithm, for three different resource allocation scenarios, is described for the DAS-SFR system. The transmit powers are optimized in order to maximize the spectral efficiency of a DAS-SFR and maximize the number of satisfied users under different user distributions in some embodiments. The PSO algorithm is able to guarantee a high Quality of Service (QoS) that concentrates on the number of satisfied users as well as the capacity of satisfied users as the two Key Performance Indicators (KPIs). Analytical derivations and simulations are discussed and used to evaluate the system performance for different traffic scenarios, and the results are presented. Embodiments of the present invention provide a method and system for adjusting and potentially optimizing the powers of multiple carriers in a DAS-SFR system. By adjusting the power associated with the carriers provided by the central antenna of each cell, the SFR system enables higher system performance and an improved user experience as a result of higher system bandwidth. Numerous benefits are achieved by way of the present invention over conventional techniques. For instance, embodiments of the present invention control the amount of resources allocated to users located in different areas, thereby increasing the frequency efficiency and also improving the data rate for cell edge users. As another example, embodiments of the present invention are useful in adjusting the powers of carriers to increase or maximize Key Performance Indicators, which are related to Quality of Service. These and other embodiments of the invention along with many of its advantages and features are described in more detail in conjunction with the text below and attached figures. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 illustrates band width allocation to antennas for three different combinations of DAS with SFR, HFR and FFR according to embodiments of the present invention; FIG. 2 illustrates the structure of a Distributed Antenna System according to an embodiment of the present invention; FIG. 3 illustrates a block diagram of the Received Signals with Interference Signals and Noises according to an embodiment of the present invention; FIG. 4 is a simplified flowchart illustrating the PSO algorithm according to an embodiment of the present invention; FIGS. 5A-5B illustrate plots of ergodic capacity versus the normalized distance from the DRU0 according to embodiments of the present invention; FIGS. 6A-6D illustrate KPIs versus the ΔP for different distribution users scheme where Cth=0.01WRB according to embodiments of the present invention; and FIGS. 7A-7D illustrate KPIs versus the ΔP for different distribution users scheme where Cth=0.07WRB according to embodiments of the present invention. DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS In existing networks, parameters are manually adjusted to obtain a high level of network operational performance. 3GPP LTE is the preferred candidate for the next generation wireless networks. In the last 15 years, there has been substantial growth in cellular mobile communication systems. It is imperative to provide a high quality of service (QoS) at a minimum cost. With the substantial increase in cellular users, unbalanced throughput distributions are common in wireless networks which decrease the number of satisfied users. As traffic environments change, the network performance will not be optimum. Therefore, it is necessary to perform inter-cell optimization of the network dynamically according to the traffic environment, especially when cell traffic is not uniformly distributed. This is one of the important optimization issues in self-organizing networks (SON) for 3GPP LTE. In SON, parameter tuning is done automatically based on measurements. The use of throughput-balancing is meant to deliver extra gain in terms of network performance. For throughput-balancing this is achieved by adjusting the network control parameters in such a way that ultra-high throughput users can offload to ultra-low throughput users inside the cell. In a live network, high throughput fluctuations occur. A SON enabled network, where the proposed SON algorithm monitors the network and reacts to these changes in throughput, can achieve better performance by distributing the throughput among users. When the traffic loads among cells are not balanced, the satisfaction probability of heavily loaded cells may be lower, since their neighboring cells cause high inter-cell interference on cell edge users. In this case, throughput balancing can be conducted to alleviate and even avoid this problem. Inter-cell interference, experienced by cell-edge users, is very high when this interference is a result of using the same subcarriers in the adjacent cell in the same time slot. High inter-cell interference means severe degradation of the cell-edge throughput since Mobile 3GPP LTE adopts a frequency reuse factor of one which is called Full Frequency Reuse (FFR), in which each cell serves users using the entire system bandwidth. To mitigate the inter-cell interference in cellular systems, several techniques have been incorporated in these standards. Advanced receiver techniques such as Maximum Likelihood (ML) Multiuser Detection (MUD), the MMSE Receiver MUD and Other-cell interference cancellation are the three potential ways to reduce interference in cellular systems; however, these require a more complicated receiver. Advanced transmitter techniques such as Cooperative Encoding (CA), Closed-Loop MIMO Diversity Schemes(CLMD) and Beam forming are three other techniques to overcome the interference problem in cellular systems but CA requires very accurate channel state knowledge and real time inter-cell coordination, CLMD and Beam forming sacrifice spatial dimensions and require channel state knowledge. One possible strategy to alleviate interference, both in the uplink and the downlink of cellular networks, is to reduce the overall transmit power by using a Distributed Antenna Systems (DAS), which also has the additional advantage of improving capacity and coverage. The other possible strategy is a Soft Frequency Reuse technique; this technique effectively reduces the inter-cell interference by geographically spacing the competing transmissions farther apart, which benefits users near the cell boundaries. A. Distributed Antenna System (DAS): Distributed antenna systems (DAS) have been widely implemented in state-of-the art cellular communication systems to cover dead spots in wireless communications systems. A DAS breaks the traditional radio base station architecture into two pieces: a central processing facility and a set of distributed antenna (DA), connected to the central facility by a high-bandwidth network. The DAS network transports radio signals, in either analog or digital form, to/from the central facility where all the base station's processing is performed. By replacing a single high-power antenna with several low-power antennas, distributed to give the same coverage as the single antenna, a DAS is able to provide more-reliable wireless services within a geographic area or structure while reducing its power consumption. DAS has the following potential advantages such as: throughput improvement, coverage improvement, increased cellphone battery life and a reduction in transmitter power. Recent research has shown the benefits of using DAS in a cellular system for extending coverage, reducing call blocking rate and reducing inter-cell interference. An extension to a traditional DAS system is an Intelligent DAS, wherein each remote has the added flexibility of independently transmitting preselected carriers. Most of the research on DAS has focused on investigating SINR advantages of DAS and analyzing its performance. Some research on DAS has focused on the analysis of the uplink performance due to its analytical simplicity, while there are few studies on the downlink performance of DAS, although the demand for high-speed data rate will be dominant in the downlink path. There is also very little research that considers the advantages of DAS in a multi-cell context. B. Soft Frequency Reuse (SFR) Technique: SFR has been proposed as an inter-cell interference mitigation technique in OFDMA based wireless networks. In SFR, the frequency band is divided into a fixed number of sub-bands; all sub-bands are used by all eNBs to serve “near” users; the other sub-bands are dedicated to “far” users. All sub-bands are allocated to the cells according to some predefined reuse factor. The SFR assigns sub-bands limited amount of transmit power to reduce inter-cell interference. The transmit power needs to be reduced enough to provide the required throughput to cell edge users of neighboring cells. Also, the sub-bands of reduced transmit power are used for the inner cell users. Hard Frequency Reuse (HFR) suffers from a reduced spectral efficiency in such a way that, in HFR, the frequency band is divided into a fixed number of sub-bands that are allocated to the cells according to some predefined reuse factor and lets neighboring cells transmit on different sub-bands. On the other hand, SFR has the benefit of a full spectral efficiency and is a strong mechanism for inter-cell interference mitigation. The capacity of the SFR was evaluated in assuming the offset in the transmit powers of different sub-bands. Self-organization of the transmit power in the uncoordinated systems was illustrated in where some transient time is required to converge on the equilibrium state of power allocation. Recent research on SFR has focused on optimal system design utilizing advanced techniques such as graph theory and convex optimization to maximize network throughput. Additional work on FFR and SFR consider alternative schedulers and the authors determined the frequency partitions in a two-stage heuristic approach. Accordingly, this paper proposes a new architecture to suppress inter-cell interference. The proposed architecture combines DAS and SFR for an OFDMA system (e.g. LTE). We analyze the potential gains of DAS-SFR in a multi-cell environment. The proposed architecture divides the entire spectral bandwidth F into 3 parts (F1, F2, F3). The system assigns the eNB the full-reused frequency (all 3 parts) to the central antenna and the other 6 edge antennas work only on 1 part based on a reuse factor of Δ (ie. Δ=3) in such a way that neighbor cell edge antennas do not use the same frequency, FIG. 1 (a). Two other combinations of DAS with HFR and FFR are also demonstrated in FIG. 1 (b) and FIG. 1 (c), respectively. In order to attain user satisfaction, a minimum throughput should be provided for all users. In this publication, the system QoS is a function of the number of satisfied users. For a DAS-SFR architecture, the cell-edge throughput can be improved due to the reduced inter-cell interference as well as from the boosted cell-center transmission power. However, as compared to FFR the overall network throughput decreases at the same time, since the improvement is obtained at the cost of the cell-center user throughput. Thus, an efficient resource allocation and power allocation scheme is required to achieve the optimum overall network throughput in the DAS-SFR implementation. Therefore, to improve the throughput for the cell edge users and further increase the number of satisfied users (the users that can achieve a targeted service bitrate), a downlink Power Self-Optimization (PSO) algorithm for three different resource allocation scenarios is proposed for the DAS-SFR. The transmit powers are allocated so that the spectral efficiency is maximized for the DAS-SFR, and the number of satisfied users is also maximized. The spectral efficiency represented by the ergodic capacity is obtained for the different scenarios. The results show that a DAS-SFR architecture effectively addresses inter-cell interference in a multi-cell environment, especially at the cell boundaries when compared to a HFR cellular architecture. The results also show that a DAS-SFR architecture achieves a non-trivial capacity enhancement over a HFR cellular architecture for a frequency reuse factor of 3. A contribution of this work is the development of an analytical framework to evaluate the ergodic capacity of a DAS-SFR architecture. This is an important metric to consider, especially for users at the cell-edge since modern cellular networks are increasingly required to provide users with high data-rate and a guaranteed quality-of-service (QoS). This work presents a strategy for optimally allocating frequency RBs to edge users in a DAS-SFR architecture, based on a chosen performance threshold, which we define as Tp. A system model is presented in section II. In section III, the achievable capacity is derived for a distributed antenna system. Formulation of the Power allocation algorithm is discussed in section IV. Analytical and simulation results are shown in section V and a conclusion is provided in section VI. II. System Model A. System Architecture: The general architecture of an intelligent DAS in a multi-cell environment is shown in FIG. 2, where 7 Digital Remote Units (DRUs) are connected to an eNB via an optical fiber and a Digital Access Unit (DAU). The DAUs are interconnected and connected to multiple sectors. This capability enables the virtualization of the eNB resources at the independent DRUs. The eNBs are linked to a public switched telephone network or a mobile switching center. DRUs are sectorized in such a way that each DRU allocated to a given eNB sector can be simulcast. For the simulcasting operation, the access network between each eNB and its DRUs should have a multi-drop bus topology. In contrast, the same area (7 DRUs) is covered by a single high-power eNB in a traditional cellular system. The total transmit power of the n-th DRU of i-th cell in f-th frequency part is denoted Pn(i,f), where the central DRU of each cell is index by n=0. We also consider the 2-tier cellular structure, where two continuous tiers of eighteen cells surround a given cell. Although this assumption of only 2-tiers of interfering cells is optimistic, a pessimistic assumption that all the DRUs and the eNB are transmitting full power all the time easily compensates. B. Resource Allocation Scenarios: In a multiuser DAS-SFR system, different users are located at varying distances from the DRUs and have varying channel conditions on the subcarriers. Therefore, resource allocation allows for efficient exploitation of multiuser diversity in the system. Much of the research on SFR system design has focused on how to determine the size of the frequency partitions, for example, in a typical LTE system with a bandwidth of 5 MHz, 25 RBs may be available to serve users for each frequency part (Fi, i=1, 2, 3). For a typical central cell, we can assume that the center DRU is assigned to the full-reused frequency and the other six edge DRUs are assigned to F1. Now, we consider three resource allocation scenarios: Scenario 1: F1, F2 F3 RBs are assigned to all users in the cell. Note that in this scenario, the very low SINR exterior users are inefficiently using the F2 and F3 RBs. Scenario 2: F1 RBs are assigned to all users but F2 and F3 RBs are solely assigned to interior users. Note that in this scenario, the available RBs are fully assigned to the interior users, which leads to a big gap between the numbers of allocated RBs to the interior users as compared to the exterior users. Scenario 3: F1 RBs are solely assigned to the exterior users, whereas the F2 and F3 RBs are assigned to the interior users. In this scenario, all RBs are more fairly assigned between all users, as compared to the previously mentioned scenario. Moreover, in this scenario the RBs are allocated to the users following a SINR-based approach, in which the edge users using the F1 RBs, and the interior users using the F2 and F3 RBs have a high SINR. We primarily assume a single user scenario, and further extend it to a uniformly distributed multiuser LTE system. In a multiuser scenario, we investigate both the analytical and the simulation results in order to verify the system's capacity improvement. Received Signal and Channel Model The downlink path of a DAS can be considered as an equivalent MIMO system with additive interference and noise (FIG. 3). The received signal vector of the user in the central cell at frequency f can be expressed as, y ( 0 , f ) =  signal + interference + noise =  H ( 0 , f )  x ( 0 , f ) + ∑ i = 1 18  H ( i , f )  x ( i , f ) + n ( f ) ( 1 ) where H(i,f)εC1×7, i=0, 1, . . , 18, denotes the channel matrix between the DRUs in the i-th cell and the user in the central cell, x(i,f)=[x0(i,f), x1(i,f), . . . , x6(i,f)]TεC7×1, i=0, 1, . . . , 18 is the transmitted signal vector of the DRUs in the i-th cell, n(f)εC1×1 denotes the white noise vector with distribution CN(0,σn(f)2I1). The distributed antenna power constraint is considered, we have E  [  x n ( i , f )  2 ] ≤ P n ( i , f ) , n = 0 , 1 , …  , 6 ,  i = 0 , 1 , …  , 18 , ( 2 ) where in DAS-SFR, xn(i,F1)=0, Pn(i,F1)=0 when (n=1, 2, . . . , 6 and i=1, 2, . . . , 7, 9, 11, 13, 15, 17), xn(i,F2)=0, Pn(i,F2)=0 when (n=1, 2, . . . , 6 and i=0, 2, 4, 6, 7, 8, 10, 11, 12, 14, 15, 16, 18), xn(i,F3)=0, Pn(i,F3)=0 when (n=1, 2, . . . , 6 and i=0, 2, 4, 6, 7, 8, 10, 11, 12, 14, 15, 16, 18), in DAS-HFR3 (frequency reuse factor 3), xn(i,F1)=0, Pn(i,F1)=0 when (n=1, 2, . . . , 6 and i=1, 2, . . . , 7, 9, 11, 13, 15, 17), xn(i,F2)=0, Pn(i,F2)=0 when (n=1, 2, . . . , 6 and i=1, 2, . . . , 7, 9, 11, 12, 14, 15, 16, 18), xn(i,F3)=0, Pn(i,F3)=0 when (n=1, 2, . . . , 6 and i=1, 2, . . . , 7, 9, 11, 13, 14, 16, 17, 18), in DAS-FFR, xn(i,f)≠0, Pn(i,f)≠0 when (n=0, 1, . . . , 6 and i=0, 1, . . . , 18, f=F1, F2, F3, where Pn(i,f) denotes the power constraint of the n-th DRU in the i-th cell for frequency band f. The composite fading channel matrix H(i,f), i=0, 1, . . . , 18, encompasses not only small-scale fading (fast fading) but also large-scale fading (slow fading), which is modeled as H ( i , f ) =  H w ( i , f )  L ( i , f ) =  [ h 0 ( i , f ) , h 1 ( i , f ) , …  , h 6 ( i , f ) ] · diag  { l 0 ( i , f ) , l 1 ( i , f ) , …  , l 6 ( i , f ) } ( 3 ) where, Hw(if) and L(i,f) reflect the small-scale channel fading and the large-scale channel fading between the DRUs in the i-th cell and the user in the central cell, respectively. {hj(i,f)|j=0, 1, . . , 6; i=0, 1, . . . , 18; f=F1, F2, F3} are independent and identically distributed (i.i.d) circularly symmetric complex Gaussian variables with zero mean and unit variance, and {lj(i,f)|j=0, 1, . . . , 6; i=0, 1, . . . , 18, f=F1, F2, F3} can be modeled as ln(if)=√{square root over ([Dn(k)]−γXn(i,f))}, n=0, 1, . . . , 6, i=0, 1, . . . , 18 (4) Where Dn(i) and Xn(i,f) are independent random variables representing the distance and the shadowing between the user in the central cell and the n-th DRU in the i-th cell, respectively. γ denotes the path loss exponent {χj(i,f)≡j=0, 1, . . . , 6; i=0, 1, . . . , 18; f=F1, F2, F3} are i.i.d random variables with probability density function (PDF) f χ  ( χ ) = 1 2  π  λσ χ  χ  exp  ( - ( ln   χ ) 2 2  λ 2  σ χ 2 ) , χ > 0 , ( 5 ) Where σχ is the shadowing standard deviation and λ = ln   1   0 10 . Since the number of interfering sources is sufficiently large and interfering sources are independent with each other, the interference plus noise is assumed to be a complex Gaussian random vector as follows: N ( f ) = ∑ i = 1 18  H ( i , f )  x ( i , f ) + n ( f ) ( 6 ) The variance of N is derived by Central Limit Theorem as Var  ( N ( f ) ) =  [ ∑ i = 1 18  ∑ n = 0 6  [ l n ( i , f ) ] 2  P n ( i , f ) + σ n ( f ) 2 ]  I 1 =  [ σ ( f ) ] 2  I 1 ( 7 ) Therefore, the received signal at the mobile station at a given symbol duration is given by y(0,f)=Hw(0,f)L(0,f)x(0,f)+N(f) (8) Dynamic Power Allocation In DAS-SFR, it is important to dynamically change the frequency bands power of each DRU to cope with a dynamically changing distribution of traffic and to balance the throughput in each cell. Thus, it is necessary to dynamically change the frequency bands power such that the maximum number of users in each cell could be satisfied (number of users that can achieve the targeted service bitrate). In this study we are interested in a proper power allocation which maximizes the number of satisfied users and their capacity. Without proper power allocation, there may be cases of unbalanced capacity (throughput) where a few users can have ultra-high throughput and most of the users have ultra-low throughput. In some cases, for the existence of very large interference, some users will be always unsatisfied. Therefore, a proper power allocation can increase the throughput of the rest of the users. However, the number of unsatisfied users' throughput will be decreased. III. Achievable capacity of Distributed Antenna System If we assume that the channel state information is known only at the receiver (CSIR) and the channel is ergodic, the ergodic Shannon capacity at a given location of the target mobile station for the central cell can be calculated by C ( f ) = E H w ( 0 , f )  [ log 2  det  ( I 1 + 1 [ σ ( f ) ] 2  ( H w ( 0 , f )  L ( 0 , f ) )  P ( 0 , f )  ( H w ( 0 , f )  L ( 0 , f ) ) H ) ] ( 9 ) where P(0,f) is the covariance matrix of the transmitted vector x and given by diag{P0(0,f), P1(0,f), . . . , Py(0,f)}. If ergodicity of the channel is assumed, the ergodic capacity can be obtained as C ( f ) =  E H w ( 0 , f )  [ log 2  ( 1 + 1 [ σ ( f ) ] 2  ∑ i = 0 6   h i ( 0 , f )  2  [ l i ( 0 , f ) ] 2  P i ( 0 , f ) ) ] =  ∫ γ f = 0 ∞  log 2  ( 1 + γ f )  f γ f  ( γ f )  d   γ f ( 10 ) where γ f = 1 [ σ ( f ) ] 2  ∑ i = 0 6   h i ( 0 , f )  2  [ l i ( 0 , f ) ] 2  P i ( 0 , f ) is a weighted chi-squared distributed random variable with p.d.f given by f γ f  ( γ f ) = ∑ i = 0 6  [ σ ( f ) ] 2  π i [ l i ( 0 , f ) ] 2  P i ( 0 , f )  exp  ( - [ σ ( f ) ] 2  γ f [ l i ( 0 , f ) ] 2  P i ( 0 , f  ) ) , ( 11 ) where π i = ∏ k = 0 , k ≠ i 6   [ l i ( 0 , f ) ] 2  P i ( 0 , f ) [ l i ( 0 , f ) ] 2  P i ( 0 , f ) - [ l i ( 0 , f ) ] 2  P k ( 0 , f ) . Then the ergodic capacity for MISO vector channel can be obtained in a simple form by MISO  :   C ( f ) = - 1 ln   2  ∑ i = 0 6  π i  exp  ( - [ σ ( f ) ] 2 [ l i ( 0 , f ) ] 2  P i ( 0 , f ) )  Ei  ( - [ σ ( f ) ] 2 [ l i ( 0 , f ) ] 2  P i ( 0 , f ) ) ,   f = F 1 , F 2 , F 3 ( 12 ) where, Ei(t) is the exponential integral function ( Ei  ( t ) = - ∫ - x ∞  e - t / tdt ) and can be easily calculated with popular numerical tools such as MATLAB and MAPLE. Since the derivation for this MISO vector channel is a generalization of a SISO channel, the ergodic capacity for SISO channel is given, respectively, by SISO  :   C ( f ) = - 1 ln   2  exp  ( - [ σ ( f ) ] 2 [ l 0 ( 0 , f ) ] 2  P 0 ( 0 , f ) )  Ei  ( - [ σ ( f ) ] 2 [ l 0 ( 0 , f ) ] 2  P 0 ( 0 , f ) ) ,   f = F 1 , F 2 , F 3 ( 13 ) Hence, the total ergodic capacity of the system can be obtained by adding the capacity of the individual carriers, Ctotal=C(F1)+C(F2)+C(F3H) (14) where, for DAS-SFR at the central cell, C(F1): MISO, C(F2): SISO, C(F3): SISO for DAS-HFR3 (frequency reuse factor 3) at the central cell, C(F1): MISO, C(F2): nothing, C(F3): nothing for DAS-FFR at the central cell. C(F1): MISO, C(F2): MISO, C(F3): MISO In the following section, we present the analytical and numerical results using a simulation to corroborate the theoretical analysis. IV. Formulation of Power Allocation In this section, we formulate the power allocation problem to maximize the number of satisfied users and also maximize the total satisfied users capacity. For the problem formulation we consider a service area with nineteen cells shown in FIG. 2. In a multiusers scenario, we can directly map the ergodic capacity of each user to what we obtained in section III depending on the position and the power. Therefore, having a number of f resource blocks assigned to user k(NkRB(f)), the real throughput at user k can be written in terms of bps (bit per second) as follow, C k real  ( P ) = W RB  ∑ i = 1 3  N k RB  ( F i ) · C k ( F i )  ( P ) ( 15 ) where, WRB is the resource block bandwidth. Ck(F1) (P) is the ergodic capacity of user k where P={Pn(i,f)|n=0,1, . . . , 6, i=0, 1, . . . , 18, f=1, 2, 3}. We consider the following key performance indicators (KPIs) in the power allocation system: 1. KPISU (Number of Satisfied Users): We can derive a metric defining a percent of satisfied users (i.e., users that can achieve the targeted service bit rate, for example, 1 Mbits/s). The percent of satisfied users (out of m users) would be, KPI SU  ( P ) = ∑ k = 1 m  G k  ( P ) N user total ( 16 ) where Nusertotal is total number of users and G k  ( P ) = { 1 when   C k real  ( P ) > C th 0 otherwise Using these equations, Cth is a threshold capacity (targeted service bit rate) and Gk(P) is unity when the capacity for a user (indexed by k) exceeds the threshold capacity and is equal to zero when the capacity is less than or equal to the threshold capacity. 2. KPICSU (Capacity of Satisfied Users): The total capacity of satisfied users would be, KPI CSU  ( P ) = ∑ k ∈ SUS  C k real  ( P ) ( W ( F 1 ) + W ( F 2 ) + W ( F 3 ) ) / 3 ( 17 ) where Wf is the bandwidth of frequency band f and SUS={k|Gk=1, k=1,2, . . . , m} is the satisfied users set. If more than three carriers are utilized in a cell, the number of carriers and the divisor in the denominator will increase as appropriate. Now, our QoS function is the weighted combination of the two KPIs (cost factors) which we have already introduced. Obviously our objective function is to maximize the QoS function. Maximize P   QoS  ( P ) = w 1 · KPI SU  ( P ) + w 2 · KPI CSU  ( P ) ( 18 ) We can further simplify the objective functions in Eq. 18 based on the following arguments: Use round robin scheduling and equal bandwidth frequency for all frequency bands, therefore, we can rewrite the real capacity in Eq. 15.as, C k real  ( P ) = W RB  ∑ i = 1 3  N k RB  ( F i ) · C k ( F i )  ( P )   Round   Robin  W RB  ∑ i = 1 3  N RB ( F i ) N user ( F i )  C k ( F i )  ( P )   W RB  N RB ( F i ) = W ( F i )  ∑ i = 1 3  W ( F i ) N user ( F i )   C k ( F i )  ( P )   W ( F 1 ) = W ( F 2 ) = W ( F 3 ) = W F  W F ∑ i = 1 3  C k ( F i )  ( P ) N user ( F i ) ( 19 ) Where Nuser(f) is the number of users which can be supported by frequency band f. Since it is not practical to calculate the ergodic capacity for the individual users, the aforementioned simplification is valid for the theoretical analysis and cannot be extended to practical applications. However, in practice, the number of the satisfied users and therefore the KPIs, are found based on the real users' throughput (Ckread(P)) the power allocation procedure. Note that, the optimization problem variable (P) is 171=19×19, where the first term in the product is due to the fact that we have 19 cells, and the second term is because each cell of DAS-SFR has 9 changeable user frequency band powers. These 9 changeable user frequency band powers are comprised of 6 frequency band powers for the edge DRUs and 3 frequency band powers for central DRUs. We decrease the optimization problem variable from 171 to 1 in such a way that only the central DRU's frequency bands power, which are not assigned to the edge DRUs, are perturbed. The central DRU's F2 and F3 power, which are not assigned to the edge DRUs, are perturbed for the central cell (eNB0) in a DAS-SFR configuration. So the optimization problem is simplified to, Maximixe Δ   P   QoS  ( Δ   P ) = w 1 · KPI SU  ( Δ   P ) + w 2 · KPI CSU  ( Δ   P ) ( 20 ) where in DAS-SFR, Δ   P  ( dB ) = P ′  ( dBm ) - P  ( dBm ) P n ( i , f ) = { P when ( n = 0 , 1 , …  , 6 and i = 0 , 8 , 10 , 12 , 14 , 16 , 18 and   f = F 1 )   or ( n = 0 , 1 , …  , 6 and i = 1 , 3 , 5 , 9 , 13 , 17 and   f = F 2 )   or ( n = 0 , 1 , …  , 6 and i = 2 , 4 , 6 , 7 , 11 , 15 and   f = F 3 ) , P ′ when ( n = 0 and i = 1 , 2 , …  , 7 , 9 , 11 , 13 , 15 , 17 and   f = F 1 )   or ( n = 0 and i = 0 , 2 , 4 , 6 , 7 , 8 , 10 , 11 , 12 , 14 , 15 , 16 , 18 and   f = F 2 )   or ( n = 0 and i = 0 , 1 , 3 , 5 , 8 , 9 , 10 , 12 , 13 , 14 , 16 , 17 , 18 and   f = F 3 ) , 0 otherwise   KPI SU  ( Δ   P ) = ∑ k = 1 m  G k  ( Δ   P ) N user total   where   G k  ( Δ   P ) = { 1 when   ∑ i = 1 3  C k ( F i )  ( Δ   P ) N user ( F i ) > C th W F 0 otherwise ,  KPI CSU  ( Δ   P ) = ∑ k ∈ SUS  ∑ i = 1 3  C k ( F i )  ( Δ   P ) N user ( F i ) In our analysis, we assume that P is fixed and only P′ changes in magnitude. In multiuser systems, we need to consider the different resource allocation scenarios which were defined in section II. B In LTE systems, eNB distinguishes between the interior and the exterior users based on their corresponding uplink power received at the central DRU. Particularly in DAS-SFR, since none of the DRUs except the central DRU operates in F2and F3, it is possible to apply the above-mentioned method (distinguishing between the interior and the exterior users) using the received CQIs (Channel Quality Indicator) from F2 andF3. To implement these techniques, we propose a threshold Tp as a parameter in the eNB such that users with uplink power higher than Tp are assigned as interior users, and vice versa. In a DAS-SFR, Tp can play the same role as a threshold for CQI such that users with CQI higher than Tp are assigned as interior users, and vice versa. A. The Power Self-Optimization Algorithm According to the above intuitive analysis, we propose a power self-optimization (PSO) technique which is based on a simple and decentralized algorithm that runs on the application layer. In the PSO algorithm, the expected network gain, which is based on one or both system KPIs, is used in order to determine whether to increase or decrease the transmission power of the central DRUs. To do so, the PSO technique uses the KPI associated with each eNB to compute the system KPI. Finally, the central DRUs are in charge of adjusting ΔP based on system KPI by performing the PSO algorithm. FIG. 4 depicts the block diagram of the self-optimization algorithm. As illustrated in FIG. 4, both KPIs are functions of ΔP. Observing the block diagram shown in FIG. 4, it is possible to note that the transmission power is adjusted by comparing the current KPI, calculated at the end of current phase, and the last KPI, calculated at the end of last phase. Moreover, it is important to highlight that the central DRUs have a predefined minimum and maximum transmission power (pmin and pmax), which cannot be exceeded by the algorithm. Thus, the self-optimization algorithm increases or decreases the ΔP step-by-step by p(dB) for each central DRUs. Parameter t can take two values, 1 and −1, where 1 shows that algorithm starts by increasing the power level. Conversely, −1 indicates that the algorithm starts by decreasing the power level. Since we do not want the power to oscillate around the optimal power forever, we define the parameter c to help the algorithm stop. Whenever the algorithm starts off by increasing the power level, the central DRUs increase the ΔP by the fixed parameter p. The central DRU keep increasing the power by the fixed parameters p as long as the current calculated KPISU is greater than the last calculated KPISU. If the current calculated KPISU is equal to last calculated KPISU, the central DRUs keep increasing the power as long as the current calculated KPICSU is not smaller than the last calculated KPICSU , otherwise it decreases its power level. Note that whenever the algorithm starts off by increasing the power level, all the above mentioned statements should be reversed i.e. the decreasing behavior should be changed to an increasing behavior and vice versa. The PSO algorithm seeks to maximize the number of satisfied users meanwhile it seeks to maximize the capacity of the satisfied users in order to have a better QoS. Even though some embodiments do not achieve an optimal solution, the methods described herein provide stable power updates toward the optimal solution. In other embodiments, the optimal solution is obtained. Referring to FIG. 4, KPISU is the Key Performance Indicator for Satisfied Users and KPICSU is the key performance indicator for the Capacity of Satisfied Users. ΔP is the change in power of the carriers. By adjusting the power of the carriers, the number of satisfied users and the capacity of the satisfied users can be increased or optimized. Initially, t is set to 1, c is set to zero, ΔP=0, and p=1 (i.e., the power increments are made in 1 dBm steps). In the illustrated embodiment, the maximum and minimum values of power (measured in dBm in an embodiment) are 20 and −10, respectively. In some implementations, the maximum and minimum power are set by the user and the values provided herein are merely given by way of example. Thus, depending on the system parameters, different values will be utilized for the maximum and minimum power. One of ordinary skill in the art would recognize many variations, modifications, and alternatives. A measurement of the KPISU given ΔP (initially zero, for which the power of the various carriers is equal) is made and the result is assigned to KPI*SU. Thus, the performance for the users in a given cell is measured to determine the number of satisfied users in the cell. The capacity for the satisfied users is also measured at this value of ΔP (KPICSU given ΔP) and assigned to KPI*CSU. The difference in power is then modified (ΔP+(t*p)) in order to iterate on the difference in power. t is an updating index that has values of positive or negative one, indicating if the difference in power is being increased or decreased. Referring to FIG. 4, movement through the left hand side of the loop results in increases in power and movement through the right hand side of the loop results in decreases in power. In order to determine if the power is in the correct range, a comparison is made between ΔP and the maximum power (ΔP>pmax), between ΔP and the minimum power (ΔP<pmin), and that an oscillation indicator (c) is not reached. If any of these conditions are true, then the method is terminated. Otherwise, if the power is within the predetermined range (less than maximum power and greater than the minimum power) and oscillation has not been detected, the method continues. A measurement is made of the number of satisfied users given the new ΔP (KPISU(ΔP)) and this measured value is compared to the previous number of satisfied users. If the change in power (an increase in this example) has resulted in a decrease in the number of satisfied users, then the right hand loop is used to toggle the updating index (t), which will enable the power to be decreased in the subsequent flow. If, on the other hand, the number of satisfied users given the new ΔP is greater than or equal to the previous number of satisfied users, indicating no change or an increase in the number of satisfied users, the method proceeds to the next comparison to determine if the number of satisfied users given the new ΔP is equal to the previous number of satisfied users. If the comparison is not equal, then the left hand side of the loop is used to increase the power differential in the subsequent flow. If the number of satisfied users given the new ΔP is equal to the previous number of satisfied users, then a measurement is made of the capacity of the satisfied users and this value is compared to the previous capacity. If the measured capacity is less than the previous capacity, the right hand side of the loop is used to decrease the power differential in the subsequent flow. If the measured capacity is greater than or equal to the previous capacity, then the left hand side of the loop is used to increase the power differential in the subsequent flow. Referring to FIG. 1, the method illustrated in FIG. 4 will be applied in relation to the carriers used in the central antenna (eNB0) of the cell (i.e., hexagon). For each cell, the carrier used in the peripheral portions of the cell will be used as a reference and the other carriers will have their power set by optimizing the number and capacity of satisfied users using the algorithm described herein. In some embodiments, the carriers used in the central antenna that are not used in the peripheral portions of the cell will have the same power, providing a single ΔP for the central antenna with the carrier used in the peripheral portions of the cell providing the reference. In some implementations, the carriers used only in the central antenna can have differing powers with the algorithm applied to the carriers individually (e.g., F1 compared to F3 and F2 compared to F3 for the rightmost cell in FIG. 1A). Referring to FIG. 1A, F1 is the reference for the top left cell, F2 is the reference for the bottom left cell, and F3 is the reference for the rightmost cell. One of ordinary skill in the art would recognize many variations, modifications, and alternatives. Embodiments of the present invention provide methods and systems in which the number of carriers in a cell can be increased, thereby increasing bandwidth. The algorithm is then used to set the power level of the added carriers to a level that reduced interference with adjacent cells to an acceptable level. It should be appreciated that the specific steps illustrated in FIG. 4 provide a particular method of increasing a number and capacity of satisfied users by varying power between carriers according to an embodiment of the present invention. Other sequences of steps may also be performed according to alternative embodiments. For example, alternative embodiments of the present invention may perform the steps outlined above in a different order. Moreover, the individual steps illustrated in FIG. 4 may include multiple sub-steps that may be performed in various sequences as appropriate to the individual step. Furthermore, additional steps may be added or removed depending on the particular applications. One of ordinary skill in the art would recognize many variations, modifications, and alternatives. V. Analytical and Simulation Results FIGS. 5A-5B represent the ergodic capacity of a cellular DAS's central cell for different frequency reuse techniques versus the normalized distance from the eNB0 DRU0 in the direction of the worst case position X, for a path loss exponent of 3.76. Each scenario is plotted for the individual capacities C(F1), C(F2), C(F3) and also for the total capacity Ctotal. These figures show an interesting non-monotonic relationship between capacity and the normalized distance from the base station. This is due to the fact that the signal from a distributed antenna module becomes dominant around 0.6R. As it can be observed in FIG. 5A, when applying the SFR methods, by increasing ΔP from −10 dB to 20 dB, the central cell's C(F2) and C(F3) increase. This, however, increases the interference associated with the edge DAUs of the neighboring cells which are using F2 and F3 as their main frequency band. It is necessary to note that, increasing ΔP from −10 dB to 20 dB, significantly increases the associated interference with the F1 frequency band in the central cell, imposed from the neighboring cells, and thus decreases the central cell's C(F1). It is important to notice that, considering SFR methods, as power increases, Ctotal does not change harmonically, which means the ergodic capacity associated with the cell's interior regions increases, and that of the cell's exterior regions decreases. Therefore, the users' distribution within the cell's area plays a significant role when deciding the optimal ΔP. A secondary consideration when deciding the optimal ΔP is the minimum required capacity (Cth). As an example, with a high Cth (ergodic capacity=20 bit/Hz in FIGS. 5A and 5B), as ΔP increases, a wider radiance in a cell will be covered by ergodic capacity higher than 20. With a low Cth (ergodic capacity=3 bit/Hz in FIGS. 5A and 5B), as ΔP increases, a shorter radiance in the cells will be covered by ergodic capacity higher than 3. The FFR method fully uses the frequency bands, therefore, the cell's interior regions' achieved an ergodic capacity higher than ergodic capacity in the cell's interior regions when applying the HFR3 method. For example, at ergodic capacity=20, the FFR method outperforms the HFR3 method, considering the users' satisfaction probability. However, when applying the FFR method, due to the interference caused by the neighboring cells, the edge cells frequently experience dead spots. As an example, considering the users' satisfaction probability, for ergodic capacity=3, the HFR3 method outperforms the FFR method. FIGS. 6A-D and 7A-7D demonstrate the two KPISU and KPICSU for different ΔP, considering four different user distributions. The only parameter that is different in the aforementioned figures is their Cth, i.e. we consider low Cth=0.01 WRB and high Cth=0.07 WRB, in FIGS. 6A-6D and FIGS. 7A-7D, respectively. In theoretical analysis, the interior region is distinguished from the exterior region, based on Tp. In other words, the region with ergodic capacity higher than Tp is considered as interior region, and the region with ergodic capacity lower than Tp is considered as exterior region. This Tp is associated to the region's ergodic capacity of the frequency bands that are only allocated to the central DRUs. We assume Tp=2 (bit/Hz) in our theoretical analyses. Since both KPI functions are dependent on Gk, it is reasonable to consider each of these functions as a criteria to measure the QoS. We analyze two different cases, i.e. (w1=1, w2=0) and (w1=0, w2=1). In the first case, we presume KPISU as our QoS function whereas in the second case we consider KPICSU as our QoS function. We define our user distributions as depicted in Table 1. where N user total = ∑ i  X i  S i , i ∈ { region   A , region   B , region   C , region   D } , Si is the area of region i and Xi=(# users of region i)/Si. We perform Monte Carlo simulations to corroborate the analytical results. It is assumed that the total number of users (Nusertotal) is 200. As it is seen in FIGS. 6A-6D, when Cth takes a low value, i.e. Cth=0.01 WRB, except for the FFR method, applying the rest of the frequency reuse methods (HFR3, SFR) results in the highest number of the satisfied users (KPISU). Note that, as ΔP increases, when applying DAS-SFR, the number of the satisfied users asymptotically decreases. The above mentioned results hold for all four different user distributions: FIG. 6A: User's Distribution=Uniformity; FIG. 6B: User's Distribution=Dense at the Center; FIG. 6C: User's Distribution=Dense at the middle of Center and Edge Cell; and FIG. 6D: User's Distribution=Dense at the Edge Cell. As was shown in FIGS. 6A-6D, there exists an optimal ΔP at which the KPICSU is maximum, for all four different distributions. For instance, when applying the DAS-SFR-Scenario3 method, for the UD, DCD, DCED and DED, the maximum KPICSU happens at ΔP==−5 dB, 2 dB, 8 dB, and −4 dB, respectively. One has to consider, the optimal ΔP is different for dissimilar distribution scenarios. Moreover, the DAS-SFR-Scenario3 method outperforms the other two DAS-SFR methods, for all the distributions under consideration. FIGS. 7A-7D reveal that, when Cth takes a large value, i.e. Cth=0.07 WRB, the FFR method outperforms the HFR3 method, considering the number of the satisfied users (KPISU). This corroborates our analytical results from FIGS. 5A-5B, as it was explained previously. However, the DAS-SFR-Scenario2 method outperforms all the other methods, at different optimal ΔP values for dissimilar distribution scenarios. As it can be perceived from FIGS. 7A-7D, there exists an optimal ΔP at which the KPISU and KPICSU are maximum, for all four different distributions: FIG. 7A: User's Distribution=Uniformity; FIG. 7B: User's Distribution=Dense at the Center; FIG. 7C: User's Distribution=Dense at the middle of Center and Edge Cell; and FIG. 7D: User's Distribution=Dense at the Edge Cell. As an example, when applying the DAS-SFR-Scenario2 method, for the UD, DCD, DCED and DED, the maximum KPISU and KPICSU happen at ΔP=6 dB, 4 dB, −2 dB, and 13 dB, respectively. Note that, the optimal ΔP is different for different distribution scenarios. Moreover, the DAS-SFR-Scenario2 method outperforms the other two SFR methods, for all distributions under consideration. Since the DAS-SFR-Scenario2 uses all the frequency bands in the interior cell region, along with the fact that the users with throughput above the Cth are mainly located in the interior cell region, leads to the final conclusion that DAS-SFR-Scenario2 outperforms the other methods. The capacity of the above mentioned architectures is also investigated through system level simulations. We consider the two-ring hexagonal cellular system with nineteen eNBs, such that each cell has 7 DRUs, as depicted in FIG. 2, where the eNBs distance is 500 meters. The 200 UEs are distributed for 4 user distribution methods which are defined in Table 1. An eNB allocates the available RBs to UEs by estimating the signaling and uplink power of UEs. We use the simulation parameters listed in Table 2. At a TTI (Transmission Time Interval) for the simulation, the eNB in a cell gathers the CQI (Channel Quality Indicator) information of UEs and allocates the RBs to each UE, using the Round Robin scheduling technique. The throughput of a UE is obtained based on the SINR of the UE in the assigned RB. In system level simulation, SINR is determined by the path loss and lognormal fading measured in RB. The throughput of a UEm is estimated using the Shannon capacity as follows Cm(F)=WRB(f) log (1+SINRm(f)), f=F1, F2, F3 (21) where, WRB(f) is the bandwidth of RBs assigned to a UE and SINRm(f) is the SINR of a UEm. The cell capacity in each region is the total throughput of UEs in the corresponding region and is expressed as follows C total = ∑ i = 1 3  ∑ m = 1 M  C m ( F i ) ( 22 ) Where M is the number of UEs in a group. The presented numerical results corroborate the analytical results depicted in FIG. 6 and FIG. 7. Embodiments of the present invention provide a new cell architecture combining two inter-cell interference mitigation techniques, Distributed Antenna System and Soft Frequency Reuse, to improve cell edge user's throughput when the system has full spectral efficiency. A power self-optimization algorithm that aims at maximizing the number of satisfied users while trying to increase their capacity was also proposed. In more detail, the self-optimization algorithm uses the KPIs computed by the server in the last phase and current phase to adjust the power level for the next phase. An analytical framework is derived to evaluate the user throughput leading to tractable expressions. A natural extension of this work is to address the cellular uplink. The overall capacity increases by using the SFR technique, since the spectral efficiency in the interior region is higher than that in the exterior region when compared to HFR3 technique. The cell edge user's throughput increases by using the SFR technique; since the interference signal from neighbor cells is lower than that the time we use FFR technique. Analytical and simulation results demonstrated the advantage of using the self-optimization algorithm instead of setting a fixed power level. When a DAS-SFR without the PSO algorithm is considered, the transmission power is set at the beginning of the communication and remains the same during its entire network lifetime. This characteristic can be negative considering a DAS-SFR in a real environment where the inherent user distribution is not constant. Due to the fact that the inherent environment user distribution is completely variable, the PSO algorithm always guarantees the maximum number of satisfied users during the communication, while the algorithm serves to maximize their capacity as well. TABLE 2 Simulation Parameters PARAMETERS VALUE Channel Bandwidth for each 5 MHz Frequency Part Carrier Frequency 2.14 GHz FFT size 1024 Number of Resource Blocks 25 for each Frequency Part Subcarrier Spacing 15 kHz Cellular Layout Hexagonal grid, 19 sites Inter-eNB Distance 500 meters Log-normal Shadowing 8 dB Propagation loss 128.1 + 37.6 log10(R(km)) White Noise Power Density −174 dBm/Hz Scheduling Round Robin TTI 1 ms Tp (CQI) 2 CQI
<SOH> SUMMARY OF THE INVENTION <EOH>According to an embodiment of the present invention, a method of determining a carrier power in a communications system including a processor is provided. The method includes a) setting a power differential between a reference carrier and one or more carriers, b) measuring a number of satisfied users at the power differential, and c) measuring a capacity for the satisfied users at the power differential, which may be referred to as an initial power differential. The method also includes d) adjusting the power differential by a predetermined amount and e) determining, using the processor, that the number of satisfied users at the adjusted power differential is greater than or equal to the number of satisfied users at the initial power differential. The method further includes f) repeating a)-e) and g) setting the carrier power at an iterated power level. As described herein, unbalanced traffic distributions inside cellular networks are common occurrences. Embodiments of the present invention provide a throughput-balancing system that optimizes cellular performance according to the geographic traffic distribution in order to provide a high quality of service (QoS). The throughput of an Orthogonal Frequency Division Multiple Access (OFDMA) based architecture (DAS-SFR) that utilizes a combination Soft Frequency Reuse (SFR) technique and a Distributed Antenna System (DAS) is analyzed in light of embodiments of the present invention. A concept employed by this architecture is to distribute the antennas in a hexagonal cell in such a way that the central antenna is responsible for serving a special area, using all of the frequency bands, while the remaining antennas utilize only a subset of the frequency bands based on a frequency reuse factor. A DAS-SFR has the ability to distribute the cellular capacity (throughput) over a given geographic area. To enable throughput balancing among Distributed Antennas (DAs), embodiments of the present invention dynamically change the DA's carrier power to manage the inter-cell interference, as a function of the time-varying traffic. A Downlink Power Self-Optimization (PSO) algorithm, for three different resource allocation scenarios, is described for the DAS-SFR system. The transmit powers are optimized in order to maximize the spectral efficiency of a DAS-SFR and maximize the number of satisfied users under different user distributions in some embodiments. The PSO algorithm is able to guarantee a high Quality of Service (QoS) that concentrates on the number of satisfied users as well as the capacity of satisfied users as the two Key Performance Indicators (KPIs). Analytical derivations and simulations are discussed and used to evaluate the system performance for different traffic scenarios, and the results are presented. Embodiments of the present invention provide a method and system for adjusting and potentially optimizing the powers of multiple carriers in a DAS-SFR system. By adjusting the power associated with the carriers provided by the central antenna of each cell, the SFR system enables higher system performance and an improved user experience as a result of higher system bandwidth. Numerous benefits are achieved by way of the present invention over conventional techniques. For instance, embodiments of the present invention control the amount of resources allocated to users located in different areas, thereby increasing the frequency efficiency and also improving the data rate for cell edge users. As another example, embodiments of the present invention are useful in adjusting the powers of carriers to increase or maximize Key Performance Indicators, which are related to Quality of Service. These and other embodiments of the invention along with many of its advantages and features are described in more detail in conjunction with the text below and attached figures.
H04W52243
20170814
20180329
98936.0
H04W5224
1
KAMARA, MOHAMED A
SELF-OPTIMIZING DISTRIBUTED ANTENNA SYSTEM USING SOFT FREQUENCY REUSE
SMALL
1
CONT-ACCEPTED
H04W
2,017
15,676,976
PENDING
BODY LIMB PROTECTION SYSTEM
A body limb protection system includes an outer layer, an inner layer, and a force dampening and defusing structure. The outer layer includes a first material composition and has an exterior surface that includes a substantially planer area. The inner layer includes a second material composition and has a shape corresponding to a body limb portion. The force dampening and defusing structure is positioned between the inner layer and the outer layer. The force dampening and defusing structure has a shape corresponding to a difference between the shapes of the inner and outer layers. The force dampening and defusing structure includes a plurality of components arranged to reduce pressure on the body limb portion when a force is applied to the substantially planer area.
1. A body limb protection system comprises: an outer layer including a first material composition and having an exterior surface that includes a substantially planer area; an inner layer including a second material composition and having a shape corresponding to a body limb portion, wherein the inner layer is adjacent to the body limb portion when the body limb protection system is worn; and a force dampening and defusing structure positioned between the inner layer and the outer layer, wherein the force dampening and defusing structure has a shape corresponding to a difference between the shapes of the inner and outer layers, wherein the force dampening and defusing structure includes a plurality of components arranged to reduce pressure on the body limb portion when a force is applied to the substantially planer area by reducing a body part impact force resulting from the force and by increasing a body part impact area with respect to a body limb protection system impact area receiving the force. 2. The body limb protection system of claim 1 further comprises: the second material composition being substantially equal to the material composition. 3. The body limb protection system of claim 1, wherein the second material composition comprises one or more of: a rubber material; a foam material; a padding material; a plastic material; a gel material; a carbon fiber material; a cloth material; a polyester material; a moisture absorbing material; a moisture wicking material; and a silicon material. 4. The body limb protection system of claim 1 further comprises: the plurality of components of the force dampening and defusing structure is arranged to create a collision angle between the force and the body limb portion thereby dividing the force into a normal force component and a tangential force component. 5. The body limb protection system of claim 1, wherein the force dampening and defusing structure comprises: a first layer of a first set of components of the plurality of components arranged in a first pattern; a second layer of a second set of components of the plurality of components arranged in a second pattern that is complimentary to the first pattern with respect to reducing pressure on the body limb portion; and an intermediate layer between the first and second layers of the first and second sets of components, wherein the intermediate layer includes a third material composition. 6. The body limb protection system of claim 5, wherein the force dampening and defusing structure further comprises: a third layer of a third set of components of the plurality of components arranged in a third pattern that is complimentary to the second pattern with respect to reducing pressure on the body limb portion; and a second intermediate layer between the second and third layers of the second and third sets of components. 7. The body impact protection system of claim 1, wherein a component of the plurality of components comprises: a three-dimensional geometric shape including an impact receiving surface area and a body impact surface area, wherein the body impact surface area is larger than, and a distance “d” from, the impact receiving surface area to facilitate increasing the body part impact area with respect to the body impact protection system impact area receiving the impact force. 8. The body limb protection system of claim 1 further comprises: a first component of the plurality of components; a second component of the plurality of components; and a third component of the plurality of components, wherein the first component is positioned to receive at least a portion of the impact force, wherein the second and third components are positioned at an angle with respect to the first component such that, when the first component receives the at least the portion of the impact force, the first component collides with the second and third components to produce a plurality of multi-dimensional collisions. 9. The body limb protection system of claim 1, wherein the outer layer further comprises: a concave area that at least partially encompassing the substantially planer area. 10. The body limb protection system of claim 1, wherein the plurality of components further comprises: a first perimeter group of components having a first length corresponding to a first difference between the inner layer and a perimeter of the substantially planer area; and a second perimeter group of components having a second length corresponding to a second difference between the inner layer and a next inner perimeter of the substantially planer area. 11. The body limb protection system of claim 1, wherein the body limb portion comprises one or more of: a knee; a shin; an elbow; an ankle; a forearm; an upper arm; a thigh; and a calf. 12. A body limb protection system comprises: an outer layer including a first material composition and having an exterior surface that includes a substantially planer area; an inner layer including a second material composition and having a shape corresponding to a body limb portion, wherein the inner layer is adjacent to the body limb portion when the body limb protection system is worn; and a force dampening and defusing structure positioned between the inner layer and the outer layer, wherein the force dampening and defusing structure includes a plurality of layers of components arranged to reduce pressure on the body limb portion when a force is applied to the substantially planer area by reducing a body part impact force resulting from the force and by increasing a body part impact area with respect to a body limb protection system impact area receiving the force, wherein the plurality of layers of components includes: a first layer of components; a second layer of components; and a third partial layer of components, wherein the first layer of components is positioned closest to the substantially planer area, the second layer of components is juxtaposed to the first layer of components, and the third partial layer of components is closest to the inner layer and substantially accommodates a difference between the shapes of the inner and outer layers. 13. The body limb protection system of claim 12 further comprises: the plurality of components of the force dampening and defusing structure is arranged to create a collision angle between the force and the body limb portion thereby dividing the force into a plurality of normal force components and a plurality of tangential force components. 14. The body impact protection system of claim 12, wherein a component of the plurality of components comprises: a three-dimensional geometric shape including an impact receiving surface area and a body impact surface area, wherein the body impact surface area is larger than, and a distance “d” from, the impact receiving surface area to facilitate increasing the body part impact area with respect to the body impact protection system impact area receiving the impact force. 15. The body limb protection system of claim 12 further comprises: a first component of the plurality of components; a second component of the plurality of components; and a third component of the plurality of components, wherein the first component is positioned to receive at least a portion of the impact force, wherein the second and third components are positioned at an angle with respect to the first component such that, when the first component receives the at least the portion of the impact force, the first component collides with the second and third components to produce a plurality of multi-dimensional collisions. 16. The body limb protection system of claim 12, wherein the outer layer further comprises: a concave area that at least partially encompassing the substantially planer area.
CROSS REFERENCE TO RELATED PATENTS The present U.S. Utility Patent Application claims priority pursuant to 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62/375,767, entitled “BODY IMPACT PROTECTION SYSTEM”, filed Aug. 16, 2016, which is hereby incorporated herein by reference in its entirety and made part of the present U.S. Utility Patent Application for all purposes. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT—NOT APPLICABLE INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISC—NOT APPLICABLE BACKGROUND OF THE INVENTION Technical Field of the Invention This invention relates generally to impact protection and more particularly to a protection system that reduces impact pressure resulting from an impact force. Description of Related Art Impact protection devices are known to reduce injury to a body part as a result of an impact. Most impact protecting devices include an outer shell and padding to protect the body part, which may be a limb, a joint, a portion of a limb, the back, ribs, the chest, the abdomen, the neck, and/or the head. For example, the impact protecting device is a helmet when the body part is a head. For most helmets, the outer shell is a rigid material such as plastic, polycarbonate, etc. and the padding includes foam, air bladders, or a combination thereof. Vicis™ makes a football helmet that includes a softer outer shell, a 1½ inch thick core layer, and a foam based form liner. As is generally accepted in the medical community, a concussion results from a sudden acceleration or deceleration of the head. Such rapid acceleration and declaration of the head can result from a car cash or violent shaking. This medical premise forms the basis for which helmets are tested. The testing of football helmets and other helmets involves dropping a headform wearing the helmet from various heights on to a platform and measuring g-forces from the impact. Thus, helmets are designed to pass g-force based testing. G-force, however, is not a measure of force. It is a measure of acceleration or deceleration with respect to earth's gravitational field. Thus, for an impact, G-force is a measure of how fast the object decelerations with respect to the earth's gravity. In equation for, G-Force=a/g, where “g” is gravitational force of 32.2 ft/s2 and “a” is the deceleration of the object from impact, where a=v2/2*d, where “v” is the velocity at impact and “d” is the impact distance. With G-force being the unit of measure for testing helmets, the only variable in reducing G-Force is impact distance “d”. Thus, increasing impact distance is the only way to improve G-force based testing result of helmets. Accordingly, helmets are designed to increase impact distance. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S) FIG. 1 is a schematic diagram of an example of a conventional impact protection device receiving an impact force; FIG. 2 is a diagram of an example graph of the impact protection device of FIG. 1 that plots impact force versus impact area; FIG. 3 is a schematic block diagram, in a side view, of an embodiment of a body impact protection system in accordance with the present invention; FIG. 4 is a schematic block diagram, in a side view, of an embodiment of a defusing cell (i.e., component) of a layer of a body impact protection system in accordance with the present invention; FIG. 5 is a schematic block diagram, in a side view, of an example of force dampening and diffusion by a defusing cell (i.e., component) of a layer of a body impact protection system in accordance with the present invention; FIG. 6 is a schematic block diagram, in a top view, of an embodiment of a body impact protection system in accordance with the present invention; FIG. 7 is a schematic block diagram, in a side view, of another embodiment of a body impact protection system in accordance with the present invention; FIG. 8 is a schematic block diagram, in a side view, of an example of force components within a body impact protection system in accordance with the present invention; FIG. 9 is a schematic block diagram, in a side view, of another example of force components within a body impact protection system in accordance with the present invention; FIG. 10 is a graph of an example of impact force components v. body impact area of a body impact protection system in accordance with the present invention; FIG. 11 is a schematic block diagram, in a side view, of another embodiment of a body impact protection system in accordance with the present invention; FIG. 12 is a schematic block diagram, in a top view, of another embodiment of a body impact protection system in accordance with the present invention; FIG. 13 is a schematic block diagram, in a side view, of another example of force components within a body impact protection system in accordance with the present invention; FIGS. 14A-14B are a schematic block diagram of an example of force defusing and distribution layer by layer within a body impact protection system in accordance with the present invention; FIG. 15 is a schematic block diagram, in a side view, of another embodiment of a body impact protection system in accordance with the present invention; FIG. 16A is a graph of an example of an impact force pulse v. time; FIG. 16B is a graph of an examples of frequency responses of different layers of a body impact protection system having different resonant frequencies in accordance with the present invention; FIGS. 17A-17E are a schematic block diagram of an example of force defusing and distribution layer by layer within a body impact protection system in accordance with the present invention; FIG. 18 is a schematic block diagram, in a side view, of another embodiment of a body impact protection system in accordance with the present invention; FIG. 19 is a schematic block diagram, in a side view, of another embodiment of a defusing cell of a layer of a body impact protection system in accordance with the present invention; FIG. 20 is a schematic block diagram, in a side view, of another embodiment of a defusing cell of a layer of a body impact protection system in accordance with the present invention; FIGS. 21A-21F are a schematic block diagrams, in a top view, of other embodiments of a defusing cell of a layer of a body impact protection system in accordance with the present invention; FIGS. 21G-21J-2 are diagrams of another defusing cell or component in accordance with the present invention; FIGS. 21K-21N are diagrams of another defusing cell or component in accordance with the present invention; FIGS. 210 and 21Q-21S-2 are diagrams of another defusing cell or component in accordance with the present invention; FIG. 21T is a top and side view of a layer of components in accordance with the present invention; FIGS. 21U-21V are diagrams of another defusing cell or component in accordance with the present invention; FIGS. 21W-21X are diagrams of another defusing cell or component in accordance with the present invention; FIG. 21Y is a side view of a layer of components in accordance with the present invention; FIGS. 21Z-21AB are diagrams of another defusing cell or component in accordance with the present invention; FIG. 21AC is a top view of a layer of components in accordance with the present invention; FIG. 21AD is a top view of a layer of components in accordance with the present invention; FIG. 21AE is a top view of a layer of components in accordance with the present invention; FIG. 21AF is a top view of two overlapping layers of components in accordance with the present invention; FIG. 22 is a schematic block diagram, in a side view, of another embodiment of a layer of a body impact protection system in accordance with the present invention; FIG. 23A is a schematic block diagram, in a cross section front view, of an embodiment of a helmet at the instant of an impact. FIG. 23B is a schematic block diagram, in a cross section front view, of an embodiment of a helmet at compression of the padding as result of an impact. FIG. 23C is a schematic block diagram, in a cross section front view, of an embodiment of a helmet at movement of the brain within the skull as result of an impact. FIG. 23D is a schematic block diagram, in a side view, of an embodiment of a helmet that includes a body impact protection system in accordance with the present invention; FIG. 23E is a schematic block diagram, in a side view, of a portion of an embodiment of a helmet that includes a body impact protection system in accordance with the present invention; FIG. 23F is a schematic block diagram, in a side view, of a portion of an embodiment of a helmet that includes a body impact protection system receiving an angular impact force in accordance with the present invention; FIG. 23G is a schematic block diagram, in a side view, of a portion of an embodiment of a helmet that includes a body impact protection system dampening and defusing an angular impact force in accordance with the present invention; FIG. 24A is a schematic block diagram, in a side view, of an embodiment of a chest protector that includes a body impact protection system in accordance with the present invention; FIG. 24B is a schematic block diagram, in a side view, of an embodiment of a chest protector that includes a body impact protection system in accordance with the present invention; FIG. 25 is a schematic block diagram, in a side view, of an embodiment of a knee protection apparatus that includes a body impact protection system in accordance with the present invention; FIG. 26 is a schematic block diagram, in a side view, of another embodiment of a knee protection apparatus that includes a body impact protection system in accordance with the present invention; FIG. 27 is a schematic block diagram, in a side view, of an embodiment of a body impact protection system for use in a knee protection apparatus in accordance with the present invention; FIG. 28 is a schematic block diagram, in a side view, of an embodiment of a body limb protection apparatus that includes a body impact protection system in accordance with the present invention; FIG. 29A is a schematic block diagram, in a side view, of another embodiment of a body impact protection system in accordance with the present invention; FIG. 29B is a schematic block diagram, in a top view, of another embodiment of a body impact protection system in accordance with the present invention; FIG. 30 is a schematic block diagram, in a side view, of an embodiment of a force defusing inert for use in an impact protection system in accordance with the present invention; FIG. 31 is a schematic block diagram, in a side view, of another embodiment of a force defusing inert for use in an impact protection system in accordance with the present invention; FIG. 32 is a schematic block diagram, in a side view, of another embodiment of a force defusing inert for use in an impact protection system in accordance with the present invention; FIG. 33 is a schematic block diagram, in a side view, of another embodiment of a force defusing inert for use in an impact protection system in accordance with the present invention; FIG. 34 is a schematic block diagram, in a side view, of another embodiment of a force defusing layers for use in an impact protection system in accordance with the present invention; FIG. 35 is a schematic block diagram, in a top view, of another embodiment of a force defusing layers for use in an impact protection system in accordance with the present invention; FIG. 36 is a schematic block diagram, in a side view, of another embodiment of a force defusing layers for use in an impact protection system in accordance with the present invention; FIG. 37 is a schematic block diagram, in a side view, of another embodiment of a force defusing layers for use in an impact protection system in accordance with the present invention; FIG. 38 is a schematic block diagram, in a side view, of another embodiment of a force defusing layers for use in an impact protection system in accordance with the present invention; FIG. 39 is a schematic block diagram, in a side view, of another embodiment of a force defusing layers for use in an impact protection system in accordance with the present invention; FIG. 40 is a schematic block diagram, in a side view, of an example of force diffusion via force defusing layers for use in an impact protection system in accordance with the present invention; FIG. 41 is a schematic block diagram, in a side view, of another example of force diffusion via force defusing layers for use in an impact protection system in accordance with the present invention; FIG. 42 is a schematic block diagram, in a side view, of another embodiment of a force defusing layers for use in an impact protection system in accordance with the present invention; FIGS. 43A-43C are schematic block diagrams, in a side view, of examples of impact force dampening and diffusion via force defusing layers of an impact protection system in accordance with the present invention; FIG. 44 is a schematic block diagram, in a top view, of another embodiment of a force defusing layers for use in an impact protection system in accordance with the present invention; and FIG. 45 is a schematic block diagram, in a side view, of another embodiment of a force defusing layers for use in an impact protection system in accordance with the present invention. DETAILED DESCRIPTION OF THE INVENTION FIG. 1 is a schematic diagram of an example of a conventional impact protection device 5, which may be a helmet, receiving an impact force 11. The impact protection device 5 includes an outer surface 7 (e.g., a hard-plastic shell) and padding 9 (e.g., a foam, air bladders, or a combination thereof). For this example, assume that the impact protection device 5 is a conventional football helmet and the impact force 11 is causes by a collision with another football helmet. Given the spherical nature of football helmets, a helmet to helmet collision creates a small impact area (e.g., about the size of a dime). At impact, the impact force 11 creates a surface shock wave response 15 and a normal impact force component 17. The surface shock response 15 is a surface wave at the resonant frequency of the outer surface 7. As a practical example, the impact force 11 creates a wave pattern similar to waves created from a rock being dropped still water. The normal impact force 17 has a magnitude that is similar to that of the impact force 11 and follows a path that corresponds to the outer surface impacted area 13 towards the head (i.e., body part 21). As the normal impact force 17 is traversing this path, it is dampened by the padding. A concentration of the dampened normal impact force is asserted against the head in a primary body part impact area 19. Through conventional padding, the primary body part impact area 19 is approximately the same size as the outer surface impacted area 13. With convention football helmets being tested on G-Force measurements, the effectiveness of the padding dictates the tested effectiveness of the helmet. G-force testing, however, is an incomplete testing metric for determining concussion safety of helmets. To illustrate the incompleteness of G-Force measurements, consider a nine-inch hunting knife with a five-inch blade dropped forty-two inches into modeling clay with the blade down and then with the handle down. The following table shows that the blade down has a G-Force that is about 5 times less than the G-Force with the handle down. Using the G-Force measurements of helmet testing protocols as an indication of injury prevention, the handle down presents significantly more risk and severity of injury than the blade down. Measurement Blade Down Handle Down weight 0.3 lbs 0.3 lbs drop height 42 inches 42 inches impact distance 0.89 inches 0.18 inches velocity 15.01 ft/sec 15.01 ft/sec deceleration 1,519 ft/sec2 7,513 ft/sec2 G-Force 47 G's 221 G's average impact force (lbs) 14 lbs 66 lbs average impact area 0.032 in2 0.866 in2 average impact pressure 442.4 lbs/in2 76.6 lbs/in2 Yet, when mass, impact force, impact area, and impact pressure are taken into account, a much clearer picture of the risk and severity of injury is revealed. From the above table, the blade has a significantly smaller area than the handle. Even though the blade down has a smaller impact force, the blade down has a significantly greater impact pressure (almost 6 to 1)! Note that the impact area of the blade is an average and is significantly smaller at the tip; making the initial impact pressure of the blade even greater (e.g., over 1,000 pounds per square inch). Due to the spherical nature of the head, protective headgear is also spherical. As such, in a helmet-to-helmet impact or helmet-to-ground impact, the helmet surface impact area 13 is about the size of dime to about the size of a silver dollar. Preliminary testing indicates that conventional football helmets do little to expand the impact area from the surface of the helmet to the head. Thus, even if a helmet dampens the impact force by about 97.5%, the impact pressure to the head may still be substantial. For example, assume a 200-pound player traveling at 16 miles per hours collides head first and comes to a complete stop in 1.25 inches. This creates a G-force of 82 g's (which is at the low end of possible concussion range of 100 g's +/−30 g's). Continuing the analysis, this impact creates an external impact force 11 of about 16,400 force-pounds. Assume the padding reduces the impact force by 96% such that the normal impact force reaching the head is about 650 force-pounds. If the primary body impact area 19 is also about the size of a dime (e.g., 0.375 square inches), then the pressure (e.g., force/area) applied to the head is about 1,750 pounds per square inch (PSI)! This creates a very large localized force being applied to a small area of the head that is likely to cause a head injury. FIG. 2 is a diagram of an example graph of the impact protection device of FIG. 1 that plots impact force versus primary body part impact area. In this example, the vertical axis corresponds to impact force that reaches the body part and the horizontal axis represents the surface area of a body part (e.g., head). The dampened normal impact force 17 that reaches the body includes a plurality of impact force components dispersed over an area of the body part creating a force gradient. The force components with the largest magnitudes are concentrated in the primary body part impact area. As the distance from the primary body part impact area increases, the magnitude of the force components rapidly decrease. From this illustration, the impact pressure (i.e., impact force/impacted area) is large. To illustrate further illustrate that G-force is an incomplete measure of concussion safety and that impact pressure is a much more accurate measure, consider that a standing person turns at a velocity of 2.2 feet/second and bumps her head on an edge of a pipe. Assume that the impact distance is 1/16 inch, the impact area of 1/16 in2, and a mass of her head of 11 pounds. From these values the following metrics are obtained: G-Force of 14.4 g's, an average impact force of 158 pounds, and an average impact pressure of 2,560 PSI. While the g-force was very low, the pressure was very large, which caused a severe concussion for which the person missed weeks of work. As such, when impact force components are in a small impact area, the pressure can be very significant, which can cause severe injury. FIG. 3 is a schematic block diagram, in a side view, of an embodiment of a body impact protection system 10 that includes an impact force dampening and defusing structure 14 and an inner layer 12. The inner layer 12 supports components 16 of the impact force dampening and defusing structure 14. The components 16 may be of any size (i.e., height, width, circumference, radius, diameter, perimeter, and/or depth), any shape, and/or any material composition provided the side walls of the components are angled and the outer surface area (i.e., away from the body part 8) is less than the inner surface area (towards the body part 8). With reference to FIG. 4, a component 16, from a side view, includes an angled side wall(s) 71 (e.g., a side structure), an impact receiving surface area 70 (e.g., a top that is away from the body part), a body impact surface area 72 (e.g., a base that is towards the body part), and a distance “d” 74. The distance “d” 74 is the distance between the body impact surface area 72 and the impact receiving area 70 and ranges from 1/32 of an inch to multiple inches, depending on the application of the body impact protection system. The angled side wall(s) 71 that is/are at an angle of θ with respect to the horizontal axis, where the angle is in the range of 25 degrees to 89 degrees. Depending on the angle θ and the distance “d”, the body impact surface area 72 is two or more times larger than the impact receiving surface area 70, where the impact receiving surface area is 1/256 square inches (e.g., 1/16 by 1/16) to tens of square inches depending on the application of the body impact protection system. Various embodiments and examples of the components 16 are described in one or more subsequent figures. The component 16 is constructed (e.g., molded, press-formed, printed, etc.) of a material composition that includes one or more of a rubber material, a foam material, a padding material, a plastic material, a gel material, a carbon fiber material, a cloth material; a polyester material, a moisture absorbing material, a moisture wicking material and a silicon material. A characteristic of the material composition is that the component retains the angle θ within +/−33% and retains the ratio of Ai to Ao to within +/−33%. Distance “d” may decrease while the impact force is being applied, but substantially returns to its pre-impact force value when the impact force is removed. Returning to the discussion of FIG. 3, the inner layer 12 provides a supporting structure for the components 16 and provides some dampening of the impact force 18. The inner layer 12 is comprised of rubber, foam, air bladder, corrugated fiberboard pads, a plastic material, a gel material, a carbon fiber material, a cloth material, a polyester material, a moisture absorbing material, a moisture wicking material, an expanding polystyrene, a polypropylene, a polyethylene, a polyurethane, a rubber, a silicon, and/or a gel. In one example embodiment, the components 16 are adhered to the inner layer 12 by an adhesive, by molding, by three-dimensional printing, and/or other means. In another example embodiment, the inner layer 12 includes receptacles in which the inner surface area of the components is placed with or without an adhesive. In both examples, the components 16 on the same layer move independently from each other as a result of an impact force 18. In an example, the body impact protection system 10 is protecting a body part 8 (e.g., head, a limb, the core, etc.) from an impact force 18 created by an impacting object (e.g., another person's head, elbow, shoulder, etc., from the ground, from a ball, from a projectile, etc.). The impacting object strikes the outer surface area (or portion thereof) of one or more components creating an average impact force 18 over a system impact area 20. The average impact force 18 includes a plurality of impact force components distributed across the system impact area 20. Based on the nature of impact, some of the impact force components will have a magnitude that is greater than the magnitude of the average impact force. For example, in a sphere to sphere impact, the impact force components in the middle of the impact area will have greater magnitudes than impact force components are at the perimeter of the impact area. As another example, in a flat surface to flat surface impact, the impact force components across impact area will have about the same magnitudes. The component(s) 16 receiving the average impact force 18 dampens and defuses it. A component dampens the average impact force 18 based on the angle of the side walls and defuses it based on the difference between the outside surface area and the inside surface area. With reference to FIG. 5, the component dampens the average impact force 18 (F1) based on the sine of the angle θ. For example, of the angle θ is 45 degrees, then the impact force is dampened by sinθ=0.707. As such, the resulting average impact force (F2)=F1*sinθ, which, in the present example, is F2=0.707*F1. Impact pressure is “impact force” divided by impact area. For the outer surface, the impact pressure is F 1/Ao, where Ao is the outer surface area and, for the inner surface, the impact pressure is F2/Ai, where Ai is the inner surface area. Continuing with the example, if Ai is 9 times Ao, then the inner impact pressure is 0.707/9 (7.8%) of the outer impact pressure via just one cell or component. FIG. 6 is a schematic block diagram, in a top view, of an embodiment of a body impact protection system 10 that includes the inner layer 12 supporting a plurality of components 16 forming an impact force dampening and defusing structure 14. The components 16 are shown to have a conical shape and are all of the same size and shape. In other embodiments, the components have a shape other than conical and/or are of different sized and/or of different shapes. In another embodiment, a fill material is injected, sprayed, placed, etc. between the components 16. The fill material is softer that the material of the component (i.e., the fill material will compress more from an impact force than the component), which includes one or more of a gel, foam, etc. In an example, the impact force impacts three components 16 having a system impact area 20. Each of the three components dampens their respective portion based on the side wall angle θ, the material composition of the component, and/or the distance “d”. Each component further diffuses the dampened impact by spreading it over a larger area. In this example, the body part impact area 22 is significantly larger than the system impact area 20. As such, the pressure applied to the body part is significantly less that the pressure exerted in the system impact area 20. FIG. 7 is a schematic block diagram, in a side view, of another embodiment of a body impact protection system 10 that is similar to the body impact protection system 10 of FIG. 3 with the addition of an outer layer 24. The outer layer 24 may be comprised on the same material as the inner layer 12 or a different material. Each of the inner and outer layers 12 and 24 are 1/16 inch to ¾ inch thick depending on the application of the body impact protection system 10. FIG. 8 is a schematic block diagram, in a side view, of an example of force components within a body impact protection system 10. In this example, the body impact protection system 10 includes an inner layer 12, an impact force dampening and defusing structure 14, and an outer layer 24. The impact force dampening and defusing structure includes one or more layers of components 16 and the inner layer 12 is positioned proximal to a body part 8. When on object (e.g., another person, a ball, the ground, etc.) collides with the body impact protection system 10, it creates an average impact force 18 over a system impact area 20. The average impact force 18 is calculated as F=KE/d, where KE is the kinetic energy at impact and d is the impact distance (i.e., the distance the object travels at the moment of the collision until it stops or the collision is over). The kinetic energy (KE) is calculated as KE=0.5*m*v2, where m is the mass of the object and v is the velocity of the impact at the instant of collision. For a falling object, velocity (v) is calculated as v=(2*g*h)1/2, where g is the gravitational field of earth and his the height the object has fallen. Deceleration of the object is calculated as a=v2/2*d and the G-Force of the object is calculated as G=a/g. The components of the impact force dampening and defusing structure 14 provide a collision angle 26 between the impact force 18 and the body part 8. The impact force 18 is divided into a normal force component 28 and a tangential force component 30 based on the collision angle 26 (e.g., θ). For example, and on a layer by layer basis, the normal force component 28 is equal to the impact force times the sine of the collision angle and the tangential force component 30 is equal to the impact force times the cosine of the collision angle. In addition to dampening the impact force on a layer by layer basis, the collision angle 26 increases the impacted area. Thus, when the normal force component(s) 28 is applied to the body part 8 through the inner layer 12, its magnitude is substantially less than the magnitude of the impact force 18 and it is spread out over a much larger area (i.e., the body part impact area 22 is much larger than the system impact area 20). Since pressure is force over area, decreasing the force and increasing the area substantially reduces the impact pressure on the body. In an analogy, the body impact protection system 10 takes a hard punch and turns it into a mild slap. As another analogy and from the example of the knife being dropped into molding clay, the body impact protection system 10 takes the blade down scenario and converts it into the handle down scenario. FIG. 9 is a schematic block diagram, in a side view, of another example of force components within a body impact protection system 10. In this example, the body impact protection system 10 includes an inner layer 12, an impact force dampening and defusing structure 14, and an outer layer 24. The impact force dampening and defusing structure includes one layer of components 16 and the inner layer 12 is positioned proximal to a body part 8. When on object 21 (e.g., a ball) collides with the body impact protection system 10, it creates an average impact force 18 over a system impact area 20. As a result of the impact force 18, an outer surface shock response or wave 23 is created within the outer layer 24. The magnitude and energy of the outer surface shock response is dependent on the material of the outer layer 24 and the impact force 18. A majority of the energy of the impact force 18, however, will be concentrated in the system impact area 20 and directed toward the body part. As an analogy, consider a rock dropped into a still pond. The rock creates a rippling wave on the surface of the pond (i.e., an impact shock response or wave), but the rock continues to fall to the bottom of the pond. In this analogy, the rock is the impact force and the surface of the pond is the outer layer. In this example, the system impact area 20 corresponds to the outer or top area of a component or cell of the impact force dampening and defusing structure 14. As such, a majority of the impact force 18 is applied to one cell. The cell functions to convert the impact force 18 into an angular force 25. When the angular force 25 reaches the inner layer 12, it creates a normal force component 28 and a tangential force component 30. Depending on the material of the inner layer 12, the angular force 25 may also create a shock wave 27 in the inner layer 12. For example, if the inner layer includes a combination of padding and a non-malleable to semi-malleable plastic or the like, then a surface wave would be created in the plastic portion. In addition, the cell creates a body part impact area 22 that is larger (e.g., 2× or more) than the system impact area 20 via the angular force 25. Note that the body part impact area 22 would be even larger if the impacting object 21 impacted the system 10 between cells. In this instance, two or more cells would share the impact force 18 and respective create angular forces and collectively form a larger body part impact area 22. FIG. 10 is a graph of an example of impact force components v. body impact area of a body impact protection system. In this example, the vertical axis corresponds to force in force-pounds and the horizontal axis corresponds to a body part surface area. The thicker darker lines correspond to the body impact protection system 10 and the thinner lighter lines corresponds to conventional protective gear. For the body impact protection system 10, the impact force reaching the body is spread out over a larger area of the body and has lower magnitudes in comparison to the conventional protective gear. As such, the pressure applied to the body is less with the body impact protection system 10 than conventional protective gear. FIGS. 11 and 12 are schematic block diagrams, in a side view and a top view, of another embodiment of a body impact protection system 10 that includes two component layers 50 and 54, an intermediate layer 52, and an inner layer 12. The components of the first layer 50 are positioned to overlap (from the top view) two or more components of the second layer 54. The components 16 of both layers 50 and 54 may be of the same size, shape, and material composition, of different size, of different shape, and/or of different material composition, or a combination thereof. The intermediate layer 52 and the inner layer 12 may be of the same size, shape, and material composition, of different size, of different shape, and/or of different material composition, or a combination thereof. For example, the first component layer 50 will be subjected to a greater impact force than the second component layer 54. As such, the components 16 of the first layer have a more rigid material composition (i.e., able to withstand a large impact force) than the components of the second layer. As an optional addition, the components of the first layer have a larger side wall angle θ (i.e., larger sine value) than the components of the second layer such that the components of the second layer provide more dampening of the impact force than the components of the first layer. When an impact force 18 is applied to the first component layer 50, one or more components 16 are impacted. The component(s) 16 of the first layer (e.g., the darker component of the first layer) dampen and defuse the impact force 18, which is then applied to the intermediate layer 52. Depending on the material composition of the intermediate layer 52, the dampened and defused impact force is applied to a group of components of the second layer 54. As an example, the intermediate layer 52 is composed of a foam material that has a high dampening ratio and a low rigidity factor (i.e., the intermediate layer further dampens the impact force but does little to distribute it over a larger area than the receiving area). In this example, the group of components of the second layer 54 would be the ones having a direct overlap with the impacted component(s) of the first layer 50, which are shown as darkened cells. As another example, the intermediate layer 52 is composed of a rigid material (e.g., plastic, carbon fiber, etc.) that has a low dampening ratio and a high rigidity factor (i.e., the intermediate layer does little to further dampen the impact force but does distribute it over a larger area than the receiving area). In this example, the group of components of the second layer 54 would be the ones having a direct overlap with the impacted component(s) of the first layer 50 and another circle of components surrounding them having indirect overlap, which are shown as darker cells. In another example, the intermediate layer 52 includes a combination of foam material and rigid material. In another example, each component layer includes components arranged in a grid array (e.g., arranged in rows and columns, arranged in a repeating pattern, randomly arranged, etc. provide that, from layer to layer, the components of an outer layer overlap multiple components of an inner layer). Each of the components has a three-dimensional geometric shape that includes an impact receiving surface area and an impact defusing surface area that are separated by a distance “d”. Each of the components further includes a material composition that is the same or different from component to component or layer to layer. This example or other examples, further include an impact surface layer (e.g., an outer layer) juxtaposed to the impact receiving surface area of the components and an impact defusing surface layer (e.g., an intermediate and/or inner layer) juxtaposed to the impact defusing surface area of the components. FIG. 13 is a schematic block diagram, in a side view, of another example of force components within a body impact protection system 10 that is similar to FIG. 9 but with the addition of the intermediate layer 52 and the first component layer 50. In this example, when on object 21 (e.g., a ball) collides with the body impact protection system 10, it creates an average impact force 18 over a system impact area 20. As a result of the impact force 18, an outer surface shock response or wave 23 is created within the outer layer 24. The magnitude and energy of the outer surface shock response is dependent on the material of the outer layer 24 and the impact force 18. A majority of the energy of the impact force 18, however, will be concentrated in the system impact area 20 and directed toward the body part. In this example, the impact force is applied the outer or top area of a component or cell of the first layer 50. As such, a majority of the impact force 18 is applied to one cell. The cell functions to convert the impact force 18 into an angular force 25-1. When the angular force 25-1 reaches the intermediate layer 52, it creates a normal force component 28-1 and a tangential force component 30-1. Depending on the material of the intermediate layer 52, the angular force 25-1 may also create a shock wave (or response) 33 in the intermediate layer 52. The normal force components 28-1 are applied to two cells of the second layer 54. As such, each cell receives about one-half of the normal impact force component produced by the first layer 50. Each of the cell functions to convert the normal impact force component 28-1 into a second angular force 25-2. When the second angular force 25-2 reaches the inner layer 12, it creates second normal force components 28-2 and second tangential force components 30-2. Depending on the material of the inner layer 12, the second angular force 25-2 may also create a second shock wave (or response) 27 in the inner layer 12. In addition, the cells of the second layer 54 creates a body part impact area 22 that is significantly larger (e.g., 10× or more) than the system impact area 20 via the angular forces 25-1 and 25-2. Note that the body part impact area 22 would be even larger if the impacting object 21 impacted the system 10 between cells. In this instance, two or more cells of the first layer 50 would share the impact force 18 and respective create angular forces and collectively form a larger impact area being exerted on the intermediate layer 52 and engage more components of the second layer 54. FIGS. 14A-14B are a schematic block diagram of an example of an impact force being defused and distributed layer by layer within a body impact protection system 10. From a top view perspective and as shown in FIG. 14A, the outer (or top) surfaces of four components 16 of the first layer 50 receive the impact force in the system impact area 20. The components of the first layer are arranged in a pattern 56. The second layer 54 of components includes a second pattern of components 58 that is complimentary to the first pattern of components 56. In particular, a component of the first layer overlaps multiple components of the second layer such that, from layer to layer, more and more components are dampening and defusing the impact force. In FIG. 14B, eight components or cells of the second layer are receiving a portion of the normalized impact force created by the four components or cells of the first layer. The base of the eight cells of the second layer form the body part impact area 22, which is significantly larger than the system impact area 20. FIG. 15 is a schematic block diagram, in a side view, of another embodiment of a body impact protection system 10 that includes an inner layer 12, an outer layer 24, a plurality of component layers 50, 54, 60-64 (five in this example, but could be more or less than five); and a plurality of intermediate layers 52, 66-70 (four in this example, but could be more or less). The first component layer 50 includes a plurality of components arranged in a first pattern; the second component layer 54 includes a plurality of components arranged in a second pattern; the third component layer 60 includes a plurality of components arranged in a third pattern; the fourth component layer 62 includes a plurality of components arranged in a fourth pattern; and the fifth component layer 64 includes a plurality of components arranged in a fifth pattern. From layer to layer, the pattern of components is at least partially complimentary such that one component of an outer layer overlaps, or overlays, multiple components of an inner layer. From layer to layer, the size, shape, side wall angle θ, and/or material composition of the components may be different. For example, first layer 50, which is the outer most layer of components, has components that are comprised of a material that can withstand impact force pulses up to 50,000 force-pounds of force for 20-100 milliseconds (mSec). Continuing with the example, the side wall angle of the components of the first layer is 45 degrees, such that the normal force produced by the first layer of components is 0.0707 of the external impact force. As such, the impact force being exerted by the first layer of components on the first intermediate layer 52 will be 0.707*50,000 pounds, which equals 35,350 force-pounds. Continuing with the example, the first intermediate layer 52 has a low dampening ratio and a high rigidity factor such that a majority of the impact force received from the first layer of components is provided to components of the second layer. In this example, the side wall angle of the components of the second layer is 42.5 degrees, such that the normal force produced by the second layer of components is 0.676 of the impact force it receives. As such, the impact being exerted by the second layer of components in the second intermediate layer 66 is 0.676*35,350, which equals 23,880 force-pounds. Continuing with the example, the second intermediate layer 66 has a low dampening ratio and a high rigidity factor such that a majority of the impact force received from the second layer of components is provided to components of the third layer. In this example, the side wall angle of the components of the third layer is 40 degrees, such that the normal force produced by the third layer of components is 0.643 of the impact force it receives. As such, the impact being exerted by the third layer of components in the third intermediate layer 68 is 0.643*23,880, which equals 15,350 force-pounds. Continuing with the example, the third intermediate layer 68 has a low dampening ratio and a high rigidity factor such that a majority of the impact force received from the third layer of components is provided to components of the fourth layer. In this example, the side wall angle of the components of the fourth layer is 35 degrees, such that the normal force produced by the third layer of components is 0.536 of the impact force it receives. As such, the impact being exerted by the fourth layer of components in the fourth intermediate layer 68 is 0.574*15,350, which equals 8,804 force-pounds. Continuing with the example, the third intermediate layer 68 has a low dampening ratio and a high rigidity factor such that a majority of the impact force received from the third layer of components is provided to components of the fourth layer. In this example, the side wall angle of the components of the fourth layer is 35 degrees, such that the normal force produced by the fourth layer of components is 0.536 of the impact force it receives. As such, the impact being exerted by the fourth layer of components in the fourth intermediate layer 68 is 0.574*15,350, which equals 8,804 force-pounds. Continuing with the example, the fourth intermediate layer 68 has a low dampening ratio and a high rigidity factor such that a majority of the impact force received from the fourth layer of components is provided to components of the fifth layer. In this example, the side wall angle of the components of the fifth layer is 30 degrees, such that the normal force produced by the fifth layer of components is 0.500 of the impact force it receives. As such, the impact being exerted by the fifth layer of components in the inner layer 12 is 0.500*8,804, which equals 4,402 force-pounds. Continuing with the example, the inner layer 12 has a high dampening ratio (e.g., 0.55) and a low rigidity factor. As such, 0.55 of the impact force exerted on the inner layer is passed to the body part. In this example, the body part would receive an average impact force of 0.55*4,402, which equals 2,421 force pounds. The resulting impact force is spread out over the body impact area to produce an impact pressure. For instance, a body impact area of 5.5 square inches yields a pressure of 440 PSI (pounds per square inch). In this example, the components of the first layer will need to withstand impact forces of up to 50,000 force pounds; the components of the second layer will need to withstand an impact force of 35,350 force-pounds; the components of the third layer will need to withstand an impact force of 23,880 force-pounds; the components of the fourth layer will need to withstand an impact force of 15,350 force-pounds; and the components of the fifth layer will need to withstand an impact force of 8,804 force-pounds. To reduce the impact force and impact pressure being exerted on the body of the above example, additional layers can be added. For example, by adding three more layers, each having components with side wall angles of 30 degrees, then the body impact force is further reduced by 0.53, which equals 0.125. With the additional three layers, the resulting impact force being applied to the inner layer 12 is 0.125*4,402, which equals 550 force pounds. With the inner layer 12 having a dampening factor of 0.55, the body impact force is 302.5 force-pounds. With a body impact area of 5.5 square inches, the resulting body impact pressure is 55 PSI. Another way to reduce the impact force and impact pressure being exerted on the body of the above example is to have the intermediate layers have a high dampening ratio (e.g., 0.67). With four intermediate layers, the cumulative dampening is 0.674, which equals 0.2. Thus, the impact force being applied to the inner layer is 0.2*4,402, which equals 887 force-pounds. With the inner layer 12 having a dampening factor of 0.55, the body impact force is 487 force-pounds. With a body impact area of 5.5 square inches, the resulting body impact pressure is 89 PSI. FIG. 16A is a graph of an example of an impact force pulse v. time. In this example, the vertical axis is acceleration in G-forces (G), where G-Force is a measure of acceleration with respect to earth's gravitational field. For instance, G=a/g, where a is acceleration and g is the earth's gravitational field. The horizontal axis is time scaled in mSec. The example further includes an impact pulse that has a magnitude of about −50 G and has a pulse duration of about 10 mSec. FIG. 16B is a graph of an examples of frequency responses of different layers (e.g., layers of components, the intermediate layers, the outer layer, and/or the inner layer) of a body impact protection system having different resonant frequencies. In this example, the vertical axis is acceleration in G-forces (G) and the horizontal axis is time scaled in mSec. By varying the material composition of the layers, various resonant frequencies are obtained. With different resonant frequencies, different shock responses are produced. With proper selection of the resonant (or natural) frequencies, the resulting different shock responses destructively interfere with each other to further reduce the impact force being exerted on the body. In this example, a first layer has a first shock response, a second layer has a second shock response, and a third layer has a third shock response. In addition to selecting the resonant or natural frequency of the various layers, the quality factor (Q) can be selected. With a higher quality factor, side bands dampen faster, but the main frequency passes substantially unattenuated. With a low-quality factor, the side bands dampen slower, but the main frequency is somewhat attenuated (e.g., reduced by 10% or more). FIGS. 17A-17E are a schematic block diagram of an example of force defusing and distribution layer by layer within a body impact protection system 10 of FIG. 15. With reference to FIG. 17A, the 1st component layer 50 receives the impact force via one component or cell. As such, the system impact area 20 corresponds to the area of the top or outer surface area of the component. The component functions to dampen and defuse the received impact force based on the side wall angle θ and the distance “d” of the component (e.g., the distance between the top surface area and the bottom surface area of the component). With the patterns between the layers being complimentary, the impacted component on the first layer 50 overlaps three components of the second layer as shown in FIG. 17B. Ideally, the force exerted by the component of the first layer 50 is equally distributed among the three components of the second layer 54. Each of the components of the second layer function to dampen and defuse the received impact force based on the side wall angle θ and the distance “d” of the component. FIG. 17C illustrates seven components of the third layer 60 receiving an impact force component from the three components of the second layer 54. Each of the seven components of the third layer function to dampen and defuse the received impact force based on the side wall angle θ and the distance “d” of the component. FIG. 17D illustrates twelve components of the fourth layer 62 receiving an impact force component from the seven components of the third layer 60. Each of the twelve components of the fourth layer function to dampen and defuse the received impact force based on the side wall angle θ and the distance “d” of the component. FIG. 17E illustrates nineteen components of the fifth layer 64 receiving an impact force component from the twelve components of the fourth layer 62. Each of the nineteen components of the fifth layer function to dampen and defuse the received impact force based on the side wall angle θ and the distance “d” of the component. The body impact area 24 is the sum of the area of the base of the nineteen components. As an example, the base of a component has an area that is nine times the area of the top of the component. For this example, the body part impact area 24 is 9*19 times larger than the system impact area 20 (as shown in FIG. 17A), which is 171 times larger. As such, the resulting impact pressure applied to the body is up to 171 times less than in conventional protection gear, assuming comparable force dampening ratios. FIG. 18 is a schematic block diagram, in a side view, of another embodiment of a body impact protection system that includes a plurality of component layers, a plurality of rigid layers, and a plurality of padding layers. This example includes three groupings of two component layers, three rigid layers, and one padding layers. In a grouping, the two component layers are sandwiched between the three rigid layers. The padding layer is on the dampening and defusing side of the component layers. The number of each layer type can vary from the numbers shown in this example and may be in different layering configurations. For example, the body impact protection system could include two or four groupings. In another example, the body impact protection system includes three component layers and four rigid layers in a grouping. In yet another example, the body impact protection system includes three component layers and two rigid layers in a grouping, where one rigid layer is on the impact receiving side of the three component layers and the other rigid layer is on the dampening and defusing side of the component layers. In yet a further example, the body impact protection system does not include rigid layers, it only includes component layers and padding layers. In a still further example, the body impact protection system includes only component layers and rigid layers. These are but a few examples of the almost endless combination of component layers, rigid layers, and/or padding layers. FIG. 19 is a schematic block diagram, in a cross-section side view, of another embodiment of a defusing cell or component of a layer of a body impact protection system. The cell includes a top surface 70-1, a base surface 72-1, a side structure 76, and a distance “d” 74 that is the distance between the top surface and the base surface. In this embodiment, the center of the cell is hollow and the top and base are open. The side structure 76 is angled from the base surface to the top surface at the side wall angle θ and has a thickness such that the component, or cell, includes an outer shell and an interior volume. The interior volume can be filled with air, a gel, an oil, rubber, silicon, and/or foam. The component or cell is comprised of a material composition (as previously described) that, when an impact force is applied, retains the angle θ within +/−33% and retains the ratio of Ai to Ao to within +/−33%. FIG. 20 is a schematic block diagram, in a side view, of another embodiment of a defusing cell or component of a layer of a body impact protection system. The cell includes a top surface 70-1, a base surface 72-1, a side structure 76, and a distance “d” 74 that is the distance between the top surface and the base surface. In this embodiment, the center of the cell is hollow. The side structure 76 is angled from the base surface to the top surface at the side wall angle θ . Each of the top surface 70-1, the base surface 72-1, and the side structure 76 has a thickness such that the component, or cell, includes an outer shell and an interior volume. The interior volume can be filled with air, a gel, an oil, rubber, silicon, and/or foam. The component or cell is comprised of a material composition (as previously described) that, when an impact force is applied, retains the angle θ within +/−33% and retains the ratio of Ai to Ao to within +/−33%. FIGS. 21A-21F are a schematic block diagrams, in a top view, of other embodiments of a defusing cell of a layer of a body impact protection system. Each of the defusing cells or components includes a top perimeter that outlines the top surface area and a base perimeter that outlines the base surface area. The top surface area is the impact force receiving surface and the base surface area is the dampening and defusing side. FIG. 21A illustrates the defusing cell or component having a circular shape from a top perspective. As such, the top perimeter 80 and the bottom perimeter 82 each have a circular shape. The radius of the bottom perimeter 82 is at least 1.414 times the radius of the top perimeter 80 such that the base surface area is at least 2 times the surface area of the top surface area. With a circular shape for the top and base perimeters, the cell or component has a conical shape. FIG. 21B illustrates the defusing cell or component having an elliptical or oval shape from a top perspective. As such, the top perimeter 80-1 and the bottom perimeter 82-1 each have an elliptical or oval shape. The dimensions of the bottom perimeter 82-1 and of the top perimeter 80-1 are selected such that the base surface area is at least 2 times the surface area of the top surface area. With an elliptical or oval shape for the top and base perimeters, the cell or component has an elliptical or oval conical shape. FIG. 21C illustrates the defusing cell or component having a square shape from a top perspective. As such, the top perimeter 80-2 and the bottom perimeter 82-2 each have a square shape. The dimensions of the bottom perimeter 82-2 and of the top perimeter 80-2 are selected such that the base surface area is at least twice the surface area of the top surface area. With a square shape for the top and base perimeters, the cell or component has a pyramid shape. FIG. 21D illustrates the defusing cell or component having a rectangular shape from a top perspective. As such, the top perimeter 80-3 and the bottom perimeter 82-3 each have a rectangular shape. The dimensions of the bottom perimeter 82-3 and of the top perimeter 80-3 are selected such that the base surface area is at least twice the surface area of the top surface area. With a rectangular shape for the top and base perimeters, the cell or component has an elongated pyramid shape. FIG. 21E illustrates the defusing cell or component having a triangular shape from a top perspective. As such, the top perimeter 80-4 and the bottom perimeter 82-4 each have a triangular shape. The dimensions of the bottom perimeter 82-4 and of the top perimeter 80-4 are selected such that the base surface area is at least twice the surface area of the top surface area. With a triangular shape for the top and base perimeters, the cell or component has a three-dimensional triangular shape. FIG. 21F illustrates the defusing cell or component having an octagon shape from a top perspective. As such, the top perimeter 80-5 and the bottom perimeter 82-5 each have an octagon shape. The dimensions of the bottom perimeter 82-5 and of the top perimeter 80-5 are selected such that the base surface area is at least twice the surface area of the top surface area. With an octagon shape for the top and base perimeters, the cell or component has a three-dimensional octagon shape. FIGS. 21A-21F are a few examples of the possible shapes of the components or defusing cell. Other examples include a pentagon shape, a hexagon shape, and/or other polygon shape. As another example, the top perimeter could be one shape and the base perimeter could be another shape. FIGS. 21G-21J-2 are diagrams of another defusing cell or component. The defusing cell or component has a substantially square or rectangular shaped top perimeter 80-6 and base perimeter 82-6 with a hole running the distance “d” through the middle. The base perimeter 82-6 has angular cut corners (e.g., at θ2), has a width of “w”, and a height of “h”. The top perimeter 80-6 has a width of “w1” and a height of “h1”. The top surface area outlined by the top perimeter 80-6 is the distance “d” from the base surface area outlined by the base perimeter 82-6. The side walls of the cell are angled at the side wall angle of θ1., where θ1 is readily calculable from w, h, w1, h1, and d, or d is readily calculable from w, h, w1, h1, and θ1. The hole at the top surface has a width of “w2” and a height of “h2”. In an example, the hole runs straight through the cell as shown in the cross-sectional side view of FIG. 21J-1. In another example, the hole increases in sizes as it traverses from the top surface to the base surface of the cell as shown in the cross-sectional side view of FIG. 21J-2. The combination of the hole and the angled corners of the base surface allow air flow from layer to layer. FIGS. 21K-21N are diagrams of another defusing cell or component that is similar to the cell of FIGS. 21G-21J-2 with the addition of perforation holes or vents to improve air flow and/or reduce weight of the cell. The perforation holes or vents may be circular, rectangular, square, or other polygon shape and pass through the cell from the top surface to the bottom surface. Alternatively, some or all of the perforation holes do not pass fully from the top surface to the base surface. These holes may only pass 50%-90% of the way through the cell to reduce weight. FIGS. 21O and 21Q-21S-2 are diagrams of another defusing cell or component. The defusing cell or component has, from a top perspective, a substantially square or rectangular shaped top perimeter 80-6 and base perimeter 82-6 with a hole running the distance “d” through the middle. From the side view and/or the front view, the defusing cell or component has an arch shape, which allows for a layer of such cells to be fitted to a curved and/or spherical shaped body part. Note that the cell may only have on arched perspective from the side or front view. The base perimeter 82-7 has angular cut corners (e.g., at θ2), has a width of “w”, and a height of “h”. The top perimeter 80-7 has a width of “w1” and a height of “h1”. The top surface area outlined by the top perimeter 80-7 is the distance “d” from the base surface area outlined by the base perimeter 82-7. The side walls of the cell are angled at the side wall angle of θ1., where θ1 is readily calculable from w, h, w1, h1, and d, or d is readily calculable from w, h, w1, h1, and θ1. The hole at the top surface has a width of “w2” and a height of “h2”. In an example, the hole runs straight through the cell as shown in the cross-sectional side view of FIG. 21S-1. In another example, the hole increases in sizes as it traverses from the top surface to the base surface of the cell as shown in the cross-sectional side view of FIG. 21S-2. The combination of the hole and the angled corners of the base surface allow air flow from layer to layer. As shown in FIGS. 21S-1 and 21S-2, the arced perspective includes an inner radius r1 and an outer radius r2. The inner radius r1 is dependent on the radius of the body part it is protecting, the inner layer thickness, the layer in which the cell lies, the distance “d” between the top and base surface areas, and the thickness of any intermediate layers. The outer radius r2 is dependent on the inner radius r1 and the distance “d” between the top and base surface areas. For example, assume that the body part being protected is the head with a radius of 3 inches, the inner layer is 0.25 inches thick, the cell is in the second layer, the intermediate layer is 0.125 inches thick, and “d” is 0.125 inches. Based on these parameters, the inner radius r1 is (3+0.25+0.125+0.125)=3.5 inches and the outer radius r2 is 3.625 inches. FIG. 21T is a top and side view of a layer of components or cells as shown in FIGS. 21G-21J-2. The layer includes a plurality of components and a component layer support. The component layer support functions to align the components and may further function to provide some dampening of the impact force. For example, the component layer support is comprised of a rubber material that includes locating holes, slots, and/or other aligning mechanisms for positioning the cells, or components. With the use of a rubber material, the component layer support has a degree of flexibility to allow for custom fitting of the layers and further provides dampening of the impact force. In an embodiment, the component layer support is an intermediate layer as previously described. FIGS. 21U-21V are diagrams of another defusing cell or component 16 that includes a plurality of spherical elements 85, a suspension material 87, and a housing 89. The housing 89 has an overall size and shape corresponding to one of the components previously described. The spherical elements 85 are comprised of a material composition that will substantially maintain a spherical shape (e.g., up to 25% compression) when an impact force is exerted on the cell. For example, the spherical elements are comprised of a rubber material, a plastic material, stainless steel, aluminum, and/or a carbon fiber material. The spherical elements 85 may be solid or hollow. The suspension material 87 may be a liquid and/or a solid that, when no force is applied to the cell, keeps the spherical elements 85 in a distributed pattern. When a force is applied to the cell, the suspension material 87 allows the spherical elements 85 to come in contact with each other and propagate the impact force through the colliding spheres and provide a fairly even distribution of the resulting dampened and defused impact force across the base surface area. When the force is removed, the suspension material 87 causes the spherical elements 85 to return to the distributed pattern. FIGS. 21W-21X are side view diagrams of another defusing cell or component that include a flexible shell 99 and a cell platform 101. Each of the flexible shell 99 and cell platform 101 is comprised of a material composition that includes a rubber material, a plastic material, stainless steel, aluminum, and/or a carbon fiber material. The base of the flexible shell 99 fits within the cell platform 101 and is held within the cell platform via the encircling lip 103. When no force is exerted on the cell, as shown in FIG. 21W, the flexible shell 99 is uncompressed and is not pushing on the encircling lip 103 of the cell platform 101. When an impact force is exerted on the cell, as shown in FIG. 21X, the flexible shell 99 is compressed and its edges are contained with the cell platform 101 via the encircling lip 103. The material composition of the flexible shell 99 is such that it can withstand the impact force, be compressed as shown in FIG. 21X, retained its shape (e.g., maintains a side wall angle), and substantially returns to the uncompressed state as shown in FIG. 21W when the force is removed. In an example, the flexible shell 99 has a side wall angle of θu when it in the uncompressed state and has a side wall angle of θc when in the compress state. For instance, θu is 45 degrees and θc is 35 degrees. FIG. 21Y is a side view of layers 103 of flexible cells or components. The cells are compressible cells as discussed with reference to FIGS. 21W and 21X. Intermediate layers 105 are between one or more flexible cell layers 103. In this example, intermediate layers 105 are between the second and third flexible cell layers 103 and between the fourth and fifth flexible cell layers 103. FIGS. 21Z-21AB are top, front, and side view diagrams of another defusing cell or component that has a triangular shape. The cell may be of any size (i.e., height, width, perimeter, and/or distance between the top and base surfaces) and/or of any material composition provided the side walls of the components are angled and the top surface area is less than the base surface area. The distance “d” between the top surface area and the base surface area ranges from 1/32 of an inch to multiple inches, depending on the application of the body impact protection system. The angled side wall(s) are at an angle of θ with respect to the horizontal axis, where the angle is in the range of 25 degrees to 89 degrees. Depending on the angle θ and the distance “d”, the base surface area is two or more times larger than the top surface area, where the top surface area is 1/256 square inches to tens of square inches depending on the application of the body impact protection system. The cell is constructed (e.g., molded, press-formed, printed, etc.) of a material composition that includes one or more of a rubber material, a foam material, a padding material, a plastic material, a gel material, a carbon fiber material, a cloth material; a polyester material, a moisture absorbing material, a moisture wicking material and a silicon material. A characteristic of the material composition is that the cell retains the angle θ within +/−33% and retains the ratio of Ai (i.e., the base surface area) to Ao (i.e., the top surface area) to within +/−33%. Distance “d” may decrease while the impact force is being applied, but substantially returns to its pre-impact force value when the impact force is removed. FIG. 21AC is a top view of a layer of the triangular components of FIGS. 21Z-21AB. With the triangular shape of the cells, the layer can be formed around complex surfaces (e.g., a head, an arm, an elbow, etc.). FIG. 21AD is a top view of another layer of the triangular components of FIGS. 21Z-21AB. In this example, the layer would be used for any layer but the one closes to the body part. For the inner most component layer, there should be as few gaps between cells and possible, and each impacted cell should, as evenly as possible, distribute the force across its base surface area. FIG. 21AE is a top view of another layer of the triangular components of FIGS. 21Z-21AB. In this example, the layer would be used for any layer but the one closes to the body part and is a complimentary layer to the layer of FIG. 21AD. FIG. 21AF is a top view of two overlapping layers of components of FIGS. 21AD and 21AE. The first layer 91 is that of FIG. 21AD and the second layer 93 is that of FIG. 21 AE. When a cell of the second layer 93 receives an impact force, it spreads the dampened and defused impact force to three cells of the first layer 91. FIG. 22 is a schematic block diagram, in a side view, of a portion of another embodiment of a layer of a body impact protection system 10. The portion includes a 1″ spherical component 90 of a first layer of the system 10 and two spherical components 92 and 94 of a second layer of the system 10. Each of the spherical components 90-94 is comprised of a material composition that will substantially maintain a spherical shape (e.g., up to 25% compression) when an impact force 96 is exerted on the components. For example, the spherical components are comprised of a rubber material, a plastic material, stainless steel, aluminum, and/or a carbon fiber material. Further, the spherical components 90-94 may be solid or hollow. In an example, the first component 90 receives an impact force 96 and collides with the second and third components 92 and 94 at first and second collision angles 98 and 100, respectively. As a result of the collision between the first and second components, the second component 92 creates a 1st normal force component 28-1 and a 1st tangential force component 30-1. As a result of the collision between the first and third components, the third component 94 creates a 2nd normal force component 28-2 and a 2nd tangential force component 30-2. If each of the first and second collision angles 98 and 100 is 45 degrees and the 1st component 90 impacts the 2nd and 3rd components equally, then each of the second and third components receives ½ of the impact force at an angle of 45 degrees. Accordingly, the normal force components produced by each of the second and third components is 0.5*F*sinθ, where F is the impact force 96 and θ is the collision angle. As such, when the first spherical shaped object collides with the two or more second spherical shaped objects, a multi-dimensional collision is created that dampens and defuses the impact force 96. Protective headgear (e.g., a helmet) was originally created to reduce the risk of skull fractures, but was not designed to reduce the incidence of concussion. Since the turn of the 21st century, a helmet's ability to mitigate the incidence of concussions has been studied and, as a result, improvements have been made in helmets. It is generally accepted in the medical field that a concussion occurs as a result of a rapid acceleration and deceleration of the brain against the skull. When object (e.g., another person's body part, another helmet, the ground, a ball, etc.) collides with protective headgear (e.g., a helmet) it produces an impact force that results in three collisions. The first collision is between the object and the helmet as shown in FIG. 23A, the second collision is between the helmet and the skull as shown in FIG. 23B, and third collision is between the skull and the brain as shown in FIG. 23C. The helmet includes an outer shell 77 and padding 79 and the head is shown generically to include a brain 75. FIG. 23A illustrates, in a cross section front view, of an embodiment of a helmet at the instant it collides with an object. The average impact force created by the object colliding with the helmet is F1. The reactive force of the helmet, which includes the force dampening of the padding 79 and the surface wave dissipation of the outer shell 77, which is designated F3. The resulting force applied to the skull is F2. The average impact force F1 of the object is calculated as m*a, where “m” is the mass of the object and “a” is the deceleration of the object as a result of the collision. Note that if the object is the ground, then mass and deceleration are of the person wearing the helmet. The deceleration is calculated as v2/2*d, where “d” is impact distance (i.e., the distance the object travels from the start of the collision until the collision is over), and “v” is velocity at the instant of collision. FIG. 23B illustrates, in a cross section front view, the helmet to skull collision. In this collision, the padding 79 of the helmet is compressed as a result of the impact force F1. The force exerted on the skull F2 is equal to the negative of the impact force Fi minus the reactive force F3 of the helmet. In equation form, F2=−(F1-F3). As such, the greater F3, the less force F2 that exerted on the skull. FIG. 23C illustrates, in a cross section front view, the skull to brain collision. In this collision, the brain has a force F5 exerted on it, which is the force exerted on the skull F2 less the reactive force of the cerebrospinal fluid F4. In equation form, F5=−(F2-F4). Via substitution, −F5=−(F1-F3)−F4. Thus, by reducing F2 (i.e., the force on the skull), which is accomplished by increasing F3 (i.e., the reactive force of the helmet), the force on the brain F5 is reduced, which should reduce the risk of a concussion. As previously discussed, however, current helmet testing protocols are based on G-Force measurements taken via a drop test and/or via a projectile test. As also previously discussed, G-Force is a ratio of deceleration versus earth's gravitational field. Many assumptions in the helmet testing are made to equate G-Force to reducing the impact force on the brain F5. One assumption that is made in the testing is the mass of the object or the player. In testing, an 11 pound headform, which includes an accelerometer in its core, wears the helmet as the drop test and/or projectile test are performed. Another assumption is that the impact force F1 and the force exerted on the skull F2 are average forces and evenly distributed across the entire surface of the helmet and head, respectively. In actuality and as discussed with reference to FIG. 1, the impact force F1 is received in a very small area of the helmet and a conventional helmet does little to expand the impact area as it reaches the skull. Thus, even if the G-Force measurements are in acceptable ranges and F2 seems relatively mild, a concussion can still result of the skull impact area is small (e.g., less than a few square inches) and the risk for concussion increases as the skull impact area decreases. FIG. 23D is a schematic block diagram, in a side view, of an embodiment of a helmet 115 that includes a body impact protection system 10. In general, the helmet 115 includes an outer layer, an inner layer, and an impact force dampening and defusing structure. The outer layer includes a first material composition and has a geometric shape to form an exterior surface of the helmet. The inner layer includes a second material composition and, when the helmet is worn, the inner layer is adjacent to a head. In an embodiment, the outer layer includes a rubber material and/or a plastic material and the inner layer includes a foam material and/or a gel material. The impact force dampening and defusing structure is positioned between the inner layer and the outer layer. It includes a plurality of components arranged into more or more layers. The layer(s) of components function to reduce pressure on the head from a collision with an object. For example, the collision with the object creates an impact force on the outer layer of the helmet in a given area (e.g., a helmet impact area). Layer by layer, the components dampen the impact force and diffuse it over a larger and larger area. Thus, when the impact force reaches the head, it has been substantially reduced and spread out over a larger area creating a low impact pressure to substantially reducing the risk of concussion and the severity of a concussion if one did occur. FIG. 23E is a schematic block diagram, in a side view, of a portion of an embodiment of a helmet 115 that includes a force dampening and defusing outer shell 117, force dampening and defusing layers 121, dampening viscous layers 123, and a padding layer 125. The dampening and defusing layers 121 includes four layers of cells, or components 16. The dampening viscous layers 123 include gel and/or padding that further dampens the impact force in both the linear direction and rotational direction as will be discussed in greater detail with reference to FIGS. 23F and 23G. The force dampening and defusing outer shell 117 includes a plurality of cells, or components 16, that are laminated, encased, or impregnated with a rubber material, a plastic material, and/or other material to create a smooth, but compressible surface. The cells of the outer shell 117 and the cells of the force dampening and defusing layers 121 convert the external impact force, which is exerted on the helmet in an outer surface impact area 119, into a substantially reduced impact force spread out over a much larger area (i.e., the body impact area 127). The impact force is further reduced by the dampening viscous layers 123. As an example, the side wall angle θ for the cells of each layer is 45 degrees, the mass of the player wearing the helmet is 200 pounds, is traveling at 16 miles per hour (mph), and collides head first with an object and has an impact distance of 1.25 inches. Further, the dampening factor of each layer of the viscous layers is 0.667 and the dampening factor of the padding layer is 0.5. From these parameters, F2 ≅(0.707)5*F1 *(0.667)(5-1)*0.5=0.017* F1. The 200-pound player creates a G-Force of 82 G's, which is borderline concussion level based on research that suggests a concussion in football can occur from an impact that produces a G-Force of 100 g's +/−30 g's. This equates to an external impact force F1 of 16.4K force-pounds and, as result of the dampening of the helmet, creates a head impact force F2 of about 290 force-pounds. With a convention helmet that does not increase the impact area, an impact area of 0.375 square inches yields an impact pressure of 770 PSI. In contrast, the helmet with the dampening and defusing system 10, produces an impact pressure of about 36 PSI. 36 PSI presents substantially less risk of an injury than 770 PSI, even though both have the same G-Force measurements and head impact force. FIG. 23F is a schematic block diagram, in a side view, of a portion of an embodiment of a helmet of FIGS. 23D and 23E. In this illustration, the helmet is receiving an angular impact force. In conventional helmets, this creates a rotational force that studies suggest increase the risk of injury. FIG. 23G is a schematic block diagram, in a side view, of the portion of the helmet of FIG. 23F. In this illustration, the viscous layers 123 slide along the force dampening and defusing layers 121 to dampen the angular and rotational forces produced by the angular impact force. FIG. 24A is a schematic block diagram, in a side view, of an embodiment of a chest protector 135 that includes a body impact protection system 10. The chest protector 135 may be used for baseball, football practice, hockey, motor-cross, mountain bicycling, riot gear, combat gear, and/or other applications where the chest needs to be protected from impacting objects. Further, the materials and implementation of the body impact protection system 10 create flexible chest protector 135 that allow for form fitting and movement with the person wearing the chest protector. In general, the chest protector 135 includes an outer layer, an inner layer, and an impact force dampening and defusing structure. The outer layer includes a first material composition and has a geometric shape to conform to the shape of a human torso. The inner layer includes a second material composition and, when the chest protector is worn, the inner layer is adjacent to the chest. In an embodiment, each of the inner layer and the outer layer includes a rubber material, a foam material, a padding material, a plastic material, a gel material, a carbon fiber material, a cloth material, a polyester material, a moisture absorbing material, a moisture wicking material, and/or a silicon material. In an embodiment, the first and second material compositions are the same. In another embodiment, the first and second material compositions are different. The impact force dampening and defusing structure 137 is positioned between the inner layer and the outer layer. It includes a plurality of components arranged into more or more layers. The layer(s) of components function to reduce pressure on the chest from a collision with an object. For example, the collision with the object creates an impact force on the outer layer of the chest protector in a given area (e.g., a system impact area). Layer by layer, the components dampen the impact force and diffuse it over a larger and larger area. Thus, when the impact force reaches the chest, it has been substantially reduced and spread out over a larger area creating a low impact pressure to substantially reducing the risk of injury and the severity of an injury if one did occur. FIG. 24B is a schematic block diagram, in a side view, of an embodiment of a chest protector 135 that includes a vest 141 and a plurality of dampening and defusing sheets 139. A dampening and defusing sheet 139 includes one or more component layers and may further include the inner layer and/or the outer layer. Further, the sheet 139 may have a variety of top or front view perimeter shapes (a front view is the shown the present figure). Still further, each dampening and defusing sheet 139 has an overall width and an overall height, where the overall width is in the range of 1 inch to 10 inches or more and the overall height is in the range of 1 inch to 8 inches or more. The vest 141 has a shape corresponding to the torso and is comprised of a foam material, a padding material, a cloth material, a polyester material, a moisture absorbing material, and/or a moisture wicking material. The vest 141 includes a plurality of receptacles for receiving the plurality of dampening and defusing sheets 139. For example, the vest 141 includes a plurality of re-sealable pockets for receiving the sheets 139. In another example, the vest 141 includes pockets that, once the sheets are inserted, are sealed. The size and positioning of the sheets 139 are on the vest 141 may vary based on the application of the chest protector 135. Further, the outer layer of the sheets may include a bullet-proof material when the chest protector is used in combat or as riot gear. Still further, the area around the heart may include a special sheet that includes more component layers than other sheets, may include a different outer layer than other sheets, and/or may include a different inner layer than other sheets to provide more protection for the heart than other parts of the torso. FIG. 25 is a schematic block diagram, in a side view, of an embodiment of a knee protection apparatus 151 that includes an outer layer 153, an inner layer 155, and a force dampening and defusing structure 157. The outer layer 153 includes a first material composition and has an exterior surface that includes a substantially planer area. The first material composition includes a rubber material, a foam material, a padding material, a plastic material, a gel material, a carbon fiber material, and/or a silicon material. The inner layer 155 includes a second material composition and has a shape corresponding to the shape of a knee. The second material composition includes a rubber material, a foam material, a padding material, a plastic material, a gel material, a cloth material, a polyester material, a moisture absorbing material, a moisture wicking material, and/or a silicon material. Note that the inner layer is adjacent to the knee when the knee protection apparatus 151 is worn. The force dampening and defusing structure 157 is positioned between the inner layer 155 and the outer layer 153. From the front and side views, the force dampening and defusing structure 157 has a shape corresponding to a difference between the shapes of the inner and outer layers. In particular, the structure 157 includes components 16 that are arranged to reduce pressure on the knee when a force is applied to the outer layer. As shown, to achieve the desired shape of the structure 157, some components are longer than others. The substantially planar area of the outer layer 153 allows the knee protection apparatus to have a large impact area with the ground or other surface on which the knee protection apparatus will be used. As shown in FIG. 27, the planar area 161 has, from a front view perspective, a rectangular shape, but could have a different polygonal shape. In the cross-section view the player area 161 provides a flat surface on which to kneel. As is further shown, the outer layer 153 also includes a concave area 163 that at least partially encompassing the substantially planer area. FIG. 26 is a schematic block diagram, in a side view, of another embodiment of a knee protection apparatus 151 that includes an outer layer 153, an inner layer 155, a multi-layered force dampening and defusing structure 157, and an intermediate layer 159. The intermediate layer 159 includes a third material composition that includes a rubber material, a foam material, a padding material, a plastic material, a gel material, a carbon fiber material, and/or a silicon material. The multi-layer force dampening and defusing structure 157 includes one layer of components between the inner layer 155 and the intermediate layer 159 and includes a second layer of components between the intermediate layer 159 and the outer layer 153. From the front and side views, the first layer of components has a shape corresponding to a difference between the shapes of the inner and intermediate layers. In particular, the first layer of components 157 includes components 16 that are arranged to reduce pressure and where some components are longer than others. The second layer of components includes that are arranged to further reduce pressure and the components are of the same size. Note that the outer layer 153 may have a configuration as described with reference to FIG. 27. FIG. 28 is a schematic block diagram, in a side view, of an embodiment of a body limb protection apparatus 165 that includes an outer layer 171, an inner layer 169, and a force dampening and defusing structure 173 that includes one or more component layers. The outer layer 171 including a first material composition and has an exterior surface that includes a substantially planer area 167. The inner layer 169 includes a second material composition and has a shape corresponding to a body limb portion 175 (e.g., knee, shin, elbow, ankle, forearm, upper arm, thigh, calf, etc.). When the apparatus 165 is worn on the body limb portion, the inner layer 169 is adjacent to the body limb portion. The force dampening and defusing structure 173 is positioned between the inner layer 169 and the outer layer 171 and includes a plurality of layers of components. For an example of multiple component layers, an inner layer, and an outer layer, refer to Figure 15. The apparatus 165 functions to reduce pressure on the body limb portion when a force is applied from an impacting object (e.g., a baseball, a helmet, the ground, etc.). On a layer by layer basis, the apparatus dampens and defuses the impact force such that, by the time it reaches the body part, the impact force is substantially attenuated and distributed over a large area. FIGS. 29A and 29B are side and top views of a layer of components 16 arranged in a pattern 181 to produce a layer of an impact force dampening and defusing structure. In this embodiment, the components have a flat-top pyramid shape and are arranged in a pattern 181 of rows and columns. A component 16, from the side view of FIG. 29A, includes angled side walls, a top surface area (e.g., away from the body part), a base surface area (e.g., towards the body part), and a distance “d” 74. The distance “d” is the distance between the top surface area and the base surface area and ranges from 1/32 of an inch to multiple inches depending on the application of the body impact protection system. The angled side walls are at an angle of θ with respect to the horizontal axis, where the angle is in the range of 25 degrees to 89 degrees. Depending on the angle θ and the distance “d”, the base surface area is two or more times larger than the top surface area, where the top surface area is 1/256 square inches (e.g., 1/16 by 1/16) to tens of square inches depending on the application of the body impact protection system. The components are placed on an inner or intermediate layer that is flexible and allows each cell to move independently. This allows sheets of layers to be flexible and form fitting to a particular body part. Such layers of components may be molded, casted, printed, etc. as individual pieces and then adhered to the supporting layer. Alternatively, a layer of components is produced via or molding, casting, printing, etc. as a single piece. FIG. 30 is a schematic block diagram, in a side view, of an embodiment of a force defusing inert 185 for use in a variety of impact protection gear (e.g., as thigh pads, as shoulder padding, as rib padding, as shin padding, as elbow padding, etc.). The insert includes one or more layers of components 16, an outer layer 171, an inner layer 169, and an encasing 191. The one or more layers of components 16, an outer layer 171, an inner layer 169 are implemented in accordance with one or more embodiments previously discussed and/or as subsequently discussed. Note that the outer layer is on the impact receiving side 187 of the insert 185 and the inner layer 169 is on the impact defusing side 189. The encasing 191 houses the one or more layers of components 16, an outer layer 171, an inner layer 169 and is comprised of one or more materials that are flexible, provides additional padding, are moisture wicking, and/or are moisture absorbent. For example, the encasing 191 is comprised of a foam material, a padding material, a gel material, a cloth material, a polyester material, a moisture absorbing material, and/or a moisture wicking material. FIG. 31 is a schematic block diagram, in a side view, of another embodiment of a force defusing inert 185 that is similar to the one of FIG. 30 with the addition of a second component layer, an intermediate layer 195, and a padding layer 193. The two layers of components 16, the outer layer 171, the inner layer 169, the intermediate layer 195, and the padding layer 193 are implemented in accordance with one or more embodiments previously discussed and/or as subsequently discussed. FIG. 32 is a schematic block diagram, in a side view, of another embodiment of a force defusing inert 185 that includes eight layers of components 16, seven intermediate layers 195, the outer layer 171, the inner layer 169, and the encasing 191. The various elements of this insert 185 are implemented in accordance with one or more embodiments previously discussed and/or as subsequently discussed. FIG. 33 is a schematic block diagram, in a side view, of another embodiment of a force defusing inert 185 that includes a plurality of layers of components 16 (five in this example, but could be more or less), an inner layer 169, an outer layer 171, and an encasing 191. In this embodiment, the layers of components are in direct contact with each other (i.e., no intermediate layers). The various elements of this insert 185 are implemented in accordance with one or more embodiments previously discussed and/or as subsequently discussed. FIGS. 34 and 35 are side and front views of another embodiment of two force defusing layers for use in an impact protection system. The first layer includes 1st spherical objects 110 and the second layer includes 2nd spherical objects 112. Each layer is arranged in an array that, from layer to layer, is complimentary. Each of the spherical objects 110-112 is comprised of a material composition that will substantially maintain a spherical shape (e.g., up to 25% compression) when an impact force is exerted on the objects. For example, the spherical objects are comprised of a rubber material, a plastic material, stainless steel, aluminum, and/or a carbon fiber material. Further, the spherical objects 110-112 may be solid or hollow. Still further, the material composition is such that, as a result the collision, the magnitude of the impact force is reduced. In an example, one or more objects of the first spherical objects 110 receives an impact force and collides with two or more objects of the second spherical objects 112 at collision angles, respectively. As a result of the collision between spherical objects of the first and second spherical objects 110 and 112, each of the impact spherical objects of the second spherical objects 112 92 creates a normal force component and a tangential force component. If each of the first and second collision angles is 45 degrees and the spherical object of the first spherical objects 110 impacts the two or more objects of the second spherical objects 112 equally, then each of the objects in the second spherical objects receives an equal portion of the impact force at an angle of 45 degrees. Accordingly, the normal force components produced by each of the impacted spherical objects of the second spherical objects 112 is 1/x*F*sinθ, where F is the impact force, xis the number objects in the second layer of spherical objects that are impacted, and e is the collision angle. FIG. 36 is a schematic block diagram, in a side view, of another embodiment of a force defusing layers for use in an impact protection system that includes the first and second layers of spherical objects of FIGS. 34 and 35 and further includes an inner padding layer 116 and an outer layer 114. Note that the first spherical objects 110 and the second spherical objects 112 are of substantially identical spherical shapes, where the spherical shapes include a sphere, an ellipsoid, and/or a spheroid. The outer shell 114 is juxtaposed to the first layer of spherical objects 110 and is comprised of a material as used for other outer layers as described herein. The inner padding layer 116 is juxtaposed to the second layer of spherical objects 112 and is towards the body part being protected. The inner padding layer 116 is comprised on a material composition that includes a rubber material, a foam material, a padding material, a gel material, a cloth material, a polyester material, a moisture absorbing material, and/or a moisture wicking material. FIG. 37 is a schematic block diagram, in a side view, of another embodiment of a force defusing layers for use in an impact protection system that is similar to one of FIG. 36 with the addition of a third layer of spherical objects 118. A spherical object of the third layer 118 has a sphere shape, an ellipse shape, and/or a spheroid shape. The spherical object is comprised of a rubber material, a plastic material, stainless steel, aluminum, and/or a carbon fiber material. Further, the third spherical objects 118 may be solid or hollow. Still further, the material composition of the third spherical object is such that, as a result the collision, the magnitude of the impact force is reduced. FIG. 38 is a schematic block diagram, in a side view, of another embodiment of a force defusing layers for use in an impact protection system that is similar to one of FIG. 36 with the addition of a fill material 120. The fill material 120 at least partially encases at least some of the first spherical objects 110 and at least some of the second spherical shaped objects 112. The fill material has a force dampening property (e.g., a force dampening ratio of 0.5 to 0.95) and is comprised of a rubber material, a foam material, a padding material, and/or a gel material. FIG. 39 is a schematic block diagram, in a side view, of another embodiment of a force defusing layers for use in an impact protection system that is similar to one of FIG. 38 with the addition of a padding layer 122. The padding layer 122 force dampening property (e.g., a force dampening ratio of 0.5 to 0.95) and is comprised of a rubber material, a foam material, a padding material, and/or a gel material. FIG. 40 is a schematic block diagram, in a side view, of an example of an impact protection system that includes a plurality of component layers 50 54 60-64, an outer layer 24, an inner layer 12, and a plurality of intermediate layers 52 66-70. While the present example shows 5 component layers and 4 intermediate layers, the system could have more or less component layers and/or more or less intermediate layers. Each component layer 50 54 60-64 includes a first layer of spherical objects 110 and a second layer of spherical objects 112 as described with reference to FIGS. 34 and 35. When a force 96 impacts the outer layer, the component layers, on a layer by layer basis dampens and defuses the impact force 96. The intermediate layers 52 66-70 may further reduce the impact force such that, by the time the impact reaches the body part, it is substantially attenuated and spread out over a large area. The gray shaded spheres depict the diffusing of the impact force over a large and larger area with each layer. FIG. 41 is a schematic block diagram, in a side view, of another example of force diffusion via force defusing layers for use in an impact protection system, which is similar to the one of FIG. 40 with the subtraction of the intermediate layers. As, each layer of spherical objects are in direct contact with the next layer. The gray shaded spheres depict the diffusing of the impact force 96 over a large and larger area with each layer such that, by the time it reaches the inner layer 12, it has been spread out over a large area. FIG. 42 is a schematic block diagram, in a side view, of another embodiment of a force defusing layers for use in an impact protection system that includes a first component layer 50, a second component layer 54, an intermediate layer 52, and an inner padding layer 116. The first component layer 50 includes a first layer of spherical objects 110 and a second layer of spherical objects 112. The second component layer 54 also includes a first layer of spherical objects and a second layer of spherical objects, but are larger than the first and second layer spherical objects 110 and 112. FIGS. 43A-43C are schematic block diagrams, in a side view, of examples of impact force dampening and diffusion via force defusing layers of an impact protection system. FIG. 43A depicts the embodiment of FIG. 38 just prior to impact. FIG. 43B illustrates the embodiment of FIG. 38 having a rigid outer shell 114 that bows a little due to the impact force. Even though the outer shell does not bow much, a majority of the impact force is still applied to the spheres closest to the impact area. FIG. 43C illustrates the embodiment of FIG. 38 having a softer outer shell 114 bows due to the impact force. With the bowing the outer shell 114, the impact force is applied to the spheres within the impact area. FIGS. 44 and 45 are top and side views of another embodiment of a force defusing layers for use in an impact protection system. In this embodiment, spherical objects or components are grouped to produce an individual component group. Each component group is a separate piece that can be individually places to create various patterns and/or configurations. The groups 130 can be configured into layers 132, which can be stacked to create further patterns for the protection system. The impact protection system described herein has been directed towards the use of protecting body parts from injury due to an impact with an object. The impact protection system works equally well to protect parts of animals from an impacting object. The impact protection system further works to inanimate things from impacting objects, from being dropped during shipping, etc. It is noted that terminologies as may be used herein such as bit stream, stream, signal sequence, etc. (or their equivalents) have been used interchangeably to describe digital information whose content corresponds to any of a number of desired types (e.g., data, video, speech, audio, etc. any of which may generally be referred to as ‘data’). As may be used herein, the terms “substantially” and “approximately” provides an industry-accepted tolerance for its corresponding term and/or relativity between items. Such an industry-accepted tolerance ranges from less than one percent to fifty percent and corresponds to, but is not limited to, component values, integrated circuit process variations, temperature variations, rise and fall times, and/or thermal noise. Such relativity between items ranges from a difference of a few percent to magnitude differences. As may also be used herein, the term(s) “configured to”, “operably coupled to”, “coupled to”, and/or “coupling” includes direct coupling between items and/or indirect coupling between items via an intervening item (e.g., an item includes, but is not limited to, a component, an element, a circuit, and/or a module) where, for an example of indirect coupling, the intervening item does not modify the information of a signal but may adjust its current level, voltage level, and/or power level. As may further be used herein, inferred coupling (i.e., where one element is coupled to another element by inference) includes direct and indirect coupling between two items in the same manner as “coupled to”. As may even further be used herein, the term “configured to”, “operable to”, “coupled to”, or “operably coupled to” indicates that an item includes one or more of power connections, input(s), output(s), etc., to perform, when activated, one or more its corresponding functions and may further include inferred coupling to one or more other items. As may still further be used herein, the term “associated with”, includes direct and/or indirect coupling of separate items and/or one item being embedded within another item. As may be used herein, the term “compares favorably”, indicates that a comparison between two or more items, signals, etc., provides a desired relationship. For example, when the desired relationship is that signal 1 has a greater magnitude than signal 2, a favorable comparison may be achieved when the magnitude of signal 1 is greater than that of signal 2 or when the magnitude of signal 2 is less than that of signal 1. As may be used herein, the term “compares unfavorably”, indicates that a comparison between two or more items, signals, etc., fails to provide the desired relationship. One or more embodiments have been described above with the aid of method steps illustrating the performance of specified functions and relationships thereof. The boundaries and sequence of these functional building blocks and method steps have been arbitrarily defined herein for convenience of description. Alternate boundaries and sequences can be defined so long as the specified functions and relationships are appropriately performed. Any such alternate boundaries or sequences are thus within the scope and spirit of the claims. Further, the boundaries of these functional building blocks have been arbitrarily defined for convenience of description. Alternate boundaries could be defined as long as the certain significant functions are appropriately performed. Similarly, flow diagram blocks may also have been arbitrarily defined herein to illustrate certain significant functionality. The one or more embodiments are used herein to illustrate one or more aspects, one or more features, one or more concepts, and/or one or more examples. A physical embodiment of an apparatus, an article of manufacture, a machine, and/or of a process may include one or more of the aspects, features, concepts, examples, etc. described with reference to one or more of the embodiments discussed herein. Further, from figure to figure, the embodiments may incorporate the same or similarly named functions, steps, modules, etc. that may use the same or different reference numbers and, as such, the functions, steps, modules, etc. may be the same or similar functions, steps, modules, etc. or different ones. While particular combinations of various functions and features of the one or more embodiments have been expressly described herein, other combinations of these features and functions are likewise possible. The present disclosure is not limited by the particular examples disclosed herein and expressly incorporates these other combinations.
<SOH> BACKGROUND OF THE INVENTION <EOH>
<SOH> BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S) <EOH>FIG. 1 is a schematic diagram of an example of a conventional impact protection device receiving an impact force; FIG. 2 is a diagram of an example graph of the impact protection device of FIG. 1 that plots impact force versus impact area; FIG. 3 is a schematic block diagram, in a side view, of an embodiment of a body impact protection system in accordance with the present invention; FIG. 4 is a schematic block diagram, in a side view, of an embodiment of a defusing cell (i.e., component) of a layer of a body impact protection system in accordance with the present invention; FIG. 5 is a schematic block diagram, in a side view, of an example of force dampening and diffusion by a defusing cell (i.e., component) of a layer of a body impact protection system in accordance with the present invention; FIG. 6 is a schematic block diagram, in a top view, of an embodiment of a body impact protection system in accordance with the present invention; FIG. 7 is a schematic block diagram, in a side view, of another embodiment of a body impact protection system in accordance with the present invention; FIG. 8 is a schematic block diagram, in a side view, of an example of force components within a body impact protection system in accordance with the present invention; FIG. 9 is a schematic block diagram, in a side view, of another example of force components within a body impact protection system in accordance with the present invention; FIG. 10 is a graph of an example of impact force components v. body impact area of a body impact protection system in accordance with the present invention; FIG. 11 is a schematic block diagram, in a side view, of another embodiment of a body impact protection system in accordance with the present invention; FIG. 12 is a schematic block diagram, in a top view, of another embodiment of a body impact protection system in accordance with the present invention; FIG. 13 is a schematic block diagram, in a side view, of another example of force components within a body impact protection system in accordance with the present invention; FIGS. 14A-14B are a schematic block diagram of an example of force defusing and distribution layer by layer within a body impact protection system in accordance with the present invention; FIG. 15 is a schematic block diagram, in a side view, of another embodiment of a body impact protection system in accordance with the present invention; FIG. 16A is a graph of an example of an impact force pulse v. time; FIG. 16B is a graph of an examples of frequency responses of different layers of a body impact protection system having different resonant frequencies in accordance with the present invention; FIGS. 17A-17E are a schematic block diagram of an example of force defusing and distribution layer by layer within a body impact protection system in accordance with the present invention; FIG. 18 is a schematic block diagram, in a side view, of another embodiment of a body impact protection system in accordance with the present invention; FIG. 19 is a schematic block diagram, in a side view, of another embodiment of a defusing cell of a layer of a body impact protection system in accordance with the present invention; FIG. 20 is a schematic block diagram, in a side view, of another embodiment of a defusing cell of a layer of a body impact protection system in accordance with the present invention; FIGS. 21A-21F are a schematic block diagrams, in a top view, of other embodiments of a defusing cell of a layer of a body impact protection system in accordance with the present invention; FIGS. 21G-21J-2 are diagrams of another defusing cell or component in accordance with the present invention; FIGS. 21K-21N are diagrams of another defusing cell or component in accordance with the present invention; FIGS. 210 and 21Q-21S-2 are diagrams of another defusing cell or component in accordance with the present invention; FIG. 21T is a top and side view of a layer of components in accordance with the present invention; FIGS. 21U-21V are diagrams of another defusing cell or component in accordance with the present invention; FIGS. 21W-21X are diagrams of another defusing cell or component in accordance with the present invention; FIG. 21Y is a side view of a layer of components in accordance with the present invention; FIGS. 21Z-21AB are diagrams of another defusing cell or component in accordance with the present invention; FIG. 21AC is a top view of a layer of components in accordance with the present invention; FIG. 21AD is a top view of a layer of components in accordance with the present invention; FIG. 21AE is a top view of a layer of components in accordance with the present invention; FIG. 21AF is a top view of two overlapping layers of components in accordance with the present invention; FIG. 22 is a schematic block diagram, in a side view, of another embodiment of a layer of a body impact protection system in accordance with the present invention; FIG. 23A is a schematic block diagram, in a cross section front view, of an embodiment of a helmet at the instant of an impact. FIG. 23B is a schematic block diagram, in a cross section front view, of an embodiment of a helmet at compression of the padding as result of an impact. FIG. 23C is a schematic block diagram, in a cross section front view, of an embodiment of a helmet at movement of the brain within the skull as result of an impact. FIG. 23D is a schematic block diagram, in a side view, of an embodiment of a helmet that includes a body impact protection system in accordance with the present invention; FIG. 23E is a schematic block diagram, in a side view, of a portion of an embodiment of a helmet that includes a body impact protection system in accordance with the present invention; FIG. 23F is a schematic block diagram, in a side view, of a portion of an embodiment of a helmet that includes a body impact protection system receiving an angular impact force in accordance with the present invention; FIG. 23G is a schematic block diagram, in a side view, of a portion of an embodiment of a helmet that includes a body impact protection system dampening and defusing an angular impact force in accordance with the present invention; FIG. 24A is a schematic block diagram, in a side view, of an embodiment of a chest protector that includes a body impact protection system in accordance with the present invention; FIG. 24B is a schematic block diagram, in a side view, of an embodiment of a chest protector that includes a body impact protection system in accordance with the present invention; FIG. 25 is a schematic block diagram, in a side view, of an embodiment of a knee protection apparatus that includes a body impact protection system in accordance with the present invention; FIG. 26 is a schematic block diagram, in a side view, of another embodiment of a knee protection apparatus that includes a body impact protection system in accordance with the present invention; FIG. 27 is a schematic block diagram, in a side view, of an embodiment of a body impact protection system for use in a knee protection apparatus in accordance with the present invention; FIG. 28 is a schematic block diagram, in a side view, of an embodiment of a body limb protection apparatus that includes a body impact protection system in accordance with the present invention; FIG. 29A is a schematic block diagram, in a side view, of another embodiment of a body impact protection system in accordance with the present invention; FIG. 29B is a schematic block diagram, in a top view, of another embodiment of a body impact protection system in accordance with the present invention; FIG. 30 is a schematic block diagram, in a side view, of an embodiment of a force defusing inert for use in an impact protection system in accordance with the present invention; FIG. 31 is a schematic block diagram, in a side view, of another embodiment of a force defusing inert for use in an impact protection system in accordance with the present invention; FIG. 32 is a schematic block diagram, in a side view, of another embodiment of a force defusing inert for use in an impact protection system in accordance with the present invention; FIG. 33 is a schematic block diagram, in a side view, of another embodiment of a force defusing inert for use in an impact protection system in accordance with the present invention; FIG. 34 is a schematic block diagram, in a side view, of another embodiment of a force defusing layers for use in an impact protection system in accordance with the present invention; FIG. 35 is a schematic block diagram, in a top view, of another embodiment of a force defusing layers for use in an impact protection system in accordance with the present invention; FIG. 36 is a schematic block diagram, in a side view, of another embodiment of a force defusing layers for use in an impact protection system in accordance with the present invention; FIG. 37 is a schematic block diagram, in a side view, of another embodiment of a force defusing layers for use in an impact protection system in accordance with the present invention; FIG. 38 is a schematic block diagram, in a side view, of another embodiment of a force defusing layers for use in an impact protection system in accordance with the present invention; FIG. 39 is a schematic block diagram, in a side view, of another embodiment of a force defusing layers for use in an impact protection system in accordance with the present invention; FIG. 40 is a schematic block diagram, in a side view, of an example of force diffusion via force defusing layers for use in an impact protection system in accordance with the present invention; FIG. 41 is a schematic block diagram, in a side view, of another example of force diffusion via force defusing layers for use in an impact protection system in accordance with the present invention; FIG. 42 is a schematic block diagram, in a side view, of another embodiment of a force defusing layers for use in an impact protection system in accordance with the present invention; FIGS. 43A-43C are schematic block diagrams, in a side view, of examples of impact force dampening and diffusion via force defusing layers of an impact protection system in accordance with the present invention; FIG. 44 is a schematic block diagram, in a top view, of another embodiment of a force defusing layers for use in an impact protection system in accordance with the present invention; and FIG. 45 is a schematic block diagram, in a side view, of another embodiment of a force defusing layers for use in an impact protection system in accordance with the present invention. detailed-description description="Detailed Description" end="lead"?
A41D13015
20170814
20180222
94510.0
A41D13015
0
VANATTA, AMY B
BODY LIMB PROTECTION SYSTEM
SMALL
0
PENDING
A41D
2,017
15,677,081
PENDING
STANDARD MOBILE COMMUNICATION DEVICE DISTRACTION PREVENTION AND SAFETY PROTOCOLS
Methods and systems for providing standardized mobile device distraction prevention and safety protocols are disclosed. In particular, an embodiment of a method for activating a distraction prevention or safety protocol behavior in a mobile device when the mobile device satisfies a specific condition is disclosed. The method includes discovering one or more protocol activators configured to transmit discovery information associated with a specific condition. The method further includes activating distraction prevention safety protocol behavior in the mobile device based at least in part on the discovery information. In an implementation, the specific condition may be a specified environment itself and or include an event when the mobile device enters a specified environment or a specified sequence of numbers is dialed from the mobile device.
1. A method of activating a protocol behavior in a mobile device within a specified environment comprising: broadcasting, by a protocol activator, a first trigger signal in the specified environment; and including, by the protocol activator, a discovery information in the first trigger signal, wherein the discovery information associated with the first trigger signal corresponds to a modified universally unique identification (UUID) code of the protocol activator, and wherein at least a portion of the modified UUID code identifies at least one of: a specified environment in which the protocol activator operates, and a specified working group information in the specified environment in which the protocol activator operates; and wherein the discovery information broadcast from the protocol activator in the first trigger signal causes activation of the protocol behavior in the mobile device within the specified environment. 2. The method of claim 1, further comprising broadcasting, by the protocol activator, a second trigger signal in the specified environment. 3. The method of claim 2, wherein the first trigger signal is broadcast over a first wireless medium and the second trigger signal is broadcast over a second wireless medium, wherein the second wireless medium is different than the first wireless medium. 4. The method of claim 3, wherein at least one of the first wireless medium and the second wireless medium is acoustic or radio frequency (RF). 5. The method of claim 3, wherein at least one of the first trigger signal and the second trigger signal is broadcast over a frequency other than one or more frequencies used within the specified environment for talk and text. 6. The method of claim 5, wherein at least one of the first trigger signal and the second trigger signal is broadcast using at least one of Bluetooth, Radio Frequency Identification (RFID), EdOcean, TransferJet, Ultra Wideband (UWB), Wireless USB, DSRC, IrDAa, Wireless Fidelity (WiFi), Zigbee, Near Field Communication (NFC), and Wireless Personal Area Network (WPAN). 7. The method of claim 1, further comprising responding, by the protocol activator, to a query for information. 8. The method of claim 1, wherein the protocol behavior corresponds to at least a partial disablement of functionality of the mobile device. 9. The method of claim 1, wherein the specified environment corresponds to at least one of a transportation vehicle, a school, a class room, a correctional facility (prison), an airport, an airplane, a court room, a hospital, a church, a theatre, a fly zone, a danger zone, a bedroom, and an auditorium. 10. A protocol activator for activating a protocol behavior in a mobile device within a specified environment, comprising: a memory configured to store software instructions; and a processor configured to access the software instructions from the memory; the processor configured to access the software instructions from the memory to: broadcast at least two trigger signals within the specified environment, each trigger signal of the at least two trigger signals comprising discovery information associated with the respective trigger signal corresponding to a modified universally unique identification (UUID) code, and wherein at least a portion of the modified UUID code identifies at least one of: a specified environment in which the protocol activator operates, and a specified working group information in the specified environment in which the protocol activator operates; wherein the discovery information broadcast in at least one of the at least two trigger signals causes activation of the protocol behavior in the mobile device within the specified environment; and wherein each of the at least two trigger signals is broadcast via a different wireless medium. 11. The protocol activator of claim 10, wherein the processor is further configured to execute the software instructions from the memory to further respond to a query for information. 12. The protocol activator of claim 10, wherein the protocol behavior corresponds to at least a partial disablement of functionality of the mobile device. 13. The protocol activator of claim 10, wherein the specified environment corresponds to at least one of a transportation vehicle, a school, a class room, a correctional facility (prison), an airport, an airplane, a court room, a hospital, a church, a theatre, a fly zone, a danger zone, a bedroom, and an auditorium. 14. A mobile device comprising: a memory configured to store software instructions in at least one program module; and a processor configured to executed the software instructions from the at least one program module in the memory; wherein the processor is configured to execute the software instructions in the at least one program module to: discover at least one discovery information trigger signal transmitted by at least one protocol activator corresponding to a modified universally unique identification (UUID) code, wherein at least a portion of the modified UUID code identifies a specified environment corresponding to a protocol behavior; and activate the protocol behavior in the mobile device based on the modified UUID code. 15. The mobile device of claim 14, wherein one or more of the at least one discovery information trigger signal is received via Bluetooth or Wi-Fi. 16. The mobile device of claim 14, wherein one or more of the at least one discovery information trigger signal is received via satellite. 17. The mobile device of claim 14, wherein the protocol behavior corresponds to at least a partial disablement of functionality of the mobile device. 18. The mobile device of claim 14, wherein the specified environment corresponds to at least one of a transportation vehicle, a school, a class room, a correctional facility (prison), an airport, an airplane, a court room, a hospital, a church, a theatre, a fly zone, a danger zone, a bedroom, and an auditorium. 19. The mobile device of claim 14, wherein the activation comprises determining, from a look up table, the protocol behavior corresponding to the discovery information trigger signal. 20. The mobile device of claim 14, wherein the discovering comprises searching for at least one protocol activator in the specified environment. 21. The mobile device of claim 14, wherein the discovering is in response to the mobile device entering a proximity range of at least one protocol activator. 22. The mobile device of claim 14, wherein the processor is further configured to execute the software instructions from the memory to further query the at least one protocol activator.
PRIORITY APPLICATIONS This application is a continuation application of and claims priority to U.S. patent application Ser. No. 15/368,856 filed on Dec. 5, 2016, which is a continuation of and claims priority to U.S. patent application Ser. No. 15/075,327 filed on Mar. 21, 2016, now issued as U.S. Pat. No. 9,584,652, which is a continuation application of and claims priority to U.S. patent application Ser. No. 12/883,583 filed on Sep. 16, 2010, now issued as U.S. Pat. No. 9,294,603, which is a continuation-in-part application of and claims priority to U.S. patent application Ser. No. 12/585,503 filed on Sep. 16, 2009, now abandoned, all of which are incorporated herein by reference in their entireties. U.S. patent application Ser. No. 12/883,583 filed on Sep. 16, 2010, now issued as U.S. Pat. No. 9,294,603, also claims priority to U.S. Provisional Patent Application Ser. No. 61/343,490 filed Apr. 29, 2010, U.S. Provisional Patent Application Ser. No. 61/284,635 filed Dec. 21, 2009, U.S. Provisional Patent Application Ser. No. 61/283,286 filed Dec. 2, 2009, U.S. Provisional Patent Application Ser. No. 61/277,664 filed Sep. 28, 2009, and U.S. Provisional Patent Application Ser. No. 61/277,156 filed Sep. 21, 2009, all of which are incorporated herein by reference in their entireties. FIELD OF INVENTION The present invention generally relates to standard cellular/mobile device distraction prevention and safety protocols. In particular, the present invention relates to the development and standardization of mobile device protocols and protocol sensors to control functionalities of a mobile communication device (also known and referred to as mobile device, cell phone, smart phone, mobile phone, skype phone, satellite phone, laptop, net book, net pad, etc.) when the mobile device satisfies a specific condition, such as, entering a specified environment or location or area, etc. containing a protocol enabled sensor. BACKGROUND Over the past few decades, the cellular/wireless industry has advanced by leaps and bounds. Throughout the world, mobile devices have become a ubiquitous part of everyday life. The enormous proliferation of the mobile device is nothing short of incredible. But, with it has surfaced a host of major problems much to the detriment of society. Every technical advancement and development has certain associated challenges and the cell phone is no exception. Many inherent life threatening problems are gaining light speed momentum. Such problems include increased accidents from driver distraction due to mobile devices, increased disruption and cheating in the classroom, increased contraband, gang activity, and death threats from inside the prison system etc. These problems come with a magnificent cost. For example, the World Health Organization (WHO) estimates that distracted driving alone costs developed countries between one and three percent of GDP. A few mobile application attempts have been made to solve the problem behind the wheel and some cell frequency jamming attempts have been tried in various prison systems. Such solutions, however, face impenetrable obstacles such as: current law in various countries, uninstalling the application, turning off the Bluetooth, Bluetooth pairing requirements, GPS latency and signal lapses, large number of varied mobile platforms, continuous updating, closed platforms, battery drain, and the inability to affect Skype™ and satellite phones which prisoners easily obtain. The most significant obstacle facing all solution providers is the lack of universal standards within the mobile device industry. Currently, the mobile device manufacturers have no universal platform for developing standard safety technologies. Since there are no standards, even a simple safety feature cannot be universally applied across all mobile devices. And since safety is a global concern, a solution which can only be applied to select mobile devices is not preferred. In order to combat these societal problems, there exists a well felt need to design and implement universal distraction prevention and safety technologies for all mobile communication devices. Because there are hundreds of different cell phone makes and models combined with open, closed & partially closed configurations, developing a single simple comprehensive solution for all mobile phone architectures is considered impossible. Notwithstanding such impediments, the task to effectively implement safety standards and methods to prevent cellular distractions to benefit society must be carried out in a timely and undisruptive manner. In addition, other current obstacles include but are not limited to quick detection and connectionless non-pairing communication with Bluetooth devices, deterioration of cellular battery life, quick and easy application disablement. Moreover, existing systems and methods only provide a partial solution for a single environment. For example, jamming in prisons which is illegal in many countries prohibits emergency calling and is therefore undesirable for schools and hospitals and such. Art to provide solutions for distracted driving requires some form of pairing which makes an automatic universal application impossible. The pairing dilemma in essence makes each mobile device car specific. For example, even if such a system is installed on a teen's car, should the teen drive the parent's car or sibling's car or friend's car, the mobile application will not work unless an entirely new pairing is involved for that specific car. It also creates the problem requiring a new software upload for each system change or system upgrade to correspond to the changed system. Such a system leaves parents and employers frustrated as the system no longer works properly. Also, parents and employers won't have any available working system if they happen to purchase a phone with a closed architecture thereby preventing system functionality inhibition. There is, therefore, a need for a simple, cost effective improvement to mobile communication technologies to adopt and implement a standardized set of safety protocols such that new safety enhancement systems and methods to prevent mobile distractions can easily be engineered and adopted for all new and existing mobile phones. There is also a need for a simple, cost effective improvement to Bluetooth technology devices to apply a universal set of address codes to work in tandem with the mobile device embedded distraction prevention protocols. SUMMARY OF INVENTION It is, therefore an object of the present invention, to provide a set of standard mobile communication device distraction prevention and safety protocols to be embedded in the mobile device firmware (system memory or system image) and to provide various applicable sensors to be adopted universally throughout the mobile communications industry for providing safety enhancement systems and methods to prevent mobile device distractions. It is a further object of the present invention to provide a new and useful set of standard Bluetooth address codes to work in conjunction with protocol enabled mobile devices and facilitate communication with the proposed mobile distraction prevention protocols. It is yet another object of the present invention to provide a safety enforcement system that produces a signal visible outside a vehicle whenever the driver is operating the vehicle in an unsafe or unlawful manner. It is also an object of the present invention, to provide a set of mobile device safety protocols to be embedded in the mobile device firmware for the purpose of simple uniform adoption of future safety enhancements. Methods and systems for providing standard mobile communication device safety and distraction prevention protocols are disclosed. In an embodiment, a method for activating a distraction prevention safety protocol behavior in a mobile device when the mobile device satisfies a specific condition is disclosed. The method includes discovering at least one protocol activators configured to transmit discovery information associated with the specific condition. The method further includes activating safety protocol behavior in the mobile device based at least in part on the discovery information. In an implementation, the specific condition corresponds to at least one of two events being when the mobile device enters a specified environment and when the mobile device enters or a specified sequence of numbers is dialed from the mobile device. A method of controlling functionality of a mobile device within a specified environment is disclosed. In an implementation, the method includes broadcasting a trigger signal within the specified environment and determining discovery information associated with the trigger signal and the specified environment. The method further includes implementing a set of protocol instructional behaviors in the mobile device based at least in part on the discovery information and the specified environment. Such an implementation of the set of protocol instructional behavior results in a restricted functionality of the mobile device. A system for implementing safety protocols in a mobile device is disclosed. According to an embodiment, the system includes a call authorization module configured to execute a protocol behavior in the mobile device based at least in part on discovery information. The discovery information is transmitted by one or more sensors in the specified environment and corresponds to a specified environment in which the mobile device operates. A method for controlling behavior of a mobile device inside a transportation vehicle is disclosed. According to an implementation, the method includes activating a sensor configured to broadcast a trigger signal within a pre-determined limited range inside the vehicle. The method further includes implementing a protocol behavior in the mobile device based at least in part on the trigger signal. The activation of the sensor is based on a state or a position of one or more vehicular components and/or a tilt switch mechanism configured to determine vehicular movement. A vehicle occupant safety system is disclosed. In an implementation, the system includes a smart phone comprising a first computing system for signal processing and a trigger signal emitter for use by a passenger of a vehicle. The trigger signal emitter is in communication with a second computing system when the passenger is inside the vehicle. The second computing system is configured to control operational functions of the vehicle. The system further includes a processing logic associated with the second computing system for determining when the vehicle concluded operation and for detecting a signal from the trigger signal emitter. The detection occurs in such a manner that the second computing system is activated to send a distress signal when the passenger has remained inside the vehicle for a predetermined time subsequent to concluded operation of the vehicle. A system for enforcement of safety protocols is disclosed. In an implementation, the system includes a mobile device configured to communicate with at least one vehicular component inside a transportation vehicle to determine an unsafe driving based on safety protocols configured in the mobile device. The system further includes an exterior vehicle warning signal indicator (WSI) configured to issue visible warning signals based on the determination by the mobile device. A system for implementing mobile safety protocols is disclosed. In an embodiment, the system includes a self-powered Bluetooth sensor assembly configured to transmit discovery information without an external power supply. The system further includes a mobile device configured to determine and implement a safety protocol behavior based on the discovery information. The discovery information corresponds to a name of the self-powered Bluetooth sensor and a class of a specified environment in which the self-powered Bluetooth sensor operates. To the accomplishment of the above and related objects, this invention may be embodied in the form illustrated in the accompanying drawings, attention being called to the fact, however, that the drawings are illustrative only, and that changes may be made in the specific construction illustrated. BRIEF DESCRIPTION OF FIGURES To further clarify the above and other advantages and features of the present invention, a more particular description of the invention will be rendered with reference to specific embodiments thereof, which are illustrated in the appended drawings. It is appreciated that these drawings depict only typical embodiments of the invention and are therefore not to be considered limiting of its scope. The invention will be described and explained with additional specificity and detail with the accompanying drawings in which: FIG. 1 illustrates a system for providing standard mobile device safety protocols according to an embodiment; FIG. 2 illustrates a block diagram of a mobile device in accordance with an embodiment; FIG. 3 illustrates Bluetooth address codes implemented in Bluetooth sensors in an embodiment; FIG. 4 illustrates a self-powered Bluetooth sensor assembly according to an implementation; FIG. 5 illustrates a system for enforcement of safety protocols according to an embodiment; FIG. 6 illustrates location of vehicular components, engine control unit, and mobile device in a vehicle according to an embodiment; FIG. 7 illustrates a system for ensuring safety of child or vehicle occupant in an embodiment; FIG. 8 illustrates a method for activating a safety protocol behavior in mobile device according to an embodiment; FIG. 9 illustrates a method of controlling functionality of mobile device within specified environment according to an embodiment; and FIG. 10 illustrates a method for controlling behavior of mobile device inside transportation vehicle according to an embodiment. DETAILED DESCRIPTION OF DRAWINGS As described earlier, numerous benefits that a mobile device offers coexist with certain life threatening problems like accidents due to driver distraction, security breach in prisons, cheating in classrooms, etc. Conventional solutions have proved to be unsatisfactory due to lack of universality, simplicity, and cost effectiveness. The biggest challenge faced in the mobile industry today is the lack of a standard platform for development of safety protocols that can be implemented across mobile devices from different manufacturers. To this end, standard safety methods and systems are proposed for activating a safety protocol behavior in a mobile device when the mobile device satisfies a specific condition. In an embodiment, the method includes discovering at least one protocol activators configured to transmit discovery information associated with the specific condition. The method further includes activating safety protocol behavior in the mobile device based at least in part on the discovery information. In an implementation, the specific condition corresponds to at least one of two events being when the mobile device enters a specified environment and when the mobile device enters or a specified sequence of numbers is dialed from the mobile device. The disclosed safety protocol behavior permits emergency calls to one or more pre-determined or programmable numbers. For example, in any case of specified environment, the safety protocols allow calls to be made to special numbers during emergency, such as, “911” in United States, “112” in India, etc. Such special numbers can be preprogrammed and included as exceptions to any protocol instructional behavior. FIG. 1 illustrates a system 100 for providing standard cellular safety protocols according to an embodiment. As shown, the system 100 includes a mobile device 102 that implements the safety protocol(s) when the mobile device satisfies specific condition(s). Throughout the text, the term “mobile device” can refer to cellular phone, smart phone, cell phone, wireless phone or other similar devices offering capabilities of calling, text messaging, etc. using wireless medium via a communication network. In addition, for purposes of the ongoing description, the mobile device 102 corresponds to a communication device with inbuilt capabilities for sending and receiving signals in addition to the device's talk/text frequency band. Capable methods include but are not limited to NFC, Bluetooth, WiFi, Satellite, Skype, RFID, ZigBee, EdOcean, TransferJet, Ultra Wideband (UWB), Wireless USB, DSRC, IrDAa, and Wireless Personal Area Network (WPAN) etc. For example, the mobile device 102 can be Bluetooth enabled capable of Bluetooth transmission and reception. In an embodiment, the specific conditions include event such as, the mobile device 102 entering a specified environment or dialing a specific sequence of numbers from the mobile device, etc. The specific conditions may also correspond to events such as, but not limited to, an unlawful or unsafe operation of vehicle, an accident, a fight, deployment of an airbag in a vehicle, or other conditions that need immediate or timely attention. The proposed standard mobile device safety protocols can be so implemented that any set of specific conditions can be included by the standard approving body. Although, only a few cases of specific conditions have been disclosed, it may be appreciated that the proposed systems and methods for implementing mobile device safety protocols allow for future modification and/or update of the set of specific conditions to accommodate future needs of the society and law enforcement agencies. The specified environment includes a transportation vehicle, a school, a class room, a correctional facility, an airport, an airplane, a court room, a hospital, a church, a theatre, a fly zone, a danger zone, an auditorium, a room in a house or any other environment for which disabling operational functions on a mobile device may be desired. In an exemplary scenario for a safety protocol implementation, a user 104 carries the mobile device 102 and enters a specified environment such as a prison, or a hospital (thereby satisfies the specific condition). The system 100 includes one or more protocol activators (or “sensors”) 106 (e.g. 106a, 106b, and 106c) installed at various locations in the specified environment. In an embodiment, the one or more protocol activators 106 correspond to one or more sensors capable of transmitting and receiving signals pertaining to technologies such as, but not limited to, a Bluetooth sensor, Radio Frequency Identification (RFID) tag reader, a EdOcean sensor, a TransferJet sensor, an Ultra Wideband sensor, a UWB, a Wireless USB, a DSRC sensor, an IrDAa sensor, Wireless Fidelity (WiFi) sensor, a Zigbee sensor, a Near Field Communication (NFC) sensor, and a Wireless Personal Area Network (WPAN) sensor, etc. It may be appreciated that the mobile device 102 is pre-equipped with such safety and distraction prevention protocols and in various embodiments, supports a communication between the mobile device 102 and the protocol activators 106 within a pre-determined communication range. In addition, the protocol activators 106 are characterized by a pre-determined device name or class or address, etc. associated with the specified environment. The mobile device 102 includes a Call Authorization Module (CAM) (also referred to as software instructions, mobile application, etc.) 108 that coordinates the activation of the safety protocols in the mobile device 102. In the exemplary implementation, the protocol activators 106 transmit discovery information (sending a trigger signal) associated with the specified environment. The discovery information may include device name or class, or address associated with the protocol activators 106. The class of the protocol activators 106 provides information about the specified environment. The call authorization module 108 discovers (or receives the discovery information or trigger signal from) the protocol activators 106 as soon as the mobile device 102 enters the communication range of the protocol activators 106. In an alternative embodiment, the call authorization module 108 may instruct the mobile device 102 to transmit one or more request signals to obtain additional discovery information in cases where the protocol activators 106 correspond to passive sensors. The CAM 108 determines distraction prevention safety protocol behavior(s) corresponding to the discovery information and activates the safety protocol behavior in the mobile device 102. Safety protocol behavior can correspond to enabling or disabling partially or wholly one or more functionalities associated with the mobile device 102. Such functionalities may include existing calling function, text function, a switching “on” or “off” function, a silent operation mode, etc. Safety protocol behavior may also correspond to a special mode of operation of the mobile device 102 in which the mobile device 102 is configured to automatically perform or not perform certain functions. Special mode of operation can correspond to a code of predetermined conduct associated with the specified environment or other special actions that the mobile device 102 performs automatically upon the onset of specific condition. It may be desirable to implement safety protocol(s) in a manner that differentiates each user based on certain identification process or tagging. For instance, the user may wear an RFID tag 110 which enables the system 100 to identify the user as belonging to a particular working group. It may be appreciated that the user 104 of the mobile device 102 can correspond to different groups of people such as but not limited to an intruder, a guard, a driver, a thief or the like. In one of the implementations, the CAM 108 gathers additional information associated with specified working group in the specified environment. The working group may correspond to a designated group of people who will carry mobile devices that can be treated as exceptions to the safety protocol behavior. The system 100 allows the creation of such working groups who will have special privileges even when they carry mobile devices into the specified environment. For instance, a guard or official in a specified environment, such as, a prison may need to use a mobile device 102 under emergencies (in cases of prison riot, etc.). In such cases, the CAM 108, upon identification of the working group, may implement a safety protocol behavior corresponding to the class of the specified environment and the identified working group. In an implementation, the protocol instructional behaviors implemented in the mobile device 102 permits emergency calls to one or more pre-determined or programmable numbers. For example, in any case of specified environment, the safety protocols allow calls to be made to special numbers during emergency, such as, “911” in United States, “112” in India, etc. Such special numbers can be preprogrammed and included as exceptions to any protocol instructional behavior. In another example, the safety protocols can allow calls to a special number (parent's number) if the mobile device is carried by a child. The programming of such special numbers may be a feature that is provided by the mobile phone manufacturer or the service provider. The safety protocols can be so configured to accommodate such features. FIG. 2 illustrates a block diagram of a mobile device 102 in accordance with an embodiment. The mobile device 102 can correspond to any communication device, cellular phone, smart phone, personal digital assistant (PDA), mobile paging device, mobile gaming device, netbook, netpad, laptop, or computer that offers one or more capabilities to make/receive calls, send/receive text messages or electronic mails, play video games, etc. In a very basic configuration, mobile device 102 typically includes at least one processing unit 202 and system memory 204. Depending on the exact configuration and type of mobile device, system memory 204 may be volatile (such as RAM), non-volatile (such as ROM, flash memory, etc.), or some combination of the two. System memory 204 typically includes an operating system or system image; one or more program modules 206, and may include program data 208. The processor 202 accesses the memory 204 to execute instructions or applications stored as program modules 206 to perform one or more predetermined functions. The memory 204 stores associated data in program data 208. The program module(s) 206 includes the call authorization module 108, query module 210, safety protocol module 212, communication module 214, and other modules 216. The program data 208 includes discovery information 218, look up tables (LUT) 220, Bluetooth address codes 222, other data (flag values, variables) 224. In addition, the mobile device 102 also includes an inbuilt antenna 226. It may be appreciated that the mobile device 102 may have various features available in all modern day mobile phones or smart phones. Only selected few of the features, functionalities, and modules have been disclosed that find relevance with respect to the ongoing description. For example, mobile device 102 may also have input device(s) such as keypad, stylus, or a pen, voice input device, touch input device, etc. Output device(s) such as a display 228, speakers, etc. may also be included. The display 228 may be a liquid crystal display, or any other type of display commonly used in mobile devices. The display 228 may be touch-sensitive, and would then act as an input device. The mobile device 102 also includes RFID reader 230 configured to detect and read RFID tags on employee badges worn by a user of the mobile device 102. Such devices are well known in the art and need not be discussed at length here. The communication module 214 allows the mobile device 102 to communicate with other devices over a network. The communication module 214 is an example of a communication media. Communication media may typically be embodied by computer readable instructions, data structures, program modules, or other data in a modulated data signal, such as a carrier wave or other transport mechanism, and include any information delivery media. The term “modulated data signal” means a signal that has one or more of its characteristics set or changed in such a manner as to encode information in the signal. By way of example, and not limitation, communication media includes wired media such as a wired network or direct-wired connection, and wireless media such as acoustic, RF, Bluetooth, Zigbee, Wi-Fi, Skype, Satellite and other wireless media. The term computer readable media as used herein includes both storage media and communication media. One or more application programs may be loaded into memory 204 and run on the operating system stored in other modules 216. Examples of application programs include phone dialer programs, email programs, scheduling programs, PIM (personal information management) programs, word processing programs, spreadsheet programs, Internet browser programs, and so forth. The mobile device 102 also includes non-volatile storage (not shown) within the memory 204. The non-volatile storage may be used to store persistent information which should not be lost if the mobile device 102 is powered down/off. The applications may use and store information in the storage, such as e-mail or other messages used by an e-mail application, contact information used by a PIM, appointment information used by a scheduling program, documents used by a word processing program, and the like. The mobile device 102 includes a power supply (not shown), which may be implemented as one or more batteries. The power supply might further include an external power source, such as an AC adapter or a powered docking cradle that supplements or recharges the batteries. The mobile device 102 may also include external notification mechanisms such as an LED and an audio interface. Such devices may be directly coupled to the power supply so that when activated, they remain on for a duration dictated by the notification mechanism even though the processor 202 and other components might shut down to conserve battery power. The LED may be programmed to remain on indefinitely until the user takes action to indicate the powered-on status of the device. The audio interface can be used to provide audible signals to and receive audible signals from the user. For example, the audio interface may be coupled to a speaker for providing audible output and to a microphone for receiving audible input, such as to facilitate a telephone conversation. The communication module 214 performs the function of transmitting and receiving radio frequency communications. The communication module 214 facilitates wireless connectivity between the mobile device 102 and the outside world, via. a communications carrier or service provider. Transmissions to and from the communications module 214 can be conducted under control of the operating system in other module 216. In other words, communications received by the communication module 214 may be disseminated to application programs via the operating system, and vice versa. In operation, the call authorization module (CAM) 108 manages the implementation of safety protocol behavior when the mobile device 102 satisfies specific condition. For instance, whenever the mobile device 102 enters a specified environment, such as a prison, the call authorization module 108 instructs the communication module 214 to discover one or more sensors (or protocol activators) 106 deployed at various locations in the specified environment. The communication module 214 provides the mobile device 102 with communication capabilities with the one or more sensors 106 via. Bluetooth transmission or RFID, WiFi, Zigbee, and Near Field transmissions depending on the type of sensors deployed. It may be noted that each of the one or more sensors 106 can be characterized by a Universally Unique Identifier (UUID), such as Media Access Control addresses in case of Bluetooth sensors. Alternatively, the one or more sensors 106 can be standardized to implement the safety protocols by assigning a specific code for a specified device name, device class, and device type. As described earlier, the one or more sensors 106 are configured to transmit trigger signals in the specified environment. The communication module 214 receives such trigger signals and the discovery information transmitted by the one or more sensors 106. In an alternative embodiment, the query module 210 queries the one or more sensors 106 for discovery information. Such a querying comes handy in case of passive sensors 106. The discovery information corresponds to device name of the sensors and class information associated with the specified environment. The one or more sensors 106 broadcast the discovery information in the form of a set of alphanumeric characters. Each such set would correspond to a specified environment and a protocol behavior. Another case where such a query would be possible is when there are different working groups having different desirable behaviors associated with their mobile devices. In such cases, the query module 210 instructs RFID reader 230 to detect and read RFID tags on the employee badges of the people to determine working group. The discovery information is saved in discovery information 218 of program data 208. Upon receipt of the discovery information, the call authorization module 108 is configured to determine a protocol behavior in the mobile device 102 based on the discovery information. In an embodiment, the discovery information may also include working group information in addition to the class of the specified environment. In operation, the CAM 108 instructs the safety protocol module 212 to determine a protocol behavior corresponding to the received discovery information. Standard Mobile Communication Device Safety Protocols Table 1 illustrates an exemplary representation of a set of standard mobile device safety and distraction prevention protocols. The working group may be standardized and included in the firmware of all mobile devices 102 from different manufacturers. The first column corresponds to a code, the second column corresponds to a working group, the third column refers to the contents corresponding to a given code, and forth column refers to the protocol behavior for the mobile device 102. Consider an example of a typical MAC address: UUID-11:A2:23:FE:40 As shown in the table, “11:A2” represents the working group, and depending upon the contents, corresponding protocol behavior can be selected. TABLE 1 Working Code group Contents Meanings 2 11:A2 11111111 Tells the phone that it is located in a defined area of driver's seat. Functions will be inhibited 3 22222222 Tells the phone the vehicle's trans- mission is not in park. Functions will be inhibited. 4 33333333 Rings the phone a child is in danger. Sensor is attached to child. If a parents forgets and leaves a child in the vehicle, phone rings 5 44444444 Tells the phone it is inside of a prison. Functions inhibited. 6 55555555 Tells the phone of defined school zone area. Functions inhibited 7 66666666 Tells the phone it is in a classroom. Functions inhibited 8 77777777 Tells the phone it is in a Public Transit Vehicle driver's seat area. Functions inhibited. 9 88888888 Tells the phone it is in corporate vehicle driver's seat area. Functions inhibited 10 99999999 Tells the phone it is in a church or auditorium. Service disallowed during specified mass or prayer service time. 11 00000000 Tells the phone it is in a court house. Service disallowed 12 AAAAAAAA Tells the phone it is in a movie theatre. Service disallowed during specified movie times. 13 BBBBBBBB Tells the phone bedtime/Parent wants off. Functions inhibited. 14 CCCCCCCC Airbag deployment. Tells phone to dial emergency number. 15 DDDDDDDD Reserved for future It is desired for the proposed protocols to be applied globally across all mobile devices, and for unregistered and incompatible phones to be removed from the system by making them inoperable or non-functional in the network. Accordingly, it is also desirable that all mobile device manufacturers implement software based on the suggested protocols. The state or law enforcement agencies could select which protocols to activate for all mobile devices entering their specific state. For example, if a device is activated in the state of California and the CAM 108 detects code “11111111,” then the CAM 108 automatically searches for code “22222222,” If both codes are discovered by the CAM 108, then the TEXTING and EMAILING functions of the mobile device can be inhibited in accordance with the safety protocols specified in Table 1. It is also desirable that the specified environments where safety protocols need to be activated have one or more sensors or protocol activators 106 installed at prominent locations. Each such sensor also needs to be standardized as described earlier to be compatible with the safety protocols implemented in the mobile device 102. For instance, auto manufacturers, schools, court houses, prisons, public transit systems, hospitals, etc. can have one or more protocol activators 106 configured to transmit signals according to their suggested protocol and desired behavior in the mobile devices. Specified environments such as churches and theatres can have one or more sensors 106 configured to transmit according to time clocks for scheduled services and movies respectively. Parents could have a child's room sensor configured according to a time clock for scheduled bedtime which may be different on a night preceding a school day and a preceding a non-school night. A typical scenario can be inhibited functions of the mobile device 102 in a prison or a class room where it may be desirable to disallow mobile device activity. Bluetooth sensors or other transmitters may be strategically placed within the environment preventing inmates and students from using their mobile devices. RFID tag embedded in employee badges for guards and teachers can permit usage of their phones in the respective specified environment. In another embodiment, the system 100 can be used to ensure the safety of a passenger or a vehicle occupant other than the driver in a transportation vehicle. There may be cases when the vehicle occupant is a child or a physically handicapped or incapacitated person who might need attention and care all the time. In a case where the driver or the parent forgets a sleeping child in the vehicle and goes beyond an allowed distance from the vehicle, the safety protocols enable the system to notify the parent or the driver that the child is still inside the vehicle. As shown in table 1, when the CAM 108 interprets the contents as “33333333” then the parent of the child is notified by ringing the mobile device 102 carried by the parent. The cell phone rings and displays “Child left in Car” and prevents accidents to the sleeping child. A sensor (e.g. Bluetooth emitter) is attached to child that is in communication with the system. Bluetooth Address Codes Since, all the specified environments included in the protocol definition will have one or more protocol activators or sensors, the system and method of controlling functionality of a mobile device 102 may require a standardization of a specific set of sensors with regard to their identification. Standardization could involve providing a new and useful set of standard address codes. In the example case of Bluetooth devices being deployed as sensors in the specified environment, the MAC addresses of the Bluetooth devices serves as Universal Unique Identification Code (UUID). An exemplary address code system is illustrated in FIG. 3. As shown, the address code 300 contains 6 bytes (a typical MAC address) with the 1st byte being the Least Significant Byte and the 6th byte being the Most Significant Byte. Bytes 1 to 4 represent issued random binary values to avoid collisions with other Bluetooth devices. Bytes 1-4 are not used by safety protocols. The 5th byte represents type of device (or the class of the specified environment) as per the definitions in the safety protocols. For example, bits of the 5th byte can correspond to the following device types or specified environments as shown below in Table 2: TABLE 2 5th Byte Protocol Device Type [b8 b7 b6 b5 b4 b3 b2 b1] or Specified Environment 00000001 Car 00000011 Classroom 00000101 Court Room 00001000 Church 00001011 Reserved 00000010 Teen Car 00000100 Prison 00000111 Hospital ICU 00001001 Theatre 00001111 Parent The 8 bits of the most significant byte (or the 6th byte) of the address code 300 can be configured to define modes of transmission and scope of the identifier. For instance, the least significant bit (LSB) b1 of the 6th byte may represent “unicast” transmission if the bit value corresponds to binary 1 and “multicast” transmission if the bit value corresponds to binary 0 as shown in the bit value block 302. Similarly, second bit b2 of the 6th byte may represent a “global unique identifier (OUI enforced)” if the bit value corresponds to binary 0 and “locally administered” identifier if the bit value corresponds to binary 1 as shown in the bit value block 304. Bits b3 to b8 represent cellular distraction prevention ID (binary 0 or 1). In an alternative embodiment, the six-byte long address code (or MAC address) can include a 3-byte long Network Interface Controller (NIC) specific part and a 3-byte long Organizationally Unique Identifier (OUI) part. In yet another embodiment, there may be a case where an active Bluetooth sensor broadcasts a MAC address and or device name as the trigger signal within the defined parameters of a specified environment. In such case the protocol enabled mobile device automatically responds to such trigger signal based on the device name only thus carrying out the specified protocol instruction. Proper mobile device protocol instruction is carried out with no pairing required. In yet another embodiment, there may be a case where the one or more sensors 106 in the range have no identifiable MAC address. In such a case, the query module 210 can issue additional requests to obtain device name and or Bluetooth class. The one or more sensors 106 or other devices in the range respond with their corresponding information. The call authorization module 108 subsequently recognizes the discovery information thus received and implements the safety corresponding protocol behavior. An alternative address code, in such a case, can include 6 bytes as shown in FIG. 3. In this alternative address code, bytes 1 to 4 correspond to issued random binary values to avoid collisions with other devices. The bits of the 5th byte [b1-b8] represent safety protocol device type name (or specified environment) which will be unique for each device type. An exemplary nomenclature corresponding to different bit values is shown below in Table 3 as follows: TABLE 3 Device Device type (specified Unique Type Name Environment) number tsf.car Car 9011 tsf.prison Prison 9014 tsf.church Church 9017 tsf.reserved Reserved 9023 tsf.teencar Teen car 9012 tsf.court Court room 9015 tsf.theatre Theatre 9018 tsf.airbag Accident scene 9019 tsf.school School room 9013 tsf.icu Hospital ICU 9016 tsf.parent Child bedroom 9020 tsf.child Child Monitor 9021 The 8 bits of the most significant byte (or the 6th byte) of the address code 300 can be configured to define modes transmission and scope of the identifier. For instance, the least significant bit (LSB) of the 6th byte may represent “unicast” transmission if the bit value corresponds to binary 1 and “multicast” transmission if the bit value corresponds to binary 0 as shown in the bit value block 302. Similarly, second bit of the 6th byte may represent a “global unique identifier (OUI enforced)” if the bit value corresponds to binary 0 and “locally administered” identifier if the bit value corresponds to binary 1 as shown in the bit value block 304. Bits b3 to b8 represent cellular distraction prevention ID (binary 0 or 1). The Bluetooth address codes as illustrated in table 2 and Table 3 can be pre-stored in Bluetooth Address codes 222 in program data 208. Look Up Table (LUT) It may be noted that the standard cellular safety protocols can be implemented by using appropriate hardware and software modules, application software, Operating System (OS), and data structures. The exemplary mobile device 102 would have all such functional blocks that would enable the universal implementation of the safety protocols. Since, the proposed protocols are preferred to be implemented universally; the protocols are preferred to be adopted as a device manufacturing standard. In consequence, all mobile devices from all different manufactures are preferred to conform to the standard. On the other hand, the specified environment, such as, prison, schools, hospitals, transportation vehicles, etc., should have the protocol activators 106 at strategic locations for an effective implementation of the safety protocols. In addition, the protocol activators 106 should be standardized according to the proposed address codes to work in tandem with the mobile device 102. In an embodiment, the set of safety protocol behavior defined by the safety protocols are represented by means of a look up table (LUT) stored in program data 208 in LUT 220. An exemplary LUT is shown in table 4 below. TABLE 4 DEVICE NAME DEVICE ACTION TO BE TAKEN Line Hex DESIGNATION (PROTOCOL BEHAVIOR) 1 01 VEHICLE 1 2 02 VEHICLE 2 “AND” function of any 2 devices of 3 03 VEHICLE 3 Line 1 and Line 3 inhibits texting 4 04 VEHICLE 4 behind the wheel 5 05 VEHICLE 5 6 06 VEHICLE 6 “AND” function of any 2 devices of 7 07 VEHICLE 7 Line 4 to Line 9 inhibits mobile 8 08 VEHICLE 8 device 9 09 VEHICLE 9 10 0A CLASS ROOM 1 11 0B CLASS ROOM 2 12 0C CLASS ROOM 3 13 0D CLASS ROOM 4 14 0E CLASS ROOM 5 15 0F CLASS ROOM 6 16 10 CLASS ROOM 7 Inhibit mobile device during class 17 11 CLASS ROOM 8 hours if any ID of Line 10 to Line 18 12 CLASS ROOM 9 22 is detected 19 13 CLASS ROOM 10 20 14 PRISON 1 21 15 PRISON 2 22 16 PRISON 3 23 17 PRISON 4 24 18 PRISON 5 25 19 PRISON 6 Disable mobile device if any ID 26 1A PRISON 7 from Line 20 to Line 29 is detected 27 1B PRISON 8 28 1C PRISON 9 29 1D PRISON 10 30 1E COURT 1 31 1F COURT 2 32 20 COURT 3 33 21 COURT 4 34 22 COURT 5 35 23 COURT 6 36 24 COURT 7 Silence mobile device if any ID 37 25 COURT 8 from Line 30 to Line 39 is detected 38 26 COURT 9 39 27 COURT 10 40 28 HOSPITAL 1 41 29 HOSPITAL 2 42 2A HOSPITAL 3 43 2B HOSPITAL 4 44 2C HOSPITAL 5 45 2D HOSPITAL 6 46 2E HOSPITAL 7 Silence mobile device if any ID 47 2F HOSPITAL 8 from Line 40 to Line 49 is detected 48 30 HOSPITAL 9 49 31 HOSPITAL 10 50 32 CHURCH 1 51 33 CHURCH 2 52 34 CHURCH 3 53 35 CHURCH 4 54 36 CHURCH 5 Silence mobile device during church 55 37 CHURCH 6 hours if any ID from Line 50 to 56 38 CHURCH 7 Line 59 is detected 57 39 CHURCH 8 58 3A CHURCH 9 59 3B CHURCH 10 60 3C THEATRE 1 61 3D THEATRE 2 62 3E THEATRE 3 63 3F THEATRE 4 64 40 THEATRE 5 65 41 THEATRE 6 66 42 THEATRE 7 Silence mobile device during show 67 43 THEATRE 8 times if any ID from Line 60 to 68 44 THEATRE 9 Line 69 is detected 69 45 THEATRE 10 70 46 RESERVED 46 to FF HEX are reserved for future use As shown in the LUT, the device name in HEX is transmitted by the one or more sensors 106 as discovery information. The call authorization module 108 can also instruct the query module 210 to request for device name of the one or more sensors 106 in the specified environment. Upon receipt of the device name, the safety protocol module 212 accesses the LUT 220 (e.g. Table 4) and determines the device designation or the specified environment corresponding to the device name. For instance, a device name “07” in HEX would correspond to a “vehicle 7”. The protocol behavior or the action to be taken by the call authorization module 108 correspondingly would be to completely inhibit the mobile device 102. Similarly, device name “28” in HEX would correspond to device designation “Hospital 1” and the corresponding protocol behavior would be to silence the mobile device 102. It may be noted that different device designations correspond to different devices in the same or different specified environment. For instance, device names “14” to “1D” in HEX correspond to different sensors deployed at various locations in a prison. Device name “46” to “FF” in HEX are reserved for future use. The other data 224 includes flag values, variables that are initialized during the process of implementing the standard mobile device distraction prevention and safety protocols. Self-powered Bluetooth Sensor FIG. 4 illustrates the components to be used to create a self-powered Bluetooth sensor 400 according to an implementation. One of the major challenges faced in the implementation of safety protocols and the system 100 is the need to supply power to a Bluetooth sensor(s) which works in tandem with the mobile device 102. In the existing systems, the Bluetooth sensor is powered by direct wiring to a power source or simple replacement batteries which can be time consuming and costly given the universality of the proposed safety protocol. In conventional systems, there exists no simple and cost effective way to power the one or more sensor(s) 106 without having to hard wire or replace batteries. Hence, there is a well felt need for developing a self-powered Bluetooth sensor that does not require hard wiring or battery replacement. To this end, the exemplary self-powered Bluetooth sensor assembly 400 includes a coil assembly 402. The coil assembly 402 includes a magnet 404 and copper wire winding 406. The magnet 404 is placed coaxially and the copper wire winding 406 is wound in a tubular shape wax paper and becomes impregnated in a plastic cylindrical tube. The self-powered Bluetooth sensor assembly 400 further includes a rectifier module 408 electrically connected to the coil assembly 402. The rectifier module 408 is installed laterally to harness the kinetic energy of all movements via. the magnetic core. The rectifier module 408 includes an ultra capacitor and a back-up battery. The rectifier module 408 connects to the Bluetooth sensor 410 that is configured to transmit or receive signals. Such a Bluetooth sensor is capable of powering itself for long periods without requiring hard wire hook up or battery replacement. When the Bluetooth sensor assembly 400 experiences movement (such as from the motion due to acceleration or deceleration inside a car or the movement caused due to opening or closing of a door or ceiling fan turning, etc.) the magnet 404 slides inside the coil assembly 402 creating a magnetic field. The expanding and collapsing magnetic field creates an AC voltage which is fed to the rectifier module 408 to be rectified and stored in the ultra capacitor. Excessive voltage in the ultra capacitor is used to charge the backup battery. The output of the rectifier module 408 is a DC voltage which is used to power the Bluetooth sensor 410. Safety Protocol Enforcement: In an example embodiment, the specified environment can correspond to a transportation vehicle such as, a car. Studies and statistics have shown that numerous accidents take place due to distraction caused by usage of mobile devices while driving. The proposed safety protocols can be configured to prevent the use of a mobile device 102 when the call authorization module 108 senses a driving mode. The manner in which such vehicle safety system functions is disclosed in a co-pending U.S. patent application Ser. No. 12/585,503 and is incorporated herein by reference. For years, research studies have shown that seat belt save lives and prevent damage to life. In addition, many laws have been enacted to require seat belt usage while driving a car. More recently, many studies are coming forth detailing the terrible dangers presented when a driver uses text messaging and email functions on a cell phone during the commute of driving. Many states are passing laws prohibiting such dangerous cell phone usage when operating a vehicle. A major problem with both seat belt laws and cell phone laws is the inherent difficulty of proper enforcement. There exist no easy definitive means of detection or notification for safety officials and other drivers to be warned when a driver is operating a transportation vehicle or a car in an unsafe or unlawful manner either by not wearing their seatbelt or by using text messaging and email functions on a cell phone when operating the vehicle. There is, therefore, a need for a simple, cost effective solution to easily alert safety officials and passerby drivers of vehicles whose driver operates a vehicle in an unsafe or unlawful manner. To this end, FIG. 5 illustrates an apparatus for giving a vehicle owner the ability to force mobile device restrictions when allowing others to operate their vehicles. A driver of the vehicle carries a mobile device 502 (an embodiment of mobile device 102) that implements the safety protocols. The mobile device 502 includes the call authorization module 108 and the safety protocols embedded as a part of firmware. A typical vehicle would have one or more vehicular components that indicate the state of the transportation vehicle. Vehicular components can include a parking brake, a transmission gear, an accelerator, brake, an odometer, a tachometer, a wheel, engine components, and steering wheel or other such components that are capable of undergoing a state or a position change associated with the motion of the vehicle. As would be appreciated by a person skilled in the art, such vehicular components would have an associated change in state or position when the vehicle either starts to move or comes to a complete halt. The change of state or position in the vehicular components is sensed and utilized by the CAM 108 to control the behavior of the mobile device 502 inside of the vehicle. The vehicular components have associated one or more sensors 106 that transmit discovery information, such as, state and/or position information or a trigger signal. Turning now to the FIG. 5, the system 500 prevents use of mobile device 102 by drivers of vehicles thereby providing greater safety during the driving operation of the vehicle. Accordingly, the system 500 includes the mobile device 502 with CAM 108, and Bluetooth communication technology. The system 500 further includes a driver seat sensor (DSS) 504 with an RFID transponder tag embedded in the driver seat and an RFID tag reader 506 on one of the sides of the driver's seat. The system 500 further includes a circuited seat belt (CSB) assembly 508, a transmission gear shift detection assembly (TA) 510, and warning signal indicator (WSI) 512. The transmission gear shift detection assembly 510 transmits the gearshift position or state via a gearshift transmitter 514. The system 500 may include additional vehicular components such as, owner's compliance key (OCK), ignition, horn, light, radio, etc. that are not shown but may be configured to indicate a state or position that enables the system in determining unsafe and unlawful driving. The CAM 108 sends and receives signals to and from the one or more vehicular components such as, DSS 504, the transmission gear shift detection assembly 510, the CSB assembly 508, and the WSI 512 to implement the safety protocols inside the vehicle. For instance, the DSS 504 with RFID transponder tag invisibly embedded in the driver's seat area notifies the CAM 108 that the mobile device 502 is in driver's seat area. The transmission gear shift detection assembly 510 includes a series of magnetic switches strategically placed within the confinement of the transmission gear shifting apparatus designed to open or close a magnetic field depending on the gear in which the vehicle operates. In the event of the vehicle being taken out of parking position, the circuit will close immediately sending a notification to the CAM 108. The CSB assembly 508 includes a circuited seat belt buckle, a seat belt locking tongue, an anti-cheat seat belt harness embedded with an RFID tag and the stationary RFID tag reader 506. The anti-cheat CSB circuit becomes complete (or safe) when the locking buckle and tongue engage in proper locked position and the anti-cheat RFID field is open. The anti-cheat RFID tag embedded in the seat belt harness can be stretched beyond the stationary RFID tag reader 506 creating an open field. The WSI 512 corresponds to a visible light, a visible antenna, or a notification device to be effectively seen by safety enforcement officials and passerby vehicles. In operation, when the vehicle driver enters the car, the mobile device 102 with CAM 108 detects the DSS Driver's Seat Sensor 504. Once the driver takes the vehicle transmission out of “park”, the transmission gear shift detection assembly 510 sends a notification to the CAM 108. The CAM 108 then sends a signal seeking confirmation that the CSB assembly 508 is properly engaged. In case the CSB assembly 508 is not properly engaged, the WSI 512 is notified which casts a distinct visible signal to alert safety officials and passerby vehicles of non-seat belt driver operation. The warning signal continues until either the vehicle is placed back into “park” or the anti-cheat CSB 508 becomes fully engaged as described earlier. In case the CSB assembly 508 is fully engaged in the prescribed manner, the CAM 108 continues to poll to determine if the driver is texting or sending and receiving emails. If the driver is engaging in texting or sending and receiving emails, the CAM 108 notifies the WSI 512 which casts yet another distinct visible signal to alert safety officials and passerby vehicles of unsafe or unlawful mobile device usage. The WSI 512 continues its alert status for a determined period after the unsafe or unlawful cell phone activity ceases. The CAM 108 determines breach of safety rules by referring to the safety protocols embedded in the firmware of the mobile device 502. For example, the safety protocol module 212 includes logic that determines the safety code corresponding to a position of the CSB assembly 508 or the transmission gear shift detection assembly 510. The safety protocol module 212 determines the corresponding warning code which the CAM 108 sends to the WSI 512. An engine control unit (ECU) in the vehicle can be configured to monitor and communicate with the vehicular components and communicate with the CAM 108 to enforce safety protocols. FIG. 6 illustrates the location of vehicular components, engine control unit, and the mobile device 502 in a vehicle according to an embodiment. As shown, the WSI 512 can be at location 602 on the exterior of the vehicle so that safety officials and other passerby vehicles can easily see the warning signals issued by the WSI 512. The WSI 512 can also be deployed at multiple locations so that attention can be easily attracted to an unsafe and unlawful driving of the vehicle. The mobile device 502 would be at location 604 near to the driver seat. The ECU can be at a location 606 on the front side of the vehicular chassis. The transmission gear shift detection assembly 510 can be at a location 608 near the driver's seat. In an embodiment, the behavior of the mobile device 102 can be controlled based on the position of emergency/parking brake of the transportation vehicle. For example, a car safety apparatus system can be installed in a transportation vehicle. The car safety apparatus system can be installed in line with the emergency braking system. When the vehicle's emergency brake is set, the mobile device in the driver's seat area can be used without any inhibition. As soon as the emergency/parking brake is released, the electronic sensor (e.g. emergency brake sensor) installed will send a trigger signal to the CAM 108 to completely or partially disable the driver's mobile device 102. Vehicle Occupant Safety System FIG. 7 illustrates a system 700 for ensuring safety of a child or a vehicle occupant in an embodiment. Accordingly, the system 700 comprises a mobile device 702 (an embodiment of mobile device 102) carried by a user 704. The mobile device 702 includes a first computing system for signal processing. The user 704 can be a driver of a car or a parent of a child travelling in a transportation vehicle. The system 700 further includes a sensor 706 which may be worn by the child or attached to a pressure activation sensor that is activated by the weight of the child as shown in the figure. In an exemplary embodiment, the sensor 706 can be a Bluetooth sensor emitting discovery information “tsf.child” (part of the protocol, with reference to table 3). The system 700 also includes a second computing system (ECU) 708 in communication with the sensor 706 and one or more vehicular components 710. As described earlier, the vehicular components 710 may correspond to gear shift transmission assembly, parking brake, etc. The vehicular components 710 are configured to give an indication of whether the vehicle is out of parking or is being driven. When the vehicle is in drive mode and a child is in a car, the phone receives the discovery information that includes “tsf.child” signal. The CAM 108 flags and activates the child monitor option as shown in table 3. At the destination when the car engine is shutdown, the driver walks away from the car. If the CAM 108 does not detect “tsf.car” at predetermined time intervals from the child sensor 706, it activates the mobile device 102 to warn the driver that the child is still in the car. When the child is removed from the car, the CAM 108 will time out and reset the child monitor option. Exemplary Methods The description of the following methods would be provided with specific references to FIG. 1, FIG. 2, FIG. 3, FIG. 4, FIG. 5, FIG. 6, and FIG. 7 and the corresponding description. FIG. 8 illustrates a method 800 for activating a safety protocol behavior in a mobile device 102 according to an embodiment. The distraction prevention and safety protocol actionable behavior of the mobile device will take effect upon satisfaction of a specific condition. In an embodiment, the specific condition may correspond to entering a specified environment. The specified environment can correspond to a class room, a correctional facility, an airport, an airplane, a court room, a hospital, a church, a theatre, a fly zone, a danger zone, an auditorium, a bedroom, or any other arena or environment where it is desirable to control the behavior of the mobile device 102. Additionally, satisfaction of a specific condition may correspond to an event inside a transportation vehicle. Such event may include movement of one or more vehicular components that may indicate the state of the transportation vehicle. Vehicular components may include, but not limited to a parking brake, a transmission gear, an accelerator, brake, an odometer, a tachometer, a wheel, engine components, and steering wheel or other such components that are capable of undergoing a state or a position change associated with the motion of the vehicle. As would be appreciated by a person skilled in the art, such vehicular components would have an associated change in state or position when the vehicle either starts to move or comes to a complete halt. The satisfaction of a specific condition may also correspond to the dialing of a specified sequence of numbers or pressing a specific speed dial. The specific sequence of numbers can be predetermined set of numbers that denote a specific case of criminal emergency. For instance, if a mobile phone receives a threatening call, text, or e-mail, an immediate action can be automatically taken. Immediate action may correspond to sending the contact details (number, e-mail etc. of the sender) to a data bank for potential processing of criminal action. Such an automatic action can be configured as a safety protocol behavior in the mobile phone 102. Turning to FIG. 8, at block 805, at least one or more protocol activators are discovered. The one or more protocol activators 106 are configured to transmit discovery information associated with the specific condition. In an embodiment, the protocol activators can correspond to pre-standardized Bluetooth sensors characterized by a predetermined device name and or class associated with the specified environment. In an embodiment, the discovering includes searching for the one or more protocol activators in the specified environment. The CAM 108 instructs the communication module 214 to search for the protocol activators or sensors 106 in the specified environment. In such an implementation, the communication module 214 transmits one or more requests to obtain the discovery information from the one or more protocol activators 106. The discovery information corresponds to device name and or class of the protocol activators 106, the class being informative of the specified environment. The discovery process also includes accessing a look up table (LUT), such as, Table 4, and determining an entry corresponding to the discovery information associated with the specified environment. At block 810, distraction prevention safety protocol behavior is activated in the mobile device based at least in part on the discovery information. The CAM 108 upon receipt of the discovery information instructs the safety protocol module 212 to determine from the LUT the safety protocol behavior corresponding to the discovery information. In a successive progression, the CAM 108 activates the determined safety protocol behavior in the mobile device 102. In an implementation, activating the safety protocol behavior includes disabling partially or wholly one or more functionalities associated with the mobile device 102. The safety protocol behavior corresponds to one or more of: a partial or complete disabling of the mobile device, disabling text sending functionality, disabling mail sending functionality, disabling calling functionality, enabling a safety protocol enforcement mode, and child safety mode respectively in the mobile device. In certain cases, it may be desirable to differentiate different working groups and implementing different set of protocol behavior for different working groups. The discovery information may include such information, or the CAM 108 can instruct the RFID reader 230 to gather additional information associated with a specified working group in the specified environment. Thereafter, the safety protocol module 212 determines the protocol behavior corresponding to the specified working group, device name, and class respectively. In yet another embodiment, the activating includes issuing a warning signal when the discovery information corresponds to an unlawful or unsafe operation in the specified environment. For instance, in the case of a transportation vehicle, the one or more sensors or protocol activators can correspond to various vehicular components that provide state or position information indicating an unlawful or unsafe mode of driving. The driver may ignore the seat belt or may be sending text messages or mails while driving. In such a scenario, the CAM 108 upon detection of unsafe or unlawful mode, issues a warning signal to warning signal indicator (WSI) 512. The WSI 512 then sends out warning signals to be seen by safety enforcement officials and passerby vehicles. FIG. 9 illustrates a method 900 of controlling functionality of a mobile device within a specified environment. Accordingly, at block 905, a trigger signal is broadcasted within the specified environment. The one more sensors 106 may be activated to send trigger signals by an actuating mechanism that detects the onset of specific conditions. In an implementation, such actuating mechanism may be a tilt switch in case of a transportation vehicle. At block 910, a class associated with the trigger signal and the specified environment is determined. The CAM 108 determines the class associated with the specified environment and a working group from the trigger signal. At block 915, a set of protocol instructional behaviors are implemented in the mobile device based at least in part on the determined class and/or the specified environment. The CAM implements the set of protocol instructional behavior corresponding to the trigger signal, the determined class, and working group. In an embodiment, the implementing includes partly or completely disabling the functionality associated with the mobile device 102. The protocol instructional behaviors permits emergency calls to one or more pre-determined or programmable numbers. For example, in any case of specified environment, the safety protocols allow calls to be made to special numbers during emergency, such as, “911” in United States, “112” in India, etc. Such special numbers can be preprogrammed and included as exceptions to any protocol instructional behavior. In another example, the safety protocols can allow calls to a special number (parent's number) if the mobile device is carried by a child. The programming of such special numbers may be a feature that is provided by the mobile phone manufacturer or the service provider. The safety protocols can be so configured to accommodate such features. FIG. 10 illustrates a method 1000 for controlling behavior of a mobile device inside a transportation vehicle in an embodiment. At block 1005, a sensor configured to broadcast a trigger signal within a pre-determined limited range inside the vehicle is activated. In an embodiment, the activation is based at least on a state or a position of one or more vehicular components and/or a tilt switch mechanism configured to determine vehicular movement. The one or more vehicular components include parking brake, transmission gear assembly, accelerator, brake, odometer, tachometer, wheel, seat belt assembly, engine components, and steering wheel. At block 1010, a protocol behavior based at least in part on the trigger signal is implemented in the mobile device 102. In an embodiment, the CAM 108 implements the protocol behavior in the mobile device 102 inside a predetermined limited range of the sensor 106 only. The protocol behavior implementation includes disabling one or more functionalities associated with the mobile device. Such functionalities include calling, answering a call, emailing, browsing, reading, text messaging, or any other functionalities associated with the mobile device 102. It will be appreciated that the teachings of the present invention can be implemented as a combination of hardware and software. The software is preferably implemented as an application program comprising a set of program instructions tangibly embodied in a computer readable medium. The application program is capable of being read and executed by hardware such as a computer or processor of suitable architecture. Similarly, it will be appreciated by those skilled in the art that any examples, functional block diagrams and the like represent various exemplary functions, which may be substantially embodied in a computer readable medium executable by a computer or processor, whether or not such computer or processor is explicitly shown. The processor can be a Digital Signal Processor (DSP) or any other processor used conventionally capable of executing the application program or data stored on the computer-readable medium. The example computer-readable medium can be, but is not limited to, (Random Access Memory) RAM, (Read Only Memory) ROM, (Compact Disk) CD or any magnetic or optical storage disk capable of carrying application program executable by a machine of suitable architecture. It is to be appreciated that computer readable media also includes any form of wired transmission. Further, in another implementation, the method in accordance with the present invention can be incorporated on a hardware medium using ASIC or FPGA technologies. It is also to be appreciated that the subject matter of the claims are not limited to the various examples and or language used to recite the principle of the invention, and variants can be contemplated for implementing the claims without deviating from the scope. Rather, the embodiments of the invention encompass both structural and functional equivalents thereof. While certain present preferred embodiments of the invention and certain present preferred methods of practicing the same have been illustrated and described herein, it is to be distinctly understood that the invention is not limited thereto but may be otherwise variously embodied and practiced within the scope of the following claims.
<SOH> BACKGROUND <EOH>Over the past few decades, the cellular/wireless industry has advanced by leaps and bounds. Throughout the world, mobile devices have become a ubiquitous part of everyday life. The enormous proliferation of the mobile device is nothing short of incredible. But, with it has surfaced a host of major problems much to the detriment of society. Every technical advancement and development has certain associated challenges and the cell phone is no exception. Many inherent life threatening problems are gaining light speed momentum. Such problems include increased accidents from driver distraction due to mobile devices, increased disruption and cheating in the classroom, increased contraband, gang activity, and death threats from inside the prison system etc. These problems come with a magnificent cost. For example, the World Health Organization (WHO) estimates that distracted driving alone costs developed countries between one and three percent of GDP. A few mobile application attempts have been made to solve the problem behind the wheel and some cell frequency jamming attempts have been tried in various prison systems. Such solutions, however, face impenetrable obstacles such as: current law in various countries, uninstalling the application, turning off the Bluetooth, Bluetooth pairing requirements, GPS latency and signal lapses, large number of varied mobile platforms, continuous updating, closed platforms, battery drain, and the inability to affect Skype™ and satellite phones which prisoners easily obtain. The most significant obstacle facing all solution providers is the lack of universal standards within the mobile device industry. Currently, the mobile device manufacturers have no universal platform for developing standard safety technologies. Since there are no standards, even a simple safety feature cannot be universally applied across all mobile devices. And since safety is a global concern, a solution which can only be applied to select mobile devices is not preferred. In order to combat these societal problems, there exists a well felt need to design and implement universal distraction prevention and safety technologies for all mobile communication devices. Because there are hundreds of different cell phone makes and models combined with open, closed & partially closed configurations, developing a single simple comprehensive solution for all mobile phone architectures is considered impossible. Notwithstanding such impediments, the task to effectively implement safety standards and methods to prevent cellular distractions to benefit society must be carried out in a timely and undisruptive manner. In addition, other current obstacles include but are not limited to quick detection and connectionless non-pairing communication with Bluetooth devices, deterioration of cellular battery life, quick and easy application disablement. Moreover, existing systems and methods only provide a partial solution for a single environment. For example, jamming in prisons which is illegal in many countries prohibits emergency calling and is therefore undesirable for schools and hospitals and such. Art to provide solutions for distracted driving requires some form of pairing which makes an automatic universal application impossible. The pairing dilemma in essence makes each mobile device car specific. For example, even if such a system is installed on a teen's car, should the teen drive the parent's car or sibling's car or friend's car, the mobile application will not work unless an entirely new pairing is involved for that specific car. It also creates the problem requiring a new software upload for each system change or system upgrade to correspond to the changed system. Such a system leaves parents and employers frustrated as the system no longer works properly. Also, parents and employers won't have any available working system if they happen to purchase a phone with a closed architecture thereby preventing system functionality inhibition. There is, therefore, a need for a simple, cost effective improvement to mobile communication technologies to adopt and implement a standardized set of safety protocols such that new safety enhancement systems and methods to prevent mobile distractions can easily be engineered and adopted for all new and existing mobile phones. There is also a need for a simple, cost effective improvement to Bluetooth technology devices to apply a universal set of address codes to work in tandem with the mobile device embedded distraction prevention protocols.
<SOH> SUMMARY OF INVENTION <EOH>It is, therefore an object of the present invention, to provide a set of standard mobile communication device distraction prevention and safety protocols to be embedded in the mobile device firmware (system memory or system image) and to provide various applicable sensors to be adopted universally throughout the mobile communications industry for providing safety enhancement systems and methods to prevent mobile device distractions. It is a further object of the present invention to provide a new and useful set of standard Bluetooth address codes to work in conjunction with protocol enabled mobile devices and facilitate communication with the proposed mobile distraction prevention protocols. It is yet another object of the present invention to provide a safety enforcement system that produces a signal visible outside a vehicle whenever the driver is operating the vehicle in an unsafe or unlawful manner. It is also an object of the present invention, to provide a set of mobile device safety protocols to be embedded in the mobile device firmware for the purpose of simple uniform adoption of future safety enhancements. Methods and systems for providing standard mobile communication device safety and distraction prevention protocols are disclosed. In an embodiment, a method for activating a distraction prevention safety protocol behavior in a mobile device when the mobile device satisfies a specific condition is disclosed. The method includes discovering at least one protocol activators configured to transmit discovery information associated with the specific condition. The method further includes activating safety protocol behavior in the mobile device based at least in part on the discovery information. In an implementation, the specific condition corresponds to at least one of two events being when the mobile device enters a specified environment and when the mobile device enters or a specified sequence of numbers is dialed from the mobile device. A method of controlling functionality of a mobile device within a specified environment is disclosed. In an implementation, the method includes broadcasting a trigger signal within the specified environment and determining discovery information associated with the trigger signal and the specified environment. The method further includes implementing a set of protocol instructional behaviors in the mobile device based at least in part on the discovery information and the specified environment. Such an implementation of the set of protocol instructional behavior results in a restricted functionality of the mobile device. A system for implementing safety protocols in a mobile device is disclosed. According to an embodiment, the system includes a call authorization module configured to execute a protocol behavior in the mobile device based at least in part on discovery information. The discovery information is transmitted by one or more sensors in the specified environment and corresponds to a specified environment in which the mobile device operates. A method for controlling behavior of a mobile device inside a transportation vehicle is disclosed. According to an implementation, the method includes activating a sensor configured to broadcast a trigger signal within a pre-determined limited range inside the vehicle. The method further includes implementing a protocol behavior in the mobile device based at least in part on the trigger signal. The activation of the sensor is based on a state or a position of one or more vehicular components and/or a tilt switch mechanism configured to determine vehicular movement. A vehicle occupant safety system is disclosed. In an implementation, the system includes a smart phone comprising a first computing system for signal processing and a trigger signal emitter for use by a passenger of a vehicle. The trigger signal emitter is in communication with a second computing system when the passenger is inside the vehicle. The second computing system is configured to control operational functions of the vehicle. The system further includes a processing logic associated with the second computing system for determining when the vehicle concluded operation and for detecting a signal from the trigger signal emitter. The detection occurs in such a manner that the second computing system is activated to send a distress signal when the passenger has remained inside the vehicle for a predetermined time subsequent to concluded operation of the vehicle. A system for enforcement of safety protocols is disclosed. In an implementation, the system includes a mobile device configured to communicate with at least one vehicular component inside a transportation vehicle to determine an unsafe driving based on safety protocols configured in the mobile device. The system further includes an exterior vehicle warning signal indicator (WSI) configured to issue visible warning signals based on the determination by the mobile device. A system for implementing mobile safety protocols is disclosed. In an embodiment, the system includes a self-powered Bluetooth sensor assembly configured to transmit discovery information without an external power supply. The system further includes a mobile device configured to determine and implement a safety protocol behavior based on the discovery information. The discovery information corresponds to a name of the self-powered Bluetooth sensor and a class of a specified environment in which the self-powered Bluetooth sensor operates. To the accomplishment of the above and related objects, this invention may be embodied in the form illustrated in the accompanying drawings, attention being called to the fact, however, that the drawings are illustrative only, and that changes may be made in the specific construction illustrated.
H04M172577
20170815
20180111
61619.0
H04M1725
0
LEE, JOHN J
STANDARD MOBILE COMMUNICATION DEVICE DISTRACTION PREVENTION AND SAFETY PROTOCOLS
SMALL
1
CONT-ACCEPTED
H04M
2,017
15,677,143
PENDING
SELF-CHECKOUT STATION AIR CIRCULATION
A self-checkout system comprises a cabinet housing, the cabinet including a ventilated region; a point of sale (POS) station at the cabinet housing, the POS station including heat-generating components, the ventilated region of the cabinet housing removing heat generated from the POS components from the cabinet housing; and an air flow system at an interior of the cabinet housing that outputs air through the ventilated region.
1. A self-checkout system, comprising: a cabinet housing, the cabinet including a ventilated region; a point of sale (POS) station at the cabinet housing, the POS station including heat-generating components, the ventilated region of the cabinet housing removing heat generated from the heat-generating components from the cabinet housing; and an air flow system at an interior of the cabinet housing that outputs air through the ventilated region, the air flow system including a perforated region at one side of the cabinet housing for exchanging the air with an ambient environment and for providing an air flow path for removing the heat between the ventilated region, the perforated region, and the ambient environment. 2. The self-checkout system of claim 1, wherein the cabinet housing includes a sidewall, and wherein the sidewall includes a plurality of vents of the ventilated region, and wherein the air flow system includes both the vents and the perforated region. 3. The self-checkout system of claim 2, wherein the sidewall is removable and replaceable with a different vent configuration to change the air flow system. 4. The self-checkout system of claim 1, wherein the cabinet housing includes a door that exposes the interior of the cabinet housing when in an open state, and wherein the door includes a plurality of vents of the ventilated region. 5. The self-checkout system of claim 1, wherein the air flow system comprises a plurality of electric fans that circulate the air in the interior of the cabinet housing and through the ventilated region. 6. The self-checkout system of claim 5, wherein the electric fans are proximal the ventilated region. 7. The self-checkout system of claim 6, wherein the ventilated region includes a sidewall of the cabinet, and wherein the electric fans are coupled to the sidewall. 8. The self-checkout system of claim 1, further comprising a recyclable collection system in the housing adjacent the ventilated region. 9. The self-checkout system of claim 1, wherein the cabinet housing is under and supports at least one of a register area, a belt system, a self-checkout scale platform, or a pay area system. 10. The self-checkout system of claim 1, further comprising a bagging station adjacent the cabinet housing, the bagging station including: a carousel top; a center piece; and a plurality of bag holding elements extending from the center piece. 11. A self-checkout system at a host pay-station area of a store, comprising: an itemization station including a point of sale system; a bagging station on one side of the itemization station; a ventilated region upstream of and an air flow system on an opposite side of the itemization station as the bagging station that outputs heated air from the itemization station; and an air flow system including a perforated region at one side of the cabinet housing for exchanging the air with an ambient environment and for providing an air flow path for removing the heat between the ventilated region, the perforated region, and the ambient environment. 12. The self-checkout system of claim 11, wherein the air flow system forms a heat transfer path from the itemization station to the ventilated region at the register belt station. 13. A self-checkout system, comprising: a ventilation system comprising a first set of ventilation openings in a door of a checkout system housing and a second set of ventilation openings in a sidewall of the checkout system housing; and an air flow system that forms a heat transfer path from the first set of ventilation openings to the second set of ventilation openings. 14. The self-checkout system of claim 13, wherein the air flow system comprises a plurality of electric fans that circulate the air in the interior of the housing and through the ventilated region. 15. The self-checkout system of claim 13, wherein a bottom region of the housing includes heat-generating devices, and wherein the second set of ventilation openings is at a mid-section of the sidewall of the checkout system housing for removing heated air generated by the heat-generating device from the housing.
RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent No. 62/377,305, filed Aug. 19, 2016, entitled “Self-Checkout Station Air Circulation,” the contents of which are incorporated by reference herein in their entirety. This application is related to Design Patent application Ser. No. 29/574,947, filed Aug. 19, 2016, entitled “Self-Checkout Station,” the contents of which are incorporated by reference herein in their entirety. BACKGROUND OF THE INVENTION Technical Field The present inventive concepts relate to self-checkout systems and, more specifically, to air flow configurations for cooling a self-checkout system. State Of The Art Self-checkout stations at a retail store permit customers to process their store purchases as an alternative to a cashier-staffed checkout counter. SUMMARY In one aspect, provided is a self-checkout system, comprising: a cabinet housing, the cabinet including a ventilated region; a point of sale (POS) station at the cabinet housing, the POS station including heat-generating components, the ventilated region of the cabinet housing removing heat generated from the heat-generating components from the cabinet housing; and an air flow system at an interior of the cabinet housing that outputs air through the ventilated region. The air flow system included a perforated region at one side of the cabinet housing for exchanging the air with an ambient environment and for providing an air flow path for removing the heat between the ventilated region, the perforated region, and the ambient environment. In some embodiments, the cabinet housing includes a sidewall, and wherein the sidewall includes a plurality of vents of the ventilated region. The air flow system includes both the vents and the perforated region. In some embodiments, the sidewall is removable and replaceable with a different vent configuration to change the air flow system. In some embodiments, the cabinet housing includes a door that exposes the interior of the cabinet housing when in an open state, and wherein the door includes a plurality of vents of the ventilated region. In some embodiments, the air flow system comprises a plurality of electric fans that circulate the air in the interior of the cabinet housing and through the ventilated region. In some embodiments, the electric fans are proximal the ventilated region. In some embodiments, the ventilated region includes a sidewall of the cabinet, and wherein the electric fans are coupled to the sidewall. In some embodiments, the self-checkout system further comprises a recyclable collection system in the housing adjacent the ventilated region. In some embodiments, the cabinet housing is under and supports at least one of a register area, a belt system, a self-checkout scale platform, or a pay area system. In some embodiments, the self-checkout system further comprises a bagging station adjacent the cabinet housing, the bagging station including: a carousel top; a center piece; and a plurality of bag holding elements extending from the center piece. In another aspect, a self-checkout system at a host pay-station area of a store comprises an itemization station including a point of sale system; a bagging station on one side of the itemization station; a ventilated region upstream and an air flow system on an opposite side of the itemization station as the bagging station that outputs heated air from the itemization station; and an air flow system including a perforated region at one side of the cabinet housing for exchanging the air with an ambient environment and for providing an air flow path for removing the heat between the ventilated region, the perforated region, and the ambient environment. In some embodiments, the air flow system forms a heat transfer path from the itemization station to the ventilated region at the register belt station. In another aspect, a self-checkout system comprises a ventilation system comprising a first set of ventilation openings in a door of a checkout system housing and a second set of ventilation openings in a sidewall of the checkout system housing; and an air flow system that forms a heat transfer path from the first set of ventilation openings to the second set of ventilation openings. In some embodiments, wherein the air flow system comprises a plurality of electric fans that circulate the air in the interior of the housing and through the ventilated region. In some embodiments, a bottom region of the housing includes heat-generating devices, and the second set of ventilation openings is at a mid-section of the sidewall of the checkout system housing for removing heated air generated by the heat-generating device from the housing. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows a perspective view of a self-checkout system, in accordance with some embodiments. FIG. 2 is a front view of a self-checkout system, in accordance with other embodiments. FIG. 3 is an exploded view of the self-checkout system of FIG. 2. FIG. 4 is a view of an interior of a self-checkout system, and illustrating air flows through the self-checkout system, in accordance with some embodiments. FIG. 5 is a side view of an interior of a self-checkout system having electric fans, and illustrating air flows through the self-checkout system, in accordance with some embodiments. DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION FIG. 1 shows a perspective view of a self-checkout system 10, in accordance with some embodiments. In some embodiments, for example, as shown in FIG. 1, a self-checkout system 10 includes a cabinet housing 20, an itemization station 12, also referred to as a point of sale (POS) station, at the cabinet housing 20, and a bagging station 30 adjacent the cabinet housing 20. The self-checkout system 10 may include other elements, for example, described with reference to U.S. Provisional Patent Application No. 62/349940 filed Jun. 14, 2016 and entitled “Self-Checkout Register Configurations,” and U.S. patent application Ser. No. 15/622,136 filed Jun. 14, 2017 and entitled “Self-Checkout Register Configurations,” the contents of each of which are incorporated by reference herein in their entirety. The cabinet housing 20 may be a single housing 20. For example, the housing 20 may include a metal frame to which sidewalls 31, 32, back wall 33, top 34, and/or bottom 35 may be attached. Alternatively, the housing 20 may be formed of multiple units coupled together to form a single housing 20. Here, the multiple units include an air flow pathway or otherwise uninterrupted path therebetween to allow the exchange of airflow, cables, and/or other elements between the contents in the enclosures of the multiple units. This may be part of an air flow system at an interior of the cabinet housing that outputs air through a ventilated region, described herein. The cabinet housing 20 may include a first region 40 and a second region 52. As shown in FIGS. 3 and 4, the cabinet housing 20 may include a dividing wall 54 that separates the first region 40 from the second region 52. The first region 40 may have one or more shelves 43 or other storage space, for example, for a cash drawer 42. The first region 40 may include electronic components, point of sale (POS) computers, power supplies, connectivity components, electronic article surveillance, checkpoint security devices, and/or other equipment used as part of an operation performed at the self-checkout station. The second region 52 includes an opening under a POS system or other element of an itemization station 12 for receiving a garbage collection system 50 or other assembly. In some embodiments, only heat-generating components of the electronic components, point of sale (POS) computers, power supplies, connectivity components, electronic article surveillance, checkpoint security devices, and/or other equipment is co-located in the first region 40, the second region 52, or other common region of the cabinet housing, and wherein an air flow path produced by an air flow system removes the heat from the common region of the cabinet housing. A door 36 is positioned at the first region 40, more specifically, at an opening to the interior of the first region 40 of the housing 20. The door 36 exposes the interior of the first region 40 of the cabinet housing 20 when in an open state. The door 36 may include a handle 61 for opening and/or closing the door 36. In some embodiments, as shown in FIG. 1, the handle 61 is at a periphery of the door 36. In other embodiments, as shown in the station 10′ of FIG. 2, a handle 61′ is at a center region of a door 36′. The door 36, 36′ (generally, 36) may open and close according to a hinge at a corner of the door 36, or the door 36 may be part of an assembly, and may slide along rails for opening and closing. At least a portion of the door 36 may include a layer or coating of material, such as metal, plastic, or chemical compound, for example, providing a scratch or damage-resistant guard. A garbage collection system 50 may be positioned at the second region 52 of the opening of the housing 20. Although a garbage collection system is referred to, the system 50 can collect recyclable items such as coat hangers, plastics, metals, cardboard, bottles, cans, and so on. In some embodiments, the garbage collection system 50 is the same or similar to a garbage collection system described at U.S. Provisional Patent Application No. 62/295,866 filed Feb. 16, 2016 entitled “Waste Collection System and Method,” the contents of which are incorporated by reference herein in their entirety. For example, the garbage collection system 50 may include a set of rails 104, ball bearing slides, or the like, for permitting one or more garbage bins 112, 113 and door 103 to slide linearly relative to the interior of the second region 52 in the housing 20. The garbage collection system 50 can be constructed and arranged for one or more of garbage collection, recyclable collection, hangers collection, returns collection (for example, bottles, cans, and so on), or anything else having a size and configuration for insertion into one or both bins 112, 113. The air flow system, including air flow paths, air or circulation-producing elements such as fans or the like, and ventilated or perforated panels, doors, or the like, may operate to remove heat from the housing 20 regardless of the presence of the garbage collection system 50. For example, as described herein, a different vent configuration may be implemented to change the air flow system due to the presence of the garbage collection system 50 in the housing 20. The cabinet housing 20 may be under and provide structural or other support at least one of an itemization station 12, and/or related register area, a self-checkout scale platform, or a pay area system. The cabinet housing 20 may be formed of one or more materials sufficient for receiving and supporting the weight of the itemization station 12, the garbage collection system 50, and the contents of the interior of the housing 20, for example, wood, metal, plastic or related composites, or a combination thereof. The itemization station 12 can include a scanning device for scanning items, for example, scanning barcodes, universal product code (UPC) and so on that are identified with the item to be purchased. The itemization station 12 may also include a product scale 15 in communication with the scanner. The product scale 15 may be used to determine the weight of the item. The scale 15 may be integrally connected with, or independent from and in electronic communication with, an identification-code reader, such as an optical-code reader, laser scanner, a radio frequency identification (RFID) tag reader, or any other type of machine code reader, which can decode a indicia or tag on a store item for purchase. In use, the identification-code reader identifies an item in the store by decoding an item code associated with the item. An item code signal is then communicated to a store computer (not shown) for processing. Similar to the abovementioned example, a different vent configuration may be implemented to change the air flow system due to the presence or absence of the product scale 15 and/or other heat-generating components in the housing 20. In doing so, the air flow path produced by the air flow system may deviate, redirect, or otherwise accommodate for the presence or absence of the product scale 15 and/or other heat-generating components in the housing 20. For example, a different door or side panel may include vents when the product scale 15 is present, but may not include such vents when the product scale 15 is not part of the itemization station 12 in the cabinet housing 20. In addition to the product scale 15 and scanning device, the itemization station 12 may include, but not be limited to, an interactive customer interface terminal or public view monitor 14 electrically coupled to the scanner, an electronic payment terminal, credit card, bill, and/or coin detector and processor, printer, receipt generator, item sensors, point of sale (POS) terminal or related computer having a display, processor, memory, input/output devices, storage device, scanner, printer, electronic payment processing device, cash tray, and credit card reader or related processing module, and so on. In some embodiments, the bagging station 30 may be similar to or the same as U.S. Provisional Patent Application No. 62/349,933 filed Jun. 14, 2016 entitled “Modular Bagging Stations,” the contents of which are incorporated by reference herein in their entirety. The bagging station 30, for example, may a rotatable carousel top 123, a center piece 126, and a plurality of bag holding elements 120 extending from the center piece 126. The carousel top 123 may be positioned on a collection system base 70, for example, shown in FIGS. 2-3B. Carousel top 123 may hold center piece 126, and is constructed and arranged to support one or more bags, for example, paper shopping bags, while a bag is being filled with store items for purchase. In some embodiments, the collection system base 70 may be integral with and part of the housing 20. In other embodiments, as shown, the collection system base 70 is separate from the housing 20, and coupled to a sidewall of the second region 52 of the housing 20. The collection system base 70 may include an interior for housing miscellaneous components, such as wires from the public view monitor 14, scale 15, or other electronic accessories of the itemization station 12. In some embodiments, the carousel top 123 may rotate due to a bearing plate (not shown) or the like that permits the carousel top 123 to rotate relative to the stationary base 70. The bag holding elements 120 may include hooks, rods, clamps, spring clips or other extensions for holding a shopping bag and its contents. A shopping bag may be paper, plastic, recyclable material, and/or other well-known material. The elements 120 may include bag upper edge holders that grasp the upper edge of an open bag in order to hold the bag open and in place while items are placed in the bag so the bag can be filled. The bag holding elements 120 and/or bag edge holders may be of various sizes and shapes for supporting the weight of a shopping bag filled with store items. In some embodiments, the bag holding elements 120 may be removable, for example, removed from the top portion of the center piece 126 and replaced with different the bag holding elements. As previously described, the housing 20 includes heat generating components, e.g., electrical equipment and the like, in particular, located in at least one of the first region 40 and the second region 52 of the housing 20. The self-checkout system 10 includes an air flow system that includes one or more vented regions for controlling an amount and/or direction of air heated by the components in the housing 20. For example, as shown in FIG. 4, the air flow system forms a heat transfer path illustrated by air flow arrows (AF) from the itemization station 12 to the ventilated region at the housing 20. For example, the air flow system is constructed and arranged to receive a flow of air via the vents 41 in the door 36 and output a flow of heated air through one or more vents 39 in a sidewall 31 of the housing 30, or vice versa where the air flow system is constructed and arranged to receive a flow of air via the sidewall vents 39 and output a flow of heated air through the door vents 41. This configuration where vents are located at two different regions of the housing 20 obviate the need for air to enter and leave the same vent region, for example, where the sidewall has vents but not the door. In some embodiments, as shown in FIG. 1, the vents 39 in the sidewall 31 are arranged as vent regions. In other embodiments, as shown in FIG. 4, the sidewall 31 includes a plurality of perforations, slots, perforations, or related ventilation openings for allowing the release of heated air. The sidewall 31 is opposite sidewall 32 at which the bagging station 30 abuts. In some embodiments, the vented region of the housing 20 includes some or all of the first region 40 of the housing 20. In some embodiments, an air flow path, or heat transfer path, may extend between shelves 43, for example, shown in FIG. 4. Heat-generating components at a bottom of the housing 20 may generate heat that rises toward a top region of the housing 20. Ventilation openings in a vent region 39′ along a height of the housing sidewall 31′ may permit the heated air to be removed from the housing above, below, and/or between the shelves 43. In some embodiments, as shown in FIG. 1, the door 36 of the housing 20 includes at least one vent 41. In other embodiments, as shown in FIG. 2, a door 36′ may include a plurality of perforations. In some embodiments, both the sidewall 31 and the door 36 each includes at least one vent 39, 41, respectively. Here, a flow of heated air is output through both sets of vents 39, 41. The configuration of the vents 39, 41 may be to provide a varied airflow through the interior of the housing 20 and the sidewall 31 and/or door 36. In some embodiments, the door 36, 36′ (generally, 36) may include one or more vents 41, or vent regions, configured in a same or similar manner as the cabinet housing 20, for example, housing sidewall 31. In other embodiments, the size, shape, and/or number of vents 41 in the door 36 is different than the vents 39 in the housing sidewall 31. For example, the vents 39 in the sidewall may be configured for communicating with electric fans coupled thereto for forming an air flow path from the interior of the housing 20 to the ambient environment external to the housing 20. In some embodiments, the sidewall 31 and/or door 36 is removable and replaceable with a sidewall and/or door having a different vent configuration. In other embodiments, the sidewall 31 and/or door 36 may have regions, or openings, in which vent modules (not shown) may be inserted, removed, and/or replaced, referred to as “plug-and-play” vent sections or regions. For example, the door 36 shown in FIG. 1, or a vent section in the door 36, may be removed and replaced with the door 36′ shown in FIG. 2, or a different “plug-and-play” vent region, in order to change the air flow system. Similarly the sidewall 31 having the three vent regions 39 in FIG. 1 may be replaced with a sidewall 31′ having a single larger vent region 39′ shown in FIG. 4 for changing the air flow system. The air flow system may be changed in this manner to accommodate for changes in temperature inside the housing 20 caused by heat-generating equipment. For example, the self-checkout system 10 may be modified to include a bagging station carousel that rotates automatically (instead of manually), which requires a power supply located in the housing 20 as well as wiring extending from the power supply in the housing to the bagging station 30. The addition of the power supply may require an increase in air flow through the housing 20, which can be achieved by a different door 36 and/or side wall 31. As shown in FIG. 5, the air flow system may comprise one or more electric fans 60, or blowers, that circulate the air, shown by air flow arrows (AF) through the interior of the cabinet housing 20 to a ventilated region, and more specifically, the vents 39 of the sidewall and/or vents 41 of the door 36. The fans 60 may draw power from a power source, for example, power supply via an electric outlet, batteries, and so on, which are located at one region of the housing 20. Here, the power source of the fans 60 may contribute to the heat output inside the housing 20 and therefore the generated heat is removed in a similar manner as other components inside the housing 20 in accordance with embodiments of the present inventive concepts. Alternatively, the fans 60 may rely on solar panels or other alternative energy source for powering the fans 60. The fans 60, or blowers, provide control over the flow of exhausting heated air. The flow of cooling air may flow from the front of the housing 20, e.g., where the door 36 is located, through the housing interior where the air is heated by the power supplies, electronics, and so on in the housing 20, and exits through the vents 39 in the housing sidewall 31. The housing 20 is configured, for example, divided into regions as described with reference to FIGS. 3 and 4, to allow for maximum cooling. To achieve maximum cooling, in some embodiments, the electric fans 60 are proximal the ventilated region, or are coupled to the inside of the sidewall 31 of the housing 20. Alternatively, or in addition, the electric fans 60 are positioned in the interior of the housing 20 at locations that permit the formation of a circulating air path, or heat transfer path, from heat-generating components in the interior of the housing 20 to the vents 39 and/or 41. For example, this configuration permits the positioning of two electric fans 60 in the bottom region of the housing 20 and one fan 60 in top or middle region of the housing 20, each fan 30 positioned over a vent region 39 as shown in FIGS. 1 and 5. The location of the vents 39, 41 are to permit cooling air to be received inside the housing 20 for cooling the interior where heat-generating components are located. For example, batteries, computers, and/or other heat-generating components may be located at or near the bottom region the housing 20. It is well-known that hot air rises. Thus, two vent regions may be at the bottom and one vent region in the mid-section of the sidewall 31 as shown in FIG. 1 to provide maximum cooling based on this configuration. Accordingly, one or more air flow paths are formed, for example, from the door 36 to the housing sidewall 31, or vice versa, to remove hot air from the housing interior in view of such configurations and locations of heat-generating equipment. The embodiments and examples set forth herein were presented in order to best explain the present invention and its practical application and to thereby enable those of ordinary skill in the art to make and use the invention. However, those of ordinary skill in the art will recognize that the foregoing description and examples have been presented for the purposes of illustration and example only. The description as set forth is not intended to be exhaustive or to limit the invention to the precise form disclosed. Many modifications and variations are possible in light of the teachings above
<SOH> BACKGROUND OF THE INVENTION <EOH>
<SOH> SUMMARY <EOH>In one aspect, provided is a self-checkout system, comprising: a cabinet housing, the cabinet including a ventilated region; a point of sale (POS) station at the cabinet housing, the POS station including heat-generating components, the ventilated region of the cabinet housing removing heat generated from the heat-generating components from the cabinet housing; and an air flow system at an interior of the cabinet housing that outputs air through the ventilated region. The air flow system included a perforated region at one side of the cabinet housing for exchanging the air with an ambient environment and for providing an air flow path for removing the heat between the ventilated region, the perforated region, and the ambient environment. In some embodiments, the cabinet housing includes a sidewall, and wherein the sidewall includes a plurality of vents of the ventilated region. The air flow system includes both the vents and the perforated region. In some embodiments, the sidewall is removable and replaceable with a different vent configuration to change the air flow system. In some embodiments, the cabinet housing includes a door that exposes the interior of the cabinet housing when in an open state, and wherein the door includes a plurality of vents of the ventilated region. In some embodiments, the air flow system comprises a plurality of electric fans that circulate the air in the interior of the cabinet housing and through the ventilated region. In some embodiments, the electric fans are proximal the ventilated region. In some embodiments, the ventilated region includes a sidewall of the cabinet, and wherein the electric fans are coupled to the sidewall. In some embodiments, the self-checkout system further comprises a recyclable collection system in the housing adjacent the ventilated region. In some embodiments, the cabinet housing is under and supports at least one of a register area, a belt system, a self-checkout scale platform, or a pay area system. In some embodiments, the self-checkout system further comprises a bagging station adjacent the cabinet housing, the bagging station including: a carousel top; a center piece; and a plurality of bag holding elements extending from the center piece. In another aspect, a self-checkout system at a host pay-station area of a store comprises an itemization station including a point of sale system; a bagging station on one side of the itemization station; a ventilated region upstream and an air flow system on an opposite side of the itemization station as the bagging station that outputs heated air from the itemization station; and an air flow system including a perforated region at one side of the cabinet housing for exchanging the air with an ambient environment and for providing an air flow path for removing the heat between the ventilated region, the perforated region, and the ambient environment. In some embodiments, the air flow system forms a heat transfer path from the itemization station to the ventilated region at the register belt station. In another aspect, a self-checkout system comprises a ventilation system comprising a first set of ventilation openings in a door of a checkout system housing and a second set of ventilation openings in a sidewall of the checkout system housing; and an air flow system that forms a heat transfer path from the first set of ventilation openings to the second set of ventilation openings. In some embodiments, wherein the air flow system comprises a plurality of electric fans that circulate the air in the interior of the housing and through the ventilated region. In some embodiments, a bottom region of the housing includes heat-generating devices, and the second set of ventilation openings is at a mid-section of the sidewall of the checkout system housing for removing heated air generated by the heat-generating device from the housing.
A47F9048
20170815
20180222
66102.0
A47F904
0
DANNEMAN, PAUL
SELF-CHECKOUT STATION AIR CIRCULATION
UNDISCOUNTED
0
ACCEPTED
A47F
2,017
15,677,957
PENDING
METHODS FOR ANALYZING NUCLEIC ACIDS FROM SINGLE CELLS
Aspects of the present invention include analyzing nucleic acids from single cells using methods that include using tagged polynucleotides containing multiplex identifier sequences.
1. A method of analyzing nucleic acids from a plurality of single cells, the method comprising: (a) providing a sample comprising a plurality of single cells, wherein each single cell of the plurality of single cells comprises a plurality of sample polynucleotides; (b) generating a plurality of tagged polynucleotides from the plurality of sample polynucleotides, wherein each tagged polynucleotide comprises: (i) a sequence from a sample polynucleotide of the plurality of sample polynucleotides; and (ii) a multiplex identifier (MID) sequence comprising: I. a first tag sequence associated with the single cell from which the sample polynucleotide is derived; and II. a second tag sequence distinguishing the sample polynucleotide from other pluralities of sample polynucleotides derived from the same single cell; (c) sequencing the plurality of tagged polynucleotides to obtain a plurality of identified polynucleotide sequences; (d) using the first tag sequence to correlate the identified polynucleotide sequence with the single cell from which the polynucleotide sequence is derived; and (e) using the second tag sequence to correlate the identified polynucleotide sequence with the plurality of sample polynucleotides from which the polynucleotide sequence is derived. 2. The method of claim 1, wherein the method further comprises amplifying the tagged polynucleotides prior to the sequencing step (c). 3. The method of claim 1, wherein the sample polynucleotides are selected from DNA and RNA. 4. The method of claim 3, wherein the sample polynucleotides comprise mRNA. 5. The method of claim 1, wherein the tagged polynucleotides are generated through at least one ligation reaction. 6. The method of claim 1, wherein the tagged polynucleotides are generated through PCR or linear amplification of the plurality of sample polynucleotides using an adapter sequence comprising the MID sequence and an amplification primer.
BACKGROUND OF THE INVENTION We have previously described methods that enable tagging each of a population of fragmented genomes and then combining them together to create a ‘population library’ that can be processed and eventually sequenced as a mixture. The population tags enable analysis software to parse the sequence reads into files that can be attributed to a particular genome in the population. One limitation of the overall process stems from limitations of existing DNA sequencing technologies. In particular, if fragments in the regions of interest of the genome are longer than the lengths that can be sequenced by a particular technology, then such fragments will not be fully analyzed (since sequencing proceeds from an end of a fragment inward). Furthermore, a disadvantage of any sequencing technology dependent on fragmentation is that sequence changes in one part of a particular genomic region may not be able to be linked to sequence changes in other parts of the same genome (e.g., the same chromosome) because the sequence changes reside on different fragments. (See FIG. 5 and its description below). The present invention removes the limitations imposed by current sequencing technologies as well as being useful in a number of other nucleic acid analyses. SUMMARY OF THE INVENTION Aspects of the present invention are drawn to processes for moving a region of interest in a polynucleotide from a first position to a second position with regard to a domain within the polynucleotide, also referred to as a “reflex method” (or reflex process, reflex sequence process, reflex reaction, and the like). In certain embodiments, the reflex method results in moving a region of interest into functional proximity to specific domain elements present in the polynucleotide (e.g., primer sites and/or MID). Compositions, kits and systems that find use in carrying out the reflex processes described herein are also provided. BRIEF DESCRIPTION OF THE DRAWINGS The invention is best understood from the following detailed description when read in conjunction with the accompanying drawings. It is emphasized that, according to common practice, the various features of the drawings are not to scale. Indeed, the dimensions of the various features are arbitrarily expanded or reduced for clarity. Included in the drawings are the following figures: FIG. 1: Panel A is a schematic diagram illustrating moving a first domain from one site to another in a nucleic acid molecule using a reflex sequence. Panel B is a schematic diagram depicting the relative position of primer pairs (An-Bn primers) that find use in aspects of the reflex process described herein. FIG. 2 shows an exemplary embodiment of using binding partner pairs (biotin/streptavidin) to isolate single stranded polynucleotides of interest. FIG. 3 is a schematic diagram illustrating an exemplary embodiment for moving a primer site and a MID to a specific location in a nucleic acid of interest. FIG. 4 shows a schematic diagram illustrating an exemplary use of the reflex process for generating a sample enriched for fragments having a region of interest (e.g., from a population of randomly fragmented and asymmetrically tagged polynucleotides). FIG. 5 shows a comparison of methods for identifying nucleic acid polymorphisms in homologous nucleic acids in a sample (e.g., the same region derived from a chromosomal pair of a diploid cell or viral genomes/transcripts). The top schematic shows two nucleic acid molecules in a sample (1 and 2) having a different assortment of polymorphisms in polymorphic sites A, B and C (A1, B1, C1 and C2). Standard sequencing methods using fragmentation (left side) can identify the polymorphisms in these nucleic acids but do not retain linkage information. Employing the reflex process described herein to identify polymorphisms (right side) maintains linkage information. FIG. 6: Panel A is a schematic showing expected structures and sizes of nucleic acid species in the reflex process; Panel B is a polyacrylamide gel showing the nucleic acid species produced in the reflex process described in Example 1. FIG. 7: Panel A is a schematic showing the structure of the nucleic acid and competitor used in the reflex process; Panel B is a polyacrylamide gel showing the nucleic acid species produced in the reflex process described in Example 1. FIG. 8 shows a flow chart of a reflex process (left) in which the T7 exonuclease step is optional. The gel on the right shows the resultant product of the reflex process either without the T7 exonuclease step (lane 1) or with the T7 exonuclease step (lane 2). FIG. 9 shows an exemplary reflex process workflow with indications on the right as to where purification of reaction products is employed (e.g., using Agencourt beads to remove primer oligos). FIG. 10 shows the starting material (left panel) and the resultant product generated (right panel) using a reflex process without using a T7 exonuclease step (as described in Example II). The reflex site in the starting material is a sequence normally present in the polynucleotide being processed (also called a “non-artificial” reflex site). This figure shows that the 755 base pair starting nucleic acid was processed to the expected 461 base pair product, thus confirming that a “non-artificial” reflex site is effective in transferring an adapter domain from one location to another in a polynucleotide of interest in a sequence specific manner. FIG. 11 shows a schematic and results of an experiment in which the reflex process is performed on a single large initial template (a “parent” fragment) to generate five different products (“daughter” products) each having a different region of interest (i.e., daughter products are produced having either region 1, 2, 3, 4 or 5). FIG. 12 shows a schematic and results of experiments performed to determine the prevalence of intramolecular rearrangement during the reflex process (as desired) vs. intermolecular rearrangement (MID switching). FIG. 13 shows a diagram of exemplary workflows for preparing material for and performing the reflex process. DEFINITIONS Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Still, certain elements are defined for the sake of clarity and ease of reference. Terms and symbols of nucleic acid chemistry, biochemistry, genetics, and molecular biology used herein follow those of standard treatises and texts in the field, e.g. Kornberg and Baker, DNA Replication, Second Edition (W.H. Freeman, New York, 1992); Lehninger, Biochemistry, Second Edition (Worth Publishers, New York, 1975); Strachan and Read, Human Molecular Genetics, Second Edition (Wiley-Liss, New York, 1999); Eckstein, editor, Oligonucleotides and Analogs: A Practical Approach (Oxford University Press, New York, 1991); Gait, editor, Oligonucleotide Synthesis: A Practical Approach (IRL Press, Oxford, 1984); and the like. “Amplicon” means the product of a polynucleotide amplification reaction. That is, it is a population of polynucleotides, usually double stranded, that are replicated from one or more starting sequences. The one or more starting sequences may be one or more copies of the same sequence, or it may be a mixture of different sequences. Amplicons may be produced by a variety of amplification reactions whose products are multiple replicates of one or more target nucleic acids. Generally, amplification reactions producing amplicons are “template-driven” in that base pairing of reactants, either nucleotides or oligonucleotides, have complements in a template polynucleotide that are required for the creation of reaction products. In one aspect, template-driven reactions are primer extensions with a nucleic acid polymerase or oligonucleotide ligations with a nucleic acid ligase. Such reactions include, but are not limited to, polymerase chain reactions (PCRs), linear polymerase reactions, nucleic acid sequence-based amplification (NASBAs), rolling circle amplifications, and the like, disclosed in the following references that are incorporated herein by reference: Mullis et al, U.S. Pat. Nos. 4,683,195; 4,965,188; 4,683,202; 4,800,159 (PCR); Gelfand et al, U.S. Pat. No. 5,210,015 (real-time PCR with “TAQMAN™” probes); Wittwer et al, U.S. Pat. No. 6,174,670; Kacian et al, U.S. Pat. No. 5,399,491 (“NASBA”); Lizardi, U.S. Pat. No. 5,854,033; Aono et al, Japanese patent publ. JP 4-262799 (rolling circle amplification); and the like. In one aspect, amplicons of the invention are produced by PCRs. An amplification reaction may be a “real-time” amplification if a detection chemistry is available that permits a reaction product to be measured as the amplification reaction progresses, e.g. “real-time PCR” described below, or “real-time NASBA” as described in Leone et al, Nucleic Acids Research, 26: 2150-2155 (1998), and like references. As used herein, the term “amplifying” means performing an amplification reaction. A “reaction mixture” means a solution containing all the necessary reactants for performing a reaction, which may include, but not be limited to, buffering agents to maintain pH at a selected level during a reaction, salts, co-factors, scavengers, and the like. The term “assessing” includes any form of measurement, and includes determining if an element is present or not. The terms “determining”, “measuring”, “evaluating”, “assessing” and “assaying” are used interchangeably and includes quantitative and qualitative determinations. Assessing may be relative or absolute. “Assessing the presence of” includes determining the amount of something present, and/or determining whether it is present or absent. As used herein, the terms “determining,” “measuring,” and “assessing,” and “assaying” are used interchangeably and include both quantitative and qualitative determinations. Polynucleotides that are “asymmetrically tagged” have left and right adapter domains that are not identical. This process is referred to generically as attaching adapters asymmetrically or asymmetrically tagging a polynucleotide, e.g., a polynucleotide fragment. Production of polynucleotides having asymmetric adapter termini may be achieved in any convenient manner. Exemplary asymmetric adapters are described in: U.S. Pat. Nos. 5,712,126 and 6,372,434; U.S. Patent Publications 2007/0128624 and 2007/0172839; and PCT publication WO/2009/032167; all of which are incorporated by reference herein in their entirety. In certain embodiments, the asymmetric adapters employed are those described in U.S. patent application Ser. No. 12/432,080, filed on Apr. 29, 2009, incorporated herein by reference in its entirety. As one example, a user of the subject invention may use an asymmetric adapter to tag polynucleotides. An “asymmetric adapter” is one that, when ligated to both ends of a double stranded nucleic acid fragment, will lead to the production of primer extension or amplification products that have non-identical sequences flanking the genomic insert of interest. The ligation is usually followed by subsequent processing steps so as to generate the non-identical terminal adapter sequences. For example, replication of an asymmetric adapter attached fragment(s) results in polynucleotide products in which there is at least one nucleic acid sequence difference, or nucleotide/nucleoside modification, between the terminal adapter sequences. Attaching adapters asymmetrically to polynucleotides (e.g., polynucleotide fragments) results in polynucleotides that have one or more adapter sequences on one end (e.g., one or more region or domain, e.g., a primer site) that are either not present or have a different nucleic acid sequence as compared to the adapter sequence on the other end. It is noted that an adapter that is termed an “asymmetric adapter” is not necessarily itself structurally asymmetric, nor does the mere act of attaching an asymmetric adapter to a polynucleotide fragment render it immediately asymmetric. Rather, an asymmetric adapter-attached polynucleotide, which has an identical asymmetric adapter at each end, produces replication products (or isolated single stranded polynucleotides) that are asymmetric with respect to the adapter sequences on opposite ends (e.g., after at least one round of amplification/primer extension). Any convenient asymmetric adapter, or process for attaching adapters asymmetrically, may be employed in practicing the present invention. Exemplary asymmetric adapters are described in: U.S. Pat. Nos. 5,712,126 and 6,372,434; U.S. Patent Publications 2007/0128624 and 2007/0172839; and PCT publication WO/2009/032167; all of which are incorporated by reference herein in their entirety. In certain embodiments, the asymmetric adapters employed are those described in U.S. patent application Ser. No. 12/432,080, filed on Apr. 29, 2009, incorporated herein by reference in its entirety. “Complementary” or “substantially complementary” refers to the hybridization or base pairing or the formation of a duplex between nucleotides or nucleic acids, such as, for instance, between the two strands of a double stranded DNA molecule or between an oligonucleotide primer and a primer site on a single stranded nucleic acid. Complementary nucleotides are, generally, A and T (or A and U), or C and G. Two single stranded RNA or DNA molecules are said to be substantially complementary when the nucleotides of one strand, optimally aligned and compared and with appropriate nucleotide insertions or deletions, pair with at least about 80% of the nucleotides of the other strand, usually at least about 90% to 95%, and more preferably from about 98 to 100%. Alternatively, substantial complementarity exists when an RNA or DNA strand will hybridize under selective hybridization conditions to its complement. Typically, selective hybridization will occur when there is at least about 65% complementary over a stretch of at least 14 to 25 nucleotides, preferably at least about 75%, more preferably at least about 90% complementary. See, M. Kanehisa Nucleic Acids Res. 12:203 (1984), incorporated herein by reference. “Duplex” means at least two oligonucleotides and/or polynucleotides that are fully or partially complementary undergo Watson-Crick type base pairing among all or most of their nucleotides so that a stable complex is formed. The terms “annealing” and “hybridization” are used interchangeably to mean the formation of a stable duplex. “Perfectly matched” in reference to a duplex means that the poly- or oligonucleotide strands making up the duplex form a double stranded structure with one another such that every nucleotide in each strand undergoes Watson-Crick base pairing with a nucleotide in the other strand. A stable duplex can include Watson-Crick base pairing and/or non-Watson-Crick base pairing between the strands of the duplex (where base pairing means the forming hydrogen bonds). In certain embodiments, a non-Watson-Crick base pair includes a nucleoside analog, such as deoxyinosine, 2,6-diaminopurine, PNAs, LNA's and the like. In certain embodiments, a non-Watson-Crick base pair includes a “wobble base”, such as deoxyinosine, 8-oxo-dA, 8-oxo-dG and the like, where by “wobble base” is meant a nucleic acid base that can base pair with a first nucleotide base in a complementary nucleic acid strand but that, when employed as a template strand for nucleic acid synthesis, leads to the incorporation of a second, different nucleotide base into the synthesizing strand (wobble bases are described in further detail below). A “mismatch” in a duplex between two oligonucleotides or polynucleotides means that a pair of nucleotides in the duplex fails to undergo Watson-Crick bonding. “Genetic locus,” “locus,” or “locus of interest” in reference to a genome or target polynucleotide, means a contiguous sub-region or segment of the genome or target polynucleotide. As used herein, genetic locus, locus, or locus of interest may refer to the position of a nucleotide, a gene or a portion of a gene in a genome, including mitochondrial DNA or other non-chromosomal DNA (e.g., bacterial plasmid), or it may refer to any contiguous portion of genomic sequence whether or not it is within, or associated with, a gene. A genetic locus, locus, or locus of interest can be from a single nucleotide to a segment of a few hundred or a few thousand nucleotides in length or more. In general, a locus of interest will have a reference sequence associated with it (see description of “reference sequence” below). “Kit” refers to any delivery system for delivering materials or reagents for carrying out a method of the invention. In the context of reaction assays, such delivery systems include systems that allow for the storage, transport, or delivery of reaction reagents (e.g., probes, enzymes, etc. in the appropriate containers) and/or supporting materials (e.g., buffers, written instructions for performing the assay etc.) from one location to another. For example, kits include one or more enclosures (e.g., boxes) containing the relevant reaction reagents and/or supporting materials. Such contents may be delivered to the intended recipient together or separately. For example, a first container may contain an enzyme for use in an assay, while a second container contains probes. “Ligation” means to form a covalent bond or linkage between the termini of two or more nucleic acids, e.g. oligonucleotides and/or polynucleotides, in a template-driven reaction. The nature of the bond or linkage may vary widely and the ligation may be carried out enzymatically or chemically. As used herein, ligations are usually carried out enzymatically to form a phosphodiester linkage between a 5′ carbon of a terminal nucleotide of one oligonucleotide with 3′ carbon of another oligonucleotide. A variety of template-driven ligation reactions are described in the following references, which are incorporated by reference: Whiteley et al, U.S. Pat. No. 4,883,750; Letsinger et al, U.S. Pat. No. 5,476,930; Fung et al, U.S. Pat. No. 5,593,826; Kool, U.S. Pat. No. 5,426,180; Landegren et al, U.S. Pat. No. 5,871,921; Xu and Kool, Nucleic Acids Research, 27: 875-881 (1999); Higgins et al, Methods in Enzymology, 68: 50-71 (1979); Engler et al, The Enzymes, 15: 3-29 (1982); and Namsaraev, U.S. patent publication 2004/0110213. “Multiplex Identifier” (MID) as used herein refers to a tag or combination of tags associated with a polynucleotide whose identity (e.g., the tag DNA sequence) can be used to differentiate polynucleotides in a sample. In certain embodiments, the MID on a polynucleotide is used to identify the source from which the polynucleotide is derived. For example, a nucleic acid sample may be a pool of polynucleotides derived from different sources, (e.g., polynucleotides derived from different individuals, different tissues or cells, or polynucleotides isolated at different times points), where the polynucleotides from each different source are tagged with a unique MID. As such, a MID provides a correlation between a polynucleotide and its source. In certain embodiments, MIDs are employed to uniquely tag each individual polynucleotide in a sample. Identification of the number of unique MIDs in a sample can provide a readout of how many individual polynucleotides are present in the sample (or from how many original polynucleotides a manipulated polynucleotide sample was derived; see, e.g., U.S. Pat. No. 7,537,897, issued on May 26, 2009, incorporated herein by reference in its entirety). MIDs can range in length from 2 to 100 nucleotide bases or more and may include multiple subunits, where each different MID has a distinct identity and/or order of subunits. Exemplary nucleic acid tags that find use as MIDs are described in U.S. Pat. No. 7,544,473, issued on Jun. 6, 2009, and titled “Nucleic Acid Analysis Using Sequence Tokens”, as well as U.S. Pat. No. 7,393,665, issued on Jul. 1, 2008, and titled “Methods and Compositions for Tagging and Identifying Polynucleotides”, both of which are incorporated herein by reference in their entirety for their description of nucleic acid tags and their use in identifying polynucleotides. In certain embodiments, a set of MIDs employed to tag a plurality of samples need not have any particular common property (e.g., Tm, length, base composition, etc.), as the methods described herein can accommodate a wide variety of unique MID sets. It is emphasized here that MIDs need only be unique within a given experiment. Thus, the same MID may be used to tag a different sample being processed in a different experiment. In addition, in certain experiments, a user may use the same MID to tag a subset of different samples within the same experiment. For example, all samples derived from individuals having a specific phenotype may be tagged with the same MID, e.g., all samples derived from control (or wildtype) subjects can be tagged with a first MID while subjects having a disease condition can be tagged with a second MID (different than the first MID). As another example, it may be desirable to tag different samples derived from the same source with different MIDs (e.g., samples derived over time or derived from different sites within a tissue). Further, MIDs can be generated in a variety of different ways, e.g., by a combinatorial tagging approach in which one MID is attached by ligation and a second MID is attached by primer extension. Thus, MIDs can be designed and implemented in a variety of different ways to track polynucleotide fragments during processing and analysis, and thus no limitation in this regard is intended. “Nucleoside” as used herein includes the natural nucleosides, including 2′-deoxy and 2′-hydroxyl forms, e.g. as described in Kornberg and Baker, DNA Replication, 2nd Ed. (Freeman, San Francisco, 1992). “Analogs” in reference to nucleosides includes synthetic nucleosides having modified base moieties and/or modified sugar moieties, e.g. described by Scheit, Nucleotide Analogs (John Wiley, New York, 1980); Uhlman and Peyman, Chemical Reviews, 90: 543-584 (1990), or the like, with the proviso that they are capable of specific hybridization. Such analogs include synthetic nucleosides designed to enhance binding properties, reduce complexity, increase specificity, and the like. Polynucleotides comprising analogs with enhanced hybridization or nuclease resistance properties are described in Uhlman and Peyman (cited above); Crooke et al, Exp. Opin. Ther. Patents, 6: 855-870 (1996); Mesmaeker et al, Current Opinion in Structual Biology, 5: 343-355 (1995); and the like. Exemplary types of polynucleotides that are capable of enhancing duplex stability include oligonucleotide phosphoramidates (referred to herein as “amidates”), peptide nucleic acids (referred to herein as “PNAs”), oligo-2′-O-alkylribonucleotides, polynucleotides containing C-5 propynylpyrimidines, locked nucleic acids (“LNAs”), and like compounds. Such oligonucleotides are either available commercially or may be synthesized using methods described in the literature. “Polymerase chain reaction,” or “PCR,” means a reaction for the in vitro amplification of specific DNA sequences by the simultaneous primer extension of complementary strands of DNA. In other words, PCR is a reaction for making multiple copies or replicates of a target nucleic acid flanked by primer sites, such reaction comprising one or more repetitions of the following steps: (i) denaturing the target nucleic acid, (ii) annealing primers to the primer sites, and (iii) extending the primers by a nucleic acid polymerase in the presence of nucleoside triphosphates. Usually, the reaction is cycled through different temperatures optimized for each step in a thermal cycler instrument. Particular temperatures, durations at each step, and rates of change between steps depend on many factors well-known to those of ordinary skill in the art, e.g. exemplified by the references: McPherson et al, editors, PCR: A Practical Approach and PCR2: A Practical Approach (IRL Press, Oxford, 1991 and 1995, respectively). For example, in a conventional PCR using Taq DNA polymerase, a double stranded target nucleic acid may be denatured at a temperature >90° C., primers annealed at a temperature in the range 50-75° C., and primers extended at a temperature in the range 72-78° C. The term “PCR” encompasses derivative forms of the reaction, including but not limited to, RT-PCR, real-time PCR, nested PCR, quantitative PCR, multiplexed PCR, and the like. Reaction volumes range from a few hundred nanoliters, e.g. 200 nL, to a few hundred μL, e.g. 200 μL. “Reverse transcription PCR,” or “RT-PCR,” means a PCR that is preceded by a reverse transcription reaction that converts a target RNA to a complementary single stranded DNA, which is then amplified, e.g. Tecott et al, U.S. Pat. No. 5,168,038, which patent is incorporated herein by reference. “Real-time PCR” means a PCR for which the amount of reaction product, i.e. amplicon, is monitored as the reaction proceeds. There are many forms of real-time PCR that differ mainly in the detection chemistries used for monitoring the reaction product, e.g. Gelfand et al, U.S. Pat. No. 5,210,015 (“TAQMAN™”); Wittwer et al, U.S. Pat. Nos. 6,174,670 and 6,569,627 (intercalating dyes); Tyagi et al, U.S. Pat. No. 5,925,517 (molecular beacons); which patents are incorporated herein by reference. Detection chemistries for real-time PCR are reviewed in Mackay et al, Nucleic Acids Research, 30: 1292-1305 (2002), which is also incorporated herein by reference. “Nested PCR” means a two-stage PCR wherein the amplicon of a first PCR becomes the sample for a second PCR using a new set of primers, at least one of which binds to an interior location of the first amplicon. As used herein, “initial primers” in reference to a nested amplification reaction mean the primers used to generate a first amplicon, and “secondary primers” mean the one or more primers used to generate a second, or nested, amplicon. “Multiplexed PCR” means a PCR wherein multiple target sequences (or a single target sequence and one or more reference sequences) are simultaneously carried out in the same reaction mixture, e.g. Bernard et al, Anal. Biochem., 273: 221-228 (1999)(two-color real-time PCR). Usually, distinct sets of primers are employed for each sequence being amplified. “Quantitative PCR” means a PCR designed to measure the abundance of one or more specific target sequences in a sample or specimen. Quantitative PCR includes both absolute quantitation and relative quantitation of such target sequences. Quantitative measurements are made using one or more reference sequences that may be assayed separately or together with a target sequence. The reference sequence may be endogenous or exogenous to a sample or specimen, and in the latter case, may comprise one or more competitor templates. Typical endogenous reference sequences include segments of transcripts of the following genes: β-actin, GAPDH, β2-microglobulin, ribosomal RNA, and the like. Techniques for quantitative PCR are well-known to those of ordinary skill in the art, as exemplified in the following references that are incorporated by reference: Freeman et al, Biotechniques, 26: 112-126 (1999); Becker-Andre et al, Nucleic Acids Research, 17: 9437-9447 (1989); Zimmerman et al, Biotechniques, 21: 268-279 (1996); Diviacco et al, Gene, 122: 3013-3020 (1992); Becker-Andre et al, Nucleic Acids Research, 17: 9437-9446 (1989); and the like. “Polynucleotide” or “oligonucleotide” is used interchangeably and each means a linear polymer of nucleotide monomers. Monomers making up polynucleotides and oligonucleotides are capable of specifically binding to a natural polynucleotide by way of a regular pattern of monomer-to-monomer interactions, such as Watson-Crick type of base pairing, base stacking, Hoogsteen or reverse Hoogsteen types of base pairing, wobble base pairing, or the like. As described in detail below, by “wobble base” is meant a nucleic acid base that can base pair with a first nucleotide base in a complementary nucleic acid strand but that, when employed as a template strand for nucleic acid synthesis, leads to the incorporation of a second, different nucleotide base into the synthesizing strand. Such monomers and their internucleosidic linkages may be naturally occurring or may be analogs thereof, e.g. naturally occurring or non-naturally occurring analogs. Non-naturally occurring analogs may include peptide nucleic acids (PNAs, e.g., as described in U.S. Pat. No. 5,539,082, incorporated herein by reference), locked nucleic acids (LNAs, e.g., as described in U.S. Pat. No. 6,670,461, incorporated herein by reference), phosphorothioate internucleosidic linkages, bases containing linking groups permitting the attachment of labels, such as fluorophores, or haptens, and the like. Whenever the use of an oligonucleotide or polynucleotide requires enzymatic processing, such as extension by a polymerase, ligation by a ligase, or the like, one of ordinary skill would understand that oligonucleotides or polynucleotides in those instances would not contain certain analogs of internucleosidic linkages, sugar moieties, or bases at any or some positions. Polynucleotides typically range in size from a few monomeric units, e.g. 5-40, when they are usually referred to as “oligonucleotides,” to several thousand monomeric units. Whenever a polynucleotide or oligonucleotide is represented by a sequence of letters (upper or lower case), such as “ATGCCTG,” it will be understood that the nucleotides are in 5′->3′ order from left to right and that “A” denotes deoxyadenosine, “C” denotes deoxycytidine, “G” denotes deoxyguanosine, and “T” denotes thymidine, “I” denotes deoxyinosine, “U” denotes uridine, unless otherwise indicated or obvious from context. Unless otherwise noted the terminology and atom numbering conventions will follow those disclosed in Strachan and Read, Human Molecular Genetics 2 (Wiley-Liss, New York, 1999). Usually polynucleotides comprise the four natural nucleosides (e.g. deoxyadenosine, deoxycytidine, deoxyguanosine, deoxythymidine for DNA or their ribose counterparts for RNA) linked by phosphodiester linkages; however, they may also comprise non-natural nucleotide analogs, e.g. including modified bases, sugars, or internucleosidic linkages. It is clear to those skilled in the art that where an enzyme has specific oligonucleotide or polynucleotide substrate requirements for activity, e.g. single stranded DNA, RNA/DNA duplex, or the like, then selection of appropriate composition for the oligonucleotide or polynucleotide substrates is well within the knowledge of one of ordinary skill, especially with guidance from treatises, such as Sambrook et al, Molecular Cloning, Second Edition (Cold Spring Harbor Laboratory, New York, 1989), and like references. “Primer” means an oligonucleotide, either natural or synthetic, that is capable, upon forming a duplex with a polynucleotide template, of acting as a point of initiation of nucleic acid synthesis and being extended from its 3′ end along the template so that an extended duplex is formed. The sequence of nucleotides added during the extension process is determined by the sequence of the template polynucleotide. Usually primers are extended by a DNA polymerase. Primers are generally of a length compatible with their use in synthesis of primer extension products, and are usually are in the range of between 8 to 100 nucleotides in length, such as 10 to 75, 15 to 60, 15 to 40, 18 to 30, 20 to 40, 21 to 50, 22 to 45, 25 to 40, and so on, more typically in the range of between 18-40, 20-35, 21-30 nucleotides long, and any length between the stated ranges. Typical primers can be in the range of between 10-50 nucleotides long, such as 15-45, 18-40, 20-30, 21-25 and so on, and any length between the stated ranges. In some embodiments, the primers are usually not more than about 10, 12, 15, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, or 70 nucleotides in length. Primers are usually single-stranded for maximum efficiency in amplification, but may alternatively be double-stranded. If double-stranded, the primer is usually first treated to separate its strands before being used to prepare extension products. This denaturation step is typically affected by heat, but may alternatively be carried out using alkali, followed by neutralization. Thus, a “primer” is complementary to a template, and complexes by hydrogen bonding or hybridization with the template to give a primer/template complex for initiation of synthesis by a polymerase, which is extended by the addition of covalently bonded bases linked at its 3′ end complementary to the template in the process of DNA synthesis. A “primer pair” as used herein refers to first and second primers having nucleic acid sequence suitable for nucleic acid-based amplification of a target nucleic acid. Such primer pairs generally include a first primer having a sequence that is the same or similar to that of a first portion of a target nucleic acid, and a second primer having a sequence that is complementary to a second portion of a target nucleic acid to provide for amplification of the target nucleic acid or a fragment thereof. Reference to “first” and “second” primers herein is arbitrary, unless specifically indicated otherwise. For example, the first primer can be designed as a “forward primer” (which initiates nucleic acid synthesis from a 5′ end of the target nucleic acid) or as a “reverse primer” (which initiates nucleic acid synthesis from a 5′ end of the extension product produced from synthesis initiated from the forward primer). Likewise, the second primer can be designed as a forward primer or a reverse primer. “Primer site” (e.g., a sequencing primer site, and amplification primer site, etc.) as used herein refers to a domain in a polynucleotide that includes the sequence of a primer (e.g., a sequencing primer) and/or the complementary sequence of a primer. When present in single stranded form (e.g., in a single stranded polynucleotide), a primer site can be either the identical sequence of a primer or the complementary sequence of a primer. When present in double stranded form, a primer site contains the sequence of a primer hybridized to the complementary sequence of the primer. Thus, a primer site is a region of a polynucleotide that is either identical to or complementary to the sequence of a primer (when in a single stranded form) or a double stranded region formed between a primer sequence and its complement. Primer sites may be present in an adapter attached to a polynucleotide. The specific orientation of a primer site can be inferred by those of ordinary skill in the art from the structural features of the relevant polynucleotide and/or context in which it is used. “Readout” means a parameter, or parameters, which are measured and/or detected that can be converted to a number or value. In some contexts, readout may refer to an actual numerical representation of such collected or recorded data. For example, a readout of fluorescent intensity signals from a microarray is the address and fluorescence intensity of a signal being generated at each hybridization site of the microarray; thus, such a readout may be registered or stored in various ways, for example, as an image of the microarray, as a table of numbers, or the like. “Reflex site”, “reflex sequence” and equivalents are used to indicate sequences in a polynucleotide that are employed to move a domain intramolecularly from its initial location to a different location in the polynucleotide. The sequence of a reflex site can be added to a polynucleotide of interest (e.g., present in an adapter ligated to the polynucleotide), be based on a sequence naturally present within the polynucleotide of interest (e.g., a genomic sequence in the polynucleotide), or a combination of both. The reflex sequence is chosen so as to be distinct from other sequences in the polynucleotide (i.e., with little sequence homology to other sequences likely to be present in the polynucleotide, e.g., genomic or sub-genomic sequences to be processed). As such, a reflex sequence should be selected so as to not hybridize to any sequence except its complement under the conditions employed in the reflex processes herein described. As described later in this application, the complement to the reflex sequence is inserted on the same strand of the polynucleotide (e.g., the same strand of a double-stranded polynucleotide or on the same single stranded polynucleotide) in a particular location so as to facilitate an intramolecular binding event on such particular strand. Reflex sequences employed in the reflex process described herein can thus have a wide range of lengths and sequences. Reflex sequences may range from 5 to 200 nucleotide bases in length. “Solid support”, “support”, and “solid phase support” are used interchangeably and refer to a material or group of materials having a rigid or semi-rigid surface or surfaces. In many embodiments, at least one surface of the solid support will be substantially flat, although in some embodiments it may be desirable to physically separate synthesis regions for different compounds with, for example, wells, raised regions, pins, etched trenches, or the like. According to other embodiments, the solid support(s) will take the form of beads, resins, gels, microspheres, or other geometric configurations. Microarrays usually comprise at least one planar solid phase support, such as a glass microscope slide. “Specific” or “specificity” in reference to the binding of one molecule to another molecule, such as a labeled target sequence for a probe, means the recognition, contact, and formation of a stable complex between the two molecules, together with substantially less recognition, contact, or complex formation of that molecule with other molecules. In one aspect, “specific” in reference to the binding of a first molecule to a second molecule means that to the extent the first molecule recognizes and forms a complex with another molecule in a reaction or sample, it forms the largest number of the complexes with the second molecule. Preferably, this largest number is at least fifty percent. Generally, molecules involved in a specific binding event have areas on their surfaces or in cavities giving rise to specific recognition between the molecules binding to each other. Examples of specific binding include antibody-antigen interactions, enzyme-substrate interactions, formation of duplexes or triplexes among polynucleotides and/or oligonucleotides, biotin-avidin or biotin-streptavidin interactions, receptor-ligand interactions, and the like. As used herein, “contact” in reference to specificity or specific binding means two molecules are close enough that weak noncovalent chemical interactions, such as Van der Waal forces, hydrogen bonding, base-stacking interactions, ionic and hydrophobic interactions, and the like, dominate the interaction of the molecules. As used herein, the term “Tm” is used in reference to the “melting temperature.” The melting temperature is the temperature (e.g., as measured in ° C.) at which a population of double-stranded nucleic acid molecules becomes half dissociated into single strands. Several equations for calculating the T. of nucleic acids are known in the art (see e.g., Anderson and Young, Quantitative Filter Hybridization, in Nucleic Acid Hybridization (1985). Other references (e.g., Allawi, H. T. & SantaLucia, J., Jr., Biochemistry 36, 10581-94 (1997)) include alternative methods of computation which take structural and environmental, as well as sequence characteristics into account for the calculation of Tm. “Sample” means a quantity of material from a biological, environmental, medical, or patient source in which detection, measurement, or labeling of target nucleic acids is sought. On the one hand it is meant to include a specimen or culture (e.g., microbiological cultures). On the other hand, it is meant to include both biological and environmental samples. A sample may include a specimen of synthetic origin. Biological samples may be animal, including human, fluid, solid (e.g., stool) or tissue, as well as liquid and solid food and feed products and ingredients such as dairy items, vegetables, meat and meat by-products, and waste. Biological samples may include materials taken from a patient including, but not limited to cultures, blood, saliva, cerebral spinal fluid, pleural fluid, milk, lymph, sputum, semen, needle aspirates, and the like. Biological samples may be obtained from all of the various families of domestic animals, as well as feral or wild animals, including, but not limited to, such animals as ungulates, bear, fish, rodents, etc. Environmental samples include environmental material such as surface matter, soil, water and industrial samples, as well as samples obtained from food and dairy processing instruments, apparatus, equipment, utensils, disposable and non-disposable items. These examples are not to be construed as limiting the sample types applicable to the present invention. The terms “upstream” and “downstream” in describing nucleic acid molecule orientation and/or polymerization are used herein as understood by one of skill in the art. As such, “downstream” generally means proceeding in the 5′ to 3′ direction, i.e., the direction in which a nucleotide polymerase normally extends a sequence, and “upstream” generally means the converse. For example, a first primer that hybridizes “upstream” of a second primer on the same target nucleic acid molecule is located on the 5′ side of the second primer (and thus nucleic acid polymerization from the first primer proceeds towards the second primer). It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely”, “only” and the like in connection with the recitation of claim elements, or the use of a “negative” limitation. DETAILED DESCRIPTION OF THE INVENTION The invention is drawn to compositions and methods for intramolecular nucleic acid rearrangement that find use in various applications of genetic analysis, including sequencing, as well as general molecular biological manipulations of polynucleotide structures. Before the present invention is described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, some potential and preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. It is understood that the present disclosure supersedes any disclosure of an incorporated publication to the extent there is a contradiction. It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a nucleic acid” includes a plurality of such nucleic acids and reference to “the compound” includes reference to one or more compounds and equivalents thereof known to those skilled in the art, and so forth. The practice of the present invention may employ, unless otherwise indicated, conventional techniques and descriptions of organic chemistry, polymer technology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology, which are within the skill of the art. Such conventional techniques include polymer array synthesis, hybridization, ligation, and detection of hybridization using a label. Specific illustrations of suitable techniques can be had by reference to the example herein below. However, other equivalent conventional procedures can, of course, also be used. Such conventional techniques and descriptions can be found in standard laboratory manuals such as Genome Analysis: A Laboratory Manual Series (Vols. I-IV), Using Antibodies: A Laboratory Manual, Cells: A Laboratory Manual, PCR Primer: A Laboratory Manual, and Molecular Cloning: A Laboratory Manual (all from Cold Spring Harbor Laboratory Press), Stryer, L. (1995) Biochemistry (4th Ed.) Freeman, New York, Gait, “Oligonucleotide Synthesis: A Practical Approach” 1984, IRL Press, London, Nelson and Cox (2000), Lehninger, A., Principles of Biochemistry 3rd Ed., W. H. Freeman Pub., New York, N.Y. and Berg et al. (2002) Biochemistry, 5th Ed., W. H. Freeman Pub., New York, N.Y., all of which are herein incorporated in their entirety by reference for all purposes. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed. As summarized above, aspects of the present invention are drawn to the use of a ‘reflex’ sequence present in a polynucleotide (e.g., in an adapter structure of the polynucleotide, in a genomic region of the polynucleotide, or a combination of both) to move a domain of the polynucleotide intra-molecularly from a first location to a second location. The reflex process described herein finds use in any number of applications, e.g., placing functional elements of a polynucleotide (e.g., sequencing primer sites and/or MID tags) into proximity to a desired sub-region of interest. Nucleic Acids The reflex process (as described in detail below) can be employed for the manipulation and analysis of nucleic acid sequences of interest from virtually any nucleic acid source, including but not limited to genomic DNA, complementary DNA (cDNA), RNA (e.g., messenger RNA, ribosomal RNA, short interfering RNA, microRNA, etc.), plasmid DNA, mitochondrial DNA, synthetic DNA, etc. Furthermore, any organism, organic material or nucleic acid-containing substance can be used as a source of nucleic acids to be processed in accordance with the present invention including, but not limited to, plants, animals (e.g., reptiles, mammals, insects, worms, fish, etc.), tissue samples, bacteria, fungi (e.g., yeast), phage, viruses, cadaveric tissue, archaeological/ancient samples, etc. In certain embodiments, the nucleic acids in the nucleic acid sample are derived from a mammal, where in certain embodiments the mammal is a human. In certain embodiments, the nucleic acid sequences are enriched prior to the reflex sequence process. By enriched is meant that the nucleic acid is subjected to a process that reduces the complexity of the nucleic acids, generally by increasing the relative concentration of particular nucleic acid species in the sample (e.g., having a specific locus of interest, including a specific nucleic acid sequence, lacking a locus or sequence, being within a specific size range, etc.). There are a wide variety of ways to enrich nucleic acids having a specific characteristic(s) or sequence, and as such any convenient method to accomplish this may be employed. The enrichment (or complexity reduction) can take place at any of a number of steps in the process, and will be determined by the desires of the user. For example, enrichment can take place in individual parental samples (e.g., untagged nucleic acids prior to adaptor ligation) or in multiplexed samples (e.g., nucleic acids tagged with primer sites, MID and/or reflex sequences and pooled; MID are described in further detail below). In certain embodiments, nucleic acids in the nucleic acid sample are amplified prior to analysis. In certain of these embodiments, the amplification reaction also serves to enrich a starting nucleic acid sample for a sequence or locus of interest. For example, a starting nucleic acid sample can be subjected to a polymerase chain reaction (PCR) that amplifies one or more region of interest. In certain embodiments, the amplification reaction is an exponential amplification reaction, whereas in certain other embodiments, the amplification reaction is a linear amplification reaction. Any convenient method for performing amplification reactions on a starting nucleic acid sample can be used in practicing the subject invention. In certain embodiments, the nucleic acid polymerase employed in the amplification reaction is a polymerase that has proofreading capability (e.g., phi29 DNA Polymerase, Thermococcus litoralis DNA polymerase, Pyrococcus furiosus DNA polymerase, etc.). In certain embodiments, the nucleic acid sample being analyzed is derived from a single source (e.g., a single organism, virus, tissue, cell, subject, etc.), whereas in other embodiments, the nucleic acid sample is a pool of nucleic acids extracted from a plurality of sources (e.g., a pool of nucleic acids from a plurality of organisms, tissues, cells, subjects, etc.), where by “plurality” is meant two or more. As such, in certain embodiments, a nucleic acid sample can contain nucleic acids from 2 or more sources, 3 or more sources, 5 or more sources, 10 or more sources, 50 or more sources, 100 or more sources, 500 or more sources, 1000 or more sources, 5000 or more sources, up to and including about 10,000 or more sources. In certain embodiments, nucleic acid fragments that are to be pooled with nucleic acid fragments derived from a plurality of sources (e.g., a plurality of organisms, tissues, cells, subjects, etc.), where by “plurality” is meant two or more. In such embodiments, the nucleic acids derived from each source includes a multiplex identifier (MID) such that the source from which the each tagged nucleic acid fragment was derived can be determined. In such embodiments, each nucleic acid sample source is correlated with a unique MID, where by unique MID is meant that each different MID employed can be differentiated from every other MID employed by virtue of at least one characteristic, e.g., the nucleic acid sequence of the MID. Any type of MID can be used, including but not limited to those described in co-pending U.S. patent application Ser. No. 11/656,746, filed on Jan. 22, 2007, and titled “Nucleic Acid Analysis Using Sequence Tokens”, as well as U.S. Pat. No. 7,393,665, issued on Jul. 1, 2008, and titled “Methods and Compositions for Tagging and Identifying Polynucleotides”, both of which are incorporated herein by reference in their entirety for their description of nucleic acid tags and their use in identifying polynucleotides. In certain embodiments, a set of MIDs employed to tag a plurality of samples need not have any particular common property (e.g., Tm, length, base composition, etc.), as the asymmetric tagging methods (and many tag readout methods, including but not limited to sequencing of the tag or measuring the length of the tag) can accommodate a wide variety of unique MID sets. In certain embodiments, each individual polynucleotide (e.g., double-stranded or single-stranded, as appropriate to the methodological details employed) in a sample to be analyzed is tagged with a unique MID so that the fate of each polynucleotide can be tracked in subsequent processes (where, as noted above, unique MID is meant to indicate that each different MID employed can be differentiated from every other MID employed by virtue of at least one characteristic, e.g., the nucleic acid sequence of the MID). For example (and as described below), having each nucleic acid tagged with a unique MID allows analysis of the sequence of each individual nucleic acid using the reflex sequence methods described herein. This allows the linkage of sequence information for large nucleic acid fragments that cannot be sequenced in a single sequencing run. Reflex Sequence Process As summarized above, aspects of the present invention include methods and compositions for moving a domain in a polynucleotide from a first location to a second location in the polynucleotide. An exemplary embodiment is shown in FIG. 1A. FIG. 1A shows a single stranded polynucleotide 100 comprising, in a 5′ to 3′ orientation, a first domain (102; the domain to be moved); a reflex sequence 104; a nucleic acid sequence 106 having a site distal to the first domain (Site A), and a complement of the reflex sequence 108 (positioned at the 3′ terminus of the polynucleotide). The steps of the reflex method described below will move the first domain into closer proximity to Site A. It is noted here that the prime designation in FIG. 1A denotes a complementary sequence of a domain. For example, First Domain' is the complement of the First Domain. In Step 1, the reflex sequence and its complement in the polynucleotide are annealed intramolecularly to form polynucleotide structure 112, with the polynucleotide folding back on itself and hybridizing to form a region of complementarity (i.e., double stranded reflex/reflex' region). In this configuration, the 3′ end of the complement of the reflex sequence can serve as a nucleic acid synthesis priming site. Nucleic acid synthesis from this site is then performed in extension Step 2 producing a complement of the first domain at the 3′ end of the nucleic acid extension (shown in polynucleotide 114; extension is indicated with dotted arrow labeled “extend”). Denaturation of polynucleotide 114 (e.g., by heat) generates linear single stranded polynucleotide 116. As shown in FIG. 1, resultant polynucleotide 116 contains a complement of the first domain at a position proximal to Site A (i.e., separated by only the complement of the reflex sequence). This resultant polynucleotide may be used for any subsequent analysis or processing steps as desired by the user (e.g., sequencing, as a template for amplification (linear, PCR, etc.), sequence specific extraction, etc.). In alternative embodiments, the first domain and reflex sequence are removed from the 5′ end of the double-stranded region of polynucleotide 114 (shown in polynucleotide 118; removal is shown in the dotted arrow labeled “remove”). Removal of this region may be accomplished by any convenient method, including, but not limited to, treatment (under appropriate incubation conditions) of polynucleotide structure 114 with T7 exonuclease or by treatment with Lambda exonuclease; the Lambda exonuclease can be employed so long as the 5′ end of the polynucleotide is phosphorylated. If the region is removed enzymatically, resultant polynucleotide 118 is used in place of polynucleotide 116 in subsequent steps (e.g., copying to reverse polarity). In certain embodiments, polynucleotide 116 or 118 is used as a template to produce a double stranded polynucleotide, for example by performing a nucleic acid synthesis reaction with a primer that primes in the complement of the first domain. This step is sometimes referred to as copying to reverse polarity of a single stranded polynucleotide, and in some instances, the double-stranded intermediate product of this copying is not shown (see, e.g., FIG. 3). For example, copying to reverse the polarity of polynucleotide 116 results in single-stranded polynucleotide 120 having, in a 5′ to 3′ orientation, the first domain (122); the reflex sequence (124); the complement of polynucleotide 106 (oriented with the complement of Site A (Site A′; 126) proximal to the reflex sequence); the complement of the reflex sequence (128); and the complement of the first domain (130). In certain embodiments, the first domain in the polynucleotide comprises one or more elements that find use in one or more subsequent processing or analysis steps. Such sequences include, but are not limited to, restriction enzyme sites, PCR primer sites, linear amplification primer sites, reverse transcription primer sites, RNA polymerase promoter sites (such as for T7, T3 or SP6 RNA polymerase), MID tags, sequencing primer sites, etc. Any convenient element can be included in the first domain and, in certain embodiments, is determined by the desires of the user of the methods described herein. As an exemplary embodiment, suppose we want to sequence a specific polynucleotide region from multiple genomes in a pooled sample where the polynucleotide region is too long to sequence in a single reaction. For example, sequencing a polynucleotide region that is 2 kilobases or more in length using Roche 454 (Branford, Conn.) technology, in which the length of a single sequencing run is about 400 bases. In this scenario, we can design a set of left hand primers (An) and right hand primers (Bn) specific for the polynucleotide region that are positioned in such a way that we can obtain direct sequences of all parts of the insert, as shown in FIG. 1B. Note that the polynucleotide shown in FIG. 1B (140) has a domain (142) containing a primer site and an MID denoting from which original sample(s) the polynucleotide is derived. Site 142 thus represents an example of a First Domain site such identified as 122 in the FIG. 1A. The polynucleotide also includes a reflex site (144), which can be part of the polynucleotide region itself (e.g., a genomic sequence), added in a ligated adapter domain along with the primer site and the MID (an artificial sequence), or a combination of both (a sequence spanning the adapter/polynucleotide junction). It is noted here that polynucleotide 140 can be categorized as a precursor to polynucleotide 100 in FIG. 1A, as it does not include a 3′ reflex sequence complementary to the reflex site (domain 108 in FIG. 1A). As detailed below, polynucleotide 140 can be converted to a polynucleotide having the structural configuration of polynucleotide 100, a polynucleotide suitable as a substrate for the reflex process described herein (e.g., by primer extension using a Bn primer and reversal of polarity). In an exemplary embodiment, each An-Bn primer pair defines a nucleic acid region that is approximately 400 bases in length or less. This size range is within the single-sequencing run read length of the current Roche 454 sequencing platform; a different size range for the defined nucleic acid region may be utilized for a different sequencing platform. Thus, each product from each reflex process can be sequenced in a single run. It is noted here that primer pairs as shown in FIG. 1B can be used to define regions 1 to 5 shown in FIG. 3 (described in further detail below). In certain embodiments, to obtain the first part of the sequence of the polynucleotide region (i.e., in the original structure, that part of the polynucleotide closest to the first domain), we only need a right hand primer (e.g., B0) and we do not need to transfer the MID as it is within reach of this sequencing primer (i.e., the MID is within 400 bases of sequencing primer B0). All other Bn primers have the reflex sequence added to their 5′ ends (“R” element shown on B primers) so that they read 5′ reflex-Bn. However, in certain embodiments, the Bo primer does include the reflex sequence and is used in the reflex process (along with a corresponding Ao primer) as detailed below. As described above, we obtain a single stranded polynucleotide having, in the 5′ to 3′ orientation, a primer site (e.g., for Roche 454 sequencing), an MID, a reflex sequence and the polynucleotide to be sequenced. Numerous methods for obtaining single-stranded polynucleotides of interest have been described and are known in the art, including in U.S. Pat. No. 7,217,522, issued on May 15, 2007; U.S. patent application Ser. No. 11/377,462, filed on Mar. 16, 2006; and U.S. patent application Ser. No. 12/432,080, filed on Apr. 29, 2009; each of which is incorporated by reference herein in their entirety. For example, a single stranded product can be produced using linear amplification with a primer specific for the primer site of the template. In certain embodiments, the primer includes a binding moiety to facilitate isolation of the single stranded nucleic acid of interest, e.g., to immobilize the top strand on a binding partner of the binding moiety immobilized on a solid support. Removal of a hybridized, non-biotinylated strand by denaturation using heat or high pH (or any other convenient method) serves to isolate the biotinylated strand. Binding moieties and their corresponding binding partners are sometimes referred to herein as binding partner pairs. Any convenient binding partner pairs may be used, including but not limited to biotin/avidin (or streptavidin), antigen/antibody pairs, etc. It is noted here that while the figures and description of the reflex process provided herein depict manipulations with regard to a single stranded polynucleotide, it is not necessarily required that the single stranded polynucleotide described or depicted in the figures be present in the sample in an isolated form (i.e., isolated from its complementary strand). In other words, double stranded polynucleotides may be used where only one strand is described/depicted, which will generally be determined by the user. The implementation of a single strand isolation step using the methods described above or variations thereof (or any other convenient single strand isolation step) will generally be based on the desires of the user. One example of isolating single stranded polynucleotides is shown in FIG. 2. In this Figure, a starting double stranded template (with 5′ to 3′ orientation shown as an arrow) is denatured and primed with a biotinylated synthesis primer specific for the primer site. After extension of the primer (i.e., nucleic acid synthesis), the sample is contacted with a solid support having streptavidin bound to it. The biotin moiety (i.e., the binding partner of streptavidin) on the extended strands will bind to the solid-phase streptavidin. Denaturation and washing is then performed to remove all non-biotinylated polynucleotide strands. If desired, the bound polynucleotide, which can be used in subsequent reflex process steps (e.g., as a template for Bn primer extension reactions), may be eluted from the streptavidin support. Alternatively, the bound polynucleotide may be employed in subsequent steps of the desired process while still bound to the solid support (e.g., in solid phase extension reactions using Bn primers). This process, with minor variations depending on the template being used and the identity of the desired single stranded polynucleotide, may be employed at any of a number of steps in which a single stranded product is to be isolated. It is noted that in certain embodiments, substrate bound biotinylated polynucleotide can be used to produce and isolate non-biotinylated single stranded products (i.e., by eluting the non-biotinylated products while leaving the biotinylated templates bound to the streptavidin on the solid support). Thus, the specifics of how binding partners are used to isolate single stranded polynucleotides of interest will vary depending on experimental design parameters. Additional single-stranded isolation/production methods include asymmetric PCR, strand-specific enzymatic degradation, and the use of in-vitro transcription followed by reverse transcriptase (IVT-RT) with subsequent destruction of the RNA strand. As noted above, any convenient single stranded production/isolation method may be employed. To the single stranded polynucleotide shown in FIG. 1B we anneal one of the Bn primers having the appended reflex sequence, denoted with a capital “R” (e.g., B1) and extend the primer under nucleic acid synthesis conditions to produce a copy of the polynucleotide that has a reflex sequence at its 5′ end. A single stranded copy of this polynucleotide is then produced to reverse polarity using a primer specific for the primer site in the first domain′ (complement of the first domain 102). The resulting nucleic acid has structure 100 shown in FIG. 1A, where the first domain 102 includes the primer site and the MID. Site A (110) in FIG. 1 is determined by the specificity of the 5′ reflex-Be primer used. The reflex process (e.g., as shown in FIG. 1) is then performed to produce a product in which the primer site and the MID are now in close proximity to the desired site (or region of interest (ROI)) within the original polynucleotide (i.e., the site defined by the primer used, e.g., B1). The resulting polynucleotide can be used in subsequent analyses as desired by the user (e.g., Roche 454 sequencing technology). It is noted here that, while not shown in FIGS. 1A and 1B, any convenient method for adding adapters to a polynucleotide to be processed as described herein may be used in the practice of the reflex process (adapters containing, e.g., primer sites, polymerase sites, MIDs, restriction enzyme sites, and reflex sequences). For example, adapters can be added at a particular position by ligation. For double stranded polynucleotides, an adapter can be configured to be ligated to a particular restriction enzyme cut site. Where a single stranded polynucleotide is employed, a double stranded adapter construct that possesses an overhang configured to bind to the end of the single-stranded polynucleotide can be used. For example, in the latter case, the end of a single stranded polynucleotide can be modified to include specific nucleotide bases that are complementary to the overhang in the double stranded adaptor using terminal transferase and specific nucleotides. In other embodiments, PCR or linear amplification methods using adapter-conjugated primers is employed to add an adapter at a site of interest. Again, any convenient method for producing a starting polynucleotide may be employed in practicing the methods of the subject invention. In certain embodiments, the nucleic acid may be sequenced directly using a sequencing primer specific for the primer site. This sequencing reaction will read through the MID and desired site in the insert. In certain embodiments, the polynucleotide may be isolated (or fractionated) using an appropriate An primer (e.g., when using B1 as the first primer, primer A1 can be used). In certain embodiments, the An primed polynucleotide is subjected to nucleic acid synthesis conditions to produce a copy of the fragment produced in the reflex process. In certain of these embodiments, the An primer has appended on its 5′ end a primer site that can be used in subsequent steps, including sequencing reactions. Providing a primer site in the An primer allows amplifying and/or sequencing from both ends of the resultant fragment: from the primer site in the first domain 102 and the primer site in the An primer (not shown in FIG. 1B). Because of the position of the primer sites and their distance apart (i.e., less than one sequencing run apart), sequencing from both ends will usually capture the sequence of the desired site (or ROI) and the sequence of the MID, which can be used for subsequent bioinformatic analyses, e.g., to positively identify the sample of origin. It is noted here that while sequencing in both directions is possible, it is not necessary, as sequencing from either primer site alone will capture the sequence of the ROI as well as its corresponding MID sequence. Note that in certain embodiments, the first fragment obtained by amplification/extension from primer B0 directly, the polarity of the ROI in the resulting fragment is reversed as compared to the ROI in fragments obtained by primers B1-Bn. This is because the B0-generated fragment, unlike the B1-Bn generated fragments, has not been subjected to a reflex process which reverses the orientation of the ROI sequence with respect to the first domain/reflex sequence (as described above). Therefore, the B0 primer may have appended to it a primer site (e.g., at its 5′ end) that can be used for subsequent amplification and/or sequencing reactions (e.g., in Roche 454 sequencing system) rather than a reflex sequence as with primers B1-Bn. However, in certain embodiments, as noted above, the reflex process may be used with a corresponding B0-A0 primer pair as described above, i.e., using a B0 primer having a 5′ reflex sequence and a corresponding A0 primer with its corresponding 5′ adapter domain (e.g., a primer site). It is noted here that because the particular sections of sequence to be analyzed are defined by the An-Bn primer pairs (as shown and described above), a much higher sequence specificity is achieved as compared to using previous extraction methods that employ only a single oligo binding event (e.g., using probes on a microarray). FIG. 3 provides a detailed flow chart for an exemplary embodiment that employs reflex sequences for use in sequencing multiple specific regions in a polynucleotide (i.e., regions 1, 2, 3, 4 and 5 in an 11 kb region of lambda DNA). A single parent DNA fragment 202 is generated that includes adapter domains (i.e., a Roche 454 sequencing primer site, a single MID, and a reflex sequence) and the sequence of interest. In the example shown, the sequence of interest is from lambda DNA and the reflex sequence is present on the top strand (with its complement shown in the bottom strand). Any convenient method for producing this parent DNA fragment may be used, including amplification with a primer that includes the adapter domains (e.g., using PCR), cloning the fragment into a vector that includes the adapter domains (e.g., a vector with the adapter domains adjacent to a cloning site), or by attaching adapters to polynucleotide fragments (e.g., fragment made by random fragmentation, by sequence-specific restriction enzyme digestion, or combinations thereof). While only a single fragment with a single MID is shown, the steps in FIG. 3 are applicable to samples having multiple different fragments each with a different MID, e.g., a sample having a population of homologous fragments from any number of different sources (e.g., different individuals). FIG. 3 describes the subsequent enzymatic steps involved in creating the five daughter fragments in which regions 1, 2, 3, 4 and 5 (shown in polynucleotide 204) are rearranged to be placed within a functional distance of the adapter domains (i.e., close enough to the adapter domains to be sequenced in a single Roche 454 sequencing reaction). Note that certain steps are shown for region 4 only (206). In step 1, the five regions of interest are defined within the parent fragment (labeled 1 to 5 in polynucleotide 204) and corresponding primer pairs are designed for each. The distance of each region of interest from the reflex sequence is shown below polynucleotide 204. The primer pairs are designed as described and shown in FIG. 1B (i.e., the An-Bn primer pairs). For clarity, only primer sites for region 4 are shown in FIG. 3 (“primer sites” surrounding region 4). In step 2, sequence specific primer extensions are performed (only region 4 is shown) with corresponding Bn primers to produce single stranded polynucleotides having structure 208 (i.e., having the reflex sequence on the 5′ terminus). As shown, the Bn primer for region 4 will include a sequence specific primer site that primes at the 3′-most primer site noted for region 4 (where “3′-most” refers to the template strand, which in FIG. 3 is the top strand). This polynucleotide is copied back to produce polynucleotide 210 having reversed polarity (e.g., copied using a primer that hybridizes to the 454A′ domain). Polynucleotide 210 has structure similar to polynucleotide 100 shown at the top of FIG. 1. Step 4 depicts the result of the intramolecular priming between the reflex sequence and its complement followed by extension to produce the MID′ and 454A′ structures at the 3′ end (polynucleotide 212). In the embodiments shown in FIG. 3, polynucleotide 212 is treated with T7 exonuclease to remove double stranded DNA from the 5′ end (as indicated above, this step is optional). The polynucleotide formed for region 4 is shown as 216 with polynucleotides for the other regions also shown (214). It is noted here that the formation of each of the polynucleotides 214 may be accomplished either in separate reactions (i.e., structure with region 1 in proximity to the adapter domains is in a first sample, the structure with region 2 in proximity to the adapter region is in a second sample, etc.) or in one or more combined sample. In step 6 the polynucleotides 214 are copied to reverse polarity to form polynucleotides 218. In step 7, each of these products are then primed with the second primer of the specific primer pair (see An primers as shown in FIG. 1B) each having a second Roche 454 primer site (454B) attached at the 5′ end, and extended to form products 220. Steps 6 and 7 may be combined (e.g., in a single PCR or other amplification reaction). In summary, FIG. 3 shows how the reflex process can be employed to produce five daughter fragments 220 of similar length (e.g., ˜500 bp) each of which contain DNA sequences that differ in their distance from the reflex sequence in the starting structure 202 while maintaining the original MID. FIG. 4 shows another exemplary use of the reflex process as described herein. In the embodiment shown in FIG. 4, a target sequence (i.e., containing region of interest “E”) is enriched from a pool of adapter-attached fragments. In certain embodiments, the fragments are randomly sheared, selected for a certain size range (e.g., DNA having a length from 100 to 5000 base pairs), and tagged with adapters (e.g., asymmetric adapters, e.g., as described in U.S. patent application Ser. No. 12/432,080, filed on Apr. 29, 2009). The asymmetric adaptor employed in FIG. 4 contains a sequencing primer site (454A, as used in the Roche 454 sequencing platform), an MID, an X sequence, and an internal stem region (ISR), which denotes the region of complementarity for the asymmetric adapter that is adjacent to the adapter attachment site (see, e.g., the description in U.S. application Ser. No. 12/432,080, filed on Apr. 29, 2009, incorporated herein by reference in its entirety). The X sequence can be any sequence that can serve as a binding site for a polynucleotide containing the complement of the X sequence (similar to a primer site). As described below, the X sequence allows for the annealing of an oligonucleotide having a 5′ overhang that can serve as a template for extension of the 3′ end of the adaptor oligonucleotide. The sequencing direction of the sequencing primer site (454A primer site in structure 401 of FIG. 4) is oriented such that amplification of the adapter ligated fragment using the sequencing primer site proceeds away from the ligated genomic insert. This has the effect of making the initial asymmetric adapter ligated library ‘inert’ to amplification using this primer, e.g., in a PCR reaction. To extract a region of interest (the “E” region), the library is mixed with an oligonucleotide (403) containing a 3′ X′ sequence and a target specific priming sequence (the 1′ sequence) under hybridization/annealing conditions. The target specific sequence 1′ is designed to flank one side of the region of interest (the 1′ sequence adjacent to E in the genomic insert; note that only the E-containing polynucleotide fragment is shown in FIG. 4), much like a PCR primer. After annealing primer 403, the hybridized complex is extended, whereby all of the adaptor tagged fragments will obtain the complement of the target specific sequence (i.e., the 1 sequence) on the 3′ end (see structure 405; arrows denote the direction of extension). Extended products 405 are then denatured and the 1/1′ regions allowed to hybridize intramolecularly in a reflex process priming event, after which nucleic acid extension is performed to form structure 407 (extension is from the 1 priming site; shown with an arrow). This reflex reaction creates a product (407) that, unlike its parent structure (405), has a sequencing primer site (454A) that is oriented such the extension using this primer sequence proceeds towards the region of interest. Thus, in the absence of a priming and extension reflex reaction, extension with a sequencing primer will not generate a product containing the region of interest (the E region). In other words, only E-region containing target polynucleotides will have a 454A sequence that can amplify genomic material (structure 407). After completing the reflex process (using 1/1′ as the reflex sequences), a PCR amplification reaction is performed to amplify the region of interest (with associated adapter domains). However, before performing the PCR reaction, the fragment sample is “inactivated” from further extension using terminal transferase and ddNTPs. This inactivation prevents non-target adaptor tagged molecules from performing primer extension from the 3′ primer 1 site. Once inactivated, a PCR reaction is performed using a sequencing primer (i.e., 454A primer 409) and a second primer that primes and extends from the opposite side of the region of interest (i.e., primer 411, which includes a 5′ 454B sequencing primer site and a 3′ “2” region that primes on the opposite end of E from the 1 region). Only fragments that have undergone the reflex process and contain the E region will be suitable templates for the PCR reaction and produce the desired product (413). Thus, the process exemplified in FIG. 4 allows for the movement of an adapter domain (e.g., containing functional elements and/or MID) into proximity to a desired region of interest. The reflex process described herein can be used to perform powerful linkage analysis by combining it with nucleic acid counting methods. Any convenient method for tagging and /or counting individual nucleic acid molecules with unique tags may be employed (see, e.g., U.S. Pat. No. 7,537,897, issued on May 26, 2009; U.S. Pat. No. 7,217,522, issued on May 15, 2007; U.S. patent application Ser. No. 11/377,462, filed on Mar. 16, 2006; and U.S. patent application Ser. No. 12/432,080, filed on Apr. 29, 2009; each of which is incorporated by reference herein in their). All of this can be conducted in parallel thus saving on the cost of labor, time and materials. In one exemplary embodiment, a large collection of sequences is tagged with MID such that each polynucleotide molecule in the sample has a unique MID. In other words, each polynucleotide in the sample (e.g., each individual double stranded or single stranded polynucleotide) is tagged with a MID that is different from every other MID on every other polynucleotide in the sample. In general, to accomplish such molecular tagging the number of distinct MID tags to be used should be many times greater than the actual number of molecules to be analyzed. This will result in the majority of individual nucleic acid molecules being labeled with a unique ID tag (see, e.g., Brenner et al., Proc. Natl. Acad. Sci. USA. 2000 97(4):1665-70). Any sequences that then result from the reflex process on that particular molecule (e.g., as described above) will thus be labeled with the same unique MID tag and thus inherently linked. Note that once all molecules in a sample are individually tagged, they can be manipulated and amplified as much as needed for processing so long as the MID tag is maintained in the products generated. For example, we might want to sequence one thousand viral genomes (or a specific genomic region) or one thousand copies of a gene present in somatic cells. After tagging each polynucleotide in the sample with a sequencing primer site, MID and reflex sequence (as shown in the figures and described above), we use the reflex process to break each polynucleotide into lengths appropriate to the sequencing procedure being used, transferring the sequencing primer site and MID to each fragment (as described above). Obtaining sequence information from all of the reflex-processed samples can be used to determine the sequence of each individual polynucleotide in the starting sample, using the MID sequence to defining linkage relationships between sequences from different regions in the polynucleotide being sequenced. Using a sequencing platform with longer read lengths can minimize the number of primers to be used (and reflex fragments generated). The advantages noted above are shown in FIG. 5. This figure shows a comparison of methods for identifying nucleic acid polymorphisms in homologous nucleic acids in a sample (e.g., the same region derived from a chromosomal pair of a diploid cell or viral genomes/transcripts). The top schematic shows two nucleic acid molecules in a sample (1 and 2) having a different assortment of polymorphisms in polymorphic sites A, B and C (A1, B1, C1 and C2). Standard sequencing methods using fragmentation (left side) can identify the polymorphisms in these nucleic acids but do not retain linkage information. Employing the reflex process described herein to identify polymorphisms (right side) maintains linkage information. It is noted that not all domain structures and steps are shown in the reflex process for simplicity. Kits and Systems Also provided by the subject invention are kits and systems for practicing the subject methods, as described above, such vectors configured to add reflex sequences to nucleic acid inserts of interest and regents for performing any steps in the cloning or reflex process described herein (e.g., restriction enzymes, nucleotides, polymerases, primers, exonucleases, etc.). The various components of the kits may be present in separate containers or certain compatible components may be precombined into a single container, as desired. The subject systems and kits may also include one or more other reagents for preparing or processing a nucleic acid sample according to the subject methods. The reagents may include one or more matrices, solvents, sample preparation reagents, buffers, desalting reagents, enzymatic reagents, denaturing reagents, where calibration standards such as positive and negative controls may be provided as well. As such, the kits may include one or more containers such as vials or bottles, with each container containing a separate component for carrying out a sample processing or preparing step and/or for carrying out one or more steps of a nucleic acid variant isolation assay according to the present invention. In addition to above-mentioned components, the subject kits typically further include instructions for using the components of the kit to practice the subject methods, e.g., to prepare nucleic acid samples for perform the reflex process according to aspects of the subject methods. The instructions for practicing the subject methods are generally recorded on a suitable recording medium. For example, the instructions may be printed on a substrate, such as paper or plastic, etc. As such, the instructions may be present in the kits as a package insert, in the labeling of the container of the kit or components thereof (i.e., associated with the packaging or sub-packaging) etc. In other embodiments, the instructions are present as an electronic storage data file present on a suitable computer readable storage medium, e.g. CD-ROM, diskette, etc. In yet other embodiments, the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, e.g. via the internet, are provided. An example of this embodiment is a kit that includes a web address where the instructions can be viewed and/or from which the instructions can be downloaded. As with the instructions, this means for obtaining the instructions is recorded on a suitable substrate. In addition to the subject database, programming and instructions, the kits may also include one or more control samples and reagents, e.g., two or more control samples for use in testing the kit. Utility The reflex process described herein provides significant advantages in numerous applications, a few of which are noted below (as well as described above). For example, as described above, certain aspects of the reflex process define the particular sections of sequence to be analyzed by a primer pair, as in PCR (e.g., the two oligos shown as An-Bn in FIG. 1B). This results in higher sequence specificity as compared to other extraction methods (e.g., using probes on a microarray) that only use a single oligo sequence. The separation of the probes defines a length that can be relatively uniform (hence making subsequent handling including amplification more uniform) and can also be tailored to the particular sequencing platform being employed. Further, as described above, aspects of the present invention can be used to analyze homologous genomic locations in a multiplexed sample (i.e., a sample having polynucleotides from different genomic samples) in which the polynucleotides are tagged with the MID. This is possible because the reflex process, which operates intramolecularly, maintains the MID thus linking any particular fragment to the sample from which it originates. Finally, as the reflex processes described herein function intramolecularly, one can determine the genetic linkage between different regions on the same large fragment that are too far apart to be sequenced in one sequence read. Such a determination of linkage may be of great value in plant or animal genetics (e.g., to decide if a particular set of variations are linked together on the same stretch of chromosome) or in viral studies (e.g., to determine if particular variations are linked together on the same stretch of a viral genome/transcripts, e.g., HIV, hepatitis virus, etc.). EXAMPLES Example I FIGS. 6 and 7 provide experimental data and validation of the reflex process described herein using synthetic polynucleotide substrates. Methods Substrate: The 100 base oligonucleotide substrate (as shown diagrammatically in FIG. 6A) was synthesized with internal fluorescein-dT positioned between the REFLEX and REFLEX′ sequences. This label provides convenient and sensitive method of detection of oligonucleotide species using polyacrylamide gel electrophoresis. Extension Reactions: Reactions were prepared which contained 1 μM of the 100 base oligonucleotide substrate, 200 μM dNTPs, presence or absence of 1 μM competitor oligonucleotide, 0.5 μl of each DNA polymerase (“DNAP”): Vent (NEB, 2 units/μl), Taq (Qiagen HotStarTaq 5 units/μl) and Herculase (Stratagene), and made up to 50 μl with the appropriate commercial buffers for each polymerase and dH20. For Taq titrations 0.5 μl, 1 μl, 2 μl, and 3 μl enzyme was used in the same 50 μl volume. Reactions were heated in a Biometra thermocycler to 95° C. for 15 minutes (Taq) or 5 minutes (Herculase, Vent), followed by 55° C. or 50° C. for 30 seconds, and a final incubation at 72° C. for 10 minutes. T7 Exonuclease Digestions: Reactions were prepared with 10 μl extension reactions above, 0.5 μl T7 exonuclease (NEB, 10 units/μl), and made up to 50 μl using NEB Buffer 4 and dH20. Reactions were incubated at 25° C. for 30 minutes. Gel Electrophoresis Analysis: An 8% denaturing polyacrylamide gel was used to analyze reaction species. 0.4 μl of extension reactions, and 2 μl of digestion reactions were loaded and ran at 800V for ˜1.5 hours. Gels were analyzed for fluorescein using an Amersham/General Electric Typhoon imager. Results FIG. 6A shows the structure of each stage of reflex sequence processing with the expected nucleic acid size shown on the left. The initial single stranded nucleic acid having a sequencing primer site (the Roche 454 sequencing primer A site; listed as 454A); an MID; a reflex sequence; the insert; and a complement of the reflex sequence is 100 nucleotides in length. After self-annealing and extension, the product is expected to be 130 nucleotides in length. After removal of the double stranded region from the 5′ end, the nucleic acid is expected to be 82 bases in length. FIG. 6B shows the results of three experiments using three different nucleic acid polymerases (Vent, Herculase and Taq, indicated at the top of the lanes). The temperature at which the annealing was carried out is shown at the top of each lane (either 50° C. or 55° C.). The sizes of the three nucleic acids as noted above are indicated on the left and right side of the gel. As shown in FIG. 6B, extension appears to be most efficient under the conditions used with Herculase (Herculase is a mixture of two enzymes: modified Pfu DNAP and Archaemax (dUTPase)). Most (or all) of the initial 100 base pair nucleic acid are converted to the 130 base pair product (see lanes 6 and 7). However, after T7 exonuclease digestion the 3′-5′ exonuclease activity of Herculase results in partial digestion of the desired 82 base product (note bands at and below the 82 base pairs in lanes 8 and 9). Taq, which lacks 3′-5′ exonuclease activity, shows a stronger band at the expected size of the final product after T7 exonuclease digestion (see lane 13). FIG. 7 shows the effect on the reflex process of increasing amounts of Taq polymerase as well as the use of a reflex sequence competitor (schematically shown in FIG. 7A). As shown in lanes 2 to 5, increased Taq concentration improves extension to ˜90% conversion of the starting nucleic acid (see lane 5). Lanes 7 to 8 show that T7 exonuclease digestion does not leave a perfect 82 base product. This may be due to collapse of dsDNA when T7 exonuclease has nearly completed its digestion from the 5′ end in the double stranded region of the fold-back structure. It is noted that in many embodiments, the removal of a few additional bases from the 5′ end of the polynucleotide will not interfere with subsequent analyses, as nucleotide bases at the 5′ end are often removed during subsequent steps. As shown in Lanes 11-14, addition of a competitor (which can interfere with annealing of the reflex sequences to form the fold-back structure) results in only a small decrease (˜5-10%) of fully extended product. Thus, as expected, the intramolecular reaction is heavily favored. Although not shown, we have observed that the competitor oligonucleotide also gets extended by the same amount (˜5-10%). The concentration of the competitor, the concentration of the reflex substrate, and the overall genetic complexity, will all likely affect specific results. The experiments shown in FIGS. 6 and 7 demonstrate that the core parts of the reflex processes as described herein is functional and can be implemented. Example II FIG. 8 shows the reflex workflow (diagram at left) and exemplary results of the workflow (gel at right) for a specific region of interest (ROI). The starting material is a double stranded nucleic acid molecule (700) that contains a 454A primer site, an MID, a reflex site, and a polynucleotide of interest having three ROIs (2, 3 and 4) at different locations therein. This starting material was subjected to reflex processes (as described in above) specific for ROI 2 as shown in the diagram at the left of the figure, both with and without the use of a T7 exonuclease step (the T7 exonuclease step is shown in the diagram is indicated as “Optional”). Completion of all steps shown in the reflex process should result in a double stranded polynucleotide of 488 base pairs (702) with or without the T7 exonuclease step. As shown in the gel on the right of FIG. 8, the 488 base pair product was produced in reflex processes with and without the T7 exonuclease step. FIG. 9 shows an exemplary protocol for a reflex process based on the results discussed above. The diagram shows specific reflex process steps with indications on the right as to where purification of reaction products is employed (e.g., using Agencourt SPRI beads to remove primer oligos). One reason for performing such purification steps is to reduce the potential for generating side products in a reaction (e.g., undesirable amplicons). While FIG. 9 indicates three purification steps, fewer or additional purification steps may be employed depending on the desires of the user. It is noted that the steps of reversing polarity, reflex priming and extension, and “stretch out” (or denaturation)/second reversing polarity step can be performed without intervening purification steps. The protocol shown in FIG. 9 includes the following steps: annealing a first primer containing a 5′ reflex sequence (or reflex tail, as noted in the figure) specific for the 3′ primer site for the R′ region to the starting polynucleotide and extending (the primer anneals to the top strand at the primer site at the right of R in polynucleotide 902, indicated with a *; this step represents the first denature, anneal and extend process indicated on the right); after purification, adding a 454A primer and performing three cycles of denaturing, annealing and extending: the first cycle results in the copy-back from the 454A primer to reverse the polarity of the strand just synthesized; the second cycle breaks apart the double stranded structure produced, allows the reflex structure to form and then extend; the third cycle results in another copy-back using the same 454A primer originally added; after purification, adding a second primer specific for the second primer site for the R′ region having a 5′ 454B tail (this primer anneals to the primer site 3′ of the R′ region in polynucleotide 904, indicated with a *) and denaturing, annealing and extending resulting in a polynucleotide product having 454A and 454B sites surrounding the MID, the reflex sequence, and R′. Note that the first primer specific for the R′ region and the second primer specific for the R′ region define its boundaries, as described above and depicted in FIG. 1B); after another purification, adding 454A and 454B primers and performing a PCR amplification reaction. Example III As described above, a reflex sequence can be an “artificial” sequence added to a polynucleotide as part of an adapter or can be based on a sequence present in the polynucleotide of interest being analyzed, e.g., a genomic sequence (or “non-artificial”). The data shown in prior Examples used “artificial” reflex sites. In this Example, the reflex site is a genomic sequence present in the polynucleotide being analyzed. The starting material is a double stranded DNA containing a 454A site, an MID and a polynucleotide to be analyzed. The 454A and MID were added by adapter ligation to parent polynucleotide fragments followed by enrichment of the polynucleotide to be analyzed by a hybridization-based pull-out reaction and subsequent secondary PCR amplification (see Route 1 in FIG. 13). Thus, the reflex site employed in this example is a sequence normally present at the 5′ end of the subject polynucleotide (a genomic sequence). The polynucleotide being analyzed includes a region of interest distal to the 454A and MID sequences that is 354 base pairs in length. This starting double stranded nucleic acid is 755 base pairs in length. Based on the length of each of the relevant domains in this starting nucleic acid, the reflex process should result in a product of 461 base pairs. FIG. 10 shows the starting material for the reflex process (left panel) and the resultant product generated using the reflex process (right panel; reflex process was performed as described in Example II, without using a T7 exonuclease step). A size ladder is included in the left hand lane of each gel to allow estimation of the size of the test material. This figure shows that the 755 base pair starting nucleic acid was processed to the expected 461 base pair product, thus confirming that a “non-artificial” reflex site is effective in moving an adapter domain from one location to another in a polynucleotide of interest in a sequence specific manner. Example IV FIG. 11 shows a schematic of an experiment in which the reflex process is performed on a single large initial template (a “parent” fragment) to generate 5 different products (“daughter” products) each having a different region of interest (i.e., daughter products are produced having either region 1, 2, 3, 4 or 5). The schematic in FIG. 11 shows the starting fragment (11,060 base pairs) and resulting products (each 488 base pairs) generated from each of the different region of interest-specific reflex reactions (reflex reactions are performed as described above). The panel (gel) on the bottom of FIG. 11 shows the larger starting fragment (Lane 1) and the resulting daughter products for each region-specific reflex reaction (lanes 2 to 6, with the region of interest noted in each in the box), where the starting and daughter fragments have the expected lengths. Sequencing of the products confirmed the identity of the region of interest in each of the reflex products shown in the gel. These results demonstrate that multiple different reflex products can be generated from a single, asymmetrically tagged parent fragment while maintaining the adapter domains (e.g., the primer sites and MID). Example V FIG. 12 details experiments performed to determine the prevalence of intramolecular rearrangement (as desired in the reflex process) vs. intermolecular rearrangement. Intermolecular rearrangement is undesirable because it can lead to the transfer of an MID from one fragment to another (also called MID switching). MID switching can occur if a reflex sequence in a first fragment hybridizes to its complement in a second fragment during the reflex process, leading to appending the MID from the second fragment to the first fragment. Thus, intermolecular rearrangement, or MID switching, should be minimized to prevent the transfer of an MID from one fragment in the sample to another, which could lead to a misrepresentation of the source of a fragment. To measure the prevalence of MID switching under different reflex conditions, fragments having different sizes were generated that included two different MIDs, as shown in the top panel of FIG. 12. The common sequence on these fragments serves as the priming site for the first extension reaction to add the second reflex sequence (see, e.g., step 2 of FIG. 3). Three exemplary fragments are shown in FIG. 12 for each different fragment size (i.e., 800 base pairs with an MIDB and MIDA combination; 1900 base pairs with MDC and MIDA combination; and 3000 base pairs with MIDD and MIDA combination). For each MID family (A, B, C and D), there are 10 different members (i.e., MIDA had 10 different members, MIDB has 10 different members, etc.). A set of 10 dual MID fragments for each different size fragment (i.e., 800, 1900 and 3000 base pairs) were generated, where the MID pairs (i.e., MIDA/MIDB, MIDA/MIDC, and MIDA/MIDD) were designated as 1/1, 2/2, 3/3, 4/4, 5/5, 6/6, 7/7, 8/8, 9/9, and 10/10. All 10 fragments of the same size were then mixed together and a reflex protocol was performed. Due to the domain structure of the fragments, a successful reflex process results in the two MIDs for each fragment being moved to within close enough proximity to be sequenced in a single read using the Roche 454 sequencing platform (see the reflex products shown in the schematic of FIG. 12). The reflex reactions for each fragment size were performed at four different fragment concentrations to determine the effect of this parameter, as well as fragment length, in the prevalence of MID switching. The reflex products from each reaction performed were subjected to 454 sequencing to determine the identity of both MIDs on each fragment, and thereby the proportion of MID switching that occurred. The panel on the bottom left of FIG. 12 shows the rate of MID switching (Y axis, shown in % incorrect (or switched) MID pair) for each different length fragment at each different concentration (X axis; 300, 30, 3 and 0.3 nM). As shown in this panel, the MID switch rate decreases with lower concentrations, as would be expected, because intermolecular, as opposed to intramolecular, binding events are concentration dependent (i.e., lower concentrations lead to reduced intermolecular hybridization/binding). In addition, the MID switch rate decreases slightly with length. This is somewhat unexpected as the ends of longer DNA fragments are effectively at a lower concentration with respect to one another. The reasons for why we do not see this is probably because the production of reflex priming intermediates continues during the final PCR, which means that reflex priming reactions are happening continuously which contributes to MID switching. It is probably the case that the shorter reflex products are able to undergo a higher rate of ‘background’ reflexing, and therefore increase the overall MID switch rate a little. These results demonstrate that MID switching can be minimized (e.g., to below 2%, below 1% or even to nearly undetectable levels) by altering certain parameters of the reaction, e.g., by reducing fragment concentration and/or fragment length. The panel on the bottom right of FIG. 12 shows the frequency of MID switching in the reflex process for the 800 base pair fragments (i.e., MIDA/MIDB containing fragments). In this figure, the area of each circle is proportional to the number of reads containing the corresponding MIDA and MIDB species (e.g., MIDA1/MIDB1; MIDA1/MIDB2; etc.). Thus, a circle representing 200 reads will be 40 times larger in terms of area than a circle representing 5 reads. As noted above, the MIDA/MIDB combinations having the same number (shown on the X and Y axis, respectively) represent the MIDA/MIDB combinations present in the sample prior to the reflex process being performed (i.e., MIDA/MIDB combinations 1/1, 2/2, 3/3, 4/4, 5/5, 6/6, 7/7, 8/8, 9/9, and 10/10 were present in the starting sample). All other MIDA/MIDB combinations identified by Roche 454 sequencing were the result of MID switching. This figure shows that the MID switching that occurs during the reflex process is random, i.e., that MID switching is not skewed based on the identity of the MIDs in the reaction). Exemplary Reflex Protocols FIG. 13 shows a diagram of exemplary protocols for performing the reflex process on pools of nucleic acids, for example, pools of nucleic acids from different individuals, each of which are labeled with a unique MID. In Route 3, a pooled and tagged extended library is subjected directly to a reflex process. In Route 2, the pooled library is enriched by target-specific hybridization followed by performing the reflex process. In Route 1 employs enrichment by PCR amplification. As shown in FIG. 13, PCR enrichment can be performed directly on the pooled tagged extended library or in a secondary PCR reaction after a hybridization-based enrichment step has been performed (as in Route 2) to generate an amplicon substrate that is suitable for the reflex process. Additional routes for preparing a polynucleotide sample for performing a reflex process can be implemented (e.g., having additional amplification, purification, and/or enrichment steps), which will generally be dependent on the desires of the user. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. Accordingly, the preceding merely illustrates the principles of the invention. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of present invention is embodied by the appended claims.
<SOH> BACKGROUND OF THE INVENTION <EOH>We have previously described methods that enable tagging each of a population of fragmented genomes and then combining them together to create a ‘population library’ that can be processed and eventually sequenced as a mixture. The population tags enable analysis software to parse the sequence reads into files that can be attributed to a particular genome in the population. One limitation of the overall process stems from limitations of existing DNA sequencing technologies. In particular, if fragments in the regions of interest of the genome are longer than the lengths that can be sequenced by a particular technology, then such fragments will not be fully analyzed (since sequencing proceeds from an end of a fragment inward). Furthermore, a disadvantage of any sequencing technology dependent on fragmentation is that sequence changes in one part of a particular genomic region may not be able to be linked to sequence changes in other parts of the same genome (e.g., the same chromosome) because the sequence changes reside on different fragments. (See FIG. 5 and its description below). The present invention removes the limitations imposed by current sequencing technologies as well as being useful in a number of other nucleic acid analyses.
<SOH> SUMMARY OF THE INVENTION <EOH>Aspects of the present invention are drawn to processes for moving a region of interest in a polynucleotide from a first position to a second position with regard to a domain within the polynucleotide, also referred to as a “reflex method” (or reflex process, reflex sequence process, reflex reaction, and the like). In certain embodiments, the reflex method results in moving a region of interest into functional proximity to specific domain elements present in the polynucleotide (e.g., primer sites and/or MID). Compositions, kits and systems that find use in carrying out the reflex processes described herein are also provided.
C12Q16874
20170815
20180322
67988.0
C12Q168
2
DINES, KARLA A
METHODS FOR ANALYZING NUCLEIC ACIDS FROM SINGLE CELLS
SMALL
1
CONT-ACCEPTED
C12Q
2,017
15,679,054
PENDING
System and Method for Real-Time Optimization and Industry Benchmarking for Campaign Management
A system for collecting brand awareness and advertising campaign performance results in real-time. Embodiments allow the system to adapt (e.g., machine learning) to target advertisements to users that are most likely to be influenced by exposure to a brand awareness advertising campaign, and present results, in real-time, via a data exchange for an advertiser to monitor performance and benchmark performance against similar campaigns across the industry.
1. A method for real-time data optimization and campaign benchmarking, the method comprising: receiving a selected content request associated with a user identifier from a user device; retrieving a user profile associated with the user identifier from a profile store; determining whether to deliver a survey to the user device based at least on a population group associated with the retrieved user profile, wherein the retrieved user profile further includes at least one of a location, a location history, a device history, a list of mobile applications, biographical data, a number of advertisement views, a number of retail store visits, and previous user feedback; providing the selected content to the user device. 2. The method of claim 1, further comprising: building a predictive model based on all user interactions maintained in the profile store, the predictive model representing a function of independent variables and dependent variables, the independent variables representing at least a user's interaction history and the dependent variables representing one or more brand awareness scores, the one or more brand awareness scores predicting the values of survey results; and determining a selected brand awareness score based on the generated predictive model and the retrieved user profile, and wherein said providing the selected content to the user device is based on the determined brand awareness score, and the selected content comprising at least an advertisement portion. 3. The method of claim 2, wherein said determining whether to deliver a survey to the user device further comprises determining whether the user profile has previously requested and received the selected content; and further comprising delivering the survey to the user device if it is determined that the user profile has previously requested and received the selected content once before. 4. The method of claim 3, wherein said determining whether to deliver a survey to the user device further comprises determining whether the user profile is a consumer panel member, and wherein said delivering the survey to the user device occurs if it is determined that the user profile is associated with a consumer panel member. 5. The method of claim 3, wherein said delivering the survey to the user device occurs after a predetermined time. 6. The method of claim 3, further comprising: receiving survey results of the delivered survey from the user device; and updating the predictive model based on the received survey results. 7. The method of claim 2, wherein said building the predictive model is based on at least one of linear regression, logistic regression, decision tree, random forest, neural network, support vector machine, and Bayesian networks. 8. The method of claim 2, wherein said building the predictive model includes generating the independent variables that represent at least one of location, location history, device history, mobile applications, biographical data, number of advertisement views, number of retail store visits, and previous user feedback. 9. The method of claim 1, wherein said retrieving the user profile comprises obtaining at least one of mobile application usage, website page view data, device type, and location data associated with the user identifier. 10. The method of claim 1, wherein said receiving a selected content request comprises receiving a request from at least one of a web page and a mobile application. 11. The method of claim 1, further comprising assigning the retrieved user profile to a population group in the store. 12. A system for real-time data optimization and campaign benchmarking, the system comprising: a survey server for receiving a selected content request associated with a user identifier from a user device over a data network; an ad server in operable communication with said survey server; and a profile store in communication with said ad server and said survey server for maintaining a user profile associated with the user identifier, wherein said survey server determines whether to deliver a survey to the user device based at least on a population group associated with the user profile retrieved by the ad server from the profile store, wherein the retrieved user profile further includes at least one of a location, a location history, a device history, a list of mobile applications, biographical data, a number of advertisement views, a number of retail store visits, and previous user feedback, and said ad server provides the selected content to the user device. 13. The system of claim 12, further comprising a model builder in communication with said ad server and said survey server for building a predictive model based on all user interactions maintained in the profile store, the predictive model representing a function of independent variables and dependent variables, the independent variables representing at least a user's interaction history and the dependent variables representing one or more brand awareness scores, the one or more brand awareness scores predicting the values of survey results, wherein said ad server further comprises a model scorer for determining a selected brand awareness score based on the generated predictive model and the retrieved user profile, and provides the selected content to the user device is based on the determined brand awareness score, and the selected content comprising at least an advertisement portion. 14. The system of claim 13, wherein said survey server determines whether to deliver a survey to the user device by determining whether the user profile has previously requested and received the selected content, and delivers the survey to the user device if it is determined that the user profile has previously requested and received the selected content once before. 15. The system of claim 14, wherein said survey server determines whether to deliver a survey to the user device by determining whether the user profile is a consumer panel member, and delivers the survey to the user device occurs if it is determined that the user profile is associated with a consumer panel member. 16. The system of claim 14, wherein said survey server delivers the survey to the user device after a predetermined time. 17. The system of claim 14, wherein said survey server receives survey results of the delivered survey from the user device, and said model builder updates the predictive model based on the received survey results. 18. The system of claim 13, wherein said model builder builds the predictive model based on at least one of linear regression, logistic regression, decision tree, random forest, neural network, support vector machine, and Bayesian networks. 19. The system of claim 13, wherein said model builder generates the independent variables that represent at least one of location, location history, device history, mobile applications, biographical data, number of advertisement views, number of retail store visits, and previous user feedback. 20. The system of claim 12, further comprising a brand performance exchange server in communication with the survey server over the data network for exchanging benchmark performance between one or more registered users.
CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62/375,864, filed Aug. 16, 2016, which application is hereby incorporated herein by reference in its entirety and for all purposes. This application is also a continuation-in-part of U.S. patent application Ser. No. 14/409,709, which was filed Dec. 19, 2014 as a national phase entry of PCT Application No. IB2013/001297 that claims the benefit of U.S. Provisional Application No. 61/662,262, filed Jun. 20, 2012, which applications are hereby incorporated herein by reference in their entirety and for all purposes. FIELD The present disclosure relates generally to advertising and more particularly, but not exclusively, to systems and methods for real-time optimization and industry benchmarking for campaign management. BACKGROUND Consumers are inundated with various types of advertising content on television, mobile devices, and while accessing the internet, but typically lack the ability to actively control and interact with such advertising content. For example, consumers are conventionally served with advertising content, regardless of whether the user would have an interest in the content. Accordingly, a large majority of advertising is wasted on viewers who have no interest in the goods or services being advertised, or would not be eligible buyers for such goods and services. Additionally, consumers lack the ability to provide feedback about advertising content or about the goods or services being advertised. Unfortunately, advertisers are therefore unable to determine which advertising campaigns are more successfully engaging consumers, and are unable to provide personalized and more relevant advertising content to consumers. Moreover, advertisers are unable to reward consumers for providing valuable feedback regarding advertising content. Many consumers also desire to share advertising content with friends because they may enjoy the content, or because they may like the products or services being advertised. Conventional advertising can be difficult to share among friends, and there is no way to track, incentivize and reward consumers who share advertising with their friends. Additionally, there is no way to provide sharing consumers with further rewards and incentives for having friends purchase goods or services associated with advertising content or for sharing consumers to leverage the buying power of a group of users to receive rewards and incentives. Conventional advertising also fails to allow consumers to socially discover and search for advertising based on feedback of friends and other users, nor does conventional advertising provide for discovery of advertising that is promoted, disliked or shared by enthusiasts, experts, friends or celebrities. Furthermore, the effectiveness of brand and similar advertising is typically evaluated by surveys sent to a consumer panel once the advertising campaign has terminated. The surveys are designed to measure the nebulous quantity of brand awareness. Some members of the consumer panel are exposed to the advertising; and some members of the consumer panel are not. The difference in survey results from these two groups forms the basis of the analysis of effectiveness. However, evaluating the campaign after a single iteration of the campaign is inaccurate. For example, targeting advertisements automatically relies on a prediction of the value of displaying the advertisement to any individual based on examples of high and low value users. This information is not available until the survey has been conducted, making automated targeting of brand advertisements is very difficult. Typically, unsatisfactory surrogates for the value of displaying an advertisement to a particular user (e.g., clicks or video completes) are used, and the correlation between these and the subsequent survey results can be very weak. As an additional drawback, external factors (e.g., major news stories regarding food safety) can affect the survey results during the time the campaign ends and the survey questions are sent. Additionally, brand awareness generally decreases over time after the advertisement campaign is viewed. Accordingly, the time between exposure to the campaign and the survey can affect the effectiveness of the campaign. The lack of a standardized framework makes it very difficult for an advertiser to compare the effectiveness of a campaign against the norm across similar industries—or even the advertiser's own historical campaigns. In view of the foregoing, a need exists for improved systems and methods for collecting brand awareness and advertising campaign performance results in real-time, in an effort to overcome the aforementioned obstacles and deficiencies of conventional user account registration systems. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an exemplary top-level block diagram illustrating an embodiment of a content feedback, incentive, and reward system. FIG. 2 is an exemplary data flow diagram illustrating an embodiment of a data flow path between a user device, the list server and content server of FIG. 1, in which a content list is generated and presented. FIG. 3 depicts a user interface presenting a content list in accordance with an embodiment. FIG. 4 is an exemplary flow chart illustrating an embodiment of a method executed by the list server of FIG. 1, for generating and providing a content list. FIG. 5 is an exemplary flow chart illustrating an embodiment of a method executed by the content server of FIG. 1, for generating a content list. FIG. 6 is an exemplary data flow diagram illustrating an embodiment, in which content feedback is received and a feedback reward is generated. FIG. 7a depicts a user interface presenting content in accordance with an embodiment. FIG. 7b depicts a user interface for content feedback in accordance with an embodiment. FIG. 7c depicts a user interface for sharing content in accordance with an embodiment. FIG. 8 is an exemplary flow chart illustrating an embodiment of a method executed by the content server of FIG. 1, for content feedback. FIG. 9 is an exemplary flow chart illustrating an embodiment of a method executed by a user device of FIG. 1, for content feedback. FIG. 10 is an exemplary data flow diagram illustrating an embodiment of a data flow path between the first and second user device and the list server and content server of FIG. 1, in which a user reward is provided. FIG. 11 is an exemplary data flow diagram illustrating an embodiment of a data flow path between a user device, the list server and content server of FIG. 1, in which a user reward is presented on the user device. FIG. 12 is an exemplary flow chart illustrating an embodiment of a method executed by the content server of FIG. 1, for generating a user reward associated with a user profile. FIG. 13 is an exemplary flow chart illustrating an embodiment of a method, executed by a user device of FIG. 1, for initiating a content action related to received shared content. FIG. 14 is an exemplary top-level diagram illustrating one embodiment of a data optimization system. FIG. 15 is an exemplary top-level block diagram illustrating one embodiment of the survey server of the data optimization system of FIG. 14. FIG. 16 is an exemplary top-level block diagram illustrating one embodiment of the ad server of FIG. 14. FIG. 17 is an exemplary data flow diagram illustrating one embodiment of a configuration of the data optimization system of FIG. 14. FIG. 18 is an exemplary data flow diagram illustrating one embodiment for building and providing feedback for predictive models that can be used with the data optimization system of FIG. 14. FIG. 19A depicts a user interface presenting content in accordance with an embodiment that can be used with the data optimization system of FIG. 14. FIG. 19B depicts a user interface presenting survey in accordance with an embodiment that can be used with the data optimization system of FIG. 14. FIG. 20 is an exemplary data flow diagram illustrating an embodiment of a data flow path illustrating one embodiment of a process for survey logic shown in FIG. 18. FIG. 21A is an exemplary data flow diagram illustrating an embodiment of a data flow path for the survey logic of FIG. 20 where the survey logic is configured to “next-time-same-user-seen”. FIG. 21B is an exemplary data flow diagram illustrating an alternative embodiment of a data flow path for the survey logic of FIG. 20 where the survey logic is configured to “consumer panel”. FIG. 21C is an exemplary data flow diagram illustrating an alternative embodiment of a data flow path for the survey logic of FIG. 20 where the survey logic is configured to “after-predetermined-time”. It should be noted that the figures are not drawn to scale and that elements of similar structures or functions are generally represented by like reference numerals for illustrative purposes throughout the figures. It also should be noted that the figures are only intended to facilitate the description of the preferred embodiments. The figures do not illustrate every aspect of the described embodiments and do not limit the scope of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Since currently-available user account systems fail to effectively provide for advertising content feedback, incentives and rewards, a system that provides for such functionalities can prove desirable and provide a basis for a wide range of applications, such as providing a personalized presentation of advertising content, providing the ability to easily provide feedback regarding advertising content, sharing advertising content with friends, and receiving incentives and/or rewards for providing feedback, sharing content, and having friends purchase goods or services related to advertising content, or the like. Such results can be achieved, according to one embodiment disclosed herein, by a system 100 as illustrated in FIG. 1. Turning to FIG. 1, the system 100 is shown as including at least one user device 110. As an example, FIG. 1 depicts a first and second user device 110A, 110B, a list server 120 and a content server 130 that are operably connected via a network 140. The user devices 110, servers 120, 130, and network 140 each can be provided as conventional communication devices of any type. For example, the user devices 110A, 110B may be smart-phones as depicted in FIG. 1; however, in various embodiments, the user devices 110A, 110B may be various suitable devices including a tablet computer, laptop computer, desktop computer, gaming device, or the like without limitation. The user devices 110 also may include uniform and/or different devices. In other words, two user devices may be smart phones, but a third device could be a laptop computer. Additionally, the servers 120, 130 may be any suitable device, may comprise a plurality of devices, or may be a cloud-based data storage system. As discussed in further detail herein, servers 120, 130 may be operated by the same company or group, or may be operated by different companies or groups. In various embodiments, the network 140 may comprise one or more suitable wireless or wired networks, including the Internet, a local-area network (LAN), a wide-area network (WAN), or the like. In various embodiments, there may be a plurality of any of the user devices 110, the list server 120, and/or the content server 130. For example, in an embodiment, there may be a plurality of users that are associated with one or more user devices 110, and the users (via user devices 110) and list server 120 may communicate with or interact with a plurality of content servers 130. Although embodiments described herein include actions performed by the list server 120 or content server 130, in some embodiments any of these described actions may be performed by either of the list server 120 or content server 130. Additionally, in further embodiments, the list server 120 and content server 130 may be the same server. As discussed in further detail herein, the user devices 110A, 110B, the list server 120, and the content server 130, can intercommunicate to achieve functionalities such as providing advertisement feedback, incentives, rewards, and the like. FIG. 2 is an exemplary data flow diagram illustrating an embodiment of a data flow path 200 between a user device 110, the list server 120 and content server 130 of FIG. 1, in which a content list is generated and presented. The data flow path 200 begins where the user device 110 initiates an application session at 205, and at 210, in an optional step, login data is sent to the list server 120. For example, the user device 110 may store and execute various software applications, which may be configured to present a user interface as discussed herein and which may be operable to facilitate any of the communications or functionalities described herein. Some embodiments may allow or require a user to log in to a user account or the like, which may include inputting a user name, a password, or the like. Returning to the data flow path 200, at 215, a content list request associated with a user profile is sent to the list server 120, where a content list request is generated at 220, which is associated with the user profile. The content list request associated with the user profile is sent to the content server 130, at 225, where a content list is generated based on the user profile. For example, in an embodiment, a user may want to receive an updated list of content as further described herein, and the application running on the user device may request an updated content list from the list server 120. The list server 120 may then communicate with one or more content server 130 to obtain a portion of the content list. A content server 130 may store a plurality of user profiles, which may allow for personalized content lists to be generated for each user profile. For example, as described herein, a user may provide feedback regarding content, which may include positive or negative feedback regarding advertising content, positive or negative feedback regarding goods or services associated with advertising content, or the like. Accordingly, in some embodiments, a content list may be generated based on user profile data. For example, user profile data may include content feedback, advertising content feedback, feedback related to goods and services; likes or dislikes of advertising content along with advertisement metadata (e.g., metadata indicating type of advertisement); user share actions, which may be related to advertisement metadata; user block actions, which may be related to advertisement metadata; and user save actions, which may related to advertisement metadata. Additionally, in some embodiments, a content list may be generated based on other user profile data which may include user biographical data, user location data, other user preference data, information in or related to other user accounts (e.g., Facebook, Twitter, LinkedIn), or the like. User profile data or other data may be used to determine a user's propensity to interact with certain types of advertisements, types of advertisers, types of goods or services, or the like; may be used to determine a user preference of types of advertisements, types of advertisers, types of goods or services, or the like; may be used to determine a user's propensity to share types of advertisements, types of advertisers, types of goods or services, or the like; may be used to determine a user's propensity to endorse types of advertisements, types of advertisers, types of goods or services, or the like; may be used to determine a user's propensity to interact with certain types of advertisements, types of advertisers, types of goods or services, or the like based on endorsements or sharing from friends or other users. In various embodiments, content may be selected based on user endorsement or “liking” of a given advertisement. For example, another user, which may include an associated “friend” user, unrelated user, enthusiast, expert or celebrity user, may endorse or “like” a given advertisement, and such advertisements may be selected as a portion of a content list. Accordingly, various embodiments allow user profile data, or other data to be used to select and provide content tailored for each consumer that the consumer is more likely to have an affinity for in terms of the advertising vehicle, advertising content, goods and services advertised, persons or other entities associated with the advertising content, person or other entity that shared or endorsed the content, or the like. In addition to receiving selected advertisements, a user may discover advertisements by searching for or browsing user profiles. For example, a user may view a user profile of an associated “friend” user, unrelated user, enthusiast, expert, celebrity user, or the like, and view a history of advertisements or other content that the user has liked, disliked, endorsed, or otherwise provided feedback on. Viewing such user profiles may be done via a user interface or software application described herein, or via a social network or other website in some embodiments. Returning to the data flow path 200, content list data is sent to the list server 120 at 235 and a content list presentation is generated based on the content list data at 240. Content list presentation data is sent to the user device 110, at 245, and the user device 110 presents the content list, at 250. In some embodiments, generating a content list presentation may include formatting content list data, selecting a content presentation order, removing one or more item from a content list. Generating a content list may also include adding or removing fields, metadata, or the like as discussed in further detail herein. In some embodiments, where content list data is received from a plurality of content servers 130, generating a content list may include combining, filtering, ordering, or otherwise formatting content list data received from a plurality of content servers 130. FIG. 3 depicts a user device 110 presenting a content list 305 in accordance with an embodiment. The content list includes a plurality of content items 310 (e.g., three content items 310A, 310B, 310C). Each content item includes an advertisement portion 320 (e.g., the three advertising portions 320A, 320B, 320C) and a content action portion 315 (e.g., the three content action portions 315A, 315B, 315C). The content action portion 315 may include one or more button that allows a user to provide positive or negative feedback about advertising portion 320; block an advertisement, company, or goods or services associated with an advertisement; discover similar advertisements, companies or goods or services associated with an advertisement; share an advertisement presented in the advertising portion 320; save an advertisement presented in the advertising portion 320; or the like. The content action portion 315 may also present various suitable messages or data. For example, the content action portion may indicate a number of users that have provided positive feedback, negative feedback, saved content items, or the like. Additionally, the content action portion 315 may also indicate one or more user that has liked, endorsed, or provided positive feedback related to a given content item 310. For example, celebrity endorsements or “friend” user endorsements may be indicated. FIG. 4 is an exemplary flow chart illustrating an embodiment of a method 400 executed by the list server 120 of FIG. 1, for generating and providing a content list. The method 400 begins in block 410 where a content list request with a user profile identifier is received from a user device 110. In block 420, a content list request associated with the user profile is generated, and in block 430, the content list request is sent to the content server 130. In decision block 440, a determination is made whether content list data is received. If content list data is not received, then the method 400 waits until content list data is received. However, if content list data is received, at 450, a content list presentation is generated based on the content list data, and at 460, the content list presentation data is sent to the user device 110. The method 400 is done in block 499. FIG. 5 is an exemplary flow chart illustrating an embodiment of a method 500 executed by the content server 130 of FIG. 1, for generating a content list. The method 500 begins in block 510 where a content list request associated with a user profile is received from the list server 120. In block 520, a content list is generated based on the user profile, and in block 530, content list data is sent to the list server 120. The method 500 is done in block 599. FIG. 6 is an exemplary data flow diagram illustrating an embodiment of a data flow path 600 between a user device 110, the list server 120 and content server 130 of FIG. 1, in which content feedback is received and a feedback reward is generated. The data flow 600 begins at 605 where content list presentation data is sent to the user device 110, and at 610, the user device 110 presents the content list (e.g., as depicted in FIG. 3). At 615, a content list item 310 (FIG. 3) is selected, and at 620, a selected content request associated with a user profile is sent to the content server 130. At 625, the selected content is retrieved and sent to the user device 110, at 630, where the selected content is presented, at 635. For example, as depicted in FIG. 7a, selected content 710 may be presented, which includes an advertising portion 320, a content action portion 315, and an incentive action portion 725. Returning to the data flow 600, a content feedback selection is made, and content feedback selection data associated with the user profile is sent to the content server 130, at 650. For example, referring to FIGS. 7a and 7b, a content feedback selection may include a feedback selection such as positive or negative feedback selected via the content action portion 315. In some embodiments, the incentive action portion 725 may display an incentive message such as “provide feedback to get a discount.” The user may click the incentive action portion 725, which may present a feedback menu 740, which allows for selection of one or more feedback items 730 (e.g., feedback items 730A-E). One or more feedback items may be selected to indicate that the user has purchased or owns the advertised good, or has received the advertised services (e.g., “GOT IT” feedback item 730A); to indicate positive or negative feedback about advertising content 320 (e.g., 730B, 730C); or provide positive or negative feedback about an advertised product or service (e.g., 730D, 730E). In some embodiments, feedback may also include positive or negative feedback regarding a company associated with advertising content 320; feedback regarding likelihood of purchasing an advertised good or service; feedback regarding an advertised price; or the like. In some embodiments, feedback may include a sliding scale, text input, yes/no questions, positive feedback, neutral feedback; negative feedback, a star rating, or the like. Returning to the data flow path 600, feedback data is stored associated with the user profile, at 650, and a user feedback reward associated with the user profile is generated and stored at 655. Feedback reward data is sent to the user device 110, at 660, where the feedback reward is presented, at 665. For example, a user may select a feedback item 730 as shown in FIG. 7b, and the interface may then return to the selected content 710, and the incentive action portion 725 may indicate or present a feedback award (e.g., “you have received 5% off this advertisement”). FIG. 8 is an exemplary flow chart illustrating an embodiment of a method 800 executed by the content server of FIG. 1, for content feedback. The method 800 begins in block 810, where a selected content request associated with a user profile is received, and at 820, selected content is retrieved. At 830, selected content is sent to a user device 110, and in decision block 840 a determination is made whether a content feedback selection indication associated with a user profile is received. If a content feedback selection indication associated with a user profile is not received, the method 800 waits until a content feedback selection indication associated with a user profile is received. If a content feedback selection indication associated with a user profile is received, then in block 850, the received feedback selection indication is stored. At 860, a user feedback reward associated with the user profile is generated and stored, and at 870, user feedback reward data is sent to the user device 110. FIG. 9 is an exemplary flow chart illustrating an embodiment of a method 900 executed by a user device of FIG. 1, for content feedback. The method 900 begins in block 910, where content list presentation data is received, and in block 920, the content list is presented. In block 930, a content list item selection is made, and in block 940, a selected content request associated with the user profile is sent to the content server 130. In block 950, selected content is received and presented, and in block 960, a content feedback selection is generated. In block 970, a content feedback selection is sent to the content server 130, and the method 900 is done in block 999. FIG. 10 is an exemplary data flow diagram illustrating an embodiment of a data flow path 1000 between the first and second user device 110A, 110B and the list server 120 and content server 130 of FIG. 1, in which a user reward is provided. The data flow path 1000 begins where selected content is sent to the first user device 110A, at 1005, and the selected content is presented, at 1010. For example, presentation of selected content may be as depicted in FIG. 7a. At 1015, sharing with a second user is selected and a content sharing message is sent to the second user device 110B, at 1020. For example, a user may select sharing with a second user via the incentive action portion 725 or via the content action portion 315 as shown in FIG. 7a. In some embodiments, the incentive action portion 725 may provide a message indicating a sharing incentive, which may include a message such as “share this advertisement with a friend to receive a discount.” The user may click the incentive action portion 725 and be presented with a sharing menu 750 as depicted in FIG. 7c, which includes a plurality of sharing buttons 735, which may provide an option to share via email 735A, a text message 735B, a social network such as Facebook 735C, or the like. Clicking a sharing button 735 may initiate communicating a sharing message. A sharing message may include a link to content, and may also include or be associated with a user profile or user profile identifier associated with the sending user. Although FIG. 10 depicts a content sharing message being provided directly to a second user device 110B, in various embodiments, one or more devices, servers, networks or the like may be used to send a sharing message to a second user device 110B. For example, sending an e-mail sharing message may include one or more e-mail server; sending a sharing message via a social network may include a social network server; sending a sharing message may involve the list server 120 or content server 130 in some embodiments; or the like. Accordingly, sending messages via conventional means is contemplated as part of the present disclosure. Returning to the data flow path 1000 of FIG. 10, at 1025, the content sharing message is activated at the second user device 110B, and a content request is sent to the content server 130, at 1030. Shared content data is provided to the second user device 110B, at 1035 and at 1040, the shared content is presented at the second user device 110B. In some embodiments, presenting the shared content may be via a user interface as depicted in FIG. 7a, and the second user device 110B may have a copy of a device application on the first user device 110A that facilitated sending the content sharing message. However, in some embodiments, content may be presented on the second user device 110B in any suitable way, including by clicking a link and presenting content in a web browser or the like. Activation of the content sharing message, at 1025, may or may not include user interaction. For example the content sharing message may self activate and present content without user interaction. In other embodiments, a hyperlink, file, or the like may be received, which may be executed or clicked by a user to present or initiate presentation of the shared content. Returning to the data flow path 1000, a content action is initiated, at 1045, and a content action message with a first user profile identifier is sent to the content server 130, at 1050. A first user reward is generated, at 1055, which is associated with the first user profile. For example, in addition to possibly receiving a reward for sharing content or an advertisement with a friend, a sharing user may also receive a reward when the friend performs an action with the shared content. A content action may include buying a product or service, viewing media, visiting a website, viewing shared content, a social network action, or the like. For purposes of tracking and ensuring that the appropriate user is provided with a reward, a user profile indicator may be included in content sharing messages and in features of shared content so that actions by the second user may be tracked in relation to the first sharing user. The first user may then be rewarded based on various behaviors of the second user, and may receive a greater reward for greater interaction or additional sharing of the content by the second user. For example, if the second user simply views the shared content, there may be less of a reward than if the second user purchases a good or service associated with an advertisement or if the second user shares the content with other users. As discussed herein, rewards and incentives may include any suitable reward or incentive, and may include a monetary reward, free goods or services, discounted goods and services, a coupon, entry into a raffle, free or discounted tickets or admittance to a venue, virtual currency, points, an award, publicity, or the like. FIG. 11 is an exemplary data flow diagram illustrating an embodiment of a data flow path 1100 between a user device 110, the list server 120 and content server 130 of FIG. 1, in which a reward list is generated and presented. The data flow path 1100 begins where the user device 110 initiates an application session at 1105, and at 1110, in an optional step, login data is sent to the list server 120. At 1115, a reward list request associated with a user profile is sent to the list server 120, where a reward list request is generated at 1120, which is associated with the user profile. The reward list request associated with the user profile is sent to the content server 130, at 1125, where a reward list is generated based on the user profile. For example, in an embodiment, a user may want to receive an updated list of rewards received by the user, and the application running on the user device 110 may request an updated reward list from the list server 120. The list server 120 may then communicate with one or more content servers 130 to obtain a portion of the reward list. User reward data may also be stored on the list server 120 in some embodiments. Reward list data is sent to the list server 120, at 1135, and a reward list presentation is generated based on the reward list data, at 1140. Reward list presentation data is sent to the user device 110, at 1145, and the user device 110 presents the reward list, at 1150. Users may be informed of rewards that they have earned in other ways. For example, users may also receive an e-mail, text message, or the like, which informs the user of earned user rewards. Additionally, reward data may be presented via a content presentation (e.g., FIG. 7a-c). For example, an earned reward may be displayed in an incentive action portion 725, or other portion of a content presentation. FIG. 12 is an exemplary flow chart illustrating an embodiment of a method 1200 executed by the content server of FIG. 1, for generating a user reward associated with a user profile. The method 1200 begins in block 1210 where a shared content request associated with a user profile is received, and in block 1220, the shared content is retrieved. In block 1230, the shared content is sent to a user device 110, and in decision block 1240, a determination is made whether a content action indication associated with the user profile is received, and if not, the method 1200 waits until a content action indication associated with the user profile is received. However, if a content action indication associated with the user profile is received, then in block 1250, a user reward associated with the user profile is generated, and the method 1200 is done in block 1299. FIG. 13 is an exemplary flow chart illustrating an embodiment of a method 1300, executed by a user device of FIG. 1, for initiating a content action related to received shared content. The method 1300 begins in block 1310, where a content sharing message is received, and in block 1320, the content sharing message is activated. In block 1330, a content request is sent to the content server 130, and in block 1340, shared content is received and presented. In block 1350, a shared content action is initiated, and the method 1300 is done in block 1399. Turning to FIG. 14, an alternative embodiment of the system 100 is shown. As shown, a data optimization system 1400 for collecting brand awareness and advertising campaign performance results in real-time is shown. The data optimization system 1400 can accurately assess an advertising campaign's effectiveness, in real-time, by use of concurrent surveys while the campaign is running. Although not limited to advertising, the data optimization system 1400 is preferably applied in any field where survey results are used for assessing effectiveness of an action taken by a company or institution intended to inform or alter behavior. For example, the data optimization system 1400 is particularly well suited to determine the effectiveness of public information campaigns by a government, new product or functionality notifications by companies for current subscribers or product owners, security advisory messages from banks to their existing customers, and so on. In the following description, brand advertising is used as a specific example for illustrative purposes only. As shown, the data optimization system 1400 includes a brand awareness platform 1406 that comprises a data platform 1401. The data platform 1401 includes a profile store 1402, a model store 1405, a survey store 1404, and an ad store 1403. The profile store 1402 can be the source of behavioral user data that the data optimization system 1400 uses to build predictive models. The profile store 1402 can also manage other objective user data such as age, income, place of residence, etc. The model store 1405 maintains predictive models that the model builder 1422 builds for targeting content to individuals. An advertising campaign comprises a set of brand awareness ads and/or other content, provided by the advertisers 1441 that the system serves to the users. The ad store 1403 includes the brand awareness ads and/or other content. The data optimization system 1400 serves the brand awareness ads and/or other content to the end users 1420. With each advertising campaign, a set of survey questions can be used to measure the effectiveness of that advertising campaign. The survey store 1404 includes all the surveys defined for individual campaigns from the advertisers 1441. The data optimization system 1400 also includes a control logic unit 1430. A selected end user 1420 can send a content request, such as an ad request, via a user device (not shown) to the control logic unit 1430. The control logic unit 1430 determines whether the selected end user 1420 receives an ad or a survey, as described with reference to FIG. 20. Additionally, the data optimization system 1400 includes a survey server 1410 in communication with the data platform 1401 and the control logic unit 1430 to handle the transmission of surveys and storage of the responses. Although shown as a separate schematic block in FIG. 14, the survey server 1410 can reside on and/or share resources of the data platform 1401. The data optimization system 1400 further comprises an ad server 1415 in communication with the data platform 1401 and the control logic unit 1430. When the control logic unit 1430 determines that an ad should be served to a user (rather than a survey), the ad server 1415 determines which ad to serve using the predictive models stored in the model store 1405. End users 1420 can interact with the data platform 1401 via the ad server 1415 or the survey server 1410. The data optimization system 1400 shown in FIG. 14 also includes a model builder 1422 in communication with the data platform 1401. The model builder 1422 creates and/or updates a predictive model representing users that are most likely to be influenced by exposure to one of the available ads. This can occur either as an online or offline process. The function of the model is to maximize any brand awareness metric that a system operator wishes to increase. For example, a brand awareness metric can include an intent to purchase or the likelihood of visiting a retail store. The data optimization system 1400 can provide benchmarking information on the performance of various brand advertisements in a brand performance exchange 1440. Advertisers 1441 can monitor the performance of their own campaigns during the campaign, compare performance with that of participating competitors, both at the general market average level (and the individual campaign level), view the characteristics of individuals that are influenced by brand advertising, and understand the messages that drive brand awareness. Stated in another way, the brand performance exchange 1440 allows companies to exchange benchmark performance data with other similar registered companies. A process for survey optimization can be triggered by receipt of a content request, such as an ad request, associated with a user identification (user ID). The content request can include a request to display an advertisement in real-time on a user's device, where the data optimization system 1400 decides whether to fill this advertisement request or whether to ignore it. The brand awareness platform 1406 listens for content requests. On receipt of a content request, the brand awareness platform 1406 retrieves any user data from the profile store 1402 for the selected user identifier associated with the request. Any user identifier can be used to identify the selected end user 1420 that made the content request; however, exemplary user identifiers include a deviceID associated with a mobile device when communicating with advertising platforms. Additionally and/or alternatively, the user identifier includes a cookie from a desktop computer or any other unique string that identifies the sending device. The brand awareness platform 1406 passes the content request with the corresponding profile data to the control logic unit 1430, waits for a response, returns this response, if there is one, to the selected end user 1420. The brand awareness platform 1406 also updates the brand performance exchange 1440 with real-time performance results. An exemplary advertisement campaign is shown in FIG. 19A. In operation, the brand awareness platform 1406 can listen for content requests from the user device of a selected end user 1420. These content requests can be received through a well specified application programming interface (“API”) or any other digital communication channel, such as communication ports (COM), Common Object Request Broker Architecture (CORBA), Enterprise JavaBeans (EJBs), and the like. For handling a survey request, an exemplary block diagram illustrating the survey server 1410 in further detail is shown in FIG. 15. Turning to FIG. 15, the survey server 1410 includes a survey logic module 1502 that receives one or more content requests 1501. The survey logic module 1502 determines whether a survey will be sent and, if so, which particular survey. According to one embodiment, the survey logic module 1502 can select a small random sample of end users 1420 to be surveyed from those for which a content request is received. According to other embodiments, this sampling can occur before the survey request is received by the survey server 1410. If the survey server 1410 determines that the identified user should be surveyed, a survey instruction is communicated to a survey handler 1505. The survey handler 1505 retrieves the appropriate survey from the survey store 1404 and transmits it to the identified user. A selected survey can be sent directly to a user's device, in place of an ad, and/or by text message (or a succession of messages), an email, a pop-up on a web browser, or via any other channel. Once the survey is received, the identified user can respond and the survey handler 1505 can receive and forward the response to be maintained in the profile store 1402. The profile store 1402 maintains all profile information that the brand awareness platform 1406 has on each user having a user identifier. The profiles stored in the profile store 1402 include any population group a user is assigned to and what/when content or ads were shown to each user. Returning to FIG. 14, the ad server 1415 can score each content request to determine whether they are likely to be influenced by exposure to a brand advertisement. For example, if a campaign has a requirement to achieve a specified number of ad views over a specific time, the ad server 1415 will make sure this number of ad views are served to the best prospects (e.g., the users most likely to increase the brand awareness metric). For handling content requests, an exemplary top-level diagram illustrating the ad server 1415 in further detail is shown in FIG. 16. Turning to FIG. 16, the ad server 1415 includes a request handler 1602 in communication with a model scorer 1603. Although not shown, the content request includes a user identifier and a location. A location can identify where the ad is going to be displayed. The content request can also include details of the application or web page where the request originated, the format of the ad (e.g., html, jpg, etc.), the size of the display spot, and any other information available in the request. The model builder 1422 and model scorer 1603 can use this information, along with the profile data, to decide which ads are suitable and which ads are not suitable to display to maximize the brand awareness metric. The request handler 1602 receives the content request 1601 via the control logic 1430 from the user device. The request handler 1602 first retrieves profile information, if present, from the profile store 1402 for the selected user. The profile is retrieved using the user ID sent with the request. The request handler 1602 retrieves the set of available ads that can be served for the particular location, from the ad store 1403. Once the request handler 1602 has determined the available set of ads that can be served at this location, this set of available ads is passed to the model scorer 1603. The model scorer 1603 determines which of these advertisements, if any, to return to the user. The model scorer 1603 evaluates the predictive model learned by the model builder 1422 and thus can preferentially serve ads to those users more likely to increase the brand awareness metric associated with that particular campaign. In some embodiments, the data optimization system 1400 collects survey data from a sample of users and uses machine learning to build predictive models to infer brand awareness level or other metrics (e.g., intent to purchase, intent to visit retail store, etc.) of any user, not only those in the surveyed sample, and determine a score for the metric. An appropriate score can be determined in real-time, whenever a user is seen. This real-time prediction is then used to automatically determine which advertisement, if any, to show to a particular user. The data optimization system 1400 can collect brand awareness and advertising scores in any suitable manner discussed above, including the processes shown below with reference to FIGS. 17-18 and 20-21C. Although each of the methods below illustrates a plurality of processes, each process need not be performed in the order depicted. For example, each process can be distributed across multiple processors in a variety of ways and not necessarily separated into the operations illustrated for exemplary purposes only. FIG. 17, an exemplary process 1700 for configuring the data optimization system 1400. For a new campaign, one or more survey points are received at the survey store 1404, for example, from a system operator (not shown) (at step 1701) as configuration for the control logic 1430. For a particular campaign, a user may see a series of brand awareness ads and one or more surveys. Each view of an ad or survey is hereafter referred to as an interaction. Survey points are the subset of interactions, within a series of interactions where the user could be sent a survey. For example, a survey point can be defined as occurring a certain number of exposures or a certain length of time after the last exposure of the ad. The survey store 1404 can also receive one or more brand awareness metrics (at step 1702) that are stored in the model builder 1422 and used to build the predictive models for targeting. Brand awareness metrics can include metrics that can be determined using survey data, for example brand awareness level, intent to purchase or intention to visit retail store. The configuration operation may also include the determination of a threshold for each metric, which can be used in conjunction with the model score to determine which content requests to serve an ad to and which to ignore. More than one threshold may be determined for a metric. For example, different thresholds may be used for different groups of users. The survey store 1404 then receives one or more surveys (at step 1703) to test one or more of the metrics defined at step 1702. These surveys might include the text for questions to be put to users, ranges of possible responses, and other presentation data. FIG. 18 shows an exemplary embodiment of a process for the data optimization system 1400 to survey a selection of users and present relevant advertisements. Referring to FIG. 18, a sample of users is surveyed (at step 1801) at one or more points in their series of interactions. Surveys can be sent in various ways using one or more channels including, but not limited to, presentation of a survey in place of an advertisement to a mobile or other device, email, text and telephone call. Surveying can include one or more questions and can be sent automatically, as discussed in FIGS. 20-21C. An example of surveying direct to a mobile device in place of an advertisement is illustrated in FIG. 19B which shows a question with answers presented on the screen of a smart phone. The question or questions asked in a survey can relate to the brand awareness metric. The question or questions can require a textual or numerical value in response or a response that can be represented as a numerical value. For example, “yes” and “no” can be represented in binary form and a range of descriptors from “excellent” to “very poor” can be represented on a scale of 1 to 10. A predetermined percentage of users (e.g., between 1% and 10%) can be surveyed once they have been exposed to the advertisement a certain number of times or at a chosen time of surveying. According to some embodiments, the control logic 1502 ensures that the surveying is random, for example, to ensure a representative sample and/or to avoid over-surveying users. For example, a die can be thrown in any manner (e.g., weighted or unweighted) each time a user arrives at a survey point to determine whether the user should be surveyed. The fall of the die indicates whether the user can receive a survey question or questionnaire. To avoid over-surveying, rules can be applied for example to avoid surveying users who have recently received another feedback request, or have been served several brand awareness advertisements within a short period of time, for example. Each content request received by the brand awareness platform 1406 includes user behavioral data and other descriptive data. This data is recorded (at step 1802) in the profile store 1402 for use in the model builder 1422. For example, user behavioral and/or other descriptive data can include web pages viewed, mobile apps used, phone make and version, previously acquired data based on previous interactions with users. Additionally and/or alternatively, user behavioral and/or other descriptive data can be obtained in real time in operations running in parallel to the surveying of users or it can be inferred from advertisements shared by one user to another. Behavioral data can include mobile application usage or website page view data, location data, and a wide range of other recordable data relating to user behavior, such as previous clicks or other interactions with campaigns, direct feedback to ads (as in step 850 shown in FIG. 8) or the sharing of ads with other users (as shown in step 1050 of FIG. 10). Behavioral data can also be retrieved from a database, such as the profile store 1402. In some embodiments, the model builder 1422 obtains all, or a subset of, the data stored in the profile store 1402. For example, only the most recent data, defined by a predetermined time period (e.g., last 24 hours), can be retrieved. The model builder 1422 builds a set of predictive models that can be used to estimate the brand awareness metric for all, including previously unseen, users (at step 1803). For example, the model builder 1422 uses behavioral data from historical user interactions with relevant advertisements, together with the survey results, to build and/or update models that can predict a metric. According to embodiments, predictive models, such as shown in equation (1) below, can be used to determine a brand awareness metric for any user. Advantageously, the model scorer 1603 can determine a brand awareness metric based on predictive models even for users having no survey data. That is, the predictive models can be used to extrapolate obtained survey results to the remainder of the population who were not surveyed. For example, the model builder 1422 can determine that the presence of certain features in the profile data is associated with an increased likelihood of responding positively to the survey question. The presence, or otherwise, of these features in the profile data of unsurveyed users enables the model scorer 1603 to estimate the likelihood of any individual user to respond positively to the survey question. According to some embodiments, at each user interaction point, the predictive models are used to determine a brand awareness score in real-time. Each brand awareness score produces an estimate, or prediction, of a dependent variable, the metric, for an individual. For example, a linear regression model can be represented by equation (1): prediction=c1x1+c2x2+ . . . +cnxn (1) where c1, c2 . . . cn are coefficients and x1, x2 . . . xn are independent variables including descriptive variables such as location, device type and behavioral variables built from previous interaction history. In some embodiments, the predictive model can include a weighted sum, such as shown in equation (1), but is not limited to such models. In other embodiments, the predictive model can use any modeling technique, including but not limited to linear regression, logistic regression, decision tree, random forest, neural network, support vector machine, and Bayesian network. In some embodiments, the predictive model represents a combination of scores derived using different modeling techniques. For example a regression model (as shown in equation 1) may be combined with a neural network, or any other predictive model, to create a multi-stage model. In a preferred embodiment, the independent variables can characterize the user interaction history, or can be any other factors that can affect the user's brand awareness. Any number of variables can be taken into account in determining a brand awareness score. Examples of variables include, but are not limited to: Location and location history Previous mobile phone apps used Device type, model, etc. Biographical data such as age and gender Number of previous brand ad views Number of previous retail store visits Previous relevant ad feedback events Previous relevant ad sharing events with other users. Etc. Some models do not require any user-specific data, in which case, the building of the model or models can take place before the surveying of users and obtaining of user data at steps 1801 and 1802. Any subsequent user survey data, behavioral data, and/or descriptive data can then be used to update a previously created model. Accordingly, one or more models can be continually updated using any machine learning techniques in order to improve the accuracy of prediction as more data is gathered. This is shown in FIG. 18 (e.g., the returning loop from step 1803 to step 1801). The processes shown in FIG. 18 can be part of a continuous loop and can be performed in any order. Sending surveys can be a synchronous process where the survey is sent in direct response to a content request. Alternatively, the process can be asynchronous where a survey is sent at some predetermined time after exposure to a brand ad exposure, possibly by a different channel (e.g., email or SMS). In some embodiments, the first time a user is seen, as identified by a user ID, or other identifier, the user is allocated to a selected group, called a population group. These groups are used primarily for measurement of the effect of the campaign, such as shown in FIG. 20. Turning to FIG. 20, an exemplary process 2000 for handling a content request is shown. When the control logic 1430 receives a content request (at step 2010), the survey handler 1505 queries the profile store 1402 to retrieve whatever data is known about this user ID 2020. If this is a previously unseen user, (at step 2030), a population group is assigned (step 2032). If the user is known, the user's existing population group is retrieved (at step 2031). The user can be assigned to the selected group permanently. The user can be randomly allocated to a selected group according to a predefined probability distribution, for example 40%, 40% and 10%. There can be any number of groups and for exemplary purposes only, the groups can include: Group 1—Exposed users. These users always receive the brand advertisement. Group 2—Exposed users using optimization. These users only receive the brand advertisement if the optimization system determines they are a good prospect. Group 3—Control users. These users are not shown the brand advertisement. The system does not attempt to respond allowing the ad spot to be filled by some other provider showing some other content. In some embodiments, the size of these groups will depend on the size of the campaign and the number of people it is desirable to survey. In a preferred embodiment, most users would be assigned to Group 2, using optimization to choose who receives the ad. However, the other groups can be large enough to ensure usable models are built during the campaign and statistically significant results seen at the end of the campaign. The control logic unit 1430 determines which group the user is placed in. Once the group is chosen or retrieved, the survey from the survey store 1404 is retrieved 2040. The control logic unit 1430 then determines when and to whom a survey is sent, running the survey logic (at step 2050). The survey logic is described with reference to FIGS. 21A-21C. The content is delivered to the user (at step 2060). Surveys can be sent during a subsequent visit by the same user, only to a consumer of panel participants or after a predetermined time. Respectively, survey logic for: “Next-Time-Same-User-Seen”, “Consumer-Panel-Participant”, or “After-Predetermined-Time” are shown below. FIG. 21A illustrates an exemplary process 2040A providing an exemplary data flow of retrieving the survey logic 2040 for a “Next-Time-Same-User-Seen” survey. If the survey is only to be sent to a subset of the population, the survey logic 1502 randomly determines (e.g., dice throw) whether a survey is to be sent to this user (at step 2110). If the survey is to be sent continue, otherwise exit. If this is the second time the survey logic 1502 has received a content request from this user, then having been exposed to the ad, the user is eligible for a survey. The second visit condition is tested in step 2120. If the user is a first time visitor, an ad is served at step 2160. If the user is a second-time visitor, the survey is sent at step 2130. The survey handler 1505 waits for a response at step 2140. Finally, the response is recorded in the profile store 1402 at step 2150. For example, a multi-choice question (as shown in FIG. 19B) can be provided such that on selection of an answer, the answer is immediately sent back (at step 2040) to the brand awareness platform 1401. For third and subsequent requests, the ad is displayed at step 2160. FIG. 21B illustrates another exemplary process 2040B providing an exemplary data flow of the survey logic 2040 for a “Consumer-Panel-Participant” survey. If this is the second time the survey handler 1505 has seen this user and the user is a consumer panel member, then the survey handler 1505 schedules a survey to be sent after a predetermined delay time via a predetermined preferred channel. If the user is not a second time visitor (decision block 2120), an ad is served at step 2160. The survey is sent at 2130. The system waits for a response at 2140. Finally, the response recorded in the profile store 1402 at step 2150. FIG. 21C illustrates another exemplary process 2040C providing an exemplary data flow of the survey logic 2040 for an “After-Predetermined-Time” survey. If this is the second time the data optimization system 1400 has received a content request from this user, the survey handler 1505 randomly determines (e.g., dice throw) whether a survey is to be sent to this user (at step 2110). Next, an ad is sent at step 2160. The survey logic 1505 tests the send survey condition at step 2180. If false end. If true, the system waits a predetermined time (e.g., immediately, 24 or 48 hours) 2190. The survey is sent at step 2130. The system waits for a response 2140. And finally, the response recorded in the profile store 1402 at step 2150. In other embodiments, survey can include any narrative (e.g., asking for comments), and the response can be received by any channel, such as SMS, email, face to face interview, and so on. This could simply be a survey question tagged on the end of a brand ad video. Additionally and/or alternatively, the survey handler 1505 delivers a pop-up on the user's screen to display the survey. Survey results can be consumed in any desired method, such as for example: surveys are fed into an online or offline model building process which continually reconstructs models that predict those users who are more likely to respond more positively to the survey if they were shown the brand ad. To build the predictive models, the model builder 1422 accesses the profile store 1402 to retrieve the user's ID, any data maintained for the user associated with the user ID (e.g., demographic, environmental, etc.), the ad shown, and the associated survey response. The survey response can be translated as a dependent variable in any model built, such as a binary or real number. In the example used below, the user is sent the question: “which of the following brands will you purchase in the next 30 days? Brand A, brand B, brand C, or brand D”. The response can be translated into a binary variable; TRUE if the intended brand is selected, FALSE otherwise. To build a predictive model, sufficient data can be collected such that statistically valid patterns can be recognized in the data. Every modeling scenario will have different data requirements. As soon as sufficient data has been collected to enable a valid predictive model to be built then these models can be used to target the remaining brand ads at those users most likely to change behavior after exposure during the course of the campaign. The actual model building technique used could be any suitable technique to predict the value of displaying an advertisement to an individual user. However, in a preferred embodiment, Uplift Modeling (where the likelihood to change behavior after exposure to the advertisement is modeled) is preferred as this will directly ensure that content is served to those where exposure is most likely to change behavior. Additional information regarding Uplift Modeling can be found in Radcliffe, N.J. (2007); Using Control Groups to Target on Predicted Lift: Building and Assessing Uplift Models, Direct Marketing Analytics Journal, Direct Marketing Association, which article is hereby incorporated by reference in its entirety and for all purposes. Performance of the overall effectiveness of the campaign can be measured by comparison of positive and negative survey results between the various population groups. The added value of the real-time optimization in the ad serving process can be measured by comparison of positive and negative survey results between those who received targeted content and those who received control. For example, the positive response rate of the exposed group divided by the positive response rate of the control group gives the basic effectiveness of the campaign. Campaigns can be benchmarked against a variety of measures representing the industry norm for similar campaigns, performance of historical campaigns, etc. The described embodiments are susceptible to various modifications and alternative forms, and specific examples thereof have been shown by way of example in the drawings and are herein described in detail. It should be understood, however, that the described embodiments are not to be limited to the particular forms or methods disclosed, but to the contrary, the present disclosure is to cover all modifications, equivalents, and alternatives.
<SOH> BACKGROUND <EOH>Consumers are inundated with various types of advertising content on television, mobile devices, and while accessing the internet, but typically lack the ability to actively control and interact with such advertising content. For example, consumers are conventionally served with advertising content, regardless of whether the user would have an interest in the content. Accordingly, a large majority of advertising is wasted on viewers who have no interest in the goods or services being advertised, or would not be eligible buyers for such goods and services. Additionally, consumers lack the ability to provide feedback about advertising content or about the goods or services being advertised. Unfortunately, advertisers are therefore unable to determine which advertising campaigns are more successfully engaging consumers, and are unable to provide personalized and more relevant advertising content to consumers. Moreover, advertisers are unable to reward consumers for providing valuable feedback regarding advertising content. Many consumers also desire to share advertising content with friends because they may enjoy the content, or because they may like the products or services being advertised. Conventional advertising can be difficult to share among friends, and there is no way to track, incentivize and reward consumers who share advertising with their friends. Additionally, there is no way to provide sharing consumers with further rewards and incentives for having friends purchase goods or services associated with advertising content or for sharing consumers to leverage the buying power of a group of users to receive rewards and incentives. Conventional advertising also fails to allow consumers to socially discover and search for advertising based on feedback of friends and other users, nor does conventional advertising provide for discovery of advertising that is promoted, disliked or shared by enthusiasts, experts, friends or celebrities. Furthermore, the effectiveness of brand and similar advertising is typically evaluated by surveys sent to a consumer panel once the advertising campaign has terminated. The surveys are designed to measure the nebulous quantity of brand awareness. Some members of the consumer panel are exposed to the advertising; and some members of the consumer panel are not. The difference in survey results from these two groups forms the basis of the analysis of effectiveness. However, evaluating the campaign after a single iteration of the campaign is inaccurate. For example, targeting advertisements automatically relies on a prediction of the value of displaying the advertisement to any individual based on examples of high and low value users. This information is not available until the survey has been conducted, making automated targeting of brand advertisements is very difficult. Typically, unsatisfactory surrogates for the value of displaying an advertisement to a particular user (e.g., clicks or video completes) are used, and the correlation between these and the subsequent survey results can be very weak. As an additional drawback, external factors (e.g., major news stories regarding food safety) can affect the survey results during the time the campaign ends and the survey questions are sent. Additionally, brand awareness generally decreases over time after the advertisement campaign is viewed. Accordingly, the time between exposure to the campaign and the survey can affect the effectiveness of the campaign. The lack of a standardized framework makes it very difficult for an advertiser to compare the effectiveness of a campaign against the norm across similar industries—or even the advertiser's own historical campaigns. In view of the foregoing, a need exists for improved systems and methods for collecting brand awareness and advertising campaign performance results in real-time, in an effort to overcome the aforementioned obstacles and deficiencies of conventional user account registration systems.
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is an exemplary top-level block diagram illustrating an embodiment of a content feedback, incentive, and reward system. FIG. 2 is an exemplary data flow diagram illustrating an embodiment of a data flow path between a user device, the list server and content server of FIG. 1 , in which a content list is generated and presented. FIG. 3 depicts a user interface presenting a content list in accordance with an embodiment. FIG. 4 is an exemplary flow chart illustrating an embodiment of a method executed by the list server of FIG. 1 , for generating and providing a content list. FIG. 5 is an exemplary flow chart illustrating an embodiment of a method executed by the content server of FIG. 1 , for generating a content list. FIG. 6 is an exemplary data flow diagram illustrating an embodiment, in which content feedback is received and a feedback reward is generated. FIG. 7 a depicts a user interface presenting content in accordance with an embodiment. FIG. 7 b depicts a user interface for content feedback in accordance with an embodiment. FIG. 7 c depicts a user interface for sharing content in accordance with an embodiment. FIG. 8 is an exemplary flow chart illustrating an embodiment of a method executed by the content server of FIG. 1 , for content feedback. FIG. 9 is an exemplary flow chart illustrating an embodiment of a method executed by a user device of FIG. 1 , for content feedback. FIG. 10 is an exemplary data flow diagram illustrating an embodiment of a data flow path between the first and second user device and the list server and content server of FIG. 1 , in which a user reward is provided. FIG. 11 is an exemplary data flow diagram illustrating an embodiment of a data flow path between a user device, the list server and content server of FIG. 1 , in which a user reward is presented on the user device. FIG. 12 is an exemplary flow chart illustrating an embodiment of a method executed by the content server of FIG. 1 , for generating a user reward associated with a user profile. FIG. 13 is an exemplary flow chart illustrating an embodiment of a method, executed by a user device of FIG. 1 , for initiating a content action related to received shared content. FIG. 14 is an exemplary top-level diagram illustrating one embodiment of a data optimization system. FIG. 15 is an exemplary top-level block diagram illustrating one embodiment of the survey server of the data optimization system of FIG. 14 . FIG. 16 is an exemplary top-level block diagram illustrating one embodiment of the ad server of FIG. 14 . FIG. 17 is an exemplary data flow diagram illustrating one embodiment of a configuration of the data optimization system of FIG. 14 . FIG. 18 is an exemplary data flow diagram illustrating one embodiment for building and providing feedback for predictive models that can be used with the data optimization system of FIG. 14 . FIG. 19A depicts a user interface presenting content in accordance with an embodiment that can be used with the data optimization system of FIG. 14 . FIG. 19B depicts a user interface presenting survey in accordance with an embodiment that can be used with the data optimization system of FIG. 14 . FIG. 20 is an exemplary data flow diagram illustrating an embodiment of a data flow path illustrating one embodiment of a process for survey logic shown in FIG. 18 . FIG. 21A is an exemplary data flow diagram illustrating an embodiment of a data flow path for the survey logic of FIG. 20 where the survey logic is configured to “next-time-same-user-seen”. FIG. 21B is an exemplary data flow diagram illustrating an alternative embodiment of a data flow path for the survey logic of FIG. 20 where the survey logic is configured to “consumer panel”. FIG. 21C is an exemplary data flow diagram illustrating an alternative embodiment of a data flow path for the survey logic of FIG. 20 where the survey logic is configured to “after-predetermined-time”. detailed-description description="Detailed Description" end="lead"? It should be noted that the figures are not drawn to scale and that elements of similar structures or functions are generally represented by like reference numerals for illustrative purposes throughout the figures. It also should be noted that the figures are only intended to facilitate the description of the preferred embodiments. The figures do not illustrate every aspect of the described embodiments and do not limit the scope of the present disclosure.
G06Q300245
20170816
20180222
65555.0
G06Q3002
0
DAGNEW, SABA
System and Method for Real-Time Optimization and Industry Benchmarking for Campaign Management
SMALL
0
PENDING
G06Q
2,017
15,679,696
ACCEPTED
ELEVATOR ROLLER INSERT SYSTEM
A device, system, and/or method for reducing friction required to rotate a tubular within an elevator during the process of running tubulars in an oil and gas well are provided. An elevator roller insert may be used in conjunction with an elevator, such as a single joint elevator. Such an insert may comprise upper and lower rollers which are positioned on upper and lower roller sets or a combination roller set containing multiple upper and/or lower rollers. The result is the provision of a plurality of rollers which bear the weight of a tubular yet still allow the tubular to rotate rather freely, facilitating the maintenance of proper thread integrity of the connections while making up a stand to a string of tubulars as well as preventing the loss of resources due to galled or crushed threads or a tubing segment or stand falling to the rig floor.
1. An elevator roller system for a drilling rig, comprising: a tubular having a first outer diameter and a second outer diameter, wherein the first outer diameter is smaller than the second outer diameter; an elevator having: a first arm having an interior surface; a second arm having an interior surface, the first and second arms hingedly interconnected and rotatable between an open position and a closed position, wherein the interior surfaces of the arms form an aperture with a central axis in the closed position; a plurality of first rollers disposed in the interior surfaces of the first and second arms and positioned about the central axis of the aperture, wherein the plurality of first rollers forms an inner diameter; a plurality of second rollers disposed in the interior surfaces of the first and second arms and positioned about the central axis of the aperture, wherein the plurality of second rollers forms an inner diameter that is smaller than the second outer diameter of the tubular; and wherein the pluralities of first and second rollers are configured to contact the tubular when the arms are in the closed position and further wherein the tubular is capable of freely rotating relative to the elevator when the arms are in the closed position. 2. The elevator roller system of claim 1, wherein the rollers in the plurality of first rollers each have an axis oriented substantially perpendicular with the central axis of the aperture. 3. The elevator roller system of claim 1, wherein the rollers in the plurality of first rollers each have an axis oriented at a nonzero angle with the central axis, and the rollers in the plurality of second rollers each have an axis oriented substantially parallel with the central axis. 4. The elevator roller system of claim 1, wherein the rollers in the plurality of first rollers are each one of a thrust bearing, a radial bearing, and a cam follower roller, and wherein the rollers in the plurality of second rollers are each one of a thrust bearing, a radial bearing, and a cam follower roller. 5. The elevator roller system of claim 1, wherein the rollers in the plurality of first rollers are upper rollers, and wherein the rollers in the plurality of second rollers are lower rollers positioned below the upper rollers. 6. The elevator roller system of claim 5, wherein the inner diameter formed by the plurality of upper rollers is larger than the inner diameter formed by the plurality of lower rollers. 7. The elevator roller system of claim 1, wherein the rollers in the plurality of first rollers are arranged in a common plane, and wherein the rollers in the plurality of second rollers are arranged in a common plane. 8. The elevator roller system of claim 1, wherein the inner diameter formed by the plurality of first rollers and the inner diameter formed by the plurality of second rollers are identical. 9. The elevator roller system of claim 1, wherein the pluralities of first and second rollers are disposed in the interior surfaces of inserts configured to selectively interconnect to the interior surface of the first and second arms. 10. The elevator roller system of claim 1, wherein the second outer diameter of the tubular is an elevator upset area or coupling of the tubular, and wherein the first outer diameter of the tubular is a body of the tubular. 11. An elevator roller insert, comprising: an insert having an interior surface and an exterior surface, wherein the interior surface forms an aperture with a central axis, and wherein the exterior surface of the insert is configured to selectively interconnect to an interior surface of an elevator; a plurality of first rollers disposed on the interior surface of the insert and positioned about the central axis, wherein the plurality of first rollers forms an inner diameter, and the rollers in the plurality of first rollers are freely rotatable; a plurality of second rollers disposed on the interior surface of the insert and positioned about the central axis, wherein the plurality of second rollers forms an inner diameter, and the rollers in the plurality of second rollers are freely rotatable; and wherein the pluralities of first and second rollers are configured to contact a tubular and facilitate free rotation of the tubular relative to the elevator. 12. The elevator roller insert of claim 11, wherein the insert is comprised of a plurality upper roller sets and lower roller sets; further wherein the plurality of first rollers are disposed on the upper roller sets and the plurality of second rollers are disposed on the lower roller sets. 13. The elevator roller insert of claim 12, wherein each upper roller set is disposed between two lower roller sets and each lower roller set is disposed between two upper roller sets, wherein the plurality of upper and lower roller sets are disposed about the central axis. 14. The elevator roller insert of claim 11, wherein the elevator roller insert is comprised of at least one combination roller set, further wherein the combination roller set is comprised of a combination roller block and at least one upper roller and at least one lower roller. 15. The elevator roller insert of claim 11, wherein the rollers in the plurality of first rollers each have an axis oriented substantially perpendicular with the central axis. 16. The elevator roller insert of claim 11, wherein the rollers in the plurality of first rollers each have an axis oriented at a nonzero angle with the central axis, and the rollers in the plurality of second rollers each have an axis oriented substantially parallel with the central axis. 17. The elevator roller insert of claim 11, wherein the rollers in the plurality of first rollers are each one of a thrust bearing, a radial bearing, and a cam follower roller, and wherein the rollers in the plurality of second rollers are each one of a thrust bearing, a radial bearing, and a cam follower roller. 18. The elevator roller insert of claim 11, wherein the rollers in the plurality of first rollers are arranged in a common plane, and wherein the rollers in the plurality of second rollers are arranged in a common plane. 19. The elevator roller insert of claim 11, wherein the rollers in the plurality of first rollers are upper rollers, and wherein the rollers in the plurality of second rollers are lower rollers positioned below the upper rollers, and further wherein the inner diameter formed by the plurality of first rollers is larger than the inner diameter formed by the plurality of second rollers. 20. The elevator roller insert of claim 11, wherein the rollers in the plurality of first rollers are upper rollers, and wherein the rollers in the plurality of second rollers are lower rollers positioned below the upper rollers, and further wherein the inner diameter formed by the plurality of first rollers and the inner diameter formed by the plurality of second rollers are identical. 21. A method of assembling tubulars using an elevator, comprising: providing an elevator having: a first arm having an interior surface; a second arm having an interior surface, the first and second arms hingedly interconnected and rotatable between an open position and a closed position, wherein the interior surfaces of the arms form an aperture with a central axis in the closed position; a plurality of first rollers disposed in the interior surfaces of the first and second arms and positioned about the central axis of the aperture, wherein the rollers in the plurality of first rollers are freely rotatable; a plurality of second rollers disposed in the interior surfaces of the first and second arms and positioned about the central axis of the aperture, wherein the rollers in the plurality of second rollers are freely rotatable; positioning a first tubular in the aperture of the first and second arms of the elevator such that the first tubular contacts the pluralities of first and second rollers, the first tubular having a box end and a pin end, wherein the box end of the first tubular has an outer diameter that is greater than an inner diameter formed by the plurality of second rollers; and freely rotating the first tubular relative to the elevator and selectively interconnecting the pin end of the first tubular to a box end of a second tubular. 22. The method of claim 21, wherein the rollers in the plurality of first rollers are upper rollers, and wherein the rollers in the plurality of second rollers are lower rollers positioned below the upper rollers, and further wherein an inner diameter formed by the plurality of first rollers is larger than the inner diameter formed by the plurality of second rollers. 23. The method of claim 21, wherein the rollers in the plurality of first rollers are upper rollers, and wherein the rollers in the plurality of second rollers are lower rollers positioned below the upper rollers, and further wherein an inner diameter formed by the plurality of first rollers and the inner diameter formed by the plurality of second rollers are identical. 24. The method of claim 21, wherein the pluralities of first and second rollers are disposed in the interior surfaces of inserts configured to selectively interconnect to the interior surface of the first and second arms. 25. The method of claim 21, wherein the rollers in the plurality of first rollers are each one of a thrust bearing, a radial bearing, and a cam follower roller, and wherein the rollers in the plurality of second rollers are each one of a thrust bearing, a radial bearing, and a cam follower roller. 26. A method of assembling tubulars using an elevator, comprising: providing an elevator having: a plurality of first rollers positioned about a central axis of an aperture of the elevator, wherein the rollers in the plurality of first rollers are freely rotatable; a plurality of second rollers positioned about the central axis of the aperture of the elevator, wherein the rollers in the plurality of second rollers are freely rotatable; positioning at least one tubular in the elevator such that the at least one tubular contacts the pluralities of first and second rollers, wherein a box end of the at least one tubular has an outer diameter that is greater than an inner diameter formed by the plurality of second rollers; and freely rotating, by an operator, the at least one tubular relative to the elevator to start a selective interconnection between a pin end of the at least one tubular and a box end of another tubular. 27. The method of claim 26, wherein the at least one tubular is a plurality of tubulars. 28. The method of claim 26, wherein the operator freely rotates the at least one tubular using a strap wrench. 29. The method of claim 26, wherein the rollers in the plurality of first rollers are upper rollers, and wherein the rollers in the plurality of second rollers are lower rollers positioned below the upper rollers, and further wherein an inner diameter formed by the plurality of first rollers is larger than an inner diameter formed by the plurality of second rollers. 30. The method of claim 26, wherein the rollers in the plurality of first rollers are upper rollers, and wherein the rollers in the plurality of second rollers are lower rollers positioned below the upper rollers, and further wherein an inner diameter formed by the plurality of first rollers and an inner diameter formed by the plurality of second rollers are identical.
CROSS REFERENCE TO RELATED APPLICATION This application is a continuation application under 35 U.S.C. §111(a) of PCT Application No. PCT/US2016/023686 having an international filing date of Mar. 23, 2016, which designated the United States, which PCT application claims the benefit of U.S. Application Ser. No. 62/136,978, filed on Mar. 23, 2015 and U.S. Application Ser. No. 62/292,988, filed Feb. 9, 2016, all of which are incorporated by reference in their entirety. FIELD OF THE INVENTION The invention relates to an apparatus and methods, in certain embodiments, to reduce the friction required to rotate a tubular within a single joint elevator during the process of running tubulars in an oil and gas well. The invention would eliminate the need for the elevator to have to rotate and reduce the amount of torque required to rotate the tubular on stationary elevators. This would allow most tubular connections to be started by hand with the use of a strap wrench. In particular, but not exclusively, the invention relates to a tool for, and a method of, reducing the torque required to rotate a tubular within an elevator while running and making up tubulars in the oil and gas industry. This tool may complement elevators that utilize die sets or inserts to adjust the internal diameter of the elevator to match a range of tubular sizes. This tool may be used to run any sized tubular, including tubulars from 2⅜ inches to 20 inches. BACKGROUND AND SUMMARY OF THE INVENTION In the oil and gas industry, wellbores are drilled into the earth using drilling rigs, where tubulars are threaded together to form long tubular strings that are inserted into the wellbore to extract the desired fluid. The tubing string is generally suspended in the borehole using a rig floor-mounted spider, such that each new tubular segment or stand may be threaded onto the end of the previous tubular just above the spider. A segment is generally considered one joint of tubing and a stand is generally considered to be two or three joints of tubing combined together. A single joint elevator is commonly used to grip and secure the segment or stand to a hoist to lift the segment or stand into position for threading the tubulars together. Sometimes compensators are used in combination with elevators to reduce the weight of the stand on the connection of the previous string. Once set into position the tubular is rotated with a power tong in the elevator or the entire elevator is allowed to rotate on a swivel with the tubular to allow the connections to be threaded. In general, single joint elevators are specifically adapted for securing and lifting tubular segments having a conventional connection, such as an internally threaded sleeve that receives and secures an externally threaded end from each of two tubular segments to secure the segments in a generally abutting relationship. The internally threaded sleeve is first threaded onto the end of a first tubular string to form a “box-end.” The externally threaded “pin end” of a second tubular string is then threaded into the box end to complete the connection between the two strings. These elevators have a circumferential shoulder that forms a circle upon closure of the hinged body halves. The shoulder of the elevator engages the shoulder formed between the end of the sleeve and the pipe segment. Other elevators are specifically adapted for securing and lifting tubular segments having integral connections. These integral connections are generally permanently fixed to each end of the tubular, one end having an internally threaded end or “box-end” and the other end having an externally threaded end or “pin-end”, in a generally abutting relationship. The externally threaded pin-end of the first tubular segment is then threaded into the internally threaded box-end of the tubular string. These elevators generally have a beveled or angled shoulder that forms a circle upon closure of the hinged body halves. The beveled shoulder engages the beveled end of the integral connection of the pipe segment. At least one challenge encountered by those in the industry is maintaining proper thread integrity of the connections while making up the stand to the string of tubulars. Generally, if the threads of the two connecting tubulars are not properly aligned when the rotation with power tongs begins, the threads of both connections will usually gall or be crushed to a state of non-compliance with industry standards. Typically these connections will have to be removed from the string and discarded or sent back to the manufacturer to be re-threaded. This removal of tubulars and connections from the string can be time consuming and very costly to the rig operator. Another such challenge to those in the industry is the ability to run segments or stands of very heavy weight tubing. Generally the face of the internally threaded sleeve of a conventional connection rests on the top of the elevator. If the weight of the tubing segment or stand is too great, the friction between the face of the sleeve and the shoulder of the elevator will cause the sleeve to “stick” and the sleeve will not rotate with the tubing. This eventually causes the sleeve to “back-off” or become disconnected from the tubing, possibly allowing the tubing segment or stand to fall to the rig floor. Yet another challenge is the safety issue that may arise when allowing the single joint to rotate on a swivel. The possibility exists that if the swivel, or the cable holding the swivel, becomes worn or fatigued to the point of failure, the elevator and the tubing would fall to the rig floor. Therefore, there is a need for an apparatus or system that allows the tubulars to rotate within the elevator with little required torque. This will allow the operator the ability to start the connection of the tubulars by hand with a strap wrench. Thus, the operator may determine whether or not the threads are aligned properly prior to connecting the power tongs and finishing the make-up of the connection. An objective of the invention is to provide a system comprising multiple rollers that may be seamlessly integrated into existing elevators which encompass inserts or dies to aid in the process of running tubulars. A further objective is to provide a means of allowing the tubulars to rotate within the elevator without the need for additional pneumatic or hydraulic control lines or actuation. A further objective is to provide a means to rotate a stand of multiple tubulars that would have been too heavy or unsafe to rotate using conventional methods. A further objective is to provide a means to run stands of two or three segments of heavy weight tubing instead of a single segment, significantly reducing the time required to run the tubing in the well. An apparatus of this nature may also significantly reduce the amount of loss time and money due to galled or destroyed connections. An apparatus of this nature may significantly reduce safety concerns by replacing the need to hang the elevator with cables and a swivel, and also to reduce the possibility of spinning off the upper collar holding the stand on the elevator. An apparatus of this nature may comprise rollers that encompass a shaft with an arrangement of radial and/or thrust bearings contained within a cylindrical hub. An apparatus of this nature may comprise rollers that encompass a single ball bearing fixed within a housing. An apparatus of this nature may typically have rollers that will be oriented vertically or at a specified angle from the vertical in combination with rollers that will be aligned with the vertical or horizontal. An apparatus of this nature may have interchangeable components that can be replaced in the field thus reducing downtime and ensure proper rotation of the tubular. These and other advantages will be apparent from the disclosure of the invention(s) contained herein. The above-described embodiments, objectives, and configurations are neither complete nor exhaustive. The Summary of the Invention is neither intended nor should it be construed as being representative of the full extent and scope of the invention. Moreover, references made herein to “the invention” or aspects thereof should be understood to mean certain embodiments of the invention and should not necessarily be construed as limiting all embodiments to a particular description. The invention is set forth in various levels of detail in the Summary of the Invention as well as in the attached drawings and Detailed Description and no limitation as to the scope of the invention is intended by either the inclusion or non-inclusion of elements, components, etc. in this Summary of the Invention. Additional aspects of the invention will become more readily apparent from the Detailed Description particularly when taken together with the drawings. BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate certain embodiments of the disclosure and together with the general description of the disclosure given above and the detailed description of the drawings given below, serve to explain the principles of the disclosures. FIG. 1a is a section view of a single upper roller block in accordance with embodiments of the invention; FIG. 1b is a section view of a single lower roller block in accordance with embodiments of the invention; FIG. 2a is a section view of a single upper roller block utilizing a cam follower roller in accordance with embodiments of the invention; FIG. 2b is a section view of a single lower roller block utilizing a cam follower roller in accordance with embodiments of the invention; FIG. 3 is a top view of an elevator roller insert utilizing an arrangement of single upper and lower roller blocks in accordance with embodiments of the invention; FIG. 4 is a top view of an elevator roller insert utilizing an arrangement of multiple roller blocks in accordance with embodiments of the invention; and FIG. 5 is a section view of a segment of tubing having an integral (beveled) connection within the roller insert in accordance with embodiments of the invention; FIG. 6 is a section view of a segment of tubing having a conventional (collared) connection within the roller insert in accordance with embodiments of the invention; FIG. 7a is a top view of a single joint elevator encompassing an elevator roller insert in a closed position in accordance with embodiments of the invention; and FIG. 7b is a top view of a single joint elevator encompassing an elevator roller insert in an open position in accordance with embodiments of the invention. It should be understood that the drawings are not necessarily to scale, and various dimensions may be altered. In certain instances, details that are not necessary for an understanding of the invention or that render other details difficult to perceive may have been omitted. It should be understood, of course, that the invention is not necessarily limited to the particular embodiments illustrated herein. DETAILED DESCRIPTION The invention has significant benefits across a broad spectrum of endeavors. It is the Applicant's intent that this specification and the claims appended hereto be accorded a breadth in keeping with the scope and spirit of the invention being disclosed despite what might appear to be limiting language imposed by the requirements of referring to the specific examples disclosed. To acquaint persons skilled in the pertinent arts most closely related to the invention, a preferred embodiment that illustrates the best mode now contemplated for putting the invention into practice is described herein by, and with reference to, the annexed drawings that form a part of the specification. The exemplary embodiment is described in detail without attempting to describe all of the various forms and modifications in which the invention might be embodied. As such, the embodiments described herein are illustrative, and as will become apparent to those skilled in the arts, and may be modified in numerous ways within the scope and spirit of the invention. Although the following text sets forth a detailed description of numerous different embodiments, it should be understood that the detailed description is to be construed as exemplary only and does not describe every possible embodiment since describing every possible embodiment would be impractical, if not impossible. Numerous alternative embodiments could be implemented, using either current technology or technology developed after the filing date of this patent, which would still fall within the scope of the claims. To the extent that any term recited in the claims at the end of this patent is referred to in this patent in a manner consistent with a single meaning, that is done for sake of clarity only so as to not confuse the reader, and it is not intended that such claim term by limited, by implication or otherwise, to that single meaning. Various embodiments of the invention are described herein and as depicted in the drawings. It is expressly understood that although the figures depict tubulars, inserts, and elevators, the invention is not limited to these embodiments. Now referring to FIG. 1a, an upper roller set 26 is provided with an upper roller 4 positioned within a recess of the upper roller block 2, the upper roller 4 having a rotational axis 6 about which the upper roller 4 rotates to accommodate tubulars being handled by an elevator. In some embodiments, upper roller 4 may comprise a combination of axial and thrust bearings encased within a roller housing and rotating about a central shaft 8. Also, as it can be appreciated by one skilled in the art, in certain embodiments, the types and sequence of bearings may be different than discussed herein to accommodate the different types of tubing and tubing connections being handled by an elevator. A plurality of upper roller sets 26 can form an elevator roller insert 30 (shown in FIG. 3 below) that bears the weight of a tubular yet still allows the tubular to rotate rather freely. To bear the weight of the tubular and to allow free rotation of the tubular, the upper roller 4 is configured to have a maximum operating weight and a maximum load rating. In some embodiments, the maximum operation weight for an upper roller 4 is 4,350 lbs and the maximum load rating is 6,300 lbs. It will be appreciated that in other embodiments, the maximum operation weight and the maximum load rating for an upper roller 4 may be greater or less than 4,350 lbs and 6,300 lbs, respectively. In the embodiment shown in FIG. 1a, the rotational axis 6 of the upper roller 4 is offset in a transverse direction from a central axis 8 of a complete elevator roller insert 22 (shown in FIGS. 3 and 4 below). Also, rotational axis 6 of the upper roller 4 may be offset from the vertical by an upper roller angle 10. In various embodiments, the upper roller angle 10 is approximately 0, 5, 12 or 18 degrees to match common tubular connection angles. In other embodiments, the upper roller angle 10 ranges from 0 to 90 degrees. In some embodiments, the upper roller set 26 is also comprised of a connection 12 which allows the roller block to be fixed to the elevator in some abutting fashion. In some embodiments this connection will be a dovetail type connection. In other embodiments the connection type may match that of the elevator that the inserts will be used in. Now referring to FIG. 1b, a lower roller set 28 is provided with a lower roller 16 positioned within a recess of the lower roller block 14. The lower roller 16 has a rotational axis 18 about which the lower roller 16 rotates to prevent a tubular from binding against the elevator roller insert 30 should the elevator be tilted or off center. The lower roller 16 may comprise a combination of axial and thrust bearings encased within a roller housing and rotating about a central shaft 20. Also, as it can be appreciated, in certain embodiments, the types and sequence of bearings may be different than discussed here to accommodate the different types of tubing and tubing connections being handled by an elevator. In the embodiment shown in FIG. 1b, the rotational axis 18 of the lower roller 16 is substantially parallel with a central axis of the complete elevator roller insert 30 (shown in FIGS. 3 and 4 below), or a central axis of a roller set. However, in some embodiments, the rotational axis 18 of the lower roller 16 may form a lower roller angle similar to the upper roller angle 10. In various embodiments, the lower roller angle may be between approximately 0 and 90 degrees. In some embodiments, the lower roller set 28 may also be comprised of a connection 12 which allows the roller block to be fixed to the elevator in some abutting fashion. In some embodiments this connection will be a dovetail type connection. In other embodiments the connection type will match that of the elevator that the inserts will be used in. Now referring to FIG. 2a, some embodiments of the upper roller set 26 may utilize a cam follower roller 22 instead of an upper roller 4 with bearings as depicted in FIG. 1a. Cam follower rollers are well known to those skilled in the art, and an exemplary cam follower roller is disclosed by U.S. Pat. No. 4,152,953, which is incorporated herein in its entirety by reference. The cam follower roller 22 would be threaded or otherwise secured into the upper roller block 2 and would bear the weight of the tubular being handled by the elevator 40. The cam follower roller would be oriented along a rotational axis 6 similar to that of the upper roller 2 in FIG. 1a, and its utilization would also be similar. Now referring to FIG. 2b, some embodiments of the lower roller block 14 may utilize a cam follower roller 24 instead of a lower roller 16 with bearings as depicted in FIG. 1b. The cam follower roller 24 would be threaded or otherwise secured into the lower roller block 14 and rotate to prevent a tubular from binding against an insert should the elevator be tilted or off center. In some embodiments, the cam follower roller is oriented along a rotational axis 18 similar to that of the lower roller in FIG. 1b, and its utilization would also be similar. Now referring to FIG. 3, a combination of upper roller sets 26 and a combination of lower roller sets 28 may be combined to form an elevator roller insert 30. A plurality of upper roller blocks 2 are arranged about the central axis 8 of the elevator roller insert 22 to form the upper roller set 28, and similarly, a plurality of lower roller blocks 14 are arranged about the central axis 8 of the elevator roller insert 30 to form the lower roller set 28. The upper and lower roller sets 26, 28 may then combine to form a complete elevator roller insert 30. In some embodiments the upper rollers may be combined in the same block with the lower rollers (combination block 32) in a single or multiple block set as can be seen in FIG. 4. In other embodiments there may be no lower roller sets 28 included in the elevator roller insert 30. The elevator roller insert 30 may comprise various numbers of upper roller sets 26 and lower roller sets 28. For example, in some embodiments, the elevator roller insert 30 comprises four upper roller sets 26 and four lower roller sets 28. It will be appreciated that in other embodiments, the number of upper roller sets 26 and/or the number of lower roller sets 28 may be greater or less than four. Further, the number of upper roller sets 26 may be distinct from the number of lower roller sets 28. In addition, FIG. 4 depicts an elevator roller insert 30 having three combination roller sets 32, but it will be appreciated that the elevator roller insert 30 may have more or less than three combination roller sets 32. As stated above, the rollers may have a maximum operating load and/or a maximum load rating, and similarly, the complete elevator roller insert 30 may also have a maximum operating load and/or a maximum load rating. Now referring to FIG. 5, a cross section is shown comprising of a tubing 34 with an integral connection 36 being held in place by the upper rollers 4 in a generally abutting relationship. Due to the weight bearing rotational capabilities of the upper roller 4, the tubing 34 will be allowed to rotate rather freely within the elevator roller insert 30. The upper roller angle 10 is designed such that it will closely match the angle of the integral connection 36. The lower rollers 16 will then hold the tubing 34 centrally within the elevator roller insert 30 and, in the same manner as the upper rollers 4, would allow the tubular 34 to rotate rather freely. Also the upper 26 and lower roller sets 28 (or combination roller sets 32 in some embodiments) are radially aligned in a manner that the minimum internal diameter 38 of the elevator roller insert 30 is less than the greatest outer diameter of the integral connection 36. The internal diameter 38 of the elevator roller insert 30 keeps the tubular 34 from slipping through the insert 30 and falling to the rig floor. Now referring to FIG. 6, a cross section is shown comprising of tubing 40 with an internally threaded sleeve 42 being held in place by the upper rollers 4 in a generally abutting relationship. Due to the weight bearing rotational capabilities of the upper roller 4, the tubing 40 will be allowed to rotate rather freely within the elevator roller insert 30. The lower rollers 16 will then hold the tubing 40 centrally within the elevator roller insert 30 and, in the same manner as the upper rollers 4, would allow the tubular 40 to rotate rather freely. Also the upper 26 and lower 28 roller sets (or combination roller sets 32 in some embodiments) are radially aligned in a manner that the minimum internal diameter 38 of the elevator roller insert 30 is less than the greatest outer diameter of the sleeve 42. The internal diameter 38 of the elevator roller insert 30 keeps the tubular 40 from slipping through the elevator roller insert 30 and falling to the rig floor. And now referring to FIGS. 7a and 7b, an elevator roller insert 30 is shown within a single joint elevator 44 in the closed and opened position respectively. The elevator roller insert 30 is generally segmented to allow the elevator be opened, to accept the tubular, and closed, to contain the tubular within the elevator. The invention has significant benefits across a broad spectrum of endeavors. It is the Applicant's intent that this specification and the claims appended hereto be accorded a breadth in keeping with the scope and spirit of the invention being disclosed despite what might appear to be limiting language imposed by the requirements of referring to the specific examples disclosed. The phrases “at least one”, “one or more”, and “and/or”, as used herein, are open-ended expressions that are both conjunctive and disjunctive in operation. For example, each of the expressions “at least one of A, B, and C”, “at least one of A, B, or C”, “one or more of A, B, and C”, “one or more of A, B, or C,” and “A, B, and/or C” means A alone, B alone, C alone, A and B together, A and C together, B and C together, or A, B, and C together. Unless otherwise indicated, all numbers expressing quantities, dimensions, conditions, and so forth used in the specification, drawings, and claims are to be understood as being modified in all instances by the term “about.” The term “a” or “an” entity, as used herein, refers to one or more of that entity. As such, the terms “a” (or “an”), “one or more” and “at least one” can be used interchangeably herein. The use of “including,” “comprising,” or “having,” and variations thereof, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. Accordingly, the terms “including,” “comprising,” or “having” and variations thereof can be used interchangeably herein. It shall be understood that the term “means” as used herein shall be given its broadest possible interpretation in accordance with 35 U.S.C. §112(f). Accordingly, a claim incorporating the term “means” shall cover all structures, materials, or acts set forth herein, and all of the equivalents thereof. Further, the structures, materials, or acts, and the equivalents thereof, shall include all those described in the summary of the invention, brief description of the drawings, detailed description, abstract, and claims themselves. The foregoing description of the invention has been presented for illustration and description purposes. However, the description is not intended to limit the invention to only the forms disclosed herein. In the foregoing Detailed Description for example, various features of the invention are grouped together in one or more embodiments for the purpose of streamlining the disclosure. This method of disclosure is not to be interpreted as reflecting an intention that the claimed invention requires more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive aspects lie in less than all features of a single foregoing disclosed embodiment. Thus, the following claims are hereby incorporated into this Detailed Description, with each claim standing on its own as a separate preferred embodiment of the invention. Consequently, variations and modifications commensurate with the above teachings and skill and knowledge of the relevant art are within the scope of the invention. The embodiments described herein above are further intended to explain best modes of practicing the invention and to enable others skilled in the art to utilize the invention in such a manner, or include other embodiments with various modifications as required by the particular application(s) or use(s) of the invention. Thus, it is intended that the claims be construed to include alternative embodiments to the extent permitted by the prior art.
<SOH> BACKGROUND AND SUMMARY OF THE INVENTION <EOH>In the oil and gas industry, wellbores are drilled into the earth using drilling rigs, where tubulars are threaded together to form long tubular strings that are inserted into the wellbore to extract the desired fluid. The tubing string is generally suspended in the borehole using a rig floor-mounted spider, such that each new tubular segment or stand may be threaded onto the end of the previous tubular just above the spider. A segment is generally considered one joint of tubing and a stand is generally considered to be two or three joints of tubing combined together. A single joint elevator is commonly used to grip and secure the segment or stand to a hoist to lift the segment or stand into position for threading the tubulars together. Sometimes compensators are used in combination with elevators to reduce the weight of the stand on the connection of the previous string. Once set into position the tubular is rotated with a power tong in the elevator or the entire elevator is allowed to rotate on a swivel with the tubular to allow the connections to be threaded. In general, single joint elevators are specifically adapted for securing and lifting tubular segments having a conventional connection, such as an internally threaded sleeve that receives and secures an externally threaded end from each of two tubular segments to secure the segments in a generally abutting relationship. The internally threaded sleeve is first threaded onto the end of a first tubular string to form a “box-end.” The externally threaded “pin end” of a second tubular string is then threaded into the box end to complete the connection between the two strings. These elevators have a circumferential shoulder that forms a circle upon closure of the hinged body halves. The shoulder of the elevator engages the shoulder formed between the end of the sleeve and the pipe segment. Other elevators are specifically adapted for securing and lifting tubular segments having integral connections. These integral connections are generally permanently fixed to each end of the tubular, one end having an internally threaded end or “box-end” and the other end having an externally threaded end or “pin-end”, in a generally abutting relationship. The externally threaded pin-end of the first tubular segment is then threaded into the internally threaded box-end of the tubular string. These elevators generally have a beveled or angled shoulder that forms a circle upon closure of the hinged body halves. The beveled shoulder engages the beveled end of the integral connection of the pipe segment. At least one challenge encountered by those in the industry is maintaining proper thread integrity of the connections while making up the stand to the string of tubulars. Generally, if the threads of the two connecting tubulars are not properly aligned when the rotation with power tongs begins, the threads of both connections will usually gall or be crushed to a state of non-compliance with industry standards. Typically these connections will have to be removed from the string and discarded or sent back to the manufacturer to be re-threaded. This removal of tubulars and connections from the string can be time consuming and very costly to the rig operator. Another such challenge to those in the industry is the ability to run segments or stands of very heavy weight tubing. Generally the face of the internally threaded sleeve of a conventional connection rests on the top of the elevator. If the weight of the tubing segment or stand is too great, the friction between the face of the sleeve and the shoulder of the elevator will cause the sleeve to “stick” and the sleeve will not rotate with the tubing. This eventually causes the sleeve to “back-off” or become disconnected from the tubing, possibly allowing the tubing segment or stand to fall to the rig floor. Yet another challenge is the safety issue that may arise when allowing the single joint to rotate on a swivel. The possibility exists that if the swivel, or the cable holding the swivel, becomes worn or fatigued to the point of failure, the elevator and the tubing would fall to the rig floor. Therefore, there is a need for an apparatus or system that allows the tubulars to rotate within the elevator with little required torque. This will allow the operator the ability to start the connection of the tubulars by hand with a strap wrench. Thus, the operator may determine whether or not the threads are aligned properly prior to connecting the power tongs and finishing the make-up of the connection. An objective of the invention is to provide a system comprising multiple rollers that may be seamlessly integrated into existing elevators which encompass inserts or dies to aid in the process of running tubulars. A further objective is to provide a means of allowing the tubulars to rotate within the elevator without the need for additional pneumatic or hydraulic control lines or actuation. A further objective is to provide a means to rotate a stand of multiple tubulars that would have been too heavy or unsafe to rotate using conventional methods. A further objective is to provide a means to run stands of two or three segments of heavy weight tubing instead of a single segment, significantly reducing the time required to run the tubing in the well. An apparatus of this nature may also significantly reduce the amount of loss time and money due to galled or destroyed connections. An apparatus of this nature may significantly reduce safety concerns by replacing the need to hang the elevator with cables and a swivel, and also to reduce the possibility of spinning off the upper collar holding the stand on the elevator. An apparatus of this nature may comprise rollers that encompass a shaft with an arrangement of radial and/or thrust bearings contained within a cylindrical hub. An apparatus of this nature may comprise rollers that encompass a single ball bearing fixed within a housing. An apparatus of this nature may typically have rollers that will be oriented vertically or at a specified angle from the vertical in combination with rollers that will be aligned with the vertical or horizontal. An apparatus of this nature may have interchangeable components that can be replaced in the field thus reducing downtime and ensure proper rotation of the tubular. These and other advantages will be apparent from the disclosure of the invention(s) contained herein. The above-described embodiments, objectives, and configurations are neither complete nor exhaustive. The Summary of the Invention is neither intended nor should it be construed as being representative of the full extent and scope of the invention. Moreover, references made herein to “the invention” or aspects thereof should be understood to mean certain embodiments of the invention and should not necessarily be construed as limiting all embodiments to a particular description. The invention is set forth in various levels of detail in the Summary of the Invention as well as in the attached drawings and Detailed Description and no limitation as to the scope of the invention is intended by either the inclusion or non-inclusion of elements, components, etc. in this Summary of the Invention. Additional aspects of the invention will become more readily apparent from the Detailed Description particularly when taken together with the drawings.
<SOH> BACKGROUND AND SUMMARY OF THE INVENTION <EOH>In the oil and gas industry, wellbores are drilled into the earth using drilling rigs, where tubulars are threaded together to form long tubular strings that are inserted into the wellbore to extract the desired fluid. The tubing string is generally suspended in the borehole using a rig floor-mounted spider, such that each new tubular segment or stand may be threaded onto the end of the previous tubular just above the spider. A segment is generally considered one joint of tubing and a stand is generally considered to be two or three joints of tubing combined together. A single joint elevator is commonly used to grip and secure the segment or stand to a hoist to lift the segment or stand into position for threading the tubulars together. Sometimes compensators are used in combination with elevators to reduce the weight of the stand on the connection of the previous string. Once set into position the tubular is rotated with a power tong in the elevator or the entire elevator is allowed to rotate on a swivel with the tubular to allow the connections to be threaded. In general, single joint elevators are specifically adapted for securing and lifting tubular segments having a conventional connection, such as an internally threaded sleeve that receives and secures an externally threaded end from each of two tubular segments to secure the segments in a generally abutting relationship. The internally threaded sleeve is first threaded onto the end of a first tubular string to form a “box-end.” The externally threaded “pin end” of a second tubular string is then threaded into the box end to complete the connection between the two strings. These elevators have a circumferential shoulder that forms a circle upon closure of the hinged body halves. The shoulder of the elevator engages the shoulder formed between the end of the sleeve and the pipe segment. Other elevators are specifically adapted for securing and lifting tubular segments having integral connections. These integral connections are generally permanently fixed to each end of the tubular, one end having an internally threaded end or “box-end” and the other end having an externally threaded end or “pin-end”, in a generally abutting relationship. The externally threaded pin-end of the first tubular segment is then threaded into the internally threaded box-end of the tubular string. These elevators generally have a beveled or angled shoulder that forms a circle upon closure of the hinged body halves. The beveled shoulder engages the beveled end of the integral connection of the pipe segment. At least one challenge encountered by those in the industry is maintaining proper thread integrity of the connections while making up the stand to the string of tubulars. Generally, if the threads of the two connecting tubulars are not properly aligned when the rotation with power tongs begins, the threads of both connections will usually gall or be crushed to a state of non-compliance with industry standards. Typically these connections will have to be removed from the string and discarded or sent back to the manufacturer to be re-threaded. This removal of tubulars and connections from the string can be time consuming and very costly to the rig operator. Another such challenge to those in the industry is the ability to run segments or stands of very heavy weight tubing. Generally the face of the internally threaded sleeve of a conventional connection rests on the top of the elevator. If the weight of the tubing segment or stand is too great, the friction between the face of the sleeve and the shoulder of the elevator will cause the sleeve to “stick” and the sleeve will not rotate with the tubing. This eventually causes the sleeve to “back-off” or become disconnected from the tubing, possibly allowing the tubing segment or stand to fall to the rig floor. Yet another challenge is the safety issue that may arise when allowing the single joint to rotate on a swivel. The possibility exists that if the swivel, or the cable holding the swivel, becomes worn or fatigued to the point of failure, the elevator and the tubing would fall to the rig floor. Therefore, there is a need for an apparatus or system that allows the tubulars to rotate within the elevator with little required torque. This will allow the operator the ability to start the connection of the tubulars by hand with a strap wrench. Thus, the operator may determine whether or not the threads are aligned properly prior to connecting the power tongs and finishing the make-up of the connection. An objective of the invention is to provide a system comprising multiple rollers that may be seamlessly integrated into existing elevators which encompass inserts or dies to aid in the process of running tubulars. A further objective is to provide a means of allowing the tubulars to rotate within the elevator without the need for additional pneumatic or hydraulic control lines or actuation. A further objective is to provide a means to rotate a stand of multiple tubulars that would have been too heavy or unsafe to rotate using conventional methods. A further objective is to provide a means to run stands of two or three segments of heavy weight tubing instead of a single segment, significantly reducing the time required to run the tubing in the well. An apparatus of this nature may also significantly reduce the amount of loss time and money due to galled or destroyed connections. An apparatus of this nature may significantly reduce safety concerns by replacing the need to hang the elevator with cables and a swivel, and also to reduce the possibility of spinning off the upper collar holding the stand on the elevator. An apparatus of this nature may comprise rollers that encompass a shaft with an arrangement of radial and/or thrust bearings contained within a cylindrical hub. An apparatus of this nature may comprise rollers that encompass a single ball bearing fixed within a housing. An apparatus of this nature may typically have rollers that will be oriented vertically or at a specified angle from the vertical in combination with rollers that will be aligned with the vertical or horizontal. An apparatus of this nature may have interchangeable components that can be replaced in the field thus reducing downtime and ensure proper rotation of the tubular. These and other advantages will be apparent from the disclosure of the invention(s) contained herein. The above-described embodiments, objectives, and configurations are neither complete nor exhaustive. The Summary of the Invention is neither intended nor should it be construed as being representative of the full extent and scope of the invention. Moreover, references made herein to “the invention” or aspects thereof should be understood to mean certain embodiments of the invention and should not necessarily be construed as limiting all embodiments to a particular description. The invention is set forth in various levels of detail in the Summary of the Invention as well as in the attached drawings and Detailed Description and no limitation as to the scope of the invention is intended by either the inclusion or non-inclusion of elements, components, etc. in this Summary of the Invention. Additional aspects of the invention will become more readily apparent from the Detailed Description particularly when taken together with the drawings.
E21B1906
20170817
20180605
20171130
59492.0
E21B1906
2
MALIKASIM, JONATHAN L
ELEVATOR ROLLER INSERT SYSTEM
SMALL
1
CONT-ACCEPTED
E21B
2,017
15,679,748
PENDING
SYSTEM AND METHOD FOR MANAGING GRATUITIES
A computer-implemented method for allocating gratuities is disclosed that includes employing at least one processor configured to execute computer-executable instructions stored in memory to perform the following acts: receiving transaction information from a point of sale, wherein the transaction information comprises at least gratuity data for each of a plurality of transactions during an accounting period; receiving employee information from the point of sale, wherein the employee information comprises at least hours worked for each of a plurality of employees during the accounting period; receiving gratuity distribution rules for allocating gratuities among at least a portion of the employees; and determining a gratuity allocation for each applicable employee of the plurality of employees based on at least the received transaction information, the received employee information, and the received gratuity distribution rules. Also disclosed is a computer-implemented system for managing gratuity allocations.
1-21. (canceled) 22. A computer-implemented system for managing gratuity allocations comprising: at least one processor coupled to at least one memory configured to execute the following computer-executable components stored in the at least one memory: a database configured to store transaction information and employee information, wherein the transaction information comprises at least gratuity data for each of a plurality of transactions during an accounting period, and wherein the employee information comprises at least hours worked for each of a plurality of employees during the accounting period; a configuration module configured to receive gratuity distribution rules for allocating gratuities among at least a portion of the employees; an allocation module configured to determine a gratuity allocation for each of the plurality of employees based at least on the transaction information, the employee information, and the distribution rules; and a reporting module configured to report the determined gratuity allocation for each of the plurality of employees. 23. The computer-implemented system for managing gratuity allocations of claim 22 further comprising: an interface component configured to receive the transaction information from the point of sale and to communicate the transaction information to the database to be stored. 24. The computer-implemented system for managing gratuity allocations of claim 22 further comprising: an interface component configured to receive the employee information from the point of sale and to communicate the employee information to the database to be stored. 25. The computer-implemented system for managing gratuity allocations of claim 22 further comprising: means for receiving transaction information from a point of sale and storing the received transaction information in the database. 26. The computer-implemented system for managing gratuity allocations of claim 22 further comprising: means for receiving employee information from a point of sale and storing the received employee information in the database. 27. The computer-implemented system for managing gratuity allocations of claim 22, wherein the reporting module further comprises: a web-portal configured to be accessed by employees, wherein the web-portal is configured to display the determined gratuity allocation for a given employee. 28. The computer-implemented system for managing gratuity allocations of claim 22, wherein the reporting module further comprises: a web-portal configured to be accessed by an employer, wherein the web-portal is configured to display the determined gratuity allocation for the plurality of employees. 29. The computer-implemented system for managing gratuity allocations of claim 22, wherein the reporting module is configured to communicate with an employer payroll system and to communicate the determined gratuity allocations to the employer payroll system.
RELATED APPLICATION This application is a continuation application of and claims priority to and the benefit of U.S. patent application Ser. No. 13/834,466, filed Mar. 15, 2013, now U.S. Pat. No. 9,741,050, and to U.S. Patent Application No. 61/696,569, filed Sep. 4, 2012, the disclosures of which are incorporated herein by reference in their entirety. BACKGROUND AND SUMMARY The present disclosure is related to a system and method for managing gratuities, and more particularly to calculating, allocating, and distributing gratuities among service employees. In the hospitality industry and many other service based businesses, it is customary for customers to give a gratuity or tip to one or more employees who perform the purchased service. Although a customer may primarily interact with one employee of the business, such as a waiter or waitress, many other employees have assisted to varying degrees in supporting the service provided to the customer. In a restaurant, for example, a host may seat the customer, a busser may clear the table, a food runner may deliver food to a table, a bartender may prepare and/or serve alcoholic beverages, and other employees may similarly provide specific services for the benefit of the customer during their dining experience. At the conclusion of a restaurant transaction, the customer generally gives a gratuity to the server or adds the gratuity to the amount paid for the meal. The gratuity may then be shared among the employees who assisted in providing service to the customer, or aggregated and distributed among the employees according to customs or practices of a given business or industry. The sharing of gratuities has often been manually calculated and documented with ad hoc record keeping, complicating compliance with tax and labor regulations. Even when properly computed, existing systems for gratuity sharing have not provided easy access to the gratuity sharing data. As such, there remains a need for systems and methods for managing gratuities that provide both employers and employees with accurate and timely allocations of gratuities in a cost-effective manner. Presently disclosed is a computer-implemented method for allocating gratuities that includes employing at least one processor configured to execute computer-executable instructions stored in memory to perform the following acts: receiving transaction information from a point of sale, wherein the transaction information comprises at least gratuity data for each of a plurality of transactions during an accounting period; receiving employee information from the point of sale, wherein the employee information comprises at least hours worked for each of a plurality of employees during the accounting period; receiving gratuity distribution rules for allocating gratuities among at least a portion of the employees; and determining a gratuity allocation for each applicable employee of the plurality of employees based on at least the received transaction information, the received employee information, and the received gratuity distribution rules. The method may also include allocating to each applicable employee the determined gratuity allocation for that employee. In embodiments, the transaction information is sales data for the plurality of transactions during the accounting period, and the transactions are service transactions provided by the plurality of employees. In an embodiment, at least one processor is remote from the point of sale and may be a cloud computing system. Receiving the transaction information and employee information for the accounting period may further include receiving a computer-readable file containing the transaction information and the employee information for the accounting period, and storing the received transaction information and the received employee information in a database, and may include receiving the computer readable file from the point of sale via the Internet. The method may also include determining a total gratuity amount for the accounting period from the transaction information, and determining the gratuity allocation for each of the plurality of employees based on the total gratuity amount for the accounting period. The method may also include classifying each of the plurality of employees to one of a plurality of gratuity groups based on a job function of the employee; and wherein determining the gratuity allocation for each employee further comprises: allocating gratuities to form a gratuity pool for each gratuity group based on the gratuity distribution rules and allocating the gratuity pool for each gratuity group between the employees of the gratuity group based on the distribution rules. Allocating the determined group gratuity between the employees of the group may also include determining a total of the hours worked by each employee of the group for the accounting period, and allocating a portion of the gratuity pool for the gratuity group to each employee of the group corresponding to a ratio of the hours worked by that employee to the total hours worked of the group. Allocating the determined group gratuity between the employees of the group may also include receiving an assigned gratuity factor for each of the plurality of employees, and allocating at least a portion of the gratuity pool for the gratuity group to each employee based upon the employee's assigned gratuity factor. Determining the gratuity allocation for each of the plurality of employees may further include determining a total of gratuities received by a first group of employees; and allocating a portion of the total of gratuities received by the first group of employees to a second group of employees based on the distribution rules. Determining the gratuity allocation for each of the plurality of employees may further include determining total cash sales during the accounting period from the transaction information, determining a total cash gratuity from the total cash sales, and allocating the total cash gratuity to the plurality of employees based on the distribution rules. The method for allocating gratuities may also include communicating the determined gratuity allocation for each employee to an employer payroll system and distributing the determined gratuity allocation to each employee through a payroll check. The method may also include providing a web-portal configured to be accessed by employees, wherein the web-portal is configured to display the determined gratuity allocation for a given employee, and providing a web-portal configured to be accessed by an employer, wherein the web-portal is configured to display the determined gratuity allocation for the plurality of employees. The method may also include, upon determining the gratuity allocation for a given employee, notifying the employee via at least one of a text message, an email, or an instant message of the determined gratuity allocation. In embodiments, the method is used for each of a plurality of employers and gratuity distribution rules may be received from each of the plurality of employers, with the gratuity distribution rules received from one employer being different than the gratuity distribution rules received from at least one other employer. Also disclosed is a computer-implemented system for managing gratuity allocations that includes at least one processor coupled to at least one memory configured to execute the following computer-executable components stored in the at least one memory: a database configured to store transaction information and employee information, wherein the transaction information comprises gratuity data for each of a plurality of transactions during an accounting period, and wherein the employee information comprises at least hours worked for each of a plurality of employees during the accounting period; a configuration module configured to receive gratuity distribution rules for allocating gratuities among at least a portion of the employees; a processor configured to determine a gratuity allocation for each of the plurality of employees based at least on the transaction information, the employee information, and the distribution rules; and a reporting module configured to report the determined gratuity allocation for each of the plurality of employees. In embodiments, the system for managing gratuities also includes an interface component configured to receive the transaction information from the point of sale and to communicate the transaction information to the database to be stored, and configured to receive the employee information from the point of sale and to communicate the employee information to the database to be stored. The system may also include means for receiving transaction information from a point of sale and storing the received transaction information in the database, and means for receiving employee information from a point of sale and storing the received employee information in the database. In some embodiments, the reporting module may include web-portal configured to be accessed by employees, wherein the web-portal is configured to display the determined gratuity allocation for a given employee, and a web-portal configured to be accessed by an employer, wherein the web-portal is configured to display the determined gratuity allocation for the plurality of employees. In another embodiment, the reporting module is configured to communicate with an employer payroll system and to communicate the determined gratuity allocations to the employer payroll system. BRIEF DESCRIPTION OF THE DRAWINGS Reference is made to the accompanying drawings in which particular embodiments of the invention are illustrated as described in more detail in the description below, in which: FIG. 1 is a schematic view of a gratuity management system; FIG. 2A is another schematic view of a gratuity management system; FIG. 2B is another schematic view of a gratuity management system; FIG. 3 is a graphic illustration of a exemplary distribution rules; FIG. 4 is a flow diagram illustrating application of the gratuity management system; FIG. 5 is a first screen of an exemplary configuration module; FIG. 6 is a second screen of an exemplary configuration module; FIG. 7 is a third screen of an exemplary configuration module; FIG. 8 is a first screen of an exemplary employer web-portal; and FIG. 9 is a second screen of an exemplary employer web-portal. DETAILED DESCRIPTION OF THE DRAWINGS Embodiments of the presently disclosed system and method relate to the management of gratuities. Referring generally to FIGS. 1 through 3, embodiments of the system and method for managing gratuities are illustrated. For purposes of illustration, the system and method may be described with reference to a restaurant setting. The system and method may be applied in other settings, such as hotels, casinos or other organizations in the hospitality or other industries that receive and distribute gratuities among at least a portion of the employees. Referring now to FIG. 1, a system 100 for managing gratuities is illustrated. In an embodiment the gratuity management system 100 includes a processor 102 and a database 104. The system 100 communicates with systems to receive transaction information and employee information for managing gratuities. By way of illustration, the system 100 may receive transaction information from a point of sale system 110. The point of sale system 110 may provide a record of sales transactions. Each transaction information associated with the sales records may include the type of transaction (e.g., cash or credit card), the amount of the transaction, and the amount of a gratuity associated with the transaction. The transaction information may also include the employee who processed the transaction (e.g., a server or bartender) as well as the date and time of the transaction. Other information, such as credit card processing fees or items purchased, may be include in the transaction information as desired. The gratuity management system 100 may receive employee information from an employee records system 112. The employee information may include biographic information about each employee such as a job title or code (e.g. server, host, busser) that may be used to determine how the employee participates in the gratuity system. The employee information may also include work record data, such as the hours for each employee. The employee records system 112 may be a time keeping system used to track the hours worked by employee. In some embodiments, the employee records system 112 and the point of sale system 110 may be components of a management system used for administering the service business. In embodiments, the point of sale system 110 and the employee records system 112 may be discrete systems in communication with the presently disclosed system for managing gratuities. In other embodiments, the point of sale system 110, the employee records system 112, and perhaps other systems are integrated into a restaurant management system 108. As such, the gratuity management system 100 may interface with one or more components of such a restaurant management system 108 to acquire the necessary transaction and employee information. In the restaurant context, a combined point of sale system 110 and employee records system 112 may assign each employee a unique user identification number, which may be used both for logging that employee's working hours (e.g. a time-clock application) as well as recording transactions (e.g. customer orders) entered and completed by the employee. In some embodiments, the point of sale system 110 and/or the employee records system 112 may be implemented in cloud computing systems reducing the burden on businesses to host these systems using local computing resources. The gratuity management system 100 may similarly be implemented in a cloud computing system that interfaced with the cloud-based point of sale and/or employee records systems. A business or other user of the gratuity management system may therefore select computing resources to implement various elements of the systems, and the gratuity management system presently disclosed is contemplated to operate in conjunction with both local and cloud-based point of sale and/or employee records systems. The management of gratuities for a given business or organization may be defined by the customs and practices of the business as well as applicable regulations. To account for the variation in gratuity management practices, the gratuity management system 100 receives gratuity distribution rules, such as from a client (e.g. a restaurant), that are used to determine the allocation of gratuities for the client's business. In one embodiment, the gratuity management system 100 includes a configuration module 106 that may be used to establish the distribution rules to be applied by the system as described in more detail below. The gratuity management system 100 receives the transaction information, employee information, and distribution rules as noted above. Using this information, the system 100 determines a gratuity allocation for each employee who should receive a portion of the gratuities collected. For purposes of this disclosure, employees may be generally characterized as a gratuity-generating employee, a gratuity-receiving employee, or a non-participating employee. A gratuity-generating employee may be defined as an employee who receives a gratuity from a customer. Servers, bartenders and valets are common examples of gratuity-generating employees. A gratuity-receiving employee is defined as an employee who is allocated at least a portion of a gratuity received by a gratuity generating employee. Hosts, bussers and barbacks are common examples of gratuity-receiving employees. Servers, bartenders and valets are also gratuity-receiving employees, as such, any given employee may be both gratuity-generating and gratuity-receiving, depending upon the service provided and the nature of the business. In addition, a business may have non-participating employees who neither receive nor benefit from gratuities. Such non-participating employees may include kitchen or cleaning staff and employees in management level positions. The customs and practices of a given business or industry, as well as, applicable labor regulations may determine whether a given individual is eligible to participate in the distribution of gratuities. The gratuity management system 100 determines how to allocate the gratuities collected by or on behalf of the gratuity-generating employees among the gratuity-receiving employees based upon the transaction information, employee information, and distribution rules for the given business. The determined gratuity allocation for each employee represents the amount of gratuity to be allocated to that employee based on the transaction information, employee information, and distribution rules discussed above. Gratuity allocations may be performed on a periodic basis, referred to herein as the accounting period. Some businesses may allocate gratuities for each shift, each day or each week. Gratuities are typically allocated at least as frequently as the payroll period for the business so that gratuities may be distributed in the employees' paychecks. In one embodiment, the gratuity management system 100 is configured to allow an employer to “cash-out” one or more employees at the end of an employee's shift so that the gratuity allocation may be determined and the gratuity distributed to the employee. In this embodiment, the gratuity management system 100 may rely on transaction and employee information already received to determine the cashed-out employee's allocation. If additional transaction information or employee information is received that would affect the allocation to the cashed-out employee, the gratuity management system 100 may recalculate the gratuity for the previously cashed-out employee and apply any adjustment or correction to a future gratuity or payroll distribution to ensure the proper distribution of income to that employee. The employer is therefore able to determine and distribute gratuity allocations in real-time or near real-time benefiting the employees and reducing the burden on the employers. After the conclusion of an accounting period, the gratuity allocation for each employee may be determined. The gratuity management system 100 may then communicate with a business records system 116 that may include a payroll component 118. The business records system 116 is configured to receive the determine gratuity allocations for use in distributing the gratuity payments to employees. In some instances, the business records system 116 may determine that an employee has received an insufficient allocation of gratuities to comply with applicable regulations and an adjustment may be made to that employee's pay to compensate for the shortfall in gratuities received. Embodiments of the system 100 may interface directly with a payroll component 118. For example, the system 100 may communicate with a payroll system so that the determined gratuity allocation is added to the employee's next paycheck. In some embodiments, the payroll component 118 of the business records system 116 may be a third-party payroll management system, however, the gratuity management system 100 may be configured to communicate with a third-party system in the same manner as described above. In a similar manner, the gratuity management system 100 may generate a report of employee's gratuity income, where the report is configured for submission to the Internal Revenue Service and/or state or local tax authorities for purposes of reporting gratuity income. In some embodiments, the business records system 116 and/or payroll component 118 may be integrated with the point of sale system 110 and the employee records system 112, all as part of an integrated restaurant management system 108. In other embodiments, one or more of the business records system 116 and/or the payroll component 118 may be separate systems. In one example, the payroll component 118 may be a third-party payroll service selected by the restaurant to process payroll for its employees, and the gratuity management system 100 may communicate directly with the payroll processor to distribute gratuities to the employees. The gratuity management system 100 may also allow for employees and employers to access relevant portions of the data stored in the system. In one embodiment, the system 100 includes a web-portal 120. The web-portal 120 may be configured to allow employees access to their own determined gratuity allocation so that the employee may view their accumulated gratuities following an accounting period. The system 100 may also be configured to notify an employee of the employee's gratuity allocation through a text message, an email, an instant message or other similar notifications. In other embodiments, the system 100 may be configured to post the gratuity allocation for an employee to the employee's web-based social network profile where the employee may access the information. Employee access to the gratuity allocation data may be limited through the use of usernames and passwords such that each employee may access only the gratuity information relative to that employee. The system 100 may also permit an employee to view the data from which the gratuity allocation was determined, such as the employee's hours worked or total gratuities received that employee. In some embodiments, a fee may be assessed for the employee's use of the system, which may be deducted from the gratuities otherwise allocated to the employee. Other information may be made accessible as appropriate for the employee and the business involved. The web-portal 120 may also provide for access by an employer, such as the manager or owner of the business. Through the portal, the employer may access information on all employees and the data from which the gratuity allocations were made. The system 100 may also include a reporting module configured to report the determined gratuity allocation for each of the plurality of employees. The reporting module may also be configured to provide other management reports. In one embodiment, the system 100 generates a report of total gratuities allocated to each employee during a payroll period to assist in documenting compliance with minimum wage regulations and income tax withholding requirements. The system 100 may also include non-web based means for accessing the data and may generate notifications or alerts to assist an employer in managing the business. In this manner, the gratuity management system 100 may substantially streamline the process of calculating and distribution gratuities, while also generating timely and accurate business compliance records. The gratuity management system 100 may store the gratuity data, as well as the transaction information and employee information from which the gratuity allocations were produced. The information stored and the duration of that storage may be selected based upon the requirements of the business and regulatory or tax requirements. In one embodiment, the gratuity data is retained for at least six years. Employees may retain access to the gratuity data for the required duration even after termination of their employment. In this manner, the gratuity management system allows a business, such as a restaurant, to ensure that gratuity data will be available to both current and former employees without requiring the former employees to contact the business directly. Referring now to FIG. 2A, a logical view of a gratuity management system is illustrated. A client, such as a restaurant, may have a server 200 and a database 202 for storing transaction information and employee information, as well as a back office accounting management system 204 that handles accounting and payroll functions. In embodiments, the gratuity management system includes an interface component 206 that integrates with the business's systems to extract the transaction information and employee information to be used in determining the gratuity allocations. In an embodiment, the interface component 206 extracts transaction and employee information and creates a computer-readable file containing at least a portion of the transaction information and the employee information for use by the gratuity management system. The computer-readable file is communicated to the database 214 and stored for use by the processor 212 in determining the gratuity allocations for each of the employees. The computer-readable file may be an XML, file containing transaction information and the employee information in a standardized format for communication to the database. Other file formats may be used, such as text or database files, and may include proprietary or standardized file formats. In this manner, the interface component 206 may be adapted to interface with a variety of client systems of different types without requiring modification to the database or processor. In yet other embodiments, the interface component 206 gather configuration and setting information from rest of the gratuity management system on a periodic basis. In one embodiment, the interface component 206 initiates all communication with other components of the gratuity management system improving the security of the system. In other embodiments, one or more of the business's systems and the gratuity management system may be cloud-based, and the communication between the gratuity management system and cloud-based business system may be through dedicated interfaces. In such embodiments, the interface component 206 may include an application programming interface defined and implemented so that the gratuity management system is able to extract the necessary transaction information and employee information from the cloud-based business systems. In one embodiment, the processor 212 and the database 214 are provided in a cloud computing system 210 accessible over the Internet 208. The processor 212 and/or the database 214 may accept incoming data from the interface component 206. The incoming data may be preprocessed and/or stored in the database 214 for further subsequent use. The system may then provide access to the determined gratuity allocations through an employee interface 216, that may include a web-portal, text message, email, instant message, or posting on social media website. The system may also provide an employer interface 218, such as the web-portal for employer use described in FIG. 1. The employer interfaced 218 may also provide access to the configurations module (shown in FIG. 1) for establishing the distribution rules and configuration the gratuity management system for a given business or organization. Depending upon the level of security required, the employer interface 218 may also communicate with the back office accounting management system 204, which may include business records and a payroll system for distributing the allocated gratuities to the employees. In this manner, the interface module enables the system to automatically gather the transaction information and employee information, and communicate the determined gratuity allocations back to the client's systems. As illustrated in FIG. 2A, the processor 212 is remote from the client's point of sale. In this manner, the processor 212 may service multiple points of sale for a client as well as multiple clients. In yet other embodiments, the point of sale system may be implemented in a cloud computing system, and the gratuity management system 100 interfaces with the cloud-based point of sale system using a cloud to cloud replication or synchronization. In a cloud to cloud system, the interface component 206 still facilitates transfer of the data from the point of sale system to the gratuity management system for use in determining the gratuity allocations. Referring to FIG. 2B, in another embodiment, the gratuity management system may be implemented to operate locally on a client's computing system, where the client server 200 and database 202 may provide the processor and database for the gratuity management system. This configuration may be particularly effective for cruise ships or other environments with limited connectivity to external computing resources. The gratuity management system may also be integrated into a restaurant management system, such as the restaurant management system 108 that includes a point of sale system and an employee records system. By way of illustration, the operator of a cruise ship may prefer to host the gratuity management system using onboard computing systems to reduce the need for communication to or from the cruise ship while the ship is at sea. Other businesses may also prefer locally implemented systems due to connection limitations, security concerns, or preferences regarding the business's information technology infrastructure. Regardless of the particular implementation selected, the gratuity management system provides a valuable service to the employees of the business by providing accurate and timely determinations of gratuity allocations. The operation of the gratuity management system may be further illustrated through selected examples. By way of example, a business may elect to organize its gratuity-receiving employees into groups. As used herein, a “group” represents a set of employees who are given similar treatment for the purpose of determining gratuity allocations. A group may have one or more employees (i.e. members). An employee may belong to a different group depending upon the function the employee is performing during an accounting period. For example, an employee may work as a server during one shift, and work as a bartender during a different shift. In one example, a business may define five groups using the configuration module of the system, with the five groups being: servers, bartenders, food runners/bussers/barbacks, sommelier/stewarts/captains, and hosts. Each gratuity group may be associated with a gratuity pool. As used herein a gratuity “pool” represents an aggregation of gratuities to be distributed to the employees of the group associated with the pool. For example, a portion of the gratuities generated by servers and bartenders may be allocated to a host pool, and the total gratuities in the hosts pool may be distributed among the members of the hosts group for a given accounting period. In one example, the gratuity management system determines from the transaction information the total cash sales during an accounting period. The system may receive the total cash sales as part of the transaction information communicated to the system, or alternatively, the system may determine the total cash sales from individual transaction data contained in the transaction information. The system then determines a total cash gratuity amount from the total cash sales by applying a distribution rule. In one example, the system receives a distribution rule specifying that eight percent (8%) of total cash sales are to be deemed as cash gratuities. In other examples, the system may determine an average gratuity percentage for all credit card transactions in the accounting period, and that average gratuity percentage may be applied to the total cash sales to determine the total cash gratuity. The total cash gratuity may then be allocated to one or more employees or one or more gratuity pools to be distributed among the employees in accordance with the distribution rules. In another example, the gratuity management system determines a total cash gratuity amount, at least in part, from declared cash gratuities received from the employees and uses the declared cash gratuities to determine a gratuity allocation for each employee. Some businesses require gratuity generating employees to report, or declare, the total amount of cash gratuities received by the employee during a given accounting period. This declared cash gratuity is often recorded along with the transaction information or employee information discussed above. Because a declared cash gratuity is associated with a particular employee, the gratuity management system may apply the appropriate distribution rules to that cash gratuity. In addition, the gratuity management system may treat the declared cash gratuity as money received by the employee, and deduct the amount of the declared cash gratuity from the total gratuity allocated for that employee when distributing the allocated gratuities to the employees. If the declared cash gratuity exceeds the total gratuity allocated to an employee, the employer may require the employee to turn over a portion of the cash gratuity or otherwise offset the employee's compensation to achieve the appropriate gratuity allocation. In other embodiments, a business may impose an imputed cash gratuity distribution rule. An imputed cash gratuity is the minimum amount of cash gratuity deemed to have been received based on the total cash sales by a particular employee. An imputed cash gratuity may be used in lieu of or in addition to declared cash gratuities. For example, a business may establish a distribution rule that requires employees to declare cash gratuities but that imposes an imputed cash gratuity if the declared cash gratuities are less than a value established by government regulation (e.g. 8%). Alternatively, the minimum value for imputed cash gratuity may be established by the customs of a given business or industry, or may be agreed to by a service employees union. The imputed cash gratuity is used to determine an employee's required contributions or tip-outs to other employees or pools. In addition, the imputed cash gratuity may be deducted from the total gratuity amount due to a given employee based upon the assumption that the employee received at least that amount in cash gratuities. The application of imputed cash gratuities may result in a negative gratuity allocation for a given employee, which indicates that the employee has retained a portion of the total gratuity that should be distributed to other employees. A business may elect to require the employee to contribute the deficiency to the employer for redistribution, or alternatively, the gratuity management system may carry the deficiency forward to the next accounting period to offset future gratuity allocations to the employee. In this manner, the gratuity management system may be used to promote accurate reporting of cash gratuities resulting in improvements in the equitable distribution of gratuities among employees, and improvements in account and tax records for the business. In another example, the gratuity management system determines a total gratuity amount for the accounting period from the transaction information and determines the gratuity allocation for each of the plurality of employees based on the total gratuity amount for the accounting period. A distribution rule may specify that gratuities are to be allocated based on the hours worked by each employee relative to the total hours worked by all gratuity-receiving employees in the accounting period. In yet another example, the gratuity management system receives a classification of the plurality of employees into one of a plurality of groups based on the job function of the employee. The classification may be received with the employee information or with the distribution rules, but in either case, the classification identifies which group, if any, each employee belongs to for purposes of allocating gratuities. After defining the groups, the system may allocate the received gratuities to form a gratuity pool for each gratuity group based on the gratuity distribution rules and then allocate the gratuity pool for each gratuity group between the employees of the gratuity group based on the distribution rules. By way of illustration, in a restaurant having two groups, servers and bussers, the gratuities received by the servers may be allocated 75% to a servers pool and 25% to a bussers pool. The servers pool may then be allocated to the employees in the server group based on the percentage of total gratuities generated by each employee in the server group. In contrast, the bussers pool may be allocated to the employees in the bussers group based on the number of hours worked by a given busser divided by the total hours worked by all bussers in the bussers group during the accounting period. In this manner, separate distribution rules may be defined for the allocation of each gratuity pool. In another example, the gratuity management system allows the portion of the total gratuities received by a first group of employees to be allocated to a second group of employees based on the number of members in the second group of employees. By way of illustration, the portion of the gratuities received by the servers group may be allocated to the bussers group based on the number of members in the bussers group. The bussers may receive an allocation of 15% if there are greater than or equal to five (5) bussers working during a given shift. If fewer bussers are working, the allocation may be reduced to account for the increased burden on the servers due to the lack of support from the bussers. For example, if only four (4) or only three (3) bussers work during a shift, the allocation may be reduced to 12% or 9% respectively. The specific numbers and percentage may be specified in the distribution rules, and the number of employees may be determined based on hours worked during the given period. In this manner, gratuity management system implements a dynamic tip-out system, where the percentage allocated to a group is determined at least in part by the number of members in that group according to the contribution made by that group to providing the service to the customers. In another example, determining the gratuity allocation for each of the plurality of employees may include allocating a fixed amount of the gratuities received by a member of a first group to a second group of employees provided that the gratuities received by the member of the first group are greater than or equal to a threshold. By way of illustration, a restaurant may have a gratuity distribution rule that requires each server to contribute a fixed amount to a host pool. The host pool may then be allocated among the one or more hosts who participate in the host pool. In this manner, the gratuity allocation to the host pool is not determined as a percentage of sales but as a fixed amount contributed by each server. A restaurant may further define the distribution rule such that a server is only required to contribute the fixed amount if that server receives total gratuities greater than or each to a defined threshold. This may result in a distribution rule that requires a server to contribute $10.00 the host pool, but only if that server received at least $50.00 in gratuities during the shift. The distribution rules may also define other variations and permutations such as modifying the fixed contribution, or providing both fixed and percentage contributions as may be appropriate for the specific business. In this manner, the gratuity management system is able to efficiently implement a wide variety of economic arrangements that may be desired by businesses that engage in the allocation of gratuities among various groups of employees. In yet another example, the gratuity management system receives a gratuity factor for each employee, or each employee in a gratuity group. The system then allocates at least a portion of the gratuity pool for a given gratuity group to the employees of that group based on the gratuity factor for each employee. The gratuity factor may correspond to an assessment of the employee's skill level in a particular job function. Alternatively, the gratuity factor may correspond to the employee's seniority with the business. The gratuity factor may be used alone or in combination with other factors, such as hours worked or percent of gratuities generated to determine the allocation for a given employee. In one example, an employee who worked 8 hours out of total of 80 hours may receive an allocation of 10% of the gratuities for a given gratuity pool. If, however, that employee was a senior employee with responsibility for training new employees, the senior employee may be assigned a gratuity factor of 1.5 such that the senior employee receives 50% more credit for hours worked. As a result, the senior employee would be deemed to have worked 12 hours out of a total of 84 hours resulting in an allocation of 14.3% of the gratuities for a given gratuity pool. In this manner, the gratuity factor may be used to adjust the allocation of gratuities to reward seniority, skill, or special assignments such as training, as may be appropriate for certain businesses. In another example, two employees benefit from a gratuity pool containing $500. Employee #1 worked eight hours and twenty-two minutes, and is assigned a gratuity factor of 2. Employee #2 worked six hours and fifteen minutes, and is assigned a gratuity factor of 3. For each employee, a weighted time worked is calculated by multiplying the actual time worked by the gratuity factor resulting in weighted time worked for 964 minutes for Employee #1 and 1125 minutes for Employee #2. Each employee is then allocated a percentage of the gratuity pool based on the weighted time worked for that employee divided by the total weighted time worked by both employees in this example. As noted above, the gratuity factor to be may be based on one or more criteria, such as seniority, job responsibilities or others that may be determined by a given business as relevant to the allocation of gratuities within a given pool. This example is summarized in the following table. Employee #1 Employee #2 Time Worked (t) 8 hr. 22 min. 6 hr. 15 min. Gratuity Factor (f) 2 3 Weighted Time Worked = 964 min. 1125 min. (t*f) Total Weighted Time 2089 min. Worked (T) Percent of Gratuity Pool 46.15% 53.85% Allocated = ((t*f)/T) Allocated Gratuity $230.73 $269.27 In yet another example, the gratuity factor may be determined from a job code, such that the gratuity allocation favors certain job codes over others. The gratuity factor may be communicated to the system with the employee data or the distribution rules. In yet another example, the gratuity management system determines a gratuity allocation based upon total sales by a given employee. As with hours worked or gratuities generated, the gratuity management system may determine the total sales attributable to an employee and allocate at least a portion of the received gratuities to that employee based on the total sales by that employee. By way of illustration, servers are typically responsible for food sales. A portion of the gratuities generated by a servers group may be allocated to the servers pool according to a distribution rule based upon the food sales generated by each server. The percent of total food sales by each server in the servers group is calculated, and the servers pool may be distributed to each server based upon their respective percentage of total food sales. In various embodiments, distribution rules based on various sales may be used, such as beverage, wine or liquor sales. In yet other embodiments, sales of products or novelty items may be factored into the distribution of gratuities. Moreover, either net sales or gross sales, or a custom definition of sales, may be used in the computation of the gratuity allocation for each employee. In yet another example, the gratuity management system receives a classification of one or more employees as part of a team. As used herein, a “team” represents a set of employees who work together and are treated as single unit for purposes of allocating gratuities. In one example, multiple servers handing a large party or banquet may be grouped as a team. A team may be a member of a gratuity group and may benefit from a gratuity pool just as an individual employee would as previously described. Within a team, however, gratuities may be allocated uniformly to all members. As with groups, teams may be configured and reconfigured through the configurations module of the gratuity management system as employees are assigned and reassigned to different roles. In yet another example, a restaurant may organize its employees into a servers group that generates gratuities and a non-servers group that does not generate gratuities. The restaurant may establish a distribution rule that each server retains a certain percentage, such as 75%, of the total gratuities generated by that individual server, with the remainder (i.e. 25%) of the generated gratuity being transferred to a pool to be allocated among the members of the non-servers group. The non-server pool may then be allocated to the non-server employees based on another distribution rule. For example, the non-servers pool may be allocated according to the number of hours worked by each employee in the group relative to the total number of hours worked by all employees in the group. In various embodiments, the gratuity management system implements one or more of the distribution rules described above to determine the allocation of gratuities among the gratuity-receiving employees of the business. The interaction of example distribution rules may be illustrated through an example of a restaurant that uses a point of sale system that tracks credit card transactions by server or bartender, but that is unable to track cash sales by server or bartender. The restaurant classifies its gratuity-receiving employees into five groups, namely, servers, bartenders, food runners/bussers/barbacks, sommelier/stewarts/captains, and hosts. Using the configuration module, the restaurant establishes a set of distribution rules as explained below. For purposes of illustration, one possible set of distribution rules is depicted in FIG. 3 to illustrate the operation of the gratuity management system. For all credit card originating gratuities received by a member of the server group, the generated gratuities are allocated 75% to the individual server (illustrated by line 300), 15% to the food runner/busser/barback pool (line 302), 5% to the bartender pool (line 304), 2.5% to the sommelier/stewarts/captains pool (line 306) and 2.5% to the host pool (308). For all credit card originating gratuities received by a member of the bartenders group, the generated gratuities are allocated 90% to the bartenders pool (line 310) and 10% to the food runner/busser/barback pool (312). Based upon the restaurant's operating procedures, no other groups are expected to be allowed to receive gratuities from customers. For cash sales, the restaurant establishes a distribution rule that 15% of the total cash sales by members of the servers group are deemed to be generated gratuities by the servers group. The servers cash gratuities are distributed in the same percentages as credit card gratuities, however, the 75% of cash gratuities are allocated to a servers pool rather than to the individual server as the transaction data does not identify the server for individual cash transactions (line 314). Similarly, the restaurant establishes a distribution rule that 15% of the total cash sales by members of the bartenders group are deemed to be generated gratuities by the bartenders group and are distributed in the same percentages as credit card gratuities. After the completion of an accounting period, the interfaced component extracts the transaction information, which includes at least the cash sale data, credit card sale data, and gratuity data, as well as, the employee information that includes at least hours worked and group classification for each employee. The system then determines a gratuity allocation for each employee by applying the distribution rules (such as those illustrated in FIG. 3) to the transaction information and the employee information. The host pool is allocated to each member of the host group based upon the number of hours worked by a given host compared to the total number of hours worked by all hosts in the group. The food runner/busser/barback pool is allocated to each member of the pool based on hours worked with a gratuity factor applied that rewards those senior bussers who were assigned a trainee during their shift. The sommeliers/stewards/captains pool is allocated to each member of the pool based on the hours worked by each member of the group during the accounting period. The bartenders pool is allocated to each bartender based on the percent of hours worked by each bartender without consideration of a gratuity factor. Finally, each member of the server group is allocated the portion of the credit card gratuities generated by that server. Each member of the server group is also allocated a portion of the server pool, which includes a portion of the calculated cash gratuities, according to the total hours worked by the given server compared to the total number of hours worked by all servers in the group during the accounting period. In other embodiments, the gratuity allocations may be determined by other distribution rules based on any of the factors discussed above, such as hours, sales, gratuity factors based on skills, points, or other metrics deemed important for a given business. Once the gratuity allocations have been determined for each employee, the system communicates the determined gratuity allocations to a business records system to be distributed to the employees, such as in the next scheduled payroll. The system also makes the determined gratuity allocations available for the employees and employer to review so that all interested parties can review the gratuity allocations. For ease of illustration, the gratuity allocation process has been illustrated with a limited number of employees, groups, and distribution rules. As the number of employees, groups, and distribution rules increase, the gratuity allocation process may become exponentially more complex. The presently disclosed system, however, extracts the necessary information, determines the gratuity allocations according to customizable distribution rules that may be specified by an employer, and provides the determined gratuity allocation for distribution and reporting. In this manner, the system substantially reduces the time and expense associated with managing gratuities and improves the accuracy of record keeping systems. Referring now to FIG. 4, another illustration of the gratuity management process is provided. As illustrated in FIG. 4, as a first step 402, the employees are assigned to groups and the characteristics of each group are defined, such as by using the configuration module previously discussed. As shown, each employee is categorized into one of seven groups: server, bartender, bar manager, busser, bar backs, hosts, or wine steward. Each group may be further classified regarding whether the group generates sales, tips or both. Each group may also be configured with regard to how the group members contribute to or benefit from a gratuity pool. The configuration of employees, groups and the relationships between them form at least a portion of the distribution rules defined by the employer for a given business. In step 404, the business conducts operations during an accounting period generating transaction information and employee information. As shown, employees clock in and later clock out. This time entry may be through a restaurant management system that includes both a point of sale system and an employee records system as previously discussed. In one embodiment, an employee is limited to belonging to one group for the duration of an accounting period. In other embodiments, however, an employee may be classified into more than one group, such as when an employee is working in different roles during a single accounting period. If an employee is assigned to more than one group, the gratuity allocation may be performed for each role in which the employee worked. At the end of a given accounting period, a report may be generated that includes that transaction information and the employee information. In step 406, the transaction information and employee information is compiled, for example, by the integration component. The transaction information and employee information may then be communicated as needed to the processor and database for use in determining the gratuity allocations. In step 408, the gratuity management system applies the distribution rules to the transaction information and the employee information to determine the gratuity allocation for each employee. This may include determining the total of gratuities charged to credit cards and the total of cash sales. From the total of cash sales, a total cash gratuity may be determined by applying a percentage specified in a distribution rule. The gratuities may then be distributed among the employees, either directly or through groups and pools as specified by the distribution rules. For those employees whose gratuity allocation is determined by hours worked, a gratuity factor, or sales, the appropriate computations may be performed to determine the allocation for the given employee. Finally, in step 410, the determined gratuity allocations may be stored in the database and/or communicated to a business records system, payroll component, or otherwise reported for use by the business. The determined gratuity allocations may also be accessed through a web-portal by the employer and/or employee to facilitate access to the data. The distribution rules received by the gratuity management system are used to determine the gratuity allocation for a given employee. In one embodiment, the gratuity management system determines the gratuity allocation for a given employee by constructing a formula based upon the distribution rules, and then applying the formula to the transaction information and employee information received. By way of illustration, the gratuity management system may define the following variables, which are calculated or provided as described below: Ett—Total tips generated by Employee Ecct—Total credit card tips generated by Employee Ect—Total cash tips generated by Employee Ecs—Total cash sales generated by Employee Ets—Total Sales (net sale before taxes) generated by Employee Etfs—Total Food Sales (net Food Sale only and before taxes) generated by Employee Etbs—total Beverage Sales (net Beverage Sale only and before taxes) generated by Employee Etws—total Wine Sales (net Wine Sales only and before Taxes) αcs—Percent to take from total Cash Sales (αcs: 0-100, but normally it is 15) αts—Percent to take from total Sales (αts: 0-100) αtfs—Percent to take from total Food Sales (αtfs: 0-100) αtbs—Percent to take from total Beverage Sales (αtbs: 0-100) αtws—Percent to take from total Beverage Sales (αtws: 0-100) PG—Pool group with Employees. One pool group can contain Employees with various Job Codes. PGtime—Total work time of all Employees within Pool group. Ttime—Total team time. JC—Job Codes p—Percent represented as number divided by 100 (e.g. p=15%=15/100=0.15) Using these defined variables, the total tips generated by an employee may be computed using one or more of several methods. In one embodiment, total tips generated by an employee is determined from total credit card tips and a percentage of cash sales: Ett = Ecct + α cs * Ecs 100 = Ecct + Ect In another embodiment, total tips generated by the employee may be determined as a percent of total sales: Ett = α ts * Ets 100 In yet another embodiment, total tips generated by the employee may be determined as a percent of total food sales: Ett = α tfs * Etfs 100 In yet another embodiment, total tips generated by the employee may be determined as a percent of total beverage sales: Ett = α tbs * Etbs 100 In yet another embodiment, total tips generated by the employee may be determined as a percent of total wine sales: Ett = α tws * Etws 100 As will be appreciated, the total tips generated by the employee may be defined in multiple ways, and may include combinations (e.g. food and beverage; beverage and wine). In this manner, the gratuity management system provides flexibility in selecting the criteria to be used in determining gratuity allocations so that the allocation method may be customized to the needs of a particular business. The gratuity management system may also take into account the use of gratuity pools and their associated gratuity groups. In one embodiment, each gratuity pool/group (“PG”) is defined by a union of job codes (“JC”). PG1,PG2,PG3 . . . PGK; K—total number of PGs PGK=UZZJCZk; Z—Number of Job Codes in PGk In this manner, the gratuity pool/group definitions may be determined by the job code assigned to each employee and reported in the employee information. The distribution rules may require those gratuity groups that generate gratuities distribute a portion of the generated gratuities to other groups. These relationships may be mathematically represented as follows: PG 1  ( P 1 ) → PG 2   Pool   Group   1   gives   certain   percent   ( P 1 )   of   total   tips   to   Pool   Group   2  PG 1  ( P 2 ) → PG 3  PG 2  ( P 3 ) → PG 3  …  PG l  ( p j ) → PG k ; k ≠ l ; k , l ∈ { 1   …   M } ; M < K ;  M - total   number   of   PGs   that   receive   tips ;  0 ≤ p j ≤ 100 ; p 1 + p 2 + … + p j ≤ 100 As noted above, gratuity group 1 (PG1) transfers a percentage (p1) of its generated gratuities to gratuity pool 2 (PG2). In embodiments, if a gratuity group had no members working during an accounting period then any transfers to that gratuity groups pool are cancelled, and may be retained by the generating group or distributed in another manner among those employees who did work during the accounting period. Applying the above formulas and definitions, the percentage of generated gratuities to be deducted from a given group or employee to be distributed to other groups or employees may be represented as follows: P=Σj=1mpj; m—number of Pool Groups that receive tips The gratuity pool/group designations may also define how gratuities are distributed among employees with that group. In an embodiment, the gratuities may be distributed by time worked or individually. In addition, for those gratuity groups whose members generate sales, the members may be classified into teams that split generated gratuities equally. In one scenario, a gratuity pool/group contains only employees that generate sales and do not receive tips from other groups (e.g. servers). The gratuity pool/group also gives a percentage to other gratuity pool/groups, and teams are possible. The members of the gratuity pool/group share tips individually. In this scenario, the tips to be allocated to a given employee (“Ei”) may be defined as follows: a) Employee Isn't Part of a Team: Ei=Ett*(1−Σj=1mpj)−Ect=Ett*(1−P)−Ect: iϵ{1 . . . n}; n—number of Empl in Group b) Employee is Part of a Team: Ei=[Σk=1qEttk*(1−Σj=1mpj)−Σk=1qEctk]/q=[Σk=1qEttk*(1−P)−Σk=1qEctk]/q iϵ{1 . . . q}; q—number of Empl in Team In another scenario, a gratuity pool/group doesn't generate sales, but receives tips from other groups (e.g. bussers). The gratuity pool/group shares tips based on the hours worked by each member of the group. In this scenario, the tips to be allocated to a given employee may be defined as follows: E i = [ ∑ l = 1 r  PG l * p l ] * Etime l PGtime PGTime = ∑ i = 1 n  Etime i ;  n - number   of   Empl   in   Group PG l =  ∑ i = 1 n l  Ett i ; n l = number   of   Empl   in   Group   l  ′ ′ In a modification of the above scenario, the gratuity pool/group contains multiple job codes and each job code is assigned a gratuity factor. For example, a bussers group may be comprised of job codes (“JC”) for senior busser, busser, and junior busser. Each of these job codes may be assigned a gratuity factor (“β”) that is used to weight the gratuity allocation in favor of more experience employees. More generally, the job code and gratuity factor relationship may be depicted as follows: JC1:JC2:JC3 . . . JCZ=β1:β2:β3 . . . βZ Z—number of Job Codes in Pool Group Using the job codes and gratuity factors, each employees time is multiplied with the corresponding weight (i.e. gratuity factor), and the total worked tip for the group is computed as the total of the weighted times for each employee. In this modified scenario, the tips to be allocated to a given employee may be defined as follows: E i = [ ∑ l = 1 r  PG l * p l ] * Etime l * β z PGtime **   PGtime ** = ∑ i = 1 n  Etime i * β z ; n   total   Employees   in   Pool   Group , and z   corresponds   to   JC z   whose   member   is   E i In yet another scenario, a gratuity pool/group generates sales, receives tips from other gratuity groups, and gives a percent of their tips to other gratuity pools. The gratuity pool/group also allows for teams, and the gratuities are distributed with the group by time worked. In this scenario, the tips to be allocated to a given employee may be defined as follows:  a )   Employee   is   not   part   of   the   team   and   there   is   no   other    teams   in   Pool   group  :   E i = [ ∑ k = 1 n  Ett k * ( 1 - ∑ j = 1 m  p j ) + ∑ l = 1 r  PG l * p l - ∑ k = 1 n  Ect k ] * Etime l PGtime    b )   Group   has   some   teams  :  Employee   is   not   part   of   any   team  : E i = [ ∑ k = 1 n  Ett k * ( 1 - ∑ j = 1 m  p j ) + ( 1 - ∑ j = 1 s  Ttime j PGtime )  ∑ l - 1 r  PG l * p l - ∑ k = 1 n  Ect k ] * Etime l PGtime - ∑ j = 1 s  Ttime j ;  s - total   number   of   teams   in   Pool   Group  Ttime j = ∑ k = 1 q j  Etime k ; q j - number   of   Empl   in   Team   j  ′ ′  PGtime = ∑ i = 1 n  Etime i ; n - number   of   Empl   in   Group  Employee   is   part   of   some   team  :  E i = [ ∑ k = 1 q  Ett k * ( 1 - ∑ j = 1 m  p j ) + Ttime PGtime  ∑ l = 1 r  PG l * p l - ∑ k = 1 q  Ect k ] / q In yet another scenario, a gratuity pool/group generates sales, receives tips from other gratuity groups, gives a percent of tips to other gratuity pools and contains different job codes with corresponding gratuity factors. The gratuity pool/group shares tips by time worked and does not have teams. In this scenario, the tips to be allocated to a given employee may be defined as follows: E i = [ ∑ k = 1 n  Ett k * ( 1 - ∑ j = 1 m  p j ) + ∑ l = 1 r  PG l * p l - ∑ N k = 1  Ect k ] * Etime l * β z PGtime **  PGtime ** = ∑ i = 1 n  Etime i * β z where z corresponds to JCz whose member is Ei Combining all of the foregoing, the gratuity to be allocated to a given employee may be determined by one of two equations depending on whether the employee shares tips based on time worked or individually. For employees that share tips based on time worked, the gratuity allocation may be defined as: E i = [ ∑ k = 1 n  Ett k * ( 1 - ∑ j = 1 m  p j ) + ( 1 - ∑ j = 1 s  Ttime j ** PGtime ** )  ∑ l = 1 r  PG l * p l - ∑ k = 1 n  Ect k ] * Etime l * β z PGtime ** - ∑ j = 1 s  Ttime j ** For employees that share tips individual or in teams, the gratuity allocation may be defined as: E i = [ ∑ k = 1 q  Ett k * ( 1 - ∑ j = 1 m  p j ) + Ttime ** PGtime **  ∑ l = 1 r  PG l * p l - ∑ k = 1 q  Ect k ] / q  Ttime j ** = ∑ k = 1 qj  Etime k * β z ; q j - number   of   Empl   in   Team   j  ′ ′  PGtime ** = ∑ i = 1 n  Etime i * β z Where the following are defined as follows: n—total of Employees in group that do not belong to any team, s—total number of teams in group z—corresponds to JCz whose member is Ei q—number of employee in team As shown by the above example, the gratuity management system may determine the gratuity allocation for a given employee based on a multitude of factors as defined by the distribution rules for a given business, which may result in numerous variations and alterations of the above formulas depending upon the distribution rules to be applied in a given business. Referring now to FIGS. 5 through 7, an exemplary implementation of a configuration module is depicted. FIG. 5 illustrates one possible screen of a configuration module with which settings for various groups (identified as JOB) may be defined. As shown, each JOB may be configured to indicate whether the job generates sales, whether the job receives tips from a tip pool, whether the formula for calculating tips includes cash sales, and whether the members of the group will be treated separately or as a team. By way of explanation, the group “barback” does not generate sales, receives tips from a tip pool, does not generate cash tips, and the barbacks are treated as a team. In contrast, the group “food” server generates sales, receives tips from a pool, includes cash sales in the tip calculation, and each server is treated individually in the allocation. Other groups are similarly defined according to the gratuity allocation rules of the given business. Referring now to FIG. 6, the rule for distributing gratuities from a gratuity pool to employees of a group may be defined. As shown, the food servers group has a distribution type of “equally,” whereas the bartender group has a distribution type of “by generated hours.” In an embodiment, the distribution type for a pool only applies to those employees who benefit from a gratuity pool. If an employee, such as a server, is treated individually and does not benefit from a servers pool, then the distribution type may be unnecessary for that pool. Referring now to FIG. 7, another screen of the configuration module allows for the definition of the percentage of gratuities to be transferred from one group to another. As illustrated, the food servers group transfers 8% of its generated gratuities to the bartender pool, 1% to the host pool, 3 percent to the sommelier pool, 5 percent to the bussers pool, and 10 percent to the runner pool. Similarly, the bartender group transfers 7% to the barback pool, and 6% to the runner pool. If the business includes other gratuity-generating employee groups, those groups may be included here and the distribution to each of the gratuity-receiving groups defined accordingly. In embodiments, distribution rules may vary between different accounting periods. FIG. 7 illustrates distribution rules for a breakfast shift. The distribution rules for the lunch and dinner shifts may be the same or different. On another screen (not shown), the employees of the business may be identified through the configuration module. Alternatively, employees may be identified through the received employee information allowing the business to add employees using only its internal restaurant management system software. Referring now to FIGS. 8 and 9, example screens of an employer web-portal are illustrated. In FIG. 8, an employer may view a summary of employee and transaction information, such as each employee with the shift worked, job function (corresponding to a gratuity group or pool), hours worked, credit card tips generated, and total cash sales attributed to the employee. The information displayed may be selected to correspond with the information used to determine the gratuity allocation. Referring to FIG. 9, another screen of the employer web-portal is illustrated, which reflects the determination of the gratuity allocation for a given employee. For each employee, the screen shows the total credit card tips generated by that employee (Total CC Tips), and the portion of those credit card tips to be distributed to other groups (CC Tip Out). Similarly, the Total Cash Sales generated by each employee, the Total Cash Tips determined by applying the appropriate distribution rule, and the portion of the cash tips to be distributed to other groups (Cash Tip Out). In this example, the computed credit card and cash tips outs will be reduced because no member of the barback group, the host group, or the sommelier group worked during the accounting period. Once the generated gratuities have been determined and allocated between the gratuity pools, the total of the gratuity pool in which each employee participates is shown (Pool). The employee's share of the pool is then determined (Pool Share). Because there is only one bartender and one runner, they each receive the full amount of their respective pools. The food servers in this example do not participate in pooling of their tips and, therefore, each is treated individually. The two bussers, Edgar and Samantha, share the busser pool of $26.75 according to the hours worked by each reflect in FIG. 8. Finally, the gratuity share to be distributed is determined after taking into account any retained cash gratuities by the employee. In this example, the food servers are assumed to have retained their total cash gratuity and, therefore, the amount of the gratuity to be distributed, such as through a subsequent payroll, is reduced accordingly. FIGS. 8 and 9, illustrate one example of an employer a web-portal. In an embodiment, an employee web-portal (not shown) is provided in substantially the same format but with the employee limited to viewing only the data corresponding to the given employee. In all of the foregoing, references to specific percentages are for illustration purposes only. The implementation of the gratuity management system may allow for the use any value (such as between 0% and 100%) to be used as part of the distribution rules. In addition, values may be expressed as percentages, decimals, or in any other form appropriate for use in the implementation of the gratuity management system. The use of examples herein is intended to illuminate aspects of the system and its operation and do not suggest any specific values that must or should be used by a given business in defining distribution rules or determining a gratuity allocation for employees. In the specification and claims, reference will be made to a number of terms that have the following meanings. The singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. Approximating language, as used herein throughout the specification and claims, may be applied to modify any feature that could permissibly vary without resulting in a change in the basic function to which it is related. Moreover, unless specifically stated otherwise, any use of the terms “first,” “second,” etc., do not denote any order or importance, but rather the terms “first,” “second,” etc., are used to distinguish one element from another. As used herein, the terms “may” and “may be” indicate a possibility of an occurrence within a set of circumstances; a possession of a specified property, characteristic or function; and/or qualify another verb by expressing one or more of an ability, capability, or possibility associated with the qualified verb. Accordingly, usage of “may” and “may be” indicates that a modified term is apparently appropriate, capable, or suitable for an indicated capacity, function, or usage, while taking into account that in some circumstances the modified term may sometimes not be appropriate, capable, or suitable. For example, in some circumstances an event or capacity can be expected, while in other circumstances, the event or capacity cannot occur—this distinction is captured by the terms “may” and “may be.” The term “instructions” as used herein with respect to a controller or processor may refer to computer executable instructions. The terms module and component as used herein refer to a collection of computer-executable instructions that implement one or more functions of the disclosed system. While certain embodiments have been described, it must be understood that various changes may be made and equivalents may be substituted without departing from the spirit or scope of the present disclosure. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the disclosure without departing from its spirit or scope.
<SOH> BACKGROUND AND SUMMARY <EOH>The present disclosure is related to a system and method for managing gratuities, and more particularly to calculating, allocating, and distributing gratuities among service employees. In the hospitality industry and many other service based businesses, it is customary for customers to give a gratuity or tip to one or more employees who perform the purchased service. Although a customer may primarily interact with one employee of the business, such as a waiter or waitress, many other employees have assisted to varying degrees in supporting the service provided to the customer. In a restaurant, for example, a host may seat the customer, a busser may clear the table, a food runner may deliver food to a table, a bartender may prepare and/or serve alcoholic beverages, and other employees may similarly provide specific services for the benefit of the customer during their dining experience. At the conclusion of a restaurant transaction, the customer generally gives a gratuity to the server or adds the gratuity to the amount paid for the meal. The gratuity may then be shared among the employees who assisted in providing service to the customer, or aggregated and distributed among the employees according to customs or practices of a given business or industry. The sharing of gratuities has often been manually calculated and documented with ad hoc record keeping, complicating compliance with tax and labor regulations. Even when properly computed, existing systems for gratuity sharing have not provided easy access to the gratuity sharing data. As such, there remains a need for systems and methods for managing gratuities that provide both employers and employees with accurate and timely allocations of gratuities in a cost-effective manner. Presently disclosed is a computer-implemented method for allocating gratuities that includes employing at least one processor configured to execute computer-executable instructions stored in memory to perform the following acts: receiving transaction information from a point of sale, wherein the transaction information comprises at least gratuity data for each of a plurality of transactions during an accounting period; receiving employee information from the point of sale, wherein the employee information comprises at least hours worked for each of a plurality of employees during the accounting period; receiving gratuity distribution rules for allocating gratuities among at least a portion of the employees; and determining a gratuity allocation for each applicable employee of the plurality of employees based on at least the received transaction information, the received employee information, and the received gratuity distribution rules. The method may also include allocating to each applicable employee the determined gratuity allocation for that employee. In embodiments, the transaction information is sales data for the plurality of transactions during the accounting period, and the transactions are service transactions provided by the plurality of employees. In an embodiment, at least one processor is remote from the point of sale and may be a cloud computing system. Receiving the transaction information and employee information for the accounting period may further include receiving a computer-readable file containing the transaction information and the employee information for the accounting period, and storing the received transaction information and the received employee information in a database, and may include receiving the computer readable file from the point of sale via the Internet. The method may also include determining a total gratuity amount for the accounting period from the transaction information, and determining the gratuity allocation for each of the plurality of employees based on the total gratuity amount for the accounting period. The method may also include classifying each of the plurality of employees to one of a plurality of gratuity groups based on a job function of the employee; and wherein determining the gratuity allocation for each employee further comprises: allocating gratuities to form a gratuity pool for each gratuity group based on the gratuity distribution rules and allocating the gratuity pool for each gratuity group between the employees of the gratuity group based on the distribution rules. Allocating the determined group gratuity between the employees of the group may also include determining a total of the hours worked by each employee of the group for the accounting period, and allocating a portion of the gratuity pool for the gratuity group to each employee of the group corresponding to a ratio of the hours worked by that employee to the total hours worked of the group. Allocating the determined group gratuity between the employees of the group may also include receiving an assigned gratuity factor for each of the plurality of employees, and allocating at least a portion of the gratuity pool for the gratuity group to each employee based upon the employee's assigned gratuity factor. Determining the gratuity allocation for each of the plurality of employees may further include determining a total of gratuities received by a first group of employees; and allocating a portion of the total of gratuities received by the first group of employees to a second group of employees based on the distribution rules. Determining the gratuity allocation for each of the plurality of employees may further include determining total cash sales during the accounting period from the transaction information, determining a total cash gratuity from the total cash sales, and allocating the total cash gratuity to the plurality of employees based on the distribution rules. The method for allocating gratuities may also include communicating the determined gratuity allocation for each employee to an employer payroll system and distributing the determined gratuity allocation to each employee through a payroll check. The method may also include providing a web-portal configured to be accessed by employees, wherein the web-portal is configured to display the determined gratuity allocation for a given employee, and providing a web-portal configured to be accessed by an employer, wherein the web-portal is configured to display the determined gratuity allocation for the plurality of employees. The method may also include, upon determining the gratuity allocation for a given employee, notifying the employee via at least one of a text message, an email, or an instant message of the determined gratuity allocation. In embodiments, the method is used for each of a plurality of employers and gratuity distribution rules may be received from each of the plurality of employers, with the gratuity distribution rules received from one employer being different than the gratuity distribution rules received from at least one other employer. Also disclosed is a computer-implemented system for managing gratuity allocations that includes at least one processor coupled to at least one memory configured to execute the following computer-executable components stored in the at least one memory: a database configured to store transaction information and employee information, wherein the transaction information comprises gratuity data for each of a plurality of transactions during an accounting period, and wherein the employee information comprises at least hours worked for each of a plurality of employees during the accounting period; a configuration module configured to receive gratuity distribution rules for allocating gratuities among at least a portion of the employees; a processor configured to determine a gratuity allocation for each of the plurality of employees based at least on the transaction information, the employee information, and the distribution rules; and a reporting module configured to report the determined gratuity allocation for each of the plurality of employees. In embodiments, the system for managing gratuities also includes an interface component configured to receive the transaction information from the point of sale and to communicate the transaction information to the database to be stored, and configured to receive the employee information from the point of sale and to communicate the employee information to the database to be stored. The system may also include means for receiving transaction information from a point of sale and storing the received transaction information in the database, and means for receiving employee information from a point of sale and storing the received employee information in the database. In some embodiments, the reporting module may include web-portal configured to be accessed by employees, wherein the web-portal is configured to display the determined gratuity allocation for a given employee, and a web-portal configured to be accessed by an employer, wherein the web-portal is configured to display the determined gratuity allocation for the plurality of employees. In another embodiment, the reporting module is configured to communicate with an employer payroll system and to communicate the determined gratuity allocations to the employer payroll system.
<SOH> BACKGROUND AND SUMMARY <EOH>The present disclosure is related to a system and method for managing gratuities, and more particularly to calculating, allocating, and distributing gratuities among service employees. In the hospitality industry and many other service based businesses, it is customary for customers to give a gratuity or tip to one or more employees who perform the purchased service. Although a customer may primarily interact with one employee of the business, such as a waiter or waitress, many other employees have assisted to varying degrees in supporting the service provided to the customer. In a restaurant, for example, a host may seat the customer, a busser may clear the table, a food runner may deliver food to a table, a bartender may prepare and/or serve alcoholic beverages, and other employees may similarly provide specific services for the benefit of the customer during their dining experience. At the conclusion of a restaurant transaction, the customer generally gives a gratuity to the server or adds the gratuity to the amount paid for the meal. The gratuity may then be shared among the employees who assisted in providing service to the customer, or aggregated and distributed among the employees according to customs or practices of a given business or industry. The sharing of gratuities has often been manually calculated and documented with ad hoc record keeping, complicating compliance with tax and labor regulations. Even when properly computed, existing systems for gratuity sharing have not provided easy access to the gratuity sharing data. As such, there remains a need for systems and methods for managing gratuities that provide both employers and employees with accurate and timely allocations of gratuities in a cost-effective manner. Presently disclosed is a computer-implemented method for allocating gratuities that includes employing at least one processor configured to execute computer-executable instructions stored in memory to perform the following acts: receiving transaction information from a point of sale, wherein the transaction information comprises at least gratuity data for each of a plurality of transactions during an accounting period; receiving employee information from the point of sale, wherein the employee information comprises at least hours worked for each of a plurality of employees during the accounting period; receiving gratuity distribution rules for allocating gratuities among at least a portion of the employees; and determining a gratuity allocation for each applicable employee of the plurality of employees based on at least the received transaction information, the received employee information, and the received gratuity distribution rules. The method may also include allocating to each applicable employee the determined gratuity allocation for that employee. In embodiments, the transaction information is sales data for the plurality of transactions during the accounting period, and the transactions are service transactions provided by the plurality of employees. In an embodiment, at least one processor is remote from the point of sale and may be a cloud computing system. Receiving the transaction information and employee information for the accounting period may further include receiving a computer-readable file containing the transaction information and the employee information for the accounting period, and storing the received transaction information and the received employee information in a database, and may include receiving the computer readable file from the point of sale via the Internet. The method may also include determining a total gratuity amount for the accounting period from the transaction information, and determining the gratuity allocation for each of the plurality of employees based on the total gratuity amount for the accounting period. The method may also include classifying each of the plurality of employees to one of a plurality of gratuity groups based on a job function of the employee; and wherein determining the gratuity allocation for each employee further comprises: allocating gratuities to form a gratuity pool for each gratuity group based on the gratuity distribution rules and allocating the gratuity pool for each gratuity group between the employees of the gratuity group based on the distribution rules. Allocating the determined group gratuity between the employees of the group may also include determining a total of the hours worked by each employee of the group for the accounting period, and allocating a portion of the gratuity pool for the gratuity group to each employee of the group corresponding to a ratio of the hours worked by that employee to the total hours worked of the group. Allocating the determined group gratuity between the employees of the group may also include receiving an assigned gratuity factor for each of the plurality of employees, and allocating at least a portion of the gratuity pool for the gratuity group to each employee based upon the employee's assigned gratuity factor. Determining the gratuity allocation for each of the plurality of employees may further include determining a total of gratuities received by a first group of employees; and allocating a portion of the total of gratuities received by the first group of employees to a second group of employees based on the distribution rules. Determining the gratuity allocation for each of the plurality of employees may further include determining total cash sales during the accounting period from the transaction information, determining a total cash gratuity from the total cash sales, and allocating the total cash gratuity to the plurality of employees based on the distribution rules. The method for allocating gratuities may also include communicating the determined gratuity allocation for each employee to an employer payroll system and distributing the determined gratuity allocation to each employee through a payroll check. The method may also include providing a web-portal configured to be accessed by employees, wherein the web-portal is configured to display the determined gratuity allocation for a given employee, and providing a web-portal configured to be accessed by an employer, wherein the web-portal is configured to display the determined gratuity allocation for the plurality of employees. The method may also include, upon determining the gratuity allocation for a given employee, notifying the employee via at least one of a text message, an email, or an instant message of the determined gratuity allocation. In embodiments, the method is used for each of a plurality of employers and gratuity distribution rules may be received from each of the plurality of employers, with the gratuity distribution rules received from one employer being different than the gratuity distribution rules received from at least one other employer. Also disclosed is a computer-implemented system for managing gratuity allocations that includes at least one processor coupled to at least one memory configured to execute the following computer-executable components stored in the at least one memory: a database configured to store transaction information and employee information, wherein the transaction information comprises gratuity data for each of a plurality of transactions during an accounting period, and wherein the employee information comprises at least hours worked for each of a plurality of employees during the accounting period; a configuration module configured to receive gratuity distribution rules for allocating gratuities among at least a portion of the employees; a processor configured to determine a gratuity allocation for each of the plurality of employees based at least on the transaction information, the employee information, and the distribution rules; and a reporting module configured to report the determined gratuity allocation for each of the plurality of employees. In embodiments, the system for managing gratuities also includes an interface component configured to receive the transaction information from the point of sale and to communicate the transaction information to the database to be stored, and configured to receive the employee information from the point of sale and to communicate the employee information to the database to be stored. The system may also include means for receiving transaction information from a point of sale and storing the received transaction information in the database, and means for receiving employee information from a point of sale and storing the received employee information in the database. In some embodiments, the reporting module may include web-portal configured to be accessed by employees, wherein the web-portal is configured to display the determined gratuity allocation for a given employee, and a web-portal configured to be accessed by an employer, wherein the web-portal is configured to display the determined gratuity allocation for the plurality of employees. In another embodiment, the reporting module is configured to communicate with an employer payroll system and to communicate the determined gratuity allocations to the employer payroll system.
G06Q300214
20170817
20180510
93646.0
G06Q3002
1
WILDER, ANDREW H
SYSTEM AND METHOD FOR MANAGING GRATUITIES
SMALL
1
CONT-ACCEPTED
G06Q
2,017
15,680,300
ACCEPTED
CONTROLLING FUNCTIONS OF A USER DEVICE UTILIZING AN ENVIRONMENT MAP
A system and method is provided for using information broadcast by devices and resources in the immediate vicinity of a mobile device, or by sensors located within the mobile device itself, to ascertain and make a determination of the immediate environment and state of the mobile device. This determination may be used to control and manage the actions that the device is asked to carry out by or on behalf of the user.
1. A method for controlling access to a functionality of a user device, the method comprising: receiving a capabilities list (CL) from one or more external resources available to and in proximity with the user device, each CL specifying one or more attributes of the respective external resource from which it is received; storing each of the received CLs in a resource registry associated with the user device; dynamically updating the resource registry with one or more updated CLs; determining an environment map for the user device, the environment map comprising resource environment information obtained from the resource registry; matching access policies of the user device with the environment map to dynamically assign a profile to the user device; and controlling access to the functionality of the user device based on the profile assigned to the user device, wherein controlling access to the functionality of the user device includes limiting a communication functionality of the user device. 2. The method of claim 1, wherein the one or more external resources include a mobile resource connected to the user device via a wireless network and configured to deliver content received from the user device. 3. The method of claim 1, wherein the environment map further comprises physical environment information obtained from one or more sensors. 4. The method of claim 5, wherein the physical environment information comprises gravity information. 5. The method of claim 5, wherein the one or more sensors are located within the user device. 6. The method of claim 1, wherein the access policies comprise a determination that the user device is in a pre-defined context. 7. The method of claim 8, wherein the pre-defined context is an automobile. 8. The method of claim 8, wherein the one or more attributes include a resource type, and the determination is made based on the resource type being an automobile type. 9. The method of claim 1, wherein the communication functionality is SMS text messaging. 10. The method of claim 1, wherein limiting a communication functionality includes disabling delivery of messages to a user. 11. The method of claim 1, wherein limiting a communication functionality includes preventing display of content on a display of the user device. 12. The method of claim 1, wherein limiting a communication functionality includes displaying a warning message on a display of the user device. 13. The method of claim 1, wherein limiting a communication functionality includes preventing access to mobile applications running on the user device. 14. A user device comprising: a processor; and a non-transitory computer-readable medium comprising instructions stored thereon, that when executed on the processor, perform the steps of: receiving a capabilities list (CL) from one or more external resources available to and in proximity with the user device, each CL specifying one or more attributes of the respective external resource from which it is received; storing each of the received CLs in a resource registry associated with the user device; dynamically updating the resource registry with one or more updated CLs; determining an environment map for the user device, the environment map comprising resource environment information obtained from the resource registry; matching access policies of the user device with the environment map to dynamically assign a profile to the user device; and controlling access to the functionality of the user device based on the profile assigned to the user device, wherein controlling access to the functionality of the user device includes limiting a communication functionality of the user device. 15. The user device of claim 16, wherein the one or more external resources include a mobile resource connected to the user device via a wireless network and configured to deliver content received from the user device. 16. The user device of claim 16, wherein the environment map further comprises physical environment information obtained from one or more sensors. 17. The user device of claim 20, wherein the physical environment information comprises gravity information. 18. The user device of claim 20, wherein the one or more sensors are located within the user device. 19. The user device of claim 16, wherein the access policies comprise a determination that the user device is in a pre-defined context. 20. The user device of claim 23, wherein the pre-defined context is an automobile. 21. The user device of claim 23, wherein the one or more attributes include a resource type, and the determination is made based on the resource type being an automobile type. 22. The user device of claim 16, wherein the communication functionality is SMS text messaging. 23. The user device of claim 16, wherein limiting a communication functionality includes disabling delivery of messages to a user. 24. The user device of claim 16, wherein limiting a communication functionality includes preventing display of content on a display of the user device. 25. The user device of claim 16, wherein limiting a communication functionality includes displaying a warning message on a display of the user device. 26. The user device of claim 16, wherein limiting a communication functionality includes preventing access to mobile applications running on the user device. 27. A user device comprising: a resource registry storing capabilities lists (CLs) received from one or more external resources available to and in proximity with the user device, each CL specifying one or more attributes of the respective external resource from which it is received; an environment map comprising resource environment information obtained from the resource registry; and a recognition unit matching access policies of the user device with the environment map to dynamically assign a profile to the user device, and controlling access to a functionality of the user device based on the profile assigned to the user device, wherein controlling access to the functionality of the user device includes limiting a communication functionality of the user device. 28. The user device of claim 27, wherein the one or more external resources include a mobile resource connected to the user device via a wireless network and configured to deliver content received from the user device. 29. The user device of claim 27, wherein the access policies comprise a determination that the user device is in a pre-defined context. 30. The user device of claim 29, wherein the pre-defined context is an automobile.
BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to the delivery, discovery, management and control of information to mobile consumers, and more particularly to consumers who have access to multiple devices, capabilities and networks, and to the efficient use and control of these resources to consume and generate information. Description of the Related Art It has become customary for people to generate and consume information in a variety of contexts and situations. This need is never more prominent as when people are mobile. Starting with the simply stated need to be “reachable,” people now want to be connected to various information resources and use the associated networks and resources to carry out simple and complex tasks that they face everyday. A decade or so ago, the personal computer (PC), either desktop or laptop, was the main tool for accessing information. A necessary aspect of the PC is that it requires almost the complete attention of the user, i.e., it is difficult to do many other things at the same time as using the PC because of the tethering, weight, and form factor of the device. With the advent of mobile computing devices such as smartphones, it is now commonplace to find people attempting multiple tasks simultaneously, e.g., driving while talking on a mobile phone. In some cases multi-tasking is useful and advantageous, while in other cases it may be physically dangerous to others and oneself. Management of capabilities that are potentially available to a consumer would be an extremely valuable service. The systems and methods in use today that enable a user to be “reachable” or to have access rely heavily on the user carrying a mobile device. However, mobile devices often have limitations in bandwidth, capacity or connectivity that prevent their use in certain situations. For example, consider a mobile device that may be connected to a network that has low bandwidth but is within range of other resources, e.g., a different network that provides more bandwidth. A mobile device, however, may only support one network interface and, hence, may not be capable of utilizing the higher bandwidth network because it is connected to the lower bandwidth network. Even when a mobile device is connected to a resource (i.e., access network, display device, storage and computing resource, etc.), it may not be adequately connected since the suitability of a connection depends on the service, i.e., the application that the user intends to run on the device. In present day mobile computing environments some applications mandate a certain type of network. For example, early versions of the iPhone mandated that mobile video could only be accessed using a WiFi network. More recent versions of the iPhone support both WiFi and cellular 3G access to mobile video resources, leaving the user to decide which access network to use, or the device uses a programmed policy to choose a network type. The current trend in mobile devices and networks is to support multiple radios and multiple radio access bearers (mRAB), a feature of the so-called 3G UMTS (Universal Mobile Terrestrial System) technology. With the introduction of various types of networking technologies, it is expected that a variety of devices will broadcast information about themselves and their capabilities for other devices to use. Thus, the ability of devices to carry out multiple simultaneous tasks is expected to continue to grow. A device concurrently executing a multiplicity of tasks has need for many resources and may carry out those tasks more efficiently by switching resources around. A pre-determined policy of matching resources to tasks, however, may be too restrictive. Allowing a single application to demand a resource without knowledge of all the resource options may be of detriment to it and other concurrent applications. Further, when concurrent applications are being run on a mobile device, the service provider may choose to disallow the concurrent execution of certain applications, e.g., initiating a voice call and a mobile video session while a video session is in progress. Alternatively, certain combinations of concurrent applications may be allowed or disallowed only when certain resources are or become available. For example, in some networks, call forwarding commands were disallowed when such commands led from one device to another that was previously in the call forwarding loop. But detecting such feature interaction problems is computationally difficult and in general undefined. The problem becomes further complicated when external resources become a part of the problem specification. There is, therefore, a need for an entity to match the needs of concurrent mobile applications on a mobile device with the available resources in the device's environment in order for successfully carrying out or limiting and controlling the tasks at hand. SUMMARY OF THE INVENTION These and other drawbacks in the prior art are overcome in large part by a system and method according to embodiments of the present invention. A telecommunications method in accordance with embodiments of the present invention includes receiving registry map information of network environmental indicia from a mobile device concurrently along with location information to a home location registry; generating an environment map for the mobile device based on the registry map information, the environment map including a device, application, and network component environment; defining service provisioning based on the environment map in response to a request for service from the mobile device, the service provisioning including and excluding predetermined elements of the environment map; and providing network service in accordance with the defined service provisioning. In some embodiments, the service provisioning includes accommodating a service provider policy. In others, the service provisioning includes accommodating a user selected preference. Further embodiments include defining a user context based on the environment map and including or excluding predetermined elements for provisioning based on the user context. A telecommunications system in accordance with embodiments of the present invention includes a plurality of user devices, the user devices configured to monitor available resources and dynamically maintain a resource registry of the available resources and transmit the registry to a service provider; a service delivery platform associated with the service provider and configured to dynamically maintain profiles of a plurality of user devices based on the resource registry information and allow access to resources based on the profiles. In some embodiments, the plurality of user device configured to maintain a capabilities list of user device attributes. The user devices may include one or more sensors for identifying a physical device environment and storing physical device environment information in the registry and may be configured to transmit the resource registry information to the service provider during a home location register location update. In some embodiments, the plurality of user devices are configured to transmit the resource registry information to the service provider as binary-coded data during a home location register location update. In some embodiments, the profiles define access based on physical device environment. BRIEF DESCRIPTION OF THE DRAWINGS The present invention may be better understood, and its numerous objects, features, and advantages made apparent to those skilled in the art by referencing the accompanying drawings. The use of the same reference symbols in different drawings indicates similar or identical items. FIG. 1 illustrates an exemplary system according to embodiments of the present invention. FIG. 2 illustrates a CL according to embodiments of the present invention. FIG. 3 is a flowchart illustrating operation of embodiments of the present invention. FIG. 4 is a diagram of an exemplary system map according to embodiments of the present invention. FIG. 5 is a diagram of an exemplary system map according to embodiments of the present invention. FIG. 6 is a flowchart illustrating operation of embodiments of the present invention. FIG. 7 is an exemplary SDP in accordance with embodiments of the present invention. FIG. 8 is an exemplary user device in accordance with embodiments of the present invention. FIG. 9 is a flowchart illustrating operation of embodiments of the present invention. DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION In accordance with embodiments of the present invention, a system and method is provided for using information broadcast by devices and resources in the immediate vicinity of a mobile device, or by sensors located within the mobile device itself, to ascertain and make a determination of the immediate environment and state of the mobile device. This determination may be used to control and manage the actions that the device is asked to carry out by or on behalf of the user. Advantageously, a carrier can define hundreds of device profiles and automatically and dynamically associate them with user devices, based on the device sensing its environment. The profiles allow or disallow certain actions or combinations of actions, as will be described in greater detail below. Embodiments of the present invention address locating mobile devices in a telecommunications network that uses a mechanism of “paging requests” by certain network elements and “location updates” by mobile devices to update and maintain a database called the Home Location register (HLR). The term “location” typically refers to the cellular site (cell site) within which the mobile device was last known to be located, although other location methods may be employed. In accordance with embodiments of the present invention, paging requests and location updates include not only cell site information, but also the availability of other access networks to the mobile device such as WiFi, Bluetooth, WiMax, etc. Moreover, any other resources, e.g., display devices, that could be used in conjunction with the mobile device that are “attached” to the new access network and which “announce” their capabilities and availability are also included in the updates. Internal sensor information, such as device orientation, may also be provided. The information so obtained from the environment surrounding a mobile device is captured in a series of update messages, referred to as resource updates, by a network facility that processes and stores the messages. In an exemplary embodiment of the present invention, the mobile device contains a registry wherein all applications are authenticated and registered before they can be used in the mobile device. The registry may additionally contain a profile stating what resources an application needs. A network facility uses an application profile and the information obtained from resource updates to dynamically assign a profile to the mobile device. This profile may be re-assigned and modified whenever the resource updates or the registry information in the mobile device warrant a change based on service logic executing in the network facility. Consider, for example, a mobile device that is engaged in a voice telephone call connected to a circuit-switched network. Assume the mobile device contains applications for streaming mobile video and SMS text messaging, the applications registered within the registry of the mobile device. The mobile device will have an associated profile in the network facility that details the resources available to the mobile device, i.e., the circuit-switched network, the mobile video and SMS applications, and any resources needed by the applications. Now, assume a Bluetooth access network announces itself, its capabilities and its resources. For example, the Bluetooth network may announce its type is “automobile” and that it supports a display device with certain attributes, e.g., resolution, size, etc. Assume the mobile device attaches itself to the new network. The mobile device will update its registry to include the Bluetooth network and its associated display device. Resource updates from the mobile device to the network facility likewise now list the new access network available to the device (Bluetooth), and any resources that have become available, i.e., the new display device. This causes the network facility to assign a new profile to the mobile device wherein delivery and display of mobile video may now be effectuated on the newly discovered display device, i.e., the monitor in the automobile. Moreover, a policy restriction stated by the service provider preventing SMS messages from being received and initiated while in an automobile may cause the registry to disable the SMS application, thus preventing the user from launching or receiving SMS messages. Thus, the user may now view mobile content on the automobile display, rather than on the display of the mobile device, and may not initiate or receive SMS messages while connected to the automobile's Bluetooth network. Alternatively, the service provider may choose to display a warning message to the user without disabling any of the applications in the mobile device. Similarly, the device internal sensors may identify a particular physical orientation or other characteristic of the device, and cause the network facility to enable or disable based thereon. For example, if the device is being held to the ear, then a rule may be provided that video content is on the automobile display other than the mobile device display. Turning now to the drawings and, with particular attention to FIG. 1, a diagram of a telecommunications system 100 according to an embodiment of the present invention is shown. The telecommunications system 100 may include a network facility, such as a service delivery platform 102, which may include or be in communication with a resource map 104, a resource profile 106, and a recognition unit 115. As will be explained in greater detail below, the resource map 104 contains an environment map of resources available to particular users, while the resource profile 106 defines particularized rules for making those resources available. The recognition unit 115, as will be explained in greater detail below, contains matching rules for comparing access policies to the user device's environment maps. That is, the service delivery platform 102 makes the resources available to the user devices in accordance with the resource map 104, profile 106, and recognition unit 115. The service delivery platform 102 may include or be in communication with one or more user devices 108, and one or more Home Location register (HLR) databases 116. Typically, as will be explained in greater detail below, an HLR 116 is provided for each cell site in the network to which the user device is registered. The user devices may further include or be in communication with resource registries 110, capabilities lists (CL) 112, and resource monitors 114. As will be explained in greater detail below, the resource monitor 114 monitors the network and resource environment (either passively or actively) for devices or resources that have become available or unavailable. The capabilities lists 112 are lists maintained by all network devices and resources. Specifically, it is envisaged that networks and devices, i.e., all resources, contain an internal capability list (CL) that contains not only the identification number of the resource but also attributes that may be of interest and use to applications. For example, a network CL may show the bandwidth, average latency, etc. A storage device CL may show the amount of available storage, the random access time, etc. A display device CL may show the resolution, number of pixels, etc. Indeed, the attributes in the CL for most popular devices and networks could be standardized. A particular device or entity's CL may be updated when it receives a CL from other resources. The resource registries 110, on the other hand, are registries maintained by the user device of CLs of other devices that are currently available to it. FIG. 2 illustrates an exemplary CL for a display device that would be maintained in the registry of, say, a mobile telephone. Attributes in the CL describe the capabilities of the resource, its external interfaces, and intrinsic properties. For example, in the case of a display device, this can include resolution, display size, refresh rate, etc. In certain embodiments, the user devices 108 may be implemented as telephones, cellular telephones, PDAs, computers, hard or soft clients, etc. While typically implemented as a smartphone, the user devices 108 also may be embodied as personal computers implementing a Windows operating system and the Explorer web browser. The user devices 108 thus may include telephony and other multimedia messaging capability using, for example, peripheral cameras, Webcams, microphones, and speakers (not shown) or peripheral telephony handsets. In general, while the user devices 108 may implement one or more of the systems and methods described herein, the user devices also may implement one or more client devices or programs that communicate with services that implement such systems and methods provided remotely. In certain embodiments, the system 100 may also include other hardware and/or software components (e.g., gateways, proxy servers, registration server, presence servers, redirect servers, databases, applications, etc.). The devices may also contain sensors for the state of the device and/or the state of its immediate environment, such as temperature and orientation. For example, several current mobile devices, such as smartphones, sense WiFi and cellular networks. Others sense the orientation of the device and allow the display to be used in either a portrait or a landscape mode, using a gravity-based pendulum sensor. In addition, proximity sensors turn the display off when the device is held to the ear. In accordance with embodiments of the present invention, such physical sensors may be used to define not simply local characteristics of the telephone, but may be sent to the registry and uploaded to the network for use in implementing and/or determining network and device access policies. As will be discussed in greater detail below, in order to receive information, a mobile device must be located by the network since it could physically be anywhere in the geographical area. Each mobile device periodically generates a message called the location update that is recorded in a Home Location Register (HLR) 116. The location update message typically contains the identity of the cell site in which the mobile device is currently located and some other network-related information, e.g., signal strength, etc. Whenever the network needs to reach a mobile device, e.g., to initiate an incoming voice call, it sends a paging request to the last cell site in which the mobile device was located. Upon receiving the paging request the mobile device may respond to it. If, however, the mobile device has re-located to another cell site since the last location update, the paging request goes unanswered. In accordance with embodiments of the present invention, the location update message from a mobile device 108 is further loaded with information about other resources that are currently “available” to the mobile device 108. Specifically, resources “announce” or make available their CLs. This may be achieved either by accepting a specific request on a well-defined interface and responding to the request or by doing a broadcast. The current generation of RFID devices, by way of example, announce themselves through a broadcast mechanism, as do certain WiMax and Wifi networks. The mobile device 108 receives the announcements and aggregates them into one or more resource updates. In some embodiments of the present invention, the announcements include other device CLs. The mobile device 108 periodically broadcasts these resource updates, which are then received by the service delivery platform 102. As can be appreciated, such updates from the user devices to the service delivery platform 102 via the HLRs 116 could be bandwidth and/or processing intensive. As such, in accordance with embodiments of the present invention, any of a variety of techniques may be used to minimize such effects. For example, less-bandwidth-intensive binary encoding may be used for the uplink registry messages. Alternatively, or additionally, rather than having the uplink occur every time the HLR is updated, it may occur only every other time, or every tenth time, or any other predetermined period. Also, rather than having periodic updates, in some embodiments, the registry upload may occur only if the registry itself has actually been updated. Furthermore, the service delivery platform 102, in conjunction with the recognition unit 115, the resource map 104 and resource profile 106, may implement one or more databases (not shown) that will require speedy and frequent updates. Accordingly, embodiments of the present invention may make use of “active” databases to accommodate the heavy traffic. Turning now to FIG. 3, a flowchart 300 illustrating operation of embodiment of the present invention is shown. The particular arrangement of elements in the flowchart 300 is not meant to imply a fixed order to the elements; embodiments can be practiced in any order that is practicable. More particularly, the flowchart 300 illustrates the aggregation process in a mobile device for a plurality of CLs In a process step 302, the mobile device 108 receives or discovers a CL. Receipt or discovery may be an out-of-band process and may be accomplished through the resource broadcasting or otherwise announcing presence and/or the CL. In a process step 304, the user device 108 and, particularly, the resource monitor 114, checks if the CL is from a previously known resource. An affirmative response can lead to updating of the CL in the user device's lists (typically, the received CL may itself be updated and thus different from that previously stored), in a process step 306. Once updated, the information is integrated into the next resource update to the service delivery platform 102, as shown at process step 312. More particularly, the information is loaded with the location information to the Home Location Register 116, which provides it to the service delivery platform 102. As noted above, this may be sent with every HLR update, or on an event basis or some periodic basis, and/or using a low bandwidth binary encoding. If, in process step 304, the CL was determined to be unknown, the resource will be registered in the mobile device registry 110, in a process step 308. A new CL is created for the new resource from the received CL in a process step 310, and the new CL is integrated into a resource update, in a process step 312. Once a resource update is ready, the update is sent to another process 1000 that perpetually loops on a timer at process step 314, and periodically generates a resource update, at steps 316, 318. As noted above, resource updates from mobile devices are received and stored by the Service Delivery Platform (SDP) 102. Using information from the resource updates, the SDP 102 constructs a conceptual map 104 of the immediate environment of a mobile device, generates a resource profile 106 of a current environment of the device, and uses the recognition unit 115 to allow or disallow functionality based on the map. For example, shown in FIG. 4 is a user device 108 that has received CLs from other resources 402, 404, 406. The CLs 402, 406, 408 may be, for example, a cell site, a display resource, and a network resource. The mobile device 108 integrates these CLs into a resource update 408 which in turn is broadcast by the mobile device 108 and received and stored by the SDP 102. The stored representation of the environment is shown at 410 and includes a cell site 412, a display resource 414 and a network resource 416. The resources 412, 414, 416 correspond to the CLs 402, 404, 406, respectively. It is noted that the graphical representation of FIG. 4 is for purposes of simplicity only; the typical environment map uses internal digital computer data structures to effectively store objects such as CL 402, 404, 406. In the example illustrated, the informational attributes of CL 402 may describe a cell site of a cellular network 412 with interface 420; the informational attributes of CL 404 may describe a RFID display device depicted as 414 with interface 424; and the informational attributes of CL 406 may describe a WiFi network depicted as 416 with interface 422. The mobile device itself is shown as a unitary structure 430 for purposes of this depiction but will be discussed later. Thus, with reference to FIG. 4, the environment map 104 of the mobile device 108 shows that the device is in association with a display device 414 using interface 424, and has access to two networks 412 and 416 using interfaces 420, 422 respectively, the former being a WiFi network and the latter a cellular network. The inventions discussed herein do not presuppose that a resource is necessarily associated exclusively with a single mobile device. Resources may be shared between multiples of mobile devices. It is also envisaged that the SDP 102 maintains an environment map for a plurality of mobile devices and, typically, maintains one map for all mobile devices in its purview. As noted above, the environment map of mobile devices may be used to efficiently deliver to and receive information from the mobile devices. As an exemplary case, consider the problem of delivering video content from a source to the mobile device whose map 104 is depicted in FIG. 5. The mobile device 108 is associated with a display resource 414, a cellular network 412 and a WiFi network 416. Also shown are a variety of network paths, 101, 201, 301, 501, 601, 701. Given the environment map of mobile device 108, a service profile 106 (FIG. 1) may be associated with the device that specifies that video content from a content server 502 may be delivered to either the mobile device 108 or to the display resource 414 and may further define the network path for the delivery. In particular, the SDP 102 may choose a network path 101, 201, 301 to deliver the video content to the display resource 424. Alternatively, it may deliver the video content using the network path 101, 201, 501, 601, 301 to the mobile device 108; or it may also use the network path 701, 412. The service profile may further direct the mobile device 108 to consume the video content or to “relay” content to the display resource 424. Such a directive may be dictated by policies stated by the service provider. The SDP 102 may contain service logic using cost functions to choose any one of these paths. It may also use current network traffic and policies to prefer one path over the other possible paths. If the SDP 102 chooses to deliver the video content to the display resource 424 and not the mobile device 108, it may first seek permission from the mobile device 100 by engaging in user dialog, such as via a graphical user interface. It is thus apparent that a user of a mobile device 108 may request video content from a server and in some cases, as depicted in FIG. 5, the video content will be received and relayed by the mobile device 108, to be displayed on a device 424 in close proximity to the mobile device. Continuing with the example shown in FIG. 5, if the environment map of the mobile device 108 depicts that the device is in association with, for example, a Bluetooth (WiFi) network 416 generated by an automobile, the system and method of the present invention may employ a recognition unit 114 to examine the environment map 104 of a mobile device 108 to recognize that the mobile device 108 is in a pre-defined context, e.g., in an automobile and may limit access to features and services in response. This is explained further with reference to FIG. 6. The SDP 102 receives resource updates in step 602, and determines whether a resource update is for a new or a previously known mobile device (step 604). Steps 606 and 608 incorporate the received resource update into the environment map 104. In step 610, a recognition unit 115 containing pre-defined pattern matching rules is invoked that examines the environment map 104 for the mobile device 108 with the recently received resource update to determine if the map matches any of the pattern-rules of the recognition unit 115. If a match is found, i.e., the mobile device 108 is determined to be in a pre-defined network or context or environment, e.g., connected to an automobile wifi network 416, then the recognition unit 115 returns an affirmative response and may apply a service provider policy to the environment of the mobile device, e.g., restrict SMS usage. In another exemplary embodiment, the SDP 102 may dictate the network path chosen to deliver the video content to the display resource 424 and not to the mobile device 108. The policy enforced by the SDP 102 on behalf of the service provider may be the result of safety considerations calculated by the service provider. Thus, the user of a mobile device 108 in an automobile may view video content on the external display provided by the automobile. Continuing further with the example depicted in FIG. 5, suppose the mobile device 108 is to be used to transmit content to the network, i.e., in the uplink direction. Again, it is apparent, that the mobile device 108 may query the environment map 104 via the SDP 102 to select a suitable network interface to use for making the transmission. The present embodiment envisages that computing, display, storage and network resources may be abundantly available to a mobile consumer, and the consumer may choose to use such resources through the system and method described in the present invention. Moreover, as the consumer travels, his environment and availability of resources changes, the changes being recorded in the registries and environment map corresponding to the user's mobile device. The description of the present embodiment, so far, has concentrated on the external resources available to a mobile device 108, and not on the applications available within the device itself. It is envisaged, as previously stated, that mobile devices contain a registry of all applications that have been loaded on to a mobile device by the service provider or by the user himself. Applications that are not registered in the registry are considered as “rogue” applications and are outside the scope of the present invention. As described earlier, the environment map for a mobile device depicts the immediate environment of the mobile device and the SDP 102 assigns a network profile 106 to the mobile device based on the current environment map 104. It is envisaged by the present invention that the SDP 102 is also aware of the applications within the registry of the mobile device 108, and when assigning a service profile, may enforce one or more policies on the profile that cause the enablement or disablement of certain applications in the mobile device or impact delivery of information to the mobile device by other network elements. Continuing with the example of FIG. 5, the exemplary depiction shows mobile device 108 in association with a WiFi network resource 416 generated by an automobile. This association may be assumed to trigger a policy that disables the web browser and the SMS applications in the registry of the mobile device 108. Thus, the user of the mobile device 108 will not be capable of launching the SMS or the web browser applications from the mobile device. Furthermore, the service provider may trigger network elements to disable the delivery of messages to the mobile device in question, e.g., by marking the status of the mobile device as “unavailable” in the HLR will temporarily stop delivery of messages, including SMS messages, to the mobile device. Turning now to FIG. 9, a flowchart 900 illustrating operation of embodiment of the present invention is shown. The particular arrangement of elements in the flowchart 900 is not meant to imply a fixed order to the elements; embodiments can be practiced in any order that is practicable. In a process step 902, a user device 108 receives or detects the addition of one or more new programs, resources, or processes that may be available to it. The new additions can include new CLs 112 and result in an updated resource registry 110, as discussed above. In a process step 904, the user device transmits the update to the SDP 102. As discussed above, this can include the user device 108 transmitting a location signal to the Home Location Register and piggy-backing the CL and registry information on top. The HLR 116 in turn provides the information to the SDP 102. In a process step 906, the SDP 102's resource monitor 114 receives the update and provides the information to the resource map 104. In response, in a process step 908, the resource map 104 determines a new environment map for the user device (and other devices). In a process step 910, the SDP 102's recognition unit 115 accesses or updates the resource profile 106 of the particular device whose update has been received. As noted above, the profile includes one or more rules based on inferences from user contexts resulting from knowledge of the user position, device orientation, etc. In a process step 912, the SDP 102 can receive a service request from a user device. For example, as discussed above, this can include requests for video content or the like. In a process step 914, in response, the SDP 102's recognition unit 115 determines a user situation or device, i.e., accesses and applies the rules or policy for user access to the program or application or resource. Finally, in a process step 914, the SDP 102 can allow access per the rules. FIG. 7 shows a block diagram of components of a service delivery platform or service provider implemented as a computing device 700, e.g., personal, or laptop computer or server. In some embodiments, the computing device 700 may implement one more elements of the methods disclosed herein. The system unit 11 includes a system bus or a plurality of system buses 21 to which various components are coupled and by which communication between the various components is accomplished. A processor 22, such as a microprocessor, is coupled to the system bus 21 and is supported by the read only memory (ROM) 23 and the random access memory (RAM) 24 also connected to the system bus 21. The computer 700 may be capable of high volume transaction processing, performing a significant number of mathematical calculations in processing communications and database searches. A Pentium™ or other similar microprocessor manufactured by Intel Corporation may be used for the processor 22. Other suitable processors may be available from Freescale Semiconductor, Inc., Advanced Micro Devices, Inc., or Sun Microsystems, Inc. The processor 22 also may be embodied as one or more microprocessors, computers, computer systems, etc. The ROM 23 contains among other code the basic input output system (BIOS) which controls basic hardware operations such as the interaction of the disk drives and the keyboard. The ROM 23 may be embodied, e.g., as flash ROM. The RAM 24 is the main memory into which the operating system and applications programs are loaded. The memory management chip 25 is connected to the system bus 21 and controls direct memory access operations including passing data between the RAM 24 and hard disk drive 26 and removable drive 27 (e.g., floppy disk or flash ROM “stick”). A CD ROM drive (or DVD or other optical drive) 32 may also be coupled to the system bus 21 and is used to store a large amount of data, such as a multimedia program or a large database. Also connected to the system bus 21 are various I/O controllers: The keyboard controller 28, the mouse controller 29, the video controller 30, and the audio controller 31. The keyboard controller 28 provides the hardware interface for the keyboard; the mouse controller 29 provides the hardware interface for the mouse 13 (or other cursor pointing device); the video controller 30 is the hardware interface for the video display 14; and the audio controller 31 is the hardware interface for a speaker and microphone (not shown). It is noted that while the various I/O controllers are illustrated as discrete entities, in practice, their functions may be performed by a single I/O controller known as a “super I/O.” Thus, the figures are exemplary only. In operation, keyboard strokes are detected by the keyboard controller 28 and corresponding signals are transmitted to the microprocessor 22; similarly, mouse movements (or cursor pointing device movements) and button clicks are detected by the mouse controller and provided to the microprocessor 22. Typically, the keyboard controller 28 and the mouse controller 29 assert interrupts at the microprocessor 22. In addition, a power management system 33 may be provided which causes the computer to enter a power down mode if no activity is detected over a predetermined period. One or more network interfaces 40 enable communication over a network 46, such as a packet network like the Internet. The network interfaces 40 may be implemented as wired or wireless network interfaces operating in accordance with, for example, one or more of the IEEE 802.11x standards and may also or alternatively implement a Bluetooth interface. One embodiment of the present invention is as a set of instructions in a code module resident in the RAM 24. Until required by the computer system, the set of instructions may be stored in another computer memory, such as the hard disk 26, on an optical disk for use in the CD ROM drive 32, a removable drive 27, or the flash ROM. As shown in the figure, the operating system 50, resource monitor 104, resource map 106, resource profile(s) 114, and recognition unit 115 are resident in the RAM 24. The operating system 50 functions to generate a graphical user interface on the display 14. Execution of sequences of the instructions in the programs causes the processor 22 to perform various of the process elements described herein. In alternative embodiments, hard-wired circuitry may be used in place of, or in combination with, software instructions for implementation of some or all of the methods described herein. Thus, embodiments are not limited to any specific combination of hardware and software. The processor 22 and the data storage devices 26, 27, 32 in the computer 700 each may be, for example: (i) located entirely within a single computer or other computing device; or (ii) connected to each other by a remote communication medium, such as a serial port cable, telephone line or radio frequency transceiver. In one embodiment, the computer 100 may be implemented as one or more computers that are connected to a remote server computer. As noted above, embodiments of the present invention may be implemented in or in conjunction with a telephone, such as a wireless or cellular “smart” telephone. An exemplary cellular telephone 800 including capabilities in accordance with an embodiment of the present invention is shown in FIG. 8. In some embodiments, the cellular telephone 800 may implement one or more elements of the methods disclosed herein. As shown, the cellular telephone includes control logic 802 and cellular transceiver 804. The cellular transceiver 804 allows communication over a cellular telephone network, such as a GSM or GPRS based cellular telephone network. The control logic 802 generally controls operation of the cellular telephone and, in some embodiments, implements CLs and resource registry, as well as other services or clients in accordance with embodiments of the present invention. The control logic 802 interfaces to a memory 818 for storing, among other things, contact or address lists 107. The control logic 802 also interfaces to a user interface(s) 810. The user interface(s) 810 can include a keypad 820, speaker 822, microphone 824, and display 826. The keypad may include one or more “hard” keys, but may be implemented in whole or in part as a cursor pointing device in association with one or more “virtual” keys on the display 826. In general, a user may make use of the keypad 820 and display 826 to enter contact information, and may speak into the microphone to provide the audio input(s). It is noted that other interfaces, such as voice-activated interfaces may be provided. Thus, the figure is exemplary only. In addition, a Bluetooth or WiFi interface 806 may be provided. A memory 808 for storing program code and data, such as the CL 112 and registry 110, also may be provided. While specific implementations and hardware/software configurations for the mobile device and SDP have been illustrated, it should be noted that other implementations and hardware configurations are possible and that no specific implementation or hardware/software configuration is needed. Thus, not all of the components illustrated may be needed for the mobile device or SDP implementing the methods disclosed herein. As used herein, whether in the above description or the following claims, the terms “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” and the like are to be understood to be open-ended, that is, to mean including but not limited to. Only the transitional phrases “consisting of” and “consisting essentially of,” respectively, shall be considered exclusionary transitional phrases, as set forth, with respect to claims, in the United States Patent Office Manual of Patent Examining Procedures. Any use of ordinal terms such as “first,” “second,” “third,” etc., in the claims to modify a claim element does not by itself connote any priority, precedence, or order of one claim element over another, or the temporal order in which acts of a method are performed. Rather, unless specifically stated otherwise, such ordinal terms are used merely as labels to distinguish one claim element having a certain name from another element having a same name (but for use of the ordinal term). The above described embodiments are intended to illustrate the principles of the invention, but not to limit the scope of the invention. Various other embodiments and modifications to these preferred embodiments may be made by those skilled in the art without departing from the scope of the present invention.
<SOH> BACKGROUND OF THE INVENTION <EOH>
<SOH> SUMMARY OF THE INVENTION <EOH>These and other drawbacks in the prior art are overcome in large part by a system and method according to embodiments of the present invention. A telecommunications method in accordance with embodiments of the present invention includes receiving registry map information of network environmental indicia from a mobile device concurrently along with location information to a home location registry; generating an environment map for the mobile device based on the registry map information, the environment map including a device, application, and network component environment; defining service provisioning based on the environment map in response to a request for service from the mobile device, the service provisioning including and excluding predetermined elements of the environment map; and providing network service in accordance with the defined service provisioning. In some embodiments, the service provisioning includes accommodating a service provider policy. In others, the service provisioning includes accommodating a user selected preference. Further embodiments include defining a user context based on the environment map and including or excluding predetermined elements for provisioning based on the user context. A telecommunications system in accordance with embodiments of the present invention includes a plurality of user devices, the user devices configured to monitor available resources and dynamically maintain a resource registry of the available resources and transmit the registry to a service provider; a service delivery platform associated with the service provider and configured to dynamically maintain profiles of a plurality of user devices based on the resource registry information and allow access to resources based on the profiles. In some embodiments, the plurality of user device configured to maintain a capabilities list of user device attributes. The user devices may include one or more sensors for identifying a physical device environment and storing physical device environment information in the registry and may be configured to transmit the resource registry information to the service provider during a home location register location update. In some embodiments, the plurality of user devices are configured to transmit the resource registry information to the service provider as binary-coded data during a home location register location update. In some embodiments, the profiles define access based on physical device environment.
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LE, DANH C
CONTROLLING FUNCTIONS OF A USER DEVICE UTILIZING AN ENVIRONMENT MAP
SMALL
1
CONT-ACCEPTED
H04W
2,017
15,683,359
PENDING
SECURE AUTHENTICATION AND PAYMENT SYSTEM
A transaction and payment and processing system securely conducts transactions over the public telephone network. The transactions may be between and among entities of any type such as individuals, merchants, utilities, banks, etc. Nothing more than access to a telephone is required after initial registration of a user.
1. A server comprising: a processor, the processor including one or more program modules configured to: send a message to a client device, wherein the message provides instructions for a target to access the server to receive payment; receive one or more messages from the client device, the one or more messages including an alias assigned by the server to the target, a transaction identifier identifying a transaction, and a target financial account information; authenticate the one or more messages from the client device by searching for a stored alias and a stored transaction identifier associated with the alias in a database that matches the alias and transaction identifier in the one or more messages; and in response to authentication of the one or more messages from the client device, provide instructions to transfer a payment amount from an originator financial account to a target financial account associated with the target financial account information included in the one or more messages. 2. The server of claim 1, wherein the one or more program modules are further configured to store and link the target financial account information to the stored alias in the database. 3. The server of claim 2, wherein the one or more program modules are further configured to: receive the alias assigned by the server, a subsequent transaction identifier identifying a subsequent transaction, and a subsequent payment amount for the subsequent transaction; retrieve stored target financial account information associated with the received alias from the database; and provide instructions to transfer the subsequent payment amount from the originator financial account to the target financial account associated with the stored target financial account information. 4. The server of claim 3, wherein the subsequent transaction identifier is selected from the group consisting of an email address, a telephone number, a numeric string, an alpha-numeric string, a hash identifier, a uniform resource locator (URL), a coded URL, a coded string, and a combination thereof. 5. The server of claim 3, wherein the subsequent transaction identifier is embedded in a coded uniform resource locator (URL). 6. The server of claim 1, wherein the stored alias is an email address. 7. The server of claim 1, wherein the stored alias is a telephone number. 8. The server of claim 1, wherein the transaction identifier is selected from the group consisting of an email address, a telephone number, a numeric string, an alphanumeric string, a hash identifier, a uniform resource locator (URL), a coded URL, coded string, or a combination thereof. 9. The server of claim 1, wherein the transaction identifier is embedded in a coded uniform resource locator (URL). 10. A server comprising: a processor, the processor including one or more program modules configured to: send a message to a client device using an alias previously assigned by the processor and stored in a database, wherein the message provides instructions for a target to access the server to receive a payment amount for a transaction and the message includes a transaction identifier generated for the transaction; receive from the client device, one or more messages including at least an alias and the transaction identifier from the target for the transaction; and authenticate the one or more messages from the client device by searching for the previously stored alias and the generated transaction identifier associated with the alias in the database that matches the received alias and the received transaction identifier in the one or more messages, wherein the alias identifies a party to the transaction and the transaction identifier identifies the transaction. 11. The server of claim 10, wherein the one or more program modules are configured to: determine whether the payment amount is above a threshold; and in response to the payment amount being above a threshold, authenticating the message to be authenticated via a voiceprint previously stored in the database. 12. The server of claim 10, wherein the one or more program modules are configured to: in response to authenticating the one or more messages, provide instructions to another server to initiate transfer of the payment amount from an originator financial account to a target financial account. 13. The server of claim 12, wherein transferring the payment amount includes providing instructions to the another server to debit the payment amount from the originator financial account. 14. The server of claim 12, wherein transferring the payment amount includes crediting the payment amount to the target financial account. 15. The server of claim 10, wherein the one or more messages is selected from the group consisting of a text message, an email message, a message initiated from a web browser, a message initiated from a mobile application, a message initiated from an interactive voice response system, a wireless network message, an Internet Protocol type message, a system message, a peer to peer message, a computer originated message, and a combination thereof. 16. The server of claim 10, wherein the one or more program modules are configured to: receive one or more messages including the alias and a subsequent payment amount for a subsequent transaction; retrieve previously stored information associated with the received alias from the database; and provide instructions to transfer the subsequent payment amount from an originator financial account to a target financial account. 17. The server of claim 10, wherein the generated transaction identifier is selected from the group consisting of an email address, a telephone number, a numeric string, an alpha-numeric string, a hash identifier, a uniform resource locator (URL), a coded URL, a coded string, and a combination thereof. 18. The server of claim 17, wherein the generated transaction identifier is embedded in a coded uniform resource locator (URL). 19. A server comprising: a processor, the processor including one or more program modules configured to: send a message to a client device using an alias to a target assigned by the server, wherein the message provides instructions for the target to access the server to receive a payment amount for a transaction and the message includes a stored transaction identifier for the transaction; receive one or more messages from the client device, the one or more messages including a received transaction identifier from the target; and authenticate the one or more messages from the client device by searching for the stored transaction identifier in a database that matches the received transaction identifier in the one or more messages, wherein the alias identifies a party to the transaction and the received transaction identifier and the stored transaction identifier identifies the transaction. 20. The server of claim 19, wherein the one or more messages is selected from the group consisting of a text message, an email message, a message initiated from a web browser, a message initiated from a mobile application, a message initiated from an interactive voice response system, a wireless network message, an Internet Protocol type message, a system message, a peer to peer message, a computer originated message, and a combination thereof.
CROSS-REFERENCE TO RELATED APPLICATIONS The present application is a Continuation Application of U.S. patent application Ser. No. 13/689,308, filed Nov. 29, 2012, which is a Divisional of U.S. patent application Ser. No. 10/375,501 filed on Feb. 26, 2003, now U.S. Pat. No. 8,346,659, which is a continuation-in-part of U.S. patent application Ser. No. 09/899,905 filed on Jul. 6, 2001, now U.S. Pat. No. 7,742,984, the contents of which are herein incorporated by reference in their entireties. BACKGROUND OF THE INVENTION Field of the Invention The present application relates to authentication and payment systems and, more particularly, to secure authentication and payment systems. Background Information Authentication is a major constituent of essentially all commercial transactions. is When individuals deal with each other face to face, authentication may be implicit if the individuals know each other. If they do not, authentication at various levels may be required before the transaction is allowed to be completed. For example, a photo ID such as a driver's license may be required by a party to the transaction before the transaction is allowed to proceed. Authentication is particularly a problem if the parties do not know each other and/or are not dealing with each other face to face. In such a case, various forms of identification, such as passwords, may be required as a condition of completion. Authentication systems, of course, are adjuncts to payment systems. There are many systems used for exchange of value (payment) which include, but are not limited to, cash, checks and credit/debit cards. The latter are particularly vulnerable to fraud and theft, and account for substantial losses to merchants and financial institutions every year, despite significant efforts to authenticate the transaction of which they are a part. Businesses which sell items of comparatively low cost have an especial need for transaction authentication which is simple and minimally intrusive but nonetheless robust. Purchasers of such items are largely members of the general public, often with limited patience. While they will accept some level of authentication in connection with a transaction, the level is generally not sufficient to ensure reliable authentication of all transactions, and customers will often refuse to deal with merchants who seek to impose higher levels of authentication. Thus, merchants frequently limit the authentication requirements that they impose, and therefore knowingly incur a predictable level of loss rather than lose customers who will not accept higher levels of authentication. The cost of authenticating a transaction is also a major factor in its use. The cost of authentication must not be significant in relation to the cost of the article, else authentication may be omitted in order to induce the sale. One of the first and still most widely used systems of authentication is the bank Automated Teller Machine (ATM) system that is used by many banks. In this system a financial institution issues to an individual an ATM card which is preprogrammed by the financial institution to be accepted by the network. The individual can then access funds and banking information by inserting or swiping the card using ATM specific apparatus which is connected to the network, either in real-time or through a dial-up service. The apparatus requests a PIN (personal identification number) from the user. After the individual has keyed in the PIN, the network matches the keyed PIN with a pre-recorded PIN. If the information matches exactly, the ATM network allows the individual to check his account balance, pay a bill, or receive currency from the machine, among other available transactions. This level of authentication has been deemed acceptable to individuals and financial institutions, but it requires special apparatus (the ATM machines and the ATM cards) as well as a private communications network over which the transactions take place. Further, different banking networks belong to different ATM networks. Authentication When Not Present (AWNP) has become an important issue in increasingly complex commercial transactions. Typically enterprises such as American Express®, VISA®, MasterCard®, banks or check-clearing networks and their affiliates (referred to collectively herein as Payment Networks (PN)) provide a unique apparatus to merchants that are connected to one or more PN's. In order to obtain authorization for a payment, the PN typically requires that the cards issued by them be swiped through the apparatus or that check numbers and other details be inputted on a keyboard by the merchant or by their agent. The merchant may also simply read the card or check data over the phone to the PN agent. The unique data is then transported on a network and authorization is obtained from the appropriate PN. The merchant then typically requires the customer to sign a template document to verify the purchase and the customer's responsibility for paying for the goods to the PN or, in the case of checks, to completing a check and signing it. Sometimes a merchant will require a separate identification (ID), but in most circumstances, especially in the case of a PN card, the only authentication typically required is the PN card itself. After the customer signs the template document, the merchant relegates the responsibility for payment to the PN, relying on the authorization obtained from the PN and the signed document they have obtained from the customer. If the customer disputes the transaction, the merchant presents the document as a means of verifying the purchase. This system relies on two premises: 1. That the customer will promptly report a lost or stolen card, so that a card presented by a customer to the merchant, if not previously reported lost or stolen, can be assumed to belong to the customer presenting it. 2. That the signature on the back of the card matches the template document after authorization has been obtained by the merchant. There are many ways that fraud can occur in this arrangement. Some examples include, e.g., a card that has been stolen but not reported as such; a card that has not been signed by its authorized owner but has been signed by an unauthorized user instead; and failure of the merchant to check a signature when a customer signs the template document, among others. In the case of taking orders over a phone or on the internet, a card is not present and no signature is obtained to verify the customer; therefore, in most circumstances, if a customer disputes a transaction, the PN holds the merchant responsible, as the merchant was willing to proceed with the transaction without obtaining a signature. This is referred to in the card industry as “charge back”, and can account for 2 to 10% of the value of the goods sold by the merchant. Additionally, most PN's require a higher transaction fee for Transactions When Not Present (TWNP), or for merchant classes that have higher proportion of their sales as TWNP, and thus the merchant's transaction costs are increased. SUMMARY OF THE INVENTION Despite the widespread adoption of the internet and the significant commerce which already takes place over it, a substantial portion of the public still does not use the internet for commercial transactions. For some of these the non-use is attributable to unfamiliarity with, or access to, computers which can access the internet. For others, it is due to lack of trust in the security features of the system. Whether or not they have access to, or are able to or do, trust and use the internet, most people have long been accustomed to using the telephone and to conducting business over it. Unlike the internet, in which data can easily be intercepted by skilled hackers, telephone transmissions are difficult to intercept without specialized equipment and often then only with considerable difficulty. The main reason is that, with the telephone, communication takes place securely between two nodes within a channel, in contrast to the internet or other general public networks where multiple nodes have access to the same communication, thus allowing interception and hacking. This is the case both with land-line telephones, in which the information being transmitted travels to a local central office via a unique circuit which is difficult to “tap” unobtrusively, as well as with wireless communications which may be encoded. Telephone numbers are universally assigned uniquely to customers by the telephone company, and thus can serve as a unique identifier for a customer. The International Telecommunication Union (ITU) and all the global telephone operating companies have agreed to assigned country codes. For example, 1 identifies the United States, Canada and parts of Caribbean; 49 identifies Germany; and so forth. Furthermore, the various authorities and telephone companies in each country have decided on area codes and numbers for cities, areas or regions, e.g. 617 for Boston and 212 for parts of Manhattan. Within these areas, an individual subscriber is assigned a unique number. This numbering system allows, e.g., an individual in South Africa to simply dial the country code of the United States, the assigned area code, and finally the user number to reach a desired person or entity. This numbering system provides unique routing information which has been used primarily by Telephone Operating Companies (Telcos) for finding a subscriber, opening a circuit, and completing a call. The present application uses this unique telephone numbering system as a principal identifier in routing and completing financial transactions and other transfer of goods and services. In recent years various Telcos have made this number accessible to the users of the telephone system by way of “Caller ID” offering. In this service, the telephone number of the calling party is sent to the called party, along with the dialing information, thereby identifying the calling party. If the called party subscribes to the “Caller ID” service, he/she is thus enabled to see or otherwise ascertain the telephone number of the calling party in connection with the call. This number has been available internally to Telcos since the advent of electromagnetic switches in the early 20th century. It became more transparent through the advent of digital switching, especially the Class 5 switches in the early 1980's. The caller information was and is used for signaling, routing and billing by Telcos. Hereinafter we designate Caller ID (CID) and any other unique identifier of a Telco network subscriber such as Caller Line ID (CLID) or Automatic Number Identification (ANI) and the like simply as Caller ID. Various further uses have been proposed and/or implemented for making use of this functionality for performing authentication functions in various contexts. For example, one of the telephone companies has proposed to use it for authenticating requests for call forwarding services. See U.S. Pat. No. 6,018,570, issued Jan. 25, 2000, for “Methods And apparatus For Regulating The Remote Ordering, Authorization, Access And Control Of Services And Service Features Associated With A Terminal”. In that patent, the unauthorized ordering of call forwarding services for an unsuspecting customer, and its subsequent use to place long distance calls, is proposed to be defeated by checking the ID of the telephone from which the service is ordered and refusing to implement call forwarding on the targeted customer telephone unless the ID of the requesting telephone is the same as the ID of the customer telephone. Another proposes to use it over one network (e.g., the telephone network) to authenticate purchases over a second, separate network (e.g., the internet). See U.S. Pat. No. 6,088,683, issued Jul. 11, 2000 to Reza Jalili for “Secure Purchase Transaction Method Using Telephone Number”. In that patent, a customer contacts a merchant over a first electronic network (e.g., the internet) which either the customer, or the merchant, or both may deem insecure, and places an order. In connection with the order, the customer identifies itself by supplying its telephone number and a registration number previously issued by a central registry. The registration number is obtained by either calling or writing the central registry in advance of any transaction. The merchant then generates an invoice that includes the customer identification information and transmits it to the central registry. In order to complete the transaction, the customer must then call the central registry and confirm the order. The central registry may verify the customer by any of various techniques, one of which optionally may include use of the customer's caller ID. This proposal has a number of defects which limit its usefulness. First, the exclusive arena in which transaction occurs is the world wide web i.e. the internet. The telephone phone is used for authentication purposes only, and not as the initiator or medium of the transaction. Further, the transaction requires multiple sessions on the part of the user, allowing lapse of time which can diminish its value from both the customer's and merchant's point of view. Specifically, by separating in time the initial purchase decision and its final approval by the customer, a “second thought” on the part of the customer is more likely to occur, and thus reduce the number of transactions. Further, fraud can occur in the very registration process itself, since registration is to be accepted not only from the registrant's telephone, but also from alternate telephone numbers. Although various security checks are suggested in the latter case, use of caller ID is merely one option, leaving open the distinct possibility that information that was in fact stolen from another (e.g., a Social Security number) may form the basis of registration. It has also been proposed to use a party's caller ID as a substitute for their credit card number: see U.S. Pat. No. 6,227,447, issued May 8, 2001, for “Cardless Payment System”. In the system of that patent, a customer makes a purchase by providing his/her telephone number and a PIN to a merchant in place of the usual credit card number. The merchant then retrieves the credit card number from the credit card issuer using this information. The telephone number and PIN may be supplied in person to the merchant, in which case there is no further verification provided for, or it may be done over the phone, in which case the merchant may obtain the number from the call itself and may use this without asking the customer to repeat its input or may use it to verify the telephone number input by the customer. In either case, the transaction is ultimately dependent on the merchant's obtaining and using the credit card number to complete the transaction, and the customer's telephone number is simply a mechanism through which the credit card number is retrieved. In contrast to the above, I have developed a secure system for transaction authorization and payment. The system requires the use of only a single session by a user desiring to initiate a transaction, and in most cases a single network, and is instantly accessible via a telephone network, mobile or landline device. This device need not necessarily be a telephone; it can be a Personal Digital Assistant or other device. The device, however, must be one having a preassigned unique number on a telephone network or on an IP telephony network through a pre assigned IP gateway. For ease of use hereinafter, I refer to such a device simply as a telephone, with the clear understanding that the term is intended to encompass not only voice-transmission and reception devices commonly understood by the term “telephone” (i.e., “conventional telephones”), but also personal digital assistants and other devices used for connecting to the telephone network and each having a unique number assigned to them. Of course, the device may share a given telephone number with other telephones of a user as is now commonly done with conventional telephones in the case of extension telephones. Similarly, for convenience of reference, I refer to the person using the device to pay bills, make purchases, transfer money or other assets, etc., as “the customer”, whether an individual or an organization, and even though a particular transaction may not in fact involve the purchase or sale of goods or services. The authorization process of the present application is rapid and largely transparent to the customer. It can be implemented with a single session between the customer and a third party such as a merchant, yet is sufficient to establish and complete a transaction, together with payment for it as appropriate. It is an object of the present application to provide an improved authentication system for transactions between entities. Another object of the present application is to provide an improved authentication system which facilitates consumer transactions. Still another object of the present application is to provide an improved authentication system which is unobtrusive with respect to the user. Yet another object of the present application is to provide an improved authentication and payment system. Still a further object of this present application is to provide a simple yet relatively secure system for authenticating an individual or organization and allowing them to forward and/or swap funds, goods and services including, but not limited to, stocks, motor vehicle titles, or other assets or certificates representing value. Still a further object of the present application is to provide an improved authentication and payment system which is reliable, yet unobtrusive. Yet a further object of the present application is to provide an improved authentication and payment system which does not require the presence at a particular site of a customer using the system. Still a further object of the present application is providing an improved system for authentication and/or payment which is geographically universal. Still a further object of the present application is providing an improved system for authentication and/or payment which does not require special apparatus for its operation. The foregoing and other and further objects of the present application will be more readily understood on reference to the following detailed description of the application, when taken in connection with the accompanying drawings, in which: FIG. 1 is a block and line diagram of a first form of authentication and payment system; FIG. 2 is a block and line diagram of a second form of authentication and payment system; FIG. 3 is a system-wide view of the transfer of assets from a payer trust account to a payee trust account in accordance with the present application; FIG. 4 FIG. 4 illustrates some of the data that may be included in a user's trust account; FIG. 5 illustrates the operation of the present technique in the case of a direct transfer of assets from an initiator-payer to a target-payee; FIG. 6 illustrates an enhanced form of authentication in accordance with the present technique; FIG. 7 illustrates a further form of enhanced authentication in accordance with the present technique; and FIG. 8 is a flow chart of a process by which the value at risk in a transaction is controlled in accordance with the present technique. DETAILED DESCRIPTION OF THE INVENTION In accordance with the present application, a customer (or, more generally a “source” or “initiator”) conducts transactions securely by telephone with a “target”. Such transactions may include, for example, the ordering of merchandise from a merchant (which term should be understood in the broadest sense herein to include any entity engaged in any form of business or commerce whatever); the payment of a bill to a merchant; the transfer of money to another person or merchant; the transfer of money from one account to another; or the transfer of assets or property from one entity to another, such as by transferring ownership of shares, etc., among other types of transactions. The transaction is performed either directly with the target or indirectly through an intermediary (hereinafter called for convenience “the Facilitator”). The Facilitator includes at least a data processor programmed to handle one or more portions of the transactions to be undertaken in connection with it. Typically, the Facilitator will include programs or program modules to receive a call over a telephone network; authenticate the call as described hereinafter; and process the transaction, such as by debiting and crediting various accounts or providing the required information for others to do so, or by keeping records of the transaction or otherwise enabling the transaction in an orderly manner. As necessary, one or more of these functions may in fact be performed by a human being. The Facilitator typically maintains two separate databases, the first of which defines the customers, and the second of which defines at least some of the targets with which a customer may undertake a transaction. The customer database includes fields containing at least the customer's registered Telephone Number and a customer-selected password (PIN), as well as data pertaining to a Funding Mechanism (hereinafter, “FM”, e.g., an account or line of credit with the Facilitator or with a third party, a bank account, a credit card, debit card etc.) against which transactions undertaken by the customer may be debited. Additional fields are preferably included, however, including the customer's name and default address and shipping preferences, such as shipping address, shipping mode (e.g., parcel post, United Parcel Service®, Federal Express®); additional FM's (e.g., one or more credit cards, with their requisite identifying numbers and other information; bank accounts, bank routing numbers; credit facility provider, amount of credit available etc.) and other data useful in processing transactions. Similarly, the target database contains fields including at least a target identifier (e.g., a sequence number assigned by the Facilitator, the telephone number of the target, or simply the name of the target) and a payment destination identifier that defines the entity into which authorized payments are to be made (e.g., an account with the Facilitator, an account with a bank, etc.). Preceding completion of a transaction between two entities (which term is intended to encompass individuals as well), the Facilitator registers at least one of the parties to the transaction. Typically, this occurs before either entity uses the system, but may occur after only a single entity has registered. In the latter case, registration of the other party or parties to the transaction is preferably sought to be made part of the transaction, although completion of the transaction need not be conditioned on this. In order to register, a call is placed between the Facilitator and the entity to be registered, from which the primary identifier (i.e., the telephone number of the device to be registered to the entity) is obtained or verified. The entity then provides certain information such as a secondary identifier (e.g., password) to be associated with it and additional data such as its name, address, payment sources (in the case of a customer), destination account sources (in the case of a merchant or expected payee), or both (in case of those who will be both paying and receiving). Further data such as shipping preferences are desirably included. Where multiple alternatives are provided for a given data source (such as payment source, shipping mode, etc.), default preferences are established; these may simply be the first item listed in the respective categories. A key entry in each database is the Caller ID, which serves as the primary authenticator for the transaction, while a further preferably unique identifier such as a personal identification number (PIN) serves as the secondary authenticator for each transaction. A tertiary identifier may be provided for identification. The collection of data comprises a “voice wallet” which may thereafter be used to facilitate transactions. Some or all of this information may be obtained instead from the telephone company which stores certain data in connection with devices registered with it, or may be verified against the data maintained by the telephone company. As a specific example of a typical expected registration procedure, assume that a customer wishes to conduct transactions with or through the Facilitator. The customer preferably first registers with the Facilitator. This may include the following steps 1. The customer calls the Facilitator from a given telephone or other device to be registered. Information pertaining to the telephone number of the device used by the customer is already on record at the Telco or other entity that maintains a telephone number and subscriber database, and in most circumstances has been verified by the Telco. This information includes the telephone subscriber's name, address (in case of land-line devices, the address where the telephone line is terminated), social security or other unique identification number, and credit check in most instances, among other information. The Telco database can also contain private unique information useful for identification, e.g., the mother's maiden name, etc. Information from additional sources such as credit card companies, credit bureaus, etc. may also be obtained and utilized by the Facilitator. 2. The Facilitator retrieves the requisite information from the Telco's database and, if private information is contained in the database, such as mother's maiden name, data and amount of the last telephone company bill or payment, outstanding balance on an account with another entity, etc. may require the customer to input that information for purposes of further verification. It might also simply send a sign-up form through the mail to the customer. The Facilitator may then store some or all of this information in its database. 3. The Facilitator then requires the customer to input FM information. For example, in the case of a bank account, the Facilitator may require bank routing information and an account number. Of course more than one FM can be mapped to a telephone number (account). Additional information may also be requested from the customer by the Facilitator. 4. The Facilitator then verifies that certain key information of the Telco or other third party database matches corresponding key information input by the customer, e.g., social security or other unique identification number, banking or credit line information, etc. If it does, the Facilitator then links the requested funding mechanism to the telephone number and requests a PIN number from the customer; the linking is typically performed simply by establishing an association in the database between the customer telephone and PIN numbers and the funding information for that customer. As part of the linking process, the Facilitator preferably checks certain information (e.g., Social Security number, mother's maiden name, etc.) provided by the registering party against corresponding data on record with respect to that party at the telephone company, as well data that may be on record with the funding mechanism entity. Of course, a PIN number may already have been supplied by the customer to the Telco when the customer signed up for an account with the Telco, and in that case need not be supplied again by the customer. Further, as an additional security measure, the Facilitator may require a written confirmation via mail or email before proceeding with linking the FM identifier to the telephone subscriber's line. The registration can be also performed via the internet or by mail or email in which case after the customer fills in the information and submits it, the Facilitator verifies it against the telephone company data for the device to be registered and then, if it matches, proceeds to link the customer telephone number and PIN to the collected data. The present technique is adapted to operate primarily in either of two modes. In a first, indirect, mode, the customer deals with the Facilitator only. For example if the customer wishes to engage in a transaction with a merchant target, the customer may initiate the transaction by calling the Facilitator on a telephone or other device which the customer has previously registered with the Facilitator and whose Identity (i.e. telephone number or other identity uniquely assigned by the telephone operating company or other authorities) is thus stored in the Facilitator database. The Facilitator verifies the customer's identity at a first level of authentication by checking the Caller ID associated with the call against the information contained in the database. The customer next provides a password that is preferably unique to it; this may be done verbally, or by entry on a Touchtone® telephone. The Facilitator then verifies the password. Of course, the Facilitator may delay verification of the Caller ID until the password is received, and then verify both together. Next, the customer identifies the target and the transaction to be performed with it. For example, the customer might say: “Pay Sunshine Floral Shop of Boston $97.50 and charge my Empire Bank account number 837557”. This information may, of course, alternatively be provided at the outset of the customer call, and held by the Facilitator pending customer verification. Additional data may, of course, be provided by the customer, and used in the transaction. For example, the customer may specify an item to be purchased, the quantity, shipping terms (e.g. United Parcel Service®, U.S. mail, etc.). The Facilitator confirms these requests against the target database and processes the transaction as described above. The key, however, is the telephone number of the customer, or the target, or both, which serves to uniquely identify one or both parties to the transaction. The Facilitator responds by checking the account of the target, Sunshine Floral Shop of Boston. If no such account exists, the Facilitator may establish a default account to which the funds are temporarily credited. The default account is preferably simply defined by at least the target's telephone number. In connection with this, it preferably notifies the customer of this action. The Facilitator may also contact the target and offer it the opportunity to register an account with the Facilitator. If the target account already exists, the Facilitator verifies the data required to complete the transaction. If the registered data does not match the data given by the customer, the Facilitator notifies the customer, the target, or both, to resolve the issue. If the data does match, however, the Facilitator notifies the target of the desired transaction and requests approval by the target. This approval can be made during the call or at a time in the future. Any notification can consist of a telephone call, notification through a private network, an email, regular mail or any other means. If qualified approval is obtained (e.g., the target approves of the transaction in general, but wishes to change the account into which the money is to be paid from its default account to some other account), the customer is notified and asked for approval if the requested change affects the stated terms of the transaction (e.g., the purchase price) but may not be notified if it does not (e.g., the destination of the payment when no destination is specifically designated by the customer) or if such transfers have been explicitly or implicitly preapproved by the customer. Similarly, if the target has been provided in advance with a blanket approval of all transactions requested to be paid from customers, the approval is not necessary and a preset account is credited and the customer's account is debited. Once an account has been approved or approval dispensed with, the Facilitator debits the designated customer account, credits the designated target account, and preferably notifies both parties of the successful completion of the transaction. The customer may in fact approve of the modification of the transaction. For example, a parent who wishes to make a payment to a child for a designated purpose (e.g., payment of college tuition) may block payment of amounts it sends to a child to any account other than a designated tuition-payment account, e.g., an account of the college itself. The target need not be a member of the Facilitator's network. As long as it is a subscriber to the Telco and has a unique telephone number, that number can be used for crediting and debiting funds or other assets. If the target's account is in credit, it can always forward funds to another telephone subscriber without explicitly registering with the Facilitator. If any funds or assets must be credited against an account with a FM i.e. a bank account etc., then registration is necessary. The above transaction can be driven through an automated voice response system in a single step or in multiple steps to the extent necessary to accomplish the above task. In the above example, the transaction can be completed with a single phone call by the customer. In most instances, it is expected that the transaction will be completed without need for further input by the customer, and during the course of the call, which generally will be brief. Thus, a minimum of time is expected to elapse between the time the customer first initiates the transaction, and the time that the transaction is confirmed as complete. This minimizes the likelihood that a customer will change its mind during the transaction processing, an important consideration for merchants that deal in real-time purchases, such as goods that are advertised on the radio, on television, in print, and in other media. A significant embodiment of the present application is the transfer of value or resources from one entity to another after authentication by using the unique Telephone Numbering system. For example, a customer who wishes, as a “transferor”, to transfer money or some other resource, such as the title to a motor vehicle, or the ownership of a stock certificate to another (“the transferee”) calls the Facilitator and identifies the transferee as the target of the transaction, such as by giving the transferee's telephone number; the amount of money to be transferred and the account against which the money is to be debited, in the case of a money transfer, or the data identifying the resource to be transferred and such other information as may be necessary or desirable for the transfer of the resource. The Facilitator then preferably checks the identity of the entity associated with the target's telephone number and reports this to the transferor for final approval, thereby providing an additional level of security to the transferor. Once the transaction is approved within the transferor's account, a call or other form of notification is generated by the Facilitator to the transferee, in which the transferee is informed of funds or other resources which are available to him by transfer from the transferor. The transferee can then either register with the Facilitator (if not already registered) by providing his identity and other information, or may transfer the funds or resources to another target through the same procedure described above if this is permitted by the transferor or by the Facilitator. The transferee can be contacted by telephone, by email or by other means. As long as the target is uniquely identified through the phone numbering system, the transaction can be carried through. In all cases a pre-approved PIN may be used. Also, a request to pay another can be notified to the Facilitator by the customer by an email or a web page containing the telephone number of the target and all information required to complete the transaction. In this mode upon the receipt of the information the Facilitator generates a call and proceeds with completing the transaction. Finally, the customer can use the phone and request that a payment be made to a person where notification to the target is made through email or other modes like SMS messages on a mobile phone or through checks to be issued etc. Person-to-person (or entity-to-entity) transfers can securely be made in the course of a conversation between two parties in accordance with the present technique. For example if, during the course of a conversation, one party to the conversation decides to pay money or transfer an asset to the other, it can put the other party on hold (or initiate a three-way call), contact the Facilitator, and arrange for the transfer. The Facilitator can instantly authenticate the calling party through Caller ID and approve or complete the transaction as appropriate. In situations in which the identity of the party initiating the call is authenticated by means other than by its telephone number, a party may initiate a transaction with another is (the target) that is itself identified by a telephone number (Caller ID). In this mode, upon the receipt of the information, the Facilitator generates a call to the target and proceeds with the transaction. Alternatively, a party may initiate the transaction by calling the Facilitator using its telephone (so that its identity is established by its caller ID and password as described above) and initiate a transaction with another (the target) in a mode in which the target is communicated with other than through the telephone. Rather than having the customer initiate the call, the system may also work in reverse, i.e., the customer may be the target of a call made by the Facilitator at the request of a merchant, a landlord, a utility, etc. For example, a cable television broadcaster may use the system to present its monthly bills to customers for payment over the telephone. The broadcaster may provide the Facilitator with a list of its customers and the payments due from each. The Facilitator then dials each customer. The details of the bill such as the name of the requesting entity (here, the broadcaster), the amount of the bill, and other data as desired are then presented to the customer and the customer is asked for its assent to payment. Verification is ensured by means of the customer's telephone number which the Facilitator itself has dialed and, optionally, the password or other unique information provided by the customer when the call is answered. On receiving the assent of the customer, the requester (broadcaster) is notified for its records, and the Facilitator may directly proceed to complete the transaction by debiting and crediting the appropriate accounts if the requester so desires. The customer can request that the call be made, for example, 5 days later, or 3 days before the bill is due, or at the due date, etc. The system records this request and initiates the call in accordance with the request. The requests can also be setup on the internet at the Facilitator's web site. The customer can also directly call the Facilitator and request that the bills be paid. In this mode, the Facilitator verifies the customer's Caller ID and password, if necessary and proceeds with crediting the biller's account and debiting the customer's account. It is important to note that under most circumstances described in this application, the Facilitator can check the Telco directory (or other source, e.g., a channel partner, its own database, etc.) for a target's name or alias and report it to the subscriber. If the target's name is not listed in the directory then this can also be reported. As such, validation occurs thus building confidence for the transaction. In a second, direct, mode of operation of the technique, a customer contacts a target directly, instead of through the Facilitator. For example a customer desiring to purchase an item sold by a particular merchant calls the merchant on a registered telephone. Before placing the order, the customer may inquire as to features of the desired item, price, availability, warranty, etc. This information is provided by the merchant. If the customer desires to proceed with the transaction, the merchant transfers the call to the Facilitator for authentication of the customer. The Facilitator authenticates the customer by means of the customer's telephone number and may also verify that the customer has sufficient funds to pay for the transaction and may, if desired, debit the customer account and credit the merchant account. Following authentication, the Facilitator may transfer the call back to the merchant for completion of the transaction or may, if desired, complete the transaction itself, preferably with confirmation to both the customer and the merchant. Completion by the Facilitator may encompass only some aspects of the transaction, such as the financial aspects of debiting and crediting the customer's account and crediting the merchant's account, with the rest (e.g., shipping) being performed by the merchant, or may encompass all further aspects of the transaction in its entirety. Bill presentation and payment by a requester may be performed in the direct mode as well. Thus, the requestor calls the customer itself or the customer calls the requester but, on obtaining the customer's assent to payment of the bill (e.g., by authorizing a charge to a credit card, debit card, or other FM's), the requester transfers the call to the Facilitator for at least authentication of the customer. The Facilitator may perform only the authentication portion of the transaction, or may additionally perform some or all of the completion of the transactions (e.g., the financial aspects, accounting, and the like). In an alternative mode, the customer can be physically present at the target's (e.g., merchant's) site. In this mode the customer provides the merchant a unique identifier, preferably his phone number or an alias provided by the Facilitator. The merchant then enters this information into a specific apparatus which is connected to a private or public network or through a phone call to the Facilitator. The Facilitator then calls the customer or owner of the account for verification. The call may be made to the registered device primarily associated with the customer, or to a device whose number is associated with the customer in the customer database. Typically, the call is made to a mobile device. The customer can then approve the transaction. The approval can also be given by a surrogate for the customer such as a parent or any third party that owns the account and that is called instead of the customer. In any event, the approving entity provides a PIN and may select what FM to use for this transaction, among other attributes. The transaction may be completed by the merchant or by the Facilitator. In either case, the customer's purchase can be cleared and paid for without proceeding through any checkout line. The products can be picked up on leaving the store or shipped subsequently. The information provided by the customer about its account number can be provided verbally or through a card issued by the Facilitator, where the merchant swipes the card on a specific apparatus or reads the information via a telephone to the Facilitator. It can also be provided through infrared communication or other means of local communication, wirelessly or through coupling of the device carried by the customer to the one provided to the merchant by the Facilitator or its agent. Both direct and indirect mode of transactions can occur with this third mode. In any event, verification of the transaction is performed by telephone call by the Facilitator to the registered telephone number of the customer or the customer's surrogate (e.g., parent). The call may alternatively be made on an approved device by the customer to the Facilitator, avoiding need for a callback, since the call itself provides to the Facilitator the caller's ID; additional customer information such as a secondary ID (e.g., the customer's PIN associated with the given device) may also be obtained by the Facilitator in connection with the call. In connection with all types of transactions defined herein, the customer or target may be provided with an “alias” by the Facilitator. This alias may be used to identify the customer to the merchant as one registered with the Facilitator, without compromising the private secondary identifier (password) used by the customer to authenticate itself to the Facilitator. This may be important with certain customers that do not desire to reveal their phone number to targets for privacy or other reasons. The Facilitator can decide to provide an alias for the shipping address, for payment information, to mask the customer's information to the target for privacy, or for other purposes, if required. Either the target or the customer or both are identified by a predefined series of numbers or words or other means of unique identification, preferably the telephone number. However, the target may have been assigned more than one account, which in turn means that when a target is specified as a recipient of funds by a customer, in addition to the identifier, a specific secondary identifier may also be presented for an accurate routing of information, including funds. This may apply to corporate entities where a corporate account is set-up with many subaccounts. In certain circumstances, individuals have placed a bar on transmitting their Caller ID in connection with calls that they make. In such circumstances, the individual can often momentarily circumvent this by dialing an “opt-out” code such as *82 or the like. Further, in some circumstances, a unique number for a telephone is not identified (for example, an office which displays a single number for all the extensions of the company), or Caller ID is barred without the ability for an individual to “opt out”. In such circumstances, a call-back service may be used for all scenarios herein described. The number can be registered via phone, internet, mail, e-mail; etc after an initial account is set up. Then, when a call is generated from phone on which Caller ID is blocked, a password or secondary check, if necessary, is made. If the system is satisfied, it calls back on the prespecified number. It might then require a further password, such as a secondary password and other means of uniquely identifying an individual before proceeding with any mode of operation herein described. It is possible to have more than one account registered to a single phone number; for example, a husband, wife and child each having their own account from the same number. This is similar to a primary card holder in the credit card business, where a primary holder has an account and his/her spouse or child can have an account within the same credit line. In this circumstance the primary user, that is, the person of record with the phone company, must first register, and then allow any secondary person to register an account from the same number. Each individual may be assigned a unique PIN number, or a common number may be used. Each subaccount holder will be treated as a separate entity with their own FM and personal information. In some circumstances they can share funding sources. In order to identify the sub account a number or letter may be assigned by the Facilitator, for example 617 555 1111A, B etc. As noted above, in certain circumstances, for example, a parent-child relationship, the child may be set up with an account in which provision is made for a call back to a parent. When the child then uses the system, or indeed even uses a physical credit card for purchasing goods and services, before the purchase is authorized, the Facilitator requests parental consent/approval prior to authorizing the purchase. This relationship can be extended to manager-subordinate as well, when a purchase is done by a subordinate, but approval has to be carried through by the manager. Of course a full report of transaction and summaries will be available to the parent, manager or any subscriber as such. An individual or entity can also have multiple accounts linked together so as to operate an integrated account. This can be accomplished initially by setting up the first number, e.g., a home number, and then requesting the set up of a second number (e.g., a mobile device), a third (e.g., an office, a second home etc) or more. Each number can share FM's or have a unique FM or set of FM's linked to them. The individual can also request a callback service for any of the accounts. In this way the individual's account has a central location and can be reached via multiple devices (phone numbers), and integrated reports can be presented to the individual. It is also possible to operate the system in an IP telephony environment. IP telephony typically has a unique IP address or telephone gateway, but this can be intercepted. In certain circumstance IPs are not static. Also, in contrast with the telephone numbering system, where a central authority regulates phone number issuance and management, due to the inherent nature of the internet as an open environment, there is no central controller of IP addresses, and therefore it is prone to abuse, especially for financial transactions. In accordance with the present technique, the Facilitator may be used to provide a gateway where an unauthenticated call can be initiated by the customer to a preassigned static IP address at the Facilitator. The Facilitator, based on pre-specified guidelines (e.g., previously disclosed sender IP address, a digital signature, unique information e.g., password, mother's maiden name, etc.) can establish and authenticate the individual. In connection with the authentication, the Facilitator generates a call to a preassigned phone number of the customer on the public switched network; obtains a password from the customer; and then originates a call or a message to a target. At the point of authentication, when the Facilitator has the required information, e.g., the current Caller ID, etc., it approves the transaction. The present technique also readily lends itself to the secure and rapid transfer of money, either to the customer himself/herself or to others, or the transfer of money from one account of the customer to another within the same bank or another bank, as long as the FM/accounts have been established and registered with the Facilitator. Credit lines may be made available to a registered customer by a bank or by the Facilitator itself. Thus, when registering for service, the Facilitator itself, either directly or through a third party, e.g., a bank, may provide credit to the phone account. The customer may call on this line as desired. The credit facility functions identically to the funding mechanism of the account outlined above; functionally it acts as a FM. When undertaking a transaction the customer, rather than selecting a credit card or bank account, requests the use of the credit facility. Of course more than one credit facility can be established for a single account by various credit providers or by the same provider. The user can select the provider when engaging in a transaction, just as he selected the FM prior to completing the transaction. It is possible that either the target or the customer fund the account or receive funds in cash form directly or indirectly through a third party member of the Facilitator's network. In funding the account, the customers can 1. Go to a bank branch, a Facilitator network member store, a Facilitator itself, a network member ATM machine, or other agents, herein referred to as Network Members (NMs), pay cash, physically present a credit card to be debited, or present a check, among other acceptable payment instrument acceptable to the NM. The NM, after satisfying itself with respect to the availability of funds, will then directly, via a private or public network, provide a message to the Facilitator with the customer's account identifier, e.g., the phone number, which results in a credit to the account of the customer. The payment to the NM acts as another FM here. The NM may also simply provide the customer with a receipt containing a coded number, which can then be used by the customer in a manner similar to the funding card serial number described below. 2. Buy a pre-assigned funding card similar to the telephone cards in existence today. The funding card will have a serial number. Once registered as described previously, the customer can provide the funding card serial number to the Facilitator and receive a credit, based on the purchase price or a ratio of the purchase price, on the account which may then be used to do all the various different applications described herein, including sending funds to a target. In fact the funding card acts as another FM. In case of payout of the funds in cash to the target or recipient, the target can receive funds if: 1. The customer has provided a specific address, for example a bank branch in Wichita, Kan. In this mode the intermediary (The specific bank branch, NM store or other NM's) will receive an instruction from the Facilitator with a recipient's details. The recipient is notified via a call, email, mail or other means. The recipient will then go to the bank branch, etc. and produce an ID or other means of authentication to receive the funds 2. A check can be mailed by the Facilitator based on the target's name and address as provided by the customer instruction. A one time or limited time use card can be issued to the target at the request of the customer. The target can use this card on NM ATM networks to receive funds in full or partially until the funds are exhausted. It is not necessary that the recipient have a telephone account or register with the Facilitator in this circumstance. 3. A permanent debit or ATM card can be issued to the recipient, which enables any customer to send funds to the target. It is not necessary that the recipient have a telephone account or register with the Facilitator in this circumstance. It is possible for the present technique to be used for purchasing or transmitting funds via the internet or other networks. In this hybrid mode a call is made between a customer and the Facilitator and the customer is authenticated. The target of a transaction that is the subject of the call is identified by an email address or other preassigned electronic network address. The Facilitator emails the recipient and requests it to register with it or to establish an account, if an account has not previously been established. The procedure thereafter is identical to that described above. Similarly the customer can email funds or send funds through the internet or other networks after establishing and registering an account with the Facilitator that is linked to the customer's telephone number. The transfer can be accomplished by going to the Facilitator's web site and filling out details of the recipient, including the recipient's telephone number. After calling back the customer to authenticate the transaction, the Facilitator calls the recipient and the procedures described above used to complete the transaction. It is possible to use the system for mass distribution of promotions or funds, like check runs and rebates, to designated targets. In this mode, a mass distribution list is set up by the Facilitator which rings the target's telephone numbers as provided by the merchant and informs them that they have funds in their telephone account. The targets can then perform all the functionalities described herein, including paying bills and paying other targets etc. Similarly in another mode, a customer can receive a specific serial number from a merchant, the number being associated with, for example, a rebate on a digital camera. The customer then calls a prespecified number at the Facilitator and after providing the serial number, may obtain transfer of the funds to his/her account immediately or, based on pre-specified arrangement, at some future date. It is also possible that some personal information is then provided to the merchant from the Facilitator's database containing consumer information. It is also possible that calls could be generated by the Facilitator and products solicited to be sold on behalf of a merchant. If a customer responds to the promotion and agrees to purchase the goods, funds may be transferred from his/her account to the merchant and goods shipped accordingly. Illustrative examples of the manner in which the various entities (customer/requester, merchant, target) may interact with the Facilitator are shown in the accompanying drawings. In particular, in FIG. 1, a flow diagram of a first embodiment of a transaction processing and payment system in accordance with the present technique is shown. To begin the process, a call initiator (e.g., a registered customer such as a consumer who desires to make a purchase or to transfer money from one account to another) places a call to a transaction Facilitator (step 1) on a registered phone (i.e., one whose Caller ID is registered with the Facilitator). The latter is a service provider that facilitates transaction processing and payment for entities such as consumers and businesses by authenticating the transaction initiator, and desirably the target of the call as well. The target may be, for example, a merchant, a bank, an individual or other entity. For purposes of following the description, it may be helpful to think of the initiator as a consumer who wishes to pay a bill to a utility, although it will be understood that this example is for the purpose of explanation only, and that the present application is not so limited. The initiator provides to the Facilitator a password (e.g., a personal identification number or PIN), preferably unique to the initiator, that serves as a secondary level of authentication; the primary level of authentication is provided by the Caller ID which is associated with the telephone handset that the initiator is using to place the call. The handset is desirably a landline phone, for maximum security against illegal interception, but may comprise a wireless phone instead. Information such as a password, and possibly other information as well, is entered by the initiator by voice or by telephone keypad in the case of touch-tone telephones. The initiator identifies the target of the transaction (e.g., a public utility to which the initiator wishes to make payment of a bill) by voicing or keypad-entering an identifier for the target. This may be the target's name or it may be a unique identifier provided to the initiator by the target or from another source such as a directory and from which the target's record in the database can be accessed, either based on the identifier alone or on the identifier supplemented by additional information from the initiator or from other sources. Preferably, however, the target is identified to the Facilitator by its telephone number. This enables easy location of the target in the event that it is not already a registrant in the target database. The Facilitator authenticates the initiator (step 2) by examining the Caller ID associated with the call to determine if it is a registered initiator. This is accomplished by comparing the initiator Caller ID with the initiator Database 10. The Facilitator also verifies the Caller Identifier (e.g., PIN) in a similar manner. If these two match a specific registrant in the database, the initiator is authenticated as that registrant. If they do not, the transaction is aborted. Various other actions may then be taken, such as asking the initiator to repeat the Identifier; notifying the registrant by voice mail of one or more failed access attempts; notifying public authorities; etc. If initiator authentication is established, the Facilitator then preferably authenticates the target. This is typically accomplished in a similar manner to that of initiator authentication, but using a separate database 12. Of course the initiator and target databases may be combined in one but, because the two will generally have different data fields, it will generally be more efficient to use separate databases for them. On establishing initiator authentication, the target is notified of the initiator's desire to undertake a transaction with it. If the target is already registered with the Facilitator, the target is given the opportunity to refuse the transaction, in which case the initiator is notified and the transaction is terminated. Typically, however, the target will accept the transaction (step 3) by transmitting its assent to the Facilitator. In connection with acceptance, the target may specify the account into which any payment is to be made if this has not already been established by the user. Additionally, the target may supply other data to shape the transaction, if the user has not specified to the contrary. If the target is not already registered with the Facilitator, the target is given the opportunity to do so. It may do so in a manner similar to that in which a Call initiator registers, i.e., by providing to the Facilitator data such as a preferably unique identifier; a Caller ID (this, in fact, is provided by the telephone service provider), and other data that may be appropriate in connection with the transactions to be undertaken with or by it. After registration, which may take place wholly over the telephone and during the same session as that in which the target is notified of a desired transaction with it, and after acceptance of the transaction, the transaction is processed (step 4). Typically, this involves debiting an account of the Call initiator and crediting the account of the target. Finally, the initiator and the target are notified of completion of the processing, and the transaction is thereby completed. Of course, if registration by the target is refused, the initiator is notified and the transaction is terminated without processing such as debiting or crediting of accounts. This mode of operation is suitable for a number of the transactions described in detail above. For example, one person (e.g., a parent) wishing to send money to another (e.g., a child) may readily do so by means of a single telephone call to the Facilitator, specifying the telephone number of the child and the amount to be transferred. Specific conditions, e.g., the particular account into which the money is to be transferred, forbidding retransfer to other accounts etc., may also be specified by the parent as desired and as permitted by the Facilitator. Another example of this mode of operation is in connection with shopping at a merchant's. A customer who is in a merchant's shop and desires to purchase goods or services may call the Facilitator and provide it with a telephone number that the merchant has designated for this purpose, as well as the amount to be paid and other appropriate data (e.g., “Pay immediately.”, “Pay in thirty days.”, etc.). The Facilitator then debits or otherwise adjusts the customer's account and credit's or otherwise adjusts the merchant's account to reflect the transaction. Operation in this manner can enable the customer to avoid what may otherwise be a lengthy checkout line. FIG. 2 illustrates a second example of the technique, namely, one in which the call initiating a transaction is placed in the first instance not to the Facilitator but to a third party such as a merchant. For ease of understanding, it may be helpful to consider FIG. 2 in connection with a transaction in which a consumer calls a merchant to order a CD that it has just heard advertised, although it will be understood that the present application is not so limited. The transaction begins (step 1) with the Call initiator placing a telephone call to the merchant. The caller may make inquiry of the merchant prior to placing an order, such as to price, configuration, characteristics, warranty and the like, and may provide information to the merchant concerning itself such as name or alias, address, etc. The Caller ID of the initiator is captured in connection with the call, but it need not be used by the merchant; it may simply be transmitted to the Facilitator. In order to authenticate the initiator, the merchant transfers the call to the Facilitator. The Facilitator authenticates the parties to the proposed transaction (step 2) in the manner previously described in connection with FIG. 1, i.e., it checks the Caller ID and preferably a unique identifier of each party with the respective initiator and target databases; in the present case, the customer is the initiator and the Merchant is the target. If both checks match for each party, the Facilitator notifies the initiator of the transaction (step 3) and inquires as to acceptance. If the initiator accepts, the Facilitator notifies the target of the authentication of the initiator. At this point, the Facilitator may cease to participate further in the transaction, and the transaction may be completed by the Merchant/target. The Facilitator's role in the transaction will thus have been to provide the authentication which gives the Merchant the security needed to proceed with the transaction, knowing that it is not fraudulent. Conversely, the Merchant may desire that the Facilitator complete the transaction. In this case, the Facilitator will complete the transaction in the manner previously described in connection with FIG. 1, e.g., by debiting and crediting the accounts of the Merchant and of the Consumer, respectively, notifying them both of the action, and terminating the call. Although the above specific examples illustrate the present technique in the context of calls initiated by a customer, it will be understood that the present apparatus/technique is not so limited. For example, the initiator may be a merchant, a utility, or simply a third party who is presenting bills for payment, or a person or entity that seeks transfer of assets from another. In any event, authentication of at least one party to the transaction is accomplished by the Facilitator by means of the party's unique telephone ID (i.e., telephone number, or preassigned static IP address at the Facilitator), preferably in connection with a secondary identifier such as a PIN. A flow chart detailing the procedure 500 that the system performs in accordance with bill presentment and payment is shown in FIG. 3. Initially, in step 505, the merchant contacts the Facilitator and transfers the billing information to the Facilitator. This billing information may include one or more of, for example, the names of the customers, the payments due from each, information relating to the services rendered, the time or times at which the bill is to be presented to the customer, and the telephone number to reach the customer. In step 510, the Facilitator contacts a customer by dialing the customer's phone number through the traditional telephone network. Once contact is made with the customer, then the Facilitator presents the bill information to the customer in step 515. This presentation can include the name of the requesting entity (i.e. the merchant), amount of the bill, and any other data as desired. The Facilitator also asks that the customer also assent to the bill. If a customer requests that they be notified later (step 520), then the Facilitator waits until the requested time (step 525) before looping back to contact the customer in step 510. For example, a customer may request that he or she be contacted on the date the bill is due or, for example, three days before the bill is due or on the third Sunday of the month at 8 PM. If the customer assents to the bill payment (step 530), then the Facilitator completes the transaction in step 535. The customer has been verified by the use of the customer's telephone number which the Facilitator itself has dialed. Or alternatively the customer has dialed into the facilitator and the customer's Caller ID has thereby been obtained by the Facilitator. In alternate embodiments, the customer may additionally be verified by a user name, password, voiceprint or other unique identifying information provided by the customer when the call is answered. Once a Facilitator has completed the transaction (step 535), then the Facilitator notifies the merchant of the payment (step 540). This notification can be accomplished using, for example, a database file or other computer files transferred from the Facilitator to the merchant identifying the customer's, the amounts of payment, and other information. The present application is readily implemented using existing commercial instrumentalities to provide the necessary hardware; the software is readily assembled from existing communications, database, and financial software modules, with any desired customization well within the skill of those skilled in the art of communications and software. Conventional stored program data processors can perform the necessary processing using such software. It is expected that most transactions will be processed by the Facilitator without the need for human intervention, although the Facilitator may provide such intervention when necessary or desirable. User Trust Account As described in detail above, associated with each user of the system of the application is an account that is associated with at least a telephone number that forms part of the account's principal identity and which may be debited or credited during a transaction. For purposes of reference, such accounts will be referred to hereinafter as “trust accounts”, i.e., accounts in which records of debits and credits may be made. Each transaction involving a financial transfer that takes place in the system is reflected in at least one such account. Each account contains certain essential information as to a given user, and may contain further information as desired. In particular, each trust account contains information that uniquely identifies a given user. The user may be identified by the telephone number used to open his/her account, by name, by Social Security Number, by a unique number or other identifier assigned by the Facilitator, or by a combination of these or other information. Additional ‘phone numbers may be associated with an account. A user may have sub-accounts associated with an account. For example, a user may establish separate accounts for household purchases or other transactions, business transactions, etc. A funding mechanism is specified for each trust account. This may be a single mechanism, or it may cover a variety of complementary or alternative mechanisms, such as cash, check, credit card, debit card or other financial mechanisms for transferring money, credits, financial assets, etc. to others or from one account to another. The currency in which transactions are to be conducted is desirably specified in the trust account. A default currency, such as U.S. Dollars, British Pounds, Euros, etc. may be specified if the user does not specify a different currency. Multiple accounts may also be provided, one for each currency. Restrictions on transactions may be imposed by the user, the Facilitator, third parties, or one or more of these. For example, where an account or sub-account is funded by credit card, the Facilitator, the card issuer, the user, or one or more of these may impose limits on the amount that may be charged over a given period of time or for a given vendor, or the largest amount that may be charged at any one time. or a combination of these or other restrictions. As will be described in detail below, these or other restrictions may be associated with, and triggered by, an estimate of the uncertainty in the authentication of a given financial transaction. A record of the transactions that have been processed in connection with a given account is also maintained in connection with each trust account. This record preferably includes the date of a transaction, the amount, the payer, the payee, the funding mechanism used for the transaction (cash, credit card, etc.), and possibly other data as well. A Trust Account is established not only for each registered user, but also for each target, whether or not the target chooses to register with the Facilitator. Each account is associated with at least a telephone number that forms part of the account's principal identity. From the viewpoint of the Facilitator, a user of the system, whether its role is that of initiator or that of target, may thus be viewed simply as a telephone number, and transactions may be viewed as taking place between two telephone numbers, analogous to person-to-person voice communications but involving transfer of assets as opposed simply to voice communications. FIG. 4 illustrates some of the data that is preferably recorded in a user's trust account. Some of the data elements have referred to already; others will be described in detail subsequently. Each user has an account, the respective accounts being indicated in FIG. 4 as TA-1, TA-2, TA-3, etc. Each such account, e.g., account TA-1, preferably contains a User Account Number 10, a User Name 12, a User Address 14, Telephone Number 16, Social Security Number 18, and Personal Identification Number 20. Additional identifiers or passwords 20a may also be included. One or more Funding Mechanism 22, 24, etc., are identified in the account, as well as an account Transaction History 26 (containing relevant data for account transactions, such as transaction data, payer, payee, amount, nature of transaction, etc.), the Account Balance 28 and the Currency 30 in which the account is maintained. Also contained in, or linked to, the User Account is a voice print 32 of the User as described in more detail below. The voice print comprises a voice prompt obtained from the user, and a statistical analysis of the voice prompt to facilitate subsequent voice comparisons in identifying the speaker who provided the prompt. Additional voice prints 34 may also be stored in or associated with the Account for providing different levels of security or for use in connection with different transactions. The User Account Number can be any number capable of uniquely identifying the account, either by itself or in connection with another identifier, and may, e.g., comprise the user's telephone number, Social Security Number, a sequence number generated by the facilitator, etc. A user may interrogate an account. For example, the user may wish to retrieve an item of information it may have forgotten, such as its PIN. If the information to be retrieved is part of the information that is to be verified on log in, the Facilitator may allow the user to log in conditionally and with only a limited choice of operations that it can perform until the User establishes full verification. Typically the Facilitator will require a high level of authentication in such cases, e.g., by using one or more of the additional identifiers (passwords) 20 or Voice Prints 32. FIG. 5 illustrates the operation of the system in the case of a direct transfer of assets from an initiator-payer to a target-payee. An initiator 50 (which may comprise an individual, a business, or other entity) having a Trust Account 50a contacts (communication step 52) the Facilitator 54 to begin a transaction with a target 56. The initiator defines the transaction to be performed, e.g., pay a specific amount of money to a payee. The initiator may identify the payee by any unique identifier by which the Facilitator may retrieve the payee's telephone number, preferably the payee's telephone number itself, but permissibly by name and address or other unique identifier. The initiator may also specify a Funding Mechanism to used for the transaction, e.g., assets credited in the initiator's trust account, third party sources such as credits cards, debit cards, bank loans, etc.; or may simply rely on a default Funding Mechanism specified in the account. The Facilitator authenticates the initiator in the manner previously described, i.e., it verifies the telephone number from which the initiator called as a telephone registered to the initiator if the communication from the initiator is by telephone or places a call-back to the telephone number registered to the person or entity that the initiator claims to be in order to verify the communication. The authentication may take place at any time during communication with the initiator, i.e., at the outset, in the course of statement of the desired transaction, at the completion of the communication (including call-back), or a mixture of these. The Facilitator also examines the Trust Account 50a of the initiator in order to verify that the account has, or can obtain, sufficient assets to perform the transaction. For example, if the Funding Mechanism to be used for the transaction is to entail a call on funds from a third party in order to support it (e.g., the use of a credit or debit card, a loan from a bank, etc.), the Facilitator may communicate (step 58) with a credit or debit card issuer 60; a bank 62 (step 64); or with any other funding mechanism or source of potential assurance that the appropriate funds are available to the initiator for the particular transaction in question. Alternatively, as opposed to verification of each transaction, where a block of funds can be committed to an initiator's Trust Account in advance of a transaction, the Facilitator need only verify that the funds available within the particular Funding Mechanism designated by the initiator are sufficient to support the transaction. The Facilitator also authenticates the target. Typically, this is done after the initiator has been authenticated and the availability of the necessary funds has been verified, but may be done at any stage of the transaction. Preferably, the Facilitator first searches its own database (step 64) to determine whether the target is already known to it, i.e., whether it already has a Trust Account 56a associated with it. If the target does have a pre-existing account, funds are transferred into it in accordance with the initiator's request. The Facilitator then preferably notifies the target of this action (step 66), and desirably notifies the initiator as well. If no preexisting account is found for the target in the subscriber database, a Trust Account 26 will be created for it. This may be a temporary account if the target chooses not wish to register as a subscriber to the system, and will be a permanent account if the target does wish to register. In the latter case, the registration process will generally be the same as that of non-target subscribers, i.e., the target will be asked to provide information that will assist in identifying it and associating it with a specific telephone number. During this process, third party entities such as a Telephone Company (Telco) 72 may be contacted (step 72) to verify information provided by, or concerning, the target account being created. In the course of a transaction between an initiator and a target, records of the transaction are made in both accounts. Assets that are transferred into the target's account may be then released from the account at the direction of the target, subject to any restrictions imposed by the initiator or by the Facilitator. Enhanced Authentication While the level of authentication provided by basic Caller ID monitoring (i.e., verifying that the Caller ID transmitted over the voice line (the “voice-line Caller ID”) with a call matches a Caller ID associated with a registered user as recorded in a database) may be adequate for transactions of lesser value or infrequent occurrence, it is desirable to provide an enhanced level of authentication for transactions of a given value either because of the risk associated with the transaction or because the frequency of transactions by a user quickly aggregate to a substantial amount. The exact extent of what is “substantial” may be established by the Facilitator or by others (e.g., a credit card issuer), and may vary from time to time, or among subscribers, or in accordance with experience with particular subscribers. In the present embodiment, either or both of two forms of enhancement are specifically provided for. In a first form of enhanced authentication, basic Caller ID monitoring is enhanced by further matching the voice-line Caller ID transmitted with a communication from a user with a Caller ID transmitted separately from the communication, preferably over a different channel, in particular, via the SS7 signaling network that is in common use throughout the United States for telephone communications. This network provides for transmission of Caller ID information over a voice line along with the called number and preceding the desired communication. It also provides the telephone numbers of the call initiator and the called party on a separate control channel (“control-channel ANI” which is the equivalent of Caller ID and so referred to herein). The latter channel is less susceptible to unauthorized monitoring or interception by third parties. In a further embodiment of the present application, the Facilitator not only checks the voice-line Caller ID against a user database to authenticate the telephone being used to effectuate a financial transaction, but also checks the voice-line Caller ID against the control-channel Caller ID. A match between the two confirms that the instrument being used for the communication (such instrument being referred to here as a “telephone” or “phone”, regardless of the form it takes, as long as it is used transmit voice or data over a telephone line) is indeed an instrument associated with a recognized user, and thus increases the reliability of the verification. Thus, referring to FIG. 6, a communication between an initiator 100 and the Facilitator 102 will typically pass through one or more telephone company exchanges 104, 106 over voice communication lines 108, 110, 112. At the first exchange, 104, the telephone service provider or “Telco” adds certain information to the call that is transmitted with the call on its transportation to the destination. This information includes, inter alia, the Caller ID of the call initiator. At the same time, the Telco also transmits control and other information over a separate control channel, referred to here as the “SS7 control channel”, element 114 in FIG. 6. This information is used, among other purposes, to control the set up of the call, its switching through other Telco offices, and the like. It also includes information about the receiver and sender that is the same as the Caller-ID of the sender and receiver. In accordance with the present technique, the Facilitator, with permission of the Telco, is connected (communication channel 116) to the SS7 control channel 114 to enable the Facilitator to retrieve from that channel the Caller-ID transmitted over that channel in connection with a call that is received over voice-communication line 108. This data, as well as the voice channel data, may be buffered (i.e., temporarily stored) in order to accommodate differences in transmission times. The Facilitator then compares the control channel Caller ID with the voice channel Caller ID to determine whether they match. If they do, the transaction with the initiator 100 is allowed to proceed in the manner described generally above. If they do not match, however, an exception is noted and appropriate action is taken. For example, the Facilitator may request that the initiator place a new call to it to verify that the Telco system has not simply malfunctioned; may request that the initiator call the Facilitator on another telephone that is registered with the Facilitator; may terminate the attempted transaction; or may take other action as appropriate. In a second form of enhanced authentication, a voice prompt of a subscriber's voice is recorded, preferably at the time of subscriber enrollment but permissibly at other times as well, and from time to time, and is stored in connection with a subscriber's record. The voice prompt may then be accessed in connection with communications with the Facilitator by a user to verify that the person speaking on the phone is indeed the person associated with that phone as stored in the Facilitator database associated with the voice-print. The voiceprint is typically obtained from a subscriber at the time of registration, but may be obtained at any time and added to the account information. Although shown as part of the Trust Account itself, it may, of course, be stored in a separate database linked with the subscriber. The voice prompt may comprise any short segment of speech selected by the Facilitator or by the user. It need only be long enough to provide a reasonable level of confidence that a user placing a call to the Facilitator to affect funds in a user account (whether payment into the account or withdrawal form it) is indeed the person the user claims to be. Typically, a few seconds of speech will suffice for this purpose. FIG. 7 illustrates a number of modes in which a voice prompt may advantageously be used. In one mode, the Facilitator verifies for itself, through a voice prompt, either the initiator or the target or both. Thus, assume that an initiator 120 wishes to conduct a transaction with a target 122 through the Facilitator 124. In addition to the verification earlier described (or even in place of it), the Facilitator may search for the initiator's Trust Account 120a and retrieve (step 126) the initiator's voice print. It then statistically compares (comparison 128) this with the voice of the initiator 120 in the current transaction as transmitted over the voice communication channel (e.g., telephone line) 130. If the comparison succeeds, the transaction is allowed to proceed. Otherwise, it may be aborted, or other action may be taken by the Facilitator. Similarly, if the target 122 is a subscriber, the Facilitator can authenticate, or further authenticate, the target by searching for the target's Trust Account 122a and retrieving (step 132) a voice print of the target. The Facilitator then statistically compares (comparison 128) this voice print with the voice of the target 122 in the current transaction as transmitted over a voice communication channel (e.g., telephone line) 134 between the Facilitator and the target. If the comparison succeeds, the transaction is allowed to proceed. Otherwise, it may be aborted, or other action may be taken by the Facilitator. In another mode, a voice prompt may be used to authenticate one party directly to another. For example, an initiator that is familiar with the voice of an entity with which it desires to conduct a transaction may desire assurance that the Facilitator contacts the correct target. To provide this assurance, prior to transferring funds or assets to the target, the Facilitator may retrieve a voice prompt of the target that it has identified and thereafter play it back to the initiator. This is preferably done while the initiator is still in contact with the Facilitator on initiating a transaction, but may be done subsequently, e.g., by way of callback from the Facilitator. The initiator, after hearing the voice prompt of the target, may then instruct the Facilitator to proceed with the transaction or, alternatively, may cause its termination without transfer of funds or assets to the target. Conversely, on being contacted by the Facilitator on behalf of an initiator with whose voice a target is familiar, the target may be provided assurance that it is dealing with an entity known to it by receiving from the Facilitator a play of a voice prompt of the initiator. The voice prompt may be a general voice prompt of the initiator not restricted to the particular transaction or it may be one that has been recorded specifically for this transaction or for this and a specified class of other transactions. The latter (i.e., specially recorded) form not only serves to authenticate the initiator, but also to authenticate the Facilitator as authorized to deal on behalf of the initiator. A user's voice prompt may also be useful in assuring an initiator that it is dealing with an authentic Facilitator. In particular, when existing subscribers receive a call from the Facilitator, the latter typically requests certain information from them, such as a User ID, PIN, etc., before authorizing a transaction. To prevent an unauthorized party posing as the Facilitator from obtaining this information by trick, the Facilitator preferably plays back to the user at least some portion of the user's pre-recorded voice prompt to thereby verify that the entity to which the user is connecting is indeed the Facilitator. This may be the user's name, or it may be a word or phrase selected and recorded by the user specifically for this purpose. If the user does not hear the correct voice selection in connection with a log-in, it immediately knows that it is connected to an entity other than the Facilitator and can take action appropriately. The user can also request information unique to itself and generally private that it has previously supplied to the Facilitator in order to authenticate the calling entity. In the case of an unregistered target, of course, no pre-existing voice-print will be available for that user. In that case, the Facilitator may require that the sender and the receiver agree among themselves on a personal code that must be used by the receiver in order to access funds deposited to the receiver's trust account by the sender. Alternatively or additionally, the sender and receiver may conduct the transaction as a bridge call (i.e., a call in which both parties and the Facilitator are on the line), so that the sender and receiver may hear and identify each other's voices. As an alternative to a bridge call, the sender may record his or her voice with a message for subsequent use by the Facilitator in contacting the receiver to thereby provide an enhanced level of security for the transaction. If no information is found for the designated target, the Facilitator may search for the target in a name-telephone number database of all telephone users, and provide to the Facilitator information from this database. For example, if the initiator provides to the Facilitator the telephone number of the target, and the target is not otherwise listed with the Facilitator, the Facilitator may provide to the initiator the name and address associated with that telephone number in the name-telephone number database, so that the initiator can confirm or reject or modify the transaction. In some circumstances it will be useful to provide a concurrent three-way bridge among the initiator, the Facilitator, and the target. The bridge may be established by the initiator or by the Facilitator. During the bridge, the initiator can immediately verify the target to the Facilitator (or the target can confirm the initiator to the Facilitator) so that the transaction can proceed. This mode of operation, for example, may be particularly appropriate where the target has not registered with the Facilitator. The target may then register with the Facilitator during the call, or afterwards, or may be provided with a password that will enable it to claim the assets transferred to it by the initiator without formal registration. In any event, a Trust Account is established for the target to receive and hold the assets until at least such time as they are claimed by the target. The association of voice prints with telephone numbers, particularly voice prints indexed by telephone numbers, is itself a useful and desirable feature. Thus, a registrant whose voice print is on record with the Facilitator, may use this facility to provide further identification when requested. For example, a user desiring to complete a transaction at a bank or merchant who is asked for further identification may call the Facilitator (or arrange to receive a call-back from the Facilitator at a registered phone) and speak a word or phrase which the Facilitator can check against its voice print database to verify the user. Applications of Enhanced Authentication Active authentication of a communication (such as checking a voice-line Caller ID against a subscriber database; checking a voice-line Caller ID against a control-channel Caller ID; checking a user's voice against a pre-recorded voice-print, etc.) enables the Facilitator to control and limit the risk that it and others dealing with it undertake in connection with transactions to which it is a party. In accordance with a further embodiment of the present application, in connection with at least certain of the transactions, e.g., those for which the subscriber, the Facilitator, or others, may be put at risk of financial loss from a particular transaction, the Facilitator makes use of the enhanced security to put constraints on the transaction in order to minimize, or eliminate, the risk of loss. This embodiment is illustrated in connection with FIG. 8, beginning with a request (step 805) that a transaction be undertaken. In connection with the transaction, the Facilitator calculates (step 810) the value of the transaction, i.e., the “value at risk” if the risk of loss falls on it, and then takes further action dependent on the results of the calculation. For example, at the outset, the Facilitator may assign a certain maximum or “threshold” value for the acceptable amount at risk for a given subscriber. If the threshold exceeds the value at risk of the transaction, the Facilitator proceeds (step 815) with the transaction. If not, enhanced authentication may be required before the transaction is allowed to proceed. This will be illustrated in FIG. 8 in terms of voiceprint authentication (steps 820, 825) but other forms of enhanced authentication may be used, as will be described below. The threshold amount may be a certain standard initial amount for all subscribers, or may be a variable amount that is dependent on the particular subscriber or group of subscribers. For example, a subscriber's prior credit history may be used to determine the initial amount, or the initial amount may be determined by the subscriber's credit profile, among other criteria for setting the amount. The amount may be changed from time to time, in accordance with the Facilitator's experience with the subscriber in connection with processing subscriber transactions. Whenever the outstanding debits in the subscriber's account exceed this amount, the Facilitator may take various actions. For example, it may merely provide a warning that the subscriber has exceeded the permissible limits for outstanding debits, and ask the subscriber to rectify this within a certain period of time. It may, instead, block all further transactions in the subscribers trust account until the debit is reduced below the allowable maximum. Other forms of action are, of course, possible. In one embodiment of the present application, calculation of the value at risk is based at least in part on the level of security that has been determined to be associated with a particular type of communication. This determines, at least in part, the “trust level” to be assigned to said transaction. In particular, each degree of security is characterized by a number from 0 to 1 which may be considered to represent the probability that a given communication is indeed authentic, i.e., is with a verified telephone, or a verified user, or both. A communication that has been authenticated by basic Caller ID monitoring only (i.e., voice-line Caller ID verification against a database) may be assigned a probability of, e.g., 0.90. A communication that has been verified by both basic and control-channel (e.g., SS7) Caller ID monitoring, in contrast, may be assigned a probability of 0.95. A communication that has been verified by call-back may be assigned a probability of 0.99. Other probabilities may be defined on other criteria. The value at risk is then calculated as A=TV*(1−P), where A is the value at risk, TV the transaction value, and P the probability assigned to or calculated for the communication, 0<P<1. Action may then be taken by the Facilitator dependent on whether the value at risk exceeds the permissible threshold for the subscriber associated with the communication. Furthermore, the Facilitator may establish certain probability requirements for various levels of transactions. For example, for transactions between $5,000 and $10,000, the Facilitator may require an authentication probability of 70%, while for transactions above $10,000 the Facilitator may require a probability of 80% or greater. These probabilities can be customized as the Facilitator desires and for amounts or other classifications. If the probability generated in step 825 is sufficient, then the Facilitator will perform the desired transaction (step 835). However, if the generated probability is not sufficient to meet the requirements determined by the Facilitator, then the Facilitator will obtain additional details (step 840). These additional details can be obtained by asking the user for certain information, such as a secondary personal identification number (PIN), a mother's maiden name, a portion of the user's social security number, or other personal/private information. The user can enter the information either by, for example, using dual-tone modulated frequency (DTMF) keys on a telephone keypad or by speaking the user's answers. The results of the additional questions are used to modify the probability that the user is in fact the person he or she is claiming to be. After a newly revised probability is generated, then another determination is made (step 850) as to whether the probability is sufficient to enable the transaction to continue. If the probability is now sufficiently high to enable the transaction to continue, then the Facilitator performs the requested transaction (step 855). However, if the newly revised probability is still not sufficient then the Facilitator will fail and not perform the transaction (step 860). However, in alternate embodiments, if the probability is still not sufficient, then the Facilitator may loop back to step 840 to obtain additional details in order to further refine the probability estimate that the user is an authenticated and permissible user. An important consideration for a Facilitator is the total outstanding liability generated due to spurious or faked transaction requests. For any given transaction the expected value of the transaction is given by the following formula: E(x)=V×P1×P2 where V is the value of the transaction, P1 is the probability associated with the direction of the telephone call (described further below) and P2 is a probability associated with the voice print. This probability is generated from a voice print taken of the user at the time of the transaction. A Facilitator can set up a threshold limit for various types of transactions. For example, it may determine that no transaction will be performed if the total probability (P1×P2) is less than a certain amount, e.g., 0.50. Additionally, the Facilitator can assign various probabilities for P1. For example, if a call-back is performed with automatic number identification (ANI), the Facilitator may assign P1=1.0. However, if a call back is performed and no Caller ID from the callback number is available, then the facilitator may assign a value of P1=0.95. These probabilities reflect the level of verification achieved by performing a call back with or without Caller ID. Similarly, if a sender calls into the Facilitator's system, then a value of P1=0.90 might be assigned, for example. The Facilitator may also have a transaction-wide or daily exposure aggregate limit which it adheres to. If a user exceeds the limit, the Facilitator may refuse the transaction or may require further authentication, e.g., through a voice print. CONCLUSION From the foregoing, it will be seen that an authentication and payment system is provided with a significant degree of security without the need for special devices. The system uses a unique identifier that is nearly universally available and that itself typically has undergone at least some level of scrutiny by independent third parties (e.g., Telcos) in connection with associating it with a particular device, e.g., a telephone, and with a particular individual or entity. Desired transactions can typically be initiated , authenticated, and authorized during a single phone call by a customer, and may frequently be completed during that call as well. Travel to specific facilities to initiate a transaction is not required, yet a security level higher than that commonly associated with “Authorization When Not Present” transactions is maintained.
<SOH> BACKGROUND OF THE INVENTION <EOH>
<SOH> SUMMARY OF THE INVENTION <EOH>Despite the widespread adoption of the internet and the significant commerce which already takes place over it, a substantial portion of the public still does not use the internet for commercial transactions. For some of these the non-use is attributable to unfamiliarity with, or access to, computers which can access the internet. For others, it is due to lack of trust in the security features of the system. Whether or not they have access to, or are able to or do, trust and use the internet, most people have long been accustomed to using the telephone and to conducting business over it. Unlike the internet, in which data can easily be intercepted by skilled hackers, telephone transmissions are difficult to intercept without specialized equipment and often then only with considerable difficulty. The main reason is that, with the telephone, communication takes place securely between two nodes within a channel, in contrast to the internet or other general public networks where multiple nodes have access to the same communication, thus allowing interception and hacking. This is the case both with land-line telephones, in which the information being transmitted travels to a local central office via a unique circuit which is difficult to “tap” unobtrusively, as well as with wireless communications which may be encoded. Telephone numbers are universally assigned uniquely to customers by the telephone company, and thus can serve as a unique identifier for a customer. The International Telecommunication Union (ITU) and all the global telephone operating companies have agreed to assigned country codes. For example, 1 identifies the United States, Canada and parts of Caribbean; 49 identifies Germany; and so forth. Furthermore, the various authorities and telephone companies in each country have decided on area codes and numbers for cities, areas or regions, e.g. 617 for Boston and 212 for parts of Manhattan. Within these areas, an individual subscriber is assigned a unique number. This numbering system allows, e.g., an individual in South Africa to simply dial the country code of the United States, the assigned area code, and finally the user number to reach a desired person or entity. This numbering system provides unique routing information which has been used primarily by Telephone Operating Companies (Telcos) for finding a subscriber, opening a circuit, and completing a call. The present application uses this unique telephone numbering system as a principal identifier in routing and completing financial transactions and other transfer of goods and services. In recent years various Telcos have made this number accessible to the users of the telephone system by way of “Caller ID” offering. In this service, the telephone number of the calling party is sent to the called party, along with the dialing information, thereby identifying the calling party. If the called party subscribes to the “Caller ID” service, he/she is thus enabled to see or otherwise ascertain the telephone number of the calling party in connection with the call. This number has been available internally to Telcos since the advent of electromagnetic switches in the early 20 th century. It became more transparent through the advent of digital switching, especially the Class 5 switches in the early 1980's. The caller information was and is used for signaling, routing and billing by Telcos. Hereinafter we designate Caller ID (CID) and any other unique identifier of a Telco network subscriber such as Caller Line ID (CLID) or Automatic Number Identification (ANI) and the like simply as Caller ID. Various further uses have been proposed and/or implemented for making use of this functionality for performing authentication functions in various contexts. For example, one of the telephone companies has proposed to use it for authenticating requests for call forwarding services. See U.S. Pat. No. 6,018,570, issued Jan. 25, 2000, for “Methods And apparatus For Regulating The Remote Ordering, Authorization, Access And Control Of Services And Service Features Associated With A Terminal”. In that patent, the unauthorized ordering of call forwarding services for an unsuspecting customer, and its subsequent use to place long distance calls, is proposed to be defeated by checking the ID of the telephone from which the service is ordered and refusing to implement call forwarding on the targeted customer telephone unless the ID of the requesting telephone is the same as the ID of the customer telephone. Another proposes to use it over one network (e.g., the telephone network) to authenticate purchases over a second, separate network (e.g., the internet). See U.S. Pat. No. 6,088,683, issued Jul. 11, 2000 to Reza Jalili for “Secure Purchase Transaction Method Using Telephone Number”. In that patent, a customer contacts a merchant over a first electronic network (e.g., the internet) which either the customer, or the merchant, or both may deem insecure, and places an order. In connection with the order, the customer identifies itself by supplying its telephone number and a registration number previously issued by a central registry. The registration number is obtained by either calling or writing the central registry in advance of any transaction. The merchant then generates an invoice that includes the customer identification information and transmits it to the central registry. In order to complete the transaction, the customer must then call the central registry and confirm the order. The central registry may verify the customer by any of various techniques, one of which optionally may include use of the customer's caller ID. This proposal has a number of defects which limit its usefulness. First, the exclusive arena in which transaction occurs is the world wide web i.e. the internet. The telephone phone is used for authentication purposes only, and not as the initiator or medium of the transaction. Further, the transaction requires multiple sessions on the part of the user, allowing lapse of time which can diminish its value from both the customer's and merchant's point of view. Specifically, by separating in time the initial purchase decision and its final approval by the customer, a “second thought” on the part of the customer is more likely to occur, and thus reduce the number of transactions. Further, fraud can occur in the very registration process itself, since registration is to be accepted not only from the registrant's telephone, but also from alternate telephone numbers. Although various security checks are suggested in the latter case, use of caller ID is merely one option, leaving open the distinct possibility that information that was in fact stolen from another (e.g., a Social Security number) may form the basis of registration. It has also been proposed to use a party's caller ID as a substitute for their credit card number: see U.S. Pat. No. 6,227,447, issued May 8, 2001, for “Cardless Payment System”. In the system of that patent, a customer makes a purchase by providing his/her telephone number and a PIN to a merchant in place of the usual credit card number. The merchant then retrieves the credit card number from the credit card issuer using this information. The telephone number and PIN may be supplied in person to the merchant, in which case there is no further verification provided for, or it may be done over the phone, in which case the merchant may obtain the number from the call itself and may use this without asking the customer to repeat its input or may use it to verify the telephone number input by the customer. In either case, the transaction is ultimately dependent on the merchant's obtaining and using the credit card number to complete the transaction, and the customer's telephone number is simply a mechanism through which the credit card number is retrieved. In contrast to the above, I have developed a secure system for transaction authorization and payment. The system requires the use of only a single session by a user desiring to initiate a transaction, and in most cases a single network, and is instantly accessible via a telephone network, mobile or landline device. This device need not necessarily be a telephone; it can be a Personal Digital Assistant or other device. The device, however, must be one having a preassigned unique number on a telephone network or on an IP telephony network through a pre assigned IP gateway. For ease of use hereinafter, I refer to such a device simply as a telephone, with the clear understanding that the term is intended to encompass not only voice-transmission and reception devices commonly understood by the term “telephone” (i.e., “conventional telephones”), but also personal digital assistants and other devices used for connecting to the telephone network and each having a unique number assigned to them. Of course, the device may share a given telephone number with other telephones of a user as is now commonly done with conventional telephones in the case of extension telephones. Similarly, for convenience of reference, I refer to the person using the device to pay bills, make purchases, transfer money or other assets, etc., as “the customer”, whether an individual or an organization, and even though a particular transaction may not in fact involve the purchase or sale of goods or services. The authorization process of the present application is rapid and largely transparent to the customer. It can be implemented with a single session between the customer and a third party such as a merchant, yet is sufficient to establish and complete a transaction, together with payment for it as appropriate. It is an object of the present application to provide an improved authentication system for transactions between entities. Another object of the present application is to provide an improved authentication system which facilitates consumer transactions. Still another object of the present application is to provide an improved authentication system which is unobtrusive with respect to the user. Yet another object of the present application is to provide an improved authentication and payment system. Still a further object of this present application is to provide a simple yet relatively secure system for authenticating an individual or organization and allowing them to forward and/or swap funds, goods and services including, but not limited to, stocks, motor vehicle titles, or other assets or certificates representing value. Still a further object of the present application is to provide an improved authentication and payment system which is reliable, yet unobtrusive. Yet a further object of the present application is to provide an improved authentication and payment system which does not require the presence at a particular site of a customer using the system. Still a further object of the present application is providing an improved system for authentication and/or payment which is geographically universal. Still a further object of the present application is providing an improved system for authentication and/or payment which does not require special apparatus for its operation. The foregoing and other and further objects of the present application will be more readily understood on reference to the following detailed description of the application, when taken in connection with the accompanying drawings, in which: FIG. 1 is a block and line diagram of a first form of authentication and payment system; FIG. 2 is a block and line diagram of a second form of authentication and payment system; FIG. 3 is a system-wide view of the transfer of assets from a payer trust account to a payee trust account in accordance with the present application; FIG. 4 FIG. 4 illustrates some of the data that may be included in a user's trust account; FIG. 5 illustrates the operation of the present technique in the case of a direct transfer of assets from an initiator-payer to a target-payee; FIG. 6 illustrates an enhanced form of authentication in accordance with the present technique; FIG. 7 illustrates a further form of enhanced authentication in accordance with the present technique; and FIG. 8 is a flow chart of a process by which the value at risk in a transaction is controlled in accordance with the present technique. detailed-description description="Detailed Description" end="lead"?
G06Q203821
20170822
20171207
70763.0
G06Q2038
3
HAMILTON, LALITA M
SECURE AUTHENTICATION AND PAYMENT SYSTEM
SMALL
1
CONT-ACCEPTED
G06Q
2,017
15,683,623
ACCEPTED
FASTER STATE TRANSITIONING FOR CONTINUOUS ADJUSTABLE 3DEEPS FILTER SPECTACLES USING MULTI-LAYERED VARIABLE TINT MATERIALS
An electrically controlled spectacle includes a spectacle frame and optoelectronic lenses housed in the frame. The lenses include a left lens and a right lens, each of the optoelectrical lenses having a plurality of states, wherein the state of the left lens is independent of the state of the right lens. The electrically controlled spectacle also includes a control unit housed in the frame, the control unit being adapted to control the state of each of the lenses independently.
1. An apparatus comprising: a storage adapted to: store one or more image frames; a processor adapted to: obtain a first image frame and a second image frame from a first video stream; generate a first modified image frame by expanding the first image frame, wherein the first modified image frame is different from the first image frame; generate a second modified image frame by expanding the second image frame, wherein the second modified image frame is different from the second image frame; generate a bridge frame, wherein the bridge frame is a solid color, wherein the bridge frame is different from the first image frame and different from the second image frame; display the first modified image frame; display the bridge frame; and display the second modified image frame. 2. The apparatus of claim 1, wherein the bridge frame is black. 3. An apparatus comprising: a storage adapted to: store one or more image frames; a processor adapted to: obtain a first image frame and a second image frame from a first video stream; generate a first modified image frame by shrinking the first image frame, removing a portion of the first image frame, wherein the first modified image frame is different from the first image frame; generate a second modified image frame by shrinking the second image frame, removing a portion of the second image frame, wherein the second modified image frame is different from the second image frame; generate a bridge frame, wherein the bridge frame is a solid color, wherein the bridge frame is different from the first image frame and different from the second image frame; display the first modified image frame; display the bridge frame; and display the second modified image frame. 4. The apparatus of claim 3, wherein the bridge frame is black. 5. An apparatus comprising: a storage adapted to: store one or more image frames; a processor adapted to: obtain a first image frame and a second image frame from a first video stream; generate a first modified image frame by removing a portion of the first image frame, wherein the first modified image frame is different from the first image frame; generate a second modified image frame by removing a portion of the second image frame, wherein the second modified image frame is different from the second image frame; generate a bridge frame, wherein the bridge frame is a solid color, wherein the bridge frame is different from the first image frame and different from the second image frame; display the first modified image frame; display the bridge frame; and display the second modified image frame. 6. The apparatus of claim 5, wherein the bridge frame is black. 7. An apparatus comprising: a storage adapted to: store one or more image frames; a processor adapted to: obtain a first image frame and a second image frame from a first video stream; generate a first modified image frame by stitching together the first image frame with a third image frame, wherein the first modified image frame is different from the first image frame; generate a second modified image frame by stitching together the second image frame with a fourth image frame, wherein the second modified image frame is different from the second image frame; generate a bridge frame, wherein the bridge frame is a solid color, wherein the bridge frame is different from the first image frame and different from the second image frame; display the first modified image frame; display the bridge frame; and display the second modified image frame. 8. The apparatus of claim 7, wherein the bridge frame is black. 9. An apparatus comprising: a storage adapted to: store one or more image frames; a processor adapted to: obtain a first image frame and a second image frame from a first video stream; generate a first modified image frame by inserting a selected image into the first image frame, wherein the first modified image frame is different from the first image frame; generate a second modified image frame by inserting a selected image into the second image frame, wherein the second modified image frame is different from the second image frame; generate a bridge frame, wherein the bridge frame is a solid color, wherein the bridge frame is different from the first image frame and different from the second image frame; display the first modified image frame; display the bridge frame; and display the second modified image frame. 10. The apparatus of claim 9, wherein the bridge frame is black. 11. An apparatus comprising: a storage adapted to: store one or more image frames; a processor adapted to: obtain a first image frame and a second image frame from a first video stream; generate a first modified image frame by reshaping the first image frame, wherein the first modified image frame is different from the first image frame; generate a second modified image frame by reshaping the second image frame, wherein the second modified image frame is different from the second image frame; generate a bridge frame, wherein the bridge frame is a solid color, wherein the bridge frame is different from the first image frame and different from the second image frame; display the first modified image frame; display the bridge frame; and display the second modified image frame. 12. The apparatus of claim 11, wherein the bridge frame is black.
CROSS REFERENCE TO RELATED APPLICATIONS This application is a Continuation of U.S. patent application Ser. No. 15/606,850, filed May 26, 2017, which is (I) a Continuation-In-Part application of U.S. patent application Ser. No. 15/217,612, filed Jul. 22, 2016, now U.S. Pat. No. 9,699,444, which is a Continuation of U.S. patent application Ser. No. 14/850,750, filed Sep. 10, 2015, now U.S. Pat. No. 9,426,452, which is a Continuation of U.S. patent application Ser. No. 14/451,048, filed Aug. 4, 2014, now U.S. Pat. No. 9,167,235, which is a Continuation of U.S. patent application Ser. No. 14/155,505, filed Jan. 15, 2014, now U.S. Pat. No. 8,864,304, which is a Continuation of U.S. patent application Ser. No. 13/746,393, filed Jan. 22, 2013, now U.S. Pat. No. 8,657,438, which is a Continuation of U.S. patent application Ser. No. 12/938,495, filed Nov. 3, 2010, which is a Divisional of U.S. patent application Ser. No. 12/555,545, filed Sep. 8, 2009, now U.S. Pat. No. 7,850,304, which is a Continuation-In-Part application of U.S. patent application Ser. No. 12/274,752, filed Nov. 20, 2008, now U.S. Pat. No. 7,604,348, which is a Continuation-In-Part application of U.S. patent application Ser. No. 11/928,152, filed Oct. 30, 2007, now U.S. Pat. No. 7,508,485, which is (a) a Continuation-In-Part of U.S. patent application Ser. No. 11/373,702, filed Mar. 10, 2006, now U.S. Pat. No. 7,405,801, which (1) is a nonprovisional of and claims priority to U.S. Provisional Application No. 60/661,847 filed Mar. 15, 2005, and (2) is a Continuation-In-Part application of U.S. application Ser. No. 10/054,607, filed Jan. 22, 2002, now U.S. Pat. No. 7,030,902, which is a nonprovisional of and claims priority to U.S. Provisional Application No. 60/263,498 filed Jan. 23, 2001; and (b) a Continuation-In-Part of U.S. patent application Ser. No. 11/372,723, filed Mar. 10, 2006, now U.S. Pat. No. 7,522,257, which (1) is a nonprovisional of and claims priority to U.S. Provisional Application No. 60/664,369, filed Mar. 23, 2005, and (2) is a Continuation-In-Part application of U.S. application Ser. No. 10/054,607, filed Jan. 22, 2002, now U.S. Pat. No. 7,030,902, which is a nonprovisional of and claims priority to U.S. Provisional Application No. 60/263,498 filed Jan. 23, 2001; (II) a Continuation-In-Part application of U.S. patent application Ser. No. 14/850,629, filed Sep. 10, 2015, which is a Continuation of U.S. patent application Ser. No. 14/268,423, filed May 2, 2014, now U.S. Pat. No. 9,167,177, which is a Continuation of U.S. patent application Ser. No. 13/168,493, filed Jun. 24, 2011, now U.S. Pat. No. 8,750,382, which is (a) a Continuation-In-Part application of U.S. patent application Ser. No. 12/938,495, filed Nov. 3, 2010, the priority information for which is recited above, (b) a Continuation-In-Part application of U.S. patent application Ser. No. 12/555,482, filed Sep. 8, 2009, now U.S. Pat. No. 7,976,159, which is a Divisional of U.S. patent application Ser. No. 12/274,752, filed Nov. 20, 2008, now U.S. Pat. No. 7,604,348, the priority information for which is recited above, and (c) a nonprovisional of and claims priority to U.S. Provisional Application No. 61/398,981, filed Jul. 2, 2010; and (III) a Continuation-In-Part application of U.S. patent application Ser. No. 15/212,114, filed Jul. 15, 2016, now U.S. Pat. No. 9,716,874, which is a Divisional of U.S. patent application Ser. No. 14/566,205, filed Dec. 10, 2014, now U.S. Pat. No. 9,426,442, which is a Continuation of U.S. patent application Ser. No. 14/333,266, filed Jul. 16, 2014, now U.S. Pat. No. 8,941,919, which is a Continuation of U.S. patent application Ser. No. 14/149,293, filed Jan. 7, 2014, now U.S. Pat. No. 8,913,319, which is a Continuation of U.S. patent application Ser. No. 13/632,333, filed Oct. 1, 2012, now U.S. Pat. No. 8,657,439, which is a Continuation of U.S. patent application Ser. No. 13/151,736, filed Jun. 2, 2011, now U.S. Pat. No. 8,303,112, which is a Continuation of U.S. patent application Ser. No. 12/555,482, filed Sep. 8, 2009, now U.S. Pat. No. 7,976,159, the priority information for which is recited above, the entire contents of each of which are herein incorporated by reference for all purposes. FIELD OF THE INVENTION This invention relates to the field of motion pictures and to a system called 3Deeps that will allow almost any motion picture filmed in 2D (single image) to be viewed with the visual effect of 3-dimensions when viewed through 3Deeps Filter Spectacles. More specifically, the invention relates to (i) the presentation of motion pictures and to the use of multiple layers of electronically controlled variable tint materials to fabricate the right and left lenses of the 3Deeps Filter Spectacle to achieve faster transition times than may be achieved by the use of only a single layer, (ii) various means by which a motion vector and/or luminance measure that are associated with frames of the movie can be used to select an optimal optical density for the neutral density lens of the 3Deeps Filter Spectacles, and (iii) visual art and, more particularly, to systems, apparatus, and methods for producing an appearance of continuous movement using a finite number of images, i.e., as few as two images. BACKGROUND This invention is, in part, directed to Continuous Adjustable 3Deeps Filter spectacles for viewing 2D movies as 3D movies. 3Deeps Filter Spectacles provide a system by which ordinary 2-dimensional motion pictures can be viewed in part as a 3-dimensional motion pictures. They however were a sub-optimal solution. In the presence of screen motion, they only developed 3D from a 2D movie by a difference in optical density between the right and left lens, but did not describe any objective optimal target for those optical densities. Neither did the previous version or 3Deeps Filter spectacles address optimization of the spectacles to account for the materials from which the lenses are fabricated. 3Deeps Filter Spectacles that incorporate such double optimization are called Continuous Adjustable 3Deeps Filter Spectacles. Previously, related patent applications for Continuous Adjustable 3Deeps Filter spectacles have been disclosed that use electronically controlled variable tint materials for fabrication of the right and left lenses of the viewing spectacles. Generally, electronically controlled variable tint materials change the light transmission properties of the material in response to voltage applied across the material, and include but are not limited to electrochromic devices, suspended particle devices, and polymer dispersed liquid crystal devices. Such material provides precise electronic control over the amount of light transmission. 3Deeps spectacles adjust the optical properties so that the left and right lenses of the 3Deeps spectacles take on one of 3 states in synchronization to lateral motion occurring within the movie; a clear-clear state (clear left lens and clear right lens) when there is no lateral motion in successive frames of the motion picture; a clear-darkened state when there is left-to-right lateral motion in successive frame of the motion picture; and, a darkened-clear state when there is right-to-left lateral motion in successive frames of the motion picture. We note that clear is a relative term and even clear glass will block a small percentage of light transmission. A clear lens is then one that transmits almost all light through the material. Continuous Adjustable 3Deeps Filter spectacles are improved 3Deeps spectacles in that the darkened state continuously changes to take an optical density to provide the maximum Pulfrich stereoscopic 3D illusion optimized for (a) the speed and direction of lateral motion, and (b) the transition time of the electrochromic material from which the lenses are fabricated. Thus, Continuous Adjustable 3Deeps Filter Spectacles doubly optimize 3Deeps Filter Spectacles to maximize the target optical densities of the lenses, and to account for the lens material. Double optimization of the 3Deeps Filter Spectacles has substantial benefits and Continuous Adjustable 3Deeps Filter Spectacles solves substantial problems that 3Deeps Filter Spectacles could not address. One problem addressed by this invention is that of slow transition time when transitioning between different optical densities of the lenses of the Continuous Adjustable 3Deeps Filter spectacles. Optimal control of Continuous Adjustable 3Deeps Filter spectacles is achieved by adjusting the right- and left-lenses to the optimal optical density synchronized to maximize the 3D effect of the Pulfrich illusion between frames of the motion picture with respect to the transition time properties of the electrochromic material. As an example, a movie that is shown on a 100 Hz digital TV may require as many as 100 different optical density controlled lens transitions per second to optimally synchronize to the speed and direction of lateral motion in the motion picture. Most often the transitions in synchronization to the movie are small minor adjustments to the optical density of the lens that can be accomplished in the allotted time. A problem arises when 3Deeps Filter spectacles are fabricated from electronically controlled variable tint materials that are incapable of the fast transition times that are sometimes required as for instance between scene changes. While electronically controlled variable tint materials may be able to achieve fast transitions from one optical density state to another optical density state that are near or close to each other, it may be incapable of transition between optical density states that are far apart. However, faster transition times using any electronically controlled variable tint material can be achieved by the simple expedient of using 2 or more layers—or multi-layers—of such material. Using multiple layers of material does result in a darker clear state, but the difference is minimal and barely perceptible, so the tradeoff between a slightly darker clear state and faster transition time is considered and warranted. Another problem relates to the cycle life (number of clear-dark cycles before failure) of some optoelectronic materials that may be limited. The cycle life may be increased by using multiple layers of optoelectronic materials since the electric potential applied to the material to achieve a target optical density will be for a shorter period of time. Another problem addressed by an alternate embodiment of this invention is that different methods of 3D require distinct viewing spectacles. However, with electronically controlled viewing spectacles, a single viewing spectacle can be switch selectable for different optical effects. For instance, to view a 3D movie that uses the anaglyph method to achieve 3D stereoscopy requires use of a different pair of spectacles (red-blue lenses) than that used for 3Deeps viewing. Other preferred embodiments of the invention relate to multi-use of the spectacles. The use of multi-layers of electronically controlled variable tint materials where different layers relate to different viewing methods, allow a single spectacle to be selectable to achieve different optical effects. For instance, while one or more layers of electronically controlled variable tint materials may be used for Continuous Adjustable 3Deeps Filter spectacles, another layer of materials may be used for anaglyph 3D spectacles. This would extend the use of a single pair spectacles so it can be selectively used for either Continuous Adjustable 3Deeps Filter spectacles viewing of 2D filmed movies or for anaglyph viewing of 3D filmed movies. It would also allow switching within any motion picture between 2D and 3D for a specific method, and/or switching within any motion picture between different methods of 3D. Till now a 3D motion picture may have been filmed in its entirety as anaglyph. With this invention the motion picture could have been filmed in part 2D with the multi-layer specs then set by signalization to a clear-clear state, and another part of the motion picture could have been filmed in 3D anaglyph with the multi-layer spectacles then set by signalization to a red-blue state. In another embodiment the picture may be filmed in part in 2D and 3D anaglyph, and shown to viewers in 2D, 3D using 3Deeps spectacle, and 3D anaglyph with the spectacles set accordingly. Movies are generally made from a series of single, non-repetitive pictures which are viewed at a speed that provides the viewer with the appearance of continuous movement. These series of single pictures are positioned in adjacent picture frames, in sequential order, wherein adjacent pictures are substantially similar to each other and vary only slightly from each other. Usually, movies are created using movie cameras, which capture the actual movement of the object; with animated movies, a series of individual pictures or cells are created, usually by hand or computer, and assembled in sequential order where adjacent pictures of a scene are substantially similar to each other and vary only slightly. Standard film projection is 24 frames per second, American video standard NTSC is 30 f.p.s. The appearance of continuous movement, using only two substantially similar pictures, has been accomplished in live performance by simultaneous projection of both images onto a screen, wherein one picture may be slightly off-set from the other picture as they appear on the screen, and by rotating a two-bladed propeller, wherein the propeller blades are set off from one another by 180 degrees, in front of and between the two projectors such that the two images are made to both alternate and overlap in their appearances, with both images in turn alternating with an interval of complete darkness onscreen when both projections are blocked by the spinning propeller. A viewer, using no special spectacles or visual aids, perceives a scene of limited action (with a degree of illusionary depth) that can be sustained indefinitely in any chosen direction: an evolving yet limited action appears to be happening continually without visible return-and-start-over repetition. Thus the viewer sees a visual illusion of an event impossible in actual life. Similarly, the manner in which things appear in depth are likely to be at odds, often extremely so, with the spatial character of the original photographed scene. Further, the character of movement and of depth has been made malleable in the hands of the projectionist during performance (so much so that such film-performance has been likened to a form of puppetry); the physical shifting of one of the two projections changes the visual relationship between them and thereby the character of the screen event produced. Similarly, small changes during performance in speed, placement and direction of propeller spin will cause radical changes in the visual event produced onscreen. Other visual arts which relate to the present invention are the Pulfrich filter. For one program, titled Bitemporal Vision: The Sea, viewers were invited to place a Pulfrich light-reducing filter before one eye to both enhance and transform the already apparent depth character of the presentation. Limited to presentation in live performance, such unique visual phenomena as described has been transient theater. Attempts to capture the phenomena by way of video-camera recording of the screen-image have been disappointingly compromised, so that—in over 25 years of such presentation (of so-called Nervous System Film Performances) no attempt has been made to commercialize such recordings. In addition, a number of products and methods have been developed for producing 3-D images from two-dimensional images. Steenblik in U.S. Pat. Nos. 4,597,634, 4,717,239, and 5,002,364 teaches the use of diffractive optical elements with double prisms, one prism being made of a low-dispersion prism and the second prism being made of a high-dispersion prism. Takahaski, et al in U.S. Pat. No. 5,144,344 teaches the use of spectacles based on the Pulfrich effect with light filtering lens of different optical densities. Beard in U.S. Pat. No. 4,705,371 teaches the use of gradients of optical densities going from the center to the periphery of a lens. Hirano in U.S. Pat. No. 4,429,951 teaches the use of spectacles with lenses that can rotate about a vertical axis to create stereoscopic effects. Laden in U.S. Pat. No. 4,049,339 teaches the use of spectacles with opaque temples and an opaque rectangular frame, except for triangular shaped lenses positioned in the frame adjacent to a nosepiece. Davino, U.S. Pat. No. 6,598,968, 3-Dimensional Movie and Television Viewer, teaches an opaque frame that can be placed in front of a user's eyes like a pair of glasses for 3-D viewing to take advantage of the Pulfrich effect. The frame has two rectangular apertures. These apertures are spaced to be in directly in front of the user's eyes. One aperture is empty; the other opening has plural vertical strips, preferably two, made of polyester film. Between the outer edge of the aperture and the outermost vertical strip is diffractive optical material. The surface of the strips facing away from the person's face might be painted black. Images from a television set or a movie screen appear three dimensional when viewed through the frame with both eyes open. Dones, U.S. Pat. No. 4,805,988, Personal Viewing Video Device, teaches a personal video viewing device which allows the simultaneous viewing of a stereoscopic external image as well as a monoscopic electronic image. This is accomplished using two optical systems which share particular components. The relative intensity of both images may be adjusted using a three-iris system where each iris may be a mechanical diaphragm, an electronically controlled liquid crystal device, or a pair of polarized discs whose relative rotational orientation controls the transmissivity of the disc pair. Beard in U.S. Pat. No. 4,893,898 teaches a method for creating a 3-D television effect in which a scene is recorded with a relative lateral movement between the scene and the recording mechanism. The recording is played back and viewed through a pair of viewer glasses in which one of the lenses is darker and has a spectral transmission characterized by a reduced transmissivity in at least one, and preferably all three, of the television's peak radiant energy wavebands. The lighter lens, on the other hand, has a spectral transmission characterized by a reduced transmissivity at wavelengths removed from the television energy peaks. The result is a substantially greater effective optical density differential between the two lenses when viewing television than in normal ambient light. This produces a very noticeable 3-D effect for television scenes with the proper movement, while avoiding the prior “dead eye” effect associated with too great a density differential in ordinary light. Further enhancement is achieved by providing the darker lens with a higher transmissivity in the blue and red regions than in the yellow or green regions. Other patents deal with image processing to measure motion in a moving picture and include Iue U.S. Pat. No. 5,717,415, Nagaya U.S. Pat. No. 5,721,692 and Gerard De Haan U.S. Pat. No. 6,385,245. Iue in U.S. Pat. No. 5,717,415 teaches a method of converting two-dimensional images into three-dimensional images. A right eye image signal and a left eye image signal between which there is relatively a time difference or a luminance difference are produced from a two-dimensional image signal, thereby to convert two-dimensional images into three-dimensional images. In U.S. Pat. No. 5,721,692, Nagaya et al present a “Moving Object Detection Apparatus”. In that disclosed invention, a moving object is detected from a movie that has a complicated background. In order to detect the moving object, there is provided a unit for inputting the movie, a display unit for outputting a processed result, a unit for judging an interval which is predicted to belong to the background as part of a pixel region in the movie, a unit for extracting the moving object and a unit for calculating the moving direction and velocity of the moving object. Even with a complicated background in which not only a change in illumination condition, but also a change in structure occurs, the presence of the structure change of the background can be determined so as to detect and/or extract the moving object in real time. Additionally, the moving direction and velocity of the moving object can be determined. De Haan U.S. Pat. No. 6,385,245 teaches a method of estimating motion in which at least two motion parameter sets are generated from input video data. A motion parameter set is a set of parameters describing motion in an image, and by means of which motion can be calculated. Visual effects are important in motion pictures and have the potential to expand the viewing enjoyment of moviegoers. For example, the movement effect “Bullet Time” utilized in the movie “The Matrix” was critical to the appeal of the movie. Visual effects for 3-dimensional motion pictures include such motion pictures as “Charge at Feather River”, starring Guy Madison. The Vincent Price movie “House of Wax” was originally released as a 3-D thriller. The 3-D movie fad of the early to mid-1950s however soon faded due to complexity of the technologies and potential for improper synchronization, and misalignment of left and right eye images as delivered to the viewer. TV 3-D motion pictures have been attempted from time-to-time. Theatric Support produced the first TV Pulfrich event in 1989 for Fox Television—“The Rose Parade in 3D Live.” In order to sustain the illusion of realistic depth these 3-D Pulfrich effect TV shows require all foreground screen action to move in one consistent direction, matched to the fixed light-diminishing lens of special spectacles provided to viewers for each broadcast. This enormous constraint (for all screen action to proceed in one direction) placed on the producers of the motion picture is due to the realistic expectation that viewers were not going to invert their spectacles so as to switch the light-diminishing filter from one eye to another for each change in screen-action direction. For the great majority of viewers the limitation of spectacles with a fixed filter, either left or right, meant the 3D effect would be available only with movies produced specifically for that viewing spectacles design. With the exception of Sony I-max 3-D presentations, which require special theater/screening facilities unique to the requirements of I-Max technology, 3-dimensional motion pictures remain a novelty. Despite the wide appeal to viewers, the difficulties and burden on motion picture producers, distributors, TV networks, motion picture theaters, and on the viewers has been a barrier to their wide scale acceptance. Among the problems and constraints involving the production, projection, and viewing of 3-dimensional motion pictures are: Production: The commonly used anaglyph 3-dimensional movie systems require special cameras that have dual lenses, and capture 2-images on each frame. To have a version of the motion picture that can be viewed without special glasses requires that a separate version of the motion picture be shot with a regular camera so there is only one image per video frame and not simply the selection of one or the other perspective. Similarly, IMAX and shutter glass systems require special cameras and processing with separate versions of the motion picture for 2D and 3D viewing. Filming movies in 3D add as much as $10 million dollars to production costs, it has been reported. Projection: Some 3-dimensional systems require the synchronization and projection by more than 2 cameras in order to achieve the effect. “Hitachi, Ltd has developed a 3D display called Transpost 3D which can be viewed from any direction without wearing special glasses, and utilize twelve cameras and rotating display that allow Transpost 3D motion pictures that can be seen to appear as floating in the display. The principle of the device is that 2D images of an object taken from 24 different directions are projected to a special rotating screen. On a large scale this is commercially unfeasible, as special effects in a motion picture must be able to be projected with standard projection equipment in a movie theater, TV or other broadcast equipment. Viewing: As a commercial requirement, any special effect in a motion picture must allow viewing on a movie screen, and other viewing venues such as TV, DVD, VCR, PC computer screen, plasma and LCD displays. From the viewer's vantage, 3-dimensional glasses, whether anaglyph glasses or Pulfrich glasses, which are used in the majority of 3-dimensional efforts, if poorly made or worn incorrectly are uncomfortable and may cause undue eyestrain or headaches. Experiencing such headache motivates people to shy away from 3-D motion pictures. Because of these and other problems, 3-dimensional motion pictures have never been more than a novelty. The inconvenience and cost factors for producers, special equipment projection requirements, and viewer discomfort raise a sufficiently high barrier to 3-dimensional motion pictures that they are rarely produced. One object of this invention is to overcome these problems and constraints. The Human Eye and Depth Perception The human eye can sense and interpret electromagnetic radiation in the wavelengths of about 400 to 700 nanometers—visual light to the human eye. Many electronic instruments, such as camcorders, cell phone cameras, etc., are also able to sense and record electromagnetic radiation in the band of wavelengths 400-700 nanometer. To facilitate vision, the human eye does considerable image processing before the brain gets the image. When light ceases to stimulate the eyes photoreceptors, the photoreceptors continue to send signals, or fire for a fraction of a second afterwards. This is called “persistence of vision”, and is key to the invention of motion pictures that allows humans to perceive rapidly changing and flickering individual images as a continuous moving image. The photoreceptors of the human eye do not “fire” instantaneously. Low light conditions can take a few thousands of a second longer to transmit signals than under higher light conditions. Causing less light to be received in one eye than another eye, thus causing the photoreceptors of the right and left eyes to transmit their “pictures” at slightly different times, explains in part the Pulfrich 3-D illusion, which is utilized in the invention of the 3Deeps system. This is also cause of what is commonly referred to as “night vision”. Once signals are sent to the eyes, the brain processes the dual images together (images received from the left and right eye) presenting the world to the mind in 3-dimensions or with “Depth Perception”. This is accomplished by several means that have been long understood. Stereopsis is the primary means of depth perception and requires sight from both eyes. The brain processes the dual images, and triangulates the two images received from the left and right eye, sensing how far inward the eyes are pointing to focus the object. Perspective uses information that if two objects are the same size, but one object is closer to the viewer than the other object, then the closer object will appear larger. The brain processes this information to provide clues that are interpreted as perceived depth. Motion parallax is the effect that the further objects are away from us, the slower they move across our field of vision. The brain processes motion parallax information to provide clues that are interpreted as perceived depth. Shadows provide another clue to the human brain, which can be perceived as depth. Shading objects, to create the illusions of shadows and thus depth, is widely used in illustration to imply depth without actually penetrating (perceptually) the 2-D screen surface. SUMMARY OF THE INVENTION A method has now been discovered for originating visual illusions of figures and spaces in continuous movement in any chosen direction using a finite number of pictures (as few as two pictures) that can be permanently stored and copied and displayed on motion picture film or electronic media. The method of the present invention entails repetitive presentation to the viewer of at least two substantially similar image pictures alternating with a third visual interval or bridging picture that is substantially dissimilar to the other substantially similar pictures in order to create the appearance of continuous, seamless and sustained directional movement. Specifically, two or more image pictures are repetitively presented together with a bridging interval (a bridging picture) which is preferably a solid black or other solid-colored picture, but may also be a strongly contrasting image-picture readily distinguished from the two or more pictures that are substantially similar. In electronic media, the bridge-picture may simply be a timed unlit-screen pause between serial re-appearances of the two or more similar image pictures. The rolling movements of pictorial forms thus created (figures that uncannily stay in place while maintaining directional movement, and do not move into a further phase of movement until replaced by a new set of rotating units) is referred to as Eternalisms, and the process of composing such visual events is referred to as Eternalizing. The three film or video picture-units are arranged to strike the eyes sequentially. For example, where A and B are the image pictures and C is the bridging picture, the picture units are arranged (A, B, C). This arrangement is then repeated any number of times, as a continuing loop. The view of this continuing loop allows for the perception of a perceptual combining and sustained movement of image pictures (A, B). Naturally, if this loop is placed on a film strip, then it is arranged and repeated in a linear manner (A, B, C, A, B, C, A, B, C, A, B, C, etc.). The repetition of the sequence provides an illusion of continuous movement of the image pictures (A, B); with bridging picture (C), preferably in the form of a neutral or black frame, not consciously noticed by the viewer at all, except perhaps as a subtle flicker. A more fluid or natural illusion of continuous movement from a finite number of image pictures is provided by using two of each of the three pictures and repeating the cycle of the pairs sequentially, or by blending adjacent pictures together on an additional picture-frame and placing the blended picture between the pictures in sequential order. The two image pictures (A, B) are now blended with each other to produce (A/B); the two image pictures are also blended with the bridging picture to produce (C/A and B/C), and then all pictures repeat in a series starting with the bridging picture (C, C/A, A, A/B, B, B/C) each blended picture being represented by the two letters with a slash therebetween). This series is repeated a plurality of times to sustain the illusion as long as desired. Repeating the sequence with additional blended frames provides more fluid illusion of continuous movement of the (optically combined) two image pictures (A, B). Additionally, various arrangements of the pictures and the blends can be employed in the present invention and need not be the same each time. By varying the order of pictures in the sequence, the beat or rhythm of the pictures is changed. For example, A, B, C can be followed by A, A/B, B, B/C, C which in turn is followed by A, A, A/B, B, B, B, B/C, C, C, C, C, i.e. A, B, C, A, A/B, B, B/C, C, A, A, A/B, B, B, B, B/C, B/C, C, C, C, C, A, B, C, A, etc. With A and B frames being similar images (such as a pair of normal two-eye perspective views of a three-dimensional scene from life), and frame C a contrasting frame (preferably a solid-color picture instead of an image-picture) relative to A,B, frame C acts as essentially a bridge-interval placed between recurrences of A,B. Any color can be used for the contrasting frame C: for example, blue, white, green; however, black is usually preferred. The contrasting frame can also be chosen from one of the colors in one of the two image pictures. For example, if one of the image pictures has a large patch of dark blue, then the color of the contrasting frame, bridging picture, may be dark blue. Blending of the pictures is accomplished in any manner which allows for both pictures to be merged in the same picture frame. Thus, the term blending as used in the specification and claims can also be called superimposing, since one picture is merged with the other picture. Blending is done in a conventional manner using conventional equipment, suitably, photographic means, a computer, an optical printer, or a rear screen projection device. For animated art, the blending can be done by hand as in hand drawing or hand painting. Preferably, a computer is used. Suitable software programs include Adobe Photoshop, Media 100 and Adobe After Affects. Good results have been obtained with Media 100 from Multimedia Group Data Translations, Inc. of Marlborough, Mass., USA. When using Media 100, suitable techniques include additive dissolving, cross-dissolving, and dissolving-fast fix and dither dissolving. In blending the pictures, it is preferred to use 50% of one and 50% of the other. However, the blending can be done on a sliding scale, for example with three blended pictures, a sliding scale of quarters, i.e. 75% A/25% B, 50% A/50% B, 25% A/75% B. Good results have been obtained with a 50%/50% mix, i.e. a blend of 50% A/50% B. The two image pictures, A and B, which are visually similar to each other, are preferably taken from side-by-side frame exposures from a motion picture film of an object or image or that is moving such that when one is overlaid with the other, only a slight difference is noted between the two images. Alternatively, the two image pictures are identical except that one is off-center from the other. The direction of the off-center, e.g. up, down, right, or left, will determine which direction the series provides the appearance of movement, e.g. if image picture B is off-center from image picture A to the right of A, the series of C, C/A, A, A/B, B, B/C will have the appearance of moving from left to right. Likewise, if you reverse the order of appearance then the appearance of movement will be to the left. More than two image pictures can be used in the invention. Likewise, more than one bridging picture can be used in the present invention. For example, four image pictures can be used along with one bridging picture. In this case, the series for the four image pictures, designated A, B, D and E, would be: C, A, B, D, E; or a 50/50 blend C, C/A, A, A/B, B, B/D, D, D/E, E, E/C; or side-by-side pairs, C, C, A, A, B, B, D, D, E, E. The image picture need not fill the picture frame. Furthermore, more than one image picture can be employed per frame. Thus, the picture frame can contain a cluster of images and the image or images need not necessarily filling up the entire frame. Also, only portions of image pictures can be used to form the image used in the present invention. Also, image pictures and portions of the image picture can be combined such that the combination is used as the second image picture. The portion of the image picture is offset from the first image picture when they are combined such that there is an appearance of movement. For example, a window from image picture A can be moved slightly while the background remains the same, the picture with the moved window is designated image picture B and the two combined to create the appearance of the window moving and/or enlarging or shrinking in size. In this case, both picture A and picture B are identical except for the placement of the window in the image picture. The same can also be done by using an identical background in both image pictures and superimposing on both pictures an image which is positioned slightly different in each picture. The image could be a window, as before, of a man walking, for example. The number of series which are put together can be finite if it is made on a length of film or infinite if it is set on a continuous cycle or loop wherein it repeats itself. In accordance with an embodiment, an electrically controlled spectacle for viewing a video is provided. The electrically controlled spectacle includes a spectacle frame and optoelectronic lenses housed in the frame. The lenses comprise a left lens and a right lens, each of the optoelectrical lenses having a plurality of states, wherein the state of the left lens is independent of the state of the right lens. The electrically controlled spectacle also includes a control unit housed in the frame, the control unit being adapted to control the state of each of the lenses independently. In one embodiment, each of the lenses has a dark state and a light state. In another embodiment, when viewing a video the control unit places both the left lens and the right lens to a dark state. In another embodiment, a method for viewing a video is provided. A user wears the electrically controlled spectacle described above, and the wearer is shown a video having dissimilar bridge frames and similar image frames. In accordance with another embodiment, a first modified image frame is determined by removing a first portion of a selected image frame. A second modified image frame different from the first modified image frame is determined by removing a second portion of the selected image frame. A third modified image frame different from the first and second modified image frames is determined by removing a third portion of the selected image frame. A first bridge image frame different from the selected image frame and different from the first, second, and third modified image frames is determined. A second bridge image frame different from the selected image frame, different from the first, second, and third modified image frames, and different from the first bridge image frame is determined. The first bridge image frame is blended with the first modified image frame, generating a first blended image frame. The first bridge image frame is blended with the second modified image frame, generating a second blended image frame. The first bridge image frame is blended with the third modified image frame, generating a third blended image frame. The first blended image frame, the second blended image frame, and the third blended image frame are overlaid to generate an overlayed image frame. The overlayed image frame and the second bridge image frame are displayed. In one embodiment, the first bridge image frame comprises a non-solid color. In another embodiment, each of the optoelectronic lenses comprises a plurality of layers of optoelectronic material. In accordance with another embodiment, a first modified image frame is determined by removing a first portion of a selected image frame. A second modified image frame different from the first modified image frame is determined by removing a second portion of the selected image frame. A third modified image frame is determined by removing a third portion of the first modified image frame. A fourth modified image frame different from the third modified image frame is determined by removing a fourth portion of the first modified image frame. A fifth modified image frame different from the third and fourth modified image frames is determined by removing a fifth portion of the first modified image frame. A sixth modified image frame is determined by removing a sixth portion of the second modified image frame. A seventh modified image frame different from the sixth modified image frame is determined by removing a seventh portion of the second modified image frame. An eighth modified image frame different from the sixth and seventh modified image frames is determined by removing an eighth portion of the second modified image frame. A first bridge image frame different from the first and second modified image frames is determined. A second bridge image frame different from the first and second modified image frames, and different from the first bridge image frame is determined. A third bridge image frame different from the first and second modified image frames, and different from the first and second bridge image frames is determined. A fourth bridge image frame different from the first and second modified image frames, and different from the first, second and third bridge image frames is determined. A first blended image frame is generated by blending the third modified image frame with the first bridge image frame. A second blended image frame is generated by blending the fourth modified image frame with the second bridge image frame. A third blended image frame is generated by blending the fifth modified image frame with the third bridge image frame. The first blended image frame, the second blended image frame, the third blended image frame, and the fourth bridge image frame are displayed. A fourth blended image frame is generated by blending the sixth modified image frame with the first bridge image frame. A fifth blended image frame is generated by blending the seventh modified image frame with the second bridge image frame. A sixth blended image frame is generated by blending the eighth modified image frame with the third bridge image frame. The fourth blended image frame, the fifth blended image frame, the sixth blended image frame, and the fourth bridge image frame are displayed. In one embodiment, the fourth bridge image frame is solid white, and the spectacle frame comprises a sensor adapted to receive synchronization signals embedded in the video and provide the synchronization signals to the control unit. In accordance with another embodiment, a first modified image frame is determined by removing a first portion of a selected image frame. A second modified image frame different from the first modified image frame is determined by removing a second portion of the selected image frame. A third modified image frame different from the first and second modified image frames is determined by removing a third portion of the selected image frame. A bridge image frame different from the selected image frame and different from the first, second, and third modified image frames is determined. The first modified image frame, the second modified image frame, and the third modified image frame are overlaid, to generate an overlayed image frame. The overlayed image frame and the bridge image frame are displayed. In accordance with another embodiment, a bridge image frame that is different from a first image frame and different from a second image frame is determined, the first and second image frames being consecutive image frames in a video. A first modified image frame is determined by removing a first portion of the first image frame. A second modified image frame different from the first modified image frame is determined by removing a second portion of the first image frame. A third modified image frame different from the first and second modified image frames is determined by removing a third portion of the first image frame. The first, second, and third modified image frames are overlaid to generate a first overlayed image frame. The first overlayed image frame and the bridge image frame are displayed. A fourth modified image frame is determined by removing a fourth portion of the second image frame. A fifth modified image frame different from the fourth modified image frame is determined by removing a fifth portion of the second image frame. A sixth modified image frame different from the fourth and fifth modified image frames is determined by removing a sixth portion of the second image frame. The fourth, fifth, and sixth modified image frames are overlaid to generate a second overlayed image frame. The second overlayed image frame and the bridge image frame are displayed. In accordance with another embodiment, a first modified image frame is determined by removing a first portion of a selected image frame. A second modified image frame different from the first modified image frame is determined by removing a second portion of the selected image frame. A third modified image frame different from the first and second modified image frames is determined by removing a third portion of the selected image frame. A first bridge image frame different from the first, second, and third modified image frames is determined. A second bridge image frame different from the first, second, and third modified image frames, and different from the first bridge image frame is determined. A third bridge image frame different from the first, second, and third modified image frames, and different from the first and second bridge image frames is determined. A fourth bridge image frame different from the first, second, and third modified image frames, and different from the first, second and third bridge image frames is determined. The first modified image frame is blended with the first bridge image frame to generate a first blended image frame. The second modified image frame is blended with the second bridge image frame to generate a second blended image frame. The third modified image frame is blended with the third bridge image frame to generate a third blended image frame. The first blended image frame, the second blended image frame, and the third blended image frame are overlaid to generate an overlayed image frame. The overlayed image frame and the fourth bridge image frame are displayed. In one embodiment, the fourth bridge image frame is solid white, and the spectacle frame comprises a sensor adapted to receive synchronization signals embedded in the video and provide the synchronization signals to the control unit. In accordance with another embodiment, a first modified image frame is determined by removing a first portion of a selected image frame. A second modified image frame different from the first modified image frame is determined by removing a second portion of the selected image frame. A third modified image frame is determined by removing a third portion of the first modified image frame. A fourth modified image frame different from the third modified image frame is determined by removing a fourth portion of the first modified image frame. A fifth modified image frame different from the third and fourth modified image frames is determined by removing a fifth portion of the first modified image frame. A sixth modified image frame is determined by removing a sixth portion of the second modified image frame. A seventh modified image frame different from the sixth modified image frame is determined by removing a seventh portion of the second modified image frame. An eighth modified image frame different from the sixth and seventh modified image frames is determined by removing an eighth portion of the second modified image frame. A first bridge image frame different from the first, second, third, fourth, fifth, sixth, seventh, and eight modified image frames is determined. A second bridge image frame different from the first bridge image frame and different from the first, second, third, fourth, fifth, sixth, seventh, and eight modified image frames is determined. The first bridge image frame is blended with the third modified image frame to generate a first blended image frame. The first bridge image frame is blended with the fourth modified image frame to generate a second blended image frame. The first bridge image frame is blended with the fifth modified image frame to generate a third blended image frame. The first blended image frame, the second blended image frame, and the third blended image frame are overlaid to generate a first overlayed image frame. The first overlayed image frame and the second bridge image frame are displayed. The first bridge image frame is blended with the sixth modified image frame to generate a fourth blended image frame. The first bridge image frame is blended with the seventh modified image frame to generate a fifth blended image frame. The first bridge image frame is blended with the eighth modified image frame to generate a sixth blended image frame. The fourth blended image frame, the fifth blended image frame, and the sixth blended image frame are overlaid to generate a second overlayed image frame. The second overlayed image frame and the second bridge image frame are displayed. In one embodiment, the first bridge image frame comprises a non-solid color. In accordance with another embodiment, one or more of the following actions may be performed in performing one or more of the methods described above: generating a blended image frame by blending a plurality of image frames, generating a combined image frame by combining a plurality of image frames, generating a combined image sequence by combining a plurality of image sequences, generating one or more doubled image frames by doubling one or more image frames, generating an overlayed image frame by overlaying a plurality of image frames, generating a modified image frame by removing a portion of an image frame, repeating one of an image frame or a series of image frames, generating a sequence of image frames, generating a collage based on one or more portions of one or more image frames, stitching together one or more portions of one or more image frames, superimposing a first image frame on a second image frame, determining a transitional frame, inserting and/or lifting a portion of a first image frame into a second image frame, reshaping a portion of an image frame, and relocating a portion of an image frame. In accordance with an embodiment, an apparatus includes a storage adapted to store one or more image frames, and a processor. The processor is adapted to determine a first modified image frame by removing a first portion of a selected image frame, determine a second modified image frame different from the first modified image frame by removing a second portion of the selected image frame, determine a third modified image frame different from the first and second modified image frames by removing a third portion of the selected image frame, determine a first bridge image frame different from the selected image frame and different from the first, second, and third modified image frames, determine a second bridge image frame different from the selected image frame, different from the first, second, and third modified image frames, and different from the first bridge image frame, blend the first bridge image frame with the first modified image frame, generating a first blended image frame, blend the first bridge image frame with the second modified image frame, generating a second blended image frame, blend the first bridge image frame with the third modified image frame, generating a third blended image frame, overlay the first blended image frame, the second blended image frame, and the third blended image frame to generate an overlayed image frame, display the overlayed image frame, and display the second bridge image frame. In one embodiment, the apparatus also includes an electrically controlled spectacle to be worn by a viewer. The electrically controlled spectacle includes a spectacle frame, optoelectronic lenses housed in the frame, the lenses comprising a left lens and a right lens, each of the optoelectrical lenses having a plurality of states, wherein the state of the left lens is independent of the state of the right lens, and a control unit housed in the frame, the control unit being adapted to control the state of each of the lenses independently. Each of the lenses has a dark state and a light state, and when viewing a video the control unit places both the left lens and the right lens to a dark state. In another embodiment, the first bridge image frame comprises a non-solid color. In accordance with another embodiment, an apparatus includes a storage adapted to store one or more image frames, and a processor. The processor is adapted to determine a first modified image frame by removing a first portion of a selected image frame, determine a second modified image frame different from the first modified image frame by removing a second portion of the selected image frame, determine a third modified image frame by removing a third portion of the first modified image frame, determine a fourth modified image frame different from the third modified image frame by removing a fourth portion of the first modified image frame, determine a fifth modified image frame different from the third and fourth modified image frames by removing a fifth portion of the first modified image frame, determine a sixth modified image frame by removing a sixth portion of the second modified image frame, determine an seventh modified image frame different from the sixth modified image frame by removing a seventh portion of the second modified image frame, determine an eighth modified image frame different from the sixth and seventh modified image frames by removing an eighth portion of the second modified image frame, determine a first bridge image frame different from the first, second, third, fourth, fifth, sixth, seventh, and eight modified image frames, determine a second bridge image frame different from the first bridge image frame and different from the first, second, third, fourth, fifth, sixth, seventh, and eight modified image frames, blend the first bridge image frame with the third modified image frame to generate a first blended image frame, blend the first bridge image frame with the fourth modified image frame to generate a second blended image frame, blend the first bridge image frame with the fifth modified image frame to generate a third blended image frame, overlay the first blended image frame, the second blended image frame, and the third blended image frame to generate a first overlayed image frame, display the first overlayed image frame and the second bridge image frame, blend the first bridge image frame with the sixth modified image frame to generate a fourth blended image frame, blend the first bridge image frame with the seventh modified image frame to generate a fifth blended image frame, blend the first bridge image frame with the eighth modified image frame to generate a sixth blended image frame, overlay the fourth blended image frame, the fifth blended image frame, and the sixth blended image frame to generate a second overlayed image frame, and display the second overlayed image frame and the second bridge image frame. In one embodiment, the apparatus also includes an electrically controlled spectacle to be worn by a viewer. In another embodiment, the first bridge image frame comprises a non-solid color. In accordance with another embodiment, a system for presenting a video is provided. The system includes an apparatus comprising a storage adapted to store one or more image frames associated with a video, and a processor. The processor is adapted to reshape a portion of at least one of the one or more image frames. The system also includes an electrically controlled spectacle which includes a spectacle frame, optoelectronic lenses housed in the frame, the lenses comprising a left lens and a right lens, each of the optoelectrical lenses having a plurality of states, wherein the state of the left lens is independent of the state of the right lens, and a control unit housed in the frame, the control unit being adapted to control the state of each of the lenses independently. Each of the lenses has a dark state and a light state. When viewing the video the control unit places both the left lens and the right lens to a dark state. In accordance with another embodiment, an apparatus includes a storage adapted to store one or more image frames, and a processor. The processor is adapted to obtain a first image from a first video stream, obtain a second image from a second video stream, wherein the first image is different from the second image, stitching together the first image and the second image to generate a stitched image frame, generating a first modified image frame by removing a first portion of the stitched image frame, generating a second modified image frame by removing a second portion of the stitched image frame, generating a third modified image frame by removing a third portion of the stitched image frame, wherein the first modified image frame, the second modified image frame, and the third modified image frame are different from each other, identify a bridge frame, blend the first modified image frame with the bridge frame to generate a first blended frame, blend the first modified image frame with the bridge frame to generate a first blended frame, blend the first modified image frame with the bridge frame to generate a first blended frame, overlay the first blended frame, the second blended frame, and the third blended frame to generate a combined frame, and display the combined frame. In one embodiment, the apparatus also includes spectacles adapted to be worn by a viewer of a video. In another embodiment, the bridge frame includes a non-solid color. In accordance with yet another embodiment, a method of displaying one or more frames of a video is provided. Data comprising a compressed image frame and temporal redundancy information is received. The image frame is decompressed. A plurality of bridge frames that are visually dissimilar to the image frame are generated. The image frame and the plurality of bridge frames are blended, generating a plurality of blended frames, and the plurality of blended frames are displayed. In one embodiment, the image frame is decompressed based on the temporal redundancy information. In another embodiment, the data comprises a compressed video file associated with a compression format that uses temporal redundancy to achieve compression of video data. For example, the data may comprise an MPEG compressed video file. In another embodiment, each bridge frame comprises a solid black picture, a solid colored picture, or a timed unlit-screen pause. In another embodiment, the plurality of blended frames are displayed in accordance with a predetermined pattern. In another embodiment, the plurality of blended frames are displayed in accordance with a predetermined pattern that includes a first pattern comprising the plurality of blended frames, and a second pattern that comprises repetition of the first pattern. In accordance with another embodiment, an apparatus includes a storage configured to store a compressed image frame and temporal redundancy information, and a processor configured to receive the compressed image frame and the temporal redundancy information, decompress the image frame, and generate a plurality of bridge frames that are visually dissimilar to the image frame. The plurality of bridge frames includes a first bridge frame having a first width, the first bridge frame comprising a first white rectangle in an upper portion of the first bridge frame, the first white rectangle having the first width, and a second bridge frame having a second width, the second bridge frame comprising a second dark rectangle in an upper portion of the second bridge frame, the second dark rectangle having the second width. The processor is further configured to blend the image frame and the plurality of bridge frames, generating a plurality of blended frames, wherein the plurality of blended frames include a first blended frame that includes the first portion of the image frame in an upper portion of the first blended frame, and a second blended frame that includes the second dark rectangle in an upper portion of the second blended frame. The processor is also configured to display the plurality of blended frames consecutively within a video. In another embodiment, the processor is further configured to decompress the image frame based on the temporal redundancy information. In another embodiment, the data comprises a compressed video file associated with a compression format that uses temporal redundancy to achieve compression of video data. In another embodiment, each bridge frame comprises a timed unlit-screen pause. In another embodiment, the processor is further configured to display the plurality of blended frames in accordance with a predetermined pattern. In another embodiment, the processor is further configured to display the blended frames in accordance with a predetermined pattern that includes a first pattern comprising the plurality of blended frames, and a second pattern that comprises repetition of the first pattern. In another embodiment, the plurality of bridge frames comprise a first bridge frame having a first pattern and a second bridge frame having a second pattern that is complementary to the first pattern. In accordance with still a further embodiment of the invention, a method for generating modified video is provided. A source video comprising a sequence of 2D image frames is acquired, and an image frame that includes two or more motion vectors that describe motion in the image frame is obtained from the source video, wherein each of the motion vectors is associated with a region of the image frame. A respective parameter is calculated for each of the following: (a) a lateral speed of the image frame, using the two or more motion vectors, and (b) a direction of motion of the image frame, using the two or more motion vectors. A deformation value is generated by applying an algorithm that uses both of the parameters, and the deformation value is applied to the image frame to identify a modified image frame. The modified image frame is blended with a bridge frame that is a non-solid color and is different from the modified image frame, to generate a blended frame. The direction of motion and velocity of motion parameters in the calculating step are calculated only from the motion vectors input along with the image frame. In one embodiment, a viewer views the modified video through spectacles. The spectacles have a left and right lens, and each of the left lens and right lens has a darkened state. Each of the left and right lenses has a darkened state and a light state, the state of the left lens being independent of the state of the right lens. In another embodiment, the spectacles also include a battery, a control unit and a signal receiving unit. The control unit may be adapted to control the state of the each of the lenses independently. In another embodiment, the left and right lenses comprise one or more electro-optical materials. In another embodiment, the blended frame is displayed to a viewer. In accordance with another embodiment, a method for generating modified video is provided. A source video including a sequence of 2D image frames is acquired, and a modified image frame is obtained based on a selected one of the image frames of the source video. The modified image frame is blended with a bridge frame that is a non-solid color and is different from the modified image frame, to generate a blended frame. In one embodiment, the selected image frame comprises two or more motion vectors that describe motion in the selected image frame, wherein each of the motion vectors is associated with a region of the selected image frame. A respective parameter is calculated for each of the following: (a) a lateral speed of the selected image frame, using the two or more motion vectors, and (b) a direction of motion of the selected image frame, using the two or more motion vectors. A deformation value is generated by applying an algorithm that uses both of the parameters, and the deformation value is applied to the image frame to identify a modified image frame. In one embodiment, the direction of motion and velocity of motion parameters in the calculation step are calculated only from the motion vectors. In accordance with another embodiment, a method for generating modified video is provided. A source video comprising a sequence of 2D image frames is acquired, a first image frame and a second image frame in the source video are identified, the first image frame and the second image frame are combined to generate a modified image frame, and the modified image frame is blended with a bridge frame that is a non-solid color, different from the modified image frame, different from the first image frame, and different from the second image frame, to generate a blended frame. In one embodiment, the first image frame and the second image frame are similar. Many advantages, features, and applications of the invention will be apparent from the following detailed description of the invention that is provided in connection with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a perspective view of the preferred embodiment of the Continuous Adjustable 3Deeps Filter Spectacles. FIG. 2a shows a left lens of Continuous Adjustable 3Deeps Filter Spectacles fabricated from a single layer of electrochromic material. FIG. 2b shows details of an electrochromic device for fabricating the electronically controlled variable tint material of the right and left lenses of the Continuous Adjustable 3Deeps Filter Spectacles. FIG. 3 is a block diagram of the operation of the Continuous Adjustable 3Deeps Filter Spectacles. FIG. 4 is a flow chart showing the operation of the Control Unit of the Continuous Adjustable 3Deeps Filter Spectacles. FIG. 5 is a perspective view of the second preferred embodiment of the Continuous Adjustable 3Deeps Filter Spectacles fabricated from multiple layers of electrochromic material. FIG. 6a shows a left lens of Continuous Adjustable 3Deeps Filter Spectacles fabricated from multiple layers of electrochromic material. FIG. 6b shows details of a multiple layered electrochromic device for fabricating the electronically controlled variable tint material of the right and left lenses of the Continuous Adjustable 3Deeps Filter Spectacles. FIG. 7 is a block diagram of the operation of the Continuous Adjustable 3Deeps Filter Spectacles using a multiple layered electrochromic device for fabricating the electronically controlled variable tint material of the right and left lenses. FIG. 8 is a flow chart showing the operation of the Control Unit of the Continuous Adjustable 3Deeps Filter Spectacles using a multiple layered electrochromic device for fabricating the electronically controlled variable tint material of the right and left lenses. FIG. 9 is a transition time curve for a single layer of electrochromic material with transition time as a function of transmissivity. FIG. 10 is a transition time curve for a double layer (multi-layer) of electrochromic material with transition time as a function of transmissivity. FIG. 11 is a perspective view of the third preferred embodiment of the multi-use Continuous Adjustable 3Deeps Filter Spectacles with single-layered lenses. FIG. 12 is a block diagram of the operation of the multi-use Continuous Adjustable 3Deeps Filter Spectacles with single-layered lenses. FIG. 13 is a flow chart showing the operation of the Control Unit of the multi-use Continuous Adjustable 3Deeps Filter Spectacles with single-layered lenses. FIG. 14 is a perspective view of the fourth preferred embodiment of the multi-use Continuous Adjustable 3Deeps Filter Spectacles with multi-layered lenses. FIG. 15a shows a left lens of Multi-Use Electrically Controlled Continuous Adjustable 3Deeps Filter Spectacles fabricated from multiple layers of electrochromic materials. FIG. 15b shows details of a Multi-Use electrochromic device for fabricating the electronically controlled variable tint material of the right and left lenses of the Multi-Use Electrically Controlled 3Deeps Continuous Adjustable 3Deeps Filter Spectacles using multi-layered lenses. FIG. 16 is a block diagram of the operation of the multi-use Continuous Adjustable 3Deeps Filter Spectacles with multi-layered lenses. FIG. 17 is a flow chart showing the operation of the Control Unit of the Multi-Use Electrically Controlled Continuous Adjustable 3Deeps Filter Spectacles with multi-layered lenses. FIGS. 18 a-18 c illustrates the present invention with three pictures. FIGS. 19 a-19 c illustrates the present invention using three pictures along with blended pictures. FIGS. 20 a-20 c illustrates the present invention using the same picture wherein one is offset from the other. FIGS. 21 a-21 b illustrates the present invention with side-by-side pairs of pictures. FIGS. 22 a-22 c illustrates the present invention wherein pictures G and H are identical but image F has been imposed in a slightly different location. FIGS. 23 a-23 c illustrates pictures of two women in Eternalism with two pictures. FIGS. 24 a-24 c illustrates the women of FIG. 6 with a 50-50 blend between the women and the women and the bridging frame. FIGS. 25 a-25 c illustrates the same women in two different perspectives (not apparent to normal viewing as pictured here), joined to create an Eternalism. FIGS. 26 a-26 b illustrates the doubling of the frames from FIG. 6. FIGS. 27 a-27 c illustrates the two women with a smaller frame depicting a portion of one woman repeated and overlayed in the upper left-hand corner of the frame to create a separate depth-configuration within the larger frame. FIG. 28 illustrates a combination of the two women with a portion of the one woman both in the bridging frame as well as in one of the frames that contain both women. FIG. 29 illustrates Eternalism with two women and a circle moving through the frames. FIG. 30 illustrates the Pulfrich filter. FIG. 31 shows components of a video display manager in accordance with an embodiment. FIG. 32 is a flowchart of a method of decompressing and displaying one or more image frames in accordance with an embodiment. FIG. 33 shows an image frame in accordance with an embodiment; FIGS. 34A-34B show respective bridge frames in accordance with an embodiment. FIGS. 35A-35B show respective blended frames in accordance with an embodiment. FIG. 35C shows a pattern comprising a plurality of blended frames in accordance with an embodiment. FIG. 35D shows a predetermined pattern that includes repetition of a second pattern that comprises a plurality of blended frames in accordance with an embodiment. FIG. 36 is a high-level block diagram of an exemplary computer that may be used to implement certain embodiments. FIG. 37 shows a typical curve of retinal reaction time as a function of luminosity. FIG. 38A shows the operation of the Pulfrich illusion when there is no horizontal foreground motion in the motion picture. FIG. 38B shows the operation of the Pulfrich illusion when the motion picture exhibits horizontal foreground motion from the right to the left. FIG. 38C shows the operation of the Pulfrich illusion when the motion picture exhibits horizontal foreground motion from the left to the right. FIG. 39 uses the typical curve of retinal reaction time as a function of luminosity to explain the operation of cardboard Pulfrich Filter spectacles with fixed lenses. FIG. 40 uses the typical curve of retinal reaction time as a function of luminosity to demonstrate how to compute from a motion vector and luminosity the optimal optical density for the neutral density lens of the preferred embodiment of the Continuous Adjustable 3Deeps Filter Spectacles so that the difference in retinal reaction time between the viewer's eyes results in instant and lagging images that correspond to a separation on the display monitor of exactly 2½ inches. FIG. 41 shows an algorithm that can be used to calculate the optimal optical density for the neutral density filter of the preferred embodiment of the Continuous Adjustable 3Deeps Filter Spectacles. FIG. 42 is an illustration of an alternate algorithm to characterize lateral motion in a motion picture. FIG. 43 uses the typical curve of retinal reaction time as a function of luminosity to demonstrate a first alternate embodiment for computing an optimal optical density for the neutral density lens of the Continuous Adjustable 3Deeps Filter Spectacles so that the difference in retinal reaction time between the viewer's eyes is a constant value. FIG. 44 shows Continuous Adjustable 3Deeps Filter Spectacles that include a photo-detector. FIG. 45 uses the typical curve of retinal reaction time as a function of luminosity to demonstrate a second alternate embodiment for computing an optimal optical density for the neutral density lens of the Continuous Adjustable 3Deeps Filter Spectacles so that the difference in retinal reaction time between the viewer's eyes corresponds to a fixed number of frames of the motion picture. FIG. 46 is a flowchart showing the use of a format conversion semiconductor chip to compute the Continuous Adjustable 3Deeps Filter Spectacles synchronization information. FIG. 47 is a block diagram showing the operation of the Video and 3Deeps processing used to calculate the optimal optical density of the neutral density filter in the preferred embodiment of the Continuous Adjustable 3Deeps Filter Spectacles. FIG. 48 is a table showing control information for the Continuous Adjustable 3Deeps Filter Spectacles. FIG. 49 shows a typical operating characteristic curve for an electrochromic material with optical density as a function of voltage. FIG. 50 is a first example of a transition time curve for an electrochromic material with transition time as a function of optical density. FIG. 51 is a second example of a transition time curve for an electrochromic material with transition time as a function of optical density. FIG. 52 is a block diagram showing the operation of the control unit of the Continuous Adjustable 3Deeps Filter Spectacles. FIG. 53 is a block diagram showing the operation of a typical the Continuous Adjustable 3Deeps Filter Spectacles system. FIG. 54 is a block diagram for a preferred embodiment of an IC Chip generating optimum optical density signals for each individual lens of a Continuous Adjustable 3Deeps Filter Spectacle. FIG. 55 is a block diagram of an alternate embodiment of an IC chip generating the change in optical density signals for each individual lens of a Continuous Adjustable 3Deeps Filter Spectacle. FIG. 56 shows Continuous Adjustable 3Deeps Filter Spectacles that include an IC chip generating the change in optical density signals for each individual lens of a Continuous Adjustable 3Deeps Filter Spectacle. FIG. 57 shows components of a video display manager in accordance with an embodiment. FIG. 58 is a flowchart of a method of displaying one or more image frames in accordance with an embodiment. FIGS. 59A-59B comprise a flowchart of a method of generating modified video in accordance with an embodiment. DETAILED DESCRIPTION References will now be made in detail to the preferred embodiments of the invention, examples of which are illustrated in the accompanying drawings. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts. To help understand the invention the following summary of inventive work from the previous related patent disclosures is provided. The purpose of this section then is to explain the ground that has been covered in previous related patents and then identify the problems that this current patent application addresses and solves. The Pulfrich Illusion There is a well-studied stereoscopic illusion called the Pulfrich illusion in which the illusion of 3D is invoked by differentially shading the left and right eye. Anyone watching TV through special viewing glasses can see the illusion. One way to construct the special Pulfrich viewing glasses is to take sunglasses and remove the left lens, so that the left eye views the TV screen unobstructed and the right eye views the TV screen through the darkened sunglass lens. With such Pulfrich viewing spectacles all screen motion from left-to-right will be in 3D. The illusion is based on basic eye mechanics—the shaded lens causes the eye to send the image to the brain later than unshaded eye. If the time difference is 1/10 second than on a 100 Hz digital TV the difference is 10 screen images, which is enough to produce a vivid illusion of 3D in the presence of moderate lateral motion. The image processing part of the brain puts the two disparate images together as depth. This is a pure optical illusion that has nothing to do with how a motion picture is filmed. The Pulfrich illusion has been used for more than 50 years to produce 3D movies, using cardboard viewing spectacles with a clear left lens and dark transparent right lens. Pulfrich 3D motion pictures have been produced including such offerings as the 1971 feature length movie I, Monster Starring Christopher Lee as well as selected scenes from the 1997 second season finale of the network TV sitcom Third Rock From The Sun. However there is a problem in that the special Pulfrich viewing glasses impose severe constraints on both the movie and viewing venue. More specifically, the problem then is that for any special viewing spectacles with lenses of a fixed optical density, the lighting, and speed and direction of screen motion have to be in exactly proper alignment to get an optimal 3D effect that is comparable to other 3D methods such as anaglyph (blue-red viewing spectacles). That conjunction of light and motion rarely happens so Pulfrich is not considered a viable approach to 3D movies or TV. Movies made for viewing using the Pulfrich illusion are best viewed in darkened venues, and if the same movie is viewed in a brightly lit venue the illusion is diminished or may even totally disappear. These problems could be addressed if dynamic Pulfrich viewing spectacles could be constructed that self-configured themselves to the light and motion instant in a motion picture. However, such dynamic viewing spectacles still must be totally passive to the viewer. 3Deeps Systems Proposed in the Earliest Related Patent Applications Early solutions provided dynamic Pulfrich viewing spectacles (called 3Deeps viewing spectacles) that could be synchronized to the movies. These solutions utilized neutral optoelectronic lenses (transmissivity of visible light) that are controllable by an electric potential. The lenses could take any of three states; clear left lens and clear right lens (clear-clear) when there is no screen motion; clear left lens and dark right lens (clear-dark) when screen motion is from left to right; and, dark left lens and clear right lens (dark-clear) when the screen motion is from right to left. Wired or wireless signals (Infrared, radio, or sound) synchronized the 3Deeps viewing spectacles to the movies. These early solutions also addressed how to calculate the lateral motion between frames of a motion picture and the synchronization controllers that calculated and transmitted the motion vector information to the 3Deeps viewing spectacles. The proposed solution had significant benefits and advantages including: Every movie ever made—without additional alteration or processing—could be viewed in 3D when wearing 3Deeps spectacles A movie could be viewed simultaneously by viewers with or without 3Deeps spectacles, and No changes are required to any broadcast standards, cinema formatting, viewing venue, or viewing monitors It should be understood, that the natural view of the world that viewer's expect of cinema is 3-dimensional, and to any movie viewer with binocular vision, it is the screen flatness of 2D that is strange and unnatural. From the earliest days of motion pictures cinematographers have used light and lateral movement as cues to help the viewer translate 2D screen flatness into their binocular vision expectations. But light and lateral motion are precisely the factors that elicit the Pulfrich illusion, so when movies are produced, cinematographers and lighting specialists stress precisely the features that the 3Deeps systems can translate into the natural sense of depth that the viewer is expecting. That is to say, since the advent of moving pictures, filmmakers have been unknowingly preparing their movies for advantageous 3D viewing using 3Deeps spectacles. However, the early 3Deeps spectacles did not address how to calculate an optical density for the lenses of the 3Deeps spectacles that would maximize the Pulfrich stereoscopic illusion. A Second Solution—Continuous Adjustable 3Deeps Filter Spectacles The most recent related 3Deeps patent applications disclose how to construct better 3Deeps viewing spectacles that maximize the Pulfrich stereoscopic illusion and are referred to as Continuous Adjustable 3Deeps Filter Spectacles. To construct these improved 3Deeps viewing spectacles we utilize the body of existing knowledge about (1) the human eye retinal reaction time, and (2) the operating characteristics of the optoelectronic material of the 3Deeps lens. Retinal Reaction Time While each eye is stimulated by light continuously, there is a time delay called the retinal reaction time until the information is triggered and transmitted to the brain. Retinal reaction time is primarily dependent on the amount of light (brightness) that falls on the eye. For instance, in the presence of the bright light of a “Clear Sky at noon” the retinal reaction time is about 100 milliseconds ( 1/10-th of a second) and the eye will trigger about every 100 milliseconds and send the image from the eye to the brain. In the presence of light from a “Clear Sky” the retinal reaction time is slower—about 200 milliseconds. And in the presence of light that approximates a “Night sky with a full moon” the retinal reaction time is slower still—almost 400 milliseconds. The darker is the illumination, the retinal reaction time become increasingly slower. While the retinal reaction mechanisms are independent for each eye, in normal viewing both eyes are unobstructed and the luminance value is the same and the eyes trigger at about the same time. However, if one eye is shaded so the eyes have unequal retinal illuminance, then the two eyes will trigger at different speeds and different times. Using lens filters with different optical density shading causes this to happen and results in a difference in retinal reaction time for each eye. The difference in retinal reaction time between the two eyes is one factor in the commonly accepted explanation for the Pulfrich illusion. The second factor is simultaneity. The brain will take two eye images and put them together in a simultaneous fashion to generate the image that we perceive. Thus in normal viewing, if both eyes see the same 2D image without any filtered obstruction, the brain gets two identical images and there is no information by which the brain may infer depth. However, if one eye is differently shaded, than the eyes send two different images to the brain, and the mind places them together and interprets the two different images as depth. These two factors, retinal reaction time, and simultaneity are the two factors that explain Pulfrich illusion. If the scene being viewed is static with no moving object, then the “instant” image of the unshaded eye and the “lagging image” of the shaded eye will still see the same image and the retinal reaction delay and simultaneity factors will not provide any depth information. Thus, the Pulfrich illusion does not work in the absence of motion. But if the scene being viewed has horizontal motion (also called lateral motion) then the shaded eye will see an image that is “lagging” the instant image. In this case the “lagging image” caused by retinal reaction delay of the shaded eye, when juxtaposed with the “instant image” perceived by the unshaded eye will, through the mechanism of simultaneity, be reconciled by the brain as a perception of depth. This is the Pulfrich illusion. Well-researched retinal reaction curves describing this phenomenon are available and are used by the Continuous Adjustable 3Deeps Filter Spectacles to select the optical density of the lens to maximize the Pulfrich illusion. This is done in the following exemplary manner. First we measure the ambient light optical density and use that with the retinal reaction curve to get the retinal delay for the eye viewing through the “clear” lens. We then use the direction of lateral motion to determine which of the right and left lenses is clear (with the other lens the dark lens.) If the lateral motion is from the left-to-right direction on the screen then the “clear” lens of the Continuous Adjustable 3Deeps Filter Spectacles will be the left lens, and if the lateral motion is in the opposite direction then the “clear” lens will be the right lens. To set the optical density of the dark lens we now utilize the magnitude of the motion. As an example, if lateral motion of the major object in the frame is measured as moving at 0.25 inches per frame then it will take 10 frames to move 2.5 inches—the average inter-ocular distance. In this case the Continuous Adjustable 3Deeps Filter Spectacles use the retinal reaction curve to determine an optical density setting for the darkened lens so the motion-direction eye will see a lagging image that is 10 frames behind that of the unshielded eye. If the TV screen has a refresh rate of 100 Hz then 10 frames is precisely 100 milliseconds, so if the ambient light is that of a “Clear Sky at noon” with a retinal reaction time of 100 milliseconds, then we would set the dark lens to have an optical density of a “Clear Sky” which corresponds to a retinal reaction time of 200 milliseconds. Depending upon the ambient illumination, the optical density of the dark lens can always be calculated and precisely determined from the retinal reaction curve and the objective function that maximizes the Pulfrich illusion. Once the optimal optical density values are known for the lenses of the Continuous Adjustable 3Deeps Filter Spectacles, the Operating Characteristic curve of the optoelectronic material of the lenses can be utilized to apply the correct potential to the lenses so the lenses of the viewing spectacles have the optical density so the movie is viewed with a maximal Pulfrich stereoscopic illusion. In previous patent applications, retinal reaction time is used to calculate the optimal optical density value (a first optimization) and the operating characteristic curve is used for control over the lenses of the Continuous Adjustable 3Deeps Filter Spectacles (a second optimization). However, other problems are not address and are the subject of this pending patent application. There is a problem that many optoelectronic materials often do not change state instantaneously. While frame-to-frame display of a motion picture may be 100 Hz (100 frames a second or 10 milliseconds per frame) a typical optoelectronic material made from electrochromic material may have a “slow” response time and take several seconds to change from a clear state to a much darker state. A second problem may relate to a limited “cycle life” (number of clear-dark cycles) of some optoelectronic materials that may be limited. Both of these problems can be addressed by using multiple layers of optoelectronic material in fabricating the lenses of the Continuous Adjustable 3Deeps Filter Spectacles, and this patent discloses how to implement such a solution. Both problems relate to the viewing spectacle side of the solution that implements the already independently calculated optical density that maximizes the 3D Pulfrich stereoscopic illusion. Variable Tint and Optoelectronic Devices Optoelectronic devices (or materials) that control the transmission of light through the device may be referred to as a variable tint device or variable tint material. Neutral variable tint devices reduce the transmission of light approximately equally along the entire spectrum of visible light and thus do not noticeably distort color. Other variable tint devices may allow transmission of light in a restricted spectrum of visible light and block light outside the restricted range, such as blue variable tint devices that allows the passage of light in the blue spectrum (λ˜490-450 nm). Devices that control properties of light other than the transmission of light through the medium will be referred to simply as optoelectronic devices. Methods of Producing 3-D Illusion in Moving Pictures Motion pictures are images in 2-dimensions. However, several methods have been developed for providing the illusion of depth in motion pictures. These include the Anaglyph, Intru3D (also called ColorCode 3D), IMAX (Polaroid), shutter glasses and Pulfrich 3-dimensional illusions. Anaglyph 3-Dimensional Illusion “Anaglyph” refers to the red/blue (red/cyan or red/green) glasses that are used in comic books and in cereal packets etc. The glasses consist of nothing more than one piece of transparent blue plastic and one piece of transparent red plastic. These glasses are easy to manufacture and have been around since the 1920s. An anaglyph stereo picture starts as a normal stereo pair of images, two images of the same scene, shot from slightly different positions. One image is then made all green/blue and the other is made all red, the two are then seen together. When the image is viewed through the glasses the red parts are seen by one eye and the other sees the green/blue parts. The visual cortex of the brain fuses this into perception of a three-dimensional scene or composition. This effect is fairly simple to do with photography, and extremely easy to do on a PC, and it can even be hand-drawn. The main limitation of this technique is that because the color is used in this way, the true color content of the image is usually lost and the resulting images are usually in black and white. As the colors compete for dominance they may appear unstable and monochromatic. A few images can retain a resemblance to their original color content, but the photographer has to be very selective with color and picture content. Intru3D-Intel Intel's Intru3D uses the ColorCode 3D method that is an update to the more familiar Anaglyph method of 3D stereoscopy. It is similar to the Anaglyph method of stereoscopy but rather than make one image green/blue and the other image red, Intru3D records the two images as amber and blue. This provides generally truer color than typical Red/Blue anaglyphs, particularly where Red image components are concerned. IMAX (Polaroid) 3-Dimensional Illusion IMAX creates the illusion of 3-dimensional depth by recording the motion pictures on two separate rolls of film with two camera lenses to represent the left and right eyes. These lenses are separated by an interocular distance of about 2.5 in., the average distance between a human's eyes. By recording on two separate rolls of film for the left and right eyes, and then projecting them simultaneously, IMAX can create a 3-Dimensional illusion for viewers. IMAX uses either of two different methods to create the 3D illusion in the theatre. The first method relies on polarization. During projection, the left eye image is polarized in one direction and the right eye image polarized perpendicular to the left eye image as they are projected on the IMAX screen. By wearing special viewing glasses with lenses polarized in their respective directions to match the projection, the left eye image can be viewed only by the left eye since the polarization of the left lens will cancel out that of the right eye projection, and the right eye image can be viewed only by the right eye since the polarization of the right lens will cancel out that of the left eye projection. IMAX also uses another method—shutter glasses—for 3D viewing. This method of 3D projection involves the use of LCD shutter glasses that use similarly polarized lenses for both eyes. The left and right eye images are projected on the viewing screen in alternate frames. These LCD shutter glasses are synchronized to the projector. The projector displays the left and right images that are momentarily viewed by the appropriate eye by allowing that LCD lens to become transparent while the other remains opaque. That is when the left eye frame is projected on the screen, the left lens of the shutter glasses becomes transparent and the right lens of the shutter glasses becomes opaque. When the next frame is projected on the screen—a frame for the right eye—the left lens becomes opaque and the right lens becomes transparent. In both the IMAX 3D systems only the correct eye is allowed to view the correct image while the other eye is “blinded”. The “transparent” state is actually quite dark, and occludes about 35% of the projected light to the viewing eye while the non-viewing eye is supposed to view no image at all. Shutter Glasses Different formulations of shutter glasses have been implemented over the last few decades, but without much large-scale commercial success. A shutter glasses solution generally require two images for each image of video, with shutter covering or uncovering each eye of the viewer. This allows one eye to see, than the other, with the shutters timed and synchronized with the video so that each eye only sees the image intended for it. Some shutter glass systems are wired to a control device while some shutter glass systems use wireless infrared signaling to control the state of the lenses. CrystalEyes is the name of a stereoscopic viewing product produced by the StereoGraphics Corporation of San Rafael, Calif. They are lightweight, wireless liquid crystal shuttering eyewear that are used to allow the user to view alternating field sequential stereo images. The source of the images alternately displays a left-eye view followed by a right-eye view. CrystalEyes' shutters can block either of the user's eyes so that only images appropriate for each eye are allowed to pass. A wireless infrared communications link synchronizes the shuttering of the eyewear to the images displayed on the monitor or other viewing screen. CrystalEyes shutter glasses, weight only 3.3 ounces, use two 3V lithium/manganese dioxide batteries, and have a battery life of 250 hours. This demonstrates the robustness and potential of any viewer glass solution. Because shutter glasses only expose each eye to every other frame, the refresh rate of the video is effectively cut in half. On a TV with refresh rates of 30 frames per second (for an NTSC TV) or 25 frames per second (for a PAL TV), this is hard on the eyes because of the continual flicker. This problem is eliminated with higher refresh rates, such as on PC monitors. However, shutter systems have not been overwhelmingly commercially successful. Motion pictures that use such stereo shutter systems require two frames for each frame of regular film. Motion pictures would then have to be produced in at least 2 versions. Also, except on high refresh rate systems, such as expensive PC monitors, the viewer sees too much flicker causing distraction and annoyance. An additional requirement and burden is the wired or wireless signaling to control the state of the lens. LCD screens that are used on laptops generally do not have high enough refresh rates for stereoscopic shutter 3D systems. Shutter systems generally do not work well with LCD or movie projectors. Electronically Controlled Variable Tint Materials Numerous materials have been identified that have the property that the transmission of light through the material can be controlled by the application of an electronic voltage or potential across the material. These include the classes of materials typically named electrochromic, suspended particle and polymer dispersed liquid crystal devices. Within each class of electronically controlled variable tint material there are numerous formularies. Other classes of materials may be found in the future. Any material for which the transmission of light or other optical property of light can be controlled by an electronic potential may be utilized in the invention. Electrochromic Devices (EDs) Electrochromic devices change light transmission properties in response to voltage and thus allow control of the amount of light passing through the material. A burst of electricity is required for changing the tint of the material, but once the change has been occurred, no electricity is needed for maintaining the particular shade that has been reached. Electrochromic materials provide visibility even in the darkened state, and thus preserves visible contact with the outside environment. It has been used in small-scale applications such as rearview mirrors. Electrochromic technology also finds use in indoor applications, for example, for protection of objects under the glass of museum display cases and picture frame glass from the damaging effects of the UV and visible wavelengths of artificial light. Recent advances in electrochromic materials pertaining to transition-metal hydride electrochromics have led to the development of reflective hydrides, which become reflective rather than absorbing, and thus switch states between transparent and mirror-like. Suspended Particle Devices (SPDs) In suspended particle devices (SPDs), a thin film laminate of rod-like particles suspended in a fluid is placed between two glass or plastic layers, or attached to one layer. When no voltage is applied, the suspended particles are arranged in random orientations and tend to absorb light, so that the glass panel looks dark (or opaque), blue or, in more recent developments, gray or black color. When voltage is applied, the suspended particles align and let light pass. SPDs can be dimmed, and allow instant control of the amount of light and heat passing through. A small but constant electrical current is required for keeping the SPD in its transparent stage. Polymer Dispersed Liquid Crystal Devices (PDLCs) In polymer dispersed liquid crystal devices (PDLCs), liquid crystals are dissolved or dispersed into a liquid polymer followed by solidification or curing of the polymer. During the change of the polymer from a liquid to solid, the liquid crystals become incompatible with the solid polymer and form droplets throughout the solid polymer. The curing conditions affect the size of the droplets that in turn affect the final operating properties of the variable tint material. Typically, the liquid mix of polymer and liquid crystals is placed between two layers of glass or plastic that include a thin layer of a transparent, conductive material followed by curing of the polymer, thereby forming the basic sandwich structure of the smart window. This structure is in effect a capacitor. Electrodes from a power supply are attached to the transparent electrodes. With no applied voltage, the liquid crystals are randomly arranged in the droplets, resulting in scattering of light as it passes through the smart window assembly. This results in the translucent, “milky white” appearance. When a voltage is applied to the electrodes, the electric field formed between the two transparent electrodes on the glass cause the liquid crystals to align, thereby allowing light to pass through the droplets with very little scattering, resulting in a transparent state. The degree of transparency can be controlled by the applied voltage. This is possible because at lower voltages, only a few of the liquid crystals are able to be aligned completely in the electric field, so only a small portion of the light passes through while most of the light is scattered. As the voltage is increased, fewer liquid crystals remain out of alignment thus resulting in less light being scattered. It is also possible to control the amount of light and heat passing through when tints and special inner layers are used. Most of the devices offered today operate in on or off states only, even though the technology to provide for variable levels of transparency is easily applied. This technology has been used in interior and exterior settings for privacy control (for example conference rooms, intensive-care areas, bathroom/shower doors) and as a temporary projection screen. A new generation of switchable film and glass called 3G Switchable Film is available from Scienstry, using a non-linear technology to increase transparency, lower the required driving voltage and extend the lifetime. A First Preferred Embodiment of the Invention FIG. 1 is a perspective view 100 of the preferred embodiment of the Continuous Adjustable 3Deeps Filter Spectacles. It is comprised of a frame 101 that is used as the housing for the lenses and control circuitry. Such frames are a well-known means by which lenses can be fixed before a person's eyes for viewing. On the frame 101 is battery device 104 to power all circuitry of the Continuous Adjustable 3Deeps Filter Spectacles. Also, on the frame 101 is a receiver 102 labeled “Rx” that is powered by the battery 104. The receiver 102 has apparatus to receive radio-frequency (RF) 110 waves with synchronization and control information used to control the Continuous Adjustable 3Deeps Filter Spectacles. Such receivers are well known in the art of electronics. Also on the frame 101 is a control unit 103 powered by the battery 104 that transforms the continuing optical density signals into the electronic potentials used to control the optical density of each individual lens. Also on the frame 101 is an on/off switch 112 that controls whether the electronic circuits of the 3Deeps spectacles 101 receive power (on position) from the battery or not (power off). Other embodiments may replace RF communications with other communications means, including but not limited to infrared, or audio sound. Two lenses are fixed in the frames—a right lens (from the movie viewer's vantage point) 105 and a left lens 106. In the preferred embodiment, each lens is made of an electrochromic material for which the optical density can be reliably and precisely controlled by the application of an electronic potential across the material. The lens has circuitry so that the control unit 103 can independently control the transmissivity of each lens. Other embodiment may use optoelectronic materials other than electrochromics. A second preferred embodiment of Continuous Adjustable 3Deeps Filter Spectacles using multi-layered lenses is disclosed starting in FIG. 5. A third preferred embodiment of Continuous Adjustable 3Deeps spectacles using single-layered lenses for a multi-use application is disclosed starting in FIG. 11. A fourth preferred embodiment of Continuous Adjustable 3Deeps Filter Spectacles using multi-layered lenses for a multi-use application is disclosed starting in FIG. 14. For exemplary purposes, FIG. 1 shows the Continuous Adjustable 3Deeps Filter Spectacles in just one of the three states that the lenses can take. FIG. 1 shows the right lens 105 darkened and the left lens 106 as clear with the clear lens allowing more light transmission than the darkened lens. This is the configuration to view a motion picture with a 3-dimensional effect in which the lateral motion in the motion picture is moving from left-to-right on the viewing screen. Other embodiments of the invention may have Continuous Adjustable 3Deeps Filter Spectacles that fit over regular prescription glasses in a manner similar to that in which snap-on or clip-on sunglasses are configured. In still another embodiment the lenses of the Continuous Adjustable 3Deeps Filter Spectacles may also be prescription lenses customized for the viewer vision impairments. Also, while the preferred embodiment of the invention uses Continuous Adjustable 3Deeps Filter Spectacles that are wireless, other embodiments may use wired connections. What is required is that the Continuous Adjustable 3Deeps Filter Spectacles can receive and respond to synchronization signals from the controller, and whether that is by wired or wireless means is immaterial to the invention. Earlier versions of 3Deeps Filter Spectacles (also called Pulfrich Filter Spectacles) have been previously described in co-pending patent applications and patents U.S. patent application Ser. No. 12/274,752, U.S. patent application Ser. No. 11/928,152, U.S. patent application Ser. No. 11/372,723, U.S. patent application Ser. No. 11/372,702, and U.S. Pat. Nos. 7,030,902 and 7,218,339. There are 3 lens settings used by the Continuous Adjustable 3Deeps Filter Spectacles. One setting is that both the right 105 and left lens 106 are clear. Neither lens is darkened. This is the lens state that is used in the preferred embodiment when there is no significant lateral motion in the motion picture. The second setting is the left lens 106 clear and the right lens 105 darkened. This is the lens state that is used in the preferred embodiment when foreground lateral motion in the motion picture is moving from the left to the right direction, as seen from the viewer's perspective. The third setting is the left lens 106 darkened and the right lens 105 clear. This is the lens state that is used in the preferred embodiment when the foreground lateral motion in the motion picture is moving from the right to the left direction, as seen from the viewer's perspective. The lens state consisting of both left and the right lens darkened is not used by any of the 3Deeps spectacles. However, this lens state can be achieved by the Continuous Adjustable 3Deeps Filter Spectacles, and may have uses in other embodiments of the invention. In the third preferred embodiment of the invention, this lens state is used to provide an alternate use for 3Deeps viewing spectacle—sunglasses. In that embodiment, “multi-use” 3Deeps spectacles are switch selectable as either (Use 1) 3Deeps viewing spectacles using the 3 lens settings described in the preceding paragraph for 3Deeps viewing, or (Use 2) sunglasses using the left and right lens darkening to a pre-set optical density. In Continuous Adjustable 3Deeps Filter Spectacles, the right and left lenses of the viewing glasses may independently take a multiplicity of different levels of darkness to achieve different effects, resulting in many different lens states. In particular, the darkening of the non-clear lens can be optimized according to the speed of lateral motion and/or luminance, so as to optimize the degree of 3-dimensional effect (a first optimization). Also, the Control Unit 103 can control the electrochromic lenses so that they reach their target state in an optimal manner (a second optimization). Various consumer-based control units may be utilized with the Continuous Adjustable 3Deeps Filter Spectacles that can both display the audio/video of the associated motion picture, as well as perform the Continuous Adjustable 3Deeps Filter Spectacles synchronization to identify 3Deeps synchronization events and issue control signals to the Continuous Adjustable 3Deeps Filter Spectacles. This includes, but is not limited to; DVD-based control units; Digital Movie Projector control units; Television-based control units; hand-held and operated control units; spectacle-based control units; software-based processing that parses compressed digital video file and uses its motion estimation information (e.g. MPEG); and, cell-phone based control units. FIG. 2a 200 shows a left lens 106 of Continuous Adjustable 3Deeps Filter Spectacles fabricated from a single layer of electrochromic material. Its fabrication using electrochromic material is shown in adjoining FIG. 2b. FIG. 2b 225 shows the cross-sectional detail of the electrochromic device of FIG. 2a used for fabricating the electronically controlled variable tint material of the right and left lenses of the Continuous Adjustable 3Deeps Filter Spectacles. The Figure shows a typical dual-polymer electrochromic device consisting of seven layers of material. In the preferred embodiment of the invention, the right lens 105 and left lens 106 of the Continuous Adjustable 3Deeps Filter Spectacles 100 are fabricated from such material. The first layer 201 of the electrochromic material 225 is a glass, plastic (or other clear insulating material.) The second layer 202 is a conducting layer, followed by a third layer 203 of polymer. The fourth layer 204 is an electrolytic layer that depending upon the electrochromic material may be a liquid or gel. This layer provides the ion transport whose direction is determined by the application of potential across the conducting layers. The fifth layer 205 is the complementary polymer layer, followed by a sixth layer 206 of conducting material. The last layer 207 of the electrochromic is another insulting layer of glass, plastic or other clear insulating material. While FIG. 2b 225 show a typical dual-polymer electrochromic device, as previously indicated, there are numerous such electrochromic devices, and any electrochromic may be favorably utilized in the invention. Some electrochromic devices may not have seven layers as shown in FIG. 2b. For instance, some variable tint materials may be in the form of a flexible film or laminate that can be applied to a single layer of clear glass or plastic. Also, any electronically controlled variable tint material may be used in the invention rather than the displayed electrochromic device. Any material whose optical property of transmissivity of light may be controlled by the application of an electric potential may be favorably use to fabricate the lenses of the Continuous Adjustable 3Deeps Filter Spectacles 100. FIG. 3 is a block diagram 300 of the operation of the Continuous Adjustable 3Deeps Filter Spectacles of FIG. 1. All circuits on the Continuous Adjustable 3Deeps Filter Spectacles 101 are powered 301 by the Power Unit 104 (if the power on/off switch 112 is in the on position), including the Control Unit 103, Signal Receiving Unit 102, the Left Lens 106, and the Right Lens 105. The control information 110 is received by the Signal Receiving Unit 102 and sent 302 to the Control Unit 103. The control unit 103 implements an algorithm that is specific for the lens materials used in the fabrication of the Right Lens 105 and the Left lens 106 of the Continuous Adjustable 3Deeps Filter Spectacles, and controls the Left Lens 106 over a control circuit 303, and the Right Lens over a control circuit 305. FIG. 4 is a flow chart 400 showing the operation of the Control Unit 103 of the Continuous Adjustable 3Deeps Filter Spectacles of the first preferred embodiment. The input to the Control Unit 103 is the synchronization signal 302. The output is the control signal sent to the left lens 106 over the control left lens control circuit 303, and the control signal sent to the right lens 105 over the right lens control circuit 305. The synchronization signals 302 are received and stored by the Read and Store 3Deeps Signal block 401 of the Control Unit 103 and stored in a LIFO (Last In First Out) memory stack 403. Control then passes to Store and Manage Signal processing 405 that “pops” the top of the stack (read the value and eliminates it from storage) and processes the synchronization signal by storing it in a 3Deeps Signal memory storage 407. Processing control then passes to Parse and Store Left and Right OD in which the 3Deeps signal memory storage 407 is parsed and stored in the Left OD value 411, and the Right OD value 413. Processing then continues with the Right Lens Control 417 in which the right lens value 413 is converted to an electronic signal 305 that controls the optical density of the right lens. Processing then continues with the Left Lens Control 415 in which the left lens value 411 is converted to an electronic signal 303 that controls the optical density of the left lens. Processing in the Control Unit 103 then is passed back to the Read and Store 3Deeps Signal. It should be understood that different control circuits might be utilized by other embodiments. For instance other embodiments may have no need for LIFO signal store and management since control of the 3Deeps spectacles is in real-time and there is no need to switch the lenses to past setting. Also, better emphasize the logical operation of the control unit some functions have not been shown. For instance, the control unit may cycle at a much faster rate then the received synchronization signals resulting in an empty stack. The handling of such an empty stack state is not shown in the flow diagram but would be handled as well-known in the art by detecting that the stack is empty and passing control in the Control Unit 103 back to the Read and Store 3Deeps Signal state 401 rather than passing control as shown in the flow diagram 400. Continuous Adjustable 3Deeps Filter Spectacles have great advantages. The control information 110 is spectacle-agnostic; i.e. all spectacles receive the same transmitted control information. The control unit 103 on the spectacles performs a final view-spectacle-specific optimization, translating the control information into control signals specific to the lens material used to fabricate the Continuous Adjustable 3Deeps Filter Spectacles. Two viewers sitting side-by-side and watching the same video on a digital TV but wearing Continuous Adjustable 3Deeps Filter Spectacles that have lens material with totally different characteristics, will each see the movie with an illusion of 3D optimized for their spectacles. A Second Preferred Embodiment of the Invention FIG. 5 is a perspective view 500 of the second preferred embodiment of the Continuous Adjustable 3Deeps Filter Spectacles 550 with multi-layered lenses. The difference between FIG. 5 (multi-layered lens) and FIG. 1 (single layer lens) is in their respective right lens (505 of FIG. 5), left lens (506 of FIG. 5), and control unit (503 of FIG. 5). Like numbered items in FIG. 5 and FIG. 1 have the same function and definition. The lenses for the second preferred embodiment (505 and 506) are described in greater detail in FIGS. 6a and 6b, and the control unit for the second preferred embodiment is described in greater detail in FIG. 8. FIG. 6a 600 shows a left lens 506 of Continuous Adjustable 3Deeps Filter Spectacles fabricated from multiple layers of electrochromic material. Its fabrication using electrochromic material is shown in adjoining FIG. 6b. Since only a single layer of insulating glass material will be required between the different layers of the multi-layered electrochromic lens, the drawing of the top layer is slightly different than that of FIG. 2a to emphasize that only one layer of such insulating material is necessary. FIG. 6a therefore shows the lens 106 as two layers where the first active layer 611 is separated by the second active layer 601 by an insulating layer 610. The first active layer 611 and the insulating layer 610 comprise the single layer lens 106 of FIG. 2a. FIG. 6b 625 shows the cross-sectional details of the multiple layered electrochromic device of FIG. 6a that is used for fabricating the electronically controlled variable tint material of the right and left lenses of the Continuous Adjustable 3Deeps Filter Spectacles. The 7 layers of the electrochromic left lens 106 of FIG. 2b are shown in FIG. 6b as the 6 active layers 611, and the (seventh) insulating layer 201. Each layer is identical to their like numbered description accompanying FIG. 2b. A second active layer 601 is included in the multi-layered electrochromic lens. In the second preferred embodiment of the invention, the second layer 601 of the lens is fabricated from identical electrochromic material as used to fabricate the first layer 611 of the left lens 506 so that each layer has the same Operating Characteristic curve 900 as shown in FIG. 9. The six layers of electrochromic material for the second layer are identical to their like numbered description accompanying FIG. 2b. Other embodiments may use electrochromic material with different material so that the two layers have different Operating Characteristic curves. Also, other embodiments may have more than 2 layers. FIG. 7 is a block diagram 700 of the operation of the Continuous Adjustable 3Deeps Filter Spectacles of FIG. 5 using a multiple layered electrochromic device for fabricating the electronically controlled variable tint material of the right 505 and left lenses 506. All circuits on the Continuous Adjustable 3Deeps Filter Spectacles 550 are powered 301 by the battery 104, including the Control Unit 503, Signal Receiving Unit 102, the Left Lens 506, and the Right Lens 505. The control information 110 is received by the Signal Receiving Unit 102 and sent 302 to the Control Unit 503. The control unit 503 implements an algorithm that is specific for the multi-layered lens materials used in the fabrication of the Right Lens 505 and the Left lens 506 of the multi-layered Continuous Adjustable 3Deeps Filter Spectacles, and controls the Left Lens 506 with a control circuit 703, and the Right Lens 505 with a control circuit 704. The difference between FIG. 7 (multi-layered lens) and FIG. 3 (single layer lens) is in their respective right and left lenses, control units, and control circuits. For the right lens 505 and left lens 506, the lenses are fabricated from multiple layers of electrochromic material. In the second preferred embodiment of the invention these are the same as the lens fabrication shown in FIG. 6. The control unit for the multi-layered lens 503 must control multiple layers while the control unit for the single-layered lens 103 only need control a single layer electrochromic lens. In this second preferred embodiment of the invention, both layers of the multi-layered electrochromic lens are made of the same material with the same Operating Characteristic curve and both lenses have applied to them identical voltage across each layer. However, since there are multi-layers of material, it will be shown using the Operating Characteristic curve of FIGS. 9 and 10, that to achieve a target optical density for each lens, the control unit 503 will only need apply voltage to the multi-layers for less time than for the single layer. For the control circuits, the multi-lens control circuits need to apply voltage across multiple layered assemblies, not just a single lens assembly. FIG. 8 is a flow chart 800 showing the operation of the Control Unit 503 of the Continuous Adjustable 3Deeps Filter Spectacles 550 using a multiple layered electrochromic device for fabricating the electronically controlled variable tint material of the right lens 505 and left lens 506. This flow chart 800 is very similar to the flow chart of the control unit for the Continuous Adjustable 3Deeps Filter Spectacles using a single layered electrochromic device of FIG. 4. The memory storage LIFO Signal Stack 403, 3Deeps Signal 407, Left OD 411, and Right OD 413 are the same as previously described for FIG. 4. The processing modules Read & Store 3Deeps Signal 401, Store and Manage 3Deeps Signal 405, and Parse and Store Left and Right OD 409 are the same as previously described for FIG. 4. The difference between FIG. 4 and FIG. 8 is in the Left Lens Multilayer circuitry 815 and the left lens 506 that the circuit controls, and in the Right Lens Multilayer Control circuitry 817 and the right lens 505 that the circuit controls. In this multi-layer embodiment of the invention, the Left Lens Multilayer circuitry 815 must control two layers of the electrochromic left lens 506, and the Right Lens Multilayer circuitry 817 must control two layers of the electrochromic right lens 505. It will be shown later in FIGS. 9 and 10 that the target optical densities for the left lens 411 and the right lens 409 can be achieved more rapidly. This approach has the same advantages as for single-layer Continuous Adjustable 3Deeps Filter Spectacles. The control information 110 is spectacle-agnostic; i.e. all spectacles receive the same transmitted control information. The control unit 503 on the spectacles performs a final view-spectacle-specific optimization, translating the control information into control signals specific to the multi-layered lens material used to fabricate the Continuous Adjustable 3Deeps Filter Spectacles. Two viewers sitting side-by-side and watching the same video on a digital TV but wearing Continuous Adjustable 3Deeps Filter Spectacles that have lens material with totally different characteristics, will each see the movie with an illusion of 3D optimized for their spectacles. It also has the additional advantage that since a multi-layer lens is used, the transition time between optical density states will be faster than the corresponding transition time for a single-layer lens. The second preferred embodiment of the Optical Density Continuing Adjustable 3Deeps Filter Spectacles use electrochromic lenses. Additional detail about Electrochromism is now provided. Electrochromism is the phenomenon displayed by some chemicals of reversibly changing color when an electric potential is applied. Electrochromism has a history dating back to the nineteenth century and there are thousands of chemical systems that have already been identified electrochromic. A narrow definition limits electrochromic devices to chemical processes for which there is a redox reaction that undergo an electron uptake reduction or electron release when potential is applied and the reverse or oxidation with a reverse potential. Most redox processes are electrochromic and are candidate electrochromes and potential 3Deeps lenses. While the preferred embodiments of this invention use such narrowly defined electrochromic devices, any device for which the transmission of light may be controlled by an electronic potential may be utilized in the invention. For instance, Liquid Crystal Device (LCD) lenses may be used in the invention since they may be controlled by an electronic potential, even though they use a totally different mechanism to control the optical properties of the material. LCDs rely on an interference effect (block the transmission of light), while the narrow definition of electrochromic device is limited to materials that rely on a redox reaction to change the color of the material. Either redox or LCD material, or any material for which the transmission of light may be controlled by an electronic potential can be advantageously utilized in the invention. There are many different families of chemicals that exhibit such properties—both organic and inorganic. These include but are not limited to polyaniline, viologens, polyoxotungstates's and tungsten oxide. Oxides of many transition metals are electrochromic including cerium, chromium, cobalt, copper, iridium, iron, manganese, molybdenum, nickel, niobium, palladium, rhodium, ruthenium, tantalum, titanium, tungsten, and vanadium. Within each family, different mixtures of chemicals produce different properties that affect the color, transmissivity, and transition time. Some electrochromics may only affect ultraviolet light—not visible light—appearing clear to an observer since they do not affect visible light. Electrochromics have been the object of intense study for over 40 years, and have found their chief commercial success for use in “smart windows” where they can reliably control the amount of light and heat allowed to pass through windows, and has also been used in the automobile industry to automatically tint rear-view mirrors in various lighting conditions. Other embodiments of the inventions may advantageously use multiple-color electrochromic devices or materials that exhibit electropolychromism. Some electrochromic devices may take a whole series of different colors, each colored state generated at a characteristic applied potential. One example is methyl viologen, which has electron potential states that are correspondingly colorless, blue, and red-brown. Electrochromic viologens have been synthesized with as many as six different colors. The operating characteristics of each formulation of any of the thousands of different electrochromic material will be different. Some of the operating characteristics that should be considered when selecting materials for 3Deeps lenses include; Response time (the time required to change from its clear to darkened state or vice versa); Power consumption; Memory effect (when power is off between write cycles there is no redox process and the electrochromic material retains its optical properties); Coloration efficiency (the amount of electrochromic darkening formed by the charge); Cycle life (The number of write-erase cycles that can be performed before any noticeable degradation has occurred); and, write-erase efficiency (the fraction of the originally formed darkening that can be subsequently electro-cleared. For 3Deeps viewing spectacles this should be 100%). The operating characteristics of each formulation of any of the 1000s of different electrochromic material will be different. FIG. 9 shows a typical Operating Characteristic curve relating transmissivity (% transmission of light) to transmission time when a potential of 2 volts is applied across the electrochromic device. Some electrochromic materials may take several seconds to change state from one optical density to another—others may be near instantaneous. For many electrochromic materials the color change is persistent and electric potential need only be applied to effect a change. For such persistent optoelectronic materials, only an electronic on-off pulse is needed, while non-persistent materials require the application of a continuing electronic potential. Other materials may attain state under the presence of electric potential, but then slowly leak and change back. These materials may require a maintenance potential to maintain state but one that is different from that to attain the optical density state. The second preferred embodiment of the Continuing Adjustable 3Deeps Filter Spectacles is fabricated from a persistent electrochromic material (material that has a so-called memory effect) that takes up to 1.85 seconds to change state from its lightest to darkest optical density, and up to 1.85 seconds to change state from its lightest to darkest optical density. In moving between states the preferred embodiment will always seek to optimize transition time. While electrochromic material is used in the second preferred embodiment of the optical density Continuous Adjustable 3Deeps Filter Spectacles, any optoelectronic materials that change optical density in response to an applied potential may be used. This includes but is not limited to PDLCs (Polymer Dispersed Liquid Crystal devices) or SPDs (Suspended Particle Devices.) In the future, new optoelectronic materials will be discovered and may be advantageously used in the practice of this invention. FIG. 9 is a transition time curve 900 for a single layer of electrochromic material with transition time as a function of transmissivity when a potential of 2.0V is applied to the electrochromic material. It is for a slow electrochromic material with transition time 902 as a function of transmissivity 901 (or percent transmission of light). This transition time curve 900 has a lightest state 906 with a transmissivity of 100% density (clear) and its darkest state 905 is 0% in which all light is blocked from passing through the electrochromic material. The electrochromic material cannot however attain either of the extreme values (0% or 100%) of transmissivity. The Operating Characteristic curve 903 shows a material that can attain about 99% transmissivity 904 (almost clear) and 10% transmissivity 915 (almost dark). The material can then take any optical density in between the blocking only 1% of the light (99% transmissivity) and blocking 90% of light (10% transmissivity) by the application of 2V for the proper length of time. If the material is in its clearest state 904, and, and a 2V potential is applied to the material, it will take about 1.8 seconds to change state and achieve its darkest state 915 or 10% transmissivity. This is shown on the transition time curve 903 of the Operating Characteristic of the material in FIG. 9. As another example, if the material is in its clearest state 904, and the control signal 110 received on the frames receiving unit 102 indicates that the subject lens should change to an optical density associated with transmissivity of 70% 923, then the transition time curve 903 would be implemented by the control unit 103 to apply 2V potential to the lens for 1.35 seconds. A value of 70% 923 transmissivity intercepts the Operating Characteristic curve 903 at a point on the curve 921 that corresponds to a transition time 922 of 1.35 seconds. Once a potential of 2V has been applied for 1.35 seconds, no potential need further be applied since the electrochromic lens will latch in the new state. This is an example of how an algorithm implemented in the Control Unit 103 of the Continuous Adjustable 3Deeps Filter Spectacles with a single layer of lens material (FIG. 1-4) would use the transition time curve 903 to control the right lens 105 and the left lens 106. To transition a lens from and optical density associated with a clear state 904 to the optical density associated with a transmissivity of 70% the Control Unit 103 would apply 2V potential to the lens for 1.35 seconds. This is a simplified example for illustrative and teaching purposes. Other electrochromic materials may have other operating characteristics that have characteristic exponential, negative exponential, or logistic (s-shaped) relationships. In this example, 2V potential is used to move between states. It is used under the assumptions that (a) for this electrochromic formulation the higher the electronic potential the more rapid will be the change from a lighter to a darker optical density, and (b) change of state from a lighter to a darker optical density is to be optimized. Other materials may require different potentials to be applied to move from between states. In any of these cases, the principle of operation is identical and the Control Unit 103 on the frames of the lenses uses the operating characteristics of the material used in the right 105 and left 106 lenses to determine the potential and the length of time the potential is to be applied to transition between lens control states. FIG. 10 is a transition time curve 1000 for a double layer (multi-layer) of electrochromic material with transition time as a function of transmissivity. FIG. 10 is similar to FIG. 9 with the addition of a second Operating Characteristic curve 1003. The numbered elements of FIG. 10 have the same description as their like numbered elements of FIG. 9. The Operating Characteristic curve for the double layer 1003 (multi-layer) lenses of the preferred embodiment are shown along with the Operating Characteristic curve of the single layer 903 to better emphasize the transition time Benefit and Loss of using the double layer of electrochromic material. The example shows that doubling the lens material results in a 44% decrease in Transmission Time (Benefit) when moving from a clear to a 70% transmissivity state for only a 1% loss in the Clear State (Loss). As an example, if the multi-layer material is in its clearest state 1015, and the control signal 110 received on the frames receiving unit 102 indicates that the subject lens should change to an optical density associated with transmissivity of 70% 923, then the transition time curve 1003 would be implemented by the control unit 503 to apply 2V potential to the lens for 0.75 seconds. A value of 70% 923 transmissivity intercepts the Operating Characteristic curve 1003 at a point on the curve 1011 that corresponds to a transition time 1012 of 0.75 seconds. Once a potential of 2V has been applied for 0.75 seconds, no potential need further be applied since the electrochromic lens will latch in the new state. In summary, for a single layer lens then, to move from a clear state to a 70% transmissivity state 2V potential is applied for 1.35 seconds to a single layer material. For the double layer lens of the preferred embodiment to move from a clear state to a 70% transmissivity state 2V potential is applied for 0.75 seconds. Using two layers of electrochromic material results in a beneficial 44% decrease in transmission time for only a 1% loss in the clear state. A Third Preferred Embodiment of the Invention It has previously been observed in this disclosure that the lens state consisting of both left and the right lens darkened is not used by any of the 3Deeps spectacles. The third preferred embodiment of the invention uses this lens state that is not used by any of various 3Deeps spectacles previously described, and extends the first preferred embodiment (single layer Continuous Adjustable 3Deeps Filter Spectacles) so they may also be switch selectable to function as sunglasses. In particular, a switch 1101 is added to the Continuous Adjustable 3Deeps Filter Spectacles described in FIG. 1. In a first switch position the spectacles operate precisely as described in the first preferred embodiment. In a second switch position the spectacles operate as sunglasses. Toggling the switch changes the spectacles to operate with the switched characteristics. The lenses of the third preferred embodiment are single-layer, and are precisely the same as described in FIG. 2a and FIG. 2b. The control unit 103 of the first preferred embodiment is modified and presented as a new Control Unit 1103. This control unit takes as an additional input the position of the selection Switch 1101. If the Switch is positioned so the spectacles operate as Continuous Adjustable 3Deeps Filter Spectacles then the Control Unit controls the lenses of the spectacles in precisely the same fashion as previous described in FIG. 4. If the Switch is positioned so that the spectacles operate as sunglasses, then the Control Unit controls the lenses so that they both take the same pre-specified dark optical density and operate as ordinary sunglasses. FIG. 11 is a perspective view 1100 of the third preferred embodiment of the Continuous Adjustable 3Deeps Filter Spectacles 1150 with single-layered lenses. The difference between the single-layered lenses of FIG. 1 and FIG. 11 is that in the third preferred embodiment a selection Switch 1101 has been added to the spectacles, and the control unit 1103 has been expanded to include control of the sunglasses. All like numbered items in FIG. 11 and FIG. 1 have the same function and definition. The selection switch 1101 may take either of two positions. In the first position, the spectacles will operate as Continuous Adjustable 3Deeps Filter Spectacles precisely as described in the first preferred embodiment. In the second position, the spectacles will operate as sunglasses. The third preferred embodiment uses lenses identical to the lenses used in the first preferred embodiment and described in FIG. 2a and FIG. 2b. FIG. 12 is a block diagram 1200 of the operation of the Continuous Adjustable 3Deeps Filter Spectacles 1150 of FIG. 11 using a single layered electrochromic device for fabricating the electronically controlled variable tint material of the right 105 and left lenses 106. All circuits on the Continuous Adjustable 3Deeps Filter Spectacles 1150 are powered 301 by the battery 104, including the Control Unit 1103, Signal Receiving Unit 102, the Left Lens 106, and the Right Lens 105. The control information 110 is received by the Signal Receiving Unit 102 and sent 302 to the Control Unit 1103. The switch 1101 position is also powered 301 by the battery 104, and its position is output to the Control Unit 1103. The Control Unit 1103 implements an algorithm that is specific for the multi-use (Use 1: 3Deeps spectacles or Use 2: sunglasses) single-layered Continuous Adjustable 3Deeps Filter Spectacles, and controls the Left Lens 106 with a control circuit 1203, and the Right Lens 105 with a control circuit 1205. FIG. 13 is a flow chart 1300 showing the operation of the Control Unit 1103 of the multi-use Continuous Adjustable 3Deeps Filter Spectacles 1150 with single-layered lenses. The switch position 1202 is input to the Control Unit 1103 and processing commences with Switch 1 or Switch 2 1370 that can parse the switch position and determine which position the Switch 1101 is in. If the Switch position is in the first position then the control processing 103 is used. This is the same as the control processing for the First Preferred Embodiment and is described in FIG. 4. Only the input and output to the control processing 103 is shown in FIG. 13—not the details of the processing that is the same as shown in FIG. 4. If the Switch position is in the second position then the control processing 1240 for sunglasses is used. Pre-selected Optical densities for the left lens 106 and right lens 105 are stored in the controller as the Left OD 1311 and the Right OD 1313. First the Right OD 1313 is read by the Right Lens Control processing 1317 and an electronic signal is issued on circuit 1205 to change the Right Lens 105 to that associated Optical Density. Processing then passes to the Left Lens Control 1315 that reads the pre-stored value Left OD 1311 and an electronic signal is issued on circuit 1203 to change the Left Len 106 to that associated value. This exemplary Control Unit 1103 has been purposely simplified for clarity and to show the principles of the control operation. It shows two separate control circuits—the first 103 for control of Continuous Adjustable 3Deeps Filter Spectacles, and the second 1240 for control of sunglasses. The Control Unit 1103 has two separate memory storages for the Left and Right optical densities. It should be understood that good engineering design would reuse as much circuitry as possible for two controlling functions of the Control Unit 1103. So for instance, another implementation of the Control Unit 1103 may only have a single memory storage for the Left and Right optical densities that are used by both the circuitry controlling the 3Deeps Filter Spectacles and the circuitry controlling the sunglasses. A Fourth Preferred Embodiment of the Invention In the second preferred embodiment of the invention the right and left lenses of the 3Deeps spectacles are fabricated from multiple layers of the same electrochromic material. In a fourth preferred embodiment of the invention, the lenses are fabricated from two layers with electrochromic devices that have different optical characteristics. In this fourth preferred embodiment of the invention the first layer of electrochromic uses the same material to fabricate the lenses as has previously been described—a neutral density filters that block the transmission of light approximately equally along the entire visible spectrum. The second layer uses electrochromic material that can be electronically controlled so the left lens is clear or can be set to allow transmission of light in the visible red spectrum and the right lens is clear or can be set to allow the transmission of light in the visible blue spectrum. The two layers of material are switch selectable so that either of the layers may be activated, but not both layers at the same time. These Multi-Use Electrically Controlled Continuous Adjustable 3Deeps Filter Spectacles thus are switch selectable so they can be used to watch 2D (single image viewed by right and left eyes) movies in 3D using the 3Deeps methodology or alternatively to watch specially made 3D movies (separate left and right images) formatted for anaglyph 3D viewing. FIG. 14 is a perspective view 1400 of the fourth preferred embodiment of the Multi-Use Electrically Controlled Continuous Adjustable 3Deeps Filter Spectacles 1450. Like numbered items in FIG. 5 and FIG. 1 have the same function and definition. The primary difference between this embodiment and previous embodiments is in the use of different electrochromic devices for the layers of the lenses (described further in FIG. 15a and FIG. 15b), and in the Control Unit 1403 that controls the operation of the spectacles based on the position of the Switch 1101. The toggle switch 1101 allows either the first layer 411 of the multi-use 3Deeps spectacles 1450 to be activated (3Deeps method of viewing 3D) or it allows the second layer 1501 of the multi-use 3Deeps spectacles to be activated (anaglyph 3D viewing.) In this fourth preferred embodiment of the invention, only one layer may be activated at a time. Other embodiments may allow more than one layer of material to be active at one time. The control unit 1403 has all the functionality of control unit 103 when the first layer is active. When the first layer is active both lenses of the second layer are set to their clear state. When the second layer of is activated the control unit 1403 will run a control program specific to the control of anaglyph 3D viewing. In particular when the second layer is activated for anaglyph viewing, both lenses of the first layer of material are set to their clear state, and the left lens 1406 of the second layer is set to a red and the right lens 1405 of the second layer is set to blue. This state is maintained throughout the viewing of the anaglyph 3D movie and no additional switch of state is required of the control program as is the case with 3Deeps viewing. In this way the left lens is red and the right lens is blue as required for anaglyph 3D movies. FIG. 15a 1500 shows a left lens 1006 of Multi-Use Electrically Controlled Continuous Adjustable 3Deeps Filter Spectacles fabricated from multiple layers of electrochromic material. Its fabrication using electrochromic material is shown in adjoining FIG. 15b. Since only a single layer of insulating glass material will be required between the different layers of the multi-layered electrochromic lens, the drawing of the top layer is slightly different than that of FIG. 2a to emphasize that only one layer of such insulating material is necessary. FIG. 15a therefore shows the lens 1006 as two layers where the first active layer 411 is separated by the second active layer 1501 by an insulating layer 410. The first active layer 411 and the insulating layer 410 comprise the single layer lens 106 of FIG. 2a. FIG. 15b 1525 shows the cross-sectional details of the Multi-use electrochromic device of FIG. 15a for fabricating the electronically controlled variable tint material of the right and left lenses of the Continuous Adjustable 3Deeps Filter Spectacles using multiple layers of electrochromic material. The 7 layers of the electrochromic left lens 106 of FIG. 2a are shown in FIG. 15b as the 6 active layers 411, and the (seventh) insulating layer 201. Each layer is identical to their like numbered description accompanying FIG. 2b. A second active layer 1501 is included in the multi-layered electrochromic lens. In this fourth preferred embodiment of the invention, the second layer 1501 of the lens is fabricated from electrochromic material that is totally different from the neutral density electrochromic material of the first layer. This second layer of electrochromic material will have its own Operating Characteristic curve and electronically control properties of light differently from that of the first layer. In particular, FIG. 15b shows the left lens 1406 of the Multi-Use Electrically Controlled Continuous Adjustable 3Deeps Filter Spectacles with a second layer of electrochromic material. The second layer is fabricated from electrochromic material that can be electronically controlled to allow the transmission of light in the clear or visible red spectrum. (A right lens that is not shown would be fabricated from electrochromic material that can be electronically controlled to allow the transmission of light in the clear or visible blue spectrum.) The second multi-layer of electrochromics of the multi-use lens is made from 6 layers of material. The top layer 1501 is made from an insulting layer of glass, plastic or other clear insulating material. This is followed by layer 1502 of a conducting layer, followed by a third layer 1603 of polymer. A fourth layer 1504 provides the ion transport whose direction is determined by the application of potential across the conducting layers. The fifth layer 1505 is the complementary polymer layer, and is then followed by another conducting layer 1506. The polymer layers 1503 and complimentary polymer layer 1505 provide the electronically controllable tinting of the lens as either clear or red. The right lens—not shown—would have polymer and complimentary polymer layers to provide electronically controllable tinting for the right lens as either clear or blue. TABLE 1 shows the different types of Optoelectronic materials that may be used in the fabrication of Multi-Use Electrically Controlled Continuous Adjustable 3Deeps Filter Spectacles. The first column of the TABLE 1 is a numbering of the methods—but no preference is to attributed to the ordering. The Method Number is used for reference in the disclosure. The second column of TABLE 1 labeled Viewing Method and is the type of viewing that may be attained through the use of the associated optoelectronic device that is described in the third column of TABLE 1. The third column of TABLE 1 labeled OptoElectronic Device is a brief description of the controllable optical characteristic necessary to achieve the associated viewing method. TABLE 1 Method No. Viewing Method OptoElectronic Device 1 3Deeps movies (2D Single or multi-layers variable tint device images viewed as 3D) 2 Anaglyph 3D movies Right Lens Blue; Left Len Red device 3 Intru3D 3D movies Right Lens Blue; Left Lens Amber device 4 Optimum emissive colors Optimized to emissive colors of TV of TV phosphors (for Methods 1, 2, 3) 5 Polarized Lenses 3D Right and left lenses at 90% polarization movies device 6 Vision correction Near- or far-sightedness correction device 7 Shutter glasses Rapid shuttering between clear and totally dark device 8 Sunglasses Single layer variable tint device 9 Optical property of light Electro Optical control of a property (or properties) of light With respect to the Method No. 1 of the table, the use of an electrochromic optoelectronic device for viewing 3Deeps movies with a single-layer of variable tint lenses has been previously described in the first preferred embodiment of the invention, and the use of an electrochromic optoelectronic device for viewing 3Deeps movies with multi-layers of variable tint lenses has been previously described in the second preferred embodiment of the invention. With respect to Method No. 2 of the table, the use of an electrochromic optoelectronic device for viewing anaglyph 3D movies (left lens red and right lens blue) with Multi-Use Electrically Controlled 3Deeps Continuous Adjustable 3Deeps Filter Spectacles has been previously described in the third preferred embodiment of the invention. The Multi-Use Electrically Controlled 3Deeps Continuous Adjustable 3Deeps Filter Spectacles described may also replace the layers of materials described or add additional layers of materials (with corresponding changes to the manual switches of the spectacles and the control program) to achieve other methods of electronically assisted viewing spectacles. Such methods may include; Intru3D 3D movies (Method No. 3) with left lens amber and right lens blue; optoelectronic devices (Method No. 4) that are tuned to the optimum emissive colors of a TV phosphor; optoelectronic devices (Method No. 5) that allow viewing of 3D movies using polarized lenses in which the right and left lenses have polarizations that are perpendicular to each other; optoelectronic devices that provide prescription glasses that correct vision such as near- or far-sightedness (Method No. 6); optoelectronic devices that allow viewing of 3D movies by the shutter glass method (Method No. 7) in which there is rapid shuttering between a clear and totally dark state for one eye, while the other eye has corresponding states of totally dark and clear in synchronization with right and left images of the displayed motion picture. The spectacles have a layer (Method No. 8) that when activated provides sunglasses. Any other optical property of light that can be beneficially controlled by an optoelectronic device (Method No. 9) can be used as a layer of the Multi-Use Electrically Controlled 3Deeps Continuous Adjustable 3Deeps Filter Spectacles. In some embodiments of the invention several methods may be operable at the same time as when Vision correction optoelectronics (Method No. 6) is active at the same time as any of the methods for viewing 3D movies. FIG. 16 is a block diagram 1600 of the operation of the multi-use Continuous Adjustable 3Deeps Filter Spectacles 1450 with multi-layered lenses. All circuits on the multi-use Continuous Adjustable 3Deeps Filter Spectacles 1450 are powered 301 by the battery 104, including the Control Unit 1403, Signal Receiving Unit 102, the Left Lens 1406, and the Right Lens 1405. The control information 110 is received by the Signal Receiving Unit 102 and sent 302 to the Control Unit 1403. The switch 1101 position is also powered 301 by the battery 104, and its position is output 1202 to the Control Unit 1403. The Control Unit 1403 implements an algorithm that is specific for the multi-use (Use 1: 3Deeps spectacles or Use 2: Anaglyph 3D viewing) multi-layered Continuous Adjustable 3Deeps Filter Spectacles, and controls the Left Lens 1406 with a control circuit 1603, and the Right Lens 1405 with a control circuit 1605. FIG. 17 is a flow chart 1700 showing the operation of the Control Unit 1403 of the Multi-Use Electrically Controlled Continuous Adjustable 3Deeps Filter Spectacles 1450 with multi-layered electrochromic lenses. The switch position 1202 is input to the Control Unit 1403. Processing commences with Change both right and left lens of layer land 2 to clear 1761 by switching both the right lens 1505 and left lens 1506 of the first electrochromic layer 411 and the second electrochromic layer 1501 to clear. Processing is then transferred to a control circuit Switch 1 or Switch 2 1763 that can parse the switch position and determine which position the Switch 1101 is in. If the Switch position is in the first position (3Deeps viewing) then a first control processing unit 103 is used to control the first layer 411 of the lenses of the Multi-Use Electrically Controlled Continuous Adjustable 3Deeps Filter Spectacles 1450. If the Switch position is in the second position (anaglyph viewing) then a second control processing unit 103a that is similar to the control processing unit 103 shown in FIG. 4) is used to control the second layer 1501 of the lenses of the Multi-Use Electrically Controlled Continuous Adjustable 3Deeps Filter Spectacles 1450. The two control processing units 103 and 103a of the Control Unit 1403 are the same as the control processing unit for the First Preferred Embodiment and is described in FIG. 4. The first control processing unit controls the spectacles for 3Deeps viewing and the second control processing unit control the spectacles for anaglyph 3D viewing. Only the input and output to the control processing 103 is shown in FIG. 17—not the details of the processing that is the same as shown in FIG. 4. If the Switch position is in the first position then the control processing unit electronically synchronizes to the movie using 3Deeps technology by controlling the left 1406 and right lenses 1405 of the first layer 411 of the multi-use Continuous Adjustable 3Deeps Filter Spectacles 1450 over the control circuits for the left lens 1603 and control circuit for the right lens 1605. In this case the second layer 1501 has been set so both right and left lenses of the second layer are clear. If the Switch position is in the second position then the control processing unit electronically controls the 3Deeps spectacles for anaglyph 3D viewing by switching the left lens 1406 to red and right lens 1405 to blue of the second layer 1501 of the multi-use Continuous Adjustable 3Deeps Filter Spectacles 1450 over the control circuits for the left lens 1603 and control circuit for the right lens 1605. In this case the first layer 411 has been set so both right and left lenses of the first layer are clear. This exemplary Control Unit 1403 has been purposely simplified for clarity and to show the principles of the control operation. It shows two separate control circuits 103 and 103a—the first 103 control circuit for control of Continuous Adjustable 3Deeps Filter Spectacles (first layer 411), and the second 103a control circuit for anaglyph 3D viewing (second layer 1501). FIG. 17 shows each circuit 103 and 103a with its own circuits for control of the left lens 1406 and control of the right lens 1405. It should be understood that good engineering design would reuse as much circuitry as possible for two controlling functions of the Control Unit 1403. TABLE 2 shows control information for Multi-Use Electrically Controlled Continuous Adjustable 3Deeps Filter Spectacles. Such control information is necessary when the Multi-Use Electrically Controlled Continuous Adjustable 3Deeps Filter Spectacles are under remote control rather than a manually control 1101 as shown in FIG. 14. TABLE 2 Method Control No. Viewing Method Code Control Information 1 3Deeps movies (2D images Ctrl-1 Optical Density for left and right viewed as 3D) lens 2 Anaglyph 3D movies Ctrl-2 None 3 Intru3D 3D movies Ctrl-3 None 4 Optimum emissive colors of TV Ctrl-4 Real-time setting of optical density phosphors (for Methods 1, 2, 3) of right and left lens 5 Polarized Lenses 3D movies Ctrl-5 None 6 Vision correction Ctrl-6 Real-time optical property of density of right and left lens 7 Shutter glasses Ctrl-7 Shutter synchronization 8 Sunglasses Ctrl-8 Real-time setting of sunglass color of right and left lens 9 Optical property of light Ctrl-9 Optical property of right and left lens Control information for Continuous Adjustable 3Deeps Filter Spectacles has been previously shown in the related patent application Ser. No. 12/274,752. In that related disclosure no multi-layer or multi-use information was required of the spectacle control protocol since the Continuous Adjustable 3Deeps Filter Spectacles had only a single-layer and a single-use. With Multi-Use Electrically Controlled Continuous Adjustable 3Deeps Filter Spectacles that are under remote control, a control code sequence may be transmitted to signal the Control Unit 1403—which layer of the multi-layered spectacles the controlling information references. The first column of the TABLE 2 is a numbering of the methods—but no preference is to attributed to the ordering. The Method Number is used for reference in the disclosure. The second column of TABLE 2 labeled Viewing Method identifies the viewing method. Columns 1 and 2 of TABLE 2 are the same as in the like labeled column of TABLE 1. The third column of TABLE 2 labeled Control Code has the control code in the RF sequence that is utilized by the Control Unit 1403 to switch control to the associated lens. For instance, when the Multi-Use Electrically Controlled Continuous Adjustable 3Deeps Filter Spectacles of FIG. 10, receive a Ctrl-2 sequence it switch to control of the associated method—in this can Anaglyph 3D movies. Once the Multi-Use Electrically Controlled Continuous Adjustable 3Deeps Filter Spectacles have received a Control Code sequence, all the control information that then follows will be interpreted to control the associated method. In the current example where a Ctrl-2 sequence is received switching the spectacles into Anaglyph 3D mode, all follow-on control information received by the spectacles would be interpreted to as controlling the Anaglyph 3D spectacle method and lens layer. Such follow-on control information references the switched method until another control-code is received. A description of the contents of the Follow-on control information associated with each of the viewing methods is indicated in column 4 of the table, labeled Control Information. When the Control Unit 1403 of the spectacles receive a Ctrl-2 sequence indicating it is to switch to anaglyph mode, the control unit 1403 changes the left lens 1406 to a red and the right lens 1405 to a blue color. The spectacles stay in this mode until another CTRL-code is received switching the spectacles to another method. Since the Anaglyph method, activated by Control Code, CTRL-2 requires no further or follow-on controlling information, the entry for Anaglyph in the Control Information column is None indicating that no further control information is required for the Anaglyph mode. Similarly, no additional control information is required for Intru3D 3D movies; and, Polarized lenses. Control Information is required for methods 3Deeps Movies; Optimum emissive colors of TV; Vision correction; shutter glasses; sunglasses; and, Optical Property of Light. The control information that is received wirelessly 102 by the Multi-Use Electrically Controlled Continuous Adjustable 3Deeps Filter Spectacles of FIG. 14 may be transmitted by any of the means disclosed in the related patent applications including but not limited to; DVD-based control units; Digital Movie Projector control units; Television-based control units, hand-held and operated control units; spectacle-based control units, and cell-phone based control units. Other Embodiments While the preferred embodiments have been described using electrochromic materials, other electro-optical (optoelectronics) materials may be utilized. Any material for which the optical properties can be controlled by the application of a potential across the material may be advantageously used in the invention. While the preferred embodiment uses 2 layers of electrochromic materials, even faster switching time can be achieved by using 3 or more layers. While the preferred embodiment uses the same voltage applied to each of the multi-layers of the lenses, other embodiments may achieve control over the switching time to the optical optimal density by the application of different voltage across each layer of the multi-layered lenses of the Continuous Adjustable 3Deeps Filter spectacles. In some embodiments of the invention, several different layers of multi-use-electronic materials may be switch selectable and active at the same time to achieve different optical effects. For instance electronically controllable vision correction may be combined with Continuous Adjustable 3Deeps Filtering to provide a single pair of viewing spectacles that both correct vision while at the same time providing optimal 3Deeps viewing of 2D motion pictures as 3D motion pictures. In yet another embodiment of the invention, rather than use electrochromic materials that have the same optical properties (transmission OC curve), materials with different optical properties may be beneficially utilized. As lenses get older their OC curve may change. In another embodiment the control program may tune the control OC curve based on age or time of use so that the spectacles do not appear to degrade in performance as they get older. The switch selection for the Multi-Use Electrically Controlled Continuous Adjustable 3Deeps Filter Spectacles was shown on the spectacles. Alternatively, the switch selection can be activated by the viewing media by broadcasting a Rx signal that is picked up by the receiving unit of the 3Deeps spectacles 102, passed to the control unit of the spectacles, and which are read and acted upon by the control program that controls the operation of the spectacles. For instance, a control code at the beginning of an anaglyph motion picture may allow the spectacles to respond by taking the proper configuration for viewing of anaglyph 3D encoded motion pictures without any manual intervention by the viewer. In other embodiment of the invention the multi-layered or multi-use lenses may be in the form of clip-on lenses that readily fit over normal prescription lenses. In still another embodiment of the invention, multi-use 3Deeps viewing spectacles are fabricated from a single layer of an electropolychromism device. Previous related patent applications (such as U.S. Pat. No. 7,508,485) have disclosed systems and methods by which a motion estimation value that characterizes movement in a frame of a 2D motion picture may be extracted from successive frames of the motion picture. The motion estimation value and a luminance value are used to calculate an optical density for the lens of the Pulfrich Filter spectacles and are transmitted to the Pulfrich Filter spectacles. The transmitted values are used to control the optical density of the lenses of the Pulfrich Filter spectacles. In still another embodiments of the invention, the motion estimation value is calculated from the motion estimation values that are part of the MPEG digital video compression standards. In another embodiment of the invention, the 3Deeps electrochromic sunglasses have additional variable brightness controls. In one case, the sunglasses have means by which the user can set the darkness level of the sunglasses. That is, rather than a have Pre-selected optical densities value for the left lens and right lens stored in the control unit (as in FIG. 13, the optical density value of the lenses of the sunglasses is under the control of the user. A rotary or slide switch could be utilized to select any optical density between the low and high values of the switch. In another embodiment a multi-pole switch is used so that user can select one of a set of pre-selected optical densities for the lenses of the sunglasses. In another embodiment of the invention the 3Deeps electrochromic sunglasses, the variable brightness of the lenses of the sunglasses operate similarly as an electrochromic version of photochromatic lenses. That is, the optical density of the 3Deeps sunglasses is set in accordance with a continuum of the ambient surrounding light. In low light (dark) there would be a minimum of little or not darkening of the lenses, while in intense sunlight such as at noon on a cloudless sunny day the lenses would take an extreme dark value. Lighting situations in-between would result in the optical density values for the lenses in-between the minimum and maximum values. This could be achieved for instance by incorporating a photodiode on the 3Deeps spectacles that measures the ambient light at the spectacle frames, and inputs that value to the control unit on the spectacles. In another embodiment of the invention, the Continuous Adjustable 3Deeps Filter Spectacles may not respond to every synchronization signal. While some electrochromic materials may have been reported that have a cycle life of up to 50 million changes—and even higher values can be obtained—if the Continuous Adjustable 3Deeps Filter Spectacles are made from a material with a shortened cycle life it may be necessary to also additionally consider and optimize for the operation of the spectacles for the cycle life. While the synchronization signals would still be broadcast for every frame, the Continuous Adjustable 3Deeps Filter Spectacles may be set to only process and respond to some of those changes so as efficiently use cycle life. This make sense, as scenes that exhibit movement may be on the order of 10-30 seconds long, or longer, and the same optical density setting will provide a near-optimal setting for the Continuous Adjustable 3Deeps Filter Spectacles. To address cycle time then, the Continuous Adjustable 3Deeps Filter Spectacles may use a combination of ad-hoc rules such as (a) responding only to every nth synchronization event; (b) responding to only synchronization events with changes to the optical density of more than a pre-set percent; (c) responding to synchronization events in which there is a change to direction of motion; (d) responding to synchronization events in which there is a change in presence or absence of motion; (e) scene change, or (f) some other motion picture frame event. As noted above, in accordance with certain embodiments, a method is provided for originating visual illusions of figures and spaces in continuous movement in any chosen direction using a finite number of pictures (as few as two pictures) that can be permanently stored and copied and displayed on motion picture film or electronic media. The method of the present invention entails repetitive presentation to the viewer of at least two substantially similar image pictures alternating with a third visual interval or bridging picture that is substantially dissimilar to the other substantially similar pictures in order to create the appearance of continuous, seamless and sustained directional movement. Specifically, two or more image pictures are repetitively presented together with a bridging interval (a bridging picture) which is preferably a solid black or other solid-colored picture, but may also be a strongly contrasting image-picture readily distinguished from the two or more pictures that are substantially similar. In electronic media, the bridge-picture may simply be a timed unlit-screen pause between serial re-appearances of the two or more similar image pictures. The rolling movements of pictorial forms thus created (figures that uncannily stay in place while maintaining directional movement, and do not move into a further phase of movement until replaced by a new set of rotating units) is referred to as Eternalisms, and the process of composing such visual events is referred to as Eternalizing. The three film or video picture-units are arranged to strike the eyes sequentially. For example, where A and B are the image pictures and C is the bridging picture, the picture units are arranged (A, B, C). This arrangement is then repeated any number of times, as a continuing “loop”. The view of this continuing loop allows for the perception of a perceptual combining and sustained movement of image pictures (A, B). Naturally, if this loop is placed on a film strip, then it is arranged and repeated in a linear manner (A, B, C, A, B, C, A, B, C, A, B, C, etc.). The repetition of the sequence provides an illusion of continuous movement of the image pictures (A, B); with bridging picture (C), preferably in the form of a neutral or black frame, not consciously noticed by the viewer at all, except perhaps as a subtle flicker. A more fluid or natural illusion of continuous movement from a finite number of image pictures is provided by using two of each of the three pictures and repeating the cycle of the pairs sequentially, or by blending adjacent pictures together on an additional picture-frame and placing the blended picture between the pictures in sequential order. The two image pictures (A, B) are now blended with each other to produce (A/B); the two image pictures are also blended with the bridging picture to produce (C/A and B/C), and then all pictures repeat in a series starting with the bridging picture (C, C/A, A, A/B, B, B/C) each blended picture being represented by the two letters with a slash therebetween). This series is repeated a plurality of times to sustain the illusion as long as desired. Repeating the sequence with additional blended frames provides more fluid illusion of continuous movement of the (optically combined) two image pictures (A, B). Additionally, various arrangements of the pictures and the blends can be employed in the present invention and need not be the same each time. By varying the order of pictures in the sequence, the beat or rhythm of the pictures is changed. For example, A, B, C can be followed by A, A/B, B, B/C, C which in turn is followed by A, A, A/B, B, B, B, B/C, C, C, C, C, i.e. A, B, C, A, A/B, B, B/C, C, A, A, A/B, B, B, B, B/C, B/C, C, C, C, C, A, B, C, A, etc. With A and B frames being similar images (such as a pair of normal two-eye perspective views of a three-dimensional scene from life), and frame C a contrasting frame (preferably a solid-color picture instead of an image-picture) relative to A,B, frame C acts as essentially a “bridge-interval” placed between recurrences of A,B. Any color can be used for the contrasting frame C: for example, blue, white, green; however, black is usually preferred. The contrasting frame can also be chosen from one of the colors in one of the two image pictures. For example, if one of the image pictures has a large patch of dark blue, then the color of the contrasting frame, bridging picture, may be dark blue. Blending of the pictures is accomplished in any manner which allows for both pictures to be merged in the same picture frame. Thus, the term “blending” as used in the specification and claims can also be called superimposing, since one picture is merged with the other picture. Blending is done in a conventional manner using conventional equipment, suitably, photographic means, a computer, an optical printer, or a rear screen projection device. For animated art, the blending can be done by hand as in hand drawing or hand painting. Preferably, a computer is used. Suitable software programs include Adobe Photoshop, Media 100 and Adobe After Affects. Good results have been obtained with Media 100 from Multimedia Group Data Translations, Inc. of Marlborough, Mass., USA. When using Media 100, suitable techniques include additive dissolving, cross-dissolving, and dissolving-fast fix and dither dissolving. In blending the pictures, it is preferred to use 50% of one and 50% of the other. However, the blending can be done on a sliding scale, for example with three blended pictures, a sliding scale of quarters, i.e. 75% A/25% B, 50% A/50% B, 25% A/75% B. Good results have been obtained with a 50%/50% mix, i.e. a blend of 50% A/50% B. The two image pictures, A and B, which are visually similar to each other, are preferably taken from side-by-side frame exposures from a motion picture film of an object or image or that is moving such that when one is overlaid with the other, only a slight difference is noted between the two images. Alternatively, the two image pictures are identical except that one is off-center from the other. The direction of the off-center, e.g. up, down, right, or left, will determine which direction the series provides the appearance of movement, e.g. if image picture B is off-center from image picture A to the right of A, the series of C, C/A, A, A/B, B, B/C will have the appearance of moving from left to right. Likewise, if you reverse the order of appearance then the appearance of movement will be to the left. More than two image pictures can be used in the invention. Likewise, more than one bridging picture can be used in the present invention. For example, four image pictures can be used along with one bridging picture. In this case, the series for the four image pictures, designated A, B, D and E, would be: C, A, B, D, E; or a 50/50 blend C, C/A, A, A/B, B, B/D, D, D/E, E, E/C; or side-by-side pairs, C, C, A, A, B, B, D, D, E, E. The image picture need not fill the picture frame. Furthermore, more than one image picture can be employed per frame. Thus, the picture frame can contain a cluster of images and the image or images need not necessarily filling up the entire frame. Also, only portions of image pictures can be used to form the image used in the present invention. Also, image pictures and portions of the image picture can be combined such that the combination is used as the second image picture. The portion of the image picture is offset from the first image picture when they are combined such that there is an appearance of movement. For example, a window from image picture A can be moved slightly while the background remains the same, the picture with the moved window is designated image picture B and the two combined to create the appearance of the window moving and/or enlarging or shrinking in size. In this case, both picture A and picture B are identical except for the placement of the window in the image picture. The same can also be done by using an identical background in both image pictures and superimposing on both pictures an image which is positioned slightly different in each picture. The image could be a window, as before, of a man walking, for example. The number of series which are put together can be finite if it is made on a length of film or infinite if it is set on a continuous cycle or loop wherein it repeats itself. Broadly, an embodiment of the invention is a method for creating an appearance of continuous movement with a plurality of picture frames using three or more pictures, said method comprising: a) selecting at least two image pictures, a first image picture and a second image picture, which are visually similar; b) selecting a bridging picture which is dissimilar to said image pictures; c) arranging said pictures in a sequential order to create a first series of pictures, said sequential order being one or more first image pictures, one or more second image pictures, one or more bridging pictures; d) placing said first series of pictures on a plurality of picture frames wherein each picture of said first series is placed on a single frame; and e) repeating the first series of pictures a plurality of times to create a continuous plurality of picture frames having said first series thereon, such that when said plurality of picture frames are viewed, an appearance of continuous movement is perceived by a viewer. Preferably, step (c) is replaced with the steps comprising: (c1) blending said first image picture with said bridging picture to obtain one or more blended first-bridging picture; (c2) blending said first image picture with said second image picture to obtain one or more blended first-second picture; (c3) blending said second image picture with said bridging picture to obtain one or more blended second-bridging picture; (c4) arranging said pictures in a sequential order of one or more bridging pictures, one or more of said blended first-bridging picture, one or more of said first image picture, one or more of said blended first-second pictures, one or more of said second image picture, one or more of said blended second-bridging picture to create a first series of pictures. An artificial 3-D image can be achieved by the present invention, as will be described in more detail below. Another way to obtain an artificial 3-D image is by a method of electronic switching of Pulfrich light-filtering before right or left eye, synchronized with screen action. The start or end of the sequences doesn't matter since the sequence is placed in a continuous loop, however, the order of the pictures in the loop is critical in the practice of the present invention. FIG. 18a illustrates three pictures that are employed in a method in accordance with an embodiment of the invention. Picture A, illustrated with lines slanting upward left to right, and Picture B, illustrated with lines slanting downward from left to right. Both pictures A and B are single frame photographs such as two side-by-side frames taken from a movie film showing movement of an object, for example, a woman walking down a street or a man walking his dog. Such side-by-side frames would be similar to each other but not identical. Picture C is a solid black picture. In FIG. 18b pictures A, B and C are arranged in sequential order, and placed on picture frames to form a series. In FIG. 18 c this series is then repeated to produce the appearance of movement by pictures A and B. Turning to FIG. 19a and the use of blended pictures, the three pictures are combined to produce a blend of CIA, blend of A/B and a blend of B/C by using Adobe Photoshop or another program to make a 50/50 blend of the three pictures. In FIG. 19b, all six pictures are placed side-by-side to create a series and the series is copied to create a continuous or semi-continuous film video or computer sequence where the series is repeated a plurality of times as shown in FIG. 19c. FIGS. 20a-20c illustrates an alternative three pictures that are employed in the method of this invention. Picture D and Picture E both illustrate a capital A, however, in Picture D, the capital A is aligned with the center of the frame while in Picture E the A is off-set to the right of the center of the frame (exaggerated here to be visible; in actual practice the displacement of figures might be so subtle as to not be discernable as illustrated here). Picture C is identical to Picture C in FIG. 18a. The capital A is chosen for FIGS. 20a-20c for illustration purposes and could be a single photograph of anything. The three pictures are placed side-by-side to form a series. Finally, the series is copied a plurality of times to form a repeating series. The repeating series in FIG. 20 c creates the optical illusion that the letter A is moving from left to right and, if one letter A were to be slightly different in size from the other, the letter would appear to be moving in depth, i.e. given a third dimension. In FIGS. 20a-20c the background of Picture E is identical to the background of Picture D except that the image A is off-set slightly to the right. FIGS. 21a-21b illustrates the present invention where the series is two of each picture placed in side-by-side frames. It has been found that two pictures side-by-side are visually equivalent to a blend. In other words, a series of A, A, B, B, C, C is visually equivalent to a series of C/A, A, A/B, B, B/C, C. Additionally, a series made in accordance with the present invention need not be uniform in that the pictures can be arranged to provide a different rhythm or beat to the film. For example, the series could be: C/A, C/A, A, A/B, A/B, B, B, B, B/C, C, C, C. Different arrangements provide different visual perceptions. Furthermore, a plurality of different series can be combined together, i.e. C/A, A, B, B, C with C/A, C/A, A, B, B, C, C to form C/A, A, B, B, C, C/A, C/A, A, B, B, C, C. FIGS. 22a-22c illustrates the invention where both pictures are identical except for the position of a superimposed image F on the pictures. Image F could be taken from the original picture G or could be taken from another picture, which is separate and distinct from pictures G and H. For example, pictures G and H could have the common background of a country side road while image F is a man walking his dog. In picture G, the man and his dog is placed at one location while on picture H the man and his dog is placed at a different location on the country road. By viewing the repeating of a series of G, H, C, a viewer is given with the impression that the man is walking his dog down the road, from top of the frame towards the bottom of the frame, appearing to be continually moving in the same direction without changing his actual position. Furthermore, image pictures can be identical except that when they are arranged in the frame, one is oriented slightly tilted relative to the other. The repeating series provides the visual perception that the picture is spinning. Also, the size of or the orientation of image F in FIGS. 22a-22c can be varied while maintaining the location of image F. Varying the size gives the viewer the impression that the man is walking forward or backward, depending on the order in which pictures are arranged. Changing the orientation or tilting of image F leaves the viewer with the impression that the man is spinning. The repeating series can be viewed in any media, it could be digitalized or placed on conventional film for viewing. The movement created by the invention is seamless movement, sustained fluid entirely on-going movement. Continuous movement means the illusion of a progressive action that can sustain as such into infinite time. For instance, a door beginning to open, it keeps beginning to open without ever progressing to the stage of actually opening. A door, in reality, in order to repeat this very limited movement, would have to move back and forth, recovering territory in order to go forward again, but in this visual illusion the door only moves forward. A normal film or video might approach this effect by multiple printing of the picture frames depicting only the forward motion, so that a return motion would be hidden from audience eyes, but the effect would be of a visual stutter; the action would be repeating, and not continuous. The stutter could be made less obvious and percussive by dissolving head frames of the shot into tail frames, but only with some subject matter (i.e., a waterfall) might the repeat character of the motion not be apparent. The appearance of transfixed continuous motion (a going without going anywhere) is created in this invention from a specific employment of flicker, the contrast created by viewing the slight shifting of a pictured form or forms between the image pictures in opposition to the bridging picture. Movies have always been dependent for their illusion of continuity on flicker-rates; silent movies filmed at 16 frames per second required 3-bladed shutters not only to block projection light during the successive replacing of frames but also to twice interrupt the display of each frame so as to achieve a flicker rate that the viewer would mistakenly see as uninterrupted light. Slow cranking of the film through the projector gave rise to “the flickers” as a pejorative. Video and computer image-continuity depends likewise on rapid on-off display. The present invention purposely makes flicker apparent, utilizing the effects of emphatic flicker on the human optical/nervous system to create uncanny time and space illusions. Simple alternation of a single image picture with intervals of blackness (or any other interrupting color/s) is enough to create subtle illusions of continual sliding movement across the screen. Alternations of two image pictures with an interrupting interval of a solid colored picture provides any number of continuous motions, including motion into illusionistic depth. While such screening-illusions of movement and depth resemble movements and depths as seen in actuality; this is a creative artistic method and not intended as a reliable way of reporting the actuality that may have existed in front of a camera. As noted above, no special viewing devices are required to view the present invention, although certain effects can be enhanced or put through interesting changes when viewed with a filter intercepting and reducing light to one eye; the Pulfrich Effect. Remarkably, with the present invention, depth illusions can be experienced even by the single-eyed person. Normally our perception of depth, stereopsis, depends on properly functioning binocular vision, two eyes working in tandem with each other; one of the benefits of this invention is to offer visual depth experience to those deprived of such experiences by physical defect. Because contrasting perspectival information is available to both or either eye, a single eye becomes sufficient to deliver the information to the brain when employing the present invention. The present invention is best created on the computer, to be viewed on the computer or transferred to film or any video format. It can also be created directly onto film or video but the precision control possible with the computer is lacking. The present invention can employ very small shifts in the placement of objects as seen in one picture in relationship to another similar picture. Such small object-placement shifts are also to be found in the simultaneously exposed pairs of frames made with a stereo still-camera, its two lenses placed horizontally apart approximately the distance between human eyes. The stereo still-camera offers object-placement differences derived, as with our two eyes, from a fixed interval of space: the twin perspectives recorded by lenses 2½ inches apart. The degree of inter-ocular distance, as it is called, enormously affects the character of depth to be seen when the stereo-pair is properly viewed one picture to each eye; depth would seem very distorted, either too shallow or too extended (with other depth aberrations) if the distance between our eyes was not being matched by the two-lens stereo-camera. In contrast to stereo-camera photography, with the single-lens motion picture camera (film or video), exploitable difference between like images arises from the interval of time between picture-exposures, during which the objects filmed shift in spatial relationship to each other; or/and the camera itself moves, capturing the 3-dimensional scene from another perspective, and thus shifting two-dimensional placement of pictured objects (which may not have moved in actuality) as recorded exposure to exposure. Because distance or direction traversed by the camera between exposures is not constant, nor movement by subjects recorded under photographer control, the visual equation of two-dimensional similarities and differences from which 3-dimensional movements will be constructed cannot produce scenes as reliably life-like as can simultaneous stereo-exposures with a fixed horizontal distance of 2½ inches between a pair of lenses. Eternalism 3-D movements made from sequential exposures are not intended to offer scientific data pertaining to reality but instead to provide odd and expressive impossible-in-reality impressions. The stereo still-camera provides a pair of mentally combinable left and right eye flat image pictures; viewed one picture to each eye, similarities and differences are automatically assessed and a semblance of familiar depth is seen. We gaze from plane to plane into a seeming depth, the angling of our two eyes crossing for close objects and spreading to parallel alignment for very distant ones (Yet we remain focused on the same plane in depth, the actual plane of the picture surface; in life, we constantly refocus as well as angle for different distances.) We are not conscious, either in actual life or when looking into such artificial depths, of the doubling of forms (as they fall back into 2-dimensionality) at distances that we are not at the moment angling for. This automatic angling operation of the eyes cannot happen when looking with both eyes at the same territory of flat picture surface. The coinciding of opposing 2-dimensional perspectival viewings of an object (by which volume can be conceived by the mind) must be done for the viewer, a task greatly enabled by the computer. The present invention revolves each set of picture-units in place, but if a figure from one perspective is not placed in a correspondingly similar position in its frame (and in matching horizontal alignment) with its representation as recorded from another perspective, there is only a 2-dimensional jiggering with no volume illusion or continuous direction of movement created. With the computer, one can slide and place one picture, or an area of that picture, into exact relationship with a matching picture or area so as to achieve the precise effect desired. (A recorded object becomes an area within a flat picture-image.) The slightest advance in a particular direction of the contour of one area in relation to its match-up area determines movement in that direction. Slight shrinking or enlargement of one area compared to the other creates a zooming in or out effect. A problem in overlaying one entire picture over another in order to match up one area usually means other areas will not coincide, not synchronize; but the computer allows for each area to be matched separately and inlaid into the scene according to one's depth-movement intentions for each area. The crazy-quilt artificiality of a scene can be hidden or obvious, its parts drawn from a single-pair source of related images or from as many sources as desired. Photo-images can be mixed with or replaced by drawn and painted imagery. The scene can imitate real life one moment and veer off into impossibility the next. Again, although only two image pictures are usually cycled, more than two can be worked into a cycle to create a particular effect. Following and inventing variants on the directions above, and the formula as described below for sequencing frames, will create the impression of solid entities moving in a charmed dimension where normally transient physical gestures can endure forever. In fact, computer interactivity can mean the viewer deciding how long the effects of each series continues. Further interactivity will give the viewer the option to place picture of his/her own choice into this unique cycling system. FIGS. 23a-23c shows two phases of an action, A & B, plus black bridge-frame C. We see the pictures separately in FIG. 23a; made sequentially adjacent to each other in FIG. 23b and presented as a repeating series of pictures, as a loop or cycle, in FIG. 23c. FIG. 24a demonstrates the creation of intermediary or blended frames between A, B and C, which are 50-50% blends producing A/C, AB & B/C. FIG. 24b shows them in sequence and FIG. 24c shows them repeating as an ongoing loop. FIG. 25a shows one figure in isolation, removed from the previous scene. Pictures D & E may appear identical but are actually two different perspectives which together make possible a 3-dimensional figure. While the recording camera remained in a fixed position the figure moved before it, frame after frame, making two perspectives possible. Because the figure moved to different positions in the two film frames, it was necessary to move one figure in one frame so that both figures would occupy the same location in both frames. It is now possible to see them as a single 3-dimensional figure when the frames cycle in quick succession together with the bridge frame as shown in FIGS. 25b and 25c. FIGS. 26a and 26b represents the doubling of each frame in an A, B, C series. FIGS. 27a-27c shows a section of picture G & H is repeated in the upper left corner. When observed in quick succession this series will show the two center figures in one configuration of depth and the inset series as an opposing configuration of depth. Left eye/right eye views as placed in G & H are reversed in the inset figure, so that parts of the figure that (3-dimensionally) approach the viewer in the larger picture are seen to retreat away from the viewer in the smaller picture, and vice versa. FIG. 28 illustrates two sets of four; with both similarities (J, K, M) and differences (L, N) between the sets, including in the upper left corner an action that straddles bridging frame (M) and picture frame (J). Note the bridging frame is not completely blank or colored. Frame J has a smaller frame in the upper left corner of a larger frame and is an example of a combined frame that may be generated by stitching a first frame and a second frame together. FIG. 29 illustrates an example of an Eternalism effect coexisting with more normal screen action, and of an Eternalism repetition taking place but with no two frames exactly alike: a visual element (the circle) proceeds frame to frame throughout as it would in a normal movie, unaffected by Eternalism looping. Again, note that the bridging frame is not completely blank. FIG. 30 is an illustration of Pulfrich filter spectacles: (1) clear; (2) activated to partly block light reaching figure's right eye; (3) activated to partly bock light reaching figure's left eye. Liquid crystal reaction is one method of achieving the blocking effect. Certain embodiments may be described as follows: In the Pulfrich filter effect, interference by the light-reducing filter has the effect of retarding the light that does pass through it to the eye. As long as forms and objects are changing position relative to each other as pictured frame to frame, a delayed picture seen in combination with a present-moment picture offers two slightly different pictures simultaneously to the mind. Thus an artificial three-dimensional image can be produced by the mind utilizing the same mechanisms that allow it, in viewing actuality, to produce a three-dimensional mental image from the pair of two-dimensional perspective-images received from horizontally adjacent eyes. The artificial 3-D image can be said to depend on a variable report of actuality. A Pulfrich filter used to view actual three-dimensional space will distort that space (assuming the scene is in motion). Similarly, depth in a screen image can be distorted, and in manifold ways, including reversal of near and far and direction of motion flow. Such distortions can have expressive artistic value. The Pulfrich Effect, triggered (as described above) to accord with pictured directional motion on-screen, would have applications beyond use with Eternalized movies. Video games and other video movies featuring extended screen movements to left or right could, in many instances, be enhanced for viewers by Pulfrich projection into three-dimensional depth. For many such screen events for instance, a scene filmed or videotaped from a moving vehicle, especially perpendicularly, with the camera aimed at or close to a 90 degree angle from the side of the vehicle, convincingly realistic deep space would result. A stipulation of realistic deep space, as made available by the Pulfrich Effect, is that the partial light-absorbing filter be before the eye on the side to which the pictured foreground objects are seen to move. If filming or videotaping was to be done with the camera aimed perpendicular to a vehicle's path of movement, and the camera was on the driver's side, motion onscreen would flow screen-left, and the Pulfrich filtering would therefore have to take place before the left eye; thus the need to switch dark-filter placement from eye to eye in accordance with direction of screen movement. The filter works best when there is essentially horizontal movement; when viewing an unmoving or inappropriate image, both left and right eye filters should clear. Presented as electronic media, such images would benefit from timed application of appropriate Pulfrich filtering. This aspect of the invention would allow 3-dimensional movies to be created and presented (less spectacles) with the same cinema technology used for making and presenting ordinary 2-dimensional movies. Description of the Eternalism Optical Phenomena The idea of an interval of action running in place without apparent beginning, middle and end, forever swelling or turning or rising or opening, forever seeming to evolve without ever actually doing so (until given a determined release into a further phase of development), can be literally unimaginable, so alien is it to our experience. Neither in life or on film or in electronic imagery has it been possible to create the optical illusion of a door forever cracking open or a muscle rippling or head turning or any other limited gesture continuing as such into potentially unlimited time—until advent of this invention. We have termed this phenomenon Eternalism, and we speak of pictured forms or objects, scenes or gesture being Eternalized into Eternalisms. A further benefit of this invention is enhanced 3-Dimensionality of Eternalized images, a 3-D that can be reasonably life-like or radically at odds with depth as we know it. Consider, for example, the action of a door opening. And select from that entire action only the fraction of time that it would take for the door to just begin to open, as it cracks open a narrow space alongside the doorframe, with the outer edge of the door swinging over little more than an inch of flooring. Designating this very limited time-space interval as a movie shot. The most minimal movie shot possible, it consists of only two running frames of film or video. In reality, there would be no way to sustain into unlimited time the very limited action of the door cracking open; to keep opening and only opening yet never moving past that very limited phase of just cracking open. This motion is not repeated but sustained. The reality, of course, is that to remain in motion, and in forward motion only, one would have to move the door to a further phase of motion: the door would have to open wider. And the designated space-time interval would be left behind. This is similar to someone walking against the direction of a conveyer belt walkway (as at an airport) and at exactly the same speed of the conveyer belt, continually walking forward yet getting nowhere. The Eternalism technique is a sort of cinematic conveyer belt moving in an opposing direction to any moving image placed on it. It is a conveyer belt with a beat, a flicker, a visual beat capable of supple changes. In the history of cinema, flicker—referring to visible intervals of darkness between flashes of successive film-frames, intrusive reminders of the mechanical basis of the cinematic illusion—has been a pejorative term. To commercially entertain, the technology needed to quickly outgrow flicker. Yet in doing so some other illusionistic potentials of the art, very curious departures from life-like representation, were never discovered, their expressive potential left untapped, until now. Method Visible flicker is essential to Eternalism technique, which investigates and utilizes different intensities of emphasis, frame choices and frame-counts of flicker in order to create entirely new illusions to augment cinema's repertoire of visual effects. Today's audiences are entirely receptive to non-realistic representation, the textures of visual technologies are no longer unwelcome onscreen. Visible flicker does sometimes appear in movies in purposeful ways, usually representing lightning or machine-gun bursts, and even as rhythmic hits of light-energy, but not with the methodology and results of Eternalisms. No less than three basic units, two pictures and a bridge-interval (A, B, C), are necessary to create an Eternalism, even when picture B might be only a slight modification, a shifting or size reduction or expansion or tilting, etc. of picture A. On the simplest level, the series of units would proceed: A, B, C, A, B, C, A and so on. Each unit interval may be of any effective time duration, an effective smooth-working duration for computer assembling is two frames per unit, shown here as A,A, B,B, C,C, A,A, B,B, C,C, A,A and so on. It is sometimes desired to insert transitional frames, usually 50/50% (percentage mixture may vary) superimposed frames of adjacent units, shown here as: A, A/B, B, B/C, C, C/A, A and so on. Additionally, all re-appearances of the basic cycling units comprising an Eternalism needn't be exactly the same. Strict mechanical repetition can give way to flexible variation within the limits imposed by what is necessary to sustain the motion/depth illusion (unless one chooses to abandon the illusion entirely for a period of time; it is expected that for commercial movie use of the method, that the effect would be used intermittently, for selected scenes). Any number of factors comprising a unit-sequence may be altered from appearance to appearance as it cycles, including colors, shapes, placement of shapes, objects pictures, unit duration, etc., so that the same Eternalism would seem to remain in play while going through subtle or even vibrant internal changes, before being replaced by a successive phase of motion or a distinctly other selection of picture/interval units. Change in the order of units, such as A, B, C, A, B, C, A being replaced by B, A, C, B, A, C, B would initiate an immediate reversal in direction of pictured movement. Varying durations of units within an Eternalism or traveling from Eternalism to Eternalism may not only make for desired beat and rhythm changes but also affect the apparent character of motion and/or depth in interesting ways. A composer of a series may even choose to play against its smooth continuity by momentary unit-replacement or interjection by other picture units, as for instance: A,A, B,B, C,C, A,D, B,B, C,E,C, A,A. The entire screen may Eternalize with the same sequential rhythm (usually the case) or different parts may sequence with different rhythms to different pictorial effect. Many techniques commonly in use in computer and hand-crafted movie animation can be adapted to Eternalism use. For instance, similar to screen combinations of photographed reality with animation cartooning, only a section or sections of the screen image may be Eternalized while normal movie motion proceeds in other sections. Or a figure in normal motion may move through an Eternalized scene. Or, among other combination possibilities, a smaller Eternalism (which can be an object or shape or a separately framed scene) may be imbedded within a larger Eternalism, or may float before it, or move—substantial yet ghostlike—through it. Stereo Vision and Special Requirements of Eternalism Composition Eternalism images may be so composed as to create an impression of 3-dimensional volume, designed to appear more or less realistic, but never with the degree of realism as to fool anyone that they are other than images. No one will ever attempt to sink a hand into one to grab at passing fish as children do at Sony I-MAX. Eternalism depth is readily apparent and yet more problematic, as is its character of movement. Depth isn't simple there to be taken for granted, but seems constantly caught in the act of being generated out of flat elements. Eternalism is an illusion of depth. Our minds are given the task of entertaining together two conflicting impressions: of things simultaneously appearing both flat and deep. However, the degree of 3-dimensionality that is there can be seen without need of special viewing devices of any sort, and in fact can be seen by many persons normally deprived of any 3-dimensional vision (those missing sight in one eye, for instance). Depth as well as ongoing movement must be artificially composed in the making of Eternalisms. Calculated placement of areas to be brought into working correspondence within a picture A and picture B is of paramount importance. It does happen that images are recorded on film or in electronic media that work effectively enough when sequentially overlayed with each other as-is, so as to need little or no cut-and-paste rearrangement. But more often there are areas not adequately corresponding in sequential location and therefore, when alternated quickly, will merely bounce back and forth from place (in A-frame) to place (in B-frame). In normal stereo-vision ones two eyes angle in and out from parallel alignment as they match corresponding areas on their two retinal images. Each retinal image is in fact 2-dimensional; 3-dimension vision is a result of this muscular matching, this pulling-into-alignment activity performed by muscles surrounding the eyes (as dictated to by viewers focus of interest) activity by the eyes and the mental comparing and processing of like and unlike information sent by each eye to the brain. Only within a very limited interval of actual depth, up to about twenty five feet distance for most humans, can we effectively shift and overlay forms so as to discriminate depth accurately (eyes work in parallel beyond that distance, with greatly reduced depth distinction). The closer to the eyes the target of focus, the more the eyes have to cross, and the different degrees or angles of crossing demanded as things approach or recede means that while one layer of depth will be properly shifted to overlay figures, others will not be. Selective focusing and shift in real-life visual experience, selectively attending to the 3-D figures creates in the mind, while ignoring—helped by a “dominant eye”—the remaining non-overlayed and doubled flat figures remaining in the twin fields of vision, peripheral to the focus of attention. Ignoring such peripheral mismatchings in Eternalisms does not come so naturally. Because the image pictures alternate in appearance, they don't quietly superimpose (with one image largely discarded from mind due to our having a “dominant eye”): non-overlayed areas will tend to jiggle and bounce, usually a distraction. Unless that is the effect wanted in a particular instance, the procedures of artificially overlaying A and B picture-areas for the viewer will be carried out throughout an Eternalism composition, into all peripheral areas of the picture. Again, this can be done employing computer graphics cut-and-paste techniques, with the filling of areas left emptied (by removal or shifting of a form) usually accomplished by the extending of adjacent colors. Picture-frames A and B may be near-identical or have only some elements with close visual correspondence. Similarity of shape and location within the frame are important factors determining the effect. This is true to the point that entirely different pictured objects but of similar shape and on-screen location will give better results than two images of the same object recorded from perspectives too far apart or placed too far apart within consecutive frames, in which case the images will be seen to vibrate or bounce back and forth without visually combining into a single moving form. While matching image elements in pictures A and B must occupy almost the exact screen-space in order to combine properly, it will be the differences between them (within close tolerances) that will produce and determine the character of movement and dimensionality. Computer graphics cut-and-paste techniques can be used to select and place, shrink and expand and otherwise manipulate matching elements (from any source) into effective screen-locations relative to each other. One or both pictures may be collaged or stitched together from multiple sources, parts may be removed or inserted, lifted and reshaped or/and relocated. Even when the image is photographed from life and appears life-like, the process of composition can be as exacting and labor-intensive and involved with techniques of artifice as cartoon animation. Embodiments In practice, the implementation of this technique opens up a new world of visual effects. Its uncanniness may be emphasized to create unsettling time-space aberrations for comic or dramatic effect in movies. Or, aiming for more realistic appearance, the method could be used to provide more lively snapshots of familiar things and events. For instance, people could carry, programmed into a Palm Pilot-type electronic wallet, a great many (low memory demanding) moving replicas of loved ones in characteristic living gestures, with heightened 3-dimensional presence. Even very limited movement, limited 3-dimensionality, can enormously augment and reinforce visual information: i.e., a child's face breaks into a smile. Again, the very low demand of electronic memory by an Eternalism (cycling as few as two picture-frames with an interval of darkness), makes possible extensively illustrated electronic catalogues or even encyclopedias, supporting hundreds and eventually thousands of Eternalized illustrations. A reader-viewer might observe a home appliance in operation. Or study a visual sampling of an ocean wave breaking in its sweep to shore, study it as has never been possible before, forever breaking from peak ascendancy. One may study a springing cat, sheath of muscles sliding over ribs continually, available for sustained observation; or follow a clear demonstration of the direction a screwdriver must turn to further imbed a screw. Any number of instances where stereo-dimensional action (often audio-accompanied, as audio also demands little computer-memory) would communicate so much more than a still and flat image, or even a moving but flat image. In accordance with another embodiment, a method of displaying one or more frames of a video is provided. Data comprising a compressed image frame and temporal redundancy information is received. The image frame is decompressed. A plurality of bridge frames that are visually dissimilar to the image frame are generated. The image frame and the plurality of bridge frames are blended, generating a plurality of blended frames, and the plurality of blended frames are displayed. The basic idea of video compression is to remove spatial area redundancy within a video frame (e.g. as done with Fax transmissions) and temporal redundancy between video frames. Since the successive frames in a video stream usually do not change much within small time intervals, the temporal redundancies can be used to encode and compress a video frame based on other video frames temporally (successively or previously) close to it. As an example, MPEG compressed video files record a 16×16 pixel area (referred to as a macro block) of a frame of a motion picture, and then for successive frames only record a motion vector describing the motion of the macro block. In MPEG compression the motion vector has a horizontal and vertical part, each part ranging from −64 to +63 with a positive value indicating that the macro block moves to the right or downward respectively. Any macro block can move up to 64 pixels laterally and vertically between frames. (MPEG compression tracks not just rigid rotation but also macro block rotation.) High compression rates are achievable for moving pictures in part because the next successive frame of a motion video consists in the main of identical information. For instance, if the camera is fixed, the background information for a scene will be mostly identical between the frames of the scene. Most macro blocks will have an associated numerical motion vector indicating the macro block has not moved. In those cases where the macro block exhibits motion between frames, the macro block will have an associated numerical motion vector quantifying where the macro block has moved. In either case, only the motion vector needs to be recorded in the compressed file, not the redundant macro block. Software-based (e.g. Microsoft Media Player) and hardware-based (e.g., DVD) video players can read a compressed file and decompress it back to a video stream for display on a monitor device for viewing. This has great advantages over previously described methods since it relies on motion vector descriptors that are pre-calculated and stored in the compressed video file, and does not require real-time image processing. The discussion herein refers to MPEG compressed video files as two examples of video file formats that could be used by this invention. While the preferred embodiment of the invention will demonstrate the principle using just the MPEG format, it should be clearly understood that the principles disclosed in the invention could be used by any video compression technique that relies on temporal redundancies. Other formats, such as QuickTime, may be used. Video File Data Compression Video compression refers to reducing the quantity of data used to represent digital video images, and is a combination of spatial image compression and temporal motion compensation. Compressed video can effectively reduce the bandwidth required to transmit video via terrestrial broadcast, via cable TV, or via satellite TV services. Most video compression is lossy—it operates on the premise that much of the data present before compression is not necessary for achieving good perceptual quality. For example, DVDs use a video coding standard that can compress around two hours of video data by 15 to 30 times, while still producing a picture quality that is generally considered high-quality for standard-definition video. Video compression is a tradeoff between disk space, video quality, and the cost of hardware required to decompress the video in a reasonable time. However, if the video is over-compressed in a lossy manner, visible (and sometimes distracting) artifacts can appear. Video compression typically operates on square-shaped groups of neighboring pixels, usually called macro-blocks. These pixel groups or blocks of pixels are compared from one frame to the next and the video compression records only the differences within those blocks. This works extremely well if the video has no motion. A still frame of text, for example, can be repeated with very little transmitted data. In areas of video with more motion, more pixels change from one frame to the next. When more pixels change, the video compression scheme must send more data to keep up with the larger number of pixels that are changing. If the video content includes an explosion, flames, a flock of thousands of birds, or any other image with a great deal of high-frequency detail, the quality will decrease, or the variable bitrate must be increased to render this added information with the same level of detail. Video data contains spatial and temporal redundancy. Similarities can thus be encoded by merely registering differences within a frame (spatial), and/or between frames (temporal). Spatial encoding is performed by taking advantage of the fact that the human eye is unable to distinguish small differences in color as easily as it can perceive changes in brightness, so that very similar areas of color can be “averaged out” in a similar way to jpeg images. With temporal compression only the changes from one frame to the next are encoded as often a large number of the pixels will be the same on a series of frames. One of the most powerful techniques for compressing video is interframe compression. Interframe compression uses one or more earlier or later frames in a sequence to compress the current frame, while intraframe compression uses only the current frame, which is effectively image compression. The most commonly used method works by comparing each frame in the video with the previous one. If the frame contains areas where nothing has moved, the system simply issues a short command that copies that part of the previous frame, bit-for-bit, into the next one. If sections of the frame move in a simple manner, the compressor emits a (slightly longer) command that tells the decompresser to shift, rotate, lighten, or darken the copy—a longer command, but still much shorter than intraframe compression. MPEG-1 Video Compression Standard The Moving Picture Experts Group (MPEG) was formed by the International Organization for Standards (ISO) to set standards for audio and video compression and transmission. Its first meeting was in May 1988, and by 2005, MPEG included approximately 350 members per meeting from various industries, universities, and research institutions. MPEG's has developed several sets of standards referred to as MPEG-1, MPEG-2, MPEG-3 and MPEG-4, and is continuing to work on other video compression standards. MPEG-1 is an ISO/IEC (International Organization for Standardization/International Electrotechnical Commission) standard for medium quality and medium bit rate video and audio compression. It allows video to be compressed by the ratios in the range of 50:1 to 100:1, depending on image sequence type and desired quality. The MPEG-1 standard is one of many video file compression technique that use spatial redundancy and temporal redundancy to reduce the size of the digital video file with little noticeable loss from the originally uncompressed digital version. The MPEG-1 standard is still widely used even though it is more than 15 years old is still widely used. The preferred embodiment of the invention will use the MPEG-1 video compression standard to demonstrate the principles of the invention. However, it should be clearly understood that the principles disclosed in the invention could be used by any video compression technique that relies on temporal redundancies to achieve compression of video data. Thus, the invention is not restricted to just MPEG-1 or other MPEG compression standards. The invention may be applied using any compressed video file associated with a compression format that uses temporal redundancy to achieve compression of video data. In MPEG-1, a video stream is a sequence of video frames. Each frame is a still image, and a video player decompresses an MPEG-1 bit stream and displays one frame after another to produce the motion video. When a motion video is compressed, MPEG-1 video compression removes both spatial redundancy within a video frame and temporal redundancy between video frames. The compression algorithms exploit several techniques to remove spatial redundancy but most importantly for this invention is its use of motion-compensation to remove temporal redundancy. Since the images in a video stream usually do not change much within small time intervals, and the idea of MPEG-1 motion-compensation is to encode a video frame based on other video frames temporally close to it. A MPEG-1 compressed digital file is a sequence of three kinds of frames: an I-frame, a P-frame, and a B-frame. The I-frames are intra-coded, i.e. they can be reconstructed without any reference to other frames. The P-frames are forward predicted from the last I-frame or P-frame, i.e. it is impossible to reconstruct them without the data of another frame (I or P). The B-frames are both forward predicted and backward predicted from the last/next I-frame or P-frame, i.e. there are two other frames necessary to reconstruct them. P-frames and B-frames are referred to as inter-coded frames. Whether a frame of video is coded as an I-frame, P-frame, or B-frame, the frame is processed as micro-blocks. A micro-block is a square array of 16×16 pixels, and is the unit for motion-compensated compression. If a video frame has a resolution of 320×240 pixels the MPEG-1 bit stream will reference this frame with respect to 20×15=300 macro-blocks. An I-frame is encoded as a single image, with no reference to any past or future frames. The encoding scheme used is similar to JPEG compression. Each 8×8 block is encoded independently with one exception explained below. The block is first transformed from the spatial domain into a frequency domain using the DCT (Discrete Cosine Transform), which separates the signal into independent frequency bands. Most frequency information is in the upper left corner of the resulting 8×8 block. After this, the data is quantized. Quantization can be thought of as ignoring lower-order bits (though this process is slightly more complicated). Quantization is the only lossy part of the whole compression process other than subsampling. The resulting data is then run-length encoded in a zig-zag ordering to optimize compression. This zig-zag ordering produces longer runs of 0's by taking advantage of the fact that there should be little high-frequency information (more 0's as one zig-zags from the upper left corner towards the lower right corner of the 8×8 block). The afore-mentioned exception to independence is that the coefficient in the upper left corner of the block, called the DC coefficient, is encoded relative to the DC coefficient of the previous block (DCPM coding). A P-frame is encoded relative to the past reference frame. A reference frame is a P- or I-frame. The past reference frame is the closest preceding reference frame. Each macro-block in a P-frame can be encoded either as an I-macro-block or as a P-macro-block. An I-macro-block is encoded just like a macro-block in an I-frame. A P-macro-block is encoded as a 16×16 area of the past reference frame, plus an error term. To specify the 16×16 area of the reference frame, a motion vector is included. A motion vector (0, 0) means that the 16×16 area is in the same position as the macro-block we are encoding. Other motion vectors are relative to that position. Motion vectors may include half-pixel values, in which case pixels are averaged. The error term is encoded using the DCT, quantization, and run-length encoding. A macro-block may also be skipped which is equivalent to a (0, 0) vector and an all-zero error term. The search for good motion vector (the one that gives small error term and good compression) is the heart of any MPEG-1 video encoder and it is the primary reason why encoders are slow. A B-frame is encoded relative to the past reference frame, the future reference frame, or both frames. The future reference frame is the closest following reference frame (I or P). The encoding for B-frames is similar to P-frames, except that motion vectors may refer to areas in the future reference frames. For macro-blocks that use both past and future reference frames, the two 16×16 areas are averaged. The MPEG-1 bit stream for both P-frames (forward predicted), and B-frames (forward and backward predicted) have motion vectors explicitly or implicitly associated with each macro-block. A P-frame of the motion video file with a resolution of 320×240 may have as many as 300 motion vectors describing the movement of the macro-blocks from the most recent I-frame or P-frame. A B-frame of the motion video file will similarly have up to 300 motion vectors describing the movement of the macro-blacks from last/next I-frame or P-frame. As an example, consider a single macro-block. A following P-frame shows the same triangle but at another position. Prediction means to supply a motion vector that determines how to move the macro-block from an I-frame to the P-frame. This motion vector is part of the MPEG stream and it is divided in a horizontal and a vertical part. These parts can be positive or negative. A positive value means motion to the right or motion downwards, respectively. A negative value means motion to the left or motion upwards, respectively. The parts of the motion vector are in the range of −64 . . . +63. So the referred area can be up to 64×64 pixels away. An I-frame is intra-coded and cannot refer to another frame so it cannot have any motion vectors. However, the inter-coded P-frames and B-frames have motion vectors for each macro-block and are used by this invention to calculate for their respective frames the Characteristic 3Deeps Motion Vector necessary to calculate the optical densities of the lenses of the 3Deeps Filter Spectacles. In accordance with an embodiment, data comprising a compressed image frame and temporal redundancy information is received. The image frame is decompressed. A plurality of bridge frames that are visually dissimilar to the image frame are generated. The image frame and the plurality of bridge frames are blended, generating a plurality of blended frames, and the blended frames are displayed. FIG. 31 shows a video display manager that may be used to implement certain embodiments in accordance with an embodiment. Video display manager 3100 comprises a processor 3110, a decompression module 3120, a bridge frame generator 3130, a frame display module 3150, and a storage 3140. FIG. 32 is a flowchart of a method of decompressing and displaying one or more image frames in accordance with an embodiment. In an illustrative embodiment, a compressed video file 2500 is stored in storage 3140. Compressed video file 2500 may be generated by video display manager 3100 or, alternatively, received from another device or via a network such as the Internet. At step 3210, data comprising a compressed image frame and temporal redundancy information is received. In the illustrative embodiment, processor 3110 retrieves compressed video file 2500 from storage 3140. At step 3220, the image frame is decompressed. Decompression module 3120 decompresses compressed video file 2500, generating a video image frame. FIG. 33 shows an image frame 3350 showing a man against a background of clouds and sky. At step 3230, a plurality of bridge frames that are visually dissimilar to the image frame are generated. Bridge frame generator 3130 generates two or more bridge frames that are dissimilar from image frame 3350. FIGS. 34A and 34B show two bridge frames 3410 and 3420 that may be generated. In the illustrative embodiment, bridge frame 3410 has a first pattern and a bridge frame 3420 has a second pattern that is complementary to the first pattern of bridge frame 3410. In other embodiments, bridge frames may be retrieved from a storage. At step 3240, the image frame and the plurality of bridge frames are blended, generating a plurality of blended frames. In the illustrative embodiment, frame display module 3150 blends image frame 3350 and bridge frame 3410 to generate blended frame 3510, shown in FIG. 35A. Frame display module 3150 also blends image frame 3350 and bridge frame 3420 to generate blended frame 3520, shown in FIG. 35B. At step 3250, the plurality of blended frames are displayed. Frame display module 3150 now displays blended frames 3510 and 3520 in a manner similar to that described above. For example, blended frames 3510 and 3520 may be displayed in accordance with a predetermined pattern, for example. In an embodiment illustrated in FIG. 35C, blended frames 3510, 3520 consecutively in a predetermined pattern. In other embodiments, blended frames 3510 may be displayed in a pattern that includes a plurality of blended frames and image frame 3350, or in a pattern that includes other bridge frames. In accordance with another embodiment, a plurality of blended frames may be displayed in accordance with a predetermined pattern that includes a first pattern comprising the plurality of blended frames, and a second pattern that includes repetition of the first pattern. In an embodiment illustrated in FIG. 35D, blended frames 3510 and 3520 are displayed in a repeating pattern that includes blended frame 3510, blended frame 3520, and a bridge frame 3590. In various embodiments, the method steps described herein, including the method steps described in FIG. 32, may be performed in an order different from the particular order described or shown. In other embodiments, other steps may be provided, or steps may be eliminated, from the described methods. Systems, apparatus, and methods described herein may be implemented using digital circuitry, or using one or more computers using well-known computer processors, memory units, storage devices, computer software, and other components. Typically, a computer includes a processor for executing instructions and one or more memories for storing instructions and data. A computer may also include, or be coupled to, one or more mass storage devices, such as one or more magnetic disks, internal hard disks and removable disks, magneto-optical disks, optical disks, etc. Systems, apparatus, and methods described herein may be implemented using computers operating in a client-server relationship. Typically, in such a system, the client computers are located remotely from the server computer and interact via a network. The client-server relationship may be defined and controlled by computer programs running on the respective client and server computers. Systems, apparatus, and methods described herein may be used within a network-based cloud computing system. In such a network-based cloud computing system, a server or another processor that is connected to a network communicates with one or more client computers via a network. A client computer may communicate with the server via a network browser application residing and operating on the client computer, for example. A client computer may store data on the server and access the data via the network. A client computer may transmit requests for data, or requests for online services, to the server via the network. The server may perform requested services and provide data to the client computer(s). The server may also transmit data adapted to cause a client computer to perform a specified function, e.g., to perform a calculation, to display specified data on a screen, etc. Systems, apparatus, and methods described herein may be implemented using a computer program product tangibly embodied in an information carrier, e.g., in a non-transitory machine-readable storage device, for execution by a programmable processor; and the method steps described herein, including one or more of the steps of FIG. 32, may be implemented using one or more computer programs that are executable by such a processor. A computer program is a set of computer program instructions that can be used, directly or indirectly, in a computer to perform a certain activity or bring about a certain result. A computer program can be written in any form of programming language, including compiled or interpreted languages, and it can be deployed in any form, including as a stand-alone program or as a module, component, subroutine, or other unit suitable for use in a computing environment. A high-level block diagram of an exemplary computer that may be used to implement systems, apparatus and methods described herein is illustrated in FIG. 36. Computer 3600 includes a processor 3601 operatively coupled to a data storage device 3602 and a memory 3603. Processor 3601 controls the overall operation of computer 3600 by executing computer program instructions that define such operations. The computer program instructions may be stored in data storage device 3602, or other computer readable medium, and loaded into memory 3603 when execution of the computer program instructions is desired. Thus, the method steps of FIG. 32 can be defined by the computer program instructions stored in memory 3603 and/or data storage device 3602 and controlled by the processor 3601 executing the computer program instructions. For example, the computer program instructions can be implemented as computer executable code programmed by one skilled in the art to perform an algorithm defined by the method steps of FIG. 32. Accordingly, by executing the computer program instructions, the processor 3601 executes an algorithm defined by the method steps of FIG. 32. Computer 3600 also includes one or more network interfaces 3604 for communicating with other devices via a network. Computer 3600 also includes one or more input/output devices 3605 that enable user interaction with computer 3600 (e.g., display, keyboard, mouse, speakers, buttons, etc.). Processor 3601 may include both general and special purpose microprocessors, and may be the sole processor or one of multiple processors of computer 3600. Processor 3601 may include one or more central processing units (CPUs), for example. Processor 3601, data storage device 3602, and/or memory 3603 may include, be supplemented by, or incorporated in, one or more application-specific integrated circuits (ASICs) and/or one or more field programmable gate arrays (FPGAs). Data storage device 3602 and memory 3603 each include a tangible non-transitory computer readable storage medium. Data storage device 3602, and memory 3603, may each include high-speed random access memory, such as dynamic random access memory (DRAM), static random access memory (SRAM), double data rate synchronous dynamic random access memory (DDR RAM), or other random access solid state memory devices, and may include non-volatile memory, such as one or more magnetic disk storage devices such as internal hard disks and removable disks, magneto-optical disk storage devices, optical disk storage devices, flash memory devices, semiconductor memory devices, such as erasable programmable read-only memory (EPROM), electrically erasable programmable read-only memory (EEPROM), compact disc read-only memory (CD-ROM), digital versatile disc read-only memory (DVD-ROM) disks, or other non-volatile solid state storage devices. Input/output devices 3605 may include peripherals, such as a printer, scanner, display screen, etc. For example, input/output devices 1905 may include a display device such as a cathode ray tube (CRT) or liquid crystal display (LCD) monitor for displaying information to the user, a keyboard, and a pointing device such as a mouse or a trackball by which the user can provide input to computer 3600. Any or all of the systems and apparatus discussed herein, including video display manager 3100, and components thereof, may be implemented using a computer such as computer 3600. One skilled in the art will recognize that an implementation of an actual computer or computer system may have other structures and may contain other components as well, and that FIG. 36 is a high-level representation of some of the components of such a computer for illustrative purposes. Further embodiments are now described. As is apparent from the foregoing, most systems for 3D stereoscopy are dual-image systems; that is the motion picture has a separate right-eye and left-eye image that are directed to the correct eye. Embodiments of the invention are single-image systems; that is the identical image is directed to both eyes of the viewer. All 3Deeps Filter Spectacles have the important advantage over traditional 3D viewing systems that two viewers sitting next to each other can both view the same movie, one in 3D wearing the 3Deeps Filter Spectacles, and the other in 2D not wearing the 3Deeps Filter Spectacles. Hence, we use the terminology introduced above: “instant image” and “lagging image”. These images are different from “right-eye image” and “left-eye image”, and should not be confused. In the instant invention both eyes see the same identical image, but the difference in retinal reaction time causes the images to be transmitted to the brain at slightly different times. The image that is transmitted to the brain from the eye covered by the clear lens of the Continuous Adjustable 3Deeps Filter Spectacles is termed the instant image. The image that is transmitted to the brain from the eye that is covered by a neutral density filter lens of the Continuous Adjustable 3Deeps Filter Spectacles is termed the lagging image. The viewer's brain sees the instant image and lagging image as a single eye image that displays 3-D depth characteristics when lateral motion is present. More particularly, Continuous Adjustable 3Deeps Filter Spectacles use a dual optimization of the spectacle apparatus to achieve 3D that optimizes the Pulfrich illusion for the viewer. A First Optimization One embodiment of the invention teaches how to use a retinal reaction time curve to calculate an optimal optical density for use in setting the neutral density filter of the Continuous Adjustable 3Deeps Filter Spectacles. More specifically, three teaching methods are presented, including: a. Computing an optical density for the neutral density filter so the difference in retinal reaction time between the instant image and the lagging image is 2½ inches (the average inter-ocular distance between the right and left eyes) and thereby imparting 3-D depth characteristics to the scene. This embodiment requires as input both direction and speed of motion between frames of a motion picture, and luminance. b. Computing an optical density for the neutral density filter so the difference in retinal reaction time between the instant image and the lagging image is a constant value and thereby imparting 3-D depth characteristics to the scene. This embodiment only requires luminance as input. c. Computing an optical density for the neutral density filters so the difference in retinal reaction time between the instant image and the lagging image corresponds to a fixed number of picture frames and thereby imparting 3-D depth characteristics to the scene. This embodiment only requires luminance as input. Such methods are only exemplary and not exhaustive. Other methods of using the retinal reaction time curve to calculate the optical density of the neutral density filter of the Continuous Adjustable 3Deeps Filter Spectacles may be employed. Similar methods using factors other than direction and speed of motion between frames of a motion picture, and luminance of the frame of the motion picture may also be advantageously used. Each method optimizes to a specific feature and characteristic of Continuous Adjustable 3Deeps Filter Spectacles. The invention further encompasses the use of a photo-detector, such as a photodiode, on the spectacles as an alternate means of estimating luminance for Continuous Adjustable 3Deeps Filter Spectacles. A Second Optimization The invention further directs to showing how a controller uses the optimal optical density, and the operating characteristics of the electrochromic material used in the fabrication of the spectacles, to optimize the operation of the Continuous Adjustable 3Deeps Filter Spectacles. More specifically, the invention further directs to showing how the Operating Characteristic curve and the Transition Time curve of the electrochromic material are used to control the neutral density filter lens of the Continuous Adjustable 3Deeps Filter Spectacles. Other Features The invention further directs to showing how video format conversion chips, used for real-time image processing in High Definition LCD, Plasma, and Projection TV's, as well as Digital Cinema Projectors can be utilized in calculation of the optical density of the neutral optical filter lens of the Continuous Adjustable 3Deeps Filter Spectacles. While the calculation of the optical density of the neutral density filter may be done in software, it can advantageously be performed using electronic circuitry. The circuitry can (a) be included within the video format conversion chip, (b) be embedded in a separate chip that couples to a video format conversion chip on an IC board and connects directly to the Continuous Adjustable 3Deeps Filter Spectacles, or (c) be embedded in a separate chip that couple to another IC chip that connects to the spectacles. Also, a general luminance reduction has been used in a dual image systems. No precise continuous luminance control has been disclosed. Furthermore, in such a dual image system embodiment, rather than use the optimal OD value for the Continuous Adjustable 3Deeps Filter Spectacles, the value is used to generate a second frame of a dual image 3D motion picture. We use the terminology neutral filter (or neutral density filter) to mean a darkened, gray or colored transparent filter. In this invention a neutral filter reduces light by the approximately the same amount for all wavelengths over the visual spectrum. For a neutral density filter with optical density d the amount of optical power transmitted through the filter is given by 10−d. For reference, a neutral filter with an optical density of 0.3 allows transmission of about 50% of the light; an optical density of 0.6 allows transmission of about 25% of the light, and an optical density of 0.9 allows transmission of about 12.5% of the light. We also use the term clear to refer to a filter that is much clearer than the neutral filter and seemingly does not block light. However, all filters block the transmission or reduce the passage of light to some extent. For instance, clear glass reduces light by about 1%. By clear then it should be understood we refer to a filter that reduces light less than the neutral density filter. That is all that is required to actuate the Pulfrich illusion. Throughout the disclosure we use interchangeably the terms 3Deeps Filter Spectacles and Pulfrich Filter Spectacles'—both referring to the earlier spectacles of this invention that allow 2D movies to be viewed with the visual effect of 3 dimensions. The term Continuous Adjustable 3Deeps Filter Spectacles refers to the improved 3Deeps Filter Spectacles that use double optimization to solve problems inherent in earlier 3Deeps Filter Spectacles. In the embodiments of the invention the direction of motion is used to determine which of the two viewing lenses is clear and which is darkened to a neutral density. If the motion on the screen is determined to be left-to-right then the left lens of the spectacles is clear and the right lens darkened. If the motion on the screen is determined to be right-to-left then the right lens of the spectacles is clear and the left lens darkened. If there is no motion in the scene then both lenses are set to clear. We may also use the term action directed eye. When the motion on the screen is from left-to-right then the right eye that views the scene through the neutral density filter is the action directed eye. When the motion on the screen is from right-to-left then the left eye that views the scene through the neutral density filter is the action directed eye. Pulfrich 3-Dimensional Illusion Pulfrich was a physicist that recognized that an image that travels through a dark lens or filter takes longer to register with the brain than it does for an image that passes without interruption. The delay is not great—just milliseconds—but enough for a frame of video to arrive and register on the mind one frame later from an eye looking through a dark filter than from an unobstructed eye. Pulfrich spectacles then have one clear lens (or is absent a lens) that does not cause a delay, and one darkened lens that slightly delays the image that arrives to the other eye. In a motion picture viewed through Pulfrich lenses, for an object moving laterally across the screen, one eye sees the current frame and the other eye sees a previous frame. The clear lens may block some light. Even clear glass blocks some light. What is important and necessary for the invention to show passages of a 2D motion picture in 3D is that the clear lens be clearer than the other darkened lens and not diminish as much light as the darkened lens. The invention will produce a 3D effect as long as the clear light diminishing lens diminishes less light than the darkened light diminishing lens. As with normal two-eye parallel viewing, the disparity between the two images is perceived as depth information. The faster a screen-object moves in contrast to its background, the more separation there is between the instant image and the lagging image, and the closer or further the object appears according to the eye being intercepted by the dark filter (closer if on the side to which the object is moving). The fact that faster objects can appear closer than slower objects also coincides with the principles of motion parallax. Generally, however, the greater displacements frame to frame (and now eye to eye) result from degrees of closeness to the recording camera (proximity magnifies), so that Pulfrich viewing can deliver an approximately correct and familiar depth likeness. While the depth likeness is unquestionably 3-D, it may differ from the fixed constant of an individual's inter-ocular distance when observing the world directly. Few observers will notice this anymore than they are bothered by the spatial changes resulting from use of telephoto or wide-angle lens in filming scenes. Motion pictures made for the Pulfrich method can be viewed without any special glasses—appearing as regular motion pictures minus the 3-D effect. Also, motion pictures made without regard for the Pulfrich effect, will still show the 3-D visual effect if lenses are worn and appropriately configured. The limitation of the Pulfrich technique is that the 3-dimensional illusion works only for objects moving horizontally or laterally across the screen. Motion pictures made to take advantage of these glasses contain lots of horizontal tracking shots or lateral picture-subject motion to create the effect. The illusion does not work if the camera doesn't shift location while subject matter remains static, but vertical camera movement will create horizontal movement as the field of view expands or contracts. Pulfrich, who first described this illusion, was blind in one eye, and was never able to view the illusion, though he accurately predicted and described it. The 3-dimensional visual effect is produced by the 3Deeps System regardless of whether the motion picture was shot on regular or digital film; regardless of whether the presentation media is film, digital film, VCR tape, or DVD, and; regardless of whether the motion picture is viewed in the movie theater, home TV, Cable TV, iPod or PDA, or on a computer monitor. A basic example of the Pulfrich illusion can be seen by viewing either of two TV stations. The news headlines on the CNN Television network or the stock market quotations on CNBC scroll in from the right of the TV screen and across and off the screen to the left. The news or quotations appear in a small band across the bottom of the screen while the network show appears above the scrolling information. When either of these network stations is viewed through Pulfrich glasses, with the darkened lens covering the left eye and the clear lens covering the right eye, the scrolling information appears in vivid 3-dimensions appearing to be in front of the TV screen. If the lenses are reversed with the clear lens covering the left eye and the darkened lens covering the right eye, the scrolling information appears to the viewer as receded, and behind the TV screen. Another example of the Pulfrich illusion can be seen in the movie The Terminator, starring Arnold Schwarzenegger. Any off-the-shelf copy of the movie—VCR tape, or DVD—can be viewed on a TV or PC playback display monitor as originally intended by the filmmaker. But, viewing scenes that include lateral motion from The Terminator, such as the scene when Sarah Connors enters a bar to call police (about 29 minutes into the movie) when viewed through Pulfrich glasses (left eye clear lens and right eye dark lens) shows the scene vividly in 3-dimensions, even though this visual effect was totally unanticipated by the director and cinematographer. Another stunning example is the famous railroad yard scene from “Gone with the Wind”, in which Scarlett O'Hara played by Vivien Leigh walks across the screen from the right as the camera slowly pulls back to show the uncountable wounded and dying confederate soldiers. When viewed through Pulfrich glasses (with left eye clear lens and right eye dark lens), the scene appears to the user in 3-dimensions, even thought it was totally unintended by the director and cinematographer. Interesting here is that the main movement of this scene was created by the camera lifting and receding and so expanding the view. Effective lateral motion resulting from such camera movement would in fact be to only one side of the screen, which the viewers will utilize to interpret the entire scene as in depth. The Continuous Adjustable 3Deeps system will allow any movie, such as “Gone with the Wind” which was shot in 1939, to be viewed in part in 3-dimensions. And with the Continuous Adjustable 3Deeps system this new viewing experience does not require any additional effort on the part of the owners, producers, distributors, or projectionists of the motion picture—just that the viewer don the 3Deeps viewing glasses (also called 3Deeps viewing spectacles). Note that the Pulfrich 3-D effect will operate when the left or right filtering does not correspond with the direction of foreground screen movement. The depth-impression created is unnatural, a confusion of sold and open space, of forward and rear elements. When confronted by such anomalous depth scenes, most minds will turn off, and not acknowledge the confusion. For normal appearing 3-D, mismatched image darkening and foreground direction must be avoided. We have described the need to match horizontal direction of foreground screen-movement to Left or Right light-absorbing lens. This, however, is a rule that often has to be judiciously extended and even bent, because all screen-action appropriate to Pulfrich 3-D is not strictly horizontal; horizontal movements that angle up or down, that have a large or even dominant element of the vertical, may still be seen in depth. Even a single moving element in an otherwise static scene can be lifted into relief by way of an adroit application of a corresponding Pulfrich filter. There would even be times when a practiced operator would choose to schedule instances of lens-darkening contrary to the matching-with-foreground-direction rule; the explanation for this lies in the fact that the choice of left or right filter-darkening will pull forward any object or plane of action moving in a matching direction, and there are times when the most interesting action in a picture for seeing in 3D could be at some distance from the foreground, even requiring a Left/Right filter-match at odds with the filter-side that foreground-movement calls for. For instance, if one wished to see marchers in a parade marching Left, to lift them forward of their background would require darkening of the Left lens, but foreground movement could be calling for a Right lens darkening; this would be a situation when a choice might be made to over-ride the foreground-matching rule. In most instances the rule is to be followed, but not mechanically; screen movement is often compound and complex, and an observant individual could arrange a Pulfrich timing for a movie with an alertness to such subtleties that did not limit decisions to recognition of foreground direction alone. As mentioned earlier, there would even be times, when the recording camera had moved either forward or backwards through space, when both Left and Right lenses would half-darken to either side of their centers, outer halves darkening moving forward (with picture elements moving out to both sides from picture-center) or both inner halves darkening when retreating backwards (with picture elements moving in towards center from each side). One of the advantages of optical density Continuous Adjustable 3Deeps Filter Spectacles over the 3Deeps Filter Spectacles previously described is that they obviate the necessity of many of the heuristic rules that would govern the operation of the Continuous Adjustable 3Deeps Filter Spectacles. Heuristic rules were used to address the problems of 3Deeps Spectacles in rapidly transitioning the state of the lenses for the viewer. In previous co-pending 3Deeps applications, we had described the use of such heuristics. For instance, in U.S. Pat. No. 7,405,801 “System and method for Pulfrich Filter Spectacles”, heuristic embodiments for 3Deeps Filter Spectacle were described as follows: [Col 23, Line 45] “Other embodiment may have synchronization algorithms that utilize various heuristic rules in determining a synchronization event. For instance, if the viewer lenses responding to rapidly detected changing lateral motion, switch states too rapidly, this may cause undue discomfort to the viewer. Other embodiments may allow the user to override the synchronization signals placed in the motion picture, and require that any single state remain active for a minimum period of time. This may be important for people that are photosensitive—people who are sensitive to flickering or intermittent light stimulation. Photosensitivity is estimated to affect one in four thousand people, and can be triggered by the flicker from a television set. While photosensitive people may simply remove the Pulfrich Filter Spectacles, heuristic rules could be employed to reduce flicker and eliminate any additional photosensitivity from the Pulfrich Filter Spectacles. For instance, such a heuristic rules may implement logic in the synchronization decision rule that require that no change to a synchronization event can take place for a set number of seconds after the last synchronization event—i.e. a lens state must be active for a minimum length of time before a new state may be implemented.” The use of Continuous Adjusting 3Deeps Filter Spectacles as described herein eliminate the need for such heuristic rules since the lenses are now continually changing to conform to an optimal optical density. The following technologies can be used in the present invention: Substances that Change Color and Transparency Objects that change color have been well known for a long time. Animate creatures such as cephalopods (squid) have long been known for their ability to change color seemingly at will, by expanding or retracting chromatophore cells in their body. There are many different technologies that are used to cause physical materials to change their color and transparency. These may react to heat, light, ultraviolet light, or electronic means to change their state, which in turn affect how they reflect and refract light, or their properties of transparency, or translucency. For instance, photochromatic lenses automatically darken in sunlight and lighten when indoors, and have been utilized in sunglasses for many years. Some may darken instantaneously, and others have lenses that take several different shades depending upon the intensity of the light presented. Thermochromatic materials are heat activated, causing the color to change when the activation temperature is reached, and reverse the color change when the area begins to cool. These are used in such products as inks, and strip thermometers. LEDs (Light Emitting Diodes) are electronic diodes that allow current to flow in one direction and not the other. LEDs have the unique “side effect” of producing light while electricity is flowing through them. Thus they have two states—when electricity flows through them they are on and emit light, or off when no electricity flows through them and they do not emit light. Phosphors are emissive materials that are used especially in display technologies and that, when exposed to radiation, emits light. Any fluorescent color is really a phosphor. Fluorescent colors absorb invisible ultraviolet light and emit visible light at a characteristic color. In a CRT, phosphor coats the inside of the screen. When the electron beam strikes the phosphor, it makes the screen glow. In a black-and-white screen, there is one phosphor that glows white when struck. In a color screen, there are three phosphors arranged as dots or stripes that emit red, green and blue light. In color screens, there are also three electron beams to illuminate the three different colors together. There are thousands of different phosphors that have been formulated, and that are characterized by their emission color and the length of time emission lasts after they are excited. Liquid crystals are composed of molecules that tend to be elongated and shaped like a cigar, although scientists have identified a variety of other, highly exotic shapes as well. Because of their elongated shape, under appropriate conditions the molecules can exhibit orientational order, such that all the axes line up in a particular direction. One feature of liquid crystals is that electric current affects them. A particular sort of nematic liquid crystal, called twisted nematics (TN), is naturally twisted. Applying an electric current to these liquid crystals will untwist them to varying degrees, depending on the current's voltage. These crystals react predictably to electric current in such a way as to control light passage. Still another way to alter the amount of light that passes through a lens is with Polaroid lenses. Polaroids are materials that preferentially transmit light with polarization along one direction that is called the polarization axis of the polaroid. Passing unpolarized light through a polaroid produces transmitted light that is linearly polarized, and reduces the intensity of the light passing through it by about one-half. This reduction in light from a first polaroid does not depend on the filter orientation. Readily available optically active materials are cellophane, clear plastic tableware, and most dextrose sugars (e.g. Karo syrup). Materials that alter the polarization of light transmitted through them are said to be optically active. If two polaroids are placed immediately adjacent to each other at right angles (crossed) no light is transmitted through the pair. If two similar polaroids immediately adjacent to each other are in complete alignment, then the second polaroid does not further reduce the intensity of light passing through the first lens. Additional reduction of light intensity passing through the first polaroid lens will occur if the two similar polaroids immediately adjacent to each other are in other then complete or right angle alignment. This can be beneficially used in other embodiments of the invention to more precisely control the intensity of light passing through the 3Deeps spectacles lenses. Polaroids can be actively controlled by electronic currents, and are used in such products as LCD displays. For example digital watches often use LCD display for the display of time. In such products, there is a light source behind two layers of LCD materials. Electronic current is used to control the polarity of specific areas of the two layers. Any area of the screen for which the two polaroid layers are at right angles to each other will not pass any light—other areas will allow light to pass. In this manner, the alphanumeric information of LCD can be electronically controlled and displayed on an LCD display. Another technology to control the intensity of light passing through the lenses includes directional filters such as the micro-louver. In embodiment of this invention, we utilize electrochromics that change transparency when an electronic current is passed through them. In particular, we use a substance that is darkened (allowing some light to pass through) when current is applied across it, but is clearer and transparent and allows more light to pass unhindered when no current is applied to it. In other embodiments of the invention, other substances and technologies could be used that allow the lenses to change their color, or their properties of transparency or translucency. Algorithms to Detect Movement in Motion Pictures Early motion detectors were entirely analog in nature but completely suitable to monitor situations where no motion is to be expected, such as restricted areas in museums, and stores when they are closed for the evening. Recent advances in digital photography and computers have allowed new means to monitor such situations, and incorporate digital video systems that can passively record images at set time intervals (e.g. 15 frames per second), computer processors to process the image and detect motion, and cause appropriate action to be taken if motion is detected. Many different algorithms have been developed for computer processing of images that can be used to determine the presence of lateral movement in a motion picture, as well as identifying the direction of lateral motion. In the future new algorithms will continue to be developed. Any algorithm that can process sequences of digital images, and detect motion and the direction of motion can be used in the invention. Out of necessity, algorithms to detect movement in a motion picture have had to be developed. The problem is that movies for TV, cine, digital cameras, etc. use many different formats. To show these different formats with the highest quality possible in a home or movie theater venue requires that the problem of format conversion between the input format and the output screen format be deftly handled to optimize the quality of the viewing. Detailed descriptions of the problem and various digital image processing solutions can be found in the magazine articles Electronic Design Strategy News articles by Brian Dipert, “Video improvements obviate big bit streams”, Mar. 15, 2001, pp 83-102 and Electronic Design Strategy News, article by Brian Dipert, “Video quality: a hands-on view, Jun. 7, 2001, pp 83-96”. A simplified example will however help to explain the problem and the approaches take to a solution. Consider an input signal to a TV which is 30 frames per second (analog TV) but that is being output and shown on a high-end digital LCD TV running at 120 frames per second. Showing a TV input signal of 30 fps at an output of 120 fps is an example of a format conversion problem. One simple way to address this problem of format conversion is to simply add 3 exact copies of each frame to the output stream. That works if there is no motion, but if a screen object exhibits any motion between frames then the 3 new frames have the moving object in the wrong place. If this solution is used, then the better and more expensive the digital TV, the worse this problem appears to the viewer. So digital TVs incorporate format conversion image processing, generally implemented as format-conversion chips that perform complex frame-to-frame image processing and track speed and direction of motion and then use that information to better construct the 3 new frames. At least two different approaches are taken to detect and quantify motion between frames of a moving picture. They include edge-based algorithms and region-based algorithms. Any algorithm that quantifies motion between frames of a motion picture can be used with the algorithms of the preferred and alternate embodiments to set the optimal optical density of the neutral density filter of 3Deeps Filter Spectacles. Edge-based algorithms have been used in digital cameras as part of the means to implement functions such as auto-focus. Edge-based algorithms utilize information that can be calculated from the discontinuities between adjoining pixels of the digitized image. For instance, consider a person standing against a light background. The edge pixels of the person can be clearly identified because of the sudden change in pixel value. Edge-based algorithms generally identify such intensity edges in the image, eliminate all other pixels (for instance by changing them from their recorded value to white), and then process the image based solely on the identified intensity edges. The MELZONIC chip from Philips is one example of a region-based algorithm. The Philips MELZONIC chip uses a technique for motion estimation, which they call 3-D Recursive Search Block-Matching. By analyzing two successive TV fields to locate blocks of pixels in the second field that match blocks in the first, 3-D Recursive Search Block-Matching is able to assign a velocity vector to each block of pixels in the first field. These velocity vectors can then be used to interpolate the correct spatial position of each pixel block in a new field that is positioned temporally between the two original fields—i.e. to create new movement phases. The Philips MELZONIC chip, or the methods, systems and apparatus in the previously described US patents of Iue (U.S. Pat. No. 5,717,415), Nagaya (U.S. Pat. No. 5,721,692), or De Haan (U.S. Pat. No. 6,385,245), or in other inventions or algorithms for motion object detection, may be incorporated in embodiments of the 3Deeps System as a means control the optical density of the neutral density filter of the 3Deeps Filter Spectacles. One might think that alternating between the screen-flatness of a dialogue scene and the deep space of an action scene would disrupt the flow of a story. In fact, just as accompanying movie-music can be intermittent while entirely supporting a story development, dialogue is best attended to with the screen flat and action-spectacle is most effective given the dimension and enhanced clarity of depth. Usually a function of lighting specialists, it is always necessary to make objects and spaces on a flat screen appear distinct from each other; besides making a scene more convincing, 3-D separation of forms and of spatial volumes one from the other speeds up the “reading” of what are essentially spatial events. This is to say: flat can best enable concentration on dialogue; depth-dimension can most effectively deliver action scenes. Alternating between 2-D and 3-D awareness is something we even do, to a degree, in our experience of actuality, as a function of our changing concentration of attention; just as we hear things differently when we concentrate on listening. Then, too, making sense of movies is a thing we learn to do, as different from life-experience as a movie is with its sudden close-ups and change of angle and of scene, its flashbacks, et cetera. Movie viewing is a learned language, a form of thinking; the alternating of flat-screen information with depth-information will be as readily adapted to as any other real-world-impossibility accepted without question as natural to the screen. Synchronization and Control The preferred embodiment of the Continuous Adjustable 3Deeps system makes use of signals to synchronize the lens filters of the viewing spectacles to the lateral motion in the motion picture, and thus control the 3-dimensional visual effect for the viewer. The signals are developed in real-time, and does not require any alteration to the motion picture, or that any control information is placed in the motion picture. The information that is calculated is used to determine synchronization events that are used to control the state of darkening individually of the left and right lenses of the Continuous Adjustable 3Deeps system. Motion pictures have benefited from other types of synchronization and control information that is placed within the frames of motion pictures. However, these are characteristically different than the synchronization and control used in this invention. In many motion pictures, to alert the movie theater projectionist that it is time to change reels, movie producers would place visible control information, in the form of a white circle appearing in the upper right upper hand corner of successive frames of the movie. When the projectionist sees this information, they know that it is time to start a second projector that has the next reel of the movie, and thus maintain an uninterrupted motion picture presentation. Another means of communicating control information in motion picture frames is with the clapper slate board that indicates the start of a new scene when filming a motion picture. When filming motion picture or other type of video production, video and audio have been recorded separately. The two separate recordings must be precisely synchronized to insure that the audio recording matches the video image. Synchronization of the video and audio recordings has been accomplished using a clapper slate board. The audible clap created when a technician snaps the slate board in front of the camera is used during editing to manually synchronize the audio recording with the video recording. The editor simply views the video image of the snapping clapper slate, and then manually adjusts the timing of the audio recording such that the image of the clapper snapping shut and the sound of the clapper snapping shut are synchronized. Such synchronization can now be accomplished using electronic clapper slates. Electronic clapper slates display a Society of Motion Picture and Television Engineers (SMPTE) code, usually in large red light emitting diode numerals. The SMPTE code displayed is then used to electronically synchronize the video recording with a separate audio recording. These types of synchronization and control information solve problems related to the synchronization of sound with filmed action during the production and editing of motion pictures, and related to changing reels of film during the presentation of motion pictures. Overview As described above, FIG. 1 is a perspective view of an embodiment of the Continuous Adjustable 3Deeps Filter Spectacles that are the ocular mechanism through which 2D movies may be viewed as 3D. FIG. 37 shows a typical curve of retinal reaction time as a function of luminosity. In FIG. 37 and FIG. 38A-38C, we will explain the working of the Pulfrich illusion that occurs when viewing with one eye through a filtered lens and the other eye unobstructed or through a clear or unfiltered lens. The image seen through the clear lens is termed the instant image and the image seen through the darker lens is termed the lagging image. While previous related co-pending applications have taught this well-known illusion, we re-explain it in terms of a general retinal reaction time curve. Fully understanding the retinal reaction time curve is key to understanding how the instant invention uses this relationship to select optimal values for the optical density of the neutral density filter. As previously described, the terminology instant image and lagging image of the disclosed invention should not be confused with left-eye image and right-eye image of other 3D systems. Dual image systems have separate right-eye and left-eye images that are directed to the appropriate eye. The present invention is a single-image system so that the right-eye and the left-eye always view the identical image. The eye however transmits delayed images to the brain that are termed the instant image and the lagging image and are organized by the brain as the eye image. Thus, the present single-image invention works with any motion picture ever made, while most 3D systems must have specially prepared, produced, processed and displayed dual image motion pictures. Additionally, a viewer cannot watch a dual-image 3D system such as Anaglyph, IMAX or Polaroid, or shutter-glass system with Continuous Adjustable 3Deeps Filter Spectacles. Similarly a viewer cannot watch a regular movie with the special viewing spectacles used with dual-image 3D systems such as Anaglyph, IMAX or Polaroid, or shutter-glass and view the movie 3D. In FIG. 39 we use the retinal reaction time curve to explain the working of cardboard Pulfrich spectacles. Cardboard Pulfrich Spectacles have been used for many years prior to the invention of 3Deeps Filter Spectacles (and are sometimes also called TV spectacles). We explain the shortcomings and problems of the cardboard spectacle approach. The current invention overcomes most of the problems and shortcomings of the cardboard spectacles. In FIG. 40 and FIG. 41 the retinal reaction time curve is used to explain how to calculate an optical density for the controllable neutral density filter that optimizes the Pulfrich illusion. This preferred embodiment requires as input measures the horizontal speed and direction of lateral motion, and a luminance or brightness measure. Since the average inter-ocular distance between a person's eyes is 2.5 inches, this method computes an optical density for the neutral density filter so the lagging image seen through the filtered eye lags the instant image seen through the unfiltered eye by the average inter-ocular distance of 2.5 inches. This method optimizes the depth perception of Continuous Adjusting 3Deeps Filter Spectacles, and overcomes the shortcomings and problems of the cardboard Pulfrich spectacles. FIG. 42 is an illustration of an alternate algorithm to characterize lateral motion in a motion picture. In FIG. 43 we use the retinal reaction time curve to show a first alternate method to calculate an optical density for the controllable neutral density filter. This method only requires that we know the direction of lateral motion and luminance value—but not the speed of motion. This approach sets the optical density of the neutral density lenses at a value so the difference in retinal reaction time is constant even as luminance changes. This method also overcomes shortcomings and problems of the cardboard Pulfrich spectacles. In FIG. 44 we show how this method operates when incorporated with a photo-detector that is included directly into the Continuous Adjusting 3Deeps Filter Spectacles. In FIG. 45 we use the retinal reaction time curve to show a second alternate method to calculate an optical density for the controllable neutral density filter. This method only requires that we know the direction of lateral motion and luminance value—not the speed of motion—and using the retinal reaction time curve, selects values so the instant and lagging images are separated by a pre-specified number of frames of the motion picture. This method also overcomes the shortcomings and problems of the cardboard Pulfrich spectacles. The video industry has for many decades used Video Format Converters (semiconductor chips, and apparatus such as up-converters) to reformat movies for showing in different venues. FIG. 46 teaches how to incorporate methods of this invention with such video formatters. FIG. 46 is a flowchart of how to incorporate the methods of the invention with such a semi-conductor video format converter chips that is able to report out the detected motion vectors. In method of the invention may also be incorporated directly into the video format conversion chip to calculate control information for the Continuous Adjustable 3Deeps Filter Spectacles. FIG. 47 is a block diagram showing operation of a Video and 3Deeps processing used to calculate the optimal optical density of the neutral density filter in the preferred embodiment of the Continuous Adjustable 3Deeps Filter Spectacles. In FIG. 48-53 we focus on the operation of the Continuous Adjustable 3Deeps Filter Spectacles, and specifically the means by which we optimize the operation of the lenses of the spectacles to the characteristics of the material from which the lenses are fabricated. FIG. 48 is a table showing the control information provided to the Continuous Adjustable 3Deeps Filter Spectacles by the Video and 3Deeps Processing, and referring back to FIG. 3, a block diagram of the operation of the Continuous Adjustable 3Deeps Filter Spectacles is provided. For a typical electrochromic material FIG. 49 provides a typical Operating Characteristic curve (input Voltage and output optical density) for electrochromic material and shows how it is used by the 3Deeps Filter Spectacle to set the optical density of the neutral filter lens. FIG. 50 is a typical transition time curve for an electrochromic material with transition time as a function of optical density and for an electric potential that provides the most rapid change from a lower to higher optical density. FIG. 51 is a typical transition time curve for an electrochromic material with transition time as a function of optical density and for an electric potential that provides the most rapid change from a higher to a lower optical density. FIG. 52 is a block diagram showing the operation of the control unit of the Continuous Adjustable 3Deeps Filter Spectacles, and describes how the operating characteristic curve of FIG. 49 and the transition time curves of FIG. 50 and FIG. 51 are used to optimize the operation of the lenses of the Continuous Adjustable 3Deeps Filter Spectacles. FIG. 53 shows the operation of an entire system—a typical Continuous Adjustable 3Deeps Filter Spectacles system—from input of the video frame, through Video and 3Deeps Processing to calculate the optimal optical density, the transmission and reception of the control information, and the operation of the Control Unit of the Continuous Adjustable 3Deeps Filter Spectacles. FIGS. 54-56 shows hardware implementations of algorithms that calculate an optical density for the controllable neutral density filters. FIG. 54 shows an IC implementation selectable for either the algorithm described in FIG. 40 and FIG. 41, or the algorithm described in FIG. 43. The chip may be coupled to a video format conversion chip for input, and for output to the Continuous Adjustable 3Deeps Filter Spectacles, or another chip that outputs to the spectacles. FIG. 55 shows an alternate IC chip embodiment using the algorithm of FIG. 43. In this embodiment only the change in optical density is transmitted to the Control Unit of the Continuous Adjustable 3Deeps Filter Spectacles. While this IC chip may be coupled to a video format conversion chip, FIG. 56 shows how it may be implemented and coupled to the Control Unit of the Continuous Adjustable 3Deeps Filter Spectacles. Calculating the Optical Optimal Density of Continuous Adjustable 3Deeps Filter Spectacles FIG. 37 shows a typical retinal reaction time curve 3700. While each eye is stimulated by light continuously, there is a time delay till the information is triggered and transmitted to the brain. This time delay occurs when we view fix-eyed (as during movie viewing), and is called the “Retinal Reaction Time”. The retinal reaction time is dependent on the amount of light (brightness) that falls on the eye. Luminance is measured in log [candela per square metre (dc/m.sup.2)] as has been presented in FIG. 37 on the abscissa scale 3701. (In studies of perception and psychophysics luminance is often measured in Trolands which is a unit of conventional retinal illuminance, but corrects the measurements of luminance values impinging on the human eye by scaling them by the effective pupil size.) To aid the reader, we have included a second abscissa scale 3702 in FIG. 37 that translates Luminance into commonly understood terms. For instance a luminance reading of 0 approximates the amount of ambient light from a “clear sky” 3713. Other commonly understood values are also presented including a luminance reading of −2 that approximates the amount of ambient light from a “night sky with a full moon” 204. The ordinate scale 3703 of the retinal reaction time curve shows in milliseconds the amount of time till the corresponding amount of light triggers and sends the information to the brain. For instance in a clear sky 3713 having a luminance measure of 0, the eye will trigger about every 200 msec and send the image to the brain. A night sky with a full moon 3704 has a luminance measure of −2 and the eye will trigger about every 325 msec and send the image to the brain. While the retinal reaction mechanisms are independent for each eye, when both eyes are unobstructed the luminance value is the same and they trigger at about the same time. However, if one eye is shaded so the eyes have unequal retinal illuminance, then the two eyes will trigger at different speeds and different times. As explained above, the terminology we use is instant image for the image sent to the brain by an unshaded eye, and lagging image for that image sent to the brain by the shaded eye. Using filters with different optical density shading results in a difference in retinal reaction time. The difference in retinal reaction time between the two eyes is one factor in the commonly accepted explanation for the Pulfrich illusion. The second factor is simultaneity. The brain will take the two eye images and put them together in a ‘simultaneous’ fashion to generate the image that we perceive. Thus in normal viewing, if both eyes see the same image without any filtered obstruction, the brain gets two approximately identical ‘instant images’. These images only differ by the inter-ocular distance between the eyes (about 2½ inches), and the mind puts these two simultaneous images together to perceive depth. However, if one eye is shaded than the mind will perceive one instant image and one lagging image and put those together simultaneously to perceive depth. These two factors, retinal reaction time, and simultaneity are the two factors that explain Pulfrich illusion. If the scene being viewed is static with no moving object, then the instant image of the unshaded eye and the lagging image of the shaded eye will still see the same image and the retinal reaction delay and simultaneity factors will not provide any depth information. Thus, the Pulfrich illusion cannot work in the absence of motion. But if the scene being viewed has horizontal motion (also called lateral motion) then the shaded eye will see an image that is lagging the instant image. In this case the lagging image caused by retinal reaction delay of the shaded eye, when juxtaposed with the instant image perceived by the unshaded eye will, through the mechanism of simultaneity, be reconciled by the brain as a perception of depth. This is the Pulfrich illusion. This will be diagrammatically explained in FIGS. 38A-38C. Note from the typical retinal reaction time curve 3710 the potential of the Pulfrich illusion. Retinal reaction time from the illumination of light from a clear sky at noon ( 1/10th of a second) is approximately half as long as retinal reaction time from a clear sky (⅕th of a second). On a TV with a 100 Hz refresh rate that is 10 frames. The instant invention uses the retinal reaction time curve to select the optical density of the neutral shaded lens to optimize the Pulfrich illusion. The retinal reaction time curve 3710 in FIG. 37 is a typical curve provided for teaching purposes and may be further refined in the future. The effect of luminance on retinal reaction time has been extensively studied as in “Simple Reaction Time As A Function Of Luminance”, Alfred Lit, et al, in Perception & Psychophysics, 1971, Vol 10(6), p 397. The relationship will differ from person-to-person, and also exhibits variability within the same person as they age, or even exhibit intra-day variation due to factors such as eyestrain, etc. The retinal reaction time curve 3710 exhibits a reciprocal relationship with retinal illuminance, and also has a discontinuity at a retinal illumination of about −1 the threshold at which the cone sensors of the eye turn off and only rod sensors (that do not see color) are operational. For the teaching purposes of this disclosure however, the smooth retinal reaction time curve 3710 of FIG. 37 will be used. FIG. 37 shows the general relationship 3710 between reaction time (in milliseconds) as a function of luminance. For either eye, the magnitude of the visual latent period is a reciprocal function of the prevailing level of retinal illumination. The figure shows a slow retinal reaction time at low luminance, with retinal reaction time progressively increasing as luminance levels increase. The relationship shown by this figure is used in various embodiments to calculate the optical density of the neutral filter. In the preferred embodiment, this relationship will be used to approximate normal stereoscopic vision by calculating the optical density of the neutral filter to using an average inter-ocular separation between the eyes (about 2½ inches). FIGS. 38A-38C show in more detail the geometry 3800 of how the Pulfrich illusion works. The geometry of the Pulfrich illusion has been well described as for instance in “The Magnitude Of The Pulfrich Stereo-Phenomenon As A Function Of Target Velocity”, Alfred Lit, Journal of Experimental Psychology, Vol. 59, No 3, 1960. Placing a neutral density filter 3812 over one eye and allowing the other eye to view the motion picture unobstructed actuates the Pulfrich illusion. We again note that with the Pulfrich illusion both eyes view the same single image on a screen 3810. The difference in retinal reaction time allows the eyes to view a single image, but the mind is fooled into thinking it is seeing two different images (the lagged and instant images) when lateral motion is present. Simultaneity allows the mind to put the two images together to get a depth-perceived eye-target image with depth perception. We stress that the Pulfrich illusion will not work if separate right-eye and left-eye images are presented to the viewer, as is the case with other dual image 3D viewing systems. 3Deeps is incompatible with any dual image 3D system. FIG. 38A shows the geometry of a viewer wearing 3Deeps Filter Spectacle 101 in which the left eye 3802 has a shaded filter 3812 and the right eye 3804 is unobstructed. At the top of the figure is a schematic showing the spectacles 101 with the left lens shaded 106 and the right lens clear 105. In this figure there is no lateral motion in the motion picture. The right eye 3804 focuses on an object in the motion picture that we call the instant image 3830 in a 2D plane on the screen 3810. Even though the left eye 3802 views through a shaded filter lens 3812 causing a retinal delay, because there is no motion, the left eye 3802 sees a lagging image 3820 that is coincident with the instant image 3830, and the brain simultaneously interprets them as the eye target 3855 in a 2D plane on the screen. In this case no illusion of depth is provided by the Pulfrich illusion. FIG. 38B shows the geometry of a viewer wearing Continuous Adjustable 3Deeps Filter Spectacle 101 in which the left eye 3802 has a shaded filter 3812, and the right eye 3804 is unobstructed. At the top of the figure is a schematic showing the spectacles 101 with the left lens shaded 106 and the right lens 105 clear. In this figure the direction of lateral motion on the screen is from right-to-left. The right eye 304 focuses on an object in the motion picture that we call the instant image 3830 in a 2D plane on the screen 310. Because the left eye 3802 views through a shaded lens 3812, the retinal delay causes the left eye 3802 to see the image lagging behind the instant image 3830 also called the lagging image 3820. The brain receives the instant image 3830 and the lagging image 3820 and places them together as an eye target 3855 with an illusion of depth in front of the 2D plane of the screen 3810. In FIG. 38B the distance dScreen 3880 measures the distance between the viewer and the screen, and the distance d 3885 measures the perceived distance of the eye target 3855 away from the screen 3810. The distances d 3885 and dScreen 3880 can be used to provide a measure of the degree of the depth illusion. One measure of the 3D depth effect is d/dScreen as a percentage. For example if d 3885 is ½ foot, and dScreen 3880 is 10 feet, then d/dSceeen is 1/20 and the degree of depth perception is 5%. With this configuration, if another object in the movie has a frame-to-frame lateral motion from right-to-left that is faster than the instant image than it will lag the instant image even more and appear to the viewer even closer than the eye image. If another object in the movie has a frame-to-frame lateral motion from right-to-left that is slower than the instant image than it will lag the instant image less and appear to the viewer further away than the eye image. This is in complete agreement with how the mind interprets motion parallax as a cue for depth perception. FIG. 38C shows the geometry of a viewer wearing Continuous Adjustable 3Deeps Filter Spectacle 101 in which the left eye 3802 has a shaded filter 3812, and the right eye 3804 is unobstructed. At the top of the figure is a schematic showing the spectacle with the left lens 106 shaded and the right lens 105 clear. The only difference between FIG. 38C and FIG. 38B is that in this figure the direction of lateral motion on the screen is from left-to-right. The right eye still focuses on an object in the motion picture that we call the instant image 3830 in a 2D plane on the screen 3810 in the same place as in FIG. 38B. Because the left eye 3802 is shaded, the retinal delay causes the left eye 3802 to see the image lagging 3820 behind the instant image 3830. The brain receives the instant image 3830 and the lagging image 3820 and places them together as an eye target 3855 appearing in 3D behind the 2D plane of the screen 3810. The distance dScreen 3880 measures the distance between the viewer and the screen and is shown as the same distance as in FIG. 38B. The distance d 3890 is a negative number since it is behind the screen, and d/dScreen measures the degree of the depth illusion. The geometry for a viewer wearing Continuous Adjustable 3Deeps Filter Spectacles in which the right eye has a shaded filter and the left eye has a clear filter is similar. If in FIG. 38B the filter had been shown filtering the right eye rather than the left eye, then the right eye would see a lagging image so that the eye image would appear behind the 2D plane of the screen. If in FIG. 3C the filter had been shown filtering the right eye rather than the left eye, then the right eye would see a lagging image so that the eye image would appear in front of the 2D plane of the screen. In FIG. 39, curve 3900 uses the typical curve 3710 of retinal reaction time 3703 as a function of luminosity 3701 to explain the working of Cardboard Pulfrich Spectacles 3990 with fixed lenses. The standard cardboard Pulfrich spectacle 3990 comes with a clear lens (usually the left eye) and a neutral density lens of fixed optical density (usually covering the right eye). There is no provision to change the lens. The optical densities of the clear and neutral lens filters 3990 are fixed and the only variable is the retinal luminance. Different luminance will occur for instance depending upon the lighting of the viewing venue. One immediate problem is that because the gray filter lens is fixed in the frames and cannot be changed, all motion must be in a single direction—usually from left-to-right. To address this problem, movies viewed through cardboard Pulfrich filters 3990 have been limited to scenes that have either no motion or motion in only a single direction. This problem can be termed the direction of motion constraint. A second problem is that for a given speed of lateral motion, as the luminosity changes, the amount of depth perception will change. This problem is demonstrated by looking at the retinal reaction curve 3710 in FIG. 39. It shows the difference in retinal reaction time c 3915 and Δ2 3925 between the two eyes for two different values of ambient light (unaided eye). With bright ambient light the cardboard Pulfrich spectacles 3990 indicated on the figure by bracket 3910 produce a difference in retinal delay of Ai 3915. Luminance of the clear lens intersects 3930 the retinal reaction curve 3710 and the luminance through the neutral density filter intersects 3933 the retinal reaction curve 3710 to yield a difference 3915 in retinal reaction time of Δ1. Similarly if the luminance is darker then the difference 3925 in retinal reaction time is a value Δ2. Darker ambient light indicated on the figure by bracket 3920 produces a difference in retinal delay of Δ2 3925 that is significantly greater than Δ1. This is a function of the relationship between luminance 3701 and retinal reaction time 3703. Increasing luminance results in an increase in the visual latency period. Note that with bright ambient light, the difference (Δ1) 3915 in retinal reaction time is smaller than the difference (Δ2) 3925 in retinal reaction time, so the depth illusion is greater in a darker room rather than a lighter room. A related problem is that as speed of lateral motion changes but for a fixed luminosity, the amount of depth perception will also change. This is unnatural and another problem with cardboard Pulfrich spectacles 3990. A scene should maintain the same amount of depth perception independent of the speed of objects in the scene. To address these problems, movies produced for viewing through cardboard Pulfrich filter 3990 may try to maintain a constant luminosity and speed of motion. That is these problems severely constrain the content of the movie. This can be referred to as oscillating visualization of depth. Also, since cardboard Pulfrich Spectacles 3990 only has one neutral density filter it is usually very dark resulting in more loss of light than is necessary to actuate the proper 3D depth illusion. This problem can be referred to as over-darkening. Another problem is that the depth perception will change depending on the lighting of the venue in which the motion picture is shown. In darkened theaters, the perception of depth will be larger than when viewing the movie in a brightly lit home environment, since the difference in retinal delay is greater in a darkened environment than a well-lit environment. This may mean the 3D depth illusion will be attenuated in a dark movie theater and muted in a well-lit home theater. The implication is that the same movie, viewed through cardboard Pulfrich spectacles 3990, will view 3D depth differently depending on the lighting of the venue. This problem can be referred to as a venue-dependency. One way to illustrate the problem with cardboard Pulfrich spectacles 3990 with a fixed neutral density filter is that as luminance changes the degree of depth perception is also constantly changing and will only rarely and per chance be at the level of normal stereoscopic vision. Note that in FIG. 39 the horizontal lines that give the readings on the retinal reaction time scale all have their arrows pointing towards the scale which is due to the fact that with cardboard Pulfrich spectacles 3990 there is no control over the retinal reaction rime for either eye, and no control for the difference in retinal reaction time between the eyes. FIG. 40 and FIG. 41 use the retinal reaction time curve 3710 to show how to calculate an optical density for the controllable neutral density filter that optimizes the Pulfrich illusion. The approach that is described solves the problems with the cardboard Pulfrich spectacles 3990, including the direction of motion constraint, oscillating visualization of depth, over-darkening, and venue-dependency problems. In this embodiment of the invention, the Continuous Adjusting 3Deeps Filter Spectacles are controlled to provide a neutral density filter that has an optical density so that the distance between the lagged image that is seen by the eye obstructed by the neutral filter, and the image seen by the unobstructed image, is 2½ inches. This distance, 2½ inches, is the average distance between a viewer's eyes—also called the inter-ocular distance. That is, the optical density of the neutral filter is chosen dependent on (1) speed of motion on the screen, (2) the luminance reaching the unobstructed eye, and (3) so that the delayed image from the filtered eye appears 2½ inches behind image from the unfiltered eye. Consider the following—normal stereoscopic vision is obtained by viewing a 3-dimensional world from the vantage point of a left and right eye that are about 2½ inches apart (the average inter-ocular distance). Each eye sees the same image but from the slightly different vantage of eyes that are separated by approximately 2½ inches. To get an optimal 3Deeps stereoscopic depth illusion we turn this around. When viewing a motion picture on a TV or in a movie theater each eye is viewing the exact same image in a 2-dimensional plane of the screen. An optimal Pulfrich illusion will occur via the Pulfrich illusion when the difference in retinal reaction time results in instant and lagging images that appear 2½ inches apart. This number, 2½ inches, is also used in other 3D viewing systems. Cameras for recording dual-image 3D systems that are viewed using anaglyph spectacles, shutter-glasses, IMAX, or Polaroid spectacles use cameras with lenses that are lashed together to have a separation of 2½ inches between the lenses that record same scene right-eye and ‘left-eye images. Geometrically, in normal stereoscopic vision the eyes, separated by the inter-ocular distance, triangulate on an object. In the preferred embodiment of the invention each eye sees instant and lagging images separated by the inter-ocular distance and the mind triangulates to get a stereoscopic eye image. In the two cases we have the same triangulation and geometry so the 3Deeps visualization is what the mind expects to see. The calculations for this preferred embodiment are shown in FIG. 40. This provides depth perception that is entirely natural. In FIG. 40, curve 4000 uses the typical curve 3710 of retinal reaction time 3703 as a function of luminosity 3701 to demonstrate how to compute from a motion vector and luminosity the optimal optical density for the neutral density lens of the preferred embodiment of the Continuous Adjustable 3Deeps Filter Spectacles so that the difference in retinal reaction time between the viewer's eyes results in instant and lagging images correspond to a separation on the display monitor of exactly 2½ inches. The figure describes an algorithm fPrefEmb(Luminance, LatScrMotion) that has luminance and a motion vector as input (negative value for right-to-left lateral motion and a positive value for left-to-right lateral motion. The algorithm fPrefEmb(Luminance, LatScrMotion) is described in more detail in FIG. 41. First we measure the ambient luminance or brightness 4010. This is the first input parameter. Luminance represents the amount of light that the unaided eye will see through the clear lens. Using the retinal reaction time curve 3710 we can establish the retinal reaction time delay. In our example we have an input luminance measure 4010 of 0.52 cd/m2, that from the retinal reaction time curve 3710 corresponds 4011 to a retinal reaction time delay 4012 of 120 msec. The second input parameter is the speed of lateral motion. For this example we assume a left-to-right lateral screen motion of 100 dots (pixels) per frame. That is the major object on the screen (for example a speeding car) is traveling across the screen from frame to frame at the speed of 100 dots per frame. We assume the motion picture is being viewed on a quality monitor with a pixel resolution of 100 dots per inch. This computes to taking 2½ frames to move 2½ inches across the screen. If the TV has a refresh rate of 60 Hz (60 frames per second) then it will take 2.5/60= 1/24 or approximately 42 msec for the screen object to traverse 2½ inches on the screen. That is, we want the retinal reaction time difference 4018 between the two eyes to be 42 milliseconds. Adding the 42 msec to 120 msec computes to 162 msec retinal reaction time 4013 to affect a 42 millisecond retinal reaction time difference 518 between the two eyes. Now going back to the intercept 4014 on the retinal reaction curve 3710 we see that we need to choose an optical density for the neutral density lens that will give us a luminance reading 4015 of about −0.6 on the luminance scale. If the direction of the lateral motion is from left-to-right, the right lens will take this optical density and the right lens will be clear. The algorithm fPrefEmb(Luminance, LatScrMotion) provides the computation of the optical density of the neutral density lens fPrefEmb(Luminance, LatScrMotion) and more detail is provided in FIG. 41. This is then the method by which we can compute the optical density of the neutral density lens that is optimal in that the 3D depth perception as viewed through the 3Deeps Filter Spectacles will be exactly the same as for normal human stereoscopic vision. FIG. 41 provides some more detail of the steps of the algorithm 4100 but in tabular form. In Step 1 4110 the direction and speed of motion is calculated. The search for a moving object is limited to an upper bounded region 4111 and a lower bounded region 4112 of the movie. The upper bounded region 4111 is a surrogate for the image background and the lower bounded region 4112 a surrogate for the image foreground. The single most prominent moving object 4115 in the background 4111, and the single most prominent object 4116 in the foreground 4112 surrogate regions are tracked between frames of the motion picture and the horizontal component of the motion is calculated as direction (right- to left or left-to-right) and speed (in units of pixels per inch or dots per inch). A negative horizontal speed motion represents motion from right-to-left, and a positive horizontal speed motion represents motion from left-to-right. A reading of 0 for speed of motion means that there is no discernable foreground of background object in motion. The method presented in Step 1 4110 to find the measure the motion in the frame of the moving picture is only exemplary and is over-simplified to teach the principle. Any algorithm that allows us to quantify the direction and speed of lateral motion in a motion picture frame can be used. The video industry has expended considerable resources on R&D to develop image processing algorithms used for video format conversion to track motion of objects between frames of a motion picture, and Step 1 would derive benefit from use of that body of research. Many of the video format conversion chips used in digital TVs, up-converters, and digital projectors track numerous moving objects from frame-to-frame to perform the best possible format conversion of object in motion. In alternate embodiments it would be beneficial to use a subset pr the entire set of motion vectors to calculate a single speed and direction of motion that characterizes motion in the moving picture. In Step 2 4120, the background horizontal vector LatScrMotionTop 4115 is subtracted from the foreground horizontal vector LatScrMotionBot 4116 to get an overall measure (LatScrMotion) of the instantaneous motion associated with the frame of the motion picture, and the value is stored. In step 3 4130 the Luminance value is calculated and stored. In this teaching example the Luminance is estimated as the average brightness of all Pixels in the frame. Other embodiments may use other means to quantify luminance. In step 4 4140 the two input value, speed of lateral motion (LatScrMotion) and Luminance are used as input value in the algorithm described in FIG. 40 to get the value of the optical density for the neutral density lens—i.e. the value of fPrefEmb(Luminance, LatScrMotion) from FIG. 40. A decision procedure 4150 is then used to get the optical density for each of the 3Deeps spectacle lenses. If the lateral screen motion (LatScrMotion) is zero (dpi) or near-zero (−10 dpi<LatScrMotion<10 dpi) then both lenses will be set to the ClearState optical density value (OD). If the lateral screen motion in a direction from right-to-left then set the left lens to the calculated value fPrefEmb(Luminance, LatScrMotion) 4140 and the right lens to clear. If the lateral screen motion is in a direction from left-to-right then set the right lens to the calculated value fPrefEmb(Luminance, LatScrMotion) 4140 and the left lens to clear. This overcomes the problems with cardboard Pulfrich lenses 3990. Firstly, the 3Deeps Filter Spectacle lenses always take the correct state consonant with the direction of motion on the screen. Secondly, rather than the depth perception fluctuating as with cardboard Pulfrich filter 3990, the optical density of the neutral density lens fluctuates to provide the constant degree of depth perception that the mind expects from its everyday vision of reality. Third, the 3Deeps Filter Spectacle lenses do not over-darken but always take an optical value since they can conform to speed of motion and luminance. And finally, since luminance is accounted for, the motion picture will view the same regardless of whether viewed in a darkened movie theater, or a well-lit home theater environ. Before describing alternate means to select the optical density for a filter to produce the Pulfrich illusion, it is useful to consider further how to determine the parameters that are used to calculate an optimal optical density for the neutral lens of the Pulfrich Filter Spectacles. The two parameters are (a) a motion vector that describes the speed and direction of lateral motion in the motion picture, and (b) luminance or brightness of the motion picture. Motion Measures in a Motion Picture In order to address de-interlacing and up-conversion format problems with motion picture recording, broadcast and display, various algorithms have been developed to determine the direction and speed of motion in a motion picture, and many of these algorithms have been implemented in software and hardware devices. Consider an input signal to a TV which is 30 frames per second (for example as from analog TV) but that is being output and shown on a high-end digital LCD TV running at 120 frames per second. Showing a TV input signal of 30 fps at an output of 120 fps is an example of format conversion that is done by many different format conversion apparatus. One simple way to do this format conversion is for the chip to simply add 3 exact copies of each frame to the output stream. That works if there is no motion, but if a screen object exhibits any motion between frames then the 3 new frames have the moving object in the wrong place. The better and more expensive the digital TV, the worse this problem appears to the viewer. So the better format-conversion chips perform complex frame-to-frame image processing and track speed and direction of motion and then use that information to better construct the 3 new frames. But estimating speed and direction of motion between frames (which these devices already do) is also sufficient information to calculate the timing and optimal optical density for the neutral (shaded) density lens of the 3Deeps (which the devices do not do). This is an oversimplified example of video format conversion, but that is useful for teaching purposes. State-of-the art format-conversion chips may also have functions to do some or all of the following—adaptive motion de-interlacing, edge smoothing, intelligent image scaling, black level extension, digital noise reduction, auto flesh-tone correction, as well as other complex image processing functions. Many companies have already developed the image processing algorithms and implemented them in Integrated Chip circuitry. Philips described their semiconductor MELZONIC chip in the following way: “After exhaustive investigation and computer simulation, researchers at Philips developed a totally new technique for motion estimation which they have called ‘3-D Recursive Search Block-Matching’. By analyzing two successive TV fields to locate blocks of pixels in the second field that match blocks in the first, 3-D Recursive Search Block-Matching is able to assign a velocity vector to each block of pixels in the first field. These velocity vectors can then be used to interpolate the correct spatial position of each pixel block in a new field that is positioned temporally between the two original fields—i.e. to create new movement phases.” In U.S. Pat. No. 5,717,415, Iue describes “Motion Vector Detecting” by analysis of successive frames of a motion picture. The motion vectors are used to develop separate left-eye and right-eye images so that 2D movies may be viewed as 3D movies. There is no disclosure nor suggestion that the motion vectors be used in a single-image system with controllable Pulfrich spectacles. In essence, digital TV and digital cinema rely upon various implementation of video format conversion, and make extensive use of motion adaptive algorithms implemented as hardware and software to detect and quantify motion between frames. They use such information to enhance the quality of the video output signal. All such hardware and software implementation that detect and quantify a motion vector can be used advantageously for Continuous Adjustable 3Deeps Filter Spectacles. Luminance Measures in a Motion Picture By luminance we mean brightness. However since the motion picture is viewed through 3Deeps spectacles, luminance of the screen picture may be calculated in many different ways. We could use the screen luminance of the motion picture, the ambient light of the room, or a measure of light arriving at the eye of the viewer. For standard analog TV signals, every raster point on the TV screen has an attached luminance value as part of the TV signal. Screen luminance may be calculated as an average of all screen luminance values. Other means may be used to calculate a luminance measure of each screen frame for analog TVs. Similarly, different means may be used to calculate an overall luminance measure for digital TVs. While luminance of the picture is one factor in setting the optical density of the neutral lens of the Pulfrich Filter Spectacles, ambient light of the room or theater in which the motion picture is viewed need also be considered. Many TVs already have built in luminance control. The Philips Electronics Ambilight technology used in their flat-panels is an RGB backlight that changes color based on the on-screen image. A filter is used to calculate the average color on the top, left and right border of the screen that is then sent to a micro controller that controls three separate banks of red, green and blue cold-cathodes. Also, some TVs will sense ambient light and can use that information to adjust the brightness of the picture. In a bright room they will show a brighter picture while when they sense a darkened room they can present a more subdued picture. This is done in part to extend the life of the LCD and plasma screens that are used in digital TVs and projectors. Recalling that the primary mechanism by which the Pulfrich illusion works is the difference in retinal reaction time triggered by a neutral lens covering one eye, the retinal illuminance is a more important factor than screen luminance in developing depth perspective via 3Deeps Filter Spectacles. In FIG. 44, described later, we use a photodiode located on the Continuous Adjusting 3Deeps Filter Spectacles as a surrogate measure for retinal luminance. Each of the algorithmic embodiments shown in FIG. 40, FIG. 43, and FIG. 45 could preferably use luminance measures of the display venue or retinal illuminance rather than the luminance of the motion picture in their calculations. If we were using the algorithm of the preferred embodiment, speed and direction of motion would need to be transmitted to the 3Deeps Filter Spectacles that would then use luminance and the motion vector with the algorithm of the preferred embodiment to calculate and set the optical value of the neutral density lens of the 3Deeps Filter Spectacles. FIG. 42 is an illustration of an alternate algorithm 4200 that can be used to characterize lateral motion in a motion picture. It estimates 4 motion vectors—an upper-right (UR) 4232 and upper-left (UL) 4231 motion vectors to estimate background lateral motion, and a lower-right (LR) 4233 and lower-left (LL) 4234 motion vectors to estimate foreground lateral motion. Each vector is estimated from its non-overlapping regions in the frame of the movie. In this sample algorithm the most prominent motion vector in the Upper Right 4222, Upper Left 4221, Lower Right 4224, and Lower Left 4223 regions are identified. Each of these 4 vectors can take any of 3 value; it may be moving either right-to-left (negative lateral speed motion 4242) or moving left-to-right (positive lateral speed motion 4243), or if there is no motion the lateral component of the vector has a value of 0 4245. That is there are 81 (34) possible combinations. Each of the 81 combinations might have separate and distinct computation in this alternate algorithm. One of the 81 possible combinations has the UR 4232, UL 4231, LR 4233 and LL 4234 each having a value of 0. This is what would be expected when there is no motion on the screen as for instance during a close-up on a single character speaking. This case would be result in both lenses of the 3Deeps Filter Spectacles taking the same or clear state (ClearStateOD). Another of the 81 possible combinations would have both the UR 4232 and LR 4233 vector showing right-to-left motion (negative values), and both the UL 4231 and LL 4234 showing left-to-right motion (positive values). This is what would be expected when the camera is receding and expanding a scene and the primary component of motion comes from the action of the camera panning. (This is exactly the scenario in the famous railroad yard scene from “Gone with the Wind”, in which Scarlett O'Hara played by Vivien Leigh walks across the screen from the right as the camera slowly pulls back to show the uncountable wounded and dying confederate soldiers.) In this case the alternate algorithm would calculate the value UL+LL+UR+LR as the LatScrMotion 4120. If this value were negative then the algorithm 4150 would set the right lens to the ClearStateOD and the left lens to a darkened state in accordance with the value fPrefEmb(Luminance, LatScrMotion) 4140. If this value were positive then the algorithm 4150 would set the left lens to the ClearStateOD and the right lens to a darkened state in accordance with this value fPrefEmb(Luminance, LatScrMotion) 4140. Each of the other 79 cases would similarly have appropriate calculations. Each of the 2 algorithms presented for teaching use the notion of selecting the most prominent motion vector in a region. In these algorithms we define that as the longest edge in the search region that is exhibiting motion. Other definitions may be used. For instance, within a scene the algorithm may use this definition to first identify a prominent edge. The identified edge may then persist throughout other frames as long as it continues to appear in subsequent frames, even if that edge is no longer the longest edge in the region. Other algorithm may continue to track this edge through subsequent frames, even were it to move out of the search region. While two algorithms have been used to characterize lateral motion in a motion picture from a set of motion vectors, other algorithms may be advantageously employed. Motion pictures are filmed so that the major action takes place in the center of the screen. Other algorithms to characterize lateral motion in a motion picture from a set of motion vectors may then search for the major vector of motion in the center of the screen and use motion vectors from the top of the screen (a surrogate for background) and motion vectors from the bottom of the screen (a surrogate for foreground) to estimate parallax in the frame of the motion picture. The major vector of motion and estimate of parallax can then be used to determine the optimal optical density of the neutral density filter. In another approach, an algorithm to characterize lateral motion in a motion picture would focus on the regions of the movie that are well lit. Cinematographers compose film, using light to focus attention and highlight the most important action in the scene. This may be useful in delimiting the portion of the frame of the motion picture to which an algorithm to characterize lateral motion in a motion picture frame is restricted. It should be appreciated that from the large number of motion vectors between frames of a motion picture, there are many different algorithms that can be advantageously used to quantify a motion vector that characterizes motion in a frame of a motion picture that is used to determine the optimal optical density of the neutral density filter. A First Alternate Embodiment Motion pictures are often viewed on small, personal devices such as an Apple iPod. Such devices have small screens and are held within arms reach for viewing. For such devices the preferred embodiment that optimizes the Optical Density of the neutral density lens to an average inter-ocular distance may be inappropriate. We provide other alternate embodiments, either of which is appropriate for small viewing devices, as well as for TV or movie theater viewing. FIG. 43 shows the use of the retinal reaction time curve 3710 for a first alternate embodiment algorithm 4300 to calculate the optical density of the neutral density lens. The x-axis 3701 shows luminance, and the y-axis 3703 shows retinal reaction time. Observe that the amount of light produced by a motion picture is constantly changing. Some night scenes in a movie produce low light, and other scenes such on the open seas at noon are much brighter. In this first alternate embodiment, rather choose an optical density for the neutral filter so that there is a separation of 2½ inches between the instant and delayed image to the eye (as in the preferred embodiment), we may choose to fix the difference (Δ) 4320 between retinal reaction time of the eyes. Then as retinal illumination to the unfiltered eye changes, the optical density of the neutral filter is chosen to produce a constant difference in reaction time between the right and left eyes. It will be seen that this has some advantages. In this example, assume as in FIG. 40 that the luminance 4310 is 0.54. As demonstrated in FIG. 40 that relates 4311 to a retinal reaction time 4312 for the unaided eye of 120 msec. For this example choose a fixed difference Δ 4320 between the retinal reaction time of the two eyes of 100 msec, which computes to a retinal reaction time 4313 for the filtered eye of 220 msec (120+100). Then going back to the intercept 4314 on the retinal reaction time curve 3710, we need to pick an optical density for the neutral density filter so the luminance 4315 to the eye is −1.3. Similarly as the measured value of luminance changes, this algorithm can be used with new values of luminance to calculate a changing optical density for the neutral density filter. This algorithm only uses an estimate of retinal luminance as input. One benefit of this algorithm is that it only requires the luminance and direction of motion, but not the speed of lateral motion. Thus it is much less computationally intensive, but will provide Continuous Adjustable 3Deeps spectacles that take states conforming to the direction of motion and conforms to the value of luminance. It also affords a means by which the calculation of optical density for the neutral density filter can be implemented on the Continuous Adjustable 3Deeps Filter Spectacles, since luminance can be sensed by the spectacles. This may lessen the computational requirement for the Phenomenoscope described in U.S. patent application Ser. No. 11/372,723. In FIG. 44, 4400 shows 3Deeps Filter Spectacles 4410 that include a photodiode 4420 on the frame of the Continuous Adjustable 3Deeps Filter Spectacles. A photodiode 4420 is a type of photodetector capable of converting light into either current or voltage, depending upon the mode of operation. The output of the photodiode 4420 provides a measure of the amount of light arriving at the frame of the Continuous Adjustable 3Deeps Filter Spectacles 4410, and is a good surrogate measure of retinal illuminance. This surrogate luminosity measure is input to a Lens Control Unit 103, also on the spectacles, and used with the algorithm described in the first alternate embodiment to calculate the optical density of the neutral density filter. In this example the direction of motion must still be determined and depending upon the direction of motion the Right Len 105 and the Left Lens 106 will take an optical density of either the ClearStateOD or the calculated neutral density optical density. If this value is determined by a control device external to the Continuous Adjustable 3Deeps Filter Spectacles then such information must be communicated to the Continuous Adjustable 3Deeps Filter Spectacles according to one of the various methods as described in co-pending patents and patent applications. If the Continuous Adjustable 3Deeps Filter Spectacles are the Phenomenoscope described in U.S. patent application Ser. No. 11/372,723, then the Continuous Adjustable 3Deeps Filter Spectacles themselves can determine if inter-frame motion is present, and if so in which direction. A Second Alternate Embodiment FIG. 45 uses the typical curve 3710 of retinal reaction time 3703 as a function of Luminance 3701 to demonstrate a second alternate embodiment 4500 for computing an optimal optical densities for the neutral density lens of the Continuous Alternating 3Deeps Filter Spectacles so that the difference (Δ) 4518 in retinal reaction time between the viewer's eyes corresponds to a fixed number of frames of the motion picture. In this second alternate embodiment, rather choose an optical density for the neutral filter so that there is a separation of the average inter-ocular distance (2½ inches) between the instant and delayed image to the eye (as in the preferred embodiment), we may choose to have a difference (Δ) 4518 between retinal reaction time chosen so that the instant and lagging image are a fixed number of movie frames. It will be seen that this has some advantages. In this example, assume as in FIG. 40 that the luminance 4510 is 0.54. This is at a point 4511 on the retinal reaction time curve 3710 of (0.54, 0.120). As demonstrated in FIG. 40 that relates to a retinal reaction time 4512 for the unaided eye of 120 msec. Assuming for this example a screen refresh rate of 60 Hz, a delay of 10 frames can be achieved by having a difference in retinal reaction time 4518 of 166 msec. (That is 10/60=⅙ second=166 msec). From a base of 120 msec that is 120+166=286 msec (4513). Taking that as the ordinate value, the retinal reaction time 3710 curve intercept is at a point 4514 on the retinal reaction curve 3710, and we need to select an optical density of the neutral density lens of −1.7 4515. As the measured value of luminance changes, this algorithm can be used as the only input to calculate optical density for the neutral density filter. The benefit of this algorithm is that it also only requires the luminance and direction of motion, but not the speed of lateral motion. Thus it is much less computationally intensive, will provide Continuous Alternating 3Deeps Filter Spectacles that take states conforming to the direction of motion and conforms to the value of luminance. It also affords a means by which the calculation of optical density for the neutral density filter can be performed by the Continuous Alternating 3Deeps Filter Spectacles. This may greatly lessen the computational requirement for the Phenomenoscope described in U.S. patent application Ser. No. 11/372,723. Video and 3Deeps Processing Various algorithms have been described to determine the optimal density for the neutral density filter of the Continuous Alternating 3Deeps Filter Spectacles. Whether the calculations are performed by embedded dedicated hardware, or by software running on a CPU, the Video and 3Deeps processing of the preferred embodiment will have the following functions; (1) take as video input the frames of a motion picture, (2) perform video format conversions to address de-interlacing and up-converter conversion problems, (3) output the converted video, (4) calculate a motion vector, luminance, and optimal optical density, (5) and output the 3Deeps control information to the Continuous Alternating 3Deeps Filter Spectacles. FIG. 46 teaches how to incorporate methods of this invention with such video formatters. FIG. 47 is a block diagram showing operation of a Video and 3Deeps processing used to calculate the optimal optical density of the neutral density filter in the preferred embodiment of the Continuous Adjustable 3Deeps Filter Spectacles. FIG. 46 is a flowchart 4600 showing the use of a format conversion semiconductor chip 4620 to compute the Continuous Adjustable 3Deeps Filter Spectacles synchronization information. Video Format conversion chips are used to convert a movie from one format such as interlaced 60 Hz to another format such as non-interlaced 120 Hz. Across the top, the flowchart shows the video format conversion chip 4620 in its normal operation. To emphasize that the step is performed by a semiconductor chip, it is shown with a depiction of the pins 4690 of a semiconductor chip. As is typical with format conversion chip, it inputs frames (analog or digital) 4610 of the motion picture, and outputs suitably reformatted digital versions 4630 of the movie. Within the format conversion semiconductor chip 4620 image processing algorithms perform motion vector detection and quantify and extract the motion vector(s) and Luminosity values (4621) and use them to reformat the video (4622) for output. The motion vector(s) (MV) and Luminosity value (L) are output by the format conversion IC and are read and stored 4651 by another processing unit that implements any of the previously described algorithms to calculate the optical density value of the neutral density frame. The output motion vector (MV) and luminosity (L) measures are stored 4652. They are then read by a computing device 4653, which incorporates any of the teaching algorithms herein described, or uses another algorithm to compute the LatScrMotion for each frame and output the value of the optical density of the neutral density filter. A decision rule 4654 will then determine the setting for the right and left lenses of the 3Deeps Filter Spectacles. If the LatScrMotion=0 (4661) then both lenses are set to a clear optical density (4671). If the LatScrMotion<0 (4660) then screen motion is from right-to-left and the left lens will be set to the corresponding darkened optical density and the right lens will have the clear optical density (4670). If the LatScrMotion>0 (4662) then screen motion is from left-to-right and the right lens will be set to the corresponding darkened optical density and the left lens will have the clear optical density (4672). The results are formulated 4680 into Continuous Alternating 3Deeps Filter Spectacle control information, and transmitted 4695 synchronously with the motion picture. The control information is described in FIG. 3. In one embodiment, the control information is transmitted wirelessly, but other embodiments may use wired means. In another embodiment (not shown) the algorithm to compute the 3DeepsFilter Spectacle synchronization information is included entirely within the format conversion semiconductor rather than on a second computer processor. In this case the format conversion chip not only inputs frames (analog or digital) of the motion picture, and outputs suitably reformatted versions of the movie, but also calculates and reports out the 3Deeps Filter Spectacle synchronization information. FIG. 47 is a block diagram 4700 showing more detail of the operation of the Video and 3Deeps processing module 4790 used to calculate the optimal optical density of the neutral density filter in the preferred embodiment of the Continuous Adjustable 3Deeps Filter Spectacles. If the motion picture is analogue then it is input using the Analogue Audio/Video input 4701. The analogue is fed to an Analogue to Digital Converter 4705 module that converts it to digital format frame by frame. A Memory-Control-In module 4710 stores the digital frames in Memory 4715. Each successive frame is stored in a different memory section denoted f1-f4. Other embodiments may have significantly more frame memory. The first frame of the motion picture would be stored in memory section f1, the second frame in f2, the third frame in f3, and the fourth frame stored in memory section f4. The frame memory will then roll over—with frame 5 stored in frame memory f1, frame 6 stored in f2, and so on. While this is happening in real-time other module of the Video and 3Deeps Processing module 4790 will also be accessing the frame memory, and performing the required calculations for each frame. Once the motion vector detection 4725, Luminance 4730, and 3Deeps OD and Synchronization 4735 calculations are performed, the associated motion picture frame stored in frame memory fi 4715 is no longer needed and can be overwritten by rolling over the storage location number in frame memory 4715. The analogue 4701 is also directed unchanged to an analogue audio/video out module 4740. The analogue A/V out 4740 data is precisely the same as the Analogue A/V In 4701, without any format conversion. Other embodiments of the Video and 3Deeps Processing module 4790 may perform format conversion or reformatting of the analogue input signal before output of the analogue signal. Also, the output from the Analogue to Digital Converter is routed to the Digital Audio/Video Out module 4759. Before it is output at the Digital A/V Out 4759, it is processed by the Reformat Video module 4780 using as input the output from the Luminance 4730 and Motion Vector Detection 4725 modules. In this way the motion picture Analogue A/V 4701 is available for output both as the original Analogue A/V out 4740, and also in a reformatted digital A/V out 4759. The Video and 3Deeps Processing module 4790 may also accept the motion picture in a digital format using module Digital A/V In 4702. In this case the Analogue to Digital converter 4705 is not used. The Digital A/V will be routed to the Digital A/V Out 4759 in the same way as previously described. That is before it is output at the Digital A/V Out 4759, it passes through Reformat Video module 4780 using as input the output from the Luminance 4730 and Motion Vector Detection 4725 modules. The Digital A/V 4702 will also be processed by the Memory-Control-In module 4710, and stored in the digital frame memory 4715. The frames will be stored as previously described with successive frames stored in high labeled frame buffers, and rolling over when the highest frame numbered frame buffer has been reached. Consider now the processing of a current frame. The Memory-Control-Out module 4720 will fetch the corresponding current frame from the frame memory 4715 and input it for processing to the Luminance calculation module 4730, and the Motion Vector Detection module 4725. The motion detection module 4725 will also reference the previous frame from frame memory 4715. In this simplified preferred embodiment, for teaching purposes, only two frames of the motion picture are used to estimate a lateral motion vector in the motion picture. In other embodiment many more frames may be used to estimate the lateral motion vector. Algorithms for the calculation of the lateral motion vector have been described in this and co-pending patent applications. Any of those algorithms may be used or other algorithms well known in the art, or that are already in use by format conversion chips. Whichever algorithm is used, it is implemented in the Motion Vector Detection module 4735. The calculation of Luminance is as described previously, and this algorithm is implemented in the Luminance module 4730. Alternate algorithms for the calculation of Luminance may be implemented in other embodiments. The Luminance module 4730, and the motion vector detection module 4725 are also input to the 3Deeps Optical Density and Synchronization module 4735. For the preferred embodiment, and the current frame, the algorithm described in FIG. 40 and FIG. 41 is implemented in the 3Deeps Optical Density and Synchronization module 4725 that take as input the Motion Vector Detection 4725 and Luminance 4730 and calculate the optimal optical density for the motion-directed lens of the Continuous Alternating 3Deeps Viewing spectacles. If no lateral motion is detected then the output for the right lens is set to a digital value representing the clear state, and the output for the left lens is set to a digital value representing the clear state. The control information calculated by the 3Deeps OD and synchronization module 4735 is further described in FIG. 48. If the motion vector is in the left to right direction then the output for the left lens is set to a digital value representing the clear state and the output for the right lens is set to a value representing the optimal optical density calculated by the algorithm in the module of the 3Deeps OD and synchronization module. If the motion vector is in the right to left direction then the output for the left lens is set to a digital value representing the optimal optical density calculated by the algorithm of the 3Deeps OD and synchronization module, and the right lens is set to a digital value representing the clear state. The control information is output and transmitted 4695 to the Continuous Alternating 3Deeps Filter Spectacles. All output values are synchronized for the same frame. That is, when the Video and 3Deeps processing module 4790 outputs a frame of the motion picture on the Digital Audio/Video Out 4759, and the same frame on the Analogue Audio/Video out 4740, it will also output and transmit 4695 the Continuous Alternating 3Deeps Filter Spectacle control information for that same frame. In other embodiments, the Video and 3Deeps processing module 4790 may be embedded wholly or partially embedded in the circuitry of a video format conversion chip. Optimal Control of the Continuous Adjustable 3Deeps Filter Spectacles Optical Density Continuous Adjustable 3Deeps Filter Spectacles are advanced 3Deeps Filter Spectacles. They are characterized by the reception and utilization of control information that continually adjust the 3Deeps Filter Spectacles to the optimal optical density to maximize the Pulfrich illusion for viewing 2D motion video as 3D. But Digital TVs have refresh rates of up to 120 Hz, and many electrochromic materials are unable to change optical density that fast. Even were the materials able to change that fast, it may be desirable to continuously moderate the optical density of the Continuous Adjustable 3Deeps Filter Spectacles so there is a continuity and they do not change state too abruptly. The algorithms implemented in the Control Unit 103 of the Continuous Adjustable 3Deeps Filter Spectacles optimally handle the synchronization of the refresh rate of a movie to the viewing spectacles. Analogous to the way in which format conversion chips takes an input format and converts to an output format appropriate for the viewing monitor, Continuous Adjustable 3Deeps Filter Spectacles take the optimal optical density for the viewing spectacles and ‘render’ them to the viewing spectacles in a manner appropriate to the lens material from which they are fabricated. In one embodiment of the Continuous Adjustable 3Deeps Filter Spectacles, control information for the spectacles lenses is updated in synchronization with each and every frame of the motion picture. The Control Unit (described in FIG. 52) of the Continuous Adjustable 3Deeps Filter Spectacles implements algorithms that utilize this information to optimize 3D viewing, and provides significant advantage over earlier, but less active 3Deeps Filter Spectacles. One important advantage is that different Continuous Adjustable 3Deeps Filter Spectacles made from different electro-optical lenses can each receive the same control information and but still each operate in an optimal manner appropriate to the lens material from which they are fabricated. In typical operation, the Continuous Alternating 3Deeps Filter Spectacles may receive the new control and synchronization states for the lenses even before they have finished transitioning to a previous state. While Continuous Adjustable 3Deeps Filter Spectacles may synchronize with every frame of the movie, as do shutter glasses, they are totally different from the operation of shutter glasses. Shutter-glass is a dual image system that synchronizes to the left and right eye frame images. While the preferred embodiment of Continuous Adjustable 3Deeps Filter Spectacles synchronize to every single frame of the motion picture, they provide a continuously changing optical density with transmission of light controlled for each eye. Shutter-glass systems always have a light-intercepted state—dependent on whether the image is a right eye or left eye image, and in which no transmission of light is allowed through the lens. In contrast, Continuous Adjustable 3Deeps Filter Spectacles require that there always be transmission of light through both lenses, but are continually adjusting the transmissivity of the lenses synchronized to motion in the movie. A movie made for shutter-glasses cannot be viewed with Optical Density Continuing Adjustable 3Deeps Filter Spectacles, and shutter-glasses cannot be used for any movie that can be viewed in 3D using Optical Density Continuing Adjustable 3Deeps Filter Spectacles. FIG. 48 is a table 4800 showing control information for the Continuous Adjustable 3Deeps Filter Spectacles. The control information is organized by frame 4820 of the motion picture—that is control information is transmitted synchronous with the output frames of the motion picture. If the movie is input at 60 Hz but output to the screen monitor after format conversion at 100 Hz, then the Continuous Adjustable 3Deeps Filter Spectacle control information will be synchronized to the output frame rate of 100 Hz. For each frame 4820 the frame number 4801, optical density of the Left Lens 4803, optical density of the right lens 4805, scalar value of the motion vector 4807, direction of the motion vector 4809 (‘−’ for right-to-left lateral motion, ‘+’ for left-to-right lateral motion, or ‘0’ for not motion), and Luminance 4811 are provided. The control information requires very low bandwidth. If the information is transmitted in character format with 9 characters for the frame number 4801, 5 characters each for the left lens OD 4803, right lens OD 4805, Motion Vector 4807, Luminance 4811, and 1 character for the direction 4809, that is a total of 30 characters for each frame. For a fast output format at 120 Hz that is still a low-bandwidth of 3600 characters per second easily handled by inexpensive off-the-shelf digital Transmit/Receive (Tx/Rx) chip pairs. This control information is sufficient for all the different embodiments of Continuous Adjustable 3Deeps Filter Spectacles. In the preferred embodiment the control unit 103 on the Continuous Adjustable 3Deeps Filter Spectacles 100 will receive the control information 4800 but only use the subset of the information that is required. In the preferred embodiment of the Continuous Adjustable 3Deeps Filter Spectacles, the only control information that is required is the Left Len OD 4803 and Right Lens OD 4805. In another embodiment, a photodiode 4420 on the frames of the Continuous Adjustable 3Deeps Filter Spectacles may be used to provide the Luminance calculation to the algorithm of the first alternate embodiment described in FIG. 43 implemented in the Control Unit 103. In this case, the Optical Densities calculated and transmitted by the Video and 3Deeps Processing Module are not used, but must be re-calculated by the Control Unit 103 of the Continuous Adjustable 3Deeps Filter Spectacles. Using the algorithm of the first alternate embodiment running on the Control Unit 103, the direction of motion 4809 for each frame will be input along with the luminance measure from the photodiode 4420 to provide control of the right 105 and left 106 lenses of the Continuous Adjustable 3Deeps Filter Spectacles 101. Similarly, other embodiments may use different subsets of the control information 4800 to control the Continuous Adjustable 3Deeps Filter Spectacles 101. An advantage of Continuous Adjustable 3Deeps Filter Spectacles is that if two viewers are sitting side-by-side, one with spectacles that incorporate in the control unit 103 the algorithm of the preferred embodiment (FIG. 40 and FIG. 41), and the second viewer with spectacles that incorporate in the control unit 103 the algorithm of the first alternate embodiment (FIG. 43), both will view the movie optimally for their respective spectacles. Recall from FIG. 3 that all circuits on the Continuous Adjustable 3Deeps Filter Spectacles 101 are powered by the battery 104, including the Control Unit 103, Signal Receiving Unit 102, the Left Lens 106, and the Right Lens 105. The control information 110 previously described in FIG. 48 is received by the Signal Receiving Unit 102 and to the Control Unit 103. The control unit 103 implements an algorithm that is specific for the lens materials used in the fabrication of the right lens 105 and the left lens 106 of the Continuous Adjustable 3Deeps Filter Spectacles, and controls the left lens 106 with a control circuit 303, and the right lens with a control circuit 305. This approach has great advantages. The control information 110 is spectacle-agnostic; i.e. all spectacles receive the same transmitted control information. The control unit 103 on the spectacles performs a final view-spectacle-specific optimization, translating the control information into control signals specific to the lens material used to fabricate the Continuous Adjustable 3Deeps Filter Spectacles. Two viewers sitting side-by-side and watching the same video on a digital TV but wearing Continuous Adjustable 3Deeps Filter Spectacles that have lens material with totally different characteristics, will each see the movie with an illusion of 3D optimized for their spectacles. Electro-Optical Lenses Some embodiments of the Optical Density Continuing Adjustable 3Deeps Filter Spectacles use electrochromic lenses. Electrochromism is the phenomenon displayed by some chemicals of reversibly changing color when an electric potential is applied. There are many different families of chemicals that exhibit such properties including but not limited to polyaniline, viologens, polyoxotungstates's and tungsten oxide. Within each family, different mixtures of chemicals produce different properties that affect the color, transmissivity, and transition time. For instance Some electrochromics may only affect ultraviolet light—not visible light—appearing as a clear plastic to an observer since they do not affect visible light. Electrochromics have been the object of study for several decades, and have found their chief use in smart windows where they can reliably control the amount of light and heat allowed to pass through windows, and has also been used in the automobile industry to automatically tint rear-view mirrors in various lighting conditions. The operating characteristics of each formulation of an electrochromic material will be different. Some electrochromic materials may take several seconds to change state from one optical density to another—others may be near instantaneous. For many electrochromic materials the color change is persistent and electric potential need only be applied to effect a change. For such persistent electro-optical materials, only an electronic on-off pulse is needed, while non-persistent materials require the application of a continuing electronic potential. Other materials may attain state under the presence of electric potential, but then slowly leak potential and change back. These materials may require a maintenance potential to maintain state but one that is different from that to attain the optical density state. One embodiment of the Continuing Adjustable 3Deeps Filter Spectacles can be fabricated from a persistent electrochromic material. For some electrochromic materials, the transition time moving from a lighter to a darker optical density (FIG. 50) is different from that of the transition time moving from a darker to a lighter optical density (FIG. 51). While electrochromic material can be used in the preferred embodiment of the optical density Continuous Adjustable 3Deeps Filter Spectacles, any electro-optical materials that change optical density in response to an applied potential may be used. This includes but is not limited to LCDs or SPDs (Suspended Particle Devices). SPDs are a different material with almost instantaneous response but need a much higher potential to change state faster opto-electrical material. In selecting the lens material, one should seek materials with shorter transition time. The optical transmission time of the lens material should be taken into account in optimizing the operation of the Continuing Adjustable 3Deeps Filter Spectacles with lenses in electrochromic or electro-optical formulations. In the future, new electro-optical materials will be discovered and may be advantageously used in the practice of this invention. FIG. 49 4900 shows a typical operating characteristic curve 4910 of an electrochromic material with output optical density 4903 (y-axis) as a function of voltage 4901 (x-axis). An optical density of 0.3 corresponds to about 50% transmission of light (4923). An optical density of 0.6 corresponds to about 25% transmission of light (4922). And an optical density of 0.9 corresponds to about 12.5% transmission of light (4921). To get a specific desired optical density, one only need apply the correct voltage across the material. In this example, were the lenses of the 3Deeps Filter Spectacles made from such electrochromic material then if the desired optical density were 50% transmission of light 4923, the 3Deeps Filter Spectacle controller would cause 1 Volt 4934 to be applied across the electrochromic lenses. One volt 4934 intersect 4932 the operating characteristic curve 4910 resulting in an optical density of 0.3 (4903) that corresponds with 50% transmission of light 4923. FIG. 49 is a typical operating characteristic curve. Depending on the chemical formulation of the material the operating characteristic curves may differ. Other embodiments may use more than one layer of material where each material can respond to controlling signals. For instance, one layer may impinge light over a restricted range of visible light and another layer may impinge light over a different range of visible light. The operating characteristic curve of FIG. 49 will provide sufficient control if the electrochromic lenses change state near instantaneously. But, many electrochromic materials do not respond instantaneously to an applied potential and take a finite time to transition to the desired optical density state. Continuous Adjustable 3Deeps Filter Spectacles need also account for the transition time of the material from which the lenses are fabricated. FIG. 50 shows 5000 a typical transition time curve 5003 for an electrochromic material with transition time as a function of optical density when a potential of 2.0V is applied to the electrochromic material. It is for a slow electrochromic material with transition time 5002 as a function of optical density 5001. This hypothetical electrochromic material has a ‘lightest’ state with an optical density of 0.0, or clear, 5004 and its darkest state 5005 is an optical density of 1.5 or dark. The material can take any optical density between 0.0 and 1.5 by the application of 2V for the proper length of time. If the material has an optical density of 0.0 or clear 5004, and 2V potential is applied to the material, it will take 2 seconds for the material to change state and darken to a optical density of 1.5 (dark) 5005. This is shown on the transition time curve 5003. As an example, if the material has an optical density of 0.3, and the control signal 110 received on the frames receiving unit 102 indicates that the subject lens should change to an optical density of 0.6, then the transition time curve 5003 would be implemented by the control unit 103 to apply 2V potential to the lens for 0.4 seconds. An optical density 0.3 1610 intercepts the transition time curve 5003, at a point 5011 on the curve corresponding to 0.4 seconds 5012. An optical density 0.6 5020 intercepts the transition time curve 5003, at a point 5021 on the curve corresponding to 0.8 seconds 5022. The absolute value of the difference abs(0.8−0.4)=0.4 seconds then is the length of time that 2V potential needs to be applied to the lens to change its optical density from 0.3 5010 to 0.6 5020. After that length of time has elapsed no potential is applied since the electrochromic will ‘latch’ in the new state. This is an example of how an algorithm implemented in the Control Unit 103 of the Continuous Adjustable 3Deeps Filter Spectacles would use the transition time curve 5003 to control the right lens 105 and the left lens 106. To transition a lens from and optical density of 0.3 to an optical density of 0.6 the Control Unit would apply 2V potential to the lens for 400 msec. This is a simplified example for illustrative and teaching purposes. Other electrochromic materials may have other operating characteristics that have characteristic exponential, negative exponential, or logistic (s-shaped) relationships. In this example, 2V potential is used to move between states. It is used under the assumptions that (a) for this electrochromic formulation the higher the electronic potential the more rapid will be the change from a lighter to a darker optical density, and (b) change of state from a lighter to a darker optical density is to be optimized. Other materials may require different potentials to be applied to move from between states. In any of these cases, the principle of operation is identical and the Control Unit 103 on the frames of the lenses uses the operating characteristics of the material used in the right 105 and left 106 lenses to determine the potential and the length of time the potential is to be applied to transition between lens control states. In the example above, it took 400 msec (0.4 sec) for the Continuous Adjustable 3Deeps Filter Spectacles to change from an optical density of 0.3 and optical density of 0.6. That is in the length of time it will take to change optical density, 48 frames of video will have been shown. The lenses are operating much slower than a digital TV with a refresh rate of 120 Hz (8.3 msec). This apparent problem is actually an advantage. In this example, at each frame of video (every 8.3 msec), the Continuous Adjustable 3Deeps Filter Spectacles are receiving new control values. These advanced 3Deeps spectacles are then continuously moving to their optimum value, and this has real advantages for 2D/3D viewing. First, note that within a scene, motion will exhibit consistency, and the target optical density will likely will not change very much. Consider a car speeding across through the scene; the luminosity and the speed and direction of motion will stay at about the same value, so the control and synchronization information for the lenses will be about the same. In this example, while it will take 4 tenths of a second for the lenses to reach their target OD, and there will be 48 3Deeps lens control values, corresponding and synchronized to the intervening 48 frame of video, they will likely target about the same lens OD. Once the target is reached, successive lens setting will be similar and thus the lenses will quickly respond and conform to such values—often within the 8.3 msec between successive frames of video. The lenses are then continuously moving towards the optimal value, and that has distinct viewing advantages over lenses that appear to instantaneously and abruptly change OD value at each frame. Also, since the Control Unit of the Continuous Adjustable 3Deeps Filter Spectacles transforms the control signals for the specific lenses, the control signals will not contain any 3Deeps spectacle specific information. Thus, 2 people watching the same Sunday afternoon football game, but each wearing Continuous Adjustable 3Deeps Filter Spectacles (for instance made by different vendors, or different models from the same vendor) that differ only by the operating characteristics of the electrochromic material, will each have optimal viewing from their specific 3Deeps spectacles. In other embodiments the transmitted control and synchronization information may be other than for every frame. This might be the case with a different vendor TV. In this case no changes are necessary to the Continuous Adjustable 3Deeps Filter Spectacles, and they will continue to operate optimally for the combination of received control signals and electrochromic materials. Consider again our 2 hypothetical viewers above. Were they at half-time to move to another viewing venue, with a digital TV that has a refresh rate of 60 Hz and that only transmits 3Deeps Filter Spectacle control information every other frame (30 times a second), they would each still have optimal viewing for their specific 3Deeps spectacles. FIG. 49 shows an alternate means to transition from an optical density of 0.3 to an optical density of 0.6 is to apply a potential of 1.18V. The target optical density 0.6 4942 intersects the operating characteristic curve 4944 of the electrochromic material at a voltage of 1.18V 4946. So applying a voltage of 1.18 Volts will transition the lens from an optical density of 0.3 to an optical density of 0.6. The transition time curve for a voltage of 1.18V is not shown, but would be used similarly to the transition time curve of FIG. 50 (that is for an applied potential of 2.0V) to determine the length of time that 1.18V is to be applied to the lens. In general, any potential greater than 1.18V and less than 2.0V will be applied for the proper transition time will serve to change the state of the lenses. In one embodiment, to transition the lenses from an optical density of 0.3 to 0.6 we use the transition time curve for an applied potential of 2.0V, since we have assumed a lens material with the characteristic that the higher the applied potential the more rapid is the transition time. In the preferred embodiment, we seek to maximize transition time. Other embodiments may maximize other characteristics of the electro-optical material. FIG. 51 shows 5100 a typical transition time curve 5103 for an electrochromic material with transition time as a function of optical density when a negative potential of −2.0V is applied to the electrochromic material (draining the lens material of potential). It is for a ‘slow’ electrochromic material with transition time 5002 as a function of optical density 5001. This hypothetical electrochromic material has a ‘lightest’ state with an optical density of 0.0, or clear, 5004 and its darkest state 5005 is an optical density of 1.5 or dark. The material can take any optical density between 0.0 and 1.5 by the application of −2V for the proper length of time. If the material has an optical density of 2.0 or dark 5006, and −2V potential is applied to the material, it will take 2 seconds for the material to change state and lighten to an optical density of 0 (dark) 5004. This is shown on the transition time curve 5103. As an example, if the material has an optical density of 0.6, and the control signal 110 received on the frames receiving unit 102 indicates that the subject lens should change to an optical density of 0.3, then the transition time curve 5103 would be implemented by the control unit 103 to apply −2V potential to the lens for 1.1 seconds. An optical density 0.6 5120 intercepts the transition time curve 5103, at a point 5121 on the curve corresponding to 1.35 seconds 5122. An optical density 0.3 5110 intercepts the transition time curve 5103, at a point 5111 on the curve corresponding to 0.25 seconds 5112. The absolute value of the difference abs(1.35−0.25)=1.1 seconds then is the length of time that −2V potential needs to be applied to the lens to change its optical density from 0.6 5120 to 0.3 5110. After that length of time has elapsed no potential is applied since the electrochromic will latch in the new state. This is an example of how an algorithm implemented in the Control Unit 103 of the Continuous Adjustable 3Deeps Filter Spectacles would use the transition time curve 5103 to control the right lens 105 and the left lens 106. To transition a lens from and optical density of 0.36 to an optical density of 0.3 the Control unit would apply −2V potential to the lens for 1.1 seconds. In the general case, the relationship between optical density (x-axis) and transition time (y-axis) for any specific formulation of electro-optical material may be represented functionally by a response surface as y=f(x,v). The first derivative df(x,v)/dy provides the transition time rate for any value of voltage V. To get the transition time for the material to change state and move from optical density OD1 to OD2 by the application of a potential v to the material, the control unit 103 would evaluate to the integral: Min(response time)=min∫∫df(x,v)dxdv over the range OD1 to OD2, and for all {v: −2 v<v<+2}. The representation of such response surfaces, and the evaluation of integrals by numerical or analytical methods are well known in the art, and any method may be used. In the preferred embodiment the optimization is done to minimize the response time. However other embodiments may optimize on other characteristics of the material. For instance, the use of the maximum and minimum voltage to change state may have a detrimental effect on the life of the lenses. In such cases, boundary conditions may limit the range of voltage to values that have a lesser impact on lens life. For other materials in which battery life may depend upon the applied transition voltage it may make sense to optimize to get longer battery life. While the preferred embodiment optimizes to minimize response time for the lenses to change state, other embodiments may use the same principles to optimize on other characteristics of the electro-optical material from which the lenses are fabricated. In any embodiments however, a dual approach is used in which first the optimal optical densities are calculated, and then the Control Unit 103 of the Continuous Adjustable 3Deeps Filter Spectacles 101 optimize those values to a characteristic(s) of material from which the lenses are fabricated in order to control the spectacle lenses. FIG. 52 is a block diagram 5200 showing the operation of the Control Unit 103 for the preferred embodiment of the Continuous Adjustable 3Deeps Filter Spectacles 101. The preferred embodiment uses electrochromic lenses that; (a) latch to state once the desired optical density is reached, (b) have an operating characteristic curve as shown in FIG. 49, (c) have a transition time curve as shown in FIG. 50 for an applied potential of 2.0V that provides the lenses with the most rapid change from a lower to a higher optical density, and (d) have a the transition time curve as shown in FIG. 51 for an applied potential of −2.0V that provides the lenses with the most rapid change from a higher to a lower optical density. When the control unit is started 5201 it transitions to a Signal Receiving Unit Module 5203 and inputs the Next Frame Signal 5221. This will have the Control Information 1300 for a single frame n 4820 and will include the frame number 4801, optical density of the Left Lens 4803, optical density of the right lens 4805, scalar value of the motion vector 4807, direction of the motion vector 4809, and Luminance 4811. After the information is received it is passed to the processing for the Left Lens. First the Left Lens Potential is assigned in the Set Left Lens Potential Module 5205. In one embodiment we will use either a +2V potential if the change for the left lens is from a lower to higher optical density, or −2V if the change is from a higher to a lower optical density. The value is stored as the Left Potential 5222. Then in the Calculate Left Lens Duration module 5207, we use the value of the optical density of the Left Lens 4803 from the prior frame (n−1) and the value of the optical density of the Left Lens for the current frame, and the appropriate transmission time curve to calculate and store the value of the Left Duration 5223. If the change for the left lens is from a lower to higher optical density then we use the Transmission Time curve 5000 described in FIG. 50, and if the change for the left lens is from higher to a lower optical density then we use the Transmission Time curve 5100 described in FIG. 51. The Control Unit 103 then transitions to processing for the Right Lens. First the Right Len potential is calculated. The Right Lens Potential is assigned in the Set Right Lens Potential Module 5209. In one embodiment we will use either a +2V potential if the change for the left lens is from a lower to higher optical density, or −2V if the change is from a higher to a lower optical density. The value is stored as the Right Potential 5232. Then in the Calculate Right Lens Duration module 5211, we use the value of the optical density of the Right Lens 4805 from the prior frame (n−1) and the value of the optical density of the Right Lens for the current frame, and the appropriate transmission time curve to calculate and store the value of the Right Duration 5233. If the change for the left lens is from a lower to higher optical density then we use the Transmission Time curve 5000 described in FIG. 50, and if the change for the left lens is from higher to a lower optical density then we use the Transmission Time curve 5100 described in FIG. 51. The Control Unit 103 then transitions to the Right Lens Control 5213 and causes the circuitry to provide the Right Potential 5232 to the right lens 105 for a duration equal to the value of Right Duration 5233. The Control Unit 103 then transitions to the Left Lens Control 5215 and causes the circuitry to provide the Left Potential 5222 to the left lens 106 for a duration equal to the value of Left Duration 5223. The Control Unit then transitions reads the Next Frame Signal 5221 and performs the same processing for frame n+1 that it performed for frame n. FIG. 53 is a block diagram 5300 showing the operation of a typical the Continuous Adjustable 3Deeps Filter Spectacles system. This is the complete system. It follows the operation of the 2D/3D 3Deeps viewing systems through three consecutive frames of video and shows the processing Video and 3Deeps Processing, display of the motion picture in synchronization with transmission of the Control Information for the Continuous Adjustable 3Deeps Filter Spectacles, and reception and control of lenses. The first column is labeled Time′ and shows three consecutive frames of video at time tn 5301, tn+1 5311, and tn+2 5321. As an example, if the video is being shown at 60 Frame per second then the time between each frame (e.g. tn+1−tn) is 16.667 msec. First consider the processing of the frame n 5303 at time tn 5301. The Video Frame 5302 is read 5303 by the Video and 3Deeps Processing module 5320. The Video processing format conversion is output 5304 and displayed as Display Frame 5305. In this teaching example, the Video/3Deeps Processing consists only of de-interlacing so no new frames are created in the Display Video output stream. If the Video/3Deeps Processing module also performed up-conversion (or down-conversion) then the number of output frames would increase (decrease). The Video and 3Deeps Processing module has been previously described in FIG. 46 and FIG. 47. The Video/3Deeps Processing also calculates the Control Information 4800 described in FIG. 48. The control information is transmitted 4695 synchronous with the output display frames 5305. The Continuous Adjustable 3Deeps Filter Spectacles 101 receive the signal 110 and the Control Unit 103 implements the electrochromic specific algorithm to optimally control the Continuous Adjusting 3Deeps Filter Spectacles and generate the signal synchronous with motion picture to set the dark optical density of the right lens 5309 and the left lens to clear. The operation of the Control Unit 103 has been described in FIGS. 3, 49, 50, 51, and 52. Similarly is the processing of the next frame n+1 5312 at time tn+1 5311. The Video Frame 5312 is read 5313 by the Video and 3Deeps Processing module 5320. The Video processing format conversion is output 5314 and displayed as Display Frame 5315. The Video/3Deeps Processing calculates the Control Information 4800 described in FIG. 48. The control information is transmitted 4695 synchronous with the output display frames 5315. The Continuous Adjustable 3Deeps Filter Spectacles 101 receive the signal 110 and generate the signal to set the dark optical density of the right lens 5319 and the left lens to clear. In this example the right lens 5319 associated with frame n+1 is a darker optical density than the right lens 5309 that is associated with frame n. Similarly is the processing of the next frame n+2 5322 at time tn+2 5321. The Video Frame 5322 is read 5323 by the Video and 3Deeps Processing module 5320. The Video processing format conversion is output 5324 and displayed as Display Frame 5325. The Video/3Deeps Processing calculates the Control Information 4800 described in FIG. 48. The control information is transmitted 4695 synchronous with the output display frames 5325. The Continuous Adjustable 3Deeps Filter Spectacles 101 receive the signal 110 and generate the signal to set the dark optical density of the right lens 5329 and the left lens to clear. In this example the right lens 5329 associated with frame n+2 is an even darker optical density than the right lens 5319 that is associated with frame n+1. FIG. 54 5400 is a block diagram 5401 for a preferred embodiment of an IC Chip generating optimum optical density signals for each individual lens of a Continuous Adjustable 3Deeps Filter Spectacle 101. One embodiment of the chip is a self-contained optical density calculator that calculates and outputs the OD density values for the Right 5463 and Left lenses 5464 of Continuous Adjustable 3Deeps Filter Spectacles synchronized 5462 to the A/V 5461 of the motion picture. The chip 5401 performs the calculations selectively based on the optimal OD algorithms described in FIG. 40 and FIG. 41, or selectively based on the optimal OD algorithm described in FIG. 43. The chip has configurable Frame Search parameters (parms) 5404 used to identify and determine the single motion vector (direction 5432 and velocity 5431) that characterizes lateral motion in the frame of the motion picture as described in FIG. 41. Additionally, the preferred embodiment of the chip 5401 is configurable with parameters necessary for the algorithmic calculations 5403 such as the pixel resolution of the viewing screen. Power 5485 is provided to the IC chip 5401. The chip has an input port for the A/V Frame-In 5402 for the current frame of the motion picture coupled to the output port of a frame register. The input frame signal 5402 is passed unchanged through the chip 5401, and output on the A/V Frame-Out 5461 synchronized 5462 with the calculated output values of the Right Lens OD 5463 and the Left Lens OD 5464 of Continuous Adjustable 3Deeps Filter Spectacles 101. The chip has an input port 5407 to receive the Motion Vector Values of the current frame coupled to the output of a motion vector estimation module. As previously related, Video format conversion chips calculate motion vector values to compensate for motion when de-interlacing and up-converting video, and the subject IC chip 5401 will often be coupled to such a format conversion chip. The chip 5401 also has an input port to receive the luminance values 5405 coupled to the output of a luminance determination module possibly as calculated by a video format conversion chip. The Motion Vector values 5407 and Luminance values 5405 are stored in Volatile memory 5412 contained on the chip. Other embodiments of the chip 5401 may use off-chip memory for storage of these values. The preferred embodiment of the chip 5401 has non-volatile memory 5410 to store the Frame Search parameters 5404 of the algorithm implemented in the Lateral Motion Determining Unit 5420. The Frame Search parameters 5404 have been previously described in FIG. 40 and FIG. 41, and are the regions of the current frame of the motion picture that delimits the search for lateral motion vector that characterizes motion in the frame of the motion picture. The parameters include the boundaries of the upper bounded region that is a surrogate for the background in the frame of the movie and the lower bounded region that is a surrogate for the foreground of the frame of movie. The input port for the Frame Search parameters 5404 provides a means to input the Frame Search parameters, and the input includes a binary switch to control whether the chip will input, store and use new values for the Frame Search parameters or use the already stored values. In normal usage it would be unusual for the Frame Search parameters 5404 to be changed within any single presentation. Also stored in the non-volatile memory 5410 are the parameters necessary to compute the Optical Density Calculations. This includes (a) the threshold values for determining whether lateral motion is present or not (e.g. the −10 dpi and 10 dpi values 4150 of FIG. 41), (b) refresh rate of the viewing monitor (e.g. 60 Hz of FIG. 40), and (c) the pixel resolution of the viewing monitor (e.g. 100 dpi of FIG. 40). The input port for the algorithm parameters 5403 provides a means to input the algorithm parameters and includes a binary switch to control whether the chip will input, store and use new values for the algorithm or use the already stored values. In normal usage the algorithm parameters primarily characterize the viewing display (e.g. TV screen) and once set will rarely change. The Algorithm Select 5406 input allows the chip 5401 to configure itself to use either the circuitry that performs the calculation described in FIG. 40 and FIG. 41 5441, or in FIG. 43 5442. The algorithm described in FIG. 40 and FIG. 41 requires as input the direction and velocity of lateral motion in the motion picture and the luminance in the frame of the motion picture, while the algorithm described in FIG. 43 requires as input only the direction and luminance of the frame of the motion picture, but not the velocity. In other embodiment the Algorithm Select 5406 input may be stored in the non-volatile memory 5410 and then only changed as necessary. The operation of the units of circuitry on the chip 5401 using these input values follows. The A/V Frame 5402 is input to the chip so that the Right 5463 and Left OD 5464 values calculated and output with the frame may be synchronized 2062 with the A/V output 5461. No calculations or reformatting is performed on the A/V signal. The Lateral Motion Determining Unit 5420 has circuitry to implement the previously described algorithm to determine the single most prominent moving object in the background region of the frame and the single most prominent object in the foreground region of the frame and then process these identified values to calculate the direction and velocity that characterizes lateral motion in the frame. Input to the Lateral Motion Determining Unit 2020 is the Frame Search Parameters 5404 stored in the non-volatile memory 5410, and the Motion Vector Values 5407 stored in volatile memory 5412. The output is the calculated Velocity (Vel in dpi units) 5431 and the direction of motion 5432 (die negative for right-to-left motion and positive for left-to-right motion). These values may be stored in volatile memory in some embodiments. The Optical Density Calc Unit 5440 implements the Optical Density Calculation to determine the setting of the lenses of the Continuous Adjustable 3Deeps Filter Spectacles 101. In one embodiment both of the algorithms described in FIG. 40 and FIG. 41 5441, and in FIG. 43 5442 are implemented within the unit's circuitry. The Algorithm Select input port 5406 determines which of the calculation circuits is used. If the Algorithm described in FIG. 40 and FIG. 41 5441 is used, then the values of Velocity 5431 (Vel) and Direction 5432 (Dir) of lateral motion are read from the output of the Lateral Motion Determining circuitry 5420. Also, the Luminance (Lum) 5433 value stored in volatile memory 5412 is read, along with the Algorithm parameters 5403 stored in Non Volatile memory 5410. With these input values the Optical Density Calc Unit 5440 circuitry calculates the optimal optical values for the Right lens (OD R) 5451 and Left Len (OD L) 5452 and passes them to the Sync Unit 5450. If the Algorithm described in FIG. 43 5442 is used then the values of Direction 5432 (Dir) of the lateral motion is read from the output of the Lateral Motion Determining circuitry 5420, the Luminance 5433 (Lum) value stored in volatile memory 5412 and the Algorithm parameters 5403 stored in non-volatile memory 5410. With these input values the Optical Density Calc Unit 5440 circuitry calculates the optimal optical values for the Right Lens (OD R) 5451 and the Left Len (OD L) 5452 and passes them to the Sync Unit 5450. The Sync Unit 5450 synchronizes the output of the Video Frame 5461 with the output of the calculated values of the Right Lens OD 5463, and the Left Lens OD 5464. Along with a sync signal 5462, the unit also outputs the frame on the A/V Frame-Out 5461, and the calculated values of the Optical Density for the right lens (Right Lens OD) 5463 and the left lens (Left Lens OD 5464). While the Optical Density Calc Unit 5440 has circuitry to implement the Optical Density algorithms described in accompanying FIG. 40 and FIG. 41 5441, and FIG. 43 5442, other embodiments may include other algorithms to calculate the optical density of the Right 5463 and Left lenses 5464 of the Continuous Adjustable 3Deeps Filter Spectacle 101. Also, while the Lateral Motion Determining Unit 5420 only uses the Algorithm described in FIG. 40 and FIG. 41 to characterize the lateral motion (direction and speed) in a frame of a motion picture, other embodiments may alternatively use algorithms such as that described in FIG. 42 to characterize the lateral motion in a frame of a motion picture. The IC chip 5401 has separate outputs for the optimal Left Len OD 5463 and Right Len OD 5464. Rather than use these values to control Continuous Alternating 3Deeps Filter Spectacles, the values can alternatively be used to determine the frames of a dual image 3D viewing systems as is also described below. One embodiment of the chip has Input 5402 and Output 5461 ports for the A/V frame of the movie and the chip is able to synchronize 5462 the output frame with the output of the calculated value of the Right 5463 and Left Len 5464 optical densities. Other embodiments may use other means to synchronize the Continuous Adjustable 3Deeps Filter Spectacles 101 to the frame of the motion picture without input of the picture frame A/V Frame In 5402. While FIG. 54 shows the Calculation of the Optimum Optical Density Signals for Each Individual Lens Of A Continuous Adjustable 3Deeps Filter Spectacles 101 embodied as a chip coupled with other chips such as video format conversion chips, the circuitry could have been included within the circuitry of such a chip. Also the circuitry of FIG. 54 may connect to other IC chips on an IC board. FIG. 55 5500 is a block diagram 5501 of an alternate embodiment of an IC chip 5501 generating the change in optical density signals 5540 for each individual lens of a Continuous Adjustable 3Deeps Filter Spectacle 101. This alternate embodiment of an IC chip 5501 implements the optical density calculation algorithm of FIG. 43 5531, and has the benefits that (1) it only requires direction and not speed of lateral motion, and (2) it can be implemented directly on the a Continuous Adjustable 3Deeps Filter Spectacle 101 using a photodiode 4420 to provide a measure of luminance. Power 5485 is provided to the IC chip 5501. Since the algorithm of FIG. 43 requires the refresh rate and pixel resolution of the viewing monitor, these values are provided through the circuitry of the Algorithm Parms 5403 and stored in non-volatile memory 5510. Once updated, there is no necessity to refresh the values until there is a change of viewing monitor. A chip on the projection or viewing device such as a video format chip calculates and provides the Direction Values 5505, and the Luminance Values 5405. Note that the speed of lateral motion is not required for the algorithm described in FIG. 43, and is not input. The Direction Value 5505, and the Luminance Values 5405 are read and stored in volatile memory 5520. In this embodiment, rather than calculate and output values for the Left Lens OD and the Right Lens OD, only a single Delta Difference value 5540 is calculated and output. This will allow the alternate embodiment chip to have fewer output legs and thus a smaller package with lessened power requirements. To indicate whether the Delta change is to be applied to the Left lens, or the Right Lens, a Lens Change Indicator 5542 is also output. If the Value of the Lens Change Indicator is 0 then both lenses are set back to a default clear state. If the Value of the Lens change Indicator is 1 then only the Left Lens is affected and it is set from its last state (ODLast) to a new state (ODcurrent) by adding the Delta Lens Change value 5540 (a value of ODcurrent−ODLast) to the last value of the Left Lens (ODLast). If the Value of the Lens change Indicator is 2 then only the Right Lens is affected and it is set from its last state (ODLast) to a new state (ODcurrent) by adding the Delta Lens Change value 5540 (a value of ODcurrent−ODLast) to the last value of the Right Lens (ODLast). The Value of Delta Change Lens OD 5540 and the Lens Change Indicator 5542 are calculated by the Optical Density Calc Unit 5530 that implements the Algorithm of FIG. 43 5531. It reads the algorithm parameters 5403 stored in non-volatile Memory 5510, the Direction Value 5505 stored in volatile memory 5522, and the Luminance Value 5405 stored volatile memory 5521. The Unit 5530 performs the calculations and stores the Calculated OD values in volatile memory as OD Current 5523, keeping track of the last calculated OD values. The Unit 5530 output the Delta Len OD 5540 and the Lens Change Indicator 5542 as previously described. FIG. 56 5600 shows Continuous Adjustable 3Deeps Filter Spectacles 101 that include an IC chip 5501 generating the change in optical density signals for each individual lens of a Continuous Adjustable 3Deeps Filter Spectacle. It shows the same perspective view of Continuous Alternating 3Deeps Filter Spectacles 101 shown in FIG. 44, but with the addition of the IC Chip 5501 of FIG. 55 and a connector 5502 between the IC Chip 5501 and the Control Unit 103. The receiver 102 labeled Rx is coupled to the IC chip 5501. The receiver 102 outputs the Algorithm parameters 5403, and the direction value 5505 to the IC chip 5501 that performs the calculations and outputs the Delta change (A Lens OD) 5540 to the IC chip 5501 (labeled ODIC), along with a Lens Change Indicator 5542 as to whether it is the Right Lens 105 or the Left Lens 106 of the Continuous Alternating 3Deeps Filter Spectacles 101 that is to be change to a new state. The Control Unit 103 and the IC Chip 5501 are connected 5602, that is used to output the calculations from the IC chip 5501 to the Control Unit 103. The IC chip 5501 performs the calculations as described in FIG. 55. The advantage of this embodiment, as previously indicated, is that the Luminous Reading from the Photodiode, can be used for the calculations, and since the photodiode 4420 is on the frame of the spectacles, it will have the best surrogate value for luminance reaching the frames of the spectacles. Other Embodiments Other embodiments may develop other means to optimally set the transmissivity of the neutral density filter lens. For instance for special venues it may be desirable to have lenses that optimize the darker and lighter filters for different light wavelengths. Also, other factors, not part of the retinal reaction curve may be considered to compute an optimal value of the neutral density filter. In the teaching example of the preferred embodiment, luminance is the only factor determining the retinal reaction time. However, research has found other less important factors that affect retinal reaction time including, but not limited to, prolonged readiness, certain common drugs, temperature, and sleep conditions. Knowledge of factors may be advantageously used. Alternately, the Continuous Adjustable 3Deeps Filter Spectacles may have controls allowing customization of values used by the algorithms such as thresholds, parameters of the retinal reaction curve, etc, so that the Continuous Adjustable 3Deeps Filter Spectacles may be customized to individual use. While one above-described embodiment uses a fixed distance of 2½ inches to lag the delayed image, other embodiments may preferably use other fixed distances. Specifically and advantageously some alternate embodiments may also use the distance between the viewer and the viewing device—that is a preferred distance from the screen. Rather than the exact distance, surrogate distances may be employed. For instance for viewing with an IPOD like personal movie device a distance of about 1 foot may be used. When Continuous Adjustable 3Deeps Filter spectacles are used with a personal computer or a personal DVD player, a distance of 1½ feet between the viewer and display screen may be assumed. When viewing on a large-screen digital or projection TV, a distance based on the size of the display monitor may be used. In a movie theater venue the distance may be set to 50 feet. The above-described embodiments are for teaching purposes. Other more sophisticated algorithms may be used to calculate the setting of the filter lens. These algorithms may not only have speed of motion, direction or motion, and luminance as input parameters, but may also allow for input of other values, or for the setting of constants such as inter-ocular distance, in their calculations. Continuous Adjustable 3Deeps Filter Spectacles can benefit from the inclusion of controls that would allow the viewer to customize the specs to individual differences. For instance, while the average inter-ocular distance is 2.5 inches, there is a lot of variation between individuals in this value. Alternate embodiments of Continuous Adjustable 3Deeps Filter Spectacles can beneficially account for individual differences by allowing customized control for this value, either through a physical thumbwheel type setting, or input parameters to the 3Deeps Filter Spectacles controller. For instance, there may be a 3-position manually controlled switch that allows the viewer to change the inter-ocular distance used in the lens calculations to 2¼ inches (small), 2½ inches (average), or 2¾ inches (large). In other embodiments, a computer connects to a master computing appliance to set the Continuous Adjustable 3Deeps Filter Spectacle customization parameters. In another alternate embodiment, it has been shown that the degree of the depth effect of the Pulfrich illusion is due to the difference in retinal reaction time between the two eyes. That means that there are innumerable settings of the Continuous Adjustable 3Deeps Filter Spectacle lenses that will provide the same depth illusion. For instance FIG. 40 shows an optimal setting of the lenses has one lens clear with a retinal reaction time of 120 msec (input luminance of 0.52) and the neutral lens is chosen with an optical density producing a luminance of −0.6 so the difference in retinal reaction time is 42 msec or 162 msec. Another setting with the same depth perception is if the 0.42 msec retinal reaction time difference is from one lens that is darkened so that the eye receive a luminance of 0.0 corresponding to a retinal reaction time of 150 msec and the other eye has a retinal reaction time of 192 msec (150+42=192 msec), that corresponds to a lens with optical density so the eye receives −0.95 on the luminance scale. The first case is optimal in that we have a clear and dark lens and the eyes receive the maximum amount of light for the desired depth effect. In the second case both lenses obstruct light, though the clear lens obstructs less light than the darker lens. In some instances however, this approach may be beneficial, as for example, to better control the response time of the lenses. While some electro-optical materials change state seemingly instantaneously (e.g. LCD materials), other materials may have a slow response time. In these cases the Continuous Adjustable 3Deeps Filter Spectacles may be more responsive by taking lens states that have the desired difference in retinal illumination for the two eyes, but may use a gray clear state that is lighter than the darker lens in order to achieve a threshold responsiveness when the lenses change state. That is, if achieving the clearest state takes too long, it may be preferable to have more responsive Continuous Adjustable 3Deeps Filter Spectacles with a clear lens that obstructs some light, and a dark lens chosen to provide the desired difference in retinal reaction time. In another embodiment, rather than fix the distance d between an object in different frames on the screen, it may be desirable to choose an optical density so the degree of depth illusion remains a constant throughout all frames of the movie that exhibit motion. In another embodiment, the motion vectors of multiple objects are used to provide an estimate of parallax that is then used to select criteria for the optimization of the optical density of the neutral density lens. In other embodiments, the viewer may control the degree of darkening allowed. For instance, rather slow movement from left-to-right may require that the neutral density filter be considerably darkened. For some viewers this may be problematical or undesirable and for such viewers allowing them a degree of control over the darkening of the lenses is reasonable. One such control would allow the user to specify an upper limit on the degree of darkening allowed, with exemplary options allowing 5 settings corresponding to a maximum darkening of 50%, 60%, 70%, 80% and 90%. Any of the algorithmic embodiments may also include the judicious use of heuristics to achieve a best 3D presentation for the viewer. For instance, in a darkened theater and with a dark scene exhibiting motion, the optimal setting for the neutral density lens may take a value that is deemed either too dark for the best 3D presentation for the viewer. Or, the optimal setting for the neutral density lens may take a value that is deemed to take too long to transition to such a dark state for the best 3D presentation. In either of these cases threshold values may be incorporated to override the optimal settings so that the neutral density filter cannot take values outside a specific range. These are exemplary and other heuristics may be incorporated for beneficial purposes. Heuristics may also be required to address other issues. For instance, it has been observed that the Pulfrich illusion will turn off when lateral motion is too fast. This phenomenon is not entirely understood, but to address it a heuristic rule may be used in any of the algorithms that determine the optical density of the neutral density filter so that when the lateral motion is too fast the Continuous Adjustable 3Deeps Filter Spectacles take their clear-clear state. This is exemplary and other heuristics may be incorporated for beneficial purposes. We note that cinematographers have long recognized that action that is too fast does not record well, and so movies generally will not exhibit this problem. Some embodiments provide an example for when such heuristics may be used. The goal of such embodiments is to provide constant depth perception that is normal in the sense that it is in accordance with an individual's normal inter-ocular distance. As previously described this is achieved by optimally controlling the optical density of the neutral density filter. However, if the viewer is in a darkened venue, viewing a darkened movie and/or lateral screen motion is too slow, it may not be possible to maintain this constant depth perception and heuristic rules may be used to slowly degrade the degree of depth perceived. As noted before, few observers will notice this anymore than they are bothered by the spatial changes resulting from use of telephoto or wide-angle lens in filming scenes. In still another embodiment, the algorithm to calculate the optical density to optimize the single image 3Deeps Filter Spectacles may be advantageously used in a dual image system. Dual image systems require two images (or frames) for each frame of a traditional movie. One of the two images is a left eye image and the other is a right eye image. Dual image systems have twice as many frames of video as in a single image system, require special format, projectors, and except in the case of lenticular viewing screens, special viewing devices. Using the preferred embodiment of this invention, based on luminosity and direction and speed of motion, we have described how to determine the optimal optical density of a neutral density filter. Rather than use this calculation to control and synchronize Continuous Adjustable 3Deeps Filter Spectacles, we can use the value to generate a second frame of video for a dual image systems. For clarity the result of the calculation is referred to as OD-optimal and has a value that provides the optimal optical density of the neutral density filter of the Continuous Adjustable 3Deeps Filter Spectacles. In this dual image system embodiment, rather than use the OD-optimal value for the Continuous Adjustable 3Deeps Filter Spectacles, the result is used to generate a second frame of a dual image 3D motion picture. If the result of the algorithm is that there is no lateral movement in the single frame of the motion picture, then the frame image is duplicated resulting in two frame images, and the frame images is then used as both the right eye image and the left eye image. If the result of the algorithm is that the direction of lateral motion is left to right, then the second frame will be duplicated but with the added shading of OD-optimal. The duplicated shaded image will be used as the right eye image, and the unchanged frame used as the left eye image. If the result of the algorithm is that the direction of lateral motion is right to left, then the second frame will be duplicated but with the added shading of OD-optimal. The duplicated shaded image will be used as the left eye image, and the unchanged frame used as the right eye image. Since this alternate embodiment is for a dual image system, the right eye image and the left eye image must be directed to the appropriate eye, and this can be done using any of the dual image viewing systems including shutter glasses, head mounted displays, Polaroid or lenticular screens. Since this embodiment is for a dual image system it cannot be used if the viewer is wearing Continuous Adjustable 3Deeps Filter spectacles. Some 3D viewing systems have darkened lenses and so the calculation of OD-optimal will be slightly different for such systems. While lenticular and head mounted displays will work as previously described, shutter glass and polaroid 3D viewing systems have darkened lenses, and this additional reduction in luminosity must be accounted for in the input to the algorithm. In still another embodiment, 3D Viewing spectacles are manufactured that may be switched between electronic (1) single image Continuous Alternating 3Deeps Viewing Spectacles, and (2) dual image viewing spectacles. As an example consider an anaglyph dual image system, and two electrochromic materials, one that is either clear or darkens to red, and another that is either clear or darkens to blue. Such materials can be used to build electronically operated anaglyph spectacles. If the Continuous Alternating 3Deeps Viewing Spectacles are manufactured with a second layer of such color changing electrochromic materials then the spectacles may be switched to operate as either Continuous Alternating 3Deeps Viewing Spectacles or anaglyph 3D viewing spectacles. In yet another embodiment, a connector for earphones is included on the Continuous Alternating 3Deeps Viewing Spectacles allowing an audio signal to be played through earphones. Embodiments of the invention may implement the Video and 3Deeps Processing directly on a video format conversion semiconductor chip. Alternatively the output from such a video format conversion semiconductor may be used as input to a semiconductor chip dedicated to the Video and 3Deeps Processing. Also the dual image alternate embodiment can similarly use the video image processing of a video conversion chip described in such embodiments to generate the value OD-optimal to generate the second image for this dual image embodiment, and assign the image to the correct eye. In accordance with another embodiment, a method of displaying one or more frames of a video is provided. Data representing an image frame is obtained. A plurality of bridge frames that are visually dissimilar to the image frame are generated. The image frame and the plurality of bridge frames are blended, generating a plurality of blended frames, and the plurality of blended frames are displayed. In one embodiment, the plurality of bridge frames are also different from each other. FIG. 57 shows a video display manager that may be used to implement certain embodiments in accordance with an embodiment. Video display manager 5700 comprises a processor 5710, a bridge frame generator 5730, a frame display module 5750, and a storage 5740. FIG. 58 is a flowchart of a method of displaying one or more image frames in accordance with an embodiment. In an illustrative embodiment, a video file 47000 is stored in storage 5740. Video file 47000 may be generated by video display manager 5700 or, alternatively, received from another device or via a network such as the Internet. At step 5810, data comprising an image frame is received. In the illustrative embodiment, processor 5710 retrieves video file 47000 from storage 5740. FIG. 33 shows an image frame 3350 showing a man against a background of clouds and sky. At step 5820, a plurality of bridge frames that are visually dissimilar to the image frame are generated. Bridge frame generator 5730 generates two or more bridge frames that are dissimilar from image frame 3350. In one embodiment, the two bridge frames are also different from each other. FIGS. 34A and 34B show two bridge frames 3410 and 3420 that may be generated. In the illustrative embodiment, bridge frame 3410 has a first pattern and a bridge frame 3420 has a second pattern that is different from and complementary to the first pattern of bridge frame 3410. In other embodiments, bridge frames may be retrieved from a storage. At step 5830, the image frame and the plurality of bridge frames are blended, generating a plurality of blended frames. In the illustrative embodiment, frame display module 5750 blends image frame 3350 and bridge frame 3410 to generate blended frame 3510, shown in FIG. 35A. Frame display module 5750 also blends image frame 3350 and bridge frame 3420 to generate blended frame 3520, shown in FIG. 35B. At step 5840, the plurality of blended frames are displayed. Frame display module 5750 now displays blended frames 3510 and 3520 in a manner similar to that described above. For example, blended frames 3510 and 3520 may be displayed in accordance with a predetermined pattern, for example. In an embodiment illustrated in FIG. 35C, blended frames 3510, 3520 are displayed consecutively in a predetermined pattern. In other embodiments, blended frames 3510 may be displayed in a pattern that includes a plurality of blended frames and image frame 3350, or in a pattern that includes other bridge frames. In accordance with another embodiment, a plurality of blended frames may be displayed in accordance with a predetermined pattern that includes a first pattern comprising the plurality of blended frames, and a second pattern that includes repetition of the first pattern. In an embodiment illustrated in FIG. 35D, blended frames 3510 and 3520 are displayed in a repeating pattern that includes blended frame 3510, blended frame 3520, and a bridge frame 3590. Systems and methods described herein may be used advantageously to provide particular benefits. For example, in accordance with one embodiment, a method for generating modified video is provided. FIGS. 59A-59B comprise a flowchart of a method in accordance with an embodiment. At step 5910, a source video comprising a sequence of 2D image frames is acquired. At step 5920, a value for an inter-ocular distance of a viewer is determined. At step 5930, an image frame is obtained from the source video that includes two or more motion vectors that describe motion in the image frame where each of the motion vectors is associated with a region of the image frame. At step 5940, a single parameter is calculated for each of the following: a lateral speed of the image frame, using the two or more motion vectors, and a direction of motion of the image frame, using the two or more motion vectors. At step 5950, a deformation value is generated by applying an algorithm that uses the inter-ocular distance and both of the parameters. At step 5960, the deformation value is applied to the image frame to identify a modified image frame. At step 5970, the modified image frame is blended with a first bridge frame that is different from the modified image frame to generate a first blended frame. At step 5980, the modified image frame is blended with a second bridge frame that is different from the modified image frame and different from the first bridge frame to generate a second blended frame. At step 5990, the first blended frame and the second blended frame are displayed to the viewer. The direction of motion and velocity of motion parameters in the calculation step are calculated only from the motion vectors input along with the image frame. In one embodiment, the viewer views the modified video through spectacles. In another embodiment, the spectacles have a left and right lens, and each of the left and right lens has a darkened state. In another embodiment, each of the left and right lenses has a darkened state and a light state, the state of the left lens being independent of the state of the right lens. In another embodiment, the spectacles further comprise a battery, a control unit and a signal receiving unit. The control unit is adapted to control the state of the each of the lenses independently. In another embodiment, the left and right lenses comprise one or more electro-optical materials. In accordance with another embodiment, a method for generating modified video is provided. A source video comprising a sequence of 2D image frames is acquired. A value for an inter-ocular distance of a viewer and factors for a display resolution and a video frame speed are determined. An image frame is obtained from the source video that includes two or more motion vectors that describe motion in the image frame where each of the motion vectors is associated with a region of the image frame. A single parameter is calculated for each of the following: a lateral speed of the image frame, using the two or more motion vectors, and a direction of motion of the image frame, using the two or more motion vectors. A deformation value is generated by applying an algorithm that uses the inter-ocular distance, both of the factors, and both of the parameters, and the deformation value is applied to the image frame to identify a first modified image frame, the first modified image frame being different from any of the sequence of 2D image frames. A second modified image frame is identified based on the first modified image frame, and the second modified image frame is displayed to the viewer. The direction of motion and velocity of motion parameters in the calculation step are calculated only from the motion vectors input along with the image frame. In accordance with another embodiment, a system comprises at least one processor for generating modified video, the processor adapted to acquire a source video comprising a sequence of 2D image frames, determine a value for an inter-ocular distance of a viewer, obtain an image frame from the source video that includes two or more motion vectors that describe motion in the image frame where each of the motion vectors is associated with a region of the image frame, and calculate a single parameter for each of the following: a lateral speed of the image frame, using the two or more motion vectors, and a direction of motion of the image frame, using the two or more motion vectors. The at least one processor is further adapted to generate a deformation value by applying an algorithm that uses the inter-ocular distance and both of the parameters, apply the deformation value to the image frame to identify a modified image frame, blend the modified image frame with a first bridge frame that is different from the modified image frame to generate a first blended frame, blend the modified image frame with a second bridge frame that is different from the modified image frame and different from the first bridge frame to generate a second blended frame, and display the first blended frame and the second blended frame to a viewer. The direction of motion and velocity of motion parameters in the calculation step are calculated only from the motion vectors input along with the image frame. The system also includes spectacles for viewing the modified video, the spectacles comprising a left and right lens, each of the lenses having a dark state and a light state, and a control unit adapted to control the state of the each of the lenses independently. In accordance with another embodiment, a method of displaying video content to a viewer, comprises: obtaining source video content comprised of 2D frames of video; transmitting the source video to a receiver; analyzing the 2D frames of the source video content to measure parameters for direction of motion, velocity of motion and luminance; calculating a deformation value using an algorithm that uses at least two of the measured parameters in combination with values for display resolution and video frame speed; processing the source video content using the deformation value; and displaying the processed video content to a viewer. The method may include, wherein the direction of motion and velocity of motion parameters in the analysis step are calculated only from motion vectors in the source video content. The method may include, wherein the luminance parameter in the analysis step is calculated only from luminance values in the source video content. The method may include, wherein the processed video content in the displaying step is presented to a viewer through spectacles. In accordance with another embodiment, a system for displaying modified video content to a viewer, comprises: a receiver which receives a 2D video signal comprised of 2D frames; a video signal processor which processes the 2D video signal; and a display unit which displays the processed video signal to a user; wherein the processing step comprises using an algorithm to calculate parameters for direction of motion, velocity of motion and luminance for the 2D frames in said 2D video signal; calculating a deformation value using at least two of said calculated parameters in combination with values for display resolution and video frame speed; and modifying the 2D video signal using the deformation value. In accordance with another embodiment, a method of displaying video content to a viewer, comprises: obtaining a source video signal comprised of 2D frames; analyzing 2D frames from said source video signal to measure direction of motion, velocity of motion and luminance parameters; calculating a deformation value using an algorithm that includes at least two of said measured parameters in combination with values for display resolution and video frame speed; processing the video source signal using the deformation value; and displaying the processed video signal to a viewer. A method according to item 6, wherein the direction of motion and velocity of motion parameters in the analysis step are calculated only from motion vectors in the source video content. The method may include, wherein the luminance parameter in the analysis step is calculated only from luminance values in the source video content. The method may include, wherein in the processed video content in the displaying step is presented to a viewer through spectacles. In accordance with another embodiment, a display apparatus comprises: a receiver which receives a source video signal comprised of 2D frames; a video signal processor which processes the source video signal; and a display unit which displays the processed video signal to a user; wherein said processing step comprises analyzing 2D frames from the video signal to measure direction of motion, velocity of motion and luminance parameters; and calculating a deformation value using an algorithm that includes at least two of the measured parameters in combination with values for display resolution and video frame speed. In accordance with another embodiment, a method for generating modified video, comprises: acquiring a source video comprised of a sequence of 2D frames; calculating parameters for direction of motion, velocity of motion and luminance of the source video; determining factors for display resolution and video frame speed; generating a deformation value by applying an algorithm that uses at least two of the parameters and both of the factors; applying the deformation value to the source video to produce a modified video; and displaying the modified video to a viewer. The method may include, wherein the direction of motion and velocity of motion parameters in the calculation step are calculated only from motion vectors in said source video. The method may include, wherein the luminance parameter in the calculation step is calculated only from luminance values in the source video. The method may include, wherein in the modified video in the displaying step is presented to a viewer through spectacles. In accordance with another embodiment, an apparatus which transforms a 2D source video signal, comprises: a video processing means for performing the transformation on the 2D source video signal; and a display means for displaying the transformed video to a viewer; wherein the transformation comprises analyzing the source video signal to generate parameters for direction of motion, velocity of motion and luminance; calculating a deformation value using an algorithm that includes at least two of the parameters in combination with factors for both display resolution and video frame speed; modifying the source video signal using the deformation value; and outputting the transformed video to the display means. In accordance with another embodiment, a method for generating modified video is provided. A source video comprising a sequence of 2D image frames is acquired, a value for an inter-ocular distance of a viewer is determined, and an image frame is obtained from the source video that includes two or more motion vectors that describe motion in the image frame where each of the motion vectors is associated with a region of the image frame. A single parameter is calculated for each of the following: a lateral speed of the image frame, using the two or more motion vectors, and a direction of motion of the image frame, using the two or more motion vectors. A deformation value is generated by applying an algorithm that uses the inter-ocular distance and both of the parameters, and the deformation value is applied to the image frame to identify a modified image frame. The modified image frame is blended with a first bridge frame that is different from the modified image frame to generate a first blended frame, and the modified image frame is blended with a second bridge frame that is different from the modified image frame and different from the first bridge frame to generate a second blended frame. The first blended frame and the second blended frame are displayed to a viewer. The direction of motion and velocity of motion parameters in the calculation step are calculated only from the motion vectors input along with the image frame. In various embodiments, the method steps described herein, including the method steps described in FIG. 58, may be performed in an order different from the particular order described or shown. In other embodiments, other steps may be provided, or steps may be eliminated, from the described methods. Systems, apparatus, and methods described herein may be implemented using digital circuitry, or using one or more computers using well-known computer processors, memory units, storage devices, computer software, and other components. Typically, a computer includes a processor for executing instructions and one or more memories for storing instructions and data. A computer may also include, or be coupled to, one or more mass storage devices, such as one or more magnetic disks, internal hard disks and removable disks, magneto-optical disks, optical disks, etc. Systems, apparatus, and methods described herein may be implemented using computers operating in a client-server relationship. Typically, in such a system, the client computers are located remotely from the server computer and interact via a network. The client-server relationship may be defined and controlled by computer programs running on the respective client and server computers. Systems, apparatus, and methods described herein may be used within a network-based cloud computing system. In such a network-based cloud computing system, a server or another processor that is connected to a network communicates with one or more client computers via a network. A client computer may communicate with the server via a network browser application residing and operating on the client computer, for example. A client computer may store data on the server and access the data via the network. A client computer may transmit requests for data, or requests for online services, to the server via the network. The server may perform requested services and provide data to the client computer(s). The server may also transmit data adapted to cause a client computer to perform a specified function, e.g., to perform a calculation, to display specified data on a screen, etc. Systems, apparatus, and methods described herein may be implemented using a computer program product tangibly embodied in an information carrier, e.g., in a non-transitory machine-readable storage device, for execution by a programmable processor; and the method steps described herein, including one or more of the steps of FIG. 58, may be implemented using one or more computer programs that are executable by such a processor. A computer program is a set of computer program instructions that can be used, directly or indirectly, in a computer to perform a certain activity or bring about a certain result. A computer program can be written in any form of programming language, including compiled or interpreted languages, and it can be deployed in any form, including as a stand-alone program or as a module, component, subroutine, or other unit suitable for use in a computing environment. A high-level block diagram of an exemplary computer that may be used to implement systems, apparatus and methods described herein is illustrated in FIG. 36. Computer 3600 includes a processor 3601 operatively coupled to a data storage device 3602 and a memory 3603. Processor 3601 controls the overall operation of computer 3600 by executing computer program instructions that define such operations. The computer program instructions may be stored in data storage device 3602, or other computer readable medium, and loaded into memory 3603 when execution of the computer program instructions is desired. Thus, the method steps of FIG. 58 can be defined by the computer program instructions stored in memory 3603 and/or data storage device 3602 and controlled by the processor 3601 executing the computer program instructions. For example, the computer program instructions can be implemented as computer executable code programmed by one skilled in the art to perform an algorithm defined by the method steps of FIG. 58. Accordingly, by executing the computer program instructions, the processor 3601 executes an algorithm defined by the method steps of FIG. 58. Computer 3600 also includes one or more network interfaces 3604 for communicating with other devices via a network. Computer 3600 also includes one or more input/output devices 3605 that enable user interaction with computer 3600 (e.g., display, keyboard, mouse, speakers, buttons, etc.). Any or all of the systems and apparatus discussed herein, including video display manager 5700, and components thereof, may be implemented using a computer such as computer 3600. One skilled in the art will recognize that an implementation of an actual computer or computer system may have other structures and may contain other components as well, and that FIG. 36 is a high-level representation of some of the components of such a computer for illustrative purposes. While preferred and alternate embodiments of the invention have been described and illustrated, it should be apparent that many modifications to the embodiments and implementations of the invention could be made without departing from the spirit or scope of the invention. In various embodiments, methods, apparatus and systems are provided as described below. The foregoing Detailed Description is to be understood as being in every respect illustrative and exemplary, but not restrictive, and the scope of the invention disclosed herein is not to be determined from the Detailed Description, but rather from the claims as interpreted according to the full breadth permitted by the patent laws. It is to be understood that the embodiments shown and described herein are only illustrative of the principles of the present invention and that various modifications may be implemented by those skilled in the art without departing from the scope and spirit of the invention. Those skilled in the art could implement various other feature combinations without departing from the scope and spirit of the invention.
<SOH> BACKGROUND <EOH>This invention is, in part, directed to Continuous Adjustable 3Deeps Filter spectacles for viewing 2D movies as 3D movies. 3Deeps Filter Spectacles provide a system by which ordinary 2-dimensional motion pictures can be viewed in part as a 3-dimensional motion pictures. They however were a sub-optimal solution. In the presence of screen motion, they only developed 3D from a 2D movie by a difference in optical density between the right and left lens, but did not describe any objective optimal target for those optical densities. Neither did the previous version or 3Deeps Filter spectacles address optimization of the spectacles to account for the materials from which the lenses are fabricated. 3Deeps Filter Spectacles that incorporate such double optimization are called Continuous Adjustable 3Deeps Filter Spectacles. Previously, related patent applications for Continuous Adjustable 3Deeps Filter spectacles have been disclosed that use electronically controlled variable tint materials for fabrication of the right and left lenses of the viewing spectacles. Generally, electronically controlled variable tint materials change the light transmission properties of the material in response to voltage applied across the material, and include but are not limited to electrochromic devices, suspended particle devices, and polymer dispersed liquid crystal devices. Such material provides precise electronic control over the amount of light transmission. 3Deeps spectacles adjust the optical properties so that the left and right lenses of the 3Deeps spectacles take on one of 3 states in synchronization to lateral motion occurring within the movie; a clear-clear state (clear left lens and clear right lens) when there is no lateral motion in successive frames of the motion picture; a clear-darkened state when there is left-to-right lateral motion in successive frame of the motion picture; and, a darkened-clear state when there is right-to-left lateral motion in successive frames of the motion picture. We note that clear is a relative term and even clear glass will block a small percentage of light transmission. A clear lens is then one that transmits almost all light through the material. Continuous Adjustable 3Deeps Filter spectacles are improved 3Deeps spectacles in that the darkened state continuously changes to take an optical density to provide the maximum Pulfrich stereoscopic 3D illusion optimized for (a) the speed and direction of lateral motion, and (b) the transition time of the electrochromic material from which the lenses are fabricated. Thus, Continuous Adjustable 3Deeps Filter Spectacles doubly optimize 3Deeps Filter Spectacles to maximize the target optical densities of the lenses, and to account for the lens material. Double optimization of the 3Deeps Filter Spectacles has substantial benefits and Continuous Adjustable 3Deeps Filter Spectacles solves substantial problems that 3Deeps Filter Spectacles could not address. One problem addressed by this invention is that of slow transition time when transitioning between different optical densities of the lenses of the Continuous Adjustable 3Deeps Filter spectacles. Optimal control of Continuous Adjustable 3Deeps Filter spectacles is achieved by adjusting the right- and left-lenses to the optimal optical density synchronized to maximize the 3D effect of the Pulfrich illusion between frames of the motion picture with respect to the transition time properties of the electrochromic material. As an example, a movie that is shown on a 100 Hz digital TV may require as many as 100 different optical density controlled lens transitions per second to optimally synchronize to the speed and direction of lateral motion in the motion picture. Most often the transitions in synchronization to the movie are small minor adjustments to the optical density of the lens that can be accomplished in the allotted time. A problem arises when 3Deeps Filter spectacles are fabricated from electronically controlled variable tint materials that are incapable of the fast transition times that are sometimes required as for instance between scene changes. While electronically controlled variable tint materials may be able to achieve fast transitions from one optical density state to another optical density state that are near or close to each other, it may be incapable of transition between optical density states that are far apart. However, faster transition times using any electronically controlled variable tint material can be achieved by the simple expedient of using 2 or more layers—or multi-layers—of such material. Using multiple layers of material does result in a darker clear state, but the difference is minimal and barely perceptible, so the tradeoff between a slightly darker clear state and faster transition time is considered and warranted. Another problem relates to the cycle life (number of clear-dark cycles before failure) of some optoelectronic materials that may be limited. The cycle life may be increased by using multiple layers of optoelectronic materials since the electric potential applied to the material to achieve a target optical density will be for a shorter period of time. Another problem addressed by an alternate embodiment of this invention is that different methods of 3D require distinct viewing spectacles. However, with electronically controlled viewing spectacles, a single viewing spectacle can be switch selectable for different optical effects. For instance, to view a 3D movie that uses the anaglyph method to achieve 3D stereoscopy requires use of a different pair of spectacles (red-blue lenses) than that used for 3Deeps viewing. Other preferred embodiments of the invention relate to multi-use of the spectacles. The use of multi-layers of electronically controlled variable tint materials where different layers relate to different viewing methods, allow a single spectacle to be selectable to achieve different optical effects. For instance, while one or more layers of electronically controlled variable tint materials may be used for Continuous Adjustable 3Deeps Filter spectacles, another layer of materials may be used for anaglyph 3D spectacles. This would extend the use of a single pair spectacles so it can be selectively used for either Continuous Adjustable 3Deeps Filter spectacles viewing of 2D filmed movies or for anaglyph viewing of 3D filmed movies. It would also allow switching within any motion picture between 2D and 3D for a specific method, and/or switching within any motion picture between different methods of 3D. Till now a 3D motion picture may have been filmed in its entirety as anaglyph. With this invention the motion picture could have been filmed in part 2D with the multi-layer specs then set by signalization to a clear-clear state, and another part of the motion picture could have been filmed in 3D anaglyph with the multi-layer spectacles then set by signalization to a red-blue state. In another embodiment the picture may be filmed in part in 2D and 3D anaglyph, and shown to viewers in 2D, 3D using 3Deeps spectacle, and 3D anaglyph with the spectacles set accordingly. Movies are generally made from a series of single, non-repetitive pictures which are viewed at a speed that provides the viewer with the appearance of continuous movement. These series of single pictures are positioned in adjacent picture frames, in sequential order, wherein adjacent pictures are substantially similar to each other and vary only slightly from each other. Usually, movies are created using movie cameras, which capture the actual movement of the object; with animated movies, a series of individual pictures or cells are created, usually by hand or computer, and assembled in sequential order where adjacent pictures of a scene are substantially similar to each other and vary only slightly. Standard film projection is 24 frames per second, American video standard NTSC is 30 f.p.s. The appearance of continuous movement, using only two substantially similar pictures, has been accomplished in live performance by simultaneous projection of both images onto a screen, wherein one picture may be slightly off-set from the other picture as they appear on the screen, and by rotating a two-bladed propeller, wherein the propeller blades are set off from one another by 180 degrees, in front of and between the two projectors such that the two images are made to both alternate and overlap in their appearances, with both images in turn alternating with an interval of complete darkness onscreen when both projections are blocked by the spinning propeller. A viewer, using no special spectacles or visual aids, perceives a scene of limited action (with a degree of illusionary depth) that can be sustained indefinitely in any chosen direction: an evolving yet limited action appears to be happening continually without visible return-and-start-over repetition. Thus the viewer sees a visual illusion of an event impossible in actual life. Similarly, the manner in which things appear in depth are likely to be at odds, often extremely so, with the spatial character of the original photographed scene. Further, the character of movement and of depth has been made malleable in the hands of the projectionist during performance (so much so that such film-performance has been likened to a form of puppetry); the physical shifting of one of the two projections changes the visual relationship between them and thereby the character of the screen event produced. Similarly, small changes during performance in speed, placement and direction of propeller spin will cause radical changes in the visual event produced onscreen. Other visual arts which relate to the present invention are the Pulfrich filter. For one program, titled Bitemporal Vision: The Sea, viewers were invited to place a Pulfrich light-reducing filter before one eye to both enhance and transform the already apparent depth character of the presentation. Limited to presentation in live performance, such unique visual phenomena as described has been transient theater. Attempts to capture the phenomena by way of video-camera recording of the screen-image have been disappointingly compromised, so that—in over 25 years of such presentation (of so-called Nervous System Film Performances) no attempt has been made to commercialize such recordings. In addition, a number of products and methods have been developed for producing 3-D images from two-dimensional images. Steenblik in U.S. Pat. Nos. 4,597,634, 4,717,239, and 5,002,364 teaches the use of diffractive optical elements with double prisms, one prism being made of a low-dispersion prism and the second prism being made of a high-dispersion prism. Takahaski, et al in U.S. Pat. No. 5,144,344 teaches the use of spectacles based on the Pulfrich effect with light filtering lens of different optical densities. Beard in U.S. Pat. No. 4,705,371 teaches the use of gradients of optical densities going from the center to the periphery of a lens. Hirano in U.S. Pat. No. 4,429,951 teaches the use of spectacles with lenses that can rotate about a vertical axis to create stereoscopic effects. Laden in U.S. Pat. No. 4,049,339 teaches the use of spectacles with opaque temples and an opaque rectangular frame, except for triangular shaped lenses positioned in the frame adjacent to a nosepiece. Davino, U.S. Pat. No. 6,598,968, 3-Dimensional Movie and Television Viewer, teaches an opaque frame that can be placed in front of a user's eyes like a pair of glasses for 3-D viewing to take advantage of the Pulfrich effect. The frame has two rectangular apertures. These apertures are spaced to be in directly in front of the user's eyes. One aperture is empty; the other opening has plural vertical strips, preferably two, made of polyester film. Between the outer edge of the aperture and the outermost vertical strip is diffractive optical material. The surface of the strips facing away from the person's face might be painted black. Images from a television set or a movie screen appear three dimensional when viewed through the frame with both eyes open. Dones, U.S. Pat. No. 4,805,988, Personal Viewing Video Device, teaches a personal video viewing device which allows the simultaneous viewing of a stereoscopic external image as well as a monoscopic electronic image. This is accomplished using two optical systems which share particular components. The relative intensity of both images may be adjusted using a three-iris system where each iris may be a mechanical diaphragm, an electronically controlled liquid crystal device, or a pair of polarized discs whose relative rotational orientation controls the transmissivity of the disc pair. Beard in U.S. Pat. No. 4,893,898 teaches a method for creating a 3-D television effect in which a scene is recorded with a relative lateral movement between the scene and the recording mechanism. The recording is played back and viewed through a pair of viewer glasses in which one of the lenses is darker and has a spectral transmission characterized by a reduced transmissivity in at least one, and preferably all three, of the television's peak radiant energy wavebands. The lighter lens, on the other hand, has a spectral transmission characterized by a reduced transmissivity at wavelengths removed from the television energy peaks. The result is a substantially greater effective optical density differential between the two lenses when viewing television than in normal ambient light. This produces a very noticeable 3-D effect for television scenes with the proper movement, while avoiding the prior “dead eye” effect associated with too great a density differential in ordinary light. Further enhancement is achieved by providing the darker lens with a higher transmissivity in the blue and red regions than in the yellow or green regions. Other patents deal with image processing to measure motion in a moving picture and include Iue U.S. Pat. No. 5,717,415, Nagaya U.S. Pat. No. 5,721,692 and Gerard De Haan U.S. Pat. No. 6,385,245. Iue in U.S. Pat. No. 5,717,415 teaches a method of converting two-dimensional images into three-dimensional images. A right eye image signal and a left eye image signal between which there is relatively a time difference or a luminance difference are produced from a two-dimensional image signal, thereby to convert two-dimensional images into three-dimensional images. In U.S. Pat. No. 5,721,692, Nagaya et al present a “Moving Object Detection Apparatus”. In that disclosed invention, a moving object is detected from a movie that has a complicated background. In order to detect the moving object, there is provided a unit for inputting the movie, a display unit for outputting a processed result, a unit for judging an interval which is predicted to belong to the background as part of a pixel region in the movie, a unit for extracting the moving object and a unit for calculating the moving direction and velocity of the moving object. Even with a complicated background in which not only a change in illumination condition, but also a change in structure occurs, the presence of the structure change of the background can be determined so as to detect and/or extract the moving object in real time. Additionally, the moving direction and velocity of the moving object can be determined. De Haan U.S. Pat. No. 6,385,245 teaches a method of estimating motion in which at least two motion parameter sets are generated from input video data. A motion parameter set is a set of parameters describing motion in an image, and by means of which motion can be calculated. Visual effects are important in motion pictures and have the potential to expand the viewing enjoyment of moviegoers. For example, the movement effect “Bullet Time” utilized in the movie “The Matrix” was critical to the appeal of the movie. Visual effects for 3-dimensional motion pictures include such motion pictures as “Charge at Feather River”, starring Guy Madison. The Vincent Price movie “House of Wax” was originally released as a 3-D thriller. The 3-D movie fad of the early to mid-1950s however soon faded due to complexity of the technologies and potential for improper synchronization, and misalignment of left and right eye images as delivered to the viewer. TV 3-D motion pictures have been attempted from time-to-time. Theatric Support produced the first TV Pulfrich event in 1989 for Fox Television—“The Rose Parade in 3D Live.” In order to sustain the illusion of realistic depth these 3-D Pulfrich effect TV shows require all foreground screen action to move in one consistent direction, matched to the fixed light-diminishing lens of special spectacles provided to viewers for each broadcast. This enormous constraint (for all screen action to proceed in one direction) placed on the producers of the motion picture is due to the realistic expectation that viewers were not going to invert their spectacles so as to switch the light-diminishing filter from one eye to another for each change in screen-action direction. For the great majority of viewers the limitation of spectacles with a fixed filter, either left or right, meant the 3D effect would be available only with movies produced specifically for that viewing spectacles design. With the exception of Sony I-max 3-D presentations, which require special theater/screening facilities unique to the requirements of I-Max technology, 3-dimensional motion pictures remain a novelty. Despite the wide appeal to viewers, the difficulties and burden on motion picture producers, distributors, TV networks, motion picture theaters, and on the viewers has been a barrier to their wide scale acceptance. Among the problems and constraints involving the production, projection, and viewing of 3-dimensional motion pictures are: Production: The commonly used anaglyph 3-dimensional movie systems require special cameras that have dual lenses, and capture 2-images on each frame. To have a version of the motion picture that can be viewed without special glasses requires that a separate version of the motion picture be shot with a regular camera so there is only one image per video frame and not simply the selection of one or the other perspective. Similarly, IMAX and shutter glass systems require special cameras and processing with separate versions of the motion picture for 2D and 3D viewing. Filming movies in 3D add as much as $10 million dollars to production costs, it has been reported. Projection: Some 3-dimensional systems require the synchronization and projection by more than 2 cameras in order to achieve the effect. “Hitachi, Ltd has developed a 3D display called Transpost 3D which can be viewed from any direction without wearing special glasses, and utilize twelve cameras and rotating display that allow Transpost 3D motion pictures that can be seen to appear as floating in the display. The principle of the device is that 2D images of an object taken from 24 different directions are projected to a special rotating screen. On a large scale this is commercially unfeasible, as special effects in a motion picture must be able to be projected with standard projection equipment in a movie theater, TV or other broadcast equipment. Viewing: As a commercial requirement, any special effect in a motion picture must allow viewing on a movie screen, and other viewing venues such as TV, DVD, VCR, PC computer screen, plasma and LCD displays. From the viewer's vantage, 3-dimensional glasses, whether anaglyph glasses or Pulfrich glasses, which are used in the majority of 3-dimensional efforts, if poorly made or worn incorrectly are uncomfortable and may cause undue eyestrain or headaches. Experiencing such headache motivates people to shy away from 3-D motion pictures. Because of these and other problems, 3-dimensional motion pictures have never been more than a novelty. The inconvenience and cost factors for producers, special equipment projection requirements, and viewer discomfort raise a sufficiently high barrier to 3-dimensional motion pictures that they are rarely produced. One object of this invention is to overcome these problems and constraints. The Human Eye and Depth Perception The human eye can sense and interpret electromagnetic radiation in the wavelengths of about 400 to 700 nanometers—visual light to the human eye. Many electronic instruments, such as camcorders, cell phone cameras, etc., are also able to sense and record electromagnetic radiation in the band of wavelengths 400-700 nanometer. To facilitate vision, the human eye does considerable image processing before the brain gets the image. When light ceases to stimulate the eyes photoreceptors, the photoreceptors continue to send signals, or fire for a fraction of a second afterwards. This is called “persistence of vision”, and is key to the invention of motion pictures that allows humans to perceive rapidly changing and flickering individual images as a continuous moving image. The photoreceptors of the human eye do not “fire” instantaneously. Low light conditions can take a few thousands of a second longer to transmit signals than under higher light conditions. Causing less light to be received in one eye than another eye, thus causing the photoreceptors of the right and left eyes to transmit their “pictures” at slightly different times, explains in part the Pulfrich 3-D illusion, which is utilized in the invention of the 3Deeps system. This is also cause of what is commonly referred to as “night vision”. Once signals are sent to the eyes, the brain processes the dual images together (images received from the left and right eye) presenting the world to the mind in 3-dimensions or with “Depth Perception”. This is accomplished by several means that have been long understood. Stereopsis is the primary means of depth perception and requires sight from both eyes. The brain processes the dual images, and triangulates the two images received from the left and right eye, sensing how far inward the eyes are pointing to focus the object. Perspective uses information that if two objects are the same size, but one object is closer to the viewer than the other object, then the closer object will appear larger. The brain processes this information to provide clues that are interpreted as perceived depth. Motion parallax is the effect that the further objects are away from us, the slower they move across our field of vision. The brain processes motion parallax information to provide clues that are interpreted as perceived depth. Shadows provide another clue to the human brain, which can be perceived as depth. Shading objects, to create the illusions of shadows and thus depth, is widely used in illustration to imply depth without actually penetrating (perceptually) the 2-D screen surface.
<SOH> SUMMARY OF THE INVENTION <EOH>A method has now been discovered for originating visual illusions of figures and spaces in continuous movement in any chosen direction using a finite number of pictures (as few as two pictures) that can be permanently stored and copied and displayed on motion picture film or electronic media. The method of the present invention entails repetitive presentation to the viewer of at least two substantially similar image pictures alternating with a third visual interval or bridging picture that is substantially dissimilar to the other substantially similar pictures in order to create the appearance of continuous, seamless and sustained directional movement. Specifically, two or more image pictures are repetitively presented together with a bridging interval (a bridging picture) which is preferably a solid black or other solid-colored picture, but may also be a strongly contrasting image-picture readily distinguished from the two or more pictures that are substantially similar. In electronic media, the bridge-picture may simply be a timed unlit-screen pause between serial re-appearances of the two or more similar image pictures. The rolling movements of pictorial forms thus created (figures that uncannily stay in place while maintaining directional movement, and do not move into a further phase of movement until replaced by a new set of rotating units) is referred to as Eternalisms, and the process of composing such visual events is referred to as Eternalizing. The three film or video picture-units are arranged to strike the eyes sequentially. For example, where A and B are the image pictures and C is the bridging picture, the picture units are arranged (A, B, C). This arrangement is then repeated any number of times, as a continuing loop. The view of this continuing loop allows for the perception of a perceptual combining and sustained movement of image pictures (A, B). Naturally, if this loop is placed on a film strip, then it is arranged and repeated in a linear manner (A, B, C, A, B, C, A, B, C, A, B, C, etc.). The repetition of the sequence provides an illusion of continuous movement of the image pictures (A, B); with bridging picture (C), preferably in the form of a neutral or black frame, not consciously noticed by the viewer at all, except perhaps as a subtle flicker. A more fluid or natural illusion of continuous movement from a finite number of image pictures is provided by using two of each of the three pictures and repeating the cycle of the pairs sequentially, or by blending adjacent pictures together on an additional picture-frame and placing the blended picture between the pictures in sequential order. The two image pictures (A, B) are now blended with each other to produce (A/B); the two image pictures are also blended with the bridging picture to produce (C/A and B/C), and then all pictures repeat in a series starting with the bridging picture (C, C/A, A, A/B, B, B/C) each blended picture being represented by the two letters with a slash therebetween). This series is repeated a plurality of times to sustain the illusion as long as desired. Repeating the sequence with additional blended frames provides more fluid illusion of continuous movement of the (optically combined) two image pictures (A, B). Additionally, various arrangements of the pictures and the blends can be employed in the present invention and need not be the same each time. By varying the order of pictures in the sequence, the beat or rhythm of the pictures is changed. For example, A, B, C can be followed by A, A/B, B, B/C, C which in turn is followed by A, A, A/B, B, B, B, B/C, C, C, C, C, i.e. A, B, C, A, A/B, B, B/C, C, A, A, A/B, B, B, B, B/C, B/C, C, C, C, C, A, B, C, A, etc. With A and B frames being similar images (such as a pair of normal two-eye perspective views of a three-dimensional scene from life), and frame C a contrasting frame (preferably a solid-color picture instead of an image-picture) relative to A,B, frame C acts as essentially a bridge-interval placed between recurrences of A,B. Any color can be used for the contrasting frame C: for example, blue, white, green; however, black is usually preferred. The contrasting frame can also be chosen from one of the colors in one of the two image pictures. For example, if one of the image pictures has a large patch of dark blue, then the color of the contrasting frame, bridging picture, may be dark blue. Blending of the pictures is accomplished in any manner which allows for both pictures to be merged in the same picture frame. Thus, the term blending as used in the specification and claims can also be called superimposing, since one picture is merged with the other picture. Blending is done in a conventional manner using conventional equipment, suitably, photographic means, a computer, an optical printer, or a rear screen projection device. For animated art, the blending can be done by hand as in hand drawing or hand painting. Preferably, a computer is used. Suitable software programs include Adobe Photoshop, Media 100 and Adobe After Affects. Good results have been obtained with Media 100 from Multimedia Group Data Translations, Inc. of Marlborough, Mass., USA. When using Media 100, suitable techniques include additive dissolving, cross-dissolving, and dissolving-fast fix and dither dissolving. In blending the pictures, it is preferred to use 50% of one and 50% of the other. However, the blending can be done on a sliding scale, for example with three blended pictures, a sliding scale of quarters, i.e. 75% A/25% B, 50% A/50% B, 25% A/75% B. Good results have been obtained with a 50%/50% mix, i.e. a blend of 50% A/50% B. The two image pictures, A and B, which are visually similar to each other, are preferably taken from side-by-side frame exposures from a motion picture film of an object or image or that is moving such that when one is overlaid with the other, only a slight difference is noted between the two images. Alternatively, the two image pictures are identical except that one is off-center from the other. The direction of the off-center, e.g. up, down, right, or left, will determine which direction the series provides the appearance of movement, e.g. if image picture B is off-center from image picture A to the right of A, the series of C, C/A, A, A/B, B, B/C will have the appearance of moving from left to right. Likewise, if you reverse the order of appearance then the appearance of movement will be to the left. More than two image pictures can be used in the invention. Likewise, more than one bridging picture can be used in the present invention. For example, four image pictures can be used along with one bridging picture. In this case, the series for the four image pictures, designated A, B, D and E, would be: C, A, B, D, E; or a 50/50 blend C, C/A, A, A/B, B, B/D, D, D/E, E, E/C; or side-by-side pairs, C, C, A, A, B, B, D, D, E, E. The image picture need not fill the picture frame. Furthermore, more than one image picture can be employed per frame. Thus, the picture frame can contain a cluster of images and the image or images need not necessarily filling up the entire frame. Also, only portions of image pictures can be used to form the image used in the present invention. Also, image pictures and portions of the image picture can be combined such that the combination is used as the second image picture. The portion of the image picture is offset from the first image picture when they are combined such that there is an appearance of movement. For example, a window from image picture A can be moved slightly while the background remains the same, the picture with the moved window is designated image picture B and the two combined to create the appearance of the window moving and/or enlarging or shrinking in size. In this case, both picture A and picture B are identical except for the placement of the window in the image picture. The same can also be done by using an identical background in both image pictures and superimposing on both pictures an image which is positioned slightly different in each picture. The image could be a window, as before, of a man walking, for example. The number of series which are put together can be finite if it is made on a length of film or infinite if it is set on a continuous cycle or loop wherein it repeats itself. In accordance with an embodiment, an electrically controlled spectacle for viewing a video is provided. The electrically controlled spectacle includes a spectacle frame and optoelectronic lenses housed in the frame. The lenses comprise a left lens and a right lens, each of the optoelectrical lenses having a plurality of states, wherein the state of the left lens is independent of the state of the right lens. The electrically controlled spectacle also includes a control unit housed in the frame, the control unit being adapted to control the state of each of the lenses independently. In one embodiment, each of the lenses has a dark state and a light state. In another embodiment, when viewing a video the control unit places both the left lens and the right lens to a dark state. In another embodiment, a method for viewing a video is provided. A user wears the electrically controlled spectacle described above, and the wearer is shown a video having dissimilar bridge frames and similar image frames. In accordance with another embodiment, a first modified image frame is determined by removing a first portion of a selected image frame. A second modified image frame different from the first modified image frame is determined by removing a second portion of the selected image frame. A third modified image frame different from the first and second modified image frames is determined by removing a third portion of the selected image frame. A first bridge image frame different from the selected image frame and different from the first, second, and third modified image frames is determined. A second bridge image frame different from the selected image frame, different from the first, second, and third modified image frames, and different from the first bridge image frame is determined. The first bridge image frame is blended with the first modified image frame, generating a first blended image frame. The first bridge image frame is blended with the second modified image frame, generating a second blended image frame. The first bridge image frame is blended with the third modified image frame, generating a third blended image frame. The first blended image frame, the second blended image frame, and the third blended image frame are overlaid to generate an overlayed image frame. The overlayed image frame and the second bridge image frame are displayed. In one embodiment, the first bridge image frame comprises a non-solid color. In another embodiment, each of the optoelectronic lenses comprises a plurality of layers of optoelectronic material. In accordance with another embodiment, a first modified image frame is determined by removing a first portion of a selected image frame. A second modified image frame different from the first modified image frame is determined by removing a second portion of the selected image frame. A third modified image frame is determined by removing a third portion of the first modified image frame. A fourth modified image frame different from the third modified image frame is determined by removing a fourth portion of the first modified image frame. A fifth modified image frame different from the third and fourth modified image frames is determined by removing a fifth portion of the first modified image frame. A sixth modified image frame is determined by removing a sixth portion of the second modified image frame. A seventh modified image frame different from the sixth modified image frame is determined by removing a seventh portion of the second modified image frame. An eighth modified image frame different from the sixth and seventh modified image frames is determined by removing an eighth portion of the second modified image frame. A first bridge image frame different from the first and second modified image frames is determined. A second bridge image frame different from the first and second modified image frames, and different from the first bridge image frame is determined. A third bridge image frame different from the first and second modified image frames, and different from the first and second bridge image frames is determined. A fourth bridge image frame different from the first and second modified image frames, and different from the first, second and third bridge image frames is determined. A first blended image frame is generated by blending the third modified image frame with the first bridge image frame. A second blended image frame is generated by blending the fourth modified image frame with the second bridge image frame. A third blended image frame is generated by blending the fifth modified image frame with the third bridge image frame. The first blended image frame, the second blended image frame, the third blended image frame, and the fourth bridge image frame are displayed. A fourth blended image frame is generated by blending the sixth modified image frame with the first bridge image frame. A fifth blended image frame is generated by blending the seventh modified image frame with the second bridge image frame. A sixth blended image frame is generated by blending the eighth modified image frame with the third bridge image frame. The fourth blended image frame, the fifth blended image frame, the sixth blended image frame, and the fourth bridge image frame are displayed. In one embodiment, the fourth bridge image frame is solid white, and the spectacle frame comprises a sensor adapted to receive synchronization signals embedded in the video and provide the synchronization signals to the control unit. In accordance with another embodiment, a first modified image frame is determined by removing a first portion of a selected image frame. A second modified image frame different from the first modified image frame is determined by removing a second portion of the selected image frame. A third modified image frame different from the first and second modified image frames is determined by removing a third portion of the selected image frame. A bridge image frame different from the selected image frame and different from the first, second, and third modified image frames is determined. The first modified image frame, the second modified image frame, and the third modified image frame are overlaid, to generate an overlayed image frame. The overlayed image frame and the bridge image frame are displayed. In accordance with another embodiment, a bridge image frame that is different from a first image frame and different from a second image frame is determined, the first and second image frames being consecutive image frames in a video. A first modified image frame is determined by removing a first portion of the first image frame. A second modified image frame different from the first modified image frame is determined by removing a second portion of the first image frame. A third modified image frame different from the first and second modified image frames is determined by removing a third portion of the first image frame. The first, second, and third modified image frames are overlaid to generate a first overlayed image frame. The first overlayed image frame and the bridge image frame are displayed. A fourth modified image frame is determined by removing a fourth portion of the second image frame. A fifth modified image frame different from the fourth modified image frame is determined by removing a fifth portion of the second image frame. A sixth modified image frame different from the fourth and fifth modified image frames is determined by removing a sixth portion of the second image frame. The fourth, fifth, and sixth modified image frames are overlaid to generate a second overlayed image frame. The second overlayed image frame and the bridge image frame are displayed. In accordance with another embodiment, a first modified image frame is determined by removing a first portion of a selected image frame. A second modified image frame different from the first modified image frame is determined by removing a second portion of the selected image frame. A third modified image frame different from the first and second modified image frames is determined by removing a third portion of the selected image frame. A first bridge image frame different from the first, second, and third modified image frames is determined. A second bridge image frame different from the first, second, and third modified image frames, and different from the first bridge image frame is determined. A third bridge image frame different from the first, second, and third modified image frames, and different from the first and second bridge image frames is determined. A fourth bridge image frame different from the first, second, and third modified image frames, and different from the first, second and third bridge image frames is determined. The first modified image frame is blended with the first bridge image frame to generate a first blended image frame. The second modified image frame is blended with the second bridge image frame to generate a second blended image frame. The third modified image frame is blended with the third bridge image frame to generate a third blended image frame. The first blended image frame, the second blended image frame, and the third blended image frame are overlaid to generate an overlayed image frame. The overlayed image frame and the fourth bridge image frame are displayed. In one embodiment, the fourth bridge image frame is solid white, and the spectacle frame comprises a sensor adapted to receive synchronization signals embedded in the video and provide the synchronization signals to the control unit. In accordance with another embodiment, a first modified image frame is determined by removing a first portion of a selected image frame. A second modified image frame different from the first modified image frame is determined by removing a second portion of the selected image frame. A third modified image frame is determined by removing a third portion of the first modified image frame. A fourth modified image frame different from the third modified image frame is determined by removing a fourth portion of the first modified image frame. A fifth modified image frame different from the third and fourth modified image frames is determined by removing a fifth portion of the first modified image frame. A sixth modified image frame is determined by removing a sixth portion of the second modified image frame. A seventh modified image frame different from the sixth modified image frame is determined by removing a seventh portion of the second modified image frame. An eighth modified image frame different from the sixth and seventh modified image frames is determined by removing an eighth portion of the second modified image frame. A first bridge image frame different from the first, second, third, fourth, fifth, sixth, seventh, and eight modified image frames is determined. A second bridge image frame different from the first bridge image frame and different from the first, second, third, fourth, fifth, sixth, seventh, and eight modified image frames is determined. The first bridge image frame is blended with the third modified image frame to generate a first blended image frame. The first bridge image frame is blended with the fourth modified image frame to generate a second blended image frame. The first bridge image frame is blended with the fifth modified image frame to generate a third blended image frame. The first blended image frame, the second blended image frame, and the third blended image frame are overlaid to generate a first overlayed image frame. The first overlayed image frame and the second bridge image frame are displayed. The first bridge image frame is blended with the sixth modified image frame to generate a fourth blended image frame. The first bridge image frame is blended with the seventh modified image frame to generate a fifth blended image frame. The first bridge image frame is blended with the eighth modified image frame to generate a sixth blended image frame. The fourth blended image frame, the fifth blended image frame, and the sixth blended image frame are overlaid to generate a second overlayed image frame. The second overlayed image frame and the second bridge image frame are displayed. In one embodiment, the first bridge image frame comprises a non-solid color. In accordance with another embodiment, one or more of the following actions may be performed in performing one or more of the methods described above: generating a blended image frame by blending a plurality of image frames, generating a combined image frame by combining a plurality of image frames, generating a combined image sequence by combining a plurality of image sequences, generating one or more doubled image frames by doubling one or more image frames, generating an overlayed image frame by overlaying a plurality of image frames, generating a modified image frame by removing a portion of an image frame, repeating one of an image frame or a series of image frames, generating a sequence of image frames, generating a collage based on one or more portions of one or more image frames, stitching together one or more portions of one or more image frames, superimposing a first image frame on a second image frame, determining a transitional frame, inserting and/or lifting a portion of a first image frame into a second image frame, reshaping a portion of an image frame, and relocating a portion of an image frame. In accordance with an embodiment, an apparatus includes a storage adapted to store one or more image frames, and a processor. The processor is adapted to determine a first modified image frame by removing a first portion of a selected image frame, determine a second modified image frame different from the first modified image frame by removing a second portion of the selected image frame, determine a third modified image frame different from the first and second modified image frames by removing a third portion of the selected image frame, determine a first bridge image frame different from the selected image frame and different from the first, second, and third modified image frames, determine a second bridge image frame different from the selected image frame, different from the first, second, and third modified image frames, and different from the first bridge image frame, blend the first bridge image frame with the first modified image frame, generating a first blended image frame, blend the first bridge image frame with the second modified image frame, generating a second blended image frame, blend the first bridge image frame with the third modified image frame, generating a third blended image frame, overlay the first blended image frame, the second blended image frame, and the third blended image frame to generate an overlayed image frame, display the overlayed image frame, and display the second bridge image frame. In one embodiment, the apparatus also includes an electrically controlled spectacle to be worn by a viewer. The electrically controlled spectacle includes a spectacle frame, optoelectronic lenses housed in the frame, the lenses comprising a left lens and a right lens, each of the optoelectrical lenses having a plurality of states, wherein the state of the left lens is independent of the state of the right lens, and a control unit housed in the frame, the control unit being adapted to control the state of each of the lenses independently. Each of the lenses has a dark state and a light state, and when viewing a video the control unit places both the left lens and the right lens to a dark state. In another embodiment, the first bridge image frame comprises a non-solid color. In accordance with another embodiment, an apparatus includes a storage adapted to store one or more image frames, and a processor. The processor is adapted to determine a first modified image frame by removing a first portion of a selected image frame, determine a second modified image frame different from the first modified image frame by removing a second portion of the selected image frame, determine a third modified image frame by removing a third portion of the first modified image frame, determine a fourth modified image frame different from the third modified image frame by removing a fourth portion of the first modified image frame, determine a fifth modified image frame different from the third and fourth modified image frames by removing a fifth portion of the first modified image frame, determine a sixth modified image frame by removing a sixth portion of the second modified image frame, determine an seventh modified image frame different from the sixth modified image frame by removing a seventh portion of the second modified image frame, determine an eighth modified image frame different from the sixth and seventh modified image frames by removing an eighth portion of the second modified image frame, determine a first bridge image frame different from the first, second, third, fourth, fifth, sixth, seventh, and eight modified image frames, determine a second bridge image frame different from the first bridge image frame and different from the first, second, third, fourth, fifth, sixth, seventh, and eight modified image frames, blend the first bridge image frame with the third modified image frame to generate a first blended image frame, blend the first bridge image frame with the fourth modified image frame to generate a second blended image frame, blend the first bridge image frame with the fifth modified image frame to generate a third blended image frame, overlay the first blended image frame, the second blended image frame, and the third blended image frame to generate a first overlayed image frame, display the first overlayed image frame and the second bridge image frame, blend the first bridge image frame with the sixth modified image frame to generate a fourth blended image frame, blend the first bridge image frame with the seventh modified image frame to generate a fifth blended image frame, blend the first bridge image frame with the eighth modified image frame to generate a sixth blended image frame, overlay the fourth blended image frame, the fifth blended image frame, and the sixth blended image frame to generate a second overlayed image frame, and display the second overlayed image frame and the second bridge image frame. In one embodiment, the apparatus also includes an electrically controlled spectacle to be worn by a viewer. In another embodiment, the first bridge image frame comprises a non-solid color. In accordance with another embodiment, a system for presenting a video is provided. The system includes an apparatus comprising a storage adapted to store one or more image frames associated with a video, and a processor. The processor is adapted to reshape a portion of at least one of the one or more image frames. The system also includes an electrically controlled spectacle which includes a spectacle frame, optoelectronic lenses housed in the frame, the lenses comprising a left lens and a right lens, each of the optoelectrical lenses having a plurality of states, wherein the state of the left lens is independent of the state of the right lens, and a control unit housed in the frame, the control unit being adapted to control the state of each of the lenses independently. Each of the lenses has a dark state and a light state. When viewing the video the control unit places both the left lens and the right lens to a dark state. In accordance with another embodiment, an apparatus includes a storage adapted to store one or more image frames, and a processor. The processor is adapted to obtain a first image from a first video stream, obtain a second image from a second video stream, wherein the first image is different from the second image, stitching together the first image and the second image to generate a stitched image frame, generating a first modified image frame by removing a first portion of the stitched image frame, generating a second modified image frame by removing a second portion of the stitched image frame, generating a third modified image frame by removing a third portion of the stitched image frame, wherein the first modified image frame, the second modified image frame, and the third modified image frame are different from each other, identify a bridge frame, blend the first modified image frame with the bridge frame to generate a first blended frame, blend the first modified image frame with the bridge frame to generate a first blended frame, blend the first modified image frame with the bridge frame to generate a first blended frame, overlay the first blended frame, the second blended frame, and the third blended frame to generate a combined frame, and display the combined frame. In one embodiment, the apparatus also includes spectacles adapted to be worn by a viewer of a video. In another embodiment, the bridge frame includes a non-solid color. In accordance with yet another embodiment, a method of displaying one or more frames of a video is provided. Data comprising a compressed image frame and temporal redundancy information is received. The image frame is decompressed. A plurality of bridge frames that are visually dissimilar to the image frame are generated. The image frame and the plurality of bridge frames are blended, generating a plurality of blended frames, and the plurality of blended frames are displayed. In one embodiment, the image frame is decompressed based on the temporal redundancy information. In another embodiment, the data comprises a compressed video file associated with a compression format that uses temporal redundancy to achieve compression of video data. For example, the data may comprise an MPEG compressed video file. In another embodiment, each bridge frame comprises a solid black picture, a solid colored picture, or a timed unlit-screen pause. In another embodiment, the plurality of blended frames are displayed in accordance with a predetermined pattern. In another embodiment, the plurality of blended frames are displayed in accordance with a predetermined pattern that includes a first pattern comprising the plurality of blended frames, and a second pattern that comprises repetition of the first pattern. In accordance with another embodiment, an apparatus includes a storage configured to store a compressed image frame and temporal redundancy information, and a processor configured to receive the compressed image frame and the temporal redundancy information, decompress the image frame, and generate a plurality of bridge frames that are visually dissimilar to the image frame. The plurality of bridge frames includes a first bridge frame having a first width, the first bridge frame comprising a first white rectangle in an upper portion of the first bridge frame, the first white rectangle having the first width, and a second bridge frame having a second width, the second bridge frame comprising a second dark rectangle in an upper portion of the second bridge frame, the second dark rectangle having the second width. The processor is further configured to blend the image frame and the plurality of bridge frames, generating a plurality of blended frames, wherein the plurality of blended frames include a first blended frame that includes the first portion of the image frame in an upper portion of the first blended frame, and a second blended frame that includes the second dark rectangle in an upper portion of the second blended frame. The processor is also configured to display the plurality of blended frames consecutively within a video. In another embodiment, the processor is further configured to decompress the image frame based on the temporal redundancy information. In another embodiment, the data comprises a compressed video file associated with a compression format that uses temporal redundancy to achieve compression of video data. In another embodiment, each bridge frame comprises a timed unlit-screen pause. In another embodiment, the processor is further configured to display the plurality of blended frames in accordance with a predetermined pattern. In another embodiment, the processor is further configured to display the blended frames in accordance with a predetermined pattern that includes a first pattern comprising the plurality of blended frames, and a second pattern that comprises repetition of the first pattern. In another embodiment, the plurality of bridge frames comprise a first bridge frame having a first pattern and a second bridge frame having a second pattern that is complementary to the first pattern. In accordance with still a further embodiment of the invention, a method for generating modified video is provided. A source video comprising a sequence of 2D image frames is acquired, and an image frame that includes two or more motion vectors that describe motion in the image frame is obtained from the source video, wherein each of the motion vectors is associated with a region of the image frame. A respective parameter is calculated for each of the following: (a) a lateral speed of the image frame, using the two or more motion vectors, and (b) a direction of motion of the image frame, using the two or more motion vectors. A deformation value is generated by applying an algorithm that uses both of the parameters, and the deformation value is applied to the image frame to identify a modified image frame. The modified image frame is blended with a bridge frame that is a non-solid color and is different from the modified image frame, to generate a blended frame. The direction of motion and velocity of motion parameters in the calculating step are calculated only from the motion vectors input along with the image frame. In one embodiment, a viewer views the modified video through spectacles. The spectacles have a left and right lens, and each of the left lens and right lens has a darkened state. Each of the left and right lenses has a darkened state and a light state, the state of the left lens being independent of the state of the right lens. In another embodiment, the spectacles also include a battery, a control unit and a signal receiving unit. The control unit may be adapted to control the state of the each of the lenses independently. In another embodiment, the left and right lenses comprise one or more electro-optical materials. In another embodiment, the blended frame is displayed to a viewer. In accordance with another embodiment, a method for generating modified video is provided. A source video including a sequence of 2D image frames is acquired, and a modified image frame is obtained based on a selected one of the image frames of the source video. The modified image frame is blended with a bridge frame that is a non-solid color and is different from the modified image frame, to generate a blended frame. In one embodiment, the selected image frame comprises two or more motion vectors that describe motion in the selected image frame, wherein each of the motion vectors is associated with a region of the selected image frame. A respective parameter is calculated for each of the following: (a) a lateral speed of the selected image frame, using the two or more motion vectors, and (b) a direction of motion of the selected image frame, using the two or more motion vectors. A deformation value is generated by applying an algorithm that uses both of the parameters, and the deformation value is applied to the image frame to identify a modified image frame. In one embodiment, the direction of motion and velocity of motion parameters in the calculation step are calculated only from the motion vectors. In accordance with another embodiment, a method for generating modified video is provided. A source video comprising a sequence of 2D image frames is acquired, a first image frame and a second image frame in the source video are identified, the first image frame and the second image frame are combined to generate a modified image frame, and the modified image frame is blended with a bridge frame that is a non-solid color, different from the modified image frame, different from the first image frame, and different from the second image frame, to generate a blended frame. In one embodiment, the first image frame and the second image frame are similar. Many advantages, features, and applications of the invention will be apparent from the following detailed description of the invention that is provided in connection with the accompanying drawings.
H04N130431
20170822
20180417
20171228
67162.0
H04N1304
10
DANG, HUNG XUAN
FASTER STATE TRANSITIONING FOR CONTINUOUS ADJUSTABLE 3DEEPS FILTER SPECTACLES USING MULTI-LAYERED VARIABLE TINT MATERIALS
UNDISCOUNTED
1
CONT-ACCEPTED
H04N
2,017
15,684,369
ACCEPTED
SOUND VERIFICATION
In some examples, sound verification may include a speaker device that may be configured to transmit sound at a dynamic volume level and a listening device that may be configured to receive the sound and provide feedback to the speaker device based on the received sound. The primary transceiver device may be further configured to adjust the dynamic volume level based on the feedback provided by the secondary transceiver device.
1. A sound verification system, comprising: a plurality of speaker devices, wherein each of the plurality of speaker devices is configured to transmit sound at a dynamic volume level; and one or more listener devices configured to: receive the sound from the plurality of speaker devices; distinguish the received sound from the respective plurality of speaker devices; and provide, based on the distinguished sound, feedback to at least one of the plurality of speaker devices, wherein the provided feedback is used to verify a quality of the received sound of the at least one of the plurality of speaker devices, and wherein the at least one of the plurality of speaker devices is further configured to adjust the dynamic volume level of the transmitted sound based on the feedback provided by the one or more listener devices. 2. The sound verification system of claim 1, wherein the dynamic volume level corresponds to a volume level that is automatically adjustable. 3. The sound verification system of claim 1, wherein the one or more listener devices are configured to receive the sound from the respective plurality of speaker devices based on respective proximity of the one or more listener devices to the plurality of speaker devices. 4. The sound verification system of claim 1, wherein the feedback is provided based on parameters that include at least one of: a particular number of words, words spoken over a defined time period, and words spoken at a specified time period. 5. The sound verification system of claim 4, wherein the provided feedback is tagged with metadata to indicate the parameters associated with the received sound of the at least one of the plurality of speaker devices. 6. A method to verify audio transmission, the method comprising: receiving, by one or more first transceivers, one or more audio signals transmitted from respective one or more second transceivers; and transmitting, by the one or more first transceivers, feedback to the respective one or more second transceivers to cause dynamic adjustment of respective volumes of the received one or more audio signals, wherein the transmitted feedback is based on respective proximity of the one or more first transceivers to the one or more second transceivers. 7. The method of claim 6, wherein the method is repeated periodically. 8. The method of claim 6, wherein the transmitting the feedback to cause the dynamic adjustment includes transmitting the feedback to cause manual or automatic adjustment of the respective volumes of the received one or more audio signals. 9. The method of claim 6, further comprising distinguishing, by the one or more first transceivers, the one or more audio signals transmitted from the respective one or more second transceivers. 10. A method to verify audio transmission, the method comprising, by a primary device: transmitting audio signals at an initial volume; receiving feedback, from one or more secondary devices, based on the transmitted audio signals; determining scores based on a comparison between the transmitted audio signals and the received feedback; and adjusting a volume applied to the transmission based on the determined scores. 11. The method of claim 10, wherein the adjusting includes determining whether the initial volume, at which the audio signals are transmitted by the primary device, should remain same or be increased based on the determined scores. 12. The method of claim 11, wherein the adjusting includes adjusting the initial volume further based on different threshold values. 13. The method of claim 11, wherein the adjusting includes adjusting the initial volume further based on a specific threshold value. 14. The method of claim 13, wherein the adjusting includes increasing the volume in response to a determination that one of the determined scores indicative of a number of errors per sample is greater than the specific threshold value. 15. The method of claim 13, wherein the adjusting includes maintaining the transmission of the audio signals at the initial volume in response to a determination that one of the determined scores indicative of a number of errors per sample is less than the specific threshold value. 16. The method of claim 13, wherein the determining the scores includes determining scores greater than the specific threshold value, which are indicative of a poor transmission quality or a low volume of the transmitted audio signals. 17. The method of claim 13, wherein the determining the scores includes determining scores less than the specific threshold value, which are indicative of acceptable transmission quality or acceptable volume of the transmitted audio signals. 18. The method of claim 10, wherein the adjusting includes adjusting the volume to accommodate a majority of values obtained after the comparison, relative to a specific threshold value. 19. The method of claim 10, wherein the adjusting includes adjusting the volume to accommodate respective one of the one or more secondary devices having a score that represents a highest number of errors per sample. 20. The method of claim 10, wherein the adjusting includes adjusting the volume to accommodate respective one of the one or more secondary devices having a score that represents a lowest number of errors per sample.
CROSS-REFERENCE TO RELATED APPLICATIONS This Application is a continuation application under 35 U.S.C. §120 of U.S. application Ser. No. 14/440,236, filed on May 1, 2015, which is the U.S. National Stage filing under 35 U.S.C. §371 of International Application No. PCT/US14/33316, filed on Apr. 8, 2014. The disclosures of U.S. application Ser. No. 14/440,236 and International Application No. PCT/US14/33316 are hereby incorporated herein by reference in their entirety. TECHNICAL FIELD The embodiments described herein pertain generally to verifying the quality of media transmission, including sound transmission. BACKGROUND Unless otherwise indicated herein, the approaches described in this section are not prior art to the claims in this application and are not admitted to be prior art by inclusion in this section. Acoustics in open forums may be unpredictable. For example, in an outdoor setting, weather conditions such as wind, cloud cover, and even precipitation may influence how well sound transmitted from a speaker device is heard by one or more persons in a listening audience. As another example, in an indoor setting, conditions such as room size, audience size, furnishings (e.g., size and/or placement), and even the building materials for the walls may affect how well sound from the speaker device may be heard by one or more persons in the listening audience. SUMMARY In one example embodiment, a sound verification system may include: a speaker device that is configured to transmit sound at a dynamic volume level; and a listening device that is configured to receive the sound and provide feedback to the speaker device based on the received sound, wherein the speaker device is further configured to adjust the dynamic volume level based on the feedback provided by the listening device. In another example embodiment, another sound verification system may include: a primary transceiver device that is configured to: transmit sound signals, and convert the sound signals into a primary text version of the transmitted sound signals; the sound verification system may also include a secondary transceiver device that is configured to: receive the sound signals transmitted by the primary transceiver device, convert the received sound signals into a secondary text version of the received sound signals, and transmit the secondary text version of the received sound signals to the primary transceiver device. In yet another example embodiment, a method to verify audio transmission may include a primary device: transmitting audio signals at an initial volume; converting the audio signals into a source text; receiving, respectively from one or more secondary devices, secondary text converted from the transmitted audio signals; comparing the source text to the secondary text received from each of the one or more secondary devices; and adjusting a volume applied to the transmitting based on a result of the comparing. In still another example embodiment, a non-transitory computer-readable medium may be configured to store instructions that, when executed, cause one or more processors to perform operations that include: transmit media signals; store a text version of the media signals; receive, respectively from one or more secondary devices, secondary text converted from the transmitted media signals; compare the stored text version of the media signals to the secondary text received from each of the one or more secondary devices; and adjust an intensity applied to a continued transmitting of the media signals based on a comparison result. The foregoing summary is illustrative only and is not intended to be in any way limiting. In addition to the illustrative aspects, embodiments, and features described above, further aspects, embodiments, and features will become apparent by reference to the drawings and the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS In the detailed description that follows, embodiments are described as illustrations only since various changes and modifications will become apparent to those skilled in the art from the following detailed description. The use of the same reference numbers in different figures indicates similar or identical items. FIG. 1 shows an example configuration of a system by which sound verification may be implemented, arranged in accordance with at least some embodiments described herein; FIG. 2 shows another example configuration of a system by which sound verification may be implemented, arranged in accordance with at least some embodiments described herein; FIG. 3 shows an example configuration of a speaker device by which sound verification may be implemented, arranged in accordance with at least some embodiments described herein; FIG. 4 shows an example configuration of a listening device by which sound verification may be implemented, arranged in accordance with at least some embodiments described herein; FIG. 5 shows an example processing flow by which at least some variations of sound verification may be implemented, arranged in accordance with at least some embodiments described herein; and FIG. 6 shows a block diagram illustrating an example computing device by which various example solutions described herein may be implemented, arranged in accordance with at least some embodiments described herein. DETAILED DESCRIPTION In the following detailed description, reference is made to the accompanying drawings, which form a part of the description. In the drawings, similar symbols typically identify similar components, unless context dictates otherwise. Furthermore, unless otherwise noted, the description of each successive drawing may reference features from one or more of the previous drawings to provide clearer context and a more substantive explanation of the current example embodiment. Still, the example embodiments described in the detailed description, drawings, and claims are not meant to be limiting. Other embodiments may be utilized, and other changes may be made, without departing from the spirit or scope of the subject matter presented herein. It will be readily understood that the aspects of the present disclosure, as generally described herein and illustrated in the drawings, may be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are explicitly contemplated herein. There are many settings, both outdoor and indoor, in which sound may be disseminated to a listening audience. For example, a person may speak or even sing into a microphone to electronically generate sounds that may be transmitted to a listening audience via one or more speakers. Non-limiting examples of settings for such electronic dissemination of generated sound may include, but not be limited to, conference rooms, auditoriums, indoor arenas, outdoor stadiums, public squares or forums, airports, train stations, bus stations, walking or mobile tours of college or corporate campuses, walking or mobile tours of museums, parade routes, etc. However, because acoustics in such settings may vary for reasons ranging, as non-limiting examples, from weather to audience size to building materials, the embodiments described herein may enable listener feedback to facilitate dynamic volume adjustments in the electronic dissemination of the generated sound. FIG. 1 shows an example configuration of a system 100 by which sound verification may be implemented, arranged in accordance with at least some embodiments described herein. Non-limiting examples of system 100 may be configured in a conference room, an auditorium, an indoor arena, an outdoor stadium, a public squares or forum, airports, train stations, bus stations, a college or corporate campus, a museum, a parade route, etc. As depicted, FIG. 1 shows primary transceiver device 105, e.g., a speaker device 105, and secondary transceiver devices 110A-110N, e.g., listening devices 110A-110N. Unless context of an embodiment requires specific reference to one or more of secondary transceiver devices 110A-110N, e.g., listening devices 110A-110N, individual reference may be made to representative “secondary transceiver device 110 e.g., listening device 110” and corporate reference may be made to collective “secondary transceiver devices 110 e.g., listening devices 110.” Although FIG. 1 shows four representations of secondary transceiver devices 110A-110N, e.g. listening devices 110A-110N, embodiments of sound verification are in no way limited to such quantity. System 100 may represent a sound verification system that includes a primary transceiver device 105, e.g., a speaker device, which may be configured to transmit sound at a dynamic volume level, and a secondary transceiver device 110 e.g., a listening device, that may be configured to receive the sound and provide feedback to the speaker device based on the received sound. The primary transceiver device may be further configured to adjust the dynamic volume level based on the feedback provided by the secondary transceiver device. Alternatively, system 100 may be a sound verification system that includes a primary transceiver device 105, e.g., a speaker device, which may be configured to transmit sound signals and convert the sound signals into a primary text version of the transmitted sound signals. The sound verification system may also include a secondary transceiver device 110, e.g., a listening device, that may be configured to receive the sound signals transmitted by the primary transceiver device, convert the received sound signals into a secondary text version of the received sound signals, and transmit the secondary text version of the received sound signals to the primary transceiver device. Speaker device 105 may refer to an electro-mechanical transceiver device that may be configured to produce sound in response to electrical audio input signals, and to transmit the produced sound at dynamic volume level. Speaker device 105 may produce sound by converting electrical signals into audible signals. As referenced herein, a dynamic volume level may refer to a volume level that is either automatically or manually adjustable. As non-limiting examples, embodiments of speaker device 105 may be used to produce and/or transmit audible representations of songs, public announcements, speeches, lectures, discussions, etc., in various public and private forums such as schools, classrooms, offices, conference rooms, lecture halls, theaters, arenas, stadiums, airports, airplanes, train stations, trains, bus terminals, busses, sidewalks, etc. One or more of the aforementioned non-limiting examples of speaker device 105 may be affixed to a structure. Alternatively, speaker device 105 may be portable, and therefore additional non-limiting examples of speaker device 105 may be hand-held, externally and temporarily affixed to a vehicle, temporarily placed in a room, etc. Non-limiting examples of speaker devices 105 may include audio speakers for classrooms, conference rooms, theaters, auditoriums, etc., used to transmit sound in one or more of the above-listed public and private forums. Alternatively, further non-limiting examples of speaker device may 105 may include cell phones, smartphones, tablet computers, laptop computers, or any other device capable of transmitting sound in one or more of the above-listed forums. Speaker device 105 may be further configured to convert the produced sound to text. That is, for embodiments of sound verification, speaker device 105 may be capable of converting locally produced sounds into a text representation thereof. The produced sounds may be audio representations of words, which may be spoken, whispered, rapped, sung, chanted, etc. To generate an accurate audio-to-text conversion, speaker device 105 may be equipped with at least a receiver, e.g., a microphone, configured to capture the locally produced sound, and a converter configured to convert the captured sound into text. The audio-to-text conversion may be executed by speaker device 105 or, alternatively, by a conversion device that is external to speaker device 105. The present description will refer to the audio-to-text conversion being executed by speaker device 105, although alternative embodiments of sound verification are not limited to such configuration. Further, as will be described below, the converter may be implemented as a software component, a hardware feature, or a combination thereof. Speaker device 105 may still further be configured to compare the text representation of the produced sound converted at speaker device 105 to other text representations of the same produced sound. The other text representations of the same produced sound may be converted at one or more of secondary transceiver devices 110 e.g., listening devices, which may be configured to execute similar audio-to-text conversions as speaker device 105; and the text representations generated by listening devices 110 may be transmitted to speaker device 105, as will be described further below. Results of the comparisons of the text representations of the produced sound, respectively converted by speaker device 105 and one or more of listening devices 110, may influence a dynamic adjustment of the volume for continued transmission of sound produced by speaker device 105. The dynamic adjustment of sound transmitted from speaker device 105 may be manually or automatically executed. Listening devices 110 may each respectively refer to electro-mechanical transceiver devices that may be configured to receive the sound transmitted by speaker device 105, and to provide feedback to verify the quality, e.g., volume, of the received sound. Embodiments of listening devices 110 may be hand-held, portable, and/or affixed in various public and private forums such as schools, classrooms, offices, conference rooms, lecture halls, theaters, arenas, stadiums, airports, airplanes, train stations, trains, bus terminals, busses, sidewalks, etc. One or more of the aforementioned non-limiting examples of listening device 110 may be affixed to a structure. Non-limiting examples of listening devices 110 may include cell phones, smartphones, tablet computers, laptop computers, specialized listening devices, e.g., individual headsets used for museum tours, headphones, etc. Listening devices 110 may be configured to convert the produced sound received from speaker device 105 into a text representation thereof. To generate an accurate audio-to-text conversion, listening devices 110 may be equipped with at least a receiver, e.g., a microphone, configured to capture at least portions of the produced sound received from speaker device 105, which may then be converted into a text representation. Listening devices 110 may also be configured to transmit the text representation of the produced sound to speaker device 105, as will be described further below, by various protocols including, but not limited to, text message (via short-messaging-service (SMS)), Bluetooth, email, etc. Results of the comparisons of text representations of the produced sound, respectively converted by speaker device 105 and one or more of listening devices 110, may influence a dynamic adjustment of the volume at which sound produced by speaker device 105 is transmitted. FIG. 2 shows another example configuration of a system 200 by which sound verification may be implemented, arranged in accordance with at least some embodiments described herein. Similar to system 100 described above with regard to FIG. 1, non-limiting examples of system 200 may be configured in a conference room, an auditorium, a theater, an indoor arena, an outdoor stadium, a public square or forum, a college or corporate campus, a museum, a parade route, etc. FIG. 2 shows primary transceiver devices 105A and 105B, e.g., speaker device 105A and 105B, as well as listening devices 110. Unless context of a corresponding description requires specific reference to one or more of speaker devices 105A and 105B, individual reference may be made to representative “speaker device 105” and corporate reference may be made to collective “speaker devices 105.” Further, although FIG. 2 shows two representations of speaker devices 105A and 105B, embodiments of sound verification are in no way limited to such quantity. System 200 may be a sound verification system that includes multiple primary transceiver devices, e.g., speaker devices that may each be configured to transmit sound at a dynamic volume level, and one or more secondary transceiver devices, e.g., listening devices that may each be configured to receive the sound and provide feedback to at least one of the primary transceiver devices, e.g., the speaker devices based on the received sound. The primary transceiver devices, e.g., speaker devices may be further configured to adjust the dynamic volume level based on the feedback provided by the one or more secondary transceiver devices, e.g., listening devices. Alternatively, system 200 may be a sound verification system that includes multiple primary transceiver devices, e.g., speaker devices that may each be configured to transmit sound signals and convert the sound signals into a primary text version of the transmitted sound signals. The sound verification system may also include one or more secondary transceiver devices, e.g., listening devices that may be configured to receive the sound signals transmitted by the primary transceiver devices, e.g., speaker devices, convert the received sound signals into a secondary text version of the received sound signals, and transmit the secondary text version of the received sound signals to at least one of the primary transceiver devices, e.g., speaker devices. Speaker devices 105A and 105B represent multiple embodiments of speaker device 105, which is described above with regard to FIG. 1. Thus, as described above with regard to FIG. 1, speaker devices 105 may be primary transceiver devices configured to transmit sound at dynamic volume level by producing sound in response to electrical audio signal input. Further, speaker devices 105 may be configured to convert the produced sound to a text representation thereof. Further still, speaker device 105 may be configured to compare the text representation of the produced sound converted at speaker device 105 to other text representations of the same produced sound. Listening devices 110 are the same as described above with regard to FIG. 1. However, in system 200, listening devices 110 may be secondary transceiver devices configured to receive sound transmitted by one or more embodiments of speaker devices 105, and provide feedback to verify the quality, e.g., volume, of the received sound to at least one of speaker devices 105. Because, for example, listening device 110A is unlikely to receive produced sound transmitted from speaker device 105A at the same time as it receives produced sound transmitted from speaker device 105B, depending on the respective proximity of listening device 110A to speaker device 105A and speaker device 105B, listening devices 110 may be further configured to distinguish produced sound received from respective embodiments of speaker devices 105. That is, listening devices 110 may be configured to distinguish sound received from different sources due to latencies caused by the speed at which sound travels, reverberations in sound waves, etc. As described above with regard to FIG. 1, listening devices 110 may be configured to convert the produced sound received from speaker device 105 into text representations thereof. To distinguish the produced sound transmitted from speaker device 105A from the produced sound transmitted from speaker device 105B, the receiver, e.g., a microphone, corresponding to listening device 110 may be configured to capture sound, for transmittal to the converter (described below), received at either of a same volume or a same frequency. Thus, listening device 110 may distinguish sound from different sources. As described above with regard to FIG. 1, listening devices 110 may be configured to provide feedback to verify the quality, e.g., volume, of the received sound to one or more of speaker devices 105, by various protocols including, but not limited to, text message (via SMS), Bluetooth, email, etc. Results of the comparisons of text representations of the produced sound, respectively converted by speaker device 105 and one or more of listening devices 110, may influence a dynamic adjustment of the volume at which sound produced by speaker device 105 is transmitted. FIG. 3 shows an example configuration of primary transceiver device 105 by which sound verification may be implemented, arranged in accordance with at least some embodiments described herein. As illustrated in FIG. 3, primary transceiver device 105 may correspond to speaker device 105 shown in, and described with regard to, FIGS. 1 and 2. As depicted, primary transceiver device 105 may be configured to include a transmitter 305, a converter 310, a receiver 315, a comparator 320, and an adjustor 325. In accordance with the embodiments described herein, primary transceiver device 105 and the components thereof shown in FIG. 3 may be implemented as hardware, software, firmware, or any combination thereof. Further, it will be readily understood that the components of primary transceiver device 105, as generally described herein and illustrated in FIG. 3, may be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are explicitly contemplated herein. Transmitter 305 may represent a component or module configured to produce or generate sound in response to electrical audio input signals, and to transmit the produced sound at dynamic volume level. That is, transmitter 305 may function as an audio transmitter. Converter 310 may represent a component or module configured to convert words included in the produced sound, transmitted by transmitter 305, into a localized text representation. Converter 310 may convert sounds captured by, e.g., a microphone, corresponding to primary transceiver device 105 that is configured to capture or receive the locally produced sound. The words included in the produced sound may be spoken, whispered, rapped, sung, chanted, etc. Further, converter 310 may produce a sound-to-text conversion of the transmitted sound using known conversion applications. Further still, converter 310 may be implemented for multiple languages. Alternative embodiments of converter 310 may be configured to directly convert sound from an MP3, MP4, or other digital recording format into a text representation thereof. Similarly, converter 310 may be configured to directly convert sounds, e.g., words, from any digitally streamed media content into a text representation, either before, during, or after the sounds are transmitted by transmitter 305. The localized text representation of words included in the produced sound, transmitted by transmitter 305, may be stored in a local or remote storage component. When stored, the localized text representation may be divided into one or more samples. Non-limiting examples of parameters for such samples may include a particular number of words, e.g., 25 words; words spoken over a predetermined period of time, e.g., every 30 seconds; or words spoken at a specified time period, e.g., from 04:10:15 to 04:10:45. Regardless of how the sampling sizes are determined, converter 310 may attach metadata to the tag to the respective samples to indicate parameters of the sample. Receiver 315 may represent a component or module configured to receive text representations of the produced sounds converted at one or more receiving transceiver devices, which may be configured to execute similar audio-to-text conversions as primary transceiver 105. The received text representations may be received by various protocols including, but not limited to, text message (via SMS), Bluetooth, email, etc. The received text representations may be similarly sampled as the localized text representations. Thus, as non-limiting examples, the received text representations may be tagged with metadata to indicate parameters thereof including, but not limited to, a particular number of words, words spoken over a predetermined period of time, or words spoken at a specified time period. Comparator 320 may represent a component or module configured to compare samples of the localized text representation to similar samples of one or more received text representations of the transmitted produced sound that are received from one or more listening devices 110. To perform the comparisons, comparator 320 may regard the samples of the localized text representation as the most accurate representations of the transmitted produced sound. Thus, the result of any comparison between a sample of the localized text representation and to a sample of a received text representation of the transmitted produced sound may include a score that indicates a number of errors per sample. In accordance with the example embodiment described above with regard to FIG. 2, the per-sample scores may be recorded with respect to listening devices 110 from which the respective samples of the received text representations are received. Adjustor 325 may represent a component or module configured to determine whether the dynamic volume level at which the produced sound is transmitted from transmitter 305 should remain the same or be increased. Such determination may be made based on the scores determined by comparator 320. Various embodiments of sound verification may include different thresholds by which a determination is made to increase the dynamic volume level. As non-limiting examples, a determination to increase the volume may be made if 5 errors were recorded in a sampling of the most recent 25 words, if 7 errors were recorded over the past 30 seconds, or if 3 errors were recorded between 04:10:15 to 04:10:45. Above-threshold scores may be indicative of poor sound transmission quality, e.g., low volume; and a prescribed solution may be to increase the dynamic volume at which the produced sound is transmitted from transmitter 305. Scores that are below the threshold may be indicative of sufficient or acceptable sound transmission quality, and therefore the dynamic volume at which the produced sound is transmitted from transmitter 305 may remain the same. In accordance with the example embodiment described above with regard to FIG. 2, when comparator 320 compares one or more samples of the localized text representation of the transmitted sound to corresponding samples received from more than one of listening devices 110, adjustor 325 may adjust the dynamic volume level to accommodate a respective one of listening devices 110 having a score that represents a highest number of errors per sample, a lowest number of errors per sample, or an average number of errors per sample. As described above, the actual adjusting of the dynamic volume level by which produced sounds are transmitted by transmitter 305 may be performed automatically or manually. In one or more alternative embodiments of primary transceiver device 105, one or more of components 305, 310, 315, 320, and 325 may be combined, eliminated, or even separated into one or more different devices, depending on the desired implementation. For example, comparator 320 and adjustor 325 may be hosted on an application or program that is configured to execute on a separate device. Non-limiting examples of such a separate device may include cell phones, smartphones, tablet computers, laptop computers, or any other device capable of transmitting volume adjusting instructions to primary transceiver device 105 by various protocols including, but not limited to, text message (via SMS), Bluetooth, email, etc. FIG. 4 shows an example configuration of secondary transceiver device 110 by which sound verification may be implemented, arranged in accordance with at least some embodiments described herein. As illustrated in FIG. 4, secondary transceiver device 110 may correspond to listening device 110 shown in, and described with regard to, FIGS. 1 and 2. As depicted, secondary transceiver device 110 may be configured to include a receiver 405, a converter 410, and a transmitter 415. In accordance with the embodiments described herein, secondary transceiver device 110 and the components thereof shown in FIG. 4 may be implemented as hardware, software, firmware, or any combination thereof. Further, it will be readily understood that the components of secondary transceiver device 110, as generally described herein and illustrated in FIG. 4, may be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are explicitly contemplated herein. Receiver 405 may represent a component or module configured to receive sounds transmitted from primary transceiver device 105. Receiver 405 may capture sounds using, e.g., a microphone, corresponding to secondary transceiver device 110. Converter 410 may represent a component or module configured to convert words included in the received sound, received by receiver 405, into a text representation thereof. The sound received by receiver 405 may or may not be a sound transmitted by primary transceiver device 105. The words included in the received sound may be spoken, whispered, rapped, sung, chanted, etc., and the sound-to-text conversion may be executed using known conversion applications. The converted text representations of the received sound may be divided into one or more samples. Non-limiting examples of parameters for such samples may include a particular number of words, e.g., 25 words; words spoken over a predetermined period of time, e.g., every 30 seconds; or words spoken at a specified time period, e.g., from 04:10:15 to 04:10:45. Regardless of how the sampling sizes are determined, converter 410 may attach metadata to tag the respective samples to indicate parameters of the sample. Transmitter 415 may represent a component or module configured to transmit one or more of the samples of the converted text representations of the received sound to primary transceiver device 105 by various protocols including, but not limited to, text message (via SMS), Bluetooth, email, etc. As described above with regard to FIG. 3, the text representation samples transmitted by transmitter 415 may be compared to corresponding text representations samples produced by primary transceiver device 105. The results of such comparisons may determine whether the dynamic volume level at which produced sound is transmitted from primary transceiver device 105 is to remain the same or be increased. In or more alternative embodiments of secondary transceiver device 110, one or more of components 405, 410, and 415 may be combined, eliminated, or even separated into one or more different devices, depending on the desired implementation. FIG. 5 shows an example processing flow 500 by which at least some variations of sound verification may be implemented, arranged in accordance with at least some embodiments described herein. Processing flow 500 may refer in part to a method, performed by primary transceiver device 105, to verify audio transmission, that includes: transmitting audio signals at an initial volume; converting the audio signals into a source text; receiving, respectively from one or more of secondary transceiver devices 110, secondary text converted from the transmitted audio signals; comparing the source text to the secondary text received from each of the one or more secondary transceiver devices; and adjusting a volume applied to the transmitting based on a result of the comparison. Alternatively, processing flow may refer to a method to verify audio transmission, that includes: transmitting media signals; storing a text version of the media signals; receiving, respectively from one or more of secondary transceiver devices 110, secondary text converted from the transmitted media signals; comparing the stored text version of the media signals to the secondary text received from each of the one or more secondary transceiver devices; and adjusting an intensity applied to a continued transmitting of the media signals based on a comparison result. Processing flow 500 may include one or more operations, actions, or functions depicted by one or more blocks 505, 507, 509, 510, 511, 515, 520, and 525. Further, the operations, actions, or functions depicted by blocks 505, 510, 515, 520, and 525 may be attributed to primary transceiver device 105 described above with regard to FIGS. 1, 2, and 3; and the operations, actions, or functions depicted by blocks 507, 509, and 511 may be attributed to secondary transceiver device 110 described above with regard to FIGS. 1, 2, and 4. Although illustrated as discrete blocks, various blocks may be performed sequentially, performed in parallel, divided into additional blocks, combined into fewer blocks, or eliminated, depending on the desired implementation. Processing may begin at block 505. Block 505 (Transmit) may refer to transmitter 305 corresponding to primary transceiver device 105 producing sound in response to electrical audio input signals and transmitting the produced sound at a dynamic volume level. The transmitted sounds may include words that may be spoken, whispered, rapped, sung, chanted, etc. Block 505 may be followed by block 510 at primary transceiver device 105; and block 505 may be followed by block 507 at secondary transceiver device 110. Block 507 (Receive) may refer to receiver 405 corresponding to secondary transceiver device 110 receiving the produced sounds transmitted from transmitter 305 corresponding to at least one embodiment of primary transceiver device 105. Block 507 may be followed by block 509 at secondary transceiver device 110. Block 509 (Convert to Text) may refer to converter 410 corresponding to secondary transceiver device 110 converting words included in the received sound, transmitted by primary transceiver device 105, into a text representation thereof. The words included in the received sound may be spoken, whispered, rapped, sung, chanted, etc., and the sound-to-text conversion may be executed using known conversion applications. Further, the converted text representations of the received sound may be divided into one or more samples. Non-limiting examples of parameters for such samples may include a particular number of words, words spoken over a predetermined period of time, or words spoken at a specified time period. Block 509 may further include metadata being attached to tag the respective samples to indicate parameters of the sample. Block 509 may be followed by block 511 at secondary transceiver device 110. Block 510 (Convert to Text & Store Text) may refer to converter 310 corresponding to primary transceiver device 105 converting words included in the produced sound, transmitted by transmitter 305, into a localized text representation thereof. The words included in the produced sound may be spoken, whispered, rapped, sung, chanted, etc. Block 510 may be executed using known conversion applications. The localized text representation of words included in the produced sound may be stored in a local or remote storage component. When stored, the localized text representation may be divided into one or more samples. Non-limiting examples of parameters for such samples may include a particular number of words, words spoken over a predetermined period of time, or words spoken at a specified time period. Block 510 may further include metadata being attached to tag the respective samples to indicate parameters of the sample. Block 510 may be followed by block 515 at primary transceiver device 105. Block 511 (Transmit Text) may refer to transmitter 415 corresponding to secondary transceiver device 110 transmitting one or more of the samples of the converted text representations of the received sound to primary transceiver device 105. Block 511 may be followed by block 515 at primary transceiver device 105. Block 515 (Receive Text From Secondary Device) may refer to receiver 315 corresponding to primary transceiver device 105 text representations of the produced sounds converted at one or more receiving transceiver devices, which may be configured to execute similar audio-to-text conversions as primary transceiver 105. The received text representations may be similarly sampled as the localized text representations. Thus, as non-limiting examples, the received text representations may be tagged with metadata to indicate parameters thereof including, but not limited to, a particular number of words, words spoken over a predetermined period of time, or words spoken at a specified time period. Accordingly, block 515 may further refer to receiver 315 and/or comparator 320 corresponding to primary transceiver device 105 matching samples of the localized text representations to samples of the received text representations, based on at least the metadata used to tag the respective samples. Block 515 may be followed by decision block 520 at primary transceiver device 105. Decision block 520 may refer to comparator corresponding to primary transceiver device 105 comparing samples of the localized text representation to samples of one or more received text representations of the transmitted produced sound that are received from one or more receiving transceiver devices. The samples of the localized text representation are matched, for the purpose of being compared, to the samples of the received text representations based on at least the metadata used to tag the respective samples. The result of any comparison between a sample of the localized text representation and to a sample of a received text representation of the transmitted produced sound may include a score that indicates a number of errors per sample. Various embodiments of sound verification may include different thresholds by which a determination is made to increase the dynamic volume level. As non-limiting examples, a determination to increase the volume may be made if 5 errors were recorded in a sampling of the most recent 25 words, if 7 errors were recorded over the past 30 seconds, or if 3 errors were recorded between 04:10:15 to 04:10:45. A positive determination, i.e., yes, at decision block 520, may be followed by block 525 at primary transceiver device 105. A negative determination, i.e., no, at decision block 520, may advance processing flow 500 back to block 505. That is, if the comparison results in a number of errors per sample that falls within an acceptable range, e.g., below the threshold level, a determination may be made that the volume of sound transmission from transmission 305 is sufficient for the embodiment of secondary transceiver device 110 from which the received text representation sample was received. Block 525 (Adjust) may refer to adjustor 325 corresponding to primary transceiver device 105 determining that the dynamic volume level at which the produced sound is transmitted from primary transceiver device 105 should be increased based on the scores determined by comparator 320. Various embodiments of sound verification may include different thresholds by which a determination is made to increase the dynamic volume level. Thus, when the comparison results in a number of errors per sample that exceeds an acceptable threshold level, a determination may be made that the volume of sound transmission from transmitter 305 should be increased because the produced sound is not being heard clearly at the embodiment of secondary transceiver device 110 from which the received text representation sample was received. FIG. 6 shows a block diagram illustrating an example computing device by which various example solutions described herein may be implemented, arranged in accordance with at least some embodiments described herein. In a very basic configuration 602, computing device 600 typically includes one or more processors 604 and a system memory 606. A memory bus 608 may be used for communicating between processor 604 and system memory 606. Depending on the desired configuration, processor 604 may be of any type including but not limited to a microprocessor (μP), a microcontroller (μC), a digital signal processor (DSP), or any combination thereof. Processor 604 may include one or more levels of caching, such as a level one cache 610 and a level two cache 612, a processor core 614, and registers 616. An example processor core 614 may include an arithmetic logic unit (ALU), a floating point unit (FPU), a digital signal processing core (DSP Core), or any combination thereof. An example memory controller 618 may also be used with processor 604, or in some implementations, memory controller 618 may be an internal part of processor 604. Depending on the desired configuration, system memory 606 may be of any type including but not limited to volatile memory (such as RAM), non-volatile memory (such as ROM, flash memory, etc.) or any combination thereof. System memory 606 may include an operating system 620, one or more applications 622, and program data 624. Application 622 may include one or more comparison algorithms 626 that may be arranged to perform the functions as described herein including those described with respect to processing flow 500 of FIG. 5. Program data 624 may include sample matching data 628 that may be utilized for matching samples of the localized text representations and received text representations for execution of the comparison algorithm 626 as described herein. Sample matching data 628 may include data for matching received sample in accordance with metadata that may include parameters described above with regard to FIGS. 1-4, as well as volume and frequency matching. In some embodiments, application 622 may be arranged to operate with program data 624 on operating system 620 such that samples may be matched and accurate comparisons may be provided, as described herein. This described basic configuration 602 is illustrated in FIG. 6 by those components within the inner dashed line. Computing device 600 may have additional features or functionality, and additional interfaces to facilitate communications between basic configuration 602 and any required devices and interfaces. For example, a bus/interface controller 630 may be used to facilitate communications between basic configuration 602 and one or more data storage devices 632 via a storage interface bus 634. Data storage devices 632 may be removable storage devices 636, non-removable storage devices 638, or a combination thereof. Examples of removable storage and non-removable storage devices include magnetic disk devices such as flexible disk drives and hard-disk drives (HDD), optical disk drives such as compact disk (CD) drives or digital versatile disk (DVD) drives, solid state drives (SSD), and tape drives to name a few. Example computer storage media may include volatile and nonvolatile, removable and non-removable media implemented in any method or technology for storage of information, such as computer readable instructions, data structures, program modules, or other data. System memory 606, removable storage devices 636 and non-removable storage devices 638 are examples of computer storage media. Computer storage media includes, but is not limited to, RAM, ROM, EEPROM, flash memory or other memory technology, CD-ROM, DVD or other optical storage, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage devices, or any other medium which may be used to store the desired information and which may be accessed by computing device 600. Any such computer storage media may be part of computing device 600. Computing device 600 may also include an interface bus 640 for facilitating communication from various interface devices (e.g., output devices 642, peripheral interfaces 644, and communication devices 646) to basic configuration 602 via bus/interface controller 630. Example output devices 642 include a graphics processing unit 648 and an audio processing unit 650, which may be configured to communicate to various external devices such as a display or speakers via one or more A/V ports 652. Example peripheral interfaces 644 include a serial interface controller 654 or a parallel interface controller 656, which may be configured to communicate with external devices such as input devices (e.g., keyboard, mouse, pen, voice input device, touch input device, etc.) or other peripheral devices (e.g., printer, scanner, etc.) via one or more I/O ports 658. An example communication device 646 includes a network controller 660, which may be arranged to facilitate communications with one or more other computing devices 662 over a network communication link via one or more communication ports 664. The network communication link may be one example of a communication media. Communication media may typically be embodied by computer readable instructions, data structures, program modules, or other data in a modulated data signal, such as a carrier wave or other transport mechanism, and may include any information delivery media. A modulated data signal may be a signal that has one or more of its characteristics set or changed in such a manner as to encode information in the signal. By way of example, and not limitation, communication media may include wired media such as a wired network or direct-wired connection, and wireless media such as acoustic, radio frequency (RF), microwave, infrared (IR) and other wireless media. The term computer readable media as used herein may include both storage media and communication media. Computing device 600 may be implemented as a portion of a small-form factor portable (or mobile) electronic device such as a cell phone, a personal data assistant (PDA), a personal media player device, a wireless web-watch device, a personal headset device, an application specific device, or a hybrid device that include any of the above functions. Computing device 600 may also be implemented as a server or a personal computer including both laptop computer and non-laptop computer configurations. According to some examples, a sound verification system may include a speaker device and a listening device. The speaker device may be configured to transmit sound at a dynamic volume level. The listening device may be configured to receive the sound and provide feedback to the speaker device based on the received sound, wherein the speaker device may be further configured to adjust the dynamic volume level based on the feedback provided by the listening device. In other examples of the sound verification system, the feedback provided by the listening device to the speaker device may be a sound-to-text conversion of the received sound. In still other examples of the sound verification system, the speaker device may be further configured to convert the transmitted sound to a localized text version of the transmitted sound, and to adjust the dynamic volume level based on a comparison of the localized text version of the transmitted sound to the sound-to-text version of the received sound provided by the listening device. According to various examples, a sound verification system may include a primary transceiver device and a secondary transceiver device. The primary transceiver device may be configured to transmit sound signals, and convert the sound signals into a primary text version of the transmitted sound signals. The secondary transceiver device may be configured to receive the sound signals transmitted by the primary transceiver device, convert the received sound signals into a secondary text version of the received sound signals, and transmit the secondary text version of the received sound signals to the primary transceiver device. In other examples of the sound verification system, the primary transceiver device may be configured to receive the secondary text version of the received sound signals from the secondary transceiver device, grade a level of accuracy of a comparison of the primary text version of the transmitted sound signals relative to the secondary text version of the received sound signals, and adjust a volume level based on the grade as transmission of sound signals continues. According to some examples, a method to verify audio transmission by a computing device may include transmitting audio signals at an initial volume; converting the audio signals into a source text, receiving; respectively from one or more secondary devices, secondary text converted from the transmitted audio signals; comparing the source text to the secondary text received from each of the one or more secondary devices; and adjusting a volume applied to the transmitting based on a result of the comparing. In some examples, the method to verify audio transmission by a computing device may be repeated periodically. In still other examples, the method to verify audio transmission by a computing device may be repeated periodically by multiple primary devices. In further examples, in the method to verify audio transmission by a computing device, the comparing may include assigning a score to a comparison between the source text to the secondary text received from a respective one of the secondary devices, and the adjusting may include increasing the volume in response to one of the scores being less than a threshold value. In some examples, in the method to verify audio transmission by a computing device, the comparing may include assigning a score to a comparison between the source text to the secondary text received from a respective one of the secondary devices, and the adjusting may include increasing the volume in response to the majority of the scores being less than a threshold value. In various examples, in the method to verify audio transmission by a computing device, the comparing may include assigning a score to a comparison between the source text to the secondary text received from a respective one of the secondary devices, and the adjusting may include decreasing the volume in response to the majority of the scores being greater than a threshold value. In some examples, a non-transitory computer-readable medium may be configured to store instructions. The instructions, when executed, may cause one or more processors to transmit media signals; store a text version of the media signals; receive, respectively from one or more secondary devices, secondary text converted from the transmitted media signals; compare the stored text version of the media signals to the secondary text received from each of the one or more secondary devices; and adjust an intensity applied to a continued transmitting of the media signals based on a comparison result. In other examples, the media signals include audio signals, and the adjusting may include adjusting a dynamic volume applied to the continued transmitting of the audio signals based on the comparison result; or the adjusting may include accommodating a majority of values of the comparison result, relative to a threshold value. In still other examples, the one or more processors may be configured to periodically repeat execution of the instructions. In further examples, the one or more processors may be configured to periodically repeat execution of the instructions in concert with the one or more processors of one or more other devices. In still further examples, the adjusting includes accommodating a lowest value of the comparison result or accommodating a highest value of the comparison result. There is little distinction left between hardware and software implementations of aspects of systems; the use of hardware or software is generally (but not always, in that in certain contexts the choice between hardware and software can become significant) a design choice representing cost vs. efficiency tradeoffs. There are various vehicles by which processes and/or systems and/or other technologies described herein may be implemented, e.g., hardware, software, and/or firmware, and that the preferred vehicle may vary with the context in which the processes and/or systems and/or other technologies are deployed. For example, if an implementer determines that speed and accuracy are paramount, the implementer may opt for a mainly hardware and/or firmware vehicle; if flexibility is paramount, the implementer may opt for a mainly software implementation; or, yet again alternatively, the implementer may opt for some combination of hardware, software, and/or firmware. The foregoing detailed description has set forth various embodiments of the devices and/or processes for system configuration 100 via the use of block diagrams, flowcharts, and/or examples. Insofar as such block diagrams, flowcharts, and/or examples contain one or more functions and/or operations, it will be understood by those within the art that each function and/or operation within such block diagrams, flowcharts, or examples can be implemented, individually and/or collectively, by a wide range of hardware, software, firmware, or virtually any combination thereof. In one embodiment, several portions of the subject matter described herein may be implemented via Application Specific Integrated Circuits (ASICs), Field Programmable Gate Arrays (FPGAs), digital signal processors (DSPs), or other integrated formats. However, those skilled in the art will recognize that some aspects of the embodiments disclosed herein, in whole or in part, can be equivalently implemented in integrated circuits, as one or more computer programs running on one or more computers, e.g., as one or more programs running on one or more computer systems, as one or more programs running on one or more processors, e.g., as one or more programs running on one or more microprocessors, as firmware, or as virtually any combination thereof, and that designing the circuitry and/or writing the code for the software and/or firmware would be well within the skill of one of skill in the art in light of this disclosure. In addition, those skilled in the art will appreciate that the mechanisms of the subject matter described herein are capable of being distributed as a program product in a variety of forms, and that an illustrative embodiment of the subject matter described herein applies regardless of the particular type of signal bearing medium used to actually carry out the distribution. Examples of a signal bearing medium include, but are not limited to, the following: a recordable type medium such as a floppy disk, a hard disk drive (HDD), a compact disk (CD), a digital versatile disk (DVD), a digital tape, a computer memory, etc.; and a transmission type medium such as a digital and/or an analog communication medium, e.g., a fiber optic cable, a waveguide, a wired communication link, a wireless communication link, etc. Those skilled in the art will recognize that it is common within the art to describe devices and/or processes in the fashion set forth herein, and thereafter use engineering practices to integrate such described devices and/or processes into data processing systems. That is, at least a portion of the devices and/or processes described herein can be integrated into a data processing system via a reasonable amount of experimentation. Those having skill in the art will recognize that a typical data processing system generally includes one or more of a system unit housing, a video display device, a memory such as volatile and non-volatile memory, processors such as microprocessors and digital signal processors, computational entities such as operating systems, drivers, graphical user interfaces, and applications programs, one or more interaction devices, such as a touch pad or screen, and/or control systems including feedback loops and control motors, e.g., feedback for sensing location and/or velocity; control motors for moving and/or adjusting components and/or quantities. A typical data processing system may be implemented utilizing any suitable commercially available components, such as those typically found in data computing/communication and/or network computing/communication systems. The herein described subject matter sometimes illustrates different components contained within, or connected with, different other components. It is to be understood that such depicted architectures are merely examples, and that in fact many other architectures can be implemented which achieve the same functionality. In a conceptual sense, any arrangement of components to achieve the same functionality is effectively “associated” such that the desired functionality is achieved. Hence, any two components herein combined to achieve a particular functionality can be seen as “associated with” each other such that the desired functionality is achieved, irrespective of architectures or intermedial components. Likewise, any two components so associated can also be viewed as being “operably connected”, or “operably coupled”, to each other to achieve the desired functionality, and any two components capable of being so associated can also be viewed as being “operably couplable”, to each other to achieve the desired functionality. Specific examples of operably couplable include but are not limited to physically mateable and/or physically interacting components and/or wirelessly interactable and/or wirelessly interacting components and/or logically interacting and/or logically interactable components. Lastly, with respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims, e.g., bodies of the appended claims, are generally intended as “open” terms, e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc. It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation, no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an,” e.g., “a” and/or “an” should be interpreted to mean “at least one” or “one or more;” the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number, e.g., the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations. Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general, such a construction is intended in the sense one having skill in the art would understand the convention, e.g., “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc. In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general, such a construction is intended in the sense one having skill in the art would understand the convention, e.g., “a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc. It will be further understood by those within the art that virtually any disjunctive word and/or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.” From the foregoing, it will be appreciated that various embodiments of the present disclosure have been described herein for purposes of illustration, and that various modifications may be made without departing from the scope and spirit of the present disclosure. Accordingly, the various embodiments disclosed herein are not intended to be limiting, with the true scope and spirit being indicated by the following claims.
<SOH> BACKGROUND <EOH>Unless otherwise indicated herein, the approaches described in this section are not prior art to the claims in this application and are not admitted to be prior art by inclusion in this section. Acoustics in open forums may be unpredictable. For example, in an outdoor setting, weather conditions such as wind, cloud cover, and even precipitation may influence how well sound transmitted from a speaker device is heard by one or more persons in a listening audience. As another example, in an indoor setting, conditions such as room size, audience size, furnishings (e.g., size and/or placement), and even the building materials for the walls may affect how well sound from the speaker device may be heard by one or more persons in the listening audience.
<SOH> SUMMARY <EOH>In one example embodiment, a sound verification system may include: a speaker device that is configured to transmit sound at a dynamic volume level; and a listening device that is configured to receive the sound and provide feedback to the speaker device based on the received sound, wherein the speaker device is further configured to adjust the dynamic volume level based on the feedback provided by the listening device. In another example embodiment, another sound verification system may include: a primary transceiver device that is configured to: transmit sound signals, and convert the sound signals into a primary text version of the transmitted sound signals; the sound verification system may also include a secondary transceiver device that is configured to: receive the sound signals transmitted by the primary transceiver device, convert the received sound signals into a secondary text version of the received sound signals, and transmit the secondary text version of the received sound signals to the primary transceiver device. In yet another example embodiment, a method to verify audio transmission may include a primary device: transmitting audio signals at an initial volume; converting the audio signals into a source text; receiving, respectively from one or more secondary devices, secondary text converted from the transmitted audio signals; comparing the source text to the secondary text received from each of the one or more secondary devices; and adjusting a volume applied to the transmitting based on a result of the comparing. In still another example embodiment, a non-transitory computer-readable medium may be configured to store instructions that, when executed, cause one or more processors to perform operations that include: transmit media signals; store a text version of the media signals; receive, respectively from one or more secondary devices, secondary text converted from the transmitted media signals; compare the stored text version of the media signals to the secondary text received from each of the one or more secondary devices; and adjust an intensity applied to a continued transmitting of the media signals based on a comparison result. The foregoing summary is illustrative only and is not intended to be in any way limiting. In addition to the illustrative aspects, embodiments, and features described above, further aspects, embodiments, and features will become apparent by reference to the drawings and the following detailed description.
G10L210364
20170823
20180529
20171207
70527.0
G10L210364
1
HUBER, PAUL W
SOUND VERIFICATION
UNDISCOUNTED
1
CONT-ACCEPTED
G10L
2,017
15,685,566
PENDING
Combination Therapy with Glutaminase Inhibitors
The invention relates to novel heterocyclic compounds and pharmaceutical preparations thereof. The invention further relates to methods of treating or preventing cancer using the novel heterocyclic compounds of the invention.
1. A method of treating or preventing cancer in a subject, comprising administering a glutaminase inhibitor and a taxane to the subject, wherein the subject is refractory to at least one prior chemotherapy treatment. 2. The method of claim 1, wherein the glutaminase inhibitor is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: L represents CH2SCH2, CH2CH2, CH2CH2CH2, CH2, CH2S, SCH2, CH2NHCH2, CH═CH, or preferably CH2CH2, wherein any hydrogen atom of a CH or CH2 unit may be replaced by alkyl or alkoxy, any hydrogen of an NH unit may be replaced by alkyl, and any hydrogen atom of a CH2 unit of CH2CH2, CH2CH2CH2 or CH2 may be replaced by hydroxy; X, independently for each occurrence, represents S, O or CH═CH, preferably S or CH═CH, wherein any hydrogen atom of a CH unit may be replaced by alkyl; Y, independently for each occurrence, represents H or CH2O(CO)R7; R7, independently for each occurrence, represents H or substituted or unsubstituted alkyl, alkoxy, aminoalkyl, alkylaminoalkyl, heterocyclylalkyl, arylalkyl, or heterocyclylalkoxy; Z represents H or R3(CO); R1 and R2 each independently represent H, alkyl, alkoxy or hydroxy; R3, independently for each occurrence, represents substituted or unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl or C(R8)(R9)(R10), N(R4)(R5) or OR6, wherein any free hydroxyl group may be acylated to form C(O)R7; R4 and R5 each independently represent H or substituted or unsubstituted alkyl, hydroxyalkyl, acyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(O)R7; R6, independently for each occurrence, represents substituted or unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(O)R7; and R8, R9 and R10 each independently represent H or substituted or unsubstituted alkyl, hydroxy, hydroxyalkyl, amino, acylamino, aminoalkyl, acylaminoalkyl, alkoxycarbonyl, alkoxycarbonylamino, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, or R8 and R9 together with the carbon to which they are attached, form a carbocyclic or heterocyclic ring system, wherein any free hydroxyl group may be acylated to form C(O)R7, and wherein at least two of R8, R9 and R10 are not H. 3-24. (canceled) 25. The method of claim 1, wherein the glutaminase inhibitor is a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein: L represents CH2SCH2, CH2CH2, CH2CH2CH2, CH2, CH2S, SCH2, CH2NHCH2, CH═CH, or preferably CH2CH2, wherein any hydrogen atom of a CH or CH2 unit may be replaced by alkyl or alkoxy, any hydrogen of an NH unit may be replaced by alkyl, and any hydrogen atom of a CH2 unit of CH2CH2, CH2CH2CH2 or CH2 may be replaced by hydroxy; X represents S, O or CH═CH, preferably S or CH═CH, wherein any hydrogen atom of a CH unit may be replaced by alkyl; Y, independently for each occurrence, represents H or CH2O(CO)R7; R7, independently for each occurrence, represents H or substituted or unsubstituted alkyl, alkoxy, aminoalkyl, alkylaminoalkyl, heterocyclylalkyl, arylalkyl, or heterocyclylalkoxy; Z represents H or R3(CO); R1 and R2 each independently represent H, alkyl, alkoxy or hydroxy, preferably H; R3 represents substituted or unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl or C(R8)(R9)(R10), N(R4)(R5) or OR6, wherein any free hydroxyl group may be acylated to form C(O)R7; R4 and R5 each independently represent H or substituted or unsubstituted alkyl, hydroxyalkyl, acyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(O)R7; R6, independently for each occurrence, represents substituted or unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(O)R7; and R8, R9 and R10 each independently represent H or substituted or unsubstituted alkyl, hydroxy, hydroxyalkyl, amino, acylamino, aminoalkyl, acylaminoalkyl, alkoxycarbonyl, alkoxycarbonylamino, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, or R8 and R9 together with the carbon to which they are attached, form a carbocyclic or heterocyclic ring system, wherein any free hydroxyl group may be acylated to form C(O)R7, and wherein at least two of R8, R9 and R10 are not H; R11 represents substituted or unsubstituted aryl, arylalkyl, aryloxy, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, or C(R12)(R13)(R14), N(R4)(R14) or OR14, wherein any free hydroxyl group may be acylated to form C(O)R7; R12 and R13 each independently respresent H or substituted or unsubstituted alkyl, hydroxy, hydroxyalkyl, amino, acylamino, aminoalkyl, acylaminoalkyl, alkoxycarbonyl, alkoxycarbonylamino, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(O)R7, and wherein both of R12 and R13 are not H; and R14 represents substituted or unsubstituted aryl, arylalkyl, aryloxy, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl. 26. The method of claim 25, wherein R11 represents substituted or unsubstituted arylalkyl. 27. The method of claim 26, wherein R11 represents substituted or unsubstituted benzyl. 28. (canceled) 29. The method of claim 25, wherein L represents CH2CH2. 30. The method of claim 25, wherein each Y represents H. 31. (canceled) 32. The method of claim 25, wherein X represents S. 33. The method of claim 25, wherein Z represents R3(CO). 34. The method of claim 33, wherein R3 and R11 are not identical. 35. The method of claim 25, wherein R1 and R2 each represent H. 36. The method of claim 33, wherein R3 represents substituted or unsubstituted arylalkyl, heteroarylalkyl, cycloalkyl or heterocycloalkyl. 37. The method of claim 36, wherein R3 represents substituted or unsubstituted heteroarylalkyl. 38-49. (canceled) 50. The method of claim 1, wherein the taxane is paclitaxel, nab-paclitaxel, cabazitaxel or docetaxel. 51. The method of claim 1, wherein the subject is refractory to the taxane. 52. The method of any preceding claim 1, wherein the cancer is biliary cancer, bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma, esophageal cancer, gastric cancer, gallbladder cancer, head & neck cancer, Kaposi's sarcoma, lung cancer, melanoma, occult primary or cancer of unknown primary, ovarian cancer, pancreatic cancer, penile cancer, prostate cancer, testicular germcell cancer, thymoma, thymic carcinoma and uterine cancer. 53. The method of claim 52, wherein the cancer is breast cancer. 54. The method of claim 53, wherein the breast cancer is triple-negative breast cancer. 55. The method of claim 1, wherein the taxane is paclitaxel. 56. The method of claim 1, wherein the taxane is docetaxel. 57. The method of claim 1, wherein the prior chemotherapy treatment comprised administration of a taxane as a single chemotherapeutic agent or in combination with one or more other chemotherapeutic agents. 58. (canceled) 59. (canceled) 60. The method of any preceding claim 1, wherein the prior chemotherapy treatment comprised administration of one or more chemotherapeutic agents selected from a PARP inhibitor, carboplatin, tamoxifen, paclitaxel, docetaxel, cyclophosphanamide and doxorubicin. 61. The method of claim 1, further comprising conjointly administering one or more additional chemotherapeutic agents. 62-67. (canceled) 68. The method of claim 61, wherein the one or more additional chemotherapeutic agents are selected from bortezomib, capecitabine, carboplatin, carfilzomib, cyclophosphamide, daunorubicin, doxorubicin, epirubicin, eribulin, fluorouracil, gemcitabine, ixabepilone, lenalidomide, methotrexate, mitoxantrone, mutamycin, rituximab, thiotepa, vincristine, and vinorelbine. 69. The method of claim 68, wherein the one or more additional chemotherapeutic agents are selected from bortezomib, carfilzomib, doxorubicin, lenalidomide, and rituximab. 70. The method of claim 61, wherein the additional chemotherapeutic agent is an immuno-oncology agent.
BACKGROUND Glutamine supports cell survival, growth and proliferation through metabolic and non-metabolic mechanisms. In actively proliferating cells, the metabolism of glutamine to lactate, also referred to as “glutaminolysis” is a major source of energy in the form of NADPH. The first step in glutaminolysis is the deamination of glutamine to form glutamate and ammonia, which is catalyzed by the glutaminase enzyme (GLS). Thus, deamination via glutaminase is a control point for glutamine metabolism. Ever since Warburg's observation that ascites tumor cells exhibited high rates of glucose consumption and lactate secretion in the presence of oxygen (Warburg, 1956), researchers have been exploring how cancer cells utilize metabolic pathways to be able to continue actively proliferating. Several reports have demonstrated how glutamine metabolism supports macromolecular synthesis necessary for cells to replicate (Curthoys, 1995; DeBardinis, 2008). Thus, glutaminase has been theorized to be a potential therapeutic target for the treatment of diseases characterized by actively proliferating cells, such as cancer. The lack of suitable glutaminase inhibitors has made validation of this target impossible. Therefore, the creation of glutaminase inhibitors that are specific and capable of being formulated for in vivo use could lead to a new class of therapeutics. SUMMARY OF INVENTION The present invention provides a method of treating or preventing cancer, such as triple-negative breast cancer (TNBC), in a subject, comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: L represents CH2SCH2, CH2CH2, CH2CH2CH2, CH2, CH2S, SCH2, CH2NHCH2, CH═CH, or preferably CH2CH2, wherein any hydrogen atom of a CH or CH2 unit may be replaced by alkyl or alkoxy, any hydrogen of an NH unit may be replaced by alkyl, and any hydrogen atom of a CH2 unit of CH2CH2, CH2CH2CH2 or CH2 may be replaced by hydroxy; X, independently for each occurrence, represents S, O or CH═CH, preferably S or CH═CH, wherein any hydrogen atom of a CH unit may be replaced by alkyl; Y, independently for each occurrence, represents H or CH2O(CO)R7; R7, independently for each occurrence, represents H or substituted or unsubstituted alkyl, alkoxy, aminoalkyl, alkylaminoalkyl, heterocyclylalkyl, arylalkyl, or heterocyclylalkoxy; Z represents H or R3(CO); R1 and R2 each independently represent H, alkyl, alkoxy or hydroxy; R3, independently for each occurrence, represents substituted or unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl or C(R8)(R9)(R10), N(R4)(R5) or OR6, wherein any free hydroxyl group may be acylated to form C(O)R7; R4 and R5 each independently represent H or substituted or unsubstituted alkyl, hydroxyalkyl, acyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(O)R7; R6, independently for each occurrence, represents substituted or unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(O)R7; and R8, R9 and R10 each independently represent H or substituted or unsubstituted alkyl, hydroxy, hydroxyalkyl, amino, acylamino, aminoalkyl, acylaminoalkyl, alkoxycarbonyl, alkoxycarbonylamino, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, or R8 and R9 together with the carbon to which they are attached, form a carbocyclic or heterocyclic ring system, wherein any free hydroxyl group may be acylated to form C(O)R7, and wherein at least two of R8, R9 and R10 are not H; and a taxane, such as paclitaxel, protein-bound paclitaxel (nab-paclitaxel), cabazitaxel or docetaxel; wherein the subject is refractory to at least one prior chemotherapy treatment, preferably to treatment with a taxane. In certain embodiments, the present invention provides a pharmaceutical preparation suitable for use in a human patient in the treatment or prevention of cancer, such as triple-negative breast cancer, comprising an effective amount of any of the compounds described herein (e.g., a compound of the invention, such as a compound of formula I), and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparations may be for use in treating or preventing a condition or disease as described herein. In certain embodiments, the pharmaceutical preparations have a low enough pyrogen activity to be suitable for intravenous use in a human patient. DETAILED DESCRIPTION OF THE DRAWINGS FIG. 1 shows the GLS activity in TNBC cell lines, which correlates with sensitivity to CB-839. FIG. 2 shows that CB-839 enhances the anti-tumor activity of paclitaxel in an in vivo TNBC model. FIG. 3 shows the time TNBC patients remained in a clinical study of treatment with CB-839 and paclitaxel. FIG. 4 shows the RECIST response for TNBC patients by dose in a clinical study of treatment with CB-839 and paclitaxel. FIG. 5 shows the RECIST response for TNBC patients over time in a clinical study of treatment with CB-839 and paclitaxel. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method of treating or preventing cancer, such as triple-negative breast cancer in a subject, comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: L represents CH2SCH2, CH2CH2, CH2CH2CH2, CH2, CH2S, SCH2, CH2NHCH2, CH═CH, or preferably CH2CH2, wherein any hydrogen atom of a CH or CH2 unit may be replaced by alkyl or alkoxy, any hydrogen of an NH unit may be replaced by alkyl, and any hydrogen atom of a CH2 unit of CH2CH2, CH2CH2CH2 or CH2 may be replaced by hydroxy; X, independently for each occurrence, represents S, O or CH═CH, preferably S or CH═CH, wherein any hydrogen atom of a CH unit may be replaced by alkyl; Y, independently for each occurrence, represents H or CH2O(CO)R7; R7, independently for each occurrence, represents H or substituted or unsubstituted alkyl, alkoxy, aminoalkyl, alkylaminoalkyl, heterocyclylalkyl, arylalkyl, or heterocyclylalkoxy; Z represents H or R3(CO); R1 and R2 each independently represent H, alkyl, alkoxy or hydroxy; R3, independently for each occurrence, represents substituted or unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl or C(R8)(R9)(R10), N(R4)(R5) or OR6, wherein any free hydroxyl group may be acylated to form C(O)R7; R4 and R5 each independently represent H or substituted or unsubstituted alkyl, hydroxyalkyl, acyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(O)R7; R6, independently for each occurrence, represents substituted or unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(O)R7; and R8, R9 and R10 each independently represent H or substituted or unsubstituted alkyl, hydroxy, hydroxyalkyl, amino, acylamino, aminoalkyl, acylaminoalkyl, alkoxycarbonyl, alkoxycarbonylamino, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, or R8 and R9 together with the carbon to which they are attached, form a carbocyclic or heterocyclic ring system, wherein any free hydroxyl group may be acylated to form C(O)R7, and wherein at least two of R8, R9 and R10 are not H; and a taxane, such as paclitaxel, nab-paclitaxel, cabazitaxel or docetaxel; wherein the subject is refractory to at least one prior chemotherapy treatment, preferably refractory to treatment with a taxane. In certain embodiments wherein alkyl, hydroxyalkyl, amino, acylamino, aminoalkyl, acylaminoalkyl, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl are substituted, they are substituted with one or more substituents selected from substituted or unsubstituted alkyl, such as perfluoroalkyl (e.g., trifluoromethyl), alkenyl, alkoxy, alkoxyalkyl, aryl, aralkyl, arylalkoxy, aryloxy, aryloxyalkyl, hydroxyl, halo, alkoxy, such as perfluoroalkoxy (e.g., trifluoromethoxy), alkoxyalkoxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkoxy, amino, aminoalkyl, alkylamino, aminoalkylalkoxy, aminoalkoxy, acylamino, acylaminoalkyl, such as perfluoro acylaminoalkyl (e.g., trifluoromethylacylaminoalkyl), acyloxy, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, heteroaryloxy, heteroaryloxyalkyl, heterocyclylaminoalkyl, heterocyclylaminoalkoxy, amido, amidoalkyl, amidine, imine, oxo, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl, including perfluoroacyl (e.g., C(O)CF3)), carbonylalkyl (such as carboxyalkyl, alkoxycarbonylalkyl, formylalkyl, or acylalkyl, including perfluoroacylalkyl (e.g., -alkylC(O)CF3)), carbamate, carbamatealkyl, urea, ureaalkyl, sulfate, sulfonate, sulfamoyl, sulfone, sulfonamide, sulfonamidealkyl, cyano, nitro, azido, sulfhydryl, alkylthio, thiocarbonyl (such as thioester, thioacetate, or thioformate), phosphoryl, phosphate, phosphonate or phosphinate. In certain embodiments, L represents CH2SCH2, CH2CH2, CH2CH2CH2, CH2, CH2S, SCH2, or CH2NHCH2, wherein any hydrogen atom of a CH2 unit may be replaced by alkyl or alkoxy, and any hydrogen atom of a CH2 unit of CH2CH2, CH2CH2CH2 or CH2 may be replaced by hydroxyl. In certain embodiments, L represents CH2SCH2, CH2CH2, CH2S or SCH2. In certain embodiments, L represents CH2CH2. In certain embodiments, L is not CH2SCH2. In certain embodiments, Y represents H. In certain embodiments, X represents S or CH═CH. In certain embodiments, one or both X represents CH═CH. In certain embodiments, each X represents S. In certain embodiments, one X represents S and the other X represents CH═CH. In certain embodiments, Z represents R3(CO). In certain embodiments wherein Z is R3(CO), each occurrence of R3 is not identical (e.g., the compound of formula I is not symmetrical). In certain embodiments, R1 and R2 each represent H. In certain embodiments, R3 represents arylalkyl, heteroarylalkyl, cycloalkyl or heterocycloalkyl. In certain embodiments, R3 represents C(R8)(R9)(R10), wherein R8 represents aryl, arylalkyl, heteroaryl or heteroaralkyl, such as aryl, arylalkyl or heteroaryl, R9 represents H, and R10 represents hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl, such as hydroxy, hydroxyalkyl or alkoxy. In certain embodiments, L represents CH2SCH2, CH2CH2, CH2S or SCH2, such as CH2CH2, CH2S or SCH2, Y represents H, X represents S, Z represents R3(CO), R1 and R2 each represent H, and each R3 represents arylalkyl, heteroarylalkyl, cycloalkyl or heterocycloalkyl. In certain such embodiments, each occurrence of R3 is identical. In certain embodiments, L represents CH2SCH2, CH2CH2, CH2S or SCH2, Y represents H, X represents S, Z represents R3(CO), R1 and R2 each represent H, and each R3 represents C(R8)(R9)(R10), wherein R8 represents aryl, arylalkyl, heteroaryl or heteroaralkyl, such as aryl, arylalkyl or heteroaryl, R9 represents H, and R10 represents hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl, such as hydroxy, hydroxyalkyl or alkoxy. In certain such embodiments, each occurrence of R3 is identical. In certain embodiments, L represents CH2CH2, Y represents H, X represents S or CH═CH, Z represents R3(CO), R1 and R2 each represent H, and each R3 represents substituted or unsubstituted arylalkyl, heteroarylalkyl, cycloalkyl or heterocycloalkyl. In certain such embodiments, each X represents S. In other embodiments, one or both occurrences of X represents CH═CH, such as one occurrence of X represents S and the other occurrence of X represents CH═CH. In certain embodiments of the foregoing, each occurrence of R3 is identical. In other embodiments of the foregoing wherein one occurrence of X represents S and the other occurrence of X represents CH═CH, the two occurrences of R3 are not identical. In certain embodiments, L represents CH2CH2, Y represents H, X represents S, Z represents R3(CO), R1 and R2 each represent H, and each R3 represents C(R8)(R9)(R10), wherein R8 represents aryl, arylalkyl or heteroaryl, R9 represents H, and R10 represents hydroxy, hydroxyalkyl or alkoxy. In certain such embodiments, R8 represents aryl and R10 represents hydroxyalkyl. In certain such embodiments, each occurrence of R3 is identical. In certain embodiments wherein L represents CH2, CH2CH2CH2 or CH2CH2, X represents O, and Z represents R3(CO), both R3 groups are not alkyl, such as methyl, or C(R8)(R9)(R10), wherein R8, R9 and R10 are each independently hydrogen or alkyl. In certain embodiments wherein L represents CH2CH2, X represents S, and Z represents R3(CO), both R3 groups are not phenyl or heteroaryl, such as 2-furyl. In certain embodiments wherein L represents CH2CH2, X represents O, and Z represents R3(CO), both R3 groups are not N(R4)(R5) wherein R4 is aryl, such as phenyl, and R5 is H. In certain embodiments wherein L represents CH2SCH2, X represents S, and Z represents R3(CO), both R3 groups are not aryl, such as optionally substituted phenyl, aralkyl, such as benzyl, heteroaryl, such as 2-furyl, 2-thienyl or 1,2,4-trizole, substituted or unsubstituted alkyl, such as methyl, chloromethyl, dichloromethyl, n-propyl, n-butyl, t-butyl or hexyl, heterocyclyl, such as pyrimidine-2,4(1H,3H)-dione, or alkoxy, such as methoxy, pentyloxy or ethoxy. In certain embodiments wherein L represents CH2SCH2, X represents S, and Z represents R3(CO), both R3 groups are not N(R4)(R5) wherein R4 is aryl, such as substituted or unsubstituted phenyl (e.g., phenyl, 3-tolyl, 4-tolyl, 4-bromophenyl or 4-nitrophenyl), and R5 is H. In certain embodiments wherein L represents CH2CH2CH2, X represents S, and Z represents R3(CO), both R3 groups are not alkyl, such as methyl, ethyl, or propyl, cycloalkyl, such as cyclohexyl, or C(R8)(R9)(R10), wherein any of R8, R9 and R10 together with the C to which they are attached, form any of the foregoing. In certain embodiments, the compound is not one of the following: The present invention further provides a method of treating or preventing cancer, such as triple-negative breast cancer, in a subject, comprising administering a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein: L represents CH2SCH2, CH2CH2, CH2CH2CH2, CH2, CH2S, SCH2, CH2NHCH2, CH═CH, or preferably CH2CH2, wherein any hydrogen atom of a CH or CH2 unit may be replaced by alkyl or alkoxy, any hydrogen of an NH unit may be replaced by alkyl, and any hydrogen atom of a CH2 unit of CH2CH2, CH2CH2CH2 or CH2 may be replaced by hydroxy; X represents S, O or CH═CH, preferably S or CH═CH, wherein any hydrogen atom of a CH unit may be replaced by alkyl; Y, independently for each occurrence, represents H or CH2O(CO)R7, R7, independently for each occurrence, represents H or substituted or unsubstituted alkyl, alkoxy, aminoalkyl, alkylaminoalkyl, heterocyclylalkyl, arylalkyl, or heterocyclylalkoxy; Z represents H or R3(CO); R1 and R2 each independently represent H, alkyl, alkoxy or hydroxy, preferably H; R3 represents substituted or unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl or C(R8)(R9)(R10), N(R4)(R5) or OR6, wherein any free hydroxyl group may be acylated to form C(O)R7; R4 and R5 each independently represent H or substituted or unsubstituted alkyl, hydroxyalkyl, acyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(O)R7; R6, independently for each occurrence, represents substituted or unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(O)R7; and R8, R9 and R10 each independently represent H or substituted or unsubstituted alkyl, hydroxy, hydroxyalkyl, amino, acylamino, aminoalkyl, acylaminoalkyl, alkoxycarbonyl, alkoxycarbonylamino, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, or R5 and R9 together with the carbon to which they are attached, form a carbocyclic or heterocyclic ring system, wherein any free hydroxyl group may be acylated to form C(O)R7, and wherein at least two of R8, R9 and R10 are not H; R11 represents substituted or unsubstituted aryl, arylalkyl, aryloxy, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, or C(R12)(R13)(R14), N(R4)(R14) or OR14, wherein any free hydroxyl group may be acylated to form C(O)R7; R12 and R13 each independently respresent H or substituted or unsubstituted alkyl, hydroxy, hydroxyalkyl, amino, acylamino, aminoalkyl, acylaminoalkyl, alkoxycarbonyl, alkoxycarbonylamino, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(O)R7, and wherein both of R12 and R13 are not H; and R14 represents substituted or unsubstituted aryl, arylalkyl, aryloxy, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl; and a taxane, such as paclitaxel, nab-paclitaxel, cabazitaxel or docetaxel; wherein the subject is refractory to at least one prior chemotherapy treatment, preferably to treatment with a taxane. In certain embodiments wherein alkyl, hydroxyalkyl, amino, acylamino, aminoalkyl, acylaminoalkyl, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl are substituted, they are substituted with one or more substituents selected from substituted or unsubstituted alkyl, such as perfluoroalkyl (e.g., trifluoromethyl), alkenyl, alkoxy, alkoxyalkyl, aryl, aralkyl, arylalkoxy, aryloxy, aryloxyalkyl, hydroxyl, halo, alkoxy, such as perfluoroalkoxy (e.g., trifluoromethylalkoxy), alkoxyalkoxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkoxy, amino, aminoalkyl, alkylamino, aminoalkylalkoxy, aminoalkoxy, acylamino, acylaminoalkyl, such as perfluoro acylaminoalkyl (e.g., trifluoromethylacylaminoalkyl), acyloxy, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, heteroaryloxy, heteroaryloxyalkyl, heterocyclylaminoalkyl, heterocyclylaminoalkoxy, amido, amidoalkyl, amidine, imine, oxo, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl, including perfluoroacyl (e.g., C(O)CF3)), carbonylalkyl (such as carboxyalkyl, alkoxycarbonylalkyl, formylalkyl, or acylalkyl, including perfluoroacylalkyl (e.g., -alkylC(O)CF3)), carbamate, carbamatealkyl, urea, ureaalkyl, sulfate, sulfonate, sulfamoyl, sulfone, sulfonamide, sulfonamidealkyl, cyano, nitro, azido, sulfhydryl, alkylthio, thiocarbonyl (such as thioester, thioacetate, or thioformate), phosphoryl, phosphate, phosphonate or phosphinate. In certain embodiments, Ru represents substituted or unsubstituted arylalkyl, such as substituted or unsubstituted benzyl. In certain embodiments, L represents CH2SCH2, CH2CH2, CH2CH2CH2, CH2, CH2S, SCH2, or CH2NHCH2, wherein any hydrogen atom of a CH2 unit may be replaced by alkyl or alkoxy, and any hydrogen atom of a CH2 unit of CH2CH2, CH2CH2CH2 or CH2 may be replaced by hydroxyl. In certain embodiments, L represents CH2SCH2, CH2CH2, CH2S or SCH2, preferably CH2CH2. In certain embodiments, L is not CH2SCH2 In certain embodiments, each Y represents H. In other embodiments, at least one Y is CH2O(CO)R7. In certain embodiments, X represents S or CH═CH. In certain embodiments, X represents S. In certain embodiments, R1 and R2 each represent H. In certain embodiments, Z represents R3(CO). In certain embodiments wherein Z is R3(CO), R3 and R11 are not identical (e.g., the compound of formula I is not symmetrical). In certain embodiments, Z represents R3(CO) and R3 represents arylalkyl, heteroarylalkyl, cycloalkyl or heterocycloalkyl. In certain embodiments, Z represents R3(CO) and R3 represents C(R8)(R9)(R10), wherein R8 represents aryl, arylalkyl, heteroaryl or heteroaralkyl, such as aryl, arylalkyl or heteroaryl, R9 represents H, and R10 represents hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl, such as hydroxy, hydroxyalkyl or alkoxy. In certain embodiments, Z represents R3(CO) and R3 represents heteroarylalkyl. In certain embodiments, L represents CH2SCH2, CH2CH2, CH2S or SCH2, such as CH2CH2, Y represents H, X represents S, Z represents R3(CO), R1 and R2 each represent H, R3 represents arylalkyl, heteroarylalkyl, cycloalkyl or heterocycloalkyl, and R11 represents arylalkyl. In certain such embodiments, R3 represents heteroarylalkyl. In certain embodiments, L represents CH2SCH2, CH2CH2, CH2S or SCH2, such as CH2CH2, Y represents H, X represents S, Z represents R3(CO), R1 and R2 each represent H, and R3 represents C(R8)(R9)(R10), wherein R8 represents aryl, arylalkyl, heteroaryl or heteroaralkyl, such as aryl, arylalkyl or heteroaryl, R9 represents H, and R10 represents hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl, such as hydroxy, hydroxyalkyl or alkoxy, and R11 represents arylalkyl. In certain such embodiments, R8 represents heteroaryl. In certain embodiments, L represents CH2CH2, Y represents H, X represents S or CH═CH, such as S, Z represents R3(CO), R1 and R2 each represent H, R3 represents substituted or unsubstituted arylalkyl, heteroarylalkyl, cycloalkyl or heterocycloalkyl, and R11 represents arylalkyl. In certain such embodiments, R3 represents heteroarylalkyl. In certain embodiments, L represents CH2CH2, Y represents H, X represents S, Z represents R3(CO), R1 and R2 each represent H, R3 represents C(R8)(R9)(R10), wherein R8 represents aryl, arylalkyl or heteroaryl, R9 represents H, and R10 represents hydroxy, hydroxyalkyl or alkoxy, and R11 represents arylalkyl. In certain such embodiments, R8 represents aryl and R10 represents hydroxyalkyl. In certain other embodiments, R8 represents heteroaryl. In certain embodiments, the glutaminase inhibitor is selected from any one of the compounds disclosed in Table 3 of PCT Application Publication Number WO 2013/078123, published May 30, 2013, the contents of which are incorporated herein by reference in their entirety. Preferably, the compound is selected from compound 1, 2, 6, 7, 8, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 35, 36, 38, 39, 40, 41, 43, 44, 47, 48, 50, 51, 52, 54, 55, 58, 63, 64, 65, 67, 68, 69, 70, 71, 72, 73, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 92, 93, 94, 95, 97, 99, 100, 102, 105, 107, 111, 112, 114, 115, 116, 117, 118, 120, 121, 122, 123, 126, 127, 133, 135, 136, 138, 140, 141, 143, 146, 147, 148, 152, 153, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 168, 169, 170, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 185, 186, 187, 188, 189, 190, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 208, 210, 211, 213, 214, 216, 217, 219, 220, 226, 227, 228, 229, 231, 232, 234, 235, 236, 237, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 273, 274, 275, 276, 278, 279, 280, 281, 282, 283, 285, 286, 287, 288, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 302, 304, 1038, 306, 307, 308, 309, 310, 311, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 327, 329, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 527, 347, 348, 349, 350, 351, 352, 353, 354, 355, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 638, 639, 640, 641, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, 705, 707, 708, 709, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, or 730. In certain embodiments, the compound of formula (I) is Compound 354, also known as CB-839: In certain embodiments, the invention provides a method of treating or preventing cancer, such as triple-negative breast cancer, in a subject, comprising administering a compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein: X is a bond, —S—, —S(O)—, —SO2—, —CH═CH—, or —C(O)—; each W, Y and Z is independently —S—, —CH═, —O—, —N═, or —NH—, provided that (1) at least one of W, Y and Z is not —CH═and (2) when one of W is —S— and the Y in the same ring is N, then the Z in the same ring is not —CH═; each R1 and R2 is independently C1-6 alkylene-R4, —N(R3)—R4, —N(R3)—C(O)—R4, —C(O)—N(R3)—R4, —N(R3)—C(O)—O—R4, —N(R3)—C(O)—N(R3)—R4, —O—C(O)—N(R3)—R4, —N(R3)—C(O)—C1-6 alkylene-C(O)—R4, —N(R3)—C(O)—C1-6 alkylene-N(R3)—C(O)—R4 or —N(R3a)—C(O)—CH2—N(R3)—C(O)—R4; each R3 is independently hydrogen, C1-6 alkyl or aryl; each R4 is independently C1-6 alkyl, C1-6 alkenyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyl, cycloalkyl or cycloalkylalkyl, each of which is substituted with 0-3 occurrences of R5, or two adjacent R5 moieties, taken together with the atoms to which they are attached form a heterocyclyl, heteroaryl, cycloalkyl or aryl; each R5 is independently oxo (═O), C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, cyano, halo, —OH, —SH, —OCF3, —SO2—C1-6 alkyl, —NO2, —N(R7)—C(O)—C1-6 alkyl, —N(R6)2, —O—C(O)—C1-6 alkyl, C3-7 cycloalkyl, (C3-7cycloalkyl)alkyl, aryl, aryloxy, —C(O)-aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclylalkyl or heterocyclyl, wherein each aryl, heteroaryl or heterocyclyl is further substituted with 0-3 occurrences of R7; each R6 is independently hydrogen, fluoro, OH or C1-6 alkyl; each R7 is independently hydrogen, C1-6 alkyl, —OH, —SH, cyano, halo, —CF3, —OCF3, —SO2—C1-6 alkyl, —NO2, —N(R7)—C(O)—C1-6 alkyl, —N(R6)2 or C1-6 alkoxy; m is 1, 2 or 3; n is 1, 2 or 3; provided that when X is bond, the sum of m and n is from 3 to 6 and when X is —S—, —S(O)—, —SO2—, —CH═CH—, or —C(O)—, the sum of m and n is from 2 to 4; o is 1, 2 or 3; and p is 1, 2 or 3; with the proviso that: (1) when X is —S—, m and n are both 2, each R6 is H, then (i) R1 and R2 are not both —NHC(O)—R4, wherein R4 is C1-6 alkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic aralkyl, monocyclic heteroaralkyl and each member of R4 is substituted with 0-3 occurrences of R5; and (ii) R1 and R2 are not both —NHC(O)O-methyl, —NHC(O)O-ethyl, —NHC(±)-6-pyrimidine-2,4(1H,3H)-dionyl, or —NHC(O)NH-phenyl wherein said phenyl of the —NHC(O)NH-phenyl moiety is optionally substituted with 1 or 2 groups selected from methyl, nitro, and halo; (2) when X is —S—, m and n are both 1, each R6 is H, then (i) R1 and R2 are not both —NH-phenyl or —NH-4-methoxy-phenyl; (3) when X is a bond, the sum of m and n is 3, each R6 is H, then R1 and R2 are not both NHC(O)-phenyl; (4) when X is a bond, m and n are both 2, each R6 is H, then R1 and R2 are not both —NHC(O)-furanyl, —NHC(O)-phenyl, —NHC(O)-o-methoxy-phenyl, —NHC(O)—C1-6 alkyl, —NH-benzyl, or —NH-phenyl wherein said phenyl of the —NH-phenyl moiety is substituted with 0-3 occurrences of R5; (5) when X is a bond, the sum of m and n is 5, each R6 is H, then R1 and R2 are not both —NHC(O)—C1-6 alkyl, —NHC(O)-cyclohexyl, or —NH-phenyl wherein said phenyl of the —NH-phenyl moiety is optionally substituted with methyl; and (6) when X is a bond, m and n are both 3, each R6 is H, then R1 and R2 are not both NH-phenyl; preferably wherein the compound of formula (II) is administered with a meal; and a taxane, such as paclitaxel, nab-paclitaxel, cabazitaxel or docetaxel; wherein the subject is refractory to at least one prior chemotherapy treatment, preferably to treatment with a taxane. In certain embodiments, W is —S—, each Y is —N═, and each Z is —N═. In certain embodiments, W is —CH═, each Z is —O—, and each Y is —N═. In certain embodiments, o is 1 and p is 1. In certain embodiments, R1 and R2 are each —N(R3)—C(O)—O—R4. In certain embodiments, the compound having the structure of Formula (II) has the structure of Formula(IIa): In certain embodiments, R1 and R2 are the same. In certain embodiments, the compound having the structure of Formula (II) is a compound having the structure of Formula (IIb): In certain embodiments, the invention provides a method of treating or preventing cancer, such as triple-negative breast cancer, in a subject, comprising administering a compound of formula (III): wherein: X is C3—C7 cycloalkylene; each W, Y and Z is independently —S—, —CH═, —O—, —N═, or —NH—, provided that at least one of W, Y and Z is not —CH═; each R1 and R2 is independently —NH2, —N(R3)—C(O)—R4, —C(O)—N(R3)—R4, —N(R3)—C(O)—O—R4, —N(R3)—C(O)—N(R3)—R4 or —N(R3)—C(O)—SR4; each R3 is independently hydrogen, C1-6 alkyl or aryl; each R4 is independently C1-6 alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, or heterocyclyl, each of which is substituted with 0-3 occurrences of R5; each R5 is independently C1-6 alkyl, C1-6 alkoxy, —O—C1-6 alkyleneC1-6 alkoxy, C1-6thioalkoxy, C1-6 haloalkyl, C3-7 cycloalkyl, C3-7 cycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyl, cyano, halo, oxo, —OH, —OCF3, —OCHF2, —SO2—C1-6 alkyl, —NO2, —N(R7)—C(O)—C1-6 alkyl, —C(O)N(R7)2, —N(R7)S(O)1-2—C1-6 alkyl, —S(O)2N(R7)2, —N(R7)2, —C1-6 alkylene-N(R7)2, wherein said alkyl, C1-6 alkoxy, —O—C1-6alkyleneC1-6alkoxy, C1-6 thioalkoxy, C1-6 haloalkyl, C3-7 cycloalkyl, C3-7cycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyl, —SO2—C1-6alkyl, —NO2, —N(R7)—C(O)—C1-6 alkyl, —C(O)N(R7)2, —N(R7)S(O)1-2—C1-6alkyl, —S(O)2N(R7)2, —N(R7)2, or —C1-6alkylene-N(R7)2 is optionally substituted with 0-3 occurrences of R8; or two adjacent R5 moieties, taken together with the atoms to which they are attached form a cycloalkyl or heterocyclyl; each R6 is independently hydrogen, fluoro, C1-6 alkyl, —OH, —NH2, —NH(CH3), —N(CH3)2, or C1-6 alkoxy; each R7 is independently hydrogen or C1-6 alkyl; each R8 is independently halo, C1-6 alkyl, C1-6haloalkyl, —OH, —N(R7)2, or C1-6alkoxy, —O—C1-6 alkyleneC1-6 alkoxy, CN, NO2, —N(R7)—C(O)—C1-6alkyl, —C(O)N(R7)2, —N(R7)S(O)1-2C1-6 alkyl, or —S(O)2N(R7)2; m is 0, 1, or 2; n is 0, 1, or 2; o is 1, 2 or 3; and p0 p is 1, 2 or 3; provided that (1) when X is unsubstituted cyclopropyl, R1 and R2 are not both NH-phenyl; and (2) X is other than substituted cyclobutyl or substituted cyclopentyl; preferably wherein the compound of formula (III) is administered with a meal; and a taxane, such as paclitaxel, nab-paclitaxel, cabazitaxel or docetaxel; wherein the subject is refractory to at least one prior chemotherapy treatment, preferably to treatment with a taxane. In certain embodiments, W is —S—, each Y is —N═, and each Z is In certain embodiments, o is 1 and p is 1. In certain embodiments, m is O and n is O. Alternatively, m and n can each be 1. In certain embodiments, R1 and R2 are different. Alternatively, R1 and R2 can be the same. In certain embodiments, R1 and R2 are each —N(R3)—C(O)—O—R4, wherein each R3 is hydrogen and each R4 is aralkyl or heteroaralkyl, each of which is substituted with 0-3 occurrences of R5. In certain embodiments, the compound having the structure of Formula (III) is a compound having the structure of Formula (IIIa): In certain embodiments, the compound having the structure of Formula (III) is a compound having the structure of Formula (IIIb): In certain embodiments, the compound having the structure of Formula (III) has the structure of formula (IIIc): In certain embodiments, the compound of formula (III) is a compound of formula (IV): wherein q is 0, 1, 2, 3, or 4. In certain embodiments, the compound of formula (III) has the structure of formula (IVa): wherein q is 0, 1, 2, 3, or 4. In certain embodiments, the compound of formula (III) has the structure of formula (IVb): wherein q is 0, 1, 2, 3, or 4. In certain embodiments, the compound of formula (III) has the structure of formula (IVc): wherein q is 0, 1, 2, 3, or 4. Compounds of any of Formulae (II) to (IV) are alternatively referred to herein as “glutaminase inhibitors.” Taxanes are a class of chemotherapeutics that share a complex functionalized bicyclic ring system. Taxanes have been used in treating a number of cancers, such as bladder cancer, breast cancer, esophageal cancer, gastric cancer, head & neck cancer, Kaposi's sarcoma, lung cancer (including non-small cell lung cancer and small cell lung cancer), melanoma, ovarian cancer, pancreatic cancer, penile cancer, prostate cancer, testicular germcell cancer, thymoma and thymic carcinoma. Further cancers include cholangiocarcinoma, biliary cancer, gallbladder cancer, uterine cancer, cervical cancer, and occult primary or cancer of unknown primary. Representative taxanes include paclitaxel, docetaxel, cabazitaxel, larotaxel, tesetaxel, BMS-184476, and NBT-287. In certain embodiments, the taxane is docetaxel. In certain embodiments, the taxane is cabazitaxel. In certain embodiments, the taxane is nab-paclitaxel. In certain preferred embodiments, the taxane is paclitaxel. In most preferred embodiments, the method comprises administering the taxane to which the subject is refractory. As used herein, the term “refractory” describes a subject whose disease (e.g., tumor) is unresponsive to a particular therapy. Refractory subjects can have a lesser response than the treatment's efficacy in typical, responsive patients, a response that diminishes or terminates after an initial period of responsiveness to the treatment, or no response to the treatment (e.g., the tumor continues to grow). A “response” to a method of treatment can include a decrease in or amelioration of negative symptoms, a decrease in the progression of a disease or symptoms thereof, an increase in beneficial symptoms or clinical outcomes, a lessening of side effects, stabilization of disease, partial or complete remedy of disease, among others. In the treatment of cancer, a response typically indicates a reduced rate of growth for a tumor, a cessation of tumor growth, or a shrinkage of a tumor. Similarly, a response may indicate a lack of new tumors (metastases). A refractory subject, on the other hand, may experience tumor growth or the appearance of additional tumors (metastases) despite receiving the therapeutic treatment. Subjects that are refractory to a treatment may have responded initially but then became resistant to the treatment over time. Other subjects never significantly respond to the treatment. In certain embodiments, a subject may be refractory to any known chemotherapeutic treatment as disclosed above and herein, including paclitaxel, nab-paclitaxel, cabazitaxel or docetaxel monotherapy. Subjects as described herein have already been dosed with one or more chemotherapeutic agents that are not a compound of formula (I) and they are refractory to one or more of those agent(s). The prior chemotherapy treatment can be selected from one or more of the additional chemotherapeutic agents that are, in some embodiments, administered conjointly with the compound of formula (I) and the taxane. These additional chemotherapeutic agents and their administration are further discussed herein and below. In certain embodiments, the prior chemotherapy treatment can be administration of one or more chemotherapeutic agents selected from a PARP inhibitor, carboplatin, tamoxifen, paclitaxel, cyclophosphanamide and doxorubicin. In certain embodiments, the prior chemotherapy treatment comprised administration of paclitaxel as a single chemotherapeutic agent or in combination with one or more other chemotherapeutic agents. The methods described herein are useful for the treatment of a wide variety of cancers, including bladder cancer, breast cancer, esophageal cancer, gastric cancer, head & neck cancer, Kaposi's sarcoma, lung cancer (including non-small cell lung cancer and small cell lung cancer), melanoma, ovarian cancer, pancreatic cancer, penile cancer, prostate cancer, testicular germcell cancer, thymoma and thymic carcinoma. In certain embodiments, the subject has breast cancer, such as triple-negative breast cancer, that is locally advanced. In other embodiments, the subject has metastatic breast cancer, such as metastatic triple-negative breast cancer. In certain embodiments, compounds of the invention may be prodrugs of the compounds of formula I or Ia, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. In certain such embodiments, the prodrug is metabolized to the active parent compound in vivo (e.g., the ester is hydrolyzed to the corresponding hydroxyl, or carboxylic acid). In certain embodiments, compounds of the invention may be racemic. In certain embodiments, compounds of the invention may be enriched in one enantiomer. For example, a compound of the invention may have greater than about 30% ee, about 40% ee, about 50% ee, about 60% ee, about 70% ee, about 80% ee, about 90% ee, or even about 95% or greater ee. In certain embodiments, compounds of the invention may have more than one stereocenter. In certain such embodiments, compounds of the invention may be enriched in one or more diastereomer. For example, a compound of the invention may have greater than about 30% de, about 40% de, about 50% de, about 60% de, about 70% de, about 80% de, about 90% de, or even about 95% or greater de. In certain embodiments, the present invention relates to methods of treating or preventing cancer, such as triple-negative breast cancer, with a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, and a taxane, such as paclitaxel, nab-paclitaxel, cabazitaxel or docetaxel. In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound (e.g., of formula I or Ia). An enantiomerically enriched mixture may comprise, for example, at least about 60 mol percent of one enantiomer, or more preferably at least about 75, about 90, about 95, or even about 99 mol percent. In certain embodiments, the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than about 10%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture. For example, if a composition or compound mixture contains about 98 grams of a first enantiomer and about 2 grams of a second enantiomer, it would be said to contain about 98 mol percent of the first enantiomer and only about 2% of the second enantiomer. In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound (e.g., of formula I or Ia). A diastereomerically enriched mixture may comprise, for example, at least about 60 mol percent of one diastereomer, or more preferably at least about 75, about 90, about 95, or even about 99 mol percent. In certain embodiments, the present invention provides a pharmaceutical preparation suitable for use in a human patient, comprising any of the compounds shown above (e.g., a compound of the invention, such as a compound of formula I or Ia), and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparations may be for use in treating or preventing a condition or disease as described herein. In certain embodiments, the pharmaceutical preparations have a low enough pyrogen activity to be suitable for use in a human patient. Any of the disclosed compounds may be used in the manufacture of medicaments for the treatment of any diseases or conditions disclosed herein. Uses of Enzyme Inhibitors In certain embodiments, the method of treating or preventing cancer, such as triple-negative breast cancer, may comprise administering a compound of the invention conjointly with one or more other chemotherapeutic agent(s). Chemotherapeutic agents that may be conjointly administered with compounds of the invention include: ABT-263, afatinib dimaleate, axitinib, aminoglutethimide, amsacrine, anastrozole, asparaginase, AZD5363, Bacillus Calmette-Guérin vaccine (bcg), bicalutamide, bleomycin, bortezomib, buserelin, busulfan, cabozantinib, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gefitinib, gemcitabine, genistein, goserelin, GSK1120212, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, MK-2206, mutamycin, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pemexetred, pentostatin, perifosine, PF-04691502, plicamycin, pomalidomide, porfimer, procarbazine, raltitrexed, ramucirumab, rituximab, romidepsin, rucaparib, selumetinib, sirolimus, sorafenib, streptozocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, topotecan, trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine, vindesine, vinorelbine, and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that may be conjointly administered with compounds of the invention include: ABT-263, dexamethasone, 5-fluorouracil, PF-04691502, romidepsin, and vorinostat (SAHA). In certain embodiments of the methods of the invention described herein, the chemotherapeutic agent conjointly administered with compounds of the invention is a taxane chemotherapeutic agent, such as paclitaxel, nab-paclitaxel, cabazitaxel or docetaxel. In certain embodiments of the methods of the invention described herein, the chemotherapeutic agent conjointly administered with compounds of the invention is doxorubicin. In certain embodiments of the methods of the invention described herein, a compound of the invention is administered conjointly with a taxane chemotherapeutic agent (e.g., paclitaxel) and doxorubicin. Many combination therapies have been developed for the treatment of cancer. In certain embodiments, compounds of the invention may be conjointly administered with a combination therapy. Examples of combination therapies with which compounds of the invention may be conjointly administered are included in Table 1. TABLE 1 Exemplary combinatorial therapies for the treatment of cancer. Name Therapeutic agents ABV Doxorubicin, Bleomycin, Vinblastine ABVD Doxorubicin, Bleomycin, Vinblastine, Dacarbazine AC (Breast) Doxorubicin, Cyclophosphamide AC (Sarcoma) Doxorubicin, Cisplatin AC (Neuroblastoma) Cyclophosphamide, Doxorubicin ACE Cyclophosphamide, Doxorubicin, Etoposide ACe Cyclophosphamide, Doxorubicin AD Doxorubicin, Dacarbazine AP Doxorubicin, Cisplatin ARAC-DNR Cytarabine, Daunorubicin B-CAVe Bleomycin, Lomustine, Doxorubicin, Vinblastine BCVPP Carmustine, Cyclophosphamide, Vinblastine, Procarbazine, Prednisone BEACOPP Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, Prednisone, Filgrastim BEP Bleomycin, Etoposide, Cisplatin BIP Bleomycin, Cisplatin, Ifosfamide, Mesna BOMP Bleomycin, Vincristine, Cisplatin, Mitomycin CA Cytarabine, Asparaginase CABO Cisplatin, Methotrexate, Bleomycin, Vincristine CAF Cyclophosphamide, Doxorubicin, Fluorouracil CAL-G Cyclophosphamide, Daunorubicin, Vincristine, Prednisone, Asparaginase CAMP Cyclophosphamide, Doxorubicin, Methotrexate, Procarbazine CAP Cyclophosphamide, Doxorubicin, Cisplatin CAV Cyclophosphamide, Doxorubicin, Vincristine CAVE ADD CAV and Etoposide CA-VP16 Cyclophosphamide, Doxorubicin, Etoposide CC Cyclophosphamide, Carboplatin CDDP/VP-16 Cisplatin, Etoposide CEF Cyclophosphamide, Epirubicin, Fluorouracil CEPP(B) Cyclophosphamide, Etoposide, Prednisone, with or without/Bleomycin CEV Cyclophosphamide, Etoposide, Vincristine CF Cisplatin, Fluorouracil or Carboplatin Fluorouracil CHAP Cyclophosphamide or Cyclophosphamide, Altretamine, Doxorubicin, Cisplatin ChlVPP Chlorambucil, Vinblastine, Procarbazine, Prednisone CHOP Cyclophosphamide, Doxorubicin, Vincristine, Prednisone CHOP-BLEO Add Bleomycin to CHOP CISCA Cyclophosphamide, Doxorubicin, Cisplatin CLD-BOMP Bleomycin, Cisplatin, Vincristine, Mitomycin CMF Methotrexate, Fluorouracil, Cyclophosphamide CMFP Cyclophosphamide, Methotrexate, Fluorouracil, Prednisone CMFVP Cyclophosphamide, Methotrexate, Fluorouracil, Vincristine, Prednisone CMV Cisplatin, Methotrexate, Vinblastine CNF Cyclophosphamide, Mitoxantrone, Fluorouracil CNOP Cyclophosphamide, Mitoxantrone, Vincristine, Prednisone COB Cisplatin, Vincristine, Bleomycin CODE Cisplatin, Vincristine, Doxorubicin, Etoposide COMLA Cyclophosphamide, Vincristine, Methotrexate, Leucovorin, Cytarabine COMP Cyclophosphamide, Vincristine, Methotrexate, Prednisone Cooper Regimen Cyclophosphamide, Methotrexate, Fluorouracil, Vincristine, Prednisone COP Cyclophosphamide, Vincristine, Prednisone COPE Cyclophosphamide, Vincristine, Cisplatin, Etoposide COPP Cyclophosphamide, Vincristine, Procarbazine, Prednisone CP(Chronic Chlorambucil, Prednisone lymphocytic leukemia) CP (Ovarian Cancer) Cyclophosphamide, Cisplatin CVD Cisplatin, Vinblastine, Dacarbazine CVI Carboplatin, Etoposide, Ifosfamide, Mesna CVP Cyclophosphamide, Vincristine, Prednisome CVPP Lomustine, Procarbazine, Prednisone CYVADIC Cyclophosphamide, Vincristine, Doxorubicin, Dacarbazine DA Daunorubicin, Cytarabine DAT Daunorubicin, Cytarabine, Thioguanine DAV Daunorubicin, Cytarabine, Etoposide DCT Daunorubicin, Cytarabine, Thioguanine DHAP Cisplatin, Cytarabine, Dexamethasone DI Doxorubicin, Ifosfamide DTIC/Tamoxifen Dacarbazine, Tamoxifen DVP Daunorubicin, Vincristine, Prednisone EAP Etoposide, Doxorubicin, Cisplatin EC Etoposide, Carboplatin EFP Etoposie, Fluorouracil, Cisplatin ELF Etoposide, Leucovorin, Fluorouracil EMA 86 Mitoxantrone, Etoposide, Cytarabine EP Etoposide, Cisplatin EVA Etoposide, Vinblastine FAC Fluorouracil, Doxorubicin, Cyclophosphamide FAM Fluorouracil, Doxorubicin, Mitomycin FAMTX Methotrexate, Leucovorin, Doxorubicin FAP Fluorouracil, Doxorubicin, Cisplatin F-CL Fluorouracil, Leucovorin FEC Fluorouracil, Cyclophosphamide, Epirubicin FED Fluorouracil, Etoposide, Cisplatin FL Flutamide, Leuprolide FZ Flutamide, Goserelin acetate implant HDMTX Methotrexate, Leucovorin Hexa-CAF Altretamine, Cyclophosphamide, Methotrexate, Fluorouracil IDMTX/6-MP Methotrexate, Mercaptopurine, Leucovorin IE Ifosfamide, Etoposie, Mesna IfoVP Ifosfamide, Etoposide, Mesna IPA Ifosfamide, Cisplatin, Doxorubicin M-2 Vincristine, Carmustine, Cyclophosphamide, Prednisone, Melphalan MAC-III Methotrexate, Leucovorin, Dactinomycin, Cyclophosphamide MACC Methotrexate, Doxorubicin, Cyclophosphamide, Lomustine MACOP-B Methotrexate, Leucovorin, Doxorubicin, Cyclophosphamide, Vincristine, Bleomycin, Prednisone MAID Mesna, Doxorubicin, Ifosfamide, Dacarbazine m-BACOD Bleomycin, Doxorubicin, Cyclophosphamide, Vincristine, Dexamethasone, Methotrexate, Leucovorin MBC Methotrexate, Bleomycin, Cisplatin MC Mitoxantrone, Cytarabine MF Methotrexate, Fluorouracil, Leucovorin MICE Ifosfamide, Carboplatin, Etoposide, Mesna MINE Mesna, Ifosfamide, Mitoxantrone, Etoposide mini-BEAM Carmustine, Etoposide, Cytarabine, Melphalan MOBP Bleomycin, Vincristine, Cisplatin, Mitomycin MOP Mechlorethamine, Vincristine, Procarbazine MOPP Mechlorethamine, Vincristine, Procarbazine, Prednisone MOPP/ABV Mechlorethamine, Vincristine, Procarbazine, Prednisone, Doxorubicin, Bleomycin, Vinblastine MP (multiple myeloma) Melphalan, Prednisone MP (prostate cancer) Mitoxantrone, Prednisone MTX/6-MO Methotrexate, Mercaptopurine MTX/6-MP/VP Methotrexate, Mercaptopurine, Vincristine, Prednisone MTX-CDDPAdr Methotrexate, Leucovorin, Cisplatin, Doxorubicin MV (breast cancer) Mitomycin, Vinblastine MV (acute myelocytic Mitoxantrone, Etoposide leukemia) M-VAC Methotrexate Vinblastine, Doxorubicin, Cisplatin MVP Mitomycin Vinblastine, Cisplatin MVPP Mechlorethamine, Vinblastine, Procarbazine, Prednisone NFL Mitoxantrone, Fluorouracil, Leucovorin NOVP Mitoxantrone, Vinblastine, Vincristine OPA Vincristine, Prednisone, Doxorubicin OPPA Add Procarbazine to OPA. PAC Cisplatin, Doxorubicin PAC-I Cisplatin, Doxorubicin, Cyclophosphamide PA-CI Cisplatin, Doxorubicin PCV Lomustine, Procarbazine, Vincristine PFL Cisplatin, Fluorouracil, Leucovorin POC Prednisone, Vincristine, Lomustine ProMACE Prednisone, Methotrexate, Leucovorin, Doxorubicin, Cyclophosphamide, Etoposide ProMACE/cytaBOM Prednisone, Doxorubicin, Cyclophosphamide, Etoposide, Cytarabine, Bleomycin, Vincristine, Methotrexate, Leucovorin, Cotrimoxazole PRoMACE/MOPP Prednisone, Doxorubicin, Cyclophosphamide, Etoposide, Mechlorethamine, Vincristine, Procarbazine, Methotrexate, Leucovorin Pt/VM Cisplatin, Teniposide PVA Prednisone, Vincristine, Asparaginase PVB Cisplatin, Vinblastine, Bleomycin PVDA Prednisone, Vincristine, Daunorubicin, Asparaginase SMF Streptozocin, Mitomycin, Fluorouracil TAD Mechlorethamine, Doxorubicin, Vinblastine, Vincristine, Bleomycin, Etoposide, Prednisone TTT Methotrexate, Cytarabine, Hydrocortisone Topo/CTX Cyclophosphamide, Topotecan, Mesna VAB-6 Cyclophosphamide, Dactinomycin, Vinblastine, Cisplatin, Bleomycin VAC Vincristine, Dactinomycin, Cyclophosphamide VACAdr Vincristine, Cyclophosphamide, Doxorubicin, Dactinomycin, Vincristine VAD Vincristine, Doxorubicin, Dexamethasone VATH Vinblastine, Doxorubicin, Thiotepa, Flouxymesterone VBAP Vincristine, Carmustine, Doxorubicin, Prednisone VBCMP Vincristine, Carmustine, Melphalan, Cyclophosphamide, Prednisone VC Vinorelbine, Cisplatin VCAP Vincristine, Cyclophosphamide, Doxorubicin, Prednisone VD Vinorelbine, Doxorubicin VelP Vinblastine, Cisplatin, Ifosfamide, Mesna VIP Etoposide, Cisplatin, Ifosfamide, Mesna VM Mitomycin, Vinblastine VMCP Vincristine, Melphalan, Cyclophosphamide, Prednisone VP Etoposide, Cisplatin V-TAD Etoposide, Thioguanine, Daunorubicin, Cytarabine 5 + 2 Cytarabine, Daunorubicin, Mitoxantrone 7 + 3 Cytarabine with/, Daunorubicin or Idarubicin or Mitoxantrone “8 in 1” Methylprednisolone, Vincristine, Lomustine, Procarbazine, Hydroxyurea, Cisplatin, Cytarabine, Dacarbazine Examples of combination therapies with which compounds of the invention may be conjointly administered include cisplatin and fluorouracil; and ifosfamide, mesna, and cisplatin. In certain embodiments, the conjoint therapies of the invention further comprise conjoint administration with other types of chemotherapeutic agents, such as immuno-oncology agents. Cancer cells often have specific cell surface antigens that can be recognized by the immune system. Thus, immuno-oncology agents, such as monoclonal antibodies, can selectively bind to cancer cell antigens and effect cell death. Other immuno-oncology agents can suppress tumor-mediated inhibition of the native immune response or otherwise activate the immune response and thus facilitate recognition of the tumor by the immune system. Exemplary immuno-oncology agents, include, but are not limited to, abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, and tremelimumab. Thus, in some embodiments, the methods of the invention further comprise conjoint administration of one or more immuno-oncology agents, such as the agents mentioned above. In certain embodiments, a compound of the invention may be conjointly administered with non-chemical methods of cancer treatment. In certain embodiments, a compound of the invention may be conjointly administered with radiation therapy. In certain embodiments, a compound of the invention may be conjointly administered with surgery, with thermoablation, with focused ultrasound therapy, with cryotherapy, or with any combination of these. In certain embodiments, different compounds of the invention may be conjointly administered with one or more other compounds of the invention. Moreover, such combinations may be conjointly administered with other therapeutic agents, such as other agents suitable for the treatment of cancer, immunological or neurological diseases, such as the agents identified above. In certain embodiments, conjointly administering one or more additional chemotherapeutic agents with a compound of the invention provides a synergistic effect. In certain embodiments, conjointly administering one or more additional chemotherapeutics agents provides an additive effect. In certain embodiments, the present invention provides a kit comprising: a) one or more single dosage forms of a glutaminase inhibitor; b) one or more single dosage forms of a taxane such as paclitaxel, nab-paclitaxel, cabazitaxel or docetaxel, as mentioned above; and c) instructions for the administration of the glutaminase inhibitor and the taxane for the treatment of cancer, such as triple-negative breast cancer. The present invention provides a kit comprising: a) a pharmaceutical formulation (e.g., one or more single dosage forms) comprising a glutaminase inhibitor and a taxane; and b) instructions for the administration of the pharmaceutical formulation, e.g., for treating or preventing cancer, such as triple-negative breast cancer. In certain embodiments, the kit further comprises instructions for the administration of the pharmaceutical formulation comprising a glutaminase inhibitor conjointly with a taxane as mentioned above. In certain embodiments, the kit further comprises a second pharmaceutical formulation (e.g., as one or more single dosage forms) comprising a chemotherapeutic agent as mentioned above. Definitions The term “acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)—, preferably alkylC(O)—. The term “acylamino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH—. The term “acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O—, preferably alkylC(O)O—. The term “alkoxy” refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like. The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl. The term “alkenyl”, as used herein, refers to an aliphatic group containing at least one double bond and is intended to include both “unsubstituted alkenyls” and “substituted alkenyls”, the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated. An “alkyl” group or “alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise defined. Examples of straight chained and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A C1-C6 straight chained or branched alkyl group is also referred to as a “lower alkyl” group. Moreover, the term “alkyl” (or “lower alkyl”) as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, if not otherwise specified, can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), —CF3, —CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, —CF3, —CN, and the like. The term “Cx-y” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. For example, the term “Cx-yalkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-tirfluoroethyl, etc. C0alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms “C2-yalkenyl” and “C2-yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively. The term “alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group. The term “alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS—. The term “alkynyl”, as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both “unsubstituted alkynyls” and “substituted alkynyls”, the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated. The term “amide”, as used herein, refers to a group wherein each R10 independently represents a hydrogen or hydrocarbyl group, or two R10 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by wherein each R10 independently represents a hydrogen or a hydrocarbyl group, or two R10 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. The term “aminoalkyl”, as used herein, refers to an alkyl group substituted with an amino group. The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group. The term “aryl” as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. The term “carbamate” is art-recognized and refers to a group wherein R9 and R10 independently represent hydrogen or a hydrocarbyl group, such as an alkyl group, or R9 and R10 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure. The terms “carbocycle”, and “carbocyclic”, as used herein, refers to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond. The term “carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles” may be susbstituted at any one or more positions capable of bearing a hydrogen atom. A “cycloalkyl” group is a cyclic hydrocarbon which is completely saturated. “Cycloalkyl” includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined. The second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused cycloalkyl” refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. A “cycloalkenyl” group is a cyclic hydrocarbon containing one or more double bonds. The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group. The term “carbonate” is art-recognized and refers to a group —OCO2—R10, wherein R10 represents a hydrocarbyl group. The term “carboxy”, as used herein, refers to a group represented by the formula —CO2H. The term “ester”, as used herein, refers to a group —C(O)OR10 wherein R10 represents a hydrocarbyl group. The term “ether”, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O—. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl. The terms “halo” and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo. The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group. The term “heteroalkyl”, as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent. The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heteroaryl” and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur. The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like. The term “heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group. The term “hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a ═O or ═S substituent, and typically has at least one carbon-hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a ═O substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof. The term “hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group. The term “lower” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably six or fewer. A “lower alkyl”, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent). The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7. The term “silyl” refers to a silicon moiety with three hydrocarbyl moieties attached thereto. The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants. The term “sulfate” is art-recognized and refers to the group —OSO3H, or a pharmaceutically acceptable salt thereof. The term “sulfonamide” is art-recognized and refers to the group represented by the general formulae wherein R9 and R19 independently represents hydrogen or hydrocarbyl, such as alkyl, or R9 and R10 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure. The term “sulfoxide” is art-recognized and refers to the group —S(O)—R10, wherein R10 represents a hydrocarbyl. The term “sulfonate” is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof. The term “sulfone” is art-recognized and refers to the group —S(O)2—R10, wherein R10 represents a hydrocarbyl. The term “thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group. The term “thioester”, as used herein, refers to a group —C(O)SR10 or —SC(O)R10 wherein R10 represents a hydrocarbyl. The term “thioether”, as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur. The term “urea” is art-recognized and may be represented by the general formula wherein R9 and R10 independently represent hydrogen or a hydrocarbyl, such as alkyl, or either occurrence of R9 taken together with R10 and the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure. The term “protecting group” refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”) and the like. Representative hydroxyl protecting groups include, but are not limited to, those where the hydroxyl group is either acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers. The term “healthcare providers” refers to individuals or organizations that provide healthcare services to a person, community, etc. Examples of “healthcare providers” include doctors, nurses, nurse practitioners, hospitals, continuing care retirement communities, skilled nursing facilities, subacute care facilities, clinics, multispecialty clinics, freestanding ambulatory centers, home health agencies, HMO's and PPO's. The term “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and/or turkeys. Preferred subjects are humans. As used herein, a therapeutic that “prevents” a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample. The term “treating” includes prophylactic and/or therapeutic treatments. The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the subject of one or more of the disclosed compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the subject) then the treatment is prophylactic (i.e., it protects the subject against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof). The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into the therapeutically active agents of the present invention (e.g., a compound of formula I). A common method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the subject. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present invention. In certain embodiments, some or all of the compounds of formula I in a formulation represented above can be replaced with the corresponding suitable prodrug, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate or carboxylic acid present in the parent compound is presented as an ester. Pharmaceutical Compositions The compositions and methods of the present invention may be utilized to treat a subject in need thereof. In certain embodiments, the subject is a mammal such as a human, or a non-human mammal. When administered to subject, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop. A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a selfemulsifying drug delivery system or a selfmicroemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin, or as an eye drop). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent. Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste. To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients. Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Formulations of the pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound. Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment. Alternatively or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine. Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate. Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required. The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel. Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. Exemplary ophthalmic formulations are described in U.S. Publication Nos. 2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S. Pat. No. 6,583,124, the contents of which are incorporated herein by reference. If desired, liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatable with such fluids. A preferred route of administration is local administration (e.g., topical administration, such as eye drops, or administration via an implant). The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue. For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier. Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinacious biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site. Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well known in the medical arts. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By “therapeutically effective amount” is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the subject's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference). In general, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present invention, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily. In certain embodiments, the dosing follows a 3+3 design. The traditional 3+3 design requires no modeling of the dose-toxicity curve beyond the classical assumption for cytotoxic drugs that toxicity increases with dose. This rule-based design proceeds with cohorts of three patients; the first cohort is treated at a starting dose that is considered to be safe based on extrapolation from animal toxicological data, and the subsequent cohorts are treated at increasing dose levels that have been fixed in advance. In some embodiments, the three doses of a compound of formula (I) range from about 100 mg to about 1000 mg orally, such as about 200 mg to about 800 mg, such as about 400 mg to about 700 mg, such as about 100 mg to about 400 mg, such as about 500 mg to about 1000 mg, and further such as about 500 mg to about 600 mg. Dosing can be three times a day when taken with without food, or twice a day when taken with food. In certain embodiments, the three doses of a compound of formula (I) range from about 400 mg to about 800 mg, such as about 400 mg to about 700 mg, such as about 500 mg to about 800 mg, and further such as about 500 mg to about 600 mg twice a day. In certain preferred embodiments, a dose of greater than about 600 mg is dosed twice a day. If none of the three patients in a cohort experiences a dose-limiting toxicity, another three patients will be treated at the next higher dose level. However, if one of the first three patients experiences a dose-limiting toxicity, three more patients will be treated at the same dose level. The dose escalation continues until at least two patients among a cohort of three to six patients experience dose-limiting toxicities (ie, ≧about 33% of patients with a dose-limiting toxicity at that dose level). The recommended dose for phase II trials is conventionally defined as the dose level just below this toxic dose level. In certain embodiments, the dosing schedule can be about 40 mg/m2 to about 100 mg/m2, such as about 50 mg/m2 to about 80 mg/m2, and further such as about 70 mg/m2 to about 90 mg/m2 by IV for 3 weeks of a 4 week cycle. In certain embodiments, compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent. As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the subject, which may include synergistic effects of the two compounds). For example, the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially. In certain embodiments, the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another. Thus, a subject who receives such treatment can benefit from a combined effect of different therapeutic compounds. In certain embodiments, conjoint administration of compounds of the invention with one or more additional therapeutic agent(s) (e.g., one or more additional chemotherapeutic agent(s)) provides improved efficacy relative to each individual administration of the compound of the invention (e.g., compound of formula I or Ia) or the one or more additional therapeutic agent(s). In certain such embodiments, the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the compound of the invention and the one or more additional therapeutic agent(s). This invention includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts. The pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions. Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. In certain embodiments, the invention relates to a method for conducting a pharmaceutical business, by manufacturing a formulation of a compound of the invention, or a kit as described herein, and marketing to healthcare providers the benefits of using the formulation or kit for treating or preventing any of the diseases or conditions as described herein. In certain embodiments, the invention relates to a method for conducting a pharmaceutical business, by providing a distribution network for selling a formulation of a compound of the invention, or kit as described herein, and providing instruction material to patients or physicians for using the formulation for treating or preventing any of the diseases or conditions as described herein. In certain embodiments, the invention comprises a method for conducting a pharmaceutical business, by determining an appropriate formulation and dosage of a compound of the invention for treating or preventing any of the diseases or conditions as described herein, conducting therapeutic profiling of identified formulations for efficacy and toxicity in animals, and providing a distribution network for selling an identified preparation as having an acceptable therapeutic profile. In certain embodiments, the method further includes providing a sales group for marketing the preparation to healthcare providers. In certain embodiments, the invention relates to a method for conducting a pharmaceutical business by determining an appropriate formulation and dosage of a compound of the invention for treating or preventing any of the disease or conditions as described herein, and licensing, to a third party, the rights for further development and sale of the formulation. EXAMPLES Example 1 Synthesis of CB-839: 2-phenyl-N-(6-(4-(5-(2-(pyridin-2-yflacetamido)-1,3,4-thiadiazol-2-yl)butyl)pyridazin-3-yl)acetamide The synthesis of CB-839 is as described for compound 354 in WO/2014/089048, incorporated herein by reference in its entirety. Example 2 GLC Activity in TNBC Cell Lines Glutaminase activity was measured in homogenates prepared from tumor cell lines using the coupled assay as described in Gross et al. (2014) Mol Cancer Ther 13: 890. In measuring glutaminase activity in homogenates, the background activity that is independent of glutaminase was measured from reactions that lacked glutamine. Background activity was subtracted from activity in the presence of glutamine. The specific activity of glutaminase was calculated by dividing the background-subtracted glutaminase activity by the total protein amount present in the reaction. The extent of cell growth or cell loss (i.e., a decrease in cell number relative to the time of compound addition) was determined following treatment with 1 μM CB-839 for 72 h. In FIG. 1, the correlation between cell proliferation or loss measured after CB-839 treatment is plotted on the x-axis and glutaminase specific activity plotted on the y-axis. Example 3 CB-839 Enhances the Anti-Tumor Activity of Paclitaxel in an In Vivo TNBC Model In the JIMT-1 xenograft model, the antitumor efficacy was evaluated by treating established tumors (125 mm3 at the start of dosing) with CB-839 both as a single agent and in combination with paclitaxel, a standard-of-care chemotherapeutic agent for the treatment of TNBC. The regimen for paclitaxel (five doses at 10 mg/kg delivered every other day at the start of study) was chosen to provide suboptimal efficacy to ensure a window to evaluate the potential impact of combination treatment. As shown in FIG. 2, oral dosing of CB-839 alone (200 mg/kg BID) resulted in 54% tumor growth inhibition (TGI) relative to vehicle control at study end (P=0.004). Single agent paclitaxel caused an initial regression of the JIMT-1 tumors that was followed by a rapid regrowth resulting in a TGI of 73% relative to vehicle control at the end of study (P=0.0002). Combination of CB-839 with paclitaxel largely suppressed the regrowth of the tumors resulting in a TGI relative to vehicle control of 100% at the end of study (P<0.0001 vs. vehicle and P=0.0025 vs. paclitaxel alone). Example 4 Clinical Study of TNBC Patient Treatment with CB-839+Paclitaxel A Phase 1 study of CB-839 in advanced solid tumors (CX-839-001) was initiated using a “3+3” dose escalation as monotherapy and in combination with standard of care agents. For the TNBC cohort, the key eligibility criteria was locally advanced/metastatic TNBC, refractory disease with prior paclitaxel therapy allowed. Presented in FIG. 3 is the length of time patients receiving CB-839 in combination with weekly paclitaxel (80 mg/m2 IV for three weeks of a four week cycle stayed on the study. Response status was determined using the RECIST criteria (Eisenhauer et al. (2009) EJC 45:228). Example 5 RECIST Response for TNBC Patients in a Clinical Study of Treatment with CB-839+paclitaxel The RECIST response for each TNBC patient receiving CB-839 in combination with paclitaxel was determined according to percent change in target tumors as described in Eisenhauer et al (2009). The percent change was then correlated to the dose of CB-839 received (FIG. 4) or the length of time the patient stayed on the study (FIG. 5). Incorporation by Reference All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. The compounds, synthetic methods, and experimental protocols and results of U.S. application Ser. No. 13/680,582, filed Nov. 19, 2012, are hereby incorporated by reference. Equivalents While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.
<SOH> BACKGROUND <EOH>Glutamine supports cell survival, growth and proliferation through metabolic and non-metabolic mechanisms. In actively proliferating cells, the metabolism of glutamine to lactate, also referred to as “glutaminolysis” is a major source of energy in the form of NADPH. The first step in glutaminolysis is the deamination of glutamine to form glutamate and ammonia, which is catalyzed by the glutaminase enzyme (GLS). Thus, deamination via glutaminase is a control point for glutamine metabolism. Ever since Warburg's observation that ascites tumor cells exhibited high rates of glucose consumption and lactate secretion in the presence of oxygen (Warburg, 1956), researchers have been exploring how cancer cells utilize metabolic pathways to be able to continue actively proliferating. Several reports have demonstrated how glutamine metabolism supports macromolecular synthesis necessary for cells to replicate (Curthoys, 1995; DeBardinis, 2008). Thus, glutaminase has been theorized to be a potential therapeutic target for the treatment of diseases characterized by actively proliferating cells, such as cancer. The lack of suitable glutaminase inhibitors has made validation of this target impossible. Therefore, the creation of glutaminase inhibitors that are specific and capable of being formulated for in vivo use could lead to a new class of therapeutics.
<SOH> SUMMARY OF INVENTION <EOH>The present invention provides a method of treating or preventing cancer, such as triple-negative breast cancer (TNBC), in a subject, comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: L represents CH 2 SCH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 , CH 2 S, SCH 2 , CH 2 NHCH 2 , CH═CH, or preferably CH 2 CH 2 , wherein any hydrogen atom of a CH or CH 2 unit may be replaced by alkyl or alkoxy, any hydrogen of an NH unit may be replaced by alkyl, and any hydrogen atom of a CH 2 unit of CH 2 CH 2 , CH 2 CH 2 CH 2 or CH 2 may be replaced by hydroxy; X, independently for each occurrence, represents S, O or CH═CH, preferably S or CH═CH, wherein any hydrogen atom of a CH unit may be replaced by alkyl; Y, independently for each occurrence, represents H or CH 2 O(CO)R 7 ; R 7 , independently for each occurrence, represents H or substituted or unsubstituted alkyl, alkoxy, aminoalkyl, alkylaminoalkyl, heterocyclylalkyl, arylalkyl, or heterocyclylalkoxy; Z represents H or R 3 (CO); R 1 and R 2 each independently represent H, alkyl, alkoxy or hydroxy; R 3 , independently for each occurrence, represents substituted or unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl or C(R 8 )(R 9 )(R 10 ), N(R 4 )(R 5 ) or OR 6 , wherein any free hydroxyl group may be acylated to form C(O)R 7 ; R 4 and R 5 each independently represent H or substituted or unsubstituted alkyl, hydroxyalkyl, acyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(O)R 7 ; R 6 , independently for each occurrence, represents substituted or unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(O)R 7 ; and R 8 , R 9 and R 10 each independently represent H or substituted or unsubstituted alkyl, hydroxy, hydroxyalkyl, amino, acylamino, aminoalkyl, acylaminoalkyl, alkoxycarbonyl, alkoxycarbonylamino, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, or R 8 and R 9 together with the carbon to which they are attached, form a carbocyclic or heterocyclic ring system, wherein any free hydroxyl group may be acylated to form C(O)R 7 , and wherein at least two of R 8 , R 9 and R 10 are not H; and a taxane, such as paclitaxel, protein-bound paclitaxel (nab-paclitaxel), cabazitaxel or docetaxel; wherein the subject is refractory to at least one prior chemotherapy treatment, preferably to treatment with a taxane. In certain embodiments, the present invention provides a pharmaceutical preparation suitable for use in a human patient in the treatment or prevention of cancer, such as triple-negative breast cancer, comprising an effective amount of any of the compounds described herein (e.g., a compound of the invention, such as a compound of formula I), and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparations may be for use in treating or preventing a condition or disease as described herein. In certain embodiments, the pharmaceutical preparations have a low enough pyrogen activity to be suitable for intravenous use in a human patient.
A61K31501
20170824
20180301
62726.0
A61K31501
0
WANG, SHENGJUN
COMBINATION THERAPY WITH GLUTAMINASE INHIBITORS
SMALL
0
ACCEPTED
A61K
2,017
15,686,198
ACCEPTED
SHORT-WAVE INFRARED SUPER-CONTINUUM LASERS FOR EARLY DETECTION OF DENTAL CARIES
A wearable device for use with a smart phone or tablet includes LEDs for measuring physiological parameters by modulating the LEDs and generating a near-infrared multi-wavelength optical beam. At least one LED emits at a first wavelength having a first penetration depth and at least another LED emits at a second wavelength having a second penetration depth into tissue. The device includes lenses that deliver the optical beam to the tissue, which reflects the first and second wavelengths. A receiver is configured to capture light while the LEDs are off and while at least one of the LEDs is on and to difference corresponding signals to improve a signal-to-noise ratio of the optical beam reflected from the tissue. The signal-to-noise ratio is further increased by increasing light intensity of at least one of the LEDs. The device generates an output signal representing a non-invasive measurement on blood within the tissue.
1. A wearable device for use with a smart phone or tablet, the wearable device comprising: a measurement device including a light source comprising a plurality of light emitting diodes (LEDs) for measuring one or more physiological parameters, the measurement device configured to generate, by modulating at least one of the LEDs having an initial light intensity, an optical beam having a plurality of optical wavelengths, wherein at least one of the LEDs emits at a first wavelength having a first penetration depth into tissue and at least another of the LEDs emits at a second wavelength having a second penetration depth into the tissue different from the first penetration depth, wherein at least a portion of the optical beam includes a near-infrared wavelength between 700 nanometers and 2500 nanometers; the measurement device comprising one or more lenses configured to receive and to deliver at least a portion of each of the first and of the second wavelengths to tissue, wherein the tissue reflects at least a portion of each of the first and of the second wavelengths; the measurement device further comprising a receiver configured to: capture light while the LEDs are off and convert the captured light into a first signal and capture light while at least one of the LEDs is on and to convert the captured light into a second signal, the captured light including at least a portion of one of the first or second wavelengths reflected from the tissue; the measurement device configured to improve a signal-to-noise ratio of the optical beam reflected from the tissue by differencing the first signal and the second signal; the light source configured to further improve the signal-to-noise ratio of the optical beam reflected from the tissue by increasing the light intensity relative to the initial light intensity from at least one of the LEDs; the measurement device further configured to generate an output signal representing at least in part a non-invasive measurement on blood contained within the tissue. 2. The wearable device of claim 1, wherein the measurement device is adapted to be placed on a wrist of a user. 3. The wearable device of claim 1, wherein the measurement device is adapted to be placed on an ear of a user. 4. The wearable device of claim 1, wherein the second wavelength is between 900 nanometers and 1150 nanometers. 5. The wearable device of claim 1, wherein the wearable device is configured to communicate with the smart phone or tablet, the smart phone or tablet comprising a wireless receiver, a wireless transmitter, a display, a voice input module, a speaker, and a touch screen, the smart phone or tablet configured to receive and to process at least a portion of the output signal, wherein the smart phone or tablet is configured to store and display the processed output signal, wherein at least a portion of the processed output signal is configured to be transmitted over a wireless transmission link. 6. The wearable device of claim 1, wherein the receiver is configured to be synchronized to the modulation of at least one of the LEDs. 7. The wearable device of claim 1, wherein the receiver is located a first distance from a first one of the LEDs and a different distance from a second one of the LEDs such that the receiver can capture a third signal from the first LED and a fourth signal from the second LED, and wherein the output signal is generated in part by comparing the third and fourth signals. 8. The wearable device of claim 1, wherein the output signal is generated in part by comparing the reflected light at the first wavelength with the reflected light at the second wavelength. 9. A wearable device for use with a smart phone or tablet, the wearable device comprising: a measurement device including a light source comprising a plurality of light emitting diodes (LEDs) for measuring one or more physiological parameters, the measurement device configured to generate, by modulating at least one of the LEDs having an initial light intensity, an optical beam having a plurality of optical wavelengths, wherein at least a portion of the plurality of optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers; the measurement device comprising one or more lenses configured to receive and to deliver a portion of the optical beam to tissue, wherein the tissue reflects at least a portion of the optical beam delivered to the tissue, and wherein the measurement device is adapted to be placed on a wrist or an ear of a user; the measurement device further comprising a receiver configured to: capture light while the LEDs are off and convert the captured light into a first signal and capture light while at least one of the LEDs is on and convert the captured light into a second signal, the captured light including at least a portion of the optical beam reflected from the tissue; the measurement device configured to improve a signal-to-noise ratio of the optical beam reflected from the tissue by differencing the first signal and the second signal; the light source configured to further improve the signal-to-noise ratio of the optical beam reflected from the tissue by increasing the light intensity relative to the initial light intensity from at least one of the LEDs; the measurement device further configured to generate an output signal representing at least in part a non-invasive measurement on blood contained within the tissue. 10. The wearable device of claim 9, wherein at least one LED emits at a first wavelength and at least another LED emits at a second wavelength, and wherein the first wavelength has a first penetration depth into the tissue and wherein the second wavelength has a second penetration depth into the tissue different from the first penetration depth. 11. The wearable device of claim 10, wherein the output signal is generated in part by comparing the reflected light at the first wavelength with the reflected light at the second wavelength. 12. The wearable device of claim 10, wherein the second wavelength is between 900 nanometers and 1150 nanometers. 13. The wearable device of claim 9, wherein the wearable device is configured to communicate with the smart phone or tablet, the smart phone or tablet comprising a wireless receiver, a wireless transmitter, a display, a voice input module, a speaker, and a touch screen, the smart phone or tablet configured to receive and to process at least a portion of the output signal, wherein the smart phone or tablet is configured to store and display the processed output signal, wherein at least a portion of the processed output signal is configured to be transmitted over a wireless transmission link. 14. The wearable device of claim 9, wherein the receiver is configured to be synchronized to the modulation of the at least one of the LEDs. 15. The wearable device of claim 9, wherein the receiver is located a first distance from a first one of the LEDs and a different distance from a second one of the LEDs such that the receiver can capture a third signal from the first LED and a fourth signal from the second LED, and wherein the output signal is generated in part by comparing the third and fourth signals. 16. A wearable device for use with a smart phone or tablet, the wearable device comprising: a measurement device including a light source comprising a plurality of light emitting diodes (LEDs) for measuring one or more physiological parameters, the measurement device configured to generate, by modulating at least one of the LEDs having an initial light intensity, an optical beam having a plurality of optical wavelengths, wherein at least a portion of the plurality of optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers; the measurement device comprising one or more lenses configured to receive and to deliver a portion of the optical beam to tissue, wherein the tissue reflects at least a portion of the optical beam delivered to the tissue, and wherein the measurement device is adapted to be placed on a wrist or an ear of a user; the measurement device further comprising a receiver configured to: capture light while the LEDs are off and convert the captured light into a first signal and capture light while at least one of the LEDs is on and convert the captured light into a second signal, the captured light including at least a portion of the optical beam reflected from the tissue; the measurement device configured to improve a signal-to-noise ratio of the optical beam reflected from the tissue by differencing the first signal and the second signal; the light source configured to further improve the signal-to-noise ratio of the optical beam reflected from the tissue by increasing the light intensity relative to the initial light intensity from at least one of the LEDs; the measurement device further configured to generate an output signal representing at least in part a non-invasive measurement on blood contained within the tissue; and wherein the receiver includes a plurality of spatially separated detectors, wherein at least one analog to digital converter is coupled to the spatially separated detectors. 17. The wearable device of claim 16, wherein at least one LED emits at a first wavelength and at least another LED emits at a second wavelength, and wherein the first wavelength has a first penetration depth into the tissue and wherein the second wavelength has a second penetration depth into the tissue different from the first penetration depth. 18. The wearable device of claim 17, wherein the output signal is generated in part by comparing the reflected light at the first wavelength with the reflected light at the second wavelength. 19. The wearable device of claim 16, wherein the receiver is configured to be synchronized to the modulating of at least one of the LEDs. 20. The wearable device of claim 16, wherein the receiver is located a first distance from a first one of the LEDs and a different distance from a second one of the LEDs such that the receiver can capture a third signal from the first LED and a fourth signal from the second LED, and wherein the output signal is generated in part by comparing the third and fourth signals.
CROSS-REFERENCE TO RELATED APPLICATIONS This application is a Continuation of U.S. application Ser. No. 15/357,136 filed Nov. 21, 2016, which is a Continuation of U.S. application Ser. No. 14/651,367 filed Jun. 11, 2015, which is the U.S. national phase of PCT Application No. PCT/US2013/075736 filed Dec. 17, 2013, which claims the benefit of U.S. provisional application Ser. No. 61/747,477 filed Dec. 31, 2012 and U.S. provisional application Ser. No. 61/754,698 filed Jan. 21, 2013, the disclosures of which are hereby incorporated by reference in their entirety. This application is related to U.S. provisional application Ser. No. 61/747,472 filed Dec. 31, 2012; Ser. No. 61/747,481 filed Dec. 31, 2012; Ser. No. 61/747,485 filed Dec. 31, 2012; Ser. No. 61/747,487 filed Dec. 31, 2012; Ser. No. 61/747,492 filed Dec. 31, 2012; and Ser. No. 61/747,553 filed Dec. 31, 2012, the disclosures of which are hereby incorporated in their entirety in their entirety by reference herein. This application has a common priority date with commonly owned U.S. Application Ser. No. 14/650,897 filed Jun. 10, 2015, which is the U.S. national phase of International Application PCT/US2013/075700 entitled Near-Infrared Lasers For Non-Invasive Monitoring Of Glucose, Ketones, HBA1C, And Other Blood Constituents (Attorney Docket No. OMNI0101PCT); U.S. application Ser. No. 14/108,995 filed December 17, 2013, now U.S. Pat. No. 9,164,032 entitled Focused Near-Infrared Lasers For Non-Invasive Vasectomy And Other Thermal Coagulation Or Occlusion Procedures (Attorney Docket No. OMNI0103PUSP); U.S. Application Ser. No. 14/650,981 filed Jun. 10, 2015, which is the U.S. national phase of International Application PCT/US2013/075767 entitled Short-Wave Infrared Super-Continuum Lasers For Natural Gas Leak Detection, Exploration, And Other Active Remote Sensing Applications (Attorney Docket No. OMNI0104PCT); U.S. application Ser. No. 14/108,986 filed Dec. 17, 2013 entitled Short-Wave Infrared Super-Continuum Lasers For Detecting Counterfeit Or Illicit Drugs And Pharmaceutical Process Control (Attorney Docket No. OMNI0105PUSP); U.S. application Ser. No. 14/108,974 filed Dec. 17, 2013 entitled Non-Invasive Treatment Of Varicose Veins (Attorney Docket No. OMNI0106PUSP); and U.S. application Ser. No. 14/109,007 filed Dec. 17, 2013 entitled Near-Infrared Super-Continuum Lasers For Early Detection Of Breast And Other Cancers (Attorney Docket No. OMNI0107PUSP), the disclosures of which are hereby incorporated in their entirety by reference herein. TECHNICAL FIELD This disclosure relates to lasers and light sources for healthcare, medical, dental, or bio-technology applications, including systems and methods for using near-infrared or short-wave infrared light sources for early detection of dental caries, often called cavities. BACKGROUND AND SUMMARY Dental care and the prevention of dental decay or dental caries has changed in the United States over the past several decades, due to the introduction of fluoride to drinking water, the use of fluoride dentifrices and rinses, application of topical fluoride in the dental office, and improved dental hygiene. Despite these advances, dental decay continues to be the leading cause of tooth loss. With the improvements over the past several decades, the majority of newly discovered carious lesions tend to be localized to the occlusal pits and fissures of the posterior dentition and the proximal contact sites. These early carious lesions may be often obscured in the complex and convoluted topography of the pits and fissures or may be concealed by debris that frequently accumulates in those regions of the posterior teeth. Moreover, such lesions are difficult to detect in the early stages of development. Dental caries may be a dynamic disease that is characterized by tooth demineralization leading to an increase in the porosity of the enamel surface. Leaving these lesions untreated may potentially lead to cavities reaching the dentine and pulp and perhaps eventually causing tooth loss. Occlusal surfaces (bite surfaces) and approximal surfaces (between the teeth) are among the most susceptible sites of demineralization due to acid attack from bacterial by-products in the biofilm. Therefore, there is a need for detection of lesions at an early stage, so that preventive agents may be used to inhibit or reverse the demineralization. Traditional methods for caries detection include visual examination and tactile probing with a sharp dental exploration tool, often assisted by radiographic (x-ray) imaging. However, detection using these methods may be somewhat subjective; and, by the time that caries are evident under visual and tactile examination, the disease may have already progressed to an advanced stage. Also, because of the ionizing nature of x-rays, they are dangerous to use (limited use with adults, and even less used with children). Although x-ray methods are suitable for approximal surface lesion detection, they offer reduced utility for screening early caries in occlusal surfaces due to their lack of sensitivity at very early stages of the disease. Some of the current imaging methods are based on the observation of the changes of the light transport within the tooth, namely absorption, scattering, transmission, reflection and/or fluorescence of light. Porous media may scatter light more than uniform media. Taking advantage of this effect, the Fiber-optic trans-illumination is a qualitative method used to highlight the lesions within teeth by observing the patterns formed when white light, pumped from one side of the tooth, is scattered away and/or absorbed by the lesion. This technique may be difficult to quantify due to an uneven light distribution inside the tooth. Another method called quantitative light-induced fluorescence—QLF—relies on different fluorescence from solid teeth and caries regions when excited with bright light in the visible. For example, when excited by relatively high intensity blue light, healthy tooth enamel yields a higher intensity of fluorescence than does demineralized enamel that has been damaged by caries infection or any other cause. On the other hand, for excitation by relatively high intensity of red light, the opposite magnitude change occurs, since this is the region of the spectrum for which bacteria and bacterial by-products in carious regions absorb and fluoresce more pronouncedly than do healthy areas. However, the image provided by QLF may be difficult to assess due to relatively poor contrast between healthy and infected areas. Moreover, QLF may have difficulty discriminating between white spots and stains because both produce similar effects. Stains on teeth are commonly observed in the occlusal sites of teeth, and this obscures the detection of caries using visible light. As described in this disclosure, the near-infrared region of the spectrum offers a novel approach to imaging carious regions because scattering is reduced and absorption by stains is low. For example, it has been demonstrated that the scattering by enamel tissues reduces in the form of 1/(wavelength)3, e.g., inversely as the cube of wavelength. By using a broadband light source in the short-wave infrared (SWIR) part of the spectrum, which corresponds approximately to 1400 nm to 2500 nm, lesions in the enamel and dentine may be observed. In one embodiment, intact teeth have low reflection over the SWIR wavelength range. In the presence of caries, the scattering increases, and the scattering is a function of wavelength; hence, the reflected signal decreases with increasing wavelength. Moreover, particularly when caries exist in the dentine region, water build up may occur, and dips in the SWIR spectrum corresponding to the water absorption lines may be observed. The scattering and water absorption as a function of wavelength may thus be used for early detection of caries and for quantifying the degree of demineralization. SWIR light may be generated by light sources such as lamps, light emitting diodes, one or more laser diodes, super-luminescent laser diodes, and fiber-based super-continuum sources. The SWIR super-continuum light sources advantageously may produce high intensity and power, as well as being a nearly transform-limited beam that may also be modulated. Also, apparatuses for caries detection may include C-clamps over teeth, a handheld device with light input and light detection, which may also be attached to other dental equipment such as drills. Alternatively, a mouth-guard type apparatus may be used to simultaneously illuminate one or more teeth. Fiber optics may be conveniently used to guide the light to the patient as well as to transport the signal back to one or more detectors and receivers. In one embodiment, a wearable device for use with a smart phone or tablet comprises a measurement device including a light source comprising a plurality of light emitting diodes (LEDs) for measuring one or more physiological parameters, the measurement device configured to generate, by modulating at least one of the LEDs having an initial light intensity, an optical beam having a plurality of optical wavelengths. At least one of the LEDs emits at a first wavelength having a first penetration depth into tissue and at least another of the LEDs emits at a second wavelength having a second penetration depth into the tissue , wherein at least a portion of the optical beam includes a near-infrared wavelength between 700 nanometers and 2500 nanometers. The measurement device comprises one or more lenses configured to receive and to deliver at least a portion of each of the first and of the second wavelengths to tissue, wherein the tissue reflects at least a portion of each of the first and of the second wavelengths. The measurement device further comprises a receiver configured to capture light while the LEDs are off and convert the captured light into a first signal and capture light while at least one of the LEDs is on and to convert the captured light into a second signal, the captured light including at least a portion of one of the first or second wavelengths reflected from the tissue. The measurement device is configured to improve a signal-to-noise ratio of the optical beam reflected from the tissue by differencing the first signal and the second signal. The light source is configured to further improve the signal-to-noise ratio of the optical beam reflected from the tissue by increasing the light intensity relative to the initial light intensity from at least one of the LEDs. The measurement device is further configured to generate an output signal representing at least in part a non-invasive measurement on blood contained within the tissue. In another embodiment, a wearable device for use with a smart phone or tablet comprises a measurement device including a light source comprising a plurality of light emitting diodes (LEDs) for measuring one or more physiological parameters, the measurement device configured to generate, by modulating at least one of the LEDs having an initial light intensity, an optical beam having a plurality of optical wavelengths, wherein at least a portion of the plurality of optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers. The measurement device comprises one or more lenses configured to receive and to deliver a portion of the optical beam to tissue, wherein the tissue reflects at least a portion of the optical beam delivered to the tissue, and wherein the measurement device is adapted to be placed on a wrist or an ear of a user. The measurement device further comprises a receiver configured to capture light while the LEDs are off and convert the captured light into a first signal and capture light while at least one of the LEDs is on and convert the captured light into a second signal, the captured light including at least a portion of the optical beam reflected from the tissue. The measurement device is configured to improve a signal-to-noise ratio of the optical beam reflected from the tissue by differencing the first signal and the second signal. The light source is configured to further improve the signal-to-noise ratio of the optical beam reflected from the tissue by increasing the light intensity relative to the initial light intensity from at least one of the LEDs. The measurement device is further configured to generate an output signal representing at least in part a non-invasive measurement on blood contained within the tissue. In one embodiment, a wearable device for use with a smart phone or tablet comprises a measurement device including a light source comprising a plurality of light emitting diodes (LEDs) for measuring one or more physiological parameters, the measurement device configured to generate, by modulating at least one of the LEDs having an initial light intensity, an optical beam having a plurality of optical wavelengths, wherein at least a portion of the plurality of optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers. The measurement device comprises one or more lenses configured to receive and to deliver a portion of the optical beam to tissue, wherein the tissue reflects at least a portion of the optical beam delivered to the tissue, and wherein the measurement device is adapted to be placed on a wrist or an ear of a user. The measurement device further comprises a receiver configured to capture light while the LEDs are off and convert the captured light into a first signal and capture light while at least one of the LEDs is on and convert the captured light into a second signal, the captured light including at least a portion of the optical beam reflected from the tissue. The measurement device is configured to improve a signal-to-noise ratio of the optical beam reflected from the tissue by differencing the first signal and the second signal. The light source is configured to further improve the signal-to-noise ratio of the optical beam reflected from the tissue by increasing the light intensity relative to the initial light intensity from at least one of the LEDs. The measurement device is further configured to generate an output signal representing at least in part a non-invasive measurement on blood contained within the tissue. The receiver includes a plurality of spatially separated detectors, wherein at least one analog to digital converter is coupled to the spatially separated detectors. In one embodiment, a wearable device for use with a smart phone or tablet includes a measurement device including a light source comprising a plurality of light emitting diodes for measuring one or more physiological parameters, the measurement device configured to generate an input optical beam with one or more optical wavelengths, wherein at least a portion of the one or more optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers. The measurement device comprises one or more lenses configured to receive and to deliver a portion of the input optical beam to a sample comprising skin or tissue, wherein the sample reflects at least a portion of the input optical beam delivered to the sample. The measurement device further comprises a reflective surface configured to receive and redirect at least a portion of light reflected from the sample, and a receiver configured to receive at least a portion of the input optical beam reflected from the sample. The light source is configured to increase a signal-to-noise ratio of the input optical beam reflected from the sample, wherein the increased signal-to-noise ratio results from an increase to the light intensity from at least one of the plurality of light emitting diodes and from modulation of at least one of the plurality of light emitting diodes. The measurement device is configured to generate an output signal representing at least in part a non-invasive measurement on blood contained within the sample. The wearable device is configured to communicate with the smart phone or tablet, the smart phone or tablet comprising a wireless receiver, a wireless transmitter, a display, a voice input module, a speaker, and a touch screen. The smart phone or tablet is configured to receive and to process at least a portion of the output signal, wherein the smart phone or tablet is configured to store and display the processed output signal, and wherein at least a portion of the processed output signal is configured to be transmitted over a wireless transmission link. In another embodiment, a wearable device for use with a smart phone or tablet includes a measurement device including a light source comprising a plurality of light emitting diodes for measuring one or more physiological parameters, the measurement device configured to generate an input optical beam with one or more optical wavelengths, wherein at least a portion of the one or more optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers. The measurement device comprises one or more lenses configured to receive and to deliver a portion of the input optical beam to a sample comprising skin or tissue, wherein the sample reflects at least a portion of the input optical beam delivered to the sample. The measurement device further comprises a reflective surface configured to receive and redirect at least a portion of light reflected from the sample. The measurement device further comprises a receiver configured to receive at least a portion of the input optical beam reflected from the sample, the receiver being located a first distance from a first one of the plurality of light emitting diodes and a different distance from a second one of the plurality of light emitting diodes such that the receiver receives a first signal from the first light emitting diode and a second signal from the second light emitting diode. The measurement device is configured to generate an output signal representing at least in part a non-invasive measurement on blood contained within the sample. The wearable device is configured to communicate with the smart phone or tablet. The smart phone or tablet comprises a wireless receiver, a wireless transmitter, a display, a voice input module, a speaker, and a touch screen, and is configured to receive and to process at least a portion of the output signal. The smart phone or tablet is configured to store and display the processed output signal, wherein at least a portion of the processed output signal is configured to be transmitted over a wireless transmission link. In one embodiment, a method of measuring physiological information comprises providing a wearable device for use with a smart phone or tablet, the smart phone or tablet comprising a wireless receiver, a wireless transmitter, a display, a voice input module, a speaker, and a touch screen. The wearable device is capable of performing all of the steps comprising: generating an input optical beam having one or more optical wavelengths using a light source comprising a plurality of light emitting diodes, wherein at least a portion of the one or more optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers; delivering a portion of the input optical beam to a sample comprising skin or tissue using one or more lenses; receiving and reflecting at least a portion of the input optical beam reflected from the sample; receiving a portion of the input optical beam reflected from the sample to generate an output signal representing at least in part a non-invasive measurement on blood contained within the sample; increasing the signal-to-noise ratio of the input optical beam reflected from the sample by increasing a light intensity from at least one of the plurality of light emitting diodes and by modulating at least one of the plurality of light emitting diodes; and transmitting at least a portion of the output signal to the smart phone or tablet for processing to generate a processed output signal and for transmitting from the smart phone or tablet at least a portion of the processed output signal over a wireless transmission link. In another embodiment, a method of measuring physiological information comprises providing a wearable device for use with a smart phone or tablet, the smart phone or tablet comprising a wireless receiver, a wireless transmitter, a display, a voice input module, a speaker, and a touch screen. The wearable device is capable of performing all of the steps comprising: generating a first and a second input optical beam each having one or more optical wavelengths using a light source comprising a plurality of light emitting diodes, wherein at least a portion of the one or more optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers; delivering a portion of the first input optical beam and a portion of the second input optical beam to a sample comprising skin or tissue using one or more lenses; receiving and reflecting at least a portion of the input optical beam reflected from the sample; receiving a portion of the first input optical beam reflected from the sample from a first one of the plurality of light emitting diodes located at a first distance and receiving a portion of the second input optical beam reflected from the sample from a different one of the plurality of light emitting diodes located at a distance different from the first distance to generate an output signal representing at least in part a non-invasive measurement on blood contained within the sample; and transmitting at least a portion of the output signal to the smart phone or tablet for processing to generate a processed output signal and for transmitting from the smart phone or tablet at least a portion of the processed output signal over a wireless transmission link. BRIEF DESCRIPTION OF THE DRAWINGS For a more complete understanding of the present disclosure, and for further features and advantages thereof, reference is now made to the following description taken in conjunction with the accompanying drawings, in which: FIG. 1 illustrates the structure of a tooth. FIG. 2A shows the attenuation coefficient for dental enamel and water versus wavelength from approximately 600 nm to 2600 nm. FIG. 2B illustrates the absorption spectrum of intact enamel and dentine in the wavelength range of approximately 1.2 to 2.4 microns. FIG. 3 shows the near infrared spectral reflectance over the wavelength range of approximately 800 nm to 2500 nm from an occlusal tooth surface. The black diamonds correspond to the reflectance from a sound, intact tooth section. The asterisks correspond to a tooth section with an enamel lesion. The circles correspond to a tooth section with a dentine lesion. FIG. 4 illustrates a hand-held dental tool design of a human interface that may also be coupled with other dental tools. FIG. 5A illustrates a clamp design of a human interface to cap over one or more teeth and perform a non-invasive measurement for dental caries. FIG. 5B shows a mouth guard design of a human interface to perform a non-invasive measurement for dental caries. FIG. 6A illustrates the dorsal of a hand for performing a differential measurement for measuring blood constituents or analytes. FIG. 6B illustrates the dorsal of a foot for performing a differential measurement for measuring blood constituents or analytes. FIG. 7 illustrates a block diagram or building blocks for constructing high power laser diode assemblies. FIG. 8 shows a platform architecture for different wavelength ranges for an all-fiber-integrated, high powered, super-continuum light source. FIG. 9 illustrates one embodiment for a short-wave infrared super-continuum light source. FIG. 10 shows the output spectrum from the SWIR SC laser of FIG. 9 when about 10 m length of fiber for SC generation is used. This fiber is a single-mode, non-dispersion shifted fiber that is optimized for operation near 1550 nm. FIG. 11A illustrates a schematic of the experimental set-up for measuring the diffuse reflectance spectroscopy using the SWIR-SC light source of FIGS. 9 and 10. FIG. 11B shows exemplary reflectance from a sound enamel region, an enamel lesion region, and a dentine lesion region. The spectra are normalized to have equal value near 2050 nm. FIGS. 12A-B illustrate high power SWIR-SC lasers that may generate light between approximately 1.4-1.8 microns (FIG. 12A) or approximately 2-2.5 microns (FIG. 12B). FIG. 12C shows a reflection-spectroscopy based stand-off detection system having an SC laser source. FIG. 13 schematically shows that the medical measurement device can be part of a personal or body area network that communicates with another device (e.g., smart phone or tablet) that communicates with the cloud. The cloud may in turn communicate information with the user, dental or healthcare providers, or other designated recipients. DETAILED DESCRIPTION OF EXAMPLE EMBODIMENTS As required, detailed embodiments of the present disclosure are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the disclosure that may be embodied in various and alternative forms. The figures are not necessarily to scale; some features may be exaggerated or minimized to show details of particular components. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a representative basis for teaching one skilled in the art to variously employ the present disclosure. Near-infrared (NIR) and SWIR light may be preferred for caries detection compared to visible light imaging because the NIR/SWIR wavelengths generally have lower absorption by stains and deeper penetration into teeth. Hence, NIR/SWIR light may provide a caries detection method that can be non-invasive, non-contact and relatively stain insensitive. Broadband light may provide further advantages because carious regions may demonstrate spectral signatures from water absorption and the wavelength dependence of porosity in the scattering of light. The wavelength of light should be selected appropriately to achieve a non-invasive procedure. For example, the light should be able to penetrate deep enough to reach through the dermis and subcutaneous fat layers to reach varicose veins. For example, the penetration depth may be defined as the inverse of the absorption coefficient, although it may also be necessary to include the scattering for the calculation. To achieve penetration deep enough to reach the varicose veins, wavelengths may correspond to local minima in water 501 and adipose 502 absorption, as well as potentially local minima in collagen 503 and elastin 504 absorption. For example, wavelengths near approximately 1100 nm, 1310 nm, or 1650 nm may be advantageous for non-invasive procedures. More generally, wavelength ranges of approximately 900 nm to 1150 nm, 1280 nm to 1340 nm, or 1550 nm to 1680 nm may be advantageous for non-invasive procedures. In general, the near-infrared region of the electromagnetic spectrum covers between approximately 0.7 microns (700 nm) to about 2.5 microns (2500 nm). However, it may also be advantageous to use just the short-wave infrared between approximately 1.4 microns (1400 nm) and about 2.5 microns (2500 nm). One reason for preferring the SWIR over the entire NIR may be to operate in the so-called “eye safe” window, which corresponds to wavelengths longer than about 1400 nm. Therefore, for the remainder of the disclosure the SWIR will be used for illustrative purposes. However, it should be clear that the discussion that follows could also apply to using the NIR wavelength range, or other wavelength bands. In particular, wavelengths in the eye safe window may not transmit down to the retina of the eye, and therefore, these wavelengths may be less likely to create permanent eye damage from inadvertent exposure. The near-infrared wavelengths have the potential to be dangerous, because the eye cannot see the wavelengths (as it can in the visible), yet they can penetrate and cause damage to the eye. Even if a practitioner is not looking directly at the laser beam, the practitioner's eyes may receive stray light from a reflection or scattering from some surface. Hence, it can always be a good practice to use eye protection when working around lasers. Since wavelengths longer than about 1400 nm are substantially not transmitted to the retina or substantially absorbed in the retina, this wavelength range is known as the eye safe window. For wavelengths longer than 1400 nm, in general only the cornea of the eye may receive or absorb the light radiation. FIG. 1 illustrates the structure of an exemplary cross-section of a tooth 100. The tooth 100 has a top layer called the crown 101 and below that a root 102 that reaches well into the gum 106 and bone 108 of the mouth. The exterior of the crown 101 is an enamel layer 103, and below the enamel is a layer of dentine 104 that sits atop a layer of cementum 107. Below the dentine 104 is a pulp region 105, which comprises within it blood vessels 109 and nerves 110. If the light can penetrate the enamel 103 and dentine 104, then the blood flow and blood constituents may be measured through the blood vessels in the dental pulp 105. While the amount of blood flow in the capillaries of the dental pulp 105 may be less than an artery or vein, the smaller blood flow could still be advantageous for detecting or measuring blood constituents as compared to detection through the skin if there is less interfering spectral features from the tooth. Although the structure of a molar tooth is illustrated in FIG. 1, other types of teeth also have similar structure. For example, different types of teeth include molars, pre-molars, canine and incisor teeth. As used throughout this document, the term “couple” and or “coupled” refers to any direct or indirect communication between two or more elements, whether or not those elements are physically connected to one another. As used throughout this disclosure, the term “spectroscopy” means that a tissue or sample is inspected by comparing different features, such as wavelength (or frequency), spatial location, transmission, absorption, reflectivity, scattering, refractive index, or opacity. In one embodiment, “spectroscopy” may mean that the wavelength of the light source is varied, and the transmission, absorption, or reflectivity of the tissue or sample is measured as a function of wavelength. In another embodiment, “spectroscopy” may mean that the wavelength dependence of the transmission, absorption or reflectivity is compared between different spatial locations on a tissue or sample. As an illustration, the “spectroscopy” may be performed by varying the wavelength of the light source, or by using a broadband light source and analyzing the signal using a spectrometer, wavemeter, or optical spectrum analyzer. As used throughout this disclosure, the term “fiber laser” refers to a laser or oscillator that has as an output light or an optical beam, wherein at least a part of the laser comprises an optical fiber. For instance, the fiber in the “fiber laser” may comprise one of or a combination of a single mode fiber, a multi-mode fiber, a mid-infrared fiber, a photonic crystal fiber, a doped fiber, a gain fiber, or, more generally, an approximately cylindrically shaped waveguide or light-pipe. In one embodiment, the gain fiber may be doped with rare earth material, such as ytterbium, erbium, and/or thulium, for example. In another embodiment, the mid-infrared fiber may comprise one or a combination of fluoride fiber, ZBLAN fiber, chalcogenide fiber, tellurite fiber, or germanium doped fiber. In yet another embodiment, the single mode fiber may include standard single-mode fiber, dispersion shifted fiber, non-zero dispersion shifted fiber, high-nonlinearity fiber, and small core size fibers. As used throughout this disclosure, the term “pump laser” refers to a laser or oscillator that has as an output light or an optical beam, wherein the output light or optical beam is coupled to a gain medium to excite the gain medium, which in turn may amplify another input optical signal or beam. In one particular example, the gain medium may be a doped fiber, such as a fiber doped with ytterbium, erbium, and/or thulium. In one embodiment, the “pump laser” may be a fiber laser, a solid state laser, a laser involving a nonlinear crystal, an optical parametric oscillator, a semiconductor laser, or a plurality of semiconductor lasers that may be multiplexed together. In another embodiment, the “pump laser” may be coupled to the gain medium by using a fiber coupler, a dichroic mirror, a multiplexer, a wavelength division multiplexer, a grating, or a fused fiber coupler. As used throughout this document, the term “super-continuum” and or “supercontinuum” and or “SC” refers to a broadband light beam or output that comprises a plurality of wavelengths. In a particular example, the plurality of wavelengths may be adjacent to one-another, so that the spectrum of the light beam or output appears as a continuous band when measured with a spectrometer. In one embodiment, the broadband light beam may have a bandwidth or at least 10 nm. In another embodiment, the “super-continuum” may be generated through nonlinear optical interactions in a medium, such as an optical fiber or nonlinear crystal. For example, the “super-continuum” may be generated through one or a combination of nonlinear activities such as four-wave mixing, the Raman effect, modulational instability, and self-phase modulation. As used throughout this disclosure, the terms “optical light” and or “optical beam” and or “light beam” refer to photons or light transmitted to a particular location in space. The “optical light” and or “optical beam” and or “light beam” may be modulated or unmodulated, which also means that they may or may not contain information. In one embodiment, the “optical light” and or “optical beam” and or “light beam” may originate from a fiber, a fiber laser, a laser, a light emitting diode, a lamp, a pump laser, or a light source. Transmission or Reflection Through Teeth The transmission, absorption and reflection from teeth has been studied in the near infrared, and, although there are some features, the enamel and dentine appear to be fairly transparent in the near infrared (particularly SWIR wavelengths between about 1400 and 2500 nm). For example, the absorption or extinction ratio for light transmission has been studied. FIG. 2A illustrates the attenuation coefficient 200 for dental enamel 201 (filled circles) and the absorption coefficient of water 202 (open circles) versus wavelength. Near-infrared light may penetrate much further without scattering through all the tooth enamel, due to the reduced scattering coefficient in normal enamel. Scattering in enamel may be fairly strong in the visible, but decreases as approximately 1/(wavelength)3 [i.e., inverse of the cube of the wavelength] with increasing wavelength to a value of only 2-3 cm-1 at 1310 nm and 1550 nm in the near infrared. Therefore, enamel may be virtually transparent in the near infrared with optical attenuation 1-2 orders of magnitude less than in the visible range. As another example, FIG. 2B illustrates the absorption spectrum 250 of intact enamel 251 (dashed line) and dentine 252 (solid line) in the wavelength range of approximately 1.2 to 2.4 microns. In the near infrared there are two absorption bands in the areas of about 1.5 and 2 microns. The band with a peak around 1.57 microns may be attributed to the overtone of valent vibration of water present in both enamel and dentine. In this band, the absorption is greater for dentine than for enamel, which may be related to the large water content in this tissue. In the region of 2 microns, dentine may have two absorption bands, and enamel one. The band with a maximum near 2.1 microns may belong to the overtone of vibration of PO hydroxyapatite groups, which is the main substance of both enamel and dentine. Moreover, the band with a peak near 1.96 microns in dentine may correspond to water absorption (dentine may contain substantially higher water than enamel). In addition to the absorption coefficient, the reflectance from intact teeth and teeth with dental caries (e.g., cavities) has been studied. In one embodiment, FIG. 3 shows the near infrared spectral reflectance 300 over the wavelength range of approximately 800 nm to 2500 nm from an occlusal (e.g., top) tooth surface 304. The curve with black diamonds 301 corresponds to the reflectance from a sound, intact tooth section. The curve with asterisks (*) 302 corresponds to a tooth section with an enamel lesion. The curve with circles 303 corresponds to a tooth section with a dentine lesion. Thus, when there is a lesion, more scattering occurs and there may be an increase in the reflected light. For wavelengths shorter than approximately 1400 nm, the shapes of the spectra remain similar, but the amplitude of the reflection changes with lesions. Between approximately 1400 nm and 2500 nm, an intact tooth 301 has low reflectance (e.g., high transmission), and the reflectance appears to be more or less independent of wavelength. On the other hand, in the presence of lesions 302 and 303, there is increased scattering, and the scattering loss may be wavelength dependent. For example, the scattering loss may decrease as the inverse of some power of wavelength, such as 1/(wavelength)3—so, the scattering loss decreases with longer wavelengths. When there is a lesion in the dentine 303, more water can accumulate in the area, so there is also increased water absorption. For example, the dips near 1450 nm and 1900 nm may correspond to water absorption, and the reflectance dips are particularly pronounced in the dentine lesion 303. FIG. 3 may point to several novel techniques for early detection and quantification of carious regions. One method may be to use a relatively narrow wavelength range (for example, from a laser diode or super-luminescent laser diode) in the wavelength window below 1400 nm. In one embodiment, wavelengths in the vicinity of 1310 nm may be used, which is a standard telecommunications wavelength where appropriate light sources are available. Also, it may be advantageous to use a super-luminescent laser diode rather than a laser diode, because the broader bandwidth may avoid the production of laser speckle that can produce interference patterns due to light's scattering after striking irregular surfaces. As FIG. 3 shows, the amplitude of the reflected light (which may also be proportional to the inverse of the transmission) may increase with dental caries. Hence, comparing the reflected light from a known intact region with a suspect region may help identify carious regions. However, one difficulty with using a relatively narrow wavelength range and relying on amplitude changes may be the calibration of the measurement. For example, the amplitude of the reflected light may depend on many factors, such as irregularities in the dental surface, placement of the light source and detector, distance of the measurement instrument from the tooth, etc. In one embodiment, use of a plurality of wavelengths can help to better calibrate the dental caries measurement. For example, a plurality of laser diodes or super-luminescent laser diodes may be used at different center wavelengths. Alternately, a lamp or alternate broadband light source may be used followed by appropriate filters, which may be placed after the light source or before the detectors. In one example, wavelengths near 1090 nm, 1440 nm and 1610 nm may be employed. The reflection from the tooth 305 appears to reach a local maximum near 1090 nm in the representative embodiment illustrated. Also, the reflectance near 1440 nm 306 is higher for dental caries, with a distinct dip particularly for dentine caries 303. Near 1610 nm 307, the reflection is also higher for carious regions. By using a plurality of wavelengths, the values at different wavelengths may help quantify a caries score. In one embodiment, the degree of enamel lesions may be proportional to the ratio of the reflectance near 1610 nm divided by the reflectance near 1090 nm. Also, the degree of dentine lesion may be proportional to the difference between the reflectance near 1610 nm and 1440 nm, with the difference then divided by the reflectance near 1090 nm. Although one set of wavelengths has been described, other wavelengths may also be used and are intended to be covered by this disclosure. In yet another embodiment, it may be further advantageous to use all of some fraction of the SWIR between approximately 1400 and 2500 nm. For example, a SWIR super-continuum light source could be used, or a lamp source could be used. On the receiver side, a spectrometer and/or dispersive element could be used to discriminate the various wavelengths. As FIG. 3 shows, an intact tooth 301 has a relatively low and featureless reflectance over the SWIR. On the other hand, with a carious region there is more scattering, so the reflectance 302,303 increases in amplitude. Since the scattering is inversely proportional to wavelength or some power of wavelength, the carious region reflectance 302, 303 also decreases with increasing wavelength. Moreover, the carious region may contain more water, so there are dips in the reflectance near the water absorption lines 306 and 308. The degree of caries or caries score may be quantified by the shape of the spectrum over the SWIR, taking ratios of different parts of the spectrum, or some combination of this and other spectral processing methods. Although several methods of early caries detection using spectral reflectance have been described, other techniques could also be used and are intended to be covered by this disclosure. For example, transmittance may be used rather than reflectance, or a combination of the two could be used. Moreover, the transmittance, reflectance and/or absorbance could also be combined with other techniques, such as quantitative light-induced fluorescence or fiber-optic trans-illumination. Also, the SWIR could be advantageous, but other parts of the infrared, near-infrared or visible wavelengths may also be used consistent with this disclosure. One other benefit of the absorption, transmission or reflectance in the near infrared and SWIR may be that stains and non-calcified plaque are not visible in this wavelength range, enabling better discrimination of defects, cracks, and demineralized areas. For example, dental calculus, accumulated plaque, and organic stains and debris may interfere significantly with visual diagnosis and fluorescence-based caries detection schemes in occlusal surfaces. In the case of using quantitative light-induced fluorescence, such confounding factors typically may need to be removed by prophylaxis (abrasive cleaning) before reliable measurements can be taken. Surface staining at visible wavelengths may further complicate the problem, and it may be difficult to determine whether pits and fissures are simply stained or demineralized. On the other hand, staining and pigmentation generally interfere less with NIR or SWIR imaging. For example, NIR and SWIR light may not be absorbed by melanin and porphyrins produced by bacteria and those found in food dyes that accumulate in dental plaque and are responsible for the pigmentation. Human Interface for Measurement System A number of different types of measurements may be used to image for dental caries, particularly early detection of dental caries. A basic feature of the measurements may be that the optical properties are measured as a function of wavelength at a plurality of wavelengths. As further described below, the light source may output a plurality of wavelengths, or a continuous spectrum over a range of wavelengths. In one embodiment, the light source may cover some or all of the wavelength range between approximately 1400 nm and 2500 nm. The signal may be received at a receiver, which may also comprise a spectrometer or filters to discriminate between different wavelengths. The signal may also be received at a camera, which may also comprise filters or a spectrometer. In one embodiment, the spectral discrimination using filters or a spectrometer may be placed after the light source rather than at the receiver. The receiver usually comprises one or more detectors (optical-to-electrical conversion element) and electrical circuitry. The receiver may also be coupled to analog to digital converters, particularly if the signal is to be fed to a digital device. Referring to FIG. 1, one or more light sources 111 may be used for illumination. In one embodiment, a transmission measurement may be performed by directing the light source output 111 to the region near the interface between the gum 106 and dentine 104. In one embodiment, the light may be directed using a light guide or a fiber optic. The light may then propagate through the dental pulp 105 to the other side, where the light may be incident on one or more detectors or another light guide to transport the signal to 112 a spectrometer, receiver, and/or camera, for example. In one embodiment, the light source may be directed to one or more locations near the interface between the gum 106 and dentine 104 (in one example, could be from the two sides of the tooth). The transmitted light may then be detected in the occlusal surface above the tooth using a 112 spectrometer, receiver, or camera, for example. In another embodiment, a reflectance measurement may be conducted by directing the light source output 111 to, for example, the occlusal surface of the tooth, and then detecting the reflectance at a 113 spectrometer, receiver or camera. Although a few embodiments for imaging the tooth are described, other embodiments and techniques may also be used and are intended to be covered by this disclosure. These optical techniques may measure optical properties such as reflectance, transmittance, absorption, or luminescence. In one embodiment, FIG. 4 shows that the light source and/or detection system may be integrated with a dental hand-piece 400. The hand-piece 400 may also include other dental equipment, such as a drill, pick, air spray or water cooling stream. The dental hand-piece 400 may include a housing 401 and a motor housing 402 (in some embodiments such as with a drill, a motor may be placed in this section). The end of hand-piece 403 that interfaces with the tooth may be detachable, and it may also have the light input and output end. The dental hand-piece 400 may also have an umbilical cord 404 for connecting to power supplies, diagnostics, or other equipment, for example. A light guide 405 may be integrated with the hand-piece 400, either inside the housing 401, 402 or adjacent to the housing. In one embodiment, a light source 410 may be contained within the housing 401, 402. In an alternative embodiment, the hand-piece 400 may have a coupler 410 to couple to an external light source 411 and/or detection system or receiver 412. The light source 411 may be coupled to the hand-piece 400 using a light guide or fiber optic cable 406. In addition, the detection system or receiver 412 may be coupled to the hand-piece 400 using one or more light guides, fiber optic cable or a bundle of fibers 407. The light incident on the tooth may exit the hand-piece 400 through the end 403. The end 403 may also have a lens system or curved mirror system to collimate or focus the light. In one embodiment, if the light source is integrated with a tool such as a drill, then the light may reach the tooth at the same point as the tip of the drill. The reflected or transmitted light from the tooth may then be observed externally and/or guided back through the light guide 405 in the hand-piece 400. If observed externally, there may be a lens system 408 for collecting the light and a detection system 409 that may have one or more detectors and electronics. If the light is to be guided back through the hand-piece 400, then the reflected light may transmit through the light guide 405 back to the detection system or receiver 412. In one embodiment, the incident light may be guided by a fiber optic through the light guide 405, and the reflected light may be captured by a series of fibers forming a bundle adjacent to or surrounding the incident light fiber. In another embodiment, a “clamp” design 500 may be used as a cap over one or more teeth, as illustrated in FIG. 5A. The clamp design may be different for different types of teeth, or it may be flexible enough to fit over different types of teeth. For example, different types of teeth include the molars (toward the back of the mouth), the premolars, the canine, and the incisors (toward the front of the mouth). One embodiment of the clamp-type design is illustrated in FIG. 5A for a molar tooth 508. The C-clamp 501 may be made of a plastic or rubber material, and it may comprise a light source input 502 and a detector output 503 on the front or back of the tooth, for example. The light source input 502 may comprise a light source directly, or it may have light guided to it from an external light source. Also, the light source input 502 may comprise a lens system to collimate or focus the light across the tooth. The detector output 503 may comprise a detector directly, or it may have a light guide to transport the signal to an external detector element. The light source input 502 may be coupled electrically or optically through 504 to a light input 506. For example, if the light source is external in 506, then the coupling element 504 may be a light guide, such as a fiber optic. Alternately, if the light source is contained in 502, then the coupling element 504 may be electrical wires connecting to a power supply in 506. Similarly, the detector output 503 may be coupled to a detector output unit 507 with a coupling element 505, which may be one or more electrical wires or a light guide, such as a fiber optic. This is just one example of a clamp over one or more teeth, but other embodiments may also be used and are intended to be covered by this disclosure. For example, if reflectance from the teeth is to be used in the measurement, then the light input 502 and detected light input 503 may be on the same side of the tooth. In yet another embodiment, one or more light source ports and sensor ports may be used in a mouth-guard type design. For example, one embodiment of a dental mouth guard 550 is illustrated in FIG. 5B. The structure of the mouth guard 551 may be similar to mouth guards used in sports (e.g., when playing football or boxing) or in dental trays used for applying fluoride treatment, and the mouth guard may be made from plastic, rubber, or any other suitable materials. As an example, the mouth guard may have one or more light source input ports 552, 553 and one or more detector output ports 554, 555. Although six input and output ports are illustrated, any number of ports may be used. Similar to the clamp design described above, the light source inputs 552, 553 may comprise one or more light sources directly, or they may have light guided to them from an external light source. Also, the light source inputs 552, 553 may comprise lens systems to collimate or focus the light across the teeth. The detector outputs 554, 555 may comprise one or more detectors directly, or they may have one or more light guides to transport the signals to an external detector element. The light source inputs 552, 553 may be coupled electrically or optically through 556 to a light input 557. For example, if the light source is external in 557, then the one or more coupling elements 556 may be one or more light guides, such as a fiber optic. Alternately, if the light sources are contained in 552, 553, then the coupling element 556 may be one or more electrical wires connecting to a power supply in 557. Similarly, the detector outputs 554, 555 may be coupled to a detector output unit 559 with one or more coupling elements 558, which may be one or more electrical wires or one or more light guides, such as a fiber optic. This is just one example of a mouth guard design covering a plurality of teeth, but other embodiments may also be used and are intended to be covered by this disclosure. For instance, the position of the light source inputs and detector output ports could be exchanged, or some mixture of locations of light source inputs and detector output ports could be used. Also, if reflectance from the teeth is to be measured, then the light sources and detectors may be on the same side of the tooth. Moreover, it may be advantageous to pulse the light source with a particular pulse width and pulse repetition rate, and then the detection system can measure the pulsed light returned from or transmitted through the tooth. Using a lock-in type technique (e.g., detecting at the same frequency as the pulsed light source and also possibly phase locked to the same signal), the detection system may be able to reject background or spurious signals and increase the signal-to-noise ratio of the measurement. Other elements may be added to the human interface designs of FIGS. 4-6 and are also intended to be covered by this disclosure. For instance, in one embodiment it may be desirable to have replaceable inserts that may be disposable. Particularly in a dentist's or doctor's office or hospital setting, the same instrument may be used with a plurality of patients. Rather than disinfecting the human interface after each use, it may be preferable to have disposable inserts that can be thrown away after each use. In one embodiment, a thin plastic coating material may enclose the clamp design of FIG. 5A or mouth guard design of FIG. 5B. The coating material may be inserted before each use, and then after the measurement is exercised the coating material may be peeled off and replaced. The coating or covering material may be selected based on suitable optical properties that do not affect the measurement, or known optical properties that can be calibrated or compensated for during measurement. Such a design may save the dentist or physician or user considerable time, while at the same time provide the business venture with a recurring cost revenue source. Thus, beyond the problem of other blood constituents or analytes having overlapping spectral features, it may be difficult to observe glucose spectral signatures through the skin and its constituents of water, adipose, collagen and elastin. One approach to overcoming this difficulty may be to try to measure the blood constituents in veins that are located at relatively shallow distances below the skin. Veins may be more beneficial for the measurement than arteries, since arteries tend to be located at deeper levels below the skin. Also, in one embodiment it may be advantageous to use a differential measurement to subtract out some of the interfering absorption lines from the skin. For example, an instrument head may be designed to place one probe above a region of skin over a blood vein, while a second probe may be placed at a region of the skin without a noticeable blood vein below it. Then, by differencing the signals from the two probes, at least part of the skin interference may be cancelled out. Two representative embodiments for performing such a differential measurement are illustrated in FIG. 6A and FIG. 6B. In one embodiment shown in FIG. 6A, the dorsal of the hand 600 may be used for measuring blood constituents or analytes. The dorsal of the hand 600 may have regions that have distinct veins 601 as well as regions where the veins are not as shallow or pronounced 602. By stretching the hand and leaning it backwards, the veins 601 may be accentuated in some cases. A near-infrared diffuse reflectance measurement may be performed by placing one probe 603 above the vein-rich region 601. To turn this into a differential measurement, a second probe 604 may be placed above a region without distinct veins 602. Then, the outputs from the two probes may be subtracted 605 to at least partially cancel out the features from the skin. The subtraction may be done preferably in the electrical domain, although it can also be performed in the optical domain or digitally/mathematically using sampled data based on the electrical and/or optical signals. Although one example of using the dorsal of the hand 600 is shown, many other parts of the hand can be used within the scope of this disclosure. For example, alternate methods may use transmission through the webbing between the thumb and the fingers 606, or transmission or diffuse reflection through the tips of the fingers 607. In another embodiment, the dorsal of the foot 650 may be used instead of the hand. One advantage of such a configuration may be that for self-testing by a user, the foot may be easier to position the instrument using both hands. One probe 653 may be placed over regions where there are more distinct veins 651, and a near-infrared diffuse reflectance measurement may be made. For a differential measurement, a second probe 654 may be placed over a region with less prominent veins 652, and then the two probe signals may be subtracted, either electronically or optically, or may be digitized/sampled and processed mathematically depending on the particular application and implementation. As with the hand, the differential measurements may be intended to compensate for or subtract out (at least in part) the interference from the skin. Since two regions are used in close proximity on the same body part, this may also aid in removing some variability in the skin from environmental effects such as temperature, humidity, or pressure. In addition, it may be advantageous to first treat the skin before the measurement, by perhaps wiping with a cloth or treated cotton ball, applying some sort of cream, or placing an ice cube or chilled bag over the region of interest. Although two embodiments have been described, many other locations on the body may be used using a single or differential probe within the scope of this disclosure. In yet another embodiment, the wrist may be advantageously used, particularly where a pulse rate is typically monitored. Since the pulse may be easily felt on the wrist, there is underlying the region a distinct blood flow. Other embodiments may use other parts of the body, such as the ear lobes, the tongue, the inner lip, the nails, the eye, or the teeth. Some of these embodiments will be further described below. The ear lobes or the tip of the tongue may be advantageous because they are thinner skin regions, thus permitting transmission rather than diffuse reflection. However, the interference from the skin is still a problem in these embodiments. Other regions such as the inner lip or the bottom of the tongue may be contemplated because distinct veins are observable, but still the interference from the skin may be problematic in these embodiments. The eye may seem as a viable alternative because it is more transparent than skin. However, there are still issues with scattering in the eye. For example, the anterior chamber of the eye (the space between the cornea and the iris) comprises a fluid known as aqueous humor. However, the glucose level in the eye chamber may have a significant temporal lag on changes in the glucose level compared to the blood glucose level. Light Sources for Near Infrared There are a number of light sources that may be used in the near infrared. To be more specific, the discussion below will consider light sources operating in the short wave infrared (SWIR), which may cover the wavelength range of approximately 1400 nm to 2500 nm. Other wavelength ranges may also be used for the applications described in this disclosure, so the discussion below is merely provided as exemplary types of light sources. The SWIR wavelength range may be valuable for a number of reasons. First, the SWIR corresponds to a transmission window through water and the atmosphere. Second, the so-called “eye-safe” wavelengths are wavelengths longer than approximately 1400 nm. Third, the SWIR covers the wavelength range for nonlinear combinations of stretching and bending modes as well as the first overtone of C-H stretching modes. Thus, for example, glucose and ketones among other substances may have unique signatures in the SWIR. Moreover, many solids have distinct spectral signatures in the SWIR, so particular solids may be identified using stand-off detection or remote sensing. For instance, many explosives have unique signatures in the SWIR. Different light sources may be selected for the SWIR based on the needs of the application. Some of the features for selecting a particular light source include power or intensity, wavelength range or bandwidth, spatial or temporal coherence, spatial beam quality for focusing or transmission over long distance, and pulse width or pulse repetition rate. Depending on the application, lamps, light emitting diodes (LEDs), laser diodes (LD's), tunable LD's, super-luminescent laser diodes (SLDs), fiber lasers or super-continuum sources (SC) may be advantageously used. Also, different fibers may be used for transporting the light, such as fused silica fibers, plastic fibers, mid-infrared fibers (e.g., tellurite, chalcogenides, fluorides, ZBLAN, etc), or a hybrid of these fibers. Lamps may be used if low power or intensity of light is required in the SWIR, and if an incoherent beam is suitable. In one embodiment, in the SWIR an incandescent lamp that can be used is based on tungsten and halogen, which have an emission wavelength between approximately 500 nm to 2500 nm. For low intensity applications, it may also be possible to use thermal sources, where the SWIR radiation is based on the black body radiation from the hot object. Although the thermal and lamp based sources are broadband and have low intensity fluctuations, it may be difficult to achieve a high signal-to-noise ratio due to the low power levels. Also, the lamp based sources tend to be energy inefficient. In another embodiment, LED's can be used that have a higher power level in the SWIR wavelength range. LED's also produce an incoherent beam, but the power level can be higher than a lamp and with higher energy efficiency. Also, the LED output may more easily be modulated, and the LED provides the option of continuous wave or pulsed mode of operation. LED's are solid state components that emit a wavelength band that is of moderate width, typically between about 20 nm to 40 nm. There are also so-called super-luminescent LEDs that may even emit over a much wider wavelength range. In another embodiment, a wide band light source may be constructed by combining different LEDs that emit in different wavelength bands, some of which could preferably overlap in spectrum. One advantage of LEDs as well as other solid state components is the compact size that they may be packaged into. In yet another embodiment, various types of laser diodes may be used in the SWIR wavelength range. Just as LEDs may be higher in power but narrower in wavelength emission than lamps and thermal sources, the LDs may be yet higher in power but yet narrower in wavelength emission than LEDs. Different kinds of LDs may be used, including Fabry-Perot LDs, distributed feedback (DFB) LDs, distributed Bragg reflector (DBR) LDs. Since the LDs have relatively narrow wavelength range (typically under 10 nm), in one embodiment a plurality of LDs may be used that are at different wavelengths in the SWIR. The various LDs may be spatially multiplexed, polarization multiplexed, wavelength multiplexed, or a combination of these multiplexing methods. Also, the LDs may be fiber pig-tailed or have one or more lenses on the output to collimate or focus the light. Another advantage of LDs is that they may be packaged compactly and may have a spatially coherent beam output. Moreover, tunable LDs that can tune over a range of wavelengths are also available. The tuning may be done by varying the temperature, or electrical current may be used in particular structures such as distributed Bragg reflector (DBR) LDs, for example. In another embodiment, external cavity LDs may be used that have a tuning element, such as a fiber grating or a bulk grating, in the external cavity. In another embodiment, super-luminescent laser diodes may provide higher power as well as broad bandwidth. An SLD is typically an edge emitting semiconductor light source based on super-luminescence (e.g., this could be amplified spontaneous emission). SLDs combine the higher power and brightness of LDs with the low coherence of conventional LEDs, and the emission band for SLD's may be 5 to 100 nm wide, preferably in the 60 to 100 nm range. Although currently SLDs are commercially available in the wavelength range of approximately 400 nm to 1700 nm, SLDs could and may in the future be made to cover a broader region of the SWIR. In yet another embodiment, high power LDs for either direct excitation or to pump fiber lasers and SC light sources may be constructed using one or more laser diode bar stacks. FIG. 7 shows an example of a block diagram 700 or building blocks for constructing the high power LDs. In this embodiment, one or more diode bar stacks 701 may be used, where the diode bar stack may be an array of several single emitter LDs. Since the fast axis (e.g., vertical direction) may be nearly diffraction limited while the slow-axis (e.g., horizontal axis) may be far from diffraction limited, different collimators 702 may be used for the two axes. Then, the brightness may be increased by spatially combining the beams from multiple stacks 703. The combiner may include spatial interleaving, it may include wavelength multiplexing, or it may involve a combination of the two. Different spatial interleaving schemes may be used, such as using an array of prisms or mirrors with spacers to bend one array of beams into the beam path of the other. In another embodiment, segmented mirrors with alternate high-reflection and anti-reflection coatings may be used. Moreover, the brightness may be increased by polarization beam combining 704 the two orthogonal polarizations, such as by using a polarization beam splitter. In a particular embodiment, the output may then be focused or coupled into a large diameter core fiber. As an example, typical dimensions for the large diameter core fiber range from diameters of approximately 100 microns to 400 microns or more. Alternatively or in addition, a custom beam shaping module 705 may be used, depending on the particular application. For example, the output of the high power LD may be used directly 706, or it may be fiber coupled 707 to combine, integrate, or transport the high power LD energy. These high power LDs may grow in importance because the LD powers can rapidly scale up. For example, instead of the power being limited by the power available from a single emitter, the power may increase in multiples depending on the number of diodes multiplexed and the size of the large diameter fiber. Although FIG. 7 is shown as one embodiment, some or all of the elements may be used in a high power LD, or additional elements may also be used. Swir Super-Continuum Lasers Each of the light sources described above have particular strengths, but they also may have limitations. For example, there is typically a trade-off between wavelength range and power output. Also, sources such as lamps, thermal sources, and LEDs produce incoherent beams that may be difficult to focus to a small area and may have difficulty propagating for long distances. An alternative source that may overcome some of these limitations is an SC light source. Some of the advantages of the SC source may include high power and intensity, wide bandwidth, spatially coherent beam that can propagate nearly transform limited over long distances, and easy compatibility with fiber delivery. Supercontinuum lasers may combine the broadband attributes of lamps with the spatial coherence and high brightness of lasers. By exploiting a modulational instability initiated supercontinuum (SC) mechanism, an all-fiber-integrated SC laser with no moving parts may be built using commercial-off-the-shelf (COTS) components. Moreover, the fiber laser architecture may be a platform where SC in the visible, near-infrared/SWIR, or mid-IR can be generated by appropriate selection of the amplifier technology and the SC generation fiber. But until recently, SC lasers were used primarily in laboratory settings since typically large, table-top, mode-locked lasers were used to pump nonlinear media such as optical fibers to generate SC light. However, those large pump lasers may now be replaced with diode lasers and fiber amplifiers that gained maturity in the telecommunications industry. In one embodiment, an all-fiber-integrated, high-powered SC light source 800 may be elegant for its simplicity (FIG. 8). The light may be first generated from a seed laser diode 801. For example, the seed LD 801 may be a distributed feedback (DFB) laser diode with a wavelength near 1542 or 1550 nm, with approximately 0.5-2.0 ns pulsed output, and with a pulse repetition rate between about one kilohertz to about 100 MHz or more. The output from the seed laser diode may then be amplified in a multiple-stage fiber amplifier 802 comprising one or more gain fiber segments. In one embodiment, the first stage pre-amplifier 803 may be designed for optimal noise performance. For example, the pre-amplifier 803 may be a standard erbium-doped fiber amplifier or an erbium/ytterbium doped cladding pumped fiber amplifier. Between amplifier stages 803 and 806, it may be advantageous to use band-pass filters 804 to block amplified spontaneous emission and isolators 805 to prevent spurious reflections. Then, the power amplifier stage 806 may use a cladding-pumped fiber amplifier that may be optimized to minimize nonlinear distortion. The power amplifier fiber 806 may also be an erbium-doped fiber amplifier, if only low or moderate power levels are to be generated. The SC generation 807 may occur in the relatively short lengths of fiber that follow the pump laser. The SC fiber length may range from around a few millimeters to 100 m or more. In one embodiment, the SC generation may occur in a first fiber 808 where the modulational-instability initiated pulse break-up occurs primarily, followed by a second fiber 809 where the SC generation and spectral broadening occurs primarily. In one embodiment, one or two meters of standard single-mode fiber (SMF) after the power amplifier stage may be followed by several meters of SC generation fiber. For this example, in the SMF the peak power may be several kilowatts and the pump light may fall in the anomalous group-velocity dispersion regime—often called the soliton regime. For high peak powers in the anomalous dispersion regime, the nanosecond pulses may be unstable due to a phenomenon known as modulational instability, which is basically parametric amplification in which the fiber nonlinearity helps to phase match the pulses. As a consequence, the nanosecond pump pulses may be broken into many shorter pulses as the modulational instability tries to form soliton pulses from the quasi-continuous-wave background. Although the laser diode and amplification process starts with approximately nanosecond-long pulses, modulational instability in the short length of SMF fiber may form approximately 0.5 ps to several-picosecond-long pulses with high intensity. Thus, the few meters of SMF fiber may result in an output similar to that produced by mode-locked lasers, except in a much simpler and cost-effective manner. The short pulses created through modulational instability may then be coupled into a nonlinear fiber for SC generation. The nonlinear mechanisms leading to broadband SC may include four-wave mixing or self-phase modulation along with the optical Raman effect. Since the Raman effect is self-phase-matched and shifts light to longer wavelengths by emission of optical photons, the SC may spread to longer wavelengths very efficiently. The short-wavelength edge may arise from four-wave mixing, and often times the short wavelength edge may be limited by increasing group-velocity dispersion in the fiber. In many instances, if the particular fiber used has sufficient peak power and SC fiber length, the SC generation process may fill the long-wavelength edge up to the transmission window. Mature fiber amplifiers for the power amplifier stage 806 include ytterbium-doped fibers (near 1060 nm), erbium-doped fibers (near 1550 nm), erbium/ytterbium-doped fibers (near 1550 nm), or thulium-doped fibers (near 2000 nm). In various embodiments, candidates for SC fiber 809 include fused silica fibers (for generating SC between 0.8-2.7 μm), mid-IR fibers such as fluorides, chalcogenides, or tellurites (for generating SC out to 4.5 μm or longer), photonic crystal fibers (for generating SC between 0.4 and 1.7 μm), or combinations of these fibers. Therefore, by selecting the appropriate fiber-amplifier doping for 806 and nonlinear fiber 809, SC may be generated in the visible, near-IR/SWIR, or mid-IR wavelength region. The configuration 800 of FIG. 8 is just one particular example, and other configurations can be used and are intended to be covered by this disclosure. For example, further gain stages may be used, and different types of lossy elements or fiber taps may be used between the amplifier stages. In another embodiment, the SC generation may occur partially in the amplifier fiber and in the pig-tails from the pump combiner or other elements. In yet another embodiment, polarization maintaining fibers may be used, and a polarizer may also be used to enhance the polarization contrast between amplifier stages. Also, not discussed in detail are many accessories that may accompany this set-up, such as driver electronics, pump laser diodes, safety shut-offs, and thermal management and packaging. In one embodiment, one example of the SC laser that operates in the SWIR is illustrated in FIG. 9. This SWIR SC source 900 produces an output of up to approximately 5 W over a spectral range of about 1.5 to 2.4 microns, and this particular laser is made out of polarization maintaining components. The seed laser 901 is a distributed feedback (DFB) laser operating near 1542 nm producing approximately 0.5 nsec pulses at an about 8 MHz repetition rate. The pre-amplifier 902 is forward pumped and uses about 2 m length of erbium/ytterbium cladding pumped fiber 903 (often also called dual-core fiber)with an inner core diameter of 12 microns and outer core diameter of 130 microns. The pre-amplifier gain fiber 903 is pumped using a 10 W laser diode near 940 nm 905 that is coupled in using a fiber combiner 904. In this particular 5 W unit, the mid-stage between amplifier stages 902 and 906 comprises an isolator 907, a band-pass filter 908, a polarizer 909 and a fiber tap 910. The power amplifier 906 uses an approximately 4 m length of the 12/130 micron erbium/ytterbium doped fiber 911 that is counter-propagating pumped using one or more 30 W laser diodes near 940 nm 912 coupled in through a combiner 913. An approximately 1-2 meter length of the combiner pig-tail helps to initiate the SC process, and then a length of PM-1550 fiber 915 (polarization maintaining, single-mode, fused silica fiber optimized for 1550 nm) is spliced 914 to the combiner output. If an output fiber of about 10 m in length is used, then the resulting output spectrum 1000 is shown in FIG. 10. The details of the output spectrum 1000 depend on the peak power into the fiber, the fiber length, and properties of the fiber such as length and core size, as well as the zero dispersion wavelength and the dispersion properties. For example, if a shorter length of fiber is used, then the spectrum actually reaches to longer wavelengths (e.g., a 2 m length of SC fiber broadens the spectrum to about 2500 nm). Also, if extra-dry fibers are used with less O-H content, then the wavelength edge may also reach to a longer wavelength. To generate more spectra toward the shorter wavelengths, the pump wavelength (in this case ˜1542 nm) should be close to the zero dispersion wavelength in the fiber. For example, by using a dispersion shifted fiber or so-called non-zero dispersion shifted fiber, the short wavelength edge may shift to shorter wavelengths. In one particular embodiment, the SWIR-SC light source of FIG. 9 with output spectrum in FIG. 10 was used in preliminary experiments for examining the reflectance from different dental samples. A schematic of the experimental set-up 1100 for measuring the diffuse reflectance spectroscopy is illustrated in FIG. 11A. The SC source 1101 in this embodiment was based on the design of FIG. 9 and delivered approximately 1.6 W of light over the wavelength range from about 1500-2400 nm. The output beam 1102 was collimated, and then passed through a chopper 1103 (for lock-in detection at the receiver after the spectrometer 1106) and an aperture 1104 for localizing the beam on the tooth location. Different teeth 1105 with different lesions and caries were placed in front of the aperture 1104, and the scattered light was passed through a spectrometer 1106 and collected on a detector, whose signal was sent to a receiver. The tooth samples 1105 were mounted in clay or putty for standing upright. Different types of teeth could be used, including molars, premolars, canine and incisor teeth. FIG. 11B shows exemplary reflectance spectra 1150 from a sound enamel region 1151 (e.g., without dental caries), an enamel lesion region 1152, and a dentine lesion region 1153 of various teeth. The spectra are normalized to have equal value near 2050 nm. In this particular embodiment, the slope from the sound enamel 1151 is steepest between about 1500 and 1950 nm, with a lesser slope in the presence of an enamel lesion 1152. When there is a sample with dentine lesion 1153, more features appear in the spectrum from the presence of water absorption lines from water that collects in the dentine. For this experiment, the spectra 1151, 1152, and 1153 are flatter in the wavelength region between about 1950 nm and 2350 nm. These are preliminary results, but they show the benefit of using broadband sources such as the SWIR-SC source for diagnosing dental caries. Although the explanation behind the different spectra 1150 of FIG. 11B may not be understood as yet, it is clear that the spectra 1151, 1152 and 1153 are distinguishable. Therefore, the broadband reflectance may be used for detection of dental caries and analyzing the region of the caries. Although diffuse reflectance has been used in this experiment, other signals, such as transmission, reflectance or a combination, may also be used and are covered by this disclosure. Although one particular example of a 5 W SWIR-SC has been described, different components, different fibers, and different configurations may also be used consistent with this disclosure. For instance, another embodiment of the similar configuration 900 in FIG. 9 may be used to generate high powered SC between approximately 1060 and 1800 nm. For this embodiment, the seed laser 901 may be a distributed feedback laser diode of about 1064 nm, the pre-amplifier gain fiber 903 may be a ytterbium-doped fiber amplifier with 10/125 microns dimensions, and the pump laser 905 may be a 10 W laser diode near 915 nm. A mode field adapter may be including in the mid-stage, in addition to the isolator 907, band pass filter 908, polarizer 909 and tap 910. The gain fiber 911 in the power amplifier may be an about 20 m length of ytterbium-doped fiber with 25/400 microns dimension. The pump 912 for the power amplifier may be up to six pump diodes providing 30 W each near 915 nm. For this much pump power, the output power in the SC may be as high as 50 W or more. In an alternate embodiment, it may be desirous to generate high power SWIR SC over 1.4-1.8 microns and separately 2-2.5 microns (the window between 1.8 and 2 microns may be less important due to the strong water and atmospheric absorption). For example, the SC source of FIG. 12A can lead to bandwidths ranging from about 1400 nm to 1800 nm or broader, while the SC source of FIG. 12B can lead to bandwidths ranging from about 1900 nm to 2500 nm or broader. Since these wavelength ranges are shorter than about 2500 nm, the SC fiber can be based on fused silica fiber. Exemplary SC fibers include standard single-mode fiber (SMF), high-nonlinearity fiber, high-NA fiber, dispersion shifted fiber, dispersion compensating fiber, and photonic crystal fibers. Non-fused-silica fibers can also be used for SC generation, including chalcogenides, fluorides, ZBLAN, tellurites, and germanium oxide fibers. In one embodiment, FIG. 12A illustrates a block diagram for an SC source 1200 capable of generating light between approximately 1400 and 1800 nm or broader. As an example, a pump fiber laser similar to FIG. 9 can be used as the input to a SC fiber 1209. The seed laser diode 1201 can comprise a DFB laser that generates, for example, several milliwatts of power around 1542 nm or 1553 nm. The fiber pre-amplifier 1202 can comprise an erbium-doped fiber amplifier or an erbium/ytterbium doped double clad fiber. In this example a mid-stage amplifier 1203 can be used, which can comprise an erbium/ytterbium doped double-clad fiber. A bandpass filter 1205 and isolator 1206 may be used between the pre-amplifier 1202 and mid-stage amplifier 1203. The power amplifier stage 1204 can comprise a larger core size erbium/ytterbium doped double-clad fiber, and another bandpass filter 1207 and isolator 1208 can be used before the power amplifier 1204. The output of the power amplifier can be coupled to the SC fiber 1209 to generate the SC output 1210. This is just one exemplary configuration for an SC source, and other configurations or elements may be used consistent with this disclosure. In yet another embodiment, FIG. 12B illustrates a block diagram for an SC source 1250 capable of generating light between approximately 1900 and 2500 nm or broader. As an example, the seed laser diode 1251 can comprise a DFB or DBR laser that generates, for example, several milliwatts of power around 1542 nm or 1553 nm. The fiber pre-amplifier 1252 can comprise an erbium-doped fiber amplifier or an erbium/ytterbium doped double-clad fiber. In this example a mid-stage amplifier 1253 can be used, which can comprise an erbium/ytterbium doped double-clad fiber. A bandpass filter 1255 and isolator 1256 may be used between the pre-amplifier 1252 and mid-stage amplifier 1253. The power amplifier stage 1254 can comprise a thulium doped double-clad fiber, and another isolator 1257 can be used before the power amplifier 1254. Note that the output of the mid-stage amplifier 1253 can be approximately near 1542 nm, while the thulium-doped fiber amplifier 1254 can amplify wavelengths longer than approximately 1900 nm and out to about 2100 nm. Therefore, for this configuration wavelength shifting may be required between 1253 and 1254. In one embodiment, the wavelength shifting can be accomplished using a length of standard single-mode fiber 1258, which can have a length between approximately 5 and 50 meters, for example. The output of the power amplifier 1254 can be coupled to the SC fiber 1259 to generate the SC output 1260. This is just one exemplary configuration for an SC source, and other configurations or elements can be used consistent with this disclosure. For example, the various amplifier stages can comprise different amplifier types, such as erbium doped fibers, ytterbium doped fibers, erbium/ytterbium co-doped fibers and thulium doped fibers. FIG. 12C illustrates a reflection-spectroscopy based stand-off detection system having an SC laser source. The set-up 1270 for the reflection-spectroscopy-based stand-off detection system includes an SC source 1271. First, the diverging SC output is collimated to a 1 cm diameter beam using a 25 mm focal length, 90 degrees off-axis, gold coated, parabolic mirror 1272. To reduce the effects of chromatic aberration, refractive optics are avoided in the setup. All focusing and collimation is done using metallic mirrors that have almost constant reflectivity and focal length over the entire SC output spectrum. The sample 1274 is kept at a distance from the collimating mirror 1272, which provides a total round trip path length of twice the distance before reaching the collection optics 1275. A 12 cm diameter silver coated concave mirror 1275 with a 75 cm focal length is kept 20 cm to the side of the collimation mirror 1272. The mirror 1275 is used to collect a fraction of the diffusely reflected light from the sample, and focus it into the input slit of a monochromator 1276. Thus, the beam is incident normally on the sample 1274, but detected at a reflection angle of tan−1(0.2/5) or about 2.3 degrees. Appropriate long wavelength pass filters mounted in a motorized rotating filter wheel are placed in the beam path before the input slit 1276 to avoid contribution from higher wavelength orders from the grating (300 grooves/mm, 2 μm blaze). The output slit width is set to 2 mm corresponding to a spectral resolution of 10.8 nm, and the light is detected by a 2 mm×2 mm liquid nitrogen cooled (77K) indium antimonide (InSb) detector 1277. The detected output is amplified using a trans-impedance pre-amplifier 1277 with a gain of about 105 V/A and connected to a lock-in amplifier 1278 setup for high sensitivity detection. The chopper frequency is 400 Hz, and the lock-in time constant is set to 100 ms corresponding to a noise bandwidth of about 1 Hz. These are exemplary elements and parameter values, but other or different optical elements may be used consistent with this disclosure. By use of an active illuminator, a number of advantages may be achieved, such as higher signal-to-noise ratios. For example, one way to improve the signal-to-noise ratio would be to use modulation and lock-in techniques. In one embodiment, the light source may be modulated, and then the detection system would be synchronized with the light source. In a particular embodiment, the techniques from lock-in detection may be used, where narrow band filtering around the modulation frequency may be used to reject noise outside the modulation frequency. In an alternate embodiment, change detection schemes may be used, where the detection system captures the signal with the light source on and with the light source off. Again, for this system the light source may be modulated. Then, the signal with and without the light source is differenced. This may enable the sun light changes to be subtracted out. In addition, change detection may help to identify objects that change in the field of view. In the following some exemplary detection systems are described. One advantage of the SC lasers illustrated in FIGS. 8, 9, and 12 is that they may use all-fiber components, so that the SC laser can be all-fiber, monolithically integrated with no moving parts. The all-integrated configuration can consequently be robust and reliable. FIGS. 8, 9, and 12 are examples of SC light sources that may advantageously be used for SWIR light generation in various medical and dental diagnostic and therapeutic applications. However, many other versions of the SC light sources may also be made that are intended to also be covered by this disclosure. For example, the SC generation fiber could be pumped by a mode-locked laser, a gain-switched semiconductor laser, an optically pumped semiconductor laser, a solid state laser, other fiber lasers, or a combination of these types of lasers. Also, rather than using a fiber for SC generation, either a liquid or a gas cell might be used as the nonlinear medium in which the spectrum is to be broadened. Even within the all-fiber versions illustrated such as in FIG. 9, different configurations could be used consistent with the disclosure. In an alternate embodiment, it may be desirous to have a lower cost version of the SWIR SC laser of FIG. 9. One way to lower the cost could be to use a single stage of optical amplification, rather than two stages, which may be feasible if lower output power is required or the gain fiber is optimized. For example, the pre-amplifier stage 902 might be removed, along with at least some of the mid-stage elements. In yet another embodiment, the gain fiber could be double passed to emulate a two stage amplifier. In this example, the pre-amplifier stage 902 might be removed, and perhaps also some of the mid-stage elements. A mirror or fiber grating reflector could be placed after the power amplifier stage 906 that may preferentially reflect light near the wavelength of the seed laser 901. If the mirror or fiber grating reflector can transmit the pump light near 940 nm, then this could also be used instead of the pump combiner 913 to bring in the pump light 912. The SC fiber 915 could be placed between the seed laser 901 and the power amplifier stage 906 (SC is only generated after the second pass through the amplifier, since the power level may be sufficiently high at that time). In addition, an output coupler may be placed between the seed laser diode 901 and the SC fiber, which now may be in front of the power amplifier 906. In a particular embodiment, the output coupler could be a power coupler or divider, a dichroic coupler (e.g., passing seed laser wavelength but outputting the SC wavelengths), or a wavelength division multiplexer coupler. This is just one further example, but a myriad of other combinations of components and architectures could also be used for SC light sources to generate SWIR light that are intended to be covered by this disclosure. Wireless Link to the Cloud The non-invasive dental caries measurement device may also benefit from communicating the data output to the “cloud” (e.g., data servers and processors in the web remotely connected) via wireless means. The non-invasive devices may be part of a series of biosensors applied to the patient, and collectively these devices form what might be called a body area network or a personal area network. The biosensors and non-invasive devices may communicate to a smart phone, tablet, personal data assistant, computer and/or other microprocessor-based device, which may in turn wirelessly or over wire and/or fiber optic transmit some or all of the signal or processed data to the internet or cloud. The cloud or internet may in turn send the data to dentists, doctors or health care providers as well as the patients themselves. Thus, it may be possible to have a panoramic, high-definition, relatively comprehensive view of a patient that doctors and dentists can use to assess and manage disease, and that patients can use to help maintain their health and direct their own care. In a particular embodiment 1300, the non-invasive measurement device 1301 may comprise a transmitter 1303 to communicate over a first communication link 1304 in the body area network or personal area network to a receiver in a smart phone, tablet, cell phone, PDA, and/or computer 1305, for example. For the measurement device 1301, it may also be advantageous to have a processor 1302 to process some of the measured data, since with processing the amount of data to transmit may be less (hence, more energy efficient). The first communication link 1304 may operate through the use of one of many wireless technologies such as Bluetooth, Zigbee, WiFi, IrDA (infrared data association), wireless USB, or Z-wave, to name a few. Alternatively, the communication link 1304 may occur in the wireless medical band between 2360 MHz and 2390 MHz, which the FCC allocated for medical body area network devices, or in other designated medical device or WMTS bands. These are examples of devices that can be used in the body area network and surroundings, but other devices could also be used and are included in the scope of this disclosure. The personal device 1305 may store, process, display, and transmit some of the data from the measurement device 1301. The device 1305 may comprise a receiver, transmitter, display, voice control and speakers, and one or more control buttons or knobs and a touch screen. Examples of the device 1305 include smart phones such as the Apple iPhones® or phones operating on the Android or Microsoft systems. In one embodiment, the device 1305 may have an application, software program, or firmware to receive and process the data from the measurement device 1301. The device 1305 may then transmit some or all of the data or the processed data over a second communication link 1306 to the internet or “cloud” 1307. The second communication link 1306 may advantageously comprise at least one segment of a wireless transmission link, which may operate using WiFi or the cellular network. The second communication link 1306 may additionally comprise lengths of fiber optic and/or communication over copper wires or cables. The internet or cloud 1307 may add value to the measurement device 1301 by providing services that augment the measured data collected. In a particular embodiment, some of the functions performed by the cloud include: (a) receive at least a fraction of the data from the device 1305; (b) buffer or store the data received; (c) process the data using software stored on the cloud; (d) store the resulting processed data; and (e) transmit some or all of the data either upon request or based on an alarm. As an example, the data or processed data may be transmitted 1308 back to the originator (e.g., patient or user), it may be transmitted 1309 to a health care provider or doctor or dentist, or it may be transmitted 1310 to other designated recipients. Service providers coupled to the cloud 1307 may provide a number of value-add services. For example, the cloud application may store and process the dental data for future reference or during a visit with the dentist or healthcare provider. If a patient has some sort of medical mishap or emergency, the physician can obtain the history of the dental or physiological parameters over a specified period of time. In another embodiment, alarms, warnings or reminders may be delivered to the user 1308, the healthcare provider 1309, or other designated recipients 1310. These are just some of the features that may be offered, but many others may be possible and are intended to be covered by this disclosure. As an example, the device 1305 may also have a GPS sensor, so the cloud 1307 may be able to provide time, date, and position along with the dental or physiological parameters. Thus, if there is a medical or dental emergency, the cloud 1307 could provide the location of the patient to the dental or healthcare provider 1309 or other designated recipients 1310. Moreover, the digitized data in the cloud 1307 may help to move toward what is often called “personalized medicine.” Based on the dental or physiological parameter data history, medication or medical/dental therapies may be prescribed that are customized to the particular patient. Another advantage for commercial entities may be that by leveraging the advances in wireless connectivity and the widespread use of handheld devices such as smart phones that can wirelessly connect to the cloud, businesses can build a recurring cost business model even using non-invasive measurement devices. Described herein are just some examples of the beneficial use of near-infrared or SWIR lasers for non-invasive measurements of dental caries and early detection of carious regions. However, many other dental or medical procedures can use the near-infrared or SWIR light consistent with this disclosure and are intended to be covered by the disclosure. Although the present disclosure has been described in several embodiments, a myriad of changes, variations, alterations, transformations, and modifications may be suggested to one skilled in the art, and it is intended that the present disclosure encompass such changes, variations, alterations, transformations, and modifications as falling within the spirit and scope of the appended claims. While exemplary embodiments are described above, it is not intended that these embodiments describe all possible forms of the disclosure. Rather, the words used in the specification are words of description rather than limitation, and it is understood that various changes may be made without departing from the spirit and scope of the disclosure. Additionally, the features of various implementing embodiments may be combined to form further embodiments of the disclosure. While various embodiments may have been described as providing advantages or being preferred over other embodiments with respect to one or more desired characteristics, as one skilled in the art is aware, one or more characteristics may be compromised to achieve desired system attributes, which depend on the specific application and implementation. These attributes include, but are not limited to: cost, strength, durability, life cycle cost, marketability, appearance, packaging, size, serviceability, weight, manufacturability, ease of assembly, etc. The embodiments described herein that are described as less desirable than other embodiments or prior art implementations with respect to one or more characteristics are not outside the scope of the disclosure and may be desirable for particular applications.
<SOH> BACKGROUND AND SUMMARY <EOH>Dental care and the prevention of dental decay or dental caries has changed in the United States over the past several decades, due to the introduction of fluoride to drinking water, the use of fluoride dentifrices and rinses, application of topical fluoride in the dental office, and improved dental hygiene. Despite these advances, dental decay continues to be the leading cause of tooth loss. With the improvements over the past several decades, the majority of newly discovered carious lesions tend to be localized to the occlusal pits and fissures of the posterior dentition and the proximal contact sites. These early carious lesions may be often obscured in the complex and convoluted topography of the pits and fissures or may be concealed by debris that frequently accumulates in those regions of the posterior teeth. Moreover, such lesions are difficult to detect in the early stages of development. Dental caries may be a dynamic disease that is characterized by tooth demineralization leading to an increase in the porosity of the enamel surface. Leaving these lesions untreated may potentially lead to cavities reaching the dentine and pulp and perhaps eventually causing tooth loss. Occlusal surfaces (bite surfaces) and approximal surfaces (between the teeth) are among the most susceptible sites of demineralization due to acid attack from bacterial by-products in the biofilm. Therefore, there is a need for detection of lesions at an early stage, so that preventive agents may be used to inhibit or reverse the demineralization. Traditional methods for caries detection include visual examination and tactile probing with a sharp dental exploration tool, often assisted by radiographic (x-ray) imaging. However, detection using these methods may be somewhat subjective; and, by the time that caries are evident under visual and tactile examination, the disease may have already progressed to an advanced stage. Also, because of the ionizing nature of x-rays, they are dangerous to use (limited use with adults, and even less used with children). Although x-ray methods are suitable for approximal surface lesion detection, they offer reduced utility for screening early caries in occlusal surfaces due to their lack of sensitivity at very early stages of the disease. Some of the current imaging methods are based on the observation of the changes of the light transport within the tooth, namely absorption, scattering, transmission, reflection and/or fluorescence of light. Porous media may scatter light more than uniform media. Taking advantage of this effect, the Fiber-optic trans-illumination is a qualitative method used to highlight the lesions within teeth by observing the patterns formed when white light, pumped from one side of the tooth, is scattered away and/or absorbed by the lesion. This technique may be difficult to quantify due to an uneven light distribution inside the tooth. Another method called quantitative light-induced fluorescence—QLF—relies on different fluorescence from solid teeth and caries regions when excited with bright light in the visible. For example, when excited by relatively high intensity blue light, healthy tooth enamel yields a higher intensity of fluorescence than does demineralized enamel that has been damaged by caries infection or any other cause. On the other hand, for excitation by relatively high intensity of red light, the opposite magnitude change occurs, since this is the region of the spectrum for which bacteria and bacterial by-products in carious regions absorb and fluoresce more pronouncedly than do healthy areas. However, the image provided by QLF may be difficult to assess due to relatively poor contrast between healthy and infected areas. Moreover, QLF may have difficulty discriminating between white spots and stains because both produce similar effects. Stains on teeth are commonly observed in the occlusal sites of teeth, and this obscures the detection of caries using visible light. As described in this disclosure, the near-infrared region of the spectrum offers a novel approach to imaging carious regions because scattering is reduced and absorption by stains is low. For example, it has been demonstrated that the scattering by enamel tissues reduces in the form of 1/(wavelength) 3 , e.g., inversely as the cube of wavelength. By using a broadband light source in the short-wave infrared (SWIR) part of the spectrum, which corresponds approximately to 1400 nm to 2500 nm, lesions in the enamel and dentine may be observed. In one embodiment, intact teeth have low reflection over the SWIR wavelength range. In the presence of caries, the scattering increases, and the scattering is a function of wavelength; hence, the reflected signal decreases with increasing wavelength. Moreover, particularly when caries exist in the dentine region, water build up may occur, and dips in the SWIR spectrum corresponding to the water absorption lines may be observed. The scattering and water absorption as a function of wavelength may thus be used for early detection of caries and for quantifying the degree of demineralization. SWIR light may be generated by light sources such as lamps, light emitting diodes, one or more laser diodes, super-luminescent laser diodes, and fiber-based super-continuum sources. The SWIR super-continuum light sources advantageously may produce high intensity and power, as well as being a nearly transform-limited beam that may also be modulated. Also, apparatuses for caries detection may include C-clamps over teeth, a handheld device with light input and light detection, which may also be attached to other dental equipment such as drills. Alternatively, a mouth-guard type apparatus may be used to simultaneously illuminate one or more teeth. Fiber optics may be conveniently used to guide the light to the patient as well as to transport the signal back to one or more detectors and receivers. In one embodiment, a wearable device for use with a smart phone or tablet comprises a measurement device including a light source comprising a plurality of light emitting diodes (LEDs) for measuring one or more physiological parameters, the measurement device configured to generate, by modulating at least one of the LEDs having an initial light intensity, an optical beam having a plurality of optical wavelengths. At least one of the LEDs emits at a first wavelength having a first penetration depth into tissue and at least another of the LEDs emits at a second wavelength having a second penetration depth into the tissue , wherein at least a portion of the optical beam includes a near-infrared wavelength between 700 nanometers and 2500 nanometers. The measurement device comprises one or more lenses configured to receive and to deliver at least a portion of each of the first and of the second wavelengths to tissue, wherein the tissue reflects at least a portion of each of the first and of the second wavelengths. The measurement device further comprises a receiver configured to capture light while the LEDs are off and convert the captured light into a first signal and capture light while at least one of the LEDs is on and to convert the captured light into a second signal, the captured light including at least a portion of one of the first or second wavelengths reflected from the tissue. The measurement device is configured to improve a signal-to-noise ratio of the optical beam reflected from the tissue by differencing the first signal and the second signal. The light source is configured to further improve the signal-to-noise ratio of the optical beam reflected from the tissue by increasing the light intensity relative to the initial light intensity from at least one of the LEDs. The measurement device is further configured to generate an output signal representing at least in part a non-invasive measurement on blood contained within the tissue. In another embodiment, a wearable device for use with a smart phone or tablet comprises a measurement device including a light source comprising a plurality of light emitting diodes (LEDs) for measuring one or more physiological parameters, the measurement device configured to generate, by modulating at least one of the LEDs having an initial light intensity, an optical beam having a plurality of optical wavelengths, wherein at least a portion of the plurality of optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers. The measurement device comprises one or more lenses configured to receive and to deliver a portion of the optical beam to tissue, wherein the tissue reflects at least a portion of the optical beam delivered to the tissue, and wherein the measurement device is adapted to be placed on a wrist or an ear of a user. The measurement device further comprises a receiver configured to capture light while the LEDs are off and convert the captured light into a first signal and capture light while at least one of the LEDs is on and convert the captured light into a second signal, the captured light including at least a portion of the optical beam reflected from the tissue. The measurement device is configured to improve a signal-to-noise ratio of the optical beam reflected from the tissue by differencing the first signal and the second signal. The light source is configured to further improve the signal-to-noise ratio of the optical beam reflected from the tissue by increasing the light intensity relative to the initial light intensity from at least one of the LEDs. The measurement device is further configured to generate an output signal representing at least in part a non-invasive measurement on blood contained within the tissue. In one embodiment, a wearable device for use with a smart phone or tablet comprises a measurement device including a light source comprising a plurality of light emitting diodes (LEDs) for measuring one or more physiological parameters, the measurement device configured to generate, by modulating at least one of the LEDs having an initial light intensity, an optical beam having a plurality of optical wavelengths, wherein at least a portion of the plurality of optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers. The measurement device comprises one or more lenses configured to receive and to deliver a portion of the optical beam to tissue, wherein the tissue reflects at least a portion of the optical beam delivered to the tissue, and wherein the measurement device is adapted to be placed on a wrist or an ear of a user. The measurement device further comprises a receiver configured to capture light while the LEDs are off and convert the captured light into a first signal and capture light while at least one of the LEDs is on and convert the captured light into a second signal, the captured light including at least a portion of the optical beam reflected from the tissue. The measurement device is configured to improve a signal-to-noise ratio of the optical beam reflected from the tissue by differencing the first signal and the second signal. The light source is configured to further improve the signal-to-noise ratio of the optical beam reflected from the tissue by increasing the light intensity relative to the initial light intensity from at least one of the LEDs. The measurement device is further configured to generate an output signal representing at least in part a non-invasive measurement on blood contained within the tissue. The receiver includes a plurality of spatially separated detectors, wherein at least one analog to digital converter is coupled to the spatially separated detectors. In one embodiment, a wearable device for use with a smart phone or tablet includes a measurement device including a light source comprising a plurality of light emitting diodes for measuring one or more physiological parameters, the measurement device configured to generate an input optical beam with one or more optical wavelengths, wherein at least a portion of the one or more optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers. The measurement device comprises one or more lenses configured to receive and to deliver a portion of the input optical beam to a sample comprising skin or tissue, wherein the sample reflects at least a portion of the input optical beam delivered to the sample. The measurement device further comprises a reflective surface configured to receive and redirect at least a portion of light reflected from the sample, and a receiver configured to receive at least a portion of the input optical beam reflected from the sample. The light source is configured to increase a signal-to-noise ratio of the input optical beam reflected from the sample, wherein the increased signal-to-noise ratio results from an increase to the light intensity from at least one of the plurality of light emitting diodes and from modulation of at least one of the plurality of light emitting diodes. The measurement device is configured to generate an output signal representing at least in part a non-invasive measurement on blood contained within the sample. The wearable device is configured to communicate with the smart phone or tablet, the smart phone or tablet comprising a wireless receiver, a wireless transmitter, a display, a voice input module, a speaker, and a touch screen. The smart phone or tablet is configured to receive and to process at least a portion of the output signal, wherein the smart phone or tablet is configured to store and display the processed output signal, and wherein at least a portion of the processed output signal is configured to be transmitted over a wireless transmission link. In another embodiment, a wearable device for use with a smart phone or tablet includes a measurement device including a light source comprising a plurality of light emitting diodes for measuring one or more physiological parameters, the measurement device configured to generate an input optical beam with one or more optical wavelengths, wherein at least a portion of the one or more optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers. The measurement device comprises one or more lenses configured to receive and to deliver a portion of the input optical beam to a sample comprising skin or tissue, wherein the sample reflects at least a portion of the input optical beam delivered to the sample. The measurement device further comprises a reflective surface configured to receive and redirect at least a portion of light reflected from the sample. The measurement device further comprises a receiver configured to receive at least a portion of the input optical beam reflected from the sample, the receiver being located a first distance from a first one of the plurality of light emitting diodes and a different distance from a second one of the plurality of light emitting diodes such that the receiver receives a first signal from the first light emitting diode and a second signal from the second light emitting diode. The measurement device is configured to generate an output signal representing at least in part a non-invasive measurement on blood contained within the sample. The wearable device is configured to communicate with the smart phone or tablet. The smart phone or tablet comprises a wireless receiver, a wireless transmitter, a display, a voice input module, a speaker, and a touch screen, and is configured to receive and to process at least a portion of the output signal. The smart phone or tablet is configured to store and display the processed output signal, wherein at least a portion of the processed output signal is configured to be transmitted over a wireless transmission link. In one embodiment, a method of measuring physiological information comprises providing a wearable device for use with a smart phone or tablet, the smart phone or tablet comprising a wireless receiver, a wireless transmitter, a display, a voice input module, a speaker, and a touch screen. The wearable device is capable of performing all of the steps comprising: generating an input optical beam having one or more optical wavelengths using a light source comprising a plurality of light emitting diodes, wherein at least a portion of the one or more optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers; delivering a portion of the input optical beam to a sample comprising skin or tissue using one or more lenses; receiving and reflecting at least a portion of the input optical beam reflected from the sample; receiving a portion of the input optical beam reflected from the sample to generate an output signal representing at least in part a non-invasive measurement on blood contained within the sample; increasing the signal-to-noise ratio of the input optical beam reflected from the sample by increasing a light intensity from at least one of the plurality of light emitting diodes and by modulating at least one of the plurality of light emitting diodes; and transmitting at least a portion of the output signal to the smart phone or tablet for processing to generate a processed output signal and for transmitting from the smart phone or tablet at least a portion of the processed output signal over a wireless transmission link. In another embodiment, a method of measuring physiological information comprises providing a wearable device for use with a smart phone or tablet, the smart phone or tablet comprising a wireless receiver, a wireless transmitter, a display, a voice input module, a speaker, and a touch screen. The wearable device is capable of performing all of the steps comprising: generating a first and a second input optical beam each having one or more optical wavelengths using a light source comprising a plurality of light emitting diodes, wherein at least a portion of the one or more optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers; delivering a portion of the first input optical beam and a portion of the second input optical beam to a sample comprising skin or tissue using one or more lenses; receiving and reflecting at least a portion of the input optical beam reflected from the sample; receiving a portion of the first input optical beam reflected from the sample from a first one of the plurality of light emitting diodes located at a first distance and receiving a portion of the second input optical beam reflected from the sample from a different one of the plurality of light emitting diodes located at a distance different from the first distance to generate an output signal representing at least in part a non-invasive measurement on blood contained within the sample; and transmitting at least a portion of the output signal to the smart phone or tablet for processing to generate a processed output signal and for transmitting from the smart phone or tablet at least a portion of the processed output signal over a wireless transmission link.
<SOH> BACKGROUND AND SUMMARY <EOH>Dental care and the prevention of dental decay or dental caries has changed in the United States over the past several decades, due to the introduction of fluoride to drinking water, the use of fluoride dentifrices and rinses, application of topical fluoride in the dental office, and improved dental hygiene. Despite these advances, dental decay continues to be the leading cause of tooth loss. With the improvements over the past several decades, the majority of newly discovered carious lesions tend to be localized to the occlusal pits and fissures of the posterior dentition and the proximal contact sites. These early carious lesions may be often obscured in the complex and convoluted topography of the pits and fissures or may be concealed by debris that frequently accumulates in those regions of the posterior teeth. Moreover, such lesions are difficult to detect in the early stages of development. Dental caries may be a dynamic disease that is characterized by tooth demineralization leading to an increase in the porosity of the enamel surface. Leaving these lesions untreated may potentially lead to cavities reaching the dentine and pulp and perhaps eventually causing tooth loss. Occlusal surfaces (bite surfaces) and approximal surfaces (between the teeth) are among the most susceptible sites of demineralization due to acid attack from bacterial by-products in the biofilm. Therefore, there is a need for detection of lesions at an early stage, so that preventive agents may be used to inhibit or reverse the demineralization. Traditional methods for caries detection include visual examination and tactile probing with a sharp dental exploration tool, often assisted by radiographic (x-ray) imaging. However, detection using these methods may be somewhat subjective; and, by the time that caries are evident under visual and tactile examination, the disease may have already progressed to an advanced stage. Also, because of the ionizing nature of x-rays, they are dangerous to use (limited use with adults, and even less used with children). Although x-ray methods are suitable for approximal surface lesion detection, they offer reduced utility for screening early caries in occlusal surfaces due to their lack of sensitivity at very early stages of the disease. Some of the current imaging methods are based on the observation of the changes of the light transport within the tooth, namely absorption, scattering, transmission, reflection and/or fluorescence of light. Porous media may scatter light more than uniform media. Taking advantage of this effect, the Fiber-optic trans-illumination is a qualitative method used to highlight the lesions within teeth by observing the patterns formed when white light, pumped from one side of the tooth, is scattered away and/or absorbed by the lesion. This technique may be difficult to quantify due to an uneven light distribution inside the tooth. Another method called quantitative light-induced fluorescence—QLF—relies on different fluorescence from solid teeth and caries regions when excited with bright light in the visible. For example, when excited by relatively high intensity blue light, healthy tooth enamel yields a higher intensity of fluorescence than does demineralized enamel that has been damaged by caries infection or any other cause. On the other hand, for excitation by relatively high intensity of red light, the opposite magnitude change occurs, since this is the region of the spectrum for which bacteria and bacterial by-products in carious regions absorb and fluoresce more pronouncedly than do healthy areas. However, the image provided by QLF may be difficult to assess due to relatively poor contrast between healthy and infected areas. Moreover, QLF may have difficulty discriminating between white spots and stains because both produce similar effects. Stains on teeth are commonly observed in the occlusal sites of teeth, and this obscures the detection of caries using visible light. As described in this disclosure, the near-infrared region of the spectrum offers a novel approach to imaging carious regions because scattering is reduced and absorption by stains is low. For example, it has been demonstrated that the scattering by enamel tissues reduces in the form of 1/(wavelength) 3 , e.g., inversely as the cube of wavelength. By using a broadband light source in the short-wave infrared (SWIR) part of the spectrum, which corresponds approximately to 1400 nm to 2500 nm, lesions in the enamel and dentine may be observed. In one embodiment, intact teeth have low reflection over the SWIR wavelength range. In the presence of caries, the scattering increases, and the scattering is a function of wavelength; hence, the reflected signal decreases with increasing wavelength. Moreover, particularly when caries exist in the dentine region, water build up may occur, and dips in the SWIR spectrum corresponding to the water absorption lines may be observed. The scattering and water absorption as a function of wavelength may thus be used for early detection of caries and for quantifying the degree of demineralization. SWIR light may be generated by light sources such as lamps, light emitting diodes, one or more laser diodes, super-luminescent laser diodes, and fiber-based super-continuum sources. The SWIR super-continuum light sources advantageously may produce high intensity and power, as well as being a nearly transform-limited beam that may also be modulated. Also, apparatuses for caries detection may include C-clamps over teeth, a handheld device with light input and light detection, which may also be attached to other dental equipment such as drills. Alternatively, a mouth-guard type apparatus may be used to simultaneously illuminate one or more teeth. Fiber optics may be conveniently used to guide the light to the patient as well as to transport the signal back to one or more detectors and receivers. In one embodiment, a wearable device for use with a smart phone or tablet comprises a measurement device including a light source comprising a plurality of light emitting diodes (LEDs) for measuring one or more physiological parameters, the measurement device configured to generate, by modulating at least one of the LEDs having an initial light intensity, an optical beam having a plurality of optical wavelengths. At least one of the LEDs emits at a first wavelength having a first penetration depth into tissue and at least another of the LEDs emits at a second wavelength having a second penetration depth into the tissue , wherein at least a portion of the optical beam includes a near-infrared wavelength between 700 nanometers and 2500 nanometers. The measurement device comprises one or more lenses configured to receive and to deliver at least a portion of each of the first and of the second wavelengths to tissue, wherein the tissue reflects at least a portion of each of the first and of the second wavelengths. The measurement device further comprises a receiver configured to capture light while the LEDs are off and convert the captured light into a first signal and capture light while at least one of the LEDs is on and to convert the captured light into a second signal, the captured light including at least a portion of one of the first or second wavelengths reflected from the tissue. The measurement device is configured to improve a signal-to-noise ratio of the optical beam reflected from the tissue by differencing the first signal and the second signal. The light source is configured to further improve the signal-to-noise ratio of the optical beam reflected from the tissue by increasing the light intensity relative to the initial light intensity from at least one of the LEDs. The measurement device is further configured to generate an output signal representing at least in part a non-invasive measurement on blood contained within the tissue. In another embodiment, a wearable device for use with a smart phone or tablet comprises a measurement device including a light source comprising a plurality of light emitting diodes (LEDs) for measuring one or more physiological parameters, the measurement device configured to generate, by modulating at least one of the LEDs having an initial light intensity, an optical beam having a plurality of optical wavelengths, wherein at least a portion of the plurality of optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers. The measurement device comprises one or more lenses configured to receive and to deliver a portion of the optical beam to tissue, wherein the tissue reflects at least a portion of the optical beam delivered to the tissue, and wherein the measurement device is adapted to be placed on a wrist or an ear of a user. The measurement device further comprises a receiver configured to capture light while the LEDs are off and convert the captured light into a first signal and capture light while at least one of the LEDs is on and convert the captured light into a second signal, the captured light including at least a portion of the optical beam reflected from the tissue. The measurement device is configured to improve a signal-to-noise ratio of the optical beam reflected from the tissue by differencing the first signal and the second signal. The light source is configured to further improve the signal-to-noise ratio of the optical beam reflected from the tissue by increasing the light intensity relative to the initial light intensity from at least one of the LEDs. The measurement device is further configured to generate an output signal representing at least in part a non-invasive measurement on blood contained within the tissue. In one embodiment, a wearable device for use with a smart phone or tablet comprises a measurement device including a light source comprising a plurality of light emitting diodes (LEDs) for measuring one or more physiological parameters, the measurement device configured to generate, by modulating at least one of the LEDs having an initial light intensity, an optical beam having a plurality of optical wavelengths, wherein at least a portion of the plurality of optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers. The measurement device comprises one or more lenses configured to receive and to deliver a portion of the optical beam to tissue, wherein the tissue reflects at least a portion of the optical beam delivered to the tissue, and wherein the measurement device is adapted to be placed on a wrist or an ear of a user. The measurement device further comprises a receiver configured to capture light while the LEDs are off and convert the captured light into a first signal and capture light while at least one of the LEDs is on and convert the captured light into a second signal, the captured light including at least a portion of the optical beam reflected from the tissue. The measurement device is configured to improve a signal-to-noise ratio of the optical beam reflected from the tissue by differencing the first signal and the second signal. The light source is configured to further improve the signal-to-noise ratio of the optical beam reflected from the tissue by increasing the light intensity relative to the initial light intensity from at least one of the LEDs. The measurement device is further configured to generate an output signal representing at least in part a non-invasive measurement on blood contained within the tissue. The receiver includes a plurality of spatially separated detectors, wherein at least one analog to digital converter is coupled to the spatially separated detectors. In one embodiment, a wearable device for use with a smart phone or tablet includes a measurement device including a light source comprising a plurality of light emitting diodes for measuring one or more physiological parameters, the measurement device configured to generate an input optical beam with one or more optical wavelengths, wherein at least a portion of the one or more optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers. The measurement device comprises one or more lenses configured to receive and to deliver a portion of the input optical beam to a sample comprising skin or tissue, wherein the sample reflects at least a portion of the input optical beam delivered to the sample. The measurement device further comprises a reflective surface configured to receive and redirect at least a portion of light reflected from the sample, and a receiver configured to receive at least a portion of the input optical beam reflected from the sample. The light source is configured to increase a signal-to-noise ratio of the input optical beam reflected from the sample, wherein the increased signal-to-noise ratio results from an increase to the light intensity from at least one of the plurality of light emitting diodes and from modulation of at least one of the plurality of light emitting diodes. The measurement device is configured to generate an output signal representing at least in part a non-invasive measurement on blood contained within the sample. The wearable device is configured to communicate with the smart phone or tablet, the smart phone or tablet comprising a wireless receiver, a wireless transmitter, a display, a voice input module, a speaker, and a touch screen. The smart phone or tablet is configured to receive and to process at least a portion of the output signal, wherein the smart phone or tablet is configured to store and display the processed output signal, and wherein at least a portion of the processed output signal is configured to be transmitted over a wireless transmission link. In another embodiment, a wearable device for use with a smart phone or tablet includes a measurement device including a light source comprising a plurality of light emitting diodes for measuring one or more physiological parameters, the measurement device configured to generate an input optical beam with one or more optical wavelengths, wherein at least a portion of the one or more optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers. The measurement device comprises one or more lenses configured to receive and to deliver a portion of the input optical beam to a sample comprising skin or tissue, wherein the sample reflects at least a portion of the input optical beam delivered to the sample. The measurement device further comprises a reflective surface configured to receive and redirect at least a portion of light reflected from the sample. The measurement device further comprises a receiver configured to receive at least a portion of the input optical beam reflected from the sample, the receiver being located a first distance from a first one of the plurality of light emitting diodes and a different distance from a second one of the plurality of light emitting diodes such that the receiver receives a first signal from the first light emitting diode and a second signal from the second light emitting diode. The measurement device is configured to generate an output signal representing at least in part a non-invasive measurement on blood contained within the sample. The wearable device is configured to communicate with the smart phone or tablet. The smart phone or tablet comprises a wireless receiver, a wireless transmitter, a display, a voice input module, a speaker, and a touch screen, and is configured to receive and to process at least a portion of the output signal. The smart phone or tablet is configured to store and display the processed output signal, wherein at least a portion of the processed output signal is configured to be transmitted over a wireless transmission link. In one embodiment, a method of measuring physiological information comprises providing a wearable device for use with a smart phone or tablet, the smart phone or tablet comprising a wireless receiver, a wireless transmitter, a display, a voice input module, a speaker, and a touch screen. The wearable device is capable of performing all of the steps comprising: generating an input optical beam having one or more optical wavelengths using a light source comprising a plurality of light emitting diodes, wherein at least a portion of the one or more optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers; delivering a portion of the input optical beam to a sample comprising skin or tissue using one or more lenses; receiving and reflecting at least a portion of the input optical beam reflected from the sample; receiving a portion of the input optical beam reflected from the sample to generate an output signal representing at least in part a non-invasive measurement on blood contained within the sample; increasing the signal-to-noise ratio of the input optical beam reflected from the sample by increasing a light intensity from at least one of the plurality of light emitting diodes and by modulating at least one of the plurality of light emitting diodes; and transmitting at least a portion of the output signal to the smart phone or tablet for processing to generate a processed output signal and for transmitting from the smart phone or tablet at least a portion of the processed output signal over a wireless transmission link. In another embodiment, a method of measuring physiological information comprises providing a wearable device for use with a smart phone or tablet, the smart phone or tablet comprising a wireless receiver, a wireless transmitter, a display, a voice input module, a speaker, and a touch screen. The wearable device is capable of performing all of the steps comprising: generating a first and a second input optical beam each having one or more optical wavelengths using a light source comprising a plurality of light emitting diodes, wherein at least a portion of the one or more optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers; delivering a portion of the first input optical beam and a portion of the second input optical beam to a sample comprising skin or tissue using one or more lenses; receiving and reflecting at least a portion of the input optical beam reflected from the sample; receiving a portion of the first input optical beam reflected from the sample from a first one of the plurality of light emitting diodes located at a first distance and receiving a portion of the second input optical beam reflected from the sample from a different one of the plurality of light emitting diodes located at a distance different from the first distance to generate an output signal representing at least in part a non-invasive measurement on blood contained within the sample; and transmitting at least a portion of the output signal to the smart phone or tablet for processing to generate a processed output signal and for transmitting from the smart phone or tablet at least a portion of the processed output signal over a wireless transmission link.
A61B50088
20170825
20180109
20171228
90729.0
A61B500
2
RAHMAN, MD M
SHORT-WAVE INFRARED SUPER-CONTINUUM LASERS FOR EARLY DETECTION OF DENTAL CARIES
SMALL
1
CONT-ACCEPTED
A61B
2,017
15,686,268
PENDING
STORAGE MEDIUM STORING GAME PROGRAM, GAME PROCESSING METHOD, AND INFORMATION PROCESSING APPARATUS
A non-transitory computer readable recording medium stores game program code instructions for a game in which a first user and a second user do battle, and when the game program code instructions are executed by a computer, the game program code instructions cause the computer to perform a data storage function of storing a first panel data that includes a plurality of panels associated with the first user to a storage unit; a control function of receiving information regarding a selection by the first user, the selection being for one or more panels indicating characters to be disposed in one or more divisions of a game display screen including a display region formed by the divisions; the data storage function further stores the panel associated with information of motion to the storage unit, and the control function transmits information for displaying the panel as a moving character according to the information of motion associated with the panel when the panel is disposed in a target division.
1. A non-transitory computer readable recording medium storing game program code instructions for a game in which a first user and a second user do battle, and when the game program code instructions are executed by a computer, the game program code instructions cause the computer to perform: a data storage function of storing a first panel data that includes a plurality of panels associated with the first user to a storage unit; a control function of receiving information regarding a selection by the first user, the selection being for one or more panels indicating characters to be disposed in one or more divisions of a game display screen including a display region formed by the divisions; the data storage function further stores the panel associated with information of motion to the storage unit, and the control function transmits information for displaying the panel as a moving character according to the information of motion associated with the panel when the panel is disposed in a target division. 2. The recording medium according to claim 1, wherein the control function disposes the panel in the target division or receives an instruction for disposing the panel in the target division when the panel selected by the first user is allowed to be disposed in the target division. 3. The recording medium according to claim 1, wherein the data storage function further stores the panel associated with information of text to be displayed to overlap the panel to the storage unit, and the control function transmits information for displaying the game display screen in which the panel overlapped with the text is disposed in the target division on the basis of the panel selected by the first user and the information of text to be displayed to overlap the panel. 4. The recording medium according to claim 1, wherein the data storage function further stores the panel associated with information of cost points that is reduced by disposing the panel to the storage unit, the data storage function compares the information of cost points associated with the panel selected by the first user and information of possessing cost points associated with the first user when the control function receives information regarding the selection by the first user, and stores a value obtained by subtracting a value according to the information of cost points from a value according to the information of possessing cost points by updating as the information of possessing cost point to the storage unit when the value according to the information of possessing cost points is greater than or equal to the value according to the information of cost points as a result of above comparison, and the control function transmits information for displaying the value according to the updated information of possessing cost points in the game display screen. 5. The recording medium according to claim 1, wherein the data storage function further stores the panel associated with information of effect points that indicates effect on a character of the second user by disposing the panel to the storage unit, the data storage function compares the information of effect points associated with the panel selected by the first user and information of hit points associated with the character of the second user when the control function receives information regarding the selection by the first user, and stores a value obtained by subtracting a value according to the information of effect points from a value according to the information of hit points by updating as the information of hit point to the storage unit when the value according to the information of hit points is greater than or equal to the value according to the information of effect points as a result of above comparison, and the control function transmits information for displaying the value according to the updated information of hit points in the game display screen. 6. A game processing method for a game in which a first user and a second user do battle, and when executed by a computer, the game processing method causes the computer to perform: a data storage step of storing a first panel data that includes a plurality of panels associated with the first user to a storage unit; a control step of receiving information regarding a selection by the first user, the selection being for one or more panels indicating characters to be disposed in one or more divisions of a game display screen including a display region formed by the divisions; the data storage step further stores the panel associated with information of motion to the storage unit, and the control step transmits information for displaying the panel as a moving character according to the information of motion associated with the panel when the panel is disposed in a target division. 7. A server apparatus that controls a game in which a first user and a second user do battle, comprising: a data storage unit that stores a first panel data that includes a plurality of panels associated with the first user; a control unit that receives information regarding a selection by the first user, the selection being for one or more panels indicating characters to be disposed in one or more divisions of a game display screen including a display region formed by the divisions; the data storage unit further stores the panel associated with information of motion, and the control unit transmits information for displaying the panel as a moving character according to the information of motion associated with the panel when the panel is disposed in a target division. 8. A non-transitory computer readable recording medium storing game program code instructions for a game in which a first user and a second user do battle, and when the game program code instructions are executed by a computer, the game program code instructions cause the computer to perform: a data storage function of storing a first panel data that includes a plurality of panels associated with the first user to a storage unit; a panel selection function of receiving a selection by the first user, the selection being for one or more panels indicating characters to be disposed in one or more divisions of a game display screen including a display region formed by the divisions; a panel layout function of disposing the panels in the divisions on the basis of the selection received by the panel selection function; and a screen display control function of controlling the game display screen on a screen display unit on the basis of information regarding the layout by the panel layout function; the data storage function further stores the panel associated with information of motion to the storage unit, and the screen display control function controls for displaying the panel as a moving character according to the information of motion associated with the panel when the panel is disposed in a target division. 9. The recording medium according to claim 8, wherein the panel layout function disposes the panel in the target division or receives an instruction for disposing the panel in the target division when the panel selected by the first user is allowed to be disposed in the target division. 10. The recording medium according to claim 8, wherein the data storage function further stores the panel associated with information of text to be displayed to overlap the panel to the storage unit, and the screen display control function displays the game display screen in which the panel overlapped with the text is disposed in the target division on the basis of the panel selected by the first user and the information of text to be displayed to overlap the panel. 11. The recording medium according to claim 8, wherein the data storage function further stores the panel associated with information of cost points that is reduced by disposing the panel to the storage unit, the data storage function compares the information of cost points associated with the panel selected by the first user and information of possessing cost points associated with the first user when the panel selection function receives information regarding the selection by the first user and stores a value obtained by subtracting a value according to the information of cost points from a value according to the information of possessing cost points by updating as the information of possessing cost point to the storage unit when the value according to the information of possessing cost points is greater than or equal to the value according to the information of cost points as a result of above comparison, and the screen display control function controls for displaying the value according to the updated information of possessing cost points in the game display screen. 12. The recording medium according to claim 8, wherein the data storage function further stores the panel associated with information of effect points that indicates effect on a character of the second user by disposing the panel to the storage unit, the data storage function compares the information of effect points associated with the panel selected by the first user and information of hit points associated with the character of the second user when the panel selection function receives information regarding the selection by the first user, and stores a value obtained by subtracting a value according to the information of effect points from a value according to the information of hit points by updating as the information of hit point to the storage unit when the value according to the information of hit points is greater than or equal to the value according to the information of effect points as a result of above comparison, and the screen display control function controls for displaying the value according to the updated information of hit points in the game display screen. 13. The recording medium according to claim 8, wherein the receiving of the selection by the panel selection function is performed on the basis of information inputted from a touch panel display. 14. A game processing method for a game in which a first user and a second user do battle, and when executed by a computer, the game processing method causes the computer to perform: a data storage step of storing a first panel data that includes a plurality of panels associated with the first user to a storage unit; a panel selection step of receiving a selection by the first user, the selection being for one or more panels indicating characters to be disposed in one or more divisions of a game display screen including a display region formed by the divisions; a panel layout step of disposing the panels in the divisions on the basis of the selection received by the panel selection step; and a screen display control step of controlling the game display screen on a screen display unit on the basis of information regarding the layout by the panel layout step; the data storage step further stores the panel associated with information of motion to the storage unit, and the screen display control step controls for displaying the panel as a moving character according to the information of motion associated with the panel when the panel is disposed in a target division. 15. An information processing apparatus that controls a game in which a first user and a second user do battle, comprising: a data storage unit that stores a first panel data that includes a plurality of panels associated with the first user; a panel selection unit that receives a selection by the first user, the selection being for one or more panels indicating characters to be disposed in one or more divisions of a game display screen including a display region formed by the divisions; a panel layout unit that disposes the panels in the divisions on the basis of the selection received by the panel selection unit; and a screen display control unit that controls the game display screen on a screen display unit on the basis of information regarding the layout by the panel layout unit; the data storage unit further stores the panel associated with information of motion, and the screen display control unit controls for displaying the panel as a moving character according to the information of motion associated with the panel when the panel is disposed in a target division.
CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 15/391,123, filed Dec. 27, 2016, which is a continuation of U.S. patent application Ser. No. 15/253,964, filed Sep. 1, 2016, now U.S. Pat. No. 9,636,583, which is a continuation of U.S. patent application Ser. No. 14/291,358, filed May 30, 2014, now U.S. Pat. No. 9,457,273, that claims the benefit of JP 2013-116039, filed on May 31, 2013, JP 2013-268385, filed on Dec. 26, 2013, and JP 2014-42491, filed on Mar. 5, 2014, the entire contents of which are hereby incorporated by reference. TECHNICAL FIELD This disclosure relates to a storage medium storing a game program, a game processing method, and an information processing apparatus and, in particular, to a storage medium storing a game program and a game processing method of a game in which a plurality of characters battle against each other, and an information processing apparatus that controls the game. BACKGROUND In recent years, with the spread of electronic apparatuses such as smart phones and tablets, games played on these electronic apparatuses have been actively developed. As an example of such a game, there is a card game in which the user plays against other users or against the computer using cards collected in the game. Japanese Unexamined Patent Application Publication No. 2007-252696 discloses a technique regarding the card game described above. According to that technique, the user configures a deck with cards used in a play which is selected from a plurality of cards that the user owns, and plays a rock-paper-scissors game or the like with an opponent using the deck. Such a card game system is familiar to many users today. However, since the use of a two-dimensional card in the battle scene is sometimes boring, there have been calls for improvement. It could therefore be helpful to provide a storage medium storing a game program and a game processing method of a game that gives a user a high visual effect, and an information processing apparatus that controls the game. SUMMARY I provide: (1) A non-transitory computer readable recording medium storing game program code instructions for a game in which a first user and a second user do battle, and when the game program code instructions are executed by a computer, the game program code instructions cause the computer to perform a data storage function of storing a first panel data that includes a plurality of panels associated with the first user to a storage unit; a control function of receiving information regarding a selection by the first user, the selection being for one or more panels indicating characters to be disposed in one or more divisions of a game display screen including a display region formed by the divisions; the data storage function further stores the panel associated with information of motion to the storage unit, and the control function transmits information for displaying the panel as a moving character according to the information of motion associated with the panel when the panel is disposed in a target division; (2) The recording medium according to (1), wherein the control function disposes the panel in the target division or receives an instruction for disposing the panel in the target division when the panel selected by the first user is allowed to be disposed in the target division; (3) The recording medium according to (1), wherein the data storage function further stores the panel associated with information of text to be displayed to overlap the panel to the storage unit, and the control function transmits information for displaying the game display screen in which the panel overlapped with the text is disposed in the target division on the basis of the panel selected by the first user and the information of text to be displayed to overlap the panel; (4) The recording medium according to (1), wherein the data storage function further stores the panel associated with information of cost points that is reduced by disposing the panel to the storage unit, the data storage function compares the information of cost points associated with the panel selected by the first user and information of possessing cost points associated with the first user when the control function receives information regarding the selection by the first user, and stores a value obtained by subtracting a value according to the information of cost points from a value according to the information of possessing cost points by updating as the information of possessing cost point to the storage unit when the value according to the information of possessing cost points is greater than or equal to the value according to the information of cost points as a result of above comparison, and the control function transmits information for displaying the value according to the updated information of possessing cost points in the game display screen; (5) The recording medium according to (1), wherein the data storage function further stores the panel associated with information of effect points that indicates effect on a character of the second user by disposing the panel to the storage unit, the data storage function compares the information of effect points associated with the panel selected by the first user and information of hit points associated with the character of the second user when the control function receives information regarding the selection by the first user, and stores a value obtained by subtracting a value according to the information of effect points from a value according to the information of hit points by updating as the information of hit point to the storage unit when the value according to the information of hit points is greater than or equal to the value according to the information of effect points as a result of above comparison, and the control function transmits information for displaying the value according to the updated information of hit points in the game display screen; (6) A game processing method for a game in which a first user and a second user do battle, and when executed by a computer, the game processing method causes the computer to perform a data storage step of storing a first panel data that includes a plurality of panels associated with the first user to a storage unit; a control step of receiving information regarding a selection by the first user, the selection being for one or more panels indicating characters to be disposed in one or more divisions of a game display screen including a display region formed by the divisions; the data storage step further stores the panel associated with information of motion to the storage unit, and the control step transmits information for displaying the panel as a moving character according to the information of motion associated with the panel when the panel is disposed in a target division; (7) A server apparatus that controls a game in which a first user and a second user do battle, including a data storage unit that stores a first panel data that includes a plurality of panels associated with the first user; a control unit that receives information regarding a selection by the first user, the selection being for one or more panels indicating characters to be disposed in one or more divisions of a game display screen including a display region formed by the divisions; the data storage unit further stores the panel associated with information of motion, and the control unit transmits information for displaying the panel as a moving character according to the information of motion associated with the panel when the panel is disposed in a target division; (8) A non-transitory computer readable recording medium storing game program code instructions for a game in which a first user and a second user do battle, and when the game program code instructions are executed by a computer, the game program code instructions cause the computer to perform a data storage function of storing a first panel data that includes a plurality of panels associated with the first user to a storage unit; a panel selection function of receiving a selection by the first user, the selection being for one or more panels indicating characters to be disposed in one or more divisions of a game display screen including a display region formed by the divisions; a panel layout function of disposing the panels in the divisions on the basis of the selection received by the panel selection function; and a screen display control function of controlling the game display screen on a screen display unit on the basis of information regarding the layout by the panel layout function; the data storage function further stores the panel associated with information of motion to the storage unit, and the screen display control function controls for displaying the panel as a moving character according to the information of motion associated with the panel when the panel is disposed in a target division; (9) The recording medium according to (8), wherein the panel layout function disposes the panel in the target division or receives an instruction for disposing the panel in the target division when the panel selected by the first user is allowed to be disposed in the target division; (10) The recording medium according to (8), wherein the data storage function further stores the panel associated with information of text to be displayed to overlap the panel to the storage unit, and the screen display control function displays the game display screen in which the panel overlapped with the text is disposed in the target division on the basis of the panel selected by the first user and the information of text to be displayed to overlap the panel; (11) The recording medium according to (8), wherein the data storage function further stores the panel associated with information of cost points that is reduced by disposing the panel to the storage unit, the data storage function compares the information of cost points associated with the panel selected by the first user and information of possessing cost points associated with the first user when the panel selection function receives information regarding the selection by the first user and stores a value obtained by subtracting a value according to the information of cost points from a value according to the information of possessing cost points by updating as the information of possessing cost point to the storage unit when the value according to the information of possessing cost points is greater than or equal to the value according to the information of cost points as a result of above comparison, and the screen display control function controls for displaying the value according to the updated information of possessing cost points in the game display screen; (12) The recording medium according to (8), wherein the data storage function further stores the panel associated with information of effect points that indicates effect on a character of the second user by disposing the panel to the storage unit, the data storage function compares the information of effect points associated with the panel selected by the first user and information of hit points associated with the character of the second user when the panel selection function receives information regarding the selection by the first user, and stores a value obtained by subtracting a value according to the information of effect points from a value according to the information of hit points by updating as the information of hit point to the storage unit when the value according to the information of hit points is greater than or equal to the value according to the information of effect points as a result of above comparison, and the screen display control function controls for displaying the value according to the updated information of hit points in the game display screen; (13) The recording medium according to (8), wherein the receiving of the selection by the panel selection function is performed on the basis of information inputted from a touch panel display; (14) A game processing method for a game in which a first user and a second user do battle, and when executed by a computer, the game processing method causes the computer to perform a data storage step of storing a first panel data that includes a plurality of panels associated with the first user to a storage unit; a panel selection step of receiving a selection by the first user, the selection being for one or more panels indicating characters to be disposed in one or more divisions of a game display screen including a display region formed by the divisions; a panel layout step of disposing the panels in the divisions on the basis of the selection received by the panel selection step; and a screen display control step of controlling the game display screen on a screen display unit on the basis of information regarding the layout by the panel layout step; the data storage step further stores the panel associated with information of motion to the storage unit, and the screen display control step controls for displaying the panel as a moving character according to the information of motion associated with the panel when the panel is disposed in a target division; (15) An information processing apparatus that controls a game in which a first user and a second user do battle, including a data storage unit that stores a first panel data that includes a plurality of panels associated with the first user; a panel selection unit that receives a selection by the first user, the selection being for one or more panels indicating characters to be disposed in one or more divisions of a game display screen including a display region formed by the divisions; a panel layout unit that disposes the panels in the divisions on the basis of the selection received by the panel selection unit; and a screen display control unit that controls the game display screen on a screen display unit on the basis of information regarding the layout by the panel layout unit; the data storage unit further stores the panel associated with information of motion, and the screen display control unit controls for displaying the panel as a moving character according to the information of motion associated with the panel when the panel is disposed in a target division. According to the storage medium, the game processing method, and the information processing apparatus, it is possible to provide a game that gives a user a high visual effect. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a flowchart showing an example of a game program. FIG. 2 is a block diagram showing an example of an information processing apparatus. FIG. 3 is a schematic diagram showing an example of a game display screen. FIG. 4 is a schematic diagram showing an example of the game display screen. FIGS. 5A and 5B are schematic diagrams showing examples of a panel. FIG. 6 is a schematic diagram showing an example of the panel. FIG. 7 is a schematic diagram explaining an example of the game. FIG. 8 is a schematic diagram explaining an example of the game. FIG. 9 is a schematic diagram explaining an example of the game. FIG. 10 is a schematic diagram explaining an example of the game. FIGS. 11A and 11B are schematic diagrams explaining examples of the game. FIG. 12 is a schematic diagram explaining an example of the game. DETAILED DESCRIPTION A game program according to examples will be described with reference to the accompanying diagrams. The game program is for a game in which the first and second characters battle against each other, and causes a computer to realize a data storage function, a panel selection function, a panel layout function, a screen display control function, and an emphasized display function. FIG. 1 is a flowchart showing an example of a game program 100. Using the data storage function, a first panel database including a plurality of panels that the first character possesses and a second panel database including a plurality of panels that the second character possesses are stored (STEP 110). This function can be realized by a data storage unit to be described later. Using the panel selection function, panels to be disposed in frames of the game display screen including a battle display region formed by one or more frames are selected from the first panel database including a plurality of panels that the first character possesses and the second panel database including a plurality of panels that the second character possesses (STEP 120). This function can be realized by a panel selection section to be described later. Using the panel layout function, the panels selected by the panel selection function are disposed in the frames (STEP 130). This function can be realized by a panel layout section to be described later. Using the screen display control function, the game display screen is displayed on a screen display unit (STEP 140). The screen display unit receives a signal output from a screen display control section of an information processing apparatus, which will be described later. For example, a display device provided in a user terminal can be used. In addition, it is possible to use a touch panel type display that also serves as an input unit to be described later. This function can be realized by the screen display control section to be described later. Using the emphasized display function, the panel disposed by the panel layout function is emphasized and displayed on the screen display unit based on the panel information indicating the characteristics of the panel (STEP 150). “Emphasized display” refers to displaying a specific panel of the panels disposed in the frames noticeably compared with the other panels. As examples of emphasized display, it is possible to display a movie or display a frame to surround the panel. This function can be realized by an emphasized display section to be described later. The game program can be executed in a server apparatus or a user terminal to perform each process of the game described above. In addition, the game program can be provided in a state where the game program is recorded on a computer-readable recording medium. Recording media is not particularly limited as long as the recording media can be read by the computer such as a CD-ROM and a DVD. Next, a game processing method according to an example will be described. The game processing method is for a game in which the first and second characters battle against each other, and includes a data storage step, a panel selection step, a panel layout step, a screen display control step, and an emphasized display step. In the data storage step, a first panel database including a plurality of panels that the first character possesses and a second panel database including a plurality of panels that the second character possesses are stored. This step can be processed by the data storage unit to be described later. In the panel selection step, panels to be disposed in frames of the game display screen including a battle display region formed by one or more frames are selected from the first and second panel databases. This step can be processed by the panel selection section to be described later. In the panel layout step, the panels selected in the panel selection step are disposed in the frames. This step can be processed by the panel layout section to be described later. In the screen display control step, the game display screen is displayed on the screen display unit. This step can be processed by the screen display control section to be described later. In the emphasized display step, the panel disposed in the panel layout step is emphasized and displayed on the screen display unit based on the panel information indicating the characteristics of the panel. This step can be processed by the emphasized display section to be described later. Next, an information processing apparatus according to an example will be described with reference to the accompanying diagrams. FIG. 2 is a block diagram schematically showing an example of the information processing apparatus. An information processing apparatus 200 controls a game in which the first and second characters battle against each other, and includes a data storage unit 210 and a control unit 220. The data storage unit 210 stores a first panel database 211 that includes a plurality of panels that the first character possesses, and a second panel database 212 that includes a plurality of panels that the second character possesses. The control unit 220 includes: a screen display control section 221 that displays a game display screen that includes a battle display region formed by one or more frames on the screen display unit; a panel selection section 222 that selects panels to be disposed in the frames of the battle display region, from the first panel databases 211 and second panel databases 212; a panel layout section 223 that disposes the panels selected by the panel selection section 222 in the frames; and an emphasized display section 224 that emphasizes and displays the panels disposed by the panel layout section 223 on the screen display unit based on the panel information indicating the characteristics of the panels. As the screen display unit, a display device and the like can be mentioned. In addition, it is possible to use a touch panel type display that also serves as an input unit to be described later. A first panel group configured to include a plurality of panels that the first character possesses is stored in the first panel database 211. A second panel group configured to include a plurality of panels that the second character possesses is stored in the second panel database 212. Although not shown in the diagram, the information processing apparatus 200 can include an input receiving unit that receives an input to give an instruction to the control unit 220. As means for the input received by the input receiving unit, everything that the information processing apparatus operated by the user may have such as buttons, a keyboard or a mouse, is included. In addition, as described above, it is also possible to use a touch panel type input. While the information processing apparatus 200 can be a server apparatus or a user terminal such as a mobile phone or a smart phone, the information processing apparatus 200 can also be configured to include a user terminal and a server apparatus. FIG. 3 is a diagram schematically showing an example of a game display screen 300 displayed on the screen display unit. As shown in FIG. 3, the game display screen 300 is a game display screen of a game in which the first and second characters battle against each other. The game display screen 300 includes a battle display region 310 formed by one or more frames (in FIG. 3, frames A to G). As shown in FIG. 3, a character (PLAYER) that the user uses can be set as the first character, and a character (ENEMY) that the computer uses can be set as the second character. Alternatively, although not shown in the diagram, the character (PLAYER) that the user uses can be set as the first character, and a character (FRIEND) that another user uses can be set as the second character. Panels selected from the first panel group configured to include a plurality of panels that the first character possesses and the second panel group configured to include a plurality of panels that the second character possesses are disposed in the frames A to G. In the example shown in FIG. 3, panels selected from the first panel group are disposed in the frames A, B, D, and F, and panels selected from the second panel group are disposed in the frames C, E, and G. The emphasized display section 224 can execute the frames in predetermined order, and emphasize and display the panels disposed in the executed frames. The battle proceeds by executing the frames A to Gin order of the frames A, B, C, D, E, F, and G. That is, according to the game display screen 300 according to the example, the battle between the first and second characters proceeds in a format like a cartoon. Therefore, since the user can play the game with a sense of reading a cartoon, the visual effect that the user receives is greatly improved compared to known games. In the game display screen 300, the battle can be performed based on the panel information regarding the panel that is emphasized and displayed by the emphasized display section 224. In this case, the panel information is assumed to include information regarding the size of the panel. In addition, each panel described above can have an arbitrary size. In the example shown in FIG. 4, the game display screen 300 includes the battle display region 310 formed by frames H to O. In the battle display region 310 divided into cells of “4 columns×4 rows,” each of panels disposed in the frames H and N has a size corresponding to four cells. Similarly, each of panels disposed in the frames J and O has a size corresponding to two cells, and each of panels disposed in the frames I, K, L, and M has a size corresponding to one cell. Specifically, assuming that each row indicates a turn of a battle, the occupancy of action in each turn in horizontally long frames such as the frames H, N, and O, is high compared to that in horizontally short frames such as the frames I, J, K, L, and M. Accordingly, for example, in the first turn, only the action of the first player is performed. In the vertically long frames such as the frames J and N, their actions are first performed in the previous turn. That is, for example, the frame J over the second and third turns is executed prior to the frame M disposed in the third turn. That is, a panel the size of which is larger and presents at a position where a turn number is earlier leads a battle advantageously. In addition, although the case where the battle proceeds from the upper left to the lower right is shown in the example described above, the battle may proceed from the upper right to the lower left. As described above, it is preferable that the battle display region 310 be divided by the turn indicating the unit of the progress of the battle. In addition, it is preferable that the shape of the panel be a rectangle. Panels can have various shapes such as a circle, a triangle, and a polygon, as well as the rectangle (including a square) such as a card in the related art. In addition, it is preferable that the panel information described above include information on the capability of the panel. The capability information refers to information including attack, defense (avoidance), attributes, recovery, and skills to disable or replace the frame, for example. The effect of the capability is assumed to correspond to the size of the panel. Accordingly, the effect of the frames H and N with a large panel size is higher than that of the other frames. In addition, the panel can display a still image. As an example of the still image, as shown in FIGS. 5A and 5B, the action described above can be assumed to be expressed by way of illustration. FIG. 5A shows a still image of a panel with information of attack, and the illustration of the character to make a punch attack is drawn. Similarly, FIG. 5B shows a still image of a panel with information of defense, and the illustration of the character to avoid the attack of the enemy is drawn. Preferably, these panels display a movie when the panels are emphasized and displayed. The movie is an animation that displays a plurality of still images consecutively. FIG. 6 is a diagram schematically showing the panel of the frame F shown in FIG. 3. As shown in FIG. 6, it is preferable that the frame described above further have a text display portion 10 to display texts. Preferably, the text display portion 10 is displayed to overlap the panel disposed in the frame. In addition to the panel described above, the frame preferably has a sound effect display portion 20 to display the texts showing the sound effect and/or an effect display portion 30 to display the effect. These portions can be displayed with a movie when the frame is emphasized and displayed. Due to these portions, the visual effect given to the user is further improved. In addition, the information processing apparatus operated by the user may be vibrated in conjunction with the sound effect display portion 20 or the like. It is preferable that the panel, which is emphasized and displayed, be disposed in the middle of the game display screen 300. That is, the panel that is emphasized and displayed is displayed to zoom in. Accordingly, the visual effect given to the user is further improved. In addition, it is preferable that the frame have a frame portion. In this frame portion, it is preferable that a frame portion of a frame in which the panel selected from the first panel group is disposed, and a frame portion of a frame in which the panel selected from the second panel group is disposed, be constructed in different colors. In this case, the panel of the first character and the panel of the second character can be visually easily distinguished. In addition, as shown in FIG. 3, when the battle does not fit in the battle display region 310, it is preferable to provide a page turn portion 40 to proceed to the next page in a part of the frame executed at the end. Preferably, the panels described above are automatically disposed in the frames by a computer. In this case, it is possible to save the time and effort taken for the user to dispose the panels. The battle result is preferably determined based on the panel information at a stage where the panels are disposed. In addition, it is also possible to change the battle result by changing the panel, which is displayed on the next page, by the operation (action for recovery or the like) of the user during the battle. In addition, as shown in FIGS. 3 and 4, the game display screen 300 can include a gauge display portion 320 to display the gauge of the character. This gauge shows hit points (hereinafter, described as HP) indicating the strength of the character or character points (hereinafter, described as CP) indicating the action force of the character. The HP is decreased by receiving the action of the attack of the opponent, and is increased by taking action for recovery. On the other hand, the CP is decreased by placing a large panel. In FIG. 4, an example is shown in which all sizes of the panel objects can be expressed as an integral multiple of the cell. However, this disclosure is not limited to this. Next, the basic flow of a game displayed on the game display screen will be described. A game described as an example herein has a main cycle and a sub-cycle. In the main cycle, as shown in FIG. 7, the user selects one character from a plurality of characters presented, and collects panels while advancing the quest. For a plurality of characters, it is possible to set the characteristics such as power type, speed type, stamina type and balanced type. FIG. 8 shows an example of the quest and the character selected by the user does battle with a boss character after a battle with a plurality of enemy characters. A panel can be acquired as a reward for the battle with the enemy characters and the boss character. In addition, it is also possible to acquire the panel in a specific event or the like. Thus, the user acquires the panel by advancing the game. Then, in the sub-cycle, the user can use the acquired panel to strengthen the deck for the battle or can use the acquired panel to develop a character. Developing the character refers to combining the character selected by the user with the acquired panel. As shown in FIG. 9, panels are used to strengthen each part (body, arms, legs, skill, and the like) of the body of the character. For example, a panel with information of the strength is used to strengthen the body of the character, a panel with information of the attack is used to strengthen the arms of the character, a panel with information of the defense is used to strengthen the legs of the character, and a panel with information of special technique effects during the battle is used to reinforce the skills of the character. In addition, a setting to make it possible to select a larger number of other characters or to use a stronger panel as the level of the character rises can also be made. As shown in FIG. 10, as a reward for the battle or the event, there is an evolution material in addition to the panel. By using this evolution material, the selected character can be evolved into a character wearing a different costume. The character after evolution can have a capability exceeding the upper limit of the capability of the selected character before evolution. As shown in FIG. 11A, even before the battle, it is possible to advance the story in a format like a cartoon. Then, after a battle start screen is displayed as shown in FIG. 11B, the battle is started. In such a flow of the game, when a battle starts, the battle using the game display screen described above is performed. FIG. 12 shows another example of the game display screen. For the enemy character and the character selected by the user, it is possible to set the compatibility according to the attributes. In addition, when three or more specific panels are disposed within one game display screen, it is also possible to generate a combo exhibiting the effect beyond the effects of these cards. Those described above show example of the representative configurations, and my storage media, game programs, methods and apparatus are not limited to the example.
<SOH> BACKGROUND <EOH>In recent years, with the spread of electronic apparatuses such as smart phones and tablets, games played on these electronic apparatuses have been actively developed. As an example of such a game, there is a card game in which the user plays against other users or against the computer using cards collected in the game. Japanese Unexamined Patent Application Publication No. 2007-252696 discloses a technique regarding the card game described above. According to that technique, the user configures a deck with cards used in a play which is selected from a plurality of cards that the user owns, and plays a rock-paper-scissors game or the like with an opponent using the deck. Such a card game system is familiar to many users today. However, since the use of a two-dimensional card in the battle scene is sometimes boring, there have been calls for improvement. It could therefore be helpful to provide a storage medium storing a game program and a game processing method of a game that gives a user a high visual effect, and an information processing apparatus that controls the game.
<SOH> SUMMARY <EOH>I provide: (1) A non-transitory computer readable recording medium storing game program code instructions for a game in which a first user and a second user do battle, and when the game program code instructions are executed by a computer, the game program code instructions cause the computer to perform a data storage function of storing a first panel data that includes a plurality of panels associated with the first user to a storage unit; a control function of receiving information regarding a selection by the first user, the selection being for one or more panels indicating characters to be disposed in one or more divisions of a game display screen including a display region formed by the divisions; the data storage function further stores the panel associated with information of motion to the storage unit, and the control function transmits information for displaying the panel as a moving character according to the information of motion associated with the panel when the panel is disposed in a target division; (2) The recording medium according to (1), wherein the control function disposes the panel in the target division or receives an instruction for disposing the panel in the target division when the panel selected by the first user is allowed to be disposed in the target division; (3) The recording medium according to (1), wherein the data storage function further stores the panel associated with information of text to be displayed to overlap the panel to the storage unit, and the control function transmits information for displaying the game display screen in which the panel overlapped with the text is disposed in the target division on the basis of the panel selected by the first user and the information of text to be displayed to overlap the panel; (4) The recording medium according to (1), wherein the data storage function further stores the panel associated with information of cost points that is reduced by disposing the panel to the storage unit, the data storage function compares the information of cost points associated with the panel selected by the first user and information of possessing cost points associated with the first user when the control function receives information regarding the selection by the first user, and stores a value obtained by subtracting a value according to the information of cost points from a value according to the information of possessing cost points by updating as the information of possessing cost point to the storage unit when the value according to the information of possessing cost points is greater than or equal to the value according to the information of cost points as a result of above comparison, and the control function transmits information for displaying the value according to the updated information of possessing cost points in the game display screen; (5) The recording medium according to (1), wherein the data storage function further stores the panel associated with information of effect points that indicates effect on a character of the second user by disposing the panel to the storage unit, the data storage function compares the information of effect points associated with the panel selected by the first user and information of hit points associated with the character of the second user when the control function receives information regarding the selection by the first user, and stores a value obtained by subtracting a value according to the information of effect points from a value according to the information of hit points by updating as the information of hit point to the storage unit when the value according to the information of hit points is greater than or equal to the value according to the information of effect points as a result of above comparison, and the control function transmits information for displaying the value according to the updated information of hit points in the game display screen; (6) A game processing method for a game in which a first user and a second user do battle, and when executed by a computer, the game processing method causes the computer to perform a data storage step of storing a first panel data that includes a plurality of panels associated with the first user to a storage unit; a control step of receiving information regarding a selection by the first user, the selection being for one or more panels indicating characters to be disposed in one or more divisions of a game display screen including a display region formed by the divisions; the data storage step further stores the panel associated with information of motion to the storage unit, and the control step transmits information for displaying the panel as a moving character according to the information of motion associated with the panel when the panel is disposed in a target division; (7) A server apparatus that controls a game in which a first user and a second user do battle, including a data storage unit that stores a first panel data that includes a plurality of panels associated with the first user; a control unit that receives information regarding a selection by the first user, the selection being for one or more panels indicating characters to be disposed in one or more divisions of a game display screen including a display region formed by the divisions; the data storage unit further stores the panel associated with information of motion, and the control unit transmits information for displaying the panel as a moving character according to the information of motion associated with the panel when the panel is disposed in a target division; (8) A non-transitory computer readable recording medium storing game program code instructions for a game in which a first user and a second user do battle, and when the game program code instructions are executed by a computer, the game program code instructions cause the computer to perform a data storage function of storing a first panel data that includes a plurality of panels associated with the first user to a storage unit; a panel selection function of receiving a selection by the first user, the selection being for one or more panels indicating characters to be disposed in one or more divisions of a game display screen including a display region formed by the divisions; a panel layout function of disposing the panels in the divisions on the basis of the selection received by the panel selection function; and a screen display control function of controlling the game display screen on a screen display unit on the basis of information regarding the layout by the panel layout function; the data storage function further stores the panel associated with information of motion to the storage unit, and the screen display control function controls for displaying the panel as a moving character according to the information of motion associated with the panel when the panel is disposed in a target division; (9) The recording medium according to (8), wherein the panel layout function disposes the panel in the target division or receives an instruction for disposing the panel in the target division when the panel selected by the first user is allowed to be disposed in the target division; (10) The recording medium according to (8), wherein the data storage function further stores the panel associated with information of text to be displayed to overlap the panel to the storage unit, and the screen display control function displays the game display screen in which the panel overlapped with the text is disposed in the target division on the basis of the panel selected by the first user and the information of text to be displayed to overlap the panel; (11) The recording medium according to (8), wherein the data storage function further stores the panel associated with information of cost points that is reduced by disposing the panel to the storage unit, the data storage function compares the information of cost points associated with the panel selected by the first user and information of possessing cost points associated with the first user when the panel selection function receives information regarding the selection by the first user and stores a value obtained by subtracting a value according to the information of cost points from a value according to the information of possessing cost points by updating as the information of possessing cost point to the storage unit when the value according to the information of possessing cost points is greater than or equal to the value according to the information of cost points as a result of above comparison, and the screen display control function controls for displaying the value according to the updated information of possessing cost points in the game display screen; (12) The recording medium according to (8), wherein the data storage function further stores the panel associated with information of effect points that indicates effect on a character of the second user by disposing the panel to the storage unit, the data storage function compares the information of effect points associated with the panel selected by the first user and information of hit points associated with the character of the second user when the panel selection function receives information regarding the selection by the first user, and stores a value obtained by subtracting a value according to the information of effect points from a value according to the information of hit points by updating as the information of hit point to the storage unit when the value according to the information of hit points is greater than or equal to the value according to the information of effect points as a result of above comparison, and the screen display control function controls for displaying the value according to the updated information of hit points in the game display screen; (13) The recording medium according to (8), wherein the receiving of the selection by the panel selection function is performed on the basis of information inputted from a touch panel display; (14) A game processing method for a game in which a first user and a second user do battle, and when executed by a computer, the game processing method causes the computer to perform a data storage step of storing a first panel data that includes a plurality of panels associated with the first user to a storage unit; a panel selection step of receiving a selection by the first user, the selection being for one or more panels indicating characters to be disposed in one or more divisions of a game display screen including a display region formed by the divisions; a panel layout step of disposing the panels in the divisions on the basis of the selection received by the panel selection step; and a screen display control step of controlling the game display screen on a screen display unit on the basis of information regarding the layout by the panel layout step; the data storage step further stores the panel associated with information of motion to the storage unit, and the screen display control step controls for displaying the panel as a moving character according to the information of motion associated with the panel when the panel is disposed in a target division; (15) An information processing apparatus that controls a game in which a first user and a second user do battle, including a data storage unit that stores a first panel data that includes a plurality of panels associated with the first user; a panel selection unit that receives a selection by the first user, the selection being for one or more panels indicating characters to be disposed in one or more divisions of a game display screen including a display region formed by the divisions; a panel layout unit that disposes the panels in the divisions on the basis of the selection received by the panel selection unit; and a screen display control unit that controls the game display screen on a screen display unit on the basis of information regarding the layout by the panel layout unit; the data storage unit further stores the panel associated with information of motion, and the screen display control unit controls for displaying the panel as a moving character according to the information of motion associated with the panel when the panel is disposed in a target division. According to the storage medium, the game processing method, and the information processing apparatus, it is possible to provide a game that gives a user a high visual effect.
A63F1352
20170825
20171207
99434.0
A63F1352
1
ELISCA, PIERRE E
STORAGE MEDIUM STORING GAME PROGRAM, GAME PROCESSING METHOD, AND INFORMATION PROCESSING APPARATUS
UNDISCOUNTED
1
CONT-ACCEPTED
A63F
2,017
15,686,426
PENDING
DIRECT INJECTION ENGINE AND CONTROL METHOD THEREOF
A direct injection engine includes a fuel injection valve configured to inject fuel into a cylinder, a water injection valve configured to inject water into the cylinder, and a valve variable mechanism configured to change an operation timing of each of an intake valve and an exhaust valve. During an operation in a low load range, a negative overlap period when both of the intake valve and the exhaust valve are closed across an exhaust top dead center is formed by the valve variable mechanism, and fuel is injected from the fuel injection valve and water is injected from the water injection valve respectively during the negative overlap period. This causes a steam reforming reaction such that at least a part of injected fuel and injected water turns to hydrogen and carbon monoxide within the cylinder during the negative overlap period.
1. A direct injection engine, comprising: a cylinder configured to accommodate a piston to be reciprocally movable; a fuel injection valve configured to inject fuel containing gasoline into the cylinder; a water injection valve configured to inject water into the cylinder; an intake valve configured to open and close an intake port for introducing air into the cylinder; an exhaust valve configured to open and close an exhaust port for discharging combusted gas from the cylinder; a valve variable mechanism configured to change an operation timing of each of the intake valve and the exhaust valve; a fuel injection control module configured to control the fuel injection valve; a water injection control module configured to control the water injection valve; a valve control module configured to control the valve variable mechanism; and a calculation module configured to perform various calculations based on an operating condition of the engine, wherein during an operation in a low load range where a load of the engine is lower than a predetermined load, the valve control module controls the valve variable mechanism in such a manner that a negative overlap period when both of the intake valve and the exhaust valve are closed across an exhaust top dead center is formed, during the operation in the low load range, the calculation module determines, as an injection timing of fuel by the fuel injection valve and an injection timing of water by the water injection valve, an injection timing when a steam reforming reaction occurs within the cylinder during the negative overlap period, the steam reforming reaction being such that at least a part of injected fuel and injected water turns to hydrogen and carbon monoxide, and during the operation in the low load range, the fuel injection control module and the water injection control module respectively control to inject fuel from the fuel injection valve and control to inject water from the water injection valve at a timing within the negative overlap period determined by the calculation module. 2. The direct injection engine according to claim 1, wherein during the operation in the low load range, the fuel injection control module controls to inject fuel from the fuel injection valve at a same time as water injection from the water injection valve or at a time later than water injection from the water injection valve. 3. The direct injection engine according to claim 2, wherein during the operation in the low load range, the water injection control module controls to inject water from the water injection valve at a point of time when a temperature within the cylinder is increased to a temperature included in a temperature range where a low temperature oxidation reaction of fuel occurs, or to a temperature exceeding the temperature range. 4. The direct injection engine according to claim 3, wherein during the operation in the low load range, the water injection control module controls to inject water from the water injection valve during a former part of the negative overlap period, the former part being a period from a closing timing of the exhaust valve to the exhaust top dead center. 5. The direct injection engine according to claim 3, wherein a geometric compression ratio of the cylinder is set to be not smaller than 16 but not larger than 30. 6. The direct injection engine according to claim 1, wherein during the operation in the low load range, the valve control module controls to open and close the intake valve and the exhaust valve via the valve variable mechanism in such a manner that a crank angle range from the exhaust top dead center to an opening timing of the intake valve is larger than a crank angle range from a closing timing of the exhaust valve to the exhaust top dead center. 7. The direct injection engine according to claim 2, wherein during the operation in the low load range, the valve control module controls to open and close the intake valve and the exhaust valve via the valve variable mechanism in such a manner that a crank angle range from the exhaust top dead center to an opening timing of the intake valve is larger than a crank angle range from a closing timing of the exhaust valve to the exhaust top dead center. 8. The direct injection engine according to claim 3, wherein during the operation in the low load range, the valve control module controls to open and close the intake valve and the exhaust valve via the valve variable mechanism in such a manner that a crank angle range from the exhaust top dead center to an opening timing of the intake valve is larger than a crank angle range from a closing timing of the exhaust valve to the exhaust top dead center. 9. The direct injection engine according to claim 1, further comprising: a water supply device configured to supply water to the water injection valve while heating and pressurizing the water, wherein during the operation in the low load range, the water injection valve is operative to inject water of a temperature of 100° C. or higher and a pressure of 5 MPa or higher supplied from the water supply device. 10. The direct injection engine according to claim 2, further comprising: a water supply device configured to supply water to the water injection valve while heating and pressurizing the water, wherein during the operation in the low load range, the water injection valve is operative to inject water of a temperature of 100° C. or higher and a pressure of 5 MPa or higher supplied from the water supply device. 11. The direct injection engine according to claim 3, further comprising: a water supply device configured to supply water to the water injection valve while heating and pressurizing the water, wherein during the operation in the low load range, the water injection valve is operative to inject water of a temperature of 100° C. or higher and a pressure of 5 MPa or higher supplied from the water supply device. 12. The direct injection engine according to claim 1, further comprising: a spark plug configured to discharge spark in a latter stage of a compression stroke or in an initial stage of an expansion stroke to ignite fuel within the cylinder, wherein during the operation in the low load range, the valve control module controls to close the intake valve via the valve variable mechanism at a timing when an effective compression ratio capable of performing SPCCI combustion is achieved, the SPCCI combustion being such that after a flame kernel is formed within the cylinder by forcible ignition due to the spark ignition, fuel around the flame kernel is self-ignited. 13. The direct injection engine according to claim 5, further comprising: a spark plug configured to discharge spark in a latter stage of a compression stroke or in an initial stage of an expansion stroke to ignite fuel within the cylinder, wherein during the operation in the low load range, the valve control module controls to close the intake valve via the valve variable mechanism at a timing when an effective compression ratio capable of performing SPCCI combustion is achieved, the SPCCI combustion being such that after a flame kernel is formed within the cylinder by forcible ignition due to the spark ignition, fuel around the flame kernel is self-ignited. 14. The direct injection engine according to claim 12, wherein during the operation in the low load range, the fuel injection control module controls to inject fuel from the fuel injection valve at a timing when a fuel reforming rate is from 40 to 60%, the fuel reforming rate being a ratio of fuel that turns to hydrogen and carbon monoxide with respect to fuel injected within the cylinder. 15. The direct injection engine according to claim 1, wherein during the operation in the low load range, the water injection control module controls to inject water from the water injection valve at a timing included in a former part of the negative overlap period and included in a period when a temperature within the cylinder is from 500 to 700° C., the former part being a period from a closing timing of the exhaust valve to the exhaust top dead center. 16. A control method of a direct injection engine provided with a cylinder configured to accommodate a piston to be reciprocally movable, a fuel injection valve configured to inject fuel containing gasoline into the cylinder, a water injection valve configured to inject water into the cylinder, an intake valve configured to open and close an intake port for introducing air into the cylinder, an exhaust valve configured to open and close an exhaust port for discharging combusted gas from the cylinder, and a valve variable mechanism configured to change an operation timing of each of the intake valve and the exhaust valve, the control method comprising: during an operation in a low load range where a load of the engine is lower than a predetermined load, controlling the valve variable mechanism in such a manner that a negative overlap period when both of the intake valve and the exhaust valve are closed across an exhaust top dead center is formed; determining, as an injection timing of fuel by the fuel injection valve and an injection timing of water by the water injection valve, an injection timing when a steam reforming reaction occurs within the cylinder during the negative overlap period, the steam reforming reaction being such that at least a part of injected fuel and injected water turns to hydrogen and carbon monoxide; and controlling to inject fuel from the fuel injection valve and to inject water from the water injection valve respectively at a timing within the negative overlap period determined by the determination. 17. The control method of the direct injection engine according to claim 16, wherein during the operation in the low load range, fuel is injected from the fuel injection valve at a same time as water injection from the water injection valve or at a time later than water injection from the water injection valve. 18. The control method of the direct injection engine according to claim 16, wherein the engine further includes a spark plug configured to discharge spark in a latter stage of a compression stroke or in an initial stage of an expansion stroke to ignite fuel within the cylinder, wherein during the operation in the low load range, the intake valve is closed via the valve variable mechanism at a timing when an effective compression ratio capable of performing SPCCI combustion is achieved, the SPCCI combustion being such that after a flame kernel is formed within the cylinder by forcible ignition due to the spark ignition, fuel around the flame kernel is self-ignited. 19. The control method of the direct injection engine according to claim 18, wherein during the operation in the low load range, fuel is injected from the fuel injection valve at a timing when a fuel reforming rate is from 40 to 60%, the fuel reforming rate being a ratio of fuel that turns to hydrogen and carbon monoxide with respect to fuel injected within the cylinder. 20. The control method of the direct injection engine according to claim 16, wherein during the operation in the low load range, water is injected from the water injection valve at a point of time when a temperature within the cylinder is increased to a temperature included in a temperature range where a low temperature oxidation reaction of fuel occurs, or to a temperature exceeding the temperature range.
TECHNICAL FIELD The present invention relates to an engine configured to combust fuel containing gasoline after reforming the fuel. BACKGROUND ART As an engine configured to combust reformed fuel as described above, there is known an engine disclosed in Japanese Unexamined Patent Publication No. 2010-25031. The engine disclosed in Japanese Unexamined Patent Publication No. 2010-25031 includes a cylinder, an intake passage and an exhaust passage connected to the cylinder, an injector configured to inject fuel to a downstream end (an intake port) of the intake passage, a reforming chamber formed at a midway of the exhaust passage, a reforming catalyst disposed in the reforming chamber, an exhaust gas inlet passage for connecting between the reforming chamber and the exhaust passage on the upstream side of the reforming chamber, a reformed gas inlet pipe for connecting between the reforming chamber and the intake passage, and a water injection nozzle and a fuel supply device mounted to the exhaust gas inlet passage. Water injected from the water injection nozzle and fuel supplied from the fuel supply device react each other while undergoing an endothermic reaction during passing through the reforming chamber (the reforming catalyst), and turn to hydrogen and carbon monoxide (a steam reforming reaction). Reformed fuel containing hydrogen and carbon monoxide, in other words, reformed gas is introduced into the intake passage through the reformed gas inlet pipe, and is introduced into the cylinder (the combustion chamber) after being mixed with fuel injected from the injector. Reformed gas containing hydrogen and carbon monoxide has a high lean limit, as compared with fuel before reforming, and a calorific value of reformed gas is high. Therefore, an effect of improving fuel economy of an engine is expected by introducing fuel containing reformed gas into a cylinder for combustion. In the engine disclosed in Japanese Unexamined Patent Publication No. 2010-25031, however, fuel is reformed in the reforming chamber formed at a midway of the exhaust passage, and reformed fuel, in other words, reformed gas is introduced into the cylinder through the reformed gas inlet pipe. This may make it difficult to introduce the entirety of reformed gas into the cylinder. For instance, a part of reformed gas may flow into another path (an exhaust passage on the downstream side of the reforming chamber) other than the introduction path to the cylinder, or unreformed fuel may adhere and remain in the exhaust passage or on an inner wall of the reforming chamber. When the aforementioned condition occurs, only a part of reformed gas is used for combustion. This may offset the effect by reforming fuel, and may make it difficult to obtain a sufficient effect of improving fuel economy. SUMMARY OF INVENTION In view of the above, an object of the present invention is to provide a direct injection engine and a control method thereof, which enable to improve fuel economy of the engine by using reformed fuel without waste. A direct injection engine according to an aspect of the present invention includes a cylinder configured to accommodate a piston to be reciprocally movable; a fuel injection valve configured to inject fuel containing gasoline into the cylinder; a water injection valve configured to inject water into the cylinder; an intake valve configured to open and close an intake port for introducing air into the cylinder; an exhaust valve configured to open and close an exhaust port for discharging combusted gas from the cylinder; a valve variable mechanism configured to change an operation timing of each of the intake valve and the exhaust valve; a fuel injection control module configured to control the fuel injection valve; a water injection control module configured to control the water injection valve; a valve control module configured to control the valve variable mechanism; and a calculation module configured to perform various calculations based on an operating condition of the engine. During an operation in a low load range where a load of the engine is lower than a predetermined load, the valve control module controls the valve variable mechanism in such a manner that a negative overlap period when both of the intake valve and the exhaust valve are closed across an exhaust top dead center is formed. During the operation in the low load range, the calculation module determines, as an injection timing of fuel by the fuel injection valve and an injection timing of water by the water injection valve, an injection timing when a steam reforming reaction occurs within the cylinder during the negative overlap period, the steam reforming reaction being such that at least a part of injected fuel and injected water turns to hydrogen and carbon monoxide. During the operation in the low load range, the fuel injection control module and the water injection control module respectively control to inject fuel from the fuel injection valve and control to inject water from the water injection valve at a timing within the negative overlap period determined by the calculation module. Further, a control method according to another aspect of the present invention is applied to a direct injection engine provided with a cylinder configured to accommodate a piston to be reciprocally movable, a fuel injection valve configured to inject fuel containing gasoline into the cylinder, a water injection valve configured to inject water into the cylinder, an intake valve configured to open and close an intake port for introducing air into the cylinder, an exhaust valve configured to open and close an exhaust port for discharging combusted gas from the cylinder, and a valve variable mechanism configured to change an operation timing of each of the intake valve and the exhaust valve. The control method includes, during an operation in a low load range where a load of the engine is lower than a predetermined load, controlling the valve variable mechanism in such a manner that a negative overlap period when both of the intake valve and the exhaust valve are closed across an exhaust top dead center is formed; determining, as an injection timing of fuel by the fuel injection valve and an injection timing of water by the water injection valve, an injection timing when a steam reforming reaction occurs within the cylinder during the negative overlap period, the steam reforming reaction being such that at least a part of injected fuel and injected water turns to hydrogen and carbon monoxide; and controlling to inject fuel from the fuel injection valve and to inject water from the water injection valve respectively at a timing within the negative overlap period determined by the determination. These and other objects, features and advantages of the present invention will become more apparent upon reading the following detailed description along with the accompanying drawings. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a diagram illustrating an overall configuration of a direct injection engine according to an embodiment of the present invention; FIG. 2 is a sectional view of an engine body; FIG. 3 is a diagram illustrating an example of setting lift characteristics of an intake valve and an exhaust valve; FIG. 4 is a block diagram illustrating a control system of the engine; FIG. 5 is a map diagram illustrating differences in control depending on an operating condition of the engine; FIG. 6 is a time chart for describing contents of control to be performed in a low to middle load range (a first operating range) of the engine; FIG. 7 is a graph for describing that enthalpy (a calorific value) increases by reforming fuel; and FIG. 8 is a graph for describing that a timing of self-ignition changes depending on a fuel reforming rate. DESCRIPTION OF EMBODIMENTS (1) Overall Configuration of Engine FIG. 1 and FIG. 2 are diagrams illustrating a direct injection engine according to an embodiment of the present invention. The engine illustrated in FIG. 1 and FIG. 2 is a 4-cycle gasoline engine mounted in a vehicle as a power source for traveling. The engine includes an in-line multi-cylinder engine body 1 having four cylinders 2 arranged in a row, an intake passage 20 for passing intake air to be introduced to the engine body 1, an exhaust passage 30 for passing exhaust gas discharged from the engine body 1, and a water supply device 50 for supplying water extracted from exhaust gas passing through the exhaust passage 30 to each cylinder 2 of the engine body 1. As illustrated in FIG. 2, the engine body 1 includes a cylinder block 3 in which the cylinders 2 are formed, a cylinder head 4 mounted on a top surface of the cylinder block 3 in such a manner as to cover the cylinders 2 from above, and a piston 5 accommodated in each cylinder 2 to be reciprocally movable. A combustion chamber C is defined above the piston 5. In the combustion chamber C, gasoline injected from a fuel injection valve 11 to be described later is supplied as fuel. Further, supplied fuel (gasoline) is combusted in the combustion chamber C, and the piston 5 that is pushed down by an expansion force by the combustion is reciprocally moved up and down. A crankshaft 15 as an output shaft of the engine body 1 is disposed below the piston 5. The crankshaft 15 is connected to the piston 5 via a connecting rod 14, and is rotated around a central axis thereof as the piston 5 reciprocates. A crank angle sensor SN1 for detecting a rotational angle (a crank angle) of the crankshaft 15 is disposed in the cylinder block 3. Note that the crank angle sensor SN1 also serves as a sensor for detecting a rotational speed of the crankshaft 15, in other words, an output rotational speed of the engine body 1. A cavity 10 recessed downwardly on the side opposite to the cylinder head 4 is formed in a center portion of a crown surface (a top surface) of the piston 5. The cavity 10 is formed to have a volume that occupies a large part of the combustion chamber C when the piston 5 is lifted to the top dead center. In the cylinder head 4, a fuel injection valve 11 configured to inject fuel (gasoline) supplied from an unillustrated fuel pump into the combustion chamber C is disposed for each cylinder 2 (four fuel injection valves 11 in total). Each fuel injection valve 11 is disposed to inject fuel from laterally on the intake side into the combustion chamber C. Further, in the cylinder head 4, a water injection valve 13 configured to inject water supplied from the water supply device 50 into the combustion chamber C is disposed for each cylinder 2 (four water injection valves 13 in total). Each water injection valve 13 is disposed to inject water from laterally on the exhaust side into the combustion chamber C. In other words, the water injection valve 13 is disposed to face the fuel injection valve 11 with respect to the central axis of the cylinder 2. Further, in the cylinder head 4, a spark plug 12 configured to discharge spark to the combustion chamber C is disposed for each cylinder 2 (four spark plugs 12 in total). Each spark plug 12 has an electrode exposed to the combustion chamber C in the vicinity of the central axis of the cylinder 2. Each spark plug 12 forcibly ignites fuel injected from the fuel injection valve 11 by supplying spark generated on the electrode as ignition energy. When spark is discharged from an electrode of the spark plug 12, a flame kernel is formed near the electrode, and a combustion area gradually spreads from the flame kernel outwardly (flame propagation). Note that in the embodiment, not all the fuel injected into the combustion chamber C is combusted by flame propagation, and at least a part of fuel is combusted by self-ignition. As described above, in the embodiment, so-called SPCCI (Spark Controlled Compression Ignition) combustion such that a flame kernel formed by spark ignition (forcible ignition) causes fuel around the flame kernel to be self-ignited is performed in all the operating ranges of the engine. In order to perform SPCCI combustion as described above, it is necessary to secure a sufficiently high temperature by compression with the piston 5, as an internal temperature of the cylinder 2 (hereinafter, referred to as a cylinder temperature) immediately before spark ignition. In view of the above, in the embodiment, a geometric compression ratio of each cylinder 2, in other words, a ratio between a volume of the combustion chamber C when the piston 5 is at the top dead center, and a volume of the combustion chamber C when the piston 5 is at the bottom dead center is set to be not smaller than 16but not larger than 30. As illustrated in FIG. 2, in the cylinder head 4, an intake port 6 for introducing air supplied from the intake passage 20 into the combustion chamber C, an exhaust port 7 for discharging combusted gas (exhaust gas) generated in the combustion chamber C into the exhaust passage 30, an intake valve 8 for opening and closing an opening of the intake port 6 on the side of the combustion chamber C, and an exhaust valve 9 for opening and closing an opening of the exhaust port 7 on the side of the combustion chamber C are provided for each cylinder 2. The intake valve 8 and the exhaust valve 9 are driven to open and close in association with rotation of the crankshaft 15 by an unillustrated valve drive device. A valve drive device for the intake valve 8 internally includes, as a type of a valve variable mechanism, a switching mechanism 18 (see FIG. 4) for switching lift characteristics of the intake valve 8 between two stages. Although detailed description is omitted, the switching mechanism 18 includes two types of cams whose profiles are different from each other, and a shift driving unit for shifting one of the two cams to press the intake valve 8. Further, causing the shift driving unit to switch the cam for pressing the intake valve 8 makes it possible to switch lift characteristics of the intake valve 8 between first characteristics indicated by a solid-line waveform IN1 in FIG. 3, and second characteristics indicated by a broken-line waveform IN2 in FIG. 3. The second characteristics IN2 are such that the lift amount is large, and the valve opening period is long, as compared with the first characteristics IN1. When the second characteristics IN2 are selected, the intake valve 8 is driven in such a manner that the valve opening period overlaps the entire period of an intake stroke, in other words, the intake valve 8 is opened earlier than the exhaust top dead center (TDC) and is closed later than the intake bottom dead center (the right-side BDC). On the other hand, when the first characteristics IN1 are selected, the intake valve 8 is driven in such a manner that the intake valve 8 is opened later than the exhaust top dead center (during an intake stroke), and is closed later than the intake bottom dead center. In other words, the first characteristics IN1 of the intake valve 8 are set such that the valve opening timing is shifted to the retard side (accordingly, the peak of a lift amount is shifted to the retard side) while keeping the valve closing timing substantially unchanged with respect to the second characteristics IN2. Likewise, a valve drive device for the exhaust valve 9 internally includes, as a type of a valve variable mechanism, a switching mechanism 19 (see FIG. 4) for switching opening and closing characteristics of the exhaust valve 9 between two stages. The switching mechanism 19 has the same structure as the switching mechanism 18 for an intake valve. Switching a cam for pressing the exhaust valve 9 between two types of cams makes it possible to switch lift characteristics of the exhaust valve 9 between first characteristics indicated by a solid-line waveform EX1 in FIG. 3, and second characteristics indicated by a broken-line waveform EX2 in FIG. 3. The second characteristics EX2 are such that the lift amount is large and the valve opening period is long, as compared with the first characteristics EX1. When the second characteristics EX2 are selected, the exhaust valve 9 is driven in such a manner that the valve opening period overlaps the entire period of an exhaust stroke, in other words, the exhaust valve 9 is opened earlier than the expansion bottom dead center (the left-side BDC) and is closed later than the exhaust top dead center (TDC). On the other hand, when the first characteristics EX1 are selected, the exhaust valve 9 is driven in such a manner that the exhaust valve 9 is opened earlier than the expansion bottom dead center, and is closed earlier than the exhaust top dead center (during an exhaust stroke). In other words, the first characteristics EX1 of the exhaust valve 9 are set to characteristics such that the valve closing timing is shifted to the advance side (accordingly, the peak of a lift amount is shifted to the advance side) while keeping the valve opening timing substantially unchanged with respect to the second characteristics EX2. Note that in the specification, an opening timing and a closing timing of the intake valve 8/the exhaust valve 9 are respectively an opening timing and a closing timing in a case where a portion other than ramp portions formed at the beginning and the end of a valve lift curve (buffer zones where a change in the valve lift amount is moderate) is defined as a valve opening period. The opening timing and the closing timing do not indicate a timing when the lift amount is completely zero. In the embodiment, a point of time when the valve lift amount is increased from 0 mm to 0. 4 mm is an opening timing, and a point of time when the valve lift amount is decreased to 0.4 mm thereafter is a valve closing timing. When lift characteristics of the intake valve 8 and lift characteristics of the exhaust valve 9 are respectively set to the first characteristics IN1 and the first characteristics EX1, both of the intake valve 8 and the exhaust valve 9 are kept in a closed state during a predetermined period from a certain point in an exhaust stroke to a certain point in an intake stroke. In other words, a negative overlap period X when both of the intake valve 8 and the exhaust valve 9 are closed across the exhaust top dead center is formed. When the negative overlap period X as described above is formed, a part of combusted gas generated by combustion in an immediately preceding expansion stroke is not discharged from the cylinder 2 and remains within the cylinder 2. In other words, internal EGR such that a part of combusted gas is allowed to remain within the cylinder 2 so as to bring the inside of the cylinder 2 to a high temperature state is performed. When it is assumed that a part of the negative overlap period X corresponding to a crank angle range from a closing timing of the exhaust valve 9 to the exhaust top dead center is a former part X1, and a part of the negative overlap period X corresponding to a crank angle range from the exhaust top dead center to an opening timing of the intake valve 8 is a latter part X2, in the embodiment, lift characteristics of the intake valve 8 and the exhaust valve 9 (the first characteristics IN1 and the first characteristics EX1) are set in such a manner that the latter part X2 is longer than the former part X1. As illustrated in FIG. 1, the intake passage 20 includes a common intake pipe 22 as a single pipe, and an intake manifold 21 formed to be branched from a downstream end of the common intake pipe 22. Each branch pipe of the intake manifold 21 is connected to the engine body 1 (the cylinder head 4) in such a manner as to communicate with each cylinder 2 via the intake port 6. A downstream end of the common intake pipe 22 is connected to a gathering portion of branch pipes of the intake manifold 21 (a portion where upstream ends of branch pipes gather). Note that in the specification, upstream (or downstream) of the intake passage 20 indicates upstream (or downstream) in the flow direction of intake air flowing through the intake passage 20. An air cleaner 25 for removing foreign matter contained in intake air, and a throttle valve 27 operable to open and close so as to adjust the flow rate of intake air flowing through the common intake pipe 22 are disposed on the common intake pipe 22 in this order from the upstream side. Further, an airflow sensor SN2 for detecting a flow rate of intake air flowing through the common intake pipe 22, and an intake temperature sensor SN3 for detecting a temperature of intake air are disposed on the downstream side of the common intake pipe 22 with respect to the throttle valve 27. The exhaust passage 30 includes a common exhaust pipe 32 as a single pipe, and an exhaust manifold 31 formed to be branched from an upstream end of the common exhaust pipe 32. Each branch pipe of the exhaust manifold 31 is connected to the engine body 1 (the cylinder head 4) in such a manner as to communicate with each cylinder 2 via the exhaust port 7. An upstream end of the common exhaust pipe 32 is connected to a gathering portion of branch pipes of the exhaust manifold 31 (a portion where downstream ends of branch pipes gather). Note that in the specification, upstream (or downstream) of the exhaust passage 30 indicates upstream (or downstream) in the flow direction of exhaust gas flowing through the exhaust passage 30. A catalyst device 35, a heat exchanger 54, and a condenser 51 are disposed in this order from the upstream side on the common exhaust pipe 32. The catalyst device 35 is configured to purify harmful components contained in exhaust gas. The catalyst device 35 internally includes one of a three-way catalyst, an oxidation catalyst, and an NOx catalyst, or any combination thereof. The catalyst device 35 may include a filter for trapping PM contained in exhaust gas, in addition to the aforementioned catalyst. The condenser 51 is configured to condense steam contained in exhaust gas. The heat exchanger 54 is configured to heat condensed water generated in the condenser 51. The condenser 51 and the heat exchanger 54 are elements constituting a part of the water supply device 50, which will be described later in detail. (2) Specific Configuration of Water Supply Device As illustrated in FIG. 1, the water supply device 50 includes the condenser 51, the heat exchanger 54, a water tank 52 for storing condensed water generated in the condenser 51, a water feeding pump 53 for pumping out condensed water stored in the water tank 52 toward the heat exchanger 54, an accumulator rail 56 for storing high-temperature and high-pressure water which is pressurized by the water feeding pump 53 and heated by the heat exchanger 54 while keeping the water temperature and the water pressure, a first water pipe 61 for connecting between the condenser 51 and the water tank 52, a second water pipe 62 for connecting between the water tank 52 and the heat exchanger 54, a third water pipe 63 for connecting between the heat exchanger 54 and the accumulator rail 56, and a plurality of (four) distribution pipes 64 for connecting between the accumulator rail 56 and the water injection valve 13 of each cylinder 2. The condenser 51 is a heat exchanger for condensing steam contained in exhaust gas flowing through the common exhaust pipe 32. The condenser 51 condenses steam contained in exhaust gas by cooling the exhaust gas by heat exchange with a predetermined coolant (e.g. engine cooling water). Condensed water generated in the condenser 51 flows downstream through the first water pipe 61, and is stored in the water tank 52. The water feeding pump 53 is disposed at a midway of the second water pipe 62, and is configured to feed condensed water stored in the water tank 52 toward the heat exchanger 54, while pressurizing the condensed water. The heat exchanger 54 is configured to heat water supplied from the water feeding pump 53 by heat exchange with exhaust gas before the exhaust gas flows into the condenser 51. Although detailed illustration is omitted, the heat exchanger 54 includes a small-diameter and long-shaped thin pipe 54a, which is inserted in a portion of the common exhaust pipe 32 at a position between the catalyst device 35 and the condenser 51, and an insulation case 54b formed to cover the portion of the common exhaust pipe 32 where the thin pipe 54a is inserted. Water heated by the heat exchanger 54 is fed downstream through the third water pipe 63, and is stored in the accumulator rail 56. A water pressure sensor SN4 for detecting a pressure of water inside the accumulator rail 56 is disposed on the accumulator rail 56. The temperature and the pressure of water stored in the accumulator rail 56 are increased to 200° C. or higher and to 10 MPa or higher through heating by the heat exchanger 54 and pressurization by the water feeding pump 53 as described above. Since the pressure of water stored in the accumulator rail 56 is as high as 10 MPa or higher, water does not boil even if being heated to 200° C. or higher, and is kept in a liquid state. Further, water stored in the accumulator rail 56 in the aforementioned state is injected into the cylinder 2 through the water injection valve 13 as necessary. Specifically, in the embodiment, water injected into the cylinder 2 from the water injection valve 13 is high-temperature and high-pressure liquefied water of a temperature of 200° C. or higher and a pressure of 10 MPa or higher. (3) Control System of Engine FIG. 4 is a block diagram illustrating a control system of the engine. A PCM 100 illustrated in FIG. 4 is a microprocessor for integrally controlling the engine, and is constituted by a well-known CPU, ROM, RAM, and the like. Detection signals by various sensors are input to the PCM 100. For instance, the PCM 100 is electrically connected to the crank angle sensor SN1, the airflow sensor SN2, the intake temperature sensor SN3, and the water pressure sensor SN4. Information (i.e. a crank angle, an intake flow rate, an intake temperature, a water pressure, etc.) detected by these sensors is successively input to the PCM 100 as an electrical signal. Further, a vehicle includes an accelerator sensor SN5 for detecting an opening angle of an accelerator pedal (not illustrated) to be operated by a driver driving the vehicle. A detection signal by the accelerator sensor SN5 is also input to the PCM 100. The PCM 100 controls the units of the engine while performing various determinations and calculations based on input signals from the various sensors. Specifically, the PCM 100 is electrically connected to the fuel injection valves 11, the water injection valves 13, the switching mechanisms 18 and 19 for the intake valves 8 and the exhaust valves 9, the throttle valve 27, the water feeding pump 53, the spark plugs 12, and the like. The PCM 100 outputs signals for respectively controlling these devices based on a result of the calculation or the like. As functional elements relating to the aforementioned control, the PCM 100 includes a calculation module 101, a fuel injection control module 102, a water injection control module 103, a valve control module 104, and an ignition control module 105. The calculation module 101 performs various calculations based on an operating condition of the engine to be specified from detection values of the sensors SN1 to SN5. The fuel injection control module 102 controls the fuel injection valve 11, based on a calculation result by the calculation module 101. The water injection control module 103 controls the water injection valve 13 and the water supply device 50 (the water feeding pump 53) based on a calculation result by the calculation module 101. The valve control module 104 controls the switching mechanisms 18 and 19 based on a calculation result by the calculation module 101. The ignition control module 105 controls the spark plug 12 based on a calculation result by the calculation module 101. More specifically, the calculation module 101 determines an injection amount and an injection timing of fuel by the fuel injection valve 11, based on an engine load to be specified from detection values (an intake flow rate and an accelerator opening angle) of the airflow sensor SN2 and the accelerator sensor SN5, and based on an engine speed detected by the crank angle sensor SN1. The fuel injection control module 102 controls the fuel injection valve 11 in accordance with the determination by the calculation module 101. Further, the calculation module 101 determines an injection amount and an injection timing of water by the water injection valve 13, based on the engine load and the engine speed, and based on an intake temperature detected by the intake temperature sensor SN3. The water injection control module 103 controls the water injection valve 13 in accordance with the determination by the calculation module 101. In addition to the above, the water injection control module 103 drives the water feeding pump 53 in such a manner that an inner pressure of the accumulator rail 56 (a pressure of water stored in the accumulator rail 56) is retained to a required pressure (10 MPa) or higher, based on the inner pressure of the accumulator rail 56 detected by the water pressure sensor SN4. Further, the calculation module 101 determines which one of a state such that lift characteristics of the intake valve 8 and lift characteristics of the exhaust valve 9 are respectively the first characteristics IN1 and the first characteristics EX1, and a state such that lift characteristics of the intake valve 8 and lift characteristics of the exhaust valve 9 are respectively the second characteristics IN2 and the second characteristics EX2 is to be selected, based on the engine load, the engine speed, and the like. The valve control module 104 controls the switching mechanisms 18 and 19 in accordance with the determination by the calculation module 101. Further, the calculation module 101 determines a timing (an ignition timing) when spark is discharged from the spark plug 12 based on the engine load, the engine speed, and the like. The ignition control module 105 controls the spark plug 12 in accordance with the determination by the calculation module 101. (4) Control depending on Operating Condition Next, control of the fuel injection valve 11, the switching mechanisms 18 and 19, and the water injection valve 13 by the PCM 100 is described in detail. FIG. 5 is a map diagram for describing differences in control depending on an operating condition of the engine (an engine load/an engine speed). As described above, in the embodiment, SPCCI combustion such that an air-fuel mixture is ignited by the spark plug 12 to cause self-ignition of the air-fuel mixture around a spark point is performed in all the operating ranges of the engine. In the embodiment, SPCCI combustion of different modes is performed in a first operating range A1 including a low load range of the engine, and in a second operating range A2 where the load is higher than that in the first operating range A1. Specifically, in the first operating range A1 on the low load side, SPCCI combustion such that fuel is self-ignited after the fuel is reformed is performed, and in the second operating range A2 on the high load side, SPCCI combustion such that fuel is self-ignited without a reforming process is performed. Therefore, the presence or absence of water injection by the water injection valve 13, valve characteristics of the intake valve 8 and the exhaust valve 9, and a fuel injection timing by the fuel injection valve 11 differ from each other between the first operating range A1 and the second operating range A2. (i) Control in First Operating Range FIG. 6 is a time chart for describing contents of control to be performed in the first operating range A1 on the low load side. As illustrated in FIG. 6, in the first operating range A1, the switching mechanisms 18 and 19 are controlled in such a manner that lift characteristics of the intake valve 8 and lift characteristics of the exhaust valve 9 respectively become the first characteristics IN1 and the first characteristics EX1, and the negative overlap period X is formed in a period including the exhaust top dead center (the left-side TDC). Further, during the negative overlap period X, water is injected from the water injection valve 13, and fuel is injected from the fuel injection valve 11. Further, spark is discharged from the spark plug 12 in the vicinity of the compression top dead center (the right-side TDC). Specifically, water injection by the water injection valve 13 is performed within the former part X1 of the negative overlap period X, which is a period from a closing timing of the exhaust valve 9 to the exhaust top dead center, specifically, is performed at a point of time within the former part X1 when the cylinder temperature is increased to a temperature included in a temperature range where a low temperature oxidation reaction of fuel occurs, or to a temperature exceeding the temperature range. Specifically, in the former part X1 of the negative overlap period X, the piston 5 is lifted in a state that both of the intake valve 8 and the exhaust valve 9 are closed. Therefore, gas (mainly, combusted gas) within the cylinder 2 is compressed accompanied by lifting of the piston 5. Then, the cylinder temperature is increased to a temperature included in a temperature range where a low temperature oxidation reaction of fuel occurs, or to a temperature exceeding the temperature range at a point of time before the piston 5 reaches the exhaust top dead center. Note that the low temperature oxidation reaction is a slow oxidation reaction, which occurs at a stage before a high temperature oxidation reaction i.e. a reaction such that fuel vigorously oxidizes (a reaction accompanying flame generation) occurs, and is a reaction that occurs in a temperature range of about not lower than 500° C. but not higher than 650° C. In the following, a temperature range (about 500 to 650° C.) where the aforementioned low temperature oxidation reaction occurs is referred to as a low temperature oxidation reaction range. In order to perform water injection at the aforementioned timing, the calculation module 101 determines, by calculation, a specific crank angle at which the cylinder temperature is increased to a predetermined temperature (e.g. a temperature within a range of from 500 to 750° C.), which is included in the low temperature oxidation reaction range or to a temperature exceeding the low temperature oxidation reaction range, based on an engine load/an engine speed, an intake temperature, and the like at each point of time to be specified by the crank angle sensor SN1, the airflow sensor SN2, the accelerator sensor SN5, and the intake temperature sensor SN3. Thereafter, the water injection control module 103 controls to inject water of a predetermined amount from the water injection valve 13 at a point of time when the specific crank angle determined by the calculation module 101 is reached. Fuel injection by the fuel injection valve 11 is performed at a timing slightly later than water injection by the water injection valve 13. Specifically, the calculation module 101 determines, as a timing of fuel injection by the fuel injection valve 11, a specific crank angle at which the timing is later than the timing of water injection by the water injection valve 13 and is earlier than the exhaust top dead center. Thereafter, the fuel injection control module 102 controls to inject fuel from the fuel injection valve 11 at a point of time when the specific crank angle determined by the calculation module 101 is reached. Further, the amount of fuel to be injected in this case is determined based on an engine load/an engine speed, and is determined in such a manner that the higher the engine load is, the more the injection amount is at a same engine speed, for instance. A part of fuel and water injected into the cylinder 2 as described above reacts in a high temperature environment during a negative overlap period, and turns to hydrogen and carbon monoxide. This reaction is referred to as a so-called steam reforming reaction such that fuel (gasoline) is reformed by using water. The reaction is represented by the following formula (1). Note that the formula (1) indicates a reforming reaction of isooctane (C8H18), which is a representative component of gasoline. C8H18+8H2O→8CO+17H2+11MJ/kg (1) where “+11 MJ/kg” on the right side indicates that heat of 11 MJ is absorbed each time reaction of 1 kg progresses. In other words, this reaction is an endothermic reaction. The aforementioned steam reforming reaction is likely to progress, as the maximum value of a cylinder temperature during the negative overlap period X increases, and is likely to progress, as a period when the cylinder temperature exceeds the low temperature oxidation reaction range increases after fuel injection. In view of the above, when it is assumed that a ratio of fuel that turns to hydrogen (H2) and carbon monoxide (CO) with respect to injected fuel (gasoline) is a fuel reforming rate, it is possible to adjust the fuel reforming rate by changing the injection timing of fuel. For instance, in a condition where the maximum value of a cylinder temperature during the negative overlap period X is the same, the earlier the fuel injection timing is, the higher the fuel reforming rate is, and the later the fuel injection timing is, the lower the fuel reforming rate is. In other words, even in a case where the maximum value of a cylinder temperature differs due to a difference in the engine load or the like, it is possible to make the fuel reforming rate substantially equal by adjusting the fuel injection timing. Specifically, in a case where the maximum value of a cylinder pressure is high, it is possible to make the fuel reforming rate substantially equal by retarding the fuel injection timing, as compared with a case where the maximum value of a cylinder pressure is low. In the embodiment, the fuel injection timing is adjusted in such a manner that the aforementioned fuel reforming rate is substantially not lower than 40% but not higher than 60%. This is because the aforementioned range is appropriate for obtaining characteristics of fuel suitable for SPCCI combustion, which will be described later in detail. Setting the fuel reforming rate from 40% to 60% allows reformed fuel to be a mixture in which hydrogen (H2), carbon monoxide (CO),and gasoline (C8H18) are mixed. Fuel (a mixture of gasoline, hydrogen, and carbon monoxide) that is reformed during the negative overlap period X as described above is mixed with air to be introduced into the cylinder 2 accompanied by opening of the intake valve 8, which is performed following the reforming operation. Then, when the time of compression stroke has come and the intake valve 8 is closed, gas within the cylinder 2 (a mixture of reformed fuel, air, and combusted gas) substantially starts to be compressed from the point of time when the intake valve 8 is closed, and the inside of the cylinder 2 is brought to a high-temperature and high-pressure state until immediately before fuel is self-ignitable in the vicinity of the compression top dead center (the right-side TDC). In other words, in the embodiment, an effective compression ratio of each cylinder 2, in other words, a ratio between the volume of the combustion chamber C when the piston 5 is at the top dead center, and the volume of the combustion chamber C at a point of time when the intake valve 8 is closed is set to a value at which the inside of the cylinder 2 is brought to a high-temperature and high-pressure state until immediately before fuel is self-ignitable (until a state that fuel is easily self-ignited by spark ignition). At a point of time when the inside of the cylinder 2 is brought to a high-temperature and high-pressure state as described above, spark ignition by the spark plug 12 is performed. For instance, the calculation module 101 determines, as an ignition timing by the spark plug 12, a specific crank angle at which a target fuel ignition timing is obtainable, based on a map or the like in which the target fuel ignition timing is determined in advance for each operating condition (an engine load/an engine speed). Thereafter, the ignition control module 105 energizes the spark plug 12 to discharge spark from an electrode of the spark plug 12 at a point of time when the specific crank angle determined by the calculation module 101 is reached. FIG. 6 exemplifies a case in which spark ignition is performed substantially simultaneously with the compression top dead center. A flame kernel is formed in the vicinity of an electrode of the spark plug 12 by forcible ignition due to spark ignition, and the inside of the cylinder 2 is further brought to a high-temperature and high-pressure state by formation of the flame kernel. Then, fuel in a state immediately before self-ignition at a point of time when spark ignition occurs is self-ignited around the flame kernel in a multiple simultaneous manner, triggered by formation of the flame kernel. Specifically, SPCCI combustion such that fuel is self-ignited and combusted, triggered by spark ignition (formation of a flame kernel) is performed. In the example illustrated in FIG. 6, the ignition timing is set to a timing substantially coincident with the compression top dead center. Alternatively, the ignition timing may be set to a timing shifted to the advance side from the compression top dead center, or may be set to a timing shifted to the retard side from the compression top dead center depending on an operating condition of the engine (an engine load/an engine speed). In any of the cases, the ignition timing is set to be included in one of a latter stage of a compression stroke, and an initial stage of an expansion stroke. Note that in the specification, a latter stage of a compression stroke is a range from 60° CA before the compression top dead center (BTDC) until the compression top dead center, and an initial stage of an expansion stroke is a range from the compression top dead center to 60° CA after the compression top dead center (ATDC). Specifically, in the embodiment, the spark plug 12 is controlled in such a manner that the ignition timing is included in a latter stage of a compression stroke or in an initial stage of an expansion stroke (BTDC 60° CA to ATDC 60° CA). (ii) Control in Second Operating Range In the second operating range A2 where the load is higher than that in the first operating range A1, ordinary SPCCI combustion that does not accompany a fuel reforming process is performed. Specifically, in the second operating range A2, the switching mechanisms 18 and 19 are controlled in such a manner that lift characteristics of the intake valve 8 and lift characteristics of the exhaust valve 9 respectively are the second characteristics IN2 and the second characteristics EX2 (see FIG. 3). This is performed in order to of the negative overlap period X, and to introduce a large amount of air (fresh air) sufficient for a high load state into the cylinder 2. Further, for instance, fuel is injected from the fuel injection valve 11 during a period from a closing timing of the intake valve 8 to the compression top dead center (in other words, during a compression stroke), and spark ignition by the spark plug 12 is performed after the fuel injection. Then, SPCCI combustion such that a flame kernel is formed by forcible ignition due to spark ignition, and fuel around the flame kernel is self-ignited is performed. Note that in the second operating range A2, it is not necessary to perform a fuel reforming process by a steam reforming reaction. Therefore, it is needless to say that water injection by the water injection valve 13 is stopped. (5) Advantageous Effects As described above, in the engine of the embodiment, the intake valve 8 and the exhaust valve 9 are controlled in such a manner that the negative overlap period X when both of the intake valve 8 and the exhaust valve 9 are closed across the exhaust top dead center during an operation in the first operating range A1 where the load is relatively low. Further, fuel and water are respectively injected from the fuel injection valve 11 and the water injection valve 13 during the negative overlap period X, and a part of injected fuel reacts with water within the cylinder 2, and is converted to hydrogen and carbon monoxide (a steam reforming reaction). The aforementioned configuration makes it possible to use reformed fuel without waste, and is advantageous in improving fuel economy of the engine. Specifically, in the embodiment, the negative overlap period X when both of the intake valve 8 and the exhaust valve 9 are closed across the exhaust top dead center is formed, whereby internal EGR such that combusted gas is allowed to remain within the cylinder 2 is performed. Further, the remaining combusted gas (internal EGR gas) is compressed by lifting of the piston 5 during the negative overlap period X, and the inside of the cylinder 2 is brought to a high-temperature and high-pressure state. Further, injecting fuel and water into the cylinder 2 in a high-temperature and high-pressure state allows a part of injected fuel to react with water while absorbing heat from around the fuel, whereby the part of fuel is converted to hydrogen and carbon monoxide (a steam reforming reaction). Note that hydrogen and carbon monoxide have high enthalpy, as compared with fuel (gasoline) before reforming. For instance, as illustrated in FIG. 7, when it is assumed that the whole amount of isooctane (C8H18), which is a representative component of gasoline, is converted to hydrogen and carbon monoxide (H2+CO), reformed fuel has enthalpy higher than the enthalpy of isooctane before reforming by 24%. When reformed fuel as described above is combusted in an expansion stroke, a larger amount of heat is generated accompanied by the combustion. Therefore, as compared with a case where fuel is not reformed, work (expansion work) of pushing down the piston 5 increases. This means that a part of heat (waste heat), which is supposed to be discharged from the cylinder 2, is extracted as work, in other words, waste heat recovery is carried out. Specifically, it is possible to improve the indicated efficiency i.e. a ratio at which energy supplied as fuel is converted to work, by the waste heat recovery. In addition to the above, fuel is reformed within the cylinder 2. Therefore, for instance, unlike a case where fuel is reformed on the outside of the cylinder 2, and the reformed fuel is introduced into the cylinder 2, it is possible to combust basically the whole amount of reformed fuel within the cylinder 2, and to efficiently extract work by using the combustion energy. Furthermore, heat is absorbed accompanied by progress of a reforming reaction. Therefore, it is possible to suppress an increase in the cylinder temperature during the negative overlap period X, and to reduce cooling loss of the engine. As described above, in the embodiment, it is possible to improve the indicated efficiency by waste heat recovery, and to reduce cooling loss. This is advantageous in improving fuel economy of the engine. Further, in the embodiment, fuel is injected from the fuel injection valve 11 at a timing slightly later than water injection from the water injection valve 13. This makes it possible to supply a sufficient amount of water into the cylinder 2 before a fuel reforming reaction starts, and to promote the fuel reforming reaction. Further, in the embodiment, after the negative overlap period X starts, water is injected from the water injection valve 13 at a point of time when the cylinder temperature is increased to a temperature included in the low temperature oxidation reaction range (a temperature range where a low temperature oxidation reaction of fuel occurs), or to a temperature exceeding the temperature range. Therefore, for instance, unlike a case where water is injected in an initial stage of the negative overlap period X, it is possible to suppress that an increase in the cylinder temperature is obstructed by water injection, and to efficiently increase the cylinder temperature. Specifically, in an initial stage of the negative overlap period X, the piston 5 is lifted at a relatively high speed within the cylinder 2 in a sealed state. Therefore, the cylinder temperature is rapidly increased accompanied by lifting (compression) of the piston 5. However, when it is assumed that water injection is performed in a period when the cylinder temperature is likely to increase as described above, a temperature increase may be obstructed by absorption of latent heat by injected water, and the cylinder temperature may not be increased to a sufficiently high level. On the other hand, in the embodiment, water is injected at a point of time when the cylinder temperature is increased to a sufficiently high temperature in the low temperature oxidation reaction range or to a temperature exceeding the low temperature oxidation reaction range. This makes it possible to efficiently increase the cylinder temperature in an initial stage of the negative overlap period X, and to realize a cylinder environment where the inside of the cylinder is brought to a high-temperature and high-pressure state necessary for reforming fuel with a high probability. Further, in the embodiment, the latter part X2 (a crank angle range from the exhaust top dead center to an opening timing of the intake valve 8) of the negative overlap period X is set longer than the former part X1 (a crank angle range from the closing timing of the exhaust valve 9 to the exhaust top dead center) of the negative overlap period X. This is advantageous in preventing backflow of gas containing fuel within the cylinder 2 to the intake port 6 accompanied by opening of the intake valve 8. Specifically, in the embodiment, fuel and water are injected during the negative overlap period X. In other words, the amount of gas within the cylinder 2 is increased during the negative overlap period X. When it is assumed that the former part X1 and the latter part X2 of the negative overlap period X are set equal to each other, the cylinder pressure is high at the end of the negative overlap period X (at an opening timing of the intake valve 8), as compared with the start of the negative overlap period X (at a closing timing of the exhaust valve 9). This may cause a phenomenon such that gas within the cylinder 2 flows back to the intake port 6 immediately after the intake valve 8 is opened. This may lead to reduction of the amount of fuel existing in the cylinder 2. On the other hand, in the embodiment, in which the latter part X2 is set longer than the former part X1 of the negative overlap period X, it is possible to prevent a phenomenon such that gas flows back to the intake port 6 as described above. This makes it possible to secure fuel of an intended amount within the cylinder 2, and to generate a sufficient output torque. Further, in the embodiment, water heated and pressurized by the water supply device 50 is supplied to the water injection valve 13 so as to inject water of a temperature of 200° C. or higher and a pressure of 10 MPa or higher from the water injection valve 13. This makes it possible to appropriately supply water of a required amount into the cylinder 2, while suppressing lowering of the cylinder temperature. Specifically, water is injected from the water injection valve 13 at a pressure of 10 MPa or higher. This makes it possible to inject water, without hindrance, from the water injection valve 13 into the cylinder 2, which is brought to a pressurized state during the negative overlap period X. Further, water to be injected from the water injection valve 13 is high-temperature water of 200° C. or higher. This makes it possible to suppress lowering of the cylinder temperature accompanied by the water injection, and to prevent obstruction of a fuel reforming reaction by temperature lowering. Further, in the embodiment, the geometric compression ratio of each cylinder 2 is set to be not smaller than 16 but not larger than 30. Therefore, it is possible to secure a stroke amount (a compression amount) of a piston during a period from a closing timing of the exhaust valve 9 to the exhaust top dead center, and to sufficiently increase the cylinder temperature during the negative overlap period X without excessively increasing the negative overlap period X. This makes it possible to securely reform fuel within the cylinder 2 in a high-temperature state during the negative overlap period X, while avoiding an excessive reduction of the amount of intake air to be introduced into the cylinder 2. Further, in the embodiment, SPCCI combustion such that a flame kernel is formed within a cylinder by forcible ignition due to spark ignition, and fuel around the flame kernel is self-ignited is performed in the first operating range A1 where control for reforming fuel (water injection and fuel injection during the negative overlap period X) is performed. Therefore, it is possible to perform combustion with enhanced thermal efficiency and with high controllability by using characteristics of reformed fuel containing hydrogen and carbon monoxide. Specifically, hydrogen contained in reformed fuel has characteristics such that the flame propagation speed is high, as compared with fuel (gasoline) before reforming. Therefore, performing spark ignition with respect to reformed fuel containing hydrogen having the aforementioned characteristics makes it possible to speedily and securely form a flame kernel. When a flame kernel is formed, fuel around the flame kernel is self-ignited in a multiple simultaneous manner by a high-temperature and high-pressure treatment within the cylinder 2 accompanied by formation of the flame kernel. This makes it possible to complete combustion in a short period, and to perform combustion with less exhaust loss and with enhanced thermal efficiency. In addition to the above, it is possible to control the timing when fuel is self-ignited by spark ignition. This makes it easy to obtain an intended combustion pattern for each operating condition, and to enhance combustion controllability. In particular, in the embodiment, the fuel reforming rate i.e. a ratio of fuel that turns to hydrogen and carbon monoxide with respect to injected fuel (gasoline) is set to be not lower than 40% but not higher than 60%. Therefore, it is possible to prevent a situation such that fuel is accidentally self-ignited before spark ignition, and to enhance fuel controllability. FIG. 8 is a graph illustrating a relationship between an ignition timing and a fuel reforming rate in a case where fuel is self-ignited without being assisted by spark ignition (i.e. only by compression). It is clear from the graph of FIG. 8 that an ignition timing is retarded in a case where fuel is reformed, in other words, reformed fuel has characteristics such that fuel is less likely to be self-ignited in a range where the reforming rate is lower than about 70%. More specifically, an ignition timing is retarded as the reforming rate is gradually increased from 0%, and a most retarded ignition timing is obtained when the reforming rate reaches about 20%. Thereafter, a retard width of the ignition timing is gradually decreased, as the reforming rate is increased. When the reforming rate reaches about 70%, the ignition timing is the same as the ignition timing of fuel before reforming (in other words, the fuel reforming rate=0%). Further, in a case where the reforming rate is larger than 70%, the ignition timing is advanced, as compared with a case of fuel before reforming. In the embodiment, in which fuel having the aforementioned relationship between a reforming rate and an ignition timing is used, in a case where the reforming rate is set from 40% to 60%, reformed fuel has characteristics such that fuel is less likely to be self-ignited, as compared with fuel before reforming. According to this configuration, it is possible to avoid a situation such that fuel may be self-ignited before spark ignition, while setting an effective compression ratio of the engine to a relatively high value; and to perform combustion with high controllability such that the timing of self-ignition is adjustable by spark ignition. Further, about a half amount of fuel is converted to hydrogen and carbon monoxide having high enthalpy. This makes it possible to enhance the efficiency of waste heat recovery, and is advantageous in improving fuel economy. (6) Modifications In the embodiment, high-temperature water of a temperature of 200° C. or higher is injected at a pressure of 10 MPa or higher from the water injection valve 13. Water to be injected from a water injection valve may have a temperature at least higher than the temperature of engine cooling water in a warm state. Further, an injection pressure of water may be a pressure at which water is injectable into a cylinder (a cylinder in a high-pressure state by compression) during a negative overlap period. In view of these points, the temperature of water to be injected from a water injection valve may be 100° C. or higher, and the injection pressure of water may be 5 MPa or higher. Further, in the embodiment, water is injected from the water injection valve 13 at a point of time, within the negative overlap period X, when the cylinder temperature is increased to a temperature (e.g. a temperature from 500 to 750° C.), which is included in the low temperature oxidation reaction range, or to a temperature exceeding the low temperature oxidation reaction range. The water injection timing, however, is not limited to the above. Water may be injected before the cylinder temperature reaches the low temperature oxidation reaction range (in other words, at a point of time before the cylinder temperature reaches 500° C.). Further, in the embodiment, fuel is injected from the fuel injection valve 11 at a timing later than water injection from the water injection valve 13. The fuel injection timing, however, is not limited to the above. Fuel may be injected simultaneously with water injection. Alternatively, fuel may be injected before water injection. In any of the cases, it is possible to change each of the water injection timing and the fuel injection timing to an appropriate timing, as far as both of water and fuel are injected during a negative overlap period, and a reforming reaction such that at least a part of injected fuel (gasoline) turns to hydrogen and carbon monoxide occurs. Further, in the embodiment, there is described an example, in which the present invention is applied to a gasoline engine, in which SPCCI combustion such that a flame kernel is formed within a cylinder by forcible ignition due to spark ignition, and fuel around the flame kernel is self-ignited is performed in all the operating ranges of the engine. The engine to which the present invention is applicable, however, is not limited to the aforementioned engine. For instance, the present invention is applicable to a gasoline engine, in which HCCI combustion such that fuel is self-ignited without being assisted by spark ignition is performed, a gasoline engine, in which SI combustion such that fuel is combusted only by flame propagation after spark ignition is performed, and a gasoline engine, in which the combustion mode is switched between two or more combustion modes out of SPCCI combustion, HCCI combustion, and SI combustion depending on an operating condition of the engine. Further, in the embodiment, there is described an example, in which the present invention is applied to an engine, in which gasoline is used as fuel. The engine to which the present invention is applicable, however, may be an engine, in which fuel containing ethanol as a sub component is used in addition to gasoline, as far as the engine uses fuel containing gasoline as a main component. (7) Summary The following is a summary of the embodiment and the modifications thereof. A direct injection engine includes a cylinder configured to accommodate a piston to be reciprocally movable; a fuel injection valve configured to inject fuel containing gasoline into the cylinder; a water injection valve configured to inject water into the cylinder; an intake valve configured to open and close an intake port for introducing air into the cylinder; an exhaust valve configured to open and close an exhaust port for discharging combusted gas from the cylinder; a valve variable mechanism configured to change an operation timing of each of the intake valve and the exhaust valve; a fuel injection control module configured to control the fuel injection valve; a water injection control module configured to control the water injection valve; a valve control module configured to control the valve variable mechanism; and a calculation module configured to perform various calculations based on an operating condition of the engine. During an operation in a low load range where a load of the engine is lower than a predetermined load, the valve control module controls the valve variable mechanism in such a manner that a negative overlap period when both of the intake valve and the exhaust valve are closed across an exhaust top dead center is formed. During the operation in the low load range, the calculation module determines, as an injection timing of fuel by the fuel injection valve and an injection timing of water by the water injection valve, an injection timing when a steam reforming reaction occurs within the cylinder during the negative overlap period, the steam reforming reaction being such that at least a part of injected fuel and injected water turns to hydrogen and carbon monoxide. During the operation in the low load range, the fuel injection control module and the water injection control module respectively control to inject fuel from the fuel injection valve and control to inject water from the water injection valve at a timing within the negative overlap period determined by the calculation module. According to the aforementioned configuration, the negative overlap period when both of the intake valve and the exhaust valve are closed across the exhaust top dead center is formed, whereby internal EGR such that combusted gas is allowed to remain within the cylinder is performed. Further, the remaining combusted gas (internal EGR gas) is compressed by lifting the piston during the negative overlap period to bring the inside of the cylinder to a high-temperature and high-pressure state. Further, by injecting fuel and water into the cylinder in a high-temperature and high-pressure state, a part of injected fuel reacts with water while absorbing heat from around the fuel, and is converted to hydrogen and carbon monoxide (a steam reforming reaction). Note that hydrogen and carbon monoxide have high enthalpy, as compared with fuel (gasoline) before reforming. When reformed fuel having high enthalpy as described above is combusted in an expansion stroke, a larger amount of heat is generated accompanied by the combustion. Therefore, as compared with a case where fuel is not reformed, work (expansion work) of pushing down the piston increases. This means that a part of heat (waste heat), which is supposed to be discharged from the cylinder, is extracted as work, in other words, waste heat recovery is carried out. Specifically, it is possible to improve the indicated efficiency i.e. a ratio at which energy supplied as fuel is converted to work, by the waste heat recovery. In addition to the above, fuel is reformed within the cylinder. Therefore, for instance, unlike a case where fuel is reformed on the outside of the cylinder, and the reformed fuel is introduced into the cylinder, it is possible to combust basically the whole amount of reformed fuel within the cylinder, and to efficiently extract work by using the combustion energy. Furthermore, heat is absorbed accompanied by progress of a reforming reaction. Therefore, it is possible to suppress an increase in the cylinder temperature during the negative overlap period, and to reduce cooling loss of the engine. As described above, in the present invention, it is possible to improve the indicated efficiency by waste heat recovery, and to reduce cooling loss. This is advantageous in improving fuel economy of the engine. Preferably, during the operation in the low load range, the fuel injection control module may control to inject fuel from the fuel injection valve at a same time as water injection from the water injection valve or at a time later than water injection from the water injection valve. According to the aforementioned configuration, it is possible to supply a sufficient amount of water into the cylinder before a fuel reforming reaction starts. This is advantageous in promoting the fuel reforming reaction. In the aforementioned configuration, more preferably, during the operation in the low load range, the water injection control module may control to inject water from the water injection valve at a point of time when a temperature within the cylinder is increased to a temperature included in a temperature range where a low temperature oxidation reaction of fuel occurs, or to a temperature exceeding the temperature range. Specifically, the timing of water injection in this case may be a timing included in a former part of the negative overlap period and included in a period when a temperature within the cylinder is from 500 to 700° C., wherein the former part is a period from a closing timing of the exhaust valve to the exhaust top dead center. As described above, in a case where water is injected after the cylinder temperature is increased to a temperature included in the temperature range (the low temperature oxidation reaction range) where the low temperature oxidation reaction of fuel occurs, or to a temperature exceeding the temperature range, for instance, unlike a case where water is injected in an initial stage of the negative overlap period, it is possible to suppress that an increase in the cylinder temperature may be obstructed by water injection, and to efficiently increase the cylinder temperature. Specifically, in an initial stage of the negative overlap period, the piston is lifted at a relatively high speed within the cylinder in a sealed state. Therefore, the cylinder temperature is rapidly increased accompanied by lifting (compression) of the piston. However, when it is assumed that water injection is performed in a period when the cylinder temperature is likely to increase as described above, a temperature increase may be obstructed by absorption of latent heat by injected water, and the cylinder temperature may not be increased to a sufficiently high level. On the other hand, in the aforementioned configuration, water is injected at a point of time when the cylinder temperature is increased to a sufficiently high temperature in the low temperature oxidation reaction range or to a temperature exceeding the low temperature oxidation reaction range. This makes it possible to efficiently increase the cylinder temperature in an initial stage of the negative overlap period, and to realize a cylinder environment where the inside of the cylinder is brought to a high-temperature and high-pressure state necessary for reforming fuel with a high probability. Preferably, during the operation in the low load range, the valve control module may control to open and close the intake valve and the exhaust valve via the valve variable mechanism in such a manner that a crank angle range from the exhaust top dead center to an opening timing of the intake valve is larger than a crank angle range from a closing timing of the exhaust valve to the exhaust top dead center. As described above, in a case where the latter part of the negative overlap period (the crank angle range from the exhaust top dead center to the opening timing of the intake valve) is set longer than the former part of the negative overlap period (the crank angle range from the closing timing of the exhaust valve to the exhaust top dead center), it is possible to efficiently prevent that gas containing fuel within the cylinder may flow back to an intake port accompanied by opening of the intake valve. Specifically, in the present invention, fuel and water are injected during the negative overlap period. In other words, the amount of gas within the cylinder is increased. When it is assumed that the former part and the latter part of the negative overlap period are set equal to each other, the cylinder pressure is high at the end of the negative overlap period (at the opening timing of the intake valve), as compared with the start of the negative overlap period (at the closing timing of the exhaust valve). This may cause a phenomenon such that gas within the cylinder flows back to the intake port immediately after the intake valve is opened. This may lead to reduction of the amount of fuel existing in the cylinder. On the other hand, in the aforementioned configuration, in which the latter part is set longer than the former part of the negative overlap period, it is possible to prevent a phenomenon such that gas may flow back to the intake port as described above. This makes it possible to secure fuel of an intended amount within the cylinder, and to generate a sufficient output torque. Preferably, the direct injection engine may further include a water supply device configured to supply water to the water injection valve while heating and pressurizing the water. During the operation in the low load range, the water injection valve may be operative to inject water of a temperature of 100° C. or higher and a pressure of 5 MPa or higher supplied from the water supply device. As described above, in a case where relatively high-temperature and high-pressure water is injected from the water injection valve, it is possible to inject water, without hindrance, into the cylinder in a high-pressure state during the negative overlap period. Further, it is possible to suppress lowering of the cylinder temperature accompanied by the water injection. This makes it possible to prevent obstruction of a fuel reforming reaction by temperature lowering. A geometric compression ratio of the cylinder may be preferably set to be not smaller than 16 but not larger than 30. According to the aforementioned configuration, it is possible to secure a stroke amount (a compression amount) of the piston during the period from the closing timing of the exhaust valve to the exhaust top dead center, without excessively increasing the negative overlap period, and to sufficiently increase the cylinder temperature during the negative overlap period. This makes it possible to securely reform fuel within the cylinder in a high-temperature state during the negative overlap period, while avoiding an excessive reduction of the amount of intake air to be introduced into the cylinder. Preferably, the direct injection engine may further include a spark plug configured to discharge spark in a latter stage of a compression stroke or in an initial stage of an expansion stroke to ignite fuel within the cylinder. During the operation in the low load range, the valve control module may control to close the intake valve via the valve variable mechanism at a timing when an effective compression ratio capable of performing SPCCI combustion is achieved, the SPCCI combustion being such that after a flame kernel is formed within the cylinder by forcible ignition due to the spark ignition, fuel around the flame kernel is self-ignited. According to the aforementioned configuration, it is possible to perform combustion with enhanced thermal efficiency and with high controllability by using characteristics of reformed fuel containing hydrogen and carbon monoxide. Specifically, hydrogen contained in reformed fuel has characteristics such that the flame propagation speed is high, as compared with fuel (gasoline) before reforming. Therefore, performing spark ignition with respect to reformed fuel containing hydrogen having the aforementioned characteristics makes it possible to speedily and securely form a flame kernel. When a flame kernel is formed, fuel around the flame kernel is self-ignited in a multiple simultaneous manner by a high-temperature and high-pressure treatment within the cylinder accompanied by formation of the flame kernel. This makes it possible to complete combustion in a short period, and to perform combustion with less exhaust loss and with enhanced thermal efficiency. In addition to the above, it is possible to control the timing when fuel is self-ignited by spark ignition. This makes it easy to obtain an intended combustion pattern for each operating condition, and to enhance combustion controllability. As described above, in the engine in which SPCCI combustion is performed during the operation in the low load range, it is preferable to reform 40 to 60% of fuel injected into the cylinder. Specifically, preferably, during the operation in the low load range, the fuel injection control module may control to inject fuel from the fuel injection valve at a timing when a fuel reforming rate is from 40 to 60%, wherein the fuel reforming rate is a ratio of fuel that turns to hydrogen and carbon monoxide with respect to fuel injected within the cylinder. This application is based on Japanese Patent Application No. 2016-172755 filed on Sep. 5, 2016, the contents of which are hereby incorporated by reference. Although the present invention has been fully described by way of example with reference to the accompanying drawings, it is to be understood that various changes and modifications will be apparent to those skilled in the art. Therefore, unless otherwise such changes and modifications depart from the scope of the present invention hereinafter defined, they should be construed as being included therein.
<SOH> BACKGROUND ART <EOH>As an engine configured to combust reformed fuel as described above, there is known an engine disclosed in Japanese Unexamined Patent Publication No. 2010-25031. The engine disclosed in Japanese Unexamined Patent Publication No. 2010-25031 includes a cylinder, an intake passage and an exhaust passage connected to the cylinder, an injector configured to inject fuel to a downstream end (an intake port) of the intake passage, a reforming chamber formed at a midway of the exhaust passage, a reforming catalyst disposed in the reforming chamber, an exhaust gas inlet passage for connecting between the reforming chamber and the exhaust passage on the upstream side of the reforming chamber, a reformed gas inlet pipe for connecting between the reforming chamber and the intake passage, and a water injection nozzle and a fuel supply device mounted to the exhaust gas inlet passage. Water injected from the water injection nozzle and fuel supplied from the fuel supply device react each other while undergoing an endothermic reaction during passing through the reforming chamber (the reforming catalyst), and turn to hydrogen and carbon monoxide (a steam reforming reaction). Reformed fuel containing hydrogen and carbon monoxide, in other words, reformed gas is introduced into the intake passage through the reformed gas inlet pipe, and is introduced into the cylinder (the combustion chamber) after being mixed with fuel injected from the injector. Reformed gas containing hydrogen and carbon monoxide has a high lean limit, as compared with fuel before reforming, and a calorific value of reformed gas is high. Therefore, an effect of improving fuel economy of an engine is expected by introducing fuel containing reformed gas into a cylinder for combustion. In the engine disclosed in Japanese Unexamined Patent Publication No. 2010-25031, however, fuel is reformed in the reforming chamber formed at a midway of the exhaust passage, and reformed fuel, in other words, reformed gas is introduced into the cylinder through the reformed gas inlet pipe. This may make it difficult to introduce the entirety of reformed gas into the cylinder. For instance, a part of reformed gas may flow into another path (an exhaust passage on the downstream side of the reforming chamber) other than the introduction path to the cylinder, or unreformed fuel may adhere and remain in the exhaust passage or on an inner wall of the reforming chamber. When the aforementioned condition occurs, only a part of reformed gas is used for combustion. This may offset the effect by reforming fuel, and may make it difficult to obtain a sufficient effect of improving fuel economy.
<SOH> SUMMARY OF INVENTION <EOH>In view of the above, an object of the present invention is to provide a direct injection engine and a control method thereof, which enable to improve fuel economy of the engine by using reformed fuel without waste. A direct injection engine according to an aspect of the present invention includes a cylinder configured to accommodate a piston to be reciprocally movable; a fuel injection valve configured to inject fuel containing gasoline into the cylinder; a water injection valve configured to inject water into the cylinder; an intake valve configured to open and close an intake port for introducing air into the cylinder; an exhaust valve configured to open and close an exhaust port for discharging combusted gas from the cylinder; a valve variable mechanism configured to change an operation timing of each of the intake valve and the exhaust valve; a fuel injection control module configured to control the fuel injection valve; a water injection control module configured to control the water injection valve; a valve control module configured to control the valve variable mechanism; and a calculation module configured to perform various calculations based on an operating condition of the engine. During an operation in a low load range where a load of the engine is lower than a predetermined load, the valve control module controls the valve variable mechanism in such a manner that a negative overlap period when both of the intake valve and the exhaust valve are closed across an exhaust top dead center is formed. During the operation in the low load range, the calculation module determines, as an injection timing of fuel by the fuel injection valve and an injection timing of water by the water injection valve, an injection timing when a steam reforming reaction occurs within the cylinder during the negative overlap period, the steam reforming reaction being such that at least a part of injected fuel and injected water turns to hydrogen and carbon monoxide. During the operation in the low load range, the fuel injection control module and the water injection control module respectively control to inject fuel from the fuel injection valve and control to inject water from the water injection valve at a timing within the negative overlap period determined by the calculation module. Further, a control method according to another aspect of the present invention is applied to a direct injection engine provided with a cylinder configured to accommodate a piston to be reciprocally movable, a fuel injection valve configured to inject fuel containing gasoline into the cylinder, a water injection valve configured to inject water into the cylinder, an intake valve configured to open and close an intake port for introducing air into the cylinder, an exhaust valve configured to open and close an exhaust port for discharging combusted gas from the cylinder, and a valve variable mechanism configured to change an operation timing of each of the intake valve and the exhaust valve. The control method includes, during an operation in a low load range where a load of the engine is lower than a predetermined load, controlling the valve variable mechanism in such a manner that a negative overlap period when both of the intake valve and the exhaust valve are closed across an exhaust top dead center is formed; determining, as an injection timing of fuel by the fuel injection valve and an injection timing of water by the water injection valve, an injection timing when a steam reforming reaction occurs within the cylinder during the negative overlap period, the steam reforming reaction being such that at least a part of injected fuel and injected water turns to hydrogen and carbon monoxide; and controlling to inject fuel from the fuel injection valve and to inject water from the water injection valve respectively at a timing within the negative overlap period determined by the determination. These and other objects, features and advantages of the present invention will become more apparent upon reading the following detailed description along with the accompanying drawings.
F02D413094
20170825
20180308
64397.0
F02D4130
0
STAUBACH, CARL C
DIRECT INJECTION ENGINE AND CONTROL METHOD THEREOF
UNDISCOUNTED
0
ACCEPTED
F02D
2,017
15,686,875
PENDING
EXERCISE SYSTEM AND METHOD
An exercise machine includes a processor, a first display, a deck, and a belt rotatable about the deck. The machine also includes a sensor operably connected to the processor and configured to detect a first performance parameter of a first user running on the belt of the exercise machine. The processor is configured to receive information indicative of a second performance parameter of a second user, the second performance parameter being detected at an additional exercise machine during display of the at least part of the exercise class on a display associated with the additional exercise machine. The processor is also configured to cause the second performance parameter to be displayed on the first display together with the first performance parameter.
1. A method, comprising: providing information about available exercise classes to a processor associated with a first exercise machine, the first exercise machine being located at a first remote location; receiving, from a first user of the first exercise machine and via the processor, a selection of one of the available exercise classes; providing, via a network and to the processor, digital content comprising the one of the available exercise classes; receiving, via the network, a first plurality of performance parameters detected at the first exercise machine during display of at least part of the one of the available exercise classes on a display associated with the first exercise machine, the at least part of the one of the available exercise classes requiring participants to run on a treadmill; receiving, via the network, a second plurality of performance parameters detected at a second exercise machine during display of the at least part of the one of the available exercise classes on a display associated with the second exercise machine, the second exercise machine being located at a second remote location different from the first remote location; providing, via the network, at least one parameter of the second plurality of performance parameters to the processor, wherein the processor is configured to cause the at least one parameter of the second plurality of performance parameters to be displayed on the display associated with the first exercise machine together with a corresponding at least one parameter of the first plurality of performance parameters. 2. The method of claim 1, wherein the first and second exercise machines comprise treadmills, and the one of the available exercise classes comprises a running class performed by an instructor at least partially on a treadmill. 3. The method of claim 2, wherein the one of the available exercise classes comprises a live class streamed to the first and second exercise machines substantially in real-time. 4. The method of claim 1, wherein the first plurality of performance parameters includes at least one of a speed of a belt associated with a deck of the first exercise machine, an incline of the deck, and a mile pace of the first user. 5. The method of claim 1, wherein the at least one parameter of the first plurality of performance parameters comprises an amount of energy expended by the first user while running during the at least part of the one of the available exercise classes, and wherein the amount of energy is determined based at least partly on a speed of a belt associated with a deck of the first exercise machine, and an incline of the deck. 6. The method of claim 1, further comprising providing, via the network, video chat data to the processor associated with the first exercise machine, wherein the processor is configured to cause the video chat data to be displayed on the display associated with the first exercise machine, in substantially real-time, together with the one of the available exercise classes. 7. The method of claim 1, further comprising: receiving, via the network, video chat data from the processor associated with the first exercise machine, and providing, via the network, the video chat data to a processor associated with the second exercise machine, wherein the processor associated with the second exercise machine is configured to cause the video chat data to be displayed on the display associated with the second exercise machine together with the one of the available exercise classes. 8. The method of claim 1, wherein the processor associated with the first exercise machine is configured to cause the at least one parameter of the second plurality of performance parameters to be displayed on the display associated with the first exercise machine together with the at least part of the one of the available exercise classes. 9. An exercise machine, comprising: a processor; a first display operably connected to the processor and configured to display content; a deck configured to move relative to a surface supporting the exercise machine; a belt rotatable about the deck; and a sensor operably connected to the processor, the sensor being configured to detect a first performance parameter of a first user running on the belt of the exercise machine during display of at least part of an exercise class on the first display, wherein the processor is configured to: receive, via a network, information indicative of a second performance parameter of a second user, the second performance parameter being detected at an additional exercise machine during display of the at least part of the exercise class on a display associated with the additional exercise machine, the additional exercise machine being located at location remote from the exercise machine, and cause the second performance parameter to be displayed on the first display together with the first performance parameter. 10. The exercise machine of claim 9, wherein the processor is further configured to: receive, via the network and from a server, information about a plurality of available exercise classes, the plurality of exercise classes including the exercise class; cause the first display to display the information; and receive, from the first user and via the display, an input indicating selection of the exercise class. 11. The exercise machine of claim 10, wherein the processor is further configured to: request digital content comprising the exercise class, from the server and via the network, at least partly in response to the input, the exercise class comprising a running class performed by an instructor at least partially on a treadmill. 12. The exercise machine of claim 9, wherein the sensor is configured to detect at least one of a speed of the belt and an incline of the deck relative to the support surface, and wherein the processor is configured to: determine an amount of energy expended by the first user while running during the at least part of the exercise class, and cause the amount of energy to be displayed on the first display together with the at least part of the exercise class. 13. The exercise machine of claim 9, wherein the processor is configured to cause the first display to display a segmented timeline together with the at least part of the exercise class, the segmented timeline including: a first segment corresponding to the at least part of the exercise class, and a first visual indicia indicating that the first user is to run during the at least part of the exercise class. 14. The exercise machine of claim 13, wherein the segmented timeline includes: a second segment corresponding to an additional part of the exercise class, and a second visual indicia indicating that the first user is to lift a weight during the additional part of the exercise class. 15. The exercise machine of claim 9, wherein the processor is configured to cause the first display to display a leaderboard together with the at least part of the exercise class, the leaderboard indicating: a plurality of additional users associated with the exercise class, a respective rank of each user of the plurality of additional users, and a respective amount of energy expended by each user of the plurality of additional users. 16. The exercise machine of claim 9, wherein the sensor is configured to detect a load applied to at least one of the belt, the deck, and a motor configured to drive rotation of the belt, and wherein the processor is configured to: determine, based at least partly on the load, that the first user has stepped off of the belt during the at least part of the exercise class, and cause a notification to be displayed on the first display together with the at least part of the exercise class, the notification indicating that the first user has stepped off of the belt. 17. A method, comprising: causing at least part of an exercise class to be displayed on a first display associated with a first treadmill; receiving information indicative of a first performance parameter detected by a sensor associated with the first treadmill, the first performance parameter being associated with a first user running on a belt of the first treadmill during display of the at least part of the exercise class on the first display; receiving, via a network, information indicative of a second performance parameter associated with a second user, the second performance parameter being detected at a second treadmill during display of the at least part of the exercise class on a second display associated with the second treadmill, the second treadmill being located at location remote from the first treadmill; and causing the second performance parameter to be displayed on the first display together with the first performance parameter. 18. The method of claim 17, further comprising: receiving a first input from the first user during display of the at least part of the exercise class on the first display, the first input being indicative of a request to change an incline of a deck of the first treadmill, the first treadmill including a belt rotatably connected to the deck; and activating a first motor located substantially internal to the deck at least partly in response to the first input. 19. The method of claim 18, further comprising: receiving a second input from the first user during display of the at least part of the exercise class on the first display, the second input being indicative of a request to change a speed of the belt, the belt comprising a plurality of lateral slats; and activating a second motor located substantially internal to the deck at least partly in response to the second input. 20. The method of claim 17, further comprising: determining an amount of energy expended by the first user while running during the at least part of the exercise class; and causing the amount of energy to be displayed on the first display together with the at least part of the exercise class, and a segmented timeline, the segmented timeline including a first segment corresponding to the at least part of the exercise class, and a first visual indicia indicating that the first user is to run during the at least part of the exercise class.
CROSS-REFERENCE TO RELATED APPLICATIONS This application is a nonprovisional of U.S. Provisional Application No. 62/380,412, filed Aug. 27, 2016, the entire disclosure of which is incorporated herein by reference. FIELD OF THE INVENTION This application relates generally to the field of exercise equipment and methods associated therewith. In particular, this application relates to an exercise system and method configured to provide streaming and on-demand exercise classes to one or more users. BACKGROUND Humans are competitive by nature, striving to improve their performance both as compared to their own prior efforts and as compared to others. Humans are also drawn to games and other diversions, such that even tasks that a person may find difficult or annoying can become appealing if different gaming elements are introduced. Existing home and gym-based exercise systems and methods frequently lack key features that allow participants to compete with each other, converse with each other, and that gamify exercise activities. While some existing exercise equipment incorporates diversions such as video displays that present content or performance data to the user while they exercise, these systems lack the ability to truly engage the user in a competitive or gaming scenario that improves both the user's experience and performance. Such systems also lack the ability to facilitate real-time sharing of information, conversation, data, and/or other content between users, as well as between an instructor and one or more users. To improve the experience and provide a more engaging environment, gyms offer exercise classes such as aerobics classes, yoga classes, or other classes in which an instructor leads participants in a variety of exercises. Such class-based experiences, however, are accessible only at specific times and locations. As a result, they are unavailable to many potential users, generally are very expensive, and often sell-out so that even users in a location convenient to the gym cannot reserve a class. Example embodiments of the present disclosure address these problems, providing an exercise machine, embodied by an example treadmill, that incorporates multimedia inputs and outputs for live streaming or archived instructional content, socially networked audio and video chat, networked performance metrics and competition capabilities, along with a range of gamification features. SUMMARY OF THE INVENTION In an example embodiment of the present disclosure, a method includes providing information about available exercise classes to a processor associated with a first exercise machine, the first exercise machine being located at a first remote location, receiving, from a first user of the first exercise machine and via the processor, a selection of one of the available exercise classes, and providing, via a network and to the processor, digital content comprising the one of the available exercise classes. Such an example method also includes receiving, via the network, a first plurality of performance parameters detected at the first exercise machine during display of at least part of the one of the available exercise classes on a display associated with the first exercise machine, the at least part of the one of the available exercise classes requiring participants to run on a treadmill. Such an example method further includes receiving, via the network, a second plurality of performance parameters detected at a second exercise machine during display of the at least part of the one of the available exercise classes on a display associated with the second exercise machine, the second exercise machine being located at a second remote location different from the first remote location. The method also includes providing, via the network, at least one parameter of the second plurality of performance parameters to the processor. In such methods, the processor is configured to cause the at least one parameter of the second plurality of performance parameters to be displayed on the display associated with the first exercise machine together with a corresponding at least one parameter of the first plurality of performance parameters. In another example embodiment of the present disclosure, an exercise machine includes a processor, a first display operably connected to the processor and configured to display content, a deck configured to move relative to a surface supporting the exercise machine, and a belt rotatable about the deck. Such an example exercise machine also includes a sensor operably connected to the processor. The sensor is configured to detect a first performance parameter of a first user running on the belt of the exercise machine during display of at least part of an exercise class on the first display. In such embodiments, the processor is configured to receive, via a network, information indicative of a second performance parameter of a second user, the second performance parameter being detected at an additional exercise machine during display of the at least part of the exercise class on a display associated with the additional exercise machine, the additional exercise machine being located at location remote from the exercise machine. In such embodiments, the processor is also configured to cause the second performance parameter to be displayed on the first display together with the first performance parameter. In a further example embodiment of the present disclosure, a method includes causing at least part of an exercise class to be displayed on a first display associated with a first treadmill, and receiving information indicative of a first performance parameter detected by a sensor associated with the first treadmill, the first performance parameter being associated with a first user running on a belt of the first treadmill during display of the at least part of the exercise class on the first display. Such an example method also includes receiving, via a network, information indicative of a second performance parameter associated with a second user, the second performance parameter being detected at a second treadmill during display of the at least part of the exercise class on a second display associated with the second treadmill, the second treadmill being located at location remote from the first treadmill. Such a method further includes causing the second performance parameter to be displayed on the first display together with the first performance parameter. BRIEF DESCRIPTION OF THE DRAWINGS The detailed description is described with reference to the accompanying figures. In the figures, the left-most digit of a reference number identifies the figure in which the reference number first appears. The same reference numbers in different figures indicate similar or identical items. FIG. 1 is a rear perspective view of an exemplary exercise machine as disclosed herein with a user shown. FIG. 2 is a rear perspective view of another exemplary exercise machine as disclosed herein. FIG. 3 is a rear perspective view of a portion of a further exemplary exercise machine as disclosed herein. FIG. 4 is a rear perspective view of still another exemplary exercise machine as disclosed herein with a user shown. FIG. 5 is an illustration showing an exemplary exercise machine as disclosed herein including illustrations of exemplary information displayed on a display screen, a personal digital device, as well as weights and other accessory devices. FIG. 6 is a rear view of yet another exemplary exercise machine as disclosed herein. FIG. 7 is a rear perspective view of still another exemplary exercise machine as disclosed herein with a user shown. FIG. 8 is an illustration of an exemplary user interface of the present disclosure. FIG. 9 is a schematic illustration showing exemplary components used for content creation and/or distribution. FIG. 10 is a schematic illustration of a basic network architecture according to an example embodiment of the present disclosure. FIG. 11 illustrates a chart showing an example embodiment of a method for synchronizing data among different users participating in the same live or on-demand exercise class. FIG. 12 illustrates an example user interface of the present disclosure including information related to featured exercise classes. FIG. 13 illustrates another example user interface of the present disclosure including information related to featured exercise classes. FIG. 14 illustrates a further example user interface of the present disclosure including information related to a class library. FIG. 15 illustrates another example user interface of the present disclosure including information related to a selected exercise class. FIG. 16 illustrates still another example user interface of the present disclosure showing an exercise class and a scorecard. FIG. 17 illustrates yet another example user interface of the present disclosure showing an exercise class and a scorecard. FIG. 18 illustrates a further example user interface of the present disclosure showing an exercise class and a leaderboard. FIG. 19 illustrates another example user interface of the present disclosure including information related to a just run user experience. FIG. 20 illustrates still another example user interface of the present disclosure including information related to scenic running paths associated with the just run user experience. FIG. 21 illustrates yet another example user interface of the present disclosure including information related to competitions associated with the just run user experience. FIG. 22 illustrates a further example user interface of the present disclosure including performance information associated with a particular exercise class. FIG. 23 illustrates another example user interface of the present disclosure including performance information associated with a particular exercise class. FIG. 24 illustrates still another example user interface of the present disclosure including performance information associated with a particular exercise class. FIG. 25 illustrates an exercise machine according to still another example embodiment of the present disclosure. FIG. 26 illustrates an exploded view of the example exercise machine shown in FIG. 25. FIG. 27 illustrates a belt associated with the example exercise machine shown in FIG. 25. FIG. 28 illustrates a slat associated with the example exercise machine shown in FIG. 25. FIG. 29 illustrates another view of the example exercise machine shown in FIG. 25 including one or more sensors and one or more controls. FIG. 30 illustrates a control architecture associated with the example exercise machine shown in FIG. 25. FIG. 31 illustrates an exploded view of a rotary control associated with the example exercise machine shown in FIG. 25. FIG. 32 illustrates another view of the example exercise machine shown in FIG. 25 including first and second rotary controls. FIG. 33 illustrates an exploded view of a substantially linear control associated with the example exercise machine shown in FIG. 25. FIG. 34 illustrates another view of the example exercise machine shown in FIG. 25 including first and second substantially linear controls. FIG. 35 illustrates a portion of the example exercise machine shown in FIG. 25 including a substantially linear control. DETAILED DESCRIPTION The following description is presented to enable any person skilled in the art to make and use aspects of the example embodiments described herein. For purposes of explanation, specific nomenclature is set forth to provide a thorough understanding of the present invention. Descriptions of specific embodiments or applications are provided only as examples. Various modifications to the embodiments will be readily apparent to those skilled in the art, and general principles defined herein may be applied to other embodiments and applications without departing from the spirit and scope of the present disclosure. Thus, the present disclosure is not intended to be limited to the embodiments shown, but is to be accorded the widest possible scope consistent with the principles and features disclosed herein. Example embodiments of the present disclosure include networked exercise systems and methods whereby one or more exercise devices, such as treadmills, rowing machines, stationary bicycles, elliptical trainers, or any other suitable equipment, may be equipped with an associated local system that allows a user to fully participate in live instructor-led or recorded exercise classes from any location that can access a suitable communications network. The networked exercise systems and methods may include backend systems with equipment including without limitation servers, digital storage systems, and other hardware as well as software to manage all processing, communications, database, and other functions. The networked exercise systems and methods may also include one or more studio or other recording locations with cameras, microphones, and audio and/or visual outputs where one or more instructors can lead exercise classes and in some embodiments where live exercise classes can be conducted, and where such live and previously recorded classes can be distributed via the communications network. In various embodiments there may be a plurality of recording locations that can interact with each other and/or with any number of individual users. In various embodiments, the example exercise systems and machines describe herein provide for full interactivity in all directions. Whether remote or in the same location, instructors may be able to interact with users, users may be able to interact with instructors, and users may be able to interact with other users. Through the disclosed networked exercise systems and machines, instructors may be able to solicit feedback from users, and users may be able to provide feedback to the instructor, vote or express opinions on different choices or options, and communicate regarding their experience. Such example exercise systems and machines allow for interaction through all media, including one or more video channels, audio including voice and/or music, and data including a complete range of performance data, vital statistics, chat, voice, and text-based and other communications. In various embodiments, the exercise systems and machines described herein also allow an unlimited number of remote users to view and participate in the same live or recorded content simultaneously, and in various embodiments they may be able to interact with some or all of the other users viewing same content. Remote users can participate in live exercise classes offered from any available remote recording location, or they can access previously recorded classes archived in the system database. In various embodiments, a plurality of remote users can simultaneously access the same recorded class and interact with each other in real time, or they can access the same recorded class at different times and share data and communications about their performance or other topics. Thus, the networked exercise systems and machines, and the corresponding methods described herein, provide for content creation, content management and distribution, and content consumption. Various aspects of such exercise systems and machines, and the potential interactions between such machines, will now be described in more detail. Exercise Machine Referring generally to FIGS. 1 through 7 and FIGS. 25-35, in various example embodiments of the present disclosure, a local system 100 may include an exercise machine 102, such as a treadmill, with integrated or connected digital hardware including one or more displays 104 for use in connection with an instructor lead exercise class and/or for displaying other digital content. While the exercise machine 102 may be described and/or otherwise referred to herein as a “treadmill 102,” as noted above, example exercise machines of the present disclosure may be any suitable type of exercise machine, including a rowing machine, stationary bicycle, elliptical trainer, stair climber, etc. In various example embodiments, the one or more displays 104 may be mounted directly to the exercise machine 102 or otherwise placed within view of a user 106. In various exemplary embodiments, the one or more displays 104 allow the user 106 to view content relating to a selected exercise class both while working out on the exercise machine 102 and while working out in one or more locations near or adjacent to the exercise machine 102. As will be described in greater detail below, the exercise machine 102 may also include a hinge, joint, pivot, bracket or other suitable mechanism to allow for adjustment of the position or orientation of the display 104 relative to the user 106 whether they are using the exercise machine 102 or working out near or adjacent to the exercise machine 102. In example embodiments, the exercise machine 102 may generally include a lower assembly 108 and an upper assembly 110. The lower assembly 108 may generally include a deck 112 of the exercise machine 102 that provides support for the user 106 while the use is working out on the exercise machine 102, as well as other components of bot the lower assembly 108 and the upper assembly 110. For example, as shown in at least the exploded view of FIG. 26, the deck 112 may support a first motor 114 of the exercise machine 102 configured to increase, decrease, and/or otherwise change an incline of the deck 112 relative to a support surface on which the exercise machine 102 is disposed. The deck 112 may also include one or more linkages 116 coupled to the motor 114 and configured to, for example, raise and lower the deck 112 by acting on the support surface when the motor 114 is activated. The deck 112 may also include a second motor 118 configured to increase, decrease, and/or otherwise change a rotational speed of a belt 120 connected to the deck 112. The belt 120 may be rotatable relative to the deck 112 and, in particular, may be configured to revolve or otherwise move completely around (i.e., encircle) the deck 112 during use of the exercise machine 120. For example, in embodiments in which the exercise machine 102 comprises a treadmill, the belt 120 may support the user 106 and may repeatedly encircle the deck 112 as the user 106 runs, walks, and/or otherwise works out on the treadmill. Such an example belt 120 may include one or more continuous tracks 122 movably coupled to a gear, flywheel, pulley, and/or other member 124 of the deck 112, and such a member 124 may be coupled to an output shaft or other component of the motor 118. In such examples, rotation of the output shaft or other component of the motor 118 may drive commensurate rotation of the member 124. Likewise, rotation of the member 124 may drive commensurate revolution of the one or more continuous tracks 122 and/or the belt 120 generally. The belt 120 may also include a plurality of laterally aligned slats 126 connected to the one or more continuous tracks 122. For example, as shown in FIGS. 27 and 28, each slat 126 may extend substantially parallel to at least one adjacent slat 126. Additionally, each slat 126 may be hingedly, pivotally, and/or otherwise movably coupled to the one or more continuous tracks 122 via one or more respective couplings 140. Such couplings 140 may comprise, for example, a bracket, pin, screw, clip, bolt, and/or one or more other fastening components configured to secure a respective slat 126 to the continuous track 122 while allowing the slat 126 to pivot, rotate, and/or otherwise move relative to the track 122 while the belt 120 revolves about the deck 112. As shown in at least FIG. 28, each slat 126 may also include a top pad 142 coupled thereto. The top pad 142 may comprise a plastic, rubber, polymeric, and/or other type of non-slip pad configured to reduce and/or substantially eliminate slipping of the user 106 when the user is running, walking, and/or otherwise exercising on the exercise machine 102. Such a top pad 142 may also reduce the impact associated with walking and/or running on the exercise machine 102, and may thus improve the comfort of the user 106 during various exercise classes associated with the exercise machine 102. With continued reference to FIG. 26, the exercise machine 102 may also include one or more sidewalls 128 connected to the deck 112. For example, the exercise machine 102 may include a first sidewall 128 on a left hand side of the deck 112, and a second sidewall 128 on the right hand side of the deck 112. Such sidewalls 128 may be made from cloth, foam, plastic, rubber, polymers, and/or other like material, and in some examples, the sidewalls 128 may assist in damping and/or otherwise reducing noise generated by one or more of the motors 114, 118 and/or other components of the deck 112. The exercise machine 102 may also include one or more posts 130 extending upwardly from the deck 112. For example, the exercise machine 102 may include a first post 130 on the left hand side of the deck 112, and a second post 130 on the right hand side of the deck 112. Such posts 130 may be made from a metal, alloy, plastic, polymer, and/or other like material, and similar such materials may be used to manufacture the deck 112, the slats 126, and/or other components of the exercise machine 102. In such examples, the posts 130 may be configured to support the display 104, and in some examples, the display 104 may be directly coupled to a crossbar 132 of the exercise machine 102, and the crossbar 132 may be connected to and/or otherwise supported by the posts 130. For example, the crossbar 132 may comprise one or more hand rests or handles useful in supporting the user 106 during exercise. In some examples, the crossbar 132 may be substantially C-shaped, substantially U-shaped, and/or any other configuration. In any of the examples described herein, the crossbar 132 may extend from a first one of the posts 130 to a second one of the posts 130. Further, in some examples, the posts 130 and the crossbar 132 may comprise a single integral component of the upper assembly 110. Alternatively, in other examples, the posts 130 and the crossbar 132 may comprise separate components of the upper assembly 110. In such examples, the upper assembly 110 may include one or more brackets 134, endcaps 136, and/or additional components configured to assist in coupling the one or more posts 130 to the crossbar 132. As noted above, the exercise machine 102 may also include a hinge, joint, pivot, bracket 138 and/or other suitable mechanism to allow for adjustment of the position or orientation of the display 104 relative to the user 106 whether they are using the exercise machine 102 or working out near or adjacent to the exercise machine 102. For example, such brackets 138 may include at least one component rigidly connected to the crossbar 132. Such brackets 138 may also include one or more additional components rigidly coupled to the display 104. In such examples, the components of the bracket 138 connected to the display 104 may be moveable, with the display 104 relative to the components of the bracket 138 connected to the crossbar 132. Such components may include one or more dove-tail slider mechanism, channels, and/or other components enabling the display 104 to controllably slide and/or otherwise move relative to the crossbar 132. Such components may also enable to the user 106 to fix the position of the display 104 relative to the crossbar 132 once the user 106 has positioned the display 104 as desired. As shown in at least FIG. 29, the exercise machine 102 may also include one or more controls 144, 146 configured to receive input from the user 106. The exercise machine 102 may further include one or more sensors 147 configured to sense, detect, and/or otherwise determine one or more performance parameters of the user 106 before, during, and/or after the user 106 participates in an exercise class using the exercise machine 102. In any of the examples described herein, the controls 144, 146 and the one or more sensors 147 may be operably and/or otherwise connected to one or more controllers, processors, and/or other digital hardware 148 of the exercise machine 102. The digital hardware 148 associated with the exercise machine 102 may be connected to or integrated with the exercise machine 102, or it may be located remotely and wired or wirelessly connected to the exercise machine 102. The digital hardware 148 may include digital storage, one or more processors or other like computers or controllers, communications hardware, software, and/or one or more media input/output devices such as displays, cameras, microphones, keyboards, touchscreens, headsets, and/or audio speakers. In various exemplary embodiments these components may be connected to and/or otherwise integrated with the exercise machine 102. All communications between and among such components of the digital hardware 148 may be multichannel, multi-directional, and wireless or wired, using any appropriate protocol or technology. In various exemplary embodiments, the digital hardware 148 of the exercise machine 102 may include associated mobile and web-based application programs that provide access to account, performance, and other relevant information to users from local or remote exercise machines, processors, controllers, personal computers, laptops, mobile devices, or any other digital device or digital hardware. In any of the examples described herein, the one or more controllers, processors, and/or other digital hardware 148 associated with the exercise machine 102 may be operable to perform one or more functions associated with control logic 150 of the exercise machine 102. Such control logic 150 is illustrated schematically in at least FIG. 30, and such control logic 150 may comprise one or more rules, programs, or other instructions stored in a memory of the digital hardware 148. For example, one or more processors included in the digital hardware 148 may be programmed to perform operations in accordance with rules, programs, or other instructions of the control logic 150, and such processors may also be programmed to perform one or more additional operations in accordance with and/or at least partly in response to input received via one or more of the controls 144, 146 and/or via one or more of the sensors 147. As shown in FIGS. 31 and 32, one or more such controls 144, 146 may comprise an infinity wheel-type control 144. Such a control may be useful in changing and/or otherwise controlling, for example, the incline of the deck 112, the speed of the belt 120, and/or other operations of the exercise machine 102 associated with incremental increases or decreases. In an example embodiment, such a control 144 may include a rotary dial 152 connected to a corresponding rotary encode 154. In such examples, the rotary encoder 154 may include one or more detents or other components/structures that may be tuned for a desired incremental change in a corresponding functionality of the exercise machine 102. For example, the rotary encoder 154 may be tuned such that each detent thereof may correlate to a 0.5% increase or decrease in an incline angle of the deck 112. Alternatively, the rotary encoder 154 may be tuned such that each detent thereof may correlate to a 0.1 mph increase or decrease in a speed of the belt 120. IN still further examples, percentages, speeds, and/or other increments greater than or less than those noted above may be chosen. Additionally, one or more such controls 144, 146 may include one or more additional buttons, wheels, touch pads, levers, knobs, or other components configured to receive additional inputs from the user 106, and such additional components may provide the user 106 with finer control over the corresponding functionality of the exercise machine 102. One or more such controls 144, 146 may also include a respective control housing 156 configured to assist in mounting the control 144, 146 to the crossbar 132 or other components of the exercise machine 102. As shown in FIGS. 33-35, in still further embodiments one or more of the infinity wheel-type controls 144, 146 described herein may be replaced with a capacitive slider-type control and/or other substantially linear control 158. Such controls 158 may include one or more touch pads, buttons, levers, and/or other components 160, 162, 166 configured to receive a touch, tap, push, and/or other input from the user 106. Such components 160, 162, 166 may be operably connected to respective touch and/or tactile switches of the control 158 mounted to a printed circuit board 170 thereof. Such tactile switches may be configured to generate signals indicative of the input received via such components 160, 162, 166, and to direct such signals to the processor and/or other digital hardware 148 associated with the exercise machine 102. The controls 158 may also include one or more additional touch pads 164 having a substantially linear configuration. Such touch pads 164 may also be configured to receive a touch, tap, push, and/or other input from the user 106. Additionally, the touch pads 164 may be operably connected to a respective capacitive trace 172 of the control 158 mounted to the printed circuit board 170. In such examples, the capacitive trace 172 may be configured to generate signals indicative of the input received via the touch pad 164 and to direct such signals to the processor and/or other digital hardware 148 associated with the exercise machine 102. FIG. 34 illustrates a first substantially linear control 158 disposed on the right hand side of the crossbar 132, and a second substantially linear control 174 disposed on the left hand side of the crossbar 132 opposite the control 158. In any of the examples described herein, one or more of the components 160, 162, 166 may be operable to control and/or change operating modes of the exercise machine 102. Additionally, in any of the examples described herein, one or more of the infinity wheel-type controls 144, 146 and/or one or more of the substantially linear controls 158, 174 may include light emitting diodes and/or other lighting indicating a change in operation that is affected by the respective control. With continued reference to at least FIG. 29, in various exemplary embodiments, the sensors 147 of the exercise machine 102 may be configured to sense, detect, measure, and/or otherwise determine a range of performance metrics from both the exercise machine 102 and the user 106, instantaneously and/or over time. For example, the exercise machine 102 may include one or more sensors 147 that measure the incline of the deck 112, the speed of the belt 120, a load applied to the deck 112, the belt 120, one or more of the motors 114, 118, and/or other components of the exercise machine 102, an amount of energy expended by the user 106, a power output of the exercise machine 102, user weight, steps, distance, total work, repetitions, an amount of resistance applied to the belt 120 by one or more of the motors 114, 118 and/or other components of the exercise machine 102, as well as any other suitable performance metric associated with, for example, a treadmill. The exercise machine 102 may also include sensors 147 to measure user heart-rate, respiration, hydration, calorie burn, or any other physical performance metrics, or to receive such data from sensors provided by the user 106. Where appropriate, such performance metrics can be calculated as current/instantaneous values, maximum, minimum, average, or total over time, or using any other statistical analysis. Trends can also be determined, stored, and displayed to the user, the instructor, and/or other users. Such sensors 147 may communicate with memory and/or processors of the digital hardware 148 associated with the exercise machine 102, nearby, or at a remote location, using wired or wireless connections. In various exemplary embodiments, the exercise machine 102 may also be provided with one or more indicators to provide information to the user 106. Such indicators may include lights, projected displays, speakers for audio outputs, or other output devices capable of providing a signal to a user 106 to provide the user 106 with information such as timing for performing an exercise, time to start or stop exercise, or other informational indicators. For example, as illustrated in FIG. 6, such indicators (e.g., lights or projected displays) could display information regarding the number of sets and repetitions performed by the user 106 at a location where it can be seen by the user 106 during the performance of the relevant exercise. Display and User Interface The one or more displays 104 may be driven by a user input device such as a touchscreen, mouse, voice control, or other suitable input device. In some examples, the display 104 or at least a portion thereof, may comprise a touchscreen configured to receive touch input from the user 104. The one or more displays 104 may be any size, but optimally are large enough and oriented to allow the display of a range of information including one or more video streams, a range of performance metrics corresponding to the user 106, a range of additional performance metrics associated with one or more additional users exercising on exercise machines remote from the exercise machine 102, and a range of different controls. In various exemplary embodiments, such as the embodiment illustrated in FIG. 4, the display 104 may include some or all of its area that can reflect the image of the user 106 to provide user feedback regarding their form and performance of various activities. In various exemplary embodiments the user can use the display 104 or one or more user interfaces 200 displayed on the display 104 to selectively present a range of different information including live and/or archived video, performance data, and other user and system information. As will be described below with respect to at least FIGS. 12-24, such user interfaces 200 can provide a wide range of control and informational windows that can be accessed and removed individually and/or as a group by a click, touch, voice command, or gesture. In various exemplary embodiments, such windows may provide information about the user's own performance and/or the performance of other participants in the same class both past and present. Example user interfaces 200 presented via the display 104 may be used to access member information, login and logout of the system 100, access live content such as live exercise classes and archived classes or other content. User information may be displayed in a variety of formats and may include historical and current performance and account information, social networking links and information, achievements, etc. The user interfaces described herein 200 can also be used to access the system 100 to update profile or member information, manage account settings such as information sharing, and control device settings. An example user interface 200 may also be presented on the one or more displays 104 to allow users to manage their experience, including selecting information to be displayed and arranging how such information is displayed on the display 104. Such a user interface 200 may present multiple types of information overlaid such that different types of information can be selected or deselected easily by the user 106. For example, performance metrics and/or other information may be displayed over video content using translucent or partially transparent elements so the video behind the information elements can be seen together with (i.e., simultaneously with) the performance metrics and/or other information itself. Further, example user interfaces 200 may present a variety of screens to the user 106 which the user 106 can move among quickly using the provided user input device, including by touching if a touchscreen is used. In any of the examples described herein, the processor and/or other components of the digital hardware 148 may control the display 104 and/or otherwise cause the display 104 to display the various user interfaces 200 of the present disclosure. For example, the processor or other components of the digital hardware 148 may cause the display 104 to display a user interface 200 comprising a home screen that provides basic information about the system 100 and/or the exercise machine 102, as well as available options. Such a home screen may provide direct links to information such as scheduled classes, archived classes, a leaderboard, instructors, and/or profile and account information. The home screen may also provide direct links to content such as a link to join a particular class. The user can navigate among the different portions of the home screen by selecting such links using the applicable input device such as by touching the touchscreen at the indicated location, or by swiping to bring on a new screen. An example user interface 200 providing such a home screen may also provide other information relevant to the user such as social network information, and navigation buttons that allow the user to move quickly among the different screens in the user interface. In various exemplary embodiments, the user 106 can use one or more of the user interfaces 200 to browse and select among both live and archived content. For example, as shown in FIGS. 12-14, example user interfaces 200 may include one or more toolbars 202 enabling the user 106 to access listings and/or other information regarding available exercise classes. Such example toolbars 200 may include respective tabs or other controls enabling the user 106 to browse such content. For example, the toolbar 200 may include a first tab 204 enabling the user to access featured live and archived exercise classes, a second tab 206 enabling the user to access a library of archived exercise classes, a third tab 208 enabling the user to access a schedule of live classes, a fourth tab 210 enabling the user to access a variety of quick start or “just run” content, and/or other additional or different tabs. As shown in FIGS. 12 and 13, if the user 106 selects the first tab 204 associated with featured classes, the user interface 200 may present a schedule of upcoming live or archived classes that have achieved a high ranking or other preferential (e.g., “featured”) status. The user interface 200 may include one or more drop-down menus or other display features, and such features may also allow users to find such featured classes by type, instructor, or by any other appropriate category. The user interfaces 200 associated with the featured classes tab 204 may allow the user 106 to select future classes (as illustrated by thumbnails or icons 212, 214) or to start a class that is underway or about to begin (as illustrated by thumbnails or icons 216, 218, 220). Further, the user interfaces 200 associated with the featured classes tab 204 may allow the user 106 to select an archived or on-demand class that has already taken place (as illustrated by thumbnails or icons 221). The class schedule and information regarding “featured” content or any other content may be presented via such user interfaces 200 in any suitable format, including a calendar, list, or any other appropriate layout. For example, selecting the third tab 208 associated with the live schedule of exercise classes may yield a user interface 200 presenting an upcoming schedule of live classes set forth on a calendar. As illustrated by the example user interface 200 shown in FIG. 14, if the user 106 selects the second tab 206 associated with the class library, the system 100 may provide a user interface 200 showing information related to available archived classes, and such information may be sorted in a number of different ways. As illustrated by the menu icon 222, the user interface 200 may filter the classes included in the class library such that only icons or thumbnails 225 corresponding to classes associated with running, boot camp, and off-tread are provided to the user 106. Additionally, such user interfaces 200 may include one or more drop down menus 224 enabling the user 106 to further filter the classes included in the class library. For example, such drop down menus 224 may enable the user 106 to select classes based on instructor, length, class type, music genre, body focus, exercise type, etc. Additionally, as shown in FIG. 14, the icons or thumbnails 225 may be displayed in any suitable format, and may include information including the instructor of the class, the class length, the date on which the class was originally held, the type of class, and/or other related information. Further, as shown in FIG. 15, selecting one of the thumbnails 225 may surface additional information to the user 106 via an additional window 226 of the user interface 200. Such additional information may include, for example, a rating of the class, how many times the user has taken that class in the past, the portions of the body that are focused on during the class, additional equipment (e.g., weights) that may be needed during the class, as well as other performance or class-related information. FIGS. 16-18 illustrate example user interfaces 200 that may be provided to the user 106 during a selected exercise class. When an exercise class is being played on the one or more displays 104 through the user interface 200, in various exemplary embodiments the primary video feed may be shown as the background video full-screen or in a sub-window on the display 104. Information elements may be provided on different parts of the display screen to indicate any performance metrics, including total time, elapsed time, time left, distance, speed, mile pace of the user 106, incline, elevation, resistance, power, total work, energy expended (e.g., output), cadence, heart rate, respiration, hydration, calorie burn, and/or any custom performance scores that may be developed. The displayed information may also include the trend or relationship between different performance metrics. For example, the display can indicate a particular metric in a color that indicates current performance compared to average performance for a class or over time, such as red to indicate that current performance is below average or green to indicate above average performance. Trends or relative performance can also be shown using color and graphics, such as a red down arrow to show that current performance is below average. In various exemplary embodiments, the display 104 may also display information that supports or supplements the information provided by the instructor. Examples include one or more segmented timelines 228 that are illustrated together with at least part of the selected exercise class in the user interface 200. As shown in FIGS. 16-18, an example segmented timeline 228 may include one or more segments 230a, 230b, 230c . . . 230n (collectively, “segments 230”) corresponding to respective portions or parts of the selected exercise class. The size, length, width, height, relative position, color, opacity, and/or other configurations of such segments 230 may be representative of, for example, the length of the corresponding portions or parts of the selected exercise class. The segmented timeline 228 may also provide an indication 232 of elapsed time and/or remaining time for the present workout segment and/or for the exercise class generally. The segmented timeline 228 may also include one or more visual indica 234a, 234b, 234c . . . 234n (collectively, “indicia 234”) indicating an activity and/or equipment required during a respective portion or part of the selected exercise class. For example, the indicia 234a may indicate that the segment 230a comprises a walking segment, indicia 234d may indicate that the segment 230c comprises a running segment, and the indicia 234b may indicate that weights are required for at least part of the segment 230a. In any of the examples described herein, such timelines 228 may also include one or more lists or windows identifying and/or describing upcoming workout segments or features, instructional information such as graphics or videos demonstrating how to properly perform exercises, or other information relevant to the exercise class in progress. As shown in FIGS. 16-18, the user interface 200 may include a primary window 236 configured to show the live or archived exercise class or other content that the user 106 selected. In various exemplary embodiments, the user interface 200 may further include one or more performance metric windows 238 (e.g., the “scorecard” illustrated in FIGS. 16 and 17) overlaid on and/or otherwise displayed together with the primary window 236. Such performance metric windows 238 may show a ranking, total output, current output, incline, belt speed, mile pace, and/or other specific performance metrics for the user's current class, past classes, or other performance information. Such performance metric windows 238 may be presented anywhere on the display 104, and may be user selectable such that they can be displayed or removed by a screen touch or gesture. The user interface 200 may also allow the user 106 to toggle between display of maximum, average, and total results for different performance metrics. Additionally, the user interface 200 may allow the user 106 to hide or display information elements, including performance metrics, video streams, user information, etc. all at once or individually. Performance metrics and/or other performance information can also be displayed in various display bars 240, 242 that can be hidden or displayed as a group or individually. The user interface 200 may provide for complete controls for audio volume, inputs, and outputs as well as display output characteristics. As shown in FIG. 18, a leaderboard 244 may also be displayed to allow the user 106 to see their performance in comparison to others taking the same exercise class. In various exemplary embodiments, a leaderboard 244 may comprise a separate window overlaid on and/or otherwise displayed together with the primary window 236. An example leaderboard 244 may be configured to display the relative performance of all participants, and/or of one or more subgroups of participants. For example, the user 106 may be able to select a leaderboard 244 that shows the performance of participants in a particular age group, male participants, female participants, male participants in a particular age group, participants in a particular geographic area, etc. As indicated by the example filter shown in FIG. 18, the leaderboard 244 has been configured to show the performance of a group of female participants in their 20's. Users 106 may have the ability to individually curate and/or otherwise configure a leaderboard 244, or have the system 100 curate a leaderboard 244 by selecting an appropriate group of participants relative to the user 106. Users 106 may be able to curate their own leaderboards 244 for specific previously recorded classes to create a leaderboard 244 that provides the maximum personal performance incentive to the user 106. Users 106 may be provided with the ability to deselect the leaderboard 244 entirely and remove it from the user interface 200. In various exemplary embodiments, the exercise machine 102 may incorporate various social networking aspects such as allowing the user 106 to follow other participants, or to create groups or circles of participants. User lists and information may be accessed, sorted, filtered, and used in a wide range of different ways. For example, other users can be sorted, grouped and/or classified based on any characteristic including personal information such as age, gender, weight, or based on performance such as current power output, speed, or a custom score. The leaderboard 244 may be fully interactive, allowing the user 106 to scroll up and down through the participant rankings, and to select a participant to access their detailed performance data, create a connection such as choosing to follow that participant, or establish direct communication such as through an audio and/or video connection. The leaderboard 244 may also display the user's personal best performance in the same or a comparable class, to allow the user 106 to compare their current performance to their previous personal best. In some examples, such performance information may also be displayed in one or more of the display bars 240, 242. The leaderboard 244 may also highlight certain participants, such as those that the user 106 follows, or provide other visual cues to indicate a connection or provide other information about a particular entry on the leaderboard 244. In various exemplary embodiments, the leaderboard 244 will also allow the user 106 to view their position and performance information at all times while scrolling through the leaderboard 244. For example, if the user 106 scrolls up toward the top of the leaderboard 244 such as by dragging their fingers upward on the display 104, when the user 106 reaches the bottom of the leaderboard 244, it will lock in position and the rest of the leaderboard 244 will scroll underneath it. Similarly, if the user 106 scrolls down toward the bottom of the leaderboard 244, when the user's window reaches the top of the leaderboard 244, it will lock in position and the rest of the leaderboard 244 will continue to scroll underneath it. In various exemplary embodiments, the system 100 may calculate and/or display one or more custom scores to describe one or more aspects of the users' performance. One example of such a custom score would be a decimal number calculated for a particular class or user session. Such a score could also be calculated using performance data from some or all classes or sessions over a particular period of time. In any of the examples described herein, such a custom score may be calculated and/or otherwise determined by the system 100 and/or by one or more processors of the exercise machine 102 based at least partly on an amount of time elapsed during an exercise class, a total output or total energy expended by the user 106 during such a class, and/or a number of exercise classes that the user 106 participated in within a given time period. In various exemplary embodiments, performance information about other users may also be presented on the leaderboard 244 or in any other format, including formats that can be sorted by relevant performance parameters. Users may elect whether or not to make their performance available to all users, select users, and/or instructors, or to maintain it as private so that no one else can view it. In various exemplary embodiments the user interface 200 may also present one or more video streams from a range of different sources. For example, one video stream may be the live or archived class content shown in the primary window 236, while one or more additional video streams may be displayed in other windows on the display 104. The various video streams may include live or recorded streaming instructor video or any other video content, including one or more live video chat streams. Such video content may include instructional information such as informational or demonstration content regarding how to perform a particular exercise. It may also include visual cues for the user 106 to follow in performing their exercise, such as timing indicators, counts, etc. In further examples, one or more of the in-class user interfaces 200 illustrated in FIGS. 16-18 may be configured to provide one or more notifications 246 to the user 106 during the exercise class. For example, one or more of the sensors 147 may be configured to sense, detect, and/or otherwise determine a load applied to at least one of the belt 120, the deck 112, one or both of the motors 114, 118, and/or other components of the exercise machine 102. Such sensors 147 may send one or more signals to the processor or other digital hardware 148 of the exercise machine 102 indicative of such a load and/or of a change in such a load. At least partly in response to such signals, the processor or other digital hardware 148 of the exercise machine 102 may cause the notification 246 to be displayed on the display 104 together with at least part of the exercise class selected by the user 106. Such signals may indicate, for example, that the user 106 has stepped off of the belt 120 during a run segment of the exercise class. Accordingly, such notifications 246 may indicate that the user 106 has stepped off of the belt 120 and/or the deck 112. Such notifications 246 may also request a response from the user 106. For example, such notifications 246 may request the that the user 106 confirm that he/she is not hurt and/or that the user 106 would like to continue exercising. As illustrated by the example user interfaces 200 shown in FIGS. 19-21, if the user 106 selects the fourth tab 210 associated with the “just run” functionality of the exercise machine 102, the system 100 may provide a user interface 200 showing information related to available quick-start running exercises/applications. For example, the user interface 200 may include one or more icons or thumbnails 248, 250, 252 allowing the user 106 to select a desired exercise regimen. The freestyle icon 248 may, for example, enable the user 106 to set his/her own incline, belt speed, running course, and/or other parameters, and may enable the user 106 to exercise in an undefined and unlimited way (e.g., without a specific exercise class being displayed on the display 104). The scenic icon 250, may be similar to the freestyle icon 248 in that it may enable the user 106 to exercise without a specific exercise class being displayed on the display 104. However, in response to receiving an input indicative of the selection of the scenic icon 250, the user interface 200 may present a plurality of additional icons or thumbnails 254 corresponding to respective scenic running trails stored in a memory of the exercise machine 102. Such icons or thumbnails 254 are illustrated in FIG. 20. Upon selecting one of the icons or thumbnails 254, the user interface 200 may display the selected running trail on the display 104 as the user 106 exercises on the treadmill 102. Further, the competitions icon 252 may enable the user 106 to perform a relatively high-intensity workout without a specific exercise class being displayed on the display 104. For example, in response to receiving an input indicative of the selection of the competitions icon 252, the user interface 200 may present a plurality of additional icons or thumbnails 256 corresponding to respective time-based challenges or competitions stored in a memory of the exercise machine 102. Such icons or thumbnails 256 are illustrated in FIG. 21. Upon selecting one of the icons or thumbnails 256, the user interface 200 may display belt speed, deck incline, output, elapsed time, mile pace, calories burn, and/or other performance parameters or other information on the display 104 associated with the selected competition. FIGS. 22-24 illustrate example user interfaces 200 configured to provide performance information to the user 106 before, during, or after a selected exercise class. For example, the user interface 200 illustrated in FIG. 23 provides an overview of information associated with a particular user 106 (e.g., “clementinecein”). As indicated in the user interface 200 of FIG. 23, such information may include, among other things, the number of followers the user 106 has, the number of fellow participants that the user 106 is following, the total lifetime runs, rides, circuits, or other workouts that the user 106 has done, the various achievements or rewards the user 106 has accomplished, personal best output records of the user 106, a timeline of the user's recent workout activity, and/or other such general information associated with the user's workout activities. Such information may be displayed in one or more separate portions or windows 258, 260 of the user interface 200. In further examples, on the other hand, such information may be provided in the user interface 200 in alternative formats, windows, or locations. The user interfaces 200 illustrated in FIGS. 22 and 24, on the other hand, provide performance metrics, performance information, and/or other more detailed information associated with the workout history of the particular user 106. For example, as indicated in the user interface 200 of FIG. 22, such information may include a listing of workouts or other exercise classes performed by the user 106 in the present week and/or in the present month. Such information may be displayed in a first window 262 of the user interface 200, and may further include a summary of the user's output during each exercise class, the date and time of the class, the instructor, and/or other information. The user interface 200 may also include one or more additional windows 264 and/or other formats useful in providing additional information regarding the workout history of the user 106. For example, such an additional window 264 may provide specific performance metrics (e.g., a heart rate trend line, a segmented timeline, an average heart rate, a total output, and/or other performance metrics) associated with a specific one of the previous workouts shown in the first window 262. Similarly, as illustrated in FIG. 24, one or more additional user interfaces 200 providing information associated with the workout history of the particular user 106 may include the window 262 described above, as well as one or more additional windows 266, 268 providing the achievements, output trends, and/or other workout information. For example, the window 266 may display the total output, distance run, elevation ascended, calories burned, average output and/or energy expended, average speed, average mile pace, and/or other information associated with a specific one of the previous workouts shown in the first window 262. The window 266 may also display the leaderboard rank of the user 106 corresponding to the specific one of the previous workouts, as well as various achievements earned for performing the one of the previous workouts. The window 268, on the other hand, may provide speed, output, and or other trend lines associated with the specific one of the previous workouts. As a result, the user interfaces 200 illustrated in FIGS. 22-24 may provide the user 106 with relatively detailed performance information that can be used by the user 106 to improve his/her overall health and/or abilities. Any of the information provided via the user interfaces 200 described herein may be stored in a memory or other component of the digital hardware 148 of the exercise machine 102 and/or may be stored remotely. The performance-focussed user interfaces 200 illustrated in FIGS. 22-24 may also be configured to provide information obtained from various additional sources. For example, data regarding user performance may be gathered from a variety of sources in addition to the various sensors 147 on the primary exercise machine 102. As illustrated in FIG. 5, other exercise machines 102 and devices used during an exercise class may each include one or more sensors to gather information regarding user performance. The user 106 may also use a variety of other clothing or devices attached to their body (e.g., a watch, a wrist band, a head band, a hat, shoes, etc.) including one or more additional sensors 270. The user 106 may also use other exercise equipment 272 such as weights, resistance bands, rollers, or any other suitable equipment, and such exercise equipment 272 may also include one or more such additional sensors 270. Data from all of these sources may be gathered by the local system 100 and analyzed to provide user performance feedback. One challenge with certain types of data gathered from such sensors 270 is determining the proper context for interpreting the data so that accurate information regarding user performance can be derived. For example, a sensor 270 worn on the user's wrist may provide data indicating that the user's wrist performed a series of movements consistent with several different exercises, but it may be difficult or impossible to derive which exercise the user 106 was actually performing. Without context, data showing that the user's wrist moved up and down may indicate that the user 106 was running or they may simply have been moving their arm. As a result, performance data derived from such sensors 270 can be very inaccurate. In various exemplary embodiments, data from a variety of sensors 270 on exercise equipment 272 such as free weights and on the users' body can be gathered, and the system 100 can use information regarding the instructor-led group fitness class to improve accuracy by providing context for the interpretation of sensor data gathered from all sources. If the class instructor has, for example, directed users 106 to do push-ups, the system 100 can assume that sensed movement consistent with a push-up is actually a push-up and interpret the sensor data accordingly. The context provided by the instructor-led group fitness class can substantially improve the resulting performance data. Accordingly, the one or more user interfaces 200 described with respect to at least FIGS. 22-24 may also provide one or more additional windows that can be used to display any of the performance data and/or other information obtained from the sensors 270 and/or the exercise equipment 272. Such additional windows may also be configured to display a range of content including additional performance data, information about the class, instructor, other participants, etc., or secondary video streams. Such additional windows can allow the user 106 to see a range of information regarding other current or past participants to compare performance, and open or close voice or video chat streams or other communication channels. In various exemplary embodiments the user 106 can simultaneously access and/or view other content including movies, television channels, online channels, etc. via one or more such additional windows. In various exemplary embodiments, the user interfaces 200 described herein may be run through a local program or application using a local operating system such as an Android or iOS application, or via a browser-based system. Any of the performance metrics or other information described herein with respect to the various user interfaces 200 may also be accessed remotely via any suitable network such as the internet. For example, users 106 may be able to access a website from a tablet, mobile phone, computer, and/or any other digital device, and such users 106 may be able to review historical information, communicate with other participants, schedule classes, access instructor information, and/or view any of the information described herein with respect to the various user interfaces 200 through such a website. User-Generated Content One feature of in-person group exercise classes is the ability to see other participants performing the exercises or other activities in response to the class leader's instructions. This ability to see others performing the same exercises or activities can provide motivation to maintain or improve performance, or help the user confirm that they are performing the proper exercise with proper form. In various exemplary embodiments of the present disclosure, video streams can be displayed on the one or more displays 104 of the respective exercise machines 102 showing other class participants performing the exercises as instructed by an instructor or other class leader. In various exemplary embodiments, such additional video streams may include user-generated content related to the live or previously recorded exercise class content. Referring to FIG. 8 for example, an exemplary embodiment is illustrated wherein video streams of other class participants are displayed in sub-windows 274a, 274b, 274c . . . 274n (collectively “sub-windows 274”) across a top portion of a user interface 200 shown on the display 104. Such sub-windows 274 may be displayed on the display 104 while an instructor is displayed in a primary window 276 of the user interface 200. If the class is a live class, such content may be streamed live. If the class is an archived class, such content may be streamed live if the other class participant is taking the class at the same time, or may be archived content from when the other class participant previously took the class. One or more of such video streams may be displayed on the one or more displays 104 described herein. Additionally, by touching, selecting, and/or otherwise providing input via one of the sub-windows 274, the user interface 200 may provide an additional window 278 enabling the user 106 to expand a video associated with the selected sub-window, follow a user associated with the selected sub-window, and/or perform one or more additional actions associated with the selected sub-window. In various exemplary embodiments, the user 106 may also be able to provide feedback regarding such user generated content. For example, the user 106 may be able to input positive or negative feedback such as indicating that they like or dislike the user-generated content by clicking on an icon provided via the additional window 278 indicating their opinion or otherwise inputting their opinion. In various exemplary embodiments, the user 106 may also choose whether or not to display any such user-generated content. If user-generated content is displayed, which user-generated content is displayed to a particular user 106 can be determined several different ways. In various exemplary embodiments, the user-generated content may be chosen by the user 106 by selecting it from among the available user-generated content for a particular exercise class currently be displayed via the display 104. Such user-generated content may also be chosen by the class instructor or one or more content editors, it may be presented via a content queue ordered based on any suitable criteria, or it may be chosen by the system 100 based on one or more suitable criteria. For example, the user-generated content to be displayed could simply be a time-based queue of available user-generated content without regard to quality. In various exemplary embodiments, the user-generated content to be displayed may be selected to provide the best quality user-generated content available for a particular selected exercise class at the time of viewing. At the time the class is aired live, the available user-generated content would be limited to live streamed content generated during the class itself. For archived classes, the available user-generated content could include all content generated by every user that has participated in the class at any time. The user-generated content to be displayed for an archived class may be based on accumulated ratings for that user-generated content over time, or on any other measure of popularity. Such a methodology would result in an improvement of the user-generated content displayed with any archived class over time, as the user-generated content receiving the best feedback would be selected for display while user-generated content that did not receive positive feedback would not be displayed. Local System As noted above, an example local system 100 may include an exercise machine 102, and a range of associated sensing, data storage, processing, and/or communications components (e.g., digital hardware 148). In example embodiments, such components may be disposed onboard the exercise machine 102 itself and/or located near the exercise machine 102. The processing, data storage, and/or communications components may be located within a housing of the display 104 to form a single integrated onboard computer and display screen, or they may be separately housed locally on or near the exercise machine 102. Such an example local system 100 may communicate with one or more remote servers through wired or wireless connections using any suitable network or protocol. Additionally as noted above, an example exercise machine 102 may be equipped with various sensors 147 to measure, sense, detect, and/or otherwise determine information relating to user performance metrics. Such information may be stored in memory associated with the digital hardware 148 and/or in memory associated with the remote servers, and such information may be used by the processors and/or other components of the digital hardware 148 to determine one or more of the performance metrics described herein and/or to determine other performance information. The exercise machine 102 may also be equipped with or connected to various data input devices or other user interfaces such as the display 104, touchscreens, video cameras, and/or microphones. The sensors 147 and other input devices can communicate with local and/or remote processing and storage devices via any suitable communications protocol and network, using any suitable connection including wired or wireless connections. In various exemplary embodiments, local communication may be managed using a variety of techniques. For example, local communication may be managed using wired transport with a serial protocol to communicate between sensors and the console. Local communication may also be managed using a wireless communication protocol such as the ANT or ANT+ protocol. ANT is a 2.4 GHz practical wireless networking protocol and embedded system solution specifically designed for wireless sensor networks (WSN) that require ultra-low power. Advantages include extremely compact architecture, network flexibility and scalability, ease of use and low system cost. Various combinations of wired and wireless local communication may also be used. Access to any appropriate communications network such as the internet may be used to provide information to and receive information from other exercise machines 102 or other resources such as a backend system or platform. In various exemplary embodiments, the local system 100 can access and display information relating to other users either directly through a distributed platform or indirectly through a central platform regardless of their location. Such other users may be present at the same location or a nearby location, or they may be at a remote location. Content Creation and Distribution Content for delivery to users 106 including live and archived exercise classes, live and archived instructional content such as video content explaining how to properly perform an exercise, scenic or map-based content, videos, and/or animations that can be rendered in three-dimensions from any angle may be created and stored in various local or remote locations and shared across the networked exercise system. Such an example networked exercise system is illustrated in at least FIG. 9. This overview of such a networked exercise system is exemplary only and it will be readily understood that example embodiments of the present disclosure can be implemented through a variety of different system architectures using centralized or distributed content creation and distribution techniques. In various exemplary embodiments, the networked exercise system 100 is managed through one or more networked backend servers and includes various databases for storage of user information, system information, performance information, archived content, etc. Users' local systems 100 are in communication with the networked backend servers via any appropriate network, including without limitation the internet. As an example of an alternative distribution approach, in various exemplary embodiments the backend servers could be eliminated and data could be communicated throughout the system in a distributed or peer-to-peer manner rather than via a central server network. In such a system, performance data may be broken up into small packets or “pieces” and distributed among user devices such that complete data sets are quickly distributed to all devices for display as required. Content for distribution through the network can be created in a variety of different ways. Content recording locations may include professional content recording studios or amateur and home-based locations. In various exemplary embodiments, recording studios may include space for live instructor-led exercise classes with live studio participation, or may be dedicated studios with no live, in-studio participation. As shown in FIG. 9, recording equipment including one or more video cameras 300, microphones 302, mp3 players or other music players 304, and/or other components and can be used to capture the instructor and/or participants during the class. Multiple cameras 300 can provide different views, and 3D cameras 300 can be used to create 3D content. In various exemplary embodiments, content may also be generated locally by users 106. For example, exercise machines 102 may be equipped with recording equipment including microphones 302 and cameras 300. Users 106 may generate live or recorded classes that can be transmitted, stored in the system, and distributed throughout the network. With continued reference to FIG. 9, class content may be generated by providing outputs of the one or more video cameras 300, microphones 302, and/or music players 304 as inputs to an audio mixer 306. The audio mixer 306 may output content to an analog to digital converter 308, which may provide converted data to a production switcher 310. The production switcher 310 may send the production video to a video encoder 312, which may store the encoded video to a local storage device 314, and may also send it to a video transcoder 316. The video transcoder 316 may output transcoded data to a video packetizer 318, which may then send a packetized data stream out through a content distribution network 320 to remote system users 322. In various exemplary embodiments, instructors and/or users 106 may be provided with access to a content creation platform that they can use to help them create content. Such a platform may provide tools for selecting and editing music, managing volume controls, pushing out chat or other communications to users. As described above, through the display 104 and/or other user interface on their exercise machine 102, users 106 may access lists, calendars, and schedules of live and recorded exercise classes available for delivery through the display 104. In various exemplary embodiments, once the user 106 selects a class, the local system 100 accesses and displays a primary data stream for the class. This primary data stream may include video, music, voice, text, or any other data, and may represent a live or previously recorded cycling class. The local system 100 may be equipped for hardware video accelerated encoding/decoding to manage high definition video quality at up to 1080 pixels based on existing technology. The local system 100 may automatically adjust bitrate/quality of the data stream for the class in order to bring participant the highest quality video according to user's bandwidth/hardware limitations. In various exemplary embodiments, networked exercise systems and methods of the present disclosure may include multi-directional communication and data transfer capabilities that allow video, audio, voice, and data sharing among all users and/or instructors. This allows users to access and display multi-directional video and audio streams from the instructor and/or other users regardless of location, and to establish direct communications with other users to have private or conferenced video and/or audio communications during live or recorded classes. Such data streams can be established through the local system 100 for presentation via the one or more displays 104 via one or more of the user interfaces 200 described above. In various exemplary embodiments, users 106 can manage multiple data streams to select and control inputs and outputs. The local system 100 may allow the user 106 to control the volume of primary audio stream for the class as well as other audio channels for different users or even unrelated audio streams such as telephone calls or their own music selections. For example, this would allow a user 106 to turn down the instructor volume to facilitate a conversation with other users. For live classes, in various exemplary embodiments the instructor may have the ability to communicate with the entire class simultaneously or to contact individual users, and solicit feedback from all users regardless of location in real-time. For example, instructors could ask users verbally, or text a pop-up message to users 106, seeking feedback on difficulty level, music choice, terrain, etc. Users 106 could then respond through components of the local system 100 by selecting an appropriate response, or providing verbal feedback. This allows instructors to use crowdsourcing to tailor a class to the needs of the participants, and to improve their classes by soliciting feedback or voting on particular class features or elements. In various exemplary embodiments, instructors may also be able to set performance targets, and the system can measure and display to the user 106 and the instructor their performance relative to the target. For example, the instructor may set target metrics e.g. target power and speed, then display this next to users' readings with a color coding to indicate whether or not the user is meeting this target. The system may allow the instructor to remotely adjust exercise machine settings for individual users 106. In various exemplary embodiments, the exercise machine 102 may also automatically adjust based on information from the user 106, the instructor, or based on performance. For example, the exercise machine 102 may adjust the difficulty to maintain a particular performance parameter such as heart rate within a particular range or to meet a particular performance target. In various exemplary embodiments, users 106 can control access to their own information, including sensor data, performance metrics, and personal information. Such data can be stored at the local system 100, transmitted for storage and management by a remote system and shared with other users, or stored remotely but not shared with other users. Users 106 may also elect to disclose their presence on the system to other users, or to participate in a class without making their presence known to other users. In various exemplary embodiments, users 106 can access a list of all or selected current and/or past class participants. Such lists may include performance information for such users, such as total power, speed, steps, cadence, resistance, or a custom score that provides information about relative user performance. Such lists may also include controls to allow the user to open up live streams to the user such as live video chat streams. System Features and User Resources In various exemplary embodiments, the networked exercise system and methods may allow users 106 to create accounts and save and manage their performance data. As discussed above, the system may allow users 106 to browse schedules for upcoming live classes, signup for future live streaming classes, and setup reminders. Users 106 may also be able to invite others to participate in a live class, and setup text, email, voice, or other notifications and calendar entries. Users 106 may be able to access system, account, performance, and all other data via web-based or application based interfaces for desktop and/or mobile devices, in addition to the user interface for the local system 100 associated with their exercise machine 102. In various exemplary embodiments, the system can provide for simultaneous participation by multiple users in a recorded class, synchronized by the system and allowing access to all of the same communication and data sharing features that are available for a live class. With such a feature, the participants simultaneously participating in the same archived class can compete against each other, as well as against past performances or “ghost” participants for the same class. Referring to FIGS. 10 and 11, the system may be configured to feed synchronized live and/or archived video content and live and/or archived sensor data to users over the network. In various exemplary embodiments, the networked exercise system may be configured with a plurality of user exercise equipment 400 in communication with a video chat platform 402, a video content distribution network 404 that receives audio video content from one or more content sources 406. The user exercise equipment 400 may also be in communication with various other networks and servers. For example, the user exercise equipment 400 may exchange sensor and performance data and/or signaling with various databases 408, including historical or “ghost participant” data. A control station may provide signals via the network to control the collection, storage, and management of data across the system. One challenge for the use of comparative data from live and/or historical sources is synchronization, since some users 106 may start exercising prior to the start of the actual class, while others may join after the class has started. In order to provide accurate data regarding class performance for the leaderboard, including archived performance data, each class may have a specific “go” or start signal that serves as the starting time point for the data comparison. Archived performance data may be calibrated to the same “go” signal as live participant data, allowing for comparative data to be presented through a leaderboard or other display through the end of the class. A “stop” signal at the end of the class marks the end time point for the performance comparison for both live and archived performance data. If a participant joins the class after the “go” signal, their data can be synched correctly starting at the time they join the class. FIG. 11 shows various events relative to time, which is increasing from left to right on the scale at the bottom. The timeline for the class itself, whether live or archived, is shown at the top, with timelines for four different participants below it. The video being delivered for a live or archived class may begin before the actual class starts at the video start point 420. The GO signal point 422 indicates the start of the class or the class's comparison period, the STOP signal point 424 indicates the end of the class or the end of the class's comparison period, and the end video point 426 indicates the end of the video stream. For Participants 1, 2, and 4, who all start exercising before the GO signal point, the GO signal serves as their starting time point for class performance metrics. For Participant 3, the point in time when they actually start will serve as their starting time point for class performance metrics. For Participants 1, 2, and 3 who continued past the STOP signal point, their end point for class performance metrics will be the STOP signal point, while the end point for Participant 4 will be the time when they actually stopped exercising. Using such a system, live and past performance data for the user or other participants can be provided during a class in a range of numerical and graphical formats for comparison and competition. Live and past performance data or target performance data for the user can also be displayed simultaneously to allow users to compare their performance to a benchmark in real time during or after a class. In various exemplary embodiments, the system may also allow users to establish handicapping systems to equalize the competition among different users or user groups allowing for broad based competitions. In various exemplary embodiments, the system may combine information from multiple users 106 to produce a combined or collective result. For example, different user's performance information could be combined to produce a single performance measurement such as in a relay type race, where the times for different users are collected and combined into a single time or score for a team. In various exemplary embodiments, the system may also combine the user's performance from two or more different exercise machines 102 to produce a single output or score. For example, performance information gathered from a bike and a treadmill used sequentially or as part of the same group exercise class may be combined together in a single output that reflects performance data from the plurality of exercise machines 102. In various exemplary embodiments, a mobile application may allow users on non-networked exercise machines to access the system via a mobile digital device such as a tablet computer or mobile phone and access content, live streams, and other system features. The mobile device could access the system via any appropriate network using a dedicated application or browser. In various exemplary embodiments, one or more secondary displays may be used by the system to display class content. Using a device such as CHROMECAST or a similar integrated device to enable it to display content provided by the system through the user interface, a secondary display screen may be used to display class content or other content provided by the system. The user interface could automatically detect the availability of such an enabled device and allow the user to select the display screen for particular content. Various types of rewards and honors can be created for different achievements to create incentives for improving performance or reaching other goals. In various exemplary embodiments, the instructor or users can create mini-competitions for participation by all users or just a selected subset of users such as a group of friends. Competitions such as sprints, hill climbs, maximum power output, etc. can be preset or created in real-time through the user interface. Winners can be rewarded with prizes such as badges, trophies, or biking specific honors such as a green or yellow jersey. Competitions can be created within a class or session, or across multiple classes or sessions. CLAUSES The example clauses A-T noted below set forth example embodiments of the present disclosure. Any of the clauses below, or individual features thereof, may be combined in any way. Further, the descriptions included in any of the example clauses below may be combined with one or more features described above or illustrated in FIGS. 1-35. The clauses noted below are not intended to narrow the scope of the present disclosure in any way, and merely constitute examples of the various embodiments described herein. A: In an example embodiment of the present disclosure, a method includes providing information about available exercise classes to a processor associated with a first exercise machine, the first exercise machine being located at a first remote location; receiving, from a first user of the first exercise machine and via the processor, a selection of one of the available exercise classes; providing, via a network and to the processor, digital content comprising the one of the available exercise classes; receiving, via the network, a first plurality of performance parameters detected at the first exercise machine during display of at least part of the one of the available exercise classes on a display associated with the first exercise machine, the at least part of the one of the available exercise classes requiring participants to run on a treadmill; receiving, via the network, a second plurality of performance parameters detected at a second exercise machine during display of the at least part of the one of the available exercise classes on a display associated with the second exercise machine, the second exercise machine being located at a second remote location different from the first remote location; providing, via the network, at least one parameter of the second plurality of performance parameters to the processor, wherein the processor is configured to cause the at least one parameter of the second plurality of performance parameters to be displayed on the display associated with the first exercise machine together with a corresponding at least one parameter of the first plurality of performance parameters. B: In the method of clause A, the first and second exercise machines comprise treadmills, and the one of the available exercise classes comprises a running class performed by an instructor at least partially on a treadmill. C: In the method of clause A or B, the one of the available exercise classes comprises a live class streamed to the first and second exercise machines substantially in real-time. D: In the method of clause A, B, or C, the first plurality of performance parameters includes at least one of a speed of a belt associated with a deck of the first exercise machine, an incline of the deck, and a mile pace of the first user. E: In the method of clause A, B, C, or D, the at least one parameter of the first plurality of performance parameters comprises an amount of energy expended by the first user while running during the at least part of the one of the available exercise classes, and wherein the amount of energy is determined based at least partly on a speed of a belt associated with a deck of the first exercise machine, and an incline of the deck. F: The method of clause A, B, C, D, or E, further comprises providing, via the network, video chat data to the processor associated with the first exercise machine, wherein the processor is configured to cause the video chat data to be displayed on the display associated with the first exercise machine, in substantially real-time, together with the one of the available exercise classes. G: The method of clause A, B, C, D, E, or F, further comprises receiving, via the network, video chat data from the processor associated with the first exercise machine, and providing, via the network, the video chat data to a processor associated with the second exercise machine, wherein the processor associated with the second exercise machine is configured to cause the video chat data to be displayed on the display associated with the second exercise machine together with the one of the available exercise classes. H: In the method of clause A, B, C, D, E, F, or G, the processor associated with the first exercise machine is configured to cause the at least one parameter of the second plurality of performance parameters to be displayed on the display associated with the first exercise machine together with the at least part of the one of the available exercise classes. I: An exercise machine comprises a processor; a first display operably connected to the processor and configured to display content; a deck configured to move relative to a surface supporting the exercise machine; a belt rotatable about the deck; and a sensor operably connected to the processor, the sensor being configured to detect a first performance parameter of a first user running on the belt of the exercise machine during display of at least part of an exercise class on the first display, wherein the processor is configured to: receive, via a network, information indicative of a second performance parameter of a second user, the second performance parameter being detected at an additional exercise machine during display of the at least part of the exercise class on a display associated with the additional exercise machine, the additional exercise machine being located at location remote from the exercise machine, and cause the second performance parameter to be displayed on the first display together with the first performance parameter. J: In the exercise machine of clause I, the processor is further configured to: receive, via the network and from a server, information about a plurality of available exercise classes, the plurality of exercise classes including the exercise class; cause the first display to display the information; and receive, from the first user and via the display, an input indicating selection of the exercise class. K: In the exercise machine of clause I or J, the processor is further configured to: request digital content comprising the exercise class, from the server and via the network, at least partly in response to the input, the exercise class comprising a running class performed by an instructor at least partially on a treadmill. L: In the exercise machine of clause I, J, or K, the sensor is configured to detect at least one of a speed of the belt and an incline of the deck relative to the support surface, and wherein the processor is configured to: determine an amount of energy expended by the first user while running during the at least part of the exercise class, and cause the amount of energy to be displayed on the first display together with the at least part of the exercise class. M: In the exercise machine of clause I, J, K, or L, the processor is configured to cause the first display to display a segmented timeline together with the at least part of the exercise class, the segmented timeline including: a first segment corresponding to the at least part of the exercise class, and a first visual indicia indicating that the first user is to run during the at least part of the exercise class. N: In the exercise machine of clause I, J, K, L, or M, the segmented timeline includes: a second segment corresponding to an additional part of the exercise class, and a second visual indicia indicating that the first user is to lift a weight during the additional part of the exercise class. O: In the exercise machine of clause I, J, K, L, M, or N, the processor is configured to cause the first display to display a leaderboard together with the at least part of the exercise class, the leaderboard indicating: a plurality of additional users associated with the exercise class, a respective rank of each user of the plurality of additional users, and a respective amount of energy expended by each user of the plurality of additional users. P: In the exercise machine of clause I, J, K, L, M, N, or O, the sensor is configured to detect a load applied to at least one of the belt, the deck, and a motor configured to drive rotation of the belt, and wherein the processor is configured to: determine, based at least partly on the load, that the first user has stepped off of the belt during the at least part of the exercise class, and cause a notification to be displayed on the first display together with the at least part of the exercise class, the notification indicating that the first user has stepped off of the belt. Q: A method comprises causing at least part of an exercise class to be displayed on a first display associated with a first treadmill; receiving information indicative of a first performance parameter detected by a sensor associated with the first treadmill, the first performance parameter being associated with a first user running on a belt of the first treadmill during display of the at least part of the exercise class on the first display; receiving, via a network, information indicative of a second performance parameter associated with a second user, the second performance parameter being detected at a second treadmill during display of the at least part of the exercise class on a second display associated with the second treadmill, the second treadmill being located at location remote from the first treadmill; and causing the second performance parameter to be displayed on the first display together with the first performance parameter. R: The method of clause Q, further comprises receiving a first input from the first user during display of the at least part of the exercise class on the first display, the first input being indicative of a request to change an incline of a deck of the first treadmill, the first treadmill including a belt rotatably connected to the deck; and activating a first motor located substantially internal to the deck at least partly in response to the first input. S: The method of clause Q or R, further comprises receiving a second input from the first user during display of the at least part of the exercise class on the first display, the second input being indicative of a request to change a speed of the belt, the belt comprising a plurality of lateral slats; and activating a second motor located substantially internal to the deck at least partly in response to the second input. T: The method of clause Q, R, or S, further comprises determining an amount of energy expended by the first user while running during the at least part of the exercise class; and causing the amount of energy to be displayed on the first display together with the at least part of the exercise class, and a segmented timeline, the segmented timeline including a first segment corresponding to the at least part of the exercise class, and a first visual indicia indicating that the first user is to run during the at least part of the exercise class. CONCLUSION The subject matter described above is provided by way of illustration only and should not be construed as limiting. Furthermore, the claimed subject matter is not limited to implementations that solve any or all disadvantages noted in any part of this disclosure. Various modifications and changes may be made to the subject matter described herein without following the examples and applications illustrated and described, and without departing from the spirit and scope of the present invention, which is set forth in the following claims.
<SOH> BACKGROUND <EOH>Humans are competitive by nature, striving to improve their performance both as compared to their own prior efforts and as compared to others. Humans are also drawn to games and other diversions, such that even tasks that a person may find difficult or annoying can become appealing if different gaming elements are introduced. Existing home and gym-based exercise systems and methods frequently lack key features that allow participants to compete with each other, converse with each other, and that gamify exercise activities. While some existing exercise equipment incorporates diversions such as video displays that present content or performance data to the user while they exercise, these systems lack the ability to truly engage the user in a competitive or gaming scenario that improves both the user's experience and performance. Such systems also lack the ability to facilitate real-time sharing of information, conversation, data, and/or other content between users, as well as between an instructor and one or more users. To improve the experience and provide a more engaging environment, gyms offer exercise classes such as aerobics classes, yoga classes, or other classes in which an instructor leads participants in a variety of exercises. Such class-based experiences, however, are accessible only at specific times and locations. As a result, they are unavailable to many potential users, generally are very expensive, and often sell-out so that even users in a location convenient to the gym cannot reserve a class. Example embodiments of the present disclosure address these problems, providing an exercise machine, embodied by an example treadmill, that incorporates multimedia inputs and outputs for live streaming or archived instructional content, socially networked audio and video chat, networked performance metrics and competition capabilities, along with a range of gamification features.
<SOH> SUMMARY OF THE INVENTION <EOH>In an example embodiment of the present disclosure, a method includes providing information about available exercise classes to a processor associated with a first exercise machine, the first exercise machine being located at a first remote location, receiving, from a first user of the first exercise machine and via the processor, a selection of one of the available exercise classes, and providing, via a network and to the processor, digital content comprising the one of the available exercise classes. Such an example method also includes receiving, via the network, a first plurality of performance parameters detected at the first exercise machine during display of at least part of the one of the available exercise classes on a display associated with the first exercise machine, the at least part of the one of the available exercise classes requiring participants to run on a treadmill. Such an example method further includes receiving, via the network, a second plurality of performance parameters detected at a second exercise machine during display of the at least part of the one of the available exercise classes on a display associated with the second exercise machine, the second exercise machine being located at a second remote location different from the first remote location. The method also includes providing, via the network, at least one parameter of the second plurality of performance parameters to the processor. In such methods, the processor is configured to cause the at least one parameter of the second plurality of performance parameters to be displayed on the display associated with the first exercise machine together with a corresponding at least one parameter of the first plurality of performance parameters. In another example embodiment of the present disclosure, an exercise machine includes a processor, a first display operably connected to the processor and configured to display content, a deck configured to move relative to a surface supporting the exercise machine, and a belt rotatable about the deck. Such an example exercise machine also includes a sensor operably connected to the processor. The sensor is configured to detect a first performance parameter of a first user running on the belt of the exercise machine during display of at least part of an exercise class on the first display. In such embodiments, the processor is configured to receive, via a network, information indicative of a second performance parameter of a second user, the second performance parameter being detected at an additional exercise machine during display of the at least part of the exercise class on a display associated with the additional exercise machine, the additional exercise machine being located at location remote from the exercise machine. In such embodiments, the processor is also configured to cause the second performance parameter to be displayed on the first display together with the first performance parameter. In a further example embodiment of the present disclosure, a method includes causing at least part of an exercise class to be displayed on a first display associated with a first treadmill, and receiving information indicative of a first performance parameter detected by a sensor associated with the first treadmill, the first performance parameter being associated with a first user running on a belt of the first treadmill during display of the at least part of the exercise class on the first display. Such an example method also includes receiving, via a network, information indicative of a second performance parameter associated with a second user, the second performance parameter being detected at a second treadmill during display of the at least part of the exercise class on a second display associated with the second treadmill, the second treadmill being located at location remote from the first treadmill. Such a method further includes causing the second performance parameter to be displayed on the first display together with the first performance parameter.
A63B240075
20170825
20180301
94831.0
A63B2400
1
ATKINSON, GARRETT K
EXERCISE SYSTEM AND METHOD
SMALL
0
ACCEPTED
A63B
2,017
15,687,132
ACCEPTED
METHODS OF THERAPEUTIC MONITORING OF NITROGEN SCAVENGING DRUGS
The present disclosure provides methods for evaluating daily ammonia exposure based on a single fasting ammonia blood level measurement, as well as methods that utilize this technique to adjust the dosage of a nitrogen scavenging drug, determine whether to administer a nitrogen scavenging drug, and treat nitrogen retention disorders.
1-11. (canceled) 12. A method of treating a subject with a urea cycle disorder (UCD) who has a fasting morning plasma ammonia level less than the upper limit of normal, the method comprising: a) administering an initial dosage of glyceryl tri-[4-phenylbutyrate]; b) after a time period sufficient for the glyceryl tri-[4-phenylbutyrate] to reach steady state, measuring a fasting morning plasma ammonia level for the subject; c) comparing the fasting morning plasma ammonia level to the upper limit of normal; and d) administering an adjusted dosage of glyceryl tri-[4-phenylbutyrate], wherein the adjusted dosage is greater than the initial dosage if the fasting morning plasma ammonia level is greater than half the upper limit of normal for plasma ammonia level. 13. The method of claim 12, wherein the time period sufficient for the glyceryl tri-[4-phenylbutyrate] to reach steady state is 48 hours. 14. The method of claim 12, wherein the time period sufficient for the glyceryl tri-[4-phenylbutyrate] to reach steady state is 48 to 72 hours. 15. The method of claim 12, wherein the time period sufficient for the glyceryl tri-[4-phenylbutyrate] to reach steady state is 72 hours to 1 week. 16. The method of claim 12, wherein the time period sufficient for the glyceryl tri-[4-phenylbutyrate] to reach steady state is 1 week to 2 weeks. 17. The method of claim 12, wherein the time period sufficient for the glyceryl tri-[4-phenylbutyrate] to reach steady state is greater than 2 weeks. 18. The method of claim 12, further comprising repeating steps (b) to (d) until the subject exhibits a fasting morning plasma ammonia level at or below half the upper limit of normal for plasma ammonia level. 19. The method of claim 12, wherein the upper limit of normal for plasma ammonia level is 35 μmol/L. 20. The method of claim 12, wherein the adjusted dosage of glyceryl tri-[4-phenylbutyrate] is administered orally.
RELATED APPLICATIONS The present application is a divisional of U.S. patent application Ser. No. 13/417,137, filed Mar. 9, 2012 and now pending, which claims the benefit of U.S. Provisional Application No. 61/564,668, filed Nov. 29, 2011, and U.S. Provisional Application No. 61/542,100, filed Sep. 30, 2011, the disclosures of which are incorporated by reference herein in their entirety, including drawings. BACKGROUND Nitrogen retention disorders associated with elevated ammonia levels include urea cycle disorders (UCDs) and hepatic encephalopathy (HE). UCDs include several inherited deficiencies of enzymes or transporters necessary for the synthesis of urea from ammonia, including enzymes involved in the urea cycle. The urea cycle is depicted in FIG. 1, which also illustrates how certain ammonia-scavenging drugs act to assist in elimination of excessive ammonia. With reference to FIG. 1, N-acetyl glutamine synthetase (NAGS)-derived N-acetylglutamate binds to carbamyl phosphate synthetase (CPS), which activates CPS and results in the conversion of ammonia and bicarbonate to carbamyl phosphate. In turn, carbamyl phosphate reacts with ornithine to produce citrulline in a reaction mediated by ornithine transcarbamylase (OTC). A second molecule of waste nitrogen is incorporated into the urea cycle in the next reaction, mediated by arginosuccinate synthetase (ASS), in which citrulline is condensed with aspartic acid to form argininosuccinic acid. Argininosuccinic acid is cleaved by argininosuccinic lyase (ASL) to produce arginine and fumarate. In the final reaction of the urea cycle, arginase (ARG) cleaves arginine to produce ornithine and urea. Of the two atoms of nitrogen incorporated into urea, one originates from free ammonia (NH4+) and the other from aspartate. UCD individuals born with no meaningful residual urea synthetic capacity typically present in the first few days of life (neonatal presentation). Individuals with residual function typically present later in childhood or even in adulthood, and symptoms may be precipitated by increased dietary protein or physiological stress (e.g., intercurrent illness). Hepatic encephalopathy (HE) refers to a spectrum of neurologic signs and symptoms believed to result from hyperammonemia, which frequently occur in subjects with cirrhosis or certain other types of liver disease. Subjects with HE typically show altered mental status ranging from subtle changes to coma, features similar to subjects with UCDs. Subjects with nitrogen retention disorders whose ammonia levels and/or symptoms are not adequately controlled by dietary restriction of protein and/or dietary supplements are generally treated with nitrogen scavenging agents such as sodium phenylbutyrate (NaPBA, approved in the United States as BUPHENYL® and in Europe as AMMONAPS®) or sodium benzoate. These are often referred to as alternate pathway drugs because they provide the body with an alternate pathway to urea for excretion of waste nitrogen (Brusilow 1980; Brusilow 1991). NaPBA is a phenylacetic acid (PAA) prodrug. Another nitrogen scavenging drug currently in development for the treatment of nitrogen retention disorders is glyceryl tri-[4-phenylbutyrate](HPN-100), which is described in U.S. Pat. No. 5,968,979. HPN-100, which is commonly referred to as GT4P or glycerol PBA, is a prodrug of PBA and a pre-prodrug of PAA. HPN-100 and NaPBA share the same general mechanism of action: PBA is converted to PAA via beta oxidation, and PAA is conjugated enzymatically with glutamine to form phenylacetylglutamine (PAGN), which is excreted in the urine. The structures of PBA, PAA, and PAGN are set forth below. The clinical benefit of NaPBA and HPN-100 with regard to nitrogen retention disorders derives from the ability of PAGN to effectively replace urea as a vehicle for waste nitrogen excretion and/or to reduce the need for urea synthesis (Brusilow 1991; Brusilow 1993). Because each glutamine contains two molecules of nitrogen, the body rids itself of two waste nitrogen atoms for every molecule of PAGN excreted in the urine. Therefore, two equivalents of nitrogen are removed for each mole of PAA converted to PAGN. PAGN represents the predominant terminal metabolite, and one that is stoichiometrically related to waste nitrogen removal, a measure of efficacy in the case of nitrogen retention states. The difference between HPN-100 and NaPBA with respect to metabolism is that HPN-100 is a triglyceride and requires digestion, presumably by pancreatic lipases, to release PBA (McGuire 2010). In contrast to NaPBA or HPN-100, sodium benzoate acts when benzoic acid is combined enzymatically with glycine to form hippuric acid. For each molecule of hippuric acid excreted in the urine, the body rids itself of one waste nitrogen atom. Methods of determining an effective dosage of PAA prodrugs such as NaPBA or HPN-100 for a subject in need of treatment for a nitrogen retention disorder are described in WO09/1134460 and WO10/025303. Daily ammonia levels, however, may vary greatly in a subject. This can lead to overestimation by the physician of the average daily ammonia levels, which may result in overtreatment. Thus, there is a need in the art for improved methods for PAA prodrug dose determination and adjustment based on ammonia levels in subjects with nitrogen retention disorders such as UCDs or HE. SUMMARY Provided herein in certain embodiments are methods for determining whether to increase a dosage of a nitrogen scavenging drug in a subject with a nitrogen retention disorder by measuring a fasting blood ammonia level and comparing the fasting blood ammonia level to the upper limit of normal (ULN) for blood ammonia, where a fasting blood ammonia level that is greater than half the ULN for blood ammonia indicates that the dosage needs to be increased. In certain embodiments, the nitrogen retention disorder is a UCD or HE. In certain embodiments, the nitrogen scavenging drug is HPN-100, PBA, NaPBA, sodium benzoate, or any combination thereof (i.e., any combination of two or more of HPN-100, PBA, NaPBA). In certain embodiments, the ULN is around 35 μmol/L or 59 μg/mL. In certain embodiments, the methods include an additional step of administering an increased dosage of the nitrogen scavenging drug if the need exists, and in certain of these embodiments administration of the nitrogen scavenging drug produces a normal average daily ammonia level in the subject. In certain embodiments wherein a determination is made to administer an increased dosage of nitrogen scavenging drug and wherein the nitrogen scavenging drug is a PAA prodrug, the methods include an additional step of measuring urinary PAGN excretion and determining an effective dosage of the PAA prodrug based on a mean conversion of PAA prodrug to urinary PAGN of 60-75%. Provided herein in certain embodiments are methods for determining whether to administer a nitrogen scavenging drug to a subject with a nitrogen retention disorder by measuring a fasting blood ammonia level and comparing the fasting blood ammonia level to the ULN for blood ammonia, where a fasting blood ammonia level that is greater than half the ULN for blood ammonia indicates that the nitrogen scavenging drug needs to be administered. In certain embodiments, the nitrogen retention disorder is a UCD or HE. In certain embodiments, the nitrogen scavenging drug is HPN-100, PBA, NaPBA, sodium benzoate, or any combination thereof (i.e., any combination of two or more of HPN-100, PBA, NaPBA). In certain embodiments, the ULN is around 35 μmol/L or 59 μg/mL. In certain embodiments, the methods include an additional step of administering a nitrogen scavenging drug if the need exists, and in certain of these embodiments administration of the nitrogen scavenging drug produces a normal average daily ammonia level in the subject. In certain embodiments wherein a determination is made to administer a nitrogen scavenging drug and wherein the nitrogen scavenging drug is a PAA prodrug, the methods further include a step of determining an effective initial dosage of the PAA prodrug by determining a target urinary PAGN output based on a target nitrogen output and calculating an effective initial dosage that results in the target urinary PAGN output based on a mean conversion of PAA prodrug to urinary PAGN of 60-75%. In certain embodiments, the methods include a step of administering the calculated effective initial dosage. Provided herein in certain embodiments are methods for treating a nitrogen retention disorder in a subject who has previously been administered a nitrogen scavenging drug by measuring a fasting blood ammonia level, comparing the fasting blood ammonia level to the ULN for blood ammonia, and administering an increased dosage of the nitrogen scavenging drug if the fasting ammonia level is greater than half the ULN for blood ammonia. In certain embodiments, administration of an increased dosage of the nitrogen scavenging drug produces a normal average daily ammonia level in the subject. In certain embodiments, the nitrogen retention disorder is a UCD or HE. In certain embodiments, the nitrogen scavenging drug is HPN-100, PBA, NaPBA, sodium benzoate, or any combination thereof (i.e., any combination of two or more of HPN-100, PBA, NaPBA). In certain embodiments, the ULN is around 35 μmol/L or 59 μg/mL. In certain embodiments wherein the nitrogen scavenging drug is a PAA prodrug, the methods include an additional step of measuring urinary PAGN excretion and determining an effective dosage of the PAA prodrug based on a mean conversion of PAA prodrug to urinary PAGN of 60-75%. In certain embodiments, the methods include a step of administering the calculated effective dosage. BRIEF DESCRIPTION OF DRAWINGS FIG. 1: The urea cycle and how certain nitrogen-scavenging drugs may assist in elimination of excessive ammonia. FIG. 2: Relationship between fasting ammonia and average ammonia UCD patients. FIG. 3: Venous blood ammonia values over 24 hours in (A) adult and (B) pediatric UCD patients. DETAILED DESCRIPTION The following description of the invention is merely intended to illustrate various embodiments of the invention. As such, the specific modifications discussed are not to be construed as limitations on the scope of the invention. It will be apparent to one skilled in the art that various equivalents, changes, and modifications may be made without departing from the scope of the invention, and it is understood that such equivalent embodiments are to be included herein. In subjects with a nitrogen retention disorder, the desired effect of treatment with a nitrogen scavenging drug is control of blood ammonia level. Control of blood ammonia level generally refers to ammonia values within the normal range and avoidance of hyperammonemic crises, which are often defined in the art as transient ammonia values exceeding 100 μmol/L or 178 μg/mL accompanied by clinical signs and symptoms of hyperammonemia. Dosing of nitrogen scavenging drugs is usually based upon clinical assessment and measurement of ammonia. However, assessment of treatment effect and interpretation of ammonia levels is confounded by the fact that individual ammonia values vary several-fold over the course of a day and are impacted by timing of the blood draw in relation to the last meal and dose of drug (see, e.g., Lee 2010; Lichter-Konecki 2011; Diaz 2011). A random ammonia value obtained during an outpatient visit may fail to provide a reliable measure of a subject's status and the drug effect. For example, basing treatment on a blood sample taken after eating a meal might overestimate average daily ammonia level and result in overtreatment. Conversely, basing treatment on a blood sample taken after drug administration might underestimate average daily ammonia level and result in undertreatment. A fasting ammonia level at or near the ULN might be taken as an indication of satisfactory control without appreciating the fact that the ammonia burden during the day (average and/or highest possible value) might be significantly higher. Thus, a fasting level at or near the ULN may actually reflect undertreatment in a subject already a receiving nitrogen scavenging drug or the need for treatment in a subject not currently prescribed a nitrogen scavenging drug. A more accurate view of daily ammonia level could be obtained by multiple blood draws in a controlled setting over an extended period of time. Although this is currently done in clinical trials, it is clinically impractical. As set forth below, the relationship between fasting ammonia levels and daily ammonia exposure was evaluated in subjects with nitrogen retention disorders. It was found that fasting ammonia correlates strongly with daily ammonia exposure, assessed as a 24 hour area under the curve for ammonia, daily average, or maximal daily concentration, and that a target fasting value which does not exceed half of the ULN is a clinically useful and practical predictor of ammonia values over 24 hours. As such, provided herein are clinically practical methods of evaluating ammonia exposure in subjects with nitrogen retention disorders based on fasting ammonia levels, as well as methods of using the resultant information to adjust the dosage of a nitrogen scavenging drug, determine whether to administer a nitrogen scavenging drug, treat a nitrogen retention disorder, and predict daily ammonia burden. The use of fasting ammonia levels to predict ammonia exposure provides a significant advantage over previously developed methods by reducing the number of required blood draws and eliminating the confusion associated with conflicting ammonia levels over the course of the day. As further disclosed herein, the relationship between ammonia control and neurocognitive outcome was evaluated in UCD patients. Previous research has demonstrated that UCD patients often exhibit lower IQ overall and deficient executive function manifested by difficulty in goal setting, planning, monitoring progress and purposeful problem solving. As set forth herein, it was found that ammonia control with GPB resulted in a significant improvement in executive functions in pediatric patients. Based on these results, methods are provided herein for improving executive function in a pediatric subject with a UCD by administering one or more nitrogen scavenging drugs. As further disclosed herein, the relationship between elevated PAA levels and neurological adverse events (AEs) was analyzed. Many of the over 30 reports of administration of NaPBA and/or sodium PAA to humans describe AEs, particularly when administered intravenously. IV administration of PAA to cancer patients was shown previously to result in AEs that included fatigue, dizziness, dysgeusia, headache, somnolence, lightheadedness, pedal edema, nausea, vomiting, and rash (Thibault 1994; Thibault 1995). These AEs correlated with PAA levels from 499 to 1285 μg/mL. Although NaPBA has been used in UCD treatment for over two decades and AEs reportedly associated with PAA are similar to those associated with hyperammonemia, little was known previously about the relationship between PAA levels and neurological AEs in UCD patients. As shown herein, increased PAA levels did not correlate with increased neurological AEs in subjects with UCD. However, PAA levels were associated with an increase in neurological AEs in healthy subjects. Based on these results, methods are provided herein for predicting or diagnosing AEs in a subject by measuring PAA levels. Further provided herein are methods of treating and/or preventing AEs in a subject with elevated PAA levels by administering one or more nitrogen scavenging drugs. Provided herein are specific target values for blood ammonia upon which an effective dosage of a nitrogen scavenging drug can be based. In certain embodiments, an effective dosage of a nitrogen scavenging drug may be an initial dosage, subsequent/maintenance dosage, improved dosage, or a dosage determined in combination with other factors. In certain embodiments, the effective dosage may be the same as or different than the initial dosage. In other embodiments, the effective dosage may be higher or lower than the initial dosage. In certain embodiments, methods are provided for adjusting the dose or regimen of a nitrogen scavenging drug to achieve a target ammonia level that is predictive of the average daily ammonia level and/or the highest ammonia value that the subject is likely to experience during the day. Using the methods herein, a subject's fasting blood ammonia level may be used as a predictor of daily ammonia burden, average daily ammonia level, and/or highest daily ammonia value. Whether a subject with a nitrogen retention disorder is receiving an optimum dosage of nitrogen scavenging drug may be determined based on predicted daily ammonia exposure. By optimizing the therapeutic efficacy of a nitrogen scavenging drug, the therapeutic dosage of the nitrogen scavenging drug is adjusted so that the subject experiences the desired nitrogen scavenging effect. In particular, the dose is adjusted so that the subject may experience a normal average daily ammonia level. In certain embodiments, the effective dosage of nitrogen scavenging drug is determined by adjusting (e.g., increasing) a dosage to achieve a fasting blood ammonia level for a subject that is less than or equal to half the ULN for blood ammonia. Provided herein in certain embodiments are methods of determining whether the dosage of a nitrogen scavenging drug needs to be increased in a subject with a nitrogen retention disorder comprising comparing a fasting blood ammonia level for the subject to a ULN for blood ammonia. If the fasting blood ammonia level has a value that greater than half the ULN, the dosage of the nitrogen scavenging drug needs to be increased. In certain embodiments, the methods further comprise increasing the dosage of the nitrogen scavenging drug if the need exists, and in certain of these embodiments the methods further comprise administering the increased dosage. In certain of these embodiments, administration of the increased dosage results in a normal average daily ammonia level in the subject. Provided herein in certain embodiments are methods of determining whether the dosage of a nitrogen scavenging drug needs to be increased in a subject with a nitrogen retention disorder comprising measuring a fasting blood ammonia level for the subject and comparing the fasting blood ammonia level to a ULN for blood ammonia. If the fasting blood ammonia level has a value that is greater than half the ULN, the dosage of the nitrogen scavenging drug needs to be increased. In certain embodiments, the methods further comprise increasing the dosage of the nitrogen scavenging drug if the need exists, and in certain of these embodiments the methods further comprise administering the increased dosage. In certain of these embodiments, administration of the increased dosage results in a normal average daily ammonia level in the subject. Provided herein in certain embodiments are methods of adjusting the dosage of a nitrogen scavenging drug in a subject with a nitrogen retention disorder comprising comparing a fasting blood ammonia level for the subject to a ULN for blood ammonia. If the fasting blood ammonia level has a value that is greater than half the ULN, the dosage of the nitrogen scavenging drug is increased, and if the dosage is less than or equal to half the ULN the dosage of the nitrogen scavenging drug is not increased. In certain embodiments, the methods further comprise administering the increased dosage. In certain of these embodiments, administration of the increased dosage results in a normal average daily ammonia level in the subject. Provided herein in certain embodiments are methods of adjusting the dosage of a nitrogen scavenging drug in a subject with a nitrogen retention disorder comprising measuring a fasting blood ammonia level for the subject and comparing the fasting blood ammonia level to a ULN for blood ammonia. If the fasting blood ammonia level has a value that is greater than half the ULN, the dosage of the nitrogen scavenging drug is increased, and if the dosage is less than or equal to half the ULN the dosage of the nitrogen scavenging drug is not increased. In certain embodiments, the methods further comprise administering the increased dosage. In certain of these embodiments, administration of the increased dosage results in a normal average daily ammonia level in the subject. Provided herein in certain embodiments are methods of adjusting the dosage of a nitrogen scavenging drug in a subject with a nitrogen retention disorder comprising measuring a fasting blood ammonia level for the subject and comparing the fasting blood ammonia level to a ULN for blood ammonia. If the fasting blood ammonia level has a value that is greater than half the ULN, the dosage of the nitrogen scavenging drug is increased, and if the dosage is significantly less than half the ULN, the dosage of the nitrogen scavenging drug may be decreased. In certain embodiments, the methods further comprise administering the adjusted dosage. In certain of these embodiments, administration of the adjusted dosage results in a normal average daily ammonia level in the subject. Provided herein in certain embodiments are methods of adjusting the dosage of a nitrogen scavenging drug in a subject with a nitrogen retention disorder comprising administering an initial dosage of the nitrogen scavenging drug, measuring fasting blood ammonia level, and comparing the fasting blood ammonia level to a ULN for blood ammonia. If the fasting blood ammonia level has a value that is greater than half the ULN, subsequent maintenance dosages of the nitrogen scavenging drug are adjusted to be greater than the initial dosage. In certain embodiments, the methods further comprise administering the increased maintenance dosage, and in certain of these embodiments, administration of the increased maintenance dosage results in a normal average daily ammonia level in the subject. Provided herein in certain embodiments are methods of adjusting the dosage of a nitrogen scavenging drug in a subject with a nitrogen retention disorder to achieve a fasting blood ammonia level that is less than or equal to half the ULN for blood ammonia comprising measuring a fasting blood ammonia level for the subject and comparing the fasting blood ammonia level to a ULN for blood ammonia. If the fasting blood ammonia level has a value that is greater than half the ULN, the subject is administered an increased dosage of the nitrogen scavenging drug. After a time period sufficient for the drug to reach steady state (e.g., 48 hours, 48 to 72 hours, 72 hours to 1 week, 1 week to 2 weeks, greater than 2 weeks), fasting blood ammonia level is measured again and compared to a ULN for blood ammonia. If the fasting blood ammonia level has a value that is greater than half the ULN, the dosage of the nitrogen scavenging drug is increased. This process is repeated until a fasting blood ammonia level of less than or equal to half the ULN is obtained. Provided herein in certain embodiments are methods for assessing whether a subject with a nitrogen retention disorder is more or less likely to need a dosage adjustment of a nitrogen scavenging drug comprising measuring a fasting blood ammonia level for the subject and comparing the fasting blood ammonia level to a ULN for blood ammonia, wherein a fasting blood ammonia level that is greater than half the value of ULN indicates that the subject is more likely to need a dosage adjustment and a fasting blood ammonia level less than or equal to half the value of ULN indicates that the subject is less likely to need a dosage adjustment. Provided herein in certain embodiments are methods of determining whether to administer a nitrogen scavenging drug to a subject with nitrogen retention disorder comprising comparing a fasting blood ammonia level for the subject to a ULN for blood ammonia. If the fasting blood ammonia level has a value that is greater than half the ULN, a nitrogen scavenging drug needs to be administered to the subject. In certain embodiments, these methods further comprise administering the nitrogen scavenging drug. In certain embodiments, the subject may not have been administered any nitrogen scavenging drugs prior to the determination. In other embodiments, the subject may have previously been administered a nitrogen scavenging drug other than the one being evaluated. In these embodiments, the methods provided herein can be used to determine whether to administer a new nitrogen scavenging drug to a subject. Provided herein in certain embodiments are methods of determining whether to administer a nitrogen scavenging drug to a subject with nitrogen retention disorder comprising measuring a fasting blood ammonia level for the subject and comparing the fasting blood ammonia level to a ULN for blood ammonia. If the fasting blood ammonia level has a value that is greater than half the ULN, a nitrogen scavenging drug needs to be administered to the subject. In certain embodiments, these methods further comprise administering the nitrogen scavenging drug. In certain embodiments, the subject may not have been administered any nitrogen scavenging drugs prior to the determination. In other embodiments, the subject may have previously been administered a nitrogen scavenging drug other than the one being evaluated. In these embodiments, the methods provided herein can be used to determine whether to administer a new nitrogen scavenging drug to a subject. Provided herein in certain embodiments are methods for selecting a dosage of a nitrogen scavenging drug for treating a nitrogen retention disorder in a subject based on blood ammonia levels comprising selecting a dosage that results in a fasting blood ammonia level that is less than or equal to half the ULN for blood ammonia. In certain embodiments, selecting the effective dosage is further based on diet, endogenous waste nitrogen excretion capacity, or any combination thereof. In certain embodiments, the methods further comprise administering the selected dosage. Provided herein in certain embodiments are methods of treating a subject with a nitrogen retention disorder who has previously been administered a nitrogen scavenging drug comprising measuring a fasting blood ammonia level for the subject and comparing the fasting blood ammonia level to a ULN for blood ammonia. If the fasting blood ammonia level has a value that is greater than half the ULN, the subject is administered an increased dosage of the nitrogen scavenging drug. If the fasting blood ammonia level has a value that is less than or equal to half the ULN, the subject is administered the same dosage or a decreased dosage of the nitrogen scavenging drug. In certain embodiments, administration of an increased dosage results in a normal average daily ammonia level in the subject. Provided herein in certain embodiments are methods of treating a subject with a nitrogen retention disorder who has previously been administered an initial dosage of a nitrogen scavenging drug comprising measuring a fasting blood ammonia level for the subject and comparing the fasting blood ammonia level to a ULN for blood ammonia. If the fasting blood ammonia level has a value that is greater than half the ULN, the subject is administered a maintenance dosage that is greater than the initial dosage of the nitrogen scavenging drug. If the fasting blood ammonia level has a value that is less than or equal to half the ULN, the subject is administered the initial dosage or a lower dosage. In certain embodiments, administration of an increased maintenance dosage results in a normal average daily ammonia level in the subject. Provided herein in certain embodiments are methods of treating a subject with a nitrogen retention disorder comprising administering a nitrogen scavenging drug, then measuring a fasting blood ammonia level for the subject at some point after drug administration and comparing the fasting blood ammonia level to a ULN for blood ammonia. If the fasting blood ammonia level has a value that is greater than half the ULN, the subject is administered an increased dosage of the nitrogen scavenging drug. If the fasting blood ammonia level has a value that is less than or equal to half the ULN, the subject is administered the original or a lower dosage of the drug. Provided herein in certain embodiments are methods of treating a subject with a nitrogen retention disorder comprising administering a first dosage of a nitrogen scavenging drug, measuring a fasting blood ammonia level for the subject, and comparing the fasting blood ammonia level to a ULN for blood ammonia. If the fasting blood ammonia level has a value that is greater than half the ULN, a second dosage of a nitrogen scavenging drug that is greater than the first dosage is administered to the subject. A fasting ammonia blood level is measured again in the subject and compared to a ULN for blood ammonia. If the fasting blood ammonia level has a value that is greater than half the ULN, a third dosage of a nitrogen scavenging drug that is greater than the second dosage is administered to the subject. This process is repeated until the subject exhibits a fasting blood ammonia level with a value less than or equal to half the ULN. Provided herein in certain embodiments are methods of monitoring the efficacy of nitrogen scavenging drug administration in a subject with a nitrogen retention disorder who has previously been administered a nitrogen scavenging drug comprising measuring a fasting blood ammonia level for the subject and comparing the fasting blood ammonia level to a ULN for blood ammonia. If the fasting blood ammonia level has a value that is greater than half the ULN, the previously administered dosage of the nitrogen scavenging drug is considered inadequate to treat the nitrogen retention disorder. If the fasting blood ammonia level has a value that is less than or equal to half the ULN, the previously administered dosage is considered adequate to treat the nitrogen retention disorder. In certain embodiments where the previously administered dosage is considered inadequate to treat the nitrogen retention disorder, the methods provided herein further comprise administering an increased dosage of the nitrogen scavenging drug. Provided herein in certain embodiments are methods for monitoring therapy with a nitrogen scavenging drug in a subject having a nitrogen retention disorder comprising measuring a fasting blood ammonia level from the subject and comparing the fasting blood ammonia level to a ULN for blood ammonia, wherein a fasting blood ammonia level that is greater than half the ULN indicates that the subject is more likely to need a dosage adjustment of the nitrogen scavenging drug, and wherein a fasting blood ammonia level less than or equal to half the ULN indicates that the subject is less likely to need a dosage adjustment. A nitrogen retention disorder as used herein refers to any condition associated with elevated blood nitrogen/ammonia levels. In certain embodiments, a nitrogen retention disorder may be a UCD. In other embodiments, a nitrogen retention disorder may be HE. A nitrogen scavenging drug as used herein refers to any drug that decreases blood nitrogen and/or ammonia levels. In certain embodiments, a nitrogen scavenging drug may remove nitrogen in the form of PAGN, and in certain of these embodiments the nitrogen scavenging drug may be an orally administrable drug that contains or is metabolized to PAA. For example, a nitrogen scavenging drug may be a PAA prodrug such as PBA or HPN-100, a pharmaceutically acceptable salt of PBA such as NaPBA, or a pharmaceutically acceptable ester, acid, or derivative of a PAA prodrug. In other embodiments, a nitrogen scavenging drug may remove nitrogen via hippuric acid. In certain of these embodiments, a nitrogen scavenging drug may be benzoic acid, a pharmaceutically acceptable salt of benzoic acid such as sodium benzoate, or a pharmaceutically acceptable ester, acid, or derivative of benzoic acid. Increasing the dosage of a nitrogen scavenging drug may refer to increasing the amount of drug per administration (e.g., an increase from a 3 mL dosage to a 6 mL dosage), increasing the number of administrations of the drug (e.g., an increase from once-a-day dosing to twice- or three-times-a-day), or any combination thereof. A subject that has previously been administered a nitrogen scavenging drug may have been administered the drug for any duration of time sufficient to reach steady state. For example, the subject may have been administered the drug over a period of 2 to 7 days, 1 week to 2 weeks, 2 weeks to 4 weeks, 4 weeks to 8 weeks, 8 weeks to 16 weeks, or longer than 16 weeks. In certain embodiments of the methods disclosed herein, the fasting period for obtaining a fasting blood ammonia level is overnight. In certain embodiments, the fasting period is 4 hours or more, 5 hours or more, 6 hours or more, 7 hours or more, 8 hours or more, 9 hours or more, 10 hours or more, 11 hours or more, or 12 hours or more, and in certain embodiments the fasting period is 4-8 hours, 6-8 hours, or 8-12 hours. During the fasting period, the subject preferably does not ingest any food. In certain embodiments, the subject may also refrain from ingesting certain non-food substances during the fasting period. For example, in certain embodiments the subject does not ingest any supplements and/or nitrogen scavenging drugs during the fasting period. In certain of these embodiments, the subject may nonetheless ingest one or more drugs other than nitrogen scavenging drugs during the fasting period. In certain embodiments, the subject does not ingest any high calorie liquids during the fasting period. In certain of these embodiments, the subject does not ingest any liquids other than water during the fasting period. In other embodiments, the subject may ingest small amounts of low calorie beverages, such as tea, coffee, or diluted juices. In certain embodiments of the methods disclosed herein, blood samples used for measuring fasting blood ammonia levels and/or ULN blood ammonias are venous blood samples. In certain embodiments, a blood sample is a plasma blood sample. Any methods known in the art may be used to obtain a plasma blood sample. For example, blood from a subject may be drawn into a tube containing heparin or ethylenediaminetetraacetic acid (EDTA). In certain embodiments, the sample can be placed on ice and centrifuged to obtain plasma within 15 minutes of collection, stored at 2-8° C. (36-46° F.) and analyzed within 3 hours of collection. In other embodiments, the blood plasma sample is snap frozen, stored at ≦−18° C. (≦0° F.) and analyzed at a later time. For example, the sample may be analyzed at 0-12 hours, 12-24 hours, 24-48, 48-96 hours after freezing, or within any other timeframe over which the sample has demonstrated stability. In certain embodiments, blood samples are taken in a laboratory or hospital setting. In certain embodiments, a single fasting blood sample is used to measure fasting blood ammonia level. However, in other embodiments, multiple fasting blood samples may be obtained. In certain embodiments, a subject's blood ammonia level may be monitored throughout the day. Further, in certain embodiments, the methods disclosed herein comprise an additional step of obtaining one or more blood samples from a subject prior to or after measuring fasting blood ammonia level. In certain embodiments, a blood sample is analyzed immediately after collection. In other embodiments, the blood sample is stored for some period between collection and analysis. In these embodiments, the sample may be stored for less than 1 hour, 1 hour to 6 hours, 1 hour to 12 hours, 1 hour to 24 hours, or 1 hour to 48 hours. In certain of these embodiments, the blood sample is stored at a temperature between 0-15° C., such as 2-8° C. In other embodiments, the blood sample is stored below 0° C. or below −18° C. Measurement of ammonia levels in a fasting blood sample is carried out using techniques known in the art. For example, ammonia levels may be measured using a colorimetric reaction or an enzymatic reaction. In certain embodiments, a colorimetric reaction may involve the use of bromophenol blue as an ammonia indicator. In these embodiments, ammonia may react with bromophenol blue to yield a blue dye. In certain embodiments, an enzymatic reaction may involve glutamate dehydrogenase catalyzing the reductive amination of 2-oxoglutarate with NH4+ and NADPH to form glutamate and NADP+. The formation of NADP+ formed is directly proportional to the amount of ammonia present in the blood sample. Therefore, the concentration of ammonia is measured based on a decrease in absorbance. In certain embodiments of the methods disclosed herein, a subject exhibiting a fasting blood ammonia level less than or equal to half the ULN for blood ammonia has an average likelihood within a confidence interval that their average daily ammonia level will remain within a normal average daily ammonia level. In certain embodiments, the average likelihood of having a normal daily ammonia value is 80% to 90%. In certain embodiments, one may predict with 95% confidence that a blood ammonia level will fall within a certain range. In certain embodiments, one can predict with 95% confidence that a true probability of predicting normal values based on fasting blood ammonia is between 65% and 93%. In other embodiments, one can predict with 80% confidence that a true probability of predicting normal values based on fasting blood ammonia is at least 70%. In certain embodiments, the average likelihood of predicting normal ammonia value based on fasting blood ammonia is about 84% with 95% confidence that the true probability is between 65% and 93%. In certain embodiments of the methods disclosed herein, a subject exhibiting a fasting blood ammonia level less than or equal to half the ULN for blood ammonia has an average likelihood within a confidence interval that their maximum daily blood ammonia level will not exceed 1.5 times the ULN for blood ammonia. In certain of these embodiments, the average likelihood is about 70% to 80%. In certain embodiments, the confidence interval is a 95% confidence interval. In certain embodiments, the average likelihood is about 75% with 95% confidence that the true probability is between 58% and 86%. In certain embodiments of the methods disclosed herein, a subject exhibiting a fasting blood ammonia level less than or equal to half the ULN for blood ammonia has an average likelihood within a confidence interval that their maximum daily blood ammonia level will be less than 100 μmol/L. In certain of these embodiments, the average likelihood is 90% to 98%. In certain embodiments, the confidence interval is 95%. In certain embodiments, the average likelihood is about 93% with 95% confidence that the true probability is between 77% and 100%. The maximal ammonia value refers to the maximum amount of ammonia that may be detected in a subject following consumption of meals, if repeated measurement of blood ammonia can be instituted to detect such maximum value over an extended period of time. Based on well-controlled clinical trials with repeated blood sampling over 24 hours, the maximum blood ammonia has been observed to occur following the third major meal of the day in the early to mid evening hours (4-8 PM, assuming that breakfast is approximately 8 AM; see, e.g., Lee 2010; Lichter-Konecki 2011). The ULN for blood ammonia typically represents the highest level in the range of normal values, which may be influenced by a variety of factors such as the assay method, types of regents, standard reference samples used, and specifications and calibration of equipment used to perform the measurement. In certain embodiments of the methods disclosed herein, the ULN for blood ammonia is determined for a subject individually. In other embodiments, the ULN for blood ammonia may be based on measurements obtained across a range of subjects (i.e., subjects with UCD or with a particular subtype of UCD, subjects with HE, healthy subjects, etc.). In certain embodiments, the ULN for blood ammonia may represent a standard reference value disclosed in the art, such as a mean ULN developed across a particular subset of subjects. In other embodiments, the ULN for blood ammonia may represent a standard measurement that has been developed by a particular entity that performs blood draws and/or blood evaluations, such as a particular clinical laboratory. In certain embodiments, the ULN is a standard reference value utilized by the same entity that measures the fasting blood ammonia level. In these embodiments, one skilled in the art will appreciate that interpretation of average daily ammonia in subject with a nitrogen retention disorder must be made relative to the reference range of normal values at the laboratory in which the ammonia was measured. Furthermore, the units of ammonia measurement may also vary from lab to lab (e.g., μg/mL or μmol/L), emphasizing the importance of interpreting the subject's ammonia levels relative to the ULN at the laboratory in which the measurement was performed. In certain embodiments, the ULN for blood ammonia may be in the range of 26-64 μmol/L. In certain of these embodiments, the ULN for blood ammonia may be in the range of 32-38 μmol/L or 34-36 μmol/L, and in certain of these embodiments the ULN for blood ammonia is 35 μmol/L. In certain embodiments, the ULN for blood ammonia may be in the range of 50-65 μg/mL. In certain of these embodiments, the ULN for blood ammonia may be in the range of 55-63 μg/mL or 57-61 μg/mL, and in certain of these embodiments the ULN for blood ammonia is 59 μg/mL. In certain embodiments, the average daily ammonia is the average amount of ammonia an individual may experience during the day, if serial blood sampling were performed for ammonia measurements. In well-controlled clinical studies, it has been established that ammonia fluctuates several fold during the day, depending on the timing of blood draw relative to food and drug intake. Due to these fluctuations, the timing of individual or serial blood sampling should be controlled relative to the timing of food and drug intake. Even serial sampling may not be enough to capture the peaks and troughs of the fluctuating ammonia values, unless samples are taken frequently enough. Therefore, obtaining a simple average of several measurements may provide inadequate or misleading information regarding the total ammonia burden a subject may experience during the day. Provided herein are methods to better estimate a subject's average daily ammonia assessed as the area under the curve for 24-hr ammonia (ammonia AUC0-24 hr) obtained from adequate and well-spaced samples over 24 hours. This ammonia AUC0-24 hr can be further normalized for the entire actual period of sampling, i.e., ammonia AUC0-24 hr is divided by the sampling period (e.g., 24 hours). For example, if an AUC of 1440 μmol*hr/L is calculated using the trapezoidal rule based on 8-11 ammonia values obtained over 24 hours, then the average daily ammonia value or time-normalized AUC0-24 hr would be equal to 1440 μmol*hr/ml divided by the sampling time of 24 hr, or 60 μmol/L. If the normal reference range at the laboratory which performed the ammonia analysis was 10-35 μmol/L, then the average daily ammonia value for this subject would be approximately 1.71 times the ULN of 35 μmol/L. Similarly, if the ammonia AUC0-24 hr was determined to be equal to 840 μmol*hr/L based on multiple, well-spaced samples over 24 hours and analyzed at the same laboratory, and the sampling period was 24 hours, then the time-normalized AUC0-24 hr would be 35 μmol/L. This corresponds to an average ammonia or daily ammonia burden within the ULN. Finally, subjects with nitrogen retention disorders such as UCDs may experience a hyperammonemic crisis, which is often defined clinically as a blood level exceeding 100 μmol/L and clinical manifestations of hyperammonemia, which may require intervention to prevent irreversible hard and enable recovery. Provided herein are methods of adjusting nitrogen scavenging drug dosage by measuring fasting blood ammonia to minimize the likelihood a subject may experience an ammonia value (Cmax) over 24 hours that exceeds 100 μmol/L. It has been found that 100 μmol/L corresponds to approximately 2-3 times the ULN in most laboratories. Previously, if a subject with a nitrogen retention disorder such as UCD had a blood ammonia level within or slightly above the normal reference range for the laboratory which performed the analysis, the subject was considered to be in good clinical control regardless of the timing of the blood draw in relation to meals and last administration of drug dose. However, it has been shown that a subject with a UCD who has a fasting blood ammonia level between the ULN and 1.5 times the ULN (e.g., 35 to 52 μmol/L) has an average likelihood of only 45% (with a 95% confidence interval of 21% to 70%) that his or her average daily ammonia is within the normal range; an average likelihood of only 35% (with a 95% confidence interval of 13% to 60%) that his or her maximal level of ammonia during the day is less than 1.5 times the ULN (e.g., 52 μmol/L); and an average likelihood of 25% that his or her maximal daily ammonia level exceeds 100 μmol/L during the day. Thus, after measuring a UCD subject's fasting blood ammonia, the dosage of a nitrogen scavenging drug may be progressively increased and/or his or her protein intake progressively decreased until the fasting ammonia value is less than or equal to half of the ULN for the local laboratory in which the ammonia analysis was performed. In certain embodiments of the methods disclosed herein, one or more factors other than ammonia level may be taken into consideration when evaluating nitrogen scavenging drug dosage. For example, blood ammonia measurements may be combined with urinary PAGN measurements in determining whether to administer a nitrogen scavenging drug, adjusting the dosage of a nitrogen scavenging drug, or treating a nitrogen retention disorder. US Patent Publication No. 2010/0008859 discloses that urinary PAGN levels correlate more closely to PBA prodrug dosage than plasma PAA, PBA, or PAGN levels, and further discloses that PBA prodrugs are converted to urinary PAGN with a mean efficiency of 60-75%. Therefore, certain embodiments of the methods disclosed herein comprise an additional step wherein urinary PAGN levels are measured. In certain of these embodiments, calculation of an effective dosage of nitrogen scavenging drug is based in part on a mean 60-75% conversion of PAA prodrug to urinary PAGN. For example, in certain embodiments the methods disclosed herein for determining whether to administer a nitrogen scavenging drug to a subject comprise an additional step of measuring urinary PAGN and calculating an effective initial dosage based on a mean conversion of PAA prodrug to urinary PAGN of 60-75%. Similarly, in certain embodiments the methods disclosed herein for adjusting the dosage of a nitrogen scavenging drug comprise an additional step of measuring urinary PAGN and calculating an effective dosage based on a mean conversion of PAA prodrug to urinary PAGN of 60-75%. In certain of these embodiments, the effective dosage is calculated based on a target nitrogen output. In certain embodiments, urinary PAGN may be determined as a ratio of the concentration of urinary PAGN to urinary creatinine. In certain embodiments, urinary PAGN is a factor that is taken into consideration when determining whether to administer or increase the dosage of a nitrogen scavenging drug, i.e., urinary PAGN is evaluated in combination with ammonia level to determine whether to administer or increase the dosage of the drug. In other embodiments, ammonia level alone is used to determine whether to administer or increase the dosage of a nitrogen scavenging drug, and urinary PAGN is simply used to calculate the initial or adjusted dosage. One skilled in the art will recognize that a variety of other factors may be taken into consideration when determining the effective dosage of a nitrogen scavenging drug. For example, factors such as diet (e.g., protein intake) and endogenous waste nitrogen capacity (e.g., urea synthesis capacity) may be considered. Provided herein in certain embodiments are kits for carrying out the methods disclosed herein. In certain embodiments, kits are provided for determining whether to administer or adjust the dosage of a nitrogen scavenging drug for a subject with a nitrogen retention disorder. The kits disclosed herein may include one or more nitrogen scavenging drugs and/or one or more reagents (e.g., bromophenol blue) or enzymes (e.g., glutamate dehydrogenase) to measure blood ammonia levels in a sample. The kit may additionally include other pigments, binders, surfactants, buffers, stabilizers, and/or chemicals necessary to obtain a blood sample and to measure the ammonia level in the sample. In certain embodiments, the kits provided herein comprise instructions in a tangible medium. One of ordinary skill in the art will recognize that the various embodiments described herein can be combined. The following examples are provided to better illustrate the claimed invention and are not to be interpreted as limiting the scope of the invention. To the extent that specific materials are mentioned, it is merely for purposes of illustration and is not intended to limit the invention. One skilled in the art may develop equivalent means or reactants without the exercise of inventive capacity and without departing from the scope of the invention. It will be understood that many variations can be made in the procedures herein described while still remaining within the bounds of the present invention. It is the intention of the inventors that such variations are included within the scope of the invention. EXAMPLES Example 1: Analysis of Predictability of Pharmacodynamic Ammonia Values from Fasting Ammonia in UCD Patients This example demonstrates the relationship between fasting ammonia and the pharmacodynamic (PD) profile of daily ammonia in patients receiving PAA prodrugs for UCDs. Ammonia values vary many-fold over the course of 24 hours in UCD patients. As depicted in FIGS. 3a and 3b, venous ammonia was measured for 24 hours following one week of dosing with either NaPBA or glycerol phenylbutyrate (GPB). The graphs display ammonia values as mean±SD over 24 hours, where time zero corresponds to just prior to dosing and breakfast (i.e., fasting state). In view of this variability in daily ammonia levels, a single measurement may not be very informative in determining whether a UCD patient is optimally dosed. The ability to predict the highest potential ammonia a UCD patient may experience during the day and the average 24-hour ammonia from a single measurement such as fasting levels has important practical implications for nitrogen scavenging drug dosing guidelines and patient management. Data from two Phase 2 studies and one Phase 3 study comparing ammonia control assessed by 24-hour sampling during steady state treatment with HPN-100 versus NaPBA in 65 UCD patients were used for the analysis. The two Phase 2 studies include protocols UP 1204-003 and HPN-100-005 (Lee 2010; Lichter-Konecki 2011). The Phase 3 study includes protocols from HPN-100-006 (Diaz 2011). Ammonia values obtained from different hospital laboratories with different normal ranges were normalized to a standard laboratory range of 9-35 μmol/L. The patient population included a broad range of ages, UCD subtypes, and doses of drug, and is summarized in Table 1 below. TABLE 1 UCD demographics in studies UP 1204-003, HPN-100-005, and HPN-100-006: Gender Male 18 (27.7) n (%) Female 47 (72.3) Age at screening N 65 (years) Mean (SD) 29.46 (15.764) Median 24.00 Range 6.0-75.0 UCD diagnosis OTC deficiency 57 (87.7) n (%) CPS1 deficiency 1 (1.5) ASS deficiency 5 (7.7) ASL deficiency 1 (1.5) Missing 1 (1.5) Duration of NaPBA N 63 treatment Mean (SD) 114.14 (90.147) (months) Median 101.00 Range 0.2-300.0 Daily dose NaPBA N 64 Mean (SD) 14.10 (6.255) Median 13.50 Range 1.5-36.0 Exploratory Analysis: Several PD parameters for steady-state ammonia were explored: AUC0-24 hr, time-normalized AUC, log AUC, maximal ammonia value over 24 hours (Cmax), and average ammonia. Data from 65 subjects from all three studies with steady-state ammonia and fasting ammonia were used. Missing data were imputed per procedures specified in the protocol and statistical analysis plan, except that no imputations were made for subjects who had no PK sampling conducted while on a given study drug. Sample collection times of 0-hr (before first daily dose) and 24-hours post-dose (before first daily dose of the following day) were both evaluated as representative of fasting ammonia. No noticeable difference in the shape or quality of the relationship due to the choice of time point was observed. The relationship between fasting ammonia and pharmacokinetic profile was evaluated separately for HPN-100 and NaPBA, with no apparent difference in the strength or magnitude of the relationship. Therefore, all data from both HPN-100 and NaPBA treatments were used and conclusions regarding fasting ammonia pertain to both HPN-100 and NaPBA. The relationships between (1) fasting ammonia and AUC0-24 hr and (2) fasting ammonia and maximum observed ammonia (Cmax) were visually explored for the whole population. The effects of the following covariates were also observed: age, weight, gender, and dietary protein intake. A positive and strong relationship was observed between fasting ammonia and AUC0-24 hr, with increasing fasting ammonia being associated with higher AUC0-24 hr and maximum observed ammonia (FIG. 2). Prediction of AUC0-24 hr Through GEE Modeling: The aim of this modeling was to predict average daily or highest achieved ammonia based on the subject's fasting ammonia. In order to take into account the differences in normal ranges at different laboratories, all ammonia values were normalized to a reference range of 9-35 μmol/L, and the predictions were referenced to the ULN rather than a fixed value. Generalized Estimating Equations (GEE) were used to model the predictive ability of fasting ammonia against various ammonia PD properties. GEE methodology can be used to analyze repeated measures of categorical data, in which the repeated measures are assumed to be correlated (Liang 1986). The model allows for the specification of the assumed correlation structure without the knowledge of the magnitude of the correlation. The 24-hour ammonia profile was divided into ordered categories using a variety of endpoints and cutpoints as follows: 1) AUC [0-1.0*ULN, >1.0*ULN]; 2) AUC [0-1.5*ULN, >1.5*ULN]; 3) Cmax [0-1.0*ULN, >1.0*ULN]; 4) Cmax [0-1.5*ULN, >1.5*ULN]; and 5) Cmax [0-100] μmol/L. Three levels of fasting ammonia were considered in separate models as input: 1) [0-0.5*ULN]; 2) [>0.5*ULN-<1.0 ULN]; and 3) [>1.0*ULN-1.5*ULN]. Using Statistical Analysis Software (SAS) Proc Genmod, generalized linear models were fit with a logit link function. Pre-dose fasting ammonia was the only predictor variable in the model. The repeated nature of the data (two study periods per subject) was modeled using GEE with exchangeable correlation matrix. ULN for fasting ammonia was set at 35 μmol/L. ULN for AUC over 24 hours was taken as 840 (35 μmol/L*24 hours); i.e., the AUC which corresponds to an average daily ammonia less than or equal to 35 μmol/L, which was the normalized ULN among the participating study sites and is derived by dividing the 24-hour area under the curve by the sampling time of 24 hours. The GEE model was bootstrap-resampled 1,000 times according to the method outlined in Davison, A. C. & Hinkley, D. V., Bootstrap Methods and their Application, Cambridge University Press, London (1997), pp. 358-362. The results of these models are shown in Table 2 below. TABLE 2 Summary of results from GEE model to predict ability of fasting ammonia against various ammonia PD properties: Fasting Probability of Bootstrap Model ammonia Ammonia outcome in Bootstrap Bootstrap pred. error # level PK outcome category 95% c.i. 80% c.i. rate* (%) 1 [0-0.5 AUC in 24 0.84 0.67, 0.93 0.71, 0.89 11.5 ULN] hours [0-1.0 ULN] 2 AUC in 24 Did not converge hours [0-1.5 ULN] 3 Cmax 0.53 0.38, 0.65 0.42, 0.61 45.8 observed [0-1.0 ULN] 4 Cmax 0.76 0.61, 0.86 0.66, 0.82 23.3 observed [0-1.5 ULN] 5 Cmax 0.93 0.78, 1.00 0.85, 0.97 5.7 observed [0-100] 6 [0-<1.0 AUC in 24 0.58 0.42, 0.73 0.48, 0.68 42.8 ULN] hours [0-1.0 ULN] 7 AUC in 24 0.88 0.78, 0.97 0.82, 0.94 11.1 hours [0-1.5 ULN] 8 AUC in 24 0.97 0.90, 1.00 0.93, 1.00 2.2 hours [0-2 ULN] 9 Cmax 0.21 0.11, 0.38 0.14, 0.33 20.0 observed [0-1.0 ULN] 10 Cmax 0.52 0.35, 0.66 0.42, 0.61 46.0 observed [0-1.5 ULN] 11 Cmax 0.74 0.62, 0.85 0.91, 1.00 27.2 observed [0-2.0 ULN] 12 Cmax 0.95 0.88, 1.00 0.66, 0.81 4.3 observed [0-100] 13 [>1.0-1.5 AUC in 24 0.45 0.24, 0.71 0.30, 0.63 43 ULN] hours [0-1.0 ULN] 14 AUC in 24 Did not converge hours [0-1.5 ULN] 15 AUC in 24 0.80 0.49, 0.99 0.63, 0.92 27 hours [0-2 ULN] 16 Cmax Did not converge observed [0-1.0 ULN] 17 Cmax 0.35 0.16, 0.58 0.23, 0.51 33 observed [0-1.5 ULN] 18 Cmax Did not converge observed [0-2.0 ULN] 19 Cmax Did not converge observed [0-100] From Table 2 above, we can conclude that in the population of UCD patients described in Table 1, we can be 95% confident that, given a fasting ammonia less than or equal to half the ULN, the true probability of having an AUC in the range [0-840] is on average 84%, at least 67%, and as high as 93%. Row 1 of Table 2 above suggests that a UCD patient with a fasting ammonia of 17 μmol/L as determined by a laboratory with a normal reference range of 9-35 μmol/L (i.e., a fasting ammonia in the range [0-0.5 ULN]) has an 84% chance (with a 95% confidence interval of 67% to 93%) of having a time normalized AUC0-24 hr in the normal range [AUC0-24 hr of 0-840 or an average daily ammonia of 35 μmol/L], a 76% chance (with a 95% confidence interval of 61% to 86%) of having a Cmax of less than 1.5 ULN, and a 93% chance (with a 95% confidence interval of 78% to 100%) of never having an ammonia of more than 100 μmol/L. Therefore, this patient would be optimally controlled and unlikely to suffer from high ammonia during the day. This Example shows that fasting ammonia correlates strongly with daily ammonia exposure, assessed as a daily average or as maximal daily concentration, and that a target fasting value which does not exceed half of the upper level of normal for the local lab appears to be a clinically useful as well as practical predictor of ammonia values over 24 hours as well. Furthermore, this Example shows that a subject with a fasting ammonia in the range 0-0.5 ULN has an 84% chance of having an AUC0-24 hr in the normal range (0-840 or an average daily ammonia of 35 μmol/L). Example 2: Selecting and Adjusting HPN-100 Dosage Based on Fasting Blood Ammonia Levels in a Patient with UCD Patient A is an adult with UCD being managed with amino acid supplements and dietary protein restriction only. Patient A consumes neither his supplements nor food for approximately 8 hours prior to a fasting morning blood draw. A venous blood draw is performed, and fasting blood ammonia level is determined to be 52 μmol/L. This fasting blood ammonia level is compared to the ULN for blood ammonia in the laboratory performing the blood draw, which is 35 μmol/L. Based on the correlation of fasting ammonia level to average ammonia level, it is determined that Patient A's fasting blood ammonia level of approximately 1.5 times the ULN represents only a 45% chance on average of having an average ammonia during the day within the normal range. Thus, the ratio of fasting blood ammonia level to ULN for blood ammonia indicates that Patient A will benefit from treatment with a nitrogen scavenging drug. The physician elects to treat Patient A with HPN-100. Initial dosage is determined based on body surface area or as otherwise instructed according to HPN-100 drug labeling. Patient A's body surface area is 1.4 m2, and therefore the initial dosage is determined to be 9 mL per day or 3 mL TID, which is approximately 60% of the maximum allowed dosage per HPN-100 label. Patient A is treated with 9 mL/day of HPN-100 for at least 7 days, and returns for an additional blood draw. The fasting blood ammonia level at this time is 33 μmol/L, which is slightly below the ULN and falls into the range of 0.5 to 1.0 times normal. Patient A's blood ammonia level is monitored throughout the day after administration of a 3 mL dose of HPN-100 with each meal. It is observed that Patient A's maximum ammonia reaches 95 μmol/L after dinner with an average daily ammonia of 66 μmol/L, which is almost two times the upper normal range. Therefore, Patient A's dosage of HPN-100 is increased by approximately one-third to 12 mL total or 4 mL TID. Patient A returns after at least 7 days of treatment with HPN-100. Patient A's fasting ammonia level is 15 μmol/L, which is less than half of the ULN range. It is determined that Patient A has reached satisfactory ammonia control. It is expected that if Patient A adheres to his prescribed diet, his maximal daily ammonia is not expected to exceed approximately 52 μmol/L, i.e., approximately 1.5 times the ULN, with an average likelihood of 75% with 95% confidence. The average ammonia level during the day is expected to remain within normal range with greater than 84% likelihood and 95% confidence. Moreover, Patient A's maximal daily ammonia is highly unlikely to reach 100 μmol/L during the day. Example 3: Adjusting HPN-100 Dosage Based on Fasting Blood Ammonia Levels in a Patient with UCD Patient B is an 11-year UCD patient receiving 24 pills of BUPHENYL® per day, amino acid supplements, and restricted dietary protein intake. Patient B does not consume BUPHENYL®, supplements, or food for approximately 6 hours prior to a fasting morning blood draw. A venous blood draw is performed, and fasting blood ammonia level is determined to be 40 μmol/L. This fasting blood ammonia level is compared to the ULN for blood ammonia for the laboratory performing the blood draw, which is 35 μmol/L. Based on the correlation of fasting ammonia level to average ammonia level, it is determined that Patient B's fasting blood ammonia level falling between 1 and 1.5 times the ULN represents a 55% chance of having an average ammonia during the day that is greater than the normal range, and as high as a 65% chance that her ammonia will go above 52 μmol/L or 1.5 times ULN during the day. Based on discussion with the patient and her mother, the physician suspects that Patient B is noncompliant with her medication, and decides to change her to HPN-100. The initial dosage is determined based on the amount of BUPHENYL® Patient B was receiving, and it is determined that Patient B needs to take 10.5 mL of HPN-100 per day. Patient B is treated with 3.5 mL of HPN-100 3 times a day for at least 7 days, and returns for additional blood draws. Her fasting blood ammonia level at this time is 17 μmol/L, which is below the ULN and falls into the range of 0 to 0.5 times normal. It is determined that Patient B has reached satisfactory ammonia control. It is expected that if Patient B adheres to her prescribed diet, her maximal daily ammonia will not go above approximately 50 μmol/L, which is less than 1.5 times the ULN. Her average ammonia level during the day is expected with greater than 84% average likelihood to remain within normal range. Moreover, there is only a small chance (7%) that Patient B's maximal daily ammonia will exceed 100 μmol/L during the day. Example 4: Selecting and Adjusting Sodium Benzoate Dosage Based on Fasting Blood Ammonia Levels in a Patient with UCD Patient C is an adult UCD patient who is allergic to PBA and is therefore being managed with amino acid supplements and dietary protein restriction only. Patient C complains of chronic headache and frequent nausea. Patient C consumes neither his supplements nor food for approximately 8 hours prior to a fasting morning blood draw. A venous blood draw is performed, and fasting blood ammonia level is determined to be 77 μmol/L. This fasting blood ammonia level is compared to the ULN for blood ammonia for the laboratory performing the blood draw, which is 35 μmol/L. Based on the correlation of fasting ammonia level to average ammonia level, it is determined that Patient C's fasting blood ammonia level of approximately 2 times the ULN represents a high likelihood of ammonia levels going over 100 μmol/L during the day. Thus, the ratio of fasting blood ammonia level to ULN for blood ammonia indicates that Patient C will benefit from treatment with a nitrogen scavenging drug. The physician decides to treat Patient C with 15 g of sodium benzoate per day since the patient is allergic to PBA. Patient C is treated with 15 g/day of sodium benzoate for at least 7 days, and returns for additional blood draws. Fasting blood ammonia level at this time is 35 μmol/L, which is equal to the ULN. Patient C's dosage of sodium benzoate is increased by approximately 30% to 18 grams per day. After at least 7 days of treatment, Patient C's fasting ammonia level is 15 μmol/L, which is less than half of the ULN. It is determined that Patient C has reached satisfactory ammonia control. It is expected that if Patient C adheres to his prescribed diet and medication, his maximal daily ammonia will not exceed approximately 52 μmol/L, which is approximately 1.5 times the ULN. His average ammonia level during the day is expected with greater than 80% likelihood to remain within normal range. Moreover, Patient C's maximal daily ammonia is highly unlikely to reach 100 μmol/L during the day. Example 5: Evaluation of the Effect of Ammonia Control on Neurocognitive Outcome It has been shown that UCD patients are likely to suffer from diminished intelligence and impaired neurocognitive functions (Kirvitsky 2009). These neuropsychological impairments have been attributed to repeated episodes of acute hyperammonemia interspersed on chronically elevated ammonia. Abnormalities in neuropsychological function and/or brain imaging have been detected even in UCD patients with mild disorders who exhibit normal IQ and/or appear clinical normal (Gropman 2008a; Gropman 2008b). Therefore, it was hypothesized that maintaining average daily ammonia within normal limits and thereby reducing the long term ammonia burden could result in improved cognition. The relationship between reducing ammonia burden by maintaining fasting ammonia at or close to half ULN and neuropsychological outcomes in pediatric UCD patients was explored in clinical trials. Eleven pediatric patients ages 6-17 were enrolled in short term switch over comparison of NaPBA and HPN-100 in controlling ammonia. These patients underwent 24-hr serial sample collection in a confined setting where the last sample at 24 hr was considered fasting and under supervision of the study personnel. At the end of treatment with HPN-100 the average fasting ammonia at 24-hr time point was 15.5 μmol/L or less than half ULN, indicating good clinical control. These 11 patients along with another 15 pediatric patients were enrolled in two long term studies and received HPN-100 for 12 months, during which monthly fasting ammonia were collected. At the time of enrollment and at the end of the study, all patients underwent assessment for neuropsychological outcomes including the following: BRIEF (Behavior Rating Inventory of Executive Function) to assess day-to-day executive functioning, CBCL (Child Behavior Checklist) to evaluate internalizing (e.g., mood/anxiety) and externalizing behaviors, and WASI (Wechsler Abbreviated Scale of Intelligence) to estimate of intellectual ability. During the 12 month treatment with HPN-100, pediatric UCD patients experienced fewer episodes of acute hyperammonemia than in the 12 months preceding enrollment (5 episodes during the study versus 9 before enrollment), with peak ammonia dropping from a mean of 233 μmol/L before enrollment to 166 μmol/L during the study. Fasting ammonia remained controlled and monthly averages were at or close to half ULN, ranging from 17 to 22 μmol/L. Although patients had been instructed to remain fasting before monthly study visits, some ammonia samples were taken in a non-fasted state, resulting in average monthly ammonia of slightly above half ULN. In pediatric patients, WASI and CBCL scores were stable in comparison to baseline. The majority of the BRIEF subscales at baseline were at or close to 65, consistent with borderline and/or clinically significant dysfunction. Among 22 pediatric subjects who completed the neuropsychological testing at 12 months, all BRIEF domains were improved (lower T scores) with means (SD) at end of study compared to baseline for Behavioral Regulation Index 53.7 (9.79) vs. 60.4 (14.03) (p<0.05); Metacognition Index 57.5 (9.84) vs. 67.5 (13.72) (p<0.001), and Global Executive Scale 56.5 (9.71) vs. 66.2 (14.02) (p<0.001). The significant improvement in executive functions in this group of pediatric UCD patients indicates the importance of long term ammonia control and achieving target levels of fasting ammonia. Example 6: Correlation of Elevated PAA Levels to Neurological AEs in UCD and Healthy Subjects Elevated plasma levels of PAA may cause symptoms that mimic those associated with hyperammonemia, including headache, nausea, somnolence, etc. Since such symptoms are common and nonspecific, an ammonia level below half the upper limit of normal in a subject with a nitrogen retention disorder who exhibits such symptoms and is receiving a PAA prodrug would prompt a physician to check plasma PAA levels. The relationship between elevated PAA levels and neurological AEs was evaluated in three populations: (1) 130 healthy adults dosed with 4 to 12 mL TID of GPB in a thorough QTc study, (2) 54 adult and 11 pediatric UCD patients (ages 6-17) enrolled in one of 3 protocols involving short term (2-4 week) switchover comparisons of NaPBA vs. GPB, and (3) 77 patients enrolled in two nearly identical 12-month GPB treatment protocols. In populations 1 and 2, maximal PAA (i.e., Cmax) levels were analyzed in relation to neurological AEs as defined by MEDDRA using an Exact non-parametric Mann-Whitney test and Generalized Estimating Equations (GEE) with a logit link function and effects for dose and PAA level. The relationship between PAA levels and the occurrence of the AEs reported by Thiebault was also explored in population 3. No statistically significant relationship was observed between neurological AEs and PAA levels for either GPB or NaPBA. The odds ratio of a neurological AE occurring for each 20 μg/mL increase in PAA levels for the two drugs combined was 0.95, very close to 1. Thus, among UCD patients dosed with HPN-100 or NaPBA over the ranges used in these studies, increasing levels of PAA (ranging up to 244 μg/mL) were not associated with an increase in neurological AEs. Similarly, in population 3, PAA levels did not increase over time and exhibited no apparent relationship to neurological AEs, which also did not increase in frequency over time. The pediatric patient with the highest PAA level (410 μg/mL) did not report neurological AEs close to the timing of the blood draw. Unlike UCD subjects, healthy adult volunteers who reported a nervous system AE had statistically significantly higher PAA Cmax levels than those who did not. While this analysis in healthy adults is compromised by the fact that PAA levels were not always available at the time of occurrence of the AEs, as well as by the small sample size in the higher dose groups, the odds ratio of 1.75 (p=0.006) suggests that increasing levels of PAA are associated with increased probability of experiencing a nervous system AE among healthy adults. AEs reported by healthy adults generally began within 36 hours of dosing and, among those adults who remained on study, most resolved with continued dosing. A significant relationship between PAA levels and occurrence of neurological AEs, which generally resolved with continued dosing, was detected in healthy volunteers. Unlike in healthy adults, PAA Cmax did not correlate with nervous system AEs in UCD patients over a similar range of doses and PAA levels. These findings may reflect metabolic differences among the populations (e.g., UCD patients exhibit high glutamine levels compared with healthy humans) and/or metabolic adaptation with continued dosing. Population PK model building was performed on 65 UCD patients who participated in the short-term switchover Hyperion studies using NONMEM (version 7.2) based on 2981 ([PBA], [PAA], [PAGN], and urine PAGN [UPAGN])) data points from 53 adult and 11 pediatric UCD patients (ages 6-17) who participated in 3 switchover studies of NaPBA and GPB. The median GPB dose, expressed as grams of PBA per m2, was 8.85 and 7.01 for pediatric and adult subjects, respectively. Diagnostic plots and statistical comparisons were used to select among candidate models, and covariates were assessed by graphical analyses and covariate modeling. Using the final popPK model and parameter estimates, Monte Carlo simulations were performed in ˜1000 virtual patients for a range of NaPBA and GPB doses to predict systemic metabolite exposure and UPAGN output. The final model that best fit the data was characterized by (a) partial conversion of PBA to PAGN prior to reaching the systemic circulation, (b) saturable conversion of PAA to PAGN (Km ˜161 ug/ml), and (c) ˜60% slower PBA absorption when delivered as GPB vs. NaPBA. Body surface area (BSA) was a significant covariate such that metabolite clearance was proportionally related to BSA. Fractional presystemic metabolism of PBA was higher for adults than for pediatric patients receiving GPB (43% vs. 14%), whereas the reverse was true for NaPBA (23% vs. 43%). Predicted median PAA exposure based on simulated GPB dosing at the PBA equivalent of 13 g/m2 of NaPBA was ˜13%-22% lower in adults than NaPBA (Cmax=82 vs. 106 μg/mL; AUC0-24=649 vs. 829 μg·h/m) and ˜13% higher in pediatric subjects ages 6-17 than NaPBA (Cmax=154 vs. 138 μg/mL; AUC0-24=1286 vs. 1154 μg·h/ml); predicted upper 95th percentile PAA exposure was below 500 μg/mL and 25%-40% lower for adult subjects on GPB versus NaPBA and similar for pediatric subjects. Simulated dosing at the PBA equivalent of ˜5 g/m2 of NaPBA yielded similar and less variable PAA exposure for both drugs and for pediatric and adult patients. Recovery of PBA as UPAGN was very similar whether delivered orally as GPB or NaPBA. These findings based on PopPK modeling and dosing simulations suggest that while most patients treated with PAA prodrugs including NaPBA or HPN-100 will have PAA levels below those reportedly associated with toxicity and while no relationship between PAA levels and neurological AEs was found on a population basis, individual patients exhibiting symptoms such as headache or nausea might be suffering from either hyperammonemia or high PAA levels and that a fasting ammonia level equal to or below half the upper limit of normal would prompt the physician to check plasma PAA levels. As stated above, the foregoing is merely intended to illustrate various embodiments of the present invention. The specific modifications discussed above are not to be construed as limitations on the scope of the invention. It will be apparent to one skilled in the art that various equivalents, changes, and modifications may be made without departing from the scope of the invention, and it is understood that such equivalent embodiments are to be included herein. All references cited herein are incorporated by reference as if fully set forth herein. REFERENCES 1. Brusilow Science 207:659 (1980) 2. Brusilow Pediatr Res 29:147 (1991) 3. Diaz Mol Genet Metab 102:276 (2011) 4. Gropman Mol Genet Metab 94:52 (2008a) 5. Gropman Mol Genet Metab 95:21 (2008b) 6. Lee Mol Genet Metab 100:221 (2010) 7. Liang Biometrika 73:13 (1986) 8. Lichter-Konecki Mol Genet Metab 103:323 (2011) 9. McGuire Hepatology 51:2077 (2010) 10. Thibault Cancer Res 54:1690 (1994) 11. Thibault Cancer 75:2932 (1995)
<SOH> BACKGROUND <EOH>Nitrogen retention disorders associated with elevated ammonia levels include urea cycle disorders (UCDs) and hepatic encephalopathy (HE). UCDs include several inherited deficiencies of enzymes or transporters necessary for the synthesis of urea from ammonia, including enzymes involved in the urea cycle. The urea cycle is depicted in FIG. 1 , which also illustrates how certain ammonia-scavenging drugs act to assist in elimination of excessive ammonia. With reference to FIG. 1 , N-acetyl glutamine synthetase (NAGS)-derived N-acetylglutamate binds to carbamyl phosphate synthetase (CPS), which activates CPS and results in the conversion of ammonia and bicarbonate to carbamyl phosphate. In turn, carbamyl phosphate reacts with ornithine to produce citrulline in a reaction mediated by ornithine transcarbamylase (OTC). A second molecule of waste nitrogen is incorporated into the urea cycle in the next reaction, mediated by arginosuccinate synthetase (ASS), in which citrulline is condensed with aspartic acid to form argininosuccinic acid. Argininosuccinic acid is cleaved by argininosuccinic lyase (ASL) to produce arginine and fumarate. In the final reaction of the urea cycle, arginase (ARG) cleaves arginine to produce ornithine and urea. Of the two atoms of nitrogen incorporated into urea, one originates from free ammonia (NH 4 + ) and the other from aspartate. UCD individuals born with no meaningful residual urea synthetic capacity typically present in the first few days of life (neonatal presentation). Individuals with residual function typically present later in childhood or even in adulthood, and symptoms may be precipitated by increased dietary protein or physiological stress (e.g., intercurrent illness). Hepatic encephalopathy (HE) refers to a spectrum of neurologic signs and symptoms believed to result from hyperammonemia, which frequently occur in subjects with cirrhosis or certain other types of liver disease. Subjects with HE typically show altered mental status ranging from subtle changes to coma, features similar to subjects with UCDs. Subjects with nitrogen retention disorders whose ammonia levels and/or symptoms are not adequately controlled by dietary restriction of protein and/or dietary supplements are generally treated with nitrogen scavenging agents such as sodium phenylbutyrate (NaPBA, approved in the United States as BUPHENYL® and in Europe as AMMONAPS®) or sodium benzoate. These are often referred to as alternate pathway drugs because they provide the body with an alternate pathway to urea for excretion of waste nitrogen (Brusilow 1980; Brusilow 1991). NaPBA is a phenylacetic acid (PAA) prodrug. Another nitrogen scavenging drug currently in development for the treatment of nitrogen retention disorders is glyceryl tri-[4-phenylbutyrate](HPN-100), which is described in U.S. Pat. No. 5,968,979. HPN-100, which is commonly referred to as GT4P or glycerol PBA, is a prodrug of PBA and a pre-prodrug of PAA. HPN-100 and NaPBA share the same general mechanism of action: PBA is converted to PAA via beta oxidation, and PAA is conjugated enzymatically with glutamine to form phenylacetylglutamine (PAGN), which is excreted in the urine. The structures of PBA, PAA, and PAGN are set forth below. The clinical benefit of NaPBA and HPN-100 with regard to nitrogen retention disorders derives from the ability of PAGN to effectively replace urea as a vehicle for waste nitrogen excretion and/or to reduce the need for urea synthesis (Brusilow 1991; Brusilow 1993). Because each glutamine contains two molecules of nitrogen, the body rids itself of two waste nitrogen atoms for every molecule of PAGN excreted in the urine. Therefore, two equivalents of nitrogen are removed for each mole of PAA converted to PAGN. PAGN represents the predominant terminal metabolite, and one that is stoichiometrically related to waste nitrogen removal, a measure of efficacy in the case of nitrogen retention states. The difference between HPN-100 and NaPBA with respect to metabolism is that HPN-100 is a triglyceride and requires digestion, presumably by pancreatic lipases, to release PBA (McGuire 2010). In contrast to NaPBA or HPN-100, sodium benzoate acts when benzoic acid is combined enzymatically with glycine to form hippuric acid. For each molecule of hippuric acid excreted in the urine, the body rids itself of one waste nitrogen atom. Methods of determining an effective dosage of PAA prodrugs such as NaPBA or HPN-100 for a subject in need of treatment for a nitrogen retention disorder are described in WO09/1134460 and WO10/025303. Daily ammonia levels, however, may vary greatly in a subject. This can lead to overestimation by the physician of the average daily ammonia levels, which may result in overtreatment. Thus, there is a need in the art for improved methods for PAA prodrug dose determination and adjustment based on ammonia levels in subjects with nitrogen retention disorders such as UCDs or HE.
<SOH> SUMMARY <EOH>Provided herein in certain embodiments are methods for determining whether to increase a dosage of a nitrogen scavenging drug in a subject with a nitrogen retention disorder by measuring a fasting blood ammonia level and comparing the fasting blood ammonia level to the upper limit of normal (ULN) for blood ammonia, where a fasting blood ammonia level that is greater than half the ULN for blood ammonia indicates that the dosage needs to be increased. In certain embodiments, the nitrogen retention disorder is a UCD or HE. In certain embodiments, the nitrogen scavenging drug is HPN-100, PBA, NaPBA, sodium benzoate, or any combination thereof (i.e., any combination of two or more of HPN-100, PBA, NaPBA). In certain embodiments, the ULN is around 35 μmol/L or 59 μg/mL. In certain embodiments, the methods include an additional step of administering an increased dosage of the nitrogen scavenging drug if the need exists, and in certain of these embodiments administration of the nitrogen scavenging drug produces a normal average daily ammonia level in the subject. In certain embodiments wherein a determination is made to administer an increased dosage of nitrogen scavenging drug and wherein the nitrogen scavenging drug is a PAA prodrug, the methods include an additional step of measuring urinary PAGN excretion and determining an effective dosage of the PAA prodrug based on a mean conversion of PAA prodrug to urinary PAGN of 60-75%. Provided herein in certain embodiments are methods for determining whether to administer a nitrogen scavenging drug to a subject with a nitrogen retention disorder by measuring a fasting blood ammonia level and comparing the fasting blood ammonia level to the ULN for blood ammonia, where a fasting blood ammonia level that is greater than half the ULN for blood ammonia indicates that the nitrogen scavenging drug needs to be administered. In certain embodiments, the nitrogen retention disorder is a UCD or HE. In certain embodiments, the nitrogen scavenging drug is HPN-100, PBA, NaPBA, sodium benzoate, or any combination thereof (i.e., any combination of two or more of HPN-100, PBA, NaPBA). In certain embodiments, the ULN is around 35 μmol/L or 59 μg/mL. In certain embodiments, the methods include an additional step of administering a nitrogen scavenging drug if the need exists, and in certain of these embodiments administration of the nitrogen scavenging drug produces a normal average daily ammonia level in the subject. In certain embodiments wherein a determination is made to administer a nitrogen scavenging drug and wherein the nitrogen scavenging drug is a PAA prodrug, the methods further include a step of determining an effective initial dosage of the PAA prodrug by determining a target urinary PAGN output based on a target nitrogen output and calculating an effective initial dosage that results in the target urinary PAGN output based on a mean conversion of PAA prodrug to urinary PAGN of 60-75%. In certain embodiments, the methods include a step of administering the calculated effective initial dosage. Provided herein in certain embodiments are methods for treating a nitrogen retention disorder in a subject who has previously been administered a nitrogen scavenging drug by measuring a fasting blood ammonia level, comparing the fasting blood ammonia level to the ULN for blood ammonia, and administering an increased dosage of the nitrogen scavenging drug if the fasting ammonia level is greater than half the ULN for blood ammonia. In certain embodiments, administration of an increased dosage of the nitrogen scavenging drug produces a normal average daily ammonia level in the subject. In certain embodiments, the nitrogen retention disorder is a UCD or HE. In certain embodiments, the nitrogen scavenging drug is HPN-100, PBA, NaPBA, sodium benzoate, or any combination thereof (i.e., any combination of two or more of HPN-100, PBA, NaPBA). In certain embodiments, the ULN is around 35 μmol/L or 59 μg/mL. In certain embodiments wherein the nitrogen scavenging drug is a PAA prodrug, the methods include an additional step of measuring urinary PAGN excretion and determining an effective dosage of the PAA prodrug based on a mean conversion of PAA prodrug to urinary PAGN of 60-75%. In certain embodiments, the methods include a step of administering the calculated effective dosage.
A61K31235
20170825
20180508
20180118
81418.0
A61K31235
1
RAO, SAVITHA M
METHODS OF THERAPEUTIC MONITORING OF NITROGEN SCAVENGING DRUGS
UNDISCOUNTED
1
CONT-ACCEPTED
A61K
2,017
15,687,719
PENDING
METHODS OF USING GAP JUNCTIONS AS THERAPEUTIC TARGETS FOR THE TREATMENT OF DEGENERATIVE DISORDERS OF THE RETINA
The disclosure provides methods of treating a condition of the retina by administering an inhibitor of connexin 36 and/or an inhibitor of connexin 45 to a subject with a retinal condition. This disclosure further provides compositions for the treatment of a retinal condition which include an inhibitor of connexin 36 and/or an inhibitor of connexin 45.
1. A method of treating a condition of the retina comprising administering an inhibitor of connexin 36 and/or an inhibitor of connexin 45 to a subject in need thereof. 2. The method of claim 1, comprising administration of both an inhibitor of connexin 36 and an inhibitor of connexin 45. 3. The method of claims 1 or 2 wherein said condition of the retina is selected from glaucoma, macular degeneration, retinitis pigmentosa, diabetic retinopathy and retinal ischemia. 4.-8. (canceled) 9. The method of any of claims 1-3 wherein said inhibitor is a small molecule inhibitor. 10. The method of claim 9 wherein said small molecule inhibitor is selected from 18-Beta-glycyrrhetinic acid (18Beta-GA) and meclofenamic acide (MFA). 11. The method of claim 1, comprising repeat administration of said inhibitor or inhibitors for a period of 1 week to 1 year. 12. The method of claim 2, wherein said administration is topical administration or intraocular injection. 13.-19. (canceled)
CROSS-REFERENCE TO RELATED APPLICATIONS The present application is a divisional of a co-pending application having U.S. Ser. No. 15/317,171, filed Dec. 8, 2016, which is a 371 of International application having Serial No. PCT/2015/035226, filed Jun. 11, 2015, which claims priority to U.S. provisional application 62/011,354, filed Jun. 12, 2014, which is incorporated herein in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under grant number R01 EY007360 awarded by the National Institutes of Health. The government has certain rights in the invention. INCORPORATION BY REFERENCE OF SEQUENCE LISTING The Sequence Listing in the ASCII text file, named as 31144A_SequenceListing.txt of 12 KB bytes, created on Aug. 24, 2017, and submitted to the United States Patent and Trademark Office via EFS-Web, is incorporated herein by reference. BACKGROUND OF THE DISCLOSURE In addition to the intrinsic mechanisms underlying primary cell death, intercellular communication appears to play a major, but presently unclear, role in so-called secondary cell death (Andrade-Rozental A F, et al., Brain Res. Rev 32:308-315 (2000)). Damage in the central nervous system (CNS) leads to the death of a limited cohort of vulnerable cells, which, in turn, pass toxic molecules via gap junctions (GJs) to coupled neighbors. There is now substantial evidence that cells that are clustered and can thereby communicate via GJs tend to die en mass under a broad range of neurodegenerative conditions (Frantseva et al., J. Cereb. Blood Flow Metab. 22:453-462 (2002); Cusato et al., Cell Death Differ 13:1707-1714 (2006); Lei et al., Br J Ophthalmol. 93:1676-1679 (2009); Wang et al., J Neurophysiol 104:3551-3556 (2010). In this scheme, GJs act as portals for the passage of apoptotic signals from injured cells to those to which they are coupled, which can ultimately be the cause of most cell loss (Kenner et al., Cell Tissue Res 298:383-395 (1999); Perez Velazquez et al., Neuroscientist 9:5-9 (2003); Decrock et al., Cell Death Differ 16:524-536 (2009); Belousov and Fontes, Trends Neurosci 36:227-236 (2013)). There is increasing evidence that GJs are involved in various neurodegenerative ocular disorders, including ischemic retinopathy and glaucoma (Krysko, Apoptosis 10:459-469 (2005); Malone, Glia 55:1085-1098 (2007); Das et al., Biochem Biophys Res Commun 373:504-508 (2008); Kerr et al., J Clin Neurosci 18:102-108(2011); Danesh-Meyer et al., Brain 135:506-520 (2012)). The topography of neuronal loss in the inner retina seen with these pathologies often includes both a diffuse, but clustered pattern suggesting that dying retinal ganglion cells (RGCs) influence neighboring cells, resulting in secondary neuronal degeneration (Levkovitch-Verbin, Invest Ophthalmol Vis Sci 42:975-982 (2001); Lei et al., Br J Ophthalmol. 93:1676-1679 (2009); Vander et al., Curr Eye Res 37:740-748 (2012)). The GJ-mediated secondary cell death, or so-called “bystander effect”, has also been implicated in the programmed cell death in the developing retina. Like in the adult, dying cells in developing retina are spatially clustered into distinct networks (Cusato et al., Cell Death Differ 13:1707-1714 (2003); de Rivero Vaccari et al., J. Neurophysiol 98:2878-2886 (2007)). Dopamine, which is a modulator of al communication, as well as the GJ blockers octant and carbenoxolone significantly reduce the rate of programmed and induced cell death in young retinas and the clustering of the remaining dying cells (Varella et al., J Neurochem 73:485-492 (1999); Cusato, Cell Death Differ 13:1707-1714 (2003)). Amacrine cells (ACs) form the largest cohort of retinal neurons, comprising over 30 distinct morphological subtypes that subserve complex synaptic interactions in the inner plexiform layer (In), which are largely responsible for the diverse physiological properties expressed by RGCs (Demb J B, et al., Vis Neurosci. 29:51-60 (2012)). Studies of glaucomatous human retinas have reported an apparent delayed or secondary degeneration of amacrine cells subsequent to RGC cell loss (Schwartz Eur J Ophthalmol Suppl 3:S27-31 (2002); Kielczewski et al., Invest Ophthahnol Vis Sci 46:3188-3196 (2005); Moon et al., Cell Tissue Res. 320:51-59 (2005)). However, whether ACs are adversely affected in glaucoma remains unclear as conflicting experimental results have been reported (Kielczewski J L, et al., Invest Ophthalmol Vis Sci. 46:3188-96 (2005); GA, Barnett N L., et al. Clin Experiment Ophthalmol. 39:555-63 (2011); Moon J I, et al., Cell Tissue Res. 320:51-9 (2005); Jakobs T C, et al., J Cell Biol. 171:313-25 (2005)). One explanation for the discrepant findings may be the difficulty in clearly identifying ACs and thereby measuring their loss. For example, in addition to RGCs, displaced amacrine cells (dACs) comprise about 50% of the neurons found in the GCL of the mouse retina (Schlamp C L, et al., Mol Vis. 19:1387-96 (2013)) and no single labeling method can provide complete coverage due to their wide morphological diversity. Interestingly, it has been reported that 16 of the 22 morphological subtypes of RGCs in the mouse retina are coupled to ACs (Völgyi B, et al., J Comp Neurol. 512:664-87 (2009)). This extensive coupling suggests that GJ-mediated secondary cell death would likely progress from RGCs to their coupled AC neighbors or vice versa. A downregulation of calretinin (CR), calbindin (CB), and choline acetyltransferase (ChAT) have been reported in ischemic retinas (Dijk and Kamphius, Brain Res. 1026:194-204 (2004); Bernstein and Guo, Invest Ophthalmol Vis Sci 52:904-910 (2011); Lee et al., Apoptosis 11:1215-1229 (2011)), suggesting that the loss of the AC immunoreactivity may be due to reduced protein detection rather than cell death. Changes in the expression and function of certain connexin subtypes in CNS have been reported under a variety of pathological conditions (Rouach et al., Biol. Cell. 94:457-475 (2002); Petrash-Parwez et al., J. Comp Neurol 479:181-197 (2004); Eugenin et al., J. Neuroimmune Pharmacol 7:499-518 (2012); Kerr et al., J. Clin Neurosci 28:102-108 (2012)). In addition, the conductance of GJ hemichannels, related to their connexin makeup, appears related to their ability to support bystander cell death (Kameritsch et al., Cell Death Dis 4:1-9 (2013)). The conductance of GJs, based on their connexin makeup, appears related to their ability to support bystander cell death (Kameritsch P, et al., Cell Death Dis. 4:e584 (2013)). In addition, changes in the expression of certain connexin subtypes in CNS have been reported under a variety of pathological conditions (Kerr N M, et al., Exp Neurol. 234:144-52, (2012); Rouach N, et al., Biol Cell. 94:457-75 (2002); Petrasch-Parwez et al., J Comp Neurol. 479:181-97 (2004); Eugenin E A, et al., J Neuroimmune Pharmacol. 7:499-518 (2012)). Thus, the degree to which a particular GJ contributes to secondary cell death is likely dependent on which of the different types of connexin subunits it expresses as well as the insult condition. The fact that at least three connexin subtypes are expressed in the IPL of the retina raises the notion that different cohorts of GJs, based on their connexin profile, may be responsible for secondary cell death in the inner retina arising from different primary insults. In contrast, some studies have reported that GJs may actually protect cells. Evidence for this “good Samaritan” role include the findings that GJ inhibitors can induce apoptosis (Lee et al., Anat Cell Biol 44:25-34 (2006); Hutnik et al., Invest Ophthalmol Vis Sci 49:800-806 (2008)) and that deletion of GJ connexins can increase neuronal loss (Naus et al., Cell Commun. Adhes 8:325-328 (2001); Striedinger et al., Eur J Neurosci 22:605-6016 (2005)). It has been posited that GJs are portals by which healthy cells provide dying neighbors with rescue signals or that the coupled syncytium can dilute toxic substances (Krysko et al., PLoS One 8:e57163 (2005)). Apoptotic conditions induce various changes in the structure of GJs, including phosphorylation of connexins (Lin et al., Exp Eye Res 85:113-122 (2007)), suggesting that the connexin makeup of a GJ may be a critical factor in determining its contribution to cell death or survival. The retina displays arguably the highest expression of GJs in the CNS, which are widely distributed amongst the five neuronal types and express a variety of connexin subunits (Bloomfield and Völgyi, Nat Rev Neurosci 10:495-506 (2009)). GJ-mediated secondary cell death has been implicated in retinal neuron loss seen under a number of degenerative conditions, including retinitis pigmentosa, glaucoma, and ischemia (Ripps, Exp Eye Res 74:327-336 (2002); Das et al., Biochem Biophys Res Commun 373:504-508 (2008)). On the other hand, deletion of connexins have failed to increase the survivability of cone photoreceptors in a mouse model of retinitis pigmentosa (Kranz et al., PLoS One 8:e57163 (2013)) and has been reported to increase cell loss after retinal trauma (Striedinger et al., Eur J Neurosci 22:605-6016 (2005)), suggesting that GJs can in fact be neuroprotective. Thus, the role of retinal GJs in cell death and survival, and in the development or worsening of ocular conditions, remains unclear. BRIEF SUMMARY OF THE DISCLOSURE Disclosed herein are methods for treating a condition of the retina, by administering an inhibitor of connexin 36 and/or an inhibitor of connexin 45 to a subject with a retinal condition. In some embodiments, both an inhibitor of connexin 36 and an inhibitor of connexin 45 are administered. The condition of the retina can be selected, for example, from glaucoma, macular degeneration, retinitis pigmentosa, diabetic retinopathy and retinal ischemia. In any of the above methods, the inhibitor can be selected from an antisense polynucleotide directed to connexin 36 messenger ribonucleic acid (mRNA), an antisense polynucleotide directed to connexin 45 mRNA, and combinations thereof. Preferred antisense polynucleotide inhibitors are those that selectively bind the sequence of SEQ ID NO: 1 or SEQ ID NO: 2. The antisense polynucleotide can be complementary to all of or a portion of connexin 36 mRNA and/or connexin 45 mRNA. The antisense polynucleotide can be the exact complement of all or a portion of connexin 36 mRNA and/or connexin 45 mRNA. The antisense polynucleotide can hybridize to connexin 36 mRNA and/or connexin 45 mRNA with a melting temperature of greater than 20° C., 30° C. or 40° C. under physiological conditions. Alternatively, the inhibitor can be a small molecule inhibitor. Exemplary small molecule inhibitors include 18-Beta-glycyrrhetinic acid (18Beta-GA or 18β-GA) and meclofenamic acid (MFA). Any of the above methods can include repeat administration of the inhibitor or inhibitors for a period of one week to one year. Any of the above methods can further include topical administration, such as a drop to be administered to the eye, or intraocular injection. Further disclosed herein are pharmaceutical compositions for treatment of a retinal condition. The compositions can include an inhibitor of connexin 36 and/or an inhibitor of connexin 45. In one example, the inhibitor or inhibitors can be selected from an antisense molecule directed to connexin 36 mRNA, an antisense molecule directed to connexin 45 mRNA, and combinations thereof. In another example, the composition includes a small molecule inhibitor of connexin 36 and/or a small molecule inhibitor of connexin 45. The small molecule inhibitor or inhibitors can be selected, for example, from 18-Beta-glycyrrhetinic acid (18Beta-GA) and meclofenamic acide (MFA). Any of the disclosed compositions can be formulated for intraocular injection or topical administration to the eye. Further disclosed herein are uses of any of the disclosed compositions for the treatment of a condition of the retina. In some examples, the condition of the retina can be selected from glaucoma, macular degeneration, retinitis pigmentosa, diabetic retinopathy and retinal ischemia. BRIEF DESCRIPTION OF THE FIGURES The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. FIGS. 1A-1I. Injection of cytochrome C (CytC) into single cells results in GJ-mediated apoptosis of neighboring coupled cells. A-F, Representative photomicrographs of uncoupled (A-C), and coupled (D-F) RGCs in whole mount retina injected with the mixture of Neurobiotin (NB) and CytC to visualize GJ coupling and to induce cell apoptosis, respectively. C, Overlay of panels (A), and (B) shows apoptosis of the impaled RGC (asterisk), but not any neighboring cells. F, Overlay of panels (D) and (E) shows that apoptosis was spread amongst neighboring cells coupled to impaled RGC. G-I, Representative confocal image of coupled Müller cells in retinal vertical section, one of which (asterisk) was injected with NB+ CytC (G) and then labeled with anti-caspase 3 antibody (H) to detect apoptotic cells. (I), Overlay of panels (G) and (H) shows spread of death in coupled neighboring Müller cells. Scale bars=20 μm (A-C and G-I) and 50 m (D-F). FIGS. 2A-2E. N-methyl-D-aspartate (NMDA)-induced excitotoxic cell death is significantly reduced by gap junction blockers. (A, C), NMDA-induced cell death in the GCL of control retinas, and those treated for 30 min with 25 μM of 18β-GA (B), or 50 μM of MFA (D) prior exposing to NMDA (300 μM). In experiments illustrated on upper panels, live and dead cells are marked with calcein-AM (green) and ethidium homodimer (EthD, red), respectively. In experiments on lower panels, retrograde labeling through optic nerve cut with LY was used to label RGCs and then retinas processed with EthD to detect dead cells. (E), Histogram summarizes the protective effect of GJ blockers on RGCs against NMDA-induced excitotoxicity. The number of dead cells was counted manually per unit area from 5 different visual fields in the GCL of whole-mount retinas pretreated with 18β-GA (n=12/3), or MFA (n=42/5), and numbers were normalized to one obtained in retinas exposed to NMDA alone (control, n=44/5). **p<0.001 vs. control. Scale bar=100 μm. FIGS. 3A-3E. Blockade of GJs reduced retinal injury and cell death following ischemia-reperfusion. (A) In control retinas, glial fibrillary acidic protein (GFAP) expression was confined exclusively to astrocytes in the GCL and nerve fiber layer (NFL). (B) Seven days after reperfusion the inner retinal thickness was reduced and the GFAP immunoreactivity appeared to traverse throughout the retinal layers and in the Müller cell processes. (C), Intravitreal injection of MFA (500 μM, 2 μl) prevented changes in the retinal morphology and reduced GFAP immunoreactivity. (D) Histogram shows the nuclear counts in the GCL of vertical sections of control (n=19/5; sections/retinas), and ischemic retinas in the presence (n=16/5) or absence (n=16/5) of MFA. (E) Histogram quantifies the GFAP immunofluorescence intensity throughout the vertical section in control and ischemic retinas with or without MFA treatment. MFA was injected intravitreally either once 30 min before (blue, n=16/5), or twice at 3 and 24 hours after (yellow, n=12/3) ischemic insult vs. untreated ischemic retina). Retinal sections were counterstained with PI. *p<0.01. Scale bar=50 μm. FIGS. 4A-4G. Visualization of AC subpopulations with low and high degrees of coupling to retrograde labeled RGCs. (A, C), Retinal GCs in control eyes were retrograde labeled for 40 min with NB, and double labeled with antibodies against amacrine cell marker calretinin (CR), or choline acetyltransferase (ChAT). Cells positive to both NB and corresponding AC markers are shown by arrowheads. (B, D), Blockade of GJs with MFA significantly reduced the number of Neurobiotin-labeled, DR-IR amacrine cells in the INL, but had little effect on ChAT-IR cell numbers. (E), Histogram shows that while the total number of CR-IR cells (per 500 μm section) in the inner nuclear layer (INL) of MFA-treated retinas was comparable to that in control (n=18/4, p>0.1), the number of those labeled with Neurobiotin was significantly reduced by MFA-treatment (n=8/3). (F), There was no significant difference in the number of NB-positive ChAT-IR cells in control (n=16/3), and MFA-treated retinas (n=6/3, p>0.1). (G), Histogram quantifying the percentage of CR-IR and ChAT-IR amacrine cells in the INL that are coupled to RGCs under control conditions. *p<0.01. Scale bars=50 μm. FIGS. 5A-5L. Amacrine cells that are extensively coupled to RGCs show higher susceptibility to NMDA-induced excitotoxicity. (A), Calretinin (CR) labels a large number of cells in the INL and GCL of control retina. (B), In retinas exposed for 1 h to NMDA (300 μM), the number of CR-positive cells was significantly reduced. (C), In vitro treatment of retinas with MFA (50 μM, 30 min) prevented reduction in the number of CR-IR cells in the INL. (D), Histogram summarizing NMDA-induced changes in the number of CR-positive ACs in the INL of untreated (n=18/3) and MFA-treated retinas (n=10/3). (E), Calbindin (CB) labeled horizontal cells in control retina. (F), Exposure to NMDA reduced the number of CB-IR cells in the proximal INL. (G), Blockade of GJs with MFA prevented such reduction. (H), Histogram summarizing NMDA-induced changes in the number of CB-positive ACs in the INL of untreated (n=22/3) and MFA treated retinas (n=6/3). The number of ChAT-IR ACs in control retinas (I-L), No significant change in the number of ChAT-IR ACs was observed in NMDA-treated retinas compared to controls (n=20/4). Retinal sections were counterstained with PI. *p<0.01 vs. control. Scale bars=50 μm. FIGS. 6A-6L. Amacrine cells with a high degree of coupling to RGCs show higher susceptibility to ischemia-reperfusion injury. (A-C), Calretinin-IR cells in control retinas and in those subjected to ischemia-reperfusion injury in the absence and presence of MFA. (D), Histogram summarizing alteration in the number of CR-IR ACs in the INL of ischemic retinas with (n=26/5) or without (n=48/5) MFA-treatment. (E), Calbindin (CB) immunoreactivity was localized to the horizontal cells and ACs in the INL and sparse GCs. Three strata in the IPL were labeled as well. (F), Changes in retinal morphology and the number of CB-IR cells following ischemia/reperfusion. (G), Blockade of GJs by MFA largely prevented a reduction in the number of CB-IR cells. (H), Histogram summarizing changes in CB-IR cells in the INL of control and ischemic retinas untreated (n=17/3), or treated (n=21/3) with MFA. (I-L), No detectable change in the number of ChAT-IR ACs was observed in ischemic retinas compared to levels in controls (n=25/4 each, p>0.1). Retinal sections were counterstained with PI. *p<0.001 vs. control. Scale bars=50 μm. FIGS. 7A-7E. Gap junctions formed by Cx36 mediate bystander cell death under excitotoxic conditions. (A-D), Neuronal death was measured by EthD staining in whole-mount retinas of heterozygous (Het), Cx36−/−, Cx36−/−/45−/− double knock-out (dKO), and Cx45−/− mice. (E), Histogram quantifying excitotoxic cell death in the GCL of retinas from Het and connexin knock out (KO) mice. Compared to Hets (n=35/3), the reduction in NMDA-induced cell death was statistically significant in retinas of Cx36−/− (n=35/3), and Cx36−/−/Cx45−/− dKO (n=13/3) mice, but not in Cx45−/− (n=17/3; p>0.1). *p<0.001 vs. Het. Scale bar=50 μm. FIGS. 8A-8J. Gap junctions formed by Cx45 mediate bystander cell death under ischemic conditions. (A), lucifer yellow (LY) retrogradely labeled RGC somas and their axons in control retina of Het mouse, ischemic Het retina (B), Cx36−/− retina (C), and Cx45−/− retina (D). (E), Immunoreactivity of GFAP in vertical sections of control retina and ischemic retinas of Het (F), Cx36−/− (G), and Cx45−/− (H) mice. Following ischemia-reperfusion, the GFAP immunoreactivity was upregulated throughout the retinal layers of Het and Cx36−/−, but not Cx45−/− mice. (I), Histogram shows the nuclear cell count (per 500 μm length of vertical sections) in the GCL of control (n=54/5), and ischemic retinas of Het (n=28/3), Cx36−/− (n=24/4) and Cx45−/− (n=74/5) mice. (J), Quantification of GFAP immunofluorescence intensity in the ischemic retinas of Het (n=24/4), Cx36−/− (n=24/4), and Cx45−/− (n=22/4, p>0.1) mice. *p<0.001 vs. control. Scale bars=100 μm (A-D), 50 μm (E-H). FIGS. 9A-9L. Changes in the immunolabeling of Cx36 and Cx45 in the IPL of retinas subjected to excitotoxic or ischemic insults. (A), In control retina Cx36 immunoreactivity appeared as punctate labeling predominantly in the inner half of the IPL. (B), In ischemic retinas the punctuate pattern of Cx36 labeling appeared as large clusters surrounding the cell nucleus. (C), NMDA-induced excitotoxicity had little effect on the pattern of Cx36 immunolabeling. (D), Histogram shows significant reduction in the intensity of punctate Cx36 immunoreactivity in the IPL of ischemic retinas (n=7/3) compared to that in controls (n=21/3). No detectable change in the Cx36 immunolabeling was observed under excitotoxic conditions (n=8/3). (E), There was no significant difference in NMDA-induced cell death in the Het and Cx36−/− retinas (n=21/3; p>0.1). (F), NMDA-induced cell death was significantly less in Cx36−/− (n=35/3) compared to Het retina (n=14/3). (G), Punctate immunolabeling for Cx45 was observed throughout the IPL of control retina. (H), The punctuate pattern and the intensity Cx45 labeling were not altered by ischemia-reperfusion. I, NMDA markedly reduced Cx45 immunolabeling. (J), Histogram quantifies Cx45 immunoreactivity in the IPL of retinas exposed to NMDA (n=8/4), compared to those in control (n=28/4), and ischemic retinas (n=26/4). (K), Cell death was significantly less in ischemic retinas of Cx45−/− mice (n=24/5) as compared to that in Het mice (n=30/5). (L), There was no statistically significant difference in NMDA-induced cell death between Het and Cx45−/− retinas (n=18/3, p>0.1). **p<0.001. *p<0.01. Scale bars=20 μm. FIGS. 10A-10D. Elevation of intraocular pressure (IOP) and progressive cell loss in an experimental model of glaucoma induced by microbead injection into the eye. (A), Mean IOP measured over an 8 week period following injection of microbeads (red) or control phosphate buffered saline (PBS) (black) into eyes of wild type (WT) mice. The elevated IOP produced by microbead injection started to decline at 2 weeks and so a second injection was performed at 4 weeks following initial procedure. (B), Expression of GFAP in control retinas was limited mainly to astrocytes in the GCL and nerve fiber layer (NFL). Calibration bar for B=50 μm and pertains to C as well. (C), Eight weeks after microbead injection, the GFAP expression expanded to Müller cell processes that extended vertically through the retinal layers. (D), Normalized cell counts in the GCL (per 630 μm length) of retinal sections made under control conditions and 1, 4 and 8 weeks after first microbead injection. There was a 20% decrease in total cell count in the GCL at 4 weeks and a 36% decrease at 8 weeks after microbead injection compared to control values. Bars represent mean±SD. **p<0.01; ***p<0.001 (Student's t-test). FIGS. 11A-11F. Blockade of gap junctions with MFA prevents loss of cells in GCL in microbead-injected eyes. Pharmacological blockade of GJs with MFA promotes RGC protection in experimental glaucoma. (A), Vertical sections of retinas from WT mice under control conditions and those subjected to microbead injection without (B), or with (C) intravitreal injection of MFA. Under control conditions or 8 weeks after the initial microbead injection, eyes were retrogradely labeled with Neurobiotin (red), to visualize RGCs and the ACs and dACs to which they are coupled via GJs. Sections were then subsequently immunolabeled for Brn3a (green), to identify RGCs, and counter-stained with the nuclear fluorogen 4′,6′-diamidino-2-phenylindole (DAPI) (blue), to visualize nuclei of all cells for cell counts. D-E. Histograms comparing the total cell (RGC+dAC) and RGC counts in the GCL of microbead-injected retinas from WT mice untreated (D) or treated with MFA (E) to block GJs. Microbead injection clearly induced cell loss in the GCL, but blockade of GJs prevented the loss. (F), Brn3A immunolabeling of RGCs in flat mount view. Calibration bar in A=50 μm and pertains to B and C. Cell counts are per 1.3 mm length of retinal section. Bars represent mean±standard error of the mean (SEM). **p<0.01 (Student's t-test). FIGS. 12A-12I. Experimental glaucoma results in cell loss with AC populations. Immunolabels for AC populations, including CR, ChAT, and GABA were made in retinas of WT mice under control conditions (A, D, G) and 8 weeks after initial microbead injection (B, E, H). Cell counts were carried out in both the INL for ACs and GCL for dACs in vertical sections (C, F, I). There was a significant reduction of cells within all the different populations of ACs/dACs after microbead injection. Cells counts are per 630 μm length of retinal section. Calibration bar in A=50 μm and pertains to B-H. Histogram bars represent mean±SEM. *p<0.05, **p<0.01 (Student's t-test). FIGS. 13A-13B. Ablation of Cx45 prevents loss of coupled dACs in experimental glaucoma. Cell counts of total cells in the GCL based on DAPI label and coupled and uncoupled dACs taken as those labeled by retrograde Neurobiotin injection and those not labeled by Neurobiotin nor Brn3a, respectively. Counts were made in WT (A) and Cx45−/− mice (B) under control conditions and 8 weeks after initial microbead injection. Microbead injection resulted in a loss of coupled dACs, but there was a small increase in uncoupled dACs. However, there was no loss in coupled or uncoupled dACs in the Cx45−/− mouse retinas. Bars represent mean±SEM. Differences in cell count values between control and microbead-injected WT mice were all significant (p<0.05; Students t-test). None of the differences in cell count values between control and microbead-in-jected Cx45−/− mice were significant (p>0.1 for each, Students t-test). FIGS. 14A-14E. Genetic ablation of Cx36, Cx45 or both Cx36/45 significantly reduces cell loss in experimental glaucoma. (A), Normalized (to control) total cell counts in the GCL of WT under control conditions and WT and connexin KO mice retinas 8 weeks after initial microbead injection to elevate IOP. There was a decrease in cell loss of 45% and 50%, respectively, in Cx36−/− and Cx45−/− glaucomatous mouse retinas compared to values in glaucomatous WT retinas. We observed a 94% reduction in cell loss in glaucomatous Cx36−/−/Cx45−/− retinas indicating an additive effect of ablating both connexins. (B-C), Confocal images of vertical sections immunolabeled with Brn3a illustrating a significant protection of RGCs in microbead-injected retinas of Cx36−/−/Cx45−/− mouse retina compared to WT. Calibration bar in B=50 μm and pertains to C as well. (D-E), Histograms showing changes in the number of total cells and RGCs in the GCL in WT and Cx36−/−/Cx45−/− mice under control conditions and 8 weeks after initial microbead injection. Total cells counts were based on measures of DAPI-positive nuclei in the GCL. Values represent mean±SEM **p<0.01 (Student's t-test). FIGS. 15A-15E. Injury-induced GFAP expression in the retina following microbead injection is significantly reduced by deletion of Cx36 and Cx45. (A), Before microbead injection, GFAP expression in WT mouse retinas is restricted to astrocytes and end feet of the Müller cells at the inner limiting membrane. (B), Eight weeks after microbead injection there is an upregulation of GFAP in Müller cell processes that span the retinal layers. (C), This increase in GFAP expression was not seen in Cx36−/−/Cx45−/− retinas 8 weeks after initial microbead injection indicating a decrease in retinal injury. (D-E), Curves quantifying the expression of GFAP in the retinas of the WT and KO mice under control and microbead-injected conditions. The profiles show a clear reduction in GFAP in the IPL of KO mice as compared to values in the WT after induction of experimental glaucoma. Scale bar in A=50 μm, and pertains to B and C as well. Values represent mean±SEM **p<0.01 (Student's t-test). DETAILED DESCRIPTION OF THE DISCLOSURE Disclosed herein are methods for treating a condition of the retina by administration of an inhibitor of connexin-36 and/or an inhibitor of connexin-45 to a subject who could benefit from the administration thereof. The disclosure provides results of a comprehensive study of the role of gap junctions (GJs) in secondary neuronal death in the retina initiated by excitotoxic or ischemic conditions. Significant numbers of retinal ganglion cells are lost followed by subsequent loss of coupled amacrine cells after being subjected to excitotoxic or ischemic conditions. However, in accordance with the present disclosure, pharmacological blockade of gap junctions or genetic deletion of connexins increased survivability of neurons by up to about 90%. The disclosure provides methods of targeting specific connexins to reduce progressive cell loss initiated by diverse neurodegenerative conditions. Moreover, the present disclosure reveals that apoptosis in a single cell can spread to neighboring cells via functional gap junctions and furthermore that gap junctions mediate secondary cell-death in a connexin-specific manner. Therefore, in accordance with the present disclosure, it has been determined that gap junctions represent a novel, important target for neuroprotection. The inventors have investigated the hypothesis that GJ-mediated secondary cell death forms a principle mechanism for the progressive loss of cells under experimental glaucoma. The inventors have discovered that secondary or “bystander” cell death via GJs play a critical role in the progressive loss of retinal ganglion cells (RGCs) and amacrine cells (ACs) in retinal conditions such as glaucoma. This disclosure reveals the unexpected vulnerability of RGCs and ACs in glaucoma, the role of GJ coupling in the progression of cell loss, and which GJs, based on their connexin make-up, can be targeted to protect cells. This disclosure thus defines a new mechanism for retinal bystander cell death, and thus provides novel therapeutic targets for neuroprotection to preserve cell health and visual function in glaucomatous retinas. This level of analysis of the bystander effect has not been previously performed at any CNS locus. The retina, due to its GJ diversity, offers a unique venue to study this mechanism. Provided are treatments for many neurodegenerative diseases of the retina, such as glaucoma, retinitis pigmentosa and ischemic retinopathy, as well as those associated with other CNS loci. Connexins, or gap junction proteins, are a family of structurally related transmembrane proteins that assemble to form vertebrate gap junctions. Connexins are four-pass transmembrane proteins with cytoplasmic C- and N-termini, a cytoplasmic loop (CL) and two extra-cellular loops, (EL-1) and (EL-2). Connexins assemble into groups of six to form hemichannels, or connexons, and two hemichannels then combine to form a gap junction. The connexin gene family is diverse, with twenty-one identified members in the sequenced human genome, and twenty in the mouse. The various connexins have been observed to combine into both homomeric and heteromeric gap junctions, each of which may exhibit different functional properties including pore conductance, size selectivity, charge selectivity, voltage gating, and chemical gating, depending at least in part on the combination of connexins present in the GJ. Connexin 36 (Cx36), also known as gap junction protein delta 2, is a connexin with the nucleic acid sequence of SEQ ID NO: 1. The nucleic acid and amino acid sequence of Cx36 are available at Genbank Accession No. NM_020660. Connexin 45 (Cx45), also known as gap junction protein, gamma 1, is a connexin with the nucleic acid sequence of SEQ ID NO: 2. The nucleic acid and amino acid sequence of Cx45 are available at Genbank Accession No. NM_005497. Accordingly, disclosed herein are methods for treating a condition of the retina, by administering an inhibitor of connexin 36 and/or an inhibitor of connexin 45 to a subject with a retinal condition. In some embodiments, both an inhibitor of connexin 36 and an inhibitor of connexin 45 are administered. The condition of the retina can be selected, for example, from glaucoma, macular degeneration, retinitis pigmentosa, diabetic retinopathy and retinal ischemia. In any of the above methods, the inhibitor can be selected from an antisense molecule directed to connexin 36 mRNA, an antisense molecule directed to connexin 45 mRNA, and combinations thereof. Preferred antisense molecule inhibitors are those that selectively bind the mRNA sequence of connexin 36 (SEQ ID NO: 1) or the mRNA sequence of connexin 45 (SEQ ID NO: 2). A “connexin inhibitor” is a molecule that modulates or down-regulates one or more functions or activities of a connexin or a connexin hemichannel (connexon) comprising a connexin of interest. Connexin inhibitors include, without limitation, antisense compounds (e.g., antisense polynucleotides), RNA interference (RNAi) and small interfering RNA (siRNA) compounds, antibodies and binding fragments thereof, and peptides and polypeptides (including “peptidomimetics” and peptide analogs). Preferred connexin inhibitors are inhibitors of connexins found in neural GJs. Most preferred are inhibitors of connexin 36 and/or connexin 45. In one embodiment, the connexin inhibitors of the present invention can modulate or prevent the transport of molecules, particularly molecules that initiate cell death, into and out of neural cells. Certain connexin inhibitors provide downregulation of connexin expression, for example, by downregulation of mRNA transcription or translation, or decrease or inhibit a connexin protein, a connexin hemichannel or neural signaling activity (Asazuma-Nakamura et al, Exp Cell Res., 2009, 315: 1190-1199; Nakano et al., Invest Ophthalmol Vis Sci., 2007, 49: 93-104; Zhang et al., Oncogene, 2001, 20: 4138-4149). Anti-connexin polynucleotides include connexin antisense polynucleotides as well as polynucleotides having functionalities that enable them to downregulate connexin expression. Other suitable anti-connexin polynucleotides include RNAi polynucleotides, siRNA polynucleotides, and short hairpin RNA (shRNA) polynucleotides. Synthesis of antisense polynucleotides and other anti-connexin polynucleotides (RNAi, siRNA, and ribozyme polynucleotides as well as polynucleotides having modified and mixed backbones) is known to those of skill in the art. See, e.g., Stein C. A. and Krieg A. M. (Eds.), Applied Antisense Oligonucleotide Technology, 1998 (Wiley-Hiss). Methods of synthesizing antibodies and binding fragments as well as peptides and polypeptides (including peptidomimetics and peptide analogs) are known to those of skill in the art. See, e.g., Lihu Yang et al., Proc. Natl. Acad. Sci. U.S.A., 1; 95(18): 10836-10841 (Sep. 1, 1998); Harlow and Lane (1988) “Antibodies: A Laboratory Manual” Cold Spring Harbor Publications, New York; Harlow and Lane (1999) “Using Antibodies” A Laboratory Manual, Cold Spring Harbor Publications, New York. In one example, the downregulation of connexin expression is enacted by use of antisense polynucleotides (such as DNA or RNA polynucleotides), and more particularly upon the use of antisense oligodeoxynucleotides (ODN). These polynucleotides (e.g., ODN) target the connexin protein(s) to be downregulated. Typically, the polynucleotides are single-stranded, but may be double-stranded. The antisense polynucleotide may inhibit transcription and/or translation of a connexin. Preferably, the polynucleotide is a specific inhibitor of transcription and/or translation from the connexin gene or mRNA, and does not inhibit transcription and/or translation from other genes or mRNAs. The product may bind to the connexin gene or mRNA either 5′ to the coding sequence; and/or within the coding sequence, and/or 3′ to the coding sequence. Administration of such connexin-targeted antisense polynucleotides inhibits bystander cell death in the retina. The antisense polynucleotide is generally antisense to a connexin mRNA. Such a polynucleotide may be capable of hybridizing to the connexin mRNA, and may thus inhibit the expression of connexin by interfering with one or more aspects of connexin mRNA metabolism (including transcription, mRNA processing, mRNA transport from the nucleus, translation or mRNA degradation). The antisense polynucleotide typically hybridizes to the connexin mRNA to form a duplex that can cause direct inhibition of translation and/or destabilization of the mRNA. Such a duplex may be susceptible to degradation by nucleases. The antisense polynucleotide may hybridize to all or part of the connexin mRNA. Typically, the antisense polynucleotide hybridizes to the ribosome binding region or the coding region of the connexin mRNA. The polynucleotide may be complementary to all of or a region of the connexin mRNA. For example, the polynucleotide may be the exact complement of all or a part of connexin mRNA. However, absolute complementarity is not required, and polynucleotides that have sufficient complementarity to form a duplex having a melting temperature of greater than about 20° C., 30° C. or 40° C. under physiological conditions (that is, under standard cellular conditions of salt, pH, etc., such as 0.09-0.15 M sodium phosphate, pH 6.5-7.2) are particularly suitable for use in the present invention. Thus, the polynucleotide is typically a homologue of a sequence complementary to the mRNA. The polynucleotide may be a polynucleotide that hybridizes to the connexin mRNA under conditions of medium to high stringency, such as 0.03 M sodium chloride and 0.03 M sodium citrate at from about 50° C. to about 60° C. For certain aspects, suitable polynucleotides are typically from about 6 to 40 nucleotides in length. Preferably, a polynucleotide may be from about 12 to about 35 nucleotides in length, or more preferably from about 18 to about 32 nucleotides in length. According to another aspect, the polynucleotide may be at least about 40, for example, at least about 60 or at least about 80 nucleotides in length; and up to about 100, about 200, about 300, about 400, about 500, about 1,000, about 2,000 or about 3,000 or more nucleotides in length. In one preferred aspect, the antisense polynucleotides are targeted to the mRNA of only one connexin protein. Most preferably, this connexin protein is connexin 36 or 45. Polynucleotides targeted to connexins 36 and 45 proteins may be used in combination. In addition, antisense nucleotides targeted to connexins 36 and 45, in combination with antisense nucleotides targeted to one or more additional connexin proteins (such as connexins 26, 30, 30.3, 31.1, 32, 37, 40, 43, 45, and 47), are used. These are examples of human connexin proteins. In the case of other animal species, mRNA of the corresponding connexin is targeted. In one embodiment, the combination of antisense nucleotides does not include an antisense nucleotide targeted to connexin 43. Individual antisense polynucleotides may be specific to connexin 36 or 45, or may hybridize to connexin 36 and/or 45 and 1, 2, 3 or more additional connexins. Specific polynucleotides will generally target sequences in the connexin gene or mRNA that are not conserved between connexins, whereas non-specific polynucleotides will target conserved sequences for various connexins. The antisense polynucleotides may be chemically modified. This may enhance their resistance to nucleases and may enhance their ability to enter cells. For example, phosphorothioate oligonucleotides may be used. Other deoxynucleotide analogs include methylphosphonates, phosphoramidates, phosphorodithioates, N3′P5′-phosphoramidates and oligoribonucleotide phosphorothioates, and their 2′-O-alkyl analogs and 2′-O-methylribonucleotide methylphosphonates. Alternatively, mixed backbone oligonucleotides (“MBOs”) may be used. MBOs contain segments of phosphorothioate oligodeoxynucleotides and appropriately placed segments of modified oligodeoxy- or oligoribonucleotides. MBOs have segments of phosphorothioate linkages and segments of other modified oligonucleotides, such as methylphosphonate, which is non-ionic, and very resistant to nucleases or 2′-O-alkyloligoribonucleotides. Methods of preparing modified backbone and mixed backbone oligonucleotides are known in the art. Polynucleotides (including ODNs) directed to connexin proteins can be selected in terms of their nucleotide sequence by any suitable approach. For example, the computer programs MacVector and OligoTech (from Oligos Etc., Eugene, Oreg., USA) can be used. Once selected, the ODNs can be synthesized using a DNA synthesizer. For example, the polynucleotide may be a homologue of a complement to a sequence of connexin 36 or connexin 45 mRNA. Such a polynucleotide typically has at least about 70% homology, preferably at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98% or at least about 99% homology with a portion of SEQ ID NO: 1 or SEQ ID NO: 2, for example, over a region of more than at least about 15, at least about 20, at least about 40, or at least about 100 contiguous nucleotides of SEQ ID NO: 1 or SEQ ID NO: 2. Homology may be calculated based on any method in the art. For example, the UWGCG Package provides the BESTFIT program, which can be used to calculate homology (for example, used on its default settings) (Devereux et al. (1984) Nucleic Acids Research 12, p 387-395). The PILEUP and basic local alignment search tool (BLAST) algorithms can be used to calculate homology or line up sequences (typically on their default settings), for example, as described in Altschul, S. F. (1993) J Mol Evol 36: 290-300; Altschul, S. F. et al. (1990) J Mol Biol 215: 403-10. Software for performing BLAST analyses is publicly available online through the National Center for Biotechnology Information. This algorithm involves first identifying high-scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence that either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul, S. F. (1993) J Mol Evol 36: 290-300; Altschul, S. F. et al. (1990) J Mol Biol 215: 403-10). These initial neighborhood word hits act as seeds for initiating searches to find HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. The BLAST algorithm parameters W, T and X determine the sensitivity and speed of the alignment. The BLAST program uses as defaults a word length (W), the BLOSUM62 scoring matrix (Henikoff and Henikoff (1992) Proc. Natl. Acad. Sci USA 89: 10915-10919), alignments (B) of 50, expectation (E) of 10, M=5, N=4, and a comparison of both strands. The BLAST algorithm performs a statistical analysis of the similarity between two sequences. See, e.g., Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90: 5873-5787. One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a sequence is considered similar to another sequence if the smallest sum probability in comparison of the first sequence to a second sequence is less than about 1, preferably less than about 0.1, more preferably less than about 0.01, and most preferably less than about 0.001. The homologous sequence typically differs from the relevant sequence by at least about 2, 5, 10, 15, 20 or more mutations (which may be substitutions, deletions or insertions). These mutations may be measured across any of the regions mentioned above in relation to calculating homology. The homologous sequence typically hybridizes selectively to the original sequence at a level significantly above background. Selective hybridization is typically achieved using conditions of medium to high stringency (for example, 0.03M sodium chloride and 0.03 M sodium citrate at from, about 50° C. to about 60° C.). However, such hybridization may be carried out under any suitable conditions known in the art (see Sambrook et al. (1989), Molecular Cloning: A Laboratory Manual). For example, if high stringency is required, suitable conditions include 0.2×SSC at 60° C. If lower stringency is required, suitable conditions include 2×SSC at 60° C. Alternatively, the inhibitor can be a small molecule inhibitor or a connexin binding protein (including peptides, peptidomimetics, antibodies, antibody fragments, and the like). The term “small molecule” as used herein refers to molecules that exhibit a molecular weight of less than 5000 Da, more preferred less than 2000 Da, even more preferred less than 1000 Da and most preferred less than 500 Da. Compounds or competitor compounds that are synthetic and/or naturally occurring “small molecule” compounds, e.g. drugs, metabolites, prodrugs, potential drugs, potential metabolites, potential prodrugs and the like, are preferred for use in the methods described and claimed herein. Preferably, said compounds or competitor compounds are selected from the group consisting of synthetic or naturally occurring chemical compounds or organic synthetic drugs, more preferably small molecules, organic drugs or natural small molecule compounds. Exemplary small molecule inhibitors include 18-Beta-glycyrrhetinic acid (18Beta-GA) and meclofenamic acid (MFA). Small molecule inhibitors may be screened from small molecule libraries available in the art for ability to inhibit connexin 36 and/or connexin 45. Further disclosed herein are use of inhibitors of connexin 36 and/or connexin 45, including, but not limited to, antisense polynucleotides, RNAi and siRNA compounds, antibodies and binding fragments thereof, peptides and polypeptides, and small molecules, in the preparation of a pharmaceutical composition for the treatment of retinal conditions, such as glaucoma, macular degeneration, retinitis pigmentosa, diabetic retinopathy and retinal ischemia. Additionally disclosed are methods of treatment for retinal conditions, involving administration of inhibitors of connexin 36 and/or connexin 45. As used herein, “treatment” refers to clinical intervention in an attempt to alter the disease course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Therapeutic effects of treatment include without limitation, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. Any of the above methods can include repeat administration of the inhibitor or inhibitors for a period of 1 week to 1 year, such as 1-4 weeks, 1-3 months, 1-6 months, 6 months to 1 year, or a year or more. Administration can be, for example, one, two, or three times daily, once every 2-3 days, or once per week. Particularly contemplated is topical administration, such as a drop to be administered to the eye. Topical administration includes directly applying, laying, or spreading on or around the eye, e.g., by use of an applicator such as a wipe, a contact lens, a dropper, or a spray. Also disclosed herein are pharmaceutical compositions for treatment of a retinal condition. The compositions include an inhibitor of connexin 36 and/or an inhibitor of connexin 45. The inhibitor or inhibitors can be selected from an antisense molecule directed to connexin 36 mRNA, an antisense molecule directed to connexin 45 mRNA, and combinations thereof. In another example, the composition includes a small molecule inhibitor of connexin 36 and/or a small molecule inhibitor of connexin 45. In a further example, the inhibitor or inhibitors can be selected from 18-Beta-glycyrrhetinic acid (18Beta-GA) and meclofenamic acide (MFA). Any of the disclosed compositions can be formulated for topical administration or intraocular injection to the eye. Particularly contemplated are compositions that include an inhibitor of connexin 36 and/or an inhibitor of connexin 45 in a pharmaceutically acceptable carrier. As used herein, the phrase “pharmaceutically acceptable” means the carrier, or vehicle, does not cause an adverse reaction when administered to a mammal. Such carriers are non-toxic and do not create an inflammatory or anergic response in the body. Pharmaceutically acceptable carriers for practicing the invention include well known components such as, for example, culture media and phosphate buffered saline. Additional pharmaceutically acceptable carriers and their formulations are well-known and generally described in, for example, Remington's Pharmaceutical Science (18th Ed., ed. Gennaro, Mack Publishing Co., Easton, Pa., 1990) and the Handbook of Pharmaceutical Excipients (4th ed., Ed. Rowe et al. Pharmaceutical Press, Washington, D.C.), each of which is incorporated by reference. A composition containing an inhibitor of connexin 36 and/or an inhibitor of connexin 45 can be formulated for topical administration. Forms of the composition include, but are not limited to, solutions, ointments, gels, emulsions, suspensions, gel shields, and the like. In one embodiment, the composition is formulated as an aqueous-based cream excipient, which can be applied to the eye at bedtime, but may also be applied any time throughout the day. In another embodiment, the composition is formulated as a solution or suspension and is applied topically in the form of eye drops. Any solution suitable for topical application in which a disclosed inhibitor is soluble can be used; e.g., sterile water, Sorenson's phosphate buffer, and the like. In other embodiments, a composition is formulated to have properties such as sustained-release or improved stability. For example, a polymeric matrix composition containing an inhibitor of connexin 36 and/or an inhibitor of connexin 45 can be topically applied to the eye to achieve sustained release. Compositions containing an inhibitor of connexin 36 and/or an inhibitor of connexin 45 can include additional ingredients, additives or carrier suitable for use in contact on or around the eye without undue toxicity, incompatibility, instability, irritation, allergic response, and the like. Additives such as solvents, bases, solution adjuvants, suspending agents, thickening agents, emulsifying agents, stabilizing agents, buffering agents, isotonicity adjusting agents, soothing agents, preservatives, corrigents, olfactory agents, coloring agents, excipients, binding agents, lubricants, surfactants, absorption-promoting agents, dispersing agents, preservatives, solubilizing agents, and the like, can be added to a formulation where appropriate. The compositions of the present invention can include other active agents for treatment of retinal conditions, including, but not limiting to, anti-infective agents, antibiotics, antiviral agents, anti-inflammatory drugs, anti-allergic agents including anti-histamines, vasoconstrictors, vasodilators, local anesthetics, analgesics, intraocular pressure-lowering agents, immunoregulators, anti-oxidants, vitamins and minerals, proteases and peptidases that breakdown endogenous opioids, and the like. Further disclosed herein are uses of any of the disclosed compositions for the treatment of a condition of the retina. In some examples, the condition of the retina can be selected from glaucoma, macular degeneration, retinitis pigmentosa, diabetic retinopathy and retinal ischemia. The present disclosure is further illustrated by the following non-limiting examples. EXAMPLES Example 1. Materials and Methods Animals: Experiments were performed on: (1) wild type (WT) C57BL/6 mice; (2) connexin knockout (KO) mice Cx36−/−, Cx45−/−, and Cx36−/−/45−/− (double KO) and their heterozygous (Het) littermates; (3) the hereditary glaucoma model DBA/2J mouse strain; and (4) transgenic CB2, Grik4, and Kokcng (Kcng4, Potassium voltage-gated channel subfamily G member 4)-cre lines in which select RGC and (d)AC subtypes express fluorescent markers and can be visualized for histological or electrophysiologic experiments. All strains are currently maintained by our lab in the SUNY College of Optometry animal facility. The Cx36−/− mice and littermates were derived from F2 C57BL/6-129SvEv mixed background litters (Kameritsch P, et al., Cell Death Dis. 4:e584(2013)). The Cx45−/− were generated by crossing Cx45fl/fl mice with mice expressing Cre recombinase under control of the neuron-directed nestin promoter to yield Cx45fl/fl:Nestin-cre mice (Blankenship A G, et al., J Neurosci. 31:9998-10008 (2011); Pang J J, et al., Invest Ophthalmol Vis Sci. 54:5151-5162. (2013)). All experiments were performed in adult mice of either sex. Retina-Eyecup Preparation. All animal procedures were in compliance with the NIH Guide for the Care and Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committees at SUNY College of Optometry. Experiments were performed on retinas of wild type (WT), connexin knockout (KO) mice (Cx36−/−, Cx45−/−, and Cx36−/−/45−/− dKO), and their heterozygous (Het) littermates. The methods used to impale and label neurons have been described previously (Hu et al., J Neurosci 23:6768-2777 (2003); Völgyi et al., Journal of Comparative Neurology 512:664-687 (2009)). Briefly, flattened retina-eyecups were placed in a superfusion chamber, which was mounted on the stage of a BX51WI light microscope (Olympus) within a light-tight Faraday cage. An IR-sensitive CCD camera (Dage) captured the retinal image, which was displayed on a video monitor. The retina-eyecups were superfused with a modified, oxygenated Ames medium maintained at 35° C. Intracellular Injections. For intracellular injections, neurons were visualized and impaled with standard, sharp glass microelectrodes filled with cytochrome C (CytC, 10 mg/ml) and Neurobiotin (4%) in 0.1 M Tris buffer. Substances were injected iontophoretically for 15-20 min using a sinusoidal current (3 Hz, 1-5 nA p-p). Microbead Injection. Experimental glaucoma in mice is induced by IOP elevation achieved by intracameral injections of 10 μm polystyrene microbeads (Invitrogen) as previously described (Chen H, et al., Invest Ophthalmol Vis Sci. 52:36-44 (2011)). The intracameral injections are made unilaterally with 2 μl of microbead suspension containing ˜7.2×106 beads using a glass micropipette attached to a microliter syringe. An equivalent volume of phosphate-buffered saline (PBS) is injected in contralateral eyes to serve as a control. Measurements of IOP are made with the commercially-available Tonolab tonometer (Colonial Medical Supply) and are performed weekly for up to 8 weeks after the microbeads injection. Measurements are made between 10 μM and 12 PM, to minimize the effect of diurnal IOP variations. Six IOP measurements are made at each interval and averaged. Immunocytochemistry. After experimental treatment, retinas were fixed with 4% paraformaldehyde in a 0.1 M phosphate buffer solution (PBS; pH 7.4) for 30 minutes at room temperature, cryoprotected in 30% sucrose, embedded in Tissue-Tek OCT Compound (Andwin Scientific) and frozen. Cryosections (18-20 μm thick) were cut and mounted on microscope slides. For immunostaining, sections were blocked in 3% donkey serum in 0.1M PBS supplemented with 0.5% Triton X-100, and 0.1% NaN3 for 1 h at room temperature. Primary antibodies were diluted in 0.1M PBS with 0.5% Triton X-100, 0.1% NaN3 and 1% donkey or goat serum. Tissues were then incubated with primary antibodies for 3 hours at room temperature or overnight at 4° C. The following primary antibodies were used: rabbit anti-calretinin 1:2000, rabbit anti-calbindin 1:1000, goat ant-ChAT 1:100 (all from Millipore), rabbit anti-GFAP 1:1000 (Invitrogen), rabbit anti-active caspase 3 1:200 (Abcam); mouse anti-Cx35/36 1:300, mouse anti-Cx45 1:300 (both from Millipore). After extensive washing with 0.1M PBS, tissues were incubated for 1 hour in secondary anti-goat/rabbit/mouse antibodies conjugated to Alexa-488 or Alexa-594 (1:200, Molecular Probes). Retinal sections were counterstained with the nuclear dye propidium iodide (PI, Molecular Probes). Neurobiotin was visualized with Alexa-488/594 conjugated streptavidin (Molecular Probes, 1:200). Tissues were then flat-mounted in Vectashield media (Vector Labs) and fluorescent images were taken using a fluorescent microscope or an Olympus FV1200 MPE confocal microscope. Induction of Cell Death. Various methods were employed to produce cell death. (1) Single cell apoptosis: CytC was injected into individual RGCs or Müller cells for 15 minutes after which retinas were incubated for 4 hours in oxygenated Ames medium before fixation. After streptavidin histology, apoptotic cells were detected with an anti-active caspase 3 antibody or with Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. (2) Excitotoxicity: To assess the contribution of GJs to cell death within populations of RGCs and amacrine cells we conducted parallel experiments in which retinas were preincubated for 20 minutes in normal Ames medium or in one containing the GJ blockers meclofenamic acid (MFA; 50 μM) or 18-beta-glycyrrhetinic acid (18Beta-GA; 25 μM). Both control and drug-treated retinas were then exposed for 1 hour to NMDA (100-300 μM) to induce excitotoxicity followed by 4 hours in the control Ames solution. (3) Retinal ischemia: Transient in vivo retinal ischemia was induced by introducing into the anterior chamber a 33-gauge needle attached to a saline-filled reservoir (0.9% sodium chloride) that was raised above the animal so as to increase intraocular pressure (IOP) to a level 120 mm Hg above systolic blood pressure. MFA (2 μl, 500 μM) was administered intravitreally either 30 minutes before or 3 and 24 hours following the ischemic insult. The opposite eye was cannulated, but maintained at normal IOP to serve as a normotensive control. After 40-50 minutes, the needle was withdrawn and ischemia was evidenced by corneal whitening. After 7 days of reperfusion, mice were sacrificed and eyes were processed to assess retinal damage and neuronal death. We also employed oxygen-glucose deprivation (OGD) to induce in vitro ischemia, in which retina-eyecups or isolated retinal whole-mounts were exposed continuously to either a control, oxygenated Ringer solution, or one that was glucose-free and deoxygenated by bubbling extensively with 95% N2/5% CO2 at 34° C. Following 60 minutes in the OGD environment, retinas were transferred to a control, oxygenated Ames medium for 4 hours before processing to evaluate cell death. Retrograde Labeling and Visualization of Coupled Cells. We used retrograde labeling of RGCs with Neurobiotin to visualize populations of amacrine cells in the inner nuclear layer (INL) to which they were coupled. Globes with attached optic nerves were submersed in oxygenated Ames medium and a drop of Neurobiotin (4% in 0.1 M Tris buffer) was applied to the cut optic nerve for 40 minutes. For retrograde labeling limited to RGCs, Neurobiotin was replaced with Lucifer yellow (LY, 3%). In separate experiments, retrograde labeling was performed in both eyes prior to incubating one eye in Ames medium containing MFA (50 μM for 30 minutes) after which both eyes were exposed to NMDA (300 μM) for 1 hour. Frozen retinal sections (20 μm thick) were cut on a cryostat and processed for assessment of cell death in the inner nuclear layer (INL) and ganglion cell layer (GCL). Assessment of Cell Injury and Cell Death. Apoptotic and necrotic cell death were assessed by cell counts following: (1) staining with Live/Death Viability Assay (calcein AM/ethidium homodimer (EthD) (Invitrogen); (2) TUNEL, or, (3) labeling for activated caspase 3. For population studies, dead cells were counted manually within 500×500 μm areas (5 areas per retina) from micrographs of whole-mounts using images acquired by confocal microscope. Nuclear cell counts were made per unit length (500 μm) of frozen retinal cross-sections labeled with propidium iodide (2 μg/ml). In some experiments, cells counts were limited to retrograde labeled RGCs in the GCL or certain subpopulation of amacrine cells, identified by specific markers, such as calretinin (CR), calbindin (CB) and choline acetyltransferase (ChAT) in the INL. Fluorescence intensity measures were made of glial fibrillary acidic protein (GFAP), which is overexpressed in Müller glial cells following retinal injury. Expression of GFAP and connexins were quantified by analysis of confocal images with Metavue software (Molecular Devices). Average pixel fluorescence intensities were measured by using uniform rectangular areas (3-5 per image) extending either from the GCL to the outer limiting membrane for GFAP or through the IPL for connexins. The intensity values were then averaged for at least 5 images from 3-5 independent experiments and data were normalized to controls. Microbead-Induced Glaucoma. Experimental glaucoma was induced by intracameral injections of polystyrene microbeads (Chen H, et al., Invest Ophthalmol Vis Sci. 52:36-44 (2011)) in one eye of wild type (WT) mice, connexin knockout (KO) mice and their heterologous (HET) control littermates, with sham injection of the second eye as control. IOP measurements were performed weekly and animals were sacrificed at 1, 4, or 8 weeks after initial bead injection. To access cell loss, RGCs and coupled ACs were retrogradely labeled with optic nerve injection of Neurobiotin and vertical retinal sections were counterstained with DAPI to determine overall nuclear counts. RGCs were also labeled by Brn3a antibody for identification. In addition to cell counts, overall retinal damage was assessed by GFAP expression. In some experiments gap junctions were blocked with meclofenamic acid (MFA) intravitreal weekly injections or genetically ablated in connexin KO mice (Cx36−/−, Cx45−/−, and Cx36−/−/Cx45−/− mice). Statistics. Data are presented as mean±standard mean error. The number of measurements carried out for a given experiment (n) are given as x/y where x is the total number of samples in which the measures were made (e.g., flat mount areas or sectional lengths) and y is number of retinas. For microbead injection experiments, data are presented as mean±SEM per 1.3 mm length of vertical section. Statistical comparisons were assessed using Student's t-test. Values of p≦0.05 are considered statistically significant. Example 2. Gap Junctions Mediate Secondary Cell Death in the Retina We initially examined whether GJ-mediated secondary cell death occurred in the retina. In these experiments, we performed intracellular injections of single RGCs with CytC to stimulate apoptosis and Neurobiotin to assess GJ coupling. To determine whether apoptosis in a single cell could spread to neighbors through a mechanism other than GJs, we first examined RGCs that were not tracer coupled to other cells (FIG. 1A). We found that injection of CytC initiated cell death in the injected cell within the experimental timeframe of 3-4 hours, but no other neuron neighbors were lost (FIG. 1B,C). In contrast, injection of CytC into RGCs that were coupled to ganglion and/or amacrine cells resulted in the death of not only the injected cell, but also the coupled neighbors (FIG. 1D-F). These results confirmed that secondary cell death does occur in the retina and is dependent on functional GJs. It is important to note that CytC, at 12,000 Daltons, is far too large a molecule to pass across a GJ, indicating that other toxic molecules must be moving intercellularly to promote cell death in coupled neighbors. We also found that secondary cell death occurred in coupled Müller cells, indicating that this mechanism can result in progressive death of glia in addition to neurons (FIG. 1G-I). Example 3. Pharmacological Blockage of Gap Junctions Reduces RGC Death Under Excitotoxic or Ischemic Conditions To determine the contribution of secondary cell death to the loss of RGCs produced under different neurodegenerative conditions, we examined the effect of GJ blockade on cell loss in the GCL. In initial experiments, we induced excitotoxic cell death by incubating retina-eyecups in 100-300 μM NMDA (FIG. 2A,C). Cell death counts were then performed in these retinas (n=44/5) and compared to retinas that were incubated in the non-selective GJ blockers 18Beta-GA (25 μM) or MFA (50 μm) prior to exposure to excitotoxic conditions (FIG. 2B,D). We found that prior blockade of GJs with either 18Beta-GA (n=12/3) or MFA (n=42/5) significantly reduced (p<0.001 for both drugs) cell death in the GCL induced by excitotoxicity (FIG. 2E). Overall, NMDA-induced cell death was reduced dramatically in the GCL of mouse retinas pretreated with 18Beta-GA or MFA compared to those treated with NMDA alone. In control experiments, application of 18Beta-GA or MFA alone did not affect cell viability (p>0.1), supporting the notion that the GJ blockers had no spurious toxic effects. In addition, MFA, at the concentrations tested here, shows no inhibitory effect on NMDA receptors in neurons, suggesting that the attenuation of NMDA-induced cell death by GJ blockade was not due to reduced NMDA receptor activity. Overall, the significant protective effects of pharmacological GJ blockade suggest that secondary cell death is responsible for the progressive loss of the vast majority of RGCs under excitotoxic conditions. In a second phase of experiments, we examined the role of secondary cell death in RGCs loss associated with ischemic conditions of the retina. We assessed retinal damage subsequent to ischemia induced in vivo by raising IOP above normal systolic levels. In control retinas (n=19/5), GFAP expression was confined exclusively to astrocytes in the GCL (FIG. 3A,E). Expression of GFAP in ischemic retinas, however, was significantly upregulated as evidenced by the spread of immunolabeling to Müller cell processes at all retinal layers (p<0.01) (FIG. 3B, E). Ischemia also produced a significant reduction in nuclear counts in the GCL (p<0.01) accompanied by a marked thinning of the retina, particularly the inner layers (FIG. 3A,B,D). To assess the role of GJ-mediated secondary cell damage in ischemic injury of the retina, eyes were injected intravitreally with MFA either before or after insult. Treatment with MFA prior to ischemic induction preserved retinal thickness, cell counts in the GCL, and GFAP expression to levels seen in control retinas (FIG. 3C,D,E). Moreover, the protective effect of MFA administered 3 and 24 hours after transient ischemia was evidenced by maintenance of normal levels of retinal thickness, GFAP expression, and cell counts in the GCL measured one week after insult; p<0.01 for all measures (FIG. 3C,D,E). Example 4. Gap Junctions Mediate Amacrine Cell Loss Following Retinal Injury 15 of the 22 morphological subtypes of RGCs in the mouse retina are coupled to amacrine cells. This extensive coupling suggests that the GJ-mediated secondary cell death may also progress from RGCs to coupled amacrine cell neighbors. To test this idea, we examined the loss of amacrine cell populations immunolabeled with calretinin (CR), calbindin (CB) or choline acetyltransferase (ChAT). Initial experiments were carried out to determine whether CR-, CB-, and ChAT-immunopositive amacrine cells (ACs) were indeed coupled to RGCs. Ganglion cell somata were retrogradely labeled with Neurobiotin through the cut optic nerve. A large number of cells in the INL and GCL were immunoreactive to CR and ChAT with three distinct IPL bands of CR-labeled dendritic processes and two clear ChAT bands of starburst-a and starburst-b ACs (FIG. 4A,C). In addition to CR-positive RGCs (or displaced amacrine cells) in the GCL, we found (n=18/4) that approximately one-half of the CR-positive, presumed ACs in the INL showed Neurobiotin labeling (FIG. 4A, E, G), suggesting that they were coupled to RGCs. Indeed, blockade of GJs with MFA prior to retrograde labeling effectively eliminated all colocalized labeling of CR-positive ACs in the INL with Neurobiotin (n=8/3, p<0.01) (FIG. 4B,E). CB-immunoreactive labeling in the mouse retina is known to mimic labeling for CR, suggesting that they may label the same subpopulations of ACs and RGCs. Our results from CB-immunolabeled retinas were similar to those described for CR. Although starburst ACs in the rabbit retina are not coupled to RGCs, we found a small number (less than 10%) of ChAT-positive cells in the INL of the mouse retina that were labeled with Neurobiotin (n=16/3) (FIG. 4C, F, G). However, application of MFA did not produce a significant reduction in the number of ChAT-positive ACs labeled with Neurobiotin (n=6/3; p>0.1) (FIG. 4D, F). We conclude that, at best, only a small number of starburst-a ACs are coupled to RGCs. In the next set of experiments, we examined how AC death due to excitotoxicity was affected by blockade of GJs with MFA. Application of NMDA produced a significant reduction of CR- (n=18/3; p<0.01) and CB-immunopositive (n=22/3; p<0.01) subpopulations of ACs in the INL (FIG. 5A-H). However, blockade of GJs with MFA prevented the loss of CR- (n=10/3) or CB-immunolabeled (n=6/3) ACs (p<0.01), preserving levels seen in control retinas (FIG. 5C, D, G, H). In contrast, NMDA-induced excitoxicity did not produce a significant reduction in the number of ChAT-positive ACs in the INL (n=20/4; p>0.1), nor was this affected by GJ blockade with MFA (n=17/4; p>0.1) (FIG. 5L). Amacrine cell death following transient ischemia paralleled the results seen following excitotoxic insult. Ischemia produced a significant loss of CR- (n=48/5; p<0.001) and CB-immunoreactive (n=17/3; p<0.001) subpopulations of ACs in the INL and a disorganization of the dendritic bands in the IPL (FIG. 6A-H). Application of MFA prevented the loss of both the CR- (n=26/5; p<0.001) and CB-immunoreactive (n=21/3; p<0.001) ACs, maintaining levels to that seen in control retinas (FIG. 6C, D, G, H). In contrast, induction of ischemia had no statistically significant impact on the number of ChAT-immunopositive amacrine cells in the INL (n=25/4; p>0.1) (FIG. 6L). As expected, treatment of ischemic retinas with MFA had no effect on the number of ChAT-positive ACs in the INL (n=23/4; p>0.1) (FIG. 6K, L). Example 5. Gap Junctions Mediate Secondary Cell Death in a Connexin-Specific Manner The inner plexiform layer (IPL) of the retina contains an assortment of GJs formed between RGCs, ACs, and bipolar cell axon terminals that express at least three different connexin subunits. This diversity raises the notion that different cohorts of GJs, possibly based on their connexin profiles, may be responsible for secondary cell death in the inner retina arising from different primary insults. Our results using the GJ blockers MFA and 18Beta-GA did not address this issue. To test this idea, we therefore examined the extent of excitotoxic and ischemic cell death in mice in which Cx36 and/or Cx45, the two most highly expressed subtypes in the IPL, were genetically deleted. We induced excitotoxic cell death as described above by application of NMDA to retinas of Cx36−/−, Cx45−/−, and Cx36−/−/Cx45−/− dKO mouse retinas and their heterozygous littermates. Detection of dead cells in the GCL showed that NMDA-induced excitotoxic cell death was markedly reduced in Cx36−/− mouse retinas (n=35/3) as compared to levels found in Het littermates (n=35/3) or WT mice (n=14/3; p<0.001 for both) (FIG. 7A, B, E). In contrast, the extent of cell death in the GCL of Cx45−/− mouse retinas following exposure to NMDA was not statistically different from control levels in Het or WT mice (n=17/3; p>0.1) (FIG. 7A, C, E). We next induced excitotoxic cell death in Cx36−/−/Cx45−/− dKO mouse retinas (n=13/3) and found that the level of cell death in the GCL was indistinguishable from those found in NMDA-treated retinas of Cx36−/− mice (p>0.1) (FIG. 7B, D, E). Thus, the degree of cell death was not additive when both Cx36- and Cx45-expressing gap junctions were deleted. Overall, these results indicated that whereas GJs expressing Cx36 played a role in secondary cell death associated with excitotoxicity, those expressing Cx45 made no significant contribution. In the next phase of experiments, we induced transient retinal ischemia in vivo in Cx36−/− and Cx45−/− mice and their Het littermates. After 7 days of survival, evaluation of retrograde labeling of GCs with Lucifer yellow (LY) in whole mount retinas revealed a significant loss of axonal processes in Cx36−/− and Het mouse retinas as compared to control levels (FIG. 8A-C). In contrast, ischemic retinas from Cx45−/− mice showed axonal labeling that was comparable to that seen in control retinas (FIG. 8A, D). Consistent with these findings, ischemia resulted in a marked reduction of cells in the GCL of Cx36−/− (n=24/4) and Het littermate mouse retinas (n=28/3; p<0.001 for both), but no significant loss in the GCL of Cx45−/− mice (n=74/5), when compared to control levels (n=54/5; p>0.1) (FIG. 8I). The GFAP immunoreactivity was also markedly increased in Müller cell processes following ischemic insult of Cx36−/− (n=24/4) and Het (n=24/4) mouse retinas (p<0.001), but showed levels in Cx45−/− mouse retinas (n=22/4) that were indistinguishable from that measured in control retinas (p>0.1) (FIG. 8E-H, J). A differential contribution of Cx36- and Cx45-expressing GJs to secondary neuronal death was also observed under condition of oxygen-glucose deprivation (OGD), an in vitro model of ischemia. Exposure to OGD conditions produced a significant loss of neurons in the GCL of Cx36−/−(n=12/3) and Het mouse retinas (n=12/3; p<0.001), but produced no significant loss of cells in the GCL of Cx45−/− mouse retinas (n=10/3; p>0.1). We then investigated any changes in the distribution of Cx36- and Cx45-expressing GJs under excitotoxic and ischemic insult that could instruct their differential roles in secondary cell death (FIG. 9E, F, K, L). Induction of ischemia produced a dramatic reduction in the expression of Cx36 puncta in the IPL (n=7/3), compared to that in control retinas (n=21/3; p<0.001) (FIG. 9A, B). Instead, we found intense Cx36 immunolabeling in RGC somata indicating an accumulation of the protein in the cytoplasm (FIG. 9B, inset). The expression of Cx45 puncta in the IPL was unaffected by ischemic insult (n=26/4; p>0.1) (FIG. 9G, H, J). However, exposure of retinas to NMDA to induce excitotoxicity had no effect on the expression of Cx36 puncta in the IPL (n=8/3; p>0.1), but dramatically reduced the expression of Cx45 (n=8/4), compared to control levels (n=28/4; p<0.001) (FIG. 91, J). Thus, ischemic and excitotoxic insult had opposite effects on the expression of Cx36- and Cx45-expressing GJs in the inner retina, consistent with their differential roles in mediating secondary cell death under these two pathological conditions (FIG. 9E, F, K, L). Example 6. Secondary Cell Death Via GJs Plays a Critical Role in the Progressive Loss of RGCs and ACs in Experimental Glaucoma We next studied the role of secondary cell death in the progressive loss of RGCs and ACs in a mouse model of glaucoma and determined whether pharmacologic or genetic blockade of GJs forms a novel approach for protection of neurons in glaucomatous retinas. We posited that GJ-mediated secondary cell death forms a critical mechanism in the loss of retinal neurons seen in glaucoma and thus blockade of GJs could offer a novel strategy for protecting cells. Experimental glaucoma was induced by intracameral injections of polystyrene microbeads in one eye of wild type (WT) mice, connexin knockout (KO) mice and their heterologous (Het) control littermates, with sham injection of the second eye as control. Injection of polystyrene beads significantly raised IOP from 11.4±0.3 to 21.9±0.5 mm Hg, which remained elevated for at least 8 weeks following injection (FIG. 10A). We found no significant change in the RGC count from control levels (50±1; p>0.1) within 1 week of bead injection. However, there was a significant decrease in RGC count 4 weeks (40±3; p<0.05) and 8 weeks after bead injection (33±1; p<0.001), a 20% and 36% population decrease, respectively (FIG. 10D). Overall retinal injury following bead injection was evidenced by an upregulation of GFAP in Muller cell processes spanning all retinal levels (FIG. 10B-C). To test the role of secondary cell death via GJs in the loss of RGCs we next blocked GJs before and after bead injection with MFA (50 μM). Blockade of GJs with MFA prevented the loss of RGCs by bead injection as evidenced by cell counts of 47±4 (p>0.1) at 8 weeks, comparable to those in control retinas (FIGS. 11A-11F). Injection of MFA alone in control eyes had no detectable effect on RGC counts. FIGS. 11D-E show histograms comparing the total cell (RGC+dAC) and RGC counts in the GCL of microbead-injected retinas from WT mice untreated (D) or treated with MFA (E) to block GJs. Microbead injection clearly induced cell loss in the GCL, but blockade of GJs prevented the loss. Thus, pharmacological blockade of GJs with MFA promotes RGC protection in experimental glaucoma. To determine whether the contribution of GJs to RGC death was connexin-specific, we induced experimental glaucoma in connexin KO mice (FIGS. 14A-14E). At 8 weeks after bead injections the RGC count was 40±1 in Cx36 KOs, 43±1 for Cx45 KOs, and 49±3 for Cx36/45 dKO, indicating a 41%, 59%, and 94% increase in survivability, respectively (FIG. 14A). GFAP expression was also significantly reduced in connexin KO mouse indicating an overall reduction in cell death (FIGS. 15A-15E). Since the majority of RGCs subtypes are coupled to (ACs) in the mouse retina, we examined whether RGC could lead to AC death in experimental glaucoma. We observed a 20-30% loss of ACs in bead-injected WT mouse retinas, which was significantly prevented in Cx36 KO mice (FIGS. 12A-12I). Ablation of Cx45 also prevented loss of coupled dACs (FIGS. 13A-13B). Microbead injection resulted in a loss of coupled dACs in wild-type, and a small increase in uncoupled dACs (FIG. 13A). However, there was no loss in coupled or uncoupled dACs in the Cx45−/− mouse retinas (FIG. 13B). Our results provide clear evidence that GJ-mediated secondary cell death plays a significant role in the propagation of cell loss in the adult retina seen under a number of different primary insult conditions. First, we observed that injection of the apoptotic agent CytC into individual RGCs and glia led to the exclusive loss of neighboring neurons to which they were coupled via GJs. Second, pharmacological blockade of GJs under excitotoxic and ischemic insult increased the survival of RGCs by approximately 70%, indicating that GJ-mediated secondary cell death plays a major role in cell loss. Further, under these same insult conditions, blockade of GJs prevented nearly all AC death presumably by eliminating the propagation of toxic signals from RGCs to which they were coupled. Finally, selective genetic ablation of the GJ subunits Cx36 or Cx45 found in the inner retina resulted in a significant reduction in the loss of RGCs normally seen following excitotoxic or ischemic insult. Studies of glaucomatous human retinas have reported an apparent delayed or secondary degeneration of amacrine cells subsequent to RGC cell loss. Consistent with this scenario is our present finding that CR- and CB-immunopositive amacrine cell lose due to excitoxicity or ischemia could be largely blocked by GJ blockade. These data suggest that while RGCs were most vulnerable under our experimental insult conditions, the loss of ACs was consequent to GJ-mediated bystander cell death. This hypothesis is supported by our finding that ChAT-immunopositive ACs, which showed only minimal coupling to RGCs, were not significantly affected by excitotoxic or ischemic insult nor by disruption of GJs. A downregulation of CR, CB, and ChAT have been reported in ischemic retinas; however, we found that ChAT-immunoreactve cells were unaffected under our ischemic conditions and that MFA could maintain cell counts at control levels. These findings argue that the loss of CR and CB immunolabeling in ischemic retinas more likely reflected cell loss associated with GJ-mediated bystander cell death and not a downregulation of the protein markers. In contrast to a role in secondary cell death, GJs have been reported to sometimes play a neuroprotective role. This raises the possibility that the role played by GJs in subserving cell death or neuroprotection may depend on the nature of the primary insult. Our results revealed another important difference between GJs in terms of their role in secondary cell death under different insult conditions. We found that whereas genetic ablation of Cx36, but not Cx45, could significantly reduce cell loss under excitotoxic insult, ablation of Cx45, but not Cx36, protected cells from ischemic injury. These data indicate that different cohorts of GJs, dependent on their connexin makeup, subserve the bystander effect under different pathological conditions. Our results are the first to show that different cohorts of GJs, based on the connexin they express, subserve secondary cell death under different primary insult conditions. Our immunolabeling data suggests that this differential contribution of GJs under excitotoxic and ischemic conditions reflects changes in connexin protein expression and manifestation. Under ischemic insult, we found that Cx36 protein was accumulated mainly in a perinuclear region of RGCs, but the normal punctate immunolabeling in the IPL indicative of dendritic GJs was absent. A similar cytoplasmic internalization has been reported for Cx43 in ischemic cardiac tissue, resulting from a dysfunction in Cx43 trafficking linked to altered serine phosphorylation (Smyth et al., Traffic; 15(6):684-99 (2014); Cone et al., J Biol Chem 289:8781-8798 (2014)). Thus, in our experiments, while Cx36 protein was still manufactured under ischemic conditions, it appears to have not been inserted in the membrane as functional GJs. In contrast, Cx45 punctate labeling in the IPL appeared normal. These findings can explain why ischemic cell loss was reduced in the Cx45−/− mouse retina, but not by ablation of Cx36, namely that Cx36-expressing GJs were already disrupted by the insult. In contrast, we found that Cx45 immunolabeling under excitotoxic insult was abnormal, with punctate labeling absent from the IPL, whereas Cx36 expression appeared normal. These data suggest a downregulation of Cx45 under excitotoxicity and a lack of functional GJs they constitute, which can explain why ablating Cx45 did not reduce cell loss after NMDA-induced excitotoxicity. The finding that bystander cell death in the retina is ultimately responsible for the loss of most retinal neurons reveals that GJs form a novel, important target for neuroprotection. The identification of GJs as a therapeutic target is lent support by our ability to significantly limit neuronal cell loss by blocking GJs with MFA administered after ischemic insult. Moreover, the finding that limited cohorts of GJs, specifically GJs expressing Cx36 and/or Cx45, are responsible for bystander death is propitious, as it shows that targeting of GJs, by inhibition of these specific connexins, has the potential for treating retinal conditions associated with bystander cell death.
<SOH> BACKGROUND OF THE DISCLOSURE <EOH>In addition to the intrinsic mechanisms underlying primary cell death, intercellular communication appears to play a major, but presently unclear, role in so-called secondary cell death (Andrade-Rozental A F, et al., Brain Res. Rev 32:308-315 (2000)). Damage in the central nervous system (CNS) leads to the death of a limited cohort of vulnerable cells, which, in turn, pass toxic molecules via gap junctions (GJs) to coupled neighbors. There is now substantial evidence that cells that are clustered and can thereby communicate via GJs tend to die en mass under a broad range of neurodegenerative conditions (Frantseva et al., J. Cereb. Blood Flow Metab. 22:453-462 (2002); Cusato et al., Cell Death Differ 13:1707-1714 (2006); Lei et al., Br J Ophthalmol. 93:1676-1679 (2009); Wang et al., J Neurophysiol 104:3551-3556 (2010). In this scheme, GJs act as portals for the passage of apoptotic signals from injured cells to those to which they are coupled, which can ultimately be the cause of most cell loss (Kenner et al., Cell Tissue Res 298:383-395 (1999); Perez Velazquez et al., Neuroscientist 9:5-9 (2003); Decrock et al., Cell Death Differ 16:524-536 (2009); Belousov and Fontes, Trends Neurosci 36:227-236 (2013)). There is increasing evidence that GJs are involved in various neurodegenerative ocular disorders, including ischemic retinopathy and glaucoma (Krysko, Apoptosis 10:459-469 (2005); Malone, Glia 55:1085-1098 (2007); Das et al., Biochem Biophys Res Commun 373:504-508 (2008); Kerr et al., J Clin Neurosci 18:102-108(2011); Danesh-Meyer et al., Brain 135:506-520 (2012)). The topography of neuronal loss in the inner retina seen with these pathologies often includes both a diffuse, but clustered pattern suggesting that dying retinal ganglion cells (RGCs) influence neighboring cells, resulting in secondary neuronal degeneration (Levkovitch-Verbin, Invest Ophthalmol Vis Sci 42:975-982 (2001); Lei et al., Br J Ophthalmol. 93:1676-1679 (2009); Vander et al., Curr Eye Res 37:740-748 (2012)). The GJ-mediated secondary cell death, or so-called “bystander effect”, has also been implicated in the programmed cell death in the developing retina. Like in the adult, dying cells in developing retina are spatially clustered into distinct networks (Cusato et al., Cell Death Differ 13:1707-1714 (2003); de Rivero Vaccari et al., J. Neurophysiol 98:2878-2886 (2007)). Dopamine, which is a modulator of al communication, as well as the GJ blockers octant and carbenoxolone significantly reduce the rate of programmed and induced cell death in young retinas and the clustering of the remaining dying cells (Varella et al., J Neurochem 73:485-492 (1999); Cusato, Cell Death Differ 13:1707-1714 (2003)). Amacrine cells (ACs) form the largest cohort of retinal neurons, comprising over 30 distinct morphological subtypes that subserve complex synaptic interactions in the inner plexiform layer (In), which are largely responsible for the diverse physiological properties expressed by RGCs (Demb J B, et al., Vis Neurosci. 29:51-60 (2012)). Studies of glaucomatous human retinas have reported an apparent delayed or secondary degeneration of amacrine cells subsequent to RGC cell loss (Schwartz Eur J Ophthalmol Suppl 3:S27-31 (2002); Kielczewski et al., Invest Ophthahnol Vis Sci 46:3188-3196 (2005); Moon et al., Cell Tissue Res. 320:51-59 (2005)). However, whether ACs are adversely affected in glaucoma remains unclear as conflicting experimental results have been reported (Kielczewski J L, et al., Invest Ophthalmol Vis Sci. 46:3188-96 (2005); GA, Barnett N L., et al. Clin Experiment Ophthalmol. 39:555-63 (2011); Moon J I, et al., Cell Tissue Res. 320:51-9 (2005); Jakobs T C, et al., J Cell Biol. 171:313-25 (2005)). One explanation for the discrepant findings may be the difficulty in clearly identifying ACs and thereby measuring their loss. For example, in addition to RGCs, displaced amacrine cells (dACs) comprise about 50% of the neurons found in the GCL of the mouse retina (Schlamp C L, et al., Mol Vis. 19:1387-96 (2013)) and no single labeling method can provide complete coverage due to their wide morphological diversity. Interestingly, it has been reported that 16 of the 22 morphological subtypes of RGCs in the mouse retina are coupled to ACs (Völgyi B, et al., J Comp Neurol. 512:664-87 (2009)). This extensive coupling suggests that GJ-mediated secondary cell death would likely progress from RGCs to their coupled AC neighbors or vice versa. A downregulation of calretinin (CR), calbindin (CB), and choline acetyltransferase (ChAT) have been reported in ischemic retinas (Dijk and Kamphius, Brain Res. 1026:194-204 (2004); Bernstein and Guo, Invest Ophthalmol Vis Sci 52:904-910 (2011); Lee et al., Apoptosis 11:1215-1229 (2011)), suggesting that the loss of the AC immunoreactivity may be due to reduced protein detection rather than cell death. Changes in the expression and function of certain connexin subtypes in CNS have been reported under a variety of pathological conditions (Rouach et al., Biol. Cell. 94:457-475 (2002); Petrash-Parwez et al., J. Comp Neurol 479:181-197 (2004); Eugenin et al., J. Neuroimmune Pharmacol 7:499-518 (2012); Kerr et al., J. Clin Neurosci 28:102-108 (2012)). In addition, the conductance of GJ hemichannels, related to their connexin makeup, appears related to their ability to support bystander cell death (Kameritsch et al., Cell Death Dis 4:1-9 (2013)). The conductance of GJs, based on their connexin makeup, appears related to their ability to support bystander cell death (Kameritsch P, et al., Cell Death Dis. 4:e584 (2013)). In addition, changes in the expression of certain connexin subtypes in CNS have been reported under a variety of pathological conditions (Kerr N M, et al., Exp Neurol. 234:144-52, (2012); Rouach N, et al., Biol Cell. 94:457-75 (2002); Petrasch-Parwez et al., J Comp Neurol. 479:181-97 (2004); Eugenin E A, et al., J Neuroimmune Pharmacol. 7:499-518 (2012)). Thus, the degree to which a particular GJ contributes to secondary cell death is likely dependent on which of the different types of connexin subunits it expresses as well as the insult condition. The fact that at least three connexin subtypes are expressed in the IPL of the retina raises the notion that different cohorts of GJs, based on their connexin profile, may be responsible for secondary cell death in the inner retina arising from different primary insults. In contrast, some studies have reported that GJs may actually protect cells. Evidence for this “good Samaritan” role include the findings that GJ inhibitors can induce apoptosis (Lee et al., Anat Cell Biol 44:25-34 (2006); Hutnik et al., Invest Ophthalmol Vis Sci 49:800-806 (2008)) and that deletion of GJ connexins can increase neuronal loss (Naus et al., Cell Commun. Adhes 8:325-328 (2001); Striedinger et al., Eur J Neurosci 22:605-6016 (2005)). It has been posited that GJs are portals by which healthy cells provide dying neighbors with rescue signals or that the coupled syncytium can dilute toxic substances (Krysko et al., PLoS One 8:e57163 (2005)). Apoptotic conditions induce various changes in the structure of GJs, including phosphorylation of connexins (Lin et al., Exp Eye Res 85:113-122 (2007)), suggesting that the connexin makeup of a GJ may be a critical factor in determining its contribution to cell death or survival. The retina displays arguably the highest expression of GJs in the CNS, which are widely distributed amongst the five neuronal types and express a variety of connexin subunits (Bloomfield and Völgyi, Nat Rev Neurosci 10:495-506 (2009)). GJ-mediated secondary cell death has been implicated in retinal neuron loss seen under a number of degenerative conditions, including retinitis pigmentosa, glaucoma, and ischemia (Ripps, Exp Eye Res 74:327-336 (2002); Das et al., Biochem Biophys Res Commun 373:504-508 (2008)). On the other hand, deletion of connexins have failed to increase the survivability of cone photoreceptors in a mouse model of retinitis pigmentosa (Kranz et al., PLoS One 8:e57163 (2013)) and has been reported to increase cell loss after retinal trauma (Striedinger et al., Eur J Neurosci 22:605-6016 (2005)), suggesting that GJs can in fact be neuroprotective. Thus, the role of retinal GJs in cell death and survival, and in the development or worsening of ocular conditions, remains unclear.
<SOH> BRIEF SUMMARY OF THE DISCLOSURE <EOH>Disclosed herein are methods for treating a condition of the retina, by administering an inhibitor of connexin 36 and/or an inhibitor of connexin 45 to a subject with a retinal condition. In some embodiments, both an inhibitor of connexin 36 and an inhibitor of connexin 45 are administered. The condition of the retina can be selected, for example, from glaucoma, macular degeneration, retinitis pigmentosa, diabetic retinopathy and retinal ischemia. In any of the above methods, the inhibitor can be selected from an antisense polynucleotide directed to connexin 36 messenger ribonucleic acid (mRNA), an antisense polynucleotide directed to connexin 45 mRNA, and combinations thereof. Preferred antisense polynucleotide inhibitors are those that selectively bind the sequence of SEQ ID NO: 1 or SEQ ID NO: 2. The antisense polynucleotide can be complementary to all of or a portion of connexin 36 mRNA and/or connexin 45 mRNA. The antisense polynucleotide can be the exact complement of all or a portion of connexin 36 mRNA and/or connexin 45 mRNA. The antisense polynucleotide can hybridize to connexin 36 mRNA and/or connexin 45 mRNA with a melting temperature of greater than 20° C., 30° C. or 40° C. under physiological conditions. Alternatively, the inhibitor can be a small molecule inhibitor. Exemplary small molecule inhibitors include 18-Beta-glycyrrhetinic acid (18Beta-GA or 18β-GA) and meclofenamic acid (MFA). Any of the above methods can include repeat administration of the inhibitor or inhibitors for a period of one week to one year. Any of the above methods can further include topical administration, such as a drop to be administered to the eye, or intraocular injection. Further disclosed herein are pharmaceutical compositions for treatment of a retinal condition. The compositions can include an inhibitor of connexin 36 and/or an inhibitor of connexin 45. In one example, the inhibitor or inhibitors can be selected from an antisense molecule directed to connexin 36 mRNA, an antisense molecule directed to connexin 45 mRNA, and combinations thereof. In another example, the composition includes a small molecule inhibitor of connexin 36 and/or a small molecule inhibitor of connexin 45. The small molecule inhibitor or inhibitors can be selected, for example, from 18-Beta-glycyrrhetinic acid (18Beta-GA) and meclofenamic acide (MFA). Any of the disclosed compositions can be formulated for intraocular injection or topical administration to the eye. Further disclosed herein are uses of any of the disclosed compositions for the treatment of a condition of the retina. In some examples, the condition of the retina can be selected from glaucoma, macular degeneration, retinitis pigmentosa, diabetic retinopathy and retinal ischemia.
A61K38177
20170828
20171214
57985.0
A61K3817
0
SHIN, DANA H
METHODS OF USING GAP JUNCTIONS AS THERAPEUTIC TARGETS FOR THE TREATMENT OF DEGENERATIVE DISORDERS OF THE RETINA
SMALL
1
CONT-PENDING
A61K
2,017
15,688,305
ACCEPTED
VASOPRESSIN FORMULATIONS FOR USE IN TREATMENT OF HYPOTENSION
Provided herein are peptide formulations comprising polymers as stabilizing agents. The peptide formulations can be more stable for prolonged periods of time at temperatures higher than room temperature when formulated with the polymers. The polymers used in the present invention can decrease the degradation of the constituent peptides of the peptide formulations.
1-15. (canceled) 16. A method of increasing blood pressure in a human in need thereof, the method comprising: administering to the human a pharmaceutical composition that comprises, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; dextrose; acetate; and iv) SEQ ID NO.: 2, wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute, wherein the vasopressin or the pharmaceutically-acceptable salt thereof and SEQ ID NO.: 2 are present in the unit dosage form at a ratio of about 1000:about 1 to about 30:about 1; and the human is hypotensive. 17. The method of claim 16, wherein the unit dosage form further comprises a pH adjusting agent. 18. The method of claim 16, wherein the unit dosage form further comprises hydrochloric acid. 19. The method of claim 16, wherein the unit dosage further comprises sodium hydroxide. 20. The method of claim 16, wherein the unit dosage form further comprises acetic acid. 21. The method of claim 16, wherein the dextrose is present at 5%. 22. The method of claim 16, wherein the vasopressin or the pharmaceutically-acceptable salt thereof and SEQ ID NO.: 2 are present in the unit dosage form at a ratio of about 950:about 1. 23. The method of claim 16, wherein the vasopressin or the pharmaceutically-acceptable salt thereof and SEQ ID NO.: 2 are present in the unit dosage form at a ratio of about 70:about 1. 24. The method of claim 16, wherein the vasopressin or the pharmaceutically-acceptable salt thereof and SEQ ID NO.: 2 are present in the unit dosage form at a ratio of about 35:about 1. 25. The method of claim 16, wherein the administration to the human is over about one day. 26. The method of claim 16, wherein the administration to the human is over about one week. 27. The method of claim 16, wherein the administration is intravenous. 28. The method of claim 16, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. 29. The method of claim 16, wherein the human's hypotension is associated with vasodilatory shock. 30. The method of claim 29, wherein the vasodilatory shock is post-cardiotomy shock. 31. The method of claim 30, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. 32. The method of claim 29, wherein the vasodilatory shock is septic shock. 33. The method of claim 32, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute.
CROSS REFERENCE This application is a continuation of U.S. application Ser. No. 15/612,649, filed Jun. 2, 2017, which is a continuation-in-part of U.S. application Ser. No. 15/426,693, filed Feb. 7, 2017, which is a continuation-in-part of U.S. application Ser. No. 15/289,640, filed Oct. 10, 2016, which is a continuation-in-part of U.S. application Ser. No. 14/717,877, filed May 20, 2015, which is a continuation of U.S. application Ser. No. 14/610,499, filed Jan. 30, 2015, each of which is incorporated herein by reference in its entirety. BACKGROUND Vasopressin is a potent endogenous hormone, responsible for maintaining plasma osmolality and volume in most mammals. Vasopressin can be used clinically in the treatment of sepsis and cardiac conditions, and in the elevation of patient's suffering from low blood pressure. Current formulations of vasopressin suffer from poor long-term stability. INCORPORATION BY REFERENCE Each patent, publication, and non-patent literature cited in the application is hereby incorporated by reference in its entirety as if each was incorporated by reference individually. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Aug. 25, 2017, is named 47956702303_SL.txt and is 5260 bytes in size. SUMMARY OF THE INVENTION In some embodiments, the invention provides a pharmaceutical composition comprising, in a unit dosage form: a) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin, or a pharmaceutically-acceptable salt thereof; and b) a polymeric pharmaceutically-acceptable excipient in an amount that is from about 1% to about 10% by mass of the unit dosage form or the pharmaceutically-acceptable salt thereof, wherein the unit dosage form exhibits from about 5% to about 10% less degradation of the vasopressin or the pharmaceutically-acceptable salt thereof after storage for about 1 week at about 60° C. than does a corresponding unit dosage form, wherein the corresponding unit dosage form consists essentially of: A) vasopressin, or a pharmaceutically-acceptable salt thereof; and B) a buffer having acidic pH. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: intravenously administering to the human a pharmaceutical composition that consists essentially of, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; iii) acetic acid, sodium acetate, or a combination thereof; and iv) optionally hydrochloric acid or sodium hydroxide, wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 5° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 1% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 5° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 25° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 2% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 25° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. BRIEF DESCRIPTION OF THE FIGURES FIG. 1 is a chromatogram of a diluent used in vasopressin assay. FIG. 2 is a chromatogram of a sensitivity solution used in a vasopressin assay. FIG. 3 is a chromatogram of an impurity marker solution used in a vasopressin assay. FIG. 4 is a zoomed-in depiction of the chromatogram in FIG. 3. FIG. 5 is a chromatogram of a vasopressin standard solution. FIG. 6 is a chromatogram of a sample vasopressin preparation. FIG. 7 is a UV spectrum of a vasopressin sample. FIG. 8 is a UV spectrum of a vasopressin standard. FIG. 9 plots vasopressin stability across a range of pH as determined experimentally. FIG. 10 illustrates the effects of various stabilizers on vasopressin stability. FIG. 11 plots vasopressin stability across a range of pH at 25° C. FIG. 12 plots vasopressin impurities across a range of pH at 25° C. FIG. 13 plots vasopressin stability across a range of pH at 40° C. FIG. 14 plots vasopressin impurities across a range of pH at 40° C. FIG. 15 illustrates vasopressin impurities across a range of pH at 25° C. FIG. 16 illustrates vasopressin impurities across a range of pH at 40° C. FIG. 17 illustrates the effect of pH on vasopressin at 25° C. FIG. 18 illustrates the effect of pH on vasopressin at 40° C. FIG. 19 depicts the % LC of vasopressin formulations stored for 15 months at 25° C. FIG. 20 is a chromatogram of a diluent used in a vasopressin assay. FIG. 21 is a chromatogram of a sensitivity solution used in a vasopressin assay. FIG. 22 is a chromatogram of an impurity marker solution used in a vasopressin assay. FIG. 23 is a zoomed-in depiction of the chromatogram in FIG. 22. FIG. 24 is a chromatogram of a working solution. FIG. 25 is a chromatogram of a placebo sample. FIG. 26 is a chromatogram of a vasopressin sample. FIG. 27 depicts the estimated shelf-life of a vasopressin sample described herein at 5° C. FIG. 28 depicts the estimated shelf-life of a vasopressin sample described herein at 25° C. FIG. 29 shows the % LC of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 30 shows the % LC of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 31 shows the % LC of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 32 shows the total impurities of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 33 shows the total impurities of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 34 shows the total impurities of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 35 shows the % Gly9-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 36 shows the % Gly9-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 37 shows the % Gly9-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 38 shows the % Asp5-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 39 shows the % Asp5-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 40 shows the % Asp5-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 41 shows the % Glu4-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 42 shows the % Glu4-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 43 shows the % Glu4-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 44 shows the % Acetyl-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 45 shows the % Acetyl-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 46 shows the % Acetyl-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 47 shows the % AVP-dimer of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 48 shows the % AVP-dimer of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 49 depicts the estimated shelf-life of a vasopressin sample described herein at 5° C. FIG. 50 depicts the estimated shelf-life of a vasopressin sample described herein at 25° C. FIG. 51 shows the % LC of vasopressin after storage at 5° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 52 shows the % LC of vasopressin after storage at 25° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 53 shows the % LC of vasopressin after storage at 40° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 54 shows the % Gly9-AVP of vasopressin after storage at 5° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 55 shows the % Gly9-AVP of vasopressin after storage at 25° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 56 shows the % Gly9-AVP of vasopressin after storage at 40° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 57 shows the % Glu4-AVP of vasopressin after storage at 5° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 58 shows the % Glu4-AVP of vasopressin after storage at 25° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 59 shows the % Glu4-AVP of vasopressin after storage at 40° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 60 shows the total impurities of vasopressin after storage at 5° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 61 shows the total impurities of vasopressin after storage at 25° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 62 shows the total impurities of vasopressin after storage at 40° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. DETAILED DESCRIPTION Vasopressin and Peptides of the Invention. Vasopressin, a peptide hormone, acts to regulate water retention in the body and is a neurotransmitter that controls circadian rhythm, thermoregulation, and adrenocorticotrophic hormone (ACTH) release. Vasopressin is synthesized as a pro-hormone in neurosecretory cells of the hypothalamus, and is subsequently transported to the pituitary gland for storage. Vasopressin is released upon detection of hyperosmolality in the plasma, which can be due to dehydration of the body. Upon release, vasopressin increases the permeability of collecting ducts in the kidney to reduce renal excretion of water. The decrease in renal excretion of water leads to an increase in water retention of the body and an increase in blood volume. At higher concentrations, vasopressin raises blood pressure by inducing vasoconstriction. Vasopressin acts through various receptors in the body including, for example, the V1, V2, V3, and oxytocin-type (OTR) receptors. The V1 receptors occur on vascular smooth muscle cells, and the major effect of vasopressin action on the V1 receptor is the induction of vasoconstriction via an increase of intracellular calcium. V2 receptors occur on the collecting ducts and the distal tubule of the kidney. V2 receptors play a role in detection of plasma volume and osmolality. V3 receptors occur in the pituitary gland and can cause ACTH release upon vasopressin binding. OTRs can be found on the myometrium and vascular smooth muscle. Engagement of OTRs via vasopressin leads to an increase of intracellular calcium and vasoconstriction. Vasopressin is a nonapeptide, illustrated below (SEQ ID NO. 1): At neutral to acidic pH, the two basic groups of vasopressin, the N-terminal cysteine, and the arginine at position eight, are protonated, and can each carry an acetate counterion. The amide groups of the N-terminal glycine, the glutamine at position four, and the asparagine at position five, are susceptible to modification when stored as clinical formulations, such as unit dosage forms. The glycine, glutamine, and asparagine residues can undergo deamidation to yield the parent carboxylic acid and several degradation products as detailed in EXAMPLE 1 and TABLE 1 below. Deamidation is a peptide modification during which an amide group is removed from an amino acid, and can be associated with protein degradation, apoptosis, and other regulatory functions within the cell. Deamidation of asparagine and glutamine residues can occur in vitro and in vivo, and can lead to perturbation of the structure and function of the affected proteins. The susceptibility to deamidation can depend on primary sequence of the protein, three-dimensional structure of the protein, and solution properties including, for example, pH, temperature, ionic strength, and buffer ions. Deamidation can be catalyzed by acidic conditions. Under physiological conditions, deamidation of asparagine occurs via the formation of a five-membered succinimide ring intermediate by a nucleophilic attack of the nitrogen atom in the following peptide bond on the carbonyl group of the asparagine side chain. Acetylation is a peptide modification whereby an acetyl group is introduced into an amino acid, such as on the N-terminus of the peptide. Vasopressin can also form dimers in solution and in vivo. The vasopressin dimers can occur through the formation of disulfide bridges that bind a pair of vasopressin monomers together. The dimers can form between two parallel or anti-parallel chains of vasopressin. Vasopressin and associated degradation products or peptides are listed in TABLE 1 below. All amino acids are L-stereoisomers unless otherwise denoted. TABLE 1 Name Sequence SEQ ID NO. Vasopressin (AVP; CYFQNCPRG-NH2 1 arginine vasopressin) Gly9-vasopressin CYFQNCPRG 2 (Gly9-AVP) Asp5-vasopressin CYFQDCPRG-NH2 3 (Asp5-AVP) Glu4-vasopressin CYFENCPRG-NH2 4 (Glu4-AVP) Glu4Gly9-vasopressin CYFENCPRG 5 (Glu4Gly9-AVP) AcetylAsp5-vasopressin Ac-CYFQDCPRG-NH2 6 (AcetylAsp5-AVP) Acetyl-vasopressin Ac-CYFQNCPRG-NH2 7 (Acetyl-AVP) His2-vasopressin CHFQNCPRG-NH2 8 (His2-AVP) Leu7-vasopressin CYFQNCLRG-NH2 9 (Leu7-AVP) D-Asn-vasopressin CYFQ(D-Asn)CPRG-NH2 10 (DAsn-AVP) D-Cys1-vasopressin (D-Cys)YFQNCPRG-NH2 11 D-Tyr-vasopressin C(D-Tyr)FQNCPRG-NH2 12 D-Phe-vasopressin CY(D-Phe)QNCPRG-NH2 13 D-Gln-vasopressin CYF(D-Gln)NCPRG-NH2 14 D-Cys6-vasopressin CYFQN(D-cys)PRG-NH2 15 D-Pro-vasopressin CYFQNC(D-pro)RG-NH2 16 D-Arg-vasopressin CYFQNCP(D-Arg)G-NH2 17 Therapeutic Uses. A formulation of vasopressin can be used to regulate plasma osmolality and volume and conditions related to the same in a subject. Vasopressin can be used to modulate blood pressure in a subject, and can be indicated in a subject who is hypotensive despite treatment with fluid and catecholamines. Vasopressin can be used in the treatment of, for example, vasodilatory shock, post-cardiotomy shock, sepsis, septic shock, cranial diabetes insipidus, polyuria, nocturia, polydypsia, bleeding disorders, Von Willebrand disease, haemophilia, platelet disorders, cardiac arrest, liver disease, liver failure, hypovolemia, hemorrhage, oesophageal variceal haemorrhage, hypertension, pulmonary hypertension, renal disease, polycystic kidney disease, blood loss, injury, hypotension, meniere disease, uterine myomas, brain injury, mood disorder. Formulations of vasopressin can be administered to a subject undergoing, for example, surgery or hysterectomy. Plasma osmolality is a measure of the plasma's electrolyte-water balance and relates to blood volume and hydration of a subject. Normal plasma osmolality in a healthy human subject range from about 275 milliosmoles/kg to about 295 milliosmoles/kg. High plasma osmolality levels can be due to, for example, diabetes insipidus, hyperglycemia, uremia, hypernatremia, stroke, and dehydration. Low plasma osmolality can be due to, for example, vasopressin oversecretion, improper functioning of the adrenal gland, lung cancer, hyponatremia, hypothyroidism, and over-consumption of water or other fluids. Septic shock can develop due to an extensive immune response following infection and can result in low blood pressure. Causes of sepsis can include, for example, gastrointestinal infections, pneumonia, bronchitis, lower respiratory tract infections, kidney infection, urinary tract infections, reproductive system infections, fungal infections, and viral infections. Risk factors for sepsis include, for example, age, prior illness, major surgery, long-term hospitalization, diabetes, intravenous drug use, cancer, use of steroidal medications, and long-term use of antibiotics. The symptoms of sepsis can include, for example, cool arms and legs, pale arms and legs, extreme body temperatures, chills, light-headedness, decreased urination, rapid breathing, edema, confusion, elevated heart rate, high blood sugar, metabolic acidosis, respiratory alkalosis, and low blood pressure. Vasopressin can also be administered to regulate blood pressure in a subject. Blood pressure is the measure of force of blood pushing against blood vessel walls. Blood pressure is regulated by the nervous and endocrine systems and can be used as an indicator of a subject's health. Chronic high blood pressure is referred to as hypertension, and chronic low blood pressure is referred to as hypotension. Both hypertension and hypotension can be harmful if left untreated. Blood pressure can vary from minute to minute and can follow the circadian rhythm with a predictable pattern over a 24-hour period. Blood pressure is recorded as a ratio of two numbers: systolic pressure (mm Hg), the numerator, is the pressure in the arteries when the heart contracts, and diastolic pressure (mm Hg), the denominator, is the pressure in the arteries between contractions of the heart. Blood pressure can be affected by, for example, age, weight, height, sex, exercise, emotional state, sleep, digestion, time of day, smoking, alcohol consumption, salt consumption, stress, genetics, use of oral contraceptives, and kidney disease. Blood pressure for a healthy human adult between the ages of 18-65 can range from about 90/60 to about 120/80. Hypertension can be a blood pressure reading above about 120/80 and can be classified as hypertensive crisis when there is a spike in blood pressure and blood pressure readings reach about 180/110 or higher. Hypertensive crisis can be precipitated by, for example, stroke, myocardial infarction, heart failure, kidney failure, aortic rupture, drug-drug interactions, and eclampsia. Symptoms of hypertensive crisis can include, for example, shortness of breath, angina, back pain, numbness, weakness, dizziness, confusion, change in vision, nausea, and difficulty speaking. Vasodilatory shock can be characterized by low arterial blood pressure due to decreased systemic vascular resistance. Vasodilatory shock can lead to dangerously low blood pressure levels and can be corrected via administration of catecholamines or vasopressin formulations. Vasodilatory shock can be caused by, for example, sepsis, nitrogen intoxication, carbon monoxide intoxication, hemorrhagic shock, hypovolemia, heart failure, cyanide poisoning, metformin intoxication, and mitochondrial disease. Post-cardiotomy shock can occur as a complication of cardiac surgery and can be characterized by, for example, inability to wean from cardiopulmonary bypass, poor hemodynamics in the operating room, development of poor hemodynamics post-surgery, and hypotension. Pharmaceutical Formulations. Methods for the preparation of compositions comprising the compounds described herein can include formulating the compounds with one or more inert, pharmaceutically-acceptable excipients. Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives. Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, elixir, nanosuspension, aqueous or oily suspensions, drops, syrups, and any combination thereof. Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include granulating agents, binding agents, lubricating agents, disintegrating agents, anti-adherents, anti-static agents, surfactants, anti-oxidants, coloring agents, flavoring agents, plasticizers, preservatives, suspending agents, emulsifying agents, plant cellulosic material and spheronization agents, and any combination thereof. Vasopressin can be formulated as an aqueous formulation or a lyophilized powder, which can be diluted or reconstituted just prior to use. Upon dilution or reconstitution, the vasopressin solution can be refrigerated for long-term stability for about one day. Room temperature incubation or prolonged refrigeration can lead to the generation of degradation products of vasopressin. In some embodiments, a pharmaceutical composition of the invention can be formulated for long-term storage of vasopressin at room temperature in the presence of a suitable pharmaceutically-acceptable excipient. The pharmaceutically-acceptable excipient can increase the half-life of vasopressin when stored at any temperature, such as room temperature. The presence of the pharmaceutical excipient can decrease the rate of decomposition of vasopressin at any temperature, such as room temperature. In some embodiments, a pharmaceutical composition has a shelf life of at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, at least about 25 months, at least about 26 months, at least about 27 months, at least about 28 months, at least about 29 months, or at least about 30 months. The shelf life can be at any temperature, including, for example, room temperature and refrigeration (i.e., 2-8° C.). As used herein, “shelf life” means the period beginning from manufacture of a formulation beyond which the formulation cannot be expected beyond reasonable doubt to yield the therapeutic outcome approved by a government regulatory agency In some embodiments, a vasopressin formulation of the invention comprises a pharmaceutically-acceptable excipient, and the vasopressin has a half-life that is at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, or at least about 1000% greater than the half-life of vasopressin in a corresponding formulation that lacks the pharmaceutically-acceptable excipient. In some embodiments, a vasopressin formulation of the invention has a half-life at about 5° C. to about 8° C. that is no more than about 1%, no more than about 5%, no more than about 10%, no more than about 15%, no more than about 20%, no more than about 25%, no more than about 30%, no more than about 35%, no more than about 40%, no more than about 45%, no more than about 50%, no more than about 55%, no more than about 60%, no more than about 65%, no more than about 70%, no more than about 75%, no more than about 80%, no more than about 85%, no more than about 90%, no more than about 95%, no more than about 100%, no more than about 150%, no more than about 200%, no more than about 250%, no more than about 300%, no more than about 350%, no more than about 400%, no more than about 450%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000% greater than the half-life of the formulation at another temperature, such as room temperature. The half-life of the compounds of the invention in a formulation described herein at a specified temperature can be, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, or about one week. A formulation described herein can be stable for or be stored for, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years prior to administration to a subject. A unit dosage form described herein can be stable for or be stored for, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years prior to administration to a subject. A diluted unit dosage form described herein can be stable for or be stored for, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years prior to administration to subject. The stability of a formulation described herein can be measured after, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years. A formulation or unit dosage form described herein can exhibit, for example, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9% about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% degradation over a specified period of time. The degradation of a formulation or a unit dosage form disclosed herein can be assessed after about 24 hours, about 36 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years of storage. The degradation of a formulation or a unit dosage form disclosed herein can be assessed at a temperature of, for example, about 0° C., about 1° C., about 2° C., about 3° C., about 4° C., about 5° C., about 6° C., about 7° C., about 8° C., about 9° C., about 10° C., about 11° C., about 12° C., about 13° C., about 14° C., about 15° C., about 16° C., about 17° C., about 18° C., about 19° C., about 20° C., about 21° C., about 22° C., about 23° C., about 24° C., about 25° C., about 26° C., about 27° C., about 28° C., about 29° C., about 30° C., about 31° C., about 32° C., about 33° C., about 34° C., about 35° C., about 36° C., about 37° C., about 38° C., about 39° C., about 40° C., about 41° C., about 42° C., about 43° C., about 44° C., about 45° C., about 46° C., about 47° C., about 48° C., about 49° C., about 50° C., or about 0° C. to about 5° C., about 1° C. to about 6° C., about 2° C. to about 7° C., about 2° C. to about 8° C., about 3° C. to about 8° C., about 4° C. to about 9° C., about 5° C. to about 10° C., about 6° C. to about 11° C., about 7° C. to about 12° C., about 8° C. to about 13° C., about 9° C. to about 14° C., about 10° C. to about 15° C., about 11° C. to about 16° C., about 12° C. to about 17° C., about 13° C. to about 18° C., about 14° C. to about 19° C., about 15° C. to about 20° C., about 16° C. to about 21° C., about 17° C. to about 22° C., about 18° C. to about 23° C., about 19° C. to about 24° C., about 20° C. to about 25° C., about 21° C. to about 26° C., about 22° C. to about 27° C., about 23° C. to about 28° C., about 24° C. to about 29° C., about 25° C. to about 30° C., about 26° C. to about 31° C., about 27° C. to about 32° C., about 28° C. to about 33° C., about 29° C. to about 34° C., about 30° C. to about 35° C., about 31° C. to about 36° C., about 32° C. to about 37° C., about 33° C. to about 38° C., about 34° C. to about 39° C., about 35° C. to about 40° C., about 36° C. to about 41° C., about 37° C. to about 42° C., about 38° C. to about 43° C., about 39° C. to about 44° C., about 40° C. to about 45° C., about 41° C. to about 46° C., about 42° C. to about 47° C., about 43° C. to about 48° C., about 44° C. to about 49° C., about 45° C. to about 50° C. In some embodiments, a vasopressin formulation of the invention comprises an excipient and the vasopressin has a level of decomposition at a specified temperature that is about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% less than the level of decomposition of a formulation of the invention in the absence of the excipient. Pharmaceutical compositions of the invention can be used, stored, tested, analyzed or assayed at any suitable temperature. Non-limiting examples of temperatures include about 0° C., about 1° C., about 2° C., about 3° C., about 4° C., about 5° C., about 6° C., about 7° C., about 8° C., about 9° C., about 10° C., about 11° C., about 12° C., about 13° C., about 14° C., about 15° C., about 16° C., about 17° C., about 18° C., about 19° C., about 20° C., about 21° C., about 22° C., about 23° C., about 24° C., about 25° C., about 26° C., about 27° C., about 28° C., about 29° C., about 30° C., about 31° C., about 32° C., about 33° C., about 34° C., about 35° C., about 36° C., about 37° C., about 38° C., about 39° C., about 40° C., about 41° C., about 42° C., about 43° C., about 44° C., about 45° C., about 46° C., about 47° C., about 48° C., about 49° C., about 50° C., about 51° C., about 52° C., about 53° C., about 54° C., about 55° C., about 56° C., about 57° C., about 58° C., about 59° C., about 60° C., about 61° C., about 62° C., about 63° C., about 64° C., about 65° C., about 66° C., about 67° C., about 68° C., about 69° C., about 70° C., about 71° C., about 72° C., about 73° C., about 74° C., or about 75° C. Pharmaceutical compositions of the invention can be used, stored, tested, analyzed or assayed at any suitable temperature. Non-limiting examples of temperatures include from about 0° C. to about 5° C., about 1° C. to about 6° C., about 2° C. to about 7° C., about 2° C. to about 8° C., about 3° C. to about 8° C., about 4° C. to about 9° C., about 5° C. to about 10° C., about 6° C. to about 11° C., about 7° C. to about 12° C., about 8° C. to about 13° C., about 9° C. to about 14° C., about 10° C. to about 15° C., about 11° C. to about 16° C., about 12° C. to about 17° C., about 13° C. to about 18+° C., about 14° C. to about 19° C., about 15° C. to about 20° C., about 16° C. to about 21° C., about 17° C. to about 22° C., about 18° C. to about 23° C., about 19° C. to about 24° C., about 20° C. to about 25° C., about 21° C. to about 26° C., about 22° C. to about 27° C., about 23° C. to about 28° C., about 24° C. to about 29° C., about 25° C. to about 30° C., about 26° C. to about 31° C., about 27° C. to about 32° C., about 28° C. to about 33° C., about 29° C. to about 34° C., about 30° C. to about 35° C., about 31° C. to about 36° C., about 32° C. to about 37° C., about 33° C. to about 38° C., about 34° C. to about 39° C., about 35° C. to about 40° C., about 36° C. to about 41° C., about 37° C. to about 42° C., about 38° C. to about 43° C., about 39° C. to about 44° C., about 40° C. to about 45° C., about 41° C. to about 46° C., about 42° C. to about 47° C., about 43° C. to about 48° C., about 44° C. to about 49° C., about 45° C. to about 50° C., about 46° C. to about 51° C., about 47° C. to about 52° C., about 48° C. to about 53° C., about 49° C. to about 54° C., about 50° C. to about 55° C., about 51° C. to about 56° C., about 52° C. to about 57° C., about 53° C. to about 58° C., about 54° C. to about 59° C., about 55° C. to about 60° C., about 56° C. to about 61° C., about 57° C. to about 62° C., about 58° C. to about 63° C., about 59° C. to about 64° C., about 60° C. to about 65° C., about 61° C. to about 66° C., about 62° C. to about 67° C., about 63° C. to about 68° C., about 64° C. to about 69° C., about 65° C. to about 70° C., about 66° C. to about 71° C., about 67° C. to about 72° C., about 68° C. to about 73° C., about 69° C. to about 74° C., about 70° C. to about 74° C., about 71° C. to about 76° C., about 72° C. to about 77° C., about 73° C. to about 78° C., about 74° C. to about 79° C., or about 75° C. to about 80° C. Pharmaceutical compositions of the invention can be used, stored, tested, analyzed or assayed at room temperature. The room temperature can be, for example, about 20.0° C., about 20.1° C., about 20.2° C., about 20.3° C., about 20.4° C., about 20.5° C., about 20.6° C., about 20.7° C., about 20.8° C., about 20.9° C., about 21.0° C., about 21.1° C., about 21.2° C., about 21.3° C., about 21.4° C., about 21.5° C., about 21.6° C., about 21.7° C., about 21.8° C., about 21.9° C., about 22.0° C., about 22.1° C., about 22.2° C., about 22.3° C., about 22.4° C., about 22.5° C., about 22.6° C., about 22.7° C., about 22.8° C., about 22.9° C., about 23.0° C., about 23.1° C., about 23.2° C., about 23.3° C., about 23.4° C., about 23.5° C., about 23.6° C., about 23.7° C., about 23.8° C., about 23.9° C., about 24.0° C., about 24.1° C., about 24.2° C., about 24.3° C., about 24.4° C., about 24.5° C., about 24.6° C., about 24.7° C., about 24.8° C., about 24.9° C., or about 25.0° C. A pharmaceutical composition of the disclosed can be supplied, stored, or delivered in a vial or tube that is, for example, about 0.5 mL, about 1 mL, about 2 mL, about 3 mL, about 4 mL, about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, about 10 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about 18 mL, about 19 mL, or about 20 mL in volume. A pharmaceutical composition of the disclosure can be a combination of any pharmaceutical compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can be administered in therapeutically-effective amounts, for example, intravenous, subcutaneous, intramuscular, transdermal, or parenteral administration. Pharmaceutical preparations can be formulated for intravenous administration. The pharmaceutical compositions can be in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in oily or aqueous vehicles, and can contain formulation agents such as suspending, stabilizing, and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Suspensions of the active compounds can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. The suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use. Comparison Formulations. A pharmaceutical composition described herein can be analyzed by comparison to a reference formulation. A reference formulation can be generated from any combination of compounds, peptides, excipients, diluents, carriers, and solvents disclosed herein. Any compound, peptide, excipient, diluent, carrier, or solvent used to generate the reference formulation can be present in any percentage, ratio, or amount, for example, those disclosed herein. The reference formulation can comprise, consist essentially of, or consist of any combination of any of the foregoing. A non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: an amount, such as about 20 Units or about 0.04 mg, of vasopressin or a pharmaceutically-acceptable salt thereof, an amount, such as about 5 mg, of chlorobutanol (for example, hydrous), an amount, such as about 0.22 mg, of acetic acid or a pharmaceutically-acceptable salt thereof or a quantity sufficient to bring pH to about 3.4 to about 3.6, and water as needed. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof, chlorobutanol, acetic acid, and a solvent such as water. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof, chlorobutanol, and a solvent such as water. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof, acetic acid, and a solvent such as water. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof and a solvent such as water. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof and a buffer having acidic pH, such as pH 3.5 or any buffer or pH described herein. Methods. Any formulation described herein can be diluted prior to administration to a subject. Diluents that can be used in a method of the invention include, for example, compound sodium lactate solution, 6% dextran, 10% dextran, 5% dextrose, 20% fructose, Ringer's solution, 5% saline, 1.39% sodium bicarbonate, 1.72% sodium lactate, or water. Upon dilution, any diluted formulation disclosed herein can be stored for, for example, about 24 hours, about 36 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years of storage. Upon dilution, any diluted formulation disclosed herein can be stored at, for example, about 0° C., about 1° C., about 2° C., about 3° C., about 4° C., about 5° C., about 6° C., about 7° C., about 8° C., about 9° C., about 10° C., about 11° C., about 12° C., about 13° C., about 14° C., about 15° C., about 16° C., about 17° C., about 18° C., about 19° C., about 20° C., about 21° C., about 22° C., about 23° C., about 24° C., about 25° C., about 26° C., about 27° C., about 28° C., about 29° C., about 30° C., about 31° C., about 32° C., about 33° C., about 34° C., about 35° C., about 36° C., about 37° C., about 38° C., about 39° C., about 40° C., about 41° C., about 42° C., about 43° C., about 44° C., about 45° C., about 46° C., about 47° C., about 48° C., about 49° C., about 50° C., or about 0° C. to about 5° C., about 1° C. to about 6° C., about 2° C. to about 7° C., about 2° C. to about 8° C., about 3° C. to about 8° C., about 4° C. to about 9° C., about 5° C. to about 10° C., about 6° C. to about 11° C., about 7° C. to about 12° C., about 8° C. to about 13° C., about 9° C. to about 14° C., about 10° C. to about 15° C., about 11° C. to about 16° C., about 12° C. to about 17° C., about 13° C. to about 18° C., about 14° C. to about 19° C., about 15° C. to about 20° C., about 16° C. to about 21° C., about 17° C. to about 22° C., about 18° C. to about 23° C., about 19° C. to about 24° C., about 20° C. to about 25° C., about 21° C. to about 26° C., about 22° C. to about 27° C., about 23° C. to about 28° C., about 24° C. to about 29° C., about 25° C. to about 30° C., about 26° C. to about 31° C., about 27° C. to about 32° C., about 28° C. to about 33° C., about 29° C. to about 34° C., about 30° C. to about 35° C., about 31° C. to about 36° C., about 32° C. to about 37° C., about 33° C. to about 38° C., about 34° C. to about 39° C., about 35° C. to about 40° C., about 36° C. to about 41° C., about 37° C. to about 42° C., about 38° C. to about 43° C., about 39° C. to about 44° C., about 40° C. to about 45° C., about 41° C. to about 46° C., about 42° C. to about 47° C., about 43° C. to about 48° C., about 44° C. to about 49° C., about 45° C. to about 50° C. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about two weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about three weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about six weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about three months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about six months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about two years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about three years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 24 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 48 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 96 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 1 week; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 months; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 months; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least one year; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least two years; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least three years; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 24 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 48 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 96 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least one week; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 months; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 months; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 1 year; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 years; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 years; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 24 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 48 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 96 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 1 week; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 months; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 months; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 1 year; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 years; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 years; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 24 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 48 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 96 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least one week; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 months; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 months; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least one year; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 years; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 years; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 24 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 48 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 96 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 1 week; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 2 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 months; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 6 months; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 1 year; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 2 years; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 years; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about two weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about three weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 24 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 48 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C. for about, for example, 5° C., 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 96 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 1 week; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 2 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 months; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 6 months; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 1 year; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 2 years; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 years; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. A formulation described herein can be used without initial vasopressin dilution for use in, for example, intravenous drip-bags. The formulation can be premixed, already-diluted, and ready for use as provided in, for example, a bottle or intravenous drip-bag. The formulation supplied in the bottle can then be transferred to an intravenous drip-bag for administration to a subject. The formulation can be stable for about 24 hours, about 36 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years prior to discarding. The premixed formulation described herein can be disposed in a container or vessel, which can be sealed. The container or vessel can maintain the sterility of, or reduce the likelihood of contamination of, the premixed formulation. The premixed formulation described herein can be disposed in a container or vessel and is formulated as, for example, a single use dosage or a multiple use dosage. The container or vessel can be, for example, a glass vial, an ampoule, or a plastic flexible container. The plastic flexible container can be made of, for example, PVC (polyvinyl chloride), or polypropylene. A premixed vasopressin formulation described herein can be stored as a liquid in an aliquot having a total volume of between about 1 and about 500 mL, between about 1 and about 250 mL, between about 1 and about 200 mL, between about 1 and about 150 mL, between about 1 and about 125 mL, between about 1 and about 120 mL, between about 1 and about 110 mL, between about 1 and about 100 mL, between about 1 and about 90 mL, between about 1 and about 80 mL, between about 1 and about 70 mL, between about 1 and about 60 mL, between about 1 and about 50 mL, between about 1 and about 40 mL, between about 1 and about 30 mL, between about 1 and about 20 mL, between about 1 and about 10 mL, or between about 1 and about 5 mL. A premixed vasopressin formulation described herein can be administered as, for example, a single continuous dose over a period of time. For example, the premixed vasopressin formulation can be administered for a period of time of between about 1 and about 10 minutes, between about 1 and about 20 minutes, between about 1 and about 30 minutes, between about 1 and about 2 hours, between about 1 and about 3 hours, between about 1 and about 4 hours, between about 1 and about 5 hours, between about 1 and about 6 hours, between about 1 and about 7 hours, between about 1 and about 8 hours, between about 1 and about 9 hours, between about 1 and about 10 hours, between about 1 and about 11 hours, between about 1 and about 12 hours, between about 1 and about 13 hours, between about 1 and about 14 hours, between about 1 and about 15 hours, between about 1 and about 16 hours, between about 1 and about 17 hours, between about 1 and about 18 hours, between about 1 and about 19 hours, between about 1 and about 20 hours, between about 1 and about 21 hours, between about 1 and about 22 hours, between about 1 and about 23 hours, between about 1 and about 1 day, between about 1 and about 32 hours, between about 1 and about 36 hours, between about 1 and about 42 hours, between about 1 and about 2 days, between about 1 and about 54 hours, between about 1 and about 60 hours, between about 1 and about 66 hours, between about 1 and about 3 days, between about 1 and about 78 hours, between about 1 and about 84 hours, between about 1 and about 90 hours, between about 1 and about 4 days, between about 1 and about 102 hours, between about 1 and about 108 hours, between about 1 and about 114 hours, between about 1 and about 5 days, between about 1 and about 126 hours, between about 1 and about 132 hours, between about 1 and about 138 hours, between about 1 and about 6 days, between about 1 and about 150 hours, between about 1 and about 156 hours, between about 1 and about 162 hours, or between about 1 and about 1 week. A premixed vasopressin formulation described herein can be administered as a loading dose followed by a maintenance dose over a period of time. For example, the loading dose can comprise administration of the premixed vasopressin formulation at a first dosage amount for a first period of time, followed by administration of the maintenance dose at a second dosage amount for a second period of time. The loading dose can be administered for a period of time of between about 1 and about 5 minutes, between about 1 and about 10 minutes, between about 1 and about 15 minutes, between about 1 and about 20 minutes, between about 1 and about 25 minutes, between about 1 and about 30 minutes, between about 1 and about 45 minutes, between about 1 and about 60 minutes, between about 1 and about 90 minutes, between 1 minute and about 2 hours, between 1 minute about 2.5 hours, between 1 minute and about 3 hours, between 1 minute and about 3.5 hours, between 1 minute and about 4 hours, between 1 minute and about 4.5 hours, between 1 minute and about 5 hours, between 1 minute and about 5.5 hours, between 1 minute and about 6 hours, between 1 minute and about 6.5 hours, between 1 minute and about 7 hours, between 1 minute and about 7.5 hours, between 1 minute and about 8 hours, between 1 minute and about 10 hours, between 1 minute and about 12 hours, between 1 minute about 14 hours, between 1 minute and about 16 hours, between 1 minute and about 18 hours, between 1 minute and about 20 hours, between 1 minute and about 22 hours, or between 1 minute and about 24 hours. Following the loading dose, the maintenance dose can be administered for a period of time as described above for a single continuous dose. A premixed vasopressin formulation described herein, when administered as a single continuous, loading, or maintenance dose, can be administered for about 1 hour to about 7 days, about 1 hour to about 4 days, about 1 hour to about 48 hours, about 1 hour to about 36 hours, about 1 hour to about 24 hours, about 1 hour to about 12 hours, about 24 hours to about 120 hours, about 24 hours to about 108 hours, about 24 hours to about 96 hours, about 24 hours to about 72 hours, about 24 hours to about 48 hours, or about 24 hours to about 36 hours. The volume of the premixed formulation can be, for example, about 25 mL, about 30 mL, about 35 mL, about 40 mL, about 45 mL, about 50 mL, about 55 mL, about 60 mL, about 65 mL, about 70 mL, about 75 mL, about 80 mL, about 85 mL, about 90 mL, about 95 mL, about 100 mL, about 110 mL, about 120 mL, about 130 mL, about 140 mL, about 150 mL, about 175 mL, about 200 mL, about 225 mL, about 250 mL, about 275 mL, about 300 mL, about 350 mL, about 400 mL, about 450 mL, about 500 mL, about 550 mL, about 600 mL, about 650 mL, about 700 mL, about 750 mL, about 800 mL, about 850 mL, about 900 mL, about 950 mL, or about 1 L. In some embodiments, the volume of the vasopressin formulation formulated for use without initial vasopressin dilution is 100 mL. The concentration of vasopressin in the container or vessel in which the premixed vasopressin formulation is disposed can be, for example, about 0.1 units/mL, about 0.2 units/mL, about 0.3 units/mL, about 0.4 units/mL, about 0.5 units/mL, about 0.6 units/mL, about 0.7 units/mL, about 0.8 units/mL, about 0.9 units/mL, about 1 unit/mL, about 2 units/mL, about 3 units/mL, about 4 units/mL, about 5 units/mL, about 6 units/mL, about 7 units/mL, about 8 units/mL, about 9 units/mL, about 10 units/mL, about 11 units/mL, about 12 units/mL, about 13 units/mL, about 14 units/mL, about 15 units/mL, about 16 units/mL, about 17 units/mL, about 18 units/mL, about 19 units/mL, about 20 units/mL, about 21 units/mL, about 22 units/mL, about 23 units/mL, about 24 units/mL about 25 units/mL, about 30 units/mL, about 35 units/mL, about 40 units/mL, about 45 units/mL, or about 50 units/mL. In some embodiments, the concentration of vasopressin in the container or vessel is 0.4 units/mL. In some embodiments, the concentration of vasopressin in the container or vessel is 0.6 units/mL. The concentration of vasopressin in the container or vessel in which the premixed vasopressin formulation is disposed can be, for example, about 0.01 μg/mL, about 0.05 μg/mL, about 0.1 μg/mL, about 0.15 μg/mL, about 0.2 μg/mL, about 0.25 μg/mL, about 0.3 μg/mL, about 0.35 μg/mL, about 0.4 μg/mL, about 0.5 μg/mL, about 0.6 μg/mL, about 0.7 μg/mL, about 0.8 μg/mL, about 0.9 μg/mL, about 1 μg/mL, about 2 μg/mL, about 3 μg/mL, about 4 μg/mL, about 5 μg/mL, about 10 μg/mL, about 15 μg/mL, about 20 μg/mL, about 25 μg/mL, about 30 μg/mL, about 35 μg/mL, about 40 μg/mL, about 45 μg/mL, about 50 μg/mL, about 60 μg/mL, about 70 μg/mL, about 80 μg/mL, about 90 μg/mL, about 100 μg/mL, about 125 μg/mL, about 150 μg/mL, about 175 μg/mL, about 200 μg/mL, about 250 μg/mL, about 300 μg/mL, about 350 μg/mL, about 400 μg/mL, about 450 μg/mL, about 500 μg/mL, about 600 μg/mL, about 700 μg/mL, about 800 μg/mL, about 900 μg/mL, about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, or about 10 mg/mL. A formulation formulated for use without initial vasopressin dilution can be administered as intravenous drip therapy for about 15 min, about 20 min, about 25 min, about 30 min, about 35 min, about 40 min, about 45 min, about 50 min, about 55 min, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 1 year. A formulation for use in a drip-bag can be replaced up to, for example, one time, two times, three times, four times, five times, six times, seven times, eight times, nine times, ten times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, or 20 times during the course of the treatment period. The formulation can be used for continuous or intermittent intravenous infusion. A formulation formulated for use without initial vasopressin dilution can be modified using an excipient, for example, any excipient disclosed herein, to improve the stability of vasopressin for long-term storage and use. Non-limiting examples of excipients that can be used in an intravenous drip-bag include dextrose, saline, half-strength saline, quarter-strength saline, Ringers Lactate solution, sodium chloride, and potassium chloride. In some embodiments, dextrose is used as an excipient for the vasopressin formulation formulated for use without initial vasopressin dilution. A formulation formulated for use without initial vasopressin dilution can be modified using a buffer, for example, any buffer disclosed herein, to adjust the pH of the formulation. A non-limiting example of a buffer that can be used in the formulation includes acetate buffer. The concentration of buffer used in the formulation can be, for example, about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, or about 30 mM. In some embodiments, the concentration of the acetate buffer is 1 mM. In some embodiments, the concentration of the acetate buffer is 10 mM. In some embodiments, an additive that is used in a formulation described herein is dextrose. The concentration of dextrose used in the formulation can be, for example, about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, or about 30 mM. In some embodiments, the concentration of dextrose is 1 mM. In some embodiments, the concentration of dextrose is 10 mM. The concentration of dextrose used in the formulation can be, for example, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%. In some embodiments, a formulation described herein contains 5% dextrose. In some embodiments, an additive that is used in a formulation described herein is sodium chloride. The concentration of sodium chloride used in the formulation can be, for example, about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, or about 30 mM. In some embodiments, the concentration of the sodium chloride is 1 mM. In some embodiments, the concentration of sodium chloride is 10 mM. In some embodiments, a combination of dextrose and sodium chloride is used in a formulation described herein. When used in combination, the concentration of sodium chloride and dextrose can be the same or different. In some embodiments, the concentration of dextrose or sodium chloride is 1 mM, or any value above 1 mM, when dextrose and sodium chloride are used in a combination in a formulation described herein. A formulation formulated for use without initial vasopressin dilution can be modified using a pH adjusting agent, for example, any pH adjusting agent disclosed herein, to adjust the pH of the formulation. Non-limiting examples of a pH adjusting agent that can be used in the formulation include acetic acid, sodium acetate, hydrochloric acid, and sodium hydroxide. The concentration of buffer used in the formulation can be, for example, about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, or about 30 mM. In some embodiments, the concentration of the acetate buffer is 1 mM. In some embodiments, the concentration of the acetate buffer is 10 mM. The formulation can be stable for and have a shelf-life of about 24 hours, about 36 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years of storage at any temperature. In some embodiments, the shelf-life of the formulation is 2 years under refrigeration. In some embodiments, the shelf-life of the formulation is 6 months at room temperature. In some embodiments, the total shelf-life of the formulation is 30 months, where the formulation is stored for 2 years under refrigeration and 6 months at room temperature. Dosage Amounts. In practicing the methods of treatment or use provided herein, therapeutically-effective amounts of the compounds described herein are administered in pharmaceutical compositions to a subject having a disease or condition to be treated. A therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors. Subjects can be, for example, humans, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, or neonates. A subject can be a patient. Pharmaceutical compositions of the invention can be formulated in any suitable volume. The formulation volume can be, for example, about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1 mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, about 1.4 mL, about 1.5 mL, about 1.6 mL, about 1.7 mL, about 1.8 mL, about 1.9 mL, about 2 mL, about 2.1 mL, about 2.2 mL, about 2.3 mL, about 2.4 mL, about 2.5 mL, about 2.6 mL, about 2.7 mL, about 2.8 mL, about 2.9 mL, about 3 mL, about 3.1 mL, about 3.2 mL, about 3.3 mL, about 3.4 mL, about 3.5 mL, about 3.6 mL, about 3.7 mL, about 3.8 mL, about 3.9 mL, about 4 mL, about 4.1 mL, about 4.2 mL, about 4.3 mL, about 4.4 mL, about 4.5 mL, about 4.6 mL, about 4.7 mL, about 4.8 mL, about 4.9 mL, about 5 mL, about 5.1 mL, about 5.2 mL, about 5.3 mL, about 5.4 mL, about 5.5 mL, about 5.6 mL, about 5.7 mL, about 5.8 mL, about 5.9 mL, about 6 mL, about 6.1 mL, about 6.2 mL, about 6.3 mL, about 6.4 mL, about 6.5 mL, about 6.6 mL, about 6.7 mL, about 6.8 mL, about 6.9 mL, about 7 mL, about 7.1 mL, about 7.2 mL, about 7.3 mL, about 7.4 mL, about 7.5 mL, about 7.6 mL, about 7.7 mL, about 7.8 mL, about 7.9 mL, about 8 mL, about 8.1 mL, about 8.2 mL, about 8.3 mL, about 8.4 mL, about 8.5 mL, about 8.6 mL, about 8.7 mL, about 8.8 mL, about 8.9 mL, about 9 mL, about 9.1 mL, about 9.2 mL, about 9.3 mL, about 9.4 mL, about 9.5 mL, about 9.6 mL, about 9.7 mL, about 9.8 mL, about 9.9 mL, about 10 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about 18 mL, about 19 mL, or about 20 mL. A therapeutically-effective amount of a compound described herein can be present in a composition at a concentration of, for example, about 0.1 units/mL, about 0.2 units/mL, about 0.3 units/mL, about 0.4 units/mL, about 0.5 units/mL, about 0.6 units/mL, about 0.7 units/mL, about 0.8 units/mL, about 0.9 units/mL, about 1 unit/mL, about 2 units/mL, about 3 units/mL, about 4 units/mL, about 5 units/mL, about 6 units/mL, about 7 units/mL, about 8 units/mL, about 9 units/mL, about 10 units/mL, about 11 units/mL, about 12 units/mL, about 13 units/mL, about 14 units/mL, about 15 units/mL, about 16 units/mL, about 17 units/mL, about 18 units/mL, about 19 units/mL, about 20 units/mL, about 21 units/mL, about 22 units/mL, about 23 units/mL, about 24 units/mL about 25 units/mL, about 30 units/mL, about 35 units/mL, about 40 units/mL, about 45 units/mL, or about 50 units/mL. A therapeutically-effective amount of a compound described herein can be present in a composition of the invention at a mass of about, for example, about 0.01 μg, about 0.05 μg, about 0.1 μg, about 0.15 μg, about 0.2 μg, about 0.25 μg, about 0.3 μg, about 0.35 μg, about 0.4 μg, about 0.5 μg, about 0.6 μg, about 0.7 μg, about 0.8 μg, about 0.9 μg, about 1 μg, about 2 μg, about 3 μg, about 4 μg, about 5 μg, about 10 μg, about 15 μg, about 20 μg, about 25 μg, about 30 μg, about 35 μg, about 40 μg, about 45 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 125 μg, about 150 μg, about 175 μg, about 200 μg, about 250 μg, about 300 μg, about 350 μg, about 400 μg, about 450 μg, about 500 μg, about 600 μg, about 700 μg, about 800 μg, about 900 μg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg. A therapeutically-effective amount of a compound described herein can be present in a composition of the invention at a concentration of, for example, about 0.001 mg/mL, about 0.002 mg/mL, about 0.003 mg/mL, about 0.004 mg/mL, about 0.005 mg/mL, about 0.006 mg/mL, about 0.007 mg/mL, about 0.008 mg/mL, about 0.009 mg/mL, about 0.01 mg/mL, about 0.02 mg/mL, about 0.03 mg/mL, about 0.04 mg/mL, about 0.05 mg/mL, about 0.06 mg/mL, about 0.07 mg/mL, about 0.08 mg/mL, about 0.09 mg/mL, about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 1.5 mg/mL, about 2 mg/mL, about 2.5 mg/mL, about 3 mg/mL, about 3.5 mg/mL, about 4 mg/mL, about 4.5 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, or about 10 mg/mL. A therapeutically-effective amount of a compound described herein can be present in a composition of the invention at a unit of active agent/unit of active time. Non-limiting examples of therapeutically-effective amounts can be, for example, about 0.01 units/minute, about 0.02 units/minute, about 0.03 units/minute, about 0.04 units/minute, about 0.05 units/minute, about 0.06 units/minute, about 0.07 units/minute, about 0.08 units/minute, about 0.09 units/minute or about 0.1 units/minute. Pharmaceutical compositions of the invention can be formulated at any suitable pH. The pH can be, for example, about 2, about 2.05, about 2.1, about 2.15, about 2.2, about 2.25, about 2.3, about 2.35, about 2.4, about 2.45, about 2.5, about 2.55, about 2.6, about 2.65, about 2.7, about 2.75, about 2.8, about 2.85, about 2.9, about 2.95, about 3, about 3.05, about 3.1, about 3.15, about 3.2, about 3.25, about 3.3, about 3.35, about 3.4, about 3.45, about 3.5, about 3.55, about 3.6, about 3.65, about 3.7, about 3.75, about 3.8, about 3.85, about 3.9, about 3.95, about 4, about 4.05, about 4.1, about 4.15, about 4.2, about 4.25, about 4.3, about 4.35, about 4.4, about 4.45, about 4.5, about 4.55, about 4.6, about 4.65, about 4.7, about 4.75, about 4.8, about 4.85, about 4.9, about 4.95, or about 5 pH units. Pharmaceutical compositions of the invention can be formulated at any suitable pH. The pH can be, for example, from about 2 to about 2.2, about 2.05 to about 2.25, about 2.1 to about 2.3, about 2.15 to about 2.35, about 2.2 to about 2.4, about 2.25 to about 2.45, about 2.3 to about 2.5, about 2.35 to about 2.55, about 2.4 to about 2.6, about 2.45 to about 2.65, about 2.5 to about 2.7, about 2.55 to about 2.75, about 2.6 to about 2.8, about 2.65 to about 2.85, about 2.7 to about 2.9, about 2.75 to about 2.95, about 2.8 to about 3, about 2.85 to about 3.05, about 2.9 to about 3.1, about 2.95 to about 3.15, about 3 to about 3.2, about 3.05 to about 3.25, about 3.1 to about 3.3, about 3.15 to about 3.35, about 3.2 to about 3.4, about 3.25 to about 3.45, about 3.3 to about 3.5, about 3.35 to about 3.55, about 3.4 to about 3.6, about 3.45 to about 3.65, about 3.5 to about 3.7, about 3.55 to about 3.75, about 3.6 to about 3.8, about 3.65 to about 3.85, about 3.7 to about 3.9, about 3.7 to about 3.8, about 3.75 to about 3.95, about 3.75 to about 3.8, about 3.8 to about 3.85, about 3.75 to about 3.85, about 3.8 to about 4, about 3.85 to about 4.05, about 3.9 to about 4.1, about 3.95 to about 4.15, about 4 to about 4.2, about 4.05 to about 4.25, about 4.1 to about 4.3, about 4.15 to about 4.35, about 4.2 to about 4.4, about 4.25 to about 4.45, about 4.3 to about 4.5, about 4.35 to about 4.55, about 4.4 to about 4.6, about 4.45 to about 4.65, about 4.5 to about 4.7, about 4.55 to about 4.75, about 4.6 to about 4.8, about 4.65 to about 4.85, about 4.7 to about 4.9, about 4.75 to about 4.95, about 4.8 to about 5, about 4.85 to about 5.05, about 4.9 to about 5.1, about 4.95 to about 5.15, or about 5 to about 5.2 pH units. In some embodiments, the addition of an excipient can change the viscosity of a pharmaceutical composition of the invention. In some embodiments the use of an excipient can increase or decrease the viscosity of a fluid by at least 0.001 Pascal-second (Pa·s), at least 0.001 Pa·s, at least 0.0009 Pa·s, at least 0.0008 Pa·s, at least 0.0007 Pa·s, at least 0.0006 Pa·s, at least 0.0005 Pa·s, at least 0.0004 Pa·s, at least 0.0003 Pa·s, at least 0.0002 Pa·s, at least 0.0001 Pa·s, at least 0.00005 Pa·s, or at least 0.00001 Pa·s. In some embodiments, the addition of an excipient to a pharmaceutical composition of the invention can increase or decrease the viscosity of the composition by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In some embodiments, the addition of an excipient to a pharmaceutical composition of the invention can increase or decrease the viscosity of the composition by no greater than 5%, no greater than 10%, no greater than 15%, no greater than 20%, no greater than 25%, no greater than 30%, no greater than 35%, no greater than 40%, no greater than 45%, no greater than 50%, no greater than 55%, no greater than 60%, no greater than 65%, no greater than 70%, no greater than 75%, no greater than 80%, no greater than 85%, no greater than 90%, no greater than 95%, or no greater than 99%. Any compound herein can be purified. A compound can be at least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 43% pure, at least 44% pure, at least 45% pure, at least 46% pure, at least 47% pure, at least 48% pure, at least 49% pure, at least 50% pure, at least 51% pure, at least 52% pure, at least 53% pure, at least 54% pure, at least 55% pure, at least 56% pure, at least 57% pure, at least 58% pure, at least 59% pure, at least 60% pure, at least 61% pure, at least 62% pure, at least 63% pure, at least 64% pure, at least 65% pure, at least 66% pure, at least 67% pure, at least 68% pure, at least 69% pure, at least 70% pure, at least 71% pure, at least 72% pure, at least 73% pure, at least 74% pure, at least 75% pure, at least 76% pure, at least 77% pure, at least 78% pure, at least 79% pure, at least 80% pure, at least 81% pure, at least 82% pure, at least 83% pure, at least 84% pure, at least 85% pure, at least 86% pure, at least 87% pure, at least 88% pure, at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least 99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, or at least 99.9% pure. Compositions of the invention can be packaged as a kit. In some embodiments, a kit includes written instructions on the administration or use of the composition. The written material can be, for example, a label. The written material can suggest conditions methods of administration. The instructions provide the subject and the supervising physician with the best guidance for achieving the optimal clinical outcome from the administration of the therapy. In some embodiments, the label can be approved by a regulatory agency, for example the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other regulatory agencies. Pharmaceutically-Acceptable Excipients. Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety. In some embodiments, the pharmaceutical composition provided herein comprises a sugar as an excipient. Non-limiting examples of sugars include trehalose, sucrose, glucose, lactose, galactose, glyceraldehyde, fructose, dextrose, maltose, xylose, mannose, maltodextrin, starch, cellulose, lactulose, cellobiose, mannobiose, and combinations thereof. In some embodiments, the pharmaceutical composition provided herein comprises a buffer as an excipient. Non-limiting examples of buffers include potassium phosphate, sodium phosphate, saline sodium citrate buffer (SSC), acetate, saline, physiological saline, phosphate buffer saline (PBS), 4-2-hydroxyethyl-1-piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), and piperazine-N,N′-bis(2-ethanesulfonic acid) buffer (PIPES), or combinations thereof. In some embodiments, a pharmaceutical composition of the invention comprises a source of divalent metal ions as an excipient. A metal can be in elemental form, a metal atom, or a metal ion. Non-limiting examples of metals include transition metals, main group metals, and metals of Group 1, Group 2, Group 3, Group 4, Group 5, Group 6, Group 7, Group 8, Group 9, Group 10, Group 11, Group 12, Group 13, Group 14, and Group 15 of the Periodic Table. Non-limiting examples of metals include lithium, sodium, potassium, cesium, magnesium, calcium, strontium, scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, palladium, silver, cadmium, tungsten, rhenium, osmium, iridium, platinum, gold, mercury, cerium, and samarium. In some embodiments, the pharmaceutical composition provided herein comprises an alcohol as an excipient. Non-limiting examples of alcohols include ethanol, propylene glycol, glycerol, polyethylene glycol, chlorobutanol, isopropanol, xylitol, sorbitol, maltitol, erythritol, threitol, arabitol, ribitol, mannitol, galactilol, fucitol, lactitol, and combinations thereof. Pharmaceutical preparations can be formulated with polyethylene glycol (PEG). PEGs with molecular weights ranging from about 300 g/mol to about 10,000,000 g/mol can be used. Non-limiting examples of PEGs include PEG 200, PEG 300, PEG 400, PEG 540, PEG 550, PEG 600, PEG 1000, PEG 1450, PEG 1500, PEG 2000, PEG 3000, PEG 3350, PEG 4000, PEG 4600, PEG 6000, PEG 8000, PEG 10,000, and PEG 20,000. Further excipients that can be used in a composition of the invention include, for example, benzalkonium chloride, benzethonium chloride, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorobutanol, dehydroacetic acid, ethylenediamine, ethyl vanillin, glycerin, hypophosphorous acid, phenol, phenylethyl alcohol, phenylmercuric nitrate, potassium benzoate, potassium metabisulfite, potassium sorbate, sodium bisulfite, sodium metabisulfite, sorbic acid, thimerasol, acetic acid, aluminum monostearate, boric acid, calcium hydroxide, calcium stearate, calcium sulfate, calcium tetrachloride, cellulose acetate pthalate, microcrystalline celluose, chloroform, citric acid, edetic acid, and ethylcellulose. In some embodiments, the pharmaceutical composition provided herein comprises an aprotic solvent as an excipient. Non-limiting examples of aprotic solvents include perfluorohexane, α,α,α-trifluorotoluene, pentane, hexane, cyclohexane, methylcyclohexane, decalin, dioxane, carbon tetrachloride, freon-11, benzene, toluene, carbon disulfide, diisopropyl ether, diethyl ether, t-butyl methyl ether, ethyl acetate, 1,2-dimethoxyethane, 2-methoxyethyl ether, tetrahydrofuran, methylene chloride, pyridine, 2-butanone, acetone, N-methylpyrrolidinone, nitromethane, dimethylformamide, acetonitrile, sulfolane, dimethyl sulfoxide, and propylene carbonate. The amount of the excipient in a pharmaceutical composition of the invention can be about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% by mass of the vasopressin in the pharmaceutical composition. The amount of the excipient in a pharmaceutical composition of the invention can be about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% by mass or by volume of the unit dosage form. The ratio of vasopressin to an excipient in a pharmaceutical composition of the invention can be about 100:about 1, about 95:about 1, about 90:about 1, about 85:about 1, about 80:about 1, about 75:about 1, about 70:about 1, about 65:about 1, about 60:about 1, about 55:about 1, about 50:about 1, about 45:about 1, about 40:about 1, about 35:about 1 about 30:about 1, about 25:about 1, about 20:about 1, about 15:about 1, about 10:about 1, about 9:about 1, about 8:about 1, about 7:about 1, about 6:about 1, about 5:about 1, about 4:about 1, about 3:about 1, about 2:about 1, about 1:about 1, about 1:about 2, about 1:about 3, about 1:about 4, about 1:about 5, about 1:about 6, about 1:about 7, about 1:about 8, about 1:about 9, or about 1:about 10. Pharmaceutically-Acceptable Salts. The invention provides the use of pharmaceutically-acceptable salts of any therapeutic compound described herein. Pharmaceutically-acceptable salts include, for example, acid-addition salts and base-addition salts. The acid that is added to the compound to form an acid-addition salt can be an organic acid or an inorganic acid. A base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base. In some embodiments, a pharmaceutically-acceptable salt is a metal salt. In some embodiments, a pharmaceutically-acceptable salt is an ammonium salt. Metal salts can arise from the addition of an inorganic base to a compound of the invention. The inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc. In some embodiments, a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt. Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the invention. In some embodiments, the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrrazole, pipyrrazole, imidazole, pyrazine, or pipyrazine. In some embodiments, an ammonium salt is a triethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrrazole salt, a pipyrrazole salt, an imidazole salt, a pyrazine salt, or a pipyrazine salt. Acid addition salts can arise from the addition of an acid to a compound of the invention. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid. In some embodiments, the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a glucaronate salt, a saccarate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate (mesylate) salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-toluenesulfonate salt, a citrate salt, an oxalate salt, or a maleate salt. Peptide Sequence. As used herein, the abbreviations for the L-enantiomeric and D-enantiomeric amino acids are as follows: alanine (A, Ala); arginine (R, Arg); asparagine (N, Asn); aspartic acid (D, Asp); cysteine (C, Cys); glutamic acid (E, Glu); glutamine (Q, Gln); glycine (G, Gly); histidine (H, His); isoleucine (I, Ile); leucine (L, Leu); lysine (K, Lys); methionine (M, Met); phenylalanine (F, Phe); proline (P, Pro); serine (S, Ser); threonine (T, Thr); tryptophan (W, Trp); tyrosine (Y, Tyr); valine (V, Val). In some embodiments, the amino acid is a L-enantiomer. In some embodiments, the amino acid is a D-enantiomer. A peptide of the disclosure can have about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% amino acid sequence homology to SEQ ID NO. 1. In some embodiments, a pharmaceutical composition of the invention comprises one or a plurality of peptides having about 80% to about 90% sequence homology to SEQ ID NO. 1, about 88% to about 90% sequence homology to SEQ ID NO. 1 or 88% to 90% sequence homology to SEQ ID NO. 1. In some embodiments, a pharmaceutical composition of the invention comprises vasopressin and one or more of a second, third, fourth, fifth, sixth, seventh, eighth, ninth, and tenth peptide. The ratio of vasopressin to another peptide in a pharmaceutical composition of the invention can be, for example, about 1000:about 1, about 990:about 1, about 980:about 1, about 970:about 1, about 960:about 1, about 950:about 1, about 800:about 1, about 700:about 1, about 600:1, about 500:about 1, about 400:about 1, about 300:about 1, about 200:about 1, about 100:about 1, about 95:about 1, about 90:about 1, about 85:about 1, about 80:about 1, about 75:about 1, about 70:about 1, about 65:about 1, about 60:about 1, about 55:about 1, about 50:about 1, about 45:about 1, about 40:about 1, about 35:about 1, about 30:about 1, about 25:about 1, about 20:about 1, about 19:about 1, about 18:about 1, about 17:about 1, about 16:about 1, about 15:about 1, about 14:about 1, about 13:about 1, about 12:about 1, about 11:about 1, or about 10:about 1. The amount of another peptide or impurity in a composition of the invention can be, for example, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% by mass of vasopressin. Another peptide or impurity present in a composition described herein can be, for example, SEQ ID NO.: 2, SEQ ID NO.: 3, SEQ ID NO.: 4, SEQ ID NO.: 5, SEQ ID NO.: 6, SEQ ID NO.: 7, SEQ ID NO.: 8, SEQ ID NO.: 9, SEQ ID NO.: 10, SEQ ID NO.: 11, SEQ ID NO.: 12, SEQ ID NO.: 13, SEQ ID NO.: 14, SEQ ID NO.: 15, SEQ ID NO.: 16, SEQ ID NO.: 17, a dimer of SEQ ID NO.: 1, an unidentified impurity, or any combination thereof. Non-limiting examples of methods that can be used to identify peptides of the invention include high-performance liquid chromatography (HPLC), mass spectrometry (MS), Matrix Assisted Laser Desorption Ionization Time-of-Flight (MALDI-TOF), electrospray ionization Time-of-flight (ESI-TOF), gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), and two-dimensional gel electrophoresis. HPLC can be used to identify peptides using high pressure to separate components of a mixture through a packed column of solid adsorbent material, denoted the stationary phase. The sample components can interact differently with the column based upon the pressure applied to the column, material used in stationary phase, size of particles used in the stationary phase, the composition of the solvent used in the column, and the temperature of the column. The interaction between the sample components and the stationary phase can affect the time required for a component of the sample to move through the column. The time required for component to travel through the column from injection point to elution is known as the retention time. Upon elution from the column, the eluted component can be detected using a UV detector attached to the column. The wavelength of light at which the component is detected, in combination with the component's retention time, can be used to identify the component. Further, the peak displayed by the detector can be used to determine the quantity of the component present in the initial sample. Wavelengths of light that can be used to detect sample components include, for example, about 200 nM, about 225 nm, about 250 nm, about 275 nm, about 300 nm, about 325 nm, about 350 nm, about 375 nm, and about 400 nm. Mass spectrometry (MS) can also be used to identify peptides of the invention. To prepare samples for MS analysis, the samples, containing the proteins of interest, are digested by proteolytic enzymes into smaller peptides. The enzymes used for cleavage can be, for example, trypsin, chymotrypsin, glutamyl endopeptidase, Lys-C, and pepsin. The samples can be injected into a mass spectrometer. Upon injection, all or most of the peptides can be ionized and detected as ions on a spectrum according to the mass to charge ratio created upon ionization. The mass to charge ratio can then be used to determine the amino acid residues present in the sample. The present disclosure provides several embodiments of pharmaceutical formulations that provide advantages in stability, administration, efficacy, and modulation of formulation viscosity. Any embodiments disclosed herein can be used in conjunction or individually. For example, any pharmaceutically-acceptable excipient, method, technique, solvent, compound, or peptide disclosed herein can be used together with any other pharmaceutically-acceptable excipient, method, technique, solvent, compound, or peptide disclosed herein to achieve any therapeutic result. Compounds, excipients, and other formulation components can be present at any amount, ratio, or percentage disclosed herein in any such formulation, and any such combination can be used therapeutically for any purpose described herein and to provide any viscosity described herein. EXAMPLES Example 1: Impurities of Vasopressin as Detected by HPLC To analyze degradation products of vasopressin that can be present in an illustrative formulation of vasopressin, gradient HPLC was performed to separate vasopressin from related peptides and formulation components. TABLE 2 below depicts the results of the experiment detailing the chemical formula, relative retention time (RRT), molar mass, and structure of vasopressin and detected impurities. Vasopressin was detected in the eluent using UV absorbance. The concentration of vasopressin in the sample was determined by the external standard method, where the peak area of vasopressin in sample injections was compared to the peak area of vasopressin reference standards in a solution of known concentration. The concentrations of related peptide impurities in the sample were also determined using the external standard method, using the vasopressin reference standard peak area and a unit relative response factor. An impurities marker solution was used to determine the relative retention times of identified related peptides at the time of analysis. Experimental conditions are summarized in TABLE 2 below. TABLE 2 Column YMC-Pack ODS-AM, 3 μm, 120Å pore, 4.6 × 100 mm Column Temperature 25° C. Flow Rate 1.0 mL/min Detector 215 nm Note: For Identification a Diode Array Detector (DAD) was used with the range of 200-400 nm. Injection Volume 100 μL Run time 55 minutes Auto sampler Vials Polypropylene vials Pump (gradient) Time (min) % A % B Flow 0 90 10 1.0 40 50 50 1.0 45 50 50 1.0 46 90 10 1.0 55 90 10 1.0 The diluent used for the present experiment was 0.25% v/v Acetic Acid, which was prepared by transferring 2.5 mL of glacial acetic acid into a 1-L volumetric flask containing 500 mL of water. The solution was diluted to the desired volume with water. Phosphate buffer at pH 3.0 was used for mobile phase A. The buffer was prepared by weighing approximately 15.6 g of sodium phosphate monobasic monohydrate into a beaker. 1000 mL of water was added, and mixed well. The pH was adjusted to 3.0 with phosphoric acid. The buffer was filtered through a 0.45 μm membrane filter under vacuum, and the volume was adjusted as necessary. An acetonitrile:water (50:50) solution was used for mobile phase B. To prepare mobile phase B, 500 mL of acetonitrile was mixed with 500 mL of water. The working standard solution contained approximately 20 units/mL of vasopressin. The standard solution was prepared by quantitatively transferring the entire contents of 1 vial of USP Vasopressin RS with diluent to a 50-mL volumetric flask. The intermediate standard solution was prepared by pipetting 0.5 mL of the working standard solution into a 50-mL volumetric flask. The sensitivity solution was prepared by pipetting 5.0 mL of the intermediate standard solution into a 50-mL volumetric flask. The solution was diluted to the volume with Diluent and mixed well. A second working standard solution was prepared as directed under the standard preparation. A portion of the vasopressin control sample was transferred to an HPLC vial and injected. The control was stable for 120 hours when stored in autosampler vials at ambient laboratory conditions. To prepare the impurities marker solution, a 0.05% v/v acetic acid solution was prepared by pipetting 200.0 mL of a 0.25% v/v acetic acid solution into a 1-L volumetric flask. The solution was diluted to the desired volume with water and mixed well. To prepare the vasopressin impurity stock solutions, the a solution of each impurity was prepared in a 25 mL volumetric flask and diluted with 0.05% v/v acetic acid to a concentration suitable for HPLC injection. To prepare the MAA/H-IBA (Methacrylic Acid/α-Hydroxy-isobutyric acid) stock solution, a stock solution containing approximately 0.3 mg/mL H-IBA and 0.01 mg/mL in 0.05% v/v acetic acid was made in a 50 mL volumetric flask. To prepare the chlorobutanol diluent, about one gram of hydrous chlorobutanol was added to 500 mL of water. Subsequently, 0.25 mL of acetic acid was added and the solution was stirred to dissolve the chlorobutanol. To prepare the impurity marker solution, vasopressin powder was mixed with the impurity stock solutions prepared above. The solutions were diluted to volume with the chlorobutanol diluent. The solutions were aliquoted into individual crimp top vials and stored at 2-8° C. At time of use, the solutions were removed from refrigeration (2-8° C.) and allowed to reach room temperature. The vasopressin impurity marker solution was stable for at least 120 hours when stored in auto-sampler vials at ambient laboratory conditions. The solution was suitable for use as long as the chromatographic peaks could be identified based on comparison to the reference chromatogram. To begin the analysis, the HPLC system was allowed to equilibrate for at least 30 minutes using mobile phase B, followed by time 0 min gradient conditions until a stable baseline was achieved. The diluent was injected at the beginning of the run, and had no peaks that interfered with Vasopressin at around 18 minutes as shown in FIG. 1. A single injection of the sensitivity solution was performed, wherein the signal-to-noise ratio of the Vasopressin was greater than or equal to ten as shown in FIG. 2. A single injection of the impurities marker solution was then made. The labeled impurities in the reference chromatogram were identified in the chromatogram of the marker solution based on their elution order and approximate retention times shown in FIG. 3 and FIG. 4. FIG. 4 is a zoomed in chromatograph of FIG. 3 showing the peaks that eluted between 15 and 30 minutes. The nomenclature, structure, and approximate retention times for individual identified impurities are detailed in TABLE 3. A single injection of the working standard solution was made to ensure that the tailing factor of the vasopressin peak was less than or equal to about 2.0 as shown in FIG. 5. A total of five replicate injections of the working standard solution were made to ensure that the relative standard deviation (% RSD) of the five replicate vasopressin peak areas was not more than 2.0%. Two replicate injections of the check standard preparation were to confirm that the check standard conformity was 99.0%-101.0%. One injection of the control sample was made to confirm that the assay of the control sample met the control limits established for the sample. Then, one injection of the working standard solution was made. Following the steps above done to confirm system suitability, a single injection of each sample preparation was made. The chromatograms were analyzed to determine the vasopressin and impurity peak areas. The chromatogram is depicted in FIG. 6. The working standard solution was injected after 1 to 4 sample injections, and the bracketing standard peak areas were averaged for use in the calculations to determine peak areas of vasopressin and associated impurities. The relative standard deviation (% RSD) of vasopressin peak areas for the six injections of working standard solution was calculated by including the initial five injections from the system suitability steps above and each of the subsequent interspersed working standard solution injections. The calculations were done to ensure that each of the % RSD were not more than 2.0%. The retention time of the major peak in the chromatogram of the sample preparation corresponded to that of the vasopressin peak in the working standard solution injection that preceded the sample preparation injection. The UV spectrum (200-400 nm) of the main peak in the chromatogram of the sample preparation compared to the UV spectrum of vasopressin in the working standard preparation. FIG. 7 depicts a UV spectrum of a vasopressin sample and FIG. 8 depicts a UV spectrum of vasopressin standard. To calculate the vasopressin units/mL, the following formula was used: Vasopressin   units  /  mL = R U R S × Conc   STD where: RU=Vasopressin peak area response of Sample preparation. RS=average vasopressin peak area response of bracketing standards. Conc STD=concentration of the vasopressin standard in units/mL To identify the impurities, the % Impurity and identity for identified impurities (TABLE 3) that are were greater than or equal to 0.10% were reported. Impurities were truncated to 3 decimal places and then rounded to 2 decimal places, unless otherwise specified. The impurities were calculated using the formula below: %   impurity = R I R S × Conc   STD 20   U  /  mL × 100  % where: RI=Peak area response for the impurity 20 U/mL=Label content of vasopressin TABLE 3 below details the chemical formula, relative retention time (RRT in minutes), molar mass, and structure of vasopressin and detected impurities. TABLE 3 Molar Name Formula Appr. RRT Mass (g) Vasopressin C46H65N15O12S2 1.00 1084.23 (Arginine Vasopressin, AVP) CYFQNCPRG-NH2 SEQ ID NO.: 1 (disulfide bridge between cys residues) Gly9-vasopressin C46H64N14O13S2 1.07 1085.22 (Gly9-AVP) CYFQNCPRG SEQ ID NO.: 2 (disulfide bridge between cys residues) Asp5-vasopressin C46H64N14O13S2 1.09 1085.22 (Asp5-AVP) CYFQDCPRG-NH2 SEQ ID NO.: 3 (disulfide bridge between cys residues) Glu4-vasopressin C46H64N14O13S2 1.12 1085.22 (Glu4-AVP) CYFENCPRG-NH2 SEQ ID NO.: 4 (disulfide bridge between cys residues) Acetyl-vasopressin C48H67N15O13S2 1.45 1126.27 (Acetyl-AVP) Ac-CYFQNCPRG-NH2 SEQ ID NO.: 7 (disulfide bridge between cys residues) D-Asn-vasopressin C46H65N15O12S2 0.97 1084.23 (DAsn-AVP) CYFQ(D-Asn)CPRG-NH2 SEQ ID NO.: 10 (disulfide bridge between cys residues) Dimeric-vasopressin C92H130N30O24S4 1.22 2168.46 (Dimer-AVP) (monomers cross linked by disulfide bridges) Example 2: Investigation of pH To determine a possible pH for a vasopressin formulation with good shelf life, vasopressin formulations were prepared in 10 mM citrate buffer diluted in isotonic saline across a range of pH. Stability was assessed via HPLC as in EXAMPLE 1 after incubation of the formulations at 60° C. for one week. FIG. 9 illustrates the results of the experiment. The greatest level of stability was observed at pH 3.5. At pH 3.5, the percent label claim (% LC) of vasopressin was highest, and the proportion of total impurities was lowest. Example 3: Effect of Peptide Stabilizers on Vasopressin Formulation To observe the effect of stabilizers on the degradation of vasopressin, a series of peptide stabilizers were added to a vasopressin formulation as detailed in TABLE 4. Stability of vasopressin was assessed via HPLC after incubation of the formulations at 60° C. for one week. TABLE 4 PEG Poloxamer n-Methylpyrrolidone Ethanol 400 Glycerol 188 HPbCDa (NMP) 1% 1% 1% 1% 1% 1% 10% 10% 10% 10% 10% 10% aHydroxypropyl beta-Cyclodextrin FIG. 10 illustrates the stability of vasopressin in terms of % label claim at varying concentrations of stabilizer. The results indicate that the tested stabilizers provided a greater stabilizing effect at 1% concentration than at 10%. Also, in several cases the stabilization effect was about 5% to about 10% greater than that observed in the experiments of EXAMPLE 2. Example 4: Effect of Buffer and Divalent Metals on Vasopressin Formulation To determine whether different combinations of buffers and use of divalent metals affect vasopressin stability, vasopressin formulations with varying concentrations of citrate and acetate buffers and variable concentrations of calcium, magnesium, and zinc ions were prepared. Solutions of 0 mM, 10 mM, 20 mM, and 80 mM calcium, magnesium, and zinc were prepared and each was combined with 1 mM or 10 mM of citrate or acetate buffers to test vasopressin stability. The tested combinations provided vasopressin stability comparable to that of a vasopressin formulation lacking buffers and divalent metals. However, that the addition of divalent metal ions was able to counteract the degradation of vasopressin caused by the use of a citrate buffer. Example 5: Illustrative Formulations for Assessment of Vasopressin Stability An aqueous formulation of vasopressin is prepared using 10% trehalose, 1% sucrose, or 5% NaCl and incubated at 60° C. for one week, at which point stability of vasopressin is assessed using HPLC. A formulation containing 50 units of vasopressin is lyophilized. The lyophilate is reconstituted with water and either 100 mg of sucrose or 100 mg of lactose, and the stability of vasopressin is tested via HPLC after incubation at 60° C. for one week. Co-solvents are added to a vasopressin solution to assess vasopressin stability. 95% solvent/5% 20 mM acetate buffer solutions are prepared using propylene glycol, DMSO, PEG300, NMP, glycerol, and glycerol:NMP (1:1), and used to create formulations of vasopressin. The stability of vasopressin is tested after incubation at 60° C. for one week. Amino acid and phosphate buffers are tested with vasopressin to assess vasopressin stability. Buffers of 10 mM glycine, aspartate, phosphate are prepared at pH 3.5 and 3.8 and used to create formulations of vasopressin. The stability of vasopressin is tested after incubation at 60° C. for one week. A vasopressin formulation in 10% polyvinylpyrrolidone is prepared to assess vasopressin stability. The stability of vasopressin will be tested after incubation at 60° C. for one week. A vasopressin formulation that contains 0.9% saline, 10 mM acetate buffer, 0.2 unit/mL API/mL in 100 mL of total volume is prepared. The pH of the solution is varied from pH 3.5-3.8 to test the stability of vasopressin. A vasopressin formulation in about 50% to about 80% DMSO (for example, about 80%), about 20% to about 50% ethyl acetate (for example, about 20%), and about 5% to about 30% polyvinylpyrrolidone (PVP) (for example, about 10% by mass of the formulation) is prepared to assess vasopressin stability. PVP K12 and PVP K17 are each independently tested in the formulation. The stability of vasopressin is tested after incubation at 60° C. for one week. A vasopressin formulation in about 70% to about 95% ethyl acetate, and about 5% to about 30% PVP is prepared to assess vasopressin stability. PVP K12 and PVP K17 are each independently tested in the formulation. The stability of vasopressin is tested after incubation at 60° C. for one week. A vasopressin formulation in 90% DMSO and 10% PVP is prepared to test vasopressin stability. PVP K12 and PVP K17 are each independently tested in the formulation. The stability of vasopressin is tested after incubation at 60° C. for one week. Example 6: Illustrative Vasopressin Formulation for Clinical Use A formulation for vasopressin that can be used in the clinic is detailed in TABLE 5 below: TABLE 5 Ingredient Function Amount (per mL) Vasopressin, USP Active Ingredient 20 Units (~0.04 mg) Chlorobutanol, Hydrous NF Preservative 5.0 mg Acetic Acid, NF pH Adjustment To pH 3.4-3.6 (~0.22 mg) Water for injection, USP/EP Diluent QS Example 7: Illustrative Regimen for Therapeutic Use of a Vasopressin Formulation Vasopressin is indicated to increase blood pressure in adults with vasodilatory shock (for example, adults who are post-cardiotomy or septic) who remain hypotensive despite fluids and catecholamines. Preparation and Use of Vasopressin. Vasopressin is supplied in a carton of 25 multi-dose vials each containing 1 mL vasopressin at 20 units/mL. Vasopressin is stored between 15° C. and 25° C. (59° F. and 77° F.), and is not frozen. Alternatively, a unit dosage form of vasopressin can be stored between 2° C. and 8° C. for about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. Vials of vasopressin are to be discarded 48 hours after first puncture. Vasopressin is prepared according to TABLE 6 below: TABLE 6 Mix Fluid Restriction? Final Concentration Vasopressin Diluent No 0.1 units/mL 2.5 mL (50 units) 500 mL Yes 1 unit/mL 5 mL (100 units) 100 mL Vasopressin is diluted in normal saline (0.9% sodium chloride) or 5% dextrose in water (D5W) prior to use to either 0.1 units/mL or 1 unit/mL for intravenous administration. Unused diluted solution is discarded after 18 hours at room temperature or after 24 hours under refrigeration. Diluted vasopressin should be inspected for particulate matter and discoloration prior to use whenever solution and container permit. The goal of treatment with vasopressin is optimization of perfusion to critical organs, but aggressive treatment can compromise perfusion of organs, like the gastrointestinal tract, for which function is difficult to monitor. Titration of vasopressin to the lowest dose compatible with a clinically-acceptable response is recommended. For post-cardiotomy shock, a dose of 0.03 units/minute is used as a starting point. For septic shock, a dose of 0.01 units/minute is recommended. If the target blood pressure response is not achieved, titrate up by 0.005 units/minute at 10- to 15-minute intervals. The maximum dose for post-cardiotomy shock is 0.1 units/minute and for septic shock 0.07 units/minute. After target blood pressure has been maintained for 8 hours without the use of catecholamines, taper vasopressin by 0.005 units/minute every hour as tolerated to maintain target blood pressure. Vasopressin is provided at 20 units per mL of diluent, which is packaged as 1 mL of vasopressin per vial, and is diluted prior to administration. Contraindications, Adverse Reactions, and Drug-Drug Interactions. Vasopressin is contraindicated in patients with known allergy or hypersensitivity to 8-L-arginine vasopressin or chlorobutanol. Additionally, use of vasopressin in patients with impaired cardiac response can worsen cardiac output. Adverse reactions have been observed with the use of vasopressin, which adverse reactions include bleeding/lymphatic system disorders, specifically, hemorrhagic shock, decreased platelets, intractable bleeding; cardiac disorders, specifically, right heart failure, atrial fibrillation, bradycardia, myocardial ischemia; gastrointestinal disorders, specifically, mesenteric ischemia; hepatobiliary disorders, specifically, increased bilirubin levels; renal/urinary disorders, specifically, acute renal insufficiency; vascular disorders, specifically, distal limb ischemia; metabolic disorders, specifically, hyponatremia; and skin disorders, specifically, and ischemic lesions. These reactions are reported voluntarily from a population of uncertain size. Thus, reliable estimation of frequency or establishment of a causal relationship to drug exposure is unlikely. Vasopressin has been observed to interact with other drugs. For example, use of vasopressin with catecholamines is expected to result in an additive effect on mean arterial blood pressure and other hemodynamic parameters. Use of vasopressin with indomethacin can prolong the effect of vasopressin on cardiac index and systemic vascular resistance. Indomethacin more than doubles the time to offset for vasopressin's effect on peripheral vascular resistance and cardiac output in healthy subjects. Further, use of vasopressin with ganglionic blocking agents can increase the effect of vasopressin on mean arterial blood pressure. The ganglionic blocking agent tetra-ethylammonium increases the pressor effect of vasopressin by 20% in healthy subjects. Use of vasopressin with furosemide increases the effect of vasopressin on osmolar clearance and urine flow. Furosemide increases osmolar clearance 4-fold and urine flow 9-fold when co-administered with exogenous vasopressin in healthy subjects. Use of vasopressin with drugs suspected of causing SIADH (Syndrome of inappropriate antidiuretic hormone secretion), for example, SSRIs, tricyclic antidepressants, haloperidol, chlorpropamide, enalapril, methyldopa, pentamidine, vincristine, cyclophosphamide, ifosfamide, and felbamate can increase the pressor effect in addition to the antidiuretic effect of vasopressin. Additionally, use of vasopressin with drugs suspected of causing diabetes insipidus for example, demeclocycline, lithium, foscarnet, and clozapine can decrease the pressor effect in addition to the antidiuretic effect of vasopressin. Halothane, morphine, fentanyl, alfentanyl and sufentanyl do not impact exposure to endogenous vasopressin. Use of Vasopressin in Specific Populations. Vasopressin is a Category C drug for pregnancy. Due to a spillover into the blood of placental vasopressinase, the clearance of exogenous and endogenous vasopressin increases gradually over the course of a pregnancy. During the first trimester of pregnancy the clearance is only slightly increased. However, by the third trimester the clearance of vasopressin is increased about 4-fold and at term up to 5-fold. Due to the increased clearance of vasopressin in the second and third trimester, the dose of vasopressin can be up-titrated to doses exceeding 0.1 units/minute in post-cardiotomy shock and 0.07 units/minute in septic shock. Vasopressin can produce tonic uterine contractions that could threaten the continuation of pregnancy. After delivery, the clearance of vasopressin returns to preconception levels. Overdosage. Overdosage with vasopressin can be expected to manifest as a consequence of vasoconstriction of various vascular beds, for example, the peripheral, mesenteric, and coronary vascular beds, and as hyponatremia. In addition, overdosage of vasopressin can lead less commonly to ventricular tachyarrhythmias, including Torsade de Pointes, rhabdomyolysis, and non-specific gastrointestinal symptoms. Direct effects of vasopressin overdose can resolve within minutes of withdrawal of treatment. Pharmacology of Vasopressin. Vasopressin is a polypeptide hormone that causes contraction of vascular and other smooth muscles and antidiuresis, which can be formulated as a sterile, aqueous solution of synthetic arginine vasopressin for intravenous administration. The 1 mL solution contains vasopressin 20 units/mL, chlorobutanol, NF 0.5% as a preservative, and water for injection, USP adjusted with acetic acid to pH 3.4-3.6. The chemical name of vasopressin is Cyclo (1-6) L-Cysteinyl-L-Tyrosyl-L-Phenylalanyl-L-Glutaminyl-L-Asparaginyl-L-Cysteinyl-L-Prolyl-L-Arginyl-L-Glycinamide. Vasopressin is a white to off-white amorphous powder, freely soluble in water. The structural formula of vasopressin is: Molecular Formula: C46H65N15O12S2; Molecular Weight: 1084.23 One mg of vasopressin is equivalent to 530 units. Alternatively, one mg of vasopressin is equivalent to 470 units. The vasoconstrictive effects of vasopressin are mediated by vascular V1 receptors. Vascular V1 receptors are directly coupled to phopholipase C, resulting in release of calcium, leading to vasoconstriction. In addition, vasopressin stimulates antidiuresis via stimulation of V2 receptors which are coupled to adenyl cyclase. At therapeutic doses, exogenous vasopressin elicits a vasoconstrictive effect in most vascular beds including the splanchnic, renal, and cutaneous circulation. In addition, vasopressin at pressor doses triggers contractions of smooth muscles in the gastrointestinal tract mediated by muscular V1-receptors and release of prolactin and ACTH via V3 receptors. At lower concentrations typical for the antidiuretic hormone, vasopressin inhibits water diuresis via renal V2 receptors. In patients with vasodilatory shock, vasopressin in therapeutic doses increases systemic vascular resistance and mean arterial blood pressure and reduces the dose requirements for norepinephrine. Vasopressin tends to decrease heart rate and cardiac output. The pressor effect is proportional to the infusion rate of exogenous vasopressin. Onset of the pressor effect of vasopressin is rapid, and the peak effect occurs within 15 minutes. After stopping the infusion, the pressor effect fades within 20 minutes. There is no evidence for tachyphylaxis or tolerance to the pressor effect of vasopressin in patients. At infusion rates used in vasodilatory shock (0.01-0.1 units/minute), the clearance of vasopressin is 9 to 25 mL/min/kg in patients with vasodilatory shock. The apparent half-life of vasopressin at these levels is ≦10 minutes. Vasopressin is predominantly metabolized and only about 6% of the dose is excreted unchanged in urine. Animal experiments suggest that the metabolism of vasopressin is primarily by liver and kidney. Serine protease, carboxipeptidase and disulfide oxido-reductase cleave vasopressin at sites relevant for the pharmacological activity of the hormone. Thus, the generated metabolites are not expected to retain important pharmacological activity. Carcinogenesis, Mutagenesis, Impairment of Fertility. Vasopressin was found to be negative in the in vitro bacterial mutagenicity (Ames) test and the in vitro Chinese hamster ovary (CHO) cell chromosome aberration test. In mice, vasopressin can have an effect on function and fertilizing ability of spermatozoa. Clinical Studies. Increases in systolic and mean blood pressure following administration of vasopressin were observed in seven studies in septic shock and eight studies in post-cardiotomy vasodilatory shock. Example 8: Effect of Temperature on Vasopressin Formulations To test the effect of temperature on the stability of vasopressin formulation, solutions containing 20 units/mL vasopressin and chlorobutanol, adjusted to pH 3.5 with acetic acid, were prepared. One mL of each vasopressin formulations was then filled into 3 cc vials. Each Vasopressin Formulation was stored either inverted or upright for at least three months, up to 24 months, at: (i) 5° C.; (ii) 25° C. and 60% relative humidity; or (iii) 40° C. and 75% humidity, and the amount of vasopressin (U/mL) and % total impurities were measured periodically. TABLES 7-12 below display the results of the experiments at 5° C. The results of the experiments at 25° C. are included in TABLES 13-18. All of the experiments were performed in triplicate. The results of the experiments at 40° C. are included in TABLES 19-24. For each temperature tested, three lots of the vasopressin formulation were stored for 24 months (5° C. and 25° C.) and 3 months (40° C.), and measurements were taken at regular intervals during the testing periods. “NMT” as used in the tables denotes “not more than.” The vasopressin and impurity amounts observed in the experiments conducted at 5° C. are shown in TABLES 7-12 below (AVP=Vasopressin). TABLE 7 Samples stored inverted at 5° C. Time in months Test Initial 1 2 3 6 9 12 18 24 AVP 19.4 19.4 19.4 19.3 19.5 19.4 19.5 19.4 19.3 Assay Total 2.3% 2.0% 2.1% 2.3% 2.2% 2.3% 2.6% 2.9% 2.9% Im- purities TABLE 8 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 U/mL 19.7 19.7 19.7 19.7 19.9 19.7 19.8 19.7 19.5 Assay Total 2.7% 2.2% 2.3% 2.4% 2.1% 2.3% 2.7% 2.9% 2.9% Impurities: NMT 17.0% TABLE 9 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 U/mL 19.7 19.7 19.6 19.7 19.8 19.7 19.9 19.8 19.5 Assay Total 2.2% 1.9% 2.0% 2.2% 2.0% 2.1% 2.4% 2.6% 2.8% Impurities: NMT 17.0% TABLE 10 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 U/mL 19.4 19.5 19.4 19.4 19.5 19.5 19.5 19.4 19.3 Assay Total 2.3% 2.1% 2.1% 2.3% 2.1% 2.3% 2.5% 2.9% 2.9% Impurities: NMT 17.0% TABLE 11 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 19.7 19.7 19.6 19.7 19.8 19.7 19.8 19.7 19.5 Assay U/mL Total 2.7% 2.1% 2.2% 2.2% 2.2% 2.3% 2.6% 2.9% 2.8% Impurities: NMT 17.0% TABLE 12 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 19.7 19.7 19.6 19.7 19.8 19.7 19.9 19.8 19.5 Assay U/mL Total 2.2% 1.8% 2.0% 2.2% 2.2% 2.1% 2.4% 2.8% 2.7% Impurities: NMT 17.0% The vasopressin and impurity amounts observed in the experiments conducted at 25° C. and 60% relative humidity are shown in TABLES 13-18 below. TABLE 13 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 19.8 19.4 19.1 18.8 18.3 17.5 17.3 Assay U/mL Total 1.1% 2.4% 3.7% 4.7% 5.9% 9.0% 13.6% Impurities: NMT 17.0% TABLE 14 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 20.1 19.7 19.3 19 18.6 17.6 17.6 Assay U/mL Total 1.3% 2.5% 3.4% 4.6% 5.6% 9.0% 13.4% Impurities: NMT 17.0% TABLE 15 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 19.9 19.6 19.2 19 18.7 18 17.4 Assay U/mL Total 1.5% 2.6% 3.3% 4.6% 5.9% 9.0% 12.9% Impurities: NMT 17.0% TABLE 16 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 19.8 19.4 19.1 18.8 18.3 17.5 17.4 Assay U/mL Total 1.1% 2.4% 3.2% 4.8% 5.6% 9.2% 13.1% Impurities: NMT 17.0% TABLE 17 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 20.1 19.7 19.4 18.9 18.6 17.8 17.7 Assay U/mL Total 1.3% 2.5% 3.3% 4.5% 5.7% 9.1% 13.3% Impurities: NMT 17.0% TABLE 18 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 19.9 19.6 19.2 19 18.5 18.1 17.4 Assay U/mL Total 1.5% 2.5% 3.7% 4.7% 5.9% 9.1% 13.3% Impurities: NMT 17.0% The vasopressin and impurity amounts observed in the experiments conducted at 40° C. and 75% relative humidity are shown in TABLES 19-24 below. TABLE 19 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.8 19.1 18.6 17.3 Assay Total Impurities: 1.1% 3.7% 7.3% 10.6% NMT 17.0% TABLE 20 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.8 18.9 18.5 17.2 Assay Total Impurities: 1.1% 3.6% 7.2% 10.3% NMT 17.0% TABLE 21 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 20.1 19.3 18.7 17.6 Assay Total Impurities: 1.3% 3.6% 7.3% 10.3% NMT 17.0% TABLE 22 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 20.1 18.9 18.7 17.4 Assay Total Impurities: 1.3% 3.5% 7.1% 10.2% NMT 17.0% TABLE 23 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.9 19.2 18.3 17.4 Assay Total Impurities: 1.5% 3.7% 6.3% 10.3% NMT 17.0% TABLE 24 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.9 19.2 18.3 17.5 Assay Total Impurities: 1.5% 3.8% 6.3% 10.5% NMT 17.0% The results of the above experiments suggested that storage in either an upright or inverted position did not markedly affect the stability of vasopressin. The samples held at 5° C. exhibited little fluctuation in vasopressin amounts over 24 months, and the amount of total impurities did not increase above 3% during the testing period (TABLES 7-12). The samples held at 25° C. and 60% relative humidity exhibited a decrease in vasopressin amount of about 10-12% after 24 months (TABLES 13-18). The amount of impurities observed in the samples stored at 25° C. and 60% relative humidity after 24 months exceeded 13% in some samples, whereas the amount of impurities observed in the samples stored at 5° C. did not exceed 3% after 24 months. After about three months, the samples held at 40° C. exhibited a decrease in the amount of vasopressin of about 10-12%. The amount of impurities observed at 40° C. exceeded 10% after three months, whereas the amount of impurities observed in the samples stored at 5° C. was less than 3% after three months (TABLES 19-24). Experiments were also conducted on the same samples above over the course of the experiments to measure the amount of individual impurities in the samples, pH of the samples, chlorobutanol content, particulate matter, antimicrobial effectiveness, and bacterial endotoxin levels (TABLES 25-42). (NR=no reading; ND=not determined; UI=unidentified impurity). The anti-microbial effectiveness of the solution was established to determine the amount of antimicrobial agents in the formulation that protect against bacterial contamination. The bullets in the tables below indicate that the sample was not tested for anti-microbial effectiveness at that specific time point. The bacterial endotoxin levels were also measured for some of the formulations. The bullets in the tables below indicate that the sample was not tested for bacterial endotoxin levels at that specific time point. TABLE 25 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.4 19.4 19.4 19.3 19.5 19.4 19.5 19.4 19.3 Assay U/mL Related SEQ ID 0.5% 0.5% 0.6% 0.6% 0.6% 0.6% 0.7% 0.8% 0.9% Substances NO.: 2 NMT 6.0% SEQ ID 0.6% 0.6% 0.6% 0.7% 0.7% 0.7% 0.8% 0.9% 1.0% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP- NR NR NR NR NR NR NR NR NR Dimer: NMT 1.0% Acetyl- 0.3% 0.2% 0.3% 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.84: NR NR 0.1% NR NR NR NR NR NR NMT 1.0% UI-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.1% NR 0.1% NR NR NR NR NR NR NMT 1.0% Total 2.3% 2.0% 2.1% 2.3% 2.2% 2.3% 2.6% 2.9% 2.9% Impurities: NMT 17.0% pH 2.5-4.5 3.5 3.5 3.5 3.5 3.5 3.5 3.5 3.8 3.5 Chlorobutanol 0.25-0.60% 0.48% 0.49% 0.48% 0.48% 0.47% 0.48% 0.48% 0.49% 0.49% w/v Particulate NMT 6000 0 1 1 1 2 16 2 4 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 26 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.7 19.7 19.7 19.7 19.9 19.7 19.8 19.7 19.5 Assay U/mL Related SEQ ID 0.6% 0.5% 0.5% 0.6% 0.5% 0.6% 0.7% 0.8% 0.8% Substances NO.: 2: NMT 6.0% SEQ ID 0.6% 0.6% 0.6% 0.6% 0.6% 0.7% 0.7% 0.8% 0.9% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.4% 0.3% 0.4% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR NR NR NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.75- 0.2% 0.2% 0.2% 0.2% NR 0.1% 0.2% 0.2% 0.2% 0.78: NMT 1.0% UI-0.83- 0.1% 0.1% 0.1% NR 0.1% NR NR NR NR 0.84: NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% Total 2.7% 2.2% 2.3% 2.4% 2.1% 2.3% 2.7% 2.9% 2.9% Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 Chlorobutanol 0.25-0.60% 0.48% 0.48% 0.48% 0.47% 0.48% 0.48% 0.49% 0.48% 0.49% w/v Particulate NMT 6000 1 1 1 1 1 15 2 3 2 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 27 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.7 19.7 19.6 19.7 19.8 19.7 19.9 19.8 19.5 Assay U/mL Related SEQ ID 0.5% 0.5% 0.5% 0.5% 0.5% 0.6% 0.6% 0.8% 0.8% Substances NO.: 2: NMT 6.0% SEQ ID 0.5% 0.5% 0.5% 0.6% 0.6% 0.7% 0.7% 0.8% 0.9% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR NR NR NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.75- NR NR NR NR NR NR NR NR NR 0.78: NMT 1.0% UI-0.83- NR NR 0.1% NR NR NR NR NR 0.1% 0.84: NMT 1.0% UI-1.02- 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% 1.03: NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.76: NR NR NR 0.1% NR NR NR NR NR NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.1% NR NR NR NR NR NR NR NR NMT 1.0% Total 2.2% 1.9% 2.0% 2.2% 2.0% 2.1% 2.4% 2.6% 2.8% Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.5 3.6 3.5 3.5 3.5 3.6 3.5 3.5 Chlorobutanol 0.25-0.60% 0.47% 0.48% 0.47% 0.47% 0.47% 0.47% 0.48% 0.48% 0.48% w/v Particulate NMT 6000 1 2 1 2 1 4 2 1 3 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 28 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.4 19.5 19.4 19.4 19.5 19.5 19.5 19.4 19.3 Assay U/mL Related SEQ ID 0.5% 0.6% 0.6% 0.6% 0.6% 0.6% 0.7% 0.8% 0.9% Substances NO.: 2: NMT 6.0% SEQ ID 0.6% 0.6% 0.6% 0.7% 0.7% 0.7% 0.7% 0.9% 1.0% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP- NR NR NR NR NR NR NR NR NR Dimer: NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.84: NR NR 0.1% NR NR NR NR NR NR NMT 1.0% UI-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.1% NR NR NR NR NR NR NR NR NMT 1.0% Total 2.3% 2.1% 2.1% 2.3% 2.1% 2.3% 2.5% 2.9% 2.9% Impurities: NMT 17.0% pH 2.5-4.5 3.5 3.5 3.5 3.5 3.5 3.5 3.5 3.8 3.5 Chlorobutanol 0.25-0.60% 0.48% 0.48% 0.48% 0.48% 0.48% 0.48% 0.48% 0.49% 0.49% w/v Particulate NMT 6000 0 2 2 2 1 2 2 4 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 29 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.7 19.7 19.6 19.7 19.8 19.7 19.8 19.7 19.5 Assay U/mL Related SEQ ID 0.6% 0.5% 0.5% 0.5% 0.6% 0.6% 0.6% 0.8% 0.7% Substances NO.: 2: NMT 6.0% SEQ ID 0.6% 0.6% 0.6% 0.6% 0.6% 0.7% 0.7% 0.8% 0.8% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR NR NR NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.2% 0.3% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.75- 0.2% 0.2% NR 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% 0.78: NMT 1.0% UI-0.83- 0.1% NR 0.1% NR NR NR NR NR NR 0.84: NMT 1.0% UI-1.02- 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% 0.3% 0.3% 0.2% 1.03: NMT 1.0% UI-1.67: NR NR NR 0.2% NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% Total 2.7% 2.1% 2.2% 2.2% 2.2% 2.3% 2.6% 2.9% 2.8% Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 Chlorobutanol 0.25-0.60% 0.48% 0.48% 0.48% 0.48% 0.48% 0.48% 0.49% 0.49% 0.49% w/v Particulate NMT 6000 1 1 1 2 2 6 4 4 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 30 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.7 19.7 19.6 19.7 19.8 19.7 19.9 19.8 19.5 Assay U/mL Related SEQ ID 0.5% 0.5% 0.5% 0.5% 0.5% 0.6% 0.6% 0.8% 0.8% Substances NO.: 2: NMT 6.0% SEQ ID 0.5% 0.5% 0.5% 0.6% 0.6% 0.7% 0.7% 0.8% 0.9% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% NR 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR NR NR NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.2% 0.3% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.75- NR NR NR NR 0.2% NR NR NR NR 0.78: NMT 1.0% UI-0.83- NR NR 0.1% NR NR NR NR 0.1% NR 0.84: NMT 1.0% UI-1.02- 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% 1.03: NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.76: NR NR NR 0.1% NR NR NR NR NR NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.1% NR NR NR NR NR NR NR NR NMT 1.0% Total 2.2% 1.8% 2.0% 2.2% 2.2% 2.1% 2.4% 2.8% 2.7% Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.5 3.6 3.5 3.5 3.5 3.6 3.5 3.5 Chlorobutanol 0.25-0.60% 0.47% 0.48% 0.47% 0.47% 0.48% 0.47% 0.48% 0.48% 0.48% w/v Particulate NMT 6000 1 1 1 1 1 3 2 1 3 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 31 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 19.8 19.4 19.1 18.8 18.3 17.5 17.3 — Assay Related SEQ ID NO.: 2: 0.1% 0.5% 1.1% 1.6% 2.0% 3.3% 4.6% — Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 0.6% 1.2% 1.8% 2.2% 3.7% 5.2% — NMT 6.0% SEQ ID NO.: 10: 0.3% 0.4% 0.5% 0.5% 0.4% 0.2% 0.3% — NMT 1.0% Asp5-AVP: NR 0.1% 0.3% 0.4% 0.5% 0.7% 1.0% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% 0.2% 0.2% 0.3% — NMT 1.0% UI-0.83: NR NR <0.10 NR NR NR 0.1% — NMT 1.0% UI-0.99: NR NR NR NR 0.1% NR NR — NMT 1.0% UI-1.03: 0.2% 0.2% 0.3% 0.3% 0.3% 0.2% 0.2% — NMT 1.0% UI-1.14: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% — NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.22: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.56-1.57: NR NR <0.10 0.1% 0.1% 0.2% 0.2% — NMT 1.0% UI-1.60: NR NR NR 0.1% 0.1% 0.2% NR — NMT 1.0% UI-1.74: NR NR NR NR NR 0.2% NR — NMT 1.0% UI-1.85-1.88: NR 0.2% NR NR NR 0.1% 0.1% — NMT 1.0% UI-2.09-2.10: NR 0.2% NR NR NR NR 0.4% — NMT 1.0% UI-2.15-2.16: NR NR 0.1% NR NR NR 0.5% — NMT 1.0% Total Impurities: 1.1% 2.4% 3.7% 4.7% 5.9% 9.0% 13.6% — NMT 17.0% pH 2.5-4.5 3.5 3.5 3.5 3.5 3.4 3.3 3.2 — Chlorobutanol 0.25-0.60% w/v 0.49% 0.48% 0.48% 0.47% 0.47% 0.48% 0.47 — Particulate NMT 6000 1 1 1 1 8 4 1 — Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) AntiMicrobial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 32 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 20.1 19.7 19.3 19 18.6 17.6 17.6 — Assay Related SEQ ID NO.: 2: 0.1% 0.5% 0.9% 1.5% 1.9% 3.1% 4.4% — Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 0.5% 1.1% 1.6% 2.2% 3.4% 4.9% — NMT 6.0% SEQ ID NO.: 10: 0.3% 0.4% 0.3% 0.4% 0.3% 0.4% 0.3% — NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.3% 0.4% 0.7% 0.9% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% 0.2% 0.2% 0.3% — NMT 1.0% UI-0.75-0.76: NR 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% — NMT 1.0% UI-0.83: 0.2% NR 0.1% NR NR 0.1% 0.1% — NMT 1.0% UI-0.99: NR NR NR NR 0.1% NR NR — NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.3% 0.2% — NMT 1.0% UI-1.14: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% — NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.22: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.56-1.57: NR NR 0.1% 0.1% 0.2% 0.2% 0.2% — NMT 1.0% UI-1.60: NR NR 0.1% 0.1% 0.2% 0.2% NR — NMT 1.0% UI-1.74: NR NR NR NR NR 0.2% NR — NMT 1.0% UI-1.85-1.88: NR 0.2% NR NR NR 0.1% 0.1% — NMT 1.0% UI-2.09-2.10: NR 0.2% NR NR NR NR 0.4% — NMT 1.0% UI-2.15-2.16: NR NR NR NR NR NR 0.6% — NMT 1.0% Total Impurities: 1.3% 2.5% 3.4% 4.6% 5.6% 9.0% 13.4% — NMT 17.0% pH 2.5-4.5 3.6 3.6 3.5 3.5 3.2 3.3 3.4 — Chlorobutanol 0.25-0.60% w/v 0.48% 0.49% 0.48% 0.47% 0.47% 0.47% 0.47 — Particulate NMT 6000 2 1 1 3 4 1 2 — Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) AntiMicrobial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 33 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 19.9 19.6 19.2 19 18.7 18 17.4 — Assay Related SEQ ID NO.: 2: 0.2% 0.5% 1.0% 1.5% 2.0% 3.2% 4.5% — Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 0.6% 1.1% 1.8% 2.2% 3.7% 5.0% — NMT 6.0% SEQ ID NO.: 10: 0.4% 0.4% 0.3% 0.4% 0.4% 0.3% 0.5% — NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.4% 0.5% 0.7% 1.0% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR 0.1% — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% — NMT 1.0% UI-0.12: NR 0.1% NR NR NR NR NR NMT 1.0% UI-0.75-0.76: NR NR NR NR NR NR NR NMT 1.0% UI-0.83-0.84: NR 0.1% 0.1% 0.1% 0.1% 0.1% NMT 1.0% UI-0.93: NR NR NR NR NR NR 0.1% NMT 1.0% UI-0.99: NR NR NR NR NR NR NR NMT 1.0% UI-1.02-1.03: 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% 0.3% — NMT 1.0% UI-1.15: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% NMT 1.0% UI-1.20: NR NR NR NR NR NR NR NMT 1.0% UI-1.22: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.26: NR NR NR NR NR NR NMT 1.0% UI-1.35: 0.3% NR NR NR NR NR NR NMT 1.0% UI-1.56-1.57: NR NR 0.1% NR 0.1% 0.2% 0.3% NMT 1.0% UI-1.60: NR NR 0.1% NR 0.1% NR NR — NMT 1.0% UI-1.74: NR NR NR NR NR NR NR NMT 1.0% UI-1.84-1.89: NR 0.1% NR NR NR NR 0.2% NMT 1.0% UI-1.96: 0.2% NR NR NR NR NR NR NMT 1.0% UI-2.09-2.10: NR 20.0% NR NR NR <0.10 0.1% NMT 1.0% UI-2.15-2.16: NR NR 0.1% NR NR 0.1% NR NMT 1.0% Total Impurities: 1.5% 2.6% 3.3% 4.6% 5.9% 9.0% 12.9% — NMT 17.0% pH 2.5-4.5 3.6 3.5 3.5 3.5 3.4 3.4 3.3 — Chlorobutanol 0.25-0.60% w/v 0.48% 0.47% 0.47% 0.46% 0.46% 0.46% 0.45% — Particulate NMT 6000 1 2 3 3 3 1 2 — Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) Anti-Microbial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 34 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 19.8 19.4 19.1 18.8 18.3 17.5 17.4 — Assay Related SEQ ID NO.: 2: 0.1% 0.5% 1.1% 1.6% 2.0% 3.2% 4.5% — Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 0.6% 1.2% 1.8% 2.3% 3.6% 5.0% — NMT 6.0% SEQ ID NO.: 10: 0.3% 0.4% 0.3% 0.4% 0.3% 0.2% 0.3% — NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.4% 0.4% 0.7% 0.9% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% 0.2% 0.2% 0.3% — NMT 1.0% UI-0.83: NR NR <0.10 NR NR 0.1% 0.1% — NMT 1.0% UI-0.99: NR NR NR NR NR NR NR — NMT 1.0% UI-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.2% — NMT 1.0% UI-1.14: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% — NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.22: NR NR NR NR NR NR NR — NMT 1.0% UI-1.56-1.57: NR NR NR 0.1% 0.1% 0.2% 0.2% — NMT 1.0% UI-1.60: NR NR NR NR NR 0.1% NR — NMT 1.0% UI-1.74: NR NR NR NR NR 0.2% NR — NMT 1.0% UI-1.85-1.88: NR 0.2% NR NR NR 0.1% 0.1% — NMT 1.0% UI-2.09-2.10: NR 0.2% NR NR NR NR 0.3% — NMT 1.0% UI-2.15-2.16: NR NR NR NR NR NR 0.5% — NMT 1.0% Total Impurities: 1.1% 2.4% 3.2% 4.8% 5.6% 9.2% 13.1% — NMT 17.0% pH 2.5-4.5 3.5 3.5 3.5 3.5 3.4 3.3 3.3 — Chlorobutanol 0.25-0.60% w/v 0.49% 0.48% 0.48% 0.48% 0.47% 0.48% 0.47 — Particulate NMT 6000 1 2 2 2 2 4 2 — Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) AntiMicrobial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 35 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 20.1 19.7 19.4 18.9 18.6 17.8 17.7 — Assay Related SEQ ID NO.: 2: 0.1% 0.5% 0.9% 1.4% 1.9% 3.1% 4.3% — Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 0.5% 1.1% 1.6% 2.2% 3.4% 4.9% — NMT 6.0% D-Asn-AVP: 0.3% 0.4% 0.3% 0.3% 0.3% 0.4% 0.3% — NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.3% 0.4% 0.7% 0.9% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl-AVP: 0.30% 0.30% 0.30% 0.20% 0.20% 0.20% 0.3% — NMT 1.0% UI-0.75-0.76: NR 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% NMT 1.0% UI-0.83: 0.2% NR <0.10 NR NR 0.1% 0.1% NMT 1.0% UI-0.99: NR NR NR NR 0.1% NR NR NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.2% 0.2% 0.3% 0.2% — NMT 1.0% UI-1.14: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.22: NR NR NR NR NR NR 0.4% NMT 1.0% UI-1.56-1.57: NR NR 0.1% 0.1% 0.2% 0.2% 0.3% NMT 1.0% UI-1.60: NR NR 0.1% 0.1% 0.2% 0.2% NR — NMT 1.0% UI-1.74: NR NR NR NR NR 0.2% NR NMT 1.0% UI-1.85-1.88: NR 0.2% NR NR NR 0.1% 0.1 NMT 1.0% UI-2.09-2.10: NR 0.2% NR NR NR 0.1% 0.3 NMT 1.0% UI-2.15-2.16: NR NR NR NR NR 0.5 NMT 1.0% Total Impurities: 1.3% 2.5% 3.3% 4.5% 5.7% 9.1% 13.3% — NMT 17.0% pH 2.5-4.5 3.6 3.6 3.5 3.5 3.4 3.3 3.3 — Chlorobutanol 0.25-0.60% w/v 0.48% 0.49% 0.48% 0.47% 0.47% 0.48% 0.46 — Particulate NMT 6000 2 1 1 2 5 1 4 — Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) Anti-Microbial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 36 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 19.9 19.6 19.2 19 18.5 18.1 17.4 — Assay Related SEQ ID NO.: 2: 0.2% 0.5% 1.0% 1.5% 2.1% 3.3% 4.7% — Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 0.6% 1.1% 1.7% 2.3% 3.7% 5.3% — NMT 6.0% D-Asn-AVP: 0.4% 0.4% 0.3% 0.4% 0.4% 0.3% 0.5% — NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.3% 0.5% 0.7% 1.0% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% — NMT 1.0% UI-0.12: NR NR NR NR NR NR NR NMT 1.0% UI-0.75-0.76: NR NR NR NR NR NR NR NMT 1.0% UI-0.83-0.84: NR 0.1% 0.1% 0.1% NR 0.1% 0.1% NMT 1.0% UI-0.93: NR NR NR NR NR NR 0.1% NMT 1.0% UI-0.99: NR NR NR NR NR NR NR NMT 1.0% UI-1.02-1.03: 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% 0.3% — NMT 1.0% UI-1.15: NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.22: NR NR NR NR NR NR NR NMT 1.0% UI-1.26: NR NR 0.4% NR NR NR NR NMT 1.0% UI-1.35: 0.1% NR NR NR NR NR NR NMT 1.0% UI-1.56-1.57: NR NR 0.1% 0.1% NR 0.2% 0.3% NMT 1.0% UI-1.60: NR NR NR NR NR NR NR — NMT 1.0% UI-1.74: NR NR NR NR NR NR NR NMT 1.0% UI-1.84-1.89: NR 0.1% NR NR NR NR 0.2% NMT 1.0% UI-1.96: 0.2% NR NR NR NR NR NR NMT 1.0% UI-2.09-2.10: NR NR NR NR NR <0.10 NR NMT 1.0% UI-2.15-2.16: NR NR 0.1% NR NR 0.2% NR NMT 1.0% Total Impurities: 1.5% 2.5% 3.7% 4.7% 5.9% 9.1% 13.3% — NMT 17.0% pH 2.5-4.5 3.6 3.5 3.5 3.5 3.4 3.4 3.3 — Chlorobutanol 0.25-0.60% w/v 0.48% 0.48% 0.47% 0.47% 0.46% 0.45 0.46 — Particulate NMT 6000 1 0 1 3 7 0 3 — Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) Anti-Microbial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 37 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.8 19.1 18.6 17.3 Assay Related SEQ ID NO.: 2: 0.1% 1.0% 2.4% 3.8% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.1% 2.7% 4.3% NMT 6.0% D-Asn-AVP: 0.3% 0.4% 0.3% 0.3% NMT 1.0% Asp5-AVP: NMT ND 0.2% 0.5% 0.8% 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.2% 0.2% 0.2% NMT 1.0% UI-0.13: NMT ND 0.1% ND ND 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.83-0.84: ND ND ND ND NMT 1.0% UI-1.02-1.03: 0.2% 0.3% 0.2% 0.3% NMT 1.0% UI-1.18: NMT ND ND ND 0.2% 1.0% UI-1.56-1.57: ND 0.2% 0.4% 0.4% NMT 1.0% UI-1.67: NMT ND ND ND ND 1.0% UI-1.76: NMT ND ND ND ND 1.0% UI-1.83-1.85: ND ND 0.2% 0.2% NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT 1.0% UI-1.93: NMT ND 0.1% ND ND 1.0% UI-2.05-2.08: ND ND 0.2% ND NMT 1.0% Total Impurities: 1.1% 3.7% 7.3% 10.6% NMT 17.0% pH 2.5-4.5 3.5 3.3 3.2 3.1 Chlorobutanol 0.25-0.60 % w/v 0.49% 0.48% 0.50% 0.47% Particulate NMT 6000 (≧10 1 1 1 1 Matter (USP) μm) NMT 600 (≧25 0 0 0 0 μm) TABLE 38 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 20.1 19.3 18.7 17.6 Assay Related SEQ ID NO.: 2: 0.1% 0.9% 2.2% 3.6% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.0% 2.5% 3.9% NMT 6.0% D-Asn-AVP: 0.3% 0.4% 0.3% 0.3% NMT 1.0% Asp5-AVP: NMT ND 0.2% 0.5% 0.8% 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.2% 0.3% 0.2% NMT 1.0% UI-0.13: NMT ND 0.1% ND ND 1.0% UI-0.75-0.78: ND ND 0.2% 0.2% NMT 1.0% UI-0.80-0.84: 0.2% 0.2% ND ND NMT 1.0% UI-1.02-1.03: 0.2% 0.3% 0.2% 0.3% NMT 1.0% UI-1.18: NMT ND ND 0.3% 0.2% 1.0% UI-1.56-1.57: ND 0.2% ND 0.4% NMT 1.0% UI-1.67: NMT ND ND ND ND 1.0% UI-1.76: NMT ND ND ND ND 1.0% UI-1.81-1.85: ND ND 0.2% 0.2% NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT 1.0% UI-1.93: NMT ND 0.1% ND ND 1.0% UI-2.03-2.08: ND ND 0.2% 0.1% NMT 1.0% UI-2.14: NMT ND ND 0.2% ND 1.0% Total Impurities: 1.3% 3.6% 7.3% 10.3% NMT 17.0% pH 2.5-4.5 3.6 3.3 3.2 3.1 Chlorobutanol 0.25-0.60 % w/v 0.48% 0.48% 0.50% 0.47% Particulate NMT 6000 (≧10 2 2 1 1 Matter (USP) μm) NMT 600 (≧25 0 0 0 0 μm) TABLE 39 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.9 19.2 18.3 17.4 Assay Related SEQ ID NO.: 2: 0.2% 0.9% 2.2% 3.8% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.0% 2.4% 4.0% NMT 6.0% D-Asn-AVP: 0.4% 0.3% 0.3% 0.3% NMT 1.0% Asp5-AVP: NMT ND 0.2% 0.5% 0.8% 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% NMT 1.0% UI-0.13: NMT ND ND ND ND 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.80-0.84: ND ND ND ND NMT 1.0% UI-1.02-1.03: 0.3% 0.2% 0.2% 0.3% NMT 1.0% UI-1.18: NMT ND ND ND 0.2% 1.0% UI-1.35: NMT 0.1% ND ND ND 1.0% UI-1.52-1.58: ND 0.2% 0.3% 0.4% NMT 1.0% UI-1.67: NMT ND ND ND ND 1.0% UI-1.76: NMT ND ND ND ND 1.0% UI-1.81-1.85: ND ND ND ND NMT 1.0% UI-1.86-1.88: ND 0.1% 0.2% ND NMT 1.0% UI-1.91-1.96: 0.2% 0.2% ND ND NMT 1.0% UI-2.02-2.08: ND ND ND 0.2% NMT 1.0% UI-2.11-2.14: ND 0.2% ND ND NMT 1.0% Total Impurities: 1.5% 3.7% 6.3% 10.3% NMT 17.0% pH 2.5-4.5 3.6 3.4 3.2 3.1 Chlorobutanol 0.25-0.60 % w/v 0.48% 0.47% 0.46% 0.46% Particulate NMT 6000 (≧10 2 2 1 1 Matter (USP) μm) NMT 600 (≧25 0 0 0 0 μm) TABLE 40 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.8 18.9 18.5 17.2 Assay Related SEQ ID NO.: 2: 0.1% 1.0% 2.4% 3.8% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.1% 2.7% 4.3% NMT 6.0% D-Asn-AVP: 0.3% 0.3% 0.3% 0.3% NMT 1.0% Asp5-AVP: NMT ND 0.2% 0.5% 0.8% 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% UI-0.13: NMT ND 0.1% ND ND 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.83-0.84: ND ND ND ND NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.2% NMT 1.0% UI-1.18: NMT ND ND ND 0.2% 1.0% UI-1.56-1.57: ND 0.2% 0.3% 0.3% NMT 1.0% UI-1.67: NMT ND ND ND ND 1.0% UI-1.76: NMT ND ND ND ND 1.0% UI-1.83-1.85: ND ND 0.2% ND NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT 1.0% UI-1.93: NMT ND 0.1% ND ND 1.0% UI-2.05-2.08: ND ND 0.2% ND NMT 1.0% Total Impurities: 1.1% 3.6% 7.2% 10.3% NMT 17.0% Total Impurities: 1.1% 3.6% 7.2% 10.3% NMT 17.0% pH 2.5-4.5 3.5 3.3 3.2 3.1 Chlorobutanol 0.25-0.60 % w/v 0.49% 0.48% 0.50% 0.48% Particulate NMT 6000 (≧10 1 1 1 1 Matter (USP) μm) NMT 600 (≧25 0 0 0 0 μm) TABLE 41 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 20.1 18.9 18.7 17.4 Assay Related SEQ ID NO.: 2: 0.1% 0.9% 2.3% 3.7% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.0% 2.5% 3.9% NMT 6.0% D-Asn-AVP: 0.3% 0.4% 0.3% 0.3% NMT 1.0% Asp5-AVP: NMT ND 0.2% 0.5% 0.8% 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.2% 0.3% 0.2% NMT 1.0% UI-0.13: NMT ND ND ND ND 1.0% UI-0.75-0.78: ND ND 0.2% 0.2% NMT 1.0% UI-0.80-0.84: 0.2% 0.2% ND ND NMT 1.0% UI-1.02-1.03: 2.0% 0.3% 0.2% 0.3% NMT 1.0% UI-1.18: NMT ND ND ND 0.2% 1.0% UI-1.56-1.57: ND 0.2% 0.4% 0.4% NMT 1.0% UI-1.67: NMT ND ND ND ND 1.0% UI-1.76: NMT ND ND ND ND 1.0% UI-1.83-1.85: ND ND 0.2% 0.1% NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT 1.0% UI-1.93: NMT ND 0.1% ND ND 1.0% UI-2.05-2.08: ND ND 0.2% ND NMT 1.0% UI-2.14: NMT ND ND ND ND 1.0% Total Impurities: 1.3% 3.5% 7.1% 10.2% NMT 17.0% pH 2.5-4.5 3.6 3.3 3.2 3.1 Chlorobutanol 0.25-0.60 % w/v 0.48% 0.48% 0.49% 0.47% Particulate NMT 6000 (≧10 2 1 1 1 Matter (USP) μm) NMT 600 (≧25 0 0 0 0 μm) TABLE 42 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.9 19.2 18.3 17.5 Assay Related SEQ ID NO.: 2: 0.2% 1.0% 2.2% 3.9% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.1% 2.4% 4.2% NMT 6.0% D-Asn-AVP: 0.4% 0.3% 0.3% 0.3% NMT 1.0% Asp5-AVP: NMT ND 0.2% 50.0% 0.8% 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% NMT 1.0% UI-0.13: NMT ND ND ND ND 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.80-0.84: ND ND ND ND NMT 1.0% UI-1.02-1.03: 0.3% 0.2% 0.2% 0.3% NMT 1.0% UI-1.18: NMT ND ND ND 0.2% 1.0% UI-1.35: NMT 0.1% ND ND ND 1.0% UI-1.52-1.58: ND 0.2% 0.3% 0.4% NMT 1.0% UI-1.67: NMT ND ND ND ND 1.0% UI-1.76: NMT ND ND ND ND 1.0% UI-1.83-1.85: ND ND ND ND NMT 1.0% UI-1.86-1.88: ND 0.1% 0.2% ND NMT 1.0% UI-1.91-1.96: 0.2% 0.2% ND ND NMT 1.0% UI-2.02-2.08: ND ND ND 0.1% NMT 1.0% UI-2.11-2.14: ND 0.2% ND ND NMT 1.0% Total Impurities: 1.5% 3.8% 6.3% 10.5% NMT 17.0% pH 2.5-4.5 3.6 3.4 3.2 3.1 Chlorobutanol 0.25-0.60 % w/v 0.48% 0.47% 0.47% 0.45% Particulate NMT 6000 (≧10 1 2 1 1 Matter (USP) μm) NMT 600 (≧25 0 0 0 0 μm) Example 9: Effect of pH 3.5-4.5 on Vasopressin Formulations To test of effect of pH on vasopressin formulations, solutions containing 20 units/mL vasopressin, adjusted to pH 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, or 4.5 with 10 mM acetate buffer, were prepared. One mL of each of the vasopressin formulations was then filled into 10 cc vials. The vasopressin formulations were stored for four weeks at: (i) 25° C.; or (ii) 40° C., and the assay (% label claim; vasopressin remaining) and % total impurities after four weeks were measured using the methods described in EXAMPLE 1. FIGS. 11 and 12 below display the results of the experiments at 25° C. The results of the experiments at 40° C. are included in FIGS. 13 and 14. The results of the experiments suggested that the stability of a vasopressin formulation was affected by pH. At 25° C., the remaining vasopressin after four weeks was highest between pH 3.6 and pH 3.8 (FIG. 11). Within the range of pH 3.6 to pH 3.8, the level of impurities was lowest at pH 3.8 (FIG. 12). At 25° C., pH 3.7 provided the highest stability for vasopressin (FIG. 11). At 40° C., the remaining vasopressin after four weeks was highest between pH 3.6 and pH 3.8 (FIG. 13). Within the range of pH 3.6 to pH 3.8, the level of impurities was lowest at pH 3.8 (FIG. 14). At 40° C., pH 3.6 provided the highest stability for vasopressin (FIG. 13), Example 10: Effect of pH 2.5-4.5 of Vasopressin Formulations To test of effect of pH on vasopressin formulations, solutions containing 20 units/mL vasopressin, adjusted to pH 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, or 3.4 with 10 mM acetate buffer were also prepared. One mL of each of the vasopressin formulations was then filled into 10 cc vials. The amount of vasopressin, impurities, and associated integration values were determined using the methods describes in EXAMPLE 1. The results from the stability tests on the vasopressin formulations from pH 2.5 to 3.4 were plotted against the results from the stability tests on vasopressin formulations from pH 3.5 to 4.5 as disclosed in EXAMPLE 9, and are displayed in FIGS. 15-18. The assay (% label claim; vasopressin remaining) and % total impurities in the vasopressin pH 2.5 to 3.4 formulations after four weeks are reported in TABLE 43. TABLE 43 Target Vasopressin % Total Batch pH Week Condition (% LC) Impurities 1A 2.5 0 25° C. 100.57 2.48 1B 2.6 0 25° C. 101.25 2.24 1C 2.7 0 25° C. 101.29 2.26 1D 2.8 0 25° C. 101.53 2.00 1E 2.9 0 25° C. 102.33 1.95 1F 3 0 25° C. 102.32 1.89 1G 3.1 0 25° C. 102.59 2.06 1H 3.2 0 25° C. 102.60 1.85 1I 3.3 0 25° C. 102.73 1.81 1J 3.4 0 25° C. 101.93 1.75 1A 2.5 0 40° C. 100.57 2.48 1B 2.6 0 40° C. 101.25 2.24 1C 2.7 0 40° C. 101.29 2.26 1D 2.8 0 40° C. 101.53 2.00 1E 2.9 0 40° C. 102.33 1.95 1F 3 0 40° C. 102.32 1.89 1G 3.1 0 40° C. 102.59 2.06 1H 3.2 0 40° C. 102.60 1.85 1I 3.3 0 40° C. 102.73 1.81 1J 3.4 0 40° C. 101.93 1.75 1A 2.5 4 25° C. 95.70 6.66 1B 2.6 4 25° C. 98.58 5.29 1C 2.7 4 25° C. 98.94 4.26 1D 2.8 4 25° C. 99.14 3.51 1E 2.9 4 25° C. 100.08 3.41 1F 3 4 25° C. 100.29 2.92 1G 3.1 4 25° C. 100.78 2.55 1H 3.2 4 25° C. 100.74 2.16 1I 3.3 4 25° C. 100.46 2.14 1J 3.4 4 25° C. 100.25 2.03 1A 2.5 4 40° C. 81.89 19.41 1B 2.6 4 40° C. 90.10 15.60 1C 2.7 4 40° C. 92.19 13.46 1D 2.8 4 40° C. 94.89 10.98 1E 2.9 4 40° C. 96.03 9.78 1F 3 4 40° C. 97.26 8.09 1G 3.1 4 40° C. 99.61 6.39 1H 3.2 4 40° C. 98.58 5.25 1I 3.3 4 40° C. 97.81 4.41 1J 3.4 4 40° C. 97.35 3.85 The % total impurities for the pH 2.5 to 3.4 formulations and the pH 3.5 to 4.5 formulations observed in the experiments conducted at 25° C. and 40° C. are shown in FIGS. 15 (25° C.) and 16 (40° C.). The vasopressin assay amount for the vasopressin pH 2.5 to 3.4 formulations and the vasopressin pH 3.5 to 4.5 formulations observed in the experiments conducted at 25° C. and 40° C. are shown in FIGS. 17 (25° C.) and 18 (40° C.). The vasopressin assay is presented as a % assay decrease of vasopressin over the four-week study period, rather than absolute assay, because the amount of starting vasopressin varied between the vasopressin pH 2.5 to 3.4 formulations and the vasopressin pH 3.5 to 4.5 formulations. The results of the above experiments suggested that the stability of a vasopressin formulation was affected by pH. At 25° C., the percent decrease in vasopressin after four weeks was lowest between pH 3.7 and pH 3.8 (FIG. 17). Within the range of pH 3.7 to pH 3.8, the level of impurities was lowest at pH 3.8 (FIG. 15). At 40° C., the percent decrease in vasopressin after four weeks was lowest between pH 3.6 and pH 3.8 (FIG. 18). Within the range of pH 3.6 to pH 3.8, the level of impurities was lowest at pH 3.8 (FIG. 16). Example 11: Intra-Assay and Inter-Analysis Precision of Vasopressin pH Experiments The methods used to determine the % assay decrease and amount of impurities in the vasopressin solutions over time in EXAMPLE 10 had both intra-assay and inter-analyst precision. Intra-assay precision was demonstrated by performing single injections of aliquots of a vasopressin formulation (n=6; Chemist 1) from a common lot of drug product and determining the assay and repeatability (% RSD; relative standard deviation). Inter-analyst precision was demonstrated by two different chemists testing the same lot of drug product; however, the chemists used different instruments, reagents, standard preparations, columns, and worked in different laboratories. The procedure included a common pooling of 20 vials of vasopressin, which were assayed by the two chemists using different HPLC systems and different HPLC columns. The vasopressin assay results (units/mL) and repeatability (% RSD for n=6) were recorded and are reported in the TABLE 44 below. TABLE 44 Precision of Vasopressin Results. Chemist 1 Chemist 2 Sample (units/mL) (units/mL) 1 19.74 19.65 2 19.76 19.66 3 19.77 19.66 4 19.75 19.72 5 19.97 19.73 6 19.65 19.73 Mean 19.8 19.7 % RSD (≦2.0%) 0.5% 0.2% % Difference = 0.5% (acceptance criteria: ≦3.0%) %   Difference = ( Chemist   1 Mean - Chemist   2 Mean ) ( Chemist   1 Mean + Chemist   2 Mean ) × 200 The intra-assay repeatability met the acceptance criteria (% RSD ≦2.0%) with values of 0.5% and 0.2%. The inter-analyst repeatability also met the acceptance criteria (% difference ≦3.0%) with a difference of 0.5%. Example 12: Effect of Citrate Versus Acetate Buffer on Vasopressin Formulations To test the effect of citrate and acetate buffer on vasopressin formulations, a total of twelve solutions of 20 Units/mL vasopressin were prepared in 1 mM citrate buffer, 10 mM citrate buffer, 1 mM acetate buffer, and 10 mM acetate buffer. All of the solutions were prepared in triplicate. Each solution was adjusted to pH 3.5 with hydrochloric acid. The vasopressin formulations were stored at 60° C. for 7 days, and the assay (% label claim; vasopressin remaining) and % total impurities after 7 days were analyzed by HPLC using the procedure and experimental conditions described in EXAMPLE 1. The assay (% label claim; vasopressin remaining) and % total impurities for each of the Vasopressin Buffered Formulations are reported in the TABLES 45 and 46 below. TABLE 45 Assay (% label claim; vasopressin remaining) in the vasopressin formulations after storage at 60° C. for 7 days. Sample Buffer 1 2 3 Average 1 mM citrate buffer 89.5% 89.7% 90.6% 89.9% 10 mM citrate buffer 84.1% 84.4% 84.5% 84.3% 1 mM acetate buffer 90.5% 91.1% 91.9% 91.2% 10 mM acetate buffer 90.9% 90.9% 92.4% 91.4% TABLE 46 % Total Impurities in the vasopressin formulations after storage at 60° C. for 7 days. Sample Buffer 1 2 3 Average 1 mM citrate buffer 3.4% 3.5% 2.5% 3.1% 10 mM citrate buffer 9.5% 9.0% 9.4% 9.3% 1 mM acetate buffer 3.3% 2.8% 3.2% 3.1% 10 mM acetate buffer 2.9% 2.6% 3.1% 2.9% The data indicated that the vasopressin assay in the vasopressin formulations with citrate buffer was lower than in the vasopressin formulations with acetate buffer. For example, at 10 mM of either citrate or acetate buffer, the average vasopressin assay was 91.4% in acetate buffer, but was 84.3% in citrate buffer. The data also indicated that % total impurities in the vasopressin formulations with citrate buffer were higher than in the vasopressin formulations with acetate buffer. For example, at 10 mM of either citrate or acetate buffer, the average % total impurities was 2.9% in acetate buffer, but was 9.3% in citrate buffer. Further, as the citrate buffer concentration increased, the vasopressin assay further decreased (from an average of 89.9% to 84.3%), and the % total impurities increased (from an average of 3.1% to 9.3%). This effect was not observed in the vasopressin formulations with acetate buffer, where the average and % total impurities stayed fairly constant. Example 13: Multi-Dose Vasopressin Formulation A multi-dose formulation (10 mL) for vasopressin that can be used in the clinic is detailed in TABLE 47 below: TABLE 47 Drug Product Description Vasopressin, Active Ingredient 20 Units USP (~0.04 mg) Dosage Form Injection — Route of Intravenous — Administration Description Clear colorless to practically colorless solution supplied in a 10 mL clear glass vial with flip-off cap The composition of a 10 mL formulation of vasopressin is provided below. TABLE 48 Drug Product Composition Ingredient Grade Function Batch Quantity Unit Formula Vasopressin, USP USP Active 3,000,000 Units 20 Units Sodium Acetate Trihydrate USP Buffer 214.2 g 1.36 mg Sodium Hydroxide NF pH Adjustor 40 g QS to pH 3.8 Hydrochloric Acid NF/EP pH Adjustor 237.9 g QS to pH 3.8 Chlorobutanol NF Preservative 0.8274 kg 5 mg Water for Injection USP Solvent QS QS to 1 mL Nitrogen NF Processing Aid — — The 10 mL vasopressin formulation was compared to the guidelines for inactive ingredients provided by the Food and Drug Administration (FDA). The results are shown in TABLE 49 below. TABLE 49 Vasopressin 10 mL Concentration (% Inactive Ingredients Ingredient Formulation (mg/mL) w/v) Guideline Acceptable Level Sodium Acetate 1.36 0.136% IV (infusion); Injection Trihydrate 0.16% Sodium Hydroxide QS to pH 3.8 QS to pH 3.8 N/A Hydrochloric Acid QS to pH 3.8 QS to pH 3.8 N/A Chlorobutanol 5 mg 0.5% IV (Infusion); Injection 1% Water for Injection QS to 1 mL QS to target N/A volume Example 14: Alternative Vasopressin Formulation for Clinical Use A 1 mL dosage of vasopressin was prepared. A description of the formulation is shown in TABLE 50 below. TABLE 50 Drug Product Description Vasopressin, 20 Units/mL USP Active Ingredient (~0.04 mg) Dosage Form Injection — Route of Intravenous — Administration Description Clear colorless to practically — colorless solution supplied in a 3 mL vial with flip-off cap The drug composition of the formulation is provided in TABLE 51. TABLE 51 Drug Product Composition Ingredient Function Quantity (mg/mL) Vasopressin, USP Active 20 Units Sodium Acetate Buffer 1.36 Trihydrate, USP Sodium Hydroxide pH Adjustor QS for pH adjustment NF/EP to pH 3.8 Hydrochloric Acid, pH Adjustor QS for pH adjustment NF/EP to pH 3.8 Water for Injection Solvent QS to 1 mL The 1 mL vasopressin formulation was compared to the guidelines for inactive ingredients provided by the Food and Drug Administration (FDA). The results are shown in TABLE 52 below. TABLE 52 Vasopressin Inactive 1 mL Concen- Ingredients Formulation tration Guideline Ingredient (mg/mL) (% w/v) Acceptable Level Sodium Acetate 1.36 0.136% 0.16% Trihydrate Sodium QS to QS to 8% Hydroxide pH 3.8 pH 3.8 Hydrochloric QS to QS to 10% Acid pH 3.8 pH 3.8 Water for QS to 1 mL QS to target N/A Injection volume Example 15: 15-Month Stability Data for Vasopressin Formulations The drug product detailed in TABLE 51 was tested for stability over a 15-month period. Three different lots (X, Y, and Z) of the vasopressin drug formulation were stored at 25° C. for 15 months in an upright or inverted position. At 0, 1, 2, 3, 6, 9, 12, 13, 14, and 15 months, the amount of vasopressin (AVP), % label claim (LC), amount of various impurities, and pH was measured. The vasopressin and impurity amounts were determined using the HPLC method described above in EXAMPLE 1. The results of the stability experiment are shown in TABLES 53-54 below. TABLE 53 Inverted Storage of Vasopressin Formulations at 25° C. UI- UI UI- UI- UI- UI- UI- UI- AVP Ace- 0.81- 0.97 1.02- 1.72- 1.81- 1.90- 2.05- 2.09- Total (U/ % Gly9 Glu4 D-Asn Asp5 Dimer tyl 0.86 0.99 1.03 1.76 1.89 1.96 2.07 2.10 Impuri- Lot Month mL) LC (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) ties pH X 0 19.6 97.9 0.3 0.4 0.3 1.0 3.8 Y 0 19.7 98.6 0.3 0.4 0.3 1.1 3.8 Z 0 19.9 99.3 0.1 0.5 0.2 0.8 3.8 X 1 19.6 98.1 0.2 0.2 0.1 0.4 0.4 0.3 1.6 3.8 Y 1 19.6 97.9 0.2 0.2 0.1 0.4 0.4 0.3 1.6 3.9 Z 1 19.8 99 0.2 0.2 0.6 0.1 0.2 1.4 3.8 X 2 19.6 98.1 0.3 0.3 0.1 0.3 0.4 0.3 1.7 3.7 Y 2 19.5 97.5 0.2 0.3 0.1 0.3 0.4 0.3 1.6 3.8 Z 2 19.8 99 0.3 0.4 0.5 0.2 1.3 3.8 X 3 19.6 97.8 0.4 0.5 0.1 0.1 0.3 0.4 0.4 2.2 Y 3 19.5 97.4 0.4 0.4 0.1 0.3 0.4 0.4 2.0 3.8 Z 3 19.7 98.6 0.4 0.4 0.5 0.3 1.6 X 6 19.3 96.5 0.7 0.8 0.1 0.2 0.3 0.4 0.4 2.9 3.8 Y 6 19.2 95.9 0.6 0.7 0.1 0.1 0.1 0.3 0.4 0.4 2.5 3.9 Z 6 19.6 98 0.6 0.7 0.1 0.5 0.2 2.3 3.9 X 9 19 95 1.0 1.0 0.2 0.3 0.4 0.4 0.1 3.6 Y 9 18.9 94.5 0.8 1.0 0.2 0.3 0.4 0.4 0.1 3.1 3.9 Z 9 19.2 96 1.0 1.1 0.2 0.5 0.3 3.1 3.8 X 12 18.7 93.5 1.4 1.5 0.1 0.3 0.3 0.4 0.5 0.2 4.8 3.8 Y 12 18.6 93 1.1 1.2 0.2 0.2 0.3 0.4 0.5 0.3 0.2 4.4 3.8 Z 12 18.9 94.5 1.2 1.3 0.3 0.5 0.3 0.3 0.1 4.0 3.8 X 13 18.6 93 1.5 1.6 0.2 0.3 0.4 0.4 0.1 0.4 0.2 0.1 5.2 3.8 Y 13 18.5 92.5 1.2 1.3 0.2 0.3 0.3 0.4 0.1 0.5 0.1 0.4 0.2 0.2 5.2 3.9 Z 13 19 95 1.3 1.5 0.1 0.3 0.5 0.1 0.3 0.1 0.3 0.2 0.2 4.9 3.8 X 14 18.6 93 1.5 1.7 0.1 0.3 0.3 0.5 0.1 0.4 0.4 0.1 0.1 5.5 3.8 Y 14 18.5 92.5 1.2 1.4 0.1 0.3 0.3 0.5 0.1 0.4 0.5 0.2 0.2 5.3 3.9 Z 14 18.9 94.5 1.3 1.6 0.3 0.5 0.2 0.3 0.4 0.2 0.2 5.0 3.8 X 15 18.5 92.5 1.6 1.8 0.1 0.4 0.3 0.4 0.1 0.4 0.3 0.2 0.2 5.9 3.8 Y 15 18.4 92 1.3 1.5 0.1 0.3 0.3 0.4 0.1 0.4 0.5 0.3 0.1 5.3 3.9 Z 15 18.8 94 1.5 1.6 0.3 0.5 0.3 0.4 0.2 0.1 4.9 3.9 TABLE 54 Upright Storage of Vasopressin Formulations at 25° C. UI- UI UI- UI- UI- UI- UI- UI- AVP Ace- 0.81- 0.97 1.02- 1.72- 1.81- 1.90- 2.05- 2.09- Total (U/ % Gly9 Glu4 D-Asn Asp5 Dimer tyl 0.86 0.99 1.03 1.76 1.89 1.96 2.07 2.10 Impuri- Lot Month mL) LC (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) ties pH X 0 19.6 97.9 0.3 0.4 0.3 1.0 3.8 Y 0 19.7 98.6 0.3 0.4 0.3 1.1 3.8 Z 0 19.9 99.3 0.1 0.5 0.2 0.8 3.8 X 1 19.6 98 0.2 0.2 0.1 0.3 0.4 0.3 1.6 3.8 Y 1 19.5 97.7 0.2 0.2 0.3 0.4 0.3 1.4 3.9 Z 1 19.7 98.3 0.2 0.2 0.6 0.2 1.2 3.8 X 2 19.6 98.2 0.3 0.3 0.3 0.4 0.3 1.6 3.7 Y 2 19.5 97.4 0.2 0.3 0.1 0.4 0.4 0.3 1.6 3.8 Z 2 19.8 99 0.3 0.3 0.5 0.2 1.3 3.8 X 3 19.5 97.6 0.4 0.4 0.1 0.3 0.4 0.4 2.1 3.7 Y 3 19.5 97.5 0.4 0.4 0.1 0.4 0.4 1.9 3.8 Z 3 19.7 98.7 0.4 0.4 0.1 0.5 0.3 1.7 X 6 19.3 96.5 0.7 0.8 0.1 0.2 0.3 0.4 0.4 2.9 3.8 Y 6 19.2 96 0.5 0.7 0.1 0.1 0.3 0.4 0.4 2.5 3.9 Z 6 19.5 97.5 0.7 0.7 0.2 0.5 0.3 2.3 3.9 X 9 18.9 94.5 1.0 1.1 0.2 0.3 0.4 0.2 0.1 3.7 3.8 Y 9 18.9 94.5 0.8 0.9 0.2 0.4 0.4 0.2 3.1 3.9 Z 9 19.2 96 0.9 1.0 0.2 0.5 0.3 2.9 3.8 X 12 18.6 93 1.4 1.5 0.1 0.3 0.3 0.4 0.5 0.2 0.1 4.8 3.7 Y 12 18.7 93.5 1.1 1.2 0.1 0.3 0.3 0.4 0.5 0.2 0.2 4.6 3.9 Z 12 18.9 94.5 1.3 1.4 0.3 0.5 0.4 0.3 0.2 4.2 3.8 X 13 18.4 92 1.5 1.6 0.2 0.3 0.3 0.4 0.1 0.4 0.3 0.1 0.1 5.4 3.8 Y 13 18.6 93 1.1 1.3 0.2 0.3 0.3 0.4 0.1 0.4 0.3 0.2 4.6 3.9 Z 13 18.8 94 1.3 1.5 0.3 0.5 0.1 0.3 0.4 0.2 0.1 4.7 3.8 X 14 18.6 93 1.5 1.7 0.1 0.4 0.3 0.4 0.1 0.4 0.3 0.1 5.4 3.8 Y 14 18.5 92.5 1.2 1.4 0.1 0.3 0.3 0.5 0.4 0.5 0.3 0.3 5.4 3.9 Z 14 18.8 94 1.3 1.5 0.3 0.5 0.1 0.3 0.5 0.2 0.2 5.0 3.8 X 15 18.4 92 1.6 1.8 0.1 0.4 0.3 0.4 0.1 0.4 0.3 0.2 5.7 3.8 Y 15 18.4 92 1.3 1.5 0.2 0.3 0.3 0.4 0.1 0.4 0.5 0.3 0.3 5.4 3.9 Z 15 18.6 93 1.5 1.6 0.3 0.5 0.2 0.4 0.2 0.3 5.1 3.9 The results from TABLES 53-54 indicate that stability of the vasopressin formulations was not significantly affected by either inverted or upright storage. The impurities detected included Gly9 (SEQ ID NO.: 2), Glu4 (SEQ ID NO.: 4), D-Asn (SEQ ID NO.: 10), Asp5 (SEQ ID NO.: 3), Acetyl-AVP (SEQ ID NO.: 7), vasopressin dimer, and several unidentified impurities (UI). The unidentified impurities are labeled with a range of relative retention times at which the impurities eluted from the column. The results indicate that the pH remained fairly constant over the 15-month period, fluctuating between 3.8 and 3.9 throughout the 15 months. The total impurities did not increase over 5.9%, and the % LC of vasopressin did not decrease below 92%. FIG. 19 shows a graph depicting the % LC over the 15-month study period for the results provided in TABLES 53-54. The starting amounts of vasopressin were 97.9% LC for lot X, 98.6% LC for lot Y, and 99.3% LC for lot Z. The results indicate that the % LC of vasopressin decreased over the 15-month study period, but did not decrease below 92% LC. The formula for the trend line of lot X was: % LC=98.6−0.4262(month) The formula for the trend line of lot Y was: % LC=98.47−0.4326(month) The formula for the trend line of lot Z was: % LC=99.54−0.3906(month) Example 16: Vasopressin Formulation for Bottle or Intravenous Drip-Bag The following formulations can be used without initial vasopressin dilution in drip-bags for intravenous therapy. TABLE 55 Formulation A (40 IU/100 mL) (10 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Sodium chloride (mg) 8.7 Acetic acid (mg) 0.546 Sodium Acetate Trihydrate (mg) 0.12 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 56 Formulation B (60 IU/100 mL) (10 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.6 Sodium chloride (mg) 8.7 Acetic acid (mg) 0.546 Sodium Acetate Trihydrate (mg) 0.12 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 57 Formulation C (40 IU/100 mL) (10 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Dextrose Anhydrous (mg) 50 Acetic acid (mg) 0.546 Sodium Acetate Trihydrate (mg) 0.12 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 58 Formulation D (60 IU/100 mL) (10 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.6 Dextrose Anhydrous (mg) 50 Acetic acid (mg) 0.546 Sodium Acetate Trihydrate (mg) 0.12 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 59 Formulation E (40 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Sodium chloride (mg) 8.7 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 60 Formulation F (60 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.6 Sodium chloride (mg) 8.7 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 61 Formulation G (40 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Dextrose Anhydrous (mg) 50 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 62 Formulation H (60 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.6 Dextrose Anhydrous (mg) 50 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 63 Formulation 9 (60 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Dextrose Anhydrous (mg) 45 Sodium Chloride (mg) 0.9 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Example 17: Impurity Measurement for Vasopressin Formulation for Bottle or Intravenous Drip-Bag Gradient HPLC was used to determine the concentration of vasopressin and associated impurities in vasopressin formulations similar to those outlined in TABLES 55-63 above. Vasopressin was detected in the eluent using UV absorbance at a short wavelength. The concentration of vasopressin in the sample was determined by the external standard method, where the peak area of vasopressin in sample injections was compared to the peak area of a vasopressin reference standard in a solution of known concentration. The concentrations of related peptide impurities in the sample were also determined using the external standard method, using the vasopressin reference standard peak area and a unit relative response factor. An impurities marker solution was used to determine the relative retention times of identified related peptides at the time of analysis. The chromatographic conditions used for the analysis are shown in TABLE 64 below: TABLE 64 Column Phenomenex Kinetex XB-C18, 2.6 μm, 100Å pore, 4.6 × 150 mm, Part No. 00F-4496-E0 Column 35° C. Temperature Flow Rate 1.0 mL/min Detector VWD: Signal at 215 nm Injection Volume 500 μL Run time 55 minutes Auto sampler Vials Amber glass vial Auto Sampler 10° C. Temperature Pump (gradient) Time (min) % A % B Flow 0 90 10 1.0 40 50 50 1.0 45 50 50 1.0 46 90 10 1.0 55 90 10 1.0 Diluent A was 0.25% v/v acetic acid, which was prepared by pipetting 2.5 mL of glacial acetic acid into a 1 L volumetric flask containing 500 mL of water. The volume was diluted with water and mixed well. Diluent B was prepared by weighing and transferring about 3 g of sodium chloride into a 1 L volumetric flask and then adding 2.5 mL of glacial acetic acid. The solution was diluted to volume with water and mixed well. Phosphate buffer at pH 3.0 was used for mobile phase A. The buffer was prepared by weighing approximately 15.6 g of sodium phosphate monobasic monohydrate into a beaker. 1000 mL of water was added, and mixed well. The pH was adjusted to 3.0 with phosphoric acid. The buffer was filtered through a 0.45 μm membrane filter under vacuum, and the volume was adjusted as necessary. An acetonitrile:water (50:50) solution was used for mobile phase B. To prepare mobile phase B, 500 mL of acetonitrile was mixed with 500 mL of water. The stock standard solution was prepared at 20 units/mL of vasopressin. A solution of vasopressin in diluent was prepared at a concentration of about 20 units/mL. The stock standard solution was prepared by quantitatively transferring the entire contents of 5 vials of USP Vasopressin RS with diluent A to the same 250-mL volumetric flask. The solution was diluted to volume with diluent A and mixed well. 10 mL aliquots of the standard solution was transferred into separate polypropylene tubes. The aliquots were stored at 2-8° C. The stock standard solution was stable for 6 months from the date of preparation when stored in individual polypropylene tubes at 2-8° C. The working standard solution contained about 0.5 units/mL of vasopressin. Aliquots of the stock standard solution were allowed to warm to room temperature and then mixed well. 2.5 mL of the stock standard solution was transferred into a 100 mL volumetric flask and diluted to volume with Diluent B, and the resultant mixture was denoted as the Working Standard Solution. The stock standard solution and working standard solution can also be prepared from a single vasopressin vial in the following manner. One vial of vasopressin with diluent A can be quantitatively transferred to a 50-mL volumetric flask. The solution can be dissolved in and diluted to volume with diluent A and mixed well, and denoted as the stock standard solution. To prepare the working standard solution, 2.5 mL of the stock standard solution was diluted to 100 mL with diluent B and mixed well. The working standard solution was stable for at least 72 hours when stored in refrigerator or in autosampler vial at 10° C. The intermediate standard solution was prepared by pipetting 1 mL of the working standard solution into a 50 mL volumetric flask. The solution was diluted to volume with diluent B and mixed well. The sensitivity solution (0.1% of 0.4 units/mL vasopressin formulation) was prepared by pipetting 2 mL of the intermediate standard solution into a 50 mL volumetric flask. The solution was diluted to the volume with diluent B and mixed well. The sensitivity solution was stable for at least 72 hours when stored in the refrigerator. To prepare the impurities marker solution, a 0.05% v/v acetic acid solution was prepared by pipetting 200 mL of a 0.25% v/v acetic acid solution into a 1 L volumetric flask. The solution was diluted to the desired volume with water and mixed well. To prepare the vasopressin impurity stock solutions, the a solution of each impurity as shown below was prepared in a 25 mL volumetric flask and diluted with 0.05% v/v acetic acid to a concentration suitable for HPLC injection. Gly-9 AVP: 0.09 mg/mL Glu-4 AVP: 0.08 mg/mL Asp-5 AVP: 0.1 mg/mL D-Asn AVP: 0.08 mg/mL Dimer AVP: 0.07 mg/mL Acetyl AVP: 0.08 mg/mL To prepare the MAA/H-IBA (Methacrylic Acid/α-Hydroxy-isobutyric acid) stock solution, a stock solution containing approximately 0.3 mg/mL H-IBA and 0.01 mg/mL in 0.05% v/v acetic acid was made in a 50 mL volumetric flask. To prepare the chlorobutanol diluent, about one gram of hydrous chlorobutanol was added to 500 mL of water. Subsequently, 0.25 mL of acetic acid was added and the solution was stirred to dissolve the chlorobutanol. To prepare the stock impurity marker solutions, 6.5 mg of vasopressin powder was added to a 500 mL volumetric flask. To the flask, the following quantities of the above stock solutions were added: Gly-9 AVP: 20.0 mL Glu-4 AVP: 20.0 mL Asp-5 AVP: 10.0 mL D-Asn AVP: 10.0 mL Dimer AVP: 10.0 mL Acetyl AVP: 20.0 mL H-IBA/MAA: 30.0 mL The solutions were diluted to volume with the chlorobutanol diluent. The solutions were aliquoted into individual crimp top vials and stored at 2-8° C. The solutions, stored at 2-8° C., were suitable for use as long as the chromatographic peaks could be identified based on comparison to the reference chromatogram. At time of use the solutions were removed from refrigerated (2-8° C.) storage and allowed to reach room temperature. The vasopressin stock impurity marker solution was stable for at least 120 hours when stored in autosampler vials at room temperature. The impurity marker solution were prepared by diluting 1 mL of the stock impurity marker solution to 50 mL with diluent B, and mixed well. The vasopressin impurity marker solution was stable for at least 72 hours when stored in the refrigerator. To begin the analysis, the HPLC system was allowed to equilibrate for at least 30 minutes using mobile phase B, followed by time 0 min gradient conditions until a stable baseline was achieved. Diluent B was injected at the beginning of the run, and had no peaks that interfered with vasopressin as shown in FIG. 20. A single injection of the sensitivity solution was performed, wherein the signal-to-noise ratio of the vasopressin was greater than or equal to ten as shown in FIG. 21. A single injection of the impurities marker solution was then made. The labeled impurities in the reference chromatogram were identified in the chromatogram of the marker solution based on their elution order and approximate retention times shown in FIG. 22 and FIG. 23. FIG. 23 is a zoomed-in chromatograph of FIG. 22 showing the peaks that eluted between 16 and 28 minutes. The nomenclature, structure, and approximate retention times for individual identified impurities are detailed in TABLE 3. A single injection of the working standard solution was made to ensure that the tailing factor of the vasopressin peak was less than or equal to about 2.0 as shown in FIG. 24. A total of five replicate injections of the working standard solution were made to ensure that the relative standard deviation (% RSD) of the five replicate vasopressin peak areas was not more than 2.0%. Following the steps above done to confirm system suitability, a single injection of the placebo and sample preparations was made. The chromatograms were analyzed to determine the vasopressin and impurity peak areas. The chromatogram for the placebo is depicted in FIG. 25, and the chromatogram for the sample preparation is shown in FIG. 26. Then, the working standard solution was injected after 1 to 10 sample injections, and the average of the bracketing standard peak areas were used in the calculations for vasopressin and impurity amounts. Additional injections of the impurities marker solution could be made to help track any changes in retention time for long chromatographic sequences. The relative standard deviation (% RSD) of vasopressin peak areas for the six injections of working standard solution was calculated by including the initial five injections from the system suitability steps above and each of the subsequent interspersed working standard solution injections. The calculations were done to ensure that each of the % RSD were not more than 2.0%. The retention time of the major peak in the chromatogram of the sample preparation corresponded to that of the vasopressin peak in the working standard solution injection that preceded the sample preparation injection. To calculate the vasopressin units/mL, the following formula was used: Vasopressin   units  /  mL = R U R S × Conc   STD where: RU=Vasopressin peak area response of Sample preparation. RS=average vasopressin peak area response of bracketing standards. Conc STD=concentration of the vasopressin standard in units/mL To identify the impurities, the % Impurity and identity for identified impurities (TABLE 3) that are were greater than or equal to 0.10% were reported. Impurities were truncated to 3 decimal places and then rounded to 2 decimal places, unless otherwise specified. The following formula was used: %   impurity = R 1 R s × Conc   STD LC × 100  % where R1=Peak area response for the impurity; LC=label content of vasopressin (units/mL). The formulations used for the vasopressin and impurity studies are summarized in TABLE 65 below and correspond to several of the formulations detailed above in TABLES 55-63. TABLE 65 Vasopressin Buffer Conc. Lot (units/100 mL) (mM) Vehicle A 40 10 NaCl B 60 10 NaCl C 40 10 Dextrose D 60 10 Dextrose E 40 1 NaCl F 60 1 NaCl G 40 1 Dextrose H 60 1 Dextrose A1 40 1 Dextrose B1 60 1 Dextrose C1 40 1 Dextrose/NaCl The drug products detailed in TABLE 65 were tested for stability over a six month period. The vasopressin drug formulations were stored at 5° C., 25° C., or 40° C. for up to six months. At 0, 1, 2, 3, 4, 5, and 6 months, the amount of vasopressin (AVP), % label claim (LC), amount of various impurities, pH, and % reference standard was measured. The vasopressin and impurity amounts were determined using the HPLC method described above. The results of the stability experiment are shown in TABLES 66-72 below. TABLE 66 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT Condition Time Vasopressin 0.30 0.33 0.34 0.35 0.362 0.37 0.38 0.39 0.40 0.42 0.44 Lot (°C.) (m) pH (% LC) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 5 0 3.63 102.5 0.36 0.14 0.13 A 25 0 3.63 102.5 0.36 0.14 0.13 A 40 0 3.63 102.5 0.36 0.14 0.13 B 5 0 3.64 102.2 0.24 0.09 0.08 0.10 B 25 0 3.64 102.2 0.24 0.09 0.08 0.10 B 40 0 3.64 102.2 0.24 0.09 0.08 0.10 C 5 0 3.64 98.2 0.34 0.13 0.56 0.20 C 25 0 3.64 98.2 0.34 0.13 0.56 0.20 C 40 0 3.64 98.2 0.34 0.13 0.56 0.20 D 5 0 3.65 100.1 0.24 0.08 0.15 0.06 D 25 0 3.65 100.1 0.24 0.08 0.15 0.06 D 40 0 3.65 100.1 0.24 0.08 0.15 0.06 E 5 0 3.67 100.5 0.13 E 25 0 3.67 100.5 0.13 E 40 0 3.67 100.5 0.13 F 5 0 3.71 101.5 0.09 F 25 0 3.71 101.5 0.09 F 40 0 3.71 101.5 0.09 G 5 0 3.75 99.5 G 25 0 3.75 99.5 G 40 0 3.75 99.5 H 5 0 3.74 100.2 H 25 0 3.74 100.2 H 40 0 3.74 100.2 A1 5 0 3.86 97.5 A1 25 0 3.86 97.5 A1 40 0 3.86 97.5 B1 5 0 3.84 97.6 B1 25 0 3.84 97.6 B1 40 0 3.84 97.6 C1 5 0 3.78 99.3 C1 25 0 3.78 99.3 C1 40 0 3.78 99.3 A 5 1 3.62 101.6 0.37 0.15 0.11 A 25 1 3.63 101.5 0.34 0.19 A 40 1 3.61 98.2 0.27 0.18 B 5 1 3.61 102.2 0.25 0.12 0.06 0.13 B 25 1 3.63 101.0 0.24 0.11 B 40 1 3.63 97.2 0.19 0.65 C 5 1 3.66 99.7 0.37 0.11 0.79 C 25 1 3.65 98.7 0.36 0.17 C 40 1 3.66 93.8 0.60 0.19 D 5 1 3.66 101.1 0.24 0.08 D 25 1 3.65 99.8 0.24 0.11 D 40 1 3.66 92.4 0.41 0.11 E 5 1 3.67 101.0 E 25 1 3.67 99.2 E 40 1 3.68 95.5 F 5 1 3.71 101.5 0.08 F 25 1 3.72 100.1 F 40 1 3.71 96.6 0.12 G 5 1 3.71 99.8 G 25 1 3.76 99.0 G 40 1 3.75 94.2 0.34 0.26 H 5 1 3.76 99.8 H 25 1 3.77 99.5 H 40 1 3.77 97.0 0.23 A1 5 1 3.81 97.0 A1 25 1 3.82 96.8 A1 40 1 3.83 91.8 B1 5 1 3.82 97.5 B1 25 1 3.82 97.1 B1 40 1 3.82 92.0 C1 5 1 3.80 99.2 C1 25 1 98.5 C1 40 1 3.82 94.7 A 5 2 3.59 101.7 0.11 A 25 2 3.59 99.5 0.14 A 40 2 3.60 92.9 0.15 B 5 2 3.60 101.1 0.12 B 25 2 3.60 98.8 0.10 B 40 2 3.60 92.1 0.11 C 5 2 3.59 99.3 0.18 C 25 2 3.62 97.3 0.14 C 40 2 3.64 89.2 0.15 D 5 2 3.67 100.0 0.10 D 25 2 3.66 97.3 0.09 D 40 2 3.62 89.9 0.09 E 5 2 3.65 99.5 E 25 2 3.67 95.8 E 40 2 3.67 90.6 0.07 F 5 2 3.67 100.6 F 25 2 3.71 97.9 0.14 F 40 2 3.70 92.3 0.33 G 5 2 3.70 98.9 G 25 2 3.73 97.0 G 40 2 3.71 90.5 H 5 2 3.72 99.7 H 25 2 3.74 98.0 H 40 2 3.74 91.9 A1 5 2 3.77 97.3 A1 25 2 3.77 95.9 A1 40 2 3.78 86.1 B1 5 2 3.79 97.3 B1 25 2 3.78 96.5 B1 40 2 3.79 87.4 C1 5 2 3.73 99.3 C1 25 2 3.73 98.1 C1 40 2 3.74 91.0 A 5 3 3.59 102.0 0.31 A 25 3 3.61 99.5 0.30 A 40 3 3.60 90.8 0.30 B 5 3 3.59 101.8 0.24 B 25 3 3.60 98.8 0.22 B 40 3 3.60 90.3 0.22 C 5 3 3.62 99.8 0.16 C 25 3 3.62 95.5 0.15 C 40 3 3.62 87.0 0.16 D 5 3 3.62 91.4 0.10 D 25 3 3.63 97.7 0.20 D 40 3 3.63 87.6 0.18 E 5 3 3.63 96.9 E 25 3 3.64 96.3 E 40 3 3.65 88.8 0.23 F 5 3 3.67 100.8 F 25 3 3.68 97.9 0.23 F 40 3 3.70 90.0 0.20 G 5 3 3.73 98.8 0.16 G 25 3 3.72 97.5 0.07 G 40 3 3.74 88.6 H 5 3 3.71 99.8 0.04 H 25 3 3.74 98.5 H 40 3 3.75 89.1 A 5 4 3.59 99.9 0.22 A 25 4 3.56 96.8 0.20 A 40 4 3.70 84.5 0.31 B 5 4 3.58 99.4 0.11 B 25 4 3.56 95.4 0.17 B 40 4 3.67 83.0 1.37 C 5 4 3.61 98.5 0.18 C 25 4 3.63 94.9 0.18 C 40 4 3.64 81.3 0.18 D 5 4 3.62 98.9 0.12 D 25 4 3.62 94.5 0.07 0.09 D 40 4 3.61 82.1 0.13 E 5 4 3.63 97.6 E 25 4 3.69 94.0 E 40 4 3.63 83.2 0.26 F 5 4 3.68 98.9 0.08 F 25 4 3.69 95.3 0.19 F 40 4 3.70 84.6 0.24 G 5 4 3.68 98.1 G 25 4 3.69 95.8 G 40 4 3.84 83.2 H 5 4 3.67 98.6 H 25 4 3.62 93.1 0.13 0.12 H 40 4 3.76 83.6 A 5 5 3.63 99.7 0.10 A 25 5 3.63 95.8 B 5 5 3.63 99.0 0.25 B 25 5 3.64 95.1 C 5 5 3.68 98.2 C 25 5 3.67 93.7 D 5 5 3.67 98.7 D 25 5 3.69 94.6 E 5 5 3.69 97.5 E 25 5 3.69 93.1 0.09 F 5 5 3.71 98.4 0.05 0.14 F 25 5 3.74 94.4 0.15 G 5 5 3.74 97.2 G 25 5 3.78 93.1 1.73 H 5 5 3.76 97.7 H 25 5 3.76 95.7 A 5 6 3.57 101.0 A 25 6 3.49 95.4 A 5 6 3.57 100.0 A 25 6 3.49 94.5 B 5 6 3.54 100.2 B 25 6 3.49 95.7 B 5 6 3.54 99.3 0.12 0.13 B 25 6 3.49 94.6 C 5 6 3.59 98.1 C 25 6 3.56 95.1 C 5 6 3.59 98.0 C 25 6 3.56 93.5 D 5 6 3.55 100.0 D 25 6 3.56 95.8 D 5 6 3.55 98.6 0.10 D 25 6 3.56 94.2 E 5 6 3.54 98.1 E 25 6 3.56 94.1 E 5 6 3.54 97.0 E 25 6 3.56 92.3 F 5 6 3.60 99.0 F 25 6 3.61 95.0 F 5 6 3.60 98.2 0.10 0.14 F 25 6 3.61 93.8 0.21 G 5 6 3.61 98.2 G 25 6 3.66 96.1 G 5 6 3.61 96.5 G 25 6 3.66 94.4 H 5 6 3.64 98.6 H 25 6 3.65 97.0 H 5 6 3.64 96.9 H 25 6 3.65 95.3 Min 3.49 81.258 0 0 0 0.053 0.042 0 0.104 0 0.116 Max 3.84 102.047 0 0 0 0.153 1.371 0 1.731 0 0.116 TABLE 67 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT 0.47 0.48 0.49 0.50 0.510 0.52 0.56 0.57 0.58 0.61 0.63 0.64 0.646 0.67 0.68 0.70 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.63 A 0.63 A 0.63 B 0.20 B 0.20 B 0.20 C 0.18 8.74 C 0.18 8.74 C 0.18 8.74 D 0.10 9.43 D 0.10 9.43 D 0.10 9.43 E 1.55 E 1.55 E 1.55 F 0.23 0.22 F 0.23 0.22 F 0.23 0.22 G 0.12 0.44 G 0.12 0.44 G 0.12 0.44 H 0.08 0.27 H 0.08 0.27 H 0.08 0.27 A1 0.06 A1 0.06 A1 0.06 B1 B1 B1 C1 C1 C1 A 0.67 A 0.82 0.56 A 0.81 0.40 B 0.53 B 0.46 0.21 B 0.47 0.34 C 0.13 0.31 C 0.18 0.25 C 0.23 0.29 D 0.09 0.34 D 0.13 0.35 D 0.12 0.11 0.20 E 0.53 E 0.30 0.50 E 0.32 0.49 F 0.22 F 0.17 0.23 F 0.18 0.24 G 0.12 0.35 G 0.46 0.37 G 0.45 0.35 H 0.08 0.28 H 0.16 0.24 H 0.15 0.25 A1 A1 A1 0.06 B1 B1 B1 C1 C1 C1 A 0.24 0.76 A 0.06 0.73 A 0.05 0.83 B 0.04 0.40 B 0.04 0.42 B 0.12 0.45 0.05 C 0.17 0.13 C 0.15 0.16 C 0.10 0.07 D 0.14 D 0.05 0.13 D 0.04 0.05 E 0.26 E 0.27 E 0.09 F 0.15 F 0.07 0.18 F 0.29 G 0.56 G 0.06 0.54 0.08 G H 0.20 H 0.21 H 0.04 A1 A1 0.14 A1 B1 B1 B1 C1 C1 C1 A 0.09 0.72 A 0.14 0.49 A 0.12 0.47 B 0.07 0.36 B 0.06 0.47 B 0.05 0.44 0.05 C 0.14 0.41 C 0.13 0.57 C 0.09 0.39 D 0.99 0.28 D 0.05 0.42 D 0.27 0.05 E 0.06 0.60 E 0.57 E 1.03 F 0.42 0.31 F 0.10 0.33 F 0.10 0.35 G 0.39 G 0.09 0.51 G 0.50 H 0.32 H 0.37 H 0.25 A 0.84 0.59 A 0.82 0.29 A 0.87 0.39 B 0.47 0.23 B 0.50 0.43 B 0.55 0.45 0.08 C 0.21 0.15 C 0.23 0.25 C 0.25 0.34 D 0.18 0.27 D 0.24 0.39 D 0.19 0.25 0.08 E 0.31 0.58 E 0.33 0.51 E 0.36 0.67 F 0.18 0.21 F 0.19 0.27 F 0.20 0.26 G 0.59 0.40 G 0.59 0.36 G 0.62 0.40 H 0.20 0.22 H 0.25 0.20 0.31 0.11 H 0.25 0.26 0.09 A 0.61 A 0.48 B 0.27 B 0.43 C 0.29 C 0.15 0.30 D 0.14 0.28 D 0.08 0.40 E 0.53 E 0.49 F 0.24 F 0.24 G 0.14 0.39 G 0.17 0.44 H 0.10 0.23 H 0.13 0.28 A 0.62 A 0.30 A 0.65 0.62 A 0.70 0.30 0.19 B 0.61 B 0.26 B 0.38 0.62 B 0.38 0.26 0.11 C 0.49 C 0.17 0.30 C 0.14 C 0.25 0.31 0.21 D 0.10 0.26 D 0.10 0.31 D 0.11 0.26 0.09 D 0.09 0.13 0.32 0.12 E 1.04 E 0.64 E 0.21 1.07 E 0.22 0.60 F 0.08 0.21 F 0.22 F 0.11 0.08 0.19 F 0.12 0.19 G 0.14 0.38 G 0.14 0.18 0.36 G 0.45 0.16 0.42 0.22 G 0.45 0.18 0.19 0.35 0.35 H 0.10 0.20 H 0.10 0.28 H 0.15 0.11 0.20 0.12 H 0.15 0.12 0.28 0.22 Min 0.035 0 0.125 0 0.42 0.077 0.064 0.23 0.14 0.051 0.048 Max 0.986 0 0.555 0 0.42 0.203 0.064 0.624 1.03 0.052 0.109 TABLE 68 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT 0.71 0.72 0.74 0.76 0.77 0.78 0.79 0.80 0.82 0.84 0.86 0.87 0.88 0.91 0.94 0.95 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.15 0.29 A 0.15 0.29 A 0.15 0.29 B 0.08 0.32 B 0.08 0.32 B 0.08 0.32 C 0.15 0.29 C 0.15 0.29 C 0.15 0.29 D 0.10 0.30 D 0.10 0.30 D 0.10 0.30 E 0.28 E 0.28 E 0.28 F 0.32 F 0.32 F 0.32 G 0.20 0.31 G 0.20 0.31 G 0.20 0.31 H 0.12 0.30 H 0.12 0.30 H 0.12 0.30 A1 0.32 A1 0.32 A1 0.32 B1 0.30 B1 0.30 B1 0.30 C1 0.31 C1 0.31 C1 0.31 A 0.10 0.31 A 0.36 A 0.17 0.39 B 0.30 B 0.35 B 0.36 C 0.32 0.31 C 0.40 C 0.16 0.40 D 0.10 0.31 D 0.34 D 0.36 E 0.32 E 0.34 E 0.37 F 0.30 F 0.34 F 0.33 G 0.18 0.29 0.31 G 0.20 0.38 G 0.27 0.42 H 0.09 0.31 H 0.13 0.35 H 0.14 0.36 A1 0.10 0.29 A1 0.30 A1 0.29 B1 0.30 B1 0.30 B1 0.33 C1 0.31 C1 0.30 C1 0.30 A 0.12 0.33 A 0.12 0.36 A 0.15 0.42 B 0.34 B 0.07 0.36 B 0.10 0.41 C 0.12 0.41 C 0.15 0.36 C 0.17 0.40 D 0.09 0.36 D 0.11 0.35 D 0.10 0.37 E 0.33 E 0.21 0.31 0.05 E 0.10 0.36 F 0.36 F 0.34 F 0.37 G 0.20 0.33 G 0.22 0.34 G 0.33 0.41 H 0.11 0.35 H 0.13 0.34 H 0.19 0.36 A1 0.30 A1 0.31 A1 0.31 0.18 B1 0.30 B1 0.31 B1 0.29 0.15 C1 0.31 C1 0.31 C1 0.30 A A A B B B C C C D 0.49 D D E 0.25 0.16 0.38 E E F F F G G G H H H A 0.16 0.33 A 0.18 0.33 A 0.25 0.40 B 0.32 B 0.09 0.32 B 0.17 0.38 C 0.34 C 0.19 0.35 C 0.25 0.42 D 0.10 0.32 D 0.12 0.36 D 0.16 0.45 E 0.30 E 0.32 E 0.19 0.40 F 0.31 F 0.33 F 0.11 0.37 G 0.19 0.35 G 0.29 0.37 G 0.46 0.45 H 0.11 0.34 H 0.19 0.36 0.08 H 0.26 0.45 A 0.16 0.28 A 0.17 0.28 B 0.29 B 0.29 C 0.18 0.27 C 0.18 0.29 D 0.29 D 0.11 0.29 E 0.27 E 0.30 F 0.31 F 0.30 G 0.23 0.28 G 0.29 0.29 H 0.12 0.29 H 0.18 0.29 A 0.33 A 0.14 0.32 A 0.32 A 0.28 B 0.32 B 0.30 B 0.33 B 0.28 C 0.17 0.31 C 0.14 0.32 C 0.14 0.26 C 0.24 D 0.30 D 0.32 D 0.32 D 0.33 E 0.34 E 0.12 0.31 E 0.30 E 0.28 F 0.07 0.33 F 0.32 F 0.30 F 0.28 G 0.32 G 0.18 0.32 G 0.30 G 0.24 H 0.30 H 0.09 0.31 H 0.32 H 0.26 Min 0.112 0.252 0.087 0.092 0.213 0.301 0.161 0.053 Max 0.287 0.252 0.33 0.456 0.328 0.453 0.161 0.487 TABLE 69 D- Asn- RRT RRT RRT RRT RRT RRT Gly9- Asp5- Glu4- RRT RRT RRT RRT RRT RRT AVP 0.99 1.02 1.03 1.04 1.05 1.06 AVP AVP AVP 1.09 1.10 1.095 1.12 1.13 1.14 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.35 0.21 0.17 0.58 0.41 A 0.35 0.21 0.17 0.58 0.41 A 0.35 0.21 0.17 0.58 0.41 B 0.20 0.43 0.15 0.20 0.19 0.25 B 0.20 0.43 0.15 0.20 0.19 0.25 B 0.20 0.43 0.15 0.20 0.19 0.25 C 0.42 0.30 0.48 0.17 C 0.42 0.30 0.48 0.17 C 0.42 0.30 0.48 0.17 D 0.15 0.41 0.11 0.11 0.18 0.19 D 0.15 0.41 0.11 0.11 0.18 0.19 D 0.15 0.41 0.11 0.11 0.18 0.19 E 0.22 0.34 0.19 0.14 0.93 0.24 E 0.22 0.34 0.19 0.14 0.93 0.24 E 0.22 0.34 0.19 0.14 0.93 0.24 F 0.15 0.33 0.07 0.13 0.12 0.19 F 0.15 0.33 0.07 0.13 0.12 0.19 F 0.15 0.33 0.07 0.13 0.12 0.19 G 0.38 0.19 0.24 G 0.38 0.19 0.24 G 0.38 0.19 0.24 H 0.16 0.42 0.08 0.12 0.14 H 0.16 0.42 0.08 0.12 0.14 H 0.16 0.42 0.08 0.12 0.14 A1 0.12 0.12 0.24 0.08 0.10 0.09 A1 0.12 0.12 0.24 0.08 0.10 0.09 A1 0.12 0.12 0.24 0.08 0.10 0.09 B1 0.11 0.12 0.24 0.07 0.07 0.07 B1 0.11 0.12 0.24 0.07 0.07 0.07 B1 0.11 0.12 0.24 0.07 0.07 0.07 C1 0.12 0.12 0.25 0.09 0.10 0.08 C1 0.12 0.12 0.25 0.09 0.10 0.08 C1 0.12 0.12 0.25 0.09 0.10 0.08 A 0.47 0.63 0.39 0.70 0.51 A 0.33 0.41 0.46 0.61 0.44 A 0.31 1.28 0.65 1.52 0.18 B 0.19 0.43 0.26 0.25 0.58 0.27 B 0.12 0.31 0.39 0.20 0.52 B 0.11 0.31 0.29 0.44 1.47 0.23 C 0.42 0.21 0.20 0.15 C 0.66 0.19 0.24 0.40 0.16 C 0.16 1.71 0.58 0.55 0.43 0.86 0.17 D 0.43 0.09 0.18 0.17 D 0.13 0.75 0.23 0.13 0.38 0.17 D 0.18 1.71 0.57 1.43 0.82 0.14 E 0.34 0.17 0.25 0.23 E 0.32 0.32 0.25 0.41 0.23 E 0.28 1.06 0.39 1.21 0.29 F 0.17 0.36 0.12 0.17 0.14 0.20 F 0.17 0.35 0.36 0.18 0.41 0.11 F 0.14 0.29 1.06 0.34 1.13 G 0.36 0.17 0.26 G 0.45 0.18 0.25 0.20 G 0.68 0.38 0.33 0.52 H 0.37 0.07 0.11 0.16 H 0.15 0.45 0.15 0.24 0.13 H 0.17 0.82 0.45 0.18 0.60 A1 0.12 0.12 0.25 0.08 0.07 0.08 A1 0.11 0.12 0.24 0.14 0.13 0.10 A1 0.09 0.11 0.21 0.31 0.34 0.09 0.45 0.33 B1 0.11 0.12 0.25 0.07 0.07 0.07 B1 0.11 0.12 0.24 0.07 0.13 0.16 0.18 B1 0.10 0.11 0.21 0.33 0.33 0.09 0.41 0.72 C1 0.12 0.13 0.26 0.08 0.10 0.08 C1 0.11 0.13 0.25 0.18 0.18 0.10 C1 0.11 0.12 0.23 0.27 0.52 0.13 0.64 0.10 A 0.10 0.55 0.43 0.66 0.26 0.54 A 0.06 0.38 0.81 0.66 0.90 0.05 A 0.26 2.40 0.87 0.19 B 0.14 0.36 0.20 0.18 0.27 0.13 B 0.12 0.30 0.68 0.31 0.77 0.07 B 0.20 0.32 2.42 0.74 2.51 C 0.37 0.15 0.21 0.21 0.05 0.22 C 0.10 0.88 0.29 0.17 0.49 0.15 C 0.14 2.08 1.00 0.46 1.42 D 0.14 0.52 0.19 0.11 0.21 0.11 D 0.13 1.04 0.38 0.21 0.50 0.16 D 0.13 2.15 1.03 0.50 1.41 E 0.44 0.25 0.27 0.24 0.30 E 0.41 0.71 0.33 0.73 0.24 E 0.23 2.09 0.58 2.38 F 0.11 0.34 0.17 0.11 0.19 0.09 F 0.19 0.33 0.58 0.25 0.60 0.07 F 0.14 0.24 2.08 0.63 2.06 G 0.06 0.38 0.16 0.22 0.20 0.17 G 0.54 0.28 0.20 0.34 0.11 G 0.12 0.90 0.83 0.57 1.18 H 0.21 0.54 0.21 0.10 0.19 0.12 H 0.22 0.69 0.30 0.10 0.32 0.14 H 0.16 0.91 0.74 0.29 1.05 A1 0.11 0.14 0.24 0.08 0.08 A1 0.13 0.14 0.23 0.18 0.20 0.20 A1 0.10 0.12 0.21 0.50 0.56 0.14 0.67 0.10 B1 0.12 0.12 0.24 0.08 0.08 B1 0.12 0.13 0.23 0.18 0.20 0.04 0.21 B1 0.10 0.11 0.20 0.52 0.55 0.15 0.73 0.06 C1 0.12 0.13 0.25 0.10 0.09 C1 0.14 0.13 0.24 0.28 0.29 C1 0.10 0.13 0.21 0.43 0.89 0.22 1.14 0.07 A 0.10 0.29 0.31 0.52 0.36 0.62 A 0.10 0.97 0.62 1.17 0.19 A 0.09 3.45 1.20 3.64 0.20 B 0.11 0.25 0.21 0.31 0.11 0.06 B 0.12 0.94 0.37 1.13 0.22 B 0.09 3.37 0.88 0.36 0.22 C 0.09 0.15 0.10 0.20 0.15 C 0.10 0.93 0.45 0.24 0.61 0.19 C 0.08 2.15 1.29 0.66 2.00 D 5.25 0.31 0.16 D 0.10 1.05 0.46 0.23 0.66 0.11 D 0.09 2.18 1.29 0.56 1.77 E 0.82 0.30 0.22 0.27 0.28 E 0.09 0.87 0.47 0.99 0.21 E 0.09 2.93 0.77 3.30 F 0.11 0.22 0.12 0.25 0.08 F 0.11 0.81 0.36 0.84 0.09 F 0.09 2.79 0.73 2.91 G 0.10 0.14 0.15 0.15 0.13 G 0.10 0.37 0.34 0.53 0.12 G 0.73 0.89 0.64 1.22 0.07 H 0.11 0.11 0.06 0.16 0.08 H 0.09 0.31 0.08 0.43 0.08 H 0.69 0.86 0.34 1.26 A 0.33 0.18 0.22 0.07 0.18 0.25 A 0.29 1.14 0.31 1.24 0.17 A 0.27 4.38 1.21 4.48 B 0.12 0.32 0.19 0.14 0.15 B 0.14 0.30 1.16 0.34 0.95 0.05 B 0.14 0.27 4.31 1.01 4.71 0.06 C 0.38 0.10 0.12 0.08 0.09 C 0.38 0.95 0.51 0.26 0.48 C 2.09 1.48 0.68 2.32 D 0.14 0.42 0.13 0.07 0.09 D 0.16 0.41 0.94 0.53 0.34 0.52 D 2.10 1.47 0.54 2.29 E 0.32 0.17 0.21 0.09 0.17 E 0.29 1.02 0.34 1.29 E 0.24 3.78 0.89 4.08 F 0.14 0.32 0.19 0.06 0.15 F 0.12 0.29 0.95 0.26 1.08 F 0.14 0.27 3.55 0.84 3.64 G 0.36 0.11 0.07 0.10 G 0.48 0.18 0.39 0.17 0.37 G 0.43 0.47 1.06 0.42 1.66 0.17 H 0.16 0.39 0.11 0.09 H 0.23 0.46 0.21 0.45 0.39 0.61 H 0.18 0.45 0.52 1.08 0.48 1.72 A 0.15 0.51 0.26 0.62 0.27 0.24 A 0.14 0.52 1.41 0.40 1.71 0.28 B 0.19 0.49 0.06 0.27 0.24 0.28 B 0.20 0.55 1.53 0.38 1.54 0.37 C 0.64 0.13 0.20 0.16 C 0.16 1.86 0.69 0.20 0.75 0.24 D 0.14 0.66 0.18 0.20 0.18 D 0.15 1.76 0.72 0.25 0.80 0.16 E 0.19 0.43 0.25 0.40 0.27 E 0.35 1.24 0.55 1.37 F 0.16 0.41 0.26 0.18 0.29 F 0.12 0.38 1.15 0.39 1.23 G 0.10 0.41 0.12 0.21 0.17 G 0.74 0.52 0.11 0.68 0.24 H 0.11 0.44 0.12 0.14 0.17 H 0.13 0.77 0.51 0.16 0.60 0.16 A 0.12 0.13 0.27 0.09 0.84 0.22 A 0.10 0.13 0.24 1.84 0.31 1.57 0.15 A 0.30 0.21 0.48 0.13 A 0.75 1.62 0.45 1.38 B 0.13 0.13 0.25 0.07 0.77 0.22 B 0.12 0.13 0.23 1.67 0.33 1.61 B 0.19 0.33 0.24 0.56 0.20 B 0.12 0.37 1.64 0.42 1.73 C 0.12 0.13 0.24 0.21 0.22 0.14 0.10 C 0.12 0.13 0.20 1.31 0.90 0.12 0.77 C 0.16 0.90 0.25 0.34 0.31 C 1.70 0.71 0.40 0.79 D 0.13 0.13 0.23 0.12 0.28 0.13 0.06 D 0.11 0.13 0.21 1.32 0.81 0.13 0.79 0.05 D 0.15 0.46 0.19 0.16 0.14 D 0.15 1.72 0.75 0.33 0.83 E 0.11 0.13 0.25 0.12 0.86 0.20 0.06 E 0.12 0.24 1.65 0.25 1.41 E 0.30 0.09 0.21 0.66 0.20 E 0.34 1.44 0.59 1.51 F 0.15 0.14 0.25 0.06 0.30 0.20 0.06 F 0.12 0.12 0.25 1.36 0.26 1.30 0.05 F 0.17 0.35 0.25 0.13 0.21 F 0.19 0.36 0.39 1.30 1.40 G 0.13 0.14 0.24 0.39 0.11 0.13 G 0.12 0.14 0.22 0.33 0.72 0.09 0.64 G 0.36 0.17 0.19 0.12 G 0.27 0.76 0.33 0.58 0.54 H 0.12 0.13 0.24 0.24 0.12 0.05 H 0.13 0.13 0.22 0.39 0.59 0.09 0.56 0.06 H 0.18 0.43 0.21 0.15 0.16 H 0.15 0.81 0.30 0.56 0.61 Min 0.057 0.234 0.055 0.079 0.042 0.071 0.182 0.051 0.059 Max 0.231 2.177 0.501 4.376 5.246 4.713 0.182 0.622 0.1 TABLE 70 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT AVP Acetyl- RRT RRT RRT RRT 1.16 1.168 1.19 1.20 1.206 1.23 1.24 1.25 1.26 1.27 Dimer AVP 1.32 1.33 1.34 1.35 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.33 0.35 A 0.33 0.35 A 0.33 0.35 B 0.07 0.33 B 0.07 0.33 B 0.07 0.33 C 0.22 0.22 C 0.22 0.22 C 0.22 0.22 D 0.08 0.23 D 0.08 0.23 D 0.08 0.23 E 0.55 0.53 E 0.55 0.53 E 0.55 0.53 F 0.34 F 0.34 F 0.34 G 0.23 G 0.23 G 0.23 H 0.23 H 0.23 H 0.23 A1 0.21 0.28 A1 0.21 0.28 A1 0.21 0.28 B1 0.21 0.29 B1 0.21 0.29 B1 0.21 0.29 C1 0.14 0.29 C1 0.14 0.29 C1 0.14 0.29 A 0.37 0.22 0.13 A 0.20 0.60 A 0.59 B 0.26 0.35 B 0.49 B 0.48 C 0.24 C 0.46 0.26 C 0.44 0.73 0.25 D 0.07 0.22 D 0.35 0.25 D 0.41 0.27 E 0.12 0.43 E 0.72 E 0.68 F 0.07 0.35 F 0.55 F 0.53 G 0.29 G 0.54 0.27 G 0.54 0.40 H 0.21 0.12 H 0.56 0.17 H 0.55 0.17 A1 0.23 0.28 A1 0.21 0.27 A1 0.25 0.27 B1 0.22 0.28 B1 0.21 0.28 B1 0.13 0.27 C1 0.14 0.27 C1 0.15 0.28 C1 0.15 0.28 A 0.58 0.47 A 0.76 A 0.06 0.08 0.32 0.51 B 0.34 B 0.07 0.51 B 0.06 0.07 0.25 0.52 C 0.54 0.25 0.26 C 0.58 0.19 0.20 C 0.41 0.26 D 0.49 0.15 0.23 D 0.47 0.25 0.24 D 0.32 0.03 0.25 E 0.34 0.40 E 0.20 0.51 E 0.06 0.76 F 0.12 0.33 F 0.10 0.77 F 0.04 0.58 G 0.62 0.25 0.23 G 0.62 0.18 G 0.52 0.25 H 0.56 0.09 0.42 H 0.59 0.16 0.38 H 0.56 0.46 A1 0.20 0.30 A1 0.20 0.29 A1 0.28 0.29 B1 0.23 0.32 B1 0.23 0.28 B1 0.12 0.28 C1 0.13 0.28 C1 0.13 0.32 C1 0.16 0.28 A 0.08 0.62 0.55 A 0.32 0.80 A 0.14 0.21 0.51 B 0.18 0.42 B 0.45 0.64 B 0.13 0.22 0.49 0.05 C 0.42 0.27 C 0.39 0.31 0.28 C 0.38 0.19 0.29 D 0.37 0.21 D 0.40 0.15 0.23 D 0.39 0.09 0.24 E 0.19 0.31 E 0.25 0.93 E 0.10 0.22 0.77 F 0.23 0.51 F 0.69 F 0.09 0.07 0.51 G 0.52 0.22 0.24 G 0.52 0.32 0.24 G 0.51 0.06 0.46 H 0.53 0.04 0.46 H 0.53 0.42 H 0.55 0.50 A 0.29 0.43 A 0.55 A 0.23 0.11 0.58 B 0.10 0.39 B 0.24 0.31 B 0.24 0.13 0.14 0.50 C 0.35 0.44 0.21 C 0.42 0.95 0.22 C 0.39 0.49 0.24 D 0.39 0.11 0.22 D 0.39 0.82 0.24 D 0.38 0.70 0.25 E 0.23 0.50 E 0.57 0.88 E 0.18 0.17 0.73 F 0.26 0.32 F 0.08 0.07 0.74 F 0.15 0.09 0.59 G 0.49 0.21 0.21 G 0.51 0.48 0.23 G 0.49 0.14 0.19 H 0.51 0.12 0.38 H 0.54 0.80 0.45 H 0.53 0.30 0.49 A 0.22 0.56 A 0.14 0.21 0.70 B 0.08 0.41 B 0.21 0.12 0.53 C 0.65 0.21 C 0.17 0.21 D 0.38 0.22 D 0.53 0.23 E 0.16 0.14 0.46 E 0.11 0.19 0.99 0.10 F 0.06 0.13 0.45 F 0.07 0.12 0.65 0.07 G 0.80 0.21 G 0.42 0.23 0.15 H 0.48 0.20 0.15 H 0.67 0.21 0.12 A 0.22 0.37 0.25 A 0.29 0.23 A 0.30 0.54 A 0.69 B 0.17 0.41 0.23 B 0.14 0.22 B 0.34 0.28 B 0.52 C 0.24 0.34 C 0.29 0.37 0.25 C 0.19 0.25 C 0.42 0.21 D 0.24 0.22 D 0.20 0.26 0.23 D 0.30 0.20 D 0.37 0.23 E 0.32 0.57 0.22 E 0.23 0.18 0.20 E 0.43 0.65 E 0.16 0.91 F 0.14 0.14 0.21 F 0.14 0.09 0.21 F 0.44 F 0.70 0.08 G 0.33 0.39 0.22 G 0.26 0.35 0.23 G 0.37 0.24 G 0.37 0.20 H 0.14 0.32 0.22 0.16 H 0.14 0.33 0.21 0.23 H 0.40 0.19 0.18 H 0.42 0.21 0.20 Min 0.086 0 0.057 0 0.034 0.042 0.193 0.047 0.147 Max 0.341 0 0.796 0 0.061 0.623 0.986 0.047 0.147 TABLE 71 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT 1.37 1.44 1.45 1.46 1.47 1.48 1.55 1.57 1.59 1.62 1.68 1.70 1.71 1.72 1.80 1.82 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.32 A 0.32 A 0.32 B 0.18 B 0.18 B 0.18 C 0.15 C 0.15 C 0.15 D 0.16 D 0.16 D 0.16 E 0.61 E 0.61 E 0.61 F 0.58 F 0.58 F 0.58 G 1.34 G 1.34 G 1.34 H 1.05 H 1.05 H 1.05 A1 A1 A1 B1 B1 B1 C1 C1 C1 A 0.21 2.16 A A B 1.67 B B C 3.37 C C D 2.40 D D E 0.16 3.70 E E F 2.61 F F G 4.10 G G H 2.79 H H A1 A1 A1 B1 B1 B1 0.06 C1 C1 C1 A 0.10 A A B B B C C C D D D E E E 0.14 F F F 0.10 G G G H H H A1 0.09 A1 0.09 A1 0.10 B1 0.06 B1 0.07 B1 0.05 C1 0.14 C1 0.13 C1 0.12 A 0.25 A 0.32 A 0.35 B 0.16 B 0.14 B 0.14 C C C D 0.14 D D E 0.09 E 0.12 E 0.20 F 0.06 0.08 F 0.10 F 0.14 G G G H H H 0.07 0.13 A 0.19 0.16 A 0.29 0.16 A 0.24 B 0.07 B 0.07 0.11 B 0.21 0.12 C C 0.14 C D 0.11 D 0.10 0.07 D 0.08 0.16 E E 0.13 E 0.13 F 0.12 F 0.08 F 0.08 0.06 0.23 G 0.16 G G 0.17 H H 0.20 0.14 H 0.11 0.21 A 0.23 A 0.33 B 0.12 B 0.11 C C D D E 0.11 E 0.13 F F 0.09 G G 0.36 H H A 0.44 0.32 0.16 A 0.48 0.23 0.21 0.12 A 0.26 A 0.27 B 0.12 0.16 B 0.33 0.15 0.10 0.07 B B 0.16 C 0.21 C 0.20 C C 2.69 D 0.08 D 0.30 0.08 D D 1.83 E 0.51 0.13 0.16 0.10 E 0.73 0.14 0.72 E 0.11 E 0.16 2.74 F 0.34 0.10 0.07 F 0.53 0.09 0.06 F F 0.10 1.80 G 0.36 G 0.15 G G 2.69 H H 0.17 H H 1.81 Min 0 0.059 0.077 0.07 0.128 Max 0 0.347 0.213 0.07 0.138 TABLE 72 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT Total 1.85 1.89 1.93 1.96 2.00 2.01 2.04 2.08 2.11 2.12 2.13 2.15 2.16 2.17 2.304 Imp Lot (%) %) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 4.44 A 4.44 A 4.44 B 3.10 B 3.10 B 3.10 C 12.55 C 12.55 C 12.55 D 0.07 0.09 0.55 0.15 12.92 D 0.07 0.09 0.55 0.15 12.92 D 0.07 0.09 0.55 0.15 12.92 E 0.18 5.89 E 0.18 5.89 E 0.18 5.89 F 2.77 F 2.77 F 2.77 G 3.45 G 3.45 G 3.45 H 0.69 3.66 H 0.69 3.66 H 0.69 3.66 A1 1.61 A1 1.61 A1 1.61 B1 1.48 B1 1.48 B1 1.48 C1 1.50 C1 1.50 C1 1.50 A 0.66 8.15 A 5.34 A 6.74 B 5.67 B 3.40 B 5.33 C 6.91 C 3.72 C 7.74 D 4.71 D 3.55 D 6.86 E 6.24 E 3.38 E 5.09 F 4.78 F 2.86 F 4.35 G 6.42 G 1.08 4.39 G 4.93 H 4.60 H 2.73 H 4.07 A1 1.60 A1 1.63 A1 2.80 B1 1.50 B1 1.80 B1 0.44 3.53 C1 1.49 C1 1.66 C1 2.85 A 5.25 A 5.03 A 6.29 B 2.52 B 3.83 B 8.35 C 3.27 C 0.85 4.84 C 6.65 D 2.80 D 4.10 D 6.47 E 0.23 2.82 E 3.98 E 6.87 F 1.96 F 3.61 F 6.85 G 3.37 G 3.51 G 5.10 H 3.10 H 3.57 H 4.76 A1 1.53 A1 2.10 A1 3.55 B1 1.56 B1 1.98 B1 3.31 C1 1.57 C1 1.97 C1 4.05 A 4.82 A 5.39 A 10.68 B 2.48 B 4.73 B 6.71 C 2.09 C 4.34 C 7.69 D 8.29 D 4.06 D 7.10 E 3.57 7.50 E 4.50 E 9.64 F 2.39 F 3.65 F 7.97 G 2.19 G 3.21 G 5.08 H 1.91 H 2.31 H 4.64 A 0.17 0.14 0.06 4.79 A 5.96 A 13.72 B 2.60 B 0.65 5.84 B 14.85 C 2.66 C 5.50 C 9.14 D 2.67 D 0.08 1.22 7.08 D 9.22 E 2.87 E 5.66 E 12.07 F 2.35 F 4.64 F 10.81 G 3.23 G 4.42 G 7.12 H 2.63 H 0.31 0.11 0.08 6.71 H 0.08 7.46 A 4.23 A 6.75 B 2.94 B 0.09 6.36 C 2.72 C 0.13 5.32 D 2.67 D 5.46 E 3.19 E 5.90 F 2.66 F 4.95 G 3.05 G 6.37 H 2.55 H 4.20 A 4.36 A 6.67 A 3.81 A 6.62 B 3.60 B 5.66 B 3.71 B 5.98 C 0.14 3.05 C 5.58 C 2.93 C 0.18 8.12 D 2.28 D 5.34 D 2.48 D 7.20 E 5.11 E 6.93 E 4.22 E 8.94 F 2.83 F 5.10 F 2.47 F 7.12 G 3.26 G 4.42 G 2.98 G 7.49 H 2.35 H 4.04 H 2.80 H 6.09 Min 0 0 0 3.565 0 0 1.533 Max 0 0 0 3.565 0 0 14.845 TABLE 73 RRT RRT RRT RRT D-ASN- RRT RRT RRT RRT Condition Time AVP 0.64 0.86 0.87 0.95 AVP 0.99 1.03 1.04 1.05 Lot (° C.) (m) pH (% LC) (%) (%) (%) (%) (%) (%) (%) (%) (%) A1 5 0 3.86 97.5 0.06 0.32 0.12 0.12 0.24 A1 25 0 3.86 97.5 0.06 0.32 0.12 0.12 0.24 A1 40 0 3.86 97.5 0.06 0.32 0.12 0.12 0.24 B1 5 0 3.84 97.6 0.30 0.11 0.12 0.24 B1 25 0 3.84 97.6 0.30 0.11 0.12 0.24 B1 40 0 3.84 97.6 0.30 0.11 0.12 0.24 C1 5 0 3.78 99.3 0.31 0.12 0.12 0.25 C1 25 0 3.78 99.3 0.31 0.12 0.12 0.25 C1 40 0 3.78 99.3 0.31 0.12 0.12 0.25 A1 5 1 3.81 97.0 0.10 0.29 0.12 0.12 0.25 A1 25 1 3.82 96.8 0.30 0.11 0.12 0.24 A1 40 1 3.83 91.8 0.06 0.29 0.09 0.11 0.21 B1 5 1 3.82 97.5 0.30 0.11 0.12 0.25 B1 25 1 3.82 97.1 0.30 0.11 0.12 0.24 B1 40 1 3.82 92.0 0.33 0.10 0.11 0.21 C1 5 1 3.80 99.2 0.31 0.12 0.13 0.26 C1 25 1 98.5 0.30 0.11 0.13 0.25 C1 40 1 3.82 94.7 0.30 0.11 0.12 0.23 A1 5 2 3.77 97.3 0.30 0.11 0.14 0.24 A1 25 2 3.77 95.9 0.14 0.31 0.13 0.14 0.23 0.18 A1 40 2 3.78 86.1 0.31 0.18 0.10 0.12 0.21 0.50 B1 5 2 3.79 97.3 0.30 0.12 0.12 0.24 B1 25 2 3.78 96.5 0.31 0.12 0.13 0.23 0.18 B1 40 2 3.79 87.4 0.29 0.15 0.10 0.11 0.20 0.52 C1 5 2 3.73 99.3 0.31 0.12 0.13 0.25 C1 25 2 3.73 98.1 0.31 0.14 0.13 0.24 C1 40 2 3.74 91.0 0.30 0.10 0.13 0.21 0.43 A1 5 3 3.80 95.8 0.28 0.12 0.22 A1 25 3 3.78 94.0 0.28 0.13 0.21 0.11 A1 40 3 3.81 82.2 0.28 0.16 0.11 0.15 0.29 B1 5 3 3.82 96.5 0.28 0.11 0.13 0.23 B1 25 3 3.82 94.8 0.29 0.12 0.13 0.21 0.11 B1 40 3 3.83 82.0 0.27 0.06 0.09 0.11 0.14 0.33 C1 5 3 3.75 97.5 0.29 0.12 0.13 0.24 C1 25 3 3.75 96.8 0.29 0.13 0.14 0.22 C1 40 3 3.75 85.5 0.27 0.11 0.16 0.26 Min 3.78 91.842 0.061 0.093 0 Max 3.86 99.282 0.063 0.124 0 TABLE 74 RRT GLY9- ASP5- GLU4- RRT RRT RRT RRT RRT RRT RRT RRT 1.06 AVP AVP AVP 1.12 1.13 1.23 1.24 1.25 ACETYL- 1.57 1.71 1.77 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) AVP (%) (%) (%) (%) A1 0.08 0.10 0.09 0.21 0.28 A1 0.08 0.10 0.09 0.21 0.28 A1 0.08 0.10 0.09 0.21 0.28 B1 0.07 0.07 0.07 0.21 0.29 B1 0.07 0.07 0.07 0.21 0.29 B1 0.07 0.07 0.07 0.21 0.29 C1 0.09 0.10 0.08 0.14 0.29 C1 0.09 0.10 0.08 0.14 0.29 C1 0.09 0.10 0.08 0.14 0.29 A1 0.08 0.07 0.08 0.23 0.28 A1 0.14 0.13 0.10 0.21 0.27 A1 0.31 0.34 0.09 0.45 0.33 0.25 0.27 B1 0.07 0.07 0.07 0.22 0.28 B1 0.07 0.13 0.16 0.18 0.21 0.28 B1 0.33 0.33 0.09 0.41 0.72 0.13 0.27 0.06 C1 0.08 0.10 0.08 0.14 0.27 C1 0.18 0.18 0.10 0.15 0.28 C1 0.27 0.52 0.13 0.64 0.10 0.15 0.28 A1 0.08 0.08 0.20 0.30 0.09 A1 0.20 0.20 0.20 0.29 0.09 A1 0.56 0.14 0.67 0.10 0.28 0.29 0.10 B1 0.08 0.08 0.23 0.32 0.06 B1 0.20 0.04 0.21 0.23 0.28 0.07 B1 0.55 0.15 0.73 0.06 0.12 0.28 0.05 C1 0.10 0.09 0.13 0.28 0.14 C1 0.28 0.29 0.13 0.32 0.13 C1 0.89 0.22 1.14 0.07 0.16 0.28 0.12 A1 0.09 0.09 0.18 0.29 A1 0.26 0.29 0.21 0.28 A1 0.73 0.18 0.82 0.19 0.11 0.27 B1 0.09 0.09 0.19 0.28 B1 0.25 0.25 0.20 0.28 B1 0.73 0.19 0.82 0.09 0.09 0.07 0.28 0.06 C1 0.10 0.10 0.13 0.28 C1 0.35 0.38 0.11 0.28 C1 1.22 0.30 1.56 0.12 0.15 0.27 Min 0.07 0.089 0.067 0.073 0 0.27 Max 0.344 0.089 0.448 0.326 0 0.288 TABLE 75 RRT RRT RRRT RRT Total Lot 1.85 (%) 1.91 (%) 2.02 (%) 2.37 (%) RS (%) A1 1.61 A1 1.61 A1 1.61 B1 1.48 B1 1.48 B1 1.48 C1 1.50 C1 1.50 C1 1.50 A1 1.60 A1 1.63 A1 2.80 B1 1.50 B1 1.80 B1 0.44 3.53 C1 1.49 C1 1.66 C1 2.85 A1 1.53 A1 2.10 A1 3.55 B1 1.56 B1 1.98 B1 3.31 C1 1.57 C1 1.97 C1 4.05 A1 1.26 A1 1.76 A1 3.29 B1 1.40 B1 1.82 B1 0.10 0.10 0.17 3.68 C1 1.38 C1 1.89 C1 4.41 Min 1.483 Max 2.799 The appearance for all of the tested lots through the duration of the experiment was clear and colorless. The results above provided an estimated shelf life at 5° C. of about 16.1 months (FIG. 27) and at 25° C. of about eight months (FIG. 28). The results indicated that the dextrose vehicle with 1 mM acetate buffer provided a lower rate of degradation and a lower rate of impurities accumulation for the vasopressin formulations at 5° C., 25° C., and 40° C. compared to NaCl or a combination of dextrose and NaCl in either 1 mM or 10 mM acetate buffer Graphical depictions of TABLES 66-72 are shown in FIGS. 29-48 below. FIGS. 29-31 show the vasopressin (% LC) levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 32-34 show the total impurities (total RS (%)) levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 35-37 show the Gly9-AVP levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 38-40 show the Asp5-AVP levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 41-43 show the Glu4-AVP levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 44-46 show the Acetyl-AVP levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 47-48 show the AVP dimer levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. Based on the data from FIGS. 29-48, the estimated shelf-life at 5° C. is about 16.1 months, and the estimated shelf-life at 25° C. is about 8 months. TABLES 73-75 display data of further studies on Formulations A1, B1, and C1 as detailed in TABLE 65. The appearance for all of the tested lots through the duration of the experiment was clear and colorless. The estimated shelf life at 5° C. of about 15 months and at 25° C. of about 7.7 months is shown below in FIG. 49 and FIG. 50, respectively. The results indicated that the dextrose vehicle provided a lower rate of degradation and a lower rate of impurities accumulation for the vasopressin formulations at 5° C., 25° C., and 40° C. compared to a combination of dextrose and NaCl. Graphical depictions of TABLES 73-75 are shown in FIGS. 51-62 below. FIGS. 51-53 show the vasopressin (% LC) levels in the samples prepared in dextrose or dextrose and NaCl at 5° C., 25° C., and 40° C., respectively. FIGS. 54-56 show the Gly9-AVP levels in the samples prepared in dextrose or dextrose and NaCl at 5° C., 25° C., and 40° C., respectively. FIGS. 57-59 show the Glu4-AVP levels in the samples prepared in dextrose or dextrose and NaCl at 5° C., 25° C., and 40° C., respectively. FIGS. 60-62 show the total impurities (% RS) levels in the samples prepared in dextrose or dextrose and NaCl at 5° C., 25° C., and 40° C., respectively. EMBODIMENTS The following non-limiting embodiments provide illustrative examples of the invention, but do not limit the scope of the invention. In some embodiments, the invention provides a pharmaceutical composition comprising, in a unit dosage form: a) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin, or a pharmaceutically-acceptable salt thereof; and b) a polymeric pharmaceutically-acceptable excipient in an amount that is from about 1% to about 10% by mass of the unit dosage form or the pharmaceutically-acceptable salt thereof, wherein the unit dosage form exhibits from about 5% to about 10% less degradation of the vasopressin or the pharmaceutically-acceptable salt thereof after storage for about 1 week at about 60° C. than does a corresponding unit dosage form, wherein the corresponding unit dosage form consists essentially of: A) vasopressin, or a pharmaceutically-acceptable salt thereof; and B) a buffer having acidic pH. In some embodiments, the polymeric pharmaceutically-acceptable excipient comprises a polyalkylene oxide moiety. In some embodiments, the polymeric pharmaceutically-acceptable excipient is a polyethylene oxide. In some embodiments, the polymeric pharmaceutically-acceptable excipient is a poloxamer. In some embodiments, the unit dosage form has an amount of the polymeric pharmaceutically-acceptable excipient that is about 1% the amount of the vasopressin or the pharmaceutically-acceptable salt thereof. In some embodiments, the first unit dosage form exhibits about 10% less degradation of the vasopressin or the pharmaceutically-acceptable salt thereof after storage for about 1 week at about 60° C. than does the corresponding unit dosage form. In some embodiments, the unit dosage form further comprises SEQ ID NO. 2. In some embodiments, the composition further comprises SEQ ID NO. 3. In some embodiments, the composition further comprises SEQ ID NO. 4. In some embodiments, the unit dosage form is an injectable of about 1 mL volume. In some embodiments, the unit dosage form consists essentially of: a) about 0.04 mg/mL of vasopressin, or the pharmaceutically-acceptable salt thereof; b) the polymeric pharmaceutically-acceptable excipient in an amount that is from about 1% to about 10% by mass of the vasopressin or the pharmaceutically-acceptable salt thereof; and c) a plurality of peptides, wherein each of the peptides has from 88% to 90% sequence homology to the vasopressin or the pharmaceutically-acceptable salt thereof. In some embodiments, one of the plurality of peptides is SEQ ID NO.: 2. In some embodiments, one of the plurality of peptides is SEQ ID NO.:3. In some embodiments, wherein one of the plurality of peptides is SEQ ID NO.: 4. In some embodiments, the buffer has a pH of about 3.5. Embodiment 1 A method of increasing blood pressure in a human in need thereof, the method comprising: intravenously administering to the human a pharmaceutical composition comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; and ii) acetic acid, sodium acetate, or a combination thereof, wherein: the pharmaceutical composition is at about room temperature; the administration to the human is longer than 18 hours; the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. Embodiment 2 The method of embodiment 1, wherein the administration to the human is for about one day. Embodiment 3 The method of embodiment 1, wherein the administration to the human is for about one week. Embodiment 4 The method of any one of embodiments 1-3, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. Embodiment 5 The method of any one of embodiments 1-4, wherein the human's hypotension is associated with vasodilatory shock. Embodiment 6 The method of embodiment 5, wherein the vasodilatory shock is post-cardiotomy shock. Embodiment 7 The method of any one of embodiments 1-6, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 8 The method of embodiment 5, wherein the vasodilatory shock is septic shock. Embodiment 9 The method of any one of embodiments 1-8, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 10 The method of any one of embodiments 1-9, wherein the unit dosage form further comprises dextrose. Embodiment 11 The method of any one of embodiments 1-10, wherein the unit dosage form further comprises about 5% dextrose. Embodiment 12 A method of increasing blood pressure in a human in need thereof, the method comprising: intravenously administering to the human a pharmaceutical composition that consists essentially of, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; iii) acetic acid, sodium acetate, or a combination thereof; and iv) optionally hydrochloric acid or sodium hydroxide, wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. Embodiment 13 The method of embodiment 12, wherein the unit dosage form consists essentially of hydrochloric acid. Embodiment 14 The method of embodiment 12, wherein the unit dosage form consists essentially of sodium hydroxide. Embodiment 15 The method of any one of embodiments 12-14, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. Embodiment 16 The method of any one of embodiments 12-15, wherein the human's hypotension is associated with vasodilatory shock. Embodiment 17 The method of embodiment 16, wherein the vasodilatory shock is post-cardiotomy shock. Embodiment 18 The method of any one of embodiments 12-17, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 19 The method of embodiment 16, wherein the vasodilatory shock is septic shock. Embodiment 20 The method of any one of embodiments 12-19 wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. Embodiment 21 The method of any one of embodiments 12-20, wherein the unit dosage form consists essentially of 5% dextrose. Embodiment 22 A method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 5° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 1% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 5° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. Embodiment 23 The method of embodiment 22, wherein the administration to the human is for about one day. Embodiment 24 The method of embodiment 22, wherein the administration to the human is for about one week. Embodiment 25 The method of any one of embodiments 22-24, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. Embodiment 26 The method of any one of embodiments 22-25, wherein the human's hypotension is associated with vasodilatory shock. Embodiment 27 The method of embodiment 26, wherein the vasodilatory shock is post-cardiotomy shock. Embodiment 28 The method of any one of embodiments 22-27, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 29 The method of embodiment 26, wherein the vasodilatory shock is septic shock. Embodiment 30 The method of any one of embodiments 22-29, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. Embodiment 31 The method of any one of embodiments 22-30, wherein the pharmaceutical composition exhibits no more than about 2% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after storage of the pharmaceutical composition at 5° C. for about two months. Embodiment 32 A method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 25° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 2% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 25° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. Embodiment 33 The method of embodiment 32, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. Embodiment 34 The method of any one of embodiments 32-33, wherein the human's hypotension is associated with vasodilatory shock. Embodiment 35 The method of embodiment 34, wherein the vasodilatory shock is post-cardiotomy shock. Embodiment 36 The method of any one of embodiments 32-35, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 37 The method of embodiment 35, wherein the vasodilatory shock is septic shock. Embodiment 38 The method of any one of embodiments 32-37, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. Embodiment 39 The method of any one of embodiments 32-38, wherein the pharmaceutical composition exhibits no more than about 5% degradation after storage of the pharmaceutical composition at 25° C. for about two months.
<SOH> BACKGROUND <EOH>Vasopressin is a potent endogenous hormone, responsible for maintaining plasma osmolality and volume in most mammals. Vasopressin can be used clinically in the treatment of sepsis and cardiac conditions, and in the elevation of patient's suffering from low blood pressure. Current formulations of vasopressin suffer from poor long-term stability.
<SOH> SUMMARY OF THE INVENTION <EOH>In some embodiments, the invention provides a pharmaceutical composition comprising, in a unit dosage form: a) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin, or a pharmaceutically-acceptable salt thereof; and b) a polymeric pharmaceutically-acceptable excipient in an amount that is from about 1% to about 10% by mass of the unit dosage form or the pharmaceutically-acceptable salt thereof, wherein the unit dosage form exhibits from about 5% to about 10% less degradation of the vasopressin or the pharmaceutically-acceptable salt thereof after storage for about 1 week at about 60° C. than does a corresponding unit dosage form, wherein the corresponding unit dosage form consists essentially of: A) vasopressin, or a pharmaceutically-acceptable salt thereof; and B) a buffer having acidic pH. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: intravenously administering to the human a pharmaceutical composition that consists essentially of, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; iii) acetic acid, sodium acetate, or a combination thereof; and iv) optionally hydrochloric acid or sodium hydroxide, wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 5° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 1% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 5° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 25° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 2% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 25° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive.
A61K3811
20170828
20180529
20180104
67193.0
A61K3811
1
BRADLEY, CHRISTINA
VASOPRESSIN FORMULATIONS FOR USE IN TREATMENT OF HYPOTENSION
UNDISCOUNTED
1
CONT-ACCEPTED
A61K
2,017
15,688,314
ACCEPTED
VASOPRESSIN FORMULATIONS FOR USE IN TREATMENT OF HYPOTENSION
Provided herein are peptide formulations comprising polymers as stabilizing agents. The peptide formulations can be more stable for prolonged periods of time at temperatures higher than room temperature when formulated with the polymers. The polymers used in the present invention can decrease the degradation of the constituent peptides of the peptide formulations.
1-15. (canceled) 16. A method of increasing blood pressure in a human in need thereof, the method comprising: administering to the human a pharmaceutical composition that comprises, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; dextrose; acetate; and iv) a plurality of peptides in an amount of about 1.5% to about 12.9%, wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. 17. The method of claim 16, wherein the plurality of peptides is present at about 1.5% to about 5%. 18. The method of claim 16, wherein the unit dosage form further comprises a pH adjusting agent. 19. The method of claim 16, wherein the unit dosage form further comprises hydrochloric acid. 20. The method of claim 16, wherein the unit dosage form further comprises sodium hydroxide. 21. The method of claim 16, wherein the unit dosage form further comprises acetic acid. 22. The method of claim 16, wherein the dextrose is present at 5%. 23. The method of claim 16, wherein the administration to the human is over about one day. 24. The method of claim 16, wherein the administration to the human is over about one week. 25. The method of claim 16, wherein the administration is intravenous. 26. The method of claim 16, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. 27. The method of claim 16, wherein the human's hypotension is associated with vasodilatory shock. 28. The method of claim 27, wherein the vasodilatory shock is post-cardiotomy shock. 29. The method of claim 28, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. 30. The method of claim 27, wherein the vasodilatory shock is septic shock. 31. The method of claim 30, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute.
CROSS REFERENCE This application is a continuation of U.S. application Ser. No. 15/612,649, filed Jun. 2, 2017, which is a continuation-in-part of U.S. application Ser. No. 15/426,693, filed Feb. 7, 2017, which is a continuation-in-part of U.S. application Ser. No. 15/289,640, filed Oct. 10, 2016, which is a continuation-in-part of U.S. application Ser. No. 14/717,877, filed May 20, 2015, which is a continuation of U.S. application Ser. No. 14/610,499, filed Jan. 30, 2015, each of which is incorporated herein by reference in its entirety. BACKGROUND Vasopressin is a potent endogenous hormone, responsible for maintaining plasma osmolality and volume in most mammals. Vasopressin can be used clinically in the treatment of sepsis and cardiac conditions, and in the elevation of patient's suffering from low blood pressure. Current formulations of vasopressin suffer from poor long-term stability. INCORPORATION BY REFERENCE Each patent, publication, and non-patent literature cited in the application is hereby incorporated by reference in its entirety as if each was incorporated by reference individually. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Aug. 25, 2017, is named 47956702304_SL.txt and is 5260 bytes in size. SUMMARY OF THE INVENTION In some embodiments, the invention provides a pharmaceutical composition comprising, in a unit dosage form: a) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin, or a pharmaceutically-acceptable salt thereof; and b) a polymeric pharmaceutically-acceptable excipient in an amount that is from about 1% to about 10% by mass of the unit dosage form or the pharmaceutically-acceptable salt thereof, wherein the unit dosage form exhibits from about 5% to about 10% less degradation of the vasopressin or the pharmaceutically-acceptable salt thereof after storage for about 1 week at about 60° C. than does a corresponding unit dosage form, wherein the corresponding unit dosage form consists essentially of: A) vasopressin, or a pharmaceutically-acceptable salt thereof; and B) a buffer having acidic pH. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: intravenously administering to the human a pharmaceutical composition that consists essentially of, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; iii) acetic acid, sodium acetate, or a combination thereof; and iv) optionally hydrochloric acid or sodium hydroxide, wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 5° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 1% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 5° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 25° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 2% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 25° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. BRIEF DESCRIPTION OF THE FIGURES FIG. 1 is a chromatogram of a diluent used in vasopressin assay. FIG. 2 is a chromatogram of a sensitivity solution used in a vasopressin assay. FIG. 3 is a chromatogram of an impurity marker solution used in a vasopressin assay. FIG. 4 is a zoomed-in depiction of the chromatogram in FIG. 3. FIG. 5 is a chromatogram of a vasopressin standard solution. FIG. 6 is a chromatogram of a sample vasopressin preparation. FIG. 7 is a UV spectrum of a vasopressin sample. FIG. 8 is a UV spectrum of a vasopressin standard. FIG. 9 plots vasopressin stability across a range of pH as determined experimentally. FIG. 10 illustrates the effects of various stabilizers on vasopressin stability. FIG. 11 plots vasopressin stability across a range of pH at 25° C. FIG. 12 plots vasopressin impurities across a range of pH at 25° C. FIG. 13 plots vasopressin stability across a range of pH at 40° C. FIG. 14 plots vasopressin impurities across a range of pH at 40° C. FIG. 15 illustrates vasopressin impurities across a range of pH at 25° C. FIG. 16 illustrates vasopressin impurities across a range of pH at 40° C. FIG. 17 illustrates the effect of pH on vasopressin at 25° C. FIG. 18 illustrates the effect of pH on vasopressin at 40° C. FIG. 19 depicts the % LC of vasopressin formulations stored for 15 months at 25° C. FIG. 20 is a chromatogram of a diluent used in a vasopressin assay. FIG. 21 is a chromatogram of a sensitivity solution used in a vasopressin assay. FIG. 22 is a chromatogram of an impurity marker solution used in a vasopressin assay. FIG. 23 is a zoomed-in depiction of the chromatogram in FIG. 22. FIG. 24 is a chromatogram of a working solution. FIG. 25 is a chromatogram of a placebo sample. FIG. 26 is a chromatogram of a vasopressin sample. FIG. 27 depicts the estimated shelf-life of a vasopressin sample described herein at 5° C. FIG. 28 depicts the estimated shelf-life of a vasopressin sample described herein at 25° C. FIG. 29 shows the % LC of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 30 shows the % LC of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 31 shows the % LC of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 32 shows the total impurities of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 33 shows the total impurities of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 34 shows the total impurities of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 35 shows the % Gly9-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 36 shows the % Gly9-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 37 shows the % Gly9-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 38 shows the % Asp5-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 39 shows the % Asp5-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 40 shows the % Asp5-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 41 shows the % Glu4-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 42 shows the % Glu4-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 43 shows the % Glu4-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 44 shows the % Acetyl-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 45 shows the % Acetyl-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 46 shows the % Acetyl-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 47 shows the % AVP-dimer of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 48 shows the % AVP-dimer of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 49 depicts the estimated shelf-life of a vasopressin sample described herein at 5° C. FIG. 50 depicts the estimated shelf-life of a vasopressin sample described herein at 25° C. FIG. 51 shows the % LC of vasopressin after storage at 5° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 52 shows the % LC of vasopressin after storage at 25° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 53 shows the % LC of vasopressin after storage at 40° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 54 shows the % Gly9-AVP of vasopressin after storage at 5° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 55 shows the % Gly9-AVP of vasopressin after storage at 25° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 56 shows the % Gly9-AVP of vasopressin after storage at 40° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 57 shows the % Glu4-AVP of vasopressin after storage at 5° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 58 shows the % Glu4-AVP of vasopressin after storage at 25° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 59 shows the % Glu4-AVP of vasopressin after storage at 40° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 60 shows the total impurities of vasopressin after storage at 5° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 61 shows the total impurities of vasopressin after storage at 25° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 62 shows the total impurities of vasopressin after storage at 40° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. DETAILED DESCRIPTION Vasopressin and Peptides of the Invention. Vasopressin, a peptide hormone, acts to regulate water retention in the body and is a neurotransmitter that controls circadian rhythm, thermoregulation, and adrenocorticotrophic hormone (ACTH) release. Vasopressin is synthesized as a pro-hormone in neurosecretory cells of the hypothalamus, and is subsequently transported to the pituitary gland for storage. Vasopressin is released upon detection of hyperosmolality in the plasma, which can be due to dehydration of the body. Upon release, vasopressin increases the permeability of collecting ducts in the kidney to reduce renal excretion of water. The decrease in renal excretion of water leads to an increase in water retention of the body and an increase in blood volume. At higher concentrations, vasopressin raises blood pressure by inducing vasoconstriction. Vasopressin acts through various receptors in the body including, for example, the V1, V2, V3, and oxytocin-type (OTR) receptors. The V1 receptors occur on vascular smooth muscle cells, and the major effect of vasopressin action on the V1 receptor is the induction of vasoconstriction via an increase of intracellular calcium. V2 receptors occur on the collecting ducts and the distal tubule of the kidney. V2 receptors play a role in detection of plasma volume and osmolality. V3 receptors occur in the pituitary gland and can cause ACTH release upon vasopressin binding. OTRs can be found on the myometrium and vascular smooth muscle. Engagement of OTRs via vasopressin leads to an increase of intracellular calcium and vasoconstriction. Vasopressin is a nonapeptide, illustrated below (SEQ ID NO. 1): At neutral to acidic pH, the two basic groups of vasopressin, the N-terminal cysteine, and the arginine at position eight, are protonated, and can each carry an acetate counterion. The amide groups of the N-terminal glycine, the glutamine at position four, and the asparagine at position five, are susceptible to modification when stored as clinical formulations, such as unit dosage forms. The glycine, glutamine, and asparagine residues can undergo deamidation to yield the parent carboxylic acid and several degradation products as detailed in EXAMPLE 1 and TABLE 1 below. Deamidation is a peptide modification during which an amide group is removed from an amino acid, and can be associated with protein degradation, apoptosis, and other regulatory functions within the cell. Deamidation of asparagine and glutamine residues can occur in vitro and in vivo, and can lead to perturbation of the structure and function of the affected proteins. The susceptibility to deamidation can depend on primary sequence of the protein, three dimensional structure of the protein, and solution properties including, for example, pH, temperature, ionic strength, and buffer ions. Deamidation can be catalyzed by acidic conditions. Under physiological conditions, deamidation of asparagine occurs via the formation of a five-membered succinimide ring intermediate by a nucleophilic attack of the nitrogen atom in the following peptide bond on the carbonyl group of the asparagine side chain. Acetylation is a peptide modification whereby an acetyl group is introduced into an amino acid, such as on the N-terminus of the peptide. Vasopressin can also form dimers in solution and in vivo. The vasopressin dimers can occur through the formation of disulfide bridges that bind a pair of vasopressin monomers together. The dimers can form between two parallel or anti-parallel chains of vasopressin. Vasopressin and associated degradation products or peptides are listed in TABLE 1 below. All amino acids are L-stereoisomers unless otherwise denoted. TABLE 1 SEQ ID Name Sequence NO. Vasopressin (AVP; arginine CYFQNCPRG-NH2 1 vasopressin) Gly9-vasopressin (Gly9-AVP) CYFQNCPRG 2 Asp5-vasopressin (Asp5-AVP) CYFQDCPRG-NH2 3 Glu4-vasopressin (Glu4-AVP) CYFENCPRG-NH2 4 Glu4Gly9-vasopressin CYFENCPRG 5 (Glu4Gly9-AVP) AcetylAsp5-vasopressin Ac-CYFQDCPRG-NH2 6 (AcetylAsp5-AVP) Acetyl-vasopressin Ac-CYFQNCPRG-NH2 7 (Acetyl-AVP) His2-vasopressin (His2-AVP) CHFQNCPRG-NH2 8 Leu7-vasopressin (Leu7-AVP) CYFQNCLRG-NH2 9 D-Asn-vasopressin CYFQ(D-Asn)CPRG-NH2 10 (DAsn-AVP) D-Cys1-vasopressin (D-Cys)YFQNCPRG-NH2 11 D-Tyr-vasopressin C(D-Tyr)FQNCPRG-NH2 12 D-Phe-vasopressin CY(D-Phe)QNCPRG-NH2 13 D-Gln-vasopressin CYF(D-Gln)NCPRG-NH2 14 D-Cys6-vasopressin CYFQN(D-cys)PRG-NH2 15 D-Pro-vasopressin CYFQNC(D-pro)RG-NH2 16 D-Arg-vasopressin CYFQNCP(D-Arg)G-NH2 17 Therapeutic Uses. A formulation of vasopressin can be used to regulate plasma osmolality and volume and conditions related to the same in a subject. Vasopressin can be used to modulate blood pressure in a subject, and can be indicated in a subject who is hypotensive despite treatment with fluid and catecholamines. Vasopressin can be used in the treatment of, for example, vasodilatory shock, post-cardiotomy shock, sepsis, septic shock, cranial diabetes insipidus, polyuria, nocturia, polydypsia, bleeding disorders, Von Willebrand disease, haemophilia, platelet disorders, cardiac arrest, liver disease, liver failure, hypovolemia, hemorrhage, oesophageal variceal haemorrhage, hypertension, pulmonary hypertension, renal disease, polycystic kidney disease, blood loss, injury, hypotension, meniere disease, uterine myomas, brain injury, mood disorder. Formulations of vasopressin can be administered to a subject undergoing, for example, surgery or hysterectomy. Plasma osmolality is a measure of the plasma's electrolyte-water balance and relates to blood volume and hydration of a subject. Normal plasma osmolality in a healthy human subject range from about 275 milliosmoles/kg to about 295 milliosmoles/kg. High plasma osmolality levels can be due to, for example, diabetes insipidus, hyperglycemia, uremia, hypernatremia, stroke, and dehydration. Low plasma osmolality can be due to, for example, vasopressin oversecretion, improper functioning of the adrenal gland, lung cancer, hyponatremia, hypothyroidism, and over-consumption of water or other fluids. Septic shock can develop due to an extensive immune response following infection and can result in low blood pressure. Causes of sepsis can include, for example, gastrointestinal infections, pneumonia, bronchitis, lower respiratory tract infections, kidney infection, urinary tract infections, reproductive system infections, fungal infections, and viral infections. Risk factors for sepsis include, for example, age, prior illness, major surgery, long-term hospitalization, diabetes, intravenous drug use, cancer, use of steroidal medications, and long-term use of antibiotics. The symptoms of sepsis can include, for example, cool arms and legs, pale arms and legs, extreme body temperatures, chills, light-headedness, decreased urination, rapid breathing, edema, confusion, elevated heart rate, high blood sugar, metabolic acidosis, respiratory alkalosis, and low blood pressure. Vasopressin can also be administered to regulate blood pressure in a subject. Blood pressure is the measure of force of blood pushing against blood vessel walls. Blood pressure is regulated by the nervous and endocrine systems and can be used as an indicator of a subject's health. Chronic high blood pressure is referred to as hypertension, and chronic low blood pressure is referred to as hypotension. Both hypertension and hypotension can be harmful if left untreated. Blood pressure can vary from minute to minute and can follow the circadian rhythm with a predictable pattern over a 24-hour period. Blood pressure is recorded as a ratio of two numbers: systolic pressure (mm Hg), the numerator, is the pressure in the arteries when the heart contracts, and diastolic pressure (mm Hg), the denominator, is the pressure in the arteries between contractions of the heart. Blood pressure can be affected by, for example, age, weight, height, sex, exercise, emotional state, sleep, digestion, time of day, smoking, alcohol consumption, salt consumption, stress, genetics, use of oral contraceptives, and kidney disease. Blood pressure for a healthy human adult between the ages of 18-65 can range from about 90/60 to about 120/80. Hypertension can be a blood pressure reading above about 120/80 and can be classified as hypertensive crisis when there is a spike in blood pressure and blood pressure readings reach about 180/110 or higher. Hypertensive crisis can be precipitated by, for example, stroke, myocardial infarction, heart failure, kidney failure, aortic rupture, drug-drug interactions, and eclampsia. Symptoms of hypertensive crisis can include, for example, shortness of breath, angina, back pain, numbness, weakness, dizziness, confusion, change in vision, nausea, and difficulty speaking. Vasodilatory shock can be characterized by low arterial blood pressure due to decreased systemic vascular resistance. Vasodilatory shock can lead to dangerously low blood pressure levels and can be corrected via administration of catecholamines or vasopressin formulations. Vasodilatory shock can be caused by, for example, sepsis, nitrogen intoxication, carbon monoxide intoxication, hemorrhagic shock, hypovolemia, heart failure, cyanide poisoning, metformin intoxication, and mitochondrial disease. Post-cardiotomy shock can occur as a complication of cardiac surgery and can be characterized by, for example, inability to wean from cardiopulmonary bypass, poor hemodynamics in the operating room, development of poor hemodynamics post-surgery, and hypotension. Pharmaceutical Formulations. Methods for the preparation of compositions comprising the compounds described herein can include formulating the compounds with one or more inert, pharmaceutically-acceptable excipients. Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives. Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, elixir, nanosuspension, aqueous or oily suspensions, drops, syrups, and any combination thereof. Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include granulating agents, binding agents, lubricating agents, disintegrating agents, anti-adherents, anti-static agents, surfactants, anti-oxidants, coloring agents, flavoring agents, plasticizers, preservatives, suspending agents, emulsifying agents, plant cellulosic material and spheronization agents, and any combination thereof. Vasopressin can be formulated as an aqueous formulation or a lyophilized powder, which can be diluted or reconstituted just prior to use. Upon dilution or reconstitution, the vasopressin solution can be refrigerated for long-term stability for about one day. Room temperature incubation or prolonged refrigeration can lead to the generation of degradation products of vasopressin. In some embodiments, a pharmaceutical composition of the invention can be formulated for long-term storage of vasopressin at room temperature in the presence of a suitable pharmaceutically-acceptable excipient. The pharmaceutically-acceptable excipient can increase the half-life of vasopressin when stored at any temperature, such as room temperature. The presence of the pharmaceutical excipient can decrease the rate of decomposition of vasopressin at any temperature, such as room temperature. In some embodiments, a pharmaceutical composition has a shelf life of at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, at least about 25 months, at least about 26 months, at least about 27 months, at least about 28 months, at least about 29 months, or at least about 30 months. The shelf life can be at any temperature, including, for example, room temperature and refrigeration (i.e., 2-8° C.). As used herein, “shelf life” means the period beginning from manufacture of a formulation beyond which the formulation cannot be expected beyond reasonable doubt to yield the therapeutic outcome approved by a government regulatory agency In some embodiments, a vasopressin formulation of the invention comprises a pharmaceutically-acceptable excipient, and the vasopressin has a half-life that is at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, or at least about 1000% greater than the half-life of vasopressin in a corresponding formulation that lacks the pharmaceutically-acceptable excipient. In some embodiments, a vasopressin formulation of the invention has a half-life at about 5° C. to about 8° C. that is no more than about 1%, no more than about 5%, no more than about 10%, no more than about 15%, no more than about 20%, no more than about 25%, no more than about 30%, no more than about 35%, no more than about 40%, no more than about 45%, no more than about 50%, no more than about 55%, no more than about 60%, no more than about 65%, no more than about 70%, no more than about 75%, no more than about 80%, no more than about 85%, no more than about 90%, no more than about 95%, no more than about 100%, no more than about 150%, no more than about 200%, no more than about 250%, no more than about 300%, no more than about 350%, no more than about 400%, no more than about 450%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000% greater than the half-life of the formulation at another temperature, such as room temperature. The half-life of the compounds of the invention in a formulation described herein at a specified temperature can be, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, or about one week. A formulation described herein can be stable for or be stored for, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years prior to administration to a subject. A unit dosage form described herein can be stable for or be stored for, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years prior to administration to a subject. A diluted unit dosage form described herein can be stable for or be stored for, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years prior to administration to subject. The stability of a formulation described herein can be measured after, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years. A formulation or unit dosage form described herein can exhibit, for example, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9% about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% degradation over a specified period of time. The degradation of a formulation or a unit dosage form disclosed herein can be assessed after about 24 hours, about 36 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years of storage. The degradation of a formulation or a unit dosage form disclosed herein can be assessed at a temperature of, for example, about 0° C., about 1° C., about 2° C., about 3° C., about 4° C., about 5° C., about 6° C., about 7° C., about 8° C., about 9° C., about 10° C., about 11° C., about 12° C., about 13° C., about 14° C., about 15° C., about 16° C., about 17° C., about 18° C., about 19° C., about 20° C., about 21° C., about 22° C., about 23° C., about 24° C., about 25° C., about 26° C., about 27° C., about 28° C., about 29° C., about 30° C., about 31° C., about 32° C., about 33° C., about 34° C., about 35° C., about 36° C., about 37° C., about 38° C., about 39° C., about 40° C., about 41° C., about 42° C., about 43° C., about 44° C., about 45° C., about 46° C., about 47° C., about 48° C., about 49° C., about 50° C., or about 0° C. to about 5° C., about 1° C. to about 6° C., about 2° C. to about 7° C., about 2° C. to about 8° C., about 3° C. to about 8° C., about 4° C. to about 9° C., about 5° C. to about 10° C., about 6° C. to about 11° C., about 7° C. to about 12° C., about 8° C. to about 13° C., about 9° C. to about 14° C., about 10° C. to about 15° C., about 11° C. to about 16° C., about 12° C. to about 17° C., about 13° C. to about 18° C., about 14° C. to about 19° C., about 15° C. to about 20° C., about 16° C. to about 21° C., about 17° C. to about 22° C., about 18° C. to about 23° C., about 19° C. to about 24° C., about 20° C. to about 25° C., about 21° C. to about 26° C., about 22° C. to about 27° C., about 23° C. to about 28° C., about 24° C. to about 29° C., about 25° C. to about 30° C., about 26° C. to about 31° C., about 27° C. to about 32° C., about 28° C. to about 33° C., about 29° C. to about 34° C., about 30° C. to about 35° C., about 31° C. to about 36° C., about 32° C. to about 37° C., about 33° C. to about 38° C., about 34° C. to about 39° C., about 35° C. to about 40° C., about 36° C. to about 41° C., about 37° C. to about 42° C., about 38° C. to about 43° C., about 39° C. to about 44° C., about 40° C. to about 45° C., about 41° C. to about 46° C., about 42° C. to about 47° C., about 43° C. to about 48° C., about 44° C. to about 49° C., about 45° C. to about 50° C. In some embodiments, a vasopressin formulation of the invention comprises an excipient and the vasopressin has a level of decomposition at a specified temperature that is about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% less than the level of decomposition of a formulation of the invention in the absence of the excipient. Pharmaceutical compositions of the invention can be used, stored, tested, analyzed or assayed at any suitable temperature. Non-limiting examples of temperatures include about 0° C., about 1° C., about 2° C., about 3° C., about 4° C., about 5° C., about 6° C., about 7° C., about 8° C., about 9° C., about 10° C., about 11° C., about 12° C., about 13° C., about 14° C., about 15° C., about 16° C., about 17° C., about 18° C., about 19° C., about 20° C., about 21° C., about 22° C., about 23° C., about 24° C., about 25° C., about 26° C., about 27° C., about 28° C., about 29° C., about 30° C., about 31° C., about 32° C., about 33° C., about 34° C., about 35° C., about 36° C., about 37° C., about 38° C., about 39° C., about 40° C., about 41° C., about 42° C., about 43° C., about 44° C., about 45° C., about 46° C., about 47° C., about 48° C., about 49° C., about 50° C., about 51° C., about 52° C., about 53° C., about 54° C., about 55° C., about 56° C., about 57° C., about 58° C., about 59° C., about 60° C., about 61° C., about 62° C., about 63° C., about 64° C., about 65° C., about 66° C., about 67° C., about 68° C., about 69° C., about 70° C., about 71° C., about 72° C., about 73° C., about 74° C., or about 75° C. Pharmaceutical compositions of the invention can be used, stored, tested, analyzed or assayed at any suitable temperature. Non-limiting examples of temperatures include from about 0° C. to about 5° C., about 1° C. to about 6° C., about 2° C. to about 7° C., about 2° C. to about 8° C., about 3° C. to about 8° C., about 4° C. to about 9° C., about 5° C. to about 10° C., about 6° C. to about 11° C., about 7° C. to about 12° C., about 8° C. to about 13° C., about 9° C. to about 14° C., about 10° C. to about 15° C., about 11° C. to about 16° C., about 12° C. to about 17° C., about 13° C. to about 18+° C., about 14° C. to about 19° C., about 15° C. to about 20° C., about 16° C. to about 21° C., about 17° C. to about 22° C., about 18° C. to about 23° C., about 19° C. to about 24° C., about 20° C. to about 25° C., about 21° C. to about 26° C., about 22° C. to about 27° C., about 23° C. to about 28° C., about 24° C. to about 29° C., about 25° C. to about 30° C., about 26° C. to about 31° C., about 27° C. to about 32° C., about 28° C. to about 33° C., about 29° C. to about 34° C., about 30° C. to about 35° C., about 31° C. to about 36° C., about 32° C. to about 37° C., about 33° C. to about 38° C., about 34° C. to about 39° C., about 35° C. to about 40° C., about 36° C. to about 41° C., about 37° C. to about 42° C., about 38° C. to about 43° C., about 39° C. to about 44° C., about 40° C. to about 45° C., about 41° C. to about 46° C., about 42° C. to about 47° C., about 43° C. to about 48° C., about 44° C. to about 49° C., about 45° C. to about 50° C., about 46° C. to about 51° C., about 47° C. to about 52° C., about 48° C. to about 53° C., about 49° C. to about 54° C., about 50° C. to about 55° C., about 51° C. to about 56° C., about 52° C. to about 57° C., about 53° C. to about 58° C., about 54° C. to about 59° C., about 55° C. to about 60° C., about 56° C. to about 61° C., about 57° C. to about 62° C., about 58° C. to about 63° C., about 59° C. to about 64° C., about 60° C. to about 65° C., about 61° C. to about 66° C., about 62° C. to about 67° C., about 63° C. to about 68° C., about 64° C. to about 69° C., about 65° C. to about 70° C., about 66° C. to about 71° C., about 67° C. to about 72° C., about 68° C. to about 73° C., about 69° C. to about 74° C., about 70° C. to about 74° C., about 71° C. to about 76° C., about 72° C. to about 77° C., about 73° C. to about 78° C., about 74° C. to about 79° C., or about 75° C. to about 80° C. Pharmaceutical compositions of the invention can be used, stored, tested, analyzed or assayed at room temperature. The room temperature can be, for example, about 20.0° C., about 20.1° C., about 20.2° C., about 20.3° C., about 20.4° C., about 20.5° C., about 20.6° C., about 20.7° C., about 20.8° C., about 20.9° C., about 21.0° C., about 21.1° C., about 21.2° C., about 21.3° C., about 21.4° C., about 21.5° C., about 21.6° C., about 21.7° C., about 21.8° C., about 21.9° C., about 22.0° C., about 22.1° C., about 22.2° C., about 22.3° C., about 22.4° C., about 22.5° C., about 22.6° C., about 22.7° C., about 22.8° C., about 22.9° C., about 23.0° C., about 23.1° C., about 23.2° C., about 23.3° C., about 23.4° C., about 23.5° C., about 23.6° C., about 23.7° C., about 23.8° C., about 23.9° C., about 24.0° C., about 24.1° C., about 24.2° C., about 24.3° C., about 24.4° C., about 24.5° C., about 24.6° C., about 24.7° C., about 24.8° C., about 24.9° C., or about 25.0° C. A pharmaceutical composition of the disclosed can be supplied, stored, or delivered in a vial or tube that is, for example, about 0.5 mL, about 1 mL, about 2 mL, about 3 mL, about 4 mL, about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, about 10 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about 18 mL, about 19 mL, or about 20 mL in volume. A pharmaceutical composition of the disclosure can be a combination of any pharmaceutical compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can be administered in therapeutically-effective amounts, for example, intravenous, subcutaneous, intramuscular, transdermal, or parenteral administration. Pharmaceutical preparations can be formulated for intravenous administration. The pharmaceutical compositions can be in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in oily or aqueous vehicles, and can contain formulation agents such as suspending, stabilizing, and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Suspensions of the active compounds can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. The suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use. Comparison Formulations. A pharmaceutical composition described herein can be analyzed by comparison to a reference formulation. A reference formulation can be generated from any combination of compounds, peptides, excipients, diluents, carriers, and solvents disclosed herein. Any compound, peptide, excipient, diluent, carrier, or solvent used to generate the reference formulation can be present in any percentage, ratio, or amount, for example, those disclosed herein. The reference formulation can comprise, consist essentially of, or consist of any combination of any of the foregoing. A non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: an amount, such as about 20 Units or about 0.04 mg, of vasopressin or a pharmaceutically-acceptable salt thereof, an amount, such as about 5 mg, of chlorobutanol (for example, hydrous), an amount, such as about 0.22 mg, of acetic acid or a pharmaceutically-acceptable salt thereof or a quantity sufficient to bring pH to about 3.4 to about 3.6, and water as needed. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof, chlorobutanol, acetic acid, and a solvent such as water. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof, chlorobutanol, and a solvent such as water. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof, acetic acid, and a solvent such as water. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof and a solvent such as water. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof and a buffer having acidic pH, such as pH 3.5 or any buffer or pH described herein. Methods. Any formulation described herein can be diluted prior to administration to a subject. Diluents that can be used in a method of the invention include, for example, compound sodium lactate solution, 6% dextran, 10% dextran, 5% dextrose, 20% fructose, Ringer's solution, 5% saline, 1.39% sodium bicarbonate, 1.72% sodium lactate, or water. Upon dilution, any diluted formulation disclosed herein can be stored for, for example, about 24 hours, about 36 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years of storage. Upon dilution, any diluted formulation disclosed herein can be stored at, for example, about 0° C., about 1° C., about 2° C., about 3° C., about 4° C., about 5° C., about 6° C., about 7° C., about 8° C., about 9° C., about 10° C., about 11° C., about 12° C., about 13° C., about 14° C., about 15° C., about 16° C., about 17° C., about 18° C., about 19° C., about 20° C., about 21° C., about 22° C., about 23° C., about 24° C., about 25° C., about 26° C., about 27° C., about 28° C., about 29° C., about 30° C., about 31° C., about 32° C., about 33° C., about 34° C., about 35° C., about 36° C., about 37° C., about 38° C., about 39° C., about 40° C., about 41° C., about 42° C., about 43° C., about 44° C., about 45° C., about 46° C., about 47° C., about 48° C., about 49° C., about 50° C., or about 0° C. to about 5° C., about 1° C. to about 6° C., about 2° C. to about 7° C., about 2° C. to about 8° C., about 3° C. to about 8° C., about 4° C. to about 9° C., about 5° C. to about 10° C., about 6° C. to about 11° C., about 7° C. to about 12° C., about 8° C. to about 13° C., about 9° C. to about 14° C., about 10° C. to about 15° C., about 11° C. to about 16° C., about 12° C. to about 17° C., about 13° C. to about 18° C., about 14° C. to about 19° C., about 15° C. to about 20° C., about 16° C. to about 21° C., about 17° C. to about 22° C., about 18° C. to about 23° C., about 19° C. to about 24° C., about 20° C. to about 25° C., about 21° C. to about 26° C., about 22° C. to about 27° C., about 23° C. to about 28° C., about 24° C. to about 29° C., about 25° C. to about 30° C., about 26° C. to about 31° C., about 27° C. to about 32° C., about 28° C. to about 33° C., about 29° C. to about 34° C., about 30° C. to about 35° C., about 31° C. to about 36° C., about 32° C. to about 37° C., about 33° C. to about 38° C., about 34° C. to about 39° C., about 35° C. to about 40° C., about 36° C. to about 41° C., about 37° C. to about 42° C., about 38° C. to about 43° C., about 39° C. to about 44° C., about 40° C. to about 45° C., about 41° C. to about 46° C., about 42° C. to about 47° C., about 43° C. to about 48° C., about 44° C. to about 49° C., about 45° C. to about 50° C. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about two weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about three weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about six weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about three months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about six months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about two years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about three years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 24 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 48 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 96 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 1 week; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 months; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 months; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least one year; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least two years; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least three years; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 24 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 48 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 96 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least one week; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 months; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 months; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 1 year; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 years; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 years; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 24 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 48 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 96 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 1 week; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 months; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 months; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 1 year; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 years; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 years; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 24 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 48 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 96 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least one week; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 months; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 months; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least one year; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 years; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 years; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 24 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 48 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 96 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 1 week; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 2 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 months; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 6 months; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 1 year; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 2 years; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 years; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about two weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about three weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 24 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 48 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C. for about, for example, 5° C., 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 96 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 1 week; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 2 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 months; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 6 months; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 1 year; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 2 years; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 years; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. A formulation described herein can be used without initial vasopressin dilution for use in, for example, intravenous drip-bags. The formulation can be premixed, already-diluted, and ready for use as provided in, for example, a bottle or intravenous drip-bag. The formulation supplied in the bottle can then be transferred to an intravenous drip-bag for administration to a subject. The formulation can be stable for about 24 hours, about 36 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years prior to discarding. The premixed formulation described herein can be disposed in a container or vessel, which can be sealed. The container or vessel can maintain the sterility of, or reduce the likelihood of contamination of, the premixed formulation. The premixed formulation described herein can be disposed in a container or vessel and is formulated as, for example, a single use dosage or a multiple use dosage. The container or vessel can be, for example, a glass vial, an ampoule, or a plastic flexible container. The plastic flexible container can be made of, for example, PVC (polyvinyl chloride), or polypropylene. A premixed vasopressin formulation described herein can be stored as a liquid in an aliquot having a total volume of between about 1 and about 500 mL, between about 1 and about 250 mL, between about 1 and about 200 mL, between about 1 and about 150 mL, between about 1 and about 125 mL, between about 1 and about 120 mL, between about 1 and about 110 mL, between about 1 and about 100 mL, between about 1 and about 90 mL, between about 1 and about 80 mL, between about 1 and about 70 mL, between about 1 and about 60 mL, between about 1 and about 50 mL, between about 1 and about 40 mL, between about 1 and about 30 mL, between about 1 and about 20 mL, between about 1 and about 10 mL, or between about 1 and about 5 mL. A premixed vasopressin formulation described herein can be administered as, for example, a single continuous dose over a period of time. For example, the premixed vasopressin formulation can be administered for a period of time of between about 1 and about 10 minutes, between about 1 and about 20 minutes, between about 1 and about 30 minutes, between about 1 and about 2 hours, between about 1 and about 3 hours, between about 1 and about 4 hours, between about 1 and about 5 hours, between about 1 and about 6 hours, between about 1 and about 7 hours, between about 1 and about 8 hours, between about 1 and about 9 hours, between about 1 and about 10 hours, between about 1 and about 11 hours, between about 1 and about 12 hours, between about 1 and about 13 hours, between about 1 and about 14 hours, between about 1 and about 15 hours, between about 1 and about 16 hours, between about 1 and about 17 hours, between about 1 and about 18 hours, between about 1 and about 19 hours, between about 1 and about 20 hours, between about 1 and about 21 hours, between about 1 and about 22 hours, between about 1 and about 23 hours, between about 1 and about 1 day, between about 1 and about 32 hours, between about 1 and about 36 hours, between about 1 and about 42 hours, between about 1 and about 2 days, between about 1 and about 54 hours, between about 1 and about 60 hours, between about 1 and about 66 hours, between about 1 and about 3 days, between about 1 and about 78 hours, between about 1 and about 84 hours, between about 1 and about 90 hours, between about 1 and about 4 days, between about 1 and about 102 hours, between about 1 and about 108 hours, between about 1 and about 114 hours, between about 1 and about 5 days, between about 1 and about 126 hours, between about 1 and about 132 hours, between about 1 and about 138 hours, between about 1 and about 6 days, between about 1 and about 150 hours, between about 1 and about 156 hours, between about 1 and about 162 hours, or between about 1 and about 1 week. A premixed vasopressin formulation described herein can be administered as a loading dose followed by a maintenance dose over a period of time. For example, the loading dose can comprise administration of the premixed vasopressin formulation at a first dosage amount for a first period of time, followed by administration of the maintenance dose at a second dosage amount for a second period of time. The loading dose can be administered for a period of time of between about 1 and about 5 minutes, between about 1 and about 10 minutes, between about 1 and about 15 minutes, between about 1 and about 20 minutes, between about 1 and about 25 minutes, between about 1 and about 30 minutes, between about 1 and about 45 minutes, between about 1 and about 60 minutes, between about 1 and about 90 minutes, between 1 minute and about 2 hours, between 1 minute about 2.5 hours, between 1 minute and about 3 hours, between 1 minute and about 3.5 hours, between 1 minute and about 4 hours, between 1 minute and about 4.5 hours, between 1 minute and about 5 hours, between 1 minute and about 5.5 hours, between 1 minute and about 6 hours, between 1 minute and about 6.5 hours, between 1 minute and about 7 hours, between 1 minute and about 7.5 hours, between 1 minute and about 8 hours, between 1 minute and about 10 hours, between 1 minute and about 12 hours, between 1 minute about 14 hours, between 1 minute and about 16 hours, between 1 minute and about 18 hours, between 1 minute and about 20 hours, between 1 minute and about 22 hours, or between 1 minute and about 24 hours. Following the loading dose, the maintenance dose can be administered for a period of time as described above for a single continuous dose. A premixed vasopressin formulation described herein, when administered as a single continuous, loading, or maintenance dose, can be administered for about 1 hour to about 7 days, about 1 hour to about 4 days, about 1 hour to about 48 hours, about 1 hour to about 36 hours, about 1 hour to about 24 hours, about 1 hour to about 12 hours, about 24 hours to about 120 hours, about 24 hours to about 108 hours, about 24 hours to about 96 hours, about 24 hours to about 72 hours, about 24 hours to about 48 hours, or about 24 hours to about 36 hours. The volume of the premixed formulation can be, for example, about 25 mL, about 30 mL, about 35 mL, about 40 mL, about 45 mL, about 50 mL, about 55 mL, about 60 mL, about 65 mL, about 70 mL, about 75 mL, about 80 mL, about 85 mL, about 90 mL, about 95 mL, about 100 mL, about 110 mL, about 120 mL, about 130 mL, about 140 mL, about 150 mL, about 175 mL, about 200 mL, about 225 mL, about 250 mL, about 275 mL, about 300 mL, about 350 mL, about 400 mL, about 450 mL, about 500 mL, about 550 mL, about 600 mL, about 650 mL, about 700 mL, about 750 mL, about 800 mL, about 850 mL, about 900 mL, about 950 mL, or about 1 L. In some embodiments, the volume of the vasopressin formulation formulated for use without initial vasopressin dilution is 100 mL. The concentration of vasopressin in the container or vessel in which the premixed vasopressin formulation is disposed can be, for example, about 0.1 units/mL, about 0.2 units/mL, about 0.3 units/mL, about 0.4 units/mL, about 0.5 units/mL, about 0.6 units/mL, about 0.7 units/mL, about 0.8 units/mL, about 0.9 units/mL, about 1 unit/mL, about 2 units/mL, about 3 units/mL, about 4 units/mL, about 5 units/mL, about 6 units/mL, about 7 units/mL, about 8 units/mL, about 9 units/mL, about 10 units/mL, about 11 units/mL, about 12 units/mL, about 13 units/mL, about 14 units/mL, about 15 units/mL, about 16 units/mL, about 17 units/mL, about 18 units/mL, about 19 units/mL, about 20 units/mL, about 21 units/mL, about 22 units/mL, about 23 units/mL, about 24 units/mL about 25 units/mL, about 30 units/mL, about 35 units/mL, about 40 units/mL, about 45 units/mL, or about 50 units/mL. In some embodiments, the concentration of vasopressin in the container or vessel is 0.4 units/mL. In some embodiments, the concentration of vasopressin in the container or vessel is 0.6 units/mL. The concentration of vasopressin in the container or vessel in which the premixed vasopressin formulation is disposed can be, for example, about 0.01 μg/mL, about 0.05 μg/mL, about 0.1 μg/mL, about 0.15 μg/mL, about 0.2 μg/mL, about 0.25 μg/mL, about 0.3 μg/mL, about 0.35 μg/mL, about 0.4 μg/mL, about 0.5 μg/mL, about 0.6 μg/mL, about 0.7 μg/mL, about 0.8 μg/mL, about 0.9 μg/mL, about 1 μg/mL, about 2 μg/mL, about 3 μg/mL, about 4 μg/mL, about 5 μg/mL, about 10 μg/mL, about 15 μg/mL, about 20 μg/mL, about 25 μg/mL, about 30 μg/mL, about 35 μg/mL, about 40 μg/mL, about 45 μg/mL, about 50 μg/mL, about 60 μg/mL, about 70 μg/mL, about 80 μg/mL, about 90 μg/mL, about 100 μg/mL, about 125 μg/mL, about 150 μg/mL, about 175 μg/mL, about 200 μg/mL, about 250 μg/mL, about 300 μg/mL, about 350 μg/mL, about 400 μg/mL, about 450 μg/mL, about 500 μg/mL, about 600 μg/mL, about 700 μg/mL, about 800 μg/mL, about 900 μg/mL, about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, or about 10 mg/mL. A formulation formulated for use without initial vasopressin dilution can be administered as intravenous drip therapy for about 15 min, about 20 min, about 25 min, about 30 min, about 35 min, about 40 min, about 45 min, about 50 min, about 55 min, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 1 year. A formulation for use in a drip-bag can be replaced up to, for example, one time, two times, three times, four times, five times, six times, seven times, eight times, nine times, ten times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, or 20 times during the course of the treatment period. The formulation can be used for continuous or intermittent intravenous infusion. A formulation formulated for use without initial vasopressin dilution can be modified using an excipient, for example, any excipient disclosed herein, to improve the stability of vasopressin for long-term storage and use. Non-limiting examples of excipients that can be used in an intravenous drip-bag include dextrose, saline, half-strength saline, quarter-strength saline, Ringers Lactate solution, sodium chloride, and potassium chloride. In some embodiments, dextrose is used as an excipient for the vasopressin formulation formulated for use without initial vasopressin dilution. A formulation formulated for use without initial vasopressin dilution can be modified using a buffer, for example, any buffer disclosed herein, to adjust the pH of the formulation. A non-limiting example of a buffer that can be used in the formulation includes acetate buffer. The concentration of buffer used in the formulation can be, for example, about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, or about 30 mM. In some embodiments, the concentration of the acetate buffer is 1 mM. In some embodiments, the concentration of the acetate buffer is 10 mM. In some embodiments, an additive that is used in a formulation described herein is dextrose. The concentration of dextrose used in the formulation can be, for example, about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, or about 30 mM. In some embodiments, the concentration of dextrose is 1 mM. In some embodiments, the concentration of dextrose is 10 mM. The concentration of dextrose used in the formulation can be, for example, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%. In some embodiments, a formulation described herein contains 5% dextrose. In some embodiments, an additive that is used in a formulation described herein is sodium chloride. The concentration of sodium chloride used in the formulation can be, for example, about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, or about 30 mM. In some embodiments, the concentration of the sodium chloride is 1 mM. In some embodiments, the concentration of sodium chloride is 10 mM. In some embodiments, a combination of dextrose and sodium chloride is used in a formulation described herein. When used in combination, the concentration of sodium chloride and dextrose can be the same or different. In some embodiments, the concentration of dextrose or sodium chloride is 1 mM, or any value above 1 mM, when dextrose and sodium chloride are used in a combination in a formulation described herein. A formulation formulated for use without initial vasopressin dilution can be modified using a pH adjusting agent, for example, any pH adjusting agent disclosed herein, to adjust the pH of the formulation. Non-limiting examples of a pH adjusting agent that can be used in the formulation include acetic acid, sodium acetate, hydrochloric acid, and sodium hydroxide. The concentration of buffer used in the formulation can be, for example, about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, or about 30 mM. In some embodiments, the concentration of the acetate buffer is 1 mM. In some embodiments, the concentration of the acetate buffer is 10 mM. The formulation can be stable for and have a shelf-life of about 24 hours, about 36 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years of storage at any temperature. In some embodiments, the shelf-life of the formulation is 2 years under refrigeration. In some embodiments, the shelf-life of the formulation is 6 months at room temperature. In some embodiments, the total shelf-life of the formulation is 30 months, where the formulation is stored for 2 years under refrigeration and 6 months at room temperature. Dosage Amounts. In practicing the methods of treatment or use provided herein, therapeutically-effective amounts of the compounds described herein are administered in pharmaceutical compositions to a subject having a disease or condition to be treated. A therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors. Subjects can be, for example, humans, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, or neonates. A subject can be a patient. Pharmaceutical compositions of the invention can be formulated in any suitable volume. The formulation volume can be, for example, about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1 mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, about 1.4 mL, about 1.5 mL, about 1.6 mL, about 1.7 mL, about 1.8 mL, about 1.9 mL, about 2 mL, about 2.1 mL, about 2.2 mL, about 2.3 mL, about 2.4 mL, about 2.5 mL, about 2.6 mL, about 2.7 mL, about 2.8 mL, about 2.9 mL, about 3 mL, about 3.1 mL, about 3.2 mL, about 3.3 mL, about 3.4 mL, about 3.5 mL, about 3.6 mL, about 3.7 mL, about 3.8 mL, about 3.9 mL, about 4 mL, about 4.1 mL, about 4.2 mL, about 4.3 mL, about 4.4 mL, about 4.5 mL, about 4.6 mL, about 4.7 mL, about 4.8 mL, about 4.9 mL, about 5 mL, about 5.1 mL, about 5.2 mL, about 5.3 mL, about 5.4 mL, about 5.5 mL, about 5.6 mL, about 5.7 mL, about 5.8 mL, about 5.9 mL, about 6 mL, about 6.1 mL, about 6.2 mL, about 6.3 mL, about 6.4 mL, about 6.5 mL, about 6.6 mL, about 6.7 mL, about 6.8 mL, about 6.9 mL, about 7 mL, about 7.1 mL, about 7.2 mL, about 7.3 mL, about 7.4 mL, about 7.5 mL, about 7.6 mL, about 7.7 mL, about 7.8 mL, about 7.9 mL, about 8 mL, about 8.1 mL, about 8.2 mL, about 8.3 mL, about 8.4 mL, about 8.5 mL, about 8.6 mL, about 8.7 mL, about 8.8 mL, about 8.9 mL, about 9 mL, about 9.1 mL, about 9.2 mL, about 9.3 mL, about 9.4 mL, about 9.5 mL, about 9.6 mL, about 9.7 mL, about 9.8 mL, about 9.9 mL, about 10 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about 18 mL, about 19 mL, or about 20 mL. A therapeutically-effective amount of a compound described herein can be present in a composition at a concentration of, for example, about 0.1 units/mL, about 0.2 units/mL, about 0.3 units/mL, about 0.4 units/mL, about 0.5 units/mL, about 0.6 units/mL, about 0.7 units/mL, about 0.8 units/mL, about 0.9 units/mL, about 1 unit/mL, about 2 units/mL, about 3 units/mL, about 4 units/mL, about 5 units/mL, about 6 units/mL, about 7 units/mL, about 8 units/mL, about 9 units/mL, about 10 units/mL, about 11 units/mL, about 12 units/mL, about 13 units/mL, about 14 units/mL, about 15 units/mL, about 16 units/mL, about 17 units/mL, about 18 units/mL, about 19 units/mL, about 20 units/mL, about 21 units/mL, about 22 units/mL, about 23 units/mL, about 24 units/mL about 25 units/mL, about 30 units/mL, about 35 units/mL, about 40 units/mL, about 45 units/mL, or about 50 units/mL. A therapeutically-effective amount of a compound described herein can be present in a composition of the invention at a mass of about, for example, about 0.01 μg, about 0.05 μg, about 0.1 μg, about 0.15 μg, about 0.2 μg, about 0.25 μg, about 0.3 μg, about 0.35 μg, about 0.4 μg, about 0.5 μg, about 0.6 μg, about 0.7 μg, about 0.8 μg, about 0.9 μg, about 1 μg, about 2 μg, about 3 μg, about 4 μg, about 5 μg, about 10 μg, about 15 μg, about 20 μg, about 25 μg, about 30 μg, about 35 μg, about 40 μg, about 45 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 125 μg, about 150 μg, about 175 μg, about 200 μg, about 250 μg, about 300 μg, about 350 μg, about 400 μg, about 450 μg, about 500 μg, about 600 μg, about 700 μg, about 800 μg, about 900 μg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg. A therapeutically-effective amount of a compound described herein can be present in a composition of the invention at a concentration of, for example, about 0.001 mg/mL, about 0.002 mg/mL, about 0.003 mg/mL, about 0.004 mg/mL, about 0.005 mg/mL, about 0.006 mg/mL, about 0.007 mg/mL, about 0.008 mg/mL, about 0.009 mg/mL, about 0.01 mg/mL, about 0.02 mg/mL, about 0.03 mg/mL, about 0.04 mg/mL, about 0.05 mg/mL, about 0.06 mg/mL, about 0.07 mg/mL, about 0.08 mg/mL, about 0.09 mg/mL, about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 1.5 mg/mL, about 2 mg/mL, about 2.5 mg/mL, about 3 mg/mL, about 3.5 mg/mL, about 4 mg/mL, about 4.5 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, or about 10 mg/mL. A therapeutically-effective amount of a compound described herein can be present in a composition of the invention at a unit of active agent/unit of active time. Non-limiting examples of therapeutically-effective amounts can be, for example, about 0.01 units/minute, about 0.02 units/minute, about 0.03 units/minute, about 0.04 units/minute, about 0.05 units/minute, about 0.06 units/minute, about 0.07 units/minute, about 0.08 units/minute, about 0.09 units/minute or about 0.1 units/minute. Pharmaceutical compositions of the invention can be formulated at any suitable pH. The pH can be, for example, about 2, about 2.05, about 2.1, about 2.15, about 2.2, about 2.25, about 2.3, about 2.35, about 2.4, about 2.45, about 2.5, about 2.55, about 2.6, about 2.65, about 2.7, about 2.75, about 2.8, about 2.85, about 2.9, about 2.95, about 3, about 3.05, about 3.1, about 3.15, about 3.2, about 3.25, about 3.3, about 3.35, about 3.4, about 3.45, about 3.5, about 3.55, about 3.6, about 3.65, about 3.7, about 3.75, about 3.8, about 3.85, about 3.9, about 3.95, about 4, about 4.05, about 4.1, about 4.15, about 4.2, about 4.25, about 4.3, about 4.35, about 4.4, about 4.45, about 4.5, about 4.55, about 4.6, about 4.65, about 4.7, about 4.75, about 4.8, about 4.85, about 4.9, about 4.95, or about 5 pH units. Pharmaceutical compositions of the invention can be formulated at any suitable pH. The pH can be, for example, from about 2 to about 2.2, about 2.05 to about 2.25, about 2.1 to about 2.3, about 2.15 to about 2.35, about 2.2 to about 2.4, about 2.25 to about 2.45, about 2.3 to about 2.5, about 2.35 to about 2.55, about 2.4 to about 2.6, about 2.45 to about 2.65, about 2.5 to about 2.7, about 2.55 to about 2.75, about 2.6 to about 2.8, about 2.65 to about 2.85, about 2.7 to about 2.9, about 2.75 to about 2.95, about 2.8 to about 3, about 2.85 to about 3.05, about 2.9 to about 3.1, about 2.95 to about 3.15, about 3 to about 3.2, about 3.05 to about 3.25, about 3.1 to about 3.3, about 3.15 to about 3.35, about 3.2 to about 3.4, about 3.25 to about 3.45, about 3.3 to about 3.5, about 3.35 to about 3.55, about 3.4 to about 3.6, about 3.45 to about 3.65, about 3.5 to about 3.7, about 3.55 to about 3.75, about 3.6 to about 3.8, about 3.65 to about 3.85, about 3.7 to about 3.9, about 3.7 to about 3.8, about 3.75 to about 3.95, about 3.75 to about 3.8, about 3.8 to about 3.85, about 3.75 to about 3.85, about 3.8 to about 4, about 3.85 to about 4.05, about 3.9 to about 4.1, about 3.95 to about 4.15, about 4 to about 4.2, about 4.05 to about 4.25, about 4.1 to about 4.3, about 4.15 to about 4.35, about 4.2 to about 4.4, about 4.25 to about 4.45, about 4.3 to about 4.5, about 4.35 to about 4.55, about 4.4 to about 4.6, about 4.45 to about 4.65, about 4.5 to about 4.7, about 4.55 to about 4.75, about 4.6 to about 4.8, about 4.65 to about 4.85, about 4.7 to about 4.9, about 4.75 to about 4.95, about 4.8 to about 5, about 4.85 to about 5.05, about 4.9 to about 5.1, about 4.95 to about 5.15, or about 5 to about 5.2 pH units. In some embodiments, the addition of an excipient can change the viscosity of a pharmaceutical composition of the invention. In some embodiments the use of an excipient can increase or decrease the viscosity of a fluid by at least 0.001 Pascal-second (Pa·s), at least 0.001 Pa·s, at least 0.0009 Pa·s, at least 0.0008 Pa·s, at least 0.0007 Pa·s, at least 0.0006 Pa·s, at least 0.0005 Pa·s, at least 0.0004 Pa·s, at least 0.0003 Pa·s, at least 0.0002 Pa·s, at least 0.0001 Pa·s, at least 0.00005 Pa·s, or at least 0.00001 Pa·s. In some embodiments, the addition of an excipient to a pharmaceutical composition of the invention can increase or decrease the viscosity of the composition by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In some embodiments, the addition of an excipient to a pharmaceutical composition of the invention can increase or decrease the viscosity of the composition by no greater than 5%, no greater than 10%, no greater than 15%, no greater than 20%, no greater than 25%, no greater than 30%, no greater than 35%, no greater than 40%, no greater than 45%, no greater than 50%, no greater than 55%, no greater than 60%, no greater than 65%, no greater than 70%, no greater than 75%, no greater than 80%, no greater than 85%, no greater than 90%, no greater than 95%, or no greater than 99%. Any compound herein can be purified. A compound can be at least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 43% pure, at least 44% pure, at least 45% pure, at least 46% pure, at least 47% pure, at least 48% pure, at least 49% pure, at least 50% pure, at least 51% pure, at least 52% pure, at least 53% pure, at least 54% pure, at least 55% pure, at least 56% pure, at least 57% pure, at least 58% pure, at least 59% pure, at least 60% pure, at least 61% pure, at least 62% pure, at least 63% pure, at least 64% pure, at least 65% pure, at least 66% pure, at least 67% pure, at least 68% pure, at least 69% pure, at least 70% pure, at least 71% pure, at least 72% pure, at least 73% pure, at least 74% pure, at least 75% pure, at least 76% pure, at least 77% pure, at least 78% pure, at least 79% pure, at least 80% pure, at least 81% pure, at least 82% pure, at least 83% pure, at least 84% pure, at least 85% pure, at least 86% pure, at least 87% pure, at least 88% pure, at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least 99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, or at least 99.9% pure. Compositions of the invention can be packaged as a kit. In some embodiments, a kit includes written instructions on the administration or use of the composition. The written material can be, for example, a label. The written material can suggest conditions methods of administration. The instructions provide the subject and the supervising physician with the best guidance for achieving the optimal clinical outcome from the administration of the therapy. In some embodiments, the label can be approved by a regulatory agency, for example the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other regulatory agencies. Pharmaceutically-Acceptable Excipients. Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety. In some embodiments, the pharmaceutical composition provided herein comprises a sugar as an excipient. Non-limiting examples of sugars include trehalose, sucrose, glucose, lactose, galactose, glyceraldehyde, fructose, dextrose, maltose, xylose, mannose, maltodextrin, starch, cellulose, lactulose, cellobiose, mannobiose, and combinations thereof. In some embodiments, the pharmaceutical composition provided herein comprises a buffer as an excipient. Non-limiting examples of buffers include potassium phosphate, sodium phosphate, saline sodium citrate buffer (SSC), acetate, saline, physiological saline, phosphate buffer saline (PBS), 4-2-hydroxyethyl-1-piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), and piperazine-N,N′-bis(2-ethanesulfonic acid) buffer (PIPES), or combinations thereof. In some embodiments, a pharmaceutical composition of the invention comprises a source of divalent metal ions as an excipient. A metal can be in elemental form, a metal atom, or a metal ion. Non-limiting examples of metals include transition metals, main group metals, and metals of Group 1, Group 2, Group 3, Group 4, Group 5, Group 6, Group 7, Group 8, Group 9, Group 10, Group 11, Group 12, Group 13, Group 14, and Group 15 of the Periodic Table. Non-limiting examples of metals include lithium, sodium, potassium, cesium, magnesium, calcium, strontium, scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, palladium, silver, cadmium, tungsten, rhenium, osmium, iridium, platinum, gold, mercury, cerium, and samarium. In some embodiments, the pharmaceutical composition provided herein comprises an alcohol as an excipient. Non-limiting examples of alcohols include ethanol, propylene glycol, glycerol, polyethylene glycol, chlorobutanol, isopropanol, xylitol, sorbitol, maltitol, erythritol, threitol, arabitol, ribitol, mannitol, galactilol, fucitol, lactitol, and combinations thereof. Pharmaceutical preparations can be formulated with polyethylene glycol (PEG). PEGs with molecular weights ranging from about 300 g/mol to about 10,000,000 g/mol can be used. Non-limiting examples of PEGs include PEG 200, PEG 300, PEG 400, PEG 540, PEG 550, PEG 600, PEG 1000, PEG 1450, PEG 1500, PEG 2000, PEG 3000, PEG 3350, PEG 4000, PEG 4600, PEG 6000, PEG 8000, PEG 10,000, and PEG 20,000. Further excipients that can be used in a composition of the invention include, for example, benzalkonium chloride, benzethonium chloride, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorobutanol, dehydroacetic acid, ethylenediamine, ethyl vanillin, glycerin, hypophosphorous acid, phenol, phenylethyl alcohol, phenylmercuric nitrate, potassium benzoate, potassium metabisulfite, potassium sorbate, sodium bisulfite, sodium metabisulfite, sorbic acid, thimerasol, acetic acid, aluminum monostearate, boric acid, calcium hydroxide, calcium stearate, calcium sulfate, calcium tetrachloride, cellulose acetate pthalate, microcrystalline celluose, chloroform, citric acid, edetic acid, and ethylcellulose. In some embodiments, the pharmaceutical composition provided herein comprises an aprotic solvent as an excipient. Non-limiting examples of aprotic solvents include perfluorohexane, α,α,α-trifluorotoluene, pentane, hexane, cyclohexane, methylcyclohexane, decalin, dioxane, carbon tetrachloride, freon-11, benzene, toluene, carbon disulfide, diisopropyl ether, diethyl ether, t-butyl methyl ether, ethyl acetate, 1,2-dimethoxyethane, 2-methoxyethyl ether, tetrahydrofuran, methylene chloride, pyridine, 2-butanone, acetone, N-methylpyrrolidinone, nitromethane, dimethylformamide, acetonitrile, sulfolane, dimethyl sulfoxide, and propylene carbonate. The amount of the excipient in a pharmaceutical composition of the invention can be about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% by mass of the vasopressin in the pharmaceutical composition. The amount of the excipient in a pharmaceutical composition of the invention can be about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% by mass or by volume of the unit dosage form. The ratio of vasopressin to an excipient in a pharmaceutical composition of the invention can be about 100:about 1, about 95:about 1, about 90:about 1, about 85:about 1, about 80:about 1, about 75:about 1, about 70:about 1, about 65:about 1, about 60:about 1, about 55:about 1, about 50:about 1, about 45:about 1, about 40:about 1, about 35:about 1 about 30:about 1, about 25:about 1, about 20:about 1, about 15:about 1, about 10:about 1, about 9:about 1, about 8:about 1, about 7:about 1, about 6:about 1, about 5:about 1, about 4:about 1, about 3:about 1, about 2:about 1, about 1:about 1, about 1:about 2, about 1: about 3, about 1:about 4, about 1:about 5, about 1:about 6, about 1:about 7, about 1:about 8, about 1:about 9, or about 1:about 10. Pharmaceutically-Acceptable Salts. The invention provides the use of pharmaceutically-acceptable salts of any therapeutic compound described herein. Pharmaceutically-acceptable salts include, for example, acid-addition salts and base-addition salts. The acid that is added to the compound to form an acid-addition salt can be an organic acid or an inorganic acid. A base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base. In some embodiments, a pharmaceutically-acceptable salt is a metal salt. In some embodiments, a pharmaceutically-acceptable salt is an ammonium salt. Metal salts can arise from the addition of an inorganic base to a compound of the invention. The inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc. In some embodiments, a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt. Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the invention. In some embodiments, the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrrazole, pipyrrazole, imidazole, pyrazine, or pipyrazine. In some embodiments, an ammonium salt is a triethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrrazole salt, a pipyrrazole salt, an imidazole salt, a pyrazine salt, or a pipyrazine salt. Acid addition salts can arise from the addition of an acid to a compound of the invention. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid. In some embodiments, the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a glucaronate salt, a saccarate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate (mesylate) salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-toluenesulfonate salt, a citrate salt, an oxalate salt, or a maleate salt. Peptide Sequence. As used herein, the abbreviations for the L-enantiomeric and D-enantiomeric amino acids are as follows: alanine (A, Ala); arginine (R, Arg); asparagine (N, Asn); aspartic acid (D, Asp); cysteine (C, Cys); glutamic acid (E, Glu); glutamine (Q, Gln); glycine (G, Gly); histidine (H, His); isoleucine (I, Ile); leucine (L, Leu); lysine (K, Lys); methionine (M, Met); phenylalanine (F, Phe); proline (P, Pro); serine (S, Ser); threonine (T, Thr); tryptophan (W, Trp); tyrosine (Y, Tyr); valine (V, Val). In some embodiments, the amino acid is a L-enantiomer. In some embodiments, the amino acid is a D-enantiomer. A peptide of the disclosure can have about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% amino acid sequence homology to SEQ ID NO. 1. In some embodiments, a pharmaceutical composition of the invention comprises one or a plurality of peptides having about 80% to about 90% sequence homology to SEQ ID NO. 1, about 88% to about 90% sequence homology to SEQ ID NO. 1 or 88% to 90% sequence homology to SEQ ID NO. 1. In some embodiments, a pharmaceutical composition of the invention comprises vasopressin and one or more of a second, third, fourth, fifth, sixth, seventh, eighth, ninth, and tenth peptide. The ratio of vasopressin to another peptide in a pharmaceutical composition of the invention can be, for example, about 1000:about 1, about 990:about 1, about 980:about 1, about 970:about 1, about 960:about 1, about 950:about 1, about 800:about 1, about 700: about 1, about 600:1, about 500:about 1, about 400:about 1, about 300:about 1, about 200: about 1, about 100:about 1, about 95:about 1, about 90:about 1, about 85:about 1, about 80: about 1, about 75:about 1, about 70:about 1, about 65:about 1, about 60:about 1, about 55: about 1, about 50:about 1, about 45:about 1, about 40:about 1, about 35:about 1, about 30: about 1, about 25:about 1, about 20:about 1, about 19:about 1, about 18:about 1, about 17: about 1, about 16:about 1, about 15:about 1, about 14:about 1, about 13:about 1, about 12: about 1, about 11:about 1, or about 10:about 1. The amount of another peptide or impurity in a composition of the invention can be, for example, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% by mass of vasopressin. Another peptide or impurity present in a composition described herein can be, for example, SEQ ID NO.: 2, SEQ ID NO.: 3, SEQ ID NO.: 4, SEQ ID NO.: 5, SEQ ID NO.: 6, SEQ ID NO.: 7, SEQ ID NO.: 8, SEQ ID NO.: 9, SEQ ID NO.: 10, SEQ ID NO.: 11, SEQ ID NO.: 12, SEQ ID NO.: 13, SEQ ID NO.: 14, SEQ ID NO.: 15, SEQ ID NO.: 16, SEQ ID NO.: 17, a dimer of SEQ ID NO.: 1, an unidentified impurity, or any combination thereof. Non-limiting examples of methods that can be used to identify peptides of the invention include high-performance liquid chromatography (HPLC), mass spectrometry (MS), Matrix Assisted Laser Desorption Ionization Time-of-Flight (MALDI-TOF), electrospray ionization Time-of-flight (ESI-TOF), gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), and two-dimensional gel electrophoresis. HPLC can be used to identify peptides using high pressure to separate components of a mixture through a packed column of solid adsorbent material, denoted the stationary phase. The sample components can interact differently with the column based upon the pressure applied to the column, material used in stationary phase, size of particles used in the stationary phase, the composition of the solvent used in the column, and the temperature of the column. The interaction between the sample components and the stationary phase can affect the time required for a component of the sample to move through the column. The time required for component to travel through the column from injection point to elution is known as the retention time. Upon elution from the column, the eluted component can be detected using a UV detector attached to the column. The wavelength of light at which the component is detected, in combination with the component's retention time, can be used to identify the component. Further, the peak displayed by the detector can be used to determine the quantity of the component present in the initial sample. Wavelengths of light that can be used to detect sample components include, for example, about 200 nM, about 225 nm, about 250 nm, about 275 nm, about 300 nm, about 325 nm, about 350 nm, about 375 nm, and about 400 nm. Mass spectrometry (MS) can also be used to identify peptides of the invention. To prepare samples for MS analysis, the samples, containing the proteins of interest, are digested by proteolytic enzymes into smaller peptides. The enzymes used for cleavage can be, for example, trypsin, chymotrypsin, glutamyl endopeptidase, Lys-C, and pepsin. The samples can be injected into a mass spectrometer. Upon injection, all or most of the peptides can be ionized and detected as ions on a spectrum according to the mass to charge ratio created upon ionization. The mass to charge ratio can then be used to determine the amino acid residues present in the sample. The present disclosure provides several embodiments of pharmaceutical formulations that provide advantages in stability, administration, efficacy, and modulation of formulation viscosity. Any embodiments disclosed herein can be used in conjunction or individually. For example, any pharmaceutically-acceptable excipient, method, technique, solvent, compound, or peptide disclosed herein can be used together with any other pharmaceutically-acceptable excipient, method, technique, solvent, compound, or peptide disclosed herein to achieve any therapeutic result. Compounds, excipients, and other formulation components can be present at any amount, ratio, or percentage disclosed herein in any such formulation, and any such combination can be used therapeutically for any purpose described herein and to provide any viscosity described herein. EXAMPLES Example 1: Impurities of Vasopressin as Detected by HPLC To analyze degradation products of vasopressin that can be present in an illustrative formulation of vasopressin, gradient HPLC was performed to separate vasopressin from related peptides and formulation components. TABLE 2 below depicts the results of the experiment detailing the chemical formula, relative retention time (RRT), molar mass, and structure of vasopressin and detected impurities. Vasopressin was detected in the eluent using UV absorbance. The concentration of vasopressin in the sample was determined by the external standard method, where the peak area of vasopressin in sample injections was compared to the peak area of vasopressin reference standards in a solution of known concentration. The concentrations of related peptide impurities in the sample were also determined using the external standard method, using the vasopressin reference standard peak area and a unit relative response factor. An impurities marker solution was used to determine the relative retention times of identified related peptides at the time of analysis. Experimental conditions are summarized in TABLE 2 below. TABLE 2 Column YMC-Pack ODS-AM, 3 μm, 120Å pore, 4.6 × 100 mm Column Temperature 25° C. Flow Rate 1.0 mL/min Detector 215 nm Note: For Identification a Diode Array Detector (DAD) was used with the range of 200-400 nm. Injection Volume 100 μL Run time 55 minutes Auto sampler Vials Polypropylene vials Pump (gradient) Time (min) % A % B Flow 0 90 10 1.0 40 50 50 1.0 45 50 50 1.0 46 90 10 1.0 55 90 10 1.0 The diluent used for the present experiment was 0.25% v/v Acetic Acid, which was prepared by transferring 2.5 mL of glacial acetic acid into a 1-L volumetric flask containing 500 mL of water. The solution was diluted to the desired volume with water. Phosphate buffer at pH 3.0 was used for mobile phase A. The buffer was prepared by weighing approximately 15.6 g of sodium phosphate monobasic monohydrate into a beaker. 1000 mL of water was added, and mixed well. The pH was adjusted to 3.0 with phosphoric acid. The buffer was filtered through a 0.45 μm membrane filter under vacuum, and the volume was adjusted as necessary. An acetonitrile:water (50:50) solution was used for mobile phase B. To prepare mobile phase B, 500 mL of acetonitrile was mixed with 500 mL of water. The working standard solution contained approximately 20 units/mL of vasopressin. The standard solution was prepared by quantitatively transferring the entire contents of 1 vial of USP Vasopressin RS with diluent to a 50-mL volumetric flask. The intermediate standard solution was prepared by pipetting 0.5 mL of the working standard solution into a 50-mL volumetric flask. The sensitivity solution was prepared by pipetting 5.0 mL of the intermediate standard solution into a 50-mL volumetric flask. The solution was diluted to the volume with Diluent and mixed well. A second working standard solution was prepared as directed under the standard preparation. A portion of the vasopressin control sample was transferred to an HPLC vial and injected. The control was stable for 120 hours when stored in autosampler vials at ambient laboratory conditions. To prepare the impurities marker solution, a 0.05% v/v acetic acid solution was prepared by pipetting 200.0 mL of a 0.25% v/v acetic acid solution into a 1-L volumetric flask. The solution was diluted to the desired volume with water and mixed well. To prepare the vasopressin impurity stock solutions, the a solution of each impurity was prepared in a 25 mL volumetric flask and diluted with 0.05% v/v acetic acid to a concentration suitable for HPLC injection. To prepare the MAA/H-IBA (Methacrylic Acid/α-Hydroxy-isobutyric acid) stock solution, a stock solution containing approximately 0.3 mg/mL H-IBA and 0.01 mg/mL in 0.05% v/v acetic acid was made in a 50 mL volumetric flask. To prepare the chlorobutanol diluent, about one gram of hydrous chlorobutanol was added to 500 mL of water. Subsequently, 0.25 mL of acetic acid was added and the solution was stirred to dissolve the chlorobutanol. To prepare the impurity marker solution, vasopressin powder was mixed with the impurity stock solutions prepared above. The solutions were diluted to volume with the chlorobutanol diluent. The solutions were aliquoted into individual crimp top vials and stored at 2-8° C. At time of use, the solutions were removed from refrigeration (2-8° C.) and allowed to reach room temperature. The vasopressin impurity marker solution was stable for at least 120 hours when stored in auto-sampler vials at ambient laboratory conditions. The solution was suitable for use as long as the chromatographic peaks could be identified based on comparison to the reference chromatogram. To begin the analysis, the HPLC system was allowed to equilibrate for at least 30 minutes using mobile phase B, followed by time 0 min gradient conditions until a stable baseline was achieved. The diluent was injected at the beginning of the run, and had no peaks that interfered with Vasopressin at around 18 minutes as shown in FIG. 1. A single injection of the sensitivity solution was performed, wherein the signal-to-noise ratio of the Vasopressin was greater than or equal to ten as shown in FIG. 2. A single injection of the impurities marker solution was then made. The labeled impurities in the reference chromatogram were identified in the chromatogram of the marker solution based on their elution order and approximate retention times shown in FIG. 3 and FIG. 4. FIG. 4 is a zoomed in chromatograph of FIG. 3 showing the peaks that eluted between 15 and 30 minutes. The nomenclature, structure, and approximate retention times for individual identified impurities are detailed in TABLE 3. A single injection of the working standard solution was made to ensure that the tailing factor of the vasopressin peak was less than or equal to about 2.0 as shown in FIG. 5. A total of five replicate injections of the working standard solution were made to ensure that the relative standard deviation (% RSD) of the five replicate vasopressin peak areas was not more than 2.0%. Two replicate injections of the check standard preparation were to confirm that the check standard conformity was 99.0%-101.0%. One injection of the control sample was made to confirm that the assay of the control sample met the control limits established for the sample. Then, one injection of the working standard solution was made. Following the steps above done to confirm system suitability, a single injection of each sample preparation was made. The chromatograms were analyzed to determine the vasopressin and impurity peak areas. The chromatogram is depicted in FIG. 6. The working standard solution was injected after 1 to 4 sample injections, and the bracketing standard peak areas were averaged for use in the calculations to determine peak areas of vasopressin and associated impurities. The relative standard deviation (% RSD) of vasopressin peak areas for the six injections of working standard solution was calculated by including the initial five injections from the system suitability steps above and each of the subsequent interspersed working standard solution injections. The calculations were done to ensure that each of the % RSD were not more than 2.0%. The retention time of the major peak in the chromatogram of the sample preparation corresponded to that of the vasopressin peak in the working standard solution injection that preceded the sample preparation injection. The UV spectrum (200-400 nm) of the main peak in the chromatogram of the sample preparation compared to the UV spectrum of vasopressin in the working standard preparation. FIG. 7 depicts a UV spectrum of a vasopressin sample and FIG. 8 depicts a UV spectrum of vasopressin standard. To calculate the vasopressin units/mL, the following formula was used: Vasopressin   units  /  mL = R U R S × Conc   STD where: RU=Vasopressin peak area response of Sample preparation. RS=average vasopressin peak area response of bracketing standards. Conc STD=concentration of the vasopressin standard in units/mL To identify the impurities, the % Impurity and identity for identified impurities (TABLE 3) that are were greater than or equal to 0.10% were reported. Impurities were truncated to 3 decimal places and then rounded to 2 decimal places, unless otherwise specified. The impurities were calculated using the formula below: %   impurity = R I R S × Conc   STD 20   U  /  mL × 100  % where: RI=Peak area response for the impurity 20 U/mL=Label content of vasopressin TABLE 3 below details the chemical formula, relative retention time (RRT in minutes), molar mass, and structure of vasopressin and detected impurities. TABLE 3 Appr. Molar Name Formula RRT Mass (g) Vasopressin C46H65N15O12S2 1.00 1084.23 (Arginine Vasopressin, AVP) CYFQNCPRG—NH2 SEQ ID NO.: 1 (disulfide bridge between cys residues) Gly9-vasopressin C46H64N14O13S2 1.07 1085.22 (Gly9-AVP) CYFQNCPRG SEQ ID NO.: 2 (disulfide bridge between cys residues) Asp5-vasopressin C46H64N14O13S2 1.09 1085.22 (Asp5-AVP) CYFQDCPRG—NH2 SEQ ID NO.: 3 (disulfide bridge between cys residues) Glu4-vasopressin C46H64N14O13S2 1.12 1085.22 (Glu4-AVP) CYFENCPRG—NH2 SEQ ID NO.: 4 (disulfide bridge between cys residues) Acetyl-vasopressin C48H67N15O13S2 1.45 1126.27 (Acetyl-AVP) Ac—CYFQNCPRG—NH2 SEQ ID NO.: 7 (disulfide bridge between cys residues) D-Asn-vasopressin C46H65N15O12S2 0.97 1084.23 (DAsn-AVP) CYFQ(D-Asn)CPRG—NH2 SEQ ID NO.: 10 (disulfide bridge between cys residues) Dimeric-vasopressin C92H130N30O24S4 1.22 2168.46 (Dimer-AVP) (monomers cross linked by disulfide bridges) Example 2: Investigation of pH To determine a possible pH for a vasopressin formulation with good shelf life, vasopressin formulations were prepared in 10 mM citrate buffer diluted in isotonic saline across a range of pH. Stability was assessed via HPLC as in EXAMPLE 1 after incubation of the formulations at 60° C. for one week. FIG. 9 illustrates the results of the experiment. The greatest level of stability was observed at pH 3.5. At pH 3.5, the percent label claim (% LC) of vasopressin was highest, and the proportion of total impurities was lowest. Example 3: Effect of Peptide Stabilizers on Vasopressin Formulation To observe the effect of stabilizers on the degradation of vasopressin, a series of peptide stabilizers were added to a vasopressin formulation as detailed in TABLE 4. Stability of vasopressin was assessed via HPLC after incubation of the formulations at 60° C. for one week. TABLE 4 PEG Poloxamer n-Methylpyrrolidone Ethanol 400 Glycerol 188 HPbCDa (NMP) 1% 1% 1% 1% 1% 1% 10% 10% 10% 10% 10% 10% aHydroxypropyl beta-Cyclodextrin FIG. 10 illustrates the stability of vasopressin in terms of % label claim at varying concentrations of stabilizer. The results indicate that the tested stabilizers provided a greater stabilizing effect at 1% concentration than at 10%. Also, in several cases the stabilization effect was about 5% to about 10% greater than that observed in the experiments of EXAMPLE 2. Example 4: Effect of Buffer and Divalent Metals on Vasopressin Formulation To determine whether different combinations of buffers and use of divalent metals affect vasopressin stability, vasopressin formulations with varying concentrations of citrate and acetate buffers and variable concentrations of calcium, magnesium, and zinc ions were prepared. Solutions of 0 mM, 10 mM, 20 mM, and 80 mM calcium, magnesium, and zinc were prepared and each was combined with 1 mM or 10 mM of citrate or acetate buffers to test vasopressin stability. The tested combinations provided vasopressin stability comparable to that of a vasopressin formulation lacking buffers and divalent metals. However, that the addition of divalent metal ions was able to counteract the degradation of vasopressin caused by the use of a citrate buffer. Example 5: Illustrative Formulations for Assessment of Vasopressin Stability An aqueous formulation of vasopressin is prepared using 10% trehalose, 1% sucrose, or 5% NaCl and incubated at 60° C. for one week, at which point stability of vasopressin is assessed using HPLC. A formulation containing 50 units of vasopressin is lyophilized. The lyophilate is reconstituted with water and either 100 mg of sucrose or 100 mg of lactose, and the stability of vasopressin is tested via HPLC after incubation at 60° C. for one week. Co-solvents are added to a vasopressin solution to assess vasopressin stability. 95% solvent/5% 20 mM acetate buffer solutions are prepared using propylene glycol, DMSO, PEG300, NMP, glycerol, and glycerol:NMP (1:1), and used to create formulations of vasopressin. The stability of vasopressin is tested after incubation at 60° C. for one week. Amino acid and phosphate buffers are tested with vasopressin to assess vasopressin stability. Buffers of 10 mM glycine, aspartate, phosphate are prepared at pH 3.5 and 3.8 and used to create formulations of vasopressin. The stability of vasopressin is tested after incubation at 60° C. for one week. A vasopressin formulation in 10% polyvinylpyrrolidone is prepared to assess vasopressin stability. The stability of vasopressin will be tested after incubation at 60° C. for one week. A vasopressin formulation that contains 0.9% saline, 10 mM acetate buffer, 0.2 unit/mL API/mL in 100 mL of total volume is prepared. The pH of the solution is varied from pH 3.5-3.8 to test the stability of vasopressin. A vasopressin formulation in about 50% to about 80% DMSO (for example, about 80%), about 20% to about 50% ethyl acetate (for example, about 20%), and about 5% to about 30% polyvinylpyrrolidone (PVP) (for example, about 10% by mass of the formulation) is prepared to assess vasopressin stability. PVP K12 and PVP K17 are each independently tested in the formulation. The stability of vasopressin is tested after incubation at 60° C. for one week. A vasopressin formulation in about 70% to about 95% ethyl acetate, and about 5% to about 30% PVP is prepared to assess vasopressin stability. PVP K12 and PVP K17 are each independently tested in the formulation. The stability of vasopressin is tested after incubation at 60° C. for one week. A vasopressin formulation in 90% DMSO and 10% PVP is prepared to test vasopressin stability. PVP K12 and PVP K17 are each independently tested in the formulation. The stability of vasopressin is tested after incubation at 60° C. for one week. Example 6: Illustrative Vasopressin Formulation for Clinical Use A formulation for vasopressin that can be used in the clinic is detailed in TABLE 5 below: TABLE 5 Ingredient Function Amount (per mL) Vasopressin, USP Active Ingredient 20 Units (~0.04 mg) Chlorobutanol, Hydrous NF Preservative 5.0 mg Acetic Acid, NF pH Adjustment To pH 3.4-3.6 (~0.22 mg) Water for injection, USP/EP Diluent QS Example 7: Illustrative Regimen for Therapeutic Use of a Vasopressin Formulation Vasopressin is indicated to increase blood pressure in adults with vasodilatory shock (for example, adults who are post-cardiotomy or septic) who remain hypotensive despite fluids and catecholamines. Preparation and Use of Vasopressin. Vasopressin is supplied in a carton of 25 multi-dose vials each containing 1 mL vasopressin at 20 units/mL. Vasopressin is stored between 15° C. and 25° C. (59° F. and 77° F.), and is not frozen. Alternatively, a unit dosage form of vasopressin can be stored between 2° C. and 8° C. for about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. Vials of vasopressin are to be discarded 48 hours after first puncture. Vasopressin is prepared according to TABLE 6 below: TABLE 6 Fluid Final Mix Restriction? Concentration Vasopressin Diluent No 0.1 units/mL 2.5 mL (50 units) 500 mL Yes 1 unit/mL 5 mL (100 units) 100 mL Vasopressin is diluted in normal saline (0.9% sodium chloride) or 5% dextrose in water (D5W) prior to use to either 0.1 units/mL or 1 unit/mL for intravenous administration. Unused diluted solution is discarded after 18 hours at room temperature or after 24 hours under refrigeration. Diluted vasopressin should be inspected for particulate matter and discoloration prior to use whenever solution and container permit. The goal of treatment with vasopressin is optimization of perfusion to critical organs, but aggressive treatment can compromise perfusion of organs, like the gastrointestinal tract, for which function is difficult to monitor. Titration of vasopressin to the lowest dose compatible with a clinically-acceptable response is recommended. For post-cardiotomy shock, a dose of 0.03 units/minute is used as a starting point. For septic shock, a dose of 0.01 units/minute is recommended. If the target blood pressure response is not achieved, titrate up by 0.005 units/minute at 10- to 15-minute intervals. The maximum dose for post-cardiotomy shock is 0.1 units/minute and for septic shock 0.07 units/minute. After target blood pressure has been maintained for 8 hours without the use of catecholamines, taper vasopressin by 0.005 units/minute every hour as tolerated to maintain target blood pressure. Vasopressin is provided at 20 units per mL of diluent, which is packaged as 1 mL of vasopressin per vial, and is diluted prior to administration. Contraindications, Adverse Reactions, and Drug-Drug Interactions. Vasopressin is contraindicated in patients with known allergy or hypersensitivity to 8-L-arginine vasopressin or chlorobutanol. Additionally, use of vasopressin in patients with impaired cardiac response can worsen cardiac output. Adverse reactions have been observed with the use of vasopressin, which adverse reactions include bleeding/lymphatic system disorders, specifically, hemorrhagic shock, decreased platelets, intractable bleeding; cardiac disorders, specifically, right heart failure, atrial fibrillation, bradycardia, myocardial ischemia; gastrointestinal disorders, specifically, mesenteric ischemia; hepatobiliary disorders, specifically, increased bilirubin levels; renal/urinary disorders, specifically, acute renal insufficiency; vascular disorders, specifically, distal limb ischemia; metabolic disorders, specifically, hyponatremia; and skin disorders, specifically, and ischemic lesions. These reactions are reported voluntarily from a population of uncertain size. Thus, reliable estimation of frequency or establishment of a causal relationship to drug exposure is unlikely. Vasopressin has been observed to interact with other drugs. For example, use of vasopressin with catecholamines is expected to result in an additive effect on mean arterial blood pressure and other hemodynamic parameters. Use of vasopressin with indomethacin can prolong the effect of vasopressin on cardiac index and systemic vascular resistance. Indomethacin more than doubles the time to offset for vasopressin's effect on peripheral vascular resistance and cardiac output in healthy subjects. Further, use of vasopressin with ganglionic blocking agents can increase the effect of vasopressin on mean arterial blood pressure. The ganglionic blocking agent tetra-ethylammonium increases the pressor effect of vasopressin by 20% in healthy subjects. Use of vasopressin with furosemide increases the effect of vasopressin on osmolar clearance and urine flow. Furosemide increases osmolar clearance 4-fold and urine flow 9-fold when co-administered with exogenous vasopressin in healthy subjects. Use of vasopressin with drugs suspected of causing SIADH (Syndrome of inappropriate antidiuretic hormone secretion), for example, SSRIs, tricyclic antidepressants, haloperidol, chlorpropamide, enalapril, methyldopa, pentamidine, vincristine, cyclophosphamide, ifosfamide, and felbamate can increase the pressor effect in addition to the antidiuretic effect of vasopressin. Additionally, use of vasopressin with drugs suspected of causing diabetes insipidus for example, demeclocycline, lithium, foscarnet, and clozapine can decrease the pressor effect in addition to the antidiuretic effect of vasopressin. Halothane, morphine, fentanyl, alfentanyl and sufentanyl do not impact exposure to endogenous vasopressin. Use of Vasopressin in Specific Populations. Vasopressin is a Category C drug for pregnancy. Due to a spillover into the blood of placental vasopressinase, the clearance of exogenous and endogenous vasopressin increases gradually over the course of a pregnancy. During the first trimester of pregnancy the clearance is only slightly increased. However, by the third trimester the clearance of vasopressin is increased about 4-fold and at term up to 5-fold. Due to the increased clearance of vasopressin in the second and third trimester, the dose of vasopressin can be up-titrated to doses exceeding 0.1 units/minute in post-cardiotomy shock and 0.07 units/minute in septic shock. Vasopressin can produce tonic uterine contractions that could threaten the continuation of pregnancy. After delivery, the clearance of vasopressin returns to preconception levels. Overdosage. Overdosage with vasopressin can be expected to manifest as a consequence of vasoconstriction of various vascular beds, for example, the peripheral, mesenteric, and coronary vascular beds, and as hyponatremia. In addition, overdosage of vasopressin can lead less commonly to ventricular tachyarrhythmias, including Torsade de Pointes, rhabdomyolysis, and non-specific gastrointestinal symptoms. Direct effects of vasopressin overdose can resolve within minutes of withdrawal of treatment. Pharmacology of Vasopressin. Vasopressin is a polypeptide hormone that causes contraction of vascular and other smooth muscles and antidiuresis, which can be formulated as a sterile, aqueous solution of synthetic arginine vasopressin for intravenous administration. The 1 mL solution contains vasopressin 20 units/mL, chlorobutanol, NF 0.5% as a preservative, and water for injection, USP adjusted with acetic acid to pH 3.4-3.6. The chemical name of vasopressin is Cyclo (1-6) L-Cysteinyl-L-Tyrosyl-L-Phenylalanyl-L-Glutaminyl-L-Asparaginyl-L-Cysteinyl-L-Prolyl-L-Arginyl-L-Glycinamide. Vasopressin is a white to off-white amorphous powder, freely soluble in water. The structural formula of vasopressin is: Molecular Formula: C46H65N15O12S2; Molecular Weight: 1084.23 One mg of vasopressin is equivalent to 530 units. Alternatively, one mg of vasopressin is equivalent to 470 units. The vasoconstrictive effects of vasopressin are mediated by vascular V1 receptors. Vascular V1 receptors are directly coupled to phopholipase C, resulting in release of calcium, leading to vasoconstriction. In addition, vasopressin stimulates antidiuresis via stimulation of V2 receptors which are coupled to adenyl cyclase. At therapeutic doses, exogenous vasopressin elicits a vasoconstrictive effect in most vascular beds including the splanchnic, renal, and cutaneous circulation. In addition, vasopressin at pressor doses triggers contractions of smooth muscles in the gastrointestinal tract mediated by muscular V1-receptors and release of prolactin and ACTH via V3 receptors. At lower concentrations typical for the antidiuretic hormone, vasopressin inhibits water diuresis via renal V2 receptors. In patients with vasodilatory shock, vasopressin in therapeutic doses increases systemic vascular resistance and mean arterial blood pressure and reduces the dose requirements for norepinephrine. Vasopressin tends to decrease heart rate and cardiac output. The pressor effect is proportional to the infusion rate of exogenous vasopressin. Onset of the pressor effect of vasopressin is rapid, and the peak effect occurs within 15 minutes. After stopping the infusion, the pressor effect fades within 20 minutes. There is no evidence for tachyphylaxis or tolerance to the pressor effect of vasopressin in patients. At infusion rates used in vasodilatory shock (0.01-0.1 units/minute), the clearance of vasopressin is 9 to 25 mL/min/kg in patients with vasodilatory shock. The apparent half-life of vasopressin at these levels is ≦10 minutes. Vasopressin is predominantly metabolized and only about 6% of the dose is excreted unchanged in urine. Animal experiments suggest that the metabolism of vasopressin is primarily by liver and kidney. Serine protease, carboxipeptidase and disulfide oxido-reductase cleave vasopressin at sites relevant for the pharmacological activity of the hormone. Thus, the generated metabolites are not expected to retain important pharmacological activity. Carcinogenesis, Mutagenesis, Impairment of Fertility. Vasopressin was found to be negative in the in vitro bacterial mutagenicity (Ames) test and the in vitro Chinese hamster ovary (CHO) cell chromosome aberration test. In mice, vasopressin can have an effect on function and fertilizing ability of spermatozoa. Clinical Studies. Increases in systolic and mean blood pressure following administration of vasopressin were observed in seven studies in septic shock and eight studies in post-cardiotomy vasodilatory shock. Example 8: Effect of Temperature on Vasopressin Formulations To test the effect of temperature on the stability of vasopressin formulation, solutions containing 20 units/mL vasopressin and chlorobutanol, adjusted to pH 3.5 with acetic acid, were prepared. One mL of each vasopressin formulations was then filled into 3 cc vials. Each Vasopressin Formulation was stored either inverted or upright for at least three months, up to 24 months, at: (i) 5° C.; (ii) 25° C. and 60% relative humidity; or (iii) 40° C. and 75% humidity, and the amount of vasopressin (U/mL) and % total impurities were measured periodically. TABLES 7-12 below display the results of the experiments at 5° C. The results of the experiments at 25° C. are included in TABLES 13-18. All of the experiments were performed in triplicate. The results of the experiments at 40° C. are included in TABLES 19-24. For each temperature tested, three lots of the vasopressin formulation were stored for 24 months (5° C. and 25° C.) and 3 months (40° C.), and measurements were taken at regular intervals during the testing periods. “NMT” as used in the tables denotes “not more than.” The vasopressin and impurity amounts observed in the experiments conducted at 5° C. are shown in TABLES 7-12 below (AVP=Vasopressin). TABLE 7 Samples stored inverted at 5° C. Time in months Test Initial 1 2 3 6 9 12 18 24 AVP 19.4 19.4 19.4 19.3 19.5 19.4 19.5 19.4 19.3 Assay Total 2.3% 2.0% 2.1% 2.3% 2.2% 2.3% 2.6% 2.9% 2.9% Impu- rities TABLE 8 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 U/mL 19.7 19.7 19.7 19.7 19.9 19.7 19.8 19.7 19.5 Assay Total 2.7% 2.2% 2.3% 2.4% 2.1% 2.3% 2.7% 2.9% 2.9% Impurities: NMT 17.0% TABLE 9 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 U/mL 19.7 19.7 19.6 19.7 19.8 19.7 19.9 19.8 19.5 Assay Total 2.2% 1.9% 2.0% 2.2% 2.0% 2.1% 2.4% 2.6% 2.8% Impurities: NMT 17.0% TABLE 10 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 U/mL 19.4 19.5 19.4 19.4 19.5 19.5 19.5 19.4 19.3 Assay Total 2.3% 2.1% 2.1% 2.3% 2.1% 2.3% 2.5% 2.9% 2.9% Impurities: NMT 17.0% TABLE 11 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 19.7 19.7 19.6 19.7 19.8 19.7 19.8 19.7 19.5 Assay U/mL Total 2.7% 2.1% 2.2% 2.2% 2.2% 2.3% 2.6% 2.9% 2.8% Impurities: NMT 17.0% TABLE 12 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 19.7 19.7 19.6 19.7 19.8 19.7 19.9 19.8 19.5 Assay U/mL Total 2.2% 1.8% 2.0% 2.2% 2.2% 2.1% 2.4% 2.8% 2.7% Impurities: NMT 17.0% The vasopressin and impurity amounts observed in the experiments conducted at 25° C. and 60% relative humidity are shown in TABLES 13-18 below. TABLE 13 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 19.8 19.4 19.1 18.8 18.3 17.5 17.3 Assay U/mL Total 1.1% 2.4% 3.7% 4.7% 5.9% 9.0% 13.6% Impurities: NMT 17.0% TABLE 14 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 20.1 19.7 19.3 19 18.6 17.6 17.6 Assay U/mL Total 1.3% 2.5% 3.4% 4.6% 5.6% 9.0% 13.4% Impurities: NMT 17.0% TABLE 15 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 19.9 19.6 19.2 19 18.7 18 17.4 Assay U/mL Total 1.5% 2.6% 3.3% 4.6% 5.9% 9.0% 12.9% Impurities: NMT 17.0% TABLE 16 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 19.8 19.4 19.1 18.8 18.3 17.5 17.4 Assay U/mL Total 1.1% 2.4% 3.2% 4.8% 5.6% 9.2% 13.1% Impurities: NMT 17.0% TABLE 17 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 20.1 19.7 19.4 18.9 18.6 17.8 17.7 Assay U/mL Total 1.3% 2.5% 3.3% 4.5% 5.7% 9.1% 13.3% Impurities: NMT 17.0% TABLE 18 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 19.9 19.6 19.2 19 18.5 18.1 17.4 Assay U/mL Total 1.5% 2.5% 3.7% 4.7% 5.9% 9.1% 13.3% Impurities: NMT 17.0% The vasopressin and impurity amounts observed in the experiments conducted at 40° C. and 75% relative humidity are shown in TABLES 19-24 below. TABLE 19 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.8 19.1 18.6 17.3 Assay Total Impurities: 1.1% 3.7% 7.3% 10.6% NMT 17.0% TABLE 20 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.8 18.9 18.5 17.2 Assay Total Impurities: 1.1% 3.6% 7.2% 10.3% NMT 17.0% TABLE 21 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 20.1 19.3 18.7 17.6 Assay Total Impurities: 1.3% 3.6% 7.3% 10.3% NMT 17.0% TABLE 22 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 20.1 18.9 18.7 17.4 Assay Total Impurities: 1.3% 3.5% 7.1% 10.2% NMT 17.0% TABLE 23 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.9 19.2 18.3 17.4 Assay Total Impurities: 1.5% 3.7% 6.3% 10.3% NMT 17.0% TABLE 24 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.9 19.2 18.3 17.5 Assay Total Impurities: 1.5% 3.8% 6.3% 10.5% NMT 17.0% The results of the above experiments suggested that storage in either an upright or inverted position did not markedly affect the stability of vasopressin. The samples held at 5° C. exhibited little fluctuation in vasopressin amounts over 24 months, and the amount of total impurities did not increase above 3% during the testing period (TABLES 7-12). The samples held at 25° C. and 60% relative humidity exhibited a decrease in vasopressin amount of about 10-12% after 24 months (TABLES 13-18). The amount of impurities observed in the samples stored at 25° C. and 60% relative humidity after 24 months exceeded 13% in some samples, whereas the amount of impurities observed in the samples stored at 5° C. did not exceed 3% after 24 months. After about three months, the samples held at 40° C. exhibited a decrease in the amount of vasopressin of about 10-12%. The amount of impurities observed at 40° C. exceeded 10% after three months, whereas the amount of impurities observed in the samples stored at 5° C. was less than 3% after three months (TABLES 19-24). Experiments were also conducted on the same samples above over the course of the experiments to measure the amount of individual impurities in the samples, pH of the samples, chlorobutanol content, particulate matter, antimicrobial effectiveness, and bacterial endotoxin levels (TABLES 25-42). (NR=no reading; ND=not determined; UI=unidentified impurity). The anti-microbial effectiveness of the solution was established to determine the amount of antimicrobial agents in the formulation that protect against bacterial contamination. The bullets in the tables below indicate that the sample was not tested for anti-microbial effectiveness at that specific time point. The bacterial endotoxin levels were also measured for some of the formulations. The bullets in the tables below indicate that the sample was not tested for bacterial endotoxin levels at that specific time point. TABLE 25 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.4 19.4 19.4 19.3 19.5 19.4 19.5 19.4 19.3 Assay U/mL Related SEQ ID 0.5% 0.5% 0.6% 0.6% 0.6% 0.6% 0.7% 0.8% 0.9% Substances NO.: 2 NMT 6.0% SEQ ID 0.6% 0.6% 0.6% 0.7% 0.7% 0.7% 0.8% 0.9% 1.0% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP- NR NR NR NR NR NR NR NR NR Dimer: NMT 1.0% Acetyl- 0.3% 0.2% 0.3% 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.84: NR NR 0.1% NR NR NR NR NR NR NMT 1.0% UI-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.1% NR 0.1% NR NR NR NR NR NR NMT 1.0% Total 2.3% 2.0% 2.1% 2.3% 2.2% 2.3% 2.6% 2.9% 2.9% Impurities: NMT 17.0% pH 2.5-4.5 3.5 3.5 3.5 3.5 3.5 3.5 3.5 3.8 3.5 Chlorobutanol 0.25-0.60% 0.48% 0.49% 0.48% 0.48% 0.47% 0.48% 0.48% 0.49% 0.49% w/v Particulate NMT 6000 0 1 1 1 2 16 2 4 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 26 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.7 19.7 19.7 19.7 19.9 19.7 19.8 19.7 19.5 Assay U/mL Related SEQ ID 0.6% 0.5% 0.5% 0.6% 0.5% 0.6% 0.7% 0.8% 0.8% Substances NO.: 2: NMT 6.0% SEQ ID 0.6% 0.6% 0.6% 0.6% 0.6% 0.7% 0.7% 0.8% 0.9% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.4% 0.3% 0.4% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR NR NR NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.75- 0.2% 0.2% 0.2% 0.2% NR 0.1% 0.2% 0.2% 0.2% 0.78: NMT 1.0% UI-0.83- 0.1% 0.1% 0.1% NR 0.1% NR NR NR NR 0.84: NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% Total 2.7% 2.2% 2.3% 2.4% 2.1% 2.3% 2.7% 2.9% 2.9% Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 Chlorobutanol 0.25-0.60% 0.48% 0.48% 0.48% 0.47% 0.48% 0.48% 0.49% 0.48% 0.49% w/v Particulate NMT 6000 1 1 1 1 1 15 2 3 2 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 27 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.7 19.7 19.6 19.7 19.8 19.7 19.9 19.8 19.5 Assay U/mL Related SEQ ID 0.5% 0.5% 0.5% 0.5% 0.5% 0.6% 0.6% 0.8% 0.8% Substances NO.: 2: NMT 6.0% SEQ ID 0.5% 0.5% 0.5% 0.6% 0.6% 0.7% 0.7% 0.8% 0.9% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR NR NR NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.75- NR NR NR NR NR NR NR NR NR 0.78: NMT 1.0% UI-0.83- NR NR 0.1% NR NR NR NR NR 0.1% 0.84: NMT 1.0% UI-1.02- 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% 1.03: NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.76: NR NR NR 0.1% NR NR NR NR NR NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.1% NR NR NR NR NR NR NR NR NMT 1.0% Total 2.2% 1.9% 2.0% 2.2% 2.0% 2.1% 2.4% 2.6% 2.8% Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.5 3.6 3.5 3.5 3.5 3.6 3.5 3.5 Chlorobutanol 0.25-0.60% 0.47% 0.48% 0.47% 0.47% 0.47% 0.47% 0.48% 0.48% 0.48% w/v Particulate NMT 6000 1 2 1 2 1 4 2 1 3 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 28 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.4 19.5 19.4 19.4 19.5 19.5 19.5 19.4 19.3 Assay U/mL Related SEQ ID 0.5% 0.6% 0.6% 0.6% 0.6% 0.6% 0.7% 0.8% 0.9% Substances NO.: 2: NMT 6.0% SEQ ID 0.6% 0.6% 0.6% 0.7% 0.7% 0.7% 0.7% 0.9% 1.0% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP- NR NR NR NR NR NR NR NR NR Dimer: NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.84: NR NR 0.1% NR NR NR NR NR NR NMT 1.0% UI-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.1% NR NR NR NR NR NR NR NR NMT 1.0% Total 2.3% 2.1% 2.1% 2.3% 2.1% 2.3% 2.5% 2.9% 2.9% Impurities: NMT 17.0% pH 2.5-4.5 3.5 3.5 3.5 3.5 3.5 3.5 3.5 3.8 3.5 Chlorobutanol 0.25-0.60% 0.48% 0.48% 0.48% 0.48% 0.48% 0.48% 0.48% 0.49% 0.49% w/v Particulate NMT 6000 0 2 2 2 1 2 2 4 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 29 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.7 19.7 19.6 19.7 19.8 19.7 19.8 19.7 19.5 Assay U/mL Related SEQ ID 0.6% 0.5% 0.5% 0.5% 0.6% 0.6% 0.6% 0.8% 0.7% Substances NO.: 2: NMT 6.0% SEQ ID 0.6% 0.6% 0.6% 0.6% 0.6% 0.7% 0.7% 0.8% 0.8% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR NR NR NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.2% 0.3% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.75- 0.2% 0.2% NR 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% 0.78: NMT 1.0% UI-0.83- 0.1% NR 0.1% NR NR NR NR NR NR 0.84: NMT 1.0% UI-1.02- 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% 0.3% 0.3% 0.2% 1.03: NMT 1.0% UI-1.67: NR NR NR 0.2% NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% Total 2.7% 2.1% 2.2% 2.2% 2.2% 2.3% 2.6% 2.9% 2.8% Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 Chlorobutanol 0.25-0.60% 0.48% 0.48% 0.48% 0.48% 0.48% 0.48% 0.49% 0.49% 0.49% w/v Particulate NMT 6000 1 1 1 2 2 6 4 4 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 30 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.7 19.7 19.6 19.7 19.8 19.7 19.9 19.8 19.5 Assay U/mL Related SEQ ID 0.5% 0.5% 0.5% 0.5% 0.5% 0.6% 0.6% 0.8% 0.8% Substances NO.: 2: NMT 6.0% SEQ ID 0.5% 0.5% 0.5% 0.6% 0.6% 0.7% 0.7% 0.8% 0.9% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% NR 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR NR NR NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.2% 0.3% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.75- NR NR NR NR 0.2% NR NR NR NR 0.78: NMT 1.0% UI-0.83- NR NR 0.1% NR NR NR NR 0.1% NR 0.84: NMT 1.0% UI-1.02- 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% 1.03: NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.76: NR NR NR 0.1% NR NR NR NR NR NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.1% NR NR NR NR NR NR NR NR NMT 1.0% Total 2.2% 1.8% 2.0% 2.2% 2.2% 2.1% 2.4% 2.8% 2.7% Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.5 3.6 3.5 3.5 3.5 3.6 3.5 3.5 Chlorobutanol 0.25-0.60% 0.47% 0.48% 0.47% 0.47% 0.48% 0.47% 0.48% 0.48% 0.48% w/v Particulate NMT 6000 1 1 1 1 1 3 2 1 3 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 31 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 19.8 19.4 19.1 18.8 18.3 17.5 17.3 — Assay Related SEQ ID NO.: 2: 0.1% 0.5% 1.1% 1.6% 2.0% 3.3% 4.6% — Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 0.6% 1.2% 1.8% 2.2% 3.7% 5.2% — NMT 6.0% SEQ ID NO.: 10: 0.3% 0.4% 0.5% 0.5% 0.4% 0.2% 0.3% — NMT 1.0% Asp5-AVP: NR 0.1% 0.3% 0.4% 0.5% 0.7% 1.0% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% 0.2% 0.2% 0.3% — NMT 1.0% UI-0.83: NR NR <0.10 NR NR NR 0.1% — NMT 1.0% UI-0.99: NR NR NR NR 0.1% NR NR — NMT 1.0% UI-1.03: 0.2% 0.2% 0.3% 0.3% 0.3% 0.2% 0.2% — NMT 1.0% UI-1.14: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% — NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.22: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.56-1.57: NR NR <0.10 0.1% 0.1% 0.2% 0.2% — NMT 1.0% UI-1.60: NR NR NR 0.1% 0.1% 0.2% NR — NMT 1.0% UI-1.74: NR NR NR NR NR 0.2% NR — NMT 1.0% UI-1.85-1.88: NR 0.2% NR NR NR 0.1% 0.1% — NMT 1.0% UI-2.09-2.10: NR 0.2% NR NR NR NR 0.4% — NMT 1.0% UI-2.15-2.16: NR NR 0.1% NR NR NR 0.5% — NMT 1.0% Total Impurities: 1.1% 2.4% 3.7% 4.7% 5.9% 9.0% 13.6% — NMT 17.0% pH 2.5-4.5 3.5 3.5 3.5 3.5 3.4 3.3 3.2 — Chlorobutanol 0.25-0.60% w/v 0.49% 0.48% 0.48% 0.47% 0.47% 0.48% 0.47 — Particulate NMT 6000 1 1 1 1 8 4 1 — Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) AntiMicrobial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 32 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 20.1 19.7 19.3 19 18.6 17.6 17.6 — Assay Related SEQ ID NO.: 2: 0.1% 0.5% 0.9% 1.5% 1.9% 3.1% 4.4% — Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 0.5% 1.1% 1.6% 2.2% 3.4% 4.9% — NMT 6.0% SEQ ID NO.: 10: 0.3% 0.4% 0.3% 0.4% 0.3% 0.4% 0.3% — NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.3% 0.4% 0.7% 0.9% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% 0.2% 0.2% 0.3% — NMT 1.0% UI-0.75-0.76: NR 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% — NMT 1.0% UI-0.83: 0.2% NR 0.1% NR NR 0.1% 0.1% — NMT 1.0% UI-0.99: NR NR NR NR 0.1% NR NR — NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.3% 0.2% — NMT 1.0% UI-1.14: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% — NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.22: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.56-1.57: NR NR 0.1% 0.1% 0.2% 0.2% 0.2% — NMT 1.0% UI-1.60: NR NR 0.1% 0.1% 0.2% 0.2% NR — NMT 1.0% UI-1.74: NR NR NR NR NR 0.2% NR — NMT 1.0% UI-1.85-1.88: NR 0.2% NR NR NR 0.1% 0.1% — NMT 1.0% UI-2.09-2.10: NR 0.2% NR NR NR NR 0.4% — NMT 1.0% UI-2.15-2.16: NR NR NR NR NR NR 0.6% — NMT 1.0% Total Impurities: 1.3% 2.5% 3.4% 4.6% 5.6% 9.0% 13.4% — NMT 17.0% pH 2.5-4.5 3.6 3.6 3.5 3.5 3.2 3.3 3.4 — Chlorobutanol 0.25-0.60% w/v 0.48% 0.49% 0.48% 0.47% 0.47% 0.47% 0.47 — Particulate NMT 6000 2 1 1 3 4 1 2 — Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) AntiMicrobial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 33 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 19.9 19.6 19.2 19 18.7 18 17.4 — Assay Related SEQ ID NO.: 2: 0.2% 0.5% 1.0% 1.5% 2.0% 3.2% 4.5% — Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 0.6% 1.1% 1.8% 2.2% 3.7% 5.0% — NMT 6.0% SEQ ID NO.: 10: 0.4% 0.4% 0.3% 0.4% 0.4% 0.3% 0.5% — NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.4% 0.5% 0.7% 1.0% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR 0.1% — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% — NMT 1.0% UI-0.12: NR 0.1% NR NR NR NR NR NMT 1.0% UI-0.75-0.76: NR NR NR NR NR NR NR NMT 1.0% UI-0.83-0.84: NR 0.1% 0.1% 0.1% 0.1% 0.1% NMT 1.0% UI-0.93: NR NR NR NR NR NR 0.1% NMT 1.0% UI-0.99: NR NR NR NR NR NR NR NMT 1.0% UI-1.02-1.03: 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% 0.3% — NMT 1.0% UI-1.15: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% NMT 1.0% UI-1.20: NR NR NR NR NR NR NR NMT 1.0% UI-1.22: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.26: NR NR NR NR NR NR NMT 1.0% UI-1.35: 0.3% NR NR NR NR NR NR NMT 1.0% UI-1.56-1.57: NR NR 0.1% NR 0.1% 0.2% 0.3% NMT 1.0% UI-1.60: NR NR 0.1% NR 0.1% NR NR — NMT 1.0% UI-1.74: NR NR NR NR NR NR NR NMT 1.0% UI-1.84-1.89: NR 0.1% NR NR NR NR 0.2% NMT 1.0% UI-1.96: 0.2% NR NR NR NR NR NR NMT 1.0% UI-2.09-2.10: NR 20.0% NR NR NR <0.10 0.1% NMT 1.0% UI-2.15-2.16: NR NR 0.1% NR NR 0.1% NR NMT 1.0% Total Impurities: 1.5% 2.6% 3.3% 4.6% 5.9% 9.0% 12.9% — NMT 17.0% pH 2.5-4.5 3.6 3.5 3.5 3.5 3.4 3.4 3.3 — Chlorobutanol 0.25-0.60% w/v 0.48% 0.47% 0.47% 0.46% 0.46% 0.46% 0.45% — Particulate NMT 6000 1 2 3 3 3 1 2 — Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) Anti-Microbial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 34 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 19.8 19.4 19.1 18.8 18.3 17.5 17.4 — Assay Related SEQ ID NO.: 2: 0.1% 0.5% 1.1% 1.6% 2.0% 3.2% 4.5% — Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 0.6% 1.2% 1.8% 2.3% 3.6% 5.0% — NMT 6.0% SEQ ID NO.: 10: 0.3% 0.4% 0.3% 0.4% 0.3% 0.2% 0.3% — NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.4% 0.4% 0.7% 0.9% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% 0.2% 0.2% 0.3% — NMT 1.0% UI-0.83: NR NR <0.10 NR NR 0.1% 0.1% — NMT 1.0% UI-0.99: NR NR NR NR NR NR NR — NMT 1.0% UI-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.2% — NMT 1.0% UI-1.14: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% — NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.22: NR NR NR NR NR NR NR — NMT 1.0% UI-1.56-1.57: NR NR NR 0.1% 0.1% 0.2% 0.2% — NMT 1.0% UI-1.60: NR NR NR NR NR 0.1% NR — NMT 1.0% UI-1.74: NR NR NR NR NR 0.2% NR — NMT 1.0% UI-1.85-1.88: NR 0.2% NR NR NR 0.1% 0.1% — NMT 1.0% UI-2.09-2.10: NR 0.2% NR NR NR NR 0.3% — NMT 1.0% UI-2.15-2.16: NR NR NR NR NR NR 0.5% — NMT 1.0% Total Impurities: 1.1% 2.4% 3.2% 4.8% 5.6% 9.2% 13.1% — NMT 17.0% pH 2.5-4.5 3.5 3.5 3.5 3.5 3.4 3.3 3.3 — Chlorobutanol 0.25-0.60% w/v 0.49% 0.48% 0.48% 0.48% 0.47% 0.48% 0.47 — Particulate NMT 6000 1 2 2 2 2 4 2 — Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) AntiMicrobial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 35 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 20.1 19.7 19.4 18.9 18.6 17.8 17.7 — Assay Related SEQ ID NO.: 2: 0.1% 0.5% 0.9% 1.4% 1.9% 3.1% 4.3% — Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 0.5% 1.1% 1.6% 2.2% 3.4% 4.9% — NMT 6.0% D-Asn-AVP: 0.3% 0.4% 0.3% 0.3% 0.3% 0.4% 0.3% — NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.3% 0.4% 0.7% 0.9% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl-AVP: 0.30% 0.30% 0.30% 0.20% 0.20% 0.20% 0.3% — NMT 1.0% UI-0.75-0.76: NR 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% NMT 1.0% UI-0.83: 0.2% NR <0.10 NR NR 0.1% 0.1% NMT 1.0% UI-0.99: NR NR NR NR 0.1% NR NR NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.2% 0.2% 0.3% 0.2% — NMT 1.0% UI-1.14: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.22: NR NR NR NR NR NR 0.4% NMT 1.0% UI-1.56-1.57: NR NR 0.1% 0.1% 0.2% 0.2% 0.3% NMT 1.0% UI-1.60: NR NR 0.1% 0.1% 0.2% 0.2% NR — NMT 1.0% UI-1.74: NR NR NR NR NR 0.2% NR NMT 1.0% UI-1.85-1.88: NR 0.2% NR NR NR 0.1% 0.1 NMT 1.0% UI-2.09-2.10: NR 0.2% NR NR NR 0.1% 0.3 NMT 1.0% UI-2.15-2.16: NR NR NR NR NR 0.5 NMT 1.0% Total Impurities: 1.3% 2.5% 3.3% 4.5% 5.7% 9.1% 13.3% — NMT 17.0% pH 2.5-4.5 3.6 3.6 3.5 3.5 3.4 3.3 3.3 — Chlorobutanol 0.25-0.60% w/v 0.48% 0.49% 0.48% 0.47% 0.47% 0.48% 0.46 — Particulate NMT 6000 2 1 1 2 5 1 4 — Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) Anti-Microbial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 36 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 19.9 19.6 19.2 19 18.5 18.1 17.4 — Assay Related SEQ ID NO.: 2: 0.2% 0.5% 1.0% 1.5% 2.1% 3.3% 4.7% — Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 0.6% 1.1% 1.7% 2.3% 3.7% 5.3% — NMT 6.0% D-Asn-AVP: 0.4% 0.4% 0.3% 0.4% 0.4% 0.3% 0.5% — NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.3% 0.5% 0.7% 1.0% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% — NMT 1.0% UI-0.12: NR NR NR NR NR NR NR NMT 1.0% UI-0.75-0.76: NR NR NR NR NR NR NR NMT 1.0% UI-0.83-0.84: NR 0.1% 0.1% 0.1% NR 0.1% 0.1% NMT 1.0% UI-0.93: NR NR NR NR NR NR 0.1% NMT 1.0% UI-0.99: NR NR NR NR NR NR NR NMT 1.0% UI-1.02-1.03: 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% 0.3% — NMT 1.0% UI-1.15: NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.22: NR NR NR NR NR NR NR NMT 1.0% UI-1.26: NR NR 0.4% NR NR NR NR NMT 1.0% UI-1.35: 0.1% NR NR NR NR NR NR NMT 1.0% UI-1.56-1.57: NR NR 0.1% 0.1% NR 0.2% 0.3% NMT 1.0% UI-1.60: NR NR NR NR NR NR NR — NMT 1.0% UI-1.74: NR NR NR NR NR NR NR NMT 1.0% UI-1.84-1.89: NR 0.1% NR NR NR NR 0.2% NMT 1.0% UI-1.96: 0.2% NR NR NR NR NR NR NMT 1.0% UI-2.09-2.10: NR NR NR NR NR <0.10 NR NMT 1.0% UI-2.15-2.16: NR NR 0.1% NR NR 0.2% NR NMT 1.0% Total Impurities: 1.5% 2.5% 3.7% 4.7% 5.9% 9.1% 13.3% — NMT 17.0% pH 2.5-4.5 3.6 3.5 3.5 3.5 3.4 3.4 3.3 — Chlorobutanol 0.25-0.60% w/v 0.48% 0.48% 0.47% 0.47% 0.46% 0.45 0.46 — Particulate NMT 6000 1 0 1 3 7 0 3 — Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) Anti-Microbial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 37 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin Assay 18.0-21.0 U/mL 19.8 19.1 18.6 17.3 Related Substances SEQ ID NO.: 2: 0.1% 1.0% 2.4% 3.8% NMT 6.0% SEQ ID NO.: 4: 0.1% 1.1% 2.7% 4.3% NMT 6.0% D-Asn-AVP: 0.3% 0.4% 0.3% 0.3% NMT 1.0% Asp5-AVP: ND 0.2% 0.5% 0.8% NMT 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.2% 0.2% 0.2% NMT 1.0% UI-0.13: ND 0.1% ND ND NMT 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.83-0.84: ND ND ND ND NMT 1.0% UI-1.02-1.03: 0.2% 0.3% 0.2% 0.3% NMT 1.0% UI-1.18: ND ND ND 0.2% NMT 1.0% UI-1.56-1.57: ND 0.2% 0.4% 0.4% NMT 1.0% UI-1.67: ND ND ND ND NMT 1.0% UI-1.76: ND ND ND ND NMT 1.0% UI-1.83-1.85: ND ND 0.2% 0.2% NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT 1.0% UI-1.93: ND 0.1% ND ND NMT 1.0% UI-2.05-2.08: ND ND 0.2% ND NMT 1.0% Total Impurities: 1.1% 3.7% 7.3% 10.6% NMT 17.0% pH 2.5-4.5 3.5 3.3 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.49% 0.48% 0.50% 0.47% Particulate Matter (USP) NMT 6000 1 1 1 1 (≧10 μm) NMT 600 0 0 0 0 (≧25 μm) TABLE 38 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin Assay 18.0-21.0 U/mL 20.1 19.3 18.7 17.6 Related Substances SEQ ID NO.: 2: 0.1% 0.9% 2.2% 3.6% NMT 6.0% SEQ ID NO.: 4: 0.1% 1.0% 2.5% 3.9% NMT 6.0% D-Asn-AVP: 0.3% 0.4% 0.3% 0.3% NMT 1.0% Asp5-AVP: ND 0.2% 0.5% 0.8% NMT 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.2% 0.3% 0.2% NMT 1.0% UI-0.13: ND 0.1% ND ND NMT 1.0% UI-0.75-0.78: ND ND 0.2% 0.2% NMT 1.0% UI-0.80-0.84: 0.2% 0.2% ND ND NMT 1.0% UI-1.02-1.03: 0.2% 0.3% 0.2% 0.3% NMT 1.0% UI-1.18: ND ND 0.3% 0.2% NMT 1.0% UI-1.56-1.57: ND 0.2% ND 0.4% NMT 1.0% UI-1.67: ND ND ND ND NMT 1.0% UI-1.76: ND ND ND ND NMT 1.0% UI-1.81-1.85: ND ND 0.2% 0.2% NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT 1.0% UI-1.93: ND 0.1% ND ND NMT 1.0% UI-2.03-2.08: ND ND 0.2% 0.1% NMT 1.0% UI-2.14: ND ND 0.2% ND NMT 1.0% Total Impurities: 1.3% 3.6% 7.3% 10.3% NMT 17.0% pH 2.5-4.5 3.6 3.3 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.48% 0.48% 0.50% 0.47% Particulate Matter (USP) NMT 6000 2 2 1 1 (≧10 μm) NMT 600 0 0 0 0 (≧25 μm) TABLE 39 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin Assay 18.0-21.0 U/mL 19.9 19.2 18.3 17.4 Related Substances SEQ ID NO.: 2: 0.2% 0.9% 2.2% 3.8% NMT 6.0% SEQ ID NO.: 4: 0.1% 1.0% 2.4% 4.0% NMT 6.0% D-Asn-AVP: 0.4% 0.3% 0.3% 0.3% NMT 1.0% Asp5-AVP: ND 0.2% 0.5% 0.8% NMT 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% NMT 1.0% UI-0.13: ND ND ND ND NMT 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.80-0.84: ND ND ND ND NMT 1.0% UI-1.02-1.03: 0.3% 0.2% 0.2% 0.3% NMT 1.0% UI-1.18: ND ND ND 0.2% NMT 1.0% UI-1.35: 0.1% ND ND ND NMT 1.0% UI-1.52-1.58: ND 0.2% 0.3% 0.4% NMT 1.0% UI-1.67: ND ND ND ND NMT 1.0% UI-1.76: ND ND ND ND NMT 1.0% UI-1.81-1.85: ND ND ND ND NMT 1.0% UI-1.86-1.88: ND 0.1% 0.2% ND NMT 1.0% UI-1.91-1.96: 0.2% 0.2% ND ND NMT 1.0% UI-2.02-2.08: ND ND ND 0.2% NMT 1.0% UI-2.11-2.14: ND 0.2% ND ND NMT 1.0% Total Impurities : 1.5% 3.7% 6.3% 10.3% NMT 17.0% pH 2.5-4.5 3.6 3.4 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.48% 0.47% 0.46% 0.46% Particulate Matter (USP) NMT 6000 2 2 1 1 (≧10 μm) NMT 600 0 0 0 0 (≧25 μm) TABLE 40 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin Assay 18.0-21.0 U/mL 19.8 18.9 18.5 17.2 Related Substances SEQ ID NO.: 2: 0.1% 1.0% 2.4% 3.8% NMT 6.0% SEQ ID NO.: 4: 0.1% 1.1% 2.7% 4.3% NMT 6.0% D-Asn-AVP: 0.3% 0.3% 0.3% 0.3% NMT 1.0% Asp5-AVP: ND 0.2% 0.5% 0.8% NMT 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% UI-0.13: ND 0.1% ND ND NMT 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.83-0.84: ND ND ND ND NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.2% NMT 1.0% UI-1.18: ND ND ND 0.2% NMT 1.0% UI-1.56-1.57: ND 0.2% 0.3% 0.3% NMT 1.0% UI-1.67: ND ND ND ND NMT 1.0% UI-1.76: ND ND ND ND NMT 1.0% UI-1.83-1.85: ND ND 0.2% ND NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT 1.0% UI-1.93: ND 0.1% ND ND NMT 1.0% UI-2.05-2.08: ND ND 0.2% ND NMT 1.0% Total Impurities: 1.1% 3.6% 7.2% 10.3% NMT 17.0% Total Impurities: 1.1% 3.6% 7.2% 10.3% NMT 17.0% pH 2.5-4.5 3.5 3.3 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.49% 0.48% 0.50% 0.48% Particulate Matter (USP) NMT 6000 1 1 1 1 (≧10 μm) NMT 600 0 0 0 0 (≧25 μm) TABLE 41 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin Assay 18.0-21.0 U/mL 20.1 18.9 18.7 17.4 Related Substances SEQ ID NO.: 2: 0.1% 0.9% 2.3% 3.7% NMT 6.0% SEQ ID NO.: 4: 0.1% 1.0% 2.5% 3.9% NMT 6.0% D-Asn-AVP: 0.3% 0.4% 0.3% 0.3% NMT 1.0% Asp5-AVP: ND 0.2% 0.5% 0.8% NMT 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.2% 0.3% 0.2% NMT 1.0% UI-0.13: ND ND ND ND NMT 1.0% UI-0.75-0.78: ND ND 0.2% 0.2% NMT 1.0% UI-0.80-0.84: 0.2% 0.2% ND ND NMT 1.0% UI-1.02-1.03: 2.0% 0.3% 0.2% 0.3% NMT 1.0% UI-1.18: ND ND ND 0.2% NMT 1.0% UI-1.56-1.57: ND 0.2% 0.4% 0.4% NMT 1.0% UI-1.67: ND ND ND ND NMT 1.0% UI-1.76: ND ND ND ND NMT 1.0% UI-1.83-1.85: ND ND 0.2% 0.1% NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT 1.0% UI-1.93: ND 0.1% ND ND NMT 1.0% UI-2.05-2.08: ND ND 0.2% ND NMT 1.0% UI-2.14: ND ND ND ND NMT 1.0% Total Impurities: 1.3% 3.5% 7.1% 10.2% NMT 17.0% pH 2.5-4.5 3.6 3.3 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.48% 0.48% 0.49% 0.47% Particulate Matter (USP) NMT 6000 2 1 1 1 (≧10 μm) NMT 600 0 0 0 0 (≧25 μm) TABLE 42 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin Assay 18.0-21.0 U/mL 19.9 19.2 18.3 17.5 Related Substances SEQ ID NO.: 2: 0.2% 1.0% 2.2% 3.9% NMT 6.0% SEQ ID NO.: 4: 0.1% 1.1% 2.4% 4.2% NMT 6.0% D-Asn-AVP: 0.4% 0.3% 0.3% 0.3% NMT 1.0% Asp5-AVP: ND 0.2% 50.0% 0.8% NMT 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% NMT 1.0% UI-0.13: ND ND ND ND NMT 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.80-0.84: ND ND ND ND NMT 1.0% UI-1.02-1.03: 0.3% 0.2% 0.2% 0.3% NMT 1.0% UI-1.18: ND ND ND 0.2% NMT 1.0% UI-1.35: 0.1% ND ND ND NMT 1.0% UI-1.52-1.58: ND 0.2% 0.3% 0.4% NMT 1.0% UI-1.67: ND ND ND ND NMT 1.0% UI-1.76: ND ND ND ND NMT 1.0% UI-1.83-1.85: ND ND ND ND NMT 1.0% UI-1.86-1.88: ND 0.1% 0.2% ND NMT 1.0% UI-1.91-1.96: 0.2% 0.2% ND ND NMT 1.0% UI-2.02-2.08: ND ND ND 0.1% NMT 1.0% UI-2.11-2.14: ND 0.2% ND ND NMT 1.0% Total Impurities: 1.5% 3.8% 6.3% 10.5% NMT 17.0% pH 2.5-4.5 3.6 3.4 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.48% 0.47% 0.47% 0.45% Particulate Matter (USP) NMT 6000 1 2 1 1 (≧10 μm) NMT 600 0 0 0 0 (≧25 μm) Example 9: Effect of pH 3.5-4.5 on Vasopressin Formulations To test of effect of pH on vasopressin formulations, solutions containing 20 units/mL vasopressin, adjusted to pH 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, or 4.5 with 10 mM acetate buffer, were prepared. One mL of each of the vasopressin formulations was then filled into 10 cc vials. The vasopressin formulations were stored for four weeks at: (i) 25° C.; or (ii) 40° C., and the assay (% label claim; vasopressin remaining) and % total impurities after four weeks were measured using the methods described in EXAMPLE 1. FIGS. 11 and 12 below display the results of the experiments at 25° C. The results of the experiments at 40° C. are included in FIGS. 13 and 14. The results of the experiments suggested that the stability of a vasopressin formulation was affected by pH. At 25° C., the remaining vasopressin after four weeks was highest between pH 3.6 and pH 3.8 (FIG. 11). Within the range of pH 3.6 to pH 3.8, the level of impurities was lowest at pH 3.8 (FIG. 12). At 25° C., pH 3.7 provided the highest stability for vasopressin (FIG. 11). At 40° C., the remaining vasopressin after four weeks was highest between pH 3.6 and pH 3.8 (FIG. 13). Within the range of pH 3.6 to pH 3.8, the level of impurities was lowest at pH 3.8 (FIG. 14). At 40° C., pH 3.6 provided the highest stability for vasopressin (FIG. 13), Example 10: Effect of pH 2.5-4.5 of Vasopressin Formulations To test of effect of pH on vasopressin formulations, solutions containing 20 units/mL vasopressin, adjusted to pH 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, or 3.4 with 10 mM acetate buffer were also prepared. One mL of each of the vasopressin formulations was then filled into 10 cc vials. The amount of vasopressin, impurities, and associated integration values were determined using the methods describes in EXAMPLE 1. The results from the stability tests on the vasopressin formulations from pH 2.5 to 3.4 were plotted against the results from the stability tests on vasopressin formulations from pH 3.5 to 4.5 as disclosed in EXAMPLE 9, and are displayed in FIGS. 15-18. The assay (% label claim; vasopressin remaining) and % total impurities in the vasopressin pH 2.5 to 3.4 formulations after four weeks are reported in TABLE 43. TABLE 43 Target Vasopressin % Total Batch pH Week Condition (% LC) Impurities 1A 2.5 0 25° C. 100.57 2.48 1B 2.6 0 25° C. 101.25 2.24 1C 2.7 0 25° C. 101.29 2.26 1D 2.8 0 25° C. 101.53 2.00 1E 2.9 0 25° C. 102.33 1.95 1F 3 0 25° C. 102.32 1.89 1G 3.1 0 25° C. 102.59 2.06 1H 3.2 0 25° C. 102.60 1.85 1I 3.3 0 25° C. 102.73 1.81 1J 3.4 0 25° C. 101.93 1.75 1A 2.5 0 40° C. 100.57 2.48 1B 2.6 0 40° C. 101.25 2.24 1C 2.7 0 40° C. 101.29 2.26 1D 2.8 0 40° C. 101.53 2.00 1E 2.9 0 40° C. 102.33 1.95 1F 3 0 40° C. 102.32 1.89 1G 3.1 0 40° C. 102.59 2.06 1H 3.2 0 40° C. 102.60 1.85 1I 3.3 0 40° C. 102.73 1.81 1J 3.4 0 40° C. 101.93 1.75 1A 2.5 4 25° C. 95.70 6.66 1B 2.6 4 25° C. 98.58 5.29 1C 2.7 4 25° C. 98.94 4.26 1D 2.8 4 25° C. 99.14 3.51 1E 2.9 4 25° C. 100.08 3.41 1F 3 4 25° C. 100.29 2.92 1G 3.1 4 25° C. 100.78 2.55 1H 3.2 4 25° C. 100.74 2.16 1I 3.3 4 25° C. 100.46 2.14 1J 3.4 4 25° C. 100.25 2.03 1A 2.5 4 40° C. 81.89 19.41 1B 2.6 4 40° C. 90.10 15.60 1C 2.7 4 40° C. 92.19 13.46 1D 2.8 4 40° C. 94.89 10.98 1E 2.9 4 40° C. 96.03 9.78 1F 3 4 40° C. 97.26 8.09 1G 3.1 4 40° C. 99.61 6.39 1H 3.2 4 40° C. 98.58 5.25 1I 3.3 4 40° C. 97.81 4.41 1J 3.4 4 40° C. 97.35 3.85 The % total impurities for the pH 2.5 to 3.4 formulations and the pH 3.5 to 4.5 formulations observed in the experiments conducted at 25° C. and 40° C. are shown in FIGS. 15 (25° C.) and 16 (40° C.). The vasopressin assay amount for the vasopressin pH 2.5 to 3.4 formulations and the vasopressin pH 3.5 to 4.5 formulations observed in the experiments conducted at 25° C. and 40° C. are shown in FIGS. 17 (25° C.) and 18 (40° C.). The vasopressin assay is presented as a % assay decrease of vasopressin over the four-week study period, rather than absolute assay, because the amount of starting vasopressin varied between the vasopressin pH 2.5 to 3.4 formulations and the vasopressin pH 3.5 to 4.5 formulations. The results of the above experiments suggested that the stability of a vasopressin formulation was affected by pH. At 25° C., the percent decrease in vasopressin after four weeks was lowest between pH 3.7 and pH 3.8 (FIG. 17). Within the range of pH 3.7 to pH 3.8, the level of impurities was lowest at pH 3.8 (FIG. 15). At 40° C., the percent decrease in vasopressin after four weeks was lowest between pH 3.6 and pH 3.8 (FIG. 18). Within the range of pH 3.6 to pH 3.8, the level of impurities was lowest at pH 3.8 (FIG. 16). Example 11: Intra-Assay and Inter-Analysis Precision of Vasopressin pH Experiments The methods used to determine the % assay decrease and amount of impurities in the vasopressin solutions over time in EXAMPLE 10 had both intra-assay and inter-analyst precision. Intra-assay precision was demonstrated by performing single injections of aliquots of a vasopressin formulation (n=6; Chemist 1) from a common lot of drug product and determining the assay and repeatability (% RSD; relative standard deviation). Inter-analyst precision was demonstrated by two different chemists testing the same lot of drug product; however, the chemists used different instruments, reagents, standard preparations, columns, and worked in different laboratories. The procedure included a common pooling of 20 vials of vasopressin, which were assayed by the two chemists using different HPLC systems and different HPLC columns. The vasopressin assay results (units/mL) and repeatability (% RSD for n=6) were recorded and are reported in the TABLE 44 below. TABLE 44 Precision of Vasopressin Results. Chemist 1 Chemist 2 Sample (units/mL) (units/mL) 1 19.74 19.65 2 19.76 19.66 3 19.77 19.66 4 19.75 19.72 5 19.97 19.73 6 19.65 19.73 Mean 19.8 19.7 % RSD (≦2.0%) 0.5% 0.2% % Difference = 0.5% (acceptance criteria: ≦3.0%) %   Difference = ( Chemist   1 Mean - Chemist   2 Mean ) ( Chemist   1 Mean + Chemist   2 Mean ) × 200 The intra-assay repeatability met the acceptance criteria (% RSD≦2.0%) with values of 0.5% and 0.2%. The inter-analyst repeatability also met the acceptance criteria (% difference≦3.0%) with a difference of 0.5%. Example 12: Effect of Citrate Versus Acetate Buffer on Vasopressin Formulations To test the effect of citrate and acetate buffer on vasopressin formulations, a total of twelve solutions of 20 Units/mL vasopressin were prepared in 1 mM citrate buffer, 10 mM citrate buffer, 1 mM acetate buffer, and 10 mM acetate buffer. All of the solutions were prepared in triplicate. Each solution was adjusted to pH 3.5 with hydrochloric acid. The vasopressin formulations were stored at 60° C. for 7 days, and the assay (% label claim; vasopressin remaining) and % total impurities after 7 days were analyzed by HPLC using the procedure and experimental conditions described in EXAMPLE 1. The assay (% label claim; vasopressin remaining) and % total impurities for each of the Vasopressin Buffered Formulations are reported in the TABLES 45 and 46 below. TABLE 45 Assay (% label claim; vasopressin remaining) in the vasopressin formulations after storage at 60° C. for 7 days. Sample Buffer 1 2 3 Average 1 mM citrate buffer 89.5% 89.7% 90.6% 89.9% 10 mM citrate buffer 84.1% 84.4% 84.5% 84.3% 1 mM acetate buffer 90.5% 91.1% 91.9% 91.2% 10 mM acetate buffer 90.9% 90.9% 92.4% 91.4% TABLE 46 % Total Impurities in the vasopressin formulations after storage at 60° C. for 7 days. Sample Buffer 1 2 3 Average 1 mM citrate buffer 3.4% 3.5% 2.5% 3.1% 10 mM citrate buffer 9.5% 9.0% 9.4% 9.3% 1 mM acetate buffer 3.3% 2.8% 3.2% 3.1% 10 mM acetate buffer 2.9% 2.6% 3.1% 2.9% The data indicated that the vasopressin assay in the vasopressin formulations with citrate buffer was lower than in the vasopressin formulations with acetate buffer. For example, at 10 mM of either citrate or acetate buffer, the average vasopressin assay was 91.4% in acetate buffer, but was 84.3% in citrate buffer. The data also indicated that % total impurities in the vasopressin formulations with citrate buffer were higher than in the vasopressin formulations with acetate buffer. For example, at 10 mM of either citrate or acetate buffer, the average % total impurities was 2.9% in acetate buffer, but was 9.3% in citrate buffer. Further, as the citrate buffer concentration increased, the vasopressin assay further decreased (from an average of 89.9% to 84.3%), and the % total impurities increased (from an average of 3.1% to 9.3%). This effect was not observed in the vasopressin formulations with acetate buffer, where the average and % total impurities stayed fairly constant. Example 13: Multi-Dose Vasopressin Formulation A multi-dose formulation (10 mL) for vasopressin that can be used in the clinic is detailed in TABLE 47 below: TABLE 47 Drug Product Description Vasopressin, 20 Units USP Active Ingredient (~0.04 mg) Dosage Form Injection — Route of Intravenous — Administration Description Clear colorless to practically colorless solution supplied in a 10 mL clear glass vial with flip-off cap The composition of a 10 mL formulation of vasopressin is provided below. TABLE 48 Drug Product Composition Ingredient Grade Function Batch Quantity Unit Formula Vasopressin, USP Active 3,000,000 Units 20 Units USP Sodium Acetate USP Buffer 214.2 g 1.36 mg Trihydrate Sodium NF pH Adjustor 40 g QS to pH 3.8 Hydroxide Hydrochloric NF/EP pH Adjustor 237.9 g QS to pH 3.8 Acid Chlorobutanol NF Preservative 0.8274 kg 5 mg Water for USP Solvent QS QS to 1 mL Injection Nitrogen NF Processing — — Aid The 10 mL vasopressin formulation was compared to the guidelines for inactive ingredients provided by the Food and Drug Administration (FDA). The results are shown in TABLE 49 below. TABLE 49 Vasopressin Inactive 10 mL Ingredients Formulation Concentration Guideline Ingredient (mg/mL) (% w/v) Acceptable Level Sodium Acetate 1.36 0.136% IV (infusion); Trihydrate Injection 0.16% Sodium Hydroxide QS to pH 3.8 QS to pH 3.8 N/A Hydrochloric Acid QS to pH 3.8 QS to pH 3.8 N/A Chlorobutanol 5 mg 0.5% IV (Infusion); Injection 1% Water for Injection QS to 1 mL QS to target N/A volume Example 14: Alternative Vasopressin Formulation for Clinical Use A 1 mL dosage of vasopressin was prepared. A description of the formulation is shown in TABLE 50 below. TABLE 50 Drug Product Description Vasopressin, 20 Units/mL USP Active Ingredient (~0.04 mg) Dosage Form Injection — Route of Intravenous — Administration Description Clear colorless to practically colorless — solution supplied in a 3 mL vial with flip-off cap The drug composition of the formulation is provided in TABLE 51. TABLE 51 Drug Product Composition Ingredient Function Quantity (mg/mL) Vasopressin, USP Active 20 Units Sodium Acetate Trihydrate, USP Buffer 1.36 Sodium Hydroxide NF/EP pH Adjustor QS for pH adjustment to pH 3.8 Hydrochloric Acid, NF/EP pH Adjustor QS for pH adjustment to pH 3.8 Water for Injection Solvent QS to 1 mL The 1 mL vasopressin formulation was compared to the guidelines for inactive ingredients provided by the Food and Drug Administration (FDA). The results are shown in TABLE 52 below. TABLE 52 Vasopressin 1 mL Inactive Ingredients Formulation Concentration Guideline Ingredient (mg/mL) (% w/v) Acceptable Level Sodium Acetate 1.36 0.136% 0.16% Trihydrate Sodium Hydroxide QS to pH 3.8 QS to pH 3.8 8% Hydrochloric Acid QS to pH 3.8 QS to pH 3.8 10% Water for Injection QS to 1 mL QS to target N/A volume Example 15: 15-Month Stability Data for Vasopressin Formulations The drug product detailed in TABLE 51 was tested for stability over a 15-month period. Three different lots (X, Y, and Z) of the vasopressin drug formulation were stored at 25° C. for 15 months in an upright or inverted position. At 0, 1, 2, 3, 6, 9, 12, 13, 14, and 15 months, the amount of vasopressin (AVP), % label claim (LC), amount of various impurities, and pH was measured. The vasopressin and impurity amounts were determined using the HPLC method described above in EXAMPLE 1. The results of the stability experiment are shown in TABLES 53-54 below. TABLE 53 Inverted Storage of Vasopressin Formulations at 25° C. UI- UI UI- UI- UI- UI- UI- UI- AVP Ace- 0.81- 0.97 1.02- 1.72- 1.81- 1.90- 2.05- 2.09- Total (U/ % Gly9 Glu4 D-Asn Asp5 Dimer tyl 0.86 0.99 1.03 1.76 1.89 1.96 2.07 2.10 Impuri- Lot Month mL) LC (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) ties pH X 0 19.6 97.9 0.3 0.4 0.3 1.0 3.8 Y 0 19.7 98.6 0.3 0.4 0.3 1.1 3.8 Z 0 19.9 99.3 0.1 0.5 0.2 0.8 3.8 X 1 19.6 98.1 0.2 0.2 0.1 0.4 0.4 0.3 1.6 3.8 Y 1 19.6 97.9 0.2 0.2 0.1 0.4 0.4 0.3 1.6 3.9 Z 1 19.8 99 0.2 0.2 0.6 0.1 0.2 1.4 3.8 X 2 19.6 98.1 0.3 0.3 0.1 0.3 0.4 0.3 1.7 3.7 Y 2 19.5 97.5 0.2 0.3 0.1 0.3 0.4 0.3 1.6 3.8 Z 2 19.8 99 0.3 0.4 0.5 0.2 1.3 3.8 X 3 19.6 97.8 0.4 0.5 0.1 0.1 0.3 0.4 0.4 2.2 Y 3 19.5 97.4 0.4 0.4 0.1 0.3 0.4 0.4 2.0 3.8 Z 3 19.7 98.6 0.4 0.4 0.5 0.3 1.6 X 6 19.3 96.5 0.7 0.8 0.1 0.2 0.3 0.4 0.4 2.9 3.8 Y 6 19.2 95.9 0.6 0.7 0.1 0.1 0.1 0.3 0.4 0.4 2.5 3.9 Z 6 19.6 98 0.6 0.7 0.1 0.5 0.2 2.3 3.9 X 9 19 95 1.0 1.0 0.2 0.3 0.4 0.4 0.1 3.6 Y 9 18.9 94.5 0.8 1.0 0.2 0.3 0.4 0.4 0.1 3.1 3.9 Z 9 19.2 96 1.0 1.1 0.2 0.5 0.3 3.1 3.8 X 12 18.7 93.5 1.4 1.5 0.1 0.3 0.3 0.4 0.5 0.2 4.8 3.8 Y 12 18.6 93 1.1 1.2 0.2 0.2 0.3 0.4 0.5 0.3 0.2 4.4 3.8 Z 12 18.9 94.5 1.2 1.3 0.3 0.5 0.3 0.3 0.1 4.0 3.8 X 13 18.6 93 1.5 1.6 0.2 0.3 0.4 0.4 0.1 0.4 0.2 0.1 5.2 3.8 Y 13 18.5 92.5 1.2 1.3 0.2 0.3 0.3 0.4 0.1 0.5 0.1 0.4 0.2 0.2 5.2 3.9 Z 13 19 95 1.3 1.5 0.1 0.3 0.5 0.1 0.3 0.1 0.3 0.2 0.2 4.9 3.8 X 14 18.6 93 1.5 1.7 0.1 0.3 0.3 0.5 0.1 0.4 0.4 0.1 0.1 5.5 3.8 Y 14 18.5 92.5 1.2 1.4 0.1 0.3 0.3 0.5 0.1 0.4 0.5 0.2 0.2 5.3 3.9 Z 14 18.9 94.5 1.3 1.6 0.3 0.5 0.2 0.3 0.4 0.2 0.2 5.0 3.8 X 15 18.5 92.5 1.6 1.8 0.1 0.4 0.3 0.4 0.1 0.4 0.3 0.2 0.2 5.9 3.8 Y 15 18.4 92 1.3 1.5 0.1 0.3 0.3 0.4 0.1 0.4 0.5 0.3 0.1 5.3 3.9 Z 15 18.8 94 1.5 1.6 0.3 0.5 0.3 0.4 0.2 0.1 4.9 3.9 TABLE 54 Upright Storage of Vasopressin Formulations at 25° C. UI- UI UI- UI- UI- UI- UI- UI- AVP Ace- 0.81- 0.97 1.02- 1.72- 1.81- 1.90- 2.05- 2.09- Total (U/ % Gly9 Glu4 D-Asn Asp5 Dimer tyl 0.86 0.99 1.03 1.76 1.89 1.96 2.07 2.10 Impuri- Lot Month mL) LC (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) ties pH X 0 19.6 97.9 0.3 0.4 0.3 1.0 3.8 Y 0 19.7 98.6 0.3 0.4 0.3 1.1 3.8 Z 0 19.9 99.3 0.1 0.5 0.2 0.8 3.8 X 1 19.6 98 0.2 0.2 0.1 0.3 0.4 0.3 1.6 3.8 Y 1 19.5 97.7 0.2 0.2 0.3 0.4 0.3 1.4 3.9 Z 1 19.7 98.3 0.2 0.2 0.6 0.2 1.2 3.8 X 2 19.6 98.2 0.3 0.3 0.3 0.4 0.3 1.6 3.7 Y 2 19.5 97.4 0.2 0.3 0.1 0.4 0.4 0.3 1.6 3.8 Z 2 19.8 99 0.3 0.3 0.5 0.2 1.3 3.8 X 3 19.5 97.6 0.4 0.4 0.1 0.3 0.4 0.4 2.1 3.7 Y 3 19.5 97.5 0.4 0.4 0.1 0.4 0.4 1.9 3.8 Z 3 19.7 98.7 0.4 0.4 0.1 0.5 0.3 1.7 X 6 19.3 96.5 0.7 0.8 0.1 0.2 0.3 0.4 0.4 2.9 3.8 Y 6 19.2 96 0.5 0.7 0.1 0.1 0.3 0.4 0.4 2.5 3.9 Z 6 19.5 97.5 0.7 0.7 0.2 0.5 0.3 2.3 3.9 X 9 18.9 94.5 1.0 1.1 0.2 0.3 0.4 0.2 0.1 3.7 3.8 Y 9 18.9 94.5 0.8 0.9 0.2 0.4 0.4 0.2 3.1 3.9 Z 9 19.2 96 0.9 1.0 0.2 0.5 0.3 2.9 3.8 X 12 18.6 93 1.4 1.5 0.1 0.3 0.3 0.4 0.5 0.2 0.1 4.8 3.7 Y 12 18.7 93.5 1.1 1.2 0.1 0.3 0.3 0.4 0.5 0.2 0.2 4.6 3.9 Z 12 18.9 94.5 1.3 1.4 0.3 0.5 0.4 0.3 0.2 4.2 3.8 X 13 18.4 92 1.5 1.6 0.2 0.3 0.3 0.4 0.1 0.4 0.3 0.1 0.1 5.4 3.8 Y 13 18.6 93 1.1 1.3 0.2 0.3 0.3 0.4 0.1 0.4 0.3 0.2 4.6 3.9 Z 13 18.8 94 1.3 1.5 0.3 0.5 0.1 0.3 0.4 0.2 0.1 4.7 3.8 X 14 18.6 93 1.5 1.7 0.1 0.4 0.3 0.4 0.1 0.4 0.3 0.1 5.4 3.8 Y 14 18.5 92.5 1.2 1.4 0.1 0.3 0.3 0.5 0.4 0.5 0.3 0.3 5.4 3.9 Z 14 18.8 94 1.3 1.5 0.3 0.5 0.1 0.3 0.5 0.2 0.2 5.0 3.8 X 15 18.4 92 1.6 1.8 0.1 0.4 0.3 0.4 0.1 0.4 0.3 0.2 5.7 3.8 Y 15 18.4 92 1.3 1.5 0.2 0.3 0.3 0.4 0.1 0.4 0.5 0.3 0.3 5.4 3.9 Z 15 18.6 93 1.5 1.6 0.3 0.5 0.2 0.4 0.2 0.3 5.1 3.9 The results from TABLES 53-54 indicate that stability of the vasopressin formulations was not significantly affected by either inverted or upright storage. The impurities detected included Gly9 (SEQ ID NO.: 2), Glu4 (SEQ ID NO.: 4), D-Asn (SEQ ID NO.: 10), Asp5 (SEQ ID NO.: 3), Acetyl-AVP (SEQ ID NO.: 7), vasopressin dimer, and several unidentified impurities (UI). The unidentified impurities are labeled with a range of relative retention times at which the impurities eluted from the column. The results indicate that the pH remained fairly constant over the 15-month period, fluctuating between 3.8 and 3.9 throughout the 15 months. The total impurities did not increase over 5.9%, and the % LC of vasopressin did not decrease below 92%. FIG. 19 shows a graph depicting the % LC over the 15-month study period for the results provided in TABLES 53-54. The starting amounts of vasopressin were 97.9% LC for lot X, 98.6% LC for lot Y, and 99.3% LC for lot Z. The results indicate that the % LC of vasopressin decreased over the 15-month study period, but did not decrease below 92% LC. The formula for the trend line of lot X was: % LC=98.6−0.4262(month) The formula for the trend line of lot Y was: % LC=98.47−0.4326(month) The formula for the trend line of lot Z was: % LC=99.54−0.3906(month) Example 16: Vasopressin Formulation for Bottle or Intravenous Drip-Bag The following formulations can be used without initial vasopressin dilution in drip-bags for intravenous therapy. TABLE 55 Formulation A (40 IU/100 mL) (10 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Sodium chloride (mg) 8.7 Acetic acid (mg) 0.546 Sodium Acetate Trihydrate (mg) 0.12 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 56 Formulation B (60 IU/100 mL) (10 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.6 Sodium chloride (mg) 8.7 Acetic acid (mg) 0.546 Sodium Acetate Trihydrate (mg) 0.12 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 57 Formulation C (40 IU/100 mL) (10 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Dextrose Anhydrous (mg) 50 Acetic acid (mg) 0.546 Sodium Acetate Trihydrate (mg) 0.12 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 58 Formulation D (60 IU/100 mL) (10 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.6 Dextrose Anhydrous (mg) 50 Acetic acid (mg) 0.546 Sodium Acetate Trihydrate (mg) 0.12 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 59 Formulation E (40 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Sodium chloride (mg) 8.7 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 60 Formulation F (60 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.6 Sodium chloride (mg) 8.7 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 61 Formulation G (40 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Dextrose Anhydrous (mg) 50 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 62 Formulation H (60 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.6 Dextrose Anhydrous (mg) 50 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 63 Formulation 9 (60 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Dextrose Anhydrous (mg) 45 Sodium Chloride (mg) 0.9 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Example 17: Impurity Measurement for Vasopressin Formulation for Bottle or Intravenous Drip-Bag Gradient HPLC was used to determine the concentration of vasopressin and associated impurities in vasopressin formulations similar to those outlined in TABLES 55-63 above. Vasopressin was detected in the eluent using UV absorbance at a short wavelength. The concentration of vasopressin in the sample was determined by the external standard method, where the peak area of vasopressin in sample injections was compared to the peak area of a vasopressin reference standard in a solution of known concentration. The concentrations of related peptide impurities in the sample were also determined using the external standard method, using the vasopressin reference standard peak area and a unit relative response factor. An impurities marker solution was used to determine the relative retention times of identified related peptides at the time of analysis. The chromatographic conditions used for the analysis are shown in TABLE 64 below: TABLE 64 Column Phenomenex Kinetex XB-C18, 2.6 μm, 100 Å pore, 4.6 × 150 mm, Part No. 00F-4496-E0 Column 35° C. Temperature Flow Rate 1.0 mL/min Detector VWD: Signal at 215 nm Injection Volume 500 μL Run time 55 minutes Auto sampler Vials Amber glass vial Auto Sampler 10° C. Temperature Pump (gradient) Time (min) % A % B Flow 0 90 10 1.0 40 50 50 1.0 45 50 50 1.0 46 90 10 1.0 55 90 10 1.0 Diluent A was 0.25% v/v acetic acid, which was prepared by pipetting 2.5 mL of glacial acetic acid into a 1 L volumetric flask containing 500 mL of water. The volume was diluted with water and mixed well. Diluent B was prepared by weighing and transferring about 3 g of sodium chloride into a 1 L volumetric flask and then adding 2.5 mL of glacial acetic acid. The solution was diluted to volume with water and mixed well. Phosphate buffer at pH 3.0 was used for mobile phase A. The buffer was prepared by weighing approximately 15.6 g of sodium phosphate monobasic monohydrate into a beaker. 1000 mL of water was added, and mixed well. The pH was adjusted to 3.0 with phosphoric acid. The buffer was filtered through a 0.45 μm membrane filter under vacuum, and the volume was adjusted as necessary. An acetonitrile:water (50:50) solution was used for mobile phase B. To prepare mobile phase B, 500 mL of acetonitrile was mixed with 500 mL of water. The stock standard solution was prepared at 20 units/mL of vasopressin. A solution of vasopressin in diluent was prepared at a concentration of about 20 units/mL. The stock standard solution was prepared by quantitatively transferring the entire contents of 5 vials of USP Vasopressin RS with diluent A to the same 250-mL volumetric flask. The solution was diluted to volume with diluent A and mixed well. 10 mL aliquots of the standard solution was transferred into separate polypropylene tubes. The aliquots were stored at 2-8° C. The stock standard solution was stable for 6 months from the date of preparation when stored in individual polypropylene tubes at 2-8° C. The working standard solution contained about 0.5 units/mL of vasopressin. Aliquots of the stock standard solution were allowed to warm to room temperature and then mixed well. 2.5 mL of the stock standard solution was transferred into a 100 mL volumetric flask and diluted to volume with Diluent B, and the resultant mixture was denoted as the Working Standard Solution. The stock standard solution and working standard solution can also be prepared from a single vasopressin vial in the following manner. One vial of vasopressin with diluent A can be quantitatively transferred to a 50-mL volumetric flask. The solution can be dissolved in and diluted to volume with diluent A and mixed well, and denoted as the stock standard solution. To prepare the working standard solution, 2.5 mL of the stock standard solution was diluted to 100 mL with diluent B and mixed well. The working standard solution was stable for at least 72 hours when stored in refrigerator or in autosampler vial at 10° C. The intermediate standard solution was prepared by pipetting 1 mL of the working standard solution into a 50 mL volumetric flask. The solution was diluted to volume with diluent B and mixed well. The sensitivity solution (0.1% of 0.4 units/mL vasopressin formulation) was prepared by pipetting 2 mL of the intermediate standard solution into a 50 mL volumetric flask. The solution was diluted to the volume with diluent B and mixed well. The sensitivity solution was stable for at least 72 hours when stored in the refrigerator. To prepare the impurities marker solution, a 0.05% v/v acetic acid solution was prepared by pipetting 200 mL of a 0.25% v/v acetic acid solution into a 1 L volumetric flask. The solution was diluted to the desired volume with water and mixed well. To prepare the vasopressin impurity stock solutions, the a solution of each impurity as shown below was prepared in a 25 mL volumetric flask and diluted with 0.05% v/v acetic acid to a concentration suitable for HPLC injection. Gly-9 AVP: 0.09 mg/mL Glu-4 AVP: 0.08 mg/mL Asp-5 AVP: 0.1 mg/mL D-Asn AVP: 0.08 mg/mL Dimer AVP: 0.07 mg/mL Acetyl AVP: 0.08 mg/mL To prepare the MAA/H-IBA (Methacrylic Acid/α-Hydroxy-isobutyric acid) stock solution, a stock solution containing approximately 0.3 mg/mL H-IBA and 0.01 mg/mL in 0.05% v/v acetic acid was made in a 50 mL volumetric flask. To prepare the chlorobutanol diluent, about one gram of hydrous chlorobutanol was added to 500 mL of water. Subsequently, 0.25 mL of acetic acid was added and the solution was stirred to dissolve the chlorobutanol. To prepare the stock impurity marker solutions, 6.5 mg of vasopressin powder was added to a 500 mL volumetric flask. To the flask, the following quantities of the above stock solutions were added: Gly-9 AVP: 20.0 mL Glu-4 AVP: 20.0 mL Asp-5 AVP: 10.0 mL D-Asn AVP: 10.0 mL Dimer AVP: 10.0 mL Acetyl AVP: 20.0 mL H-IBA/MAA: 30.0 mL The solutions were diluted to volume with the chlorobutanol diluent. The solutions were aliquoted into individual crimp top vials and stored at 2-8° C. The solutions, stored at 2-8° C., were suitable for use as long as the chromatographic peaks could be identified based on comparison to the reference chromatogram. At time of use the solutions were removed from refrigerated (2-8° C.) storage and allowed to reach room temperature. The vasopressin stock impurity marker solution was stable for at least 120 hours when stored in autosampler vials at room temperature. The impurity marker solution were prepared by diluting 1 mL of the stock impurity marker solution to 50 mL with diluent B, and mixed well. The vasopressin impurity marker solution was stable for at least 72 hours when stored in the refrigerator. To begin the analysis, the HPLC system was allowed to equilibrate for at least 30 minutes using mobile phase B, followed by time 0 min gradient conditions until a stable baseline was achieved. Diluent B was injected at the beginning of the run, and had no peaks that interfered with vasopressin as shown in FIG. 20. A single injection of the sensitivity solution was performed, wherein the signal-to-noise ratio of the vasopressin was greater than or equal to ten as shown in FIG. 21. A single injection of the impurities marker solution was then made. The labeled impurities in the reference chromatogram were identified in the chromatogram of the marker solution based on their elution order and approximate retention times shown in FIG. 22 and FIG. 23. FIG. 23 is a zoomed-in chromatograph of FIG. 22 showing the peaks that eluted between 16 and 28 minutes. The nomenclature, structure, and approximate retention times for individual identified impurities are detailed in TABLE 3. A single injection of the working standard solution was made to ensure that the tailing factor of the vasopressin peak was less than or equal to about 2.0 as shown in FIG. 24. A total of five replicate injections of the working standard solution were made to ensure that the relative standard deviation (% RSD) of the five replicate vasopressin peak areas was not more than 2.0%. Following the steps above done to confirm system suitability, a single injection of the placebo and sample preparations was made. The chromatograms were analyzed to determine the vasopressin and impurity peak areas. The chromatogram for the placebo is depicted in FIG. 25, and the chromatogram for the sample preparation is shown in FIG. 26. Then, the working standard solution was injected after 1 to 10 sample injections, and the average of the bracketing standard peak areas were used in the calculations for vasopressin and impurity amounts. Additional injections of the impurities marker solution could be made to help track any changes in retention time for long chromatographic sequences. The relative standard deviation (% RSD) of vasopressin peak areas for the six injections of working standard solution was calculated by including the initial five injections from the system suitability steps above and each of the subsequent interspersed working standard solution injections. The calculations were done to ensure that each of the % RSD were not more than 2.0%. The retention time of the major peak in the chromatogram of the sample preparation corresponded to that of the vasopressin peak in the working standard solution injection that preceded the sample preparation injection. To calculate the vasopressin units/mL, the following formula was used: Vasopressin   units  /  mL = R U R S × Conc   STD where: RU=Vasopressin peak area response of Sample preparation. RS=average vasopressin peak area response of bracketing standards. Conc STD=concentration of the vasopressin standard in units/mL To identify the impurities, the % Impurity and identity for identified impurities (TABLE 3) that are were greater than or equal to 0.10% were reported. Impurities were truncated to 3 decimal places and then rounded to 2 decimal places, unless otherwise specified. The following formula was used: %   impurity = R 1 R s × Conc   STD LC × 100  % where R1=Peak area response for the impurity; LC=label content of vasopressin (units/mL). The formulations used for the vasopressin and impurity studies are summarized in TABLE 65 below and correspond to several of the formulations detailed above in TABLES 55-63. TABLE 65 Lot Vasopressin (units/100 mL) Buffer Conc. (mM) Vehicle A 40 10 NaCl B 60 10 NaCl C 40 10 Dextrose D 60 10 Dextrose E 40 1 NaCl F 60 1 NaCl G 40 1 Dextrose H 60 1 Dextrose A1 40 1 Dextrose B1 60 1 Dextrose C1 40 1 Dextrose/NaCl The drug products detailed in TABLE 65 were tested for stability over a six month period. The vasopressin drug formulations were stored at 5° C., 25° C., or 40° C. for up to six months. At 0, 1, 2, 3, 4, 5, and 6 months, the amount of vasopressin (AVP), % label claim (LC), amount of various impurities, pH, and % reference standard was measured. The vasopressin and impurity amounts were determined using the HPLC method described above. The results of the stability experiment are shown in TABLES 66-72 below. TABLE 66 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT Condition Time Vasopressin 0.30 0.33 0.34 0.35 0.362 0.37 0.38 0.39 0.40 0.42 0.44 Lot (°C.) (m) pH (% LC) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 5 0 3.63 102.5 0.36 0.14 0.13 A 25 0 3.63 102.5 0.36 0.14 0.13 A 40 0 3.63 102.5 0.36 0.14 0.13 B 5 0 3.64 102.2 0.24 0.09 0.08 0.10 B 25 0 3.64 102.2 0.24 0.09 0.08 0.10 B 40 0 3.64 102.2 0.24 0.09 0.08 0.10 C 5 0 3.64 98.2 0.34 0.13 0.56 0.20 C 25 0 3.64 98.2 0.34 0.13 0.56 0.20 C 40 0 3.64 98.2 0.34 0.13 0.56 0.20 D 5 0 3.65 100.1 0.24 0.08 0.15 0.06 D 25 0 3.65 100.1 0.24 0.08 0.15 0.06 D 40 0 3.65 100.1 0.24 0.08 0.15 0.06 E 5 0 3.67 100.5 0.13 E 25 0 3.67 100.5 0.13 E 40 0 3.67 100.5 0.13 F 5 0 3.71 101.5 0.09 F 25 0 3.71 101.5 0.09 F 40 0 3.71 101.5 0.09 G 5 0 3.75 99.5 G 25 0 3.75 99.5 G 40 0 3.75 99.5 H 5 0 3.74 100.2 H 25 0 3.74 100.2 H 40 0 3.74 100.2 A1 5 0 3.86 97.5 A1 25 0 3.86 97.5 A1 40 0 3.86 97.5 B1 5 0 3.84 97.6 B1 25 0 3.84 97.6 B1 40 0 3.84 97.6 C1 5 0 3.78 99.3 C1 25 0 3.78 99.3 C1 40 0 3.78 99.3 A 5 1 3.62 101.6 0.37 0.15 0.11 A 25 1 3.63 101.5 0.34 0.19 A 40 1 3.61 98.2 0.27 0.18 B 5 1 3.61 102.2 0.25 0.12 0.06 0.13 B 25 1 3.63 101.0 0.24 0.11 B 40 1 3.63 97.2 0.19 0.65 C 5 1 3.66 99.7 0.37 0.11 0.79 C 25 1 3.65 98.7 0.36 0.17 C 40 1 3.66 93.8 0.60 0.19 D 5 1 3.66 101.1 0.24 0.08 D 25 1 3.65 99.8 0.24 0.11 D 40 1 3.66 92.4 0.41 0.11 E 5 1 3.67 101.0 E 25 1 3.67 99.2 E 40 1 3.68 95.5 F 5 1 3.71 101.5 0.08 F 25 1 3.72 100.1 F 40 1 3.71 96.6 0.12 G 5 1 3.71 99.8 G 25 1 3.76 99.0 G 40 1 3.75 94.2 0.34 0.26 H 5 1 3.76 99.8 H 25 1 3.77 99.5 H 40 1 3.77 97.0 0.23 A1 5 1 3.81 97.0 A1 25 1 3.82 96.8 A1 40 1 3.83 91.8 B1 5 1 3.82 97.5 B1 25 1 3.82 97.1 B1 40 1 3.82 92.0 C1 5 1 3.80 99.2 C1 25 1 98.5 C1 40 1 3.82 94.7 A 5 2 3.59 101.7 0.11 A 25 2 3.59 99.5 0.14 A 40 2 3.60 92.9 0.15 B 5 2 3.60 101.1 0.12 B 25 2 3.60 98.8 0.10 B 40 2 3.60 92.1 0.11 C 5 2 3.59 99.3 0.18 C 25 2 3.62 97.3 0.14 C 40 2 3.64 89.2 0.15 D 5 2 3.67 100.0 0.10 D 25 2 3.66 97.3 0.09 D 40 2 3.62 89.9 0.09 E 5 2 3.65 99.5 E 25 2 3.67 95.8 E 40 2 3.67 90.6 0.07 F 5 2 3.67 100.6 F 25 2 3.71 97.9 0.14 F 40 2 3.70 92.3 0.33 G 5 2 3.70 98.9 G 25 2 3.73 97.0 G 40 2 3.71 90.5 H 5 2 3.72 99.7 H 25 2 3.74 98.0 H 40 2 3.74 91.9 A1 5 2 3.77 97.3 A1 25 2 3.77 95.9 A1 40 2 3.78 86.1 B1 5 2 3.79 97.3 B1 25 2 3.78 96.5 B1 40 2 3.79 87.4 C1 5 2 3.73 99.3 C1 25 2 3.73 98.1 C1 40 2 3.74 91.0 A 5 3 3.59 102.0 0.31 A 25 3 3.61 99.5 0.30 A 40 3 3.60 90.8 0.30 B 5 3 3.59 101.8 0.24 B 25 3 3.60 98.8 0.22 B 40 3 3.60 90.3 0.22 C 5 3 3.62 99.8 0.16 C 25 3 3.62 95.5 0.15 C 40 3 3.62 87.0 0.16 D 5 3 3.62 91.4 0.10 D 25 3 3.63 97.7 0.20 D 40 3 3.63 87.6 0.18 E 5 3 3.63 96.9 E 25 3 3.64 96.3 E 40 3 3.65 88.8 0.23 F 5 3 3.67 100.8 F 25 3 3.68 97.9 0.23 F 40 3 3.70 90.0 0.20 G 5 3 3.73 98.8 0.16 G 25 3 3.72 97.5 0.07 G 40 3 3.74 88.6 H 5 3 3.71 99.8 0.04 H 25 3 3.74 98.5 H 40 3 3.75 89.1 A 5 4 3.59 99.9 0.22 A 25 4 3.56 96.8 0.20 A 40 4 3.70 84.5 0.31 B 5 4 3.58 99.4 0.11 B 25 4 3.56 95.4 0.17 B 40 4 3.67 83.0 1.37 C 5 4 3.61 98.5 0.18 C 25 4 3.63 94.9 0.18 C 40 4 3.64 81.3 0.18 D 5 4 3.62 98.9 0.12 D 25 4 3.62 94.5 0.07 0.09 D 40 4 3.61 82.1 0.13 E 5 4 3.63 97.6 E 25 4 3.69 94.0 E 40 4 3.63 83.2 0.26 F 5 4 3.68 98.9 0.08 F 25 4 3.69 95.3 0.19 F 40 4 3.70 84.6 0.24 G 5 4 3.68 98.1 G 25 4 3.69 95.8 G 40 4 3.84 83.2 H 5 4 3.67 98.6 H 25 4 3.62 93.1 0.13 0.12 H 40 4 3.76 83.6 A 5 5 3.63 99.7 0.10 A 25 5 3.63 95.8 B 5 5 3.63 99.0 0.25 B 25 5 3.64 95.1 C 5 5 3.68 98.2 C 25 5 3.67 93.7 D 5 5 3.67 98.7 D 25 5 3.69 94.6 E 5 5 3.69 97.5 E 25 5 3.69 93.1 0.09 F 5 5 3.71 98.4 0.05 0.14 F 25 5 3.74 94.4 0.15 G 5 5 3.74 97.2 G 25 5 3.78 93.1 1.73 H 5 5 3.76 97.7 H 25 5 3.76 95.7 A 5 6 3.57 101.0 A 25 6 3.49 95.4 A 5 6 3.57 100.0 A 25 6 3.49 94.5 B 5 6 3.54 100.2 B 25 6 3.49 95.7 B 5 6 3.54 99.3 0.12 0.13 B 25 6 3.49 94.6 C 5 6 3.59 98.1 C 25 6 3.56 95.1 C 5 6 3.59 98.0 C 25 6 3.56 93.5 D 5 6 3.55 100.0 D 25 6 3.56 95.8 D 5 6 3.55 98.6 0.10 D 25 6 3.56 94.2 E 5 6 3.54 98.1 E 25 6 3.56 94.1 E 5 6 3.54 97.0 E 25 6 3.56 92.3 F 5 6 3.60 99.0 F 25 6 3.61 95.0 F 5 6 3.60 98.2 0.10 0.14 F 25 6 3.61 93.8 0.21 G 5 6 3.61 98.2 G 25 6 3.66 96.1 G 5 6 3.61 96.5 G 25 6 3.66 94.4 H 5 6 3.64 98.6 H 25 6 3.65 97.0 H 5 6 3.64 96.9 H 25 6 3.65 95.3 Min 3.49 81.258 0 0 0 0.053 0.042 0 0.104 0 0.116 Max 3.84 102.047 0 0 0 0.153 1.371 0 1.731 0 0.116 TABLE 67 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT 0.47 0.48 0.49 0.50 0.510 0.52 0.56 0.57 0.58 0.61 0.63 0.64 0.646 0.67 0.68 0.70 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.63 A 0.63 A 0.63 B 0.20 B 0.20 B 0.20 C 0.18 8.74 C 0.18 8.74 C 0.18 8.74 D 0.10 9.43 D 0.10 9.43 D 0.10 9.43 E 1.55 E 1.55 E 1.55 F 0.23 0.22 F 0.23 0.22 F 0.23 0.22 G 0.12 0.44 G 0.12 0.44 G 0.12 0.44 H 0.08 0.27 H 0.08 0.27 H 0.08 0.27 A1 0.06 A1 0.06 A1 0.06 B1 B1 B1 C1 C1 C1 A 0.67 A 0.82 0.56 A 0.81 0.40 B 0.53 B 0.46 0.21 B 0.47 0.34 C 0.13 0.31 C 0.18 0.25 C 0.23 0.29 D 0.09 0.34 D 0.13 0.35 D 0.12 0.11 0.20 E 0.53 E 0.30 0.50 E 0.32 0.49 F 0.22 F 0.17 0.23 F 0.18 0.24 G 0.12 0.35 G 0.46 0.37 G 0.45 0.35 H 0.08 0.28 H 0.16 0.24 H 0.15 0.25 A1 A1 A1 0.06 B1 B1 B1 C1 C1 C1 A 0.24 0.76 A 0.06 0.73 A 0.05 0.83 B 0.04 0.40 B 0.04 0.42 B 0.12 0.45 0.05 C 0.17 0.13 C 0.15 0.16 C 0.10 0.07 D 0.14 D 0.05 0.13 D 0.04 0.05 E 0.26 E 0.27 E 0.09 F 0.15 F 0.07 0.18 F 0.29 G 0.56 G 0.06 0.54 0.08 G H 0.20 H 0.21 H 0.04 A1 A1 0.14 A1 B1 B1 B1 C1 C1 C1 A 0.09 0.72 A 0.14 0.49 A 0.12 0.47 B 0.07 0.36 B 0.06 0.47 B 0.05 0.44 0.05 C 0.14 0.41 C 0.13 0.57 C 0.09 0.39 D 0.99 0.28 D 0.05 0.42 D 0.27 0.05 E 0.06 0.60 E 0.57 E 1.03 F 0.42 0.31 F 0.10 0.33 F 0.10 0.35 G 0.39 G 0.09 0.51 G 0.50 H 0.32 H 0.37 H 0.25 A 0.84 0.59 A 0.82 0.29 A 0.87 0.39 B 0.47 0.23 B 0.50 0.43 B 0.55 0.45 0.08 C 0.21 0.15 C 0.23 0.25 C 0.25 0.34 D 0.18 0.27 D 0.24 0.39 D 0.19 0.25 0.08 E 0.31 0.58 E 0.33 0.51 E 0.36 0.67 F 0.18 0.21 F 0.19 0.27 F 0.20 0.26 G 0.59 0.40 G 0.59 0.36 G 0.62 0.40 H 0.20 0.22 H 0.25 0.20 0.31 0.11 H 0.25 0.26 0.09 A 0.61 A 0.48 B 0.27 B 0.43 C 0.29 C 0.15 0.30 D 0.14 0.28 D 0.08 0.40 E 0.53 E 0.49 F 0.24 F 0.24 G 0.14 0.39 G 0.17 0.44 H 0.10 0.23 H 0.13 0.28 A 0.62 A 0.30 A 0.65 0.62 A 0.70 0.30 0.19 B 0.61 B 0.26 B 0.38 0.62 B 0.38 0.26 0.11 C 0.49 C 0.17 0.30 C 0.14 C 0.25 0.31 0.21 D 0.10 0.26 D 0.10 0.31 D 0.11 0.26 0.09 D 0.09 0.13 0.32 0.12 E 1.04 E 0.64 E 0.21 1.07 E 0.22 0.60 F 0.08 0.21 F 0.22 F 0.11 0.08 0.19 F 0.12 0.19 G 0.14 0.38 G 0.14 0.18 0.36 G 0.45 0.16 0.42 0.22 G 0.45 0.18 0.19 0.35 0.35 H 0.10 0.20 H 0.10 0.28 H 0.15 0.11 0.20 0.12 H 0.15 0.12 0.28 0.22 Min 0.035 0 0.125 0 0.42 0.077 0.064 0.23 0.14 0.051 0.048 Max 0.986 0 0.555 0 0.42 0.203 0.064 0.624 1.03 0.052 0.109 TABLE 68 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT 0.71 0.72 0.74 0.76 0.77 0.78 0.79 0.80 0.82 0.84 0.86 0.87 0.88 0.91 0.94 0.95 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.15 0.29 A 0.15 0.29 A 0.15 0.29 B 0.08 0.32 B 0.08 0.32 B 0.08 0.32 C 0.15 0.29 C 0.15 0.29 C 0.15 0.29 D 0.10 0.30 D 0.10 0.30 D 0.10 0.30 E 0.28 E 0.28 E 0.28 F 0.32 F 0.32 F 0.32 G 0.20 0.31 G 0.20 0.31 G 0.20 0.31 H 0.12 0.30 H 0.12 0.30 H 0.12 0.30 A1 0.32 A1 0.32 A1 0.32 B1 0.30 B1 0.30 B1 0.30 C1 0.31 C1 0.31 C1 0.31 A 0.10 0.31 A 0.36 A 0.17 0.39 B 0.30 B 0.35 B 0.36 C 0.32 0.31 C 0.40 C 0.16 0.40 D 0.10 0.31 D 0.34 D 0.36 E 0.32 E 0.34 E 0.37 F 0.30 F 0.34 F 0.33 G 0.18 0.29 0.31 G 0.20 0.38 G 0.27 0.42 H 0.09 0.31 H 0.13 0.35 H 0.14 0.36 A1 0.10 0.29 A1 0.30 A1 0.29 B1 0.30 B1 0.30 B1 0.33 C1 0.31 C1 0.30 C1 0.30 A 0.12 0.33 A 0.12 0.36 A 0.15 0.42 B 0.34 B 0.07 0.36 B 0.10 0.41 C 0.12 0.41 C 0.15 0.36 C 0.17 0.40 D 0.09 0.36 D 0.11 0.35 D 0.10 0.37 E 0.33 E 0.21 0.31 0.05 E 0.10 0.36 F 0.36 F 0.34 F 0.37 G 0.20 0.33 G 0.22 0.34 G 0.33 0.41 H 0.11 0.35 H 0.13 0.34 H 0.19 0.36 A1 0.30 A1 0.31 A1 0.31 0.18 B1 0.30 B1 0.31 B1 0.29 0.15 C1 0.31 C1 0.31 C1 0.30 A A A B B B C C C D 0.49 D D E 0.25 0.16 0.38 E E F F F G G G H H H A 0.16 0.33 A 0.18 0.33 A 0.25 0.40 B 0.32 B 0.09 0.32 B 0.17 0.38 C 0.34 C 0.19 0.35 C 0.25 0.42 D 0.10 0.32 D 0.12 0.36 D 0.16 0.45 E 0.30 E 0.32 E 0.19 0.40 F 0.31 F 0.33 F 0.11 0.37 G 0.19 0.35 G 0.29 0.37 G 0.46 0.45 H 0.11 0.34 H 0.19 0.36 0.08 H 0.26 0.45 A 0.16 0.28 A 0.17 0.28 B 0.29 B 0.29 C 0.18 0.27 C 0.18 0.29 D 0.29 D 0.11 0.29 E 0.27 E 0.30 F 0.31 F 0.30 G 0.23 0.28 G 0.29 0.29 H 0.12 0.29 H 0.18 0.29 A 0.33 A 0.14 0.32 A 0.32 A 0.28 B 0.32 B 0.30 B 0.33 B 0.28 C 0.17 0.31 C 0.14 0.32 C 0.14 0.26 C 0.24 D 0.30 D 0.32 D 0.32 D 0.33 E 0.34 E 0.12 0.31 E 0.30 E 0.28 F 0.07 0.33 F 0.32 F 0.30 F 0.28 G 0.32 G 0.18 0.32 G 0.30 G 0.24 H 0.30 H 0.09 0.31 H 0.32 H 0.26 Min 0.112 0.252 0.087 0.092 0.213 0.301 0.161 0.053 Max 0.287 0.252 0.33 0.456 0.328 0.453 0.161 0.487 TABLE 69 D-Asn- RRT RRT RRT RRT RRT RRT Gly9- Asp5- Glu4- RRT RRT RRT RRT RRT RRT AVP 0.99 1.02 1.03 1.04 1.05 1.06 AVP AVP AVP 1.09 1.10 1.095 1.12 1.13 1.14 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.35 0.21 0.17 0.58 0.41 A 0.35 0.21 0.17 0.58 0.41 A 0.35 0.21 0.17 0.58 0.41 B 0.20 0.43 0.15 0.20 0.19 0.25 B 0.20 0.43 0.15 0.20 0.19 0.25 B 0.20 0.43 0.15 0.20 0.19 0.25 C 0.42 0.30 0.48 0.17 C 0.42 0.30 0.48 0.17 C 0.42 0.30 0.48 0.17 D 0.15 0.41 0.11 0.11 0.18 0.19 D 0.15 0.41 0.11 0.11 0.18 0.19 D 0.15 0.41 0.11 0.11 0.18 0.19 E 0.22 0.34 0.19 0.14 0.93 0.24 E 0.22 0.34 0.19 0.14 0.93 0.24 E 0.22 0.34 0.19 0.14 0.93 0.24 F 0.15 0.33 0.07 0.13 0.12 0.19 F 0.15 0.33 0.07 0.13 0.12 0.19 F 0.15 0.33 0.07 0.13 0.12 0.19 G 0.38 0.19 0.24 G 0.38 0.19 0.24 G 0.38 0.19 0.24 H 0.16 0.42 0.08 0.12 0.14 H 0.16 0.42 0.08 0.12 0.14 H 0.16 0.42 0.08 0.12 0.14 A1 0.12 0.12 0.24 0.08 0.10 0.09 A1 0.12 0.12 0.24 0.08 0.10 0.09 A1 0.12 0.12 0.24 0.08 0.10 0.09 B1 0.11 0.12 0.24 0.07 0.07 0.07 B1 0.11 0.12 0.24 0.07 0.07 0.07 B1 0.11 0.12 0.24 0.07 0.07 0.07 C1 0.12 0.12 0.25 0.09 0.10 0.08 C1 0.12 0.12 0.25 0.09 0.10 0.08 C1 0.12 0.12 0.25 0.09 0.10 0.08 A 0.47 0.63 0.39 0.70 0.51 A 0.33 0.41 0.46 0.61 0.44 A 0.31 1.28 0.65 1.52 0.18 B 0.19 0.43 0.26 0.25 0.58 0.27 B 0.12 0.31 0.39 0.20 0.52 B 0.11 0.31 0.29 0.44 1.47 0.23 C 0.42 0.21 0.20 0.15 C 0.66 0.19 0.24 0.40 0.16 C 0.16 1.71 0.58 0.55 0.43 0.86 0.17 D 0.43 0.09 0.18 0.17 D 0.13 0.75 0.23 0.13 0.38 0.17 D 0.18 1.71 0.57 1.43 0.82 0.14 E 0.34 0.17 0.25 0.23 E 0.32 0.32 0.25 0.41 0.23 E 0.28 1.06 0.39 1.21 0.29 F 0.17 0.36 0.12 0.17 0.14 0.20 F 0.17 0.35 0.36 0.18 0.41 0.11 F 0.14 0.29 1.06 0.34 1.13 G 0.36 0.17 0.26 G 0.45 0.18 0.25 0.20 G 0.68 0.38 0.33 0.52 H 0.37 0.07 0.11 0.16 H 0.15 0.45 0.15 0.24 0.13 H 0.17 0.82 0.45 0.18 0.60 A1 0.12 0.12 0.25 0.08 0.07 0.08 A1 0.11 0.12 0.24 0.14 0.13 0.10 A1 0.09 0.11 0.21 0.31 0.34 0.09 0.45 0.33 B1 0.11 0.12 0.25 0.07 0.07 0.07 B1 0.11 0.12 0.24 0.07 0.13 0.16 0.18 B1 0.10 0.11 0.21 0.33 0.33 0.09 0.41 0.72 C1 0.12 0.13 0.26 0.08 0.10 0.08 C1 0.11 0.13 0.25 0.18 0.18 0.10 C1 0.11 0.12 0.23 0.27 0.52 0.13 0.64 0.10 A 0.10 0.55 0.43 0.66 0.26 0.54 A 0.06 0.38 0.81 0.66 0.90 0.05 A 0.26 2.40 0.87 0.19 B 0.14 0.36 0.20 0.18 0.27 0.13 B 0.12 0.30 0.68 0.31 0.77 0.07 B 0.20 0.32 2.42 0.74 2.51 C 0.37 0.15 0.21 0.21 0.05 0.22 C 0.10 0.88 0.29 0.17 0.49 0.15 C 0.14 2.08 1.00 0.46 1.42 D 0.14 0.52 0.19 0.11 0.21 0.11 D 0.13 1.04 0.38 0.21 0.50 0.16 D 0.13 2.15 1.03 0.50 1.41 E 0.44 0.25 0.27 0.24 0.30 E 0.41 0.71 0.33 0.73 0.24 E 0.23 2.09 0.58 2.38 F 0.11 0.34 0.17 0.11 0.19 0.09 F 0.19 0.33 0.58 0.25 0.60 0.07 F 0.14 0.24 2.08 0.63 2.06 G 0.06 0.38 0.16 0.22 0.20 0.17 G 0.54 0.28 0.20 0.34 0.11 G 0.12 0.90 0.83 0.57 1.18 H 0.21 0.54 0.21 0.10 0.19 0.12 H 0.22 0.69 0.30 0.10 0.32 0.14 H 0.16 0.91 0.74 0.29 1.05 A1 0.11 0.14 0.24 0.08 0.08 A1 0.13 0.14 0.23 0.18 0.20 0.20 A1 0.10 0.12 0.21 0.50 0.56 0.14 0.67 0.10 B1 0.12 0.12 0.24 0.08 0.08 B1 0.12 0.13 0.23 0.18 0.20 0.04 0.21 B1 0.10 0.11 0.20 0.52 0.55 0.15 0.73 0.06 C1 0.12 0.13 0.25 0.10 0.09 C1 0.14 0.13 0.24 0.28 0.29 C1 0.10 0.13 0.21 0.43 0.89 0.22 1.14 0.07 A 0.10 0.29 0.31 0.52 0.36 0.62 A 0.10 0.97 0.62 1.17 0.19 A 0.09 3.45 1.20 3.64 0.20 B 0.11 0.25 0.21 0.31 0.11 0.06 B 0.12 0.94 0.37 1.13 0.22 B 0.09 3.37 0.88 0.36 0.22 C 0.09 0.15 0.10 0.20 0.15 C 0.10 0.93 0.45 0.24 0.61 0.19 C 0.08 2.15 1.29 0.66 2.00 D 5.25 0.31 0.16 D 0.10 1.05 0.46 0.23 0.66 0.11 D 0.09 2.18 1.29 0.56 1.77 E 0.82 0.30 0.22 0.27 0.28 E 0.09 0.87 0.47 0.99 0.21 E 0.09 2.93 0.77 3.30 F 0.11 0.22 0.12 0.25 0.08 F 0.11 0.81 0.36 0.84 0.09 F 0.09 2.79 0.73 2.91 G 0.10 0.14 0.15 0.15 0.13 G 0.10 0.37 0.34 0.53 0.12 G 0.73 0.89 0.64 1.22 0.07 H 0.11 0.11 0.06 0.16 0.08 H 0.09 0.31 0.08 0.43 0.08 H 0.69 0.86 0.34 1.26 A 0.33 0.18 0.22 0.07 0.18 0.25 A 0.29 1.14 0.31 1.24 0.17 A 0.27 4.38 1.21 4.48 B 0.12 0.32 0.19 0.14 0.15 B 0.14 0.30 1.16 0.34 0.95 0.05 B 0.14 0.27 4.31 1.01 4.71 0.06 C 0.38 0.10 0.12 0.08 0.09 C 0.38 0.95 0.51 0.26 0.48 C 2.09 1.48 0.68 2.32 D 0.14 0.42 0.13 0.07 0.09 D 0.16 0.41 0.94 0.53 0.34 0.52 D 2.10 1.47 0.54 2.29 E 0.32 0.17 0.21 0.09 0.17 E 0.29 1.02 0.34 1.29 E 0.24 3.78 0.89 4.08 F 0.14 0.32 0.19 0.06 0.15 F 0.12 0.29 0.95 0.26 1.08 F 0.14 0.27 3.55 0.84 3.64 G 0.36 0.11 0.07 0.10 G 0.48 0.18 0.39 0.17 0.37 G 0.43 0.47 1.06 0.42 1.66 0.17 H 0.16 0.39 0.11 0.09 H 0.23 0.46 0.21 0.45 0.39 0.61 H 0.18 0.45 0.52 1.08 0.48 1.72 A 0.15 0.51 0.26 0.62 0.27 0.24 A 0.14 0.52 1.41 0.40 1.71 0.28 B 0.19 0.49 0.06 0.27 0.24 0.28 B 0.20 0.55 1.53 0.38 1.54 0.37 C 0.64 0.13 0.20 0.16 C 0.16 1.86 0.69 0.20 0.75 0.24 D 0.14 0.66 0.18 0.20 0.18 D 0.15 1.76 0.72 0.25 0.80 0.16 E 0.19 0.43 0.25 0.40 0.27 E 0.35 1.24 0.55 1.37 F 0.16 0.41 0.26 0.18 0.29 F 0.12 0.38 1.15 0.39 1.23 G 0.10 0.41 0.12 0.21 0.17 G 0.74 0.52 0.11 0.68 0.24 H 0.11 0.44 0.12 0.14 0.17 H 0.13 0.77 0.51 0.16 0.60 0.16 A 0.12 0.13 0.27 0.09 0.84 0.22 A 0.10 0.13 0.24 1.84 0.31 1.57 0.15 A 0.30 0.21 0.48 0.13 A 0.75 1.62 0.45 1.38 B 0.13 0.13 0.25 0.07 0.77 0.22 B 0.12 0.13 0.23 1.67 0.33 1.61 B 0.19 0.33 0.24 0.56 0.20 B 0.12 0.37 1.64 0.42 1.73 C 0.12 0.13 0.24 0.21 0.22 0.14 0.10 C 0.12 0.13 0.20 1.31 0.90 0.12 0.77 C 0.16 0.90 0.25 0.34 0.31 C 1.70 0.71 0.40 0.79 D 0.13 0.13 0.23 0.12 0.28 0.13 0.06 D 0.11 0.13 0.21 1.32 0.81 0.13 0.79 0.05 D 0.15 0.46 0.19 0.16 0.14 D 0.15 1.72 0.75 0.33 0.83 E 0.11 0.13 0.25 0.12 0.86 0.20 0.06 E 0.12 0.24 1.65 0.25 1.41 E 0.30 0.09 0.21 0.66 0.20 E 0.34 1.44 0.59 1.51 F 0.15 0.14 0.25 0.06 0.30 0.20 0.06 F 0.12 0.12 0.25 1.36 0.26 1.30 0.05 F 0.17 0.35 0.25 0.13 0.21 F 0.19 0.36 0.39 1.30 1.40 G 0.13 0.14 0.24 0.39 0.11 0.13 G 0.12 0.14 0.22 0.33 0.72 0.09 0.64 G 0.36 0.17 0.19 0.12 G 0.27 0.76 0.33 0.58 0.54 H 0.12 0.13 0.24 0.24 0.12 0.05 H 0.13 0.13 0.22 0.39 0.59 0.09 0.56 0.06 H 0.18 0.43 0.21 0.15 0.16 H 0.15 0.81 0.30 0.56 0.61 Min 0.057 0.234 0.055 0.079 0.042 0.071 0.182 0.051 0.059 Max 0.231 2.177 0.501 4.376 5.246 4.713 0.182 0.622 0.1 TABLE 70 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT AVP Acetyl- RRT RRT RRT RRT 1.16 1.168 1.19 1.20 1.206 1.23 1.24 1.25 1.26 1.27 Dimer AVP 1.32 1.33 1.34 1.35 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.33 0.35 A 0.33 0.35 A 0.33 0.35 B 0.07 0.33 B 0.07 0.33 B 0.07 0.33 C 0.22 0.22 C 0.22 0.22 C 0.22 0.22 D 0.08 0.23 D 0.08 0.23 D 0.08 0.23 E 0.55 0.53 E 0.55 0.53 E 0.55 0.53 F 0.34 F 0.34 F 0.34 G 0.23 G 0.23 G 0.23 H 0.23 H 0.23 H 0.23 A1 0.21 0.28 A1 0.21 0.28 A1 0.21 0.28 B1 0.21 0.29 B1 0.21 0.29 B1 0.21 0.29 C1 0.14 0.29 C1 0.14 0.29 C1 0.14 0.29 A 0.37 0.22 0.13 A 0.20 0.60 A 0.59 B 0.26 0.35 B 0.49 B 0.48 C 0.24 C 0.46 0.26 C 0.44 0.73 0.25 D 0.07 0.22 D 0.35 0.25 D 0.41 0.27 E 0.12 0.43 E 0.72 E 0.68 F 0.07 0.35 F 0.55 F 0.53 G 0.29 G 0.54 0.27 G 0.54 0.40 H 0.21 0.12 H 0.56 0.17 H 0.55 0.17 A1 0.23 0.28 A1 0.21 0.27 A1 0.25 0.27 B1 0.22 0.28 B1 0.21 0.28 B1 0.13 0.27 C1 0.14 0.27 C1 0.15 0.28 C1 0.15 0.28 A 0.58 0.47 A 0.76 A 0.06 0.08 0.32 0.51 B 0.34 B 0.07 0.51 B 0.06 0.07 0.25 0.52 C 0.54 0.25 0.26 C 0.58 0.19 0.20 C 0.41 0.26 D 0.49 0.15 0.23 D 0.47 0.25 0.24 D 0.32 0.03 0.25 E 0.34 0.40 E 0.20 0.51 E 0.06 0.76 F 0.12 0.33 F 0.10 0.77 F 0.04 0.58 G 0.62 0.25 0.23 G 0.62 0.18 G 0.52 0.25 H 0.56 0.09 0.42 H 0.59 0.16 0.38 H 0.56 0.46 A1 0.20 0.30 A1 0.20 0.29 A1 0.28 0.29 B1 0.23 0.32 B1 0.23 0.28 B1 0.12 0.28 C1 0.13 0.28 C1 0.13 0.32 C1 0.16 0.28 A 0.08 0.62 0.55 A 0.32 0.80 A 0.14 0.21 0.51 B 0.18 0.42 B 0.45 0.64 B 0.13 0.22 0.49 0.05 C 0.42 0.27 C 0.39 0.31 0.28 C 0.38 0.19 0.29 D 0.37 0.21 D 0.40 0.15 0.23 D 0.39 0.09 0.24 E 0.19 0.31 E 0.25 0.93 E 0.10 0.22 0.77 F 0.23 0.51 F 0.69 F 0.09 0.07 0.51 G 0.52 0.22 0.24 G 0.52 0.32 0.24 G 0.51 0.06 0.46 H 0.53 0.04 0.46 H 0.53 0.42 H 0.55 0.50 A 0.29 0.43 A 0.55 A 0.23 0.11 0.58 B 0.10 0.39 B 0.24 0.31 B 0.24 0.13 0.14 0.50 C 0.35 0.44 0.21 C 0.42 0.95 0.22 C 0.39 0.49 0.24 D 0.39 0.11 0.22 D 0.39 0.82 0.24 D 0.38 0.70 0.25 E 0.23 0.50 E 0.57 0.88 E 0.18 0.17 0.73 F 0.26 0.32 F 0.08 0.07 0.74 F 0.15 0.09 0.59 G 0.49 0.21 0.21 G 0.51 0.48 0.23 G 0.49 0.14 0.19 H 0.51 0.12 0.38 H 0.54 0.80 0.45 H 0.53 0.30 0.49 A 0.22 0.56 A 0.14 0.21 0.70 B 0.08 0.41 B 0.21 0.12 0.53 C 0.65 0.21 C 0.17 0.21 D 0.38 0.22 D 0.53 0.23 E 0.16 0.14 0.46 E 0.11 0.19 0.99 0.10 F 0.06 0.13 0.45 F 0.07 0.12 0.65 0.07 G 0.80 0.21 G 0.42 0.23 0.15 H 0.48 0.20 0.15 H 0.67 0.21 0.12 A 0.22 0.37 0.25 A 0.29 0.23 A 0.30 0.54 A 0.69 B 0.17 0.41 0.23 B 0.14 0.22 B 0.34 0.28 B 0.52 C 0.24 0.34 C 0.29 0.37 0.25 C 0.19 0.25 C 0.42 0.21 D 0.24 0.22 D 0.20 0.26 0.23 D 0.30 0.20 D 0.37 0.23 E 0.32 0.57 0.22 E 0.23 0.18 0.20 E 0.43 0.65 E 0.16 0.91 F 0.14 0.14 0.21 F 0.14 0.09 0.21 F 0.44 F 0.70 0.08 G 0.33 0.39 0.22 G 0.26 0.35 0.23 G 0.37 0.24 G 0.37 0.20 H 0.14 0.32 0.22 0.16 H 0.14 0.33 0.21 0.23 H 0.40 0.19 0.18 H 0.42 0.21 0.20 Min 0.086 0 0.057 0 0.034 0.042 0.193 0.047 0.147 Max 0.341 0 0.796 0 0.061 0.623 0.986 0.047 0.147 TABLE 71 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT 1.37 1.44 1.45 1.46 1.47 1.48 1.55 1.57 1.59 1.62 1.68 1.70 1.71 1.72 1.80 1.82 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.32 A 0.32 A 0.32 B 0.18 B 0.18 B 0.18 C 0.15 C 0.15 C 0.15 D 0.16 D 0.16 D 0.16 E 0.61 E 0.61 E 0.61 F 0.58 F 0.58 F 0.58 G 1.34 G 1.34 G 1.34 H 1.05 H 1.05 H 1.05 A1 A1 A1 B1 B1 B1 C1 C1 C1 A 0.21 2.16 A A B 1.67 B B C 3.37 C C D 2.40 D D E 0.16 3.70 E E F 2.61 F F G 4.10 G G H 2.79 H H A1 A1 A1 B1 B1 B1 0.06 C1 C1 C1 A 0.10 A A B B B C C C D D D E E E 0.14 F F F 0.10 G G G H H H A1 0.09 A1 0.09 A1 0.10 B1 0.06 B1 0.07 B1 0.05 C1 0.14 C1 0.13 C1 0.12 A 0.25 A 0.32 A 0.35 B 0.16 B 0.14 B 0.14 C C C D 0.14 D D E 0.09 E 0.12 E 0.20 F 0.06 0.08 F 0.10 F 0.14 G G G H H H 0.07 0.13 A 0.19 0.16 A 0.29 0.16 A 0.24 B 0.07 B 0.07 0.11 B 0.21 0.12 C C 0.14 C D 0.11 D 0.10 0.07 D 0.08 0.16 E E 0.13 E 0.13 F 0.12 F 0.08 F 0.08 0.06 0.23 G 0.16 G G 0.17 H H 0.20 0.14 H 0.11 0.21 A 0.23 A 0.33 B 0.12 B 0.11 C C D D E 0.11 E 0.13 F F 0.09 G G 0.36 H H A 0.44 0.32 0.16 A 0.48 0.23 0.21 0.12 A 0.26 A 0.27 B 0.12 0.16 B 0.33 0.15 0.10 0.07 B B 0.16 C 0.21 C 0.20 C C 2.69 D 0.08 D 0.30 0.08 D D 1.83 E 0.51 0.13 0.16 0.10 E 0.73 0.14 0.72 E 0.11 E 0.16 2.74 F 0.34 0.10 0.07 F 0.53 0.09 0.06 F F 0.10 1.80 G 0.36 G 0.15 G G 2.69 H H 0.17 H H 1.81 Min 0 0.059 0.077 0.07 0.128 Max 0 0.347 0.213 0.07 0.138 TABLE 72 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT Total 1.85 1.89 1.93 1.96 2.00 2.01 2.04 2.08 2.11 2.12 2.13 2.15 2.16 2.17 2.304 Imp Lot (%) %) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 4.44 A 4.44 A 4.44 B 3.10 B 3.10 B 3.10 C 12.55 C 12.55 C 12.55 D 0.07 0.09 0.55 0.15 12.92 D 0.07 0.09 0.55 0.15 12.92 D 0.07 0.09 0.55 0.15 12.92 E 0.18 5.89 E 0.18 5.89 E 0.18 5.89 F 2.77 F 2.77 F 2.77 G 3.45 G 3.45 G 3.45 H 0.69 3.66 H 0.69 3.66 H 0.69 3.66 A1 1.61 A1 1.61 A1 1.61 B1 1.48 B1 1.48 B1 1.48 C1 1.50 C1 1.50 C1 1.50 A 0.66 8.15 A 5.34 A 6.74 B 5.67 B 3.40 B 5.33 C 6.91 C 3.72 C 7.74 D 4.71 D 3.55 D 6.86 E 6.24 E 3.38 E 5.09 F 4.78 F 2.86 F 4.35 G 6.42 G 1.08 4.39 G 4.93 H 4.60 H 2.73 H 4.07 A1 1.60 A1 1.63 A1 2.80 B1 1.50 B1 1.80 B1 0.44 3.53 C1 1.49 C1 1.66 C1 2.85 A 5.25 A 5.03 A 6.29 B 2.52 B 3.83 B 8.35 C 3.27 C 0.85 4.84 C 6.65 D 2.80 D 4.10 D 6.47 E 0.23 2.82 E 3.98 E 6.87 F 1.96 F 3.61 F 6.85 G 3.37 G 3.51 G 5.10 H 3.10 H 3.57 H 4.76 A1 1.53 A1 2.10 A1 3.55 B1 1.56 B1 1.98 B1 3.31 C1 1.57 C1 1.97 C1 4.05 A 4.82 A 5.39 A 10.68 B 2.48 B 4.73 B 6.71 C 2.09 C 4.34 C 7.69 D 8.29 D 4.06 D 7.10 E 3.57 7.50 E 4.50 E 9.64 F 2.39 F 3.65 F 7.97 G 2.19 G 3.21 G 5.08 H 1.91 H 2.31 H 4.64 A 0.17 0.14 0.06 4.79 A 5.96 A 13.72 B 2.60 B 0.65 5.84 B 14.85 C 2.66 C 5.50 C 9.14 D 2.67 D 0.08 1.22 7.08 D 9.22 E 2.87 E 5.66 E 12.07 F 2.35 F 4.64 F 10.81 G 3.23 G 4.42 G 7.12 H 2.63 H 0.31 0.11 0.08 6.71 H 0.08 7.46 A 4.23 A 6.75 B 2.94 B 0.09 6.36 C 2.72 C 0.13 5.32 D 2.67 D 5.46 E 3.19 E 5.90 F 2.66 F 4.95 G 3.05 G 6.37 H 2.55 H 4.20 A 4.36 A 6.67 A 3.81 A 6.62 B 3.60 B 5.66 B 3.71 B 5.98 C 0.14 3.05 C 5.58 C 2.93 C 0.18 8.12 D 2.28 D 5.34 D 2.48 D 7.20 E 5.11 E 6.93 E 4.22 E 8.94 F 2.83 F 5.10 F 2.47 F 7.12 G 3.26 G 4.42 G 2.98 G 7.49 H 2.35 H 4.04 H 2.80 H 6.09 Min 0 0 0 3.565 0 0 1.533 Max 0 0 0 3.565 0 0 14.845 TABLE 73 RRT RRT RRT RRT D-ASN- RRT RRT RRT RRT Condition Time AVP 0.64 0.86 0.87 0.95 AVP 0.99 1.03 1.04 1.05 Lot (° C.) (m) pH (% LC) (%) (%) (%) (%) (%) (%) (%) (%) (%) A1 5 0 3.86 97.5 0.06 0.32 0.12 0.12 0.24 A1 25 0 3.86 97.5 0.06 0.32 0.12 0.12 0.24 A1 40 0 3.86 97.5 0.06 0.32 0.12 0.12 0.24 B1 5 0 3.84 97.6 0.30 0.11 0.12 0.24 B1 25 0 3.84 97.6 0.30 0.11 0.12 0.24 B1 40 0 3.84 97.6 0.30 0.11 0.12 0.24 C1 5 0 3.78 99.3 0.31 0.12 0.12 0.25 C1 25 0 3.78 99.3 0.31 0.12 0.12 0.25 C1 40 0 3.78 99.3 0.31 0.12 0.12 0.25 A1 5 1 3.81 97.0 0.10 0.29 0.12 0.12 0.25 A1 25 1 3.82 96.8 0.30 0.11 0.12 0.24 A1 40 1 3.83 91.8 0.06 0.29 0.09 0.11 0.21 B1 5 1 3.82 97.5 0.30 0.11 0.12 0.25 B1 25 1 3.82 97.1 0.30 0.11 0.12 0.24 B1 40 1 3.82 92.0 0.33 0.10 0.11 0.21 C1 5 1 3.80 99.2 0.31 0.12 0.13 0.26 C1 25 1 98.5 0.30 0.11 0.13 0.25 C1 40 1 3.82 94.7 0.30 0.11 0.12 0.23 A1 5 2 3.77 97.3 0.30 0.11 0.14 0.24 A1 25 2 3.77 95.9 0.14 0.31 0.13 0.14 0.23 0.18 A1 40 2 3.78 86.1 0.31 0.18 0.10 0.12 0.21 0.50 B1 5 2 3.79 97.3 0.30 0.12 0.12 0.24 B1 25 2 3.78 96.5 0.31 0.12 0.13 0.23 0.18 B1 40 2 3.79 87.4 0.29 0.15 0.10 0.11 0.20 0.52 C1 5 2 3.73 99.3 0.31 0.12 0.13 0.25 C1 25 2 3.73 98.1 0.31 0.14 0.13 0.24 C1 40 2 3.74 91.0 0.30 0.10 0.13 0.21 0.43 A1 5 3 3.80 95.8 0.28 0.12 0.22 A1 25 3 3.78 94.0 0.28 0.13 0.21 0.11 A1 40 3 3.81 82.2 0.28 0.16 0.11 0.15 0.29 B1 5 3 3.82 96.5 0.28 0.11 0.13 0.23 B1 25 3 3.82 94.8 0.29 0.12 0.13 0.21 0.11 B1 40 3 3.83 82.0 0.27 0.06 0.09 0.11 0.14 0.33 C1 5 3 3.75 97.5 0.29 0.12 0.13 0.24 C1 25 3 3.75 96.8 0.29 0.13 0.14 0.22 C1 40 3 3.75 85.5 0.27 0.11 0.16 0.26 Min 3.78 91.842 0.061 0.093 0 Max 3.86 99.282 0.063 0.124 0 TABLE 74 RRT GLY9- ASP5- GLU4- RRT RRT RRT RRT RRT RRT RRT RRT 1.06 AVP AVP AVP 1.12 1.13 1.23 1.24 1.25 ACETYL- 1.57 1.71 1.77 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) AVP (%) (%) (%) (%) A1 0.08 0.10 0.09 0.21 0.28 A1 0.08 0.10 0.09 0.21 0.28 A1 0.08 0.10 0.09 0.21 0.28 B1 0.07 0.07 0.07 0.21 0.29 B1 0.07 0.07 0.07 0.21 0.29 B1 0.07 0.07 0.07 0.21 0.29 C1 0.09 0.10 0.08 0.14 0.29 C1 0.09 0.10 0.08 0.14 0.29 C1 0.09 0.10 0.08 0.14 0.29 A1 0.08 0.07 0.08 0.23 0.28 A1 0.14 0.13 0.10 0.21 0.27 A1 0.31 0.34 0.09 0.45 0.33 0.25 0.27 B1 0.07 0.07 0.07 0.22 0.28 B1 0.07 0.13 0.16 0.18 0.21 0.28 B1 0.33 0.33 0.09 0.41 0.72 0.13 0.27 0.06 C1 0.08 0.10 0.08 0.14 0.27 C1 0.18 0.18 0.10 0.15 0.28 C1 0.27 0.52 0.13 0.64 0.10 0.15 0.28 A1 0.08 0.08 0.20 0.30 0.09 A1 0.20 0.20 0.20 0.29 0.09 A1 0.56 0.14 0.67 0.10 0.28 0.29 0.10 B1 0.08 0.08 0.23 0.32 0.06 B1 0.20 0.04 0.21 0.23 0.28 0.07 B1 0.55 0.15 0.73 0.06 0.12 0.28 0.05 C1 0.10 0.09 0.13 0.28 0.14 C1 0.28 0.29 0.13 0.32 0.13 C1 0.89 0.22 1.14 0.07 0.16 0.28 0.12 A1 0.09 0.09 0.18 0.29 A1 0.26 0.29 0.21 0.28 A1 0.73 0.18 0.82 0.19 0.11 0.27 B1 0.09 0.09 0.19 0.28 B1 0.25 0.25 0.20 0.28 B1 0.73 0.19 0.82 0.09 0.09 0.07 0.28 0.06 C1 0.10 0.10 0.13 0.28 C1 0.35 0.38 0.11 0.28 C1 1.22 0.30 1.56 0.12 0.15 0.27 Min 0.07 0.089 0.067 0.073 0 0.27 Max 0.344 0.089 0.448 0.326 0 0.288 TABLE 75 Lot RRT 1.85 (%) RRT 1.91 (%) RRRT 2.02 (%) RRT 2.37 (%) Total RS (%) A1 1.61 A1 1.61 A1 1.61 B1 1.48 B1 1.48 B1 1.48 C1 1.50 C1 1.50 C1 1.50 A1 1.60 A1 1.63 A1 2.80 B1 1.50 B1 1.80 B1 0.44 3.53 C1 1.49 C1 1.66 C1 2.85 A1 1.53 A1 2.10 A1 3.55 B1 1.56 B1 1.98 B1 3.31 C1 1.57 C1 1.97 C1 4.05 A1 1.26 A1 1.76 A1 3.29 B1 1.40 B1 1.82 B1 0.10 0.10 0.17 3.68 C1 1.38 C1 1.89 C1 4.41 Min 1.483 Max 2.799 The appearance for all of the tested lots through the duration of the experiment was clear and colorless. The results above provided an estimated shelf life at 5° C. of about 16.1 months (FIG. 27) and at 25° C. of about eight months (FIG. 28). The results indicated that the dextrose vehicle with 1 mM acetate buffer provided a lower rate of degradation and a lower rate of impurities accumulation for the vasopressin formulations at 5° C., 25° C., and 40° C. compared to NaCl or a combination of dextrose and NaCl in either 1 mM or 10 mM acetate buffer Graphical depictions of TABLES 66-72 are shown in FIGS. 29-48 below. FIGS. 29-31 show the vasopressin (% LC) levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 32-34 show the total impurities (total RS (%)) levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 35-37 show the Gly9-AVP levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 38-40 show the Asp5-AVP levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 41-43 show the Glu4-AVP levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 44-46 show the Acetyl-AVP levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 47-48 show the AVP dimer levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. Based on the data from FIGS. 29-48, the estimated shelf-life at 5° C. is about 16.1 months, and the estimated shelf-life at 25° C. is about 8 months. TABLES 73-75 display data of further studies on Formulations A1, B1, and C1 as detailed in TABLE 65. The appearance for all of the tested lots through the duration of the experiment was clear and colorless. The estimated shelf life at 5° C. of about 15 months and at 25° C. of about 7.7 months is shown below in FIG. 49 and FIG. 50, respectively. The results indicated that the dextrose vehicle provided a lower rate of degradation and a lower rate of impurities accumulation for the vasopressin formulations at 5° C., 25° C., and 40° C. compared to a combination of dextrose and NaCl. Graphical depictions of TABLES 73-75 are shown in FIGS. 51-62 below. FIGS. 51-53 show the vasopressin (% LC) levels in the samples prepared in dextrose or dextrose and NaCl at 5° C., 25° C., and 40° C., respectively. FIGS. 54-56 show the Gly9-AVP levels in the samples prepared in dextrose or dextrose and NaCl at 5° C., 25° C., and 40° C., respectively. FIGS. 57-59 show the Glu4-AVP levels in the samples prepared in dextrose or dextrose and NaCl at 5° C., 25° C., and 40° C., respectively. FIGS. 60-62 show the total impurities (% RS) levels in the samples prepared in dextrose or dextrose and NaCl at 5° C., 25° C., and 40° C., respectively. EMBODIMENTS The following non-limiting embodiments provide illustrative examples of the invention, but do not limit the scope of the invention. In some embodiments, the invention provides a pharmaceutical composition comprising, in a unit dosage form: a) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin, or a pharmaceutically-acceptable salt thereof; and b) a polymeric pharmaceutically-acceptable excipient in an amount that is from about 1% to about 10% by mass of the unit dosage form or the pharmaceutically-acceptable salt thereof, wherein the unit dosage form exhibits from about 5% to about 10% less degradation of the vasopressin or the pharmaceutically-acceptable salt thereof after storage for about 1 week at about 60° C. than does a corresponding unit dosage form, wherein the corresponding unit dosage form consists essentially of: A) vasopressin, or a pharmaceutically-acceptable salt thereof; and B) a buffer having acidic pH. In some embodiments, the polymeric pharmaceutically-acceptable excipient comprises a polyalkylene oxide moiety. In some embodiments, the polymeric pharmaceutically-acceptable excipient is a polyethylene oxide. In some embodiments, the polymeric pharmaceutically-acceptable excipient is a poloxamer. In some embodiments, the unit dosage form has an amount of the polymeric pharmaceutically-acceptable excipient that is about 1% the amount of the vasopressin or the pharmaceutically-acceptable salt thereof. In some embodiments, the first unit dosage form exhibits about 10% less degradation of the vasopressin or the pharmaceutically-acceptable salt thereof after storage for about 1 week at about 60° C. than does the corresponding unit dosage form. In some embodiments, the unit dosage form further comprises SEQ ID NO. 2. In some embodiments, the composition further comprises SEQ ID NO. 3. In some embodiments, the composition further comprises SEQ ID NO. 4. In some embodiments, the unit dosage form is an injectable of about 1 mL volume. In some embodiments, the unit dosage form consists essentially of: a) about 0.04 mg/mL of vasopressin, or the pharmaceutically-acceptable salt thereof; b) the polymeric pharmaceutically-acceptable excipient in an amount that is from about 1% to about 10% by mass of the vasopressin or the pharmaceutically-acceptable salt thereof; and c) a plurality of peptides, wherein each of the peptides has from 88% to 90% sequence homology to the vasopressin or the pharmaceutically-acceptable salt thereof. In some embodiments, one of the plurality of peptides is SEQ ID NO.: 2. In some embodiments, one of the plurality of peptides is SEQ ID NO.: 3. In some embodiments, wherein one of the plurality of peptides is SEQ ID NO.: 4. In some embodiments, the buffer has a pH of about 3.5. Embodiment 1 A method of increasing blood pressure in a human in need thereof, the method comprising: intravenously administering to the human a pharmaceutical composition comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; and ii) acetic acid, sodium acetate, or a combination thereof, wherein: the pharmaceutical composition is at about room temperature; the administration to the human is longer than 18 hours; the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. Embodiment 2 The method of embodiment 1, wherein the administration to the human is for about one day. Embodiment 3 The method of embodiment 1, wherein the administration to the human is for about one week. Embodiment 4 The method of any one of embodiments 1-3, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. Embodiment 5 The method of any one of embodiments 1-4, wherein the human's hypotension is associated with vasodilatory shock. Embodiment 6 The method of embodiment 5, wherein the vasodilatory shock is post-cardiotomy shock. Embodiment 7 The method of any one of embodiments 1-6, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 8 The method of embodiment 5, wherein the vasodilatory shock is septic shock. Embodiment 9 The method of any one of embodiments 1-8, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 10 The method of any one of embodiments 1-9, wherein the unit dosage form further comprises dextrose. Embodiment 11 The method of any one of embodiments 1-10, wherein the unit dosage form further comprises about 5% dextrose. Embodiment 12 A method of increasing blood pressure in a human in need thereof, the method comprising: intravenously administering to the human a pharmaceutical composition that consists essentially of, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; iii) acetic acid, sodium acetate, or a combination thereof; and iv) optionally hydrochloric acid or sodium hydroxide, wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. Embodiment 13 The method of embodiment 12, wherein the unit dosage form consists essentially of hydrochloric acid. Embodiment 14 The method of embodiment 12, wherein the unit dosage form consists essentially of sodium hydroxide. Embodiment 15 The method of any one of embodiments 12-14, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. Embodiment 16 The method of any one of embodiments 12-15, wherein the human's hypotension is associated with vasodilatory shock. Embodiment 17 The method of embodiment 16, wherein the vasodilatory shock is post-cardiotomy shock. Embodiment 18 The method of any one of embodiments 12-17, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 19 The method of embodiment 16, wherein the vasodilatory shock is septic shock. Embodiment 20 The method of any one of embodiments 12-19 wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. Embodiment 21 The method of any one of embodiments 12-20, wherein the unit dosage form consists essentially of 5% dextrose. Embodiment 22 A method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 5° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 1% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 5° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. Embodiment 23 The method of embodiment 22, wherein the administration to the human is for about one day. Embodiment 24 The method of embodiment 22, wherein the administration to the human is for about one week. Embodiment 25 The method of any one of embodiments 22-24, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. Embodiment 26 The method of any one of embodiments 22-25, wherein the human's hypotension is associated with vasodilatory shock. Embodiment 27 The method of embodiment 26, wherein the vasodilatory shock is post-cardiotomy shock. Embodiment 28 The method of any one of embodiments 22-27, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 29 The method of embodiment 26, wherein the vasodilatory shock is septic shock. Embodiment 30 The method of any one of embodiments 22-29, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. Embodiment 31 The method of any one of embodiments 22-30, wherein the pharmaceutical composition exhibits no more than about 2% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after storage of the pharmaceutical composition at 5° C. for about two months. Embodiment 32 A method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 25° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 2% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 25° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. Embodiment 33 The method of embodiment 32, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. Embodiment 34 The method of any one of embodiments 32-33, wherein the human's hypotension is associated with vasodilatory shock. Embodiment 35 The method of embodiment 34, wherein the vasodilatory shock is post-cardiotomy shock. Embodiment 36 The method of any one of embodiments 32-35, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 37 The method of embodiment 35, wherein the vasodilatory shock is septic shock. Embodiment 38 The method of any one of embodiments 32-37, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. Embodiment 39 The method of any one of embodiments 32-38, wherein the pharmaceutical composition exhibits no more than about 5% degradation after storage of the pharmaceutical composition at 25° C. for about two months.
<SOH> BACKGROUND <EOH>Vasopressin is a potent endogenous hormone, responsible for maintaining plasma osmolality and volume in most mammals. Vasopressin can be used clinically in the treatment of sepsis and cardiac conditions, and in the elevation of patient's suffering from low blood pressure. Current formulations of vasopressin suffer from poor long-term stability.
<SOH> SUMMARY OF THE INVENTION <EOH>In some embodiments, the invention provides a pharmaceutical composition comprising, in a unit dosage form: a) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin, or a pharmaceutically-acceptable salt thereof; and b) a polymeric pharmaceutically-acceptable excipient in an amount that is from about 1% to about 10% by mass of the unit dosage form or the pharmaceutically-acceptable salt thereof, wherein the unit dosage form exhibits from about 5% to about 10% less degradation of the vasopressin or the pharmaceutically-acceptable salt thereof after storage for about 1 week at about 60° C. than does a corresponding unit dosage form, wherein the corresponding unit dosage form consists essentially of: A) vasopressin, or a pharmaceutically-acceptable salt thereof; and B) a buffer having acidic pH. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: intravenously administering to the human a pharmaceutical composition that consists essentially of, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; iii) acetic acid, sodium acetate, or a combination thereof; and iv) optionally hydrochloric acid or sodium hydroxide, wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 5° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 1% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 5° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 25° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 2% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 25° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive.
A61K3811
20170828
20180508
20180104
67193.0
A61K3811
1
BRADLEY, CHRISTINA
VASOPRESSIN FORMULATIONS FOR USE IN TREATMENT OF HYPOTENSION
UNDISCOUNTED
1
CONT-ACCEPTED
A61K
2,017
15,688,326
ACCEPTED
VASOPRESSIN FORMULATIONS FOR USE IN TREATMENT OF HYPOTENSION
Provided herein are peptide formulations comprising polymers as stabilizing agents. The peptide formulations can be more stable for prolonged periods of time at temperatures higher than room temperature when formulated with the polymers. The polymers used in the present invention can decrease the degradation of the constituent peptides of the peptide formulations.
1-15. (canceled) 16. A method of increasing blood pressure in a human in need thereof, the method comprising: administering to the human a pharmaceutical composition that comprises, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; dextrose; acetate; and iv) SEQ ID NO.: 3, wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute, wherein the vasopressin or the pharmaceutically-acceptable salt thereof and SEQ ID NO.: 3 are present in the unit dosage form at a ratio of about 1000:about 1 to about 90:about 1; and the human is hypotensive. 17. The method of claim 16, wherein the unit dosage form further comprises a pH adjusting agent. 18. The method of claim 16, wherein the unit dosage form further comprises hydrochloric acid. 19. The method of claim 16, wherein the unit dosage further comprises sodium hydroxide. 20. The method of claim 16, wherein the unit dosage form further comprises acetic acid. 21. The method of claim 16, wherein the dextrose is present at 5%. 22. The method of claim 16, wherein the vasopressin or the pharmaceutically-acceptable salt thereof and SEQ ID NO.: 3 are present in the unit dosage form at a ratio of about 1000:about 1. 23. The method of claim 16, wherein the vasopressin or the pharmaceutically-acceptable salt thereof and SEQ ID NO.: 3 are present in the unit dosage form at a ratio of about 200:about 1. 24. The method of claim 16, wherein the vasopressin or the pharmaceutically-acceptable salt thereof and SEQ ID NO.: 3 are present in the unit dosage form at a ratio of about 100:about 1. 25. The method of claim 16, wherein the administration to the human is over about one day. 26. The method of claim 16, wherein the administration to the human is over about one week. 27. The method of claim 16, wherein the administration is intravenous. 28. The method of claim 16, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. 29. The method of claim 16, wherein the human's hypotension is associated with vasodilatory shock. 30. The method of claim 29, wherein the vasodilatory shock is post-cardiotomy shock. 31. The method of claim 30, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. 32. The method of claim 29, wherein the vasodilatory shock is septic shock. 33. The method of claim 32, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute.
CROSS REFERENCE This Application is a continuation of U.S. application Ser. No. 15/612,649, filed Jun. 2, 2017, which is a continuation-in-part of U.S. application Ser. No. 15/426,693, filed Feb. 7, 2017, which is a continuation-in-part of U.S. application Ser. No. 15/289,640, filed Oct. 10, 2016, which is a continuation-in-part of U.S. application Ser. No. 14/717,877, filed May 20, 2015, which is a continuation of U.S. application Ser. No. 14/610,499, filed Jan. 30, 2015, each of which is incorporated herein by reference in its entirety. BACKGROUND Vasopressin is a potent endogenous hormone, responsible for maintaining plasma osmolality and volume in most mammals. Vasopressin can be used clinically in the treatment of sepsis and cardiac conditions, and in the elevation of patient's suffering from low blood pressure. Current formulations of vasopressin suffer from poor long-term stability. INCORPORATION BY REFERENCE Each patent, publication, and non-patent literature cited in the application is hereby incorporated by reference in its entirety as if each was incorporated by reference individually. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Aug. 25, 2017, is named 47956702306_SL.txt and is 5260 bytes in size. SUMMARY OF THE INVENTION In some embodiments, the invention provides a pharmaceutical composition comprising, in a unit dosage form: a) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin, or a pharmaceutically-acceptable salt thereof; and b) a polymeric pharmaceutically-acceptable excipient in an amount that is from about 1% to about 10% by mass of the unit dosage form or the pharmaceutically-acceptable salt thereof, wherein the unit dosage form exhibits from about 5% to about 10% less degradation of the vasopressin or the pharmaceutically-acceptable salt thereof after storage for about 1 week at about 60° C. than does a corresponding unit dosage form, wherein the corresponding unit dosage form consists essentially of: A) vasopressin, or a pharmaceutically-acceptable salt thereof; and B) a buffer having acidic pH. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: intravenously administering to the human a pharmaceutical composition that consists essentially of, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; iii) acetic acid, sodium acetate, or a combination thereof; and iv) optionally hydrochloric acid or sodium hydroxide, wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 5° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 1% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 5° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 25° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 2% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 25° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. BRIEF DESCRIPTION OF THE FIGURES FIG. 1 is a chromatogram of a diluent used in vasopressin assay. FIG. 2 is a chromatogram of a sensitivity solution used in a vasopressin assay. FIG. 3 is a chromatogram of an impurity marker solution used in a vasopressin assay. FIG. 4 is a zoomed-in depiction of the chromatogram in FIG. 3. FIG. 5 is a chromatogram of a vasopressin standard solution. FIG. 6 is a chromatogram of a sample vasopressin preparation. FIG. 7 is a UV spectrum of a vasopressin sample. FIG. 8 is a UV spectrum of a vasopressin standard. FIG. 9 plots vasopressin stability across a range of pH as determined experimentally. FIG. 10 illustrates the effects of various stabilizers on vasopressin stability. FIG. 11 plots vasopressin stability across a range of pH at 25° C. FIG. 12 plots vasopressin impurities across a range of pH at 25° C. FIG. 13 plots vasopressin stability across a range of pH at 40° C. FIG. 14 plots vasopressin impurities across a range of pH at 40° C. FIG. 15 illustrates vasopressin impurities across a range of pH at 25° C. FIG. 16 illustrates vasopressin impurities across a range of pH at 40° C. FIG. 17 illustrates the effect of pH on vasopressin at 25° C. FIG. 18 illustrates the effect of pH on vasopressin at 40° C. FIG. 19 depicts the % LC of vasopressin formulations stored for 15 months at 25° C. FIG. 20 is a chromatogram of a diluent used in a vasopressin assay. FIG. 21 is a chromatogram of a sensitivity solution used in a vasopressin assay. FIG. 22 is a chromatogram of an impurity marker solution used in a vasopressin assay. FIG. 23 is a zoomed-in depiction of the chromatogram in FIG. 22. FIG. 24 is a chromatogram of a working solution. FIG. 25 is a chromatogram of a placebo sample. FIG. 26 is a chromatogram of a vasopressin sample. FIG. 27 depicts the estimated shelf-life of a vasopressin sample described herein at 5° C. FIG. 28 depicts the estimated shelf-life of a vasopressin sample described herein at 25° C. FIG. 29 shows the % LC of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 30 shows the % LC of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 31 shows the % LC of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 32 shows the total impurities of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 33 shows the total impurities of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 34 shows the total impurities of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 35 shows the % Gly9-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 36 shows the % Gly9-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 37 shows the % Gly9-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 38 shows the % Asp5-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 39 shows the % Asp5-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 40 shows the % Asp5-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 41 shows the % Glu4-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 42 shows the % Glu4-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 43 shows the % Glu4-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 44 shows the % Acetyl-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 45 shows the % Acetyl-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 46 shows the % Acetyl-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 47 shows the % AVP-dimer of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 48 shows the % AVP-dimer of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 49 depicts the estimated shelf-life of a vasopressin sample described herein at 5° C. FIG. 50 depicts the estimated shelf-life of a vasopressin sample described herein at 25° C. FIG. 51 shows the % LC of vasopressin after storage at 5° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 52 shows the % LC of vasopressin after storage at 25° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 53 shows the % LC of vasopressin after storage at 40° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 54 shows the % Gly9-AVP of vasopressin after storage at 5° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 55 shows the % Gly9-AVP of vasopressin after storage at 25° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 56 shows the % Gly9-AVP of vasopressin after storage at 40° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 57 shows the % Glu4-AVP of vasopressin after storage at 5° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 58 shows the % Glu4-AVP of vasopressin after storage at 25° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 59 shows the % Glu4-AVP of vasopressin after storage at 40° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 60 shows the total impurities of vasopressin after storage at 5° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 61 shows the total impurities of vasopressin after storage at 25° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 62 shows the total impurities of vasopressin after storage at 40° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. DETAILED DESCRIPTION Vasopressin and Peptides of the Invention. Vasopressin, a peptide hormone, acts to regulate water retention in the body and is a neurotransmitter that controls circadian rhythm, thermoregulation, and adrenocorticotrophic hormone (ACTH) release. Vasopressin is synthesized as a pro-hormone in neurosecretory cells of the hypothalamus, and is subsequently transported to the pituitary gland for storage. Vasopressin is released upon detection of hyperosmolality in the plasma, which can be due to dehydration of the body. Upon release, vasopressin increases the permeability of collecting ducts in the kidney to reduce renal excretion of water. The decrease in renal excretion of water leads to an increase in water retention of the body and an increase in blood volume. At higher concentrations, vasopressin raises blood pressure by inducing vasoconstriction. Vasopressin acts through various receptors in the body including, for example, the V1, V2, V3, and oxytocin-type (OTR) receptors. The V1 receptors occur on vascular smooth muscle cells, and the major effect of vasopressin action on the V1 receptor is the induction of vasoconstriction via an increase of intracellular calcium. V2 receptors occur on the collecting ducts and the distal tubule of the kidney. V2 receptors play a role in detection of plasma volume and osmolality. V3 receptors occur in the pituitary gland and can cause ACTH release upon vasopressin binding. OTRs can be found on the myometrium and vascular smooth muscle. Engagement of OTRs via vasopressin leads to an increase of intracellular calcium and vasoconstriction. Vasopressin is a nonapeptide, illustrated below (SEQ ID NO. 1): At neutral to acidic pH, the two basic groups of vasopressin, the N-terminal cysteine, and the arginine at position eight, are protonated, and can each carry an acetate counterion. The amide groups of the N-terminal glycine, the glutamine at position four, and the asparagine at position five, are susceptible to modification when stored as clinical formulations, such as unit dosage forms. The glycine, glutamine, and asparagine residues can undergo deamidation to yield the parent carboxylic acid and several degradation products as detailed in EXAMPLE 1 and TABLE 1 below. Deamidation is a peptide modification during which an amide group is removed from an amino acid, and can be associated with protein degradation, apoptosis, and other regulatory functions within the cell. Deamidation of asparagine and glutamine residues can occur in vitro and in vivo, and can lead to perturbation of the structure and function of the affected proteins. The susceptibility to deamidation can depend on primary sequence of the protein, three-dimensional structure of the protein, and solution properties including, for example, pH, temperature, ionic strength, and buffer ions. Deamidation can be catalyzed by acidic conditions. Under physiological conditions, deamidation of asparagine occurs via the formation of a five-membered succinimide ring intermediate by a nucleophilic attack of the nitrogen atom in the following peptide bond on the carbonyl group of the asparagine side chain. Acetylation is a peptide modification whereby an acetyl group is introduced into an amino acid, such as on the N-terminus of the peptide. Vasopressin can also form dimers in solution and in vivo. The vasopressin dimers can occur through the formation of disulfide bridges that bind a pair of vasopressin monomers together. The dimers can form between two parallel or anti-parallel chains of vasopressin. Vasopressin and associated degradation products or peptides are listed in TABLE 1 below. All amino acids are L-stereoisomers unless otherwise denoted. TABLE 1 SEQ ID Name Sequence NO. Vasopressin (AVP; CYFQNCPRG-NH2 1 arginine vasopressin) Gly9-vasopressin CYFQNCPRG 2 (Gly9-AVP) Asp5-vasopressin CYFQDCPRG-NH2 3 (Asp5-AVP) Glu4-vasopressin CYFENCPRG-NH2 4 (Glu4-AVP) Glu4Gly9-vasopressin CYFENCPRG 5 (Glu4Gly9-AVP) AcetylAsp5-vasopressin Ac-CYFQDCPRG-NH2 6 (AcetylAsp5-AVP) Acetyl-vasopressin Ac-CYFQNCPRG-NH2 7 His2-vasopressin CHFQNCPRG-NH2 8 (His2-AVP) Leu7-vasopressin CYFQNCLRG-NH2 9 (Leu7-AVP) D-Asn-vasopressin CYFQ(D-Asn)CPRG-NH2 10 (DAsn-AVP) D-Cys1-vasopressin (D-Cys)YFQNCPRG-NH2 11 D-Tyr-vasopressin C(D-Tyr)FQNCPRG-NH2 12 D-Phe-vasopressin CY(D-Phe)QNCPRG-NH2 13 D-Gln-vasopressin CYF(D-Gln)NCPRG-NH2 14 D-Cys6-vasopressin CYFQN(D-cys)PRG-NH2 15 D-Pro-vasopressin CYFQNC(D-pro)RG-NH2 16 D-Arg-vasopressin CYFQNCP(D-Arg)G-NH2 17 Therapeutic Uses. A formulation of vasopressin can be used to regulate plasma osmolality and volume and conditions related to the same in a subject. Vasopressin can be used to modulate blood pressure in a subject, and can be indicated in a subject who is hypotensive despite treatment with fluid and catecholamines. Vasopressin can be used in the treatment of, for example, vasodilatory shock, post-cardiotomy shock, sepsis, septic shock, cranial diabetes insipidus, polyuria, nocturia, polydypsia, bleeding disorders, Von Willebrand disease, haemophilia, platelet disorders, cardiac arrest, liver disease, liver failure, hypovolemia, hemorrhage, oesophageal variceal haemorrhage, hypertension, pulmonary hypertension, renal disease, polycystic kidney disease, blood loss, injury, hypotension, meniere disease, uterine myomas, brain injury, mood disorder. Formulations of vasopressin can be administered to a subject undergoing, for example, surgery or hysterectomy. Plasma osmolality is a measure of the plasma's electrolyte-water balance and relates to blood volume and hydration of a subject. Normal plasma osmolality in a healthy human subject range from about 275 milliosmoles/kg to about 295 milliosmoles/kg. High plasma osmolality levels can be due to, for example, diabetes insipidus, hyperglycemia, uremia, hypernatremia, stroke, and dehydration. Low plasma osmolality can be due to, for example, vasopressin oversecretion, improper functioning of the adrenal gland, lung cancer, hyponatremia, hypothyroidism, and over-consumption of water or other fluids. Septic shock can develop due to an extensive immune response following infection and can result in low blood pressure. Causes of sepsis can include, for example, gastrointestinal infections, pneumonia, bronchitis, lower respiratory tract infections, kidney infection, urinary tract infections, reproductive system infections, fungal infections, and viral infections. Risk factors for sepsis include, for example, age, prior illness, major surgery, long-term hospitalization, diabetes, intravenous drug use, cancer, use of steroidal medications, and long-term use of antibiotics. The symptoms of sepsis can include, for example, cool arms and legs, pale arms and legs, extreme body temperatures, chills, light-headedness, decreased urination, rapid breathing, edema, confusion, elevated heart rate, high blood sugar, metabolic acidosis, respiratory alkalosis, and low blood pressure. Vasopressin can also be administered to regulate blood pressure in a subject. Blood pressure is the measure of force of blood pushing against blood vessel walls. Blood pressure is regulated by the nervous and endocrine systems and can be used as an indicator of a subject's health. Chronic high blood pressure is referred to as hypertension, and chronic low blood pressure is referred to as hypotension. Both hypertension and hypotension can be harmful if left untreated. Blood pressure can vary from minute to minute and can follow the circadian rhythm with a predictable pattern over a 24-hour period. Blood pressure is recorded as a ratio of two numbers: systolic pressure (mm Hg), the numerator, is the pressure in the arteries when the heart contracts, and diastolic pressure (mm Hg), the denominator, is the pressure in the arteries between contractions of the heart. Blood pressure can be affected by, for example, age, weight, height, sex, exercise, emotional state, sleep, digestion, time of day, smoking, alcohol consumption, salt consumption, stress, genetics, use of oral contraceptives, and kidney disease. Blood pressure for a healthy human adult between the ages of 18-65 can range from about 90/60 to about 120/80. Hypertension can be a blood pressure reading above about 120/80 and can be classified as hypertensive crisis when there is a spike in blood pressure and blood pressure readings reach about 180/110 or higher. Hypertensive crisis can be precipitated by, for example, stroke, myocardial infarction, heart failure, kidney failure, aortic rupture, drug-drug interactions, and eclampsia. Symptoms of hypertensive crisis can include, for example, shortness of breath, angina, back pain, numbness, weakness, dizziness, confusion, change in vision, nausea, and difficulty speaking. Vasodilatory shock can be characterized by low arterial blood pressure due to decreased systemic vascular resistance. Vasodilatory shock can lead to dangerously low blood pressure levels and can be corrected via administration of catecholamines or vasopressin formulations. Vasodilatory shock can be caused by, for example, sepsis, nitrogen intoxication, carbon monoxide intoxication, hemorrhagic shock, hypovolemia, heart failure, cyanide poisoning, metformin intoxication, and mitochondrial disease. Post-cardiotomy shock can occur as a complication of cardiac surgery and can be characterized by, for example, inability to wean from cardiopulmonary bypass, poor hemodynamics in the operating room, development of poor hemodynamics post-surgery, and hypotension. Pharmaceutical Formulations. Methods for the preparation of compositions comprising the compounds described herein can include formulating the compounds with one or more inert, pharmaceutically-acceptable excipients. Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives. Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, elixir, nanosuspension, aqueous or oily suspensions, drops, syrups, and any combination thereof. Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include granulating agents, binding agents, lubricating agents, disintegrating agents, anti-adherents, anti-static agents, surfactants, anti-oxidants, coloring agents, flavoring agents, plasticizers, preservatives, suspending agents, emulsifying agents, plant cellulosic material and spheronization agents, and any combination thereof. Vasopressin can be formulated as an aqueous formulation or a lyophilized powder, which can be diluted or reconstituted just prior to use. Upon dilution or reconstitution, the vasopressin solution can be refrigerated for long-term stability for about one day. Room temperature incubation or prolonged refrigeration can lead to the generation of degradation products of vasopressin. In some embodiments, a pharmaceutical composition of the invention can be formulated for long-term storage of vasopressin at room temperature in the presence of a suitable pharmaceutically-acceptable excipient. The pharmaceutically-acceptable excipient can increase the half-life of vasopressin when stored at any temperature, such as room temperature. The presence of the pharmaceutical excipient can decrease the rate of decomposition of vasopressin at any temperature, such as room temperature. In some embodiments, a pharmaceutical composition has a shelf life of at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, at least about 25 months, at least about 26 months, at least about 27 months, at least about 28 months, at least about 29 months, or at least about 30 months. The shelf life can be at any temperature, including, for example, room temperature and refrigeration (i.e., 2-8° C.). As used herein, “shelf life” means the period beginning from manufacture of a formulation beyond which the formulation cannot be expected beyond reasonable doubt to yield the therapeutic outcome approved by a government regulatory agency In some embodiments, a vasopressin formulation of the invention comprises a pharmaceutically-acceptable excipient, and the vasopressin has a half-life that is at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, or at least about 1000% greater than the half-life of vasopressin in a corresponding formulation that lacks the pharmaceutically-acceptable excipient. In some embodiments, a vasopressin formulation of the invention has a half-life at about 5° C. to about 8° C. that is no more than about 1%, no more than about 5%, no more than about 10%, no more than about 15%, no more than about 20%, no more than about 25%, no more than about 30%, no more than about 35%, no more than about 40%, no more than about 45%, no more than about 50%, no more than about 55%, no more than about 60%, no more than about 65%, no more than about 70%, no more than about 75%, no more than about 80%, no more than about 85%, no more than about 90%, no more than about 95%, no more than about 100%, no more than about 150%, no more than about 200%, no more than about 250%, no more than about 300%, no more than about 350%, no more than about 400%, no more than about 450%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000% greater than the half-life of the formulation at another temperature, such as room temperature. The half-life of the compounds of the invention in a formulation described herein at a specified temperature can be, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, or about one week. A formulation described herein can be stable for or be stored for, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years prior to administration to a subject. A unit dosage form described herein can be stable for or be stored for, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years prior to administration to a subject. A diluted unit dosage form described herein can be stable for or be stored for, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years prior to administration to subject. The stability of a formulation described herein can be measured after, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years. A formulation or unit dosage form described herein can exhibit, for example, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9% about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% degradation over a specified period of time. The degradation of a formulation or a unit dosage form disclosed herein can be assessed after about 24 hours, about 36 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years of storage. The degradation of a formulation or a unit dosage form disclosed herein can be assessed at a temperature of, for example, about 0° C., about 1° C., about 2° C., about 3° C., about 4° C., about 5° C., about 6° C., about 7° C., about 8° C., about 9° C., about 10° C., about 11° C., about 12° C., about 13° C., about 14° C., about 15° C., about 16° C., about 17° C., about 18° C., about 19° C., about 20° C., about 21° C., about 22° C., about 23° C., about 24° C., about 25° C., about 26° C., about 27° C., about 28° C., about 29° C., about 30° C., about 31° C., about 32° C., about 33° C., about 34° C., about 35° C., about 36° C., about 37° C., about 38° C., about 39° C., about 40° C., about 41° C., about 42° C., about 43° C., about 44° C., about 45° C., about 46° C., about 47° C., about 48° C., about 49° C., about 50° C., or about 0° C. to about 5° C., about 1° C. to about 6° C., about 2° C. to about 7° C., about 2° C. to about 8° C., about 3° C. to about 8° C., about 4° C. to about 9° C., about 5° C. to about 10° C., about 6° C. to about 11° C., about 7° C. to about 12° C., about 8° C. to about 13° C., about 9° C. to about 14° C., about 10° C. to about 15° C., about 11° C. to about 16° C., about 12° C. to about 17° C., about 13° C. to about 18° C., about 14° C. to about 19° C., about 15° C. to about 20° C., about 16° C. to about 21° C., about 17° C. to about 22° C., about 18° C. to about 23° C., about 19° C. to about 24° C., about 20° C. to about 25° C., about 21° C. to about 26° C., about 22° C. to about 27° C., about 23° C. to about 28° C., about 24° C. to about 29° C., about 25° C. to about 30° C., about 26° C. to about 31° C., about 27° C. to about 32° C., about 28° C. to about 33° C., about 29° C. to about 34° C., about 30° C. to about 35° C., about 31° C. to about 36° C., about 32° C. to about 37° C., about 33° C. to about 38° C., about 34° C. to about 39° C., about 35° C. to about 40° C., about 36° C. to about 41° C., about 37° C. to about 42° C., about 38° C. to about 43° C., about 39° C. to about 44° C., about 40° C. to about 45° C., about 41° C. to about 46° C., about 42° C. to about 47° C., about 43° C. to about 48° C., about 44° C. to about 49° C., about 45° C. to about 50° C. In some embodiments, a vasopressin formulation of the invention comprises an excipient and the vasopressin has a level of decomposition at a specified temperature that is about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% less than the level of decomposition of a formulation of the invention in the absence of the excipient. Pharmaceutical compositions of the invention can be used, stored, tested, analyzed or assayed at any suitable temperature. Non-limiting examples of temperatures include about 0° C., about 1° C., about 2° C., about 3° C., about 4° C., about 5° C., about 6° C., about 7° C., about 8° C., about 9° C., about 10° C., about 11° C., about 12° C., about 13° C., about 14° C., about 15° C., about 16° C., about 17° C., about 18° C., about 19° C., about 20° C., about 21° C., about 22° C., about 23° C., about 24° C., about 25° C., about 26° C., about 27° C., about 28° C., about 29° C., about 30° C., about 31° C., about 32° C., about 33° C., about 34° C., about 35° C., about 36° C., about 37° C., about 38° C., about 39° C., about 40° C., about 41° C., about 42° C., about 43° C., about 44° C., about 45° C., about 46° C., about 47° C., about 48° C., about 49° C., about 50° C., about 51° C., about 52° C., about 53° C., about 54° C., about 55° C., about 56° C., about 57° C., about 58° C., about 59° C., about 60° C., about 61° C., about 62° C., about 63° C., about 64° C., about 65° C., about 66° C., about 67° C., about 68° C., about 69° C., about 70° C., about 71° C., about 72° C., about 73° C., about 74° C., or about 75° C. Pharmaceutical compositions of the invention can be used, stored, tested, analyzed or assayed at any suitable temperature. Non-limiting examples of temperatures include from about 0° C. to about 5° C., about 1° C. to about 6° C., about 2° C. to about 7° C., about 2° C. to about 8° C., about 3° C. to about 8° C., about 4° C. to about 9° C., about 5° C. to about 10° C., about 6° C. to about 11° C., about 7° C. to about 12° C., about 8° C. to about 13° C., about 9° C. to about 14° C., about 10° C. to about 15° C., about 11° C. to about 16° C., about 12° C. to about 17° C., about 13° C. to about 18+° C., about 14° C. to about 19° C., about 15° C. to about 20° C., about 16° C. to about 21° C., about 17° C. to about 22° C., about 18° C. to about 23° C., about 19° C. to about 24° C., about 20° C. to about 25° C., about 21° C. to about 26° C., about 22° C. to about 27° C., about 23° C. to about 28° C., about 24° C. to about 29° C., about 25° C. to about 30° C., about 26° C. to about 31° C., about 27° C. to about 32° C., about 28° C. to about 33° C., about 29° C. to about 34° C., about 30° C. to about 35° C., about 31° C. to about 36° C., about 32° C. to about 37° C., about 33° C. to about 38° C., about 34° C. to about 39° C., about 35° C. to about 40° C., about 36° C. to about 41° C., about 37° C. to about 42° C., about 38° C. to about 43° C., about 39° C. to about 44° C., about 40° C. to about 45° C., about 41° C. to about 46° C., about 42° C. to about 47° C., about 43° C. to about 48° C., about 44° C. to about 49° C., about 45° C. to about 50° C., about 46° C. to about 51° C., about 47° C. to about 52° C., about 48° C. to about 53° C., about 49° C. to about 54° C., about 50° C. to about 55° C., about 51° C. to about 56° C., about 52° C. to about 57° C., about 53° C. to about 58° C., about 54° C. to about 59° C., about 55° C. to about 60° C., about 56° C. to about 61° C., about 57° C. to about 62° C., about 58° C. to about 63° C., about 59° C. to about 64° C., about 60° C. to about 65° C., about 61° C. to about 66° C., about 62° C. to about 67° C., about 63° C. to about 68° C., about 64° C. to about 69° C., about 65° C. to about 70° C., about 66° C. to about 71° C., about 67° C. to about 72° C., about 68° C. to about 73° C., about 69° C. to about 74° C., about 70° C. to about 74° C., about 71° C. to about 76° C., about 72° C. to about 77° C., about 73° C. to about 78° C., about 74° C. to about 79° C., or about 75° C. to about 80° C. Pharmaceutical compositions of the invention can be used, stored, tested, analyzed or assayed at room temperature. The room temperature can be, for example, about 20.0° C., about 20.1° C., about 20.2° C., about 20.3° C., about 20.4° C., about 20.5° C., about 20.6° C., about 20.7° C., about 20.8° C., about 20.9° C., about 21.0° C., about 21.1° C., about 21.2° C., about 21.3° C., about 21.4° C., about 21.5° C., about 21.6° C., about 21.7° C., about 21.8° C., about 21.9° C., about 22.0° C., about 22.1° C., about 22.2° C., about 22.3° C., about 22.4° C., about 22.5° C., about 22.6° C., about 22.7° C., about 22.8° C., about 22.9° C., about 23.0° C., about 23.1° C., about 23.2° C., about 23.3° C., about 23.4° C., about 23.5° C., about 23.6° C., about 23.7° C., about 23.8° C., about 23.9° C., about 24.0° C., about 24.1° C., about 24.2° C., about 24.3° C., about 24.4° C., about 24.5° C., about 24.6° C., about 24.7° C., about 24.8° C., about 24.9° C., or about 25.0° C. A pharmaceutical composition of the disclosed can be supplied, stored, or delivered in a vial or tube that is, for example, about 0.5 mL, about 1 mL, about 2 mL, about 3 mL, about 4 mL, about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, about 10 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about 18 mL, about 19 mL, or about 20 mL in volume. A pharmaceutical composition of the disclosure can be a combination of any pharmaceutical compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can be administered in therapeutically-effective amounts, for example, intravenous, subcutaneous, intramuscular, transdermal, or parenteral administration. Pharmaceutical preparations can be formulated for intravenous administration. The pharmaceutical compositions can be in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in oily or aqueous vehicles, and can contain formulation agents such as suspending, stabilizing, and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Suspensions of the active compounds can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. The suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use. Comparison Formulations. A pharmaceutical composition described herein can be analyzed by comparison to a reference formulation. A reference formulation can be generated from any combination of compounds, peptides, excipients, diluents, carriers, and solvents disclosed herein. Any compound, peptide, excipient, diluent, carrier, or solvent used to generate the reference formulation can be present in any percentage, ratio, or amount, for example, those disclosed herein. The reference formulation can comprise, consist essentially of, or consist of any combination of any of the foregoing. A non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: an amount, such as about 20 Units or about 0.04 mg, of vasopressin or a pharmaceutically-acceptable salt thereof, an amount, such as about 5 mg, of chlorobutanol (for example, hydrous), an amount, such as about 0.22 mg, of acetic acid or a pharmaceutically-acceptable salt thereof or a quantity sufficient to bring pH to about 3.4 to about 3.6, and water as needed. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof, chlorobutanol, acetic acid, and a solvent such as water. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof, chlorobutanol, and a solvent such as water. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof, acetic acid, and a solvent such as water. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof and a solvent such as water. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof and a buffer having acidic pH, such as pH 3.5 or any buffer or pH described herein. Methods. Any formulation described herein can be diluted prior to administration to a subject. Diluents that can be used in a method of the invention include, for example, compound sodium lactate solution, 6% dextran, 10% dextran, 5% dextrose, 20% fructose, Ringer's solution, 5% saline, 1.39% sodium bicarbonate, 1.72% sodium lactate, or water. Upon dilution, any diluted formulation disclosed herein can be stored for, for example, about 24 hours, about 36 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years of storage. Upon dilution, any diluted formulation disclosed herein can be stored at, for example, about 0° C., about 1° C., about 2° C., about 3° C., about 4° C., about 5° C., about 6° C., about 7° C., about 8° C., about 9° C., about 10° C., about 11° C., about 12° C., about 13° C., about 14° C., about 15° C., about 16° C., about 17° C., about 18° C., about 19° C., about 20° C., about 21° C., about 22° C., about 23° C., about 24° C., about 25° C., about 26° C., about 27° C., about 28° C., about 29° C., about 30° C., about 31° C., about 32° C., about 33° C., about 34° C., about 35° C., about 36° C., about 37° C., about 38° C., about 39° C., about 40° C., about 41° C., about 42° C., about 43° C., about 44° C., about 45° C., about 46° C., about 47° C., about 48° C., about 49° C., about 50° C., or about 0° C. to about 5° C., about 1° C. to about 6° C., about 2° C. to about 7° C., about 2° C. to about 8° C., about 3° C. to about 8° C., about 4° C. to about 9° C., about 5° C. to about 10° C., about 6° C. to about 11° C., about 7° C. to about 12° C., about 8° C. to about 13° C., about 9° C. to about 14° C., about 10° C. to about 15° C., about 11° C. to about 16° C., about 12° C. to about 17° C., about 13° C. to about 18° C., about 14° C. to about 19° C., about 15° C. to about 20° C., about 16° C. to about 21° C., about 17° C. to about 22° C., about 18° C. to about 23° C., about 19° C. to about 24° C., about 20° C. to about 25° C., about 21° C. to about 26° C., about 22° C. to about 27° C., about 23° C. to about 28° C., about 24° C. to about 29° C., about 25° C. to about 30° C., about 26° C. to about 31° C., about 27° C. to about 32° C., about 28° C. to about 33° C., about 29° C. to about 34° C., about 30° C. to about 35° C., about 31° C. to about 36° C., about 32° C. to about 37° C., about 33° C. to about 38° C., about 34° C. to about 39° C., about 35° C. to about 40° C., about 36° C. to about 41° C., about 37° C. to about 42° C., about 38° C. to about 43° C., about 39° C. to about 44° C., about 40° C. to about 45° C., about 41° C. to about 46° C., about 42° C. to about 47° C., about 43° C. to about 48° C., about 44° C. to about 49° C., about 45° C. to about 50° C. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about two weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about three weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about six weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about three months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about six months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about two years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about three years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 24 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 48 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 96 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 1 week; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 months; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 months; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least one year; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least two years; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least three years; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 24 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 48 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 96 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least one week; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 months; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 months; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 1 year; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 years; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 years; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 24 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 48 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 96 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 1 week; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 months; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 months; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 1 year; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 years; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 years; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 24 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 48 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 96 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least one week; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 months; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 months; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least one year; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 years; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 years; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 24 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 48 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 96 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 1 week; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 2 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 months; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 6 months; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 1 year; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 2 years; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 years; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about two weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about three weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 24 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 48 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C. for about, for example, 5° C., 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 96 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 1 week; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 2 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 months; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 6 months; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 1 year; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 2 years; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 years; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. A formulation described herein can be used without initial vasopressin dilution for use in, for example, intravenous drip-bags. The formulation can be premixed, already-diluted, and ready for use as provided in, for example, a bottle or intravenous drip-bag. The formulation supplied in the bottle can then be transferred to an intravenous drip-bag for administration to a subject. The formulation can be stable for about 24 hours, about 36 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years prior to discarding. The premixed formulation described herein can be disposed in a container or vessel, which can be sealed. The container or vessel can maintain the sterility of, or reduce the likelihood of contamination of, the premixed formulation. The premixed formulation described herein can be disposed in a container or vessel and is formulated as, for example, a single use dosage or a multiple use dosage. The container or vessel can be, for example, a glass vial, an ampoule, or a plastic flexible container. The plastic flexible container can be made of, for example, PVC (polyvinyl chloride), or polypropylene. A premixed vasopressin formulation described herein can be stored as a liquid in an aliquot having a total volume of between about 1 and about 500 mL, between about 1 and about 250 mL, between about 1 and about 200 mL, between about 1 and about 150 mL, between about 1 and about 125 mL, between about 1 and about 120 mL, between about 1 and about 110 mL, between about 1 and about 100 mL, between about 1 and about 90 mL, between about 1 and about 80 mL, between about 1 and about 70 mL, between about 1 and about 60 mL, between about 1 and about 50 mL, between about 1 and about 40 mL, between about 1 and about 30 mL, between about 1 and about 20 mL, between about 1 and about 10 mL, or between about 1 and about 5 mL. A premixed vasopressin formulation described herein can be administered as, for example, a single continuous dose over a period of time. For example, the premixed vasopressin formulation can be administered for a period of time of between about 1 and about 10 minutes, between about 1 and about 20 minutes, between about 1 and about 30 minutes, between about 1 and about 2 hours, between about 1 and about 3 hours, between about 1 and about 4 hours, between about 1 and about 5 hours, between about 1 and about 6 hours, between about 1 and about 7 hours, between about 1 and about 8 hours, between about 1 and about 9 hours, between about 1 and about 10 hours, between about 1 and about 11 hours, between about 1 and about 12 hours, between about 1 and about 13 hours, between about 1 and about 14 hours, between about 1 and about 15 hours, between about 1 and about 16 hours, between about 1 and about 17 hours, between about 1 and about 18 hours, between about 1 and about 19 hours, between about 1 and about 20 hours, between about 1 and about 21 hours, between about 1 and about 22 hours, between about 1 and about 23 hours, between about 1 and about 1 day, between about 1 and about 32 hours, between about 1 and about 36 hours, between about 1 and about 42 hours, between about 1 and about 2 days, between about 1 and about 54 hours, between about 1 and about 60 hours, between about 1 and about 66 hours, between about 1 and about 3 days, between about 1 and about 78 hours, between about 1 and about 84 hours, between about 1 and about 90 hours, between about 1 and about 4 days, between about 1 and about 102 hours, between about 1 and about 108 hours, between about 1 and about 114 hours, between about 1 and about 5 days, between about 1 and about 126 hours, between about 1 and about 132 hours, between about 1 and about 138 hours, between about 1 and about 6 days, between about 1 and about 150 hours, between about 1 and about 156 hours, between about 1 and about 162 hours, or between about 1 and about 1 week. A premixed vasopressin formulation described herein can be administered as a loading dose followed by a maintenance dose over a period of time. For example, the loading dose can comprise administration of the premixed vasopressin formulation at a first dosage amount for a first period of time, followed by administration of the maintenance dose at a second dosage amount for a second period of time. The loading dose can be administered for a period of time of between about 1 and about 5 minutes, between about 1 and about 10 minutes, between about 1 and about 15 minutes, between about 1 and about 20 minutes, between about 1 and about 25 minutes, between about 1 and about 30 minutes, between about 1 and about 45 minutes, between about 1 and about 60 minutes, between about 1 and about 90 minutes, between 1 minute and about 2 hours, between 1 minute about 2.5 hours, between 1 minute and about 3 hours, between 1 minute and about 3.5 hours, between 1 minute and about 4 hours, between 1 minute and about 4.5 hours, between 1 minute and about 5 hours, between 1 minute and about 5.5 hours, between 1 minute and about 6 hours, between 1 minute and about 6.5 hours, between 1 minute and about 7 hours, between 1 minute and about 7.5 hours, between 1 minute and about 8 hours, between 1 minute and about 10 hours, between 1 minute and about 12 hours, between 1 minute about 14 hours, between 1 minute and about 16 hours, between 1 minute and about 18 hours, between 1 minute and about 20 hours, between 1 minute and about 22 hours, or between 1 minute and about 24 hours. Following the loading dose, the maintenance dose can be administered for a period of time as described above for a single continuous dose. A premixed vasopressin formulation described herein, when administered as a single continuous, loading, or maintenance dose, can be administered for about 1 hour to about 7 days, about 1 hour to about 4 days, about 1 hour to about 48 hours, about 1 hour to about 36 hours, about 1 hour to about 24 hours, about 1 hour to about 12 hours, about 24 hours to about 120 hours, about 24 hours to about 108 hours, about 24 hours to about 96 hours, about 24 hours to about 72 hours, about 24 hours to about 48 hours, or about 24 hours to about 36 hours. The volume of the premixed formulation can be, for example, about 25 mL, about 30 mL, about 35 mL, about 40 mL, about 45 mL, about 50 mL, about 55 mL, about 60 mL, about 65 mL, about 70 mL, about 75 mL, about 80 mL, about 85 mL, about 90 mL, about 95 mL, about 100 mL, about 110 mL, about 120 mL, about 130 mL, about 140 mL, about 150 mL, about 175 mL, about 200 mL, about 225 mL, about 250 mL, about 275 mL, about 300 mL, about 350 mL, about 400 mL, about 450 mL, about 500 mL, about 550 mL, about 600 mL, about 650 mL, about 700 mL, about 750 mL, about 800 mL, about 850 mL, about 900 mL, about 950 mL, or about 1 L. In some embodiments, the volume of the vasopressin formulation formulated for use without initial vasopressin dilution is 100 mL. The concentration of vasopressin in the container or vessel in which the premixed vasopressin formulation is disposed can be, for example, about 0.1 units/mL, about 0.2 units/mL, about 0.3 units/mL, about 0.4 units/mL, about 0.5 units/mL, about 0.6 units/mL, about 0.7 units/mL, about 0.8 units/mL, about 0.9 units/mL, about 1 unit/mL, about 2 units/mL, about 3 units/mL, about 4 units/mL, about 5 units/mL, about 6 units/mL, about 7 units/mL, about 8 units/mL, about 9 units/mL, about 10 units/mL, about 11 units/mL, about 12 units/mL, about 13 units/mL, about 14 units/mL, about 15 units/mL, about 16 units/mL, about 17 units/mL, about 18 units/mL, about 19 units/mL, about 20 units/mL, about 21 units/mL, about 22 units/mL, about 23 units/mL, about 24 units/mL about 25 units/mL, about 30 units/mL, about 35 units/mL, about 40 units/mL, about 45 units/mL, or about 50 units/mL. In some embodiments, the concentration of vasopressin in the container or vessel is 0.4 units/mL. In some embodiments, the concentration of vasopressin in the container or vessel is 0.6 units/mL. The concentration of vasopressin in the container or vessel in which the premixed vasopressin formulation is disposed can be, for example, about 0.01 μg/mL, about 0.05 μg/mL, about 0.1 μg/mL, about 0.15 μg/mL, about 0.2 μg/mL, about 0.25 μg/mL, about 0.3 μg/mL, about 0.35 μg/mL, about 0.4 μg/mL, about 0.5 μg/mL, about 0.6 μg/mL, about 0.7 μg/mL, about 0.8 μg/mL, about 0.9 μg/mL, about 1 μg/mL, about 2 μg/mL, about 3 μg/mL, about 4 μg/mL, about 5 μg/mL, about 10 μg/mL, about 15 μg/mL, about 20 μg/mL, about 25 μg/mL, about 30 μg/mL, about 35 μg/mL, about 40 μg/mL, about 45 μg/mL, about 50 μg/mL, about 60 μg/mL, about 70 μg/mL, about 80 μg/mL, about 90 μg/mL, about 100 μg/mL, about 125 μg/mL, about 150 μg/mL, about 175 μg/mL, about 200 μg/mL, about 250 μg/mL, about 300 μg/mL, about 350 μg/mL, about 400 μg/mL, about 450 μg/mL, about 500 μg/mL, about 600 μg/mL, about 700 μg/mL, about 800 μg/mL, about 900 μg/mL, about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, or about 10 mg/mL. A formulation formulated for use without initial vasopressin dilution can be administered as intravenous drip therapy for about 15 min, about 20 min, about 25 min, about 30 min, about 35 min, about 40 min, about 45 min, about 50 min, about 55 min, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 1 year. A formulation for use in a drip-bag can be replaced up to, for example, one time, two times, three times, four times, five times, six times, seven times, eight times, nine times, ten times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, or 20 times during the course of the treatment period. The formulation can be used for continuous or intermittent intravenous infusion. A formulation formulated for use without initial vasopressin dilution can be modified using an excipient, for example, any excipient disclosed herein, to improve the stability of vasopressin for long-term storage and use. Non-limiting examples of excipients that can be used in an intravenous drip-bag include dextrose, saline, half-strength saline, quarter-strength saline, Ringers Lactate solution, sodium chloride, and potassium chloride. In some embodiments, dextrose is used as an excipient for the vasopressin formulation formulated for use without initial vasopressin dilution. A formulation formulated for use without initial vasopressin dilution can be modified using a buffer, for example, any buffer disclosed herein, to adjust the pH of the formulation. A non-limiting example of a buffer that can be used in the formulation includes acetate buffer. The concentration of buffer used in the formulation can be, for example, about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, or about 30 mM. In some embodiments, the concentration of the acetate buffer is 1 mM. In some embodiments, the concentration of the acetate buffer is 10 mM. In some embodiments, an additive that is used in a formulation described herein is dextrose. The concentration of dextrose used in the formulation can be, for example, about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, or about 30 mM. In some embodiments, the concentration of dextrose is 1 mM. In some embodiments, the concentration of dextrose is 10 mM. The concentration of dextrose used in the formulation can be, for example, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%. In some embodiments, a formulation described herein contains 5% dextrose. In some embodiments, an additive that is used in a formulation described herein is sodium chloride. The concentration of sodium chloride used in the formulation can be, for example, about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, or about 30 mM. In some embodiments, the concentration of the sodium chloride is 1 mM. In some embodiments, the concentration of sodium chloride is 10 mM. In some embodiments, a combination of dextrose and sodium chloride is used in a formulation described herein. When used in combination, the concentration of sodium chloride and dextrose can be the same or different. In some embodiments, the concentration of dextrose or sodium chloride is 1 mM, or any value above 1 mM, when dextrose and sodium chloride are used in a combination in a formulation described herein. A formulation formulated for use without initial vasopressin dilution can be modified using a pH adjusting agent, for example, any pH adjusting agent disclosed herein, to adjust the pH of the formulation. Non-limiting examples of a pH adjusting agent that can be used in the formulation include acetic acid, sodium acetate, hydrochloric acid, and sodium hydroxide. The concentration of buffer used in the formulation can be, for example, about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, or about 30 mM. In some embodiments, the concentration of the acetate buffer is 1 mM. In some embodiments, the concentration of the acetate buffer is 10 mM. The formulation can be stable for and have a shelf-life of about 24 hours, about 36 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years of storage at any temperature. In some embodiments, the shelf-life of the formulation is 2 years under refrigeration. In some embodiments, the shelf-life of the formulation is 6 months at room temperature. In some embodiments, the total shelf-life of the formulation is 30 months, where the formulation is stored for 2 years under refrigeration and 6 months at room temperature. Dosage Amounts. In practicing the methods of treatment or use provided herein, therapeutically-effective amounts of the compounds described herein are administered in pharmaceutical compositions to a subject having a disease or condition to be treated. A therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors. Subjects can be, for example, humans, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, or neonates. A subject can be a patient. Pharmaceutical compositions of the invention can be formulated in any suitable volume. The formulation volume can be, for example, about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1 mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, about 1.4 mL, about 1.5 mL, about 1.6 mL, about 1.7 mL, about 1.8 mL, about 1.9 mL, about 2 mL, about 2.1 mL, about 2.2 mL, about 2.3 mL, about 2.4 mL, about 2.5 mL, about 2.6 mL, about 2.7 mL, about 2.8 mL, about 2.9 mL, about 3 mL, about 3.1 mL, about 3.2 mL, about 3.3 mL, about 3.4 mL, about 3.5 mL, about 3.6 mL, about 3.7 mL, about 3.8 mL, about 3.9 mL, about 4 mL, about 4.1 mL, about 4.2 mL, about 4.3 mL, about 4.4 mL, about 4.5 mL, about 4.6 mL, about 4.7 mL, about 4.8 mL, about 4.9 mL, about 5 mL, about 5.1 mL, about 5.2 mL, about 5.3 mL, about 5.4 mL, about 5.5 mL, about 5.6 mL, about 5.7 mL, about 5.8 mL, about 5.9 mL, about 6 mL, about 6.1 mL, about 6.2 mL, about 6.3 mL, about 6.4 mL, about 6.5 mL, about 6.6 mL, about 6.7 mL, about 6.8 mL, about 6.9 mL, about 7 mL, about 7.1 mL, about 7.2 mL, about 7.3 mL, about 7.4 mL, about 7.5 mL, about 7.6 mL, about 7.7 mL, about 7.8 mL, about 7.9 mL, about 8 mL, about 8.1 mL, about 8.2 mL, about 8.3 mL, about 8.4 mL, about 8.5 mL, about 8.6 mL, about 8.7 mL, about 8.8 mL, about 8.9 mL, about 9 mL, about 9.1 mL, about 9.2 mL, about 9.3 mL, about 9.4 mL, about 9.5 mL, about 9.6 mL, about 9.7 mL, about 9.8 mL, about 9.9 mL, about 10 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about 18 mL, about 19 mL, or about 20 mL. A therapeutically-effective amount of a compound described herein can be present in a composition at a concentration of, for example, about 0.1 units/mL, about 0.2 units/mL, about 0.3 units/mL, about 0.4 units/mL, about 0.5 units/mL, about 0.6 units/mL, about 0.7 units/mL, about 0.8 units/mL, about 0.9 units/mL, about 1 unit/mL, about 2 units/mL, about 3 units/mL, about 4 units/mL, about 5 units/mL, about 6 units/mL, about 7 units/mL, about 8 units/mL, about 9 units/mL, about 10 units/mL, about 11 units/mL, about 12 units/mL, about 13 units/mL, about 14 units/mL, about 15 units/mL, about 16 units/mL, about 17 units/mL, about 18 units/mL, about 19 units/mL, about 20 units/mL, about 21 units/mL, about 22 units/mL, about 23 units/mL, about 24 units/mL about 25 units/mL, about 30 units/mL, about 35 units/mL, about 40 units/mL, about 45 units/mL, or about 50 units/mL. A therapeutically-effective amount of a compound described herein can be present in a composition of the invention at a mass of about, for example, about 0.01 μg, about 0.05 μg, about 0.1 μg, about 0.15 μg, about 0.2 μg, about 0.25 μg, about 0.3 μg, about 0.35 μg, about 0.4 μg, about 0.5 μg, about 0.6 μg, about 0.7 μg, about 0.8 μg, about 0.9 μg, about 1 μg, about 2 μg, about 3 μg, about 4 μg, about 5 μg, about 10 μg, about 15 μg, about 20 μg, about 25 μg, about 30 μg, about 35 μg, about 40 μg, about 45 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 125 μg, about 150 μg, about 175 μg, about 200 μg, about 250 μg, about 300 μg, about 350 μg, about 400 μg, about 450 μg, about 500 μg, about 600 μg, about 700 μg, about 800 μg, about 900 μg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg. A therapeutically-effective amount of a compound described herein can be present in a composition of the invention at a concentration of, for example, about 0.001 mg/mL, about 0.002 mg/mL, about 0.003 mg/mL, about 0.004 mg/mL, about 0.005 mg/mL, about 0.006 mg/mL, about 0.007 mg/mL, about 0.008 mg/mL, about 0.009 mg/mL, about 0.01 mg/mL, about 0.02 mg/mL, about 0.03 mg/mL, about 0.04 mg/mL, about 0.05 mg/mL, about 0.06 mg/mL, about 0.07 mg/mL, about 0.08 mg/mL, about 0.09 mg/mL, about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 1.5 mg/mL, about 2 mg/mL, about 2.5 mg/mL, about 3 mg/mL, about 3.5 mg/mL, about 4 mg/mL, about 4.5 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, or about 10 mg/mL. A therapeutically-effective amount of a compound described herein can be present in a composition of the invention at a unit of active agent/unit of active time. Non-limiting examples of therapeutically-effective amounts can be, for example, about 0.01 units/minute, about 0.02 units/minute, about 0.03 units/minute, about 0.04 units/minute, about 0.05 units/minute, about 0.06 units/minute, about 0.07 units/minute, about 0.08 units/minute, about 0.09 units/minute or about 0.1 units/minute. Pharmaceutical compositions of the invention can be formulated at any suitable pH. The pH can be, for example, about 2, about 2.05, about 2.1, about 2.15, about 2.2, about 2.25, about 2.3, about 2.35, about 2.4, about 2.45, about 2.5, about 2.55, about 2.6, about 2.65, about 2.7, about 2.75, about 2.8, about 2.85, about 2.9, about 2.95, about 3, about 3.05, about 3.1, about 3.15, about 3.2, about 3.25, about 3.3, about 3.35, about 3.4, about 3.45, about 3.5, about 3.55, about 3.6, about 3.65, about 3.7, about 3.75, about 3.8, about 3.85, about 3.9, about 3.95, about 4, about 4.05, about 4.1, about 4.15, about 4.2, about 4.25, about 4.3, about 4.35, about 4.4, about 4.45, about 4.5, about 4.55, about 4.6, about 4.65, about 4.7, about 4.75, about 4.8, about 4.85, about 4.9, about 4.95, or about 5 pH units. Pharmaceutical compositions of the invention can be formulated at any suitable pH. The pH can be, for example, from about 2 to about 2.2, about 2.05 to about 2.25, about 2.1 to about 2.3, about 2.15 to about 2.35, about 2.2 to about 2.4, about 2.25 to about 2.45, about 2.3 to about 2.5, about 2.35 to about 2.55, about 2.4 to about 2.6, about 2.45 to about 2.65, about 2.5 to about 2.7, about 2.55 to about 2.75, about 2.6 to about 2.8, about 2.65 to about 2.85, about 2.7 to about 2.9, about 2.75 to about 2.95, about 2.8 to about 3, about 2.85 to about 3.05, about 2.9 to about 3.1, about 2.95 to about 3.15, about 3 to about 3.2, about 3.05 to about 3.25, about 3.1 to about 3.3, about 3.15 to about 3.35, about 3.2 to about 3.4, about 3.25 to about 3.45, about 3.3 to about 3.5, about 3.35 to about 3.55, about 3.4 to about 3.6, about 3.45 to about 3.65, about 3.5 to about 3.7, about 3.55 to about 3.75, about 3.6 to about 3.8, about 3.65 to about 3.85, about 3.7 to about 3.9, about 3.7 to about 3.8, about 3.75 to about 3.95, about 3.75 to about 3.8, about 3.8 to about 3.85, about 3.75 to about 3.85, about 3.8 to about 4, about 3.85 to about 4.05, about 3.9 to about 4.1, about 3.95 to about 4.15, about 4 to about 4.2, about 4.05 to about 4.25, about 4.1 to about 4.3, about 4.15 to about 4.35, about 4.2 to about 4.4, about 4.25 to about 4.45, about 4.3 to about 4.5, about 4.35 to about 4.55, about 4.4 to about 4.6, about 4.45 to about 4.65, about 4.5 to about 4.7, about 4.55 to about 4.75, about 4.6 to about 4.8, about 4.65 to about 4.85, about 4.7 to about 4.9, about 4.75 to about 4.95, about 4.8 to about 5, about 4.85 to about 5.05, about 4.9 to about 5.1, about 4.95 to about 5.15, or about 5 to about 5.2 pH units. In some embodiments, the addition of an excipient can change the viscosity of a pharmaceutical composition of the invention. In some embodiments the use of an excipient can increase or decrease the viscosity of a fluid by at least 0.001 Pascal-second (Pa·s), at least 0.001 Pa·s, at least 0.0009 Pa·s, at least 0.0008 Pa·s, at least 0.0007 Pa·s, at least 0.0006 Pa·s, at least 0.0005 Pa·s, at least 0.0004 Pa·s, at least 0.0003 Pa·s, at least 0.0002 Pa·s, at least 0.0001 Pa·s, at least 0.00005 Pa·s, or at least 0.00001 Pa·s. In some embodiments, the addition of an excipient to a pharmaceutical composition of the invention can increase or decrease the viscosity of the composition by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In some embodiments, the addition of an excipient to a pharmaceutical composition of the invention can increase or decrease the viscosity of the composition by no greater than 5%, no greater than 10%, no greater than 15%, no greater than 20%, no greater than 25%, no greater than 30%, no greater than 35%, no greater than 40%, no greater than 45%, no greater than 50%, no greater than 55%, no greater than 60%, no greater than 65%, no greater than 70%, no greater than 75%, no greater than 80%, no greater than 85%, no greater than 90%, no greater than 95%, or no greater than 99%. Any compound herein can be purified. A compound can be at least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 43% pure, at least 44% pure, at least 45% pure, at least 46% pure, at least 47% pure, at least 48% pure, at least 49% pure, at least 50% pure, at least 51% pure, at least 52% pure, at least 53% pure, at least 54% pure, at least 55% pure, at least 56% pure, at least 57% pure, at least 58% pure, at least 59% pure, at least 60% pure, at least 61% pure, at least 62% pure, at least 63% pure, at least 64% pure, at least 65% pure, at least 66% pure, at least 67% pure, at least 68% pure, at least 69% pure, at least 70% pure, at least 71% pure, at least 72% pure, at least 73% pure, at least 74% pure, at least 75% pure, at least 76% pure, at least 77% pure, at least 78% pure, at least 79% pure, at least 80% pure, at least 81% pure, at least 82% pure, at least 83% pure, at least 84% pure, at least 85% pure, at least 86% pure, at least 87% pure, at least 88% pure, at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least 99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, or at least 99.9% pure. Compositions of the invention can be packaged as a kit. In some embodiments, a kit includes written instructions on the administration or use of the composition. The written material can be, for example, a label. The written material can suggest conditions methods of administration. The instructions provide the subject and the supervising physician with the best guidance for achieving the optimal clinical outcome from the administration of the therapy. In some embodiments, the label can be approved by a regulatory agency, for example the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other regulatory agencies. Pharmaceutically-Acceptable Excipients. Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety. In some embodiments, the pharmaceutical composition provided herein comprises a sugar as an excipient. Non-limiting examples of sugars include trehalose, sucrose, glucose, lactose, galactose, glyceraldehyde, fructose, dextrose, maltose, xylose, mannose, maltodextrin, starch, cellulose, lactulose, cellobiose, mannobiose, and combinations thereof. In some embodiments, the pharmaceutical composition provided herein comprises a buffer as an excipient. Non-limiting examples of buffers include potassium phosphate, sodium phosphate, saline sodium citrate buffer (SSC), acetate, saline, physiological saline, phosphate buffer saline (PBS), 4-2-hydroxyethyl-1-piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), and piperazine-N,N′-bis(2-ethanesulfonic acid) buffer (PIPES), or combinations thereof. In some embodiments, a pharmaceutical composition of the invention comprises a source of divalent metal ions as an excipient. A metal can be in elemental form, a metal atom, or a metal ion. Non-limiting examples of metals include transition metals, main group metals, and metals of Group 1, Group 2, Group 3, Group 4, Group 5, Group 6, Group 7, Group 8, Group 9, Group 10, Group 11, Group 12, Group 13, Group 14, and Group 15 of the Periodic Table. Non-limiting examples of metals include lithium, sodium, potassium, cesium, magnesium, calcium, strontium, scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, palladium, silver, cadmium, tungsten, rhenium, osmium, iridium, platinum, gold, mercury, cerium, and samarium. In some embodiments, the pharmaceutical composition provided herein comprises an alcohol as an excipient. Non-limiting examples of alcohols include ethanol, propylene glycol, glycerol, polyethylene glycol, chlorobutanol, isopropanol, xylitol, sorbitol, maltitol, erythritol, threitol, arabitol, ribitol, mannitol, galactilol, fucitol, lactitol, and combinations thereof. Pharmaceutical preparations can be formulated with polyethylene glycol (PEG). PEGs with molecular weights ranging from about 300 g/mol to about 10,000,000 g/mol can be used. Non-limiting examples of PEGs include PEG 200, PEG 300, PEG 400, PEG 540, PEG 550, PEG 600, PEG 1000, PEG 1450, PEG 1500, PEG 2000, PEG 3000, PEG 3350, PEG 4000, PEG 4600, PEG 6000, PEG 8000, PEG 10,000, and PEG 20,000. Further excipients that can be used in a composition of the invention include, for example, benzalkonium chloride, benzethonium chloride, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorobutanol, dehydroacetic acid, ethylenediamine, ethyl vanillin, glycerin, hypophosphorous acid, phenol, phenylethyl alcohol, phenylmercuric nitrate, potassium benzoate, potassium metabisulfite, potassium sorbate, sodium bisulfite, sodium metabisulfite, sorbic acid, thimerasol, acetic acid, aluminum monostearate, boric acid, calcium hydroxide, calcium stearate, calcium sulfate, calcium tetrachloride, cellulose acetate pthalate, microcrystalline celluose, chloroform, citric acid, edetic acid, and ethylcellulose. In some embodiments, the pharmaceutical composition provided herein comprises an aprotic solvent as an excipient. Non-limiting examples of aprotic solvents include perfluorohexane, α,α,α-trifluorotoluene, pentane, hexane, cyclohexane, methylcyclohexane, decalin, dioxane, carbon tetrachloride, freon-11, benzene, toluene, carbon disulfide, diisopropyl ether, diethyl ether, t-butyl methyl ether, ethyl acetate, 1,2-dimethoxyethane, 2-methoxyethyl ether, tetrahydrofuran, methylene chloride, pyridine, 2-butanone, acetone, N-methylpyrrolidinone, nitromethane, dimethylformamide, acetonitrile, sulfolane, dimethyl sulfoxide, and propylene carbonate. The amount of the excipient in a pharmaceutical composition of the invention can be about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% by mass of the vasopressin in the pharmaceutical composition. The amount of the excipient in a pharmaceutical composition of the invention can be about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% by mass or by volume of the unit dosage form. The ratio of vasopressin to an excipient in a pharmaceutical composition of the invention can be about 100:about 1, about 95:about 1, about 90:about 1, about 85:about 1, about 80:about 1, about 75:about 1, about 70:about 1, about 65:about 1, about 60:about 1, about 55:about 1, about 50:about 1, about 45:about 1, about 40:about 1, about 35:about 1 about 30:about 1, about 25:about 1, about 20:about 1, about 15:about 1, about 10:about 1, about 9:about 1, about 8:about 1, about 7:about 1, about 6:about 1, about 5:about 1, about 4:about 1, about 3:about 1, about 2:about 1, about 1:about 1, about 1:about 2, about 1:about 3, about 1:about 4, about 1:about 5, about 1:about 6, about 1:about 7, about 1:about 8, about 1:about 9, or about 1:about 10. Pharmaceutically-Acceptable Salts. The invention provides the use of pharmaceutically-acceptable salts of any therapeutic compound described herein. Pharmaceutically-acceptable salts include, for example, acid-addition salts and base-addition salts. The acid that is added to the compound to form an acid-addition salt can be an organic acid or an inorganic acid. A base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base. In some embodiments, a pharmaceutically-acceptable salt is a metal salt. In some embodiments, a pharmaceutically-acceptable salt is an ammonium salt. Metal salts can arise from the addition of an inorganic base to a compound of the invention. The inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc. In some embodiments, a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt. Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the invention. In some embodiments, the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrrazole, pipyrrazole, imidazole, pyrazine, or pipyrazine. In some embodiments, an ammonium salt is a triethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrrazole salt, a pipyrrazole salt, an imidazole salt, a pyrazine salt, or a pipyrazine salt. Acid addition salts can arise from the addition of an acid to a compound of the invention. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid. In some embodiments, the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a glucaronate salt, a saccarate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate (mesylate) salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-toluenesulfonate salt, a citrate salt, an oxalate salt, or a maleate salt. Peptide Sequence. As used herein, the abbreviations for the L-enantiomeric and D-enantiomeric amino acids are as follows: alanine (A, Ala); arginine (R, Arg); asparagine (N, Asn); aspartic acid (D, Asp); cysteine (C, Cys); glutamic acid (E, Glu); glutamine (Q, Gln); glycine (G, Gly); histidine (H, His); isoleucine (I, Ile); leucine (L, Leu); lysine (K, Lys); methionine (M, Met); phenylalanine (F, Phe); proline (P, Pro); serine (S, Ser); threonine (T, Thr); tryptophan (W, Trp); tyrosine (Y, Tyr); valine (V, Val). In some embodiments, the amino acid is a L-enantiomer. In some embodiments, the amino acid is a D-enantiomer. A peptide of the disclosure can have about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% amino acid sequence homology to SEQ ID NO. 1. In some embodiments, a pharmaceutical composition of the invention comprises one or a plurality of peptides having about 80% to about 90% sequence homology to SEQ ID NO. 1, about 88% to about 90% sequence homology to SEQ ID NO. 1 or 88% to 90% sequence homology to SEQ ID NO. 1. In some embodiments, a pharmaceutical composition of the invention comprises vasopressin and one or more of a second, third, fourth, fifth, sixth, seventh, eighth, ninth, and tenth peptide. The ratio of vasopressin to another peptide in a pharmaceutical composition of the invention can be, for example, about 1000:about 1, about 990:about 1, about 980:about 1, about 970:about 1, about 960:about 1, about 950:about 1, about 800:about 1, about 700:about 1, about 600:1, about 500:about 1, about 400:about 1, about 300:about 1, about 200:about 1, about 100:about 1, about 95:about 1, about 90:about 1, about 85:about 1, about 80:about 1, about 75:about 1, about 70:about 1, about 65:about 1, about 60:about 1, about 55:about 1, about 50:about 1, about 45:about 1, about 40:about 1, about 35:about 1, about 30:about 1, about 25:about 1, about 20:about 1, about 19:about 1, about 18:about 1, about 17:about 1, about 16:about 1, about 15:about 1, about 14:about 1, about 13:about 1, about 12:about 1, about 11:about 1, or about 10:about 1. The amount of another peptide or impurity in a composition of the invention can be, for example, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% by mass of vasopressin. Another peptide or impurity present in a composition described herein can be, for example, SEQ ID NO.: 2, SEQ ID NO.: 3, SEQ ID NO.: 4, SEQ ID NO.: 5, SEQ ID NO.: 6, SEQ ID NO.: 7, SEQ ID NO.: 8, SEQ ID NO.: 9, SEQ ID NO.: 10, SEQ ID NO.: 11, SEQ ID NO.: 12, SEQ ID NO.: 13, SEQ ID NO.: 14, SEQ ID NO.: 15, SEQ ID NO.: 16, SEQ ID NO.: 17, a dimer of SEQ ID NO.: 1, an unidentified impurity, or any combination thereof. Non-limiting examples of methods that can be used to identify peptides of the invention include high-performance liquid chromatography (HPLC), mass spectrometry (MS), Matrix Assisted Laser Desorption Ionization Time-of-Flight (MALDI-TOF), electrospray ionization Time-of-flight (ESI-TOF), gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), and two-dimensional gel electrophoresis. HPLC can be used to identify peptides using high pressure to separate components of a mixture through a packed column of solid adsorbent material, denoted the stationary phase. The sample components can interact differently with the column based upon the pressure applied to the column, material used in stationary phase, size of particles used in the stationary phase, the composition of the solvent used in the column, and the temperature of the column. The interaction between the sample components and the stationary phase can affect the time required for a component of the sample to move through the column. The time required for component to travel through the column from injection point to elution is known as the retention time. Upon elution from the column, the eluted component can be detected using a UV detector attached to the column. The wavelength of light at which the component is detected, in combination with the component's retention time, can be used to identify the component. Further, the peak displayed by the detector can be used to determine the quantity of the component present in the initial sample. Wavelengths of light that can be used to detect sample components include, for example, about 200 nM, about 225 nm, about 250 nm, about 275 nm, about 300 nm, about 325 nm, about 350 nm, about 375 nm, and about 400 nm. Mass spectrometry (MS) can also be used to identify peptides of the invention. To prepare samples for MS analysis, the samples, containing the proteins of interest, are digested by proteolytic enzymes into smaller peptides. The enzymes used for cleavage can be, for example, trypsin, chymotrypsin, glutamyl endopeptidase, Lys-C, and pepsin. The samples can be injected into a mass spectrometer. Upon injection, all or most of the peptides can be ionized and detected as ions on a spectrum according to the mass to charge ratio created upon ionization. The mass to charge ratio can then be used to determine the amino acid residues present in the sample. The present disclosure provides several embodiments of pharmaceutical formulations that provide advantages in stability, administration, efficacy, and modulation of formulation viscosity. Any embodiments disclosed herein can be used in conjunction or individually. For example, any pharmaceutically-acceptable excipient, method, technique, solvent, compound, or peptide disclosed herein can be used together with any other pharmaceutically-acceptable excipient, method, technique, solvent, compound, or peptide disclosed herein to achieve any therapeutic result. Compounds, excipients, and other formulation components can be present at any amount, ratio, or percentage disclosed herein in any such formulation, and any such combination can be used therapeutically for any purpose described herein and to provide any viscosity described herein. EXAMPLES Example 1: Impurities of Vasopressin as Detected by HPLC To analyze degradation products of vasopressin that can be present in an illustrative formulation of vasopressin, gradient HPLC was performed to separate vasopressin from related peptides and formulation components. TABLE 2 below depicts the results of the experiment detailing the chemical formula, relative retention time (RRT), molar mass, and structure of vasopressin and detected impurities. Vasopressin was detected in the eluent using UV absorbance. The concentration of vasopressin in the sample was determined by the external standard method, where the peak area of vasopressin in sample injections was compared to the peak area of vasopressin reference standards in a solution of known concentration. The concentrations of related peptide impurities in the sample were also determined using the external standard method, using the vasopressin reference standard peak area and a unit relative response factor. An impurities marker solution was used to determine the relative retention times of identified related peptides at the time of analysis. Experimental conditions are summarized in TABLE 2 below. TABLE 2 Column YMC-Pack ODS-AM, 3 μm, 120 Å pore, 4.6 × 100 mm Column Temperature 25° C. Flow Rate 1.0 mL/min Detector 215 nm Note: For Identification a Diode Array Detector (DAD) was used with the range of 200-400 nm. Injection Volume 100 μL Run time 55 minutes Autosampler Vials Polypropylene vials Pump (gradient) Time (min) % A % B Flow 0 90 10 1.0 40 50 50 1.0 45 50 50 1.0 46 90 10 1.0 55 90 10 1.0 The diluent used for the present experiment was 0.25% v/v Acetic Acid, which was prepared by transferring 2.5 mL of glacial acetic acid into a 1-L volumetric flask containing 500 mL of water. The solution was diluted to the desired volume with water. Phosphate buffer at pH 3.0 was used for mobile phase A. The buffer was prepared by weighing approximately 15.6 g of sodium phosphate monobasic monohydrate into a beaker. 1000 mL of water was added, and mixed well. The pH was adjusted to 3.0 with phosphoric acid. The buffer was filtered through a 0.45 μm membrane filter under vacuum, and the volume was adjusted as necessary. An acetonitrile:water (50:50) solution was used for mobile phase B. To prepare mobile phase B, 500 mL of acetonitrile was mixed with 500 mL of water. The working standard solution contained approximately 20 units/mL of vasopressin. The standard solution was prepared by quantitatively transferring the entire contents of 1 vial of USP Vasopressin RS with diluent to a 50-mL volumetric flask. The intermediate standard solution was prepared by pipetting 0.5 mL of the working standard solution into a 50-mL volumetric flask. The sensitivity solution was prepared by pipetting 5.0 mL of the intermediate standard solution into a 50-mL volumetric flask. The solution was diluted to the volume with Diluent and mixed well. A second working standard solution was prepared as directed under the standard preparation. A portion of the vasopressin control sample was transferred to an HPLC vial and injected. The control was stable for 120 hours when stored in autosampler vials at ambient laboratory conditions. To prepare the impurities marker solution, a 0.05% v/v acetic acid solution was prepared by pipetting 200.0 mL of a 0.25% v/v acetic acid solution into a 1-L volumetric flask. The solution was diluted to the desired volume with water and mixed well. To prepare the vasopressin impurity stock solutions, the a solution of each impurity was prepared in a 25 mL volumetric flask and diluted with 0.05% v/v acetic acid to a concentration suitable for HPLC injection. To prepare the MAA/H-IBA (Methacrylic Acid/α-Hydroxy-isobutyric acid) stock solution, a stock solution containing approximately 0.3 mg/mL H-IBA and 0.01 mg/mL in 0.05% v/v acetic acid was made in a 50 mL volumetric flask. To prepare the chlorobutanol diluent, about one gram of hydrous chlorobutanol was added to 500 mL of water. Subsequently, 0.25 mL of acetic acid was added and the solution was stirred to dissolve the chlorobutanol. To prepare the impurity marker solution, vasopressin powder was mixed with the impurity stock solutions prepared above. The solutions were diluted to volume with the chlorobutanol diluent. The solutions were aliquoted into individual crimp top vials and stored at 2-8° C. At time of use, the solutions were removed from refrigeration (2-8° C.) and allowed to reach room temperature. The vasopressin impurity marker solution was stable for at least 120 hours when stored in auto-sampler vials at ambient laboratory conditions. The solution was suitable for use as long as the chromatographic peaks could be identified based on comparison to the reference chromatogram. To begin the analysis, the HPLC system was allowed to equilibrate for at least 30 minutes using mobile phase B, followed by time 0 min gradient conditions until a stable baseline was achieved. The diluent was injected at the beginning of the run, and had no peaks that interfered with Vasopressin at around 18 minutes as shown in FIG. 1. A single injection of the sensitivity solution was performed, wherein the signal-to-noise ratio of the Vasopressin was greater than or equal to ten as shown in FIG. 2. A single injection of the impurities marker solution was then made. The labeled impurities in the reference chromatogram were identified in the chromatogram of the marker solution based on their elution order and approximate retention times shown in FIG. 3 and FIG. 4. FIG. 4 is a zoomed in chromatograph of FIG. 3 showing the peaks that eluted between 15 and 30 minutes. The nomenclature, structure, and approximate retention times for individual identified impurities are detailed in TABLE 3. A single injection of the working standard solution was made to ensure that the tailing factor of the vasopressin peak was less than or equal to about 2.0 as shown in FIG. 5. A total of five replicate injections of the working standard solution were made to ensure that the relative standard deviation (% RSD) of the five replicate vasopressin peak areas was not more than 2.0%. Two replicate injections of the check standard preparation were to confirm that the check standard conformity was 99.0%-101.0%. One injection of the control sample was made to confirm that the assay of the control sample met the control limits established for the sample. Then, one injection of the working standard solution was made. Following the steps above done to confirm system suitability, a single injection of each sample preparation was made. The chromatograms were analyzed to determine the vasopressin and impurity peak areas. The chromatogram is depicted in FIG. 6. The working standard solution was injected after 1 to 4 sample injections, and the bracketing standard peak areas were averaged for use in the calculations to determine peak areas of vasopressin and associated impurities. The relative standard deviation (% RSD) of vasopressin peak areas for the six injections of working standard solution was calculated by including the initial five injections from the system suitability steps above and each of the subsequent interspersed working standard solution injections. The calculations were done to ensure that each of the % RSD were not more than 2.0%. The retention time of the major peak in the chromatogram of the sample preparation corresponded to that of the vasopressin peak in the working standard solution injection that preceded the sample preparation injection. The UV spectrum (200-400 nm) of the main peak in the chromatogram of the sample preparation compared to the UV spectrum of vasopressin in the working standard preparation. FIG. 7 depicts a UV spectrum of a vasopressin sample and FIG. 8 depicts a UV spectrum of vasopressin standard. To calculate the vasopressin units/mL, the following formula was used: Vasopressin   units  /  mL = R U R S × Conc   STD where: RU=Vasopressin peak area response of Sample preparation. RS=average vasopressin peak area response of bracketing standards. Conc STD=concentration of the vasopressin standard in units/mL To identify the impurities, the % Impurity and identity for identified impurities (TABLE 3) that are were greater than or equal to 0.10% were reported. Impurities were truncated to 3 decimal places and then rounded to 2 decimal places, unless otherwise specified. The impurities were calculated using the formula below: %   impurity = R I R S × Conc   STD 20   U  /  mL × 100  % where: RI=Peak area response for the impurity 20 U/mL=Label content of vasopressin TABLE 3 below details the chemical formula, relative retention time (RRT in minutes), molar mass, and structure of vasopressin and detected impurities. TABLE 3 Appr. Molar Name Formula RRT Mass (g) Vasopressin C46H65N15O12S2 1.00 1084.23 (Arginine Vasopressin, AVP) CYFQNCPRG-NH2 SEQ ID NO.: 1 (disulfide bridge between cys residues) Gly9-vasopressin C46H64N14O13S2 1.07 1085.22 (Gly9-AVP) CYFQNCPRG SEQ ID NO.: 2 (disulfide bridge between cys residues) Asp5-vasopressin C46H64N14O13S2 1.09 1085.22 (Asp5-AVP) CYFQDCPRG-NH2 SEQ ID NO.: 3 (disulfide bridge between cys residues) Glu4-vasopressin C46H64N14O13S2 1.12 1085.22 (Glu4-AVP) CYFENCPRG-NH2 SEQ ID NO.: 4 (disulfide bridge between cys residues) Acetyl-vasopressin C48H67N15O13S2 1.45 1126.27 (Acetyl-AVP) Ac-CYFQNCPRG-NH2 SEQ ID NO.: 7 (disulfide bridge between cys residues) D-Asn-vasopressin C46H65N15O12S2 0.97 1084.23 (DAsn-AVP) CYFQ(D-Asn)CPRG-NH2 SEQ ID NO.: 10 (disulfide bridge between cys residues) Dimeric-vasopressin C92H130N30O24S4 1.22 2168.46 (Dimer-AVP) (monomers cross linked by disulfide bridges) Example 2: Investigation of pH To determine a possible pH for a vasopressin formulation with good shelf life, vasopressin formulations were prepared in 10 mM citrate buffer diluted in isotonic saline across a range of pH. Stability was assessed via HPLC as in EXAMPLE 1 after incubation of the formulations at 60° C. for one week. FIG. 9 illustrates the results of the experiment. The greatest level of stability was observed at pH 3.5. At pH 3.5, the percent label claim (% LC) of vasopressin was highest, and the proportion of total impurities was lowest. Example 3: Effect of Peptide Stabilizers on Vasopressin Formulation To observe the effect of stabilizers on the degradation of vasopressin, a series of peptide stabilizers were added to a vasopressin formulation as detailed in TABLE 4. Stability of vasopressin was assessed via HPLC after incubation of the formulations at 60° C. for one week. TABLE 4 PEG Poloxamer n-Methylpyrrolidone Ethanol 400 Glycerol 188 HPbCDa (NMP) 1% 1% 1% 1% 1% 1% 10% 10% 10% 10% 10% 10% aHydroxypropyl beta-Cyclodextrin FIG. 10 illustrates the stability of vasopressin in terms of % label claim at varying concentrations of stabilizer. The results indicate that the tested stabilizers provided a greater stabilizing effect at 1% concentration than at 10%. Also, in several cases the stabilization effect was about 5% to about 10% greater than that observed in the experiments of EXAMPLE 2. Example 4: Effect of Buffer and Divalent Metals on Vasopressin Formulation To determine whether different combinations of buffers and use of divalent metals affect vasopressin stability, vasopressin formulations with varying concentrations of citrate and acetate buffers and variable concentrations of calcium, magnesium, and zinc ions were prepared. Solutions of 0 mM, 10 mM, 20 mM, and 80 mM calcium, magnesium, and zinc were prepared and each was combined with 1 mM or 10 mM of citrate or acetate buffers to test vasopressin stability. The tested combinations provided vasopressin stability comparable to that of a vasopressin formulation lacking buffers and divalent metals. However, that the addition of divalent metal ions was able to counteract the degradation of vasopressin caused by the use of a citrate buffer. Example 5: Illustrative Formulations for Assessment of Vasopressin Stability An aqueous formulation of vasopressin is prepared using 10% trehalose, 1% sucrose, or 5% NaCl and incubated at 60° C. for one week, at which point stability of vasopressin is assessed using HPLC. A formulation containing 50 units of vasopressin is lyophilized. The lyophilate is reconstituted with water and either 100 mg of sucrose or 100 mg of lactose, and the stability of vasopressin is tested via HPLC after incubation at 60° C. for one week. Co-solvents are added to a vasopressin solution to assess vasopressin stability. 95% solvent/5% 20 mM acetate buffer solutions are prepared using propylene glycol, DMSO, PEG300, NMP, glycerol, and glycerol:NMP (1:1), and used to create formulations of vasopressin. The stability of vasopressin is tested after incubation at 60° C. for one week. Amino acid and phosphate buffers are tested with vasopressin to assess vasopressin stability. Buffers of 10 mM glycine, aspartate, phosphate are prepared at pH 3.5 and 3.8 and used to create formulations of vasopressin. The stability of vasopressin is tested after incubation at 60° C. for one week. A vasopressin formulation in 10% polyvinylpyrrolidone is prepared to assess vasopressin stability. The stability of vasopressin will be tested after incubation at 60° C. for one week. A vasopressin formulation that contains 0.9% saline, 10 mM acetate buffer, 0.2 unit/mL API/mL in 100 mL of total volume is prepared. The pH of the solution is varied from pH 3.5-3.8 to test the stability of vasopressin. A vasopressin formulation in about 50% to about 80% DMSO (for example, about 80%), about 20% to about 50% ethyl acetate (for example, about 20%), and about 5% to about 30% polyvinylpyrrolidone (PVP) (for example, about 10% by mass of the formulation) is prepared to assess vasopressin stability. PVP K12 and PVP K17 are each independently tested in the formulation. The stability of vasopressin is tested after incubation at 60° C. for one week. A vasopressin formulation in about 70% to about 95% ethyl acetate, and about 5% to about 30% PVP is prepared to assess vasopressin stability. PVP K12 and PVP K17 are each independently tested in the formulation. The stability of vasopressin is tested after incubation at 60° C. for one week. A vasopressin formulation in 90% DMSO and 10% PVP is prepared to test vasopressin stability. PVP K12 and PVP K17 are each independently tested in the formulation. The stability of vasopressin is tested after incubation at 60° C. for one week. Example 6: Illustrative Vasopressin Formulation for Clinical Use A formulation for vasopressin that can be used in the clinic is detailed in TABLE 5 below: TABLE 5 Ingredient Function Amount (per mL) Vasopressin, USP Active Ingredient 20 Units (~0.04 mg) Chlorobutanol, Hydrous NF Preservative 5.0 mg Acetic Acid, NF pH Adjustment To pH 3.4-3.6 (~0.22 mg) Water for injection, USP/EP Diluent QS Example 7: Illustrative Regimen for Therapeutic Use of a Vasopressin Formulation Vasopressin is indicated to increase blood pressure in adults with vasodilatory shock (for example, adults who are post-cardiotomy or septic) who remain hypotensive despite fluids and catecholamines. Preparation and Use of Vasopressin. Vasopressin is supplied in a carton of 25 multi-dose vials each containing 1 mL vasopressin at 20 units/mL. Vasopressin is stored between 15° C. and 25° C. (59° F. and 77° F.), and is not frozen. Alternatively, a unit dosage form of vasopressin can be stored between 2° C. and 8° C. for about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. Vials of vasopressin are to be discarded 48 hours after first puncture. Vasopressin is prepared according to TABLE 6 below: TABLE 6 Mix Fluid Restriction? Final Concentration Vasopressin Diluent No 0.1 units/mL 2.5 mL (50 units) 500 mL Yes 1 unit/mL 5 mL (100 units) 100 mL Vasopressin is diluted in normal saline (0.9% sodium chloride) or 5% dextrose in water (D5W) prior to use to either 0.1 units/mL or 1 unit/mL for intravenous administration. Unused diluted solution is discarded after 18 hours at room temperature or after 24 hours under refrigeration. Diluted vasopressin should be inspected for particulate matter and discoloration prior to use whenever solution and container permit. The goal of treatment with vasopressin is optimization of perfusion to critical organs, but aggressive treatment can compromise perfusion of organs, like the gastrointestinal tract, for which function is difficult to monitor. Titration of vasopressin to the lowest dose compatible with a clinically-acceptable response is recommended. For post-cardiotomy shock, a dose of 0.03 units/minute is used as a starting point. For septic shock, a dose of 0.01 units/minute is recommended. If the target blood pressure response is not achieved, titrate up by 0.005 units/minute at 10- to 15-minute intervals. The maximum dose for post-cardiotomy shock is 0.1 units/minute and for septic shock 0.07 units/minute. After target blood pressure has been maintained for 8 hours without the use of catecholamines, taper vasopressin by 0.005 units/minute every hour as tolerated to maintain target blood pressure. Vasopressin is provided at 20 units per mL of diluent, which is packaged as 1 mL of vasopressin per vial, and is diluted prior to administration. Contraindications, Adverse Reactions, and Drug-Drug Interactions. Vasopressin is contraindicated in patients with known allergy or hypersensitivity to 8-L-arginine vasopressin or chlorobutanol. Additionally, use of vasopressin in patients with impaired cardiac response can worsen cardiac output. Adverse reactions have been observed with the use of vasopressin, which adverse reactions include bleeding/lymphatic system disorders, specifically, hemorrhagic shock, decreased platelets, intractable bleeding; cardiac disorders, specifically, right heart failure, atrial fibrillation, bradycardia, myocardial ischemia; gastrointestinal disorders, specifically, mesenteric ischemia; hepatobiliary disorders, specifically, increased bilirubin levels; renal/urinary disorders, specifically, acute renal insufficiency; vascular disorders, specifically, distal limb ischemia; metabolic disorders, specifically, hyponatremia; and skin disorders, specifically, and ischemic lesions. These reactions are reported voluntarily from a population of uncertain size. Thus, reliable estimation of frequency or establishment of a causal relationship to drug exposure is unlikely. Vasopressin has been observed to interact with other drugs. For example, use of vasopressin with catecholamines is expected to result in an additive effect on mean arterial blood pressure and other hemodynamic parameters. Use of vasopressin with indomethacin can prolong the effect of vasopressin on cardiac index and systemic vascular resistance. Indomethacin more than doubles the time to offset for vasopressin's effect on peripheral vascular resistance and cardiac output in healthy subjects. Further, use of vasopressin with ganglionic blocking agents can increase the effect of vasopressin on mean arterial blood pressure. The ganglionic blocking agent tetra-ethylammonium increases the pressor effect of vasopressin by 20% in healthy subjects. Use of vasopressin with furosemide increases the effect of vasopressin on osmolar clearance and urine flow. Furosemide increases osmolar clearance 4-fold and urine flow 9-fold when co-administered with exogenous vasopressin in healthy subjects. Use of vasopressin with drugs suspected of causing SIADH (Syndrome of inappropriate antidiuretic hormone secretion), for example, SSRIs, tricyclic antidepressants, haloperidol, chlorpropamide, enalapril, methyldopa, pentamidine, vincristine, cyclophosphamide, ifosfamide, and felbamate can increase the pressor effect in addition to the antidiuretic effect of vasopressin. Additionally, use of vasopressin with drugs suspected of causing diabetes insipidus for example, demeclocycline, lithium, foscarnet, and clozapine can decrease the pressor effect in addition to the antidiuretic effect of vasopressin. Halothane, morphine, fentanyl, alfentanyl and sufentanyl do not impact exposure to endogenous vasopressin. Use of Vasopressin in Specific Populations. Vasopressin is a Category C drug for pregnancy. Due to a spillover into the blood of placental vasopressinase, the clearance of exogenous and endogenous vasopressin increases gradually over the course of a pregnancy. During the first trimester of pregnancy the clearance is only slightly increased. However, by the third trimester the clearance of vasopressin is increased about 4-fold and at term up to 5-fold. Due to the increased clearance of vasopressin in the second and third trimester, the dose of vasopressin can be up-titrated to doses exceeding 0.1 units/minute in post-cardiotomy shock and 0.07 units/minute in septic shock. Vasopressin can produce tonic uterine contractions that could threaten the continuation of pregnancy. After delivery, the clearance of vasopressin returns to preconception levels. Overdosage. Overdosage with vasopressin can be expected to manifest as a consequence of vasoconstriction of various vascular beds, for example, the peripheral, mesenteric, and coronary vascular beds, and as hyponatremia. In addition, overdosage of vasopressin can lead less commonly to ventricular tachyarrhythmias, including Torsade de Pointes, rhabdomyolysis, and non-specific gastrointestinal symptoms. Direct effects of vasopressin overdose can resolve within minutes of withdrawal of treatment. Pharmacology of Vasopressin. Vasopressin is a polypeptide hormone that causes contraction of vascular and other smooth muscles and antidiuresis, which can be formulated as a sterile, aqueous solution of synthetic arginine vasopressin for intravenous administration. The 1 mL solution contains vasopressin 20 units/mL, chlorobutanol, NF 0.5% as a preservative, and water for injection, USP adjusted with acetic acid to pH 3.4-3.6. The chemical name of vasopressin is Cyclo (1-6) L-Cysteinyl-L-Tyrosyl-L-Phenylalanyl-L-Glutaminyl-L-Asparaginyl-L-Cysteinyl-L-Prolyl-L-Arginyl-L-Glycinamide. Vasopressin is a white to off-white amorphous powder, freely soluble in water. The structural formula of vasopressin is: Molecular Formula: C46H65N15O12S2; Molecular Weight: 1084.23 One mg of vasopressin is equivalent to 530 units. Alternatively, one mg of vasopressin is equivalent to 470 units. The vasoconstrictive effects of vasopressin are mediated by vascular V1 receptors. Vascular V1 receptors are directly coupled to phopholipase C, resulting in release of calcium, leading to vasoconstriction. In addition, vasopressin stimulates antidiuresis via stimulation of V2 receptors which are coupled to adenyl cyclase. At therapeutic doses, exogenous vasopressin elicits a vasoconstrictive effect in most vascular beds including the splanchnic, renal, and cutaneous circulation. In addition, vasopressin at pressor doses triggers contractions of smooth muscles in the gastrointestinal tract mediated by muscular V1-receptors and release of prolactin and ACTH via V3 receptors. At lower concentrations typical for the antidiuretic hormone, vasopressin inhibits water diuresis via renal V2 receptors. In patients with vasodilatory shock, vasopressin in therapeutic doses increases systemic vascular resistance and mean arterial blood pressure and reduces the dose requirements for norepinephrine. Vasopressin tends to decrease heart rate and cardiac output. The pressor effect is proportional to the infusion rate of exogenous vasopressin. Onset of the pressor effect of vasopressin is rapid, and the peak effect occurs within 15 minutes. After stopping the infusion, the pressor effect fades within 20 minutes. There is no evidence for tachyphylaxis or tolerance to the pressor effect of vasopressin in patients. At infusion rates used in vasodilatory shock (0.01-0.1 units/minute), the clearance of vasopressin is 9 to 25 mL/min/kg in patients with vasodilatory shock. The apparent half-life of vasopressin at these levels is ≦10 minutes. Vasopressin is predominantly metabolized and only about 6% of the dose is excreted unchanged in urine. Animal experiments suggest that the metabolism of vasopressin is primarily by liver and kidney. Serine protease, carboxipeptidase and disulfide oxido-reductase cleave vasopressin at sites relevant for the pharmacological activity of the hormone. Thus, the generated metabolites are not expected to retain important pharmacological activity. Carcinogenesis, Mutagenesis, Impairment of Fertility. Vasopressin was found to be negative in the in vitro bacterial mutagenicity (Ames) test and the in vitro Chinese hamster ovary (CHO) cell chromosome aberration test. In mice, vasopressin can have an effect on function and fertilizing ability of spermatozoa. Clinical Studies. Increases in systolic and mean blood pressure following administration of vasopressin were observed in seven studies in septic shock and eight studies in post-cardiotomy vasodilatory shock. Example 8: Effect of Temperature on Vasopressin Formulations To test the effect of temperature on the stability of vasopressin formulation, solutions containing 20 units/mL vasopressin and chlorobutanol, adjusted to pH 3.5 with acetic acid, were prepared. One mL of each vasopressin formulations was then filled into 3 cc vials. Each Vasopressin Formulation was stored either inverted or upright for at least three months, up to 24 months, at: (i) 5° C.; (ii) 25° C. and 60% relative humidity; or (iii) 40° C. and 75% humidity, and the amount of vasopressin (U/mL) and % total impurities were measured periodically. TABLES 7-12 below display the results of the experiments at 5° C. The results of the experiments at 25° C. are included in TABLES 13-18. All of the experiments were performed in triplicate. The results of the experiments at 40° C. are included in TABLES 19-24. For each temperature tested, three lots of the vasopressin formulation were stored for 24 months (5° C. and 25° C.) and 3 months (40° C.), and measurements were taken at regular intervals during the testing periods. “NMT” as used in the tables denotes “not more than.” The vasopressin and impurity amounts observed in the experiments conducted at 5° C. are shown in TABLES 7-12 below (AVP=Vasopressin). TABLE 7 Samples stored inverted at 5° C. Time in months Test Initial 1 2 3 6 9 12 18 24 AVP 19.4 19.4 19.4 19.3 19.5 19.4 19.5 19.4 19.3 Assay Total 2.3% 2.0% 2.1% 2.3% 2.2% 2.3% 2.6% 2.9% 2.9% Impur- ities TABLE 8 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 U/mL 19.7 19.7 19.7 19.7 19.9 19.7 19.8 19.7 19.5 Assay Total 2.7% 2.2% 2.3% 2.4% 2.1% 2.3% 2.7% 2.9% 2.9% Impurities: NMT 17.0% TABLE 9 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 U/mL 19.7 19.7 19.6 19.7 19.8 19.7 19.9 19.8 19.5 Assay Total 2.2% 1.9% 2.0% 2.2% 2.0% 2.1% 2.4% 2.6% 2.8% Impurities: NMT 17.0% TABLE 10 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 U/mL 19.4 19.5 19.4 19.4 19.5 19.5 19.5 19.4 19.3 Assay Total 2.3% 2.1% 2.1% 2.3% 2.1% 2.3% 2.5% 2.9% 2.9% Impurities: NMT 17.0% TABLE 11 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 19.7 19.7 19.6 19.7 19.8 19.7 19.8 19.7 19.5 Assay U/mL Total 2.7% 2.1% 2.2% 2.2% 2.2% 2.3% 2.6% 2.9% 2.8% Impurities: NMT 17.0% TABLE 12 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 19.7 19.7 19.6 19.7 19.8 19.7 19.9 19.8 19.5 Assay U/mL Total 2.2% 1.8% 2.0% 2.2% 2.2% 2.1% 2.4% 2.8% 2.7% Impurities: NMT 17.0% The vasopressin and impurity amounts observed in the experiments conducted at 25° C. and 60% relative humidity are shown in TABLES 13-18 below. TABLE 13 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 19.8 19.4 19.1 18.8 18.3 17.5 17.3 Assay U/mL Total 1.1% 2.4% 3.7% 4.7% 5.9% 9.0% 13.6% Impurities: NMT 17.0% TABLE 14 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 20.1 19.7 19.3 19 18.6 17.6 17.6 Assay U/mL Total 1.3% 2.5% 3.4% 4.6% 5.6% 9.0% 13.4% Impurities: NMT 17.0% TABLE 15 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 19.9 19.6 19.2 19 18.7 18 17.4 Assay U/mL Total 1.5% 2.6% 3.3% 4.6% 5.9% 9.0% 12.9% Impurities: NMT 17.0% TABLE 16 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 19.8 19.4 19.1 18.8 18.3 17.5 17.4 Assay U/mL Total 1.1% 2.4% 3.2% 4.8% 5.6% 9.2% 13.1% Impurities: NMT 17.0% TABLE 17 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 20.1 19.7 19.4 18.9 18.6 17.8 17.7 Assay U/mL Total 1.3% 2.5% 3.3% 4.5% 5.7% 9.1% 13.3% Impurities: NMT 17.0% TABLE 18 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 19.9 19.6 19.2 19 18.5 18.1 17.4 Assay U/mL Total 1.5% 2.5% 3.7% 4.7% 5.9% 9.1% 13.3% Impurities: NMT 17.0% The vasopressin and impurity amounts observed in the experiments conducted at 40° C. and 75% relative humidity are shown in TABLES 19-24 below. TABLE 19 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.8 19.1 18.6 17.3 Assay Total Impurities: 1.1% 3.7% 7.3% 10.6% NMT 17.0% TABLE 20 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.8 18.9 18.5 17.2 Assay Total Impurities: 1.1% 3.6% 7.2% 10.3% NMT 17.0% TABLE 21 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 20.1 19.3 18.7 17.6 Assay Total Impurities: 1.3% 3.6% 7.3% 10.3% NMT 17.0% TABLE 22 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 20.1 18.9 18.7 17.4 Assay Total Impurities: 1.3% 3.5% 7.1% 10.2% NMT 17.0% TABLE 23 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.9 19.2 18.3 17.4 Assay Total Impurities: 1.5% 3.7% 6.3% 10.3% NMT 17.0% TABLE 24 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.9 19.2 18.3 17.5 Assay Total Impurities: 1.5% 3.8% 6.3% 10.5% NMT 17.0% The results of the above experiments suggested that storage in either an upright or inverted position did not markedly affect the stability of vasopressin. The samples held at 5° C. exhibited little fluctuation in vasopressin amounts over 24 months, and the amount of total impurities did not increase above 3% during the testing period (TABLES 7-12). The samples held at 25° C. and 60% relative humidity exhibited a decrease in vasopressin amount of about 10-12% after 24 months (TABLES 13-18). The amount of impurities observed in the samples stored at 25° C. and 60% relative humidity after 24 months exceeded 13% in some samples, whereas the amount of impurities observed in the samples stored at 5° C. did not exceed 3% after 24 months. After about three months, the samples held at 40° C. exhibited a decrease in the amount of vasopressin of about 10-12%. The amount of impurities observed at 40° C. exceeded 10% after three months, whereas the amount of impurities observed in the samples stored at 5° C. was less than 3% after three months (TABLES 19-24). Experiments were also conducted on the same samples above over the course of the experiments to measure the amount of individual impurities in the samples, pH of the samples, chlorobutanol content, particulate matter, antimicrobial effectiveness, and bacterial endotoxin levels (TABLES 25-42). (NR=no reading; ND=not determined; UI=unidentified impurity). The anti-microbial effectiveness of the solution was established to determine the amount of antimicrobial agents in the formulation that protect against bacterial contamination. The bullets in the tables below indicate that the sample was not tested for anti-microbial effectiveness at that specific time point. The bacterial endotoxin levels were also measured for some of the formulations. The bullets in the tables below indicate that the sample was not tested for bacterial endotoxin levels at that specific time point. TABLE 25 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.4 19.4 19.4 19.3 19.5 19.4 19.5 19.4 19.3 Assay U/mL Related SEQ ID NO.: 0.5% 0.5% 0.6% 0.6% 0.6% 0.6% 0.7% 0.8% 0.9% Substances 2 NMT 6.0% SEQ ID NO.: 0.6% 0.6% 0.6% 0.7% 0.7% 0.7% 0.8% 0.9% 1.0% 4: NMT 6.0% SEQ ID NO.: 0.3% 0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR NR NR NMT 1.0% Acetyl-AVP: 0.3% 0.2% 0.3% 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% NMT 1.0% UI-0.84: NR NR 0.1% NR NR NR NR NR NR NMT 1.0% UI-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.1% NR 0.1% NR NR NR NR NR NR NMT 1.0% Total Impurities: 2.3% 2.0% 2.1% 2.3% 2.2% 2.3% 2.6% 2.9% 2.9% NMT 17.0% pH 2.5-4.5 3.5 3.5 3.5 3.5 3.5 3.5 3.5 3.8 3.5 Chlorobutanol 0.25-0.60% w/v 0.48% 0.49% 0.48% 0.48% 0.47% 0.48% 0.48% 0.49% 0.49% Particulate NMT 6000 0 1 1 1 2 16 2 4 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti-Microbial Meets Test • • • • • • • • • Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 26 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.7 19.7 19.7 19.7 19.9 19.7 19.8 19.7 19.5 Assay U/mL Related SEQ ID NO.: 0.6% 0.5% 0.5% 0.6% 0.5% 0.6% 0.7% 0.8% 0.8% Substances 2: NMT 6.0% SEQ ID NO.: 0.6% 0.6% 0.6% 0.6% 0.6% 0.7% 0.7% 0.8% 0.9% 4: NMT 6.0% SEQ ID NO.: 0.3% 0.3% 0.3% 0.4% 0.3% 0.4% 0.4% 0.4% 0.3% 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR NR NR NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% NMT 1.0% UI-0.75-0.78: 0.2% 0.2% 0.2% 0.2% NR 0.1% 0.2% 0.2% 0.2% NMT 1.0% UI-0.83-0.84: 0.1% 0.1% 0.1% NR 0.1% NR NR NR NR NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% Total Impurities: 2.7% 2.2% 2.3% 2.4% 2.1% 2.3% 2.7% 2.9% 2.9% NMT 17.0% pH 2.5-4.5 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 Chlorobutanol 0.25-0.60% w/v 0.48% 0.48% 0.48% 0.47% 0.48% 0.48% 0.49% 0.48% 0.49% Particulate NMT 6000 1 1 1 1 1 15 2 3 2 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti-Microbial Meets Test • • • • • • • • • Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 27 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.7 19.7 19.6 19.7 19.8 19.7 19.9 19.8 19.5 Assay U/mL Related SEQ ID NO.: 0.5% 0.5% 0.5% 0.5% 0.5% 0.6% 0.6% 0.8% 0.8% Substances 2: NMT 6.0% SEQ ID NO.: 0.5% 0.5% 0.5% 0.6% 0.6% 0.7% 0.7% 0.8% 0.9% 4: NMT 6.0% SEQ ID NO.: 0.3% 0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR NR NR NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% NMT 1.0% UI-0.75-0.78: NR NR NR NR NR NR NR NR NR NMT 1.0% UI-0.83-0.84: NR NR 0.1% NR NR NR NR NR 0.1% NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.76: NR NR NR 0.1% NR NR NR NR NR NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.1% NR NR NR NR NR NR NR NR NMT 1.0% Total Impurities: 2.2% 1.9% 2.0% 2.2% 2.0% 2.1% 2.4% 2.6% 2.8% NMT 17.0% pH 2.5-4.5 3.6 3.5 3.6 3.5 3.5 3.5 3.6 3.5 3.5 Chlorobutanol 0.25-0.60% w/v 0.47% 0.48% 0.47% 0.47% 0.47% 0.47% 0.48% 0.48% 0.48% Particulate NMT 6000 1 2 1 2 1 4 2 1 3 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti-Microbial Meets Test • • • • • • • • • Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 28 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.4 19.5 19.4 19.4 19.5 19.5 19.5 19.4 19.3 Assay U/mL Related SEQ ID NO.: 0.5% 0.6% 0.6% 0.6% 0.6% 0.6% 0.7% 0.8% 0.9% Substances 2: NMT 6.0% SEQ ID NO.: 0.6% 0.6% 0.6% 0.7% 0.7% 0.7% 0.7% 0.9% 1.0% 4: NMT 6.0% SEQ ID NO.: 0.3% 0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR NR NR NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% 0.3% NMT 1.0% UI-0.84: NR NR 0.1% NR NR NR NR NR NR NMT 1.0% UI-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.1% NR NR NR NR NR NR NR NR NMT 1.0% Total Impurities: 2.3% 2.1% 2.1% 2.3% 2.1% 2.3% 2.5% 2.9% 2.9% NMT 17.0% pH 2.5-4.5 3.5 3.5 3.5 3.5 3.5 3.5 3.5 3.8 3.5 Chlorobutanol 0.25-0.60% w/v 0.48% 0.48% 0.48% 0.48% 0.48% 0.48% 0.48% 0.49% 0.49% Particulate NMT 6000 0 2 2 2 1 2 2 4 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti-Microbial Meets Test • • • • • • • • • Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 29 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.7 19.7 19.6 19.7 19.8 19.7 19.8 19.7 19.5 Assay U/mL Related SEQ ID NO.: 0.6% 0.5% 0.5% 0.5% 0.6% 0.6% 0.6% 0.8% 0.7% Substances 2: NMT 6.0% SEQ ID NO.: 0.6% 0.6% 0.6% 0.6% 0.6% 0.7% 0.7% 0.8% 0.8% 4: NMT 6.0% SEQ ID NO.: 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.4% 0.4% 0.3% 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR NR NR NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.3% 0.2% 0.3% 0.3% 0.3% 0.3% NMT 1.0% UI-0.75-0.78: 0.2% 0.2% NR 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% NMT 1.0% UI-0.83-0.84: 0.1% NR 0.1% NR NR NR NR NR NR NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% 0.3% 0.3% 0.2% NMT 1.0% UI-1.67: NR NR NR 0.2% NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% Total Impurities: 2.7% 2.1% 2.2% 2.2% 2.2% 2.3% 2.6% 2.9% 2.8% NMT 17.0% pH 2.5-4.5 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 Chlorobutanol 0.25-0.60% w/v 0.48% 0.48% 0.48% 0.48% 0.48% 0.48% 0.49% 0.49% 0.49% Particulate NMT 6000 1 1 1 2 2 6 4 4 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti-Microbial Meets Test • • • • • • • • • Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 30 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.7 19.7 19.6 19.7 19.8 19.7 19.9 19.8 19.5 Assay U/mL Related SEQ ID NO.: 0.5% 0.5% 0.5% 0.5% 0.5% 0.6% 0.6% 0.8% 0.8% Substances 2: NMT 6.0% SEQ ID NO.: 0.5% 0.5% 0.5% 0.6% 0.6% 0.7% 0.7% 0.8% 0.9% 4: NMT 6.0% SEQ ID NO.: 0.3% 0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% 10: NMT 1.0% Asp5-AVP: 0.1% NR 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR NR NR NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.3% 0.2% 0.3% 0.3% 0.3% 0.3% NMT 1.0% UI-0.75-0.78: NR NR NR NR 0.2% NR NR NR NR NMT 1.0% UI-0.83-0.84: NR NR 0.1% NR NR NR NR 0.1% NR NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.76: NR NR NR 0.1% NR NR NR NR NR NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.1% NR NR NR NR NR NR NR NR NMT 1.0% Total Impurities: 2.2% 1.8% 2.0% 2.2% 2.2% 2.1% 2.4% 2.8% 2.7% NMT 17.0% pH 2.5-4.5 3.6 3.5 3.6 3.5 3.5 3.5 3.6 3.5 3.5 Chlorobutanol 0.25-0.60% w/v 0.47% 0.48% 0.47% 0.47% 0.48% 0.47% 0.48% 0.48% 0.48% Particulate NMT 6000 1 1 1 1 1 3 2 1 3 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti-Microbial Meets Test • • • • • • • • • Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 31 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 19.8 19.4 19.1 18.8 18.3 17.5 17.3 — Assay U/mL Related SEQ ID NO.: 0.1% 0.5% 1.1% 1.6% 2.0% 3.3% 4.6% — Substances 2: NMT 6.0% SEQ ID NO.: 0.1% 0.6% 1.2% 1.8% 2.2% 3.7% 5.2% — 4: NMT 6.0% SEQ ID NO.: 0.3% 0.4% 0.5% 0.5% 0.4% 0.2% 0.3% — 10: NMT 1.0% Asp5-AVP: NR 0.1% 0.3% 0.4% 0.5% 0.7% 1.0% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% 0.2% 0.2% 0.3% — NMT 1.0% UI-0.83: NR NR <0.10 NR NR NR 0.1% — NMT 1.0% UI-0.99: NR NR NR NR 0.1% NR NR — NMT 1.0% UI-1.03: 0.2% 0.2% 0.3% 0.3% 0.3% 0.2% 0.2% — NMT 1.0% UI-1.14: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% — NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.22: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.56-1.57: NR NR <0.10 0.1% 0.1% 0.2% 0.2% — NMT 1.0% UI-1.60: NR NR NR 0.1% 0.1% 0.2% NR — NMT 1.0% UI-1.74: NR NR NR NR NR 0.2% NR — NMT 1.0% UI-1.85-1.88: NR 0.2% NR NR NR 0.1% 0.1% — NMT 1.0% UI-2.09-2.10: NR 0.2% NR NR NR NR 0.4% — NMT 1.0% UI-2.15-2.16: NR NR 0.1% NR NR NR 0.5% — NMT 1.0% Total Impurities: 1.1% 2.4% 3.7% 4.7% 5.9% 9.0% 13.6% — NMT 17.0% pH 2.5-4.5 3.5 3.5 3.5 3.5 3.4 3.3 3.2 — Chlorobutanol 0.25-0.60% w/v 0.49% 0.48% 0.48% 0.47% 0.47% 0.48% 0.47 — Particulate NMT 6000 1 1 1 1 8 4 1 — Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) AntiMicrobial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 32 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 20.1 19.7 19.3 19 18.6 17.6 17.6 — Assay Related SEQ ID NO.: 2: 0.1% 0.5% 0.9% 1.5% 1.9% 3.1% 4.4% — Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 0.5% 1.1% 1.6% 2.2% 3.4% 4.9% — NMT 6.0% SEQ ID NO.: 10: 0.3% 0.4% 0.3% 0.4% 0.3% 0.4% 0.3% — NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.3% 0.4% 0.7% 0.9% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% 0.2% 0.2% 0.3% — NMT 1.0% UI-0.75-0.76: NR 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% — NMT 1.0% UI-0.83: 0.2% NR 0.1% NR NR 0.1% 0.1% — NMT 1.0% UI-0.99: NR NR NR NR 0.1% NR NR — NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.3% 0.2% — NMT 1.0% UI-1.14: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% — NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.22: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.56-1.57: NR NR 0.1% 0.1% 0.2% 0.2% 0.2% — NMT 1.0% UI-1.60: NR NR 0.1% 0.1% 0.2% 0.2% NR — NMT 1.0% UI-1.74: NR NR NR NR NR 0.2% NR — NMT 1.0% UI-1.85-1.88: NR 0.2% NR NR NR 0.1% 0.1% — NMT 1.0% UI-2.09-2.10: NR 0.2% NR NR NR NR 0.4% — NMT 1.0% UI-2.15-2.16: NR NR NR NR NR NR 0.6% — NMT 1.0% Total Impurities: 1.3% 2.5% 3.4% 4.6% 5.6% 9.0% 13.4% — NMT 17.0% pH 2.5-4.5 3.6 3.6 3.5 3.5 3.2 3.3 3.4 — Chlorobutanol 0.25-0.60% w/v 0.48% 0.49% 0.48% 0.47% 0.47% 0.47% 0.47 — Particulate NMT 6000 2 1 1 3 4 1 2 — Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) AntiMicrobial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 33 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 19.9 19.6 19.2 19 18.7 18 17.4 — Assay Related SEQ ID NO.: 2: 0.2% 0.5% 1.0% 1.5% 2.0% 3.2% 4.5% — Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 0.6% 1.1% 1.8% 2.2% 3.7% 5.0% — NMT 6.0% SEQ ID NO.: 10: 0.4% 0.4% 0.3% 0.4% 0.4% 0.3% 0.5% — NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.4% 0.5% 0.7% 1.0% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR 0.1% — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% — NMT 1.0% UI-0.12: NR 0.1% NR NR NR NR NR NMT 1.0% UI-0.75-0.76: NR NR NR NR NR NR NR NMT 1.0% UI-0.83-0.84: NR 0.1% 0.1% 0.1% 0.1% 0.1% NMT 1.0% UI-0.93: NR NR NR NR NR NR 0.1% NMT 1.0% UI-0.99: NR NR NR NR NR NR NR NMT 1.0% UI-1.02-1.03: 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% 0.3% — NMT 1.0% UI-1.15: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% NMT 1.0% UI-1.20: NR NR NR NR NR NR NR NMT 1.0% UI-1.22: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.26: NR NR NR NR NR NR NMT 1.0% UI-1.35: 0.3% NR NR NR NR NR NR NMT 1.0% UI-1.56-1.57: NR NR 0.1% NR 0.1% 0.2% 0.3% NMT 1.0% UI-1.60: NR NR 0.1% NR 0.1% NR NR — NMT 1.0% UI-1.74: NR NR NR NR NR NR NR NMT 1.0% UI-1.84-1.89: NR 0.1% NR NR NR NR 0.2% NMT 1.0% UI-1.96: 0.2% NR NR NR NR NR NR NMT 1.0% UI-2.09-2.10: NR 20.0% NR NR NR <0.10 0.1% NMT 1.0% UI-2.15-2.16: NR NR 0.1% NR NR 0.1% NR NMT 1.0% Total Impurities: 1.5% 2.6% 3.3% 4.6% 5.9% 9.0% 12.9% — NMT 17.0% pH 2.5-4.5 3.6 3.5 3.5 3.5 3.4 3.4 3.3 — Chlorobutanol 0.25-0.60% w/v 0.48% 0.47% 0.47% 0.46% 0.46% 0.46% 0.45% — Particulate NMT 6000 1 2 3 3 3 1 2 — Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) Anti-Microbial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 34 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 19.8 19.4 19.1 18.8 18.3 17.5 17.4 — Assay Related SEQ ID NO.: 2: 0.1% 0.5% 1.1% 1.6% 2.0% 3.2% 4.5% — Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 0.6% 1.2% 1.8% 2.3% 3.6% 5.0% — NMT 6.0% SEQ ID NO.: 10: 0.3% 0.4% 0.3% 0.4% 0.3% 0.2% 0.3% — NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.4% 0.4% 0.7% 0.9% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% 0.2% 0.2% 0.3% — NMT 1.0% UI-0.83: NR NR <0.10 NR NR 0.1% 0.1% — NMT 1.0% UI-0.99: NR NR NR NR NR NR NR — NMT 1.0% UI-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.2% — NMT 1.0% UI-1.14: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% — NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.22: NR NR NR NR NR NR NR — NMT 1.0% UI-1.56-1.57: NR NR NR 0.1% 0.1% 0.2% 0.2% — NMT 1.0% UI-1.60: NR NR NR NR NR 0.1% NR — NMT 1.0% UI-1.74: NR NR NR NR NR 0.2% NR — NMT 1.0% UI-1.85-1.88: NR 0.2% NR NR NR 0.1% 0.1% — NMT 1.0% UI-2.09-2.10: NR 0.2% NR NR NR NR 0.3% — NMT 1.0% UI-2.15-2.16: NR NR NR NR NR NR 0.5% — NMT 1.0% Total Impurities: 1.1% 2.4% 3.2% 4.8% 5.6% 9.2% 13.1% — NMT 17.0% pH 2.5-4.5 3.5 3.5 3.5 3.5 3.4 3.3 3.3 — Chlorobutanol 0.25-0.60% w/v 0.49% 0.48% 0.48% 0.48% 0.47% 0.48% 0.47 — Particulate NMT 6000 1 2 2 2 2 4 2 — Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) AntiMicrobial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 35 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 20.1 19.7 19.4 18.9 18.6 17.8 17.7 — Assay Related SEQ ID NO.: 2: 0.1% 0.5% 0.9% 1.4% 1.9% 3.1% 4.3% — Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 0.5% 1.1% 1.6% 2.2% 3.4% 4.9% — NMT 6.0% D-Asn-AVP: 0.3% 0.4% 0.3% 0.3% 0.3% 0.4% 0.3% — NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.3% 0.4% 0.7% 0.9% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl-AVP: 0.30% 0.30% 0.30% 0.20% 0.20% 0.20% 0.3% — NMT 1.0% UI-0.75-0.76: NR 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% NMT 1.0% UI-0.83: 0.2% NR <0.10 NR NR 0.1% 0.1% NMT 1.0% UI-0.99: NR NR NR NR 0.1% NR NR NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.2% 0.2% 0.3% 0.2% — NMT 1.0% UI-1.14: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.22: NR NR NR NR NR NR 0.4% NMT 1.0% UI-1.56-1.57: NR NR 0.1% 0.1% 0.2% 0.2% 0.3% NMT 1.0% UI-1.60: NR NR 0.1% 0.1% 0.2% 0.2% NR — NMT 1.0% UI-1.74: NR NR NR NR NR 0.2% NR NMT 1.0% UI-1.85-1.88: NR 0.2% NR NR NR 0.1% 0.1 NMT 1.0% UI-2.09-2.10: NR 0.2% NR NR NR 0.1% 0.3 NMT 1.0% UI-2.15-2.16: NR NR NR NR NR 0.5 NMT 1.0% Total Impurities: 1.3% 2.5% 3.3% 4.5% 5.7% 9.1% 13.3% — NMT 17.0% pH 2.5-4.5 3.6 3.6 3.5 3.5 3.4 3.3 3.3 — Chlorobutanol 0.25-0.60% w/v 0.48% 0.49% 0.48% 0.47% 0.47% 0.48% 0.46 — Particulate NMT 6000 2 1 1 2 5 1 4 — Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) Anti-Microbial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 36 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 19.9 19.6 19.2 19 18.5 18.1 17.4 — Assay Related SEQ ID NO.: 2: 0.2% 0.5% 1.0% 1.5% 2.1% 3.3% 4.7% — Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 0.6% 1.1% 1.7% 2.3% 3.7% 5.3% — NMT 6.0% D-Asn-AVP: 0.4% 0.4% 0.3% 0.4% 0.4% 0.3% 0.5% — NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.3% 0.5% 0.7% 1.0% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% — NMT 1.0% UI-0.12: NR NR NR NR NR NR NR NMT 1.0% UI-0.75-0.76: NR NR NR NR NR NR NR NMT 1.0% UI-0.83-0.84: NR 0.1% 0.1% 0.1% NR 0.1% 0.1% NMT 1.0% UI-0.93: NR NR NR NR NR NR 0.1% NMT 1.0% UI-0.99: NR NR NR NR NR NR NR NMT 1.0% UI-1.02-1.03: 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% 0.3% — NMT 1.0% UI-1.15: NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.22: NR NR NR NR NR NR NR NMT 1.0% UI-1.26: NR NR 0.4% NR NR NR NR NMT 1.0% UI-1.35: 0.1% NR NR NR NR NR NR NMT 1.0% UI-1.56-1.57: NR NR 0.1% 0.1% NR 0.2% 0.3% NMT 1.0% UI-1.60: NR NR NR NR NR NR NR — NMT 1.0% UI-1.74: NR NR NR NR NR NR NR NMT 1.0% UI-1.84-1.89: NR 0.1% NR NR NR NR 0.2% NMT 1.0% UI-1.96: 0.2% NR NR NR NR NR NR NMT 1.0% UI-2.09-2.10: NR NR NR NR NR <0.10 NR NMT 1.0% UI-2.15-2.16: NR NR 0.1% NR NR 0.2% NR NMT 1.0% Total Impurities: 1.5% 2.5% 3.7% 4.7% 5.9% 9.1% 13.3% — NMT 17.0% pH 2.5-4.5 3.6 3.5 3.5 3.5 3.4 3.4 3.3 — Chlorobutanol 0.25-0.60% w/v 0.48% 0.48% 0.47% 0.47% 0.46% 0.45 0.46 — Particulate NMT 6000 1 0 1 3 7 0 3 — Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) Anti-Microbial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 37 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.8 19.1 18.6 17.3 Assay Related SEQ ID NO.: 2: 0.1% 1.0% 2.4% 3.8% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.1% 2.7% 4.3% NMT 6.0% D-Asn-AVP: 0.3% 0.4% 0.3% 0.3% NMT 1.0% Asp5-AVP: ND 0.2% 0.5% 0.8% NMT 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.2% 0.2% 0.2% NMT 1.0% UI-0.13: ND 0.1% ND ND NMT 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.83-0.84: ND ND ND ND NMT 1.0% UI-1.02-1.03: 0.2% 0.3% 0.2% 0.3% NMT 1.0% UI-1.18: ND ND ND 0.2% NMT 1.0% UI-1.56-1.57: ND 0.2% 0.4% 0.4% NMT 1.0% UI-1.67: ND ND ND ND NMT 1.0% UI-1.76: ND ND ND ND NMT 1.0% UI-1.83-1.85: ND ND 0.2% 0.2% NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT 1.0% UI-1.93: ND 0.1% ND ND NMT 1.0% UI-2.05-2.08: ND ND 0.2% ND NMT 1.0% Total Impurities: 1.1% 3.7% 7.3% 10.6% NMT 17.0% pH 2.5-4.5 3.5 3.3 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.49% 0.48% 0.50% 0.47% Particulate NMT 6000 1 1 1 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 (≧25 μm) TABLE 38 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 20.1 19.3 18.7 17.6 Assay Related SEQ ID NO.: 2: 0.1% 0.9% 2.2% 3.6% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.0% 2.5% 3.9% NMT 6.0% D-Asn-AVP: 0.3% 0.4% 0.3% 0.3% NMT 1.0% Asp5-AVP: ND 0.2% 0.5% 0.8% NMT 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.2% 0.3% 0.2% NMT 1.0% UI-0.13: ND 0.1% ND ND NMT 1.0% UI-0.75-0.78: ND ND 0.2% 0.2% NMT 1.0% UI-0.80-0.84: 0.2% 0.2% ND ND NMT 1.0% UI-1.02-1.03: 0.2% 0.3% 0.2% 0.3% NMT 1.0% UI-1.18: ND ND 0.3% 0.2% NMT 1.0% UI-1.56-1.57: ND 0.2% ND 0.4% NMT 1.0% UI-1.67: ND ND ND ND NMT 1.0% UI-1.76: ND ND ND ND NMT 1.0% UI-1.81-1.85: ND ND 0.2% 0.2% NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT 1.0% UI-1.93: ND 0.1% ND ND NMT 1.0% UI-2.03-2.08: ND ND 0.2% 0.1% NMT 1.0% UI-2.14: ND ND 0.2% ND NMT 1.0% Total Impurities: 1.3% 3.6% 7.3% 10.3% NMT 17.0% pH 2.5-4.5 3.6 3.3 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.48% 0.48% 0.50% 0.47% Particulate NMT 6000 2 2 1 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 (≧25 μm) TABLE 39 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.9 19.2 18.3 17.4 Assay Related SEQ ID NO.: 2: 0.2% 0.9% 2.2% 3.8% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.0% 2.4% 4.0% NMT 6.0% D-Asn-AVP: 0.4% 0.3% 0.3% 0.3% NMT 1.0% Asp5-AVP: ND 0.2% 0.5% 0.8% NMT 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% NMT 1.0% UI-0.13: ND ND ND ND NMT 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.80-0.84: ND ND ND ND NMT 1.0% UI-1.02-1.03: 0.3% 0.2% 0.2% 0.3% NMT 1.0% UI-1.18: ND ND ND 0.2% NMT 1.0% UI-1.35: 0.1% ND ND ND NMT 1.0% UI-1.52-1.58: ND 0.2% 0.3% 0.4% NMT 1.0% UI-1.67: ND ND ND ND NMT 1.0% UI-1.76: ND ND ND ND NMT 1.0% UI-1.81-1.85: ND ND ND ND NMT 1.0% UI-1.86-1.88: ND 0.1% 0.2% ND NMT 1.0% UI-1.91-1.96: 0.2% 0.2% ND ND NMT 1.0% UI-2.02-2.08: ND ND ND 0.2% NMT 1.0% UI-2.11-2.14: ND 0.2% ND ND NMT 1.0% Total Impurities: 1.5% 3.7% 6.3% 10.3% NMT 17.0% pH 2.5-4.5 3.6 3.4 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.48% 0.47% 0.46% 0.46% Particulate NMT 6000 2 2 1 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 (≧25 μm) TABLE 40 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.8 18.9 18.5 17.2 Assay Related SEQ ID NO.: 2: 0.1% 1.0% 2.4% 3.8% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.1% 2.7% 4.3% NMT 6.0% D-Asn-AVP: 0.3% 0.3% 0.3% 0.3% NMT 1.0% Asp5-AVP: ND 0.2% 0.5% 0.8% NMT 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% UI-0.13: ND 0.1% ND ND NMT 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.83-0.84: ND ND ND ND NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.2% NMT 1.0% UI-1.18: ND ND ND 0.2% NMT 1.0% UI-1.56-1.57: ND 0.2% 0.3% 0.3% NMT 1.0% UI-1.67: ND ND ND ND NMT 1.0% UI-1.76: ND ND ND ND NMT 1.0% UI-1.83-1.85: ND ND 0.2% ND NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT 1.0% UI-1.93: ND 0.1% ND ND NMT 1.0% UI-2.05-2.08: ND ND 0.2% ND NMT 1.0% Total Impurities: 1.1% 3.6% 7.2% 10.3% NMT 17.0% Total Impurities: 1.1% 3.6% 7.2% 10.3% NMT 17.0% pH 2.5-4.5 3.5 3.3 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.49% 0.48% 0.50% 0.48% Particulate NMT 6000 1 1 1 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 (≧25 μm) TABLE 41 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 20.1 18.9 18.7 17.4 Assay Related SEQ ID NO.: 2: 0.1% 0.9% 2.3% 3.7% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.0% 2.5% 3.9% NMT 6.0% D-Asn-AVP: 0.3% 0.4% 0.3% 0.3% NMT 1.0% Asp5-AVP: ND 0.2% 0.5% 0.8% NMT 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.2% 0.3% 0.2% NMT 1.0% UI-0.13: ND ND ND ND NMT 1.0% UI-0.75-0.78: ND ND 0.2% 0.2% NMT 1.0% UI-0.80-0.84: 0.2% 0.2% ND ND NMT 1.0% UI-1.02-1.03: 2.0% 0.3% 0.2% 0.3% NMT 1.0% UI-1.18: ND ND ND 0.2% NMT 1.0% UI-1.56-1.57: ND 0.2% 0.4% 0.4% NMT 1.0% UI-1.67: ND ND ND ND NMT 1.0% UI-1.76: ND ND ND ND NMT 1.0% UI-1.83-1.85: ND ND 0.2% 0.1% NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT 1.0% UI-1.93: ND 0.1% ND ND NMT 1.0% UI-2.05-2.08: ND ND 0.2% ND NMT 1.0% UI-2.14: ND ND ND ND NMT 1.0% Total Impurities: 1.3% 3.5% 7.1% 10.2% NMT 17.0% pH 2.5-4.5 3.6 3.3 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.48% 0.48% 0.49% 0.47% Particulate NMT 6000 2 1 1 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 (≧25 μm) TABLE 42 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.9 19.2 18.3 17.5 Assay Related SEQ ID NO.: 2: 0.2% 1.0% 2.2% 3.9% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.1% 2.4% 4.2% NMT 6.0% D-Asn-AVP: 0.4% 0.3% 0.3% 0.3% NMT 1.0% Asp5-AVP: ND 0.2% 50.0% 0.8% NMT 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% NMT 1.0% UI-0.13: ND ND ND ND NMT 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.80-0.84: ND ND ND ND NMT 1.0% UI-1.02-1.03: 0.3% 0.2% 0.2% 0.3% NMT 1.0% UI-1.18: ND ND ND 0.2% NMT 1.0% UI-1.35: 0.1% ND ND ND NMT 1.0% UI-1.52-1.58: ND 0.2% 0.3% 0.4% NMT 1.0% UI-1.67: ND ND ND ND NMT 1.0% UI-1.76: ND ND ND ND NMT 1.0% UI-1.83-1.85: ND ND ND ND NMT 1.0% UI-1.86-1.88: ND 0.1% 0.2% ND NMT 1.0% UI-1.91-1.96: 0.2% 0.2% ND ND NMT 1.0% UI-2.02-2.08: ND ND ND 0.1% NMT 1.0% UI-2.11-2.14: ND 0.2% ND ND NMT 1.0% Total Impurities: 1.5% 3.8% 6.3% 10.5% NMT 17.0% pH 2.5-4.5 3.6 3.4 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.48% 0.47% 0.47% 0.45% Particulate NMT 6000 1 2 1 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 (≧25 μm) Example 9: Effect of pH 3.5-4.5 on Vasopressin Formulations To test of effect of pH on vasopressin formulations, solutions containing 20 units/mL vasopressin, adjusted to pH 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, or 4.5 with 10 mM acetate buffer, were prepared. One mL of each of the vasopressin formulations was then filled into 10 cc vials. The vasopressin formulations were stored for four weeks at: (i) 25° C.; or (ii) 40° C., and the assay (% label claim; vasopressin remaining) and % total impurities after four weeks were measured using the methods described in EXAMPLE 1. FIGS. 11 and 12 below display the results of the experiments at 25° C. The results of the experiments at 40° C. are included in FIGS. 13 and 14. The results of the experiments suggested that the stability of a vasopressin formulation was affected by pH. At 25° C., the remaining vasopressin after four weeks was highest between pH 3.6 and pH 3.8 (FIG. 11). Within the range of pH 3.6 to pH 3.8, the level of impurities was lowest at pH 3.8 (FIG. 12). At 25° C., pH 3.7 provided the highest stability for vasopressin (FIG. 11). At 40° C., the remaining vasopressin after four weeks was highest between pH 3.6 and pH 3.8 (FIG. 13). Within the range of pH 3.6 to pH 3.8, the level of impurities was lowest at pH 3.8 (FIG. 14). At 40° C., pH 3.6 provided the highest stability for vasopressin (FIG. 13), Example 10: Effect of pH 2.5-4.5 of Vasopressin Formulations To test of effect of pH on vasopressin formulations, solutions containing 20 units/mL vasopressin, adjusted to pH 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, or 3.4 with 10 mM acetate buffer were also prepared. One mL of each of the vasopressin formulations was then filled into 10 cc vials. The amount of vasopressin, impurities, and associated integration values were determined using the methods describes in EXAMPLE 1. The results from the stability tests on the vasopressin formulations from pH 2.5 to 3.4 were plotted against the results from the stability tests on vasopressin formulations from pH 3.5 to 4.5 as disclosed in EXAMPLE 9, and are displayed in FIGS. 15-18. The assay (% label claim; vasopressin remaining) and % total impurities in the vasopressin pH 2.5 to 3.4 formulations after four weeks are reported in TABLE 43. TABLE 43 Target Vasopressin % Total Batch pH Week Condition (% LC) Impurities 1A 2.5 0 25° C. 100.57 2.48 1B 2.6 0 25° C. 101.25 2.24 1C 2.7 0 25° C. 101.29 2.26 1D 2.8 0 25° C. 101.53 2.00 1E 2.9 0 25° C. 102.33 1.95 1F 3 0 25° C. 102.32 1.89 1G 3.1 0 25° C. 102.59 2.06 1H 3.2 0 25° C. 102.60 1.85 1I 3.3 0 25° C. 102.73 1.81 1J 3.4 0 25° C. 101.93 1.75 1A 2.5 0 40° C. 100.57 2.48 1B 2.6 0 40° C. 101.25 2.24 1C 2.7 0 40° C. 101.29 2.26 1D 2.8 0 40° C. 101.53 2.00 1E 2.9 0 40° C. 102.33 1.95 1F 3 0 40° C. 102.32 1.89 1G 3.1 0 40° C. 102.59 2.06 1H 3.2 0 40° C. 102.60 1.85 1I 3.3 0 40° C. 102.73 1.81 1J 3.4 0 40° C. 101.93 1.75 1A 2.5 4 25° C. 95.70 6.66 1B 2.6 4 25° C. 98.58 5.29 1C 2.7 4 25° C. 98.94 4.26 1D 2.8 4 25° C. 99.14 3.51 1E 2.9 4 25° C. 100.08 3.41 1F 3 4 25° C. 100.29 2.92 1G 3.1 4 25° C. 100.78 2.55 1H 3.2 4 25° C. 100.74 2.16 1I 3.3 4 25° C. 100.46 2.14 1J 3.4 4 25° C. 100.25 2.03 1A 2.5 4 40° C. 81.89 19.41 1B 2.6 4 40° C. 90.10 15.60 1C 2.7 4 40° C. 92.19 13.46 1D 2.8 4 40° C. 94.89 10.98 1E 2.9 4 40° C. 96.03 9.78 1F 3 4 40° C. 97.26 8.09 1G 3.1 4 40° C. 99.61 6.39 1H 3.2 4 40° C. 98.58 5.25 1I 3.3 4 40° C. 97.81 4.41 1J 3.4 4 40° C. 97.35 3.85 The % total impurities for the pH 2.5 to 3.4 formulations and the pH 3.5 to 4.5 formulations observed in the experiments conducted at 25° C. and 40° C. are shown in FIGS. 15 (25° C.) and 16 (40° C.). The vasopressin assay amount for the vasopressin pH 2.5 to 3.4 formulations and the vasopressin pH 3.5 to 4.5 formulations observed in the experiments conducted at 25° C. and 40° C. are shown in FIGS. 17 (25° C.) and 18 (40° C.). The vasopressin assay is presented as a % assay decrease of vasopressin over the four-week study period, rather than absolute assay, because the amount of starting vasopressin varied between the vasopressin pH 2.5 to 3.4 formulations and the vasopressin pH 3.5 to 4.5 formulations. The results of the above experiments suggested that the stability of a vasopressin formulation was affected by pH. At 25° C., the percent decrease in vasopressin after four weeks was lowest between pH 3.7 and pH 3.8 (FIG. 17). Within the range of pH 3.7 to pH 3.8, the level of impurities was lowest at pH 3.8 (FIG. 15). At 40° C., the percent decrease in vasopressin after four weeks was lowest between pH 3.6 and pH 3.8 (FIG. 18). Within the range of pH 3.6 to pH 3.8, the level of impurities was lowest at pH 3.8 (FIG. 16). Example 11: Intra-Assay and Inter-Analysis Precision of Vasopressin pH Experiments The methods used to determine the % assay decrease and amount of impurities in the vasopressin solutions over time in EXAMPLE 10 had both intra-assay and inter-analyst precision. Intra-assay precision was demonstrated by performing single injections of aliquots of a vasopressin formulation (n=6; Chemist 1) from a common lot of drug product and determining the assay and repeatability (% RSD; relative standard deviation). Inter-analyst precision was demonstrated by two different chemists testing the same lot of drug product; however, the chemists used different instruments, reagents, standard preparations, columns, and worked in different laboratories. The procedure included a common pooling of 20 vials of vasopressin, which were assayed by the two chemists using different HPLC systems and different HPLC columns. The vasopressin assay results (units/mL) and repeatability (% RSD for n=6) were recorded and are reported in the TABLE 44 below. TABLE 44 Precision of Vasopressin Results. Chemist 1 Chemist 2 Sample (units/mL) (units/mL) 1 19.74 19.65 2 19.76 19.66 3 19.77 19.66 4 19.75 19.72 5 19.97 19.73 6 19.65 19.73 Mean 19.8 19.7 % RSD (≦2.0%) 0.5% 0.2% % Difference = 0.5% (acceptance criteria: ≦3.0%) %   Difference = ( Chemist   1 Mean - Chemist   2 Mean ) ( Chemist   1 Mean + Chemist   2 Mean ) × 200 The intra-assay repeatability met the acceptance criteria (% RSD≦2.0%) with values of 0.5% and 0.2%. The inter-analyst repeatability also met the acceptance criteria (% difference≦3.0%) with a difference of 0.5%. Example 12: Effect of Citrate Versus Acetate Buffer on Vasopressin Formulations To test the effect of citrate and acetate buffer on vasopressin formulations, a total of twelve solutions of 20 Units/mL vasopressin were prepared in 1 mM citrate buffer, 10 mM citrate buffer, 1 mM acetate buffer, and 10 mM acetate buffer. All of the solutions were prepared in triplicate. Each solution was adjusted to pH 3.5 with hydrochloric acid. The vasopressin formulations were stored at 60° C. for 7 days, and the assay (% label claim; vasopressin remaining) and % total impurities after 7 days were analyzed by HPLC using the procedure and experimental conditions described in EXAMPLE 1. The assay (% label claim; vasopressin remaining) and % total impurities for each of the Vasopressin Buffered Formulations are reported in the TABLES 45 and 46 below. TABLE 45 Assay (% label claim; vasopressin remaining) in the vasopressin formulations after storage at 60° C. for 7 days. Sample Buffer 1 2 3 Average 1 mM citrate buffer 89.5% 89.7% 90.6% 89.9% 10 mM citrate buffer 84.1% 84.4% 84.5% 84.3% 1 mM acetate buffer 90.5% 91.1% 91.9% 91.2% 10 mM acetate buffer 90.9% 90.9% 92.4% 91.4% TABLE 46 % Total Impurities in the vasopressin formulations after storage at 60° C. for 7 days. Sample Buffer 1 2 3 Average 1 mM citrate buffer 3.4% 3.5% 2.5% 3.1% 10 mM citrate buffer 9.5% 9.0% 9.4% 9.3% 1 mM acetate buffer 3.3% 2.8% 3.2% 3.1% 10 mM acetate buffer 2.9% 2.6% 3.1% 2.9% The data indicated that the vasopressin assay in the vasopressin formulations with citrate buffer was lower than in the vasopressin formulations with acetate buffer. For example, at 10 mM of either citrate or acetate buffer, the average vasopressin assay was 91.4% in acetate buffer, but was 84.3% in citrate buffer. The data also indicated that % total impurities in the vasopressin formulations with citrate buffer were higher than in the vasopressin formulations with acetate buffer. For example, at 10 mM of either citrate or acetate buffer, the average % total impurities was 2.9% in acetate buffer, but was 9.3% in citrate buffer. Further, as the citrate buffer concentration increased, the vasopressin assay further decreased (from an average of 89.9% to 84.3%), and the % total impurities increased (from an average of 3.1% to 9.3%). This effect was not observed in the vasopressin formulations with acetate buffer, where the average and % total impurities stayed fairly constant. Example 13: Multi-Dose Vasopressin Formulation A multi-dose formulation (10 mL) for vasopressin that can be used in the clinic is detailed in TABLE 47 below: TABLE 47 Drug Product Description Vasopressin, Active Ingredient 20 Units USP (~0.04 mg) Dosage Form Injection — Route of Intravenous — Administration Description Clear colorless to practically colorless solution supplied in a 10 mL clear glass vial with flip-off cap The composition of a 10 mL formulation of vasopressin is provided below. TABLE 48 Drug Product Composition Unit Ingredient Grade Function Batch Quantity Formula Vasopressin, USP Active 3,000,000 Units 20 Units USP Sodium USP Buffer 214.2 g 1.36 mg Acetate Trihydrate Sodium NF pH Adjustor 40 g QS to Hydroxide pH 3.8 Hydrochloric NF/EP pH Adjustor 237.9 g QS to Acid pH 3.8 Chlorobutanol NF Preservative 0.8274 kg 5 mg Water for USP Solvent QS QS to 1 mL Injection Nitrogen NF Processing Aid The 10 mL vasopressin formulation was compared to the guidelines for inactive ingredients provided by the Food and Drug Administration (FDA). The results are shown in TABLE 49 below. TABLE 49 Inactive Vasopressin Ingredients 10 mL Guideline Formulation Concentration Acceptable Ingredient (mg/mL) (% w/v) Level Sodium Acetate 1.36 0.136% IV (infusion); Trihydrate Injection 0.16% Sodium Hydroxide QS to pH 3.8 QS to pH 3.8 N/A Hydrochloric Acid QS to pH 3.8 QS to pH 3.8 N/A Chlorobutanol 5 mg 0.5% IV (Infusion); Injection 1% Water for Injection QS to 1 mL QS to target N/A volume Example 14: Alternative Vasopressin Formulation for Clinical Use A 1 mL dosage of vasopressin was prepared. A description of the formulation is shown in TABLE 50 below TABLE 50 Drug Product Description Vasopressin, 20 Units/mL USP Active Ingredient (~0.04 mg) Dosage Form Injection — Route of Intravenous — Administration Description Clear colorless to practically — colorless solution supplied in a 3 mL vial with flip-off cap The drug composition of the formulation is provided in TABLE 51. TABLE 51 Drug Product Composition Ingredient Function Quantity (mg/mL) Vasopressin, USP Active 20 Units Sodium Acetate Trihydrate, USP Buffer 1.36 Sodium Hydroxide NF/EP pH QS for pH adjustment Adjustor to pH 3.8 Hydrochloric Acid, NF/EP pH QS for pH adjustment Adjustor to pH 3.8 Water for Injection Solvent QS to 1 mL The 1 mL vasopressin formulation was compared to the guidelines for inactive ingredients provided by the Food and Drug Administration (FDA). The results are shown in TABLE 52 below. TABLE 52 Inactive Vasopressin Ingredients 1 mL Guideline Formulation Concentration Acceptable Ingredient (mg/mL) (% w/v) Level Sodium Acetate 1.36 0.136% 0.16% Trihydrate Sodium Hydroxide QS to pH 3.8 QS to pH 3.8 8% Hydrochloric Acid QS to pH 3.8 QS to pH 3.8 10% Water for Injection QS to 1 mL QS to target N/A volume Example 15: 15-Month Stability Data for Vasopressin Formulations The drug product detailed in TABLE 51 was tested for stability over a 15-month period. Three different lots (X, Y, and Z) of the vasopressin drug formulation were stored at 25° C. for 15 months in an upright or inverted position. At 0, 1, 2, 3, 6, 9, 12, 13, 14, and 15 months, the amount of vasopressin (AVP), % label claim (LC), amount of various impurities, and pH was measured. The vasopressin and impurity amounts were determined using the HPLC method described above in EXAMPLE 1. The results of the stability experiment are shown in TABLES 53-54 below. TABLE 53 Inverted Storage of Vasopressin Formulations at 25° C. UI- UI UI- UI- UI- UI- UI- UI- AVP Ace- 0.81- 0.97 1.02- 1.72- 1.81- 1.90- 2.05- 2.09- Total (U/ % Gly9 Glu4 D-Asn Asp5 Dimer tyl 0.86 0.99 1.03 1.76 1.89 1.96 2.07 2.10 Impuri- Lot Month mL) LC (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) ties pH X 0 19.6 97.9 0.3 0.4 0.3 1.0 3.8 Y 0 19.7 98.6 0.3 0.4 0.3 1.1 3.8 Z 0 19.9 99.3 0.1 0.5 0.2 0.8 3.8 X 1 19.6 98.1 0.2 0.2 0.1 0.4 0.4 0.3 1.6 3.8 Y 1 19.6 97.9 0.2 0.2 0.1 0.4 0.4 0.3 1.6 3.9 Z 1 19.8 99 0.2 0.2 0.6 0.1 0.2 1.4 3.8 X 2 19.6 98.1 0.3 0.3 0.1 0.3 0.4 0.3 1.7 3.7 Y 2 19.5 97.5 0.2 0.3 0.1 0.3 0.4 0.3 1.6 3.8 Z 2 19.8 99 0.3 0.4 0.5 0.2 1.3 3.8 X 3 19.6 97.8 0.4 0.5 0.1 0.1 0.3 0.4 0.4 2.2 Y 3 19.5 97.4 0.4 0.4 0.1 0.3 0.4 0.4 2.0 3.8 Z 3 19.7 98.6 0.4 0.4 0.5 0.3 1.6 X 6 19.3 96.5 0.7 0.8 0.1 0.2 0.3 0.4 0.4 2.9 3.8 Y 6 19.2 95.9 0.6 0.7 0.1 0.1 0.1 0.3 0.4 0.4 2.5 3.9 Z 6 19.6 98 0.6 0.7 0.1 0.5 0.2 2.3 3.9 X 9 19 95 1.0 1.0 0.2 0.3 0.4 0.4 0.1 3.6 Y 9 18.9 94.5 0.8 1.0 0.2 0.3 0.4 0.4 0.1 3.1 3.9 Z 9 19.2 96 1.0 1.1 0.2 0.5 0.3 3.1 3.8 X 12 18.7 93.5 1.4 1.5 0.1 0.3 0.3 0.4 0.5 0.2 4.8 3.8 Y 12 18.6 93 1.1 1.2 0.2 0.2 0.3 0.4 0.5 0.3 0.2 4.4 3.8 Z 12 18.9 94.5 1.2 1.3 0.3 0.5 0.3 0.3 0.1 4.0 3.8 X 13 18.6 93 1.5 1.6 0.2 0.3 0.4 0.4 0.1 0.4 0.2 0.1 5.2 3.8 Y 13 18.5 92.5 1.2 1.3 0.2 0.3 0.3 0.4 0.1 0.5 0.1 0.4 0.2 0.2 5.2 3.9 Z 13 19 95 1.3 1.5 0.1 0.3 0.5 0.1 0.3 0.1 0.3 0.2 0.2 4.9 3.8 X 14 18.6 93 1.5 1.7 0.1 0.3 0.3 0.5 0.1 0.4 0.4 0.1 0.1 5.5 3.8 Y 14 18.5 92.5 1.2 1.4 0.1 0.3 0.3 0.5 0.1 0.4 0.5 0.2 0.2 5.3 3.9 Z 14 18.9 94.5 1.3 1.6 0.3 0.5 0.2 0.3 0.4 0.2 0.2 5.0 3.8 X 15 18.5 92.5 1.6 1.8 0.1 0.4 0.3 0.4 0.1 0.4 0.3 0.2 0.2 5.9 3.8 Y 15 18.4 92 1.3 1.5 0.1 0.3 0.3 0.4 0.1 0.4 0.5 0.3 0.1 5.3 3.9 Z 15 18.8 94 1.5 1.6 0.3 0.5 0.3 0.4 0.2 0.1 4.9 3.9 TABLE 54 Upright Storage of Vasopressin Formulations at 25° C. UI- UI UI- UI- UI- UI- UI- UI- AVP Ace- 0.81- 0.97 1.02- 1.72- 1.81- 1.90- 2.05- 2.09- Total (U/ % Gly9 Glu4 D-Asn Asp5 Dimer tyl 0.86 0.99 1.03 1.76 1.89 1.96 2.07 2.10 Impuri- Lot Month mL) LC (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) ties pH X 0 19.6 97.9 0.3 0.4 0.3 1.0 3.8 Y 0 19.7 98.6 0.3 0.4 0.3 1.1 3.8 Z 0 19.9 99.3 0.1 0.5 0.2 0.8 3.8 X 1 19.6 98 0.2 0.2 0.1 0.3 0.4 0.3 1.6 3.8 Y 1 19.5 97.7 0.2 0.2 0.3 0.4 0.3 1.4 3.9 Z 1 19.7 98.3 0.2 0.2 0.6 0.2 1.2 3.8 X 2 19.6 98.2 0.3 0.3 0.3 0.4 0.3 1.6 3.7 Y 2 19.5 97.4 0.2 0.3 0.1 0.4 0.4 0.3 1.6 3.8 Z 2 19.8 99 0.3 0.3 0.5 0.2 1.3 3.8 X 3 19.5 97.6 0.4 0.4 0.1 0.3 0.4 0.4 2.1 3.7 Y 3 19.5 97.5 0.4 0.4 0.1 0.4 0.4 1.9 3.8 Z 3 19.7 98.7 0.4 0.4 0.1 0.5 0.3 1.7 X 6 19.3 96.5 0.7 0.8 0.1 0.2 0.3 0.4 0.4 2.9 3.8 Y 6 19.2 96 0.5 0.7 0.1 0.1 0.3 0.4 0.4 2.5 3.9 Z 6 19.5 97.5 0.7 0.7 0.2 0.5 0.3 2.3 3.9 X 9 18.9 94.5 1.0 1.1 0.2 0.3 0.4 0.2 0.1 3.7 3.8 Y 9 18.9 94.5 0.8 0.9 0.2 0.4 0.4 0.2 3.1 3.9 Z 9 19.2 96 0.9 1.0 0.2 0.5 0.3 2.9 3.8 X 12 18.6 93 1.4 1.5 0.1 0.3 0.3 0.4 0.5 0.2 0.1 4.8 3.7 Y 12 18.7 93.5 1.1 1.2 0.1 0.3 0.3 0.4 0.5 0.2 0.2 4.6 3.9 Z 12 18.9 94.5 1.3 1.4 0.3 0.5 0.4 0.3 0.2 4.2 3.8 X 13 18.4 92 1.5 1.6 0.2 0.3 0.3 0.4 0.1 0.4 0.3 0.1 0.1 5.4 3.8 Y 13 18.6 93 1.1 1.3 0.2 0.3 0.3 0.4 0.1 0.4 0.3 0.2 4.6 3.9 Z 13 18.8 94 1.3 1.5 0.3 0.5 0.1 0.3 0.4 0.2 0.1 4.7 3.8 X 14 18.6 93 1.5 1.7 0.1 0.4 0.3 0.4 0.1 0.4 0.3 0.1 5.4 3.8 Y 14 18.5 92.5 1.2 1.4 0.1 0.3 0.3 0.5 0.4 0.5 0.3 0.3 5.4 3.9 Z 14 18.8 94 1.3 1.5 0.3 0.5 0.1 0.3 0.5 0.2 0.2 5.0 3.8 X 15 18.4 92 1.6 1.8 0.1 0.4 0.3 0.4 0.1 0.4 0.3 0.2 5.7 3.8 Y 15 18.4 92 1.3 1.5 0.2 0.3 0.3 0.4 0.1 0.4 0.5 0.3 0.3 5.4 3.9 Z 15 18.6 93 1.5 1.6 0.3 0.5 0.2 0.4 0.2 0.3 5.1 3.9 The results from TABLES 53-54 indicate that stability of the vasopressin formulations was not significantly affected by either inverted or upright storage. The impurities detected included Gly9 (SEQ ID NO.: 2), Glu4 (SEQ ID NO.: 4), D-Asn (SEQ ID NO.: 10), Asp5 (SEQ ID NO.: 3), Acetyl-AVP (SEQ ID NO.: 7), vasopressin dimer, and several unidentified impurities (UI). The unidentified impurities are labeled with a range of relative retention times at which the impurities eluted from the column. The results indicate that the pH remained fairly constant over the 15-month period, fluctuating between 3.8 and 3.9 throughout the 15 months. The total impurities did not increase over 5.9%, and the % LC of vasopressin did not decrease below 92%. FIG. 19 shows a graph depicting the % LC over the 15-month study period for the results provided in TABLES 53-54. The starting amounts of vasopressin were 97.9% LC for lot X, 98.6% LC for lot Y, and 99.3% LC for lot Z. The results indicate that the % LC of vasopressin decreased over the 15-month study period, but did not decrease below 92% LC. The formula for the trend line of lot X was: %LC=98.6−0.4262(month) The formula for the trend line of lot Y was: %LC=98.47−0.4326(month) The formula for the trend line of lot Z was: %LC=99.54−0.3906(month) Example 16: Vasopressin Formulation for Bottle or Intravenous Drip-Bag The following formulations can be used without initial vasopressin dilution in drip-bags for intravenous therapy. TABLE 55 Formulation A (40 IU/100 mL) (10 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Sodium chloride (mg) 8.7 Acetic acid (mg) 0.546 Sodium Acetate Trihydrate (mg) 0.12 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 56 Formulation B (60 IU/100 mL) (10 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.6 Sodium chloride (mg) 8.7 Acetic acid (mg) 0.546 Sodium Acetate Trihydrate (mg) 0.12 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 57 Formulation C (40 IU/100 mL) (10 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Dextrose Anhydrous (mg) 50 Acetic acid (mg) 0.546 Sodium Acetate Trihydrate (mg) 0.12 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 58 Formulation D (60 IU/100 mL) (10 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.6 Dextrose Anhydrous (mg) 50 Acetic acid (mg) 0.546 Sodium Acetate Trihydrate (mg) 0.12 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 59 Formulation E (40 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Sodium chloride (mg) 8.7 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 60 Formulation F (60 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.6 Sodium chloride (mg) 8.7 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 61 Formulation G (40 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Dextrose Anhydrous (mg) 50 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 62 Formulation H (60 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.6 Dextrose Anhydrous (mg) 50 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 63 Formulation 9 (60 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Dextrose Anhydrous (mg) 45 Sodium Chloride (mg) 0.9 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Example 17: Impurity Measurement for Vasopressin Formulation for Bottle or Intravenous Drip-Bag Gradient HPLC was used to determine the concentration of vasopressin and associated impurities in vasopressin formulations similar to those outlined in TABLES 55-63 above. Vasopressin was detected in the eluent using UV absorbance at a short wavelength. The concentration of vasopressin in the sample was determined by the external standard method, where the peak area of vasopressin in sample injections was compared to the peak area of a vasopressin reference standard in a solution of known concentration. The concentrations of related peptide impurities in the sample were also determined using the external standard method, using the vasopressin reference standard peak area and a unit relative response factor. An impurities marker solution was used to determine the relative retention times of identified related peptides at the time of analysis. The chromatographic conditions used for the analysis are shown in TABLE 64 below: TABLE 64 Column Phenomenex Kinetex XB-C18, 2.6 μm, 100 Å pore, 4.6 × 150 mm, Part No. 00F-4496-E0 Column 35° C. Temperature Flow Rate 1.0 mL/min Detector VWD: Signal at 215 nm Injection Volume 500 μL Run time 55 minutes Auto sampler Vials Amber glass vial Auto Sampler 10° C. Temperature Pump (gradient) Time (min) % A % B Flow 0 90 10 1.0 40 50 50 1.0 45 50 50 1.0 46 90 10 1.0 55 90 10 1.0 Diluent A was 0.25% v/v acetic acid, which was prepared by pipetting 2.5 mL of glacial acetic acid into a 1 L volumetric flask containing 500 mL of water. The volume was diluted with water and mixed well. Diluent B was prepared by weighing and transferring about 3 g of sodium chloride into a 1 L volumetric flask and then adding 2.5 mL of glacial acetic acid. The solution was diluted to volume with water and mixed well. Phosphate buffer at pH 3.0 was used for mobile phase A. The buffer was prepared by weighing approximately 15.6 g of sodium phosphate monobasic monohydrate into a beaker. 1000 mL of water was added, and mixed well. The pH was adjusted to 3.0 with phosphoric acid. The buffer was filtered through a 0.45 μm membrane filter under vacuum, and the volume was adjusted as necessary. An acetonitrile:water (50:50) solution was used for mobile phase B. To prepare mobile phase B, 500 mL of acetonitrile was mixed with 500 mL of water. The stock standard solution was prepared at 20 units/mL of vasopressin. A solution of vasopressin in diluent was prepared at a concentration of about 20 units/mL. The stock standard solution was prepared by quantitatively transferring the entire contents of 5 vials of USP Vasopressin RS with diluent A to the same 250-mL volumetric flask. The solution was diluted to volume with diluent A and mixed well. 10 mL aliquots of the standard solution was transferred into separate polypropylene tubes. The aliquots were stored at 2-8° C. The stock standard solution was stable for 6 months from the date of preparation when stored in individual polypropylene tubes at 2-8° C. The working standard solution contained about 0.5 units/mL of vasopressin. Aliquots of the stock standard solution were allowed to warm to room temperature and then mixed well. 2.5 mL of the stock standard solution was transferred into a 100 mL volumetric flask and diluted to volume with Diluent B, and the resultant mixture was denoted as the Working Standard Solution. The stock standard solution and working standard solution can also be prepared from a single vasopressin vial in the following manner. One vial of vasopressin with diluent A can be quantitatively transferred to a 50-mL volumetric flask. The solution can be dissolved in and diluted to volume with diluent A and mixed well, and denoted as the stock standard solution. To prepare the working standard solution, 2.5 mL of the stock standard solution was diluted to 100 mL with diluent B and mixed well. The working standard solution was stable for at least 72 hours when stored in refrigerator or in autosampler vial at 10° C. The intermediate standard solution was prepared by pipetting 1 mL of the working standard solution into a 50 mL volumetric flask. The solution was diluted to volume with diluent B and mixed well. The sensitivity solution (0.1% of 0.4 units/mL vasopressin formulation) was prepared by pipetting 2 mL of the intermediate standard solution into a 50 mL volumetric flask. The solution was diluted to the volume with diluent B and mixed well. The sensitivity solution was stable for at least 72 hours when stored in the refrigerator. To prepare the impurities marker solution, a 0.05% v/v acetic acid solution was prepared by pipetting 200 mL of a 0.25% v/v acetic acid solution into a 1 L volumetric flask. The solution was diluted to the desired volume with water and mixed well. To prepare the vasopressin impurity stock solutions, the a solution of each impurity as shown below was prepared in a 25 mL volumetric flask and diluted with 0.05% v/v acetic acid to a concentration suitable for HPLC injection. Gly-9 AVP: 0.09 mg/mL Glu-4 AVP: 0.08 mg/mL Asp-5 AVP: 0.1 mg/mL D-Asn AVP: 0.08 mg/mL Dimer AVP: 0.07 mg/mL Acetyl AVP: 0.08 mg/mL To prepare the MAA/H-IBA (Methacrylic Acid/α-Hydroxy-isobutyric acid) stock solution, a stock solution containing approximately 0.3 mg/mL H-IBA and 0.01 mg/mL in 0.05% v/v acetic acid was made in a 50 mL volumetric flask. To prepare the chlorobutanol diluent, about one gram of hydrous chlorobutanol was added to 500 mL of water. Subsequently, 0.25 mL of acetic acid was added and the solution was stirred to dissolve the chlorobutanol. To prepare the stock impurity marker solutions, 6.5 mg of vasopressin powder was added to a 500 mL volumetric flask. To the flask, the following quantities of the above stock solutions were added: Gly-9 AVP: 20.0 mL Glu-4 AVP: 20.0 mL Asp-5 AVP: 10.0 mL D-Asn AVP: 10.0 mL Dimer AVP: 10.0 mL Acetyl AVP: 20.0 mL H-IBA/MAA: 30.0 mL The solutions were diluted to volume with the chlorobutanol diluent. The solutions were aliquoted into individual crimp top vials and stored at 2-8° C. The solutions, stored at 2-8° C., were suitable for use as long as the chromatographic peaks could be identified based on comparison to the reference chromatogram. At time of use the solutions were removed from refrigerated (2-8° C.) storage and allowed to reach room temperature. The vasopressin stock impurity marker solution was stable for at least 120 hours when stored in autosampler vials at room temperature. The impurity marker solution were prepared by diluting 1 mL of the stock impurity marker solution to 50 mL with diluent B, and mixed well. The vasopressin impurity marker solution was stable for at least 72 hours when stored in the refrigerator. To begin the analysis, the HPLC system was allowed to equilibrate for at least 30 minutes using mobile phase B, followed by time 0 min gradient conditions until a stable baseline was achieved. Diluent B was injected at the beginning of the run, and had no peaks that interfered with vasopressin as shown in FIG. 20. A single injection of the sensitivity solution was performed, wherein the signal-to-noise ratio of the vasopressin was greater than or equal to ten as shown in FIG. 21. A single injection of the impurities marker solution was then made. The labeled impurities in the reference chromatogram were identified in the chromatogram of the marker solution based on their elution order and approximate retention times shown in FIG. 22 and FIG. 23. FIG. 23 is a zoomed-in chromatograph of FIG. 22 showing the peaks that eluted between 16 and 28 minutes. The nomenclature, structure, and approximate retention times for individual identified impurities are detailed in TABLE 3. A single injection of the working standard solution was made to ensure that the tailing factor of the vasopressin peak was less than or equal to about 2.0 as shown in FIG. 24. A total of five replicate injections of the working standard solution were made to ensure that the relative standard deviation (% RSD) of the five replicate vasopressin peak areas was not more than 2.0%. Following the steps above done to confirm system suitability, a single injection of the placebo and sample preparations was made. The chromatograms were analyzed to determine the vasopressin and impurity peak areas. The chromatogram for the placebo is depicted in FIG. 25, and the chromatogram for the sample preparation is shown in FIG. 26. Then, the working standard solution was injected after 1 to 10 sample injections, and the average of the bracketing standard peak areas were used in the calculations for vasopressin and impurity amounts. Additional injections of the impurities marker solution could be made to help track any changes in retention time for long chromatographic sequences. The relative standard deviation (% RSD) of vasopressin peak areas for the six injections of working standard solution was calculated by including the initial five injections from the system suitability steps above and each of the subsequent interspersed working standard solution injections. The calculations were done to ensure that each of the % RSD were not more than 2.0%. The retention time of the major peak in the chromatogram of the sample preparation corresponded to that of the vasopressin peak in the working standard solution injection that preceded the sample preparation injection. To calculate the vasopressin units/mL, the following formula was used: Vasopressin   units  /  mL = R U R S × Conc   STD where: RU=Vasopressin peak area response of Sample preparation. RS=average vasopressin peak area response of bracketing standards. Conc STD=concentration of the vasopressin standard in units/mL To identify the impurities, the % Impurity and identity for identified impurities (TABLE 3) that are were greater than or equal to 0.10% were reported. Impurities were truncated to 3 decimal places and then rounded to 2 decimal places, unless otherwise specified. The following formula was used: %   impurity = R 1 R s × Conc   STD L   C × 100  % where R1=Peak area response for the impurity; LC=label content of vasopressin (units/mL). The formulations used for the vasopressin and impurity studies are summarized in TABLE 65 below and correspond to several of the formulations detailed above in TABLES 55-63. TABLE 65 Buffer Vasopressin Conc. Lot (units/100 mL) (mM) Vehicle A 40 10 NaCl B 60 10 NaCl C 40 10 Dextrose D 60 10 Dextrose E 40 1 NaCl F 60 1 NaCl G 40 1 Dextrose H 60 1 Dextrose A1 40 1 Dextrose B1 60 1 Dextrose C1 40 1 Dextrose/NaCl The drug products detailed in TABLE 65 were tested for stability over a six month period. The vasopressin drug formulations were stored at 5° C., 25° C., or 40° C. for up to six months. At 0, 1, 2, 3, 4, 5, and 6 months, the amount of vasopressin (AVP), % label claim (LC), amount of various impurities, pH, and % reference standard was measured. The vasopressin and impurity amounts were determined using the HPLC method described above. The results of the stability experiment are shown in TABLES 66-72 below. TABLE 66 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT Condition Time Vasopressin 0.30 0.33 0.34 0.35 0.362 0.37 0.38 0.39 0.40 0.42 0.44 Lot (°C.) (m) pH (% LC) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 5 0 3.63 102.5 0.36 0.14 0.13 A 25 0 3.63 102.5 0.36 0.14 0.13 A 40 0 3.63 102.5 0.36 0.14 0.13 B 5 0 3.64 102.2 0.24 0.09 0.08 0.10 B 25 0 3.64 102.2 0.24 0.09 0.08 0.10 B 40 0 3.64 102.2 0.24 0.09 0.08 0.10 C 5 0 3.64 98.2 0.34 0.13 0.56 0.20 C 25 0 3.64 98.2 0.34 0.13 0.56 0.20 C 40 0 3.64 98.2 0.34 0.13 0.56 0.20 D 5 0 3.65 100.1 0.24 0.08 0.15 0.06 D 25 0 3.65 100.1 0.24 0.08 0.15 0.06 D 40 0 3.65 100.1 0.24 0.08 0.15 0.06 E 5 0 3.67 100.5 0.13 E 25 0 3.67 100.5 0.13 E 40 0 3.67 100.5 0.13 F 5 0 3.71 101.5 0.09 F 25 0 3.71 101.5 0.09 F 40 0 3.71 101.5 0.09 G 5 0 3.75 99.5 G 25 0 3.75 99.5 G 40 0 3.75 99.5 H 5 0 3.74 100.2 H 25 0 3.74 100.2 H 40 0 3.74 100.2 A1 5 0 3.86 97.5 A1 25 0 3.86 97.5 A1 40 0 3.86 97.5 B1 5 0 3.84 97.6 B1 25 0 3.84 97.6 B1 40 0 3.84 97.6 C1 5 0 3.78 99.3 C1 25 0 3.78 99.3 C1 40 0 3.78 99.3 A 5 1 3.62 101.6 0.37 0.15 0.11 A 25 1 3.63 101.5 0.34 0.19 A 40 1 3.61 98.2 0.27 0.18 B 5 1 3.61 102.2 0.25 0.12 0.06 0.13 B 25 1 3.63 101.0 0.24 0.11 B 40 1 3.63 97.2 0.19 0.65 C 5 1 3.66 99.7 0.37 0.11 0.79 C 25 1 3.65 98.7 0.36 0.17 C 40 1 3.66 93.8 0.60 0.19 D 5 1 3.66 101.1 0.24 0.08 D 25 1 3.65 99.8 0.24 0.11 D 40 1 3.66 92.4 0.41 0.11 E 5 1 3.67 101.0 E 25 1 3.67 99.2 E 40 1 3.68 95.5 F 5 1 3.71 101.5 0.08 F 25 1 3.72 100.1 F 40 1 3.71 96.6 0.12 G 5 1 3.71 99.8 G 25 1 3.76 99.0 G 40 1 3.75 94.2 0.34 0.26 H 5 1 3.76 99.8 H 25 1 3.77 99.5 H 40 1 3.77 97.0 0.23 A1 5 1 3.81 97.0 A1 25 1 3.82 96.8 A1 40 1 3.83 91.8 B1 5 1 3.82 97.5 B1 25 1 3.82 97.1 B1 40 1 3.82 92.0 C1 5 1 3.80 99.2 C1 25 1 98.5 C1 40 1 3.82 94.7 A 5 2 3.59 101.7 0.11 A 25 2 3.59 99.5 0.14 A 40 2 3.60 92.9 0.15 B 5 2 3.60 101.1 0.12 B 25 2 3.60 98.8 0.10 B 40 2 3.60 92.1 0.11 C 5 2 3.59 99.3 0.18 C 25 2 3.62 97.3 0.14 C 40 2 3.64 89.2 0.15 D 5 2 3.67 100.0 0.10 D 25 2 3.66 97.3 0.09 D 40 2 3.62 89.9 0.09 E 5 2 3.65 99.5 E 25 2 3.67 95.8 E 40 2 3.67 90.6 0.07 F 5 2 3.67 100.6 F 25 2 3.71 97.9 0.14 F 40 2 3.70 92.3 0.33 G 5 2 3.70 98.9 G 25 2 3.73 97.0 G 40 2 3.71 90.5 H 5 2 3.72 99.7 H 25 2 3.74 98.0 H 40 2 3.74 91.9 A1 5 2 3.77 97.3 A1 25 2 3.77 95.9 A1 40 2 3.78 86.1 B1 5 2 3.79 97.3 B1 25 2 3.78 96.5 B1 40 2 3.79 87.4 C1 5 2 3.73 99.3 C1 25 2 3.73 98.1 C1 40 2 3.74 91.0 A 5 3 3.59 102.0 0.31 A 25 3 3.61 99.5 0.30 A 40 3 3.60 90.8 0.30 B 5 3 3.59 101.8 0.24 B 25 3 3.60 98.8 0.22 B 40 3 3.60 90.3 0.22 C 5 3 3.62 99.8 0.16 C 25 3 3.62 95.5 0.15 C 40 3 3.62 87.0 0.16 D 5 3 3.62 91.4 0.10 D 25 3 3.63 97.7 0.20 D 40 3 3.63 87.6 0.18 E 5 3 3.63 96.9 E 25 3 3.64 96.3 E 40 3 3.65 88.8 0.23 F 5 3 3.67 100.8 F 25 3 3.68 97.9 0.23 F 40 3 3.70 90.0 0.20 G 5 3 3.73 98.8 0.16 G 25 3 3.72 97.5 0.07 G 40 3 3.74 88.6 H 5 3 3.71 99.8 0.04 H 25 3 3.74 98.5 H 40 3 3.75 89.1 A 5 4 3.59 99.9 0.22 A 25 4 3.56 96.8 0.20 A 40 4 3.70 84.5 0.31 B 5 4 3.58 99.4 0.11 B 25 4 3.56 95.4 0.17 B 40 4 3.67 83.0 1.37 C 5 4 3.61 98.5 0.18 C 25 4 3.63 94.9 0.18 C 40 4 3.64 81.3 0.18 D 5 4 3.62 98.9 0.12 D 25 4 3.62 94.5 0.07 0.09 D 40 4 3.61 82.1 0.13 E 5 4 3.63 97.6 E 25 4 3.69 94.0 E 40 4 3.63 83.2 0.26 F 5 4 3.68 98.9 0.08 F 25 4 3.69 95.3 0.19 F 40 4 3.70 84.6 0.24 G 5 4 3.68 98.1 G 25 4 3.69 95.8 G 40 4 3.84 83.2 H 5 4 3.67 98.6 H 25 4 3.62 93.1 0.13 0.12 H 40 4 3.76 83.6 A 5 5 3.63 99.7 0.10 A 25 5 3.63 95.8 B 5 5 3.63 99.0 0.25 B 25 5 3.64 95.1 C 5 5 3.68 98.2 C 25 5 3.67 93.7 D 5 5 3.67 98.7 D 25 5 3.69 94.6 E 5 5 3.69 97.5 E 25 5 3.69 93.1 0.09 F 5 5 3.71 98.4 0.05 0.14 F 25 5 3.74 94.4 0.15 G 5 5 3.74 97.2 G 25 5 3.78 93.1 1.73 H 5 5 3.76 97.7 H 25 5 3.76 95.7 A 5 6 3.57 101.0 A 25 6 3.49 95.4 A 5 6 3.57 100.0 A 25 6 3.49 94.5 B 5 6 3.54 100.2 B 25 6 3.49 95.7 B 5 6 3.54 99.3 0.12 0.13 B 25 6 3.49 94.6 C 5 6 3.59 98.1 C 25 6 3.56 95.1 C 5 6 3.59 98.0 C 25 6 3.56 93.5 D 5 6 3.55 100.0 D 25 6 3.56 95.8 D 5 6 3.55 98.6 0.10 D 25 6 3.56 94.2 E 5 6 3.54 98.1 E 25 6 3.56 94.1 E 5 6 3.54 97.0 E 25 6 3.56 92.3 F 5 6 3.60 99.0 F 25 6 3.61 95.0 F 5 6 3.60 98.2 0.10 0.14 F 25 6 3.61 93.8 0.21 G 5 6 3.61 98.2 G 25 6 3.66 96.1 G 5 6 3.61 96.5 G 25 6 3.66 94.4 H 5 6 3.64 98.6 H 25 6 3.65 97.0 H 5 6 3.64 96.9 H 25 6 3.65 95.3 Min 3.49 81.258 0 0 0 0.053 0.042 0 0.104 0 0.116 Max 3.84 102.047 0 0 0 0.153 1.371 0 1.731 0 0.116 TABLE 67 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT 0.47 0.48 0.49 0.50 0.510 0.52 0.56 0.57 0.58 0.61 0.63 0.64 0.646 0.67 0.68 0.70 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.63 A 0.63 A 0.63 B 0.20 B 0.20 B 0.20 C 0.18 8.74 C 0.18 8.74 C 0.18 8.74 D 0.10 9.43 D 0.10 9.43 D 0.10 9.43 E 1.55 E 1.55 E 1.55 F 0.23 0.22 F 0.23 0.22 F 0.23 0.22 G 0.12 0.44 G 0.12 0.44 G 0.12 0.44 H 0.08 0.27 H 0.08 0.27 H 0.08 0.27 A1 0.06 A1 0.06 A1 0.06 B1 B1 B1 C1 C1 C1 A 0.67 A 0.82 0.56 A 0.81 0.40 B 0.53 B 0.46 0.21 B 0.47 0.34 C 0.13 0.31 C 0.18 0.25 C 0.23 0.29 D 0.09 0.34 D 0.13 0.35 D 0.12 0.11 0.20 E 0.53 E 0.30 0.50 E 0.32 0.49 F 0.22 F 0.17 0.23 F 0.18 0.24 G 0.12 0.35 G 0.46 0.37 G 0.45 0.35 H 0.08 0.28 H 0.16 0.24 H 0.15 0.25 A1 A1 A1 0.06 B1 B1 B1 C1 C1 C1 A 0.24 0.76 A 0.06 0.73 A 0.05 0.83 B 0.04 0.40 B 0.04 0.42 B 0.12 0.45 0.05 C 0.17 0.13 C 0.15 0.16 C 0.10 0.07 D 0.14 D 0.05 0.13 D 0.04 0.05 E 0.26 E 0.27 E 0.09 F 0.15 F 0.07 0.18 F 0.29 G 0.56 G 0.06 0.54 0.08 G H 0.20 H 0.21 H 0.04 A1 A1 0.14 A1 B1 B1 B1 C1 C1 C1 A 0.09 0.72 A 0.14 0.49 A 0.12 0.47 B 0.07 0.36 B 0.06 0.47 B 0.05 0.44 0.05 C 0.14 0.41 C 0.13 0.57 C 0.09 0.39 D 0.99 0.28 D 0.05 0.42 D 0.27 0.05 E 0.06 0.60 E 0.57 E 1.03 F 0.42 0.31 F 0.10 0.33 F 0.10 0.35 G 0.39 G 0.09 0.51 G 0.50 H 0.32 H 0.37 H 0.25 A 0.84 0.59 A 0.82 0.29 A 0.87 0.39 B 0.47 0.23 B 0.50 0.43 B 0.55 0.45 0.08 C 0.21 0.15 C 0.23 0.25 C 0.25 0.34 D 0.18 0.27 D 0.24 0.39 D 0.19 0.25 0.08 E 0.31 0.58 E 0.33 0.51 E 0.36 0.67 F 0.18 0.21 F 0.19 0.27 F 0.20 0.26 G 0.59 0.40 G 0.59 0.36 G 0.62 0.40 H 0.20 0.22 H 0.25 0.20 0.31 0.11 H 0.25 0.26 0.09 A 0.61 A 0.48 B 0.27 B 0.43 C 0.29 C 0.15 0.30 D 0.14 0.28 D 0.08 0.40 E 0.53 E 0.49 F 0.24 F 0.24 G 0.14 0.39 G 0.17 0.44 H 0.10 0.23 H 0.13 0.28 A 0.62 A 0.30 A 0.65 0.62 A 0.70 0.30 0.19 B 0.61 B 0.26 B 0.38 0.62 B 0.38 0.26 0.11 C 0.49 C 0.17 0.30 C 0.14 C 0.25 0.31 0.21 D 0.10 0.26 D 0.10 0.31 D 0.11 0.26 0.09 D 0.09 0.13 0.32 0.12 E 1.04 E 0.64 E 0.21 1.07 E 0.22 0.60 F 0.08 0.21 F 0.22 F 0.11 0.08 0.19 F 0.12 0.19 G 0.14 0.38 G 0.14 0.18 0.36 G 0.45 0.16 0.42 0.22 G 0.45 0.18 0.19 0.35 0.35 H 0.10 0.20 H 0.10 0.28 H 0.15 0.11 0.20 0.12 H 0.15 0.12 0.28 0.22 Min 0.035 0 0.125 0 0.42 0.077 0.064 0.23 0.14 0.051 0.048 Max 0.986 0 0.555 0 0.42 0.203 0.064 0.624 1.03 0.052 0.109 TABLE 68 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT 0.71 0.72 0.74 0.76 0.77 0.78 0.79 0.80 0.82 0.84 0.86 0.87 0.88 0.91 0.94 0.95 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.15 0.29 A 0.15 0.29 A 0.15 0.29 B 0.08 0.32 B 0.08 0.32 B 0.08 0.32 C 0.15 0.29 C 0.15 0.29 C 0.15 0.29 D 0.10 0.30 D 0.10 0.30 D 0.10 0.30 E 0.28 E 0.28 E 0.28 F 0.32 F 0.32 F 0.32 G 0.20 0.31 G 0.20 0.31 G 0.20 0.31 H 0.12 0.30 H 0.12 0.30 H 0.12 0.30 A1 0.32 A1 0.32 A1 0.32 B1 0.30 B1 0.30 B1 0.30 C1 0.31 C1 0.31 C1 0.31 A 0.10 0.31 A 0.36 A 0.17 0.39 B 0.30 B 0.35 B 0.36 C 0.32 0.31 C 0.40 C 0.16 0.40 D 0.10 0.31 D 0.34 D 0.36 E 0.32 E 0.34 E 0.37 F 0.30 F 0.34 F 0.33 G 0.18 0.29 0.31 G 0.20 0.38 G 0.27 0.42 H 0.09 0.31 H 0.13 0.35 H 0.14 0.36 A1 0.10 0.29 A1 0.30 A1 0.29 B1 0.30 B1 0.30 B1 0.33 C1 0.31 C1 0.30 C1 0.30 A 0.12 0.33 A 0.12 0.36 A 0.15 0.42 B 0.34 B 0.07 0.36 B 0.10 0.41 C 0.12 0.41 C 0.15 0.36 C 0.17 0.40 D 0.09 0.36 D 0.11 0.35 D 0.10 0.37 E 0.33 E 0.21 0.31 0.05 E 0.10 0.36 F 0.36 F 0.34 F 0.37 G 0.20 0.33 G 0.22 0.34 G 0.33 0.41 H 0.11 0.35 H 0.13 0.34 H 0.19 0.36 A1 0.30 A1 0.31 A1 0.31 0.18 B1 0.30 B1 0.31 B1 0.29 0.15 C1 0.31 C1 0.31 C1 0.30 A A A B B B C C C D 0.49 D D E 0.25 0.16 0.38 E E F F F G G G H H H A 0.16 0.33 A 0.18 0.33 A 0.25 0.40 B 0.32 B 0.09 0.32 B 0.17 0.38 C 0.34 C 0.19 0.35 C 0.25 0.42 D 0.10 0.32 D 0.12 0.36 D 0.16 0.45 E 0.30 E 0.32 E 0.19 0.40 F 0.31 F 0.33 F 0.11 0.37 G 0.19 0.35 G 0.29 0.37 G 0.46 0.45 H 0.11 0.34 H 0.19 0.36 0.08 H 0.26 0.45 A 0.16 0.28 A 0.17 0.28 B 0.29 B 0.29 C 0.18 0.27 C 0.18 0.29 D 0.29 D 0.11 0.29 E 0.27 E 0.30 F 0.31 F 0.30 G 0.23 0.28 G 0.29 0.29 H 0.12 0.29 H 0.18 0.29 A 0.33 A 0.14 0.32 A 0.32 A 0.28 B 0.32 B 0.30 B 0.33 B 0.28 C 0.17 0.31 C 0.14 0.32 C 0.14 0.26 C 0.24 D 0.30 D 0.32 D 0.32 D 0.33 E 0.34 E 0.12 0.31 E 0.30 E 0.28 F 0.07 0.33 F 0.32 F 0.30 F 0.28 G 0.32 G 0.18 0.32 G 0.30 G 0.24 H 0.30 H 0.09 0.31 H 0.32 H 0.26 Min 0.112 0.252 0.087 0.092 0.213 0.301 0.161 0.053 Max 0.287 0.252 0.33 0.456 0.328 0.453 0.161 0.487 TABLE 69 D-Asn- RRT RRT RRT RRT RRT RRT Gly9- Asp5- Glu4- RRT RRT RRT RRT RRT RRT AVP 0.99 1.02 1.03 1.04 1.05 1.06 AVP AVP AVP 1.09 1.10 1.095 1.12 1.13 1.14 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.35 0.21 0.17 0.58 0.41 A 0.35 0.21 0.17 0.58 0.41 A 0.35 0.21 0.17 0.58 0.41 B 0.20 0.43 0.15 0.20 0.19 0.25 B 0.20 0.43 0.15 0.20 0.19 0.25 B 0.20 0.43 0.15 0.20 0.19 0.25 C 0.42 0.30 0.48 0.17 C 0.42 0.30 0.48 0.17 C 0.42 0.30 0.48 0.17 D 0.15 0.41 0.11 0.11 0.18 0.19 D 0.15 0.41 0.11 0.11 0.18 0.19 D 0.15 0.41 0.11 0.11 0.18 0.19 E 0.22 0.34 0.19 0.14 0.93 0.24 E 0.22 0.34 0.19 0.14 0.93 0.24 E 0.22 0.34 0.19 0.14 0.93 0.24 F 0.15 0.33 0.07 0.13 0.12 0.19 F 0.15 0.33 0.07 0.13 0.12 0.19 F 0.15 0.33 0.07 0.13 0.12 0.19 G 0.38 0.19 0.24 G 0.38 0.19 0.24 G 0.38 0.19 0.24 H 0.16 0.42 0.08 0.12 0.14 H 0.16 0.42 0.08 0.12 0.14 H 0.16 0.42 0.08 0.12 0.14 A1 0.12 0.12 0.24 0.08 0.10 0.09 A1 0.12 0.12 0.24 0.08 0.10 0.09 A1 0.12 0.12 0.24 0.08 0.10 0.09 B1 0.11 0.12 0.24 0.07 0.07 0.07 B1 0.11 0.12 0.24 0.07 0.07 0.07 B1 0.11 0.12 0.24 0.07 0.07 0.07 C1 0.12 0.12 0.25 0.09 0.10 0.08 C1 0.12 0.12 0.25 0.09 0.10 0.08 C1 0.12 0.12 0.25 0.09 0.10 0.08 A 0.47 0.63 0.39 0.70 0.51 A 0.33 0.41 0.46 0.61 0.44 A 0.31 1.28 0.65 1.52 0.18 B 0.19 0.43 0.26 0.25 0.58 0.27 B 0.12 0.31 0.39 0.20 0.52 B 0.11 0.31 0.29 0.44 1.47 0.23 C 0.42 0.21 0.20 0.15 C 0.66 0.19 0.24 0.40 0.16 C 0.16 1.71 0.58 0.55 0.43 0.86 0.17 D 0.43 0.09 0.18 0.17 D 0.13 0.75 0.23 0.13 0.38 0.17 D 0.18 1.71 0.57 1.43 0.82 0.14 E 0.34 0.17 0.25 0.23 E 0.32 0.32 0.25 0.41 0.23 E 0.28 1.06 0.39 1.21 0.29 F 0.17 0.36 0.12 0.17 0.14 0.20 F 0.17 0.35 0.36 0.18 0.41 0.11 F 0.14 0.29 1.06 0.34 1.13 G 0.36 0.17 0.26 G 0.45 0.18 0.25 0.20 G 0.68 0.38 0.33 0.52 H 0.37 0.07 0.11 0.16 H 0.15 0.45 0.15 0.24 0.13 H 0.17 0.82 0.45 0.18 0.60 A1 0.12 0.12 0.25 0.08 0.07 0.08 A1 0.11 0.12 0.24 0.14 0.13 0.10 A1 0.09 0.11 0.21 0.31 0.34 0.09 0.45 0.33 B1 0.11 0.12 0.25 0.07 0.07 0.07 B1 0.11 0.12 0.24 0.07 0.13 0.16 0.18 B1 0.10 0.11 0.21 0.33 0.33 0.09 0.41 0.72 C1 0.12 0.13 0.26 0.08 0.10 0.08 C1 0.11 0.13 0.25 0.18 0.18 0.10 C1 0.11 0.12 0.23 0.27 0.52 0.13 0.64 0.10 A 0.10 0.55 0.43 0.66 0.26 0.54 A 0.06 0.38 0.81 0.66 0.90 0.05 A 0.26 2.40 0.87 0.19 B 0.14 0.36 0.20 0.18 0.27 0.13 B 0.12 0.30 0.68 0.31 0.77 0.07 B 0.20 0.32 2.42 0.74 2.51 C 0.37 0.15 0.21 0.21 0.05 0.22 C 0.10 0.88 0.29 0.17 0.49 0.15 C 0.14 2.08 1.00 0.46 1.42 D 0.14 0.52 0.19 0.11 0.21 0.11 D 0.13 1.04 0.38 0.21 0.50 0.16 D 0.13 2.15 1.03 0.50 1.41 E 0.44 0.25 0.27 0.24 0.30 E 0.41 0.71 0.33 0.73 0.24 E 0.23 2.09 0.58 2.38 F 0.11 0.34 0.17 0.11 0.19 0.09 F 0.19 0.33 0.58 0.25 0.60 0.07 F 0.14 0.24 2.08 0.63 2.06 G 0.06 0.38 0.16 0.22 0.20 0.17 G 0.54 0.28 0.20 0.34 0.11 G 0.12 0.90 0.83 0.57 1.18 H 0.21 0.54 0.21 0.10 0.19 0.12 H 0.22 0.69 0.30 0.10 0.32 0.14 H 0.16 0.91 0.74 0.29 1.05 A1 0.11 0.14 0.24 0.08 0.08 A1 0.13 0.14 0.23 0.18 0.20 0.20 A1 0.10 0.12 0.21 0.50 0.56 0.14 0.67 0.10 B1 0.12 0.12 0.24 0.08 0.08 B1 0.12 0.13 0.23 0.18 0.20 0.04 0.21 B1 0.10 0.11 0.20 0.52 0.55 0.15 0.73 0.06 C1 0.12 0.13 0.25 0.10 0.09 C1 0.14 0.13 0.24 0.28 0.29 C1 0.10 0.13 0.21 0.43 0.89 0.22 1.14 0.07 A 0.10 0.29 0.31 0.52 0.36 0.62 A 0.10 0.97 0.62 1.17 0.19 A 0.09 3.45 1.20 3.64 0.20 B 0.11 0.25 0.21 0.31 0.11 0.06 B 0.12 0.94 0.37 1.13 0.22 B 0.09 3.37 0.88 0.36 0.22 C 0.09 0.15 0.10 0.20 0.15 C 0.10 0.93 0.45 0.24 0.61 0.19 C 0.08 2.15 1.29 0.66 2.00 D 5.25 0.31 0.16 D 0.10 1.05 0.46 0.23 0.66 0.11 D 0.09 2.18 1.29 0.56 1.77 E 0.82 0.30 0.22 0.27 0.28 E 0.09 0.87 0.47 0.99 0.21 E 0.09 2.93 0.77 3.30 F 0.11 0.22 0.12 0.25 0.08 F 0.11 0.81 0.36 0.84 0.09 F 0.09 2.79 0.73 2.91 G 0.10 0.14 0.15 0.15 0.13 G 0.10 0.37 0.34 0.53 0.12 G 0.73 0.89 0.64 1.22 0.07 H 0.11 0.11 0.06 0.16 0.08 H 0.09 0.31 0.08 0.43 0.08 H 0.69 0.86 0.34 1.26 A 0.33 0.18 0.22 0.07 0.18 0.25 A 0.29 1.14 0.31 1.24 0.17 A 0.27 4.38 1.21 4.48 B 0.12 0.32 0.19 0.14 0.15 B 0.14 0.30 1.16 0.34 0.95 0.05 B 0.14 0.27 4.31 1.01 4.71 0.06 C 0.38 0.10 0.12 0.08 0.09 C 0.38 0.95 0.51 0.26 0.48 C 2.09 1.48 0.68 2.32 D 0.14 0.42 0.13 0.07 0.09 D 0.16 0.41 0.94 0.53 0.34 0.52 D 2.10 1.47 0.54 2.29 E 0.32 0.17 0.21 0.09 0.17 E 0.29 1.02 0.34 1.29 E 0.24 3.78 0.89 4.08 F 0.14 0.32 0.19 0.06 0.15 F 0.12 0.29 0.95 0.26 1.08 F 0.14 0.27 3.55 0.84 3.64 G 0.36 0.11 0.07 0.10 G 0.48 0.18 0.39 0.17 0.37 G 0.43 0.47 1.06 0.42 1.66 0.17 H 0.16 0.39 0.11 0.09 H 0.23 0.46 0.21 0.45 0.39 0.61 H 0.18 0.45 0.52 1.08 0.48 1.72 A 0.15 0.51 0.26 0.62 0.27 0.24 A 0.14 0.52 1.41 0.40 1.71 0.28 B 0.19 0.49 0.06 0.27 0.24 0.28 B 0.20 0.55 1.53 0.38 1.54 0.37 C 0.64 0.13 0.20 0.16 C 0.16 1.86 0.69 0.20 0.75 0.24 D 0.14 0.66 0.18 0.20 0.18 D 0.15 1.76 0.72 0.25 0.80 0.16 E 0.19 0.43 0.25 0.40 0.27 E 0.35 1.24 0.55 1.37 F 0.16 0.41 0.26 0.18 0.29 F 0.12 0.38 1.15 0.39 1.23 G 0.10 0.41 0.12 0.21 0.17 G 0.74 0.52 0.11 0.68 0.24 H 0.11 0.44 0.12 0.14 0.17 H 0.13 0.77 0.51 0.16 0.60 0.16 A 0.12 0.13 0.27 0.09 0.84 0.22 A 0.10 0.13 0.24 1.84 0.31 1.57 0.15 A 0.30 0.21 0.48 0.13 A 0.75 1.62 0.45 1.38 B 0.13 0.13 0.25 0.07 0.77 0.22 B 0.12 0.13 0.23 1.67 0.33 1.61 B 0.19 0.33 0.24 0.56 0.20 B 0.12 0.37 1.64 0.42 1.73 C 0.12 0.13 0.24 0.21 0.22 0.14 0.10 C 0.12 0.13 0.20 1.31 0.90 0.12 0.77 C 0.16 0.90 0.25 0.34 0.31 C 1.70 0.71 0.40 0.79 D 0.13 0.13 0.23 0.12 0.28 0.13 0.06 D 0.11 0.13 0.21 1.32 0.81 0.13 0.79 0.05 D 0.15 0.46 0.19 0.16 0.14 D 0.15 1.72 0.75 0.33 0.83 E 0.11 0.13 0.25 0.12 0.86 0.20 0.06 E 0.12 0.24 1.65 0.25 1.41 E 0.30 0.09 0.21 0.66 0.20 E 0.34 1.44 0.59 1.51 F 0.15 0.14 0.25 0.06 0.30 0.20 0.06 F 0.12 0.12 0.25 1.36 0.26 1.30 0.05 F 0.17 0.35 0.25 0.13 0.21 F 0.19 0.36 0.39 1.30 1.40 G 0.13 0.14 0.24 0.39 0.11 0.13 G 0.12 0.14 0.22 0.33 0.72 0.09 0.64 G 0.36 0.17 0.19 0.12 G 0.27 0.76 0.33 0.58 0.54 H 0.12 0.13 0.24 0.24 0.12 0.05 H 0.13 0.13 0.22 0.39 0.59 0.09 0.56 0.06 H 0.18 0.43 0.21 0.15 0.16 H 0.15 0.81 0.30 0.56 0.61 Min 0.057 0.234 0.055 0.079 0.042 0.071 0.182 0.051 0.059 Max 0.231 2.177 0.501 4.376 5.246 4.713 0.182 0.622 0.1 TABLE 70 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT AVP Acetyl- RRT RRT RRT RRT 1.16 1.168 1.19 1.20 1.206 1.23 1.24 1.25 1.26 1.27 Dimer AVP 1.32 1.33 1.34 1.35 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.33 0.35 A 0.33 0.35 A 0.33 0.35 B 0.07 0.33 B 0.07 0.33 B 0.07 0.33 C 0.22 0.22 C 0.22 0.22 C 0.22 0.22 D 0.08 0.23 D 0.08 0.23 D 0.08 0.23 E 0.55 0.53 E 0.55 0.53 E 0.55 0.53 F 0.34 F 0.34 F 0.34 G 0.23 G 0.23 G 0.23 H 0.23 H 0.23 H 0.23 A1 0.21 0.28 A1 0.21 0.28 A1 0.21 0.28 B1 0.21 0.29 B1 0.21 0.29 B1 0.21 0.29 C1 0.14 0.29 C1 0.14 0.29 C1 0.14 0.29 A 0.37 0.22 0.13 A 0.20 0.60 A 0.59 B 0.26 0.35 B 0.49 B 0.48 C 0.24 C 0.46 0.26 C 0.44 0.73 0.25 D 0.07 0.22 D 0.35 0.25 D 0.41 0.27 E 0.12 0.43 E 0.72 E 0.68 F 0.07 0.35 F 0.55 F 0.53 G 0.29 G 0.54 0.27 G 0.54 0.40 H 0.21 0.12 H 0.56 0.17 H 0.55 0.17 A1 0.23 0.28 A1 0.21 0.27 A1 0.25 0.27 B1 0.22 0.28 B1 0.21 0.28 B1 0.13 0.27 C1 0.14 0.27 C1 0.15 0.28 C1 0.15 0.28 A 0.58 0.47 A 0.76 A 0.06 0.08 0.32 0.51 B 0.34 B 0.07 0.51 B 0.06 0.07 0.25 0.52 C 0.54 0.25 0.26 C 0.58 0.19 0.20 C 0.41 0.26 D 0.49 0.15 0.23 D 0.47 0.25 0.24 D 0.32 0.03 0.25 E 0.34 0.40 E 0.20 0.51 E 0.06 0.76 F 0.12 0.33 F 0.10 0.77 F 0.04 0.58 G 0.62 0.25 0.23 G 0.62 0.18 G 0.52 0.25 H 0.56 0.09 0.42 H 0.59 0.16 0.38 H 0.56 0.46 A1 0.20 0.30 A1 0.20 0.29 A1 0.28 0.29 B1 0.23 0.32 B1 0.23 0.28 B1 0.12 0.28 C1 0.13 0.28 C1 0.13 0.32 C1 0.16 0.28 A 0.08 0.62 0.55 A 0.32 0.80 A 0.14 0.21 0.51 B 0.18 0.42 B 0.45 0.64 B 0.13 0.22 0.49 0.05 C 0.42 0.27 C 0.39 0.31 0.28 C 0.38 0.19 0.29 D 0.37 0.21 D 0.40 0.15 0.23 D 0.39 0.09 0.24 E 0.19 0.31 E 0.25 0.93 E 0.10 0.22 0.77 F 0.23 0.51 F 0.69 F 0.09 0.07 0.51 G 0.52 0.22 0.24 G 0.52 0.32 0.24 G 0.51 0.06 0.46 H 0.53 0.04 0.46 H 0.53 0.42 H 0.55 0.50 A 0.29 0.43 A 0.55 A 0.23 0.11 0.58 B 0.10 0.39 B 0.24 0.31 B 0.24 0.13 0.14 0.50 C 0.35 0.44 0.21 C 0.42 0.95 0.22 C 0.39 0.49 0.24 D 0.39 0.11 0.22 D 0.39 0.82 0.24 D 0.38 0.70 0.25 E 0.23 0.50 E 0.57 0.88 E 0.18 0.17 0.73 F 0.26 0.32 F 0.08 0.07 0.74 F 0.15 0.09 0.59 G 0.49 0.21 0.21 G 0.51 0.48 0.23 G 0.49 0.14 0.19 H 0.51 0.12 0.38 H 0.54 0.80 0.45 H 0.53 0.30 0.49 A 0.22 0.56 A 0.14 0.21 0.70 B 0.08 0.41 B 0.21 0.12 0.53 C 0.65 0.21 C 0.17 0.21 D 0.38 0.22 D 0.53 0.23 E 0.16 0.14 0.46 E 0.11 0.19 0.99 0.10 F 0.06 0.13 0.45 F 0.07 0.12 0.65 0.07 G 0.80 0.21 G 0.42 0.23 0.15 H 0.48 0.20 0.15 H 0.67 0.21 0.12 A 0.22 0.37 0.25 A 0.29 0.23 A 0.30 0.54 A 0.69 B 0.17 0.41 0.23 B 0.14 0.22 B 0.34 0.28 B 0.52 C 0.24 0.34 C 0.29 0.37 0.25 C 0.19 0.25 C 0.42 0.21 D 0.24 0.22 D 0.20 0.26 0.23 D 0.30 0.20 D 0.37 0.23 E 0.32 0.57 0.22 E 0.23 0.18 0.20 E 0.43 0.65 E 0.16 0.91 F 0.14 0.14 0.21 F 0.14 0.09 0.21 F 0.44 F 0.70 0.08 G 0.33 0.39 0.22 G 0.26 0.35 0.23 G 0.37 0.24 G 0.37 0.20 H 0.14 0.32 0.22 0.16 H 0.14 0.33 0.21 0.23 H 0.40 0.19 0.18 H 0.42 0.21 0.20 Min 0.086 0 0.057 0 0.034 0.042 0.193 0.047 0.147 Max 0.341 0 0.796 0 0.061 0.623 0.986 0.047 0.147 TABLE 71 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT 1.37 1.44 1.45 1.46 1.47 1.48 1.55 1.57 1.59 1.62 1.68 1.70 1.71 1.72 1.80 1.82 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.32 A 0.32 A 0.32 B 0.18 B 0.18 B 0.18 C 0.15 C 0.15 C 0.15 D 0.16 D 0.16 D 0.16 E 0.61 E 0.61 E 0.61 F 0.58 F 0.58 F 0.58 G 1.34 G 1.34 G 1.34 H 1.05 H 1.05 H 1.05 A1 A1 A1 B1 B1 B1 C1 C1 C1 A 0.21 2.16 A A B 1.67 B B C 3.37 C C D 2.40 D D E 0.16 3.70 E E F 2.61 F F G 4.10 G G H 2.79 H H A1 A1 A1 B1 B1 B1 0.06 C1 C1 C1 A 0.10 A A B B B C C C D D D E E E 0.14 F F F 0.10 G G G H H H A1 0.09 A1 0.09 A1 0.10 B1 0.06 B1 0.07 B1 0.05 C1 0.14 C1 0.13 C1 0.12 A 0.25 A 0.32 A 0.35 B 0.16 B 0.14 B 0.14 C C C D 0.14 D D E 0.09 E 0.12 E 0.20 F 0.06 0.08 F 0.10 F 0.14 G G G H H H 0.07 0.13 A 0.19 0.16 A 0.29 0.16 A 0.24 B 0.07 B 0.07 0.11 B 0.21 0.12 C C 0.14 C D 0.11 D 0.10 0.07 D 0.08 0.16 E E 0.13 E 0.13 F 0.12 F 0.08 F 0.08 0.06 0.23 G 0.16 G G 0.17 H H 0.20 0.14 H 0.11 0.21 A 0.23 A 0.33 B 0.12 B 0.11 C C D D E 0.11 E 0.13 F F 0.09 G G 0.36 H H A 0.44 0.32 0.16 A 0.48 0.23 0.21 0.12 A 0.26 A 0.27 B 0.12 0.16 B 0.33 0.15 0.10 0.07 B B 0.16 C 0.21 C 0.20 C C 2.69 D 0.08 D 0.30 0.08 D D 1.83 E 0.51 0.13 0.16 0.10 E 0.73 0.14 0.72 E 0.11 E 0.16 2.74 F 0.34 0.10 0.07 F 0.53 0.09 0.06 F F 0.10 1.80 G 0.36 G 0.15 G G 2.69 H H 0.17 H H 1.81 Min 0 0.059 0.077 0.07 0.128 Max 0 0.347 0.213 0.07 0.138 TABLE 72 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT Total 1.85 1.89 1.93 1.96 2.00 2.01 2.04 2.08 2.11 2.12 2.13 2.15 2.16 2.17 2.304 Imp Lot (%) %) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 4.44 A 4.44 A 4.44 B 3.10 B 3.10 B 3.10 C 12.55 C 12.55 C 12.55 D 0.07 0.09 0.55 0.15 12.92 D 0.07 0.09 0.55 0.15 12.92 D 0.07 0.09 0.55 0.15 12.92 E 0.18 5.89 E 0.18 5.89 E 0.18 5.89 F 2.77 F 2.77 F 2.77 G 3.45 G 3.45 G 3.45 H 0.69 3.66 H 0.69 3.66 H 0.69 3.66 A1 1.61 A1 1.61 A1 1.61 B1 1.48 B1 1.48 B1 1.48 C1 1.50 C1 1.50 C1 1.50 A 0.66 8.15 A 5.34 A 6.74 B 5.67 B 3.40 B 5.33 C 6.91 C 3.72 C 7.74 D 4.71 D 3.55 D 6.86 E 6.24 E 3.38 E 5.09 F 4.78 F 2.86 F 4.35 G 6.42 G 1.08 4.39 G 4.93 H 4.60 H 2.73 H 4.07 A1 1.60 A1 1.63 A1 2.80 B1 1.50 B1 1.80 B1 0.44 3.53 C1 1.49 C1 1.66 C1 2.85 A 5.25 A 5.03 A 6.29 B 2.52 B 3.83 B 8.35 C 3.27 C 0.85 4.84 C 6.65 D 2.80 D 4.10 D 6.47 E 0.23 2.82 E 3.98 E 6.87 F 1.96 F 3.61 F 6.85 G 3.37 G 3.51 G 5.10 H 3.10 H 3.57 H 4.76 A1 1.53 A1 2.10 A1 3.55 B1 1.56 B1 1.98 B1 3.31 C1 1.57 C1 1.97 C1 4.05 A 4.82 A 5.39 A 10.68 B 2.48 B 4.73 B 6.71 C 2.09 C 4.34 C 7.69 D 8.29 D 4.06 D 7.10 E 3.57 7.50 E 4.50 E 9.64 F 2.39 F 3.65 F 7.97 G 2.19 G 3.21 G 5.08 H 1.91 H 2.31 H 4.64 A 0.17 0.14 0.06 4.79 A 5.96 A 13.72 B 2.60 B 0.65 5.84 B 14.85 C 2.66 C 5.50 C 9.14 D 2.67 D 0.08 1.22 7.08 D 9.22 E 2.87 E 5.66 E 12.07 F 2.35 F 4.64 F 10.81 G 3.23 G 4.42 G 7.12 H 2.63 H 0.31 0.11 0.08 6.71 H 0.08 7.46 A 4.23 A 6.75 B 2.94 B 0.09 6.36 C 2.72 C 0.13 5.32 D 2.67 D 5.46 E 3.19 E 5.90 F 2.66 F 4.95 G 3.05 G 6.37 H 2.55 H 4.20 A 4.36 A 6.67 A 3.81 A 6.62 B 3.60 B 5.66 B 3.71 B 5.98 C 0.14 3.05 C 5.58 C 2.93 C 0.18 8.12 D 2.28 D 5.34 D 2.48 D 7.20 E 5.11 E 6.93 E 4.22 E 8.94 F 2.83 F 5.10 F 2.47 F 7.12 G 3.26 G 4.42 G 2.98 G 7.49 H 2.35 H 4.04 H 2.80 H 6.09 Min 0 0 0 3.565 0 0 1.533 Max 0 0 0 3.565 0 0 14.845 TABLE 73 RRT RRT RRT RRT D-ASN- RRT RRT RRT RRT Condition Time AVP 0.64 0.86 0.87 0.95 AVP 0.99 1.03 1.04 1.05 Lot (° C.) (m) pH (% LC) (%) (%) (%) (%) (%) (%) (%) (%) (%) A1 5 0 3.86 97.5 0.06 0.32 0.12 0.12 0.24 A1 25 0 3.86 97.5 0.06 0.32 0.12 0.12 0.24 A1 40 0 3.86 97.5 0.06 0.32 0.12 0.12 0.24 B1 5 0 3.84 97.6 0.30 0.11 0.12 0.24 B1 25 0 3.84 97.6 0.30 0.11 0.12 0.24 B1 40 0 3.84 97.6 0.30 0.11 0.12 0.24 C1 5 0 3.78 99.3 0.31 0.12 0.12 0.25 C1 25 0 3.78 99.3 0.31 0.12 0.12 0.25 C1 40 0 3.78 99.3 0.31 0.12 0.12 0.25 A1 5 1 3.81 97.0 0.10 0.29 0.12 0.12 0.25 A1 25 1 3.82 96.8 0.30 0.11 0.12 0.24 A1 40 1 3.83 91.8 0.06 0.29 0.09 0.11 0.21 B1 5 1 3.82 97.5 0.30 0.11 0.12 0.25 B1 25 1 3.82 97.1 0.30 0.11 0.12 0.24 B1 40 1 3.82 92.0 0.33 0.10 0.11 0.21 C1 5 1 3.80 99.2 0.31 0.12 0.13 0.26 C1 25 1 98.5 0.30 0.11 0.13 0.25 C1 40 1 3.82 94.7 0.30 0.11 0.12 0.23 A1 5 2 3.77 97.3 0.30 0.11 0.14 0.24 A1 25 2 3.77 95.9 0.14 0.31 0.13 0.14 0.23 0.18 A1 40 2 3.78 86.1 0.31 0.18 0.10 0.12 0.21 0.50 B1 5 2 3.79 97.3 0.30 0.12 0.12 0.24 B1 25 2 3.78 96.5 0.31 0.12 0.13 0.23 0.18 B1 40 2 3.79 87.4 0.29 0.15 0.10 0.11 0.20 0.52 C1 5 2 3.73 99.3 0.31 0.12 0.13 0.25 C1 25 2 3.73 98.1 0.31 0.14 0.13 0.24 C1 40 2 3.74 91.0 0.30 0.10 0.13 0.21 0.43 A1 5 3 3.80 95.8 0.28 0.12 0.22 A1 25 3 3.78 94.0 0.28 0.13 0.21 0.11 A1 40 3 3.81 82.2 0.28 0.16 0.11 0.15 0.29 B1 5 3 3.82 96.5 0.28 0.11 0.13 0.23 B1 25 3 3.82 94.8 0.29 0.12 0.13 0.21 0.11 B1 40 3 3.83 82.0 0.27 0.06 0.09 0.11 0.14 0.33 C1 5 3 3.75 97.5 0.29 0.12 0.13 0.24 C1 25 3 3.75 96.8 0.29 0.13 0.14 0.22 C1 40 3 3.75 85.5 0.27 0.11 0.16 0.26 Min 3.78 91.842 0.061 0.093 0 Max 3.86 99.282 0.063 0.124 0 TABLE 74 RRT GLY9- ASP5- GLU4- RRT RRT RRT RRT RRT ACETYL- RRT RRT RRT 1.06 AVP AVP AVP 1.12 1.13 1.23 1.24 1.25 AVP 1.57 1.71 1.77 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A1 0.08 0.10 0.09 0.21 0.28 A1 0.08 0.10 0.09 0.21 0.28 A1 0.08 0.10 0.09 0.21 0.28 B1 0.07 0.07 0.07 0.21 0.29 B1 0.07 0.07 0.07 0.21 0.29 B1 0.07 0.07 0.07 0.21 0.29 C1 0.09 0.10 0.08 0.14 0.29 C1 0.09 0.10 0.08 0.14 0.29 C1 0.09 0.10 0.08 0.14 0.29 A1 0.08 0.07 0.08 0.23 0.28 A1 0.14 0.13 0.10 0.21 0.27 A1 0.31 0.34 0.09 0.45 0.33 0.25 0.27 B1 0.07 0.07 0.07 0.22 0.28 B1 0.07 0.13 0.16 0.18 0.21 0.28 B1 0.33 0.33 0.09 0.41 0.72 0.13 0.27 0.06 C1 0.08 0.10 0.08 0.14 0.27 C1 0.18 0.18 0.10 0.15 0.28 C1 0.27 0.52 0.13 0.64 0.10 0.15 0.28 A1 0.08 0.08 0.20 0.30 0.09 A1 0.20 0.20 0.20 0.29 0.09 A1 0.56 0.14 0.67 0.10 0.28 0.29 0.10 B1 0.08 0.08 0.23 0.32 0.06 B1 0.20 0.04 0.21 0.23 0.28 0.07 B1 0.55 0.15 0.73 0.06 0.12 0.28 0.05 C1 0.10 0.09 0.13 0.28 0.14 C1 0.28 0.29 0.13 0.32 0.13 C1 0.89 0.22 1.14 0.07 0.16 0.28 0.12 A1 0.09 0.09 0.18 0.29 A1 0.26 0.29 0.21 0.28 A1 0.73 0.18 0.82 0.19 0.11 0.27 B1 0.09 0.09 0.19 0.28 B1 0.25 0.25 0.20 0.28 B1 0.73 0.19 0.82 0.09 0.09 0.07 0.28 0.06 C1 0.10 0.10 0.13 0.28 C1 0.35 0.38 0.11 0.28 C1 1.22 0.30 1.56 0.12 0.15 0.27 Min 0.07 0.089 0.067 0.073 0 0.27 Max 0.344 0.089 0.448 0.326 0 0.288 TABLE 75 RRT RRT RRRT RRT Total 1.85 1.91 2.02 2.37 RS Lot (%) (%) (%) (%) (%) A1 1.61 A1 1.61 A1 1.61 B1 1.48 B1 1.48 B1 1.48 C1 1.50 C1 1.50 C1 1.50 A1 1.60 A1 1.63 A1 2.80 B1 1.50 B1 1.80 B1 0.44 3.53 C1 1.49 C1 1.66 C1 2.85 A1 1.53 A1 2.10 A1 3.55 B1 1.56 B1 1.98 B1 3.31 C1 1.57 C1 1.97 C1 4.05 A1 1.26 A1 1.76 A1 3.29 B1 1.40 B1 1.82 B1 0.10 0.10 0.17 3.68 C1 1.38 C1 1.89 C1 4.41 Min 1.483 Max 2.799 The appearance for all of the tested lots through the duration of the experiment was clear and colorless. The results above provided an estimated shelf life at 5° C. of about 16.1 months (FIG. 27) and at 25° C. of about eight months (FIG. 28). The results indicated that the dextrose vehicle with 1 mM acetate buffer provided a lower rate of degradation and a lower rate of impurities accumulation for the vasopressin formulations at 5° C., 25° C., and 40° C. compared to NaCl or a combination of dextrose and NaCl in either 1 mM or 10 mM acetate buffer Graphical depictions of TABLES 66-72 are shown in FIGS. 29-48 below. FIGS. 29-31 show the vasopressin (% LC) levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 32-34 show the total impurities (total RS (%)) levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 35-37 show the Gly9-AVP levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 38-40 show the Asp5-AVP levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 41-43 show the Glu4-AVP levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 44-46 show the Acetyl-AVP levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 47-48 show the AVP dimer levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. Based on the data from FIGS. 29-48, the estimated shelf-life at 5° C. is about 16.1 months, and the estimated shelf-life at 25° C. is about 8 months. TABLES 73-75 display data of further studies on Formulations A1, B1, and C1 as detailed in TABLE 65. The appearance for all of the tested lots through the duration of the experiment was clear and colorless. The estimated shelf life at 5° C. of about 15 months and at 25° C. of about 7.7 months is shown below in FIG. 49 and FIG. 50, respectively. The results indicated that the dextrose vehicle provided a lower rate of degradation and a lower rate of impurities accumulation for the vasopressin formulations at 5° C., 25° C., and 40° C. compared to a combination of dextrose and NaCl. Graphical depictions of TABLES 73-75 are shown in FIGS. 51-62 below. FIGS. 51-53 show the vasopressin (% LC) levels in the samples prepared in dextrose or dextrose and NaCl at 5° C., 25° C., and 40° C., respectively. FIGS. 54-56 show the Gly9-AVP levels in the samples prepared in dextrose or dextrose and NaCl at 5° C., 25° C., and 40° C., respectively. FIGS. 57-59 show the Glu4-AVP levels in the samples prepared in dextrose or dextrose and NaCl at 5° C., 25° C., and 40° C., respectively. FIGS. 60-62 show the total impurities (% RS) levels in the samples prepared in dextrose or dextrose and NaCl at 5° C., 25° C., and 40° C., respectively. EMBODIMENTS The following non-limiting embodiments provide illustrative examples of the invention, but do not limit the scope of the invention. In some embodiments, the invention provides a pharmaceutical composition comprising, in a unit dosage form: a) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin, or a pharmaceutically-acceptable salt thereof; and b) a polymeric pharmaceutically-acceptable excipient in an amount that is from about 1% to about 10% by mass of the unit dosage form or the pharmaceutically-acceptable salt thereof, wherein the unit dosage form exhibits from about 5% to about 10% less degradation of the vasopressin or the pharmaceutically-acceptable salt thereof after storage for about 1 week at about 60° C. than does a corresponding unit dosage form, wherein the corresponding unit dosage form consists essentially of: A) vasopressin, or a pharmaceutically-acceptable salt thereof; and B) a buffer having acidic pH. In some embodiments, the polymeric pharmaceutically-acceptable excipient comprises a polyalkylene oxide moiety. In some embodiments, the polymeric pharmaceutically-acceptable excipient is a polyethylene oxide. In some embodiments, the polymeric pharmaceutically-acceptable excipient is a poloxamer. In some embodiments, the unit dosage form has an amount of the polymeric pharmaceutically-acceptable excipient that is about 1% the amount of the vasopressin or the pharmaceutically-acceptable salt thereof. In some embodiments, the first unit dosage form exhibits about 10% less degradation of the vasopressin or the pharmaceutically-acceptable salt thereof after storage for about 1 week at about 60° C. than does the corresponding unit dosage form. In some embodiments, the unit dosage form further comprises SEQ ID NO. 2. In some embodiments, the composition further comprises SEQ ID NO. 3. In some embodiments, the composition further comprises SEQ ID NO. 4. In some embodiments, the unit dosage form is an injectable of about 1 mL volume. In some embodiments, the unit dosage form consists essentially of: a) about 0.04 mg/mL of vasopressin, or the pharmaceutically-acceptable salt thereof; b) the polymeric pharmaceutically-acceptable excipient in an amount that is from about 1% to about 10% by mass of the vasopressin or the pharmaceutically-acceptable salt thereof; and c) a plurality of peptides, wherein each of the peptides has from 88% to 90% sequence homology to the vasopressin or the pharmaceutically-acceptable salt thereof. In some embodiments, one of the plurality of peptides is SEQ ID NO.: 2. In some embodiments, one of the plurality of peptides is SEQ ID NO.:3. In some embodiments, wherein one of the plurality of peptides is SEQ ID NO.: 4. In some embodiments, the buffer has a pH of about 3.5. Embodiment 1 A method of increasing blood pressure in a human in need thereof, the method comprising: intravenously administering to the human a pharmaceutical composition comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; and ii) acetic acid, sodium acetate, or a combination thereof, wherein: the pharmaceutical composition is at about room temperature; the administration to the human is longer than 18 hours; the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. Embodiment 2 The method of embodiment 1, wherein the administration to the human is for about one day. Embodiment 3 The method of embodiment 1, wherein the administration to the human is for about one week. Embodiment 4 The method of any one of embodiments 1-3, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. Embodiment 5 The method of any one of embodiments 1-4, wherein the human's hypotension is associated with vasodilatory shock. Embodiment 6 The method of embodiment 5, wherein the vasodilatory shock is post-cardiotomy shock. Embodiment 7 The method of any one of embodiments 1-6, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 8 The method of embodiment 5, wherein the vasodilatory shock is septic shock. Embodiment 9 The method of any one of embodiments 1-8, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 10 The method of any one of embodiments 1-9, wherein the unit dosage form further comprises dextrose. Embodiment 11 The method of any one of embodiments 1-10, wherein the unit dosage form further comprises about 5% dextrose. Embodiment 12 A method of increasing blood pressure in a human in need thereof, the method comprising: intravenously administering to the human a pharmaceutical composition that consists essentially of, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; iii) acetic acid, sodium acetate, or a combination thereof; and iv) optionally hydrochloric acid or sodium hydroxide, wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. Embodiment 13 The method of embodiment 12, wherein the unit dosage form consists essentially of hydrochloric acid. Embodiment 14 The method of embodiment 12, wherein the unit dosage form consists essentially of sodium hydroxide. Embodiment 15 The method of any one of embodiments 12-14, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. Embodiment 16 The method of any one of embodiments 12-15, wherein the human's hypotension is associated with vasodilatory shock. Embodiment 17 The method of embodiment 16, wherein the vasodilatory shock is post-cardiotomy shock. Embodiment 18 The method of any one of embodiments 12-17, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 19 The method of embodiment 16, wherein the vasodilatory shock is septic shock. Embodiment 20 The method of any one of embodiments 12-19 wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. Embodiment 21 The method of any one of embodiments 12-20, wherein the unit dosage form consists essentially of 5% dextrose. Embodiment 22 A method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 5° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 1% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 5° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. Embodiment 23 The method of embodiment 22, wherein the administration to the human is for about one day. Embodiment 24 The method of embodiment 22, wherein the administration to the human is for about one week. Embodiment 25 The method of any one of embodiments 22-24, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. Embodiment 26 The method of any one of embodiments 22-25, wherein the human's hypotension is associated with vasodilatory shock. Embodiment 27 The method of embodiment 26, wherein the vasodilatory shock is post-cardiotomy shock. Embodiment 28 The method of any one of embodiments 22-27, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 29 The method of embodiment 26, wherein the vasodilatory shock is septic shock. Embodiment 30 The method of any one of embodiments 22-29, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. Embodiment 31 The method of any one of embodiments 22-30, wherein the pharmaceutical composition exhibits no more than about 2% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after storage of the pharmaceutical composition at 5° C. for about two months. Embodiment 32 A method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 25° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 2% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 25° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. Embodiment 33 The method of embodiment 32, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. Embodiment 34 The method of any one of embodiments 32-33, wherein the human's hypotension is associated with vasodilatory shock. Embodiment 35 The method of embodiment 34, wherein the vasodilatory shock is post-cardiotomy shock. Embodiment 36 The method of any one of embodiments 32-35, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 37 The method of embodiment 35, wherein the vasodilatory shock is septic shock. Embodiment 38 The method of any one of embodiments 32-37, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. Embodiment 39 The method of any one of embodiments 32-38, wherein the pharmaceutical composition exhibits no more than about 5% degradation after storage of the pharmaceutical composition at 25° C. for about two months.
<SOH> BACKGROUND <EOH>Vasopressin is a potent endogenous hormone, responsible for maintaining plasma osmolality and volume in most mammals. Vasopressin can be used clinically in the treatment of sepsis and cardiac conditions, and in the elevation of patient's suffering from low blood pressure. Current formulations of vasopressin suffer from poor long-term stability.
<SOH> SUMMARY OF THE INVENTION <EOH>In some embodiments, the invention provides a pharmaceutical composition comprising, in a unit dosage form: a) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin, or a pharmaceutically-acceptable salt thereof; and b) a polymeric pharmaceutically-acceptable excipient in an amount that is from about 1% to about 10% by mass of the unit dosage form or the pharmaceutically-acceptable salt thereof, wherein the unit dosage form exhibits from about 5% to about 10% less degradation of the vasopressin or the pharmaceutically-acceptable salt thereof after storage for about 1 week at about 60° C. than does a corresponding unit dosage form, wherein the corresponding unit dosage form consists essentially of: A) vasopressin, or a pharmaceutically-acceptable salt thereof; and B) a buffer having acidic pH. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: intravenously administering to the human a pharmaceutical composition that consists essentially of, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; iii) acetic acid, sodium acetate, or a combination thereof; and iv) optionally hydrochloric acid or sodium hydroxide, wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 5° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 1% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 5° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 25° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 2% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 25° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive.
A61K3811
20170828
20180703
20180104
67193.0
A61K3811
1
BRADLEY, CHRISTINA
VASOPRESSIN FORMULATIONS FOR USE IN TREATMENT OF HYPOTENSION
UNDISCOUNTED
1
CONT-ACCEPTED
A61K
2,017
15,688,336
ACCEPTED
VASOPRESSIN FORMULATIONS FOR USE IN TREATMENT OF HYPOTENSION
Provided herein are peptide formulations comprising polymers as stabilizing agents. The peptide formulations can be more stable for prolonged periods of time at temperatures higher than room temperature when formulated with the polymers. The polymers used in the present invention can decrease the degradation of the constituent peptides of the peptide formulations.
1-15. (canceled) 16. A method of increasing blood pressure in a human in need thereof, the method comprising: administering to the human a unit dosage form, wherein the unit dosage form comprises from about 0.1 units/mL to about 1 unit/mL of vasopressin or the pharmaceutically-acceptable salt thereof, wherein the unit dosage form has a pH of no greater than 4.1; the unit dosage form further comprises impurities that are present in an amount of 0.9%-1.7%, wherein the impurities have from about 85% to about 100% sequence homology to SEQ ID NO.: 1; the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. 17. The method of claim 16, wherein the impurities comprise SEQ ID NO.: 2, and SEQ ID NO.: 2 is present in the unit dosage form in an amount of 0.1% to 0.3%. 18. The method of claim 16, wherein the impurities comprise SEQ ID NO.: 3, and SEQ ID NO.: 3 is present in the unit dosage form in an amount of 0.1%. 19. The method of claim 16, wherein the impurities comprise SEQ ID NO.: 4, and SEQ ID NO.: 4 is present in the unit dosage form in an amount of 0.2% to 0.4%. 20. The method of claim 16, wherein the impurities comprise SEQ ID NO.: 7, and SEQ ID NO.: 7 is present in the unit dosage form in an amount of 0.3% to 0.6%. 21. The method of claim 16, wherein the impurities comprise SEQ ID NO.: 10, and SEQ ID NO.: 10 is present in the unit dosage form in an amount of 0.1%. 22. The method of claim 16, wherein the impurities comprise SEQ ID NO.: 2 and SEQ ID NO.: 4, and SEQ ID NO.: 2 is present in the unit dosage form in an amount of 0.1% to 0.3% and SEQ ID NO.: 4 is present in the unit dosage form in an amount of 0.2% to 0.4%. 23. The method of claim 22, wherein the impurities further comprise SEQ ID NO.: 3, SEQ ID NO.: 7, and SEQ ID NO.: 10, and SEQ ID NO.: 3 is present in the unit dosage form in an amount of 0.1%, SEQ ID NO.: 7 is present in the unit dosage form in an amount of 0.3% to 0.6%, and SEQ ID NO.: 10 is present in the unit dosage form in an amount of 0.1%. 24. The method of claim 16, wherein the human's hypotension is associated with vasodilatory shock. 25. The method of claim 24, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. 26. The method of claim 16, wherein the impurities comprise a plurality of peptides, wherein the impurities are determined based on: (a) injecting the unit dosage form into a high pressure liquid chromatography apparatus, wherein the apparatus comprises: (i) a chromatography column containing adsorbent particles as a stationary phase; (ii) a first mobile phase passing through the chromatography column, wherein the first mobile phase is phosphate buffer at pH 3; and (iii) a second mobile phase passing through the chromatography column, wherein the second mobile phase is a 50:50 acetonitrile:water solution; (b) running the unit dosage form through the chromatography column for 55 minutes; (c) eluting the vasopressin and the plurality of peptides from the chromatography column using a gradient of the first mobile phase, and a gradient of the second mobile phase, wherein each of the first and second mobile phase are run at a flow rate of 1 mL/min through the chromatography column; (d) passing the eluted vasopressin and the plurality of peptides through a UV detector to generate a UV spectrum of the eluted vasopressin and the plurality of peptides; (e) identifying a peptide of the plurality of peptides based on a retention time of the peptide of the plurality of peptides relative to a standard; and (f) calculating an amount of the peptide of the plurality of peptides based on an integration of a peak obtained for the peptide of plurality of peptides from the UV spectrum. 27. The method of claim 16, wherein the unit dosage form further comprises sodium acetate. 28. The method of claim 16, wherein the unit dosage form further comprises a pH adjusting agent. 29. The method of claim 16, wherein the pharmaceutically-acceptable salt of vasopressin is present in the unit dosage form. 30. The method of claim 16, wherein the pharmaceutically-acceptable salt of vasopressin is not present in the unit dosage form.
CROSS REFERENCE This application is a continuation of U.S. application Ser. No. 15/612,649, filed Jun. 2, 2017, which is a continuation-in-part of U.S. application Ser. No. 15/426,693, filed Feb. 7, 2017, which is a continuation-in-part of U.S. application Ser. No. 15/289,640, filed Oct. 10, 2016, which is a continuation-in-part of U.S. application Ser. No. 14/717,877, filed May 20, 2015, which is a continuation of U.S. application Ser. No. 14/610,499, filed Jan. 30, 2015, each of which is incorporated herein by reference in its entirety. BACKGROUND Vasopressin is a potent endogenous hormone, responsible for maintaining plasma osmolality and volume in most mammals. Vasopressin can be used clinically in the treatment of sepsis and cardiac conditions, and in the elevation of patient's suffering from low blood pressure. Current formulations of vasopressin suffer from poor long-term stability. INCORPORATION BY REFERENCE Each patent, publication, and non-patent literature cited in the application is hereby incorporated by reference in its entirety as if each was incorporated by reference individually. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Aug. 25, 2017, is named 47956702309_SL.txt and is 5260 bytes in size. SUMMARY OF THE INVENTION In some embodiments, the invention provides a pharmaceutical composition comprising, in a unit dosage form: a) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin, or a pharmaceutically-acceptable salt thereof; and b) a polymeric pharmaceutically-acceptable excipient in an amount that is from about 1% to about 10% by mass of the unit dosage form or the pharmaceutically-acceptable salt thereof, wherein the unit dosage form exhibits from about 5% to about 10% less degradation of the vasopressin or the pharmaceutically-acceptable salt thereof after storage for about 1 week at about 60° C. than does a corresponding unit dosage form, wherein the corresponding unit dosage form consists essentially of: A) vasopressin, or a pharmaceutically-acceptable salt thereof; and B) a buffer having acidic pH. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: intravenously administering to the human a pharmaceutical composition that consists essentially of, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; iii) acetic acid, sodium acetate, or a combination thereof; and iv) optionally hydrochloric acid or sodium hydroxide, wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 5° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 1% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 5° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 25° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 2% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 25° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. BRIEF DESCRIPTION OF THE FIGURES FIG. 1 is a chromatogram of a diluent used in vasopressin assay. FIG. 2 is a chromatogram of a sensitivity solution used in a vasopressin assay. FIG. 3 is a chromatogram of an impurity marker solution used in a vasopressin assay. FIG. 4 is a zoomed-in depiction of the chromatogram in FIG. 3. FIG. 5 is a chromatogram of a vasopressin standard solution. FIG. 6 is a chromatogram of a sample vasopressin preparation. FIG. 7 is a UV spectrum of a vasopressin sample. FIG. 8 is a UV spectrum of a vasopressin standard. FIG. 9 plots vasopressin stability across a range of pH as determined experimentally. FIG. 10 illustrates the effects of various stabilizers on vasopressin stability. FIG. 11 plots vasopressin stability across a range of pH at 25° C. FIG. 12 plots vasopressin impurities across a range of pH at 25° C. FIG. 13 plots vasopressin stability across a range of pH at 40° C. FIG. 14 plots vasopressin impurities across a range of pH at 40° C. FIG. 15 illustrates vasopressin impurities across a range of pH at 25° C. FIG. 16 illustrates vasopressin impurities across a range of pH at 40° C. FIG. 17 illustrates the effect of pH on vasopressin at 25° C. FIG. 18 illustrates the effect of pH on vasopressin at 40° C. FIG. 19 depicts the % LC of vasopressin formulations stored for 15 months at 25° C. FIG. 20 is a chromatogram of a diluent used in a vasopressin assay. FIG. 21 is a chromatogram of a sensitivity solution used in a vasopressin assay. FIG. 22 is a chromatogram of an impurity marker solution used in a vasopressin assay. FIG. 23 is a zoomed-in depiction of the chromatogram in FIG. 22. FIG. 24 is a chromatogram of a working solution. FIG. 25 is a chromatogram of a placebo sample. FIG. 26 is a chromatogram of a vasopressin sample. FIG. 27 depicts the estimated shelf-life of a vasopressin sample described herein at 5° C. FIG. 28 depicts the estimated shelf-life of a vasopressin sample described herein at 25° C. FIG. 29 shows the % LC of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 30 shows the % LC of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 31 shows the % LC of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 32 shows the total impurities of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 33 shows the total impurities of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 34 shows the total impurities of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 35 shows the % Gly9-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 36 shows the % Gly9-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 37 shows the % Gly9-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 38 shows the % Asp5-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 39 shows the % Asp5-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 40 shows the % Asp5-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 41 shows the % Glu4-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 42 shows the % Glu4-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 43 shows the % Glu4-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 44 shows the % Acetyl-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 45 shows the % Acetyl-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 46 shows the % Acetyl-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 47 shows the % AVP-dimer of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 48 shows the % AVP-dimer of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 49 depicts the estimated shelf-life of a vasopressin sample described herein at 5° C. FIG. 50 depicts the estimated shelf-life of a vasopressin sample described herein at 25° C. FIG. 51 shows the % LC of vasopressin after storage at 5° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 52 shows the % LC of vasopressin after storage at 25° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 53 shows the % LC of vasopressin after storage at 40° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 54 shows the % Gly9-AVP of vasopressin after storage at 5° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 55 shows the % Gly9-AVP of vasopressin after storage at 25° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 56 shows the % Gly9-AVP of vasopressin after storage at 40° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 57 shows the % Glu4-AVP of vasopressin after storage at 5° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 58 shows the % Glu4-AVP of vasopressin after storage at 25° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 59 shows the % Glu4-AVP of vasopressin after storage at 40° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 60 shows the total impurities of vasopressin after storage at 5° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 61 shows the total impurities of vasopressin after storage at 25° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 62 shows the total impurities of vasopressin after storage at 40° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. DETAILED DESCRIPTION Vasopressin and Peptides of the Invention. Vasopressin, a peptide hormone, acts to regulate water retention in the body and is a neurotransmitter that controls circadian rhythm, thermoregulation, and adrenocorticotrophic hormone (ACTH) release. Vasopressin is synthesized as a pro-hormone in neurosecretory cells of the hypothalamus, and is subsequently transported to the pituitary gland for storage. Vasopressin is released upon detection of hyperosmolality in the plasma, which can be due to dehydration of the body. Upon release, vasopressin increases the permeability of collecting ducts in the kidney to reduce renal excretion of water. The decrease in renal excretion of water leads to an increase in water retention of the body and an increase in blood volume. At higher concentrations, vasopressin raises blood pressure by inducing vasoconstriction. Vasopressin acts through various receptors in the body including, for example, the V1, V2, V3, and oxytocin-type (OTR) receptors. The V1 receptors occur on vascular smooth muscle cells, and the major effect of vasopressin action on the V1 receptor is the induction of vasoconstriction via an increase of intracellular calcium. V2 receptors occur on the collecting ducts and the distal tubule of the kidney. V2 receptors play a role in detection of plasma volume and osmolality. V3 receptors occur in the pituitary gland and can cause ACTH release upon vasopressin binding. OTRs can be found on the myometrium and vascular smooth muscle. Engagement of OTRs via vasopressin leads to an increase of intracellular calcium and vasoconstriction. Vasopressin is a nonapeptide, illustrated below (SEQ ID NO. 1): At neutral to acidic pH, the two basic groups of vasopressin, the N-terminal cysteine, and the arginine at position eight, are protonated, and can each carry an acetate counterion. The amide groups of the N-terminal glycine, the glutamine at position four, and the asparagine at position five, are susceptible to modification when stored as clinical formulations, such as unit dosage forms. The glycine, glutamine, and asparagine residues can undergo deamidation to yield the parent carboxylic acid and several degradation products as detailed in EXAMPLE 1 and TABLE 1 below. Deamidation is a peptide modification during which an amide group is removed from an amino acid, and can be associated with protein degradation, apoptosis, and other regulatory functions within the cell. Deamidation of asparagine and glutamine residues can occur in vitro and in vivo, and can lead to perturbation of the structure and function of the affected proteins. The susceptibility to deamidation can depend on primary sequence of the protein, three-dimensional structure of the protein, and solution properties including, for example, pH, temperature, ionic strength, and buffer ions. Deamidation can be catalyzed by acidic conditions. Under physiological conditions, deamidation of asparagine occurs via the formation of a five-membered succinimide ring intermediate by a nucleophilic attack of the nitrogen atom in the following peptide bond on the carbonyl group of the asparagine side chain. Acetylation is a peptide modification whereby an acetyl group is introduced into an amino acid, such as on the N-terminus of the peptide. Vasopressin can also form dimers in solution and in vivo. The vasopressin dimers can occur through the formation of disulfide bridges that bind a pair of vasopressin monomers together. The dimers can form between two parallel or anti-parallel chains of vasopressin. Vasopressin and associated degradation products or peptides are listed in TABLE 1 below. All amino acids are L-stereoisomers unless otherwise denoted. TABLE 1 Name Sequence SEQ ID NO. Vasopressin (AVP; arginine CYFQNCPRG-NH2 1 vasopressin) Gly9-vasopressin (Gly9-AVP) CYFQNCPRG 2 Asp5-vasopressin (Asp5-AVP) CYFQDCPRG-NH2 3 Glu4-vasopressin (Glu4-AVP) CYFENCPRG-NH2 4 Glu4Gly9-vasopressin (Glu4Gly9-AVP) CYFENCPRG 5 AcetylAsp5-vasopressin Ac-CYFQDCPRG-NH2 6 (AcetylAsp5-AVP) Acetyl-vasopressin (Acetyl-AVP) Ac-CYFQNCPRG-NH2 7 His2-vasopressin (His2-AVP) CHFQNCPRG-NH2 8 Leu7-vasopressin (Leu7-AVP) CYFQNCLRG-NH2 9 D-Asn-vasopressin (DAsn-AVP) CYFQ(D-Asn)CPRG-NH2 10 D-Cys1-vasopressin (D-Cys)YFQNCPRG-NH2 11 D-Tyr-vasopressin C(D-Tyr)FQNCPRG-NH2 12 D-Phe-vasopressin CY(D-Phe)QNCPRG-NH2 13 D-Gln-vasopressin CYF(D-Gln)NCPRG-NH2 14 D-Cys6-vasopressin CYFQN(D-cys)PRG-NH2 15 D-Pro-vasopressin CYFQNC(D-pro)RG-NH2 16 D-Arg-vasopressin CYFQNCP(D-Arg)G-NH2 17 Therapeutic Uses. A formulation of vasopressin can be used to regulate plasma osmolality and volume and conditions related to the same in a subject. Vasopressin can be used to modulate blood pressure in a subject, and can be indicated in a subject who is hypotensive despite treatment with fluid and catecholamines. Vasopressin can be used in the treatment of, for example, vasodilatory shock, post-cardiotomy shock, sepsis, septic shock, cranial diabetes insipidus, polyuria, nocturia, polydypsia, bleeding disorders, Von Willebrand disease, haemophilia, platelet disorders, cardiac arrest, liver disease, liver failure, hypovolemia, hemorrhage, oesophageal variceal haemorrhage, hypertension, pulmonary hypertension, renal disease, polycystic kidney disease, blood loss, injury, hypotension, meniere disease, uterine myomas, brain injury, mood disorder. Formulations of vasopressin can be administered to a subject undergoing, for example, surgery or hysterectomy. Plasma osmolality is a measure of the plasma's electrolyte-water balance and relates to blood volume and hydration of a subject. Normal plasma osmolality in a healthy human subject range from about 275 milliosmoles/kg to about 295 milliosmoles/kg. High plasma osmolality levels can be due to, for example, diabetes insipidus, hyperglycemia, uremia, hypernatremia, stroke, and dehydration. Low plasma osmolality can be due to, for example, vasopressin oversecretion, improper functioning of the adrenal gland, lung cancer, hyponatremia, hypothyroidism, and over-consumption of water or other fluids. Septic shock can develop due to an extensive immune response following infection and can result in low blood pressure. Causes of sepsis can include, for example, gastrointestinal infections, pneumonia, bronchitis, lower respiratory tract infections, kidney infection, urinary tract infections, reproductive system infections, fungal infections, and viral infections. Risk factors for sepsis include, for example, age, prior illness, major surgery, long-term hospitalization, diabetes, intravenous drug use, cancer, use of steroidal medications, and long-term use of antibiotics. The symptoms of sepsis can include, for example, cool arms and legs, pale arms and legs, extreme body temperatures, chills, light-headedness, decreased urination, rapid breathing, edema, confusion, elevated heart rate, high blood sugar, metabolic acidosis, respiratory alkalosis, and low blood pressure. Vasopressin can also be administered to regulate blood pressure in a subject. Blood pressure is the measure of force of blood pushing against blood vessel walls. Blood pressure is regulated by the nervous and endocrine systems and can be used as an indicator of a subject's health. Chronic high blood pressure is referred to as hypertension, and chronic low blood pressure is referred to as hypotension. Both hypertension and hypotension can be harmful if left untreated. Blood pressure can vary from minute to minute and can follow the circadian rhythm with a predictable pattern over a 24-hour period. Blood pressure is recorded as a ratio of two numbers: systolic pressure (mm Hg), the numerator, is the pressure in the arteries when the heart contracts, and diastolic pressure (mm Hg), the denominator, is the pressure in the arteries between contractions of the heart. Blood pressure can be affected by, for example, age, weight, height, sex, exercise, emotional state, sleep, digestion, time of day, smoking, alcohol consumption, salt consumption, stress, genetics, use of oral contraceptives, and kidney disease. Blood pressure for a healthy human adult between the ages of 18-65 can range from about 90/60 to about 120/80. Hypertension can be a blood pressure reading above about 120/80 and can be classified as hypertensive crisis when there is a spike in blood pressure and blood pressure readings reach about 180/110 or higher. Hypertensive crisis can be precipitated by, for example, stroke, myocardial infarction, heart failure, kidney failure, aortic rupture, drug-drug interactions, and eclampsia. Symptoms of hypertensive crisis can include, for example, shortness of breath, angina, back pain, numbness, weakness, dizziness, confusion, change in vision, nausea, and difficulty speaking. Vasodilatory shock can be characterized by low arterial blood pressure due to decreased systemic vascular resistance. Vasodilatory shock can lead to dangerously low blood pressure levels and can be corrected via administration of catecholamines or vasopressin formulations. Vasodilatory shock can be caused by, for example, sepsis, nitrogen intoxication, carbon monoxide intoxication, hemorrhagic shock, hypovolemia, heart failure, cyanide poisoning, metformin intoxication, and mitochondrial disease. Post-cardiotomy shock can occur as a complication of cardiac surgery and can be characterized by, for example, inability to wean from cardiopulmonary bypass, poor hemodynamics in the operating room, development of poor hemodynamics post-surgery, and hypotension. Pharmaceutical Formulations. Methods for the preparation of compositions comprising the compounds described herein can include formulating the compounds with one or more inert, pharmaceutically-acceptable excipients. Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives. Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, elixir, nanosuspension, aqueous or oily suspensions, drops, syrups, and any combination thereof. Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include granulating agents, binding agents, lubricating agents, disintegrating agents, anti-adherents, anti-static agents, surfactants, anti-oxidants, coloring agents, flavoring agents, plasticizers, preservatives, suspending agents, emulsifying agents, plant cellulosic material and spheronization agents, and any combination thereof. Vasopressin can be formulated as an aqueous formulation or a lyophilized powder, which can be diluted or reconstituted just prior to use. Upon dilution or reconstitution, the vasopressin solution can be refrigerated for long-term stability for about one day. Room temperature incubation or prolonged refrigeration can lead to the generation of degradation products of vasopressin. In some embodiments, a pharmaceutical composition of the invention can be formulated for long-term storage of vasopressin at room temperature in the presence of a suitable pharmaceutically-acceptable excipient. The pharmaceutically-acceptable excipient can increase the half-life of vasopressin when stored at any temperature, such as room temperature. The presence of the pharmaceutical excipient can decrease the rate of decomposition of vasopressin at any temperature, such as room temperature. In some embodiments, a pharmaceutical composition has a shelf life of at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, at least about 25 months, at least about 26 months, at least about 27 months, at least about 28 months, at least about 29 months, or at least about 30 months. The shelf life can be at any temperature, including, for example, room temperature and refrigeration (i.e., 2-8° C.). As used herein, “shelf life” means the period beginning from manufacture of a formulation beyond which the formulation cannot be expected beyond reasonable doubt to yield the therapeutic outcome approved by a government regulatory agency In some embodiments, a vasopressin formulation of the invention comprises a pharmaceutically-acceptable excipient, and the vasopressin has a half-life that is at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, or at least about 1000% greater than the half-life of vasopressin in a corresponding formulation that lacks the pharmaceutically-acceptable excipient. In some embodiments, a vasopressin formulation of the invention has a half-life at about 5° C. to about 8° C. that is no more than about 1%, no more than about 5%, no more than about 10%, no more than about 15%, no more than about 20%, no more than about 25%, no more than about 30%, no more than about 35%, no more than about 40%, no more than about 45%, no more than about 50%, no more than about 55%, no more than about 60%, no more than about 65%, no more than about 70%, no more than about 75%, no more than about 80%, no more than about 85%, no more than about 90%, no more than about 95%, no more than about 100%, no more than about 150%, no more than about 200%, no more than about 250%, no more than about 300%, no more than about 350%, no more than about 400%, no more than about 450%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000% greater than the half-life of the formulation at another temperature, such as room temperature. The half-life of the compounds of the invention in a formulation described herein at a specified temperature can be, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, or about one week. A formulation described herein can be stable for or be stored for, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years prior to administration to a subject. A unit dosage form described herein can be stable for or be stored for, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years prior to administration to a subject. A diluted unit dosage form described herein can be stable for or be stored for, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years prior to administration to subject. The stability of a formulation described herein can be measured after, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years. A formulation or unit dosage form described herein can exhibit, for example, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9% about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% degradation over a specified period of time. The degradation of a formulation or a unit dosage form disclosed herein can be assessed after about 24 hours, about 36 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years of storage. The degradation of a formulation or a unit dosage form disclosed herein can be assessed at a temperature of, for example, about 0° C., about 1° C., about 2° C., about 3° C., about 4° C., about 5° C., about 6° C., about 7° C., about 8° C., about 9° C., about 10° C., about 11° C., about 12° C., about 13° C., about 14° C., about 15° C., about 16° C., about 17° C., about 18° C., about 19° C., about 20° C., about 21° C., about 22° C., about 23° C., about 24° C., about 25° C., about 26° C., about 27° C., about 28° C., about 29° C., about 30° C., about 31° C., about 32° C., about 33° C., about 34° C., about 35° C., about 36° C., about 37° C., about 38° C., about 39° C., about 40° C., about 41° C., about 42° C., about 43° C., about 44° C., about 45° C., about 46° C., about 47° C., about 48° C., about 49° C., about 50° C., or about 0° C. to about 5° C., about 1° C. to about 6° C., about 2° C. to about 7° C., about 2° C. to about 8° C., about 3° C. to about 8° C., about 4° C. to about 9° C., about 5° C. to about 10° C., about 6° C. to about 11° C., about 7° C. to about 12° C., about 8° C. to about 13° C., about 9° C. to about 14° C., about 10° C. to about 15° C., about 11° C. to about 16° C., about 12° C. to about 17° C., about 13° C. to about 18° C., about 14° C. to about 19° C., about 15° C. to about 20° C., about 16° C. to about 21° C., about 17° C. to about 22° C., about 18° C. to about 23° C., about 19° C. to about 24° C., about 20° C. to about 25° C., about 21° C. to about 26° C., about 22° C. to about 27° C., about 23° C. to about 28° C., about 24° C. to about 29° C., about 25° C. to about 30° C., about 26° C. to about 31° C., about 27° C. to about 32° C., about 28° C. to about 33° C., about 29° C. to about 34° C., about 30° C. to about 35° C., about 31° C. to about 36° C., about 32° C. to about 37° C., about 33° C. to about 38° C., about 34° C. to about 39° C., about 35° C. to about 40° C., about 36° C. to about 41° C., about 37° C. to about 42° C., about 38° C. to about 43° C., about 39° C. to about 44° C., about 40° C. to about 45° C., about 41° C. to about 46° C., about 42° C. to about 47° C., about 43° C. to about 48° C., about 44° C. to about 49° C., about 45° C. to about 50° C. In some embodiments, a vasopressin formulation of the invention comprises an excipient and the vasopressin has a level of decomposition at a specified temperature that is about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% less than the level of decomposition of a formulation of the invention in the absence of the excipient. Pharmaceutical compositions of the invention can be used, stored, tested, analyzed or assayed at any suitable temperature. Non-limiting examples of temperatures include about 0° C., about 1° C., about 2° C., about 3° C., about 4° C., about 5° C., about 6° C., about 7° C., about 8° C., about 9° C., about 10° C., about 11° C., about 12° C., about 13° C., about 14° C., about 15° C., about 16° C., about 17° C., about 18° C., about 19° C., about 20° C., about 21° C., about 22° C., about 23° C., about 24° C., about 25° C., about 26° C., about 27° C., about 28° C., about 29° C., about 30° C., about 31° C., about 32° C., about 33° C., about 34° C., about 35° C., about 36° C., about 37° C., about 38° C., about 39° C., about 40° C., about 41° C., about 42° C., about 43° C., about 44° C., about 45° C., about 46° C., about 47° C., about 48° C., about 49° C., about 50° C., about 51° C., about 52° C., about 53° C., about 54° C., about 55° C., about 56° C., about 57° C., about 58° C., about 59° C., about 60° C., about 61° C., about 62° C., about 63° C., about 64° C., about 65° C., about 66° C., about 67° C., about 68° C., about 69° C., about 70° C., about 71° C., about 72° C., about 73° C., about 74° C., or about 75° C. Pharmaceutical compositions of the invention can be used, stored, tested, analyzed or assayed at any suitable temperature. Non-limiting examples of temperatures include from about 0° C. to about 5° C., about 1° C. to about 6° C., about 2° C. to about 7° C., about 2° C. to about 8° C., about 3° C. to about 8° C., about 4° C. to about 9° C., about 5° C. to about 10° C., about 6° C. to about 11° C., about 7° C. to about 12° C., about 8° C. to about 13° C., about 9° C. to about 14° C., about 10° C. to about 15° C., about 11° C. to about 16° C., about 12° C. to about 17° C., about 13° C. to about 18+° C., about 14° C. to about 19° C., about 15° C. to about 20° C., about 16° C. to about 21° C., about 17° C. to about 22° C., about 18° C. to about 23° C., about 19° C. to about 24° C., about 20° C. to about 25° C., about 21° C. to about 26° C., about 22° C. to about 27° C., about 23° C. to about 28° C., about 24° C. to about 29° C., about 25° C. to about 30° C., about 26° C. to about 31° C., about 27° C. to about 32° C., about 28° C. to about 33° C., about 29° C. to about 34° C., about 30° C. to about 35° C., about 31° C. to about 36° C., about 32° C. to about 37° C., about 33° C. to about 38° C., about 34° C. to about 39° C., about 35° C. to about 40° C., about 36° C. to about 41° C., about 37° C. to about 42° C., about 38° C. to about 43° C., about 39° C. to about 44° C., about 40° C. to about 45° C., about 41° C. to about 46° C., about 42° C. to about 47° C., about 43° C. to about 48° C., about 44° C. to about 49° C., about 45° C. to about 50° C., about 46° C. to about 51° C., about 47° C. to about 52° C., about 48° C. to about 53° C., about 49° C. to about 54° C., about 50° C. to about 55° C., about 51° C. to about 56° C., about 52° C. to about 57° C., about 53° C. to about 58° C., about 54° C. to about 59° C., about 55° C. to about 60° C., about 56° C. to about 61° C., about 57° C. to about 62° C., about 58° C. to about 63° C., about 59° C. to about 64° C., about 60° C. to about 65° C., about 61° C. to about 66° C., about 62° C. to about 67° C., about 63° C. to about 68° C., about 64° C. to about 69° C., about 65° C. to about 70° C., about 66° C. to about 71° C., about 67° C. to about 72° C., about 68° C. to about 73° C., about 69° C. to about 74° C., about 70° C. to about 74° C., about 71° C. to about 76° C., about 72° C. to about 77° C., about 73° C. to about 78° C., about 74° C. to about 79° C., or about 75° C. to about 80° C. Pharmaceutical compositions of the invention can be used, stored, tested, analyzed or assayed at room temperature. The room temperature can be, for example, about 20.0° C., about 20.1° C., about 20.2° C., about 20.3° C., about 20.4° C., about 20.5° C., about 20.6° C., about 20.7° C., about 20.8° C., about 20.9° C., about 21.0° C., about 21.1° C., about 21.2° C., about 21.3° C., about 21.4° C., about 21.5° C., about 21.6° C., about 21.7° C., about 21.8° C., about 21.9° C., about 22.0° C., about 22.1° C., about 22.2° C., about 22.3° C., about 22.4° C., about 22.5° C., about 22.6° C., about 22.7° C., about 22.8° C., about 22.9° C., about 23.0° C., about 23.1° C., about 23.2° C., about 23.3° C., about 23.4° C., about 23.5° C., about 23.6° C., about 23.7° C., about 23.8° C., about 23.9° C., about 24.0° C., about 24.1° C., about 24.2° C., about 24.3° C., about 24.4° C., about 24.5° C., about 24.6° C., about 24.7° C., about 24.8° C., about 24.9° C., or about 25.0° C. A pharmaceutical composition of the disclosed can be supplied, stored, or delivered in a vial or tube that is, for example, about 0.5 mL, about 1 mL, about 2 mL, about 3 mL, about 4 mL, about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, about 10 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about 18 mL, about 19 mL, or about 20 mL in volume. A pharmaceutical composition of the disclosure can be a combination of any pharmaceutical compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can be administered in therapeutically-effective amounts, for example, intravenous, subcutaneous, intramuscular, transdermal, or parenteral administration. Pharmaceutical preparations can be formulated for intravenous administration. The pharmaceutical compositions can be in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in oily or aqueous vehicles, and can contain formulation agents such as suspending, stabilizing, and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Suspensions of the active compounds can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. The suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use. Comparison Formulations. A pharmaceutical composition described herein can be analyzed by comparison to a reference formulation. A reference formulation can be generated from any combination of compounds, peptides, excipients, diluents, carriers, and solvents disclosed herein. Any compound, peptide, excipient, diluent, carrier, or solvent used to generate the reference formulation can be present in any percentage, ratio, or amount, for example, those disclosed herein. The reference formulation can comprise, consist essentially of, or consist of any combination of any of the foregoing. A non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: an amount, such as about 20 Units or about 0.04 mg, of vasopressin or a pharmaceutically-acceptable salt thereof, an amount, such as about 5 mg, of chlorobutanol (for example, hydrous), an amount, such as about 0.22 mg, of acetic acid or a pharmaceutically-acceptable salt thereof or a quantity sufficient to bring pH to about 3.4 to about 3.6, and water as needed. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof, chlorobutanol, acetic acid, and a solvent such as water. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof, chlorobutanol, and a solvent such as water. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof, acetic acid, and a solvent such as water. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof and a solvent such as water. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof and a buffer having acidic pH, such as pH 3.5 or any buffer or pH described herein. Methods. Any formulation described herein can be diluted prior to administration to a subject. Diluents that can be used in a method of the invention include, for example, compound sodium lactate solution, 6% dextran, 10% dextran, 5% dextrose, 20% fructose, Ringer's solution, 5% saline, 1.39% sodium bicarbonate, 1.72% sodium lactate, or water. Upon dilution, any diluted formulation disclosed herein can be stored for, for example, about 24 hours, about 36 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years of storage. Upon dilution, any diluted formulation disclosed herein can be stored at, for example, about 0° C., about 1° C., about 2° C., about 3° C., about 4° C., about 5° C., about 6° C., about 7° C., about 8° C., about 9° C., about 10° C., about 11° C., about 12° C., about 13° C., about 14° C., about 15° C., about 16° C., about 17° C., about 18° C., about 19° C., about 20° C., about 21° C., about 22° C., about 23° C., about 24° C., about 25° C., about 26° C., about 27° C., about 28° C., about 29° C., about 30° C., about 31° C., about 32° C., about 33° C., about 34° C., about 35° C., about 36° C., about 37° C., about 38° C., about 39° C., about 40° C., about 41° C., about 42° C., about 43° C., about 44° C., about 45° C., about 46° C., about 47° C., about 48° C., about 49° C., about 50° C., or about 0° C. to about 5° C., about 1° C. to about 6° C., about 2° C. to about 7° C., about 2° C. to about 8° C., about 3° C. to about 8° C., about 4° C. to about 9° C., about 5° C. to about 10° C., about 6° C. to about 11° C., about 7° C. to about 12° C., about 8° C. to about 13° C., about 9° C. to about 14° C., about 10° C. to about 15° C., about 11° C. to about 16° C., about 12° C. to about 17° C., about 13° C. to about 18° C., about 14° C. to about 19° C., about 15° C. to about 20° C., about 16° C. to about 21° C., about 17° C. to about 22° C., about 18° C. to about 23° C., about 19° C. to about 24° C., about 20° C. to about 25° C., about 21° C. to about 26° C., about 22° C. to about 27° C., about 23° C. to about 28° C., about 24° C. to about 29° C., about 25° C. to about 30° C., about 26° C. to about 31° C., about 27° C. to about 32° C., about 28° C. to about 33° C., about 29° C. to about 34° C., about 30° C. to about 35° C., about 31° C. to about 36° C., about 32° C. to about 37° C., about 33° C. to about 38° C., about 34° C. to about 39° C., about 35° C. to about 40° C., about 36° C. to about 41° C., about 37° C. to about 42° C., about 38° C. to about 43° C., about 39° C. to about 44° C., about 40° C. to about 45° C., about 41° C. to about 46° C., about 42° C. to about 47° C., about 43° C. to about 48° C., about 44° C. to about 49° C., about 45° C. to about 50° C. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about two weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about three weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about six weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about three months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about six months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about two years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about three years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 24 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 48 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 96 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 1 week; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 months; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 months; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least one year; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least two years; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least three years; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 24 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 48 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 96 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least one week; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 months; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 months; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 1 year; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 years; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 years; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 24 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 48 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 96 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 1 week; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 months; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 months; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 1 year; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 years; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 years; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 24 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 48 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 96 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least one week; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 months; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 months; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least one year; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 years; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 years; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 24 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 48 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 96 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 1 week; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 2 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 months; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 6 months; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 1 year; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 2 years; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 years; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about two weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about three weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 24 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 48 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C. for about, for example, 5° C., 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 96 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 1 week; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 2 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 months; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 6 months; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 1 year; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 2 years; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 years; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. A formulation described herein can be used without initial vasopressin dilution for use in, for example, intravenous drip-bags. The formulation can be premixed, already-diluted, and ready for use as provided in, for example, a bottle or intravenous drip-bag. The formulation supplied in the bottle can then be transferred to an intravenous drip-bag for administration to a subject. The formulation can be stable for about 24 hours, about 36 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years prior to discarding. The premixed formulation described herein can be disposed in a container or vessel, which can be sealed. The container or vessel can maintain the sterility of, or reduce the likelihood of contamination of, the premixed formulation. The premixed formulation described herein can be disposed in a container or vessel and is formulated as, for example, a single use dosage or a multiple use dosage. The container or vessel can be, for example, a glass vial, an ampoule, or a plastic flexible container. The plastic flexible container can be made of, for example, PVC (polyvinyl chloride), or polypropylene. A premixed vasopressin formulation described herein can be stored as a liquid in an aliquot having a total volume of between about 1 and about 500 mL, between about 1 and about 250 mL, between about 1 and about 200 mL, between about 1 and about 150 mL, between about 1 and about 125 mL, between about 1 and about 120 mL, between about 1 and about 110 mL, between about 1 and about 100 mL, between about 1 and about 90 mL, between about 1 and about 80 mL, between about 1 and about 70 mL, between about 1 and about 60 mL, between about 1 and about 50 mL, between about 1 and about 40 mL, between about 1 and about 30 mL, between about 1 and about 20 mL, between about 1 and about 10 mL, or between about 1 and about 5 mL. A premixed vasopressin formulation described herein can be administered as, for example, a single continuous dose over a period of time. For example, the premixed vasopressin formulation can be administered for a period of time of between about 1 and about 10 minutes, between about 1 and about 20 minutes, between about 1 and about 30 minutes, between about 1 and about 2 hours, between about 1 and about 3 hours, between about 1 and about 4 hours, between about 1 and about 5 hours, between about 1 and about 6 hours, between about 1 and about 7 hours, between about 1 and about 8 hours, between about 1 and about 9 hours, between about 1 and about 10 hours, between about 1 and about 11 hours, between about 1 and about 12 hours, between about 1 and about 13 hours, between about 1 and about 14 hours, between about 1 and about 15 hours, between about 1 and about 16 hours, between about 1 and about 17 hours, between about 1 and about 18 hours, between about 1 and about 19 hours, between about 1 and about 20 hours, between about 1 and about 21 hours, between about 1 and about 22 hours, between about 1 and about 23 hours, between about 1 and about 1 day, between about 1 and about 32 hours, between about 1 and about 36 hours, between about 1 and about 42 hours, between about 1 and about 2 days, between about 1 and about 54 hours, between about 1 and about 60 hours, between about 1 and about 66 hours, between about 1 and about 3 days, between about 1 and about 78 hours, between about 1 and about 84 hours, between about 1 and about 90 hours, between about 1 and about 4 days, between about 1 and about 102 hours, between about 1 and about 108 hours, between about 1 and about 114 hours, between about 1 and about 5 days, between about 1 and about 126 hours, between about 1 and about 132 hours, between about 1 and about 138 hours, between about 1 and about 6 days, between about 1 and about 150 hours, between about 1 and about 156 hours, between about 1 and about 162 hours, or between about 1 and about 1 week. A premixed vasopressin formulation described herein can be administered as a loading dose followed by a maintenance dose over a period of time. For example, the loading dose can comprise administration of the premixed vasopressin formulation at a first dosage amount for a first period of time, followed by administration of the maintenance dose at a second dosage amount for a second period of time. The loading dose can be administered for a period of time of between about 1 and about 5 minutes, between about 1 and about 10 minutes, between about 1 and about 15 minutes, between about 1 and about 20 minutes, between about 1 and about 25 minutes, between about 1 and about 30 minutes, between about 1 and about 45 minutes, between about 1 and about 60 minutes, between about 1 and about 90 minutes, between 1 minute and about 2 hours, between 1 minute about 2.5 hours, between 1 minute and about 3 hours, between 1 minute and about 3.5 hours, between 1 minute and about 4 hours, between 1 minute and about 4.5 hours, between 1 minute and about 5 hours, between 1 minute and about 5.5 hours, between 1 minute and about 6 hours, between 1 minute and about 6.5 hours, between 1 minute and about 7 hours, between 1 minute and about 7.5 hours, between 1 minute and about 8 hours, between 1 minute and about 10 hours, between 1 minute and about 12 hours, between 1 minute about 14 hours, between 1 minute and about 16 hours, between 1 minute and about 18 hours, between 1 minute and about 20 hours, between 1 minute and about 22 hours, or between 1 minute and about 24 hours. Following the loading dose, the maintenance dose can be administered for a period of time as described above for a single continuous dose. A premixed vasopressin formulation described herein, when administered as a single continuous, loading, or maintenance dose, can be administered for about 1 hour to about 7 days, about 1 hour to about 4 days, about 1 hour to about 48 hours, about 1 hour to about 36 hours, about 1 hour to about 24 hours, about 1 hour to about 12 hours, about 24 hours to about 120 hours, about 24 hours to about 108 hours, about 24 hours to about 96 hours, about 24 hours to about 72 hours, about 24 hours to about 48 hours, or about 24 hours to about 36 hours. The volume of the premixed formulation can be, for example, about 25 mL, about 30 mL, about 35 mL, about 40 mL, about 45 mL, about 50 mL, about 55 mL, about 60 mL, about 65 mL, about 70 mL, about 75 mL, about 80 mL, about 85 mL, about 90 mL, about 95 mL, about 100 mL, about 110 mL, about 120 mL, about 130 mL, about 140 mL, about 150 mL, about 175 mL, about 200 mL, about 225 mL, about 250 mL, about 275 mL, about 300 mL, about 350 mL, about 400 mL, about 450 mL, about 500 mL, about 550 mL, about 600 mL, about 650 mL, about 700 mL, about 750 mL, about 800 mL, about 850 mL, about 900 mL, about 950 mL, or about 1 L. In some embodiments, the volume of the vasopressin formulation formulated for use without initial vasopressin dilution is 100 mL. The concentration of vasopressin in the container or vessel in which the premixed vasopressin formulation is disposed can be, for example, about 0.1 units/mL, about 0.2 units/mL, about 0.3 units/mL, about 0.4 units/mL, about 0.5 units/mL, about 0.6 units/mL, about 0.7 units/mL, about 0.8 units/mL, about 0.9 units/mL, about 1 unit/mL, about 2 units/mL, about 3 units/mL, about 4 units/mL, about 5 units/mL, about 6 units/mL, about 7 units/mL, about 8 units/mL, about 9 units/mL, about 10 units/mL, about 11 units/mL, about 12 units/mL, about 13 units/mL, about 14 units/mL, about 15 units/mL, about 16 units/mL, about 17 units/mL, about 18 units/mL, about 19 units/mL, about 20 units/mL, about 21 units/mL, about 22 units/mL, about 23 units/mL, about 24 units/mL about 25 units/mL, about 30 units/mL, about 35 units/mL, about 40 units/mL, about 45 units/mL, or about 50 units/mL. In some embodiments, the concentration of vasopressin in the container or vessel is 0.4 units/mL. In some embodiments, the concentration of vasopressin in the container or vessel is 0.6 units/mL. The concentration of vasopressin in the container or vessel in which the premixed vasopressin formulation is disposed can be, for example, about 0.01 μg/mL, about 0.05 μg/mL, about 0.1 μg/mL, about 0.15 μg/mL, about 0.2 μg/mL, about 0.25 μg/mL, about 0.3 μg/mL, about 0.35 μg/mL, about 0.4 μg/mL, about 0.5 μg/mL, about 0.6 μg/mL, about 0.7 μg/mL, about 0.8 μg/mL, about 0.9 μg/mL, about 1 μg/mL, about 2 μg/mL, about 3 μg/mL, about 4 μg/mL, about 5 μg/mL, about 10 μg/mL, about 15 μg/mL, about 20 μg/mL, about 25 μg/mL, about 30 μg/mL, about 35 μg/mL, about 40 μg/mL, about 45 μg/mL, about 50 μg/mL, about 60 μg/mL, about 70 μg/mL, about 80 μg/mL, about 90 μg/mL, about 100 μg/mL, about 125 μg/mL, about 150 μg/mL, about 175 μg/mL, about 200 μg/mL, about 250 μg/mL, about 300 μg/mL, about 350 μg/mL, about 400 μg/mL, about 450 μg/mL, about 500 μg/mL, about 600 μg/mL, about 700 μg/mL, about 800 μg/mL, about 900 μg/mL, about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, or about 10 mg/mL. A formulation formulated for use without initial vasopressin dilution can be administered as intravenous drip therapy for about 15 min, about 20 min, about 25 min, about 30 min, about 35 min, about 40 min, about 45 min, about 50 min, about 55 min, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 1 year. A formulation for use in a drip-bag can be replaced up to, for example, one time, two times, three times, four times, five times, six times, seven times, eight times, nine times, ten times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, or 20 times during the course of the treatment period. The formulation can be used for continuous or intermittent intravenous infusion. A formulation formulated for use without initial vasopressin dilution can be modified using an excipient, for example, any excipient disclosed herein, to improve the stability of vasopressin for long-term storage and use. Non-limiting examples of excipients that can be used in an intravenous drip-bag include dextrose, saline, half-strength saline, quarter-strength saline, Ringers Lactate solution, sodium chloride, and potassium chloride. In some embodiments, dextrose is used as an excipient for the vasopressin formulation formulated for use without initial vasopressin dilution. A formulation formulated for use without initial vasopressin dilution can be modified using a buffer, for example, any buffer disclosed herein, to adjust the pH of the formulation. A non-limiting example of a buffer that can be used in the formulation includes acetate buffer. The concentration of buffer used in the formulation can be, for example, about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, or about 30 mM. In some embodiments, the concentration of the acetate buffer is 1 mM. In some embodiments, the concentration of the acetate buffer is 10 mM. In some embodiments, an additive that is used in a formulation described herein is dextrose. The concentration of dextrose used in the formulation can be, for example, about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, or about 30 mM. In some embodiments, the concentration of dextrose is 1 mM. In some embodiments, the concentration of dextrose is 10 mM. The concentration of dextrose used in the formulation can be, for example, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%. In some embodiments, a formulation described herein contains 5% dextrose. In some embodiments, an additive that is used in a formulation described herein is sodium chloride. The concentration of sodium chloride used in the formulation can be, for example, about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, or about 30 mM. In some embodiments, the concentration of the sodium chloride is 1 mM. In some embodiments, the concentration of sodium chloride is 10 mM. In some embodiments, a combination of dextrose and sodium chloride is used in a formulation described herein. When used in combination, the concentration of sodium chloride and dextrose can be the same or different. In some embodiments, the concentration of dextrose or sodium chloride is 1 mM, or any value above 1 mM, when dextrose and sodium chloride are used in a combination in a formulation described herein. A formulation formulated for use without initial vasopressin dilution can be modified using a pH adjusting agent, for example, any pH adjusting agent disclosed herein, to adjust the pH of the formulation. Non-limiting examples of a pH adjusting agent that can be used in the formulation include acetic acid, sodium acetate, hydrochloric acid, and sodium hydroxide. The concentration of buffer used in the formulation can be, for example, about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, or about 30 mM. In some embodiments, the concentration of the acetate buffer is 1 mM. In some embodiments, the concentration of the acetate buffer is 10 mM. The formulation can be stable for and have a shelf-life of about 24 hours, about 36 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years of storage at any temperature. In some embodiments, the shelf-life of the formulation is 2 years under refrigeration. In some embodiments, the shelf-life of the formulation is 6 months at room temperature. In some embodiments, the total shelf-life of the formulation is 30 months, where the formulation is stored for 2 years under refrigeration and 6 months at room temperature. Dosage Amounts. In practicing the methods of treatment or use provided herein, therapeutically-effective amounts of the compounds described herein are administered in pharmaceutical compositions to a subject having a disease or condition to be treated. A therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors. Subjects can be, for example, humans, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, or neonates. A subject can be a patient. Pharmaceutical compositions of the invention can be formulated in any suitable volume. The formulation volume can be, for example, about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1 mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, about 1.4 mL, about 1.5 mL, about 1.6 mL, about 1.7 mL, about 1.8 mL, about 1.9 mL, about 2 mL, about 2.1 mL, about 2.2 mL, about 2.3 mL, about 2.4 mL, about 2.5 mL, about 2.6 mL, about 2.7 mL, about 2.8 mL, about 2.9 mL, about 3 mL, about 3.1 mL, about 3.2 mL, about 3.3 mL, about 3.4 mL, about 3.5 mL, about 3.6 mL, about 3.7 mL, about 3.8 mL, about 3.9 mL, about 4 mL, about 4.1 mL, about 4.2 mL, about 4.3 mL, about 4.4 mL, about 4.5 mL, about 4.6 mL, about 4.7 mL, about 4.8 mL, about 4.9 mL, about 5 mL, about 5.1 mL, about 5.2 mL, about 5.3 mL, about 5.4 mL, about 5.5 mL, about 5.6 mL, about 5.7 mL, about 5.8 mL, about 5.9 mL, about 6 mL, about 6.1 mL, about 6.2 mL, about 6.3 mL, about 6.4 mL, about 6.5 mL, about 6.6 mL, about 6.7 mL, about 6.8 mL, about 6.9 mL, about 7 mL, about 7.1 mL, about 7.2 mL, about 7.3 mL, about 7.4 mL, about 7.5 mL, about 7.6 mL, about 7.7 mL, about 7.8 mL, about 7.9 mL, about 8 mL, about 8.1 mL, about 8.2 mL, about 8.3 mL, about 8.4 mL, about 8.5 mL, about 8.6 mL, about 8.7 mL, about 8.8 mL, about 8.9 mL, about 9 mL, about 9.1 mL, about 9.2 mL, about 9.3 mL, about 9.4 mL, about 9.5 mL, about 9.6 mL, about 9.7 mL, about 9.8 mL, about 9.9 mL, about 10 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about 18 mL, about 19 mL, or about 20 mL. A therapeutically-effective amount of a compound described herein can be present in a composition at a concentration of, for example, about 0.1 units/mL, about 0.2 units/mL, about 0.3 units/mL, about 0.4 units/mL, about 0.5 units/mL, about 0.6 units/mL, about 0.7 units/mL, about 0.8 units/mL, about 0.9 units/mL, about 1 unit/mL, about 2 units/mL, about 3 units/mL, about 4 units/mL, about 5 units/mL, about 6 units/mL, about 7 units/mL, about 8 units/mL, about 9 units/mL, about 10 units/mL, about 11 units/mL, about 12 units/mL, about 13 units/mL, about 14 units/mL, about 15 units/mL, about 16 units/mL, about 17 units/mL, about 18 units/mL, about 19 units/mL, about 20 units/mL, about 21 units/mL, about 22 units/mL, about 23 units/mL, about 24 units/mL about 25 units/mL, about 30 units/mL, about 35 units/mL, about 40 units/mL, about 45 units/mL, or about 50 units/mL. A therapeutically-effective amount of a compound described herein can be present in a composition of the invention at a mass of about, for example, about 0.01 μg, about 0.05 μg, about 0.1 μg, about 0.15 μg, about 0.2 μg, about 0.25 μg, about 0.3 μg, about 0.35 μg, about 0.4 μg, about 0.5 μg, about 0.6 μg, about 0.7 μg, about 0.8 μg, about 0.9 μg, about 1 μg, about 2 μg, about 3 μg, about 4 μg, about 5 μg, about 10 μg, about 15 μg, about 20 μg, about 25 μg, about 30 μg, about 35 μg, about 40 μg, about 45 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 125 μg, about 150 μg, about 175 μg, about 200 μg, about 250 μg, about 300 μg, about 350 μg, about 400 μg, about 450 μg, about 500 μg, about 600 μg, about 700 μg, about 800 μg, about 900 μg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg. A therapeutically-effective amount of a compound described herein can be present in a composition of the invention at a concentration of, for example, about 0.001 mg/mL, about 0.002 mg/mL, about 0.003 mg/mL, about 0.004 mg/mL, about 0.005 mg/mL, about 0.006 mg/mL, about 0.007 mg/mL, about 0.008 mg/mL, about 0.009 mg/mL, about 0.01 mg/mL, about 0.02 mg/mL, about 0.03 mg/mL, about 0.04 mg/mL, about 0.05 mg/mL, about 0.06 mg/mL, about 0.07 mg/mL, about 0.08 mg/mL, about 0.09 mg/mL, about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 1.5 mg/mL, about 2 mg/mL, about 2.5 mg/mL, about 3 mg/mL, about 3.5 mg/mL, about 4 mg/mL, about 4.5 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, or about 10 mg/mL. A therapeutically-effective amount of a compound described herein can be present in a composition of the invention at a unit of active agent/unit of active time. Non-limiting examples of therapeutically-effective amounts can be, for example, about 0.01 units/minute, about 0.02 units/minute, about 0.03 units/minute, about 0.04 units/minute, about 0.05 units/minute, about 0.06 units/minute, about 0.07 units/minute, about 0.08 units/minute, about 0.09 units/minute or about 0.1 units/minute. Pharmaceutical compositions of the invention can be formulated at any suitable pH. The pH can be, for example, about 2, about 2.05, about 2.1, about 2.15, about 2.2, about 2.25, about 2.3, about 2.35, about 2.4, about 2.45, about 2.5, about 2.55, about 2.6, about 2.65, about 2.7, about 2.75, about 2.8, about 2.85, about 2.9, about 2.95, about 3, about 3.05, about 3.1, about 3.15, about 3.2, about 3.25, about 3.3, about 3.35, about 3.4, about 3.45, about 3.5, about 3.55, about 3.6, about 3.65, about 3.7, about 3.75, about 3.8, about 3.85, about 3.9, about 3.95, about 4, about 4.05, about 4.1, about 4.15, about 4.2, about 4.25, about 4.3, about 4.35, about 4.4, about 4.45, about 4.5, about 4.55, about 4.6, about 4.65, about 4.7, about 4.75, about 4.8, about 4.85, about 4.9, about 4.95, or about 5 pH units. Pharmaceutical compositions of the invention can be formulated at any suitable pH. The pH can be, for example, from about 2 to about 2.2, about 2.05 to about 2.25, about 2.1 to about 2.3, about 2.15 to about 2.35, about 2.2 to about 2.4, about 2.25 to about 2.45, about 2.3 to about 2.5, about 2.35 to about 2.55, about 2.4 to about 2.6, about 2.45 to about 2.65, about 2.5 to about 2.7, about 2.55 to about 2.75, about 2.6 to about 2.8, about 2.65 to about 2.85, about 2.7 to about 2.9, about 2.75 to about 2.95, about 2.8 to about 3, about 2.85 to about 3.05, about 2.9 to about 3.1, about 2.95 to about 3.15, about 3 to about 3.2, about 3.05 to about 3.25, about 3.1 to about 3.3, about 3.15 to about 3.35, about 3.2 to about 3.4, about 3.25 to about 3.45, about 3.3 to about 3.5, about 3.35 to about 3.55, about 3.4 to about 3.6, about 3.45 to about 3.65, about 3.5 to about 3.7, about 3.55 to about 3.75, about 3.6 to about 3.8, about 3.65 to about 3.85, about 3.7 to about 3.9, about 3.7 to about 3.8, about 3.75 to about 3.95, about 3.75 to about 3.8, about 3.8 to about 3.85, about 3.75 to about 3.85, about 3.8 to about 4, about 3.85 to about 4.05, about 3.9 to about 4.1, about 3.95 to about 4.15, about 4 to about 4.2, about 4.05 to about 4.25, about 4.1 to about 4.3, about 4.15 to about 4.35, about 4.2 to about 4.4, about 4.25 to about 4.45, about 4.3 to about 4.5, about 4.35 to about 4.55, about 4.4 to about 4.6, about 4.45 to about 4.65, about 4.5 to about 4.7, about 4.55 to about 4.75, about 4.6 to about 4.8, about 4.65 to about 4.85, about 4.7 to about 4.9, about 4.75 to about 4.95, about 4.8 to about 5, about 4.85 to about 5.05, about 4.9 to about 5.1, about 4.95 to about 5.15, or about 5 to about 5.2 pH units. In some embodiments, the addition of an excipient can change the viscosity of a pharmaceutical composition of the invention. In some embodiments the use of an excipient can increase or decrease the viscosity of a fluid by at least 0.001 Pascal-second (Pa·s), at least 0.001 Pa·s, at least 0.0009 Pa·s, at least 0.0008 Pa·s, at least 0.0007 Pa·s, at least 0.0006 Pa·s, at least 0.0005 Pa·s, at least 0.0004 Pa·s, at least 0.0003 Pa·s, at least 0.0002 Pa·s, at least 0.0001 Pa·s, at least 0.00005 Pa·s, or at least 0.00001 Pa·s. In some embodiments, the addition of an excipient to a pharmaceutical composition of the invention can increase or decrease the viscosity of the composition by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In some embodiments, the addition of an excipient to a pharmaceutical composition of the invention can increase or decrease the viscosity of the composition by no greater than 5%, no greater than 10%, no greater than 15%, no greater than 20%, no greater than 25%, no greater than 30%, no greater than 35%, no greater than 40%, no greater than 45%, no greater than 50%, no greater than 55%, no greater than 60%, no greater than 65%, no greater than 70%, no greater than 75%, no greater than 80%, no greater than 85%, no greater than 90%, no greater than 95%, or no greater than 99%. Any compound herein can be purified. A compound can be at least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 43% pure, at least 44% pure, at least 45% pure, at least 46% pure, at least 47% pure, at least 48% pure, at least 49% pure, at least 50% pure, at least 51% pure, at least 52% pure, at least 53% pure, at least 54% pure, at least 55% pure, at least 56% pure, at least 57% pure, at least 58% pure, at least 59% pure, at least 60% pure, at least 61% pure, at least 62% pure, at least 63% pure, at least 64% pure, at least 65% pure, at least 66% pure, at least 67% pure, at least 68% pure, at least 69% pure, at least 70% pure, at least 71% pure, at least 72% pure, at least 73% pure, at least 74% pure, at least 75% pure, at least 76% pure, at least 77% pure, at least 78% pure, at least 79% pure, at least 80% pure, at least 81% pure, at least 82% pure, at least 83% pure, at least 84% pure, at least 85% pure, at least 86% pure, at least 87% pure, at least 88% pure, at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least 99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, or at least 99.9% pure. Compositions of the invention can be packaged as a kit. In some embodiments, a kit includes written instructions on the administration or use of the composition. The written material can be, for example, a label. The written material can suggest conditions methods of administration. The instructions provide the subject and the supervising physician with the best guidance for achieving the optimal clinical outcome from the administration of the therapy. In some embodiments, the label can be approved by a regulatory agency, for example the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other regulatory agencies. Pharmaceutically-Acceptable Excipients. Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety. In some embodiments, the pharmaceutical composition provided herein comprises a sugar as an excipient. Non-limiting examples of sugars include trehalose, sucrose, glucose, lactose, galactose, glyceraldehyde, fructose, dextrose, maltose, xylose, mannose, maltodextrin, starch, cellulose, lactulose, cellobiose, mannobiose, and combinations thereof. In some embodiments, the pharmaceutical composition provided herein comprises a buffer as an excipient. Non-limiting examples of buffers include potassium phosphate, sodium phosphate, saline sodium citrate buffer (SSC), acetate, saline, physiological saline, phosphate buffer saline (PBS), 4-2-hydroxyethyl-1-piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), and piperazine-N,N′-bis(2-ethanesulfonic acid) buffer (PIPES), or combinations thereof. In some embodiments, a pharmaceutical composition of the invention comprises a source of divalent metal ions as an excipient. A metal can be in elemental form, a metal atom, or a metal ion. Non-limiting examples of metals include transition metals, main group metals, and metals of Group 1, Group 2, Group 3, Group 4, Group 5, Group 6, Group 7, Group 8, Group 9, Group 10, Group 11, Group 12, Group 13, Group 14, and Group 15 of the Periodic Table. Non-limiting examples of metals include lithium, sodium, potassium, cesium, magnesium, calcium, strontium, scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, palladium, silver, cadmium, tungsten, rhenium, osmium, iridium, platinum, gold, mercury, cerium, and samarium. In some embodiments, the pharmaceutical composition provided herein comprises an alcohol as an excipient. Non-limiting examples of alcohols include ethanol, propylene glycol, glycerol, polyethylene glycol, chlorobutanol, isopropanol, xylitol, sorbitol, maltitol, erythritol, threitol, arabitol, ribitol, mannitol, galactilol, fucitol, lactitol, and combinations thereof. Pharmaceutical preparations can be formulated with polyethylene glycol (PEG). PEGs with molecular weights ranging from about 300 g/mol to about 10,000,000 g/mol can be used. Non-limiting examples of PEGs include PEG 200, PEG 300, PEG 400, PEG 540, PEG 550, PEG 600, PEG 1000, PEG 1450, PEG 1500, PEG 2000, PEG 3000, PEG 3350, PEG 4000, PEG 4600, PEG 6000, PEG 8000, PEG 10,000, and PEG 20,000. Further excipients that can be used in a composition of the invention include, for example, benzalkonium chloride, benzethonium chloride, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorobutanol, dehydroacetic acid, ethylenediamine, ethyl vanillin, glycerin, hypophosphorous acid, phenol, phenylethyl alcohol, phenylmercuric nitrate, potassium benzoate, potassium metabisulfite, potassium sorbate, sodium bisulfite, sodium metabisulfite, sorbic acid, thimerasol, acetic acid, aluminum monostearate, boric acid, calcium hydroxide, calcium stearate, calcium sulfate, calcium tetrachloride, cellulose acetate pthalate, microcrystalline celluose, chloroform, citric acid, edetic acid, and ethylcellulose. In some embodiments, the pharmaceutical composition provided herein comprises an aprotic solvent as an excipient. Non-limiting examples of aprotic solvents include perfluorohexane, α,α,α-trifluorotoluene, pentane, hexane, cyclohexane, methylcyclohexane, decalin, dioxane, carbon tetrachloride, freon-11, benzene, toluene, carbon disulfide, diisopropyl ether, diethyl ether, t-butyl methyl ether, ethyl acetate, 1,2-dimethoxyethane, 2-methoxyethyl ether, tetrahydrofuran, methylene chloride, pyridine, 2-butanone, acetone, N-methylpyrrolidinone, nitromethane, dimethylformamide, acetonitrile, sulfolane, dimethyl sulfoxide, and propylene carbonate. The amount of the excipient in a pharmaceutical composition of the invention can be about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% by mass of the vasopressin in the pharmaceutical composition. The amount of the excipient in a pharmaceutical composition of the invention can be about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% by mass or by volume of the unit dosage form. The ratio of vasopressin to an excipient in a pharmaceutical composition of the invention can be about 100:about 1, about 95:about 1, about 90:about 1, about 85:about 1, about 80:about 1, about 75:about 1, about 70:about 1, about 65:about 1, about 60:about 1, about 55:about 1, about 50:about 1, about 45:about 1, about 40:about 1, about 35:about 1 about 30:about 1, about 25:about 1, about 20:about 1, about 15:about 1, about 10:about 1, about 9:about 1, about 8:about 1, about 7:about 1, about 6:about 1, about 5:about 1, about 4:about 1, about 3:about 1, about 2:about 1, about 1:about 1, about 1:about 2, about 1:about 3, about 1:about 4, about 1:about 5, about 1:about 6, about 1:about 7, about 1:about 8, about 1:about 9, or about 1:about 10. Pharmaceutically-Acceptable Salts. The invention provides the use of pharmaceutically-acceptable salts of any therapeutic compound described herein. Pharmaceutically-acceptable salts include, for example, acid-addition salts and base-addition salts. The acid that is added to the compound to form an acid-addition salt can be an organic acid or an inorganic acid. A base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base. In some embodiments, a pharmaceutically-acceptable salt is a metal salt. In some embodiments, a pharmaceutically-acceptable salt is an ammonium salt. Metal salts can arise from the addition of an inorganic base to a compound of the invention. The inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc. In some embodiments, a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt. Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the invention. In some embodiments, the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrrazole, pipyrrazole, imidazole, pyrazine, or pipyrazine. In some embodiments, an ammonium salt is a triethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrrazole salt, a pipyrrazole salt, an imidazole salt, a pyrazine salt, or a pipyrazine salt. Acid addition salts can arise from the addition of an acid to a compound of the invention. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid. In some embodiments, the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a glucaronate salt, a saccarate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate (mesylate) salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-toluenesulfonate salt, a citrate salt, an oxalate salt, or a maleate salt. Peptide Sequence. As used herein, the abbreviations for the L-enantiomeric and D-enantiomeric amino acids are as follows: alanine (A, Ala); arginine (R, Arg); asparagine (N, Asn); aspartic acid (D, Asp); cysteine (C, Cys); glutamic acid (E, Glu); glutamine (Q, Gln); glycine (G, Gly); histidine (H, His); isoleucine (I, Ile); leucine (L, Leu); lysine (K, Lys); methionine (M, Met); phenylalanine (F, Phe); proline (P, Pro); serine (S, Ser); threonine (T, Thr); tryptophan (W, Trp); tyrosine (Y, Tyr); valine (V, Val). In some embodiments, the amino acid is a L-enantiomer. In some embodiments, the amino acid is a D-enantiomer. A peptide of the disclosure can have about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% amino acid sequence homology to SEQ ID NO. 1. In some embodiments, a pharmaceutical composition of the invention comprises one or a plurality of peptides having about 80% to about 90% sequence homology to SEQ ID NO. 1, about 88% to about 90% sequence homology to SEQ ID NO. 1 or 88% to 90% sequence homology to SEQ ID NO. 1. In some embodiments, a pharmaceutical composition of the invention comprises vasopressin and one or more of a second, third, fourth, fifth, sixth, seventh, eighth, ninth, and tenth peptide. The ratio of vasopressin to another peptide in a pharmaceutical composition of the invention can be, for example, about 1000:about 1, about 990:about 1, about 980:about 1, about 970:about 1, about 960:about 1, about 950:about 1, about 800:about 1, about 700:about 1, about 600:1, about 500:about 1, about 400:about 1, about 300:about 1, about 200:about 1, about 100:about 1, about 95:about 1, about 90:about 1, about 85:about 1, about 80:about 1, about 75:about 1, about 70:about 1, about 65:about 1, about 60:about 1, about 55:about 1, about 50:about 1, about 45:about 1, about 40:about 1, about 35:about 1, about 30:about 1, about 25:about 1, about 20:about 1, about 19:about 1, about 18:about 1, about 17:about 1, about 16:about 1, about 15:about 1, about 14:about 1, about 13:about 1, about 12:about 1, about 11:about 1, or about 10:about 1. The amount of another peptide or impurity in a composition of the invention can be, for example, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% by mass of vasopressin. Another peptide or impurity present in a composition described herein can be, for example, SEQ ID NO.: 2, SEQ ID NO.: 3, SEQ ID NO.: 4, SEQ ID NO.: 5, SEQ ID NO.: 6, SEQ ID NO.: 7, SEQ ID NO.: 8, SEQ ID NO.: 9, SEQ ID NO.: 10, SEQ ID NO.: 11, SEQ ID NO.: 12, SEQ ID NO.: 13, SEQ ID NO.: 14, SEQ ID NO.: 15, SEQ ID NO.: 16, SEQ ID NO.: 17, a dimer of SEQ ID NO.: 1, an unidentified impurity, or any combination thereof. Non-limiting examples of methods that can be used to identify peptides of the invention include high-performance liquid chromatography (HPLC), mass spectrometry (MS), Matrix Assisted Laser Desorption Ionization Time-of-Flight (MALDI-TOF), electrospray ionization Time-of-flight (ESI-TOF), gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), and two-dimensional gel electrophoresis. HPLC can be used to identify peptides using high pressure to separate components of a mixture through a packed column of solid adsorbent material, denoted the stationary phase. The sample components can interact differently with the column based upon the pressure applied to the column, material used in stationary phase, size of particles used in the stationary phase, the composition of the solvent used in the column, and the temperature of the column. The interaction between the sample components and the stationary phase can affect the time required for a component of the sample to move through the column. The time required for component to travel through the column from injection point to elution is known as the retention time. Upon elution from the column, the eluted component can be detected using a UV detector attached to the column. The wavelength of light at which the component is detected, in combination with the component's retention time, can be used to identify the component. Further, the peak displayed by the detector can be used to determine the quantity of the component present in the initial sample. Wavelengths of light that can be used to detect sample components include, for example, about 200 nM, about 225 nm, about 250 nm, about 275 nm, about 300 nm, about 325 nm, about 350 nm, about 375 nm, and about 400 nm. Mass spectrometry (MS) can also be used to identify peptides of the invention. To prepare samples for MS analysis, the samples, containing the proteins of interest, are digested by proteolytic enzymes into smaller peptides. The enzymes used for cleavage can be, for example, trypsin, chymotrypsin, glutamyl endopeptidase, Lys-C, and pepsin. The samples can be injected into a mass spectrometer. Upon injection, all or most of the peptides can be ionized and detected as ions on a spectrum according to the mass to charge ratio created upon ionization. The mass to charge ratio can then be used to determine the amino acid residues present in the sample. The present disclosure provides several embodiments of pharmaceutical formulations that provide advantages in stability, administration, efficacy, and modulation of formulation viscosity. Any embodiments disclosed herein can be used in conjunction or individually. For example, any pharmaceutically-acceptable excipient, method, technique, solvent, compound, or peptide disclosed herein can be used together with any other pharmaceutically-acceptable excipient, method, technique, solvent, compound, or peptide disclosed herein to achieve any therapeutic result. Compounds, excipients, and other formulation components can be present at any amount, ratio, or percentage disclosed herein in any such formulation, and any such combination can be used therapeutically for any purpose described herein and to provide any viscosity described herein. EXAMPLES Example 1: Impurities of Vasopressin as Detected by HPLC To analyze degradation products of vasopressin that can be present in an illustrative formulation of vasopressin, gradient HPLC was performed to separate vasopressin from related peptides and formulation components. TABLE 2 below depicts the results of the experiment detailing the chemical formula, relative retention time (RRT), molar mass, and structure of vasopressin and detected impurities. Vasopressin was detected in the eluent using UV absorbance. The concentration of vasopressin in the sample was determined by the external standard method, where the peak area of vasopressin in sample injections was compared to the peak area of vasopressin reference standards in a solution of known concentration. The concentrations of related peptide impurities in the sample were also determined using the external standard method, using the vasopressin reference standard peak area and a unit relative response factor. An impurities marker solution was used to determine the relative retention times of identified related peptides at the time of analysis. Experimental conditions are summarized in TABLE 2 below. TABLE 2 Column YMC-Pack ODS-AM, 3 μm, 120Å pore, 4.6 × 100 mm Column Temperature 25° C. Flow Rate 1.0 mL/min Detector 215 nm Note: For Identification a Diode Array Detector (DAD) was used with the range of 200-400 nm. Injection Volume 100 μL Run time 55 minutes Autosampler Vials Polypropylene vials Pump (gradient) Time (min) % A % B Flow 0 90 10 1.0 40 50 50 1.0 45 50 50 1.0 46 90 10 1.0 55 90 10 1.0 The diluent used for the present experiment was 0.25% v/v Acetic Acid, which was prepared by transferring 2.5 mL of glacial acetic acid into a 1-L volumetric flask containing 500 mL of water. The solution was diluted to the desired volume with water. Phosphate buffer at pH 3.0 was used for mobile phase A. The buffer was prepared by weighing approximately 15.6 g of sodium phosphate monobasic monohydrate into a beaker. 1000 mL of water was added, and mixed well. The pH was adjusted to 3.0 with phosphoric acid. The buffer was filtered through a 0.45 μm membrane filter under vacuum, and the volume was adjusted as necessary. An acetonitrile:water (50:50) solution was used for mobile phase B. To prepare mobile phase B, 500 mL of acetonitrile was mixed with 500 mL of water. The working standard solution contained approximately 20 units/mL of vasopressin. The standard solution was prepared by quantitatively transferring the entire contents of 1 vial of USP Vasopressin RS with diluent to a 50-mL volumetric flask. The intermediate standard solution was prepared by pipetting 0.5 mL of the working standard solution into a 50-mL volumetric flask. The sensitivity solution was prepared by pipetting 5.0 mL of the intermediate standard solution into a 50-mL volumetric flask. The solution was diluted to the volume with Diluent and mixed well. A second working standard solution was prepared as directed under the standard preparation. A portion of the vasopressin control sample was transferred to an HPLC vial and injected. The control was stable for 120 hours when stored in autosampler vials at ambient laboratory conditions. To prepare the impurities marker solution, a 0.05% v/v acetic acid solution was prepared by pipetting 200.0 mL of a 0.25% v/v acetic acid solution into a 1-L volumetric flask. The solution was diluted to the desired volume with water and mixed well. To prepare the vasopressin impurity stock solutions, the a solution of each impurity was prepared in a 25 mL volumetric flask and diluted with 0.05% v/v acetic acid to a concentration suitable for HPLC injection. To prepare the MAA/H-IBA (Methacrylic Acid/α-Hydroxy-isobutyric acid) stock solution, a stock solution containing approximately 0.3 mg/mL H-IBA and 0.01 mg/mL in 0.05% v/v acetic acid was made in a 50 mL volumetric flask. To prepare the chlorobutanol diluent, about one gram of hydrous chlorobutanol was added to 500 mL of water. Subsequently, 0.25 mL of acetic acid was added and the solution was stirred to dissolve the chlorobutanol. To prepare the impurity marker solution, vasopressin powder was mixed with the impurity stock solutions prepared above. The solutions were diluted to volume with the chlorobutanol diluent. The solutions were aliquoted into individual crimp top vials and stored at 2-8° C. At time of use, the solutions were removed from refrigeration (2-8° C.) and allowed to reach room temperature. The vasopressin impurity marker solution was stable for at least 120 hours when stored in auto-sampler vials at ambient laboratory conditions. The solution was suitable for use as long as the chromatographic peaks could be identified based on comparison to the reference chromatogram. To begin the analysis, the HPLC system was allowed to equilibrate for at least 30 minutes using mobile phase B, followed by time 0 min gradient conditions until a stable baseline was achieved. The diluent was injected at the beginning of the run, and had no peaks that interfered with Vasopressin at around 18 minutes as shown in FIG. 1. A single injection of the sensitivity solution was performed, wherein the signal-to-noise ratio of the Vasopressin was greater than or equal to ten as shown in FIG. 2. A single injection of the impurities marker solution was then made. The labeled impurities in the reference chromatogram were identified in the chromatogram of the marker solution based on their elution order and approximate retention times shown in FIG. 3 and FIG. 4. FIG. 4 is a zoomed in chromatograph of FIG. 3 showing the peaks that eluted between 15 and 30 minutes. The nomenclature, structure, and approximate retention times for individual identified impurities are detailed in TABLE 3. A single injection of the working standard solution was made to ensure that the tailing factor of the vasopressin peak was less than or equal to about 2.0 as shown in FIG. 5. A total of five replicate injections of the working standard solution were made to ensure that the relative standard deviation (% RSD) of the five replicate vasopressin peak areas was not more than 2.0%. Two replicate injections of the check standard preparation were to confirm that the check standard conformity was 99.0%-101.0%. One injection of the control sample was made to confirm that the assay of the control sample met the control limits established for the sample. Then, one injection of the working standard solution was made. Following the steps above done to confirm system suitability, a single injection of each sample preparation was made. The chromatograms were analyzed to determine the vasopressin and impurity peak areas. The chromatogram is depicted in FIG. 6. The working standard solution was injected after 1 to 4 sample injections, and the bracketing standard peak areas were averaged for use in the calculations to determine peak areas of vasopressin and associated impurities. The relative standard deviation (% RSD) of vasopressin peak areas for the six injections of working standard solution was calculated by including the initial five injections from the system suitability steps above and each of the subsequent interspersed working standard solution injections. The calculations were done to ensure that each of the % RSD were not more than 2.0%. The retention time of the major peak in the chromatogram of the sample preparation corresponded to that of the vasopressin peak in the working standard solution injection that preceded the sample preparation injection. The UV spectrum (200-400 nm) of the main peak in the chromatogram of the sample preparation compared to the UV spectrum of vasopressin in the working standard preparation. FIG. 7 depicts a UV spectrum of a vasopressin sample and FIG. 8 depicts a UV spectrum of vasopressin standard. To calculate the vasopressin units/mL, the following formula was used: Vasopressin   units  /  mL = R U R S × Conc   STD where: RU=Vasopressin peak area response of Sample preparation. RS=average vasopressin peak area response of bracketing standards. Conc STD=concentration of the vasopressin standard in units/mL To identify the impurities, the % Impurity and identity for identified impurities (TABLE 3) that are were greater than or equal to 0.10% were reported. Impurities were truncated to 3 decimal places and then rounded to 2 decimal places, unless otherwise specified. The impurities were calculated using the formula below: %   impurity = R I R S × Conc   STD 20   U  /  mL × 100  % where: RI=Peak area response for the impurity 20 U/mL=Label content of vasopressin TABLE 3 below details the chemical formula, relative retention time (RRT in minutes), molar mass, and structure of vasopressin and detected impurities. TABLE 3 Name Formula Appr. RRT Molar Mass (g) Vasopressin C46H65N15O12S2 1.00 1084.23 (Arginine Vasopressin, AVP) CYFQNCPRG-NH2 SEQ ID NO.: 1 (disulfide bridge between cys residues) Gly9-vasopressin C46H64N14O13S2 1.07 1085.22 (Gly9-AVP) CYFQNCPRG SEQ ID NO.: 2 (disulfide bridge between cys residues) Asp5-vasopressin C46H64N14O13S2 1.09 1085.22 (Asp5-AVP) CYFQDCPRG-NH2 SEQ ID NO.: 3 (disulfide bridge between cys residues) Glu4-vasopressin C46H64N14O13S2 1.12 1085.22 (Glu4-AVP) CYFENCPRG-NH2 SEQ ID NO.: 4 (disulfide bridge between cys residues) Acetyl-vasopressin C48H67N15O13S2 1.45 1126.27 (Acetyl-AVP) Ac-CYFQNCPRG-NH2 SEQ ID NO.: 7 (disulfide bridge between cys residues) D-Asn-vasopressin C46H65N15O12S2 0.97 1084.23 (DAsn-AVP) CYFQ(D-Asn)CPRG-NH2 SEQ ID NO.: 10 (disulfide bridge between cys residues) Dimeric-vasopressin C92H130N30O24S4 1.22 2168.46 (Dimer-AVP) (monomers cross linked by disulfide bridges) Example 2: Investigation of pH To determine a possible pH for a vasopressin formulation with good shelf life, vasopressin formulations were prepared in 10 mM citrate buffer diluted in isotonic saline across a range of pH. Stability was assessed via HPLC as in EXAMPLE 1 after incubation of the formulations at 60° C. for one week. FIG. 9 illustrates the results of the experiment. The greatest level of stability was observed at pH 3.5. At pH 3.5, the percent label claim (% LC) of vasopressin was highest, and the proportion of total impurities was lowest. Example 3: Effect of Peptide Stabilizers on Vasopressin Formulation To observe the effect of stabilizers on the degradation of vasopressin, a series of peptide stabilizers were added to a vasopressin formulation as detailed in TABLE 4. Stability of vasopressin was assessed via HPLC after incubation of the formulations at 60° C. for one week. TABLE 4 PEG Poloxamer n-Methylpyrrolidone Ethanol 400 Glycerol 188 HPbCDa (NMP) 1% 1% 1% 1% 1% 1% 10% 10% 10% 10% 10% 10% aHydroxypropyl beta-Cyclodextrin FIG. 10 illustrates the stability of vasopressin in terms of % label claim at varying concentrations of stabilizer. The results indicate that the tested stabilizers provided a greater stabilizing effect at 1% concentration than at 10%. Also, in several cases the stabilization effect was about 5% to about 10% greater than that observed in the experiments of EXAMPLE 2. Example 4: Effect of Buffer and Divalent Metals on Vasopressin Formulation To determine whether different combinations of buffers and use of divalent metals affect vasopressin stability, vasopressin formulations with varying concentrations of citrate and acetate buffers and variable concentrations of calcium, magnesium, and zinc ions were prepared. Solutions of 0 mM, 10 mM, 20 mM, and 80 mM calcium, magnesium, and zinc were prepared and each was combined with 1 mM or 10 mM of citrate or acetate buffers to test vasopressin stability. The tested combinations provided vasopressin stability comparable to that of a vasopressin formulation lacking buffers and divalent metals. However, that the addition of divalent metal ions was able to counteract the degradation of vasopressin caused by the use of a citrate buffer. Example 5: Illustrative Formulations for Assessment of Vasopressin Stability An aqueous formulation of vasopressin is prepared using 10% trehalose, 1% sucrose, or 5% NaCl and incubated at 60° C. for one week, at which point stability of vasopressin is assessed using HPLC. A formulation containing 50 units of vasopressin is lyophilized. The lyophilate is reconstituted with water and either 100 mg of sucrose or 100 mg of lactose, and the stability of vasopressin is tested via HPLC after incubation at 60° C. for one week. Co-solvents are added to a vasopressin solution to assess vasopressin stability. 95% solvent/5% 20 mM acetate buffer solutions are prepared using propylene glycol, DMSO, PEG300, NMP, glycerol, and glycerol:NMP (1:1), and used to create formulations of vasopressin. The stability of vasopressin is tested after incubation at 60° C. for one week. Amino acid and phosphate buffers are tested with vasopressin to assess vasopressin stability. Buffers of 10 mM glycine, aspartate, phosphate are prepared at pH 3.5 and 3.8 and used to create formulations of vasopressin. The stability of vasopressin is tested after incubation at 60° C. for one week. A vasopressin formulation in 10% polyvinylpyrrolidone is prepared to assess vasopressin stability. The stability of vasopressin will be tested after incubation at 60° C. for one week. A vasopressin formulation that contains 0.9% saline, 10 mM acetate buffer, 0.2 unit/mL API/mL in 100 mL of total volume is prepared. The pH of the solution is varied from pH 3.5-3.8 to test the stability of vasopressin. A vasopressin formulation in about 50% to about 80% DMSO (for example, about 80%), about 20% to about 50% ethyl acetate (for example, about 20%), and about 5% to about 30% polyvinylpyrrolidone (PVP) (for example, about 10% by mass of the formulation) is prepared to assess vasopressin stability. PVP K12 and PVP K17 are each independently tested in the formulation. The stability of vasopressin is tested after incubation at 60° C. for one week. A vasopressin formulation in about 70% to about 95% ethyl acetate, and about 5% to about 30% PVP is prepared to assess vasopressin stability. PVP K12 and PVP K17 are each independently tested in the formulation. The stability of vasopressin is tested after incubation at 60° C. for one week. A vasopressin formulation in 90% DMSO and 10% PVP is prepared to test vasopressin stability. PVP K12 and PVP K17 are each independently tested in the formulation. The stability of vasopressin is tested after incubation at 60° C. for one week. Example 6: Illustrative Vasopressin Formulation for Clinical Use A formulation for vasopressin that can be used in the clinic is detailed in TABLE 5 below: TABLE 5 Ingredient Function Amount (per mL) Vasopressin, USP Active Ingredient 20 Units (~0.04 mg) Chlorobutanol, Preservative 5.0 mg Hydrous NF Acetic Acid, NF pH Adjustment To pH 3.4-3.6 (~0.22 mg) Water for injection, Diluent QS USP/EP Example 7: Illustrative Regimen for Therapeutic Use of a Vasopressin Formulation Vasopressin is indicated to increase blood pressure in adults with vasodilatory shock (for example, adults who are post-cardiotomy or septic) who remain hypotensive despite fluids and catecholamines. Preparation and Use of Vasopressin. Vasopressin is supplied in a carton of 25 multi-dose vials each containing 1 mL vasopressin at 20 units/mL. Vasopressin is stored between 15° C. and 25° C. (59° F. and 77° F.), and is not frozen. Alternatively, a unit dosage form of vasopressin can be stored between 2° C. and 8° C. for about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. Vials of vasopressin are to be discarded 48 hours after first puncture. Vasopressin is prepared according to TABLE 6 below: TABLE 6 Mix Fluid Restriction? Final Concentration Vasopressin Diluent No 0.1 units/mL 2.5 mL (50 units) 500 mL Yes 1 unit/mL 5 mL (100 units) 100 mL Vasopressin is diluted in normal saline (0.9% sodium chloride) or 5% dextrose in water (D5W) prior to use to either 0.1 units/mL or 1 unit/mL for intravenous administration. Unused diluted solution is discarded after 18 hours at room temperature or after 24 hours under refrigeration. Diluted vasopressin should be inspected for particulate matter and discoloration prior to use whenever solution and container permit. The goal of treatment with vasopressin is optimization of perfusion to critical organs, but aggressive treatment can compromise perfusion of organs, like the gastrointestinal tract, for which function is difficult to monitor. Titration of vasopressin to the lowest dose compatible with a clinically-acceptable response is recommended. For post-cardiotomy shock, a dose of 0.03 units/minute is used as a starting point. For septic shock, a dose of 0.01 units/minute is recommended. If the target blood pressure response is not achieved, titrate up by 0.005 units/minute at 10- to 15-minute intervals. The maximum dose for post-cardiotomy shock is 0.1 units/minute and for septic shock 0.07 units/minute. After target blood pressure has been maintained for 8 hours without the use of catecholamines, taper vasopressin by 0.005 units/minute every hour as tolerated to maintain target blood pressure. Vasopressin is provided at 20 units per mL of diluent, which is packaged as 1 mL of vasopressin per vial, and is diluted prior to administration. Contraindications, Adverse Reactions, and Drug-Drug Interactions. Vasopressin is contraindicated in patients with known allergy or hypersensitivity to 8-L-arginine vasopressin or chlorobutanol. Additionally, use of vasopressin in patients with impaired cardiac response can worsen cardiac output. Adverse reactions have been observed with the use of vasopressin, which adverse reactions include bleeding/lymphatic system disorders, specifically, hemorrhagic shock, decreased platelets, intractable bleeding; cardiac disorders, specifically, right heart failure, atrial fibrillation, bradycardia, myocardial ischemia; gastrointestinal disorders, specifically, mesenteric ischemia; hepatobiliary disorders, specifically, increased bilirubin levels; renal/urinary disorders, specifically, acute renal insufficiency; vascular disorders, specifically, distal limb ischemia; metabolic disorders, specifically, hyponatremia; and skin disorders, specifically, and ischemic lesions. These reactions are reported voluntarily from a population of uncertain size. Thus, reliable estimation of frequency or establishment of a causal relationship to drug exposure is unlikely. Vasopressin has been observed to interact with other drugs. For example, use of vasopressin with catecholamines is expected to result in an additive effect on mean arterial blood pressure and other hemodynamic parameters. Use of vasopressin with indomethacin can prolong the effect of vasopressin on cardiac index and systemic vascular resistance. Indomethacin more than doubles the time to offset for vasopressin's effect on peripheral vascular resistance and cardiac output in healthy subjects. Further, use of vasopressin with ganglionic blocking agents can increase the effect of vasopressin on mean arterial blood pressure. The ganglionic blocking agent tetra-ethylammonium increases the pressor effect of vasopressin by 20% in healthy subjects. Use of vasopressin with furosemide increases the effect of vasopressin on osmolar clearance and urine flow. Furosemide increases osmolar clearance 4-fold and urine flow 9-fold when co-administered with exogenous vasopressin in healthy subjects. Use of vasopressin with drugs suspected of causing SIADH (Syndrome of inappropriate antidiuretic hormone secretion), for example, SSRIs, tricyclic antidepressants, haloperidol, chlorpropamide, enalapril, methyldopa, pentamidine, vincristine, cyclophosphamide, ifosfamide, and felbamate can increase the pressor effect in addition to the antidiuretic effect of vasopressin. Additionally, use of vasopressin with drugs suspected of causing diabetes insipidus for example, demeclocycline, lithium, foscarnet, and clozapine can decrease the pressor effect in addition to the antidiuretic effect of vasopressin. Halothane, morphine, fentanyl, alfentanyl and sufentanyl do not impact exposure to endogenous vasopressin. Use of Vasopressin in Specific Populations. Vasopressin is a Category C drug for pregnancy. Due to a spillover into the blood of placental vasopressinase, the clearance of exogenous and endogenous vasopressin increases gradually over the course of a pregnancy. During the first trimester of pregnancy the clearance is only slightly increased. However, by the third trimester the clearance of vasopressin is increased about 4-fold and at term up to 5-fold. Due to the increased clearance of vasopressin in the second and third trimester, the dose of vasopressin can be up-titrated to doses exceeding 0.1 units/minute in post-cardiotomy shock and 0.07 units/minute in septic shock. Vasopressin can produce tonic uterine contractions that could threaten the continuation of pregnancy. After delivery, the clearance of vasopressin returns to preconception levels. Overdosage. Overdosage with vasopressin can be expected to manifest as a consequence of vasoconstriction of various vascular beds, for example, the peripheral, mesenteric, and coronary vascular beds, and as hyponatremia. In addition, overdosage of vasopressin can lead less commonly to ventricular tachyarrhythmias, including Torsade de Pointes, rhabdomyolysis, and non-specific gastrointestinal symptoms. Direct effects of vasopressin overdose can resolve within minutes of withdrawal of treatment. Pharmacology of Vasopressin. Vasopressin is a polypeptide hormone that causes contraction of vascular and other smooth muscles and antidiuresis, which can be formulated as a sterile, aqueous solution of synthetic arginine vasopressin for intravenous administration. The 1 mL solution contains vasopressin 20 units/mL, chlorobutanol, NF 0.5% as a preservative, and water for injection, USP adjusted with acetic acid to pH 3.4-3.6. The chemical name of vasopressin is Cyclo (1-6) L-Cysteinyl-L-Tyrosyl-L-Phenylalanyl-L-Glutaminyl-L-Asparaginyl-L-Cysteinyl-L-Prolyl-L-Arginyl-L-Glycinamide. Vasopressin is a white to off-white amorphous powder, freely soluble in water. The structural formula of vasopressin is: Molecular Formula: C46H65N15O12S2; Molecular Weight: 1084.23 One mg of vasopressin is equivalent to 530 units. Alternatively, one mg of vasopressin is equivalent to 470 units. The vasoconstrictive effects of vasopressin are mediated by vascular V1 receptors. Vascular V1 receptors are directly coupled to phopholipase C, resulting in release of calcium, leading to vasoconstriction. In addition, vasopressin stimulates antidiuresis via stimulation of V2 receptors which are coupled to adenyl cyclase. At therapeutic doses, exogenous vasopressin elicits a vasoconstrictive effect in most vascular beds including the splanchnic, renal, and cutaneous circulation. In addition, vasopressin at pressor doses triggers contractions of smooth muscles in the gastrointestinal tract mediated by muscular V1-receptors and release of prolactin and ACTH via V3 receptors. At lower concentrations typical for the antidiuretic hormone, vasopressin inhibits water diuresis via renal V2 receptors. In patients with vasodilatory shock, vasopressin in therapeutic doses increases systemic vascular resistance and mean arterial blood pressure and reduces the dose requirements for norepinephrine. Vasopressin tends to decrease heart rate and cardiac output. The pressor effect is proportional to the infusion rate of exogenous vasopressin. Onset of the pressor effect of vasopressin is rapid, and the peak effect occurs within 15 minutes. After stopping the infusion, the pressor effect fades within 20 minutes. There is no evidence for tachyphylaxis or tolerance to the pressor effect of vasopressin in patients. At infusion rates used in vasodilatory shock (0.01-0.1 units/minute), the clearance of vasopressin is 9 to 25 mL/min/kg in patients with vasodilatory shock. The apparent half-life of vasopressin at these levels is <10 minutes. Vasopressin is predominantly metabolized and only about 6% of the dose is excreted unchanged in urine. Animal experiments suggest that the metabolism of vasopressin is primarily by liver and kidney. Serine protease, carboxipeptidase and disulfide oxido-reductase cleave vasopressin at sites relevant for the pharmacological activity of the hormone. Thus, the generated metabolites are not expected to retain important pharmacological activity. Carcinogenesis, Mutagenesis, Impairment of Fertility. Vasopressin was found to be negative in the in vitro bacterial mutagenicity (Ames) test and the in vitro Chinese hamster ovary (CHO) cell chromosome aberration test. In mice, vasopressin can have an effect on function and fertilizing ability of spermatozoa. Clinical Studies. Increases in systolic and mean blood pressure following administration of vasopressin were observed in seven studies in septic shock and eight studies in post-cardiotomy vasodilatory shock. Example 8: Effect of Temperature on Vasopressin Formulations To test the effect of temperature on the stability of vasopressin formulation, solutions containing 20 units/mL vasopressin and chlorobutanol, adjusted to pH 3.5 with acetic acid, were prepared. One mL of each vasopressin formulations was then filled into 3 cc vials. Each Vasopressin Formulation was stored either inverted or upright for at least three months, up to 24 months, at: (i) 5° C.; (ii) 25° C. and 60% relative humidity; or (iii) 40° C. and 75% humidity, and the amount of vasopressin (U/mL) and % total impurities were measured periodically. TABLES 7-12 below display the results of the experiments at 5° C. The results of the experiments at 25° C. are included in TABLES 13-18. All of the experiments were performed in triplicate. The results of the experiments at 40° C. are included in TABLES 19-24. For each temperature tested, three lots of the vasopressin formulation were stored for 24 months (5° C. and 25° C.) and 3 months (40° C.), and measurements were taken at regular intervals during the testing periods. “NMT” as used in the tables denotes “not more than.” The vasopressin and impurity amounts observed in the experiments conducted at 5° C. are shown in TABLES 7-12 below (AVP=Vasopressin). TABLE 7 Samples stored inverted at 5° C. Time in months Test Initial 1 2 3 6 9 12 18 24 AVP 19.4 19.4 19.4 19.3 19.5 19.4 19.5 19.4 19.3 Assay Total 2.3% 2.0% 2.1% 2.3% 2.2% 2.3% 2.6% 2.9% 2.9% Im- purities TABLE 8 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 19.7 19.7 19.7 19.7 19.9 19.7 19.8 19.7 19.5 Assay U/mL Total Impurities: 2.7% 2.2% 2.3% 2.4% 2.1% 2.3% 2.7% 2.9% 2.9% NMT 17.0% TABLE 9 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 19.7 19.7 19.6 19.7 19.8 19.7 19.9 19.8 19.5 Assay U/mL Total Impurities: 2.2% 1.9% 2.0% 2.2% 2.0% 2.1% 2.4% 2.6% 2.8% NMT 17.0% TABLE 10 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 19.4 19.5 19.4 19.4 19.5 19.5 19.5 19.4 19.3 Assay U/mL Total Impurities: 2.3% 2.1% 2.1% 2.3% 2.1% 2.3% 2.5% 2.9% 2.9% NMT 17.0% TABLE 11 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 19.7 19.7 19.6 19.7 19.8 19.7 19.8 19.7 19.5 Assay U/mL Total Impurities: 2.7% 2.1% 2.2% 2.2% 2.2% 2.3% 2.6% 2.9% 2.8% NMT 17.0% TABLE 12 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 19.7 19.7 19.6 19.7 19.8 19.7 19.9 19.8 19.5 Assay U/mL Total Impurities: 2.2% 1.8% 2.0% 2.2% 2.2% 2.1% 2.4% 2.8% 2.7% NMT 17.0% The vasopressin and impurity amounts observed in the experiments conducted at 25° C. and 60% relative humidity are shown in TABLES 13-18 below. TABLE 13 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 19.8 19.4 19.1 18.8 18.3 17.5 17.3 Assay U/mL Total 1.1% 2.4% 3.7% 4.7% 5.9% 9.0% 13.6% Impurities: NMT 17.0% TABLE 14 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 20.1 19.7 19.3 19 18.6 17.6 17.6 Assay U/mL Total 1.3% 2.5% 3.4% 4.6% 5.6% 9.0% 13.4% Impurities: NMT 17.0% TABLE 15 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 19.9 19.6 19.2 19 18.7 18 17.4 Assay U/mL Total 1.5% 2.6% 3.3% 4.6% 5.9% 9.0% 12.9% Impurities: NMT 17.0% TABLE 16 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 19.8 19.4 19.1 18.8 18.3 17.5 17.4 Assay U/mL Total 1.1% 2.4% 3.2% 4.8% 5.6% 9.2% 13.1% Impurities: NMT 17.0% TABLE 17 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 20.1 19.7 19.4 18.9 18.6 17.8 17.7 Assay U/mL Total 1.3% 2.5% 3.3% 4.5% 5.7% 9.1% 13.3% Impurities: NMT 17.0% TABLE 18 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP 16.0-21.0 19.9 19.6 19.2 19 18.5 18.1 17.4 Assay U/mL Total 1.5% 2.5% 3.7% 4.7% 5.9% 9.1% 13.3% Impurities: NMT 17.0% The vasopressin and impurity amounts observed in the experiments conducted at 40° C. and 75% relative humidity are shown in TABLES 19-24 below. TABLE 19 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.8 19.1 18.6 17.3 Assay Total Impurities: 1.1% 3.7% 7.3% 10.6% NMT 17.0% TABLE 20 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.8 18.9 18.5 17.2 Assay Total Impurities: 1.1% 3.6% 7.2% 10.3% NMT 17.0% TABLE 21 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 20.1 19.3 18.7 17.6 Assay Total Impurities: 1.3% 3.6% 7.3% 10.3% NMT 17.0% TABLE 22 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 20.1 18.9 18.7 17.4 Assay Total Impurities: 1.3% 3.5% 7.1% 10.2% NMT 17.0% TABLE 23 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.9 19.2 18.3 17.4 Assay Total Impurities: 1.5% 3.7% 6.3% 10.3% NMT 17.0% TABLE 24 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.9 19.2 18.3 17.5 Assay Total Impurities: 1.5% 3.8% 6.3% 10.5% NMT 17.0% The results of the above experiments suggested that storage in either an upright or inverted position did not markedly affect the stability of vasopressin. The samples held at 5° C. exhibited little fluctuation in vasopressin amounts over 24 months, and the amount of total impurities did not increase above 3% during the testing period (TABLES 7-12). The samples held at 25° C. and 60% relative humidity exhibited a decrease in vasopressin amount of about 10-12% after 24 months (TABLES 13-18). The amount of impurities observed in the samples stored at 25° C. and 60% relative humidity after 24 months exceeded 13% in some samples, whereas the amount of impurities observed in the samples stored at 5° C. did not exceed 3% after 24 months. After about three months, the samples held at 40° C. exhibited a decrease in the amount of vasopressin of about 10-12%. The amount of impurities observed at 40° C. exceeded 10% after three months, whereas the amount of impurities observed in the samples stored at 5° C. was less than 3% after three months (TABLES 19-24). Experiments were also conducted on the same samples above over the course of the experiments to measure the amount of individual impurities in the samples, pH of the samples, chlorobutanol content, particulate matter, antimicrobial effectiveness, and bacterial endotoxin levels (TABLES 25-42). (NR=no reading; ND=not determined; UI=unidentified impurity). The anti-microbial effectiveness of the solution was established to determine the amount of antimicrobial agents in the formulation that protect against bacterial contamination. The bullets in the tables below indicate that the sample was not tested for anti-microbial effectiveness at that specific time point. The bacterial endotoxin levels were also measured for some of the formulations. The bullets in the tables below indicate that the sample was not tested for bacterial endotoxin levels at that specific time point. TABLE 25 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.4 19.4 19.4 19.3 19.5 19.4 19.5 19.4 19.3 Assay U/mL Related SEQ ID 0.5% 0.5% 0.6% 0.6% 0.6% 0.6% 0.7% 0.8% 0.9% Substances NO.: 2 NMT 6.0% SEQ ID 0.6% 0.6% 0.6% 0.7% 0.7% 0.7% 0.8% 0.9% 1.0% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP- NR NR NR NR NR NR NR NR NR Dimer: NMT 1.0% Acetyl- 0.3% 0.2% 0.3% 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.84: NR NR 0.1% NR NR NR NR NR NR NMT 1.0% UI-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.1% NR 0.1% NR NR NR NR NR NR NMT 1.0% Total 2.3% 2.0% 2.1% 2.3% 2.2% 2.3% 2.6% 2.9% 2.9% Impurities: NMT 17.0% pH 2.5-4.5 3.5 3.5 3.5 3.5 3.5 3.5 3.5 3.8 3.5 Chlorobutanol 0.25-0.60% 0.48% 0.49% 0.48% 0.48% 0.47% 0.48% 0.48% 0.49% 0.49% w/v Particulate NMT 6000 0 1 1 1 2 16 2 4 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 26 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.7 19.7 19.7 19.7 19.9 19.7 19.8 19.7 19.5 Assay U/mL Related SEQ ID 0.6% 0.5% 0.5% 0.6% 0.5% 0.6% 0.7% 0.8% 0.8% Substances NO.: 2: NMT 6.0% SEQ ID 0.6% 0.6% 0.6% 0.6% 0.6% 0.7% 0.7% 0.8% 0.9% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR NR NR NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.75- 0.2% 0.2% 0.2% 0.2% NR 0.1% 0.2% 0.2% 0.2% 0.78: NMT 1.0% UI-0.83- 0.1% 0.1% 0.1% NR 0.1% NR NR NR NR 0.84: NMT 1.0% UI-1.02- 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% 1.03: NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% Total 2.7% 2.2% 2.3% 2.4% 2.1% 2.3% 2.7% 2.9% 2.9% Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 Chlorobutanol 0.25-0.60% 0.48% 0.48% 0.48% 0.47% 0.48% 0.48% 0.49% 0.48% 0.49% w/v Particulate NMT 6000 1 1 1 1 1 15 2 3 2 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 27 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.7 19.7 19.6 19.7 19.8 19.7 19.9 19.8 19.5 Assay U/mL Related SEQ ID 0.5% 0.5% 0.5% 0.5% 0.5% 0.6% 0.6% 0.8% 0.8% Substances NO.: 2: NMT 6.0% SEQ ID 0.5% 0.5% 0.5% 0.6% 0.6% 0.7% 0.7% 0.8% 0.9% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR NR NR NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.75- NR NR NR NR NR NR NR NR NR 0.78: NMT 1.0% UI-0.83- NR NR 0.1% NR NR NR NR NR 0.1% 0.84: NMT 1.0% UI-1.02- 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% 1.03: NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.76 NR NR NR 0.1% NR NR NR NR NR NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.1% NR NR NR NR NR NR NR NR NMT 1.0% Total 2.2% 1.9% 2.0% 2.2% 2.0% 2.1% 2.4% 2.6% 2.8% Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.5 3.6 3.5 3.5 3.5 3.6 3.5 3.5 Chlorobutanol 0.25-0.60% 0.47% 0.48% 0.47% 0.47% 0.47% 0.47% 0.48% 0.48% 0.48% w/v Particulate NMT 6000 1 2 1 2 1 4 2 1 3 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 28 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.4 19.5 19.4 19.4 19.5 19.5 19.5 19.4 19.3 Assay U/mL Related SEQ ID 0.5% 0.6% 0.6% 0.6% 0.6% 0.6% 0.7% 0.8% 0.9% Substances NO.: 2: NMT 6.0% SEQ ID 0.6% 0.6% 0.6% 0.7% 0.7% 0.7% 0.7% 0.9% 1.0% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP- NR NR NR NR NR NR NR NR NR Dimer: NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.84: NR NR 0.1% NR NR NR NR NR NR NMT 1.0% UI-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% NMT 1.0% UT-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.1% NR NR NR NR NR NR NR NR NMT 1.0% Total 2.3% 2.1% 2.1% 2.3% 2.1% 2.3% 2.5% 2.9% 2.9% Impurities: NMT 17.0% pH 2.5-4.5 3.5 3.5 3.5 3.5 3.5 3.5 3.5 3.8 3.5 Chlorobutanol 0.25-0.60 0.48% 0.48% 0.48% 0.48% 0.48% 0.48% 0.48% 0.49% 0.49% % w/v Particulate NMT 6000 0 2 2 2 1 2 2 4 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 29 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.7 19.7 19.6 19.7 19.8 19.7 19.8 19.7 19.5 Assay U/mL Related SEQ ID 0.6% 0.5% 0.5% 0.5% 0.6% 0.6% 0.6% 0.8% 0.7% Substances NO.: 2: NMT 6.0% SEQ ID 0.6% 0.6% 0.6% 0.6% 0.6% 0.7% 0.7% 0.8% 0.8% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR NR NR NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.2% 0.3% 0.3% 0.3% 0.3% AVP: NMT 1.0% UT-0.75- 0.2% 0.2% NR 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% 0.78: NMT 1.0% UI-0.83- 0.1% NR 0.1% NR NR NR NR NR NR 0.84: NMT 1.0% UI-1.02- 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% 0.3% 0.3% 0.2% 1.03: NMT 1.0% UI-1.67: NR NR NR 0.2% NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% Total 2.7% 2.1% 2.2% 2.2% 2.2% 2.3% 2.6% 2.9% 2.8% Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 Chlorobutanol 0.25-0.60 0.48% 0.48% 0.48% 0.48% 0.48% 0.48% 0.49% 0.49% 0.49% % w/v Particulate NMT 6000 1 1 1 2 2 6 4 4 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 30 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.7 19.7 19.6 19.7 19.8 19.7 19.9 19.8 19.5 Assay U/mL Related SEQ ID 0.5% 0.5% 0.5% 0.5% 0.5% 0.6% 0.6% 0.8% 0.8% Substances NO.: 2: NMT 6.0% SEQ ID 0.5% 0.5% 0.5% 0.6% 0.6% 0.7% 0.7% 0.8% 0.9% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% NR 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR NR NR NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.2% 0.3% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.75- NR NR NR NR 0.2% NR NR NR NR 0.78: NMT 1.0% UI-0.83- NR NR 0.1% NR NR NR NR 0.1% NR 0.84: NMT 1.0% UI-1.02- 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% 1.03: NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.76: NR NR NR 0.1% NR NR NR NR NR NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UT-2.05: 0.1% NR NR NR NR NR NR NR NR NMT 1.0% Total 2.2% 1.8% 2.0% 2.2% 2.2% 2.1% 2.4% 2.8% 2.7% Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.5 3.6 3.5 3.5 3.5 3.6 3.5 3.5 Chlorobutanol 0.25-0.60 0.47% 0.48% 0.47% 0.47% 0.48% 0.47% 0.48% 0.48% 0.48% % w/v Particulate NMT 6000 1 1 1 1 1 3 2 1 3 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≧25 μm) Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL TABLE 31 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 19.8 19.4 19.1 18.8 18.3 17.5 17.3 — Assay U/mL Related SEQ ID 0.1% 0.5% 1.1% 1.6% 2.0% 3.3% 4.6% — Substances NO.: 2: NMT 6.0% SEQ ID 0.1% 0.6% 1.2% 1.8% 2.2% 3.7% 5.2% — NO.: 4: NMT 6.0% SEQ ID 0.3% 0.4% 0.5% 0.5% 0.4% 0.2% 0.3% — NO.: 10: NMT 1.0% Asp5-AVP: NR 0.1% 0.3% 0.4% 0.5% 0.7% 1.0% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.2% 0.2% 0.2% 0.3% — AVP: NMT 1.0% UI-0.83: NR NR <0.10 NR NR NR 0.1% — NMT 1.0% UI-0.99: NR NR NR NR 0.1% NR NR — NMT 1.0% UI-1.03: 0.2% 0.2% 0.3% 0.3% 0.3% 0.2% 0.2% — NMT 1.0% UI-1.14: NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% — NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.22: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.56- NR NR <0.10 0.1% 0.1% 0.2% 0.2% — 1.57: NMT 1.0% UI-1.60: NR NR NR 0.1% 0.1% 0.2% NR — NMT 1.0% UI-1.74: NR NR NR NR NR 0.2% NR — NMT 1.0% UI-1.85- NR 0.2% NR NR NR 0.1% 0.1% — 1.88: NMT 1.0% UI-2.09- NR 0.2% NR NR NR NR 0.4% — 2.10: NMT 1.0% UI-2.15- NR NR 0.1% NR NR NR 0.5% — 2.16: NMT 1.0% Total 1.1% 2.4% 3.7% 4.7% 5.9% 9.0% 13.6% — Impurities: NMT 17.0% pH 2.5-4.5 3.5 3.5 3.5 3.5 3.4 3.3 3.2 — Chlorobutanol 0.25-0.60 0.49% 0.48% 0.48% 0.47% 0.47% 0.48% 0.47 — % w/v Particulate NMT 6000 1 1 1 1 8 4 1 — Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) AntiMicrobial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 32 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 20.1 19.7 19.3 19 18.6 17.6 17.6 — Assay U/mL Related SEQ ID NO.: 0.1% 0.5% 0.9% 1.5% 1.9% 3.1% 4.4% — Substances 2: NMT 6.0% SEQ ID NO.: 0.1% 0.5% 1.1% 1.6% 2.2% 3.4% 4.9% — 4: NMT 6.0% SEQ ID NO.: 0.3% 0.4% 0.3% 0.4% 0.3% 0.4% 0.3% — 10: NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.3% 0.4% 0.7% 0.9% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% 0.2% 0.2% 0.3% — NMT 1.0% UI-0.75-0.76: NR 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% — NMT 1.0% UI-0.83: 0.2% NR 0.1% NR NR 0.1% 0.1% — NMT 1.0% UI-0.99: NR NR NR NR 0.1% NR NR — NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.3% 0.2% — NMT 1.0% UI-1.14: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% — NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.22: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.56-1.57: NR NR 0.1% 0.1% 0.2% 0.2% 0.2% — NMT 1.0% UI-1.60: NR NR 0.1% 0.1% 0.2% 0.2% NR — NMT 1.0% UI-1.74: NR NR NR NR NR 0.2% NR — NMT 1.0% UI-1.85-1.88: NR 0.2% NR NR NR 0.1% 0.1% — NMT 1.0% UI-2.09-2.10: NR 0.2% NR NR NR NR 0.4% — NMT 1.0% UI-2.15-2.16: NR NR NR NR NR NR 0.6% — NMT 1.0% Total 1.3% 2.5% 3.4% 4.6% 5.6% 9.0% 13.4% — Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.6 3.5 3.5 3.2 3.3 3.4 — Chlorobutanol 0.25-0.60 0.48% 0.49% 0.48% 0.47% 0.47% 0.47% 0.47 — % w/v Particulate NMT 6000 2 1 1 3 4 1 2 — Matter (≧10 μm) (USP) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) AntiMicrobial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 33 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 19.9 19.6 19.2 19 18.7 18 17.4 — Assay U/mL Related SEQ ID NO.: 0.2% 0.5% 1.0% 1.5% 2.0% 3.2% 4.5% — Substances 2: NMT 6.0% SEQ ID No.: 0.1% 0.6% 1.1% 1.8% 2.2% 3.7% 5.0% — 4: NMT 6.0% SEQ ID NO.: 0.4% 0.4% 0.3% 0.4% 0.4% 0.3% 0.5% — 10: NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.4% 0.5% 0.7% 1.0% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR 0.1% — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% — NMT 1.0% UI-0.12: NR 0.1% NR NR NR NR NR NMT 1.0% UI-0.75-0.76: NR NR NR NR NR NR NR NMT 1.0% UI-0.83-0.84: NR 0.1% 0.1% 0.1% 0.1% 0.1% NMT 1.0% UI-0.93: NR NR NR NR NR NR 0.1% NMT 1.0% UI-0.99: NR NR NR NR NR NR NR NMT 1.0% UI-1.02-1.03: 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% 0.3% — NMT 1.0% UI-1.15: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% NMT 1.0% UI-1.20: NR NR NR NR NR NR NR NMT 1.0% UI-1.22: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.26: NR NR NR NR NR NR NMT 1.0% UI-1.35: 0.3% NR NR NR NR NR NR NMT 1.0% UI-1.56-1.57: NR NR 0.1% NR 0.1% 0.2% 0.3% NMT 1.0% UI-1.60: NR NR 0.1% NR 0.1% NR NR — NMT 1.0% UI-1.74: NR NR NR NR NR NR NR NMT 1.0% UI-1.84-1.89: NR 0.1% NR NR NR NR 0.2% NMT 1.0% UI-1.96: 0.2% NR NR NR NR NR NR NMT 1.0% UI-2.09-2.10: NR 20.0% NR NR NR <0.10 0.1% NMT 1.0% UI-2.15-2.16: NR NR 0.1% NR NR 0.1% NR NMT 1.0% Total 1.5% 2.6% 3.3% 4.6% 5.9% 9.0% 12.9% — Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.5 3.5 3.5 3.4 3.4 3.3 — Chlorobutanol 0.25-0.60 0.48% 0.47% 0.47% 0.46% 0.46% 0.46% 0.45% — % w/v Particulate NMT 6000 1 2 3 3 3 1 2 — Matter (≧10 μm) (USP) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) Anti- Meets Test Pass • • • Pass • Pass — Microbial Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL table 34 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 19.8 19.4 19.1 18.8 18.3 17.5 17.4 — Assay U/mL Related SEQ ID NO.: 0.1% 0.5% 1.1% 1.6% 2.0% 3.2% 4.5% — Substances 2: NMT 6.0% SEQ ID NO.: 0.1% 0.6% 1.2% 1.8% 2.3% 3.6% 5.0% — 4: NMT 6.0% SEQ ID NO.: 0.3% 0.4% 0.3% 0.4% 0.3% 0.2% 0.3% — 10: NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.4% 0.4% 0.7% 0.9% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% 0.2% 0.2% 0.3% — NMT 1.0% UI-0.83: NR NR <0.10 NR NR 0.1% 0.1% — NMT 1.0% UI-0.99: NR NR NR NR NR NR NR — NMT 1.0% UI-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.2% — NMT 1.0% UI-1.14: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% — NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.22: NR NR NR NR NR NR NR — NMT 1.0% UI-1.56-1.57: NR NR NR 0.1% 0.1% 0.2% 0.2% — NMT 1.0% UI-1.60: NR NR NR NR NR 0.1% NR — NMT 1.0% UI-1.74: NR NR NR NR NR 0.2% NR — NMT 1.0% UI-1.85-1.88: NR 0.2% NR NR NR 0.1% 0.1% — NMT 1.0% UT-2.09-2.10: NR 0.2% NR NR NR NR 0.3% — NMT 1.0% UI-2.15-2.16: NR NR NR NR NR NR 0.5% — NMT 1.0% Total 1.1% 2.4% 3.2% 4.8% 5.6% 9.2% 13.1% — Impurities: NMT 17.0% pH 2.5-4.5 3.5 3.5 3.5 3.5 3.4 3.3 3.3 — Chlorobutanol 0.25-0.60 0.49% 0.48% 0.48% 0.48% 0.47% 0.48% 0.47 — % w/v Particulate NMT 6000 1 2 2 2 2 4 2 — Matter (≧10 μm) (USP) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) AntiMicrobial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 35 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 20.1 19.7 19.4 18.9 18.6 17.8 17.7 — Assay U/mL Related SEQ ID 0.1% 0.5% 0.9% 1.4% 1.9% 3.1% 4.3% — Substances NO.: 2: NMT 6.0% SEQ ID 0.1% 0.5% 1.1% 1.6% 2.2% 3.4% 4.9% — NO.: 4: NMT 6.0% D-Asn- 0.3% 0.4% 0.3% 0.3% 0.3% 0.4% 0.3% — AVP: NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.3% 0.4% 0.7% 0.9% — NMT 1.5% AVP-Dimer NR NR NR NR NR NR NR — NMT 1.0% Acetyl- 0.30% 0.30% 0.30% 0.20% 0.20% 0.20% 0.3% — AVP: NMT 1.0% UI-0.75- NR 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% 0.76: NMT 1.0% UI-0.83: 0.2% NR <0.10 NR NR 0.1% 0.1% NMT 1.0% UI-0.99: NR NR NR NR 0.1% NR NR NMT 1.0% UI-1.02- 0.2% 0.2% 0.2% 0.2% 0.2% 0.3% 0.2% — 1.03: NMT 1.0% UI-1.14: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.22: NR NR NR NR NR NR 0.4% NMT 1.0% UI-1.56- NR NR 0.1% 0.1% 0.2% 0.2% 0.3% 1.57: NMT 1.0% UI-1.60: NR NR 0.1% 0.1% 0.2% 0.2% NR — NMT 1.0% UI-1.74: NMT 1.0% UI-1.85- NR 0.2% NR NR NR 0.1% 0.1 1.88: NMT 1.0% UI-2.09- NR 0.2% NR NR NR 0.1% 0.3 2.10: NMT 1.0% UI-2.15- NR NR NR NR NR 0.5 2.16: NMT 1.0% Total 1.3% 2.5% 3.3% 4.5% 5.7% 9.1% 13.3% — Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.6 3.5 3.5 3.4 3.3 3.3 — Chlorobutanol 0.25-0.60 0.48% 0.49% 0.48% 0.47% 0.47% 0.48% 0.46 — % w/v Particulate NMT 6000 2 1 1 2 5 1 4 — Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) Anti- Meets Test Pass • • • Pass • Pass — Microbial Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 36 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 19.9 19.6 19.2 19 18.5 18.1 17.4 — Assay U/mL Related SEQ ID 0.2% 0.5% 1.0% 1.5% 2.1% 3.3% 4.7% — Substances NO.: 2: NMT 6.0% SEQ ID 0.1% 0.6% 1.1% 1.7% 2.3% 3.7% 5.3% — NO.: 4: NMT 6.0% D-Asn- 0.4% 0.4% 0.3% 0.4% 0.4% 0.3% 0.5% — AVP: NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.3% 0.5% 0.7% 1.0% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% — AVP: NMT 1.0% UI-0.12: NR NR NR NR NR NR NR NMT 1.0% UI-0.75- NR NR NR NR NR NR NR 0.76: NMT 1.0% UI-0.83- NR 0.1% 0.1% 0.1% NR 0.1% 0.1% 0.84: NMT 1.0% UI-0.93: NR NR NR NR NR NR 0.1% NMT 1.0% UI-0.99: NR NR NR NR NR NR NR NMT 1.0% UI-1.02- 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% 0.3% — 1.03: NMT 1.0% UI-1.15: NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% NMT 1.0% UT-1.20: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.22: NR NR NR NR NR NR NR NMT 1.0% UI-1.26: NR NR 0.4% NR NR NR NR NMT 1.0% UI-1.35: 0.1% NR NR NR NR NR NR NMT 1.0% UI-1.56- NR NR 0.1% 0.1% NR 0.2% 0.3% 1.57: NMT 1.0% UI-1.60: NR NR NR NR NR NR NR — NMT 1.0% UI-1.74: NR NR NR NR NR NR NR — NMT 1.0% UI-1.84- NR 0.1% NR NR NR NR 0.2% 1.89: NMT 1.0% UI-1.96: 0.2% NR NR NR NR NR NR NMT 1.0% UI-2.09- NR NR NR NR NR <0.10 NR 2.10: NMT 1.0% UI-2.15- NR NR 0.1% NR NR 0.2% NR 2.16: NMT 1.0% Total 1.5% 2.5% 3.7% 4.7% 5.9% 9.1% 13.3% Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.5 3.5 3.5 3.4 3.4 3.3 — Chlorobutanol 0.25-0.60 0.48% 0.48% 0.47% 0.47% 0.46% 0.45 0.46 — % w/v Particulate NMT 6000 1 0 1 3 7 0 3 — Matter (USP) (≧10 μm) NMT 600 0 0 0 0 0 0 0 — (≧25 μm) Anti- Meets Test Pass • • • Pass • Pass — Microbial Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL TABLE 37 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.8 19.1 18.6 17.3 Assay Related SEQ ID NO.: 2: 0.1% 1.0% 2.4% 3.8% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.1% 2.7% 4.3% NMT 6.0% D-Asn-AVP: 0.3% 0.4% 0.3% 0.3% NMT 1.0% Asp5-AVP: NMT ND 0.2% 0.5% 0.8% 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.2% 0.2% 0.2% NMT 1.0% UI-0.13: NMT ND 0.1% ND ND 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.83-0.84: ND ND ND ND NMT 1.0% UI-1.02-1.03: 0.2% 0.3% 0.2% 0.3% NMT 1.0% UI-1.18: NMT ND ND ND 0.2% 1.0% UI-1.56-1.57: ND 0.2% 0.4% 0.4% NMT 1.0% UI-1.67: NMT ND ND ND ND 1.0% UI-1.76: NMT ND ND ND ND 1.0% UI-1.83-1.85: ND ND 0.2% 0.2% NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT 1.0% UI-1.93: NMT ND 0.1% ND ND 1.0% UI-2.05-2.08: ND ND 0.2% ND NMT 1.0% Total Impurities: 1.1% 3.7% 7.3% 10.6% NMT 17.0% pH 2.5-4.5 3.5 3.3 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.49% 0.48% 0.50% 0.47% Particulate NMT 6000 1 1 1 1 (≧10 μm) Matter (USP) NMT 600 0 0 0 0 (≧25 μm) TABLE 38 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 20.1 19.3 18.7 17.6 Assay Related SEQ ID NO.: 2: 0.1% 0.9% 2.2% 3.6% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.0% 2.5% 3.9% NMT 6.0% D-Asn-AVP: 0.3% 0.4% 0.3% 0.3% NMT 1.0% Asp5-AVP: NMT ND 0.2% 0.5% 0.8% 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.2% 0.3% 0.2% NMT 1.0% UI-0.13: NMT ND 0.1% ND ND 1.0% UI-0.75-0.78: ND ND 0.2% 0.2% NMT 1.0% UI-0.80-0.84: 0.2% 0.2% ND ND NMT 1.0% UI-1.02-1.03: 0.2% 0.3% 0.2% 0.3% NMT 1.0% UI-1.18: NMT ND ND 0.3% 0.2% 1.0% UI-1.56-1.57: ND 0.2% ND 0.4% NMT 1.0% UI-1.67: NMT ND ND ND ND 1.0% UI-1.76: NMT ND ND ND ND 1.0% UI-1.81-1.85: ND ND 0.2% 0.2% NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT 1.0% UI-1.93: NMT ND 0.1% ND ND 1.0% UI-2.03-2.08: ND ND 0.2% 0.1% NMT 1.0% UI-2.14: NMT ND ND 0.2% ND 1.0% Total Impurities: 1.3% 3.6% 7.3% 10.3% NMT 17.0% pH 2.5-4.5 3.6 3.3 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.48% 0.48% 0.50% 0.47% Particulate NMT 6000 2 2 1 1 (≧10 μm) Matter (USP) NMT 600 0 0 0 0 (≧25 μm) TABLE 39 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.9 19.2 18.3 17.4 Assay Related SEQ ID NO.: 2: 0.2% 0.9% 2.2% 3.8% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.0% 2.4% 4.0% NMT 6.0% D-Asn-AVP: 0.4% 0.3% 0.3% 0.3% NMT 1.0% Asp5-AVP: NMT ND 0.2% 0.5% 0.8% 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% NMT 1.0% UI-0.13: NMT ND ND ND ND 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.80-0.84: ND ND ND ND NMT 1.0% UI-1.02-1.03: 0.3% 0.2% 0.2% 0.3% NMT 1.0% UI-1.18: NMT ND ND ND 0.2% 1.0% UI-1.35: NMT 0.1% ND ND ND 1.0% UI-1.52-1.58: ND 0.2% 0.3% 0.4% NMT 1.0% UI-1.67: NMT ND ND ND ND 1.0% UI-1.76: NMT ND ND ND ND 1.0% UI-1.81-1.85: ND ND ND ND NMT 1.0% UI-1.86-1.88: ND 0.1% 0.2% ND NMT 1.0% UI-1.91-1.96: 0.2% 0.2% ND ND NMT 1.0% UI-2.02-2.08: ND ND ND 0.2% NMT 1.0% UI-2.11-2.14: ND 0.2% ND ND NMT 1.0% Total Impurities: 1.5% 3.7% 6.3% 10.3% NMT 17.0% pH 2.5-4.5 3.6 3.4 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.48% 0.47% 0.46% 0.46% Particulate NMT 6000 2 2 1 1 (≧10 μm) Matter (USP) NMT 600 0 0 0 0 (≧25 μm) TABLE 40 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.8 18.9 18.5 17.2 Assay Related SEQ ID NO.: 2: 0.1% 1.0% 2.4% 3.8% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.1% 2.7% 4.3% NMT 6.0% D-Asn-AVP: 0.3% 0.3% 0.3% 0.3% NMT 1.0% Asp5-AVP: NMT ND 0.2% 0.5% 0.8% 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% UI-0.13: NMT ND 0.1% ND ND 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.83-0.84: ND ND ND ND NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.2% NMT 1.0% UI-1.18: NMT ND ND ND 0.2% 1.0% UI-1.56-1.57: ND 0.2% 0.3% 0.3% NMT 1.0% UI-1.67: NMT ND ND ND ND 1.0% UI-1.76: NMT ND ND ND ND 1.0% UI-1.83-1.85: ND ND 0.2% ND NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT 1.0% UI-1.93: NMT ND 0.1% ND ND 1.0% UI-2.05-2.08: ND ND 0.2% ND NMT 1.0% Total Impurities: 1.1% 3.6% 7.2% 10.3% NMT 17.0% Total Impurities: 1.1% 3.6% 7.2% 10.3% NMT 17.0% pH 2.5-4.5 3.5 3.3 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.49% 0.48% 0.50% 0.48% Particulate NMT 6000 1 1 1 1 (≧10 μm) Matter (USP) NMT 600 0 0 0 0 (≧25 μm) TABLE 41 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 20.1 18.9 18.7 17.4 Assay Related SEQ ID NO.: 2: 0.1% 0.9% 2.3% 3.7% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.0% 2.5% 3.9% NMT 6.0% D-Asn-AVP: 0.3% 0.4% 0.3% 0.3% NMT 1.0% Asp5-AVP: NMT ND 0.2% 0.5% 0.8% 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.2% 0.3% 0.2% NMT 1.0% UI-0.13: NMT ND ND ND ND 1.0% UI-0.75-0.78: ND ND 0.2% 0.2% NMT 1.0% UI-0.80-0.84: 0.2% 0.2% ND ND NMT 1.0% UI-1.02-1.03: 2.0% 0.3% 0.2% 0.3% NMT 1.0% UI-1.18: NMT ND ND ND 0.2% 1.0% UI-1.56-1.57: ND 0.2% 0.4% 0.4% NMT 1.0% UI-1.67: NMT ND ND ND ND 1.0% UI-1.76: NMT ND ND ND ND 1.0% UI-1.83-1.85: ND ND 0.2% 0.1% NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT 1.0% UI-1.93: NMT ND 0.1% ND ND 1.0% UI-2.05-2.08: ND ND 0.2% ND NMT 1.0% UI-2.14: NMT ND ND ND ND 1.0% Total Impurities: 1.3% 3.5% 7.1% 10.2% NMT 17.0% pH 2.5-4.5 3.6 3.3 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.48% 0.48% 0.49% 0.47% Particulate NMT 6000 2 1 1 1 (≧10 μm) Matter (USP) NMT 600 0 0 0 0 (≧25 μm) TABLE 42 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.9 19.2 18.3 17.5 Assay Related SEQ ID NO.: 2: 0.2% 1.0% 2.2% 3.9% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.1% 2.4% 4.2% NMT 6.0% D-Asn-AVP: 0.4% 0.3% 0.3% 0.3% NMT 1.0% Asp5-AVP: NMT ND 0.2% 50.0% 0.8% 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% NMT 1.0% UI-0.13: NMT ND ND ND ND 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.80-0.84: ND ND ND ND NMT 1.0% UI-1.02-1.03: 0.3% 0.2% 0.2% 0.3% NMT 1.0% UI-1.18: NMT ND ND ND 0.2% 1.0% UI-1.35: NMT 0.1% ND ND ND 1.0% UI-1.52-1.58: ND 0.2% 0.3% 0.4% NMT 1.0% UI-1.67: NMT ND ND ND ND 1.0% UI-1.76: NMT ND ND ND ND 1.0% UI-1.83-1.85: ND ND ND ND NMT 1.0% UI-1.86-1.88: ND 0.1% 0.2% ND NMT 1.0% UI-1.91-1.96: 0.2% 0.2% ND ND NMT 1.0% UI-2.02-2.08: ND ND ND 0.1% NMT 1.0% UI-2.11-2.14: ND 0.2% ND ND NMT 1.0% Total Impurities: 1.5% 3.8% 6.3% 10.5% NMT 17.0% pH 2.5-4.5 3.6 3.4 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.48% 0.47% 0.47% 0.45% Particulate NMT 6000 1 2 1 1 (≧10 μm) Matter (USP) NMT 600 0 0 0 0 (≧25 μm) Example 9: Effect of pH 3.5-4.5 on Vasopressin Formulations To test of effect of pH on vasopressin formulations, solutions containing 20 units/mL vasopressin, adjusted to pH 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, or 4.5 with 10 mM acetate buffer, were prepared. One mL of each of the vasopressin formulations was then filled into 10 cc vials. The vasopressin formulations were stored for four weeks at: (i) 25° C.; or (ii) 40° C., and the assay (% label claim; vasopressin remaining) and % total impurities after four weeks were measured using the methods described in EXAMPLE 1. FIGS. 11 and 12 below display the results of the experiments at 25° C. The results of the experiments at 40° C. are included in FIGS. 13 and 14. The results of the experiments suggested that the stability of a vasopressin formulation was affected by pH. At 25° C., the remaining vasopressin after four weeks was highest between pH 3.6 and pH 3.8 (FIG. 11). Within the range of pH 3.6 to pH 3.8, the level of impurities was lowest at pH 3.8 (FIG. 12). At 25° C., pH 3.7 provided the highest stability for vasopressin (FIG. 11). At 40° C., the remaining vasopressin after four weeks was highest between pH 3.6 and pH 3.8 (FIG. 13). Within the range of pH 3.6 to pH 3.8, the level of impurities was lowest at pH 3.8 (FIG. 14). At 40° C., pH 3.6 provided the highest stability for vasopressin (FIG. 13), Example 10: Effect of pH 2.5-4.5 of Vasopressin Formulations To test of effect of pH on vasopressin formulations, solutions containing 20 units/mL vasopressin, adjusted to pH 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, or 3.4 with 10 mM acetate buffer were also prepared. One mL of each of the vasopressin formulations was then filled into 10 cc vials. The amount of vasopressin, impurities, and associated integration values were determined using the methods describes in EXAMPLE 1. The results from the stability tests on the vasopressin formulations from pH 2.5 to 3.4 were plotted against the results from the stability tests on vasopressin formulations from pH 3.5 to 4.5 as disclosed in EXAMPLE 9, and are displayed in FIGS. 15-18. The assay (% label claim; vasopressin remaining) and % total impurities in the vasopressin pH 2.5 to 3.4 formulations after four weeks are reported in TABLE 43. TABLE 43 Target Vasopressin % Total Batch pH Week Condition (% LC) Impurities 1A 2.5 0 25° C. 100.57 2.48 1B 2.6 0 25° C. 101.25 2.24 1C 2.7 0 25° C. 101.29 2.26 1D 2.8 0 25° C. 101.53 2.00 1E 2.9 0 25° C. 102.33 1.95 1F 3 0 25° C. 102.32 1.89 1G 3.1 0 25° C. 102.59 2.06 1H 3.2 0 25° C. 102.60 1.85 1I 3.3 0 25° C. 102.73 1.81 1J 3.4 0 25° C. 101.93 1.75 1A 2.5 0 40° C. 100.57 2.48 1B 2.6 0 40° C. 101.25 2.24 1C 2.7 0 40° C. 101.29 2.26 1D 2.8 0 40° C. 101.53 2.00 1E 2.9 0 40° C. 102.33 1.95 1F 3 0 40° C. 102.32 1.89 1G 3.1 0 40° C. 102.59 2.06 1H 3.2 0 40° C. 102.60 1.85 1I 3.3 0 40° C. 102.73 1.81 1J 3.4 0 40° C. 101.93 1.75 1A 2.5 4 25° C. 95.70 6.66 1B 2.6 4 25° C. 98.58 5.29 1C 2.7 4 25° C. 98.94 4.26 1D 2.8 4 25° C. 99.14 3.51 1E 2.9 4 25° C. 100.08 3.41 1F 3 4 25° C. 100.29 2.92 1G 3.1 4 25° C. 100.78 2.55 1H 3.2 4 25° C. 100.74 2.16 1I 3.3 4 25° C. 100.46 2.14 1J 3.4 4 25° C. 100.25 2.03 1A 2.5 4 40° C. 81.89 19.41 1B 2.6 4 40° C. 90.10 15.60 1C 2.7 4 40° C. 92.19 13.46 1D 2.8 4 40° C. 94.89 10.98 1E 2.9 4 40° C. 96.03 9.78 1F 3 4 40° C. 97.26 8.09 1G 3.1 4 40° C. 99.61 6.39 1H 3.2 4 40° C. 98.58 5.25 1I 3.3 4 40° C. 97.81 4.41 1J 3.4 4 40° C. 97.35 3.85 The % total impurities for the pH 2.5 to 3.4 formulations and the pH 3.5 to 4.5 formulations observed in the experiments conducted at 25° C. and 40° C. are shown in FIGS. 15 (25° C.) and 16 (40° C.). The vasopressin assay amount for the vasopressin pH 2.5 to 3.4 formulations and the vasopressin pH 3.5 to 4.5 formulations observed in the experiments conducted at 25° C. and 40° C. are shown in FIGS. 17 (25° C.) and 18 (40° C.). The vasopressin assay is presented as a % assay decrease of vasopressin over the four-week study period, rather than absolute assay, because the amount of starting vasopressin varied between the vasopressin pH 2.5 to 3.4 formulations and the vasopressin pH 3.5 to 4.5 formulations. The results of the above experiments suggested that the stability of a vasopressin formulation was affected by pH. At 25° C., the percent decrease in vasopressin after four weeks was lowest between pH 3.7 and pH 3.8 (FIG. 17). Within the range of pH 3.7 to pH 3.8, the level of impurities was lowest at pH 3.8 (FIG. 15). At 40° C., the percent decrease in vasopressin after four weeks was lowest between pH 3.6 and pH 3.8 (FIG. 18). Within the range of pH 3.6 to pH 3.8, the level of impurities was lowest at pH 3.8 (FIG. 16). Example 11: Intra-Assay and Inter-Analysis Precision of Vasopressin pH Experiments The methods used to determine the % assay decrease and amount of impurities in the vasopressin solutions over time in EXAMPLE 10 had both intra-assay and inter-analyst precision. Intra-assay precision was demonstrated by performing single injections of aliquots of a vasopressin formulation (n=6; Chemist 1) from a common lot of drug product and determining the assay and repeatability (% RSD; relative standard deviation). Inter-analyst precision was demonstrated by two different chemists testing the same lot of drug product; however, the chemists used different instruments, reagents, standard preparations, columns, and worked in different laboratories. The procedure included a common pooling of 20 vials of vasopressin, which were assayed by the two chemists using different HPLC systems and different HPLC columns. The vasopressin assay results (units/mL) and repeatability (% RSD for n=6) were recorded and are reported in the TABLE 44 below. TABLE 44 Precision of Vasopressin Results. Chemist 1 Chemist 2 Sample (units/mL) (units/mL) 1 19.74 19.65 2 19.76 19.66 3 19.77 19.66 4 19.75 19.72 5 19.97 19.73 6 19.65 19.73 Mean 19.8 19.7 % RSD (≦2.0%) 0.5% 0.2% % Difference = 0.5% (acceptance criteria: ≦3.0%) %   Difference = ( Chemist   1 Mean - Chemist   2 Mean ) ( Chemist   1 Mean + Chemist   2 Mean ) × 200 The intra-assay repeatability met the acceptance criteria (% RSD<2.0%) with values of 0.5% and 0.2%. The inter-analyst repeatability also met the acceptance criteria (% difference≦3.0%) with a difference of 0.5%. Example 12: Effect of Citrate Versus Acetate Buffer on Vasopressin Formulations To test the effect of citrate and acetate buffer on vasopressin formulations, a total of twelve solutions of 20 Units/mL vasopressin were prepared in 1 mM citrate buffer, 10 mM citrate buffer, 1 mM acetate buffer, and 10 mM acetate buffer. All of the solutions were prepared in triplicate. Each solution was adjusted to pH 3.5 with hydrochloric acid. The vasopressin formulations were stored at 60° C. for 7 days, and the assay (% label claim; vasopressin remaining) and % total impurities after 7 days were analyzed by HPLC using the procedure and experimental conditions described in EXAMPLE 1. The assay (% label claim; vasopressin remaining) and % total impurities for each of the Vasopressin Buffered Formulations are reported in the TABLES 45 and 46 below. TABLE 45 Assay (% label claim; vasopressin remaining) in the vasopressin formulations after storage at 60° C. for 7 days. Sample Buffer 1 2 3 Average 1 mM citrate buffer 89.5% 89.7% 90.6% 89.9% 10 mM citrate buffer 84.1% 84.4% 84.5% 84.3% 1 mM acetate buffer 90.5% 91.1% 91.9% 91.2% 10 mM acetate buffer 90.9% 90.9% 92.4% 91.4% TABLE 46 % Total Impurities in the vasopressin formulations after storage at 60° C. for 7 days. Sample Buffer 1 2 3 Average 1 mM citrate buffer 3.4% 3.5% 2.5% 3.1% 10 mM citrate buffer 9.5% 9.0% 9.4% 9.3% 1 mM acetate buffer 3.3% 2.8% 3.2% 3.1% 10 mM acetate buffer 2.9% 2.6% 3.1% 2.9% The data indicated that the vasopressin assay in the vasopressin formulations with citrate buffer was lower than in the vasopressin formulations with acetate buffer. For example, at 10 mM of either citrate or acetate buffer, the average vasopressin assay was 91.4% in acetate buffer, but was 84.3% in citrate buffer. The data also indicated that % total impurities in the vasopressin formulations with citrate buffer were higher than in the vasopressin formulations with acetate buffer. For example, at 10 mM of either citrate or acetate buffer, the average % total impurities was 2.9% in acetate buffer, but was 9.3% in citrate buffer. Further, as the citrate buffer concentration increased, the vasopressin assay further decreased (from an average of 89.9% to 84.3%), and the % total impurities increased (from an average of 3.1% to 9.3%). This effect was not observed in the vasopressin formulations with acetate buffer, where the average and % total impurities stayed fairly constant. Example 13: Multi-Dose Vasopressin Formulation A multi-dose formulation (10 mL) for vasopressin that can be used in the clinic is detailed in TABLE 47 below: TABLE 47 Drug Product Description Vasopressin, USP Active Ingredient 20 Units (~0.04 mg) Dosage Form Injection — Route of Intravenous — Administration Description Clear colorless to practically colorless solution supplied in a 10 mL clear glass vial with flip-off cap The composition of a 10 mL formulation of vasopressin is provided below. TABLE 48 Drug Product Composition Ingredient Grade Function Batch Quantity Unit Formula Vasopressin, USP USP Active 3,000,000 Units 20 Units Sodium Acetate Trihydrate USP Buffer 214.2 g 1.36 mg Sodium Hydroxide NF pH Adjuster 40 g QS to pH 3.8 Hydrochloric Acid NF/EP pH Adjuster 237.9 g QS to pH 3.8 Chlorobutanol NF Preservative 0.8274 kg 5 mg Water for Injection USP Solvent QS QS to 1 mL Nitrogen NF Processing Aid — — The 10 mL vasopressin formulation was compared to the guidelines for inactive ingredients provided by the Food and Drug Administration (FDA). The results are shown in TABLE 49 below. TABLE 49 Vasopressin Inactive 10 mL Ingredients Formulation Concentration Guideline Ingredient (mg/mL) (% w/v) Acceptable Level Sodium Acetate 1.36 0.136% IV (infusion); Trihydrate Injection 0.16% Sodium Hydroxide QS to pH 3.8 QS to pH 3.8 N/A Hydrochloric Acid QS to pH 3.8 QS to pH 3.8 N/A Chlorobutanol 5 mg 0.5% IV (Infusion); Injection 1% Water for Injection QS to 1 mL QS to target N/A volume Example 14: Alternative Vasopressin Formulation for Clinical Use A 1 mL dosage of vasopressin was prepared. A description of the formulation is shown in TABLE 50 below. TABLE 50 Drug Product Description Vasopressin, USP Active Ingredient 20 Units/mL (~0.04 mg) Dosage Form Injection — Rout of Intravenous — Administration Description Clear colorless to practically — colorless solution supplied in a 3 mL vial with flip-off cap The drug composition of the formulation is provided in TABLE 51. TABLE 51 Drug Product Composition Ingredient Function Quantity Vasopressin, USP Active 20 Units Sodium Acetate Buffer 1.36 Trihydrate, USP Sodium Hydroxide NF/EP pH Adjustor QS for pH adjustment to pH 3.8 Hydrochloric Acid, NF/EP pH Adjuster QS for pH adjustment to pH 3.8 Water for Injection Solvent QS to 1 mL The 1 mL vasopressin formulation was compared to the guidelines for inactive ingredients provided by the Food and Drug Administration (FDA). The results are shown in TABLE 52 below. TABLE 52 Vasopressin Inactive 1 mL Ingredients Formulation Concentration Guideline Ingredient (mg/mL) (% w/v) Acceptable Level Sodium Acetate 1.36 0.136% 0.16% Trihydrate Sodium Hydroxide QS to pH 3.8 QS to pH 3.8 8% Hydrochloric Acid QS to pH 3.8 QS to pH 3.8 10% Water for Injection QS to 1 mL QS to target N/A volume Example 15: 15-Month Stability Data for Vasopressin Formulations The drug product detailed in TABLE 51 was tested for stability over a 15-month period. Three different lots (X, Y, and Z) of the vasopressin drug formulation were stored at 25° C. for 15 months in an upright or inverted position. At 0, 1, 2, 3, 6, 9, 12, 13, 14, and 15 months, the amount of vasopressin (AVP), % label claim (LC), amount of various impurities, and pH was measured. The vasopressin and impurity amounts were determined using the HPLC method described above in EXAMPLE 1. The results of the stability experiment are shown in TABLES 53-54 below. TABLE 53 Inverted Storage of Vasopressin Formulations at 25° C. UI- UI UI- UI- UI- UI- UI- UI- D- 0.81- 0.97 1.02- 1.72- 1.81- 1.90- 2.05- 2.09- AVP % Gly9 Glu4 Asn Asp5 Dimer Acetyl 0.86 0.99 1.03 1.76 1.89 1.96 2.07 2.10 Total Lot Month (U/mL) LC (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) Impurities pH X 0 19.6 97.9 0.3 0.4 0.3 1.0 3.8 Y 0 19.7 98.6 0.3 0.4 0.3 1.1 3.8 Z 0 19.9 99.3 0.1 0.5 0.2 0.8 3.8 X 1 19.6 98.1 0.2 0.2 0.1 0.4 0.4 0.3 1.6 3.8 Y 1 19.6 97.9 0.2 0.2 0.1 0.4 0.4 0.3 1.6 3.9 Z 1 19.8 99 0.2 0.2 0.6 0.1 0.2 1.4 3.8 X 2 19.6 98.1 0.3 0.3 0.1 0.3 0.4 0.3 1.7 3.7 Y 2 19.5 97.5 0.2 0.3 0.1 0.3 0.4 0.3 1.6 3.8 Z 2 19.8 99 0.3 0.4 0.5 0.2 1.3 3.8 X 3 19.6 97.8 0.4 0.5 0.1 0.1 0.3 0.4 0.4 2.2 Y 3 19.5 97.4 0.4 0.4 0.1 0.3 0.4 0.4 2.0 3.8 Z 3 19.7 98.6 0.4 0.4 0.5 0.3 1.6 X 6 19.3 96.5 0.7 0.8 0.1 0.2 0.3 0.4 0.4 2.9 3.8 Y 6 19.2 95.9 0.6 0.7 0.1 0.1 0.1 0.3 0.4 0.4 2.5 3.9 Z 6 19.6 98 0.6 0.7 0.1 0.5 0.2 2.3 3.9 X 9 19 95 1.0 1.0 0.2 0.3 0.4 0.4 0.1 3.6 Y 9 18.9 94.5 0.8 1.0 0.2 0.3 0.4 0.4 0.1 3.1 3.9 Z 9 19.2 96 1.0 1.1 0.2 0.5 0.3 3.1 3.8 X 12 18.7 93.5 1.4 1.5 0.1 0.3 0.3 0.4 0.5 0.2 4.8 3.8 Y 12 18.6 93 1.1 1.2 0.2 0.2 0.3 0.4 0.5 0.3 0.2 4.4 3.8 Z 12 18.9 94.5 1.2 1.3 0.3 0.5 0.3 0.3 0.1 4.0 3.8 X 13 18.6 93 1.5 1.6 0.2 0.3 0.4 0.4 0.1 0.4 0.2 0.1 5.2 3.8 Y 13 18.5 92.5 1.2 1.3 0.2 0.3 0.3 0.4 0.1 0.5 0.1 0.4 0.2 0.2 5.2 3.9 Z 13 19 95 1.3 1.5 0.1 0.3 0.5 0.1 0.3 0.1 0.3 0.2 0.2 4.9 3.8 X 14 18.6 93 1.5 1.7 0.1 0.3 0.3 0.5 0.1 0.4 0.4 0.1 0.1 5.5 3.8 Y 14 18.5 92.5 1.2 1.4 0.1 0.3 0.3 0.5 0.1 0.4 0.5 0.2 0.2 5.3 3.9 Z 14 18.9 94.5 1.3 1.6 0.3 0.5 0.2 0.3 0.4 0.2 0.2 5.0 3.8 X 15 18.5 92.5 1.6 1.8 0.1 0.4 0.3 0.4 0.1 0.4 0.3 0.2 0.2 5.9 3.8 Y 15 18.4 92 1.3 1.5 0.1 0.3 0.3 0.4 0.1 0.4 0.5 0.3 0.1 5.3 3.9 Z 15 18.8 94 1.5 1.6 0.3 0.5 0.3 0.4 0.2 0.1 4.9 3.9 TABLE 54 Upright Storage of Vasopressin Formulations at 25° C. UI- UI UI- UI- UI- UI- UI- UI- D- 0.81- 0.97 1.02- 1.72- 1.81- 1.90- 2.05- 2.09- AVP % Gly9 Glu4 Asn Asp5 Dimer Acetyl 0.86 0.99 1.03 1.76 1.89 1.96 2.07 2.10 Total Lot Month (U/mL) LC (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) Impurities pH X 0 19.6 97.9 0.3 0.4 0.3 1.0 3.8 Y 0 19.7 98.6 0.3 0.4 0.3 1.1 3.8 Z 0 19.9 99.3 0.1 0.5 0.2 0.8 3.8 X 1 19.6 98 0.2 0.2 0.1 0.3 0.4 0.3 1.6 3.8 Y 1 19.5 97.7 0.2 0.2 0.3 0.4 0.3 1.4 3.9 Z 1 19.7 98.3 0.2 0.2 0.6 0.2 1.2 3.8 X 2 19.6 98.2 0.3 0.3 0.3 0.4 0.3 1.6 3.7 Y 2 19.5 97.4 0.2 0.3 0.1 0.4 0.4 0.3 1.6 3.8 Z 2 19.8 99 0.3 0.3 0.5 0.2 1.3 3.8 X 3 19.5 97.6 0.4 0.4 0.1 0.3 0.4 0.4 2.1 3.7 Y 3 19.5 97.5 0.4 0.4 0.1 0.4 0.4 1.9 3.8 Z 3 19.7 98.7 0.4 0.4 0.1 0.5 0.3 1.7 X 6 19.3 96.5 0.7 0.8 0.1 0.2 0.3 0.4 0.4 2.9 3.8 Y 6 19.2 96 0.5 0.7 0.1 0.1 0.3 0.4 0.4 2.5 3.9 Z 6 19.5 97.5 0.7 0.7 0.2 0.5 0.3 2.3 3.9 X 9 18.9 94.5 1.0 1.1 0.2 0.3 0.4 0.2 0.1 3.7 3.8 Y 9 18.9 94.5 0.8 0.9 0.2 0.4 0.4 0.2 3.1 3.9 Z 9 19.2 96 0.9 1.0 0.2 0.5 0.3 2.9 3.8 X 12 18.6 93 1.4 1.5 0.1 0.3 0.3 0.4 0.5 0.2 0.1 4.8 3.7 Y 12 18.7 93.5 1.1 1.2 0.1 0.3 0.3 0.4 0.5 0.2 0.2 4.6 3.9 Z 12 18.9 94.5 1.3 1.4 0.3 0.5 0.4 0.3 0.2 4.2 3.8 X 13 18.4 92 1.5 1.6 0.2 0.3 0.3 0.4 0.1 0.4 0.3 0.1 0.1 5.4 3.8 Y 13 18.6 93 1.1 1.3 0.2 0.3 0.3 0.4 0.1 0.4 0.3 0.2 4.6 3.9 Z 13 18.8 94 1.3 1.5 0.3 0.5 0.1 0.3 0.4 0.2 0.1 4.7 3.8 X 14 18.6 93 1.5 1.7 0.1 0.4 0.3 0.4 0.1 0.4 0.3 0.1 5.4 3.8 Y 14 18.5 92.5 1.2 1.4 0.1 0.3 0.3 0.5 0.4 0.5 0.3 0.3 5.4 3.9 Z 14 18.8 94 1.3 1.5 0.3 0.5 0.1 0.3 0.5 0.2 0.2 5.0 3.8 X 15 18.4 92 1.6 1.8 0.1 0.4 0.3 0.4 0.1 0.4 0.3 0.2 5.7 3.8 Y 15 18.4 92 1.3 1.5 0.2 0.3 0.3 0.4 0.1 0.4 0.5 0.3 0.3 5.4 3.9 Z 15 18.6 93 1.5 1.6 0.3 0.5 0.2 0.4 0.2 0.3 5.1 3.9 The results from TABLES 53-54 indicate that stability of the vasopressin formulations was not significantly affected by either inverted or upright storage. The impurities detected included Gly9 (SEQ ID NO.: 2), Glu4 (SEQ ID NO.: 4), D-Asn (SEQ ID NO.: 10), Asp5 (SEQ ID NO.: 3), Acetyl-AVP (SEQ ID NO.: 7), vasopressin dimer, and several unidentified impurities (UI). The unidentified impurities are labeled with a range of relative retention times at which the impurities eluted from the column. The results indicate that the pH remained fairly constant over the 15-month period, fluctuating between 3.8 and 3.9 throughout the 15 months. The total impurities did not increase over 5.9%, and the % LC of vasopressin did not decrease below 92%. FIG. 19 shows a graph depicting the % LC over the 15-month study period for the results provided in TABLES 53-54. The starting amounts of vasopressin were 97.9% LC for lot X, 98.6% LC for lot Y, and 99.3% LC for lot Z. The results indicate that the % LC of vasopressin decreased over the 15-month study period, but did not decrease below 92% LC. The formula for the trend line of lot X was: % LC=98.6−0.4262(month) The formula for the trend line of lot Y was: % LC=98.47−0.4326(month) The formula for the trend line of lot Z was: % LC=99.54−0.3906(month) Example 16: Vasopressin Formulation for Bottle or Intravenous Drip-Bag The following formulations can be used without initial vasopressin dilution in drip-bags for intravenous therapy. TABLE 55 Formulation A (40 IU/100 mL) (10 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Sodium chloride (mg) 8.7 Acetic acid (mg) 0.546 Sodium Acetate Trihydrate (mg) 0.12 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 56 Formulation B (60 IU/100 mL) (10 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.6 Sodium chloride (mg) 8.7 Acetic acid (mg) 0.546 Sodium Acetate Trihydrate (mg) 0.12 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 57 Formulation C (40 IU/100 mL) (10 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Dextrose Anhydrous (mg) 50 Acetic acid (mg) 0.546 Sodium Acetate Trihydrate (mg) 0.12 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 58 Formulation D (60 IU/100 mL) (10 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.6 Dextrose Anhydrous (mg) 50 Acetic acid (mg) 0.546 Sodium Acetate Trihydrate (mg) 0.12 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 59 Formulation E (40 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Sodium chloride (mg) 8.7 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 60 Formulation F (60 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.6 Sodium chloride (mg) 8.7 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 61 Formulation G (40 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Dextrose Anhydrous (mg) 50 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 62 Formulation H (60 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.6 Dextrose Anhydrous (mg) 50 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 63 Formulation 9 (60 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Dextrose Anhydrous (mg) 45 Sodium Chloride (mg) 0.9 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Example 17: Impurity Measurement for Vasopressin Formulation for Bottle or Intravenous Drip-Bag Gradient HPLC was used to determine the concentration of vasopressin and associated impurities in vasopressin formulations similar to those outlined in TABLES 55-63 above. Vasopressin was detected in the eluent using UV absorbance at a short wavelength. The concentration of vasopressin in the sample was determined by the external standard method, where the peak area of vasopressin in sample injections was compared to the peak area of a vasopressin reference standard in a solution of known concentration. The concentrations of related peptide impurities in the sample were also determined using the external standard method, using the vasopressin reference standard peak area and a unit relative response factor. An impurities marker solution was used to determine the relative retention times of identified related peptides at the time of analysis. The chromatographic conditions used for the analysis are shown in TABLE 64 below: TABLE 64 Column Phenomenex Kinetex XB-C18, 2.6 μm, 100Å pore, 4.6 × 150 mm, Part No. 00F-4496-E0 Column 35° C. Temperature Flow Rate 1.0 mL/min Detector VWD: Signal at 215 nm Injection Volume 500 μL Run time 55 minutes Auto sampler Vials Amber glass vial Auto Sampler 10° C. Temperature Pump (gradient) Time (min) % A % B Flow 0 90 10 1.0 40 50 50 1.0 45 50 50 1.0 46 90 10 1.0 55 90 10 1.0 Diluent A was 0.25% v/v acetic acid, which was prepared by pipetting 2.5 mL of glacial acetic acid into a 1 L volumetric flask containing 500 mL of water. The volume was diluted with water and mixed well. Diluent B was prepared by weighing and transferring about 3 g of sodium chloride into a 1 L volumetric flask and then adding 2.5 mL of glacial acetic acid. The solution was diluted to volume with water and mixed well. Phosphate buffer at pH 3.0 was used for mobile phase A. The buffer was prepared by weighing approximately 15.6 g of sodium phosphate monobasic monohydrate into a beaker. 1000 mL of water was added, and mixed well. The pH was adjusted to 3.0 with phosphoric acid. The buffer was filtered through a 0.45 μm membrane filter under vacuum, and the volume was adjusted as necessary. An acetonitrile:water (50:50) solution was used for mobile phase B. To prepare mobile phase B, 500 mL of acetonitrile was mixed with 500 mL of water. The stock standard solution was prepared at 20 units/mL of vasopressin. A solution of vasopressin in diluent was prepared at a concentration of about 20 units/mL. The stock standard solution was prepared by quantitatively transferring the entire contents of 5 vials of USP Vasopressin RS with diluent A to the same 250-mL volumetric flask. The solution was diluted to volume with diluent A and mixed well. 10 mL aliquots of the standard solution was transferred into separate polypropylene tubes. The aliquots were stored at 2-8° C. The stock standard solution was stable for 6 months from the date of preparation when stored in individual polypropylene tubes at 2-8° C. The working standard solution contained about 0.5 units/mL of vasopressin. Aliquots of the stock standard solution were allowed to warm to room temperature and then mixed well. 2.5 mL of the stock standard solution was transferred into a 100 mL volumetric flask and diluted to volume with Diluent B, and the resultant mixture was denoted as the Working Standard Solution. The stock standard solution and working standard solution can also be prepared from a single vasopressin vial in the following manner. One vial of vasopressin with diluent A can be quantitatively transferred to a 50-mL volumetric flask. The solution can be dissolved in and diluted to volume with diluent A and mixed well, and denoted as the stock standard solution. To prepare the working standard solution, 2.5 mL of the stock standard solution was diluted to 100 mL with diluent B and mixed well. The working standard solution was stable for at least 72 hours when stored in refrigerator or in autosampler vial at 10° C. The intermediate standard solution was prepared by pipetting 1 mL of the working standard solution into a 50 mL volumetric flask. The solution was diluted to volume with diluent B and mixed well. The sensitivity solution (0.1% of 0.4 units/mL vasopressin formulation) was prepared by pipetting 2 mL of the intermediate standard solution into a 50 mL volumetric flask. The solution was diluted to the volume with diluent B and mixed well. The sensitivity solution was stable for at least 72 hours when stored in the refrigerator. To prepare the impurities marker solution, a 0.05% v/v acetic acid solution was prepared by pipetting 200 mL of a 0.25% v/v acetic acid solution into a 1 L volumetric flask. The solution was diluted to the desired volume with water and mixed well. To prepare the vasopressin impurity stock solutions, the a solution of each impurity as shown below was prepared in a 25 mL volumetric flask and diluted with 0.05% v/v acetic acid to a concentration suitable for HPLC injection. Gly-9 AVP: 0.09 mg/mL Glu-4 AVP: 0.08 mg/mL Asp-5 AVP: 0.1 mg/mL D-Asn AVP: 0.08 mg/mL Dimer AVP: 0.07 mg/mL Acetyl AVP: 0.08 mg/mL To prepare the MAA/H-IBA (Methacrylic Acid/α-Hydroxy-isobutyric acid) stock solution, a stock solution containing approximately 0.3 mg/mL H-IBA and 0.01 mg/mL in 0.05% v/v acetic acid was made in a 50 mL volumetric flask. To prepare the chlorobutanol diluent, about one gram of hydrous chlorobutanol was added to 500 mL of water. Subsequently, 0.25 mL of acetic acid was added and the solution was stirred to dissolve the chlorobutanol. To prepare the stock impurity marker solutions, 6.5 mg of vasopressin powder was added to a 500 mL volumetric flask. To the flask, the following quantities of the above stock solutions were added: Gly-9 AVP: 20.0 mL Glu-4 AVP: 20.0 mL Asp-5 AVP: 10.0 mL D-Asn AVP: 10.0 mL Dimer AVP: 10.0 mL Acetyl AVP: 20.0 mL H-IBA/MAA: 30.0 mL The solutions were diluted to volume with the chlorobutanol diluent. The solutions were aliquoted into individual crimp top vials and stored at 2-8° C. The solutions, stored at 2-8° C., were suitable for use as long as the chromatographic peaks could be identified based on comparison to the reference chromatogram. At time of use the solutions were removed from refrigerated (2-8° C.) storage and allowed to reach room temperature. The vasopressin stock impurity marker solution was stable for at least 120 hours when stored in autosampler vials at room temperature. The impurity marker solution were prepared by diluting 1 mL of the stock impurity marker solution to 50 mL with diluent B, and mixed well. The vasopressin impurity marker solution was stable for at least 72 hours when stored in the refrigerator. To begin the analysis, the HPLC system was allowed to equilibrate for at least 30 minutes using mobile phase B, followed by time 0 min gradient conditions until a stable baseline was achieved. Diluent B was injected at the beginning of the run, and had no peaks that interfered with vasopressin as shown in FIG. 20. A single injection of the sensitivity solution was performed, wherein the signal-to-noise ratio of the vasopressin was greater than or equal to ten as shown in FIG. 21. A single injection of the impurities marker solution was then made. The labeled impurities in the reference chromatogram were identified in the chromatogram of the marker solution based on their elution order and approximate retention times shown in FIG. 22 and FIG. 23. FIG. 23 is a zoomed-in chromatograph of FIG. 22 showing the peaks that eluted between 16 and 28 minutes. The nomenclature, structure, and approximate retention times for individual identified impurities are detailed in TABLE 3. A single injection of the working standard solution was made to ensure that the tailing factor of the vasopressin peak was less than or equal to about 2.0 as shown in FIG. 24. A total of five replicate injections of the working standard solution were made to ensure that the relative standard deviation (% RSD) of the five replicate vasopressin peak areas was not more than 2.0%. Following the steps above done to confirm system suitability, a single injection of the placebo and sample preparations was made. The chromatograms were analyzed to determine the vasopressin and impurity peak areas. The chromatogram for the placebo is depicted in FIG. 25, and the chromatogram for the sample preparation is shown in FIG. 26. Then, the working standard solution was injected after 1 to 10 sample injections, and the average of the bracketing standard peak areas were used in the calculations for vasopressin and impurity amounts. Additional injections of the impurities marker solution could be made to help track any changes in retention time for long chromatographic sequences. The relative standard deviation (% RSD) of vasopressin peak areas for the six injections of working standard solution was calculated by including the initial five injections from the system suitability steps above and each of the subsequent interspersed working standard solution injections. The calculations were done to ensure that each of the % RSD were not more than 2.0%. The retention time of the major peak in the chromatogram of the sample preparation corresponded to that of the vasopressin peak in the working standard solution injection that preceded the sample preparation injection. To calculate the vasopressin units/mL, the following formula was used: Vasopressin   units  /  mL = R U R S × Conc   STD where: RU=Vasopressin peak area response of Sample preparation. RS=average vasopressin peak area response of bracketing standards. Conc STD=concentration of the vasopressin standard in units/mL To identify the impurities, the % Impurity and identity for identified impurities (TABLE 3) that are were greater than or equal to 0.10% were reported. Impurities were truncated to 3 decimal places and then rounded to 2 decimal places, unless otherwise specified. The following formula was used: %   impurity = R 1 R s × Conc   STD L   C × 100  % where R1=Peak area response for the impurity; LC=label content of vasopressin (units/mL). The formulations used for the vasopressin and impurity studies are summarized in TABLE 65 below and correspond to several of the formulations detailed above in TABLES 55-63. TABLE 65 Lot Vasopressin (units/100 mL) Buffer Conc. (mM) Vehicle A 40 10 NaCl B 60 10 NaCl C 40 10 Dextrose D 60 10 Dextrose E 40 1 NaCl F 60 1 NaCl G 40 1 Dextrose H 60 1 Dextrose A1 40 1 Dextrose B1 60 1 Dextrose C1 40 1 Dextrose/NaCl The drug products detailed in TABLE 65 were tested for stability over a six month period. The vasopressin drug formulations were stored at 5° C., 25° C., or 40° C. for up to six months. At 0, 1, 2, 3, 4, 5, and 6 months, the amount of vasopressin (AVP), % label claim (LC), amount of various impurities, pH, and % reference standard was measured. The vasopressin and impurity amounts were determined using the HPLC method described above. The results of the stability experiment are shown in TABLES 66-72 below. TABLE 66 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT Condition Time Vasopressin 0.30 0.33 0.34 0.35 0.362 0.37 0.38 0.39 0.40 0.42 0.44 Lot (° C.) (m) pH (% LC) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 5 0 3.63 102.5 0.36 0.14 0.13 A 25 0 3.63 102.5 0.36 0.14 0.13 A 40 0 3.63 102.5 0.36 0.14 0.13 B 5 0 3.64 102.2 0.24 0.09 0.08 0.10 B 25 0 3.64 102.2 0.24 0.09 0.08 0.10 B 40 0 3.64 102.2 0.24 0.09 0.08 0.10 C 5 0 3.64 98.2 0.34 0.13 0.56 0.20 C 25 0 3.64 98.2 0.34 0.13 0.56 0.20 C 40 0 3.64 98.2 0.34 0.13 0.56 0.20 D 5 0 3.65 100.1 0.24 0.08 0.15 0.06 D 25 0 3.65 100.1 0.24 0.08 0.15 0.06 D 40 0 3.65 100.1 0.24 0.08 0.15 0.06 E 5 0 3.67 100.5 0.13 E 25 0 3.67 100.5 0.13 E 40 0 3.67 100.5 0.13 F 5 0 3.71 101.5 0.09 F 25 0 3.71 101.5 0.09 F 40 0 3.71 101.5 0.09 G 5 0 3.75 99.5 G 25 0 3.75 99.5 G 40 0 3.75 99.5 H 5 0 3.74 100.2 H 25 0 3.74 100.2 H 40 0 3.74 100.2 A1 5 0 3.86 97.5 A1 25 0 3.86 97.5 A1 40 0 3.86 97.5 B1 5 0 3.84 97.6 B1 25 0 3.84 97.6 B1 40 0 3.84 97.6 C1 5 0 3.78 99.3 C1 25 0 3.78 99.3 C1 40 0 3.78 99.3 A 5 1 3.62 101.6 0.37 0.15 0.11 A 25 1 3.63 101.5 0.34 0.19 A 40 1 3.61 98.2 0.27 0.18 B 5 1 3.61 102.2 0.25 0.12 0.06 0.13 B 25 1 3.63 101.0 0.24 0.11 B 40 1 3.63 97.2 0.19 0.65 C 5 1 3.66 99.7 0.37 0.11 0.79 C 25 1 3.65 98.7 0.36 0.17 C 40 1 3.66 93.8 0.60 0.19 D 5 1 3.66 101.1 0.24 0.08 D 25 1 3.65 99.8 0.24 0.11 D 40 1 3.66 92.4 0.41 0.11 E 5 1 3.67 101.0 E 25 1 3.67 99.2 E 40 1 3.68 95.5 F 5 1 3.71 101.5 0.08 F 25 1 3.72 100.1 F 40 1 3.71 96.6 0.12 G 5 1 3.71 99.8 G 25 1 3.76 99.0 G 40 1 3.75 94.2 0.34 0.26 H 5 1 3.76 99.8 H 25 1 3.77 99.5 H 40 1 3.77 97.0 0.23 A1 5 1 3.81 97.0 A1 25 1 3.82 96.8 A1 40 1 3.83 91.8 B1 5 1 3.82 97.5 B1 25 1 3.82 97.1 B1 40 1 3.82 92.0 C1 5 1 3.80 99.2 C1 25 1 98.5 C1 40 1 3.82 94.7 A 5 2 3.59 101.7 0.11 A 25 2 3.59 99.5 0.14 A 40 2 3.60 92.9 0.15 B 5 2 3.60 101.1 0.12 B 25 2 3.60 98.8 0.10 B 40 2 3.60 92.1 0.11 C 5 2 3.59 99.3 0.18 C 25 2 3.62 97.3 0.14 C 40 2 3.64 89.2 0.15 D 5 2 3.67 100.0 0.10 D 25 2 3.66 97.3 0.09 D 40 2 3.62 89.9 0.09 E 5 2 3.65 99.5 E 25 2 3.67 95.8 E 40 2 3.67 90.6 0.07 F 5 2 3.67 100.6 F 25 2 3.71 97.9 0.14 F 40 2 3.70 92.3 0.33 G 5 2 3.70 98.9 G 25 2 3.73 97.0 G 40 2 3.71 90.5 H 5 2 3.72 99.7 H 25 2 3.74 98.0 H 40 2 3.74 91.9 A1 5 2 3.77 97.3 A1 25 2 3.77 95.9 A1 40 2 3.78 86.1 B1 5 2 3.79 97.3 B1 25 2 3.78 96.5 B1 40 2 3.79 87.4 C1 5 2 3.73 99.3 C1 25 2 3.73 98.1 C1 40 2 3.74 91.0 A 5 3 3.59 102.0 0.31 A 25 3 3.61 99.5 0.30 A 40 3 3.60 90.8 0.30 B 5 3 3.59 101.8 0.24 B 25 3 3.60 98.8 0.22 B 40 3 3.60 90.3 0.22 C 5 3 3.62 99.8 0.16 C 25 3 3.62 95.5 0.15 C 40 3 3.62 87.0 0.16 D 5 3 3.62 91.4 0.10 D 25 3 3.63 97.7 0.20 D 40 3 3.63 87.6 0.18 E 5 3 3.63 96.9 E 25 3 3.64 96.3 E 40 3 3.65 88.8 0.23 F 5 3 3.67 100.8 F 25 3 3.68 97.9 0.23 F 40 3 3.70 90.0 0.20 G 5 3 3.73 98.8 0.16 G 25 3 3.72 97.5 0.07 G 40 3 3.74 88.6 H 5 3 3.71 99.8 0.04 H 25 3 3.74 98.5 H 40 3 3.75 89.1 A 5 4 3.59 99.9 0.22 A 25 4 3.56 96.8 0.20 A 40 4 3.70 84.5 0.31 B 5 4 3.58 99.4 0.11 B 25 4 3.56 95.4 0.17 B 40 4 3.67 83.0 1.37 C 5 4 3.61 98.5 0.18 C 25 4 3.63 94.9 0.18 C 40 4 3.64 81.3 0.18 D 5 4 3.62 98.9 0.12 D 25 4 3.62 94.5 0.07 0.09 D 40 4 3.61 82.1 0.13 E 5 4 3.63 97.6 E 25 4 3.69 94.0 E 40 4 3.63 83.2 0.26 F 5 4 3.68 98.9 0.08 F 25 4 3.69 95.3 0.19 F 40 4 3.70 84.6 0.24 G 5 4 3.68 98.1 G 25 4 3.69 95.8 G 40 4 3.84 83.2 H 5 4 3.67 98.6 H 25 4 3.62 93.1 0.13 0.12 H 40 4 3.76 83.6 A 5 5 3.63 99.7 0.10 A 25 5 3.63 95.8 B 5 5 3.63 99.0 0.25 B 25 5 3.64 95.1 C 5 5 3.68 98.2 C 25 5 3.67 93.7 D 5 5 3.67 98.7 D 25 5 3.69 94.6 E 5 5 3.69 97.5 E 25 5 3.69 93.1 0.09 F 5 5 3.71 98.4 0.05 0.14 F 25 5 3.74 94.4 0.15 G 5 5 3.74 97.2 G 25 5 3.78 93.1 1.73 H 5 5 3.76 97.7 H 25 5 3.76 95.7 A 5 6 3.57 101.0 A 25 6 3.49 95.4 A 5 6 3.57 100.0 A 25 6 3.49 94.5 B 5 6 3.54 100.2 B 25 6 3.49 95.7 B 5 6 3.54 99.3 0.12 0.13 B 25 6 3.49 94.6 C 5 6 3.59 98.1 C 25 6 3.56 95.1 C 5 6 3.59 98.0 C 25 6 3.56 93.5 D 5 6 3.55 100.0 D 25 6 3.56 95.8 D 5 6 3.55 98.6 0.10 D 25 6 3.56 94.2 E 5 6 3.54 98.1 E 25 6 3.56 94.1 E 5 6 3.54 97.0 E 25 6 3.56 92.3 F 5 6 3.60 99.0 F 25 6 3.61 95.0 F 5 6 3.60 98.2 0.10 0.14 F 25 6 3.61 93.8 0.21 G 5 6 3.61 98.2 G 25 6 3.66 96.1 G 5 6 3.61 96.5 G 25 6 3.66 94.4 H 5 6 3.64 98.6 H 25 6 3.65 97.0 H 5 6 3.64 96.9 H 25 6 3.65 95.3 Min 3.49 81.258 0 0 0 0.053 0.042 0 0.104 0 0.116 Max 3.84 102.047 0 0 0 0.153 1.371 0 1.731 0 0.116 TABLE 67 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT 0.47 0.48 0.49 0.50 0.510 0.52 0.56 0.57 0.58 0.61 0.63 0.64 0.646 0.67 0.68 0.70 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.63 A 0.63 A 0.63 B 0.20 B 0.20 B 0.20 C 0.18 8.74 C 0.18 8.74 C 0.18 8.74 D 0.10 9.43 D 0.10 9.43 D 0.10 9.43 E 1.55 E 1.55 E 1.55 F 0.23 0.22 F 0.23 0.22 F 0.23 0.22 G 0.12 0.44 G 0.12 0.44 G 0.12 0.44 H 0.08 0.27 H 0.08 0.27 H 0.08 0.27 A1 0.06 A1 0.06 A1 0.06 B1 B1 B1 C1 C1 C1 A 0.67 A 0.82 0.56 A 0.81 0.40 B 0.53 B 0.46 0.21 B 0.47 0.34 C 0.13 0.31 C 0.18 0.25 C 0.23 0.29 D 0.09 0.34 D 0.13 0.35 D 0.12 0.11 0.20 E 0.53 E 0.30 0.50 E 0.32 0.49 F 0.22 F 0.17 0.23 F 0.18 0.24 G 0.12 0.35 G 0.46 0.37 G 0.45 0.35 H 0.08 0.28 H 0.16 0.24 H 0.15 0.25 A1 A1 A1 0.06 B1 B1 B1 C1 C1 C1 A 0.24 0.76 A 0.06 0.73 A 0.05 0.83 B 0.04 0.40 B 0.04 0.42 B 0.12 0.45 0.05 C 0.17 0.13 C 0.15 0.16 C 0.10 0.07 D 0.14 D 0.05 0.13 D 0.04 0.05 E 0.26 E 0.27 E 0.09 F 0.15 F 0.07 0.18 F 0.29 G 0.56 G 0.06 0.54 0.08 G H 0.20 H 0.21 H 0.04 A1 A1 0.14 A1 B1 B1 B1 C1 C1 C1 A 0.09 0.72 A 0.14 0.49 A 0.12 0.47 B 0.07 0.36 B 0.06 0.47 B 0.05 0.44 0.05 C 0.14 0.41 C 0.13 0.57 C 0.09 0.39 D 0.99 0.28 D 0.05 0.42 D 0.27 0.05 E 0.06 0.60 E 0.57 E 1.03 F 0.42 0.31 F 0.10 0.33 F 0.10 0.35 G 0.39 G 0.09 0.51 G 0.50 H 0.32 H 0.37 H 0.25 A 0.84 0.59 A 0.82 0.29 A 0.87 0.39 B 0.47 0.23 B 0.50 0.43 B 0.55 0.45 0.08 C 0.21 0.15 C 0.23 0.25 C 0.25 0.34 D 0.18 0.27 D 0.24 0.39 D 0.19 0.25 0.08 E 0.31 0.58 E 0.33 0.51 E 0.36 0.67 F 0.18 0.21 F 0.19 0.27 F 0.20 0.26 G 0.59 0.40 G 0.59 0.36 G 0.62 0.40 H 0.20 0.22 H 0.25 0.20 0.31 0.11 H 0.25 0.26 0.09 A 0.61 A 0.48 B 0.27 B 0.43 C 0.29 C 0.15 0.30 D 0.14 0.28 D 0.08 0.40 E 0.53 E 0.49 F 0.24 F 0.24 G 0.14 0.39 G 0.17 0.44 H 0.10 0.23 H 0.13 0.28 A 0.62 A 0.30 A 0.65 0.62 A 0.70 0.30 0.19 B 0.61 B 0.26 B 0.38 0.62 B 0.38 0.26 0.11 C 0.49 C 0.17 0.30 C 0.14 C 0.25 0.31 0.21 D 0.10 0.26 D 0.10 0.31 D 0.11 0.26 0.09 D 0.09 0.13 0.32 0.12 E 1.04 E 0.64 E 0.21 1.07 E 0.22 0.60 F 0.08 0.21 F 0.22 F 0.11 0.08 0.19 F 0.12 0.19 G 0.14 0.38 G 0.14 0.18 0.36 G 0.45 0.16 0.42 0.22 G 0.45 0.18 0.19 0.35 0.35 H 0.10 0.20 H 0.10 0.28 H 0.15 0.11 0.20 0.12 H 0.15 0.12 0.28 0.22 Min 0.035 0 0.125 0 0.42 0.077 0.064 0.23 0.14 0.051 0.048 Max 0.986 0 0.555 0 0.42 0.203 0.064 0.624 1.03 0.052 0.109 TABLE 68 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT 0.71 0.72 0.74 0.76 0.77 0.78 0.79 0.80 0.82 0.84 0.86 0.87 0.88 0.91 0.94 0.95 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.15 0.29 A 0.15 0.29 A 0.15 0.29 B 0.08 0.32 B 0.08 0.32 B 0.08 0.32 C 0.15 0.29 C 0.15 0.29 C 0.15 0.29 D 0.10 0.30 D 0.10 0.30 D 0.10 0.30 E 0.28 E 0.28 E 0.28 F 0.32 F 0.32 F 0.32 G 0.20 0.31 G 0.20 0.31 G 0.20 0.31 H 0.12 0.30 H 0.12 0.30 H 0.12 0.30 A1 0.32 A1 0.32 A1 0.32 B1 0.30 B1 0.30 B1 0.30 C1 0.31 C1 0.31 C1 0.31 A 0.10 0.31 A 0.36 A 0.17 0.39 B 0.30 B 0.35 B 0.36 C 0.32 0.31 C 0.40 C 0.16 0.40 D 0.10 0.31 D 0.34 D 0.36 E 0.32 E 0.34 E 0.37 F 0.30 F 0.34 F 0.33 G 0.18 0.29 0.31 G 0.20 0.38 G 0.27 0.42 H 0.09 0.31 H 0.13 0.35 H 0.14 0.36 A1 0.10 0.29 A1 0.30 A1 0.29 B1 0.30 B1 0.30 B1 0.33 C1 0.31 C1 0.30 C1 0.30 A 0.12 0.33 A 0.12 0.36 A 0.15 0.42 B 0.34 B 0.07 0.36 B 0.10 0.41 C 0.12 0.41 C 0.15 0.36 C 0.17 0.40 D 0.09 0.36 D 0.11 0.35 D 0.10 0.37 E 0.33 E 0.21 0.31 0.05 E 0.10 0.36 F 0.36 F 0.34 F 0.37 G 0.20 0.33 G 0.22 0.34 G 0.33 0.41 H 0.11 0.35 H 0.13 0.34 H 0.19 0.36 A1 0.30 A1 0.31 A1 0.31 0.18 B1 0.30 B1 0.31 B1 0.29 0.15 C1 0.31 C1 0.31 C1 0.30 A A A B B B C C C D 0.49 D D E 0.25 0.16 0.38 E E F F F G G G H H H A 0.16 0.33 A 0.18 0.33 A 0.25 0.40 B 0.32 B 0.09 0.32 B 0.17 0.38 C 0.34 C 0.19 0.35 C 0.25 0.42 D 0.10 0.32 D 0.12 0.36 D 0.16 0.45 E 0.30 E 0.32 E 0.19 0.40 F 0.31 F 0.33 F 0.11 0.37 G 0.19 0.35 G 0.29 0.37 G 0.46 0.45 H 0.11 0.34 H 0.19 0.36 0.08 H 0.26 0.45 A 0.16 0.28 A 0.17 0.28 B 0.29 B 0.29 C 0.18 0.27 C 0.18 0.29 D 0.29 D 0.11 0.29 E 0.27 E 0.30 F 0.31 F 0.30 G 0.23 0.28 G 0.29 0.29 H 0.12 0.29 H 0.18 0.29 A 0.33 A 0.14 0.32 A 0.32 A 0.28 B 0.32 B 0.30 B 0.33 B 0.28 C 0.17 0.31 C 0.14 0.32 C 0.14 0.26 C 0.24 D 0.30 D 0.32 D 0.32 D 0.33 E 0.34 E 0.12 0.31 E 0.30 E 0.28 F 0.07 0.33 F 0.32 F 0.30 F 0.28 G 0.32 G 0.18 0.32 G 0.30 G 0.24 H 0.30 H 0.09 0.31 H 0.32 H 0.26 Min 0.112 0.252 0.087 0.092 0.213 0.301 0.161 0.053 Max 0.287 0.252 0.33 0.456 0.328 0.453 0.161 0.487 TABLE 69 D- Asn- RRT RRT RRT RRT RRT RRT Gly9- Asp5- Glu4- RRT RRT RRT RRT RRT RRT AVP 0.99 1.02 1.03 1.04 1.05 1.06 AVP AVP AVP 1.09 1.10 1.095 1.12 1.13 1.14 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.35 0.21 0.17 0.58 0.41 A 0.35 0.21 0.17 0.58 0.41 A 0.35 0.21 0.17 0.58 0.41 B 0.20 0.43 0.15 0.20 0.19 0.25 B 0.20 0.43 0.15 0.20 0.19 0.25 B 0.20 0.43 0.15 0.20 0.19 0.25 C 0.42 0.30 0.48 0.17 C 0.42 0.30 0.48 0.17 C 0.42 0.30 0.48 0.17 D 0.15 0.41 0.11 0.11 0.18 0.19 D 0.15 0.41 0.11 0.11 0.18 0.19 D 0.15 0.41 0.11 0.11 0.18 0.19 E 0.22 0.34 0.19 0.14 0.93 0.24 E 0.22 0.34 0.19 0.14 0.93 0.24 E 0.22 0.34 0.19 0.14 0.93 0.24 F 0.15 0.33 0.07 0.13 0.12 0.19 F 0.15 0.33 0.07 0.13 0.12 0.19 F 0.15 0.33 0.07 0.13 0.12 0.19 G 0.38 0.19 0.24 G 0.38 0.19 0.24 G 0.38 0.19 0.24 H 0.16 0.42 0.08 0.12 0.14 H 0.16 0.42 0.08 0.12 0.14 H 0.16 0.42 0.08 0.12 0.14 A1 0.12 0.12 0.24 0.08 0.10 0.09 A1 0.12 0.12 0.24 0.08 0.10 0.09 A1 0.12 0.12 0.24 0.08 0.10 0.09 B1 0.11 0.12 0.24 0.07 0.07 0.07 B1 0.11 0.12 0.24 0.07 0.07 0.07 B1 0.11 0.12 0.24 0.07 0.07 0.07 C1 0.12 0.12 0.25 0.09 0.10 0.08 C1 0.12 0.12 0.25 0.09 0.10 0.08 C1 0.12 0.12 0.25 0.09 0.10 0.08 A 0.47 0.63 0.39 0.70 0.51 A 0.33 0.41 0.46 0.61 0.44 A 0.31 1.28 0.65 1.52 0.18 B 0.19 0.43 0.26 0.25 0.58 0.27 B 0.12 0.31 0.39 0.20 0.52 B 0.11 0.31 0.29 0.44 1.47 0.23 C 0.42 0.21 0.20 0.15 C 0.66 0.19 0.24 0.40 0.16 C 0.16 1.71 0.58 0.55 0.43 0.86 0.17 D 0.43 0.09 0.18 0.17 D 0.13 0.75 0.23 0.13 0.38 0.17 D 0.18 1.71 0.57 1.43 0.82 0.14 E 0.34 0.17 0.25 0.23 E 0.32 0.32 0.25 0.41 0.23 E 0.28 1.06 0.39 1.21 0.29 F 0.17 0.36 0.12 0.17 0.14 0.20 F 0.17 0.35 0.36 0.18 0.41 0.11 F 0.14 0.29 1.06 0.34 1.13 G 0.36 0.17 0.26 G 0.45 0.18 0.25 0.20 G 0.68 0.38 0.33 0.52 H 0.37 0.07 0.11 0.16 H 0.15 0.45 0.15 0.24 0.13 H 0.17 0.82 0.45 0.18 0.60 A1 0.12 0.12 0.25 0.08 0.07 0.08 A1 0.11 0.12 0.24 0.14 0.13 0.10 A1 0.09 0.11 0.21 0.31 0.34 0.09 0.45 0.33 B1 0.11 0.12 0.25 0.07 0.07 0.07 B1 0.11 0.12 0.24 0.07 0.13 0.16 0.18 B1 0.10 0.11 0.21 0.33 0.33 0.09 0.41 0.72 C1 0.12 0.13 0.26 0.08 0.10 0.08 C1 0.11 0.13 0.25 0.18 0.18 0.10 C1 0.11 0.12 0.23 0.27 0.52 0.13 0.64 0.10 A 0.10 0.55 0.43 0.66 0.26 0.54 A 0.06 0.38 0.81 0.66 0.90 0.05 A 0.26 2.40 0.87 0.19 B 0.14 0.36 0.20 0.18 0.27 0.13 B 0.12 0.30 0.68 0.31 0.77 0.07 B 0.20 0.32 2.42 0.74 2.51 C 0.37 0.15 0.21 0.21 0.05 0.22 C 0.10 0.88 0.29 0.17 0.49 0.15 C 0.14 2.08 1.00 0.46 1.42 D 0.14 0.52 0.19 0.11 0.21 0.11 D 0.13 1.04 0.38 0.21 0.50 0.16 D 0.13 2.15 1.03 0.50 1.41 E 0.44 0.25 0.27 0.24 0.30 E 0.41 0.71 0.33 0.73 0.24 E 0.23 2.09 0.58 2.38 F 0.11 0.34 0.17 0.11 0.19 0.09 F 0.19 0.33 0.58 0.25 0.60 0.07 F 0.14 0.24 2.08 0.63 2.06 G 0.06 0.38 0.16 0.22 0.20 0.17 G 0.54 0.28 0.20 0.34 0.11 G 0.12 0.90 0.83 0.57 1.18 H 0.21 0.54 0.21 0.10 0.19 0.12 H 0.22 0.69 0.30 0.10 0.32 0.14 H 0.16 0.91 0.74 0.29 1.05 A1 0.11 0.14 0.24 0.08 0.08 A1 0.13 0.14 0.23 0.18 0.20 0.20 A1 0.10 0.12 0.21 0.50 0.56 0.14 0.67 0.10 B1 0.12 0.12 0.24 0.08 0.08 B1 0.12 0.13 0.23 0.18 0.20 0.04 0.21 B1 0.10 0.11 0.20 0.52 0.55 0.15 0.73 0.06 C1 0.12 0.13 0.25 0.10 0.09 C1 0.14 0.13 0.24 0.28 0.29 C1 0.10 0.13 0.21 0.43 0.89 0.22 1.14 0.07 A 0.10 0.29 0.31 0.52 0.36 0.62 A 0.10 0.97 0.62 1.17 0.19 A 0.09 3.45 1.20 3.64 0.20 B 0.11 0.25 0.21 0.31 0.11 0.06 B 0.12 0.94 0.37 1.13 0.22 B 0.09 3.37 0.88 0.36 0.22 C 0.09 0.15 0.10 0.20 0.15 C 0.10 0.93 0.45 0.24 0.61 0.19 C 0.08 2.15 1.29 0.66 2.00 D 5.25 0.31 0.16 D 0.10 1.05 0.46 0.23 0.66 0.11 D 0.09 2.18 1.29 0.56 1.77 E 0.82 0.30 0.22 0.27 0.28 E 0.09 0.87 0.47 0.99 0.21 E 0.09 2.93 0.77 3.30 F 0.11 0.22 0.12 0.25 0.08 F 0.11 0.81 0.36 0.84 0.09 F 0.09 2.79 0.73 2.91 G 0.10 0.14 0.15 0.15 0.13 G 0.10 0.37 0.34 0.53 0.12 G 0.73 0.89 0.64 1.22 0.07 H 0.11 0.11 0.06 0.16 0.08 H 0.09 0.31 0.08 0.43 0.08 H 0.69 0.86 0.34 1.26 A 0.33 0.18 0.22 0.07 0.18 0.25 A 0.29 1.14 0.31 1.24 0.17 A 0.27 4.38 1.21 4.48 B 0.12 0.32 0.19 0.14 0.15 B 0.14 0.30 1.16 0.34 0.95 0.05 B 0.14 0.27 4.31 1.01 4.71 0.06 C 0.38 0.10 0.12 0.08 0.09 C 0.38 0.95 0.51 0.26 0.48 C 2.09 1.48 0.68 2.32 D 0.14 0.42 0.13 0.07 0.09 D 0.16 0.41 0.94 0.53 0.34 0.52 D 2.10 1.47 0.54 2.29 E 0.32 0.17 0.21 0.09 0.17 E 0.29 1.02 0.34 1.29 E 0.24 3.78 0.89 4.08 F 0.14 0.32 0.19 0.06 0.15 F 0.12 0.29 0.95 0.26 1.08 F 0.14 0.27 3.55 0.84 3.64 G 0.36 0.11 0.07 0.10 G 0.48 0.18 0.39 0.17 0.37 G 0.43 0.47 1.06 0.42 1.66 0.17 H 0.16 0.39 0.11 0.09 H 0.23 0.46 0.21 0.45 0.39 0.61 H 0.18 0.45 0.52 1.08 0.48 1.72 A 0.15 0.51 0.26 0.62 0.27 0.24 A 0.14 0.52 1.41 0.40 1.71 0.28 B 0.19 0.49 0.06 0.27 0.24 0.28 B 0.20 0.55 1.53 0.38 1.54 0.37 C 0.64 0.13 0.20 0.16 C 0.16 1.86 0.69 0.20 0.75 0.24 D 0.14 0.66 0.18 0.20 0.18 D 0.15 1.76 0.72 0.25 0.80 0.16 E 0.19 0.43 0.25 0.40 0.27 E 0.35 1.24 0.55 1.37 F 0.16 0.41 0.26 0.18 0.29 F 0.12 0.38 1.15 0.39 1.23 G 0.10 0.41 0.12 0.21 0.17 G 0.74 0.52 0.11 0.68 0.24 H 0.11 0.44 0.12 0.14 0.17 H 0.13 0.77 0.51 0.16 0.60 0.16 A 0.12 0.13 0.27 0.09 0.84 0.22 A 0.10 0.13 0.24 1.84 0.31 1.57 0.15 A 0.30 0.21 0.48 0.13 A 0.75 1.62 0.45 1.38 B 0.13 0.13 0.25 0.07 0.77 0.22 B 0.12 0.13 0.23 1.67 0.33 1.61 B 0.19 0.33 0.24 0.56 0.20 B 0.12 0.37 1.64 0.42 1.73 C 0.12 0.13 0.24 0.21 0.22 0.14 0.10 C 0.12 0.13 0.20 1.31 0.90 0.12 0.77 C 0.16 0.90 0.25 0.34 0.31 C 1.70 0.71 0.40 0.79 D 0.13 0.13 0.23 0.12 0.28 0.13 0.06 D 0.11 0.13 0.21 1.32 0.81 0.13 0.79 0.05 D 0.15 0.46 0.19 0.16 0.14 D 0.15 1.72 0.75 0.33 0.83 E 0.11 0.13 0.25 0.12 0.86 0.20 0.06 E 0.12 0.24 1.65 0.25 1.41 E 0.30 0.09 0.21 0.66 0.20 E 0.34 1.44 0.59 1.51 F 0.15 0.14 0.25 0.06 0.30 0.20 0.06 F 0.12 0.12 0.25 1.36 0.26 1.30 0.05 F 0.17 0.35 0.25 0.13 0.21 F 0.19 0.36 0.39 1.30 1.40 G 0.13 0.14 0.24 0.39 0.11 0.13 G 0.12 0.14 0.22 0.33 0.72 0.09 0.64 G 0.36 0.17 0.19 0.12 G 0.27 0.76 0.33 0.58 0.54 H 0.12 0.13 0.24 0.24 0.12 0.05 H 0.13 0.13 0.22 0.39 0.59 0.09 0.56 0.06 H 0.18 0.43 0.21 0.15 0.16 H 0.15 0.81 0.30 0.56 0.61 Min 0.057 0.234 0.055 0.079 0.042 0.071 0.182 0.051 0.059 Max 0.231 2.177 0.501 4.376 5.246 4.713 0.182 0.622 0.1 TABLE 70 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT AVP Acetyl- RRT RRT RRT RRT 1.16 1.168 1.19 1.20 1.206 1.23 1.24 1.25 1.26 1.27 Dimer AVP 1.32 1.33 1.34 1.35 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.33 0.35 A 0.33 0.35 A 0.33 0.35 B 0.07 0.33 B 0.07 0.33 B 0.07 0.33 C 0.22 0.22 C 0.22 0.22 C 0.22 0.22 D 0.08 0.23 D 0.08 0.23 D 0.08 0.23 E 0.55 0.53 E 0.55 0.53 E 0.55 0.53 F 0.34 F 0.34 F 0.34 G 0.23 G 0.23 G 0.23 H 0.23 H 0.23 H 0.23 A1 0.21 0.28 A1 0.21 0.28 A1 0.21 0.28 B1 0.21 0.29 B1 0.21 0.29 B1 0.21 0.29 C1 0.14 0.29 C1 0.14 0.29 C1 0.14 0.29 A 0.37 0.22 0.13 A 0.20 0.60 A 0.59 B 0.26 0.35 B 0.49 B 0.48 C 0.24 C 0.46 0.26 C 0.44 0.73 0.25 D 0.07 0.22 D 0.35 0.25 D 0.41 0.27 E 0.12 0.43 E 0.72 E 0.68 F 0.07 0.35 F 0.55 F 0.53 G 0.29 G 0.54 0.27 G 0.54 0.40 H 0.21 0.12 H 0.56 0.17 H 0.55 0.17 A1 0.23 0.28 A1 0.21 0.27 A1 0.25 0.27 B1 0.22 0.28 B1 0.21 0.28 B1 0.13 0.27 C1 0.14 0.27 C1 0.15 0.28 C1 0.15 0.28 A 0.58 0.47 A 0.76 A 0.06 0.08 0.32 0.51 B 0.34 B 0.07 0.51 B 0.06 0.07 0.25 0.52 C 0.54 0.25 0.26 C 0.58 0.19 0.20 C 0.41 0.26 D 0.49 0.15 0.23 D 0.47 0.25 0.24 D 0.32 0.03 0.25 E 0.34 0.40 E 0.20 0.51 E 0.06 0.76 F 0.12 0.33 F 0.10 0.77 F 0.04 0.58 G 0.62 0.25 0.23 G 0.62 0.18 G 0.52 0.25 H 0.56 0.09 0.42 H 0.59 0.16 0.38 H 0.56 0.46 A1 0.20 0.30 A1 0.20 0.29 A1 0.28 0.29 B1 0.23 0.32 B1 0.23 0.28 B1 0.12 0.28 C 1 0.13 0.28 C1 0.13 0.32 C1 0.16 0.28 A 0.08 0.62 0.55 A 0.32 0.80 A 0.14 0.21 0.51 B 0.18 0.42 B 0.45 0.64 B 0.13 0.22 0.49 0.05 C 0.42 0.27 C 0.39 0.31 0.28 C 0.38 0.19 0.29 D 0.37 0.21 D 0.40 0.15 0.23 D 0.39 0.09 0.24 E 0.19 0.31 E 0.25 0.93 E 0.10 0.22 0.77 F 0.23 0.51 F 0.69 F 0.09 0.07 0.51 G 0.52 0.22 0.24 G 0.52 0.32 0.24 G 0.51 0.06 0.46 H 0.53 0.04 0.46 H 0.53 0.42 H 0.55 0.50 A 0.29 0.43 A 0.55 A 0.23 0.11 0.58 B 0.10 0.39 B 0.24 0.31 B 0.24 0.13 0.14 0.50 C 0.35 0.44 0.21 C 0.42 0.95 0.22 C 0.39 0.49 0.24 D 0.39 0.11 0.22 D 0.39 0.82 0.24 D 0.38 0.70 0.25 E 0.23 0.50 E 0.57 0.88 E 0.18 0.17 0.73 F 0.26 0.32 F 0.08 0.07 0.74 F 0.15 0.09 0.59 G 0.49 0.21 0.21 G 0.51 0.48 0.23 G 0.49 0.14 0.19 H 0.51 0.12 0.38 H 0.54 0.80 0.45 H 0.53 0.30 0.49 A 0.22 0.56 A 0.14 0.21 0.70 B 0.08 0.41 B 0.21 0.12 0.53 C 0.65 0.21 C 0.17 0.21 D 0.38 0.22 D 0.53 0.23 E 0.16 0.14 0.46 E 0.11 0.19 0.99 0.10 F 0.06 0.13 0.45 F 0.07 0.12 0.65 0.07 G 0.80 0.21 G 0.42 0.23 0.15 H 0.48 0.20 0.15 H 0.67 0.21 0.12 A 0.22 0.37 0.25 A 0.29 0.23 A 0.30 0.54 A 0.69 B 0.17 0.41 0.23 B 0.14 0.22 B 0.34 0.28 B 0.52 C 0.24 0.34 C 0.29 0.37 0.25 C 0.19 0.25 C 0.42 0.21 D 0.24 0.22 D 0.20 0.26 0.23 D 0.30 0.20 D 0.37 0.23 E 0.32 0.57 0.22 E 0.23 0.18 0.20 E 0.43 0.65 E 0.16 0.91 F 0.14 0.14 0.21 F 0.14 0.09 0.21 F 0.44 F 0.70 0.08 G 0.33 0.39 0.22 G 0.26 0.35 0.23 G 0.37 0.24 G 0.37 0.20 H 0.14 0.32 0.22 0.16 H 0.14 0.33 0.21 0.23 H 0.40 0.19 0.18 H 0.42 0.21 0.20 Min 0.086 0 0.057 0 0.034 0.042 0.193 0.047 0.147 Max 0.341 0 0.796 0 0.061 0.623 0.986 0.047 0.147 TABLE 71 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT 1.37 1.44 1.45 1.46 1.47 1.48 1.55 1.57 1.59 1.62 1.68 1.70 1.71 1.72 1.80 1.82 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.32 A 0.32 A 0.32 B 0.18 B 0.18 B 0.18 C 0.15 C 0.15 C 0.15 D 0.16 D 0.16 D 0.16 E 0.61 E 0.61 E 0.61 F 0.58 F 0.58 F 0.58 G 1.34 G 1.34 G 1.34 H 1.05 H 1.05 H 1.05 A1 A1 A1 B1 B1 B1 C1 C1 C1 A 0.21 2.16 A A B 1.67 B B C 3.37 C C D 2.40 D D E 0.16 3.70 E E F 2.61 F F G 4.10 G G H 2.79 H H A1 A1 A1 B1 B1 B1 0.06 C1 C1 C1 A 0.10 A A B B B C C C D D D E E E 0.14 F F F 0.10 G G G H H H A1 0.09 A1 0.09 A1 0.10 B1 0.06 B1 0.07 B1 0.05 C1 0.14 C1 0.13 C1 0.12 A 0.25 A 0.32 A 0.35 B 0.16 B 0.14 B 0.14 C C C D 0.14 D D E 0.09 E 0.12 E 0.20 F 0.06 0.08 F 0.10 F 0.14 G G G H H H 0.07 0.13 A 0.19 0.16 A 0.29 0.16 A 0.24 B 0.07 B 0.07 0.11 B 0.21 0.12 C C 0.14 C D 0.11 D 0.10 0.07 D 0.08 0.16 E E 0.13 E 0.13 F 0.12 F 0.08 F 0.08 0.06 0.23 G 0.16 G G 0.17 H H 0.20 0.14 H 0.11 0.21 A 0.23 A 0.33 B 0.12 B 0.11 C C D D E 0.11 E 0.13 F F 0.09 G G 0.36 H H A 0.44 0.32 0.16 A 0.48 0.23 0.21 0.12 A 0.26 A 0.27 B 0.12 0.16 B 0.33 0.15 0.10 0.07 B B 0.16 C 0.21 C 0.20 C C 2.69 D 0.08 D 0.30 0.08 D D 1.83 E 0.51 0.13 0.16 0.10 E 0.73 0.14 0.72 E 0.11 E 0.16 2.74 F 0.34 0.10 0.07 F 0.53 0.09 0.06 F F 0.10 1.80 G 0.36 G 0.15 G G 2.69 H H 0.17 H H 1.81 Min 0 0.059 0.077 0.07 0.128 Max 0 0.347 0.213 0.07 0.138 TABLE 72 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT Total 1.85 1.89 1.93 1.96 2.00 2.01 2.04 2.08 2.11 2.12 2.13 2.15 2.16 2.17 2.304 Imp Lot (%) %) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 4.44 A 4.44 A 4.44 B 3.10 B 3.10 B 3.10 C 12.55 C 12.55 C 12.55 D 0.07 0.09 0.55 0.15 12.92 D 0.07 0.09 0.55 0.15 12.92 D 0.07 0.09 0.55 0.15 12.92 E 0.18 5.89 E 0.18 5.89 E 0.18 5.89 F 2.77 F 2.77 F 2.77 G 3.45 G 3.45 G 3.45 H 0.69 3.66 H 0.69 3.66 H 0.69 3.66 A1 1.61 A1 1.61 A1 1.61 B1 1.48 B1 1.48 B1 1.48 C1 1.50 C1 1.50 C1 1.50 A 0.66 8.15 A 5.34 A 6.74 B 5.67 B 3.40 B 5.33 C 6.91 C 3.72 C 7.74 D 4.71 D 3.55 D 6.86 E 6.24 E 3.38 E 5.09 F 4.78 F 2.86 F 4.35 G 6.42 G 1.08 4.39 G 4.93 H 4.60 H 2.73 H 4.07 A1 1.60 A1 1.63 A1 2.80 B1 1.50 B1 1.80 B1 0.44 3.53 C1 1.49 C1 1.66 C1 2.85 A 5.25 A 5.03 A 6.29 B 2.52 B 3.83 B 8.35 C 3.27 C 0.85 4.84 C 6.65 D 2.80 D 4.10 D 6.47 E 0.23 2.82 E 3.98 E 6.87 F 1.96 F 3.61 F 6.85 G 3.37 G 3.51 G 5.10 H 3.10 H 3.57 H 4.76 A1 1.53 A1 2.10 A1 3.55 B1 1.56 B1 1.98 B1 3.31 C1 1.57 C1 1.97 C1 4.05 A 4.82 A 5.39 A 10.68 B 2.48 B 4.73 B 6.71 C 2.09 C 4.34 C 7.69 D 8.29 D 4.06 D 7.10 E 3.57 7.50 E 4.50 E 9.64 F 2.39 F 3.65 F 7.97 G 2.19 G 3.21 G 5.08 H 1.91 H 2.31 H 4.64 A 0.17 0.14 0.06 4.79 A 5.96 A 13.72 B 2.60 B 0.65 5.84 B 14.85 C 2.66 C 5.50 C 9.14 D 2.67 D 0.08 1.22 7.08 D 9.22 E 2.87 E 5.66 E 12.07 F 2.35 F 4.64 F 10.81 G 3.23 G 4.42 G 7.12 H 2.63 H 0.31 0.11 0.08 6.71 H 0.08 7.46 A 4.23 A 6.75 B 2.94 B 0.09 6.36 C 2.72 C 0.13 5.32 D 2.67 D 5.46 E 3.19 E 5.90 F 2.66 F 4.95 G 3.05 G 6.37 H 2.55 H 4.20 A 4.36 A 6.67 A 3.81 A 6.62 B 3.60 B 5.66 B 3.71 B 5.98 C 0.14 3.05 C 5.58 C 2.93 C 0.18 8.12 D 2.28 D 5.34 D 2.48 D 7.20 E 5.11 E 6.93 E 4.22 E 8.94 F 2.83 F 5.10 F 2.47 F 7.12 G 3.26 G 4.42 G 2.98 G 7.49 H 2.35 H 4.04 H 2.80 H 6.09 Min 0 0 0 3.565 0 0 1.533 Max 0 0 0 3.565 0 0 14.845 TABLE 73 RRT RRT RRT RRT D-ASN- RRT RRT RRT RRT Condition Time AVP 0.64 0.86 0.87 0.95 AVP 0.99 1.03 1.04 1.05 Lot (° C.) (m) pH (% LC) (%) (%) (%) (%) (%) (%) (%) (%) (%) A1 5 0 3.86 97.5 0.06 0.32 0.12 0.12 0.24 A1 25 0 3.86 97.5 0.06 0.32 0.12 0.12 0.24 A1 40 0 3.86 97.5 0.06 0.32 0.12 0.12 0.24 B1 5 0 3.84 97.6 0.30 0.11 0.12 0.24 B1 25 0 3.84 97.6 0.30 0.11 0.12 0.24 B1 40 0 3.84 97.6 0.30 0.11 0.12 0.24 C1 5 0 3.78 99.3 0.31 0.12 0.12 0.25 C1 25 0 3.78 99.3 0.31 0.12 0.12 0.25 C1 40 0 3.78 99.3 0.31 0.12 0.12 0.25 A1 5 1 3.81 97.0 0.10 0.29 0.12 0.12 0.25 A1 25 1 3.82 96.8 0.30 0.11 0.12 0.24 A1 40 1 3.83 91.8 0.06 0.29 0.09 0.11 0.21 B1 5 1 3.82 97.5 0.30 0.11 0.12 0.25 B1 25 1 3.82 97.1 0.30 0.11 0.12 0.24 B1 40 1 3.82 92.0 0.33 0.10 0.11 0.21 C1 5 1 3.80 99.2 0.31 0.12 0.13 0.26 C1 25 1 98.5 0.30 0.11 0.13 0.25 C1 40 1 3.82 94.7 0.30 0.11 0.12 0.23 A1 5 2 3.77 97.3 0.30 0.11 0.14 0.24 A1 25 2 3.77 95.9 0.14 0.31 0.13 0.14 0.23 0.18 A1 40 2 3.78 86.1 0.31 0.18 0.10 0.12 0.21 0.50 B1 5 2 3.79 97.3 0.30 0.12 0.12 0.24 B1 25 2 3.78 96.5 0.31 0.12 0.13 0.23 0.18 B1 40 2 3.79 87.4 0.29 0.15 0.10 0.11 0.20 0.52 C1 5 2 3.73 99.3 0.31 0.12 0.13 0.25 C1 25 2 3.73 98.1 0.31 0.14 0.13 0.24 C1 40 2 3.74 91.0 0.30 0.10 0.13 0.21 0.43 A1 5 3 3.80 95.8 0.28 0.12 0.22 A1 25 3 3.78 94.0 0.28 0.13 0.21 0.11 A1 40 3 3.81 82.2 0.28 0.16 0.11 0.15 0.29 B1 5 3 3.82 96.5 0.28 0.11 0.13 0.23 B1 25 3 3.82 94.8 0.29 0.12 0.13 0.21 0.11 B1 40 3 3.83 82.0 0.27 0.06 0.09 0.11 0.14 0.33 C1 5 3 3.75 97.5 0.29 0.12 0.13 0.24 C1 25 3 3.75 96.8 0.29 0.13 0.14 0.22 C1 40 3 3.75 85.5 0.27 0.11 0.16 0.26 Min 3.78 91.842 0.061 0.093 0 Max 3.86 99.282 0.063 0.124 0 TABLE 74 RRT GLY9- ASP5- GLU4- RRT RRT RRT RRT RRT RRT RRT RRT 1.06 AVP AVP AVP 1.12 1.13 1.23 1.24 1.25 ACETYL- 1.57 1.71 1.77 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) AVP (%) (%) (%) (%) A1 0.08 0.10 0.09 0.21 0.28 A1 0.08 0.10 0.09 0.21 0.28 A1 0.08 0.10 0.09 0.21 0.28 B1 0.07 0.07 0.07 0.21 0.29 B1 0.07 0.07 0.07 0.21 0.29 B1 0.07 0.07 0.07 0.21 0.29 C1 0.09 0.10 0.08 0.14 0.29 C1 0.09 0.10 0.08 0.14 0.29 C1 0.09 0.10 0.08 0.14 0.29 A1 0.08 0.07 0.08 0.23 0.28 A1 0.14 0.13 0.10 0.21 0.27 A1 0.31 0.34 0.09 0.45 0.33 0.25 0.27 B1 0.07 0.07 0.07 0.22 0.28 B1 0.07 0.13 0.16 0.18 0.21 0.28 B1 0.33 0.33 0.09 0.41 0.72 0.13 0.27 0.06 C1 0.08 0.10 0.08 0.14 0.27 C1 0.18 0.18 0.10 0.15 0.28 C1 0.27 0.52 0.13 0.64 0.10 0.15 0.28 A1 0.08 0.08 0.20 0.30 0.09 A1 0.20 0.20 0.20 0.29 0.09 A1 0.56 0.14 0.67 0.10 0.28 0.29 0.10 B1 0.08 0.08 0.23 0.32 0.06 B1 0.20 0.04 0.21 0.23 0.28 0.07 B1 0.55 0.15 0.73 0.06 0.12 0.28 0.05 C1 0.10 0.09 0.13 0.28 0.14 C1 0.28 0.29 0.13 0.32 0.13 C1 0.89 0.22 1.14 0.07 0.16 0.28 0.12 A1 0.09 0.09 0.18 0.29 A1 0.26 0.29 0.21 0.28 A1 0.73 0.18 0.82 0.19 0.11 0.27 B1 0.09 0.09 0.19 0.28 B1 0.25 0.25 0.20 0.28 B1 0.73 0.19 0.82 0.09 0.09 0.07 0.28 0.06 C1 0.10 0.10 0.13 0.28 C1 0.35 0.38 0.11 0.28 C1 1.22 0.30 1.56 0.12 0.15 0.27 Min 0.07 0.089 0.067 0.073 0 0.27 Max 0.344 0.089 0.448 0.326 0 0.288 TABLE 75 RRT RRT RRT Total RS Lot 1.85 (%) 1.91 (%) RRRT 2.02 (%) 2.37 (%) (%) A1 1.61 A1 1.61 A1 1.61 B1 1.48 B1 1.48 B1 1.48 C1 1.50 C1 1.50 C1 1.50 A1 1.60 A1 1.63 A1 2.80 B1 1.50 B1 1.80 B1 0.44 3.53 C1 1.49 C1 1.66 C1 2.85 A1 1.53 A1 2.10 A1 3.55 B1 1.56 B1 1.98 B1 3.31 C1 1.57 C1 1.97 C1 4.05 A1 1.26 A1 1.76 A1 3.29 B1 1.40 B1 1.82 B1 0.10 0.10 0.17 3.68 C1 1.38 C1 1.89 C1 4.41 Min 1.483 Max 2.799 The appearance for all of the tested lots through the duration of the experiment was clear and colorless. The results above provided an estimated shelf life at 5° C. of about 16.1 months (FIG. 27) and at 25° C. of about eight months (FIG. 28). The results indicated that the dextrose vehicle with 1 mM acetate buffer provided a lower rate of degradation and a lower rate of impurities accumulation for the vasopressin formulations at 5° C., 25° C., and 40° C. compared to NaCl or a combination of dextrose and NaCl in either 1 mM or 10 mM acetate buffer Graphical depictions of TABLES 66-72 are shown in FIGS. 29-48 below. FIGS. 29-31 show the vasopressin (% LC) levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 32-34 show the total impurities (total RS (%)) levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 35-37 show the Gly9-AVP levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 38-40 show the Asp5-AVP levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 41-43 show the Glu4-AVP levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 44-46 show the Acetyl-AVP levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 47-48 show the AVP dimer levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. Based on the data from FIGS. 29-48, the estimated shelf-life at 5° C. is about 16.1 months, and the estimated shelf-life at 25° C. is about 8 months. TABLES 73-75 display data of further studies on Formulations A1, B1, and C1 as detailed in TABLE 65. The appearance for all of the tested lots through the duration of the experiment was clear and colorless. The estimated shelf life at 5° C. of about 15 months and at 25° C. of about 7.7 months is shown below in FIG. 49 and FIG. 50, respectively. The results indicated that the dextrose vehicle provided a lower rate of degradation and a lower rate of impurities accumulation for the vasopressin formulations at 5° C., 25° C., and 40° C. compared to a combination of dextrose and NaCl. Graphical depictions of TABLES 73-75 are shown in FIGS. 51-62 below. FIGS. 51-53 show the vasopressin (% LC) levels in the samples prepared in dextrose or dextrose and NaCl at 5° C., 25° C., and 40° C., respectively. FIGS. 54-56 show the Gly9-AVP levels in the samples prepared in dextrose or dextrose and NaCl at 5° C., 25° C., and 40° C., respectively. FIGS. 57-59 show the Glu4-AVP levels in the samples prepared in dextrose or dextrose and NaCl at 5° C., 25° C., and 40° C., respectively. FIGS. 60-62 show the total impurities (% RS) levels in the samples prepared in dextrose or dextrose and NaCl at 5° C., 25° C., and 40° C., respectively. EMBODIMENTS The following non-limiting embodiments provide illustrative examples of the invention, but do not limit the scope of the invention. In some embodiments, the invention provides a pharmaceutical composition comprising, in a unit dosage form: a) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin, or a pharmaceutically-acceptable salt thereof; and b) a polymeric pharmaceutically-acceptable excipient in an amount that is from about 1% to about 10% by mass of the unit dosage form or the pharmaceutically-acceptable salt thereof, wherein the unit dosage form exhibits from about 5% to about 10% less degradation of the vasopressin or the pharmaceutically-acceptable salt thereof after storage for about 1 week at about 60° C. than does a corresponding unit dosage form, wherein the corresponding unit dosage form consists essentially of: A) vasopressin, or a pharmaceutically-acceptable salt thereof; and B) a buffer having acidic pH. In some embodiments, the polymeric pharmaceutically-acceptable excipient comprises a polyalkylene oxide moiety. In some embodiments, the polymeric pharmaceutically-acceptable excipient is a polyethylene oxide. In some embodiments, the polymeric pharmaceutically-acceptable excipient is a poloxamer. In some embodiments, the unit dosage form has an amount of the polymeric pharmaceutically-acceptable excipient that is about 1% the amount of the vasopressin or the pharmaceutically-acceptable salt thereof. In some embodiments, the first unit dosage form exhibits about 10% less degradation of the vasopressin or the pharmaceutically-acceptable salt thereof after storage for about 1 week at about 60° C. than does the corresponding unit dosage form. In some embodiments, the unit dosage form further comprises SEQ ID NO. 2. In some embodiments, the composition further comprises SEQ ID NO. 3. In some embodiments, the composition further comprises SEQ ID NO. 4. In some embodiments, the unit dosage form is an injectable of about 1 mL volume. In some embodiments, the unit dosage form consists essentially of: a) about 0.04 mg/mL of vasopressin, or the pharmaceutically-acceptable salt thereof; b) the polymeric pharmaceutically-acceptable excipient in an amount that is from about 1% to about 10% by mass of the vasopressin or the pharmaceutically-acceptable salt thereof; and c) a plurality of peptides, wherein each of the peptides has from 88% to 90% sequence homology to the vasopressin or the pharmaceutically-acceptable salt thereof. In some embodiments, one of the plurality of peptides is SEQ ID NO.: 2. In some embodiments, one of the plurality of peptides is SEQ ID NO.:3. In some embodiments, wherein one of the plurality of peptides is SEQ ID NO.: 4. In some embodiments, the buffer has a pH of about 3.5. Embodiment 1. A method of increasing blood pressure in a human in need thereof, the method comprising: intravenously administering to the human a pharmaceutical composition comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; and ii) acetic acid, sodium acetate, or a combination thereof, wherein: the pharmaceutical composition is at about room temperature; the administration to the human is longer than 18 hours; the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. Embodiment 2. The method of embodiment 1, wherein the administration to the human is for about one day. Embodiment 3. The method of embodiment 1, wherein the administration to the human is for about one week. Embodiment 4. The method of any one of embodiments 1-3, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. Embodiment 5. The method of any one of embodiments 1-4, wherein the human's hypotension is associated with vasodilatory shock. Embodiment 6. The method of embodiment 5, wherein the vasodilatory shock is post-cardiotomy shock. Embodiment 7. The method of any one of embodiments 1-6, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 8. The method of embodiment 5, wherein the vasodilatory shock is septic shock. Embodiment 9. The method of any one of embodiments 1-8, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 10. The method of any one of embodiments 1-9, wherein the unit dosage form further comprises dextrose. Embodiment 11. The method of any one of embodiments 1-10, wherein the unit dosage form further comprises about 5% dextrose. Embodiment 12. A method of increasing blood pressure in a human in need thereof, the method comprising: intravenously administering to the human a pharmaceutical composition that consists essentially of, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; iii) acetic acid, sodium acetate, or a combination thereof; and iv) optionally hydrochloric acid or sodium hydroxide, wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. Embodiment 13. The method of embodiment 12, wherein the unit dosage form consists essentially of hydrochloric acid. Embodiment 14. The method of embodiment 12, wherein the unit dosage form consists essentially of sodium hydroxide. Embodiment 15. The method of any one of embodiments 12-14, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. Embodiment 16. The method of any one of embodiments 12-15, wherein the human's hypotension is associated with vasodilatory shock. Embodiment 17. The method of embodiment 16, wherein the vasodilatory shock is post-cardiotomy shock. Embodiment 18. The method of any one of embodiments 12-17, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 19. The method of embodiment 16, wherein the vasodilatory shock is septic shock. Embodiment 20. The method of any one of embodiments 12-19 wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. Embodiment 21. The method of any one of embodiments 12-20, wherein the unit dosage form consists essentially of 5% dextrose. Embodiment 22. A method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 5° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 1% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 5° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. Embodiment 23. The method of embodiment 22, wherein the administration to the human is for about one day. Embodiment 24. The method of embodiment 22, wherein the administration to the human is for about one week. Embodiment 25. The method of any one of embodiments 22-24, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. Embodiment 26. The method of any one of embodiments 22-25, wherein the human's hypotension is associated with vasodilatory shock. Embodiment 27. The method of embodiment 26, wherein the vasodilatory shock is post-cardiotomy shock. Embodiment 28. The method of any one of embodiments 22-27, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 29. The method of embodiment 26, wherein the vasodilatory shock is septic shock. Embodiment 30. The method of any one of embodiments 22-29, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. Embodiment 31. The method of any one of embodiments 22-30, wherein the pharmaceutical composition exhibits no more than about 2% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after storage of the pharmaceutical composition at 5° C. for about two months. Embodiment 32. A method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 25° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 2% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 25° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. Embodiment 33. The method of embodiment 32, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. Embodiment 34. The method of any one of embodiments 32-33, wherein the human's hypotension is associated with vasodilatory shock. Embodiment 35. The method of embodiment 34, wherein the vasodilatory shock is post-cardiotomy shock. Embodiment 36. The method of any one of embodiments 32-35, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 37. The method of embodiment 35, wherein the vasodilatory shock is septic shock. Embodiment 38. The method of any one of embodiments 32-37, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. Embodiment 39. The method of any one of embodiments 32-38, wherein the pharmaceutical composition exhibits no more than about 5% degradation after storage of the pharmaceutical composition at 25° C. for about two months.
<SOH> BACKGROUND <EOH>Vasopressin is a potent endogenous hormone, responsible for maintaining plasma osmolality and volume in most mammals. Vasopressin can be used clinically in the treatment of sepsis and cardiac conditions, and in the elevation of patient's suffering from low blood pressure. Current formulations of vasopressin suffer from poor long-term stability.
<SOH> SUMMARY OF THE INVENTION <EOH>In some embodiments, the invention provides a pharmaceutical composition comprising, in a unit dosage form: a) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin, or a pharmaceutically-acceptable salt thereof; and b) a polymeric pharmaceutically-acceptable excipient in an amount that is from about 1% to about 10% by mass of the unit dosage form or the pharmaceutically-acceptable salt thereof, wherein the unit dosage form exhibits from about 5% to about 10% less degradation of the vasopressin or the pharmaceutically-acceptable salt thereof after storage for about 1 week at about 60° C. than does a corresponding unit dosage form, wherein the corresponding unit dosage form consists essentially of: A) vasopressin, or a pharmaceutically-acceptable salt thereof; and B) a buffer having acidic pH. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: intravenously administering to the human a pharmaceutical composition that consists essentially of, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; iii) acetic acid, sodium acetate, or a combination thereof; and iv) optionally hydrochloric acid or sodium hydroxide, wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 5° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 1% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 5° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 25° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 2% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 25° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive.
A61K3811
20170828
20180515
20171221
67193.0
A61K3811
1
BRADLEY, CHRISTINA
VASOPRESSIN FORMULATIONS FOR USE IN TREATMENT OF HYPOTENSION
UNDISCOUNTED
1
CONT-ACCEPTED
A61K
2,017
15,688,338
ACCEPTED
VASOPRESSIN FORMULATIONS FOR USE IN TREATMENT OF HYPOTENSION
Provided herein are peptide formulations comprising polymers as stabilizing agents. The peptide formulations can be more stable for prolonged periods of time at temperatures higher than room temperature when formulated with the polymers. The polymers used in the present invention can decrease the degradation of the constituent peptides of the peptide formulations.
1-15. (canceled) 16. A pharmaceutical composition for intravenous administration comprising, in a unit dosage form: from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; impurities that are present in an amount of 0.9% to 1.7%, wherein the impurities have from about 85% to about 100% sequence homology to SEQ ID NO.: 1, and wherein the unit dosage form has a pH of no greater than 4.1. 17. The pharmaceutical composition of claim 16, wherein the impurities comprise a plurality of peptides, wherein the impurities are determined based on: (a) injecting the unit dosage form into a high pressure liquid chromatography apparatus, wherein the apparatus comprises: (i) a chromatography column containing adsorbent particles as a stationary phase; (ii) a first mobile phase passing through the chromatography column, wherein the first mobile phase is phosphate buffer at pH 3; and (iii) a second mobile phase passing through the chromatography column, wherein the second mobile phase is a 50:50 acetonitrile:water solution; (b) running the unit dosage form through the chromatography column for 55 minutes; (c) eluting the vasopressin and the plurality of peptides from the chromatography column using a gradient of the first mobile phase, and a gradient of the second mobile phase, wherein each of the first and second mobile phase are run at a flow rate of 1 mL/min through the chromatography column; (d) passing the eluted vasopressin and the plurality of peptides through a UV detector to generate a UV spectrum of the eluted vasopressin and the plurality of peptides; (e) identifying a peptide of the plurality of peptides based on a retention time of the peptide of the plurality of peptides relative to a standard; and (f) calculating an amount of the peptide of the plurality of peptides based on an integration of a peak obtained for the peptide of plurality of peptides from the UV spectrum. 18. The pharmaceutical composition of claim 16, wherein the impurities comprise SEQ ID NO.: 2, and SEQ ID NO.: 2 is present in the unit dosage form in an amount of 0.1 to 0.3%. 19. The pharmaceutical composition of claim 16, wherein the impurities comprise SEQ ID NO.: 3, and SEQ ID NO.: 3 is present in the unit dosage form in an amount of 0.1%. 20. The pharmaceutical composition of claim 16, wherein the impurities comprise SEQ ID NO.: 4, and SEQ ID NO.: 4 is present in the unit dosage form in an amount of 0.2% to 0.4%. 21. The pharmaceutical composition of claim 16, wherein the impurities comprise SEQ ID NO.: 7, and SEQ ID NO.: 7 is present in the unit dosage form in an amount of 0.3% to 0.6%. 22. The pharmaceutical composition of claim 16, wherein the impurities comprise SEQ ID NO.: 10, and SEQ ID NO.: 10 is present in the unit dosage form in an amount of 0.1%. 23. The pharmaceutical composition of claim 16, wherein the impurities comprise SEQ ID NO.: 2 and SEQ ID NO.: 4, and SEQ ID NO.: 2 is present in the unit dosage form in an amount of 0.1% to 0.3% and SEQ ID NO.: 4 is present in the unit dosage form in an amount of 0.2% to 0.4%. 24. The pharmaceutical composition of claim 23, wherein the impurities further comprise SEQ ID NO.: 3, SEQ ID NO.: 7, and SEQ ID NO.: 10, and SEQ ID NO.: 3 is present in the unit dosage form in an amount of 0.1%, SEQ ID NO.: 7 is present in the unit dosage form in an amount of 0.3% to 0.6%, and SEQ ID NO.: 10 is present in the unit dosage form in an amount of 0.1%. 25. The pharmaceutical composition of claim 16, wherein the pharmaceutically-acceptable salt of vasopressin is present in the unit dosage form. 26. The pharmaceutical composition of claim 16, wherein the pharmaceutically-acceptable salt of vasopressin is not present in the unit dosage form. 27. A pharmaceutical composition for intravenous administration comprising, in a unit dosage form: from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; impurities that are present in an amount of 0.9% to 1.7%, wherein the impurities have from about 85% to about 100% sequence homology to SEQ ID NO.: 1, and wherein the unit dosage form has a pH of no greater than 4.1. 28. The pharmaceutical composition of claim 27, wherein the impurities comprise a plurality of peptides, wherein the impurities are determined based on: (a) injecting the unit dosage form into a high pressure liquid chromatography apparatus, wherein the apparatus comprises: (i) a chromatography column containing adsorbent particles as a stationary phase; (ii) a first mobile phase passing through the chromatography column, wherein the first mobile phase is phosphate buffer at pH 3; and (iii) a second mobile phase passing through the chromatography column, wherein the second mobile phase is a 50:50 acetonitrile:water solution; (b) running the unit dosage form through the chromatography column for 55 minutes; (c) eluting the vasopressin and the plurality of peptides from the chromatography column using a gradient of the first mobile phase, and a gradient of the second mobile phase, wherein each of the first and second mobile phase are run at a flow rate of 1 mL/min through the chromatography column; (d) passing the eluted vasopressin and the plurality of peptides through a UV detector to generate a UV spectrum of the eluted vasopressin and the plurality of peptides; (e) identifying a peptide of the plurality of peptides based on a retention time of the peptide of the plurality of peptides relative to a standard; and (f) calculating an amount of the peptide of the plurality of peptides based on an integration of a peak obtained for the peptide of plurality of peptides from the UV spectrum. 29. The pharmaceutical composition of claim 27, wherein the impurities comprise SEQ ID NO.: 2, and SEQ ID NO.: 2 is present in the unit dosage form in an amount of 0.1 to 0.3%. 30. The pharmaceutical composition of claim 27, wherein the impurities comprise SEQ ID NO.: 3, and SEQ ID NO.: 3 is present in the unit dosage form in an amount of 0.1%. 31. The pharmaceutical composition of claim 27, wherein the impurities comprise SEQ ID NO.: 4, and SEQ ID NO.: 4 is present in the unit dosage form in an amount of 0.2% to 0.4%. 32. The pharmaceutical composition of claim 27, wherein the impurities comprise SEQ ID NO.: 7, and SEQ ID NO.: 7 is present in the unit dosage form in an amount of 0.3% to 0.6%. 33. The pharmaceutical composition of claim 27, wherein the impurities comprise SEQ ID NO.: 10, and SEQ ID NO.: 10 is present in the unit dosage form in an amount of 0.1%. 34. The pharmaceutical composition of claim 27, wherein the impurities comprise SEQ ID NO.: 2 and SEQ ID NO.: 4, and SEQ ID NO.: 2 is present in the unit dosage form in an amount of 0.1% to 0.3% and SEQ ID NO.: 4 is present in the unit dosage form in an amount of 0.2% to 0.4%. 35. The pharmaceutical composition of claim 34, wherein the impurities further comprise SEQ ID NO.: 3, SEQ ID NO.: 7, and SEQ ID NO.: 10, and SEQ ID NO.: 3 is present in the unit dosage form in an amount of 0.1%, SEQ ID NO.: 7 is present in the unit dosage form in an amount of 0.3% to 0.6%, and SEQ ID NO.: 10 is present in the unit dosage form in an amount of 0.1%. 36. The pharmaceutical composition of claim 27, wherein the pharmaceutically-acceptable salt of vasopressin is present in the unit dosage form. 37. The pharmaceutical composition of claim 27, wherein the pharmaceutically-acceptable salt of vasopressin is not present in the unit dosage form.
CROSS REFERENCE This application is a continuation of U.S. application Ser. No. 15/612,649, filed Jun. 2, 2017, which is a continuation-in-part of U.S. application Ser. No. 15/426,693, filed Feb. 7, 2017, which is a continuation-in-part of U.S. application Ser. No. 15/289,640, filed Oct. 10, 2016, which is a continuation-in-part of U.S. application Ser. No. 14/717,877, filed May 20, 2015, which is a continuation of U.S. application Ser. No. 14/610,499, filed Jan. 30, 2015, each of which is incorporated herein by reference in its entirety. BACKGROUND Vasopressin is a potent endogenous hormone, responsible for maintaining plasma osmolality and volume in most mammals. Vasopressin can be used clinically in the treatment of sepsis and cardiac conditions, and in the elevation of patient's suffering from low blood pressure. Current formulations of vasopressin suffer from poor long-term stability. INCORPORATION BY REFERENCE Each patent, publication, and non-patent literature cited in the application is hereby incorporated by reference in its entirety as if each was incorporated by reference individually. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Aug. 25, 2017, is named 47956702310_SL.txt and is 5260 bytes in size. SUMMARY OF THE INVENTION In some embodiments, the invention provides a pharmaceutical composition comprising, in a unit dosage form: a) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin, or a pharmaceutically-acceptable salt thereof; and b) a polymeric pharmaceutically-acceptable excipient in an amount that is from about 1% to about 10% by mass of the unit dosage form or the pharmaceutically-acceptable salt thereof, wherein the unit dosage form exhibits from about 5% to about 10% less degradation of the vasopressin or the pharmaceutically-acceptable salt thereof after storage for about 1 week at about 60° C. than does a corresponding unit dosage form, wherein the corresponding unit dosage form consists essentially of: A) vasopressin, or a pharmaceutically-acceptable salt thereof; and B) a buffer having acidic pH. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: intravenously administering to the human a pharmaceutical composition that consists essentially of, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; iii) acetic acid, sodium acetate, or a combination thereof; and iv) optionally hydrochloric acid or sodium hydroxide, wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 5° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 1% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 5° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 25° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 2% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 25° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. BRIEF DESCRIPTION OF THE FIGURES FIG. 1 is a chromatogram of a diluent used in vasopressin assay. FIG. 2 is a chromatogram of a sensitivity solution used in a vasopressin assay. FIG. 3 is a chromatogram of an impurity marker solution used in a vasopressin assay. FIG. 4 is a zoomed-in depiction of the chromatogram in FIG. 3. FIG. 5 is a chromatogram of a vasopressin standard solution. FIG. 6 is a chromatogram of a sample vasopressin preparation. FIG. 7 is a UV spectrum of a vasopressin sample. FIG. 8 is a UV spectrum of a vasopressin standard. FIG. 9 plots vasopressin stability across a range of pH as determined experimentally. FIG. 10 illustrates the effects of various stabilizers on vasopressin stability. FIG. 11 plots vasopressin stability across a range of pH at 25° C. FIG. 12 plots vasopressin impurities across a range of pH at 25° C. FIG. 13 plots vasopressin stability across a range of pH at 40° C. FIG. 14 plots vasopressin impurities across a range of pH at 40° C. FIG. 15 illustrates vasopressin impurities across a range of pH at 25° C. FIG. 16 illustrates vasopressin impurities across a range of pH at 40° C. FIG. 17 illustrates the effect of pH on vasopressin at 25° C. FIG. 18 illustrates the effect of pH on vasopressin at 40° C. FIG. 19 depicts the % LC of vasopressin formulations stored for 15 months at 25° C. FIG. 20 is a chromatogram of a diluent used in a vasopressin assay. FIG. 21 is a chromatogram of a sensitivity solution used in a vasopressin assay. FIG. 22 is a chromatogram of an impurity marker solution used in a vasopressin assay. FIG. 23 is a zoomed-in depiction of the chromatogram in FIG. 22. FIG. 24 is a chromatogram of a working solution. FIG. 25 is a chromatogram of a placebo sample. FIG. 26 is a chromatogram of a vasopressin sample. FIG. 27 depicts the estimated shelf-life of a vasopressin sample described herein at 5° C. FIG. 28 depicts the estimated shelf-life of a vasopressin sample described herein at 25° C. FIG. 29 shows the % LC of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 30 shows the % LC of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 31 shows the % LC of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 32 shows the total impurities of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 33 shows the total impurities of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 34 shows the total impurities of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 35 shows the % Gly9-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 36 shows the % Gly9-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 37 shows the % Gly9-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 38 shows the % Asp5-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 39 shows the % Asp5-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 40 shows the % Asp5-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 41 shows the % Glu4-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 42 shows the % Glu4-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 43 shows the % Glu4-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 44 shows the % Acetyl-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 45 shows the % Acetyl-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose and sodium chloride. FIG. 46 shows the % Acetyl-AVP of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 47 shows the % AVP-dimer of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in dextrose. FIG. 48 shows the % AVP-dimer of vasopressin after storage at 5° C., 25° C., and 40° C. of vasopressin formulations prepared in sodium chloride. FIG. 49 depicts the estimated shelf-life of a vasopressin sample described herein at 5° C. FIG. 50 depicts the estimated shelf-life of a vasopressin sample described herein at 25° C. FIG. 51 shows the % LC of vasopressin after storage at 5° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 52 shows the % LC of vasopressin after storage at 25° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 53 shows the % LC of vasopressin after storage at 40° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 54 shows the % Gly9-AVP of vasopressin after storage at 5° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 55 shows the % Gly9-AVP of vasopressin after storage at 25° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 56 shows the % Gly9-AVP of vasopressin after storage at 40° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 57 shows the % Glu4-AVP of vasopressin after storage at 5° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 58 shows the % Glu4-AVP of vasopressin after storage at 25° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 59 shows the % Glu4-AVP of vasopressin after storage at 40° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 60 shows the total impurities of vasopressin after storage at 5° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 61 shows the total impurities of vasopressin after storage at 25° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. FIG. 62 shows the total impurities of vasopressin after storage at 40° C. of vasopressin formulations prepared in dextrose or dextrose and sodium chloride. DETAILED DESCRIPTION Vasopressin and peptides of the invention. Vasopressin, a peptide hormone, acts to regulate water retention in the body and is a neurotransmitter that controls circadian rhythm, thermoregulation, and adrenocorticotrophic hormone (ACTH) release. Vasopressin is synthesized as a pro-hormone in neurosecretory cells of the hypothalamus, and is subsequently transported to the pituitary gland for storage. Vasopressin is released upon detection of hyperosmolality in the plasma, which can be due to dehydration of the body. Upon release, vasopressin increases the permeability of collecting ducts in the kidney to reduce renal excretion of water. The decrease in renal excretion of water leads to an increase in water retention of the body and an increase in blood volume. At higher concentrations, vasopressin raises blood pressure by inducing vasoconstriction. Vasopressin acts through various receptors in the body including, for example, the V1, V2, V3, and oxytocin-type (OTR) receptors. The V1 receptors occur on vascular smooth muscle cells, and the major effect of vasopressin action on the V1 receptor is the induction of vasoconstriction via an increase of intracellular calcium. V2 receptors occur on the collecting ducts and the distal tubule of the kidney. V2 receptors play a role in detection of plasma volume and osmolality. V3 receptors occur in the pituitary gland and can cause ACTH release upon vasopressin binding. OTRs can be found on the myometrium and vascular smooth muscle. Engagement of OTRs via vasopressin leads to an increase of intracellular calcium and vasoconstriction. Vasopressin is a nonapeptide, illustrated below (SEQ ID NO. 1): At neutral to acidic pH, the two basic groups of vasopressin, the N-terminal cysteine, and the arginine at position eight, are protonated, and can each carry an acetate counterion. The amide groups of the N-terminal glycine, the glutamine at position four, and the asparagine at position five, are susceptible to modification when stored as clinical formulations, such as unit dosage forms. The glycine, glutamine, and asparagine residues can undergo deamidation to yield the parent carboxylic acid and several degradation products as detailed in EXAMPLE 1 and TABLE 1 below. Deamidation is a peptide modification during which an amide group is removed from an amino acid, and can be associated with protein degradation, apoptosis, and other regulatory functions within the cell. Deamidation of asparagine and glutamine residues can occur in vitro and in vivo, and can lead to perturbation of the structure and function of the affected proteins. The susceptibility to deamidation can depend on primary sequence of the protein, three-dimensional structure of the protein, and solution properties including, for example, pH, temperature, ionic strength, and buffer ions. Deamidation can be catalyzed by acidic conditions. Under physiological conditions, deamidation of asparagine occurs via the formation of a five-membered succinimide ring intermediate by a nucleophilic attack of the nitrogen atom in the following peptide bond on the carbonyl group of the asparagine side chain. Acetylation is a peptide modification whereby an acetyl group is introduced into an amino acid, such as on the N-terminus of the peptide. Vasopressin can also form dimers in solution and in vivo. The vasopressin dimers can occur through the formation of disulfide bridges that bind a pair of vasopressin monomers together. The dimers can form between two parallel or anti-parallel chains of vasopressin. Vasopressin and associated degradation products or peptides are listed in TABLE 1 below. All amino acids are L-stereoisomers unless otherwise denoted. TABLE 1 SEQ Name Sequence ID NO. Vasopressin (AVP; arginine CYFQNCPRG-NH2 1 vasopressin) Gly9-vasopressin (Gly9-AVP) CYFQNCPRG 2 Asp5-vasopressin (Asp5-AVP) CYFQDCPRG-NH2 3 Glu4-vasopressin (Glu4-AVP) CYFENCPRG-NH2 4 Glu4Gly9-vasopressin (Glu4Gly9- CYFENCPRG 5 AVP) AcetylAsp5-vasopressin Ac-CYFQDCPRG-NH2 6 (AcetylAsp5-AVP) Acetyl-vasopressin (Acetyl-AVP) Ac-CYFQNCPRG-NH2 7 His2-vasopressin (His2-AVP) CHFQNCPRG-NH2 8 Leu7-vasopressin (Leu7-AVP) CYFQNCLRG-NH2 9 D-Asn-vasopressin (DAsn-AVP) CYFQ(D-Asn)CPRG-NH2 10 D-Cys1-vasopressin (D-Cys)YFQNCPRG-NH2 11 D-Tyr-vasopressin C(D-Tyr)FQNCPRG-NH2 12 D-Phe-vasopressin CY(D-Phe)QNCPRG-NH2 13 D-Gln-vasopressin CYF(D-Gln)NCPRG-NH2 14 D-Cys6-vasopressin CYFQN(D-cys)PRG-NH2 15 D-Pro-vasopressin CYFQNC(D-pro)RG-NH2 16 D-Arg-vasopressin CYFQNCP(D-Arg)G-NH2 17 Therapeutic Uses. A formulation of vasopressin can be used to regulate plasma osmolality and volume and conditions related to the same in a subject. Vasopressin can be used to modulate blood pressure in a subject, and can be indicated in a subject who is hypotensive despite treatment with fluid and catecholamines. Vasopressin can be used in the treatment of, for example, vasodilatory shock, post-cardiotomy shock, sepsis, septic shock, cranial diabetes insipidus, polyuria, nocturia, polydypsia, bleeding disorders, Von Willebrand disease, haemophilia, platelet disorders, cardiac arrest, liver disease, liver failure, hypovolemia, hemorrhage, oesophageal variceal haemorrhage, hypertension, pulmonary hypertension, renal disease, polycystic kidney disease, blood loss, injury, hypotension, meniere disease, uterine myomas, brain injury, mood disorder. Formulations of vasopressin can be administered to a subject undergoing, for example, surgery or hysterectomy. Plasma osmolality is a measure of the plasma's electrolyte-water balance and relates to blood volume and hydration of a subject. Normal plasma osmolality in a healthy human subject range from about 275 milliosmoles/kg to about 295 milliosmoles/kg. High plasma osmolality levels can be due to, for example, diabetes insipidus, hyperglycemia, uremia, hypernatremia, stroke, and dehydration. Low plasma osmolality can be due to, for example, vasopressin oversecretion, improper functioning of the adrenal gland, lung cancer, hyponatremia, hypothyroidism, and over-consumption of water or other fluids. Septic shock can develop due to an extensive immune response following infection and can result in low blood pressure. Causes of sepsis can include, for example, gastrointestinal infections, pneumonia, bronchitis, lower respiratory tract infections, kidney infection, urinary tract infections, reproductive system infections, fungal infections, and viral infections. Risk factors for sepsis include, for example, age, prior illness, major surgery, long-term hospitalization, diabetes, intravenous drug use, cancer, use of steroidal medications, and long-term use of antibiotics. The symptoms of sepsis can include, for example, cool arms and legs, pale arms and legs, extreme body temperatures, chills, light-headedness, decreased urination, rapid breathing, edema, confusion, elevated heart rate, high blood sugar, metabolic acidosis, respiratory alkalosis, and low blood pressure. Vasopressin can also be administered to regulate blood pressure in a subject. Blood pressure is the measure of force of blood pushing against blood vessel walls. Blood pressure is regulated by the nervous and endocrine systems and can be used as an indicator of a subject's health. Chronic high blood pressure is referred to as hypertension, and chronic low blood pressure is referred to as hypotension. Both hypertension and hypotension can be harmful if left untreated. Blood pressure can vary from minute to minute and can follow the circadian rhythm with a predictable pattern over a 24-hour period. Blood pressure is recorded as a ratio of two numbers: systolic pressure (mm Hg), the numerator, is the pressure in the arteries when the heart contracts, and diastolic pressure (mm Hg), the denominator, is the pressure in the arteries between contractions of the heart. Blood pressure can be affected by, for example, age, weight, height, sex, exercise, emotional state, sleep, digestion, time of day, smoking, alcohol consumption, salt consumption, stress, genetics, use of oral contraceptives, and kidney disease. Blood pressure for a healthy human adult between the ages of 18-65 can range from about 90/60 to about 120/80. Hypertension can be a blood pressure reading above about 120/80 and can be classified as hypertensive crisis when there is a spike in blood pressure and blood pressure readings reach about 180/110 or higher. Hypertensive crisis can be precipitated by, for example, stroke, myocardial infarction, heart failure, kidney failure, aortic rupture, drug-drug interactions, and eclampsia. Symptoms of hypertensive crisis can include, for example, shortness of breath, angina, back pain, numbness, weakness, dizziness, confusion, change in vision, nausea, and difficulty speaking. Vasodilatory shock can be characterized by low arterial blood pressure due to decreased systemic vascular resistance. Vasodilatory shock can lead to dangerously low blood pressure levels and can be corrected via administration of catecholamines or vasopressin formulations. Vasodilatory shock can be caused by, for example, sepsis, nitrogen intoxication, carbon monoxide intoxication, hemorrhagic shock, hypovolemia, heart failure, cyanide poisoning, metformin intoxication, and mitochondrial disease. Post-cardiotomy shock can occur as a complication of cardiac surgery and can be characterized by, for example, inability to wean from cardiopulmonary bypass, poor hemodynamics in the operating room, development of poor hemodynamics post-surgery, and hypotension. Pharmaceutical Formulations. Methods for the preparation of compositions comprising the compounds described herein can include formulating the compounds with one or more inert, pharmaceutically-acceptable excipients. Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives. Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, elixir, nanosuspension, aqueous or oily suspensions, drops, syrups, and any combination thereof. Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include granulating agents, binding agents, lubricating agents, disintegrating agents, anti-adherents, anti-static agents, surfactants, anti-oxidants, coloring agents, flavoring agents, plasticizers, preservatives, suspending agents, emulsifying agents, plant cellulosic material and spheronization agents, and any combination thereof. Vasopressin can be formulated as an aqueous formulation or a lyophilized powder, which can be diluted or reconstituted just prior to use. Upon dilution or reconstitution, the vasopressin solution can be refrigerated for long-term stability for about one day. Room temperature incubation or prolonged refrigeration can lead to the generation of degradation products of vasopressin. In some embodiments, a pharmaceutical composition of the invention can be formulated for long-term storage of vasopressin at room temperature in the presence of a suitable pharmaceutically-acceptable excipient. The pharmaceutically-acceptable excipient can increase the half-life of vasopressin when stored at any temperature, such as room temperature. The presence of the pharmaceutical excipient can decrease the rate of decomposition of vasopressin at any temperature, such as room temperature. In some embodiments, a pharmaceutical composition has a shelf life of at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, at least about 25 months, at least about 26 months, at least about 27 months, at least about 28 months, at least about 29 months, or at least about 30 months. The shelf life can be at any temperature, including, for example, room temperature and refrigeration (i.e., 2-8° C.). As used herein, “shelf life” means the period beginning from manufacture of a formulation beyond which the formulation cannot be expected beyond reasonable doubt to yield the therapeutic outcome approved by a government regulatory agency In some embodiments, a vasopressin formulation of the invention comprises a pharmaceutically-acceptable excipient, and the vasopressin has a half-life that is at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, or at least about 1000% greater than the half-life of vasopressin in a corresponding formulation that lacks the pharmaceutically-acceptable excipient. In some embodiments, a vasopressin formulation of the invention has a half-life at about 5° C. to about 8° C. that is no more than about 1%, no more than about 5%, no more than about 10%, no more than about 15%, no more than about 20%, no more than about 25%, no more than about 30%, no more than about 35%, no more than about 40%, no more than about 45%, no more than about 50%, no more than about 55%, no more than about 60%, no more than about 65%, no more than about 70%, no more than about 75%, no more than about 80%, no more than about 85%, no more than about 90%, no more than about 95%, no more than about 100%, no more than about 150%, no more than about 200%, no more than about 250%, no more than about 300%, no more than about 350%, no more than about 400%, no more than about 450%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000% greater than the half-life of the formulation at another temperature, such as room temperature. The half-life of the compounds of the invention in a formulation described herein at a specified temperature can be, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, or about one week. A formulation described herein can be stable for or be stored for, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years prior to administration to a subject. A unit dosage form described herein can be stable for or be stored for, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years prior to administration to a subject. A diluted unit dosage form described herein can be stable for or be stored for, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years prior to administration to subject. The stability of a formulation described herein can be measured after, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years. A formulation or unit dosage form described herein can exhibit, for example, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9% about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% degradation over a specified period of time. The degradation of a formulation or a unit dosage form disclosed herein can be assessed after about 24 hours, about 36 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years of storage. The degradation of a formulation or a unit dosage form disclosed herein can be assessed at a temperature of, for example, about 0° C., about 1° C., about 2° C., about 3° C., about 4° C., about 5° C., about 6° C., about 7° C., about 8° C., about 9° C., about 10° C., about 11° C., about 12° C., about 13° C., about 14° C., about 15° C., about 16° C., about 17° C., about 18° C., about 19° C., about 20° C., about 21° C., about 22° C., about 23° C., about 24° C., about 25° C., about 26° C., about 27° C., about 28° C., about 29° C., about 30° C., about 31° C., about 32° C., about 33° C., about 34° C., about 35° C., about 36° C., about 37° C., about 38° C., about 39° C., about 40° C., about 41° C., about 42° C., about 43° C., about 44° C., about 45° C., about 46° C., about 47° C., about 48° C., about 49° C., about 50° C., or about 0° C. to about 5° C., about 1° C. to about 6° C., about 2° C. to about 7° C., about 2° C. to about 8° C., about 3° C. to about 8° C., about 4° C. to about 9° C., about 5° C. to about 10° C., about 6° C. to about 11° C., about 7° C. to about 12° C., about 8° C. to about 13° C., about 9° C. to about 14° C., about 10° C. to about 15° C., about 11° C. to about 16° C., about 12° C. to about 17° C., about 13° C. to about 18° C., about 14° C. to about 19° C., about 15° C. to about 20° C., about 16° C. to about 21° C., about 17° C. to about 22° C., about 18° C. to about 23° C., about 19° C. to about 24° C., about 20° C. to about 25° C., about 21° C. to about 26° C., about 22° C. to about 27° C., about 23° C. to about 28° C., about 24° C. to about 29° C., about 25° C. to about 30° C., about 26° C. to about 31° C., about 27° C. to about 32° C., about 28° C. to about 33° C., about 29° C. to about 34° C., about 30° C. to about 35° C., about 31° C. to about 36° C., about 32° C. to about 37° C., about 33° C. to about 38° C., about 34° C. to about 39° C., about 35° C. to about 40° C., about 36° C. to about 41° C., about 37° C. to about 42° C., about 38° C. to about 43° C., about 39° C. to about 44° C., about 40° C. to about 45° C., about 41° C. to about 46° C., about 42° C. to about 47° C., about 43° C. to about 48° C., about 44° C. to about 49° C., about 45° C. to about 50° C. In some embodiments, a vasopressin formulation of the invention comprises an excipient and the vasopressin has a level of decomposition at a specified temperature that is about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% less than the level of decomposition of a formulation of the invention in the absence of the excipient. Pharmaceutical compositions of the invention can be used, stored, tested, analyzed or assayed at any suitable temperature. Non-limiting examples of temperatures include about 0° C., about 1° C., about 2° C., about 3° C., about 4° C., about 5° C., about 6° C., about 7° C., about 8° C., about 9° C., about 10° C., about 11° C., about 12° C., about 13° C., about 14° C., about 15° C., about 16° C., about 17° C., about 18° C., about 19° C., about 20° C., about 21° C., about 22° C., about 23° C., about 24° C., about 25° C., about 26° C., about 27° C., about 28° C., about 29° C., about 30° C., about 31° C., about 32° C., about 33° C., about 34° C., about 35° C., about 36° C., about 37° C., about 38° C., about 39° C., about 40° C., about 41° C., about 42° C., about 43° C., about 44° C., about 45° C., about 46° C., about 47° C., about 48° C., about 49° C., about 50° C., about 51° C., about 52° C., about 53° C., about 54° C., about 55° C., about 56° C., about 57° C., about 58° C., about 59° C., about 60° C., about 61° C., about 62° C., about 63° C., about 64° C., about 65° C., about 66° C., about 67° C., about 68° C., about 69° C., about 70° C., about 71° C., about 72° C., about 73° C., about 74° C., or about 75° C. Pharmaceutical compositions of the invention can be used, stored, tested, analyzed or assayed at any suitable temperature. Non-limiting examples of temperatures include from about 0° C. to about 5° C., about 1° C. to about 6° C., about 2° C. to about 7° C., about 2° C. to about 8° C., about 3° C. to about 8° C., about 4° C. to about 9° C., about 5° C. to about 10° C., about 6° C. to about 11° C., about 7° C. to about 12° C., about 8° C. to about 13° C., about 9° C. to about 14° C., about 10° C. to about 15° C., about 11° C. to about 16° C., about 12° C. to about 17° C., about 13° C. to about 18+° C., about 14° C. to about 19° C., about 15° C. to about 20° C., about 16° C. to about 21° C., about 17° C. to about 22° C., about 18° C. to about 23° C., about 19° C. to about 24° C., about 20° C. to about 25° C., about 21° C. to about 26° C., about 22° C. to about 27° C., about 23° C. to about 28° C., about 24° C. to about 29° C., about 25° C. to about 30° C., about 26° C. to about 31° C., about 27° C. to about 32° C., about 28° C. to about 33° C., about 29° C. to about 34° C., about 30° C. to about 35° C., about 31° C. to about 36° C., about 32° C. to about 37° C., about 33° C. to about 38° C., about 34° C. to about 39° C., about 35° C. to about 40° C., about 36° C. to about 41° C., about 37° C. to about 42° C., about 38° C. to about 43° C., about 39° C. to about 44° C., about 40° C. to about 45° C., about 41° C. to about 46° C., about 42° C. to about 47° C., about 43° C. to about 48° C., about 44° C. to about 49° C., about 45° C. to about 50° C., about 46° C. to about 51° C., about 47° C. to about 52° C., about 48° C. to about 53° C., about 49° C. to about 54° C., about 50° C. to about 55° C., about 51° C. to about 56° C., about 52° C. to about 57° C., about 53° C. to about 58° C., about 54° C. to about 59° C., about 55° C. to about 60° C., about 56° C. to about 61° C., about 57° C. to about 62° C., about 58° C. to about 63° C., about 59° C. to about 64° C., about 60° C. to about 65° C., about 61° C. to about 66° C., about 62° C. to about 67° C., about 63° C. to about 68° C., about 64° C. to about 69° C., about 65° C. to about 70° C., about 66° C. to about 71° C., about 67° C. to about 72° C., about 68° C. to about 73° C., about 69° C. to about 74° C., about 70° C. to about 74° C., about 71° C. to about 76° C., about 72° C. to about 77° C., about 73° C. to about 78° C., about 74° C. to about 79° C., or about 75° C. to about 80° C. Pharmaceutical compositions of the invention can be used, stored, tested, analyzed or assayed at room temperature. The room temperature can be, for example, about 20.0° C., about 20.1° C., about 20.2° C., about 20.3° C., about 20.4° C., about 20.5° C., about 20.6° C., about 20.7° C., about 20.8° C., about 20.9° C., about 21.0° C., about 21.1° C., about 21.2° C., about 21.3° C., about 21.4° C., about 21.5° C., about 21.6° C., about 21.7° C., about 21.8° C., about 21.9° C., about 22.0° C., about 22.1° C., about 22.2° C., about 22.3° C., about 22.4° C., about 22.5° C., about 22.6° C., about 22.7° C., about 22.8° C., about 22.9° C., about 23.0° C., about 23.1° C., about 23.2° C., about 23.3° C., about 23.4° C., about 23.5° C., about 23.6° C., about 23.7° C., about 23.8° C., about 23.9° C., about 24.0° C., about 24.1° C., about 24.2° C., about 24.3° C., about 24.4° C., about 24.5° C., about 24.6° C., about 24.7° C., about 24.8° C., about 24.9° C., or about 25.0° C. A pharmaceutical composition of the disclosed can be supplied, stored, or delivered in a vial or tube that is, for example, about 0.5 mL, about 1 mL, about 2 mL, about 3 mL, about 4 mL, about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, about 10 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about 18 mL, about 19 mL, or about 20 mL in volume. A pharmaceutical composition of the disclosure can be a combination of any pharmaceutical compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can be administered in therapeutically-effective amounts, for example, intravenous, subcutaneous, intramuscular, transdermal, or parenteral administration. Pharmaceutical preparations can be formulated for intravenous administration. The pharmaceutical compositions can be in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in oily or aqueous vehicles, and can contain formulation agents such as suspending, stabilizing, and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Suspensions of the active compounds can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. The suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use. Comparison Formulations. A pharmaceutical composition described herein can be analyzed by comparison to a reference formulation. A reference formulation can be generated from any combination of compounds, peptides, excipients, diluents, carriers, and solvents disclosed herein. Any compound, peptide, excipient, diluent, carrier, or solvent used to generate the reference formulation can be present in any percentage, ratio, or amount, for example, those disclosed herein. The reference formulation can comprise, consist essentially of, or consist of any combination of any of the foregoing. A non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: an amount, such as about 20 Units or about 0.04 mg, of vasopressin or a pharmaceutically-acceptable salt thereof, an amount, such as about 5 mg, of chlorobutanol (for example, hydrous), an amount, such as about 0.22 mg, of acetic acid or a pharmaceutically-acceptable salt thereof or a quantity sufficient to bring pH to about 3.4 to about 3.6, and water as needed. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof, chlorobutanol, acetic acid, and a solvent such as water. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof, chlorobutanol, and a solvent such as water. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof, acetic acid, and a solvent such as water. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof and a solvent such as water. Another non-limiting example of a comparison formulation comprises, consists essentially of, or consists of: vasopressin or a pharmaceutically-acceptable salt thereof and a buffer having acidic pH, such as pH 3.5 or any buffer or pH described herein. Methods. Any formulation described herein can be diluted prior to administration to a subject. Diluents that can be used in a method of the invention include, for example, compound sodium lactate solution, 6% dextran, 10% dextran, 5% dextrose, 20% fructose, Ringer's solution, 5% saline, 1.39% sodium bicarbonate, 1.72% sodium lactate, or water. Upon dilution, any diluted formulation disclosed herein can be stored for, for example, about 24 hours, about 36 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years of storage. Upon dilution, any diluted formulation disclosed herein can be stored at, for example, about 0° C., about 1° C., about 2° C., about 3° C., about 4° C., about 5° C., about 6° C., about 7° C., about 8° C., about 9° C., about 10° C., about 11° C., about 12° C., about 13° C., about 14° C., about 15° C., about 16° C., about 17° C., about 18° C., about 19° C., about 20° C., about 21° C., about 22° C., about 23° C., about 24° C., about 25° C., about 26° C., about 27° C., about 28° C., about 29° C., about 30° C., about 31° C., about 32° C., about 33° C., about 34° C., about 35° C., about 36° C., about 37° C., about 38° C., about 39° C., about 40° C., about 41° C., about 42° C., about 43° C., about 44° C., about 45° C., about 46° C., about 47° C., about 48° C., about 49° C., about 50° C., or about 0° C. to about 5° C., about 1° C. to about 6° C., about 2° C. to about 7° C., about 2° C. to about 8° C., about 3° C. to about 8° C., about 4° C. to about 9° C., about 5° C. to about 10° C., about 6° C. to about 11° C., about 7° C. to about 12° C., about 8° C. to about 13° C., about 9° C. to about 14° C., about 10° C. to about 15° C., about 11° C. to about 16° C., about 12° C. to about 17° C., about 13° C. to about 18° C., about 14° C. to about 19° C., about 15° C. to about 20° C., about 16° C. to about 21° C., about 17° C. to about 22° C., about 18° C. to about 23° C., about 19° C. to about 24° C., about 20° C. to about 25° C., about 21° C. to about 26° C., about 22° C. to about 27° C., about 23° C. to about 28° C., about 24° C. to about 29° C., about 25° C. to about 30° C., about 26° C. to about 31° C., about 27° C. to about 32° C., about 28° C. to about 33° C., about 29° C. to about 34° C., about 30° C. to about 35° C., about 31° C. to about 36° C., about 32° C. to about 37° C., about 33° C. to about 38° C., about 34° C. to about 39° C., about 35° C. to about 40° C., about 36° C. to about 41° C., about 37° C. to about 42° C., about 38° C. to about 43° C., about 39° C. to about 44° C., about 40° C. to about 45° C., about 41° C. to about 46° C., about 42° C. to about 47° C., about 43° C. to about 48° C., about 44° C. to about 49° C., about 45° C. to about 50° C. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about two weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about three weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about six weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about three months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about six months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about two years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about three years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 24 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 48 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 96 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 1 week; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 months; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 months; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least one year; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least two years; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least three years; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 24 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 48 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 96 hours; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least one week; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 months; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 months; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 1 year; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 years; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 years; c) diluting the unit dosage form in a diluent to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 24 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 48 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 96 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 1 week; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 months; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 months; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 1 year; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 years; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 years; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 24 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 48 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 96 hours; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least one week; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 months; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 6 months; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least one year; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about one year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 2 years; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) acetic acid; and iv) water; b) storing the unit dosage form at 2-8° C., for example, 5° C., for at least 3 years; c) diluting the unit dosage form in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable salt thereof; and d) administering the diluted unit dosage form to the human by intravenous administration; wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive, wherein the unit dosage form exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 24 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 48 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 96 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 1 week; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 2 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 months; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 6 months; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 1 year; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 2 years; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 years; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about two weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about three weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about four weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 24 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 24 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 48 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C. for about, for example, 5° C., 48 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 96 hours; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 96 hours. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 1 week; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 week. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 2 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 4 weeks; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 4 weeks. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 months; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 6 months; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 6 months. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 1 year; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 1 year. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 2 years; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 2 years. The present invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) acetic acid; and iii) water; and b) storing the pharmaceutical composition at 2-8° C., for example, 5° C., for at least 3 years; and c) intravenously administering the pharmaceutical composition to the human, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; wherein the human is hypotensive, wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8° C., for example, 5° C., for about 3 years. A formulation described herein can be used without initial vasopressin dilution for use in, for example, intravenous drip-bags. The formulation can be premixed, already-diluted, and ready for use as provided in, for example, a bottle or intravenous drip-bag. The formulation supplied in the bottle can then be transferred to an intravenous drip-bag for administration to a subject. The formulation can be stable for about 24 hours, about 36 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years prior to discarding. The premixed formulation described herein can be disposed in a container or vessel, which can be sealed. The container or vessel can maintain the sterility of, or reduce the likelihood of contamination of, the premixed formulation. The premixed formulation described herein can be disposed in a container or vessel and is formulated as, for example, a single use dosage or a multiple use dosage. The container or vessel can be, for example, a glass vial, an ampoule, or a plastic flexible container. The plastic flexible container can be made of, for example, PVC (polyvinyl chloride), or polypropylene. A premixed vasopressin formulation described herein can be stored as a liquid in an aliquot having a total volume of between about 1 and about 500 mL, between about 1 and about 250 mL, between about 1 and about 200 mL, between about 1 and about 150 mL, between about 1 and about 125 mL, between about 1 and about 120 mL, between about 1 and about 110 mL, between about 1 and about 100 mL, between about 1 and about 90 mL, between about 1 and about 80 mL, between about 1 and about 70 mL, between about 1 and about 60 mL, between about 1 and about 50 mL, between about 1 and about 40 mL, between about 1 and about 30 mL, between about 1 and about 20 mL, between about 1 and about 10 mL, or between about 1 and about 5 mL. A premixed vasopressin formulation described herein can be administered as, for example, a single continuous dose over a period of time. For example, the premixed vasopressin formulation can be administered for a period of time of between about 1 and about 10 minutes, between about 1 and about 20 minutes, between about 1 and about 30 minutes, between about 1 and about 2 hours, between about 1 and about 3 hours, between about 1 and about 4 hours, between about 1 and about 5 hours, between about 1 and about 6 hours, between about 1 and about 7 hours, between about 1 and about 8 hours, between about 1 and about 9 hours, between about 1 and about 10 hours, between about 1 and about 11 hours, between about 1 and about 12 hours, between about 1 and about 13 hours, between about 1 and about 14 hours, between about 1 and about 15 hours, between about 1 and about 16 hours, between about 1 and about 17 hours, between about 1 and about 18 hours, between about 1 and about 19 hours, between about 1 and about 20 hours, between about 1 and about 21 hours, between about 1 and about 22 hours, between about 1 and about 23 hours, between about 1 and about 1 day, between about 1 and about 32 hours, between about 1 and about 36 hours, between about 1 and about 42 hours, between about 1 and about 2 days, between about 1 and about 54 hours, between about 1 and about 60 hours, between about 1 and about 66 hours, between about 1 and about 3 days, between about 1 and about 78 hours, between about 1 and about 84 hours, between about 1 and about 90 hours, between about 1 and about 4 days, between about 1 and about 102 hours, between about 1 and about 108 hours, between about 1 and about 114 hours, between about 1 and about 5 days, between about 1 and about 126 hours, between about 1 and about 132 hours, between about 1 and about 138 hours, between about 1 and about 6 days, between about 1 and about 150 hours, between about 1 and about 156 hours, between about 1 and about 162 hours, or between about 1 and about 1 week. A premixed vasopressin formulation described herein can be administered as a loading dose followed by a maintenance dose over a period of time. For example, the loading dose can comprise administration of the premixed vasopressin formulation at a first dosage amount for a first period of time, followed by administration of the maintenance dose at a second dosage amount for a second period of time. The loading dose can be administered for a period of time of between about 1 and about 5 minutes, between about 1 and about 10 minutes, between about 1 and about 15 minutes, between about 1 and about 20 minutes, between about 1 and about 25 minutes, between about 1 and about 30 minutes, between about 1 and about 45 minutes, between about 1 and about 60 minutes, between about 1 and about 90 minutes, between 1 minute and about 2 hours, between 1 minute about 2.5 hours, between 1 minute and about 3 hours, between 1 minute and about 3.5 hours, between 1 minute and about 4 hours, between 1 minute and about 4.5 hours, between 1 minute and about 5 hours, between 1 minute and about 5.5 hours, between 1 minute and about 6 hours, between 1 minute and about 6.5 hours, between 1 minute and about 7 hours, between 1 minute and about 7.5 hours, between 1 minute and about 8 hours, between 1 minute and about 10 hours, between 1 minute and about 12 hours, between 1 minute about 14 hours, between 1 minute and about 16 hours, between 1 minute and about 18 hours, between 1 minute and about 20 hours, between 1 minute and about 22 hours, or between 1 minute and about 24 hours. Following the loading dose, the maintenance dose can be administered for a period of time as described above for a single continuous dose. A premixed vasopressin formulation described herein, when administered as a single continuous, loading, or maintenance dose, can be administered for about 1 hour to about 7 days, about 1 hour to about 4 days, about 1 hour to about 48 hours, about 1 hour to about 36 hours, about 1 hour to about 24 hours, about 1 hour to about 12 hours, about 24 hours to about 120 hours, about 24 hours to about 108 hours, about 24 hours to about 96 hours, about 24 hours to about 72 hours, about 24 hours to about 48 hours, or about 24 hours to about 36 hours. The volume of the premixed formulation can be, for example, about 25 mL, about 30 mL, about 35 mL, about 40 mL, about 45 mL, about 50 mL, about 55 mL, about 60 mL, about 65 mL, about 70 mL, about 75 mL, about 80 mL, about 85 mL, about 90 mL, about 95 mL, about 100 mL, about 110 mL, about 120 mL, about 130 mL, about 140 mL, about 150 mL, about 175 mL, about 200 mL, about 225 mL, about 250 mL, about 275 mL, about 300 mL, about 350 mL, about 400 mL, about 450 mL, about 500 mL, about 550 mL, about 600 mL, about 650 mL, about 700 mL, about 750 mL, about 800 mL, about 850 mL, about 900 mL, about 950 mL, or about 1 L. In some embodiments, the volume of the vasopressin formulation formulated for use without initial vasopressin dilution is 100 mL. The concentration of vasopressin in the container or vessel in which the premixed vasopressin formulation is disposed can be, for example, about 0.1 units/mL, about 0.2 units/mL, about 0.3 units/mL, about 0.4 units/mL, about 0.5 units/mL, about 0.6 units/mL, about 0.7 units/mL, about 0.8 units/mL, about 0.9 units/mL, about 1 unit/mL, about 2 units/mL, about 3 units/mL, about 4 units/mL, about 5 units/mL, about 6 units/mL, about 7 units/mL, about 8 units/mL, about 9 units/mL, about 10 units/mL, about 11 units/mL, about 12 units/mL, about 13 units/mL, about 14 units/mL, about 15 units/mL, about 16 units/mL, about 17 units/mL, about 18 units/mL, about 19 units/mL, about 20 units/mL, about 21 units/mL, about 22 units/mL, about 23 units/mL, about 24 units/mL about 25 units/mL, about 30 units/mL, about 35 units/mL, about 40 units/mL, about 45 units/mL, or about 50 units/mL. In some embodiments, the concentration of vasopressin in the container or vessel is 0.4 units/mL. In some embodiments, the concentration of vasopressin in the container or vessel is 0.6 units/mL. The concentration of vasopressin in the container or vessel in which the premixed vasopressin formulation is disposed can be, for example, about 0.01 μg/mL, about 0.05 μg/mL, about 0.1 μg/mL, about 0.15 μg/mL, about 0.2 μg/mL, about 0.25 μg/mL, about 0.3 μg/mL, about 0.35 μg/mL, about 0.4 μg/mL, about 0.5 μg/mL, about 0.6 μg/mL, about 0.7 μg/mL, about 0.8 μg/mL, about 0.9 μg/mL, about 1 μg/mL, about 2 μg/mL, about 3 μg/mL, about 4 μg/mL, about 5 μg/mL, about 10 μg/mL, about 15 μg/mL, about 20 μg/mL, about 25 μg/mL, about 30 μg/mL, about 35 μg/mL, about 40 μg/mL, about 45 μg/mL, about 50 μg/mL, about 60 μg/mL, about 70 μg/mL, about 80 μg/mL, about 90 μg/mL, about 100 μg/mL, about 125 μg/mL, about 150 μg/mL, about 175 μg/mL, about 200 μg/mL, about 250 μg/mL, about 300 μg/mL, about 350 μg/mL, about 400 μg/mL, about 450 μg/mL, about 500 μg/mL, about 600 μg/mL, about 700 μg/mL, about 800 μg/mL, about 900 μg/mL, about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, or about 10 mg/mL. A formulation formulated for use without initial vasopressin dilution can be administered as intravenous drip therapy for about 15 min, about 20 min, about 25 min, about 30 min, about 35 min, about 40 min, about 45 min, about 50 min, about 55 min, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 1 year. A formulation for use in a drip-bag can be replaced up to, for example, one time, two times, three times, four times, five times, six times, seven times, eight times, nine times, ten times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, or 20 times during the course of the treatment period. The formulation can be used for continuous or intermittent intravenous infusion. A formulation formulated for use without initial vasopressin dilution can be modified using an excipient, for example, any excipient disclosed herein, to improve the stability of vasopressin for long-term storage and use. Non-limiting examples of excipients that can be used in an intravenous drip-bag include dextrose, saline, half-strength saline, quarter-strength saline, Ringers Lactate solution, sodium chloride, and potassium chloride. In some embodiments, dextrose is used as an excipient for the vasopressin formulation formulated for use without initial vasopressin dilution. A formulation formulated for use without initial vasopressin dilution can be modified using a buffer, for example, any buffer disclosed herein, to adjust the pH of the formulation. A non-limiting example of a buffer that can be used in the formulation includes acetate buffer. The concentration of buffer used in the formulation can be, for example, about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, or about 30 mM. In some embodiments, the concentration of the acetate buffer is 1 mM. In some embodiments, the concentration of the acetate buffer is 10 mM. In some embodiments, an additive that is used in a formulation described herein is dextrose. The concentration of dextrose used in the formulation can be, for example, about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, or about 30 mM. In some embodiments, the concentration of dextrose is 1 mM. In some embodiments, the concentration of dextrose is 10 mM. The concentration of dextrose used in the formulation can be, for example, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%. In some embodiments, a formulation described herein contains 5% dextrose. In some embodiments, an additive that is used in a formulation described herein is sodium chloride. The concentration of sodium chloride used in the formulation can be, for example, about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, or about 30 mM. In some embodiments, the concentration of the sodium chloride is 1 mM. In some embodiments, the concentration of sodium chloride is 10 mM. In some embodiments, a combination of dextrose and sodium chloride is used in a formulation described herein. When used in combination, the concentration of sodium chloride and dextrose can be the same or different. In some embodiments, the concentration of dextrose or sodium chloride is 1 mM, or any value above 1 mM, when dextrose and sodium chloride are used in a combination in a formulation described herein. A formulation formulated for use without initial vasopressin dilution can be modified using a pH adjusting agent, for example, any pH adjusting agent disclosed herein, to adjust the pH of the formulation. Non-limiting examples of a pH adjusting agent that can be used in the formulation include acetic acid, sodium acetate, hydrochloric acid, and sodium hydroxide. The concentration of buffer used in the formulation can be, for example, about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, or about 30 mM. In some embodiments, the concentration of the acetate buffer is 1 mM. In some embodiments, the concentration of the acetate buffer is 10 mM. The formulation can be stable for and have a shelf-life of about 24 hours, about 36 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 3 years of storage at any temperature. In some embodiments, the shelf-life of the formulation is 2 years under refrigeration. In some embodiments, the shelf-life of the formulation is 6 months at room temperature. In some embodiments, the total shelf-life of the formulation is 30 months, where the formulation is stored for 2 years under refrigeration and 6 months at room temperature. Dosage Amounts. In practicing the methods of treatment or use provided herein, therapeutically-effective amounts of the compounds described herein are administered in pharmaceutical compositions to a subject having a disease or condition to be treated. A therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors. Subjects can be, for example, humans, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, or neonates. A subject can be a patient. Pharmaceutical compositions of the invention can be formulated in any suitable volume. The formulation volume can be, for example, about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1 mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, about 1.4 mL, about 1.5 mL, about 1.6 mL, about 1.7 mL, about 1.8 mL, about 1.9 mL, about 2 mL, about 2.1 mL, about 2.2 mL, about 2.3 mL, about 2.4 mL, about 2.5 mL, about 2.6 mL, about 2.7 mL, about 2.8 mL, about 2.9 mL, about 3 mL, about 3.1 mL, about 3.2 mL, about 3.3 mL, about 3.4 mL, about 3.5 mL, about 3.6 mL, about 3.7 mL, about 3.8 mL, about 3.9 mL, about 4 mL, about 4.1 mL, about 4.2 mL, about 4.3 mL, about 4.4 mL, about 4.5 mL, about 4.6 mL, about 4.7 mL, about 4.8 mL, about 4.9 mL, about 5 mL, about 5.1 mL, about 5.2 mL, about 5.3 mL, about 5.4 mL, about 5.5 mL, about 5.6 mL, about 5.7 mL, about 5.8 mL, about 5.9 mL, about 6 mL, about 6.1 mL, about 6.2 mL, about 6.3 mL, about 6.4 mL, about 6.5 mL, about 6.6 mL, about 6.7 mL, about 6.8 mL, about 6.9 mL, about 7 mL, about 7.1 mL, about 7.2 mL, about 7.3 mL, about 7.4 mL, about 7.5 mL, about 7.6 mL, about 7.7 mL, about 7.8 mL, about 7.9 mL, about 8 mL, about 8.1 mL, about 8.2 mL, about 8.3 mL, about 8.4 mL, about 8.5 mL, about 8.6 mL, about 8.7 mL, about 8.8 mL, about 8.9 mL, about 9 mL, about 9.1 mL, about 9.2 mL, about 9.3 mL, about 9.4 mL, about 9.5 mL, about 9.6 mL, about 9.7 mL, about 9.8 mL, about 9.9 mL, about 10 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about 18 mL, about 19 mL, or about 20 mL. A therapeutically-effective amount of a compound described herein can be present in a composition at a concentration of, for example, about 0.1 units/mL, about 0.2 units/mL, about 0.3 units/mL, about 0.4 units/mL, about 0.5 units/mL, about 0.6 units/mL, about 0.7 units/mL, about 0.8 units/mL, about 0.9 units/mL, about 1 unit/mL, about 2 units/mL, about 3 units/mL, about 4 units/mL, about 5 units/mL, about 6 units/mL, about 7 units/mL, about 8 units/mL, about 9 units/mL, about 10 units/mL, about 11 units/mL, about 12 units/mL, about 13 units/mL, about 14 units/mL, about 15 units/mL, about 16 units/mL, about 17 units/mL, about 18 units/mL, about 19 units/mL, about 20 units/mL, about 21 units/mL, about 22 units/mL, about 23 units/mL, about 24 units/mL about 25 units/mL, about 30 units/mL, about 35 units/mL, about 40 units/mL, about 45 units/mL, or about 50 units/mL. A therapeutically-effective amount of a compound described herein can be present in a composition of the invention at a mass of about, for example, about 0.01 μg, about 0.05 μg, about 0.1 μg, about 0.15 μg, about 0.2 μg, about 0.25 μg, about 0.3 μg, about 0.35 μg, about 0.4 μg, about 0.5 μg, about 0.6 μg, about 0.7 μg, about 0.8 μg, about 0.9 μg, about 1 μg, about 2 μg, about 3 μg, about 4 μg, about 5 μg, about 10 μg, about 15 μg, about 20 μg, about 25 μg, about 30 μg, about 35 μg, about 40 μg, about 45 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 125 μg, about 150 μg, about 175 μg, about 200 μg, about 250 μg, about 300 μg, about 350 μg, about 400 μg, about 450 μg, about 500 μg, about 600 μg, about 700 μg, about 800 μg, about 900 μg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg. A therapeutically-effective amount of a compound described herein can be present in a composition of the invention at a concentration of, for example, about 0.001 mg/mL, about 0.002 mg/mL, about 0.003 mg/mL, about 0.004 mg/mL, about 0.005 mg/mL, about 0.006 mg/mL, about 0.007 mg/mL, about 0.008 mg/mL, about 0.009 mg/mL, about 0.01 mg/mL, about 0.02 mg/mL, about 0.03 mg/mL, about 0.04 mg/mL, about 0.05 mg/mL, about 0.06 mg/mL, about 0.07 mg/mL, about 0.08 mg/mL, about 0.09 mg/mL, about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 1.5 mg/mL, about 2 mg/mL, about 2.5 mg/mL, about 3 mg/mL, about 3.5 mg/mL, about 4 mg/mL, about 4.5 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, or about 10 mg/mL. A therapeutically-effective amount of a compound described herein can be present in a composition of the invention at a unit of active agent/unit of active time. Non-limiting examples of therapeutically-effective amounts can be, for example, about 0.01 units/minute, about 0.02 units/minute, about 0.03 units/minute, about 0.04 units/minute, about 0.05 units/minute, about 0.06 units/minute, about 0.07 units/minute, about 0.08 units/minute, about 0.09 units/minute or about 0.1 units/minute. Pharmaceutical compositions of the invention can be formulated at any suitable pH. The pH can be, for example, about 2, about 2.05, about 2.1, about 2.15, about 2.2, about 2.25, about 2.3, about 2.35, about 2.4, about 2.45, about 2.5, about 2.55, about 2.6, about 2.65, about 2.7, about 2.75, about 2.8, about 2.85, about 2.9, about 2.95, about 3, about 3.05, about 3.1, about 3.15, about 3.2, about 3.25, about 3.3, about 3.35, about 3.4, about 3.45, about 3.5, about 3.55, about 3.6, about 3.65, about 3.7, about 3.75, about 3.8, about 3.85, about 3.9, about 3.95, about 4, about 4.05, about 4.1, about 4.15, about 4.2, about 4.25, about 4.3, about 4.35, about 4.4, about 4.45, about 4.5, about 4.55, about 4.6, about 4.65, about 4.7, about 4.75, about 4.8, about 4.85, about 4.9, about 4.95, or about 5 pH units. Pharmaceutical compositions of the invention can be formulated at any suitable pH. The pH can be, for example, from about 2 to about 2.2, about 2.05 to about 2.25, about 2.1 to about 2.3, about 2.15 to about 2.35, about 2.2 to about 2.4, about 2.25 to about 2.45, about 2.3 to about 2.5, about 2.35 to about 2.55, about 2.4 to about 2.6, about 2.45 to about 2.65, about 2.5 to about 2.7, about 2.55 to about 2.75, about 2.6 to about 2.8, about 2.65 to about 2.85, about 2.7 to about 2.9, about 2.75 to about 2.95, about 2.8 to about 3, about 2.85 to about 3.05, about 2.9 to about 3.1, about 2.95 to about 3.15, about 3 to about 3.2, about 3.05 to about 3.25, about 3.1 to about 3.3, about 3.15 to about 3.35, about 3.2 to about 3.4, about 3.25 to about 3.45, about 3.3 to about 3.5, about 3.35 to about 3.55, about 3.4 to about 3.6, about 3.45 to about 3.65, about 3.5 to about 3.7, about 3.55 to about 3.75, about 3.6 to about 3.8, about 3.65 to about 3.85, about 3.7 to about 3.9, about 3.7 to about 3.8, about 3.75 to about 3.95, about 3.75 to about 3.8, about 3.8 to about 3.85, about 3.75 to about 3.85, about 3.8 to about 4, about 3.85 to about 4.05, about 3.9 to about 4.1, about 3.95 to about 4.15, about 4 to about 4.2, about 4.05 to about 4.25, about 4.1 to about 4.3, about 4.15 to about 4.35, about 4.2 to about 4.4, about 4.25 to about 4.45, about 4.3 to about 4.5, about 4.35 to about 4.55, about 4.4 to about 4.6, about 4.45 to about 4.65, about 4.5 to about 4.7, about 4.55 to about 4.75, about 4.6 to about 4.8, about 4.65 to about 4.85, about 4.7 to about 4.9, about 4.75 to about 4.95, about 4.8 to about 5, about 4.85 to about 5.05, about 4.9 to about 5.1, about 4.95 to about 5.15, or about 5 to about 5.2 pH units. In some embodiments, the addition of an excipient can change the viscosity of a pharmaceutical composition of the invention. In some embodiments the use of an excipient can increase or decrease the viscosity of a fluid by at least 0.001 Pascal-second (Pa·s), at least 0.001 Pa·s, at least 0.0009 Pa·s, at least 0.0008 Pa·s, at least 0.0007 Pa·s, at least 0.0006 Pa·s, at least 0.0005 Pa·s, at least 0.0004 Pa·s, at least 0.0003 Pa·s, at least 0.0002 Pa·s, at least 0.0001 Pa·s, at least 0.00005 Pa·s, or at least 0.00001 Pa·s. In some embodiments, the addition of an excipient to a pharmaceutical composition of the invention can increase or decrease the viscosity of the composition by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In some embodiments, the addition of an excipient to a pharmaceutical composition of the invention can increase or decrease the viscosity of the composition by no greater than 5%, no greater than 10%, no greater than 15%, no greater than 20%, no greater than 25%, no greater than 30%, no greater than 35%, no greater than 40%, no greater than 45%, no greater than 50%, no greater than 55%, no greater than 60%, no greater than 65%, no greater than 70%, no greater than 75%, no greater than 80%, no greater than 85%, no greater than 90%, no greater than 95%, or no greater than 99%. Any compound herein can be purified. A compound can be at least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 43% pure, at least 44% pure, at least 45% pure, at least 46% pure, at least 47% pure, at least 48% pure, at least 49% pure, at least 50% pure, at least 51% pure, at least 52% pure, at least 53% pure, at least 54% pure, at least 55% pure, at least 56% pure, at least 57% pure, at least 58% pure, at least 59% pure, at least 60% pure, at least 61% pure, at least 62% pure, at least 63% pure, at least 64% pure, at least 65% pure, at least 66% pure, at least 67% pure, at least 68% pure, at least 69% pure, at least 70% pure, at least 71% pure, at least 72% pure, at least 73% pure, at least 74% pure, at least 75% pure, at least 76% pure, at least 77% pure, at least 78% pure, at least 79% pure, at least 80% pure, at least 81% pure, at least 82% pure, at least 83% pure, at least 84% pure, at least 85% pure, at least 86% pure, at least 87% pure, at least 88% pure, at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least 99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, or at least 99.9% pure. Compositions of the invention can be packaged as a kit. In some embodiments, a kit includes written instructions on the administration or use of the composition. The written material can be, for example, a label. The written material can suggest conditions methods of administration. The instructions provide the subject and the supervising physician with the best guidance for achieving the optimal clinical outcome from the administration of the therapy. In some embodiments, the label can be approved by a regulatory agency, for example the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other regulatory agencies. Pharmaceutically-acceptable excipients. Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), each of which is incorporated by reference in its entirety. In some embodiments, the pharmaceutical composition provided herein comprises a sugar as an excipient. Non-limiting examples of sugars include trehalose, sucrose, glucose, lactose, galactose, glyceraldehyde, fructose, dextrose, maltose, xylose, mannose, maltodextrin, starch, cellulose, lactulose, cellobiose, mannobiose, and combinations thereof. In some embodiments, the pharmaceutical composition provided herein comprises a buffer as an excipient. Non-limiting examples of buffers include potassium phosphate, sodium phosphate, saline sodium citrate buffer (SSC), acetate, saline, physiological saline, phosphate buffer saline (PBS), 4-2-hydroxyethyl-1-piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), and piperazine-N,N′-bis(2-ethanesulfonic acid) buffer (PIPES), or combinations thereof. In some embodiments, a pharmaceutical composition of the invention comprises a source of divalent metal ions as an excipient. A metal can be in elemental form, a metal atom, or a metal ion. Non-limiting examples of metals include transition metals, main group metals, and metals of Group 1, Group 2, Group 3, Group 4, Group 5, Group 6, Group 7, Group 8, Group 9, Group 10, Group 11, Group 12, Group 13, Group 14, and Group 15 of the Periodic Table. Non-limiting examples of metals include lithium, sodium, potassium, cesium, magnesium, calcium, strontium, scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, palladium, silver, cadmium, tungsten, rhenium, osmium, iridium, platinum, gold, mercury, cerium, and samarium. In some embodiments, the pharmaceutical composition provided herein comprises an alcohol as an excipient. Non-limiting examples of alcohols include ethanol, propylene glycol, glycerol, polyethylene glycol, chlorobutanol, isopropanol, xylitol, sorbitol, maltitol, erythritol, threitol, arabitol, ribitol, mannitol, galactilol, fucitol, lactitol, and combinations thereof. Pharmaceutical preparations can be formulated with polyethylene glycol (PEG). PEGs with molecular weights ranging from about 300 g/mol to about 10,000,000 g/mol can be used. Non-limiting examples of PEGs include PEG 200, PEG 300, PEG 400, PEG 540, PEG 550, PEG 600, PEG 1000, PEG 1450, PEG 1500, PEG 2000, PEG 3000, PEG 3350, PEG 4000, PEG 4600, PEG 6000, PEG 8000, PEG 10,000, and PEG 20,000. Further excipients that can be used in a composition of the invention include, for example, benzalkonium chloride, benzethonium chloride, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorobutanol, dehydroacetic acid, ethylenediamine, ethyl vanillin, glycerin, hypophosphorous acid, phenol, phenylethyl alcohol, phenylmercuric nitrate, potassium benzoate, potassium metabisulfite, potassium sorbate, sodium bisulfite, sodium metabisulfite, sorbic acid, thimerasol, acetic acid, aluminum monostearate, boric acid, calcium hydroxide, calcium stearate, calcium sulfate, calcium tetrachloride, cellulose acetate pthalate, microcrystalline celluose, chloroform, citric acid, edetic acid, and ethylcellulose. In some embodiments, the pharmaceutical composition provided herein comprises an aprotic solvent as an excipient. Non-limiting examples of aprotic solvents include perfluorohexane, α,α,α-trifluorotoluene, pentane, hexane, cyclohexane, methylcyclohexane, decalin, dioxane, carbon tetrachloride, freon-11, benzene, toluene, carbon disulfide, diisopropyl ether, diethyl ether, t-butyl methyl ether, ethyl acetate, 1,2-dimethoxyethane, 2-methoxyethyl ether, tetrahydrofuran, methylene chloride, pyridine, 2-butanone, acetone, N-methylpyrrolidinone, nitromethane, dimethylformamide, acetonitrile, sulfolane, dimethyl sulfoxide, and propylene carbonate. The amount of the excipient in a pharmaceutical composition of the invention can be about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% by mass of the vasopressin in the pharmaceutical composition. The amount of the excipient in a pharmaceutical composition of the invention can be about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% by mass or by volume of the unit dosage form. The ratio of vasopressin to an excipient in a pharmaceutical composition of the invention can be about 100:about 1, about 95:about 1, about 90:about 1, about 85:about 1, about 80:about 1, about 75:about 1, about 70:about 1, about 65:about 1, about 60:about 1, about 55:about 1, about 50:about 1, about 45:about 1, about 40:about 1, about 35:about 1 about 30:about 1, about 25:about 1, about 20:about 1, about 15:about 1, about 10:about 1, about 9:about 1, about 8:about 1, about 7:about 1, about 6:about 1, about 5:about 1, about 4:about 1, about 3:about 1, about 2:about 1, about 1:about 1, about 1:about 2, about 1:about 3, about 1:about 4, about 1:about 5, about 1:about 6, about 1:about 7, about 1: about 8, about 1:about 9, or about 1:about 10. Pharmaceutically-Acceptable Salts. The invention provides the use of pharmaceutically-acceptable salts of any therapeutic compound described herein. Pharmaceutically-acceptable salts include, for example, acid-addition salts and base-addition salts. The acid that is added to the compound to form an acid-addition salt can be an organic acid or an inorganic acid. A base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base. In some embodiments, a pharmaceutically-acceptable salt is a metal salt. In some embodiments, a pharmaceutically-acceptable salt is an ammonium salt. Metal salts can arise from the addition of an inorganic base to a compound of the invention. The inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc. In some embodiments, a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt. Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the invention. In some embodiments, the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrrazole, pipyrrazole, imidazole, pyrazine, or pipyrazine. In some embodiments, an ammonium salt is a triethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrrazole salt, a pipyrrazole salt, an imidazole salt, a pyrazine salt, or a pipyrazine salt. Acid addition salts can arise from the addition of an acid to a compound of the invention. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid. In some embodiments, the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a glucaronate salt, a saccarate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate (mesylate) salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-toluenesulfonate salt, a citrate salt, an oxalate salt, or a maleate salt. Peptide Sequence. As used herein, the abbreviations for the L-enantiomeric and D-enantiomeric amino acids are as follows: alanine (A, Ala); arginine (R, Arg); asparagine (N, Asn); aspartic acid (D, Asp); cysteine (C, Cys); glutamic acid (E, Glu); glutamine (Q, Gln); glycine (G, Gly); histidine (H, His); isoleucine (I, Ile); leucine (L, Leu); lysine (K, Lys); methionine (M, Met); phenylalanine (F, Phe); proline (P, Pro); serine (S, Ser); threonine (T, Thr); tryptophan (W, Trp); tyrosine (Y, Tyr); valine (V, Val). In some embodiments, the amino acid is a L-enantiomer. In some embodiments, the amino acid is a D-enantiomer. A peptide of the disclosure can have about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% amino acid sequence homology to SEQ ID NO. 1. In some embodiments, a pharmaceutical composition of the invention comprises one or a plurality of peptides having about 80% to about 90% sequence homology to SEQ ID NO. 1, about 88% to about 90% sequence homology to SEQ ID NO. 1 or 88% to 90% sequence homology to SEQ ID NO. 1. In some embodiments, a pharmaceutical composition of the invention comprises vasopressin and one or more of a second, third, fourth, fifth, sixth, seventh, eighth, ninth, and tenth peptide. The ratio of vasopressin to another peptide in a pharmaceutical composition of the invention can be, for example, about 1000:about 1, about 990:about 1, about 980:about 1, about 970:about 1, about 960:about 1, about 950:about 1, about 800:about 1, about 700:about 1, about 600:1, about 500:about 1, about 400:about 1, about 300:about 1, about 200:about 1, about 100:about 1, about 95:about 1, about 90:about 1, about 85:about 1, about 80:about 1, about 75:about 1, about 70:about 1, about 65:about 1, about 60:about 1, about 55:about 1, about 50:about 1, about 45:about 1, about 40:about 1, about 35:about 1, about 30:about 1, about 25:about 1, about 20:about 1, about 19:about 1, about 18:about 1, about 17:about 1, about 16:about 1, about 15:about 1, about 14:about 1, about 13:about 1, about 12:about 1, about 11:about 1, or about 10:about 1. The amount of another peptide or impurity in a composition of the invention can be, for example, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% by mass of vasopressin. Another peptide or impurity present in a composition described herein can be, for example, SEQ ID NO.: 2, SEQ ID NO.: 3, SEQ ID NO.: 4, SEQ ID NO.: 5, SEQ ID NO.: 6, SEQ ID NO.: 7, SEQ ID NO.: 8, SEQ ID NO.: 9, SEQ ID NO.: 10, SEQ ID NO.: 11, SEQ ID NO.: 12, SEQ ID NO.: 13, SEQ ID NO.: 14, SEQ ID NO.: 15, SEQ ID NO.: 16, SEQ ID NO.: 17, a dimer of SEQ ID NO.: 1, an unidentified impurity, or any combination thereof. Non-limiting examples of methods that can be used to identify peptides of the invention include high-performance liquid chromatography (HPLC), mass spectrometry (MS), Matrix Assisted Laser Desorption Ionization Time-of-Flight (MALDI-TOF), electrospray ionization Time-of-flight (ESI-TOF), gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), and two-dimensional gel electrophoresis. HPLC can be used to identify peptides using high pressure to separate components of a mixture through a packed column of solid adsorbent material, denoted the stationary phase. The sample components can interact differently with the column based upon the pressure applied to the column, material used in stationary phase, size of particles used in the stationary phase, the composition of the solvent used in the column, and the temperature of the column. The interaction between the sample components and the stationary phase can affect the time required for a component of the sample to move through the column. The time required for component to travel through the column from injection point to elution is known as the retention time. Upon elution from the column, the eluted component can be detected using a UV detector attached to the column. The wavelength of light at which the component is detected, in combination with the component's retention time, can be used to identify the component. Further, the peak displayed by the detector can be used to determine the quantity of the component present in the initial sample. Wavelengths of light that can be used to detect sample components include, for example, about 200 nM, about 225 nm, about 250 nm, about 275 nm, about 300 nm, about 325 nm, about 350 nm, about 375 nm, and about 400 nm. Mass spectrometry (MS) can also be used to identify peptides of the invention. To prepare samples for MS analysis, the samples, containing the proteins of interest, are digested by proteolytic enzymes into smaller peptides. The enzymes used for cleavage can be, for example, trypsin, chymotrypsin, glutamyl endopeptidase, Lys-C, and pepsin. The samples can be injected into a mass spectrometer. Upon injection, all or most of the peptides can be ionized and detected as ions on a spectrum according to the mass to charge ratio created upon ionization. The mass to charge ratio can then be used to determine the amino acid residues present in the sample. The present disclosure provides several embodiments of pharmaceutical formulations that provide advantages in stability, administration, efficacy, and modulation of formulation viscosity. Any embodiments disclosed herein can be used in conjunction or individually. For example, any pharmaceutically-acceptable excipient, method, technique, solvent, compound, or peptide disclosed herein can be used together with any other pharmaceutically-acceptable excipient, method, technique, solvent, compound, or peptide disclosed herein to achieve any therapeutic result. Compounds, excipients, and other formulation components can be present at any amount, ratio, or percentage disclosed herein in any such formulation, and any such combination can be used therapeutically for any purpose described herein and to provide any viscosity described herein. EXAMPLES Example 1: Impurities of Vasopressin as Detected by HPLC To analyze degradation products of vasopressin that can be present in an illustrative formulation of vasopressin, gradient HPLC was performed to separate vasopressin from related peptides and formulation components. TABLE 2 below depicts the results of the experiment detailing the chemical formula, relative retention time (RRT), molar mass, and structure of vasopressin and detected impurities. Vasopressin was detected in the eluent using UV absorbance. The concentration of vasopressin in the sample was determined by the external standard method, where the peak area of vasopressin in sample injections was compared to the peak area of vasopressin reference standards in a solution of known concentration. The concentrations of related peptide impurities in the sample were also determined using the external standard method, using the vasopressin reference standard peak area and a unit relative response factor. An impurities marker solution was used to determine the relative retention times of identified related peptides at the time of analysis. Experimental conditions are summarized in TABLE 2 below. TABLE 2 Column YMC-Pack ODS-AM, 3 μm, 120 Å pore, 4.6 × 100 mm Column 25° C. Temperature Flow Rate 1.0 mL/min Detector 215 nm Note: For Identification a Diode Array Detector (DAD) was used with the range of 200-400 nm. Injection Volume 100 μL Run time 55 minutes Autosampler Vials Polypropylene vials Pump (gradient) Time (min) % A % B Flow 0 90 10 1.0 40 50 50 1.0 45 50 50 1.0 46 90 10 1.0 55 90 10 1.0 The diluent used for the present experiment was 0.25% v/v Acetic Acid, which was prepared by transferring 2.5 mL of glacial acetic acid into a 1-L volumetric flask containing 500 mL of water. The solution was diluted to the desired volume with water. Phosphate buffer at pH 3.0 was used for mobile phase A. The buffer was prepared by weighing approximately 15.6 g of sodium phosphate monobasic monohydrate into a beaker. 1000 mL of water was added, and mixed well. The pH was adjusted to 3.0 with phosphoric acid. The buffer was filtered through a 0.45 μm membrane filter under vacuum, and the volume was adjusted as necessary. An acetonitrile:water (50:50) solution was used for mobile phase B. To prepare mobile phase B, 500 mL of acetonitrile was mixed with 500 mL of water. The working standard solution contained approximately 20 units/mL of vasopressin. The standard solution was prepared by quantitatively transferring the entire contents of 1 vial of USP Vasopressin RS with diluent to a 50-mL volumetric flask. The intermediate standard solution was prepared by pipetting 0.5 mL of the working standard solution into a 50-mL volumetric flask. The sensitivity solution was prepared by pipetting 5.0 mL of the intermediate standard solution into a 50-mL volumetric flask. The solution was diluted to the volume with Diluent and mixed well. A second working standard solution was prepared as directed under the standard preparation. A portion of the vasopressin control sample was transferred to an HPLC vial and injected. The control was stable for 120 hours when stored in autosampler vials at ambient laboratory conditions. To prepare the impurities marker solution, a 0.05% v/v acetic acid solution was prepared by pipetting 200.0 mL of a 0.25% v/v acetic acid solution into a 1-L volumetric flask. The solution was diluted to the desired volume with water and mixed well. To prepare the vasopressin impurity stock solutions, the a solution of each impurity was prepared in a 25 mL volumetric flask and diluted with 0.05% v/v acetic acid to a concentration suitable for HPLC injection. To prepare the MAA/H-IBA (Methacrylic Acid/α-Hydroxy-isobutyric acid) stock solution, a stock solution containing approximately 0.3 mg/mL H-IBA and 0.01 mg/mL in 0.05% v/v acetic acid was made in a 50 mL volumetric flask. To prepare the chlorobutanol diluent, about one gram of hydrous chlorobutanol was added to 500 mL of water. Subsequently, 0.25 mL of acetic acid was added and the solution was stirred to dissolve the chlorobutanol. To prepare the impurity marker solution, vasopressin powder was mixed with the impurity stock solutions prepared above. The solutions were diluted to volume with the chlorobutanol diluent. The solutions were aliquoted into individual crimp top vials and stored at 2-8° C. At time of use, the solutions were removed from refrigeration (2-8° C.) and allowed to reach room temperature. The vasopressin impurity marker solution was stable for at least 120 hours when stored in auto-sampler vials at ambient laboratory conditions. The solution was suitable for use as long as the chromatographic peaks could be identified based on comparison to the reference chromatogram. To begin the analysis, the HPLC system was allowed to equilibrate for at least 30 minutes using mobile phase B, followed by time 0 min gradient conditions until a stable baseline was achieved. The diluent was injected at the beginning of the run, and had no peaks that interfered with Vasopressin at around 18 minutes as shown in FIG. 1. A single injection of the sensitivity solution was performed, wherein the signal-to-noise ratio of the Vasopressin was greater than or equal to ten as shown in FIG. 2. A single injection of the impurities marker solution was then made. The labeled impurities in the reference chromatogram were identified in the chromatogram of the marker solution based on their elution order and approximate retention times shown in FIG. 3 and FIG. 4. FIG. 4 is a zoomed in chromatograph of FIG. 3 showing the peaks that eluted between 15 and 30 minutes. The nomenclature, structure, and approximate retention times for individual identified impurities are detailed in TABLE 3. A single injection of the working standard solution was made to ensure that the tailing factor of the vasopressin peak was less than or equal to about 2.0 as shown in FIG. 5. A total of five replicate injections of the working standard solution were made to ensure that the relative standard deviation (% RSD) of the five replicate vasopressin peak areas was not more than 2.0%. Two replicate injections of the check standard preparation were to confirm that the check standard conformity was 99.0%-101.0%. One injection of the control sample was made to confirm that the assay of the control sample met the control limits established for the sample. Then, one injection of the working standard solution was made. Following the steps above done to confirm system suitability, a single injection of each sample preparation was made. The chromatograms were analyzed to determine the vasopressin and impurity peak areas. The chromatogram is depicted in FIG. 6. The working standard solution was injected after 1 to 4 sample injections, and the bracketing standard peak areas were averaged for use in the calculations to determine peak areas of vasopressin and associated impurities. The relative standard deviation (% RSD) of vasopressin peak areas for the six injections of working standard solution was calculated by including the initial five injections from the system suitability steps above and each of the subsequent interspersed working standard solution injections. The calculations were done to ensure that each of the % RSD were not more than 2.0%. The retention time of the major peak in the chromatogram of the sample preparation corresponded to that of the vasopressin peak in the working standard solution injection that preceded the sample preparation injection. The UV spectrum (200-400 nm) of the main peak in the chromatogram of the sample preparation compared to the UV spectrum of vasopressin in the working standard preparation. FIG. 7 depicts a UV spectrum of a vasopressin sample and FIG. 8 depicts a UV spectrum of vasopressin standard. To calculate the vasopressin units/mL, the following formula was used: Vasopressin   units  /  mL = R U R S  Conc   STD where: RU=Vasopressin peak area response of Sample preparation. RS=average vasopressin peak area response of bracketing standards. Conc STD=concentration of the vasopressin standard in units/mL To identify the impurities, the % Impurity and identity for identified impurities (TABLE 3) that are were greater than or equal to 0.10% were reported. Impurities were truncated to 3 decimal places and then rounded to 2 decimal places, unless otherwise specified. The impurities were calculated using the formula below: %   impurity = R I R S  Conc   STD 20   U  /  mL  100  % where: RI=Peak area response for the impurity 20 U/mL=Label content of vasopressin TABLE 3 below details the chemical formula, relative retention time (RRT in minutes), molar mass, and structure of vasopressin and detected impurities. TABLE 3 Appr. Molar Name Formula RRT Mass (g) Vasopressin C46H65N15O12S2 1.00 1084.23 (Arginine Vasopressin, AVP) CYFQNCPRG-NH2 SEQ ID NO.: 1 (disulfide bridge between cys residues) Gly9-vasopressin C46H64N14O13S2 1.07 1085.22 (Gly9-AVP) CYFQNCPRG SEQ ID NO.: 2 (disulfide bridge between cys residues) Asp5-vasopressin C46H64N14O13S2 1.09 1085.22 (Asp5-AVP) CYFQDCPRG-NH2 SEQ ID NO.: 3 (disulfide bridge between cys residues) Glu4-vasopressin C46H64N14O13S2 1.12 1085.22 (Glu4-AVP) CYFENCPRG-NH2 SEQ ID NO.: 4 (disulfide bridge between cys residues) Acetyl-vasopressin C48H67N15O13S2 1.45 1126.27 (Acetyl-AVP) Ac-CYFQNCPRG-NH2 SEQ ID NO.: 7 (disulfide bridge between cys residues) D-Asn-vasopressin C46H65N15O12S2 0.97 1084.23 (DAsn-AVP) CYFQ(D-Asn)CPRG-NH2 SEQ ID NO.: 10 (disulfide bridge between cys residues) Dimeric-vasopressin C92H130N30O24S4 1.22 2168.46 (Dimer-AVP) (monomers cross linked by disulfide bridges) Example 2: Investigation of pH To determine a possible pH for a vasopressin formulation with good shelf life, vasopressin formulations were prepared in 10 mM citrate buffer diluted in isotonic saline across a range of pH. Stability was assessed via HPLC as in EXAMPLE 1 after incubation of the formulations at 60° C. for one week. FIG. 9 illustrates the results of the experiment. The greatest level of stability was observed at pH 3.5. At pH 3.5, the percent label claim (% LC) of vasopressin was highest, and the proportion of total impurities was lowest. Example 3: Effect of Peptide Stabilizers on Vasopressin Formulation To observe the effect of stabilizers on the degradation of vasopressin, a series of peptide stabilizers were added to a vasopressin formulation as detailed in TABLE 4. Stability of vasopressin was assessed via HPLC after incubation of the formulations at 60° C. for one week. TABLE 4 n-Meth- Poloxamer ylpyrrolidone Ethanol PEG 400 Glycerol 188 HPbCDa (NMP) 1% 1% 1% 1% 1% 1% 10% 10% 10% 10% 10% 10% aHydroxypropyl beta-Cyclodextrin FIG. 10 illustrates the stability of vasopressin in terms of % label claim at varying concentrations of stabilizer. The results indicate that the tested stabilizers provided a greater stabilizing effect at 1% concentration than at 10%. Also, in several cases the stabilization effect was about 5% to about 10% greater than that observed in the experiments of EXAMPLE 2. Example 4: Effect of Buffer and Divalent Metals on Vasopressin Formulation To determine whether different combinations of buffers and use of divalent metals affect vasopressin stability, vasopressin formulations with varying concentrations of citrate and acetate buffers and variable concentrations of calcium, magnesium, and zinc ions were prepared. Solutions of 0 mM, 10 mM, 20 mM, and 80 mM calcium, magnesium, and zinc were prepared and each was combined with 1 mM or 10 mM of citrate or acetate buffers to test vasopressin stability. The tested combinations provided vasopressin stability comparable to that of a vasopressin formulation lacking buffers and divalent metals. However, that the addition of divalent metal ions was able to counteract the degradation of vasopressin caused by the use of a citrate buffer. Example 5: Illustrative Formulations for Assessment of Vasopressin Stability An aqueous formulation of vasopressin is prepared using 10% trehalose, 1% sucrose, or 5% NaCl and incubated at 60° C. for one week, at which point stability of vasopressin is assessed using HPLC. A formulation containing 50 units of vasopressin is lyophilized. The lyophilate is reconstituted with water and either 100 mg of sucrose or 100 mg of lactose, and the stability of vasopressin is tested via HPLC after incubation at 60° C. for one week. Co-solvents are added to a vasopressin solution to assess vasopressin stability. 95% solvent/5% 20 mM acetate buffer solutions are prepared using propylene glycol, DMSO, PEG300, NMP, glycerol, and glycerol:NMP (1:1), and used to create formulations of vasopressin. The stability of vasopressin is tested after incubation at 60° C. for one week. Amino acid and phosphate buffers are tested with vasopressin to assess vasopressin stability. Buffers of 10 mM glycine, aspartate, phosphate are prepared at pH 3.5 and 3.8 and used to create formulations of vasopressin. The stability of vasopressin is tested after incubation at 60° C. for one week. A vasopressin formulation in 10% polyvinylpyrrolidone is prepared to assess vasopressin stability. The stability of vasopressin will be tested after incubation at 60° C. for one week. A vasopressin formulation that contains 0.9% saline, 10 mM acetate buffer, 0.2 unit/mL API/mL in 100 mL of total volume is prepared. The pH of the solution is varied from pH 3.5-3.8 to test the stability of vasopressin. A vasopressin formulation in about 50% to about 80% DMSO (for example, about 80%), about 20% to about 50% ethyl acetate (for example, about 20%), and about 5% to about 30% polyvinylpyrrolidone (PVP) (for example, about 10% by mass of the formulation) is prepared to assess vasopressin stability. PVP K12 and PVP K17 are each independently tested in the formulation. The stability of vasopressin is tested after incubation at 60° C. for one week. A vasopressin formulation in about 70% to about 95% ethyl acetate, and about 5% to about 30% PVP is prepared to assess vasopressin stability. PVP K12 and PVP K17 are each independently tested in the formulation. The stability of vasopressin is tested after incubation at 60° C. for one week. A vasopressin formulation in 90% DMSO and 10% PVP is prepared to test vasopressin stability. PVP K12 and PVP K17 are each independently tested in the formulation. The stability of vasopressin is tested after incubation at 60° C. for one week. Example 6: Illustrative Vasopressin Formulation for Clinical Use A formulation for vasopressin that can be used in the clinic is detailed in TABLE 5 below: TABLE 5 Ingredient Function Amount (per mL) Vasopressin, USP Active Ingredient 20 Units (~0.04 mg) Chlorobutanol, Hydrous NF Preservative 5.0 mg Acetic Acid, NF pH Adjustment To pH 3.4-3.6 (~0.22 mg) Water for injection, USP/EP Diluent QS Example 7: Illustrative Regimen for Therapeutic Use of a Vasopressin Formulation Vasopressin is indicated to increase blood pressure in adults with vasodilatory shock (for example, adults who are post-cardiotomy or septic) who remain hypotensive despite fluids and catecholamines. Preparation and Use of Vasopressin. Vasopressin is supplied in a carton of 25 multi-dose vials each containing 1 mL vasopressin at 20 units/mL. Vasopressin is stored between 15° C. and 25° C. (59° F. and 77° F.), and is not frozen. Alternatively, a unit dosage form of vasopressin can be stored between 2° C. and 8° C. for about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. Vials of vasopressin are to be discarded 48 hours after first puncture. Vasopressin is prepared according to TABLE 6 below: TABLE 6 Mix Fluid Restriction? Final Concentration Vasopressin Diluent No 0.1 units/mL 2.5 mL (50 units) 500 mL Yes 1 unit/mL 5 mL (100 units) 100 mL Vasopressin is diluted in normal saline (0.9% sodium chloride) or 5% dextrose in water (D5W) prior to use to either 0.1 units/mL or 1 unit/mL for intravenous administration. Unused diluted solution is discarded after 18 hours at room temperature or after 24 hours under refrigeration. Diluted vasopressin should be inspected for particulate matter and discoloration prior to use whenever solution and container permit. The goal of treatment with vasopressin is optimization of perfusion to critical organs, but aggressive treatment can compromise perfusion of organs, like the gastrointestinal tract, for which function is difficult to monitor. Titration of vasopressin to the lowest dose compatible with a clinically-acceptable response is recommended. For post-cardiotomy shock, a dose of 0.03 units/minute is used as a starting point. For septic shock, a dose of 0.01 units/minute is recommended. If the target blood pressure response is not achieved, titrate up by 0.005 units/minute at 10- to 15-minute intervals. The maximum dose for post-cardiotomy shock is 0.1 units/minute and for septic shock 0.07 units/minute. After target blood pressure has been maintained for 8 hours without the use of catecholamines, taper vasopressin by 0.005 units/minute every hour as tolerated to maintain target blood pressure. Vasopressin is provided at 20 units per mL of diluent, which is packaged as 1 mL of vasopressin per vial, and is diluted prior to administration. Contraindications, Adverse Reactions, and Drug-Drug Interactions. Vasopressin is contraindicated in patients with known allergy or hypersensitivity to 8-L-arginine vasopressin or chlorobutanol. Additionally, use of vasopressin in patients with impaired cardiac response can worsen cardiac output. Adverse reactions have been observed with the use of vasopressin, which adverse reactions include bleeding/lymphatic system disorders, specifically, hemorrhagic shock, decreased platelets, intractable bleeding; cardiac disorders, specifically, right heart failure, atrial fibrillation, bradycardia, myocardial ischemia; gastrointestinal disorders, specifically, mesenteric ischemia; hepatobiliary disorders, specifically, increased bilirubin levels; renal/urinary disorders, specifically, acute renal insufficiency; vascular disorders, specifically, distal limb ischemia; metabolic disorders, specifically, hyponatremia; and skin disorders, specifically, and ischemic lesions. These reactions are reported voluntarily from a population of uncertain size. Thus, reliable estimation of frequency or establishment of a causal relationship to drug exposure is unlikely. Vasopressin has been observed to interact with other drugs. For example, use of vasopressin with catecholamines is expected to result in an additive effect on mean arterial blood pressure and other hemodynamic parameters. Use of vasopressin with indomethacin can prolong the effect of vasopressin on cardiac index and systemic vascular resistance. Indomethacin more than doubles the time to offset for vasopressin's effect on peripheral vascular resistance and cardiac output in healthy subjects. Further, use of vasopressin with ganglionic blocking agents can increase the effect of vasopressin on mean arterial blood pressure. The ganglionic blocking agent tetra-ethylammonium increases the pressor effect of vasopressin by 20% in healthy subjects. Use of vasopressin with furosemide increases the effect of vasopressin on osmolar clearance and urine flow. Furosemide increases osmolar clearance 4-fold and urine flow 9-fold when co-administered with exogenous vasopressin in healthy subjects. Use of vasopressin with drugs suspected of causing SIADH (Syndrome of inappropriate antidiuretic hormone secretion), for example, SSRIs, tricyclic antidepressants, haloperidol, chlorpropamide, enalapril, methyldopa, pentamidine, vincristine, cyclophosphamide, ifosfamide, and felbamate can increase the pressor effect in addition to the antidiuretic effect of vasopressin. Additionally, use of vasopressin with drugs suspected of causing diabetes insipidus for example, demeclocycline, lithium, foscarnet, and clozapine can decrease the pressor effect in addition to the antidiuretic effect of vasopressin. Halothane, morphine, fentanyl, alfentanyl and sufentanyl do not impact exposure to endogenous vasopressin. Use of Vasopressin in Specific Populations. Vasopressin is a Category C drug for pregnancy. Due to a spillover into the blood of placental vasopressinase, the clearance of exogenous and endogenous vasopressin increases gradually over the course of a pregnancy. During the first trimester of pregnancy the clearance is only slightly increased. However, by the third trimester the clearance of vasopressin is increased about 4-fold and at term up to 5-fold. Due to the increased clearance of vasopressin in the second and third trimester, the dose of vasopressin can be up-titrated to doses exceeding 0.1 units/minute in post-cardiotomy shock and 0.07 units/minute in septic shock. Vasopressin can produce tonic uterine contractions that could threaten the continuation of pregnancy. After delivery, the clearance of vasopressin returns to preconception levels. Overdosage. Overdosage with vasopressin can be expected to manifest as a consequence of vasoconstriction of various vascular beds, for example, the peripheral, mesenteric, and coronary vascular beds, and as hyponatremia. In addition, overdosage of vasopressin can lead less commonly to ventricular tachyarrhythmias, including Torsade de Pointes, rhabdomyolysis, and non-specific gastrointestinal symptoms. Direct effects of vasopressin overdose can resolve within minutes of withdrawal of treatment. Pharmacology of Vasopressin. Vasopressin is a polypeptide hormone that causes contraction of vascular and other smooth muscles and antidiuresis, which can be formulated as a sterile, aqueous solution of synthetic arginine vasopressin for intravenous administration. The 1 mL solution contains vasopressin 20 units/mL, chlorobutanol, NF 0.5% as a preservative, and water for injection, USP adjusted with acetic acid to pH 3.4-3.6. The chemical name of vasopressin is Cyclo (1-6) L-Cysteinyl-L-Tyrosyl-L-Phenylalanyl-L-Glutaminyl-L-Asparaginyl-L-Cysteinyl-L-Prolyl-L-Arginyl-L-Glycinamide. Vasopressin is a white to off-white amorphous powder, freely soluble in water. The structural formula of vasopressin is: Molecular Formula: C46H65N15O12S2; Molecular Weight: 1084.23 One mg of vasopressin is equivalent to 530 units. Alternatively, one mg of vasopressin is equivalent to 470 units. The vasoconstrictive effects of vasopressin are mediated by vascular V1 receptors. Vascular V1 receptors are directly coupled to phopholipase C, resulting in release of calcium, leading to vasoconstriction. In addition, vasopressin stimulates antidiuresis via stimulation of V2 receptors which are coupled to adenyl cyclase. At therapeutic doses, exogenous vasopressin elicits a vasoconstrictive effect in most vascular beds including the splanchnic, renal, and cutaneous circulation. In addition, vasopressin at pressor doses triggers contractions of smooth muscles in the gastrointestinal tract mediated by muscular V1-receptors and release of prolactin and ACTH via V3 receptors. At lower concentrations typical for the antidiuretic hormone, vasopressin inhibits water diuresis via renal V2 receptors. In patients with vasodilatory shock, vasopressin in therapeutic doses increases systemic vascular resistance and mean arterial blood pressure and reduces the dose requirements for norepinephrine. Vasopressin tends to decrease heart rate and cardiac output. The pressor effect is proportional to the infusion rate of exogenous vasopressin. Onset of the pressor effect of vasopressin is rapid, and the peak effect occurs within 15 minutes. After stopping the infusion, the pressor effect fades within 20 minutes. There is no evidence for tachyphylaxis or tolerance to the pressor effect of vasopressin in patients. At infusion rates used in vasodilatory shock (0.01-0.1 units/minute), the clearance of vasopressin is 9 to 25 mL/min/kg in patients with vasodilatory shock. The apparent half-life of vasopressin at these levels is <10 minutes. Vasopressin is predominantly metabolized and only about 6% of the dose is excreted unchanged in urine. Animal experiments suggest that the metabolism of vasopressin is primarily by liver and kidney. Serine protease, carboxipeptidase and disulfide oxido-reductase cleave vasopressin at sites relevant for the pharmacological activity of the hormone. Thus, the generated metabolites are not expected to retain important pharmacological activity. Carcinogenesis, Mutagenesis, Impairment of Fertility. Vasopressin was found to be negative in the in vitro bacterial mutagenicity (Ames) test and the in vitro Chinese hamster ovary (CHO) cell chromosome aberration test. In mice, vasopressin can have an effect on function and fertilizing ability of spermatozoa. Clinical studies. Increases in systolic and mean blood pressure following administration of vasopressin were observed in seven studies in septic shock and eight studies in post-cardiotomy vasodilatory shock. Example 8: Effect of Temperature on Vasopressin Formulations To test the effect of temperature on the stability of vasopressin formulation, solutions containing 20 units/mL vasopressin and chlorobutanol, adjusted to pH 3.5 with acetic acid, were prepared. One mL of each vasopressin formulations was then filled into 3 cc vials. Each Vasopressin Formulation was stored either inverted or upright for at least three months, up to 24 months, at: (i) 5° C.; (ii) 25° C. and 60% relative humidity; or (iii) 40° C. and 75% humidity, and the amount of vasopressin (U/mL) and % total impurities were measured periodically. TABLES 7-12 below display the results of the experiments at 5° C. The results of the experiments at 25° C. are included in TABLES 13-18. All of the experiments were performed in triplicate. The results of the experiments at 40° C. are included in TABLES 19-24. For each temperature tested, three lots of the vasopressin formulation were stored for 24 months (5° C. and 25° C.) and 3 months (40° C.), and measurements were taken at regular intervals during the testing periods. “NMT” as used in the tables denotes “not more than.” The vasopressin and impurity amounts observed in the experiments conducted at 5° C. are shown in TABLES 7-12 below (AVP=Vasopressin). TABLE 7 Samples stored inverted at 5° C. Time in months Test Initial 1 2 3 6 9 12 18 24 AVP 19.4 19.4 19.4 19.3 19.5 19.4 19.5 19.4 19.3 Assay Total 2.3% 2.0% 2.1% 2.3% 2.2% 2.3% 2.6% 2.9% 2.9% Impurities TABLE 8 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 U/mL 19.7 19.7 19.7 19.7 19.9 19.7 19.8 19.7 19.5 Assay Total 2.7% 2.2% 2.3% 2.4% 2.1% 2.3% 2.7% 2.9% 2.9% Impurities: NMT 17.0% TABLE 9 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 U/mL 19.7 19.7 19.6 19.7 19.8 19.7 19.9 19.8 19.5 Assay Total 2.2% 1.9% 2.0% 2.2% 2.0% 2.1% 2.4% 2.6% 2.8% Impurities: NMT 17.0% TABLE 10 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 U/mL 19.4 19.5 19.4 19.4 19.5 19.5 19.5 19.4 19.3 Assay Total 2.3% 2.1% 2.1% 2.3% 2.1% 2.3% 2.5% 2.9% 2.9% Impurities: NMT 17.0% TABLE 11 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 U/mL 19.7 19.7 19.6 19.7 19.8 19.7 19.8 19.7 19.5 Assay Total 2.7% 2.1% 2.2% 2.2% 2.2% 2.3% 2.6% 2.9% 2.8% Impurities: NMT 17.0% TABLE 12 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 U/mL 19.7 19.7 19.6 19.7 19.8 19.7 19.9 19.8 19.5 Assay Total 2.2% 1.8% 2.0% 2.2% 2.2% 2.1% 2.4% 2.8% 2.7% Impurities: NMT 17.0% The vasopressin and impurity amounts observed in the experiments conducted at 25° C. and 60% relative humidity are shown in TABLES 13-18 below. TABLE 13 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP Assay 16.0-21.0 U/mL 19.8 19.4 19.1 18.8 18.3 17.5 17.3 Total 1.1% 2.4% 3.7% 4.7% 5.9% 9.0% 13.6% Impurities: NMT 17.0% TABLE 14 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP Assay 16.0-21.0 U/mL 20.1 19.7 19.3 19 18.6 17.6 17.6 Total 1.3% 2.5% 3.4% 4.6% 5.6% 9.0% 13.4% Impurities: NMT 17.0% TABLE 15 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP Assay 16.0-21.0 U/mL 19.9 19.6 19.2 19 18.7 18 17.4 Total 1.5% 2.6% 3.3% 4.6% 5.9% 9.0% 12.9% Impurities: NMT 17.0% TABLE 16 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP Assay 16.0-21.0 U/mL 19.8 19.4 19.1 18.8 18.3 17.5 17.4 Total 1.1% 2.4% 3.2% 4.8% 5.6% 9.2% 13.1% Impurities: NMT 17.0% TABLE 17 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP Assay 16.0-21.0 U/mL 20.1 19.7 19.4 18.9 18.6 17.8 17.7 Total 1.3% 2.5% 3.3% 4.5% 5.7% 9.1% 13.3% Impurities: NMT 17.0% TABLE 18 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP Assay 16.0-21.0 U/mL 19.9 19.6 19.2 19 18.5 18.1 17.4 Total 1.5% 2.5% 3.7% 4.7% 5.9% 9.1% 13.3% Impurities: NMT 17.0% The vasopressin and impurity amounts observed in the experiments conducted at 40° C. and 75% relative humidity are shown in TABLES 19-24 below. TABLE 19 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.8 19.1 18.6 17.3 Assay Total Impurities: 1.1% 3.7% 7.3% 10.6% NMT 17.0% TABLE 20 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.8 18.9 18.5 17.2 Assay Total Impurities: 1.1% 3.6% 7.2% 10.3% NMT 17.0% TABLE 21 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 20.1 19.3 18.7 17.6 Assay Total Impurities: 1.3% 3.6% 7.3% 10.3% NMT 17.0% TABLE 22 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 20.1 18.9 18.7 17.4 Assay Total Impurities: 1.3% 3.5% 7.1% 10.2% NMT 17.0% TABLE 23 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.9 19.2 18.3 17.4 Assay Total Impurities: 1.5% 3.7% 6.3% 10.3% NMT 17.0% TABLE 24 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.9 19.2 18.3 17.5 Assay Total Impurities: 1.5% 3.8% 6.3% 10.5% NMT 17.0% The results of the above experiments suggested that storage in either an upright or inverted position did not markedly affect the stability of vasopressin. The samples held at 5° C. exhibited little fluctuation in vasopressin amounts over 24 months, and the amount of total impurities did not increase above 3% during the testing period (TABLES 7-12). The samples held at 25° C. and 60% relative humidity exhibited a decrease in vasopressin amount of about 10-12% after 24 months (TABLES 13-18). The amount of impurities observed in the samples stored at 25° C. and 60% relative humidity after 24 months exceeded 13% in some samples, whereas the amount of impurities observed in the samples stored at 5° C. did not exceed 3% after 24 months. After about three months, the samples held at 40° C. exhibited a decrease in the amount of vasopressin of about 10-12%. The amount of impurities observed at 40° C. exceeded 10% after three months, whereas the amount of impurities observed in the samples stored at 5° C. was less than 3% after three months (TABLES 19-24). Experiments were also conducted on the same samples above over the course of the experiments to measure the amount of individual impurities in the samples, pH of the samples, chlorobutanol content, particulate matter, antimicrobial effectiveness, and bacterial endotoxin levels (TABLES 25-42). (NR=no reading; ND=not determined; UI=unidentified impurity). The anti-microbial effectiveness of the solution was established to determine the amount of antimicrobial agents in the formulation that protect against bacterial contamination. The bullets in the tables below indicate that the sample was not tested for anti-microbial effectiveness at that specific time point. The bacterial endotoxin levels were also measured for some of the formulations. The bullets in the tables below indicate that the sample was not tested for bacterial endotoxin levels at that specific time point. TABLE 25 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 U/mL 19.4 19.4 19.4 19.3 19.5 19.4 19.5 19.4 19.3 Assay Related SEQ ID 0.5% 0.5% 0.6% 0.6% 0.6% 0.6% 0.7% 0.8% 0.9% Substances NO.: 2 NMT 6.0% SEQ ID 0.6% 0.6% 0.6% 0.7% 0.7% 0.7% 0.8% 0.9% 1.0% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP- NR NR NR NR NR NR NR NR NR Dimer: NMT 1.0% Acetyl- 0.3% 0.2% 0.3% 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.84: NR NR 0.1% NR NR NR NR NR NR NMT 1.0% UI-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.1% NR 0.1% NR NR NR NR NR NR NMT 1.0% Total 2.3% 2.0% 2.1% 2.3% 2.2% 2.3% 2.6% 2.9% 2.9% Impurities: NMT 17.0% pH 2.5-4.5 3.5 3.5 3.5 3.5 3.5 3.5 3.5 3.8 3.5 Chlorobutanol 0.25-0.60% 0.48% 0.49% 0.48% 0.48% 0.47% 0.48% 0.48% 0.49% 0.49% w/v Particulate NMT 6000 0 1 1 1 2 16 2 4 1 Matter (USP) (≧10 μm) NMT 600 (≧25 μm) 0 0 0 0 0 0 0 0 0 Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 EU/mL • • • • • • • • • Endotoxin TABLE 26 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 U/mL 19.7 19.7 19.7 19.7 19.9 19.7 19.8 19.7 19.5 Assay Related SEQ ID 0.6% 0.5% 0.5% 0.6% 0.5% 0.6% 0.7% 0.8% 0.8% Substances NO.: 2: NMT 6.0% SEQ ID 0.6% 0.6% 0.6% 0.6% 0.6% 0.7% 0.7% 0.8% 0.9% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR NR NR NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.75-0.78: 0.2% 0.2% 0.2% 0.2% NR 0.1% 0.2% 0.2% 0.2% NMT 1.0% UI-0.83-0.84: 0.1% 0.1% 0.1% NR 0.1% NR NR NR NR NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% Total 2.7% 2.2% 2.3% 2.4% 2.1% 2.3% 2.7% 2.9% 2.9% Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 Chlorobutanol 0.25-0.60% 0.48% 0.48% 0.48% 0.47% 0.48% 0.48% 0.49% 0.48% 0.49% w/v Particulate NMT 6000 1 1 1 1 1 15 2 3 2 Matter (USP) (≧10 μm) NMT 600 (≧25 μm) 0 0 0 0 0 0 0 0 0 Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 EU/mL • • • • • • • • • Endotoxin TABLE 27 Samples stored inverted at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 U/mL 19.7 19.7 19.6 19.7 19.8 19.7 19.9 19.8 19.5 Assay Related SEQ ID 0.5% 0.5% 0.5% 0.5% 0.5% 0.6% 0.6% 0.8% 0.8% Substances NO.: 2: NMT 6.0% SEQ ID 0.5% 0.5% 0.5% 0.6% 0.6% 0.7% 0.7% 0.8% 0.9% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR NR NR NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.75-0.78: NR NR NR NR NR NR NR NR NR NMT 1.0% UI-0.83-0.84: NR NR 0.1% NR NR NR NR NR 0.1% NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.76: NR NR NR 0.1% NR NR NR NR NR NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.1% NR NR NR NR NR NR NR NR NMT 1.0% Total 2.2% 1.9% 2.0% 2.2% 2.0% 2.1% 2.4% 2.6% 2.8% Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.5 3.6 3.5 3.5 3.5 3.6 3.5 3.5 Chlorobutanol 0.25-0.60% 0.47% 0.48% 0.47% 0.47% 0.47% 0.47% 0.48% 0.48% 0.48% w/v Particulate NMT 6000 1 2 1 2 1 4 2 1 3 Matter (USP) (≧10 μm) NMT 600 (≧25 μm) 0 0 0 0 0 0 0 0 0 Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 EU/mL • • • • • • • • • Endotoxin TABLE 28 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 U/mL 19.4 19.5 19.4 19.4 19.5 19.5 19.5 19.4 19.3 Assay Related SEQ ID 0.5% 0.6% 0.6% 0.6% 0.6% 0.6% 0.7% 0.8% 0.9% Substances NO.: 2: NMT 6.0% SEQ ID 0.6% 0.6% 0.6% 0.7% 0.7% 0.7% 0.7% 0.9% 1.0% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP- NR NR NR NR NR NR NR NR NR Dimer: NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.84: NR NR 0.1% NR NR NR NR NR NR NMT 1.0% UI-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.1% NR NR NR NR NR NR NR NR NMT 1.0% Total 2.3% 2.1% 2.1% 2.3% 2.1% 2.3% 2.5% 2.9% 2.9% Impurities: NMT 17.0% pH 2.5-4.5 3.5 3.5 3.5 3.5 3.5 3.5 3.5 3.8 3.5 Chlorobutanol 0.25-0.60% 0.48% 0.48% 0.48% 0.48% 0.48% 0.48% 0.48% 0.49% 0.49% w/v Particulate NMT 6000 0 2 2 2 1 2 2 4 1 Matter (USP) (≧10 μm) NMT 600 (≧25 μm) 0 0 0 0 0 0 0 0 0 Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 EU/mL • • • • • • • • • Endotoxin TABLE 29 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 U/mL 19.7 19.7 19.6 19.7 19.8 19.7 19.8 19.7 19.5 Assay Related SEQ ID 0.6% 0.5% 0.5% 0.5% 0.6% 0.6% 0.6% 0.8% 0.7% Substances NO.: 2: NMT 6.0% SEQ ID 0.6% 0.6% 0.6% 0.6% 0.6% 0.7% 0.7% 0.8% 0.8% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR NR NR NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.2% 0.3% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.75-0.78: 0.2% 0.2% NR 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% NMT 1.0% UI-0.83-0.84: 0.1% NR 0.1% NR NR NR NR NR NR NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% 0.3% 0.3% 0.2% NMT 1.0% UI-1.67: NR NR NR 0.2% NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% Total 2.7% 2.1% 2.2% 2.2% 2.2% 2.3% 2.6% 2.9% 2.8% Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 Chlorobutanol 0.25-0.60% 0.48% 0.48% 0.48% 0.48% 0.48% 0.48% 0.49% 0.49% 0.49% w/v Particulate NMT 6000 1 1 1 2 2 6 4 4 1 Matter (USP) (≧10 μm) NMT 600 (≧25 μm) 0 0 0 0 0 0 0 0 0 Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 EU/mL • • • • • • • • • Endotoxin TABLE 30 Samples stored upright at 5° C. Acceptance Time in months Test Criteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 U/mL 19.7 19.7 19.6 19.7 19.8 19.7 19.9 19.8 19.5 Assay Related SEQ ID 0.5% 0.5% 0.5% 0.5% 0.5% 0.6% 0.6% 0.8% 0.8% Substances NO.: 2: NMT 6.0% SEQ ID 0.5% 0.5% 0.5% 0.6% 0.6% 0.7% 0.7% 0.8% 0.9% NO.: 4: NMT 6.0% SEQ ID 0.3% 0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1% NR 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR NR NR NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.2% 0.3% 0.3% 0.3% 0.3% AVP: NMT 1.0% UI-0.75-0.78: NR NR NR NR 0.2% NR NR NR NR NMT 1.0% UI-0.83-0.84: NR NR 0.1% NR NR NR NR 0.1% NR NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% NMT 1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.76: NR NR NR 0.1% NR NR NR NR NR NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.1% NR NR NR NR NR NR NR NR NMT 1.0% Total 2.2% 1.8% 2.0% 2.2% 2.2% 2.1% 2.4% 2.8% 2.7% Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.5 3.6 3.5 3.5 3.5 3.6 3.5 3.5 Chlorobutanol 0.25-0.60% 0.47% 0.48% 0.47% 0.47% 0.48% 0.47% 0.48% 0.48% 0.48% w/v Particulate NMT 6000 1 1 1 1 1 3 2 1 3 Matter (USP) (≧10 μm) NMT 600 (≧25 μm) 0 0 0 0 0 0 0 0 0 Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT 29 EU/mL • • • • • • • • • Endotoxin TABLE 31 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 19.8 19.4 19.1 18.8 18.3 17.5 17.3 — Assay Related SEQ ID 0.1% 0.5% 1.1% 1.6% 2.0% 3.3% 4.6% — Substances NO.: 2: NMT 6.0% SEQ ID 0.1% 0.6% 1.2% 1.8% 2.2% 3.7% 5.2% — NO.: 4: NMT 6.0% SEQ ID 0.3% 0.4% 0.5% 0.5% 0.4% 0.2% 0.3% — NO.: 10: NMT 1.0% Asp5-AVP: NR 0.1% 0.3% 0.4% 0.5% 0.7% 1.0% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.2% 0.2% 0.2% 0.3% — AVP: NMT 1.0% UI-0.83: NR NR <0.10 NR NR NR 0.1% — NMT 1.0% UI-0.99: NR NR NR NR 0.1% NR NR — NMT 1.0% UI-1.03: 0.2% 0.2% 0.3% 0.3% 0.3% 0.2% 0.2% — NMT 1.0% UI-1.14: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% — NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.22: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.56-1.57: NR NR <0.10 0.1% 0.1% 0.2% 0.2% — NMT 1.0% UI-1.60: NR NR NR 0.1% 0.1% 0.2% NR — NMT 1.0% UI-1.74: NR NR NR NR NR 0.2% NR — NMT 1.0% UI-1.85-1.88: NR 0.2% NR NR NR 0.1% 0.1% — NMT 1.0% UI-2.09-2.10: NR 0.2% NR NR NR NR 0.4% — NMT 1.0% UI-2.15-2.16: NR NR 0.1% NR NR NR 0.5% — NMT 1.0% Total 1.1% 2.4% 3.7% 4.7% 5.9% 9.0% 13.6% — Impurities: NMT 17.0% pH 2.5-4.5 3.5 3.5 3.5 3.5 3.4 3.3 3.2 — Chlorobutanol 0.25-0.60% 0.49% 0.48% 0.48% 0.47% 0.47% 0.48% 0.47 — w/v Particulate NMT 6000 1 1 1 1 8 4 1 — Matter (USP) (≧10 μm) NMT 600 (≧25 μm) 0 0 0 0 0 0 0 — AntiMicrobial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 EU/mL <1 • • • <1 • <1 — Endotoxin TABLE 32 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 20.1 19.7 19.3 19 18.6 17.6 17.6 — Assay Related SEQ ID NO.: 0.1% 0.5% 0.9% 1.5% 1.9% 3.1% 4.4% — Substances 2: NMT 6.0% SEQ ID NO.: 0.1% 0.5% 1.1% 1.6% 2.2% 3.4% 4.9% — 4: NMT 6.0% SEQ ID NO.: 0.3% 0.4% 0.3% 0.4% 0.3% 0.4% 0.3% — 10: NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.3% 0.4% 0.7% 0.9% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% 0.2% 0.2% 0.3% — NMT 1.0% UI-0.75-0.76: NR 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% — NMT 1.0% UI-0.83: 0.2% NR 0.1% NR NR 0.1% 0.1% — NMT 1.0% UI-0.99: NR NR NR NR 0.1% NR NR — NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.3% 0.2% — NMT 1.0% UI-1.14: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% — NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.22: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.56-1.57: NR NR 0.1% 0.1% 0.2% 0.2% 0.2% — NMT 1.0% UI-1.60: NR NR 0.1% 0.1% 0.2% 0.2% NR — NMT 1.0% UI-1.74: NR NR NR NR NR 0.2% NR — NMT 1.0% UI-1.85-1.88: NR 0.2% NR NR NR 0.1% 0.1% — NMT 1.0% UI-2.09-2.10: NR 0.2% NR NR NR NR 0.4% — NMT 1.0% UI-2.15-2.16: NR NR NR NR NR NR 0.6% — NMT 1.0% Total 1.3% 2.5% 3.4% 4.6% 5.6% 9.0% 13.4% — Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.6 3.5 3.5 3.2 3.3 3.4 — Chlorobutanol 0.25-0.60% 0.48% 0.49% 0.48% 0.47% 0.47% 0.47% 0.47 — w/v Particulate NMT 6000 2 1 1 3 4 1 2 — Matter (≧10 μm) (USP) NMT 600 (≧25 μm) 0 0 0 0 0 0 0 — AntiMicrobial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 EU/mL <1 • • • <1 • <1 — Endotoxin TABLE 33 Samples stored inverted at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 19.9 19.6 19.2 19 18.7 18 17.4 — Assay Related SEQ ID NO.: 0.2% 0.5% 1.0% 1.5% 2.0% 3.2% 4.5% — Substances 2: NMT 6.0% SEQ ID NO.: 0.1% 0.6% 1.1% 1.8% 2.2% 3.7% 5.0% — 4: NMT 6.0% SEQ ID NO.: 0.4% 0.4% 0.3% 0.4% 0.4% 0.3% 0.5% — 10: NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.4% 0.5% 0.7% 1.0% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR 0.1% — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% — NMT 1.0% UI-0.12: NR 0.1% NR NR NR NR NR NMT 1.0% UI-0.75-0.76: NR NR NR NR NR NR NR NMT 1.0% UI-0.83-0.84: NR 0.1% 0.1% 0.1% 0.1% 0.1% NMT 1.0% UI-0.93: NR NR NR NR NR NR 0.1% NMT 1.0% UI-0.99: NR NR NR NR NR NR NR NMT 1.0% UI-1.02-1.03: 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% 0.3% — NMT 1.0% UI-1.15: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% NMT 1.0% UI-1.20: NR NR NR NR NR NR NR NMT 1.0% UI-1.22: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.26: NR NR NR NR NR NR NMT 1.0% UI-1.35: 0.3% NR NR NR NR NR NR NMT 1.0% UI-1.56-1.57: NR NR 0.1% NR 0.1% 0.2% 0.3% NMT 1.0% UI-1.60: NR NR 0.1% NR 0.1% NR NR — NMT 1.0% UI-1.74: NR NR NR NR NR NR NR NMT 1.0% UI-1.84-1.89: NR 0.1% NR NR NR NR 0.2% NMT 1.0% UI-1.96: 0.2% NR NR NR NR NR NR NMT 1.0% UI-2.09-2.10: NR 20.0% NR NR NR <0.10 0.1% NMT 1.0% UI-2.15-2.16: NR NR 0.1% NR NR 0.1% NR NMT 1.0% Total 1.5% 2.6% 3.3% 4.6% 5.9% 9.0% 12.9% — Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.5 3.5 3.5 3.4 3.4 3.3 — Chlorobutanol 0.25-0.60% 0.48% 0.47% 0.47% 0.46% 0.46% 0.46% 0.45% — w/v Particulate NMT 6000 1 2 3 3 3 1 2 — Matter (≧10 μm) (USP) NMT 600 (≧25 μm) 0 0 0 0 0 0 0 — Anti- Meets Test Pass • • • Pass • Pass — Microbial Effectiveness Bacterial NMT 29 EU/mL <1 • • • <1 • <1 — Endotoxin TABLE 34 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 19.8 19.4 19.1 18.8 18.3 17.5 17.4 — Assay Related SEQ ID NO.: 0.1% 0.5% 1.1% 1.6% 2.0% 3.2% 4.5% — Substances 2: NMT 6.0% SEQ ID NO.: 0.1% 0.6% 1.2% 1.8% 2.3% 3.6% 5.0% — 4: NMT 6.0% SEQ ID NO.: 0.3% 0.4% 0.3% 0.4% 0.3% 0.2% 0.3% — 10: NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.4% 0.4% 0.7% 0.9% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% 0.2% 0.2% 0.3% — NMT 1.0% UI-0.83: NR NR <0.10 NR NR 0.1% 0.1% — NMT 1.0% UI-0.99: NR NR NR NR NR NR NR — NMT 1.0% UI-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.2% — NMT 1.0% UI-1.14: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% — NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.22: NR NR NR NR NR NR NR — NMT 1.0% UI-1.56-1.57: NR NR NR 0.1% 0.1% 0.2% 0.2% — NMT 1.0% UI-1.60: NR NR NR NR NR 0.1% NR — NMT 1.0% UI-1.74: NR NR NR NR NR 0.2% NR — NMT 1.0% UI-1.85-1.88: NR 0.2% NR NR NR 0.1% 0.1% — NMT 1.0% UI-2.09-2.10: NR 0.2% NR NR NR NR 0.3% — NMT 1.0% UI-2.15-2.16: NR NR NR NR NR NR 0.5% — NMT 1.0% Total 1.1% 2.4% 3.2% 4.8% 5.6% 9.2% 13.1% — Impurities: NMT 17.0% pH 2.5-4.5 3.5 3.5 3.5 3.5 3.4 3.3 3.3 — Chlorobutanol 0.25-0.60% 0.49% 0.48% 0.48% 0.48% 0.47% 0.48% 0.47 — w/v Particulate NMT 6000 1 2 2 2 2 4 2 — Matter (≧10 μm) (USP) NMT 600 (≧25 μm) 0 0 0 0 0 0 0 — AntiMicrobial Meets Test Pass • • • Pass • Pass — Effectiveness Bacterial NMT 29 EU/mL <1 • • • <1 • <1 — Endotoxin TABLE 35 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 20.1 19.7 19.4 18.9 18.6 17.8 17.7 — Assay Related SEQ ID 0.1% 0.5% 0.9% 1.4% 1.9% 3.1% 4.3% — Substances NO.: 2: NMT 6.0% SEQ ID 0.1% 0.5% 1.1% 1.6% 2.2% 3.4% 4.9% — NO.: 4: NMT 6.0% D-Asn- 0.3% 0.4% 0.3% 0.3% 0.3% 0.4% 0.3% — AVP: NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.3% 0.4% 0.7% 0.9% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl- 0.30% 0.30% 0.30% 0.20% 0.20% 0.20% 0.3% — AVP: NMT 1.0% UI-0.75-0.76: NR 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% NMT 1.0% UI-0.83: 0.2% NR <0.10 NR NR 0.1% 0.1% NMT 1.0% UI-0.99: NR NR NR NR 0.1% NR NR NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.2% 0.2% 0.3% 0.2% — NMT 1.0% UI-1.14: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.22: NR NR NR NR NR NR 0.4% NMT 1.0% UI-1.56-1.57: NR NR 0.1% 0.1% 0.2% 0.2% 0.3% NMT 1.0% UI-1.60: NR NR 0.1% 0.1% 0.2% 0.2% NR — NMT 1.0% UI-1.74: NR NR NR NR NR 0.2% NR NMT 1.0% UI-1.85-1.88: NR 0.2% NR NR NR 0.1% 0.1 NMT 1.0% UI-2.09-2.10: NR 0.2% NR NR NR 0.1% 0.3 NMT 1.0% UI-2.15-2.16: NR NR NR NR NR 0.5 NMT 1.0% Total 1.3% 2.5% 3.3% 4.5% 5.7% 9.1% 13.3% — Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.6 3.5 3.5 3.4 3.3 3.3 — Chlorobutanol 0.25-0.60% 0.48% 0.49% 0.48% 0.47% 0.47% 0.48% 0.46 — w/v Particulate NMT 6000 2 1 1 2 5 1 4 — Matter (USP) (≧10 μm) NMT 600 (≧25 μm) 0 0 0 0 0 0 0 — Anti- Meets Test Pass • • • Pass • Pass — Microbial Effectiveness Bacterial NMT 29 EU/mL <1 • • • <1 • <1 — Endotoxin TABLE 36 Samples stored upright at 25° C. and 60% Relative Humidity Acceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30 Vasopressin 16.0-21.0 U/mL 19.9 19.6 19.2 19 18.5 18.1 17.4 — Assay Related SEQ ID 0.2% 0.5% 1.0% 1.5% 2.1% 3.3% 4.7% — Substances NO.: 2: NMT 6.0% SEQ ID 0.1% 0.6% 1.1% 1.7% 2.3% 3.7% 5.3% — NO.: 4: NMT 6.0% D-Asn- 0.4% 0.4% 0.3% 0.4% 0.4% 0.3% 0.5% — AVP: NMT 1.0% Asp5-AVP: NR 0.1% 0.2% 0.3% 0.5% 0.7% 1.0% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR — NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% — AVP: NMT 1.0% UI-0.12: NR NR NR NR NR NR NR NMT 1.0% UI-0.75-0.76: NR NR NR NR NR NR NR NMT 1.0% UI-0.83-0.84: NR 0.1% 0.1% 0.1% NR 0.1% 0.1% NMT 1.0% UI-0.93: NR NR NR NR NR NR 0.1% NMT 1.0% UI-0.99: NR NR NR NR NR NR NR NMT 1.0% UI-1.02-1.03: 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% 0.3% — NMT 1.0% UI-1.15: NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.18: NR NR NR NR NR 0.1% 0.3% NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.22: NR NR NR NR NR NR NR NMT 1.0% UI-1.26: NR NR 0.4% NR NR NR NR NMT 1.0% UI-1.35: 0.1% NR NR NR NR NR NR NMT 1.0% UI-1.56-1.57: NR NR 0.1% 0.1% NR 0.2% 0.3% NMT 1.0% UI-1.60: NR NR NR NR NR NR NR — NMT 1.0% UI-1.74: NR NR NR NR NR NR NR NMT 1.0% UI-1.84-1.89: NR 0.1% NR NR NR NR 0.2% NMT 1.0% UI-1.96: 0.2% NR NR NR NR NR NR NMT 1.0% UI-2.09-2.10: NR NR NR NR NR <0.10 NR NMT 1.0% UI-2.15-2.16: NR NR 0.1% NR NR 0.2% NR NMT 1.0% Total 1.5% 2.5% 3.7% 4.7% 5.9% 9.1% 13.3% — Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.5 3.5 3.5 3.4 3.4 3.3 — Chlorobutanol 0.25-0.60% 0.48% 0.48% 0.47% 0.47% 0.46% 0.45 0.46 — w/v Particulate NMT 6000 1 0 1 3 7 0 3 — Matter (USP) (≧10 μm) NMT 600 (≧25 μm) 0 0 0 0 0 0 0 — Anti- Meets Test Pass • • • Pass • Pass — Microbial Effectiveness Bacterial NMT 29 EU/mL <1 • • • <1 • <1 — Endotoxin TABLE 37 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.8 19.1 18.6 17.3 Assay Related SEQ ID NO.: 2: 0.1% 1.0% 2.4% 3.8% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.1% 2.7% 4.3% NMT 6.0% D-Asn-AVP: 0.3% 0.4% 0.3% 0.3% NMT 1.0% Asp5-AVP: NMT ND 0.2% 0.5% 0.8% 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.2% 0.2% 0.2% NMT 1.0% UI-0.13: NMT ND 0.1% ND ND 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.83-0.84: ND ND ND ND NMT 1.0% UI-1.02-1.03: 0.2% 0.3% 0.2% 0.3% NMT 1.0% UI-1.18: NMT ND ND ND 0.2% 1.0% UI-1.56-1.57: ND 0.2% 0.4% 0.4% NMT 1.0% UI-1.67: NMT ND ND ND ND 1.0% UI-1.76: NMT ND ND ND ND 1.0% UI-1.83-1.85: ND ND 0.2% 0.2% NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT 1.0% UI-1.93: NMT ND 0.1% ND ND 1.0% UI-2.05-2.08: ND ND 0.2% ND NMT 1.0% Total Impurities: 1.1% 3.7% 7.3% 10.6% NMT 17.0% pH 2.5-4.5 3.5 3.3 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.49% 0.48% 0.50% 0.47% Particulate NMT 6000 1 1 1 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 (≧25 μm) TABLE 38 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 20.1 19.3 18.7 17.6 Assay Related SEQ ID NO.: 2: 0.1% 0.9% 2.2% 3.6% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.0% 2.5% 3.9% NMT 6.0% D-Asn-AVP: 0.3% 0.4% 0.3% 0.3% NMT 1.0% Asp5-AVP: NMT ND 0.2% 0.5% 0.8% 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.2% 0.3% 0.2% NMT 1.0% UI-0.13: NMT ND 0.1% ND ND 1.0% UI-0.75-0.78: ND ND 0.2% 0.2% NMT 1.0% UI-0.80-0.84: 0.2% 0.2% ND ND NMT 1.0% UI-1.02-1.03: 0.2% 0.3% 0.2% 0.3% NMT 1.0% UI-1.18: NMT ND ND 0.3% 0.2% 1.0% UI-1.56-1.57: ND 0.2% ND 0.4% NMT 1.0% UI-1.67: NMT ND ND ND ND 1.0% UI-1.76: NMT ND ND ND ND 1.0% UI-1.81-1.85: ND ND 0.2% 0.2% NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT 1.0% UI-1.93: NMT ND 0.1% ND ND 1.0% UI-2.03-2.08: ND ND 0.2% 0.1% NMT 1.0% UI-2.14: NMT ND ND 0.2% ND 1.0% Total Impurities: 1.3% 3.6% 7.3% 10.3% NMT 17.0% pH 2.5-4.5 3.6 3.3 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.48% 0.48% 0.50% 0.47% Particulate NMT 6000 2 2 1 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 (≧25 μm) TABLE 39 Samples stored inverted at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.9 19.2 18.3 17.4 Assay Related SEQ ID NO.: 2: 0.2% 0.9% 2.2% 3.8% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.0% 2.4% 4.0% NMT 6.0% D-Asn-AVP: 0.4% 0.3% 0.3% 0.3% NMT 1.0% Asp5-AVP: NMT ND 0.2% 0.5% 0.8% 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% NMT 1.0% UI-0.13: NMT ND ND ND ND 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.80-0.84: ND ND ND ND NMT 1.0% UI-1.02-1.03: 0.3% 0.2% 0.2% 0.3% NMT 1.0% UI-1.18: NMT ND ND ND 0.2% 1.0% UI-1.35: NMT 0.1% ND ND ND 1.0% UI-1.52-1.58: ND 0.2% 0.3% 0.4% NMT 1.0% UI-1.67: NMT ND ND ND ND 1.0% UI-1.76: NMT ND ND ND ND 1.0% UI-1.81-1.85: ND ND ND ND NMT 1.0% UI-1.86-1.88: ND 0.1% 0.2% ND NMT 1.0% UI-1.91-1.96: 0.2% 0.2% ND ND NMT 1.0% UI-2.02-2.08: ND ND ND 0.2% NMT 1.0% UI-2.11-2.14: ND 0.2% ND ND NMT 1.0% Total Impurities: 1.5% 3.7% 6.3% 10.3% NMT 17.0% pH 2.5-4.5 3.6 3.4 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.48% 0.47% 0.46% 0.46% Particulate NMT 6000 2 2 1 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 (≧25 μm) TABLE 40 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.8 18.9 18.5 17.2 Assay Related SEQ ID NO.: 2: 0.1% 1.0% 2.4% 3.8% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.1% 2.7% 4.3% NMT 6.0% D-Asn-AVP: 0.3% 0.3% 0.3% 0.3% NMT 1.0% Asp5-AVP: NMT ND 0.2% 0.5% 0.8% 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% UI-0.13: NMT ND 0.1% ND ND 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.83-0.84: ND ND ND ND NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.2% NMT 1.0% UI-1.18: NMT ND ND ND 0.2% 1.0% UI-1.56-1.57: ND 0.2% 0.3% 0.3% NMT 1.0% UI-1.67: NMT ND ND ND ND 1.0% UI-1.76: NMT ND ND ND ND 1.0% UI-1.83-1.85: ND ND 0.2% ND NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT 1.0% UI-1.93: NMT ND 0.1% ND ND 1.0% UI-2.05-2.08: ND ND 0.2% ND NMT 1.0% Total Impurities: 1.1% 3.6% 7.2% 10.3% NMT 17.0% Total Impurities: 1.1% 3.6% 7.2% 10.3% NMT 17.0% pH 2.5-4.5 3.5 3.3 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.49% 0.48% 0.50% 0.48% Particulate NMT 6000 1 1 1 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 (≧25 μm) TABLE 41 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 20.1 18.9 18.7 17.4 Assay Related SEQ ID NO.: 2: 0.1% 0.9% 2.3% 3.7% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.0% 2.5% 3.9% NMT 6.0% D-Asn-AVP: 0.3% 0.4% 0.3% 0.3% NMT 1.0% Asp5-AVP: NMT ND 0.2% 0.5% 0.8% 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.2% 0.3% 0.2% NMT 1.0% UI-0.13: NMT ND ND ND ND 1.0% UI-0.75-0.78: ND ND 0.2% 0.2% NMT 1.0% UI-0.80-0.84: 0.2% 0.2% ND ND NMT 1.0% UI-1.02-1.03: 2.0% 0.3% 0.2% 0.3% NMT 1.0% UI-1.18: NMT ND ND ND 0.2% 1.0% UI-1.56-1.57: ND 0.2% 0.4% 0.4% NMT 1.0% UI-1.67: NMT ND ND ND ND 1.0% UI-1.76: NMT ND ND ND ND 1.0% UI-1.83-1.85: ND ND 0.2% 0.1% NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT 1.0% UI-1.93: NMT ND 0.1% ND ND 1.0% UI-2.05-2.08: ND ND 0.2% ND NMT 1.0% UI-2.14: NMT ND ND ND ND 1.0% Total Impurities: 1.3% 3.5% 7.1% 10.2% NMT 17.0% pH 2.5-4.5 3.6 3.3 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.48% 0.48% 0.49% 0.47% Particulate NMT 6000 2 1 1 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 (≧25 μm) TABLE 42 Samples stored Upright at 40° C. Acceptance Time in months Test Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.9 19.2 18.3 17.5 Assay Related SEQ ID NO.: 2: 0.2% 1.0% 2.2% 3.9% Substances NMT 6.0% SEQ ID NO.: 4: 0.1% 1.1% 2.4% 4.2% NMT 6.0% D-Asn-AVP: 0.4% 0.3% 0.3% 0.3% NMT 1.0% Asp5-AVP: NMT ND 0.2% 50.0% 0.8% 1.5% AVP-Dimer: ND ND ND ND NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% NMT 1.0% UI-0.13: NMT ND ND ND ND 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.80-0.84: ND ND ND ND NMT 1.0% UI-1.02-1.03: 0.3% 0.2% 0.2% 0.3% NMT 1.0% UI-1.18: NMT ND ND ND 0.2% 1.0% UI-1.35: NMT 0.1% ND ND ND 1.0% UI-1.52-1.58: ND 0.2% 0.3% 0.4% NMT 1.0% UI-1.67: NMT ND ND ND ND 1.0% UI-1.76: NMT ND ND ND ND 1.0% UI-1.83-1.85: ND ND ND ND NMT 1.0% UI-1.86-1.88: ND 0.1% 0.2% ND NMT 1.0% UI-1.91-1.96: 0.2% 0.2% ND ND NMT 1.0% UI-2.02-2.08: ND ND ND 0.1% NMT 1.0% UI-2.11-2.14: ND 0.2% ND ND NMT 1.0% Total Impurities: 1.5% 3.8% 6.3% 10.5% NMT 17.0% pH 2.5-4.5 3.6 3.4 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.48% 0.47% 0.47% 0.45% Particulate NMT 6000 1 2 1 1 Matter (USP) (≧10 μm) NMT 600 0 0 0 0 (≧25 μm) Example 9: Effect of pH 3.5-4.5 on Vasopressin Formulations To test of effect of pH on vasopressin formulations, solutions containing 20 units/mL vasopressin, adjusted to pH 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, or 4.5 with 10 mM acetate buffer, were prepared. One mL of each of the vasopressin formulations was then filled into 10 cc vials. The vasopressin formulations were stored for four weeks at: (i) 25° C.; or (ii) 40° C., and the assay (% label claim; vasopressin remaining) and % total impurities after four weeks were measured using the methods described in EXAMPLE 1. FIGS. 11 and 12 below display the results of the experiments at 25° C. The results of the experiments at 40° C. are included in FIGS. 13 and 14. The results of the experiments suggested that the stability of a vasopressin formulation was affected by pH. At 25° C., the remaining vasopressin after four weeks was highest between pH 3.6 and pH 3.8 (FIG. 11). Within the range of pH 3.6 to pH 3.8, the level of impurities was lowest at pH 3.8 (FIG. 12). At 25° C., pH 3.7 provided the highest stability for vasopressin (FIG. 11). At 40° C., the remaining vasopressin after four weeks was highest between pH 3.6 and pH 3.8 (FIG. 13). Within the range of pH 3.6 to pH 3.8, the level of impurities was lowest at pH 3.8 (FIG. 14). At 40° C., pH 3.6 provided the highest stability for vasopressin (FIG. 13), Example 10: Effect of pH 2.5-4.5 of Vasopressin Formulations To test of effect of pH on vasopressin formulations, solutions containing 20 units/mL vasopressin, adjusted to pH 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, or 3.4 with 10 mM acetate buffer were also prepared. One mL of each of the vasopressin formulations was then filled into 10 cc vials. The amount of vasopressin, impurities, and associated integration values were determined using the methods describes in EXAMPLE 1. The results from the stability tests on the vasopressin formulations from pH 2.5 to 3.4 were plotted against the results from the stability tests on vasopressin formulations from pH 3.5 to 4.5 as disclosed in EXAMPLE 9, and are displayed in FIGS. 15-18. The assay (% label claim; vasopressin remaining) and % total impurities in the vasopressin pH 2.5 to 3.4 formulations after four weeks are reported in TABLE 43. TABLE 43 % Total Batch Target pH Week Condition Vasopressin (% LC) Impurities 1A 2.5 0 25° C. 100.57 2.48 1B 2.6 0 25° C. 101.25 2.24 1C 2.7 0 25° C. 101.29 2.26 1D 2.8 0 25° C. 101.53 2.00 1E 2.9 0 25° C. 102.33 1.95 1F 3 0 25° C. 102.32 1.89 1G 3.1 0 25° C. 102.59 2.06 1H 3.2 0 25° C. 102.60 1.85 1I 3.3 0 25° C. 102.73 1.81 1J 3.4 0 25° C. 101.93 1.75 1A 2.5 0 40° C. 100.57 2.48 1B 2.6 0 40° C. 101.25 2.24 1C 2.7 0 40° C. 101.29 2.26 1D 2.8 0 40° C. 101.53 2.00 1E 2.9 0 40° C. 102.33 1.95 1F 3 0 40° C. 102.32 1.89 1G 3.1 0 40° C. 102.59 2.06 1H 3.2 0 40° C. 102.60 1.85 1I 3.3 0 40° C. 102.73 1.81 1J 3.4 0 40° C. 101.93 1.75 1A 2.5 4 25° C. 95.70 6.66 1B 2.6 4 25° C. 98.58 5.29 1C 2.7 4 25° C. 98.94 4.26 1D 2.8 4 25° C. 99.14 3.51 1E 2.9 4 25° C. 100.08 3.41 1F 3 4 25° C. 100.29 2.92 1G 3.1 4 25° C. 100.78 2.55 1H 3.2 4 25° C. 100.74 2.16 1I 3.3 4 25° C. 100.46 2.14 1J 3.4 4 25° C. 100.25 2.03 1A 2.5 4 40° C. 81.89 19.41 1B 2.6 4 40° C. 90.10 15.60 1C 2.7 4 40° C. 92.19 13.46 1D 2.8 4 40° C. 94.89 10.98 1E 2.9 4 40° C. 96.03 9.78 1F 3 4 40° C. 97.26 8.09 1G 3.1 4 40° C. 99.61 6.39 1H 3.2 4 40° C. 98.58 5.25 1I 3.3 4 40° C. 97.81 4.41 1J 3.4 4 40° C. 97.35 3.85 The % total impurities for the pH 2.5 to 3.4 formulations and the pH 3.5 to 4.5 formulations observed in the experiments conducted at 25° C. and 40° C. are shown in FIGS. 15 (25° C.) and 16 (40° C.). The vasopressin assay amount for the vasopressin pH 2.5 to 3.4 formulations and the vasopressin pH 3.5 to 4.5 formulations observed in the experiments conducted at 25° C. and 40° C. are shown in FIGS. 17 (25° C.) and 18 (40° C.). The vasopressin assay is presented as a % assay decrease of vasopressin over the four-week study period, rather than absolute assay, because the amount of starting vasopressin varied between the vasopressin pH 2.5 to 3.4 formulations and the vasopressin pH 3.5 to 4.5 formulations. The results of the above experiments suggested that the stability of a vasopressin formulation was affected by pH. At 25° C., the percent decrease in vasopressin after four weeks was lowest between pH 3.7 and pH 3.8 (FIG. 17). Within the range of pH 3.7 to pH 3.8, the level of impurities was lowest at pH 3.8 (FIG. 15). At 40° C., the percent decrease in vasopressin after four weeks was lowest between pH 3.6 and pH 3.8 (FIG. 18). Within the range of pH 3.6 to pH 3.8, the level of impurities was lowest at pH 3.8 (FIG. 16). Example 11: Intra-Assay and Inter-Analysis Precision of Vasopressin pH Experiments The methods used to determine the % assay decrease and amount of impurities in the vasopressin solutions over time in EXAMPLE 10 had both intra-assay and inter-analyst precision. Intra-assay precision was demonstrated by performing single injections of aliquots of a vasopressin formulation (n=6; Chemist 1) from a common lot of drug product and determining the assay and repeatability (% RSD; relative standard deviation). Inter-analyst precision was demonstrated by two different chemists testing the same lot of drug product; however, the chemists used different instruments, reagents, standard preparations, columns, and worked in different laboratories. The procedure included a common pooling of 20 vials of vasopressin, which were assayed by the two chemists using different HPLC systems and different HPLC columns. The vasopressin assay results (units/mL) and repeatability (% RSD for n=6) were recorded and are reported in the TABLE 44 below. TABLE 44 Precision of Vasopressin Results. Chemist 1 Chemist 2 Sample (units/mL) (units/mL) 1 19.74 19.65 2 19.76 19.66 3 19.77 19.66 4 19.75 19.72 5 19.97 19.73 6 19.65 19.73 Mean 19.8 19.7 % RSD (≦2.0%) 0.5% 0.2% %   Difference = 0.5  %   ( acceptance   criteria  :   ≤  3.0  % ) %   Difference = ( Chemist   1 Mean - Chemist   2 Mean ) ( Chemist   1 Mean + Chemist   2 Mean ) × 200 The intra-assay repeatability met the acceptance criteria (% RSD<2.0%) with values of 0.5% and 0.2%. The inter-analyst repeatability also met the acceptance criteria (% difference<3.0%) with a difference of 0.5%. Example 12: Effect of Citrate Versus Acetate Buffer on Vasopressin Formulations To test the effect of citrate and acetate buffer on vasopressin formulations, a total of twelve solutions of 20 Units/mL vasopressin were prepared in 1 mM citrate buffer, 10 mM citrate buffer, 1 mM acetate buffer, and 10 mM acetate buffer. All of the solutions were prepared in triplicate. Each solution was adjusted to pH 3.5 with hydrochloric acid. The vasopressin formulations were stored at 60° C. for 7 days, and the assay (% label claim; vasopressin remaining) and % total impurities after 7 days were analyzed by HPLC using the procedure and experimental conditions described in EXAMPLE 1. The assay (% label claim; vasopressin remaining) and % total impurities for each of the Vasopressin Buffered Formulations are reported in the TABLES 45 and 46 below. TABLE 45 Assay (% label claim; vasopressin remaining) in the vasopressin formulations after storage at 60° C. for 7 days. Sample Buffer 1 2 3 Average 1 mM citrate buffer 89.5% 89.7% 90.6% 89.9% 10 mM citrate buffer 84.1% 84.4% 84.5% 84.3% 1 mM acetate buffer 90.5% 91.1% 91.9% 91.2% 10 mM acetate buffer 90.9% 90.9% 92.4% 91.4% TABLE 46 % Total Impurities in the vasopressin formulations after storage at 60° C. for 7 days. Sample Buffer 1 2 3 Average 1 mM citrate buffer 3.4% 3.5% 2.5% 3.1% 10 mM citrate buffer 9.5% 9.0% 9.4% 9.3% 1 mM acetate buffer 3.3% 2.8% 3.2% 3.1% 10 mM acetate buffer 2.9% 2.6% 3.1% 2.9% The data indicated that the vasopressin assay in the vasopressin formulations with citrate buffer was lower than in the vasopressin formulations with acetate buffer. For example, at 10 mM of either citrate or acetate buffer, the average vasopressin assay was 91.4% in acetate buffer, but was 84.3% in citrate buffer. The data also indicated that % total impurities in the vasopressin formulations with citrate buffer were higher than in the vasopressin formulations with acetate buffer. For example, at 10 mM of either citrate or acetate buffer, the average % total impurities was 2.9% in acetate buffer, but was 9.3% in citrate buffer. Further, as the citrate buffer concentration increased, the vasopressin assay further decreased (from an average of 89.9% to 84.3%), and the % total impurities increased (from an average of 3.1% to 9.3%). This effect was not observed in the vasopressin formulations with acetate buffer, where the average and % total impurities stayed fairly constant. Example 13: Multi-Dose Vasopressin Formulation A multi-dose formulation (10 mL) for vasopressin that can be used in the clinic is detailed in TABLE 47 below: TABLE 47 Drug Product Description Vasopressin, USP Active Ingredient 20 Units (~0.04 mg) Dosage Form Injection — Route of Intravenous — Administration Description Clear colorless to practically colorless solution supplied in a 10 mL clear glass vial with flip-off cap The composition of a 10 mL formulation of vasopressin is provided below. TABLE 48 Drug Product Composition Ingredient Grade Function Batch Quantity Unit Formula Vasopressin, USP USP Active 3,000,000 Units 20 Units Sodium Acetate Trihydrate USP Buffer 214.2 g 1.36 mg Sodium Hydroxide NF pH Adjustor 40 g QS to pH 3.8 Hydrochloric Acid NF/EP pH Adjustor 237.9 g QS to pH 3.8 Chlorobutanol NF Preservative 0.8274 kg 5 mg Water for Injection USP Solvent QS QS to 1 mL Nitrogen NF Processing Aid — — The 10 mL vasopressin formulation was compared to the guidelines for inactive ingredients provided by the Food and Drug Administration (FDA). The results are shown in TABLE 49 below. TABLE 49 Vasopressin 10 mL Concentration (% Inactive Ingredients Ingredient Formulation (mg/mL) w/v) Guideline Acceptable Level Sodium Acetate 1.36 0.136% IV (infusion); Injection Trihydrate 0.16% Sodium Hydroxide QS to pH 3.8 QS to pH 3.8 N/A Hydrochloric Acid QS to pH 3.8 QS to pH 3.8 N/A Chlorobutanol 5 mg 0.5% IV (Infusion); Injection 1% Water for Injection QS to 1 mL QS to target N/A volume Example 14: Alternative Vasopressin Formulation for Clinical Use A 1 mL dosage of vasopressin was prepared. A description of the formulation is shown in TABLE 50 below. TABLE 50 Drug Product Description Vasopressin, USP Active Ingredient 20 Units/mL (~0.04 mg) Dosage Form Injection — Route of Intravenous — Administration Description Clear colorless to practically — colorless solution supplied in a 3 mL vial with flip-off cap The drug composition of the formulation is provided in TABLE 51. TABLE 51 Drug Product Composition Ingredient Function Quantity (mg/mL) Vasopressin, USP Active 20 Units Sodium Acetate Buffer 1.36 Trihydrate, USP Sodium Hydroxide NF/EP pH Adjustor QS for pH adjustment to pH 3.8 Hydrochloric Acid, NF/EP pH Adjustor QS for pH adjustment to pH 3.8 Water for Injection Solvent QS to 1 mL The 1 mL vasopressin formulation was compared to the guidelines for inactive ingredients provided by the Food and Drug Administration (FDA). The results are shown in TABLE 52 below. TABLE 52 Vasopressin Inactive 1 mL Ingredients Formulation Concentration Guideline Ingredient (mg/mL) (% w/v) Acceptable Level Sodium Acetate 1.36 0.136% 0.16% Trihydrate Sodium QS to pH 3.8 QS to pH 3.8 8% Hydroxide Hydrochloric Acid QS to pH 3.8 QS to pH 3.8 10% Water for Injection QS to 1 mL QS to target N/A volume Example 15: 15-Month Stability Data for Vasopressin Formulations The drug product detailed in TABLE 51 was tested for stability over a 15-month period. Three different lots (X, Y, and Z) of the vasopressin drug formulation were stored at 25° C. for 15 months in an upright or inverted position. At 0, 1, 2, 3, 6, 9, 12, 13, 14, and 15 months, the amount of vasopressin (AVP), % label claim (LC), amount of various impurities, and pH was measured. The vasopressin and impurity amounts were determined using the HPLC method described above in EXAMPLE 1. The results of the stability experiment are shown in TABLES 53-54 below. TABLE 53 Inverted Storage of Vasopressin Formulations at 25° C. UI- % Gly9 Glu4 Asp5 0.81-0.86 Lot Month AVP (U/mL) LC (%) (%) D-Asn (%) (%) Dimer (%) Acetyl (%) (%) X 0 19.6 97.9 0.3 0.4 Y 0 19.7 98.6 0.3 0.4 Z 0 19.9 99.3 0.1 0.5 X 1 19.6 98.1 0.2 0.2 0.1 0.4 0.4 Y 1 19.6 97.9 0.2 0.2 0.1 0.4 0.4 Z 1 19.8 99 0.2 0.2 0.6 0.1 X 2 19.6 98.1 0.3 0.3 0.1 0.3 0.4 Y 2 19.5 97.5 0.2 0.3 0.1 0.3 0.4 Z 2 19.8 99 0.3 0.4 0.5 X 3 19.6 97.8 0.4 0.5 0.1 0.1 0.3 0.4 Y 3 19.5 97.4 0.4 0.4 0.1 0.3 0.4 Z 3 19.7 98.6 0.4 0.4 0.5 X 6 19.3 96.5 0.7 0.8 0.1 0.2 0.3 0.4 Y 6 19.2 95.9 0.6 0.7 0.1 0.1 0.1 0.3 0.4 Z 6 19.6 98 0.6 0.7 0.1 0.5 X 9 19 95 1.0 1.0 0.2 0.3 0.4 Y 9 18.9 94.5 0.8 1.0 0.2 0.3 0.4 Z 9 19.2 96 1.0 1.1 0.2 0.5 X 12 18.7 93.5 1.4 1.5 0.1 0.3 0.3 0.4 Y 12 18.6 93 1.1 1.2 0.2 0.2 0.3 0.4 Z 12 18.9 94.5 1.2 1.3 0.3 0.5 X 13 18.6 93 1.5 1.6 0.2 0.3 0.4 0.4 Y 13 18.5 92.5 1.2 1.3 0.2 0.3 0.3 0.4 Z 13 19 95 1.3 1.5 0.1 0.3 0.5 0.1 X 14 18.6 93 1.5 1.7 0.1 0.3 0.3 0.5 Y 14 18.5 92.5 1.2 1.4 0.1 0.3 0.3 0.5 Z 14 18.9 94.5 1.3 1.6 0.3 0.5 0.2 X 15 18.5 92.5 1.6 1.8 0.1 0.4 0.3 0.4 Y 15 18.4 92 1.3 1.5 0.1 0.3 0.3 0.4 Z 15 18.8 94 1.5 1.6 0.3 0.5 UI 0.97 UI- UI- UI- UI- UI- UI- 0.99 1.02-1.03 1.72-1.76 1.81-1.89 1.90-1.96 2.05-2.07 2.09-2.10 Total Lot (%) (%) (%) (%) (%) (%) (%) Impurities pH X 0.3 1.0 3.8 Y 0.3 1.1 3.8 Z 0.2 0.8 3.8 X 0.3 1.6 3.8 Y 0.3 1.6 3.9 Z 0.2 1.4 3.8 X 0.3 1.7 3.7 Y 0.3 1.6 3.8 Z 0.2 1.3 3.8 X 0.4 2.2 Y 0.4 2.0 3.8 Z 0.3 1.6 X 0.4 2.9 3.8 Y 0.4 2.5 3.9 Z 0.2 2.3 3.9 X 0.4 0.1 3.6 Y 0.4 0.1 3.1 3.9 Z 0.3 3.1 3.8 X 0.5 0.2 4.8 3.8 Y 0.5 0.3 0.2 4.4 3.8 Z 0.3 0.3 0.1 4.0 3.8 X 0.1 0.4 0.2 0.1 5.2 3.8 Y 0.1 0.5 0.1 0.4 0.2 0.2 5.2 3.9 Z 0.3 0.1 0.3 0.2 0.2 4.9 3.8 X 0.1 0.4 0.4 0.1 0.1 5.5 3.8 Y 0.1 0.4 0.5 0.2 0.2 5.3 3.9 Z 0.3 0.4 0.2 0.2 5.0 3.8 X 0.1 0.4 0.3 0.2 0.2 5.9 3.8 Y 0.1 0.4 0.5 0.3 0.1 5.3 3.9 Z 0.3 0.4 0.2 0.1 4.9 3.9 TABLE 54 Upright Storage of Vasopressin Formulations at 25° C. UI- % Gly9 Glu4 Asp5 0.81-0.86 Lot Month AVP (U/mL) LC (%) (%) D-Asn (%) (%) Dimer (%) Acetyl (%) (%) X 0 19.6 97.9 0.3 0.4 Y 0 19.7 98.6 0.3 0.4 Z 0 19.9 99.3 0.1 0.5 X 1 19.6 98 0.2 0.2 0.1 0.3 0.4 Y 1 19.5 97.7 0.2 0.2 0.3 0.4 Z 1 19.7 98.3 0.2 0.2 0.6 X 2 19.6 98.2 0.3 0.3 0.3 0.4 Y 2 19.5 97.4 0.2 0.3 0.1 0.4 0.4 Z 2 19.8 99 0.3 0.3 0.5 X 3 19.5 97.6 0.4 0.4 0.1 0.3 0.4 Y 3 19.5 97.5 0.4 0.4 0.1 0.4 Z 3 19.7 98.7 0.4 0.4 0.1 0.5 X 6 19.3 96.5 0.7 0.8 0.1 0.2 0.3 0.4 Y 6 19.2 96 0.5 0.7 0.1 0.1 0.3 0.4 Z 6 19.5 97.5 0.7 0.7 0.2 0.5 X 9 18.9 94.5 1.0 1.1 0.2 0.3 0.4 Y 9 18.9 94.5 0.8 0.9 0.2 0.4 Z 9 19.2 96 0.9 1.0 0.2 0.5 X 12 18.6 93 1.4 1.5 0.1 0.3 0.3 0.4 Y 12 18.7 93.5 1.1 1.2 0.1 0.3 0.3 0.4 Z 12 18.9 94.5 1.3 1.4 0.3 0.5 X 13 18.4 92 1.5 1.6 0.2 0.3 0.3 0.4 Y 13 18.6 93 1.1 1.3 0.2 0.3 0.3 0.4 Z 13 18.8 94 1.3 1.5 0.3 0.5 0.1 X 14 18.6 93 1.5 1.7 0.1 0.4 0.3 0.4 Y 14 18.5 92.5 1.2 1.4 0.1 0.3 0.3 0.5 Z 14 18.8 94 1.3 1.5 0.3 0.5 0.1 X 15 18.4 92 1.6 1.8 0.1 0.4 0.3 0.4 Y 15 18.4 92 1.3 1.5 0.2 0.3 0.3 0.4 Z 15 18.6 93 1.5 1.6 0.3 0.5 UI 0.97 UI- UI- UI- UI- UI- UI- 0.99 1.02-1.03 1.72-1.76 1.81-1.89 1.90-1.96 2.05-2.07 2.09-2.10 Total Lot (%) (%) (%) (%) (%) (%) (%) Impurities pH X 0.3 1.0 3.8 Y 0.3 1.1 3.8 Z 0.2 0.8 3.8 X 0.3 1.6 3.8 Y 0.3 1.4 3.9 Z 0.2 1.2 3.8 X 0.3 1.6 3.7 Y 0.3 1.6 3.8 Z 0.2 1.3 3.8 X 0.4 2.1 3.7 Y 0.4 1.9 3.8 Z 0.3 1.7 X 0.4 2.9 3.8 Y 0.4 2.5 3.9 Z 0.3 2.3 3.9 X 0.2 0.1 3.7 3.8 Y 0.4 0.2 3.1 3.9 Z 0.3 2.9 3.8 X 0.5 0.2 0.1 4.8 3.7 Y 0.5 0.2 0.2 4.6 3.9 Z 0.4 0.3 0.2 4.2 3.8 X 0.1 0.4 0.3 0.1 0.1 5.4 3.8 Y 0.1 0.4 0.3 0.2 4.6 3.9 Z 0.3 0.4 0.2 0.1 4.7 3.8 X 0.1 0.4 0.3 0.1 5.4 3.8 Y 0.4 0.5 0.3 0.3 5.4 3.9 Z 0.3 0.5 0.2 0.2 5.0 3.8 X 0.1 0.4 0.3 0.2 5.7 3.8 Y 0.1 0.4 0.5 0.3 0.3 5.4 3.9 Z 0.2 0.4 0.2 0.3 5.1 3.9 The results from TABLES 53-54 indicate that stability of the vasopressin formulations was not significantly affected by either inverted or upright storage. The impurities detected included Gly9 (SEQ ID NO.: 2), Glu4 (SEQ ID NO.: 4), D-Asn (SEQ ID NO.: 10), Asp5 (SEQ ID NO.: 3), Acetyl-AVP (SEQ ID NO.: 7), vasopressin dimer, and several unidentified impurities (UI). The unidentified impurities are labeled with a range of relative retention times at which the impurities eluted from the column. The results indicate that the pH remained fairly constant over the 15-month period, fluctuating between 3.8 and 3.9 throughout the 15 months. The total impurities did not increase over 5.9%, and the % LC of vasopressin did not decrease below 92%. FIG. 19 shows a graph depicting the % LC over the 15-month study period for the results provided in TABLES 53-54. The starting amounts of vasopressin were 97.9% LC for lot X, 98.6% LC for lot Y, and 99.3% LC for lot Z. The results indicate that the % LC of vasopressin decreased over the 15-month study period, but did not decrease below 92% LC. The formula for the trend line of lot X was: % LC=98.6−0.4262(month) The formula for the trend line of lot Y was: % LC=98.47−0.4326(month) The formula for the trend line of lot Z was: % LC=99.54−0.3906(month) Example 16: Vasopressin Formulation for Bottle or Intravenous Drip-Bag The following formulations can be used without initial vasopressin dilution in drip-bags for intravenous therapy. TABLE 55 Formulation A (40 IU/100 mL) (10 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Sodium chloride (mg) 8.7 Acetic acid (mg) 0.546 Sodium Acetate Trihydrate (mg) 0.12 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 56 Formulation B (60 IU/100 mL) (10 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.6 Sodium chloride (mg) 8.7 Acetic acid (mg) 0.546 Sodium Acetate Trihydrate (mg) 0.12 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 57 Formulation C (40 IU/100 mL) (10 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Dextrose Anhydrous (mg) 50 Acetic acid (mg) 0.546 Sodium Acetate Trihydrate (mg) 0.12 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 58 Formulation D (60 IU/100 mL) (10 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.6 Dextrose Anhydrous (mg) 50 Acetic acid (mg) 0.546 Sodium Acetate Trihydrate (mg) 0.12 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 59 Formulation E (40 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Sodium chloride (mg) 8.7 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 60 Formulation F (60 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.6 Sodium chloride (mg) 8.7 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 61 Formulation G (40 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Dextrose Anhydrous (mg) 50 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 62 Formulation H (60 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.6 Dextrose Anhydrous (mg) 50 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Water for injection QS to (mL) 1 TABLE 63 Formulation 9 (60 IU/100 mL) (1 mM Buffer) Ingredient Concentration Vasopressin (IU) 0.4 Dextrose Anhydrous (mg) 45 Sodium Chloride (mg) 0.9 Acetic acid (mg) 0.0546 Sodium Acetate Trihydrate (mg) 0.012 Hydrochloric acid QS for pH adjustment Sodium hydroxide QS for pH adjustment Example 17: Impurity Measurement for Vasopressin Formulation for Bottle or Intravenous Drip-Bag Gradient HPLC was used to determine the concentration of vasopressin and associated impurities in vasopressin formulations similar to those outlined in TABLES 55-63 above. Vasopressin was detected in the eluent using UV absorbance at a short wavelength. The concentration of vasopressin in the sample was determined by the external standard method, where the peak area of vasopressin in sample injections was compared to the peak area of a vasopressin reference standard in a solution of known concentration. The concentrations of related peptide impurities in the sample were also determined using the external standard method, using the vasopressin reference standard peak area and a unit relative response factor. An impurities marker solution was used to determine the relative retention times of identified related peptides at the time of analysis. The chromatographic conditions used for the analysis are shown in TABLE 64 below: TABLE 64 Column Phenomenex Kinetex XB-C18, 2.6 μm, 100 Å pore, 4.6 × 150 mm, Part No. 00F-4496-E0 Column 35° C. Temperature Flow Rate 1.0 mL/min Detector VWD: Signal at 215 nm Injection Volume 500 μL Run time 55 minutes Auto sampler Vials Amber glass vial Auto Sampler 10° C. Temperature Pump (gradient) Time (min) % A % B Flow 0 90 10 1.0 40 50 50 1.0 45 50 50 1.0 46 90 10 1.0 55 90 10 1.0 Diluent A was 0.25% v/v acetic acid, which was prepared by pipetting 2.5 mL of glacial acetic acid into a 1 L volumetric flask containing 500 mL of water. The volume was diluted with water and mixed well. Diluent B was prepared by weighing and transferring about 3 g of sodium chloride into a 1 L volumetric flask and then adding 2.5 mL of glacial acetic acid. The solution was diluted to volume with water and mixed well. Phosphate buffer at pH 3.0 was used for mobile phase A. The buffer was prepared by weighing approximately 15.6 g of sodium phosphate monobasic monohydrate into a beaker. 1000 mL of water was added, and mixed well. The pH was adjusted to 3.0 with phosphoric acid. The buffer was filtered through a 0.45 μm membrane filter under vacuum, and the volume was adjusted as necessary. An acetonitrile:water (50:50) solution was used for mobile phase B. To prepare mobile phase B, 500 mL of acetonitrile was mixed with 500 mL of water. The stock standard solution was prepared at 20 units/mL of vasopressin. A solution of vasopressin in diluent was prepared at a concentration of about 20 units/mL. The stock standard solution was prepared by quantitatively transferring the entire contents of 5 vials of USP Vasopressin RS with diluent A to the same 250-mL volumetric flask. The solution was diluted to volume with diluent A and mixed well. 10 mL aliquots of the standard solution was transferred into separate polypropylene tubes. The aliquots were stored at 2-8° C. The stock standard solution was stable for 6 months from the date of preparation when stored in individual polypropylene tubes at 2-8° C. The working standard solution contained about 0.5 units/mL of vasopressin. Aliquots of the stock standard solution were allowed to warm to room temperature and then mixed well. 2.5 mL of the stock standard solution was transferred into a 100 mL volumetric flask and diluted to volume with Diluent B, and the resultant mixture was denoted as the Working Standard Solution. The stock standard solution and working standard solution can also be prepared from a single vasopressin vial in the following manner. One vial of vasopressin with diluent A can be quantitatively transferred to a 50-mL volumetric flask. The solution can be dissolved in and diluted to volume with diluent A and mixed well, and denoted as the stock standard solution. To prepare the working standard solution, 2.5 mL of the stock standard solution was diluted to 100 mL with diluent B and mixed well. The working standard solution was stable for at least 72 hours when stored in refrigerator or in autosampler vial at 10° C. The intermediate standard solution was prepared by pipetting 1 mL of the working standard solution into a 50 mL volumetric flask. The solution was diluted to volume with diluent B and mixed well. The sensitivity solution (0.1% of 0.4 units/mL vasopressin formulation) was prepared by pipetting 2 mL of the intermediate standard solution into a 50 mL volumetric flask. The solution was diluted to the volume with diluent B and mixed well. The sensitivity solution was stable for at least 72 hours when stored in the refrigerator. To prepare the impurities marker solution, a 0.05% v/v acetic acid solution was prepared by pipetting 200 mL of a 0.25% v/v acetic acid solution into a 1 L volumetric flask. The solution was diluted to the desired volume with water and mixed well. To prepare the vasopressin impurity stock solutions, the a solution of each impurity as shown below was prepared in a 25 mL volumetric flask and diluted with 0.05% v/v acetic acid to a concentration suitable for HPLC injection. Gly-9 AVP: 0.09 mg/mL Glu-4 AVP: 0.08 mg/mL Asp-5 AVP: 0.1 mg/mL D-Asn AVP: 0.08 mg/mL Dimer AVP: 0.07 mg/mL Acetyl AVP: 0.08 mg/mL To prepare the MAA/H-IBA (Methacrylic Acid/α-Hydroxy-isobutyric acid) stock solution, a stock solution containing approximately 0.3 mg/mL H-IBA and 0.01 mg/mL in 0.05% v/v acetic acid was made in a 50 mL volumetric flask. To prepare the chlorobutanol diluent, about one gram of hydrous chlorobutanol was added to 500 mL of water. Subsequently, 0.25 mL of acetic acid was added and the solution was stirred to dissolve the chlorobutanol. To prepare the stock impurity marker solutions, 6.5 mg of vasopressin powder was added to a 500 mL volumetric flask. To the flask, the following quantities of the above stock solutions were added: Gly-9 AVP: 20.0 mL Glu-4 AVP: 20.0 mL Asp-5 AVP: 10.0 mL D-Asn AVP: 10.0 mL Dimer AVP: 10.0 mL Acetyl AVP: 20.0 mL H-IBA/MAA: 30.0 mL The solutions were diluted to volume with the chlorobutanol diluent. The solutions were aliquoted into individual crimp top vials and stored at 2-8° C. The solutions, stored at 2-8° C., were suitable for use as long as the chromatographic peaks could be identified based on comparison to the reference chromatogram. At time of use the solutions were removed from refrigerated (2-8° C.) storage and allowed to reach room temperature. The vasopressin stock impurity marker solution was stable for at least 120 hours when stored in autosampler vials at room temperature. The impurity marker solution were prepared by diluting 1 mL of the stock impurity marker solution to 50 mL with diluent B, and mixed well. The vasopressin impurity marker solution was stable for at least 72 hours when stored in the refrigerator. To begin the analysis, the HPLC system was allowed to equilibrate for at least 30 minutes using mobile phase B, followed by time 0 min gradient conditions until a stable baseline was achieved. Diluent B was injected at the beginning of the run, and had no peaks that interfered with vasopressin as shown in FIG. 20. A single injection of the sensitivity solution was performed, wherein the signal-to-noise ratio of the vasopressin was greater than or equal to ten as shown in FIG. 21. A single injection of the impurities marker solution was then made. The labeled impurities in the reference chromatogram were identified in the chromatogram of the marker solution based on their elution order and approximate retention times shown in FIG. 22 and FIG. 23. FIG. 23 is a zoomed-in chromatograph of FIG. 22 showing the peaks that eluted between 16 and 28 minutes. The nomenclature, structure, and approximate retention times for individual identified impurities are detailed in TABLE 3. A single injection of the working standard solution was made to ensure that the tailing factor of the vasopressin peak was less than or equal to about 2.0 as shown in FIG. 24. A total of five replicate injections of the working standard solution were made to ensure that the relative standard deviation (% RSD) of the five replicate vasopressin peak areas was not more than 2.0%. Following the steps above done to confirm system suitability, a single injection of the placebo and sample preparations was made. The chromatograms were analyzed to determine the vasopressin and impurity peak areas. The chromatogram for the placebo is depicted in FIG. 25, and the chromatogram for the sample preparation is shown in FIG. 26. Then, the working standard solution was injected after 1 to 10 sample injections, and the average of the bracketing standard peak areas were used in the calculations for vasopressin and impurity amounts. Additional injections of the impurities marker solution could be made to help track any changes in retention time for long chromatographic sequences. The relative standard deviation (% RSD) of vasopressin peak areas for the six injections of working standard solution was calculated by including the initial five injections from the system suitability steps above and each of the subsequent interspersed working standard solution injections. The calculations were done to ensure that each of the % RSD were not more than 2.0%. The retention time of the major peak in the chromatogram of the sample preparation corresponded to that of the vasopressin peak in the working standard solution injection that preceded the sample preparation injection. To calculate the vasopressin units/mL, the following formula was used: Vasopressin   units  /  mL = R U R S  Conc   STD where: RU=Vasopressin peak area response of Sample preparation. RS=average vasopressin peak area response of bracketing standards. Conc STD=concentration of the vasopressin standard in units/mL To identify the impurities, the % Impurity and identity for identified impurities (TABLE 3) that are were greater than or equal to 0.10% were reported. Impurities were truncated to 3 decimal places and then rounded to 2 decimal places, unless otherwise specified. The following formula was used: %   impurity = R 1 R s  Conc   STD LC  100  % where R1=Peak area response for the impurity; LC=label content of vasopressin (units/mL). The formulations used for the vasopressin and impurity studies are summarized in TABLE 65 below and correspond to several of the formulations detailed above in TABLES 55-63. TABLE 65 Lot Vasopressin (units/100 mL) Buffer Conc. (mM) Vehicle A 40 10 NaCl B 60 10 NaCl C 40 10 Dextrose D 60 10 Dextrose E 40 1 NaCl F 60 1 NaCl G 40 1 Dextrose H 60 1 Dextrose A1 40 1 Dextrose B1 60 1 Dextrose C1 40 1 Dextrose/NaCl The drug products detailed in TABLE 65 were tested for stability over a six month period. The vasopressin drug formulations were stored at 5° C., 25° C., or 40° C. for up to six months. At 0, 1, 2, 3, 4, 5, and 6 months, the amount of vasopressin (AVP), % label claim (LC), amount of various impurities, pH, and % reference standard was measured. The vasopressin and impurity amounts were determined using the HPLC method described above. The results of the stability experiment are shown in TABLES 66-72 below. TABLE 66 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT Condition Time Vasopressin 0.30 0.33 0.34 0.35 0.362 0.37 0.38 0.39 0.40 0.42 0.44 Lot (° C.) (m) pH (% LC) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 5 0 3.63 102.5 0.36 0.14 0.13 A 25 0 3.63 102.5 0.36 0.14 0.13 A 40 0 3.63 102.5 0.36 0.14 0.13 B 5 0 3.64 102.2 0.24 0.09 0.08 0.10 B 25 0 3.64 102.2 0.24 0.09 0.08 0.10 B 40 0 3.64 102.2 0.24 0.09 0.08 0.10 C 5 0 3.64 98.2 0.34 0.13 0.56 0.20 C 25 0 3.64 98.2 0.34 0.13 0.56 0.20 C 40 0 3.64 98.2 0.34 0.13 0.56 0.20 D 5 0 3.65 100.1 0.24 0.08 0.15 0.06 D 25 0 3.65 100.1 0.24 0.08 0.15 0.06 D 40 0 3.65 100.1 0.24 0.08 0.15 0.06 E 5 0 3.67 100.5 0.13 E 25 0 3.67 100.5 0.13 E 40 0 3.67 100.5 0.13 F 5 0 3.71 101.5 0.09 F 25 0 3.71 101.5 0.09 F 40 0 3.71 101.5 0.09 G 5 0 3.75 99.5 G 25 0 3.75 99.5 G 40 0 3.75 99.5 H 5 0 3.74 100.2 H 25 0 3.74 100.2 H 40 0 3.74 100.2 A1 5 0 3.86 97.5 A1 25 0 3.86 97.5 A1 40 0 3.86 97.5 B1 5 0 3.84 97.6 B1 25 0 3.84 97.6 B1 40 0 3.84 97.6 C1 5 0 3.78 99.3 C1 25 0 3.78 99.3 C1 40 0 3.78 99.3 A 5 1 3.62 101.6 0.37 0.15 0.11 A 25 1 3.63 101.5 0.34 0.19 A 40 1 3.61 98.2 0.27 0.18 B 5 1 3.61 102.2 0.25 0.12 0.06 0.13 B 25 1 3.63 101.0 0.24 0.11 B 40 1 3.63 97.2 0.19 0.65 C 5 1 3.66 99.7 0.37 0.11 0.79 C 25 1 3.65 98.7 0.36 0.17 C 40 1 3.66 93.8 0.60 0.19 D 5 1 3.66 101.1 0.24 0.08 D 25 1 3.65 99.8 0.24 0.11 D 40 1 3.66 92.4 0.41 0.11 E 5 1 3.67 101.0 E 25 1 3.67 99.2 E 40 1 3.68 95.5 F 5 1 3.71 101.5 0.08 F 25 1 3.72 100.1 F 40 1 3.71 96.6 0.12 G 5 1 3.71 99.8 G 25 1 3.76 99.0 G 40 1 3.75 94.2 0.34 0.26 H 5 1 3.76 99.8 H 25 1 3.77 99.5 H 40 1 3.77 97.0 0.23 A1 5 1 3.81 97.0 A1 25 1 3.82 96.8 A1 40 1 3.83 91.8 B1 5 1 3.82 97.5 B1 25 1 3.82 97.1 B1 40 1 3.82 92.0 C1 5 1 3.80 99.2 C1 25 1 98.5 C1 40 1 3.82 94.7 A 5 2 3.59 101.7 0.11 A 25 2 3.59 99.5 0.14 A 40 2 3.60 92.9 0.15 B 5 2 3.60 101.1 0.12 B 25 2 3.60 98.8 0.10 B 40 2 3.60 92.1 0.11 C 5 2 3.59 99.3 0.18 C 25 2 3.62 97.3 0.14 C 40 2 3.64 89.2 0.15 D 5 2 3.67 100.0 0.10 D 25 2 3.66 97.3 0.09 D 40 2 3.62 89.9 0.09 E 5 2 3.65 99.5 E 25 2 3.67 95.8 E 40 2 3.67 90.6 0.07 F 5 2 3.67 100.6 F 25 2 3.71 97.9 0.14 F 40 2 3.70 92.3 0.33 G 5 2 3.70 98.9 G 25 2 3.73 97.0 G 40 2 3.71 90.5 H 5 2 3.72 99.7 H 25 2 3.74 98.0 H 40 2 3.74 91.9 A1 5 2 3.77 97.3 A1 25 2 3.77 95.9 A1 40 2 3.78 86.1 B1 5 2 3.79 97.3 B1 25 2 3.78 96.5 B1 40 2 3.79 87.4 C1 5 2 3.73 99.3 C1 25 2 3.73 98.1 C1 40 2 3.74 91.0 A 5 3 3.59 102.0 0.31 A 25 3 3.61 99.5 0.30 A 40 3 3.60 90.8 0.30 B 5 3 3.59 101.8 0.24 B 25 3 3.60 98.8 0.22 B 40 3 3.60 90.3 0.22 C 5 3 3.62 99.8 0.16 C 25 3 3.62 95.5 0.15 C 40 3 3.62 87.0 0.16 D 5 3 3.62 91.4 0.10 D 25 3 3.63 97.7 0.20 D 40 3 3.63 87.6 0.18 E 5 3 3.63 96.9 E 25 3 3.64 96.3 E 40 3 3.65 88.8 0.23 F 5 3 3.67 100.8 F 25 3 3.68 97.9 0.23 F 40 3 3.70 90.0 0.20 G 5 3 3.73 98.8 0.16 G 25 3 3.72 97.5 0.07 G 40 3 3.74 88.6 H 5 3 3.71 99.8 0.04 H 25 3 3.74 98.5 H 40 3 3.75 89.1 A 5 4 3.59 99.9 0.22 A 25 4 3.56 96.8 0.20 A 40 4 3.70 84.5 0.31 B 5 4 3.58 99.4 0.11 B 25 4 3.56 95.4 0.17 B 40 4 3.67 83.0 1.37 C 5 4 3.61 98.5 0.18 C 25 4 3.63 94.9 0.18 C 40 4 3.64 81.3 0.18 D 5 4 3.62 98.9 0.12 D 25 4 3.62 94.5 0.07 0.09 D 40 4 3.61 82.1 0.13 E 5 4 3.63 97.6 E 25 4 3.69 94.0 E 40 4 3.63 83.2 0.26 F 5 4 3.68 98.9 0.08 F 25 4 3.69 95.3 0.19 F 40 4 3.70 84.6 0.24 G 5 4 3.68 98.1 G 25 4 3.69 95.8 G 40 4 3.84 83.2 H 5 4 3.67 98.6 H 25 4 3.62 93.1 0.13 0.12 H 40 4 3.76 83.6 A 5 5 3.63 99.7 0.10 A 25 5 3.63 95.8 B 5 5 3.63 99.0 0.25 B 25 5 3.64 95.1 C 5 5 3.68 98.2 C 25 5 3.67 93.7 D 5 5 3.67 98.7 D 25 5 3.69 94.6 E 5 5 3.69 97.5 E 25 5 3.69 93.1 0.09 F 5 5 3.71 98.4 0.05 0.14 F 25 5 3.74 94.4 0.15 G 5 5 3.74 97.2 G 25 5 3.78 93.1 1.73 H 5 5 3.76 97.7 H 25 5 3.76 95.7 A 5 6 3.57 101.0 A 25 6 3.49 95.4 A 5 6 3.57 100.0 A 25 6 3.49 94.5 B 5 6 3.54 100.2 B 25 6 3.49 95.7 B 5 6 3.54 99.3 0.12 0.13 B 25 6 3.49 94.6 C 5 6 3.59 98.1 C 25 6 3.56 95.1 C 5 6 3.59 98.0 C 25 6 3.56 93.5 D 5 6 3.55 100.0 D 25 6 3.56 95.8 D 5 6 3.55 98.6 0.10 D 25 6 3.56 94.2 E 5 6 3.54 98.1 E 25 6 3.56 94.1 E 5 6 3.54 97.0 E 25 6 3.56 92.3 F 5 6 3.60 99.0 F 25 6 3.61 95.0 F 5 6 3.60 98.2 0.10 0.14 F 25 6 3.61 93.8 0.21 G 5 6 3.61 98.2 G 25 6 3.66 96.1 G 5 6 3.61 96.5 G 25 6 3.66 94.4 H 5 6 3.64 98.6 H 25 6 3.65 97.0 H 5 6 3.64 96.9 H 25 6 3.65 95.3 Min 3.49 81.258 0 0 0 0.053 0.042 0 0.104 0 0.116 Max 3.84 102.047 0 0 0 0.153 1.371 0 1.731 0 0.116 TABLE 67 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT 0.47 0.48 0.49 0.50 0.510 0.52 0.56 0.57 0.58 0.61 0.63 0.64 0.646 0.67 0.68 0.70 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.63 A 0.63 A 0.63 B 0.20 B 0.20 B 0.20 C 0.18 8.74 C 0.18 8.74 C 0.18 8.74 D 0.10 9.43 D 0.10 9.43 D 0.10 9.43 E 1.55 E 1.55 E 1.55 F 0.23 0.22 F 0.23 0.22 F 0.23 0.22 G 0.12 0.44 G 0.12 0.44 G 0.12 0.44 H 0.08 0.27 H 0.08 0.27 H 0.08 0.27 A1 0.06 A1 0.06 A1 0.06 B1 B1 B1 C1 C1 C1 A 0.67 A 0.82 0.56 A 0.81 0.40 B 0.53 B 0.46 0.21 B 0.47 0.34 C 0.13 0.31 C 0.18 0.25 C 0.23 0.29 D 0.09 0.34 D 0.13 0.35 D 0.12 0.11 0.20 E 0.53 E 0.30 0.50 E 0.32 0.49 F 0.22 F 0.17 0.23 F 0.18 0.24 G 0.12 0.35 G 0.46 0.37 G 0.45 0.35 H 0.08 0.28 H 0.16 0.24 H 0.15 0.25 A1 A1 A1 0.06 B1 B1 B1 C1 C1 C1 A 0.24 0.76 A 0.06 0.73 A 0.05 0.83 B 0.04 0.40 B 0.04 0.42 B 0.12 0.45 0.05 C 0.17 0.13 C 0.15 0.16 C 0.10 0.07 D 0.14 D 0.05 0.13 D 0.04 0.05 E 0.26 E 0.27 E 0.09 F 0.15 F 0.07 0.18 F 0.29 G 0.56 G 0.06 0.54 0.08 G H 0.20 H 0.21 H 0.04 A1 A1 0.14 A1 B1 B1 B1 C1 C1 C1 A 0.09 0.72 A 0.14 0.49 A 0.12 0.47 B 0.07 0.36 B 0.06 0.47 B 0.05 0.44 0.05 C 0.14 0.41 C 0.13 0.57 C 0.09 0.39 D 0.99 0.28 D 0.05 0.42 D 0.27 0.05 E 0.06 0.60 E 0.57 E 1.03 F 0.42 0.31 F 0.10 0.33 F 0.10 0.35 G 0.39 G 0.09 0.51 G 0.50 H 0.32 H 0.37 H 0.25 A 0.84 0.59 A 0.82 0.29 A 0.87 0.39 B 0.47 0.23 B 0.50 0.43 B 0.55 0.45 0.08 C 0.21 0.15 C 0.23 0.25 C 0.25 0.34 D 0.18 0.27 D 0.24 0.39 D 0.19 0.25 0.08 E 0.31 0.58 E 0.33 0.51 E 0.36 0.67 F 0.18 0.21 F 0.19 0.27 F 0.20 0.26 G 0.59 0.40 G 0.59 0.36 G 0.62 0.40 H 0.20 0.22 H 0.25 0.20 0.31 0.11 H 0.25 0.26 0.09 A 0.61 A 0.48 B 0.27 B 0.43 C 0.29 C 0.15 0.30 D 0.14 0.28 D 0.08 0.40 E 0.53 E 0.49 F 0.24 F 0.24 G 0.14 0.39 G 0.17 0.44 H 0.10 0.23 H 0.13 0.28 A 0.62 A 0.30 A 0.65 0.62 A 0.70 0.30 0.19 B 0.61 B 0.26 B 0.38 0.62 B 0.38 0.26 0.11 C 0.49 C 0.17 0.30 C 0.14 C 0.25 0.31 0.21 D 0.10 0.26 D 0.10 0.31 D 0.11 0.26 0.09 D 0.09 0.13 0.32 0.12 E 1.04 E 0.64 E 0.21 1.07 E 0.22 0.60 F 0.08 0.21 F 0.22 F 0.11 0.08 0.19 F 0.12 0.19 G 0.14 0.38 G 0.14 0.18 0.36 G 0.45 0.16 0.42 0.22 G 0.45 0.18 0.19 0.35 0.35 H 0.10 0.20 H 0.10 0.28 H 0.15 0.11 0.20 0.12 H 0.15 0.12 0.28 0.22 Min 0.035 0 0.125 0 0.42 0.077 0.064 0.23 0.14 0.051 0.048 Max 0.986 0 0.555 0 0.42 0.203 0.064 0.624 1.03 0.052 0.109 TABLE 68 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT 0.71 0.72 0.74 0.76 0.77 0.78 0.79 0.80 0.82 0.84 0.86 0.87 0.88 0.91 0.94 0.95 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.15 0.29 A 0.15 0.29 A 0.15 0.29 B 0.08 0.32 B 0.08 0.32 B 0.08 0.32 C 0.15 0.29 C 0.15 0.29 C 0.15 0.29 D 0.10 0.30 D 0.10 0.30 D 0.10 0.30 E 0.28 E 0.28 E 0.28 F 0.32 F 0.32 F 0.32 G 0.20 0.31 G 0.20 0.31 G 0.20 0.31 H 0.12 0.30 H 0.12 0.30 H 0.12 0.30 A1 0.32 A1 0.32 A1 0.32 B1 0.30 B1 0.30 B1 0.30 C1 0.31 C1 0.31 C1 0.31 A 0.10 0.31 A 0.36 A 0.17 0.39 B 0.30 B 0.35 B 0.36 C 0.32 0.31 C 0.40 C 0.16 0.40 D 0.10 0.31 D 0.34 D 0.36 E 0.32 E 0.34 E 0.37 F 0.30 F 0.34 F 0.33 G 0.18 0.29 0.31 G 0.20 0.38 G 0.27 0.42 H 0.09 0.31 H 0.13 0.35 H 0.14 0.36 A1 0.10 0.29 A1 0.30 A1 0.29 B1 0.30 B1 0.30 B1 0.33 C1 0.31 C1 0.30 C1 0.30 A 0.12 0.33 A 0.12 0.36 A 0.15 0.42 B 0.34 B 0.07 0.36 B 0.10 0.41 C 0.12 0.41 C 0.15 0.36 C 0.17 0.40 D 0.09 0.36 D 0.11 0.35 D 0.10 0.37 E 0.33 E 0.21 0.31 0.05 E 0.10 0.36 F 0.36 F 0.34 F 0.37 G 0.20 0.33 G 0.22 0.34 G 0.33 0.41 H 0.11 0.35 H 0.13 0.34 H 0.19 0.36 A1 0.30 A1 0.31 A1 0.31 0.18 B1 0.30 B1 0.31 B1 0.29 0.15 C1 0.31 C1 0.31 C1 0.30 A A A B B B C C C D 0.49 D D E 0.25 0.16 0.38 E E F F F G G G H H H A 0.16 0.33 A 0.18 0.33 A 0.25 0.40 B 0.32 B 0.09 0.32 B 0.17 0.38 C 0.34 C 0.19 0.35 C 0.25 0.42 D 0.10 0.32 D 0.12 0.36 D 0.16 0.45 E 0.30 E 0.32 E 0.19 0.40 F 0.31 F 0.33 F 0.11 0.37 G 0.19 0.35 G 0.29 0.37 G 0.46 0.45 H 0.11 0.34 H 0.19 0.36 0.08 H 0.26 0.45 A 0.16 0.28 A 0.17 0.28 B 0.29 B 0.29 C 0.18 0.27 C 0.18 0.29 D 0.29 D 0.11 0.29 E 0.27 E 0.30 F 0.31 F 0.30 G 0.23 0.28 G 0.29 0.29 H 0.12 0.29 H 0.18 0.29 A 0.33 A 0.14 0.32 A 0.32 A 0.28 B 0.32 B 0.30 B 0.33 B 0.28 C 0.17 0.31 C 0.14 0.32 C 0.14 0.26 C 0.24 D 0.30 D 0.32 D 0.32 D 0.33 E 0.34 E 0.12 0.31 E 0.30 E 0.28 F 0.07 0.33 F 0.32 F 0.30 F 0.28 G 0.32 G 0.18 0.32 G 0.30 G 0.24 H 0.30 H 0.09 0.31 H 0.32 H 0.26 Min 0.112 0.252 0.087 0.092 0.213 0.301 0.161 0.053 Max 0.287 0.252 0.33 0.456 0.328 0.453 0.161 0.487 TABLE 69 D-Asn- RRT RRT RRT RRT RRT RRT Gly9- Asp5- Glu4- RRT RRT RRT RRT RRT RRT AVP 0.99 1.02 1.03 1.04 1.05 1.06 AVP AVP AVP 1.09 1.10 1.095 1.12 1.13 1.14 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.35 0.21 0.17 0.58 0.41 A 0.35 0.21 0.17 0.58 0.41 A 0.35 0.21 0.17 0.58 0.41 B 0.20 0.43 0.15 0.20 0.19 0.25 B 0.20 0.43 0.15 0.20 0.19 0.25 B 0.20 0.43 0.15 0.20 0.19 0.25 C 0.42 0.30 0.48 0.17 C 0.42 0.30 0.48 0.17 C 0.42 0.30 0.48 0.17 D 0.15 0.41 0.11 0.11 0.18 0.19 D 0.15 0.41 0.11 0.11 0.18 0.19 D 0.15 0.41 0.11 0.11 0.18 0.19 E 0.22 0.34 0.19 0.14 0.93 0.24 E 0.22 0.34 0.19 0.14 0.93 0.24 E 0.22 0.34 0.19 0.14 0.93 0.24 F 0.15 0.33 0.07 0.13 0.12 0.19 F 0.15 0.33 0.07 0.13 0.12 0.19 F 0.15 0.33 0.07 0.13 0.12 0.19 G 0.38 0.19 0.24 G 0.38 0.19 0.24 G 0.38 0.19 0.24 H 0.16 0.42 0.08 0.12 0.14 H 0.16 0.42 0.08 0.12 0.14 H 0.16 0.42 0.08 0.12 0.14 A1 0.12 0.12 0.24 0.08 0.10 0.09 A1 0.12 0.12 0.24 0.08 0.10 0.09 A1 0.12 0.12 0.24 0.08 0.10 0.09 B1 0.11 0.12 0.24 0.07 0.07 0.07 B1 0.11 0.12 0.24 0.07 0.07 0.07 B1 0.11 0.12 0.24 0.07 0.07 0.07 C1 0.12 0.12 0.25 0.09 0.10 0.08 C1 0.12 0.12 0.25 0.09 0.10 0.08 C1 0.12 0.12 0.25 0.09 0.10 0.08 A 0.47 0.63 0.39 0.70 0.51 A 0.33 0.41 0.46 0.61 0.44 A 0.31 1.28 0.65 1.52 0.18 B 0.19 0.43 0.26 0.25 0.58 0.27 B 0.12 0.31 0.39 0.20 0.52 B 0.11 0.31 0.29 0.44 1.47 0.23 C 0.42 0.21 0.20 0.15 C 0.66 0.19 0.24 0.40 0.16 C 0.16 1.71 0.58 0.55 0.43 0.86 0.17 D 0.43 0.09 0.18 0.17 D 0.13 0.75 0.23 0.13 0.38 0.17 D 0.18 1.71 0.57 1.43 0.82 0.14 E 0.34 0.17 0.25 0.23 E 0.32 0.32 0.25 0.41 0.23 E 0.28 1.06 0.39 1.21 0.29 F 0.17 0.36 0.12 0.17 0.14 0.20 F 0.17 0.35 0.36 0.18 0.41 0.11 F 0.14 0.29 1.06 0.34 1.13 G 0.36 0.17 0.26 G 0.45 0.18 0.25 0.20 G 0.68 0.38 0.33 0.52 H 0.37 0.07 0.11 0.16 H 0.15 0.45 0.15 0.24 0.13 H 0.17 0.82 0.45 0.18 0.60 A1 0.12 0.12 0.25 0.08 0.07 0.08 A1 0.11 0.12 0.24 0.14 0.13 0.10 A1 0.09 0.11 0.21 0.31 0.34 0.09 0.45 0.33 B1 0.11 0.12 0.25 0.07 0.07 0.07 B1 0.11 0.12 0.24 0.07 0.13 0.16 0.18 B1 0.10 0.11 0.21 0.33 0.33 0.09 0.41 0.72 C1 0.12 0.13 0.26 0.08 0.10 0.08 C1 0.11 0.13 0.25 0.18 0.18 0.10 C1 0.11 0.12 0.23 0.27 0.52 0.13 0.64 0.10 A 0.10 0.55 0.43 0.66 0.26 0.54 A 0.06 0.38 0.81 0.66 0.90 0.05 A 0.26 2.40 0.87 0.19 B 0.14 0.36 0.20 0.18 0.27 0.13 B 0.12 0.30 0.68 0.31 0.77 0.07 B 0.20 0.32 2.42 0.74 2.51 C 0.37 0.15 0.21 0.21 0.05 0.22 C 0.10 0.88 0.29 0.17 0.49 0.15 C 0.14 2.08 1.00 0.46 1.42 D 0.14 0.52 0.19 0.11 0.21 0.11 D 0.13 1.04 0.38 0.21 0.50 0.16 D 0.13 2.15 1.03 0.50 1.41 E 0.44 0.25 0.27 0.24 0.30 E 0.41 0.71 0.33 0.73 0.24 E 0.23 2.09 0.58 2.38 F 0.11 0.34 0.17 0.11 0.19 0.09 F 0.19 0.33 0.58 0.25 0.60 0.07 F 0.14 0.24 2.08 0.63 2.06 G 0.06 0.38 0.16 0.22 0.20 0.17 G 0.54 0.28 0.20 0.34 0.11 G 0.12 0.90 0.83 0.57 1.18 H 0.21 0.54 0.21 0.10 0.19 0.12 H 0.22 0.69 0.30 0.10 0.32 0.14 H 0.16 0.91 0.74 0.29 1.05 A1 0.11 0.14 0.24 0.08 0.08 A1 0.13 0.14 0.23 0.18 0.20 0.20 A1 0.10 0.12 0.21 0.50 0.56 0.14 0.67 0.10 B1 0.12 0.12 0.24 0.08 0.08 B1 0.12 0.13 0.23 0.18 0.20 0.04 0.21 B1 0.10 0.11 0.20 0.52 0.55 0.15 0.73 0.06 C1 0.12 0.13 0.25 0.10 0.09 C1 0.14 0.13 0.24 0.28 0.29 C1 0.10 0.13 0.21 0.43 0.89 0.22 1.14 0.07 A 0.10 0.29 0.31 0.52 0.36 0.62 A 0.10 0.97 0.62 1.17 0.19 A 0.09 3.45 1.20 3.64 0.20 B 0.11 0.25 0.21 0.31 0.11 0.06 B 0.12 0.94 0.37 1.13 0.22 B 0.09 3.37 0.88 0.36 0.22 C 0.09 0.15 0.10 0.20 0.15 C 0.10 0.93 0.45 0.24 0.61 0.19 C 0.08 2.15 1.29 0.66 2.00 D 5.25 0.31 0.16 D 0.10 1.05 0.46 0.23 0.66 0.11 D 0.09 2.18 1.29 0.56 1.77 E 0.82 0.30 0.22 0.27 0.28 E 0.09 0.87 0.47 0.99 0.21 E 0.09 2.93 0.77 3.30 F 0.11 0.22 0.12 0.25 0.08 F 0.11 0.81 0.36 0.84 0.09 F 0.09 2.79 0.73 2.91 G 0.10 0.14 0.15 0.15 0.13 G 0.10 0.37 0.34 0.53 0.12 G 0.73 0.89 0.64 1.22 0.07 H 0.11 0.11 0.06 0.16 0.08 H 0.09 0.31 0.08 0.43 0.08 H 0.69 0.86 0.34 1.26 A 0.33 0.18 0.22 0.07 0.18 0.25 A 0.29 1.14 0.31 1.24 0.17 A 0.27 4.38 1.21 4.48 B 0.12 0.32 0.19 0.14 0.15 B 0.14 0.30 1.16 0.34 0.95 0.05 B 0.14 0.27 4.31 1.01 4.71 0.06 C 0.38 0.10 0.12 0.08 0.09 C 0.38 0.95 0.51 0.26 0.48 C 2.09 1.48 0.68 2.32 D 0.14 0.42 0.13 0.07 0.09 D 0.16 0.41 0.94 0.53 0.34 0.52 D 2.10 1.47 0.54 2.29 E 0.32 0.17 0.21 0.09 0.17 E 0.29 1.02 0.34 1.29 E 0.24 3.78 0.89 4.08 F 0.14 0.32 0.19 0.06 0.15 F 0.12 0.29 0.95 0.26 1.08 F 0.14 0.27 3.55 0.84 3.64 G 0.36 0.11 0.07 0.10 G 0.48 0.18 0.39 0.17 0.37 G 0.43 0.47 1.06 0.42 1.66 0.17 H 0.16 0.39 0.11 0.09 H 0.23 0.46 0.21 0.45 0.39 0.61 H 0.18 0.45 0.52 1.08 0.48 1.72 A 0.15 0.51 0.26 0.62 0.27 0.24 A 0.14 0.52 1.41 0.40 1.71 0.28 B 0.19 0.49 0.06 0.27 0.24 0.28 B 0.20 0.55 1.53 0.38 1.54 0.37 C 0.64 0.13 0.20 0.16 C 0.16 1.86 0.69 0.20 0.75 0.24 D 0.14 0.66 0.18 0.20 0.18 D 0.15 1.76 0.72 0.25 0.80 0.16 E 0.19 0.43 0.25 0.40 0.27 E 0.35 1.24 0.55 1.37 F 0.16 0.41 0.26 0.18 0.29 F 0.12 0.38 1.15 0.39 1.23 G 0.10 0.41 0.12 0.21 0.17 G 0.74 0.52 0.11 0.68 0.24 H 0.11 0.44 0.12 0.14 0.17 H 0.13 0.77 0.51 0.16 0.60 0.16 A 0.12 0.13 0.27 0.09 0.84 0.22 A 0.10 0.13 0.24 1.84 0.31 1.57 0.15 A 0.30 0.21 0.48 0.13 A 0.75 1.62 0.45 1.38 B 0.13 0.13 0.25 0.07 0.77 0.22 B 0.12 0.13 0.23 1.67 0.33 1.61 B 0.19 0.33 0.24 0.56 0.20 B 0.12 0.37 1.64 0.42 1.73 C 0.12 0.13 0.24 0.21 0.22 0.14 0.10 C 0.12 0.13 0.20 1.31 0.90 0.12 0.77 C 0.16 0.90 0.25 0.34 0.31 C 1.70 0.71 0.40 0.79 D 0.13 0.13 0.23 0.12 0.28 0.13 0.06 D 0.11 0.13 0.21 1.32 0.81 0.13 0.79 0.05 D 0.15 0.46 0.19 0.16 0.14 D 0.15 1.72 0.75 0.33 0.83 E 0.11 0.13 0.25 0.12 0.86 0.20 0.06 E 0.12 0.24 1.65 0.25 1.41 E 0.30 0.09 0.21 0.66 0.20 E 0.34 1.44 0.59 1.51 F 0.15 0.14 0.25 0.06 0.30 0.20 0.06 F 0.12 0.12 0.25 1.36 0.26 1.30 0.05 F 0.17 0.35 0.25 0.13 0.21 F 0.19 0.36 0.39 1.30 1.40 G 0.13 0.14 0.24 0.39 0.11 0.13 G 0.12 0.14 0.22 0.33 0.72 0.09 0.64 G 0.36 0.17 0.19 0.12 G 0.27 0.76 0.33 0.58 0.54 H 0.12 0.13 0.24 0.24 0.12 0.05 H 0.13 0.13 0.22 0.39 0.59 0.09 0.56 0.06 H 0.18 0.43 0.21 0.15 0.16 H 0.15 0.81 0.30 0.56 0.61 Min 0.057 0.234 0.055 0.079 0.042 0.071 0.182 0.051 0.059 Max 0.231 2.177 0.501 4.376 5.246 4.713 0.182 0.622 0.1 TABLE 70 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT AVP Acetyl- RRT RRT RRT RRT 1.16 1.168 1.19 1.20 1.206 1.23 1.24 1.25 1.26 1.27 Dimer AVP 1.32 1.33 1.34 1.35 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.33 0.35 A 0.33 0.35 A 0.33 0.35 B 0.07 0.33 B 0.07 0.33 B 0.07 0.33 C 0.22 0.22 C 0.22 0.22 C 0.22 0.22 D 0.08 0.23 D 0.08 0.23 D 0.08 0.23 E 0.55 0.53 E 0.55 0.53 E 0.55 0.53 F 0.34 F 0.34 F 0.34 G 0.23 G 0.23 G 0.23 H 0.23 H 0.23 H 0.23 A1 0.21 0.28 A1 0.21 0.28 A1 0.21 0.28 B1 0.21 0.29 B1 0.21 0.29 B1 0.21 0.29 C1 0.14 0.29 C1 0.14 0.29 C1 0.14 0.29 A 0.37 0.22 0.13 A 0.20 0.60 A 0.59 B 0.26 0.35 B 0.49 B 0.48 C 0.24 C 0.46 0.26 C 0.44 0.73 0.25 D 0.07 0.22 D 0.35 0.25 D 0.41 0.27 E 0.12 0.43 E 0.72 E 0.68 F 0.07 0.35 F 0.55 F 0.53 G 0.29 G 0.54 0.27 G 0.54 0.40 H 0.21 0.12 H 0.56 0.17 H 0.55 0.17 A1 0.23 0.28 A1 0.21 0.27 A1 0.25 0.27 B1 0.22 0.28 B1 0.21 0.28 B1 0.13 0.27 C1 0.14 0.27 C1 0.15 0.28 C1 0.15 0.28 A 0.58 0.47 A 0.76 A 0.06 0.08 0.32 0.51 B 0.34 B 0.07 0.51 B 0.06 0.07 0.25 0.52 C 0.54 0.25 0.26 C 0.58 0.19 0.20 C 0.41 0.26 D 0.49 0.15 0.23 D 0.47 0.25 0.24 D 0.32 0.03 0.25 E 0.34 0.40 E 0.20 0.51 E 0.06 0.76 F 0.12 0.33 F 0.10 0.77 F 0.04 0.58 G 0.62 0.25 0.23 G 0.62 0.18 G 0.52 0.25 H 0.56 0.09 0.42 H 0.59 0.16 0.38 H 0.56 0.46 A1 0.20 0.30 A1 0.20 0.29 A1 0.28 0.29 B1 0.23 0.32 B1 0.23 0.28 B1 0.12 0.28 C1 0.13 0.28 C1 0.13 0.32 C1 0.16 0.28 A 0.08 0.62 0.55 A 0.32 0.80 A 0.14 0.21 0.51 B 0.18 0.42 B 0.45 0.64 B 0.13 0.22 0.49 0.05 C 0.42 0.27 C 0.39 0.31 0.28 C 0.38 0.19 0.29 D 0.37 0.21 D 0.40 0.15 0.23 D 0.39 0.09 0.24 E 0.19 0.31 E 0.25 0.93 E 0.10 0.22 0.77 F 0.23 0.51 F 0.69 F 0.09 0.07 0.51 G 0.52 0.22 0.24 G 0.52 0.32 0.24 G 0.51 0.06 0.46 H 0.53 0.04 0.46 H 0.53 0.42 H 0.55 0.50 A 0.29 0.43 A 0.55 A 0.23 0.11 0.58 B 0.10 0.39 B 0.24 0.31 B 0.24 0.13 0.14 0.50 C 0.35 0.44 0.21 C 0.42 0.95 0.22 C 0.39 0.49 0.24 D 0.39 0.11 0.22 D 0.39 0.82 0.24 D 0.38 0.70 0.25 E 0.23 0.50 E 0.57 0.88 E 0.18 0.17 0.73 F 0.26 0.32 F 0.08 0.07 0.74 F 0.15 0.09 0.59 G 0.49 0.21 0.21 G 0.51 0.48 0.23 G 0.49 0.14 0.19 H 0.51 0.12 0.38 H 0.54 0.80 0.45 H 0.53 0.30 0.49 A 0.22 0.56 A 0.14 0.21 0.70 B 0.08 0.41 B 0.21 0.12 0.53 C 0.65 0.21 C 0.17 0.21 D 0.38 0.22 D 0.53 0.23 E 0.16 0.14 0.46 E 0.11 0.19 0.99 0.10 F 0.06 0.13 0.45 F 0.07 0.12 0.65 0.07 G 0.80 0.21 G 0.42 0.23 0.15 H 0.48 0.20 0.15 H 0.67 0.21 0.12 A 0.22 0.37 0.25 A 0.29 0.23 A 0.30 0.54 A 0.69 B 0.17 0.41 0.23 B 0.14 0.22 B 0.34 0.28 B 0.52 C 0.24 0.34 C 0.29 0.37 0.25 C 0.19 0.25 C 0.42 0.21 D 0.24 0.22 D 0.20 0.26 0.23 D 0.30 0.20 D 0.37 0.23 E 0.32 0.57 0.22 E 0.23 0.18 0.20 E 0.43 0.65 E 0.16 0.91 F 0.14 0.14 0.21 F 0.14 0.09 0.21 F 0.44 F 0.70 0.08 G 0.33 0.39 0.22 G 0.26 0.35 0.23 G 0.37 0.24 G 0.37 0.20 H 0.14 0.32 0.22 0.16 H 0.14 0.33 0.21 0.23 H 0.40 0.19 0.18 H 0.42 0.21 0.20 Min 0.086 0 0.057 0 0.034 0.042 0.193 0.047 0.147 Max 0.341 0 0.796 0 0.061 0.623 0.986 0.047 0.147 TABLE 71 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT 1.37 1.44 1.45 1.46 1.47 1.48 1.55 1.57 1.59 1.62 1.68 1.70 1.71 1.72 1.80 1.82 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 0.32 A 0.32 A 0.32 B 0.18 B 0.18 B 0.18 C 0.15 C 0.15 C 0.15 D 0.16 D 0.16 D 0.16 E 0.61 E 0.61 E 0.61 F 0.58 F 0.58 F 0.58 G 1.34 G 1.34 G 1.34 H 1.05 H 1.05 H 1.05 A1 A1 A1 B1 B1 B1 C1 C1 C1 A 0.21 2.16 A A B 1.67 B B C 3.37 C C D 2.40 D D E 0.16 3.70 E E F 2.61 F F G 4.10 G G H 2.79 H H A1 A1 A1 B1 B1 B1 0.06 C1 C1 C1 A 0.10 A A B B B C C C D D D E E E 0.14 F F F 0.10 G G G H H H A1 0.09 A1 0.09 A1 0.10 B1 0.06 B1 0.07 B1 0.05 C1 0.14 C1 0.13 C1 0.12 A 0.25 A 0.32 A 0.35 B 0.16 B 0.14 B 0.14 C C C D 0.14 D D E 0.09 E 0.12 E 0.20 F 0.06 0.08 F 0.10 F 0.14 G G G H H H 0.07 0.13 A 0.19 0.16 A 0.29 0.16 A 0.24 B 0.07 B 0.07 0.11 B 0.21 0.12 C C 0.14 C D 0.11 D 0.10 0.07 D 0.08 0.16 E E 0.13 E 0.13 F 0.12 F 0.08 F 0.08 0.06 0.23 G 0.16 G G 0.17 H H 0.20 0.14 H 0.11 0.21 A 0.23 A 0.33 B 0.12 B 0.11 C C D D E 0.11 E 0.13 F F 0.09 G G 0.36 H H A 0.44 0.32 0.16 A 0.48 0.23 0.21 0.12 A 0.26 A 0.27 B 0.12 0.16 B 0.33 0.15 0.10 0.07 B B 0.16 C 0.21 C 0.20 C C 2.69 D 0.08 D 0.30 0.08 D D 1.83 E 0.51 0.13 0.16 0.10 E 0.73 0.14 0.72 E 0.11 E 0.16 2.74 F 0.34 0.10 0.07 F 0.53 0.09 0.06 F F 0.10 1.80 G 0.36 G 0.15 G G 2.69 H H 0.17 H H 1.81 Min 0 0.059 0.077 0.07 0.128 Max 0 0.347 0.213 0.07 0.138 TABLE 72 RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT Total 1.85 1.89 1.93 1.96 2.00 2.01 2.04 2.08 2.11 2.12 2.13 2.15 2.16 2.17 2.304 Imp Lot (%) %) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) A 4.44 A 4.44 A 4.44 B 3.10 B 3.10 B 3.10 C 12.55 C 12.55 C 12.55 D 0.07 0.09 0.55 0.15 12.92 D 0.07 0.09 0.55 0.15 12.92 D 0.07 0.09 0.55 0.15 12.92 E 0.18 5.89 E 0.18 5.89 E 0.18 5.89 F 2.77 F 2.77 F 2.77 G 3.45 G 3.45 G 3.45 H 0.69 3.66 H 0.69 3.66 H 0.69 3.66 A1 1.61 A1 1.61 A1 1.61 B1 1.48 B1 1.48 B1 1.48 C1 1.50 C1 1.50 C1 1.50 A 0.66 8.15 A 5.34 A 6.74 B 5.67 B 3.40 B 5.33 C 6.91 C 3.72 C 7.74 D 4.71 D 3.55 D 6.86 E 6.24 E 3.38 E 5.09 F 4.78 F 2.86 F 4.35 G 6.42 G 1.08 4.39 G 4.93 H 4.60 H 2.73 H 4.07 A1 1.60 A1 1.63 A1 2.80 B1 1.50 B1 1.80 B1 0.44 3.53 C1 1.49 C1 1.66 C1 2.85 A 5.25 A 5.03 A 6.29 B 2.52 B 3.83 B 8.35 C 3.27 C 0.85 4.84 C 6.65 D 2.80 D 4.10 D 6.47 E 0.23 2.82 E 3.98 E 6.87 F 1.96 F 3.61 F 6.85 G 3.37 G 3.51 G 5.10 H 3.10 H 3.57 H 4.76 A1 1.53 A1 2.10 A1 3.55 B1 1.56 B1 1.98 B1 3.31 C1 1.57 C1 1.97 C1 4.05 A 4.82 A 5.39 A 10.68 B 2.48 B 4.73 B 6.71 C 2.09 C 4.34 C 7.69 D 8.29 D 4.06 D 7.10 E 3.57 7.50 E 4.50 E 9.64 F 2.39 F 3.65 F 7.97 G 2.19 G 3.21 G 5.08 H 1.91 H 2.31 H 4.64 A 0.17 0.14 0.06 4.79 A 5.96 A 13.72 B 2.60 B 0.65 5.84 B 14.85 C 2.66 C 5.50 C 9.14 D 2.67 D 0.08 1.22 7.08 D 9.22 E 2.87 E 5.66 E 12.07 F 2.35 F 4.64 F 10.81 G 3.23 G 4.42 G 7.12 H 2.63 H 0.31 0.11 0.08 6.71 H 0.08 7.46 A 4.23 A 6.75 B 2.94 B 0.09 6.36 C 2.72 C 0.13 5.32 D 2.67 D 5.46 E 3.19 E 5.90 F 2.66 F 4.95 G 3.05 G 6.37 H 2.55 H 4.20 A 4.36 A 6.67 A 3.81 A 6.62 B 3.60 B 5.66 B 3.71 B 5.98 C 0.14 3.05 C 5.58 C 2.93 C 0.18 8.12 D 2.28 D 5.34 D 2.48 D 7.20 E 5.11 E 6.93 E 4.22 E 8.94 F 2.83 F 5.10 F 2.47 F 7.12 G 3.26 G 4.42 G 2.98 G 7.49 H 2.35 H 4.04 H 2.80 H 6.09 Min 0 0 0 3.565 0 0 1.533 Max 0 0 0 3.565 0 0 14.845 TABLE 73 RRT RRT RRT RRT D-ASN- RRT RRT RRT RRT Condition Time AVP 0.64 0.86 0.87 0.95 AVP 0.99 1.03 1.04 1.05 Lot (° C.) (m) pH (% LC) (%) (%) (%) (%) (%) (%) (%) (%) (%) A1 5 0 3.86 97.5 0.06 0.32 0.12 0.12 0.24 A1 25 0 3.86 97.5 0.06 0.32 0.12 0.12 0.24 A1 40 0 3.86 97.5 0.06 0.32 0.12 0.12 0.24 B1 5 0 3.84 97.6 0.30 0.11 0.12 0.24 B1 25 0 3.84 97.6 0.30 0.11 0.12 0.24 B1 40 0 3.84 97.6 0.30 0.11 0.12 0.24 C1 5 0 3.78 99.3 0.31 0.12 0.12 0.25 C1 25 0 3.78 99.3 0.31 0.12 0.12 0.25 C1 40 0 3.78 99.3 0.31 0.12 0.12 0.25 A1 5 1 3.81 97.0 0.10 0.29 0.12 0.12 0.25 A1 25 1 3.82 96.8 0.30 0.11 0.12 0.24 A1 40 1 3.83 91.8 0.06 0.29 0.09 0.11 0.21 B1 5 1 3.82 97.5 0.30 0.11 0.12 0.25 B1 25 1 3.82 97.1 0.30 0.11 0.12 0.24 B1 40 1 3.82 92.0 0.33 0.10 0.11 0.21 C1 5 1 3.80 99.2 0.31 0.12 0.13 0.26 C1 25 1 98.5 0.30 0.11 0.13 0.25 C1 40 1 3.82 94.7 0.30 0.11 0.12 0.23 A1 5 2 3.77 97.3 0.30 0.11 0.14 0.24 A1 25 2 3.77 95.9 0.14 0.31 0.13 0.14 0.23 0.18 A1 40 2 3.78 86.1 0.31 0.18 0.10 0.12 0.21 0.50 B1 5 2 3.79 97.3 0.30 0.12 0.12 0.24 B1 25 2 3.78 96.5 0.31 0.12 0.13 0.23 0.18 B1 40 2 3.79 87.4 0.29 0.15 0.10 0.11 0.20 0.52 C1 5 2 3.73 99.3 0.31 0.12 0.13 0.25 C1 25 2 3.73 98.1 0.31 0.14 0.13 0.24 C1 40 2 3.74 91.0 0.30 0.10 0.13 0.21 0.43 A1 5 3 3.80 95.8 0.28 0.12 0.22 A1 25 3 3.78 94.0 0.28 0.13 0.21 0.11 A1 40 3 3.81 82.2 0.28 0.16 0.11 0.15 0.29 B1 5 3 3.82 96.5 0.28 0.11 0.13 0.23 B1 25 3 3.82 94.8 0.29 0.12 0.13 0.21 0.11 B1 40 3 3.83 82.0 0.27 0.06 0.09 0.11 0.14 0.33 C1 5 3 3.75 97.5 0.29 0.12 0.13 0.24 C1 25 3 3.75 96.8 0.29 0.13 0.14 0.22 C1 40 3 3.75 85.5 0.27 0.11 0.16 0.26 Min 3.78 91.842 0.061 0.093 0 Max 3.86 99.282 0.063 0.124 0 TABLE 74 RRT GLY9- ASP5- GLU4- RRT RRT RRT RRT RRT RRT RRT RRT 1.06 AVP AVP AVP 1.12 1.13 1.23 1.24 1.25 ACETYL- 1.57 1.71 1.77 Lot (%) (%) (%) (%) (%) (%) (%) (%) (%) AVP (%) (%) (%) (%) A1 0.08 0.10 0.09 0.21 0.28 A1 0.08 0.10 0.09 0.21 0.28 A1 0.08 0.10 0.09 0.21 0.28 B1 0.07 0.07 0.07 0.21 0.29 B1 0.07 0.07 0.07 0.21 0.29 B1 0.07 0.07 0.07 0.21 0.29 C1 0.09 0.10 0.08 0.14 0.29 C1 0.09 0.10 0.08 0.14 0.29 C1 0.09 0.10 0.08 0.14 0.29 A1 0.08 0.07 0.08 0.23 0.28 A1 0.14 0.13 0.10 0.21 0.27 A1 0.31 0.34 0.09 0.45 0.33 0.25 0.27 B1 0.07 0.07 0.07 0.22 0.28 B1 0.07 0.13 0.16 0.18 0.21 0.28 B1 0.33 0.33 0.09 0.41 0.72 0.13 0.27 0.06 C1 0.08 0.10 0.08 0.14 0.27 C1 0.18 0.18 0.10 0.15 0.28 C1 0.27 0.52 0.13 0.64 0.10 0.15 0.28 A1 0.08 0.08 0.20 0.30 0.09 A1 0.20 0.20 0.20 0.29 0.09 A1 0.56 0.14 0.67 0.10 0.28 0.29 0.10 B1 0.08 0.08 0.23 0.32 0.06 B1 0.20 0.04 0.21 0.23 0.28 0.07 B1 0.55 0.15 0.73 0.06 0.12 0.28 0.05 C1 0.10 0.09 0.13 0.28 0.14 C1 0.28 0.29 0.13 0.32 0.13 C1 0.89 0.22 1.14 0.07 0.16 0.28 0.12 A1 0.09 0.09 0.18 0.29 A1 0.26 0.29 0.21 0.28 A1 0.73 0.18 0.82 0.19 0.11 0.27 B1 0.09 0.09 0.19 0.28 B1 0.25 0.25 0.20 0.28 B1 0.73 0.19 0.82 0.09 0.09 0.07 0.28 0.06 C1 0.10 0.10 0.13 0.28 C1 0.35 0.38 0.11 0.28 C1 1.22 0.30 1.56 0.12 0.15 0.27 Min 0.07 0.089 0.067 0.073 0 0.27 Max 0.344 0.089 0.448 0.326 0 0.288 TABLE 75 RRT 1.85 RRT 1.91 RRRT 2.02 RRT 2.37 Total RS Lot (%) (%) (%) (%) (%) A1 1.61 A1 1.61 A1 1.61 B1 1.48 B1 1.48 B1 1.48 C1 1.50 C1 1.50 C1 1.50 A1 1.60 A1 1.63 A1 2.80 B1 1.50 B1 1.80 B1 0.44 3.53 C1 1.49 C1 1.66 C1 2.85 A1 1.53 A1 2.10 A1 3.55 B1 1.56 B1 1.98 B1 3.31 C1 1.57 C1 1.97 C1 4.05 A1 1.26 A1 1.76 A1 3.29 B1 1.40 B1 1.82 B1 0.10 0.10 0.17 3.68 C1 1.38 C1 1.89 C1 4.41 Min 1.483 Max 2.799 The appearance for all of the tested lots through the duration of the experiment was clear and colorless. The results above provided an estimated shelf life at 5° C. of about 16.1 months (FIG. 27) and at 25° C. of about eight months (FIG. 28). The results indicated that the dextrose vehicle with 1 mM acetate buffer provided a lower rate of degradation and a lower rate of impurities accumulation for the vasopressin formulations at 5° C., 25° C., and 40° C. compared to NaCl or a combination of dextrose and NaCl in either 1 mM or 10 mM acetate buffer Graphical depictions of TABLES 66-72 are shown in FIGS. 29-48 below. FIGS. 29-31 show the vasopressin (% LC) levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 32-34 show the total impurities (total RS (%)) levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 35-37 show the Gly9-AVP levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 38-40 show the Asp5-AVP levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 41-43 show the Glu4-AVP levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 44-46 show the Acetyl-AVP levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. FIGS. 47-48 show the AVP dimer levels in the samples prepared in dextrose, dextrose and NaCl, or NaCl. Based on the data from FIGS. 29-48, the estimated shelf-life at 5° C. is about 16.1 months, and the estimated shelf-life at 25° C. is about 8 months. TABLES 73-75 display data of further studies on Formulations Al, Bl, and Cl as detailed in TABLE 65. The appearance for all of the tested lots through the duration of the experiment was clear and colorless. The estimated shelf life at 5° C. of about 15 months and at 25° C. of about 7.7 months is shown below in FIG. 49 and FIG. 50, respectively. The results indicated that the dextrose vehicle provided a lower rate of degradation and a lower rate of impurities accumulation for the vasopressin formulations at 5° C., 25° C., and 40° C. compared to a combination of dextrose and NaCl. Graphical depictions of TABLES 73-75 are shown in FIGS. 51-62 below. FIGS. 51-53 show the vasopressin (% LC) levels in the samples prepared in dextrose or dextrose and NaCl at 5° C., 25° C., and 40° C., respectively. FIGS. 54-56 show the Gly9-AVP levels in the samples prepared in dextrose or dextrose and NaCl at 5° C., 25° C., and 40° C., respectively. FIGS. 57-59 show the Glu4-AVP levels in the samples prepared in dextrose or dextrose and NaCl at 5° C., 25° C., and 40° C., respectively. FIGS. 60-62 show the total impurities (% RS) levels in the samples prepared in dextrose or dextrose and NaCl at 5° C., 25° C., and 40° C., respectively. EMBODIMENTS The following non-limiting embodiments provide illustrative examples of the invention, but do not limit the scope of the invention. In some embodiments, the invention provides a pharmaceutical composition comprising, in a unit dosage form: a) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin, or a pharmaceutically-acceptable salt thereof; and b) a polymeric pharmaceutically-acceptable excipient in an amount that is from about 1% to about 10% by mass of the unit dosage form or the pharmaceutically-acceptable salt thereof, wherein the unit dosage form exhibits from about 5% to about 10% less degradation of the vasopressin or the pharmaceutically-acceptable salt thereof after storage for about 1 week at about 60° C. than does a corresponding unit dosage form, wherein the corresponding unit dosage form consists essentially of: A) vasopressin, or a pharmaceutically-acceptable salt thereof; and B) a buffer having acidic pH. In some embodiments, the polymeric pharmaceutically-acceptable excipient comprises a polyalkylene oxide moiety. In some embodiments, the polymeric pharmaceutically-acceptable excipient is a polyethylene oxide. In some embodiments, the polymeric pharmaceutically-acceptable excipient is a poloxamer. In some embodiments, the unit dosage form has an amount of the polymeric pharmaceutically-acceptable excipient that is about 1% the amount of the vasopressin or the pharmaceutically-acceptable salt thereof. In some embodiments, the first unit dosage form exhibits about 10% less degradation of the vasopressin or the pharmaceutically-acceptable salt thereof after storage for about 1 week at about 60° C. than does the corresponding unit dosage form. In some embodiments, the unit dosage form further comprises SEQ ID NO. 2. In some embodiments, the composition further comprises SEQ ID NO. 3. In some embodiments, the composition further comprises SEQ ID NO. 4. In some embodiments, the unit dosage form is an injectable of about 1 mL volume. In some embodiments, the unit dosage form consists essentially of: a) about 0.04 mg/mL of vasopressin, or the pharmaceutically-acceptable salt thereof; b) the polymeric pharmaceutically-acceptable excipient in an amount that is from about 1% to about 10% by mass of the vasopressin or the pharmaceutically-acceptable salt thereof; and c) a plurality of peptides, wherein each of the peptides has from 88% to 90% sequence homology to the vasopressin or the pharmaceutically-acceptable salt thereof. In some embodiments, one of the plurality of peptides is SEQ ID NO.: 2. In some embodiments, one of the plurality of peptides is SEQ ID NO.:3. In some embodiments, wherein one of the plurality of peptides is SEQ ID NO.: 4. In some embodiments, the buffer has a pH of about 3.5. Embodiment 1 A method of increasing blood pressure in a human in need thereof, the method comprising: intravenously administering to the human a pharmaceutical composition comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; and ii) acetic acid, sodium acetate, or a combination thereof, wherein: the pharmaceutical composition is at about room temperature; the administration to the human is longer than 18 hours; the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. Embodiment 2 The method of embodiment 1, wherein the administration to the human is for about one day. Embodiment 3 The method of embodiment 1, wherein the administration to the human is for about one week. Embodiment 4 The method of any one of embodiments 1-3, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. Embodiment 5 The method of any one of embodiments 1-4, wherein the human's hypotension is associated with vasodilatory shock. Embodiment 6 The method of embodiment 5, wherein the vasodilatory shock is post-cardiotomy shock. Embodiment 7 The method of any one of embodiments 1-6, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 8 The method of embodiment 5, wherein the vasodilatory shock is septic shock. Embodiment 9 The method of any one of embodiments 1-8, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 10 The method of any one of embodiments 1-9, wherein the unit dosage form further comprises dextrose. Embodiment 11 The method of any one of embodiments 1-10, wherein the unit dosage form further comprises about 5% dextrose. Embodiment 12 A method of increasing blood pressure in a human in need thereof, the method comprising: intravenously administering to the human a pharmaceutical composition that consists essentially of, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; iii) acetic acid, sodium acetate, or a combination thereof; and iv) optionally hydrochloric acid or sodium hydroxide, wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. Embodiment 13 The method of embodiment 12, wherein the unit dosage form consists essentially of hydrochloric acid. Embodiment 14 The method of embodiment 12, wherein the unit dosage form consists essentially of sodium hydroxide. Embodiment 15 The method of any one of embodiments 12-14, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. Embodiment 16 The method of any one of embodiments 12-15, wherein the human's hypotension is associated with vasodilatory shock. Embodiment 17 The method of embodiment 16, wherein the vasodilatory shock is post-cardiotomy shock. Embodiment 18 The method of any one of embodiments 12-17, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 19 The method of embodiment 16, wherein the vasodilatory shock is septic shock. Embodiment 20 The method of any one of embodiments 12-19 wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. Embodiment 21 The method of any one of embodiments 12-20, wherein the unit dosage form consists essentially of 5% dextrose. Embodiment 22 A method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 5° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 1% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 5° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. Embodiment 23 The method of embodiment 22, wherein the administration to the human is for about one day. Embodiment 24 The method of embodiment 22, wherein the administration to the human is for about one week. Embodiment 25 The method of any one of embodiments 22-24, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. Embodiment 26 The method of any one of embodiments 22-25, wherein the human's hypotension is associated with vasodilatory shock. Embodiment 27 The method of embodiment 26, wherein the vasodilatory shock is post-cardiotomy shock. Embodiment 28 The method of any one of embodiments 22-27, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 29 The method of embodiment 26, wherein the vasodilatory shock is septic shock. Embodiment 30 The method of any one of embodiments 22-29, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. Embodiment 31 The method of any one of embodiments 22-30, wherein the pharmaceutical composition exhibits no more than about 2% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after storage of the pharmaceutical composition at 5° C. for about two months. Embodiment 32 A method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 25° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 2% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 25° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. Embodiment 33 The method of embodiment 32, wherein the human's mean arterial blood pressure is increased within 15 minutes of administration. Embodiment 34 The method of any one of embodiments 32-33, wherein the human's hypotension is associated with vasodilatory shock. Embodiment 35 The method of embodiment 34, wherein the vasodilatory shock is post-cardiotomy shock. Embodiment 36 The method of any one of embodiments 32-35, wherein the administration provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute Embodiment 37 The method of embodiment 35, wherein the vasodilatory shock is septic shock. Embodiment 38 The method of any one of embodiments 32-37, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. Embodiment 39 The method of any one of embodiments 32-38, wherein the pharmaceutical composition exhibits no more than about 5% degradation after storage of the pharmaceutical composition at 25° C. for about two months.
<SOH> BACKGROUND <EOH>Vasopressin is a potent endogenous hormone, responsible for maintaining plasma osmolality and volume in most mammals. Vasopressin can be used clinically in the treatment of sepsis and cardiac conditions, and in the elevation of patient's suffering from low blood pressure. Current formulations of vasopressin suffer from poor long-term stability.
<SOH> SUMMARY OF THE INVENTION <EOH>In some embodiments, the invention provides a pharmaceutical composition comprising, in a unit dosage form: a) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin, or a pharmaceutically-acceptable salt thereof; and b) a polymeric pharmaceutically-acceptable excipient in an amount that is from about 1% to about 10% by mass of the unit dosage form or the pharmaceutically-acceptable salt thereof, wherein the unit dosage form exhibits from about 5% to about 10% less degradation of the vasopressin or the pharmaceutically-acceptable salt thereof after storage for about 1 week at about 60° C. than does a corresponding unit dosage form, wherein the corresponding unit dosage form consists essentially of: A) vasopressin, or a pharmaceutically-acceptable salt thereof; and B) a buffer having acidic pH. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: intravenously administering to the human a pharmaceutical composition that consists essentially of, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; iii) acetic acid, sodium acetate, or a combination thereof; and iv) optionally hydrochloric acid or sodium hydroxide, wherein: the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 5° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 1% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 5° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive. In some embodiments, the invention provides a method of increasing blood pressure in a human in need thereof, the method comprising: a) storing at 25° C. for at least about one month a pharmaceutical composition for intravenous administration comprising, in a unit dosage form: i) from about 0.1 μg/mL to about 2 μg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; ii) dextrose; and iii) acetic acid, sodium acetate, or a combination thereof, wherein the pharmaceutical composition exhibits no more than about 2% degradation of vasopressin or the pharmaceutically-acceptable salt thereof after the storage at 25° C. for about one month; and b) administering to the human the pharmaceutical composition, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute; and the human is hypotensive.
A61K3811
20170828
20180320
20180118
67193.0
A61K3811
1
BRADLEY, CHRISTINA
VASOPRESSIN FORMULATIONS FOR USE IN TREATMENT OF HYPOTENSION
UNDISCOUNTED
1
CONT-ACCEPTED
A61K
2,017
15,688,347
PENDING
THIRD-PARTY PROVIDER METHOD AND SYSTEM
Methods and systems for processing negotiable economic credits through, or at the request of, a hand held device in association with a third-party provider communicative with the hand held device and/or a point of sale. At least one negotiable economic credit can be transferred from a third-party provider communicative with the hand held device to the hand held device and/or point of sale. The negotiable economic credit can be stored within a memory of the hand held device and/or point of sale for retrieval and processing at a point of sale associated with a retail establishment and/or by a hand held device. The negotiable economic credit can be associated with a security module for protecting the privacy of the negotiable economic credit. A user profile can be compiled for utilization during the retrieval of the negotiable economic credit.
1.-20. (canceled) 21. A device comprising: a processor; a wireless controller configured to transmit and receive data through a wireless data communication network; and a memory having instructions stored thereon that are executable by the processor to cause the device to perform operations comprising: storing a data structure, wherein the data structure encodes information indicative of a particular item of negotiable economic credit and further includes authentication information usable to authenticate the particular item of negotiable economic credit; detecting that a transaction has been initiated by a user of the device at a point-of-sale (POS) device at a particular establishment, wherein the detecting occurs via the wireless controller while the device is physically within a wireless communication range of the POS device; determining that the data structure corresponds to the transaction; and based on the determining, sending, via the wireless controller, the information indicative of the particular item of negotiable economic credit and the authentication information to a point-of-sale (POS) device, wherein the sending comprises instructing the POS device to apply the particular item of negotiable economic credit to the transaction. 22. The device of claim 21, wherein the operations further comprise receiving the data structure from a device other than the POS device. 23. The device of claim 21, further comprising an optical scanner, wherein the operations further comprise: scanning an image using the optical scanner; and generating the data structure dependent upon image data received from the optical scanner. 24. The device of claim 21, wherein the device is a cellular telephone. 25. The device of claim 21, wherein the wireless controller is further configured to transmit and receive data according to a version of the Bluetooth standard. 26. The device of claim 21, wherein to authenticate the particular item of negotiable economic credit, the authentication information is further usable to detect that the particular item of negotiable economic credit has previously been applied to a transaction. 27. The device of claim 21, wherein the device further comprises a display, and wherein the operations further comprise: receiving a message from the POS device that the particular item of negotiable economic credit has been authenticated and applied to the transaction; and based on the message, displaying a confirmation of the transaction on the display. 28. A method comprising: storing, by an electronic, portable device, a data structure, wherein the data structure encodes information indicative of a particular item of negotiable economic credit and further includes authentication information usable to authenticate the particular item of negotiable economic credit; detecting, by the electronic, portable device, that a transaction has been initiated by a user of the electronic, portable device; in response to the detecting, the electronic, portable device transmitting the information indicative of the particular item of negotiable economic credit and the authentication information to a point-of-sale (POS) device, and instructing the POS device to apply the particular item of negotiable economic credit to the transaction; and receiving, by the electronic, portable device, a message indicating that the particular item of negotiable economic credit has been authenticated by the POS device and applied to the transaction. 29. The method of claim 28, wherein the electronic, portable device is a cellular telephone comprising a display, and wherein the method further comprises: in response to receiving the message, displaying a confirmation of the transaction on the display. 30. The method of claim 28, further comprising receiving the data structure via the POS device. 31. The method of claim 28, wherein transmitting the information indicative of the particular item of negotiable economic credit to the POS device occurs without receiving an input from the user to select the particular item of negotiable economic credit. 32. The method of claim 28, wherein transmitting the information indicative of the particular item of negotiable economic credit to the POS device is performed using a wireless network. 33. The method of claim 28, further comprising receiving the information encoded in the data structure via an optical scanner. 34. An article of manufacture including a non-transitory computer-readable medium having instructions stored thereon that are executable by a device to cause the device to perform operations comprising: storing a data structure on the device, wherein the data structure encodes information indicative of a particular item of negotiable economic credit and further includes authentication information usable to authenticate the particular item of negotiable economic credit; detecting, via a wireless interface, that a transaction has been initiated by a user for the device; and sending the information indicative of the particular item of negotiable economic credit and the authentication information to a point-of-sale (POS) device, and instructing the POS device to apply the particular item of negotiable economic credit to the transaction. 35. The article of manufacture of claim 34, wherein the operations further comprise: based on receiving from the POS device an indication that the particular item of negotiable economic credit has been authenticated, displaying a confirmation message on a display of the device. 36. The article of manufacture of claim 34, wherein the operations further comprise: based on receiving from the POS device an indication that the particular item of negotiable economic credit has been authenticated, removing the data structure from the device. 37. The article of manufacture of claim 34, wherein the operations further comprise: receiving the data structure via an optical scanner. 38. The article of manufacture of claim 34, wherein the operations further comprise: receiving the data structure via a contact or contactless electronic interface. 39. The article of manufacture of claim 34, wherein the data structure further comprises one or more of: data representative of an identification number corresponding to the particular item of negotiable economic credit; data representative of a vendor that authorized issuance of the particular item of negotiable economic credit; data representative of an entity that will redeem the particular item of negotiable economic credit; data representative of an issuer of the particular item of negotiable economic credit; or any combination thereof. 40. The article of manufacture of claim 34, wherein the device is a cellular telephone.
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS This application is a continuation of U.S. application Ser. No. 13/082,243, filed Apr. 7, 2011 which is a divisional of U.S. application Ser. No. 09/962,675, filed Sep. 25, 2001 which claims priority to Provisional Application U.S. Application 60/238,568, filed Oct. 6, 2000, all of which are incorporated herein by reference in its entirety BACKGROUND 1. Technical Field The present disclosure is generally related to electronic hand held devices (hereinafter referred to as “hand held devices”) and electronic commerce (“E-commerce”). The present invention is also related to hand held devices, such as a Personal Digital Assistant (PDA), wireless telephone, pager, or other mobile computing and storage device adapted for use in E-commerce. The present invention is also related to wireless and wireline computer networks. The present invention is additionally related to the fields of electronic cash, credit, award, incentive, and/or product management usable with/for retail establishments, organizations, and customers. The present invention is also related to merchandising systems and systems for generating and redeeming negotiable economic credits and/or data (e.g., electroin product discount coupons and other negotiable economic credits, such as enterprise awards, cash, credit, etc.). 2. Description of the Related Art The recent shift in the consumer electronics industry from an emphasis on analog technology to a preference for digital technology is largely based on the fact that the former generally limits the user to a role of a passive recipient of information, while the latter is interactive and allows the user to control what, when, and how he or she receives and manipulates certain information. This shift in focus has resulted in the development and increasingly widespread use of, for example, a hand held digital device generically referred to as a “personal digital assistant” (PDA). These hand held devices are becoming increasingly popular for storing and maintaining information. Hand held devices, such as PDAs, may be connected to a desktop personal computer, networks or other PDAs via infrared, direct wire, or wireless communication links. Unlike personal computers, which are general-purpose devices geared toward refining and processing information, PDAs are designed to capture, store and display information originating from various sources. Additionally, while a certain level of skill is required to use a personal computer effectively, hand held devices, such as PDAs, are designed with the novice and non-computer user in mind. A typical PDA includes a microprocessor, a memory unit, a display, associated encoder circuitry, and selector buttons. It may optionally contain a clock and infrared emitter and receiver. A graphical user interface permits a user to store, retrieve and manipulate data via an interactive display. A PDA also typically includes a calendar, datebook, and one or more directories. The calendar shows a month of dates organized as rows and columns in the usual form. The datebook shows one day at a time and contains alphanumeric text entered in free format (typically, with a time of day and an event and/or name). Each directory contains entries consisting of a name field and a free form alphanumeric text field that can contain company names, addresses, telephone and fax numbers, email addresses, etc. Entries may be organized alphabetically according to the name field and can be scanned or searched for by specifying a specific sequence of characters in the name field. A menu displayed via the graphical user interface permits a user to choose particular functions and directories. Most PDAs come equipped with a stylus, which is a plastic-tipped pen that a user utilizes to write in a “graffiti area” of the display and tap particular graphically displayed icons. Each icon is indicative of a particular activity or function. PDAs are increasingly being utilized to access information from remote computer networks, such as the “World Wide Web” and the “Internet,” both terms well known in the computer networking arts. PDA users can, for example, download e-mail from the Internet to the PDA. Web sites also exist that permit PDA users to access and download software that may be run on the PDA. For example, some web sites offer information to PDAs in the form of compressed news articles, stock quotes, and other data obtained from a wide variety of other electronic web-based sources. Based on the foregoing, it can be appreciated that a large number of users of hand held devices, such as PDAs, pagers and mobile telephony are increasingly relying on such devices to maintain and transmit a variety of personal and business information. Discount coupons have long been distributed by manufacturers to merchandise their products and by retail stores or establishments to attract consumers to their particular stores. Discount coupons are a type of negotiable economic credit frequently utilized by enterprises for marketing products and services to the public. Enterprise awards, such as frequent flyer miles, are also negotiable economic credits relied upon by enterprises for marketing purposes. Coupons are typically distributed to attract customers to engage in commercial transactions. Such coupons are effective if utilized by a sufficiently high percentage of customers. Utilizing this gauge, free-standing inserts are not very effective. Their redemption rate is presently approximately 2.8 percent and dropping. Typically, coupons are physically collected at stores and credit is provided to the customer purchasing the corresponding product. The coupons are generally bundled and forwarded to a clearing house and then to a redemption center for sorting and counting. Reports are eventually forwarded to the manufacturers issuing the coupons in order to eventually generate a credit to the stores redeeming the coupons. It may unfortunately take several months before a store is reimbursed for coupons under present coupon redemption/processing methods. Another problem with coupons is a significant misredemption rate of between 20 and 30 percent as a result of misidentification and outright fraud. The misredemption problem is exacerbated by the enormous amount of time, usually a number of months, that it takes to reimburse the retail stores for the discount given the customer. Attempts have been made to address such problems. Such attempts, however, have resulted in additional problems, while not fully addressing the problems described above. For example, some companies have implemented a product specific micro-marketing system tied to a product point of selection and proprietary hardware in the form of an alerting platform attached to a grocery cart. A consumer within a retail establishment presses a button on the grocery cart alerting platform to select an electronic coupon when a coupon is graphically displayed at the exact product location within the retail establishment. The customer and the cart must be located at the point of selection to access the coupon. Such a micro-marketing system is proprietary in nature and requires a customer to retrieve a coupon only from the point of selection within the store. Thus, because of the proprietary nature of the system, the coupons, the alerting platform and other proprietary hardware cannot be utilized at other retail establishments. Further, the enterprise associated with the retail establishment is burdened by the maintenance, replacement, and repair of the proprietary hardware attached to the retail establishment's shopping carts due to use, abuse, the weather and so forth. Other systems known in the art utilize smart cards and card readers/writers at point of product selection for obtaining coupon data. Such systems, however, force the user to retrieve data at the point of product selection (i.e. point of selection), thereby tying their shopping activities to a proprietary system. Accordingly, alternatives are needed to traditional mass marketing and couponing techniques, and proprietary, point of selection type systems. A need exists for non-, or solely-, proprietary, based systems that are flexible, efficient and consumer friendly. Further a need exists for credit devices that are not completely owned by the enterprise or retail establishment, but owned by the customers themselves and which can be utilized at other retail establishments and enterprises. Such a device and associated systems and methods, should be ubiquitous in nature to avoid the problems inherently associated with prior micro-marketing systems. It has become apparent to the present inventors that the ability to acquire, store and use negotiable economic credits, such as coupons, on hand held devices would free users of the time consuming tasks of clipping, organizing and redeeming traditional paper coupons or credits (e.g., frequent flier redemption via paper-based request), and the problems associated with proprietary micro-marketing systems. It has also become apparent to the present inventors that for merchandisers and manufacturers, such hand held devices could be utilized to effectively market, compile and negotiate credit exchanges/redemption much more efficiently than the traditional paper processing methods or proprietary-based micro-marketing systems and methods. It is believed that aspects of the invention presently described herein solve the traditional problems associated with negotiable economic credits, including coupons, cash, credit and enterprise awards, and the problems associated with proprietary-based marketing systems thereof, while addressing an area of user control that has not yet been considered, anticipated, or utilized by coupon/credit merchandisers and manufacturers, namely, the increasing number of individuals who rely on hand held devices, such as PDAs, to maintain and store personal and business information. SUMMARY It is therefore an aspect of the present invention to provide improved methods and systems for conducting E-commerce utilizing hand held devices. It is another aspect of the present invention to provide improved methods and systems for processing negotiable economic data (e.g., coupons, cash, credits, or other financial incentives and awards) through hand held devices. It is yet another aspect of the present invention to provide improved methods and systems, which may include program products, for generating, capturing, and redeeming negotiable economic credits. It is still another aspect of the present invention to facilitate the processing of negotiable economic credits through hand held devices. The above and other aspects are achieved as are now described. Methods and systems for processing negotiable economic credits through a hand held device in association with a third-party provider communicative with the hand held device is disclosed herein. At least one negotiable economic credit may be transferred from a third-party provider communicative with the hand held device to the hand held device and/or a point of sale. The negotiable economic credit may be stored within a memory of the hand held device and/or point of sale for retrieval and processing at a point of sale associated with a retail establishment. The negotiable economic credit can be associated with a security module for protecting the privacy of the negotiable economic credit. A user profile may be compiled for utilization during the retrieval of the negotiable economic credit, in response to user input. The user profile can be stored in a database associated with the third-party provider and/or a database associated with the hand held device. The user profile can also be stored in a user profile database associated with a transaction broker. BRIEF DESCRIPTION OF THE DRAWINGS The novel features believed characteristic of this invention are set forth in the appended claims. The invention itself, however, as well as a preferred mode of use, further objects, and advantages thereof, will best be understood by reference to the following detailed description of an illustrative embodiment when read in conjunction with the accompanying drawings, wherein: FIG. 1 depicts a schematic diagram illustrating a hardware configuration of a hand held device, in accordance with preferred embodiments of the present invention; FIG. 2 illustrates a high-level block diagram generally illustrative of an electronic couponing method and system configured with a hand held device, in accordance with preferred embodiments of the present invention; FIG. 3 depicts a block diagram illustrating additional details of an electronic couponing method and system utilizing a hand held device, in accordance with preferred embodiments of the present invention; FIG. 4 illustrates a high-level block diagram illustrating a wireless electronic couponing method and system utilizing a wireless hand held device, in accordance with preferred embodiments of the present invention; FIG. 5 depicts a block diagram illustrative of an electronic couponing method and system, in accordance with preferred embodiments of the present invention; FIG. 6 illustrates a block diagram illustrative of an alternative electronic couponing method and system, in accordance with preferred embodiments of the present invention; FIG. 7 depicts a block diagram illustrating the implementation of a coupon manager module at a retail point of sale, in accordance with preferred embodiments of the present invention; FIG. 8 illustrates a block diagram illustrating the implementation of a credit manger module at a retail point of sale, in accordance with preferred embodiments of the present invention; FIG. 9 depicts a block diagram illustrating the implementation of credit manager, coupon manager, product manager, and accounting modules located away from the retail point of sale, in accordance with preferred embodiments of the present invention; FIG. 10 illustrates a block diagram illustrating the implementation of credit manager, coupon manager, product manager, and accounting modules outside a retail point of sale, in association with a hand held device configured as a PDA, in accordance with preferred embodiments of the present invention; FIG. 11 illustrates a block diagram illustrating the implementation of credit manager, coupon manager, product manager, and accounting modules located outside the retail point of sale, in association with a hand held device configured as a PDA integrated with an optical scanner, in accordance with preferred embodiments of the present invention; FIG. 12 illustrates a block diagram illustrating the implementation of credit manager, coupon manager, product manager, and accounting modules located away from the retail point of sale, in association with a hand held device configured as a wireless telephone, in accordance with preferred embodiments of the present invention; FIG. 13 depicts a system diagram illustrating an electronic coupon and credit management system, in accordance with preferred embodiments of the present invention; FIG. 14 illustrates an alternative system diagram illustrating an electronic coupon and credit management system, in accordance with preferred embodiments of the present invention; FIG. 15 depicts an alternative system diagram illustrating an electronic coupon and credit management system, in accordance with preferred embodiments of the present invention; FIG. 16 illustrates an alternative system diagram illustrating an electronic coupon and credit management system, in accordance with preferred embodiments of the present invention; FIG. 17 depicts an alternative system diagram illustrating an electronic coupon and credit management system, in accordance with preferred embodiments of the present invention; FIG. 18 illustrates an alternative system diagram illustrating an electronic coupon and credit management system, in accordance with preferred embodiments of the present invention; FIG. 19 depicts an alternative system diagram illustrating an electronic coupon and credit management system, in accordance with preferred embodiments of the present invention; FIG. 20 illustrates an alternative system diagram illustrating an electronic coupon and credit management system, in accordance with preferred embodiments of the present invention; FIG. 21 depicts a flow-chart of operations illustrating general procedural steps for implementing hand held device operations, in accordance with preferred embodiments of the present invention; FIG. 22 illustrates a flow-chart of operations illustrating detailed procedural steps for implementing hand held device operations, in accordance with preferred embodiments of the present invention; FIG. 23 depicts a flow-chart of operations illustrating additional procedural steps for carrying out hand held device operations, in accordance with preferred embodiments of the present invention; FIG. 24 illustrates a flow-chart of operations illustrating procedural steps for carrying out point of sale (POS) operations, in accordance with preferred embodiments of the present invention; FIG. 25 depicts a flow-chart of operations illustrating procedural steps for carrying out both hand device and point of sale (POS) operations, in accordance with preferred embodiments of the present invention; FIG. 26 illustrates a flow-chart of operations illustrating procedural steps for carrying out customer and retail operations, in accordance with preferred embodiments of the present invention; FIG. 27 depicts a flow-chart of operations illustrating steps for implementing a credit manager module, in accordance with preferred embodiments of the present invention; FIG. 28 illustrates an entity diagram illustrating possible attributes for a wireless network, in accordance with preferred embodiments of the present invention; FIG. 29 depicts a block diagram illustrating the interaction of a wireless network, a hand held device, and cash management modules, in accordance with preferred embodiments of the present invention; FIG. 30 illustrates a block diagram of a hand held device, in accordance with preferred embodiments of the present invention; FIG. 31 depicts a block diagram of a hand held device configured with an optical scanner module and optical scanner, in accordance with preferred embodiments of the present invention; FIG. 32 illustrates a block diagram illustrative of a client/server architecture, in accordance with preferred embodiments of the present invention; FIG. 33 depicts a detailed block diagram of a client/server architecture in accordance with preferred embodiments of the present invention; FIG. 34 illustrates a block diagram of a computer network in which a preferred embodiment of the present invention can be implemented; FIG. 35 depicts a top view of a hand held device and a smart card adapted for use with the hand held device, in accordance with preferred embodiments of the present invention; FIG. 36 depicts a side view of the hand held device depicted in FIG. 35 and a slot for inserting smart card into the hand held device, in accordance with preferred embodiments of the present invention; and FIG. 37 illustrates a hand held device configured with a smart card adapted for use with the hand held device and a scanner integrated with the hand held device, in accordance with preferred embodiments of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS FIG. 1 depicts a schematic diagram illustrating a general hardware configuration of a hand held device 11, in accordance with an embodiment of the present invention. Those skilled in the art can appreciate, however, that other hardware configurations may be utilized, and are further described herein, to implement hand held device 11. CPU 10 of hand held device 11, acts as a main controller operating under the control of operating clocks supplied from a clock oscillator (OSC) 13. CPU 10 may be configured as a 16-bit microprocessor. External pins of CPU 10 are generally coupled to an internal bus 26 so that it may be interconnected to respective components via internal bus 26. SRAM 24 may be a writeable memory that does not require a refresh operation and may be generally utilized as a working area of CPU 10. SRAM (Static RAM) may be a form of semiconductor memory (RAM) based on a logic circuit known as a flip-flop, which retains information as long as there is enough power to run the device. Font ROM 22 may be a read only memory for storing character images (e.g., font) displayable on a liquid crystal (LCD) panel 18. CPU 10 of the present embodiment drives LCD display 18 utilizing, among other media, font images from Font ROM 22. EPROM 20 may be a read only memory that may be erasable under certain conditions and may be primarily utilized for permanently storing control codes for operating respective hardware components and security data, such as a serial number. IR controller 14 may be generally configured as a dedicated controller for processing an infrared code transmitted/received by an IR transceiver 16 and for capturing the same as computer data. Wireless controller 17 may be generally configured as a dedicated controller and transceiver for processing wireless RF data transmitted from and to a wireless communications network. Port 12 may be connected to CPU 10 and can be temporarily attached, for example, to a docking station to transmit information to and from hand held device 11 to other devices, such as personal computers, retail cash registers, electronic kiosk devices, and so forth. Port 12 can also be configured, for example, to link with a modem, cradle or docking station, which are well known in the art, that permit network devices, a personal computer or other computing devices to communicate with hand held device 11. User controls 32 permit a user to enter data to hand held device 11 and initiate particular processing operations via CPU 10. In addition, CPU 10 may cause a sound generator 28 to generate sounds of predetermined frequencies from a speaker 30. Those skilled in the art can appreciate that additional electronic circuits or the like other than, or in addition to, those illustrated in FIG. 1 may be required to construct hand held device 11. Such components, however, are not described in the present specification, because they are well known in the art. Those skilled in the art can thus appreciate that because of the brevity of the drawings described herein, only a portion of the connections between the illustrated hardware blocks is depicted. In addition, those skilled in the art will appreciate that hand held device 11 can be implemented as a specific type of a hand held device, such as a Personal Digital Assistant (PDA), paging device, WAP-enabled mobile phone, and other associated hand held computing devices well known in the art. When PDAs are deployed, such PDA devices can be further configured with both wireless and wireline communications capabilities, such as those found in cellular telephone units, in accordance with carrying out embodiments of the present invention. Examples of PDA devices that can be utilized in accordance with the method and system of the present invention include the “PalmPilot” PDA, manufactured and sold by Palm Computing, the Handspring Visor, the IBM Workpad, WINDOW CE compatible devices, RIM Blackberry-family paging devices, Motorola paging devices, and the Symbol SPT-family of PDA-type organizer devices. Hand held devices may be also configured with optical scanning/capturing capabilities, in accordance with embodiments of the present invention, which will be further described below. FIG. 2 illustrates a high-level block diagram 34 generally illustrative of an electronic couponing method and system configured with a hand held device 40, in accordance with preferred embodiments of the present invention. Hand held device 40, which can be configured as a PDA or other hand held device, communicates with network 38. Network 38 communicates with a coupon database 36. Coupon data maintained in coupon database 36 can be retrieved by hand held device 40 through network 38. Those skilled in the art can appreciate that although hand held device 40 is illustrated as a PDA in FIG. 2, hand held device 40 can be implemented as a wireless application protocol (WAP) web-enabled cellular telephone, or pager or a combination thereof. Hand held device 40 can also be configured as a combination cellular phone/PDA device. An example of such a device is the Handspring palmtop and associated cellular phone attachment, which is manufactured and sold by Handspring Inc. Other such devices include the Palm-Motorola phone, which permits users to access e-mail and store calendars and contact databases. Thus, according to FIG. 2, electronic coupon data can be stored in coupon database 36. Those skilled in the art can appreciate that such electronic coupons represent one type of negotiable economic credit. Thus, the method and system described herein can apply to the processing of other negotiable economic credits, such as enterprise credits/awards (e.g., frequent flyer miles). Such negotiable economic credits can also be implemented in the form of what has been referred to as electronic cash or currency (i.e., “e-cash”). It should be understood by those skilled in the art that negotiable economic credits can be implemented as actual electronic currency requiring little or no third-party intervention for redemption, or may be implemented in the form of data needed to negotiate a credit transaction with a third-party and a retailer on behalf of a hand held device. A user can thus access coupon database 36 through network 38. Data can be transmitted to and from network 38, as illustrated by arrow 44. Data can also be transmitted to and from coupon database 36 to network 38, as indicated at arrow 42. Communication between network 38 and hand held device 40 can occur through wireless transmission or direct wireline connections, such as a PDA docking station or cradle. The user thus transmits a request to network 38 to retrieve coupon data from coupon database 36. Network 38 can thereafter access and retrieve the requested data from coupon database 36 and transmits such data to hand held device 40, in response so user input at hand held device 40. The coupon data can then be stored and/or displayed within a display area of hand held device 40 in the form of one or more electronic coupons which can be redeemed for price discounts at retail establishments associated with such electronic coupons. An electronic coupon may be essentially a token, issued by or under the authority of the issuer for the benefit of the recipient. Typically, the recipient receives the electronic coupon and subsequently redeems it for the prescribed benefit at some later point in time. Such an electronic coupon can enable or modify an anticipated transaction, such as providing a discount in the price of goods or services provided by the issuer or the issuer's agent. In addition, such an electronic coupon can enable or modify the level of access to privately held information or a server having restricted access. Alternatively, the electronic coupon can be utilized in transactions between two businesses, two governmental agencies or two governments wherein, for example, the businesses enter into an agreement relating to a transaction for goods or services or access to information, or the governmental bodies enter into an agreement relating to transactions regarding currency or information. The electronic coupon may be stored and retrieved in the form of coupon data. Such coupon data typically may be composed of a data structure which can include any or all of the following information elements: data representative of an electronic coupon serial number or identification number, data representative of a unique key that can be utilized to validate or authenticate the coupon, data representative of the vendor that authorized the coupon and will redeem the coupon, data representative of the nature of the discount or access provided by the coupon, data representative of the server or entity that issued the coupon. In one preferred embodiment of the present invention, the electronic coupon contains all the information necessary to redeem the coupon. Specifically, the electronic coupon identifies the grantor (i.e., the party of vendor that will redeem the electronic coupon), the nature of the discount or benefit provided and a unique serial number or other data structure that permits the electronic coupon to be authenticated or validated. Thus, POS-based identifying hardware and software and/or a server redeeming this type of electronic coupon can obtain all the information necessary to redeem from the electronic coupon. Such a server can even include the software necessary to authenticate or validate the electronic coupon (e.g., the coupon manager described herein). In an alternative embodiment of the present invention, the electronic coupons described herein can be issued as part of an electronic coupon book. The coupon book can include data representative of a version number for the electronic coupon book and data representative of a serial number or identification number for the electronic coupon book. Such an electronic coupon book can be configured to include a unique serial number or identification number and a data structure useful for authenticating or validating the electronic coupon book. In order to redeem this type of electronic coupon, a server and/or coupon manager at a POS, which intends to redeem the electronic coupon must connect to an authentication server, which authenticates or validates the coupon book and indicates the nature of the benefit of the electronic coupon to the server or coupon manager requesting authentication/validation. FIG. 3 depicts a block diagram 47 illustrating additional details of an electronic couponing method and system utilizing a hand held device 40, in accordance with preferred embodiments of the present invention. In FIG. 3 and FIG. 4 like parts are indicated by like numbers. Thus, block diagram 47 of FIG. 4 is analogous to block diagram 34 of FIG. 3. Hand held device 40 can communicate with a retail checkout station 46 via a docking station 48. Docking station 48 can be configured as a PDA cradle for communicating with retail checkout station 46. Docking station 48 can be implemented as a wired or wireless docking station, or a combination thereof. Docking station 48 and retail checkout station 46 are linked, such that data can be transferred from hand held device 40 to retail checkout station 46. Retail checkout station 46 may be in communication with network 38, which in turn can access coupon database 36 to retrieve coupon data. Coupon data can be retrieved from coupon database 36 and transferred through network 38 to retail checkout station 46. The coupon data can then be transferred from retail checkout station 46 through docking station 48 to hand held device 40. During a synchronization of hand held device 40 with retail checkout station 46, coupon data can be transferred from hand held device 40 to retail checkout station 46. It should be appreciated by those skilled in the art that the term “synchronization” as described throughout the disclosure herein refers generally to communication for the purpose of transferring and/or comparing data. Such coupon data may be then compared against prices of scanned products at the retail checkout station to determine if product discounts can be calculated, based on particular coupon data transferred from hand held device 40 to retail checkout station 46 through docking station 48. Alternatively, during a transaction at retail checkout station 48 in which coupon data may be transferred to retail checkout station 46 from hand held device 40, new coupon data can be retrieved from coupon database 36 via network 38 and transferred to retail checkout station 46 and thereafter to hand held device 40. FIG. 4 illustrates a high-level block diagram 50 illustrating a wireless electronic couponing method and system utilizing a wireless hand held device 40, in accordance with preferred embodiments of the present invention. In FIG. 2, FIG. 3, and FIG. 4, analogous parts are indicated by identical reference numerals. Thus, hand held device 40 can retrieve coupon data (i.e., electronic coupons) from coupon database 36 through a wireless local computer network, such as, for example, a Personal Area Network (PAN). As indicated in FIG. 4, coupon data may be transferred from hand held device 40 through local wireless network 38 to coupon database 36. An example of one type of PAN that may be utilized in accordance with preferred embodiments of the present invention is “Bluetooth,” a telecommunications standard well known in the wireless networking arts. “Bluetooth” is a telecommunications standard adopted by a consortium of wireless equipment manufacturers referred to as the Bluetooth Special Interest Group (BSIG). Bluetooth is generally a global standard for low cost wireless data and voice communications. A current specification for the Bluetooth standard is in a 2.4 GHz ISM frequency band. Bluetooth is generally based on a short-range radio transmitter/receiver capability built into small application specific circuits (ASICs) and embedded into support devices. A Bluetooth-enabled device generally has 1 mw of transmitter power and is capable of asymmetrical data transfers of up to 721 Mbps over distances of 10M. Bluetooth permits up to 100 mw of power, which increases frequency hopping of up to 1600 hops per second. FIG. 5 depicts a block diagram 70 illustrative of an electronic couponing method and system, in accordance with preferred embodiments of the present invention. According to FIG. 5, hand held device 72 retrieves a coupon or coupons (i.e., electronic coupons) in the form of electronic data from network 60. Hand held device 70 can communicate with a point of sale (POS) 88 at a retail establishment through a variety of mechanisms, such as docking station 64, infrared communications unit 68 or through a local RF wireless network 71, such as the Bluetooth-type local wireless network described herein. POS 88 receives or transmits data at input/output unit 74. Thus, any coupon data transferred from hand held device 72 may be transferred to POS 88 through input/output unit 74. Items purchased at the retail establishment are scanned at POS 88 utilizing a scanner 86 that can read and store, for example, scanned UPC codes. Those skilled in the art can appreciate that although scanner 86 is presented for purposes of describing a particular embodiment of the present invention, other types of scanning devices, e.g., bar code scanners, may also be utilized in place of scanner 86. For example, scanning devices that utilize holographic scanning configurations or RF Tags can also be utilized to scan product information. Product data (e.g., product prices) obtained as a result of scanning purchased items may be transferred to CPU 78 for processing with coupon data received from hand held device 72 at input/output unit 74. The coupon data transferred from hand held device 72 contains electronic coupons associated with particular products offered by the retail establishment. A product database containing product data may be linked to CPU 78. A coupon database 82 from which coupon data can be stored and retrieved may be also linked to CPU 78. CPU 78 compares the price of scanned products/items based on product data stored in product database 84 with the discounted price associated with user provided coupon data. If a matching product is identified in product database 84, CPU 78 subtracts the discounted price from scanned product price. When scanning is complete, CPU provides a total price, which includes coupon discounts and displays this total price at display 76 for the user to view. Thereafter, new coupon data can be retrieved from coupon database 82 by CPU 78 and transmitted to hand held device 71 through input/output unit 74. New coupon data may be used, for example, for future transactions. The coupon data originally transferred from hand held device 72 can be flagged and stored in coupon database 82 to indicate that such coupon data has already been utilized in a transaction at the retail establishment by the user of the hand held device 72. Such a flagging operation ensures that the user can only utilize the coupon data for a single purchase transaction. In addition, the coupon data retrieved from hand held device 72 and utilized during a purchase transaction can be deleted from the hand held device 72 during a synchronization of hand held device 72 and POS 88. CPU 78 can be instructed to generate and transmit a message to hand held device 72 during synchronization to indicate that the electronic coupons retrieved from hand held device 72 and utilized during the purchase transaction has been successfully utilized to discount products scanned by scanner 86 or another scanning device (e.g., holographic scanner, RF tags) utilized in accordance with preferred embodiments of the present invention. In FIG. 5 to FIG. 12, analogous parts are indicated by identical reference numerals. Those skilled in the art will appreciate that the block diagrams illustrated in FIG. 5 to FIG. 12 herein represent alternative preferred embodiments of the present invention and that similar parts may be utilized to implement such alternative preferred embodiments. Thus, FIG. 6 illustrates a block diagram 90 illustrative of an alternative electronic couponing method and system, in accordance with preferred embodiments of the present invention. Block diagram 90 of FIG. 6 is similar to block diagram 70 of FIG. 5, the difference evident in the addition of an accounting module 80, which interacts with POS 92 to keep track of purchase transactions, including coupon synchronizations with hand held devices and discounted prices thereof, that occurred at the POS 92 during a particular period of time, such as for example, a twenty-four period or during a particular shift. Accounting module 80, as illustrated in block diagram 90 of FIG. 6, is depicted outside the bounds of POS 92. CPU 78 can be linked to accounting module 80 through a wireless or direct link or through a network. Although not illustrated in FIG. 6, those skilled in the art can appreciate that accounting module 80 can be incorporated at the POS as a program product controlled by CPU 80. Accounting data can then be retrieved for use by accounting personnel/resources of the enterprise. Such modules, including the other modules discussed herein, can be implemented in the form of software modules. In the computer programming arts, a module may be typically implemented as a collection of routines and data structures that performs particular tasks or implements a particular abstract data type. Modules generally are composed of two parts. First, a software module may list the constants, data types, variable, routines, and so forth, which can be accessed by other modules or routines. Second, a software module may be configured as an implementation, which may be private (i.e., accessible only to the module), and which contains the source code that actually implements the routines or subroutines upon which the module is based. Thus, when referring to a “module” herein, the present inventors are referring so such software modules or implementations thereof. Such modules can be utilized separately or together to form a program product that can be implemented through signal-bearing media, including transmission media and recordable media. FIG. 7 depicts a block diagram 96 illustrating the implementation of a coupon manager 83 at a retail POS, in accordance with preferred embodiments of the present invention. Coupon manager 83 can be implemented as a software module located in a memory location of an authentication server, which includes software necessary to authenticate electronic coupons prior to their redemption. Likewise, coupon manager 83 can function as the authentication agent for authenticating coupons prior to their redemption. Operational and system components depicted in FIG. 5 and FIG. 6 herein are analogous to the operational and system components illustrated in FIG. 7. Block diagram 96 of FIG. 7, however, additionally includes a coupon manager module (i.e., coupon manager 83) in communication with coupon database 82 and CPU 78. Coupon Manager 83 also can communicate with accounting module 80, whether at the POS 94 or elsewhere, and product manager 87. Product manger 87 can communicate with product database 84, coupon manager 83, accounting module 80, and CPU 78. Coupon manager 83 may be implemented as a software module that instructs CPU 78 to retrieve coupon data from hand held device 72 during a synchronization with hand held device 72. Coupon manager 83 can also instruct CPU 78 to transmit data back to hand held device 72 during a synchronization with hand held device 78. In addition, coupon manager 78 can instruct CPU 78 to subtract price discounts associated with retrieved coupon data from prices associated with purchased items scanned with scanner 86. Coupon manager 83 may also retrieve new coupons from coupon database 82 that may be provided through the POS 94 to hand held device 72 for use during future purchases. Thus, coupon manager 83 provides product pricing and identification information based on, for example, UPC information retrieved from a scanned product by bar code scanner 86. Pricing information may be utilized by CPU 78 to render a subtotal of items purchased (i.e., “subtotal” meaning prior to coupon deductions). Information related to products retrieved from product database during scanning may be also utilized to associate the scanned product to the coupons retrieved as coupon data from hand held device 72. If scanned products match the coupons retrievable from hand held device 72, then a new total may be rendered based on the value of the coupons subtracted from the subtotal, and the matching coupons are retrieved from hand held device 72 for the retail establishment to obtain their credit due from associated product distributors. FIG. 8 illustrates a block diagram 100 illustrating the implementation of a credit manger 80 at a retail POS, in accordance with preferred embodiments of the present invention. Credit manager 80 may be a software module that retrieves credit data (i.e., credits or awards associated with retail/commercial transactions) from a credit database 81. Credit manager 80 can be configured to communicate with CPU 78, coupon manager 83, and product manager 87. In addition, credit manager 85 can communicate with accounting module 80. Again, those skilled in the art will appreciate that accounting module 80 can be configured at the POS 102 or at another location and linked to CPU 78 via a network link. Initially, items are scanned at POS 102. Hand held device 72 may be synchronized with POS 102 through input/output 74 and possible interfacing mechanisms, such as docking station 64, infrared communications unit 68 or through local wireless network 71. Credit manager 85 can be initialized in response to synchronization between hand held device 72 and POS 102 and/or in response to item scanning. Credit manager 85 accesses credit database 81 and determines associations between scanned items and credit or point information accessed from credit database 81. If a matching association may be identified, credit manager 85 retrieves credits from credit database 81. Credit manager 85 then instructs CPU 78 to process these credits, which are then transferred by CPU 78 through input/output unit 74 to hand held device 72. The credits can be then stored in a database associated with hand held device 72 for later retrieval by hand held device 72. When a certain number of credits are earned by the user of hand held device 72 following a particular number of transactions, the user can be eligible to receive discounts on future purchased items, or discounts or awards of products or services offered by other establishments or enterprises that have business alliances in place with the retail establishment or organization through which the credits were earned by the user. FIG. 9 depicts a block diagram 100 illustrating the implementation of credit manager 85, coupon manager 83, product manager 87, and accounting module 80 located away from the retail POS 102, in accordance with preferred embodiments of the present invention. POS 102 includes CPU 78 connected to input/output unit 74, display 76, and scanner 86. Unlike POS 102 of FIG. 8, POS 102, as illustrated in FIG. 9, may be configured to communicate with credit manager 85, coupon manager 83, product manager 87, and accounting module 80 indirectly rather than directly at POS 102. Those skilled in the art can thus appreciate that block diagram 100 of FIG. 9 may be simply an alternative preferred embodiment of the configuration depicted in FIG. 8. The various described modules can be incorporated into POS 102 at, for example, a cash register or cash register/scanning system, or can be implemented as software modules residing in computer memory in a remote computer network linked to POS 102. FIG. 10 to FIG. 12 illustrate alternative preferred embodiments of the present invention that utilize various types of hand held devices. In FIG. 10 to FIG. 12, analogous parts are indicated by like reference numerals. Thus, FIG. 10 illustrates a block diagram 100 illustrating the implementation of credit manager 85, coupon manager 83, product manager 87, and accounting module 80 located away from the retail POS 102, while credit database 81, coupon database 82 and product database 84 are configured to operate at POS 102. In FIG. 10, hand held device 73 may be configured as a PDA, in accordance with preferred embodiments of the present invention. A “PDA” may include a two-way paging device, such as the Blackberry-family of paging devices manufactured by RIM or Smart Phones proposed by numerous wireless industry manufacturers. Hand held device 73 of FIG. 10 may be configured as a PDA having wireless or wireline communications capabilities or a combination thereof, thus communicating with POS 102 through local wireless network 71, infrared (IR/IRF) communications unit 68 or docking station 64. FIG. 11, on the other hand, illustrates a hand held device 77 configured as a PDA integrated with an optical scanner, in accordance with preferred embodiments of the present invention. In FIG. 11, credit manager 85, coupon manager 83, product manager 87, and accounting module 80 are illustrated outside the retail POS, in association with hand held device 77. Hand held device 77 may be configured with an optical scanner that can scan coupon data and electronic coupons thereof from a static reference or representation, such as a newspaper, magazine, and so forth. Optical scanner 59 thus retrieves coupons 62 from static reference 57 by scanning or capturing electronic coupon data or other associated data (e.g., product data). In the case of a bar code reader, the electronic coupons (e.g., coupon data) are scanned. In the case of an optical reader with capturing capabilities, images representatives of coupons or coupon data are captured. The coupons (i.e. coupon data) are stored in a hand held device coupon database within hand held device 77 for eventual redemption at POS 102. Finally, FIG. 12 depicts a hand held device configured as a wireless telephone 79, in accordance with preferred embodiments of the present invention. Those skilled in the art can appreciate, of course, that such hand held devices can be configured to combine each of the primary features of a PDA, pager, and wireless and/or cellular telephone. In FIG. 13 to FIG. 14, analogous parts are indicated by identical reference numerals. FIG. 13 thus depicts a system diagram 130 illustrating an electronic coupon and credit management system, in accordance with preferred embodiments of the present invention. POS 140 may be linked to coupon manager 142 and credit manager 144. Coupon manager 142 is analogous to coupon manager 83 of FIG. 7 to FIG. 12. Credit manager 144 is analogous to credit manager 85 of FIG. 8 to FIG. 12 herein. POS 140, coupon manager 142, and credit manager 144 together comprise retail portion 138 of the electronic coupon and credit management system outlined in system diagram 130. POS 140 is analogous to POS 88, 92, 94, and 102 illustrated in FIG. 5 to FIG. 12 herein. A security module 152 can be linked to POS 140 to provide secure firewall protection (i.e., security 152). A firewall, well-known in the networking and computer arts, can be configured as a security module that protects an organization's network against external threats, such as hackers, coming from another network, such as the Internet. Firewalls prevent computers or other computing devices within a particular network from communicating directly with computers or other devices, such as hand held device 132, external to the network and vice versa. Instead, all communications are generally routed through a proxy server outside of the organizational network, and the proxy server determines if it is safe to let a particular message or data pass through to the network. In the configuration illustrated in FIG. 13, retail portion 138 may include a variety of POS devices (e.g., cash register/scanning systems) linked with computers and servers to provide a local enterprise network. As such, any communication with such a network may be filtered through a security module, such as security module 152. Those skilled in the art can appreciate that coupon manager 142 and credit manager 144 can be incorporated, separately or in combination, directly with POS 140 or may be linked to POS 140 through a network link, either wireless- or wireline-based. Hand held device 132 can communicate with a transaction broker 148 and a third-party provider 156 of coupons/credits. Communication between hand held device 132, transaction broker 148, and third-party provider 156 can occur utilizing a network 134 linked to a security module 136. Security module 136 can be configured as a firewall, as described herein. Transaction broker 148 and third-party provider can be configured as software modules residing in computer memory in a remote computer network, such as the Internet, or other networked configurations. Network 134 can be configured as a remote computer network, such as the Internet, or a dedicated local network. Third-party provider 156 may be linked to a provider database 158, and transaction broker 148 may be linked to a user profile database contain user profile data. User profile database 150 and transaction broker 148 together form a transaction broker portion 146 of system diagram 130. Provider database 158 and third-party provider 156 together comprise a third-party provider portion 154 of system diagram 130. If a user desires to obtain electronic coupons to store in hand held device 132, the user can communicate with transaction broker 148 or third-party provider 156 through a network 134. Data transmitted through network 134 to transaction broker 148 or third-party provider 156 may be filtered through the firewall provided by security module 136. Transaction broker 146 may be a module that can manage credits and coupons transmitted between all parties depicted in FIG. 13, including retail portion 138, third-party provider 156, and hand held device 132. A user can access third-party provider 156 directly through network 134 and security module 136 in order to retrieve coupons provided by third-party provider 156. Third-party provider 156 can be, for example, an organization or enterprise allied with a retail establishment or enterprise associated with POS 140. Retail portion may, for example, be associated with a grocery chain or shopping mall. Third-party provider 156 may, for example, be an airline company offering coupons or airline credits. Third-party provider 156 can communicate with retail portion 138 through a network 160, which again, may simply be the Internet or a dedicated network configured between POS 140 and third-party provider portion 154. Coupons and associated third-party provider information can be stored in provider database 158 and retrieved by third-party provider 156 for transmission to hand held device 132. Likewise, a user of hand held device 132 can access transaction broker 148 to download electronic coupons to hand held device 132 through security module 136 and network 134. The coupons are provided by transaction broker 148 to hand held device 132 based on a user profile that a user of hand held device 132 previously submitted to transaction broker 148. Thus, coupons transmitted by transaction broker 148 to hand held device 132 may be based on the user's preferences as indicated in an associated user profile stored in the user profile database 150. A user profile may be configured and/or obtained through a network by/from a hand held device 132, or a profile may be set up by a user at broker 148. Initial profile set up at the broker may be via a networked hand held device, personal computer or other means known in the art (e.g., telephonically). Thereafter, coupon retrieval from broker 148 may be by the hand held device 132, networked computer, POS 102 on behalf of the hand held device 132 user. In most situations, however, coupon retrieval will be from a broker 148 to the hand held device 132, and then from the hand held device 132 to the POS 102. Third-party provider 156 can also provide credit information to the retail establishment associated with POS 140 through network 160, thereby enabling credit manager 164 to maintain and handle transactions involving hand held device 132 and POS 138. The user of hand held device must, of course, have previously registered to receive such credits from third-party provider 156 either directly or with third-party provider 156 or indirectly through transaction broker 148. FIG. 14 illustrates an alternative system diagram 164 illustrating an electronic coupon and credit management system, in accordance with preferred embodiments of the present invention. As indicated earlier, in FIG. 13 and FIG. 14, like parts are indicated by identical reference numerals. As illustrated in system diagram 164, additional networks can be provided which permit hand held device 132 to communicate with transaction broker 148 or third-party provider 156. A user can retrieve electronic coupons to be stored in hand held device 132 from a coupon source 162. Coupon source 162 may simply be a web site displayed via the Internet from which coupon data may be downloaded, or coupon source 162 may simply be an implementation of third-party provider 156. Coupon source 162 may also be a static reference, such as a bar code or graphical representation of a coupon printed on a newspaper or magazine. In such a case, the bar code or graphical representation may be associated with one or more electronic coupons. An optical reader, such as a bar code scanner or other scanning device, can be integrated with a hand held device, such as a PDA or other hand held devices described herein, to retrieve electronic coupons from such a static reference. The static reference may be composed of coupon data representative of electronic coupons themselves that can be redeemed through a hand held device in accordance with the method and system described herein. The static reference may be also configured as data readable by an optical scanning device. Such data can refer the user of the hand held device to an Internet “web” page containing electronic coupons retrievable by the hand held device. Such a static reference can be configured as a 12-digit number in UPC Coupon Code format. In this format, the first digit may be a 5, designating a coupon. The next five digits may represent a manufacturer ID. The next 3 digits are a family code. The next 2 digits represent a value code. The last digit may be a check digit. The hand held device, such as a PDA, can additionally be configured with a holographic scanning device that optically reads holographic data embedded on print, magazine, cloth, or other physical material. Coupon source 162 thus illustrates the fact that coupon data (i.e., electronic coupons) are available for retrieval by hand held device 162 as indicated herein. Network 137 can be utilized to transmit data between security module 136 and transaction broker 148. Those skilled in the art can appreciate that network 137 may be analogous to network 134 (i.e., the two networks may be the same network) or the network may be a stand-alone network linked to security module 136 and transaction broker 148. Network 137 may also be a remote computer network, such as the Internet, from which data can be retrieved and transmitted. Likewise, network 135 can be implemented as a dedicated or stand alone network linking security module 136 with a security module 157, or network 135 may simply be a remote computer network, such as the Internet. Security module 157 may be configured as a firewall linked with third-provider 156 to provide additional protection to third-party provider 156 and its associated provider database 158. Those skilled in the art can appreciate that security module 157, along with the other security modules described herein, along with modifications thereof, may be equipped with encryption/decryption routines or subroutines to provide encryption/decryption capabilities to secure data transferred through such security modules. Such security modules may be further modified to include password protection routines or subroutines. FIG. 15 depicts an alternative system diagram 165 illustrating an electronic coupon and credit management system, in accordance with preferred embodiments of the present invention. FIG. 14 and FIG. 15 are similar, with the exception of an additional network 149 located between security module 157 and coupon source 162. FIG. 15 merely demonstrates the fact that coupon data may be provided by third-party provider 156 through network 149 to hand held device 162 and thereafter redeemed during a transaction involving hand held device 132 at POS 140. Again, network 149 may be composed of a dedicated network linking coupon source 162 and third-party provider portion 154 or simply the Internet. In such a case 162, coupon source 162 can be configured as a web site operated by an organization or enterprise associated with third-party provider 156. FIG. 16 illustrates an alternative system diagram 167 illustrating an electronic coupon and credit management system, in accordance with preferred embodiments of the present invention. System diagram 167 of FIG. 16 is similar to system diagram 165 of FIG. 15, with the exception of a network located between security module 157 and transaction broker 148. Transaction broker 148 can thus communicate with third-party provider 156 through network 172 and security module 157 to retrieve instructions, coupon data, credit data, and other appropriate information from third-party provider 156. Such information can then be provided to a user of hand held device 162 by transaction broker 148. Again, network 172 may be configured as a dedicated network linking security module 157 to transaction broker 148, or network 172 may simply be a remote computer network, such as the Internet. FIG. 17 depicts an alternative system diagram 169 illustrating an electronic coupon and credit management system, in accordance with preferred embodiments of the present invention. System diagram 169 of FIG. 16 is similar to system diagram 167 of FIG. 16 with the exception of an additional network 176 that permits hand held device 132 to communicate with third-party provider portion 154. Network 176 may be configured as a dedicated network linked to security module 157. In such a case, network 176 may simply be a local network located at a third-party provider establishment or premises that can be accessed by hand held device 132. Network 176 may simply be the Internet from which hand held device 176 can download appropriate third-party provider information, including electronic coupons, credit information, and other third-party provider information retrieved by third-party provider 156 from provider database 158. FIG. 18 illustrates an alternative system diagram illustrating an electronic coupon and credit management system, in accordance with preferred embodiments of the present invention. System diagram 171 of FIG. 18 is similar to system diagram 169 of FIG. 17, with the exception that security module 152 may be located with the realm of retail portion 138. In the previous illustrations, security module 152 was located outside the realm of retail portion 138 to indicate that the firewall or security arm of retail portion 138 can be configured at a location other than POS 140. For example, hand held device 152 may communicate with POS 140 through an electronic kiosk device located in a building or area away from the POS. Such an electronic kiosk device may be then linked via a network to POS 140. Alternatively, as illustrated in FIG. 18, security module 152 may be configured at the POS, depending on the needs or requirements of the retail establishment or enterprise operating POS 140. FIG. 19 depicts an alternative system diagram 173 illustrating an electronic coupon and credit management system, in accordance with preferred embodiments of the present invention. System diagram 173 differs from the previously illustrated system diagrams in the fact that the various portions that make up system diagram 173 and hence, the electronic coupon and credit management system described herein, can communicate with one another over a single network 143. Thus, transaction broker 148 can communicate with network 143 through security module 136. Third-party provider can communicate with network 143 through security module 157. POS 140 can communicate with network 143 through security module 152. Hand held device 132 can communicate with transaction broker portion 146, third-party provider portion 154 and retail portion 138 through network 143. Those skilled in the art will appreciate that network 143 can be configured as a stand-alone dedicated network or a remote computer network, such as the Internet and associated World Wide Web, paging networks and other Wireless Intelligent Networks (WINs). FIG. 20 illustrates an alternative system diagram 176 illustrating an electronic coupon and credit management system, in accordance with preferred embodiments of the present invention. System diagram 179 is similar to system diagram 173 of FIG. 19, with the exception that a coupon source 162 may be located between hand held device 132 and network 143 to illustrate the fact that coupons can be retrieved and stored in hand held device 132 from a coupon source 162 associated with network 143 or simply linked to network 143. Again, coupon source 162 may be configured as a web site from which coupon and credit data may be retrieved. Such a web site can be associated with transaction broker 146 and/or third-party provider 156 and/or POS 140 or retail portion 138. FIG. 21 depicts a flow-chart of operations 190 illustrating general procedural steps for implementing hand held device operations, in accordance with preferred embodiments of the present invention. As illustrated at block 192, the process may be initiated. A hand held device, such as the hand held devices described and illustrated herein, maintains a coupon management module that instructs a CPU, such as CPU 10 of FIG. 1, to manage the handling of coupon data received by or transmitted from the hand held device. Such a module can be configured as a software module that may be processed at the hand held device, and stored in a memory unit in the hand held device. As illustrated at decision block 196, a decision may be made, in response to initialization of the hand held device coupon management module, to determine if a coupon should be acquired by the hand held device. If it is determined not to acquire a coupon, the process terminates, as illustrated thereafter at block 202. If it is determined, however, to acquire a coupon, then as depicted next at block 198, a coupon in the form electronic coupon data may be acquired from a remote source. Thereafter, as described at block 200, the coupon may be stored in a database in the hand held device associated with the hand held device coupon module. The process then terminates, as indicated at block 202. It should be apparent after the present teachings that a decision to acquire coupons may be made manually by the user or automatically by the hand held device based on the user's profile, thereby relieving the user of manual coupon acquisition functions. FIG. 22 illustrates a flow-chart of operations 205 illustrating detailed procedural steps for implementing hand held device operations, in accordance with preferred embodiments of the present invention. As illustrated at block 206, the process may be initiated. As depicted thereafter at block 208, a hand held device having a coupon management module integrated therein communicates with a POS. Thereafter, as depicted at block 210, the hand held device may be synchronized with the POS coupon manager to negotiate a coupon exchange. It is important to distinguish between the POS coupon manager and the coupon management module integrated or associated with the hand held device. The POS coupon manager is analogous to coupon manager 142 illustrated in FIG. 20. The coupon management module described above is incorporated with the hand held device and functions as a coupon management module for the hand held device. When negotiation of the coupon exchange may be then completed, as indicated at block 212, thereafter, as depicted at block 214, a coupon database associated with the hand held device is reconciled and may also be updated with new coupons. Reconciliation operations remove used coupons and may add new ones to the device. Coupons utilized during the coupon exchange are deleted from such a coupon database. Again, such a hand held device coupon database may be distinguished from a POS associated coupon database, such as, for example, coupon database 82 of FIG. 8. Coupon database 82 of FIG. 8 operates in association with a POS. The hand held device coupon database described above may be integrated with the hand held device and stores coupon information and related coupon data in the hand held device itself. The process then terminates, as described at block 216. FIG. 30 herein illustrates the interaction of a coupon database and coupon management module associated with a hand held device. FIG. 23 depicts a flow-chart of operations 218 illustrating additional procedural steps for carrying out hand held device operations, in accordance with preferred embodiments of the present invention. As indicated at block 220, the process may be initiated. As described thereafter at block 218, a coupon in the form electronic coupon data can be acquired from a store or retail establishment directly through a docking station or through wireless means, such as, for example, a wireless tag. Acquisition of such coupon data is generally handled through the coupon management module associated with the hand held device (e.g., refer to FIG. 30). Thereafter, the hand held device can communicate with a POS, as indicated at block 222. The hand held device coupon management module may be synchronized with the POS associated coupon manager to negotiate a coupon exchange, as depicted at block 224. Negotiation with the POS can be then completed, as described at block 226. The process then terminates, as indicated at block 228. FIG. 24 illustrates a flow-chart of operations 240 illustrating procedural steps for carrying out point of sale (POS) operations, in accordance with preferred embodiments of the present invention. The process can be initiated, as indicated at block 242, and thereafter, as depicted at block 244, purchased items are scanned at the POS utilizing a scanning device, such as scanner 86 of FIG. 5 to FIG. 12. A subtotal can be then rendered, as indicated at block 246. The POS can communicate with the hand held device, as illustrated at block 248, the POS associated coupon manager can be thereby synchronized with the hand held device coupon management module to negotiate a coupon exchange, as indicated at block 250. If applicable, a new total can be calculated, as depicted at block 254, based on the subtraction of coupon discounts from the rendered subtotal. A new total can be then rendered, as illustrated at 254, which reflects any price discounts associated with the coupon data synchronized and negotiated during the coupon exchange between the hand held device and the POS. The process then terminates, as described at block 256. FIG. 25 depicts a flow-chart of operations 260 illustrating procedural steps for carrying out both hand device and point of sale (POS) operations, in accordance with preferred embodiments of the present invention. Hand held device operations are initiated, as illustrated at block 262. POS operations are initiated, as indicated at block 269. As depicted at block 264, electronic coupons are the acquired by the hand held device. The hand held device can be then taken to the POS during an item purchase, as illustrated at block 266. At the POS, the hand held device communicates with the POS by wireless transmission of data or through a dedicated wireline docking station linked with, for example, a cash register/scanning system. As depicted next at block 270, items to be purchased at the retail establishment are scanned at the POS. Thereafter, a subtotal can be rendered, as depicted at block 272. Those skilled in the art can appreciate that such operations may be performed in alternative ordering, as indicated by the dashed connecting arrows in FIG. 25. Following completion of the operation illustrated at block 272, the POS coupon manager (e.g., coupon manager 83 of FIG. 8) can be synchronized with the hand held device coupon management module (e.g., coupon management module 430 of FIG. 30) to negotiate the coupon exchange. Thereafter, as indicated at block 276 the POS coupon database (e.g., coupon database 82 of FIG. 8) can be reconciled with the hand held device coupon database (e.g., hand held device coupon database 432 of FIG. 30). Hand held device operations then terminate, as illustrated at block 277. Following completion of the operation described at block 274, a new total can be calculated which takes into account subtracted discounts based on coupons provided to the POS from the hand held device. The new total can be then rendered on, for example, a display screen of a cash register and/or the hand held device itself, as illustrated at block 278. POS operations for the transaction can be then terminated, as depicted at block 280. FIG. 26 illustrates a flow-chart of operations 290 illustrating procedural steps for carrying out customer and retail operations, in accordance with preferred embodiments of the present invention. A dashed line depicted in FIG. 26 separates customer operations from retail operations in attempt to distinguish between operations that primarily involve the hand held device and operations primarily involving the retail establishment and POS. Thus, as depicted at block 292, the process can be initiated. Thereafter, as described at block 294, a user utilizing a hand held device acquires a coupon. The hand held device can be then placed in communication with the POS, as indicated at block 296. As illustrated next at block 298, The POS coupon manager can be synchronized with the hand held device coupon management module. Thereafter, as depicted at block 300, a coupon database associated with the hand held device (e.g., hand held device coupon database 432 of FIG. 30 and FIG. 31) can be accessed. Coupon data can be then retrieved from the hand held device coupon database, as illustrated at block 302. Next, as indicated at block 304, a product manager correlates coupons retrieved from the hand held device with products scanned and to be purchased at the POS. An example of such a product manager is product manager 87 of FIG. 8. Correlating product data can be then identified, as indicated at block 306, and thereafter, as illustrated at block 308, a new total can be calculated by subtracting correlating coupon data. A new total can be then rendered, as described at block 310. The process then ends, as illustrated at block 312. FIG. 27 depicts a flow-chart of operations 320 illustrating steps for implementing a credit manager module, in accordance with preferred embodiments of the present invention. An example of such a credit manager is credit manager 144 of FIG. 5 to FIG. 12. A credit manager module (or simply “credit manager”) can be initiated, as illustrated at block 322. An item or product to be purchased can be scanned at the POS, as illustrated at block 323. A hand held device can be in communication with the POS, as indicated at block 324 and thereafter, as depicted at block 326, the credit manager associated with the POS (e.g., credit manager 85 of FIG. 8) can be initialized. In response to initialization of the credit manager, as indicated at block 328, the POS credit manager accesses a credit database (e.g., credit database 81 of FIG. 8). As illustrated next at block 330, the POS credit manager determines associations between scanned items and credit information, including credits or points, accessed from the credit database. Thereafter, as depicted at decision block 332, it must be determined if any matches are made between scanned items and credits/points accessed from the credit database. If a match is not found for a particular scanned item, then as depicted at block 324, a comparison must be performed again, as illustrated via connecting symbol 335 and block 330. If, however, a match is identified, the credit manager retrieves credits/points from the credit database, as described at block 336. The credits are then processed, as illustrated at block 338, and thereafter transferred, as described at block 340, to a credit database associated with the hand held device. Such a hand held device credit database may be integrated with the hand held device itself. The process can be then terminated, as illustrated at block 348. FIG. 28 illustrates an entity diagram 400 illustrating possible attributes for a wireless network, in accordance with preferred embodiments of the present invention. Those skilled in the art can appreciate that wireless network 414 may be utilized in place of or in association with network 143 of FIG. 19 and FIG. 20. Such a wireless network can be utilized to permit a hand held device, such as hand held device 132 of FIG. 20 to communicate with a POS, third-party provider and/or a transaction broker. Those skilled in the art can further appreciate that a variety of possible wireless communications and networking configurations may be utilized to implement wireless network 414. Wireless network 414 may be, for example, implemented according to a variety of wireless protocols, including satellite, cellular, and direct RF or IR communications. Satellite communications, for example, well known in the art and can be implemented in combination with a network. A hand held device can communicate with a POS, third-party provider of coupons/credits, retail establishment, or transaction broker to acquire, transmit, and negotiate coupon exchanges through wireless network 414. Wireless network 414 can be implemented as a single network type (e.g., Bluetooth) or a network based on a combination of network types (e.g., GSM, CDMA, etc). Wireless network 414 can be configured as a CDPD (Cellular Digital Packet Data) network 413, well-known in the networking arts. CDPD can be a TCP/IP based technology that supports Point-to-Point (PPP) or Serial Line Internet Protocol (SLIP) wireless connections to mobile devices, such as the hand held devices described and illustrated herein. Cellular service is generally available throughout the world from major service providers. Data can be transferred over switched PSTN circuits or packet-switched network utilizing CDPD protocols. Current restrictions of CDPD are not meant to limit the range or implementation of the method and system described herein, but are described herein for illustrative purposes only. It is anticipated that CDPD will be continually developed, and that such new developments can be implemented in accordance with the present invention. Wireless network 414 can be also configured as a Personal Area Network 402 or Bluetooth, as described herein. Bluetooth was adopted by a consortium of wireless equipment manufacturers referred to at the Bluetooth Special Interest Group (BSIG), and has emerged as a global standard for low cost wireless data and voice communication. Current specifications for this standard call for a 2.4 GHz ISM frequency band. Bluetooth technology is generally based on a short-range radio transmitter/receiver built into small application specific circuits (ASICS) and embedded into support devices, such as the hand held devices described and illustrated herein. The Bluetooth standard permits up to 100 mw of power, which can increase the range to 100 M. In addition, Bluetooth can support up to three voice channels. Utilizing short data packets and frequency hopping of up to 1600 hops per second, Bluetooth is a wireless technology that can be utilized to enable the implementation of the method and system described herein. Current restrictions of Bluetooth are not meant to limit the range or implementation of the present invention, but are described herein for illustrative purposes only. It is anticipated Bluetooth will be continually developed, and that such new developments can be implemented in accordance with the present invention. Wireless network 414 can also be configured as a GSM network 404. GSM (Global System for Mobile Communication) and PCS (Personal Communications Systems) networks, both well-known in the telecommunications arts, generally operate in the 800 MHz, 900 MHz, and 1900 MHz range. PCS initiates narrowband digital communications in the 900 MHz range for paging, and broadband digital communications in the 1900 MHz band for cellular telephone service. In the United States, P C S 1900 is equivalent to GSM 1900. GSM operates in the 900 MHz, 1800-1900 MHz frequency bands, while GSM 1800 is widely utilized throughout Europe and many other parts of the world. In the United States, G S M 1900 is equivalent to PCS 1900, thereby enabling the compatibility of these two types of networks. Current restrictions of GSM and PCS are not meant to limit the range or implementation of the present invention, but are described herein for illustrative purposes only. It is anticipated that GSM and PCS will be continually developed, and that such new developments can be implemented in accordance with the present invention. Wireless network 414 can be also implemented as a GPRS network 406. GPRS technology, well-known in the telecommunications arts, bridges the gap between current wireless technologies and the so-called “next generation” of wireless technologies referred to frequently as the third-generation or 3G wireless technologies. GPRS is generally implemented as a packet-data transmission network that can provide data transfer rates up to 115 Kbps. GPRS can be implemented with CDMA and TDMA technology and supports X.25 and IP communications protocols, all well-known in the telecommunications arts. GPRS also enables features, such as Voice over IP (VOIP) and multimedia services. Current restrictions of GPRS are not meant to limit the range or implementation of the present invention, but are described herein for illustrative purposes only. It is anticipated that GPRS will be continually developed and that such new developments can be implemented in accordance with the present invention. Wireless network 414 can be implemented as a CDMA network 408. CDMA (Code Division Multiple Access) is a protocol standard based on IS-95 CDMA, also referred to frequently in the telecommunications arts as CDMA-1. IS-95 CDMA is generally configured as a digital wireless network that defines how a single channel can be segmented into multiple channels utilizing a pseudo-random signal (or code) to identify information associated with each user. Because CDMA networks spread each call over more than 4.4 trillion channels across the entire frequency band, it is much more immune to interference than most other wireless networks and generally can support more users per channel. Currently, CDMA can support data at speeds up to 14.4 Kbps. Wireless network 414 can also be configured with a form of CDMA technology known as wideband CDMA (W-CDMA). Wideband CDMA is also referred to as CDMA 2000 in North America. W-CDMA can be utilized to increase transfer rates utilizing multiple 1.25 MHz cellular channels. Current restrictions of CDMA and W-CDMA are not meant to limit the range or implementation of the present invention, but are described herein for illustrative purposes only. It is anticipated that CDMA and W-CDMA will be continually developed and that such new developments can be implemented in accordance with the present invention. Wireless network 414 can be also implemented as a paging network 410. Such paging networks, well-known in the telecommunications arts, can be implemented in accordance with the present invention to enable transmission or receipt of data over the TME/X protocol, also well-known in the telecommunications arts. Such a protocol enables notification in messaging and two-way data coverage utilizing satellite technology and a network of base stations geographically located throughout a particular geographical region. Paging network 410 can be configured to process enhanced messaging applications. Unified messaging solutions can be utilized in accordance with wireless network 414 to permit carriers and Internet service providers to manage customer e-mail, voice messages and fax images and can facilitate delivery of these communications to PDAs, telephony devices, pagers, personal computers and other capable information retrieval devices, wired or wireless. Current restrictions of such paging networks are not meant to limit the range or implementation of the present invention, but are described herein for illustrative purposes only. It is anticipated that such paging networks, including those based on the TME/X protocol, will be continually developed and that such new developments can be implemented in accordance with the present invention. Wireless network 414 can also be configured as a TDMA network 412. TDMA (Time Division Multiple Access) is a telecommunications network utilized to separate multiple conversation transmissions over a finite frequency allocation of through-the-air bandwidth. TDMA can be utilized in accordance with the present invention to allocate a discrete amount of frequency bandwidth to each user in a TDMA network to permit many simultaneous conversations or transmission of data. Each user is assigned a specific timeslot for transmission. A digital cellular communications system that utilizes TDMA typically assigns 10 timeslots for each frequency channel. A hand held device operating in association with a TDMA network sends bursts or packets of information during each timeslot. Such packets of information are then reassembled by the receiving equipment into the original voice or data/information components. Current restrictions of such TDMA networks are not meant to limit the range or implementation of the present invention, but are described herein for illustrative purposes only. It is anticipated that TDMA networks will be continually developed and that such new developments can be implemented in accordance with the present invention. Wireless network 414 can also be configured as a WIN (Wireless Intelligent Network) 415. WIN is generally known as the architecture of the wireless switched network that allows carriers to provide enhanced and customized services for mobile telephones. Intelligent wireless networks generally include the use of mobile switching centers (MSCs) having access to network servers and databases such as Home Location Registers (HLRs) and Visiting Location Registers (VLRs), for providing applications and data to networks, service providers and service subscribers (wireless device users). Local number portability allows wireless subscribers to make and receive calls anywhere—regardless of their local calling area. Roaming subscribers are also able to receive more services, such as call waiting, three-way calling and call forwarding. A HLR is a database that contains semipermanent mobile subscriber (wireless device user) information for wireless carriers' entire subscriber base. HLR subscriber information includes identity, service subscription information, location information (the identity of the currently serving VLR to enable routing of communications), service restrictions and supplementary services/information. HLRs handle SS7 transactions in cooperation with Mobile Switching Centers and VLR nodes, which request information from the HLR or update the information contained within the HLR. The HLR also initiates transactions with VLRs to complete incoming calls and update subscriber data. Traditional wireless network design is based on the utilization of a single HLR for each wireless network, but growth considerations are prompting carriers to consider multiple HLR topologies. The VLR is also a database that contains temporary information concerning the mobile subscribers currently located in a given MSC serving area, but whose HLR is elsewhere. When a mobile subscriber roams away from the HLR location into a remote location, SS7 messages are used to obtain information about the subscriber from the HLR, and to create a temporary record for the subscriber in the VLR. Signaling System No. 7 (referred to as SS7 or C7) is a global standard for telecommunications. In the past the SS7 standard has defined the procedures and protocol by which network elements in the public switched telephone network (PSTN) exchange information over a digital signaling network to effect wireless and wireline call setup, routing, control, services, enhanced features and secure communications. Such systems and standards may utilized to implement wireless network 414, in accordance with the present invention. Improved operating systems and protocols allow Graphical User Interfaces (GUIs) to provide an environment that displays user options (e.g., graphical symbols, icons or photographs) on a wireless device's screen. Extensible Markup Language (“XML”) is a currently available standard that performs as a universal language for data, making documents more interchangeable. XML allows information to be used in a variety of formats for different devices, including PCs, PDAs and web-enabled mobile phones. XML enables documents to be exchanged even where the documents were created and/or are generally used by different software applications. XML may effectively enable one system to translate what another systems sends. As a result of data transfer improvements, wireless device GUIs can be utilized in accordance with a hand held device and wireless network 414, whether configured as a paging network or another network type, to render images on the hand held device that closely represent the imaging capabilities available on desktop computing devices. FIG. 29 depicts a block diagram 416 illustrating the interaction of wireless network 414, a hand held device 416, and cash management modules, in accordance with preferred embodiments of the present invention. Cash management modules include a third-party provider 418, coupon manager 450, credit manager 422, product manager 424 and POS 426. Wireless network 414 of FIG. 29 is analogous to wireless network 414 of FIG. 28. In FIG. 28 and FIG. 29, like parts are indicated by identical reference numerals. FIG. 30 illustrates a block diagram of a hand held device 416, in accordance with preferred embodiments of the present invention. Hand held device 416 includes a coupon management module 430, which can communicate with a hand held device coupon database 432. Hand held device 416 of FIG. 30 is analogous to hand held device 416 of FIG. 29 and the other hand held devices described and illustrated herein, such as hand held device 11 of FIG. 1. Thus, in FIGS. 30 and 31, like parts are indicated by like reference numerals. A user profile associated with coupon management module 430 may be stored within hand held device coupon database 432 or may be provided as a separate user profile module 433. Again, the user profile may be used to filter out unwanted coupons during hand held device synchronization with network-based coupon providers (e.g., brokers, third-party providers) or the POS. User profiling enables more personalized, targeted couponing exchanges with a use of hand held device 416. Use of a profile may allow a user to retrieve targeted (profile matching) coupons automatically from any coupon providing sources achieving communication with the hand held device 416. FIG. 31 depicts a block diagram 439 of a hand held device 431 configured with an optical scanner module 435 and optical scanner 437, in accordance with preferred embodiments of the present invention. Hand held device 431 is analogous to hand held device 416 of FIG. 30. Hand held device 431 includes a CPU 10. CPU 10 of FIG. 31 is analogous to CPU 10 of FIG. 1. Those skilled in the art will appreciate that although CPU 10 is not depicted in FIG. 30, hand held device 416 of FIG. 30 operates in association with such a CPU. Thus, FIG. 30 and FIG. 31 are merely high level representations of a hand held device. Optical scanner module 435 functions as scanning software for optical scanner 437 and communicates with CPU 10 and coupon management module 430 to retrieve and store coupon data (i.e., electronic coupons) from static references, such as a bar code. Thus, those skilled in the art can appreciate that optical scanner 437 may be configured as a bar code reader. Optical scanner 437 may also be configured as an optical scanner that retrieves images. For example, optical scanner 437 can scan an image such as a photograph or other graphical representation from a static reference source, such as a magazine or newspaper, and store such information within a database in hand held device 431. If such graphical representations contain coupon data therein or graphical representations of coupons, such graphical representations can be stored within hand held device coupon database 432 as coupon data. Optical scanner 437 may also be implemented as a holographic scanner for scanning and retrieving holographic representations embedded as holograms or holographic representations on newspapers, magazines, cloth, etc. The networks described herein can be configured also as a client/server architecture, such as the Internet, to permit users to acquire coupons or communicate with third-party providers, transaction brokers, or the retail establishment and engage in coupon exchanges initiated from the hand held device. Thus, for example, network 143 of FIG. 19 and FIG. 20 can be configured as such a client/server architecture. FIGS. 31 to 33 describe a network based on a client/server architecture that can be utilized in association with the present invention. In FIG. 32, FIG. 33, and FIG. 34, like parts are indicated by identical reference numerals. FIG. 31 illustrates a block diagram illustrative of a client/server architecture in accordance with preferred embodiments of the present invention. In FIG. 31, user requests 591 for data are sent by a client application program 592 to a server 588. Server 588 can be a remote computer system accessible over the Internet or other communication networks. Client application program 592 may be utilized in association with a hand held device. Server 588 performs scanning and searching of raw (e.g., unprocessed) information sources (e.g., newswire feeds or news groups) and, based upon these user requests, presents the filtered electronic information as server responses 593 to the client process. The client process may be active in a first computer system, and the server process may be active in a second computer system, communicating with one another over a communications medium, thus providing distributed functionality and allowing multiple clients to take advantage of the information-gathering capabilities of the server. FIG. 32 illustrates a detailed block diagram of a client/server architecture in accordance with preferred embodiments of the present invention. Although the client and server are processes that are operative within two computer systems, these processes being generated from a high-level programming language (e.g., PERL), which can be interpreted and executed in a computer system at runtime (e.g., a workstation), it can be appreciated by one skilled in the art that they may be implemented in a variety of hardware devices, either programmed or dedicated. Client 592 and server 588 communicate utilizing the functionality provided by HTTP. Active within client 592 can be a first process, browser 572, which establishes connections with server 588, and presents information to the user. Any number of commercially or publicly available browsers can be utilized in various implementations in accordance with the preferred embodiment of the present invention. For example, a browser, such as Netscape™, can provide the functionality specified under HTTP. “Netscape” is a trademark of Netscape, Inc. Server 588 executes the corresponding server software, which presents information to the client in the form of HTTP responses 590. The HTTP responses 590 correspond with the Web pages represented using HTML, or other data generated by server 588. Server 588 provides HTML 594. With certain browsers, a Common Gateway Interface (CGI) 596 can be also provided, which allows the client program to direct server 588 to commence execution of a specified program contained within server 588. This may include a search engine that scans received information in the server for presentation to the user controlling the client. By utilizing this interface, and HTTP responses 590, server 588 may notify the client of the results of that execution upon completion. Common Gateway Interface (CGI) 596 can be one form of a gateway, a device utilized to connect dissimilar networks (i.e., networks utilizing different communications protocols) so that electronic information can be passed from one network to the other. Gateways transfer electronic information, converting such information to a form compatible with the protocols used by the second network for transport and delivery. In order to control the parameters of the execution of this server-resident process, the client may direct the filling out of certain “forms” from the browser. This can be provided by the “fill-in-forms” functionality (i.e., forms 598), which can be provided by some browsers, such as the Netscape-brand browser described herein. This functionality allows the user via a client application program to specify terms in which the server causes an application program to function (e.g., terms or keywords contained in the types of stories/articles, which are of interest to the user). This functionality can be an integral part of the search engine. FIG. 34 is a diagram illustrative of a computer network, which can be implemented in accordance with preferred embodiments of the present invention. Computer network is representative of the Internet, which can be described as a known computer network based on the client-server model discussed herein. Conceptually, the Internet includes a large network of servers 588 that are accessible by clients 592, typically users of personal computers, through some private Internet access provider 584 (e.g., such as Internet America) or an on-line service provider 586 (e.g., such as America On-Line, Prodigy, Juno, and the like). Each of the clients 592 may run a browser to access servers 88 via the access providers. Each server 588 operates a so-called “Web site” that supports files in the form of documents and web pages. A network path to servers 88 is identified by a Universal Resource Locator (URL) having a known syntax for defining a network collection. Computer network 580 can thus be considered a Web-based computer network. Those skilled in the art can appreciate that the hand held devices discussed herein may be modified to incorporate other computer-based and processing features. For example, a hand held device utilized in accordance with the present invention, may be configured with so-called “smart card” technology. Smart cards are generally known in the art as credit-card sized plastic cards with an embedded computer chip. The chip can either be a microprocessor with internal memory or a memory chip with non-programmable logic. The chip connection can be configured via direct physical contact or remotely through a contactless electromagnetic interface. Smart cards may be generally configured as either a contact or contactless smart card, or a combination thereof. A contact smart card requires insertion into a smart card reader with a direct connection to a conductive micromodule on the surface of the card. Such a micromodule is generally gold plated. Transmission of commands, data, and card status takes place through such physical contact points. A contactless card requires only close proximity to a reader. Both the reader and the card may be implemented with antenna providing a contactless link that permits the devices to communicate with one another. Contactless cards can also maintain internal chip power or an electromagnetic signal (e.g., RF tagging technology). Two additional categories of smart codes, well known in the art, which are based on contact and contactless cards are the so-called Combi cards and Hybrid cards. A Hybrid card generally can be equipped with two chips, each with a respective contact and contactless interface. The two chips are not connected, but for many applications, this Hybrid serves the needs of consumers and card issuers. The Combi card can be generally based on a single chip and can be generally configured with both a contact and contactless interface. Chips utilized in such smart cards are generally based on microprocessor chips or memory chips. Smart cards based on memory chips depend on the security of the card reader for their processing and can be utilized when low to medium security requirements. A microprocessor chip can add, delete and otherwise manipulate information in its memory. Microprocessor-based memory cards typically contain microprocessor chips with 8, 16, and 32 bit architectures. Thus, a smart card in accordance with the method and system described herein would not serve to replace a hand held device, such as a PDA. The smart card would instead function as a supplementary feature of the PDA. The hand held device can be configured to operate in association with a smart card adapted for use with the hand held device. In the case of a PDA, for example, the smart card can retrieve coupon data form a contact or contactless interface. The data can be stored in a memory location with the smart card. The smart card can be then temporarily connected to the PDA through a cartridge or other hardware interface to allow coupon data to be transferred from the smart card to the PDA. The PDA can then transfer coupon data to a POS for processing and redemption, according to the method and system described herein. FIG. 35 illustrates a top view of a hand held device 700 and a smart card 706 adapted for use with hand held device 700, in accordance with preferred embodiments of the present invention. Hand held device 700 may be configured as a PDA or other hand held device. For example, hand held device 700 is analogous to hand held device 11 of FIG. 1 and other hand held device embodiments described herein, such as hand held device 431 of FIG. 31. Hand held device 700 is thus equipped with a display unit 702 interfaced with user controls, such as user control 704. Smart card 706 can be inserted through a slot in hand held device 700. Smart card 706 can be integrated with a recorder/writer for writing data to smart card 706 or reading data from smart card 706 or otherwise modifying a memory of smart card 706. Thus, smart card 706 can retrieve coupon data from hand held device 700 or transfer coupon data stored in a memory of smart card 706 to a memory location within hand held device 700, such as a hand held device coupon database. FIG. 36 depicts a side view of hand held device 700 depicted in FIG. 35 and a slot 708 for inserting smart card into hand held device 700, in accordance with preferred embodiments of the present invention. Slot 708 can be sized to receive smart card 706 into hand held device 700. FIG. 37 illustrates a hand held device 710 configured with smart card 706 adapted for use with hand held device 710 and a scanner 720 integrated with hand held device 710, in accordance with preferred embodiments of the present invention. Hand held device 710 of FIG. 37 is analogous to hand held device 700 of FIGS. 35 and 36, the difference being that hand held device 710 includes scanner 720 for scanning or capturing images from static references or representations. Scanner 720 can thus be utilized by a user to retrieve electronic coupons graphically displayed on a static reference, such as a newspaper, magazine, or so forth. Scanner 720 can be configured as a bar code scanner for retrieving coded information associated with electronic coupon data. Scanner 720 can be additionally configured as an optical scanner that captures graphical images representative of electronic coupons or associated coupon data. The captured information can be then processed and stored with a hand held device coupon database with hand held device 710. Scanner 720 can be also configured as a plug-in module, such as those utilized in the popular Handspring Visor PDA. Furthermore, a plug-in may be adapted to incorporate both a smart card read/write portal and scanning hardware and/or associated software. It should also be appreciated based on the teachings herein that a plug-in may be adapted to combine smart card reader/writer portal and RF communications capabilities in order to provide applications, such as remote wireless credit card verification. Based on the foregoing, those skilled in the art can appreciate that methods and systems can be implemented according to the present invention. Generally, according to the method and system described herein, electronic coupons are processed through hand held devices. Initially, a POS can be synchronized with a hand held device having coupon and/or credit data therein. The redemption of electronic coupons at the POS can be managed through a coupon manager associated with a coupon database linked to the POS, in response to synchronizing the POS with the hand held device. Electronic coupon in the form of coupon data can be retrieved from a hand held device coupon database within the hand held device. Coupon retrieval between a coupon management module associated with the hand held device and the coupon manager associated with the coupon database linked to the POS can thereafter be coordinated. The coupon manager associated with the POS (i.e., the coupon database linked to the POS) can be synchronized with the coupon management module associated with the hand held device. At least one electronic coupon can be then transferred from the hand held device coupon database to the POS, in response to synchronizing the coupon manager with the coupon management module associated with the hand held device. At least one item can be scanned from the POS. A product database associated with the POS can be accessed, wherein the product database contains product data therein. A subtotal can be rendered for at least one item scanned, in response to scanning the item at the POS. Electronic coupons retrieved from the hand held device coupon database are then correlated with product data accessed from the product database and the item scanned at the POS. Thereafter, correlating product data and price discounts associated with the electronic coupons retrieved from the hand held device coupon database are identified. A new total for the items scanned at the POS can be then calculated, in response to identifying correlating product data and price discounts associated with the electronic coupons retrieved from the hand held device coupon database. A new total can be then rendered in a display area of the hand held device. The coupon manager can be generally permitted to communicate with a product manager associated with the product database. The coupon manager can be also permitted to communicate with a credit manager associated with a credit database linked to the POS. A user profile can be associated with the hand held device coupon database and/or the hand held device coupon management module. The coupon manager may communicate with the POS through a network. Likewise, synchronization of the POS and the hand held device may occur through a network. Such a network may be configured as a wireless network and/or, for example, a client/server type network. The hand held device may be configured as a PDA, a wireless PDA, a pager, a WAP-enabled telecommunications device or other configurations thereof, such as a hand held device integrated with a smart card adapter. A hand held device utilized in accordance with the present invention can be also configured with an optical scanner for retrieving, scanning, and/or capturing data from static references. Such a scanner may be configured, for example, as a bar code scanner that permits a user of the hand held device to retrieve coupon data from a static reference through the bar code scanner and thereafter store the coupon data in the hand held device coupon database within the hand held device. The optical scanner may also be implemented as a holographic image scanner for reading and capturing holographic-based images containing coupon data therein. Based on the foregoing, those skilled in the art will appreciate that the present invention disclosed herein describes a method and system for processing negotiable economic credits through a hand held device in association with a third-party provider communicative with the hand held device. At least one negotiable economic credit can be transferred from a third-party provider communicative with the hand held device to the hand held device. Examples of such negotiable economic credits, as described herein, include coupons and credits thereof, such as frequent flyer miles offered by airlines and other organizations to attract and retain customers. The negotiable economic credit can be stored within a memory of the hand held device for retrieval and processing at a POS associated with a retail establishment. The negotiable economic credit can be associated with a security module for protecting the privacy of the negotiable economic credit. A user profile can be compiled for utilization during the retrieval of the negotiable economic credit, in response to user input. The user profile can be stored in a database associated with the third-party provider and a database associated with the hand held device. A negotiable economic credit or negotiable economic credits can be transferred from the third-party provider to the hand held device through a network that can be wireline, wireless or a combination thereof. Data can be transmitted through a wireless network through wireless communications, relying on telecommunications protocols, such as WAP, CDMA, Bluetooth, and so forth, as described herein. The third-party provider can be permitted to communicate with a transaction broker so that negotiable economic credits may be redeemed by the hand held device at the POS. Examples of such third-party providers and transaction brokers are provider in FIGS. 19 and 20 as third-party provider 156 and transaction broker 148. According to an embodiment of the present invention, negotiable economic credits are processed through a hand held device. At least one negotiable economic credit can be transferred to a retail enterprise for use at a POS on behalf of a credit redemption request by a hand held device. In addition the negotiable economic credit or credits can be transferred to a retail enterprise for use at a POS on behalf of a credit redemption request by a hand held device, in response to synchronization of the POS and the hand held device. The negotiable economic credits can be redeemed at the POS, in response to transferring the negotiable economic credit or credits to the POS from the hand held device. Additionally, negotiable economic credits can be transferred to a retail enterprise for use at a POS, such as POS 140 of FIG. 19 and FIG. 20 on behalf of a credit redemption request by a hand held device, in response to a request by the retail enterprise to reward purchases at the POS. A system for processing negotiable economic credits through a hand held device in association with a third-party provider communicative with the hand held device can be configured with a transfer module for transferring negotiable economic credits from a third-party provider communicative with the hand held device to the hand held device. The system can also be implemented with a storage module for storing negotiable economic credits within a memory of the hand held device for retrieval and processing at a POS. The negotiable economic credits can be associated with a security module for protecting the privacy of transferred negotiable economic credits. Such a security module (e.g., security module 157 of FIGS. 19 and 20) can be configured with encryption/decryption and password protection features, well known in the art. The system can be further configured with a user profile for utilization during retrieval of the negotiable economic credits, in response to user input. The user of the hand held device can register with the third-party provider to establish a user profile stored in a database. The user profile can be stored in a database, such as provider database 158 of FIG. 19 associated with third-party provider 156 and/or in another database, such as a database associated with a transaction broker (e.g., user profile database 150). Those skilled in the art will appreciate that the third-party provider may be associated or linked to other databases or memory locations and that user profile data may be stored therein. The system can be further configured with a storage module for storing the user profile in a database associated with the third-party provider (e.g., provider database 158). The system can also incorporate a storage module for storing the user profile in a database within the hand held device (e.g., user profile module 433 of FIG. 31). The transaction broker can be permitted to communicate with the third-party broker so that such credits may be thereafter redeemed by the hand held device at the POS. This can be particularly advantageous to the user of the hand held device because the user of the hand held device can thus communicate directly with the third-party provider or the transaction broker if he or she so chooses, utilizing a hand held device. The system can be further modified to include a transfer module for transferring at least one negotiable economic credit to a retail enterprise for use at a POS on behalf of a credit redemption request by a hand held device. Additionally, the system can be configured to operate in association with a transfer module for transferring negotiable economic credits to a retail enterprise for use at a POS on behalf of a credit redemption request by a hand held device, in response to synchronization of the POS and the hand held device. Additionally, the system can be configured with a redemption module for redeeming negotiable economic credits at the POS, in response to transferring the negotiable economic credits to the POS from the hand held device. Furthermore, the system can be configured to include a transfer module for transferring negotiable economic credits to a retail enterprise for use at a POS on behalf of a credit redemption request by a hand held device, in response to a request by the retail enterprise to thereby reward purchases at a POS associated with the retail enterprise by a hand held device. The POS itself may be configured, for example, in accordance with the methods and systems of the present invention, as a kiosk device. Such a kiosk device may comprise an internet or intranet enabled kiosk device and may include other capabilities as, for example, an ATM machine. A kiosk can be configured for example, as a freestanding computer or terminal that provides information to the public, usually through a multimedia display. The POS may actually comprise an ATM machine and/or the capabilities of an ATM machine. Additionally, the POS may be configured, for example, as or with the capabilities of a vending machine. The embodiments and examples set forth herein are presented to best explain the present invention and its practical application and to thereby enable those skilled in the art to make and utilize the invention. However, those skilled in the art will recognize that the foregoing description and examples have been presented for the purpose of illustration and example only. The description as set forth is not intended to be exhaustive or to limit the invention to the precise form disclosed. Many modifications and variations are possible in light of the above teaching without departing from the spirit and scope of the following claims.
<SOH> BACKGROUND <EOH>
<SOH> SUMMARY <EOH>It is therefore an aspect of the present invention to provide improved methods and systems for conducting E-commerce utilizing hand held devices. It is another aspect of the present invention to provide improved methods and systems for processing negotiable economic data (e.g., coupons, cash, credits, or other financial incentives and awards) through hand held devices. It is yet another aspect of the present invention to provide improved methods and systems, which may include program products, for generating, capturing, and redeeming negotiable economic credits. It is still another aspect of the present invention to facilitate the processing of negotiable economic credits through hand held devices. The above and other aspects are achieved as are now described. Methods and systems for processing negotiable economic credits through a hand held device in association with a third-party provider communicative with the hand held device is disclosed herein. At least one negotiable economic credit may be transferred from a third-party provider communicative with the hand held device to the hand held device and/or a point of sale. The negotiable economic credit may be stored within a memory of the hand held device and/or point of sale for retrieval and processing at a point of sale associated with a retail establishment. The negotiable economic credit can be associated with a security module for protecting the privacy of the negotiable economic credit. A user profile may be compiled for utilization during the retrieval of the negotiable economic credit, in response to user input. The user profile can be stored in a database associated with the third-party provider and/or a database associated with the hand held device. The user profile can also be stored in a user profile database associated with a transaction broker.
G06Q3002
20170828
20180215
65555.0
G06Q3002
3
RUDY, ANDREW J
THIRD-PARTY PROVIDER METHOD AND SYSTEM
UNDISCOUNTED
1
CONT-ACCEPTED
G06Q
2,017
15,689,076
PENDING
Process for Making Tablet Using Radiofrequency and Lossy Coated Particles
In one aspect the present invention features process for making a tablet comprising at least one pharmaceutically active agent, said method comprising the step of applying radiofrequency energy to a powder blend to sinter said powder blend into said tablet, wherein said powder blend comprises lossy coated particles and said at least one pharmaceutically active agent, wherein said lossy coated particles comprises a substrate that is at least partially coated with a lossy coating comprising at least one activator, wherein said substrate has a Q value of greater than 100 and said activator has a Q value of less than 75.
1. A tablet comprising sintered lossy coated particles and at least one pharmaceutically active agent, wherein said lossy coated particles comprise a substrate that is at least partially coated with a lossy coating comprising at least one activator, wherein said substrate has a Q value of greater than 100 and said activator has a Q value of less than 75 and wherein the surface of said lossy coated particle comprises said activator. 2. A tablet of claim 1 wherein said activator has a Q value of less than 50. 3. A tablet of claim 1 wherein said substrate has a Q value of greater than 200. 4. A tablet of claim 1 wherein said lossy coated particles have a Q value of greater than 100. 5. A tablet of claim 1 comprising at least 20%, by weight, of said lossy coated particles. 6. A tablet of claim 1 wherein said tablet disintegrates in the mouth when placed on the tongue in less than about 30 seconds. 7. A tablet of claim 1 wherein said activator is a polymer selected from the group consisting of celluloses, hydrocolloids, polymethacrylates, polyvinyls, proteins, polysaccharides, and copolymers thereof. 8. A tablet of claim 1 wherein said activator is hydroxypropylcellulose or hydroxyethylcellulose. 9. A tablet of claim 1 wherein said substrate comprises a starch, a sugar alcohol, or a sugar. 10. A tablet of claim 1 wherein said substrate comprises maltitol or mannitol. 11. A tablet of claim 1 wherein said substrate comprises said pharmaceutically active agent. 12. A tablet of claim 1 wherein the friability at 15 drops of the tablet is less than about 5%. 13. A tablet of claim 1 wherein said tablet further comprises a water scavenger. 14. A tablet of claim 1 wherein said tablet further comprises a plasticizer. 15. A tablet of claim 1 wherein said at least one pharmaceutically active agent is contained within particles separate from the lossy coated particles. 16. A tablet of claim 1 wherein said tablet has an in vitro disintegration time of about 30 seconds or less when based on the United States Pharmacopeia USP 24 NF29. 17. A tablet comprising sintered lossy coated particles and at least one pharmaceutically active agent, wherein said lossy coated particles comprise a substrate that is at least partially coated with a lossy coating comprising at least one activator, wherein the Q value of the activator is less than half the Q value of the substrate and said tablet has a friability at 15 drops of the tablet is less than about 5%.
CROSS REFERENCE TO RELATED APPLICATIONS This application is a divisional application which claims the benefit U.S. patent application Ser. No. 14/592,176, filed Jan. 8, 2015, which also claims priority of the benefits of U.S. Provisional Application Ser. No. 61/925,713, filed Jan. 10, 2014. The complete disclosure of the aforementioned related U.S. patent application is hereby incorporated by reference for all purposes. BACKGROUND OF THE INVENTION Pharmaceuticals intended for oral administration are typically provided in tablet form. Tablets can be swallowed whole, chewed in the mouth, or disintegrated in the oral cavity. Soft tablets that either are chewed or dissolve in the mouth are often employed in the administration of pharmaceuticals where it is impractical to provide a tablet for swallowing whole. With chewable tablets, the act of chewing helps to break up the tablet particles as the tablet disintegrates and may increase the rate of absorption by the digestive tract. Soft tablets are also advantageous where it is desirable to make a pharmaceutically active agent available topically in the mouth or throat for both local effects and/or systemic absorption. Soft tablets are also utilized to improve drug administration in pediatric and geriatric patients. Soft tablets designed to disintegrate in the mouth prior to swallowing are particularly useful for improving compliance of pediatric patients. Generally, soft tablets are made by compaction of a blend of powdered ingredients and typically include a pharmaceutically active agent, flavoring, and/or binders. The powder blend is typically fed into the cavity of a die of a tablet press and a tablet is formed by applying pressure. Hardness of the resulting tablet is a direct function of the compaction pressure employed and the compatibility of the ingredients in the formulation. A softer tablet, having an easier bite-through, may be prepared by employing reduced compaction pressures. The resulting tablet is softer, but also more fragile, brittle, and easily chipped and disadvantageously can involve complex and costly processing steps. Examples of soft tablets designed to disintegrate in the mouth without chewing are disclosed in U.S. Pat. Nos. 5,464,632, 5,223,264, 5,178,878, 6,589,554, and 6,224,905. There is a need for aesthetically pleasing chewable and orally disintegrating tablets that utilize commercially efficient manufacturing methods. Orally disintegrating tablets can be prepared by compression (see, e.g., U.S. Pat. Nos. 5,223,264 and 5,178,878), but these tablets can have a high density and thus can take up to 20 to 30 seconds to fully disintegrate in the mouth. Lyophilized orally disintegrating tablets (see, e.g., U.S. Pat. Nos. 6,509,040, 5,976,577, 5,738,875, and 5,631,023) tend to be less dense and, thus, faster disintegrating. However, these tablets require a long time to make a tablet, and the process of lyophilization of the tablet formulation directly in the unit dose blister package renders a dosage form that is shaped on only one face. The amount of drug loading in this lyophilization process is also limited. The present invention relates to a new process for manufacturing tablets, such as orally disintegrating tablets (“ODTs”) utilizing lossy coated particles where the lossy coating comprises an activator that is used to sinter to particles to form the tablet. As this process concentrates the activator on the surface of the particle, the amount of activator added to the tablet can be reduced and the sintering of particles can be improved, resulting in tablet properties such as improved friability, better mouthfeel, faster disintegration, higher pharmaceutically active agent loading, and/or shorter manufacturing time as compared to tablets those made by other similar processes such US Patent Application Nos. 2009/0060983, 2011/0071184, and 2013/0295175 as set forth herein. SUMMARY OF THE INVENTION In one aspect, the present invention features a process for making a tablet comprising at least one pharmaceutically active agent, said method comprising the step of applying radiofrequency energy to a powder blend to sinter said powder blend into said tablet, wherein said powder blend comprises lossy coated particles and said at least one pharmaceutically active agent, wherein said lossy coated particles comprises a substrate that is at least partially coated with a lossy coating comprising at least one activator, wherein said substrate has a Q value of greater than 100 and said activator has a Q value of less than 75. In another aspect, the present invention features a process for making a tablet comprising at least one pharmaceutically active agent, said method comprising the step of applying radiofrequency energy to a powder blend to sinter said powder blend into said tablet, wherein said powder blend comprises lossy coated particles and said at least one pharmaceutically active agent, wherein said lossy coated particles comprise of a substrate that is at least partially coated with a lossy coating comprising at least one activator, wherein the Q value of the activator is less than half the Q value of the substrate. In another aspect, the sintered tablet comprising lossy coated particles and at least one pharmaceutically active agent, wherein said lossy coated particles comprise a substrate that is at least partially coated with a lossy coating comprising at least one activator, wherein said substrate has a Q value of greater than 100 and said activator has a Q value of less than 75. In another aspect, the sintered tablet comprising lossy coated particles and at least one pharmaceutically active agent, wherein said lossy coated particles comprise a substrate that is at least partially coated with a lossy coating comprising at least one activator, wherein the Q value of the activator is less than half the Q value of the substrate. Other features and advantages of the present invention will be apparent from the detailed description of the invention and claims. DETAILED DESCRIPTION OF THE INVENTION It is believed that one skilled in the art can, based upon the description herein, utilize the present invention to its fullest extent. The following specific embodiments can be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Also, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference. As used herein, all percentages are by weight unless otherwise specified. As discussed above, in one aspect, the present invention features: Powder Blend In one embodiment, the tablet is manufactured by applying radiofrequency energy to a powder blend containing at least one pharmaceutically active agent (as discussed herein), lossy coated particles (as discussed herein), and optionally other suitable excipients. In one embodiment, the said at least one pharmaceutically active agent is contained within separate particles within the powder blend. In one embodiment, the said at least one pharmaceutically active agent is contained within the lossy coated particles. In one embodiment, the powder blend/tablet comprises at least 20%, by weight, of said lossy coated particles, such as at least 50%, by weight, such as at least 70%, by weight. Examples of suitable excipients include, but are not limited to, fillers, water scavengers, glidants, sweeteners, flavor and aromatics, antioxidants, preservatives, texture enhancers, colorants, and mixtures thereof. One or more of the above ingredients may be present on the same particle of the powder blend. Examples of fillers include but not limited to starches, sugar alcohols, bulk sweeteners, polyols, polymers and plasticizers. In one embodiment, the powder blend/tablet comprises a water scavenger such as a starch and/or a silica. A benefit of the presence of a water scavenger in the powder blend is that it can act to retain water within the powder blend following the application of radiofrequency energy. Examples of starches include, but are not limited to, vegetable starches such as pea and corn starches and modified starches (such as pregelantized, acid modified, or dextrinized starches) or derivatized starches (such as cross linked, acetylated, and hydroxy alkyl starches). Examples of silicas include fumed silicas such as Syloid® FP silicas from Grace (Columbia, Md., USA), clays such as bentonite, veegum, and neusilin. In one embodiment, the powder blend/tablet comprises from about 0.1-10%, by weight, of said water scavenger, such as from about 0.1-2%, by weight. Examples of glidants include, but are not limited to, colloidal silicon dioxide. Examples of sweeteners for the present inventions include, but are not limited to high intensity sweeteners such as synthetic or natural sugars; artificial sweeteners such as saccharin, sodium saccharin, aspartame, acesulfame, thaumatin, glycyrrhizin, sucralose, dihydrochalcone, alitame, miraculin, monellin, and stevside. Examples of flavors and aromatics include, but are not limited to, essential oils including distillations, solvent extractions, or cold expressions of chopped flowers, leaves, peel or pulped whole fruit containing mixtures of alcohols, esters, aldehydes and lactones; essences including either diluted solutions of essential oils, or mixtures of synthetic chemicals blended to match the natural flavor of the fruit (e.g., strawberry, raspberry and black currant); artificial and natural flavors of brews and liquors, e.g., cognac, whisky, rum, gin, sherry, port, and wine; tobacco, coffee, tea, cocoa, and mint; fruit juices including expelled juice from washed, scrubbed fruits such as lemon, orange, and lime; spear mint, pepper mint, wintergreen, cinnamon, cacoe/cocoa, vanilla, liquorice, menthol, eucalyptus, aniseeds nuts (e.g., peanuts, coconuts, hazelnuts, chestnuts, walnuts, cola nuts), almonds, raisins; and powder, flour, or vegetable material parts including tobacco plant parts, e.g., genus Nicotiana, in amounts not contributing significantly to the level of nicotine, and ginger. Examples of antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole, edetic acid, and edetate salts, and mixtures thereof. Examples of preservatives include, but are not limited to, citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, and sorbic acid, and mixtures thereof. Examples of texture enhancers include, but are not limited to, pectin, polyethylene oxide, and carrageenan, and mixtures thereof. In one embodiment, texture enhancers are used at levels of from about 0.1% to about 10% percent by weight. In one embodiment of the invention, the powder blend has an average particle size of less than 500 microns, such as from about 50 microns to about 500 microns, such as from about 50 microns and 300 microns. As used herein, what is meant by “substantially free” is less than 5%, such as less than 1%, such as less than 0.1%, such as completely free (e.g., 0%). In one embodiment, the powder blend/tablet is substantially free of super disintegrants. Super disintegrants include croscarmellose sodium, sodium starch glycolate, and cross-linked povidone. A composition substantially free of super-disintegrants is advantageous for enhancing mouth-feel and tablet stability due to reduced water absorbance. In one embodiment the powder blend is substantially free of lubricants such as magnesium stearate or stearic acid. Avoidance of tablet lubricants is advantageous since these materials are known to slow dissolution and have a negative impact on taste such as imparting a bitter aftertaste. Lossy Coated Particles The present invention features a powder blend/tablet comprising lossy coated particles comprising a substrate that is at least partially coated with a lossy coating comprising at least one activator. Such particles allow for controlled heating of the powder blend for the manufacture of the sintered tablet. Methods of manufacturing such lossy coated particles include, but are not limited to, top spray coating, top spray granulation, wurster coating, rotor coating, high shear granulation, spray drying, spray congealing, hot melt extrusion, microencapsulation, spinning disk coating, and extrusion/ spheronization. In one embodiment, the coating material is dissolved into solution and sprayed onto the substrate. In another embodiment, the coating is blended with the substrate and water is added to the blend, utilizing processes such as high shear granulation or spray drying. In one embodiment, the coating solution is aqueous optionally containing other solvents. In one embodiment, the activator is a cellulosic polymer. Suitable cellulosic polymers include but are not limited to, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, hypromellose, and mixtures thereof. Other suitable activators include polysaccharides and proteins such as starches, modified starches, gelling starches, and hydrocolloids; including but not limited to guar gum, carrageenan, maltodextrin, inulin, and, polyvinyl pyrrolidone. Still other suitable activators include acrylic polymers such as but not limited to: methacrylates such as polymethylmethacrylates; polyvinyls such as polyvinyl alcohols, polyvinylpyrrolidones, polyvinyl caprolactams, and polyvinyl acetates; and copolymers thereof such as copolymers of ethyl acrylate and methyl methacrylates, and polycaprolactones. In one embodiment, the weight average molecular weight of the activator is less than 360,000 daltons, such as less than 180,000 daltons. In one embodiment, the substrate (e.g., is the form of a particle) is comprised of materials selected from starches, sugars, sugar alcohols, dicalcium phosphate, and microcrystalline cellulose. Suitable sugars include but are not limited to sucrose, mannose, maltose, lactose, fructose, dextrose, and dextrose monohydrate. Suitable sugar alcohols include but are not limited to erythritol, sorbitol, xylitol, mannitol, and maltitol. In one embodiment, the substrate comprises the pharmaceutically active agent. In one embodiment, the substrate is coated with first coating prior to the addition of the lossy coating. In one embodiment, the average particle size of the lossy coated particle is from about 50 to about 500 microns, such as from about 50 to about 400 microns, such as from about 50 to about 300 microns. The lossy coated particle is at least partially coated with the coating. What is meant by at least partially coated is that at least 25% of the total surface area is covered with the coating, such as at least 50%, such as at least 75%, such as 100%. In one embodiment, the amount of activator(s) in the lossy coated particles is at least about 0.25%, by weight, of the lossy coated particles, such as at least about 0.4%, by weight. In one embodiment, the amount of activator(s) in the lossy coated particles is from about 0.1% to about 20%, by weight, of the lossy coated particles, such as from about 0.1% to about 10%, by weight, of the lossy coated particles, such as from about 0.1% to about 2%, by weight, of the lossy coated particles. In one embodiment, the lossy coated particle contains water. In this embodiment, the lossy coated particle comprises at least 0.1 percent, by weight, water, such as at least 0.3 percent, by weight, water, such as at least 0.5 percent, by weight, water when measured using loss on drying at 105° C. until the weight of the lossy coated particles has stabilized. In one embodiment, the lossy coated particle retains water when measured by loss on drying prior to sintering, such as moisture content of at least 0.1 percent by weight, such as from about 0.1 to about 3 percent, such as from about 0.5 to about 2 percent, by weight. In one embodiment the coating comprises more than one activator, such as two activators. In one embodiment, the coating comprises two polymers. In one embodiment, the coating comprises a plasticizer. Suitable plasticizers for include, but not be limited to: polyethylene glycol; propylene glycol; glycerin; sorbitol; triethyl citrate; tributyl citrate; dibutyl sebecate; vegetable oils such as castor oil, rape oil, olive oil, and sesame oil; surfactants such as polysorbates, sodium lauryl sulfates, and dioctyl-sodium sulfosuccinates; mono acetate of glycerol; diacetate of glycerol; triacetate of glycerol; natural gums; triacetin; acetyltributyl citrate; diethyloxalate; diethylmalate; diethyl fumarate; diethylmalonate; dioctylphthalate; dibutylsuccinate; glyceroltributyrate; hydrogenated castor oil; fatty acids; substituted triglycerides and glycerides. In one embodiment, the coated particle comprises from about 0.1 to about 3 percent, by weight, of plasticizer(s). In one embodiment, the coating comprises an ionic conductor, such as a salt. Examples of salts include, but are not limited to, metal salts such as sodium, calcium, magnesium, and potassium salts, such as sodium chloride and sodium citrate. In one embodiment, the coated particle comprises from about 0.1 to about 3 percent, by weight, of ion conductors(s). Q Value The property of permittivity is the measure of the resistance to forming an electric field. For purposes of comparing materials in air, it is often convenient to describe the permittivity of material in air where the permittivity is more specifically called “relative permittivity” or r. This is a complex number represented by the following equation: r=e′−je″ where e′ (the real portion of the complex number) is the dielectric constant (energy storage) and e″ (the imaginary portion of the complex number) is the dielectric loss or dissipation factor (energy dissipated as heat). The ratio of dielectric loss (e″) over the dielectric constant (e′) is called the loss tangent (tan δ) or power factor. Since loss tangent values for materials used in foods/pharmaceuticals are very low at 27 MHz, it is convenient to use the reciprocal of loss tangent or “Q value” hence, Q value=e′/e″ For purposes of this invention, the Q value is calculated for the frequency that the material is to be processed (e.g., 27 MHz). The Q value is affected by physical and chemical properties such as density (porosity/particle size), moisture (conductivity), temperature, and molecular polarizability. The measurements obtained by this method can eliminate the need to measure and evaluate these properties independently. As the Q value becomes smaller, a material will heat more readily when an external electromagnetic field is applied. For purposes of describing the components of the invention, a material which has a high Q value (e.g., which responds less to the external field) is referred to as a “passivator.” Passivators can serve to insulate or impede energy flow. Conversely, lower Q values (e.g., having higher flux) are termed “activators,” as energy is allowed to flow through more easily and do more work. For purposes of describing the present invention, passivators have Q values greater than about 100 (such as greater than 200 or greater than 300), while activators have Q values less than 75 (such as less than 50). The Q value for various materials is recited below in Table 1. The Q values were measured using a HP 805C Slotted Line as sample holder (carriage removed) connected to Agilent N5230C PNA-L to ports A and B (transmission mode). The sample holder and coaxial wires with N-type connectors are calibrated at room temperature using 8592-60008 E-cal to eliminate error in loss measurement encountered from the coax lines/sample holder itself. This process is referred to as the “Slotted Line Method.” Unless otherwise stated, the Slotted line method was used for the calculation of e′, e″, and Q value herein with the frequency range set to 26-28 MHz (31 points resolution) and values of e′ and e″ were recorded from the 27 MHz data point. TABLE 1 Loss Q Material Function e′ e″ Tangent Value Hydroxyethyl cellulose activator 2.0937 0.1574 0.0752 13 (Natrosol L250), LOD = 4.1% Hydroxypropyl cellulose activator 1.7225 0.0972 0.0564 18 (Klucel EF), LOD = 2.3% Hydroxypropyl cellulose activator 1.6404 0.0769 0.0469 21 (Klucel ELF), LOD = 1.6% Hydroxypropyl cellulose activator 1.5964 0.0723 0.0453 22 (Klucel LF), LOD = 1.8% Hydroxypropyl cellulose activator 1.6248 0.0739 0.0455 22 (Klucel JF), LOD = 1.8% Hydroxypropyl cellulose activator 1.4174 0.0520 0.0367 27 (SSL-SFP) Sucrose (Granular Table substrate 1.9314 0.0096 0.0050 201 Sugar) Acetaminophen Coated substrate 1.8625 0.0050 0.0027 373 with Ethylcellulose* Maltitol (SweetPearl substrate 1.6214 0.0035 0.0022 463 DC300) *Note -taste-masked particle has coating but the coating does not have an activator (i.e., the Q value of ethylcellulose was measured to be 98). In one embodiment, e′ of the lossy coated particle (prior to blending) is at least 1.4, such as at least 1.6, such as 1.7 when measured at 27 MHz. In one embodiment, e″ of the lossy coated particle (prior to blending) is at least 0.009, such as at least 0.015, such as at least 0.0300 when measured at 27 MHz. Another method to measure Q value is by using an Agilent 4294A impedance analyzer using specially designed dielectric sample holder. The powder is filled in an empty puck by lightly and evenly pouring in the powder. The excess powder is leveled off to get a flat and even top surface. The first measurement is made by using a thin lid (1 mm) on the powder/puck. In subsequent measurements, the lid is removed and replaced with the next thicker lid. With each lid change, the thickness of the lid increases by 1 mm and the powder is further compressed. When the powder is fully compressed and the lid will not sit flush on the puck, the test is ended. The fully compressed powder along with the puck (without cap) is then weighed. The powder is then removed from the puck and the puck is thoroughly cleaned, to avoid cross contamination, and re-weighed empty to obtain a base weight before and after each different powder test. This allows the tests to be conducted at different powder density, and the tests can be performed at different temperatures, humidity and separate days. This process is referred to as the “Parallel Plate Method.” The Q value for various materials is recited below in Table 2 TABLE 2 Loss Q Material Function e′ e″ Tangent Value Polyvinyl Alcohol1 activator 2.4277 0.1399 0.0576 17 Polyvinylalcohol- activator 1.9337 0.1116 0.0577 17 Polyethylene Glycol Graft Co-Polymer (Kollicoat IR)2 Copolymer of ethyl activator 1.7496 0.0405 0.0231 43 acrylate, methyl methacrylate (Eudragit RL30D)3 Povidone (Plasdone ® activator 1.7144 0.0239 0.0139 72 K12)4 1Available as Emprove ® from EMD Millipore Corporation 2Available as Kollicoat IR ® from the BASF Corporation 3Available as Eudragit ® RL30D from the Evonik Corporation 4Available as Plasdone ® K12 from the Ashland Corporation It has been discovered that coating a substrate comprising one or more passivators with a coating comprising one or more activators resulted in particles were surprising effective in a sintering process of forming very resilient dosage forms with fast disintegration. While not wanting to be bound by this theory, the synergy created by pre-bonding the activator(s) to the passivator (substrate) allows greater efficiency of bonding during sintering beyond simply additive effects. The substrate has a Q value of greater than 100, such as greater than 150, such as greater than 200, such as greater than 400. The activator has a Q value of less than 75, such as less than 50, such as less than 30. In one embodiment, the lossy coated particle has a Q value of greater than 50, such as greater than 150, such as greater than 200. In one embodiment, the powder blend has a Q value of greater than 50, such as greater than 150, such as greater than 200. Pharmaceutically Active Agent The powder blend/tablet of the present invention includes at least one pharmaceutically active agent containing particles. What is meant by a “pharmaceutically active agent” is an agent (e.g., a compound) that is permitted or approved by the U.S. Food and Drug Administration, European Medicines Agency, or any successor entity thereof, for the oral treatment of a condition or disease. Suitable pharmaceutically active agents include, but are not limited to, analgesics, anti-inflammatory agents, antipyretics, antihistamines, antibiotics (e.g., antibacterial, antiviral, and antifungal agents), antidepressants, antidiabetic agents, antispasmodics, appetite suppressants, bronchodilators, cardiovascular treating agents (e.g., statins), central nervous system treating agents, cough suppressants, decongestants, diuretics, expectorants, gastrointestinal treating agents, anesthetics, mucolytics, muscle relaxants, osteoporosis treating agents, stimulants, nicotine, and sedatives. Examples of suitable gastrointestinal treating agents include, but are not limited to: antacids such as aluminum-containing pharmaceutically active agents (e.g., aluminum carbonate, aluminum hydroxide, dihydroxyaluminum sodium carbonate, and aluminum phosphate), bicarbonate-containing pharmaceutically active agents, bismuth-containing pharmaceutically active agents (e.g., bismuth aluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate, and bismuth subnitrate), calcium-containing pharmaceutically active agents (e.g., calcium carbonate), glycine, magnesium-containing pharmaceutically active agents (e.g., magaldrate, magnesium aluminosilicates, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide, and magnesium trisilicate), phosphate-containing pharmaceutically active agents (e.g., aluminum phosphate and calcium phosphate), potassium-containing pharmaceutically active agents (e.g., potassium bicarbonate), sodium-containing pharmaceutically active agents (e.g., sodium bicarbonate), and silicates; laxatives such as stool softeners (e.g., docusate) and stimulant laxatives (e.g., bisacodyl); H2 receptor antagonists, such as famotidine, ranitidine, cimetadine, and nizatidine; proton pump inhibitors such as omeprazole, dextansoprazole, esomeprazole, pantoprazole, rabeprazole, and lansoprazole; gastrointestinal cytoprotectives, such as sucraflate and misoprostol; gastrointestinal prokinetics such as prucalopride; antibiotics for H. pylori, such as clarithromycin, amoxicillin, tetracycline, and metronidazole; antidiarrheals, such as bismuth sub salicylate, kaolin, diphenoxylate, and loperamide; glycopyrrolate; analgesics, such as mesalamine; antiemetics such as ondansetron, cyclizine, diphenyhydroamine, dimenhydrinate, meclizine, promethazine, and hydroxyzine; probiotic bacteria including but not limited to lactobacilli; lactase; racecadotril; and antiflatulents such as polydimethylsiloxanes (e.g., dimethicone and simethicone, including those disclosed in U.S. Pat. Nos. 4,906,478, 5,275,822, and 6,103,260); isomers thereof; and pharmaceutically acceptable salts and prodrugs (e.g., esters) thereof. Examples of suitable analgesics, anti-inflammatories, and antipyretics include, but are not limited to, non-steroidal anti-inflammatory drugs (NSAIDs) such as propionic acid derivatives (e.g., ibuprofen, naproxen, ketoprofen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, and suprofen) and COX inhibitors such as celecoxib; acetaminophen; acetyl salicylic acid; acetic acid derivatives such as indomethacin, diclofenac, sulindac, and tolmetin; fenamic acid derivatives such as mefanamic acid, meclofenamic acid, and flufenamic acid; biphenylcarbodylic acid derivatives such as diflunisal and flufenisal; and oxicams such as piroxicam, sudoxicam, isoxicam, and meloxicam; isomers thereof; and pharmaceutically acceptable salts and prodrugs thereof. Examples of antihistamines and decongestants, include, but are not limited to, bromopheniramine, chlorcyclizine, dexbrompheniramine, bromhexane, phenindamine, pheniramine, pyrilamine, thonzylamine, pripolidine, ephedrine, phenylephrine, pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, astemizole, terfenadine, fexofenadine, naphazoline, oxymetazoline, montelukast, propylhexadrine, triprolidine, clemastine, acrivastine, promethazine, oxomemazine, mequitazine, buclizine, bromhexine, ketotifen, terfenadine, ebastine, oxatamide, xylomeazoline, loratadine, desloratadine, and cetirizine; isomers thereof; and pharmaceutically acceptable salts and esters thereof. Examples of cough suppressants and expectorants include, but are not limited to, diphenhydramine, dextromethorphan, noscapine, clophedianol, menthol, benzonatate, ethylmorphone, codeine, acetylcysteine, carbocisteine, ambroxol, belladona alkaloids, sobrenol, guaiacol, and guaifenesin; isomers thereof; and pharmaceutically acceptable salts and prodrugs thereof. Examples of muscle relaxants include, but are not limited to, cyclobenzaprine and chlorzoxazone metaxalone, orphenadrine, and methocarbamol; isomers thereof; and pharmaceutically acceptable salts and prodrugs thereof. Examples of stimulants include, but are not limited to, caffeine. Examples of sedatives include, but are not limited to sleep aids such as antihistamines (e.g., diphenhydramine), eszopiclone, and zolpidem, and pharmaceutically acceptable salts and prodrugs thereof. Examples of appetite suppressants include, but are not limited to, phenylpropanolamine, phentermine, and diethylcathinone, and pharmaceutically acceptable salts and prodrugs thereof Examples of anesthetics (e.g., for the treatment of sore throat) include, but are not limited to dyclonine, benzocaine, and pectin and pharmaceutically acceptable salts and prodrugs thereof. Examples of suitable statins include but are not limited to atorvastin, rosuvastatin, fluvastatin, lovastatin, simvustatin, atorvastatin, pravastatin and pharmaceutically acceptable salts and prodrugs thereof. In one embodiment, the pharmaceutically active agent included within the tablet is selected from phenylephrine, dextromethorphan, pseudoephedrine, acetaminophen, cetirizine, aspirin, nicotine, ranitidine, ibuprofen, ketoprofen, loperamide, famotidine, calcium carbonate, simethicone, chlorpheniramine, methocarbomal, chlophedianol, ascorbic acid, pectin, dyclonine, benzocaine and menthol, and pharmaceutically acceptable salts and prodrugs thereof. As discussed above, the pharmaceutically active agents of the present invention may also be present in the form of pharmaceutically acceptable salts, such as acidic/anionic or basic/cationic salts. Pharmaceutically acceptable acidic/anionic salts include, and are not limited to acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate and triethiodide. Pharmaceutically acceptable basic/cationic salts include, and are not limited to aluminum, benzathine, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, meglumine, potassium, procaine, sodium and zinc. As discussed above, the pharmaceutically active agents of the present invention may also be present in the form of prodrugs of the pharmaceutically active agents. In general, such prodrugs will be functional derivatives of the pharmaceutically active agent, which are readily convertible in vivo into the required pharmaceutically active agent. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985. In addition to salts, the invention provides the esters, amides, and other protected or derivatized forms of the described compounds. Where the pharmaceutically active agents according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the pharmaceutically active agents possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the pharmaceutically active agents may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the pharmaceutically active agents may form solvates with water (e.g., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention. In one embodiment, the pharmaceutically active agent or agents are present in the tablet in a therapeutically effective amount, which is an amount that produces the desired therapeutic response upon oral administration and can be readily determined by one skilled in the art. In determining such amounts, the particular pharmaceutically active agent being administered, the bioavailability characteristics of the pharmaceutically active agent, the dose regime, the age and weight of the patient, and other factors must be considered, as known in the art. The pharmaceutically active agent may be present in various forms. For example, the pharmaceutically active agent may be dispersed at the molecular level, e.g. melted, within the tablet, or may be in the form of particles, which in turn may be coated or uncoated. If the pharmaceutically active agent is in form of particles, the particles (whether coated or uncoated) typically have an average particle size of from about 1 to about 500 microns. In one embodiment, such particles are crystals having an average particle size of from about 1 to about 300 microns. The pharmaceutically active agent may be present in pure crystal form or in a granulated form prior to the addition of the taste masking coating. Granulation techniques may be used to improve the flow characteristics or particle size of the pharmaceutically active agents to make it more suitable for subsequent coating. Suitable binders for making the granulation include but are not limited to starch, polyvinylpyrrolidone, polymethacrylates, hydroxypropylmethylcellulose, and hydroxypropylcellulose. The particles including pharmaceutically active agent(s) may be made by cogranulating the pharmaceutically active agent(s) with suitable substrate particles via any of the granulation methods known in the art. Examples of such granulation method include, but are not limited to, high sheer wet granulation and fluid bed granulation such as rotary fluid bed granulation. If the pharmaceutically active agent has an objectionable taste, the pharmaceutically active agent may be coated with a taste masking coating, as known in the art. Examples of suitable taste masking coatings are described in U.S. Pat. No. 4,851,226, U.S. Pat. No. 5,075,114, and U.S. Pat. No. 5,489,436. Commercially available taste masked pharmaceutically active agents may also be employed. For example, acetaminophen particles, which are encapsulated with ethylcellulose or other polymers by a coacervation process, may be used in the present invention. Coacervation-encapsulated acetaminophen may be purchased commercially from Eurand America, Inc. (Vandalia, Ohio). In one embodiment, the tablet incorporates modified release coated particles (e.g., particles containing at least one pharmaceutically active agent that convey modified release properties of such agent). As used herein, “modified release” shall apply to the altered release or dissolution of the active agent in a dissolution medium, such as gastrointestinal fluids. Types of modified release include, but are not limited to, sustained release or delayed release. In general, modified release tablets are formulated to make the active agents(s) available over an extended period of time after ingestion, which thereby allows for a reduction in dosing frequency compared to the dosing of the same active agent(s) in a conventional tablet. Modified release tablets also permit the use of active agent combinations wherein the duration of one pharmaceutically active agent may differ from the duration of another pharmaceutically active agent. In one embodiment the tablet contains one pharmaceutically active agent that is released in an immediate release manner and an additional active agent or a second portion of the same active agent as the first that is modified release. Examples of swellable, erodible hydrophilic materials for use as a release modifying excipient for use in the modified release coating include water swellable cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids, clays, and gelling starches. Examples of water swellable cellulose derivatives include sodium carboxymethylcellulose, cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose, hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose (HEC), hydroxypentylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, and hydroxypropylethylcellulose. Examples of polyalkylene glycols include polyethylene glycol. Examples of suitable thermoplastic polyalkylene oxides include poly (ethylene oxide). Examples of acrylic polymers include potassium methacrylatedivinylbenzene copolymer, polymethylmethacrylate, and high-molecular weight cross-linked acrylic acid homopolymers and copolymers. Suitable pH-dependent polymers for use as release-modifying excipients for use in the modified release coating include: enteric cellulose derivatives such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and cellulose acetate phthalate; natural resins such as shellac and zein; enteric acetate derivatives such as polyvinylacetate phthalate, cellulose acetate phthalate, and acetaldehyde dimethylcellulose acetate; and enteric acrylate derivatives such as for example polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1:2 (available from Rohm Pharma GmbH under the tradename EUDRAGIT S) and poly(methacrylic acid, methyl methacrylate) 1:1 (available from Rohm Pharma GmbH under the tradename EUDRAGIT L). In one embodiment the pharmaceutically active agent is coated with a combination of a water insoluble film forming polymer (such as but not limited to cellulose acetate or ethylcellulose) and a water soluble polymer (such as but not limited to povidone, polymethacrylic co-polymers such as those sold under the tradename Eudragit E-100 from Rohm America, and hydroxypropylcellulose). In this embodiment, the ratio of water insoluble film forming polymer to water soluble polymer is from about 50 to about 95 percent of water insoluble polymer and from about 5 to about 50 percent of water soluble polymer, and the weight percent of the coating by weight of the coated taste-masked particle is from about 5 percent to about 40 percent. In one embodiment, one or more pharmaceutically active agents or a portion of the pharmaceutically active agent may be bound to an ion exchange resin for the purposes of taste-masking the pharmaceutically active agent or delivering the active in a modified release manner. In one embodiment, the pharmaceutically active agent is capable of dissolution upon contact with a fluid such as water, stomach acid, intestinal fluid or the like. In one embodiment, the dissolution of the tablet containing the pharmaceutically active agent meets USP specifications for immediate release. For example, for acetaminophen tablets, USP 24 specifies that in pH 5.8 phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at least 80% of the acetaminophen contained in the tablet is released there from within 30 minutes after dosing, and for ibuprofen tablets, USP 24 specifies that in pH 7.2 phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at least 80% of the ibuprofen contained in the tablet is released there from within 60 minutes after dosing. See USP 24, 2000 Version, 19-20 and 856 (1999). In another embodiment, the dissolution characteristics of the pharmaceutically active agent are modified: e.g. controlled, sustained, extended, retarded, prolonged, delayed and the like. In one embodiment, the pharmaceutically active agent(s) are comprised within polymer-coated particles (e.g., taste-masked and/or sustained release coated particles). In one embodiment, the active ingredient is first coated with a taste-masking coating and subsequently coated with a second layer of a dielectric coating. In one embodiment the pharmaceutically active agent(s) is included within the substrate and/or the coating layer of the lossy coated particle. In one embodiment, the powder blend/tablet comprises from about 10% to about 40%, by weight of the pharmaceutically active agents(s), such as 15% to about 35%, by weight of the tablet/powder blend, such as 20% to about 30%, by weight of the tablet/powder blend. As discussed above, in one embodiment, the pharmaceutically active agent is or is comprised within the substrate of the lossy coated particles. In one embodiment, the amount of such coated particles comprising pharmaceutically active agents(s) may be present at level from about 10% to about 95%, by weight of the tablet/powder blend, such as 15% to about 70%, by weight of the tablet/powder blend, such as 20% to about 50%, by weight of the tablet/powder blend. In one embodiment, the pharmaceutically active agent(s) are comprised within lossy coated particles. In one embodiment, the active ingredient is first coated with a taste-masking coating in absence of an activator and subsequently coated with a second layer containing an activator. In one embodiment the active ingredient is added to the outer coating layer containing an activator. Forming the Tablet Shape In one embodiment, to obtain desired attribute of an orally disintegrating tablet, the tablet's construction may be highly porous and/or have a low density (e.g., to allow the tablet to collapse in the oral cavity). In a preferred embodiment, a minimum or no tamping is desired to achieve the orally disintegrating property. In one embodiment, the tamping step (which occurs prior to the addition of the radiofrequency energy) applies a force to the cavities holding the material to remove air from within the void space between particles and allows material to form into a shape. In one embodiment, the force is less than about 450 pounds per square inch (e.g., less than about 300 pounds per square inch, such as less than 200 pounds per square inch, such as less than 50 pounds per square inch) which comes to rest on a frame (or mechanical “stop”) preventing further deformation of material and without the RF energy no tablet is formed. In one embodiment, the energy is applied while the powder blend is under such force without the use of a mechanical stop. In one embodiment, the tamping step occurs in an indexed manner, where one set of tablets are processed simultaneously, before rotating to another indexing station. In one embodiment, the tamping step occurs at a single indexing station and the application of energy occurs at a separate indexing station. In another embodiment, a third indexing station is present wherein the ejection of the tablet or multiple tablets occurs, wherein the lower forming tool is raised up through and up to the surface of the die. In another embodiment the tamping step is performed through the addition of air pressure or hydraulic cylinder to the top of the upper forming tools. In one embodiment multiple tablets are ejected simultaneously and separated from the surface of the indexing station and removed via a take-off bar. In another embodiment, the tablet shape may be prepared by methods and apparatus described in United States Patent Application Publication No. 20040156902. Specifically, the tablet shape may be made using a rotary compression module including a fill zone, insertion zone, compression zone, ejection zone, and purge zone in a single apparatus having a double row die construction. The dies of the compression module may then be filled using the assistance of a vacuum, with filters located in or near each die. The purge zone of the compression module includes an optional powder blend recovery system to recover excess powder blend from the filters and return the powder blend to the dies. In one embodiment, the tablet shape is prepared by the methods and apparatus described in issued U.S. Pat. No. 6,767,200. Specifically, the tablet shape is made using a rotary compression module including a fill zone, compression zone, and ejection zone in a single apparatus having a double row die construction as shown in FIG. 6 therein. The dies of the compression module are preferably filled using the assistance of a vacuum, with filters located in or near each die. The tablet shape may have one of a variety of different shapes. For example, the tablet shape may be shaped as a polyhedron, such as a cube, pyramid, prism, or the like; or may have the geometry of a space figure with some non-flat faces, such as a cone, truncated cone, triangle, cylinder, sphere, torus, or the like. In certain embodiments, a tablet shape has one or more major faces. For example, the tablet shape surface typically has opposing upper and lower faces formed by contact with the upper and lower forming tool faces (e.g., die punches). In such embodiments, the tablet shape surface typically further includes a “belly-band” located between the upper and lower faces, and formed by contact with the die walls. A tablet shape/tablet may also be a multilayer. Applicants have found that sharp edges in the tooling used to make the tablets can cause arcing, and thus more rounded edges may be needed. In one embodiment a vibratory step is utilized (e.g., added after filling of the powder blend but prior to the heating or fusing step, in order to remove air from the powder blend). In one embodiment a vibration with the frequency from about 1 Hz to about 50 KHz is added with amplitude from 1 micron to 5 mm peak-to-peak to allow for the flowable powder blend to settle into the cavity of a the die platen (“forming cavity”). Radiofrequency Energy Application to Powder Blend The process includes the step of applying radiofrequency energy to a powder blend for a sufficient period of time to form such tablet. While not wanting to be bound to any particular theory, it is believed that the pre-bonding of the activator on the surface of a passivator (the substrate) may provide a more direct path for the energy to travel due to higher conductivity at the surface. Such heating may be dielectric heating (e.g., using a lossy polymer containing vinyl, esters, amides, and/or urethane functional groups) or ionic heating. For ionic heating, as the field flows through the blend over the surface of the lossy coated particles, trapped moisture in the powder blend can provide a source of storing energy (e.g., at 27 MHz, pure water has high dielectric constant) for the lossy coating. The higher loss polymer/activator can efficiently use the energy stored from the moisture to soften and flow the polymeric chains to form physical bonds through polymeric chain entanglement. The synergy provided by the configuration of the lossy coated particle can even provide enough bond strength to allow materials which do not provide a conductive path (or contain a lossy material) to be mixed into the lossy coated particle, where the invention serves as a filler. Radiofrequency heating generally refers to heating with electromagnetic field at frequencies from about 1 MHz to about 100 MHz. In one embodiment of the present invention, the RF-energy is within the range of frequencies from about 1 MHz to about 100 MHz (e.g., from about 5 MHz to 50 MHz, such as from about 10 MHz to about 30 MHz). In one embodiment, the RF-energy is used to heat the first material. RF energy generators are well known in the art. Examples of suitable RF generators include, but are not limited to, free running oscillators such as the COSMOS Model C10X16G4 (Cosmos Electronic Machine Corporation, Farmingdale, N.Y.) or a 50 Ohm RF generator. In one embodiment the RF energy is combined with a second source of heat including but not limited to infrared, induction, or convection heating. In the embodiment, the electrodes are incorporated into a chamber holding the powder blend (e.g., a cylinder, walled-sheet, or other chamber). In one embodiment, the chamber is constructed of a conductive metal. In one embodiment, the chamber has portions which are constructed of non-conductive, insulative material. In one embodiment, the chamber has an insert which is non-conductive where the body of the chamber is conductive. In one embodiment, the insert comprises a surface area which is less than that of the chamber. The conductive material may be comprised of any material which is conductive, including but not limited to aluminum, copper, iron, zinc, nickel and mixtures and alloys thereof. The non-conductive material may be comprised of a non-conductive solid material including but not limited to ceramics, polystyrene and polytetrafluoroethylene. In one embodiment, the chamber has at least one electrode embedded into the walls of the cylinder or walled sheet. The electrode may be surrounded by non-conductive material wherein the electrode is the only conductive wall portion exposed to the power blend. In one embodiment, the powder blend is tamped prior to the addition of RF-energy. In one embodiment, one chamber contains the powder blend and it is placed into a separate chamber (e.g., an oven) for the addition of energy. In another embodiment, the chamber containing the powder blend has additional heating elements incorporated into the chamber. After the application of energy, the powder blend may optionally be cooled (e.g., actively cooled or allowed to cool) prior to forming a predetermined amount of the energy-applied powder blend into the tablet. Examples of apparatuses useful for such application of energy are set forth in US Patent Application Nos. 20110068511 and 20130295211. Multi-Layer Tablet In certain embodiments, the tablet includes at least two layers, e.g., with different types and/or concentrations of the first or second material and/or other ingredients or different concentrations of pharmaceutically active agents. In one embodiment, the tablet includes two layers, one layer having orally disintegrating properties and another layer being chewable or swallowable. In one embodiment one layer is tamped at higher compaction force versus the other layer. In one embodiment, both layers have different amount of pharmaceutically active agents and/or other excipients. In one embodiment, all properties of the two layers are identical but the colors of the two layers are different. In one embodiment, not all of the layers comprise the coated particle (e.g., only one of the two layers). In one embodiment, two layers of the dosage form comprise the coated particle, but the compositions of the coated particle (e.g., the materials and/or the relative amounts of the materials comprising the coated particles) are different. Effervescent Couple In one embodiment, the powder blend/tablet further contains one or more effervescent couples. In one embodiment, effervescent couple contains one member from the group consisting of sodium bicarbonate, potassium bicarbonate, calcium carbonate, magnesium carbonate, and sodium carbonate, and one member selected from the group consisting of citric acid, malic acid, fumaric acid, tartaric acid, phosphoric acid, and alginic acid. In one embodiment, the combined amount of the effervescent couple(s) in the powder blend/tablet is from about 2 to about 20 percent by weight, such as from about 2 to about 10 percent by weight of the total weight of the powder blend/tablet. Orally Disintegrating Tablet In one embodiment, the tablet is designed to disintegrate in the mouth when placed on the tongue in less than about 60 seconds, e.g. less than about 45 seconds, e.g. less than about 30 seconds, e.g. less than about 15 seconds. In one embodiment, the tablet meets the criteria for Orally Disintegrating Tablets (ODTs) as defined by the draft Food and Drug Administration guidance, as published in April, 2007. In one embodiment, the tablet meets a two-fold definition for orally disintegrating tablets including the following criteria: 1) that the solid tablet is one which contains medicinal substances and which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue and 2) be considered a solid oral preparation that disintegrates rapidly in the oral cavity, with an in vitro disintegration time of approximately 30 seconds or less, when based on the United States Pharmacopeia (USP 24 NF 29) disintegration test method for the specific medicinal substance or substances. Tablets Coatings In one embodiment, the tablet includes an additional outer coating (e.g., a translucent coating such as a clear coating) to impart additional properties to the dosage form. Suitable materials for such coatings include, but are not limited to, hypromellose, hydroxypropylcellulose, starch, polyvinyl alcohol, polyethylene glycol, polyvinylalcohol and polyethylene glycol mixtures and copolymers, and mixtures thereof. Tablets of the present invention may include a coating from about 0.05 to about 10 percent, or about 0.1 to about 5 percent by weight of the total tablet. Hardness, Friability, and Density of Tablet In one embodiment, the tablet is prepared such that the tablet is relatively soft (e.g., capable of disintegrating in the mouth or being chewed). The hardness test (crushing hardness) is based on hardness of the dosage form measured perpendicular to the cross-section at the belly band using a modified Model 6d, Pharmatron hardness tester fitted with a 50 g force load cell (lower forces required for testing the invention). Unless otherwise indicated, testing is conducted on two stacked tablets, and the hardness is reported as 50% of the hardness measured. In one embodiment, the hardness of the tablet is less than 1 kiloponds, such as less than 0.5 kiloponds. In one embodiment, the density of the tablet is at least about 0.6 g/cc. In one embodiment, the density of the tablet is less than about 1.5 g/cc. In one embodiment, the bulk density of the lossy coated particles is from about 0.5 g/cc to about 1 g/cc. In one embodiment, the tablets have a friability of less than 10 percent, such as less than 5 percent, such as less than 3 percent. As used herein, “friability” is measured using the USP 24 NF 29 Tablet Friability (Section 1216) with the modification of using 3 tablets for 15 rotations or 3 tablets for 100 revolutions (unless otherwise noted) instead of 10 tablets for 100 rotations. Use of Tablet The tablets may be used as swallowable, chewable, or orally disintegrating tablets to administer the pharmaceutically active agent. In one embodiment, the present invention features a method of treating an ailment, the method including orally administering the above-described tablet wherein the tablet includes an amount of the pharmaceutically active agent effective to treat the ailment. Examples of such ailments include, but are not limited to, pain (such as headaches, migraines, sore throat, cramps, back aches and muscle aches), fever, inflammation, upper respiratory disorders (such as cough and congestion), infections (such as bacterial and viral infections), depression, diabetes, obesity, cardiovascular disorders (such as high cholesterol, triglycerides, and blood pressure), gastrointestinal disorders (such as nausea, diarrhea, irritable bowel syndrome and gas), sleep disorders, osteoporosis, and nicotine dependence. In one embodiment, the method is for the treatment of an upper respiratory disorder, wherein the pharmaceutically active agent is selected from the group of phenylephrine, cetirizine, loratadine, fexofenadine, diphenhydramine, dextromethorphan, chlorpheniramine, chlophedianol, and pseudoephedrine. In this embodiment, the “unit dose” is typically accompanied by dosing directions, which instruct the patient to take an amount of the pharmaceutically active agent that may be a multiple of the unit dose depending on, e.g., the age or weight of the patient. Typically the unit dose volume will contain an amount of pharmaceutically active agent that is therapeutically effective for the smallest patient. For example, suitable unit dose volumes may include one tablet. EXAMPLES Specific embodiments of the present invention are illustrated by way of the following examples. This invention was not confined to the specific limitations set forth in these examples. Example 1 Preparation of Hydroxypropylcellulose (HPC) Coated Mannitol Particles and Resulting Tablet Part A: Production of Lossy Coated Particles: A batch of 14 kg of HPC coated mannitol particles was prepared according to the procedure below. These lossy coated particles were then used to produce the orally disintegrating tablets in Part B. Lossy Coating Solution: 1. Purified Water USP was added to a suitably sized stainless steel container. 2. Hydroxypropylcellulose (“HPC”, commercially available from Ashland Specialty Ingredients as Klucel® EF), as an activator, was added with gentle agitation at concentration of 4% solid in solution. Coating of Substrate Particles (as a passivator) with Lossy Coating Solution: 1. 14000 g of mannitol, as a substrate, was added to a fluid bed, Aeromatic S2 (GEA Group) top spray granulator. 2. The Lossy Coating Solution was sprayed onto the Mannitol at a spray rate of 50 g/minute to a concentration of 0.6% weight/weight to a percent moisture of 10.4% utilizing loss on drying. 3. The coated particles were further dried to a percent moisture utilizing loss on drying of approximately 0.38%. Part B: Tablet Formulation using HPC Coated Particles: The lossy coated particles of Part A were filled into 12.5 mm round dies and sintered at a radio frequency of approximately 27 MHz for 0.8 seconds (“Sintering Time” of 0.8 seconds) to form an orally disintegrating tablet using a machine as disclosed in US Patent No. 20130295211. The electrode distance and variable capacitor was adjusted to remove air from void spaces while optimizing tuning to the tank circuit to provide adequate power transfer through material to form the tablet without causing arcing or flashing. Information regarding the resulting tablets are set forth in Tables 4-7. Comparative Example 2 Preparation of Tablets with Activator and Passivator Prepared as a Dry Blend of Separate Particles Tablets were produced to demonstrate the difference between tablets produced with HPC coated mannitol particles (as in Example 1) and those made using a dry blend of HPC (activator) and maltitol particles (passivator). The blend of HPC and maltitol particles were blended in a rigid sealed polystyrene container placed on a Turbula® mixer (Impandex, Inc. Maywood, N.J.) for five minutes. The results are reported in Table 2B. TABLE 2B % w/w Result HPC % w/w Oral USP (Friability % Example particles maltitol DT* DT1 Q value at 15 drops) Example 2A 1.0 99.0 n/a n/a 569 Too friable to handle Example 2B 2.0 98.0 n/a n/a 402 Too friable to handle Example 2C 5.0 95.0 n/a n/a 197 Too friable to handle Example 2D 10.0 90.0 n/a n/a 79 Too friable to handle Example 2E 15.0 85.0 n/a n/a 66 11 Example 2F 20.0 80.0 n/a n/a 57 4.2 Example 2G 22.0 78.0 38 42 47 3.1 *DT—Disintegration Time 1Disintegration time as determined by tablet disintegration for the United States Pharmacopeia USP 24 n/a—not applicable For dry blends below 10% w/w HPC, the resulting tablets were too friable to handle. For blends prepared at 15 to 20% w/w HPC, the resulting tablets could be sintered using radiofrequency energy and formed, but the resulting tablets were still very friable. For tablets at 22% HPC, the resulting tablets had an acceptable friability of 3.1%, but disintegration times were greater than 30 seconds, which is undesirable for an orally disintegrating tablet and does not meet USP requirements. Modifying manufacturing settings of time, tamp and tuning did not overcome the resulting long disintegration times, thus demonstrating the unexpected benefit of coating the passivator particles with the activator rather than merely blending them as separate particles. Example 3 Preparation of Hydroxyethylcellulose (HEC) Coated Mannitol Particles Part A: Production of lossy coated particles: A batch of 14 kg of HEC coated mannitol particles was prepared according to the procedure below. These lossy coated particles were then used to produce the orally disintegrating tablets in Example 3, Part B. Lossy Coating Solution: 1. Purified Water USP added to a suitably sized stainless steel container. 2. Hydroxyethylcellulose (commercially available as Natrosol 250 from Ashland Specialty Ingredients), as an activator, was added with gentle agitation at concentration of 4% solids in solution. Coating of Substrate Particles with Lossy Coating Solution: 3. 14000 g of Mannitol, as a substrate, was added to a fluid bed, top spray granulator. 4. The Lossy Coating Solution was sprayed onto the Mannitol at a spray rate of 50 g/minute to a concentration of 0.5% weight/weight to percent moisture of 2.7% utilizing loss on drying. 5. The granules were further dried to a percent moisture utilizing loss on drying of approximately 0.18%. Part B: Tablet Formulation using Hydroxyethylcellulose Coated Particles with Acetaminophen: Tablets were produced at a weight of 566 mg, according to the formula in Table 3. The blend was filled into 12.5 mm round dies and sintered at a radio frequency of 27 MHz for approximately 0.8 seconds to form an orally disintegrating tablet using the process of Example 1. The disintegration time as measured by USP 24 was less than 30 seconds and the friability of the tablets was less than 3 percent (15 drops of 3 tablets). TABLE 3 Granulation Blend % w/w Mg/Tablet Coated Mannitol Particles - Example 3, Part A 84.0 472.7 Coated Acetaminophen1 (90% potency) 16.0 93.3 TOTAL 100.0 566.0 1Available from the Aptalis Corporation as Acetaminophen Microcaps ® Example 4 Variations in Amounts of Lossy Coating and Types of Substrates Multiple batches of lossy coated particles were prepared, and tablets were prepared both with and without the further addition of pharmaceutically active agents. Information regarding these batches is described below in Tables 4-7. Disintegration time is reported as an oral (in vitro) taste-test, as well as using the United States Pharmacopeia tablet test for disintegration (USP 24). With respect to Tables 4-7: (i) dextrose was added as dextrose monohydrate; (ii) PE means phenylephrine HCl; (iii) DPH means diphenhydramine; APAP means acetaminophen; and N/A means not available. The method of calculating the geometric mean diameter was via sieve analysis was an ATM Sonic sifter, which is commercially available from by the Sepor Corporation. For the ATM Sonic sifter analysis, about 10 g of material is used. Alternatively, for larger sample sizes, the FMC Sieve Shaker is used, which is commercially available from the FMC Corporation. For the FMC Sieve Shaker analysis, about 100 g of material is used. Example 4A Lossy coated particles were prepared utilizing the procedure in Example 1 utilizing 0.5% weight/weight of hydroxypropylcellulose (Klucel® EF). Phenylephrine was added to the coating solution for the coated mannitol for a level of 12.1 mg dosage in the final form. Tablets were prepared at a tablet weight of 169 mg and sintered for 1.5 seconds. Example 4B Lossy coated particles were prepared utilizing the procedure in Example 1 wherein erythritol was substituted in lieu of mannitol as the substrate. The level of hydroxypropylcellulose (activator) was increased to 0.7% weight/weight. Tablets were prepared at a tablet weight of 486 mg and sintered for 0.8 seconds. Example 4C The coated erythritol particle from Example 4B was blended with coated Diphenhydramine HC1 at a dose of 40.5mg per tablet. Tablets were prepared at 482 mg and sintered for 1.5 seconds. Example 4D The coated mannitol particle from Example 1 was prepared with an additional 0.17% weight/weight of sodium chloride was added to the coating solution, at a hydroxypropylcellulose concentration of 0.5% weight/weight. Tablets were prepared at a tablet weight of 383mg and sintered for 1.0 seconds. Example 4E Lossy coated particles were prepared using the procedure from Example 1 with dextrose monohydrate used in lieu of mannitol as the substrate. Hydroxypropylcellulose was added at a level of 0.5% weight/weight. Tablets were prepared at a weight of 532mg and sintered for 1.0 seconds. Example 4F Lossy coated mannitol particles were prepared utilizing the procedure in Example 1 by increasing the level of hydroxypropylcellulose to 0.8% by weight of the coated mannitol. Tablets were prepared without active ingredient in the blend, at a tablet weight of 397 mg and sintered at 0.5 seconds. Example 4G Lossy coated mannitol particles were prepared utilizing the procedure in Example 1 by increasing the level of hydroxypropylcellulose to 0.9% by weight of the coated mannitol. Tablets were prepared without active ingredient in the blend, at a tablet weight of 397 mg and sintered at 0.5 seconds. Example 4H Lossy coated mannitol particles were prepared utilizing the procedure in Example 1 by increasing the level of hydroxypropylcellulose to 0.9% by weight of the coated mannitol. The coated mannitol was blended with 10% weight/weight of erythritol powder. Tablets were prepared without active ingredient in the blend, at a tablet weight of 407 mg and sintered at 0.5 seconds. Example 4I Lossy coated mannitol particles were prepared utilizing the procedure in Example 1 by increasing the level of hydroxypropylcellulose to 0.9% by weight of the coated mannitol. The coated mannitol was blended with encapsulated acetaminophen at a dose of 37 mg. Tablets were prepared without active ingredient in the blend, at a tablet weight of 416 mg and sintered at 1.0 seconds. Example 4J Lossy coated particles were prepared utilizing the procedure in Example 4I by using a grade of hydroxypropylcellulose with a lower molecular weight (approximately 40,000 Daltons under the tradename of Nisso® SSL from Nippon Soda Co.) at a weight of 0.9% by weight of the coated mannitol. Tablets were prepared without an active ingredient in the blend, at a tablet weight of 389 mg and sintered at 0.5 seconds. Example 4K Lossy coated particles were prepared using the procedure from Example 1 with maltitol in lieu of mannitol as the substrate. Maltitol is used as an example of a hygroscopic sugar. Hydroxypropylcellulose was added at a level of 0.9% by weight of the coated maltitol. Tablets were prepared at a weight of 661 mg and sintered for 1.0 seconds. Example 4L Lossy coated particles were prepared using the procedure from Example 1 with maltitol in lieu of mannitol as the substrate and at a level of Hydroxypropylcellulose of 0.9% of the coated maltitol. Glyceryl monostearate (GMS) was added as an adjunct to the coated maltitol in the coating solution at a level of 0.18% by weight of the coated maltitol. Tablets were prepared without active ingredient in the blend, at a tablet weight of 578 mg and sintered at 0.5 seconds. Example 4M Lossy coated particles were prepared using the procedure from Example 1 with maltitol in lieu of mannitol as the substrate. Hydroxypropylcellulose was added at a level of 0.9% by weight of the coated maltitol. Tablets were prepared at a weight of 631 mg and sintered for 1.5 seconds. Example 4N Lossy coated particles were prepared using the procedure from Example 1 with maltitol in lieu of mannitol as the substrate. Hydroxypropylcellulose was added at a level of 0.9% by weight of the coated maltitol. Encapsulated acetaminophen was added at a dose of 155 mg. Tablets were prepared at 609 mg and sintered for 1.5 seconds. Example 4O Lossy coated particles were prepared using the procedure from Example 1 with maltitol in lieu of mannitol as the substrate. Hydroxypropylcellulose was added at a level of 0.9% by weight of the coated maltitol. Encapsulated acetaminophen was added at a dose of 160 mg. Tablets were prepared at a weight of 625 mg and sintered for 1.5 seconds. Example 4P Lossy coated particles were prepared using the procedure from Example 1 with maltitol in lieu of mannitol as the substrate. Hydroxypropylcellulose was added at a level of 1.2% by weight of the coated mannitol. Tablets were prepared at a weight of 546 mg and sintered for 1.5 seconds. Example 4Q Lossy coated particles were prepared utilizing the procedure in Example 1 using a level of Hydroxypropylcellulose of 1.2% by weight of the coated mannitol. Encapsulated acetaminophen was added at a dose of 160 mg. Tablets were prepared at tablet weight of 694 mg and sintered at 1.5 seconds. These tablets had an oral disintegration time of 32 seconds. Example 4R Lossy coated particles were prepared utilizing the procedure in Example 1 using a level of Hydroxypropylcellulose of 1.0% by weight of the coated mannitol. Encapsulated acetaminophen was added at a dose of 325 mg. Tablets were prepared at tablet weight of 807 mg and sintered at 0.5 seconds. Example 4S Lossy coated particles were prepared utilizing the procedure in Example 1, by lowering the level of Hydroxypropylcellulose to 0.4% by weight of the coated mannitol. Encapsulated acetaminophen was added at a dose of 137 mg. Tablets were prepared at tablet weight of 509 mg and sintered at 0.5 seconds. Example 4T Lossy coated particles were prepared utilizing the procedure in Example 1 by lowering the level of Hydroxypropylcellulose to 0.4% by weight of the coated mannitol. Encapsulated acetaminophen was added at a dose of 128 mg. Tablets were prepared at tablet weight of 475 mg and sintered at 0.5 seconds. These tablets have a friability of greater than 2.0 percent (3.9 percent) at 15 drops. TABLE 4 Example Example Example Example Example Material/Output Example 1 4A 4B 4C 4D 4E Substrate Mannitol Mannitol Erythritol Erythritol Mannitol Dextrose Substrate Geometric 112 112 289 289 112 130 Mean Diameter (μm) Activator HPC HPC HPC HPC HPC HPC (Klucel (Klucel (Klucel (Klucel (Klucel (Klucel EF) EF) EF) EF) EF) + EF) NaCl Activator Concentration 0.6 0.5 0.7 0.7 0.5 0.5 (% w/w) Pharmaceutically Active None PE None DPH None None Agent Active Dose per tablet N/A 12.1 N/A 40.5 n/a n/a % Lossy Coated N/A 100.0 100.0 90.0 100.0 100.0 Particles in Powder Blend % Moisture at End of 10.4 2.7 2.2 2.2 13.4 13.0 Spraying % Moisture of Lossy 0.38 0.8 0.93 n/a 0.14 9.05 Coated Particles Before Sintering Lossy Coated Particle 154 n/a n/a n/a n/a n/a Geometric Mean Diameter (μm) Tablet Diameter (mm) 12.5 9.5 12.5 12.5 12.5 12.5 Tablet Weight (mg) 393 169 486 482 383 532 Tablet Thickness (mm) 4.34 3.21 4.80 4.82 4.24 4.96 Tablet Volume (cc) 0.53 0.23 0.59 0.59 0.52 0.61 Tablet Density (g/cc) 0.74 0.74 0.83 0.81 0.74 0.87 Sintering Time (sec) 0.5 1.5 0.8 1.5 1.0 1.0 Oral Disintegration 22 4 6 6 n/a 8 Time (sec) USP Disintegration 9 n/a n/a n/a 7 9 Time (sec) Crushing Hardness (kp) 0.46 0.25 n/a n/a n/a n/a Friability % (10 drops) n/a 1.7 0.2 1.4 n/a n/a Friability % (15 drops) 0.1 2.4 0.4 1.4 0.4 1.4 Friability % (100 drops) 0.2 n/a 3.1 13.0 0.6 n/a TABLE 5 Example Example Example Example Example Example Material/Output 4F 4G 4H 4I 4J 4K Substrate Mannitol Mannitol Mannitol Mannitol Mannitol Maltitol Substrate Geometric 112 112 112 112 112 218 Mean Diameter (μm) Activator HPC HPC HPC HPC HPC HPC (Klucel (Klucel (Klucel (Klucel (Nisso (Klucel EF) EF) EF) EF) EF) SSL) Activator Concentration 0.8 0.9 0.9 0.9 0.9 0.9 (% w/w) Pharmaceutically Active None None None APAP None None Agent Active Dose per tablet N/A N/A N/A 37.0 n/a n/a % Lossy Coated 100.0 100.0 90.0 90.0 100.0 100.0 Particles in Powder Blend % Moisture at End of 9.0 10.5 10.5 10.5 10.9 1.7 Spraying % Moisture of Lossy 0.5 0.5 0.37 0.31 0.14 0.43 Coated Particles Before Sintering Lossy Coated Particle 135 151 n/a n/a n/a n/a Geometric Mean Diameter (μm) Tablet Diameter (mm) 12.5 12.5 12.5 12.5 12.5 12.5 Tablet Weight (mg) 397 397 407 416 389 661 Tablet Thickness (mm) 4.50 4.24 4.27 4.24 4.31 5.37 Tablet Volume (cc) 0.55 0.52 0.52 0.52 0.53 0.66 Tablet Density (g/cc) 0.72 0.76 0.78 0.80 0.74 1.00 Sintering Time (sec) 0.5 0.5 0.5 1.0 0.5 1.0 Oral Disintegration 16 15 11 14 8 10 Time (sec) USP Disintegration n/a n/a n/a n/a n/a n/a Time (sec) Crushing Hardness (kp) 0.44 0.50 0.37 0.38 0.32 0.43 Friability % (10 drops) n/a n/a n/a n/a n/a n/a Friability % (15 drops) 0.2 0.1 0.0 0.2 0.2 0.3 Friability % (100 drops) 0.58 0.8 4.0 2.2 n/a 0.8 TABLE 6 Example Example Example Example Example Example Material/Output 4L 4M 4N 4O 4P 4Q Substrate Maltitol Maltitol Maltitol Maltitol Maltitol Mannitol Substrate Geometric 218 218 218 218 218 132 Mean Diameter (μm) Activator HPC HPC HPC HPC HPC HPC (Klucel (Klucel (Klucel (Klucel (Klucel (Klucel EF) + EF) EF) EF) EF EF) GMS Activator Concentration 0.9 0.9 0.9 0.9 1.2 1.2 (% w/w) Pharmaceutically Active None None APAP APAP None APAP Agent Active Dose per tablet N/A N/A 155 160 n/a 160 % Lossy Coated 100.0 100.0 72.0 72.0 100.0 56.0 Particles in Powder Blend % Moisture at End of 3.7 3.8 3.8 3.8 2.1 16.5 Spraying % Moisture of Lossy n/a 1.0 0.37 0.44 0.65 0.68 Coated Particles Before Sintering Lossy Coated Particle n/a 281 n/a n/a n/a 156 Geometric Mean Diameter (μm) Tablet Diameter (mm) 12.5 12.5 12.5 12.5 12.5 12.5 Tablet Weight (mg) 578 631 609 625 546 694 Tablet Thickness (mm) 4.39 4.74 5.08 4.86 4.00 5.93 Tablet Volume (cc) 0.54 0.58 0.62 0.60 0.49 0.73 Tablet Density (g/cc) 1.07 1.08 0.98 1.05 1.11 0.95 Sintering Time (sec) 0.5 1.5 1.0 1.5 1.5 1.5 Oral Disintegration 9 7 10 6 6 32 Time (sec) USP Disintegration n/a n/a n/a n/a n/a n/a Time (sec) Crushing Hardness (kp) 0.63 0.35 n/a n/a 0.27 0.54 Friability % (10 drops) n/a n/a n/a n/a n/a n/a Friability % (15 drops) 0.4 0.2 2.3 0.4 0.2 1.4 Friability % (100 drops) n/a n/a n/a n/a n/a n/a TABLE 7 Example Example Example Material/Output 4R 4S 4T Substrate Mannitol Mannitol Mannitol Substrate Geometric 132 132 132 Mean Diameter (μm) Activator HPC HPC HPC (Klucel (Klucel (Klucel EF) EF) EF) Activator Concentration 1.0 0.4 0.4 (% w/w) Pharmaceutically Active APAP APAP APAP Agent Active Dose per tablet 325 137 128 % Lossy Coated 41 70 70 Particles in Powder Blend % Moisture at End of 10.3 4.8 4.8 Spraying % Moisture of Lossy 0.22 0.71 0.71 Coated Particles Before Sintering Lossy Coated Particle 152 n/a 152 Geometric Mean Diameter (μm) Tablet Diameter (mm) 12.5 12.5 12.5 Tablet Weight (mg) 807 509 475 Tablet Thickness (mm) 7.56 4.40 4.83 Tablet Volume (cc) 0.93 0.54 0.59 Tablet Density (g/cc) 0.87 0.94 0.80 Sintering Time (sec) 0.5 0.5 0.50 Oral Disintegration 27 8 9 Time (sec) USP Disintegration n/a 6 5 Time (sec) Crushing Hardness (kp) 0.36 0.30 0.28 Friability % (10 drops) n/a n/a n/a Friability % (15 drops) 2.5 1.9 3.9 Friability % (100 drops) n/a n/a n/a Example 5 Production of Lossy Coated Particles using 80,000 Daltons MW 1% Hydroxypropylcellulose A batch of 6.1 kg of lossy coated maltitol particles was prepared according to the procedure below. The lossy coated particles were dielectrically characterized using the Slotted line method and reported in Table 8A. These lossy coated particles were then used to produce the orally disintegrating tablets in Examples 5A-G (Table 8A and 8B). Lossy Coating Solution: 1. Purified Water USP was added to a suitably sized stainless steel container. 2. 60 g of hydroxypropyl cellulose (commercially available as Klucel® EF from Ashland Specialty Ingredients), as an activator, was added with gentle agitation to make a concentration of 4% solids in solution. Coating of Substrate Particles with Hydroxypropylcellulose Coating Solution: 3. 6000 g of maltitol was added to a fluid bed, top spray granulator. 4. The Lossy Coating solution was sprayed onto the Mannitol at an approximate average spray rate of 115 g/minute to make a 1.0% (w/w) lossy coated particles to a target end of spray percent moisture as noted in Table 8A as measured by loss on drying. 5. The lossy coated particles were then further dried to percent moisture as recorded in Table 8A. Examples 5A-G Production of Lossy Coated Particles using 80,000 Daltons 1% Hydroxypropylcellulose as Activator Lossy coated particles were prepared utilizing the procedure in Example 5, utilizing 1.0% of weight gain of Hydroxypropylcellulose. The lossy coated particles were blended with coated APAP (90% potency) to a concentration of 20%, 30%, 40%, or 50% to make 80, 160 or 325 mg acetaminophen dose tablets (see Tables 8A and 8B). TABLE 8A Example Example Example Example Material/Output 5 5A 5B 5C Comment RF Blended Blended Blended Excipient with with with alone APAP APAP APAP Particles Particles Particles Substrate Maltitol Maltitol Maltitol Maltitol Activator HPC HPC HPC HPC Activator 1.0 1.0 1.0 1.0 Concentration (% w/w) Average Molecular 80 80 80 80 Weight of Polymer (×1000 Daltons) Pharmaceutically None APAP APAP APAP Active Agent Active Dose per tablet N/A 80 80 160 % Lossy Coated N/A 20 30 30 Particles in Powder Blend % Moisture at End of 1.4 N/A N/A N/A Spraying % Moisture of Lossy 1.4 0.79 0.79 0.79 Coated Particles Before Sintering e′ 1.7256 1.6830 1.6957 1.6957 e″ 0.0132 0.0115 0.0100 0.0100 Q value 131 146 170 170 Lossy Coated Particle 302 N/A N/A N/A Geometric Mean Diameter (μm) Tablet Diameter (mm) 12.5 12.5 12.5 12.5 Tablet Weight (mg) N/A 444 296 593 Tablet Thickness N/A 3.88 2.66 4.94 (mm) Tablet Density (g/cc) N/A 0.9 0.9 0.9 Sintering Time (sec) N/A 0.5 0.5 0.5 Oral Disintegration N/A 9 4 15 Time (sec) Friability % (15 N/A 0.4 0.2 0.6 drops) Friability % (100 N/A broke 1.3 2.0 drops) TABLE 8B Example Example Example Example Material/Output 5D 5E 5F 5G Comment Blended Blended Blended Blended with with with with APAP APAP APAP APAP Particles Particles Particles Particles Substrate Maltitol Maltitol Maltitol Maltitol Activator HPC HPC HPC HPC Activator 1.0 1.0 1.0 1.0 Concentration (% w/w) Average Molecular 80 80 80 80 Weight of Polymer (×1000 Daltons) Pharmaceutically APAP APAP APAP APAP Active Agent Active Dose per tablet 160 325 160 325 % Lossy Coated 40 40 50 50 Particles in Powder Blend % Moisture at End of N/A N/A N/A N/A Spraying % Moisture of Lossy 0.58 0.60 0.41 0.41 Coated Particles Before Sintering e′ 1.6970 1.6970 1.7037 1.7037 e″ 0.0094 0.0094 0.0081 0.0081 Q value 181 181 210 210 Lossy Coated Particle Geometric Mean Diameter (μm) N/A N/A N/A N/A Tablet Diameter (mm) 12.5 12.5 12.5 12.5 Tablet Weight (mg) 444 1000 356 722 Tablet Thickness 3.71 7.80 3.45 6.37 (mm) Tablet Density (g/cc) 0.9 1.1 0.8 0.9 Sintering Time (sec) 1.0 1.5 1.5 1.5 Oral Disintegration 8 20 N/A N/A Time (sec) Friability % (15 0.4 1.2 Broke broke drops) Friability % (100 1.3 broke N/A N/A drops) Examples 6 Production of lossy coated particles using 40,000 Daltons MW, 1% Hydroxypropyl Cellulose A batch of 6.1 kg of lossy coated maltitol particles was prepared according to the procedure below. The lossy coated particles were dielectrically characterized using the Slotted line method and reported in Table 8A. These lossy coated particles were then used to produce the orally disintegrating tablets in Examples 6A-G (Table 9A and 9B). Lossy Coating Solution: 1. Purified Water USP was added to a suitably sized stainless steel container. 2. 60 g of hydroxypropyl cellulose (commercially available as Klucel® ELF from Ashland Specialty Ingredients), as an activator, was added with gentle agitation to make a concentration of 4% solids in solution. Coating of Substrate Particles with Hydroxypropyl cellulose Coating Solution: 3. 6000 g of maltitol was added to a fluid bed, top spray granulator. 4. The Lossy Coating solution was sprayed onto the Mannitol at an approximate average spray rate of 103g/minute to make a 1.0% (w/w) lossy coated particle to a target end of spray percent moisture as noted in Table 9A as measured by loss on drying. 5. The lossy coated particles were then further dried to percent moisture as recorded in Table 9A. Examples 6A-G Production of lossy coated particles using 40,000 Daltons MW 1% Hydroxypropylcellulose as Activator The lossy coated particle was prepared utilizing the procedure in Example 6, utilizing 1.0% weight gain of Hydroxypropylcellulose. The lossy coated particles were blended with coated APAP (90% potency) to a concentration of 20%, 30%, 40%, or 50% to make 80, 160 or 325 mg acetaminophen dose tablets (see Tables 9A and 9B). TABLE 9A Example Example Example Example Material/Output 6 6A 6B 6C Comment Lossy Blended Blended Blended coated with with with particles APAP APAP APAP alone Particles Particles Particles Substrate Maltitol Maltitol Maltitol Maltitol Activator HPC HPC HPC HPC Activator 1.0 1.0 1.0 1.0 Concentration (% w/w) Average Molecular 40 40 40 40 Weight of Polymer (×1000 Daltons) Pharmaceutically N/A APAP APAP APAP Active Agent Active Dose per tablet N/A 80 80 160 % Lossy Coated N/A 20 30 30 Particles in Powder Blend % Moisture at End of 2.4 N/A N/A N/A Spraying % Moisture of Lossy 1.6 1.1 0.87 0.87 Coated Particles Before Sintering e′ 1.8016 1.7847 1.7619 1.7619 e″ 0.0157 0.0140 0.0121 0.0121 Q value 115 127 146 146 Lossy Coated Particle 305 N/A N/A N/A Geometric Mean Diameter (μm) Tablet Diameter (mm) 12.5 12.5 12.5 12.5 Tablet Weight (mg) N/A 444 296 593 Tablet Thickness N/A 3.58 2.58 4.74 (mm) Tablet Density (g/cc) N/A 1.0 0.9 1.0 Sintering Time (sec) N/A 1.0 0.5 1.0 Oral Disintegration N/A 11 9 13 Time (sec) Hardness N/A 0.33 N/A N/A Friability % (15 N/A 0.5 0.3 0.5 drops) Friability % (100 N/A 1.0 0.9 N/A drops) TABLE 9B Example Example Example Example Material/Output 6D 6E 6F 6G Comment Blended Blended Blended Blended with with with with APAP APAP APAP APAP Particles Particles Particles Particles Substrate Maltitol Maltitol Maltitol Maltitol Activator HPC HPC HPC HPC Activator 1.0 1.0 1.0 1.0 Concentration (% w/w) Average Molecular 40 40 40 40 Weight of Polymer (×1000 Daltons) Pharmaceutically APAP APAP APAP APAP Active Agent Active Dose per tablet 160 325 160 325 % Lossy Coated 40 40 50 50 Particles in Powder Blend % Moisture at End of N/A N/A N/A N/A Spraying % Moisture of Lossy 0.73 0.73 0.58 0.58 Coated Particles Before Sintering e′ 1.7551 1.7551 1.7471 1.7471 e″ 0.0107 0.0107 0.0099 0.0099 Q value 164 164 176 176 Lossy Coated Particle N/A N/A N/A N/A Geometric Mean Diameter (μm) Tablet Diameter (mm) 12.5 12.5 12.5 12.5 Tablet Weight (mg) 444 1000 356 722 Tablet Thickness 3.71 7.74 3.26 5.91 (mm) Tablet Density (g/cc) 0.9 1.0 0.9 1.0 Sintering Time (sec) 1.0 1.5 1.5 1.5 Oral Disintegration 6 N/A 9 N/A Time (sec) Hardness N/A N/A N/A N/A Friability % (15 0.9 Broke 1.5 broke drops) Friability % (100 N/A N/A N/A N/A drops) Examples 7 Production of lossy coated particles using 140,000 Daltons MW, 1% Hydroxypropyl Cellulose A batch of 6.1 kg of lossy maltitol particles was prepared according to the procedure below. The lossy coated particles were dielectrically characterized using a Slotted line method and reported in Tables 10A. These lossy coated particles were then used to produce the orally disintegrating tablets in Examples 7A-G (Tables 10A and 10B). Lossy Coating Solution: 1. Purified Water USP added to a suitably sized stainless steel container. 2. 60 g of hydroxypropylcellulose (commercially available as Klucel® JF from Ashland Specialty Ingredients), as an activator, was added with gentle agitation to make a concentration of 4% solids in solution. Coating of Substrate Particles with Hydroxypropylcellulose Coating Solution: 3. 6000 g of maltitol was added to a fluid bed, top spray granulator. 4. The Lossy Coating Solution was sprayed onto the Mannitol at an approximate average spray rate of 111 g/minute to make a 1.0% (w/w) lossy coated particle to a target end of spray percent moisture as noted in Table 10A as measured by loss on drying. 5. The granules were then further dried to percent moisture as recorded in Table 10A. Examples 7A-G Production of lossy coated particles using 140,000 Daltons, 1% Hydroxypropyl Cellulose as Activator The lossy coated particles were prepared utilizing the procedure in Example 7, utilizing 1.0% of weight gain of Hydroxypropylcellulose. The lossy coated particles were blended with coated APAP (90% potency) to a concentration of 20%, 30%, 40%, or 50% to make 80, 160 or 325 mg acetaminophen dose tablets (see Tables 10A and 10B). TABLE 10A Example Example Example Example Material/Output 7 7A 7B 7C Comment Lossy Blended Blended Blended coated with with with particles APAP APAP APAP alone Particles Particles Particles Substrate Maltitol Maltitol Maltitol Maltitol Activator HPC HPC HPC HPC Activator 1.0 1.0 1.0 1.0 Concentration (% w/w) Average Molecular 140 140 140 140 Weight of Polymer (×1000 Daltons) Pharmaceutically None APAP APAP APAP Active Agent Active Dose per tablet N/A 80 80 160 % Lossy Coated N/A 20 30 30 Particles in Powder Blend % Moisture at End of 3.1 N/A N/A N/A Spraying % Moisture of Lossy 1.0 0.7 0.7 0.8 Coated Particles Before Sintering e′ 1.8073 1.7533 1.7504 1.7504 e″ 0.0149 0.0122 0.0108 0.0108 Q value 121 144 162 162 Lossy Coated Particle 338 N/A N/A N/A Geometric Mean Diameter (μm) Tablet Diameter (mm) 12.5 12.5 12.5 12.5 Tablet Weight (mg) N/A 444 296 593 Tablet Thickness N/A 3.94 2.60 4.95 (mm) Tablet Density (g/cc) N/A 0.9 0.9 0.9 Sintering Time (sec) N/A 0.5 0.5 1.0 Oral Disintegration N/A 8 9 12 Time (sec) Hardness N/A N/A 0.53 0.33 Friability % (15 N/A 0.5 0.5 0.8 drops) Friability % (100 N/A 2.5 Broke 7.1 drops) TABLE 10B Example Example Example Example Material/Output 7D 7E 7F 7G Comment Blended Blended Blended Blended with with with with APAP APAP APAP APAP Particles Particles Particles Particles Substrate Maltitol Maltitol Maltitol Maltitol Activator HPC HPC HPC HPC Activator 1.0 1.0 1.0 1.0 Concentration (% w/w) Average Molecular 140 140 140 140 Weight of Polymer (×1000 Daltons) Pharmaceutically APAP APAP APAP APAP Active Agent Active Dose per tablet 160 325 160 325 % Lossy Coated 40 40 50 50 Particles in Powder Blend % Moisture at End of N/A N/A N/A N/A Spraying % Moisture of Lossy 0.5 0.5 0.5 0.3 Coated Particles Before Sintering e′ 1.7397 1.7397 1.7368 1.7368 e″ 0.0087 0.0087 0.0085 0.0085 Q value 200 200 204 204 Lossy Coated Particle N/A N/A N/A N/A Geometric Mean Diameter (μm) Tablet Diameter (mm) 12.5 12.5 12.5 12.5 Tablet Weight (mg) 444 1000 356 722 Tablet Thickness 3.97 7.97 3.28 5.97 (mm) Tablet Density (g/cc) 0.9 1.0 0.9 1.0 Sintering Time (sec) 1.0 1.5 1.5 1.5 Oral Disintegration 8 16 9 N/A Time (sec) Hardness 0.85 0.65 0.31 0.41 Friability % (15 0.8 0.8 2.9 broke drops) Friability % (100 Broke N/A N/A N/A drops) Examples 8 Production of Lossy Coated Particles Using 0.5% Hydroxyethyl Cellulose as Activator A batch of 6.1 kg of lossy coated maltitol particles was prepared according to the procedure below. The lossy coated particles were dielectrically characterized using the Slotted line method and reported in Table 11. These lossy coated particles were then used to produce the orally disintegrating tablets in Examples 8A-D (Table 11). Polymer Coating Solution: 1. Purified Water USP added to a suitably sized stainless steel container. 2. 60 g of hydroxyethyl cellulose (commercially available as Natrosol 250L from Ashland Specialty Ingredients), as an activator, was added with gentle agitation to make a concentration of 2% solids in solution. Coating of Substrate Particles with Hydroxyethyl cellulose Coating Solution: 3. 6000 g of maltitol was added to a fluid bed, top spray granulator. 4. The Polymer Coating solution was sprayed onto the Mannitol at an approximate average spray rate of 111 g/minute to make a 0.5% (w/w) lossy coated particle to a target end of spray percent moisture as noted in Table 11 as measured by loss on drying. 5. The granules were then further dried to percent moisture as recorded in Table 11. Examples 8A-D The lossy coated particles were prepared utilizing the procedure in Example 8, utilizing 1.0% weight gain of Hydroxyethyl cellulose. The lossy coated particles were blended with coated APAP (90% potency) to a concentration of 20%, 30%, 40%, or 50% to make 80, 160 or 325 mg acetaminophen dose tablets (see Table 11). TABLE 11 Example Example Example Example Example Material/Output 8 8A 8B 8C 8D Comment Lossy coated Blended Blended Blended Blended particles with APAP with APAP with APAP with APAP alone Particles Particles Particles Particles Substrate Maltitol Maltitol Maltitol Maltitol Maltitol Activator HEC HEC HEC HEC HEC Activator Concentration 0.5 0.5 0.5 0.5 0.5 (% w/w) Average Molecular 75 75 75 75 75 Weight of Polymer (×1000 Daltons) Pharmaceutically None APAP APAP APAP APAP Active Agent Active Dose per tablet N/A 80 80 160 160 % Lossy Coated Particles N/A 20 30 30 40 in Powder Blend % Moisture at End of 2.7 N/A N/A N/A N/A Spraying % Moisture of Lossy 1.3 0.8 0.6 0.6 0.4 Coated Particles Before Sintering e′ 1.8065 1.7854 1.7741 1.7741 1.7743 e″ 0.0275 0.0197 0.0159 0.0159 0.0130 Q value 66 91 112 112 136 Tablet Diameter (mm) N/A 12.5 12.5 12.5 12.5 Tablet Weight (mg) N/A 444 296 593 444 Tablet Thickness (mm) N/A 4.07 2.86 4.74 4.05 Tablet Density (g/cc) N/A 0.9 0.8 0.9 0.9 Sintering Time (sec) N/A 0.5 0.5 0.5 1.5 Oral Disintegration N/A 9 5 8 9 Time (sec) Hardness N/A 0.36 0.61 0.30 0.85 Friability % (15 drops) N/A 0.51 1.2 0.9 2.9 Friability % (100 drops) N/A N/A N/A N/A N/A Examples 9 Production of Lossy Coated particles Using 1% Hydroxyethyl Cellulose as Activator A batch of 6.1 kg of lossy coated maltitol particles was prepared according to the procedure below. The lossy coated particles were dielectrically characterized using the Slotted line method and reported in Table 12. These lossy coated particles were then used to produce the orally disintegrating tablets in Examples 9A-D (Table 12). Lossy Coating Solution: 1. Purified Water USP added to a suitably sized stainless steel container. 2. 120 g of hydroxyethyl cellulose (commercially available as Natrosol 250L from Ashland Specialty Ingredients), as the activator, was added with gentle agitation to make a concentration of 4% solids in solution. Coating of Substrate Particles with Hydroxyethyl cellulose Coating Solution: 3. 6000 g of maltitol was added to a fluid bed, top spray granulator. 4. The Lossy Coating Solution was sprayed onto the Mannitol at an approximate average spray rate of 111 g/minute to make a 1.0% (w/w) lossy coated particle to a target end of spray percent moisture as noted in Table 12. 5. The granules were then further dried to percent moisture as recorded in Table 12. Examples 9A-D The lossy coated particles were prepared utilizing the procedure in Example 9, utilizing 0.5% weight gain of Hydroxyethyl cellulose. The lossy coated particles were blended with coated APAP (90% potency) to a concentration of 20%, 30%, 40%, or 50% to make 80, 160 or 325 mg acetaminophen dose tablets (see Table 12). TABLE 12 Example Example Example Example Example Material/Output 9 9A 9B 9C 9D Comment Lossy coated Blended Blended Blended Blended particles with APAP with APAP with APAP with APAP alone Particles Particles Particles Particles Substrate Maltitol Maltitol Maltitol Maltitol Maltitol Activator HEC HEC HEC HEC HEC Activator 1.0 1.0 1.0 1.0 1.0 Activator Concentration (% w/w) Average Molecular 75 75 75 75 75 Weight of Polymer (×1000 Daltons) Pharmaceutically None APAP APAP APAP APAP Active Agent Active Dose per tablet N/A 80 80 160 160 % Lossy Coated Particles N/A 20 30 30 40 in Powder Blend % Moisture at End of 2.2 N/A N/A N/A N/A Spraying % Moisture of Lossy 1.3 0.7 0.6 0.6 0.5 Coated Particles Before Sintering e′ 1.7532 1.7411 1.7444 1.7444 1.7495 e″ 0.0378 0.0277 0.0250 0.0250 0.0202 Q value 46 63 70 70 87 Tablet Diameter (mm) N/A 12.5 12.5 12.5 12.5 Tablet Weight (mg) N/A 444 296 593 444 Tablet Thickness (mm) N/A 4.13 2.68 5.23 4.13 Tablet Density (g/cc) N/A 0.8 0.9 0.9 0.8 Sintering Time (sec) N/A 0.5 0.5 0.5 1.0 Oral Disintegration N/A 19 8 19 8 Time (sec) Hardness N/A 0.43 0.67 0.52 0.60 Friability % (15 drops) N/A 2.3 0.9 2.5 2.7 Friability % (100 drops) N/A N/A N/A N/A N/A Examples 10 Production of Lossy Coated particles Using 2% Hydroxypropyl Cellulose as Activator A batch of 6.1 kg of lossy coated maltitol particles was prepared according to the procedure below. The lossy coated particles were dielectrically characterized in using the Slotted line method and reported in Table 13. These lossy coated particles were then used to produce the orally disintegrating tablets in Examples 10A-D (Table 13). Lossy Coating Solution: 1. Purified Water USP added to a suitably sized stainless steel container. 2. 120 g of hydroxypropyl cellulose (commercially available as Klucel® EF from Ashland Specialty Ingredients), as an activator, was added with gentle agitation to make a concentration of 4% solids in solution. Coating of Substrate Particles with Hydroxyethyl cellulose Coating Solution: 3. 6000 g of maltitol was added to a fluid bed, top spray granulator. 4. The Lossy Coating Solution was sprayed onto the Mannitol at an approximate average spray rate of 110 g/minute to make a 2% (w/w) lossy coated particle to a target end of spray percent moisture as noted in Table 13 as measured by loss on drying. 5. The granules were then dried to percent moisture as recorded in Table 13. Examples 10A-F The lossy coated particles were prepared utilizing the procedure in Example 10, utilizing 1.0% weight gain of Hydroxyethyl cellulose. The lossy coated particles were blended with coated APAP (90% potency) to a concentration of 20%, 30%, 40%, or 50% to make 80, 160 or 325 mg acetaminophen dose tablets (see Tables 13). TABLE 13 Example Example Example Example Example Example Example Material/Output 10 10A 10B 10C 10D 10E 10F Comment Lossy Blended Blended Blended Blended Blended Blended coated with with with with with with particles APAP APAP APAP APAP APAP APAP alone Particles Particles Particles Particles Particles Particles Substrate Maltitol Maltitol Maltitol Maltitol Maltitol Maltitol Maltitol Activator HPC HPC HPC HPC HPC HPC HPC Activator 2.0 2.0 2.0 2.0 2.0 2.0 2.0 Concentration (% w/w) Average Molecular 80 80 80 80 80 80 80 Weight of Polymer (×1000 Daltons) Pharmaceutically None APAP APAP APAP APAP APAP APAP Active Agent Active Dose per tablet N/A 80 80 160 160 325 160 % Lossy Coated N/A 20 30 30 40 40 50 Particles in Powder Blend % Moisture at End of 3.4 N/A N/A N/A N/A N/A N/A Spraying % Moisture of Lossy 1.5 1.1 0.9 0.7 0.7 0.7 0.6 Coated Particles Before Sintering e′ 1.8140 1.7847 1.7792 1.7792 1.7554 1.7554 1.7601 e″ 0.0214 0.0129 0.0099 0.0099 0.0084 0.0084 0.0066 Q value 85 138 180 180 209 209 267 Tablet Diameter (mm) N/A 12.5 12.5 12.5 12.5 12.5 12.5 Tablet Weight (mg) N/A 444 296 593 444 1000 356 Tablet Thickness N/A 3.49 2.67 4.74 3.77 8.17 3.25 (mm) Tablet Density (g/cc) N/A 1.0 0.87 0.99 0.93 0.97 0.86 Sintering Time (sec) N/A 0.5 0.5 0.5 0.5 0.5 0.5 Oral Disintegration N/A 10 8 11 14 18 8 Time (sec) Friability % (15 drops) N/A 0.50 0.60 0.60 0.53 2.24 1.21 Friability % (100 N/A 1.1 N/A N/A N/A N/A N/A drops) Examples 11 Production of Lossy Coated particles Using 0-1% Hydroxyethyl Cellulose as Activator; Combined with Sodium Citrate and/or Glycerin as Adjuvants A batch of 6.1 kg of lossy coated maltitol particles was prepared according to the procedure below. The lossy coated particles were dielectrically characterized in using the Slotted line method and reported in Table 14. These lossy coated particles were then used to produce the orally disintegrating tablets in Examples 11A-E (Tables 14A-14B). Samples 11F and 11G were made as comparator blends with uncoated maltitol to demonstrate tablet samples without coated particles. These comparator blends did not sinter to form tablets. Lossy Coating Solution: 1. Purified Water USP added to a suitably sized stainless steel container. 2. 120 g of hydroxyethyl cellulose (commercially available as Natrosol® 250L), as an activator, was added with gentle agitation to make a concentration of 2.5-4% solids in solution (approximately 25 kg). Coating of Substrate Particles with Hydroxyethyl cellulose Coating Solution: 3. 6000 g of maltitol was added to a fluid bed, top spray granulator. 4. The Lossy Coating Solution was sprayed onto the Maltitol at an approximate average spray rate of 110 g/minute to make a 2% (w/w) lossy coated particle to a target end of spray percent moisture as noted in Tables 14A-14B as measured by loss on drying. 5. The granules were then dried to percent moisture as recorded in Tables 14A-14B. Examples 11, 11A-E The lossy coated particles were prepared utilizing the procedure in Example 11, utilizing 1.0% weight gain of Hydroxyethyl cellulose. The lossy coated particles were blended with coated APAP (90% potency) to a concentration of 20%, 30%, 40%, or 50% to make 80, 160 or 325 mg acetaminophen dose tablets (see Tables 14A and 14B). TABLE 14A Example Example Example Example Material/Output 11 11A 11B 11C Comment 1% HEC 1% HEC 1% HEC 1% HEC on with 1% with 1% with 2% Maltitol Glycerin Glycerin Glycerin on and 1% and 0.5% Maltitol Sodium Sodium Citrate on Citrate on Maltitol Maltitol Substrate Maltitol Maltitol Maltitol Maltitol Activator HEC HEC HEC HEC Activator 1.0 1.0 1.0 1.0 Concentration (% w/w) Average Molecular 80 80 80 80 Weight of Polymer (×1000 Daltons) Pharmaceutically APAP APAP APAP APAP Active Agent Active Dose per tablet 160 mg 160 mg 160 mg 160 mg % Lossy Coated 71.45 71.45 71.45 71.45 Particles in Powder Blend % Moisture at End of 3.00 1.89 1.78 1.79 Spraying % Moisture of Lossy 0.88 0.78 1.14 0.77 Coated Particles Before Sintering e′ 0.8093 1.8385 1.7756 — e″ 0.0408 0.0312 0.0756 — Q value 44 59 23 — Tablet Diameter (mm) 12.5 12.5 12.5 12.5 Tablet Weight (mg) 600 600 600 600 Tablet Thickness 5.25 5.25 5.44 5.44 (mm) Tablet Density (g/cc) 0.644 0.644 0.668 0.668 Sintering Time (sec) 1 1 1 1 Oral Disintegration 11 14.7 10.7 11.5 Time (sec) Friability % (15 N/A 0.50 0.60 0.60 drops) Friability % (100 N/A N/A N/A N/A drops) HEC: Hydroxyethyl cellulose TABLE 14B Example Example Example Example Material/Output 11D 11E 11F 11G Comment 1% HEC 1% HEC 0% HEC 0% HEC with 3% with 3% with 1% with 3% Glycerin Glycerin Glycerin Glycerin on and 1% on on Maltitol Sodium Maltitol Maltitol Citrate on Maltitol Substrate Maltitol Maltitol Maltitol Maltitol Activator HEC HEC None None Activator 1.0 1.0 0.0 0.0 Concentration (% w/w) Average Molecular 80 80 N/A N/A Weight of Polymer (×1000 Daltons) Pharmaceutically APAP APAP APAP APAP Active Agent Active Dose per tablet 160 mg 160 mg 160 mg 160 mg % Lossy Coated 71.45 71.45 71.45a 71.45a Particles in Powder Blend % Moisture at End of 1.75 2.03 1.54 1.87 Spraying % Moisture of Lossy 0.78 1.12 0.53 0.81 Coated Particles Before Sintering e′ 1.8463 1.8320 — — e″ 0.0333 0.0914 — — Q value 55 20 — — Tablet Diameter (mm) 12.5 12.5 12.5 12.5 Tablet Weight (mg) 600 600 600 600 Tablet Thickness 5.25 5.25 5.25 5.25 (mm) Tablet Density (g/cc) 0.644 0.644 0.644 0.644 Sintering Time (sec) 1 1 1 1 Oral Disintegration 18.5 9.3 N/Ab N/Ab Time (sec) Friability % (15 0.53 2.24 Failedb Failedb drops) Friability % (100 N/A N/A N/A N/A drops) HEC: Hydroxyethyl cellulose aparticles without HEC bcould not be tested since these blends did not sinter to form a tablet e′ and e″ tested on coated particles Examples 12 Production of Lossy Coated Particles Using Various Polymers as Activators Batches of 6.1 kg of lossy coated maltitol particles was prepared according to the procedure below. The lossy coated particles were dielectrically characterized in using the Slotted line method and reported in Tables 15A and 15B. These lossy coated particles were then used to produce the orally disintegrating tablets in Examples 12 and 12A-12H (Tables 15A and 15B). Lossy Coating Solution: 1. Purified Water USP added to a suitably sized stainless steel container. 2. 120 g of a polymer (as shown in the Table 15 below) as an activator, was added with gentle agitation to make a concentration of 2-5% solids in solution, depending on the polymer being evaluated (approximately 25 kg). Coating of Substrate Particles with Polymer Coating Solution: 3. 6000 g of maltitol was added to a fluid bed, top spray granulator. 4. The Lossy Coating Solution was sprayed onto the Maltitol at an approximate average spray rate of approximately 100-110 g/minute to make a 1% (w/w) lossy coated particle to a target end of spray percent moisture as noted in Tables 15A and 15B as measured by loss on drying. 5. The granules were then dried. Examples 12, 12A-H The lossy coated particles were prepared utilizing the procedure in Example 12, utilizing 1.0% weight gain of a polymer. TABLE 15A Example Example Example Example Example Material/Output 12 12A 12B 12C 12D Comment 1% 1% 1% 1% 1% Polyvinyl Polyvinyl Polyvinyl Polyvinyl Polyvinyl Alcohol1 Alcohol- Alcohol- Alcohol- Acetate4 on on Polyethylene Polyethylene Polyethylene Maltitol Maltitol Glycol Graft Glycol Graft Glycol Graft Co-Polymer Co-Polymer3 Co-Polymer3 “IR”2 on on Maltitol on Maltitol Maltitol Substrate Maltitol Maltitol Maltitol Maltitol Maltitol Activator Polyvinyl Kollicoat ® Kollicoat ® Kollicoat ® Kollicoat ® Alcohol IR Protect Protect SR30 Activator 1.0 1.0 1.0 1.0 1.0 Concentration (% w/w) Pharmaceutical N/A N/A N/A N/A N/A Active Agent Active Dose per N/A N/A N/A N/A N/A tablet % Lossy Coated 100.0 100.0 100.0 100.0 100.0 Particles in Powder Blend % Moisture of Lossy 0.76 1.33 1.03 1.03 1.46 Coated Particles Before Sintering e′ 1.7203 1.8520 1.7746 1.7746 1.8796 e″ 0.1071 0.0189 0.0414 0.0414 0.0938 Q value 16 98 43 43 20 Tablet Diameter 12.5 12.5 12.5 12.5 12.5 (mm) Tablet Weight (mg) 600 600 600 600 600 Sintering Time (sec) 1 1 1 1 1 Oral Disintegration 4-5 5-9 3-5 n/a 9-13 Time (sec) Friability % (15 0.83-2.73 0.28-2.78 2.0-3.9 Too soft 0.51-1.91 drops) to test e′ and e″ tested on coated particles 1Available as Emprove ® from EMD Millipore Corporation 2Available as Kollicoat IR ® from the BASF Corporation 3Available as Kollicoat Protect ® from the BASF Corporation 4Available as Kollicoat SR30 ® from the BASF Corporation TABLE 15B Material/ Example Example Example Example Output 12E 12F 12G 12H Comment 1% 1% 1% 1% Copolymer Povidone6 Polyvinyl Copolymer of ethyl (Plasdone) caprolactam- of N-vinyl-2- acrylate, on Maltitol polyvinyl pyrrolidone methyl acetate- and vinyl methacrylate5 polyethylene acetate8 on on Maltitol glycol graft Maltitol copolymer7 Maltitol Substrate Maltitol Maltitol Maltitol Maltitol Activator Eudragit ® Plasdone ® SoluPlus ® Plasdone ® RS30D K12 S630 Activator 1.0 1.0 1.0 1.0 Concentration (% w/w) Pharmaceutical N/A N/A N/A N/A Active Agent Active Dose N/A N/A N/A N/A per tablet % Lossy 100.0 100.0 100.0 100.0 Coated Particles in Powder Blend % Moisture of 1.14 1.13 1.27 1.36 Lossy Coated Particles Before Sintering e′ 1.6016 — 1.7686 1.8605 e″ 0.1133 — 0.0731 0.0332 Q value 14 — 24 56 Tablet 12.5 12.5 12.5 12.5 Diameter (mm) Tablet Weight 600 600 600 600 (mg) Sintering Time 1 1 1 1 (sec) Oral 13-22 4-5 5-11 2-3 Disintegration Time (sec) Friability % (15 0.71-2.00 3.7 0.7-4.7 1.5-3.7 drops) e′ and e″ tested on coated particles 5Available as Eudragit ® RS30D from the Evonik Corporation 6Available as Plasdone ® K12 from the Ashland Corporation 7Available as Soluplus ® from the BASF Corporation 8Available as Plasdone ® S630 from the Ashland Corporation Example 13 Preparation of Eudragit RD30D Coated Particle Blended with Encapsulated Acetaminophen The batch from Example 12D above was also blended with 29% coated acetaminophen and sintered with radiofrequency energy to produce tablets, as outlined in Example 12. Various parameters for such particles are set forth below. TABLE 16 Friability Oral (%) 15 Disintegration Sample LOD1 e′ e″ Q drops (sec) Eudragit 0.726 1.6219 0.1243 13 0.39-0.77 5-10 RS30D Coated Particles with En- capsulated APAP 1Loss on Drying (% water by weight) Example 14 Production of Lossy Coated Particles Using Various Polymers with Activators with Plasticizers Batches of 6.1 kg of lossy coated maltitol particles was prepared according to the procedure below. The lossy coated particles were dielectrically characterized in using the Slotted line method and reported in Table 17A. These lossy coated particles were then used to produce the orally disintegrating tablets in Examples 14A-H (Tables 17A-17B). Lossy Coating Solution: 1. Purified Water USP added to a suitably sized stainless steel container. 2. 120 g of a polymer (as shown in the Table below) as an activator and 47 g of plasticizer (ratio of 72:24 of activator: plasticizer) was added with gentle agitation to make a concentration of 2-5% solids in solution, depending on the polymer being evaluated. Coating of Substrate Particles with Polymer Coating Solution: 3. 6000 g of maltitol was added to a fluid bed, top spray granulator. 4. The Lossy Coating Solution was sprayed onto the Maltitol at an approximate average spray rate of approximately 100-110 g/minute to make a 1-2% (w/w) lossy coated particle to a target end of spray percent moisture as noted in Tables 17A-17B as measured by loss on drying. 5. The granules were then dried. Examples 14, 14A-H The lossy coated particles were prepared utilizing the procedure in Example 14, utilizing 1.0% weight gain of polymer (depending on type in Tables 17A-17B). TABLE 17A Example Example Example Example Example Material/Output 14 14A 14B 14C 14D Comment 2% 1% 2% 2% 1% Eudragit Eudragit Eudragit Eudragit Eudragit RL30D1 RL30D RS30D2 RS30D2 RS30D2 with with with with with DBSa on DBSa on DBSa on DBSa on DBSa on Maltitol Maltitol Maltitol Maltitol Maltitol Substrate Maltitol Maltitol Maltitol Maltitol Maltitol Activator Eudragit ® Eudragit ® Eudragit ® Eudragit ® Eudragit ® RL30D RL30D RS30D RS30D RS30D Activator Concentration 2.0 1.0 1.0 1.0 1.0 (% w/w) Pharmaceutical Active N/A N/A N/A N/A N/A Agent Active Dose per tablet N/A N/A N/A N/A N/A % Lossy Coated 100.0 100.0 100.0 100.0 100.0 Particles in Powder Blend % Moisture of Lossy 0.089 0.119 0.026 0.026 0.019 Coated Particles Before Sintering e′ 1.6623 1.7003 1.6604 1.6604 1.6467 e″ 0.0256 0.0665 0.0179 0.0179 0.0437 Q value 65 n/a 93 93 38 Tablet Diameter (mm) 12.5 12.5 12.5 12.5 12.5 Tablet Weight (mg) 600 600 600 600 600 Sintering Time (sec) 1 1 1 1 1 Oral Disintegration NR NR NR NR NR Time (sec) Friability % (15 drops) 5.2 Could Failed at 4.1-4.5 Could not make 7 drops not make tablets tablets e′ and e″ tested on coated particles aDBS: Dibuytl Sebecate (plasticizer) bPG: Propylene Glycol (plasticizer) NR—not recorded 1Eudragit ® RL30D from Evonik Corporation is copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups 2Eudragit ® RS30D from Evonik Corporation is a copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups TABLE 17B Example Example Example Example Material/Output 14E 14F 14G 14H Comment 2% 1% 2% 2% Polyvinyl Polyvinyl Polyvinyl Eudragit Alcohol- Alcohol- Alcohol- RL30D1 Polyethylene Polyethylene Polyethylene with PGb Glycol Graft Glycol Graft Glycol Graft on Co-Polymer3 Co-Polymer3 Co-Polymer Maltitol and PGb on and PGb on “IR”4 on PGb Maltitol Maltitol on Maltitol Substrate Maltitol Maltitol Maltitol Maltitol Activator Kollicoat ® Kollicoat ® Kollicoat ® Eudragit ® Protect Protect IR RL30D Activator 2.0 1.0 2.0 2.0 Concentration (% w/w) Pharmaceutical N/A N/A N/A N/A Active Agent Active Dose per N/A N/A N/A N/A tablet % Lossy Coated 100.0 100.0 100.0 100.0 Particles in Powder Blend % Moisture of 0.825 0.610 0.819 0.866 Lossy Coated Particles Before Sintering e′ 1.6708 1.6301 1.6225 1.6786 e″ 0.0217 0.0623 0.0703 0.0731 Q value 77 26 56 23 Tablet Diameter 12.5 12.5 12.5 12.5 (mm) Tablet Weight 600 600 600 600 (mg) Sintering Time 1 1 1 1 (sec) Oral 7-10 NR 10 >30 Disintegration Time (sec) Friability % (15 1.9-2.8 3.9-5.8 2.6-6.9 2.9-3.8 drops) e′ and e″ tested on coated particles aDBS: Dibuytl Sebecate (plasticizer) bPG: Propylene Glycol (plasticizer) NR—not recorded 3Available as Kollicoat Protect ® from the BASF Corporation 4Available as Kollicoat IR ® from the BASF Corporation Example 15 Evaluation of Tablet Excipients to Prevent Sticking to Tooling During Sintering, Including the Addition of Corn Starch and Mesoporous Silica The addition of corn starch and mesoporous silica allow for anti-adherence properties and the control of moisture within the sintered ODT tablet blend, preventing the tablet from sticking to the tooling during sintering with radiofrequency energy. Part A: Tablet Formulation using Hydroxyethylcellulose Coated Particles with Encapsulated Acetaminophen: Tablets were produced at a weight of 600 mg, according to the formula in Table 18. Coated maltitol was coated in a fluid bed coating unit using an aqueous solution of hydroxyethylcellulose (Example 11B) with 1% hydroxyethylcellulose, 1% glycerin and 1% sodium citrate. The blend is then prepared using the formulation in Table 18. Encapsulated Acetaminophen, sucralose and flavoring agents were manually mixed in a plastic bag with sucralose and grape flavor until homogenous. This mixture was transferred to a Turbula blender and mixed with the Corn Starch, Syloid and coated maltitol for 5 minutes. To produce the tablets, the blend was filled into 12.5mm round dies and sintered at a radio frequency of 27 MHz for approximately 0.8 seconds to form an orally disintegrating tablet. Optimal levels of Corn starch and Syloid were determined through an experimental design model, using ranges of 0.625% to 2.5% Corn Starch and 0.25% to 1.0% of Syloid in varying amounts. The disintegration time as measured by USP 24 was less than 30 seconds and the friability of the tablets was 1.68, which was less than target amount of 3 percent (15 drops of 3 tablets). TABLE 18 Granulation Blend % w/w Mg/Tablet Coated Maltitol Particles 70.08 420.48 Encapsulated Acetaminophen1 (90% potency) 27.90 167.40 Grape Flavor 0.50 3.00 Sucralose 0.15 0.90 Corn Starch B8302 0.625 3.75 Syloid ® 63FP 0.75 4.50 TOTAL 100.0 600.0 1Available from the Aptalis Corporation as Acetaminophen Microcaps ® 2Available from the Grain Processing Corporation 3Available as mesoporous silica from the W.R. Grace Corporation Specific embodiments of the present invention are illustrated by way of the following examples. This invention was not confined to the specific limitations set forth in these examples. It is understood that while the invention has been described in conjunction with the detailed description thereof, that the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the claims.
<SOH> BACKGROUND OF THE INVENTION <EOH>Pharmaceuticals intended for oral administration are typically provided in tablet form. Tablets can be swallowed whole, chewed in the mouth, or disintegrated in the oral cavity. Soft tablets that either are chewed or dissolve in the mouth are often employed in the administration of pharmaceuticals where it is impractical to provide a tablet for swallowing whole. With chewable tablets, the act of chewing helps to break up the tablet particles as the tablet disintegrates and may increase the rate of absorption by the digestive tract. Soft tablets are also advantageous where it is desirable to make a pharmaceutically active agent available topically in the mouth or throat for both local effects and/or systemic absorption. Soft tablets are also utilized to improve drug administration in pediatric and geriatric patients. Soft tablets designed to disintegrate in the mouth prior to swallowing are particularly useful for improving compliance of pediatric patients. Generally, soft tablets are made by compaction of a blend of powdered ingredients and typically include a pharmaceutically active agent, flavoring, and/or binders. The powder blend is typically fed into the cavity of a die of a tablet press and a tablet is formed by applying pressure. Hardness of the resulting tablet is a direct function of the compaction pressure employed and the compatibility of the ingredients in the formulation. A softer tablet, having an easier bite-through, may be prepared by employing reduced compaction pressures. The resulting tablet is softer, but also more fragile, brittle, and easily chipped and disadvantageously can involve complex and costly processing steps. Examples of soft tablets designed to disintegrate in the mouth without chewing are disclosed in U.S. Pat. Nos. 5,464,632, 5,223,264, 5,178,878, 6,589,554, and 6,224,905. There is a need for aesthetically pleasing chewable and orally disintegrating tablets that utilize commercially efficient manufacturing methods. Orally disintegrating tablets can be prepared by compression (see, e.g., U.S. Pat. Nos. 5,223,264 and 5,178,878), but these tablets can have a high density and thus can take up to 20 to 30 seconds to fully disintegrate in the mouth. Lyophilized orally disintegrating tablets (see, e.g., U.S. Pat. Nos. 6,509,040, 5,976,577, 5,738,875, and 5,631,023) tend to be less dense and, thus, faster disintegrating. However, these tablets require a long time to make a tablet, and the process of lyophilization of the tablet formulation directly in the unit dose blister package renders a dosage form that is shaped on only one face. The amount of drug loading in this lyophilization process is also limited. The present invention relates to a new process for manufacturing tablets, such as orally disintegrating tablets (“ODTs”) utilizing lossy coated particles where the lossy coating comprises an activator that is used to sinter to particles to form the tablet. As this process concentrates the activator on the surface of the particle, the amount of activator added to the tablet can be reduced and the sintering of particles can be improved, resulting in tablet properties such as improved friability, better mouthfeel, faster disintegration, higher pharmaceutically active agent loading, and/or shorter manufacturing time as compared to tablets those made by other similar processes such US Patent Application Nos. 2009/0060983, 2011/0071184, and 2013/0295175 as set forth herein.
<SOH> SUMMARY OF THE INVENTION <EOH>In one aspect, the present invention features a process for making a tablet comprising at least one pharmaceutically active agent, said method comprising the step of applying radiofrequency energy to a powder blend to sinter said powder blend into said tablet, wherein said powder blend comprises lossy coated particles and said at least one pharmaceutically active agent, wherein said lossy coated particles comprises a substrate that is at least partially coated with a lossy coating comprising at least one activator, wherein said substrate has a Q value of greater than 100 and said activator has a Q value of less than 75. In another aspect, the present invention features a process for making a tablet comprising at least one pharmaceutically active agent, said method comprising the step of applying radiofrequency energy to a powder blend to sinter said powder blend into said tablet, wherein said powder blend comprises lossy coated particles and said at least one pharmaceutically active agent, wherein said lossy coated particles comprise of a substrate that is at least partially coated with a lossy coating comprising at least one activator, wherein the Q value of the activator is less than half the Q value of the substrate. In another aspect, the sintered tablet comprising lossy coated particles and at least one pharmaceutically active agent, wherein said lossy coated particles comprise a substrate that is at least partially coated with a lossy coating comprising at least one activator, wherein said substrate has a Q value of greater than 100 and said activator has a Q value of less than 75. In another aspect, the sintered tablet comprising lossy coated particles and at least one pharmaceutically active agent, wherein said lossy coated particles comprise a substrate that is at least partially coated with a lossy coating comprising at least one activator, wherein the Q value of the activator is less than half the Q value of the substrate. Other features and advantages of the present invention will be apparent from the detailed description of the invention and claims. detailed-description description="Detailed Description" end="lead"?
A61K92095
20170829
20171214
80807.0
A61K920
0
VANHORN, ABIGAIL LOUISE
Process for Making Tablet Using Radiofrequency and Lossy Coated Particles
UNDISCOUNTED
1
CONT-REJECTED
A61K
2,017
15,689,491
PENDING
BOOTSTRAPPED SWITCHING CIRCUIT
The trend in wireless communication receivers is to capture more and more bandwidth to support higher throughput, and to directly sample the radio frequency (RF) signal to enable re-configurability and lower cost. Other applications like instrumentation also demand the ability to digitize wide bandwidth RF signals. These applications benefit from input circuitry which can perform well with high speed, wide bandwidth RF signals. An input buffer and bootstrapped switch are designed to service such applications, and can be implemented in 28 nm complementary metal-oxide (CMOS) technology.
1. A bootstrapped switching circuit with accelerated turn on, comprising: a sampling switch receiving a voltage input signal and a gate voltage; a bootstrapped voltage generator comprising a positive feedback loop to generate the gate voltage for turning on the sampling switch, said positive feedback loop comprising an input transistor receiving the voltage input signal and an output transistor outputting the gate voltage of the sampling switch; and a jump start circuit to turn on the output transistor for a limited period of time during which the input transistor is turning on at a startup of the positive feedback loop. 2. The bootstrapped switching circuit of claim 1, wherein the jump start circuit is coupled to a gate of the output transistor. 3. The bootstrapped switching circuit of claim 1, wherein the jump start circuit ceases to turn on the output transistor after the limited period of time and allows the positive feedback loop to operate. 4. The bootstrapped switching circuit of claim 1, wherein: the jump start circuit comprises a transistor receiving a clock signal used for activating the positive feedback loop; and the transistor is turned on by a delayed version of the clock signal to output the clock signal to turn on the output transistor for the limited period of time. 5. The bootstrapped switching circuit of claim 4, wherein the jump start circuit further comprises two inverters for generating the delayed version of the clock signal based on the clock signal. 6. The bootstrapped switching circuit of claim 1, wherein: the jump start circuit comprises a switch for connecting a gate of the output transistor to a bias voltage for turning on the output transistor; and the switch is controlled by a control signal having a pulse to close the switch. 7. The bootstrapped switching circuit of claim 1, wherein: the jump start circuit comprises a sense circuit for activating the jump start circuit based on one or more conditions of the bootstrapped switching circuit indicating the startup of the positive feedback loop. 8. The bootstrapped switching circuit of claim 7, wherein the sense circuit senses a voltage representing a voltage level at a node in the bootstrapped switching circuit. 9. The bootstrapped switching circuit of claim 8, wherein the node is at a node in the positive feedback loop. 10. The bootstrapped switching circuit of claim 8, wherein the sense circuit comprises a comparator comparing the voltage against a predetermined threshold indicating the startup of the positive feedback loop. 11. The bootstrapped switching circuit of claim 1, wherein: the positive feedback loop comprises a boot capacitor; and the positive feedback loop turns on the sampling switch by bringing the gate voltage to a boosted voltage generated based on the voltage input signal and a voltage across the boot capacitor. 12. The bootstrapped switching circuit of claim 11, wherein: the input transistor is coupled to a first plate of the boot capacitor; and the output transistor is coupled to a second plate of the boot capacitor. 13. The bootstrapped switching circuit of claim 1, wherein: the input transistor is driven by the gate voltage of the sampling switch; and the positive feedback loop further comprises a first transistor coupled to a gate of the output transistor and a drain of the input transistor, wherein the first transistor is driven by the gate voltage of the sampling switch. 14. The bootstrapped switching circuit of claim 1, wherein the positive feedback loop further comprises: an additional transistor coupled to a gate of the output transistor and a drain of the input transistor, wherein the additional transistor is controlled by a clock signal which activates the positive feedback loop. 15. A method for accelerated turn on of a sampling switch, comprising: outputting, by an output transistor of a positive feedback loop, an output voltage of a bootstrapped voltage generator for driving the sampling switch; pulling a gate voltage of the output transistor to an on-voltage level to turn on the output transistor for a period of time after the positive feedback loop is activated; and ceasing the pulling of the gate voltage after the period of time. 16. The method of claim 15, wherein: the sampling switch receives a voltage input signal; and the positive feedback loop receives the voltage input signal at an input transistor driven by the output voltage output by the output transistor, and generates a boosted voltage signal based on the voltage input signal as the output voltage of the bootstrapped voltage generator to turn on the sampling switch when the positive feedback loop is engaged. 17. The method of claim 15, wherein: pulling the gate voltage of the output transistor comprises changing the gate voltage from an off-voltage level to an on-voltage level. 18. The method of claim 15, further comprising: allowing the positive feedback loop to bring the gate voltage to a voltage level of a voltage input signal provided to the bootstrapped voltage generator and the sampling switch after the period of time. 19. The method of claim 15, further comprising: sensing one or more conditions indicating the positive feedback loop has been activated; and generating a control signal in response to sensing the one or more conditions, wherein the control signal triggers the pulling of the gate voltage of the output transistor. 20. An apparatus comprising: sampling means receiving an input signal to be sampled and a control signal which turns the sampling means on and off; means for generating a boosted voltage based on the input signal; output means for outputting the control signal; means for bringing the control signal to the boosted voltage through positive feedback action of the control signal; and means for turning on the output means for a limited period of time at a startup of the positive feedback action.
PRIORITY DATA AND RELATED APPLICATIONS This patent application receives benefit from and/or claim priority to U.S. Provisional Patent Application Ser. No. 62/393,529, filed on Sep. 12, 2016, entitled “INPUT BUFFER AND BOOTSTRAPPED SWITCHING CIRCUIT”. This U.S. Provisional Patent Application is incorporated by reference in its entirety. TECHNICAL FIELD OF THE DISCLOSURE The present disclosure relates to the field of integrated circuits, in particular to input circuitry for analog-to-digital converters (ADCs). BACKGROUND In many electronics applications, an analog-to-digital converter (ADC) converts an analog input signal to a digital output signal, e.g., for further digital signal processing or storage by digital electronics. Broadly speaking, ADCs can translate analog electrical signals representing real-world phenomenon, e.g., light, sound, temperature, electromagnetic waves, or pressure for data processing purposes. For instance, in measurement systems, a sensor makes measurements and generates an analog signal. The analog signal would then be provided to an analog-to-digital converter (ADC) as input to generate a digital output signal for further processing. In another instance, a transmitter generates an analog signal using electromagnetic waves to carry information in the air or a transmitter transmits an analog signal to carry information over a cable. The analog signal is then provided as input to an ADC at a receiver to generate a digital output signal, e.g., for further processing by digital electronics. Due to their wide applicability in many applications, ADCs can be found in places such as broadband communication systems, audio systems, receiver systems, etc. Designing circuitry in ADC is a non-trivial task because each application may have different needs in performance, power, cost, and size. ADCs are used in a broad range of applications including Communications, Energy, Healthcare, Instrumentation and Measurement, Motor and Power Control, Industrial Automation and Aerospace/Defense. As the applications needing ADCs grow, the need for fast yet accurate conversion also grows. BRIEF DESCRIPTION OF THE DRAWINGS To provide a more complete understanding of the present disclosure and features and advantages thereof, reference is made to the following description, taken in conjunction with the accompanying figures, wherein like reference numerals represent like parts, in which: FIG. 1 shows a front end to an analog-to-digital converter, according to some embodiments of the disclosure; FIG. 2 shows a bootstrapped switching circuit, according to some embodiments of the disclosure; FIG. 3 shows a bootstrapped switching circuit having accelerated turn on, according to some embodiments of the disclosure; FIGS. 4A-B show an exemplary implementation for a jump start circuit, according to some embodiments of the disclosure; FIGS. 5A-C show another exemplary implementation for a jump start circuit, according to some embodiments of the disclosure; FIG. 6 is a flow diagram illustrating a method for accelerated turn on of a sampling switch; FIG. 7 shows an exemplary input buffer, according to some embodiments of the disclosure; FIG. 8 shows an exemplary level shifter, according to some embodiments of the disclosure; FIG. 9 shows another exemplary input buffer, according to some embodiments of the disclosure; and FIG. 10 is a flow diagram for buffering an input signal, according to some embodiments of the disclosure. DESCRIPTION OF EXAMPLE EMBODIMENTS OF THE DISCLOSURE Overview The trend in wireless communication receivers is to capture more and more bandwidth to support higher throughput, and to directly sample the radio frequency (RF) signal to enable re-configurability and lower cost. Other applications like instrumentation also demand the ability to digitize wide bandwidth RF signals. These applications benefit from input circuitry which can perform well with high speed, wide bandwidth RF signals. An input buffer and bootstrapped switch are designed to service such applications, and can be implemented in 28 nm complementary metal-oxide (CMOS) technology. High Speed Analog-To-Digital Converters ADCs are electronic devices that convert a continuous physical quantity carried by an analog signal to a digital output or number that represents the quantity's amplitude (or to a digital signal carrying that digital number). An ADC can be defined by the following application requirements: its bandwidth (the range of frequencies of analog signals it can properly convert to a digital signal) and its resolution (the number of discrete levels the maximum analog signal can be divided into and represented in the digital signal). An ADC also has various specifications for quantifying ADC dynamic performance, including signal-to-noise-and-distortion ratio SINAD, effective number of bits ENOB, signal to noise ratio SNR, total harmonic distortion THD, total harmonic distortion plus noise THD+N, and spurious free dynamic range SFDR. Analog-to-digital converters (ADCs) have many different designs, which can be chosen based on the application requirements and specifications. High speed applications are particularly important in communications and instrumentation. The input signal can have a frequency in the gigahertz range, and the ADC may need to sample in the range of Giga-samples per second. High frequency input signals can impose many requirements on the circuits receiving the input signal, i.e., the “front end” circuitry of the ADC. The circuit not only has to be fast, for some applications, the circuit needs to meet certain performance requirements, such as SNR and SFDR. Designing an ADC that meets both speed and performance requirements is not trivial. FIG. 1 shows a front end to an analog-to-digital converter, according to some embodiments of the disclosure. Typically, an input signal VIN (e.g., a high frequency input signal in the gigahertz range) is provided to an input buffer 102. The output VINX of the input buffer is then provided to a sampler 106 where the input signal, in the form of VINX from the output of the input buffer, is sampled onto a sampling capacitor CS 112 A transistor MN 108 (e.g., an N-type complementary metal-oxide field-effect (CMOS) transistor, or NMOS transistor) is provided to allow the input signal VINX to be provided to the sampling capacitor CS. Transistor MN 108 is sometimes referred herein as the sampling switch. During sampling, transistor MN 108 is turned on, and switch 110 is closed. The output VINX of the input buffer may pass through a transmission line (“T-LINE”) 104 going from the output of the input buffer 102 to the sampler 106. In some cases where the ADC includes a plurality of ADCs in parallel (e.g., where the ADC is a time-interleaved ADC or a randomized time-interleaved ADC), there are multiple (matched) samplers, including sampler 106, in parallel. Multiple (matched) transmission lines can be included to provide the output signal VINX from a common input buffer 102 to each sampler. Time-interleaved ADCS or randomized time-interleaved ADCs can sample the input signal VINX one at a time. In some cases, a reference ADC and one of the time-interleaved ADCs sample the output signal VINX at substantially the same time. For time-interleaved ADCs or randomized time-interleaved ADCs, some of the samplers may be off at any given time while one or more samplers loads the input buffer. To reduce degradation of SFDR, the back gates of the transistors in the samplers coupled to receive the input signal VINX (e.g., transistor MN 108) can be tied to a negative voltage, such as −1 volts, to minimize the non-linearity in those transistors. Bootstrapped Switching Circuit Referring back to FIG. 1, the timing of the transistor MN 108 turning on quickly enough to allow VINX to be sampled onto the sampling capacitor CS 112 is critical, especially for high speed applications. Consider an example where an ADC has a sampling rate of 10 Giga-samples per second, the transistor MN 108 must turn on quickly enough to allow sampling of the input signal VINX onto sampling capacitor Cs 112 with only a hundred of picoseconds between samples. The timing for turning on transistor MN 108 can depend on the inherent transistor characteristics of transistor MN 108, and also on the signal VBSTRP driving MN 108 at the gate with respect to the signal VINX at the source. Examples herein are described where signals are referred to as going high or going low, which refers to different logic levels of the signals. FIG. 2 shows a bootstrapped switching circuit 200, according to some embodiments of the disclosure. The bootstrapped switching circuit includes the transistor MN 108 from FIG. 1, which receives input signal VINX at its source, and its drain is connected to one plate of sampling capacitor (e.g., sampling capacitor Cs 112 of FIG. 1). The bootstrapped switching circuit also includes a bootstrapped gate voltage generator (circuit) for generating a gate voltage signal VBSTRP driving the gate of transistor MN 108 (the sampling switch). The bootstrapped gate voltage generator generates the gate voltage signal VBSTRP in a manner that ensures the transistor MN 108 is turned on quickly. The bootstrapped gate voltage generator can receive VINX, and include a boot capacitor for generating a boosted voltage of VINX+VBOOT. The bootstrapped gate voltage generator has a positive feedback loop. The positive feedback loop takes VINX as input to the positive feedback loop, and the positive feedback loop includes the boot capacitor in the positive feedback loop path. An output of the positive feedback loop generates the gate voltage signal VBSTRP driving the gate of transistor MN 108 (the sampling switch). The positive feedback loop serves to bring the gate voltage signal VBSTRP high quickly to ensure fast turn on of the transistor MN 108. The positive feedback loop is bootstrapped to the input signal VINX, where the goal of the positive feedback loop is to drive gate voltage signal VBSTRP to be VINX plus the voltage VBOOT (VBOOT being the voltage across the boot capacitor CBOOT) to turn on transistor MN 108. Specifically, the positive feedback loop drives the gate voltage signal VBSTRP to be high enough to cause sufficient voltage VGS across the gate and the source for transistor MN 108 to turn on. The bootstrapped gate voltage generator is driven by a clock signal CLK, and CLKB being the inverted version of CLK. The bootstrapped gate voltage generator can also receive a charging phase clock signal CLKBBST, which controls the timing of a charging phase of the boot capacitor CBOOT. The transistor MN 108 is expected to turn on quickly when CLK goes high, and transistor MN 108 is expected to turn off when CLK goes low. During the charging phase (CLKB and CLKBBST are both high), transistors MN 224 and transistor MN 210 (e.g., NMOS transistors) are turned on to charge a voltage VBOOT across boot capacitor CBOOT (e.g., VBOOT=VDD−VSS). Turning transistor MN 224 on connects top plate of capacitor CBOOT to VDD. Turning transistor MN 210 on connects the bottom plate of capacitor CBOOT to VSS. If VSS is ground, then the boot capacitor CBOOT is charged to VDD. Just before the positive feedback loop is activated, node X was at VDD since CLK was low in the previous phase (charging phase). CLK drives the gate of transistor MP 214 (e.g., a P-type complementary metal-oxide field-effect (CMOS) transistor, or PMOS transistor). CLK being low would make the transistor MP 214 on. When transistor MP 214 was on, the drain of transistor MP 214 (which is node X) was at VDD. When node X was at VDD and CLKB was high, transistor MP 202 (e.g., PMOS transistor) is off. Herein, transistor MP 202 can be referred to as the output transistor which outputs VBSTRP driving the gate of transistor MN 108 (the sampling switch). VBSTRP was at a low state, which keeps sample switch, i.e., transistor MN 108 off. CLK going from low to high (or CLKB goes from high to low) activates the positive feedback loop. When CLKB driving the gate of transistor MP 204 (e.g., PMOS transistor) goes low (i.e., CLK goes high), transistor MP 204 (e.g., PMOS transistor) is turned on, pulling the drain of MN 208 (e.g., NMOS transistor) close to VDD (goes high) and pulling the drain of MN 206 (e.g., NMOS transistor) high (e.g., VDD), which in turns makes the VBSTRP node go high. VBSTRP drives the gates of transistors MN 216 (e.g., NMOS transistor) and MN 212 (e.g., NMOS transistor). Transistor MN 212 can be referred to as the input transistor since transistor MN 212 receives the input signal VINX. VBSTRP going high can turn on transistor MN 216 (e.g., NMOS transistor) and transistor MN 212 (e.g., NMOS transistor). Meanwhile, transistor MP 214 has been turned off since CLK went high. Effectively, through the on transistors MN 216 and MN 212, the gate of transistor MP 202, i.e., node X, gets tied to VINX. In a previous phase (i.e., the charging phase), boot capacitor CBOOT is charged to have VBOOT across the boot capacitor. When the positive feedback loop is engaged, the gate of transistor MP 202 can have VINX, the source of transistor MP 202 can have a voltage of VINX+VBOOT. Transistor MP 202 turns on, making VBTSTRP rise to VINX+VBOOT, which increases the voltage across the gate and the source VGS (i.e., VBSTRP−VINX=VBOOT) of the sampling switch, i.e., transistor MN 108, to turn on. As VBTSTRP rises, the positive feedback of VBTSTRP rising loops through transistors MN 216 and MN 212, which again in turn keeps VBSTRP rising further to turn on transistor MN 108. As a result, the positive feedback loop enables a fast turn on of transistor MN 108. In some cases, at the startup of the positive feedback loop when the gate of transistor MP 202, i.e., node X, is getting tied to VINX, the two transistors MN 216 and MN 212 in the positive feedback loop assisting in the action of bringing node X, can be slow to turn on, which greatly slows down the positive feedback loop when node X does not get tied to VINX quickly enough. Consider when VINX (i.e., at the source of transistor MN 212) is close to VDD at a particular instant in time, and the gate of transistor MN 216 and the gate of transistor MN 212 (i.e., the VBSTRP node) is also close to VDD as soon as CLKB goes low at the startup (startup meaning CLKB has just became low, or CLK has just became high). Node X is also at VDD at the start up (since CLK was low, and node X is at VDD via transistor MP 214). This scenario can make all terminals of the transistor MN 216 at roughly VDD. The transistors MN 216 and MN 212 might not see enough voltage across the gate and the source (VGS) of the respective transistors to turn on. Therefore transistors MN 216 and MN 212 would barely/weakly turn on since there is not enough VGS, slowing down the positive feedback action of the loop. The loop eventually works as transistors MN 216 and MN 212 turns on more fully to pull node X closer to VINX to turn on transistor MP 202, which serves to allow VINX+VBOOT to pass through transistor MP 202 towards the gate of transistor MN 108 and making VBSTRP rise. Jumpstarting the Positive Feedback Loop To address this slowdown of the positive feedback loop, a jump start circuit can be included to quickly turn on transistor MP 202 (the output transistor) at the startup of the positive feedback loop action to allow VINX+VBOOT to pass through transistor MP 202 towards the gate of transistor MN 108 more quickly, causing VBSTRP to rise more quickly, which in turn can turn on transistors MN 216 and MN 212 faster. The result is a much faster bootstrapped switching circuit. FIG. 3 shows a bootstrapped switching circuit 300 having accelerated turn on, according to some embodiments of the disclosure. The bootstrapped switching circuit 300 has a sampling switch, e.g., transistor MN 108, receiving a voltage input signal, e.g., VINX, and a gate voltage, e.g., VBTSTRP. The bootstrapped switching circuit also has a bootstrapped voltage generator. The bootstrapped voltage generator generates the gate voltage, e.g., VBTSTRP, for the sampling switch. The bootstrapped switching circuit comprises a positive feedback loop to generate the gate voltage for turning on the sampling switch. The positive feedback loop can include an input transistor, e.g., transistor MN 212, receiving the voltage input signal, e.g., VINX, and an output transistor, e.g., transistor MP 202, outputting the gate voltage of the sampling switch. The positive feedback loop comprises a boot capacitor, e.g., CBOOT, which can be used to generate a boosted voltage, e.g., VINX+VBOOT. Because the sampling switch, e.g., transistor MN 108, has VINX at its source, the boosted voltage being at the gate of the sampling switch would turn on the sampling switch. In other words, the positive feedback loop turns on the sampling switch, e.g., transistor MN 108, by bringing the gate voltage to the boosted voltage generated based on the voltage input signal VINX and the voltage across the boot capacitor CBOOT. The input transistor, e.g., source of transistor MN 212, is coupled to a first plate of the boot capacitor. The output transistor, e.g., source of transistor MP 202, is coupled to a second plate of the boot capacitor. The positive feedback loop operates by using the gate voltage as positive feedback to drive the transistors in the loop, e.g., transistors MN 212 and MN 216. Those transistors in turn bring the gate voltage of the output transistor, e.g., transistor MP 202, to VINX and assists the output transistor, e.g., transistor MP 202, with passing the boosted voltage or bringing the gate voltage to the boosted voltage. The boosted voltage can turn on the sampling switch, e.g., transistor MN 108. For the exemplary positive feedback loop shown, the input transistor, e.g., transistor MN 212, is driven by the gate voltage VBSTRP of the sampling switch, e.g., transistor MN 108. The positive feedback loop further comprises a first transistor, e.g., transistor MN 216, coupled to the gate of the output transistor, e.g., transistor MP 202, and a drain of the input transistor, e.g., transistor MN 212. The first transistor is also driven by the gate voltage of the sampling switch as well. Together, the first transistor and the input transistor, when turned on, brings node X to VINX during the positive feedback loop action. The bootstrapped switching circuit also includes a jump start circuit 302 to turn on the output transistor for a limited period of time during which the input transistor is turning on at a startup of the positive feedback loop. The jump start circuit 302 is coupled to node X, e.g., at the gate of transistor MP 202, where transistor MP 202 is the output transistor of the positive feedback loop. In some embodiments, the jump start circuit 302, e.g., provides/outputs a signal at node X, to turn on the transistor MP 202 momentarily when CLKB goes low to jump start the positive feedback loop action. The jump start circuit 302 ceases to turn on the output transistor, e.g., transistor MP 202, after the limited period of time and allows the positive feedback loop to operate. Phrased differently, the jump start circuit 302 engages the output transistor MP 202 for when the positive feedback loop action begins, and disengages from the output transistor MP 202 so that the positive feedback loop action can engage to drive the output transistor MP 202 (allowing the positive feedback loop action to bring node X to VINX). This jump start circuit 302 can help the positive feedback loop move faster during the (short period of) time when transistors MN 216 and MN 212 are slow to turn on. The jump start circuit 302 can jump start the positive feedback loop action by pulling the node X towards a low logic level (e.g., ground or some other bias voltage) momentarily at the gate of transistor MP 202 so that transistor MP 202 turns on to allow VINX+VBOOT (i.e., top plate voltage of the boot capacitor CBOOT) to pass through output transistor MP 202 towards the gate of transistor MN 108 more quickly, causing VBSTRP to rise more quickly. Note that jump start circuit 302 only pulls the node X towards a low logic level momentarily but preferably does not let node X get to ground or a low logic level completely. Pulling node X to ground completely can cause unwanted stress on transistor MP 202, since the source of transistor MP 202 sees VINX+VBOOT. Furthermore, the jump start circuit 302 quickly “lets go” of node X (or cease the pulling of node X towards the low logic level) to allow the positive feedback loop to operate, and preferably “lets go” prior to transistors MN 216 and MN 212 engaging fully to tie node X to VINX. The timing of the jump start circuit 302 can vary depending on the implementation. At the startup of the positive feedback loop, and just prior to CLKB going low, node X is at VDD to keep output transistor MP 202 off when boot capacitor CBOOT is charging and to keep VBSTRTP low. However, when node X starts at VDD at the startup of the positive feedback loop action, node X slows down the feedback mechanism. The jump start circuit 302 quickly turns on transistor MP 202 by pulling node X towards a suitable logic level so that node X starting at VDD no longer impedes the speed of the feedback loop action. In some cases, an additional transistor MN 218 (e.g., NMOS transistor), with its gate connected to CLK, its source connected to the drain of input transistor, e.g., transistor MN 212 (and the source of transistor MN 216), and its drain connected to node X (i.e., gate of the output transistor MP 202), can be included to assist tying node X to VINX during the positive feedback loop action. The additional transistor is controlled by a clock signal which activates the positive feedback loop, e.g., CLK. Transistor MN 218 is on when CLK goes high at the startup to assist tying node X to VINX, in an attempt to overcome the slow turn on of transistor MN 216. The jump start circuit 302 operates differently from the additional transistor MN 218, and the jump start circuit 302 can provide a greater amount of increase in speed of the bootstrapped switching circuit than the additional transistor MN 218 alone. The timing of pulling down node X towards a low logic level and quickly letting go take into account or depend on factors such as the circuit design, the process in which the circuit is fabricated, and parasitics in the bootstrapped switching circuit. The timing can be determined from simulations or testing of the circuit. The timing can be variable or controllable. In some cases, the timing can depend on one or more voltage levels or signals in the bootstrapped switching circuit, which may indicate when the jump start circuit 302 should begin the pull down action and/or cease the pull down action. If the transistor MP 202 is an NMOS transistor (in a complementary/equivalent implementation), the jump start circuit 302 can provide a momentary pull up function to quickly jump start the feedback loop. Exemplary Implementations of the Jump Start Circuit FIGS. 4A-B show an exemplary implementation for a jump start circuit, according to some embodiments of the disclosure. In this example shown in FIG. 4A, the jump start circuit includes a transistor MN 404 (e.g., NMOS transistor). Transistor MN 404 receives CLKB (used for activating the positive feedback loop, in the form of CLK and CLKB) at the source and CLKBDEL at the gate. CLKB goes low at the startup of the positive feedback loop. CLKBDEL is a delayed version of CLKB, and thus for a short period of time, CLKBDEL remains high when CLKB goes low. During this period of time, CLKBDEL being high when CLKB is low turns on transistor MN 404 and pulls node X towards CLKB's low logic level (e.g., ground). When the delay period is over, CLKBDEL goes low to turn transistor MN 404 off. This jump start circuit effectively pulls node X towards a low logic level and quickly lets go of node X to allow the positive feedback loop to continue its operation. In other words, the transistor is turned on by a delayed version of the clock signal to output the clock signal to turn on the output transistor for the limited period of time. As illustrated by FIG. 4B, the jump start circuit can include two inverters for generating the delayed version of the clock signal CLKBDEL based on the clock signal CLKB. As result, CLKBDEL can have the same polarity of CLKB but with two inverter delays. Other implementations for generating CLKBDEL with a desired amount of delay are envisioned by the disclosure, including using a pass gate, resistor-capacitor delay circuits, etc. The implementation shown in FIG. 4B is not meant to be limiting. FIGS. 5A-C show another exemplary implementation for a jump start circuit, according to some embodiments of the disclosure. In this example shown in FIG. 5A, the jump start circuit includes a switch 501 controlled by control signal CTRL. The switch 501 connects a gate of the output transistor (e.g., transistor MP 202) to a bias voltage VON for turning on the output transistor. The control signal can have a pulse to close the switch 501. The pulse can serve to jump start the output transistor for a limited period of time (pulling the gate to the bias voltage and letting go of the gate to allow the positive feedback loop to operate). FIG. 5B shows an exemplary waveform for the control signal CTRL, which has a short pulse used to close the switch and pull node X towards bias voltage VON and quickly lets go of node X (opening the switch and disconnecting node X from VON) to allow the positive feedback loop to continue its operation. Voltage VON can be a suitable bias voltage for turning transistor MP 202 on, e.g., ground, or some other suitable voltage level. Switch 501 can be implemented using transistor(s). In some embodiments, the jump start circuit includes a sense circuit 502 (as shown in FIG. 5C) so that a closed loop delay can be implemented. The sense circuit activates the jump start circuit based on one or more conditions of the bootstrapped switching circuit indicating the startup of the positive feedback loop. A closed loop delay means that the control signal CTRL, or the timing of the jump start circuit for pulling node X to a low logic level and/or letting go of node X can be depend on one or more conditions of the bootstrapped switching circuit. Preferably, the one or more conditions indicate the startup of the positive feedback loop. The sense circuit 502 can sense a voltage VSENSE and generate the control signal CTRL accordingly. The voltage VSENSE can represent a voltage level at any suitable node in the bootstrapped switching circuit. The node can be a node in the positive feedback loop. In one example, the sense circuit 502 includes a comparator coupled the source of the transistor MP 202 to compare the voltage at the source of the transistor MP 202 against a predetermined threshold, or another node in the positive feedback loop. The voltage passing across the predetermined threshold can indicate the startup of the positive feedback loop. If the voltage (e.g., the source of the transistor) rises above the predetermined threshold (indicating the positive feedback loop has begun its operation), the output of the comparator can trigger the control signal CTRL accordingly to shut off the jump start action. A Method for Accelerated Turn on of a Sampling Switch FIG. 6 is a flow diagram illustrating a method for accelerated turn on of a sampling switch. In 602, an output transistor (e.g., transistor MP 202 of FIG. 3) of a positive feedback loop, outputs an output voltage (e.g., VBSTRP of FIG. 3) of a bootstrapped voltage generator for driving the sampling switch (e.g., transistor MN 108 of FIG. 3). In some embodiments, the sampling switch receives a voltage input signal (e.g., VINX to be sampled). The positive feedback loop can receive the voltage input signal at an input transistor (e.g., transistor MN 212 of FIG. 3) driven by the output voltage (e.g., VBSTRP of FIG. 3) output by the output transistor. The positive feedback loop can generate a boosted voltage signal (e.g., bootstrapped voltage of VINX+VBOOT) based on the voltage input signal as the output voltage of the bootstrapped voltage generator to turn on the sampling switch when the positive feedback loop is engaged. In 604, a jump start circuit can pull a gate voltage of the output transistor (e.g., node X of FIG. 3) to an on-voltage level to turn on the output transistor for a period of time after the positive feedback loop is activated. In some embodiments, pulling the gate voltage of the output transistor includes changing the gate voltage from an off-voltage level to an on-voltage level. Before the positive feedback action is engaged, the gate voltage can be at VDD as illustrated by FIGS. 2 and 3, which is considered an “off-voltage level” for transistor MP 202. The jump start circuit can momentarily pull the gate voltage to an “on-voltage level”, such as a logical low voltage level to turn on the output transistor for a short period of time. In 606, the jump start circuit can cease or stop the pulling of the gate voltage after the period of time. For instance, the jump start circuit can release the gate voltage of the output transistor back to a voltage being delivered by the positive feedback loop after the period of time. For instance, the jump start circuit can let the positive feedback loop operate and bring the gate voltage close to the input signal VINX to be sampled. In some embodiments, ceasing the pulling of the gate voltage after the period of time or releasing the gate voltage of the output transistor after the period of time includes allowing the positive feedback loop to bring the gate voltage to a voltage level of a voltage input signal (e.g., VINX) provided to the bootstrapped voltage generator and the sampling switch. In some embodiments, a sense circuit (e.g., sense circuit 502 of FIG. 5C) can sense one or more conditions indicating the positive feedback loop has been activated. The sense circuit can generate a control signal in response to sensing the one or more conditions. The control signal can trigger triggers the pulling of the gate voltage of the output transistor. An Apparatus for Accelerated Turn on of a Sampling Switch For accelerated turn on of a sampling switch, an apparatus can include sampling means (e.g., transistor MN 108 of FIG. 3) receiving an input signal (e.g., VINX of FIG. 3) to be sampled and a control signal (e.g., VBSTRP of FIG. 3) which turns the sampling means on and off. The apparatus can further include means (e.g., transistor MN 210, CBOOT, and transistor MN 224 of FIG. 3) for generating a boosted voltage signal based on the input signal (e.g., bootstrapped voltage of VINX+VBOOT). The apparatus can include output means for outputting the control signal (e.g., transistor MP 202 of FIG. 3). The apparatus can include means for bringing the control signal to the boosted voltage through positive feedback action of the control signal, as illustrated by FIGS. 2 and 3. The apparatus can include means (e.g., jump start circuit 302 of FIG. 3 and associated examples seen in FIGS. 4A-B and 5A-C) for turning on the output means for a limited period of time at a startup of the positive feedback action. Input Buffer CMOS input buffers (single ended) can include a stack of NMOS transistors and a current source. The voltage input to the input buffer can be directly connected to a gate of the NMOS transistor (whose source is connected to the current source), and the source of the NMOS transistor is the output. In this kind of input buffer, the output is shifted by one voltage across the gate and the source VGS downwards via the NMOS transistor buffering the voltage input from its gate to its source, i.e., the output. This voltage shift from the input to the output means that the output voltage range depend on the input voltage range. Phrased differently, there is an offset between the input voltage and the output voltage. If the input buffer is driving circuits that require a particular voltage range, this offset can be undesirable or cumbersome to address in the circuit design. FIG. 7 shows an exemplary input buffer, according to some embodiments of the disclosure. The input buffer can be used in the manner illustrated by FIG. 1. The input buffer has an input VIN for receiving a voltage input signal. The voltage input signal can be a high frequency data signal to be converted by a data converter, such as a high speed ADC. The input buffer includes a push pull circuit outputting a voltage output signal at an output VINX. The push pull circuit comprises a first transistor of a first type, and a second transistor of a second type complementary to the first type. For instance, the first transistor can be transistor MN 702 (e.g., NMOS transistor) and the second transistor can be transistor MP 704 (e.g., PMOS transistor). The sources of the two transistors are coupled to each other, and the sources also serves as the output VINX of the input buffer providing output signal VINX. For this input buffer, the transistors MN 702 and MP 704 are not directly connected to the input VIN. Rather, the gate of transistor MN 702 is connected to the input VIN via level shifter 703, and the gate of transistor MP 704 is connected to the input VIN via level shifter 705. In some embodiments, the input buffer can include a first level shifter coupled to the input for shifting a voltage level of the voltage input signal by a first amount of voltage shift across the first level shifter and generating a first level shifted voltage signal to bias the first transistor. For example, level shifter 703 can shift VIN by a first amount of voltage shift (e.g., up by some amount of voltage) across the level shifter 703 and generate a first level shifted voltage V1 to bias the first transistor, i.e., transistor MN 702. In some embodiments, the input buffer can include a second level shifter coupled to the input for shifting the voltage level of the voltage input signal by a second amount of voltage shift across the second level shifter and generating a second level shifted voltage signal to bias the second transistor. For example, level shifter 705 can shift VIN by a second amount of voltage shift (e.g., down by some amount of voltage) across the level shifter 705 and generate a second level shifted voltage V2 to bias the second transistor, i.e., transistor MP 704. In this input buffer seen in FIG. 7, the input buffer has a push pull architecture. The push pull architecture has at least an NMOS transistor MN 702 and PMOS transistor MP 704, whose source is connected to the source of a PMOS transistor MP 704. The sources are coupled together and forms the output VINX. For 28 nm CMOS process, PMOS and NMOS devices are complementary in behavior including bandwidth, capacitances, transconductance per unit current, etc. In some other processes, the PMOS transistors can have drastically different behavior than the NMOS transistors. This complementary push pull architecture using NMOS transistor(s) on one side and PMOS transistor(s) on the other side enables a complementary buffer to have the same behavior on the PMOS side and the NMOS side, in a process like the 28 nm CMOS process. The structure offers symmetric pull up and pull down characteristics, no matter which side is supplying a current to the output VINX to drive the load. The two sides are equal in strength, therefore achieving a symmetric pull up and pull down. From a distortion perspective, the complementary structure means that there can be less even order distortions (e.g., second order harmonics are reduced). Besides the symmetric behavior, the input buffer is efficient because the NMOS transistor MN 702 and PMOS transistor MP 704, for a given amount of current going through the transistors, effectively doubles the transconductance of the input buffer. For the same amount of current, the NMOS transistor MN 702 and PMOS transistor MP 704 enables the input buffer to get two transconductances in parallel. For this input buffer, it is not possible to tie the gates of NMOS transistor MN 702 and PMOS transistor MP 704 together, since shorting the gate of NMOS transistor MN 702 and PMOS transistor MP 704), neither transistor would turn on because there would not be any voltage across the gate and the source of either transistors (insufficient VGS). Therefore, at least one of the two level shifters 703 and 705 is provided between the gates of NMOS transistor MN 702 and PMOS transistor MP 704. The level shifters pulls the gates of the two transistors apart with sufficient difference in voltage across the gate and the source to keep the transistors on. Level shifter 703 and level shifter 705 connected to VIN can be considered as (programmable) voltage shifts to bias the NMOS transistor MN 702 and PMOS transistor MP 704 at the gates of the respective transistors. In other words, the first amount of voltage shift can be programmable, and the second amount of voltage shift can be programmable. As used herein, a level shifter is a circuit which shifts a voltage level of an input to the level shifter by an amount to generate a level shifted voltage level at the output of the level shifter. Biasing the NMOS transistor MN 702 and PMOS transistor MP 704, i.e., setting appropriate voltages V1 and V2, is not trivial. If the two gates are too far apart, too much current might flow through the two transistors. But the two gates are not far enough apart (without enough VGS for both transistors, i.e., less than two VGS's) the transistors might not be turned on enough. Preferably, a desirable amount of current flows through the transistors. To ensure that the transistors have the desirable amount of current flowing through the transistors, a replica bias block can be used to set the voltages of level shifter 703 and level shifter 705 to ensure the NMOS transistor MN 702 and PMOS transistor MP 704 are running at the desired current. Preferably, the difference in voltage between the gate of the NMOS transistor MN 702 and the gate of PMOS transistor MP 704 has to be at least two VGS, e.g., threshold voltage VGS of the NMOS transistor MN 702 and threshold VGS of the PMOS transistor MP 704, and set to ensure a desired amount of current is running through the NMOS transistor MN 702 and PMOS transistor MP 704. In some embodiments, a sum of the first amount of voltage shift (e.g., of level shifter 703) and the second amount of voltage shift (e.g., of level shifter 705) is at least a sum of a first threshold voltage of the first transistor (e.g., transistor MN 702) and a second threshold voltage of the second transistor (e.g., transistor MP 704). Input to Output Offset and Design Considerations for the Level Shifters As a result of level shifter(s), the input VIN and the output VINX are independent, and the voltage range for the input and the voltage range for the output no longer have to depend on each other or have to be the same. Any offset between the input and the output can be selected by implementing appropriate level shifters (i.e., implementing level shifters 703 and 705 appropriately). By selecting appropriate first amount of voltage shift and second amount of voltage shift, the voltage output signal at VINX can be offset or have an offset from the voltage input signal at VIN. In one example, the voltage input signal can be centered at 0.5 volts, and the voltage input signal can be centered at 0.25 volts. The input buffer is more flexible. In some cases, the input voltage at VIN and the output voltage at VINX can be roughly the same voltage. For instance, VIN goes up with level shifter 703, and down a gate to source voltage VGS of transistor MN 702 at the output VINX. VIN goes down with level shifter 705, and up a gate to source voltage VGS of transistor MP 704 at the output VINX. There is no input to output offset if appropriate level shifters are used. This feature is not available in other input buffers implementing a single source follower. However, the input to output offset does not have to be zero either. Having the two level shifters means that the voltage range of the input VIN can be different from the voltage range of the output VINX. With the two level shifters, as long as the difference in voltage between the gate of the NMOS transistor MN 702 and the gate PMOS transistor MP 704 is appropriate (i.e., biasing the transistors to have the desired current running through them), the input to output voltages can be adjusted to fit the application (e.g., if the offset is desirable). The input to output offset can be variable. Used herein, variable means different over time, or different from one application to another application. The voltage shifts being provided by the level shifters can also be variable (and vice versa). A degree of freedom of the input buffer is that the level shifters 703 and 705 can be adjusted to have the particular output voltage range or voltage level. In some embodiments, level shifters 703 and level shifters 705 (and other level shifters disclosed here) are variable or programmable. In some embodiments, one amount of voltage shift by a level shifter can differ from another amount of voltage shift by another level shifter in the input buffer. The amount of voltage shift can be user adjustable, and/or on-chip controllable. The amount of voltage shift can be optimized for other factors including distortions, electrostatic discharge (ESD), etc. In some cases, one of level shifters 703 and level shifters 705 can be entirely omitted, where either the voltage at the gate of NMOS transistor MN 702 or the voltage at the gate of PMOS transistor MP 704 is level shifted to achieve the appropriate voltage difference between the gates of the two transistors. Implementing a Level Shifter One aspect of the level shifter is its ability to provide an amount of voltage shift, from the input to the gate of the transistors, independent of input frequency, or all the way to DC (i.e., zero frequency or constant input VIN). In other words, the level shifted signal would follow the input VIN across all frequencies of the input. Some other level shifters would not have such a frequency response. The level shifter can be implemented in different ways. For instance, a level shifter can include one or more of the following: one or more current sources, one or more resistors, one or more transistors, one or more diodes, one or more diode-connected transistor, one or more capacitors, one or more batteries, and one or more non-linear resistor. In some embodiments, the level shifter includes means for providing a voltage shift which is controlled by an amount of current flowing through the level shifter, and can be independent of the input frequency. For instance, a diode-connected transistor can provide a voltage level shift which depends on a current flowing through the diode-connected transistor (the current can be provided by one or more current sources). In some embodiments, the level shifter can include switched capacitor circuits. Preferably, a level shifter is implemented using passive circuit elements (as opposed to active elements involving complementary transistors as followers that shifts up or down from the input). Passive circuit elements uses less current and can be less noisy and more linear than active circuit elements. Passive circuit elements can include diode connected transistor(s), resistor(s), capacitor(s) circuits, and suitable combination thereof. FIG. 8 shows an exemplary level shifter, according to some embodiments of the disclosure. The exemplary level shifter includes current sources, with a resistor and a capacitor in parallel between the current sources. For instance, a level shifter mentioned herein can include one or more current sources (e.g., I1 and I2), and a resistor (or resistive element, e.g., R) and a capacitor (or a capacitive element, e.g., C) in parallel with the resistor. The resistor and the capacitor in parallel with the resistor are between current sources I1 and I2. Other configurations of these circuit elements are envisioned by the disclosure. Any current provided by the current sources would flow through the resistor and capacitor in parallel. The resistor and the amount of current flowing through the resistor sets the voltage shift across the level shifter (voltage shift can equal to the amount of current multiplied by the resistance). In other words, an amount of current, flowing through the resistor and provided by the current sources, sets an amount of voltage shift across the level shifter. For a programmable level shifter, the amount of current can be programmable, or the amount of resistance of the resistor can be programmable. Any one of the level shifters can be implemented in the manner described and illustrated herein. Depending on the particular application or the level shifter, the values of the different components within the level shifters may vary. Bootstrapping Back Gates of the Main Transistors Achieving high performance for an input buffer, such as good linearity, is not trivial. In some embodiments, a first back gate of the first transistor (e.g., transistor MN 702) and a second back gate of the second transistor are coupled to the output VINX or follows the voltage output signal VINX. For instance, back gates (body) of the NMOS transistor MN 702 and PMOS transistor MP 704 are tied directly to the output VINX, i.e., the back gates are bootstrapped to the output node VINX. If the back gates of NMOS transistor MN 702 and PMOS transistor MP 704 are tied to some fixed voltage, e.g., ground and VDD, as the input VIN vary, the VGS of the two transistor would also vary. The change in voltage between the source and the back gate would change the VGS of the transistors. The variation could also modulate the threshold voltage VGS and the capacitance of the transistor. The variation(s) can cause distortions. To avoid this issue, the back gate NMOS transistor MN 702 and PMOS transistor MP 604 are tied or bootstrapped to the output VINX. For all values of the input signal VIN (and VINX following VIN), the voltage between the back gate and the source of the transistors is zero. VGS no longer varies as the input signal VIN varies. Capacitance in the transistor can be shorted. Performance is improved. The input buffer seen in FIG. 7 along with at least some of the features described so far can reduce of some of the non-linearities or variations (first order). Minimizing Capacitances to Improve Performance When the input buffer is driving a high frequency input signal VIN, it is preferable to minimize all the capacitances that matter, or at least make the capacitance constant. Or, if the capacitances are going vary, it is preferable to reverse bias the junction causing the capacitance as much as possible so that the variation in the capacitance is small, or at least make the voltage across the capacitor constant to reduce the variation. Reverse biasing the junction, i.e., the voltage dependent junction capacitor, as much as possible can make the capacitance smaller and less non-linear. Tying the back gate to the source (and output VINX) of transistor MN 702 creates a capacitance between the back gate and the deep N-well. The N-well is at a fixed potential, and the back gate is moving around with the signal. NMOS transistor MN 702 can be in its own isolated P-Well (back gate), which can be inside a deep N-well isolation region. A capacitance between a back gate and a deep N-well of a first transistor (e.g., transistor MN 702) can be reversed biased. For instance, the deep N-well can be tied to a high potential, so that the capacitance between the back gate (P) and the deep N-well (N) is as strongly reversed biased as possible (for reasons mentioned above). As a result, the undesirable effect of the capacitance can be reduced (e.g., making it more linear). The input buffer seen in FIG. 7 along with at least some of the features described so far can reduce of some of the non-linearities or variations (first order). Bootstrapped Cascodes to Improve Performance If the input buffer is made using 28 nm CMOS process technology, the output conductance, or the ratio of the conductance GDS to the transconductance GM is small and highly non-linear. This can make it undesirable to tie the drain of NMOS transistor MN 702 and the drain of PMOS transistor MP 704 to a fixed supply, because as the signal VIN or VINX moves up and down, that varies the voltage across the transistor, i.e., VDS (drain to source voltage), is moving up and down. This can cause, e.g., 25-40 dBs of distortion. One way to fix this distortion is to bootstrap the drain of NMOS transistor MN 702 and the drain of PMOS transistor MP 704 (e.g., the input VIN or the output VINX), so that it is no longer fixed to some supply voltage. FIG. 9 shows another exemplary input buffer, according to some embodiments of the disclosure. The push pull circuit of the input buffer further includes a third transistor of the first type (e.g., transistor MN 706) in cascode configuration with the first transistor (e.g., transistor MN 702), and a fourth transistor of the second type (e.g., transistor MP 708) in cascode configuration with the second transistor (e.g., transistor MP 704). One or more bootstrapped cascodes, e.g., transistors in cascode configuration with the first/second transistor can be provided to boost the effective output impedance and therefore SFDR. The cascodes can require the use of higher supply voltages to improve the performance of the input buffer. Additional cascodes further improves performance. The first cascode is transistor MN 706 (e.g., NMOS transistor), which is another follower tied to the input VIN. The gate of transistor MN 706 can be tied to the input VIN via level shifter 707 and level shifter 703 in series (as shown). In some embodiments, level shifter 707 can be directly coupled to the input VIN. The level shifter 707 or the level shifters 707 and 703 in series can serve as a third level shifter coupled to the input VIN for shifting the voltage level of the voltage input signal by a third amount of voltage shift across the third level shifter and generating a third level shifted voltage signal V3 to bias the third transistor, e.g., transistor MN 706. The first cascode MN 706, its gate is being driven by the input VIN (going up and down), has a specific level shifter 707 such that the output voltage (MN 706's source), provides enough VDS for transistor MN 702 to operate in saturation under all conditions. Transistor MN 706 is bootstrapped to the input VIN to isolate the transistor MN 702 from variation in VDS. If the drain of transistor MN 706 (exactly) follows the input or the output, then VDS would be substantially constant (no variation). Depending on the level of distortion tolerated, more cascode(s) can be added to serve this function, such as transistor MN 710 (e.g., NMOS transistor). Each cascode can provide an additional 20 dB in performance. Since the input buffer has a complementary design, cascode(s) being added to the NMOS side is also added to the PMOS side. Accordingly, transistor MP 708 (e.g., PMOS transistor) can be added to bootstrap and fix VDS of transistor MP 704. The gate of transistor MP 708 can be tied to the input VIN via level shifter 709 and level shifter 705 in series. In some embodiments, level shifter 709 can be directly coupled to the input VIN. The level shifter 709 or the level shifters 709 and 705 in series can serve as a fourth level shifter coupled to the input VIN for shifting the voltage level of the voltage input signal by a fourth amount of voltage shift across the fourth level shifter and generating a fourth level shifted voltage signal V4 to bias the fourth transistor, e.g., transistor MP 708. In the example shown, the push pull circuit of the input buffer further includes a fifth transistor of the first type (e.g., transistor MN 710) in cascode configuration with the third transistor (e.g., transistor MN 706), and a sixth transistor of the second type (e.g., transistor MP 712) in cascode configuration with the fourth transistor (e.g., transistor MP 708). In other words, the second cascode on the NMOS side, i.e., transistor MN 710, finally connects to supply. Also, a second cascode on the PMOS side, i.e., transistor MP 712 (e.g., PMOS transistor), finally connects to supply. The gate of upper most cascode MN 710 is driven from the source of the first cascode on the NMOS side, e.g., via level shifter 711. Level shifter 711 can be a fifth level shifter coupled to a source of the third transistor (e.g., transistor MN 706) for shifting a voltage at the source of the third transistor by a fifth amount of voltage shift across the fifth level shifter and generating a fifth level shifted voltage signal V5 to bias the fifth transistor (e.g., transistor MN 710). The gate of lower most cascode MP 712 is driven from the source of the first cascode on the PMOS side, e.g., via level shifter 713. Level shifter 716 can be a sixth level shifter coupled to a source of the fourth transistor (e.g., transistor MP 708) for shifting a voltage at the source of the fourth transistor by a sixth amount of voltage shift across the sixth level shifter and generating a sixth level shifted voltage signal V6 to bias the sixth transistor (e.g., transistor MN 710). This bootstrapping scheme (e.g., bootstrapping to the sources of the third/fourth transistor and drains of the first/second transistor) unloads the buffer input and output (both of which are candidates to bootstrap from) from the non-bootstrapped gate-drain capacitance of the upper cascode connected to the supply, which could be a significant source of distortion. In the examples shown in FIGS. 7 and 9, the bootstrapping is done primarily by tying the gates of the transistors the input (or some other node which follows the input). This feature was selected to reduce possible ringing, which can be caused by bootstrapping the gates to the output. While the bootstrapping to the input can load the input and adds extra parasitics, high speed applications may prefer an input buffer that suffers from less ringing. While there could potentially be some ringing from the upper cascode since it is bootstrapped to the source of the first cascode, the ringing may be tolerated over an alternative solution where the distortions at the source of the upper cascode could distort the input VIN and output VINX if it was bootstrapped to the input or the output. Further, the back gate of the various cascode transistors in the input buffer are bootstrapped as shown in FIG. 9 to improve SFDR. Similar to the description of the back gates of transistors MN 702 and MP 704, the back gates of the cascodes preferably being bootstrapped as well (i.e., it is undesirable to have voltage across the back gate and the source to vary). Unfortunately, in some implementations, VSS is negative, which means that the drain of the transistor MP 708 swings negative. In 28 nm CMOS process technology, the N-well of the PMOS transistors sit in the substrate, and substrate is at 0 volts. If N-well goes negative, it forward biases the diode between the P substrate (at 0 volts) and all the N wells (cathode end of the diode). If the N terminal goes below ground, it forward biases the diode and causes distortions. Tying the back gates of the cascodes on the PMOS side to the sources of the respective cascodes (same cascode) means it can cause distortions. The solution is to tie the back gates of the cascodes to each other, i.e., the back gate of an NMOS cascode is connected to a source of corresponding/complementary PMOS cascode, and vice versa. The sources are following the input and thus tying them to each other helps to bootstrap the back gates of the cascodes (to the input). Denoted by VBGN1, a back gate of the third transistor (e.g., transistor MN 706) is coupled to a source of the fourth transistor (e.g., transistor MP 708). Denoted by VBGP1, a back gate of the fourth transistor (e.g., transistor MP 708) is coupled to a source of the third transistor (e.g., transistor MN 706). Denoted by VBGN2, a back gate of the fifth transistor (e.g., transistor MN 710) is coupled to a source of the sixth transistor (e.g., transistor MP 712). Denoted by VBGP2, a back gate of the sixth transistor (e.g., transistor MP 712) is coupled to a source of the fifth transistor (e.g., transistor MN 710). Tying the back gate to the output is less desirable because it would load it with a non-linear capacitance. Linearity is improved since there is now a large voltage across the junction. While the cascodes on the NMOS side can tie the back gates to their respective sources, the complementary design of tying the back gates to the sources of the complementary cascode is preferable to achieve a complementary design and equalize loading for symmetric pull up and pull down behavior. Method for Buffering a Voltage Input Signal FIG. 10 is a flow diagram for buffering an input signal, according to some embodiments of the disclosure. In 1002, a first voltage shift set by (one or more current sources of) a first level shifter shifts the voltage input signal to generate a first signal. In 1002, a second voltage shift set by (one or more current sources of) a second level shifter shifts the voltage input signal to generate a second signal. The first voltage shift and second voltage shift can represent the level shifters 703 and 705 of FIGS. 7 and 9. The first signal and the second signal can represent V1 and V2 of FIGS. 7 and 9. In 1004, the first signal biases a first transistor of a first type. In 1004, the second signal biases a second transistor of a second type complementary to the first type. The first transistor and the second transistor are coupled in a push pull architecture, as illustrated by transistor MN 702 and transistor MP 704 of FIGS. 7 and 9. In 1006, the first transistor and the second transistor output a voltage output signal, e.g., VINX of FIGS. 7 and 9. In some embodiments, a third signal biases a first cascode transistor coupled to the first transistor. The third signal can follow the voltage input signal. In some embodiments, a fourth signal biases a second cascode transistor coupled to the second transistor. The fourth signal can follow the voltage input signal. For instance, the third/fourth signal can be the signal V3 or V4 of FIG. 9. In some embodiments, a fifth signal biases a third cascode transistor coupled to the first cascode transistor. The fifth signal can also follow the voltage input signal. In some embodiments, a sixth signal biases a fourth cascode transistor coupled to the first cascode transistor. The fifth signal can also follow the voltage input signal. For instance, the fifth/sixth signal can be the signal V5 or V6 of FIG. 9. Apparatus for Buffering an Input Signal An apparatus for buffering an input signal can include means for implementing the methods described herein. In some embodiments, the apparatus includes means for receiving an input signal. For instance, an input node can be provided to receive an input signal (e.g., VIN of FIGS. 1, 7, and 9), such as a high frequency signal to be converted by a data converter. The apparatus can further include push pull means for generating an output signal. Push pull means can include the push pull circuit and push pull architecture described herein (e.g., transistors seen in FIGS. 7 and 9). The apparatus can further include means for generating a first signal for biasing a first transistor of the push pull means. The first signal follows the input signal across all frequencies of the input signal. Further means can be included for generating other signals for biasing other transistors of the push pull means. The means for generating signals for biasing transistors can include level shifters described in relation to FIGS. 7-9. The means for generating signals for biasing transistors (bootstrapping the transistors to the input) are distinguishable from other circuits which generate a biasing signal based on fixed/predetermined bias voltages. The means for generating the signals for biasing transistors follows the input signal or is bootstrapped to the input signal across all frequencies of the input signal, i.e., all the way to DC. In contrast, the other circuits which generate a biasing signal based on fixed/predetermined bias voltages do not follow the input signal across all frequencies of the input signal. For those other circuits, signals for biasing transistors can be generated using a fixed biasing voltage and a resistor, and a capacitor in series with the input. Such signals for biasing transistors does not buffer or follow the input signal at low frequencies because the capacitor has a high impedance at low frequencies and the resistor dominates. Therefore, the non-bootstrapped biasing signal would be set by the fixed biasing voltage and the resistor at low frequencies (and does not respond to the input signal). In contrast, the level shifters described herein as means for generating the (bootstrapped) signals for biasing transistors can respond to the input signal across all frequencies (at low and high frequencies), since the level shifters described herein have a different frequency response. Examples Example 1 is an input buffer comprising: a input receiving a voltage input signal; a push pull circuit outputting a voltage output signal at an output, wherein the push pull circuit comprises a first transistor of a first type, a second transistor of a second type complementary to the first type; and a first level shifter coupled to the input for shifting a voltage level of the voltage input signal by a first amount of voltage shift across the first level shifter and generating a first level shifted voltage signal to bias the first transistor, wherein the first amount of voltage shift provided by the first level shifter is independent of a frequency of the voltage input signal. In Example 2, Example 1 can further include a second level shifter coupled to the input for shifting the voltage level of the voltage input signal by a second amount of voltage shift across the second level shifter and generating a second level shifted voltage signal to bias the second transistor. In Example 3, Example 1 or 2 can further include the first amount of voltage shift being programmable. In Example 4, any one of Examples 1-3 can further include an amount of current, flowing through a resistive element and provided by one or more current sources, setting the first amount of voltage shift across the first level shifter. In Example 5, any one of Examples 1-4 can further include a sum of the first amount of voltage shift and the second amount of voltage shift being at least a sum of a first threshold voltage of the first transistor and a second threshold voltage of the second transistor. In Example 6, any one of Examples 1-5 can further include the first amount of voltage shift being different from the second amount of voltage shift. In Example 7, any one of Examples 1-6 can further include the voltage output signal being offset from the voltage input signal. In Example 8, any one of Examples 1-7 can further include a first back gate of the first transistor and a second back gate of the second transistor being coupled to the output or follows the voltage output signal. In Example 9, any one of Examples 1-8 can further include a capacitance between a back gate and a deep N-well of a first transistor being reversed biased. In Example 10, any one of Examples 1-9 can further include the push pull circuit further comprising: a third transistor of the first type in cascode configuration with the first transistor; and a fourth transistor of the second type in cascode configuration with the second transistor. In Example 11, any one of Examples 1-10 can further include a third level shifter coupled to the input for shifting the voltage level of the voltage input signal by a third amount of voltage shift across the third level shifter and generating a third level shifted voltage signal to bias the third transistor. In Example 12, any one of Examples 1-11 can further include the push pull circuit further comprising: a fifth transistor of the first type in cascode configuration with the third transistor; and a sixth transistor of the second type in cascode configuration with the fourth transistor. In Example 13, any one of Examples 1-12 can further include a fourth level shifter coupled to a source of the third transistor for shifting a voltage at the source of the third transistor by a fourth amount of voltage shift across the fourth level shifter and generating a fourth level shifted voltage signal to bias the fifth transistor. In Example 14, any one of Examples 1-12 can further include: a back gate of the third transistor being coupled to a source of the fourth transistor; and a back gate of the fourth transistor being coupled to a source of the third transistor. In Example 15, any one of Examples 1-14 can further include: a back gate of the fifth transistor being coupled to a source of the sixth transistor; and a back gate of the sixth transistor being coupled to a source of the fifth transistor. Example 16 is a method for buffering a voltage input signal, the method comprising: level shifting the voltage input signal by a first voltage shift of a first level shifter to generate a first signal, wherein the first voltage shift is independent of a frequency of the voltage input signal; biasing, by the first signal, a first transistor of a first type; biasing, by a second signal, a second transistor of a second type complementary to the first type, wherein the first transistor and the second transistor are coupled in a push pull architecture; and outputting, by the first transistor and the second transistor, a voltage output signal. In Example 17, Example 16 can further include level shifting the voltage input signal by a second voltage shift set by a second level shifter to generate the second signal. In Example 18, Example 16 or 17 can further include biasing, by a third signal, a first cascode transistor coupled to the first transistor, wherein the third signal follows the voltage input signal. In Example 19, any one of Examples 16-18 can further include biasing, by a fourth signal, a second cascode transistor coupled to the first cascode transistor, wherein the fourth signal follows the voltage input signal. Example 20 is an apparatus comprising: means for receiving an input signal; push pull means for generating an output signal; and (passive) means for generating a first signal for biasing a first transistor of the push pull means, wherein the first signal follows the input signal across all frequencies of the input signal. Example 21 is an apparatus comprising means for implementing/carrying out any one of the methods in Examples 16-19. Example 101 is a bootstrapped switching circuit with accelerated turn on, comprising: a sampling switch receiving a voltage input signal and a gate voltage; a bootstrapped voltage generator comprising a positive feedback loop to generate the gate voltage for turning on the sampling switch, said positive feedback loop comprising an input transistor receiving the voltage input signal and an output transistor outputting the gate voltage of the sampling switch; and a jump start circuit to turn on the output transistor for a limited period of time during which the input transistor is turning on at a startup of the positive feedback loop. In Example 102, Example 101 can further include the jump start circuit being coupled to a gate of the output transistor. In Example 103, Example 101-102 can further include the jump start circuit ceasing to turn on the output transistor after the limited period of time and allows the positive feedback loop to operate. In Example 104, any one of Examples 101-103 can further include: the jump start circuit comprising a transistor receiving a clock signal used for activating the positive feedback loop; and the transistor being turned on by a delayed version of the clock signal to output the clock signal to turn on the output transistor for the limited period of time. In Example 105, any one of Examples 101-104 can further include the jump start circuit further comprising two inverters for generating the delayed version of the clock signal based on the clock signal. In Example 106, any one of Examples 101-105 can further include: the jump start circuit comprising a switch for connecting a gate of the output transistor to a bias voltage for turning on the output transistor; and the switch is controlled by a control signal having a pulse to close the switch. In Example 107, any one of Examples 101-106 can further include the jump start circuit comprising a sense circuit for activating the jump start circuit based on one or more conditions of the bootstrapped switching circuit indicating the startup of the positive feedback loop. In Example 108, any one of Examples 101-107 can further include the sense circuit sensing a voltage representing a voltage level at a node in the bootstrapped switching circuit. In Example 109, any one of Examples 101-108 can further include the node is at a node in the positive feedback loop. In Example 110, any one of Examples 101-109 can further include the sense circuit comprising a comparator comparing the voltage against a predetermined threshold indicating the startup of the positive feedback loop. In Example 111, any one of Examples 101-110 can further include: the positive feedback loop comprising a boot capacitor; and the positive feedback loop turning on the sampling switch by bringing the gate voltage to a boosted voltage generated based on the voltage input signal and a voltage across the boot capacitor. In Example 112, any one of Examples 101-111 can further include: the input transistor being coupled to a first plate of the boot capacitor; and the output transistor being coupled to a second plate of the boot capacitor. In Example 113, any one of Examples 101-112 can further include: the input transistor being driven by the gate voltage of the sampling switch; and the positive feedback loop further comprising a first transistor coupled to a gate of the output transistor and a drain of the input transistor, wherein the first transistor is driven by the gate voltage of the sampling switch. In Example 114, any one of Examples 101-113 can further include: the positive feedback loop further comprising: an additional transistor coupled to a gate of the output transistor and a drain of the input transistor, wherein the additional transistor is controlled by a clock signal which activates the positive feedback loop. Example 115 is a method for accelerated turn on of a sampling switch, comprising: outputting, by an output transistor of a positive feedback loop, an output voltage of a bootstrapped voltage generator for driving the sampling switch; pulling a gate voltage of the output transistor to an on-voltage level to turn on the output transistor for a period of time after the positive feedback loop is activated; and ceasing the pulling of the gate voltage after the period of time. In Example 116, Example 115 can further include: the sampling switch receiving a voltage input signal; and the positive feedback loop receiving the voltage input signal at an input transistor driven by the output voltage output by the output transistor, and generates a boosted voltage signal based on the voltage input signal as the output voltage of the bootstrapped voltage generator to turn on the sampling switch when the positive feedback loop is engaged. In Example 117, Example 115 or 116 can further include pulling the gate voltage of the output transistor comprising changing the gate voltage from an off-voltage level to an on-voltage level. In Example 118, any one of Examples 115-117 can further include: allowing the positive feedback loop to bring the gate voltage to a voltage level of a voltage input signal provided to the bootstrapped voltage generator and the sampling switch after the period of time. In Example 119, any one of Examples 115-118 can further include: sensing one or more conditions indicating the positive feedback loop has been activated; and generating a control signal in response to sensing the one or more conditions, wherein the control signal triggers the pulling of the gate voltage of the output transistor. Example 120 is an apparatus comprising: sampling means receiving an input signal to be sampled and a control signal which turns the sampling means on and off; means for generating a boosted voltage based on the input signal; output means for outputting the control signal; means for bringing the control signal to the boosted voltage through positive feedback action of the control signal; and means for turning on the output means for a limited period of time at a startup of the positive feedback action. Example 121 is an apparatus comprising means for implementing/carrying out any one of the methods in Examples 115-119. Variations and Implementations A source of a transistor, e.g., metal-oxide-semiconductor field-effect transistor (MOSFET), is where charge carriers enter a channel of a transistor. A drain of the transistor is where the charge carriers leave the channel. In some cases, the source and the drain can be considered as two terminals of the transistor. A gate of a transistor can be considered a control terminal of the transistor, because the gate can control the conductivity of the channel (e.g., an amount of current through a transistor). A back gate (body) of a transistor can also be considered as a control terminal of the transistor. Gates and back gates can be used as terminals for biasing a transistor. Note that the activities discussed above with reference to the FIGURES are applicable to any integrated circuits that involve processing analog signals and converting the analog signals into digital data using one or more ADCs. In certain contexts, the features discussed herein related to ADCs in general, including, e.g., ADCs of various flavors including pipeline ADCs, delta sigma ADCs, successive approximation register ADCs, multi-stage ADCs, time-interleaved ADCs, randomized time-interleaved ADCs, etc. The features can be particularly beneficial to high speed ADCs, where input frequencies are relatively high in the gigahertz range. The ADC can be applicable to medical systems, scientific instrumentation, wireless and wired communications systems (especially systems requiring a high sampling rate), radar, industrial process control, audio and video equipment, instrumentation, and other systems which uses ADCs. The level of performance offered by high speed ADCs can be particularly beneficial to products and systems in demanding markets such as high speed communications, medical imaging, synthetic aperture radar, digital beam-forming communication systems, broadband communication systems, high performance imaging, and advanced test/measurement systems (oscilloscopes). The present disclosure encompasses apparatuses which can perform the various methods described herein. Such apparatuses can include circuitry illustrated by the FIGURES and described herein. Parts of various apparatuses can include electronic circuitry to perform the functions described herein. The circuitry can operate in analog domain, digital domain, or in a mixed-signal domain. In some cases, one or more parts of the apparatus can be provided by a processor specially configured for carrying out the functions described herein (e.g., control-related functions, timing-related functions). In some cases that processor can be an on-chip processor with the ADC. The processor may include one or more application specific components, or may include programmable logic gates which are configured to carry out the functions describe herein. In some instances, the processor may be configured to carrying out the functions described herein by executing one or more instructions stored on a non-transitory computer medium. In the discussions of the embodiments herein, the parts and components can readily be replaced, substituted, or otherwise modified in order to accommodate particular circuitry needs. Moreover, it should be noted that the use of complementary electronic devices, hardware, etc. offer an equally viable option for implementing the teachings of the present disclosure. For instance, complementary configurations using PMOS transistor(s) (p-type metal-oxide semiconductor transistor(s)) to replace NMOS transistor(s) (p-type metal-oxide semiconductor transistor(s)) or vice versa, are envisioned by the disclosure. For instance, the present disclosure/claims encompasses implementations where all NMOS devices are replaced by PMOS devices, or vice versa. Connections and the circuit can be reconfigured to achieve the same function. These implementations are equivalent to the disclosed implementations using complementary transistors devices because the implementations would perform substantially the same function in substantially the same way to yield substantially the same result. It is understood by one skilled in the art that a transistor device can be generalized as a device having three (main) terminals. Furthermore, it is understood by one skilled in the art that a switch, a transistor, or transistor device, during operation, can have a characteristic behavior of transistors corresponding to devices such as NMOS, PMOS devices (and any other equivalent transistor devices). In one example embodiment, any number of components of the FIGURES may be implemented on a board of an associated electronic device. The board can be a general circuit board that can hold various components of the internal electronic system of the electronic device and, further, provide connectors for other peripherals. More specifically, the board can provide the electrical connections by which the other components of the system can communicate electrically. Any suitable processors (inclusive of digital signal processors, microprocessors, supporting chipsets, etc.), computer-readable non-transitory memory elements, etc. can be suitably coupled to the board based on particular configuration needs, processing demands, computer designs, etc. Other components such as external storage, additional sensors, controllers for audio/video display, and peripheral devices may be attached to the board as plug-in cards, via cables, or integrated into the board itself. In various embodiments, the functionalities described herein may be implemented in emulation form as software or firmware running within one or more configurable (e.g., programmable) elements arranged in a structure that supports these functions. The software or firmware providing the emulation may be provided on non-transitory computer-readable storage medium comprising instructions to allow a processor to carry out those functionalities. In another example embodiment, the components of the FIGURES may be implemented as stand-alone modules (e.g., a device with associated components and circuitry configured to perform a specific application or function) or implemented as plug-in modules into application specific hardware of electronic devices. Note that particular embodiments of the present disclosure may be readily included in a system on-chip (SOC) package, either in part, or in whole. An SOC represents an IC that integrates components of a computer or other electronic system into a single chip. It may contain digital, analog, mixed-signal, and often radio frequency functions: all of which may be provided on a single chip substrate. Other embodiments may include a multi-chip-module (MCM), with a plurality of separate ICs located within a single electronic package and configured to interact closely with each other through the electronic package. In various other embodiments, the error calibration functionalities may be implemented in one or more silicon cores in Application Specific Integrated Circuits (ASICs), Field Programmable Gate Arrays (FPGAs), and other semiconductor chips. It is also imperative to note that all of the specifications, dimensions, and relationships outlined herein (e.g., the number of processors, logic operations, etc.) have only been offered for purposes of example and teaching only. Such information may be varied considerably without departing from the spirit of the present disclosure, or the scope of the appended claims (if any) or examples described herein. The specifications apply only to one non-limiting example and, accordingly, they should be construed as such. In the foregoing description, example embodiments have been described with reference to particular processor and/or component arrangements. Various modifications and changes may be made to such embodiments without departing from the scope of the appended claims (if any) or examples described herein. The description and drawings are, accordingly, to be regarded in an illustrative rather than in a restrictive sense. Note that with the numerous examples provided herein, interaction may be described in terms of two, three, four, or more electrical components or parts. However, this has been done for purposes of clarity and example only. It should be appreciated that the system can be consolidated in any suitable manner. Along similar design alternatives, any of the illustrated components, modules, blocks, and elements of the FIGURES may be combined in various possible configurations, all of which are clearly within the broad scope of this Specification. In certain cases, it may be easier to describe one or more of the functionalities of a given set of flows by only referencing a limited number of electrical elements. It should be appreciated that the electrical circuits of the FIGURES and its teachings are readily scalable and can accommodate a large number of components, as well as more complicated/sophisticated arrangements and configurations. Accordingly, the examples provided should not limit the scope or inhibit the broad teachings of the electrical circuits as potentially applied to a myriad of other architectures. Note that in this Specification, references to various features (e.g., elements, structures, modules, components, steps, operations, characteristics, etc.) included in “one embodiment”, “example embodiment”, “an embodiment”, “another embodiment”, “some embodiments”, “various embodiments”, “other embodiments”, “alternative embodiment”, and the like are intended to mean that any such features are included in one or more embodiments of the present disclosure, but may or may not necessarily be combined in the same embodiments. It is also important to note that the functions described herein illustrate only some of the possible functions that may be executed by, or within, systems/circuits illustrated in the FIGURES. Some of these operations may be deleted or removed where appropriate, or these operations may be modified or changed considerably without departing from the scope of the present disclosure. In addition, the timing of these operations may be altered considerably. The preceding operational flows have been offered for purposes of example and discussion. Substantial flexibility is provided by embodiments described herein in that any suitable arrangements, chronologies, configurations, and timing mechanisms may be provided without departing from the teachings of the present disclosure. Numerous other changes, substitutions, variations, alterations, and modifications may be ascertained to one skilled in the art and it is intended that the present disclosure encompass all such changes, substitutions, variations, alterations, and modifications as falling within the scope of the appended claims (if any) or examples described herein. Note that all optional features of the apparatus described above may also be implemented with respect to the method or process described herein and specifics in the examples may be used anywhere in one or more embodiments.
<SOH> BACKGROUND <EOH>In many electronics applications, an analog-to-digital converter (ADC) converts an analog input signal to a digital output signal, e.g., for further digital signal processing or storage by digital electronics. Broadly speaking, ADCs can translate analog electrical signals representing real-world phenomenon, e.g., light, sound, temperature, electromagnetic waves, or pressure for data processing purposes. For instance, in measurement systems, a sensor makes measurements and generates an analog signal. The analog signal would then be provided to an analog-to-digital converter (ADC) as input to generate a digital output signal for further processing. In another instance, a transmitter generates an analog signal using electromagnetic waves to carry information in the air or a transmitter transmits an analog signal to carry information over a cable. The analog signal is then provided as input to an ADC at a receiver to generate a digital output signal, e.g., for further processing by digital electronics. Due to their wide applicability in many applications, ADCs can be found in places such as broadband communication systems, audio systems, receiver systems, etc. Designing circuitry in ADC is a non-trivial task because each application may have different needs in performance, power, cost, and size. ADCs are used in a broad range of applications including Communications, Energy, Healthcare, Instrumentation and Measurement, Motor and Power Control, Industrial Automation and Aerospace/Defense. As the applications needing ADCs grow, the need for fast yet accurate conversion also grows.
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>To provide a more complete understanding of the present disclosure and features and advantages thereof, reference is made to the following description, taken in conjunction with the accompanying figures, wherein like reference numerals represent like parts, in which: FIG. 1 shows a front end to an analog-to-digital converter, according to some embodiments of the disclosure; FIG. 2 shows a bootstrapped switching circuit, according to some embodiments of the disclosure; FIG. 3 shows a bootstrapped switching circuit having accelerated turn on, according to some embodiments of the disclosure; FIGS. 4A-B show an exemplary implementation for a jump start circuit, according to some embodiments of the disclosure; FIGS. 5A-C show another exemplary implementation for a jump start circuit, according to some embodiments of the disclosure; FIG. 6 is a flow diagram illustrating a method for accelerated turn on of a sampling switch; FIG. 7 shows an exemplary input buffer, according to some embodiments of the disclosure; FIG. 8 shows an exemplary level shifter, according to some embodiments of the disclosure; FIG. 9 shows another exemplary input buffer, according to some embodiments of the disclosure; and FIG. 10 is a flow diagram for buffering an input signal, according to some embodiments of the disclosure. detailed-description description="Detailed Description" end="lead"?
H03K1704123
20170829
20180315
68652.0
H03K170412
1
WELLS, KENNETH B
BOOTSTRAPPED SWITCHING CIRCUIT
UNDISCOUNTED
0
ACCEPTED
H03K
2,017
15,689,779
PENDING
Selectively Locking Merchandising Member
A merchandising system includes an elongated mounting member having a wall with at least one tooth and a cooperating member having a front end receivable on the mounting member. The cooperating member can include a slot defined in the front end. A lock is received in the slot. The lock includes at least one tooth located at a first end and a resilient member located at a second end. The lock can selectively engage the mounting member so as to retard or permit a lateral movement of the cooperating member in relation to the mounting member.
1-20. (canceled) 21. A merchandising system comprising: a cooperating member including a front end defining a slot and a chamber accessible through the slot; a mounting member including a front wall at least partially defining a channel configured to receive the front end of the cooperating member, the front wall having a tooth; and a lock at least partially received in the chamber, the lock including a front end, a tab, and a resilient member, the front end including a tooth configured to selectively engage the tooth of the mounting member to inhibit movement of the cooperating member relative to the mounting member in a first direction, the tab extending from the channel of the mounting member such that urging the tab in a direction counter to the bias of said resilient member disengages the tooth of the lock from the tooth of the mounting member. 22. The merchandising system of claim 21, wherein the tab includes a front face, and wherein the tooth of the lock is disposed rearward of the front face and forward of the resilient member. 23. The merchandising system of claim 22, wherein the front face extends above the tooth of the lock. 24. The merchandising system of claim 21, wherein the front end and the tab collectively define an L-shape. 25. The merchandising system of claim 21, wherein the tab is accessible over the front wall of the mounting member. 26. The merchandising system of claim 21, wherein the front wall of the mounting member includes a rearwardly extending flange. 27. The merchandising system of claim 26, wherein the flange is operable to engage the tooth of the lock to inhibit movement of the cooperating member relative to the mounting member in a second direction. 28. The merchandising system of claim 27, wherein the second direction is perpendicular to the first direction. 29. The merchandising system of claim 27, further comprising a protrusion extending from the cooperating member and adapted to engage the mounting member to inhibit movement of the cooperating member relative to the mounting member in the second direction. 30. The merchandising system of claim 29, wherein the mounting member includes a rear wall defining a groove configured to receive the protrusion. 31. A merchandising system comprising: a cooperating member including a front end; a mounting member defining a channel and including a tooth, the channel configured to receive the front end of the cooperating member; and a lock mounted to the cooperating member and adapted to move relative to the cooperating member from an extended position to a retracted position, the lock including a front end, a tab, and a biasing member, the front end including a tooth configured to selectively engage the tooth of the mounting member to inhibit movement of the cooperating member relative to the mounting member in a first direction, the tab extending from the channel of the mounting member and adapted to be manually contacted for pushing the lock into the retracted position against the bias of the biasing member. 32. The merchandising system of claim 31, wherein the tab includes a front face, and wherein the tooth of the lock is disposed rearward of the front face and forward of the biasing member. 33. The merchandising system of claim 32, wherein the front face extends above the tooth of the biasing member. 34. The merchandising system of claim 31, wherein the front end and the tab collectively define an L-shape. 35. The merchandising system of claim 31, wherein the mounting member includes a front wall at least partially defining the channel, and wherein the tab is accessible over the front wall of the mounting member. 36. The merchandising system of claim 31, wherein the mounting member includes a front wall at least partially defining the channel and having a rearwardly extending flange. 37. The merchandising system of claim 36, wherein the flange is operable to engage the tooth of the lock to inhibit movement of the cooperating member relative to the mounting member in a second direction. 38. The merchandising system of claim 37, wherein the second direction is perpendicular to the first direction. 39. The merchandising system of claim 37, further comprising a protrusion extending from the cooperating member and adapted to engage the mounting member to inhibit movement of the cooperating member relative to the mounting member in the second direction. 40. The merchandising system of claim 39, wherein the mounting member includes a rear wall defining a groove configured to receive the protrusion.
This application claims the benefit of Provisional Application Ser. No. 62/144,672 which was filed on Apr. 8, 2015. The entire content of that application is incorporated hereinto by reference. BACKGROUND The present disclosure pertains to a merchandising system. More specifically, the disclosure relates to a base and divider assembly employed in a forward feeding display merchandising system for storing and displaying merchandise of a variety of shapes and sizes and automatically delivering the merchandise to the front of a shelf. More particularly, the disclosure pertains to a cooperating member, such as a divider or track which can be selectively locked to a front rail or mounting member of the merchandising system. Shelving is used extensively for stocking and storing products or merchandise in a variety of stores, such as grocery stores, drug stores and mass merchandisers, such as Walmart, Kmart and the like. Most consumer product stores contain fixed shelving which is arranged back to back between aisleways, on which shelving merchandise is stocked. It is desirable for merchandise to be displayed at the front edge of the shelf so that the customer can see the merchandise and be induced to purchase such merchandise. In such stores, if the shelves are not positioned at eye level, it is difficult for the customer to see the items being displayed, if the items are not located adjacent the front edge of the shelf. Also, fixed shelves make it difficult to rotate product, i.e., move the older stock to the front of the shelf and position newer stock behind the older stock. Rotating products is an important consideration if the goods are perishable or subject to becoming stale (cigarettes, fruit juices, dairy products and the like fall into this category). It is important for such articles that they be removed following a first in, first out system to maintain freshness. Forward feed devices are employed to automatically move an item forward on a shelf, as the item before it in a column of merchandise is removed from the shelf. These devices generally fall into three categories. The first category pertains to inclined tracks which rely on gravity to feed, slide, or roll products forward on the shelf. Gravity feeding, however, may be unpredictable in that various materials or packages slide more easily than others because of different weights and frictional interfaces between the products and the track. The second category employs conveyor belts which still use gravity to effect forward movement. These devices are typically cumbersome, expensive and complicated due to the need to properly tension the track and the conveyor belts. The third category uses spring biased pusher paddles to feed the product forward. Such paddle based forward feed devices have become very popular and have been found useful for a variety of merchandise. In the third category, separate dividers and tracks containing pusher paddles are usually employed, along with end dividers to separate the merchandise into columns. It has been considered advantageous to provide an integrated track and divider system because such an integrated track and divider makes assembly of the merchandising system on a shelf easier for store personnel as there are less components to handle. However, an integrated track and divider is disadvantageous from the perspective that the divider cannot be removed from the track should that become necessary. In some circumstances, such as for wide products, a drop in track is desired so that two pusher paddles urge the merchandise forward. Currently, a separate track has to be produced for this purpose. It would be desirable to automatically lock a divider to a front rail in order to retard the sideward or lateral movement of one or more dividers as product is being pushed forward on the track by the spring biased pusher paddles. In other words, it would be desirable to allow the divider to automatically engage the front rail in such a way that the divider is retarded from such sliding movement in one end position of the locking assembly but is allowed to slide sideways in relation to the front rail in another end position of the locking assembly. Ideally, the divider would be movable in a lateral direction parallel to the front rail while being secured in a direction perpendicular to the front rail when a locking member is disengaged but the divider would resist movement in the lateral direction parallel to the front rail and would remain secured in a direction perpendicular to the front rail when the locking member is engaged. It may be advantageous to provide tracks with such a feature as well. BRIEF SUMMARY OF THE DISCLOSURE In accordance with one embodiment of the present disclosure, a merchandising system comprises an elongated mounting member including a wall, the wall comprising at least one tooth and a cooperating member including a front end. The front end is adapted to be received on the mounting member and is adapted to selectively engage the wall thereof. The cooperating member includes a chamber accessible through a slot defined in the front end of the cooperating member. A lock is received in the slot. The lock includes at least one tooth located at a first end and a resilient member located at a second end, wherein the resilient member is adapted to bias the at least one tooth of the lock into engagement with the at least one tooth of the mounting member so as to retard a lateral movement of the cooperating member in relation to the mounting member. The lock is linearly movable relative to a cooperating member against a bias of the resilient member in order to selectively disengage the lock at least one tooth from the at least one tooth of the cooperating member thereby permitting a lateral movement of the cooperating member in relation to the mounting member. In accordance with another embodiment of the present disclosure, a merchandising system comprises an elongated mounting member, including a longitudinal axis, the mounting member including a front wall, a back wall and a channel defined between the front wall and the back wall, the front wall including a plurality of spaced teeth. A cooperating member includes an elongated body which is oriented in a direction generally transverse to the mounting member longitudinal axis. The cooperating member includes a front end, wherein at least a portion of the cooperating member front end is received in the channel of the mounting member and wherein the front end comprises a chamber accessible via a slot defined in the front end. A lock is received in the slot and is mounted to the cooperating member. The lock includes a first end comprising a plurality of spaced teeth and a second end comprising a biasing member adapted for biasing the lock forwardly in the chamber. The plurality of spaced teeth of the elongated mounting member selectively engages the plurality of spaced teeth of the lock to retard a lateral movement of the cooperating member in relation to the mounting member. The plurality of spaced teeth of the mounting member are disengaged from the plurality of spaced teeth of the lock when the lock is slid rearwardly away from the cooperating member front end against the bias of the biasing member thereby permitting the lateral movement of the cooperating member in relation to the mounting member. In accordance with still another embodiment of the present disclosure, there is provided a merchandising system which comprises an elongated mounting member including a first engaging member and a cooperating member configured to attach to the mounting member, the cooperating member including a front end comprising a second engaging member. A third engaging member is mounted to the cooperating member, wherein the third engaging member is adapted to move linearly along a longitudinal axis of the cooperating member from an extended position to a retracted position. The third engaging member comprises a first end including an engaging element for selectively engaging a surface of the mounting member and a second end comprising a biasing member for biasing the third engaging member to the extended position in order to retard a movement of the cooperating member in a lateral direction parallel to a longitudinal axis of the mounting member. The third engaging member also includes a tab extending over the mounting member. The tab is adapted to be manually contacted for pushing the third engaging member into a retracted position against the bias of the biasing member. BRIEF DESCRIPTION OF THE DRAWINGS The present disclosure may take physical form in certain parts and arrangements of parts, several embodiments of which will be described in detail in this specification and illustrated in the accompanying drawings which form a part hereof and wherein: FIG. 1 is an exploded perspective view of a base and divider assembly of a merchandising system which constitutes one embodiment of a cooperating member according to the present disclosure, showing an elongated base and divider, a lock and a front wall; FIG. 2 is an assembled perspective view of the cooperating member of FIG. 1; FIG. 3A is an enlarged cross-sectional side view of the cooperating member of FIG. 2 mounted on a mounting member and illustrating an engaged condition of the lock with the mounting member when a resilient member of the lock is in its natural biasing position; FIG. 3B is an assembled view of the merchandising system of FIG. 3A illustrating permissible movement of the lock in relation to the mounting member when it is desired that the lock be in a disengaged condition such that the resilient member is compressed; FIG. 4A is a bottom plan view of the cooperating member of FIG. 3A when the lock is in an engaged condition; FIG. 4B is a bottom plan view of the cooperating member of FIG. 3B when the lock is in a disengaged condition; FIG. 5 is an enlarged perspective view of a portion of the mounting member of FIGS. 3A and 3B; FIG. 6 is an enlarged cross-sectional bottom plan view of the cooperating member and the lock of FIG. 3A when the lock is in an engaged condition; FIG. 7 is a reduced perspective view of the merchandising system according to FIGS. 3A and 3B including several cooperating members located in a side by side relationship as they would be when mounted on a subjacent shelf (not shown) with an elongated mounting member, and illustrating the use of a track positioned between two cooperating members; FIG. 8 is an enlarged top plan view of the merchandising system of FIG. 7; and FIG. 9 is an exploded perspective view of a base and divider assembly of a merchandising system showing the engaging element for locking a front wall to the cooperating member of the present disclosure. DETAILED DESCRIPTION Referring now to the drawings wherein the showings are for purposes of illustrating several embodiments of the disclosure only, FIG. 1 shows a merchandising system 10 which includes a cooperating member 40 comprising a base 50. A divider 130 can be either selectively or permanently mounted on or secured to the base 50. The cooperating member 40 includes a front end 42 in which a slot 46 is defined. The slot 46 provides access to a chamber 44 defined in the base 50. As best seen in FIG. 2, located behind the chamber 44 is a groove 54 defined in the base 50. The groove 54 which is defined in the walls of the base 50 can comprise an engaging element or member. At least a portion of groove 54 can be defined by at least one resilient tab member 56. A lock 60 can be received in the slot 46 and selectively mounted within the chamber 44. At least one body 58 borders the slot 46 and retards the lock 60 from moving laterally in relation to the base 50. Also, a wall 48 can extend beneath the slot 46. In one embodiment, the lock 60 includes at least one tooth 62 located at a first or front end 64 thereof. Alternatively, a plurality of spaced teeth 62 can be provided on the first end 64. A resilient biasing member 66 is located at a second or rear end 68 of the lock 60. The resilient member 66 can comprise a generally ring-shaped element 70. The element 70 is resilient due to the resilient nature of the material from which the lock 60 is made, such as a known thermoplastic. A tab or plateau-like portion 80 can also be defined on the first end 64 of the lock. Tab 80 includes a front face 82 adapted for manual contact by digits of users such as store personnel. Defined in the front face 82 are a plurality of spaced ridges 84 which can aid in pushing the tab 80 during manual contact thereof. As is evident from FIGS. 3A, 38B, and 7, cooperating member 40 with lock 60 can be received on an elongated mounting member 20, sometimes termed a front rail. Cooperating member 40 is oriented in a direction generally transverse to a longitudinal axis of the elongated mounting member 20. It should be appreciated that while particular designs of teeth 24 and 62 are illustrated, any suitable types of engaging elements can be employed for this purpose. In other words, differently shaped teeth can be provided. In the embodiments illustrated, the teeth are shown as generally being trapezoidal in shape. If so desired, the shapes of the teeth can be rounded, or teeth 62 can be rounded while teeth 24 can have a different shape, such as a trapezoid or a rectangle. Referring again to FIG. 2, in one embodiment the divider 130 can comprise a top portion 132 and a front portion 138. With reference now also to FIG. 7, the divider 130 also comprises a rear portion 136. In one embodiment, a locking feature can be provided for selectively securing the divider 130 to the base 50. Further information concerning the locking feature can be found in U.S. Pat. No. 8,752,717 issued on Jun. 17, 2014, the subject matter of that patent is incorporated hereinto by reference in its entirety. It should be appreciated that there are also other types of connecting structures which can selectively connect a base and a divider to each other, but which allow the base to be separated from the divider when the divider is not needed. Due to the resiliency of the thermoplastic material from which at least one of the divider 130 and the base 50 are made, the divider can be selectively separated from the base and be selectively connected thereto any desired number of times within reason. If desired, a snap fit can be provided between the base 50 and the divider 130. Alternatively, the divider 130 and base 50 can be of one piece. While one embodiment of a cooperating member 40 is illustrated in FIG. 1, namely a divider, it should be appreciated that the cooperating member could, instead be a free-standing pusher track, such as track 150 illustrated in FIGS. 7 and 8. Alternatively, a combination track and divider assembly could be provided. With reference now to FIG. 8, located on a top surface of the cooperating member or track 150 can be first and second spaced rails 152 and 154. These slidably accommodate a pusher 156 which is mounted on the rails. The pusher 156 can be urged forwardly on the rails by a coil spring 158 or like biasing member. The operation of a coil spring for urging a pusher assembly forward on a track is well known in the art. With reference once more to FIG. 1, defined on the front portion 138 of the divider 130 is a first engaging portion which can be in the form of a flange or shoulder section 140. Shoulder section 140 can accommodate a front wall 110 which is oriented generally transverse to the longitudinal axis of the divider 130, as is evident from FIG. 7. The front wall 110 can be in the form of a laterally extending support section or body 112. Defined on a rear face of the front wall 110 is housing 124. A vertically oriented slot 126 can extend in the housing, as best shown in FIG. 9. The slot 126 can be located approximately equidistant between the two side edges of front wall, if so desired. The walls of the housing 124 defining the slot 126 can be considered a second engaging portion, which cooperates with the first engaging portion. As is evident from FIG. 9, the slot 126 in the housing 124 accommodates the shoulder section 140 of the divider 130. The body 112 of front wall 110 extends laterally in relation to the housing 124. The purpose of the front wall 110 is to provide a retarding wall which can be employed to retard a forward most one of a column of merchandise from falling over the mounting member 20 and off the subjacent shelf. Front wall 110 can also be made from a suitable known plastic material which is transparent, so that the merchandise abutted by the front wall can be seen. It should be appreciated that in order to form the front wall, it can be molded from the suitable known transparent plastic material so that the front wall is of one piece. With reference to FIG. 2, the body 112 of front wall 110 can be generally planar and comprises a front face 114 from which extends a gripping portion or handle 116, as well as an engaging element or protrusion 118 for locking the front wall to the cooperating member 40. The handle 116 includes a recess 120 for cooperating with the front end 42 of cooperating member 40 to further define slot 46. In one embodiment, the protrusion 118 is spaced from the handle 116, with the protrusion being located beneath the handle. With reference now to FIG. 9, in this regard, front end 42 of cooperating member 40 includes at least one body 58 which can comprise a seat portion for receiving the protrusion 128. In the orientation illustrated in FIG. 9, the protrusion 118 of the front wall 110 can include a ledge 128 having a sloped portion which contacts the front end 42 of the cooperating member. The sloped portion of ledge 128 urges the protrusion 118 forwardly as it comes into contact with the front end 42 during, for example, a linear downward sliding movement of the front wall 110. Upon further linear downward motion of the front wall 110, the ledge 128 is allowed to retract or snap into the seat portion 58 of the front end of cooperating member. The retraction of the ledge 128 into the seat portion 58 provides a locking engagement of the front wall 110 with the cooperating member 40. All of the components of the merchandising system, namely, the mounting member 20, cooperating member 40, lock 60, and front wall 110, can be made from suitable known materials such as a variety of known somewhat resilient or flexible thermoplastics although other resilient materials could also be used. The limits of movement of the front wall 110 can be regulated by the ledge 128 and how it interacts with the front end 42 of the cooperating member. More particularly, the condition or position of the merchandising system illustrated in FIG. 2, front wall 110 is fully engaged with the cooperating member 40 and the ledge 128 fits in the seat portion 58. Further downward movement of the front wall 110 past this position is, thus, prevented or at least retarded. With reference now again to FIG. 2, cooperating member 40, lock 60, front wall 110, and divider 130 are shown in assembled condition. Lock 60 is shown as being selectively mounted within chamber 40 with tab 80 extending forward from both the slot 46 and the recess 120 of front wall 110. The recess 120 additionally provides access to the tab 80 from the handle 116. In one embodiment, a connection system 90 is provided for connecting the lock 60 to the cooperating member 40. As shown in FIGS. 4A and 4B, connection system 90 can include protrusion 92 extending downwardly from the body of the base 50 such that it is located in the chamber 44 defined in the cooperating member 40. A clip 94 can be provided on the second end 68 of lock 60. With reference now also to FIG. 6, in one embodiment the clip 94 can be defined within the resilient ring-shaped element 70 of the lock. The clip 94 selectively mounts to the protrusion 92 in order to hold the lock 60 in the slot 46 of the cooperating member 40. With reference now to FIG. 5, the elongated mounting member or front rail 20 includes a vertically oriented front wall 22, a back wall 26, and a channel 26 defined between the front wall and the back wall. It should be appreciated from FIGS. 3A and 3D, for example, that the back wall 26 of the elongated mounting member or front rail 20 protrudes into the groove 54 defined in the base 50 of the cooperating member 40 when the cooperating member is mounted to the mounting member. Thus, the back wall 26 defines a first engaging member and the slot 56 defines a second engaging member, such that when the first and second engaging members are engaged with each other, a movement of the cooperating member in a direction perpendicular to a longitudinal axis of the mounting member in the plane of such longitudinal axis is retarded, if not entirely prevented. A suitable conventional fastener (not illustrated) can extend through at least one opening 30 so as to secure the mounting member in place on a subjacent shelf (not illustrated). Such a construction is shown in U.S. Pat. No. 7,216,770 which is dated May 15, 2007. That patent is incorporated herein by reference, in its entirety. Moreover, reference is made to U.S. Pat. No. 8,177,076 which is dated May 15, 2012 for its disclosure of various embodiments of a merchandising assembly. That patent is also incorporated herein by reference, in its entirety. As shown in FIGS. 3A and 5, the tab member 56 engages a groove 57 defined in the rear wall 26 of the mounting member 20. Defined on a rear face of the front wall 22 of the mounting member 20 is at least one vertically oriented tooth 24. In one embodiment, a plurality of spaced teeth 24 can be provided. As shown in FIG. 3A, the front end 42 of cooperating member 40 is adapted to be received behind the front wall 22 of the mounting member 20. Thus, at least a portion of the front end 42 can be received in the channel 26 of the mounting member 20. As can further be seen from FIGS. 3A and 3B, when front end 42 is received in channel 26, the front wall 22 of the mounting member 20 extends in front of the slot 46 of cooperating member 40 and the back wall 26 is located inside the groove 54 of cooperating member. The chamber 44 is thus located between the front wall 22 and the back wall 26 and within channel 28. The at least one tooth 24 defined in the front wall 22 of the mounting member 20 engages the at least one tooth 62 of the lock 60, which is mounted within chamber 44. The at least one resilient tab portion 56 of groove 54 locks the back wall 26 of mounting member within the groove. If desired, a snap fit can be provided between the tab 56 and the back wall 26. The protrusion 80 mounted on lock 60 extends over the front wall 22 such that the front face 82 makes the lock accessible to store personnel from the front wall of the mounting member 20, as can be seen in FIG. 7. With particular reference to FIG. 3A, the resilient member 66 of lock 60, which can also be termed a third engaging member, is naturally adapted to bias the lock forwardly in chamber 44. This natural bias causes the at least one tooth 62 of the lock 60 to enter grooves defined between the spaced teeth 24 of the mounting member or front rail 20 and come into engagement with a side wall of the at least one tooth 24 of the mounting member. In the embodiment shown, the natural bias causes the plurality of spaced teeth 62 of the lock 60 to come into engagement with the plurality of spaced teeth 24 of the mounting member 20, as best shown in FIG. 6. In the condition or position of the merchandising system illustrated in FIG. 3A, the cooperating member 40 is retarded from, and preferably prevented from, movement laterally in relation to the mounting member 20. It should be appreciated that the resilient member 66 allows the lock 60 to be resiliently biased into contact with the front wall teeth 24, due to the inherent resilient nature of the thermoplastic material from which the lock can be made. However, it should be appreciated that the lock could also be made from other suitable materials, such as various metals or the like. It should thus be appreciated that the lock could be made from a different material than the cooperating member or the mounting member. In addition, various sections of the lock could be made from different materials, if so desired. For example, the resilient member 66 could be made from a more resilient material than the tab 80. With reference now to FIG. 3B, the tab 80 of lock 60 is shown as being urged in a direction counter to the natural bias of the resilient member 66, as indicated by the arrow. A finger or digit of store personnel pushing on the tab can accomplish this action. It should be appreciated that the movement of the lock 60 is a linear movement. More particularly, the lock is slid rearwardly away from the mounting member and in a direction which is axially aligned with the longitudinal axis of the cooperating member. This counter bias causes the at least one tooth 62 of the lock 60 to disengage from the at least one tooth 24 of the mounting member 20 such that the first end 64 of the lock is spaced away from the front wall 22 of the mounting member. Once this is done, the plurality of spaced teeth 62 of the lock 60 disengage from the plurality of spaced teeth 24 of the mounting member 20 such that the first end 64 of the lock is spaced away from the front wall 22 of the mounting member. In the condition or position of the merchandising system illustrated in FIG. 3B, the cooperating member 40 is allowed to move laterally, such as via a sliding motion, in relation to the mounting member 20. However, when the tab 80 of lock 60 is no longer being contacted, as shown in FIG. 3A, the resilient member 66 automatically biases the at least one tooth or teeth 62 of the lock to re-engage the at least one tooth or teeth 24 of the mounting member. Thus, any further lateral or sideways movement of the cooperating member in relation to the mounting member is prevented or at least retarded. The locking engagement of the plurality of spaced teeth 62 of lock 60 with the plurality of spaced teeth 24 of mounting member 20 is best shown in FIG. 6. The cooperating member is allowed to slide laterally in relation to the mounting member in the condition or position of the merchandising system illustrated in FIG. 3B. However, the engagement of the cooperating member with the mounting member, via the resilient tab member 56 of groove 54 accommodating the back wall 26 of mounting member 20, retards the cooperating member from moving in a direction perpendicular to the mounting member regardless of whether lateral movement is permitted. Thus, the cooperating member is retarded from a movement perpendicular to the longitudinal axis of the mounting member, both in a direction rearwardly on the shelf away from the mounting member and in a direction upwardly away from the shelf and the mounting member, even when a lateral movement is permitted for the cooperating member, that is, a movement parallel to the longitudinal axis of the mounting member. However, when the one or more teeth 62 and 24 are disengaged, the cooperating member 40 can be lifted vertically away from the mounting member 20 and removed from the merchandising assembly by snapping the tooth or protrusion 56 out of groove 57. But, when the one or more teeth 62 and 24 are engaged, such vertical movement of the cooperating member 40 is retarded if not prevented by the engagement of the one or more teeth 62 with a flange 23 which extends rearwardly from the front wall 22 of the mounting member 20 and over the teeth 24, as can be seen from FIG. 3A. The orientation illustrated in FIG. 4A corresponds to the condition or position of the merchandising system illustrated in FIG. 3A, however the mounting member 20 is not shown for simplicity. FIG. 4A shows the resilient member 66 in its natural bias. In other words, the resilient ring-shaped element 70 of resilient member 66 naturally biases the lock 60 forwardly in chamber 44. The front face 82 of tab 80 is shown as being easily accessible from the front wall 110. Connection system 90 includes the protrusion 92 positioned rearward in the chamber 44. A clip 94, located on the resilient member or ring-shaped element 70, enables the lock 60 to be selectively mounted on the protrusion 92 extending into the chamber 44. In other words, the lock 60 can be detached from the cooperating member 40 when so desired. The clip 94 also acts to hold the lock 60 in the slot 46 of the cooperating member when tab 80 is urged in the counter bias direction, as is evident from FIG. 4B. The orientation illustrated in FIG. 4B corresponds to the condition or position of the merchandising system illustrated in FIG. 3B. Again, mounting member 20 is not shown for simplicity. FIG. 4B shows the tab 80 of lock 60 as being urged in a direction counter to the natural bias of the resilient member 66, as indicated by the arrow. In this condition, the ring-shaped element 70 compresses against the bias of the resilient member 66 such that the lock 60 can be disengaged. The limits of movement or compression of the ring-shaped element 70 can be regulated by the size and shape of the chamber 44. More particularly, connection system 90 acts against the ring-shaped element 70 as it is urged rearward. In addition, the resilient member 66 fits within the chamber 44 and movement past the chamber is, thus, prevented or at least retarded. As illustrated in FIGS. 7 and 8, a plurality of cooperating members 40 can be located on a shelf in a spaced side-by-side manner so as to allow multiple columns of merchandise to be urged forwardly on a shelf. Moreover, one or more tracks 150 can also be provided. It should be evident from FIG. 8, that cooperating members can include a type which comprises a base on which are defined rails for accommodating a pusher 156. On the other hand, cooperating members, such as at 40′ can include types which only comprise a divider portion 130′ and do not also include a track located on a base. Disposed between such cooperating members can be one or more tracks 150. In one embodiment, the tracks do not include a divider as disclosed herein, but merely include a pusher assembly 156. In the disclosed embodiment, the tracks do not have a front wall member of the type illustrated in FIGS. 1-4, nor do they have a lock member of the type illustrated in FIGS. 1-4, and 6. Of course, other embodiments of such tracks could include at least one of a front wall and/or a lock if so desired. On the other hand, cooperating member 40′ does include such a front wall 110′ and lock 60′. Disclosed has been a merchandising system which comprises an elongated mounting member selectively securable to an associated shelf and a cooperating member received on the mounting member, wherein the cooperating member extends rearwardly over the associated shelf. The mounting member comprises a wall. The cooperating member in one embodiment comprises an elongated body including at least one tooth. The at least one tooth is movably mounted to the cooperating member and selectively engages the wall of the elongated mounting member. In one embodiment, an elongated mounting member wall comprises at least one tooth which selectively engages the at least one tooth of the cooperating member. The at least one tooth is located on a front end of the cooperating member and is adapted to engage the wall of the mounting member. The cooperating member can include a chamber accessible through a slot defined in the front end. In one embodiment, a lock is mounted to the cooperating member. The lock includes at least one tooth located at a first end of a lock body and a resilient member located at a second end thereof. The resilient member is adapted to bias the at least one tooth of the lock into engagement with at least one tooth of the mounting member. If desired, a protrusion can be mounted on the lock which protrusion is accessible from a portion of the cooperating member. In one embodiment, the mounting member and the lock include a plurality of spaced teeth which are each adapted to selectively engage each other. A connection system can connect the lock to the cooperating member. In one embodiment, the connection system includes a protrusion located in the slot of the cooperating member and a clip defined on the lock. The clip selectively mounts to the protrusion in order to hold the lock in the slot. In one embodiment, a front wall is slidably mounted to a divider portion which protrudes from the base portion. If desired, the front wall can be made of a transparent material. The disclosure has been described with reference to several embodiments. Obviously, modifications and alterations will occur to others upon a reading and understanding of the preceding detailed description. It is intended that the instant disclosure be construed as including all such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.
<SOH> BACKGROUND <EOH>The present disclosure pertains to a merchandising system. More specifically, the disclosure relates to a base and divider assembly employed in a forward feeding display merchandising system for storing and displaying merchandise of a variety of shapes and sizes and automatically delivering the merchandise to the front of a shelf. More particularly, the disclosure pertains to a cooperating member, such as a divider or track which can be selectively locked to a front rail or mounting member of the merchandising system. Shelving is used extensively for stocking and storing products or merchandise in a variety of stores, such as grocery stores, drug stores and mass merchandisers, such as Walmart, Kmart and the like. Most consumer product stores contain fixed shelving which is arranged back to back between aisleways, on which shelving merchandise is stocked. It is desirable for merchandise to be displayed at the front edge of the shelf so that the customer can see the merchandise and be induced to purchase such merchandise. In such stores, if the shelves are not positioned at eye level, it is difficult for the customer to see the items being displayed, if the items are not located adjacent the front edge of the shelf. Also, fixed shelves make it difficult to rotate product, i.e., move the older stock to the front of the shelf and position newer stock behind the older stock. Rotating products is an important consideration if the goods are perishable or subject to becoming stale (cigarettes, fruit juices, dairy products and the like fall into this category). It is important for such articles that they be removed following a first in, first out system to maintain freshness. Forward feed devices are employed to automatically move an item forward on a shelf, as the item before it in a column of merchandise is removed from the shelf. These devices generally fall into three categories. The first category pertains to inclined tracks which rely on gravity to feed, slide, or roll products forward on the shelf. Gravity feeding, however, may be unpredictable in that various materials or packages slide more easily than others because of different weights and frictional interfaces between the products and the track. The second category employs conveyor belts which still use gravity to effect forward movement. These devices are typically cumbersome, expensive and complicated due to the need to properly tension the track and the conveyor belts. The third category uses spring biased pusher paddles to feed the product forward. Such paddle based forward feed devices have become very popular and have been found useful for a variety of merchandise. In the third category, separate dividers and tracks containing pusher paddles are usually employed, along with end dividers to separate the merchandise into columns. It has been considered advantageous to provide an integrated track and divider system because such an integrated track and divider makes assembly of the merchandising system on a shelf easier for store personnel as there are less components to handle. However, an integrated track and divider is disadvantageous from the perspective that the divider cannot be removed from the track should that become necessary. In some circumstances, such as for wide products, a drop in track is desired so that two pusher paddles urge the merchandise forward. Currently, a separate track has to be produced for this purpose. It would be desirable to automatically lock a divider to a front rail in order to retard the sideward or lateral movement of one or more dividers as product is being pushed forward on the track by the spring biased pusher paddles. In other words, it would be desirable to allow the divider to automatically engage the front rail in such a way that the divider is retarded from such sliding movement in one end position of the locking assembly but is allowed to slide sideways in relation to the front rail in another end position of the locking assembly. Ideally, the divider would be movable in a lateral direction parallel to the front rail while being secured in a direction perpendicular to the front rail when a locking member is disengaged but the divider would resist movement in the lateral direction parallel to the front rail and would remain secured in a direction perpendicular to the front rail when the locking member is engaged. It may be advantageous to provide tracks with such a feature as well.
<SOH> BRIEF SUMMARY OF THE DISCLOSURE <EOH>In accordance with one embodiment of the present disclosure, a merchandising system comprises an elongated mounting member including a wall, the wall comprising at least one tooth and a cooperating member including a front end. The front end is adapted to be received on the mounting member and is adapted to selectively engage the wall thereof. The cooperating member includes a chamber accessible through a slot defined in the front end of the cooperating member. A lock is received in the slot. The lock includes at least one tooth located at a first end and a resilient member located at a second end, wherein the resilient member is adapted to bias the at least one tooth of the lock into engagement with the at least one tooth of the mounting member so as to retard a lateral movement of the cooperating member in relation to the mounting member. The lock is linearly movable relative to a cooperating member against a bias of the resilient member in order to selectively disengage the lock at least one tooth from the at least one tooth of the cooperating member thereby permitting a lateral movement of the cooperating member in relation to the mounting member. In accordance with another embodiment of the present disclosure, a merchandising system comprises an elongated mounting member, including a longitudinal axis, the mounting member including a front wall, a back wall and a channel defined between the front wall and the back wall, the front wall including a plurality of spaced teeth. A cooperating member includes an elongated body which is oriented in a direction generally transverse to the mounting member longitudinal axis. The cooperating member includes a front end, wherein at least a portion of the cooperating member front end is received in the channel of the mounting member and wherein the front end comprises a chamber accessible via a slot defined in the front end. A lock is received in the slot and is mounted to the cooperating member. The lock includes a first end comprising a plurality of spaced teeth and a second end comprising a biasing member adapted for biasing the lock forwardly in the chamber. The plurality of spaced teeth of the elongated mounting member selectively engages the plurality of spaced teeth of the lock to retard a lateral movement of the cooperating member in relation to the mounting member. The plurality of spaced teeth of the mounting member are disengaged from the plurality of spaced teeth of the lock when the lock is slid rearwardly away from the cooperating member front end against the bias of the biasing member thereby permitting the lateral movement of the cooperating member in relation to the mounting member. In accordance with still another embodiment of the present disclosure, there is provided a merchandising system which comprises an elongated mounting member including a first engaging member and a cooperating member configured to attach to the mounting member, the cooperating member including a front end comprising a second engaging member. A third engaging member is mounted to the cooperating member, wherein the third engaging member is adapted to move linearly along a longitudinal axis of the cooperating member from an extended position to a retracted position. The third engaging member comprises a first end including an engaging element for selectively engaging a surface of the mounting member and a second end comprising a biasing member for biasing the third engaging member to the extended position in order to retard a movement of the cooperating member in a lateral direction parallel to a longitudinal axis of the mounting member. The third engaging member also includes a tab extending over the mounting member. The tab is adapted to be manually contacted for pushing the third engaging member into a retracted position against the bias of the biasing member.
A47F1125
20170829
20180215
73203.0
A47F112
0
NOVOSAD, JENNIFER ELEANORE
Selectively Locking Merchandising Member
UNDISCOUNTED
1
CONT-ACCEPTED
A47F
2,017
15,689,947
PENDING
LED LIGHT TUBE END CAP WITH SELF-DOCKING DRIVER COMM BOARD
An LED light tube assembly comprising an LED light tube with an LED array board in a tubular housing, and an end cap with a driver board removably secured to the end of the LED light tube. The driver board extends from a cap midpoint at a first level corresponding to an underside of the LED board in the tube, and the cap includes a connector tongue spaced from and parallel to the driver board at a second level corresponding to a portion of the sidewall of the tubular housing. The driver board further includes spring terminals that frictionally engage an upper surface of the LED board as the cap is assembled to the light tube, while remaining assembly and connection forces are borne by the cap and the tubular housing.
1. An LED light tube assembly comprising an LED light tube comprising an LED board mounted in a tubular housing including a translucent cover and a sidewall portion opposite the translucent cover, and a removable end cap assembly with external electrical connector terminals, wherein: the end cap assembly comprises an end cap having a sidewall, and a driver board extending axially from the end cap at a first midpoint level corresponding to an underside of the LED board; a connector tongue extending axially from the cap sidewall generally parallel to and spaced radially from the driver board at a second level corresponding to the sidewall portion of the tubular housing, the connector tongue configured to mate with an outer end portion of the sidewall portion of the tubular housing to axially and rotationally secure the cap assembly to the LED light tube; spring-biased power supply terminals on an upper, outer end surface of the driver board configured to engage an upper surface of an outer end of the LED board when axially assembled thereto; wherein, when the end cap is in an assembled condition on the LED light tube, the driver board extends underneath and generally parallel to the LED board, with an inner end of the driver board suspended in free fashion in the LED light tube beneath the LED board. 2. The LED light tube assembly of claim 1, wherein the connector tongue includes a detent and guide cooperating with a detent aperture and slot, respectively, on the tubular housing sidewall to align the driver and LED boards as the cap is applied, and to secure the end cap on the tube simultaneously with an engagement of the spring-biased power supply terminals with the upper, outer end surface of the LED board. 3. The LED light tube assembly of claim 1, wherein the driver board includes a status indicator light and/or a wireless communication component located on an underside of the driver board, facing away from the underside of the LED board, and the cap includes a window operatively aligned with the status indicator light and/or wireless communication component. 4. The LED light tube assembly of claim 1, wherein an upper surface of at least the inner end of the driver board is spaced from the lower surface of the LED board in the assembled condition. 5. The LED light tube assembly of claim 4, wherein an entirety of the upper surface of the driver board is spaced from the lower surface of the LED board in the assembled condition. 6. The LED light tube assembly of claim 1, wherein the driver board extends axially from the end cap farther than the connector tongue. 7. The LED light tube assembly of claim 1, wherein the end cap includes a docking structure for an outer end of the driver board, and the LED light tube includes a docking cutout area configured to mate with a portion of the end cap docking structure in the assembled condition, and further wherein the docking cutout area provides a view of an engagement of the spring-biased power supply terminals with the upper, outer end surface of the LED board through the translucent cover in the assembled condition. 8. The LED light tube assembly of claim 1, wherein the driver board and the connector tongue are located between the LED board and the light tube sidewall portion in the assembled condition. 9. The LED light tube assembly of claim 1, wherein at least one of the upper surface of the driver board and the lower surface of the LED board is free of protruding circuit and/or communication components. 10. The LED light tube assembly of claim 1, wherein sliding frictional engagement of free ends of the spring-biased power supply terminals on the driver board with contacts on the upper surface of the outer end of the LED board when axially assembled thereto is the only contact between the driver board and the LED board in the assembled condition.
RELATED APPLICATIONS/PRIORITY BENEFIT CLAIM This application claims the benefit of U.S. Provisional Application No. 62/381,111, filed Aug. 30, 2016 by the same inventor (Thiel), the entirety of which provisional application is hereby incorporated by reference. FIELD The subject matter of the present application is in the field of end caps for LED lighting fixture tubes. BACKGROUND Large scale lighting systems for businesses, industrial operations, educational institutions, hospitals and similar have traditionally used fluorescent light fixtures with replaceable fluorescent light tubes. These fluorescent tubes are increasingly being replaced with LED (light emitting diode) light tubes having arrays of board-mounted LEDs with power supply or “driver” circuits for controlling LED operating parameters. In some cases it is desirable to have driver circuitry in a driver board separate from the LED board. Prior driver boards are commonly soldered or connected by wire-and-plug terminals between the end cap and the LED board, in order to simplify replacement and to make it easier to modify or add to the functionality of the basic LED lighting in the tube by swapping out one type of driver board for another. In some prior LED tubes the driver board is built into or connected directly to the end cap, for example by being integrated with an LED array in the end cap itself (U.S. Pat. No. 7,946,729), or with slot-to-board or header connections between a driver-containing board and the end cap (Chinese patent grant CN 204460096 U; Published App. No. US2013/0230995 Al to Ivey et al). It is also known to provide circuit boards in light tubes with wireless communication chips such as Bluetooth low energy (BLE) sensor modules, in order to enable building-wide wireless communication and/or sensor networks useful for signal tracking. An example of such an LED board is described in U.S. Pat. No. 8,214,084 to Ivey et al. Another example is shown in Published App. No. US2014/0375204 A1, with a communication circuit board in the end cap connected directly to a driver board. Prior LED light tube driver and end cap arrangements are believed to be lacking in simplicity, strength, ease of replacement, and flexibility with respect to replacing malfunctioning driver boards or retrofitting existing LED light tubes for different communication and networking capabilities. BRIEF SUMMARY The present invention is an improved structure for replaceably assembling a separate LED driver and/or wireless communication board (hereafter driver board or driver comm board) to an LED light tube of the type used in large scale tube-lighting fixture environments. In a first aspect, the inventive structure comprises an LED light tube having an LED board mounted in a tubular housing with a sidewall and a translucent light-emitting cover, a removable end cap with external electrical connector terminals (e.g., pins), and a driver board separate from the LED board. The driver board is integrated with the end cap for a strong, easily assembled snap-connection to the LED board and tube. The snap-connection of the driver board to the tube via the end cap makes a simultaneous electrical and mechanical connection providing a multi-level structural bridge between end cap, driver board, and LED array. The end cap comprises a driver board extending axially from a cap midpoint at a first level corresponding to an underside of the LED board; and, a connector tongue extending from the cap sidewall, generally parallel to the driver board at a second level corresponding to the light tube sidewall opposite the translucent cover. An upper, outer (cap-side) end surface of the driver board includes spring-biased power supply terminals that mechanically and electrically engage the upper surface of an outer end of the LED board. The connector tongue includes a detent and guide cooperating with a slot and detent aperture on the light tube sidewall to align the driver and LED boards as the cap is applied, to secure the end cap on the tube simultaneously with the terminal connection between the driver and LED boards, and to resist torsion of the end cap on the tube once assembled. When the end cap is fully assembled to the LED light tube, the driver board extends underneath and generally parallel to the LED board, with the outer end of the driver board suspended in free fashion. In a further form, at least some of the circuit and/or communication components of the driver board are located on its underside, facing away from the underside of the LED board. In still a further form, the cap includes a window aligned with the connector tongue below the driver board for RF and/or light transmission, and the driver board includes an RF or similar wireless communication module and/or a function indicator light operatively aligned with the window. These and other features and advantages of the invention will become apparent from the detailed description below, in light of the accompanying drawings. Terms of orientation such as parallel, perpendicular, and the like should be understood as meaning generally so, rather than exact, unless otherwise specified. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an upper side perspective view of an exemplary end cap according to the invention, with the driver board portion shown exploded from the cap. FIG. 2 is similar to FIG. 1, showing the end cap fully assembled, the assembled cap aligned for assembly to an LED light tube. FIG. 3 is similar to FIG. 2, showing the end cap partially assembled to the light tube. FIG. 4 is similar to FIG. 3, showing the end cap fully assembled to the light tube from an upper perspective. FIG. 5 is a lower side perspective view of the end cap and light tube of FIG. 1, showing the end cap aligned for assembly to the LED light tube. FIG. 6 is similar to FIG. 5, showing the end cap partially assembled to the light tube. FIG. 7 is similar to FIG. 6, showing the end cap fully assembled to the light tube. FIG. 8 is a side elevation view, partially sectioned, showing the end cap fully assembled to the light tube. DETAILED DESCRIPTION Referring first to FIG. 1, an end cap assembly 20 is shown in exemplary form in order to teach how to make and use the claimed invention. End cap assembly 20 comprises an end cap 30 and a driver board 50. End cap 30 may be made for example from a durable molded plastic, with a sidewall 32 defining an interior shaped to mate with the open end of an LED light tube (FIG. 2). A midpoint driver board docking structure 34 is formed on the cap's interior, with “midpoint” meaning an intermediate location spaced between the upper and lower sides of cap 30, including but not limited to the center of the cap. In the illustrated example of a cap 30 with a circular sidewall 32, “upper” and “lower” sides will be used as terms of relative orientation based on the orientation of the drawing, and are not limiting as to the installed position of the light tube. It will be understood that although a tubular light tube with a circular sidewall end cap is shown, other tubular cross-sectional shapes with matching end cap configurations are possible. Cap 30 also includes a pair of electrical connector terminals 38 protruding from its outer end. Terminals 38 may be of any known type, for example metal pins commonly used for tube lighting fixture elements. Driver board docking structure 34 in the illustrated example comprises a pair of opposed axial rails 36 on the interior of sidewall 32, aligned in parallel with and bracketing the inner ends 38a of electrical connector terminals 38. Docking structure 34 is preferably an integral molded feature of the cap on sidewall 32, or projecting from the interior side of the cap outer end wall 31. Docking structure 34 may alternatively comprise separately formed structure of the same or different material attached to the cap interior. Illustrated rails 36 define generally C-shaped grooves 36a with raised, angled ramps 36b at the entrances to the grooves. Cap 30 also includes a connector tongue 40 extending axially from the lower side of sidewall 32, and therefore spaced radially from and generally parallel to driver board docking structure 34. Connector tongue 40 includes a lower side detent tab 42 projecting downwardly from its inner free end and an upper side aperture or light and/or RF transmissive window 44 at its outer base end near where it joins cap sidewall 32. Connector tongue 40 also includes a lower side guide 46 at its outer or base end, the guide 46 shaped to slidingly mate with a corresponding female alignment feature on an LED light tube (FIG. 2). Illustrated cap 30 also includes an elongated RF and/or light transmissive window 48 on its lower side (FIG. 5) aligned with and spaced outwardly from connector tongue 40, which also happens to align at least a portion of the window with the underside of driver board 50 when the driver board is assembled to cap 30. More specifically, the forward or inner end of window 48 is aligned with base guide feature 46 and aperture 44 in tongue 40 to efficiently transmit light and/or wireless signals from components on board 50 through the cap sidewall. While cap 30 can be formed from different materials such as plastic or metal, an easily molded, heat-resistant polymer is preferred except where metal is needed for electrical contact or additional strength. Windows 44 and 48 may be open apertures, or may be formed from suitably light transmissive and/or wireless signal transmissive material. In one embodiment the window 44 may be a light tube to light window 48 showing status from an interior status-indicating LED. Still referring to FIG. 1, exemplary driver board 50 has an outer end 52 configured to be removably secured in cap 30 by mating with driver board docking structure 34. Outer end 52 includes terminal-receiving slots 54 defining outer fingers 56 and center tab 58, shaped to slide into and frictionally mate with the rails 36 and to receive at least some portion of the pin terminal ends 38a of the cap-side docking structure 34. Pin ends 38a are injection molded into the end cap 30 and soldered to the board in slots 54. Inner ends of fingers 56 or underside portions of driver board 50 adjacent the fingers may include recesses or protrusions to engage and axially lock onto rail entrance ramp portions 36b for a more secure fit, and terminal ends 38a are preferably mechanically soldered to the board 50 in slots 54 in electrical connection with terminals 60 via internal or surface conductors schematically illustrated at 61 extending from terminals 60 to slots 54, for strength. Any known soldering technique can be used, and it is possible to re-flow solder any or all components that need or that can benefit from a solder connection between metal contacts in one step once the driver board 50 is first mechanically assembled to cap 30. Spring stop terminals 60 protrude from the driver board's upper surface 51, establishing spaced parallel electrical connection points in communication via internal or external conductor paths on the driver board with the LED driver and communication circuitry located elsewhere on the board. Driver board 50 may utilize conventional circuit board materials and construction, for example of the MPCB type, and includes known LED driver or power control circuitry 70 such as one or more driver chips. Driver board 50 may also include one or more types of wireless communication circuitry or modules or wireless sensors 80, for example Bluetooth® type low energy (BLE) sensor modules and/or high frequency RF modules (e.g., 915 MHz standard or similar), and may further include a button battery, rechargeable battery, or supercapacitor backup power source 90 for power interruptions or when power to the system is off. This battery or supercapacitor may also illuminate the circuit board indicator lights for specific purposes programmed by an outside source. In the illustrated example, at least some and preferably all of the circuitry 70, 80 is located on the lower face 53 of the driver board, facing connector tongue 40 and the lower side of cap 30. Illustrated driver board 50 includes an LED status indicator light 95 on its lower side 53. Status light 95 is positioned to be vertically or at least visually or optically aligned with aperture 44 and window 48. Window 48 may also be positioned or sized to provide optimal RF or other wireless transmission from wireless communication features 80 on driver board 50. Referring now to FIGS. 2 and 5, the assembled cap-and-driver board assembly 30, 50 is shown being aligned for fitting onto the open end of a mating LED light tube 100. Light tube 100 includes a lower housing sidewall 102, for example an opaque material (although a translucent material is possible), and an upper translucent or transparent (hereafter translucent) cover 104, both made of known materials generally used for light tubes. The cover portion of the light tube may be integral with or separable from the sidewall portion 102. An LED board 106 of conventional type is mounted lengthwise in tube 100, comprising for example MPCB 106a, an array of electrically connected LED lights or emitters 106b facing cover 104 to emit light therethrough, and upper surface driver board contacts 106c in electrical contact with LED lights 106b through suitable connections on or in board 106a. Light tube 100 additionally includes a pair of side rails 108 running lengthwise generally along the junction between the lower housing sidewall 102 and the upper translucent cover 104, molded for example into the material of housing sidewall 102. The outer ends 108b of side rails 108 are relieved at 108a to define a widened docking cutout area for the mating terminal portions 60 and 106c of driver board 50 and LED board 106. Docking terminal cutout 108a also allows visual confirmation of the contact between terminals 60 and 106c when the cap is assembled to the light tube. As best shown in FIG. 4, docking rails 36 on cap 30 slidingly mate with channels formed by the outer ends 108b of side rails 108 in the relieved area 108a. Cap-to-tube assembly begins as shown in FIGS. 2-3 and 5-6, by sliding the inner free end 50a of driver board 50 axially underneath LED board 106 in the light tube. If the upper surface 51 of driver board 50 and/or the lower surface of LED board 106 is free of protruding circuit and/or communication components, as shown in the illustrated example, the risk of damage to the respective boards 50, 106 is reduced. Connector tongue 40 is engaged with the inner surface of the lower housing sidewall 102. Lower detent tab 42 on tongue 40 first is aligned with alignment slot 110 on the lower housing sidewall 102 of the light tube as it proceeds into the tube, and may then slides on the interior surface of housing sidewall 102 to guide it into engagement with detent locking aperture 112 spaced inwardly from slot 110. A groove or channel (not shown) may optionally be provided on the inner surface of housing sidewall 102 in alignment with and between slot 110 and aperture 112 to help guide tab 42 into the aperture, if desired. Guide base 46 at the outer or base end of connector tongue 40 will enter slot 110 partway through the assembly process, further maintaining rotational alignment of the cap and tube until they are fully assembled. Assembly continues and is finalized as shown in FIGS. 4 and 7, where detent tab 42 on the connector tongue 40 engages detent aperture 112, and the inner end of guide 46 abuts the inner, matingly-shaped end of slot 110. At the same time, the free ends 60b of stop terminals 60 on the upper side of driver board 50 frictionally engage terminal contacts 106c on the upper side of the LED board 106, with upright portions 106a of the terminals remaining spaced from the outer end of LED board 106 so that the stop point is determined by the mechanical connection between connector tongue 40 and guide base 46 and the mating features 112, 110 on the lower inner surface of tube 100. Referring now to FIG. 8, the assembled cap 30 and LED light tube 100 form a structurally strong multi-level mechanical connection, wherein the inner end 55 of the driver board 50 is suspended in free fashion below LED board 106, with the upper surface 51 of the driver board preferably spaced from the lower surface of the LED board 106, and the driver board is only subject to the sliding frictional forces between the ends of spring terminals 60 and the electrical contacts 106c on the upper face 106a and outer end of LED board 106. All other cap-to-tube connection forces are borne by the cap and light tube housings 30, 102 and their respective mechanical connection structures. When cap 30 needs to be removed for maintenance or replacement of the driver board 50, pushing on connector tongue detent tab 42 through aperture 112 in the lower tubular housing sidewall 102 unlocks cap 30, which can then be pulled free from the LED light tube by simply overcoming the frictional force of the driver board terminals 60 on the upper surface of LED board 106, without placing any additional stress on the driver board itself. Likewise, once cap 30 is removed from light tube 100, driver board 50 can simply be pulled free from the docking structure 34 on cap 30 by overcoming the friction between docking rails 36 and the sides or fingers 56 of the driver board, and breaking any solder connection that may have been applied between terminal pin ends 38a and the driver board 50. It will finally be understood that the disclosed embodiments represent presently preferred examples of how to make and use the invention, but are intended to enable rather than limit the invention. Variations and modifications of the illustrated examples in the foregoing written specification and drawings may be possible without departing from the scope of the invention. It should further be understood that to the extent the term “invention” is used in the written specification, it is not to be construed as a limiting term as to number of claimed or disclosed inventions or discoveries or the scope of any such invention or discovery, but as a term which has long been conveniently and widely used to describe new and useful improvements in science and the useful arts. The scope of the invention supported by the above disclosure should accordingly be construed within the scope of what it teaches and suggests to those skilled in the art, and within the scope of any claims that the above disclosure supports in this application or in any other application claiming priority to this application.
<SOH> BACKGROUND <EOH>Large scale lighting systems for businesses, industrial operations, educational institutions, hospitals and similar have traditionally used fluorescent light fixtures with replaceable fluorescent light tubes. These fluorescent tubes are increasingly being replaced with LED (light emitting diode) light tubes having arrays of board-mounted LEDs with power supply or “driver” circuits for controlling LED operating parameters. In some cases it is desirable to have driver circuitry in a driver board separate from the LED board. Prior driver boards are commonly soldered or connected by wire-and-plug terminals between the end cap and the LED board, in order to simplify replacement and to make it easier to modify or add to the functionality of the basic LED lighting in the tube by swapping out one type of driver board for another. In some prior LED tubes the driver board is built into or connected directly to the end cap, for example by being integrated with an LED array in the end cap itself (U.S. Pat. No. 7,946,729), or with slot-to-board or header connections between a driver-containing board and the end cap (Chinese patent grant CN 204460096 U; Published App. No. US2013/0230995 Al to Ivey et al). It is also known to provide circuit boards in light tubes with wireless communication chips such as Bluetooth low energy (BLE) sensor modules, in order to enable building-wide wireless communication and/or sensor networks useful for signal tracking. An example of such an LED board is described in U.S. Pat. No. 8,214,084 to Ivey et al. Another example is shown in Published App. No. US2014/0375204 A1, with a communication circuit board in the end cap connected directly to a driver board. Prior LED light tube driver and end cap arrangements are believed to be lacking in simplicity, strength, ease of replacement, and flexibility with respect to replacing malfunctioning driver boards or retrofitting existing LED light tubes for different communication and networking capabilities.
<SOH> BRIEF SUMMARY <EOH>The present invention is an improved structure for replaceably assembling a separate LED driver and/or wireless communication board (hereafter driver board or driver comm board) to an LED light tube of the type used in large scale tube-lighting fixture environments. In a first aspect, the inventive structure comprises an LED light tube having an LED board mounted in a tubular housing with a sidewall and a translucent light-emitting cover, a removable end cap with external electrical connector terminals (e.g., pins), and a driver board separate from the LED board. The driver board is integrated with the end cap for a strong, easily assembled snap-connection to the LED board and tube. The snap-connection of the driver board to the tube via the end cap makes a simultaneous electrical and mechanical connection providing a multi-level structural bridge between end cap, driver board, and LED array. The end cap comprises a driver board extending axially from a cap midpoint at a first level corresponding to an underside of the LED board; and, a connector tongue extending from the cap sidewall, generally parallel to the driver board at a second level corresponding to the light tube sidewall opposite the translucent cover. An upper, outer (cap-side) end surface of the driver board includes spring-biased power supply terminals that mechanically and electrically engage the upper surface of an outer end of the LED board. The connector tongue includes a detent and guide cooperating with a slot and detent aperture on the light tube sidewall to align the driver and LED boards as the cap is applied, to secure the end cap on the tube simultaneously with the terminal connection between the driver and LED boards, and to resist torsion of the end cap on the tube once assembled. When the end cap is fully assembled to the LED light tube, the driver board extends underneath and generally parallel to the LED board, with the outer end of the driver board suspended in free fashion. In a further form, at least some of the circuit and/or communication components of the driver board are located on its underside, facing away from the underside of the LED board. In still a further form, the cap includes a window aligned with the connector tongue below the driver board for RF and/or light transmission, and the driver board includes an RF or similar wireless communication module and/or a function indicator light operatively aligned with the window. These and other features and advantages of the invention will become apparent from the detailed description below, in light of the accompanying drawings. Terms of orientation such as parallel, perpendicular, and the like should be understood as meaning generally so, rather than exact, unless otherwise specified.
F21K9272
20170829
20180301
64415.0
F21K9272
0
GUDORF, LAURA A
LED LIGHT TUBE END CAP WITH SELF-DOCKING DRIVER COMM BOARD
SMALL
0
ACCEPTED
F21K
2,017
15,690,640
PENDING
DIGITAL INFORMATION RECORDING APPARATUS, REPRODUCING APPARATUS AND TRANSMITTING APPARATUS
A digital information recording apparatus includes a recording circuit for recording information of a retention period included in the digital information and indicating a period for permitting the digital information to be held in the recording medium, starting with a time at which the digital information is recorded on the recording medium; and information of a playback permission period included in the digital information and indicating a period for permitting the digital information to be played back starting with a time at which the information is reproduced initially following recording of the digital information on the recording medium, permitting temporary recording or copying for the information permitted for “copy never” or “copy one generation.”
1. A digital information recording apparatus for recording digital information including video information and/or audio information on a first recording medium, comprising: a recording circuit for recording move permission information included in said digital information; said move permission information permitting said digital information to be moved to a second recording medium on the premise that at least a part of said digital information on said first recording medium is disabled for playback, even when said digital information is inhibited from being copied.
CROSS REFERENCE TO RELATED APPLICATION This application is a Continuation of U.S. application Ser. No. 14/713,515, filed May 15, 2015, which is a Continuation of U.S. application Ser. No. 13/649,882, filed Oct. 11, 2012, now U.S. Pat. No. 9,083,942, issued Jul. 14, 2015, which is a Continuation of U.S. application Ser. No. 11/834,340, filed Aug. 6, 2007, now U.S. Pat. No. 8,311,389, issued Nov. 13, 2012, which is a Continuation of U.S. application Ser. No. 09/982,291, filed Oct. 19, 2001, which claims priority from Japanese patent applications JP 2001-002053, filed Jan. 10, 2001, JP 2000-384891, filed on Dec. 13, 2001 and JP 2000-393271, filed Dec. 21, 2000, the contents of which are incorporated by references. BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to an apparatus for recording or reproducing digital information such as video and audio data, more particularly, to digital information recording and reproducing apparatus capable of setting a limit to playback or copying of the information to be recorded or reproduced by the authority of copyright holders and the like. Further, the present invention relates to a transmitting apparatus suitable for transmitting digital information to the recording and reproducing apparatus as above. Description of the Related Art Digital television broadcasting has been started and digital recording and reproducing apparatus for recording and reproducing digital information have been brought to market. In addition, even in the field of package medium such as movie software, package software to be used with this type of apparatus will be developed and practiced in the near future. The digital recording scheme has an advantage that the quality is not deteriorated or very less degraded in the recording and reproducing process. But in the event that many high-quality copies are prepared and circulated at a site unknown to a copyright holder, there arises a problem that profits cannot be returned to the copyrighters. This is a pending problem for which countermeasures have been discussed in various fields since a case of digital audio tape deck at issue. For example, JP-A-11-146378 discloses a method of preventing preparation of high-quality copies by degrading the quality in advance of digitally recording information. U.S. Pat. No. 5,896,454 discloses a method of adding copy control information of 2 bits to data information. In the method, any one of copy inhibition, copy approval and copy approval for only one generation is selected of volition of copyright holders or information planners to control the operation of a recording apparatus. The recording apparatus does not perform recording operation if copy inhibition is selected but performs recording operation if copy approval is selected. With copy approval for only one generation selected, the recording apparatus rewrites this control information into information for inhibiting any more copies and then operates to record. In other words, the copy control information useful for the information data planner to control copying operation by users has been proposed. For example, codes of “copy never” (copy inhibition), “copy one generation” (for permitting only one copy), “no more copies” (data once copied through “copy one generation” is not permitted for more copies) and “copy free” (approval of copying) are set in a header part of data or a watermark (WM), very difficult to detect, is embedded in an image. The above expedient is expected to solve the problem without inflicting a one-sided loss on the copyright holders or users. But, even in case the stringent inhibition, for example, “copy never” is imposed, there is obviously a spontaneous need for temporarily recording information on, for example, a hard disc of a receiving apparatus and playing back the information and therefore, with a view of mitigating a loss on the side of users, a means for this purpose is necessary. At that time, it must also be considered to mitigate a loss on the side of copyright holders. More particularly, when a visitor comes accidentally while the copy control information being set to “copy never” in broadcasting, a user in question disadvantageously looses a chance of playing back a broadcast program. Under the circumstances, JP-A-2000-149417 discloses a method of eliminating such a problem by using a means “temporary recording” even when the copy control information designates “copy never”. According to the method, information is once recorded physically on a recording medium and a limit of 90 minutes for instance is set to the period for reproduction and playback and the information is erased after a playback or at the termination of the period. In other words, the recording is not for long-term conservation and multipurpose utilization but simply permits the broadcasting to be equivalently played back 90 minutes later. Since the information on the recording medium does not remain for a long time, the aforementioned inconvenience of users can be eliminated without inflicting an unprofitableness to the copyright holders. The temporary recording is, because of its nature, carried out frequently by using a hard disc recorder built in the receiving apparatus. SUMMARY OF THE INVENTION Various kinds of expedience disclosed in the above documents give a solution to the problems. But the problem involved in copyright cannot be solved satisfactorily by the conventional methods that inflict one-sided profit or loss to copyright holders, broadcasting or software developing firms or general users. Further, the “copy one generation” conveniently gives the users a chance of backing up the information recorded temporarily on a hard disc for instance. As a rule, once the temporarily recorded information is copied, the copy control information changes to “no more copies” to prevent any more copying. But, when copying of the temporarily recorded information is permitted, though only once, the copy permission remains for a long time, giving anxiety to the copyright holders. On the other hand, when “no more copies” is once set, desired exchange of the medium storing the contents becomes impossible and disadvantageously the users are forced to suffer from inconvenience. In the light of the above problems, an object of the present invention is to provide more specifically a unit for preventing circulation of unauthorized copies and permitting the user to perform conditional playback and the like. Another object of the invention is to provide a unit for eliminating the aforementioned anxiety of the copyright holders and inconvenience of the users through a method of meeting the compatibility between profits of the user and the copyright holder. Still another object of the invention is to provide a unit for limiting a condition for permitting playback of recorded information for instance so as to enable the copyright holder to further control the range of information utilization. According to the invention, the effective period, available inside a recording medium, of information permitted for temporary recording is prescribed. The apparatus has a unit for disabling reproduction and playback after expiration of a prescribed time following recording initiation. Through this, the information temporarily recorded on the medium can be prevented from being used later for unauthorized purposes. The effective period inside the recording medium referred to herein will be called “retention period”. Further, the effective period starting with playback initiation is also prescribed. The apparatus has a unit for disabling repetitive reproduction and playback after expiration of a prescribed time following the initial start of playback. Through this, playback by many and unspecified users can be prevented. The effective period referred to herein will be called “playback permission period”. Frequently, the retention period is set to be equal to or longer than the playback permission period but this is not limitative. Many types of reproducing apparatus cause their operation to temporarily pause or stop during reproduction. Accordingly, even when reproduction is started during the playback permission period, the retention period sometimes happens to stop or end before the playback comes to an end. In that case, concurrently with the stop of the retention period, reproduction is disabled to proceed any more. Alternatively, for convenience of users, even with the retention period stopped, a part of information succeeding the stopping location is once allowed for continuous playback up to the end. In that case, conditionally, further pause and stop are inhibited. In some case, a part once subjected to playback is inhibited for repetitive playback. This can be implemented by disabling backward feed of the medium or making, in some way, a part once subjected to playback non-reproducible during backward feed. When the copyright holder originally sets a limit to copying such as “copy one generation” for instance, copying permitted for the user is limited to some extent. To prevent the temporarily recorded information from staying in the medium for a long time while being conditioned to “copy one generation”, the present invention prescribes the effective period for the information, conditioned to “copy one generation” to stay in the recording medium following, recording of the information. The apparatus has a unit for handling the information as being subject to “no more copies” after expiration of the prescribed period following recording so as to prevent copying, thereby eliminating anxiety of the copyright holder about the long-term stay of the information subject to “copy one generation”. The effective period referred to herein will be called “copy permission period”. In the medium in which the copy permission period has expired or information is copied within the copy permission period, the copy control information changes to “no more copies” to disable copying. In that case, by permitting “move” operation for moving the information to another medium on the presupposition that the original information is to be erased, inconvenience of the user can be obviated. As necessary, the period for permitting the move mode after the control information has changed to “no more copies” or the period for permitting repetitive move after the preceding move may be prescribed. The effective period referred to herein will be called “move permission period”. When the operation is caused to temporarily pause or stop during reproduction even if copying is started during the copy permission period, the move permission period will sometimes be stopped before it comes to an end. In that case, concurrently with the stoppage of the copy permission period, any more copying is inhibited. Alternatively, for convenience of the user, even with the copy permission period stopped, a part succeeding the stop location can once be allowed for continuous copying up to the end. In that case, conditionally, further pause and stop are inhibited. BRIEF DESCRIPTION OF THE DRAWINGS These and other objects, features and advantages of the present invention will become more readily apparent from the following detailed description when taken in conjunction with the accompanying drawings wherein: FIG. 1 is a block diagram showing an embodiment of the configuration of the whole of a digital information transmitting, receiving, recording and reproducing system to which digital information recording apparatus, reproducing apparatus and transmitting apparatus according to the invention are applied; FIG. 2 is a block diagram showing an embodiment of the digital information transmitting apparatus according to the invention; FIG. 3 is a block diagram of a digital information receiving side in FIG. 1; FIG. 4 is a block diagram showing an embodiment of a recording circuit in the digital information recording apparatus according to the invention; FIG. 5 is a block diagram showing an embodiment of a recording and reproducing unit in the digital information recording apparatus and reproducing apparatus according to the invention; FIG. 6 is a block diagram showing an embodiment of a reproducing circuit in the digital information reproducing apparatus according to the invention; FIG. 7 is a block diagram showing another embodiment of the reproducing circuit in the digital information reproducing apparatus according to the invention; FIG. 8 is a diagram showing an embodiment of the structure of first control information according to the invention; FIG. 9 is a diagram showing an embodiment of the structure of copy control information according to the invention; FIG. 10 is a diagram showing an embodiment of the structure of second control information according to the invention; FIG. 11 is a diagram showing an embodiment of recording data on recording medium according to the invention; FIG. 12 is a block diagram showing still another embodiment of the reproducing circuit in the digital information reproducing apparatus according to the invention; FIG. 13 is a block diagram showing another embodiment of the recording circuit in the digital information recording apparatus according to the invention; FIG. 14 is a block diagram showing another embodiment of the digital information reproducing apparatus according to the invention; and FIG. 15 is a block diagram showing an embodiment of an erasing circuit in the digital information reproducing apparatus according to the invention. DETAILED DESCRIPTION OF THE EMBODIMENTS FIG. 1 is a block diagram showing an overall configuration of a transmitting, receiving, recording and reproducing system including an information distributor. The present invention involves a recording apparatus, a reproducing apparatus and a transmitting apparatus, having a reproducing circuit 1, a recording circuit 2, an information distributor 3 such as a broadcasting station, a repeater 4, a tuner for RF (radio frequency) 5, a recording/reproducing unit 6 and a display 7. The information distributor 3 such as a broadcasting station transmits a signal electromagnetic wave modulated with information through the medium of the repeater 4 such as, for example, a broadcasting satellite. Otherwise, transmission based on a cable may be employed. The RF tuner 5 on the receiving side receives and demodulates the transmitted information and thereafter, the recording circuit 2 converts it into a signal suitable for recording on a recording medium and the recording/reproducing unit 6 records the converted signal. The recording/reproducing unit 6 also reproduces the information from the recording medium. A reproduction signal is applied to the display 7 through the reproducing circuit 1 to ensure playback of the information representing original video and audio data. Though not illustrated, the received information can also be played back directly. In case information recorded in advance on a removable recording medium is serviced, only the operation succeeding the reproducing operation by the recording/reproducing unit 6 is carried out. FIG. 2 is a block diagram showing an embodiment of the construction of the information distributor 3 (transmitting apparatus) such as a broadcasting station. The transmitting apparatus comprises a program generator 31, an encode circuit 32 for performing compression based on, for example, MPEG scheme, a scrambler circuit 33, a modulator circuit 34, a transmitting antenna 35, a service information applying circuit 36 and an input terminal 37. The amount of data in information such as video/audio information generated by the program generator 31 constituted of a camera or recording/reproducing device is compressed by the encode circuit 32 so that the information may be transmitted with a less bandwidth. As necessary, the information is encrypted by means of the scrambler circuit 33 to enable a specified audience to take part in playback. The encrypted information is modulated to a signal suitable for transmission by means of the modulator circuit 34 and then is emitted from the transmitting antenna 35 in the form of an electric wave directed to the repeater such as, for example, a broadcasting satellite. In this phase, the service information applying circuit 36 adds information such as copy control information and retention information and playback/copy permission period information. In addition to the above information, the present time information may be applied which can be utilized as a start point of the retention period and copy permission period. For example, request information is inputted to the input terminal 37 through a telephone line for instance. This is utilized for the case where the information to be transmitted is determined in response to a request from audiences as exemplified by video-on-demand. FIG. 3 is a block diagram showing an embodiment of the RF tuner 5 shown in FIG. 1. The RF tuner 5 includes an RF/IF converter circuit 51, a demodulator circuit 52, a descrambler circuit 53 for decoding or decrypting the cipher applied to the signal and an output terminal 54. An electric field from the repeater, for example, a broadcasting satellite is inputted to the RF/IF converter circuit 51. The RF-band electric wave is converted in frequency to a frequency of IF (intermediate frequency) band or is converted into a signal of a constant band independent of a receiving channel. The demodulator circuit 52 releases the modulation operation applied for the purpose of transmission. The cipher in the demodulated signal is then decrypted by the descrambler circuit 53 and then delivered to the output terminal 54. FIG. 4 is a block diagram showing an embodiment of the recording circuit 2. The recording circuit 2 has an input terminal 201 for a signal to be recorded, a memory circuit 202 such as a semiconductor memory, a recording signal processing circuit 203, an output terminal 204 for a signal to be recorded on a recording medium, an information detection circuit 205, a recording control circuit 206, a clock 107 and an input terminal 208 for records of a control signal during reproduction. The signal inputted through the input terminal 201 is applied with various control codes. As an example, a signal applied with the copy information “copy never” and designated with the aforementioned retention period and playback permission period will be described. In the case of broadcasting, the data as above is applied to the information by means of, for example, the service information applying circuit 36 of FIG. 2. The inputted data is once stored block by block in the memory circuit 202. Then, the data is fed to the information detection circuit 205 which in turn detects the control information concerning copying. Subsequently, the recording control circuit 206 decides on the basis of the data as above whether the signal is permitted for recording and sends a decision result to the recording signal processing circuit 203. The recording signal processing circuit 203 has already been applied with the data from the memory circuit 202 and on the basis of the control signal from the recording control circuit 206, it interrupts the signal when recording is inhibited but applies a modulation suitable for the medium used when recording is permitted, thus delivering a modulated signal to the output terminal 204. The output signal is recorded on a medium such as a tape or disc. For example, even when the control information is “copy never”, the output signal is recorded temporarily on the medium if the effective retention period and playback permission period are designated. Obviously, instead of being detected by the information detection circuit 205, the control signal may be applied externally, separately from video/audio data. When recording is permissible, the information including the copy control information and the retention period and playback permission period is generated by the recording control circuit 206 and is added to the recording signal by means of the recording signal processing circuit 203. As necessary, the present time during recording delivered out of the clock 107 is also recorded concurrently. If the present time is included in the received information, this data may be used or the clock 107 may be set by the received information. Through this, the present time during recording can be prevented from being altered. With the aforementioned control information being “copy any generation”, if the effective copy permission period is designated or the move permission period is designated as necessary, information is recorded temporarily on the medium while keeping “copy one generation” unchanged. In case the control information is “no more copies”, copying is inhibited as a rule and therefore, the output of, for example, the recording signal processing circuit 203 is interrupted. In the case of an apparatus in which the aforementioned move mode is permitted, however, recording of information onto the medium is permitted even for “no more copies” on the premise that a counterpart of the information on the side of the apparatus transmitting that information will be erased. In that case, it is sometimes necessary to transmit, to the apparatus on the recording side, information as to whether the erase operation of the transmitting apparatus is adapted to the move mode. Instead of detecting the control information inclusive of such information as just mentioned above by means of the information detection circuit 205, that information may be applied externally separately from the video and audio data. If the aforementioned move permission period is additionally designated, even the apparatus adapted to the move mode is not permitted to do move when the above move permission period runs out or expires. Even with the detected control information being “copy one generation”, in the absence of information such as copy permission period, the control information is changed to “no more copies” by means of the recording signal processing circuit 203 during recording. FIG. 5 is a block diagram showing an embodiment of the recording/reproducing unit 6 shown in FIG. 1. The recording/reproducing unit 6 includes an input terminal 61, a recording amplifier 62, a recording media drive 63 carrying a recording medium such as a hard disc/digital video disc/video tape, a reproducing amplifier 64, an output terminal 65, a mechanism control circuit 66 and an input terminal 67. The output signal of the recording circuit 2 is supplied to the input terminal 61. This signal is amplified by the recording amplifier 62 so as to be able to drive a laser generation device or a magnetic head and is then recorded on the recording medium as above by means of the recording media drive 63. A signal reproduced from the recording medium is amplified by the reproducing amplifier 64 up to a level that can afford to be processed in the succeeding stage of signal processing and thereafter delivered to the output terminal 65. The mechanism control circuit 66 is for a motor used to drive the recording media drive 63 and is responsive to a control signal inputted to the input terminal 67 to control the recording medium. Though not illustrated, the control signal inputted to the input terminal 67 is fed from the recording circuit 2 or reproducing circuit 1. FIG. 6 is a block diagram showing an embodiment of the recording circuit 1 of the information reproducing apparatus according to the invention. The reproducing circuit 1 includes an input terminal 101 for a reproduction signal, a reproducing signal processing circuit 102, a block detection circuit 103, a memory circuit 104 such as a semiconductor memory, an error correction circuit 105, a signal output circuit 106, a clock 107, a decoder 108 for decoding moving picture compression, a watermark detection circuit 109 for decryption of a watermark embedded in an image, an output terminal 110 for sending a signal to the display, an information detection circuit 111 for control signals, an output control circuit 112 for deciding, on the basis of a control signal, whether delivery of a reproduction signal is permissible, an output terminal 113 for the signal kept away from decoding of the cipher, an output terminal 114 for a decision result, and an output terminal 116 for the control information delivered to the input terminal 208 of recording circuit 2. The following description will be given by way of a case in which data concerning the aforementioned retention period and playback permission period are included in the reproduction signal supplied to the input terminal 101. The signal is fed to the reproducing signal processing circuit 102. In this circuit, the modulation applied on the recording side for the purpose of performing recording/reproduction on/from the medium is demodulated, the waveform equalization is carried out and data is settled by a clock. Subsequently, in the block detection circuit 103, synchronization and ID signals are detected, on the basis of these signals, reproduction data is once stored at a predetermined location in the memory circuit 104. The error correction circuit 105 detects from the stored data a code error generated in the course of recording and reproduction through arithmetic operation to provide a corrected value. Data subject to error correction is sent to the decoder 108 through the signal output circuit 106. An output of the signal output circuit 106 is also supplied to the output terminal 113 so as to be used for further copying by a different recording device connected to this terminal 113. But in the case of a signal applied with stringent copy limit as described previously, the signal delivered from this output terminal is subject to “copy never” and therefore, copying often fails to fulfill itself. An output of output control circuit 112 to be described later may be supplied to the signal output circuit 106 to prevent the signal from being delivered to the output terminal 113. On the other hand, from the data applied with the previous error correction, the information detection circuit 111 for control signal detects data indicative of the retention period and playback permission period. One data detection operation per one frame of an image suffices to provide sufficient information as will be described later and the data may be set to the header of a recording track in the case of, for example, a tape medium. Alternatively, the data detection operation as above may be once performed at intervals of a predetermined amount of data. If that data is recorded frequently, thinning-out detection operation may be carried out during reproduction. Then, the output control circuit 112 decides, on the basis of the detected retention period and playback permission period as well as playback start time, time for recording and the present time from the clock 107, whether the delivery of reproduction output is permissible, thereby controlling the output to the decoder 108. The information detection circuit 111 may also detect the control signal for “copy never” and “no more copies” in order for the output of the output control circuit 112 to control the signal output circuit 106, thus ensuring that when copying is inhibited, the delivery of the reproduction signal to the output terminal 113 can be prevented. The output of the output control circuit 112 is also applied to the output terminal 114. This output signal is used when the signal detected by the information detection circuit 111 includes information for conditionally permitting a device connected externally to carry out recording/reproduction, in order to transmit the information to the outside. When it is determined that the retention period has already expired, information indicative of this expiration may be supplied from the output terminal 114 to the aforementioned input terminal 67 of FIG. 5 to stop the recording media drive 63. The moving image data compression applied in advance of the transmission by the decoder 108 is decoded from the output of the signal output circuit 106 and a resulting signal is fed to the output terminal 110 to permit playback with the display connected to the output terminal 110. As the output from the output terminal 110, an intact decoded digital signal may be delivered or an analog signal converted from the digital signal may be delivered. When a copyright holder, copy control information and the like are embedded as a watermark in an image, the watermark detection circuit 109 operates to detect the watermark. In place of the signal detected by the information detection circuit 111, the information detected from the watermark may be used to perform a similar control operation. The clock 107 is of course required of accuracy to some extent. If the clock can easily be altered with malicious intent of the user, then it will not fulfil itself. Further, it is desirable that the clock be controllable in response to time information from, for example, the broadcasting station. The clock may be designed to make the apparatus inoperative when the time is altered intentionally. Next, in connection with the case in which the reproduction signal applied to the input terminal 101 includes data concerning the aforementioned copy permission period, only operation differing from that described as above will be described. In this case, the information detection circuit 111 for control signal detects data of the copy control information, for example, “copy one generation” and the copy permission period. The output control circuit 112 decides, on the basis of the detected control information and copy permission period as well as recording time and the present time from the clock 107, whether copying is permissible and sends a decision result to the signal output circuit 106. If the copy information “copy one generation” is available within the copy permission period, the signal output circuit 106 passes the reproduction signal. On the medium of the external device for preparation of copies, the control signal is changed to “no more copies”. If the copy information “copy one generation” is outside the copy permission period, the control information can be rewritten to “no more copies” to disable the external device to copy. As necessary, the information in the medium may be rewritten to “no more copies” by means of the recording circuit. Obviously, rewrite on the reproducing side by the signal output circuit 106 is not limitative and it may be done with another reproducing circuit block. FIG. 7 is a block diagram showing another embodiment of the reproducing circuit according to the invention. Constituent components identical to those in the FIG. 6 embodiment are designated by identical reference numerals. The present embodiment differs from the FIG. 6 embodiment in that the decoder 108, watermark detection circuit 109 and output terminal 110 are removed. These components are often built in the display 7 of FIG. 1 and in that case, the reproducing circuit is separated as a unitary circuit, leading to the construction shown in FIG. 7. On the basis of the information, such as retention period, playback permission period, copy permission period and copy control information, detected by the information detection circuit 111, the output control circuit 112 sends a control signal to the signal output circuit 106 in order to control permission/inhibition of the delivery of the signal to the outside and rewrite of the control information. The signal at the output terminal 113 can be supplied to the display as well as another external recording device as in the case of the FIG. 6 embodiment. FIG. 8 is a diagram showing an embodiment of a first control signal transmitted from the information distributor 3 and recorded on the recording medium during recording in the foregoing embodiments. In the case of a tape medium for instance, recording of one first control signal on one recording track suffices but obviously, the first control signal is recorded in a predetermined relationship with video and audio data to assure easy separation of the first control signal during reproduction. Program number 300 indicates what number is allotted to a program in question on the medium. Sector information 301 indicates numbers allotted to sectors set up by dividing the program in a predetermined unit. The division can be made in a fixed unit, for example, in a unit of 2 k bytes or in a constant unit of information, for example, in a unit of division during encoding. The numbers may be set up within the program or may be serial numbers set up throughout the recording medium. Information such as recording time 305 to be described later is added in a unit of sector. Time information 302 indicates how long the recording part of interest proceeds after start of the program. Type information 303 indicates attribute information of the program as to whether the program is sold, rental, self-made or distributed from broadcasting. Copy control information 304 indicates the aforementioned control information such as “copy never”, “copy one generation” or the like. FIG. 9 shows a structure of the copy control information 304. Version number 311 indicates which version the information belongs to. As will be described later, the copy control information 304 must be so flexible as to add some items other than those shown in FIG. 9 or to erase some items from FIG. 9, as necessary. Accordingly, with a view of determining how what information is arranged in sequence in various ways, the version is managed. For example, when 8 bits are allotted to the version information 311, the copy control information 304 can be used in 256 ways. Output control 312 controls the permission/inhibition of delivery of the output from the digital output terminal 113 or the analog output terminal 110. For control of the output delivery, it is first decided, from the form of the output and encryption conditions, whether safety can be assured and then the permission/inhibition of the output delivery is controlled. Further, the output delivery permission/inhibition may be controlled depending on resolution for instance. For example, in the case of a video signal of high resolution such as high vision video, control is such that the video signal as it is may be inhibited from being delivered but a video signal set up by degrading the resolution may be permitted for delivery. Copy control information 313 (CGNS; Copy Generation Management System) controls copying to a digital recording device. For example, when this information is of 2 bits, “11” may designate “copy never”, “10” may designate “copy one generation”, “01” may designate “no more copies” to the effect that one copy obtained through “copy one generation” is no more permitted for copying, and “00” may designate “copy free”. Different CGMS's may be provided for the digital signal output and analog signal output, respectively. Copy control information 314 (APS; Analog Protection System) controls copying to an analog recording device. A psuedo-sink pulse may be added to an analog video signal for the purpose of controlling permission/inhibition of copying. Move mode 315 is information concerning permission/inhibition of “move”. The term “move” means that information is copied onto a different medium and thereafter, a counterpart of that information recorded on the original medium is erased. This ensures that only one copied information piece can always be allowed to exist, making it possible to keep the condition that many repetitive copying operations result in substantially one copying operation. When information subject to “copy one generation” is copied in the normal copy mode, any more copying is prevented by changing the copy control information to “no more copies” but when the move mode proceeds, the copy control information is again returned to “copy one generation” so that the information of interest can be sent to the copying destination to enable the sent information to be copied and after the copying, the original information is erased. The move mode 315 may prescribe the move permission count in addition to the move permission. In that case, the move permission count information may be decremented each time that a move operation is carried out. For example, when the move mode 315 is of 4 bits, the permission count ranging from 0 to 15 can be defined. In this case, the definition may be such that even when all of the 4 bits are “1111”, the count is not 15 but is infinite. Playback count 316 is for prescribing the playback permission count and is ruled as necessary. The playback count is used when, for example, in addition to a limit set to the effective period by the aforementioned retention period, the playback count is desired to be limited. Like the move permission count, the playback permission count is decremented each time that one playback operation is carried out. When all of the bits are “1” initially, the limitation to the count can be handled as being nullified. Playback longevity period 317 is used when the playback operation is limited temporally. For example, when the playback longevity period is of 16 bits to ensure management in a unit of minute, temporal limitation up to about 45 days can be available. For all of the bits being “1”, this period can also be handled as designating unlimitedness. If the CGMS 313 is “copy never”, the rules in the aforementioned playback permission period for instance are predominant in connection with the temporal limitation to the playback operation. Accordingly, the rules in the playback longevity period 317 are used as information available in an instance excepting the above. In an alternative, the playback longevity period 317 may be incorporated into the playback permission period so as to be handled as unified information. Pause period 318 prescribes a period for permitting a pause operation (temporary stop). The pause period can be handled similarly to the playback longevity period 317. More particularly, it happens that playback operation is required to be stopped temporarily on urgent business due to a visitor. In such a case, the pause period is used to temporally limit the temporary stop. Delayed start time 319 is used, to limit time for starting working. While the aforementioned retention period sets a limit to working, starting with the recording time, the delayed start time 319 permits working, starting with absolute time such as 12.00 p.m., Jan. 1, 2001 for instance. This is suitable to permit simultaneous disclosures at a time. After the delayed start period has elapsed, information is permitted for playback and delivery for instance. As the delayed start time, the absolute time may be described or a difference time (relative time) from a time (for example, 12.00 p.m., Jan. 1, 1970) agreed by persons in the same line of business may be described. If all of the bits are “0”, the recording time may be the start time. Not all contents of the copy control information 304 are necessary and some of the contents can be omitted. Further, move permissible period 307B to be described later may arranged, for example, between the move mode 315 and the playback count 316, instead of being positioned as shown in FIG. 8. The recording time 305 in FIG. 8 records, for example, the time of the clock 107 of FIG. 4 or the time supplied from the service information applying circuit 36 of FIG. 2. The recording time 305 can be recorded in a unit of sector for instance. In the present embodiment, information covering retention period 306A, copy permission period 306B, playback permission period 307A and move permission period 307B is further used. All of the information can be used but only two of 306A and 307A, only two of 306B and 307B or only one of, for example, 306B may sometimes be used. For the information “copy never”, the copyright holder or the software producer rules the retention period 306A and the playback permission period 307A as described previously. For example, the retention period is set to 9 hours and the playback permission period is set to 2 hours. When there is no need of setting a limit to the period, a code of “no limit” may be applied. In addition to the above, limitation to the playback count may be prescribed. For the information “copy one generation”, the copy permission period 306B and move permission period 307B are ruled used similarly and the latter is applied only when needed. Also, limitation to the move permission count may be prescribed. User identification information 308 is recorded when a code inherent to a user is used with the aim of permitting information recorded on the medium to be reproduced by only the same apparatus as that used during recording or only the user. Encryption information 309 is used to decode a cipher during playback when information is encrypted and recorded on the recording medium. This will be described again later with reference to FIGS. 12 and 13. The information per se has a large amount of data and therefore, code numbers may be recorded and information corresponding to a code number stored in advance may be drawn out by means of the reproducing apparatus so as to be used. The information as above is recorded as necessary at a relatively short temporal pitch, for example, every image frame or at the rate of predetermined amount of data. With the control signal having the structure as above, the present invention can be practiced but the structure shown in FIG. 8 is for explanation only and various kinds of structure, recording position on the medium and frequency can also be applicable. FIG. 10 is a block diagram showing a structure of a second control signal recorded during reproduction in the present embodiment. The second control information includes playback start time 321, playback start sector number 322 and playback stop sector number 323. The playback start time 321 records a time counted by, for example, the clock 107 of FIG. 12 to be described later. When a playback is stopped, a sector number at that position is recorded in the playback stop sector number 323. Since playback times at sectors on the way can be calculated from the playback start time 321, playback times at all sectors subject to reproduction can be known. Of course, the playback time can be recorded in a unit of sector. In the case of the tape medium for instance, when the operation mode is returned to the stop mode during playback, individual pieces of control information shown in FIG. 10 can be recorded anywhere near the stop position. The information can also be recorded using, for example, the recording circuit of FIG. 4. Referring to FIG. 11, the recording position of the control signal on the medium will be described. FIG. 11 diagrammatically shows recording positions of the control signal and information data such as video and audio data on the recording medium. Recording positions shown at (a) in FIG. 11 are suitable for the tape medium. In this case, the block of the control signal is preferably provided, for example, every recording track. Accordingly, in each track, a block of the control signal is arranged in the header part, for instance, to precede the information such as video and audio data. Recording positions shown at (b) in FIG. 11 are suitable for a digital video disc. In this case, the control signal and video and audio data are preferably provided every sector having a certain amount of information. Accordingly, they are arranged at the header part every sector. Recording positions shown at (c) in FIG. 11 are suitable for a hard disc. In this case, the information such as video and audio data and the control signal are recorded at positions spaced apart from each other on the disc to permit the whole of the control signal to be read within a short period of time during start. In an alternative, the first control information may be recorded at the header part and the second control information may be recorded at a position spaced apart therefrom. Since the second control information is to be recorded or rewritten during reproduction, it is required to be recorded at an independent or isolated position. Alternatively, instead of being recorded in the recording medium, the second control information may be recorded in, for example, the memory device or memory circuit 104 mounted externally of the recording medium or in a memory device in an independent apparatus. Referring now to FIGS. 12 and 13, another embodiment directed to the reproducing circuit 1 and the recording circuit 2. FIG. 12 is a block diagram showing a reproducing circuit 1 according to the present embodiment and FIG. 13 is a block diagram showing a recording circuit 2 according to the present embodiment. Constituent components identical to those in FIGS. 6 and 4 are designated by identical reference numerals and will not be detailed. The present embodiment is effective when it is required that only predetermined users be allowed to take part in playback or when a fee is charged. In FIG. 12, there are provided a decryption circuit 131 and an input terminal 132 for an identification code inherent to the apparatus and in FIG. 13, there are provided an encryption circuit 233 and an input terminal 234 for an identification code inherent to the apparatus or an apparatus permitted for playback. In the encryption circuit 233 of FIG. 13, encryption is carried out with the identification code of the apparatus fed from the input terminal 234. Without performing descramble in the RF tuner 5, two kinds of encryption may be carried out in an overlap fashion. In the decryption circuit 131 of FIG. 12, decryption is carried out with the identification code of the apparatus fed from the input terminal 132. If the identification code is not an authorized one, normal decryption fails to proceed to thereby prevent the playback from being done. In the apparatus, encryption with the identification code is exemplified but this code may be added to the aforementioned block of the control signal and may be detected on the reproducing side to decide whether the delivery of signal is permissible. Encryption may be done in a unit of program but when the encryption is carried out while changing the key to the encryption in a unit of sector and individual keys are recorded, an encryption process can be performed in the unit of sector. Next, an example of operation of controlling the retention period 306A and playback permission period 307A during reproduction will be described. Firstly, when the difference between recording time 305 of a sector to be reproduced and the present time indicated by the clock 107 is within the retention period 306A at the initiation of a playback, the playback is started. At the same time, the playback start time 321 and playback start sector number 322 are recorded as the second control information. With the playback stopped, a playback stop sector number 323 is recorded. With a pause taken, a playback stop sector number 323 is recorded as in the case of the stoppage of the playback and with the pause released, a process similar to that at the initiation of the playback is carried out. More particularly, the time is again confirmed and if the time is within the retention period 306A, playback resumes. When backward feed is done, a playback time at that location is confirmed and if the difference between the playback time and the present time is within the playback permission period 307A, a playback is permitted. When fast feed is carried out, it can be known by confirming the second control information that no playback is carried out throughout a fast feed range. Therefore, when a playback is initiated, permission/inhibition of the playback is decided by only the retention period 306A regardless of the playback permission period 307A. Namely, a playback longevity period after one playback operation subject to the playback permission period 307A is controlled for a playback longevity period following recording subject to the retention period 6A. The pause period can also be controlled depending on the playback permission period 307A. In this case, permission/inhibition of the initial playback start is controlled by the retention period 306A and when a playback stop is carried out or a pause is taken after start of the playback, the period for stoppage is measured in order that resumption of playback is permitted when the measured period is within the playback permission period 307A but resumption of playback is inhibited when the measured period exceeds the playback permission period 307A. Further, by inhibiting the backward feed, it is possible to steadily permit only one playback operation. In this case, control can be undertaken without recording the second control information. In case information under the control of the retention period 306A or playback permission period 307A is reproduced and then delivered as a digital signal from the output terminal 113, it is conceivable that the retention period 306A or playback permission period 307A of control information added to the information of interest is decremented or zeroed. Operation when the copy permission period 306A and move permission period 307B are used is as follows. Firstly, if the difference between a recording time 305 of a sector to be reproduced and the present time indicated by the clock 107 is within the copy permission period 306B at the playback initiation, normal playback is started and a reproduction signal for copying is delivered to the outside. Since the copy control information “copy one generation” remains intact in the signal reproduced and delivered to the outside, recording is permissible for the external device. During recording, however, the copy control information is rewritten to “no more copies” and as a result, any more copying is prevented. In case a playback stop is carried out or a pause is taken after start of the playback, if the copy permission period has already expired at the time that the playback resumes, the copy control information can be changed to, for example, “no more copy” so as to inhibit copying. As far as one copy operation is concerned, the playback may proceed to the end with the copy control information kept to be “copy one generation” and copying may be permitted. More particularly, a copy longevity period after recording subject to the copy permission period 306B is controlled. After the copy permission period has expired, another recording apparatus is allowed to move information to another medium on the premise that the original information is erased. If expiration of the copy permission period is detected through the aforementioned method at the start of playback, information having its copy control information rewritten to “no more copies” is added with information of move permission period 307B as necessary and then moved to the external recording apparatus. The original information is erased from the medium through a method to be described later. Thereafter, if the difference between the recording time 305 and the present time indicated by the clock 107 is within the move permission period 307B, move between the media is permissible. When the move permission period expires, it is impossible to perform move any more. In the absence of the move permission period 307B, the period for move is unlimited. In other words, the move permission period after the copy permission period has stopped or expired is controlled by the move permission period 307B. As set forth so far, in copying information to the external recording apparatus within the copy permission period, the copy control information on the original recording medium is changed from “copy one generation” to “no more copies” as the copying operation proceeds. But, the copy control information can be changed at the end of the copy permission period to permit preparation of a plurality of sheets of copy of one generation. There are some methods of managing the permission/inhibition of delivery of the information to be reproduced (playback, copy or move) in a unit of time. The managing method entangles the method of recording the aforementioned control signal. If the retention period and the playback permission period or copy permission period are managed every image, that is, every frame, the most stringent management can be carried out. The management per frame, however, imposes a large load on operation of hardware, involving a problem of erase to be described later. Accordingly, by managing the control signal in a unit of certain time, the load imposed on processing can be alleviated. For example, a tolerance of one minute is set up for control of the retention period 306A or playback permission period 307A. Then, for a retention period 306A of 120 minutes or a playback permission period 307A of 120 minutes, control is allowed to be done between 120 minutes and 121 minutes and the management can be performed every minute. The tolerance may be set up in a unit of predetermined number of images or in a unit of predetermined amount of data. The move count and the playback count indicated in connection with FIG. 9 can be managed as will be described below. In the case of move, the count is decremented by one in essential each time that the move operation is carried out once and a reproduction signal is sent to the external recording apparatus. If, while the number is prescribed, the copy control information signal designates “no more copies”, the copy control information can be changed to “copy one generation” and delivered and when recording is carried out with the external recording apparatus, the copy control information can be changed to “no more copies”. Further, only when the external recording apparatus is adapted to move from the standpoint of erase operation to be described later, the count can be decremented by one and then delivered. Contrarily, in the case of the apparatus unadapted to move, the count can be rewritten to 0 and then the control signal can be delivered, thus disabling any more move. Obviously, the apparatus on the reproduction signal transmitting side must have the erase function conforming to move as will be described later. A control signal indicative of the erase function may be transmitted to the external recording apparatus. On the other hand, in the case of the playback count, the manner of management of the playback count matters in the event that, for example, an interruption occurs on the way of playback. A method is available according to which the management is carried out in a unit of contents and after playback has proceeded for a constant time, the count is decremented by one. Alternatively, at the time that a stop, putting a pause aside, is applied, the count may be decremented by one. Further, at the time that backward feed of the medium, putting a stop aside, is applied, the count may be decremented by one. A description concerning the playback longevity period 317 will be given. When, during playback operation, the playback permission period stops or ends before the program comes to an end, the reproduction output operation can be inhibited but otherwise, delivery of the reproduction output can continue to the end unless the playback operation is stopped. In the latter case, one playback operation can be carried out unless the playback longevity period has already expired at the time that the playback starts. Information for the above purposes can be detected during playback by means of the information detection circuit 111 of FIG. 6. The information can be rewritten by means of, for example, the signal output circuit 106 of FIG. 6. This can further promote the working condition management. Next, a method of erasing the information on the medium will be described. The term “erase” referred to herein not only signifies erase literally but also involves the case of rewriting at least part of the information on the medium to disable the effective information to be reproduced. Only the aforementioned effective period management in the reproducing circuit is sometimes insufficient to be versatile in the future. If the medium recorded with the information remains, then the reproducing playback will be impossible at present but there is a fear of the future advent of a method that overcomes the present-day preventive method to make playback possible. From the above point of view, the information on the medium is erased after playback or at the termination of the retention period 306A and playback permission period 307A, thus further promoting safety. In addition, when the aforementioned move mode is carried out, the information on the medium must be erased after copying. Firstly, a unit of information to be erased is considered. It is first conceivable that when the period runs out, an erase operation is carried out in a unit of frame. It is also conceivable that the information is managed in a unit of larger time. For example, the management at the rate of one minute is carried out and information confined within one minute until the expiration is erased collectively. Alternatively, the management is carried out in a unit of plural image frames and information confined within a prescribed time until the expiration may be erased collectively. A similar operation may be undertaken at the rate of predetermined amount of data. Timing of erase will be considered. As described above, the method is available according to which the erase timing linking to the retention period and playback permission period in some ways is determined. In addition to this, it is conceivable that when information once subjected to playback is not permitted for repetitive playback, the information is erased at a timing of playback even if the playback timing far precedes the effective period. In the event that the medium is removed form the apparatus at the expiration of the period and erase cannot be fulfilled, erase operation may be carried out when the medium is mounted subsequently. In the case of move, too, it is conceivable that information moved to the next medium is erased in a unit of frame. Alternatively, the information may be managed in a unit of larger time. For example, when the information is managed every minute, information confined within one minute after move may be erased collectively. In an alternative, the information may be managed in a unit of plural image frames and information confined within a prescribed time may be erased collectively. A similar operation may be performed at the rate of predetermined amount of data. Further, after one program has completed copying to the next medium, the whole of the program may be erased collectively. Next, practical erase operation will be described with reference to the drawings. Erase is made in different ways depending on the type of the medium. An example applied to a disc medium will first be described with reference to FIG. 14. FIG. 14 is a block diagram showing another embodiment of the information reproducing apparatus according to the invention. In the present embodiment, the block diagram of the reproducing circuit shown in FIG. 6 is unified with the block diagram of the circuit shown in FIG. 4, additionally having a media type detection circuit 207. Obviously, the reproducing circuit construction as shown in FIG. 7 or 12 can be used in place of the FIG. 6 reproducing circuit. FIG. 14 is adapted to a disc medium. The disc medium is sorted into an RW (or RAM) type capable of rewriting records many times and an R type incapable of rewriting information once recorded. The term “un-rewritable” means “un-erasable” and if erase is to be applied or move is to be carried out after the expiration of the presupposed effective period, recording onto the R type disc medium must be rejected initially. The media type detection circuit 207 is provided for this purpose. Thus, on the premise that the R type disc is carried and erase is made or move is carried out after the expiration of the effective period, a control signal is sent to the recording signal processing circuit 203 to prevent delivery of a code to be recorded. For detection of the medium, some methods have been known which are directed to reading a sign applied outside a recording area of the medium, reading a code precedently recorded at part of the recording area and making a decision on the basis of reflection factor, respectively. The output of the output control circuit 112 on the reproducing side is also fed to the recording signal processing circuit 203. On the basis of the previously-described retention period and playback permission period or at the time that move proceeds, the output control circuit 112 generates a control signal for commanding an erase operation. Responsive to this control signal, the recording signal processing circuit 203 generates a code for performing erase at a location of interest on the medium. This code can be a code that is meaningless as information. As described previously, the method is available which manages data in a unit of frame and erases the whole of data. This method is, however, sometimes unpractical from the viewpoint of the time for processing. Even in the case of the management in a unit of frame, the object can be attained sufficiently by erasing only the control signal part as shown in FIG. 8 for instance or especially erasing only the encryption information 309 in the control signal part. This holds true for the management in a unit of other than the frame, for example, for the management in a unit of time, in a unit of group of images or in a unit of prescribed amount of data. For example, when the information is managed in a unit of minute, data confined within one minute until the expiration of the effective period or a control signal of data within one minute after move can be erased. In case encrypted information is recorded, a method is available which erases only scramble information. Further, in case the control signal in the unit to be managed is, for example, encrypted, the scramble information is recorded collectively at a single location on the medium. This information is reproduced collectively during reproduction inclusive of move, stored at a specified location in the memory circuit 104 and erased from the medium. If the reproduction is stopped on the way, an operation for recording again a control signal for a portion not played back onto the medium is carried out to simplify the erase process. In this case, for the sake of preventing the control signal from being collapsed owing to power failure on the way, the whole or at least part of the area for storage of the information in the memory circuit 104 may preferably be implemented with a non-volatile memory circuit such as a flash memory. Especially, in the case of move, the whole of the program may be erased collectively through the method as above after the move operation has stopped. Obviously, a unit dedicated to reproduction such as a CD-ROM drive does not have the recording circuit block corresponding to the lower half in FIG. 14 but if having a component corresponding to the recording signal processing circuit 203 having the function of generating the code for erase, it can operate similarly in terms of circuitry. An apparatus using a hard disc as recording medium can of course dispense with the aforementioned media type detection circuit 207. Next, FIG. 15 is a block diagram showing another embodiment of the information reproducing apparatus according to the invention. In the present embodiment, an erasing device 115 is added to the block diagram of the reproducing circuit shown in FIG. 6. The reproducing circuit construction in FIG. 7 or 12 can of course substitute for the circuit shown in FIG. 6. The FIG. 15 embodiment is suitable for the tape medium. When the retention period and playback permission period are ruled and a portion once played back cannot be fed backward or when move is carried out, information on the tape medium is to be erased during reproduction. The erasing device 115 is for this purpose and practically implemented with an erase head. During reproduction, the output control circuit 112 sends a control signal to the erasing device 115 to decide whether an erase operation is performed. For example, when the retention period and playback permission period are prescribed, an erase operation is sometimes carried out following reproduction. As the erasing device 115, a full erase head fixed to a tape running mechanism, a flying erase head carried on the rotary drum also carrying the video head or another video head not used as reproducing head in the playback mode as described in JP-A-7-244924. If the full erase head is used, it must be mounted to a position for erase after scanning of the video head in contrast to the normal position. If the flying erase head or an unused video head is used as the erasing device, it must also be mounted to a position succeeding the reproducing head in the course of tape scanning. In the latter case, if the mount position satisfies the above condition accidentally but if not so, the height must be changed. Even in the former case, it is necessary to change the height or to mount another head. In any methods, the information to be recorded is digital information and differing from analog information, any problem in quality does not arise when erase is carried out using a DC magnetic field without using an AC magnetic field. Practically, when erase is carried out while performing reproduction, interference due to magnetic induction from the erase head to the reproducing head is difficult to prevent. But this problem can be solved using DC. Conceivably, the erasing device can be constructed of a permanent magnet. But, a mechanism is needed which moves the location when the erase operation is not done and besides tension applied to the tape changes depending on whether or not erase is carried out, thereby raising a problem that the mechanism is difficult to control. In such an event, the aforementioned head may preferably be used as an electromagnet. As described above, according to the invention, the information to which a stringent copy limit is set can be recorded temporarily by prescribing the retention period and playback permission period. Further, since the playback period is limited, the copyright holders can protect their right. In other words, compatibility between profits of the user and the copyright holder can be met. Further, by erasing the information when the period expires, security against unauthorized copying can be assured to advantage. In addition, the information can be erased collectively in a unit of time or data amount or only specified part of the recording information can be erased to simplify the erase process to advantage. Furthermore, even the information subject to copy limitation of “copy one generation” can be limited temporally by prescribing the copy permission period and therefore, uneasiness of the copyright holders caused by keeping “copy one generation” intact for a long time can be eliminated. Even when the control information changes to “no more copies”, by introducing the move mode on the premise that the information on the original medium is erased, the user can conveniently exchange the medium even under the condition that the medium used for copying is only one. As necessary, the move permission period can advantageously be limited. Furthermore, by erasing the information collectively in a unit of time or amount of data or erasing specified part of the recording information, the erase process can advantageously be simplified. In addition, by limiting the move count, playback count and playback longevity period, the management of working conditions can further be promoted. The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiment is therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description and range of equivalency of the claims are therefore intended to be embraced therein.
<SOH> BACKGROUND OF THE INVENTION <EOH>
<SOH> SUMMARY OF THE INVENTION <EOH>Various kinds of expedience disclosed in the above documents give a solution to the problems. But the problem involved in copyright cannot be solved satisfactorily by the conventional methods that inflict one-sided profit or loss to copyright holders, broadcasting or software developing firms or general users. Further, the “copy one generation” conveniently gives the users a chance of backing up the information recorded temporarily on a hard disc for instance. As a rule, once the temporarily recorded information is copied, the copy control information changes to “no more copies” to prevent any more copying. But, when copying of the temporarily recorded information is permitted, though only once, the copy permission remains for a long time, giving anxiety to the copyright holders. On the other hand, when “no more copies” is once set, desired exchange of the medium storing the contents becomes impossible and disadvantageously the users are forced to suffer from inconvenience. In the light of the above problems, an object of the present invention is to provide more specifically a unit for preventing circulation of unauthorized copies and permitting the user to perform conditional playback and the like. Another object of the invention is to provide a unit for eliminating the aforementioned anxiety of the copyright holders and inconvenience of the users through a method of meeting the compatibility between profits of the user and the copyright holder. Still another object of the invention is to provide a unit for limiting a condition for permitting playback of recorded information for instance so as to enable the copyright holder to further control the range of information utilization. According to the invention, the effective period, available inside a recording medium, of information permitted for temporary recording is prescribed. The apparatus has a unit for disabling reproduction and playback after expiration of a prescribed time following recording initiation. Through this, the information temporarily recorded on the medium can be prevented from being used later for unauthorized purposes. The effective period inside the recording medium referred to herein will be called “retention period”. Further, the effective period starting with playback initiation is also prescribed. The apparatus has a unit for disabling repetitive reproduction and playback after expiration of a prescribed time following the initial start of playback. Through this, playback by many and unspecified users can be prevented. The effective period referred to herein will be called “playback permission period”. Frequently, the retention period is set to be equal to or longer than the playback permission period but this is not limitative. Many types of reproducing apparatus cause their operation to temporarily pause or stop during reproduction. Accordingly, even when reproduction is started during the playback permission period, the retention period sometimes happens to stop or end before the playback comes to an end. In that case, concurrently with the stop of the retention period, reproduction is disabled to proceed any more. Alternatively, for convenience of users, even with the retention period stopped, a part of information succeeding the stopping location is once allowed for continuous playback up to the end. In that case, conditionally, further pause and stop are inhibited. In some case, a part once subjected to playback is inhibited for repetitive playback. This can be implemented by disabling backward feed of the medium or making, in some way, a part once subjected to playback non-reproducible during backward feed. When the copyright holder originally sets a limit to copying such as “copy one generation” for instance, copying permitted for the user is limited to some extent. To prevent the temporarily recorded information from staying in the medium for a long time while being conditioned to “copy one generation”, the present invention prescribes the effective period for the information, conditioned to “copy one generation” to stay in the recording medium following, recording of the information. The apparatus has a unit for handling the information as being subject to “no more copies” after expiration of the prescribed period following recording so as to prevent copying, thereby eliminating anxiety of the copyright holder about the long-term stay of the information subject to “copy one generation”. The effective period referred to herein will be called “copy permission period”. In the medium in which the copy permission period has expired or information is copied within the copy permission period, the copy control information changes to “no more copies” to disable copying. In that case, by permitting “move” operation for moving the information to another medium on the presupposition that the original information is to be erased, inconvenience of the user can be obviated. As necessary, the period for permitting the move mode after the control information has changed to “no more copies” or the period for permitting repetitive move after the preceding move may be prescribed. The effective period referred to herein will be called “move permission period”. When the operation is caused to temporarily pause or stop during reproduction even if copying is started during the copy permission period, the move permission period will sometimes be stopped before it comes to an end. In that case, concurrently with the stoppage of the copy permission period, any more copying is inhibited. Alternatively, for convenience of the user, even with the copy permission period stopped, a part succeeding the stop location can once be allowed for continuous copying up to the end. In that case, conditionally, further pause and stop are inhibited.
G11B2000688
20170830
20171221
61391.0
G11B2000
1
ZHAO, DAQUAN
DIGITAL INFORMATION RECORDING APPARATUS, REPRODUCING APPARATUS AND TRANSMITTING APPARATUS
UNDISCOUNTED
1
CONT-ACCEPTED
G11B
2,017
15,691,134
PENDING
ELECTRONIC EQUIPMENT DATA CENTER OR CO-LOCATION FACILITY DESIGNS AND METHODS OF MAKING AND USING THE SAME
The present invention relates to electronic equipment data center or co-location facility designs and methods of making and using the same in an environmentally aware manner, and generally provides apparatus and methods for using novel support bracket structures, and thermal panels associated with the same, that allow for distinct partitioning of air flowing in hot aisles and cold aisles, as well as for holding wiring above cabinets that are used to store electronic equipment in the facility.
1. A structure for managing heat emitted by electronic equipment comprising: at least one cluster of cabinets disposed in two separated rows such that the rows of cabinets are positioned in a back-to-back configuration to establish a hot aisle enclosure area between the two separated rows and the front side of the cabinets establishes a portion of a cold aisle, the electronic equipment disposed in the cabinets emit heated air from the cabinets into the hot aisle enclosure area; a thermal shield extending upward from the cabinets to form a hot air area above the hot aisle enclosure area by providing a wall at a height above the two separated rows of cage cabinets to trap the heated air within the hot air area and the hot aisle enclosure area and cause substantially all of the heated air between the cabinets to be contained within the hot air area and the hot aisle enclosure area, the wall fully surrounds the hot air area above the at least one cluster of cabinets; at least one cable rack located above at least one of the rows of cabinets to support cables in the cold aisle; a warm air path disposed above the hot air area, the warm air path allowing the heated air to flow from the hot air area to an air conditioning system that includes an air conditioning unit located above the cabinets and a condenser that is disposed outside the walls of the facility, such that the warm air path is bounded by a barrier and one or more openings exist in the barrier through which heated air flows into the warm air path, and wherein a top edge of the thermal shield extends from the barrier to the cabinets to further prevent the heated air from escaping; and a cool air path between the air conditioning system and the cold aisle, the cool air path delivering cool air from the air conditioning system to the cold aisle. 2. The structure of claim 1 wherein the heated air rises from the cabinets in the hot aisle enclosure area toward the air conditioning units and air cooled by the air conditioning units falls toward the cabinets in the cool aisle. 3. (canceled) 4. The structure of claim 1 further comprising at least one support brackets that extend upward from a floor to support the thermal shield. 5. The structure of claim 4 wherein the at least one support bracket also support one or more cable racks. 6. The structure of claim 4 wherein the at least one support brackets are not connected to the cabinets. 7. The structure of claim 1 wherein the barrier prevents the heated air from mixing with the cooled air. 8. The structure of claim 1 wherein the top edge of the thermal shield connects to the barrier. 9. A structure for managing heat emitted by electronic equipment comprising: at least one cluster of cabinets disposed in two separated rows such that the rows of cabinets are positioned in a back-to-back configuration to establish a hot aisle enclosure area between the two separated rows and the front side of the cage cabinets establishes a cold aisle, the electronic equipment disposed in the cabinets emit heated air from the cabinets into the hot aisle enclosure area; a thermal shield extending upward from the cabinets to form a hot air area above the hot aisle enclosure area by providing a wall at a height above the two separated rows of cage cabinets to trap the heated air within the hot air area and the hot aisle enclosure area and causes substantially all of the heated air between the cabinets to rise up and being contained within the hot air area and the hot aisle enclosure area, wherein the wall fully surrounds the hot aisle enclosure area from above the at least one cluster of cabinets; and a warm air channel disposed above the hot air area, the warm air channel providing a path for the heated air from the hot aisle enclosure area and hot air area to an air conditioning system, wherein the warm air channel is bounded by a barrier and an opening exists in the barrier through which heated air flows into the warm air channel, wherein a top edge of the thermal shield extends from the barrier to the cabinets to aid in separation of heated air from the cold aisle. 10. The structure of claim 9 wherein the air conditioning system includes a condenser that is disposed outside the walls of the facility. 11. The structure of claim 9 wherein the air conditioning system includes air conditioning units are located above the cabinets and the barrier such that heated air rises toward the air conditioning units and air cooled by the air conditioning units falls toward the cabinets in the cool aisle. 12. (canceled) 13. The structure of claim 9 further comprising at least one support bracket above the cabinets which support the thermal shield. 14. The structure of claim 9 further comprising a rack configured to supports cables in the cool aisle above at least one row of cabinets. 15. The structure of claim 9 wherein the top edge of the thermal shield connects to the barrier. 16. A structure for managing heat emitted by electronic equipment comprising: at least one cluster of cabinets disposed in two separated rows such that the rows of cabinets are positioned in a back-to-back configuration to establish a hot aisle enclosure area between the two separated rows and the front side of the cabinets establishes a portion of a cold aisle, the electronic equipment disposed in the cabinets emit heated air from the cabinets into the hot aisle enclosure area; a thermal shield extending upward from the cabinets to form a hot air area above the hot aisle enclosure area by providing a wall at a height above the two separated rows of cage cabinets to trap the heated air within the hot air area and the hot aisle enclosure area and cause substantially all of the heated air between the cabinets to be contained within the hot air area and the hot aisle enclosure area; a warm air path disposed above the hot air area, the warm air path allowing the heated air to flow from the hot air area to one or more air conditioning systems; and a cool air path between the air conditioning system and the cold aisle, the cool air path delivering cool air from the air conditioning system to the cold aisle. 17. The structure of claim 16 wherein one or more elements of the air conditioning system are located outside of a building which houses the cabinet and one or more elements of the air conditioning system are located inside the building which houses the cabinets. 18. The structure of claim 16 wherein the air conditioning units are located above the cabinets and the barrier such that heated air rises toward the air conditioning units and air cooled by the air conditioning units falls toward the cabinets in the cool aisle. 19. The structure of claim 16 wherein the air conditioning system includes a condenser that is disposed outside the walls of the facility. 20. The structure of claim 16 wherein the cabinets are disposed on a non-raised floor. 21. The structure of claim 16 further comprising one or more support brackets above the cabinets which support the thermal shield. 22. The structure of claim 21 wherein the one or more support brackets are not connected to the cabinets.
CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of and claims priority to U.S. application Ser. No. 12/168,771 filed on Jun. 13, 2008, which claims priority to U.S. Provisional Appln. No. 60/944,082 filed Jun. 14, 2007 entitled “Electronic Equipment Data Center or Co-Location Facility Designs and Methods of Making and Using the Same,” which application is expressly incorporated by reference herein. FIELD OF THE INVENTION The present invention relates to electronic equipment data center or co-location facility designs and methods of making and using the same in an environmentally aware manner. BACKGROUND Data centers and server co-location facilities are well-known. In such facilities, rows of electronics equipment, such as servers, typically owned by different entities, are stored. In many facilities, cabinets are used in which different electronics equipment is stored, so that only the owners of that equipment, and potentially the facility operator, have access therein. In many instances, the owner of the facilities manages the installation and removal of servers within the facility, and is responsible for maintaining utility services that are needed for the servers to operate properly. These utility services typically include providing electrical power for operation of the servers, providing telecommunications ports that allow the servers to connect to transmission grids that are typically owned by telecommunication carriers, and providing air-conditioning services that maintain temperatures in the facility at sufficiently low levels. There are some well-known common aspects to the designs of these facilities. For example, it is known to have the electronic equipment placed into rows, and further to have parallel rows of equipment configured back-to back so that each row of equipment generally forces the heat from the electronic equipment toward a similar area, known as a hot aisle, as that aisle generally contains warmer air that results from the forced heat from the electronics equipment. In the front of the equipment is thus established a cold aisle. There are different systems for attempting to collect hot air that results from the electronics equipment, cooling that hot air, and then introducing cool air to the electronics equipment. These air-conditioning systems also must co-exist with power and communications wiring for the electronics equipment. Systems in which the electronics equipment is raised above the floor are well-known, as installing the communications wiring from below the equipment has been perceived to offer certain advantages. Routing wiring without raised floors is also known—though not with systematic separation of power and data as described herein. SUMMARY OF THE INVENTION The present invention relates to electronic equipment data center or co-location facility designs and methods of making and using the same in an environmentally aware manner. The present invention generally provides apparatus and methods for using novel support bracket structures, and thermal panels associated with the same, that allow for distinct partitioning of air flowing in hot aisles and cold aisles, as well as for holding wiring above cabinets that are used to store electronic equipment in the facility. In one aspect, the present invention provides a facility for maintaining electronic equipment disposed in a plurality of cage cabinets at a cool temperature using a plurality of air conditioning units, the cage cabinets positioned in at least one row so that the electronic equipment disposed therein emit heated air in a predetermined direction from the cage cabinets to establish a hot aisle, and an opposite side of the row establishing a cold aisle, the plurality of air conditioning units receiving heated air and emitting cooled air. In this aspect, the facility comprises: a floor on which the plurality of cage cabinets are disposed in the at least one row, the floor being within a space that has walls that define a room; a plurality of support brackets disposed along the row, so that a portion of each of the support bracket is disposed above the plurality of cage cabinets; a thermal shield supported by the at least some of the plurality of support brackets, the thermal shield providing a contiguous wall around a hot air area above the at least one row of electronic cabinets to define a warm exhaust channel that traps the heated air within the enclosure area and causes substantially all the heated air within the enclosure area to rise up within the warm exhaust channel; a space separated from the room in which the plurality of air conditioning units are disposed; a warm air escape channel disposed above the warm exhaust channel, the warm air escape channel feeding the heated air to the plurality of air conditioning units; and a cool air channel that connects between the air conditioning system and the cold aisle, the cool air channel delivering cool air from the plurality of air conditioning units to the cool aisle. In another aspect, the invention provides an apparatus for separating warm air from cooler air, the warmer air being produced within an enclosure area bounded by a plurality of cage cabinets positioned so that electronic equipment disposed therein emit heated air into the enclosure area, the cage cabinets positioned in at least one row so that the electronic equipment disposed therein emit heated air from in each in a predetermined direction from the cage cabinets to establish a hot aisle, and an opposite side of the row establishing a cold aisle. In this aspect, the apparatus comprises: a plurality of support brackets disposed along the row, so that a portion of each of the support bracket is disposed above the plurality of cage cabinets; and a thermal shield supported by the at least some of the plurality of support brackets, the thermal shield providing a contiguous wall around a hot air area above the at least one row of electronic cabinets to define a warm exhaust channel that traps the heated air within the enclosure area and causes substantially all the heated air within the enclosure area to rise up within the warm exhaust channel. In another aspect, the plurality of support brackets according to the invention may each further include a plurality of tiered ladder rack supports having ladder racks thereover to establish a plurality of different tiers outside the contiguous wall, so that each of the different tiers is adapted to hold a different type of transmission line that is substantially shielded from the heated air. In a further aspect, the present invention includes a method of forming a facility for housing electrical equipment. This aspect of the invention comprises the steps of: determining a location for at least a one row of cage cabinets that will house the electrical equipment, the at least one row of cage cabinets defining an enclosure area so that electronic equipment disposed within the cabinets will emit heated air in a predetermined direction from the electronic cabinets toward the enclosure area; mounting a plurality of support brackets in relation to the row of cage cabinets so that at least a portion of each of the support brackets is disposed above the cage cabinets; and mounting a contiguous wall around the enclosure area above the cage cabinets using the support brackets to define the warm exhaust channel so that that substantially all warm air within the enclosure area rises up within the warm exhaust channel; and distributing wiring to at least some of the cage cabinets, the step of distributing separating each of a plurality of different types of wiring on each of a plurality of different ladder racks, each of the plurality of different ladder racks being mounted on a ladder rack support that connects to at least some of the plurality of support brackets. BRIEF DESCRIPTION OF THE DRAWINGS These and other aspects and features of the present invention will become apparent to those of ordinary skill in the art upon review of the following description of specific embodiments of the invention in conjunction with the accompanying figures, wherein: FIG. 1(a) illustrates a floor design used in a data center or co-location facility according to the present invention. FIG. 1(b) illustrates floor-based components disposed over the floor design according to the present invention. FIG. 1(c) illustrates a perspective cut-away view along line c-c from FIG. 1(a) of FIG. 1(a) according to the present invention. FIGS. 2(a)-(c) illustrate various cut-away perspective views of the thermal compartmentalization and cable and conduit routing system according to the present invention. FIGS. 3(a) and (b) illustrate modular thermal shields used in the thermal compartmentalization and cable and conduit routing system according to the present invention. FIG. 4 illustrates illustrate a telecommunication bracket used in the thermal compartmentalization and cable and conduit routing system according to the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention provides data center or co-location facility designs and methods of making and using the same. The data center or co-location facility designs have certain features that will be apparent herein and which allow many advantages in terms of efficient use of space, efficient modular structures that allow for efficiency in the set-up of co-location facility and the set-up of the electronics equipment in the facility, as well as efficient air-conditioning within the facility. Each of these features has aspects that are distinct on their own, and combinations of these features also exist that are also unique. FIG. 1(a) illustrates a floor design used in a data center or co-location facility according to the present invention. The preferred embodiment discussed herein uses parallel rows of equipment configured back-to back so that each row of equipment generally forces the heat from the electronic equipment towards a hot aisle, thus also establishing a cold aisle in the front of the equipment. The cold aisles in FIG. 1(a) are illustrated at the dotted line block 60, wherein the hot aisles are illustrated at the dotted line block 62. One feature of the present invention is the provision for marking the floor 50 to explicitly show the various areas of the facility. As illustrated, the hot aisle 62 has a central area 52 that is tiled, painted, taped or otherwise marked to indicate that it is center area of the hot aisle 62. The typical dimensions of the central area 52 are typically in the range of 2′-4′ across the width, with a row length corresponding to the number of electronic cabinets in the row. Marking with tiles is preferable as the marking will last, and tiles that are red in color, corresponding to the generation of heat, have been found preferable. Around this center area 52 is a perimeter area 54, over which the cabinets are installed. This perimeter area 54 is marked in another manner, such as using a grey tile that is different in color from the center area 52. Around the perimeter area 54 is an outside area 56, which is marked in yet a different manner, such as using a light grey tile. The placement of these markings for areas 52, 54 and 56 on the floor of the facility, preferably prior to moving any equipment onto the floor, allows for a visual correspondence on the floor of the various hot and cold aisles. In particular, when installing cabinets over the perimeter 54 are, the area that is for the front of the cabinet that will face the cold aisle, and thus the area for the back of the cabinet for the hot aisle, is readily apparent. FIG. 1(b) illustrates floor-based components disposed over the floor design of the co-location facility according to the present invention. FIG. 1(b) also shows additional area of the floor, which in this embodiment is provided to illustrate interaction of the electronics equipment with the evaporators of the air conditioning units. In the embodiment described with respect to FIG. 1(b), certain features are included so that conventional equipment, particularly conventional air conditioning equipment, can effectively be used while still creating the desired air flow patterns of the present invention as described herein. Before describing the components in FIG. 1(b), an aspect of the present invention is to isolate the hot air exhaust from the areas that require cooling as much as possible, and to also create air flows in which the air moves through the exhaust system, into the air conditioning system, through the air conditioning ducts and out to the cool equipment in a very rapid manner. In particular, the amount of circulation established according to the present invention moves air at a volume such that the entire volume of air in the facility recirculates at least once every 10 minutes, preferably once every 5 minutes, and for maximum cooling once every minute. It has been found that this amount of recirculation, in combination with the air flows established by the present invention, considerably reduce the temperature in the facility in an environmentally efficient manner, thus saving energy, as described herein. Cabinets 110 shown in FIG. 1(b) are placed generally over the sides of the perimeter 54 as described, in rows, which cabinets are formed as cages in order to allow air to flow through them. Different rows are thus shown with cabinets 110(a-f), with each letter indicating a different row. Also included within the rows are telecommunications equipment 170 to which the electronics equipment in each of the cabinets 110 connect as described further herein, as well as power equipment 180 that is used to supply power along wires to the electronics equipment in each of the cabinets 110 connect as described further herein. Air conditioning units include the evaporator units 120 (1-6) that are shown being physically separated by some type of barrier from the area 56 described previously with respect to FIG. 1(a). The condenser units of the air conditioning system that receive the warmed refrigerant/water along lines 122 and are disposed outside the walls of the facility are not shown. This physical separation is implemented in order to establish warm exhaust channel area 240 from the physical space, which warm air area connects to a separate warm air area in the ceiling and allow the warm air to flow into the exhaust channel area 240 and enter into intake ducts of evaporator air conditioning equipment 120, as will be described. This feature allows the usage of conventional evaporator air conditioning equipment that has air intakes at the bottom of the unit, as well as allows for usage of different air conditioning equipment types, while still maintaining an efficient airflow throughout the entire facility. FIG. 1(c) illustrates a perspective cut-away view along line c-c from FIG. 1(a) of the FIG. 1(a) co-location facility according to the present invention. Additionally illustrated are the false ceiling 140 and the actual ceiling 150, which have a gap that is preferably at least 1.5-3 feet and advantageously at least 15 feet, as the higher the ceiling the more the warm air rises (and thus also stays further away from the equipment in the cabinets 110). The false ceiling 140 is preferably made of tiles that can be inserted into a suspended ceiling as is known, which tiles preferably have are drywall vinyl tiles, which exhibit a greater mass than many conventional tiles. Also shown are arrows that illustrate the air flow being centrally lifted upward from the warm exhaust channel area 240 to the area between the false ceiling 140 and the actual ceiling 150, and the flow within the ceiling toward the warm exhaust channel area 240, and then downward into the warm exhaust channel area 240. Also shown are arrows that take cold air from the cold air ducts 310 and insert the air into the cold aisles 60. Though the arrows in the drawing are directed straight downward, the vents themselves can be adjusted to allow for directional downward flow at various angles. In a preferred embodiment, each of the vents have a remote controlled actuator that allows for the offsite control of the vents, both in terms of direction and volume of air let out of each vent. This allows precise control such that if a particular area is running hot, more cold air can be directed thereto, and this can be detected (using detectors not shown), and then adjusted for offsite. FIGS. 2(a)-(c) illustrate various cut-away perspective views of the thermal compartmentalization and cable and conduit routing system according to the present invention. In particular, FIG. 2(a) illustrates a cut away view of a portion of the warm exhaust channel area 240, which rests on top of the cabinets 110, and is formed of a plurality of the thermal shields 400 and 450, which are modular in construction and will be described further hereinafter. Also illustrated are shield brackets 500 that are mounted on top of the cabinets 110, and provide for the mounting of the shields 400 and 450, as well as an area on top of the cabinets 110 to run power and telecommunications cables, as will be described further herein. Before describing the cabling, FIG. 2(b) and FIG. 4 illustrate the shield bracket 500, which is made of structurally sound materials, such as steel with a welded construction of the various parts as described, molded plastic, or other materials. Ladder rack supports 510, 520, 530, 540 and 550 are used to allow ladder racks 610, 620, 630, 640, and 650 respectively, placed thereover as shown. The ladder racks are intended to allow for a segregation of data and electrical power, and therefore an easier time not only during assembly, but subsequent repair. The ladder racks are attached to the ladder rack supports using support straps shown in FIG. 4, which are typically a standard “j” hook or a variant thereof. As also illustrated in FIG. 4, a support beams structure 506 provides extra support to the ladder rack, and the holes 508 are used to secure the shields 400 and 450 thereto. Horizontal support plate 504 is used to support the bracket 500 on the cabinets 110. With respect to the cabling and conduit, these are used to provide electrical power and data to the various servers in the facility. Conduit, also typically referred to as wiring, is used to provide electricity. Cabling is used to provide data. In this system, it is preferable to keep the electrical power and the data signals separated. Within the system, ladder rack 610 is used for data cabling on the cold aisle side of the thermal shields 400. Ladder rack 620 is used for an A-source power conduit (for distribution of 110-480 volt power) on the cold aisle side of the thermal shields 400. Ladder rack 630 is used for B-source power conduit (for distribution of 110-480 volt power), which is preferably entirely independent of A-source power conduit, on the cold aisle side of the thermal shields 400. Ladder rack 640 is used for miscellaneous cabling on the cold aisle side of the thermal shields 400. Ladder rack 650 is used for data cabling on the hot aisle side of the thermal shields 400. Each ladder rack can also be used for different purposes and still be within the scope of the present invention. FIGS. 3(a) and (b) illustrate modular thermal shields 400 and 450, respectively, used in the thermal compartmentalization and cabling and conduit routing system according to the present invention. Both shields 400 and 450 are made of a structurally sound material, including but not limited to steel, a composite, or a plastic, and if a plastic, one that preferably has an air space between a front piece of plastic and a back piece of plastic for an individual shield 400. Shield 400 includes a through-hole 410 that allows for certain cabling, if needed, to run between the hot and cold aisle areas, through the shield 400. A through-hole cover (not shown) is preferably used to substantially close the hole to prevent airflow therethrough. Shield 450 has a 90 degree angle that allows the fabrication of corners. It should be appreciated that the construction of the cabinets, the shields 400 and 450, and the shield supports 500 are all uniform and modular, which allows for the efficient set-up of the facility, as well as efficient repairs if needed. Other different embodiments of data center or co-location facilities according to the present invention also exist. For example, while the false ceiling 140 is preferred, many advantageous aspects of the present invention can be achieved without it, though its presence substantially improves airflow. Furthermore, the evaporation units for the air conditioning system can also be located outside the facility, in which case the chamber 240 is not needed, but hot air from the ceiling can be delivered to evaporation units that are disposed above the ceiling, which is more efficient in that it allows the warm air to rise. If the complete air conditioning equipment is located outside, including the evaporators, the refrigerant/water lines 122 that are used to exchange the refrigerant/water if the evaporators are disposed inside the facility is not needed, which provides another degree of safety to the equipment therein. It is noted that aspects of the present invention described herein can be implemented when renovating an existing facility, and as such not all of the features of the present invention are necessarily used. Although the present invention has been particularly described with reference to embodiments thereof, it should be readily apparent to those of ordinary skill in the art that various changes, modifications and substitutes are intended within the form and details thereof, without departing from the spirit and scope of the invention. Accordingly, it will be appreciated that in numerous instances some features of the invention will be employed without a corresponding use of other features. Further, those skilled in the art will understand that variations can be made in the number and arrangement of components illustrated in the above figures.
<SOH> BACKGROUND <EOH>Data centers and server co-location facilities are well-known. In such facilities, rows of electronics equipment, such as servers, typically owned by different entities, are stored. In many facilities, cabinets are used in which different electronics equipment is stored, so that only the owners of that equipment, and potentially the facility operator, have access therein. In many instances, the owner of the facilities manages the installation and removal of servers within the facility, and is responsible for maintaining utility services that are needed for the servers to operate properly. These utility services typically include providing electrical power for operation of the servers, providing telecommunications ports that allow the servers to connect to transmission grids that are typically owned by telecommunication carriers, and providing air-conditioning services that maintain temperatures in the facility at sufficiently low levels. There are some well-known common aspects to the designs of these facilities. For example, it is known to have the electronic equipment placed into rows, and further to have parallel rows of equipment configured back-to back so that each row of equipment generally forces the heat from the electronic equipment toward a similar area, known as a hot aisle, as that aisle generally contains warmer air that results from the forced heat from the electronics equipment. In the front of the equipment is thus established a cold aisle. There are different systems for attempting to collect hot air that results from the electronics equipment, cooling that hot air, and then introducing cool air to the electronics equipment. These air-conditioning systems also must co-exist with power and communications wiring for the electronics equipment. Systems in which the electronics equipment is raised above the floor are well-known, as installing the communications wiring from below the equipment has been perceived to offer certain advantages. Routing wiring without raised floors is also known—though not with systematic separation of power and data as described herein.
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention relates to electronic equipment data center or co-location facility designs and methods of making and using the same in an environmentally aware manner. The present invention generally provides apparatus and methods for using novel support bracket structures, and thermal panels associated with the same, that allow for distinct partitioning of air flowing in hot aisles and cold aisles, as well as for holding wiring above cabinets that are used to store electronic equipment in the facility. In one aspect, the present invention provides a facility for maintaining electronic equipment disposed in a plurality of cage cabinets at a cool temperature using a plurality of air conditioning units, the cage cabinets positioned in at least one row so that the electronic equipment disposed therein emit heated air in a predetermined direction from the cage cabinets to establish a hot aisle, and an opposite side of the row establishing a cold aisle, the plurality of air conditioning units receiving heated air and emitting cooled air. In this aspect, the facility comprises: a floor on which the plurality of cage cabinets are disposed in the at least one row, the floor being within a space that has walls that define a room; a plurality of support brackets disposed along the row, so that a portion of each of the support bracket is disposed above the plurality of cage cabinets; a thermal shield supported by the at least some of the plurality of support brackets, the thermal shield providing a contiguous wall around a hot air area above the at least one row of electronic cabinets to define a warm exhaust channel that traps the heated air within the enclosure area and causes substantially all the heated air within the enclosure area to rise up within the warm exhaust channel; a space separated from the room in which the plurality of air conditioning units are disposed; a warm air escape channel disposed above the warm exhaust channel, the warm air escape channel feeding the heated air to the plurality of air conditioning units; and a cool air channel that connects between the air conditioning system and the cold aisle, the cool air channel delivering cool air from the plurality of air conditioning units to the cool aisle. In another aspect, the invention provides an apparatus for separating warm air from cooler air, the warmer air being produced within an enclosure area bounded by a plurality of cage cabinets positioned so that electronic equipment disposed therein emit heated air into the enclosure area, the cage cabinets positioned in at least one row so that the electronic equipment disposed therein emit heated air from in each in a predetermined direction from the cage cabinets to establish a hot aisle, and an opposite side of the row establishing a cold aisle. In this aspect, the apparatus comprises: a plurality of support brackets disposed along the row, so that a portion of each of the support bracket is disposed above the plurality of cage cabinets; and a thermal shield supported by the at least some of the plurality of support brackets, the thermal shield providing a contiguous wall around a hot air area above the at least one row of electronic cabinets to define a warm exhaust channel that traps the heated air within the enclosure area and causes substantially all the heated air within the enclosure area to rise up within the warm exhaust channel. In another aspect, the plurality of support brackets according to the invention may each further include a plurality of tiered ladder rack supports having ladder racks thereover to establish a plurality of different tiers outside the contiguous wall, so that each of the different tiers is adapted to hold a different type of transmission line that is substantially shielded from the heated air. In a further aspect, the present invention includes a method of forming a facility for housing electrical equipment. This aspect of the invention comprises the steps of: determining a location for at least a one row of cage cabinets that will house the electrical equipment, the at least one row of cage cabinets defining an enclosure area so that electronic equipment disposed within the cabinets will emit heated air in a predetermined direction from the electronic cabinets toward the enclosure area; mounting a plurality of support brackets in relation to the row of cage cabinets so that at least a portion of each of the support brackets is disposed above the cage cabinets; and mounting a contiguous wall around the enclosure area above the cage cabinets using the support brackets to define the warm exhaust channel so that that substantially all warm air within the enclosure area rises up within the warm exhaust channel; and distributing wiring to at least some of the cage cabinets, the step of distributing separating each of a plurality of different types of wiring on each of a plurality of different ladder racks, each of the plurality of different ladder racks being mounted on a ladder rack support that connects to at least some of the plurality of support brackets.
H05K720
20170830
20180215
92371.0
H05K720
2
PROBST, SAMANTHA A
ELECTRONIC EQUIPMENT DATA CENTER OR CO-LOCATION FACILITY DESIGNS AND METHODS OF MAKING AND USING THE SAME
UNDISCOUNTED
1
CONT-ACCEPTED
H05K
2,017
15,691,144
PENDING
COMMUNICATIVE WATER BOTTLE AND SYSTEM THEREOF
A communicative water bottle includes communication logic and wireless transmission logic technology electronically connected with a variety of sensors either on the water bottle or located remote from the water bottle. The sensors on the bottle create digital data associated with amount of fluid in the bottle and change thereof. The sensors remote from the bottle, which can be on an activity tracker, create digital data associated with an activity being performed by a user, such as running, or the absence of activity, such as remaining sedentary. A display on the bottle can indicate to the user the amount of fluid consumed or a reminder that fluid should be consumed. The fluid consumption data syncs with other remote devices such as mobile applications executable on smartphones.
1. A communicative sports water bottle system comprising: a bottle body having a base and an upwardly extending sidewall therein defining a fluid chamber and a first display coupled to the bottle body; a sensor determining one or more of the following an amount of fluid in the fluid chamber, an amount of fluid being dispensed from the fluid chamber, and a physical movement of the bottle body; fluid information logic electronically coupled with the sensor creating digital data associated with fluid in the chamber; data transmission and reception logic configured to send the digital data to a remote device and receive digital data from the remote device, wherein the data transmission and reception logic monitors wireless input sources for incoming wireless packets and analyzes any received packets in order to detect a source of the packet transmission and decide whether to sync the digital data associated with fluid in the chamber with the source of the packet; wherein the remote device is a wrist-worn health activity tracker including a second display that displays information associated with one or more of the following: the amount of fluid in the chamber, the amount of fluid dispensed from the chamber, an amount of time since fluid was last dispensed from the chamber, an amount of fluid dispensed over a given time period, a reminder notification if fluid has not been dispensed over a given time period, a reminder to consume an adjusted amount of fluid based, at least in part, on activity information obtained from the remote device; network connectivity electronically connecting the data transmission and reception logic and the remote device, wherein in the network connectivity is selected from a group comprising of: Bluetooth connection, wireless internet connection, wired internet connection, Internet, and 3G/4G connection; a record of information for a previous period at a fixed time interval, and the record of information is displayed in one of the first display and the second display; a cap repeatably attachable and detachable from the bottle body, and wherein the sensor is carried by the cap; and cap sensor placement-specific algorithms executed by the fluid information logic during the previous period to determine the one or more of the following the amount of fluid in the fluid chamber, the amount of fluid dispensed from the fluid chamber, the physical movement of the bottle body, the amount of time since fluid was last dispensed from the chamber, the amount of fluid dispensed over a given time period, and the reminder notification if fluid has not been dispensed over a given time period; and adaptive filtering logic executed during the previous period to cancel out excessive movements of the cap. 2. The communicative sports water bottle system of claim 1, further comprising: artificial intelligence configured to learn the record of information to detect behavior signatures from the previous period, which is implemented to predict a likelihood of a subject has certain activity levels at a present time. 3. The communicative sports water bottle system of claim 2, further comprising seven layers of OSI modeling including a physical layer, a data link layer, a network layer, a transport layer, a session layer, a presentation layer, and an application layer. 4. The communicative sports water bottle system of claim 3, wherein the sensor operates in one of the physical and data link layers, and the sensor initiates data collection of fluid consumption through at least one of a plurality of triggers, wherein the plurality of triggers is selected from the group comprising a first trigger of a detectable motion intensity signature of movement of bottle detected by a trigger algorithm receiving sensor output and a second trigger of a detectable motion intensity signature of exercise movement detected by a body movement algorithm performed by the remote device worn on the wrist. 5. The communicative sports water bottle of claim 4, wherein the data transmission logic operates in one of the physical, data link, network, transport, and session layers, wherein the data transmission logic receives data to be relayed including a relay indicator inherent to the data itself, wherein the relay indicator includes a certain type of encryption and the encryption type indicates that the data transmission and reception logic should forward the data to the remote device. 6. The communicative sports water bottle system of claim 1, further comprising: automatic packet detection logic monitoring input sources for packets and analyzes packets embedded within an application launched by an operating system of the bottle. 7. The communicative sports water bottle system of claim 6, wherein the automatic packet detection logic monitors input sources for incoming packets periodically in order to lower power consumption. 8. The communicative sports water bottle of claim 7, wherein the frequency of periodic listening events is varied to balance power consumption and the time to detection. 9. The communicative sports water bottle of claim 6, wherein the automatic packet detection logic monitors input sources for incoming packets continuously in order to decrease detection latency. 10. A communicative sports water bottle system comprising: a bottle body having a base and an upwardly extending sidewall therein defining a fluid chamber and a first display coupled to the bottle body; a sensor determining one or more of the following an amount of fluid in the fluid chamber, an amount of fluid being dispensed from the fluid chamber, and a physical movement of the bottle body; fluid information logic electronically coupled with the sensor creating digital data associated with fluid in the chamber; data transmission and reception logic configured to send the digital data to a remote device and receive digital data from the remote device, wherein the data transmission and reception logic monitors wireless input sources for incoming wireless packets and analyzes any received packets in order to detect a source of the packet transmission and decide whether to sync the digital data associated with fluid in the chamber with the source of the packet; wherein the remote device is a wrist-worn health activity tracker including a second display that displays information associated with one or more of the following: the amount of fluid in the chamber, the amount of fluid dispensed from the chamber, an amount of time since fluid was last dispensed from the chamber, an amount of fluid dispensed over a given time period, a reminder notification if fluid has not been dispensed over a given time period, a reminder to consume an adjusted amount of fluid based, at least in part, on activity information obtained from the remote device; network connectivity electronically connecting the data transmission and reception logic and the remote device, wherein in the network connectivity is selected from a group comprising of: Bluetooth connection, wireless internet connection, wired internet connection, internet, and 3G/4G connection; a record of information for a previous period at a fixed time interval, and the record of information is displayed in one of the first display and the second display; and bottle body sensor placement-specific algorithms executed by the fluid information logic to determine the one or more of the following the amount of fluid in the fluid chamber, the amount of fluid dispensed from the fluid chamber, the physical movement of the bottle body, the amount of time since fluid was last dispensed from the chamber, the amount of fluid dispensed over a given time period, and the reminder notification if fluid has not been dispensed over a given time period; and adaptive filtering logic to cancel out excessive movements of the bottle. 11. The communicative sports water bottle system of claim 10, further comprising: artificial intelligence configured to learn the record of information to detect behavior signatures from the previous period, which is implemented to predict a likelihood of a subject has certain activity levels at a present time. 12. A method for displaying fluid consumption by a human comprising: generating digital data associated with fluid in a communicative bottle via fluid information logic electronically coupled with a first sensor carried by the communicative bottle; sending digital data via data transmission and reception logic to the wrist-worn remote device and receiving digital data from the remote device, wherein the data transmission and reception logic monitors wireless input sources for incoming wireless packets and analyzes any received packets in order to detect a source of the packet transmission and decide whether to sync the digital data associated with fluid in the chamber with a source of the packet; displaying digital data associated with a first amount of fluid within the communicative bottle in a first display integrated in a wrist-worn remote electronic device distinct from the communicative bottle; wherein the wrist-worn remote device is a wrist-worn health activity tracker that displays information, in the first display, associated with one or more of the following: the amount of fluid in the chamber, the amount of fluid dispensed from the chamber, an amount of time since fluid was last dispensed from the chamber, an amount of fluid dispensed over a given time period, a reminder notification if fluid has not been dispensed over a given time period, a reminder to consume an adjusted amount of fluid based, at least in part, on activity information obtained from the remote device; connecting the data transmission and reception logic and the wrist-worn remote device via electronic network connectivity, wherein in the network connectivity is selected from a group comprising of: Bluetooth connection, wireless internet connection, wired internet connection, internet, and 3G/4G connection; recording the data associated with the first amount of fluid; predicting, via artificial intelligence configured to learn the recorded data associated with the first amount of fluid to detect behavior signatures, which is implemented in one or more processors, a likelihood of a subject has certain activity levels at a present time; recognizing an adjustment of the first amount of fluid in the communicative bottle by one of the following (a) fluid dispensed from the communicative bottle and (b) fluid added to the communicative bottle; sensing the amount of adjusted fluid with the first sensor coupled to the communicative bottle to create data associated with a second amount of fluid within the communicative bottle; sending data associated with the second amount of fluid to the first display in the wrist-worn remote electronic device; displaying data associated with the second amount of fluid within the communicative bottle in the first display integrated in the wrist-worn remote electronic device distinct from the communicative bottle; displaying an amount of water to be consumed determined by a difference of the data associated with the second amount of data from the predicted activity levels at the present time. 13. The method of claim 12, further comprising: receiving activity information of a person at the communicative bottle from a second sensor on the wrist-worn remote electronic device; and adjusting the data associated with the first amount of fluid, based at least in part, on the activity information received from the second sensor, and displaying data associated with a third amount of fluid in the display integrated in the wrist-worn remote electronic device distinct from the communicative bottle. 14. The method of claim 13, wherein the first sensor is integral to the communicative bottle. 15. The method of claim 13, further comprising: displaying data associated with a third amount of fluid to be consumed by a person in the first display integrated in the wrist-worn remote electronic device distinct from the communicative bottle; receiving activity information of the person from the wrist-worn remote electronic device; and adjusting the third amount of fluid to be consumed by the person based, at least in part, on the activity information received from the wrist-worn remote electronic device, and displaying a second amount of fluid to be consumed in the display integrated in the wrist-worn remote electronic device distinct from the communicative bottle. 16. The method of claim 12, wherein the first sensor is a flow sensor and the activity information is drinking the fluid by the person, further comprising the steps of: sensing the difference between the second amount of fluid and the first amount of fluid after the person has drank the fluid creating consumption data; transmitting the consumption data from the communicative bottle to the wrist-worn remote electronic device selected from a group comprising a remote activity tracker and a mobile application executable on a smartphone and an application executable on a smartwatch. 17. The method of claim 12, further comprising: syncing the communicative bottle with the wrist-worn remote electronic device based, at least in part, on the activity information obtained from the first sensor. 18. The method of claim 12, further comprising: transmitting fluid consumption instructions for increased consumption from the wrist-worn remote electronic device to the communicative bottle for display thereon when a second sensor, located on the wrist-worn remote electronic device, detects one of the following an increase in physical activity by the user and an absence of drinking activity over a certain time period by the user. 19. The method of claim 12, further comprising: tapping the bottle to initiate user input recognized by fluid information logic connected with the communicative bottle.
CROSS REFERENCE TO RELATED APPLICATION This is a continuation application from prior U.S. patent application Ser. No. 14/657,300 filed on Mar. 13, 2015; the entirety of which is herein incorporated by reference as if fully rewritten. BACKGROUND Technical Field The present disclosure relates generally to the field of health tracking and monitoring devices. More particularly, the present disclosure relates to water bottles used in the health tracking industry. Specifically, the present disclosure relates to water bottles that transmit information of the amount of water or fluid consumed therefrom to a remote health tracking device and conveying that information to a user. Background Information Proper hydration is an integral aspect of human well-being. Water consumption is the primary way humans hydrate themselves. Often, people will carry around water bottles with them so they can hydrate on-the-go when they may not be near a water source. Water bottles ordinarily include delineations thereon to indicate the amount of fluid contained in the bottle. Other water bottles may include digital representation of the amount of water contained in the bottle and consumed therefrom. One such exemplary digital water bottle is commercially available for sale under the name. of California. According to HydraCoach, their intellegent water bottle is an interactive fluid measurement device that automatically calculates, monitors and provides instant feedback on fluid consumption for athletes, amongst others. Determined by a user's weight and duration of exercise, the Hydracoach digital water bottle will generate a personal hydration goal for the day. Shifting focus now to personal health tracking monitors (also known as “activity trackers”), they are exploding in popularity amongst individuals desiring to monitor many aspects of their daily health routine. Some exemplary personal health tracking monitors/devices are: Fitbit Surge and Fitbit Charge by Fitbit, Inc.; iWatch by Apple, Inc.; and Up and UP24 by Jawbone. Additionally, some smartphone applications operate as activity trackers, and some are even configured to sync with the aforementioned monitors/devices. Some exemplary smartphone applications are MyFitnessPal by MyFitnessPal, Inc. and RunKeeper by FitnessKeeper, Inc. Further, some of the heath tracking device companies have their own smartphone applications that collect and display information obtained from their device. In these above referenced health monitoring mobile applications, there is often a line item entry for hydration (i.e., amount of water consumed). These mobile applications require the user to manually enter the amount of water they consume. SUMMARY Issues continue to exist with activity trackers and health monitoring mobile applications inasmuch as they require the manual entry of hydration information. A need continues to exist for a water bottle having the ability to calculate an amount of water consumed therefrom to directly sync with a remote device such as an activity tracker (e.g., Fitbit Surge, iWatch, or UP24, amongst many others) or a smartphone (e.g., iPhone) running a mobile health application. The present disclosure addresses these and other issues. In one aspect, an embodiment may provide a communicative sports water bottle comprising: a bottle body having a base and an upwardly extending sidewall therein defining a fluid chamber; a sensor determining one or more of the following an amount of fluid in the fluid chamber, an amount of fluid being dispensed from the fluid chamber, and a physical movement of the bottle body; fluid information logic electronically coupled with the sensor creating digital data associated with fluid in the chamber; and data transmission and reception logic configured to send the digital data to a remote device and receive digital data from the remote device. In another aspect, an embodiment may provide a method for displaying fluid consumption by a human comprising the steps of: displaying data associated with a first amount of fluid within a communicative bottle in a display; adjusting the amount of fluid in the communicative bottle by one of the following (a) dispensing fluid from the bottle and (b) adding fluid to the bottle; sensing the amount of adjusted fluid with a first sensor to create data associated with a second amount of fluid; and wirelessly sending data associated with the second amount of fluid to a remote device. In another aspect, an embodiment may provide, in combination, a wearable health activity tracker including wireless communication logic and a water bottle including wireless communication logic, wherein the activity tracker and water bottle sync to one another to therebetween transfer data associated with fluid consumption by a user, the water bottle comprising: a bottle body having a base and an upwardly extending sidewall therein defining a fluid chamber. This embodiment may also include a software application executable on a mobile computing device displaying digital data associated with one of the following: an amount of fluid in the chamber, an amount of fluid dispensed from the chamber, an amount of time since fluid was last dispensed from the chamber, an amount of fluid dispensed over a given time period, a reminder notification if fluid has not been dispensed over a given time period, a reminder to consume an adjusted amount of fluid based, at least in part, on activity information obtained from the health tracking device. Additionally, this embodiment can include fluid consumption instructions for increased consumption by the user from the remote device to the bottle for display thereon when a second sensor, located on the remote device, detects one of the following an increase in physical activity by the user and an absence of drinking activity over a certain time period by the user. In another aspect, the disclosure may provide a communicative water bottle that includes communication logic and wireless transmission logic technology electronically connected with a variety of sensors either on the water bottle or located remote from the water bottle. The sensors on the bottle create digital data associated with amount of fluid in the bottle and change thereof. The sensors remote from the bottle, which can be on an activity tracker, create digital data associated with an activity being performed by a user, such as running, or the absence of activity, such as remaining sedentary. A display on the bottle can indicate to the user the amount of fluid consumed or a reminder that fluid should be consumed. The fluid consumption data syncs with other remote devices such as mobile applications executable on smartphones. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS A sample embodiment of the disclosure is set forth in the following description, is shown in the drawings and is particularly and distinctly pointed out and set forth in the appended claims. The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate various example methods, and other example embodiments of various aspects of the disclosure. It will be appreciated that the illustrated element boundaries (e.g., boxes, groups of boxes, or other shapes) in the figures represent one example of the boundaries. One of ordinary skill in the art will appreciate that in some examples one element may be designed as multiple elements or that multiple elements may be designed as one element. In some examples, an element shown as an internal component of another element may be implemented as an external component and vice versa. Furthermore, elements may not be drawn to scale. FIG. 1 is a diagrammatic representation of a communicative bottle of the present disclosure; FIG. 2 is an exemplary display of a OSI seven layer model; and FIG. 3 is a diagrammatic representation of the communicative bottle of the present disclosure connecting to either one of a remote activity tracking device or a mobile application executable on a smart phone via a network. Similar numbers refer to similar parts throughout the drawings. DETAILED DESCRIPTION As depicted in FIG. 1, a communicative sports water bottle 10 of the present disclosure provides an improved way to communicate an amount of fluid (e.g., water) consumed by a person or otherwise dispensed over the course of a set time period. Further, bottle 10 provides an improved way to communicate the absence of fluid consumption (e.g., if a person is not drinking enough). Sports water bottle 10 comprises a sports bottle body 12 having a base 14 and an upwardly extending generally rigid sidewall 16 therein defining a fluid chamber 18. Water bottle 10 further comprises a sensor 20 determining an amount of fluid 22 in the fluid chamber 18. Base 14 is a generally circular in shape when viewed from above and may include a slight apex at the center creating a generally dome formation, however it is not necessary. Sidewall 16 forms a rigid connection with base 14 extending upwardly therefrom. Sidewall 16 includes an outwardly facing outer surface and an inwardly facing inner surface. Inner surface of sidewall 16 defines a portion of chamber 18. Bottle 10 further comprises fluid information logic 24 electronically coupled with the sensor 20 creating digital data associated with fluid 22 in the chamber 18. Bottle 10 may further comprise data transmission logic 26 configured to send the digital data to a remote device 28. The digital data may be displayed on a display 21. “Logic”, as used herein, includes but is not limited to hardware, firmware, software and/or combinations of each to perform a referenced function(s) or an action(s), and/or to cause a function or action from another logic, method, and/or system. For example, based on a desired application or needs, logic may include a software controlled microprocessor, discrete logic like a processor (e.g., microprocessor), an application specific integrated circuit (ASIC), a programmed logic device, a memory device containing instructions, an electric device having a memory, or the like. Logic may include one or more gates, combinations of gates, arrays, or other circuit components. Logic may also be fully embodied as software. Where multiple logics are described, it may be possible to incorporate the multiple logics into one physical logic. Similarly, where a single logic is described, it may be possible to distribute that single logic between multiple physical logics. Water bottle 10 may further include a cap 30 repeatably attachable and detachable from the sports bottle body 12. In one embodiment, a sensor 20A may be located on or within the cap 30. Alternatively, a sensor 20B may be located on or integrally in the sports water bottle body 12. Sensors 20A and 20B may be similar to sensor 20 made reference to above and described in further detail below. Further, bottle 10 may include an indicator display 21 on the bottle body displaying the digital data associated with the fluid in the chamber. Indicator can also communicate to the user the time elapsed since the last consumption of fluid. Cap 30 and body 12 may be formed substantially from a BPA-free material. Alternatively, cap 30 and body 12 may be constructed from another dishwasher safe material, such as stainless steel. Furthermore, the manner in which cap 30 is selectively released from engagement with body 12 can vary as one having ordinary skill in the art would understand. Cap 30 may threadedly attach and release from body 12 or may fit within the upper end of chamber 18 with a frictional interference fit including a sealing gasket. Further, cap 30 may include a nozzle permitting fluid 22 to flow therethrough. The aforementioned electrical components of bottle 10 (i.e., the sensor 20, the display 21, the fluid information logic 24, and the transmission logic 26) may be powered by a rechargeable battery as one in the art easily understands. Furthermore, the battery and the electrical components powered therefrom may be constructed to be repeatably detached and attached to bottle 10 to allow for cleaning of bottle 10 without disturbing the electrical system which would may be damaged if contacted by water during washing and cleaning. While not shown, it is contemplated that the electrical components can be carried by a housing that nests within a recessed formed in body 12 facilitating the easy removal during cleaning. As depicted in FIG. 2, communicative sports bottle 10 may be used in combination with or include logic operable in one of, some of, or all seven layers of the Open Systems Interconnection model (OSI). The OSI model is a conceptual model that characterizes and standardizes the internal functions of a communication system by partitioning said system into abstraction layers. The model is a product of the Open Systems Interconnection project at the International Organization for Standardization (ISO), maintained by the identification ISO/IEC 7498-1. The OSI modeling 200 includes a physical layer 202, a data link layer 204, a network layer 206, a transport layer 208, a session layer 210, a presentation layer 212, and an application layer 214. In one exemplary embodiment sports water bottle 10, the sensor 20A or 20B operates in one of the physical and data link layers 202, 204, respectively, or also the network layer 206. In another exemplary embodiment, the data transmission logic 26 operates in one of the physical 202, data link 204, network 206, transport 208, and session 210 layers. In another exemplary embodiment, the fluid information logic operates in one of the physical 202, data link 204, network 206, transport 208, session 210, presentation 212, and application 214 layers. As depicted in FIG. 3, the communicative sports water bottle 10 is used in combination 300 with one of a remote electronic health tracking device 28 (e.g., a Fitbit, an iWatch, or an UP24) and a mobile application 32 (e.g. MyFitnessPal) executable on a smartphone 34 (e.g., iPhone) and communication between devices occurs across network 31. The health tracking device 28 may further include a digital display 36. Both device 28 and mobile application 32 operate in one of the session, presentation, and application layers, 210, 212, and 214, respectively. Either one of device 28 and mobile app 32 display information associated with one or more of the following: an amount of fluid in the chamber, an amount of fluid dispensed from the chamber, an amount of time since fluid was last dispensed from the chamber, an amount of fluid dispensed over a given time period, and a reminder notification if fluid has not been dispensed over a given time period. The fluid information logic 24 and data transmission logic 26 communicate with one of the remote devices (either device 28 or app 32 on smartphone 34) over network 31. The network 31 connectivity electronically couples the communicative sports water bottle 10 and the remote electronic health tracking device 28, wherein in the network connectivity is selected from a group comprising of: Bluetooth connection, wireless internet connection, wired internet connection, internet, and 3G/4G connection. In operation, bottle 10 initiates data collection of water consumption through a plurality of triggers. One of the sensors 20 may include a detectable motion intensity signature. This motion intensity signature may be detected by the movement of bottle 10. An input to a trigger algorithm may come directly or indirectly from the sensor output. For example, the input may be direct output from an accelerometer or it may be processed accelerometer output. One exemplary trigger can be the lifting of the bottle 10 to activate the fluid information logic 24 which then initiates the sensor 20 to detect how much fluid or water is leaving the bottle 10. Some movement of bottle 10 is considered activity associated with different levels of motion detected by a motion sensor of on bottle 10 carried by a user. In some conditions, a user grasps bottle 10 in a moving activity and drinks some of the fluid contained therein. In such conditions, the motion intensity detected by the motion sensor can initiate a data collection sequence by sensors coupled with fluid information logic or purposefully not initiate data collection. For example, repeated or rhythmic swaying of the bottle can be programmed (such as when clipped to a back pack or held in a hand while walking) to not initiate the data collection. In operation, and during consumption, sensors 20 on bottle 10 may determine the rate of fluid exiting bottle 10 using a flow meter in cap 30. The flow-type sensors can measure fluid moving therethrough. Some exemplary manners of measuring fluid flow include determining by signal-to-noise ratio, signal norms, signal energy/power in certain frequency bands, wavelet scale parameters, and/or a number of samples exceeding one or more thresholds. In other embodiments, accelerometer output power is used to determine different rates and amounts of fluid exiting bottle, where the rate of fluid leaving is calculated as a sum of accelerometer amplitude values (or amplitude squared values) relative to an exit orifice area. In some embodiments, data from one axis, or two axes, or three axes of one or more motion sensor may be used to determine the motion intensity. In some embodiments, data from one axis are used for further analyses when the signal is relatively high, while data from two or more axis are used for further analyses when the signal is relatively low. In some embodiments, in addition to or instead of real time or near real time motion sensor data, previously processed and/or stored sensor information may be used to determine any one of the following an amount of fluid in the chamber, an amount of fluid dispensed from the chamber, an amount of time since fluid was last dispensed from the chamber, an amount of fluid dispensed over a given time period, and a reminder notification if fluid has not been dispensed over a given time period. In some embodiments, information collected from sensors may include a record of information for a previous period (e.g., 1, 2, or 3 days to 6, 7 or 8 days) at a fixed time interval (e.g., once per minute; once per half hour; once per hour). Bottle 10 may further include artificial intelligence capable of learning such that digital information may be used to detect behavior signatures from the prior information, which may then be used to predict the likelihood of a subject has certain activity levels at the present time. Some embodiments use one or more classifiers or other algorithm to combine inputs from multiple sources (e.g., accelerometer power and minutely recorded data) and to determine the probability that the user is engaged in an activity with certain characteristics. For instance, if a user tends to be drinking more frequently in the morning or during a meal but working and not drinking in the afternoon, the prior motion related data on the bottle will show data pattern reflecting the user's tendency, which tendency can be used by the bottle in a classifier connected to a computer or smartphone through the network to determine that the user is likely drinking water from bottle 10 with breakfast in the morning. In operation, bottle 10 may include sensors located different positions along the bottle body or in the cap. With each sensor on bottle 10, placement-specific algorithms are run in order to estimate one of an amount of fluid in the chamber, an amount of fluid dispensed from the chamber, an amount of time since fluid was last dispensed from the chamber, an amount of fluid dispensed over a given time period, and a reminder notification if fluid has not been dispensed over a given time period. Adaptive filtering techniques may be used to cancel out excessive movements of the bottle (such as if bottle is being carried in a backpack). A motion mode may be activated when the motion level is within a certain range. In the case of a sensor integrated into the cap, there may be three different motion level ranges corresponding to three modes; active mode, fluid movement mode, and inactive mode. The algorithmic determinations of and the transitions between the modes, which enable fluid measurement in a continuous manner. It should be noted that the three mode approach described herein is for illustration, and is not a limitation of the present disclosures. There may be fewer modes (e.g., active and not active) or greater than 3 modes. In some embodiments, algorithms operating in the frequency domain are used to determine the number of times (i.e., the frequency) a person consumes fluid over a period of time. One problem people tend to have is that they do not drink enough water over the course of a day, especially people who exercise more frequently or those that need more water consumption (such as pregnant women). Frequency logic contained within the fluid information logic 24 counts the number of times a person is drinking per day or per hour and how much fluid is consumed within a given period. By way of non-limiting example, if a pregnant woman hypothetically needs to drink about 12 ounces of water every hour, frequency logic initiates and tracks the hourly time intervals ensuring that the required intake is met by the user. In some implementations, bottle 10 may include one or more vibramotors (also referred to herein as “vibrators” or simply as “vibrating devices”) for communicating information with or to the user. For example, the processing unit fluid information logic 24 or transmission logic 26 can utilize the vibramotors to communicate one or more alarms, achieved goals, progress indicators, inactivity indicators, reminders, indications that a timer has expired, or other indicators, feedback or notifications to a user holding or drinking from bottle 10. In some such implementations, the bottle 10 can utilize the vibramotors to communicate such information to the user in addition to communicating the same or similar information via the display, the lights, or the sound-producing devices. In some other such implementations, the bottle 10 can utilize the vibramotors to communicate such information to the user instead of or in lieu of communicating the same or similar information via the display, the lights, or the sound-producing devices. For example, in the case of an alarm when it is time to consume water (for example if the frequency logic determines that a pregnant woman has not consumed 12 ounces of water in the past hour), the vibramotors can cause the bottle 10 to vibrate to alert the user. As another example, in the case of a goal-achievement or progress indicator, the vibramotors can cause the bottle 10 to vibrate to alert the user that the user's goal has been achieved or that a milestone or other progress point en route to the goal has been reached without requiring the user to look at a display or hear an indication output from a speaker. In some implementations, a user can define one or more custom vibration patterns or other vibrational characteristics and assign such differing vibration patterns or other vibrational characteristics to different alarms, goals, or other vibrating indicators so that the user can distinguish among the vibrating indicators to determine what information is being communicated by the bottle 10. In various implementations, the user can customize such patterns, characteristics, or settings or make such selections via the user interface, or via an application or program (including a web application, mobile application, or client-side software program) executing on an external computing device (for example, a personal computer, smartphone or multimedia device) communicatively coupled with the portable monitoring device via the I/O interface and one or more wired or wireless connections or networks. In some implementations, as described above, one or more of the sensors 20 themselves also can be used to implement at least a portion of the user interface. For example, one or more accelerometers or other motion sensors 20 can be used to detect when a person taps the body of bottle 10 with a finger or other object, and then interpret such data as a user input for the purposes of controlling the bottle 10. For example, double-tapping the body 12 of bottle 10 may be recognized by the fluid information logic 24 as a user input that will cause a display of the bottle 10 to turn on from an off state or that will cause the bottle 10 to transition between different monitoring states, sessions, or modes. In accordance with one aspect of the present disclosure, bottle 10 has a shape and size that is adapted to be handled or carried by a user. Bottle 10 collects one or more types of fluid data from embedded sensors and/or external devices and communicates or relays such information to other devices or other internet-viewable sources. Notably, the bottle collects data regarding fluid consumed from bottle 10 over a time period, or the absence of consumption over that time period. In one example, the user carrying bottle 10 around with them during the course of a day. A display on the bottle can show the user how much fluid is inside the bottle, how much fluid has been consumed since the user woke up that day, or how much fluid has been consumed in the past hour. Additionally, bottle 10 can sync with a remote activity device 28 and determine how much fluid should be consumed based on the activity being performed. For example, if a user is wearing a Fitbit (remote device 28) and the Fitbit knows that a user is running, then water bottle 10 can adjust the consumption requirements for that activity. Furthermore, bottle 10 can even further adjust the consumption requirements of fluid based on the activity and the user's biometrics (i.e., weight, gender, age). The consumption data or alerts may then be transmitted and displayed to the user. In accordance with another aspect of the present disclosure, bottle 10 may communicate to a user how much fluid needs to be consumed based on an activity level being performed during or over a given time period. For example, bottle 10 communicates with a remote activity device 28, such as a Fitbit. Fitbit device 28 learns and understands increases in activity by the person as the device 28 is carried or worn by a user. So for example, a predominately stationary or sedentary person may only need to consume about 64 ounces of water a day. The device 28 communicates the person's sedentary nature to bottle 10 and a first amount of water (64 ounces) is displayed to the user setting a consumption goal for the day. However, when the sedentary person decides to start exercising, the Fitbit device 28 will register and sense increased physical activity. The physical activity requires more water consumption by the user of the water bottle. The water bottle will adjust the amount of water to be consumed based, at least in part, on the activity and physical exertion performed by the person. So if the person begins running for a 30 minutes, the bottle will adjust the required fluid consumption and display a second amount, for example an additional 32 ounces for a total daily consumption of 96 ounces. Clearly, the actual amounts of the first and second consumption amounts are based on individual biometrics such as age, gender, and weight. In operation, the data transmission logic 26 communicates consumption data received from the fluid information logic 24 coupled with sensors 20 via the I/O interface to an external or remote computing device 28 or smartphone 34 (for example, a personal computer, smartphone or multimedia device) or to a back-end server over one or more computer networks. In some implementations, the I/O interface included in transmission logic 26 includes a transmitter and a receiver (also referred to collectively herein as a “transceiver” or simply as “transmitting and receiving circuitry”) that can transmit the activity data or other information through a wired or wireless connection to one or more external computing devices or to one or more back-end servers (either directly via one or more networks or indirectly via an external computing device that first receives the activity data and subsequently communicates the data via one or more networks to the back-end servers). In some implementations, the one or more computer networks include one or more local-area networks (LANs), private networks, social networks, or wide-area networks (WANs) including the Internet. The transmission logic 26 includes wireless communication functionality so that when the bottle 10 comes within range of a wireless base station or access point, or within range of certain equipped external computing devices (for example, a personal computer, smartphone 34 or remote activity device 28), certain activity data or other data is automatically synced or uploaded to the external computing device or back-end server for further analysis, processing, viewing, or storing. In various implementations, the wireless communication functionality of I/O interface may be provided or enabled via one or more communications technologies known in the art such as, for example, Wi-Fi, Bluetooth, RFID, Near-Field Communications (NFC), Zigbee, Ant, optical data transmission, among others. Additionally or alternatively, the I/O interface also can include wired-communication capability, such as, for example, a Universal Serial Bus (USB) interface. Some exemplary sensors 20 capable of being electronically coupled with bottle 10 (either integrally on bottle 10 or remotely connected thereto) may include but are not limited to: accelerometers sensing accelerations experienced during rotation, translation, velocity/speed, location traveled, elevation gained; gyroscopes sensing movements during angular orientation and/or rotation, and rotation; altimeters sensing barometric pressure, altitude change, flights of stairs, climbed, local pressure changes, submersion in liquid; impellers measuring the amount of fluid passing thereby; Pulse Oximeter sensing blood oxygen saturation (SpO2), Heart rate variability, stress levels, heart rate, blood volume active heart rate, resting heart rate, sleeping heart rate, sedentary heart rate, cardiac arrhythmia, cardiac arrest, pulse transit time, heart rate recovery time, and blood volume; Galvanic Skin sensors sensing electrical conductance of skin, perspiration, stress levels; Response Sensors sensing exertion/arousal levels; Global Positioning sensors sensing location, elevation, distance traveled, velocity/speed; Electromyography sensors sensingleectrical pulses; Muscle tension/extension sensors; Audio Sensors sensing local environmental sound levels, laugh detection, breathing detection, snoring detection, respiration type (snoring, breathing, labored breathing, gasping), voice detection, typing detection; Photo/Light sensors sensing ambient light intensity, ambient Day/night, sleep, UV exposure; TV sensors sensing light wavelength watching, indoor v. outdoor environment; Temperature sensors sensing body temperature, ambient air temperature, and environmental temperature; Respiration rate sensors sensing respiration rate; Sleep apnea detection sensors; Blood Pressure sensors, and Moisture Sensors sensing surrounding moisture levels. In the case where the data is relayed from a remote/external sensor on remote device 28 to bottle 10, or from a sensor on bottle 10 to either a remote device 28 or smartphone 34, the digital data may indicate to the bottle 10 that the data should be relayed. For example, the data transmission may contain a code that tells the bottle 10 to relay the data. In another example, the relay indicator may not be an addenda to the message, but rather something inherent to the data itself. For example, if the data has a certain type of encryption, the encryption type may indicate that the bottle 10 should forward the data to a computing device. Note that being unencrypted may be considered an encryption type. Syncing may occur through wired and/or wireless connections including but not limited to USB, Wi-Fi, WiMAX, Mobile telephony (i.e. cellular networks), Bluetooth, Bluetooth Smart, NFC, RFID, and ANT. Additionally, bottle 10 may incorporate one or more user interface and/or feedback methods such as visual methods, auditory methods, or haptic methods (such as touch input or vibration). The device may display the state of one or more of the information types available and/or being tracked. For example, information can be displayed graphically, or conveyed by the intensity and/or color of one or more light emitting diodes (LEDs). The user interface may also be used to display data from other devices or internet sources. The device may also provide haptic feedback to the user through, for instance, the vibration of a motor or a change in texture or shape of the device. In one embodiment, the bottle 10 may not have a display. The device may instead communicate information to the user using one of the other user feedback methods described herein (e.g. one or more LED's, haptic feedback, audio feedback). In another embodiment, the device may not communicate information to the user directly. Instead, the user may view their information on one or more remote computing devices (i.e., smartphone 34) in direct or indirect communication with the bottle 10. In the case that the communication is indirect, data may be transferred from the device to one or more intermediate communication devices (e.g. networks server or nodes) which then forwards the information to the secondary computing device (remote device 28 or smartphone 34) used to view data. For example, data may be transferred from the device through a smartphone to a server that hosts a website containing the user's data. One example of communications between a portable biometric device, handheld bottle 10 and computing device is illustrated in FIG. 3. Initially the bottle 10 may send a notification signal to notify any nearby handheld activity device 28 or smartphone 34 of its presence. Once an activity device 28 or smartphone 34 receives one of these alerts, bottle 10 may sync data with the activity device 28 or smartphone 34. Fluid consumption related data which is sent from bottle 10 without an indication that the data should be relayed is displayed and/or stored on a first database on the remote device 28. Data with a relay indication is forwarded onto a computing device where the data is stored in a second database. Relayed data may also be displayed and stored on the bottle 10. In one particular embodiment, data transmission logic 26 may broadcast a notification signal to remote device 28. The bottle 10 may indicate, in the notification signal or a characteristic of the notification signal, whether the bottle 10 device seeks (or requests) to sync or establish a communication link with the remote device 28 through network 31. In the case that the bottle 10 does not seek to establish a communication link with the remote device 28, the bottle 10 may still take action to establish a communication link and sync or not. Consumption data created from sensors 20 coupled to fluid information logic 24 on bottle 10 may be used by a mobile application, such as MyFitnessPal executed on the portable communication device (e.g. smart phone 34). Users of bottle 10 may have accounts on such applications or services which allow them to retrieve data relevant to themselves or other users. An account may enable a user to visualize their fluid consumption data, modify data visualizations, modify or enter additional or existing data, manage their devices, and/or interact with other users. Fluid consumption data synced from the bottle 10 may be used for account features including but not limited to a leader board where the user is ranked compared to other users such as friends, rankings of members of a group of users, and badge awards to reaching various goals, such as meeting or exceeding your consumed fluids for a the day. The user account may also automatically provide recommendations to the user so as to help them reach one or more goals including but not limited to increasing or decreasing their water consumption, weight, body fat, time asleep, quality of sleep, calorie burn, activity level, resting heart rate, active heart rate, normal heart rate, steps taken, distance walked and/or run, and floors climbed, all of which can be displayed on the water bottle display. These recommendations may aid the user in short term and/or long term goals. For example, if a user has not been consuming the proper amount of water over the few days or even the last month and has started to have headaches and other side effects from improper hydration, bottle 10 may be recommend to be more water consumption through a notification on directly to the display on bottle 10, or to the wearable remote device 28, or an health application 32 executable on smartphone 34. On a shorter time scale, a user may be recommended to drink a certain amount of water with dinner if they were did not drink much water earlier in the day. In order for such short term recommendations to be relevant to the user's current state, data synced from their device which help determine the recommendation is preferably transferred frequently and/or whenever there is new data on the device relevant to such a recommendation. In one embodiment, the bottle 10 and the remote device 28 communicate using the Bluetooth Smart protocol. The bottle 10 may intermittently broadcast one of two UUID's (universally unique identifiers) to the remote device 28 or smartphone 34 which is constantly listening for broadcasts. The first UUID corresponds to a Bluetooth service which is used to sync new data from the sensor device. This service is configured to start any programs on the smartphone 34 necessary to sync the new data from the sensor device. The second UUID corresponds to a Bluetooth service which is only used when a program on the bottle 10 needs to send data to the remote device 28 or smartphone 34. Bottle 10 may monitor its wireless input sources for incoming wireless packets and analyze any received packets in order to detect the smartphone 34 or activity tracker device 28 as the source of their transmission and decide whether to sync with the remote device. The function or functions within the bottle 10 that monitors input sources for and analyzes packets may be embedded within the operating system of the bottle 10 and/or in an application or applications that are launched by the operating system of the bottle 10 (i.e., the input monitoring and/or packet analysis functions may be implemented by execution, within one or more processors of the communications device, of programmed instructions that form part of the bottle 10 operating system and/or application programs). The packet detection functionality may be automatically launched or executed by the operating system or can be initiated or directed by the user or users of the bottle 10. If the functionality is partially or fully within an application, application or applications may be launched automatically by the operating system or launched by the user or users of the bottle 10. The packet detection functionality may also be split between the operating system and applications. The functionality can execute or run in any priority or mode (active, foreground, background, etc.) on any processor within the bottle 10. The functionality can also run simultaneously with other functions on the same bottle 10. If the functionality has already been launched (i.e., implemented through execution of programmed instructions), the operating system can choose to execute or re-execute the functionality, which might be resident in volatile or non-volatile storage or memory of the bottle 10. Listening (monitoring input sources) for incoming packets may be carried out periodically in order to lower power consumption (e.g., by powering down or otherwise disabling signal reception functions during intervals in which input sources are un-monitored), or continuously in order to decrease the time to detection (“detection latency”). Also, the frequency of periodic listening events may be varied to balance power consumption and the time to detection. During a previous interaction, a user or computer, either directly via input on the display 21 of bottle 10 or via a wired or wireless communication mechanism, may specify which aspects of the contents of a wireless packet or sequence of wireless packets should trigger a data sync by the bottle 10. Any single piece of information or combination of the information in a wireless packet or sequence of packets may trigger a data sync after receipt and analysis of the packets. When the sync is triggered, the bottle 10 may start and complete the syncing process via functionality that is embedded within the operating system of the bottle 10 or via an application that is launched by the operating system of the bottle 10. The initiation, start, and/or completion of a sync may be performed with or without user interaction using techniques described herein. The bottle 10 may determine whether or not it needs to sync based on fluid consumption goals of the user. The user may set these goals themselves or they may be set automatically based on weight, gender, age, typical activity level of a person wearing the activity tracker 28. The bottle could use the type of goal to determine when it should sync. For example, if the user has a goal based on the ounces they desire to drink in a given day, the bottle may sync only when it detects that the user consumed that amount of water. The criteria for meeting a goal may also be used by the device to determine when it should sync. For example, if a user's goal is to drink 64 ounces of water, the device may try to sync when the user has reached 50%, 75%, and 100% of their goal. This would ensure that the user can see a reasonably precise measure of the progress to their goal on computing devices, portable communication devices, and/or web-based accounts associated with their device. Bottle 10 may also sync based on when a user interacts with a remote activity tracker device 28 which displays synced data or data derived from synced data. In one embodiment, a network server, bottle 10, sensor 20 or some combination of the three may determine, based on historical data when the user views synced data or information derived from synced data on their activity device 28 or smartphone 34. In one example, the bottle 10 may sync to the user's activity device 28 or smartphone 34 every time the user wakes up their activity device 28 or smartphone 34 from sleep mode or turns on their activity device 28 or smartphone 34. This would allow the user to see the most up to date information when checking their data on the activity device 28 or smartphone 34. In another example, if a user always checks their smart phone at lunch time to see how much water they have drank that morning, the bottle 10 may learn this habit and sync data immediately before the user's lunch time so that the most up to date water consumption is displayed. The bottle 10 may determine whether or not it needs to sync based on the activity of the user. In one embodiment, for example, the bottle 10 includes a motion sensor 20 configured (e.g., through a programmable setting) to sync when the motion sensor detects that the user is active and drinking from the bottle. In a plurality of embodiments, bottle 10 is capable of changing the device identifier and/or owner identifier based on the device's intent to sync, a particularly useful feature in cases where a mobile communication device listens for and initiates sync operations solely based on device or service unique identifiers. Typically, such a mobile communication device might initiate a sync whenever the sensor device came within range or stayed within range, thus potentially syncing more frequently than desirable and consuming undue power. By enabling the sensor device to dynamically change its device, service or owner identifier, however, and to set such identifier(s) to values recognized by the mobile communication device only when new data is available to sync, the mobile communication device would only initiate a sync when necessary, since the mobile communication device would only listen for identifiers that indicated that the sensor device needed to sync. This operation also enables the sensor device sync to co-exist and sync optimally with other communications devices that could base their decisions to sync on using more information contained in a sensor device's wireless packets. The remote device 28 or smartphone 34 may communicate with bottle 10 via network servers located on private networks or public networks such as the Internet. Through an interface located on a server or a communications device that may communicate with that server, a user may change settings, data or behavior on or of a sensor device, for example by providing instructions to program or otherwise load configuration data or settings into one or more configuration registers of the sensor device. These changes may include but are not limited to parameters for algorithms, time and alarm settings, personal biometric information (weight, height, age, gender, base metabolic rate, etc.), settings for the user interface (which UI screens to show, what information to show on each screen, the order of screens, etc.). Once a change is made, this change may be synced to a sensor device. The term “sync” refers to the action of sending and/or receiving data to and/or from bottle 10 to a computing device 34 and/or remote activity tracking device 28 as seen in FIG. 3. “Sync” may also be used in reference to sending and/or receiving data to and/or from another computing device or electronic storage devices including but not limited to a personal computer, cloud based server, and database. In some embodiments, a sync from one electronic device to another may occur through the use of one or more intermediary electronic devices acting as a portal. For example, data from a bottle 10 may be transmitted to a smart phone that relays the data to a server. The data may then be viewed on other network/server-connected devices as shown in FIG. 3. Some exemplary methods for use of bottle 10 may include a method for displaying fluid consumption by a human comprising the steps of: displaying data associated with a first amount of fluid within a communicative bottle in a display; adjusting the amount of fluid in the communicative bottle by one of the following (a) dispensing fluid from the bottle and (b) adding fluid to the bottle; sensing the amount of adjusted fluid with a first sensor to create data associated with a second amount of fluid; and sending data associated with the second amount of fluid to a remote device. This method may further include the steps of receiving activity information of a person at the bottle from a second sensor on the remote device; and adjusting the data associated with the first amount of fluid, based at least in part, on the activity information received from the sensor, and displaying data associated with a third amount of fluid in the display. Alternatively, this exemplary method may include wherein the sensor is on a remote device and the activity information is associated with physical movement of a person carrying the remote device. Alternatively, this exemplary method may include wherein the first sensor is integral to the communicative water bottle. Further, this exemplary method may include the additional steps of displaying data associated with a third amount of fluid to be consumed by a person contained in the bottle in the display; receiving activity information of the person from a remote activity device; and adjusting the third amount of fluid to be consumed by the person based, at least in part, on the activity information received from the remote activity device, and displaying a second amount of fluid to be consumed in the display. Alternatively, this exemplary method may include wherein the first sensor is a flow sensor and the activity information is drinking the fluid by the person, and further comprise the steps of: sensing the difference between the second amount of fluid and the first amount of fluid after the person has drank the fluid creating consumption data; transmitting the consumption data from the communicative bottle to the remote device selected from a group comprising a remote activity tracker and a mobile application executable on a smartphone. And, this exemplary method may include the steps of syncing the water bottle with the remote device based, at least in part, on the activity information obtained from the sensor, wherein the sensor is on the bottle. In the foregoing description, certain terms have been used for brevity, clearness, and understanding. No unnecessary limitations are to be implied therefrom beyond the requirement of the prior art because such terms are used for descriptive purposes and are intended to be broadly construed. Moreover, the description and illustration of the preferred embodiment of the disclosure are an example and the disclosure is not limited to the exact details shown or described.
<SOH> BACKGROUND <EOH>
<SOH> SUMMARY <EOH>Issues continue to exist with activity trackers and health monitoring mobile applications inasmuch as they require the manual entry of hydration information. A need continues to exist for a water bottle having the ability to calculate an amount of water consumed therefrom to directly sync with a remote device such as an activity tracker (e.g., Fitbit Surge, iWatch, or UP24, amongst many others) or a smartphone (e.g., iPhone) running a mobile health application. The present disclosure addresses these and other issues. In one aspect, an embodiment may provide a communicative sports water bottle comprising: a bottle body having a base and an upwardly extending sidewall therein defining a fluid chamber; a sensor determining one or more of the following an amount of fluid in the fluid chamber, an amount of fluid being dispensed from the fluid chamber, and a physical movement of the bottle body; fluid information logic electronically coupled with the sensor creating digital data associated with fluid in the chamber; and data transmission and reception logic configured to send the digital data to a remote device and receive digital data from the remote device. In another aspect, an embodiment may provide a method for displaying fluid consumption by a human comprising the steps of: displaying data associated with a first amount of fluid within a communicative bottle in a display; adjusting the amount of fluid in the communicative bottle by one of the following (a) dispensing fluid from the bottle and (b) adding fluid to the bottle; sensing the amount of adjusted fluid with a first sensor to create data associated with a second amount of fluid; and wirelessly sending data associated with the second amount of fluid to a remote device. In another aspect, an embodiment may provide, in combination, a wearable health activity tracker including wireless communication logic and a water bottle including wireless communication logic, wherein the activity tracker and water bottle sync to one another to therebetween transfer data associated with fluid consumption by a user, the water bottle comprising: a bottle body having a base and an upwardly extending sidewall therein defining a fluid chamber. This embodiment may also include a software application executable on a mobile computing device displaying digital data associated with one of the following: an amount of fluid in the chamber, an amount of fluid dispensed from the chamber, an amount of time since fluid was last dispensed from the chamber, an amount of fluid dispensed over a given time period, a reminder notification if fluid has not been dispensed over a given time period, a reminder to consume an adjusted amount of fluid based, at least in part, on activity information obtained from the health tracking device. Additionally, this embodiment can include fluid consumption instructions for increased consumption by the user from the remote device to the bottle for display thereon when a second sensor, located on the remote device, detects one of the following an increase in physical activity by the user and an absence of drinking activity over a certain time period by the user. In another aspect, the disclosure may provide a communicative water bottle that includes communication logic and wireless transmission logic technology electronically connected with a variety of sensors either on the water bottle or located remote from the water bottle. The sensors on the bottle create digital data associated with amount of fluid in the bottle and change thereof. The sensors remote from the bottle, which can be on an activity tracker, create digital data associated with an activity being performed by a user, such as running, or the absence of activity, such as remaining sedentary. A display on the bottle can indicate to the user the amount of fluid consumed or a reminder that fluid should be consumed. The fluid consumption data syncs with other remote devices such as mobile applications executable on smartphones.
G06F193418
20170830
20171221
81456.0
G06F1900
3
GRANT, MICHAEL CHRISTOPHER
COMMUNICATIVE WATER BOTTLE AND SYSTEM THEREOF
SMALL
1
CONT-ACCEPTED
G06F
2,017
15,691,378
ACCEPTED
UNIVERSAL SECURE REGISTRY
An authentication system and method of use are provided to enable a transaction involving a first party and a user, the system comprising an electronic device comprising a communications interface and one or more processors. The one or more processors are configured to receive biometric information of the user and generate a one-time code in response to authenticating the user, wherein at least a portion of the one-time code is used to access account identifying information or user identifying information, wherein the communications interface is configured to communicate a signal comprising the one-time code to the first party in order to enable a transaction on behalf of the user, and wherein the received biometric information is verified at a point of use.
1. An authentication system to enable a transaction involving a first party and a user, the system comprising: an electronic device comprising a communications interface and one or more processors; wherein the one or more processors are configured to: receive biometric information of the user; and generate a one-time code in response to authenticating the user, wherein at least a portion of the one-time code is used to access account identifying information or user identifying information; wherein the communications interface is configured to communicate a signal comprising the one-time code to the first party in order to enable a transaction on behalf of the user; and wherein the received biometric information is verified at a point of use. 2. The system of claim 1 wherein the first party comprises a merchant or a credit card company. 3. The system of claim 1 wherein the one-time code comprises a code associated with credit or bank card information of the user. 4. The system of claim 3 wherein the code associated with credit or bank card information does not contain the credit or bank card information. 5. The system of claim 1 wherein the one-time code is selected from the group consisting of a one-time nonpredictable code, a time variant code, and a transaction-specific code, and wherein the one-time code is encrypted before communicating the signal to the first party. 6. The system of claim 1 wherein the one-time code is associated with a public identification code for a credit or bank card account, and wherein the public identification code for the credit or bank card account is communicated to a credit or bank card issuer to enable the transaction. 7. The system of claim 1 further comprising a biometric sensor configured to receive fingerprint information, voice print information, signature information, iris information, facial scan information, or DNA information. 8. A method for enabling a transaction involving a first party and a user, the method comprising: receiving authentication information of the user, wherein the authentication information comprises one or more of (a) biometric information and (b) a personal identification number (PIN) or code; authenticating an identity of the user based on the received authentication information; generating a one-time code in response to authenticating the user, wherein at least a portion of the one-time code is used to access account identifying information or user identifying information; and communicating a signal comprising the one-time code to the first party in order to enable a transaction on behalf of the user. 9. The method of claim 8 wherein communicating the signal comprising the one-time code to the first party comprises communicating a signal comprising the one-time code to a merchant or a credit card company. 10. The method of claim 8 wherein generating the one-time code comprises generating a code that is associated with credit or bank card information of the user. 11. The method of claim 10 wherein generating the code associated with credit or bank card information comprises generating a code that does not contain the credit or bank card information. 12. The method of claim 8 wherein generating the one-time code comprises generating a one-time code selected from the group consisting of a one-time nonpredictable code, a time variant code, and a transaction-specific code, and the method further comprises encrypting the one-time code before communicating the signal to the first party. 13. The method of claim 8 wherein generating the one-time code comprises generating a one-time code associated with a public identification code for a credit or bank card account, and wherein the public identification code for the credit or bank card account is communicated to a credit or bank card issuer to enable the transaction. 14. The method of claim 8 further comprising receiving fingerprint information, voice print information, signature information, iris information, facial scan information, or DNA information from a biometric sensor and authenticating the identity of the user based on the received information from the biometric sensor and the PIN or code. 15. A computer readable medium or media containing instructions for authenticating a user involved in a transaction, wherein execution of the instructions by one or more processors causes the one or more processors to carry out the steps of: receiving authentication information of the user, wherein the authentication information comprises one or more of (a) biometric information and (b) a PIN or code; authenticating an identity of the user based on the received authentication information; generating a one-time code in response to authenticating the user, wherein at least a portion of the one-time code is used to access account identifying information or user identifying information; and communicating a signal comprising the one-time code to the first party in order to enable a transaction on behalf of the user. 16. The computer readable medium or media of claim 15 wherein communicating the signal comprising the one-time code to the first party comprises communicating a signal comprising the one-time code to a merchant or a credit card company. 17. The computer readable medium or media of claim 15 wherein generating the one-time code comprises generating a code that is associated with credit or bank card information of the user. 18. The computer readable medium or media of claim 17 wherein generating the code associated with credit or bank card information comprises generating a code that does not contain the credit or bank card information. 19. The computer readable medium or media of claim 15 wherein generating the one-time code comprises generating a one-time code selected from the group consisting of a one-time nonpredictable code, a time variant code, and a transaction-specific code, and the method further comprising encrypting the one-time code before communicating the signal to the first party. 20. The computer readable medium or media of claim 15 wherein generating the one-time code comprises generating a one-time code associated with a public identification code for a credit or bank card account, and wherein the public identification code for the credit or bank card account is communicated to a credit or bank card issuer to enable the transaction. 21. The computer readable medium or media of claim 15 wherein execution of the instructions by one or more processors further causes the one or more processors to carry out the steps of receiving fingerprint information, voice print information, signature information, iris information, facial scan information, or DNA information from a biometric sensor and authenticating the identity of the user based on the received information from the biometric sensor and the PIN or code. 22. An authentication system to enable a transaction involving a first party and a user, the system comprising: an electronic device comprising a communications interface and one or more processors; wherein the one or more processors are configured to: receive biometric information of the user; and generate a one-time code in response to authenticating the user, wherein at least a portion of the one-time code is used to access account identifying information or user identifying information; and a computer system, the computer system comprising: a communications interface configured to receive the one-time code; and one or more processors configured to retrieve account information associated with the electronic device, and to use the retrieved account information to access the account identifying information or the user identifying information. 23. The system of claim 22 wherein the first party comprises a merchant or a credit card company. 24. The system of claim 22 wherein the one-time code comprises a code associated with credit or bank card information of the user. 25. The system of claim 24 wherein the code associated with credit or bank card information does not contain the credit or bank card information. 26. The system of claim 22 wherein the one-time code is selected from the group consisting of a one-time nonpredictable code, a time variant code, and a transaction-specific code, and wherein the one-time code is encrypted before communicating the signal to the first party. 27. The system of claim 22 wherein the one-time code is associated with a public identification code for a credit or bank card account, and wherein the public identification code for the credit or bank card account is communicated to a credit or bank card issuer to enable the transaction. 28. The system of claim 22 further comprising a biometric sensor configured to receive fingerprint information, voice print information, signature information, iris information, facial scan information, or DNA information.
RELATED APPLICATIONS This application is a continuation of and also claims priority under 35 U.S.C. §120 to co-pending U.S. patent application Ser. No. 15/040,873 filed on Feb. 10, 2016, entitled UNIVERSAL SECURE REGISTRY, which is a continuation of and also claims priority under 35 U.S.C. §120 to co-pending U.S. patent application Ser. No. 14/508,483 filed on Oct. 7, 2014, entitled UNIVERSAL SECURE REGISTRY, which is a continuation of and also claims priority under 35 U.S.C. §120 to U.S. patent application Ser. No. 11/768,729, filed on Jun. 26, 2007 and issued on Oct. 7, 2014 as U.S. Pat. No. 8,856,539, entitled UNIVERSAL SECURE REGISTRY, which is continuation of U.S. application Ser. No. 09/810,703, filed on Mar. 16, 2001 and issued on Jun. 26, 2007 as U.S. Pat. No. 7,237,117, entitled UNIVERSAL SECURE REGISTRY. Each of the above-identified applications is hereby incorporated herein by reference in its entirety. BACKGROUND OF INVENTION 1. Field of Invention This invention generally relates to a method and apparatus for securely storing and disseminating information regarding individuals and, more particularly, to a computer system for authenticating identity or verifying the identity of individuals and other entities seeking access to certain privileges and for selectively granting privileges and providing other services in response to such identifications/verifications. 2. Discussion of Related Art Dissemination of information regarding various entities, including individuals, in society is conventionally done in a non-centralized fashion, often requiring specialized knowledge of a likely storage location to access the information. This specialized knowledge may not be available when the information is needed, thus effectively preventing distribution of the information when required. For example, a doctor in an emergency room may desire access to a patient's medical history in determining a course of treatment. If the person is not carrying a complete medical record, which is typically the situation, the medical records may not be available to the doctor. Even if these medical records are available electronically, for example via a computer accessible in the person's regular doctor's office, the records may effectively be unavailable if the person is unconscious or otherwise incapacitated or if restrictions on access to the doctor's records cannot otherwise be overcome. The retrieval of required medical records can be further complicated by the fact that such records can be located at a number of different sites/systems which are not linked. For example, the patient's primary care physician may not have records from a specialist treating the patient, and none of these physicians may have dental records. Similar problems arise in other environments where relevant data may be scattered and/or otherwise difficult to access. Identification of a person from other persons within a society and verification of a person as being who he says he is are extremely important for many reasons. For example, determination/verification of a person's identity will typically dictate extension of credit, granting access to information, allowing entry to a restricted area, or the granting of numerous other privileges. Most people carry multiple forms of identification. For example, a typical person may carry an identification card issued by a federal, state, or local governmental entity, an identification card issued by a university or place of employment, one or more credit cards that serve to identify the person as a holder of a credit card account, one or more bank cards that serve to identify the person as holder of a bank account, medical information cards identifying the person as a member of, for example, a health maintenance organization or as a person holding an insurance policy from a specified insurance company, keys that identify the person as owner of an automobile, house, etc., and numerous other identification cards that may be used for specialized purposes, such as identifying the person as a member of a health club, a library, or a professional organization. To enable the person to function effectively in society, the person must typically have one or more of these identification devices with them if they wish to undertake an associated activity. For example, a person is not allowed to drive a car or purchase alcohol without a governmentally issued driver's license. Likewise, although cash may be used to purchase goods and/or services, the person will typically not be able to purchase goods and/or services with a credit card if the person is not physically carrying the credit card. Similarly, most hospitals and other medical facilities will require proof of insurance before rendering medical attention. Carrying these multifarious identification devices can become onerous. Additionally, if one or more of the identification devices is lost, stolen or forgotten, it can be inconvenient, making it difficult to obtain goods or services requiring the missing identification. There are also times when the individual may wish to be identified or at least verified without providing personal information. For example, a person may wish to purchase goods and/or services without publicly providing his/her credit card information for fear that the credit card information be may be stolen and used fraudulently. Likewise, the person may wish to purchase goods or order goods to be delivered to an address without revealing the address to the vendor. Unfortunately, conventional identification devices require that at least some personal information be transmitted to complete a transaction. There are other related problems. For example, when there is a need to locate a person or other entity where only limited biographical data is known, this can be difficult since relevant information is seldom available from a single database. Another potential problem is the forwarding of mail, packages, telephone calls/messages, e-mails and other items where a party is in a situation where they are changing location frequently and/or where the person does not want such information to be generally available for security or other reasons. A simple, yet secure, way of dealing with such issues does not currently exist. Another potential problem is filling in forms, particularly for an individual who frequently has to complete the same or similar form. Such forms can for example be medical forms when visiting a doctor or entering a hospital, immigration forms on entering the country, employment forms, college entry forms, etc. It would be desirable if such forms could be completed once and be available for future use, and it would be even better if the information for each such form could be automatically drawn from an existing database to complete the form. There is also a frequent requirement to periodically update information in a form, for example financial information for a line of credit. It would be desirable if such updates could be automatically performed from data in a general database. Still another potential problem is that a person may be forced to make requests on a database, for example financial requests, under duress. It would be desirable if the person could easily and undetectably signal such duress when making the request and the receiving system be able to act appropriately to assist and protect the individual. Systems capable of effectively performing all of these functions do not currently exist. SUMMARY OF INVENTION There is thus a need for an identification system that will enable a person to be identified or verified (“identification” sometimes being used hereinafter to mean either identified or verified) and/or authenticated without necessitating the provision of any personal information. Likewise, there is a need for an identification system that will enable a person to be identified universally without requiring the person to carry multiple forms of identification. Accordingly, this invention relates, in one embodiment, to an information system that may be used as a universal identification system and/or used to selectively provide personal, financial or other information about a person to authorized users. Transactions to and from the database may take place using a public key/private key security system to enable users of the system and the system itself to encrypt transaction information during the transactions. Additionally, the private key/public key security system may be used to allow users to validate their identity and/or sign instructions being sent to a universal secure registry (USR) system of the type to which this invention relates. For example, in one embodiment, a smart card such as the SecurID™ card from RSA Security, Inc. may be provided with the user's private key and the USR system's public key to enable the card to encrypt messages being sent to the USR system and to decrypt messages from the USR system 10. This USR system or database may be used to identify the person in many situations, and thus may take the place of multiple conventional forms of identification. Additionally, the USR system may enable the user's identity to be confirmed or verified without providing any identifying information about the person to the entity requiring identification. This can be advantageous where the person suspects that providing identifying information may subject the identifying information to usurpation. Enabling anonymous identification facilitates multiple new forms of transactions. For example, enabling anonymous identification enables the identified person to be telephoned by or receive e-mails from other persons without providing the other person with a telephone number or e-mail address, and will permit this to be accomplished even where there are frequent changes in the person's location. Similarly, enabling anonymous identification will enable the person to receive mail, other delivered parcels and other items without providing the recipient's address information to the sender. By restricting access to particular classes of persons/entities, the person can effectively prevent receipt of junk mail, other unsolicited mail, telemarketing calls and the like. In a financial context, providing anonymous identification of a person enables the person to purchase goods and/or services from a merchant without ever transmitting to the merchant information, such as the person's credit card number, or even the person's name, that could be intercepted and/or usurped and used in subsequent or additional unauthorized transactions or for other undesired purposes. Enabling anonymous identification may be particularly advantageous in an unsecured environment, such as the Internet, where it has been found to be relatively trivial to intercept such credit card information. In a medical context, the USR system, in addition to enabling a person seeking medical treatment to identify themselves, may be configured to provide insurance data, medical history data, and other appropriate medical information to a medical provider, once that medical provider has been established as an authorized recipient. The USR system may also contain links to other databases containing portions of the patient's medical records, for example x-rays, MRI pictures, dental records, glasses, prescriptions, etc. Access to the USR system may be by smart card, such as a SecurID™ card, or any other secure access device. The technology enabling the USR system may be physically embodied as a separate identification device such as a smart ID card, or may be incorporated into another electronic device, such as a cell phone, pager, wrist watch, computer, personal digital assistant such as a Palm Pilot™, key fob, or other commonly available electronic device. The identity of the user possessing the identifying device may be verified at the point of use via any combination of a memorized PIN number or code, biometric identification such as a fingerprint, voice print, signature, iris or facial scan, or DNA analysis, or any other method of identifying the person possessing the device. If desired, the identifying device may also be provided with a picture of the person authorized to use the device to enhance security. The USR system may be useful for numerous other identification purposes. For example, the USR anonymous identification may serve as a library card, a phone card, a health club card, a professional association membership card, a parking access card, a key for access to one's home, office, car, etc. or any one of a host of similar identification/verification and/or access functions. Additionally, equipment code information may be stored in the USR system and distributed under the user's control and at the user's discretion, to maintain personal property or public property in an operative state. BRIEF DESCRIPTION OF DRAWINGS This invention is pointed out with particularity in the appended claims. The above and further advantages of this invention may be better understood by referring to the following description when taken in conjunction with the accompanying drawings. The accompanying drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures is represented by a like numeral. For purposes of clarity, not every component may be labeled in every thawing. In the drawings: FIG. 1 is a functional block diagram of a computer system configured to implement the universal secure registry (“USR”), including a USR database, according to one embodiment of the invention; FIG. 2 is a functional block diagram of a first embodiment of a networked environment including the computer system of FIG. 1; FIG. 3 is a functional block diagram of an entry of a database forming the USR database of FIG. 1; FIG. 4 is a functional block diagram of a second embodiment of a networked environment including the computer system of FIG. 1; FIG. 5 is a flow chart illustrating steps in a process of inputting data into the USR database; FIG. 6 is a flow chart illustrating steps in a process of retrieving data from the USR database; FIG. 7 is a flow chart illustrating a first protocol for purchasing goods from a merchant via the USR database without transmitting credit card information to the merchant; FIG. 8 is a flow chart illustrating a second protocol for purchasing goods from a merchant via the USR database without transmitting credit card information to the merchant; FIG. 9 is a flow chart illustrating a protocol for purchasing goods from a merchant via the USR database by validating the user's check; FIG. 10 is a flow chart illustrating a protocol for purchasing goods from an on-line merchant via the USR database without transmitting credit card information to the on-line merchant, and enabling the on-line merchant to ship the goods to a virtual address; FIG. 11 is a flow chart illustrating a protocol for shipping goods to a virtual address via the USR database; FIG. 12 is a flow chart illustrating a protocol for telephoning a virtual phone number via the USR database; FIG. 13 is a flow chart illustrating a protocol for identifying a person via the USR database; FIG. 14 is a flow chart illustrating a protocol for identifying a person to a policeman via the USR database; FIG. 15 is a flow chart illustrating a protocol for providing information to an authorized recipient of the information via the USR database; FIG. 16 is a flow chart illustrating a protocol for providing application information to an authorized recipient of the information via the USR database; and FIG. 17 is a functional block diagram of an embodiment configured to use information in the USR system to activate or keep active property secured through the USR system. DETAILED DESCRIPTION This invention is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments and of being practiced or of being carried out in various ways. Also, the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,” “comprising,” or “having,” “containing”, “involving”, and variations thereof herein, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. In one embodiment, an information system is formed as a computer program running on a computer or group of computers configured to provide a universal secure registry (USR) system. The computer, in this instance, may be configured to run autonomously (without the intervention of a human operator), or may require intervention or approval for all, a selected subset, or particular classes of transactions. The invention is not limited to the disclosed embodiments, and may take on many different forms depending on the particular requirements of the information system, the type of information being exchanged, and the type of computer equipment employed. An information system according to this invention, may optionally, but need not necessarily, perform functions additional to those described herein, and the invention is not limited to a computer system performing solely the described functions. In the embodiment shown in FIG. 1, a computer system 10 for implementing a USR system according to the invention includes at least one main unit 12 connected to a wide area network, such as the Internet, via a communications port 14. The main unit 12 may include one or more processors (CPU 16) running USR software 18 configured to implement the USR system functionality discussed in greater detail below. The CPU 16 may be connected to a memory system including one or more memory devices, such as a random access memory system RAM 20, a read only memory system ROM 22, and one or more databases 24. In the illustrated embodiment, the database 24 contains a universal secure registry database. The invention is not limited to this particular manner of storing the USR database. Rather, the USR database may be included in any aspect of the memory system, such as in RAM 20, ROM 22 or disc and may also be separately stored on one or more dedicated data servers. The computer system may be a general purpose computer system which is programmable using a computer programming language, such as C, C++, Java, or other language, such as a scripting language or even assembly language. The computer system may also be specially programmed, special purpose hardware, an application specific integrated circuit (ASIC) or a hybrid system including both special purpose components and programmed general purpose components. In a general purpose computer system, the processor is typically a commercially available microprocessor, such as Pentium series processor available from Intel, or other similar commercially available device. Such a microprocessor executes a program called an operating system, such as UNIX, Linux, Windows NT, Windows 95, 98, or 2000, or any other commercially available operating system, which controls the execution of other computer programs and provides scheduling, debugging, input/output control, accounting, compilation, storage assignment, data management, memory management, communication control and related services, and many other functions. The processor and operating system defines a computer platform for which application programs in high-level programming languages are written. The database 24 may be any kind of database, including a relational database, object-oriented database, unstructured database, or other database. Example relational databases include Oracle 81 from Oracle Corporation of Redwood City, Calif.; Informix Dynamic Server from Informix Software, Inc. of Menlo Park, Calif.; DB2 from International Business Machines of Armonk, N.Y.; and Access from Microsoft Corporation of Redmond, Wash. An example object-oriented database is ObjectStore from Object Design of Burlington, Mass. An example of an unstructured database is Notes from the Lotus Corporation, of Cambridge, Mass. A database also may be constructed using a flat file system, for example by using files with character-delimited fields, such as in early versions of dBASE, now known as Visual dBASE from Inprise Corp. of Scotts Valley, Calif., formerly Borland International Corp. The main unit 12 may optionally include or be connected to an user interface 26 containing, for example, one or more input and output devices to enable an operator to interface with the USR system 10. Illustrative input devices include a keyboard, keypad, track ball, mouse, pen and tablet, communication device, and data input devices such as voice and other audio and video capture devices. Illustrative output devices include cathode ray tube (CRT) displays, liquid crystal displays (LCD) and other video output devices, printers, communication devices such as modems, storage devices such as a disk or tape, and audio or video output devices. Optionally, the user interface 26 may be omitted, in which case the operator may communicate with the USR system 10 in a networked fashion via the communication port 14. It should be understood that the invention is not limited to any particular manner of interfacing an operator with the USR system. It also should be understood that the invention is not limited to a particular computer platform, particular processor, or particular high-level programming language. Additionally, the computer system may be a multiprocessor computer system or may include multiple computers connected over a computer network. It further should be understood that each module or step shown in the accompanying figures and the substeps or subparts shown in the remaining figures may correspond to separate modules of a computer program, or may be separate computer programs. Such modules may be operable on separate computers. The data produced by these components may be stored in a memory system or transmitted between computer systems. Such a system may be implemented in software, hardware, or firmware, or any combination thereof. The various elements of the information system disclosed herein, either individually or in combination, may be implemented as a computer program product, such as USR software 18, tangibly embodied in a machine-readable storage device for execution by the computer processor 16. Various steps of the process may be performed by the computer processor 16 executing the program 18 tangibly embodied on a computer-readable medium to perform functions by operating on input and generating output. Computer programming languages suitable for implementing such a system include procedural programming languages, object-oriented programming languages, and combinations of the two. As shown in FIG. 2, the computer system 10 may be connected to a plurality of interface centers 27 over a wide area network 28. The wide area network 28 may be formed from a plurality of dedicated connections between the interface centers 27 and the computer system 10, or may take place, in whole or in part, over a public network such as the Internet. Communication between the interface centers 27 and the computer system 10 may take place according to any protocol, such as TCP/IP, ftp, OFX, or XML, and may include any desired level of interaction between the interface centers 27 and the computer system 10. To enhance security, especially where communication takes place over a publicly accessible network such as the Internet, communications facilitating or relating to transmission of data from/to the USR database 24 or the computer system 10 may be encrypted using an encryption algorithm, such as PGP, DES, or other conventional symmetric or asymmetric encryption algorithm. In one embodiment, the USR system 10 or USR database 24 may be able to authenticate its identity to a user or other entity accessing the system by providing an appropriate code which may be displayed on the user's smart card, for example a SecurID™ card or its equivalent, or other code generator, for example a single use code generator, being employed by the user. A comparison by the user or the code generator between the provided number and an expected number can validate, to the user (or other entity) or the code generator, that communication is with the database and not an imposter. The database 24 shown in FIG. 1 has a USR database containing entries related to persons 1-n. The data in the USR database may also be segregated, as shown in FIG. 4, according to data type to enable individual computer modules to handle discrete applications on discrete data types. Segregating the data, as illustrated in FIG. 4, may make access to the database more robust by enabling portions of the data in the USR database 24 to be accessible even when it is necessary to perform maintenance on a portion of the database. However, storing the data in the USR database 24 according to the scheme illustrated in FIG. 1 may make it easier for a user of the database to make changes to multiple types of data simultaneously or in a single session. There are advantages and disadvantages to each data structure, and the invention is not limited to a particular manner of organizing the data within the database 24, data structures other than the two shown also being possible. As shown in FIG. 3, each entry 30 in the database 24 may contain multiple types of information. For example, in the embodiment shown in FIG. 3, the entry contains validation information 32, access information 34, publicly available information 36, address information 38, credit card and other financial information. 40, medical information 42, job application information 44, and tax information 46. The invention is not limited to a USR containing entries with all of this information or only this particular information, as any information on a person or other entity such as a company, institution, etc. may be stored in USR database 24. If the database information is split between multiple databases, each database will typically include at least the validation and access information to enable the USR software to correlate a validation attempt with a verified validation, and to enable the USR software to determine access privileges to the requested data. Alternatively, databases may be linked to permit information not in a main USR database to be retrieved, with validation/identification for all databases accessed being done at the USR system. In FIG. 3, the validation information is information about the user of the database to whom the data pertains and is to be used by the USR software 18 to validate that the person attempting to access the information is the person to whom the data pertains or is otherwise authorized to receive it. The validation information may be any type of information that will reliably authenticate the identity of the individual. In one embodiment, the user of the database will carry a SecurID™ card available from RSA Security, formerly Security Dynamics Technologies, Inc., of Cambridge, Mass. Use of this card enables secure access to the USR database without requiring the user to transmit any personal information. Specifically, to access the USR database, the card retrieves a secret user code and/or time varying value from memory and obtains from the user a secret personal identification code. The card mathematically combines these three numbers using a predetermined algorithm to generate a one-time nonpredictable code which is transmitted to the computer system 10. The computer system, specifically USR software 18, utilizes the received one-time nonpredictable code to determine if the user is authorized access to the USR database and grants access to the USR database if the user is determined to be authorized. The verification information 32 in the database entry in the embodiment of the invention illustrated in FIG. 3 contains information to enable the USR software 18 to validate the user using such a card in this manner. Alternative types of identification cards or tokens may likewise be used. For example, other smart cards may be used which generate non-predictable single use codes, which may or may not be time varying, or other access code generators may be used. An algorithm generating such non-predictable codes may also be programmed onto a processor on a smart card or other computing device, such as a cell phone, pager, ID badge, wrist watch, computer, personal digital assistant, key fob, or other commonly available electronic device. For convenience, the term “electronic ID device” will be used generically to refer to any type of electronic device that may be used to obtain access to the USR database. Likewise, various types of biometric information may be stored in the verification area of the database entry to enable the identity of the user possessing the identifying device to be verified at the point of use. Examples of the type of biometric information that may be used in this situation includes a personal identification number (PIN), fingerprint, voice print, signature, iris or facial scan, or DNA analysis. If desired, the verifying section of the database may contain a picture to be transmitted back to the person seeking to validate the device to ensure the person using the device is the correct person. Optionally, the identifying device itself may also be provided with a picture of the person authorized to use the card to provide a facial confirmation of the person's right to use the card. In FIG. 3, the Access information 34 is provided to enable different levels of security to attach to different types of information stored in the entry 30 in the USR database 14. For example, the person may desire that their address information be made available only to certain classes of people, for example colleagues, friends, family, Federal Express, U.P.S., and the U.S. mail service. The names or universal identifiers for those selected individuals, companies, organizations and/or agencies may be entered into appropriate fields in the Access information to specify to the USR software 18 those individuals to whom the address information may be released. Likewise, access fields may be specified for the other types of information. For example, the individual may specify that only particular individuals and/or companies have access to the credit card and other financial information 40, medical information 42, job application information 44 and tax information 46. Additionally, the individual may specify that no one have access to that information unless the individual participates in the transaction (see FIG. 6). As shown in FIG. 1, the USR software 18 contains algorithms for execution by the CPU 16 that enables the CPU 16 to perform the methods and functions of the USR software described below in connection with FIGS. 5-16. The USR software 18, in this embodiment, performs all functions associated with validating an electronic ID card. If desired, a separate validation software module may be provided to validate electronic ID devices outside of a firewall segregating the validation information from other user information. The algorithms comprising the USR software 18 may be used to implement, in one exemplary embodiment, a USR system configured to enable selected information to be disseminated to selected individuals in a secure and dynamic fashion. This information may be used for numerous purposes, several of which are set forth below and discussed in greater detail in connection with FIGS. 5-16. For example, the USR system may be used to identify the person, enable the person to be contacted by telephone or mail anonymously, enable the person to be contacted by telephone or by mail without revealing the person's telephone number or present location, enable the person to purchase items over the Internet or in a store without revealing to the merchant any personal identification information or credit card information, enable the person to complete a job application without completing a job application form, enable the police to discern the person's identity and any outstanding warrants on the individual, and numerous other uses. The invention is not limited to these several enumerated uses, but rather extends to any use of the USR database. The methods of using the USR database 24 will now be discussed in connection with FIGS. 5-16. FIG. 5 illustrates a method of training the USR database 24. As shown in FIG. 5, the USR software 18 first validates the person's identification (500). The initial validation of the person's identification (500) may take place at the point of sale of an electronic ID device (for example, a smart card). This may be done in any conventional manner, such as by requiring the person to show a government issued identification card, passport, birth certificate, etc. Once the person's electronic ID device has been issued and initially validated, the validation process proceeds as discussed above. After the validation process (500), the USR software 18 determines if the person has rights to enter data into the system (502). This step enables the system to charge persons for maintaining information in the USR database 24. For example, the USR software 18 may poll a database of current accounts or a database of accounts that are currently in default to determine if the person has paid the access fee to enter data into the database. A similar account status inquiry process may be performed by the USR software 18 in connection with each of the other methods set forth in FIGS. 6-16. If the person is not authorized to enter data into the USR database 24, the person is notified of the status of their account and the process returns (512) to wait for further input from another person. Alternatively, a person may be permitted to enter some classes of data into the system and update such classes of data at no charge, with a fee possibly being required for other classes of data, for example medical records. This would facilitate a more robust database. If the person is authorized, the USR software 18 then enables the person to enter basic personal data into the USR database 24 (504). Optionally, personal data may be one class of data the USR software 18 allows the person to enter into the USR database 18 regardless of account status, i.e., for free. The USR software 18 will then check to see if the person has additional rights to enter additional data (506), such as data to be entered into one of the other categories of data in FIG. 3. Optionally, this step of checking the person's rights to enter data (506) may be combined with the initial check (502). If the person does not have rights to enter any further data, the USR software 18 notifies the user and returns (512). If the USR software 18 determines that the person has the right to enter additional data into the USR database 24, the person is prompted through the use of appropriate prompts, provided with forms, and otherwise enabled to enter advanced personal data into the USR database 24 (508). For each type of data entered, the person is asked to specify the type of access restrictions and/or whom should be allowed to access the advanced personal data (510). When the person has completed entering data into the database, the process returns (512) and commits the data to the database. In the situation where only one person has access to enter and/or modify data for a given person in the database, there should be no conflict with committing data to the database. If, however, multiple people have access to a given account to modify data, the database may perform an integrity check to ensure the absence of conflict in the data before committing the new data to the database. Enabling access to the information in the database will be explained in greater detail in connection with FIG. 6. As shown in FIG. 6, the database will generally allow anyone to access basic personal data on anyone without performing any authorization check (600). If information beyond that specified in the basic personal information area is requested, the USR software 18 queries whether the requestor has the right to access the type of requested data (602). The process of determining the requestor's rights (602) typically involves validating the requestor's identity and correlating the identity, the requested information and the access information 34 provided by the person to the USR database during the training process described above with respect to FIG. 5. If the USR software 18 determines that the requestor has rights to access the type of requested data (604), the USR software 18 instructs the USR database 24 to enable access to the type of requested data (606). The actual step of enabling access to the type of requested data may involve multiple steps of formulating a database query, querying the USR database 24, retrieving the results, assembling the results into a user friendly or user readable format, and transmitting the information to the user. If the USR software 18 determines that the requestor does not have the appropriate rights to access the type of requested data (604), the USR software 18 checks to see if the person is participating in the transaction (608). Checking to see if the person is participating in the transaction enables the user to authorize access to the requested data in real time. For example, a person may wish to participate in a transaction to give a potential employer one-time access to job application information 44 (see FIG. 3). If the person is not participating in the transaction, the USR software 18 determines that the requestor is not authorized to have access to the requested data, notifies the requestor of this determination, and ends (610). If the person is participating in the transaction (608), however, the USR software 18 validates the person's identity (612) and enables the person to change access rights to the data (614). If the USR software 18 is not able to validate the person's identity, the USR software 18 refuses to allow the person to update the database, notifies the person and/or requestor of this determination, and returns (610). It is also possible that a person may be required to grant access to certain data, for example financial data such as account numbers, under duress. The system may provide the person with the ability to safely signal this when accessing the system by using a selected access code or by making a known modification to the access code provided by the electronic ID device. On receiving such code, the system would take appropriate steps to protect the person, including for example alerting the police, tracking the person's location to the extent possible, providing traceable data, and the like. Once the person has had the opportunity to change access rights to the data (614), the USR software 18 again checks to see if the requestor has rights to access the type of requested data (616). Although step 616 may seem redundant, given the fact that the person is participating in the transaction and has just previously changed access rights to the database to enable the requestor to have access to the data, step 616 is actually useful at preventing a different type of fraud. Specifically, the requestor may not be forthright with the person regarding the type of information they are requesting. If step 616 were omitted, the USR software 18 may inadvertently allow access to an unauthorized type of information in the situation where the requestor has surreptitiously requested multiple types of data. If the USR software 18 determines that the requestor has rights to the type of data requested (616), it causes the USR database to enable access to the type of requested data (606). Otherwise, it notifies the requestor of the decision to deny access to the requested data and returns (610). Various applications of the USR database 24 and USR software 18 will now be discussed in connection with FIGS. 7-16. These applications are merely exemplary of the types of applications enabled by the USR software 18 and USR database 24, and the invention is not limited to these particular applications. FIG. 7 illustrates one embodiment of a method of using the USR software 18 and USR database 24 to purchase goods or services from a merchant without revealing to the merchant account information relating to the person's bank or credit card. As shown in FIG. 7, when a user initiates a purchase (700), the user enters a secret code in the user's electronic ID device (702) to cause the ID device to generate a onetime code or other appropriate code, and presents the electronic ID device with the code to the merchant or otherwise presents the code to the merchant. The merchant transmits to the credit card company (1) the code from the electronic ID device, (2) the store number, (3) the amount of the purchase (704), and the time of receipt of the code. The credit card company takes this information and passes the code from the electronic ID device to the USR software 18 (706). The USR software 18 determines if the code is valid, or was valid at the time offered, and if valid accesses the user's credit card information and transmits the appropriate credit card number to the credit card company (708). While the link between the USR system and the credit card system is a secure link, there is always a danger that the link may be penetrated and credit card numbers obtained. This may be avoided by instead transmitting, on approval, a multidigit public ID code for the credit card holder which the credit card company can map to the correct credit card number. Even if the link is violated, the public ID code is of no value and the secure link prevents this code from being improperly sent to the credit card company. The credit card company checks the credit worthiness of the user and declines the card or debits the user's account in accordance with its standard transaction processing system (710). The credit card company then notifies the merchant of the result of the transaction (712). In this embodiment, the user has been able to purchase goods or services from a merchant without ever providing to the merchant the credit card number. Since the electronic ID device generates a time variant code or otherwise generates a code that can for example only be used for a single transaction, the merchant retains no information from the transaction that may be fraudulently used in subsequent transactions. Another embodiment of a system for facilitating purchase of goods or services without providing financial information to the merchant is set forth in FIG. 8. In FIG. 8, like FIG. 7, the user initiates a purchase (800), enters a secret code in the electronic ID device (802) and presents the resultant code to the merchant. The merchant, in this embodiment, transmits to the USR software 18, (1) the code from the electronic ID, (2) the store number, and (3) the amount of the purchase (804). The USR software 18 determines if the code is valid (806) and, if valid, accesses from the USR database 24 the user's credit card information (808). The USR software then transmits to the credit card company (1) the credit card number, (2) the store number, and (3) the amount of purchase (808). The information in this embodiment transmitted to the credit card company is intended to be in a format recognizable to the credit card company. Accordingly, the invention is not limited to transferring from the USR system 10 to the credit card company the enumerated information, but rather encompasses any transfer of information that will enable the use of the USR system 10 to appear transparent to the credit card company. The credit card company then processes the transaction in a standard fashion, such as by checking the credit worthiness of the person, declining the card or debiting the user's account and transferring money to the merchant's account (810). The credit card company then notifies the USR system 10 the result of the transaction (812) and the USR software 18 in turn notifies the merchant of the result of the transaction (814). In this embodiment, like the embodiment of FIG. 7, the user can use the USR system 10 to purchase goods or services from a merchant without providing the merchant with the user's credit card number. In the embodiment of FIG. 8, the interposition of the USR system 10 between the merchant and the credit card company is transparent to the credit card company and thus requires no or minimal cooperation from the credit card company to implement. FIG. 9 illustrates one embodiment of a method of using the USR system 10 to verify funds when using a check to purchase goods or services from a merchant. In the embodiment of FIG. 9, the user initiates a purchase and writes a check to the merchant (900). The check may be a conventional check containing identifying information, or may be a check bearing a unique serial number and no identifying information to enable the check to be used anonymously. In either situation, the user enters a secret code into the electronic ID card and presents the resulting code to the merchant along with the check (902). The merchant transmits to the USR software 18 (1) the code from the electronic ID card, (2) the store number, and (3) the amount of the purchase (904). Where the check is an anonymous check, the merchant also transmits to the USR software 18 the check number. The USR software 18 then determines if the code from the electronic ID is valid (906), and if valid accesses the user's bank information and transmits to the bank: (1) the user's bank account number, (2) the store number, and (3) the amount of the purchase (908). Optionally, the USR software 18 may additionally inform the bank of the check number. The bank polls its own database to determine if there are sufficient funds in the user's account (910) and notifies the USR software 18 of the result (912). The USR software 18 then, in turn, notifies the merchant of the result of the verification (914). This check verification system may take place over an unsecured connection between the merchant and the USR system 10 since the user's bank account information is not sent over the connection between the merchant and the USR system 10. Moreover, where an anonymous check is used, the merchant is not even provided with the person's name or account information in written form. This provides additional security against unauthorized persons writing subsequent checks. The check verification system may be conducted over a telephone network, such as by having the merchant call a toll free number, or over a network connection such as over the Internet. FIG. 10 illustrates a method of conducting a transaction with a merchant without requiring the user to provide to the merchant the user's name, address, or other identifying information, while enabling the merchant to ship the goods to the user. This may be beneficially employed, for example, in connection with transactions that take place between remote parties in a networked environment, such as the Internet. As shown in FIG. 10, the user initiates an anonymous purchase by entering a secret code into the electronic ID device and transmitting the result to the on-line merchant (1000). The merchant transmits this information to the USR software 18, along with the store number and the amount of the purchase (1002). Optionally, the merchant may provide the store number and purchase price to the user and the user may send this information directly to the USR software 18 along with the code from the electronic ID. Where the number from the electronic ID device is a time varying number, the merchant may also need to input the time the number was received. Alternatively, the electronic ID device may encode or encrypt the time with the number, the USR software being able to extract time when receiving the number from the merchant. This may not be required where the time varying number varies slowly, for example changing every hour rather then every minute as for some existing such devices. In either event, the USR software 18 determines if the code is valid (1004) and, if valid, accesses the user's credit card information from the USR database 24 (1006). The USR software 18 then contacts the user's credit card company, as described above in connection with FIG. 8 (1008) and notifies the USR software 18 of the result (1000). If the user's credit is declined, the USR software 18 notifies the on-line merchant and the transaction is terminated (1012). If the user's credit is honored, the USR software 18 polls the USR database 24 for the user's address and/or address code (1014). Address codes are discussed below in greater detail with reference to FIG. 11. The merchant then packages the goods into a parcel, labels the parcel with the appropriate address and/or address code and ships the parcel to the user (1016). Having the USR system 10 provide the address and/or address code to the on-line merchant enables the user to purchase items in a networked environment without requiring the user to input address information in connection with every sale. FIG. 11 illustrates a use of the USR database 24 to deliver mail to a user without requiring the user to provide address information to the sender. This may be useful in many contexts. For example, the user may wish that the address information be known only by the post office. In this instance, using the USR database 24 according to the method of the invention described below, will enable the user to receive parcels without requiring the user to provide the merchant with the address information. Additionally, the user's address may change, temporarily, permanently, or frequently. Enabling the sender to send mail by entering a code instead of an address enables the post office to effectively deliver the coded mail to the corresponding address regardless of the frequency with which the address changes or the duration in which the address will remain valid. In FIG. 11, the user provides an address code on a public area of the USR database 24 that is available to all persons to see (1100). This code may for example be six alpha characters, which should be adequate for currently anticipated system populations. Optionally, the user may provide this code directly to a merchant or other person desirous of sending the person one or more parcels. The user also provides address information to the address information area 38 of the user's entry in the USR database 24 (1102). Access to the address information 38 is restricted by a rule or other appropriate entry in the access information 34 of the user's entry to only permit mail, parcel or other material delivery services, such as the US mail, UPS and Fed Ex to access the address information. When someone wishes to have a parcel or other items delivered to the user, the sender retrieves the user's address code from the USR database 24 or otherwise receives the address code from the user, and prints the address code on the parcel (1104). The delivery service accesses the USR software 18, validates its identity, and queries the USR database 24 for address information corresponding to the address code (1106). The USR database 24 retrieves the appropriate address data and provides the address information to the delivery service. The delivery service then either prints out an address label, prints a machine readable bar code to be attached to the package, or correlates an entry in a delivery database between the address code and the user address (1110). The delivery service then uses this retrieved information to deliver the package to the user while never supplying the merchant with the user's permanent or temporary address. A user may also assure that mail, parcels, etc. are delivered to a current location by providing only a single notice to the USR system, regardless of how frequently the person moves. The person can also automatically provide for address changes where the person moves according to a known schedule. Thus, deliveries to be made on a weekday could be directed to one address and deliveries on a weekend to another address; or deliveries during winter months to one address and during summer months to a different address. FIG. 12 illustrates a method of enabling a person to telephone a user of the USR system 10 without providing the user's telephone number to the person. In the embodiment illustrated in FIG. 12, the user provides a telephone code on the publicly available area of his entry on the USR database 24 (1200). This code may be assigned by the USR software 18 or made up by the user. The user also provides the USR database 24 with actual telephone information to enable the USR system 10 to connect callers with the user (1202). The person wishing to telephone the user of the USR system 10 calls a telephone number and enters the telephone code of the user (1204). The USR software 18, optionally, may require the person to identify themselves to see if they are authorized to call the user. Assuming that the person is authorized to call the person, or if no authorization check is performed, the USR connects the person to the telephone number in the USR database 24 without providing the person with the telephone number. Enabling the user to specify the telephone number may be advantageous for many reasons. First, the user may frequently be switching between telephone coverage areas and may wish to be reachable at all times. Simply by instructing the USR database 24 to connect incoming telephone calls to one of a myriad of numbers will facilitate connecting the incoming calls to, for example, the user's cell phone, work phone, pager, car phone or home phone, without necessitating the user to provide all these numbers to the caller. A similar system may be implemented for facsimile transmissions, e-mails or other communications. The user also may have predefined rules to enable telephone calls to follow a set pattern. For example, the user may desire to receive telephone calls only from family members during the night time at home, may wish to have all incoming calls routed to a car phone during commuting hours, and may wish to have all incoming calls routed to a cell phone during lunch. These time dependent rules may and/or caller specific rules may be entered into the USR database to specify accessibility and connectivity of incoming telephone calls. The publicly available address code and telephone code and any other codes may be the same, or may be different, there being some advantages to having a single code usable for all such applications for each person on the system. The codes could be accessible through a variety of media including telephone and the internet. Where two or more people on the system have the same name, which will frequently be the case, additional publicly available biographical data may be provided with the name to assure that the right code is selected. The system may similarly be used to provide public keys for use in a public key/private key encryption system, to provide other public codes for an individual or to provide other public information. Access to such information would typically be unrestricted. Where the system is used to provide public keys, the public code used to obtain the key, or possibly the public key itself, may be used as above to obtain the e-mail address, telephone number or the like for the person to whom the message is being sent, and the USR system may also be used to perform the encryption. When the recipient receives the message, he deencrypts it using the recipient's private key in standard fashion, including deencrypting the name of the sender. However, this does not necessarily verify the sender and such verification may be desirable for important messages, particularly ones involving large financial transactions. The USR system may accomplish such verification by also storing private keys for people in the system. The sender first authenticates himself to the system, and the system then adds a second signature to the message which is encrypted with the sender's private key. The receiving party deencrypts this signature with the sender's public key. Since the system only sends such signatures for authenticated users, the message is thus verified. FIG. 13 illustrates a general method of using the USR database 24 to authenticate a user's identification. This may be used in connection with any of the other methods disclosed herein to ensure that the electronic ID device has not been stolen and/or hacked by an unauthorized holder. Specifically, in the embodiment illustrated in FIG. 13, the user attempts to prove identification to a validator, such as to prove that the possessor of the electronic ID device is of sufficient age to purchase alcohol (1300). In connection with this attempt, the user enters a secret code into the electronic ID (1302). The validator transmits to the USR software 18 the code from the electronic ID (1304). If the USR software 18 determines that the code is valid (1306), it accesses the user's photograph, age information, or any other desired information, and transmits that information to the validator (1308). By transmitting back to the validator a picture of the person to whom the electronic ID card was issued, the validator can ensure that the person using the electronic ID card is the proper person. Likewise, the validator can ensure, based on the information provided by the USR system 10, that the person is as old as the person claims to be. A specific embodiment of this identification validation procedure is illustrated in FIG. 14. In FIG. 14, a policeman takes the place of the validator. In this scenario, however, instead of simply transmitting to the policeman a validation of the user's identity, such as their picture, the policeman may also receive additional information, such as the user's police records, records of any arrests, outstanding warrants, and other similar information that may be of use to the policeman when determining how to handle a particular individual. FIG. 15 illustrates a process for enabling the user to provide specific information to a party, such as medical staff in an emergency room. As shown in FIG. 15, if the user desires to provide information to a party (1500), the user enters a secret code in the electronic ID device and provides the electronic ID code to the party (1502). The party transmits to the USR software 18 the ID code and the party code (1504). The party code may be a code from for example an electronic device which identifies the party, may be a status code which identifies the class of users to which the party belongs, for example policeman, emergency room personnel, doctor, etc. or may be a combination of both, the status code for example being encrypted into the ID code. The USR software 18 determines if the code is valid (1506), accesses the user's information in the USR database 24 and transmits available information to the party (1508). In this scenario, the user may be provided with a plurality of different codes to enter into the electronic ID device depending on the type of information to be released to the party. For example, the user's basic code may be 1234. The fifth digit of the electronic code may specify the type of information to be provided, i.e., 1=address information, 2=medical information; 3=telephone information, 4=job application information, etc. Using multiple codes eliminates any ambiguity about the authority provided by the user to the party, but requires the user to remember additional information. The above assumes the user is able to provide an ID code when the information is required. However, in for example an emergency room situation, the user may not be in a position to provide the ID code, but would still want medical records provided. The release authorization for certain portions of the user's database could therefore specify that the information be released to certain class or classes of individuals and the USR system would release such information to individuals or organizations based only on status code. Thus, the status code of an emergency room could alone trigger release of medical data. FIG. 16 illustrates one embodiment of a method of using the USR database 24 to complete a standard application, such as a job application or an application to rent an apartment. This embodiment is a specific example of the more generic method of enabling a party to retrieve information discussed above with respect to FIG. 15. In FIG. 16, however, the party may be provided with the opportunity to provide a form to the USR software 18, the fields of which may be automatically completed with information from the job application information section of the USR database 24. As can be seen from the above, many of the users of the USR system are organizations or agencies such as carriers (post office, UPS, FedEX), communication companies, law enforcement organizations, hospitals and other medical facilities and the like. Each of these organizations can be provided with specialized software either on a disc or other suitable media or electronically, for example over the internet, which performs a number of functions, for example automatically generating status codes for data access requests, controlling information received, and formatting data received in response to a request in a desired way. This can result in an access request from such organization for a given user causing all data on the user required to complete the form being retrieved and presented to the organization in the format of their form. A user may also authorize an organization for which a form has been completed using the USR system to receive updates, either in response to a request from the organization or at selected intervals, for example once a year, so as to maintain information in the forms current. Since the user will be providing information to the system on a regular basis, this is a relatively easy and painless way for the user to maintain current information with many organizations the user deals with. Another potential use of the system is to permit a person to be located where only limited biographical information on the person is known. Users of the USR system wishing to participate in this feature could be cued to provide non-confidential biographical data when they come on the system or at any time thereafter when they decide to participate. They can also indicate whether they wish their name given out in response to such an inquiry or to merely be alerted to an inquiry which might involve them and information on the requester. A person seeking to find another person or group of people can input appropriate biographical data, for example members of 1975 Harvard University hockey team, or information of a person's last known address plus school information, etc. The system will then provide a list of persons who meet the listed criteria from which the person making the inquiry can hopefully find the person they are looking for. In the above application and others, when a person is located, the person may request that only the person's address code or general access code (i.e. a single code which is used to get current address, telephone, e-mail, etc. information) be provided when the person is located. This can further protect the individual from undesired contacts. FIG. 17 illustrates another embodiment of the invention. As shown in FIG. 17, the USR system 10 may be used to secure expensive personal equipment, such as stereos, televisions, laptop computers, cellular telephones, cars, boats, and other items of value to a person. In this embodiment, each item to be secured using the USR system is provided with a USR timer chip imbedded in the electronics. If the USR timer chip is not provided with a code within a predefined period of time, for example every 30 days, the equipment is deactivated. Thus, for example, a television, mobile phone, laptop computer, automobile, heavy equipment, weapon or facility may be provided with a security chip having an internal timer that must be reset before expiration by provision of a particular code. When reset does not occur, the timer will disable the electronic device or other device using any one of a number of known disablement methods. Exemplary codes may be transmitted in the same manner as beeper signals are conventionally transmitted or may be transmitted to wired devices over the Internet or other public network. The USR system 10 may be advantageously employed to automatically provide the secured property with the necessary codes at appropriate intervals, unless instructed by the user of the USR system 10 to cease doing so. Alternatively, the USR system 10 may require participation by the user prior to sending out the activation codes. In this embodiment, the user may provide to the USR system 10, information indicative of the codes to be transmitted, timing information, and automation information whether the codes should be sent automatically or should require user intervention. Optionally, where the user opts to require user intervention, the USR system 10 may notify the user of the upcoming deadline via e-mail or another method. This system may be useful to secure sensitive equipment other than personal equipment as well, such as military equipment, public equipment, school equipment and any other equipment that is subject to theft. It should be understood that various changes and modifications of the embodiments shown in the drawings and described in the specification may be made within the spirit and scope of the present invention. Accordingly, it is intended that all matter contained in the above description and shown in the accompanying drawings be interpreted in an illustrative and not in a limiting sense. The invention is limited only as defined in the following claims and the equivalents thereto.
<SOH> BACKGROUND OF INVENTION <EOH>
<SOH> SUMMARY OF INVENTION <EOH>There is thus a need for an identification system that will enable a person to be identified or verified (“identification” sometimes being used hereinafter to mean either identified or verified) and/or authenticated without necessitating the provision of any personal information. Likewise, there is a need for an identification system that will enable a person to be identified universally without requiring the person to carry multiple forms of identification. Accordingly, this invention relates, in one embodiment, to an information system that may be used as a universal identification system and/or used to selectively provide personal, financial or other information about a person to authorized users. Transactions to and from the database may take place using a public key/private key security system to enable users of the system and the system itself to encrypt transaction information during the transactions. Additionally, the private key/public key security system may be used to allow users to validate their identity and/or sign instructions being sent to a universal secure registry (USR) system of the type to which this invention relates. For example, in one embodiment, a smart card such as the SecurID™ card from RSA Security, Inc. may be provided with the user's private key and the USR system's public key to enable the card to encrypt messages being sent to the USR system and to decrypt messages from the USR system 10 . This USR system or database may be used to identify the person in many situations, and thus may take the place of multiple conventional forms of identification. Additionally, the USR system may enable the user's identity to be confirmed or verified without providing any identifying information about the person to the entity requiring identification. This can be advantageous where the person suspects that providing identifying information may subject the identifying information to usurpation. Enabling anonymous identification facilitates multiple new forms of transactions. For example, enabling anonymous identification enables the identified person to be telephoned by or receive e-mails from other persons without providing the other person with a telephone number or e-mail address, and will permit this to be accomplished even where there are frequent changes in the person's location. Similarly, enabling anonymous identification will enable the person to receive mail, other delivered parcels and other items without providing the recipient's address information to the sender. By restricting access to particular classes of persons/entities, the person can effectively prevent receipt of junk mail, other unsolicited mail, telemarketing calls and the like. In a financial context, providing anonymous identification of a person enables the person to purchase goods and/or services from a merchant without ever transmitting to the merchant information, such as the person's credit card number, or even the person's name, that could be intercepted and/or usurped and used in subsequent or additional unauthorized transactions or for other undesired purposes. Enabling anonymous identification may be particularly advantageous in an unsecured environment, such as the Internet, where it has been found to be relatively trivial to intercept such credit card information. In a medical context, the USR system, in addition to enabling a person seeking medical treatment to identify themselves, may be configured to provide insurance data, medical history data, and other appropriate medical information to a medical provider, once that medical provider has been established as an authorized recipient. The USR system may also contain links to other databases containing portions of the patient's medical records, for example x-rays, MRI pictures, dental records, glasses, prescriptions, etc. Access to the USR system may be by smart card, such as a SecurID™ card, or any other secure access device. The technology enabling the USR system may be physically embodied as a separate identification device such as a smart ID card, or may be incorporated into another electronic device, such as a cell phone, pager, wrist watch, computer, personal digital assistant such as a Palm Pilot™, key fob, or other commonly available electronic device. The identity of the user possessing the identifying device may be verified at the point of use via any combination of a memorized PIN number or code, biometric identification such as a fingerprint, voice print, signature, iris or facial scan, or DNA analysis, or any other method of identifying the person possessing the device. If desired, the identifying device may also be provided with a picture of the person authorized to use the device to enhance security. The USR system may be useful for numerous other identification purposes. For example, the USR anonymous identification may serve as a library card, a phone card, a health club card, a professional association membership card, a parking access card, a key for access to one's home, office, car, etc. or any one of a host of similar identification/verification and/or access functions. Additionally, equipment code information may be stored in the USR system and distributed under the user's control and at the user's discretion, to maintain personal property or public property in an operative state.
G06Q20204
20170830
20180327
20171221
77435.0
G06Q2020
1
CRAWLEY, TALIA F
UNIVERSAL SECURE REGISTRY
SMALL
1
CONT-ACCEPTED
G06Q
2,017
15,691,884
PENDING
Portable vehicle battery jump start apparatus with safety protection
A handheld device for jump starting a vehicle engine includes a rechargeable lithium ion battery pack (32) and a microcontroller (1). The lithium ion battery is coupled to a power output port of the device through a power switch circuit (15) actuated by the microcontroller. A vehicle battery isolation sensor (12) connected in circuit with positive and negative polarity outputs detects the presence of a vehicle battery (72) connected between the positive and negative polarity outputs. A reverse polarity sensor (10) connected in circuit with the positive and negative polarity outputs detects the polarity of a vehicle battery connected between the positive and negative polarity outputs, such that the microcontroller will enable power to be delivered from the lithium ion power pack to the output port only when a good battery is connected to the output port and only when the battery is connected with proper polarity of positive and negative terminals.
1. Apparatus for jump starting a vehicle engine, comprising: an internal power supply; an output port having positive and negative polarity outputs; a vehicle battery isolation sensor connected in circuit with said positive and negative polarity outputs, configured to detect presence of a vehicle battery connected between said positive and negative polarity outputs; a reverse polarity sensor connected in circuit with said positive and negative polarity outputs, configured to detect polarity of a vehicle battery connected between said positive and negative polarity outputs and to provide an output signal indicating whether positive and negative terminals of said vehicle battery are properly connected with said positive and negative polarity outputs of said output port; a power switch connected between said internal power supply and said output port; and a microcontroller configured to receive input signals from said vehicle isolation sensor and said reverse polarity sensor, and to provide an output signal to said power switch, such that said power switch is turned on to cause said internal power supply to be connected to said output port in response to signals from said sensors indicating the presence of a vehicle battery at said output port and proper polarity connection of positive and negative terminals of said vehicle battery with said positive and negative polarity outputs, and is not turned on when signals from said sensors indicate either the absence of a vehicle battery at said output port or improper polarity connection of positive and negative terminals of said vehicle battery with said positive and negative polarity outputs. 2. The apparatus of claim 1, wherein said internal power supply comprises a lithium ion battery. 3. The apparatus of claim 2, wherein said lithium ion battery comprises a battery pack of multiple lithium ion batteries. 4. The apparatus of claim 1, wherein said power switch comprises a plurality of FETs in parallel. 5. The apparatus of claim 1, wherein said vehicle isolation sensor and reverse polarity sensor comprise optically coupled isolator phototransistors. 6. The apparatus of claim 1, further comprising a plurality of power diodes coupled between said output port and said internal power supply to prevent back-charging of said internal power supply from an electrical system connected to said output port. 7. The apparatus of claim 1, further comprising a temperature sensor configured to detect temperature of said internal power supply and to provide a temperature signal to said microcontroller. 8. The apparatus of claim 1, further comprising a voltage measurement circuit configured to measure output voltage of said internal power supply and to provide a voltage measurement signal to said microcontroller. 9. The apparatus of claim 1, further comprising a voltage regulator configured to convert output voltage of said internal power supply to a voltage level appropriate to provide operating power to internal components of the apparatus. 10. The apparatus of claim 1, further comprising a USB output port configured to provide charging power from said internal power supply to a USB-chargeable device. 11. The apparatus of claim 1, further comprising a USB charging port configured to provide charging power from an external power source to said internal power supply. 12. The apparatus of claim 1, further comprising a flashlight circuit configured to provide a source of light to a user. 13. The apparatus of claim 12, wherein said source of light is at least one LED. 14. The apparatus of claim 13, wherein said microcontroller is configured to control said at least one LED to provide a visual alarm indicating an emergency situation. 15. The apparatus of claim 1, further comprising a plurality of visual indicators configured to display remaining capacity status of said internal power supply. 16. The apparatus of claim 15, wherein said plurality of visual indicators comprises a plurality of LEDs providing output light of different colors. 17. The apparatus of claim 1, further comprising a visual indicator configured to warn a user when a vehicle battery is connected with reverse polarity. 18. The apparatus of claim 1, further comprising separate visual indicators configured to display the power on status of the apparatus, and the jump start boost power status of power supplied to said output port. 19. The apparatus of claim 1, further comprising a manual override switch configured to activate a manual override mode to enable a user to connect jump start power to said output port when said vehicle battery isolation sensor is unable to detect presence of a vehicle battery. 20. The apparatus of claim 19, wherein said microcontroller is configured to detect actuation of said manual override switch for at least a predetermined period of time before activation of said manual override mode. 21. The apparatus of claim 1, further comprising a jumper cable device including a plug configured to plug into said output port, a pair of cables integrated with the plug at one respective end thereof and being configured to be connected to terminals of a battery at another respective end thereof. 22. The apparatus of claim 21, wherein said jumper cable device further comprises a pair of ring terminals configured to respectively connect said pair of cables at said another end thereof with one of a battery terminal and a battery terminal clamp. 23. The apparatus of claim 21, wherein said output port and said plug are dimensioned so that the plug will fit into the output port only in one specific orientation.
FIELD OF THE INVENTION The present invention relates generally to apparatus for jump-starting a vehicle having a depleted or discharged battery. BACKGROUND TO THE INVENTION Prior art devices are known for jump-starting a vehicle, which provide either a pair of electrical connector cables that connect a fully-charged battery of another vehicle to the engine start circuit of the dead battery vehicle, or portable booster devices which include a fully-charged battery which can be connected in circuit with the vehicle's engine starter through a pair of cables. Problems with the prior art arose when either the jumper terminals or clamps of the cables were inadvertently brought into contact with each other while the other ends were connected to a charged battery, or when the positive and negative terminals were connected to the opposite polarity terminals in the vehicle to be jumped, thereby causing a short circuit resulting in sparking and potential damage to batteries and/or bodily injury. Various attempts to eliminate these problems have been made in the prior art. U.S. Pat. No. 6,212,054 issued Apr. 3, 2001, discloses a battery booster pack that is polarity sensitive and can detect proper and improper connections before providing a path for electric current flow. The device uses a set of LEDs connected to optical couplers oriented by a control circuit. The control circuit controls a solenoid assembly controlling the path of power current. The control circuit causes power current to flow through the solenoid assembly only if the points of contact of booster cable clamp connections have been properly made. U.S. Pat. No. 6,632,103 issued Oct. 14, 2003, discloses an adaptive booster cable connected with two pairs of clips, wherein the two pairs of clips are respectively attached to two batteries to transmit power from one battery to the other battery. The adaptive booster cable includes a polarity detecting unit connected to each clip, a switching unit and a current detecting unit both provided between the two pairs of clips. After the polarity of each clip is sensed by the polarity detecting unit, the switching unit generates a proper connection between the two batteries. Therefore, the positive and negative terminals of the two batteries are correctly connected based on the detected result of the polarity detecting unit. U.S. Pat. No. 8,493,021 issued Jul. 23, 2013, discloses apparatus that monitors the voltage of the battery of a vehicle to be jump started and the current delivered by the jump starter batteries to determine if a proper connection has been established and to provide fault monitoring. Only if the proper polarity is detected can the system operate. The voltage is monitored to determine open circuit, disconnected conductive clamps, shunt cable fault, and solenoid fault conditions. The current through the shunt cable is monitored to determine if there is a battery explosion risk, and for excessive current conditions presenting an overheating condition, which may result in fire. The system includes an internal battery to provide the power to the battery of the vehicle to be jump started. Once the vehicle is started, the unit automatically electrically disconnects from the vehicle's battery. U.S. Pat. No. 5,189,359 issued Feb. 23, 1993, discloses a jumper cable device having two bridge rectifiers for developing a reference voltage, a four-input decoder for determining which terminals are to be connected based on a comparison of the voltage at each of the four terminals to the reference voltage, and a pair of relays for effecting the correct connection depending on the determination of the decoder. No connection will be made unless only one terminal of each battery has a higher voltage than the reference voltage, indicating “positive” terminals, and one has a lower voltage than the reference voltage, indicating “negative” terminals, and that, therefore, the two high voltage terminals may be connected and the two lower voltage terminals may be connected. Current flows once the appropriate relay device is closed. The relay device is preferably a MOSFET combined with a series array of photodiodes that develop MOSFET gate-closing potential when the decoder output causes an LED to light. U.S. Pat. No. 5,795,182 issued Aug. 18, 1998, discloses a polarity independent set of battery jumper cables for jumping a first battery to a second battery. The apparatus includes a relative polarity detector for detecting whether two batteries are configured cross or parallel. A three-position high current capacity crossbar pivot switch is responsive to the relative polarity detector for automatically connecting the plus terminals of the two batteries together and the minus terminals of the two batteries together regardless of whether the configuration detected is cross or parallel, and an undercurrent detector and a delay circuit for returning the device to its ready and unconnected state after the device has been disconnected from one of the batteries. The crossbar pivot switch includes two pairs of contacts, and a pivot arm that pivots about two separate points to ensure full electrical contact between the pairs of contacts. The invention can also be used to produce a battery charger that may be connected to a battery without regard to the polarity of the battery. U.S. Pat. No. 6,262,492 issued Jul. 17, 2001, discloses a car battery jumper cable for accurately coupling an effective power source to a failed or not charged battery, which includes a relay switching circuit connected to the power source and the battery by two current conductor pairs. First and second voltage polarity recognition circuits are respectively connected to the power source and the battery by a respective voltage conductor pair to recognize the polarity of the power source and the battery. A logic recognition circuit produces a control signal subject to the polarity of the power source and the battery, and a driving circuit controlled by the control signal from the logic recognition circuit drives the relay switching circuit, enabling the two poles of the power source to be accurately coupled to the two poles of the battery. U.S. Pat. No. 5,635,817 issued Jun. 3, 1997, discloses a vehicle battery charging device that includes a control housing having cables including a current limiting device to prevent exceeding of a predetermined maximum charging current of about 40 to 60 amps. The control housing includes a polarity detecting device to verify the correct polarity of the connection of the terminals of the two batteries and to electrically disconnect the two batteries if there is an incorrect polarity. U.S. Pat. No. 8,199,024 issued Jun. 12, 2012, discloses a safety circuit in a low-voltage connecting system that leaves the two low-voltage systems disconnected until it determines that it is safe to make a connection. When the safety circuit determines that no unsafe conditions exist and that it is safe to connect the two low-voltage systems, the safety circuit may connect the two systems by way of a “soft start” that provides a connection between the two systems over a period of time that reduces or prevents inductive voltage spikes on one or more of the low-voltage systems. When one of the low-voltage systems has a completely-discharged battery incorporated into it, a method is used for detection of proper polarity of the connections between the low-voltage systems. The polarity of the discharged battery is determined by passing one or more test currents through it and determining whether a corresponding voltage rise is observed. U.S. Pat. No. 5,793,185 issued Aug. 11, 1998, discloses a handheld jump starter having control components and circuits to prevent overcharging and incorrect connection to batteries. While the prior art attempted solutions to the abovementioned problems as discussed above, each of the prior art solutions suffers from other shortcomings, either in complexity, cost or potential for malfunction. Accordingly, there exists a need in the art for further improvements to vehicle jump start devices. SUMMARY OF THE INVENTION In accordance with an aspect of the invention, an apparatus is provided for jump starting a vehicle engine, comprising: an internal power supply; an output port having positive and negative polarity outputs; a vehicle battery isolation sensor connected in circuit with said positive and negative polarity outputs, configured to detect presence of a vehicle battery connected between said positive and negative polarity outputs; a reverse polarity sensor connected in circuit with said positive and negative polarity outputs, configured to detect polarity of a vehicle battery connected between said positive and negative polarity outputs and to provide an output signal indicating whether positive and negative terminals of said vehicle battery are properly connected with said positive and negative polarity outputs of said output port; a power switch connected between said internal power supply and said output port; and a microcontroller configured to receive input signals from said vehicle isolation sensor and said reverse polarity sensor, and to provide an output signal to said power switch, such that said power switch is turned on to cause said internal power supply to be connected to said output port in response to signals from said sensors indicating the presence of a vehicle battery at said output port and proper polarity connection of positive and negative terminals of said vehicle battery with said positive and negative polarity outputs, and is not turned on when signals from said sensors indicate either the absence of a vehicle battery at said output port or improper polarity connection of positive and negative terminals of said vehicle battery with said positive and negative polarity outputs. In accordance with an embodiment of the invention, the internal power supply is a rechargeable lithium ion battery pack. A jumper cable device may also be provided, having a plug configured to plug into said output port; a pair of cables integrated with the plug at one respective end thereof; said pair of cables being configured to be separately connected to terminals of a battery at another respective end thereof. Comprises/comprising and grammatical variations thereof when used in this specification are to be taken to specify the presence of stated features, integers, steps or components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a functional block diagram of a handheld vehicle battery boost apparatus in accordance with one aspect of the present invention; FIGS. 2A-2C are schematic circuit diagrams of an example embodiment of a handheld vehicle battery boost apparatus in accordance with an aspect of the invention; FIG. 3 is a perspective view of a handheld jump starter booster device in accordance with one example embodiment of the invention; and FIG. 4 is a plan view of a jumper cable usable with the handheld jump starter booster device in accordance with another aspect of the invention. DETAILED DESCRIPTION OF THE INVENTION FIG. 1 is a functional block diagram of a handheld battery booster according to one aspect of the invention. At the heart of the handheld battery booster is a lithium polymer battery pack 32, which stores sufficient energy to jump start a vehicle engine served by a conventional 12 volt lead-acid or valve regulated lead-acid battery. In one example embodiment, a high-surge lithium polymer battery pack includes three 3.7V, 2666 mAh lithium polymer batteries in a 3S1P configuration. The resulting battery pack provides 11.1V, 2666Ah (8000Ah at 3.7V, 29.6 Wh). Continuous discharge current is 25 C (or 200 amps), and burst discharge current is 50 C (or 400 amps). The maximum charging current of the battery pack is 8000 mA (8 amps). A programmable microcontroller unit (MCU) 1 receives various inputs and produces informational as well as control outputs. The programmable MCU 1 further provides flexibility to the system by allowing updates in functionality and system parameters, without requiring any change in hardware. According to one example embodiment, an 8 bit microcontroller with 2K×15 bits of flash memory is used to control the system. One such microcontroller is the HT67F30, which is commercially available from Holtek Semiconductor Inc. A car battery reverse sensor 10 monitors the polarity of the vehicle battery 72 when the handheld battery booster device is connected to the vehicle's electric system. As explained below, the booster device prevents the lithium battery pack from being connected to the vehicle battery 72 when the terminals of the battery 72 are connected to the wrong terminals of the booster device. A car battery isolation sensor 12 detects whether or not a vehicle battery 72 is connected to the booster device, and prevents the lithium battery pack from being connected to the output terminals of the booster device unless there is a good (e.g. chargeable) battery connected to the output terminals. A smart switch FET circuit 15 electrically switches the handheld battery booster lithium battery to the vehicle's electric system only when the vehicle battery is determined by the MCU 1 to be present (in response to a detection signal provided by isolation sensor 12) and connected with the correct polarity (in response to a detection signal provided by reverse sensor 10). A lithium battery temperature sensor 20 monitors the temperature of the lithium battery pack 32 to detect overheating due to high ambient temperature conditions and overextended current draw during jump starting. A lithium battery voltage measurement circuit 24 monitors the voltage of the lithium battery pack 32 to prevent the voltage potential from rising too high during a charging operation and from dropping too low during a discharge operation. Lithium battery back-charge protection diodes 28 prevent any charge current being delivered to the vehicle battery 72 from flowing back to the lithium battery pack 32 from the vehicle's electrical system. Flashlight LED circuit 36 is provided to furnish a flashlight function for enhancing light under a vehicle's hood in dark conditions, as well as providing SOS and strobe lighting functions for safety purposes when a vehicle may be disabled in a potentially dangerous location. Voltage regulator 42 provides regulation of internal operating voltage for the microcontroller and sensors. On/Off manual mode and flashlight switches 46 allow the user to control power-on for the handheld battery booster device, to control manual override operation if the vehicle has no battery, and to control the flashlight function. The manual button functions only when the booster device is powered on. This button allows the user to jump-start vehicles that have either a missing battery, or the battery voltage is so low that automatic detection by the MCU is not possible. When the user presses and holds the manual override button for a predetermined period time (such as three seconds) to prevent inadvertent actuation of the manual mode, the internal lithium ion battery power is switched to the vehicle battery connect port. The only exception to the manual override is if the car battery is connected in reverse. If the car battery is connected in reverse, the internal lithium battery power shall never be switched to the vehicle battery connect port. USB charge circuit 52 converts power from any USB charger power source, to charge voltage and current for charging the lithium battery pack 32. USB output 56 provides a USB portable charger for charging smartphones, tablets, and other rechargeable electronic devices. Operation indicator LEDs 60 provide visual indication of lithium battery capacity status as well as an indication of smart switch activation status (indicating that power is being provided to the vehicle's electrical system). Detailed operation of the handheld booster device will now be described with reference to the schematic diagrams of FIGS. 2A-2C. As shown in FIG. 2A, the microcontroller unit 1 is the center of all inputs and outputs. The reverse battery sensor 10 comprises an optically coupled isolator phototransistor (4N27) connected to the terminals of vehicle battery 72 at input pins 1 and 2 with a diode D8 in the lead conductor of pin 1 (associated with the negative terminal CB−), such that if the battery 72 is connected to the terminals of the booster device with the correct polarity, the optocoupler LED 11 will not conduct current, and is therefore turned off, providing a “1” or high output signal to the MCU 1. The car battery isolation sensor 12 comprises an optically coupled isolator phototransistor (4N27) connected to the terminals of vehicle battery 72 at input pins 1 and 2 with a diode D7 in the lead conductor of pin 1 (associated with the positive terminal CB+), such that if the battery 72 is connected to the terminals of the booster device with the correct polarity, the optocoupler LED 11A will conduct current, and is therefore turned on, providing a “0” or low output signal to the MCU, indicating the presence of a battery across the jumper output terminals of the handheld booster device. If the car battery 72 is connected to the handheld booster device with reverse polarity, the optocoupler LED 11 of the reverse sensor 10 will conduct current, providing a “0” or low signal to microcontroller unit 1. Further, if no battery is connected to the handheld booster device, the optocoupler LED 11A of the isolation sensor 12 will not conduct current, and is therefore turned off, providing a “1” or high output signal to the MCU, indicating the absence of any battery connected to the handheld booster device. Using these specific inputs, the microcontroller software of MCU 1 can determine when it is safe to turn on the smart switch FET 15, thereby connecting the lithium battery pack to the jumper terminals of the booster device. Consequently, if the car battery 72 either is not connected to the booster device at all, or is connected with reverse polarity, the MCU 1 can keep the smart switch FET 15 from being turned on, thus prevent sparking/short circuiting of the lithium battery pack. As shown in FIG. 2B, the FET smart switch 15 is driven by an output of the microcontroller 1. The FET smart switch 15 includes three FETs (Q15, Q18, and Q19) in parallel, which spreads the distribution of power from the lithium battery pack over the FETs. When that microcontroller output is driven to a logic low, FETs 16 are all in a high resistance state, therefore not allowing current to flow from the internal lithium battery negative contact 17 to the car battery 72 negative contact. When the microcontroller output is driven to a logic high, the FETs 16 (Q15, Q18, and Q19) are in a low resistant state, allowing current to flow freely from the internal lithium battery pack negative contact 17 (LB−) to the car battery 72 negative contact (CB−). In this way, the microcontroller software controls the connection of the internal lithium battery pack 32 to the vehicle battery 72 for jumpstarting the car engine. Referring back to FIG. 2A, the internal lithium battery pack voltage can be accurately measured using circuit 24 and one of the analog-to-digital inputs of the microcontroller 1. Circuit 24 is designed to sense when the main 3.3V regulator 42 voltage is on, and to turn on transistor 23 when the voltage of regulator 42 is on. When transistor 23 is conducting, it turns on FET 22, thereby providing positive contact (LB+) of the internal lithium battery a conductive path to voltage divider 21 allowing a lower voltage range to be brought to the microcontroller to be read. Using this input, the microcontroller software can determine if the lithium battery voltage is too low during discharge operation or too high during charge operation, and take appropriate action to prevent damage to electronic components. Still referring to FIG. 2A, the temperature of the internal lithium battery pack 32 can be accurately measured by two negative temperature coefficient (NTC) devices 20. These are devices that reduce their resistance when their temperature rises. The circuit is a voltage divider that brings the result to two analog-to-digital (A/D) inputs on the microcontroller 1. The microcontroller software can then determine when the internal lithium battery is too hot to allow jumpstarting, adding safety to the design. The main voltage regulator circuit 42 is designed to convert internal lithium battery voltage to a regulated 3.3 volts that is utilized by the microcontroller 1 as well as by other components of the booster device for internal operating power. Three lithium battery back charge protection diodes 28 (see FIG. 2B) are in place to allow current to flow only from the internal lithium battery pack 32 to the car battery 72, and not from the car battery to the internal lithium battery. In this way, if the car electrical system is charging from its alternator, it cannot back-charge (and thereby damage) the internal lithium battery, providing another level of safety. The main power on switch 46 (FIG. 2A) is a combination that allows for double pole, double throw operation so that with one push, the product can be turned on if it is in the off state, or turned off if it is in the on state. This circuit also uses a microcontroller output 47 to “keep alive” the power when it is activated by the on switch. When the switch is pressed the microcontroller turns this output to a high logic level to keep power on when the switch is released. In this way, the microcontroller maintains control of when the power is turned off when the on/off switch is activated again or when the lithium battery voltage is getting too low. The microcontroller software also includes a timer that turns the power off after a predefined period of time, (such as, e.g. 8 hours) if not used. The flashlight LED circuit 45 shown in FIG. 2B controls the operation of flashlight LEDs. Two outputs from the microcontroller 1 are dedicated to two separate LEDs. Thus, the LEDs can be independently software-controlled for strobe and SOS patterns, providing yet another safety feature to the booster device. LED indicators provide the feedback the operator needs to understand what is happening with the product. Four separate LEDs 61 (FIG. 2A) are controlled by corresponding individual outputs of microcontroller 1 to provide indication of the remaining capacity of the internal lithium battery. These LEDs are controlled in a “fuel gauge” type format with 25%, 50%, 75% and 100% (red, red, yellow, green) capacity indications. An LED indicator 63 (FIG. 2B) provides a visual warning to the user when the vehicle battery 72 has been connected in reverse polarity. “Boost” and on/off LEDs 62 provide visual indications when the booster device is provide jump-start power, and when the booster device is turned on, respectively. A USB output 56 circuit (FIG. 2C) is included to provide a USB output for charging portable electronic devices such as smartphones from the internal lithium battery pack 32. Control circuit 57 from the microcontroller 1 allows the USB Out 56 to be turned on and off by software control to prevent the internal lithium battery getting too low in capacity. The USB output is brought to the outside of the device on a standard USB connector 58, which includes the standard voltage divider required for enabling charge to certain smartphones that require it. The USB charge circuit 52 allows the internal lithium battery pack 32 to be charged using a standard USB charger. This charge input uses a standard micro-USB connector 48 allowing standard cables to be used. The 5V potential provided from standard USB chargers is up-converted to the 12.4 VDC voltage required for charging the internal lithium battery pack using a DC-DC converter 49. The DC-DC converter 49 can be turned on and off via circuit 53 by an output from the microcontroller 1. In this way, the microcontroller software can turn the charge off if the battery voltage is measured to be too high by the A/D input 22. Additional safety is provided for helping to eliminate overcharge to the internal lithium battery using a lithium battery charge controller 50 that provides charge balance to the internal lithium battery cells 51. This controller also provides safety redundancy for eliminating over discharge of the internal lithium battery. FIG. 3 is a perspective view of a handheld device 300 in accordance with an exemplary embodiment of the invention. 301 is a power on switch. 302 shows the LED “fuel gauge” indicators 61. 303 shows a 12 volt output port connectable to a cable device 400, described further below. 304 shows a flashlight control switch for activating flashlight LEDs 45. 305 is a USB input port for charging the internal lithium battery, and 306 is a USB output port for providing charge from the lithium battery to other portable devices such as smartphones, tablets, music players, etc. 307 is a “boost on” indicator showing that power is being provided to the 12V output port. 308 is a “reverse” indicator showing that the vehicle battery is improperly connected with respect to polarity. 309 is a “power on” indicator showing that the device is powered up for operation. FIG. 4 shows a jumper cable device 400 specifically designed for use with the handheld device 300. Device 400 has a plug 401 configured to plug into 12 volt output port 303 of the handheld device 300. A pair of cables 402a and 402b are integrated with the plug 401, and are respectively connected to battery terminal clamps 403a and 403b via ring terminals 404a and 404b. The port 303 and plug 401 may be dimensioned so that the plug 401 will only fit into the port 303 in a specific orientation, thus ensuring that clamp 403a will correspond to positive polarity, and clamp 403b will correspond to negative polarity, as indicated thereon. Additionally, the ring terminals 404a and 404b may be disconnected from the clamps and connected directly to the terminals of a vehicle battery. This feature may be useful, for example, to permanently attach the cables 302a-302b to the battery of a vehicle. In the event that the battery voltage becomes depleted, the handheld booster device 300 could be properly connected to the battery very simply by plugging in the plug 401 to the port 303. The invention having been thus described, it will be apparent to those skilled in the art that the same may be varied in many ways without departing from the spirit or scope of the invention. Any and all such variations are intended to be encompassed within the scope of the following claims.
<SOH> BACKGROUND TO THE INVENTION <EOH>Prior art devices are known for jump-starting a vehicle, which provide either a pair of electrical connector cables that connect a fully-charged battery of another vehicle to the engine start circuit of the dead battery vehicle, or portable booster devices which include a fully-charged battery which can be connected in circuit with the vehicle's engine starter through a pair of cables. Problems with the prior art arose when either the jumper terminals or clamps of the cables were inadvertently brought into contact with each other while the other ends were connected to a charged battery, or when the positive and negative terminals were connected to the opposite polarity terminals in the vehicle to be jumped, thereby causing a short circuit resulting in sparking and potential damage to batteries and/or bodily injury. Various attempts to eliminate these problems have been made in the prior art. U.S. Pat. No. 6,212,054 issued Apr. 3, 2001, discloses a battery booster pack that is polarity sensitive and can detect proper and improper connections before providing a path for electric current flow. The device uses a set of LEDs connected to optical couplers oriented by a control circuit. The control circuit controls a solenoid assembly controlling the path of power current. The control circuit causes power current to flow through the solenoid assembly only if the points of contact of booster cable clamp connections have been properly made. U.S. Pat. No. 6,632,103 issued Oct. 14, 2003, discloses an adaptive booster cable connected with two pairs of clips, wherein the two pairs of clips are respectively attached to two batteries to transmit power from one battery to the other battery. The adaptive booster cable includes a polarity detecting unit connected to each clip, a switching unit and a current detecting unit both provided between the two pairs of clips. After the polarity of each clip is sensed by the polarity detecting unit, the switching unit generates a proper connection between the two batteries. Therefore, the positive and negative terminals of the two batteries are correctly connected based on the detected result of the polarity detecting unit. U.S. Pat. No. 8,493,021 issued Jul. 23, 2013, discloses apparatus that monitors the voltage of the battery of a vehicle to be jump started and the current delivered by the jump starter batteries to determine if a proper connection has been established and to provide fault monitoring. Only if the proper polarity is detected can the system operate. The voltage is monitored to determine open circuit, disconnected conductive clamps, shunt cable fault, and solenoid fault conditions. The current through the shunt cable is monitored to determine if there is a battery explosion risk, and for excessive current conditions presenting an overheating condition, which may result in fire. The system includes an internal battery to provide the power to the battery of the vehicle to be jump started. Once the vehicle is started, the unit automatically electrically disconnects from the vehicle's battery. U.S. Pat. No. 5,189,359 issued Feb. 23, 1993, discloses a jumper cable device having two bridge rectifiers for developing a reference voltage, a four-input decoder for determining which terminals are to be connected based on a comparison of the voltage at each of the four terminals to the reference voltage, and a pair of relays for effecting the correct connection depending on the determination of the decoder. No connection will be made unless only one terminal of each battery has a higher voltage than the reference voltage, indicating “positive” terminals, and one has a lower voltage than the reference voltage, indicating “negative” terminals, and that, therefore, the two high voltage terminals may be connected and the two lower voltage terminals may be connected. Current flows once the appropriate relay device is closed. The relay device is preferably a MOSFET combined with a series array of photodiodes that develop MOSFET gate-closing potential when the decoder output causes an LED to light. U.S. Pat. No. 5,795,182 issued Aug. 18, 1998, discloses a polarity independent set of battery jumper cables for jumping a first battery to a second battery. The apparatus includes a relative polarity detector for detecting whether two batteries are configured cross or parallel. A three-position high current capacity crossbar pivot switch is responsive to the relative polarity detector for automatically connecting the plus terminals of the two batteries together and the minus terminals of the two batteries together regardless of whether the configuration detected is cross or parallel, and an undercurrent detector and a delay circuit for returning the device to its ready and unconnected state after the device has been disconnected from one of the batteries. The crossbar pivot switch includes two pairs of contacts, and a pivot arm that pivots about two separate points to ensure full electrical contact between the pairs of contacts. The invention can also be used to produce a battery charger that may be connected to a battery without regard to the polarity of the battery. U.S. Pat. No. 6,262,492 issued Jul. 17, 2001, discloses a car battery jumper cable for accurately coupling an effective power source to a failed or not charged battery, which includes a relay switching circuit connected to the power source and the battery by two current conductor pairs. First and second voltage polarity recognition circuits are respectively connected to the power source and the battery by a respective voltage conductor pair to recognize the polarity of the power source and the battery. A logic recognition circuit produces a control signal subject to the polarity of the power source and the battery, and a driving circuit controlled by the control signal from the logic recognition circuit drives the relay switching circuit, enabling the two poles of the power source to be accurately coupled to the two poles of the battery. U.S. Pat. No. 5,635,817 issued Jun. 3, 1997, discloses a vehicle battery charging device that includes a control housing having cables including a current limiting device to prevent exceeding of a predetermined maximum charging current of about 40 to 60 amps. The control housing includes a polarity detecting device to verify the correct polarity of the connection of the terminals of the two batteries and to electrically disconnect the two batteries if there is an incorrect polarity. U.S. Pat. No. 8,199,024 issued Jun. 12, 2012, discloses a safety circuit in a low-voltage connecting system that leaves the two low-voltage systems disconnected until it determines that it is safe to make a connection. When the safety circuit determines that no unsafe conditions exist and that it is safe to connect the two low-voltage systems, the safety circuit may connect the two systems by way of a “soft start” that provides a connection between the two systems over a period of time that reduces or prevents inductive voltage spikes on one or more of the low-voltage systems. When one of the low-voltage systems has a completely-discharged battery incorporated into it, a method is used for detection of proper polarity of the connections between the low-voltage systems. The polarity of the discharged battery is determined by passing one or more test currents through it and determining whether a corresponding voltage rise is observed. U.S. Pat. No. 5,793,185 issued Aug. 11, 1998, discloses a handheld jump starter having control components and circuits to prevent overcharging and incorrect connection to batteries. While the prior art attempted solutions to the abovementioned problems as discussed above, each of the prior art solutions suffers from other shortcomings, either in complexity, cost or potential for malfunction. Accordingly, there exists a need in the art for further improvements to vehicle jump start devices.
<SOH> SUMMARY OF THE INVENTION <EOH>In accordance with an aspect of the invention, an apparatus is provided for jump starting a vehicle engine, comprising: an internal power supply; an output port having positive and negative polarity outputs; a vehicle battery isolation sensor connected in circuit with said positive and negative polarity outputs, configured to detect presence of a vehicle battery connected between said positive and negative polarity outputs; a reverse polarity sensor connected in circuit with said positive and negative polarity outputs, configured to detect polarity of a vehicle battery connected between said positive and negative polarity outputs and to provide an output signal indicating whether positive and negative terminals of said vehicle battery are properly connected with said positive and negative polarity outputs of said output port; a power switch connected between said internal power supply and said output port; and a microcontroller configured to receive input signals from said vehicle isolation sensor and said reverse polarity sensor, and to provide an output signal to said power switch, such that said power switch is turned on to cause said internal power supply to be connected to said output port in response to signals from said sensors indicating the presence of a vehicle battery at said output port and proper polarity connection of positive and negative terminals of said vehicle battery with said positive and negative polarity outputs, and is not turned on when signals from said sensors indicate either the absence of a vehicle battery at said output port or improper polarity connection of positive and negative terminals of said vehicle battery with said positive and negative polarity outputs. In accordance with an embodiment of the invention, the internal power supply is a rechargeable lithium ion battery pack. A jumper cable device may also be provided, having a plug configured to plug into said output port; a pair of cables integrated with the plug at one respective end thereof; said pair of cables being configured to be separately connected to terminals of a battery at another respective end thereof. Comprises/comprising and grammatical variations thereof when used in this specification are to be taken to specify the presence of stated features, integers, steps or components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.
B60L111816
20170831
20180426
60923.0
B60L1118
2
DIAO, M BAYE
Portable vehicle battery jump start apparatus with safety protection
SMALL
1
CONT-ACCEPTED
B60L
2,017
15,692,893
PENDING
VEGF ANTAGONIST FORMULATIONS
Formulations of a vascular endothelial growth factor (VEGF)-specific fusion protein antagonist are provided including a pre-lyophilized formulation, a reconstituted lyophilized formulation, and a stable liquid formulation. Preferably, the fusion protein has the sequence of SEQ ID NO:4.
1. A mammalian cell comprising a polynucleotide that encodes a fusion protein, wherein said fusion protein comprises an immunoglobulin-like (Ig) domain 2 of a first VEGF receptor, an Ig domain 3 of a second VEGF receptor, and a multimerizing component; wherein said fusion protein does not comprise a signal peptide and does not comprise a C-terminal lysine; and wherein said fusion protein binds vascular endothelial growth factor (VEGF). 2. The mammalian cell of claim 1, wherein said mammalian cell is a Chinese hamster ovary (CHO) cell. 3. The mammalian cell of claim 1, wherein said first VEGF receptor is Flt1. 4. The mammalian cell of claim 3, wherein said second VEGF receptor is Flk1 or Flt2. 5. The mammalian cell of claim 4, wherein said fusion protein comprises amino acids 27-457 of SEQ ID NO:2. 6. The mammalian cell of claim 5, wherein said fusion protein is glycosylated at asparagine residues 59, 91, 146, 219, and 308. 7. The mammalian cell of claim 5, wherein said polynucleotide comprises nucleotides 146-1439 of SEQ ID NO:1. 8. The mammalian cell of claim 4, wherein said fusion protein comprises amino acids 27-457 of SEQ ID NO:4. 9. The mammalian cell of claim 8, wherein said fusion protein is glycosylated at asparagine residues 62, 94, 149, 222 and 308. 10. The mammalian cell of claim 8, wherein said polynucleotide comprises nucleotides 78-1371 of SEQ ID NO:3. 11. A method of manufacturing a VEGF antagonist fusion protein that comprises in order from the N-terminus to the C-terminus an immunoglobulin-like (Ig) domain 2 of a first VEGF receptor, an Ig domain 3 of a second VEGF receptor, and a multimerizing component, and does not comprise a signal peptide or a C-terminal lysine, said method comprising: a. expressing said VEGF antagonist fusion protein in a mammalian cell, wherein said mammalian cell comprises a polynucleotide that encodes said VEGF antagonist fusion protein; and b. purifying said VEGF antagonist fusion protein. 12. The method of claim 11, wherein said first VEGF receptor is Flt1 and said second VEGF receptor is Flk1 or Flt2. 13. The method of claim 11, wherein said mammalian cell is a CHO cell. 14. The method of claim 11, wherein said fusion protein is substantially free of protein contaminants. 15. The method of claim 14, wherein at least 90% of the weight of said fusion protein is not present as an aggregate. 16. The method of claim 11, wherein said VEGF antagonist fusion protein is glycosylated at one or more asparagine residues. 17. The method of claim 12, wherein said VEGF antagonist fusion protein comprises amino acids 27-457 of SEQ ID NO:4. 18. The method of claim 17, wherein said VEGF antagonist fusion protein is glycosylated at asparagine residues 62, 94, 149, 222 and 308. 19. The method of claim 12, wherein said VEGF antagonist fusion protein comprises amino acids 27-457 of SEQ ID NO:2. 20. The method of claim 19, wherein said VEGF antagonist fusion protein is glycosylated at asparagine residues 59, 91, 146, 219 and 308.s
CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 15/342,989, filed on Nov. 3, 2016, which is a continuation of U.S. patent application Ser. No. 15/064,343, filed on Mar. 8, 2016 and granted on Dec. 6, 2016 as U.S. Pat. No. 9,511,140, which is a continuation of U.S. patent application Ser. No. 14/550,385, filed on Nov. 21, 2014 and granted on Aug. 16, 2016 as U.S. Pat. No. 9,416,167, which is a continuation of U.S. patent application Ser. No. 13/909,745, filed on Jun. 4, 2013 and granted on Dec. 30, 2014 as U.S. Pat. No. 8,921,316, which is a continuation of U.S. patent application Ser. No. 13/428,510, filed on Mar. 23, 2012 and granted on Apr. 29, 2014 as U.S. Pat. No. 8,710,004, which is a continuation of U.S. patent application Ser. No. 13/343,214, filed on Jan. 4, 2012 and granted on Mar. 26, 2013 as U.S. Pat. No. 8,404,638, which is a division of U.S. patent application Ser. No. 12/835,065, filed on Jul. 13, 2010 and granted on Feb. 7, 2012 as U.S. Pat. No. 8,110,546, which is a continuation of U.S. patent application Ser. No. 11/387,256, filed on Mar. 22, 2006, which claims the benefit of priority under 35 USC §119(e) of U.S. Provisional Application No. 60/665,125, filed on Mar. 25, 2005, all of which are herein specifically incorporated by reference in their entirety. BACKGROUND OF THE INVENTION Field of the Invention The present invention is directed to pharmaceutical formulations comprising agents capable of inhibiting vascular endothelial growth factor (VEGF), and to methods for making and using such formulations. The invention includes pharmaceutical formulations having increased stability. Statement of Related Art Vascular endothelial growth factor (VEGF) expression is nearly ubiquitous in human cancer, consistent with its role as a key mediator of tumor neoangiogenesis. Blockade of VEGF function, by binding to the molecule or its VEGFR-2 receptor, inhibits growth of implanted tumor cells in multiple different xenograft models (see, for example, Gerber et al. (2000) Cancer Res. 60:6253-6258). A soluble VEGF-specific fusion protein antagonist, termed a “VEGF trap” has been described (Kim et al. (2002) Proc. Natl. Acad. Sci. USA 99:11399-404; Holash et al. (2002) Proc. Natl. Acad. Sci. USA 99:11393-8), which references are specifically incorporated by reference in their entirety. Lyophilization (freeze drying under controlled conditions) is commonly used for long term storage of proteins. The lyophilized protein is substantially resistant to degradation, aggregation, oxidation, and other degenerative processes while in the freeze-dried state (see, for example, U.S. Pat. No. 6,436,897). BRIEF SUMMARY OF THE INVENTION Stable formulations of a VEGF-specific fusion protein antagonist are herein provided. The pharmaceutically acceptable formulations of the invention comprise the VEGF “trap” antagonist with a pharmaceutically acceptable carrier. In specific embodiments, liquid and freeze-dried, or lyophilized formulations are provided. In a first aspect, the invention features a stable liquid formulation of a VEGF-specific fusion protein antagonist, comprising a fusion protein comprising a receptor component consisting essentially of an immunoglobulin-like (Ig) domain 2 of a first VEGF receptor and Ig domain 3 of a second VEGF receptor, and a multimerizing component, one or more buffers, and one or more thermal stabilizers. In a specific embodiment of the VEGF-specific fusion protein antagonist, the first VEGF receptor is Flt1 and the second VEGF receptor is Flk1 or Flt4. In a more specific embodiment the fusion protein has the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:4. In one embodiment, the buffer is a phosphate buffer and/or citrate. More preferably, the buffers are phosphate and citrate. In one embodiment, the thermal stabilizers are NaCl and/or sucrose. More preferably, the thermal stabilizers are both NaCl and sucrose. In a specific embodiment, the stable liquid formulation of a VEGF-specific fusion protein antagonist comprises 1-10 mM phosphate buffer, 1-10 mM citrate, 25-150 mM NaCl, 5-30% sucrose, 10-50 mg/ml of the fusion protein, at a pH of about 6-6.5. In a more specific embodiment, the stable liquid formulation comprises 5 mM phosphate buffer, 5 mM citrate buffer, 100 mM NaCl, 20% sucrose, 25 mg/ml of the fusion protein, at a pH of about 6.0. Additionally, polysorbate may be present, for example 0.05-0.15% polysorbate 20. The stable liquid formulation of the VEGF-specific fusion protein antagonist of the invention exhibits little or no precipitation after storage of a 25 mg/ml VEGF formulation for about 6 months at −80° C. and little or no precipitation after storage for 6 months at 5° C. In a second aspect, the invention features a high concentration stable liquid formulation of a VEGF antagonist comprising 1-50 mM histidine, 25-150 mM NaCl, 5-30% sucrose, 50-100 mg/ml of the fusion protein, at a pH of about 6-6.5, and either 0.1-0.5% polysorbate or 1-5% PEG. In a more specific embodiment, the high concentration stable liquid formulation comprises 10 mM histidine, 50 mM NaCl, 5-20% sucrose, 50-100 mg/ml of the fusion protein, at a pH of about 6.0-6.5, with either 0.1% polysorbate (e.g., polysorbate 20) or 3% PEG (e.g., PEG 3350). The high concentration stable liquid formulation of the VEGF-specific fusion protein antagonist of the invention exhibits less than about 3% degradation after 15 months of storage at 5° C. (75 or 100 mg/ml VEGF trap protein) or less than about 1.5% degradation after 24 months (50 mg/ml). In a third aspect, the invention features a pre-lyophilized formulation of a vascular endothelial growth factor (VEGF)-specific fusion protein antagonist, comprising a (i) fusion protein comprising a receptor component consisting essentially of an immunoglobulin-like (Ig) domain 2 of a first VEGF receptor and Ig domain 3 of a second VEGF receptor, and a multimerizing component, (ii) a buffer, (iii) an organic co-solvent or bulking agent, and (iv) one or more lyoprotectants. In various embodiments, the buffer is histidine, the organic co-solvent or bulking agent is PEG, and the lyoprotectant(s) is at least one of glycine and sucrose. In one embodiment, the pre-lyophilized formulation of the invention does not contain a preservative. In one embodiment of the pre-lyophilized formulation of the invention, the formulation comprises 5-50 mM histidine, 0.1-3.0% PEG, 0.25-3.0% glycine, 0.5-6.0% sucrose, and 5-75 mg/ml of the fusion protein, at a pH of about 6.0-6.5. In any embodiment, the pre-lyophilized formulation may further comprise up to 0.05 mM citrate and/or 0.003-0.005% polysorbate. The polysorbate present may be, for example, polysorbate 20. In a more specific embodiment, the pre-lyophilized formulation comprises about 10 mM histidine, about 1.5% PEG 3350, about 0.75% glycine, about 2.5% sucrose, and about 12.5 to 75 mg/ml VEGF-specific fusion protein, at a pH of about 6.25. In specific embodiments, the fusion protein comprises the protein sequence of SEQ ID NO:4, present as a multimer, e.g., a dimer. In separate embodiments, the reconstituted formulation is 2 times the concentration of the pre-lyophilized formulation, e.g., a 20 mg fusion protein/ml pre-lyophilized formulation is reconstituted to a final formulation of 60 mg fusion protein/mi. Generally, the lyophilized formulation is reconstituted with sterile water suitable for injection. In one embodiment, the reconstitution liquid may be bacteriostatic water. In a preferred embodiment, the pre-lyophilized formulation consists essentially of about 10 mM histidine, about 1.5% PEG 3350, about 0.75% glycine, about 2.5% sucrose, and about 50 mg/ml of the fusion protein having the sequence of SEQ ID NO:4 as a dimer, at a pH of about 6.25. Citrate (less than or equal to about 0.02 mM) and/or polysorbate (less than or equal to about 0.0005%) may be present. Optionally, the pre-lyophilized formulation does not contain a preservative, a phosphate buffer, and/or more than trace amounts of NaCl. In one embodiment, the pre-lyophilized formulation consists of about 10 mM histidine, about 1.5% PEG 3350, about 0.75% glycine, about 2.5% sucrose, and about 50 mg/ml of the VEGF trap protein (SEQ ID NO:4), pH 6.3, and upon reconstitution contains 20 mM histidine, 3% PEG, 1.5% glycine, about 5% sucrose, and about 100 mg/ml VEGF trap protein. In a fourth aspect, the invention features a method of producing a lyophilized formulation of a VEGF-specific fusion protein antagonist, comprising subjecting the pre-lyophilized formulation of the invention to lyophilization to generate a lyophilized formulation. The lyophilized formulation may be lyophilized by any method known in the art for lyophilizing a liquid. In a fifth related aspect, the invention features a method of producing a reconstituted lyophilized formulation of a VEGF-specific fusion protein antagonist, comprising reconstituting the lyophilized formulation of the invention to a reconstituted formulation. In one embodiment, the reconstituted formulation is twice the concentration of the pre-lyophilized formulation, e.g., the method of the invention comprises: (a) producing a pre-lyophilized formulation of a VEGF-specific fusion protein antagonist, (b) subjecting the pre-lyophilized formulation of step (a) to lyophilization; and (c) reconstituting the lyophilized formulation of step (b). In specific embodiments of the method of producing a reconstituted lyophilized formulation, a pre-lyophilized solution is present in a vial as a 25 mg VEGF-specific fusion protein antagonist per ml solution of pre-lyophilized formulation, which is lyophilized and reconstituted to an 50 mg/ml solution. In another embodiment, a 30 mg/ml pre-lyophilized solution is lyophilized and reconstituted to a 60 mg/ml solution. In another embodiment, a 40 mg/ml pre-lyophilized solution is lyophilized and reconstituted to a 80 mg/ml solution. In another embodiment, a 12.5 mg/ml pre-lyophilized solution is lyophilized and reconstituted to a 25 mg/ml solution. In another embodiment, a 50 mg/ml pre-lyophilized solution is lyophilized and reconstituted to a 100 mg/ml solution. In another embodiment, a 75 mg/ml pre-lyophilized solution is lyophilized and reconstituted to a 150 mg/ml solution. Preferably, the reconstituted lyophilized formulation does not contain a preservative. Other objects and advantages will become apparent from a review of the ensuing detailed description. DETAILED DESCRIPTION OF THE INVENTION The present invention is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting unless indicated, since the scope of the present invention will be limited only by the appended claims. As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus for example, references to “a method” include one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure. Unless stated otherwise, all technical and scientific terms and phrases used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference. GENERAL DESCRIPTION Safe handling and administration of formulations comprising proteins represent significant challenges to pharmaceutical formulators. Proteins possess unique chemical and physical properties that present stability problems: a variety of degradation pathways exist for proteins, implicating both chemical and physical instability. Chemical instability includes deamination, aggregation, clipping of the peptide backbone, and oxidation of methionine residues. Physical instability encompasses many phenomena, including, for example, aggregation. Chemical and physical stability can be promoted by removing water from the protein. Lyophilization (freeze-drying under controlled conditions) is commonly used for long-term storage of proteins. The lyophilized protein is substantially resistant to degradation, aggregation, oxidation, and other degenerative processes while in the freeze-dried state. The lyophilized protein is normally reconstituted with water optionally containing a bacteriostatic preservative (e.g., benzyl alcohol) prior to administration. Definitions The term “carrier” includes a diluent, adjuvant, excipient, or vehicle with which a composition is administered. Carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like. The term “excipient” includes a non-therapeutic agent added to a pharmaceutical composition to provide a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The term “lyophilized” or “freeze-dried” includes a state of a substance that has been subjected to a drying procedure such as lyophilization, where at least 50% of moisture has been removed. The phrase “bulking agent” includes a compound that is pharmaceutically acceptable and that adds bulk to a lyo cake. Generally, acceptable bulking agents known to the art include, for example, carbohydrates, including simple sugars such as dextrose, ribose, fructose and the like, alcohol sugars such as mannitol, inositol and sorbitol, disaccharides including trehalose, sucrose and lactose, naturally occurring polymers such as starch, dextrans, chitosan, hyaluronate, proteins (e.g, gelatin and serum albumin), glycogen, and synthetic monomers and polymers. In the formulations of the invention, PEG 3350 is an organic co-solvent which is used to stabilize the fusion protein when agitated, mixed, or handled, and as a bulking agent to help produce an acceptable bulk. The term “lyoprotectant” includes a substance that may be added to a freeze-dried or lyophilized formulation to help maintain protein structure when freeze-dried or lyophilized. A “preservative” includes a bacteriostatic, bacteriocidal, fungistatic or fungicidal compound that is generally added to formulations to retard or eliminate growth of bacteria or other contaminating microorganisms in the formulations. Preservatives include, for example, benzyl alcohol, phenol, benzalkonium chloride, m-cresol, thimerosol, chlorobutanol, methylparaben, propylparaben and the like. Other examples of pharmaceutically acceptable preservatives can be found in the USP. VEGF Antagonists An VEGF antagonist is a compound capable of blocking or inhibiting the biological action of vascular endothelial growth factor (VEGF), and includes fusion proteins capable of trapping VEGF. In a preferred embodiment, the VEGF antagonist is the fusion protein of SEQ ID NO:2 or 4; more preferably, SEQ ID NO:4. In specific embodiments, the VEGF antagonist is expressed in a mammalian cell line such as a CHO cell and may be modified posttranslationally. In a specific embodiment, the fusion protein comprises amino acids 27-457 of SEQ ID NO:4 and is glycosylated at Asn residues 62, 94, 149, 222 and 308. The VEGF antagonist of the methods and formulations of the invention can be prepared by any suitable method known in the art, or that comes to be known. The VEGF antagonist is preferably substantially free of protein contaminants at the time it is used to prepare the pharmaceutically acceptable formulation. By “substantially free of protein contaminants” is meant, preferably, that at least 90% of the weight of protein of the VEGF-specific fusion protein antagonist preparation used for making a formulation is VEGF fusion protein antagonist protein, more preferably at least 95%, most preferably at least 99%. The fusion protein is preferably substantially free of aggregates. “Substantially free of aggregates” means that at least 90% of the weight of fusion protein is not present in an aggregate at the time the fusion protein is used to prepare the pharmaceutically effective formulation. The fusion protein of the methods and formulations of the invention may contain low or trace amounts of compounds as a results of the purification process, for example, low or trace amounts of citrate and/or polysorbate. In one embodiment of the pre-lyophilized formulation of the invention containing about 50 mg of fusion protein/ml, citrate may be present at a concentration of about 0.02 mM and/or polysorbate may be present at a concentration of about 0.0005%. If the pre-lyophilized formulation is reconstituted after lyophilization to half of the original volume (e.g., 100 mg/ml of fusion protein), the resulting concentrations may be 0.04 mM citrate and/or 0.001% polysorbate. Lyophilization and Lyophilized Formulations In one aspect of the invention, a pharmaceutically acceptable formulation comprising a VEGF-specific fusion protein antagonist is provided, wherein the formulation is a freeze-dried or lyophilized formulation. Lyophilized formulations can be reconstituted into solutions, suspensions, emulsions, or any other suitable form for administration or use. Lyophilized formulations are typically first prepared as liquids, then frozen and lyophilized. The total liquid volume before lyophilization can be less, equal to, or more than, the final reconstituted volume of the lyophilized formulation. The lyophilization process is well known to those of ordinary skill in the art, and typically includes sublimation of water from a frozen formulation under controlled conditions. Lyophilized formulations can be stored at a wide range of temperatures. Lyophilized formulations may be stored below 25° C., for example, refrigerated at 4° C., or at room temperature (e.g., approximately 25° C.). Preferably, lyophilized formulations are stored below about 25° C., more preferably, at about 4-20° C.; below about 4° C.; below about −20° C.; about −40° C.; about −70° C., or about −80° C. Lyophilized formulations are typically reconstituted for use by addition of an aqueous solution to dissolve the lyophilized formulation. A wide variety of aqueous solutions can be used to reconstitute a lyophilized formulation. Preferably, lyophilized formulations are reconstituted using water. Lyophilized formulations are preferably reconstituted with a solution consisting essentially of water (e.g., USP WFI, or water for injection) or bacteriostatic water (e.g., USP WFI with 0.9% benzyl alcohol). However, solutions comprising buffers and/or excipients and/or one or more pharmaceutically acceptable carries can also be used. Freeze-dried or lyophilized formulations are typically prepared from liquids, that is, from solutions, suspensions, emulsions, and the like. Thus, the liquid that is to undergo freeze-drying or lyophilization preferably comprises all components desired in a final reconstituted liquid formulation. As a result, when reconstituted, the freeze-dried or lyophilized formulation will render a desired liquid formulation upon reconstitution. A preferred liquid formulation used to generate a freeze-dried or lyophilized formulation comprises a VEGF-specific fusion protein antagonist in a pharmaceutically effective amount, a buffer, a stabilizer, and a bulking agent. Freeze-dried or lyophilized formulations preferably comprise histidine, since histidine, in comparison to phosphate, is more effective at stabilizing the fusion protein when the fusion protein is lyophilized. Organic co-solvents, such as PEG 3350, are used to stabilize the fusion protein when agitated, mixed, or handled. A lyoprotectant is preferably used in freeze-dried or lyophilized formulations. Lyoprotectants help to maintain the secondary structure of proteins when freeze-dried or lyophilized. Two preferred example lyoprotectants are glycine and sucrose, which are preferably used together. Stable Liquid Formulations In one aspect, the invention provides a stable pharmaceutically acceptable formulation comprising a VEGF-specific fusion protein antagonist, wherein the formulation is a liquid formulation. Preferably, the liquid formulation comprises a pharmaceutically effective amount of the fusion protein. The formulation can also comprise one or more pharmaceutically acceptable carriers, buffers, bulking agents, stabilizers, preservatives, and/or excipients. An example of a pharmaceutically acceptable liquid formulation comprises a VEGF-specific fusion protein antagonist in a pharmaceutically effective amount, a buffer, a co-solvent, and one or more stabilizers. A preferred liquid formulation comprises phosphate buffer, an organic co-solvent, and one or more thermal stabilizers to minimize formation of aggregates and low molecular weight products when stored, and about 10 mg/ml to about 50 mg/ml fusion protein, wherein the formulation is from about pH 6.0-6.5. A preferred liquid formulation comprises about 5 mM phosphate buffer, about 5 mM citrate, about 100 mM NaCl, about 25% sucrose, and about 1050 mg/ml fusion protein, wherein the formulation is at a pH of about 6.0; optionally polysorbate may be present (e.g., 0.1% polysorbate 20). Although either NaCl or sucrose can be used as a stabilizer, a combination of NaCl and sucrose has been established to stabilize the fusion protein more effectively than either individual stabilizer alone. Stability is determined in a number of ways at specified time points, including determination of pH, visual inspection of color and appearance, determination of total protein content by methods known in the art, e.g., UV spectroscopy, SDS-PAGE, size-exclusion HPLC, bioassay determination of activity, isoelectric focusing, and isoaspartate quantification. In one example of a bioassay useful for determining VEGF antagonist activity, a BAF/3 VEGFR1/EPOR cell line is used to determine VEGF165 binding by the VEGF-specific fusion protein antagonist of the invention. Formulations, whether liquid or freeze-dried and lyophilized, can be stored in an oxygen-deprived environment. Oxygen-deprived environments can be generated by storing the formulations under an inert gas such as, for example, argon, nitrogen, or helium. Examples Before the present methods are described, it is to be understood that this invention is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only to the appended claims. As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus for example, a reference to “a method” includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. Example 1. Stability of a 50 mg/ml Liquid Formulation of VEGF Trap A liquid formulation containing 10 mM phosphate, 50 mM NaCl, 0.1% polysorbate 20, 20% sucrose, and 50 mg/ml VEGF trap (SEQ ID NO:4), pH 6.25, was stored at 5° C. and samples tested at 3, 6, 9, 12, 18 and 24 months. Stability was determined by SE-HPLC. The results, shown in Table 1, show that 98.6% and 98.3% of VEGF trap protein remained intact (non-degraded) at 12 and 24 months, respectively. Turbidity was measured at OD405 nm; and percent recovered protein by size exclusion HPLC. TABLE 1 Stability of 50 mg/ml VEGF Trap Protein When Stored at 5° C. (VGFT-SS065) % VEGF Visual % VEGF Trap Trap Native Months Appearance Turbidity pH Recovered Configuration 0 Pass 0.00 6.2 100 99.0 3 Pass 0.00 6.2 102 98.8 6 Pass 0.01 6.2 103 98.7 9 Pass 0.01 6.3 102 98.2 12 Pass 0.01 6.3 106 98.6 18 Pass 0.00 6.3 103 98.4 24 Pass 0.00 6.2 93 98.3 A liquid formulation containing 10 mM phosphate, 50 mM NaCl, 3% PEG 3350, 20% sucrose, and 50 mg/ml VEGF trap (SEQ ID NO:4), pH 6.25, was stored at 5° C. and samples tested at 3, 6, 9, 12, 18 and 24 months. Stability results are shown in Table 2. TABLE 2 Stability of 50 mg/ml VEGF Trap Protein When Stored at 5° C. (VGFT-SS065) % VEGF Trap Visual % VEGF Trap Native Months Appearance Turbidity pH Recovered Configuration 0 Pass 0.00 6.2 100 99.0 3 Pass 0.00 6.2 100 98.8 6 Pass 0.01 6.3 103 98.5 9 Pass 0.00 6.3 103 98.3 12 Pass 0.01 6.3 110 98.3 18 Pass 0.00 6.3 113 98.0 24 Pass 0.01 6.2 90 97.8 Example 2. Stability of a 75 mg/ml Liquid Formulation of VEGF Trap A liquid formulation containing 10 mM phosphate, 50 mM NaCl, 0.1% polysorbate 20, 20% sucrose, and 75 mg/ml VEGF trap (SEQ ID NO:4), pH 6.25, was stored at 5° C. and samples tested at 0, 1, 2.3, 3, 9, 12 and 15 months. Stability results are shown in Table 3. TABLE 3 Stability of 75 mg/ml VEGF Trap Protein When Stored at 5° C. (VGFT-SS101) % VEGF Trap Visual % VEGF Trap Native Months Appearance Turbidity pH Recovered Configuration 0 Pass 0.00 6.2 100 97.1 1 Pass 0.00 6.2 96 97.0 2.3 Pass 0.00 6.2 98 96.7 3 Pass 0.00 6.2 97 96.1 9 Pass −0.01 6.0 101 96.0 12 Pass 0.00 6.3 110 94.5 15 Pass 0.00 6.3 92 95.6 A liquid formulation containing 10 mM phosphate, 50 mM NaCl, 3% PEG 3350, 20% sucrose, and 75 mg/ml VEGF trap (SEQ ID NO:4), pH 6.25, was stored at 5° C. and samples tested at 0, 1, 2.3, 3, 9, 12 and 15 months. Stability results are shown in Table 4. TABLE 4 Stability of 75 mg/ml VEGF Trap Protein When Stored at 5° C. (VGFT-SS101) % VEGF Trap Visual % VEGF Trap Native Months Appearance Turbidity pH Recovered Configuration 0 Pass 0.00 6.2 100 96.8 1 Pass 0.00 6.2 99 96.7 2.3 Pass 0.00 6.2 97 96.3 3 Pass 0.00 6.2 89 95.6 9 Pass −0.01 6.2 98 95.4 12 Pass −0.01 6.3 112 94.1 15 Pass 0.00 6.3 98 94.8 Example 3. Stability of a 100 mg/ml Liquid Formulation of VEGF Trap A liquid formulation containing 10 mM phosphate, 50 mM NaCl, 0.1% polysorbate 20, 20% sucrose, and 100 mg/ml VEGF trap (SEQ ID NO:4), pH 6.25, was stored at 5° C. and samples tested at 0, 1, 2.3, 3, 9, 12 and 15 months. Stability results are shown in Table 5. TABLE 5 Stability of 100 mg/ml VEGF Trap Protein Stored at 5° C. (VGFT-SS101) % VEGF Trap Visual % VEGF Trap Native Months Appearance Turbidity pH Recovered Configuration 0 Pass 0.00 6.3 100 96.7 1 Pass 0.00 6.2 92 96.6 2.3 Pass 0.00 6.2 92 96.2 6 Pass 0.00 6.2 99 95.5 9 Pass −0.01 6.2 92 95.5 12 Pass −0.01 6.2 110 93.9 15 Pass 0.00 6.3 108 94.8 A liquid formulation containing 10 mM phosphate, 50 mM NaCl, 3% PEG 3350, 20% sucrose, and 100 mg/ml VEGF trap (SEQ ID NO:4), pH 6.25, was stored at 5° C. and samples tested at 0, 1, 2.3, 3, 9, 12 and 15 months. Stability results are shown in Table 6. TABLE 6 Stability of 100 mg/ml VEGF Trap Protein Stored at 5° C. (VGFT-SS101) % VEGF Trap Visual % VEGF Trap Native Months Appearance Turbidity pH Recovered Configuration 0 Pass 0.00 6.3 100 96.5 1 Pass 0.01 6.2 94 96.2 2.3 Pass 0.01 6.2 93 95.7 6 Pass 0.01 6.2 102 94.6 9 Pass 0.00 6.2 95 94.6 12 Pass 0.00 6.3 96 92.8 15 Pass 0.01 6.3 102 93.9 Example 4. Further Embodiments of Stable VEGF Trap Formulations In one embodiment, the invention provides a stable liquid VEGF-binding fusion protein (VEGF trap) formulations comprising 5 mM phosphate, 5 mM citrate, 100 mM NaCl, 0.1% Polysorbate 20, 20% sucrose, 25 mg/ml VEGF trap protein, pH 6.0. This formulation can either be delivered subcutaneously or diluted and delivered by intravenous infusion. Due to the high osmolality of this formulation, it is diluted 3-fold to achieve an iso-osmolar solution for intravenous administration. Stability studies showed less than about 1% degradation was detected after 3 years of storage at 2-8° C. In one embodiment, the invention features a lyophilized formulation which is preferably concentrated two-fold from the pre-lyophilized to the post-lyophilized formulation, e.g., 50 to 100 mg/ml; 75 to 150 mg/ml, or 100 to 200 mg/ml VEGF trap protein. In one specific embodiment, the pre-lyophilized formulation comprises 10 mM histidine, 1.5% PEG 3350, 0.75% glycine, 2.5% sucrose, 50 mg/ml VEGF trap protein, pH 6.3, and is reconstituted to a formulation comprising 20 mM histidine, 3% PEG 3350, 1.5% glycine, 5% sucrose, 100 mg/ml VEGF trap protein, pH 6.3. Stability studied showed no degradation of the VEGF trap was detected after 6 months of storage at 2-8° C. In one embodiment of a liquid formulation, the formulation comprises 10 mM histidine, 50 mM NaCl, 5-20% sucrose, 50-100 mg/ml VEGF trap, and one of 0.1% polysorbate 20 or TY ° PEG 3350. One advantage of this liquid formulation is that it provides a higher concentration of VEGF trap without requiring the manufacture of a lyophilized product. Thus, this formulation provides ease for subcutaneous delivery, for example, by allowing provision of a liquid pre-filled syringe at a concentration higher than that delivered by IV infusion. Also, this formulation could advantageously be used to provide lower infusion volumes and shorter infusion times. The amount of degradation determined by SE-HPLC following incubation at 5° C. for up to 15 or 24 months is summarized in Table 7. TABLE 7 Stability of Liquid Formulation with 50-100 mg/ml VEGF Trap (VGFT-SS101) Incubation VEGF Trap % % % (months) (mg/ml) Polysorbate 20 PEG 3350 Degradation 24 50 0.1 — 0.7 24 50 — 3 1.3 15 75 0.1 — 1.5 15 75 — 3 2.0 15 100 0.1 — 1.9 15 100 — 3 2.6 Example 5. Stability and Activity of Lyophilized and Liquid The stability of a reconstituted lyophilized formulation was determined over a 6 month period. The pre-lyophilized formulation contained 10 mM histidine, 1.5% PEG 3350, 2.5% sucrose, 0.75% glycine and 50 mg/ml VEGF trap protein. After lyophilization, the reconstituted formulation contained 20 mM histidine, 3% PEG 3350, 5% sucrose, 1.5% glycine, and 100 mg/ml VEGF trap protein (SEQ ID NO:4). The results are shown in Table 8. Activity was determined in a cell based bioassay which directly measures the ability of the VEGF trap to inhibit the biological effects of human VEGF on a mouse Baf/3 VEGFR1/EpoR cell line. Therefore, this bioassay directly measures the biological activity of the protein. The results are expresses as percent relative potency (test sample IC50/reference VEGF IC50 standard×100). The binding affinity of VEGF to the VEGF trap is measured using a sensitive ELISA that specifically measures free VEGF in equilibrated mixtures containing VEGF and various concentrations of the VEGF trap. Results are expressed as percent relative binding (IC50 of test sample/ICH, of reference×100). Measured pH ranged between 6.3-6.5. All solutions where visually clear. The concentration of VEGF trap recovered was determined with a UV spectrophotometer as mg/ml at A280 nm. The percent VEGF trap recovered in the native configuration (main peak purity) was determined with SE-HPLC. TABLE 8 Stability of VEGF Trap Lyophilized Formulation Stored at 5° C. (VGT-RS475) Binding % Native Months Bioassay Assay % Recovered Configuration 0 120 126 97.9 98.7 1 117 74 97.9 98.6 1 + 24 hr 126 72 99.0 98.5 1 + 4 hr 94 81 101.5 98.2 3 101 98 98.1 98.6 3 + 24 hr 65 94 98.1 98.2 6 + 4 hr 96.9 98.7 6 + 24 hr 98.8 98.6 A formulation containing about 5 mM phosphate, 5 mM citrate, 100 mM NaCl, 0.1% polysorbate 20, 20% sucrose, and 25 mg/ml VEGF trap protein was tested for stability and activity over 36 months when stored at 5° C. The results are shown in Table 9. All samples were clear and colorless as determined by visual inspection. pH ranged from 6.0-6.1. *Binding assay results for two measurements (1 and 2 months) are expressed directly and not as a percent of the standard. TABLE 9 Stability and Activity of Liquid Formulation (VGT-FS405) % Native Protein Content Months Configuration Bioassay Binding Assay mg/ml 0 99.7 106 72 25.0 1 99.9 119 4.4 ρM* 25.2 2 99.6 102 5.4 ρM* 25.1 3 99.6 97 88 25.1 6 99.6 101 106 25.0 9 99.4 89 126 25.4 12 99.5 85 95 25.2 18 99.4 99 81 25.5 24 99.3 75 95 25.6 36 98.8 109 79 25.6
<SOH> BACKGROUND OF THE INVENTION <EOH>
<SOH> BRIEF SUMMARY OF THE INVENTION <EOH>Stable formulations of a VEGF-specific fusion protein antagonist are herein provided. The pharmaceutically acceptable formulations of the invention comprise the VEGF “trap” antagonist with a pharmaceutically acceptable carrier. In specific embodiments, liquid and freeze-dried, or lyophilized formulations are provided. In a first aspect, the invention features a stable liquid formulation of a VEGF-specific fusion protein antagonist, comprising a fusion protein comprising a receptor component consisting essentially of an immunoglobulin-like (Ig) domain 2 of a first VEGF receptor and Ig domain 3 of a second VEGF receptor, and a multimerizing component, one or more buffers, and one or more thermal stabilizers. In a specific embodiment of the VEGF-specific fusion protein antagonist, the first VEGF receptor is Flt1 and the second VEGF receptor is Flk1 or Flt4. In a more specific embodiment the fusion protein has the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:4. In one embodiment, the buffer is a phosphate buffer and/or citrate. More preferably, the buffers are phosphate and citrate. In one embodiment, the thermal stabilizers are NaCl and/or sucrose. More preferably, the thermal stabilizers are both NaCl and sucrose. In a specific embodiment, the stable liquid formulation of a VEGF-specific fusion protein antagonist comprises 1-10 mM phosphate buffer, 1-10 mM citrate, 25-150 mM NaCl, 5-30% sucrose, 10-50 mg/ml of the fusion protein, at a pH of about 6-6.5. In a more specific embodiment, the stable liquid formulation comprises 5 mM phosphate buffer, 5 mM citrate buffer, 100 mM NaCl, 20% sucrose, 25 mg/ml of the fusion protein, at a pH of about 6.0. Additionally, polysorbate may be present, for example 0.05-0.15% polysorbate 20. The stable liquid formulation of the VEGF-specific fusion protein antagonist of the invention exhibits little or no precipitation after storage of a 25 mg/ml VEGF formulation for about 6 months at −80° C. and little or no precipitation after storage for 6 months at 5° C. In a second aspect, the invention features a high concentration stable liquid formulation of a VEGF antagonist comprising 1-50 mM histidine, 25-150 mM NaCl, 5-30% sucrose, 50-100 mg/ml of the fusion protein, at a pH of about 6-6.5, and either 0.1-0.5% polysorbate or 1-5% PEG. In a more specific embodiment, the high concentration stable liquid formulation comprises 10 mM histidine, 50 mM NaCl, 5-20% sucrose, 50-100 mg/ml of the fusion protein, at a pH of about 6.0-6.5, with either 0.1% polysorbate (e.g., polysorbate 20) or 3% PEG (e.g., PEG 3350). The high concentration stable liquid formulation of the VEGF-specific fusion protein antagonist of the invention exhibits less than about 3% degradation after 15 months of storage at 5° C. (75 or 100 mg/ml VEGF trap protein) or less than about 1.5% degradation after 24 months (50 mg/ml). In a third aspect, the invention features a pre-lyophilized formulation of a vascular endothelial growth factor (VEGF)-specific fusion protein antagonist, comprising a (i) fusion protein comprising a receptor component consisting essentially of an immunoglobulin-like (Ig) domain 2 of a first VEGF receptor and Ig domain 3 of a second VEGF receptor, and a multimerizing component, (ii) a buffer, (iii) an organic co-solvent or bulking agent, and (iv) one or more lyoprotectants. In various embodiments, the buffer is histidine, the organic co-solvent or bulking agent is PEG, and the lyoprotectant(s) is at least one of glycine and sucrose. In one embodiment, the pre-lyophilized formulation of the invention does not contain a preservative. In one embodiment of the pre-lyophilized formulation of the invention, the formulation comprises 5-50 mM histidine, 0.1-3.0% PEG, 0.25-3.0% glycine, 0.5-6.0% sucrose, and 5-75 mg/ml of the fusion protein, at a pH of about 6.0-6.5. In any embodiment, the pre-lyophilized formulation may further comprise up to 0.05 mM citrate and/or 0.003-0.005% polysorbate. The polysorbate present may be, for example, polysorbate 20. In a more specific embodiment, the pre-lyophilized formulation comprises about 10 mM histidine, about 1.5% PEG 3350, about 0.75% glycine, about 2.5% sucrose, and about 12.5 to 75 mg/ml VEGF-specific fusion protein, at a pH of about 6.25. In specific embodiments, the fusion protein comprises the protein sequence of SEQ ID NO:4, present as a multimer, e.g., a dimer. In separate embodiments, the reconstituted formulation is 2 times the concentration of the pre-lyophilized formulation, e.g., a 20 mg fusion protein/ml pre-lyophilized formulation is reconstituted to a final formulation of 60 mg fusion protein/mi. Generally, the lyophilized formulation is reconstituted with sterile water suitable for injection. In one embodiment, the reconstitution liquid may be bacteriostatic water. In a preferred embodiment, the pre-lyophilized formulation consists essentially of about 10 mM histidine, about 1.5% PEG 3350, about 0.75% glycine, about 2.5% sucrose, and about 50 mg/ml of the fusion protein having the sequence of SEQ ID NO:4 as a dimer, at a pH of about 6.25. Citrate (less than or equal to about 0.02 mM) and/or polysorbate (less than or equal to about 0.0005%) may be present. Optionally, the pre-lyophilized formulation does not contain a preservative, a phosphate buffer, and/or more than trace amounts of NaCl. In one embodiment, the pre-lyophilized formulation consists of about 10 mM histidine, about 1.5% PEG 3350, about 0.75% glycine, about 2.5% sucrose, and about 50 mg/ml of the VEGF trap protein (SEQ ID NO:4), pH 6.3, and upon reconstitution contains 20 mM histidine, 3% PEG, 1.5% glycine, about 5% sucrose, and about 100 mg/ml VEGF trap protein. In a fourth aspect, the invention features a method of producing a lyophilized formulation of a VEGF-specific fusion protein antagonist, comprising subjecting the pre-lyophilized formulation of the invention to lyophilization to generate a lyophilized formulation. The lyophilized formulation may be lyophilized by any method known in the art for lyophilizing a liquid. In a fifth related aspect, the invention features a method of producing a reconstituted lyophilized formulation of a VEGF-specific fusion protein antagonist, comprising reconstituting the lyophilized formulation of the invention to a reconstituted formulation. In one embodiment, the reconstituted formulation is twice the concentration of the pre-lyophilized formulation, e.g., the method of the invention comprises: (a) producing a pre-lyophilized formulation of a VEGF-specific fusion protein antagonist, (b) subjecting the pre-lyophilized formulation of step (a) to lyophilization; and (c) reconstituting the lyophilized formulation of step (b). In specific embodiments of the method of producing a reconstituted lyophilized formulation, a pre-lyophilized solution is present in a vial as a 25 mg VEGF-specific fusion protein antagonist per ml solution of pre-lyophilized formulation, which is lyophilized and reconstituted to an 50 mg/ml solution. In another embodiment, a 30 mg/ml pre-lyophilized solution is lyophilized and reconstituted to a 60 mg/ml solution. In another embodiment, a 40 mg/ml pre-lyophilized solution is lyophilized and reconstituted to a 80 mg/ml solution. In another embodiment, a 12.5 mg/ml pre-lyophilized solution is lyophilized and reconstituted to a 25 mg/ml solution. In another embodiment, a 50 mg/ml pre-lyophilized solution is lyophilized and reconstituted to a 100 mg/ml solution. In another embodiment, a 75 mg/ml pre-lyophilized solution is lyophilized and reconstituted to a 150 mg/ml solution. Preferably, the reconstituted lyophilized formulation does not contain a preservative. Other objects and advantages will become apparent from a review of the ensuing detailed description. detailed-description description="Detailed Description" end="lead"?
A61K3939591
20170831
20171221
66200.0
A61K39395
1
STOICA, ELLY GERALD
METHOD OF MANUFACTURING VEGF ANTAGONIST FUSION PROTEINS
UNDISCOUNTED
1
CONT-ACCEPTED
A61K
2,017
15,693,163
PENDING
SEEDING MACHINE WITH SEED DELIVERY SYSTEM
A seed delivery system for a seeding machine having a seed meter comprises a housing that defines an upper seed loading area and a lower seed discharge area. A drive pulley is mounted to rotate with respect to the housing. A belt is supported for rotation by the drive pulley within the housing. A loading wheel is mounted to rotate with respect to the housing to transfer seeds from the seed meter into the belt at the seed loading area. The belt conveys the seeds through the housing as the belt travels from the seed loading area to the seed discharge area.
1. A seed delivery system for a seeding machine having a seed meter, the system comprising: a housing defining an upper seed loading area and a lower seed discharge area; a drive pulley mounted to rotate with respect to the housing; a belt having a base supported for rotation by the drive pulley within the housing; and a loading wheel mounted to rotate with respect to the housing to transfer seeds from the seed meter into the belt at the seed loading area; wherein the belt conveys the seeds through the housing as the belt travels from the seed loading area to the seed discharge area. 2. The system of claim 1, wherein the seeds are singulated before the loading wheel transfers the seeds into the belt; and wherein the belt maintains the seeds in spaced relation in a belt travel direction as the seeds are conveyed by the belt through the housing to the seed discharge area 3. The system of claim 2, wherein the drive pulley drives the belt to discharge the seeds at a speed based on a travel speed of the seeding machine. 4. The system of claim 3, wherein at the seed discharge area the belt discharges the seeds to have a horizontal speed that is approximately the same as the travel speed of the seeding machine in a direction opposite a travel direction of the seeding machine. 5. The system of claim 1, wherein the belt has distal ends extending outward from the base; and wherein the distal ends are one of proximate and in contact with a side wall of the housing as the belt travels from the seed loading area to the seed discharge area. 6. The system of claim 5, wherein the housing side wall forms a lower opening and an exit ramp adjacent the lower opening; and wherein the housing includes an upper opening adjacent the seed loading area and the loading wheel. 7. The system of claim 1, wherein the seed meter is a disk having a plurality of apertures where the seeds are collected. 8. The system of claim 7, wherein the seeds adhere to the disk by air pressure differential at opposite sides of the disk. 9. The system of claim 8, wherein the seeds are removed from the disk during contact of the seeds by the loading wheel. 10. The system of claim 1, wherein the belt includes bristles. 11. A seed delivery system or a seeding machine having a seed meter disk, the system comprising: a housing defining an upper seed loading area and a lower seed discharge area; a drive pulley mounted to rotate with respect to the housing; a belt supported for rotation by the drive pulley within the housing; and a loading wheel mounted to rotate with respect to the housing to transfer seeds from the seed meter disk into the belt at the seed loading area, the seeds being removed from the disk during contact of the seeds by the loading wheel; wherein the belt conveys the seeds through the housing as the belt travels from the seed loading area to the seed discharge area. 12. The system of claim 11, wherein the seeds are singulated before the loading wheel transfers the seeds into the belt; and wherein the belt maintains the seeds in spaced relation in a belt travel direction as the seeds are conveyed by the belt through the housing to the seed discharge area. 13. The system of claim 12, wherein the drive pulley drives the belt to discharge the seeds at a speed based on a travel speed of the seeding machine. 14. The system of claim 13, wherein at the seed discharge area the belt discharges the seeds to have a horizontal speed that is approximately the same as the travel speed of the seeding machine in a direction opposite a travel direction of the seeding machine. 15. The system of claim 11, wherein the belt conveys the seeds through the housing within an area between a base of the belt and a housing side wall as the belt travels from the seed loading area to the seed discharge area. 16. The system of claim 15, wherein the belt has distal ends extending outward from the base; and wherein the distal ends are one of proximate and in contact with the housing side wall as the belt travels from the seed loading area to the seed discharge area. 17. The system of claim 16, wherein the seed meter disk has a plurality of apertures where the seeds are collected by air pressure differential at opposite sides of the seed meter disk. 18. A seed delivery system for a seeding machine having a seed meter disk, the system comprising: a housing defining an upper opening adjacent an upper seed loading area and a lower opening adjacent a lower seed discharge area; a drive pulley mounted to rotate with respect to the housing; a belt supported for rotation by the drive pulley within the housing; and a loading wheel mounted adjacent the upper opening and the belt to rotate with respect to the housing, the loading wheel removing singulated seeds from the seed meter disk during contact of the seeds by the loading wheel and transferring the seeds from the seed meter disk into the belt; wherein the belt maintains the seeds in spaced relation in a belt travel direction as the seeds are conveyed by the belt through the housing to the seed discharge area prior to the seeds being discharged through the lower opening. 19. The system of claim 18, wherein the seed meter disk has a plurality of apertures where the seeds are collected by air pressure differential at opposite sides of the seed meter disk. 20. The system of claim 18, wherein at the seed discharge area the belt discharges the seeds with a horizontal speed that is approximately the same as a travel speed of the seeding machine in a direction opposite a travel direction of the seeding machine.
CROSS-REFERENCE TO RELATED APPLICATIONS This application is a Continuation of U.S. patent application Ser. No. 14/616,877, filed Feb. 9, 2015, which is a Continuation of U.S. patent application Ser. No. 14/504,801, filed Oct. 2, 2014, now U.S. Pat. No. 9,686,905, which is a Continuation of U.S. patent application Ser. No. 12/364,010, filed Feb. 2, 2009, now U.S. Pat. No. 8,850,995. FIELD OF THE INVENTION The invention relates to a seeding machine having a seed metering system and a seed delivery system for delivering seed from the meter to the ground. BACKGROUND OF THE INVENTION An agricultural seeding machine such as a row crop planter or grain drill places seeds at a desired depth within a plurality of parallel seed trenches formed in soil. In the case of a row crop planter, a plurality of row crop units are typically ground driven using wheels, shafts, sprockets, transfer cases, chains and the like or powered by electric or hydraulic motors. Each row crop unit has a frame which is movably coupled with a tool bar. The frame may carry a main seed hopper, herbicide hopper and insecticide hopper. If a herbicide and insecticide are used, the metering mechanisms associated with dispensing the granular product into the seed trench are relatively simple. On the other hand, the mechanisms necessary to properly meter the seeds, and dispense the seeds at predetermined relative locations within the seed trench are relatively complicated. The mechanisms associated with metering and placing the seeds generally can be divided into a seed metering system and a seed placement system which are in series communication with each other. The seed metering system receives the seeds in a bulk manner from the seed hopper carried by the planter frame or by the row unit. Different types of seed metering systems may be used, such as seed plates, finger plates, seed disks, etc. In the case of a seed disk metering system a seed disk is formed with a plurality of seed cells spaced about the periphery of the disk. Seeds are moved into the seed cells with one or more seeds in each seed cell depending upon the size and configuration of the seed cell. A vacuum or positive air pressure differential may be used in conjunction with the seed disk to assist in movement of the seeds into the seed cell. The seeds are singulated and discharged at a predetermined rate to the seed placement or delivery system. The most common seed delivery system may be categorized as a gravity drop system. In the case of the gravity drop system, a seed tube has an inlet end which is positioned below the seed metering system. The singulated seeds from the seed metering system merely drop into the seed tube and fall via gravitational force from a discharge end thereof into the seed trench. The seed tube may have a rearward curvature to reduce bouncing of the seed as it strikes the bottom of the seed trench and to impart a horizontal velocity to the seed in order to reduce the relative velocity between the seed and the ground. Undesirable variation in resultant in-ground seed spacing can be attributed to differences in how individual seeds exit the metering system and drop through the seed tube. The spacing variation is exacerbated by higher travel speeds through the field which amplifies the dynamic field conditions. Further seed spacing variations are caused by the inherent relative velocity difference between the seeds and the soil as the seeding machine travels through a field. This relative velocity difference causes individual seeds to bounce and tumble in somewhat random patterns as each seed comes to rest in the trench. Various attempts have been made to reduce the variation in seed spacing resulting from the gravity drop. U.S. Pat. No. 6,681,706 shows two approaches. One approach uses a belt with flights to transport the seeds from the meter to the ground while the other approach uses two belts to grip the seed and transport it from the meter to the ground. While these approaches control the seed path and reduce variability due to dynamic events, neither approach seeks to deliver the seed with as small as possible horizontal velocity difference relative to the ground. U.S. Pat. Nos. 6,651,570, 7,185,596 and 7,343,868 show a seed delivery system using a brush wheel near the ground to regulate the horizontal velocity and direction of the seed as it exits the seeding machine. However, there is still a gravity drop between the seed meter and the brush wheel which produces variation in seed spacing. SUMMARY OF THE INVENTION A seed delivery system for a seeding machine having a seed meter comprises a housing that defines an upper seed loading area and a lower seed discharge area. A drive pulley is mounted to rotate with respect to the housing. A belt is supported for rotation by the drive pulley within the housing. A loading wheel is mounted to rotate with respect to the housing to transfer seeds from the seed meter into the belt at the seed loading area. The belt conveys the seeds through the housing as the belt travels from the seed loading area to the seed discharge area. A seed delivery system for a seeding machine having a seed meter disk comprises a housing that defines an upper seed loading area and a lower seed discharge area. A drive pulley is mounted to rotate with respect to the housing. A belt is supported for rotation by the drive pulley within the housing. A loading wheel is mounted to rotate with respect to the housing to transfer seeds from the seed meter disk into the belt at the seed loading area. The seeds are removed from the disk during contact of the seeds by the loading wheel. The belt conveys the seeds through the housing as the belt travels from the seed loading area to the seed discharge area. A seed delivery system for a seeding machine having a seed meter disk comprises a housing that defines an upper opening adjacent an upper seed loading area and a lower opening adjacent a lower seed discharge area. A drive pulley is mounted to rotate with respect to the housing. A belt is supported for rotation by the drive pulley within the housing. A loading wheel is mounted adjacent the upper opening and the belt to rotate with respect to the housing. The loading wheel removes singulated seeds from the seed meter disk during contact of the seeds by the loading wheel and transfers the seeds from the seed meter disk into the belt. The belt maintains the seeds in spaced relation in a belt travel direction as the seeds are conveyed by the belt through the housing to the seed discharge area prior to the seeds being discharged through the lower opening. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a plan view of a planter having the seed delivery system of the present invention; FIG. 2 is a side view of a row unit of the planter of FIG. 1; FIG. 3 is an enlarged side view of the seed delivery system of the present invention: FIG. 4 is a top view of a planter row unit showing the metering system orientation in one alternative arrangement of the metering system and delivery system of the present invention; FIG. 5 is a top view similar to FIG. 4 illustrating the delivery system with the meter housing removed; FIG. 6 is a side view of the row unit of FIG. 4; FIG. 7 is a perspective view of the seed disk used in the seed meter shown in FIGS. 4-6; FIG. 8 is a sectional view along the line 8-8 of FIG. 7 illustrating the orientation of the seed disk and brush or the seed delivery system of the present invention; FIG. 9 is a side view of a row unit showing the orientation of the delivery system of the present invention and a vacuum belt seed meter; FIG. 10 is a side view of another orientation of the seed delivery system of the invention with a vacuum belt seed meter; and FIG. 11 is a side view illustrating the orientation of the seed delivery system of the invention with a finger pick-up meter. DESCRIPTION OF THE PREFERRED EMBODIMENT With reference to FIG. 1 an example planter or seeding machine 10 is shown containing the seed delivery system of the present invention. Planter 10 includes a tool bar 12 as part of a planter frame 14. Mounted to the tool bar are multiple planting row units 16. Row units 16 are typically identical for a given planter but there may be differences. A row unit 16 is shown in greater detail in FIG. 2. The row unit 16 is provided with a central frame member 20 having a pair of upwardly extending arms 21 (FIG. 4) at the forward end thereof. The arms 21 connect to a parallelogram linkage 22 for mounting the row unit 16 to the tool bar 12 for up and down relative movement between the unit 16 and toolbar 12 in a known manner. Seed is stored in seed hopper 24 and provided to a seed meter 26. Seed meter 26 is of the type that uses a vacuum disk as are well known to meter the seed. Other types of meters can be used as well. From the seed meter 26 the seed is carried by a delivery system 28 into a planting furrow, or trench, formed in the soil by furrow openers 30. Gauge wheels 32 control the depth of the furrow. Closing wheels 34 close the furrow over the seed. The gauge wheels 32 are mounted to the frame member 20 by arms 36. The toolbar and row unit are designed to be moved over the ground in a forward working direction identified by the arrow 38. The row unit 16 further includes a chemical hopper 40, a row cleaner attachment 42 and a down force generator 44. The row unit 16 is shown as an example of the environment in which the delivery system of the present invention is used. The present invention can be used in any of a variety of planting machine types such as, but not limited to, row crop planters, grain drills, air seeders, etc. With reference to FIG. 3, the seed delivery system 28 is shown in greater detail. Delivery system 28 includes a housing 48 positioned adjacent the seed disk 50 of the seed meter. The seed disk 50 is a generally flat disk with a plurality of apertures 52 adjacent the periphery of the disk. Seeds 56 are collected on the apertures from a seed pool and adhere to the disk by air pressure differential on the opposite sides of the disk 50 in a known manner. The disk may have a flat surface at the apertures 52 or have seed cells surrounding the apertures 52. The disk rotates clockwise as viewed in FIG. 3 as shown by the arrow 54. At the top of FIG. 3, seeds 56 are shown adhered to the disk. The seed delivery system housing 48 has spaced apart front and rear walls 49 and 51 and a side wall 53 therebetween. An upper opening 58 in the housing side wall 53 admits the seed from the metering disk 50 into the housing. A pair of pulleys 60, 62 are mounted inside the housing 48. The pulleys support a belt 64 for rotation within the housing. One of the pulleys is a drive pulley while the other is an idler pulley. The belt has a base member 66 to engage the pulleys and elongated bristles 70 extending therefrom, The bristles are joined to the base member at proximal, or radially inner, ends of the bristles. Distal, or radially outer, ends 74 of the bristles touch, or are close to touching, the inner surface 76 of the housing side wall 53. A lower housing opening 78 is formed in the side wall 53 and is positioned as close to the bottom 80 of the seed trench as possible. As shown, the lower opening 78 is near or below the soil surface 82 adjacent the trench. The housing side wall forms an exit ramp 84 at the lower opening 78. Returning attention to the upper portion of FIG. 3, a loading wheel 86 is provided adjacent the upper opening 58. The loading wheel is positioned on the opposite side of the seeds 56 from the brush 64 such that the path of the seeds on the disk brings the seeds into a nip 88 formed between the loading wheel and the distal ends 74 of the bristles 70. At the location of the nip 88, the air pressure differential across the seed disk 50 is terminated, freeing the seed from the apertures 52 in the disk. The bottom surface of the loading wheel, facing the seed disk 50, has recesses 90 formed therein. The recesses 90 receive seed agitators 92 projecting from the seed disk 50. The moving agitators, by engagement with the recesses in the loading wheel, drive the loading wheel in a clockwise rotation. In operation, the belt 64 is rotated in a counterclockwise direction. As the belt curves around the pulleys, the bristles will naturally open, that is, separate from one another as the distal ends of the bristles travel a larger circumferential distance around the pulleys than the inner ends of the bristle at the belt base member. This produces two beneficial effects as described below. The seeds are transferred from the seed meter to the delivery system as the seeds are brought by the disk into the nip 88. There the seeds are pinched off the seed disk between the loading wheel and the bristles 70 to remove the seed from the seed disk and seed meter. The seeds are captured or entrapped in the bristles by insertion of the seed into the bristles in a radial direction, that is from the ends of the bristles in a direction parallel to the bristle length. This occurs just as the belt path around the pulley 60 ends, when the bristle ends are closing back together upon themselves, allowing the bristles to close upon, and capture the seeds therein. As the belt continues to move, the bristles move or convey the seeds downward to the housing lower opening. The side wall 53 of the housing cooperates with the bristles 70 to hold the seed in the brush bristles as the seed is moved to the lower opening. The lower opening 78 and the ramp 84 are positioned along the curved belt path around the pulley 62. The bristle distal ends thus cause the linear speed of the seeds to accelerate relative to the speed of the belt base member 66 and the housing as shown by the two arrows 94 and 96. The seeds are then propelled by the bristles over the ramp 84 and discharged through the lower opening 78 into the seed trench. The angle of the ramp 84 can be selected to produce the desired relationship between the seed vertical and horizontal speeds at discharge. The forward travel direction of the row unit is to the left in FIG. 3 as shown by the arrow 38. At the discharge, the horizontal speed of the seed relative to the ground is minimized to reduce roll of the seed in the trench. The belt shown in FIG. 3 has relatively long bristles. As a result of the long bristles and the seed loading point being at the end of the curved path of the brush around the pulley 60 results in the seeds being loaded into the belt while the bristles have slowed down in speed. The bristle speed at loading is thus slower than the bristle speed at the discharge opening as the belt travels around the pulley 62. This allows in the seed to be loaded into the belt at a relatively lower speed while the seed is discharged at the lower end at a desired higher speed. As described above, it is preferred that the horizontal velocity of the seed at the discharge be equal to the forward travel speed of the planter but in the rearward direction such that the horizontal velocity of the seed relative to the ground is close to or equal to zero. The long bristles can be used to increase the speed of the seed as it travels around the pulley. However, a short bristle brush can be used as well. With a short bristle brush, there will be little acceleration in the speed of the seed as the seed travels around the pulleys. The belt will have to be driven at a speed to produce the desired horizontal velocity of the seed at the discharge. Even with a short bristle brush, the seed is still accelerated in the horizontal direction. As the belt travels around the pulley, the direction of travel of the seed changes from the predominantly vertical direction, when the seed is moved downward from the seed meter, to a predominantly horizontal direction at the discharge. This produces an acceleration of the seed velocity in the horizontal direction. With the delivery system 28, the seed is captured by the delivery system to remove the seed from the seed meter. The seed is then moved by the delivery system to the seed discharge point where the seed is accelerated in a rearward horizontal direction relative to the housing. From the seed meter to the discharge, the seed travel is controlled by the delivery system, thus maintaining the seed spacing relative to one another. In the embodiment shown in FIG. 3, the seed disk and the front and rear walls 49, 51 of the housing 48 lie in planes that are generally parallel one another. As shown, the plane of the delivery system is generally parallel to the direction of travel of the row unit. Other relationships between the seed meter and delivery system are shown and described below. As shown in FIG. 3, the side wall 53 is divided by the upper and lower openings 58, 78 into two segments, 53a and 53b. Segment 53a is between the upper and lower openings in the direction of belt travel while the segment 53b is between the lower and upper openings in the direction of belt travel. It is the gaps in the side wall 53 that form the upper and lower openings. It should be understood, however, that the delivery system will function without the segment 53b of the side wall. It is only the segment 53a that functions together with the belt bristles to deliver the seed from the meter to the seed trench. Thus, the term “upper opening” shall be construed to mean an open area before the side wall segment 53a in the direction of belt travel and the term “lower opening” shall mean an open area after the side wall segment 53a in the direction of belt travel. With reference to FIGS. 4-7, the delivery system 28 is shown in combination with the seed meter and row unit structure in an alternative arrangement of the seed meter and delivery system 28. The seed meter 200 is shown mounted to the row unit with the seed disk 202 in a vertical orientation but at an angle to the forward travel direction shown by the arrow 38. FIG. 4 shows of the seed meter orientation in the row unit without the delivery system 28. The seed meter includes a housing having two halves 204 and 206 releasable joined together in a known manner. The seed meter is driven through a transmission 208 coupled to a drive cable, not shown. In FIG. 5 only the seed disk 202 of the meter is shown with the seed delivery system 28. As previously mentioned, the seed disk 202 is in a vertical orientation but it does not lie in a plane parallel to the forward direction 38. Instead, the meter is oriented such that the disk is at a 60° angle relative to the forward direction when viewed from above. The seed of delivery system 28 is generally identical to that shown in FIG. 3 and is driven by a motor 65. The delivery system, including of the brush belt 64, is generally vertical and aligned with the fore and aft direction of the planter such that the angle between the brush and the seed disk is approximately 60°. The angle between the delivery system and a seed disk produces a partial “cross feed” of the seed into the brush. That is, the seed is fed into the brush at an angle to the lengthwise direction of the bristles. This is in contrast to FIG. 3 where the seed enters the brush in a direction substantially parallel to the lengthwise direction of the brush bristles. If the brush and seed disk were oriented at 90° to one another, a total cross feed would be produced with seed entering the brush perpendicular to the bristles. The seed disk 202 is shown enlarged in FIGS. 7 and 8. The disk 202 has opposite sides, a vacuum side 216 and seed side 218. The seed side 218 has a surface 219 near the periphery that defines a reference plane. The reference plane will be used to describe the features of the disk near the disk periphery. An outer peripheral lip 220 is recessed from the reference plane. The peripheral lip 220 creates a radially outward edge face 222. A circumferential row of spaced apart apertures 224 is arranged around a circular path radially inward of the edge face 222. Each aperture extends through the disk between the vacuum side 216 and the seed side 218. Radially inward of each aperture 224, there is a radially elongated recess 226. The recess 226 is recessed axially into the disk from the reference plane. In operation, the disk rotates in a counterclockwise direction as indicated by the arrow 228. During rotation, the recesses 226 agitate the seed in the seed pool. Surrounding each aperture 224 is a tapered recess, or shallow seed cell, 232 that extends axially into the disk from the reference plane. Seed cell 232 begins at a leading edge 234 in the direction of rotation of the disk and is progressively deeper into the seed side 218 to a trailing edge formed by an axially projecting wall 236. The tapered recess or seed cell 232 reduces the vacuum needed to pick-up and retain seed in the apertures 224. The seed cell also enables the seed to sit lower relative to the seed side 218 of the disk, allowing the seed to be retained while the seed singulator removes doubles or multiples of seed from the apertures 224. In addition, the recess wall 236 agitates seed in the seed pool, further aiding in seed pick-up. The wall 236 extends lengthwise in a predominately radial direction as shown by the dashed line 238. The walls 236, while predominately radial, are inclined to the radial direction such that the inner end of the wall 236 is leading the outer end of the wall in the direction of rotation. Immediately following each wall 236, as the disk rotates, is a projection, or upstanding peg 240 extending axially from the disk seed side. The pegs engage seed in the seed pool for agitation to aide in seed pick-up. The pegs 240 are located slightly radially inward of the circular path of apertures 224 to avoid interference with the seed singulator. With reference to FIG. 8, the disk 202 is shown in operation and in position relative to the belt 64 in the delivery system 28. As seeds 244 are carried by the disk 202 into the bristles of the brush 64, the wall 236 and the pegs 240 act to push the seed 244 into the bristles of the brush 64 and assist in keeping the seed from being knocked off the disk upon the seed's initial contact with the brush bristles. Once the seed is inserted into the brush bristles, the vacuum from the opposite side of the disk is cut-off, allowing the brush to sweep the seed off the disk in a predominately radial direction relative to the disk. An insert 246 overlies the lip 220 at the point of seed release to hold the seed in the brush bristles in the transition between the disk and the side wall 53 (FIG. 3) of the delivery system housing. The disk 202 is inclined to the length of the brush bristles at approximately a 60 degree angle. This produces the partial cross-feed of the seed into the brush bristles. FIG. 9 shows the brush belt seed delivery system 28 in combination with a vacuum belt metering system having a metering belt 302. The vacuum belt meter is fully described in co-pending U.S. patent application Ser. No. 12/363,968, filed Feb. 2, 2009, now U.S. Pat. No. 7,918,168, incorporated herein by reference. The belt 302 picks-up seed at a pick-up region 304 at a lower, front location of the belt's path and transports it to the delivery system at a release region 306 at an upper, rear location of the belt's path. In this arrangement of the belt meter and the brush delivery system, the delivery system is again partially cross fed with seeds from the meter. Another arrangement of the delivery system together with a vacuum meter belt is shown in FIG. 10. The delivery system 28 is in-line with the belt meter 124. This allows the distal ends of the brush bristles to sweep over the surface of the metering belt 126 to capture the seed therefrom. The meter belt 126 is wrapped around pulleys 128. The metering belt 124 is similar and functions as the belt 302 mentioned above. The delivery system of the present invention can also be used with seed meters other than air pressure differential meters. For example, with reference to FIG. 11, a finger pick-up meter 130 is shown, such as that described in U.S. Pat. No. 3,552,601 and incorporated herein by reference. Seed is ejected from the meter through an opening 132. The delivery system 134 has a brush belt 136 wrapped about pulleys 138 and 140. As shown, the belt pulley 138 shares a common drive shaft with finger pick-up meter 130. A hub transmission such as a spherical continuously variable transmission or a three speed hub can be used to drive the belt 136 at a different speed from the meter 130. The delivery system housing includes a side wall 142. A ramp 146 is formed at the lower end of the wall 142 adjacent the lower opening 148. At the upper end of the delivery system, the upper opening is formed in the housing rear wall adjacent the opening 132 through which seeds are ejected from the seed meter. The seeds are inserted laterally into the brush bristles in a complete cross-feed. As in the other embodiments, the seed is captured in the brush bristles, moved downward to the lower opening, accelerated rearward and discharged through the lower opening 148. The endless member of the delivery system has been described as being a brush belt with bristles. In a broad sense, the bristles form an outer periphery of contiguous disjoint surfaces that engage and grip the seed. While brush bristles are the preferred embodiment, and may be natural or synthetic, other material types can be used to grip the seed such as a foam pad, expanded foam pad, mesh pad or fiber pad. Having described the preferred embodiment, it will become apparent that various modifications can be made without departing from the scope of the invention as defined in the accompanying claims.
<SOH> BACKGROUND OF THE INVENTION <EOH>An agricultural seeding machine such as a row crop planter or grain drill places seeds at a desired depth within a plurality of parallel seed trenches formed in soil. In the case of a row crop planter, a plurality of row crop units are typically ground driven using wheels, shafts, sprockets, transfer cases, chains and the like or powered by electric or hydraulic motors. Each row crop unit has a frame which is movably coupled with a tool bar. The frame may carry a main seed hopper, herbicide hopper and insecticide hopper. If a herbicide and insecticide are used, the metering mechanisms associated with dispensing the granular product into the seed trench are relatively simple. On the other hand, the mechanisms necessary to properly meter the seeds, and dispense the seeds at predetermined relative locations within the seed trench are relatively complicated. The mechanisms associated with metering and placing the seeds generally can be divided into a seed metering system and a seed placement system which are in series communication with each other. The seed metering system receives the seeds in a bulk manner from the seed hopper carried by the planter frame or by the row unit. Different types of seed metering systems may be used, such as seed plates, finger plates, seed disks, etc. In the case of a seed disk metering system a seed disk is formed with a plurality of seed cells spaced about the periphery of the disk. Seeds are moved into the seed cells with one or more seeds in each seed cell depending upon the size and configuration of the seed cell. A vacuum or positive air pressure differential may be used in conjunction with the seed disk to assist in movement of the seeds into the seed cell. The seeds are singulated and discharged at a predetermined rate to the seed placement or delivery system. The most common seed delivery system may be categorized as a gravity drop system. In the case of the gravity drop system, a seed tube has an inlet end which is positioned below the seed metering system. The singulated seeds from the seed metering system merely drop into the seed tube and fall via gravitational force from a discharge end thereof into the seed trench. The seed tube may have a rearward curvature to reduce bouncing of the seed as it strikes the bottom of the seed trench and to impart a horizontal velocity to the seed in order to reduce the relative velocity between the seed and the ground. Undesirable variation in resultant in-ground seed spacing can be attributed to differences in how individual seeds exit the metering system and drop through the seed tube. The spacing variation is exacerbated by higher travel speeds through the field which amplifies the dynamic field conditions. Further seed spacing variations are caused by the inherent relative velocity difference between the seeds and the soil as the seeding machine travels through a field. This relative velocity difference causes individual seeds to bounce and tumble in somewhat random patterns as each seed comes to rest in the trench. Various attempts have been made to reduce the variation in seed spacing resulting from the gravity drop. U.S. Pat. No. 6,681,706 shows two approaches. One approach uses a belt with flights to transport the seeds from the meter to the ground while the other approach uses two belts to grip the seed and transport it from the meter to the ground. While these approaches control the seed path and reduce variability due to dynamic events, neither approach seeks to deliver the seed with as small as possible horizontal velocity difference relative to the ground. U.S. Pat. Nos. 6,651,570, 7,185,596 and 7,343,868 show a seed delivery system using a brush wheel near the ground to regulate the horizontal velocity and direction of the seed as it exits the seeding machine. However, there is still a gravity drop between the seed meter and the brush wheel which produces variation in seed spacing.
<SOH> SUMMARY OF THE INVENTION <EOH>A seed delivery system for a seeding machine having a seed meter comprises a housing that defines an upper seed loading area and a lower seed discharge area. A drive pulley is mounted to rotate with respect to the housing. A belt is supported for rotation by the drive pulley within the housing. A loading wheel is mounted to rotate with respect to the housing to transfer seeds from the seed meter into the belt at the seed loading area. The belt conveys the seeds through the housing as the belt travels from the seed loading area to the seed discharge area. A seed delivery system for a seeding machine having a seed meter disk comprises a housing that defines an upper seed loading area and a lower seed discharge area. A drive pulley is mounted to rotate with respect to the housing. A belt is supported for rotation by the drive pulley within the housing. A loading wheel is mounted to rotate with respect to the housing to transfer seeds from the seed meter disk into the belt at the seed loading area. The seeds are removed from the disk during contact of the seeds by the loading wheel. The belt conveys the seeds through the housing as the belt travels from the seed loading area to the seed discharge area. A seed delivery system for a seeding machine having a seed meter disk comprises a housing that defines an upper opening adjacent an upper seed loading area and a lower opening adjacent a lower seed discharge area. A drive pulley is mounted to rotate with respect to the housing. A belt is supported for rotation by the drive pulley within the housing. A loading wheel is mounted adjacent the upper opening and the belt to rotate with respect to the housing. The loading wheel removes singulated seeds from the seed meter disk during contact of the seeds by the loading wheel and transfers the seeds from the seed meter disk into the belt. The belt maintains the seeds in spaced relation in a belt travel direction as the seeds are conveyed by the belt through the housing to the seed discharge area prior to the seeds being discharged through the lower opening.
A01C716
20170831
20171221
99684.0
A01C716
2
NOVOSAD, CHRISTOPHER J
SEEDING MACHINE WITH SEED DELIVERY SYSTEM
UNDISCOUNTED
1
CONT-ACCEPTED
A01C
2,017
15,693,418
PENDING
OPTICAL IMAGING SYSTEM
An optical imaging system includes, in order from an object side to an image side, a first lens element with positive refractive power, a second lens element, a third lens element, a fourth lens element, and a fifth lens element. Each of the fourth lens element and the fifth lens element includes at least one aspheric surface. The fourth lens element and the fifth lens element are made of plastic. The fifth lens element includes a concave image-side surface and at least one inflection point. An axial distance is formed between each of the first lens element, the second lens element, the third lens element, the fourth lens element, and the fifth lens element, and the optical imaging system further comprises a stop.
1. An optical imaging system comprising five lens elements, the five lens elements being, in order from an object side to an image side: a first lens element; a second lens element having an object-side surface being convex in a paraxial region thereof; a third lens element with negative refractive power having an image-side surface being concave in a paraxial region thereof; a fourth lens element having positive refractive power; and a fifth lens element with negative refractive power having an object-side surface being concave in a paraxial region thereof and an image-side surface being concave in a paraxial region thereof, wherein the image-side surface of the fifth lens element is aspheric, and the image-side surface of the fifth lens element has at least one inflection point; wherein an Abbe number of the first lens element is V1, an Abbe number of the third lens element is V3, a radius of curvature of the image-side surface of the fifth lens element is R10, a focal length of the optical imaging system is f, and the following conditions are satisfied: 29<V1−V3<45; and 0.1<R10/f<0.5. 2. The optical imaging system according to claim 1, wherein the third lens element has an object-side surface being convex in a paraxial region thereof. 3. The optical imaging system according to claim 1, wherein an axial thickness of the third lens element is CT3, an axial thickness of the fourth lens element is CT4, and the following condition is satisfied: 2<CT3/CT4<0.55. 4. The optical imaging system according to claim 1, wherein an axial distance from an object-side surface of the first lens element to the image-side surface of the fifth lens element is Td, and the following condition is satisfied: 2.00 [mm]<Td<3.00 [mm]. 5. The optical imaging system according to claim 1, further comprising an aperture stop disposed between an imaged object and the third lens element, wherein each of the five lens elements is made of plastic, and an air gap is formed on an optical axis between every two lens elements adjacent to each other among the first lens element, the second lens element, the third lens element, the fourth lens element, and the fifth lens element. 6. The optical imaging system according to claim 1, wherein an axial thickness of the fourth lens element is larger than an axial thickness of the first lens element. 7. The optical imaging system according to claim 1, wherein an absolute value of a radius of curvature of an object-side surface of the first lens element is larger than an absolute value of a radius of curvature of the image-side surface of the third lens element. 8. An optical imaging system comprising five lens elements, the five lens elements being, in order from an object side to an image side: a first lens element; a second lens element; a third lens element with negative refractive power having an image-side surface being concave in a paraxial region thereof; a fourth lens element having positive refractive power; and a fifth lens element with negative refractive power having an image-side surface being concave in a paraxial region thereof, wherein the image-side surface of the fifth lens element is aspheric, and the image-side surface of the fifth lens element has at least one inflection point; wherein the optical imaging system further comprises an aperture stop disposed between the first lens element and the second lens element, an Abbe number of the first lens element is V1, an Abbe number of the third lens element is V3, a radius of curvature of the image-side surface of the fifth lens element is R10, a focal length of the optical imaging system is f, and the following conditions are satisfied: 29<V1−V3<45; and 0.1<R10/f<0.5. 9. The optical imaging system according to claim 8, wherein the second lens element has positive refractive power. 10. The optical imaging system according to claim 8, wherein the second lens element has an image-side surface being convex in a paraxial region thereof. 11. The optical imaging system according to claim 8, wherein the third lens element has an object-side surface being convex in a paraxial region thereof. 12. The optical imaging system according to claim 8, wherein an axial distance from the aperture stop to an image plane is SL, an axial distance from an object-side surface of the first lens element to the image plane is TTL, and the following condition is satisfied: 0.84≦SL/TTL<0.90. 13. The optical imaging system according to claim 8, wherein a focal length of the first lens element and a focal length of the second lens element have opposite signs. 14. The optical imaging system according to claim 8, wherein an absolute value of a focal length of the third lens element is larger than an absolute value of a focal length of the fifth lens element. 15. The optical imaging system according to claim 8, wherein an absolute value of a radius of curvature of an object-side surface of the first lens element is larger than an absolute value of a radius of curvature of the image-side surface of the third lens element. 16. An optical imaging system comprising five lens elements, the five lens elements being, in order from an object side to an image side: a first lens element; a second lens element having an image-side surface being convex in a paraxial region thereof; a third lens element with negative refractive power having an object-side surface being convex in a paraxial region thereof and an image-side surface being concave in a paraxial region thereof; a fourth lens element having positive refractive power; and a fifth lens element with negative refractive power having an image-side surface being concave in a paraxial region thereof, wherein the image-side surface of the fifth lens element is aspheric, and the image-side surface of the fifth lens element has at least one inflection point; wherein an Abbe number of the first lens element is V1, an Abbe number of the third lens element is V3, and the following condition is satisfied: 29<V1−V3<45. 17. The optical imaging system according to claim 16, wherein the fourth lens element has an image-side surface being convex in a paraxial region thereof. 18. The optical imaging system according to claim 16, further comprising an aperture stop disposed between the first lens element and the second lens element, wherein an air gap is formed on an optical axis between every two lens elements adjacent to each other among the first lens element, the second lens element, the third lens element, the fourth lens element, and the fifth lens element. 19. The optical imaging system according to claim 16, wherein a radius of curvature of the image-side surface of the fifth lens element is R10, a focal length of the optical imaging system is f, and the following condition is satisfied: 0.1<R10/f<0.5. 20. The optical imaging system according to claim 16, wherein the first lens element has an image-side surface being convex in a paraxial region thereof. 21. The optical imaging system according to claim 16, wherein an absolute value of a focal length of the third lens element is larger than an absolute value of a focal length of the fifth lens element. 22. The optical imaging system according to claim 16, wherein an axial distance between the third lens element and the fourth lens element is larger than an axial distance between the first lens element and the second lens element. 23. The optical imaging system according to claim 16, wherein an absolute value of a focal length of the first lens element is larger than an absolute value of a focal length of the third lens element. 24. The optical imaging system according to claim 16, wherein an absolute value of a focal length of the first lens element is larger than an absolute value of a focal length of the fifth lens element.
CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation application of U.S. patent application Ser. No. 15/468,079 filed Mar. 23, 2017, entitled “OPTICAL IMAGING SYSTEM”, by Chun-Shan CHEN, Tsung-Han TSAI and Hsin-Hsuan HUANG, which is a continuation application of U.S. patent application Ser. No. 14/746,475, filed Jun. 22, 2015, entitled “OPTICAL IMAGING SYSTEM”, by Chun-Shan CHEN, Tsung-Han TSAI and Hsin-Hsuan HUANG, which is a continuation application of U.S. patent application Ser. No. 14/096,750, filed Dec. 4, 2013, entitled “OPTICAL IMAGING SYSTEM”, by Chun-Shan CHEN, Tsung-Han TSAI and Hsin-Hsuan HUANG, which is a continuation application of U.S. patent application Ser. No. 13/091,817, filed Apr. 21, 2011, entitled “OPTICAL IMAGING SYSTEM”, by Chun-Shan CHEN, Tsung-Han TSAI and Hsin-Hsuan HUANG, which claims priority under 35 U.S.C. §119(a) on patent application Ser. No(s). 09/914,0051 filed in Taiwan, R.O.C. on Nov. 19, 2010, all of which are hereby incorporated herein in its entirety by reference. BACKGROUND OF THE INVENTION Field of Invention The present invention relates to an optical imaging system, and more particularly to an optical imaging system having multiple lens elements. Related Prior Art In recent years, with the rise of mobile electronics featuring camera functionalities, the demand for miniaturized camera lenses is boosted exponentially. Photo-sensing device (sensor) of ordinary photographing camera is commonly selected from charge coupled device (CCD) or complementary metal-oxide semiconductor (CMOS). In addition, as advanced semiconductor manufacturing technology enables the minimization of pixel size of sensors, the development of the miniaturized camera lenses is also heading toward the high pixel domain. Therefore, the standards for the imaging quality are rapidly raised. U.S. Pat. No. 7,365,920 provides a miniature camera unit with a four-element lens assembly. The lens elements of the miniaturized camera are utilized in various portable electronics. However, due to the popularity of the mobile electronics such as smart phones and personal digital assistants (PDAs), the standards for the resolution and the imaging quality of the miniature camera lens assemblies have been raised, accordingly. The conventional four-element lens assembly cannot meet the requirement of the higher order camera lens module. Besides, the electronic products are continuously developed towards the trend of lightweight and high performance. Therefore, an optical imaging system capable of improving the imaging quality of mobile electronics as well as minimizing the overall size of the camera lens assembly equipped therewith is urgently needed. SUMMARY OF THE INVENTION In response to the trend of development of miniature electronics and to solve the aforementioned problems, the present invention provides an optical imaging system designed for compact portable electronics and capable of improving the imaging quality of the optical imaging system. According to an embodiment of the present invention, an optical imaging system comprises, in order from an object side to an image side, a first lens element with positive refractive power comprises an object-side surface, a second lens element, a third lens element, a fourth lens element, and a fifth lens element. The fourth lens element comprises an object-side surface and an image-side surface, at least one of the object-side surface and the image-side surface of the fourth lens element is aspheric, and the fourth lens element is made of plastic. The fifth lens element comprises an object-side and a concave image-side surface, the image-side surface of the fifth lens element comprises at least one inflection point, and at least one of the object-side surface and the image-side surface of the fifth lens element is aspheric, and the fifth lens element is made of plastic. An axial distance is formed between each of the first lens element, the second lens element, the third lens element, the fourth lens element, and the fifth lens element, and the optical imaging system further comprises a stop, Td is an axial distance from the object-side surface of the first lens element to the image-side surface of the fifth lens element, SL is an axial distance from the stop to an image plane, TTL is an axial distance from the object-side surface of the first lens element to the image plane, and the optical imaging system satisfies the following conditions: 2.00 mm<Td<3.00 mm (Condition 1): 0.65<SL/TTL<1.10 (Condition 2): According to another embodiment of the present invention, an optical imaging system comprises, in order from an object side to an image side, a first lens element comprising an object-side surface, a second lens element having positive refractive power, a third lens element, a fourth lens element, and a fifth lens element. The fourth lens element comprises an object-side surface and an image-side surface, at least one of the object-side surface and the image-side surface of the fourth lens element is aspheric, and the fourth lens element is made of plastic. The fifth lens element comprises an object-side and a concave image-side surface, the image-side surface of the fifth lens element comprises at least one inflection point, and at least one of the object-side surface and the image-side surface of the fifth lens element is aspheric, and the fifth lens element is made of plastic, and the fifth lens element is made of plastic. The optical imaging system further comprises a stop, Td is an axial distance from the object-side surface of the first lens element to the image-side surface of the fifth lens element, SL is an axial distance from the stop to an image plane, TTL is an axial distance from the object-side surface of the first lens element to the image plane, and the optical imaging system satisfies the following conditions: 2.00 mm<Td<3.00 mm (Condition 1): 0.65<SL/TTL<1.10 (Condition 2): According to another embodiment of the present invention, an optical imaging system comprises, in order from an object side to an image side, a first lens element having positive refractive power, a second lens element, a third lens element, a fourth lens element, and a fifth lens element. The first lens element comprises an object-side surface and an image-side surface, at least one of the object-side surface and the image-side surface of the first lens element is aspheric. The second lens element comprises an object-side surface and an image-side surface, at least one of the object-side surface and the image-side surface of the second lens element is aspheric. The third lens element comprises an object-side surface and an image-side surface, at least one of the object-side surface and the image-side surface of the third lens element is aspheric. The fourth lens element comprises an object-side surface and an image-side surface, at least one of the object-side surface and the image-side surface of the fourth lens element is aspheric, and the fourth lens element is made of plastic. The fifth lens element comprises an object-side and a concave image-side surface, the image-side surface of the fifth lens element comprises at least one inflection point, and at least one of the object-side surface and the image-side surface of the fifth lens element is aspheric, and the fifth lens element is made of plastic, and the fifth lens element is made of plastic. An axial distance is formed between each of the first lens element, the second lens element, the third lens element, the fourth lens element, and the fifth lens element, and the optical imaging system further comprises a stop, Td is an axial distance from the object-side surface of the first lens element to the image-side surface of the fifth lens element, SL is an axial distance from the stop to an image plane, TTL is an axial distance from the object-side surface of the first lens element to the image plane, and the optical imaging system satisfies the following conditions: 0.65<SL/TTL<1.10 (Condition 2): Td<3.00 mm (Condition 3): According to another embodiment of the present invention, an optical imaging system comprises, in order from an object side to an image side, a first lens element, a second lens element having positive refractive power, a third lens element, a fourth lens element, and a fifth lens element. The first lens element comprises an object-side surface and an image-side surface, at least one of the object-side surface and the image-side surface of the first lens element is aspheric. The second lens element comprises an object-side surface and an image-side surface, at least one of the object-side surface and the image-side surface of the second lens element is aspheric. The third lens element comprises an object-side surface and an image-side surface, at least one of the object-side surface and the image-side surface of the third lens element is aspheric. The fourth lens element comprises an object-side surface and an image-side surface, at least one of the object-side surface and the image-side surface of the fourth lens element is aspheric, and the fourth lens element is made of plastic. The fifth lens element comprises an object-side and an image-side surface. The image-side surface of the fifth lens element comprises at least one inflection point, and at least one of the object-side surface and the image-side surface of the fifth lens element is aspheric, and the fifth lens element is made of plastic The optical imaging system further comprises a stop, Td is an axial distance from the object-side surface of the first lens element to the image-side surface of the fifth lens element, SL is an axial distance from the stop to an image plane, TTL is an axial distance from the object-side surface of the first lens element to the image plane, and the optical imaging system satisfies the following conditions: 0.65<SL/TTL<1.10 (Condition 2): Td<3.00 mm (Condition 3): When the optical imaging system satisfies Condition 1 or Condition 3 can miniaturize the optical imaging system. Therefore, the optical imaging system is suitable for lightweight, slim, and portable electronics. When the result of SL/TTL is close to 1.10, an exit pupil of the optical imaging system is away from the image plane. The angle of incidence with incoming light projecting onto the sensor would be close to perpendicular and a telecentric characteristic of the image-side would be more pronounced. Therefore, when an electronic sensor is disposed on the image plane, the photo-sensing capability of the electronic sensor is improved and the shading occurrences will be minimized. Having SL/TTL close to 0.65 can widen the view angle and can correct both distortion and chromatic aberration of magnification. In addition, the sensitivity of the optical imaging system is effectively reduced. BRIEF DESCRIPTION OF THE DRAWINGS The present invention will become more fully understood from the following detailed description when taken in connection with the accompanying drawings, which show, for the purpose of illustrations only, and thus do not limit other possible applications derived from the spirit of the present invention, and wherein: FIG. 1A is a schematic structural view of a first embodiment of an optical imaging system according to the present invention; FIG. 1B is a schematic view of longitudinal spherical aberration curves when the lights having wavelengths of 486.1 nm, 587.6 nm, and 656.3 nm are respectively projected in the optical imaging system in FIG. 1A; FIG. 1C is a schematic view of astigmatic field curves when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 1A; FIG. 1D is a schematic view of a distortion curve when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 1A; FIG. 2A is a schematic structural view of a second embodiment of the optical imaging system according to the present invention; FIG. 2B is a schematic view of longitudinal spherical aberration curves when the lights having wavelengths of 486.1 nm, 587.6 nm, and 656.3 nm are respectively projected in the optical imaging system in FIG. 2A; FIG. 2C is a schematic view of astigmatic field curves when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 2A; FIG. 2D is a schematic view of a distortion curve when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 2A; FIG. 3A is a schematic structural view of a third embodiment of the optical imaging system according to the present invention; FIG. 3B is a schematic view of longitudinal spherical aberration curves when the lights having wavelengths of 486.1 nm, 587.6 nm, and 656.3 nm are respectively projected in the optical imaging system in FIG. 3A; FIG. 3C is a schematic view of astigmatic field curves when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 3A; FIG. 3D is a schematic view of a distortion curve when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 3A; FIG. 4A is a schematic structural view of a fourth embodiment of the optical imaging system according to the present invention; FIG. 4B is a schematic view of longitudinal spherical aberration curves when the lights having wavelengths of 486.1 nm, 587.6 nm, and 656.3 nm are respectively projected in the optical imaging system in FIG. 4A; FIG. 4C is a schematic view of astigmatic field curves when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 4A; FIG. 4D is a schematic view of a distortion curve when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 4A; FIG. 5A is a schematic structural view of a fifth embodiment of the optical imaging system according to the present invention; FIG. 5B is a schematic view of longitudinal spherical aberration curves when the lights having wavelengths of 486.1 nm, 587.6 nm, and 656.3 nm are respectively projected in the optical imaging system in FIG. 5A; FIG. 5C is a schematic view of astigmatic field curves when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 5A; FIG. 5D is a schematic view of a distortion curve when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 5A; FIG. 6A is a schematic structural view of a sixth embodiment of the optical imaging system according to the present invention; FIG. 6B is a schematic view of longitudinal spherical aberration curves when the lights having wavelengths of 486.1 nm, 587.6 nm, and 656.3 nm are respectively projected in the optical imaging system in FIG. 6A; FIG. 6C is a schematic view of astigmatic field curves when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 6A; FIG. 6D is a schematic view of a distortion curve when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 6A; FIG. 7A is a schematic structural view of a seventh embodiment of the optical imaging system according to the present invention; FIG. 7B is a schematic view of longitudinal spherical aberration curves when the lights having wavelengths of 486.1 nm, 587.6 nm, and 656.3 nm are respectively projected in the optical imaging system in FIG. 7A; FIG. 7C is a schematic view of astigmatic field curves when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 7A; FIG. 7D is a schematic view of a distortion curve when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 7A; FIG. 8A is a schematic structural view of an eighth embodiment of the optical imaging system according to the present invention; FIG. 8B is a schematic view of longitudinal spherical aberration curves when the lights having wavelengths of 486.1 nm, 587.6 nm, and 656.3 nm are respectively projected in the optical imaging system in FIG. 8A; FIG. 8C is a schematic view of astigmatic field curves when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 8A; and FIG. 8D is a schematic view of a distortion curve when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 8A. DETAILED DESCRIPTION OF THE INVENTION The optical imaging system of the present invention is described with FIG. 1A as an example, to illustrate that the embodiments have similar lens combination and configuration relationship, and to illustrate that the embodiments have the same conditions of the optical imaging system, and the differences are described in details in the following embodiments. Taking FIG. 1A as an example, the optical imaging system 10 comprises, from an object side to an image side along an optical axis(from left to right in FIG. 1A) in sequence, a first lens element 110, a second lens element 120, a third lens element 130, a fourth lens element 140, and a fifth lens element 150. Additionally, the optical imaging system 10 further comprises a stop 100 and an image plane 170 disposed therein. An electronic sensor (not shown) may be disposed on the image plane 170 for imaging by the optical imaging system 10. The first lens element 110 comprises an object-side surface 111 and an image-side surface 112. The first lens element 110 with positive refractive power may provide partial refractive power needed by the optical imaging system 10 and reduce the total optical length. Moreover, the object-side surface 111 of the first lens element 110 can be a convex surface to enhance the positive refractive power of the first lens element 110 and to further reduce the total length of the optical imaging system. The second lens element 120 comprises an object-side surface 121 and an image-side surface 122. The second lens element 120 with positive refractive power may enhance the positive refractive power configuration. The third lens element 130 comprises an object-side surface 131 and an image-side surface 132. The third lens element 130 with negative refractive power may favorably correct the aberration and the chromatic aberration of the optical imaging system 10 at the same time. Furthermore, the image-side surface 132 of the third lens element 130 may be a concave surface to enhance the negative refractive power of the third lens element 130, so as to correct the aberration of the optical imaging system 10. The third lens element 130 may include at least one inflection point for reducing the angle of incidence on the electronic sensor (not shown) from the off-axis field. The fourth lens element 140 comprises an object-side surface 141 and an image-side surface 142. Furthermore, at least one of the object-side surface 141 of the fourth lens element 140 and the image-side surface 142 of the fourth lens element 140 is aspheric. Moreover, the image-side surface 142 of the second lens element 140 may be a convex surface for enhancing the positive refractive power of the fourth lens element 140 and further reducing the total optical length. The fifth lens element 150 comprises an object-side surface 151 and a concave image-side surface 152. The fourth lens element 140 with positive refractive power forms a telephoto lens with the fifth lens element 150 with negative refractive power, in order to reduce the total optical length and miniaturize the optical imaging system 10. In addition, at least one of the object-side surface 151 and the image-side surface 152 of the fifth lens element 150 is aspheric. Moreover, the object-side surface 151 of the fifth lens element 150 may be convex near the optical axis, and the concave image-side surface 152 of the fifth lens element 150 can reduce the total optical length by increasing the distance from a principal point of the optical imaging system 10 to the image plane 170. Accordingly, the optical imaging system 10 becomes more compact. The fifth lens element 150 may include at least one inflection point for correcting the off-axis aberration. Furthermore, the fourth lens element 140 and the fifth lens element 150 can be plastic lens elements. Hence, the manufacturing cost and the weight of the optical imaging system 10 are reduced and it is beneficial to the manufacturing of the aspheric surface lens. The optical imaging system 10 of the present invention satisfies the following relation: 2.00 mm<Td<3.00 mm (Condition 1): 0.65<SL/TTL<1.10 (Condition 2): Td<3.00 mm (Condition 3): Td is an axial distance from the object-side surface 111 of the first lens element 110 to the image-side surface 152 of the fifth lens element 150, SL is a distance from the aperture stop 100 to the image plane 170, TTL is a distance from the object-side surface 111 of the first lens element 110 to an image plane 170. When the optical imaging system 10 satisfies Condition 1 or Condition 3 can miniaturize the optical imaging system 10. Therefore, the optical imaging system 10 is suitable for lightweight, slim, and portable electronics. In some embodiments, the optical imaging system 10 further satisfies a stricter condition: 2.20 mm<Td<2.80 mm. When the optical imaging system 10 satisfies Condition 2, the position of the aperture stop 100 is close to the third lens element 130. The view angle can be increased, and both the distortion and the chromatic aberration of magnification can be corrected. Additionally, the sensitivity of the optical imaging system 10 is effectively reduced. In some embodiments, the optical imaging system 10 further satisfies a stricter condition: 0.65<SL/TTL<1.10 or 0.90<SL/TTL<1.10. Moreover, the optical imaging system 10 of the present invention may further satisfy at least one of the following conditions: 0<v1−(v2+v3)<25 (Condition 4): 0.1<R10/f<0.5 (Condition 5): 0.77<(ΣCT)/Td<0.95 (Condition 6): 29<v1−v3<45 (Condition 7): 0.20<CT3/CT4<0.55 (Condition 8): v1 is an Abbe number of the first lens element 110, v2 is an Abbe number of the second lens element 120, and v3 is an Abbe number of the third lens element 130, f is an overall focal length of the optical imaging system 10, R10 is a radius of curvature of the image-side surface 152 of the fifth lens element 150, (ΣCT) is a sum of axial thicknesses of the first lens element 110, the second lens element 120, the third lens element 130, the fourth lens element 140, and the fifth lens element 150, Td is a distance from the object-side surface 111 of the first lens element 110 to the image-side surface 152 of the fifth lens element 150 on the optical axis, CT3 is an axial thickness of the third lens element 130, and CT4 is an axial thickness of the fourth lens element 140. When the optical imaging system 10 of the present invention satisfies Condition 4, it can correct the chromatic aberration of the optical imaging system 10. When the optical imaging system 10 of the present invention satisfies Condition 5, the principal point of the system is away from the image plane 170, and thus the total length of the system is further reduced. The optical imaging system 10 of the present invention satisfying Condition 6 can reduce the total optical length and miniaturize the optical imaging system 10. The optical imaging system 10 of the present invention satisfying Condition 7 can correct the chromatic aberration of the optical imaging system 10. When the optical imaging system 10 of the present invention satisfies Condition 8, the third lens element 130 and the fourth lens element 140 have appropriate thickness, respectively for easier lens assembling process. In the optical imaging system 10 of the present invention, all the lens elements (that is, the first lens element 110, the second lens element 120, the third lens element 130, the fourth lens element 140, and the fifth lens element 150) may be made of glass or plastic. If the lens element is made of glass, there is more freedom in distributing the refractive power for the optical imaging system 10. If a lens element of the present invention is made of plastic, the production cost is effectively reduced. In addition, the surfaces of lens elements can be aspheric and easily made into non-spherical profiles, allowing more design parameter freedom which can be used to reduce aberrations and total number of the lens elements, so that the total optical length of the assembly can be reduced effectively. In the optical imaging system 10 of the present invention, a convex surface means the surface is a convex surface at a paraxial site. A concave surface means the surface is a concave surface at a paraxial site. In addition, at least one aperture stop (such as flare stops, field stops, or other types of stops) may be disposed within the optical imaging system 10 if necessary to eliminate the stray light, to adjust the field of view, or to provide other improvements concerning the image quality. As for the optical imaging system 10 of the present invention, the specific schemes are further described with the following embodiments. Parameters in the embodiments are defined as follows. Fno is an f-number value of the optical imaging system, and HFOV is a half of a maximal viewing angle in the optical imaging system. The aspheric surface in the embodiments may be represented by, but not limited to, the following aspheric surface equation (Condition ASP): X  ( Y ) = ( Y 2 / R ) / ( 1 + sqrt  ( 1 - ( 1 + k ) * ( Y / R ) 2 ) ) + ∑ i  ( Ai ) * ( Y i ) Wherein, X is the relative distance between a point on the aspheric surface spaced at a distance Y from the optical axis and the tangential plane at the aspheric surface vertex on the optical axis; Y is the vertical distance from the point on the aspheric surface to the optical axis; R is the curvature radius; k is the conic coefficient; and Ai is the i-th aspheric coefficient, and in the embodiments, i may be, but is not limited to, 4, 6, 8, 10, 12, and 14. The First Embodiment (Embodiment 1) FIG. 1A is a schematic structural view of a first embodiment of an optical imaging system according to the present invention. As shown in FIG. 1A, the optical imaging system 10 comprises, in order from an object side to an image side (from left to right in FIG. 1A), a first lens element 110, a second lens element 120, an aperture stop 100, a third lens element 130, a fourth lens element 140, a fifth lens element 150, an infrared filter 160, and an image plane 170. In this embodiment, for example, the wavelength of the light received by the optical imaging system 10 is 587.6 nm, but the wavelength of the light received by the optical imaging system 10 may be adjusted according to actual requirements, and is not limited to the wavelength value mentioned above. Furthermore, the fourth lens element 140 and the fifth lens element 150 are aspheric, and the aspheric surfaces of the present invention may satisfy Condition ASP, but are not limited thereto. As for the parameters of the aspheric surfaces, reference is made to Table 1-1 below. TABLE 1-1 Aspheric Coefficients Surface# 1 2 3 4 6 k −3.49470E+00 −2.82962E+01 −3.59735E+01 −1.76562E+00 −1.12539E+01 A4 1.03455E−01 4.81685E−01 2.40597E−01 −7.51792E−01 −2.10166E+00 A6 −4.78603E−01 −1.69186E+00 −3.45679E−01 5.64716E−01 1.21159E+00 A8 1.84374E+00 8.88196E−01 −6.17117E+00 1.56747E+00 2.30522E+00 A10 −4.60855E+00 1.03639E+00 1.65928E+01 3.30003E−01 −1.57037E+00 A12 3.38619E+00 −3.62165E−01 1.36511E+01 −6.15946E+00 −1.26029E+01 A14 4.65221E−02 1.16385E+00 −4.59678E+01 1.82352E+01 — Surface# 7 8 9 10 11 k −1.00000E+00 −1.00000E+00 −3.09374E+00 4.35938E+00 −7.43623E+00 A4 −1.14240E+00 3.90764E−01 −6.05942E−01 2.82990E−01 −2.28405E−01 A6 1.78473E+00 −6.84571E−01 8.53946E−01 −1.55944E+00 8.85041E−02 A8 −2.13235E+00 5.35307E−02 −6.20962E−01 2.16497E+00 −3.31373E−02 A10 −5.02921E−01 1.08376E+00 −3.96314E−01 −8.41198E−01 −2.92041E−02 A12 1.00537E+00 −8.66765E−01 1.85206E+00 −1.49054E+00 1.64690E−02 A14 — 3.15569E−01 −5.17182E−01 1.15973E+00 −1.75257E−03 The image-side surface 152 of the fifth lens element 150 further comprises two inflection points 153 on the radial section of the fifth lens element 150 shown in FIG. 1A. This could control an angle at which the light of an off-axis field of view is projected onto an electronic sensor (not shown) of the image plane 170 and correct the aberration in the off-axis field of view. The detailed data of the optical imaging system 10 is as shown in Table 1-2 below. TABLE 1-2 (Embodiment 1) f = 2.01 mm, Fno = 2.10, HFOV = 37.4 deg. Surface Focal # Curvature Radius Thickness Material Index Abbe # length 0 Object Plano Infinity 1 Lens 1 3.37670 (ASP) 0.395 Plastic 1.544 55.9 3.16 2 −3.36790 (ASP) 0.064 3 Lens 2 −49.49600 (ASP) 0.300 Plastic 1.634 23.8 −52.00 4 98.96120 (ASP) −0.002 5 Ape. Stop Plano 0.179 6 Lens 3 8.33420 (ASP) 0.300 Plastic 1.634 23.8 −2.40 7 1.26774 (ASP) 0.059 8 Lens 4 20.77260 (ASP) 0.803 Plastic 1.544 55.9 0.77 9 −0.42378 (ASP) 0.050 10 Lens 5 −49.51110 (ASP) 0.350 Plastic 1.530 55.8 −1.02 11 0.54853 (ASP) 0.500 12 IR-filter Plano 0.200 Glass 1.517 64.2 — 13 Plano 0.356 14 Image Plano — Note: Reference wavelength is d-line 587.6 nm The content of Table 1-3 may be deduced from Table 1-2. TABLE 1-3 The First Embodiment f (mm) 2.01 R10/f 0.27 Fno 2.10 CT3/CT4 0.37 HFOV(deg.) 37.4 | f/f4 | + | f/f5 | 4.58 v1 − v3 32.1 SL/TTL 0.78 v1 − (v2 + v3) 8.3 Td (mm) 2.50 | R1/R2 | 1.00 (ΣCT)/Td 0.86 In this embodiment, the (ΣCT)/Td of the optical imaging system 10 is 0.86, which satisfies the range of Condition 1, 11, and 12, and indicates that the thicknesses of all the lens elements in the optical imaging system 10 is favorable and the total length of the optical imaging system 10 is effectively reduced, so as to miniaturizes the optical imaging system 10. The SL/TTL of the optical imaging system 10 is 0.78, which satisfies Condition 2, can increase the viewing angle of the optical imaging system 10. The Td of the optical imaging system 10 is 2.50 mm, which satisfies Condition 3 and 10, and miniaturizes the optical imaging system 10, so as that the optical imaging system 10 is suitable for light, thin and portable electronics. The |f/f4|+|f/f5| of the optical imaging system 10 is 4.58, which satisfies Condition 4. This prevents high order aberrations from increasing excessively. The R10/f of the optical imaging system 10 is 0.27, which satisfies Condition 5, such that the principal point of the optical imaging system 10 can be far away from the image plane 170, so as to further reduce the total length of the optical imaging system 10. The v1−v3 of the optical imaging system 10 is 32.1, which satisfies Condition 6, and corrects the chromatic aberration of the optical imaging system 10. The |R1/R2| of the optical imaging system 10 is 1.00, which satisfies Condition 7, and corrects the spherical aberration of the optical imaging system 10. The CT3/CT4 of the optical imaging system 10 is 0.37, which satisfies Condition 8, and the thicknesses of the third lens element 130 and the fourth lens element 140 are suitable. Consequently, the optical imaging system 10 is adapted t for a simpler manufacturing process. The v1−(v2+v3) of the optical imaging system 10 is 8.3, which satisfies Condition 9, and corrects the chromatic aberration of the optical imaging system 10. FIG. 1B is a schematic view of longitudinal spherical aberration curves when the lights having wavelengths of 486.1 nm, 587.6 nm, and 656.3 nm are respectively projected in the optical imaging system in FIG. 1A. The longitudinal spherical aberration curve of the light having the wavelength of 486.1 nm in the optical imaging system 10 is indicated by a solid line L in FIG. 1B. The longitudinal spherical aberration curve of the light having the wavelength of 587.6 nm in the system is indicated by a dashed line M in FIG. 1B. The longitudinal spherical aberration curve of the light having the wavelength of 656.3 nm is indicated by a dotted line N in FIG. 1B. Horizontal axis is the focus position (millimeter, mm), and vertical axis is a normalized distance from the center of the entrance pupil or aperture stop toward its outermost boundary of aperture. In other words, the differences of the focus positions of the paraxial light (the longitudinal coordinate is close to 0) and the fringe light (the longitudinal coordinate is close to 1) after entering the optical imaging system 10 can be seen from the longitudinal spherical aberration curves, in which the paraxial light and the fringe light are parallel to the optical axis. It can be known from FIG. 1B that, when different wavelengths, 486.1 nm, 587.6 nm, or 656.3 nm, of the light are received by the optical imaging system 10 of this embodiment the longitudinal spherical aberrations generated by the optical imaging system 10 are within a range of −0.025 mm to 0.015 mm. In the second embodiment to the eighth embodiment and the schematic views of the longitudinal spherical aberration curves in FIGS. 2B, 3B, 4B, 5B, 6B, 7B, and 8B, the solid line L indicates the longitudinal spherical aberration curve of the light having the wavelength of 486.1 nm, the dashed line M indicates the longitudinal spherical aberration curve of the light having the wavelength of 587.6 nm, and the dotted line N indicates the longitudinal spherical aberration curve of the light having the wavelength of 656.3 nm, which will not be repeated herein for conciseness. FIG. 1C is a schematic view of astigmatic field curves when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 1A. An astigmatic field curve of a tangential plane is a dashed line T in FIG. 1C. An astigmatic field curve of a sagittal plane is a solid line S in FIG. 1C. Horizontal axis is the focus position (mm), and vertical axis is the image height (mm). In other words, the differences of the focus positions due to different curvatures of the tangential plane and the sagittal plane can be seen from the astigmatic field curves. It can be known from FIG. 1C that, the astigmatic field curvature of the tangential plane generated when the light having the wavelength of 587.6 nm is projected in the optical imaging system 10 is within a range of −0.05 mm to 0.1 mm, and the astigmatic field curvature of the sagittal plane is within a range of −0.05 mm to 0.01 mm. In the second embodiment to the eighth embodiment and the schematic views of the astigmatic field curves in FIGS. 2C, 3C, 4C, 5C, 6C, 7C, and 8C, the solid line S indicates the astigmatic field curve of the sagittal plane, and the dashed line T indicates the astigmatic field curve of the tangential plane, which will not be repeated herein for conciseness. FIG. 1D is a schematic view of a distortion curve when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 1A. The horizontal axis is distortion ratio (%), and the vertical axis is image height (mm). In other words, the differences of the distortion ratios caused by different image heights can be seen from the distortion curve G. It can be known from FIG. 1D that, the distortion ratio generated when the light having the wavelength of 587.6 nm is projected in the optical imaging system 10 is within a range of −1.5% to 0%. As shown in FIGS. 1B to 1D, the optical imaging system 10, designed according to the first embodiment, is capable of effectively eliminating various aberrations. In the second embodiment to the eighth embodiment and the schematic views of the distortion curves in FIGS. 2D, 3D, 4D, 5D, 6D, 7D, and 8D, the solid line G indicates the distortion curve of the light having the wavelength of 587.6 nm, which will not be repeated herein for conciseness. It should be noted that, the distortion curves and the astigmatic field curves generated when the lights having the wavelength of 486.1 nm and 656.3 nm are projected in the optical imaging system 10 are highly similar to the distortion curve and the astigmatic field curves generated when the light having the wavelength of 587.6 nm is projected in the optical imaging system 10. In order to prevent the confusion of reading the figures in FIGS. 1C and 1D, the distortion curve and the astigmatic field curves of wavelengths of 486.1 nm and 656.3 nm projected in the optical imaging system 10 are not shown in FIGS. 1C and 1D, and the same is throughout the rest of the embodiments of this present invention. The Second Embodiment (Embodiment 2) FIG. 2A is a schematic structural view of a second embodiment of the optical imaging system according to the present invention. The specific implementation and elements of the second embodiment are substantially the same as those in the first embodiment, wherein the element symbols all begin with “2”, which correspond to those in the first embodiment with the same function or structure. For conciseness, only the differences among embodiments are illustrated below, and the similarities will not be repeated herein. In this embodiment, for example, the wavelength of the light received by the optical imaging system 20 is 587.6 nm, but this wavelength may be adjusted according to actual requirements, and is not limited to the wavelength value mentioned above. Furthermore, the fourth lens element 240 and the fifth lens element 250 are aspheric lens elements, and the aspheric surfaces may satisfy Condition ASP, but are not limited thereto. As for the parameters of the aspheric surfaces, reference is made to Table 2-1 below. TABLE 2-1 Aspheric Coefficients Surface# 1 2 4 5 6 k −5.00000E+01 −5.34986E+00 −5.00000E+01 −1.09880E+01 5.24184E−01 A4 −1.91529E−01 −4.03081E−01 −1.79998E−01 −3.76491E−01 −3.76322E−01 A6 −8.15244E−01 −5.30006E−01 −7.34132E−01 3.42371E−01 8.84431E−01 A8 2.73073E+00 1.36908E−01 −7.71084E−01 3.56200E−01 3.06673E+00 A10 −7.46998E+00 7.79285E−01 4.79990E+00 1.87677E+00 −5.57888E+00 A12 2.48640E−01 1.76724E−01 1.42202E+00 4.36357E−01 2.27643E+00 A14 −7.37339E−01 7.10876E−02 −7.15273E−01 −1.65611E−01 — Surface# 7 8 9 10 11 k −1.00000E+00 −1.00000E+00 −3.46151E+00 −5.00000E+01 −8.82032E+00 A4 −1.11732E−01 4.43934E−01 −4.23698E−01 2.18814E−01 −2.37348E−01 A6 1.01081E−01 −1.24042E−01 7.72757E−01 −8.52171E−01 2.03710E−01 A8 −5.38265E−02 −5.52145E−01 −3.73793E−01 1.09019E+00 −1.25819E−01 A10 −7.07412E−01 4.55300E−01 6.21951E−02 −5.36250E−01 2.38755E−03 A12 4.51057E−01 3.65190E−01 4.35235E−01 −2.83557E−01 1.65216E−02 A14 — −4.19036E−01 −1.49994E−01 1.89310E−01 −4.51254E−03 In this embodiment, the first lens element 210 has a positive refractive power, the third lens element 230 has a negative refractive power, the fourth lens element 240 has a positive refractive power, and the fifth lens element 250 has a negative refractive power. The image-side surface 232 of the third lens element 230 is a concave surface, the image-side surface 242 of the fourth lens element 240 is a convex surface, and the image-side surface 252 of the fifth lens element 250 is a concave surface. Two inflection points 253 are on the image-side surface 252 of the fifth lens element 250. As a result, the incident angle of light projected onto the electronic sensor (not shown) of the image plane 270 from the off-axis field can be effectively reduced; thereby the aberration in the off-axis field of view is further corrected. The detailed data of the optical imaging system 20 is as shown in Table 2-2 below. TABLE 2-2 Embodiment 2 f = 2.02 mm, Fno = 2.20, HFOV = 37.3 deg. Surface Focal # Curvature Radius Thickness Material Index Abbe # length 0 Object Plano Infinity 1 Lens 1 −17.00170 (ASP) 0.432 Plastic 1.544 55.9 2.86 2 −1.43684 (ASP) −0.080 3 Ape. Stop Plano 0.130 4 Lens 2 −50.00000 (ASP) 0.367 Plastic 1.632 23.4 2.88 5 1.76359 (ASP) 0.149 6 Lens 3 −1.41716 (ASP) 0.300 Plastic 1.632 23.4 −1.31 7 2.13907 (ASP) 0.071 8 Lens 4 −18.00320 (ASP) 0.757 Plastic 1.544 55.9 0.84 9 −0.45379 (ASP) 0.050 10 Lens 5 −50.00000 (ASP) 0.350 Plastic 1.530 55.8 −1.11 11 0.59539 (ASP) 0.500 12 IR-filter Plano 0.200 Glass 1.517 64.2 — 13 Plano 0.331 14 Image Plano — Note: The reference wavelength is d-line 587.6 nm The content of Table 2-3 may be deduced from Table 2-2. TABLE 2-3 The Second Embodiment f (mm) 2.02 R10/f 0.29 Fno 2.20 CT3/CT4 0.40 HFOV(deg.) 37.3 | f/f4 | + | f/f5 | 4.22 v1 − v3 32.5 SL/TTL 0.90 v1 − (v2 + v3) 9.1 Td (mm) 2.53 | R1/R2 | 11.83 (ΣCT)/Td 0.87 FIG. 2B is a schematic view of longitudinal spherical aberration curves when the lights having wavelengths of 486.1 nm, 587.6 nm, and 656.3 nm are respectively projected in the optical imaging system in FIG. 2A. It can be known from FIG. 2B that, when the different wavelengths, 486.1 nm, 587.6 nm, and 656.3 nm, of the light are received by the optical imaging system 20 of this embodiment, the longitudinal spherical aberrations generated by the optical imaging system 20 are within a range of −0.025 mm to 0.04 mm. FIG. 2C is a schematic view of astigmatic field curves when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 2A. It can be known from FIG. 2C that, the astigmatic field curvature of the tangential plane generated when the light having the wavelength of 587.6 nm is projected in the optical imaging system 20 is within a range of −0.05 mm to 0.05 mm, and the astigmatic field curvature of the sagittal plane is within a range of −0.03 mm to 0.03 mm. FIG. 2D is a schematic view of a distortion curve when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 2A. It can be known from FIG. 2D that, the distortion ratio generated when the light having the wavelength of 587.6 nm is projected in the optical imaging system 20 is within a range of −0.5% to 0.5%. As shown in FIGS. 2B to 2D, the optical imaging system 20, designed according to the second embodiment, is capable of effectively correcting various aberrations. The Third Embodiment (Embodiment 3) FIG. 3A is a schematic structural view of a third embodiment of the optical imaging system according to the present invention. The specific implementation and elements of the third embodiment are substantially the same as that in the first embodiment, wherein the element symbols all begin with “3”, which correspond to those in the first embodiment with the same function or structure. For conciseness, only the differences are illustrated below, and the similarities will not be repeated herein. In this embodiment, for example, the wavelength of the light received by the optical imaging system 30 is 587.6 nm, but the wavelength may be adjusted according to actual requirements, and is not limited to the wavelength value mentioned above. Furthermore, the fourth lens element 340 and the fifth lens element 350 are aspheric lens elements, and the aspheric surfaces may satisfy Condition ASP, but are not limited thereto. As for the parameters of the aspheric surfaces, reference is made to Table 3-1 below. TABLE 3-1 Aspheric Coefficients Surface# 1 2 3 4 6 k −1.61936E+01 −1.00002E+00 −1.19504E+01 −1.67141E+01 −4.09314E+01 A4 1.04054E−01 4.01439E−01 1.38053E−01 −7.93118E−01 −1.86401E+00 A6 −4.31394E−01 −1.37595E+00 −2.87385E−01 1.11326E+00 2.46340E+00 A8 1.65593E+00 9.54772E−01 −5.12145E+00 −2.10770E+00 −4.48049E+00 A10 −4.32735E+00 7.80713E−01 1.35862E+01 5.33869E+00 1.21175E+01 A12 3.43888E+00 −3.62174E−01 1.36511E+01 −6.15947E+00 −1.26029E+01 A14 4.65664E−02 1.16384E+00 −4.59678E+01 1.82352E+01 — Surface# 7 8 9 10 11 k −1.00000E+00 −1.00000E+00 −3.54549E+00 −1.00000E+00 −5.51825E+00 A4 −9.62754E−01 3.89014E−01 −5.60690E−01 −1.32311E−01 −3.07567E−01 A6 1.71920E+00 −6.21028E−01 8.42758E−01 −1.02946E+00 1.91408E−01 A8 −2.29204E+00 2.16311E−01 −5.51874E−01 2.01291E+00 −7.98823E−02 A10 1.04943E−01 7.90493E−01 −3.78214E−01 −1.12801E+00 −3.88229E−02 A12 1.00536E+00 −8.96128E−01 1.74651E+00 −1.41947E+00 2.54442E−02 A14 — 3.15508E−01 −7.06911E−01 1.21979E+00 −1.74346E−03 In this embodiment, the first lens element 310 has a positive refractive power, the third lens element 330 has a negative refractive power, the fourth lens element 340 has a positive refractive power, and the fifth lens element 350 has a negative refractive power. The image-side surface 332 of the third lens element 330 is a concave surface, the image-side surface 342 of the fourth lens element 340 is a convex surface, and the image-side surface 352 of the fifth lens element 350 is a concave surface. Two points of inflection 353 are on the image-side surface 352 of the fifth lens element 350. As a result, the angle at which light is projected onto the electronic sensor (not shown) of the image plane 370 from the off-axis field can be effectively reduced; thereby the aberration in the off-axis field of view is further corrected. The detailed data of the optical imaging system 30 is as shown in Table 3-2 below. TABLE 3-2 Embodiment 3 f = 2.07 mm, Fno = 2.40, HFOV = 34.2 deg. Surface Focal # Curvature Radius Thickness Material Index Abbe # length 0 Object Plano Infinity 1 Lens 1 2.86224 (ASP) 0.426 Plastic 1.544 55.9 2.56 2 −2.56876 (ASP) 0.050 3 Lens 2 −7.86780 (ASP) 0.300 Plastic 1.634 23.8 −29.72 4 −13.70710 (ASP) 0.000 5 Ape. Stop Plano 0.158 6 Lens 3 7.63570 (ASP) 0.303 Plastic 1.634 23.8 −2.23 7 1.17603 (ASP) 0.055 8 Lens 4 4.76320 (ASP) 0.891 Plastic 1.544 55.9 0.84 9 −0.47478 (ASP) 0.050 10 Lens 5 8.21940 (ASP) 0.350 Plastic 1.530 55.8 −1.04 11 0.50975 (ASP) 0.500 12 IR-filter Plano 0.200 Glass 1.517 64.2 — 13 Plano 0.236 14 Image Plano — Note: The reference wavelength is d-line 587.6 nm The content of Table 3-3 may be deduced from Table 3-2. TABLE 3-3 The Third Embodiment f (mm) 2.07 R10/f 0.25 Fno 2.40 CT3/CT4 0.34 HFOV(deg.) 34.2 | f/f4 | + | f/f5 | 4.45 v1 − v3 32.1 SL/TTL 0.78 v1 − (v2 + v3) 8.3 Td (mm) 2.58 | R1/R2 | 1.11 (ΣCT)/Td 0.88 FIG. 3B is a schematic view of longitudinal spherical aberration curves when the lights having wavelengths of 486.1 nm, 587.6 nm, and 656.3 nm are respectively projected in the optical imaging system in FIG. 3A. It can be known from FIG. 3B that, when the different wavelengths, 486.1 nm, 587.6 nm, and 656.3 nm, of the light are received by the optical imaging system 30 of this embodiment, the longitudinal spherical aberrations generated by the optical imaging system 30 are within a range of −0.005 mm to 0.025 mm. FIG. 3C is a schematic view of astigmatic field curves when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 3A. It can be known from FIG. 3C that, the astigmatic field curvature of the tangential plane generated when the light having the wavelength of 587.6 nm is projected in the optical imaging system 30 is within a range of 0.00 mm to 0.05 mm, and the astigmatic field curvature of the sagittal plane is within a range of −0.025 mm to 0.025 mm. FIG. 3D is a schematic view of a distortion curve when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 3A. It can be known from FIG. 3D that, the distortion ratio generated when the light having the wavelength of 587.6 nm is projected in the optical imaging system 30 is within a range of 0.0% to 1.5%. As shown in FIGS. 3B to 3D, the optical imaging system 30, designed according to the third embodiment, is capable of effectively correcting various aberrations. The Fourth Embodiment (Embodiment 4) FIG. 4A is a schematic structural view of a fourth embodiment of the optical imaging system according to the present invention. The specific implementation and elements of the fourth embodiment are substantially the same as that in the first embodiment wherein the element symbols all begin with “4”, which correspond to those in the first embodiment with the same function or structure. For conciseness, only the differences are illustrated below, and the similarities will not be repeated herein. In this embodiment, for example, the wavelength of the light received by the optical imaging system 40 is 587.6 nm, but the wavelength may be adjusted according to actual requirements, and is not limited to the wavelength value mentioned above. Furthermore, the fourth lens element 440 and the fifth lens element 450 are aspheric lens elements, and the aspheric surfaces may satisfy Condition ASP, but are not limited thereto. As for the parameters of the aspheric surfaces, reference is made to Table 4-1 below. TABLE 4-1 Aspheric Coefficients Surface# 1 2 4 5 6 k −2.71907E+01 −1.04613E+00 −1.00045E+00 −1.00353E+00 −1.26986E+01 A4 9.36941E−02 3.69361E−01 1.32661E−01 −8.72116E−01 −1.86014E+00 A6 −4.54025E−01 −1.41798E+00 −5.96426E−01 1.05997E+00 2.34935E+00 A8 1.42547E+00 8.27844E−01 −4.73347E+00 −2.61424E+00 −4.42468E+00 A10 −4.30223E+00 8.94293E−01 1.32218E+01 6.37421E+00 1.50494E+01 A12 3.43884E+00 −3.62137E−01 1.36511E+01 −6.15949E+00 −1.26029E+01 A14 4.65669E−02 1.16385E+00 −4.59678E+01 1.82352E+01 — Surface# 7 8 9 10 11 k −1.00000E+00 −1.00000E+00 −3.52839E+00 −1.00000E+00 −5.37084E+00 A4 −9.26431E−01 3.95906E−01 −5.46740E−01 −1.73121E−01 −3.11239E−01 A6 1.74503E+00 −6.13452E−01 8.28861E−01 −1.00465E+00 1.92385E−01 A8 −2.25472E+00 2.13018E−01 −5.71325E−01 1.95808E+00 −7.42147E−02 A10 2.25785E−01 7.60582E−01 −3.92708E−01 −1.14271E+00 −3.69924E−02 A12 9.96953E−01 −9.35940E−01 1.74869E+00 −1.36548E+00 2.81192E−02 A14 — 4.30135E−01 −6.72104E−01 1.26129E+00 −3.30159E−03 In this embodiment, the first lens element 410 has a positive refractive power, the third lens element 430 has a negative refractive power, the fourth lens element 440 has a positive refractive power, and the fifth lens element 450 has a negative refractive power. The image-side surface 432 of the third lens element 430 is a concave surface, the image-side surface 442 of the fourth lens element 440 is a convex surface, and the image-side surface452 of the fifth lens element 450 is a concave surface. Two points of inflection 453 are on the image-side surface 452 of the fifth lens element 450. As a result, the angle at which light is projected onto the electronic sensor (not shown) of the image plane 470 from the off-axis field can be effectively reduced; thereby the aberration in the off-axis field of view is further corrected. The detailed data of the optical imaging system 40 is as shown in Table 4-2 below. TABLE 4-2 Embodiment 4 f = 2.09 mm, Fno = 2.60, HFOV = 35.3 deg. Surface Focal # Curvature Radius Thickness Material Index Abbe # length 0 Object Plano Infinity 1 Lens 1 2.94368 (ASP) 0.388 Plastic 1.544 55.9 2.39 2 −2.21910 (ASP) 0.000 3 Ape. Stop Plano 0.050 4 Lens 2 −8.13710 (ASP) 0.295 Plastic 1.634 23.8 −32.50 5 −13.63530 (ASP) 0.162 6 Lens 3 9.27750 (ASP) 0.299 Plastic 1.634 23.8 −2.24 7 1.21603 (ASP) 0.056 8 Lens 4 5.52030 (ASP) 0.849 Plastic 1.544 55.9 0.84 9 −0.46878 (ASP) 0.051 10 Lens 5 14.27450 (ASP) 0.350 Plastic 1.530 55.8 −0.97 11 0.48989 (ASP) 0.500 12 IR-filter Plano 0.200 Glass 1.517 64.2 — 13 Plano 0.199 14 Image Plano — Note: The reference wavelength is d-line 587.6 nm The content of Table 4-3 may be deduced from Table 4-2. TABLE 4-3 The Fourth Embodiment f (mm) 2.09 R10/f 0.23 Fno 2.60 CT3/CT4 0.35 HFOV(deg.) 35.3 | f/f4 | + | f/f5 | 4.64 v1 − v3 32.1 SL/TTL 0.88 v1 − (v2 + v3) 8.3 Td (mm) 2.50 | R1/R2 | 1.33 (ΣCT)/Td 0.87 FIG. 4B is a schematic view of longitudinal spherical aberration curves when the lights having wavelengths of 486.1 nm, 587.6 nm, and 656.3 nm are respectively projected in the optical imaging system in FIG. 4A. It can be known from FIG. 4B that, when the different wavelengths, 486.1 nm, 587.6 nm, and 656.3 nm, of the light are received by the optical imaging system 40 of this embodiment, the longitudinal spherical aberrations generated by the optical imaging system 40 are within a range of −0.005 mm to 0.025 mm. FIG. 4C is a schematic view of astigmatic field curves when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 4A. It can be known from FIG. 4C that, the astigmatic field curvature of the tangential plane generated when the light having the wavelength of 587.6 nm is projected in the optical imaging system 40 is within a range of −0.02 mm to 0.02 mm, and the astigmatic field curvature of the sagittal plane is within a range of −0.01 mm to 0.01 mm. FIG. 4D is a schematic view of a distortion curve when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 4A. It can be known from FIG. 4D that, the distortion ratio generated when the light having the wavelength of 587.6 nm is projected in the optical imaging system 40 is within a range of 0.0% to 1.5%. As shown in FIGS. 4B to 4D, the optical imaging system 40, designed according to the fourth embodiment, is capable of effectively correcting various aberrations. The Fifth Embodiment (Embodiment 5) FIG. 5A is a schematic structural view of a fifth embodiment of the optical imaging system according to the present invention. The specific implementation and elements of the fifth embodiment are substantially the same as that in the first embodiment, wherein the element symbols all begin with “5”, which correspond to those in the first embodiment with the same function or structure. For conciseness, only the differences are illustrated below, and the similarities will not be repeated herein. In this embodiment, for example, the wavelength of the light received by the optical imaging system 50 is 587.6 nm, but the wavelength may be adjusted according to actual requirements, and is not limited to the wavelength value mentioned above. Furthermore, the fourth lens element 540 and the fifth lens element 550 are aspheric lens elements, and the aspheric surfaces may satisfy Condition ASP, but are not limited thereto. As for the parameters of the aspheric surfaces, reference is made to Table 5-1 below. TABLE 5-1 Aspheric Coefficients Surface# 1 2 3 4 6 k −1.50145E+01 −1.31106E+00 −4.02631E+01 −5.00000E+01 −5.00000E+01 A4 6.42994E−02 2.80409E−01 1.41994E−01 −5.23750E−01 −1.30890E+00 A6 −2.24829E−01 −5.43527E−01 −2.07963E−01 6.47265E−01 1.00562E+00 A8 6.19389E−01 2.76742E−01 −1.28457E+00 −1.20074E+00 −1.16549E+00 A10 −1.13564E+00 1.21952E−01 2.65205E+00 1.74842E+00 2.72020E+00 A12 7.44178E−01 −7.40818E−02 2.80360E+00 −1.26531E+00 −2.58468E+00 A14 −7.90819E−02 1.79791E−01 −7.06062E+00 2.79932E+00 — Surface# 7 8 9 10 11 k −1.00000E+00 −1.00000E+00 −3.36252E+00 −1.00000E+00 −6.05794E+00 A4 −7.05881E−01 2.50534E−01 −3.63066E−01 −5.32987E−02 −2.03209E−01 A6 8.38375E−01 −2.83129E−01 4.14809E−01 −5.40087E−01 8.72611E−02 A8 −7.06966E−01 7.59671E−02 −2.01122E−01 7.44500E−01 −2.67820E−02 A10 −9.18350E−02 2.08222E−01 −9.97632E−02 −3.10556E−01 −1.07637E−02 A12 2.05927E−01 −1.79560E−01 3.57072E−01 −3.13152E−01 5.88785E−03 A14 — 4.86768E−02 −1.09566E−01 2.07542E−01 −5.18749E−04 In this embodiment, the first lens element 510 has a positive refractive power, the third lens element 530 has a negative refractive power, the fourth lens element 540 has a positive refractive power, and the fifth lens element 550 has a negative refractive power. The image-side surface 532 of the third lens element 530 is a concave surface, the image-side surface 542 of the fourth lens element 540 is a convex surface, and the image-side surface552 of the fifth lens element 550 is a concave surface. Two points of inflection 553 are on the image-side surface 552 of the fifth lens element 550. As a result, the angle at which light is projected onto the electronic sensor (not shown) of the image plane 570 from the off-axis field can be effectively reduced; thereby the aberration in the off-axis field of view is further corrected. The detailed data of the optical imaging system 50 is as shown in Table 5-2 below. TABLE 5-2 Embodiment 5 f = 2.47 mm, Fno = 2.40, HFOV = 33.2 deg. Surface Focal # Curvature Radius Thickness Material Index Abbe # length 0 Object Plano Infinity 1 Lens 1 3.10024 (ASP) 0.506 Plastic 1.544 55.9 2.59 2 −2.42994 (ASP) 0.091 3 Lens 2 −3.96408 (ASP) 0.323 Plastic 1.634 23.8 −9.07 4 −13.16931 (ASP) −0.010 5 Ape. Stop Plano 0.186 6 Lens 3 5.35285 (ASP) 0.345 Plastic 1.634 23.8 −3.04 7 1.38252 (ASP) 0.092 8 Lens 4 10.79197 (ASP) 0.919 Plastic 1.544 55.9 1.02 9 −0.56483 (ASP) 0.092 10 Lens 5 61.60100 (ASP) 0.404 Plastic 1.530 55.8 −1.27 11 0.66453 (ASP) 0.420 12 IR-filter Plano 0.300 Glass 1.517 64.2 — 13 Plano 0.410 14 Image Plano — Note: The reference wavelength is d-line 587.6 nm The content of Table 5-3 may be deduced from Table 5-2. TABLE 5-3 The Fifth Embodiment f (mm) 2.47 R10/f 0.27 Fno 2.40 CT3/CT4 0.38 HFOV(deg.) 33.2 | f/f4 | + | f/f5 | 4.37 v1 − v3 32.1 SL/TTL 0.77 v1 − (v2 + v3) 8.3 Td (mm) 2.95 | R1/R2 | 1.28 (ΣCT)/Td 0.85 FIG. 5B is a schematic view of longitudinal spherical aberration curves when the lights having wavelengths of 486.1 nm, 587.6 nm, and 656.3 nm are respectively projected in the optical imaging system in FIG. 5A. It can be known from FIG. 5B that, when the different wavelengths, 486.1 nm, 587.6 nm, and 656.3 nm, of the light are received by the optical imaging system 50 of this embodiment, the longitudinal spherical aberrations generated by the optical imaging system 50 are within a range of −0.005 mm to 0.025 mm. FIG. 5C is a schematic view of astigmatic field curves when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 5A. It can be known from FIG. 5C that, the astigmatic field curvature of the tangential plane generated when the light having the wavelength of 587.6 nm is projected in the optical imaging system 50 is within a range of −0.02 mm to 0.02 mm, and the astigmatic field curvature of the sagittal plane is within a range of −0.01 mm to 0.01 mm. FIG. 5D is a schematic view of a distortion curve when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 5A. It can be known from FIG. 5D that, the distortion ratio generated when the light having the wavelength of 587.6 nm is projected in the optical imaging system 50 is within a range of 0.0% to 1.5%. As shown in FIGS. 5B to 5D, the optical imaging system 50, designed according to the fifth embodiment, is capable of effectively correcting various aberrations. The Sixth Embodiment (Embodiment 6) FIG. 6A is a schematic structural view of a sixth embodiment of the optical imaging system according to the present invention. The specific implementation and elements of the sixth embodiment are substantially the same as that in the first embodiment, wherein the element symbols all begin with “6”, which correspond to those in the first embodiment with the same function or structure. For conciseness, only the differences are illustrated below, and the similarities will not be repeated herein. In this embodiment, for example, the wavelength of the light received by the optical imaging system 60 is 587.6 nm, but the wavelength may be adjusted according to actual requirements, and is not limited to the wavelength value mentioned above. Furthermore, the fourth lens element 640 and the fifth lens element 650 are aspheric lens elements, and the aspheric surfaces may satisfy Condition ASP, but are not limited thereto. As for the parameters of the aspheric surfaces, reference is made to Table 6-1 below. TABLE 6-1 Aspheric Coefficients Surface# 2 3 4 5 6 k −2.56678E+01 −1.00000E+00 −5.00000E+01 −5.00000E+01 −5.00000E+01 A4 4.50882E−02 6.01413E−02 6.42924E−02 −5.34386E−01 −1.15319E+00 A6 −3.85839E−01 −7.64384E−01 −3.43783E−01 4.12840E−01 1.02913E+00 A8 8.55999E−01 2.25261E−01 −1.29643E+00 −1.18132E+00 −1.29479E+00 A10 −3.00666E+00 −2.40295E−01 1.35647E+00 1.22341E+00 3.50498E+00 A12 5.62307E−01 −5.92145E−02 2.23218E+00 −1.00718E+00 −2.06078E+00 A14 5.47981E−03 1.36921E−01 −5.40787E+00 2.14528E+00 — Surface# 7 8 9 10 11 k −1.00000E+00 −1.00000E+00 −3.74355E+00 −1.00000E+00 −5.95481E+00 A4 −5.42414E−01 2.52258E−01 −3.05618E−01 −1.37951E−01 −2.06384E−01 A6 7.81323E−01 −2.45807E−01 3.63504E−01 −4.24109E−01 8.21665E−02 A8 −6.67231E−01 7.39065E−02 −1.81575E−01 5.89907E−01 −2.02223E−02 A10 1.18737E−01 1.67186E−01 −8.80340E−02 −2.60329E−01 −8.55135E−03 A12 1.74537E−01 −1.57052E−01 2.86141E−01 −2.08140E−01 4.72643E−03 A14 — 6.53847E−02 −6.79578E−02 1.63191E−01 −4.32395E−04 In this embodiment, the first lens element 610 has a positive refractive power, the third lens element 630 has a negative refractive power, the fourth lens element 640 has a positive refractive power, and the fifth lens element 650 has a negative refractive power. The image-side surface 632 of the third lens element 630 is a concave surface, the image-side surface 642 of the fourth lens element 640 is a convex surface, and the image-side surface 652 of the fifth lens element 650 is a concave surface. Two points of inflection 653 are on the image-side surface 652 of the fifth lens element 650. As a result, the angle at which light is projected onto the electronic sensor (not shown) of the image plane 670 from the off-axis field can be effectively reduced; thereby the aberration in the off-axis field of view is further corrected. The detailed data of the optical imaging system 60 is as shown in Table 6-2 below. TABLE 6-2 Embodiment 6 f = 2.58 mm, Fno = 2.80, HFOV = 34.4 deg. Surface Focal # Curvature Radius Thickness Material Index Abbe # length 0 Object Plano Infinity 1 Ape. Stop Plano −0.015 2 Lens 1 2.84026 (ASP) 0.446 Plastic 1.544 55.9 2.53 3 −2.51521 (ASP) 0.059 4 Lens 2 34.68370 (ASP) 0.330 Plastic 1.634 23.8 −33.90 5 13.22120 (ASP) 0.131 6 Lens 3 9.36170 (ASP) 0.330 Plastic 1.634 23.8 −2.78 7 1.46213 (ASP) 0.112 8 Lens 4 21.25430 (ASP) 0.894 Plastic 1.544 55.9 1.04 9 −0.57310 (ASP) 0.059 10 Lens 5 −121.96100 (ASP) 0.413 Plastic 1.530 55.8 −1.15 11 0.61105 (ASP) 0.500 12 IR-filter Plano 0.300 Glass 1.517 64.2 — 13 Plano 0.271 14 Image Plano — Note: The reference wavelength is d-line 587.6 nm The content of Table 6-3 may be deduced from Table 6-2. TABLE 6-3 The Sixth Embodiment f (mm) 2.58 R10/f 0.24 Fno 2.80 CT3/CT4 0.37 HFOV(deg.) 34.4 | f/f4 | + | f/f5 | 4.72 v1 − v3 32.1 SL/TTL 1.00 v1 − (v2 + v3) 8.3 Td (mm) 2.77 | R1/R2 | 1.13 (ΣCT)/Td 0.87 FIG. 6B is a schematic view of longitudinal spherical aberration curves when the lights having a wavelength of 486.1 nm, 587.6 nm, and 656.3 nm are respectively projected in the optical imaging system in FIG. 6A. It can be known from FIG. 6B that, when the different wavelengths, 486.1 nm, 587.6 nm, and 656.3 nm, of the light received by the optical imaging system 60 of this embodiment, the longitudinal spherical aberrations generated by the optical imaging system 60 are within a range of −0.005 mm to 0.025 mm. FIG. 6C is a schematic view of astigmatic field curves when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 6A. It can be known from FIG. 6C that, the astigmatic field curvature of the tangential plane generated when the light having the wavelength of 587.6 nm is projected in the optical imaging system 60 is within a range of 0.00 mm to 0.05 mm, and the astigmatic field curvature of the sagittal plane is within a range of 0.00 mm to 0.01 mm. FIG. 6D is a schematic view of a distortion curve when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 6A. It can be known from FIG. 6D that, the distortion ratio generated when the light having the wavelength of 587.6 nm is projected in the optical imaging system 60 is within a range of 0.0% to 1.5%. As shown in FIGS. 6B to 6D, the optical imaging system 60, designed according to the sixth embodiment, is capable of effectively correcting various aberrations. The Seventh Embodiment (Embodiment 7) FIG. 7A is a schematic structural view of a seventh embodiment of the optical imaging system according to the present invention. The specific implementation and elements of the seventh embodiment are substantially the same as that in the first embodiment, wherein the element symbols all begin with “7”, which correspond to those in the first embodiment with the same function or structure. For conciseness, only the differences are illustrated below, and the similarities will not be repeated herein. In this embodiment, for example, the wavelength of the light received by the optical imaging system 70 is 587.6 nm, but the wavelength may be adjusted according to actual requirements, and is not limited to the wavelength value mentioned above. Furthermore, the fourth lens element 740 and the fifth lens element 750 are aspheric lens elements, and the aspheric surfaces may satisfy Condition ASP, but are not limited thereto. As for the parameters of the aspheric surfaces, reference is made to Table 7-1 below. TABLE 7-1 Aspheric Coefficients Surface# 1 2 4 5 6 k −7.22585E+00 −1.00000E+00 −1.00000E+00 −1.54784E+01 −1.00000E+00 A4 6.16997E−01 3.86788E−02 −3.74867E−03 7.19601E−02 −3.92881E−01 A6 −9.18352E−01 4.71557E−01 −2.26139E−01 −3.41956E−01 −6.21218E−01 A8 1.76699E+00 −4.64795E+00 −8.32793E−01 4.95651E−01 3.02433E+00 A10 −1.73133E+00 9.78303E+00 −8.76976E+00 −4.79255E+00 −7.87291E+00 A12 7.29073E−01 −7.66940E+00 3.36814E+01 1.05920E+01 6.81032E+00 A14 −7.25578E−01 4.51909E+00 −3.01499E+01 −7.05775E+00 — Surface# 7 8 9 10 11 k −1.00000E+00 1.41207E+01 −3.46374E+00 −2.76145E+01 −9.40106E+00 A4 −2.48174E−01 1.70360E−02 −2.75764E−01 −3.38689E−02 −1.22267E−01 A6 −4.59185E−01 3.07020E−01 7.03269E−01 −9.95705E−02 7.02073E−02 A8 1.15220E+00 −1.64137E+00 −9.27036E−01 9.52868E−02 −4.42417E−02 A10 −8.26374E−01 3.97155E+00 8.68034E−01 −1.00216E−02 1.89558E−02 A12 4.12177E−01 −4.03841E+00 −4.07510E−01 −5.19683E−03 −4.62314E−03 A14 — 1.43511E+00 5.54502E−02 2.59811E−04 5.31015E−04 In this embodiment, the first lens element 710 has a positive refractive power, the third lens element 730 has a negative refractive power, the fourth lens element 740 has a positive refractive power, and the fifth lens element 750 has a negative refractive power. The image-side surface 732 of the third lens element 730 is a concave surface, the image-side surface 742 of the fourth lens element 740 is a convex surface, and the image-side surface752 of the fifth lens element 750 is a concave surface. Two points of inflection 753 are on the image-side surface 752 of the fifth lens element 750. As a result, the angle at which light is projected onto the electronic sensor (not shown) of the image plane 770 from the off-axis field can be effectively reduced; thereby the aberration in the off-axis field of view is further corrected. The detailed data of the optical imaging system 70 is as shown in Table 7-2 below. TABLE 7-2 Embodiment 7 f = 2.97 mm, Fno = 2.80, HFOV = 33.1 deg. Surface Focal # Curvature Radius Thickness Material Index Abbe # length 0 Object Plano Infinity 1 Lens 1 1.14173 (ASP) 0.539 Plastic 1.530 55.8 2.36 2 11.11800 (ASP) 0.040 3 Ape. Stop Plano 0.070 4 Lens 2 −42.64390 (ASP) 0.290 Plastic 1.650 21.4 −4.30 5 2.99657 (ASP) 0.195 6 Lens 3 36.43440 (ASP) 0.290 Plastic 1.650 21.4 −19.94 7 9.52840 (ASP) 0.112 8 Lens 4 −5.08670 (ASP) 0.700 Plastic 1.530 55.8 1.18 9 −0.58339 (ASP) 0.110 10 Lens 5 −2.05083 (ASP) 0.437 Plastic 1.530 55.8 −1.11 11 0.88384 (ASP) 0.375 12 IR-filter Plano 0.300 Glass 1.517 64.2 — 13 Plano 0.323 14 Image Plano — Note: The reference wavelength is d-line 587.6 nm The content of Table 7-3 may be deduced from Table 7-2. TABLE 7-3 The Seventh Embodiment f (mm) 2.97 R10/f 0.30 Fno 2.80 CT3/CT4 0.41 HFOV(deg.) 33.1 | f/f4 | + | f/f5 | 5.19 v1 − v3 34.4 SL/TTL 0.84 v1 − (v2 + v3) 13.0 Td (mm) 2.78 | R1/R2 | 0.10 (ΣCT)/Td 0.81 FIG. 7B is a schematic view of longitudinal spherical aberration curves when the lights having a wavelength of 486.1 nm, 587.6 nm, and 656.3 nm are respectively projected in the optical imaging system in FIG. 7A. It can be known from FIG. 7B that, when the different wavelengths, 486.1 nm, 587.6 nm, and 656.3 nm, of the light received by the optical imaging system 70 of this embodiment, the longitudinal spherical aberrations generated by the optical imaging system 70 are within a range of −0.005 mm to 0.025 mm. FIG. 7C is a schematic view of astigmatic field curves when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 7A. It can be known from FIG. 7C that, the astigmatic field curvature of the tangential plane generated when the light having the wavelength of 587.6 nm is projected in the optical imaging system 70 is within a range of 0.00 mm to 0.05 mm, and the astigmatic field curvature of the sagittal plane is within a range of 0.00 mm to 0.01 mm. FIG. 7D is a schematic view of a distortion curve when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 7A. It can be known from FIG. 7D that, the distortion ratio generated when the light having the wavelength of 587.6 nm is projected in the optical imaging system 70 is within a range of −0.1% to 1.5%. As shown in FIGS. 7B to 7D, the optical imaging system 70, designed according to the seventh embodiment, is capable of effectively eliminate correcting aberrations. The Eighth Embodiment (Embodiment 8) FIG. 8A is a schematic structural view of an eighth embodiment of the optical imaging system according to the present invention. The specific implementation and elements of the seventh embodiment are substantially the same as that in the first embodiment, wherein the element symbols all begin with “8”, which correspond to those in the first embodiment with the same function or structure. For conciseness, only the differences are illustrated below, and the similarities will not be repeated herein. In this embodiment, for example, the wavelength of the light received by the optical imaging system 80 is 587.6 nm, but the wavelength may be adjusted according to actual requirements, and is not limited to the wavelength value mentioned above. Furthermore, the fourth lens element 840 and the fifth lens element 850 are aspheric lens elements, and the aspheric surfaces may satisfy Condition ASP, but are not limited thereto. As for the parameters of the aspheric surfaces, reference is made to Table 8-1 below. TABLE 8-1 Asphenc Coefficients Surface# 2 3 4 5 6 k −5.00000E+01 −5.43568E+00 −1.00000E+00 −1.09957E+01 5.26336E−01 A4 −1.88174E−01 −4.01755E−01 −1.80866E−01 −3.76555E−01 −3.76611E−01 A6 −7.72897E−01 −5.25703E−01 −7.37080E−01 3.42803E−01 8.82750E−01 A8 2.67101E+00 1.65696E−01 −7.82042E−01 3.57655E−01 3.06576E+00 A10 −1.04494E+01 1.02413E−01 5.01774E+00 1.87038E+00 −5.57196E+00 A12 2.48533E−01 1.76600E−01 1.50346E+00 4.29108E−01 2.30611E+00 A14 −7.37461E−01 7.09083E−02 −7.15455E−01 −2.03420E−01 — Surface# 7 8 9 10 11 k −1.00000E+00 −1.00000E+00 −3.43882E+00 −5.00000E+01 −8.13010E+00 A4 −1.11461E−01 4.43858E−01 −4.24231E−01 2.19350E−01 −2.30964E−01 A6 1.02131E−01 −1.24581E−01 7.72565E−01 −8.52536E−01 2.01741E−01 A8 −5.25530E−02 −5.52957E−01 −3.73577E−01 1.08824E+00 −1.26552E−01 A10 −7.06329E−01 4.54413E−01 6.28603E−02 −5.38700E−01 2.19035E−03 A12 4.50781E−01 3.65501E−01 4.35662E−01 −2.85034E−01 1.64353E−02 A14 — −4.17649E−01 −1.50033E−01 1.89609E−01 −4.55860E−03 In this embodiment, the first lens element 810 has a positive refractive power, the third lens element 830 has a negative refractive power, the fourth lens element 840 has a positive refractive power, and the fifth lens element 850 has a negative refractive power. The image-side surface 832 of the third lens element 830 is a concave surface, the image-side surface 842 of the fourth lens element 840 is a convex surface, and the image-side surface852 of the fifth lens element 850 is a concave surface. Two points of inflection 853 are on the image-side surface 852 of the fifth lens element 850. As a result, the angle at which light is projected onto the electronic sensor (not shown) of the image plane 870 from the off-axis field can be effectively reduced; thereby the aberration in the off-axis field of view is further corrected. The detailed data of the optical imaging system 80 is as shown in Table 8-2 below. TABLE 8-2 Embodiment 8 f = 2.00 mm, Fno = 2.80, HFOV = 37.3 deg. Surface Focal # Curvature Radius Thickness Material Index Abbe # length 0 Object Plano Infinity 1 Ape. Stop Plano 0.025 2 Lens 1 −16.94920 (ASP) 0.432 Plastic 1.544 55.9 2.84 3 −1.42930 (ASP) 0.050 4 Lens 2 −44.27610 (ASP) 0.347 Plastic 1.632 23.4 2.89 5 −1.76031 (ASP) 0.149 6 Lens 3 −1.41534 (ASP) 0.300 Plastic 1.632 23.4 −1.26 7 1.96073 (ASP) 0.071 8 Lens 4 −74.92590 (ASP) 0.757 Plastic 1.544 55.9 0.84 9 −0.45515 (ASP) 0.050 10 Lens 5 30.00000 (ASP) 0.330 Plastic 1.530 55.8 −1.13 11 0.58537 (ASP) 0.500 12 IR-filter Plano 0.200 Glass 1.517 64.2 — 13 Plano 0.341 14 Image Plano — Note: The reference wavelength is d-line 587.6 nm The content of Table 8-3 may be deduced from Table 8-2. TABLE 8-3 The Eighth Embodiment f (mm) 2.00 R10/f 0.29 Fno 2.80 CT3/CT4 0.40 HFOV(deg.) 37.3 | f/f4 | + | f/f5 | 4.15 v1 − v3 32.5 SL/TTL 1.01 v1 − (v2 + v3) 9.1 Td (mm) 2.49 | R1/R2 | 11.86 (ΣCT)/Td 0.87 FIG. 8B is a schematic view of longitudinal spherical aberration curves when the lights having a wavelength of 486.1 nm, 587.6 nm, and 656.3 nm are respectively projected in the optical imaging system in FIG. 8A. It can be known from FIG. 8B that, when the different wavelengths, 486.1 nm, 587.6 nm, and 656.3 nm, of the light are received by the optical imaging system 80 of this embodiment, the longitudinal spherical aberrations generated by the optical imaging system 80 are within a range of −0.02 mm to 0.02 mm. FIG. 8C is a schematic view of astigmatic field curves when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 8A. It can be known from FIG. 8C that, the astigmatic field curvature of the tangential plane generated when the light having the wavelength of 587.6 nm is projected in the optical imaging system 80 is within a range of −0.005 mm to 0.06 mm, and the astigmatic field curvature of the sagittal plane is within a range of −0.025 mm to 0.01 mm. FIG. 8D is a schematic view of a distortion curve when the light having the wavelength of 587.6 nm is projected in the optical imaging system in FIG. 8A. It can be known from FIG. 8D that, the distortion ratio generated when the light having the wavelength of 587.6 nm is projected in the optical imaging system 80 is within a range of −0.8% to 0.3%. As shown in FIGS. 8B to 8D, the optical imaging system 80, designed according to the eighth embodiment, is capable of effectively correcting various aberrations.
<SOH> BACKGROUND OF THE INVENTION <EOH>
<SOH> SUMMARY OF THE INVENTION <EOH>In response to the trend of development of miniature electronics and to solve the aforementioned problems, the present invention provides an optical imaging system designed for compact portable electronics and capable of improving the imaging quality of the optical imaging system. According to an embodiment of the present invention, an optical imaging system comprises, in order from an object side to an image side, a first lens element with positive refractive power comprises an object-side surface, a second lens element, a third lens element, a fourth lens element, and a fifth lens element. The fourth lens element comprises an object-side surface and an image-side surface, at least one of the object-side surface and the image-side surface of the fourth lens element is aspheric, and the fourth lens element is made of plastic. The fifth lens element comprises an object-side and a concave image-side surface, the image-side surface of the fifth lens element comprises at least one inflection point, and at least one of the object-side surface and the image-side surface of the fifth lens element is aspheric, and the fifth lens element is made of plastic. An axial distance is formed between each of the first lens element, the second lens element, the third lens element, the fourth lens element, and the fifth lens element, and the optical imaging system further comprises a stop, Td is an axial distance from the object-side surface of the first lens element to the image-side surface of the fifth lens element, SL is an axial distance from the stop to an image plane, TTL is an axial distance from the object-side surface of the first lens element to the image plane, and the optical imaging system satisfies the following conditions: in-line-formulae description="In-line Formulae" end="lead"? 2.00 mm<Td< 3.00 mm   (Condition 1): in-line-formulae description="In-line Formulae" end="tail"? in-line-formulae description="In-line Formulae" end="lead"? 0.65 <SL/TTL< 1.10   (Condition 2): in-line-formulae description="In-line Formulae" end="tail"? According to another embodiment of the present invention, an optical imaging system comprises, in order from an object side to an image side, a first lens element comprising an object-side surface, a second lens element having positive refractive power, a third lens element, a fourth lens element, and a fifth lens element. The fourth lens element comprises an object-side surface and an image-side surface, at least one of the object-side surface and the image-side surface of the fourth lens element is aspheric, and the fourth lens element is made of plastic. The fifth lens element comprises an object-side and a concave image-side surface, the image-side surface of the fifth lens element comprises at least one inflection point, and at least one of the object-side surface and the image-side surface of the fifth lens element is aspheric, and the fifth lens element is made of plastic, and the fifth lens element is made of plastic. The optical imaging system further comprises a stop, Td is an axial distance from the object-side surface of the first lens element to the image-side surface of the fifth lens element, SL is an axial distance from the stop to an image plane, TTL is an axial distance from the object-side surface of the first lens element to the image plane, and the optical imaging system satisfies the following conditions: in-line-formulae description="In-line Formulae" end="lead"? 2.00 mm< Td< 3.00 mm   (Condition 1): in-line-formulae description="In-line Formulae" end="tail"? in-line-formulae description="In-line Formulae" end="lead"? 0.65 <SL/TTL< 1.10   (Condition 2): in-line-formulae description="In-line Formulae" end="tail"? According to another embodiment of the present invention, an optical imaging system comprises, in order from an object side to an image side, a first lens element having positive refractive power, a second lens element, a third lens element, a fourth lens element, and a fifth lens element. The first lens element comprises an object-side surface and an image-side surface, at least one of the object-side surface and the image-side surface of the first lens element is aspheric. The second lens element comprises an object-side surface and an image-side surface, at least one of the object-side surface and the image-side surface of the second lens element is aspheric. The third lens element comprises an object-side surface and an image-side surface, at least one of the object-side surface and the image-side surface of the third lens element is aspheric. The fourth lens element comprises an object-side surface and an image-side surface, at least one of the object-side surface and the image-side surface of the fourth lens element is aspheric, and the fourth lens element is made of plastic. The fifth lens element comprises an object-side and a concave image-side surface, the image-side surface of the fifth lens element comprises at least one inflection point, and at least one of the object-side surface and the image-side surface of the fifth lens element is aspheric, and the fifth lens element is made of plastic, and the fifth lens element is made of plastic. An axial distance is formed between each of the first lens element, the second lens element, the third lens element, the fourth lens element, and the fifth lens element, and the optical imaging system further comprises a stop, Td is an axial distance from the object-side surface of the first lens element to the image-side surface of the fifth lens element, SL is an axial distance from the stop to an image plane, TTL is an axial distance from the object-side surface of the first lens element to the image plane, and the optical imaging system satisfies the following conditions: in-line-formulae description="In-line Formulae" end="lead"? 0.65 <SL/TTL< 1.10   (Condition 2): in-line-formulae description="In-line Formulae" end="tail"? in-line-formulae description="In-line Formulae" end="lead"? Td< 3.00 mm   (Condition 3): in-line-formulae description="In-line Formulae" end="tail"? According to another embodiment of the present invention, an optical imaging system comprises, in order from an object side to an image side, a first lens element, a second lens element having positive refractive power, a third lens element, a fourth lens element, and a fifth lens element. The first lens element comprises an object-side surface and an image-side surface, at least one of the object-side surface and the image-side surface of the first lens element is aspheric. The second lens element comprises an object-side surface and an image-side surface, at least one of the object-side surface and the image-side surface of the second lens element is aspheric. The third lens element comprises an object-side surface and an image-side surface, at least one of the object-side surface and the image-side surface of the third lens element is aspheric. The fourth lens element comprises an object-side surface and an image-side surface, at least one of the object-side surface and the image-side surface of the fourth lens element is aspheric, and the fourth lens element is made of plastic. The fifth lens element comprises an object-side and an image-side surface. The image-side surface of the fifth lens element comprises at least one inflection point, and at least one of the object-side surface and the image-side surface of the fifth lens element is aspheric, and the fifth lens element is made of plastic The optical imaging system further comprises a stop, Td is an axial distance from the object-side surface of the first lens element to the image-side surface of the fifth lens element, SL is an axial distance from the stop to an image plane, TTL is an axial distance from the object-side surface of the first lens element to the image plane, and the optical imaging system satisfies the following conditions: in-line-formulae description="In-line Formulae" end="lead"? 0.65 <SL/TTL< 1.10   (Condition 2): in-line-formulae description="In-line Formulae" end="tail"? in-line-formulae description="In-line Formulae" end="lead"? Td< 3.00 mm   (Condition 3): in-line-formulae description="In-line Formulae" end="tail"? When the optical imaging system satisfies Condition 1 or Condition 3 can miniaturize the optical imaging system. Therefore, the optical imaging system is suitable for lightweight, slim, and portable electronics. When the result of SL/TTL is close to 1.10, an exit pupil of the optical imaging system is away from the image plane. The angle of incidence with incoming light projecting onto the sensor would be close to perpendicular and a telecentric characteristic of the image-side would be more pronounced. Therefore, when an electronic sensor is disposed on the image plane, the photo-sensing capability of the electronic sensor is improved and the shading occurrences will be minimized. Having SL/TTL close to 0.65 can widen the view angle and can correct both distortion and chromatic aberration of magnification. In addition, the sensitivity of the optical imaging system is effectively reduced.
G02B130045
20170831
20171221
76070.0
G02B1300
1
PICHLER, MARIN
OPTICAL IMAGING SYSTEM
UNDISCOUNTED
1
CONT-ACCEPTED
G02B
2,017
15,694,786
PENDING
Exclusive Delivery of Content Within Geographic Areas
Application developers can request to have their applications registered for use with a content delivery platform. The operator of the content delivery platform establishes perimeters defining geographic areas, and maintains records reserving particular areas for delivery of content associated with particular sponsors. Registered applications running on mobile devices can request content from the content delivery platform. Based at least in part on the request, the content delivery platform can identify a target location, which may be the location of the mobile device, or some other location indicated in the request. A mobile device can be provided content based on the relationship of the target location to the geographic areas, so that a registered application running on a mobile device with a target location contained within a geographic area assigned to a particular sponsor will receive content related to that sponsor.
1. A mobile device comprising: memory; at least one processor operably coupled to the memory; a location-determination component; and at least one module configured for execution by the at least one processor, wherein the at least one module comprises at least one instruction for: receiving, from an application program during its execution in the mobile device, one or more requests to reserve at least one designated geographic area of interest, wherein the at least one designated geographic area of interest in each of the one or more requests is being requested via said application program to be reserved for having a particular identifier associated with the at least one designated geographic area of interest provided to said application program after it has been determined, by at least use of the at least one processor and of location information representing a physical geographic location of the mobile device as determined by the location-determination component, that the mobile device has at least entered the at least one designated geographic area of interest, and wherein each of the one or more requests comprises data representing a) said particular identifier, represented by a data string, as content provided via said application program to be associated with the at least one designated geographic area of interest, and b) at least one latitude value, at least one longitude value, and at least one radius value, each being provided via said application program, to be used for defining the at least one designated geographic area of interest; registering said application program, in the memory, for having said particular identifier provided to said application program after it has been determined, by at least use of the at least one processor and of the location information, that the mobile device has at least entered the at least one designated geographic area of interest; after it has been determined, by at least use of the at least one processor and of the location information, that the mobile device has at least entered the at least one designated geographic area of interest and has remained therein for at least a designated length of time, selecting, from the memory, said particular identifier as stored therein; and providing at least said particular identifier to said application program, subject to the selecting. 2. The mobile device of claim 1 wherein the at least one module further comprises at least one instruction for: storing, in the memory, at least one record, for said application program, associated with said particular identifier and the at least one designated geographic area of interest; obtaining mobile device location information comprising at least one physical geographic location of the mobile device as determined by the location-determination component; and determining, by at least use of the at least one processor, of the mobile device location information, and of the at least one designated geographic area of interest associated with the at least one record stored in the memory for said application program, that the mobile device has at least entered the at least one designated geographic area of interest associated with the at least one record stored in the memory and has remained therein for at least the designated length of time. 3. The mobile device of claim 2 wherein: storing the at least one record includes storing the at least one record after availability for the at least one designated geographic area of interest to be reserved per each of the one or more requests has been positively determined; and the at least one module further comprises at least one instruction for: determining availability for the at least one designated geographic area of interest to be reserved for said application program. 4. The mobile device of claim 2 wherein the at least one module further comprises at least one instruction for: after providing at least said particular identifier to said application program, subject to the selecting, displaying, on the mobile device via a graphical user interface tangibly embodied by the mobile device and via said application program, content related to the at least one designated geographic area of interest. 5. The mobile device of claim 2 wherein the at least one module further comprises at least one instruction for: creating a notification indicating that the mobile device has at least entered the at least one designated geographic area of interest associated with the at least one record stored in the memory. 6. The mobile device of claim 2 wherein the at least one module further comprises at least one instruction for: receiving a data value representing the designated length of time. 7. The mobile device of claim 2 wherein the at least one instruction for receiving, from an application program during its execution in the mobile device, one or more requests to reserve at least one designated geographic area of interest includes being at least one instruction for receiving, from at least one other application program during its execution in the mobile device, one or more other requests to reserve at least one other designated geographic area of interest. 8. The mobile device of claim 7 wherein the at least one module further comprises at least one instruction for: using the at least one designated geographic area of interest with said particular identifier to establish the at least one designated geographic area of interest in each of the one or more requests as an area reserved for content related to said application program and not an area reserved for content related to the at least one other application program. 9. The mobile device of claim 2 wherein: selecting, from the memory, said particular identifier as stored therein after it has been determined, by at least use of the at least one processor and of the location information, that the mobile device has at least entered the at least one designated geographic area of interest and has remained therein for at least a designated length of time includes selecting, from the memory, said particular identifier as stored therein after it has been determined, by at least use of the at least one processor and of the location information, that the mobile device, following a designated start time and during a designated duration of time, has at least entered the at least one designated geographic area of interest and has remained therein for at least the designated length of time; and the at least one module further comprises at least one instruction for: receiving a data value representing the designated duration of time. 10. A non-transitory computer readable medium tangibly embodying at least one program of computer executable instructions, wherein the at least one program of computer executable instructions comprises at least one instruction for: receiving, on a mobile device, from an application program during its execution in the mobile device, one or more requests to reserve at least one designated geographic area of interest, wherein the at least one designated geographic area of interest in each of the one or more requests is being requested via said application program to be reserved for having a particular identifier associated with the at least one designated geographic area of interest provided to said application program after it has been determined, by at least use of at least one processor tangibly embodied by the mobile device and of location information representing a physical geographic location of the mobile device as determined by a location-determination component tangibly embodied by the mobile device, that the mobile device has at least entered the at least one designated geographic area of interest, and wherein each of the one or more requests comprises data representing a) said particular identifier, represented by a data string, as content provided via said application program to be associated with the at least one designated geographic area of interest, and b) at least one latitude value, at least one longitude value, and at least one radius value, each being provided via said application program, to be used for defining the at least one designated geographic area of interest; registering said application program, in a memory tangibly embodied by the mobile device, for having said particular identifier provided to said application program after it has been determined, by at least use of the at least one processor and of the location information, that the mobile device has at least entered the at least one designated geographic area of interest; after it has been determined, by at least use of the at least one processor and of the location information, that the mobile device has at least entered the at least one designated geographic area of interest and has remained therein for at least a designated length of time, selecting, from the memory, said particular identifier as stored therein; and providing at least said particular identifier to said application program, subject to the selecting. 11. The computer readable medium of claim 10 wherein the at least one program of computer executable instructions further comprises at least one instruction for: storing, in the memory, at least one record, for said application program, associated with said particular identifier and the at least one designated geographic area of interest; obtaining mobile device location information comprising at least one physical geographic location of the mobile device as determined by the location-determination component; and determining, by at least use of the at least one processor, of the mobile device location information, and of the at least one designated geographic area of interest associated with the at least one record stored in the memory for said application program, that the mobile device has at least entered the at least one designated geographic area of interest associated with the at least one record stored in the memory and has remained therein for at least the designated length of time. 12. The computer readable medium of claim 11 wherein: storing the at least one record includes storing the at least one record after availability for the at least one designated geographic area of interest to be reserved per each of the one or more requests has been positively determined; and the at least one program of computer executable instructions further comprises at least one instruction for: determining availability for the at least one designated geographic area of interest to be reserved for said application program. 13. The computer readable medium of claim 11 wherein the at least one program of computer executable instructions further comprises at least one instruction for: after providing at least said particular identifier to said application program, subject to the selecting, displaying, on the mobile device via a graphical user interface tangibly embodied by the mobile device and via said application program, content related to the at least one designated geographic area of interest. 14. The computer readable medium of claim 11 wherein the at least one program of computer executable instructions further comprises at least one instruction for: creating a notification indicating that the mobile device has at least entered the at least one designated geographic area of interest associated with the at least one record stored in the memory. 15. The computer readable medium of claim 11 wherein the at least one program of computer executable instructions further comprises at least one instruction for: receiving a data value representing the designated length of time. 16. The computer readable medium of claim 11 wherein the at least one instruction for receiving, from an application program during its execution in the mobile device, one or more requests to reserve at least one designated geographic area of interest includes being at least one instruction for receiving, from at least one other application program during its execution in the mobile device, one or more other requests to reserve at least one other designated geographic area of interest. 17. The computer readable medium of claim 16 wherein the at least one program of computer executable instructions further comprises at least one instruction for: using the at least one designated geographic area of interest with said particular identifier to establish the at least one designated geographic area of interest in each of the one or more requests as an area reserved for content related to said application program and not an area reserved for content related to the at least one other application program. 18. The computer readable medium of claim 11 wherein: selecting, from the memory, said particular identifier as stored therein after it has been determined, by at least use of the at least one processor and of the location information, that the mobile device has at least entered the at least one designated geographic area of interest and has remained therein for at least a designated length of time includes selecting, from the memory, said particular identifier as stored therein after it has been determined, by at least use of the at least one processor and of the location information, that the mobile device, following a designated start time and during a designated duration of time, has at least entered the at least one designated geographic area of interest and has remained therein for at least the designated length of time; and the at least one program of computer executable instructions further comprises at least one instruction for: receiving a data value representing the designated duration of time. 19. A method comprising: sending a request, via a particular application program executing in a mobile device, to at least one program of computer executable instructions operating in the mobile device, to reserve a particular designated geographic area of interest for having a specific identifier associated with the particular designated geographic area of interest provided to the particular application program after it has been determined that the mobile device has at least entered the particular designated geographic area of interest, wherein the request comprises data representing a) the specific identifier to be associated with the particular designated geographic area of interest, and b) a particular latitude value, a particular longitude value, and a particular radius value to be used for defining the particular designated geographic area of interest, and wherein the at least one program of computer executable instructions comprises at least one instruction for: receiving, on the mobile device, from an application program during its execution in the mobile device, one or more requests to reserve at least one designated geographic area of interest, wherein the at least one designated geographic area of interest in each of the one or more requests is being requested via said application program to be reserved for having a particular identifier associated with the at least one designated geographic area of interest provided to said application program after it has been determined, by at least use of at least one processor tangibly embodied by the mobile device and of location information representing a physical geographic location of the mobile device as determined by a location-determination component tangibly embodied by the mobile device, that the mobile device has at least entered the at least one designated geographic area of interest, and wherein each of the one or more requests comprises data representing a) said particular identifier, represented by a data string, as content provided via said application program to be associated with the at least one designated geographic area of interest, and b) at least one latitude value, at least one longitude value, and at least one radius value, each being provided via said application program, to be used for defining the at least one designated geographic area of interest; registering said application program, in a memory tangibly embodied by the mobile device, for having said particular identifier provided to said application program after it has been determined, by at least use of the at least one processor and of the location information, that the mobile device has at least entered the at least one designated geographic area of interest; after it has been determined, by at least use of the at least one processor and of the location information, that the mobile device has at least entered the at least one designated geographic area of interest and has remained therein for at least a designated length of time, selecting, from the memory, said particular identifier as stored therein; and providing at least said particular identifier to said application program, subject to the selecting. 20. The method of claim 19, further comprising: implementing, in the mobile device, the at least one program of computer executable instructions.
CROSS REFERENCE TO RELATED APPLICATIONS This continuation patent application claims priority from co-pending U.S. Non-provisional patent application having Ser. No. 15/009,961, filed 29 Jan. 2016, entitled “EXCLUSIVE DELIVERY OF CONTENT WITHIN GEOGRAPHIC AREAS”, which claims priority from co-pending U.S. Non-provisional patent application having Ser. No. 14/608,285, filed 29 Jan. 2015, entitled “EXCLUSIVE DELIVERY OF CONTENT WITHIN GEOGRAPHIC AREAS”, now U.S. Pat. No. 9,286,625 issued on 15 Mar. 2016, which claims priority from co-pending U.S. Non-provisional patent application having Ser. No. 13/856,392, filed 3 Apr. 2013, entitled “EXCLUSIVE DELIVERY OF CONTENT WITHIN GEOGRAPHIC AREAS”, now U.S. Pat. No. 8,977,247 issued on 10 Mar. 2015, which claims priority from co-pending U.S. Non-provisional patent application having Ser. No. 12/434,094, filed 1 May 2009, entitled “EXCLUSIVE DELIVERY OF CONTENT WITHIN GEOGRAPHIC AREAS”, now U.S. Pat. No. 8,433,296 issued on 30 Apr. 2013, all having a common applicant herewith and being incorporated herein in their entirety by reference. FIELD This disclosure relates generally to delivery of content, and more particularly to delivery of content within reserved geographic areas. BACKGROUND Advertisements can be delivered to various devices, including mobile devices, within communications range of areas transmitters or other information providers. For example, advertisements can be delivered to cellular phones within range of a particular cellular phone provider's network area. Furthermore, advertisements can be delivered using digital billboards, or via the Internet, based on user interactions and preferences. When delivering advertisements and other content to some mobile devices, currently available technologies can broadcast the content to all devices equipped to receive them. In some cases, advertisements are broadcast to any mobile device within a city, or a similar area. When delivering non-broadcast content, for example via the Internet, it is common to deliver the content in response to a request, received from the receiving device. In some cases, push technology can be used to deliver content to multiple users concurrently. In each of these cases, a mobile device can usually receive content from multiple different content providers. Current technologies are, therefore, less than perfect. SUMMARY Various embodiments disclosed herein include registering an application program for use with a content delivery platform, establishing multiple perimeters defining respective geographic areas, and maintaining records associating sponsors with particular geographic areas. The content delivery platform can receive a request from a registered application program for content to be displayed on a mobile device, and the request can be used to determine a target location. In some embodiments, a sponsor is selected based on a relationship between the target location and one or more reserved geographic areas. Content is then provided to the application program. In some embodiments, the content delivery platform can record a request identifier associated with a received request, and provide the request identifier to the mobile device to assist in tracking future actions relating to the request for content. The content delivery platform can also receive information related to user interaction with the provided content, including the request identifier, and provide additional content in response to the received information. Content can be delivered to a mobile device running a registered application if a target location is at least partially within a predetermined radial distance of a geographical area associated with a sponsor; if the mobile device is not located within the predetermined radial distance, the radial distance can be increased. In some embodiments, content is delivered if the target location, e.g. the location of the mobile device or another location of interest, is located entirely within a geographic area exclusively reserved by a particular sponsor. In some embodiments, the content delivery platform can select from among several sponsors in deciding which content to deliver to a mobile device. In at least one embodiment, the content delivery system reserves exclusive interests in geographic areas for particular sponsors based on the sponsors' requests, and store a record of that interest. In some embodiments, the content delivery system receives, from a sponsor, content to be delivered to mobile devices based on a target location being positioned within particular geographic areas. The content delivery system can also reserve an interest in geographic areas that remain unreserved by other sponsors. Furthermore, some embodiments include time based restrictions. Various embodiments can be implemented as a system that includes memory, a communications interface, and a processor that cooperate to store and execute a program of instructions implementing various methods and techniques described herein. Furthermore, some embodiments can be implemented as a computer readable medium tangibly embodying a program of instructions. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an abstract representation of exclusive content delivery to particular reserved areas according to various embodiments of the present disclosure; FIG. 2 is a diagram illustrating a target location other than the location of the mobile device executing a registered application, according to embodiments of the present disclosure; FIG. 3 is a graph representing expanded search areas to determine which content is delivered according to various embodiments of the present disclosure; FIG. 4 is a flowchart illustrating a method of reserving a geographic area according to embodiments of the present disclosure; FIG. 5 is a flowchart illustrating registration of an application for content delivery according to embodiments of the present disclosure; FIG. 6 is a flowchart illustrating delivery of content to particular applications in a reserved area according to embodiments of the present disclosure; FIG. 7 is a diagram illustrating a processing system according to embodiments of the present disclosure. DETAILED DESCRIPTION Various embodiments of the present disclosure provide for delivering content, such as advertising, to registered applications being run on any of various mobile electronic devices configured to be readily moved, carried, or otherwise transported between different various geographic areas defined by perimeters. Sponsors can reserve an exclusive interest, or in some embodiments a semi-exclusive interest, in a geographic area, so that other sponsors' advertisements are excluded from being broadcast or otherwise provided to a registered program being executed on a mobile device located within a reserved geographic area. Referring first to FIG. 1, system 100, is illustrated. System 100 can provide for exclusive delivery of advertising or other content to registered applications running on mobile devices located within a particular proximity to a reserved geographic area. System 100, as illustrated, includes content delivery platform 112, which is in communication with developer platform 108, and systems or individuals operating under control of sponsor A 121, sponsor C 123, and sponsor B 125. Content delivery platform 112 receives a request from developer platform 108 to register a program or other application for use on mobile devices. Content delivery platform 112 can use the registered application program to provide selected content to mobile devices. In some embodiments, a registered application program is provided to mobile devices by developer platform 108, content delivery platform 112, one of sponsor A 121, sponsor C 123, or sponsor B 125, or by another desired delivery mechanism. In some embodiments, registering the application program with content delivery platform 112 allows developer 108 to receive revenue from sponsor A 121, sponsor C 123, or sponsor B 125 for content displayed on a mobile device located within, or in proximity to, a geographical area reserved by one or more of the sponsors. Sponsor A 121, sponsor C 123, or sponsor B 125 can reserve an exclusive interest in a particular geographic area by sending a request to content delivery platform 112. In some embodiments, the request can be for exclusive delivery of content to mobile devices running any registered application within given geographic areas, or for content to be delivered to particular registered applications based on a target location. The request can also include time limitations, limitations based on the length of time a mobile device remains within a given geographic area, or other desired limitations. Furthermore, the reserved interest can be either completely exclusive, or semi-exclusive. System 100 can include a network, for example Internet 131, through which content delivery platform 112, can communicate to other networked devices; and communication towers 144, which can include AM or FM broadcast towers, mobile telephone stations, or other suitable communication infrastructure, including satellites (not illustrated) that might be useful in providing content based on a target location. Content delivery platform 112 can use this communication infrastructure to communicate with various computing devices, including portable computer 179, which may include laptop computers, desktop computers, palmtop computers, tablet computers, digital video recorders (DVRs), television set-top boxes, or any of various general or dedicated purpose computers that can be carried or transported; wireless device 177, which can include personal digital assistants (PDAs), cellular telephones, personal communication system (PCS) devices, music players, video players, gaming consoles, or portable televisions; or any of various devices that may be included in, or carried by, motor vehicles 171, 173, or 175, including navigation systems, satellite radios, or the like. It should be noted that the term “mobile device” can include all computing devices as listed above that can communicate with content delivery platform 112, that the above listing of devices is not exhaustive, and that a device that qualifies as one type of device may also be considered to be of another type. For example, a mobile phone may also be a general purpose computing device, a radio, a television, and a navigation system. Still referring to FIG. 1, consider first motor vehicle 171, which is located within sponsor A's reserved geographic area 143. A driver of first motor vehicle 171 can receive advertisements or other content from Sponsor A via a registered application running on a radio, a PDA, a cellular telephone, a laptop, or a global positioning navigation device (none of which are specifically illustrated). In this example, because first motor vehicle 171 is located within sponsor A's reserved geographic area 143, content delivery platform 121 provides content exclusively related to sponsor A 121; advertisements or other content from sponsor C 123 and sponsor B 125 can be excluded. Portable computer 179 can be connected to Internet 131 via a hardwired network connection, a Wi-Fi connection or other suitable communication connection. In some embodiments, if portable computer 179 is running a registered program application, the user of portable computer 179 will receive content related exclusively to sponsor A as long as he is within sponsor A's reserved geographic area 143. In some embodiments, the driver of first motor vehicle 171 and the user of laptop 179 will still be able to receive advertisements from other sponsors through devices not running a program that has been registered on content delivery platform 112, or through non-registered programs running on the same device. In some embodiments, the location of mobile devices, or another target location, can be determined using various suitable methods. For example, a mobile device running a registered application can provide location information to content delivery platform 112 in the form of latitude or longitude coordinates, raw or processed GPS data, or other location information received and recorded by either the device itself or another device. In some embodiments, a target location, e.g. the location of a mobile device, can be determined based on signals received from cellular transmission towers, satellites, or methods such as triangulation or dead reckoning, or by IP address. Content delivery platform 112 can receive the location of mobile devices from a third source, for example a location provider, a cellular telephone network provider, or a third party tracking source, rather than from the mobile device itself. Thus, the location of a mobile device can be received from the mobile device, determined by content delivery platform 112, received from a third-party source, or determined based on a combination of these or other methods. Sponsor A's reserved geographic area 143 illustrates an embodiment in which a perimeter can be defined by streets, county boundaries, city boundaries, landmarks, or other features commonly found on maps. In contrast, sponsor B's reserved geographic area 145 can be an ellipse, circle, oval, or other geometric shape that can be determined, at least in part, based on a radius. In this example, both second motor vehicle 173 and wireless device 177 are located within sponsor B's reserved geographic area 145. The driver of second motor vehicle 173 and the user of wireless device 177 can receive advertisements or other content via towers 144. For example, if the driver of second motor vehicle 173 is operating a navigation device executing an application program registered by developer 108, advertisements and other content received on the navigation device can be determined based on the location within sponsor B's reserved geographic area 145. Likewise, the user of wireless device 177 will receive advertisements related to sponsor B from within a registered application. In some embodiments, content delivery platform 112 can prevent content from sponsor A 121 and sponsor C 123 from being delivered to a mobile device carried by second motor vehicle 173 and wireless device 177, because both motor vehicle 173 and wireless device 177 are located in sponsor B's reserved geographic area 145. Turning next to sponsor A and sponsor C's reserved geographic area 147, note that the perimeter is a square, rectangle or similarly shaped. In some embodiments, the perimeter may be defined entirely by longitude and latitude lines and/or coordinates that constitute an area. In other embodiments, sponsor A and sponsor C's reserved geographic area 147 can be partially bounded by a longitude or latitude line, a road, river, railway, county, state, parish, city, locality, or other desired boundary. In some embodiments, the perimeter of a sponsor A and sponsor C's reserved geographic area 147 can be defined by a combination of longitude or latitude lines, with one or more remaining boundaries defined based on radius or diameter. Because third motor vehicle 175 is within sponsor A and sponsor C's reserved geographic area 147, a mobile device carried by third motor vehicle 175 can receive advertising content from either or both sponsor A and sponsor C. In some embodiments, the interest in sponsor A and sponsor C's reserved geographic area 147 can be equally divided between sponsor A 121 and sponsor C 123, while in other embodiments one of sponsor A 121 and sponsor C 123 can have an interest superior to that of the other. In some embodiments, content delivery platform 112 can deliver advertisements or other content related to Sponsor A at selected times, while content related to Sponsor C is delivered at other times. Additionally, content related to sponsor A may be delivered via a first registered application, while content related to sponsor C can be delivered via a second registered application. Thus, sponsors can advertise or provide other content to members of particular demographics based on a type of application a particular demographic is more likely to use. Referring next to FIG. 2, a target location other than a mobile device in a system 200 is illustrated according to embodiments of the present disclosure. As shown in FIG. 2, a user of registered application 231 is located within the perimeter defining first sponsor's reserved area 207. Object of interest 233 is located in second sponsor's reserved area 205. In some embodiments, object of interest 233 can be any type of object of interest to the user of registered application 231. For example, object of interest 233 could be a friend of the user of registered application 231, and this friend may be employing a mobile phone, a laptop, a kiosk computer, a PDA, or any other device capable of sending location information 216 directly or indirectly to registered application 231. In some embodiments, target location information 216 can be any type of information that can be used to determine the location of the object of interest 233. In at least one embodiment, target location information 216 may be a geocoded twitter message. In another example, object of interest 233 could be an end destination on a map, and the location information 216 of this end destination can be sent to registered application 231. In response to receiving the target location information 216 from object of interest 233, registered application 231 can send a request 213 to content delivery platform 212. The request can include, but is not limited to, information indicating the location of object of interest 233, a request for content, information indicating the location of registered application 231, information indicating the identity of the registered application 231, and a previously received request identifier. Content delivery platform 212 can receive and process request 213 to identify the location of registered application 231 and the location of object of interest 233. In some embodiments, both locations need not be identified. Furthermore, in some embodiments the specific location need not be identified, as long as a determination that object of interest 233 is located within a given proximity of second sponsor's reserved area 205, or that registered application 231 is located within first sponsor's reserved area 207. Content delivery platform 212 can provide registered application information 217 to second sponsor 225 to allow second sponsor 225 to deliver second sponsor's content 214 to registered application 231. The registered application information 217 can be an application identifier, a request identifier, a target location, a communications address, or other information that can be utilized by second sponsor 225. In some embodiments, application information 217 need not be provided to second sponsor 225, but instead can be processed internally by content delivery platform 212, and a determination can be made for second sponsor's content 214 to be delivered directly to application 231 from content delivery platform 212, or a third party (not illustrated). Note that in the illustrated embodiment, despite the fact that registered application 231 is located within first sponsor's reserved area 207, the information delivered to registered application 231 can be content related exclusively to second sponsor's reserved area 205, in which object of interest 233 is located. This is because, in the illustrated embodiment, the target location is the location of object of interest 233, rather than the location of a mobile device executing registered application 231. In some embodiments, information from the first sponsor can also be delivered to registered application 231, because the locations of the device running registered application 231 and object of interest 233 are both considered target locations. Furthermore, in some embodiments content need not be delivered directly from second sponsor 225, but instead can be provided by content delivery platform 212, or a third party (not illustrated). Referring next to FIG. 3, a graph showing various geographic areas with reference to longitude and latitude is illustrated according to some embodiments of the present disclosure. The geographic areas in FIG. 3 are for illustration only and carry no particular significance with respect to their geometric shapes. Graph 300 includes a triangular area 320, reserved for sponsor A; pentagonal area 371, reserved for sponsor G; and octagonal area 330, also reserved for sponsor G. In the illustrated example, sponsor G has two physical addresses: G1 327, which lies within sponsor G's reserved octagonal area 330, and G2 328 which, lies within sponsor A's reserved triangular area 320. Furthermore, in the illustrated embodiment, sponsor A does not have a physical location within sponsor A's reserved triangular area 320. These examples help illustrate that there is not necessarily a correlation between a sponsor's physical address and a reserved geographic area, although in some embodiments there may be such a correlation. As illustrated by FIG. 3, a single target location F 333 is located within sponsor G's reserved octagonal area 330, and target location F 333 can be a mobile device running a registered application, or target location F 333 can represent a target location other than the location of a mobile device, as illustrated in FIG. 2. In some embodiments, the mobile device with target location F 333 receives advertising exclusively from advertiser G. As further illustrated by FIG. 3, there are four target locations: target location A 321, target location B 323, target location C 325, and target location G 392 within advertiser A's reserved triangular area 320. Note also, however, that target location G 392 also lies within one of sponsor G's reserved geographic areas, pentagonal area 371. Consider the following example in which target location A 321 and target location B 323 each are mobile devices executing a first application registered with a content delivery platform, such as content delivery platform 112, of FIG. 1. Further assume, for purposes of this example, that target location C 325 is a mobile device executing a second, different application, which is also registered with the content delivery platform. Because both the first and second applications are registered with the content delivery platform, each of the three devices, with target location A 321 target location B 323 and target location C 325 can receive advertisements or other content from within their respective applications. In this example, the content delivered to all three devices can be related exclusively to sponsor A, regardless of which registered application is being executed, because sponsor A has the only reserved interest in the portions of triangular area 320 occupied by mobile devices having target locations A 321 B 323 and C 325. In some embodiments, target location G 392 can be a mobile device running two or more registered applications, and can receive content related to sponsor A, because the mobile device lies within triangular area 320. But, target location G 392 also lies within pentagonal area 371, and the mobile device can therefore receive content associated with sponsor G. In some embodiments, content related to sponsor A can be delivered via one of the registered applications, while another registered application receives and displays content related to sponsor G. In other embodiments, one of sponsor A or sponsor G can have a superior interest to the other, and a preference can be given to that sponsor's content for delivery. For example, sponsor G may have a superior interest in pentagonal area 371, which also forms part of triangular area 320. In such a case, if content related to sponsor G is available for delivery to the application on the mobile device with target location G 392, that content will be delivered in preference to content related to sponsor A. However, if there is no high priority content related to sponsor G to be delivered, content related to sponsor A may be provided in its stead. Various other priority and time sharing mechanisms and methods can be implemented according to the teachings set forth herein. Note that in some embodiments, multiple registered applications are not required to implement priority and time sharing mechanisms. In some instances, a mobile device can have target locations, such as target location D 324 or target location E 356, located outside of areas reserved by sponsors. In such a case, a check can be made to determine if either target location D 340 or target location E 356 are located within a given proximity of a sponsor-reserved area such as triangular area 320 or octagonal area 330. So, for example, a check can be made to determine whether any reserved areas lie within a given radius of target location D 340, defining a search area 341, or within a given radius of target location E 356, defining a search area 351. In some embodiments, if no sponsor reserved area intersects an area within an initially small radius, further checks can be performed by incrementally increasing the radius. So, for example, after a first check finds no advertiser reserved areas within search areas 341 or 351, the search areas can be increased to encompass areas 343 and 353, respectively. In the illustrated example, there is no reserved area intersecting search area 353, but sponsor H 357 has a physical address within area 353. In some embodiments, once it is determined that a registered sponsor has a physical address location within a search radius, but there are no sponsor reserved geographic areas in proximity to or encompassing a target location, an advertisement or other content can be delivered to a mobile device, such as the device with target location 356. Another situation arises when there are no sponsor reserved geographic areas intersecting a search area, but there are multiple sponsor physical locations within a given radius. Consider area 343, which contains sponsor E's location 349, and sponsor F's location 347. Because neither sponsor E nor sponsor F has established a reserved area that intersects with search area 343, a random choice can be made between these two sponsors to determine which sponsor's content to provide to the registered application on the device with target location D 340. In other embodiments, preference may be given to one of sponsor E's location 349 and sponsor F's location 347 based on each physical locations' proximity to target location D 340, based on a travel time between the device with target location D 340 and the sponsors' locations, or based on some other desired parameter. In further embodiments, if no sponsor's reserved geographic area intersects any portion of area 343, no content is sent to mobile device D with target location 340, despite the fact that location sponsor E's location 359, and sponsor F's location 347 are both within the perimeter defining search area 343. In some embodiments, the search radius can continue to be expanded until a search area 345 intersects with a sponsor reserved geographic area. In the illustrated embodiment, search area 345 intersects sponsor A's reserved triangular area 320. Note that sponsor G2's physical location 328 is also located within search area 345. In some embodiments, content from either sponsor A or sponsor G can be selected using any of various processes, because target location D 340 is not located entirely within triangular area 320. In some embodiments, however, because the expanded search area 345 encompasses even a portion of sponsor A's reserved triangular area 320, content related to sponsor G will be excluded, and content related to sponsor A will be exclusively provided to mobile device with target location D 340. In some embodiments, because target location D 340 is not located within sponsor A's reserved triangular area 320, content related to sponsor A will be excluded, and content related to sponsor G will be exclusively provided to mobile device with target location D 340. Additional techniques accounting for the proximity of exclusively reserved advertising areas and sponsor's physical locations with respect to mobile device locations can be implemented according to the teaching set forth herein. For example, in some embodiments, sponsors may obtain an interest in all otherwise unreserved geographic areas. For example, a content delivery system can deliver content from a “default” sponsor, if it is determined that no other content is to be delivered to a mobile device. Referring next to FIG. 4, a method 400 for allowing sponsors to reserve particular geographic areas will be discussed according to embodiments of the present disclosure. Method 400 begins, as illustrated by block 401. As illustrated by block 403, a content delivery platform, for example content delivery platform 112 as illustrated in FIG. 1, can receive a request for sponsor registration, which can also include receiving physical address location from the sponsor. As illustrated by block 405, the sponsor can establish perimeters defining geographic areas of exclusive or semi-exclusive control. These geographic areas are areas the sponsor wishes to reserve for delivery of his own advertisements or other content controlled by the sponsor. The perimeters established can be based on map features, such as streets, rivers, landmarks, or any of the other various map features. The perimeters can also be defined by latitude and longitude, or various geometric constructs having a given relative position to either a point location, a map location, a physical address, or otherwise. Some embodiments allow for establishing perimeters defining areas based on a combination of the various types of constructs. So, for example, latitude, longitude and map features may be used to establish the reserved area, or a combination of coordinates and geometric constructs can be used in conjunction with other suitable boundary identifiers to establish an area that may be reserved specifically for content related to a particular advertiser or sponsor. In some embodiments, the perimeters may be generated interactively, using sponsor established perimeter definitions, or other unique sponsor requests. Some embodiments employ pre-defined areas, or allow selection of areas based on predetermined factors, and present sponsors a choice from among previously established options. As illustrated by block 407, a sponsor's request for a selected area is received. As illustrated by block 409, a check is made to determine if the selected area, or a portion of the selected area, has already been reserved by another sponsor. If the area selected by the sponsor is already owned or is otherwise unavailable, method 400 may return to block 407, and the sponsor can choose another area. In some embodiments, overlap of various sponsor areas may be allowed based on type of business, type of application used to deliver the content, or otherwise. As illustrated by block 411, if an area selected for exclusive or semi-exclusive content delivery is available, the selected geographic area can be reserved for the sponsor. And as illustrated by block 413, the sponsor can be notified that an interest in the geographic area has been reserved for him. A sponsor can provide content for delivery to mobile devices having target locations contained within its reserved area, as illustrated by block 415. This content can include advertisements, still image content, animated content, video content, audio content, alphanumeric identifiers, or other content suitable for delivery to mobile devices via registered applications. As illustrated by block 417, the content received from the sponsor can be stored for later delivery to registered applications running on mobile devices having target locations that exist within the sponsor's reserved area, which such target locations may include, but are not limited to, when the mobile device or target location physically enters or remains within the sponsor's reserved area for a desired length of time. In some embodiments, content can be delivered to a mobile device by the sponsor or another party in response to a notification that the mobile device or target location has entered or is contained within the sponsor's reserved area. Method 400 ends, as illustrated at block 419. Referring next to FIG. 5, a method 500 of registering an application program for use in conjunction with a content delivery platform is illustrated according to various embodiments of the present disclosure. Method 500 begins as illustrated by block 501. As illustrated by block 503, an application can be registered on a content delivery platform in response to a request by a developer, for example developer 108 as illustrated in FIG. 1. As illustrated by block 505, a request for content can be received from a device running a registered application. In some embodiments, the same registered application may be executed on any of various mobile devices, including mobile telephones, personal digital assistants, laptops, and the like. Furthermore, multiple devices may execute copies of the same registered application, multiple different registered applications may be executed on a single mobile device, and multiple different registered applications may be executed on multiple devices. As illustrated by block 507 a determination is made as to whether the application sending the request for content has a target location that is located within a sponsor's reserved geographic area. In some embodiments, the target location may be the location of the device. In some embodiments, the target location may be a location other than the location of the device, as illustrated in FIG. 2. As illustrated by block 509, if the target location is located within a sponsor's reserved area, content from the corresponding sponsor can be chosen for delivery to the mobile device. The content can be chosen based on a number of different parameters or combinations of parameters. In some embodiments, different sponsors may designate particular content to be provided on different days of the week or at different times of day. Some such embodiments allow a single geographic area to be shared by different advertisers or sponsors. For example, content associated with a first sponsor may be selected for delivery in a particular geographic area during the lunch hour, while content related to a second sponsor is selected for delivery in that same geographic area between the hours of midnight and 2 am. In some embodiments, content from one sponsor can be selected for delivery in a particular geographic area in specific situations, even though a different sponsor has generally reserved that same geographic area. For example, content from a first sponsor can be delivered during a football game to mobile devices located in a geographic area normally reserved by a second sponsor, effectively trumping content related to the second sponsor that would otherwise be delivered. In some embodiments, additional criteria can be applied to determine which sponsors' content will be provided to mobile devices in a particular geographic area. As illustrated by block 511, selected content can be provided to an application for display on a mobile device. In at least one embodiment, different content from the same sponsor can be provided to the same device for display within different applications, or the same content from the same sponsor can be displayed for all mobile devices running all registered applications that have target locations within the delivery area for the content. For example, a first program run on a mobile device may display a first advertisement within that program while a second program running on the same device may display a second advertisement, which is different from the first advertisement. In some embodiments in which an interest in a particular geographic area is shared between multiple sponsors, a primary sponsor's content can be exclusively displayed via a first registered application running on a particular mobile device, while content from other sponsors can be displayed via a second and subsequent applications running on the same mobile device. As illustrated by block 513, if the target location is not within a sponsor's reserved area, a determination can be made regarding whether at least one sponsor's presence is within a first predetermined radius of the target location. In some embodiments, a determination is made regarding whether a sponsor's physical location is within a predetermined radius of the target location. In some embodiments, a determination is made regarding whether a sponsor's geographic area, or a portion of a sponsor's geographic area, is contained within a predetermined radius of the target location. If at least one sponsor's presence is within a predetermined radius of the target location, a sponsor is chosen from a random or pseudo-random process, as illustrated by block 519. Content is then selected for delivery, as illustrated by block 509. As illustrated by block 515, if a sponsor's presence is not within a predetermined radius of the target location, the search radius can be increased. As illustrated by block 517, a check can be made to determine whether any more increases should be made. In some embodiments, the search radius can continue to be increased incrementally, in a logarithmic manner, or otherwise, until at least a portion of a sponsor's reserved area intersects the search area defined by the search radius. In some embodiments, the search radius can be increased a predetermined number of times, or can be limited based on system resources, time constraints, or other desired parameters. The processes illustrated by blocks 513, 515, and 517 can be repeated until a positive indication is produced by the process at block 517. As illustrated by block 519, content from a randomly or pseudo-randomly selected sponsor can be delivered to a mobile device if the target location is not within a desired proximity to a sponsor's reserved area. In some embodiments, rather than delivering content randomly, content selections can be made based on desired criteria. Content related to a sponsor that reserved all otherwise unallocated space can be delivered to a mobile device executing a registered application. In some such embodiments, if any particular geographic areas have not yet been reserved, or if any device requesting content does not have a target location contained within a reserved geographic area, the default sponsor's content can be delivered to the mobile device. Method 500 ends as illustrated by block 521. Preferring next to FIG. 6, a method of interaction between a mobile device and a content providing platform is illustrated according to various embodiments of the present disclosure. Method 600 begins as illustrated by block 601. As illustrated by block 603 an application platform key can be provided to a developer in response to the developer registering an application for use on the application platform. The developer can, in turn, provide the key to mobile devices on which the registered application is installed. As illustrated by block 605, when a mobile device requests content from the content providing platform, the mobile device can send the key along with its request. As illustrated by block 607, the content providing platform can verify that the key matches a valid key stored in its database, or elsewhere, before providing content to the application. In some embodiments, key verification can be performed by an entity other than the content providing platform. As illustrated by block 627, if a verification check on the key fails, no content is provided to the requesting application, and the method 600 ends. As illustrated by block 609, if the key is validated a session can be initiated between the application on the mobile device, and the content delivery platform. As illustrated by block 611 in at least one embodiment, the application running on the mobile device sends the mobile device's location, or another target location, to the content delivery platform. However, in some embodiments the actual location is not sent by the device, but may be provided to the content delivery platform from another source. Furthermore, the content delivery platform, or a subsystem of a communications system employed by the content delivery platform, can determine the location of the mobile device based on raw, partially, or completely processed information received from the mobile device or from another source. For example, the mobile device can forward information associated with a target location to the content delivery platform, or the content delivery server can obtain location information from a third party application or device, from a home location register (HLR), from a visiting location register (VLR), from raw, differential, processed or semi-processed GPS data, from power signals used in code-division multiple access (CDMA) or other wireless communications systems, or otherwise. As illustrated by block 613, the content delivery platform records the request from the registered application in a request identifier in the platform database, or some other suitable storage location. The request identifier can be used in some embodiments to track further interaction with the registered application, or to deliver additional content to a requesting mobile device. Thus, in some embodiments, a mobile device or other target location that is only temporarily located within a particular sponsor's reserved geographic area may continue to receive information from that sponsor after the mobile device, or the target location, exits the sponsor's reserved area. In other embodiments, content related to a sponsor is discontinued in response to a mobile device exiting, or the target location losing focus within, the sponsor's reserved area. As illustrated by block 615, the content delivery platform can deliver the request identifier to the requesting application along with the requested content. As illustrated by block 617, a user of the mobile device can interact with the provided content using any of various methods such as pressing a button, selecting a user selectable object on a graphical user interface, or otherwise. The application on the mobile device can send an indication of the interaction to the content delivery platform via the same communication channel used to send the request, or via a different communications channel. As illustrated by block 619, a registered application running on a mobile device can send an additional information request to the platform using the previously assigned request identifier. In some embodiments, using the previously assigned platform request identifier permits tracking of a series of interactions between a particular application and the content delivery platform. Furthermore, using the request identifier can allow individualized content to be delivered to different registered applications which may or may not be running on the same mobile device. As illustrated by block 621, a determination is made regarding whether a request identifier sent in conjunction with a request for further information is maintained in the platform database or other suitable storage. As illustrated by block 623, if the request identifier is contained in the database or other storage area, the content delivery platform can update a request identifier record as being complete. And as illustrated by block 625, the content delivery platform can deliver more content to the requesting application. As illustrated by block 627, method 600 can proceed to end after delivering the additional content. The methods and processes discussed previously, as well as other embodiments, may be implemented in a processing system executing a set of instructions stored in memory, or on a removable computer readable medium. An example of a system according to some embodiments is illustrated in FIG. 7. Referring now to FIG. 7, a high-level block diagram of a processing system is illustrated and discussed. Processing system 700 includes one or more central processing units, such as CPU A 705 and CPU B 707, which may be conventional microprocessors interconnected with various other units via at least one system bus 710. CPU A 705 and CPU B 707 may be separate cores of an individual, multi-core processor, or individual processors connected via a specialized bus 711. In some embodiments, CPU A 705 or CPU B 707 may be a specialized processor, such as a graphics processor, other co-processor, or the like. Processing system 700 includes random access memory (RAM) 720; read-only memory (ROM) 715, wherein the ROM 715 could also be erasable programmable read-only memory (EPROM) or electrically erasable programmable read-only memory (EEPROM); and input/output (I/O) adapter 725, for connecting peripheral devices such as disk units 730, optical drive 736, or tape drive 737 to system bus 710; a user interface adapter 740 for connecting keyboard 745, mouse 750, speaker 755, microphone 760, or other user interface devices to system bus 710; communications adapter 765 for connecting processing system 700 to an information network such as the Internet or any of various local area networks, wide area networks, telephone networks, or the like; and display adapter 770 for connecting system bus 710 to a display device such as monitor 775. Mouse 750 has a series of buttons 780, 785 and may be used to control a cursor shown on monitor 775. It will be understood that processing system 700 may include other suitable data processing systems without departing from the scope of the present disclosure. For example, processing system 700 may include bulk storage and cache memories, which provide temporary storage of at least some program code in order to reduce the number of times code must be retrieved from bulk storage during execution. Various disclosed embodiments can be implemented in hardware, software, or a combination containing both hardware and software elements. In one or more embodiments, the invention is implemented in software, which includes but is not limited to firmware, resident software, microcode, etc. Some embodiments may be realized as a computer program product, and may be implemented as a computer-usable or computer-readable medium embodying program code for use by, or in connection with, a computer, a processor, or other suitable instruction execution system. For the purposes of this description, a computer-usable or computer readable medium can be any apparatus that can contain, store, communicate, propagate, or transport the program for use by or in connection with the instruction execution system, apparatus, or device. By way of example, and not limitation, computer readable media may comprise any of various types of computer storage media, including volatile and non-volatile, removable and non-removable media implemented in any suitable method or technology for storage of information such as computer readable instructions, data structures, program modules, or other data. Computer storage media include, but are not limited to, RAM, ROM, EEPROM, flash memory or other memory technology, CD-ROM, digital versatile disks (DVD) or other optical storage, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage devices, or any other medium which can be used to store the desired information and which can be accessed by a computer. Data structures and transmission of data (including wireless transmission) particular to aspects of the disclosure are also encompassed within the scope of the disclosure. Various embodiments have been described for delivering content related to a commercial media program. Other variations and modifications of the embodiments disclosed may be made based on the description provided, without departing from the scope of the invention as set forth in the following claims.
<SOH> BACKGROUND <EOH>Advertisements can be delivered to various devices, including mobile devices, within communications range of areas transmitters or other information providers. For example, advertisements can be delivered to cellular phones within range of a particular cellular phone provider's network area. Furthermore, advertisements can be delivered using digital billboards, or via the Internet, based on user interactions and preferences. When delivering advertisements and other content to some mobile devices, currently available technologies can broadcast the content to all devices equipped to receive them. In some cases, advertisements are broadcast to any mobile device within a city, or a similar area. When delivering non-broadcast content, for example via the Internet, it is common to deliver the content in response to a request, received from the receiving device. In some cases, push technology can be used to deliver content to multiple users concurrently. In each of these cases, a mobile device can usually receive content from multiple different content providers. Current technologies are, therefore, less than perfect.
<SOH> SUMMARY <EOH>Various embodiments disclosed herein include registering an application program for use with a content delivery platform, establishing multiple perimeters defining respective geographic areas, and maintaining records associating sponsors with particular geographic areas. The content delivery platform can receive a request from a registered application program for content to be displayed on a mobile device, and the request can be used to determine a target location. In some embodiments, a sponsor is selected based on a relationship between the target location and one or more reserved geographic areas. Content is then provided to the application program. In some embodiments, the content delivery platform can record a request identifier associated with a received request, and provide the request identifier to the mobile device to assist in tracking future actions relating to the request for content. The content delivery platform can also receive information related to user interaction with the provided content, including the request identifier, and provide additional content in response to the received information. Content can be delivered to a mobile device running a registered application if a target location is at least partially within a predetermined radial distance of a geographical area associated with a sponsor; if the mobile device is not located within the predetermined radial distance, the radial distance can be increased. In some embodiments, content is delivered if the target location, e.g. the location of the mobile device or another location of interest, is located entirely within a geographic area exclusively reserved by a particular sponsor. In some embodiments, the content delivery platform can select from among several sponsors in deciding which content to deliver to a mobile device. In at least one embodiment, the content delivery system reserves exclusive interests in geographic areas for particular sponsors based on the sponsors' requests, and store a record of that interest. In some embodiments, the content delivery system receives, from a sponsor, content to be delivered to mobile devices based on a target location being positioned within particular geographic areas. The content delivery system can also reserve an interest in geographic areas that remain unreserved by other sponsors. Furthermore, some embodiments include time based restrictions. Various embodiments can be implemented as a system that includes memory, a communications interface, and a processor that cooperate to store and execute a program of instructions implementing various methods and techniques described herein. Furthermore, some embodiments can be implemented as a computer readable medium tangibly embodying a program of instructions.
G06Q300261
20170902
20171221
90633.0
G06Q3002
2
AJIBADE AKONAI, OLUMIDE
Exclusive Delivery of Content Within Geographic Areas
SMALL
1
CONT-ACCEPTED
G06Q
2,017
15,695,133
PENDING
SYSTEMS AND METHODS OF MODIFYING TURBINE ENGINE OPERATING LIMITS
The present disclosure is directed to systems and methods of modifying turbine engine operating limits due to the intake of particulate matter. More specifically, the present disclosure is directed to the use of a sensor at the inlet of a turbine engine to measure the characteristics of particulate flow into the turbine engine such as the volume, density, flow rate, size, shape, and surface type of particulate matter. Based on these measurements, the operating limits of the turbine engine are adjusted due to known degrading effects of particulate matter intake. The adjusted operating limits may include real-time operating limits such as maximum temperature and pressure, or long-range operating limits such as engine lifespan and maintenance cycles.
1. A method for modifying a life cycle schedule in a turbine engine, wherein the life cycle schedule is determined based on a predetermined operational profile of the turbine engine and empirical data, the method comprising detecting in real time the presence of particulate matter in fluid flow entering an inlet of the turbine engine and modifying the life cycle schedule based upon the presence of particulate matter. 2. The method of claim 1, further comprising the step of quantifying characteristics of the particulate matter. 3. The method of claim 2, wherein the characteristics of the particulate matter are selected from a group consisting of volume, amount, density, flow rate, particle size, particle shape, and particle surface. 4. The method of claim 1, wherein the life cycle schedule comprises a maintenance schedule. 5. The method of claim 4, wherein the maintenance schedule includes events selected from a group consisting of routine maintenance, inspection, cleaning, part replacement, overhaul, and retire. 6. The method of claim 2, wherein the step of detecting in real time the presence of particulate matter further comprises logging the characteristics of the particulate matter and duration of the particulate matter presence to create logged data. 7. The method of claim 6, further comprising comparing the logged data to a second set of empirical data, the second set of empirical data associated with the characteristics of the particulate matter and the duration. 8. The method of claim 3, further comprising positioning a sensor assembly at the inlet of the turbine engine to detect the presence of particulate matter. 9. The method of claim 8, wherein the sensor assembly comprises a laser emitter and a plurality of receivers configured to receive a reflection of a laser beam off of the particle surface. 10. The method of claim 8, wherein the sensor assembly comprises a laser emitter and a plurality of receivers configured to measure the degree to which the laser beam was not absorbed by the particle. 11. In a mission profile which requires operation of a turbine engine in high-particulate environments, a method of providing real time deleterious impact upon the turbine engine comprising the steps of: positioning a sensor suite in the inlet of the turbine engine; determining a first set of characteristics of the foreign particles ingested into the turbine engine from a first output of the sensor suite; comparing the first set of characteristics of the foreign particles to empirical data, wherein the empirical data is associated with wear on turbine engine components as a result of ingestion of foreign particles with similar characteristics to the first set of characteristics; and determining a degradation of the turbine engine based on the comparison and providing determination to an operator of the gas turbine. 12. The method of claim 11, wherein the determination comprises time to failure. 13. The method of claim 11, wherein the determination comprises reduction of performance. 14. The method of claim 11, wherein the determination comprises likelihood of mission completion. 15. The method of claim 11, further comprising determining a second set of characteristics of the foreign particles ingested into the turbine engine; wherein the second set is determined from output of the sensor suite subsequent to the first output; and comparing the second set of characteristics of the foreign particles to empirical data, wherein the empirical data is associated with wear on turbine engine components as a result of ingestion of foreign particles with similar characteristics to the second set of characteristics; determining additional degradation of the turbine engine based on the comparison of the second set of characteristics and the previously determined degradation; and providing the additional determination to the operator of the turbine engine. 16. The method of claim 11, wherein the sensor suite comprises a plurality of receivers and an emitter. 17. The method of claim 16, wherein the emitter is a laser and the plurality of receivers are configured to receive a reflection of a laser beam off the particle surface or measure the degree to which the laser beam was not absorbed by the particle. 18. A method for real time mapping of atmospheric particle distributions comprising: equipping a plurality of aircraft with a turbine inlet particulate sensor; powering the plurality of aircraft through a geographic area via the turbine engine; for each of the plurality of aircraft: detecting the presence of particulate matter in fluid flow entering the turbine inlet; and, associating the detection of particulate matter with the location of the aircraft in the geographic area; transmitting the associated data to a central station; and mapping the distribution of particles in the atmosphere based on the associated data received from the plurality of aircraft. 19. The method of claim 18, wherein the step of detecting further comprises quantifying the characteristics of the particulate matter based on the output of the turbine inlet particulate sensor, wherein the characteristics of the particulate matter are selected from the group consisting of volume, amount, density, flow rate, particle size, particle shape, and particle surface. 20. The method of claim 19, further comprising altering the flight plans of one or more turbine powered aircraft in the geographic area based upon the mapping.
CROSS REFERENCE TO RELATED APPLICATION The present application claims priority to U.S. Provisional Patent Application No. 62/383,654, filed Sep. 6, 2016, the entirety of which is hereby incorporated by reference. FIELD OF THE DISCLOSURE The present disclosure relates generally to measuring particulate matter in fluid flow, and more specifically to modifying the operating limits of a turbine engine based on measured particulate matter at the turbine inlet. BACKGROUND Turbine engines are generally operated based on a set of operating limits which can be both real-time (maximum temperature, pressure ranges, etc.) and long-term (maximum operating hours in engine lifespan). Operating limits can be adjusted based on turbine engine performance to ensure safe engine operation. Turbine engines are vulnerable to degraded performance, damage, and even destruction due to intake of atmospheric air with particulate matter such as sand, dirt, ash, debris, and the like. The use of particulate-laden atmospheric air as the working fluid of the turbine engine causes component erosion which can lead to significant reduction in the operating lifespan of the turbine engine or even engine failure. Engine operation in high particulate environments is preferably avoided altogether. For example, the 2010 eruption of the Eyjafjallajökull volcano in Iceland resulted in the cancellation of thousands of commercial flights and the closure of large portions of European airspace. However, such operational avoidance is not always possible, and turbine engines are frequently operated in more moderate particulate environments such as in dry and dusty conditions in the American West or Middle East. When it is necessary to operate a turbine engine in such an environment, there is a need in the art to quantify and qualify the particulate matter ingested into the turbine engine and to adjust operating limits accordingly. The present application discloses one or more of the features recited in the appended claims and/or the following features which, alone or in any combination, may comprise patentable subject matter. BRIEF DESCRIPTION OF THE DRAWINGS The following will be apparent from elements of the figures, which are provided for illustrative purposes and are not necessarily to scale. FIG. 1 is a flow diagram of a method of modifying engine operational limits in accordance with some embodiments of the present disclosure. FIG. 2 is a schematic diagram of a turboshaft type turbine engine assembly in accordance with some embodiments of the present disclosure. FIG. 3 is a schematic diagram of a turbofan type turbine engine assembly and inlet ducting in accordance with some embodiments of the present disclosure. FIG. 4 is a schematic diagram of a sensor for monitoring fluid flow through a control volume in accordance with some embodiments of the present disclosure. FIG. 5 is a flow diagram of a method of modifying engine operational limits in accordance with some embodiments of the present disclosure. FIG. 6 is a flow diagram of a method of modifying engine operational limits in accordance with some embodiments of the present disclosure. While the present disclosure is susceptible to various modifications and alternative forms, specific embodiments have been shown by way of example in the drawings and will be described in detail herein. It should be understood, however, that the present disclosure is not intended to be limited to the particular forms disclosed. Rather, the present disclosure is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the disclosure as defined by the appended claims. DETAILED DESCRIPTION For the purposes of promoting an understanding of the principles of the disclosure, reference will now be made to a number of illustrative embodiments illustrated in the drawings and specific language will be used to describe the same. The present disclosure is directed to systems and methods of modifying turbine engine operating limits due to the intake of particulate matter. More specifically, the present disclosure is directed to the use of a sensor at the inlet of a turbine engine to measure the characteristics of particulate flow into the turbine engine such as the volume, density, flow rate, size, shape, and surface type of particulate matter. Based on these measurements, the operating limits of the turbine engine are adjusted due to known degrading effects of particulate matter intake. The adjusted operating limits may include real-time operating limits such as maximum temperature and pressure, or long-range operating limits such as engine lifespan and maintenance cycles. A method 100 is presented in FIG. 1 for modifying turbine engine operational limits. The method starts at block 102. At block 104 a sensor or instrument is used to detect particulate matter in real time at the engine inlet. A sensor or instrument may detect the presence of particulate matter entering the engine inlet. In real time indicates that the data from the sensor is collected and transmitted to a processor immediately rather than stored for later evaluation. The engine inlet is defined by a control volume which is further illustrated in FIGS. 2 and 3. FIG. 2 presents a schematic diagram of a turboshaft type turbine engine assembly 200. FIG. 3 presents a schematic diagram of a turbofan type turbine engine assembly 300. In each of assembly 200 and assembly 300, the turbine engine 201 comprises a compressor 202, combustor 204, and turbine 206. An inlet region 208 is disposed axially forward of the compressor, and in some embodiments the inlet region 208 includes an inlet fan 218. Forward from the inlet region 208 is an inlet duct 210 configured to direct fluid flow to the inlet region 208. In the turboshaft type turbine engine assembly 200 illustrated in FIG. 2, all fluid flow through the inlet region 208 enters the compressor 202. In the turbofan type turbine engine assembly 300, a portion of the fluid flow through the inlet region 208 enters the compressor 202, while a portion of the fluid flow through the inlet region 208 enters a bypass region 212 which is defined between the fan casing 214 and the compressor 202, combustor 204, and turbine 206. A control volume 220 is defined at the inlet region 208. Control volume 220 is monitored by one or more particulate sensors as shown in FIG. 4, which is a schematic diagram of a sensor assembly 410 for monitoring fluid flow through a control volume 220. Sensor assembly 410 may be positioned at or proximate the control volume 220, or at or proximate inlet region 208. Sensor assembly 410 comprises an emitter 412 or source, and a receiver 414. The emitter 412 and receiver 414 are disposed across the control volume 220 from each other, such that signals emitted from the emitter 412 are received at the receiver 414. The emitter 412 and receiver 414 are also disposed generally perpendicular to the direction of mass airflow indicated by arrow A. The emitter 412 and receiver 414 may be mounted to a portion of the engine casing 214 at the inlet region 208. One or both of emitter 412 and receiver 414 may be coupled to a signal processor 420 either via fiber connection or wirelessly. In operation, the emitter 412 emits a signal which is subsequently received at the receiver 414. In some embodiments, sensor assembly 410 comprises a plurality of emitters 412, a plurality of receivers 414, or a plurality of emitters 412 and receivers 414. Based on distortions of the signal received at the receiver 414, the quality of the mass airflow A and characteristics of particulate matter therein may be determined. In some embodiments the emitter 412 is a laser emitter and the receivers are configured to receive a reflection of a laser beam emitted by the emitter 412 as it reflects off the particulate matter. In some embodiments, the plurality of receivers 414 are configured to measure the degree to which an emitted laser beam was or was not absorbed by a particle of the particulate matter. The disclosed sensors or sensor arrays may be compatible to operate under harsh conditions such as in sea or salt water spray, wide temperature fluctuations, extreme hot or cold temperatures, and rain or ice precipitation. The disclosed sensor or sensors must be sized to fit into the inlet ducting, engine housing, or engine casing within an acceptable space claim. Data collected from the disclosed sensors may be sent to a processor for use in an Engine Health Monitoring System or a Prognostic Health Monitoring System which collect various engine operating parameters and continuously monitor the health and performance of the engine. Returning now to the method 100 of FIG. 1, once the sensor detects particulate matter at the engine inlet the method 100 moves to block 106. The sensor, generally in combination with a processor, evaluates selected characteristics of the particulate matter passing through the control volume in order to quantify and qualify the particulate matter. Particulate matter may be evaluated for characteristics such as, but not limited to, volume, amount, density, flow rate, particle size, particle shape, and particle surface. At block 108, the particulate characteristics may be logged to create logged data which may be later compared to empirical data regarding the effects of particulate matter intake on turbine engine performance in order to adjust operating limits of the turbine engine. Logged data may include data collected from the sensor regarding, for example, volume, density, flow rate, size, shape, and surface type of particulate matter passing through the control volume and thus entering the turbine engine. Logged data may further include the duration of the particulate matter intake. Empirical data may include data regarding necessary changes to a turbine engine's operating limits, maintenance schedule, and life cycle based on the characteristics of particulate matter passing through the turbine engine. Empirical data may be associated with the characteristics of the particulate matter and/or the duration of intake. After creating logged data at block 108, the method 100 may proceed to block 110 or may end at block 112. At block 110, turbine engine operational limits are modified based on particulate characteristics. As indicated in FIG. 1, the step of modifying engine operational limits at block 110 may occur with or without the creation of logged data at block 108. The characteristics of particulate matter such as volume, density, flow rate, size, shape, and surface type of particulate matter passing through the control volume may be compared to empirical data regarding the effects of particulate matter intake on turbine engine performance in order to adjust operating limits of the turbine engine. Empirical data may include data regarding necessary changes to a turbine engine's operating limits, maintenance schedule, and life cycle based on the characteristics of particulate matter passing through the turbine engine. Based on this comparison, and thus based on the measured characteristics of particulate matter, the operating limits of the turbine engine are adjusted. Several examples of the modification of turbine engine operating limits are provided. First, when operating in high-particulate environments it may be desirable to immediately alter one or more operating parameters of the turbine engine. For example, certain particulates such as volcanic ash may melt and bond to turbine components at sustained high temperatures. It may therefore be desirable to lower the engine's operating temperature when able if passing through an area of high volcanic ash concentration. Thus, by measuring the characteristics of the particulate matter passing through the control volume, the type of particulate may be determined and a signal may be sent to the engine operator indicating a desire to lower the maximum operating temperature of the turbine engine in order to prevent damage to engine components. Second, particulate matter is known to have deleterious effects on certain engine components, such that operation in high-particulate environments makes it advisable to conduct early maintenance and/or replacement of the engine components than would otherwise be desirable. Periodic engine maintenance may include inspection, cleaning, and/or replacement of these components. During typical (i.e. non-high-particulate) operation of a turbine engine, maintenance of each of these components may occur on a periodic basis such as once every 1,000 hours of operation. However, when operating in high-particulate environments it may be desirable to increase the frequency of component inspection, cleaning, and/or replacement. By measuring characteristics of the particulate matter passing through the control volume and comparing those characteristics to empirical data, the operating limit of the engine maintenance cycle may be modified accordingly to ensure continued safe operation of the engine. Maintenance schedules may be modified to include maintenance life cycle events such as routine maintenance, periodic maintenance, inspection, cleaning, part replacement, overhaul, and retirement. Third, the lifespan of the engine itself may be modified based on measured particulate intake. Turbine engines which routinely operate in high-particulate environments such as military aircraft operating in desert regions may need to be retired hundreds or even thousands of hours early due to the degradation and damage caused by particulate matter. By measuring characteristics of the particulate matter passing through the control volume and comparing those characteristics to empirical data, the operating limit of the engine lifespan may be modified accordingly to ensure continued safe operation of the engine. Method 100 ends at block 112. A method 500 of providing real time deleterious impact on a turbine engine is presented in the flow diagram of FIG. 5. Method 500 starts at block 501 and proceeds to block 503, where a sensor suite is positioned at the inlet of a turbine engine. The sensor suite may comprise the sensor arrangements described above with reference to FIGS. 2-4. With the sensor suite positioned at the engine inlet, fluid flow is induced through the inlet of the turbine engine, for example by moving the turbine engine through the atmosphere. At block 505, the characteristics of particulate matter passing through the engine inlet are measured by the sensor suite. Such characteristics may include the volume, density, flow rate, size, shape, and surface type of particulate matter. At block 507, the measured characteristics from block 505 are compared against empirical data which may include data regarding necessary changes to a turbine engine's operating limits, maintenance schedule, and life cycle based on the characteristics of particulate matter passing through the turbine engine. Based on this comparison, at block 509 the likely engine degradation is determined. From block 509, method 500 may proceed to block 511, block 513, or both. The steps defined in block 511 and block 513 may be performed sequentially in any order or simultaneously, or only one of block 511 and block 513 may be performed. At block 511, a controller or operator of the engine is provided with information regarding the likely degradation of the engine due to intake of particulate matter. Degradation information may describe deleterious impacts such as reduced engine performance (e.g. reduced maximum power of the engine), modified real-time operating limits of the engine, time to engine failure, likelihood of mission completion, increased frequency or modification of maintenance cycles, or reduced engine lifespan as discussed above. For example with respect to a military aircraft, a mission profile including ingress, egress, loiter, payload drop etc. may be determined. Upon detection of ingestion of particulate matter and determination of any deleterious effects, any remaining portion of the mission profile may be simulated with encompassing the determined effects and the likely accumulated effects to determine if the mission profile can be performed, or should be aborted. Alternatively, a probability of completing the mission profile may be provided to the operator, or portions of the mission profile that are no longer possible may be presented to the operator. Similarly with respect to civilian aircraft passing though an area of high particulate matter, the operators may be informed whether to continue though to the destination upon a determination that the deleterious affect is minimal or take other actions. This real time information allows the operators to avoid additional damage to aircraft, avoid unnecessary rerouting or mission abort, while providing actionable information upon which life and death decisions may be aid. At block 513 engine operating limits are modified based on the likely degradation determined at block 509. Non-limiting examples of operational limits which may be modified are provided above with reference to block 110 of FIG. 1. Method 500 ends at block 515. In a further aspect of the present disclosure, a method 600 is provided in the flow diagram of FIG. 6 for mapping of particulate matter in the atmosphere. Method 600 starts at block 602 and proceeds to block 604, where a plurality of aircraft are equipped with particulate sensors at the inlet of one or more turbine engines. The particulate sensors may comprise the sensor arrangements described above with reference to FIGS. 2-4. As the plurality of aircraft equipped with particulate sensors traverse various geographic areas, particulate matter data is collected via the particulate sensors at block 606 and transmitted to a central controller at block 608. Particulate matter data may include measurements of the volume, density, flow rate, size, shape, and surface type of particulate matter. At block 610, particulate distributions are derived from the collected particulate matter data, and the particulate distributions are then mapped to show geographic distribution of particulate matter. For example, a map may be provided which shows density of particulate matter by discrete areas or regions, and such a map may be used to plan aircraft routes to avoid regions of highest density of particulate matter. Chronological iterations of this map can be used to track the movement of high-density particulate regions. As another example, a map may be generated which shows the distribution of various types or sizes of particulate matter by discrete areas or regions. At block 612, turbine engine operating limits may be adjusted based on the mapped particulate matter distribution. For example, an aircraft known to have passed through a region of relatively higher density of particulate matter which is not equipped with particulate matter sensors may nonetheless have the aircraft engine maintenance schedule and/or lifespan modified based on an estimated intake of particulate matter. At block 614, as suggested above the flight plans of one or more aircraft may be altered based on the map showing particulate matter densities. In general, it is highly desirable to avoid flight through areas of high density particulate matter due to the degrading effects of particulate matter on a turbine engine as described above. Thus, a map showing areas of relative danger to turbine engines based on collected data from a plurality of aircraft equipped with engine inlet particulate sensors would be highly valuable to aid other aircraft in avoiding flight through such areas. Method 600 ends at block 616. The present disclosure advantageously modifies turbine engine operating limits according to characteristics of particulate matter intake such as volume, density, flow rate, size, shape, and surface type. Particulate sensors may transmit collected data to an engine controller or operator, which are able to beneficially alter the operating limit of the turbine engine in an effort to ensure continued safe operation. Particulate characteristic data may be advantageously used to control inlet air particle separation devices which assist in filtering particulate matter from engine intake. The collected particulate data may be used in real-time assessment of engine health and performance, or in long-term engine maintenance and lifespan planning. According to an aspect of the present disclosure, a method for modifying a life cycle schedule in a turbine engine is disclosed. The life cycle schedule is determined based on a predetermined operational profile of the turbine engine and empirical data. The method comprises detecting in real time the presence of particulate matter in the fluid flow entering an inlet of the turbine engine and modifying the life cycle schedule based upon the presence of particulate matter. In some embodiments the method further comprises quantifying the characteristics of the particulate matter. In some embodiments the characteristics of the particulate matter are selected from the group consisting of volume, amount, density, flow rate, particle size, particle shape, and particle surface. In some embodiments the life cycle schedule comprises a maintenance schedule. In some embodiments the maintenance schedule includes events selected from the group of routine maintenance, inspection, cleaning, part replacement, overhaul, and retire. In some embodiments the step of detecting in real time the presence of particulate matter further comprises logging the characteristics of the particulate matter and duration of the particulate matter presence to create logged data. In some embodiments the method further comprises comparing the logged data to a second set of empirical data, the second set of empirical data associated with the characteristics of the particulate matter and the duration. In some embodiments the method further comprises positioning a sensor assembly at the inlet of the turbine engine to detect the presence of particulate matter. In some embodiments the sensor assembly comprises a laser emitter and a plurality of receivers configured to receive a reflection of the laser beam off of the particle surface. In some embodiments the sensor assembly comprises a laser emitter and a plurality of receivers configured to measure the degree to which the laser beam was not absorbed by the particle. According to another aspect of the present disclosure, in a mission profile which requires operation of a turbine engine in high-particulate environments, a method of providing real time deleterious impact upon the turbine engine comprises the steps of: positioning a sensor suite in the inlet of the gas turbine; determining a first set of characteristics of the foreign particles ingested into the turbine engine from a first output of the sensor suite; comparing the first set of characteristics of the foreign particles to empirical data, wherein the empirical data is associated with wear on turbine engine components as a result of ingestion of foreign particles with similar characteristics to the first set of characteristics; and determining a degradation of the turbine engine based on the comparison and providing determination to an operator of the gas turbine. In some embodiments the determination comprises time to failure. In some embodiments the determination comprises reduction of performance. In some embodiments the determination comprises likelihood of mission completion. In some embodiments the method further comprises determining a second set of characteristics of the foreign particles ingested into the turbine engine; wherein the second set is determined from output of the sensor suite subsequent to the first output; and comparing the second set of characteristics of the foreign particles to empirical data, wherein the empirical data is associated with wear on turbine engine components as a result of ingestion of foreign particles with similar characteristics to the second set of characteristics; determining additional degradation of the gas turbine based on the comparison of the second set of characteristics and the previously determined degradation; and providing the additional determination to the operator of the gas turbine. In some embodiments the sensor suite comprises a plurality of receivers and an emitter. In some embodiments the emitter is a laser and the plurality of receivers are configured to receive a reflection of the laser beam off of the particle surface or measure the degree to which the laser beam was not absorbed by the particle. According to yet another aspect of the present disclosure, a method is disclosed for real time mapping of atmospheric particle distributions. The method comprises equipping a plurality of aircraft with a turbine inlet particulate sensor; powering the plurality of aircraft through a geographic area via the turbine engine; detecting the presence of particulate matter in fluid flow entering the turbine inlet for each of the plurality of aircraft; associating the detection of particulate matter for each of the plurality of aircraft with the location of the aircraft in the geographic area; transmitting the associated data to a central station; and mapping the distribution of particles in the atmosphere based on the associated data received from the plurality of aircraft. In some embodiments the step of detecting further comprises quantifying the characteristics of the particulate matter based on the output of the turbine inlet particulate sensor, wherein the characteristics of the particulate matter are selected from the group consisting of volume, amount, density, flow rate, particle size, particle shape, and particle surface. In some embodiments the method further comprises altering the flight plans of one or more turbine powered aircraft in the geographic area based upon the mapping. Although examples are illustrated and described herein, embodiments are nevertheless not limited to the details shown, since various modifications and structural changes may be made therein by those of ordinary skill within the scope and range of equivalents of the claims.
<SOH> BACKGROUND <EOH>Turbine engines are generally operated based on a set of operating limits which can be both real-time (maximum temperature, pressure ranges, etc.) and long-term (maximum operating hours in engine lifespan). Operating limits can be adjusted based on turbine engine performance to ensure safe engine operation. Turbine engines are vulnerable to degraded performance, damage, and even destruction due to intake of atmospheric air with particulate matter such as sand, dirt, ash, debris, and the like. The use of particulate-laden atmospheric air as the working fluid of the turbine engine causes component erosion which can lead to significant reduction in the operating lifespan of the turbine engine or even engine failure. Engine operation in high particulate environments is preferably avoided altogether. For example, the 2010 eruption of the Eyjafjallajökull volcano in Iceland resulted in the cancellation of thousands of commercial flights and the closure of large portions of European airspace. However, such operational avoidance is not always possible, and turbine engines are frequently operated in more moderate particulate environments such as in dry and dusty conditions in the American West or Middle East. When it is necessary to operate a turbine engine in such an environment, there is a need in the art to quantify and qualify the particulate matter ingested into the turbine engine and to adjust operating limits accordingly. The present application discloses one or more of the features recited in the appended claims and/or the following features which, alone or in any combination, may comprise patentable subject matter.
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>The following will be apparent from elements of the figures, which are provided for illustrative purposes and are not necessarily to scale. FIG. 1 is a flow diagram of a method of modifying engine operational limits in accordance with some embodiments of the present disclosure. FIG. 2 is a schematic diagram of a turboshaft type turbine engine assembly in accordance with some embodiments of the present disclosure. FIG. 3 is a schematic diagram of a turbofan type turbine engine assembly and inlet ducting in accordance with some embodiments of the present disclosure. FIG. 4 is a schematic diagram of a sensor for monitoring fluid flow through a control volume in accordance with some embodiments of the present disclosure. FIG. 5 is a flow diagram of a method of modifying engine operational limits in accordance with some embodiments of the present disclosure. FIG. 6 is a flow diagram of a method of modifying engine operational limits in accordance with some embodiments of the present disclosure. detailed-description description="Detailed Description" end="lead"? While the present disclosure is susceptible to various modifications and alternative forms, specific embodiments have been shown by way of example in the drawings and will be described in detail herein. It should be understood, however, that the present disclosure is not intended to be limited to the particular forms disclosed. Rather, the present disclosure is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the disclosure as defined by the appended claims.
G07C50808
20170905
20180308
75849.0
G07C508
0
BLOSS, STEPHANIE E
SYSTEMS AND METHODS OF MODIFYING TURBINE ENGINE OPERATING LIMITS
UNDISCOUNTED
0
REJECTED
G07C
2,017
15,695,692
PENDING
Crimping Tool Locator and Crimping Tool
The invention relates to a crimping tool locator (12) for a crimping tool (1), especially crimping plier (2). The crimping tool locator (12) comprises an accommodating body (14) with at least one accommodation (21) for a workpiece (10), especially a plug (11). The accommodating body (14) comprises a securing device (24), by which the workpiece (10) is securable in the interior of the accommodation (21). The securing device (24) can be realized as a latching device, locking device or friction device.
1. A crimping tool locator for defining a position and/or orientation of a workpiece relative to a crimping tool, the crimping tool locator comprising an accommodating body with at least one accommodation for the workpiece, said accommodating body comprising a securing device by which the workpiece is securable in the interior of the accommodation, said securing device comprising a securing element being designed and configured for interacting with the workpiece for providing the securing effect at a location within the accommodation. 2. The crimping tool locator according to claim 1, wherein the crimping tool locator is designed and configured such that the securing element can be transferred into a) a secured position in which the workpiece arranged in the accommodation is secured with the securing effect and b) an unsecured position in which a workpiece arranged in the accommodation is not secured with the securing effect. 3. The crimping tool locator according to claim 2, wherein the securing device is a latching device and the securing element is a latching element. 4. The crimping tool locator according to claim 2, wherein the securing device is a locking device and the securing element is a locking element. 5. The crimping tool locator according to claim 2, wherein the securing element is a friction element, which is supported by a spring element and which secures the workpiece by friction at a location of interaction arranged within the accommodation. 6. The crimping tool locator according to claim 2, wherein the securing device comprises a manual actuation organ, said manual actuation organ being designed and configured for at least one of supporting the securing device with regard to the securing effect, holding the securing device in the secured position and actuating the securing device. 7. The crimping tool locator according to claim 2, wherein the securing device is designed and configured for being actuated and/or released in a motion-controlled way. 8. The crimping tool locator according to claim 7, wherein the securing device is designed and configured for being actuated in a motion-controlled way by a movement of the accommodating body relative to a pliers head by which the crimping tool locator is held. 9. The crimping tool locator according to claim 7, wherein the securing device is designed and configured for being actuated in a motion-controlled way by a movement of driving elements or tool halves of the crimping tool. 10. A Crimping tool with the crimping tool locator according to claim 1.
CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to co-pending European Patent Application No. EP 16 190 245.7 filed Sep. 22, 2016. FIELD OF THE INVENTION The invention relates to a crimping tool locator and a crimping tool with a crimping tool locator. A crimping by means of the crimping tool can be achieved due to manual actuation, pneumatic or hydraulic actuation, actuation by an electrical actuation unit or any other actuation unit. Especially, the crimping tool is realized as manually actuated pressing pliers, which covers also so called crimping pliers. By means of crimping tools, which can be equipped with a crimping tool locator according to the invention, a workpiece is crimped. For example, by means of a crimping tool workpieces embodied as plugs, contacts or pins or connectors (in the following: “plugs”) can be crimped to a partially stripped end of a cable or conductor (in the following: “cable”). In the following, preferably reference will be made to a crimping of a plug to a cable and/or the realization of the crimping tool as crimping pliers, while the same shall apply for a crimping of other workpieces and/or another crimping tool. BACKGROUND OF THE INVENTION During the crimping over a working stroke of crimping pliers, the plug is plastically deformed and pressed against the end of the cable arranged in the plug. In this way on one hand an electrical contact is established and on the other hand a mechanical connection between the plug and the end of the cable is established which is as permanent as possible. With regard to possible realizations of the crimping pliers on the one hand and the plug and the types of the cables crimped with it on the other hand it is referred especially to the embodiments shown and described in the catalogue “Werkzeuge für die professionelle Anwendung” of WEZAG GmbH Werkzeugfabrik (printing remark “Dokument Nr. Kat. 10/11”). For an exact and defined crimping of the plug it is necessary that the plug and the cable are arranged in the intended position and orientation relative to tool halves of the crimping pliers forming at least one die half, so that with the closing of the tool halves over the working stroke of the crimping pliers the desired plastic deformation can be induced and the crimping result attained on the crimped plug conforms with high standards of precision. For setting the position and orientation of the plug relative to a die formed with two corresponding die halves of a tool half at the begin of the working stroke, crimping tool positioners (also referred to as “locators” in English use) are employed. Such a crimping tool locator serves for adequately setting the position and the orientation of the plug relative to the pliers head, especially for setting the correct axial position of the plug with respect to the end of the cable and/or for setting the coaxial orientation of the plug with respect to the end of the cable. The crimping tool locator on the one hand makes sure that at the beginning of the crimping stroke the plug is already positioned correctly with respect to a die of the pliers head. On the other hand it is also possible that during the crimping stroke the crimping tool locator proper secures the relative position and orientation of the plug with respect to the die and the end of the cable at the execution of the working stroke during the plastic deformation of the plug. Known crimping tool locators comprise at least one accommodation into which the plug can be inserted in such a way that the plug has a defined position and orientation with respect to the crimping tool locator. The crimping tool locator then is also mounted with a defined position and orientation on the pliers head in which the two halves are movably guided and driven in such a way that the plug inserted into the crimping tool locator comprises a defined position and orientation with respect to the tool halves and therefore with respect to a die. With respect to the mechanical basic composition of crimping pliers and the pliers head, the realization of the crimping tool locator and the design of possible degrees of freedom of motion of the crimping tool locator from prior art multitudinous design possibilities are known (cp. also the embodiments of the crimping tools in the above-mentioned catalogue of WEZAG GmbH Werkzeugfabrik): In the simplest case, an accommodating body of a crimping tool locator is mounted on the pliers head of the crimping pliers. It is also possible, however, that a holding and guiding body of the crimping tool locator is mounted to the pliers head of the crimping pliers and an accommodating body of the crimping tool locator is movably held and guided on the holding and guiding body. Crimping pliers known from DE 27 18 165 A1 have a pliers head with a C-shaped frame so that in this case the pliers head is open on the side. In another embodiment according to DE 27 18 165 A1, crimping jaws and tool halves mounted on them move in a “scissor-like” way with respect to each other. In both cases, in the pliers head a pliers head plane is defined in which the tool halves with the die halves move. The known crimping pliers have a crimping tool locator with an accommodating body which is pivotable around a pivoting axis between an insertion position and a working position. In the insertion position, an inserting, plugging of the plug onto or into at least one accommodation of the accommodating body can be achieved. In the working position, with running through the working stroke the crimping of the plug is achieved. The pivoting axis for the pivoting of the accommodating body is oriented vertically to the pliers head plane. For a crimping of a plug, to begin with the accommodating body of the crimping tool locator is pivoted into the insertion position. The plug then is inserted into an accommodation of the accommodating body and the accommodating body with the inserted plug is pivoted back into the working position through the opened side of the pliers head. In the working position the plug takes up the intended position and orientation with respect to the die halves. Subsequently, the plastic deformation of the plug can be achieved by means of the actual crimping process by actuating the drive of the crimping pliers, which is here constituted by two hand levers pivotable with respect to each other. In order to achieve a secure holding of the plug in the accommodation, on its upper side the accommodation is reached over by a leaf spring which exerts a force onto the plug at a location outside of the accommodation. This force presses the plug against the bottom of the accommodation and holds the plug by clamping. As an alternative to the employment of a leaf spring, the document DE 27 18 165 A1 also suggests that the plug is held in the accommodation by a pin extending in the longitudinal direction of the plug. By the pin the plug can be held on its own by a contact spring arm of the plug. For the purpose to avoid that the plug glides out in a direction perpendicular to the insertion opening of the accommodation, the accommodation is realized as an insertion groove open to the upper side, where on the upper side the insertion groove is covered and closed by a small plate screwed onto it. Other crimping pliers are sold by WEZAG GmbH Werkzeugfabrik under the label CS20KS. These crimping pliers also have a C-shaped pliers head open to one side. On this pliers head, an accommodating body of a crimping tool locator is linearly guided on an axis fixed to the pliers head. The axis is oriented parallel to the lower horizontal arm of the C and is arranged in a plane parallel to the pliers head plane. The accommodating body can be moved by a pivotable lever supported on the pliers head from the working position into the insertion position. A manually induced pivoting motion of the lever via a connection between a pin guided in an elongated hole is converted into a linear motion along the axis for a linear motion of the accommodating body. Furthermore, crimping pliers of the applicant with label CS25KS are known, which also have a C-shaped pliers head. In these crimping pliers, an accommodating body of a crimping tool locator is supported for a pivoting movement with respect to the pliers head around a pivoting axis oriented vertically to the pliers head plane. Via the rotation of a knurl the accommodating body is pivotable parallel to the pliers head plane between an insertion position and a working position. DE 198 32 884 C1 (corresponding to U.S. Pat. No. 6,155,095 A) discloses crimping pliers with a pliers head in a plate construction mode—The pliers head is not C-shaped with a one-sided opening but O-shaped without an opening in the circumferential direction. According to an actuation of hand levers, a moveable tool half is slidable in the direction of a longitudinal axis relative to a tool half fixed with respect to the pliers head. DE 198 32 884 C1 proposes a crimping tool locator with an accommodating body which is pivotable around a pivoting axis which is oriented in parallel to the pliers head plane and transverse to the direction of motion of the tool halves of the crimping pliers. In a working position, the crimping tool locator is oriented generally in parallel to the pliers head plane. From this working position, the pliers head locator can be pivoted around the pivoting axis out of the pliers head plane into the insertion position. For the crimping tool locators explained before the motion of the accommodating body of the crimping tool locator necessitates holding the crimping pliers with one hand of the user, for example in the region of hand levers, while the other hand of the user moves the accommodating body of the crimping tool locator from a working position into an insertion position (or the other way around). Instead, DE 10 2008 017 366 A1 (corresponding to U.S. Pat. No. 8,161,789 B2) proposes a crimping tool locator with a pivotable accommodating body on which a cantilever is fixed. The operating surface of the cantilever is guided in proximity to the hand levers of the crimping pliers in such a way that with the thumb of the hand which holds the crimping pliers in the region of the hand levers, the accommodating body of the crimping tool locator can be pivoted, in which way a simplified operation, especially a one-handed operation is enabled. DE 10 2008 012 011 B3 (corresponding to U.S. Pat. No. 8,230,715 B2) discloses a pliers head in which tool halves with multiple die halves with different crimping contours are moveable transverse to the pliers head and transverse to the crimping axis, so that depending on the plug to be crimped different die halves can be arranged coaxially or centrally to the crimping axis in the pliers head. In this way, the force conditions for the die halves used for different plugs can be optimized and/or the number of die halves with different geometries that can be used in a tool half can be increased. DE 10 2010 061 148 A1 (corresponding to U.S. Pat. No. 8,601,856 B2) describes crimping pliers wherein the two hand levers in the end region turned towards the crimping head are supported in a pivot bearing connected to a moveable tool half. Furthermore, the hand levers are each pivotably linked to an end region of draw bars which are linked to an O-shaped frame of the pliers head in the other end region. On the frame of the pliers head, a tool half is fixed. Onto the fixed tool half, a holding and guiding body of a crimping tool locator is screwed. On the holding and guiding body, an accommodating body of the crimping tool locator is moveably supported. The accommodating body can be moved relative to the holding and guiding body in a direction transverse to the relative motion of the tool halves (and therefore transverse to the crimping axis). The tool halves each have several die halves lying next to each other in a direction transverse to the crimping axis. With the moving of the accommodating body relative to the holding and guiding body, an accommodation of the accommodating body for a plug can be arranged behind different die halves of a tool half or different accommodations of the accommodating body can be arranged behind the same die half. Therefore, depending on the position of the accommodating body, a die half can enter into interaction with different plugs, which may have been inserted in different accommodations of the accommodating body, and/or different die halves can enter into interaction with plugs inserted into the same accommodation of the accommodating body. As an alternative to using a translatory degree of freedom of the accommodating body with respect to the holding and guiding body transverse to the crimping axis, DE 10 2010 061 148 A1 also proposes that the accommodating body is rotatable in revolver-like way with respect to the holding and guiding body around a rotational axis oriented vertically to the pliers head plane. In this case, single accommodations of the accommodating body are distributed over the circumference and/or are provided with different radii from the rotational axis of the revolver on the accommodating body. Accordingly, depending on the rotational angle of the accommodating body these accommodations can be arranged behind a die half. It is possible that a latching or locking of the accommodating body with respect to the holding and guiding body is done in order to secure an operating position of the accommodating body. DE 10 2010 061 148 A1 also proposes an especially compact design of the crimping tool locator. For this design it is also possible that the extension of an accommodation of the crimping tool locator is larger than the distance between two neighboring die halves of a tool half. DE 20 2008 003 703 U1 discloses pliers in which an accommodating body of a crimping tool locator is pivotable around a pivoting axis between an insertion position and a working position. The pivoting axis is oriented in parallel to the crimping axis and the pliers head plane. A locking (unyielding or yielding in a limited way) of the accommodating body in the working position is proposed. The locking can be achieved via a blocking bar, which is supported for being pivoted around a pivoting axis oriented vertically to the pliers head plane on a pivoting bolt of the holding and guiding body. Furthermore, on the accommodating body a securing element is supported for being pivoted around a pivoting axis oriented radially to the pivoting axis for the pivoting of the accommodating body relative to the holding and guiding body and parallel to the main axis of extension of the accommodating body, which is realized as a stop rocker. In a securing position of the stop rocker, the stop rocker reaches around the accommodating body in the shape of a U. Outside of the accommodation of the accommodating body for the plug, a lug or a protrusion of a side arm of the U engages with a groove or an indentation of the plug. In this way the plug is intended to be secured against an unintended falling out of the accommodation of the accommodating body. Furthermore, the protrusion or the lug forms a further stop. In the working position of the accommodating body the further stop limits an insertion depth of the partially stripped cable. In this way, it is to be made sure that a crimping of the plug to the cable is done in a defined axial relative position of the cable in the plug. By means of a spring, the stop rocker is biased into the securing position, while it can be manually moved out of the securing position against the biasing by the spring. EP 2 672 580 A1 discloses crimping pliers with different drive kinematics, in which a crimping tool locator (here with an accommodating body which is pivotable around a pivoting axis oriented parallel to the crimping axis) can also be employed. DE 101 34 004 C1 discloses a crimping tool locator which is fixed to a moveable pliers jaw by a U-shaped holding bracket. Via two angled elongated holes in the side arms of the U-shaped holding bracket an accommodating body is guided for being moveable in a translatory way and for being pivoted. In a state pushed away from the moveable pliers jaw and additionally folded away, plugs can be inserted into accommodating pockets of the accommodating body. A clamping spring reaches over the accommodating body and clamps the plug with a clamping lip at a location outside of the accommodating pockets in order to arrest it and to hold it. Since the clamping lip engages with a correspondingly formed indentation of the plug, it also defines the insertion depth of the plug into the accommodating pocket. EP 0 125 708 A2 discloses a crimping tool locator which is fixedly mounted to a pliers jaw. An accommodation of the crimping tool locator is realized with a slit on the upper side where in the slit a slotted link is guided while biased by a spring. With the insertion of a plug through the dies of the pliers jaws into the accommodation, the front face of the plug can push the slotted link upwards or pivot it until the front face of the plug comes to rest against a protrusion of the slotted link. In this way the insertion depths of the plug into the accommodation is defined. For the use of the crimping tool locator for another plug with a larger required insertion depth, the slotted link can be moved manually further out of the accommodation, so that the protrusion does no longer hinder the insertion of the plug. In this case, the plug can be inserted into the accommodation up to a bottom of the accommodation. In this state, the slotted link can again be released by the user. In this way, due to the bias of the spring with the protrusion the slotted link presses the plug onto the bottom of the accommodation. Further prior art is known from documents U.S. Pat. No. 3,142,209 A, U.S. Pat. No. 3,457,764 A, U.S. Pat. No. 2,953,185 A and U.S. Pat. No. 3,751,963 A. SUMMARY OF THE INVENTION It is an object of the present invention to propose a crimping tool locator which is improved with respect to usage especially considering the demands of construction space. Furthermore, it is an object of the invention to propose a correspondingly improved crimping tool. The crimping tool locator according to one embodiment of the invention comprises an accommodating body. The accommodating body can be realized as one-parted or multi-parted or as one-piece or multi-piece and be fixed or moveable, especially slidable or pivotable or rotatable in a revolver-like way, be held on the crimping tool for a motion between an insertion position and a working position (cp. the prior art mentioned in the beginning). The accommodating body comprises an accommodation (or at least one accommodation) for a workpiece. The accommodation is formed especially by a recess of the accommodating body, possibly with a suitable lining, and the cross section of the accommodation is limited (with open or closed boundaries) by the material of the accommodating body. One embodiment of the present invention in particular bases on the finding that for embodiments known from prior art, a plug is loosely accommodated in the fixedly defined cross section of the accommodation, especially with a clearance fit or a transition fit. Due to the own weight of the plug and/or the chosen fit between the outer cross section of the plug and the inner cross section of the accommodation, there is friction between the plug and the accommodation, while depending on the orientation of the crimping tool the plug can also get “jammed” in the accommodation. Due to friction and a possible jamming, the plug is generally secured in the accommodation in such a way that it can be made to approach the cable with the crimping tool and be brought into effective interaction with the cable so that the crimping can be done. It has emerged, however, that the plug repeatedly falls out of the accommodation, which is for example the case when the crimping tool has to be brought to the cable in situations under tight construction room conditions and while changing its orientation. Especially under the tight construction room conditions, it can also be problematic to pick up a plug fallen out of the accommodation and to bring it back to the accommodation. According to one embodiment of the invention it is suggested that the accommodating body comprises a securing device. By the securing device the workpiece can be secured in the interior of the accommodation. Therefore, via the securing device (possibly in addition to a possible friction due to the own weight of the workpiece or a jamming of the plug) the plug is secured with respect to unintentionally falling out. The securing device especially produces a securing force which is independent of the own weight of the workpiece. Preferably, the securing device is realized in such a way that via the securing device a (partial) cross section of the accommodation is changeable between a non-securing (partial) cross section in which the plug is insertable into the accommodation while forming an insertion clearance and (together with the attached cable) can be removed from it and a securing (partial) cross section which is smaller than the non-securing (partial) cross section and in which the plug is secured in the accommodation so that it cannot easily fall out of the accommodation. Within the framework of the invention, the securing device is preferably integrated into the accommodation or adjoins an interior surface of the accommodation. The interaction between the plug and the securing device therefore is created in the interior of the accommodation (and not outside of it and especially not axially before or behind the accommodation). A cross section of the accommodation can be limited by a securing element of the securing device. In deviation to securing the plug via a stop rocker according to DE 20 2008 003 703 U1, according to one embodiment of the invention the securing is achieved via the securing device in the interior of the accommodation, in which way the demands of construction space can be reduced on the one hand with respect to the crimping tool and the crimping tool locator and on the other hand with respect to the design of the plug to be secured. Possibly, via the securing device according to the invention it can also be made possible for plugs of different types or geometries to be held in the same accommodation since the securing device can guarantee a certain adaptability. According to one embodiment of the invention, the securing device comprises a securing element. The securing element comprises two different positions, that is, a secured position and an unsecured position. In the secured position, a workpiece arranged in the accommodation is secured. On the contrary, in the unsecured position, the workpiece arranged in the accommodation is unsecured or a workpiece can be inserted into the accommodation or removed from it. Preferably, in the secured position the securing element decreases the size of the (partial) cross section of the accommodation, in which way the securing effect is achieved. To mention only some non-limiting examples, this decrease can be a decrease, or the motion of the securing element can be a motion larger than 0.01 mm, larger than 0.02 mm, larger than 0.05 mm, larger than 0.1 mm or even larger than 0.2 mm. For the realization of the securing device and therefore for achieving the securing effect, within the framework of the invention there are the following non-limiting options: For an embodiment of the invention, the securing device is realized as a latching device. As a latching device, especially a device is understood in which, while being biased by a spring element, a latching element engages with a latching recess, in which way the securing effect is created due to a latching force. Preferably, the latching element and/or the latching recess is contoured with suitable latching contours or inclined surfaces in such a way that at the application of insertion forces onto the plug, while biased by the spring element the latching device is moved in the direction of an opening position or a non-securing position and at reaching the latching position the spring element moves the latching element into the securing position, in which the latching element engages with the latching recess or reaches behind a latching protrusion, and/or at the application of removal forces onto the plug, while being biased by the spring element the latching element is moved in the direction of an opening position or non-securing position, until for reaching a threshold value of the releasing force the latching element leaves engagement with the latching recess or the latching protrusion, in which way the plug (with the cable fixed to it) can be moved out of the accommodation. For such a latching device, due to the spring element the latching element automatically takes up the securing position, while with the application of insertion forces and/or removal forces while being biased by the spring element the latching element is brought into the non-securing position, in which then possibly, however, for moving the plug friction forces between the latching element and the plug also have to be overcome. For another embodiment of the invention, the securing device is realized as a locking device. In a locking device, the plug is locked in the accommodation. As such, especially a form-locking between a locking element and a locking protrusion or a locking recess is understood, where in this case a locking cannot be released while being biased by a spring element by an application of sufficient insertion forces and/or removal forces onto the plug. Rather than that, a separate locking and/or unlocking via manual actuation of a separate locking actuation organ is necessary. For a further embodiment of the invention, the securing device is equipped with a friction element. This friction element is supported via a spring element. The spring element presses the friction element against an outer surface of the workpiece. In this way, the workpiece can be secured by friction in the accommodation. Via suitable contouring of the outer surface of the workpiece, a changeable securing effect corresponding to the friction force can be created depending on how deep the workpiece has been inserted into the accommodation. By suitable choice of the material and the surface of the friction element and/or the workpiece, there can be a constructive influence on the friction conditions. Furthermore, influencing the friction conditions can be done by the dimensioning of the spring element, especially the choice of the stiffness of the spring element, the choice of the number of inserted spring elements and/or the length of the spring element. The invention covers embodiments in which the latching element, the locking element or the friction element and/or the corresponding spring element is/are realized by the accommodating body in the region of the accommodation, while the friction surface interacting with the friction element, the latching protrusion or the latching recess for the latching engagement of the latching element or the locking protrusion or the locking recess for the present engagement of the locking element is realized by the workpiece. According to a further proposal of the invention, the securing device comprises a manual actuation organ. By the manual actuation organ the securing device can be supported with respect to the securing effect, can be held in its operating position, can be manually operated and/or released. In this way the options for the design of the securing effect and the options of handling for the user of the crimping tool are increased. In the case that the securing device is a latching device, by actuation of the actuation organ the latching effect can be increased or decreased. Preferably, the manual actuation organ serves for locking and/or unlocking of a locking device forming the securing device. It is also possible that the manual actuation organ moves an additional securing element, where in a securing position the additional securing element secures or single-sidedly blocks a securing position taken up by a latching element, a friction element, a locking element and/or a spring element. Alternatively or cumulatively to a manual actuation of the securing device via a manual actuation organ, an actuation of the securing device can be actuated and/or released in a motion-controlled way and/or a force-controlled way. This can be achieved in a way controlled by the motion of a plug in the accommodation. For example, with the insertion of the plug (motion control) a latching or locking element can be brought from a securing position into a non-securing position, in which then the complete insertion of the plug into the accommodation is possible. On the other hand, when reaching the latching or locking position, that is, also in a motion-controlled way, the return of the latching or locking element into the securing position is achieved. As explained before, a force control with the motion of the plug in the accommodation can consist of a release of a latching occurring when a threshold value of a removal force (which can be defined by a design of latching contour) is surpassed. Alternatively or cumulatively, the securing device can be actuated and/or released in a motion-controlled way controlled by a motion of the accommodating body relative to a holding and/or guiding body or relative to a pliers head on which the holding and/or guiding body is held. This shall be explained in an exemplary way on the basis of a crimping tool locator in which the accommodating body is supported for being pivoted between an insertion position and a working position on the pulling and/or guiding body mounted to the crimping tool head: When the accommodating body “claps shut” into the working position, an actuation element of the holding and/or guiding body or the crimping tool head can approach a counter actuation element of the securing device or enter into interaction with the counter actuation element. For example, the actuation element can be an actuation pin which actuates a latching device or a friction device in such a way that the latching effect or friction force is induced or increased or a locking device is locked when the working position is approached. Alternatively or cumulatively it is possible that the securing device is actuated and/or released in a motion-controlled way by a motion of driving elements or tool halves of the crimping tool. For example, for an increase of a latching effect or of friction or for the induction of a locking an actuation element can be moved together with the motion of the tool half or the die and enter into interaction with a counter actuation element of the securing device in order to induce the latching effect or the securing friction force or to increase it/them or to induce the locking. Possibly, in this way the manual actuation of the crimping tool can be used for the actuation of the securing device. Possibly, by using the transmission gear of the crimping tool, even by means of comparatively small hand forces large actuation forces for the securing device and therefore possibly large securing forces can be induced. An induction and/or increase of the securing effect with running through the working stroke and with the motion of the tool halves coming with it can for example be used in order to increase the securing effect of the workpiece in the accommodation during the plastic deformation of the workpiece, so that a change of the relative position of the workpiece with respect to the accommodation and therefore also with respect to the die due to the effective crimping forces can be avoided. For a further proposal of the invention, a crimping tool locator of the kind explained before is employed in a crimping tool. Advantageous developments of the invention result from the claims, the description and the drawings. The advantages of features and of combinations of a plurality of features mentioned at the beginning of the description only serve as examples and may be used alternatively or cumulatively without the necessity of embodiments according to the invention having to obtain these advantages. Without changing the scope of protection as defined by the enclosed claims, the following applies with respect to the disclosure of the original application and the patent: further features may be taken from the drawings, in particular from the illustrated designs and the dimensions of a plurality of components with respect to one another as well as from their relative arrangement and their operative connection. The combination of features of different embodiments of the invention or of features of different claims independent of the chosen references of the claims is also possible, and it is motivated herewith. This also relates to features which are illustrated in separate drawings, or which are mentioned when describing them. These features may also be combined with features of different claims. Furthermore, it is possible that further embodiments of the invention do not have the features mentioned in the claims. The number of the features mentioned in the claims and in the description is to be understood to cover this exact number and a greater number than the mentioned number without having to explicitly use the adverb “at least”. For example, if a die, a die half or an accommodation is mentioned, this is to be understood such that there is exactly one die, exactly one die half or exactly one accommodation, there are two dies, die halves or accommodations or there are more dies, die halves or accommodations. Additional features may be added to these features, or these features may be the only features of the respective product. The reference signs contained in the claims are not limiting the extent of the matter protected by the claims. Their sole function is to make the claims easier to understand. BRIEF DESCRIPTION OF THE DRAWINGS In the following, the invention is further explained and described with respect to preferred exemplary embodiments illustrated in the drawings. FIG. 1 in a three-dimensional view shows a pliers head of a crimping tool realized as manually actuated crimping pliers with a crimping tool locator. FIG. 2 in a three-dimensional view shows the crimping tool locator according to FIG. 1 with a workpiece realized as a plug inserted into an accommodation. FIG. 3 in a three-dimensional longitudinal section shows the pliers head with the crimping tool locator according to FIGS. 1 and 2 during a working stroke. FIG. 4 in three-dimensional longitudinal section shows the crimping tool locator according to FIGS. 1 to 3 with a latching or locking of the plug via a securing device. FIG. 5 in three-dimensional longitudinal section shows a crimping tool locator with a friction-locking securing of the plug via a securing device. FIG. 6 in a three-dimensional representation shows a crimping tool locator with a locking of the plug via a securing device which can be locked and/or unlocked via a manual actuation organ. FIG. 7 in a front view shows the crimping tool locator according to FIG. 6. FIG. 8 in a three-dimensional longitudinal section shows the crimping tool locator according to FIGS. 6 and 7. FIG. 9 in a three-dimensional longitudinal section shows a crimping tool locator with a locking of the plug via a securing device which can be locked and/or unlocked via a motion of an accommodating body relative to the pliers head. FIG. 10 in three-dimensional detailed view shows the pliers head with a crimping tool locator according to FIG. 9 held on it and a plug locked via the securing device. FIG. 11 in a three-dimensional longitudinal section shows a pliers head and crimping tool locator with a securing of the plug via a securing device which can be brought into the securing position via a motion of a die into the securing position. FIG. 12 shows the pliers head with the crimping tool locator according to FIG. 11 in a cutaway detail, where the securing device of the crimping tool locator is in the unsecured position. FIG. 13 shows the pliers head with the crimping tool locator according to FIG. 11 in a cutaway detail corresponding to FIG. 11, where the securing device of the crimping tool locator is in the secured position. DETAILED DESCRIPTION FIG. 1 shows a detail of a crimping tool 1, that is, crimping pliers 2, in the region of a pliers head 3. An actuation of the crimping pliers is done manually via hand levers (not shown here), where a use of the design according to the invention is also possible for other crimping tools 1, possibly also with a non-manual actuation. With regard to the construction of the crimping pliers 2 chosen in exemplary way here, it is referred to the documents EP 2 463 969 A2 (corresponding to U.S. Pat. No. 8,601,856 B2), DE 40 23 337 C1 (corresponding to U.S. Pat. No. 5,153,984), DE 44 27 553 C2, DE 100 56 900 C1 (corresponding to U.S. Pat. No. 6,612,147 B2), DE 101 32 413 C2 (corresponding to U.S. Pat. No. 6,877,228 B2), DE 101 40 270 B4, DE 10 2007 038 626 B3 (corresponding to U.S. Pat. No. 8,296,956 B2), DE 10 2008 017 366 A1 and DE 10 2010 061 148 A1, which with regard to the construction of the crimping pliers 2 are incorporated by this reference to the present specification. End regions of hand levers of the crimping pliers 2 are pivotably connected with each other via a hinge bolt. To each of the hand levers, an end region of a draw bar is linked. The other end region of each of the draw bars is linked to a supporting bolt 4, 5 of the pliers head 3. The supporting bolts 4, 5 are (possibly releasably) held on frame parts 6a, 6b of the pliers head 3 which in a first approximation are O-shaped. The hinge bolt pivotably connecting the hand levers of the crimping pliers 2 is supported in an accommodation 7 of a tool half 8. The tool half 8 is slidably guided along a longitudinal axis or crimping axis with respect to the frame parts 6a, 6b. Due to the mentioned draw bar connections a pivoting of the hand levers of the crimping pliers 2 towards each other leads to a motion of the tool half 8 along the longitudinal axis in a closing direction, in which way a working stroke of the crimping pliers 2 can be run through. A second tool half 9 is fixed to the frame parts 6a, 6b. On the tool halves 8, 9, at least one die half is formed each or at least one die body forming at least one die half is held. When running through the working stroke of the crimping pliers 2, the tool halves 8, 9 move towards each other until the die halves of the two tool halves 8, 9 corresponding to each other form a closed die. When running through the working stroke, the workpiece 10 (which is a plug 11 here) arranged between the tool halves 8, 9 and the corresponding die halves is crimped. On the pliers head 3, a crimping tool locator 12 is held. The crimping tool locator 12 comprises a holding and/or guiding body 13, which on the one hand serves for holding or fixing on the pliers head 3 and on the other hand serves for the guiding of a motion of an accommodating body 14 relative to the pliers head 3 between an insertion position and a working position of the accommodating body 14 (and the other way around). For the embodiment shown here, the relative motion of the accommodating body 14 with respect to the holding and/or guiding body 13 and therefore the pliers head 3 is a pivoting motion around a pivoting axis 15, which is oriented parallel to a pliers head plane defined by the frame parts 6 and vertically to the longitudinal and crimping axis. In order to achieve this, the holding and/or guiding body 13 comprises a pivoting bolt 20 which is fixedly or releasably held by the crimping tool half 8. The accommodating body 14 comprises arms 16, 17 which form bearing lugs 18, 19 oriented coaxially to the pivoting axis 15 for the pivoting bolt 20. For the embodiment shown, the bearing lugs 18, 19 are realized with open boundaries so that they can be “clicked” onto the pivoting bolt 20 under use of the elasticity of the arms 16, 17. The accommodating body 14 can be realized as one-parted or multi-parted. As can be seen in FIG. 2, the accommodating body 14 comprises several accommodations 21a, 21b, 21c, 21d arranged side by side. The distance and the position of the accommodations 21 corresponds to the distance and the position of the die halves of the tool half 8. Furthermore, the accommodations 21 are arranged in such a way that in the working position of the crimping tool locator 12 they are arranged aligned with the die halves of the tool half 8. FIG. 1 shows the working position of the crimping tool locator 12. In this working position, the main plane of extension of the accommodating body 14 is arranged parallel to the pliers head plane. The accommodations 21 are at a minimum distance from the die halves of the tool half 8 and are arranged aligned with them. Preferably, the accommodating body 14 is secured in the working position, which can be done for example by a magnet effective between the accommodating body 14 and the pliers head 3, by a latching or by a locking. From the working position, the accommodating body 14 can be pivoted around a pivoting axis 15 with a pivoting angle (for example in the region of 90° to 150°) into an insertion and removal position. in the insertion and removal position of the accommodating body 14 a plug is inserted from the side turned towards the pliers head 3 into one of the accommodations 21 (which in FIG. 2 is the accommodation 21c). After the insertion of the plug 11, the plug 11 protrudes from the accommodation 21 on the side turned towards the pliers head 3 with deformation portions 22, 23. For working on the plug 11, the accommodating body 14 is pivoted back into the working position (FIG. 1), where the deformation portions 22, 23 extending from the accommodation 21 are arranged between the tool halves 8, 9 and between corresponding die halves. By going through the working stroke of the crimping pliers 2 the deformation portions 22, 23 can be crimped onto a cable. In FIG. 4 it can be seen that in each of the accommodations 21a, 21b, 21c, 21d a securing device 24a, 24b, 24c, 24d is arranged. By the securing device 24a, 24b, 24c, 24d a plug 11 arranged in the respective accommodation 21a, 21b, 21c, 21d can be secured. For the embodiment according to FIG. 4, the securing devices 24 comprise a spring element 25, which here is an elastic spring arm 26, and a latching element 27, which here is a latching lug 28 protruding in the direction of the plug 11. For the embodiment shown, the spring arm 26 and the latching lug 28 are realized as one piece by the accommodating body 14 (without this necessarily having to be the case). The latching lug 28 comprises a latching contour 29 via which the force conditions for a latching and an unlatching and therefore the securing effect of the securing device 24 can be influenced. The plug 11 comprises a latching recess 30, which is arranged in such a way that for a sufficient insertion of the plug into the accommodation 21 in the secured position of the securing device 24 the latching lug 28 is able to engage with the latching recess 30. In the beginning of the insertion of a plug 11 into an accommodation 21, a front face and/or lower side of the plug 11 contacts an insertion inclination 31 formed by the latching contour 29 of the latching lug 28. An insertion force applied onto the plug 11 is transformed into a transverse force by the insertion inclination 31 which exerts a bending force onto the spring arm 26. When elastically biasing the spring arm 26 the latching lug 28 recedes downwards in FIG. 4, so that the front face of the plug 11 is able to pass the latching lug 28 and the plug 11 can be further inserted. The latching lug 28 while being elastically pressed by the spring arm 26 glides along the underside of the plug 11. When the latching lug 28 reaches the latching recess 30, due to the elastic biasing by the spring arm 26 the latching lug 28 latches with the latching recess 30. In this way the plug is secured in the accommodation 21 of the crimping tool locator 12. If after the execution of the crimping process and after an opening of the crimping tool locator 12 the plug 11 with the cable crimped with it is to be removed from the accommodation 21, this can be achieved by sufficient removal forces which are applied onto the cable and the plug 11 and which by a corresponding insertion inclination of the latching contour 29 arranged on the other side are transformed into a transverse force. This transverse force elastically biases the spring arm 26 and leads to result that the latching lug 28 leaves the latching recess 30. In FIG. 4, a different realization is shown in which the latching contour 29 on the side opposite the insertion inclination 31 comprises a transverse plane oriented transverse to the removal direction. This leads to the result that a removal of the plug 11 from the accommodation 21 by applying a removal force is not possible. Rather than that, for a removal it is required to slightly incline the cable with the plug 11 in the accommodation 21. In this way the mentioned transverse plane is lifted above the latching lug 28 and a removal is made possible with the passing of the latching lug 28. FIG. 5 shows a different embodiment wherein the plug 11 does not have a latching recess 30. In this case, in the free end portion the spring arm 26 forms or supports a friction element 32. With the insertion of the plug 11 into the accommodation 21 the friction element 32 is pressed against the plug 11 while elastically biasing the spring arm 26, while the plug 11 contacts the accommodation 21 on the side opposite the friction element 32. Therefore, for this embodiment the plug 11 is secured by friction in the accommodation 21. FIGS. 6 and 7 show another embodiment. The crimping tool locator 12 comprises a manual actuation organ 33 by which the securing device 24 can be supported with regard to the securing effect, be held in its operating position, be manually operated and/or released. For the embodiment shown, two lever-like actuation organs 33a, 33b are arranged on both sides of the accommodating body 14. The actuation organs 33a, 33b are rotationally fixedly coupled with each other via an actuation shaft 34. The actuation shaft 34 is supported in the accommodating body 14. The actuation shaft 34 carries cams 35a, 35b, 35c, 35d. The cams 35a, 35b, 35c, 35d are each assigned to an accommodation 21a, 21b, 21c, 21d with an assigned securing device 24a, 24b, 24c, 24d. By means of a manual rotation of the actuation organ 33 and therefore of the actuation shaft 34 and the cams 35, one cam 35 is moved into contact with the spring arm 26, the latching lug 28 (FIG. 4) or the friction element 32 (FIG. 5) and/or the spring arm 26, the latching lug 28 (FIG. 4) or the friction element 32 (FIG. 5) can be biased towards the plug 11. Therefore, via the rotation of the actuation organ 33 the latching lug 28 can be moved into the latching recess 30 (FIG. 4) or the friction element 32 can be brought into a friction connection with the plug 11 or a present friction connection can be increased (FIG. 5). Alternatively or cumulatively it is possible that with the cams 35 an assumed securing position of the securing device 24 (especially a position of the spring arm 26, the latching lug 28 or the friction element 32) is secured, so that a receding of the spring arm 26 away from the plug 11 is blocked by the cam 35. Therefore the cams 35 form an additional securing element 36, which blocks or secures an assumed securing position of the spring arm 26, the latching lug 28 or the friction element 32. It is also possible that the cam 35 is resilient or that the actuation shaft 34 is elastically supported so that it is possible to elastically clamp the cam with the spring arm 26, the latching lug 28 or the friction element 32. For the embodiment shown in FIGS. 10 and 11, the securing element 36 is realized as a kind of bar or as a wedge-shaped or trapezoidal tensioning or blocking element 37. In the direction of movement of the accommodating body 14 the tensioning or blocking element 37 is supported slidably with respect to the accommodating body 14 relative to the pliers head 3 at the closing of the crimping tool locator 12. With the closing of the crimping tool locator 12, that is, the approaching of the accommodating body 14 to the pliers head 3, a front face 38 of the tensioning or blocking element 37 contacts the pliers head 3. Due to the contact force between the pliers head 3 and the front face 38 the tensioning or blocking element 37 is biased towards the interior of the accommodation 21. The tensioning or blocking element 37 comprises an inclined surface 39 which contacts the underside of the spring arm 26, the latching lug 28 or the friction element 32 and which converts a biasing force created on the front face 38 into a force which biases the spring arm 26, the latching lug 28 and/or the friction element 32 towards the plug 11. If the crimping tool locator 12 is held in the closing position, due to the tensioning or blocking element 37 the securing device 24 is secured in the secured position. For the embodiment shown, the separate tensioning or blocking elements 37a, 37b, 37c, 37d for the securing devices 24a, 24b, 24c, 24d are realized by a common tensioning or blocking rod 40. The actuation direction of the tensioning or blocking rod 40 is oriented tangentially to the pivoting axis 15. In deviation to the embodiment shown, it is also possible that the tensioning or blocking rod 40 is mounted to the pliers head 3 and enters into interaction with the securing device 24 in the interior of the accommodating body 14. It is possible that between the pliers head 3, the tensioning or blocking elements 37a, 37b, 37c, 37d or the tensioning or blocking rod 40 and the securing device 24 an elasticity is interposed. FIGS. 11 to 13 show an embodiment of a crimping tool 2 in which at first with the closing of the crimping tool locator 12 the securing device 24 is not yet in the secured position. Rather than that, the securing device 24 is brought into the secured position in a motion-controlled and automatized way along the working stroke (that is, along the motion of the tool half 8). In order to achieve this, an actuation organ 41 (especially an actuation tappet 42) is mounted to the tool half 8. The actuation organ 41 extends through the accommodating body 14 or between the accommodating body 14 and the pliers head 3 to the accommodation 21. In the detail according to FIG. 12, an actuation position at the beginning of the working stroke of the crimping pliers 2 is shown. At the beginning of the working stroke, the tool half 8, the accommodating body 14 and the actuation organ 41 move together and in parallel to the longitudinal axis of the crimping pliers 2. At the beginning, the relative position of a front face 43 of the actuation tappet 42 and the accommodation 21 does not change, so that the actuation tappet 42 does not exert a securing effect onto the plug 11 arranged in the accommodation 21. On the contrary, towards the end of the working stroke the accommodating body 14 contacts the tool half 9 or a frame part 6. As the working stroke is further gone through and the tool half 8 and the accommodating body 14 are biased in the crimping direction, the contact between the tool half 9 and the frame part 6 leads to a relative motion between the accommodating body 14 and the tool half 8. In order to achieve this, the accommodating body 14 is connected via elongated holes extending along the longitudinal axis to the tool half 8 or is to a certain extend held elastically by the tool half 8. The mentioned relative motion has the result that there is also a relative motion between the front face 43 of the actuation tappet 41 and the accommodation 21 with the plug 11 arranged in it. This relative motion in turn results in the front face 43 of the actuation tappet 41 pressing the plug 11 against an opposite limiting surface of the accommodation 21. In this way the plug 11 is secured by friction in the accommodation 21. This securing effect then only occurs at the end of the working stroke and can be used to additionally fix the plug 11 and to keep the plug 11 in the correct orientation at the end of the plastic deformation of the plug 11 with high crimping forces being effective on the plug 11 then. Preferably, the front face 43 biases the plug 11 via a friction and/or spring element 44. For a different embodiment, an actuation organ 41 such as an actuation tappet 42 can also be mounted to the frame part 6 or the tool half 9 and extend from above through the accommodating body 14 into the accommodation 21. Then, in this way a relative motion between the accommodation 21 and the actuation organ 41 can occur over the entire working stroke. For the embodiments shown, the latching element 27, the latching lug 28, the friction element 32, a cam 35, the actuation organ 41 or the actuation tappet 42 forms a securing element 45 of the securing device 24. This securing element 45 can be brought manually by the securing device 24, in a motion-controlled way by the closing of the crimping tool locator 12 or by the relative motion of the tool halves 8, 9 during the working stroke into a secured position in which the plug 11 (possibly in addition to another way of securing) is secured in the accommodation 21 and/or into an unsecured position in which the plug 11 is not additionally secured in the accommodation 21. The securing element 45 is moveable relative to the cross section of the accommodating body 14 limiting the accommodation 21 for the plug 11. This relative motion can for example be larger than 0.01 mm, larger than 0.02 mm, larger 0.05 mm, larger than 0.1 mm or even larger than 0.2 mm and can be induced by the forces effective for the induction of the motion of the securing element 45 (that is, especially the insertion forces and/or the removal forces for the plug according to FIGS. 3 to 5, the actuation forces for the actuation organ 33 according to FIGS. 6 to 8, the forces applied manually to the crimping tool locator 12 for the closing according to FIGS. 9, 10 or the crimping forces effective onto the tool half 8). If the contact contours between the latching element 27 and the latching recess 30 comprise inclined surfaces, the securing device 24 realized with the spring element 25, the latching element 27 and the latching recess 30 is a latching device 46 which can be latched or unlatched for the application of sufficient insertion forces or removal forces onto the workpiece 10. If, on the contrary, the contact contours between the latching element 27 and the latching recess 30 comprise transverse surfaces having an orientation transverse to the longitudinal axis of the accommodation 21, the securing device 24 is a locking device 47, which cannot be unlocked by pure application of removal forces. Also in the case that the securing device 24 comprises the actuation organ 33, the actuation shaft 34 and at least one cam 35, the securing device 24 forms a locking device 47 which secures the plug 11 by friction. For the removal of the plug 11 for the reduction of the friction force at first the crimping force has to be reduced by a rotating the actuation shaft 34. The accommodating body may only comprise one accommodation 21 and one corresponding securing device 24. It is also possible that the accommodating body 14 comprises several accommodations 21a, 21b, . . . , where only single accommodations 21 or all accommodations 21 may each be equipped with a securing device 24a, 24b, . . . . In the present description the same construction elements such as the accommodations 21a, 21b, . . . and the securing devices 24a, 24b, . . . are marked with the same reference signs. A differentiation is achieved by the additional letter a, b, . . . . If then such a reference sign is used without additional letter a, b, . . . , this can mean that in this place only one such construction element or several such construction elements is/are referred to. The invention has been described on the basis of a special type of crimping pliers 2 with an O-shaped frame and tool halves driven via lugs or rods. The use of the invention, however, is not limited to this type of crimping pliers. Rather than that, the invention can be used in connection with any other type of crimping pliers, cp. the prior art mentioned in the beginning, or in any other crimping tool. Furthermore, the invention has been described on the basis of a special type of a crimping tool locator 12, that is, a crimping tool locator in which the accommodating body 14 is pivoted about a transverse axis. The use of the invention, however, is not limited to this type of crimping tool locator 12. Rather than that, the invention can generally be used in connection with any other type of a crimping tool locator 12, especially a crimping tool locator according to the prior art mentioned in the beginning and/or a crimping tool locator with a pivoting of the accommodating body 14 around a longitudinal axis or with a translatory degree of freedom of the accommodating body 14 or an accommodating body 14 rotated in revolver-like way. A crimping tool locator 12 can be an integral part of crimping pliers 2 or be mounted fixedly to a pliers head 3. It is also possible that a crimping tool locator 12 is an optional additional component which can be mounted with the crimping pliers 2 according to the variant of configuration or mode of use. Many variations and modifications may be made to the preferred embodiments of the invention without departing substantially from the spirit and principles of the invention. All such modifications and variations are intended to be included herein within the scope of the present invention, as defined by the following claims.
<SOH> BACKGROUND OF THE INVENTION <EOH>During the crimping over a working stroke of crimping pliers, the plug is plastically deformed and pressed against the end of the cable arranged in the plug. In this way on one hand an electrical contact is established and on the other hand a mechanical connection between the plug and the end of the cable is established which is as permanent as possible. With regard to possible realizations of the crimping pliers on the one hand and the plug and the types of the cables crimped with it on the other hand it is referred especially to the embodiments shown and described in the catalogue “Werkzeuge für die professionelle Anwendung” of WEZAG GmbH Werkzeugfabrik (printing remark “Dokument Nr. Kat. 10/11”). For an exact and defined crimping of the plug it is necessary that the plug and the cable are arranged in the intended position and orientation relative to tool halves of the crimping pliers forming at least one die half, so that with the closing of the tool halves over the working stroke of the crimping pliers the desired plastic deformation can be induced and the crimping result attained on the crimped plug conforms with high standards of precision. For setting the position and orientation of the plug relative to a die formed with two corresponding die halves of a tool half at the begin of the working stroke, crimping tool positioners (also referred to as “locators” in English use) are employed. Such a crimping tool locator serves for adequately setting the position and the orientation of the plug relative to the pliers head, especially for setting the correct axial position of the plug with respect to the end of the cable and/or for setting the coaxial orientation of the plug with respect to the end of the cable. The crimping tool locator on the one hand makes sure that at the beginning of the crimping stroke the plug is already positioned correctly with respect to a die of the pliers head. On the other hand it is also possible that during the crimping stroke the crimping tool locator proper secures the relative position and orientation of the plug with respect to the die and the end of the cable at the execution of the working stroke during the plastic deformation of the plug. Known crimping tool locators comprise at least one accommodation into which the plug can be inserted in such a way that the plug has a defined position and orientation with respect to the crimping tool locator. The crimping tool locator then is also mounted with a defined position and orientation on the pliers head in which the two halves are movably guided and driven in such a way that the plug inserted into the crimping tool locator comprises a defined position and orientation with respect to the tool halves and therefore with respect to a die. With respect to the mechanical basic composition of crimping pliers and the pliers head, the realization of the crimping tool locator and the design of possible degrees of freedom of motion of the crimping tool locator from prior art multitudinous design possibilities are known (cp. also the embodiments of the crimping tools in the above-mentioned catalogue of WEZAG GmbH Werkzeugfabrik): In the simplest case, an accommodating body of a crimping tool locator is mounted on the pliers head of the crimping pliers. It is also possible, however, that a holding and guiding body of the crimping tool locator is mounted to the pliers head of the crimping pliers and an accommodating body of the crimping tool locator is movably held and guided on the holding and guiding body. Crimping pliers known from DE 27 18 165 A1 have a pliers head with a C-shaped frame so that in this case the pliers head is open on the side. In another embodiment according to DE 27 18 165 A1, crimping jaws and tool halves mounted on them move in a “scissor-like” way with respect to each other. In both cases, in the pliers head a pliers head plane is defined in which the tool halves with the die halves move. The known crimping pliers have a crimping tool locator with an accommodating body which is pivotable around a pivoting axis between an insertion position and a working position. In the insertion position, an inserting, plugging of the plug onto or into at least one accommodation of the accommodating body can be achieved. In the working position, with running through the working stroke the crimping of the plug is achieved. The pivoting axis for the pivoting of the accommodating body is oriented vertically to the pliers head plane. For a crimping of a plug, to begin with the accommodating body of the crimping tool locator is pivoted into the insertion position. The plug then is inserted into an accommodation of the accommodating body and the accommodating body with the inserted plug is pivoted back into the working position through the opened side of the pliers head. In the working position the plug takes up the intended position and orientation with respect to the die halves. Subsequently, the plastic deformation of the plug can be achieved by means of the actual crimping process by actuating the drive of the crimping pliers, which is here constituted by two hand levers pivotable with respect to each other. In order to achieve a secure holding of the plug in the accommodation, on its upper side the accommodation is reached over by a leaf spring which exerts a force onto the plug at a location outside of the accommodation. This force presses the plug against the bottom of the accommodation and holds the plug by clamping. As an alternative to the employment of a leaf spring, the document DE 27 18 165 A1 also suggests that the plug is held in the accommodation by a pin extending in the longitudinal direction of the plug. By the pin the plug can be held on its own by a contact spring arm of the plug. For the purpose to avoid that the plug glides out in a direction perpendicular to the insertion opening of the accommodation, the accommodation is realized as an insertion groove open to the upper side, where on the upper side the insertion groove is covered and closed by a small plate screwed onto it. Other crimping pliers are sold by WEZAG GmbH Werkzeugfabrik under the label CS20KS. These crimping pliers also have a C-shaped pliers head open to one side. On this pliers head, an accommodating body of a crimping tool locator is linearly guided on an axis fixed to the pliers head. The axis is oriented parallel to the lower horizontal arm of the C and is arranged in a plane parallel to the pliers head plane. The accommodating body can be moved by a pivotable lever supported on the pliers head from the working position into the insertion position. A manually induced pivoting motion of the lever via a connection between a pin guided in an elongated hole is converted into a linear motion along the axis for a linear motion of the accommodating body. Furthermore, crimping pliers of the applicant with label CS25KS are known, which also have a C-shaped pliers head. In these crimping pliers, an accommodating body of a crimping tool locator is supported for a pivoting movement with respect to the pliers head around a pivoting axis oriented vertically to the pliers head plane. Via the rotation of a knurl the accommodating body is pivotable parallel to the pliers head plane between an insertion position and a working position. DE 198 32 884 C1 (corresponding to U.S. Pat. No. 6,155,095 A) discloses crimping pliers with a pliers head in a plate construction mode—The pliers head is not C-shaped with a one-sided opening but O-shaped without an opening in the circumferential direction. According to an actuation of hand levers, a moveable tool half is slidable in the direction of a longitudinal axis relative to a tool half fixed with respect to the pliers head. DE 198 32 884 C1 proposes a crimping tool locator with an accommodating body which is pivotable around a pivoting axis which is oriented in parallel to the pliers head plane and transverse to the direction of motion of the tool halves of the crimping pliers. In a working position, the crimping tool locator is oriented generally in parallel to the pliers head plane. From this working position, the pliers head locator can be pivoted around the pivoting axis out of the pliers head plane into the insertion position. For the crimping tool locators explained before the motion of the accommodating body of the crimping tool locator necessitates holding the crimping pliers with one hand of the user, for example in the region of hand levers, while the other hand of the user moves the accommodating body of the crimping tool locator from a working position into an insertion position (or the other way around). Instead, DE 10 2008 017 366 A1 (corresponding to U.S. Pat. No. 8,161,789 B2) proposes a crimping tool locator with a pivotable accommodating body on which a cantilever is fixed. The operating surface of the cantilever is guided in proximity to the hand levers of the crimping pliers in such a way that with the thumb of the hand which holds the crimping pliers in the region of the hand levers, the accommodating body of the crimping tool locator can be pivoted, in which way a simplified operation, especially a one-handed operation is enabled. DE 10 2008 012 011 B3 (corresponding to U.S. Pat. No. 8,230,715 B2) discloses a pliers head in which tool halves with multiple die halves with different crimping contours are moveable transverse to the pliers head and transverse to the crimping axis, so that depending on the plug to be crimped different die halves can be arranged coaxially or centrally to the crimping axis in the pliers head. In this way, the force conditions for the die halves used for different plugs can be optimized and/or the number of die halves with different geometries that can be used in a tool half can be increased. DE 10 2010 061 148 A1 (corresponding to U.S. Pat. No. 8,601,856 B2) describes crimping pliers wherein the two hand levers in the end region turned towards the crimping head are supported in a pivot bearing connected to a moveable tool half. Furthermore, the hand levers are each pivotably linked to an end region of draw bars which are linked to an O-shaped frame of the pliers head in the other end region. On the frame of the pliers head, a tool half is fixed. Onto the fixed tool half, a holding and guiding body of a crimping tool locator is screwed. On the holding and guiding body, an accommodating body of the crimping tool locator is moveably supported. The accommodating body can be moved relative to the holding and guiding body in a direction transverse to the relative motion of the tool halves (and therefore transverse to the crimping axis). The tool halves each have several die halves lying next to each other in a direction transverse to the crimping axis. With the moving of the accommodating body relative to the holding and guiding body, an accommodation of the accommodating body for a plug can be arranged behind different die halves of a tool half or different accommodations of the accommodating body can be arranged behind the same die half. Therefore, depending on the position of the accommodating body, a die half can enter into interaction with different plugs, which may have been inserted in different accommodations of the accommodating body, and/or different die halves can enter into interaction with plugs inserted into the same accommodation of the accommodating body. As an alternative to using a translatory degree of freedom of the accommodating body with respect to the holding and guiding body transverse to the crimping axis, DE 10 2010 061 148 A1 also proposes that the accommodating body is rotatable in revolver-like way with respect to the holding and guiding body around a rotational axis oriented vertically to the pliers head plane. In this case, single accommodations of the accommodating body are distributed over the circumference and/or are provided with different radii from the rotational axis of the revolver on the accommodating body. Accordingly, depending on the rotational angle of the accommodating body these accommodations can be arranged behind a die half. It is possible that a latching or locking of the accommodating body with respect to the holding and guiding body is done in order to secure an operating position of the accommodating body. DE 10 2010 061 148 A1 also proposes an especially compact design of the crimping tool locator. For this design it is also possible that the extension of an accommodation of the crimping tool locator is larger than the distance between two neighboring die halves of a tool half. DE 20 2008 003 703 U1 discloses pliers in which an accommodating body of a crimping tool locator is pivotable around a pivoting axis between an insertion position and a working position. The pivoting axis is oriented in parallel to the crimping axis and the pliers head plane. A locking (unyielding or yielding in a limited way) of the accommodating body in the working position is proposed. The locking can be achieved via a blocking bar, which is supported for being pivoted around a pivoting axis oriented vertically to the pliers head plane on a pivoting bolt of the holding and guiding body. Furthermore, on the accommodating body a securing element is supported for being pivoted around a pivoting axis oriented radially to the pivoting axis for the pivoting of the accommodating body relative to the holding and guiding body and parallel to the main axis of extension of the accommodating body, which is realized as a stop rocker. In a securing position of the stop rocker, the stop rocker reaches around the accommodating body in the shape of a U. Outside of the accommodation of the accommodating body for the plug, a lug or a protrusion of a side arm of the U engages with a groove or an indentation of the plug. In this way the plug is intended to be secured against an unintended falling out of the accommodation of the accommodating body. Furthermore, the protrusion or the lug forms a further stop. In the working position of the accommodating body the further stop limits an insertion depth of the partially stripped cable. In this way, it is to be made sure that a crimping of the plug to the cable is done in a defined axial relative position of the cable in the plug. By means of a spring, the stop rocker is biased into the securing position, while it can be manually moved out of the securing position against the biasing by the spring. EP 2 672 580 A1 discloses crimping pliers with different drive kinematics, in which a crimping tool locator (here with an accommodating body which is pivotable around a pivoting axis oriented parallel to the crimping axis) can also be employed. DE 101 34 004 C1 discloses a crimping tool locator which is fixed to a moveable pliers jaw by a U-shaped holding bracket. Via two angled elongated holes in the side arms of the U-shaped holding bracket an accommodating body is guided for being moveable in a translatory way and for being pivoted. In a state pushed away from the moveable pliers jaw and additionally folded away, plugs can be inserted into accommodating pockets of the accommodating body. A clamping spring reaches over the accommodating body and clamps the plug with a clamping lip at a location outside of the accommodating pockets in order to arrest it and to hold it. Since the clamping lip engages with a correspondingly formed indentation of the plug, it also defines the insertion depth of the plug into the accommodating pocket. EP 0 125 708 A2 discloses a crimping tool locator which is fixedly mounted to a pliers jaw. An accommodation of the crimping tool locator is realized with a slit on the upper side where in the slit a slotted link is guided while biased by a spring. With the insertion of a plug through the dies of the pliers jaws into the accommodation, the front face of the plug can push the slotted link upwards or pivot it until the front face of the plug comes to rest against a protrusion of the slotted link. In this way the insertion depths of the plug into the accommodation is defined. For the use of the crimping tool locator for another plug with a larger required insertion depth, the slotted link can be moved manually further out of the accommodation, so that the protrusion does no longer hinder the insertion of the plug. In this case, the plug can be inserted into the accommodation up to a bottom of the accommodation. In this state, the slotted link can again be released by the user. In this way, due to the bias of the spring with the protrusion the slotted link presses the plug onto the bottom of the accommodation. Further prior art is known from documents U.S. Pat. No. 3,142,209 A, U.S. Pat. No. 3,457,764 A, U.S. Pat. No. 2,953,185 A and U.S. Pat. No. 3,751,963 A.
<SOH> SUMMARY OF THE INVENTION <EOH>It is an object of the present invention to propose a crimping tool locator which is improved with respect to usage especially considering the demands of construction space. Furthermore, it is an object of the invention to propose a correspondingly improved crimping tool. The crimping tool locator according to one embodiment of the invention comprises an accommodating body. The accommodating body can be realized as one-parted or multi-parted or as one-piece or multi-piece and be fixed or moveable, especially slidable or pivotable or rotatable in a revolver-like way, be held on the crimping tool for a motion between an insertion position and a working position (cp. the prior art mentioned in the beginning). The accommodating body comprises an accommodation (or at least one accommodation) for a workpiece. The accommodation is formed especially by a recess of the accommodating body, possibly with a suitable lining, and the cross section of the accommodation is limited (with open or closed boundaries) by the material of the accommodating body. One embodiment of the present invention in particular bases on the finding that for embodiments known from prior art, a plug is loosely accommodated in the fixedly defined cross section of the accommodation, especially with a clearance fit or a transition fit. Due to the own weight of the plug and/or the chosen fit between the outer cross section of the plug and the inner cross section of the accommodation, there is friction between the plug and the accommodation, while depending on the orientation of the crimping tool the plug can also get “jammed” in the accommodation. Due to friction and a possible jamming, the plug is generally secured in the accommodation in such a way that it can be made to approach the cable with the crimping tool and be brought into effective interaction with the cable so that the crimping can be done. It has emerged, however, that the plug repeatedly falls out of the accommodation, which is for example the case when the crimping tool has to be brought to the cable in situations under tight construction room conditions and while changing its orientation. Especially under the tight construction room conditions, it can also be problematic to pick up a plug fallen out of the accommodation and to bring it back to the accommodation. According to one embodiment of the invention it is suggested that the accommodating body comprises a securing device. By the securing device the workpiece can be secured in the interior of the accommodation. Therefore, via the securing device (possibly in addition to a possible friction due to the own weight of the workpiece or a jamming of the plug) the plug is secured with respect to unintentionally falling out. The securing device especially produces a securing force which is independent of the own weight of the workpiece. Preferably, the securing device is realized in such a way that via the securing device a (partial) cross section of the accommodation is changeable between a non-securing (partial) cross section in which the plug is insertable into the accommodation while forming an insertion clearance and (together with the attached cable) can be removed from it and a securing (partial) cross section which is smaller than the non-securing (partial) cross section and in which the plug is secured in the accommodation so that it cannot easily fall out of the accommodation. Within the framework of the invention, the securing device is preferably integrated into the accommodation or adjoins an interior surface of the accommodation. The interaction between the plug and the securing device therefore is created in the interior of the accommodation (and not outside of it and especially not axially before or behind the accommodation). A cross section of the accommodation can be limited by a securing element of the securing device. In deviation to securing the plug via a stop rocker according to DE 20 2008 003 703 U1, according to one embodiment of the invention the securing is achieved via the securing device in the interior of the accommodation, in which way the demands of construction space can be reduced on the one hand with respect to the crimping tool and the crimping tool locator and on the other hand with respect to the design of the plug to be secured. Possibly, via the securing device according to the invention it can also be made possible for plugs of different types or geometries to be held in the same accommodation since the securing device can guarantee a certain adaptability. According to one embodiment of the invention, the securing device comprises a securing element. The securing element comprises two different positions, that is, a secured position and an unsecured position. In the secured position, a workpiece arranged in the accommodation is secured. On the contrary, in the unsecured position, the workpiece arranged in the accommodation is unsecured or a workpiece can be inserted into the accommodation or removed from it. Preferably, in the secured position the securing element decreases the size of the (partial) cross section of the accommodation, in which way the securing effect is achieved. To mention only some non-limiting examples, this decrease can be a decrease, or the motion of the securing element can be a motion larger than 0.01 mm, larger than 0.02 mm, larger than 0.05 mm, larger than 0.1 mm or even larger than 0.2 mm. For the realization of the securing device and therefore for achieving the securing effect, within the framework of the invention there are the following non-limiting options: For an embodiment of the invention, the securing device is realized as a latching device. As a latching device, especially a device is understood in which, while being biased by a spring element, a latching element engages with a latching recess, in which way the securing effect is created due to a latching force. Preferably, the latching element and/or the latching recess is contoured with suitable latching contours or inclined surfaces in such a way that at the application of insertion forces onto the plug, while biased by the spring element the latching device is moved in the direction of an opening position or a non-securing position and at reaching the latching position the spring element moves the latching element into the securing position, in which the latching element engages with the latching recess or reaches behind a latching protrusion, and/or at the application of removal forces onto the plug, while being biased by the spring element the latching element is moved in the direction of an opening position or non-securing position, until for reaching a threshold value of the releasing force the latching element leaves engagement with the latching recess or the latching protrusion, in which way the plug (with the cable fixed to it) can be moved out of the accommodation. For such a latching device, due to the spring element the latching element automatically takes up the securing position, while with the application of insertion forces and/or removal forces while being biased by the spring element the latching element is brought into the non-securing position, in which then possibly, however, for moving the plug friction forces between the latching element and the plug also have to be overcome. For another embodiment of the invention, the securing device is realized as a locking device. In a locking device, the plug is locked in the accommodation. As such, especially a form-locking between a locking element and a locking protrusion or a locking recess is understood, where in this case a locking cannot be released while being biased by a spring element by an application of sufficient insertion forces and/or removal forces onto the plug. Rather than that, a separate locking and/or unlocking via manual actuation of a separate locking actuation organ is necessary. For a further embodiment of the invention, the securing device is equipped with a friction element. This friction element is supported via a spring element. The spring element presses the friction element against an outer surface of the workpiece. In this way, the workpiece can be secured by friction in the accommodation. Via suitable contouring of the outer surface of the workpiece, a changeable securing effect corresponding to the friction force can be created depending on how deep the workpiece has been inserted into the accommodation. By suitable choice of the material and the surface of the friction element and/or the workpiece, there can be a constructive influence on the friction conditions. Furthermore, influencing the friction conditions can be done by the dimensioning of the spring element, especially the choice of the stiffness of the spring element, the choice of the number of inserted spring elements and/or the length of the spring element. The invention covers embodiments in which the latching element, the locking element or the friction element and/or the corresponding spring element is/are realized by the accommodating body in the region of the accommodation, while the friction surface interacting with the friction element, the latching protrusion or the latching recess for the latching engagement of the latching element or the locking protrusion or the locking recess for the present engagement of the locking element is realized by the workpiece. According to a further proposal of the invention, the securing device comprises a manual actuation organ. By the manual actuation organ the securing device can be supported with respect to the securing effect, can be held in its operating position, can be manually operated and/or released. In this way the options for the design of the securing effect and the options of handling for the user of the crimping tool are increased. In the case that the securing device is a latching device, by actuation of the actuation organ the latching effect can be increased or decreased. Preferably, the manual actuation organ serves for locking and/or unlocking of a locking device forming the securing device. It is also possible that the manual actuation organ moves an additional securing element, where in a securing position the additional securing element secures or single-sidedly blocks a securing position taken up by a latching element, a friction element, a locking element and/or a spring element. Alternatively or cumulatively to a manual actuation of the securing device via a manual actuation organ, an actuation of the securing device can be actuated and/or released in a motion-controlled way and/or a force-controlled way. This can be achieved in a way controlled by the motion of a plug in the accommodation. For example, with the insertion of the plug (motion control) a latching or locking element can be brought from a securing position into a non-securing position, in which then the complete insertion of the plug into the accommodation is possible. On the other hand, when reaching the latching or locking position, that is, also in a motion-controlled way, the return of the latching or locking element into the securing position is achieved. As explained before, a force control with the motion of the plug in the accommodation can consist of a release of a latching occurring when a threshold value of a removal force (which can be defined by a design of latching contour) is surpassed. Alternatively or cumulatively, the securing device can be actuated and/or released in a motion-controlled way controlled by a motion of the accommodating body relative to a holding and/or guiding body or relative to a pliers head on which the holding and/or guiding body is held. This shall be explained in an exemplary way on the basis of a crimping tool locator in which the accommodating body is supported for being pivoted between an insertion position and a working position on the pulling and/or guiding body mounted to the crimping tool head: When the accommodating body “claps shut” into the working position, an actuation element of the holding and/or guiding body or the crimping tool head can approach a counter actuation element of the securing device or enter into interaction with the counter actuation element. For example, the actuation element can be an actuation pin which actuates a latching device or a friction device in such a way that the latching effect or friction force is induced or increased or a locking device is locked when the working position is approached. Alternatively or cumulatively it is possible that the securing device is actuated and/or released in a motion-controlled way by a motion of driving elements or tool halves of the crimping tool. For example, for an increase of a latching effect or of friction or for the induction of a locking an actuation element can be moved together with the motion of the tool half or the die and enter into interaction with a counter actuation element of the securing device in order to induce the latching effect or the securing friction force or to increase it/them or to induce the locking. Possibly, in this way the manual actuation of the crimping tool can be used for the actuation of the securing device. Possibly, by using the transmission gear of the crimping tool, even by means of comparatively small hand forces large actuation forces for the securing device and therefore possibly large securing forces can be induced. An induction and/or increase of the securing effect with running through the working stroke and with the motion of the tool halves coming with it can for example be used in order to increase the securing effect of the workpiece in the accommodation during the plastic deformation of the workpiece, so that a change of the relative position of the workpiece with respect to the accommodation and therefore also with respect to the die due to the effective crimping forces can be avoided. For a further proposal of the invention, a crimping tool locator of the kind explained before is employed in a crimping tool. Advantageous developments of the invention result from the claims, the description and the drawings. The advantages of features and of combinations of a plurality of features mentioned at the beginning of the description only serve as examples and may be used alternatively or cumulatively without the necessity of embodiments according to the invention having to obtain these advantages. Without changing the scope of protection as defined by the enclosed claims, the following applies with respect to the disclosure of the original application and the patent: further features may be taken from the drawings, in particular from the illustrated designs and the dimensions of a plurality of components with respect to one another as well as from their relative arrangement and their operative connection. The combination of features of different embodiments of the invention or of features of different claims independent of the chosen references of the claims is also possible, and it is motivated herewith. This also relates to features which are illustrated in separate drawings, or which are mentioned when describing them. These features may also be combined with features of different claims. Furthermore, it is possible that further embodiments of the invention do not have the features mentioned in the claims. The number of the features mentioned in the claims and in the description is to be understood to cover this exact number and a greater number than the mentioned number without having to explicitly use the adverb “at least”. For example, if a die, a die half or an accommodation is mentioned, this is to be understood such that there is exactly one die, exactly one die half or exactly one accommodation, there are two dies, die halves or accommodations or there are more dies, die halves or accommodations. Additional features may be added to these features, or these features may be the only features of the respective product. The reference signs contained in the claims are not limiting the extent of the matter protected by the claims. Their sole function is to make the claims easier to understand.
H01R43042
20170905
20180322
99929.0
H01R43042
0
ISLAM, AMER
Crimping Tool Locator and Crimping Tool
SMALL
0
PENDING
H01R
2,017
15,695,898
PENDING
INDEPENDENTLY CONTROLLED METER ROLLERS AND AIR CONVEYANCE COMPONENTS SYSTEM AND METHOD
The present disclosure includes an agricultural system having first and second product meters configured to meter product to first and second lines, respectively. First and second motors are coupled to the first and second product meters and configured to drive them at first and second metering rates, respectively. An air source is configured to provide first and second airflows to the first and second lines, respectively. A controller electrically coupled to the first and second motors is configured to receive first and second inputs indicative of first and second numbers of first and second outlets fluidly coupled to the first and second lines, respectively. The controller is configured to instruct the first and second motors to drive the first and second product meters at the first and second metering rates, respectively, based on the first and second inputs, and to instruct the air source to provide the first and second airflows with first and second dynamic pressures or first and second velocities.
1. A method of operating a product distribution system of an agricultural implement, comprising: receiving, at a processor, a first signal indicative of a first number of first outlets fluidly coupled to a first meter that meters product from a product tank; receiving, at the processor, a second signal indicative of a second number of second outlets fluidly coupled to a second meter that meters product from the product tank; determining, via the processor, a first target metering rate for the first meter and a second target metering rate for the second meter based on the first and the second numbers; and outputting, via the processor, a third signal to the first meter and a fourth signal to the second meter, wherein the third and fourth signals are indicative of instructions to enable the first meter to provide the first target metering rate and the second meter to provide the second target metering rate, respectively; and outputting, via the processor, at least a fifth signal to an air source of the product distribution system, wherein the fifth signal is indicative of instructions to enable delivery, via the air source, of a first airflow having a first velocity to a first primary distribution line fluidly coupled to the first meter and a second airflow having a second velocity to a second primary distribution line fluidly coupled to the second meter, wherein the first and second velocities are based on the first and second target metering rates. 2. The method of claim 1, wherein receiving the first signal and the second signal comprises receiving a first manual input and a second manual input, respectively, from an operator. 3. The method of claim 1, wherein the third and fourth signals are output to a first motor coupled to the first meter and a second motor coupled to the second meter to drive the first and second meters at the first and second target metering rates, respectively. 4. The method of claim 1, comprising receiving the product from the product tank at the first and the second meters and using the first and second meters to meter the product at the first target metering rate and the second target metering rate, respectively. 5. The method of claim 1, wherein the air source comprises a fan configured to deliver the first airflow to the first primary distribution line and the second airflow to the second primary distribution line, wherein outputting, via the processor, at least the fifth signal to the air source of the product distribution system comprises outputting the fifth signal to a first flow regulating device configured to enable a first pressure of the first airflow and outputting a sixth signal to a second flow regulating device configured to enable a second pressure of the second airflow. 6. The method of claim 1, wherein the air source comprises a fan configured to deliver the first airflow to the first primary distribution line and the second airflow to the second primary distribution line, wherein outputting, via the processor, at least the fifth signal to the air source of the product distribution system comprises outputting the fifth signal to a first flow regulating device configured to enable the first velocity of the first airflow and outputting a sixth signal to a second flow regulating device configured to enable the second velocity of the second airflow. 7. A control system configured to control operation of an agricultural product distribution system, the control system comprising: a controller configured to receive a first input indicative of a first number of first openers fluidly coupled to a first primary distribution line and a first meter configured to meter product from a product tank, to receive a second input indicative of a second number of second openers fluidly coupled to a second primary distribution line and a second meter configured to meter product from the product tank, to determine a first target metering rate of the first meter based on the first number and a second target metering rate of the second meter based on the second number, to instruct a first motor to drive the first meter at the first target metering rate, to instruct a second motor to drive the second meter at the second target metering rate, to instruct an air source to provide a first airflow to the first primary distribution line and second airflow to the second primary distribution line based on the first and second target metering rates. 8. The control system of claim 7, wherein the controller comprises a user interface having one or more user input selections configured to enable an operator to manually enter the first and second inputs. 9. The control system of claim 7, wherein the first and second target metering rates enable distribution of the product through each of the first and second openers at a desired distribution rate. 10. The control system of claim 7, wherein the controller instructs a first fan of the air source to provide the first airflow with the first fluid pressure and a second fan of the air source to provide the second airflow with the second fluid pressure. 11. The control system of claim 7, wherein the first input and the second input are directly indicative of the first and second numbers of first and second openers, respectively. 12. A method of controlling an agricultural product distribution system, comprising: receiving, at a processor, a first input indicative of a first number of first outlets fluidly coupled to a first primary distribution line and to an air source, wherein a first motor is configured to drive a first meter to meter product from a first product tank compartment to the first primary distribution line; receiving, at the processor, a second input indicative of a second number of second outlets fluidly coupled to a second primary distribution line and to the air source, wherein a second motor is configured to drive a second meter to meter product from a second product tank compartment to the second primary distribution line; determining, via the processor, a first target metering rate for the first meter and a second target metering rate for the second meter based on the first number and the second number, respectively; and outputting, via the processor, instructions to enable the first motor to drive the first meter at the first target metering rate and the second motor to drive the second meter at the second target metering rate, respectively. 13. The method of claim 12, comprising outputting, via the processor, instructions to the air source to provide a first airflow to the first primary distribution line and a second airflow to the second primary distribution line, wherein the first and second airflows are based on the first and second target metering rates. 14. The method of claim 12, wherein receiving the first input and the second input comprises receiving a first manual input and a second manual input, respectively, from an operator at a user interface. 15. The method of claim 12, comprising fluidly coupling a first plurality of hoses to the first primary distribution line and a second plurality of hoses to the second primary distribution line, wherein the first plurality of hoses comprises the first outlets, and wherein the second plurality of hoses comprises the second outlets. 16. The method of claim 15, comprising: conveying the product to a first distribution header disposed between the first primary distribution line and the first plurality of hoses; and conveying the product to a second distribution header disposed between the second primary distribution line and the second plurality of hoses. 17. The method of claim 12, comprising driving the first motor and the second motor via a common drive shaft coupled to the first motor via a first gear assembly and the second motor via a second gear assembly. 18. The method of claim 12, comprising instructing, using the processor, a first fan of the air source to provide the first airflow with a first velocity and a second fan of the air source to provide the second airflow with a second velocity. 19. The method of claim 12, comprising instructing, using the processor, a first flow regulating device of the air source to enable a first pressure of the first airflow coupled to the first primary distribution line and a second flow regulating device of the air source to enable a second pressure of the second airflow, wherein the first flow regulating device is coupled to the first primary distribution line and the second flow regulating device is coupled to the second primary distribution line. 20. The method of claim 12, comprising determining, using the processor, an equivalent pressure and velocity based on an average of the first and second target metering rates, wherein the air source comprises a fan configured to supply a single airflow that is divided between a first airflow to the first primary distribution line and a second airflow to the second primary distribution line, and wherein the first airflow and the second airflow comprise the equivalent pressure and velocity.
CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisional of U.S. patent application Ser. No. 14/932,817, entitled “INDEPENDENTLY CONTROLLED METER ROLLERS AND AIR CONVEYANCE COMPONENTS SYSTEM AND METHOD,” filed Nov. 4, 2015, which claims priority from and the benefit of U.S. Provisional Application Ser. No. 62/074,814, entitled “INDEPENDENTLY CONTROLLED METER ROLLERS AND AIR CONVEYANCE COMPONENTS SYSTEM AND METHOD,” and filed Nov. 4, 2014. Each of the foregoing applications is hereby incorporated by reference in its entirety for all purposes. BACKGROUND The present disclosure relates generally to product distribution systems for agricultural implements and, more particularly, to independent control of meter rollers and air conveyance components of the product distribution system. Generally, agricultural implements (e.g., seeders) are configured to distribute product (e.g., seeds and fertilizer) across a field. The agricultural implement may improve crop yield and/or farming efficiency by providing an even distribution of the product across the field and/or increasing speed at which the product is distributed across the field. However, traditional product distribution systems for agricultural implements often distribute agricultural product, at any given time, to multiple rows (e.g., via multiple row units) using meters that are coupled to a single drive shaft that drives the meters at a single rate. Unfortunately, meters driven by a single drive shaft or at a single rate may reduce farming efficiency and accuracy. BRIEF DESCRIPTION Certain embodiments commensurate in scope with the present disclosure are summarized below. These embodiments are not intended to limit the scope of the disclosure, but rather these embodiments are intended only to provide a brief summary of possible forms of the disclosure. Indeed, the disclosure may encompass a variety of forms that may be similar to or different from the embodiments set forth below. In a first embodiment, an agricultural system includes first and second product meters configured to meter product from a product tank to first and second lines, respectively. First and second motors are coupled to the first and second product meters and configured to drive them at first and second metering rates, respectively. An air source is configured to provide first and second airflows to the first and second lines, respectively. A controller electrically coupled to the first and second motors is configured to receive first and second inputs indicative of first and second numbers of first and second outlets fluidly coupled to the first and second lines, respectively. The controller is configured to instruct the first and second motors to drive the first and second product meters at the first and second metering rates, respectively, based on the first and second inputs, and to instruct the air source to provide the first and second airflows with first and second dynamic pressures or first and second velocities. In a second embodiment, a control system configured to control an agricultural product distribution system includes a controller configured to receive a first input indicative of a first number of first openers fluidly coupled to a first primary distribution line and a first meter configured to meter product from a product tank, and to receive a second input indicative of a second number of second openers fluidly coupled to a second primary distribution line and a second meter configured to meter product from the product tank. The controller is configured to determine a first target metering rate of the first meter based on the first number and a second target metering rate of the second meter based on the second number. The controller is also configured to instruct a first motor to drive the first meter at the first target metering rate, to instruct a second motor to drive the second meter at the second target metering rate, and to instruct an air source to provide a first airflow to the first primary distribution line and a second airflow to the second primary distribution line based on the first and second target metering rates. In a third embodiment, a method of operating a product distribution system of an agricultural implement includes receiving, at a processor, a first signal indicative of a first number of first outlets fluidly coupled to a first meter configured to meter product from a product tank. The method also includes receiving, at the processor, a second signal indicative of a second number of second outlets fluidly coupled to a second meter configured to meter product from the product tank. Further, the method includes determining, via the processor, a first target metering rate for the first meter and a second target metering rate for the second meter based on the first and second numbers. Further still, the method includes outputting, via the processor, a third signal to the first meter and a fourth signal to the second meter, where the third and fourth signals are indicative of instructions to enable the first meter to provide the first target metering rate and the second meter to provide the second target metering rate, respectively. The method also includes outputting, via the processor, at least a fifth signal to an air source of the product distribution system, where the fifth signal is indicative of instructions to enable delivery, via the air source, of a first airflow having a first velocity to a first primary distribution line fluidly coupled to the first meter and a second airflow having a second velocity to a second primary distribution line fluidly coupled to the second meter, where the first and second velocities are based on the first and second target metering rates. DRAWINGS These and other features, aspects, and advantages of the present invention will become better understood when the following detailed description is read with reference to the accompanying drawings in which like characters represent like parts throughout the drawings, wherein: FIG. 1 is a side view of an embodiment of an agricultural implement having a product distribution system with independently controllable meter rollers and airflows; FIG. 2 is a schematic view of a portion of an embodiment of the agricultural implement of FIG. 1 having the product distribution system; FIG. 3 is a perspective view of an embodiment of a product metering system having independently controllable meter rollers for use in the product distribution system of FIG. 1; FIG. 4 is an exploded perspective view of an embodiment of a meter roller and a corresponding motor for use in the product metering system of FIG. 3; FIG. 5 is a perspective view of an embodiment of two of the product metering systems of FIG. 3 in series; FIG. 6 is a schematic view of a portion of an embodiment of the agricultural implement of FIG. 1 having the product distribution system with independently controllable meter rollers and airflows; and FIG. 7 is a process flow diagram of an embodiment of a method of operating a control system for controlling the product distribution system of FIG. 1. DETAILED DESCRIPTION One or more specific embodiments of the present disclosure will be described below. In an effort to provide a concise description of these embodiments, all features of an actual implementation may not be described in the specification. It should be appreciated that in the development of any such actual implementation, as in any engineering or design project, numerous implementation-specific decisions must be made to achieve the developers' specific goals, such as compliance with system-related and business-related constraints, which may vary from one implementation to another. Moreover, it should be appreciated that such a development effort might be complex and time consuming, but would nevertheless be a routine undertaking of design, fabrication, and manufacture for those of ordinary skill having the benefit of this disclosure. When introducing elements of various embodiments of the present disclosure, the articles “a,” “an,” “the,” and “said” are intended to mean that there are one or more of the elements. The terms “comprising,” “including,” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements. Any examples of operating parameters and/or environmental conditions are not exclusive of other parameters/conditions of the disclosed embodiments. Embodiments of the present disclosure relate generally to product distribution systems for agricultural implements and, more specifically, to independently controllable meter rollers and air conveyance components of the product distribution system. For example, the product distribution system includes a metering system with independently controllable meter rollers, each meter roller being configured to distribute product to a corresponding primary distribution line coupled to the meter roller. Each meter roller is also coupled to a respective motor configured to drive (e.g., turn) the meter roller, and each motor is electrically, hydraulically, or otherwise coupled to a controller of the product distribution system. Accordingly, the controller may independently control a turning rate of each motor, thereby independently controlling (e.g., driving) the turning rate of each meter roller. The product distribution system also includes an air conveyance system for providing airflows to convey the metered product through the primary distribution lines, secondary distribution lines coupled to the primary distribution lines, and outlets coupled to the secondary distribution lines. The airflow to each primary distribution line may be independently controllable, such that each primary distribution line receives an airflow with an air pressure and/or a velocity suitable for the particular primary distribution line and/or the amount of product metered to the particular primary line. Accordingly, the airflows in each primary distribution line can be adjusted to accommodate the amount of product metered to each primary distribution line (e.g., to effectively and efficiently deliver the product through each primary distribution line). A controller may be communicatively coupled to the air conveyance system and to each of the motors of the product distribution system. Thus, the controller may independently control each motor and/or the air conveyance system to provide customized turn rates to each motor (and, thus, metering rates to each meter) and airflows to each primary distribution line, respectively. Each airflow and turn rate, for example, may be adjusted based on an input to the controller indicative of a number of outlets coupled to each primary distribution line. It should be noted, however, that independent control of the meters may be done separately, and independent of, independent control of the one or more airflows. Further, independent control of each airflow may be done separately, and independent of, independent control of the meters. To help illustrate, a side view of a portion of an agricultural implement having a product distribution system is shown in FIG. 1. In the illustrated embodiment, an implement 10 is coupled to an air cart 12 such that the air cart 12 is towed behind (or in front of) the implement 10 during operation and transport. The implement 10 includes a tool frame 14 with a ground engaging tool 16 (e.g., opener, row unit, outlet). The ground engaging tool 16 is configured to excavate a trench into the soil 18 for seed and/or fertilizer deposition. In the illustrated embodiment, the ground engaging tool 16 receives product (e.g., seed and/or fertilizer) from a product distribution header 20 via a hose 22 (e.g., secondary line) extending between the header 20 and the ground engaging tool 16. Although only one ground engaging tool 16, product distribution header 20, and hose 22 are shown in the illustrated embodiment to facilitate discussion, it should be appreciated that the implement 10 includes additional tools 16, headers 20 and/or hoses 22 (e.g., secondary lines) to facilitate product delivery to the soil 18 in a number of rows across the field. Further, as illustrated, the implement 10 includes one or more wheel assemblies 24 which contact the soil surface 18 and enable the implement 10 to be pulled by a tow vehicle. As discussed above, the air cart 12 is coupled to the implement 10, and towed behind (or in front of) the implement 10. As will be appreciated, in certain embodiments, the air cart 12 may be towed directly behind a tow vehicle, with the implement 10 towed behind the air cart 12. Likewise, the implement 10 and the air cart 12 may be part of a single unit, or the implement 10 and the air cart 12 may be separate units that are coupled together. The air cart 12 includes a storage tank 26 (e.g., product tank), a frame 28, wheels 30, a metering system 32, and an air source 34. The frame 28 includes a towing hitch configured to couple to the implement 10 or tow vehicle. In certain configurations, the storage tank 26 includes multiple compartments for storing various flowable particulate materials. For example, one compartment may include seeds, and another compartment may include a dry fertilizer. Alternatively, the air cart 12 may include multiple tanks, each tank configured to store a different agricultural product. In either configuration, the air cart 12 may be configured to deliver both the seeds and the fertilizer to the implement 10. In general, seeds and/or fertilizer within the storage tank 26 are gravity fed into the metering system 32. In the present embodiment, the metering system 32 includes sectioned, independently controllable meter rollers to regulate the flow of material from the storage tank 26 into an airflow provided by the air source 34. The airflow (e.g., from the air source 34) then carries the material through hoses 36 (e.g., primary lines or primary distribution lines) to the implement 10, thereby supplying the ground engagement tools 16 with seeds and/or fertilizer for deposition within the soil. Although only one primary distribution line 36 is shown in the illustrated embodiment to facilitate discussion, embodiments of the present disclosure generally include multiple primary distribution lines 36, where each primary distribution line 36 is coupled to a respective header 20. For example, each meter roller of the metering system 32 may be coupled to its own primary distribution line 36, and each primary distribution line 36 may be coupled to its own header 20. Further, each header 20 may be coupled to its own set of secondary lines or hoses 22, which each includes its own ground engaging tool 16 (e.g., opener or outlet). Further still, the air source 34 is controllable such that the air source 34 may provide airflows with different pressures and/or velocities to each primary distribution line 36. For example, the air source 34 may provide an airflow with a first pressure and velocity to a first primary distribution line 36 and an airflow with a second pressure and velocity to a second primary distribution line 36, where the first pressure and velocity is different than the second pressure and velocity. It should be noted that the storage tank 26, the metering system 32, the primary distribution lines 36, the headers 20, the secondary lines 22, and the ground engaging tools 16 may all be components of what will be referred to herein as a product distribution system 50 of the combined air cart 12 and implement 10. In accordance with present embodiments, a control system or assembly may be communicatively coupled to the illustrated metering system 32 and to the air source 34 (or components thereof) to regulate metering of product from the storage tank 26 to the implement 10 and airflow from the air source 34 to the primary distribution lines 36 (and, thus, the secondary distribution lines 22). The control assembly may independently control each meter roller of the metering system 32. For example, the control assembly may independently control motors coupled to each meter roller, thereby independently controlling a turn rate of the motors and, thus, the meter rollers. In other words, each meter roller may include an independently controllable turn rate. In accordance with present embodiments, the control assembly may determine a turn rate for each motor and, thus, for each meter roller coupled to each respective motor, based at least in part on a number of outlets coupled to each meter roller. For example, the control assembly may instruct a lower metering rate (e.g., turn rate) to a first meter configured to feed seven outlets and a relatively higher second metering rate (e.g., turn rate) to a second meter of the same metering system 32 configured to feed eight outlets. Additionally, the control assembly may instruct the air source 34 to provide a first airflow with a higher velocity via fan rotational speed (and, thus, a higher dynamic pressure) to the primary distribution line 36 that includes more secondary lines 22 (and, thus, more ground engaging tools 16 (e.g., openers, outlets, row units)) and a second air flow with a relatively lower dynamic pressure to the primary distribution line 36 that includes fewer secondary lines 22 (and, thus, fewer ground engaging tools 16 (e.g., openers, outlets, row units)). The control assembly and related features will be described in detail below with reference to later figures. To facilitate a better understanding of the agricultural implement 10 and air cart 12 described above with reference to FIG. 1, a schematic diagram of an embodiment of the air cart 12 coupled to the implement 10 is shown in FIG. 2. In the illustrated embodiment, the product distribution system 50 includes at least the product metering system 32, the primary distribution lines 36, the distribution headers 20, the secondary distribution lines 22, the ground engaging tools 16 (e.g., row units, openers, outlets), and the air source 34. Product is delivered from the air cart 12 to the ground engaging tools 16 using the product distribution system 50. For example, product may initially be located in the air cart 12 (e.g., within a storage tank). The product distribution system 50 transfers the product using the product metering system 32 to primary distribution lines 36. The primary distribution lines 36 transfer the product to distribution headers 20 positioned on the implement 10. Further, the distribution headers 20 divide the product through secondary distribution hoses or lines 22 to deliver the product to the ground engaging tools 16 (e.g., outlets, openers, row units) of the implement 10. In the illustrated embodiment, the air source 34 provides airflow to the primary distribution lines 36, the headers 20, and the secondary distribution lines 22. Accordingly, the air source 34 provides a biasing force, via the airflows, to urge the product through the product distribution system 50 to the field. The product is entrained in the airflows and carried through the product distribution system 50 to the field. The air source may blow the air through the product distribution system 50 starting at or around a position of the coupling between the primary distribution lines 36 and the metering system 32. For example, in the illustrated embodiment, product is gravity fed into the metering system 32 from above the metering system 32. The air source 34 provides airflows to the primary distribution lines 36 from just behind the metering system 32. Accordingly, the metering system 32 meters product to the primary distribution lines 36, and the airflow carries the metered product toward the ground engaging tools 16 (e.g., row units). It should also be noted that the number of primary distribution lines 36, the number of distribution headers 20, the number of secondary lines 22, and the number of ground engaging tools 16 (e.g., row units) may vary depending on the embodiment. For example, the product distribution system 50 may include 2, 3, 4, 5, 6, 7, 8, 9, 10 or more primary distribution lines 36 and corresponding headers 20. Further, each header 20 may include 2, 3, 4, 5, 6, 7, 8, 9, 10, or more secondary distribution lines 22 and corresponding ground engaging tools 16 (e.g., outlets, openers, row units). It should also be noted that, in accordance with present embodiments, the illustrated product metering system 32 includes a separate, independently controllable meter (e.g., meter roller) for each primary distribution line 36, where each separate meter roller meters (e.g., dispenses) agricultural product from a product storage tank of the air cart 12 to its respective primary distribution line 36. Further, the air source 34 is controllable to provide different airflows with different airflow conditions (e.g., pressure and velocity) to each primary distribution line 36. Accordingly, the metering rates for each meter roller are independently controllable, and the airflow is independently controllable to accommodate the independent metering rates. Thus, as shown in the illustrated embodiment, if a first primary distribution line 36 provides product to a first number of ground engaging tools 16 (e.g., two ground engaging tools 16 (e.g., row units)), and a second primary distribution line 36 provides product to a second number of ground engaging tools 16 (e.g., three ground engaging tools 16 (e.g., row units)) different than the first number, the first primary distribution line 36 feeding product to fewer ground engaging tools 36 may receive less product (e.g., via a slower turn rate of the associated meter roller) than the primary distribution line 36 feeding more ground engaging tools 16. Additionally, the airflow to each primary distribution line 36 may be independently controllable to accommodate the amount of product being routed through each primary distribution line 36. For example, in the illustrated embodiment, the air source 34 (e.g., fan or blower) may be coupled to both primary distribution lines 36. Each distribution line 36 may include its own flow regulation device 40 (e.g., dampers) configured to regulate the flow through the primary distribution line 36. The flow regulation device 40 may be a valve configured to permit or restrict the airflow. Alternatively, the flow regulation device 40 may be a venting valve (e.g., pressure relief valve) configured to vent a portion of the airflow from the primary distribution line 36. Accordingly, the airflow in each primary distribution line 36 may be controlled by a control system communicatively coupled to the flow regulation devices 40. Alternatively or additionally, the air source 34 may include multiple air sources (e.g., multiple fans or blowers), each fan coupled to and providing an airflow to its own respective primary distribution line 36. The control assembly may be coupled to each separate fan or blower to independently control each fan or blower. The control assembly and related components, including the metering system 32 and the air source 34 (e.g., air conveyance system), will be described in detail below with reference to later figures. For example, a perspective view of an embodiment of the metering system 32, in accordance with the present disclosure, is shown in FIG. 3. In the illustrated embodiment, the product metering system 32 includes eight individual meter rollers 60 (e.g., meter modules). Each meter roller 60 is coupled to a respective motor 62, which is configured to drive the meter roller 60 into rotation. In the illustrated embodiment, the motors 62 are disposed behind the meter rollers 60 and, thus, are not all viewable. However, for clarity, an embodiment of one motor 62 and one corresponding meter roller 60 is shown in an exploded perspective view in FIG. 4. As shown, the motor 62 may be directly coupled to the meter roller 60, or the motor 62 may be coupled to a drive shaft that is also coupled to the respective meter roller 60. Continuing with the embodiment in FIG. 3, the motors 62 are configured to drive the meter rollers 60 into rotation about a rotational axis 66 or direction. For example, the meter rollers 60 are disposed adjacent to one another in a line extending in a direction 68. The meter rollers 60 are positioned such that they rotate about a rotational axis 66 (e.g., direction), which is perpendicular to the direction 68. As the meter rollers 60 rotate, product from the storage tank 26 above the metering system 32 is gravity fed into a hopper 70 above the meter rollers 60 and down into each meter roller 60. The meter rollers 60 may be fluted such that adjacent ridges 72 (see FIG. 4) of the fluted roller 60 define a compartment 74 (see FIG. 4) into which the product is fed. Additionally or alternatively, the meter rollers 60 may be straight flutes, spiral flutes, knobbed rollers, or may otherwise having protrusions for metering product. As the meter rollers 60 turn, the product is supported within the compartment 74 until the compartment 74 gravity feeds the product downward (e.g., in direction 70) toward the primary distribution lines 36. As previously described, an air source may provide independently controllable airflows to each of the primary distribution lines 36, where the airflow pressure and/or velocity is controlled based on the amount of product being metered by each meter roller 60. It should be noted that, in the illustrated embodiment, a top row of connectors 76 for a top row of primary distribution lines 36 and a bottom row of connectors 78 for a bottom row of primary distribution lines 35 are provided. For example, each meter roller 60 includes a top row of connectors 76 and a bottom row of connectors 78 directly below the meter roller 60. However, each meter roller 60 only accesses one of the two connectors 76, 78 and corresponding primary distribution lines 36 disposed below the meter roller 60. The metering system 32 includes the top and bottom rows of connectors 76, 78 and corresponding primary distribution lines 36 to enable isolated distribution of seed and fertilizer. For example, the seed may be distributed via the illustrated metering system 32 through the meter rollers 60 to the top row of connectors 76. Another metering system 32 may be configured to distribute fertilizer through its meter rollers 60 to the bottom row of connectors 78, which extend between the two metering systems 32. For example, a perspective view of an embodiment having two metering systems 32 to meter seed to the top row of connectors 76 and corresponding primary distribution lines 36 and fertilizer to the bottom row of connectors 78 and corresponding primary distribution lines 36 is shown in FIG. 5. In the illustrated embodiment, the metering systems 32 distribute product in direction 66. Accordingly, the metering system 32 disposed downstream, relative to direction 66, from the other metering system 32 may be referred to herein as the “downstream metering system 32.” Likewise, the metering system 32 disposed upstream, relative to direction 66, of the downstream metering system may be referred to herein as the “upstream metering system 32.” The upstream metering system 32 includes meter rollers 60 in fluid communication with the bottom row of connectors 78 and isolated from the top row of connectors 76. The meter rollers 60 are, as previously described, in fluid communication with the hopper 70 directly above the meter rollers 60 and directly below the storage tank 26, where the storage tank stores fertilizer. As the meter rollers 60 are driven into rotation via the motors 62 (see FIG. 4), fertilizer is metered to the bottom row of connectors 78 (and, thus, to the primary distribution lines 36 coupled to the top row of connectors 78). The downstream metering system 32 includes meter rollers 60 in fluid communication with the top row of connectors 76 and corresponding primary distribution lines 36 and isolated from the bottom row of connectors 78 and corresponding primary distribution lines 36. The meter rollers 60 are in fluid communication with the hopper 70 directly above the meter rollers 60 and directly below the storage tank 26, where the storage tank stores seed. As the meter rollers 60 are driven into rotation via the motors 62 (see FIG. 4), seed is metered to the primary top row of connectors 76 (and, thus, the primary distribution lines 36 coupled to the top row of connectors 76). The top rows of connectors 76 of the upstream and downstream metering systems 32 are coupled together, and the bottom rows of connectors 78 of primary distribution lines 36 of the upstream and downstream metering systems 32 are coupled together. Accordingly, both the seed and fertilizer are distributed to the row units. Depending on the embodiment, the top and bottom rows of connectors 76, 78 and respective primary distribution lines 36 may have separate headers, or they may have a common header and common secondary lines. It should be noted that the top and bottom rows of connectors 76, 78 and the upstream and downstream metering systems 32 could be used for either seed or fertilizer, or any other agricultural product metered to an agricultural implement. The illustrated configuration and the description above should not limit the scope of the present disclosure, as one of ordinary skill in the art would recognize that the systems could be used interchangeably with a number of different agricultural products. Further, it should be noted that the individual meter rollers 60 and their respective motors 62 shown in FIGS. 3-5 are independently controllable, as previously described. For example, a control assembly or control system, in accordance with present embodiments, may independently control a metering rate of each meter roller 60 by independently controlling a turn rate of each respective motor 62. Further still, as previously described, an air source (e.g., air source 34 in FIGS. 1-3) may provide independently controllable airflows to each of the primary distribution lines 36, where the airflow pressure/velocity is controllable based at least in part on the amount (e.g., product mass flow rate) of product being metered by each meter roller 60. The control assembly or system will be described in detail below with reference to later figures. A schematic diagram of an embodiment of a control system configured to control various aspects of the disclosed metering system 32, in accordance with the present disclosure, is shown in FIG. 6. In the illustrated embodiment, a controller 80 of the control system is communicatively coupled to the metering system 32, to the air source 34, and to the flow regulating devices 40 (e.g., which may be considered components of the air source 34). The controller 80 includes a processor, such as a microprocessor 76, and a memory device 78. The controller 80 may also include one or more storage devices and/or other suitable components. The processor 76 may be used to execute software, such as software for controlling the metering system 32, an airflow system (e.g., the air source 34) coupled to the metering system 32, and so forth. Moreover, the processor 76 may include multiple microprocessors, one or more “general-purpose” microprocessors, one or more special-purpose microprocessors, and/or one or more application specific integrated circuits (ASICS), or some combination thereof. For example, the processor 76 may include one or more reduced instruction set (RISC) processors and/or one or more complex instruction set (CISC). It should be noted that the controller 80 may instruct the metering system 32 to perform various functions. Accordingly, any reference herein to the controller's 80 instruction of various components or sub-components of, or in connection with, the metering system 32 may refer to control of the metering system 32 itself. The memory device 78 may include a volatile memory, such as random access memory (RAM), and/or a nonvolatile memory, such as ROM. The memory device 78 may store a variety of information and may be used for various purposes. For example, the memory device 78 may store processor-executable instructions (e.g., firmware or software) for the processor 76 to execute, such as instructions for controlling, e.g., the metering system 32. The storage device(s) (e.g., nonvolatile storage) may include read-only memory (ROM), flash memory, a hard drive, or any other suitable optical, magnetic, or solid-state storage medium, or a combination thereof. The storage device(s) may store data or inputs (as described below), instructions (e.g., software or firmware for controlling the metering system 32, the air conveyance system (e.g., the air source 34), or the like), and any other suitable data. As described above, the controller 80 may be communicatively coupled to the metering system 32, to the air source 34, and to the flow regulating devices 40. For example, the controller 80 may be electrically coupled to the metering system 32 and the air source 34, or the controller 80 may be coupled to the metering system 32 and the air source 34 via a wireless system 81 (e.g., Internet system, Wi-Fi system, Bluetooth system). Additionally or alternative, the controller 80 may be coupled to the metering system 32 and the air source 34 via a fiber optics system. In particular, the controller 80 is communicatively coupled to each of the motors 62 of the metering system 32, such that the controller 80 may control independent drive rates (e.g., turn rates) of each of the motors 62 that are then imparted to the respective meter rollers 60. Because the controller 80 is coupled to all three of the motors 62 in the illustrated embodiment, and each motor 62 drives one meter roller 60 independent of the other meter rollers 60, the controller 80 can independently control a turn rate of each meter roller 60. In other words, if desired, the controller 80 can instruct a different metering rate for each meter roller 60 by instructing, e.g., a different turn rate for each motor 62. Further, because the controller 80 is coupled to each flow regulating device 40 (e.g., of the air conveyance system), the airflow in each primary distribution line 36 may be independently controlled. Additionally or alternatively, the controller 80 may be communicatively coupled to the air source 34 to directly control the air source 34. For example, the air source 34 may include three separate fans coupled to each respective primary distribution line 36, and the controller 80 may independently control each of the three fans to provide varying airflow conditions, as described below. Further still, in some embodiments, the air source 34 may include one fan coupled to all or to a subset of the primary distribution lines 36, where the one fan is configured to supply a single airflow to all the primary distribution lines 36 coupled to the one fan based on an average of the metering rates instructed to the meter rollers 60 by the controller 80. In the illustrated embodiment, as previously described, the control system (e.g., having the controller 80) is configured to control turn rates of the motors 62 (and, thus, turn rates of the meter rollers 60 coupled to the motors 62). It should be noted that the turn rate of the motor 62 may refer to a turn rate of an output shaft of the motor 62, as the motor 62 may include an integral or internal gearbox that imparts a different turn rate to the output shaft than that of the motor 62 itself. Further, it should be noted that multiple motors 62 and/or corresponding meter rollers 60 may be coupled to a common drive shaft. For example, separate gear assemblies for the motors 62 may enable the motors 62 and/or corresponding meter rollers 60 to include different turn rates, relative to each other, even when coupled to the common drive shaft. Alternatively, each motor 62 and/or corresponding meter roller 60 may include its own drive shaft, which may be drive via instruction by the controller 80. In general, the turn rate of the motor 62 referred to herein is considered substantially the same as the turn rate of the meter roller 60. However, in some embodiments, a gear system, chain belt, or belt drive system may also couple the motor 62 to the meter roller 60, thereby imparting a different turn rate to the meter roller 60 than that of the motor 62. Accordingly, the controller 80 is configured to effectively control independent metering rates of each meter rollers 60. In particular, the controller 80 is configured to control independent metering rates of each meter roller 60 based on a number of ground engaging tools 16 disposed downstream, and fluidly coupled to, each meter roller 60 (e.g., based on the number of outlets to which the meter roller 60 provides product). In the illustrated embodiment, two of the meter rollers 60 are each fluidly coupled to three ground engaging tools 16. A third meter roller 60 is coupled to only two ground engaging tools 16. Accordingly, it may be desirable to provide a higher metering rate for the two meter rollers 60 having three ground engaging tools 16 and a relatively lower metering rate for the meter roller 60 having two ground engaging tools 16. The controller 80 is configured to receive inputs (e.g., signals) indicative of the number of ground engaging tools 16 associated with each meter roller 60, and instruct an appropriate turning rate, based on the respective numbers of ground engaging tools 16, to each motor 62 coupled to the meter rollers 60. For example, the controller 80 may be configured to receive the inputs via manual entry of the inputs into the controller 80 (e.g., via an input 84) by an operator. In some embodiments, the controller 80 may receive the inputs automatically via one or more sensors 82 communicatively coupled to the controller 80 (e.g., via electrical wiring, via the wireless system 81, and/or via a fiber optics system) and may determine the number of ground engaging tools 16 (e.g., row units) fluidly coupled to each meter roller 60 (e.g., to each respective primary line 26 of each meter roller 60). The sensors 82 may detect the number of ground engaging tools 16 in any suitable manner. For example, the sensors 82 may sense a pressure in the header 20 fluidly coupled to the ground engaging tools 16, or the sensors 82 may receive data from (e.g., read or contact) one or more information elements (e.g., microchips) of the one or more secondary lines 22 coupled to the header 20, where the information elements (e.g., microchips) provide information relating to the number of ground engaging tools 16 coupled to the header 20. The inputs may directly indicate the number of ground engaging tools 16 fluidly coupled to each primary distribution line 36, or the inputs may directly indicate a number of secondary lines 22 coupled to each header 20. For example, the inputs may be communicated from the implement 10 to the air cart 12 via CAN (controller area network) bus. Additionally, as previously described, the controller 80 is communicatively coupled to the air source 34. Based on the inputs described above (e.g., the number of ground engaging tools 16 coupled to each meter roller 60), the controller 80 may control the air source 34 to provide appropriate airflows to each primary distribution line 36. Thus, the controller 80 instructs the air source 34 to provide an appropriate airflow to effectively and efficiently convey the product being metered by each meter roller 60, as described above. It should be noted that the controller 80 may instruct the air source 34 by controlling the flow regulating devices 40 coupled to each primary distribution line 36 (e.g., as previously described), or the air source 34 may include a separate fan or blower for each primary distribution line 36 and the controller 80 may control each separate fan. Accordingly, the controller 80 may instruct airflows with specific air pressures and/or flow velocities for each distribution line 36. This may facilitate substantially uniform and/or efficient distribution of product to each ground engaging tool 16, and/or may reduce product clogs in the product distribution system 50. It should be noted that, in some conditions, it may be desirable to block metering to one or more of the primary distribution lines 36. In such conditions, the controller 80 may instruct the flow regulation device 40 of the primary distribution line 36 to block or substantially reduce the airflow to the primary distribution line 36 (e.g., via closure of the valve), the fan coupled to the primary distribution line 36 to discontinue providing the airflow, and/or the motor 62 and associated meter roller 60 to stop rotating (e.g., to stop metering of the product). In general, independent control of each meter roller 60 (via each motor 62), and control of the air source 34, as described above, enables the controller 80 to instruct turning rates and airflows that facilitate substantially uniform distribution of product to each ground engaging tool 16 of the agricultural implement 10. The controller 80, in the illustrated embodiment, may simultaneously instruct both the air source 34 and the motors 62, in accordance with the description above, based on the input(s) to the controller 80 regarding the number of ground engaging tools 16 per each primary distribution line 36. Turning now to FIG. 7, a process flow diagram illustrating a method 100 of operating the control system (e.g., having the controller 80) is shown. In the illustrated embodiment, the method 100 includes determining a number of ground engaging tools 16 fluidly coupled to each meter roller 60 (block 102). For example, the controller 80 may receive inputs indicative of the number of engaging tools 16 coupled to each meter roller 60. If the product distribution system 50 includes eight meter rollers 62, for example, the controller 80 may receive eight separate inputs. The inputs may be entered into the controller 80 via an operator, or the inputs may be automatically received by the controller 80 from a sensor configured to detect the number of ground engaging tools 16 coupled to each meter roller 60, as previously described. The inputs may directly indicate the number of ground engaging tools 16 coupled to each meter roller 60, or the inputs may indicate a number of secondary lines 22 coupled to each primary distribution line 36 extending from each meter roller 60. Further, in accordance with present embodiments, the method 100 includes independently controlling, via the controller 80, a turn rate of each motor 62 coupled to each corresponding meter roller 60 (block 104) based on the number of corresponding ground engaging tools 16. In doing so, the controller 80 controls an amount (e.g., a mass flow rate) of product metered by each meter roller 60 to each corresponding primary distribution line 36, thereby providing substantially uniform distribution of product to each ground engaging tool 16 of the agricultural implement 10. Further still, the method 100 includes controlling the airflows to each primary distribution line 36 by controlling the air source 34 and/or flow regulating devices 40 of the product distribution system 50 via the controller 80 (block 106). As previously described, the airflows are controlled, via the controller 80, to enable an appropriate airflow to each primary distribution line 36 based on the amount of product metered to each primary distribution line 36 and, thus, based on the number of ground engaging tools 16 fluidly coupled to (e.g., being fed product by) each primary distribution line 36. Accordingly, it should be understood that, in the presently described embodiment, the inputs to the controller 80 (e.g., the number of ground engaging tools 16 associated with each meter roller 60 and, thus, each primary distribution line 36) enable the controller 80 to determine control aspects for both the metering system 32 and the air source 34 of the air conveyance system substantially simultaneously. By providing the above described control system, meter rollers of the metering system may be independently controlled to enable metering of appropriate amount of product (product mass flow rate) to each primary line based on the number of outlets (e.g., ground engaging tools, openers, row units) fluidly coupled to (e.g., being fed by) each primary line (e.g., via the secondary lines). Accordingly, if one meter is fluidly coupled to fewer outlets than another meter, the controller of the control system may instruct a lower metering rate/or and a different airflow to the meter coupled to fewer outlets than the meter coupled to a greater number of outlets. In doing so, a substantially uniform amount of product is metered to each outlet of the entire agricultural implement, thereby providing substantially uniform distribution of product across all rows of a field. While only certain features of the disclosure have been illustrated and described herein, many modifications and changes will occur to those skilled in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the disclosure.
<SOH> BACKGROUND <EOH>The present disclosure relates generally to product distribution systems for agricultural implements and, more particularly, to independent control of meter rollers and air conveyance components of the product distribution system. Generally, agricultural implements (e.g., seeders) are configured to distribute product (e.g., seeds and fertilizer) across a field. The agricultural implement may improve crop yield and/or farming efficiency by providing an even distribution of the product across the field and/or increasing speed at which the product is distributed across the field. However, traditional product distribution systems for agricultural implements often distribute agricultural product, at any given time, to multiple rows (e.g., via multiple row units) using meters that are coupled to a single drive shaft that drives the meters at a single rate. Unfortunately, meters driven by a single drive shaft or at a single rate may reduce farming efficiency and accuracy.
<SOH> BRIEF DESCRIPTION <EOH>Certain embodiments commensurate in scope with the present disclosure are summarized below. These embodiments are not intended to limit the scope of the disclosure, but rather these embodiments are intended only to provide a brief summary of possible forms of the disclosure. Indeed, the disclosure may encompass a variety of forms that may be similar to or different from the embodiments set forth below. In a first embodiment, an agricultural system includes first and second product meters configured to meter product from a product tank to first and second lines, respectively. First and second motors are coupled to the first and second product meters and configured to drive them at first and second metering rates, respectively. An air source is configured to provide first and second airflows to the first and second lines, respectively. A controller electrically coupled to the first and second motors is configured to receive first and second inputs indicative of first and second numbers of first and second outlets fluidly coupled to the first and second lines, respectively. The controller is configured to instruct the first and second motors to drive the first and second product meters at the first and second metering rates, respectively, based on the first and second inputs, and to instruct the air source to provide the first and second airflows with first and second dynamic pressures or first and second velocities. In a second embodiment, a control system configured to control an agricultural product distribution system includes a controller configured to receive a first input indicative of a first number of first openers fluidly coupled to a first primary distribution line and a first meter configured to meter product from a product tank, and to receive a second input indicative of a second number of second openers fluidly coupled to a second primary distribution line and a second meter configured to meter product from the product tank. The controller is configured to determine a first target metering rate of the first meter based on the first number and a second target metering rate of the second meter based on the second number. The controller is also configured to instruct a first motor to drive the first meter at the first target metering rate, to instruct a second motor to drive the second meter at the second target metering rate, and to instruct an air source to provide a first airflow to the first primary distribution line and a second airflow to the second primary distribution line based on the first and second target metering rates. In a third embodiment, a method of operating a product distribution system of an agricultural implement includes receiving, at a processor, a first signal indicative of a first number of first outlets fluidly coupled to a first meter configured to meter product from a product tank. The method also includes receiving, at the processor, a second signal indicative of a second number of second outlets fluidly coupled to a second meter configured to meter product from the product tank. Further, the method includes determining, via the processor, a first target metering rate for the first meter and a second target metering rate for the second meter based on the first and second numbers. Further still, the method includes outputting, via the processor, a third signal to the first meter and a fourth signal to the second meter, where the third and fourth signals are indicative of instructions to enable the first meter to provide the first target metering rate and the second meter to provide the second target metering rate, respectively. The method also includes outputting, via the processor, at least a fifth signal to an air source of the product distribution system, where the fifth signal is indicative of instructions to enable delivery, via the air source, of a first airflow having a first velocity to a first primary distribution line fluidly coupled to the first meter and a second airflow having a second velocity to a second primary distribution line fluidly coupled to the second meter, where the first and second velocities are based on the first and second target metering rates.
A01C7081
20170905
20171221
66662.0
A01C708
0
DILLON JR, JOSEPH A
INDEPENDENTLY CONTROLLED METER ROLLERS AND AIR CONVEYANCE COMPONENTS SYSTEM AND METHOD
UNDISCOUNTED
1
CONT-ACCEPTED
A01C
2,017
15,696,468
PENDING
CONNECTOR
A connector includes a housing and a lock arm that extends from the housing and is engageable with a counterpart connector. The lock arm includes a first arm a has a shape of a cantilever beam and has a locking hole for being engaged with the counterpart connector at a free end side of the first arm, and a second arm that extends from an end portion on the free end side of the first arm and is capable of releasing the engagement by bending the first arm around a fixing end of the first arm. The locking hole has a hole of which the size in a width direction orthogonal to an extending direction of the first arm becomes larger as a measurement position of the size of the hole gets closer to the free end from the fixing end.
1. A connector comprising: a housing; and a lock arm that extends from the housing and is engageable with a counterpart connector, wherein the lock arm includes: a first arm that has a shape of a cantilever beam and has a locking hole for being engaged with the counterpart connector at a free end side of the first arm; and a second arm that extends from an end portion on the free end side of the first arm and is capable of releasing the engagement by bending the first arm around a fixing end of the first arm, and the locking hole has a hole of which the size in a width direction orthogonal to an extending direction of the first arm becomes larger as a measurement position of the size of the hole gets closer to the free end from the fixing end. 2. The connector according to claim 1, wherein the lock arm is formed of a hydrolysis-resistant material.
CROSS REFERENCE TO RELATED APPLICATION This application is based on Japanese Patent Application No. 2016-177773 filed on Sep. 12, 2016, the contents of which are incorporated herein by reference. BACKGROUND OF THE INVENTION 1. Technical Field The present invention relates to a connector including a housing and a lock arm which extends from the housing and is engageable with a counterpart side connector. 2. Background Art From the related art, a connector including a lock arm which is engageable with a counterpart side connector is suggested (for example, JP-A-2015-195126 and JP-A-2001-250636). For example, a lock arm included in one of the connectors of the related art (hereinafter, referred to as “connector of the related art”) includes: an engaging arm which has a shape of a cantilever beam and has a locking hole for being engaged with a counterpart side connector in the vicinity of a free end; and a releasing arm which extends from an end portion on the free end side of the engaging arm. The connector of the related art is fixed to the counterpart side connector by locking the locking hole of the lock arm to a locking piece of the counterpart side connector. Furthermore, the connector of the related art releases engagement of the locking hole and the locking piece by separating the engaging hole and the locking piece of the counterpart side connector from each other by operating the releasing arm and bending the engaging arm around a fixing end (for example, refer to JP-A-2015-195126). In the connector of the related art, when an operator performs the above-described engagement releasing, the operator applies an external force to the releasing arm, and the engaging arm is bent (deformed) by the external force around the fixing end. In the connector having such a mechanism of engagement releasing, when a part having extremely small strength exists between an operation portion (a part to which the operator applies the force) of the releasing arm and the fixing end of the engaging arm, there is a possibility that the part is preferentially bent (deformed) and the engaging arm is not bent (deformed) as assumed. In this case, even when the external force to an extent that the engagement is released when the engaging arm is bent (deformed) as assumed is applied to the releasing arm, there is a possibility that the engagement is not released. That is, the operability when performing the engagement releasing may deteriorate. In particular, in the connector of the related art, since a sectional area of the lock arm in the periphery of the locking hole is small, it is considered that the strength of the lock arm deteriorates in the periphery of the locking hole. However, in a case where the locking piece of the counterpart side connector is sufficiently small and the locking hole of the lock arm is also sufficiently small, practically, it is possible to ignore the above-described deterioration of strength. Meanwhile, as the size of the locking piece of the counterpart side connector increases, the size of the locking hole of the lock arm also increases, and there is a concern about the above-described deterioration of strength (or deterioration of operability of the engagement releasing). The invention has been made in consideration of the above-described problem, and an object thereof is to provide a connector which can maintain operability of engagement releasing as much as possible even when the size of a locking piece of a counterpart side connector is large. SUMMARY OF THE INVENTION In order to achieve the above object, a connector according to the invention is characterized as following (1) and (2) below. (1) A connector includes a housing and a lock arm that extends from the housing and is engageable with a counterpart connector. The lock arm includes a first arm that has a shape of a cantilever beam and has a locking hole for being engaged with the counterpart connector at a free end side of the first arm, and a second arm that extends from an end portion on the free end side of the first arm and is capable of releasing the engagement by bending the first arm around a fixing end of the first arm. The locking hole has a hole of which the size in a width direction orthogonal to an extending direction of the first arm becomes larger as a measurement position of the size of the hole gets closer to the free end from the fixing end. (2) In the connector of (1), the lock arm is formed of a hydrolysis-resistant material. According to the connector having the above-described configuration (1), the locking hole has the hole shape (hole width enlarging portion) of which the size in the width direction orthogonal to the extending direction of the first arm (engaging arm) increases at least at a part as approaching the free end from the fixing end of the first arm (engaging arm). Therefore, for example, when a part example, an end portion on the free end side) of the locking hole is a part having a hole width which corresponds to the size of the locking piece of the counterpart side connector, and the other part the hole width enlarging portion (that is, when the hole width decreases as being separated from the end portion on the free end side), compared to a case where the entire locking hole is the former (which has a hole width that corresponds to the size of the locking piece of the counterpart side connector), and it is possible to prevent deterioration of strength in the periphery of the locking hole as much as the sectional area of the first arm can be maintained. Therefore, the connector having the above-described configuration can maintain operability of the engagement releasing as much as possible even when the size of the locking piece of the counterpart side connector is large. Furthermore, the connector having the above-described configuration also has other effects. Specifically, according to the connector having the above-described configuration, flexibility of the first arm (engaging arm) by the hole width enlarging portion gradually changes depending on the place (that is, a stress is diffused when bending the first arm). Therefore, when performing the engagement releasing, concentration of stress is mitigated in the periphery or the like of the fixing end of the first arm (engaging arm), and further, according to the connector having the above-described configuration, when a widening degree (inclination angle) of the hole width of the hole width enlarging portion is adjusted, it is possible to arbitrarily adjust the strength of the first arm (engaging arm). Therefore, when adjusting the widening degree (inclination angle) of the hole width in accordance with the size of the locking piece of the counterpart side connector, it is possible to maintain operability of the engagement releasing regardless of the size of the locking piece of the counterpart side connector. According to the connector having the above-described configuration (2), the lock arm which is elastically deformed when performing the engagement and the engagement releasing is formed of a hydrolysis-resistant material. Therefore, it is possible to prevent damage of the lock arm which is particularly likely to be damaged (for example, breakage caused by the external force when performing the engagement releasing) due to deterioration caused by the hydrolysis of the configuration material. As a result, the connector having the configuration can prevent the damage of the lock arm even in a case of being used for a long period of time under a high-temperature and high-humidity environment compared to a case where the lock arm is not formed of the hydrolysis-resistant material. In addition, the hydrolysis-resistant material which is used in the connector may be a material having excellent hydrolysis resistance, and a specific composition or the like is not particularly limited. For example, as the hydrolysis-resistant material, a composite material obtained by adding glass fibers to PBT can be used. However, PBT is a polyester resin, and depending on the use environment, the hydrolysis caused by the moisture in the environment and a hydroxyl group and an ester bond in a molecular framework of PBT, can be generated. Here, in the above-described composite material, it is preferable that PBT to which processing of improving the hydrolysis resistance is performed is used (for example, PBT-GF15). In addition, an example of processing of improving the hydrolysis resistance includes processing of substituting a hydroxyl radical (—OH) in a carboxyl end group (—COOH) which influences the hydrolysis of PBT for other atoms and molecules that show the hydrolysis resistance (for example, refer to JP-A-2006-104363 and JP-A-H8-208816). According to the invention, it is possible to provide a connector which can maintain operability of engagement releasing even when the size of the locking piece of the counterpart side connector is large. Above, the invention was briefly described. Furthermore, by thoroughly reading the aspects (hereinafter, referred to as “embodiments”) for realizing the invention which will be described hereinafter with reference to the attached drawings, specific contents of the invention will become more apparent. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a schematic perspective view illustrating a configuration of a connector according to an embodiment of the invention; FIG. 2A is an upper view of the connector illustrated in FIG. 1, and FIG. 2B is a front view of the connector illustrated in FIG. 1; FIG. 3 is a perspective view in which a lock arm included in a housing of the connector illustrated in FIG. 1 is enlarged; FIG. 4A is an upper view of the lock arm illustrated in FIG. 3, and FIG. 4B is a front view of the lock arm illustrated in FIG. 3; FIG. 5 is a sectional view taken along a line A-A of FIG. 4A; FIG. 6 is a schematic perspective view illustrating a configuration of a counterpart side connector fitted to the connector illustrated in FIG. 1; and FIG. 7 is a view which corresponds to FIG. 5 in a state where fitting of the connector illustrated in FIG. 1 and the counterpart side connector illustrated in FIG. 6 is completed. DETAILED DESCRIPTION OF EMBODIMENTS Embodiments Hereinafter, a connector according to an embodiment of the invention will be described with reference to the drawings. As illustrated in FIGS. 1 to 29, a connector 1 according to the embodiment of the invention includes a housing 10 and a lock arm 20 which extends from the housing 10. In a state where fitting of the connector 1 and a counterpart side connector 2 (refer to FIG. 6) is completed, the lock arm 20 achieves a function of maintaining a state where the lock arm 20 is engaged with the counterpart side connector 2 and the fitting of both connectors is completed. The connector 1 (the housing 10 and the lock arm 20) is integrally molded by using a resin material made of a hydrolysis-resistant material. Specifically, by using a composite material (for example, PBT-GF15 or the like obtained by adding 15% by weight of glass fibers to PBT) obtained by adding glass fibers to PBT (polybutylene terephthalate), the connector 1 is molded to be integrated by injection molding or the like. The composite material is subjected to processing of improving the hydrolysis resistance with respect to PBT which is a base polymer. In addition, an example of processing of improving the hydrolysis resistance includes processing of substituting a hydroxyl radical (—OH) in a carboxyl end group (—COOH) which influences the hydrolysis resistance of PBT for other atoms and molecules that show the hydrolysis resistance. In addition, the hydrolysis-resistant material used in the connector 1 is not limited to the composite material, and other materials having hydrolysis resistance may be used. Hereinafter, for convenience of the description, as illustrated in FIGS. 1, 3, and 6, “fitting direction”, “width direction”, “upward-and-downward direction”, “front”, “rear”, “up”, and “down” are defined. “Fitting direction”, “width direction”, and “upward-and-downward direction” are orthogonal to each other. As illustrated in FIGS. 1 to 23, the housing 10 includes a terminal accommodation portion 11 which accommodates a terminal (not illustrated), and a hood portion 12 which has a shape of a tube that surrounds the periphery of the terminal accommodation portion 11. The terminal accommodation portion 11 has a shape of a substantial column which extends along the fitting direction. The hood portion 12 defines an annular void 13 into which a tubular portion 31 (refer to FIG. 6) of a housing 30 of the counterpart side connector 2 is inserted, in the periphery of the terminal accommodation portion 11. The hood portion 12 covers an outer circumference of the tubular portion 31 inserted into the void 13. In the tubular portion 31 of the counterpart side connector 2, a guide rib 32 which extends in the fitting direction is provided in a center portion in the width direction of the lower surface, and one pair of guide ribs 33 which extend in the fitting direction are provided on both end sides in the width direction of an upper surface thereof (refer to FIG. 6). The hood portion 12 includes a guide groove 14 which is disposed corresponding to the guide rib 32 of the counterpart side connector 2 and extends in the fitting direction, and one pair of spaces 15 (refer to FIG. 2B) which are disposed corresponding to the pair of guide ribs 33 and extends in the fitting direction. When the tubular portion 31 is inserted into the void 13 (that is, when the connector 1 and the counterpart side connector 2 are fitted to each other), the guide rib 32 is inserted into the guide groove 14, and the guide rib 33 is inserted into the space 15. As illustrated in FIGS. 3 to 5, the lock arm 20 includes an engaging arm 22 having a shape of a substantially flat plate which extends in a shape of a cantilever beam toward a front side along the fitting direction from a fixing end 21 positioned in an upper portion on a rear end side of the terminal accommodation portion 11, and a releasing arm 24 which extends in a shape of a cantilever beam toward the rear side along the fitting direction from a free end 23 of the engaging arm 22. The releasing arm 24 includes one pair of linking arm portions 25 which extend to the rear side along the fitting direction from both end portions 23a in the width direction of the end portion including the free end 23, an operation portion 26 which links rear end portions of the pair of linking arm portions 25 to each other, and one pair of stoppers 27 which protrude to an outer surface of the pair of linking arm portion 25. Below the linking arm portion 25, a void for allowing displacement of the linking arm portion 25 is ensured. In the engaging arm 22, a locking hole 28 (through hole) is provided. As will be described later, a locking surface 29 of the locking hole 28 locks a locking surface 35 of a lock projection 34 provided between the pair of guide ribs 33 on the upper surface of the tubular portion 31 of the counterpart side connector 2 in a state where the filling is completed (refer to FIGS. 6 and 7). As illustrated in FIGS. 4A and 4B, the locking hole 28 is configured of a hole width enlarging portion 28a which configures a part on the rear side of the locking hole 28, and a constant hole width portion 28b which configures a part on the front side of the locking hole 28. The hole width enlarging portion 28a has a hole side surface (that is, a trapezoidal shape) inclined only by an angle θ with respect to the fining direction such that the hole width gradually increases toward the front end side from the rear end side. The constant hole width portion 28b has a substantially constant rectangular shape of which the hole width is a width D1. The width D1 is a value (specifically, a value which is slightly greater than D2) which corresponds to the width D2 (refer to FIG. 6) of the lock projection 34. An end face on the rear side of the hole width enlarging portion 28a is positioned slightly further on a rear end side than the center position in the fitting direction of the engaging arm 22. The end face (locking surface 29, refer to FIG. 5) on the front side of the constant hole width portion 28b is positioned in the vicinity of the free end 23 of the engaging arm 22. When the tubular portion 31 of the counterpart side connector 2 is inserted into the void 13 of the connector 1 (that is, when the connector 1 and the counterpart side connector 2 are fitted to each other), in the middle of the fitting, the engaging arm 22 is elastically deformed to be bent in the upward direction (an arrow Z1 direction illustrated in FIG. 5), and accordingly, the lock projection 34 of the counterpart side connector 2 goes into the lower side of the end portion including the free end 23 of the lock arm 20. In addition, when the fitting between the connector 1 and the counterpart side connector 2 is completed, the position of the free end 23 returns to an initial position before the elastic deformation by a restoring force of the engaging arm 22. Accordingly, as illustrated in FIG. 7, the locking hole 28 and the locking projection 34 are engaged with each other, and the locking surface 29 of the locking hole 28 locks the locking surface 35 of the lock projection 34. As a result, a state where the fitting between the connector 1 and the counterpart side connector 2 is completed is maintained. In a state where the fitting is completed, by connecting the terminal accommodated in the terminal accommodation portion 11 of the connector 1 and the terminal disposed on the inside of the tubular portion 31 of the counterpart side connector 2, the connector 1 and the counterpart side connector 2 are electrically connected to each other. Meanwhile, as illustrated in FIG. 5, in a state where the fitting is completed, when the operation portion 26 of the releasing arm 24 is pressed downward (arrow Z2 direction), the releasing arm 24 rotates around a lower end portion 24a (which abuts against the surface (not illustrated) of the housing 10) of the releasing arm 24, and the free end 23 of the engaging arm 22 linked to the front end of the linking arm portion 25 rises upward (arrow Z1 direction). Accordingly, the engagement between the locking hole 28 and the lock projection 34 is released, and a state where the connector 1 and the counterpart side connector 2 can be separated from each other is achieved. In addition, the pair of stoppers 27 provided in the pair of linking arm portions 25 can abut against one pair of interference portions 16 (refer to FIG. 2B) provided in the hood portion 12 of the connector 1. Accordingly, in a case where a force in the upward direction opposite to the arrow Z2 direction is applied to the operation portion 26, it is possible to prevent the linking arm portion 25 from being excessively displaced and damaged. In the connector 1 according to the embodiment of the above-described invention, at the part on the rear side of the locking hole 28 of the engaging arm 22, the hole width enlarging portion 28a having a substantially trapezoidal shape of which the hole width gradually increases toward the front end side from the rear end side is formed, and at the part on the front side of the locking hole 28, the constant hole width portion 28b having a substantially constant rectangular shape of which the hole width is the width D1 is formed. Therefore, for example, compared to a case where the locking hole 28 has a substantially constant rectangular shape having the width D1 across the entire fitting direction, it is possible to prevent deterioration of strength of the periphery of the locking hole 28 in the engaging arm 22. Furthermore, flexibility of the engaging arm 22 gradually changes depending on the place by the hole width enlarging portion 28a (that is, the stress is diffused when bending the engaging arm 22). Therefore, when performing the engagement releasing, concentration of stress is mitigated in the periphery or the like of the fixing end 21 of the engaging arm 22. Furthermore, when adjusting a widening degree (inclination angle θ, refer to FIGS. 4A and 4B) of the hole width of the hole width enlarging portion 28a, it is possible to arbitrarily adjust the strength of the engaging arm 22. Therefore, when adjusting the widening degree of the hole width in accordance with the size of the lock projection 34 of the counterpart side connector 2, it is possible to maintain operability at the time of the engagement releasing regardless of the size of the lock projection 34. According to the connector 1, the lock arm 20 which is elastically deformed when performing the engagement (when performing the fitting) and the engagement releasing is formed of a hydrolysis-resistant material. Therefore, it is possible to prevent damage of the lock arm 20 which is particularly likely to be damaged due to deterioration caused by the hydrolysis of the configuration material. As a result, in the connector 1, it is possible to prevent the damage of the lock arm 20 even in a case of being used for a long period of time under a high-temperature and high-humidity environment compared to a case where the lock arm 20 is not formed of the hydrolysis-resistant material. <Other Aspects> The invention is not limited to each of the embodiments, various modification examples can be employed within a range of the invention. For example, the invention is not limited to the above-described embodiments, and can be appropriately deformed or improved. In addition, in the above-described embodiment, the material, the shape, the dimension, the number, or the disposition location of each configuration elements are arbitrary as long as the invention can be achieved, and are not particularly limited. For example, in the above-described embodiment, the hole width enlarging portion 28a having a substantially trapezoidal shape is formed at the part on the rear side of the locking hole 28 of the engaging arm 22, and the constant hole width portion 28b having a substantially rectangular shape is formed at the part on the front side of the locking hole 28. However, the hole width enlarging portion 28a having a substantially trapezoidal shape of which the hole width gradually increases toward the front end side from the rear end side may be formed across the entire region in the fitting direction of the locking hole 28. Furthermore, in the above-described embodiment, the connector 1 (the housing 10 and the lock arm 20) is integrally molded by using a resin material formed of the hydrolysis-resistant material. However, for example, in an aspect in which the lock arm 20 molded to be separately and independently from the housing 10 is attached (bonded) to the housing 10, only the lock arm 20 which is elastically deformed when performing the engagement (when performing the fitting) and the engagement releasing may be molded by using the hydrolysis-resistant material, and the housing 10 may be molded by using polyester such as PBT. Here, characteristics of the connector of the above-described embodiment according to the present invention are respectively briefly summarized and listed in the following (1) and (2). (1) A connector (1) including: a housing (10); and a lock arm (20) which extends from the housing (10) and is engageable with a counterpart side connector (2), in which the lock arm (20) includes a first arm (22) which has a shape of a cantilever beam and has a locking hole (28) for being engaged with the counterpart side connector (2) in the vicinity of a free end (23), and a second arm (24) which extends from an end portion on the free end side of the first arm (22) and is capable of releasing the engagement by bending the first arm (22) around a fixing end (21) of the first arm (22), and the locking hole (28) has a hole shape (28a) of which the size in a width direction orthogonal to an extending direction of the first arm (22) increases at least at a part as approaching the free end (23) from the fixing end (21). (2) The connector according to the above-described (1) in which the lock arm (20) is formed of a hydrolysis-resistant material.
<SOH> BACKGROUND OF THE INVENTION <EOH>
<SOH> SUMMARY OF THE INVENTION <EOH>In order to achieve the above object, a connector according to the invention is characterized as following (1) and (2) below. (1) A connector includes a housing and a lock arm that extends from the housing and is engageable with a counterpart connector. The lock arm includes a first arm that has a shape of a cantilever beam and has a locking hole for being engaged with the counterpart connector at a free end side of the first arm, and a second arm that extends from an end portion on the free end side of the first arm and is capable of releasing the engagement by bending the first arm around a fixing end of the first arm. The locking hole has a hole of which the size in a width direction orthogonal to an extending direction of the first arm becomes larger as a measurement position of the size of the hole gets closer to the free end from the fixing end. (2) In the connector of (1), the lock arm is formed of a hydrolysis-resistant material. According to the connector having the above-described configuration (1), the locking hole has the hole shape (hole width enlarging portion) of which the size in the width direction orthogonal to the extending direction of the first arm (engaging arm) increases at least at a part as approaching the free end from the fixing end of the first arm (engaging arm). Therefore, for example, when a part example, an end portion on the free end side) of the locking hole is a part having a hole width which corresponds to the size of the locking piece of the counterpart side connector, and the other part the hole width enlarging portion (that is, when the hole width decreases as being separated from the end portion on the free end side), compared to a case where the entire locking hole is the former (which has a hole width that corresponds to the size of the locking piece of the counterpart side connector), and it is possible to prevent deterioration of strength in the periphery of the locking hole as much as the sectional area of the first arm can be maintained. Therefore, the connector having the above-described configuration can maintain operability of the engagement releasing as much as possible even when the size of the locking piece of the counterpart side connector is large. Furthermore, the connector having the above-described configuration also has other effects. Specifically, according to the connector having the above-described configuration, flexibility of the first arm (engaging arm) by the hole width enlarging portion gradually changes depending on the place (that is, a stress is diffused when bending the first arm). Therefore, when performing the engagement releasing, concentration of stress is mitigated in the periphery or the like of the fixing end of the first arm (engaging arm), and further, according to the connector having the above-described configuration, when a widening degree (inclination angle) of the hole width of the hole width enlarging portion is adjusted, it is possible to arbitrarily adjust the strength of the first arm (engaging arm). Therefore, when adjusting the widening degree (inclination angle) of the hole width in accordance with the size of the locking piece of the counterpart side connector, it is possible to maintain operability of the engagement releasing regardless of the size of the locking piece of the counterpart side connector. According to the connector having the above-described configuration (2), the lock arm which is elastically deformed when performing the engagement and the engagement releasing is formed of a hydrolysis-resistant material. Therefore, it is possible to prevent damage of the lock arm which is particularly likely to be damaged (for example, breakage caused by the external force when performing the engagement releasing) due to deterioration caused by the hydrolysis of the configuration material. As a result, the connector having the configuration can prevent the damage of the lock arm even in a case of being used for a long period of time under a high-temperature and high-humidity environment compared to a case where the lock arm is not formed of the hydrolysis-resistant material. In addition, the hydrolysis-resistant material which is used in the connector may be a material having excellent hydrolysis resistance, and a specific composition or the like is not particularly limited. For example, as the hydrolysis-resistant material, a composite material obtained by adding glass fibers to PBT can be used. However, PBT is a polyester resin, and depending on the use environment, the hydrolysis caused by the moisture in the environment and a hydroxyl group and an ester bond in a molecular framework of PBT, can be generated. Here, in the above-described composite material, it is preferable that PBT to which processing of improving the hydrolysis resistance is performed is used (for example, PBT-GF15). In addition, an example of processing of improving the hydrolysis resistance includes processing of substituting a hydroxyl radical (—OH) in a carboxyl end group (—COOH) which influences the hydrolysis of PBT for other atoms and molecules that show the hydrolysis resistance (for example, refer to JP-A-2006-104363 and JP-A-H8-208816). According to the invention, it is possible to provide a connector which can maintain operability of engagement releasing even when the size of the locking piece of the counterpart side connector is large. Above, the invention was briefly described. Furthermore, by thoroughly reading the aspects (hereinafter, referred to as “embodiments”) for realizing the invention which will be described hereinafter with reference to the attached drawings, specific contents of the invention will become more apparent.
H01R1362966
20170906
20180315
76069.0
H01R13629
0
HARCUM, MARCUS E
CONNECTOR WITH A LOCK ARM
UNDISCOUNTED
0
ACCEPTED
H01R
2,017
15,696,581
PENDING
METAL EXTRUSION PLATE AND DISPLAY STAND FORMED BY THE SAME
A metal extrusion plate for a display stand and the display stand are provided. The metal extrusion plate extends along a first direction and comprises N of flat plate sections and N−1 of connecting sections, wherein the flat plate sections are integrally formed with the connecting sections, and N is a positive integer greater than 1. The flat plate sections are interlaced with the connecting sections, and each of the connecting sections is connected to the two adjacent flat plate sections therebetween. Each of the connecting sections has a groove extending along a second direction being perpendicular to the first direction and forming a first incline and a second incline opposite to the first incline. The metal extrusion plate is capable of being bent at the connecting section so that the two adjacent flat plate sections form a first included angle. The metal extrusion plate is bent to form as a supporting frame to be disposed on a base. The flat plate sections and the connecting sections encompass and form a receiving space for an elevating module disposed therein so as to move up and down with respect to the supporting frame.
1. A metal extrusion plate for a display stand, the metal extrusion plate extending along a first direction and comprising N flat plate sections and N−1 connecting sections, wherein the flat plate sections are integrally formed with the connecting sections, N is a positive integer greater than 1, the flat plate sections are interlaced with the connecting sections, each of the connecting sections is connected to and configured between the two adjacent flat plate sections, and each of the connecting sections has a groove extending along a second direction being perpendicular to the first direction and forming a first incline and a second incline opposite to the first incline wherein the metal extrusion plate is capable of being bent at the connecting section so that the two adjacent flat plate sections form a first included angle. 2. The metal extrusion plate as claimed in claim 1, wherein the connecting section is defined with a first block, a second block, and a third block, which are integrally formed, wherein a side of the first block is connected to one of the two adjacent flat plate sections, a side of the second block is connected to the other one of the two adjacent flat plate sections, and two opposite sides of the third block are connected to the two adjacent flat plate sections respectively so that the first block, the second block, and the third block collaboratively define the groove, and the flat plate section has a first thickness greater than a second thickness of the third block. 3. The metal extrusion plate as claimed in claim 2, wherein the first incline is formed on the first block, and the second incline is formed on the second block, wherein before being bent at the connecting section, the first incline and the second incline form a second included angle in which value of the second included angle is complementary to value of the first included angle. 4. The metal extrusion plate as claimed in claim 3, wherein the flat plate section that locates at either end of the metal extrusion plate is formed with a first engagement structure. 5. The metal extrusion plate as claimed in claim 4, further comprising a first surface and a second surface opposite to the first surface, wherein the groove is formed on the first surface or the second surface. 6. The metal extrusion plate as claimed in claim 1, wherein the material of the metal extrusion plate is aluminum or aluminum alloy. 7. A display stand, comprising: a base; a supporting frame, being formed by bending the metal extrusion plate as claimed in any one of claim 1, and the supporting frame being disposed on the base so that the flat plate sections and the connecting sections encompassing and forming a receiving space, wherein the first incline and the second incline of the connecting section abut against each other so that the two adjacent flat plate sections form the first included angle; and an elevating module, being disposed in the receiving space so as to move up and down with respect to the supporting frame. 8. The display stand as claimed in claim 7, further comprising a supporting structure being disposed in the receiving space to be secured to the supporting frame, wherein the supporting structure at least abuts against two of the flat plate sections to support the supporting frame. 9. The display stand as claimed in claim 8, wherein the flat plate section located at either end of the metal extrusion plate is formed with a first engagement structure, and the base has a second engagement structure so that the first engagement structure and the second engagement structure are engaged to each other. 10. The display stand as claimed in claim 9, wherein the metal extrusion plate further comprises a first surface and a second surface opposite to the first surface, the groove is formed on the first surface or the second surface, the elevating module further has a slide element and a holder connected to the slide element, and the slide element slides along a slide with respect to the supporting frame. 11. The display stand as claimed in claim 7, wherein the material of the metal extrusion plate is aluminum or aluminum alloy. 12. The display stand as claimed in claim 7, wherein each of the connecting sections is defined with a first block, a second block, and a third block, which are integrally formed, wherein a side of the first block is connected to one of the two adjacent flat plate sections, a side of the second block is connected to the other one of the two adjacent flat plate sections, and two opposite sides of the third block are connected to the two adjacent flat plate sections respectively so that the first block, the second block, and the third block collaboratively define the groove, and the flat plate section has a first thickness greater than a second thickness of the third block. 13. The display stand as claimed in claim 12, further comprising a supporting structure being disposed in the receiving space to be secured to the supporting frame, wherein the supporting structure at least abuts against two of the flat plate sections to support the supporting frame. 14. The display stand as claimed in claim 13, wherein the flat plate section located at either end of the metal extrusion plate is formed with a first engagement structure, and the base has a second engagement structure so that the first engagement structure and the second engagement structure are engaged to each other. 15. The display stand as claimed in claim 14, wherein the metal extrusion plate further comprises a first surface and a second surface opposite to the first surface, the groove is formed on the first surface or the second surface, the elevating module further has a slide element and a holder connected to the slide element, and the slide element slides along a slide with respect to the supporting frame. 16. The display stand as claimed in claim 12, wherein the material of the metal extrusion plate is aluminum or aluminum alloy.
CROSS REFERENCE TO RELATED APPLICATION This application claims the benefit of U.S. Provisional Application Ser. No. 62/399,905 filed on Sep. 26, 2016, and the benefit of Taiwan Patent Application Serial No. 105216808 filed on Nov. 3, 2016. The entirety of each said application is incorporated herein by reference. BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a metal extrusion plate and a display stand including the metal extrusion plate being bent as a supporting frame. More specifically, the present invention relates to a stand for holding a display. 2. Description of Related Art A conventional stand for a display is shown in FIG. 1. A plurality of boards are individually formed by pressing and then be secured to each other to assemble the stand 1. As shown in FIG. 1, the stand 1 includes a main board 11, two side boards 12, and a top board 13. The main board 11 is formed with a plurality of screw holes 111. The side boards 12 and the top board 13 are formed with a plurality of holes 121 and 131. A plurality of screws 14 are capable of passing through the holes 121 and 131, and then be secured in the screw holes 111 so as to fasten the side boards 12 and the top board 13 to the main board 11. However, the conventional stand 1 has disadvantages of being structurally complex and bulky. Furthermore, the plates or boards should have certain thickness in the manner of fastening with the screws, which is unfavorable in the trend of having the slim stand. In another aspect, the conventional stand is not possible to be integrally formed because a single and large mold for manufacturing a conventional stand is too expensive and lacks production efficiency. Given the above, it is desirable to provide an improved display stand to have a slim structure with low manufacturing costs. SUMMARY OF THE INVENTION One objective of the present invention is to provide a display stand which has a slim structure and is capable of minimizing the unfavorable visual effect occupied by the stand from the view of the user. Another objective of the present invention is to provide a metal extrusion plate for the display stand. The metal extrusion plate is capable of being bent as a supporting frame of the display stand. Merely a small mold can be used to manufacture the metal extrusion plate as a semi-finished product. The semi-finished metal extrusion plate can be further processed with grooving and bending to form the support frame. Thus, using the small molds can reduce the manufacturing cost and simplify the manufacturing processes. To achieve the abovementioned objectives, the present invention discloses a metal extrusion plate for a display stand. The metal extrusion plate extending along a first direction and comprises N of flat plate sections and N−1 of connecting sections, wherein the flat plate sections are integrally formed with the connecting sections, N is a positive integer greater than 1. The flat plate sections are interlaced with the connecting sections, and each of the connecting sections is connected to the two adjacent flat plate sections therebetween. Each of the connecting sections has a groove extending along a second direction being perpendicular to the first direction and forming a first incline and a second incline opposite to the first incline. The metal extrusion plate is capable of being bent at the connecting section so that the two adjacent flat plate sections form a first included angle. The connecting section is defined with a first block, a second block and a third block which are integrally formed. A side of the first block is connected to one of the two adjacent flat plate sections, a side of the second block is connected to the other one of the two adjacent flat plate sections, and two opposite sides of the third block are connected to the two adjacent flat plate sections respectively. The first block, the second block, and the third block collaboratively define the groove. The flat plate section has a first thickness greater than a second thickness of the third block. The first incline is formed on the first block, and the second incline is formed on the second block. Before being bent at the connecting section, the first incline and the second incline form a second included angle in which value of the second included angle is complementary to value of the first included angle. Preferably, in the metal extrusion plate of the present invention, the flat plate section that locates at either end of the metal extrusion plate is formed with a first engagement structure. The metal extrusion plate further comprises a first surface and a second surface opposite to the first surface, wherein the groove is formed on the first surface or the second surface. The material of the metal extrusion plate is aluminum or aluminum alloy. In another embodiment, the present invention discloses a display stand comprising a base, a supporting frame being formed by bending the abovementioned metal extrusion plate for being disposed on the base, and an elevating module. The flat plate sections and the connecting sections of the supporting frame encompass and form a receiving space. The first incline and the second incline of the connecting section abut against to each other so that the two adjacent flat plate sections form the first included angle. The elevating module is disposed in the receiving space so as to move up and down with respect to the supporting frame. The display stand further comprises a supporting structure disposed in the receiving space to be secured to the supporting frame. The supporting structure at least abuts against two of the flat plate sections to support the supporting frame. Preferably, in the display stand of this embodiment, the flat plate section located at either end of the metal extrusion plate is formed with a first engagement structure, and the base has a second engagement structure. The first engagement structure and the second engagement structure are capable of being engaged to each other. The metal extrusion plate further comprises a first surface and a second surface opposite to the first surface, and the groove is formed on the first surface or the second surface. The elevating module further has a slide element and a holder connecting with the slide element. The slide element is capable of sliding along a slide with respect to the supporting frame. The material of the metal extrusion plate is aluminum or aluminum alloy. In more detail, in the display stand of this embodiment, each of the connecting sections is defined with a first block, a second block, and a third block, which are integrally formed, wherein a side of the first block is connected to one of the two adjacent flat plate sections, a side of the second block is connected to the other one of the two adjacent flat plate sections, and two opposite sides of the third block are connected to the two adjacent flat plate sections respectively so that the first block, the second block, and the third block collaboratively define the groove, and the flat plate section has a first thickness greater than a second thickness of the third block. The detailed technology and preferred embodiments implemented for the subject invention are described in the following paragraphs accompanying the appended drawings for people skilled in this field to well appreciate the features of the claimed invention. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic view illustrating a conventional stand; FIG. 2 is a schematic view illustrating the display stand of the present invention; FIG. 3 is an exploded view illustrating the display stand of the present invention; FIG. 4 and FIG. 5 are schematic views illustrating the metal extrusion plate of the present invention; FIG. 6 is a partially enlarged view illustrating the metal extrusion plate of the present invention along the A-A′ cross-sectional line in FIG. 5; FIG. 7 is a schematic view illustrating supporting frame formed by bending the metal extrusion plate; and FIG. 8 is a schematic view illustrating another embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT The present invention discloses a metal extrusion plate and a display stand. Please refer to FIG. 2 and FIG. 3, wherein FIG. 2 shows the schematic view illustrating the display stand 2000, and FIG. 3 shows the exploded view illustrating the display stand 2000. The display stand 2000 preferably includes a base 3, a supporting frame 5, an elevating module 7, and a supporting structure 8. One of the characteristics of the present invention is that the supporting frame 5 is formed by bending the metal extrusion plate, which will be illustrated hereinafter. In the first embodiment of the present invention, as shown in FIG. 4 and FIG. 5, the metal extrusion plate 50 is disclosed. The metal extrusion plate 50 is manufactured in a manner of metallic extrusion to form an elongated plate extending along a first direction D1. Then, the metal extrusion plate 50 is further processed to form a plurality of flat plate sections 51 and connecting sections 53 which are interlaced and are still integrated. Each of the connecting sections 53 connects the two adjacent flat plate sections 51. Subsequently, the metal extrusion plate 50 is adequately bent at the connecting sections 53 so that the two adjacent flat plate sections 51 form a first included angle θ1 (as shown in FIG. 7). In the present embodiment as shown in FIG. 5, there are three flat plate sections 51 and two connecting sections 53 for illustration. However, in other embodiments, the metal extrusion plate 50 includes N flat plate sections 51 and N−1 connecting sections 53, wherein N is a positive integer greater than 1. FIG. 6 further shows a partially enlarged view along the A-A′ cross-sectional line in FIG. 5. Before bending the connecting sections 53, each of the connecting sections 53 is formed with a groove 530 extending along a second direction D2 which is perpendicular to the first direction D1. Each of the grooves 530 forms a first incline 531 and a second incline 532 opposite to the first incline 531. The first incline 531 and the second incline 532 form a second included angle θ2 therebetween. For the illustration, the connecting section 53 could be further defined with a first block 533, a second block 534, and a third block 535 which are integrally formed. A side of the first block 533 is connected to one of the two adjacent flat plate sections 51. A side of the second block 534 is connected to the other one of the two adjacent flat plate sections 51. Two opposite sides of the third block 535 are connected to the two adjacent flat plate sections 51 respectively. Thus, the first block 533, the second block 534, and the third block 535 collaboratively define the groove 530. The first incline 531 is located on the first block 533, and the second incline 532 is located on the second block 534. Furthermore, the flat plate section 51 has a first thickness T1, and the third block 535 has a second thickness T2, wherein the first thickness T1 is greater than the second thickness T2. That is to say, the groove 530 does not cut off the connecting section 53. The flat plate sections 51 and the connecting section 53 are maintained as being as a whole. The third block 535 should have a sufficient thickness so as to prevent any fraction occurs during or after bending. As shown in FIG. 7, the aforesaid metal extrusion plate 50 is bent at the connecting section 53 so that the first incline 531 and the second incline 532 abut against each other (that is the first incline 531 and the second incline 532 attach to each other) so that the two adjacent flat plate sections 51 form the first included angle θ1 to form the supporting frame 5 of the display stand 2000. It is understandable that the first included angle θ1 is the supplementary angle of the second included angle θ2, and vice versa. In the present embodiment, the first included angle θ1 and the second included angle θ2 are both about 90 degrees. Please refer to FIG. 5. Preferably, at the two ends of the metal extrusion plate 50, either of the flat plate section 51 is formed with a first engagement structures 58. The first engagement structures 58 could be easily formed as a notch or a protrusion by post-processing. Furthermore, the metal extrusion plate 50 comprises a first surface S1 and a second surface S2 opposite to the first surface S1. In this embodiment, the groove 530 is formed on the first surface S1; however, in other embodiments, the groove 530 could be formed on the second surface S2. Preferably, the material of the metal extrusion plate 50 is aluminum or aluminum alloy. With reference to FIG. 2, FIG. 3, and FIG. 7, the second embodiment of the present invention discloses the supporting frame 5 of the display stand 2000. The metal extrusion plate 50 is bent to form the supporting frame 5 which is disposed on the base 3. Thus, the flat plate sections 51 and the connecting sections 53 encompass and form a receiving space 59. The elevating module 7 is disposed in the receiving space 59 so as to move up and down with respect to the supporting frame 5. The supporting structure 8 is, but not limited, an iron frame disposed in the receiving space 59 and fastened to the supporting frame 5. In this embodiment, the supporting structure 8 abuts against all the flat plate sections 51 of the supporting frame 5 to enhance the overall strength. Practically, the objective of enhancing structural strength is achieved through that the supporting structure 8 abuts against at least two of the flat plate sections 51. The base 3 further has a second engagement structure 38 which could be, for example, protrusions or screws. The first engagement structures 58 of the supporting frame 5 are adapted to engage to the second engagement structure 38 so that the supporting frame 5 could be secured onto the base 3. The elevating module 7 further comprises a slide element 71 and a holder 73 connected to the slide element 71. The slide element 71 slides along a slide 9 with respect to the supporting frame 5. The slide element 71 and the slide 9 are both disposed on the supporting structure 8, and the holder 73 is utilized to connect to a display (not shown). The third embodiment of the present invention is shown in FIG. 8. The difference is that the grooves 530 could be optionally formed on the first surface S1 or the second surface S2 so that the supporting frame 5 may have more variations to meet the user's requirements. As shown in FIG. 8, a plurality of flat plate sections 51 and connecting sections 53 are integrally formed and bent as the supporting frame 5. Because a portion of the grooves 530 of the metal extrusion plate 50 are formed on the first surface S1 and others are formed on the second surface S2, the bending orientations could be changed. Moreover, the second included angle θ2 of the metal extrusion plate 50 could also be varied according to the requirements. The first included angles θ1 shown in FIG. 8 include right angles with 90 degrees, and obtuse angles larger than 90 degrees. For example, if one of the first included angles θ1 is required in 120 degrees, the second included angle θ2 at the groove 530 is designed as 60 degrees before bending. It could be understood that the metallic extrusion processes for manufacturing the metal extrusion plate 50 merely need small molds. Actually, the molds merely need to meet the requirements of the cross-section of the metal extrusion plate 50. The subsequent manufacture processes of grooving and bending are both simple so that the costs of manufacture can be reduced as well as a slim stand can be obtained. The above disclosure is related to the detailed technical contents and inventive features thereof. People skilled in this field may proceed with a variety of modifications and replacements based on the disclosures and suggestions of the invention as described without departing from the characteristics thereof. Nevertheless, although such modifications and replacements are not fully disclosed in the above descriptions, they have substantially been covered in the following claims as appended.
<SOH> BACKGROUND OF THE INVENTION <EOH>
<SOH> SUMMARY OF THE INVENTION <EOH>One objective of the present invention is to provide a display stand which has a slim structure and is capable of minimizing the unfavorable visual effect occupied by the stand from the view of the user. Another objective of the present invention is to provide a metal extrusion plate for the display stand. The metal extrusion plate is capable of being bent as a supporting frame of the display stand. Merely a small mold can be used to manufacture the metal extrusion plate as a semi-finished product. The semi-finished metal extrusion plate can be further processed with grooving and bending to form the support frame. Thus, using the small molds can reduce the manufacturing cost and simplify the manufacturing processes. To achieve the abovementioned objectives, the present invention discloses a metal extrusion plate for a display stand. The metal extrusion plate extending along a first direction and comprises N of flat plate sections and N−1 of connecting sections, wherein the flat plate sections are integrally formed with the connecting sections, N is a positive integer greater than 1. The flat plate sections are interlaced with the connecting sections, and each of the connecting sections is connected to the two adjacent flat plate sections therebetween. Each of the connecting sections has a groove extending along a second direction being perpendicular to the first direction and forming a first incline and a second incline opposite to the first incline. The metal extrusion plate is capable of being bent at the connecting section so that the two adjacent flat plate sections form a first included angle. The connecting section is defined with a first block, a second block and a third block which are integrally formed. A side of the first block is connected to one of the two adjacent flat plate sections, a side of the second block is connected to the other one of the two adjacent flat plate sections, and two opposite sides of the third block are connected to the two adjacent flat plate sections respectively. The first block, the second block, and the third block collaboratively define the groove. The flat plate section has a first thickness greater than a second thickness of the third block. The first incline is formed on the first block, and the second incline is formed on the second block. Before being bent at the connecting section, the first incline and the second incline form a second included angle in which value of the second included angle is complementary to value of the first included angle. Preferably, in the metal extrusion plate of the present invention, the flat plate section that locates at either end of the metal extrusion plate is formed with a first engagement structure. The metal extrusion plate further comprises a first surface and a second surface opposite to the first surface, wherein the groove is formed on the first surface or the second surface. The material of the metal extrusion plate is aluminum or aluminum alloy. In another embodiment, the present invention discloses a display stand comprising a base, a supporting frame being formed by bending the abovementioned metal extrusion plate for being disposed on the base, and an elevating module. The flat plate sections and the connecting sections of the supporting frame encompass and form a receiving space. The first incline and the second incline of the connecting section abut against to each other so that the two adjacent flat plate sections form the first included angle. The elevating module is disposed in the receiving space so as to move up and down with respect to the supporting frame. The display stand further comprises a supporting structure disposed in the receiving space to be secured to the supporting frame. The supporting structure at least abuts against two of the flat plate sections to support the supporting frame. Preferably, in the display stand of this embodiment, the flat plate section located at either end of the metal extrusion plate is formed with a first engagement structure, and the base has a second engagement structure. The first engagement structure and the second engagement structure are capable of being engaged to each other. The metal extrusion plate further comprises a first surface and a second surface opposite to the first surface, and the groove is formed on the first surface or the second surface. The elevating module further has a slide element and a holder connecting with the slide element. The slide element is capable of sliding along a slide with respect to the supporting frame. The material of the metal extrusion plate is aluminum or aluminum alloy. In more detail, in the display stand of this embodiment, each of the connecting sections is defined with a first block, a second block, and a third block, which are integrally formed, wherein a side of the first block is connected to one of the two adjacent flat plate sections, a side of the second block is connected to the other one of the two adjacent flat plate sections, and two opposite sides of the third block are connected to the two adjacent flat plate sections respectively so that the first block, the second block, and the third block collaboratively define the groove, and the flat plate section has a first thickness greater than a second thickness of the third block. The detailed technology and preferred embodiments implemented for the subject invention are described in the following paragraphs accompanying the appended drawings for people skilled in this field to well appreciate the features of the claimed invention.
F16M11046
20170906
20180329
87489.0
F16M1104
1
STERLING, AMY JO
METAL EXTRUSION PLATE AND DISPLAY STAND FORMED BY THE SAME
UNDISCOUNTED
0
ACCEPTED
F16M
2,017
15,696,591
PENDING
CODING/DECODING METHOD, APPARATUS, AND SYSTEM FOR AUDIO SIGNAL
Embodiments of the present application provide a coding/decoding method, apparatus, and system. According to the coding method, de-emphasis processing is performed on a full band signal by using a de-emphasis parameter determined according to a characteristic factor of an input audio signal, and then the full band signal is coded and sent to a decoder, so that the decoder performs corresponding de-emphasis decoding processing on the full band signal according to the characteristic factor of the input audio signal and restores the input audio signal. This resolves a prior-art problem that an audio signal restored by a decoder is apt to have signal distortion, and implements adaptive de-emphasis processing on the full band signal according to the characteristic factor of the audio signal to enhance coding performance, so that the input audio signal restored by the decoder has relatively high fidelity and is closer to an original signal.
1. A coding method performed by a coder, comprising: obtaining an input audio signal; determining one or more characteristic factors of a low frequency band signal of the input audio signal; coding a high frequency band signal of the input audio signal to obtain a first full band signal; performing de-emphasis processing on the first full band signal, wherein a de-emphasis parameter of the de-emphasis processing is based on the one or more characteristic factors; calculating a first energy of the first full band signal after the de-emphasis processing; band-pass filtering the input audio signal to obtain a second full band signal; calculating a second energy of the second full band signal; calculating an energy ratio between the second energy and the first energy; and sending the energy ratio. 2. The method according to claim 1, further comprising: obtaining an average value of the one or more characteristic factors; and determining the de-emphasis parameter by calculating an average value of the one or more characteristic factors. 3. The method according to claim 1, wherein coding a high frequency band signal of the input audio signal to obtain a first full band signal comprises: obtaining a linear predictive coding (LPC) coefficient and a full band excitation signal; and performing coding processing on the LPC coefficient and the full band excitation signal to obtain the first full band signal. 4. The method according to claim 1, wherein the performing de-emphasis processing on the first full band signal comprises: performing frequency spectrum movement correction on the first full band signal, and performing frequency spectrum reflection processing on the corrected first full band signal; and performing the de-emphasis processing on the first full band signal that has undergone frequency spectrum reflection processing. 5. The method according to claim 1, wherein the characteristic factor is used to reflect a characteristic of the audio signal, and comprises a voicing factor, a spectral tilt, a short-term average energy, or a short-term zero-crossing rate. 6. A decoding method performed by a decoder, comprising: receiving an encoded audio signal bitstream; obtaining one or more characteristic factors, high frequency band coding information, and an energy ratio corresponding to an audio signal of the encoded audio signal; decoding, according to the one or more characteristic factors, the audio signal bitstream to obtain a low frequency band signal; decoding, according to the high frequency band coding information, the audio signal bitstream to obtain a high frequency band signal; predicting the high frequency band signal to obtain a first full band signal; performing de-emphasis processing on the first full band signal based on a de-emphasis parameter that is determined according to the one or more characteristic factors; calculating a first energy of the first full band signal that has undergone de-emphasis processing; obtaining a second full band signal according to the energy ratio, the first full band signal that has undergone de-emphasis processing, and the first energy; and restoring the audio signal according to the second full band signal, the low frequency band signal, and the high frequency band signal. 7. The method according to claim 6, further comprising: obtaining an average value of the one or more characteristic factors; and determining the de-emphasis parameter according to the average value of the characteristic factors. 8. The method according to claim 6, wherein the performing prediction on the high frequency band signal to obtain a first full band signal comprises: obtaining, according to the high frequency band signal, a linear predictive coding (LPC) coefficient and a full band excitation signal; and performing decoding processing on the LPC coefficient and the full band excitation signal to obtain the first full band signal. 9. The method according to claim 6, wherein the performing de-emphasis processing on the first full band signal comprises: performing frequency spectrum movement correction on the first full band signal, and performing frequency spectrum reflection processing on the corrected first full band signal; and performing the de-emphasis processing on the first full band signal that has undergone frequency spectrum reflection processing. 10. The method according to claim 6, wherein the characteristic factor is used to reflect a characteristic of the audio signal, and comprises a voicing factor, a spectral tilt, a short-term average energy, or a short-term zero-crossing rate. 11. A coding apparatus, comprising: a processor configured to execute computer instructions stored in memory, wherein, when the processor executes the computer instructions, to processor operates to: code a low frequency band signal of an input audio signal to obtain one or more characteristic factors of the input audio signal; perform coding and prediction on a high frequency band signal of the input audio signal to obtain a first full band signal; perform de-emphasis processing on the first full band signal, wherein a de-emphasis parameter of the de-emphasis processing is determined according to the one or more characteristic factors; and calculate a first energy of the first full band signal that has undergone de-emphasis processing; perform band-pass filtering on the input audio signal to obtain a second full band signal; calculate a second energy of the second full band signal; calculate an energy ratio between the second energy and the first energy. 12. The coding apparatus according to claim 11, wherein the processor further operates to: obtain an average value of the one or more characteristic factors; and determine the de-emphasis parameter according to the average value of the characteristic factors. 13. The coding apparatus according to claim 11, wherein the processor operates to: obtain a linear predictive coding (LPC) coefficient and a full band excitation signal; and perform coding processing on the LPC coefficient and the full band excitation signal to obtain the first full band signal. 14. The coding apparatus according to claim 11, wherein the processor operates to: perform frequency spectrum movement correction on the first full band signal, and perform frequency spectrum reflection processing on the corrected first full band signal; and perform the de-emphasis processing on the first full band signal that has undergone frequency spectrum reflection processing. 15. The coding apparatus according to claim 11, wherein the characteristic factor is used to reflect a characteristic of the audio signal, and comprises a voicing factor, a spectral tilt, a short-term average energy, or a short-term zero-crossing rate. 16. A decoder, comprising: a receiver, configured to receive an audio signal bitstream; a processor that operates on stored computer instructions to: obtain one or more characteristic factors, high frequency band coding information, and an energy ratio corresponding to an audio signal according to the audio signal bitstream; perform, according to the one or more characteristic factors, decoding on the audio signal bitstream to obtain a low frequency band signal; perform, according to the high frequency band coding information, decoding on the audio signal bitstream to obtain a high frequency band signal, and perform prediction on the high frequency band signal to obtain a first full band signal; perform de-emphasis processing on the first full band signal, wherein a de-emphasis parameter of the de-emphasis processing is determined according to the one or more characteristic factors; calculate a first energy of the first full band signal that has undergone de-emphasis processing; and obtain a second full band signal according to the energy ratio, the first full band signal that has undergone de-emphasis processing, and the first energy; and restore the audio signal according to the second full band signal, the low frequency band signal, and the high frequency band signal. 17. The decoder according to claim 16, wherein the processor further operates to: obtain an average value of the characteristic factors; and determine the de-emphasis parameter according to the average value of the characteristic factors. 18. The decoder according to claim 16, wherein the processor operates to: obtain, according to the high frequency band signal, a linear predictive coding (LPC) coefficient and a full band excitation signal; and perform decoding processing on the LPC coefficient and the full band excitation signal to obtain the first full band signal. 19. The decoder according to claim 16, wherein the wherein the processor operates to: perform frequency spectrum movement correction on the first full band signal, and perform frequency spectrum reflection processing on the corrected first full band signal; and perform the de-emphasis processing on the first full band signal that has undergone frequency spectrum reflection processing. 20. The decoder according to claim 16, wherein the characteristic factor is used to reflect a characteristic of the audio signal, and comprises a voicing factor, a spectral tilt, a short-term average energy, or a short-term zero-crossing rate.
CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 15/391,339, filed on Dec. 27, 2016, which is a continuation of International Application No. PCT/CN2015/074704, filed on Mar. 20, 2015. The International Application claims priority to Chinese Patent Application No. 201410294752.3, filed on Jun. 26, 2014. All of the afore-mentioned patent applications are hereby incorporated by reference in their entireties. TECHNICAL FIELD The present application relates to audio signal processing technologies, and in particular, to a time domain based coding/decoding method, apparatus, and system. BACKGROUND To save channel capacity and storage space, considering that human ears are less sensitive to high frequency information than to low frequency information of an audio signal, the high frequency information is usually cut, resulting in decreased audio quality. Therefore, a bandwidth extension technology is introduced to reconstruct the cut high frequency information, so as to improve the audio quality. As the rate increases, with coding performance ensured, a wider band of a high frequency part that can be coded enables a receiver to obtain a wider-band and higher-quality audio signal. In the foregoing solution, the input audio signal restored by the decoder may be apt to have relatively severe signal distortion. SUMMARY Embodiments of the present application provide a coding/decoding method, apparatus, and system, so as to relieve or resolve a prior-art problem that an input audio signal restored by a decoder is apt to have relatively severe signal distortion. According to a first aspect, the present application provides a coding method, including: coding, by a coding apparatus, a low frequency band signal of an input audio signal to obtain a characteristic factor of the input audio signal; performing, by the coding apparatus, coding and spread spectrum prediction on a high frequency band signal of the input audio signal to obtain a first full band signal; performing, by the coding apparatus, de-emphasis processing on the first full band signal, where a de-emphasis parameter of the de-emphasis processing is determined according to the characteristic factor; calculating, by the coding apparatus, a first energy of the first full band signal that has undergone de-emphasis processing; performing, by the coding apparatus, band-pass filtering processing on the input audio signal to obtain a second full band signal; calculating, by the coding apparatus, a second energy of the second full band signal; calculating, by the coding apparatus, an energy ratio of the second energy of the second full band signal to the first energy of the first full band signal; and sending, by the coding apparatus to a decoding apparatus, a bitstream resulting from coding the input audio signal, where the bitstream includes high frequency band coding information and the energy ratio of the input audio signal. With reference to the first aspect, in a first possible implementation manner of the first aspect, the method further includes: obtaining, by the coding apparatus, a quantity of characteristic factors; determining, by the coding apparatus, an average value of the characteristic factors according to the characteristic factors and the quantity of the characteristic factors; and determining, by the coding apparatus, the de-emphasis parameter according to the average value of the characteristic factors. With reference to the first aspect or the first possible implementation manner of the first aspect, in a second possible implementation manner of the first aspect, the performing, by the coding apparatus, spread spectrum prediction on a high frequency band signal of the input audio signal to obtain a first full band signal includes: determining, by the coding apparatus according to the high frequency band signal, an LPC coefficient and a full band excitation signal that are used to predict a full band signal; and performing, by the coding apparatus, coding processing on the LPC coefficient and the full band excitation signal to obtain the first full band signal. With reference to any one of the first aspect or the first or the second possible implementation manner of the first aspect, in a third possible implementation manner of the first aspect, the performing, by the coding apparatus, de-emphasis processing on the first full band signal includes: performing, by the coding apparatus, frequency spectrum movement correction on the first full band signal, and performing frequency spectrum reflection processing on the corrected first full band signal; and performing, by the coding apparatus, the de-emphasis processing on the first full band signal that has undergone frequency spectrum reflection processing. With reference to any one of the first aspect or the first to the third possible implementation manners of the first aspect, in a fourth possible implementation manner of the first aspect, the characteristic factor is used to reflect a characteristic of the audio signal, and includes a voicing factor, a spectral tilt, a short-term average energy, or a short-term zero-crossing rate. According to a second aspect, the present application provides a decoding method, including: receiving, by a decoding apparatus, an audio signal bitstream sent by a coding apparatus, where the audio signal bitstream includes high frequency band coding information and an energy ratio of an audio signal corresponding to the audio signal bitstream; obtaining a characteristic factor according to the bitstream; performing, by the decoding apparatus, low frequency band decoding on the audio signal bitstream by using the characteristic factor to obtain a low frequency band signal; performing, by the decoding apparatus, high frequency band decoding on the audio signal bitstream by using the high frequency band coding information to obtain a high frequency band signal; performing, by the decoding apparatus, spread spectrum prediction on the high frequency band signal to obtain a first full band signal; performing, by the decoding apparatus, de-emphasis processing on the first full band signal, where a de-emphasis parameter of the de-emphasis processing is determined according to the characteristic factor; calculating, by the decoding apparatus, a first energy of the first full band signal that has undergone de-emphasis processing; obtaining, by the decoding apparatus, a second full band signal according to the energy ratio included in the audio signal bitstream, the first full band signal that has undergone de-emphasis processing, and the first energy, where the energy ratio is an energy ratio of an energy of the second full band signal to the first energy; and restoring, by the decoding apparatus, the audio signal corresponding to the audio signal bitstream according to the second full band signal, the low frequency band signal, and the high frequency band signal. With reference to the second aspect, in a first possible implementation manner of the second aspect, the method further includes: obtaining, by the decoding apparatus, a quantity of characteristic factors through decoding; determining, by the decoding apparatus, an average value of the characteristic factors according to the characteristic factors and the quantity of the characteristic factors; and determining, by the decoding apparatus, the de-emphasis parameter according to the average value of the characteristic factors. With reference to the second aspect or the first possible implementation manner of the second aspect, in a second possible implementation manner of the second aspect, the performing, by the decoding apparatus, spread spectrum prediction on the high frequency band signal to obtain a first full band signal includes: determining, by the decoding apparatus according to the high frequency band signal, an LPC coefficient and a full band excitation signal that are used to predict a full band signal; and performing, by the decoding apparatus, coding processing on the LPC coefficient and the full band excitation signal to obtain the first full band signal. With reference to any one of the second aspect or the first or the second possible implementation manner of the second aspect, in a third possible implementation manner of the second aspect, the performing, by the decoding apparatus, de-emphasis processing on the first full band signal includes: performing, by the decoding apparatus, frequency spectrum movement correction on the first full band signal, and performing frequency spectrum reflection processing on the corrected first full band signal; and performing, by the decoding apparatus, the de-emphasis processing on the first full band signal that has undergone frequency spectrum reflection processing. With reference to any one of the second aspect or the first to the third possible implementation manners of the second aspect, in a fourth possible implementation manner of the second aspect, the characteristic factor is used to reflect a characteristic of the audio signal, and includes a voicing factor, a spectral tilt, a short-term average energy, or a short-term zero-crossing rate. According to a third aspect, the present application provides a coding apparatus, including: a first coding module, configured to code a low frequency band signal of an input audio signal to obtain a characteristic factor of the input audio signal; a second coding module, configured to perform coding and spread spectrum prediction on a high frequency band signal of the input audio signal to obtain a first full band signal; a de-emphasis processing module, configured to perform de-emphasis processing on the first full band signal, where a de-emphasis parameter of the de-emphasis processing is determined according to the characteristic factor; a calculation module, configured to calculate a first energy of the first full band signal that has undergone de-emphasis processing; a band-pass processing module, configured to perform band-pass filtering processing on the input audio signal to obtain a second full band signal, where the calculation module is further configured to calculate a second energy of the second full band signal; and calculate an energy ratio of the second energy of the second full band signal to the first energy of the first full band signal; and a sending module, configured to send to a decoding apparatus, a bitstream resulting from coding the input audio signal, where the bitstream includes the high frequency band coding information and the energy ratio of the input audio signal. With reference to the third aspect, in a first possible implementation manner of the third aspect, the coding apparatus further includes a de-emphasis parameter determining module, configured to: obtain a quantity of characteristic factors; determine an average value of the characteristic factors according to the characteristic factors and the quantity of the characteristic factors; and determine the de-emphasis parameter according to the average value of the characteristic factors. With reference to the third aspect or the first possible implementation manner of the third aspect, in a second possible implementation manner of the third aspect, the second coding module is configured to: determine, according to the high frequency band signal, an LPC coefficient and a full band excitation signal that are used to predict a full band signal; and perform coding processing on the LPC coefficient and the full band excitation signal to obtain the first full band signal. With reference to any one of the third aspect or the first or the second possible implementation manner of the third aspect, in third possible implementation manner of the third aspect, the de-emphasis processing module is configured to: perform frequency spectrum movement correction on the first full band signal obtained by the second coding module, and perform frequency spectrum reflection processing on the corrected first full band signal; and perform the de-emphasis processing on the first full band signal that has undergone frequency spectrum reflection processing. With reference to any one of the third aspect or the first to the third possible implementation manners of the third aspect, in a fourth possible implementation manner of the third aspect, the characteristic factor is used to reflect a characteristic of the audio signal, and includes a voicing factor, a spectral tilt, a short-term average energy, or a short-term zero-crossing rate. According to a fourth aspect, the present application provides a decoding apparatus, including: a receiving module, configured to receive an audio signal bitstream sent by a coding apparatus, where the audio signal bitstream includes high frequency band coding information and an energy ratio of an audio signal corresponding to the audio signal bitstream; obtaining a characteristic factor according to the bitstream; a first decoding module, configured to perform low frequency band decoding on the audio signal bitstream by using the characteristic factor to obtain a low frequency band signal; a second decoding module, configured to: perform high frequency band decoding on the audio signal bitstream by using the high frequency band coding information to obtain a high frequency band signal, and perform spread spectrum prediction on the high frequency band signal to obtain a first full band signal; a de-emphasis processing module, configured to perform de-emphasis processing on the first full band signal, where a de-emphasis parameter of the de-emphasis processing is determined according to the characteristic factor; a calculation module, configured to calculate a first energy of the first full band signal that has undergone de-emphasis processing; and obtain a second full band signal according to the energy ratio included in the audio signal bitstream, the first full band signal that has undergone de-emphasis processing, and the first energy, where the energy ratio is an energy ratio of an energy of the second full band signal to the first energy; and a restoration module, configured to restore the audio signal corresponding to the audio signal bitstream according to the second full band signal, the low frequency band signal, and the high frequency band signal. With reference to the fourth aspect, in a first possible implementation manner of the fourth aspect, the decoding apparatus further includes a de-emphasis parameter determining module, configured to: obtain a quantity of characteristic factors through decoding; determine an average value of the characteristic factors according to the characteristic factors and the quantity of the characteristic factors; and determine the de-emphasis parameter according to the average value of the characteristic factors. With reference to the fourth aspect or the first possible implementation manner of the fourth aspect, in a second possible implementation manner of the fourth aspect, the second decoding module is configured to: determine, according to the high frequency band signal, an LPC coefficient and a full band excitation signal that are used to predict a full band signal; and perform coding processing on the LPC coefficient and the full band excitation signal to obtain the first full band signal. With reference to any one of the fourth aspect or the first or the second possible implementation manner of the fourth aspect, in third possible implementation manner of the fourth aspect, the de-emphasis processing module is configured to: perform frequency spectrum movement correction on the first full band signal, and perform frequency spectrum reflection processing on the corrected first full band signal; and perform the de-emphasis processing on the first full band signal that has undergone frequency spectrum reflection processing. With reference to any one of the fourth aspect or the first to the third possible implementation manners of the fourth aspect, in a fourth possible implementation manner of the fourth aspect, the characteristic factor is used to reflect a characteristic of the audio signal, and includes a voicing factor, a spectral tilt, a short-term average energy, or a short-term zero-crossing rate. According to a fifth aspect, the present application provides a coding/decoding system, including the coding apparatus according to any one of the third aspect or the first to the fourth possible implementation manners of the third aspect and the decoding apparatus according to any one of the fourth aspect or the first to the fourth possible implementation manners of the fourth aspect. According to the codec method, apparatus, and system provided in the embodiments of the present application, de-emphasis processing is performed on a full band signal by using a de-emphasis parameter determined according to a characteristic factor of an input audio signal, and then the full band signal is coded and sent to a decoder, so that the decoder performs corresponding de-emphasis decoding processing on the full band signal according to the characteristic factor of the input audio signal and restores the input audio signal. This application implements adaptive de-emphasis processing on the full band signal according to the characteristic factor of the audio signal to enhance coding performance, so that the input audio signal restored by the decoder has relatively high fidelity and is closer to an original signal. BRIEF DESCRIPTION OF DRAWINGS To describe the technical solutions in the embodiments of the present application more clearly, the following briefly introduces the accompanying drawings required for describing the embodiments. Apparently, the accompanying drawings in the following description show some embodiments of the present application, and a person of ordinary skill in the art may still derive other drawings from these accompanying drawings without creative efforts. FIG. 1 is a flowchart of an embodiment of a coding method according to an embodiment of the present application; FIG. 2 is a flowchart of an embodiment of a decoding method according to an embodiment of the present application; FIG. 3 is a schematic structural diagram of Embodiment 1 of a coding apparatus according to an embodiment of the present application; FIG. 4 is a schematic structural diagram of Embodiment 1 of a decoding apparatus according to an embodiment of the present application; FIG. 5 is a schematic structural diagram of Embodiment 2 of a coding apparatus according to an embodiment of the present application; FIG. 6 is a schematic structural diagram of Embodiment 2 of a decoding apparatus according to an embodiment of the present application; and FIG. 7 is a schematic structural diagram of an embodiment of a coding/decoding system according to the present application. DESCRIPTION OF EMBODIMENTS To make the objectives, technical solutions, and advantages of the embodiments of the present application clearer, the following clearly describes the technical solutions in the embodiments of the present application with reference to the accompanying drawings in the embodiments of the present application. Apparently, the described embodiments are a part rather than all of the embodiments of the present application. FIG. 1 is a schematic flowchart of an embodiment of a coding method according to an embodiment of the present application. As shown in FIG. 1, the method embodiment includes the following steps: S101: A coding apparatus codes a low frequency band signal of an input audio signal to obtain a characteristic factor of the input audio signal. The coded signal is an audio signal. The characteristic factor is used to reflect a characteristic of the audio signal, and includes, but is not limited to, a “voicing factor”, a “spectral tilt”, a “short-term average energy”, or a “short-term zero-crossing rate”. The characteristic factor may be obtained by the coding apparatus by coding the low frequency band signal of the input audio signal. Using the voicing factor as an example, the voicing factor may be obtained through calculation according to a pitch period, an algebraic codebook, and their respective gains extracted from low frequency band coding information that is obtained by coding the low frequency band signal. S102: The coding apparatus performs coding and spread spectrum prediction on a high frequency band signal of the input audio signal to obtain a first full band signal. When the high frequency band signal is coded, high frequency band coding information is further obtained. S103: The coding apparatus performs de-emphasis processing on the first full band signal, where a de-emphasis parameter of the de-emphasis processing is determined according to the characteristic factor. S104: The coding apparatus calculates a first energy of the first full band signal that has undergone de-emphasis processing. S105: The coding apparatus performs band-pass filtering processing on the input audio signal to obtain a second full band signal. S106: The coding apparatus calculates a second energy of the second full band signal. S107: The coding apparatus calculates an energy ratio of the second energy of the second full band signal to the first energy of the first full band signal. S108: The coding apparatus sends, to a decoding apparatus, a bitstream resulting from coding the input audio signal, where the bitstream includes the characteristic factor, high frequency band coding information, and the energy ratio of the input audio signal. Further, the method embodiment further includes: obtaining, by the coding apparatus, a quantity of characteristic factors; determining, by the coding apparatus, an average value of the characteristic factors according to the characteristic factors and the quantity of the characteristic factors; and determining, by the coding apparatus, the de-emphasis parameter according to the average value of the characteristic factors. The coding apparatus may obtain one of the characteristic factors. Using an example in which the characteristic factor is the voicing factor, the coding apparatus obtains a quantity of voicing factors, and determines, according to the voicing factors and the quantity of the voicing factors, an average value of the voicing factors of the input audio signal, and further determines the de-emphasis parameter according to the average value of the voicing factors. Further, the performing, by the coding apparatus, coding and spread spectrum prediction on a high frequency band signal of the input audio signal to obtain a first full band signal in S102 includes: determining, by the coding apparatus according to the high frequency band signal, an LPC coefficient and a full band excitation signal that are used to predict a full band signal; and performing, by the coding apparatus, coding processing on the LPC coefficient and the full band excitation signal to obtain the first full band signal. Further, S103 includes: performing, by the coding apparatus, frequency spectrum movement correction on the first full band signal, and performing frequency spectrum reflection processing on the corrected first full band signal; and performing, by the coding apparatus, the de-emphasis processing on the first full band signal that has undergone frequency spectrum reflection processing. Optionally, after S103, the method embodiment further includes: performing, by the coding apparatus, upsampling and band-pass processing on the first full band signal that has undergone de-emphasis processing; and correspondingly, S104 includes: calculating, by the coding apparatus, a first energy of the first full band signal that has undergone de-emphasis processing, upsampling, and band-pass processing. An embodiment is described below by using an example in which the characteristic factor is the voicing factor. For other characteristic factors, their implementation processes are similar thereto, and details are not further described. After receiving an input audio signal, a signaling coding apparatus of a coding apparatus extracts a low frequency band signal from the input audio signal, where a corresponding frequency spectrum range is [0, f1], and codes the low frequency band signal to obtain a voicing factor of the input audio signal. The signaling coding apparatus codes the low frequency band signal to obtain low frequency band coding information; calculates according to a pitch period, an algebraic codebook, and their respective gains included in the low frequency band coding information to obtain the voicing factor; and determines a de-emphasis parameter according to the voicing factor. The signaling coding apparatus extracts a high frequency band signal from the input audio signal, where a corresponding frequency spectrum range is [f1, f2]; performs coding and spread spectrum prediction on the high frequency band signal to obtain high frequency band coding information; determines, according to the high frequency band signal, an LPC coefficient and a full band excitation signal that are used to predict a full band signal; performs coding processing on the LPC coefficient and the full band excitation signal to obtain a predicted first full band signal; and performs de-emphasis processing on the first full band signal, where the de-emphasis parameter of the de-emphasis processing is determined according to the voicing factor. After the first full band signal is determined, frequency spectrum movement correction and frequency spectrum reflection processing may be performed on the first full band signal, and then de-emphasis processing may be performed. Optionally, upsampling and band-pass filtering processing may be performed on the first full band signal that has undergone de-emphasis processing. Later, the coding apparatus calculates a first energy Ener0 of the processed first full band signal; performs band-pass filtering processing on the input audio signal to obtain a second full band signal, whose frequency spectrum range is [f2, f3]; determines a second energy Ener1 of the second full band signal; determines an energy ratio of Ener1 to Ener0; and includes the characteristic factor, the high frequency band coding information, and the energy ratio of the input audio signal in a bitstream resulting from coding the input audio signal, and sends the bitstream to the decoding apparatus, so that the decoding apparatus restores the audio signal according to the received bitstream, characteristic factor, high frequency band coding information, and energy ratio. Generally, for a 48-Kilo Hertz (KHz) input audio signal, a corresponding frequency spectrum range [0, f1] of a low frequency band signal of the input audio signal may be [0, 8 KHz], and a corresponding frequency spectrum range [f1, f2] of a high frequency band signal of the input audio signal may be [8 KHz, 16 KHz]. The corresponding frequency spectrum range [f2, f3] corresponding to the second full band signal may be [16 KHz, 20 KHz]. The following describes in detail an implementation manner of the method embodiment by using the frequency spectrum ranges as an example. It should be noted that the present application is applicable to this implementation manner, but is not limited thereto. In an implementation, the low frequency band signal corresponding to [0, 8 KHz] may be coded by using a code excited linear prediction (CELP) core encoder, so as to obtain low frequency band coding information. A coding algorithm used by the core encoder may be an existing algebraic code excited linear prediction (ACELP) algorithm, but is not limited thereto. The pitch period, the algebraic codebook, and their respective gains are extracted from the low frequency band coding information, the voicing factor is obtained through calculation by using the existing algorithm, and details of the algorithm are not further described. After the voicing factor is determined, a de-emphasis factor μ used to calculate the de-emphasis parameter is determined. The following describes, in detail by using the voicing factor as an example, a calculation process in which the de-emphasis factor μ is determined. A quantity M of obtained voicing factors is first determined, which usually may be 4 or 5. The M voicing factors are summed and averaged, so as to determine an average value varvoiceshape of the voicing factors. The de-emphasis factor μ is determined according to the average value, and a de-emphasis parameter H(Z) may be further obtained according to μ, as indicated by the following formula (1): H(Z)=1/(1−μZ−1) (1) where H(Z) is an expression of a transfer function in a Z domain, Z−1 represents a delay unit, and μ is determined according to varvoiceshape. Any value related to varvoiceshape may be selected as μ which may be: μ=varvoiceshape3, μ=varvoiceshape2, μ=varvoiceshape, or μ=1−varvoiceshape. The high frequency band signal corresponding to [8 KHz, 16 KHz] may be coded by using a super wide band time band extension (TBE) encoder. This includes: extracting the pitch period, the algebraic codebook, and their respective gains from the core encoder to restore a high frequency band excitation signal; extracting a high frequency band signal component to perform an LPC analysis to obtain a high frequency band LPC coefficient; integrating the high frequency band excitation signal and the high frequency band LPC coefficient to obtain a restored high frequency band signal; comparing the restored high frequency band signal with the high frequency band signal in the input audio signal to obtain a gain adjustment parameter gain; and quantizing, by using a small quantity of bits, the high frequency band LPC coefficient and the gain parameter gain to obtain high frequency band coding information. Further, the SWB encoder determines, according to the high frequency band signal of the input audio signal, the full band LPC coefficient and the full band excitation signal that are used to predict the full band signal, and performs integration processing on the full band LPC coefficient and the full band excitation signal to obtain a predicted first full band signal, and then frequency spectrum movement correction may be performed on the first full band signal by using the following formula (2): S2k=S1k×cos(2×PI×fn×k/fs) (2) where k represents the kth time sample point, k is a positive integer, S2 is a first frequency spectrum signal after the frequency spectrum movement correction, S1 is the first full band signal, PI is a ratio of a circumference of a circle to its diameter, fn indicates that a distance that a frequency spectrum needs to move is n time sample points, n is a positive integer, and fs represents a signal sampling rate. After the frequency spectrum movement correction, frequency spectrum reflection processing is performed on S2 to obtain a first full band signal S3 that has undergone frequency spectrum reflection processing, amplitudes of frequency spectrum signals of corresponding time sample points before and after the frequency spectrum movement are reflected. An implementation manner of the frequency spectrum reflection may be the same as common frequency spectrum reflection, so that the frequency spectrum is arranged in a structure the same as that of an original frequency spectrum, and details are not described further. Later, de-emphasis processing is performed on S3 by using the de-emphasis parameter H(Z) determined according to the voicing factor, to obtain a first full band signal S4 that has undergone de-emphasis processing, and then energy Ener0 of S4 is determined. The de-emphasis processing may be performed by using a de-emphasis filter having the de-emphasis parameter. Optionally, after S4 is obtained, upsampling processing may be performed, by means of zero insertion, on the first full band signal S4 that has undergone de-emphasis processing, to obtain a first full band signal S5 that has undergone upsampling processing, then band-pass filtering processing may be performed on S5 by using a band pass filter (BPF) having a pass range of [16 KHz, 20 KHz] to obtain a first full band signal S6, and then an energy Ener0 of S6 is determined. The upsampling and the band-pass processing are performed on the first full band signal that has undergone de-emphasis processing, and then the energy of the first full band signal is determined, so that a frequency spectrum energy and a frequency spectrum structure of a high frequency band extension signal may be adjusted to enhance coding performance. The second full band signal may be obtained by the coding apparatus by performing band-pass filtering processing on the input audio signal by using the band pass filter (BPF) having the pass range of [16 KHz, 20 KHz]. After the second full band signal is obtained, the coding apparatus determines energy Ener1 of the second full band signal, and calculates a ratio of the energy Ener1 to the energy Ener0. After quantization processing is performed on the energy ratio, the energy ratio, the characteristic factor and the high frequency band coding information of the input audio signal are packaged into the bitstream and sent to the decoding apparatus. In the prior art, the de-emphasis factor μ of the de-emphasis filtering parameter H(Z) usually has a fixed value, and a signal type of the input audio signal is not considered, resulting that the input audio signal restored by the decoding apparatus is apt to have signal distortion. According to the method embodiment, de-emphasis processing is performed on a full band signal by using a de-emphasis parameter determined according to a characteristic factor of an input audio signal, and then the full band signal is coded and sent to a decoder, so that the decoder performs corresponding de-emphasis decoding processing on the full band signal according to the characteristic factor of the input audio signal and restores the input audio signal. This resolves a prior-art problem that an audio signal restored by a decoder is apt to have signal distortion is resolved, and implements adaptive de-emphasis processing on the full band signal according to the characteristic factor of the audio signal to enhance coding performance, so that the input audio signal restored by the decoder has relatively high fidelity and is closer to an original signal. FIG. 2 is a flowchart of an embodiment of a decoding method according to an embodiment of the present application, and is a decoder side method embodiment corresponding to the method embodiment shown in FIG. 1. As shown in FIG. 2, the method embodiment includes the following steps: S201: A decoding apparatus receives an audio signal bitstream sent by a coding apparatus, where the audio signal bitstream includes a characteristic factor, high frequency band coding information, and an energy ratio of an audio signal corresponding to the audio signal bitstream. The characteristic factor is used to reflect a characteristic of the audio signal, and includes, but is not limited to, a “voicing factor”, a “spectral tilt”, a “short-term average energy”, or a “short-term zero-crossing rate”. The characteristic factor is the same as the characteristic factor in the method embodiment shown in FIG. 1, and details are not described again. S202: The decoding apparatus performs low frequency band decoding on the audio signal bitstream by using the characteristic factor to obtain a low frequency band signal. S203: The decoding apparatus performs high frequency band decoding on the audio signal bitstream by using the high frequency band coding information to obtain a high frequency band signal. S204: The decoding apparatus performs spread spectrum prediction on the high frequency band signal to obtain a first full band signal. S205: The decoding apparatus performs de-emphasis processing on the first full band signal, where a de-emphasis parameter of the de-emphasis processing is determined according to the characteristic factor. S206: The decoding apparatus calculates a first energy of the first full band signal that has undergone de-emphasis processing. S207: The decoding apparatus obtains a second full band signal according to the energy ratio included in the audio signal bitstream, the first full band signal that has undergone de-emphasis processing, and the first energy, where the energy ratio is an energy ratio of an energy of the second full band signal to the first energy. S208: The decoding apparatus restores the audio signal corresponding to the audio signal bitstream according to the second full band signal, the low frequency band signal, and the high frequency band signal. Further, the method embodiment further includes: obtaining, by the decoding apparatus, a quantity of characteristic factors through decoding; determining, by the decoding apparatus, an average value of the characteristic factors according to the characteristic factors and the quantity of the characteristic factors; and determining, by the decoding apparatus, the de-emphasis parameter according to the average value of the characteristic factors. Further, S204 includes: determining, by the decoding apparatus according to the high frequency band signal, an LPC coefficient and a full band excitation signal that are used to predict a full band signal; and performing, by the decoding apparatus, coding processing on the LPC coefficient and the full band excitation signal to obtain the first full band signal. Further, S205 includes: performing, by the decoding apparatus, frequency spectrum movement correction on the first full band signal, and performing frequency spectrum reflection processing on the corrected first full band signal; and performing, by the decoding apparatus, the de-emphasis processing on the first full band signal that has undergone frequency spectrum reflection processing. Optionally, after S205, the method embodiment further includes: performing, by the decoding apparatus, upsampling and band-pass filtering processing on the first full band signal that has undergone de-emphasis processing; and correspondingly, S206 includes: determining, by the decoding apparatus, a first energy of the first full band signal that has undergone de-emphasis processing, upsampling, and band-pass processing. The method embodiment corresponds to the technical solution in the method embodiment shown in FIG. 1. An implementation manner of the method embodiment is described by using an example in which the characteristic factor is a voicing factor. For other characteristic factors, their implementation processes are similar thereto, and details are not described further. A decoding apparatus receives an audio signal bitstream sent by a coding apparatus, where the audio signal bitstream includes a characteristic factor, high frequency band coding information, and an energy ratio of an audio signal corresponding to the audio signal bitstream. Later, the decoding apparatus extracts the characteristic factor of the audio signal from the audio signal bitstream, performs low frequency band decoding on the audio signal bitstream by using the characteristic factor of the audio signal to obtain a low frequency band signal, and performs high frequency band decoding on the audio signal bitstream by using the high frequency band coding information to obtain a high frequency band signal. The decoding apparatus determines a de-emphasis parameter according to the characteristic factor; performs full band signal prediction according to the high frequency band signal obtained through decoding to obtain a first full band signal S1, performs frequency spectrum movement correction processing on S1 to obtain a first full band signal S2 that has undergone frequency spectrum movement correction processing, performs frequency spectrum reflection processing on S2 to obtain a signal S3, performs de-emphasis processing on S3 by using the de-emphasis parameter determined according to the characteristic factor, to obtain a signal S4, and calculates a first energy Ener0 of S4. Optionally, the decoding apparatus performs upsampling processing on the signal S4 to obtain a signal S5, performs band-pass filtering processing on S5 to obtain a signal S6, and then calculates a first energy Ener0 of S6. Later, a second full band signal is obtained according to the signal S4 or S6, Ener0, and the received energy ratio, and the audio signal corresponding to the audio signal bitstream is restored according to the second full band signal, and the low frequency band signal and the high frequency band signal that are obtained through decoding. In an implementation, the low frequency band decoding may be performed by a core decoder on the audio signal bitstream by using the characteristic factor to obtain the low frequency band signal. The high frequency band decoding may be performed by a SWB decoder on the high frequency band coding information to obtain the high frequency band signal. After the high frequency band signal is obtained, spread spectrum prediction is performed directly according to the high frequency band signal or after the high frequency band signal is multiplied by an attenuation factor, to obtain a first full band signal, and the frequency spectrum movement correction processing, the frequency spectrum reflection processing, and the de-emphasis processing are performed on the first full band signal. Optionally, the upsampling processing and the band-pass filtering processing are performed on the first full band signal that has undergone de-emphasis processing. In an implementation, an implementation manner similar to that in the method embodiment shown in FIG. 1 may be used for processing, and details are not described again. The obtaining a second full band signal according to the signal S4 or S6, Ener0, and the received energy ratio is: performing energy adjustment on the first full band signal according to the energy ratio R and the first energy Ener0 to restore an energy of the second full band signal Ener1=Ener0×R, and obtaining the second full band signal according to a frequency spectrum of the first full band signal and the energy Ener1. According to the method embodiment, a decoding apparatus determines a de-emphasis parameter by using a characteristic factor of an audio signal that is included in an audio signal bitstream, performs de-emphasis processing on a full band signal, and obtains a low frequency band signal through decoding by using the characteristic factor, so that an audio signal restored by the decoding apparatus is closer to an original input audio signal and has higher fidelity. FIG. 3 is a schematic structural diagram of Embodiment 1 of a coding apparatus according to an embodiment of the present application. As shown in FIG. 3, the coding apparatus 300 includes a first coding module 301, a second coding module 302, a de-emphasis processing module 303, a calculation module 304, a band-pass processing module 305, and a sending module 306, where the first coding module 301 is configured to code a low frequency band signal of an input audio signal to obtain a characteristic factor of the input audio signal, where the characteristic factor is used to reflect a characteristic of the audio signal, and includes a voicing factor, a spectral tilt, a short-term average energy, or a short-term zero-crossing rate; the second coding module 302 is configured to perform coding and spread spectrum prediction on a high frequency band signal of the input audio signal to obtain a first full band signal; the de-emphasis processing module 303 is configured to perform de-emphasis processing on the first full band signal, where a de-emphasis parameter of the de-emphasis processing is determined according to the characteristic factor; the calculation module 304 is configured to calculate a first energy of the first full band signal that has undergone de-emphasis processing; the band-pass processing module 305 is configured to perform band-pass filtering processing on the input audio signal to obtain a second full band signal; the calculation module 304 is further configured to calculate a second energy of the second full band signal; and calculate an energy ratio of the second energy of the second full band signal to the first energy of the first full band signal; and the sending module 306 is configured to send to a decoding apparatus, a bitstream resulting from coding the input audio signal, where the bitstream includes the characteristic factor, high frequency band coding information, and the energy ratio of the input audio signal. Further, the coding apparatus 300 further includes a de-emphasis parameter determining module 307, configured to: obtain a quantity of characteristic factors; determine an average value of the characteristic factors according to the characteristic factors and the quantity of the characteristic factors; and determine the de-emphasis parameter according to the average value of the characteristic factors. Further, the second coding module 302 is configured to: determine, according to the high frequency band signal, an LPC coefficient and a full band excitation signal that are used to predict a full band signal; and perform coding processing on the LPC coefficient and the full band excitation signal to obtain the first full band signal. Further, the de-emphasis processing module 303 is configured to: perform frequency spectrum movement correction on the first full band signal obtained by the second coding module 302, and perform frequency spectrum reflection processing on the corrected first full band signal; and perform the de-emphasis processing on the first full band signal that has undergone frequency spectrum reflection processing. The coding apparatus provided in this embodiment may be configured to execute the technical solution in the method embodiment shown in FIG. 1. Their implementation principles and technical effects are similar, and details are not described again. FIG. 4 is a schematic structural diagram of Embodiment 1 of a decoding apparatus according to an embodiment of the present application. As shown in FIG. 4, the decoding apparatus 400 includes a receiving module 401, a first decoding module 402, a second decoding module 403, a de-emphasis processing module 404, a calculation module 405, and a restoration module 406, where the receiving module 401 is configured to receive an audio signal bitstream sent by a coding apparatus, where the audio signal bitstream includes a characteristic factor, high frequency band coding information, and an energy ratio of an audio signal corresponding to the audio signal bitstream, where the characteristic factor is used to reflect a characteristic of the audio signal, and includes a voicing factor, a spectral tilt, a short-term average energy, or a short-term zero-crossing rate; the first decoding module 402 is configured to perform low frequency band decoding on the audio signal bitstream by using the characteristic factor to obtain a low frequency band signal; the second decoding module 403 is configured to: perform high frequency band decoding on the audio signal bitstream by using the high frequency band coding information to obtain a high frequency band signal, and perform spread spectrum prediction on the high frequency band signal to obtain a first full band signal; the de-emphasis processing module 404 is configured to perform de-emphasis processing on the first full band signal, where a de-emphasis parameter of the de-emphasis processing is determined according to the characteristic factor; the calculation module 405 is configured to calculate a first energy of the first full band signal that has undergone de-emphasis processing; and obtain a second full band signal according to the energy ratio included in the audio signal bitstream, the first full band signal that has undergone de-emphasis processing, and the first energy, where the energy ratio is an energy ratio of an energy of the second full band signal to the first energy; and the restoration module 406 is configured to restore the audio signal corresponding to the audio signal bitstream according to the second full band signal, the low frequency band signal, and the high frequency band signal. Further, the decoding apparatus 400 further includes a de-emphasis parameter determining module 407, configured to: obtain a quantity of characteristic factors through decoding; determine an average value of the characteristic factors according to the characteristic factors and the quantity of the characteristic factors; and determine the de-emphasis parameter according to the average value of the characteristic factors. Further, the second decoding module 403 is configured to: determine, according to the high frequency band signal, an LPC coefficient and a full band excitation signal that are used to predict a full band signal; and perform coding processing on the LPC coefficient and the full band excitation signal to obtain the first full band signal. Further, the de-emphasis processing module 404 is configured to: perform frequency spectrum movement correction on the first full band signal, and perform frequency spectrum reflection processing on the corrected first full band signal; and perform the de-emphasis processing on the first full band signal that has undergone frequency spectrum reflection processing. The decoding apparatus provided in this embodiment may be configured to execute the technical solution in the method embodiment shown in FIG. 2. Their implementation principles and technical effects are similar, and details are not described again. FIG. 5 is a schematic structural diagram of Embodiment 2 of a coding apparatus according to an embodiment of the present application. As shown in FIG. 5, the coding apparatus 500 includes a processor 501, a memory 502, and a communications interface 503. The processor 501, the memory 502, and communications interface 503 are connected by means of a bus (a bold solid line shown in the figure). The communications interface 503 is configured to receive input of an audio signal and communicate with a decoding apparatus. The memory 502 is configured to store program code. The processor 501 is configured to call the program code stored in the memory 502 to execute the technical solution in the method embodiment shown in FIG. 1. Their implementation principles and technical effects are similar, and details are not described again. FIG. 6 is a schematic structural diagram of Embodiment 2 of a coding apparatus according to an embodiment of the present application. As shown in FIG. 6, the decoding apparatus 600 includes a processor 601, a memory 602, and a communications interface 603. The processor 601, the memory 602, and communications interface 603 are connected by means of a bus (a bold solid line shown in the figure). The communications interface 603 is configured to communicate with a coding apparatus and output a restored audio signal. The memory 602 is configured to store program code. The processor 601 is configured to call the program code stored in the memory 602 to execute the technical solution in the method embodiment shown in FIG. 2. Their implementation principles and technical effects are similar, and details are not described again. FIG. 7 is a schematic structural diagram of an embodiment of a coding/decoding system according to the present application. As shown in FIG. 7, the codec system 700 includes a coding apparatus 701 and a decoding apparatus 702. The coding apparatus 701 and the decoding apparatus 702 may be respectively the coding apparatus shown in FIG. 3 and the decoding apparatus shown in FIG. 4, and may be respectively configured to execute the technical solutions in the method embodiments shown in FIG. 1 and FIG. 2. Their implementation principles and technical effects are similar, and details are not described again. With descriptions of the foregoing embodiments, a person skilled in the art may clearly understand that the present application may be implemented by hardware, firmware or a combination thereof. When the present application is implemented by software, the foregoing functions may be stored in a computer-readable medium or transmitted as one or more instructions or code in the computer-readable medium. The computer-readable medium includes a computer storage medium and a communications medium, where the communications medium includes any medium that enables a computer program to be transmitted from one place to another. The storage medium may be any available medium accessible to a computer. The following provides an example but does not impose a limitation: The computer-readable medium may include a RAM, a ROM, an EEPROM, a CD-ROM, or another optical disc storage or disk storage medium, or another magnetic storage device, or any other medium that can carry or store expected program code in a form of instructions or data structures and can be accessed by a computer. In addition, any connection may be appropriately defined as a computer-readable medium. For example, if software is transmitted from a website, a server or another remote source by using a coaxial cable, an optical fiber/cable, a twisted pair, a digital subscriber line (DSL) or wireless technologies such as infrared ray, radio and microwave, the coaxial cable, optical fiber/cable, twisted pair, DSL or wireless technologies such as infrared ray, radio and microwave are included in the definition of the medium. For example, a disk and disc used by the present application includes a compact disc CD, a laser disc, an optical disc, a digital versatile disc (DVD), a floppy disk and a Blu-ray disc, where the disk generally copies data by a magnetic means, and the disc copies data optically by a laser means. The foregoing combination should also be included in the protection scope of the computer-readable medium. Moreover, it should be understood that depending on the embodiments, some actions or events of any method described in this specification may be executed according to different sequences, or may be added, combined, or omitted (for example, to achieve some particular objectives, not all described actions or events are necessary). Moreover, in some embodiments, actions or events may undergo hyper-threading processing, interrupt processing, or simultaneous processing by multiple processors, and the simultaneous processing may be non-sequential execution. In addition, in view of clarity, embodiments of the present application are described as a function of a single step or module, but it should be understood that technologies of the present application may be combined execution of multiple steps or modules described above. Finally, it should be noted that the foregoing embodiments are merely intended for describing the technical solutions of the present application other than limiting the present application. Although the present application is described in detail with reference to the foregoing embodiments, persons of ordinary skill in the art should understand that they may still make modifications to the technical solutions described in the foregoing embodiments or make equivalent replacements to some or all technical features thereof, without departing from the scope of the technical solutions of the embodiments of the present application.
<SOH> BACKGROUND <EOH>To save channel capacity and storage space, considering that human ears are less sensitive to high frequency information than to low frequency information of an audio signal, the high frequency information is usually cut, resulting in decreased audio quality. Therefore, a bandwidth extension technology is introduced to reconstruct the cut high frequency information, so as to improve the audio quality. As the rate increases, with coding performance ensured, a wider band of a high frequency part that can be coded enables a receiver to obtain a wider-band and higher-quality audio signal. In the foregoing solution, the input audio signal restored by the decoder may be apt to have relatively severe signal distortion.
<SOH> SUMMARY <EOH>Embodiments of the present application provide a coding/decoding method, apparatus, and system, so as to relieve or resolve a prior-art problem that an input audio signal restored by a decoder is apt to have relatively severe signal distortion. According to a first aspect, the present application provides a coding method, including: coding, by a coding apparatus, a low frequency band signal of an input audio signal to obtain a characteristic factor of the input audio signal; performing, by the coding apparatus, coding and spread spectrum prediction on a high frequency band signal of the input audio signal to obtain a first full band signal; performing, by the coding apparatus, de-emphasis processing on the first full band signal, where a de-emphasis parameter of the de-emphasis processing is determined according to the characteristic factor; calculating, by the coding apparatus, a first energy of the first full band signal that has undergone de-emphasis processing; performing, by the coding apparatus, band-pass filtering processing on the input audio signal to obtain a second full band signal; calculating, by the coding apparatus, a second energy of the second full band signal; calculating, by the coding apparatus, an energy ratio of the second energy of the second full band signal to the first energy of the first full band signal; and sending, by the coding apparatus to a decoding apparatus, a bitstream resulting from coding the input audio signal, where the bitstream includes high frequency band coding information and the energy ratio of the input audio signal. With reference to the first aspect, in a first possible implementation manner of the first aspect, the method further includes: obtaining, by the coding apparatus, a quantity of characteristic factors; determining, by the coding apparatus, an average value of the characteristic factors according to the characteristic factors and the quantity of the characteristic factors; and determining, by the coding apparatus, the de-emphasis parameter according to the average value of the characteristic factors. With reference to the first aspect or the first possible implementation manner of the first aspect, in a second possible implementation manner of the first aspect, the performing, by the coding apparatus, spread spectrum prediction on a high frequency band signal of the input audio signal to obtain a first full band signal includes: determining, by the coding apparatus according to the high frequency band signal, an LPC coefficient and a full band excitation signal that are used to predict a full band signal; and performing, by the coding apparatus, coding processing on the LPC coefficient and the full band excitation signal to obtain the first full band signal. With reference to any one of the first aspect or the first or the second possible implementation manner of the first aspect, in a third possible implementation manner of the first aspect, the performing, by the coding apparatus, de-emphasis processing on the first full band signal includes: performing, by the coding apparatus, frequency spectrum movement correction on the first full band signal, and performing frequency spectrum reflection processing on the corrected first full band signal; and performing, by the coding apparatus, the de-emphasis processing on the first full band signal that has undergone frequency spectrum reflection processing. With reference to any one of the first aspect or the first to the third possible implementation manners of the first aspect, in a fourth possible implementation manner of the first aspect, the characteristic factor is used to reflect a characteristic of the audio signal, and includes a voicing factor, a spectral tilt, a short-term average energy, or a short-term zero-crossing rate. According to a second aspect, the present application provides a decoding method, including: receiving, by a decoding apparatus, an audio signal bitstream sent by a coding apparatus, where the audio signal bitstream includes high frequency band coding information and an energy ratio of an audio signal corresponding to the audio signal bitstream; obtaining a characteristic factor according to the bitstream; performing, by the decoding apparatus, low frequency band decoding on the audio signal bitstream by using the characteristic factor to obtain a low frequency band signal; performing, by the decoding apparatus, high frequency band decoding on the audio signal bitstream by using the high frequency band coding information to obtain a high frequency band signal; performing, by the decoding apparatus, spread spectrum prediction on the high frequency band signal to obtain a first full band signal; performing, by the decoding apparatus, de-emphasis processing on the first full band signal, where a de-emphasis parameter of the de-emphasis processing is determined according to the characteristic factor; calculating, by the decoding apparatus, a first energy of the first full band signal that has undergone de-emphasis processing; obtaining, by the decoding apparatus, a second full band signal according to the energy ratio included in the audio signal bitstream, the first full band signal that has undergone de-emphasis processing, and the first energy, where the energy ratio is an energy ratio of an energy of the second full band signal to the first energy; and restoring, by the decoding apparatus, the audio signal corresponding to the audio signal bitstream according to the second full band signal, the low frequency band signal, and the high frequency band signal. With reference to the second aspect, in a first possible implementation manner of the second aspect, the method further includes: obtaining, by the decoding apparatus, a quantity of characteristic factors through decoding; determining, by the decoding apparatus, an average value of the characteristic factors according to the characteristic factors and the quantity of the characteristic factors; and determining, by the decoding apparatus, the de-emphasis parameter according to the average value of the characteristic factors. With reference to the second aspect or the first possible implementation manner of the second aspect, in a second possible implementation manner of the second aspect, the performing, by the decoding apparatus, spread spectrum prediction on the high frequency band signal to obtain a first full band signal includes: determining, by the decoding apparatus according to the high frequency band signal, an LPC coefficient and a full band excitation signal that are used to predict a full band signal; and performing, by the decoding apparatus, coding processing on the LPC coefficient and the full band excitation signal to obtain the first full band signal. With reference to any one of the second aspect or the first or the second possible implementation manner of the second aspect, in a third possible implementation manner of the second aspect, the performing, by the decoding apparatus, de-emphasis processing on the first full band signal includes: performing, by the decoding apparatus, frequency spectrum movement correction on the first full band signal, and performing frequency spectrum reflection processing on the corrected first full band signal; and performing, by the decoding apparatus, the de-emphasis processing on the first full band signal that has undergone frequency spectrum reflection processing. With reference to any one of the second aspect or the first to the third possible implementation manners of the second aspect, in a fourth possible implementation manner of the second aspect, the characteristic factor is used to reflect a characteristic of the audio signal, and includes a voicing factor, a spectral tilt, a short-term average energy, or a short-term zero-crossing rate. According to a third aspect, the present application provides a coding apparatus, including: a first coding module, configured to code a low frequency band signal of an input audio signal to obtain a characteristic factor of the input audio signal; a second coding module, configured to perform coding and spread spectrum prediction on a high frequency band signal of the input audio signal to obtain a first full band signal; a de-emphasis processing module, configured to perform de-emphasis processing on the first full band signal, where a de-emphasis parameter of the de-emphasis processing is determined according to the characteristic factor; a calculation module, configured to calculate a first energy of the first full band signal that has undergone de-emphasis processing; a band-pass processing module, configured to perform band-pass filtering processing on the input audio signal to obtain a second full band signal, where the calculation module is further configured to calculate a second energy of the second full band signal; and calculate an energy ratio of the second energy of the second full band signal to the first energy of the first full band signal; and a sending module, configured to send to a decoding apparatus, a bitstream resulting from coding the input audio signal, where the bitstream includes the high frequency band coding information and the energy ratio of the input audio signal. With reference to the third aspect, in a first possible implementation manner of the third aspect, the coding apparatus further includes a de-emphasis parameter determining module, configured to: obtain a quantity of characteristic factors; determine an average value of the characteristic factors according to the characteristic factors and the quantity of the characteristic factors; and determine the de-emphasis parameter according to the average value of the characteristic factors. With reference to the third aspect or the first possible implementation manner of the third aspect, in a second possible implementation manner of the third aspect, the second coding module is configured to: determine, according to the high frequency band signal, an LPC coefficient and a full band excitation signal that are used to predict a full band signal; and perform coding processing on the LPC coefficient and the full band excitation signal to obtain the first full band signal. With reference to any one of the third aspect or the first or the second possible implementation manner of the third aspect, in third possible implementation manner of the third aspect, the de-emphasis processing module is configured to: perform frequency spectrum movement correction on the first full band signal obtained by the second coding module, and perform frequency spectrum reflection processing on the corrected first full band signal; and perform the de-emphasis processing on the first full band signal that has undergone frequency spectrum reflection processing. With reference to any one of the third aspect or the first to the third possible implementation manners of the third aspect, in a fourth possible implementation manner of the third aspect, the characteristic factor is used to reflect a characteristic of the audio signal, and includes a voicing factor, a spectral tilt, a short-term average energy, or a short-term zero-crossing rate. According to a fourth aspect, the present application provides a decoding apparatus, including: a receiving module, configured to receive an audio signal bitstream sent by a coding apparatus, where the audio signal bitstream includes high frequency band coding information and an energy ratio of an audio signal corresponding to the audio signal bitstream; obtaining a characteristic factor according to the bitstream; a first decoding module, configured to perform low frequency band decoding on the audio signal bitstream by using the characteristic factor to obtain a low frequency band signal; a second decoding module, configured to: perform high frequency band decoding on the audio signal bitstream by using the high frequency band coding information to obtain a high frequency band signal, and perform spread spectrum prediction on the high frequency band signal to obtain a first full band signal; a de-emphasis processing module, configured to perform de-emphasis processing on the first full band signal, where a de-emphasis parameter of the de-emphasis processing is determined according to the characteristic factor; a calculation module, configured to calculate a first energy of the first full band signal that has undergone de-emphasis processing; and obtain a second full band signal according to the energy ratio included in the audio signal bitstream, the first full band signal that has undergone de-emphasis processing, and the first energy, where the energy ratio is an energy ratio of an energy of the second full band signal to the first energy; and a restoration module, configured to restore the audio signal corresponding to the audio signal bitstream according to the second full band signal, the low frequency band signal, and the high frequency band signal. With reference to the fourth aspect, in a first possible implementation manner of the fourth aspect, the decoding apparatus further includes a de-emphasis parameter determining module, configured to: obtain a quantity of characteristic factors through decoding; determine an average value of the characteristic factors according to the characteristic factors and the quantity of the characteristic factors; and determine the de-emphasis parameter according to the average value of the characteristic factors. With reference to the fourth aspect or the first possible implementation manner of the fourth aspect, in a second possible implementation manner of the fourth aspect, the second decoding module is configured to: determine, according to the high frequency band signal, an LPC coefficient and a full band excitation signal that are used to predict a full band signal; and perform coding processing on the LPC coefficient and the full band excitation signal to obtain the first full band signal. With reference to any one of the fourth aspect or the first or the second possible implementation manner of the fourth aspect, in third possible implementation manner of the fourth aspect, the de-emphasis processing module is configured to: perform frequency spectrum movement correction on the first full band signal, and perform frequency spectrum reflection processing on the corrected first full band signal; and perform the de-emphasis processing on the first full band signal that has undergone frequency spectrum reflection processing. With reference to any one of the fourth aspect or the first to the third possible implementation manners of the fourth aspect, in a fourth possible implementation manner of the fourth aspect, the characteristic factor is used to reflect a characteristic of the audio signal, and includes a voicing factor, a spectral tilt, a short-term average energy, or a short-term zero-crossing rate. According to a fifth aspect, the present application provides a coding/decoding system, including the coding apparatus according to any one of the third aspect or the first to the fourth possible implementation manners of the third aspect and the decoding apparatus according to any one of the fourth aspect or the first to the fourth possible implementation manners of the fourth aspect. According to the codec method, apparatus, and system provided in the embodiments of the present application, de-emphasis processing is performed on a full band signal by using a de-emphasis parameter determined according to a characteristic factor of an input audio signal, and then the full band signal is coded and sent to a decoder, so that the decoder performs corresponding de-emphasis decoding processing on the full band signal according to the characteristic factor of the input audio signal and restores the input audio signal. This application implements adaptive de-emphasis processing on the full band signal according to the characteristic factor of the audio signal to enhance coding performance, so that the input audio signal restored by the decoder has relatively high fidelity and is closer to an original signal.
G10L1912
20170906
20171228
74048.0
G10L1912
1
JACKSON, JAKIEDA R
CODING/DECODING METHOD, APPARATUS, AND SYSTEM FOR AUDIO SIGNAL
UNDISCOUNTED
1
CONT-ACCEPTED
G10L
2,017
15,696,662
ACCEPTED
TOPICAL GEL COMPOSITIONS INCLUDING POLYCAPROLACTONE POLYMER AND METHODS FOR ENHANCING THE TOPICAL APPLICATION OF A BENEFIT AGENT
A composition comprising: a benefit agent; at least one polymer including a polycaprolactone polymer; at least one lower alcohol; and at least one co-solvent; and a method for enhancing topical delivery of a benefit agent is disclosed.
1-23. (canceled) 24. method for enhancing the topical application of a benefit agent which comprises topically administering to a human or animal a gel composition comprising minoxidil in an amount from about 1% to about 5% by weight of the composition; polycaprolactone diol in an amount from about 1% to about 10% by weight of the composition; ethyl alcohol in an amount from about 5% to about 40% by weight of the composition; and glycerin in an amount from about 5% to about 20% by weight of the composition. 25. The method according to claim 36 wherein the polycaprolactone diol is in an amount from about 1% to about 5% by weight of the composition; the ethyl alcohol is in an amount from about 10% to about 30% by weight of the composition; and the glycerin is in an amount from about 10% to about 20% by weight of the composition.
The present invention relates to compositions and methods for enhancing the topical application of a benefit agent. The compositions may be gels including a benefit agent, at least one polymer including a polycaprolactone polymer, at least one lower alcohol, and at least one co-solvent. The compositions are useful in topically applied personal care applications. BACKGROUND OF THE INVENTION Liquid compositions for delivering benefit agents are well known. Typical formulations include solutions, emulsions, suspensions and gels. The viscosity may vary based on intended area for application, intended use (leave on or rinse off), or consumer preference. Liquids are typically easy to dispense and spread out. There is a continuing need for improved liquid compositions. There is also a need for compositions that improve skin penetration of benefit agents. U.S. Pat. No. 6,419,913 teaches micellar compositions that enhance skin penetration. Although effective, these compositions can be difficult to manufacture and the cost of the products are relatively high. Polycaprolactone (PCL) is a polymer used for implantable/injectable drug delivery systems for medical implants (M. A. Woodruff & D. W. Hutmacher, The return of a forgotten polymer—Polycaprolactone in the 21st century, Progress in Polymer Science, Vol. 35 (10), 2010, pages 1217-1256), or as a carrier to encapsulate or immoblize a drug for sustained release purpose (H. I. Chang, et. al, Delivery of the antibiotic gentamicin sulphate from precipitation cast matrices of polycaprolactone, J. Controlled Release, Vol. 110, 2:10, 2006, pages 414-421). However, PCL has not been shown as a skin permeation enhancing component in a topical composition to enhance a topical applied drug to penetrate into the intact skin. Applicants have now discovered novel compositions and a method of enhancing the topical application of benefit agents. The compositions include gels including a benefit agent, at least one polymer including a polycaprolactone polymer, at least one lower alcohol, at least one co-solvent and water. The compositions can be used in cosmetic, skin care, wound care, dermatologic, and other personal care products, as well as in other applications and industries. SUMMARY OF THE INVENTION The invention provides a topical composition comprising at least one polycaprolactone polymer, at least one lower alcohol, and at least one co-solvent. The invention also provides a personal care composition comprising the above composition and a method for enhancing the topical application of a benefit agent. DETAILED DESCRIPTION OF THE INVENTION As used herein, unless otherwise specified, all percentages are by weight based on the total weight of composition referred to. The disclosures of all patents and published applications referred to herein are incorporated by reference in their entirety. As used herein, “benefit agent” is a compound (e.g., a synthetic compound or a compound isolated from a natural source) that has a cosmetic or therapeutic effect on tissue (e.g., a material capable of exerting a biological effect on the human body) such as therapeutic drugs or cosmetic agents. Examples of benefit agents include small molecules, peptides, proteins, nucleic acid materials, and nutrients such as minerals and extracts. The amount of the benefit agent used will depend on the benefit agent and/or the intended use of the end product. Benefit agents may be liquid, solid, or semi-solid. As used herein, “pharmaceutically acceptable,” “cosmetically acceptable,” or “dermatologically acceptable” means suitable for use in contact with tissues (e.g., the skin, hair, mucosa, epithelium or the like) without undue toxicity, incompatibility, instability, irritation, or allergic response. As used herein, “safe and effective amount” means an amount sufficient to provide a desired benefit at a desired level, but low enough to avoid serious undesirable side effects. The safe and effective amount of the ingredient or composition will vary with the area being treated, the age of the end user, the duration and nature of the treatment, the specific ingredient or composition employed, the particular carrier utilized, and like factors. As used herein, the term “treating” or “treatment” means the alleviation or elimination of symptoms, cure, prevention, or inhibition of a disease or medical condition, or improvement of tissue growth/healing or cosmetic conditions such as reducing appearance of skin wrinkles/fine lines, under-eye bags, cellulites, skin marks/hyperpigmentation or uneven tone. To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about”. It is understood that whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value. To provide a more concise description, some of the quantitative expressions herein are recited as a range from about amount X to about amount Y. It is understood that wherein a range is recited, the range is not limited to the recited upper and lower bounds, but rather includes the full range from about amount X through about amount Y, or any amount or range therein. The polymers used to make the compositions of the present invention include a polycaprolactone polymer. The polycaprolactone polymer can be selected from the group consisting of hydroxypolycaprolactone; polycaprolactone diol (α, ω-dihydroxy poly(ε-caprolactone)); polycaprolactone triol; α, ω-dihydroxy oligo(ε-caprolactone); α-carboxy, ω-hydroxy poly(ε-caprolactone) α, ω-dicarboxy poly(ε-caprolactone) and mixtures thereof. Polycaprolactone [poly(ε-caprolactone)] can be made by a ring opening polymerization of the lactone monomer ε-caprolactone using an alcohol, such as dodecanol, as an initiator and a catalyst, such as stannous octoate. The resulting polymer contains an alkyl functionality at one end and an alcohol functionality at the other. If however the initiator is chosen to be a diol, both ends of the formed polymer will be hydroxy terminated. Polycaprolactone made by ring-opening polymerization using either a monol or a diol as initiator will be linear in molecular structure. The relative molar amount of the initiator present during the polymerization controls the molecular weight of the formed polymer. The higher the relative amount of initiator, the lower the molecular weight of the formed polymer. It is possible to produce polycaprolactone without hydroxyl groups at the chain ends. This could be accomplished by capping the chain ends, using for instance succinic anhydride to result in a carboxy end group instead of a hydroxyl end group, as part of the synthesis of the resin. α, ω-dicarboxy poly(ε-caprolactone) can be made by using a diol such as diethylene glycol as the polymerization initiator followed by reaction with a cyclic anhydride such as diglycolic anhydride or succinic anhydride; an alternate route to this polymer is using a hydroxy acid such as glycolic acid as the polymerization initiator followed by reaction with a cyclic anhydride such as diglycolic anhydride or succinic anhydride. Additionally the polycaprolactone polymer can be a hydroxylated polycaprolactone polymer. The polymer may have between 1 and 3 hydroxyl substitutions. The polymer can be a hydroxypolycaprolactone, polycaprolactone diol; polycaprolactone triol and mixtures thereof. The polycaprolactone triol can be made by using a triol initiator, such as glycerol, or trimethylolpropane (TMP); polycaprolactone triol does not possess a linear structure but is a branched polymer. Compositions of the present invention preferably include a polycaprolactone diol polymer. The polycaprolactone diol polymer molecular weight may range from about 500 Dalton to about 50,000 Dalton, for example from about 1,000 Dalton to about 5,000 Dalton, or from about 1,200 Dalton to about 2,500 Dalton, or from about 1,250 Dalton to about 2,000 Dalton. The amount of the polymer is sufficient to form a gel and may range from about 0.05% to about 20%, or from 0.1% to about 20%, or from about 0.5% to about 10%, or from about 1% to about 10%, or from about 1% to about 5% by weight based on the total weight of the composition. The methods for measuring the molecular weight are those known in the art. The topical compositions of the present invention also include at least one lower alcohol. Suitable alcohols include ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, amyl alcohol, benzyl alcohol, octyldocanol, hexyldecanol, butyloctanol, and mixtures thereof. The amount of alcohol may range from about 2% to about 90% or from about 5% to about 80%, or from about 5% to about 40%, or from about 10% to about 30%, or from about 15% to about 25% by weight based on the total weight of the composition. Compositions according to the present invention also include a co-solvent. Suitable co-solvents include one or more polyols. Such polyols include, but are not limited to glycerol (glycerin), polyglycerols, glycols, polyglycols, and mixtures thereof. Examples of polyglycerols include, but are not limited to diglycerol (diglycerin), triglycerol (polyglcerin-3 or polyglycerol-3), tetraglycerol (polyglycerin-4 or polyglycerol-4), other polyglycerols (polycerol-n, where n>4), and mixtures thereof. Examples of glycols include, but are not limited to propylene glycol, ethylene glycol, butylene glycol and its isomers (e.g., 1,2-butanediol, 1,3-butanediol, 1,4-butanediol and 2,3-butanediol), pentylene glycol, hexylene glycol and its isomers, propanediol, dipropylene glycol, ethoxydiglycol, methylpropanediol, isopentyldiol, and mixtures thereof. Examples of polyglycols include, but are not limited to, polyethylene glycol of various molecular weights, namely, molecular weights ranging from 300 g/mol to 10,000,000 g/mol, (e.g., PEG-200, PEG-400, PEG-1000, PEG-2000 PEG-4000, PEG-6000), polypropylene glycol (PPG) of various molecular weights, and mixtures thereof. The amount of co-solvent may range from about 1% to about 50%, or from about 5% to about 50%, or from about 10% to about 40% or from about 10% to about 20% by weight based on the total weight of the composition. The compositions of the present invention may also include water. The amount of water may range from about 20% to about 80%, or from about 30% to about 60%, or from about 40% to about 50% by weight based on the total weight of the composition. In one embodiment, the composition may further comprise at least one hydrophilic polymer, e.g., natural or synthetic hydrophilic polymers. Such hydrophilic polymer may be soluble or partially soluble in the gel. Suitable hydrophilic polymers include, but are not limited to, homo- and copolymers of vinyl pyrrolidone (e.g., PVP, or PVP/PVA copolymer), homo- or copolymers of vinyl alcohol (e.g., polyvinyl alcohol or PVA), polyacrylamide, homo- or copolymers of acrylic and/or methacrylic acids, and salts and esters thereof (e.g., CARBOPO/CARBOMER 934, 940, 941, 980, 1342, and 1382, and ULTREZ 10 and 21), cellulosic polymers (e.g., hydroxymethylcellulose, hydroxyethyl cellulose, carboxy methyl cellulose, carboxy ethyl cellulose), polyurethanes, starch and its derivatives, and synthetic and natural gums (e.g., gum arabic or xanthan gum). Preferred hydrophilic polymers are acrylate polymers and copolymers, particularly polyacrylate neutralized by anhydrous neutralizers. If used, the amount of the hydrophilic polymer is usually up to about 10%, or equal to or less than about 5%, or equal to or less than about 3%, or equal to or less than about 2%, by weight of the composition. In general, the topical composition may contain any additional ingredients (e.g., benefit agents or formulation excipients) soluble or dispersible in the gel or its components. Pharmaceutically or cosmetically acceptable benefit agents or excipients, such as extracts of plants or minerals, natural or synthetic compounds of small molecular weight or polymers, acids or bases (particularly week acids or bases) for acidity adjustment, buffers, chelators, antioxidants, thickeners or gelling agents can be used. The topical composition has great versatility in application, and can be used in many consumer and medical products for human and animal use such topical compositions (such as creams, lotions, gels, shampoos, cleansers, powders patches, bandages, and masks for application to the skin or mucosal membranes), garments (such as undergarments, underwear, bras, shirts, pants, pantyhose, socks, head caps, facial masks, gloves, and mittens), linens (such as towels, pillow covers or cases and bed sheets), sanitizing products for household and clinical settings, microcides for plants, and devices (such as toothbrushes, dental flosses, periodontal implants or inserts, orthodontic braces, joint wraps/supports, buccal patches, ocular inserts or implants such as contact lenses, nasal implants or inserts, and contact lens cleaning products, wound dressings, diapers, sanitary napkins, wipes, tampons, rectal and vaginal suppositories, and in coatings or embedded surfaces on medical devices and other surfaces where antimicrobial or other beneficial effects are desired). The topical composition may be any form suitable for application to the skin or an animal or human. The forms may include gels, solutions, lotions, ointments, mousses, foams, sprays, aerosols, shampoos, creams, pastes or other topical composition forms known in the art. When applied to the skin the topical composition is formulated to be readily absorbed into the skin with minimal amount of rubbing. The composition provides an easy to apply topical composition that can be used to delivery numerous benefit agents to the skin. The topical composition can be incorporated onto fibers, nonwovens, hydrocolloids, adhesives, films, polymers, and other substrates. In one embodiment, the composition is in contact with a tissue interface. Methods of applying the composition on substrates include spray coating, co-extrusion, and adhesive spraying. The topical composition may contain a wide range of benefit agents used for various applications as described in the sections below. The composition may be administered topically, locally (via buccal, nasal, rectal or vaginal route) to a subject (e.g., a human) in need of treatment for a condition or disease, or to otherwise provide a therapeutic effect. Such therapeutic effects include, but are not limited to: antimicrobial effects (e.g., antibacterial, antifungal, antiviral, and anti-parasitic effects); anti-inflammation effects including effects in the superficial or deep tissues (e.g., reduce or elimination of soft tissue edema or redness); elimination or reduction of pain, itch or other sensory discomfort; regeneration or healing enhancement of hard tissues (e.g., enhancing growth rate of the nail or regrowth of hair loss due to alopecia) or increase soft tissue volume (e.g., increasing collagen or elastin in the skin or lips); increasing adipocyte metabolism or improving body appearance (e.g., effects on body contour or shape, and cellulite reduction); and increasing circulation of blood or lymphocytes. In one embodiment, the composition further contains a safe and effective amount of a benefit agent, for example, from about 0.001% to about 20%, or from about 0.01% to about 10%, or from about 1% to about 5% by weight of the composition of the benefit agent. In one embodiment, the invention provides a topical composition containing the composition that is suitable for administering to mammalian skin, such as human skin. In one embodiment, such topical composition contains a safe and effective amount of (i) the composition, and (ii) a cosmetically- or pharmaceutically-acceptable carrier. The topical compositions may be made into a wide variety of products that include but are not limited to leave-on products (such as lotions, creams, gels, sticks, sprays, and ointments), skin cleansing products (such as liquid washes, solid bars, and wipes), hair products (such as shampoos, conditioners, sprays, and mousses), shaving creams, film-forming products (such as masks), make-up (such as foundations, eye liners, and eye shadows), deodorant and anti-perspirant compositions, and the like. These product types may contain any of several cosmetically- or pharmaceutically-acceptable carrier forms including, but not limited to solutions, suspensions, emulsions such as microemulsions and nanoemulsions, gels, and solids carrier forms. Other product forms can be formulated by those of ordinary skill in the art. In one embodiment, the topical composition is used for the treatment of skin conditions. Examples of such skin conditions include, but are not limited to acne (e.g., blackheads and whiteheads), rosacea, nodule-cystic, and other microbial infections of the skin; visible signs of skin aging (e.g., wrinkles, sagging, sallowness, and age-spots); loose or lax skin, folliculitis and pseudo-folliculitis barbae; excess sebum (e.g., for sebum reduction or oily/shining skin appearance inhibition or control); pigmentation (e.g., for reduction of hyperpigmentation such as freckles, melasma, actinic and senile lentigines, age-spots, post-inflammatory hypermelanosis, Becker's naevus, and facial melanosis or enhancing the pigmentation of light skin); excess hair growth (e.g., skin on the leg), or insufficient hair growth (e.g., on the scalp); dermatitis (e.g., atopic, contact, or seborrheic dermatitis), dark circles under the eye, stretch marks, cellulite, excessive sweating (e.g., hyperhidrosis), and/or psoriasis. (a) Topical Anti-Acne/Anti-Rosacea Compositions In one embodiment, the topical composition also contains an anti-acne and/or anti-rosacea active agent. Examples of anti-acne and anti-rosacea agents include, but are not limited to: retinoids such as tretinoin, isotretinoin, motretinide, adapalene, tazarotene, azelaic acid, and retinol; salicylic acid; resorcinol; sulfacetamide; urea; antibiotics such as tetracycline, clindamycin, metronidazole, and erythromycin; anti-inflammatory agents such as corticosteroids (e.g., hydrocortisone), ibuprofen, naproxen, and hetprofen; and imidazoles such as ketoconazole and elubiol; and salts and prodrugs thereof. Other examples of anti-acne active agents include essential oils, alpha-bisabolol, dipotassium glycyrrhizinate, camphor, ρ-glucan, allantoin, feverfew, flavonoids such as soy isoflavones, saw palmetto, chelating agents such as EDTA, lipase inhibitors such as silver and copper ions, hydrolyzed vegetable proteins, inorganic ions of chloride, iodide, fluoride, and their nonionic derivatives chlorine, iodine, fluorine, and synthetic phospholipids and natural phospholipids such as ARLASILK™ phospholipids CDM, SV, EFA, PLN, and GLA (commercially available from Uniqema, ICI Group of Companies, Wilton, UK). (b) Topical Anti-Aging Compositions In one embodiment, the topical composition also contains an anti-aging agent. Examples of suitable anti-aging agents include, but are not limited to; retinoids; dimethylaminoethanol (DMAE), copper containing peptides, vitamins such as vitamin E, vitamin A (retinol and its derivatives, e.g., retinyl palmitate), vitamin C (ascorbic acid and its derivative, e.g., Ascorbic Acid 2-Glucoside/AA2G), and vitamin B (e.g., niacinamide, niacin) and vitamin salts or derivatives such as ascorbic acid di-glucoside and vitamin E acetate or palmitate; alpha hydroxy acids and their precursors such as glycolic acid, citric acid, lactic acid, malic acid, mandelic acid, ascorbic acid, alpha-hydroxybutyric acid, alpha-hydroxyisobutyric acid, alpha-hydroxyisocaproic acid, atrrolactic acid, alpha-hydroxyisovaleric acid, ethyl pyruvate, galacturonic acid, glucoheptonic acid, glucoheptono 1,4-lactone, gluconic acid, gluconolactone, glucuronic acid, glucuronolactone, isopropyl pyruvate, methyl pyruvate, mucic acid, pyruvic acid, saccharic acid, saccharic acid 1,4-lactone, tartaric acid, and tartronic acid; beta hydroxy acids such as beta-hydroxybutyric acid, beta-phenyl-lactic acid, and beta-phenylpyruvic acid; tetrahydroxypropyl ethylenediamine, N,N,N′,N′-Tetrakis(2-hydroxypropyl)ethylenediamine (THPED); and botanical extracts such as green tea, soy, milk thistle, algae, aloe, angelica, bitter orange, coffee, goldthread, grapefruit, hoellen, honeysuckle, Job's tears, lithospermum, mulberry, peony, puerarua, nice, and safflower; and salts and prodrugs thereof. (c) Topical Depigmentation Compositions In one embodiment, the topical composition contains a depigmentation agent. Examples of suitable depigmentation agents include, but are not limited to: soy extract; soy isoflavones; retinoids such as retinol; kojic acid; kojic dipalmitate; hydroquinone; arbutin; transexamic acid; vitamins such as niacinamide, niacin and vitamin C (ascorbic acid and AA2G; azelaic acid; linolenic acid and linoleic acid; placertia; licorice; and extracts such as chamomile, grape seeds and green tea; and salts and prodrugs thereof. (d) Topical Antipsoriatic Compositions In one embodiment, the topical composition contains an antipsoriatic active agent. Examples of antipsoriatic active agents (e.g., for seborrheic dermatitis treatment) include, but are not limited to, corticosteroids (e.g., betamethasone dipropionate, betamethasone valerate, clobetasol propionate, diflorasone diacetate, halobetasol propionate, triamcinonide, dexamethasone, fluocinonide, fluocinolone acetonide, halcinonide, triamcinolone acetate, hydrocortisone, hydrocortisone verlerate, hydrocortisone butyrate, aclometasone dipropionte, flurandrenolide, mometasone furoate, methylprednisolone acetate), methotrexate, cyclosporine, calcipotriene, anthraline, shale oil and derivatives thereof, elubiol, ketoconazole, coal tar, salicylic acid, zinc pyrithione, selenium sulfide, hydrocortisone, sulfur, menthol, and pramoxine hydrochloride, and salts and prodrugs thereof (e) Other Topical Ingredients In one embodiment, the topical composition contains a plant extract as a benefit agent. Examples of plant extracts include, but are not limited to, feverfew, soy, glycine soja, oatmeal, what, aloe vera, cranberry, witch-hazel, alnus, arnica, artemisia capillaris, asiasarum root, birch, calendula, chamomile, cnidium, comfrey, fennel, galla rhois, hawthorn, houttuynia, hypericum, jujube, kiwi, licorice, magnolia, olive, peppermint, philodendron, salvia, sasa albo-marginata, natural isoflavonoids, soy isoflavones, and natural essential oils. In one embodiment, the topical composition contains one or more buffering agents such as citrate buffer, phosphate buffer, lactate buffer, gluconate buffer, or gelling agent, thickener, or polymer. In one embodiment, the composition or product contains a fragrance effective for reducing stress, calming, and/or affecting sleep such as lavender and chamomile. The composition can be incorporated into compositions for the treatment of periodontal disease with actives such as, but not limited to minocycline. In one embodiment, the composition is incorporated into wound dressings or bandages to provide healing enhancement or scar prevention. Wounds or lesions that may be treated include, but are not limited to acute wounds as well as chronic wounds including diabetic ulcer, venus ulcer, and pressure sores. In one embodiment, the wound dressing or bandage contains a benefit agent commonly used as for topical wound and scar treatment, such as antibiotics, anti-microbials, wound healing enhancing agents, antifungal drugs, anti-psoriatic drugs, and anti-inflammatory agents. Examples of antifungal drugs include but are not limited to miconazole, econazole, ketoconazole, sertaconazole, itraconazole, fluconazole, voriconazole, clioquinol, bifoconazole, terconazole, butoconazole, tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole, undecylenic acid, haloprogin, butenafine, tolnaftate, nystatin, ciclopirox olamine, terbinafine, amorolfine, naftifine, elubiol, griseofulvin, and their pharmaceutically acceptable salts and prodrugs. In one embodiment, the antifungal drug is an azole, an allylamine, or a mixture thereof. Examples of antibiotics (or antiseptics) include but are not limited to mupirocin, neomycin sulfate bacitracin, polymyxin B, 1-ofloxacin, tetracyclines (chlortetracycline hydrochloride, oxytetracycline-10 hydrochloride and tetrachcycline hydrochloride), clindamycin phosphate, gentamicin sulfate, metronidazole, hexylresorcinol, methylbenzethonium chloride, phenol, quaternary ammonium compounds, tea tree oil, and their pharmaceutically acceptable salts and prodrugs. Examples of antimicrobials include but are not limited to salts of chlorhexidine, such as lodopropynyl butylcarbamate, diazolidinyl urea, chlorhexidene digluconate, chlorhexidene acetate, chlorhexidene isethionate, and chlorhexidene hydrochloride. Other cationic antimicrobials may also be used, such as benzalkonium chloride, benzethonium chloride, triclocarbon, polyhexamethylene biguanide, cetylpyridium chloride, methyl and benzethonium chloride. Other antimicrobials include, but are not limited to: halogenated phenolic compounds, such as 2,4,4′,-trichloro-2-hydroxy diphenyl ether (Triclosan); parachlorometa xylenol (PCMX); and short chain alcohols, such as ethanol, propanol, and the like. In one embodiment, the alcohol is at a low concentration (e.g., less than about 10% by weight of the carrier, such as less than 5% by weight of the carrier) so that it does not cause undue drying of the barrier membrane. Examples of anti-viral agents for viral infections such as herpes and hepatitis, include, but are not limited to, imiquimod and its derivatives, podofilox, podophyllin, interferon alpha, acyclovir, famcyclovir, valcyclovir, reticulos and cidofovir, and salts and prodrugs thereof. Examples of anti-inflammatory agents include, but are not limited to, suitable steroidal anti-inflammatory agents such as corticosteroids such as hydrocortisone, hydroxyltriamcinolone alphamethyl dexamethasone, dexamethasone-phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclarolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylester, fluocortolone, fluprednidene (fluprednylidene)acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenalone acetonide, medrysone, amciafel, amcinafide, betamethasone, chlorprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylproprionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, betamethasone dipropionate, triamcinolone, and salts are prodrugs thereof. In one embodiment, the steroidal anti-inflammatory for use in the present invention is hydrocortisone. A second class of anti-inflammatory agents which is useful in the compositions of the present invention includes the nonsteroidal anti-inflammatory agents. Examples of wound healing enhancing agents include recombinant human platelet-derived growth factor (PDGF) and other growth factors, ketanserin, iloprost, prostaglandin E1 and hyaluronic acid, scar reducing agents such as mannose-6-phosphate, analgesic agents, anesthetics, hair growth enhancing agents such as minoxadil, hair growth retarding agents such as eflornithine hydrochloride, antihypertensives, drugs to treat coronary artery diseases, anticancer agents, endocrine and metabolic medication, neurologic medications, medication for cessation of chemical additions, motion sickness, protein and peptide drugs. In one embodiment, the composition is used, with or without other antifungal active agents, to treat or prevent fungal infections (e.g., dermatophytes such as trichophyton mentagrophytes), including, but not limited to, onychomycosis, sporotrichosis, tinea unguium, tinea pedis (athlete's foot), tinea cruris (jock itch), tinea corporis (ringworm), tinea capitis, tinea versicolor, and candida yeast infection-related diseases (e.g., candida albicans) such as diaper rash, oral thrushm, cutaneous and vaginal candidiasis, genital rashes, Malassezia furfur infection-related diseases such as Pityriasis versicolor, Pityriasis folliculitis, seborrhoeic dermatitis, and dandruff. In another embodiment, the composition is used, with or without other antibacterial active agents, to treat and prevent bacterial infections, including, but not limited to, acne, cellulitis, erysipelas, impetigo, folliculitis, and furuncles and carbuncles, as well as acute wounds and chronic wounds (venous ulcers, diabetic ulcers and pressure ulcers). In another embodiment, the composition is used, with or without other antiviral active agents, to treat and prevent viral infections of the skin and mucosa, including, but not limited to, molluscum contagiosum, warts, herpes simplex virus infections such as cold sores, kanker sores and genital herpes. In another embodiment, the composition is used, with or without other antiparasitic active agents, to treat and prevent parasitic infections, including, but not limited to, hookworm infection, lice, scabies, sea bathers' eruption and swimmer's itch. In one embodiment, the composition is administered to treat ear infections (such as those caused by streptococcus pneumoniae), rhinitis and/or sinusitis (such as caused by Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus and Streptococcus pneumoniae), and strep throat (such as caused by Streptococcus pyogenes). The composition can also be used to stimulate nail growth, enhance nail strength, and reduce nail infection or discoloration. The composition can be incorporated into compositions for the treatment of onychomychosis with actives such as, but not limited to miconazole, econazole, ketoconazole, sertaconazole, itraconazole, fluconazole, voricoriazole, clioquinol, bifoconazole, terconazole, butoconazole, tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole, undecylenic acid, haloprogin, butenafine, tolnaftate, nystatin, ciclopirox olamine, terbinafine, amorolfine, naftifine, elubiol, griseofulvin, and their pharmaceutically acceptable salts and prodrugs. The composition can be incorporated into compositions for improving the look and feel of nails with ingredients such as, but not limited to: biotin, calcium panthotenate, tocopheryl acetate, panthenol, phytantriol, cholecalciferol, calcium chloride, Aloe Barbadensis (Leaf Juice), silk protein, soy protein, hydrogen peroxide, carbamide peroxide, green tea extract, acetylcysteine and cysteine. The composition can be combined with certain active agents for the growth of hair, or improving or thickening of hair of the scalp, eye brow or eye lash, may be used to treat hair conditions topically. Compositions containing drug(s) and/or active agents to stimulate hair growth and/or prevent hair loss and/or regrow hair, including, but not limited to, minoxidil, finasteride, or lumigan may be employed. The composition has a unique advantage over conventional hair treatment compositions due to its excellent flowability. For example, the gel can easily reach the scalp through thinned hair in the case of alopecia treatment. The composition may contain certain analgesic active agents and as such may be prepared for topical treatment of pain, such as pain at or from the back, shoulder, joints, muscle sore/pain, menstrual cramps, or pain from cold sore or canker sore. Benefit agents to relieve pain include, but are not limited to, NonSteroidal Anti-Inflammatory Drugs (NSAIDs) such as ibuprofen, naproxen, salicylic acid, ketoprofen, and diclofenac and their pharmaceutically acceptable salts thereof. Other topical analgesic active agents for treating pain and itch include, but are not limited to, methyl salicylate, menthol, trolamine salicylate, capsaicin, lidocaine, benzocaine, pramoxine hydrochloride, and hydrocortisone. EXAMPLES Examples are set forth below to further illustrate the nature of the invention and the manner of carrying it out. However, the invention should not be considered as being limited to the details thereof. Example 1 Polycaprolactone diol was purchased from Polysciences, Inc. (Warrington, Pa.). One sample was 1,250 Daltons; the other sample was molecular weight 2,000 Daltons. A gel was made with the ingredients in Table 1 and following the procedure below: TABLE 1 Chemical Name Formula A Formula B Formula C Ethyl Alcohol 20.00 20.00 20.00 Pentylene Glycol 4.00 4.00 4.00 Glycerin 12.00 12.00 12.00 Lactic Acid 3.20 3.20 3.20 Minoxidil 5.00 5.00 5.00 Butylated 0.10 0.10 0.10 Hydroxytoluene Water 52.20 49.2 49.2 Steareth-10 1.50 1.5 1.5 Steareth-2 2.00 2.00 2.00 Polycaprolactone diol 0.0 3.0 0.0 (Mwt = 1250) Polycaprolactone diol 0.0 0.0 3.0 (Mwt = 2000) Total 100.00 100.00 100.00 Step 1—20 parts of ethyl alcohol, 4 parts of pentylene glycol, 12 parts of glycerin, 3.2 parts of lactic acid, 0.10 parts of butylated hydroxytoluene, and 5 parts of minoxidil were added to a glass container and mixed until the solution is clear at room temperature. Step 2—In a separate glass container, 49.2 parts of water, 3 parts of polycaprolactone diol (if present), 1.5 parts of steareth-10, and 2 parts of steareth-2 were added. The mixture was heated to about 75° C. to melt the contents and a mixer was used to mix it for 5-10 minutes until completely uniform. After the water phase in step 2 cooled back to room temperature the mix from step #1 was added and, using a high speed homogenizer, the mixture was homogenized for about 5 minutes. Example 2—In Vitro Skin Permeation of 5% Minoxidil Compositions Through Human Cadaver Skin A skin penetration study evaluated the penetration of minoxidil into different skin layers for the inventive samples (Formulas B and C) prepared as disclosed in Example 1 vs. a test sample without the PCL polymer (Formula A). A well-known Franz diffusion cell method (as taught in US20020006418 A1, which is hereby incorporated by reference) was used. Franz cells had a diameter of 0.5 cm2 and a volume of liquid receptor of 5 ml. A magnetic stirrer bar was added in the donor compartment. The liquid receptor was filled with Phosphate-buffered saline (PBS) solution. Air bubbles in the donor compartment were removed. The system was thermostated at 37° C. above a magnetic stirrer to ensure the homogeneity of the liquid receptor during the experiment. A cadaver skin sample from a commercial tissue bank (Ohio Valley Tissue and Skin Center, Cincinnati, Ohio, dermatomed to approximately 0.4 mm) was cut to fit the glass diffusion cell and mounted skin on the Franz cell. A test sample of 20 microliters was applied on the skin surface. Samples were collected from the receptor compartment at scheduled time points of 0, 1, 3 and 6 hours. At the end of the study the skin surface was washed with a cotton swab soaked with PBS (total four times). The cotton swabs were collected for drug analysis later. After washing, D-squame tape (CuDerm Corp., Dallas, Tex.) was used to separate the stratum corneum from epidermis by pressing the tape onto the skin surface and remove it. The same process of tape-stripping was repeated four more times (total 5 times). All the tapes were collected for each skin samples for drug extraction later. Epidermis layer was separated from dermis tissue by pressing the epidermis side of the skin onto a 60° C. hot plate for 1 minute, then peeling off the epidermis layer from the dermis tissue with a pair of forceps. Extraction was performed using methanol as extraction solvent from the collected tapes (drug on and in the stratum corneum), epidermis (drug penetrated into the epidermis tissue) and dermis (drug penetrated into the dermis tissue). Samples collected from the receptor compartment and from the extraction processes, as well as from the washing process were analyzed for minoxidil levels with a Waters High-performance liquid chromatography (HPLC) system with the procedure listed below. The results are shown in Tables 2 and 3. The final average minoxidil levels in different skin layers are reported in micrograms (μg) for 3 different replicates. A minoxidil mass balance study was also conducted and the % of recovery of minoxidil was equal or better than 94% for both the control (Formula A) and the inventive formulations (Formulas B and C). TABLE 2 Time Formula A Formula B Ratio Formula (hr) (microgram) (microgram) B/Formula A Cumulative 0 0 0 0 Minoxidil in 3 14.7 22.3 1.52 Receptor 6 37.3 48.8 1.31 Dermis 6 10.2 10.4 1.02 Epidermis 6 12.7 21.6 1.70 Tapes 6 5.2 12.4 — Wash 6 770 749 — % 6 95% 96% Recovered TABLE 3 Ratio between Time Formula A Formula C Formula C vs. (hr) (microgram) (microgram) Formula A Cumulative 0 0 0 0 Minoxidil in 3 14.7 22.6 1.54 Receptor 6 37.3 50.3 1.35 Dermis 6 10.2 15.0 1.47 Epidermis 6 12.7 21.3 1.68 Tapes 6 5.2 13.5 — Wash 6 770 764 — % 6 95% 94% — Recovered Because the target tissue for topical minoxidil delivery is the hair follicles (hair “roots”) residing deep in the dermis, only minoxidil that penetrated into and across the dermis layer could reach the hair follicles, and therefore, are of practical significance. The cumulative minoxidil in the receptor is the measurement of the total minoxidil that penetrated across all the layers of the skin including the dermis. It is surprising that the gel compositions of the present invention have enhanced minoxidil delivery deep into and across the human skin in comparison to the control formulation with the same drug concentration, as demonstrated by the results in Tables 2 and 3. This is an unexpected finding since all three formulas have the same solvents at the same amounts. HPLC Procedure for Minoxidil Quantification A HPLC System (Waters Alliance® HPLC system) was used to measure minoxidil with UV absorption response at 286 nm. A Luna 5 μM C18(2) 250×4.6-mm HPLC column (Phenomenex) was used to separate the minoxidil analyte from other impurities in the extract samples for surface rinse, stripped tape, epidermis, dermis, and receptor solution. The mobile phase was an isocratic 80% (70:29:1 water/methanol/acetic acid—pH 3.3):20% methanol. Example 3 Polycaprolactone diol was purchased from Polysciences, Inc. (Warrington, Pa.). One sample was 1,250 Daltons; the other sample was molecular weight 2,000 Daltons. Gels were made with the ingredients in Table 4 and following the procedure below: TABLE 4 Chemical Name Formula D Formula E Ethyl Alcohol, USP 20.00 20.00 (95%) Pentylene Glycol 4.00 4.00 Glycerin 12.00 12.00 Sodium Hydroxide 1.00 1.00 Ibuprofen 5.00 5.00 Butylated 0.10 0.10 Hydroxytoluene Water 51.40 51.40 Steareth-10 1.50 1.50 Steareth-2 2.00 2.00 Polycaprolactone diol 1.0 0.0 (Mwt = 1250) Polycaprolactone diol 0.0 1.0 (Mwt = 2000) Sodium Hydroxide (20% Adjust the Adjust the in water) aqueous aqueous phase to phase to pH6 pH6 Water Add To 100 Add To 100 Hydroxypropylcellulose 1.00 1.00 (KLUCEL, HF Pharm) Total 101.00 101.00 Step 1—20 parts of ethyl alcohol, 4 parts of pentylene glycol, 12 parts of glycerin, 0.10 parts of butylated hydroxytoluene, 5 parts of ibuprofen, and 30 parts of purified water were added to a glass container. The pH was adjusted to pH 6 using 20% NaOH aqueous solution at room temperature. The amount of NaOH and water added was recorded. Step 2—1 part of polycaprolactone diol, 1.5 parts of steareth-10, and 2 parts of steareth-2 were added in a separate glass container. The remaining parts of purified water were added until the total amount of the composition was equal to 100 parts. The mixture was heated to about 75° C. to melt the contents, and use a mixer was used to mix it for 5-10 minutes until completely uniform. After the water phase in step 2 cooled back to room temperature the mix from step 1 was added and a high speed homogenizer was used to homogenize the mixture for about 5 minutes. 1 part of hydroxypropylcellulose was added and mixed until a uniform translucent gel was formed. The pH was measured to confirm the final pH of the composition. While the invention has been described above with reference to specific embodiments thereof, it is apparent that many changes, modifications, and variations can be made without departing from the inventive concept disclosed herein. Accordingly, it is intended to embrace all such changes, modifications, and variations that fall within the spirit and broad scope of the appended claims.
<SOH> BACKGROUND OF THE INVENTION <EOH>Liquid compositions for delivering benefit agents are well known. Typical formulations include solutions, emulsions, suspensions and gels. The viscosity may vary based on intended area for application, intended use (leave on or rinse off), or consumer preference. Liquids are typically easy to dispense and spread out. There is a continuing need for improved liquid compositions. There is also a need for compositions that improve skin penetration of benefit agents. U.S. Pat. No. 6,419,913 teaches micellar compositions that enhance skin penetration. Although effective, these compositions can be difficult to manufacture and the cost of the products are relatively high. Polycaprolactone (PCL) is a polymer used for implantable/injectable drug delivery systems for medical implants (M. A. Woodruff & D. W. Hutmacher, The return of a forgotten polymer—Polycaprolactone in the 21st century, Progress in Polymer Science, Vol. 35 (10), 2010, pages 1217-1256), or as a carrier to encapsulate or immoblize a drug for sustained release purpose (H. I. Chang, et. al, Delivery of the antibiotic gentamicin sulphate from precipitation cast matrices of polycaprolactone, J. Controlled Release, Vol. 110, 2:10, 2006, pages 414-421). However, PCL has not been shown as a skin permeation enhancing component in a topical composition to enhance a topical applied drug to penetrate into the intact skin. Applicants have now discovered novel compositions and a method of enhancing the topical application of benefit agents. The compositions include gels including a benefit agent, at least one polymer including a polycaprolactone polymer, at least one lower alcohol, at least one co-solvent and water. The compositions can be used in cosmetic, skin care, wound care, dermatologic, and other personal care products, as well as in other applications and industries.
<SOH> SUMMARY OF THE INVENTION <EOH>The invention provides a topical composition comprising at least one polycaprolactone polymer, at least one lower alcohol, and at least one co-solvent. The invention also provides a personal care composition comprising the above composition and a method for enhancing the topical application of a benefit agent. detailed-description description="Detailed Description" end="lead"?
A61K4734
20170906
20180717
20171221
58626.0
A61K4734
0
BARSKY, JARED
TOPICAL GEL COMPOSITIONS INCLUDING POLYCAPROLACTONE POLYMER AND METHODS FOR ENHANCING THE TOPICAL APPLICATION OF A BENEFIT AGENT
UNDISCOUNTED
1
CONT-ACCEPTED
A61K
2,017
15,699,692
PENDING
COMPOSITIONS AND METHODS FOR TREATING ROSACEA AND ACNE
Provided are compositions and methods for treating rosacea and acne. Specifically, a gel or foam composition having a tetracycline antibiotic and uses thereof for treating rosacea and acne are provided.
1.-228. (canceled) 229. A method for treating acne vulgaris in a subject in need thereof, comprising administering to the subject a topical composition comprising an effective amount of a tetracycline antibiotic and a hydrophobic vehicle formulated such that the systemic plasma exposure to the tetracycline after repeated administration of the topical composition in a once-daily topical application is at least 100 times less than the systemic plasma exposure after a comparable repeated administration of an oral tetracycline 230. The method according to claim 229, wherein the hydrophobic vehicle comprises: about 35% w/w to about 65% w/w of soybean oil; and about 16.5% w/w to about 30.7% w/w of coconut oil. 231. The method according to claim 230, wherein the hydrophobic vehicle further comprises: about 1% w/w to about 5% w/w of light mineral oil; and about 3.5% w/w to about 6.5% w/w of cyclomethicone. 232. The method according to claim 229, wherein the hydrophobic vehicle comprises a wax, a fatty alcohol, a fatty acid, or a mixture thereof. 233. The method according to claim 231, wherein the hydrophobic vehicle further comprises: about 2.5% w/w to about 4.6% w/w of cetostearyl alcohol; about 2% w/w to about 4% of stearic acid; about 1.8% w/w to about 3.3% w/w of myristyl alcohol; about 1% w/w to about 3% w/w of hydrogenated castor oil; about 1% w/w to about 3% w/w of beeswax; about 1% w/w to about 2% w/w of stearyl alcohol; and about 0.5% w/w to about 1.5% w/w of behenyl alcohol. 234. The method according to claim 231, wherein the hydrophobic vehicle comprises: about 50% w/w of soybean oil; about 23.6% w/w of coconut oil; about 5% w/w of cyclomethicone; about 3.5% w/w of cetostearyl alcohol; about 3% of stearic acid; about 2.5% w/w of myristyl alcohol; about 2% w/w of hydrogenated castor oil; about 2% w/w of beeswax; about 2.5% w/w of stearyl alcohol; and about 1.1% w/w of behenyl alcohol. 235. The method according to claim 234, wherein the tetracycline antibiotic comprises minocycline hydrochloride. 236. The method according to claim 235, wherein the effective amount of minocycline hydrochloride is about 0.1% w/w to about 10% w/w. 237. The method according to claim 236, wherein the effective amount of minocycline hydrochloride is about 1% w/w to about 4% w/w. 238. The method according to claim 236, wherein the effective amount of minocycline hydrochloride is about 4%. 239. The method according to claim 229, wherein systemic plasma exposure to the minocycline hydrochloride after administering the topical composition is at least 200 times less than the systemic plasma exposure after a comparable administration of an oral minocycline. 240. The method according to claim 229, wherein systemic plasma exposure to the minocycline hydrochloride after administering the topical composition is at least 400 times less than the systemic plasma exposure after a comparable administration of an oral minocycline. 241. The method according to claim 229, wherein systemic plasma exposure to the minocycline hydrochloride after administering the topical composition is at least 600 times less than the systemic plasma exposure after a comparable administration of an oral minocycline. 242. The method according to claim 229, wherein systemic plasma exposure to the minocycline hydrochloride after administering the topical composition is at least 800 times less than the systemic plasma exposure after a comparable administration of an oral minocycline. 243. The method according to claim 229, wherein the systemic plasma exposure to the minocycline hydrochloride is a mean maximum concentration of the minocycline hydrochloride in the plasma during the 24 hour period following administration. 244. The method according to claim 229, wherein the systemic plasma exposure to the minocycline hydrochloride is calculated by determining the area under a concentration-time curve of the amount of the minocycline hydrochloride in plasma during a 24 hour period. 245. The method according to claim 229, wherein the subject is an adult. 246. The method according to claim 245, wherein the topical composition is administered for 16 days. 247. The method according to claim 245, wherein the topical composition is administered for 21 days. 248. The method according to claim 247, wherein the mean maximum concentration of the minocycline hydrochloride in the plasma is between 0.2 ng/mL and 5 ng/mL. 249. The method according to claim 247, wherein the mean maximum concentration of the minocycline hydrochloride in the plasma is between about 1.1 ng/mL and about 1.5 ng/mL. 250. The method according to claim 247, wherein the mean maximum concentration of the minocycline hydrochloride in the plasma is between about 1.2 ng/mL and about 1.7 ng/mL. 251. The method according to claim 247, wherein the method reduces relative bioavailability of the minocycline hydrochloride as compared to a comparable oral administration of minocycline hydrochloride. 252. The method according to claim 251, wherein the relative bioavailability of the minocycline hydrochloride after 12 days is about 0.126% and after 21 days is about 0.131% based on a geometric least squares mean ratio of mean maximum concentration of the minocycline hydrochloride values in the plasma at a confidence interval of 90%. 253. The method according to claim 251, wherein the relative bioavailability of the minocycline hydrochloride after 12 days is about 0.134% and after 21 days is about 0.137% based on a geometric least squares mean ratio of area under the concentration-time curve of a 24 hour time period after administration of the minocycline hydrochloride concentration values in the plasma at a confidence interval of 90%. 254. The method according to claim 247, wherein a steady state for the topical composition in the plasma after administration is achieved after about 6 days. 255. The method according to claim 247, wherein administration of the topical composition does not result in accumulation of the minocycline hydrochloride in the plasma. 256. The method according to claim 247 wherein the minocycline hydrochloride mean accumulation ratio after topical administration, as compared to a comparable administration of an oral minocycline, is about 0.85 at day 12 and about 0.79 at day 21. 257. The method according to claim 236, wherein administration of the topical composition results in less treatment-related adverse events than a comparable administration of an oral minocycline. 258. The method according to claim 229, wherein the subject is a pediatric subject. 259. The method according to claim 258, wherein the topical composition is administered for 7 days and is safe and/or well-tolerated. 260. The method of claim 259, wherein the mean maximum concentration of the minocycline hydrochloride in the plasma is between about 2 ng/mL and about 4.5 ng/mL. 261. The method of claim 259, wherein the area under the concentration-time curve 24 hours after administration of the minocycline hydrochloride concentration in the plasma is between about 40.8 ng/mL*hour and about 90.9 ng/mL*hour. 262. The method of claim 229, wherein the comparable oral minocycline is at a dose of about 1 mg/kg. 263. A method for treating rosacea in a subject in need thereof, comprising administering to the subject a topical composition comprising an effective amount of a tetracycline antibiotic in a hydrophobic vehicle. 264. The method according to claim 263, wherein the hydrophobic vehicle comprises: about 35% w/w to about 65% w/w of soybean oil; about 16.5% w/w to about 30.7% w/w of coconut oil; about 3.5% w/w to about 6.5% w/w of cyclomethicone; about 1% w/w to about 6% w/w of light mineral oil; about 2.5% w/w to about 4.6% w/w of cetostearyl alcohol; about 2% w/w to about 4% w/w of stearic acid; about 1.8% w/w to about 3.3% w/w of myristyl alcohol; about 1% w/w to about 3% w/w of hydrogenated castor oil; about 1% w/w to about 3% w/w of beeswax; about 1% w/w to about 2% w/w of stearyl alcohol; about 0.5% w/w to about 1.5% w/w of behenyl alcohol; and about 0.1% w/w to about 10% w/w of minocycline hydrochloride, doxycycline hyclate, or a mixture thereof. 265. The method according to claim 264, wherein the composition comprises about 1.5% w/w to about 3% w/w minocycline hydrochloride. 266. The method according to claim 264, wherein administering the topical composition results in at least about 26% reduction in lesions, relative to placebo, after a treatment duration ranging from about two weeks to about twelve weeks. 267. The method according to claim 264, wherein administering the topical composition results in a significant reduction of papules and pustules, relative to treatment with placebo, after a treatment duration ranging from about two weeks to about twelve weeks. 268. The method according to claim 264, wherein the systemic plasma exposure to the minocycline hydrochloride, doxycycline hyclate, or mixture thereof, after administering the topical composition, is at least 200 times less than the systemic plasma exposure after administration of an oral minocycline at a dose of 1 mg/kg. 269. The method according to claim 236, wherein the topical composition comprises about 0.5%, about 1%, about 1.5%, about 3%, about 4%, about 5%, about 6%, or about 7% w/w of a tetracycline. 270. The method according to claim 236, wherein the topical composition further comprises a retinoid. 271. The method according to claim 264, wherein the topical composition further comprises a retinoid. 272. The method according to claim 264, wherein the topical composition is administered once daily. 273. The method according to claim 232, wherein the fatty alcohol comprises a stearyl alcohol. 274. The method according to claim 232, wherein the fatty alcohol comprises a behenyl alcohol. 275. The method according to claim 232, wherein the fatty alcohol comprises a stearyl alcohol, a myristyl alcohol, a behenyl alcohol, a cetostearyl alcohol, or a mixture thereof. 276. The method according to claim 232, wherein the wax comprises a hydrogenated castor oil, a beeswax, or a mixture thereof. 277. The method according to claim 232, wherein the fatty acid comprises a stearic acid. 278. The method according to claim 235, wherein the hydrophobic vehicle contributes to cutaneous bioavailability and the achievement of therapeutic levels of minocycline hydrochloride in the pilosebaceous unit. 279. A method for treating acne vulgaris in a subject in need thereof, comprising administering to the subject a breakable foam obtained from a foamable topical composition comprising an effective amount of a tetracycline antibiotic formulated such that the systemic plasma exposure to the tetracycline after repeated administration of the topical composition in a once-daily topical application is at least 100 times less than the systemic plasma exposure after a comparable administration of an oral tetracycline, wherein the foamable topical composition comprises: a hydrophobic vehicle comprising: about 35% w/w to about 65% w/w of soybean oil; about 16.5% w/w to about 30.7% w/w of coconut oil; about 3.5% w/w to about 6.5% w/w of cyclomethicone; about 1% w/w to about 6% w/w of light mineral oil; about 2.5% w/w to about 4.6% w/w of cetostearyl alcohol; about 2% w/w to about 4% w/w of stearic acid; about 1.8% w/w to about 3.3% w/w of myristyl alcohol; about 1% w/w to about 3% w/w of hydrogenated castor oil; about 1% w/w to about 3% w/w of beeswax; about 1% w/w to about 2% w/w of stearyl alcohol; and about 0.5% w/w to about 1.5% w/w of behenyl alcohol, and a propellant in an amount ranging from about 3% to about 25% w/w.
The present application claims the benefit of priority to U.S. Provisional Patent Application No. 62/385,189 filed Sep. 8, 2016; U.S. Provisional Patent Application No. 62/393,545 filed Sep. 12, 2016; U.S. Provisional Patent Application No. 62/444,960 filed Jan. 11, 2017; and U.S. Provisional Patent Application No. 62/550,158 filed Aug. 25, 2017; the entire contents of each are incorporated herein by reference. BACKGROUND Rosacea is a chronic acneiform disorder affecting skin and potentially the eye. It is a syndrome of undetermined etiology characterized by both vascular and papulopustular components involving the face and occasionally the neck, scalp, ears and upper trunk. Clinical findings include mid facial erythema, telangiectasis, papules and pustules, and sebaceous gland hypertrophy. Rosacea is characterized by episodic flushing of affected areas, which can be triggered by various factors, such as consumption of alcohol, hot drinks, spicy foods or physical exercise. Facial rosacea is classified/graded in multiple clinical forms: (1) erythematotelangiectatic rosacea which is characterized by (semi-) permanent erythema and/or flushing; (2) papulopustular rosacea, characterized by presence of inflammatory lesions such as papules and pustules; (3) phymatous rosacea characterized by circumscribed permanent swelling/thickening of skin areas, typically the nose; and (4) ocular rosacea characterized by the appearance of redness in eyes and eyelids due to telangiectasias and inflammation, feeling of dryness, irritation, or gritty, foreign body sensations, itching, burning, stinging, and sensitivity to light, eyes being susceptible to infection, or blurry vision. Rosacea occurs most commonly in adult life, between the ages of 30 and 60 years. It is very common in skin types I-II (according Fitzpatrick) and more common in Caucasians, with a prevalence of up to 5% in the U.S. and in Europe. It is estimated that from 10 to 20 million Americans have the condition. Topical treatments for rosacea include metronidazole, azelaic acid and brimonidine tartrate. However, approved topical therapies rarely show sufficient clinical efficacy or provide only cosmetic relief for several hours. Mainstays of treatment for rosacea are the oral tetracyclines: doxycycline and minocycline. Low-dose systemic doxycycline (Oracea® resp. Oraycea®) is approved for rosacea whereas systemic minocycline is used in many cases for rosacea off-label. Minocycline is generally regarded as having less photosensitivity than doxycycline. The long-term use of systemic antibiotics is limited by potential liver toxicity, phototoxicity, drug-drug interactions and development of antibacterial resistance. Hence, an efficacious topical tetracycline formulation is highly warranted to close this medical gap. “Acne” is a general term that describes another very common skin disorder, which afflicts many people. The prevalence of adult acne is about 3% in men and between about 11% and 12% in women. Moderate to severe acne is observed in 14% of acne patients. There are various types of acne recognized in the field, including, for example: acne vulgaris and acne conglobata. Acne vulgaris (cystic acne or simply acne) is generally characterized by areas of skin with seborrhea (scaly red skin), comedones (blackheads and whiteheads), papules (pinheads), pustules (pimples), nodules (large papules) and/or possibly scarring. Acne vulgaris may affect the face, the upper part of the chest, and the back. Severe acne vulgaris is inflammatory, but acne vulgaris can also manifest in non-inflammatory forms. Acne conglobata is a severe form of acne, and may involve many inflamed nodules that are connected under the skin to other nodules. Acne conglobata often affects the neck, chest, arms, and buttocks. There are typically three levels of acne vulgaris: mild, moderate, and severe. Mild acne vulgaris is characterized by the presence of few to several papules and pustules, but no nodules. Patients with moderate acne typically have several to many papules and pustules, along with a few to several nodules. With severe acne vulgaris, patients typically have numerous or extensive papules and pustules, as well as many nodules. Acne may also be classified by the type of lesion: comedonal, papulopustular, and nodulocystic. Pustules and cysts are considered inflammatory acne. Mild to moderate acne is often treated topically, using, e.g., retinoids, benzoyl peroxide and some antibiotics. Topical retinoids are comedolytic and anti-inflammatory. Antibiotics such as tetracycline antibiotics are generally only available orally or by injection. Topical antibiotics are mainly used for their role against P. acnes. Benzoyl peroxide products are also effective against P. acnes. Unfortunately, these medications can lack satisfactory safety and efficacy profiles. In one or more embodiments, there are provided herein new and better topical anti-acne treatments and formulations. Diagnosis of acne vulgaris may begin with a visual inspection to determine the presence and amount of comedones, papules, pustules, nodules, and other inflammatory lesions. A diagnosis of acne vulgaris may also be confirmed via clinical laboratory tests, for example, measurement of testosterone levels and performing skin lesion cultures. Systemic antibiotics are generally indicated for moderate or severe acne. The most commonly used systemic antibiotics are tetracycline and their derivatives (e.g., minocycline). These agents have anti-inflammatory properties and they are effective against P. acnes. The more lipophilic antibiotics, such as minocycline and doxycycline, are generally more effective than tetracycline. Greater efficacy may also be due to less P. acnes resistance to minocycline. Oral tetracycline antibiotics are generally not recommended in the treatment of minor mild acne, primarily because they cause hyper-pigmentation, erythema and dryness. Oral tetracycline therapy may induce hyperpigmentation in many organs, including nails, bone, skin, eyes, thyroid, visceral tissue, oral cavity (teeth, mucosa, alveolar bone), sclerae and heart valves. Skin and oral pigmentation have been reported to occur independently of time or amount of drug administration, whereas other tissue pigmentation has been reported to occur upon prolonged administration. Skin pigmentation includes diffuse pigmentation as well as over sites of scars or injury. Oral tetracyclines should not be used for pregnant women or nursing mothers due to teratogenic effects. Accordingly, there exists a need for topical formulations with tetracyclines which can avoid the side effects observed with oral applications. For example, SOLODYN®, a commercially available product, is indicated to treat only inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 12 years of age or older. Adverse side effects from the use of SOLODYN® include, inter alia, diarrhea, dizziness, lightheadedness, and nausea, in addition to allergic reactions, bloody stool, blurred vision, rectal or genital irritation, and red, swollen, blistered, or peeling skin. Because of these side effects, the Food and Drug Administration added oral minocycline to its Adverse Event Reporting System (AERS), a list of medications under investigation by the FDA for potential safety issues. Thus, a product that requires a shorter treatment period, has no or fewer adverse effects, does not cause or causes less skin irritation, and treats both inflammatory and non-inflammatory lesions would be advantageous and could improve patient compliance. There also exists a need for improved compositions and methods for treating rosacea, as well as acne. Provided herein are compositions and methods to address those needs. SUMMARY In one aspect, provided is a method for treating rosacea or acne in a subject in need thereof, the method comprising: administering to said subject a topical composition comprising an effective amount of a tetracycline antibiotic. In another aspect, provided is a hydrophobic gel or foam composition comprising: a tetracycline antibiotic, wherein said tetracycline antibiotic is present in said gel or foam composition in an amount effective to treat rosacea or acne in a subject. In an exemplary embodiment, the gel or foam composition provided herein further comprises at least one hydrophobic solvent, at least one viscosity-modifying agent, or a combination thereof. In some embodiments, the composition comprises silicon dioxide (SiO2). In a particular embodiment, the tetracycline antibiotic is minocycline hydrochloride or doxycycline hyclate, or a combination thereof. In yet another aspect, provided is a method of manufacturing a gel or foam composition having a tetracycline antibiotic, the method comprising: providing a composition having one or more hydrophobic solvents; heating said composition; adding fatty alcohols, fatty acids, and waxes; cooling said composition; adding SiO2; and adding tetracycline antibiotic. In a further aspect, provided is a method for treating rosacea or acne in a subject in need thereof, the method comprising: administering to said subject a topical composition comprising an effective amount of a tetracycline antibiotic, wherein said tetracycline antibiotic is minocycline. In a yet further aspect, provided is a hydrophobic foam or gel composition comprising: about 50% by weight of soybean oil; about 23.6% by weight of coconut oil; about 5% by weight of cyclomethicone; about 2.8 to 4.3% by weight of light mineral oil; about 3.5% by weight of cetostearyl alcohol; about 3% by weight of stearic acid; about 2.5% by weight of myristyl alcohol; about 2% by weight of hydrogenated castor oil; about 2% by weight of beeswax; about 1.5% by weight of stearyl alcohol; about 1.1% by weight of behenyl alcohol; and about 1.5 to 3% by weight of minocycline. In an additional aspect, provided is a method for treating a rosacea in a subject in need thereof, the method comprising: administering to said subject a hydrophobic foam or gel composition comprising about 50% by weight of soybean oil; about 23.6% by weight of coconut oil; about 5% by weight of cyclomethicone; about 2.8 to 4.3% by weight of light mineral oil; about 3.5% by weight of cetostearyl alcohol; about 3% by weight of stearic acid; about 2.5% by weight of myristyl alcohol; about 2% by weight of hydrogenated castor oil; about 2% by weight of beeswax; about 1.5% by weight of stearyl alcohol; about 1.1% by weight of behenyl alcohol; and about 1.5 to 3% by weight of minocycline. In an additional aspect, provided is a method for reducing papules and pustules in a subject in need thereof, the method comprising: administering to said subject a topical composition comprising an effective amount of a tetracycline antibiotic to treat, ameliorate, reduce, or cure acne or rosacea. In an additional aspect, provided is a method for reducing skin lesion in a subject in need thereof, the method comprising: administering to said subject a topical composition comprising an effective amount of a tetracycline antibiotic. In an additional aspect, provided is a method for reducing skin redness in a subject in need thereof, the method comprising: administering to said subject a topical composition comprising an effective amount of a tetracycline antibiotic. In an additional aspect, provided is a method for treating erythema in a subject in need thereof, the method comprising: administering to said subject a topical composition comprising an effective amount of a tetracycline antibiotic. In an additional aspect, provided is a method for treating a rosacea in a subject in need thereof, the method comprising: administering to said subject a placebo topical composition, wherein said composition is free of a tetracycline antibiotic. In an additional aspect, provided is a method for reducing papules and pustules in a subject in need thereof, the method comprising: administering to said subject a placebo topical composition, wherein said composition is free of a tetracycline antibiotic. In an additional aspect, provided is a method for reducing skin lesions in a subject in need thereof, the method comprising: administering to said subject a placebo topical composition, wherein said composition is free of a tetracycline antibiotic. In an additional aspect, provided is a method for reducing skin redness in a subject in need thereof, the method comprising: administering to said subject a placebo topical composition, wherein said composition is free of a tetracycline antibiotic. In an additional aspect, provided is a method for treating erythema in a subject in need thereof, the method comprising: administering to said subject a placebo topical composition, wherein said composition is free of a tetracycline antibiotic. Other features and advantages of the compositions and methods will become apparent from the following detailed description examples and figures. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. BRIEF DESCRIPTION OF THE FIGURES The disclosure will be better understood from a reading of the following detailed description taken in conjunction with the drawings below: FIG. 1A-FIG. 1B show significant decrease in the number of papules and pustules after treatment with a 1.5% and 3% minocycline foam. Specifically, FIG. 1A shows absolute change in papules and pustules, while FIG. 1B shows pecent reduction in papules and pustules. FIG. 2A-FIG. 2B show investigator's global assessment (IGA) results. FIG. 2A shows subjects with IGA improvement ≥2 grades and FIG. 2B shows subjects with IGA improvement of at least two grades which resulted in clear (0) to almost clear (1) score. FIG. 3 shows clinical erythema assessment change from the baseline after 12 weeks of treatment. FIG. 4A-FIG. 4B show mean plasma minocycline concentration vs time profiles following a single oral dose of minocycline during Period 1 (FIG. 4A) and topical application of minocycline foam 4% daily for 21 days during Period 2 (FIG. 4B). FIG. 4 C shows comparison of mean plasma minocycline concentration over the first 24 hours after oral minocycline dose or topical minocycline foam 4% administration over the 24 hours at day 1, day 12 and day 21. Graphs are shown with semi-log scale. FIG. 5 shows mean plasma minocycline pre-dose concentration-vs-time profile for topical minocycline foam 4% from day 1 through day 21 (linear scale). FIG. 6 shows changes in RosaQoL (Rosacea Quality of Life) index score at Week 12 of treatment with two doses of FMX103 (1.5% and 3%) and vehicle foam as compared to baseline (prior to treatment). DETAILED DESCRIPTION Provided herein are compositions and methods for treating rosacea. Specifically, provided herein are gel and foam compositions having a tetracycline antibiotic and uses thereof for treating rosacea and/or acne. The method provided herein includes administering topically to a surface having the disorder a therapeutic hydrophobic composition comprising a tetracycline antibiotic. In one or more embodiments, the hydrophobic composition comprises a carrier comprising about 60% to about 99% by weight of at least one hydrophobic solvent; at least one viscosity-modifying agent selected from the group consisting of a fatty alcohol, a fatty acid and a wax; and a tetracycline antibiotic. In some embodiments, the composition comprises silicon dioxide (SiO2). Further provided herein is a method of treating human skin disorders such as rosacea or rosacea related diseases or disorders by topical application of a foam or gel or liquid gel as described herein to a patient in need thereof. According to one or more embodiments provided herein, the tetracycline is a minocycline or doxycycline, which are semi-synthetic tetracycline antibiotic. In a particular embodiment, the tetracycline is minocycline. The tetracycline drug is usually bacteriostatic in action. It can, among other options, exert its antimicrobial activity by inhibiting protein synthesis. It can also have an antiviral effect. According to one or more embodiments, the minocycline is minocycline hydrochloride (minocycline HCl; hereinafter “MCH”). MCH is a yellow crystalline powder that is sparingly soluble in water, slightly soluble in alcohol and practically insoluble in chloroform and in ether. Minocycline is known to be highly sensitive to air and light and undergoes rapid degradation. Therefore, storage of foamable formulations in airtight sealed containers under pressure with propellant can contribute to preserving stability subject to selection of compatible canisters and accessories. Likewise, production and/or filling under vacuum in an oxygen free environment can help. The ingredients of the carrier are selected for their compatibility with tetracycline antibiotics as described. Since it is not sufficient to identify single ingredients that are compatible with tetracycline antibiotics, formulations had to be found in which the ingredients in combination were also compatible with tetracycline antibiotics. The hydrophobic foamable composition (e.g., foam or gel) provided herein comprises: a) about 60% to about 99% by weight of at least one hydrophobic solvent; b) about 1% to about 22% by weight of at least one viscosity modifying agent; and c) about 0.1% to about 18% of a tetracycline antibiotic (e.g., minocycline HCl or doxycycline). The hydrophobic foamable composition or gel provided herein comprises: a) about 70% to about 90% by weight of at least one hydrophobic solvent; b) about 10 to about 22% by weight of at least one viscosity modifying agent; and c) about 0.5% to about 8% of a tetracycline antibiotic (e.g., minocycline HCl or doxycycline). In one or more embodiments, a hydrophobic foamable composition or gel provided herein comprises: a) about 75% to about 90% by weight of at least one hydrophobic solvent; b) about 10 to about 22% by weight of at least one viscosity modifying agent; and c) about 1% to about 4% of a tetracycline antibiotic (e.g., minocycline HCl or doxycycline). The hydrophobic foamable composition or gel provided herein comprises: a) about 72% to about 88% by weight of at least one hydrophobic solvent; b) about 10 to about 22% by weight of at least one viscosity modifying agent; and c) about 2% to about 6% of a tetracycline antibiotic (e.g., minocycline HCl or doxycycline). According to one or more embodiments, there are provided substantially surfactant-free oleaginous formulations comprising a tetracycline, such as a minocycline, for use in treatment of a rosacea disease, and/or acne related symptoms, and/or a tetracycline antibiotic responsive rosacea related disorder, and/or a tetracycline antibiotic responsive skin disorder, and/or skin disorder caused by a bacteria, and/or a tetracycline antibiotic responsive disorder, and other superficial infections, including skin infections. In one or more embodiments the tetracycline acts to reduce oxidative stress and/or inflammation in skin pathologies. In one or more embodiments the tetracycline is effective where the condition is accompanied by apoptotic cell death. In one or more embodiments, the tetracycline is minocycline HCl at a concentration of about 1.5% or about 3%, or any concentration in between. Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All ranges disclosed herein include the endpoints. The use of the term “or” shall be construed to mean “and/or” unless the specific context indicates otherwise. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. All % values are provided on a weight (w/w) basis. Various carriers and compositions or formulations are described herein. They are often described for use in a method. A reference to or example of a carrier, composition or formulation for use in one method does not in any way limit the carrier, composition or formulation for use just in that method, but it can be for use in any other method or embodiment described herein. The carriers, compositions or formulations described herein are in one or more embodiments provided as carriers, compositions or formulations and are in one or more embodiments provided as a product even where they are described only in relation to their use in a method. As used herein, the term “about” has its usual meaning in the context of pharmaceutical and cosmetic formulations to allow for reasonable variations in amounts that can achieve the same effect. By the term “about” herein it is meant as indicated above and also that a figure or range of figures can vary in an embodiment plus or minus up to 30%. For example, if an amount of “about 1” is provided, then the amount can be up to 1.3 or from 0.70. In other embodiments, it can reflect a variation of plus or minus 20%, in which case “about 2” can reflect a variation of 1.6 to 2.4. In still further embodiments, it can describe a variation of plus or minus 10%, in which case “about 1” can reflect a variation of 0.9 to 1.1. In still further embodiments, it can describe a variation of plus or minus 5%, in which case “about 5” can reflect a variation of 4.75 to 5.25. In cases where “about X” will lead to a figure of above 100%, the term in one or more embodiments can be read as reflecting up to 100% by weight less the total of the minimum amount of the other ingredients. Likewise, it will be appreciated by one skilled in the art to the extent X is reduced from that upper level the amounts of the other ingredients are increased appropriately. As will be appreciated by one of skill in the art, there is some reasonable flexibility in formulating compositions such that where one or more ingredients are varied, successful formulations can still be made even if an amount falls slightly outside the range. Therefore, to allow for this possibility, amounts are qualified by about. In one or more other embodiments, the figures can be read without the term “about.” As used herein, the terms “composition(s)” and “formulation(s)” can be used interchangeably depending on the context in which they are used as would be appreciated by a person skilled in the art. The term “room temperature” as used herein, means 20° C. to 25° C. In an embodiment it is 20° C. In an embodiment it is 21° C. In an embodiment it is 22° C. In an embodiment it is 23° C. In an embodiment it is 24° C. In an embodiment it is 25° C. The term “thixotropic,” as used herein, means that the formulation shows a decrease in viscosity upon application of shear force. The structure of the formulation breaks down, leading to a reduction in viscosity. When the formulation is standing without shear force, this decrease in viscosity is recovered over time. As used herein, the term “gel” means a jelly-like material that can have properties ranging from soft and fluid to hard and tough. Gels can be in a liquid, a semi-liquid, a semi-solid or a solid state. Solid gels are defined as a substantially diluted cross-linked system, which exhibits no flow when in the steady-state. By weight, gels are mostly liquid, yet they behave like semi-solids due to a three-dimensional cross-linked network of a solidifying, gelling or thickening agent within the liquid. It is the crosslinks within the fluid that give a gel its structure (hardness) and contribute to stickiness (tack). Depending on the amounts of gelling agent in a formulation, the gel can be semi-solid with some limited flowability, such that when the semi-solid gel is placed in a tube and is inclined horizontally from a vertical position it will slowly flow from the vertical towards the horizontal or it can be a liquid gel where the amount of gelling agent or gelling effect is lower, such that the gel structure or connections are weaker or loose so that when placed in a tube and tilted from a vertical position to a horizontal position, the gel readily flows and adapts to the horizontal position. The rheological properties of gels at different surface temperatures can influence the release and bioabsorption of drugs therefrom. The term “liquid gel” refers, inter alia, to a formulation after propellant is added (whereas, prior to adding the propellant, the formulation is a gel), or where the gel is loose or fluid or such that when subjected to gravity, it will pour or become liquid. The terms “waterless” or “water-free” as used herein, mean that the composition contains no free or unassociated or absorbed water. The terms “substantially water-free” or “substantially waterless” refer to carriers that contain at most incidental or trace amounts of water. As used herein, “low water” means the composition contains about or less than 1% by weight; about or less than 0.9% by weight; about or less than 0.8% by weight; about or less than 0.7% by weight; or about or less than 0.6% by weight. As used herein, “substantially waterless” or “substantially water free” means the composition contains about or less than 0.5% by weight; about or less than 0.4% by weight; about or less than 0.3% by weight; about or less than 0.2% by weight; or about or less than 0.1% by weight. In one or more embodiments, the composition is “essentially water-free,” meaning about or less than 0.05% by weight; or about or less than 0.01% water is present in the composition, by weight. By the term “single phase” it is meant that after addition of propellant to the composition or carrier, the liquid components of the foamable composition or carrier are fully miscible, and the solid components, if any, are either dissolved or homogeneously suspended in the composition so that only one phase is visible. By the term “substantially a single phase” it is meant that the composition or carrier, after addition of propellant, is primarily or essentially a single phase as explained above, but can also have present a small amount of material which is capable of forming a separate phase amounting to less than about 5% by weight of the composition or carrier after the addition of propellant, or less than about 3% by weight, and/or less than about 1% by weight of the composition. The term “unstable” as used herein, means a compound, e.g., an active agent, which is oxidized and/or degraded within less than a day, and in some cases, in less than an hour, upon exposure to air, light, skin, or water or a pharmaceutical excipient under ambient conditions. The term “unstable active agent” as used herein, means an active agent which is oxidized and/or degraded within less than a day, and in some cases, in less than an hour upon exposure to air, light, skin, water, or a pharmaceutical excipient under ambient conditions. It should be noted that the terms “surfactant,” “surface active agent,” and “emulsifier” in the context used herein, refer to stand alone compounds used to reduce surface tension between two substances or phases, and which are also capable of stabilizing an emulsion of water and oil. Reduction of surface tension can be significant in foam technology in relation to the ability to create small stable bubbles. “Surfactant” and “emulsifier,” as used herein, do not include compounds which do not function effectively as standalone compounds for reducing surface tension between two substances or phases and which are not capable of stabilizing an emulsion of water and oil. For example, a surfactant or emulsifier as provided herein does not include fatty acids, does not include fatty alcohols, and does not include propoxylated lanolin oil derivatives. In the context of the present disclosure, fatty acids and fatty alcohols are defined as foam adjuvants. Similarly, propoxylated lanolin oil derivatives in the context herein are defined as emollients. “Standard surfactant,” “customary surfactant” or “stand alone surfactant” refer to customary non-ionic, ionic, anionic, cationic, zwitterionic, amphoteric and amphiphilic surfactants. Many standard surfactants are derivatives of fatty alcohols or fatty acids, such as ethers or esters formed from such fatty alcohols or fatty acids with hydrophilic moieties, such as polyethylene glycol (PEG). However, a native (non-derivatized) fatty alcohol or fatty acid, as well as waxes are not regarded as a standard surfactant. The term “co-surfactant” as used herein means a molecule which on its own is not able to form and stabilize satisfactorily an oil-in-water emulsion, but when used in combination with a surfactant as defined herein, the co-surfactant has properties which can allow it to help a surfactant create an emulsion and can boost the stabilizing power or effect of the surfactant. Examples of co-surfactants include fatty alcohols, such as cetyl alcohol, or fatty acids, such as stearic acid. Cetyl alcohol is a waxy hydrophobic substance that can be emulsified with water using a surfactant. Some substances can have more than one function and for example, fatty alcohols can in some formulations act as a co-solvent. In certain circumstances, a co-surfactant can itself be converted into a surfactant or soap by, for example, adding a base, such as, triethanolamine to a fatty acid like stearic acid. The term “viscosity-modifying agent” in the context of the present disclosure is an agent which, when added to a hydrophobic oil, facilitates the creation of a hydrophobic breakable vehicle in the form of a breakable gel or breakable foam. According to the present disclosure, the viscosity-modifying agent is a “foamer complex,” which is also referred as a “foam stabilizer” in this application, comprising a fatty alcohol, a fatty acid and/or a wax. In one or more alternative embodiments the foamer complex is a fatty alcohol and a wax or a fatty acid and a wax. In some embodiments it is a wax. In one or more embodiments the foamer complex or viscosity modifying agent comprises at least one of a fatty alcohol, a wax or a fatty acid. In one or more embodiments the foamer complex or viscosity modifying agent is selected from a group consisting of a fatty alcohol, a wax and a fatty acid. In some embodiments, it is a fatty alcohol. In some embodiments, it is a fatty acid. In some embodiments a fatty alcohol, and/or a fatty acid and/or a wax is an adjuvant. In the context of the present disclosure fatty alcohols, fatty acids and waxes that are compatible with tetracycline antibiotics, and in particular with a minocycline or a doxycycline, are compatible adjuvants. The term “breakable” refers to a property of a gel or foam wherein the gel or foam is stable upon dispensing from a container, yet breaks and spreads easily upon application of shear or mechanical force, which can be mild, such as a simple rub. The term “water activity” as used herein represents the hygroscopic nature of a substance, or the tendency of a substance to absorb water from its surroundings. Microorganisms require water to grow and reproduce, and such water requirements are best defined in terms of water activity of the substrate. The water activity of a solution is expressed as Aw=P/Po, where P is the water vapor pressure of the solution and Po is the vapor pressure of pure water at the same temperature. Every microorganism has a limiting Aw, below which it will not grow; e.g., for Streptococci, Klebsiella spp, Escherichia coli, Clostridium perfringens, and Pseudomonas spp, the Aw value is 0.95. Staphylococcus aureus is most resistant and can proliferate with an Aw as low as 0.86, and fungi can survive at an Aw of at least 0.7. The identification of a “solvent,” as used herein, is not intended to characterize the solubilization capabilities of the solvent for any specific active agent or any other component of the foamable composition. Rather, such information is provided to aid in the identification of materials suitable for use as a component of the foamable composition described herein. As used herein, the term “preventing” refers to avoiding the onset of a disorder or condition from occurring in a subject that has not yet been diagnosed as having the disorder or condition, but who may be susceptible to it. As used herein, the term “treatment” refers to inhibiting the disorder or condition, i.e., arresting its development; relieving the disorder or condition, i.e., causing regression of the disorder or condition or reversing the progression of the disorder or condition; or relieving or reducing one or more symptoms of the disorder or condition. It should be noted that the term “a method of preventing, treating a disease or a disorder” as provided throughout the specification is interchangeable with the term “use of the composition as a medicament for preventing or treating a disease.” It should be noted that the term “disease” is used interchangeably with the term “disorder.” It should be noted that the term “substantially free of” an ingredient as provided throughout the specification is intended to mean that the composition comprises less than about 0.5% by weight, e.g., less than about 0.4% by weight, less than about 0.3% by weight, less than about 0.2% by weight, or less than about 0.1% by weight, of an ingredient unless specifically indicated otherwise. As used herein, the term “essentially free of” an ingredient as provided throughout the specification is intended to mean that the composition comprises less than about 0.05% by weight, less than about 0.01% by weight, less than about 0.001% by weight, or 0% by weight, or insignificant or negligible amounts of the ingredient, unless specifically indicated otherwise. As used herein, the term “free of” an ingredient as provided throughout the specification is intended to mean that the composition does not comprise any amount of the ingredient, unless specifically indicated otherwise. The terms “surfactant-free” or “emulsifier-free” or “non-surfactant” refer to compositions which comprise no or negligible levels of surfactants, emulsifiers, or surface active agents. Where a formulation includes insignificant or de minimis amounts of surfactants, emulsifiers, or surface active agents it is considered to be essentially surfactant-free. As used herein, “essentially free” indicates less than about 0.05% by weight, less than about 0.01% by weight, less than about 0.001% by weight, or 0% by weight of a surfactant selected from the group consisting of customary non-ionic, ionic, anionic, cationic, zwitterionic, amphoteric and ampholytic surfactants. The term “substantially surfactant-free” relates to a composition wherein the ratio between the viscosity-modifying agent and the surfactant is between 10:1 or 5:1; or between 20:1 and 10:1 or between 100:1 and 20:1. In additional embodiments, the term relates to a composition that contains a total of about or less than 0.5% by weight; about or less than 0.4% by weight; or about or less than 0.3% by weight of a surfactant selected from the group consisting of customary non-ionic, ionic, anionic, cationic, zwitterionic, amphoteric and ampholytic surfactants. In some embodiments, the composition comprises about or less than 0.2% by weight of a standard or customary surfactant; about or less than 0.15% by weight; about or less than 0.1% by weight; about or less than 0.05% by weight; or about or less than 0.01% by weight. By “de minimis” it is meant to be so minor that its effect is to be disregarded. The terms “hydrophobic gel composition” or “hydrophobic foam composition” or “hydrophobic composition” are intended to mean that the composition has a low solubility in water. In one embodiment, 100 to 1000 parts of water are needed to dissolve or render miscible 1 part of the composition. In another embodiment, 1000 to 10,000 parts of water are needed to dissolve or render miscible 1 part of the composition. In yet another embodiment, more than 10,000 parts of water are needed to dissolve or render miscible 1 part of the composition. The term “clinical response to treatment”, (“clinical success” or “clinical failure”) in the context of rosacea treatment is derived from efficacy evaluation endpoints. The term “lesion count” relates to the number of inflammatory lesions (e.g., papules and pustules) present in a designated area of the body (e.g., in case of face, on the forehead, left and right cheeks, nose and chin). The terms “high rates of clinical response” or “high efficacy” or “substantial decrease” in the context herein can relate to an absolute change in inflammatory lesion count of at least 19 compared to baseline, a reduction of about 45% or more in inflammatory lesions count or to where subjects met a success criterion of “clear” or “almost clear” or to an “improvement of 2 grades from the baseline”; or to where subjects receive an excellent score according to Investigator's Global Improvement Assessment; or to where patients receive a two step drop in Patient's Global Improvement Assessment (IGA) score; or wherein according to any of the aforementioned endpoints a statistically significant reduction or improvement is demonstrated as compared to placebo. By “regular basis” it is meant a repeated or repeatable interval of time which can be by way of illustration, a part of a day, daily, once daily, twice daily, alternative daily, alternate daily, twice weekly, trice weekly, weekly, fortnightly, monthly or some other repeated or repeatable interval for an appropriate period of time wherein a dose is to be applied. The repeated applications can be determined according to the needs of the subject and the disease or disorder. In some circumstances as little as three repeat doses can be required. In other cases, between 3 and 14, in other cases between 14 and 28, in other cases between 28 and 50, in other cases between 50 and 75, in other cases between 75 and 100, and in other cases, such as where prolonged treatment or a long period of maintenance dosing is needed, as many as one, two, or three hundred repeat doses can be needed. The term “adverse events” describes any unfavorable or unintended sign, symptom, or disease that appears or worsens in a subject after the subject has commenced using the formulation. Examples of what can be considered an adverse event (AE) include any of the following: A new illness, an exacerbation of a sign or symptom of an underlying condition or of a concomitant illness unrelated to participation in the clinical study, a sign or symptom as an effect of the study drug or comparator drug The common term for such problems is “side effects,” and used by patients and physicians. The term “serious adverse events” describes any adverse effect that: Results in death, is life-threatening (Note: The term “life-threatening” refers to any adverse event that, as it occurs, puts the subject at immediate risk of death. It does not refer to an adverse event that hypothetically might have caused death if it were more severe.), results in hospitalization or prolongation of current hospitalization (not including hospitalization for a pre-existing condition that has not increased in severity or frequency from the subject's underlying medical condition prior to entry into the study), results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect in the offspring of a subject, is an important medical event (Note: Important medical events may not be immediately life-threatening or result in death or hospitalization but may be considered serious when, based upon appropriate medical judgment, they may jeopardize the subject or require medical or surgical intervention to prevent one of the outcomes listed above. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient hospitalization; or development of drug dependency or drug abuse.) The term “safe” in the context herein means having no or essentially no adverse events (e.g., any unfavorable or unintended sign, symptom, or disease that appears or worsens on the course of treatment). It should be noted that the term “polyol” as used herein is an organic substance that contains at least two hydroxyl groups in its molecular structure. The terms “local safety” or “tolerable” or “enhanced tolerability” in the context herein means having no or essentially no skin irritation symptoms such as telangiectasis, burning or stinging, flushing or blushing, or alternatively, when such symptoms arise they are mild and disappear without interrupting treatment. The score for such symptoms is measured by the investigator at baseline, 2, 4, 8, and 12 weeks and is according to a scale of none, mild, moderate and severe. The score represents the subject's condition at the time of evaluation. The score for burning or stinging and flushing or blushing is based on the subject's symptoms reported for the previous three days. These symptoms should not be included as adverse events, unless a symptom is believed to have been related to the study medication or is the reason for discontinuation from the study. By “essentially no” in the context of tolerability includes insignificant or de minimis occurrences of skin irritation events manifested in symptoms such as telangiectasis, burning or stinging, flushing or blushing, or mild transient events connected with the application of topical tetracyclines or vehicle. By “essentially no” in the context of safety includes insignificant or de minimis occurrences of systemic or serious adverse events connected with the application of topical tetracyclines or vehicle. The clinical response was determined at each study visit inter alia by an absolute inflammatory lesion count, by % change in inflammatory lesion count, by Investigator global assessment, by improvement assessment (by the Investigator) and improvement assessment (by the patient). Photographs were also used to assess the clinical improvement. The improvement assessment by the investigator includes scoring rosacea severity based on the number of inflammatory lesions and level of erythema. The improvement assessment by the patient involves measuring the health-related quality of life of patients through Rosacea Quality of Life (RosaQoL), a self-administered questionnaire. The term clinical failure is defined as insufficient improvement or deterioration (i.e., an increase or no change in the number of lesions). By “on average,” with reference to dosage regimes, it is intended to reflect and/or take into account human nature and that a subject may forget to apply a dose or not strictly adhere to the regime, such that even if a subject forgets a dose or does not strictly adhere to the regime it will still be considered as if the regime has been applied. For example, if a subject misses an occasional dose but does not make it up, or alternatively, if having missed a dose applies a compensatory dose on a different day, it is still counted as having complied with the dosage regime. Compositions Gel or foam compositions having tetracycline antibiotic are well-known in the art and fully described in U.S. Patent Application Publication Nos. 2014/0121188 and 2013/0225536, which are herein incorporated by reference in their entirety. In one or more embodiments there is provided a hydrophobic gel or foam composition comprising a tetracycline antibiotic for use in treating a rosacea in a human subject suffering therefrom comprising topically administering the composition to the human subject in a sufficient amount and for a sufficient time to decrease the number of rosacea lesions. Tetracycline Antibiotic Any tetracycline antibiotic known to one of skilled in the art can be used. Examples of a tetracycline antibiotic include, for example, but not limited to tetracycline, oxytetracycline, demeclocycline, doxycycline, lymecycline, meclocycline, methacycline, minocycline, rolitetracycline, chlorotetracycline, and tigecycline. In a particular example, the tetracycline is a minocycline or doxycycline, which are semi-synthetic tetracycline antibiotic. According to one or more embodiments, the tetracycline is minocycline. The tetracycline drug is usually bacteriostatic in action. It can, amongst other options, exert its antimicrobial activity by inhibiting protein synthesis. It can also have an antiviral effect. According to one or more embodiments, the minocycline is minocycline hydrochloride (minocycline HCl; (hereinafter “MCH”)). In some embodiments, MCH is a yellow crystalline powder that is sparingly soluble in water, slightly soluble in alcohol and practically insoluble in chloroform and in ether. Minocycline and MCH is known to be highly sensitive to air and light and undergoes rapid degradation. Therefore, storage of foamable formulations in airtight sealed containers under pressure with propellant can contribute to preserving stability, subject to selection of compatible canisters and accessories. Likewise, production and/or filing under vacuum in an oxygen free environment can help. Thus, it was unexpectedly demonstrated that topical minocycline foam offered a safe and effective alternative to topical compositions containing for example, ivermectin, metronidazole, azelaic acid and brimonidine tartrate for the topical treatment of rosacea. The ease of use, with once daily dosing, as well as its broad spectrum of activity, early onset, the low level of adverse events and the rapid reduction in the number of lesions make it an attractive choice and a potentially valuable medication for the treatment of acute bacterial skin infections. Examples of bacterial infections that can be effectively treated by topical tetracycline antibiotics include, but not limited to, cellulitis, acute lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses, necrotizing subcutaneous infections, staphylococcal scalded skin syndrome, folliculitis, furuncles, hidradenitis suppurativa, carbuncles, paronychial infections, erythrasma, disorders of hair follicles and sebaceous glands, acne, impetigo, rosacea, perioral dermatitis, hypertrichosis (hirsutism), alopecia, including male pattern baldness, alopecia greata, alopecia universalis and alopecia totalis, pseudofolliculitis barbae, and keratinous cyst. For example, rosacea involves papules and pustules, which can be treated with an antibiotic agent, as well as erythema, telangiectasia, and redness, which partially respond to treatment with an antibiotic agent. In one or more embodiments, the active agent can be a placebo or a cosmetic agent. The foamable composition is suitable for use in the manufacture of a medicament including a placebo or active agent. In one or more embodiments, the tetracycline antibiotic is hydrophobic. In one or more embodiments, the Log of the distribution constant of the tetracycline antibiotic at pH 7.0 (buffer/chloroform) is equal to or less than about 0.2. In one or more embodiments, tetracycline antibiotic forms suitable for use according to the methods and compositions of the present disclosure include, but are not limited to, a free base form, a hydrate form, a salt form, a chelate complex form or a coordination complex form. In one or more embodiments, the tetracycline antibiotic does not comprise a hydroxyl group at carbons 5, 6, and 7. In one or more embodiments, the tetracycline antibiotic comprises or is selected from the group consisting of minocycline and doxycycline. In some embodiments, the tetracycline antibiotic is minocycline. In some embodiments, the concentration of minocycline is in a range between about 0.1% to about 10% by weight (e.g., about 0.1% to about 8% by weight, about 0.1% to about 5% by weight, about 0.1% to about 3% by weight, about 0.1% to about 2% by weight, about 0.1% to about 1% by weight, about 0.1% to about 0.75% by weight, about 0.1% to about 0.5% by weight, about 0.1% to about 0.25% by weight, about 0.25% to about 10% by weight, about 0.5% to about 10% by weight, about 0.5% to about 5% by weight, about 0.5% to about 4% by weight, about 0.5% to about 3% by weight, about 1% to about 10% by weight, about 2% to about 10% by weight, about 4% to about 10% by weight, about 6% to about 10% by weight, about 7% to about 10% by weight, about 8% to about 10% by weight, about 0.5% to about 2.0% by weight, about 0.75% to about 1.5% by weight, about 1% to about 3% by weight, about 1% to about 4% by weight, and about 2% to about 6% by weight). In some embodiments, the concentration of minocycline is at least about 0.05% by weight, is at least about 0.1% by weight, at least about 0.5% by weight, at least about 1% by weight, at least about 2% by weight, at least about 4% by weight, at least about 6% by weight, at least about 8% by weight or at least about 10% by weight. In one or more embodiments, the minocycline is micronized. In one or more embodiments, the initial dose of tetracycline is about 18%, or about 17.5%, or about 16.5%, or about 15.5%, or about 14.5%, or about 13.5% or about 12.5%, or about 11.5%, or about 10.5% or about 9.5% or about 8.5% or about 7.5% or about 6.5% or about 5.5% or about 4.5% or about 3.5% or about 2.5% or about 1.5%, or about 17%, or about 16%, or about 15%, or about 14%, or about 13% or about 12%, or about 11%, or about 10% or about 9% or about 8% or about 7% or about 6% or about 5% or about 4% or about 3% or about 2% or about 1% or about 0.75% or about 0.5% or about 0.25% or about 0.2% by weight of the composition. In one or more embodiments, the maintenance dose of tetracycline is about 7.5% or about 6.5% or about 5.5% or about 4.5% or about 3.5% or about 2.5% or about 1.5%, 7% or about 6% or about 5% or about 4% or about 3% or about 2% or about 1% or about 0.5%, or about 1.9%, or about 1.8%, or about 1.7%, or about 1.6%, or about 1.55 or about 1.4% or about 1.3% or about 1.2% or about 1.1%, or about 0.9% or about 0.8%, or about 0.7%, or about 0.6% or about 0.4% or about 0.35 or about 0.25% or about 0.2% or about 0.15% or about 0.1% by weight of the composition. According to one or more embodiments, provided are substantially surfactant-free oleaginous formulations comprising a tetracycline, such as a minocycline, for use in treatment of rosacea, and/or rosacea related symptoms, and/or a tetracycline antibiotic responsive rosacea related disorder, and/or a tetracycline antibiotic responsive skin disorder, and/or skin disorder caused by a bacteria, and/or a tetracycline antibiotic responsive disorder, and/or a sebaceous gland disorder. In one or more embodiments the tetracycline is used for the treatment of rosacea. In one or more embodiments the tetracycline is used for the treatment of impetigo. In one or more embodiments the tetracycline is used for the treatment of acne. In one or more embodiments the tetracycline acts to reduce oxidative stress and/or inflammation in skin pathologies. In one or more embodiments the tetracycline is effective where the condition is accompanied by apoptotic cell death. In one or more embodiments there is provided a hydrophobic gel or foam composition comprising a minocycline antibiotic for use in treating a disorder selected from the group consisting of rosacea, and/or rosacea related symptoms, and/or a tetracycline antibiotic responsive rosacea related disorder, and/or a tetracycline antibiotic responsive skin disorder, and/or skin disorder caused by a bacteria, and/or a tetracycline antibiotic responsive disorder, and/or a sebaceous gland disorder, wherein the hydrophobic gel or foam composition is administered topically at least alternate days or at least once daily for at least two weeks to the skin, wherein the hydrophobic gel or foam composition is waterless and does not comprise a silicone other than cyclomethicone. In one or more embodiments there is provided a hydrophobic gel or foam composition comprising a minocycline antibiotic for use in treating a disorder selected from the group consisting of rosacea, and/or rosacea related symptoms, and/or a tetracycline antibiotic responsive rosacea related disorder, and/or a tetracycline antibiotic responsive skin disorder, and/or skin disorder caused by a bacteria, and/or a tetracycline antibiotic responsive disorder, and/or a sebaceous gland disorder, wherein the hydrophobic gel or foam composition is administered topically at least alternate days or at least once daily for at least two weeks to the skin, mucosa, or eye, wherein the hydrophobic gel or foam composition is waterless and does not comprise a polyethylene gelling agent or polyethylene homopolymer or polyethylene copolymer or a customary surfactant. Foam Vehicle It is postulated, without being bound by any theory, that the use of a hydrophobic oil based foam vehicle contributes to cutaneous bioavailability, including the achievement of therapeutic levels of minocycline in the pilosebaceous unit. Specific targeting of hydrophobic oil based foam vehicle to the pilosebaceous unit is enabled due the hydrophobic nature of the pilosebaceous gland. Thus, provided in various embodiments is a vehicle for delivering a therapeutically effective amount of active agent to the sebaceous gland or the sebaceous gland area or the pilosebaceous unit comprising: a) about 60% to about 99% by weight of at least one hydrophobic solvent; b) at least one viscosity-modifying agent, wherein said agent is a wax, a fatty alcohol, a fatty acid, or mixtures of any two or more thereof. Provided herein in various embodiments is a vehicle for delivering a therapeutically effective amount of active agent to the sebaceous gland or the sebaceous gland area or the pilosebaceous unit comprising: a) about 60% to about 99% by weight of at least one hydrophobic solvent; b) at least one viscosity-modifying agent comprising a wax and a fatty alcohol or a fatty acid, or both; wherein the active agent is a tetracycline antibiotic. Additionally, provided herein in various embodiments is a vehicle for delivering a therapeutically effective amount of active agent to the sebaceous gland or the sebaceous gland area or the pilosebaceous unit comprising: a) about 60% to about 99% by weight of at least one hydrophobic solvent; b) at least one viscosity-modifying agent, wherein said agent is a wax, a fatty alcohol, a fatty acid, or mixtures of any two or more thereof; wherein the active agent is a minocycline. Hydrophobic Solvent In certain embodiments, a hydrophobic solvent can be useful. For example, some essential oils can kill microorganisms or can prevent of conditions that involve microbial infection. Additionally, hydrophobic solvents can useful for the treatment of conditions which involve damaged skin, such as psoriasis or atopic dermatitis. The combination of a hydrophobic solvent and a fatty alcohol or fatty acid can be of possible help in conditions characterized, for example, by infection and/or inflammation. In one or more embodiments, the at least one hydrophobic solvent comprises or is selected from the group consisting of a mineral oil, a hydrocarbon oil, an ester oil, an ester of a dicarboxylic acid, a triglyceride oil, an oil of plant origin, an oil from animal origin, an unsaturated or polyunsaturated oil, a diglyceride, a PPG alkyl ether, an essential oil, a silicone oil, liquid paraffin, an isoparaffin, a polyalphaolefin, a polyolefin, polyisobutylene, a synthetic isoalkane, isohexadecane, isododecane, alkyl benzoate, alkyl octanoate, C12-C15 alkyl benzoate, C12-C15 alkyl octanoate, arachidyl behenate, arachidyl propionate, benzyl laurate, benzyl myristate, benzyl palmitate, bis(octyldodecyl stearoyl)dimer dilinoleate, butyl myristate, butyl stearate, cetearyl ethylhexanoate, cetearyl isononanoate, cetyl acetate, cetyl ethylhexanoate, cetyl lactate, cetyl myristate, cetyl octanoate, cetyl palmitate, cetyl ricinoleate, decyl oleate, diethyleneglycol diethylhexanoate, diethyleneglycol dioctanoate, diethyleneglycol diisononanoate, diethyleneglycol diisononanoate, diethylhexanoate, diethylhexyl adipate, diethylhexyl malate, diethylhexyl succinate, diisopropyl adipate, diisopropyl dimerate, diisopropyl sebacate, diisostearyl dimer dilinoleate, diisostearyl fumerate, dioctyl malate, dioctyl sebacate, dodecyl oleate, ethylhexyl palmitate, ester derivatives of lanolic acid, ethylhexyl cocoate, ethylhexyl ethylhexanoate, ethylhexyl hydroxystearate, ethylhexyl isononanoate, ethylhexyl palmitate, ethylhexyl pelargonate, ethylhexyl stearate, hexadecyl stearate, hexyl laurate, isoamyl laurate, isocetyl behenate, isocetyl lanolate, isocetyl palmitate, isocetyl stearate, isocetyl salicylate, isocetyl stearate, isocetyl stearoyl stearate, isocetearyl octanoate, isodecyl ethylhexanoate, isodecyl isononanoate, isodecyl oleate, isononyl isononanoate, isodecyl oleate, isohexyl decanoate, isononyl octanoate, isopropyl isostearate, isopropyl lanolate, isopropyl laurate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, isostearyl behenate, isostearyl citrate, isostearyl erucate, isostearyl glycolate, isostearyl isononanoate, isostearyl isostearate, isostearyl lactate, isostearyl linoleate, isostearyl linolenate, isostearyl malate, isostearyl neopentanoate, isostearyl palmitate, isostearyl salicylate, isostearyl tartrate, isotridecyl isononanoate, isotridecyl isononanoate, lauryl lactate, myristyl lactate, myristyl myristate, myristyl neopentanoate, myristyl propionate, octyldodecyl myristate, neopentylglycol dicaprate, octyl dodecanol, octyl stearate, octyl palmitate, octyldodecyl behenate, octyldodecyl hydroxystearate, octyldodecyl myristate, octyldodecyl stearoyl stearate, oleyl erucate, oleyl lactate, oleyl oleate, propyl myristate, propylene glycol myristyl ether acetate, propylene glycol dicaprate, propylene glycol dicaprylate, propylene glycol dicaprylate, maleated soybean oil, stearyl caprate, stearyl heptanoate, stearyl propionate, tocopheryl acetate, tocopheryl linoleate, glyceryl oleate, tridecyl ethylhexanoate, tridecyl isononanoate, triisocetyl citrate, alexandria laurel tree oil, avocado oil, apricot stone oil, barley oil, borage seed oil, calendula oil, cannelle nut tree oil, canola oil, caprylic/capric triglyceride castor oil, coconut oil, corn oil, cotton oil, cottonseed oil, evening primrose oil, flaxseed oil, groundnut oil, hazelnut oil, glycereth triacetate, glycerol triheptanoate, glyceryl trioctanoate, glyceryl triundecanoate, hempseed oil, jojoba oil, lucerne oil, maize germ oil, marrow oil, millet oil, neopentylglycol dicaprylate/dicaprate, olive oil, palm oil, passionflower oil, pentaerythrityl tetrastearate, poppy oil, propylene glycol ricinoleate, rapeseed oil, rye oil, safflower oil, sesame oil, shea butter, soya oil, soybean oil, sweet almond oil, sunflower oil, sisymbrium oil, syzygium aromaticum oil, tea tree oil, walnut oil, wheat germ glycerides, wheat germ oil, PPG-2 butyl ether, PPG-4 butyl ether, PPG-5 butyl ether, PPG-9 butyl ether, PPG-12 butyl ether, PPG-14 butyl ether, PPG-15 butyl ether, PPG-15 stearyl ether, PPG-16 butyl ether, PPG-17 butyl ether, PPG-18 butyl ether, PPG-20 butyl ether, PPG-22 butyl ether, PPG-24 butyl ether, PPG-26 butyl ether, PPG-30 butyl ether, PPG-33 butyl ether, PPG-40 butyl ether, PPG-52 butyl ether, PPG-53 butyl ether, PPG-10 cetyl ether, PPG-28 cetyl ether, PPG-30 cetyl ether, PPG-50 cetyl ether, PPG-30 isocetyl ether, PPG-4 lauryl ether, PPG-7 lauryl ether, PPG-2 methyl ether, PPG-3 methyl ether, PPG-3 myristyl ether, PPG-4 myristyl ether, PPG-10 oleyl ether, PPG-20 oleyl ether, PPG-23 oleyl ether, PPG-30 oleyl ether, PPG-37 oleyl ether, PPG-40 butyl ether, PPG-50 oleyl ether, PPG-11 stearyl ether, herring oil, cod-liver oil, salmon oil, cyclomethicone, a dimethyl polysiloxane, dimethicone, an epoxy-modified silicone oil, a fatty acid-modified silicone oil, a fluoro group-modified silicone oil, a methylphenylpolysiloxane, phenyl trimethicone and a polyether group-modified silicone oil or mixtures of any two or more thereof. In some embodiments, the hydrophobic solvent comprises or is selected from the group consisting of soybean oil, a coconut oil, a cyclomethicone, a light mineral oil, and mixtures of any two or more thereof. In one or more embodiments the solvent is tested individually for compatibility with a tetracycline antibiotic and is only used if it passes a compatibility test as described below in the Methods. As contemplated herein, the concentration of the hydrophobic solvent and/or viscosity modifying agent in the composition is selected to provide an Aw value selected from the ranges between or of (1) about 0.8 and about 0.9; (2) about 0.7 and about 0.8; and (3) less than about 0.7. Delivering the formulation in a pressurized package does not allow for humidity to be absorbed by the preparation, and therefore, the water free character of the composition is not altered or compromised. In one embodiment, no preservative is needed in the formulations provided herein because the formulation is a waterless hydrophobic solvent or oil-based formulation having an Aw (water activity) value of less than 0.9, or less than about 0.8, or less than about 0.7, or less than about 0.6, and/or less than about 0.5, which is below the level of microbial proliferation. In one or more embodiments, the hydrophobic solvent is at a concentration of about 75% to about 90% by weight. In one or more embodiments, the hydrophobic solvent is at a concentration of at least about 40% by weight, at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 90% by weight. In some embodiments, the hydrophobic solvent is at a concentration of less than about 90% by weight, less than about 80% by weight, less than about 70% by weight, less than about 60% by weight, less than about 50% by weight. In some embodiments, the formulation can include a fatty alcohol. Long chain saturated and mono unsaturated fatty alcohols, e.g., stearyl alcohol, erucyl alcohol, arachidyl alcohol and behenyl alcohol (docosanol) have been reported to possess antiviral, anti-infective, ant proliferative and anti-inflammatory properties (see, U.S. Pat. No. 4,874,794). Longer chain fatty alcohols, e.g., tetracosanol, hexacosanol, heptacosanol, octacosanol, triacontanol, etc., are also known for their metabolism modifying properties, and tissue energizing properties. In one or more embodiments, the fatty alcohol and/or fatty acid have a melting point of at least about 40° C. In one or more embodiments, the fatty alcohol comprises or is selected from the group consisting of lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl, arachidyl alcohol, behenyl alcohol, tetracosanol, hexacosanol, octacosanol, triacontanol, and tetratriacontanol or mixtures of any two or more thereof. In one or more embodiments, the fatty acid comprises or is selected from the group consisting of dodecanoic acid, tetradecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoic acid, eicosanoic acid, docosanoic acid, tetracosanoic acid, hexacosanoic acid, heptacosanoic acid, octacosanoic acid, triacontanoic acid, dotriacontanoic acid, tritriacontanoic acid, tetratriacontanoic acid, and pentatriacontanoic acid or mixtures of any two or more thereof. In one or more embodiments, the carbon chain of the fatty alcohol or the fatty acid is substituted with a hydroxyl group. In one or more embodiments, the fatty acid is 12-hydroxy stearic acid. Viscosity-Modifying Agent As contemplated herein, the gel is stable and it retains its viscosity upon dispensing from a container, such as a tube, yet, it liquefies and spreads easily upon application of shear force, which can be mild, such as a simple rub. Further, while the gel is oily, it absorbs into the site of application, such as the skin or mucosa membrane, and after minutes the surface does not appear and/or feel significantly oily or greasy. In some embodiments, formulations comprising a hydrophobic oil and viscosity-modifying agents demonstrated increased viscosity of such oil, and to which when even small amounts of a suspended tetracycline antibiotic were added, a substantial or synergistic increase in the viscosity of the composition was observed. In one or more embodiments, the viscosity-modifying agent is a wax comprising or selected from the group consisting of a plant wax, carnauba wax, candelilla wax, ouricury wax, sugarcane wax, retamo wax, jojoba oil, an animal waxes, beeswax, a hydrogenated castor oil, a petroleum derived wax, a paraffin wax, polyethylene, and derivatives thereof. In one or more embodiments, the viscosity-modifying agent is a combination comprising (i) at least one fatty alcohol and at least one fatty acid; or (ii) at least one fatty alcohol and at least one wax; or (iii) at least one fatty acid and at least one wax; or (iv) at least one fatty alcohol, at least one fatty acid, and at least one wax. In one or more embodiments the at least one viscosity-modifying agent comprises or is selected from the group consisting of a fatty alcohol, a fatty acid and a wax, wherein the fatty alcohols and/or fatty acids have at least 12 carbon atoms in their carbon backbone. In certain embodiments the viscosity modifying agent is a combination of a fatty alcohol and a fatty acid and/or a wax. In one or more embodiments, the viscosity-modifying agent is at a concentration of about 0.1% to about 22%, about 0.4 to about 18%, about 0.5% to 16%, about 0.6% to 14%, about 0.7% to 13%, about 0.8 to about 12%, about 0.9% to about 11%, about 1% to about 10%, about 10% to about 22% by weight. In one or more embodiments, the viscosity-modifying agent is a fatty alcohol having at least 12 carbon atoms in its carbon backbone. In one or more embodiments, the viscosity-modifying agent is a fatty acid having at least 12 carbon atoms in its carbon backbone. In one or more embodiments, the viscosity-modifying agent is at a concentration of about 9.5% or about 8.5% or about 7.5% or about 6.5% or about 5.5% or about 4.5% or about 3.5% or about 2.5% or about 1.5%, about 7% or about 6% or about 5% or about 4% or about 3% or about 2% or about 1% or about 0.5%, or about 1.9%, or about 1.8%, or about 1.7%, or about 1.6%, or about 1.55 or about 1.4% or about 1.3% or about 1.2% or about 1.1%, or about 0.9% or about 0.8%, or about 0.7%, or about 0.6% or about 0.5% by weight of the composition or less than any of the aforesaid amounts. Preferably, the fatty alcohol and/or fatty acid and/or wax are solid at ambient temperature. In certain embodiments, the fatty alcohol and/or the fatty acid and/or the wax or the mixture of them have a melting point of more than about 40° C. Propellant In one or more embodiments, the composition is a foamable composition, and further comprises a propellant. Any compatible propellant can be used. In one or more embodiments, the propellant is a gas at room temperature under normal pressure and which can be liquefied at increased pressure at room temperature. Examples of propellants include, without limitation, hydrocarbon propellants such as butane, propane, isobutane, dimethyl ether, fluorocarbons such as 1,1,1,2 tetrafluoroethane (Dymel 134a), and 1,1,1,2,3,3,3 heptafluoropropane (Dymel 227), and mixtures thereof. In one or more embodiments, a hydrocarbon mixture AP-70 (a mixture of about 30% w/w butane, 20% w/w isobutane and 50% w/w propane) is used. In one or more embodiments, the composition comprises about 0.1% w/w to about 0.3% w/w of fumed (modified) silica. In one or more embodiments, the composition comprises about 1% w/w to about 4% w/w of minocycline hydrochloride or a doxycycline or a tetracycline antibiotic. In one or more embodiments, the composition comprises about 3% w/w to about 15% w/w of propellant based on the weight of the total composition. In one or more embodiments, the composition comprises about 3% w/w to about 25% w/w of propellant based on the weight of the total composition. In one or more embodiments, the composition comprises about 3% w/w to about 35% w/w of propellant based on the weight of the total composition. In one or more embodiments, the composition comprises about 5% w/w to about 30% w/w of propellant based on the weight of the total composition. Other Ingredients In certain embodiments, the composition is free of one or more of a petrolatum, surface active agents, protic solvents, certain polar aprotic solvents, isopropyl myristate, polyethylene gelling agents, polyethylene homopolymers, polyethylene copolymers, selenium derivatives and silicone thickening agents; and in certain embodiments, the foamable composition is substantially free of such excipients. In the context herein, the term “substantially-free” relates to a composition that contains a total of less than about 0.4% of a petrolatum, surface active agents, protic solvents, certain polar aprotic solvents, isopropyl myristate, polyethylene gelling agents, polyethylene homopolymers, polyethylene copolymers, selenium derivatives and silicone thickening agents cumulatively. Preferably, the composition comprises less than about 0.2% of two or more or all thereof by weight of petrolatum, surface active agents, protic solvents, certain polar aprotic solvents, isopropyl myristate, polyethylene gelling agents, polyethylene homopolymers, polyethylene copolymers, selenium derivatives and silicone thickening agents cumulatively or, and more preferably less than about 0.1% individually or of two or more or all thereof cumulatively. In one or more embodiments, the composition is substantially alcohol-free, i.e., free of short chain alcohols having up to 5 carbon atoms in their carbon chain skeleton. In other embodiments, the composition comprises less than about 5% by weight final concentration of short chain alcohols, for example, less than 2% by weight, or less than 1% by weight. In certain embodiments, the composition is free or substantially free of ethanol, propanol, butanol and pentanol. Surface Active Agents For clarification, in the context herein whilst the term “standard surfactant” or “customary surfactant” refers herein to customary non-ionic, ionic, anionic, cationic, zwitterionic, amphoteric and amphiphilic surfactants. A fatty alcohol or a fatty acid and certain waxes are not regarded as a standard surfactant. However, in contrast, ethers or esters formed from such fatty alcohols or fatty acids can be regarded as a customary surfactant. Surfactants of all kinds are undesirable in accordance with the present compositions and methods as (i) they were found to cause degradation of the tetracycline antibiotic; and (ii) they are generally known to possess irritation potential. Non-limiting examples of classes of non-ionic surfactants that are undesirable according to the present invention include: (i) polyoxyethylene sorbitan esters (polysorbates), such as polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80; (ii) sorbitan esters, such as sorbitan monolaurate and sorbitan monooleate; (iii) polyoxyethylene fatty acid esters, such as, PEG-8 stearate, PEG-20 stearate, PEG-40 stearate, PEG-100 stearate, PEG-150 distearate, PEG-8 laurate, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-8 oleate, PEG-9 oleate, PEG-10 oleate, PEG-12 oleate, PEG-15 oleate and PEG-20 oleate; (iv) PEG-fatty acid diesters; (v) polyethylene glycol (PEG) ethers of fatty alcohols; (vi) glycerol esters, such as glyceryl monostearate, glyceryl monolaurate, glyceryl monopalmitate and glyceryl monooleate; (vii) PEG-fatty acid mono- and di-ester mixtures; (viii) polyethylene glycol glycerol fatty acid esters; (ix) propylene glycol fatty acid esters; (x) mono- and diglycerides; (xi) sugar esters (mono-, di- and tri-esters of sucrose with fatty acids) and (xii) PEG alkyl phenols. As disclosed herein, in the context of the compositions and methods provided herein, while fatty alcohols, fatty acids, and certain waxes are somewhat amphiphilic, these substances are not effective as stand-alone surfactants that can stabilize an emulsion, let alone foamable emulsion compositions, because of their very weak emulsifying capacity and further due to their weak foaming capacity on their own. They are occasionally used in a supporting role as co-emulsifiers, i.e., in combination with a standard surfactant but are commonly used as thickeners and have successfully been used as foam adjuvants to assist customary surfactants to boost foam quality and stability. For the purposes of forming an emulsion they are usually regarded as an oil and thus have a “required” HLB value for the purpose of determining what standard surfactant might be appropriate to use with the oil phase. Generally, surfactants are known to possess irritation potential. One way to try and reduce or minimize potential irritation and drying of the skin or mucosa due to surfactants and their repeated use, especially when formulations are to be left on the skin or mucosa rather than being washed off, is to use essentially or primarily nonionic surfactants at significant concentrations, although preferably below 5%. The identification of formulations which produce gels and quality breakable foam yet omit customary surfactants from a composition can contribute to improved tolerability of such a composition and can be an important advantage. This is especially so when a formulation is to be applied to a very sensitive target site, and particularly so on a repeated basis. In certain embodiments, the composition is free of customary surfactants, also known as “surfactant-free,” and in certain embodiments, the foamable composition is substantially free of customary surfactants, also known as “substantially surfactant-free”. In certain embodiments, the composition is free or substantially free of an ionic surfactant. In certain embodiments, the composition is free or substantially free of a zwitterionic surfactant. In certain embodiments, the composition is free or substantially free of a non-ionic surfactant. Protic Solvents Protic solvents, such as short chain alcohols, glycols and glycerin are incompatible with tetracyclines and therefore are undesirable. In certain embodiments, the composition is free or substantially free of protic solvents. Aprotic Polar Solvents It was discovered in PCT Publication No. WO11/039637 that certain polar aprotic solvents are incompatible with tetracycline antibiotics. Thus, aprotic polar solvents, such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), acetonitrile, acetone, methyl ethyl ketone, 1,4-Dioxane and tetrahydrofuran (THF), N-methylpyrrolidone, pyridine, piperidine, dimethylformamide, N-methyl-2-pyrrolidone and 1-methyl-2-pyrrolidinone) and azone (1-dodecylazacycloheptan-2-one) are undesirable. In certain embodiments, the composition is free or substantially free of aprotic polar solvents. Silicone Thickening Agents Silicone thickening agents comprise one or more polysiloxane-derived components. Such polysiloxanes are typically cross-linked and they have rubber-like characteristics, which require their solubilization in an oil, usually a silicone oil. An example of such a silicone thickening agent is ST-Elastomer 10 (Dow Corning), which is a mixture of high molecular weight dimethicone crosspolymer (12%), in cyclopentasiloxane (cyclomethicone, silicone solvent). With reference to bioavailability of an active agent in the skin following topical application, it is conceivable that cross co-polymers will create a non-permeable film which should block skin penetration and therefore, it is undesirable. Further, in the context of a breakable foam, cyclomethicone is known as a defoamer and therefore its presence in high concentrations in the breakable hydrophobic composition is undesirable. In certain embodiments, the composition is free or substantially free of silicone thickening agents other than cyclomethicone. In one or more other specific embodiments, the drug carrier is formulated substantially free of elastomers. In one or more other specific embodiments, the drug carrier is formulated essentially free of elastomers. In one or more other specific embodiments, the drug carrier is formulated substantially free of silicones. In one or more other specific embodiments, the drug carrier is formulated essentially free of silicones. In one or more other specific embodiments, the drug carrier is formulated with less than about 30% silicones, or less than about 25% silicones, or less than about 20% silicones, or less than about 15% silicones, or less than about 10% silicones, or less than about 7.5% silicones, or less than about 5% silicones or less than about 2% silicones; or less than about 1% silicones; or less than about 0.5% silicones; or about 1% to about 5% silicones; or about 0.5% to about 3% silicones. In one or more other specific embodiments, the drug carrier does not comprise a silicone other than cyclomethicone. In one or more other embodiments, the drug carrier does not comprise one or more volatile silicones. In other embodiments, volatile silicones are present at about 3% or less. In one or more embodiments, semi-solid hydrophobic oils are a subsidiary component in the composition, for example being present at less than about 45%, at less than about 40%, at less than about 35%, at less than about 30%, at less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5% by weight of the composition. In one or more alternative embodiments, semi-solid oils are omitted. Polyols The identification of a “polyol,” as used herein, is an organic substance that contains at least two hydroxyl groups in its molecular structure. In one or more embodiments, the polyol is a diol (a compound that contains two hydroxyl groups in its molecular structure). Examples of diols include propylene glycol (e.g., 1,2-propylene glycol and 1,3-propylene glycol), butanediol (e.g., 1,2-butanediol, 1,3-butanediol, 2,3-butanediol and 1,4-butanediol), butanediol (e.g., 1,3-butanediol and 1,4-butenediol), butynediol, pentanediol (e.g., pentane-1,2-diol, pentane-1,3-diol, pentane-1,4-diol, pentane-1,5-diol, pentane-2,3-diol and pentane-2,4-diol), hexanediol (e.g., hexane-1,6-diol hexane-2,3-diol and hexane-2,56-diol), octanediol (e.g., 1,8-octanediol), neopentyl glycol, 2-methyl-1,3-propanediol,diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol and dibutylene glycol. In one or more embodiments, the polyol is a triol (a compound that contains three hydroxyl groups in its molecular structure), such as glycerin, butane-1,2,3-triol, butane-1,2,4-triol and hexane-1,2,6-triol. In one or more embodiments, the polyol is a saccharide. Exemplary saccharides include, but are not limited to, monosaccharides, disaccharides, oligosaccharides, and sugar alcohols. A monosaccharide is a simple sugar that cannot be hydrolyzed to smaller units. The empirical formula is (CH2O)n and can range in size from trioses (n=3) to heptoses (n=7). Exemplary monosaccharide compounds are ribose, glucose, fructose, and galactose. Disaccharides are made up of two monosaccharides joined together, such as sucrose, maltose, and/or lactose. In one or more embodiments, the polyol is a sugar alcohol (also known as a polyol, polyhydric alcohol, or polyalcohol) or a hydrogenated form of saccharide, whose carbonyl group (aldehyde or ketone, reducing sugar) has been reduced to a primary or secondary hydroxyl group. They are commonly used for replacing sucrose in foodstuffs, often in combination with high intensity artificial sweeteners to counter the low sweetness. Some exemplary sugar alcohols, which are suitable for use according to the present disclosure are mannitol, sorbitol, xylitol, maltitol, lactitol. (Maltitol and lactitol are not completely hydrogenated compounds—they are a monosaccharide combined with a polyhydric alcohol.) Mixtures of polyols, including (1) at least one polyol comprises or selected from a diol and a triol; and (2) a saccharide are contemplated within the scope of the present disclosure. According to some embodiments, the composition is polyol free, i.e., free of polyols. In other embodiments, the composition is substantially free and comprises less than about 5% final concentration of polyols, preferably less than 2%, more preferably less than 1%; or about 1% to about 5% polyols; or about 0.5% to about 3% polyols. In some embodiments the composition comprises de minimis amounts of polyols. Where a formulation includes insignificant or de minimis amounts of polyols, such as less than 0.05%, the formulation is considered to be essentially free of them. In an embodiment, the polyol is linked to a hydrophobic moiety. In the context of the present disclosure, a polyol linked to a hydrophobic moiety is still defined as a “polyol” as long as it still contains two or more free hydroxyl groups. In an embodiment, the polyol is linked to a hydrophilic moiety. In the context of the present disclosure, a polyol linked to a hydrophilic moiety is still defined “polyol” as long as it still contains two or more free hydroxyl groups. In one or more embodiments, the hydrophobic composition further contains an anti-infective agent, comprises or selected from the group of an antibiotic agent, an antibacterial agent, an antifungal agent, an agent that controls yeast, an antiviral agent, and an antiparasitic agent. In an embodiment, the anti-infective agent comprises a tricyclic antibiotic. Not only can combining the anti-infective effect of a hydrophobic composition, with an anti-infective agent result in a synergistic effect and consequently higher success rate of the treatment but the combination with the viscosity modifying agent achieves a formulation in which the active pharmaceutical ingredient is chemically stable and the formulation is physically stable as demonstrated herein in the Examples. Moreover, the use of hydrophobic based water-free formulation can maximize the antimicrobial and antiviral potentials of the formulations. Delivery topically can be improved by using a hydrophobic carrier with a hydrophobic API. Storage in sealed, light and airtight canisters can assist in preserving the formulations. In one or more embodiments, the hydrophobic composition is substantially free of at least one or more of surface active agents, protic solvents, polar aprotic solvents, and silicone thickening agents. In one or more embodiments, the hydrophobic composition is substantially free of at least one or more of surface active agents, polymeric gelling agents, polyols, short chain alcohols, and silicone thickening agents. In one or more embodiments, the hydrophobic composition contains less than about 0.4% by weight of the composition; or less than about 0.2% by weight of the composition; or less than about 0.1% by weight of the composition of one of or a combination of two, three or all of surface active agents, protic solvents, polar aprotic solvents, and silicone thickening agents. In one or more embodiments, any composition of the present disclosure can also contain a fragrance. In one or more embodiments, the fragrance is at a concentration of about 0.1% by weight to about 1% by weight. In one or more embodiments, the composition comprises about 35% w/w to about 65% w/w of soybean oil. In one or more embodiments, the composition comprises about 16.5% w/w to about 30.7% w/w of coconut oil. In one or more embodiments, the composition comprises about 3.5% w/w to about 6.5% w/w of cyclomethicone. In one or more embodiments, the composition comprises about 2% w/w to about 3.7% w/w of light mineral oil. In one or more embodiments, the composition comprises about 2.5% w/w to about 4.6% w/w of cetostearyl alcohol. In one or more embodiments, the composition comprises about 2% w/w to about 4% w/w of stearic acid. In one or more embodiments, the composition comprises about 1.8% w/w to about 3.3% w/w of myristyl alcohol. In one or more embodiments, the composition comprises about 1% w/w to about 2% w/w of stearyl alcohol. In one or more embodiments, the composition comprises about 0.5% w/w to about 1.5% w/w of behenyl alcohol. In one or more embodiments, the composition comprises about 1% w/w to about 3% w/w of hydrogenated castor oil. In one or more embodiments, the composition comprises about 1% w/w to about 3% w/w of beeswax. In one or more embodiments, the composition comprises about 48% w/w to about 51% w/w of soybean oil. In one or more embodiments, the composition comprises about 23% w/w to about 24% w/w of coconut oil. In one or more embodiments, the composition comprises about 4% w/w to about 6% w/w of cyclomethicone. In one or more embodiments, the composition comprises about 1% w/w to about 5% w/w of light mineral oil. In one or more embodiments, the composition comprises about 3% w/w to about 4% w/w of cetostearyl alcohol. In one or more embodiments, the composition comprises about 2% w/w to about 4% w/w of stearic acid. In one or more embodiments, the composition comprises about 2% w/w to about 3% w/w of myristyl alcohol. In one or more embodiments, the composition comprises about 1% w/w to about 2% w/w of stearyl alcohol. In one or more embodiments, the composition comprises about 0.5% w/w to about 1.5% w/w of behenyl alcohol. In one or more embodiments, the composition comprises about 1% w/w to about 3% w/w of hydrogenated castor oil. In one or more embodiments, the composition comprises about 1% w/w to about 3% w/w of beeswax. In one or more embodiments, the composition comprises about 0.1% w/w to about 0.3% w/w of fumed (modified) silica. In one or more embodiments, the composition comprises about 1% w/w to about 4% w/w of minocycline hydrochloride or a doxycycline or a tetracycline antibiotic. In one or more embodiments, the composition comprises about 3% w/w to about 15% w/w of propellant based on the weight of the total composition. In one or more embodiments the tetracycline composition further comprises an additional active agent selected from the group consisting of an anti parasitic agent, an azole, an anti-histamine, α1 and α2 adrenergic receptor agonist, a vasoconstrictor and mixtures of any two or more thereof. In one or more embodiments the tetracycline composition further comprises an additional active agent selected from the group consisting of ivermectine, metronidazole, azelastine, oxymetazoline, brimonidine and mixtures of any two or more thereof. In one or more embodiments the tetracycline composition further comprises at least one of an additional active selected from an anti parasitic agent, an azole, an anti-histamine, α1 and α2 adrenergic receptor agonist or a vasoconstrictor. In one or more embodiments the tetracycline composition further comprises at least one of an additional active selected from ivermectine, metronidazole, azelastine, oxymetazoline or brimonidine. In one or more embodiments the tetracycline composition further comprises at least one of an additional active selected from an anti parasitic agent, an azole, an anti-histamine, α1 and α2 adrenergic receptor agonist or a vasoconstrictor, wherein the composition is configured for the treatment of rosacea. In one or more embodiments the tetracycline composition further comprises at least one of an additional active selected from ivermectine, metronidazole, azelastine, oxymetazoline or brimonidine, wherein the composition is configured for the treatment of rosacea. In one or more embodiments the composition comprises an active agent selected from the group consisting of an anti parasitic agent, an azole, an anti-histamine, α1 and α2 adrenergic receptor agonist, a vasoconstrictor and mixtures of any two or more thereof. In one or more embodiments the composition comprises an active agent selected from the group consisting of ivermectine, metronidazole, azelastine, oxymetazoline, brimonidine and mixtures of any two or more thereof. In one or more embodiments the composition comprises at least one active agent selected from an anti parasitic agent, an azole, an anti-histamine, α1 and α2 adrenergic receptor agonist and a vasoconstrictor. In one or more embodiments the composition comprises at least one active agent selected from the group consisting of ivermectine, metronidazole, azelastine, oxymetazoline, brimonidine and mixtures of any two or more thereof. In one or more embodiments the composition comprises at least one active agent selected from an anti parasitic agent, an azole, an anti-histamine, α1 and α2 adrenergic receptor agonist and a vasoconstrictor, wherein the composition is configured for the treatment of rosacea. In one or more embodiments the composition comprises at least one active agent selected from ivermectine, metronidazole, azelastine, oxymetazoline and brimonidine, wherein the composition is configured for the treatment of rosacea. In one or more embodiments the composition is configured to treat a disorder selected from an inflammatory disorders, non inflammatory disorders, atopic dermatitis, acne, dermatitis, impetigo, psoriasis and rosacea. In one or more embodiments the composition is configured to treat at least one disorder selected from an inflammatory disorder, non inflammatory disorder, atopic dermatitis, acne, dermatitis, impetigo, psoriasis and rosacea. In one or more embodiments a method for treatment of rosacea, wherein the tetracycline compositon comprises an additional agent, wherein the additional agent is selected from tetracycline antibiotic, ivermectin, azelaic acid, azelastine, isotretinoin, metronidazole, brimonidine, oxymetazoline, xylometazolin, sodium sulfacetamide and sulfur, tretinoin, a retinoid, an anti parasitic agent, an azole, an anti-histamine, α1 and α2 adrenergic receptor agonist and a vasoconstrictor. In another aspect, the ingredients of the carrier can be selected for their compatibility with tetracycline antibiotics as described. In one or more embodiments it was not sufficient to identify single ingredients that were compatible with tetracycline antibiotics but formulations had to be found in which the ingredients in combination were also compatible with tetracycline antibiotics. In one or embodiments, topical tetracycline treatments can be given with or followed by application of a steroid or a hyaluronic acid or a collagen or a silicone, clindamycin, or metronidazole, or erythromycin, or ivermectin, or azelaic acid, or brimonidine, or sodium sulfacetamide and sulfur, or tretinoin, or a retinoid or mixtures of any two or more thereof, for example to ameliorate or reduce scarring or skin damage effects. In an embodiment treatment with topical tetracycline of dry eyes caused by ocular rosacea could be followed with liquid tears and cleaning of eyelids every day with warm water. Therapeutic topical compositions must stay on the skin for a sufficient period of time to allow the active agent to be absorbed onto the skin, to perform its activity and to further exert a preventative effect. They should preferably not irritate the skin; and they should be perceived by the patient as pharmaceutically convenient in order to achieve sufficient patient compliance. By “pharmaceutically convenient”, it is meant that the skin look and feel to the patient is good, i.e., it must not be too watery or too greasy and it must easily be applied. A disadvantage of known compositions having an ointment base is greasiness; these compositions are generally considered less usable in the case of facial treatment of rosacea. Another disadvantage is that many known compositions contain surfactants, which can be irritants. It is therefore an advantage of the compositions provided herein that they are breakable gels or foams; and therefore are easy to apply to the skin and also avoid skin irritation that has been associated with compositions containing surfactants Breakable gels, which comprise liquid oils and a thickening agent, are also very convenient for use, as they liquefy on application of mild shear force such as gentle rubbing, and in turn, they readily absorb onto the skin. Foam is advantageous in the topical treatment of skin diseases, especially in skin afflicted with rosacea, since it is light and easy to apply and collapses and spreads with a minor mechanical force like a simple rub. When dispensed, even in small quantities, drug delivery in the form of foam can also cover a larger surface area of application while also facilitating better product application in areas where conventional topical products cannot be as effective. Foam absorbs rapidly—without the need of repeated rubbing—which is helpful and important for treatment of damaged or irritated skin, sores, and lesions. As the composition is absorbed quickly, this can contribute to a positive treatment effect by the vehicle alone, or when in combination with the active agent, a higher percentage effect by the active agent may be ob served. Thermally stable foam which breaks upon application of mild shear force is extremely advantageous in the topical treatment of skin diseases. It can be applied directly onto skin or hands of the patient without collapsing. The hydrophobic compositions according to the description provided herein facilitate easy application and even distribution of the active agent, thereby improving treatment convenience. This is in contrast to a temperature sensitive foam that collapses immediately on the skin so that it must first be applied onto a cool surface and then quickly applied using fingertips onto the surface, which can impede patient compliance The formulation packaged into an aerosol container is devoid of any contact with air, light, or any other form of contamination (e.g., moisture) as it is a completely sealed system throughout the life of the product. Thus, light and oxidation sensitive active agents can be effectively stabilized in the aerosol system. It should be noted that hydrophobic compositions disclosed herein can be applied to the target site as a gel or a semi-solid gel or foam. In certain other embodiments, it can be applied as a liquid gel or as a collapsed foam. In one or more embodiments, the composition is thixotropic. In one or more embodiments, the gel formulation subjected to constant shear rate shows a reduction in viscosity with time. In one or more further embodiments, after the material is allowed to rest for a period of time, the viscosity increases again. In one or more embodiments, there is provided prior to adding propellant a solid or semi-solid composition or gel. In one or more embodiments, the composition or gel is a liquid. In one or more embodiments the propellant is miscible with and dilutes the composition. Upon packaging of the foamable composition in an aerosol container and adding a propellant, a shakable and homogenous foamable composition results, which upon dispensing, forms a breakable foam with good to excellent quality. The resulting foam is pharmaceutically equivalent to the respective gel (prior to adding the propellant), since immediately upon dispensing of the foam the propellant evaporates and the composition, upon collapse, is similar or identical to that of the gel. This is an important pragmatic advantage because many drug development activities, including expensive and lengthy toxicology studies with numerous animals and clinical trials with thousands of patients can be saved by conducting such studies once for either the gel or foam presentation instead of twice (for each presentation). In one or more embodiments, such a composition is presented as a breakable gel, which breaks down with mild mechanical force. In one or more embodiments, the hydrophobic composition when packaged in an aerosol container to which is added a liquefied or compressed gas propellant the composition provides upon release from the container a breakable foam of at least good quality that breaks easily upon application of mechanical force. In one or more embodiments, the composition is a foamable composition that is thermally stable at skin temperature. In one or more embodiments, when the above composition is filled into an aerosol can or canister and pressurized with a propellant a foamable composition is produced. In one or more embodiments, a hydrophobic foamable composition (e.g., foam or gel) provided herein comprises: a) about 60% to about 99% by weight of at least one hydrophobic solvent; b) about 1% to about 22% by weight of at least one viscosity modifying agent; and c) about 0.1% to about 18% of a tetracycline antibiotic (e.g., minocycline HCl or doxycycline hyclate). In one or more embodiments, a hydrophobic foamable composition (e.g., foam or gel) provided herein comprises: a) about 60% to about 99% by weight of at least one hydrophobic solvent or carrier; b) about 1% to about 22% by weight of at least one viscosity modifying agent; c) about 0.1% to about 18% by weight of a tetracycline antibiotic (e.g., minocycline HCl or doxycycline hyclate); and d) an additional active agent. In one or more embodiments, a hydrophobic foamable composition or gel provided herein comprises: a) about 70% to about 90% by weight of at least one hydrophobic solvent; b) about 10 to about 22% by weight of at least one viscosity modifying agent; and c) about 0.5% to about 8% of a tetracycline antibiotic (e.g., minocycline HCl or doxycycline hyclate). In one or more embodiments, a hydrophobic foamable composition or gel provided herein comprises: a) about 70% to about 90% by weight of at least one hydrophobic solvent or carrier; b) about 10 to about 22% by weight of at least one viscosity modifying agent; c) about 0.5% to about 8% by weight of a tetracycline antibiotic (e.g., minocycline HCl or doxycycline hyclate); and d) an additional active agent. In one or more embodiments, a hydrophobic foamable composition or gel provided herein comprises: a) about 75% to about 90% by weight of at least one hydrophobic solvent; b) about 10 to about 22% by weight of at least one viscosity modifying agent; and c) about 0.5% to about 2% of a tetracycline antibiotic (e.g., minocycline HCl or doxycycline hyclate). In one or more embodiments, a hydrophobic foamable composition or gel provided herein comprises: a) about 75% to about 90% by weight of at least one hydrophobic solvent or carrier; b) about 10 to about 22% by weight of at least one viscosity modifying agent; c) about 0.5% to about 2% by weight of a tetracycline antibiotic (e.g., minocycline HCl or doxycycline hyclate); and d) an additional active agent. In one or more embodiments, a hydrophobic foamable composition or gel provided herein comprises: a) about 72% to about 88% by weight of at least one hydrophobic solvent; b) about 10 to about 22% by weight of at least one viscosity modifying agent; and c) about 2% to about 6% of a tetracycline antibiotic (e.g., minocycline HCl or doxycycline hyclate). In one or more embodiments, a hydrophobic foamable composition or gel provided herein comprises: a) about 72% to about 98% by weight of at least one hydrophobic solvent; b) about 1% to about 18% by weight of at least one viscosity modifying agent; and c) about 1% to about 10% of a tetracycline antibiotic (e.g., minocycline HCl or doxycycline hyclate). In one or more embodiments, a hydrophobic foamable composition or gel provided herein comprises: a) about 72% to about 88% by weight of at least one hydrophobic solvent or carrier; b) about 10 to about 22% by weight of at least one viscosity modifying agent; c) about 2% to about 6% by weight of a tetracycline antibiotic (e.g., minocycline HCl or doxycycline hyclate); and d) an additional active agent. In one or more embodiments, the hydrophobic gel or foam composition for use in the method comprises: a) about 60% to about 95% by weight of at least one hydrophobic solvent or carrier; b) at least one viscosity-modifying agent selected from the group consisting of a fatty alcohol, a fatty acid, and a wax; c) a therapeutically effective amount of a tetracycline antibiotic; and d) an additional active agent. In one or more embodiments, there is provided a hydrophobic foam or gel composition comprising: a) about 50% by weight of soybean oil; b) about 23.6% by weight of coconut oil; c) about 5% by weight of cyclomethicone; d) about 2.8% by weight of light mineral oil; e) about 3.5% by weight of cetostearyl alcohol; f) about 3% by weight of stearic acid; g) about 2.5% by weight of myristyl alcohol; about 2% by weight of hydrogenated castor oil; h) about 2% by weight of beeswax; i) about 1.5% by weight of stearyl alcohol; j) about 1.1% by weight of behenyl alcohol; and k) about 3% by weight of minocycline. In one or more embodiments, there is provided a hydrophobic foam or gel composition comprising: a) about 50% by weight of soybean oil; b) about 23.6% by weight of coconut oil; c) about 5% by weight of cyclomethicone; d) about 4.3% by weight of light mineral oil; e) about 3.5% by weight of cetostearyl alcohol; f) about 3% by weight of stearic acid; g) about 2.5% by weight of myristyl alcohol; h) about 2% by weight of hydrogenated castor oil; i) about 2% by weight of beeswax; j) about 1.5% by weight of stearyl alcohol; k) about 1.1% by weight of behenyl alcohol; and 1) about 1.5% by weight of minocycline. In one or more embodiments, there is provided a hydrophobic foam or gel composition comprising: a) about 35% to about 65% by weight of soybean oil; b) about 16.5% to about 30.7% by weight of coconut oil; c) about 3.5% to about 6.5% by weight of cyclomethicone; d) about 2% to about 3.7% by weight of light mineral oil; e) about 2.5% to about 4.6% by weight of cetostearyl alcohol; f) about 2.1% to about 4% by weight of stearic acid; g) about 1.8% to about 3.3% by weight of myristyl alcohol; h) about 1.4% to about 2.6% by weight of hydrogenated castor oil; i) about 1.4% to about 2.6% by weight of beeswax; j) about 1% to about 2% by weight of stearyl alcohol; k) about 0.8% to about 1.4% by weight of behenyl alcohol; and 1) about 2.1% to about 4% by weight of minocycline. In one or more embodiments, there is provided a hydrophobic foam or gel composition comprising: a) about 35% to about 65% by weight of soybean oil; b) about 16.5% to about 30.7% by weight of coconut oil; c) about 3.5% to about 6.5% by weight of cyclomethicone; d) about 3% to about 5.6% by weight of light mineral oil; e) about 2.5% to about 4.6% by weight of cetostearyl alcohol; f) about 2.1% to about 4% by weight of stearic acid; g) about 1.8% to about 3.3% by weight of myristyl alcohol; h) about 1.4% to about 2.6% by weight of hydrogenated castor oil; i) about 1.4% to about 2.6% by weight of beeswax; j) about 1% to about 2% by weight of stearyl alcohol; k) about 0.8% to about 1.4% by weight of behenyl alcohol; and 1) about 1% to about 2% by weight of minocycline. In one or more embodiments there is provided a method of treatment for reducing skin redness in a subject having a disorder in which one of the etiological factors is skin redness comprising applying a topical composition to an area of skin with the disorder, wherein the topical composition comprises: a) about 50% by weight of soybean oil; b) about 23.6% by weight of coconut oil; c) about 5% by weight of cyclomethicone; d) about 2.8% by weight of light mineral oil; e) about 3.5% by weight of cetostearyl alcohol; f) about 3% by weight of stearic acid; g) about 2.5% by weight of myristyl alcohol; h) about 2% by weight of hydrogenated castor oil; i) about 2% by weight of beeswax; j) about 1.5% by weight of stearyl alcohol; k) about 1.1% by weight of behenyl alcohol; and 1) about 3% by weight of minocycline. In one or more embodiments there is provided a method of treatment for reducing skin redness in a subject having a disorder in which one of the etiological factors is skin redness comprising applying a topical composition to an area of skin with the disorder, wherein the topical composition comprises: a) about 50% by weight of soybean oil; b) about 23.6% by weight of coconut oil; c) about 5% by weight of cyclomethicone; d) about 4.3% by weight of light mineral oil; e) about 3.5% by weight of cetostearyl alcohol; f) about 3% by weight of stearic acid; g) about 2.5% by weight of myristyl alcohol; h) about 2% by weight of hydrogenated castor oil; i) about 2% by weight of beeswax; j) about 1.5% by weight of stearyl alcohol; k) about 1.1% by weight of behenyl alcohol; and 1) about 1.5% by weight of minocycline. In one or more embodiments there is provided a method of treatment for reducing skin redness in a subject having a disorder in which one of the etiological factors is skin redness comprising applying a topical composition to an area of skin with the disorder, wherein the topical composition comprises: a) about 35% to about 65% by weight of soybean oil; b) about 16.5% to about 30.7% by weight of coconut oil; c) about 3.5% to about 6.5% by weight of cyclomethicone; d) about 2% to about 3.7% by weight of light mineral oil; e) about 2.5% to about 4.6% by weight of cetostearyl alcohol; f) about 2.1% to about 4% by weight of stearic acid; g) about 1.8% to about 3.3% by weight of myristyl alcohol; about 1.4% to about 2.6% by weight of hydrogenated castor oil; i) about 1.4% to about 2.6% by weight of beeswax; j) about 1% to about 2% by weight of stearyl alcohol; k) about 0.8% to about 1.4% by weight of behenyl alcohol; and 1) about 2.1% to about 4% by weight of minocycline. In one or more embodiments there is provided a method of treatment for reducing skin redness in a subject having a disorder in which one of the etiological factors is skin redness comprising applying a topical composition to an area of skin with the disorder, wherein the topical composition comprises: a) about 35% to about 65% by weight of soybean oil; b) about 16.5% to about 30.7% by weight of coconut oil; c) about 3.5% to about 6.5% by weight of cyclomethicone; d) about 3% to about 5.6% by weight of light mineral oil; e) about 2.5% to about 4.6% by weight of cetostearyl alcohol; f) about 2.1% to about 4% by weight of stearic acid; g) about 1.8% to about 3.3% by weight of myristyl alcohol; h) about 1.4% to about 2.6% by weight of hydrogenated castor oil; i) about 1.4% to about 2.6% by weight of beeswax; j) about 1% to about 2% by weight of stearyl alcohol; k) about 0.8% to about 1.4% by weight of behenyl alcohol; and 1) about 1% to about 2% by weight of minocycline. In one or more embodiments, the hydrophobic gel or foam composition for use in the methods provided herein comprises: a) about 57.6% to about 87.5% by weight of heavy mineral oil; b) about 3.5% to about 6.5% by weight of light mineral oil; c) about 3.2% to about 5.9% by weight of stearyl alcohol; d) about 1.75% to about 3.25% by weight of stearic acid; e) about 0.8% to about 1.4% by weight of behenyl alcohol; and f) about 3.3% to about 6.1% by weight of minocycline hydrochloride or doxycycline hyclate. In one or more embodiments, the hydrophobic gel or foam composition for use in the methods provided herein comprises: a) about 65.8% to about 86% by weight of heavy mineral oil; b) about 4% to about 6% by weight of light mineral oil; c) about 3.6% to about 5.4% by weight of stearyl alcohol; d) about 2% to about 3% by weight of stearic acid; e) about 0.9% to about 1.3% by weight of behenyl alcohol; and f) about 3.7% to about 5.6% by weight of minocycline hydrochloride or doxycycline hyclate. In one or more embodiments, the hydrophobic gel or foam composition for use in the methods provided herein comprises: a) about 74% to about 84% by weight of heavy mineral oil; b) about 4.5% to about 5.5% by weight of light mineral oil; c) about 4.1% to about 5% by weight of stearyl alcohol; d) about 2.3% to about 2.8% by weight of stearic acid; e) about 1% to about 1.2% by weight of behenyl alcohol; and f) about 4.2% to about 5.1% by weight of minocycline hydrochloride or doxycycline hyclate. In one or more embodiments, the hydrophobic gel or foam composition for use in the methods provided herein comprises: a) about 31.8% to about 59.2% by weight of light mineral oil; b) about 31.5% to about 58.5% by weight of soybean oil; c) about 2.8% to about 5.2% by weight of stearyl alcohol; d) about 0.2% to about 0.8% by weight of behenyl alcohol; and e) about 3.3% to about 6.2% by weight of minocycline hydrochloride or doxycycline hyclate. In one or more embodiments, the hydrophobic gel or foam composition for use in the methods provided herein comprises: a) about 82.24% by weight of heavy mineral oil; b) about 5% by weight of light mineral oil; c) about 4.5% by weight of stearyl alcohol; d) about 2.5% by weight of stearic acid; e) about 1.1% by weight of behenyl alcohol; and f) about 4.66% by weight of minocycline hydrochloride or doxycycline hyclate. In one or more embodiments, the hydrophobic gel or foam composition for use in the methods provided herein comprises: a) about 62% to about 91.7% by weight of heavy mineral oil, light mineral oil or combinations thereof; b) about 2.6% to about 4.8% by weight of stearyl alcohol; c) about 1.75% to about 3.25% by weight of stearic acid; d) about 0.5% to about 0.9% by weight of behenyl alcohol; e) about 0.14% to about 0.26% by weight of paraffin 51-53; and f) about 3.3% to about 6.1% by weight of minocycline hydrochloride or doxycycline hyclate. In one or more embodiments, the hydrophobic gel or foam composition for use in the methods provided herein comprises: a) about 70.6% to about 90.6% by weight of heavy mineral oil, light mineral oil or combinations thereof; b) about 3% to about 4.4% by weight of stearyl alcohol; c) about 2% to about 3% by weight of stearic acid; d) about 0.56% to about 0.84% by weight of behenyl alcohol; e) about 0.16% to about 0.24% by weight of paraffin 51-53; and f) about 3.7% to about 5.6% by weight of minocycline hydrochloride or doxycycline hyclate. In one or more embodiments, the hydrophobic gel or foam composition for use in the methods provided herein comprises: a) about 79.4% to about 89.4% by weight of heavy mineral oil, light mineral oil or combinations thereof; b) about 3.3% to about 4.1% by weight of stearyl alcohol; c) about 2.3% to about 2.8% by weight of stearic acid; d) about 0.63% to about 0.77% by weight of behenyl alcohol; e) about 0.18% to about 0.22% by weight of paraffin 51-53; and f) about 4.2% to about 5.6% by weight of minocycline hydrochloride or doxycycline hyclate. In one or more embodiments, the hydrophobic gel or foam composition for use in the methods provided herein comprises: a) about 63% to about 98% by weight of heavy mineral oil; b) about 0.1% to about 15% by weight of light mineral oil; c) about 0.5% to about 7% by weight of stearyl alcohol; d) about 0.5% to about 5% by weight of stearic acid; e) about 0.2% to about 2% by weight of behenyl alcohol; and f) about 1% to about 8% by weight of minocycline hydrochloride or doxycycline hyclate. In one or more embodiments, the hydrophobic gel or foam composition for use in the methods provided herein comprises: a) about 73% to about 98% by weight of heavy mineral oil, light mineral oil or combinations thereof; b) about 0.5% to about 7% by weight of stearyl alcohol; c) about 0.5% to about 5% by weight of stearic acid; d) about 0.2% to about 2% by weight of behenyl alcohol; e) about 0.1% to about 5% by weight of paraffin 51-53; and f) about 1% to about 8% by weight of minocycline hydrochloride or doxycycline hyclate. In one or more embodiments, the hydrophobic gel or foam composition for use in the methods provided herein comprises: a) about 81.94% by weight of heavy mineral oil; b) about 5% by weight of light mineral oil; c) about 4.5% by weight of stearyl alcohol; d) about 2.5% by weight of stearic acid; e) about 1.1% by weight of behenyl alcohol; f) about 4.66% by weight of minocycline hydrochloride or doxycycline hyclate; and g) about 0.3% by weight of adapalene. In one or more embodiments, the hydrophobic gel or foam composition for use in the methods provided herein comprises: a) about 82% by weight of heavy mineral oil; b) about 5% by weight of light mineral oil; c) about 4.5% by weight of stearyl alcohol; d) about 2.5% by weight of stearic acid; e) about 1.1% by weight of behenyl alcohol; f) about 4.8% by weight of minocycline hydrochloride or doxycycline hyclate; and g) about 0.1% by weight of adapalene. In one or more embodiments, the hydrophobic gel or foam composition for use in the methods provided herein comprises: a) about 88.6% by weight of heavy mineral oil; b) about 3.6% by weight of stearyl alcohol; c) about 2.4% by weight of stearic acid; d) about 0.5% by weight of behenyl alcohol; e) about 4.8% by weight of minocycline hydrochloride or doxycycline hyclate; and f) about 0.1% by weight of adapalene. In one or more embodiments, the hydrophobic gel or foam composition for use in the methods provided herein comprises: a) about 50% by weight of soybean oil; b) about 23.6% by weight of coconut oil; c) about 5% by weight of cyclomethicone; d) about 0.7% by weight of light mineral oil; e) about 3.5% by weight of cetostearyl alcohol; f) about 3% by weight of stearic acid; g) about 2.5% by weight of myristyl alcohol; h) about 2% by weight of hydrogenated castor oil; i) about 2% by weight of beeswax; j) about 1.5% by weight of stearyl alcohol; k) about 1.1% by weight of behenyl alcohol; 1) about 4.8% by weight of minocycline hydrochloride or doxycycline hyclate; and m) about 0.3% by weight of adapalene. In one or more embodiments, the hydrophobic gel or foam composition for use in the methods provided herein comprises: a) about 49% by weight of heavy mineral oil; b) about 39% by weight of light mineral oil; c) about 3.8% by weight of stearyl alcohol; d) about 2.4% by weight of stearic acid; e) about 0.7% by weight of behenyl alcohol; f) about 4.8% by weight of minocycline hydrochloride or doxycycline hyclate; and g) about 0.3% by weight of adapalene. In one or more embodiments, the hydrophobic gel or foam composition for use in the methods provided herein comprises: a) about 43.4% by weight of heavy mineral oil; b) about 39% by weight of light mineral oil; c) about 4.3% by weight of stearyl alcohol; d) about 2.5% by weight of stearic acid; e) about 5% by weight of cyclomethicone; f) about 0.7% by weight of behenyl alcohol; g) about 4.8% by weight of minocycline hydrochloride or doxycycline hyclate; and h) about 0.3% by weight of adapalene. In one or more embodiments, the hydrophobic gel or foam composition for use in the methods provided herein comprises: a) about 45.55% by weight of light mineral oil; b) about 45.05% by weight of soybean oil; c) about 4.0% by weight of stearyl alcohol; d) about 0.6% by weight of behenyl alcohol; e) about 4.8% by weight of minocycline hydrochloride or doxycycline hyclate. In one or more embodiments, the compositions provided or described herein comprise a carrier and a propellant. In one or more embodiments, the carrier comprises or is a hydrophobic gel or foamable composition provided or described herein. In one or more embodiments, the composition is a gel, paste, lotion, cream, soap, spray, mask, patch, powder, pomade, ointment, oil, foam or mousse. In one or more embodiments, the composition is hydrophobic. In one or more embodiments, the composition comprises hydrophobic oils and waxes. In one or more embodiments, the composition comprises fatty alcohols. In one or more embodiments, the composition comprises hydrophobic oils and fatty alcohols. In one or more embodiments, the composition comprises fatty acids. In one or more embodiments, the composition comprises hydrophobic oils and fatty acids. In one or more embodiments, the composition is surfactant free. In one or more embodiments, the composition is substantially free of a fatty acid or of a fatty alcohol or of a wax or any two thereof. In one or more embodiments, the composition is essentially free of a fatty acid or of a fatty alcohol or of a wax or any two thereof. In one or more embodiments, the composition is free of a fatty acid or of a fatty alcohol or of a wax or any two thereof. In one or more embodiments, the hydrophobic composition comprises a gelled oil. In one or more embodiments, the gelled oil is a gelled mineral oil. In one or more embodiments, the gelled mineral oil is a VERSAGEL®. VERSAGELs® are gelled oils or emollients that can come in different product forms including, for example, the VERSAGEL® m, VERSAGEL® p, VERSAGEL® r, and VERSAGEL® s series, and provide various viscosity grades. There are also VERSAGELs® with isohexadecane, or with isododecane, or with hydrogenated polyisobutene, or with isopropylpalmitate. In an embodiment, it is VERSAGEL® 750 m. In an embodiment, it is VERSAGEL® 200 m. In an embodiment, it is VERSAGEL® 500 m. In an embodiment, it is VERSAGEL® 1600 m. VERSAGEL® m contains a mixture of mineral oil plus one or two or more of e.g., Ethylene/Propylene/Styrene Copolymer plus e.g., Butylene/Ethylene/Styrene Copolymer plus e.g., butylated hydroxyl toluene or similar gelling agents. In one or more embodiments, the gelled oil is at a concentration of about 55% to about 85% by weight. In one or more embodiments, the gelled oil is at a concentration of about 60% to about 80% by weight. In one or more embodiments, gelled oil is at a concentration of about 65% to about 75% by weight. In one or more embodiments, the hydrophobic solvent is at a concentration of about 75% to about 90% by weight. In one or more embodiments, the hydrophobic solvent is at a concentration of about 21% to about 39% by weight. In one or more embodiments, the hydrophobic solvent is at a concentration of about 26% to about 34% by weight. In one or more embodiments, the hydrophobic solvent is at a concentration of about 9% to about 24% by weight. In one or more embodiments, the hydrophobic solvent comprises a petrolatum at a concentration of about 9% to about 24% by weight, or about 26% to about 34% by weight or about 21% to about 39% by weight, or about 45% by weight, or about 50% by weight or about 55% by weight or about 60% by weight. Topical hydrophobic therapeutic breakable gel and foamable compositions comprising tetracycline, including those without surfactants, have been described, for example in U.S. application Ser. Nos. 13/499,501, 13/499,727, 13/499,475, and 13/499,709, U.S. Publication No. 2011/0281827, WO 11/039637, WO 11/039638, WO 11/138678 and WO 2011/064631, all of which are herein incorporated in their entirety by reference. More particularly, any of the active ingredients, carriers, solvents, surfactants, foam adjuvants, fatty acids, fatty alcohols, polymeric agents, penetration enhancers, preservatives, humectants, moisturizers, and other excipients, as well as the propellants and methods listed therein can be applied herein and are incorporated by reference. Other carriers and compositions are described in: U.S. Publication No. 2005/0232869, published on Oct. 20, 2005, entitled NONSTEROIDAL IMMUNOMODULATING KIT AND COMPOSITION AND USES THEREOF; U.S. Publication No. 2005/0205086, published on Sep. 22, 2005, entitled RETINOID IMMUNOMODULATING KIT AND COMPOSITION AND USES THEREOF; U.S. Publication No. 2006/0018937, published on Jan. 26, 2006, entitled STEROID KIT AND FOAMABLE COMPOSITION AND USES THEREOF; U.S. Publication No. 2005/0271596, published on Dec. 8, 2005, entitled VASOACTIVE KIT AND COMPOSITION AND USES THEREOF; U.S. Publication No. 2006/0269485, published on Nov. 30, 2006, entitled ANTIBIOTIC KIT AND COMPOSITION AND USES THEREOF; U.S. Publication No. 2007/0292355, published on Dec. 20, 2007, entitled ANTI-INFECTION AUGMENTATION OF FOAMABLE COMPOSITIONS AND KIT AND USES THEREOF; U.S. Publication No. 2008/0317679, published on Dec. 25, 2008, entitled FOAMABLE COMPOSITIONS AND KITS COMPRISING ONE OR MORE OF A CHANNEL AGENT, A CHOLINERGIC AGENT, A NITRIC OXIDE DONOR, AND RELATED AGENTS AND THEIR USES; U.S. Publication No. 2008/0044444, published on Feb. 21, 2008, entitled DICARBOXYLIC ACID FOAMABLE VEHICLE AND PHARMACEUTICAL COMPOSITIONS THEREOF; U.S. Publication No. 2008/0069779, published on Mar. 20, 2008, entitled FOAMABLE VEHICLE AND VITAMIN AND FLAVONOID PHARMACEUTICAL COMPOSITIONS THEREOF; U.S. Publication No. 2008/0206159, published on Aug. 28, 2008, entitled COMPOSITIONS WITH MODULATING AGENTS; U.S. Publication No. 2008/0206161, published on Aug. 28, 2008, entitled QUIESCENT FOAMABLE COMPOSITIONS, STEROIDS, KITS AND USES THEREOF; U.S. Publication No. 2008/0260655, published on Oct. 23, 2008, entitled SUBSTANTIALLY NON-AQUEOUS FOAMABLE PETROLATUM BASED PHARMACEUTICAL AND COSMETIC COMPOSITIONS AND THEIR USES; U.S. Publication No. 2011/0268665, published on Nov. 3, 2011, entitled OIL-BASED FOAMABLE CARRIERS AND FORMULATIONS; U.S. Publication No. 2012/0087872, published on Apr. 12, 2012, entitled FOAMABLE VEHICLES AND PHARMACEUTICAL COMPOSITIONS COMPRISING APROTIC POLAR SOLVENTS AND USES THEREOF; U.S. Publication No. 2012/0213709, published on Aug. 23, 2012, entitled NON SURFACTANT HYDRO-ALCOHOLIC FOAMABLE COMPOSITIONS, BREAKABLE FOAMS AND THEIR USES; U.S. Publication No. 2012/0213710, published on Aug. 23, 2012, entitled SURFACE ACTIVE AGENT NON POLYMERIC AGENT HYDRO-ALCOHOLIC FOAMABLE COMPOSITIONS, BREAKABLE FOAMS AND THEIR USES; U.S. Publication No. 2013/0064777, published on Mar. 14, 2013, entitled SURFACTANT-FREE WATER-FREE FOAMABLE COMPOSITIONS, BREAKABLE FOAMS AND GELS AND THEIR USES; U.S. Publication No. 2013/0053353, published on Feb. 28, 2013, entitled COMPOSITIONS, GELS AND FOAMS WITH RHEOLOGY MODULATORS AND USES THEREOF; U.S. Publication No. 2011/0281827, published on Nov. 17, 2011, entitled COMPOSITIONS, GELS AND FOAMS WITH RHEOLOGY MODULATORS AND USES THEREOF; U.S. Publication No. 2013/0028850, published on Jan. 31, 2013, entitled TOPICAL TETRACYCLINE COMPOSITIONS; U.S. Publication No. 2013/0011342, published on Jan. 10, 2013, entitled SURFACTANT-FREE, WATER-FREE, FOAMABLE COMPOSITIONS AND BREAKABLE FOAMS AND THEIR USES; U.S. Publication No. 2013/0225536, published on Aug. 29, 2013, entitled COMPOSITIONS FOR THE IMPROVED TREATMENT OF ACNE AND RELATED DISORDERS; U.S. Publication No. 2014/0121188, published on May 1, 2014, entitled METHODS FOR ACCELERATED RETURN OF SKIN INTEGRITY AND FOR THE TREATMENT OF IMPETIGO; U.S. Publication No. 2015/0164922, published on Jun. 18, 2015, entitled USE OF TETRACYCLINE COMPOSITIONS FOR WOUND TREATMENT AND SKIN RESTORATION, all of which are incorporated herein by reference in their entirety. More particularly, any of the active ingredients, carriers, solvents, surfactants, foam adjuvants, polymeric agents, penetration enhancers, preservatives, humectants, moisturizers, and other excipients, as well as the propellants and methods listed therein can be applied herein and are incorporated by reference. Manufacture The present disclosure also provides a method of manufacturing a gel or foam composition having a tetracycline antibiotic, the method comprising: providing a composition having one or more hydrophobic solvents; heating said composition; adding fatty alcohols, fatty acids and waxes; cooling said composition; optionally adding SiO2; and adding a tetracycline antibiotic. The compositions provided herein are manufactured according to the methods described in the art and as described in Example 1. Gels are usually packaged in a tube but can also be packaged in any other convenient delivery form including for example, bottles with a pump mechanism or canisters such as bag in can devices where propellant is separate from the gel. Foam formulations are usually packed in a container with an outlet valve e.g., aerosol canister. Possible containers and valves are likewise described in the literature as known by those skilled in the art. According to another aspect, both the minocycline and the foamable compositions containing minocycline can be manufactured under current Good Manufacturing Principles (cGMP) conditions. The foamable composition was provided in aluminum aerosol canisters mounted with valve and actuator. Each canister was filled with 25 g of product and 3 g of propellant. Upon actuation of the canister an aliquot of quality foam was released. Administration In one or more embodiments there is provided a method of administering a tetracycline foam composition to a target area such as skin of a patient comprising releasing foam, applying it to the area, and collapsing the foam. In one or embodiments, the foam is applied by spreading. In the course of spreading mechanical shear can cause the foam to collapse. In one or more embodiments, the collapsed foam is not washed off. In one or more embodiments it is absorbed onto the area of skin. In one or more embodiments it avoids skin irritation or an ointment sensation. In one or more embodiments, there is provided a method of applying a tetracycline gel composition to an area of skin of a patient comprising releasing a gel, applying it to the area, and collapsing or liquefying the gel. In one or more embodiments, the collapsed or liquefied gel is not washed off. In one or more embodiments, the collapsed or liquefied gel is readily absorbed and does not leave an ointment sensation. In one or more embodiments, there is provided a method for reducing the number of rosacea lesions, by applying topically an effective amount of a tetracycline gel, liquid gel or foam to an afflicted area of a patient in need. In one or more embodiments, the method involves applying a gel, liquid, gel or foam formulation topically to a target surface in need of treatment and breaking the gel or foam over the target site. In one or more embodiments the gel or foam is collapsed and spread by application of a mechanical force, which can be mild or slight such as a simple rub and the active agent is then absorbed. In one or more embodiments the foam or gel is absorbed. In one or more embodiments, a gel or a liquid gel or a collapsed foam is absorbed within 240 seconds, or within 200 seconds, or within 180 seconds, or within 150 seconds, within 120 seconds, or within 100 seconds, or within 80 seconds, or within 60 seconds, or within 50 seconds, or within 40 seconds, or within 30 seconds, or within 20 seconds, or within 10 seconds, or within 5 seconds, or within 2 seconds or less. The term “absorbed” means that the composition enters onto and into an area of skin, mucosa or eye, often forming a thin coating on the surface. In one or more embodiments, the method uses an additional step of pre cleaning and drying the lesions and surrounding area before applying the gel, liquid gel or foam. In one or more embodiments, the method uses a sterile applicator or prior to the steps of administering and/or collapsing and/or spreading, the hands of the person spreading are sterilized in order to avoid cross contamination. In one or more other embodiments, the method comprises an additional step of applying an active agent to the lesions and surrounding area after the gel, liquid gel or foam has been absorbed, wherein the active agent is a hyaluronic acid or a retinoid or BPO or salicylic acid, or an alpha hydroxy acid, or azelaic acid, or nicotinamide, or a keratolytic agent, or clindamycin, or metronidazole, or doxycycline, or erythromycin, or ivermectin, or brimonidine, or sodium sulfacetamide and sulfur, or tretinoin. In some embodiments, the active agent, such as, for example, a hyaluronic acid, a retinoid, BPO, salicylic acid, an alpha hydroxy acid, azelaic acid, a nicotinamide, a keratolytic agent, clindamycin, metronidazole, erythromycin, ivermectin, brimonidine, sodium sulfacetamide and sulfur, tretinoin, or mixtures of two or more thereof, is applied once daily at least 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 hours after the tetracycline antibiotic formulation has been absorbed. In further embodiments, the active agent, such as, for example, a hyaluronic acid or a retinoid or BPO or salicylic acid, or an alpha hydroxy acid, or azelaic acid, or nicotinamide, or a keratolytic, or clindamycin, or metronidazole, or erythromycin, or ivermectin, or brimonidine, or sodium sulfacetamide and sulfur, or tretinoin, is applied after the third day. In yet additional embodiments, the active agent, such as, for example, a hyaluronic acid or a retinoid or BPO or salicylic acid, or an alpha hydroxy acid, or azelaic acid, or nicotinamide, or a keratolytic agent, or clindamycin, or metronidazole, or erythromycin, or ivermectin, or brimonidine, or sodium sulfacetamide and sulfur, or tretinoin, is applied during the maintenance stage. In an alternative embodiment, the active agent, such as, for example, a hyaluronic acid or a retinoid or BPO or salicylic acid, or an alpha hydroxy acid, or azelaic acid, or nicotinamide, or a keratolytic agent, or clindamycin, or metronidazole, or erythromycin, or ivermectin, or brimonidine, or sodium sulfacetamide and sulfur, or tretinoin, is replaced with or supplemented by a steroid. In an alternative embodiment, the active agent, such as, for example, a hyaluronic acid or a retinoid or BPO or salicylic acid, or an alpha hydroxy acid, or azelaic acid, or nicotinamide, or a keratolytic agent or steroid, or clindamycin, or metronidazole, or erythromycin, or ivermectin, or brimonidine, or sodium sulfacetamide and sulfur, or tretinoin, is replaced with or supplemented by an antibiotic. In an embodiment, the antibiotic, which is in addition to one or more tetracycline antibiotics, is selected from the group consisting of mupirocin, fusidic acid, a penicillin or penicillin derivative, augmentin, an anti staphylococcal penicillin, amoxicillin/clavulanate, a cephalosporin, cephalexin, a macrolide, erythromycin, clindamycin, trimethoprim-sulfamethoxazole penicillin, retapamulin, and mixtures of any two or more thereof. In an embodiment the antibiotic is applied topically. In another embodiment it is applied orally or by injection or by infusion. In another embodiment more than one antibiotic is applied. For example, one is applied topically and another is given orally. The latter can be appropriate for example where there is a systemic as well as a topical bacterial infection. Frequency In one or more embodiments there is provided a regime or regimen for treating a patient having one or more of rosacea, and/or rosacea related symptoms, and/or a tetracycline antibiotic responsive rosacea related disorder, and/or a tetracycline antibiotic responsive skin disorder, and/or skin disorder caused by a bacteria, and/or a tetracycline antibiotic responsive disorder, and/or a sebaceous gland disorder, which comprises applying to the afflicted area on a regular basis a hydrophobic gel or foam composition, said composition comprising a therapeutically effective amount of a tetracycline antibiotic. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, once a day, to a surface having rosacea a composition comprising a tetracycline antibiotic. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, twice a day, to a surface having rosacea a composition comprising a tetracycline antibiotic. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, alternate-day or intermittently, to a surface having rosacea a composition comprising a tetracycline antibiotic. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, gradual reduction to a lower maintenance dose, which can be increased if further outbreaks occur, to a surface having rosacea a composition comprising a tetracycline antibiotic. In one or more embodiments, a maintenance dose can be applied topically, daily, alternate daily, twice weekly or weekly for a month, two months, quarterly, six months or indefinitely. A maintenance dose can include about 0.9%, or about 0.8%, or about 0.7%, or about 0.6%, or about 0.5%, or about 0.4%, or about 0.3%, or about 0.2%, or about 0.1%, or about 0.09%, or about 0.08%, or about 0.07%, or about 0.06%, or about 0.05% by weight of a tetracycline antibiotic. In one or more embodiments, the maintenance dose can be commenced after four weeks of treatment, or after five weeks of treatment, or after six weeks of treatment, or after seven weeks of treatment, or after eight weeks of treatment, or after nine weeks of treatment, or after ten weeks of treatment, or after eleven weeks of treatment, or after twelve weeks of treatment, or after thirteen weeks of treatment, or after fourteen weeks of treatment, or after fifteen weeks of treatment, or after sixteen weeks of treatment. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, once daily for at least four weeks, to a surface having rosacea a composition comprising a tetracycline antibiotic. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, once daily up to four weeks, to a surface having rosacea a composition comprising a tetracycline antibiotic. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, once daily for twelve weeks or less than twelve weeks, to a surface having rosacea a composition comprising a tetracycline antibiotic. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, once daily for four weeks or less than four weeks, to a surface having rosacea a composition comprising a tetracycline antibiotic. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, once daily for three weeks or less than three weeks, to a surface having rosacea a composition comprising a tetracycline antibiotic. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, once daily for two weeks or less than two weeks, to a surface having rosacea a composition comprising a tetracycline antibiotic In one or more embodiments, there is provided a method for treating a condition involving inflammation of the skin or mucosa (the disorder), including administering topically, once daily for six weeks or less than six weeks, to a surface having the disorder a gel of foam composition comprising a tetracycline antibiotic. Application can be, hourly, every twelve hours (e.g., twice daily), once daily, alternate-day or intermittent, according to the condition of the patient. For reasons of compliance, less frequent applications, where possible, are preferable, e.g., daily single applications. In certain cases, where prolonged or long term treatment is required, an initial dose is provided followed by a gradual reduction to a lower maintenance dose, which can be increased if further outbreaks occur. In one or more embodiments there is provided a hydrophobic gel or foam composition comprising a tetracycline antibiotic for use in treating one or more of rosacea, and/or rosacea related symptoms, and/or a tetracycline antibiotic responsive rosacea related disorder, and/or a tetracycline antibiotic responsive skin disorder, and/or skin disorder caused by a bacteria, and/or a tetracycline antibiotic responsive disorder, and/or a sebaceous gland disorder, including skin infections, wherein the hydrophobic gel or foam composition is administered topically at least alternate days or at least once daily for twelve weeks or less than twelve weeks of treatment. In one or more embodiments there is provided a hydrophobic gel or foam composition comprising a minocycline antibiotic for use in treating a disorder selected from the group consisting of rosacea, and/or rosacea related symptoms, and/or a tetracycline antibiotic responsive rosacea related disorder, and/or a tetracycline antibiotic responsive skin disorder, and/or skin disorder caused by a bacteria, and/or a tetracycline antibiotic responsive disorder, and/or a sebaceous gland disorder, wherein the hydrophobic gel or foam composition is administered topically at least alternate days or at least once daily for at least six weeks to the skin, wherein the minocycline antibiotic is the sole active ingredient present in the composition. In one or more embodiments there is provided a hydrophobic foam composition or gel comprising a tetracycline antibiotic for use in retarding, arresting, or reversing the progression of one or more of rosacea, and/or rosacea related symptoms, and/or a tetracycline antibiotic responsive rosacea related disorder, and/or a tetracycline antibiotic responsive skin disorder, and/or skin disorder caused by a bacteria, and/or a tetracycline antibiotic responsive disorder, and/or a sebaceous gland disorder, wherein the hydrophobic foam composition or gel is applied topically to the skin at least alternate days or at least once a day for at least six weeks. In one or more embodiments, the method uses a once daily dosage regime for twelve weeks or less than twelve weeks. In one or more embodiments the twelve-week dosage regime is followed by a once daily maintenance dose for one, two, three, four or more weeks according to the condition and response of the patient. In one or more embodiments, the method uses a once daily dosage regime for six weeks or less than six weeks. In one or more embodiments the six-week dosage regime is followed by a once daily maintenance dose for one, two, three, four or more weeks according to the condition and response of the patient. In one or more embodiments, the method uses a once daily dosage regime of for six weeks or less than six weeks followed by a once weekly maintenance dose for one, two, three, four, five, six, seven, eight, nine, ten, eleven or more weeks according to the condition and response of the patient. In one or more embodiments, the method uses a once daily dosage regime of for three weeks or less than three weeks followed by a once weekly maintenance dose for one, two, three, four, five, six, seven, eight, nine, ten, eleven or more weeks according to the condition and response of the patient. In one or more embodiments, the method uses a once daily dosage regime of for two weeks followed by a daily maintenance dose for one, two, three or more weeks according to the condition and response of the patient. In one or more embodiments the method uses a once daily dosage regime of for twelve weeks wherein the treatment is every alternate week. Combination Therapy Several disorders involve a combination of more than one etiological factor; and therefore, the use of more than one active agent is advantageous. For example, psoriasis involves excessive cell proliferation and inadequate cell differentiation as well as inflammation. Atopic dermatitis involves keratinocyte growth abnormality, skin dryness and inflammation. Bacterial, fungal and viral infections involve pathogen colonization at the affected site and inflammation. Hence, in many cases, the inclusion of a combination of active agents in the pharmaceutical composition can be desirable. Thus, in one or more embodiments, the composition includes at least two active agents, in a therapeutically effective concentration. In one or more embodiments, a combination of any two or more of an antibacterial, an anti-inflammatory, an antifungal, and an antiviral agent is contemplated. In one or more embodiments, a tetracycline antibiotic is the sole active ingredient present in the composition. In one or more embodiments, a minocycline is the sole active ingredient present in the composition. In one or more embodiments, a doxycycline is the sole active ingredient present in the composition. In one or more embodiments minocycline and doxycycline are used in combination. In one or more embodiments, a combination of any two or more of a minocycline, retinoids, and benzoyl peroxide is contemplated In one or more embodiments, a combination of any two or more of a tetracycline, retinoids, and benzoyl peroxide is contemplated. In one or more embodiments, a combination of any two or more of benzoyl peroxide, antibiotics, retinoids, antiseborrheic medications, anti-androgen medications, hormonal treatments, salicylic acid, alpha hydroxy acid, azelaic acid, nicotinamide, and a keratolytic agent is contemplated. In one or more embodiments the tetracycline is combined with adapalene. Disease Indications The diseases or disorders treated by the composition provided herein include, for example, rosacea. Rosacea may begin as redness on the central face across the cheeks, nose, or forehead, but can also less commonly affect the neck, chest, ears, and scalp. In some cases, the symptoms can include additional signs, such as, for example, semi-permanent redness, dilation of superficial blood vessels on the face, red domed papules (small bumps) and pustules, red gritty eyes, burning and stinging sensations, and in some advanced cases, a red lobulated nose (rhinophyma), may develop. Rosacea may affect all ages. Based on the location, rosacea generally has four subtypes, three affecting the skin and the fourth affecting the eyes (ocular rosacea). There are several subtypes of rosacea including, for example, but not limited to, erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea, ocular rosacea, pyoderma faciale (also known as rosacea fulminans), rosacea conglobata, phymatous rosacea. For the purposes of this specification, rosacea can include any of the known subtypes, known to one of skilled in the art. In one embodiment, rosacea is associated with the elevated levels of cathelicidins. In another embodiment, rosacea is associated with the elevated levels of a stratum corneum tryptic enzyme (SCTE). In yet another embodiment, rosacea is associated with parasitic mite, intestinal bacteria, or a combination thereof. A rosacea related disorder is any disorder which can occur in parallel with rosacea or be a contributing factor to the outbreak of rosacea or can resemble rosacea. Perioral dermatitis is an erythematous, papulopustular facial eruption that resembles rosacea and/or acne but typically starts around the nose. Rosacea (acne rosacea) is a chronic inflammatory disorder characterized by facial flushing, telangiectasias, erythema, papules, pustules, and in severe cases, rhinophyma. Rosacea related symptoms include, papules, pustules, blackheads, whiteheads or milia, nodules and cysts. Pyoderma faciale (also called rosacea fulminans) occurs suddenly on the midface of young women. It can be analogous to acne fulminans. The eruption consists of erythematous plaques and pustules. A number of other skin disorders and diseases can be treated with the composition provided herein such as rosacea, wounds, burns, inflammatory skin dermatoses superficial infections, including skin infections, such as impetigo, antibiotic responsive dermatoses and sebaceous gland disorders. Minocycline can also have skin regenerating and healing properties responsible for restoration of skin integrity. The combination of minocycline together with a hydrophobic solvent and a fatty alcohol or fatty acid can afford a beneficial effect in conditions characterized, for example, by infection and/or inflammation. Additionally, provided is a method of maintenance therapy, to prevent rosacea recurrence or reduce the severity of the rosacea recurrence, applied to a patient in need which comprises applying to the skin on a regular basis (as defined above) a hydrophobic gel or foam composition comprising a therapeutically effective amount of a tetracycline antibiotic Chemical Stability, Pharmacokinetics, Safety, and Efficacy Chemical Stability The stability of foamable composition containing minocycline was monitored at 5° C., 25° C., 40° C., and 50° C. during and after the clinical trials and satisfactory stability results were obtained (see, e.g., Example 4). Pharmacokinetics In some embodiments, the systemic exposure of a Minocycline and/or Doxycylcine foam as disclosed herein (e.g., 1%, 1.5%, 3%, or 4% minocycline or doxycycline by weight) is equal to or lower than that of an orally administered tetracycline (e.g., minocycline or doxycylcine), as evaluated in a PK Study. In some embodiments, the terms “systemic exposure,” “systemic absorption,” and “absorption” are used interchangeably. The systemic exposure of an oral tetracycline or tetracycline foam (e.g., Minocycline or Doxycylcine foam) may be determined based on a pharmacokinetic (PK) study as described in the Examples, e.g., Examples 5, 6 and 9. For example, the minocycline or doxycycline foam may be administered to a subject once or multiple times and blood samples are obtained at various time points to determine the level of minocycline or doxycycline in plasma. Various pharmacokinetic parameters can be calculated and used as an indicator of the systemic exposure, and compared to a control or base line (e.g., the level prior to treatment or the level after administration of an oral tetracycline). One or more of the following pharmacokinetic parameters may be used as an indicator of the systemic exposure: Cmax (maximum plasma concentration), tmax (time of maximum measured plasma concentration), AUC0-inf (area under the plasma concentration vs time curve [AUC] from time 0 to infinity), AUC0-tldc (AUC from time 0 to the time of last detectable concentration), t1/2 (terminal phase half-life), C24 (minocycline concentration 24 hours after topical application of minocycline foam 4%), AUC0-tau (AUC during the 24-hour dosing interval for topical minocycline foam), and bioavailability. At the end of the PK study, the safety of the foam may be evaluated by surveying any treatment-emergent adverse events (TEAEs). In some embodiments, a Cmax value is used as an indicator of the systemic exposure of a tetracycline (e.g., minocycline) foam described herein. In some embodiments, an AUC0-inf value is used as an indicator of the systemic exposure of a tetracycline foam described herein. In some embodiments, an AUC0-tldc value is used as an indicator of the systemic exposure of a tetracycline foam described herein. In some embodiments, an AUC0-tau value is used as an indicator of the systemic exposure of a tetracycline foam described herein. In some embodiments, PK measurements are taken at one or more time points following administration of a tetracycline foam descired herein, e.g., 1 hour, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more days after administration, or any time period in between. In some embodiments, a tetracycline foam described herein is administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more days after a single dose of an oral tetracycline and PK measurements are taken at one or more time points following administration of the tetracycline foam, e.g., about 1 hour, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more days after administration, or any time period in between. In some embodiments, a 4% Doxycycline foam pharmacokinetic (PK) study similar to that of a 4% Minocycline foam PK Study is undertaken. In some embodiments, a 1% or 2% or 3% Doxycycline foam PK Study is similar to that of a 1% or 2% or 3%, respectively, Minocycline foam PK Study is undertaken. In some embodiments, a 1% or 2% or 3% Minocycline foam PK Study is similar to that of a 4%, Minocycline foam PK Study. In some embodiments the systemic exposure in a 1% or 2% or 3% Minocycline foam PK Study is lower than that of a 4% Minocycline foam PK Study. In some embodiments, a 1% or 2% or 3% Doxycycline foam PK Study is similar to that of a 4%, Doxycycline foam PK Study. In some embodiments the systemic exposure in a 1% or 2% or 3% Doxycycline foam PK Study is lower than that of a 4% Doxycycline foam PK Study. In some embodiments, absorption of a foam described herein (e.g., a foam comprising 1-4% tetracycline antibiotic such as doxycycline or minocycline foam or combinations thereof) is low as determined by a PK Study in comparison to a comparable dose of an orally administered tetracycline. In some embodiments, the Cmax determined on Day 1 after the first dose is about 0.2 ng/mL to about 5 ng/mL. For example, is about 0.2 ng/mL, or about 0.4 ng/mL, or about 0.6 ng/mL, or about 0.8 ng/mL, or about 1 ng/mL, or about 1.2 ng/mL, or about 1.4 ng/mL, or about 1.6 ng/mL, or about 1.8 ng/mL, or about 2 ng/mL, or about 2.2 ng/mL, or about 2.4 ng/mL, or about 2.6 ng/mL, or about 2.8 ng/mL, or about 3 ng/mL, or about 3.2 ng/mL, or about 3.4 ng/mL, or about 3.6 ng/mL, or about 3.8 ng/mL, or about 4 ng/mL, or about 4.2 ng/mL, or about 4.4 ng/mL, or about 4.8 ng/mL, or about 5 ng/mL. In some embodiments, absorption of a foam described herein (e.g., a foam comprising 1-4% tetracycline antibiotic such as doxycycline or minocycline or combinations thereof) is low as determined by a PK study in comparison to a comparable dose of an orally administered tetracycline. In some embodiments, a Cmax is identified on Day 16 after the administration of the foam once a day for sixteen consecutive days and is about 0.2 ng/mL to about 12 ng/mL. For example, is about 0.2 ng/mL, or about 0.4 ng/mL, or about 0.6 ng/mL, or about 0.8 ng/mL, or about 1 ng/mL, or about 1.2 ng/mL, or about 1.4 ng/mL, or about 1.6 ng/mL, or about 1.8 ng/mL, or about 2 ng/mL, or about 2.2 ng/mL, or about 2.4 ng/mL, or about 2.6 ng/mL, or about 2.8 ng/mL, or about 3 ng/mL, or about 3.2 ng/mL, or about 3.4 ng/mL, or about 3.6 ng/mL, or about 3.8 ng/mL, or about 4 ng/mL, or about 4.2 ng/mL, or about 4.4 ng/mL, or about 4.8 ng/mL, or about 5 ng/mL, or about 5.2 ng/mL, or about 5.4 ng/mL, or about 5.6 ng/mL, or about 5.8 ng/mL, or about 6 ng/mL, or about 6.2 ng/mL, or about 6.4 ng/mL, or about 6.6 ng/mL, or about 6.8 ng/mL, or about 7 ng/mL, or about 7.2 ng/mL, or about 7.4 ng/mL, or about 7.6 ng/mL, or about 7.8 ng/mL, or about 8 ng/mL, or about 8.2 ng/mL, or about 8.4 ng/mL, or about 8.6 ng/mL, or about 8.8 ng/mL, or about 9 ng/mL, or about 9.2 ng/mL, or about 9.4 ng/mL, or about 9.6 ng/mL, or about 9.8 ng/mL, or about 10 ng/mL, or about 10.2 ng/mL, or about 10.4 ng/mL, or about 10.6 ng/mL, or about 10.8 ng/mL, or about 11 ng/mL, or about 11.2 ng/mL, or about 11.4 ng/mL, or about 11.6 ng/mL, or about 11.8 ng/mL, or about 12 ng/mL. In some embodiments, absorption of a foam described herein (e.g., a foam comprising 1-4% tetracycline antibiotic such as doxycycline or minocycline or combinations thereof) is low as determined by a PK Study in comparison to a comparable dose of an orally administered tetracycline. In some embodiments, absorption is determined by a PK Study, and a Cmax is determined on Day 12 after the administration of the foam once a day for twelve consecutive days and is about 0.2 ng/mL to about 5 ng/mL. For example, is about 0.2 ng/mL, or about 0.4 ng/mL, or about 0.6 ng/mL, or about 0.8 ng/mL, or about 1 ng/mL, or about 1.1 ng/mL, or about 1.2 ng/mL, or about 1.4 ng/mL, or about 1.6 ng/mL, or about 1.8 ng/mL, or about 2 ng/mL, or about 2.2 ng/mL, or about 2.4 ng/mL, or about 2.6 ng/mL, or about 2.8 ng/mL, or about 3 ng/mL, or about 3.2 ng/mL, or about 3.4 ng/mL, or about 3.6 ng/mL, or about 3.8 ng/mL, or about 4 ng/mL, or about 4.2 ng/mL, or about 4.4 ng/mL, or about 4.8 ng/mL, or about 5 ng/mL. In some embodiments, absorption of a foam described herein (e.g., a foam comprising 1-4% tetracycline antibiotic such as doxycycline or minocycline or combinations thereof) is low as determined by a PK Study in comparison to a comparable dose of an orally administered tetracycline. In some embodiments, absorption is determined by a PK Study, and a Cmax is determined on Day 21 after the administration of the foam once a day for 21 consecutive days and is about 0.2 ng/mL to about 5 ng/mL. For example, is about 0.2 ng/mL, or about 0.4 ng/mL, or about 0.6 ng/mL, or about 0.8 ng/mL, or about 1 ng/mL, or about 1.1 ng/mL, or about 1.2 ng/mL, or about 1.4 ng/mL, or about 1.6 ng/mL, or about 1.8 ng/mL, or about 2 ng/mL, or about 2.2 ng/mL, or about 2.4 ng/mL, or about 2.6 ng/mL, or about 2.8 ng/mL, or about 3 ng/mL, or about 3.2 ng/mL, or about 3.4 ng/mL, or about 3.6 ng/mL, or about 3.8 ng/mL, or about 4 ng/mL, or about 4.2 ng/mL, or about 4.4 ng/mL, or about 4.8 ng/mL, or about 5 ng/mL. In some embodiments, the foam is FMX-101, 4%. In some embodiments, absorption of a 4% tetracycline antibiotic, e.g., minocycline or doxycycline foam as determined by a PK Study is about 800 times to about 50 times lower than that of a comparable dose of an oral doxycycline. In some embodiments, the 4% tetracycline antibiotic is a composition described herein. In some embodiments, the 4% tetracycline antibiotic is FMX-101, 4%, described herein. In some embodiments, a 4% tetracycline antibiotic foam described herein has about 800 times to about 50 times lower Cmax and/or AUC values as compared to the Cmax and/or AUC values of a comparable dose of an oral doxycycline (e.g., an approved dose of Oracea® such as 40 mg). For example, it may be about 800 times lower, or about 750 times lower, or about 700 times lower, or about 650 times lower, or about 600 times lower, or about 550 times lower, or about 500 times lower, or about 450 times lower, or about 400 times lower, or about 350 times lower, or about 300 times lower, or about 250 times lower, or about 200 times lower, or about 150 times lower, or about 100 times lower, or about 50 times lower, than the Cmax and AUC for the approved dose of the oral extended release doxycycline (Oracea® 40 mg). In some embodiments, absorption of a 4% tetracycline antibiotic, e.g., minocycline or doxycycline foam as determined by a PK Study is about 800 times to about 50 times lower than that of a comparable dose of an oral minocycline. In some embodiments, the 4% tetracycline antibiotic is a composition described herein. In some embodiments, the 4% tetracycline antibiotic is FMX-101, 4%, described herein. In some embodiments, a 4% tetracycline antibiotic foam described herein has about 800 times to about 25 times lower Cmax and/or AUC values as compared to the Cmax and/or AUC values of a comparable dose of an oral minocycline (e.g., an approved dose of SOLODYN® such as 1 mg/kg). For example, it may be about 800 times lower, or about 750 times lower, or about 700 times lower, or about 650 times lower, or about 600 times lower, or about 550 times lower, or about 500 times lower, or about 450 times lower, or about 400 times lower, or about 350 times lower, or about 300 times lower, or about 250 times lower, or about 200 times lower, or about 150 times lower, or about 100 times lower, or about 50 times lower, or about 25 times lower, than the Cmax and AUC for the approved dose of the oral minocycline (SOLODYN® 1 mg/kg). In some embodiments, absorption of a 4% foam tetracycline antibiotic, e.g., minocycline or doxycycline foam as determined by a PK Study is about 850 times to about 50 times lower than that of the approved dose of an oral minocycline. In some embodiments, a 4% tetracycline antibiotic foam described herein has about 850 times to about 50 times lower Cmax and/or AUC values as compared to the Cmax and/or AUC values of the approved dose of an oral minocycline (e.g., Solodyn® 1 mg/kg). For example, is about 850 times lower, or about 800 times lower, or about 750 times lower, or about 730 times lower or about 700 times lower, or about 650 times lower, or about 600 times lower, or about 550 times lower, or about 500 times lower, or about 450 times lower, or about 400 times lower, or about 350 times lower, or about 300 times lower, or about 250 times lower, or about 200 times lower, or about 150 times lower, or about 100 times lower, or about 50 times lower, than the Cmax and AUC for the approved dose of the oral extended release minocycline (Solodyn® 1 mg/kg). In some embodiments, a foam described herein (e.g., a foam comprising 1-4% tetracycline antibiotic such as doxycycline or minocycline or combinations thereof, e.g., FMX-101, 4%) achieves good efficacy comparable to or better than an approved dose of an oral tetracycline (e.g., Oracea® 40 mg or Solodyn® 1 mg/kg) while avoiding systemic adverse events. In some embodiments, the foam exhibits fewer adverse events than a comparable dose of oral tetracycline. In some embodiments, the treatment of rosecea using a composition disclosed herein is superior to a comparable dose of the oral tetracycline while exhibiting fewer adverse events or serious adverse events and/or exhibiting lower systemic exposure as compared to the oral tetracycline. In some embodiments, the treatment of acne using a composition disclosed herein is superior to a comparable dose of an oral tetracycline while exhibiting fewer adverse events and/or exhibiting lower systemic exposure as compared to the oral tetracycline (e.g., Oracea® 40 mg or Solodyn® 1 mg/kg). In some embodiments, the treatment of acne vulgaris using a composition disclosed herein is superior to a comparable dose of the oral tetracycline while exhibiting fewer adverse events and/or exhibiting lower systemic exposure as compared to the oral tetracycline. In some embodiments, the treatment of rosecea or acne using FMX-101 or FMX-103, as disclosed herein, is superior to a comparable dose of an oral tetracycline while exhibiting fewer adverse events or serious adverse events and/or exhibiting lower systemic exposure as compared to the oral tetracycline. In some embodiments, the treatment of acne using FMX-101, 4% disclosed herein is superior to a comparable dose of the oral tetracycline while exhibiting fewer adverse events and/or exhibiting lower systemic exposure as compared to the oral tetracycline. In some embodiments, the treatment of acne vulgaris using FMX-101, 4% disclosed herein is superior to a comparable dose of the oral tetracycline while exhibiting fewer adverse events and/or exhibiting lower systemic exposure as compared to the oral tetracycline. Safety In various embodiments, clinical studies confirm that the once-daily treatment regimen with minocycline foam (1.5% or 3%) is safe even for a prolonged treatment period. During twelve weeks of treatment, no drug-related systemic adverse events or serious adverse events were reported, and the observed occurrences of telangiectasia, burning/stinging, or flushing/blushing resolved before the end of the study. Thus, administration of the minocycline topical foam is efficient, safe, and well-tolerated. The gel, liquid gel, and foamable compositions disclosed herein meet a long-felt need for a shorter treatment regimen having an earlier onset and a higher percentage reduction in lesions, while maintaining high levels of safety and efficacy. Thus, provided herein in various embodiments, are methods for treating rosacea or acne, including administering topically, to a surface having the disorder, a composition comprising a tetracycline antibiotic, wherein an enhanced safety and good tolerability of the topical foamable minocycline compositions is demonstrated. In vitro skin penetration studies (see, e.g., PCT Publication No. WO 11/039637) show that topical administration of minocycline brings appreciable amounts of the drug to its target site of action (the skin), thus possibly avoiding the undesirable high systemic exposure and the negative consequences of the oral dosage route. The topical compositions provided herein avoid, reduce, minimize or do not cause adverse effects, which are attributed to oral tetracycline antibiotics. Photosensitivity, for example, is a known side effect of oral minocycline. It is manifested as an exaggerated sunburn reaction on areas of the body exposed to direct sunlight or ultraviolet light, resulting in muddy brown skin discoloration. Use of oral minocycline over an extended period of time can also lead to skin pigmentation, e.g., manifested as blue-gray skin and blue-gray staining in areas of scarring and inflammation associated with rosacea. Tooth staining potential of oral minocycline in adult populations has also been acknowledged in recent literature. In contrast, no tooth staining was reported during the period of topical application of 1% or 4% minocycline foam or on follow-up to the study. In one or more embodiments provided herein, the topical minocycline composition avoids tooth staining. Topical delivery also means that lower doses can be used again, contributing to the elimination or reduction of unwanted side effects. Accordingly, the foamable compositions provided herein can be beneficial for the treatment of a range of skin conditions, including rosacea, wounds, burns, inflammation, superficial infections, antibiotic responsive diseases or dermatoses, skin diseases caused by bacteria, and other skin infections, such as impetigo. Likewise, the foamable compositions provided herein can be beneficial in mucosal infections and in eye infections and inflammatory conditions. Surprisingly, it has been previously demonstrated by Applicants in U.S. Pat. No. 8,871,184, that minimal to no skin pigmentation was noticed following rubbing of 4% minocycline foam onto the skin when observed after about 30 seconds. It has been surprisingly further discovered that no photosensitivity or skin discoloration was noticed following application of 1% or 4% minocycline foam onto the skin once daily for 12 weeks. Similarly, drug-related pigmentation was not observed. Thus, the compositions provided herein can have protective properties in the case of UVB-induced sun damage or any other condition associated with sunlight or other light (e.g., laser) exposure. The formulations and methods of treatment provided herein can potentially reduce skin photo damage and photo aging, and more generally reduce oxidative stress and inflammation in skin pathologies which are known to be accompanied by apoptotic cell death. It is surprisingly shown that therapeutic effects can be achieved with low concentrations of minocycline, such as 1.5%. Thus, it is possible to use lower concentrations of minocycline, thereby reducing toxicity and increasing safety. In some embodiments, the absolute mean lesion count change for the 1.5% and 3% minocycline compositions is about the same. In some embodiments, the perecent reduction of lesion count for the 1.5% and 3% minocycline compositions is about the same. In some embodiments, the reduction of IGA score for the 1.5% and 3% minocycline compositions is about the same. It is now surprisingly shown that topically administering a foam formulation having minocycline at 1.5% or 3% significantly decreases the number of lesions (absolute lesion count and percent change lesion count), and also significantly improves investigator's global assessment (IGA) results (reducing the IGA score by 2 grades and reaching a “clear or “almost clear” rating) in comparision to the vehicle. Further, the difference between the 1.5% and 3% formulations, with respect to decrease in the number of lesions and improvement of IGA score, is not statistically significant. The efficacy of FMX103 in the treatment of rosacea is surprising, as rosacea is a syndrome of undetermined etiology characterized by both vascular and papulopustular components, i.e., it is a chronic inflammatory condition of facial skin affecting both the blood vessels and pilosebaceous unit. Moreover, the observed dose independence of effectiveness in treatment of rosacea is surprising and unexpected in light of dose dependency observed with acne, where 4% minocycline is more effective than 1% minocycline. Also, the effectiveness in the treatment of rosacea is also surprising in view of the lack of bacterial involvement in rosacea, as is the case of acne and impetigo. It is shown herein that a topically administered foam formulation containing minocycline at 1.5% or 3% is safe and well tolerated. No drug related serious adverse events or systemic adverse events were reported in a clinical study of the formulations. There were only a few treatment-related dermal reactions reported (none in the 1.5% group, three patients in the 3% group and four patients in the vehicle group). These reactions resolved before the end of the study. A total of four subjects discontinued the study due to an adverse event (three patients in the 3% group and one in the vehicle group). In an embodiment, provided is a hydrophobic gel or foam composition comprising: a tetracycline antibiotic, wherein the tetracycline antibiotic is present in the gel or foam composition in an amount effective to treat rosacea in a subject, which is safe and well-tolerated. In an embodiment, provided is a hydrophobic gel or foam composition comprising: a tetracycline antibiotic, wherein substantially no treatment-related dermal reactions are observed. In an embodiment, provided is a hydrophobic gel or foam composition comprising: a tetracycline antibiotic, wherein no systemic drug-related side effects and no serious adverse reactions are observed. In an embodiment, provided is a hydrophobic gel or foam composition comprising: a tetracycline antibiotic, wherein the tetracycline antibiotic is present in the gel or foam composition at a concentration of 1.5% or 3% to treat rosacea. In an embodiment, provided is a hydrophobic gel or foam composition comprising: a tetracycline antibiotic, wherein the tetracycline is minocycline hydrochloride. In an embodiment, provided is a hydrophobic gel or foam composition comprising: a tetracycline antibiotic wherein the 1.5% and 3% concentrations are equally effective in reducing the number of papules and pustules, as compared to the placebo vehicle. In another embodiment, provided is a hydrophobic gel or foam composition comprising: a tetracycline antibiotic, wherein the 1.5% dose is more effective the 3% dose in reducing the number of papules and pustules, as compared to the placebo vehicle. In another embodiment, provided is a hydrophobic gel or foam composition comprising: a tetracycline antibiotic, wherein the 3% dose is more effective the 1.5% dose in reducing the number of papules and pustules, as compared to the placebo vehicle. In one or more embodiments the reduction in the papules and pustules is statistically significant as compared to placebo. In one or more embodiments the reduction in the papules and pustules is statistically significant as compared to placebo. In an embodiment, provided is a hydrophobic gel or foam composition comprising: a tetracycline antibiotic, wherein the tetracycline is minocycline hydrochloride. In an embodiment, provided is a hydrophobic gel or foam composition comprising: a tetracycline antibiotic wherein the 1.5% and 3% concentrations are equally effective in reducing IGA score by two levels, as compared to the placebo vehicle. In another embodiment, provided is a hydrophobic gel or foam composition comprising: a tetracycline antibiotic, wherein the 1.5% dose is more effective that the 3% dose in reducing the IGA score by two levels, as compared to the placebo vehicle. In another embodiment, provided is a hydrophobic gel or foam composition comprising: a tetracycline antibiotic, wherein the 3% dose is more effective the 1.5% dose in reducing the IGA score by two levels, as compared to the placebo vehicle. In one or more embodiments the reduction in IGA score by two levels is statistically significant as compared to placebo. In one or more embodiments the reduction in IGA score by two levels results in clear or almost clear compared to baseline. In an embodiment, provided is a hydrophobic gel or foam composition comprising: a tetracycline antibiotic, wherein said tetracycline is minocycline hydrochloride. In an embodiment, provided is a hydrophobic gel or foam composition comprising: a tetracycline antibiotic, wherein said tetracycline antibiotic is present in said gel or foam composition in an amount effective to treat moderate-to-severe papulopustular rosacea (IGA score 3-4). In an embodiment, more than half of the tetracycline-treated subjects have severe rosacea at baseline. In an embodiment, there is no statistical significant difference between treatment groups with regard to IGA severity at baseline. Erythema is redness of the skin or mucous membranes, caused by hyperemia (increased blood flow) in superficial capillaries. It occurs with any skin injury. There are different types of erythema for example erythema nodosum and erythema multiforme. Visible redness of the skin is observed in patients with medium and severe rosacea. In one or more embodiments, there is provided a method of treatment for reducing skin redness in a subject having a disorder in which one of the etiological factors is skin redness comprising applying a topical composition to an area of skin with the disorder, wherein the topical composition comprises a tetracycline antibiotic, for example, minocycline or doxycycline, at the concentration of, for example, about 1.5% to 3%. In some embodiments, the redness is moderate redness. In some embodiments, the redness is severe redness. In some embodiments, the redness is a symptom of Rosacea. In some embodiments, it is a symptom of an infection. In some embodiments, it is a symptom of a bacterial infection. In some embodiments, it is a symptom of a fungal infection. In some embodiments, it is a symptom of a viral infection. In some embodiments, it is a symptom of an allergic reaction. In an embodiment, provided is a hydrophobic gel or foam composition comprising: a tetracycline antibiotic wherein the 1.5% and 3% concentrations are equally effective in reducing the severity of erythema, as compared to the placebo vehicle. In another embodiment, provided is a hydrophobic gel or foam composition comprising: a tetracycline antibiotic, wherein the 1.5% dose is more effective than the 3% dose in reducing in reducing the severity of erythema, as compared to the placebo vehicle. In another embodiment, provided is a hydrophobic gel or foam composition comprising: a tetracycline antibiotic, wherein the 3% dose is more effective than the 1.5% dose in reducing the severity of erythema, as compared to the placebo vehicle. In one or more embodiments, the reduction of erythema severity is statistically significant as compared to placebo. In some embodiments, a foam composition described herein is sufficient to reduce the severity of skin redness or erythema by at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or more as compared to the severity of skin redness or erythema before the treatment and/or as compared to a vehicle or oral doxycycline treatment. In an embodiment, provided is a hydrophobic gel or foam composition comprising: a tetracycline antibiotic, wherein the tetracycline is minocycline hydrochloride. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having the disorder, a composition comprising a tetracycline antibiotic, wherein essentially no skin irritation such as telangiectasia, burning/stinging, or flushing/blushing, or essentially no adverse events, or no serious adverse events are observed. In one or more embodiments, good tolerability was demonstrated with relatively few reports of skin irritation, such as telangiectasis, burning or stinging, flushing or blushing. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein an enhanced efficacy of the topical foamable minocycline compositions is demonstrated. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein better efficacy of the topical foamable minocycline compositions is demonstrated as compared to other topical treatments. Oral doxycycline administration may cause common side effects, including upset stomach, nausea, diarrhea and mild headache. Since doxycycline hyclate is a larger molecule compared to minocycline HCl, in some embodiments it can have a reduced penetration and hence the maximum plasma concentrations can be less than those obtained for minocycline HCl. In some embodiments, doxycycline hyclate penetrates better than minocycline HCl and hence the maximum plasma concentrations can be more than those obtained for minocycline HCl. In some embodiments, doxycycline hyclate penetration is similar to that of minocycline HCl and hence the maximum plasma concentrations can be similar to those obtained for minocycline HCl. Efficacy In one or more embodiments, there is provided an effective method for treating rosacea, as set out herein, to patients with more than twenty inflammatory lesions on the face (papules and/or pustules) and up to 2 nodules, with more than twelve but not more than a nineteen inflammatory lesions on the face and no nodules, and receiving a score of at least Moderate on the Investigator's Global Assessment Scale. In one or more embodiments, provided herein is an effective method for treating acne using a composition described herein. In one or more embodiments, provided herein is an effective method for treating acne vulgaris using a composition described herein. In some embodiments, the composition is FMX-101. In some embodiments, the composition is FMX-101, 4%. In one or more embodiments, the methods for treating rosacea, as set out herein, are able to deliver effective amounts of a tetracycline antibiotic into the skin or mucosal surface. In one or more embodiments, the methods for treating rosacea, as set out herein, are able to deliver effective amounts of a tetracycline antibiotic into and around the hair follicle or the hair follicle area. In one or more embodiments, the methods for treating rosacea, as set out herein, are able to deliver effective amounts of a tetracycline antibiotic into or around the sebaceous gland or the sebaceous gland area or the pilosebaceous unit. In one or more embodiments, the methods for treating rosacea, as set out herein, are able to deliver effective amounts of a minocycline, wherein the minocycline composition targets the sebaceous gland or the sebaceous gland area or the pilosebaceous unit. In one or more embodiments, there is provided a method for treating rosacea, as set out herein, wherein the hydrophobic gel or foam composition targets the hair follicle or the hair follicle area. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having the disorder, a composition comprising a tetracycline antibiotic, wherein a reduction in the number of lesions is observed after twelve weeks or less than twelve weeks of treatment compared to baseline. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having the disorder, a composition comprising a tetracycline antibiotic, wherein an improvement in the skin condition is observed after twelve weeks or less than twelve weeks of treatment and wherein an improvement is considered as restoration of visible, normal cutaneous topographic features, indicating the return of skin integrity. In an embodiment the improvement is after two weeks after three weeks, or after four weeks, or after five weeks, or after six weeks or after seven weeks, or after eight weeks, or after nine weeks, or after ten weeks, or after eleven weeks, or after twelve weeks. In one or more embodiments there is provided a hydrophobic gel or foam composition comprising a therapeutically effective amount of tetracycline antibiotic for use in treating rosacea in a human subject comprising topically administering the composition at least alternate days or at least once daily, wherein a decrease in the number of rosacea papule and pustules is observed after at least twelve weeks of treatment. In an embodiment the decrease in the number of rosacea papule and pustules is after two weeks, after three weeks, or after four weeks, or after five weeks, or after six weeks or after seven weeks, or after eight weeks, or after nine weeks, or after ten weeks, or after eleven weeks, or after twelve weeks. In one or more embodiments, there is provided a hydrophobic gel or foam composition comprising a therapeutically effective amount of tetracycline antibiotic for use in treating rosacea in a human subject comprising topically administering the composition at least alternate days or at least once daily, wherein a decrease the total number of rosacea lesions is observed after at least three weeks of treatment or after at least two weeks of treatment. In one or more embodiments, there is provided a hydrophobic gel or foam composition comprising a therapeutically effective amount of tetracycline antibiotic for use in treating rosacea in a human subject comprising topically administering the composition at least alternate days or at least once daily, wherein a decrease the number of inflammatory rosacea lesions is observed after at least three weeks of treatment or after at least two weeks of treatment. In one or more embodiments, the human subject is 60 or less than 60 years old, is 50 or less than 50 years old, is 40 or less than 40 years old, is 30 or less than 30 years old, or is 25 or less than 25 years old, or is 22 or is less than 22 years old, or is 20 or less than 20 years old, or is 18 or less than 18 years old, or 15 or is less than 15 years old, or is between 8 to 25 years old or is between 9 to 22 years old. In an embodiment the subject is a female. In an embodiment the female is under the age of forty-six and optionally is a pregnant or breastfeeding female. In an embodiment the subject is a male. In an embodiment the subject is a teenager. In another embodiment the subject is a child. In one or more embodiments, there is provided a method for treating rosacea, including administering topically to a surface having rosacea a composition comprising a tetracycline antibiotic, wherein after twelve weeks of treatment, at least about 40% of the treated rosacea lesions disappear (in other words, a 40% decrease in the number of lesions) so that no further antimicrobial therapy is necessary. In some embodiments, at least about 50%, at least about 60%, at least about 70% or at least about 80% of the treated rosacea lesions disappear. In one or more embodiments, at least about 90% of the treated rosacea lesions disappear. In other embodiments, a decrease of at least about 60% in the number of rosacea lesions is observed after twelve weeks or less than twelve weeks of treatment. In one or more embodiments, there is provided a method for treating rosacea, including administering topically to a surface having rosacea a composition comprising a tetracycline antibiotic, wherein after twelve weeks or less than twelve weeks of treatment, at least about 45% of the treated rosacea lesions disappear (in other words, a 45% decrease in the number of lesions) so that no further antimicrobial therapy is necessary. In some embodiments, at least about 50%, at least about 60%, at least about 70% or at least about 80% of the treated rosacea lesions disappear after six week or less than six weeks of treatment. In one or more embodiments, at least about 90% of the treated rosacea lesions disappear after twelve week or less than twelve weeks of treatment. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein a percent of total number lesions that disappeared is at least about 30%, at least about 40%, or at least about 50% or at least about 60%, or at least about 70% or at least about 75% or at least about 80% after twelve weeks or less than twelve weeks of treatment. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein a percent of total number lesions that disappeared is at least about 50%, or at least about 60%, or at least about 70%, or at least about 80% after four weeks after the end of the treatment. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein a percent of total number lesions that disappeared at the end of treatment is statistically significant compared to baseline in both 1.5% and 3% dose groups. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein a percent of total number lesions that disappeared at the end of treatment compared to baseline is statistically significant in both 1.5% and 3% dose groups when compared to placebo. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein a percent of total number lesions that disappeared at the end of treatment compared to baseline is statistically significant in the 3% dose group when compared to placebo. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein the baseline severity of rosacea is at least moderate to severe, as judged by the number of rosaceas and investigator's global severity assessment (IGA). In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein the mean number of rosacea papule and pustules at baseline is at least about 30-34 or at least about 34-35. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein the number of papule and pustules is at least 20 papule and pustules. In other embodiments there is at least one papule and pustules, or at least 5, or at least 10 or at least 15 papule and pustules and in further embodiments there are at least 25, or at least 30 or at least 40 or at least 50 papule and pustules. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein the rosacea is low to moderate rosacea. In other embodiments the composition can be applied as aforesaid as a method of protecting the skin, for example, by preventing microbial infection or rosacea In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein the IGA score as assessed by the investigator at baseline is between 3-4, indicating moderate to severe rosacea at baseline. In other embodiments the composition can be applied to mild rosacea and in still further embodiments it can be applied to very severe rosacea. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein the daily application of topical minocycline foam (3% and 1.5%) on facial skin with moderate to severe rosacea results in a significant improvement of the disease, for example, as indicated by the primary and secondary endpoints. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein there is a clinically and statistically significant reduction in a lesion count, after twelve weeks of treatment in the subjects receiving minocycline foam compared to Placebo. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein a clinically and statistically significant improvement in the investigator global assessment of rosacea severity is observed after 12 treatment weeks in the subjects receiving minocycline foam compared to Placebo. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein a clinically and statistically significant improvement in the investigator global assessment of rosacea severity is observed after 12 treatment weeks in the subjects receiving minocycline foam compared to Placebo, and wherein a clinically significant improvement in the investigator global assessment of rosacea severity comprises improvement by at least two levels. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein the effect of the minocycline foam is dose dependent, and the effect of 3% minocycline foam is generally greater than 1.5% minocycline foam. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein the effect of the minocycline foam is dose dependent, and the effect 1.5% minocycline foam is generally greater than 3% minocycline foam. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein the effect of the minocycline foam on rosacea is dose independent (in a surprising and unexpected contrast to dose dependency observed with acne), and the effect of 1.5% minocycline foam is similar to 3% minocycline foam. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein, a clinically and statistically significant reduction in the number of inflammatory lesions can be seen after 12 weeks of treatment in subjects receiving the 1.5-3%, or about 1.5% or about 3% minocycline foam, as compared to Placebo and/or compared to baseline prior to treatment. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein, more than a 60% reduction in inflammatory lesion counts can be seen following twelve weeks of treatment in subjects receiving the 1.5-3% minocycline foam compared to Placebo. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein, the percent of subjects who had a decrease of more than 40%, 50%, 60%, or 70% in the inflammatory lesions count was statistically significantly higher in the 1.5-3% treatment group compared to Placebo after 6 treatment weeks and onward. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein, the percent of subjects who had a decrease of more than 50% or 60%, in the inflammatory lesions count was statistically significantly higher in the 1.5-3% treatment group compared to Placebo only at twelve treatment weeks. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein according to the investigator's global assessment at 12 weeks, more than 20% of the subjects have “clear” or “almost clear” skin in subjects receiving the 1.5-3% minocycline foam and wherein this change is statistically significant compared to subjects in the Placebo group. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein, according to the investigator's global assessment at 12 weeks, the number of the subjects having “severe” or “moderate” rosacea has decreased at least 50% in subjects receiving the 1.5-3% minocycline foam and wherein this change is statistically significant compared to subjects in the Placebo group. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein, according to the investigator's global assessment at 12 weeks, the number of the subjects having “severe” or “moderate” rosacea has decreased at least 60% in subjects receiving the 1.5-3% minocycline foam and wherein this change is statistically significant compared to subjects in the Placebo group. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein, according to the investigator's global assessment at 12 weeks, the number of the subjects having “severe” or “moderate” rosacea has decreased at least 70% in subjects receiving the 1.5-3% minocycline foam and wherein this change is statistically significant compared to subjects in the Placebo group. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein, according to the investigator's global assessment at 12 weeks, the number of the subjects having “severe” rosacea has decreased at least 50% in subjects receiving the 1.5-3% minocycline foam and wherein this change is statistically significant compared to subjects in the Placebo group. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein, according to the investigator's global assessment at 12 weeks, the number of the subjects having “severe” rosacea has decreased at least 60% in subjects receiving the 1.5-3% minocycline foam and wherein this change is statistically significant compared to subjects in the Placebo group. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein according to the investigator's global assessment at 12 weeks, the number of the subjects having improvement is statistically significantly higher in the 1.5-3% treatment group compared to Placebo after 8 treatment weeks and onward. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein according to the investigator's global assessment at 12 weeks, the number of the subjects having improvement by of at least 2 grades is statistically significantly higher in the 1.5-3% treatment group compared to Placebo after 12 treatment weeks and onward. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein improvement of at least 2 grades in the investigator's global assessment score is observed in at least 20% of the subjects receiving 1.5-3% minocycline foam and wherein this is statistically more frequent than in subjects receiving Placebo. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein improvement of at least 2 grades in the investigator's global assessment score is in at least 15% of the subjects receiving 1.5-3% minocycline foam and wherein this is statistically more frequent than in subjects receiving Placebo. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein improvement of at least 3 grades in the investigator's global assessment score is in at least 10% of the subjects receiving 1.5-3% minocycline foam and wherein this is statistically more frequent than in subjects receiving Placebo. In one or more embodiments, provided is a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein according to secondary endpoint relating to rosacea improvement, assessment by the investigator after twelve weeks of treatment indicates improvement in at least 70% of subjects receiving the 1.5-3% minocycline foam, wherein this is statistically significant compared to the Placebo group. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein according to secondary endpoint relating to rosacea improvement assessment by the investigator after 12 treatment weeks indicates improvement in at least 60% of subjects in subjects receiving the 1.5-3% minocycline foam and wherein this is statistically significant compared to the Placebo group. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein at least half the subjects receiving the 1.5-3% minocycline foam evaluated their rosacea as ‘much better than prior to study’ and wherein this is statistically significant when compared to the Placebo group. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein the effect was most notably shown on severe rosacea subjects receiving the 1.5-3% minocycline foam. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein a percent of total number of inflammatory lesions and that disappeared at the end of treatment compared to baseline is higher than placebo in both 1.5% and 3% dose groups. In one or more embodiments, the placebo formulation has a beneficial effect. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a placebo composition being a vehicle composition described herein for the delivery of a tetracycline that does not comprise a tetracycline antibiotic, wherein a percent of number of inflammatory lesions that disappeared at the end of treatment compared to baseline is higher than on a surface having rosacea that is untreated. In one embodiment placebo is statistically better than no treatment. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein a percent of total number of inflammatory lesions that disappeared in the 3% dose group at the end of treatment is significantly statistically higher than that of the 1.5% dose group. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein a percent of total number of inflammatory lesions that disappeared in the 1.5% dose group at the end of treatment is significantly statistically higher than that of the 3% dose group. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein a percent of total number of inflammatory lesions that disappeared in the 3% dose group at the end of treatment is significantly statistically higher than that of placebo. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein a percent of total number of inflammatory lesions that disappeared in the 1.5% dose group at the end of treatment is significantly statistically higher than that of placebo. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein a percent of total number of inflammatory lesions that disappeared in both 1.5% and 3% dose groups at the end of treatment is statistically significant when compared to placebo. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein at least about 30%, or at least about 40%, or at least about 50%, or at least about 55%, or at least about 58%, or at least about 60%, or at least about 62%, or at least about 70%, or at least about 75% of total number of inflammatory lesions disappear after twelve weeks after the end of the treatment (F/U). In one or more embodiments these changes at F/U are statistically significant compared to baseline in both 1.5% and 3% dose groups. In one or more embodiments these changes at F/U are statistically significant compared to placebo in both 1.5% and 3% dose groups. In one or more embodiments the number of inflammatory lesions at F/U is the same or similar compared to end of treatment (“EOT”) in both 1.5% and 3% dose groups. In one or more embodiments the number of inflammatory lesions at F/U increases compared to EOT. In one or more embodiments there is the number of inflammatory lesions at F/U decreases compared to EOT. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein according to the investigator's global assessment of erythema at 12 weeks, more than 15% of the subjects have “clear” or “almost clear” skin in subjects receiving the 1.5-3% minocycline foam and wherein this change is statistically significant compared to subjects in the Placebo group. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein according to the investigator's global assessment of erythema at 12 weeks, more than 10% of the subjects have “clear” or “almost clear” skin in subjects receiving the 1.5-3% minocycline foam and wherein this change is statistically significant compared to subjects in the Placebo group. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein, according to the investigator's global assessment of erythema at 12 weeks, the number of the subjects having “severe” or “moderate” rosacea has decreased at least 70% in subjects receiving the 1.5-3% minocycline foam and wherein this change is statistically significant compared to subjects in the Placebo group. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein, according to the investigator's global assessment of erythema at 12 weeks, the number of the subjects having “severe” or “moderate” rosacea has decreased at least 50% in subjects receiving the 1.5-3% minocycline foam and wherein this change is statistically significant compared to subjects in the Placebo group. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein, according to the investigator's global assessment of erythema at 12 weeks, the number of the subjects having “severe” rosacea has decreased at least 70% in subjects receiving the 1.5-3% minocycline foam and wherein this change is statistically significant compared to subjects in the Placebo group. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein, according to the investigator's global assessment of erythema at 12 weeks, the number of the subjects having “severe” rosacea has decreased at least 80% in subjects receiving the 1.5-3% minocycline foam and wherein this change is statistically significant compared to subjects in the Placebo group. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein according to the investigator's global assessment of erythema at 12 weeks, the number of the subjects having improvement by of at least 2 grades is statistically significantly higher in the 1.5-3% treatment group compared to Placebo after 12 treatment weeks and onward. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein according to the investigator's global assessment of erythema at 12 weeks, the number of the subjects having improvement by of at least 2 grades is in at least 10% of the subjects receiving 1.5-3% minocycline foam and wherein this is statistically more frequent than in subjects receiving Placebo. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein according to the investigator's global assessment of erythema at 12 weeks, the number of the subjects having improvement by of at least 2 grades is in at least 15% of the subjects receiving 1.5-3% minocycline foam and wherein this is statistically more frequent than in subjects receiving Placebo. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein treating said rosacea in said subject results in no adverse event. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein at treating said rosacea in said subject results in more than about 30% reduction in lesions, relative to placebo, after about two to twelve weeks of treatment. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein treating said rosacea in said subject results about 30-60% reduction in lesions, relative to placebo, after about two to twelve weeks of treatment. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein treating said rosacea, in said subject, with said composition having 1.5% or 3% minocycline, results in about 33% reduction in the incidence of erythema, relative to 7% reduction in placebo, after two weeks of treatment. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein treating said rosacea, in said subject, with said composition having 1.5% or 3% minocycline, results in a significant reduction in papules and pustules, relative to placebo, after about two to twelve weeks of treatment. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein treating said rosacea in said subject results in reduction in the number of lesions ranging from about 10 to about 30, relative to a baseline. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein treating said rosacea in said subject results in reduction in the number of lesions of about 10, 15, 20, or 30, relative to a baseline. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein treating said rosacea, in said subject, with said composition having 1.5% or 3% minocycline, results reduction in the number of lesions of about 19-22, relative to placebo, after about two to twelve weeks of treatment. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein treating said rosacea in said subject results in lesion count ranging from about 10 to about 20. In one or more embodiments, there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic, wherein treating said rosacea in said subject results in lesion count of about 10, 13, 14, 15, 18, or 20. As with other therapeutic regimens, patient compliance is essential in the effectiveness of prescribed antibiotics. With poor compliance, therapeutic goals are less likely to be achieved, resulting in poorer patient outcomes. Poor compliance is associated with deteriorating skin condition, the need for additional consultations, the emergence of bacterial resistance, extra drugs, additional expenses on cosmeticians and increases in direct and indirect costs of healthcare management. In general, patients are more compliant with simple and shorter dosing regimens. Both the dosage schedule and the patient's daily routine should be considered when prescribing antibiotics. Topical agents can also be more attractive than oral therapy because they reduce the potential for systemic side effects, typically nausea and diarrhea, which are commonly associated with many systemic antibiotics. They can also help provide a reduction in cross contamination by providing a barrier with antibiotic over the infected area. In one or more embodiments there is provided a method for treating rosacea, including administering topically, to a surface having rosacea, a composition comprising a tetracycline antibiotic administered at least alternate days or once daily which has a high or improved patient compliance compared with existing treatments. In one or more embodiments, one or more of the methods provided herein for treating or alleviating rosacea or acne can also be used for treating a disorder including one or more of the following: rosacea related or associated disorder, rosacea-like symptoms, rosacea related symptoms, a tetracycline antibiotic responsive rosacea related disorder, skin disorder caused by a bacteria, and a tetracycline antibiotic responsive sebaceous gland disease. A multi-center, randomized, double blind, placebo controlled, parallel group, dose finding Phase II clinical study conducted in patients afflicted with papulopustular rosacea is reported in Example 3 below. The study is designed to assess the efficacy, safety and tolerability of foamable composition comprising minocycline at one of two different concentrations (strengths): a lower concentration of minocycline of 1.5% by weight of the formulation and higher concentration of minocycline 3% by weight of the formulation, in comparison with a placebo. The concentrations of minocycline in the composition were selected according to formulation integrity and stability considerations. In some embodiments similar Phase II clinical studies for additional tetracycline antibiotic formulations such as DOX331, DOX332, DOD-003, MCD-037, MCD-045, MCD-052 MCD-053, MCD-065 and MCD-058 are undertaken. In some embodiments, Phase II studies in rosacea for other tetracycline antibiotic formulations (such as DOX331, DOX332, DOD-003, MCD-037, MCD-045, MCD-052 MCD-053, MCD-065 and MCD-058) provide similar results to those seen for the FMX103 formulation. In some embodiments, a Phase II clinical study indicates that other tetracycline antibiotic formulations (such as DOX331, DOX332, DOD-003, MCD-037, MCD-045, MCD-052 MCD-053, MCD-065 and MCD-058) can treat moderate-to-severe rosacea. In some embodiments, a Phase II clinical study for another tetracycline antibiotic formulation such as DOX331, DOX332, DOD-003, MCD-037, MCD-045, MCD-052 MCD-053, MCD-065 and MCD-058 indicates that such a formulation can reduce papules and pustules in rosacea patients. In some embodiments, DOX331, DOX332, DOD-003, MCD-037, MCD-045, MCD-052 MCD-053, MCD-065 and MCD-058 can help patients having rosacea. In some embodiments, DOX331, DOX332, DOD-003, MCD-037, MCD-045, MCD-052 MCD-053, MCD-065 and MCD-058 are safe and well tolerated in subjects who have rosacea. In some embodiments there are no drug-related systemic side effects. DOX331, DOX332, DOD-003, MCD-037, MCD-045, MCD-052 MCD-053, MCD-065 and MCD-058 are in some embodiments superior to a vehicle in preventing rosacea. In some embodiments, compliance with DOX331, DOX332, DOD-003, MCD-037, MCD-045, MCD-052 MCD-053, MCD-065 and MCD-058 is high. In some embodiments application with one or more of topical DOX331, DOX332, DOD-003, MCD-037, MCD-045, MCD-052 MCD-053, MCD-065 and MCD-058 can improve patients' quality of life In some embodiments, other tetracycline antibiotic formulations (such as DOX331, DOX332, DOD-003, MCD-037, MCD-045, MCD-052 MCD-053, MCD-065 and MCD-058) are safe and well-tolerated in the subjects having rosacea. In some embodiments no systemic drug-related adverse events are recorded. The compositions and methods provided herein are described with reference to the following examples, in a non-limiting manner. The following examples exemplify the foamable compositions and methods described herein. The examples are for the purposes of illustration only and are not intended to be limiting. Many variations will suggest themselves and are within the full intended scope. EXAMPLES In one or more embodiments, the amounts in the examples should be read with the prefix “about.” As used herein, the term “NM” means not measured. Exemplary Ingredients Suitable for the Production of Foamable Compositions Chemical Name Function Commercial Name Supplier Beeswax white Foam Beeswax white STRAHL & PITSCH, Inc. Stabilizer Behenyl alcohol Foam Lanette 22 BASF Stabilizer Cetostearyl alcohol Foam Kolliwax ® CSA 50 BASF Stabilizer Coconut oil Carrier Coconut oil Henry Lamotte Cyclomethicone-5 Carrier ST-cyclomethicone-5 Dow Hydrogenated castor oil Foam Kolliwax ® HCO BASF Stabilizer Light Mineral Oil Carrier Pionier 2076P Hansen & Rosenthal Light Mineral Oil 15 Columbia Petro Chem PVT.LTD. Minocycline HCl Active agent Minocycline HCl Hovione Myristyl alcohol Foam Kolliwax ® MA BASF Stabilizer Propane/Isobutane/Butane Propellant AP-70 Aeropress (55:18:27) Soybean oil Carrier Soybean oil Henry Lamotte Stearic acid Foam Kolliwax ® S Fine BASF Stabilizer Stearyl Alcohol Foam Kolliwax ® SA BASF Stabilizer Example 1 General Manufacturing Procedures for a Gel or a Foam The following procedures were used to produce gel or foam samples, in which only the steps relevant to each formulation were performed depending on the type and nature of ingredients used. Step 1: Hydrophobic solvents such as mineral oils are mixed at room temperature. Others solvents such as silicones, if present, are added at room temperature under mixing until formulation homogeneity is obtained. Step 2: The formulation is warmed to 70-80° C. or 80-90° C. and solid compounds such as fatty alcohols, fatty acids and waxes are added and mixed until complete dissolution. Step 3: The formulation is cooled down to 30-40° C. Silica dioxide (SiO2), if present, and active agents such as tetracyclines are added under mixing until formulation homogeneity is obtained. Step 4: For gel compositions, the formulation is packaged in suitable containers. For foamable compositions, the formulation is packaged in aerosol canisters which are crimped with a valve, pressurized with propellant and equipped with an actuator suitable for foam dispensing. Optionally, a metered dosage unit can is utilized to achieve delivery of desirable and/or repeatable measured doses of foam. Step 5: For foamable compositions, pressurizing is carried out using a hydrocarbon gas or gas mixture. Canisters are filled and then warmed for 30 seconds in a warm bath at 50° C. and well shaken immediately thereafter. Step 6: The canisters or containers are labeled. Example 2 General Manufacturing Procedures for a Gel or a Foam The following procedures are used to produce gel or foam samples, in which only the steps relevant to each formulation are performed depending on the type and nature of ingredients used. Step 1: Hydrophobic solvents and solid compounds such as fatty alcohols, fatty acids and waxes are mixed and heated to a temperature sufficient to achieve complete dissolution. Step 2: The formulation is cooled down to 35-40° C., sensitive components such as silica dioxide (SiO2), if present, cyclomethicone and sensitive active agents such as tetracyclines are added under mixing until formulation homogeneity is obtained. Step 3: The formulation is cooled down to room temperature. Step 4: For gel compositions, the formulation is packaged in suitable containers. For foamable compositions, the formulation is packaged in aerosol canisters which are crimped with a valve, pressurized with propellant and equipped with an actuator suitable for foam dispensing. Step 5: For foamable compositions, pressurizing is carried out using a hydrocarbon gas or gas mixture. The canisters or containers are labeled. In one or more embodiments, part of the hydrophobic solvents are added during the cooling process of the formulation (step 2). In one or more embodiments, one of more of the formulation mixing steps can be done with or without vacuum and in the presence or absence of air, or an inert gas. For example, in an embodiment, one or more steps are done under vacuum, in the absence of air under an inert gas. In one or more embodiments, likewise packaging in canisters can be done with or without vacuum and in the presence or absence of air, or an inert gas. Example 3 Clinical Study Phase II (1.5% or 3% Minocycline Foam) Study Title: A Randomized, Multicenter, Double-blind, Vehicle-controlled Study to Evaluate the Safety and Efficacy of two Different Doses of a Topical Minocycline Foam Compared to Vehicle in the Treatment of Papulopustular Rosacea. Study Synopsis: In this example, topical administration of tetracycline (for example minocycline) is studied and the safety and efficacy of two different doses of minocycline foam compared to vehicle foam are evaluated in the treatment of moderate-to-severe papulopustular rosacea. Objectives: The primary objective of the study is to evaluate the efficacy of two different doses of FMX-103 minocycline foam compared to vehicle foam in subjects with moderate-to-severe papulopustular rosacea. The secondary objectives of the study are (a) to determine the relationship between the concentration(s) of topical minocycline foam and treatment response, (b) sensitivity analyses of efficacy of two different doses of FMX-103 minocycline foam compared to vehicle foam in subjects with moderate-to-severe papulopustular rosacea, and (c) to evaluate the safety and tolerability of topical minocycline foam applied daily for 12 weeks. Study Medication: Table 2. FMX103 Minocycline (3% and 1.5%) and placebo foamable compositions without silicone dioxide (SiO2), as described in Table 4. Dosage: Dosage form description Foam containing minocycline, 1.5% and 3% Vehicle foam (0%) Package description Canisters, each containing 35gr of the clinical trial supply foam either: vehicle; FMX-103 1.5% minocycline foam; or FMX-103 3% minocycline foam Daily dose Once daily application of a small amount of study drug (a diameter of a one cent coin/~1.5 cm) onto fingertip to cover the entire face. Estimated maximum is 0.5 gr of the foam containing 7.5 (1.5%) or 15 (3%) mg of minocycline Cumulative maximal dose 630 mg (1.5%) or 1,260 mg (3%) for dosing (12 weeks) Dispensing 1 canister containing 35 g of the FMX-103 minocycline formulation, 1.5% or 3% or vehicle dispensed at Visit 2 (Baseline), Visit 4, Visit 5, and optionally at other visits if required. Indication: Papulopustular rosacea. Design: A randomized, multicenter, double-blind, vehicle-controlled study assessing 232 male or non-pregnant female subjects aged greater than or equal to 18 years with a clinical diagnosis of moderate-to-severe papulopustular rosacea for at least 6 months, with at least 12 inflammatory facial lesions (i.e., papules/pustules). Patients: The study enrolls 210 male or female patients (approximately 70 subjects per arm: control, 1.5% and 3% minocycline) at approximately 14-16 sites in Germany who meet all of the inclusion criteria (Table 1) and none of the exclusion criteria (Table 2). TABLE 1 Inclusion criteria ≥18 years-of-age with moderate-to-severe rosacea (as per IGA) on the proposed facial treatment. area consisting at least 12 facial papules or pustules excluding papule and pustule s involving the eyes and scalp. Diagnosed with rosacea for at least 6 months prior to screening Women of child-bearing potential must have a negative serum pregnancy test and agree to use a highly effective method of contraception. Willing to minimize external factors that might trigger rosacea flare-ups (e.g., spicy foods, thermally hot foods and drinks, hot environments, prolonged sun exposure and extensive alcoholic beverages). Subjects who use make-up must have used the same brands/types of make-up for a minimum period of 14 days prior to study entry and must agree to use the same make-up, brand/type, or frequency of use, throughout the study. Completed and signed an appropriately administered Informed Consent Form (ICF) prior to any study- related procedures. TABLE 2 Exclusion Criteria Pregnancy or breastfeeding. Any skin condition on the face that would interfere with the diagnosis or assessment of rosacea. Moderate or severe rhinophyma, dense telangiectasis (score 3, severe), or plaque-like facial edema. An active nodule on the face >5 mm in diameter. Excessive facial hair. History of hypersensitivity or allergy to minocycline, any other tetracycline or any other component of the formulation. Severe irritation grade for erythema, dryness, scaling, pruritus, stinging/burning, and edema. Rosacea conglobata or fulminans, corticosteroid-induced rosacea or isolated pustulosis of the chin, facial erythrosis of known origin other than rosacea (e.g., known carcinoid syndrome). Ocular rosacea (e.g., conjunctivitis, blepharitis, or keratitis) Use within 6 months prior to baseline of oral retinoids. Woman of childbearing potential who has used a highly effective method of contraception for less than 3 months prior to baseline. Use within 1 month prior to baseline of topical retinoids to the face or systemic antibiotics known to have an impact on the severity of papulopustular rosacea or systemic corticosteroids or methoxyflurane. Use within 2 weeks prior to baseline of: topical corticosteroids, or topical antibiotics in the head and neck area; topical medications for rosacea. Wax epilation of the face within 2 weeks prior to Baseline and during the study. use of sauna during the 2 weeks prior to Baseline and during the study. Bacterial folliculitis. Alcohol or drug abuse Excessive or prolonged exposure to weather extremes Any other clinically significant condition or situation that may interfere with the study evaluations Uncontrolled/instable relevant arterial hypertension Participating in another investigational drug study within 30 days prior to Baseline Previously enrolled in the FX2015-10 study Prior laser therapy to the facial area within 3 months prior to Baseline. Prior cosmetic procedures which may affect the efficacy and safety profile within 2 weeks prior to Baseline Clinical Study Design Eligible subjects are assigned to 1 of 3 treatments (vehicle, 1.5% and 3% minocycline) at 1:1:1 ratio according to the randomization schedule. Subjects are to apply the study drug topically once daily for 12 weeks as directed. Subjects are advised to use the study drug at approximately the same times each day in the evening. Both the investigator and subject are blinded to the study drug identity. Subjects return for visits at Weeks, 2, 4, 8, 12, and 16. Efficacy evaluations (Investigator's Global Assessment [IGA] score and inflammatory papule and pustule counts) are performed at Weeks, 2, 4, 8, and 12 during the study, with an additional safety follow-up visit at weel 16. Other assessments are performed as described in the Study Flow Chart (Table 3). The dosing regimen is the same for all treatment groups. All patients receive at Screening Visit a guideline with detailed instructions on how to apply the medication correctly. In addition, patients are asked at each study visit about their medication application to assure a correct use of study medication. Study drug kits are dispensed at Visit 2 (Baseline), Visit 4 (Week 4), Visit 5 (Week 8), and optionally at other/unscheduled visits if required for continuous dosing. A small amount of study drug (a diameter of a one-cent coin) should be expressed from the canister onto the thoroughly washed finger tips and then applied topically as a thin layer over all parts of the face. TABLE 3 Study Flow Chart Final main Follow protocol up Assessment Screening Baselinea Visits Visitb visitf Visit 1 2 3 4 5 6 7 Week 2 4 8 12 16 −3/+5 d −3/+5 d −3/+5 d −3/+5 d −3/+5 d Informed Consent X Demographic Data X Assign subject X identification Medical/Surgical/ X Medication History Inclusion/Exclusion X X criteria Physical Exam, height, X X weightc Blood Pressure/heart rated X X X X X X Blood and urine samples X X for clinical laboratory tests Urine pregnancy test X X X X (females only) Serum pregnancy test X X (females only) Papule and pustule Count X X X X X X Investigator’s Global X X X X X X Assessment Modified IGA X X X X X X RosaQoL assessment X X Randomization X Photography of face X X X X X Concomitant Medication X X X X X X Adverse Events X X X X X X Local safety assessments X X X X X Assessments of erythema X X X X X X Perform drug Xe X X X accountability Collect empty drug X X X canister(s) Dispense Study Drug X X X Handout of Patient's X Guidelines Schedule/Confirm Next X X X X X X Visit aBaseline must occur within 6 weeks of screening. Blood results must not show clinically significant abnormalities. bIf a subject prematurely withdraws from the study, all evaluations described under Visit 6/Week 12 must be performed. cHeight to be measured only at Baseline. dMeasure blood pressure and heart rate after the subject has been sitting for at least 5 minutes at rest. eThe canister of study drug has to be weighed and given back to the patient. fIf patient is unable to come to the visit there should be at least a follow-up phone call. Efficacy The efficacy assessments include the lesion counts and IGA at Baseline and Weeks 2, 4, 8, and 12. The primary efficacy endpoint is the absolute change in inflammatory lesion count at Week 12 compared to Baseline. Lesion count is performed by the investigator. The number of papules, pustules and nodules are counted and the numbers recorded. The facial area lesion counts are made for the forehead, left and right cheeks, nose and chin at each visit. Secondary Efficacy Assessments are performed by the investigator who assesses the global severity of rosacea at Screening, Baseline, Weeks 2, 4, 8, and 12 by grading the severity on a 0-4 scale, with score 0 corresponding to “clear”, and score 1 corresponding to “almost clear”. Severity Assessment of other Rosacea Criteria will include grading Erythema of the face on a 0-4 scale, patient self-grading of Rosacea quality of life index (RosaQoL), and evaluation of standardized photographs. Patient Demographics: Patient demographics can include the individuals with diverse group, gender, height, weight and body mass index (BMI). Statistical Methodology All statistical analyses are performed using SAS® software version 9.3 (or higher). Descriptive statistics for qualitative variables (e.g., race) include the number and percentage of subjects with the qualitative response. For quantitative variables (e.g., age), descriptive statistics include the number of subjects with non-missing data, mean, standard deviation, median, and minimum and maximum values. All hypothesis testing is conducted using two-sided tests with α=0.05 level of significance. Each minocycline dose group are compared to vehicle, however, the primary comparison is the minocycline 3% treatment group versus the vehicle treatment group. The Intent-to-treat (ITT) analysis population includes all randomized subjects. The ITT population is primary for all efficacy analyses. The Per-protocol (PP) population includes all subjects in the ITT population who had at least one post-Baseline assessment, and are without any other major deviations from the protocol that can have an impact on the efficacy assessments and subjects are analyzed as treated. The PP population is secondary for all efficacy analyses. The Safety population includes all randomized subjects who received at least one application of study medication. Subjects who have no post-Baseline assessments are included in the Safety population unless all dispensed study drug is returned. All safety analyses are performed on the Safety population. Clinical Response to Treatment Escape Criteria (for Success and Failure): Success The primary efficacy endpoint is the absolute change in inflammatory lesion count at Week 12 compared to Baseline. The secondary efficacy endpoints are, hierarchically: the dichotomized IGA score where success is defined as a two-step drop in score at Week 12 compared to Baseline; the dichotomized IGA score where success is defined as a two-step drop resulting in a 0 or 1 score at Week 12 compared to Baseline; percent change in inflammatory lesion count at Week 12 compared to Baseline; the dichotomized mIGA score where success is defined as a two-step drop resulting in a 0 or 1 score at Week 12 compared to Baseline. The null hypotheses of the equality of each active treatment mean to the vehicle treatment mean for absolute change from Baseline to Week 12 in the inflammatory lesion count is tested using an Analysis of Covariance (ANCOVA) with treatment as a main effect, investigational site as a blocking factor, and Baseline inflammatory lesion count as a (linear) covariate. Treatment by (pooled) investigational site interaction is tested separately at 0.1 level of significance. The primary comparison is between the 3% minocycline treatment group and vehicle. Secondary comparison is made between the 1.5% minocycline treatment group and vehicle. The assumptions of normality and homogeneity of variance from the ANCOVA model are tested at 0.05 level of significance. This analysis is performed for the 3% minocycline group versus vehicle and, if significant, is repeated for the 1.5% minocycline group versus vehicle. Secondary dichotomized endpoints of IGA success rates at Week 12 are tested using Cochran-Mantel-Haenszel (CMH) test (row mean scores) stratified by investigational site. Comparisons of 3% minocycline versus vehicle and 1.5% minocycline versus vehicle are done using only data from the pair of treatments being compared. Continuous endpoints are analyzed using an ANCOVA model with treatment as a main effect, Baseline and (pooled) investigational site as covariates. Other secondary endpoints are tested in the order listed above, where the 3% minocycline is compared to vehicle, then the 1.5% minocycline is compared to vehicle on the same secondary endpoint. Sub-group analyses by gender, age (18-30, 31-50, >50), Baseline lesion count (≤34, 35-75). Other cut-off by baseline lesion counts may be explored. Other important demographic and baseline characteristics sub-groups analyses are conducted. Summaries of primary and important secondary endpoints are done by investigational site. Safety Tolerability and Adverse Events The safety assessments in this study are standard safety measures in clinical studies, including physical examinations, vital signs (blood pressure, heart rate), local safety assessment scores (telangiectasis, burning/stinging, and flushing/blushing), questioning on Adverse events (AEs) and serious AEs (SAES) (volunteered, observed, and elicited by general questioning), and clinical laboratory test results (serum chemistry, hematology, urinalysis). The severity of each of the following signs/symptoms is measured by an investigator at Baseline and at Weeks 2, 4, 8 and 12: telangiectasis, burning/stinging, and flushing/blushing, all scored on a 1-5 scale. The score for signs is determined by the investigator and must represent the subject's condition at the time of the evaluation. The score for symptoms, burning/stinging and flushing/blushing, should be scored based on the subject's symptoms reported for the previous three days. A complete relevant medical and surgical history is obtained at Screening Visit, which will include diseases of the head, ears, eyes, nose and throat, respiratory diseases, cardiovascular diseases, gastrointestinal diseases, hepatic diseases, genitourinary diseases, musculoskeletal diseases, endocrine diseases, neurological diseases, psychiatric diseases, skin diseases, allergies, hematological diseases, and other abnormalities. Other safety evaluation points will include a history of medication usage (including previous use of acne medications and non-medication therapies) and all medication that the subject is currently taking or any change in medication or dosage since the last visit are documented throughout the study. Safety assessments will include recording adverse events (AEs) reported spontaneously by the subject or observed by the investigator. An Adverse Event (AE) is any unfavorable or unintended sign, symptom, or disease that appears or worsens in a subject after the subject signs the ICF (and/or Assent Form) for a clinical study. AEs are recorded at each visit throughout the study on the appropriate CRF. In one or more embodiments, similar clinical studies can be conducted for any tetracycline formulations described herein, such as DOX331, DOX332, DOD-003, MCD-037, MCD-045, MCD-052 MCD-053, MCD-065 and MCD-058. Compositions The below compositions, for use in the clinical study, are prepared according to the manufacturing procedures detailed in Example 1. TABLE 4 FMX103 Minocycline (3% and 1.5%) and placebo Foamable compositions without silicone dioxide (SiO2) 3% Minocycline 1.5% Minocycline Placebo Quantitative Quantitative Quantitative CAS Composition (% Composition (% Composition (% Number w/w) w/w) w/w) Minocycline HCl (expressed as 13614987 3.00a 1.50a — minocycline) Soybean Oil 8001227 50.00 50.00 50.00 Coconut Oil 8001318 23.60 23.60 23.60 Light Mineral Oil 8012951 2.14-2.48b 3.97-4.14b 5.80 Cyclomethicone 69430246 5.00 5.00 5.00 Cetostearyl Alcohol 67762270 3.50 3.50 3.50 Stearic Acid 57114 3.00 3.00 3.00 Myristyl Alcohol 112721 2.50 2.50 2.50 Hydrogenated Castor Oil 8001783 2.00 2.00 2.00 White Wax (Beeswax) 8012893 2.00 2.00 2.00 Stearyl Alcohol 112925 1.50 1.50 1.50 Docosanol (Behenyl alcohol) 661198 1.10 1.10 1.10 Total Bulk 100.00 100.00 100.00 AP-70 (butane, butane 106978 12.0 12.0 12.0 isobutane and isobutane 75285 propane)c propane 74986 aThe amount of minocycline hydrochloride is adjusted by the potency of the minocycline hydrochloride. b.The amount of light mineral oil in the formulation is adjusted based on the amount of minocycline hydrochloride. For example, if the potency of minocycline is 100%, then the amount of minocycline hydrochloride is 3% and amount of the mineral oil is 2.8% or then the amount of minocycline hydrochloride is 1.5% and amount of the mineral oil is 4.3%. cAP-70 (CAS # 6847-86-8) is a mixture of about 27% w/w butane, 18% w/w isobutane and 55% w/w propane. TABLE 5A Formulations of 1% Minocycline and 4% Minocycline with SiO2 Formulations 244B (FXFM244-1%) 244A(FXFM244-4%) (1% Minocycline) (4% Minocycline) Ingredients % w/w % w/w Light Mineral oil 4.44 1.11 Cyclomethicone 5.00 5.00 Coconut oil 23.60 23.60 Soybean oil 50.00 50.00 Hydrogenated castor oil 2.00 2.00 Beeswax 2.00 2.00 Myristyl alcohol 2.50 2.50 Cetostearyl alcohol 3.50 3.50 Stearyl alcohol 1.50 1.50 Behenyl alcohol 1.10 1.10 Fumed Silica (SiO2) 0.25 0.25 Stearic acid 3.00 3.00 Minocycline HCl 1.11 4.44 (micronized) (90% potency) Total 100 100 Propellant AP-70 12.00 12.00 TABLE 5B Formulations of 1% Minocycline and 4% Minocycline without SiO2 (FMX-101 Foam). FMX-101 FMX-101 (1%) (4%) FOAM FOAM Quantitative Quantitative Composition Composition Component (% w/w) (% w/w) Minocycline Hydrochloride 4.00a 1.00a (micronized) (expressed as minocycline) Soybean Oil 50.00 50.00 Coconut Oil 23.60 23.60 Light Mineral Oil 0.91-1.37b 4.58-4.69b Cyclomethicone 5.00 5.00 Cetostearyl Alcohol 3.50 3.50 Stearic Acid 3.00 3.00 Myristyl Alcohol 2.50 2.50 Hydrogenated Castor Oil 2.00 2.00 White Wax (Beeswax) 2.00 2.00 Stearyl Alcohol 1.50 1.50 Docosanol(behenyl 1.10 1.10 alcohol) Total Bulk 100 100 AP-70 (butane + isobutane + 12.0 12.0 propane)C aThe amount of minocycline hydrochloride is adjusted by the potency of the minocycline hydrochloride. bThe amount of light mineral oil in the formulation is adjusted based on the amount of minocycline hydrochloride. For example if the potency of minocycline is 100%, then the amount of minocycline hydrochloride is 4% and amount of the mineral oil is 1.8% or then the amount of minocycline hydrochloride is 1% and amount of the mineral oil is 4.8%. cAP-70 (CAS # 6847-86-8) is a mixture of about 27% w/w butane, 18% w/w isobutene and 55% w/w propane. TABLE 5C Formulation of DOX-244B with SiO2 Ingredient Name % W/W Coconut oil 23.60 Mineral oil light 4.35 soybean oil 50.00 stearic acid 3.00 behenyl alcohol 1.10 hydrogenated castor oil 2.00 Beeswax 2.00 Stearyl alcohol 1.50 Cetostearyl alcohol 3.50 Myristyl alcohol 2.50 Cyclomethicone 5.00 Silicon dioxide 0.25 Doxycycline Hyclate (micronized) 1.20 TABLE 5D Formulation of FDX104 and placebo without SiO2 FDX-104 4% FOAM Quantitative FDX-104 Placebo FOAM Composition Quantitative Composition Component (% w/w) (% w/w) Doxycycline hyclate 4.00a — (micronized) (expressed as doxycycline) Soybean Oil 50.00 50.00 Coconut Oil 23.60 23.60 Light Mineral Oil 0.95-1.21b 5.80 Cyclomethicone 5.00 5.00 Cetostearyl Alcohol 3.50 3.50 Stearic Acid 3.00 3.00 Myristyl Alcohol 2.50 2.50 Hydrogenated Castor Oil 2.00 2.00 White Wax (Beeswax) 2.00 2.00 Stearyl Alcohol 1.50 1.50 Docosanol 1.10 1.10 Total Bulk 100 100 AP-70 (butane + 12.0 12.0 isobutane + propane)C aThe amount of doxycycline hyclate is adjusted by the potency of the doxycycline hyclate. bThe amount of light mineral oil in the formulation is adjusted based on the amount of doxycycline hyclate. For example if the potency of doxycycline is 100%, then the amount of doxycycline hyclate is 4% and amount of the mineral oil is 1.8%. CAP-70 (CAS # 6847-86-8) is a mixture of about 27% w/w butane, 18% w/w isobutene and 55% w/w propane. TABLE 5E Formulations of DOX331 and DOX332 without SiO2 Formulations DOX331 DOX332 Ingredient % w/w % w/w Mineral oil, heavy* 82.24 88.24 Mineral oil, light 5.00 — Stearyl alcohol 4.50 3.70 Stearic acid 2.50 2.50 Behenyl alcohol 1.10 0.70 Paraffin 51-53 — 0.20 doxycycline hyclate 4.66 4.66 (micronized)** Total 100.00 100.00 AP-70 12% 12% *The amount of heavy mineral oil in the formulation is adjusted based on the mount of doxycycline hyclate. **The amount of doxycycline hyclate is adjusted by the potency of the doxycycline hyclate. TABLE 5F Formulation of Doxycycline and adapalene without SiO2 Formulations DOD-003 Ingredient % w/w Mineral oil heavy* 81.94 Mineral oil light 5 Stearyl alcohol 4.5 Stearic acid 2.5 Behenyl alcohol 1.1 Doxycycline 4.66 hyclate (micronized)** Adapalene 0.3 Total 100 AP-70 12% *The amount of heavy mineral oil in the formulation is adjusted based on the amount of doxycycline hyclate. **The amount of doxycycline hyclate is adjusted by the potency of the doxycycline hyclate. TABLE 5G Formulations of Minocycline and adapalene without SiO2 MCD- MCD- MCD- MCD- MCD- Component 037 045 052 053 058 Mineral oil “heavy”* 82.00 88.60 49.00 43.40 Mineral oil light* 5.00 0.70 39.00 39.00 Myristyl alcohol 2.50 Cetostearyl alcohol 3.50 Stearyl alcohol 4.50 3.60 1.50 3.80 4.30 Stearic acid 2.50 2.40 3.00 2.40 2.50 Cyclomethicone 5 5.00 5.00 Coconut oil 23.60 Soybean oil 50.00 Behenyl alcohol 1.10 0.50 1.10 0.70 0.70 Beeswax 2.00 Hydrogenated castor oil 2.00 MCH (micronized)** 4.80 4.80 4.80 4.80 4.80 Adapalene 0.10 0.10 0.30 0.30 0.30 Total 100.00 100.00 100.00 100.00 100.00 AP-70 12% 12% 12% 12% 12% *The amount of heavy mineral oil or light mineral oil in the formulation is adjusted based on the amount of Minocycline hydrochloride. **The amount of minocycline hydrochloride is adjusted by the potency of the minocycline hydrochloride. TABLE 5H Formulation of Minocycline with fatty alcohol without SiO2 Component MCD-065 Mineral oil light* 45.55 Stearyl alcohol 4.00 Soybean oil 45.05 Behenyl alcohol 0.60 MCH (micronized)** 4.80 Total 100.00 AP-70 12% Foam quality G *The amount of light mineral oil in the formulation is adjusted based on the amount of Minocycline hydrochloride. **The amount of minocycline hydrochloride is adjusted by the potency of the minocycline hydrochloride. All inactive ingredients used in the formulation are intended for topical use and listed in the current FDA Inactive Ingredient Database; concentrations used do not exceed the maximum concentrations given in Database. Example 4 Chemical and Physical Stability The achievement of a long term stable foamable formulation of tetracycline antibiotics described herein, was a major challenge and required both extensive research and creativity. The chemical and physical stability results of minocycline HCl (MCH) and doxycycline hyclate (“DOX”) in SiO2-containing oleaginous formulations, MCH244 and DOX244, respectively, are described in U.S. application Ser. No. 14/147,376 (U.S. Pub. No. 2014/0121188) and incorporated by reference herein. In an accelerated stability study, samples were stored at 40° C., and the concentrations of minocycline HCl and doxycycline hyclate were determined by UPLC. Stability test for MCH244 results following 2 months, 3 months, 6 months, 9 months, 12 months, 18 months, and 24 months of storage are shown herein below. The following examples illustrate the chemical stability of minocycline HCl (“MCH”) and doxycycline hyclate (“DOX”) in oleaginous formulations, as described in Tables 6, 7, and 9-11 below. In an accelerated stability study, samples were stored at 40° C., and the concentrations of minocycline HCl and doxycycline hyclate were determined by UPLC. The stability test results following 2 months, 3 months, 6 months, 9 months, 12 months, and 18 months of storage are shown herein below. Samples of MCH244 and DOX244 1% and 4% were stored at 25° C. and 40° C. in order to test physical and chemical stability. Inspection of Formulation in Glass Bottles The use of pressurized glass bottles enables the inspection of formulations for homogeneity in the presence of propellant. Following 18 months of storage at 25° C. the formulation was found to be re-dispersible, i.e., homogeneous following slight shaking. Stability Following Storage at 25° C. and 40° C. Storage at 25° C. and 40° C. for 18 months revealed almost no change in the Minocycline concentration. Test results for chemical stability of minocycline following storage for up to 18 months at 25° C. and 40° C. are summarized in Table 6 and Table 7. There was practically no degradation of 244 1% and 4% minocycline following 18 months at 25° C. and also following 9 months at 40° C. These stability results indicate shelf life of more than two years at ambient temperature. Test results for chemical stability of doxycycline following storage for up to 9 months at 25° C. and 40° C. are summarized in Tables 9-11. There was practically no degradation of doxycycline following 6 months at 25° C. and at 40° C. These stability results likewise indicate a long shelf life of more than two years at ambient temperature. In one or more embodiments, the tetracycline composition has a shelf life of at least 6 months, or at least 9 months, or at least 12 months, or at least 15 months, or at least 18 months, or at least 21 months, or at least 24 months at ambient temperature. In one or more embodiments, the tetracycline composition has a shelf life of at least 6 months, or at least 9 months, or at least 12 months, or at least 15 months, or at least 18 months, or at least 21 months, or at least 24 months at 25° C. In one or more embodiments, the tetracycline composition has a shelf life of at least 1 month, or at least 3 months, or at least 6 months, or at least 9 months, or at least 12 months at 40° C. TABLE 6 Minocycline content in MC11244 1% (with SiO2) following storage for 18 months at 25° C. and 40° C. Minocycline content (% w/w) Temp T = 0 3M 6M 9M 12M 18M 25° C. 1.001 NM 0.986 1.007 0.972 0.959 40° C. 1.001 1.002 0.983 0.965 NM NM NM = not measured TABLE 7 Minocycline content in MC11244 4% following storage for 18 months at 25° C. and 40° C. (Lot MCH-244-100825) (with SiO2) Minocycline content (% w/w) Temp T = 0 1M 3M 6M 9M 12M 18M 25° C. 4.049 NM NM 3.993 3.991 3.886 3.701 40° C. 4.049 3.935 3.852 4.035 3.9137 NM NM Minocycline Physical Stability: The results for physical stability following storage at 25° C. and 40° C. for 18 months were as follows: Foam quality: Conformed to the foam quality specification following storage for 9 months at 40° C. Odor: Conformed to the specifications and showed no odor following storage at 40° C. for 9 months. Color: The color of the formulation remained light, slightly changed to grey-yellow following storage at 40° C. for 9 months. No change was observed at 25° C. Shakeability: Conformed to specifications following storage at 40° C. for 9 months. Density: No significant change in density was found after storage at 40° C. for 9 months. Collapse time: No change in foam collapse time (the time for the foam to reach half of its initial height) was found in any of the formulation samples tested after storage for 9 months at 40° C. Microscopic observations: No significant change in the microscopic appearance was noted following storage at 40° C. for 9 months. Corrosion and deterioration: The coated aluminum surfaces of the can and valve and the plastic housing of the valve appeared fully intact and showed no signs of corrosion or deterioration. No changes in color or deformation were observed. Doxycycline DOX-244B Physical and Chemical Stability: The results for physical stability following storage at 25° C. for 18 months and for 24 months were as follows: Foam quality: excellent. Collapse time: At least 180 seconds. Production: GMP Compliance. For the purpose of clinical supplies, the production of the compositions was performed according to the principles of current good manufacturing practice (c-GMP). Production conditions were aimed to ensure high quality of the product and to prevent any potential cross contamination. The production site was certified by the Israel Ministry of Health as suitable for GMP production and supply of small clinical batches for Phase I and Ha clinical trials. The below composition was prepared according to the manufacturing procedures detailed in Example 1. TABLE 8 Formulation of DOX-244B-111123 Ingredient Name % W/W Coconut oil 23.60 Mineral oil light 4.35 soybean oil 50.00 stearic acid 3.00 behenyl alcohol 1.10 hydrogenated castor oil 2.00 Beeswax 2.00 Stearyl alcohol 1.50 Cetostearyl alcohol 3.50 Myristyl alcohol 2.50 Cyclomethicone 5.00 Silicon dioxide 0.25 Doxycycline Hyclate (micronized) 1.20 TABLE 9 Doxycycline content (%) in DOX-244B-111123 PF following storage for 9 months at 5° C., 25° C., 40° C., and 50° C. Doxycycline content (% w/w) T = 0 1M 2M 3M Batch/Sample 5° C. 25° C. 50° C. 25° C. 50° C. 25° C. 40° C. name DOX-244- 1.0220 1.031 1.022 — — — 1.010 1.031 111123 PF DOX-244- 1.0800 1.098 1.080 1.060 — 1.045 1.082 1.046 111123 PFF Doxycycline content (% w/w) 6M 9M 12M 18M 24M Batch/Sample 25° C. 40° C. 25° C. 25° C. 25° C. 25° C. name DOX-244- 1.017 1.025 1.053 0.967 0.994 1.021 111123 PF DOX-244- 1.046 1.028 1.091 1.044 1.018 1.051 111123 PFF TABLE 10 Stability of Doxycycline Foam at 25° C. and 40° C. %1 Doxycycline Hyclate in DOX244 foam product Months 40° C. (foam) 25° C. (foam) 0 102.2 102.2 1 102.2 2 3 103.1 101.0 6 102.5 101.7 9 105.3 12 96.7 18 99.4 24 102.1 1The percentages are derived from the PF figures in Table 9. Note 1.2% doxycycline hyclate is equivalent to 1.0176%. doxycycline based on USP TABLE 11 Degradation of Doxycycline at 5° C., 25° C., 40° C., and 50° C. Degradation Batch/Sample DOX-244B- product w/w name DOX-244B-111123 PF 111123 PFF T0 RRT 0.75 0.003 0.004 RRT 0.85 0.010 0.011 1 M 5° C. 0.003 0.003 RRT 0.75 5° C. 0.010 0.010 RRT 0.85 25° C. 0.003 0.003 RRT 0.75 25° C. 0.010 0.010 RRT 0.85 50° C. — 0.003 RRT 0.75 50° C. — 0.01 RRT 0.85 2 M 50° C. — 0.003 RRT 0.75 50° C. — 0.009 RRT 0.85 3 M 25° C. 0.003 0.004 RRT 0.75 25° C. 0.01 0.011 RRT 0.85 40° C. 0.003 0.003 RRT 0.75 40° C. 0.01 0.01 RRT 0.85 6 M 25° C. 0.003 0.003 RRT 0.75 25° C. 0.01 0.01 RRT 0.85 40° C. 0.003 0.003 RRT 0.75 40° C. 0.01 0.01 RRT 0.85 9 M 25° C. 0.003 0.003 RRT 0.75 25° C. 0.009 0.01 RRT 0.85 12 M 25° C. 0.003 0.003 RRT 0.75 25° C. 0.009 0.009 RRT 0.85 18 M 25° C. 0.003 0.003 RRT 0.75 25° C. 0.009 0.009 RRT 0.85 24 M 25° C. 0.003 0.003 RRT 0.75 25° C. 0.009 0.009 RRT 0.85 TABLE 12 Appearance and Collapse time of Doxycycline at 25° C. and 40° C. Appear- Appear- Collapse Collapse ance ance time (25° C.) time (40° C.) Time (25° C.) (40° C.) Collapse Time to Collapse Time to Points Quality Quality time(sec) FG(sec) time(sec) FG(sec) T0 G — 100 150 — — 3M E G 115 90 165 90 6M E G >180 120 >180 >180 9M E — 150 120 — — 12M G — 105 120 — — 18M E — >180 >180 — — 24M E — >180 >180 — — Doxycycline DOX-330A-140331 (without SiO2) physical and chemical stability: The results for physical stability following storage at 25° C. for 9 months and for 12 months were as follows: Foam quality: Excellent. Collapse time: At least 180 seconds. Production: GMP Compliance. For the purpose of clinical supplies, the production of the compositions was performed according to the principles of current good manufacturing practice (c-GMP). Production conditions were aimed to ensure high quality of the product and to prevent any potential cross contamination. The production site was certified by the Israel Ministry of Health as suitable for GMP production and supply of small clinical batches for Phase I and IIa clinical trials. The below composition was prepared according to the manufacturing procedures detailed in Example 1. TABLE 13 Formulation of DOX-330A-140331 (FDX104 without SiO2) Ingredient Name % W/W Coconut oil 23.60 Mineral oil light 0.90 soybean oil 50.00 stearic acid 3.00 behenyl alcohol 1.10 hydrogenated castor oil 2.00 Beeswax 2.00 Stearyl alcohol 1.50 Cetostearyl alcohol 3.50 Myristyl alcohol 2.50 Cyclomethicone 5.00 Doxycycline Hyclate (micronized) 4.90 TABLE 14 Doxycycline % content in DOX-330A-140331 PF following storage for 12 months at 25° C. and 40° C. T = 0 3w 2M 3M 6M 9M 12M Batch/Sample 40° C. 40° C. 25° C. 40° C. 25° C. 40° C. 25° C. 25° C. name DOX-330A- 4.032 3.984 3.981 4.086 3.942 4.086 4.088 3.993 4.032 140331 PF TABLE 15 Stability of Doxycycline Foam Formulation without SiO2 at 25° C. and 40° C. %2 Doxycycline Hyclate in DOX330 foam product Months 40° C. (foam) 25° C. (foam) 0 100.8 100.8 0.75 99.6 2 99.5 3 98.6 102.2 6 102.2 102.2 9 99.8 12 100.8 18 24 2The percentages are derived from the PF figures in Table 14. Note 1.2% doxycycline hyclate is equivalent to 1.0176%. doxycycline based on USP TABLE 16 Degradation of Doxycycline in Formulation without SiO2 at 25° C. and 40° C. Degradation Batch/Sample product w/w name DOX-330A-140331 PF T0 RRT 0.85 — 3 w 40° C. 0.017 RRT 0.85 2 M 40° C. 0.014 RRT 0.85 3 M 25° C. 0.016 RRT 0.85 40° C. 0.016 RRT 0.85 6 M 25° C. 0.017 RRT 0.85 40° C. 0.017 RRT 0.85 9 M 25° C. 0.020 6-epi (RRT 0.85) 12 M 25° C. 0.0213 6-epi (RRT 0.85) TABLE 17 Appearance and Collapse time of Doxycycline Foam Formulation without SiO2 at 25° C. and 40° C. Appear- Appear- Collapse time Collapse time ance ance (25° C.) (40° C.) Time (25° C.) (40° C.) Collapse Time to Collapse Time to Points Quality Quality time(sec) FG(sec) time(sec) FG(sec) T0 E — 160 >180 — — 3W — E− falls a — — >180 >180 little 2M — E — — >180 >180 3M E E >180 >180 180 >180 6M E E >180 >180 >180 >180 9M E — >180 >180 — — 12M E — >180 >180 — — Doxycycline physical and chemical stability in formulation without SiO2: The results for physical stability following storage at 25° C. for 9 months and for 6 months were as follows: Foam quality: Excellent. Odor: No odor Collapse time: At least 120 seconds. Production: GMP Compliance. For the purpose of clinical supplies, the production of the compositions was performed according to the principles of current good manufacturing practice (c-GMP). Production conditions were aimed to ensure high quality of the product and to prevent any potential cross contamination. The production site was certified by the Israel Ministry of Health as suitable for GMP production and supply of small clinical batches for Phase I and IIa clinical trials. The below composition was prepared according to the manufacturing procedures detailed in Example 1. TABLE 18 Formulation of DOX-330A-140818 PF (FDX104) Ingredient Name % W/W Coconut oil 23.60 Mineral oil light 1.13 soybean oil 50.00 stearic acid 3.00 behenyl alcohol 1.10 hydrogenated castor oil 2.00 Beeswax 2.00 Stearyl alcohol 1.50 Cetostearyl alcohol 3.50 Myristyl alcohol 2.50 Cyclomethicone 5.00 Doxycycline Hyclate (micronized) 4.67 TABLE 19 Doxycycline % content in DOX-330A-140818 (FDX104) PF without SiO2 following storage for 9 months at 25° C. and 40° C. Doxycycline content (% w/w) T = 0 1M 3M 6M 9M 12M 18M 24M Batch/Sample 40° C. 25° C. 40° C. 25° C. 40° C. 25° C. 25° C. 25° C 25° C. name DOX-330A- 3.908 3.899 3.792 3.763 3.727 3.783 3.763 140818 PF TABLE 20 Stability of Doxycycline Foam at 25° C. and 40° C. %3 Doxycycline in DOX330 140818 Months 40° C. (foam) 25° C. (foam) 0 97.7 97.7 1 97.5 3 94.1 94.8 6 94.6 93.2 9 94.1 12 18 24 3The percentages are derived from the PF figures in Table 19. Note 1.2% doxycycline hyclate is equivalent to 1.0176%. doxycycline based on USP TABLE 21 Degradation of Doxycycline at 25° C. and 40° C. Degradation product w/w Batch/Sample name DOX330 140818 T = 0 RRT 0.85 0.016 (6-epi) 1 M 40° C. 0.017 RRT 0.85 (6-epi) 3 M 25° C. 0.019 6-epi 40° C. 0.019 6-epi 6 M 25° C. 0.019 6-epi 40° C. 0.019 6-epi 9 M 25° C. 0.019 6-epi TABLE 22 Appearance and Collapse time of Doxycycline at 25° C. and 40° C. Appear- Appear- Collapse time Collapse time ance ance (25° C.) (40° C.) Time (25° C.) (40° C.) Collapse Time to Collapse Time to Points Quality Quality time(sec) FG(sec) time(sec) FG(sec) T0 E — 155 180 1M E — 90 >180 3M E E 180 >180 150 >180 6M E E 180 >180 >180 >180 9M E — 120 >180 Doxycycline and Adapalene DOD-003 Physical and Chemical Stability: TABLE 23 Doxycycline % content in DOD-003 following storage for 1 month at 25° C., 40° C. and 60° C. Doxycycline content (% w/w) Batch/Sample T = 0 1 M name 25° C./40° C. 60° C. 25° C. 40° C. 60° C. DOD-003 3.850 3.880 3.949 3.860 3.824 TABLE 24 Stability of Doxycycline at 25° C., 40° C. and 60° C. %4 Doxycycline in DOD-003 Months 25° C. (foam) 40° C. (foam) 60° C. (Pre foam formulation) 0 96.3 96.3 97.0 1 98.7 96.5 95.6 4The percentages are derived from the figures in Table 23. TABLE 25 Degradation of Doxycycline at 25° C., 40° C. and 60° C. Degradation product w/w Batch/Sample name DOD-003 T = 0 25° C. 6-epi 0.021 40° C. 6-epi 0.021 60° C. 6-epi 0.022 1 M 25° C. 6-epi 0.022 40° C. 6-epi 0.021 60° C. 6-epi 0.021 TABLE 26 Appearance, Collapse time and shakeability of Doxycycline at 25° C. and 40° C. in DOD-003 Time Appearance Collapse time Pts 25° C. 40° C. 60° C. 25° C. 40° C. 60° C. 4The percentages are derived from the figures in Table 23. Collapse Time to Collapse Time to Collapse Time to Quality Quality Quality time (s) FG (s) time (s) FG (s) time (s) FG (s) T0 E E NM >180 >180 >180 >180 NM NM 1M E E NM >180 120 >180 120 NM NM Time Points Shakeability (25° C.) Shakeability (40° C.) Shakeability (60° C.) T0 2 2 NM 1M 0 2 NM TABLE 27 Adapalene % content in DOD-003 following storage for 1 month at 25° C., 40° C. and 60° C. Adapalene content (% w/w) Batch/Sample T = 0 1 M name 25° C./40° C. 60° C. 25° C. 40° C. 60° C. DOD-003 0.2948 0.2948 0.3030 0.2950 0.3076 TABLE 28 Stability of Adapalene at 25° C., 40° C. and 60° C. %5 Adapalene in DOD-003 25° C. 40° C. 60° C. (Pre foam Months (foam) (foam) formulation) 0 98.3 98.3 98.3 1 101.0 98.3 102.5 5The percentages are derived from the FIGURES in Table 27. Minocycline and Adapalene MCD-037-160320 Physical and Chemical Stability: TABLE 29 Minocycline % content in MCD-037-160320 following storage for 4 months at 25° C. and 40° C. Minocycline content (% w/w) Batch/Sample T = 0 1 M 2M 3 M 4 M name 25° C./40° C. 25° C. 40° C. 25° C. 40° C. 25° C. 40° C. 25° C. 40° C. MCD-037- 3.89 NM 3.90 NM 4.03 3.88 3.89 3.99 3.95 160320 TABLE 30 Stability of Minocycline at 25° C. and 40° C. %6 Minocycline in MCD-037-160320 Months 25° C. (foam) 40° C. (foam) 0 97.22 97.22 1 NM 97.62 2 NM 100.68 3 97.01 97.30 4 99.66 98.79 6The percentages are derived from the figures in Table 29. TABLE 31 Degradation of Minocycline at 25° C. and 40° C. Degradation product w/w Batch/Sample name MCD-037-160320 T = 0 25° C. 4-epi 0.06 40° C. 4-epi 0.06 1 M 25° C. 4-epi NM 40° C. 4-epi 0.10 2 M 25° C. 4-epi NM 40° C. 4-epi 0.08 3 M 25° C. 4-epi 0.07 40° C. 4-epi 0.09 4 M 25° C. 4-epi 0.09 40° C. 4-epi 0.10 TABLE 32 Appearance, collapse time, shakeability and homogeneity of Minocycline at 25° C. and 40° C. in MCD-037-160320 Appearance Appearance Collapse time (25° C.) Collapse time (40° C.) Time (25° C.) (40° C.) Collapse Time to Collapse Time to Points Quality Quality time(sec) FG(sec) time(sec) FG(sec) T0 E E >180 >180 >180 >180 1M NM E NM NM >180 >180 2M NM E NM NM >180 >180 3M E E >180 >180 >180 >180 4M E E >180 >180 >180 >180 Time Shakeability Shakeability Points (25° C.) (40° C.) Homogeneity (25° C.) Homogeneity (40° C.) T0 2 2 Crystals uniformly Crystals uniformly distributed distributed 1M NM 2 NM Crystals uniformly distributed 2M NM 2 NM Crystals uniformly distributed 3M 2 2 Crystals uniformly Crystals uniformly distributed distributed 4M 2 2 Crystals uniformly Crystals uniformly distributed distributed TABLE 33 Adapalene % content in MCD-037-160320 following storage for 4 months at 25° C. and 40° C. Adapalene content (% w/w) T = 0 1M 2M 3M 4M Batch/Sample 25° C./40° C. 25° C. 40° C. 25° C. 40° C. 25° C. 40° C. 25° C. 40° C. name MCD-037- 0.09 NM 0.10 NM 0.10 0.10 0.10 0.0967 0.10 160320 TABLE 34 Stability of Adapalene at 25° C. and 40° C. %7 Adapalene in MCD-037-160320 Months 25° C. (foam) 40° C. (foam) 0 93.9 93.9 1 NM 96.9 2 NM 95.7 3 96.4 97.4 4 96.7 97.10 7The percentages are derived from the figures in Table 33. Minocycline and Adapalene MCD-045-160306 Physical and Chemical Stability: TABLE 35 Minocycline % content in MCD-045-160306 following storage for 3 months at 25° C. and 40° C. Minocycline content (% w/w) T = 0 1M 2M 3M Batch/Sample 25° C./40° C. 25° C. 40° C. 25° C. 40° C. 25° C. 40° C. name MCD-045- 3.83 NM 4.21 NM 3.93 3.91 3.96 160306 TABLE 36 Stability of Minocycline at 25° C. and 40° C. %8 Minocycline in MCD-045-160306 Months 25° C. (foam) 40° C. (foam) 0 95.76 95.76 1 NM 105.15 2 NM 98.14 3 97.79 99.08 8The percentages are derived from the figures in Table 35. TABLE 37 Degradation of Minocycline at 25° C. and 40° C. Degradation product w/w Batch/Sample name MCD-045-160306 T = 0 25° C. 4-epi 0.07 40° C. 4-epi 0.07 1 M 25° C. 4-epi NM 40° C. 4-epi 0.11 2 M 25° C. 4-epi NM 40° C. 4-epi 0.07 3 M 25° C. 4-epi 0.08 40° C. 4-epi 0.10 TABLE 38 Appearance, collapse time, shakeability and homogeneity of Minocycline at 25° C. and 40° C. in MCD-045-160306 Appearance Appearance Collapse time (25° C.) Collapse time (40° C.) Time (25° C.) (40° C.) Collapse Time to Collapse Time to Points Quality Quality time(sec) FG(sec) time(sec) FG(sec) T0 E E >180 >180 >180 >180 1M NM E NM NM >180 >180 2M NM E NM NM >180 >180 3M E E >180 >180 >180 150 4M E E >180 >180 140 120 Time Shakeability Shakeability Points (25° C.) (40° C.) Homogeneity (25° C.) Homogeneity (40° C.) T0 2 2 Crystals uniformly Crystals uniformly distributed distributed 1M NM 2 NM Crystals uniformly distributed 2M NM 2 NM Crystals uniformly distributed 3M 2 2 Crystals uniformly Crystals uniformly distributed distributed 4M 2 2 Crystals uniformly Crystals uniformly distributed distributed TABLE 39 Adapalene % content in MCD-045-160306 following storage for 3 months at 25° C. and 40° C. Adapalene content (% w/w) T = 0 1M 2M 3M Batch/Sample 25° C./40° C. 25° C. 40° C. 25° C. 40° C. 25° C. 40° C. name MCD-045- 0.10 NM 0.10 NM 0.10 0.09 0.10 160306 TABLE 40 Stability of Adapalene at 25° C. and 40° C. %9 Adapalene in MCD-045-160306 Months 25° C. (foam) 40° C. (foam) 0 95.10 95.03 1 NM 101.13 2 NM 95.80 3 94.40 95.83 9The percentages are derived from the figures in Table 39. Minocycline and Adapalene MCD-052-160410 Physical and Chemical Stability: TABLE 41 Minocycline % content in MCD-052-160410 following storage for 3 months at 25° C. and 40° C. Minocycline content (% w/w) T = 0 1M 2M 3M Batch/Sample 25° C./40° C. 25° C. 40° C. 25° C. 40° C. 25° C. 40° C. name MCD-052- 3.94 3.88 3.71 3.82 3.80 3.81 3.84 160410 TABLE 42 Stability of Minocycline at 25° C. and 40° C. %10 Minocycline in MCD-052-160410 Months 25° C. (foam) 40° C. (foam) 0 98.48 98.48 1 97.02 92.75 2 95.43 95.08 3 95.30 96.05 10The percentages are derived from the FIGURES in Table 41. TABLE 43 Degradation of Minocycline at 25° C. and 40° C. Degradation product w/w Batch/Sample name MCD-052-160410 T = 0 25° C. 4-epi 0.09 40° C. 4-epi 0.09 1 M 25° C. 4-epi 0.07 40° C. 4-epi 0.06 2 M 25° C. 4-epi 0.08 40° C. 4-epi 0.08 3 M 25° C. 4-epi 0.09 40° C. 4-epi 0.07 TABLE 44 Appearance, collapse time, shakeability and homogeneity of Minocycline at 25° C. and 40° C. in MCD-052-160410 Appear- Appear- Collapse time Collapse time ance ance (25° C.) (40° C.) Time (25° C.) (40° C.) Collapse Time to Collapse Time to Points Quality Quality time(sec) FG(sec) time(sec) FG(sec) T0 E E >180 >180 >180 >180 1M E E >180 >180 >180 >180 2M E E >180 >180 >180 >180 3M E E NM NM NM NM Shake- Shake- Time ability ability Homogeneity Homogeneity Points (25° C.) (40° C.) (25° C.) (40° C.) T0 2 2 Crystals uniformly Crystals uniformly distributed distributed 1M 2 2 Crystals uniformly Crystals uniformly distributed distributed 2M 2 2 Crystals uniformly Crystals uniformly distributed distributed 3M 0 0 Crystals uniformly Crystals uniformly distributed distributed TABLE 45 Adapalene % content in MCD-052-160410 following storage for 3 months at 25° C. and 40° C. Adapalene content (% w/w) Batch/ T = 0 Sample 25° C./ 1M 2M 3M name 40° C. 25° C. 40° C. 25° C. 40° C. 25° C. 40° C. MCD- 0.29 0.29 0.29 0.30 0.30 0.30 0.29 052- 160410 TABLE 46 Stability of Adapalene at 25° C. and 40° C. %11 Adapalene in MCD-052-160410 Months 25° C. (foam) 40° C. (foam) 0 97.31 97.31 1 95.50 96.74 2 98.69 99.00 3 99.16 97.78 Minocycline and Adapalene MCD-053-160413 Physical and Chemical Stability: TABLE 47 Minocycline % content in MCD-053-160413 following storage for 3 months at 25° C. and 40° C. Minocycline content (% w/w) Batch/ T = 0 Sample 25° C./ 1M 2M 3M name 40° C. 25° C. 40° C. 25° C. 40° C. 25° C. 40° C. MCD- 3.91 3.95 3.91 3.84 3.88 3.97 3.94 053- 160413 TABLE 48 Stability of Minocycline at 25° C. and 40° C. %12 Minocycline in MCD-053-160413 Months 25° C. (foam) 40° C. (foam) 0 97.79 97.79 1 98.64 97.69 2 96.03 96.98 3 99.32 98.43 TABLE 49 Degradation of Minocycline at 25° C. and 40° C. Degradation product w/w Batch/Sample name MCD-053-160413 T = 0 25° C. 4-epi 0.07 40° C. 4-epi 0.07 1 M 25° C. 4-epi 0.07 40° C. 4-epi 0.08 2 M 25° C. 4-epi 0.08 40° C. 4-epi 0.09 3 M 25° C. 4-epi 0.11 40° C. 4-epi 0.11 12The percentages are derived from the FIGURES in Table 47. TABLE 50 Appearance, collapse time, shakeability and homogeneity of Minocycline at 25° C. and 40° C. in MCD-053-160413 Collapse Collapse time (25° C.) time (40° C.) Appearance Appearance Collapse Time Collapse Time Time (25° C.) (40° C.) time to FG time to FG Points Quality Quality (sec) (sec) (sec) (sec) T0 E E >180 >180 >180 >180 1M E E >180 60 >180 >180 2M E E 175 180 180 180 Time Shakeability Shakeability Homogeneity Homogeneity Points (25° C.) (40° C.) (25° C.) (40° C.) T0 2 2 Crystals Crystals uniformly uniformly distributed distributed 1M 2 2 Crystals Crystals uniformly uniformly distributed distributed 2M 2 2 Crystals Crystals uniformly uniformly distributed distributed TABLE 51 Adapalene % content in MCD-053-160413 following storage for 3 months at 25° C. and 40° C. Adapalene content (% w/w) Batch/ T = 0 Sample 25° C./ 1M 2M 3M name 40° C. 25° C. 40° C. 25° C. 40° C. 25° C. 40° C. MCD- 0.28 0.28 0.28 0.28 0.28 0.29 0.28 053- 160413 TABLE 52 Stability of Adapalene at 25° C. and 40° C. %13 Adapalene in MCD-053-160413 Months 25° C. (foam) 40° C. (foam) 0 93.41 93.41 1 94.66 93.42 2 91.80 93.78 3 95.44 94.07 13The percentages are derived from the FIGURES in Table 51. Minocycline and Adapalene MCD-058-160414 Physical and Chemical Stability: TABLE 53 Minocycline % content in MCD-058-160414 following storage for 3 months at 25° C. and 40° C. Minocycline content (% w/w) Batch/ T = 0 Sample 25° C./ 1M 2M 3M name 40° C. 25° C. 40° C. 25° C. 40° C. 25° C. 40° C. MCD- 4.06 3.90 3.97 3.92 4.01 3.91 3.90 058- 160414 TABLE 54 Stability of Minocycline at 25° C. and 40° C. %14 Minocycline in MCD-058-160414 Months 25° C. (foam) 40° C. (foam) 0 101.61 101.61 1 97.58 99.20 2 97.88 100.36 3 97.76 97.50 14The percentages are derived from the FIGURES in Table 53. TABLE 55 Degradation of Minocycline at 25° C. and 40° C. Degradation product w/w Batch/Sample name MCD-058-160414 T = 0 25° C. 4-epi 0.09 40° C. 4-epi 0.09 1 M 25° C. 4-epi 0.09 40° C. 4-epi 0.10 2 M 25° C. 4-epi 0.09 40° C. 4-epi 0.10 3 M 25° C. 4-epi 0.12 40° C. 4-epi 0.12 TABLE 56 Appearance, Collapse time, shakeability and homogeneity of Minocycline at 25° C. and 40° C. in MCD-058-160414 Appearance Appearance Collapse time (25° C.) Collapse time (40° C.) Time (25° C.) (40° C.) Collapse Time to Collapse Time to Points Quality Quality time(sec) FG(sec) time(sec) FG(sec) T0 E E >180 150 >180 150 1M E E >180 >180 >180 >180 2M E E >180 180 >180 180 Time Shakeability Shakeability Points (25° C.) (40° C.) Homogeneity (25° C.) Homogeneity (40° C.) T0 2 2 Crystals uniformly Crystals uniformly distributed distributed 1M 2 2 Crystals uniformly Crystals uniformly distributed distributed 2M 2 2 Crystals uniformly Crystals uniformly distributed distributed TABLE 57 Adapalene % content in MCD-058-160414 following storage for 3 months at 25° C. and 40° C. Adapalene content (% w/w) Batch/ T = 0 Sample 25° C./ 1M 2M 3M name 40° C. 25° C. 40° C. 25° C. 40° C. 25° C. 40° C. MCD- 0.29 0.27 0.28 0.28 0.29 0.29 0.29 058- 160414 TABLE 58 Stability of Adapalene at 25° C. and 40° C. %15 Adapalene in MCD-058-160414 Months 25° C. (foam) 40° C. (foam) 0 95.01 95.01 1 91.47 94.05 2 93.64 95.11 3 95.87 95.09 15The percentages are derived from the FIGURES in Table 57. Doxycycline DOX331 Physical and Chemical Stability: TABLE 59 Doxycycline % content in DOX331 following storage for 1 week at 25° C. and 40° C. Doxycycline content (% w/w) Batch/Sample T = 0 1 Week name 25° C. 40° C. 25° C. 40° C. DOX331 4.146 4.146 4.103 4.106 TABLE 60 Stability of Doxycycline at 25° C. and 40° C. %16 Doxycycline in DOX331 Time 25° C. 40° C. 0 103.7 103.7 1 week 102.6 102.7 16The percentages are derived from the FIGURES in Table 59. TABLE 61 Degradation of Doxycycline at 25° C. and 40° C. Degradation product w/w Batch/Sample name DOX331 T = 0 25° C. 6-epi 0.026 40° C. 6-epi 0.026 1 Week 25° C. 6-epi 0.026 40° C. 6-epi 0.025 TABLE 62 Appearance, collapse time and shakeability of Doxycycline at 25° C. and 40° C. in DOX331 Appearance Appearance (25° C.) (40° C.) Shakeability Shakeability Time Points Quality Quality (25° C.) (40° C.) T0 E E 0 0 1 week E E 1 1 Doxycycline DOX332 Physical and Chemical Stability: TABLE 63 Doxycycline % content in DOX332 following storage for 1 week at 25° C. and 40° C. Doxycycline content (% w/w) Batch/Sample T = 0 1 Week name 25° C. 40° C. 25° C. 40° C. DOX332 4.074 4.074 4.124 4.169 TABLE 64 Stability of Doxycycline at 25° C. and 40° C. %17 Doxycycline in DOX332 Time 25° C. 40° C. 0 101.8 101.8 1 week 103.1 104.2 TABLE 65 Degradation of Doxycycline at 25° C. and 40° C. Degradation product w/w Batch/Sample name DOX332 T = 0 25° C. 6-epi 0.026 40° C. 6-epi 0.026 1 Week 25° C. 6-epi 0.026 40° C. 6-epi 0.026 TABLE 66 Appearance, collapse time and shakeability of Doxycycline at 25° C. and 40° C. in DOX332 Appearance Appearance (25° C.) (40° C.) Shakeability Shakeability Time Points Quality Quality (25° C.) (40° C.) T0 E E 1 1 1 week E E 1 1 17The percentages are derived from the figures in Table 63. Minocycline FMX103 (1.5% Minocycline) Chemical Stability: TABLE 67 Stability of Minocycline at 25° C., 30 ° C. and 40° C. % Minocycline in FMX103 (1.5% minocycline) % Minocycline in FMX103 (1.5% minocycline) Batch: 5042301 Batch: 5082401 Months 25° C. 30° C. 40° C. Months 25° C. 30° C. 40° C. 0 92.8-94.6 92.8-94.6 92.8-94.6 0 97.8 97.8 97.8 1 NM 94.8 80.2 1 NM 95.9 95.4 2 NM 91.9 88.2 2 NM 94.8 92.9 3 92.8 91.0 87.2/87.3 3 96.8 96.0 92.8 6 92.4 92.0 85.9/85.7 6 95.9 91.2 95.9 9 92.4 90.5 NM 9 NM NM NM 12 NM NM NM 12 NM NM NM TABLE 68 Degradation of Minocycline at 25° C., 30° C. and 40° C. FMX103 FMX103 (1.5% (1.5% minocycline) minocycline) Degradation Batch: Batch: product w/w Batch/Sample name 5042301 5082401 T = 0 25° C. 4-epi 0.0555 0.0465 30° C. 4-epi 0.0555 0.0465 40° C. 4-epi 0.0555 0.0465 1 M 25° C. 4-epi NM NM 30° C. 4-epi 0.06 0.042 40° C. 4-epi 0.0495 0.048 2 M 25° C. 4-epi NM NM 30° C. 4-epi 0.0585 0.0585 40° C. 4-epi 0.057 0.063 3 M 25° C. 4-epi 0.06 0.06 30° C. 4-epi 0.0555 0.057 40° C. 4-epi 0.054 0.051 6 M 25° C. 4-epi 0.069 0.0525 30° C. 4-epi 0.0615 0.0675 40° C. 4-epi 0.0285 0.0255 9 M 25° C. 4-epi 0.0555 NM 30° C. 4-epi 0.0645 NM 40° C. 4-epi NM NM 12 M 25° C. 4-epi NM NM 30° C. 4-epi NM NM 40° C. 4-epi NM NM Minocycline FMX103 (3% Minocycline) Chemical Stability: TABLE 69 Stability of Minocycline at 25° C. and 30° C. % Minocycline in FMX103 (3% minocycline) % Minocycline in FMX103 (3% minocycline) Batch: 5020901 Batch: 5082601 Months 25° C. 30° C. 40° C. Months 25° C. 30° C. 40° C. 0 96.4 96.4 96.4 0 98.8 98.8 98.8 1 NM 92.9 95.0 1 NM 95.6 96.5 2 NM NM NM 2 NM 94.5 96.6 3 94.7 93.7 92.0 3 98.2 97.9 95.5 6 93.2 90.6 87.5 6 97.8 97.1 93.6 9 92.0 88.7/91.5 NM 9 NM NM NM 12 93.4 93.5 NM 12 NM NM NM TABLE 70 Degradation of Minocycline at 25° C., 30° C. and 40° C. FMX103 (3% FMX103 (3% minocycline) minocycline) Degradation Batch: Batch: product w/w Batch/Sample name 5020901 5082601 T = 0 25° C. 4-epi 0.114 0.09 30° C. 4-epi 0.114 0.09 40° C. 4-epi 0.114 0.09 1 M 25° C. 4-epi NM NM 30° C. 4-epi 0.099 0.078 40° C. 4-epi 0.099 0.087 2 M 25° C. 4-epi NM NM 30° C. 4-epi NM 0.105 40° C. 4-epi NM 0.12 3 M 25° C. 4-epi 0.114 0.111 30° C. 4-epi 0.111 0.102 40° C. 4-epi 0.102 0.114 6 M 25° C. 4-epi 0.111 0.105 30° C. 4-epi 0.099 0.105 40° C. 4-epi 0.066 0.054 9 M 25° C. 4-epi 0.114 NM 30° C. 4-epi 0.114 NM 40° C. 4-epi NM NM 12 M 25° C. 4-epi 0.102 NM 30° C. 4-epi 0.108 NM 40° C. 4-epi NM NM Example 5 Clinical Study Phase I (FMX-101 Foam, 4% Minocycline Foam without SiO2) PK Study Under Maximum Use Conditions for 16 Days Study Synopsis In this example, topical administration of tetracycline (for example minocycline) was studied and the pharmacokinetic profile of the drug and its bioavailability was characterized. Study Title: An Open-label, Multiple Dose Study to Assess the Pharmacokinetic Profile of Minocycline from FMX-101 Foam (4%) in Male and Female Volunteers. Objectives: 1. To assess bioavailability of minocycline from FMX-101 minocycline HCl foam, 4%. 2. To characterize the pharmacokinetic profile of minocycline following multiple-dose topical administration of FMX-101 (4%) in healthy volunteers with or without acne. Study Medication: FMX-101 minocycline (4%)—approximately 4 gr per application. The composition of FMX-101 Foam (4%) is described in Table 5B above. Dosage Form: Foam. Indication: Acne vulgaris. Design: An open-label, single-center, non-randomized, multiple administrations study in males and females, some of which are with acne. Twelve (12) subjects (at least 4 subjects with acne) enrolled to receive a daily dose of topical FMX-101 minocycline (4%) foam for sixteen consecutive days. Eligible subjects were admitted to the Clinical Research Center (CRC) in the evening before the first study drug administration (Day 0), and remained in-house for 24 hours after first dosing (Day 1). Throughout this day blood samples for PK were drawn at time points specified below. After receiving the second dose (Day 2) they were released from the CRC. Subjects then arrived at the CRC on the mornings of Days 3, 5, 7, 8, 9, 10, 11, 12, 14 and 15. They remained under supervision in the CRC, with the application areas uncovered, for 30 min before being released. On Days 3, 7, 9, 11 and 14, blood was drawn for PK (trough) within 10 min before the subjects received the study drug. On days 4, 6 and 13 the drug was applied at home by the subject according to the Investigator/study staff instructions. On the evening of Day 15 the subjects were re-admitted to the CRC. On Day 16 they received the last (sixteenth) dose and went through the same procedures as in Day 1. After being released form the CRC they were required to attend three additional ambulatory PK blood sampling (36, 48 and 60 hours post-dose). PK Evaluation Timing of PK Blood Sampling Blood samples to determine plasma of minocycline were collected at the following time points: Day 1: pre-dose (within 90 min before first dosing), 30 min, 1, 2, 4, 8, 12, 16 hours post-dose and Day 2 at 24 hrs post-dose within 10 min before second dosing—a total of 9 samples). Days 3, 7, 9, 11 and 14: pre-dose (trough) samples, within 10 min before drug application. Day 16: pre-dose (within 10 min before drug application), 30 min, 1, 2, 4, 8, 12, 16 hours post-dose, Day 17, 24 (±10 min) hours post-dose (before discharge from the CRC) and additional ambulatory PKs at 36 (±15 min), (Day 17), 48 (±30 min) and 60 (±30 min) hours after last drug application (Day 18)—a total of 12 blood samples. TABLE 71 PK sampling scheme Study Day Time relative to dosing Day 1 0 h (Pre-dose) 0.5 h 1 h 2 h 4 h 8 h 12 h 16 h Day 2 Pre-dose (24 h post-dose) Day 3 Pre-dose (24 h post-dose) Day 7 Pre-dose (24 h post-dose) Day 9 Pre-dose (24 h post-dose) Day 11 Pre-dose (24 h post-dose) Day 14 Pre-dose (24 h post-dose) Day 16 0 h (Pre-dose, 24 h post-dose) 0.5 1 2 4 8 12 16 Day 17 24 36 Day 18 48 60 Throughout a period of 18 days a total of 26 samples per subject were drawn for PK. Calculation of Pharmacokinetic Parameters PK of minocycline was derived from plasma concentration versus time data. For purposes of calculating PK parameters, concentrations <LLQ were treated as zero. For purposes of tabular presentation and graphing mean profiles, concentration values <LLQ were treated as missing. The PK parameters assessed included: Cmax—Maximum plasma concentration achieved (dosing days 1 and 16). AUCT—The area under the plasma concentration versus time curve in ng*mL/h. The AUC from time zero to the last experimental time point (t*) with a detectable drug concentration equal to or greater than the limit of quantification value was designated AUCT and calculated by the linear trapezoidal rule (dosing days 1 and 16). All calculated concentration values were electronically transferred. Individual subject PK parameter values were derived by non-compartmental methods by WinNonlin 6.3 within the Phoenix 64 software package. The peak plasma concentration (Cmax) was obtained from experimental observations. FIG. 2 depicts the mean minocycline plasma concentrations from Day 1 to Day 16 for subjects who received FMX-101. Results: TABLE 72 FMX101-1 PK parameters PK Non-Compartmental Analysis Summary Statistics (Day 1, Day 16) Parameter Day 1 Day 16 Cmax [ng/mL] 2.26 ± 1.60 5.04 ± 6.19 AUCT [ng · h/mL] 33.83 ± 22.73 84.36 ± 48.36 Analysis: In general, the observed minocycline plasma concentrations throughout the study were low and close to the sensitive lower limit of quantification (LLOQ=1.1 ng/mL). The results of this study showed a very low absorption, with the Cmax (Day 16)=5 ng/mL, about 500 times lower than the Cmax and AUC for the labeled dose of the oral extended release minocycline, Solodyn® (100-135 mg, where the actual mg/kg dose corresponds to 1.07-0.99). Similar PK studies for additional tetracycline antibiotics, such as doxycycline in one or more embodiments may be undertaken. For example, PK studies for doxycycline in formulations such as FDX104, DOX331, DOX332, DOD-003, and minocycline with adapalene MCD-037, MCD-045, MCD-052 MCD-053, MCD-065 and MCD-058. Doxycycline is generally regarded as non-toxic in short term treatment, as indicated by its oral acute toxicity of LD50=1007 mg/kg (mouse). Chronic toxicity of doxycycline was evaluated in rats at oral doses up to 500 mg/kg/day for 18 months. Findings revealed no adverse effects on growth, food consumption, or survival. Example 6 PK Study Results for Tetracycline Formulations An open-label, single-center, study of the pharmacokinetics of daily applications of tetracycline formulations such as DOX331, DOX332, and DOD-003 doxycycline foam and MCD-037, MCD-045, MCD-052 MCD-053, MCD-065 and MCD-058 minocycline or doxycycline foam, is conducted for 16 consecutive days. Eligible subjects include males or females, 18 to 35 years of age, with or without papulopustular rosacea who are otherwise healthy. At least twelve subjects (preferably 6 male and 6 female), at least 9 of whom have varying degrees of papulopustular rosacea and 3 preferably without papulopustular rosacea, are enrolled to receive daily topical administration of tetracycline formulation, as indicated above. Subjects are admitted to the Clinical Research Center (CRC) in the evening before the first study drug administration (Day 0), and remain in-house for 24 hours after first dosing (Day 1). Throughout this day blood samples (6 mL) for determination of minocycline blood concentrations is drawn as follows: Day 1: pre-dose (within 60 min before first dosing), 30 min, 1, 2, 4, 8, 12, 16 hours post-dose and Day 2 at 24 hrs post-dose within 10 min before second dosing—a total of 9 samples) After receiving the second dose (Day 2) subjects are released from the CRC. Subjects then return to the CRC on the mornings of Days 3, 5, 7, 8, 9, 10, 11, 12, 14 and 15 (on Days 4, 6, and 13, subject applied the tetracycline formulation themselves). They remain in the CRC, with the application areas uncovered, for 30 min before being released. On Days 3, 7, 9, 11 and 14, blood is drawn as follows: Days 3, 7, 9, 11 and 14: pre-dose (trough) samples, within 10 min before drug application On the evening of Day 15 the subjects are re-admitted to the CRC. On Day 16 they receive the last (sixteenth) dose and undergo the same procedures as in Day 1 as follows: Day 16: pre-dose (within 30 min before drug application), 30 min, 1, 2, 4, 8, 12, 16 hours post-dose After being released from the CRC they are required to attend three additional blood samplings at 36, 48 and 60 hours post-dose as follows: Day 17: 24 (±10 min) hours post-dose (before discharge from the CRC) and additional ambulatory sample at 36 (±15 min) Day 18: 48 (±30 min) and 60 (±30 min) hours after last drug application. Blood samples are analyzed using a validated method with a lower limit of quantification (LLQ) of 1 ng/mL. An End-of Study/Safety Follow-up visit took place on 7-10 days after last dose, which also included a dermatological assessment of response to treatment. Results: The systemic exposure of a tetracycline foam as disclosed herein is equal to or lower than that of an orally administered tetracycline. There are no serious adverse events (AEs) and no withdrawals due to AEs. Example 7 Compatibility Study Procedure: Minocycline hydrochloride (“MCH”) was incubated as a suspension with various excipients at 25° C. and 40° C. for maximum of sixty days or to the point where degradation was suspected. The ratio between MCH and the tested excipient is detailed below. Visual inspection was the major criterion for indication of compatibility. The color of intact MCH suspension is pale yellow; and any change of color (e.g., to dark orange, red, green, brown and black) indicates oxidation or degradation. Hydrophilic solvents were tested for compatibility with MCH at a ratio of MCH: excipient of 1:250. Dimethyl Isosorbide, Glycerin, Ethanol, Propylene glycol, Butylene Glycol, PEG 200, Hexylene Glycol, PEG 400, Dimethyl Sulfoxide and Diethylene glycol monoethyl ether were found to be incompatible with MCH. Oily emollients and waxes were tested for compatibility with MCH at a ratio of MCH:excipient of 1:250 for oily emollients and 1:50 for waxes. Hydrogenated castor oil, Castor oil, Cocoglycerides, diisopropyl adipate, Mineral oil light, Coconut oil, Beeswax, MCT oil, Cyclomethicone, Isododecane, Cetearyl octanoate, Gelled mineral oil, Isopropyl myristate, PPG 15 stearyl ether, Mineral oil heavy, Octyl dodecanol, White Petrolatum, Petrolatum (Sofmetic), Paraffin 51-53, Paraffin 51-53, Paraffin 58-62, Calendula oil, Shea butter, Grape seed oil, Almond oil, Jojoba oil, Avocado oil, Peanut oil, Wheat germ oil and Hard Fat were found to be compatible with MCH. Pomegranate seed oil was found to be incompatible with MCH. Other than hydrogenated castor oil, beeswax, paraffin and hard fat, the aforesaid items listed are oily emollients. The compatibility of MCH with hydrophobic surfactant was tested following solubilization of the surfactant in mineral oil (mineral oil was previously shown to be compatible with MCH). Surfactants were tested for compatibility with MCH at a ratio of MCH:excipient of 1:50. PEG 150 distearate, Laureth 4, PEG 40 hydrogenated castor oil, PEG 75 lanolin, Glucam P20 distearate, PEG 100 stearate, Glyceryl monostearate, PEG 40 stearate, Montanov S (Cocoyl Alcohol (and) C12-20 Alkyl Glucoside), Alkyl lactate, Benton gel, SPAN 60, Sorbitan sesquistearate, SPAN 40, SPAN 80, Tween 20, Ceteth 2, Sucrose stearic acid esters D1813, Ceteareth 20, Steareth 2/Steareth 21, Methyl glucose sesquistearate, Oleth 20, PPG 20 methyl glucose ether, Tween 60 were found to be incompatible with MCH. Sucrose stearic acid esters D1803, Sucrose stearic acid esters D1807 and Sucrose stearic acid esters D1811 were found to be compatible with MCH; however, not all of them dissolved in oil (e.g., 1811, 1813). Foam adjuvants were tested for compatibility with MCH at a ratio of MCH:excipient of 1:50. Isostearyl alcohol, Behenyl alcohol, Stearyl alcohol, Cetyl alcohol, Oleyl alcohol, Myristyl alcohol, Cetostearyl alcohol, Palmitic acid, Stearic acid and Oleic acid were found to be compatible with MCH. Isostearic acid was not compatible with MCH. Additives were tested for compatibility with MCH at a ratio of MCH:excipient of 1:50. Aerosil and Menthol were found to be compatible with MCH. Titanium dioxide and Ethocel were not compatible with MCH. Additives were tested for compatibility with MCH. Minimal quantities of water (100 μL) were added to MCH, suspended in excipients that had demonstrated compatibility to examine whether water can enhance oxidation/degradation in the absence or presence of antioxidant. In parallel, antioxidants were added to the MCH suspensions comprising water. Antioxidants were also added to excipients which were found to be non-compatible with MCH. Addition of water caused prompt degradation of MCH. Addition of the antioxidants alpha-tocopherol, BHA/BHT and propyl gallate did not prevent MCH degradation. Compatible excipients became incompatible in the presence of water. Addition of antioxidants did not alter this result. Doxycycline A similar compatibility study was conducted for Doxycycline Hyclate and Doxycycline Monohydrate. The physicochemical properties of these two forms of Doxycycline are similar to those of other tetracycline antibiotics with the exception of differences resulting from the presence of an H2O molecule in Doxycycline Monohydrate and an H2O molecule and two HCl molecules for every water molecule in Doxycycline Hyclate. General properties of Doxycycline Hyclate and Doxycycline Monohydrate: Doxycycline Hyclate 1. Doxycycline Hyclate is a broad-spectrum antibiotic synthetically derived from oxytetracycline. 2. Doxycycline hyclate is a yellow crystalline powder soluble in water and in solutions of alkali hydroxides and carbonates. 3. Doxycycline hyclate has a high degree of lipid solubility and a low affinity for calcium binding. Doxycycline Monohydrate 1. Doxycycline monohydrate is a broad-spectrum antibiotic synthetically derived from oxytetracycline. 2. The chemical designation of the light-yellow crystalline powder is alpha-6-deoxy-5-oxytetracycline. The major degradative pathways for both types of Doxycycline are carbon-4 epimerization and oxidative processes. Doxycycline is a member of the tetracycline antibiotics group and is commonly used to treat a variety of infections, particularly effective in treating acne condition. Different compositions of hydrophilic and hydrophobic solvents containing Doxycycline Hyclate (Set I and Set II) and Doxycycline Monohydrate (Set III) were prepared by weighing the antibiotic in a glass vial and shaking overnight with each solvent investigated. Mixtures of Doxycycline salts 1.04% w/w with solid excipients were prepared in a similar way as for Minocycline HCl. The results are presented in Tables 22A-26. TABLE 73 Doxycycline Hyclate Compatibility Test (Group I) A. Mixtures of 1.04% w/w of Doxycycline Hyclate stored at 25° C., 40° C. and 50° C. for two weeks Ingredients PPG-15 stearyl Propylene Diisopropyl Group I Cyclomethicone ether Octyldodecanol Mineral oil glycol Glycerol PEG 200 PEG 400 MCT oil adipate Visual White White White White Light Light Light Light White White inspection liquid and liquid and liquid and liquid and yellow yellow yellow yellow liquid and liquid and at T-0 yellow yellow yellow yellow solution solution solution solution yellow yellow powder powder powder powder powder powder sedim. sedim. sedim. sedim. sedim. sedim. Visual White White White White Light Light Light Light White White inspection liquid and liquid and liquid and liquid and yellow yellow yellow yellow liquid and liquid and after the yellow yellow yellow yellow solution solution solution solution yellow yellow storage at powder powder powder powder powder powder 25° C. sedim. sedim. sedim. sedim. sedim. sedim. Visual White White Light White Yellow brownish Brown Orange White White inspection liquid and liquid and orange liquid and solution Yellow solution solution liquid and liquid and after the yellow yellow solution yellow solution yellow yellow storage at powder powder powder powder powder 40° C. sedim. sedim. sedim. sedim. sedim. Visual White White Orange White Brownish Light Orange Orange White White inspection liquid and liquid and solution liquid and orange brown solution solution liquid and liquid and after the yellow yellow yellow solution solution yellow yellow storage at powder powder powder powder powder 50° C. sedim. sedim. sedim. sedim. sedim. Compatibility Compat. Compat. Non Compat. Non Non Non Non Compat. Compat Results no no compat. no compat. compat. compat. compat. no no after the oxidation oxidation no oxidation oxidation oxidation oxidation oxidation oxidation oxidation storage oxidation B. Mixtures of 1.04% w/w of Doxycycline Hyclate stored at 25° C., 40° C. and 50° C. for two weeks Ingredients Group I Cetearyl octanoate Hexylene glycol Butylene glycol Sorbitan Monolaurate Dimethyl Isosorbide Visual inspection bright yellow bright yellow bright yellow bright yellow yellow solution at T-0 solution solution solution mixture Visual inspection bright yellow bright yellow bright yellow Brown solution Yellow solution after the storage solution solution solution at 25° C. Visual inspection bright yellow light yellow solution Light orange Brown solution Brownish orange after the storage solution solution at 40° C. Visual inspection White liquid and Light yellow liquid Light orange Black solution Orange solution after the storage yellow powder sedim. and yellow powder solution at 50° C. sedim. Compatibility Compat. Compat. Non compat. Non compat. Non compat. Results no oxidation no oxidation oxidation oxidation Oxidation Group II included Doxycycline Hyclate mixed with various vehicles with addition of antioxidants like alpha tocopherol, butylated hydroxytoluene (BHT), and ascorbic acid. TABLE 74 Doxycycline Hyclate Compatibility Test (Group II) Mixtures of 1.04% w/w of Doxycycline Hyclate stored at 25° C., 40° C. and 50° C. for two weeks Ingredients Propylene glycol, alpha PEG 200, alpha Ethanol 95%, BHT and tocopherol and ascorbic tocopherol and ascorbic Group II Ethanol 95% Ethanol 95% and BHT ascorbic acid acid acid Visual inspection bright yellow bright yellow bright yellow bright yellow bright yellow at T-0 solution solution solution solution solution Visual inspection bright yellow bright yellow Yellow solution bright yellow Yellow solution after the storage at solution solution solution 25° C. Visual inspection bright yellow bright yellow Yellow solution Light orange solution Orange solution after the storage at solution solution 40° C. Visual inspection bright yellow bright yellow Orange solution Light orange solution Brownish orange after the storage at solution solution solution 50° C. Compatibility compatible. compatible Non compatible. Non compatible. non compatible. Results no oxidation no oxidation Oxidation oxidation Oxidation TABLE 75 Doxycycline Hyclate Compatibility Test (Group III) Mixtures of 1.04% w/w of Doxycycline Hyclate stored at 25° C., 40° C. and 50° C. for 3 days Ingredients Myristyl Steareth alcohol and Isostearic Oleyl 20 and Hydrogenated Stearyl PEG 40 PEG 100 Sorbitan Group II Acid alcohol Steareth 2 Castor Oil alcohol Stearate Stearate Monostearate Cocoglycerides Visual inspection Yellow Yellow Yellow Yellow Yellow Yellow Yellow Yellow Yellow at T-0 suspen suspen suspen suspen suspen suspen suspen suspen suspen Visual inspection Yellow Yellow Yellow Yellow Yellow Yellow Yellow Yellow Yellow after the storage suspen suspen suspen suspen suspen suspen. suspen suspen suspen at 25° C. Visual inspection Yellow Yellow Brown Yellow Yellow Brown Yellow Yellow Yellow after the storage suspen suspen suspen suspen suspen suspen suspen suspen suspen at 40° C. Visual inspection Yellow Yellow Brown Yellow Yellow Brown Yellow Yellow Light after the storage suspen suspen suspen suspen suspen suspen suspen suspen brown at 50° C. powder Compatibility Compat.. Compat. Non Compat. Compat. Non Compat.. Compat. Non Results no No compat. No No Compat. No No Compat. oxidation oxidation Oxidation oxidation oxidation oxidation oxidation oxidation oxidation Suspen.—suspension; compat.—compatible A similar compatibility test was performed on another form of Doxycycline—Doxycycline Monohydrate. The results are presented in Tables 25A, 25B, and 26. TABLE 76 Doxycycline Monohydrate Compatibility Test (Group I) A. Mixtures of 1.04% w/w of Doxycycline Monohydrate stored at 25° C., 40° C., and 50° C. for two weeks Ingredients PPG-15 stearyl Propylene Diisopropyl Group I Cyclomethicone ether Octyldodecanol Mineral oil glycol Glycerol PEG 200 PEG 400 MCT oil adipate Visual White White White White Light yellow yellow Dark White White inspection liquid and liquid and liquid and liquid and yellow solution solution yellow liquid and liquid and at T-0 yellow yellow yellow yellow solution solution yellow yellow powder powder powder powder powder powder sedim. sedim. sedim. sedim. sedim. sedim. Visual White White White White Orange yellow Yellowish Yellowish White White inspection liquid and liquid and liquid and liquid and solution solution black brown liquid and liquid and after the yellow yellow yellow yellow solution solution yellow yellow storage at powder powder powder powder powder powder 25° C. sedim. sedim. sedim. sedim. sedim. sedim. Visual White Yellowish orange White Black black Black Brown White White inspection liquid and orange solution liquid and solution solution solution solution liquid and liquid and after the yellow mixture yellow yellow yellow storage at powder powder powder powder 40° C. sedim. sedim. sedim. sedim. Visual White Yellowish Orange White black black Black Black Dirty Brown inspection liquid and orange solution liquid and solution solution solution solution yellow mixture after the yellow mixture yellow storage at powder powder 50° C. sedim. sedim. Compatibility Compat. Non Non Compat. Non Non Non Non Non Non Results no compat. compat. no compat. compat. compat. compat. compat. compat. after the oxidation oxidation oxidation oxidation oxidation oxidation oxidation oxidation oxidation oxidation storage B. Mixtures of 1.04% w/w of Doxycycline Monohydrate stored at 25° C., 40° C., and 50° C. for two weeks Ingredients Group I Cetearyl octanoate Hexylene glycol Butylene glycol Sorbitan Monolaurate Dimethyl Isosorbide Visual White liquid and yellow White liquid and yellow White liquid and Brown mixture yellow solution inspection powder sedim. powder sedim. yellow powder at T-0 sedim. Visual White liquid and yellow bright yellow Orange solution orange solution orange solution inspection powder sedim. solution after the storage at 25° C. Visual White liquid and yellow Brownish black solution Brownish black Brown solution orange solution inspection powder sedim. solution after the storage at 40° C. Visual White liquid and yellow Black solution. black solution brown solution Orange solution inspection powder sedim. after the storage at 50° C. Compatibility compat. Non compat. Non compat. Non compat. non compat. Results no oxidation oxidation Oxidation oxidation Oxidation TABLE 77 Doxycycline Monohydrate Compatibility Test (Group II) Mixtures of 1.04% w/w of Doxycycline Monohydrate stored at 25° C., 40° C., and 50° C. for two weeks Ingredients Propylene glycol, alpha PEG 200, alpha Ethanol 95% Ethanol 95%, BHT and tocopherol and ascorbic tocopherol and ascorbic Group II Ethanol 95% and BHT ascorbic acid acid acid Visual inspection bright yellow bright yellow bright yellow bright yellow bright yellow at T-0 solution solution solution solution solution Visual inspection Brown solution Brown solution orange solution Yellowish orange Yellow solution after the storage at solution 25° C. Visual inspection Brown solution Brown solution Orange solution Orange solution Dark yellow solution after the storage at 40° C. Visual inspection Black solution Black solution Black solution Brownish orange Brown orange solution after the storage at solution 50° C. Compatibility Non compatible. Non compatible Non compatible. Non compatible. non compatible. Results oxidation oxidation Oxidation oxidation Oxidation Interesting and unexpected phenomena were found during the compatibility studies of Minocycline HCl, Doxycycline Hyclate and Doxycycline Monohydrate: 1. While minocycline displayed intensive oxidation on dissolution in glycerol, the antibiotic surprisingly revealed full compatibility with octyldodecanol, a branched chain fatty alcohol. Both molecules have similar hydroxyl units in their structures. 2. Doxycycline Hyclate and Monohydrate unexpectedly revealed different compatibility with excipients. For example, Doxycycline Hyclate was stable in a mixture with PPG-15 Stearyl Ether. Surprisingly, the Doxycycline Monohydrate was found to be non-compatible with PPG-15 Stearyl Ether during the storage at 40° C. and 50° C. for two weeks. 3. Doxycycline Hyclate was stable in a mixture with ethanol 95% and hexylene glycol. Doxycycline Monohydrate oxidized in similar mixtures. 4. Unexpectedly, addition of strong anti-oxidants like alpha-tocopherol and ascorbic acid did not prevent the oxidation of any of Minocycline HCl, Doxycycline Hyclate and Monohydrate in a waterless medium of propylene glycol and PEG 200. 5. Surprisingly, Doxycycline Hyclate revealed stability in Ethanol 95% following the storage at 40° C. and 50° C. for two weeks although both Minocycline HCl and Doxycycline Monohydrate changed their color from yellow to orange upon dissolution in Ethanol 95%. 6. In conclusion, the following non predictable substances were found to be compatible with Minocycline and Doxycycline: TABLE 78 Summary of MCH and DOX compatibility studies Compatibility tested after the storage for up to 3 weeks Minocycline Doxycycline Doxycycline Ingredient HCl Hyclate Monohydrate Comments Cyclomethicone 5 NF Yes Yes Yes All compatible PPG-15 Stearyl Ether Yes Yes No Octyldodecanol Yes No No Mineral Oil Yes Yes Yes All compatible Propylene Glycol No No No Glycerol No No No PEG 200 No No No PEG 400 No No No MCT Oil Yes Yes No Diisopropyl adipate Yes Yes No Ethanol 95% No Yes No Isostearic acid No Yes Not tested Oleyl alcohol Yes Yes Not tested Steareth 20 (Polyoxyl 20 No No Not tested Stearyl Ether) Steareth 2 (Polyoxyl 2 No No Not tested Stearyl Ether) Methyl glycose No Not tested Not tested sesquistearate (MGSS) Aluminum Starch Yes Not tested Not tested Octenylsuccinate (ASOS) Cetearyl octanoate Yes Yes Yes All compatible Hydrogenated Castor Oil Yes Yes Not tested Stearyl alcohol Yes Yes Not tested Myristyl alcohol Yes Yes Not tested Titanium Dioxide Yes Not tested Not tested PEG 40 stearate Yes No Not tested PEG 100 Stearate Yes Yes Not tested Sorbitan Monostearate Yes Yes Not tested Cocoglycerides Yes No Not tested Coconut Alcohol Yes Not tested Not tested Hexylene glycol No Yes No Butylene glycol No No No Sorbitan Monolaurate No No No Dimethyl Isosorbide No No No Titanium dioxide Yes Not tested Not tested Methyl glycose No Not tested Not tested sesquistearate (MGSS) Aluminum Starch Yes Not tested Not tested Octenylsuccinate (ASOS) Coconut alcohol Yes Not tested Not tested 7. As could be seen from Table 76, not all of the ingredients compatible with MCH are compatible with Doxycycline Hyclate or Monohydrate. For example, octyldodecanol is compatible with Minocycline HCl but revealed incompatibility with Doxycycline Hyclate and Monohydrate. Surprisingly, there are discrepancies in the list of ingredients compatible with Doxycycline Hyclate and Doxycycline Monohydrate: for example, PPG-15 Stearyl Ether is compatible with Doxycycline Hyclate and non-compatible with Doxycycline Monohydrate. 8. The data presented herein could be used for selection of active materials from tetracycline family for topical formulations. A list of ingredients that were found to be compatible with MCH and DOX could be applied to other antibiotics from the tetracycline family. The following ingredients are suitable for topical formulations: mineral oil, cyclomethicone, cetearyl octanoate. Few ingredients are compatible with both forms of doxycycline and are also compatible with minocycline. Example 8 Phase II Study for Papulopustular Rosacea A double-blind, randomized, placebo-controlled Phase 2 trial has been carried out involving 233 patients who were enrolled in 18 sites throughout Germany. Patients were randomized (1:1:1) to receive high dose FMX103 (3% minocycline foam), low dose FMX103 (1.5% minocycline foam) or vehicle foam once daily (in the evening) over 12 weeks, followed up by a 4-week post-treatment evaluation. However, one subject in the 3% group did not receive treatment and was not included in the intent to treat analysis. The study medication, dosage, inclusion/exclusion criteria, and design generally followed those outlined in Example 3 above, with the inclusion criteria of healthy males or non-preganant female aged over 18, having at least 12 papules and/or pustules for more than 6 months, and having the Investigator's Global Assessment (IGA) scores moderate to severe. The mean age of the study participants was 52.5 and 63% of the participants were female (see Table 79A and B). The efficacy endpoints were the absolute change in the number of inflammatory facial lesions (papules and pustules (primary endpoint)), improvement of the IGA of severity at 12 weeks compared to baseline (first secondary endpoint), and percent change in inflammatory lesion count at week 12 compared to baseline (second secondary endpoint). IGA score improvement by 2 or more grades and reaching an IGA score of 0 (“clear”) or 1 (“almost clear”) were considered successful. Safety and tolerability in the treatment of moderate to severe papulopustular rosacea were also evaluated. Safety and efficacy evaluations were performed at week 2, 4, 8, and 12, with an additional safety follow-up visit at week 16. TABLE 79A Summary of Analysis Populations by Treatment Minocycline 1.5% Minocycline 3% Vehicle Overall n (%) n (%) n (%) n (%) Screened 79 76 78 233 Randomized 79 76 78 233 Randomized but not treateda 0 1 0 1 Intent-to-Treat Populationb,c 79 (100.0) 75 (98.7) 78 (100.0) 232 (99.6) Per-Protocol Populationb,d 72 (91.1) 63 (82.9) 69 (88.5) 204 (87.6) Excluded from the Per-Protocol Populatione 7 (8.9) 13 (17.1) 9 (11.5) 29 (12.4) Not in ITT population 0 1 (1.3) 0 1 (0.4) Discontinued from the study 2 (2.5) 10 (13.2) 7 (9.0) 19 (8.2) Had major deviations from protocol 5 (6.3) 2 (2.6) 2 (2.6) 9 (3.9) Safety Population 79 (100.0) 75 (98.7) 78 (100.0) 232 (99.6) aSubject was randomized in error. Baseline inflammatory lesion count was 7, below inclusion criteria of 12. Subject was not dispensed study drug and was not included in the intent-to-treat population. Incomplete baseline assessment was done. bPercentages are based on the number of subjects randomized. cIncludes all randomized subjects. dIncludes all ITT subjects without any major deviations from the protocol. eSubjects may be excluded for more than one reason. TABLE 79B Summary of Demographics and Baseline Characteristics by Treatment - ITT Population Minocycline Minocycline 1.5% 3% Vehicle Overall Parameter (N = 79) (N = 75) (N = 78) (N = 232) Mean Age years (range) Range 21-82 22-78 24-80 21-82 Mean (SD) 51.2 (15.26) 51.6 (14.15) 54.8 (14.05) 52.5 (14.53) Median 51.0 52.0 53.5 52.0 Age Categories (years), [n (%)] 18-30 13 (16.5) 7 (9.3) 5 (6.4) 25 (10.8) 31-50 25 (31.6) 28 (37.3) 27 (34.6) 80 (34.5) >50 41 (51.9) 40 (53.3) 46 (59.0) 127 (54.7) Sex, [n (%)] Male 26 (32.9) 24 (32.0) 37 (47.4) 87 (37.5) Female 53 (67.1) 51 (68.0) 41 (52.6) 145 (62.5) Race, [n (%)] Caucasian 98.7 97.3 100.0 98.7 Othera 1.3 2.7 0 1.3 Female of Childbearing Potential (Females only), [n (%)] Yes 29 (54.7) 21 (41.2) 18 (43.9) 68 (46.9) No 24 (45.3) 30 (58.8) 23 (56.1) 77 (53.1) IGA of rocasea,b % Moderate 43.0 38.7 51.3 44.4 (IGA = 3) Severe 57.0 61.3 48.7 55.6 (IGA = 4) Mean range) 34.5 13-125) 34.1 12-186) 30.6 12-91) 33.1 12-186) total inflammatory lesion count aFMX-103 1.5% n = 1 Other; FMX-103 3%:n = 1American Indian or Alaska Native, n = 1 Native Hawaiian or Other Pacific Islander. bIGA grading for rosacea: 0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe. Study Baseline. The mean baseline lesion count for all groups ranged from 30.6 to 34.5 and the IGA scores were all moderate (score 3) or severe (score 4), with about 50% to about 60% of the subjects having a severe rating (Table 80A and C). Table 80B summarizes the IGA score system. TABLE 80A Summary of Subject Disposition by Treatment - ITT Population Minocycline 1.5% Minocycline 3% Vehicle Overall (N = 79) (N = 75) (N = 78) (N = 232) Completion Status n (%) n (%) n (%) n (%) Treated (at least one treatment) 79 (100.0) 75 (100.0) 78 (100.0) 232 (100.0) Completed at least 4 weeks of Treatment 76 (96.2) 68 (90.7) 73 (93.6) 217 (93.5) Completed 12 weeks of Treatment 74 (93.7) 60 (80.0) 67 (85.9) 201 (86.6) Completed Treatment and Follow-upa 73 (92.4) 60 (80.0) 67 (85.9) 200 (86.2) Discontinued 2 (2.5) 10 (13.3) 7 (9.0) 19 (8.2) Adverse Event 0 3 (4.0) 1 (1.3) 4 (1.7) Abnormal Laboratory Result 0 0 0 0 Lost to Follow-up 1 (1.3) 0 0 1 (0.4) Subject Request 1 (1.3) 6 (8.0) 3 (3.8) 10 (4.3) Protocol Deviation 0 1 (1.3) 1 (1.3) 2 (0.9) Specific Medical Reasons 0 0 0 0 Other 0 0 2 (2.6) 2 (0.9) aIncludes subjects who completed 12 weeks of treatment and had the follow-up visit. TABLE 80B IGA grading scale for papulopustular rosacea Grade Score Description Clear 0 No inflammatory papules or pustules Almost 1 1 or 2 inflammatory papules or pustules clear Mild 2 3 to 11 inflammatory papules or pustules Moderate 3 12 to 19 inflammatory papules or pustules and no nodules Severe 4 ≥20 inflammatory papules or pustules, and up to 2 nodules IGA = Investigator's Global Assessment. TABLE 80C Summary of Baseline Rosacea IGA and Total Inflammatory Lesion Count by Treatment - ITT Population Minocycline Minocycline 1.5% 3% Vehicle Overall Parameter (N = 79) (N = 75) (N = 78) (N = 232) Investigator Global Assessment (IGA) of Rosacea, [n (%)] Clear 0 0 0 0 Almost Clear 0 0 0 0 Mild 0 0 0 0 Moderate 34 (43.0) 29 (38.7) 40 (51.3) 103 (44.4) Severe 45 (57.0) 46 (61.3) 38 (48.7) 129 (55.6) Total Inflammatory Lesion Count Mean (SD) 34.5 (20.89) 34.1 (24.99) 30.6 (15.48) 33.1 (20.74) Median 28.0 27.0 26.0 27.5 Min, Max 13, 125 12, 186 12, 91 12, 186 Results: 232 subjects were randomized and received at least one dose of study drug (ITT population). 201 (86.6%) subjects completed 12 weeks of treatment and the follow-up visit. Statistically significant improvement vs. vehicle in the two most important measurements of efficacy was demonstrated for both FMX-103 doses. At the week 12 time point, designated for the primary end point analysis, both the 1.5% and 3% doses of FMX103 significantly reduced the absolute number of papules and pustules vs. the vehicle (1.5% and 3%, both p<0.001, ANCOVA, intent-to-treat analysis). The mean reduction in inflammatory lesion count (absolute change) of each treatment group vs. its baseline was 21.1 for the 1.5% dose, 19.9 for the 3% dose, and 7.8 for vehicle (FIG. 1A; Table 81A). The corresponding percent reductions were 61.4% and 55.5% for the FMX103 1.5% and 3% groups, respectively, and 29.7% for the vehicle (1.5% and 3%, both p<0.001, ANCOVA, intent-to-treat analysis). (FIG. 1B; Table 81A). A significant reduction in the mean lesion count was observed as early as week 2 for both 1.5% and 3% doses of FMX103 vs. the vehicle (1.5% and 3%, p<0.01, p<0.05 respectivelyANCOVA, intent-to-treat analysis). The mean reduction in inflammatory lesion count (absolute change) of each treatment group vs. its baseline was 10.9 for the 1.5% dose, 9 for the 3% dose, and 4 for vehicle. (see FIG. 1A; Table 81B). The corresponding percent reductions were 30% and 26% for the FMX103 1.5% and 3% groups, respectively, and 16% for the vehicle (1.5% p<0.01, ANCOVA, intent-to-treat analysis) (see FIG. 1B; Table 81C). TABLE 81A Summary of Percent and Absolute Change from Baseline in Inflammatory Lesion Count at Week 12 by Treatment in the Intent-to-Treat Population (Multiple Imputation Method) Minocycline 1.5% Minocycline 3% Vehicle Parameter (N = 79) (N = 75) (N = 78) Baseline N 79 75 78 Mean (SD) 34.5 (20.89) 34.1 (24.99) 30.6 (15.48) Median 28.0 27.0 26.0 Min, Max 13, 125 12, 186 12, 91 Week 12 N 79 75 78 Mean (SD) 13.4 (13.96) 14.2 (12.44) 22.8 (22.21) Median 9.0 12.9 16.8 Min, Max 0, 90 0, 57 0, 154 Percent Change from Baseline (%) N 79 75 78 Mean (SD) −61.4 (32.29) −55.5 (31.38) −29.7 (46.34) Median −69.6 −60.9 −37.8 Min, Max −100.0, 44.4 −100.0, 11.2 −100.0, 165.5 LSMean (SE)a −64.5 (4.55) −58.5 (4.94) −32.0 (4.83) P-valuea <0.001 <0.001 Absolute Change from Baseline N 79 75 78 Mean (SD) −21.1 (17.79) −19.9 (20.38) −7.8 (17.37) Median −17.0 −14.0 −8.0 Min, Max −95, 12 −129, 2 −44, 96 LSMean (SE)a −21.2 (1.68) −20.3 (1.75) −9.9 (1.80) P-valuea <0.001 <0.001 Interaction P-valueb: 0.665 Homogeneity P-valuec: 0.267 Normality P-valued: <0.001 Non-parametric <0.001 <0.001 ANCOVA P-valuee aFrom an analysis of covariance with main effect of treatment and covariates of baseline and pooled site. P-value is the test result for treatment effect versus vehicle. bP-value for treatment by pooled site, based on analysis of covariance on unimputed data with effects of treatment, baseline, and pooled site, and treatment by pooled site interaction. cFrom Levene's test on unimputed data. dFrom Shapiro-Wilk test on unimputed data. eFrom a non-parametric ANCOVA with effects of treatment, baseline, and pooled site. TABLE 81B Summary of Absolute Change from Baseline in Inflammatory Lesion Count Visits 2, 4 and 8 by Treatment in the Intent-to-Treat Population (Multiple Imputation Method) Visit Minocycline 1.5% Minocycline 3% Vehicle Parameter (N = 79) (N = 75) (N = 78) Baseline N 79 75 78 Mean (SD) 34.5 (20.89) 34.1 (24.99) 30.6 (15.48) Median 28.0 27.0 26.0 Min, Max 13, 125 12, 186 12, 91 Week 2 N 79 75 78 Mean (SD) 23.6 (15.20) 25.2 (21.14) 26.7 (17.83) Median 21.0 19.0 23.5 Min, Max 0, 74 2, 152 1, 103 Week 2 Change from Baseline N 79 75 78 Mean (SD) −10.9 (14.71) −9.0 (14.57) −4.0 (10.95) Median −8.0 −7.0 −4.0 Min, Max −75, 31 −82, 24 −30, 59 LSMean (SE)a −11.2 (1.36) −9.2 (1.40) −5.3 (1.37) P-valuea 0.002 0.038 Week 4 N 79 75 78 Mean (SD) 19.8 (16.14) 19.3 (19.72) 25.1 (16.38) Median 14.0 15.0 21.0 Min, Max 0, 76 1, 148 0, 81 Week 4 Change from Baseline N 79 75 78 Mean (SD) −14.8 (16.40) −14.8 (15.00) −5.5 (9.06) Median −13.0 −12.0 −7.0 Min, Max −81, 29 −84, 20 −22, 23 LSMean (SE)a −14.6 (1.36) −14.7 (1.42) −6.6 (1.36) P-valuea <0.001 <0.001 Week 8 N 79 75 78 Mean (SD) 16.0 (14.51) 15.2 (15.30) 23.1 (17.60) Median 11.2 11.0 18.5 Min, Max 0, 79 0, 96 0, 86 Week 8 Change from Baseline N 79 75 78 Mean (SD) −18.5 (17.71) −18.9 (17.60) −7.6 (13.45) Median −16.0 −17.0 −8.4 Min, Max −85, 29 −90, 16 −39, 32 LSMean (SE)a −18.4 (1.46) −19.0 (1.52) −9.3 (1.49) P-valuea <0.001 <0.001 aFrom an analysis of covariance with main effect of treatment and covariates of baseline and pooled site. P-value is the test result for treatment effect versus vehicle. TABLE 81C Summary of Percent Change from Baseline in Inflammatory Lesion Count Visits 2, 4 and 8 by Treatment in the Intent-to-Treat Population (Multiple Imputation Method) Visit Minocycline 1.5% Minocycline 3% Vehicle Parameter (N = 79) (N = 75) (N = 78) Baseline N 79 75 78 Mean (SD) 34.5 (20.89) 34.1 (24.99) 30.6 (15.48) Median 28.0 27.0 26.0 Min, Max 13, 125 12, 186 12, 91 Week 2 N 79 75 78 Mean (SD) 23.6 (15.20) 25.2 (21.14) 26.7 (17.83) Median 21.0 19.0 23.5 Min, Max 0, 74 2, 152 1, 103 Week 2 Percent Change from Baseline (%) N 79 75 78 Mean (SD) −30.0 (34.05) −25.9 (31.68) −15.8 (32.54) Median −29.6 −29.2 −16.7 Min, Max −100.0, 114.8 −87.2, 104.3 −91.7, 134.1 LSMean −32.1 (3.83) −27.5 (3.93) −17.3 (3.90) (SE)a P-valuea 0.005 0.053 Week 4 N 79 75 78 Mean (SD) 19.8 (16.14) 19.3 (19.72) 25.1 (16.38) Median 14.0 15.0 21.0 Min, Max 0, 76 1, 148 0, 81 Week 4 Percent Change from Baseline (%) N 79 75 78 Mean (SD) −42.9 (37.25) −44.1 (28.20) −20.1 (33.68) Median −46.7 −46.0 −19.8 Min, Max −100.0, 107.4 −94.4, 32.8 −100.0, 100.0 LSMean −44.5 (3.95) −45.5 (4.14) −20.9 (3.97) (SE)a P-valuea <0.001 <0.001 Week 8 N 79 75 78 Mean (SD) 16.0 (14.51) 15.2 (15.30) 23.1 (17.60) Median 11.2 11.0 18.5 Min, Max 0, 79 0, 96 0, 86 Week 8 Percent Change from Baseline (%) N 79 75 78 Mean (SD) −53.3 (36.17) −53.8 (34.33) −26.3 (37.78) Median −63.6 −58.1 −28.3 Min, Max −100.0, 107.4 −100.0, 71.4 −100.0, 69.7 LSMean −54.9 (4.36) −55.2 (4.54) −27.5 (4.41) (SE)a P-valuea <0.001 <0.001 aFrom an analysis of covariance with main effect of treatment and covariates of baseline and pooled site. P-value is the test result for treatment effect versus vehicle. Moreover, treatment resulted in significant improvement in IGA scores (FIGS. 2A and 2B; Tables 82A and 82B). Both the 1.5% and 3% doses of FMX-103 were significantly better compared to vehicle in reducing the IGA score by 2 grades and in reaching a “clear” (score=0) or “almost clear” (score=1) rating at Week 12, Both the 1.5% and 3% doses were efficacious and there was no statistically significant difference between the two minocycline doses. The results indicate that both the 1.5% and 3% doses of FMX-103 were significantly better than the vehicle in improving IGA scores by at least 2 grades at Week 12 (p=0.002 and p=0.032, respectively FIG. 2A, Table 82B). Both active doses of FMX-103 were also significantly better than the vehicle in improving the IGA scores by at least 2 grades and achieving an IGA score of “clear” (score=0) or “almost clear” (score=1) at Week 12 (p=0.001 and p=0.041 for 1.5% and 3% FMX-103, respectively FIG. 2B, Table 82B). The percent of subjects with improvement of IGA score by 2 grades at Week 12 was 41.8% and 33.3% for the FMX103 1.5% and 3% groups, respectively, and 17.9% for the vehicle (P<0.01 and P<0.05, respectively, Cochran-Mantel-Haenszel test). FIG. 2A; Tables 82A) The percent of subjects with improvement of IGA score by 2 grades and in reaching a “clear” (score=0) or “almost clear” (score=1) at Week 12 was 25.3% and 17.3% for the FMX103 1.5% and 3% groups, respectively, and 7.7% for the vehicle (P<0.01 and P<0.05, respectively, Cochran-Mantel-Haenszel test FIG. 2B; Tables 82B) Both the 1.5% and 3% doses of FMX-103 were significantly better compared to vehicle in reducing the IGA score by 2 grades as early as Week 4 (P<0.001 and P<0.01, respectively, Cochran-Mantel-Haenszel test FIG. 2A; Tables 82C). The percent improvement of IGA score by 2 grades at Week 4 was 20.3% and 18.7% for the FMX103 1.5% and 3% groups, respectively, and 2.6% for the vehicle. Both the 1.5% and 3% doses of FMX-103 were significantly better compared to vehicle in reducing the IGA score by 2 grades resulting in “clear” or “almost clear” as early as Week 8 (P<0.01 and P<0.05, respectively, Cochran-Mantel-Haenszel test FIG. 2B; Table 82D). The percent improvement of IGA score by 2 grades at Week 8 was 16.5% and 14.7% for the FMX103 1.5% and 3% groups, respectively, and 3.8% for the vehicle. TABLE 82A Summary of Investigator Global Assessment (IGA) 2-Level Improvement from Baseline to Week 12 by Treatment in the Intent-to-Treat Population (Multiple Imputation Method) Minocycline 1.5% Minocycline 3% Vehicle (N = 79) (N = 75) (N = 78) Parameter n (%) n (%) n (%) Baseline Clear 0 0 0 Almost Clear 0 0 0 Mild 0 0 0 Moderate 34 (43.0) 29 (38.7) 40 (51.3) Severe 45 (57.0) 46 (61.3) 38 (48.7) Week 12 Clear 7 (8.9) 2 (2.7) 1 (1.3) Almost Clear 13 (16.5) 11 (14.7) 5 (6.4) Mild 29 (36.7) 26 (34.7) 25 (32.1) Moderate 12 (15.2) 17 (22.7) 18 (23.1) Severe 18 (22.8) 19 (25.3) 29 (37.2) Severe Cases Change −60% −58.7% −23.7% Change from Baseline Improvement observed 58 (73) 53 (70.66) 35 (45) Improved by 4 Levels 1 (1.3) 0 0 Improved by 3 Levels 10 (12.7) 6 (8.0) 1 (1.3) Improved by 2 Levels 22 (27.8) 19 (25.3) 13 (16.7) Improved by 1 Level 25 (31.6) 28 (37.3) 21 (26.9) No Improvement 21 (26.6) 20 (26.7) 40 (51.3) Worsened by 1 Level 0 2 (2.7) 3 (3.8) Worsened by 2 Levels 0 0 0 Improved at Least 2 Levels 33 (41.8) 25 (33.3) 14 (17.9) Did Not Improve at Least 2 Levels 46 (58.2) 50 (66.7) 64 (82.1) P-valuea 0.002 0.032 Investigator Global Assessment (IGA) scores are 0-4 (Clear to Severe) aFrom a CMH test stratified by pooled site. Only treatment groups being compared included in the analysis. TABLE 82B Summary of Investigator Global Assessment (IGA) 2-Level Improvement that Results in Clear or Almost Clear from Baseline to Week 12 by Treatment Intent-to-Treat Population (Multiple Imputation Method) Clear or Almost Clear Minocycline 1.5% Minocycline 3% Vehicle and Improved at (N = 79) (N = 75) (N = 78) Least 2 Levels n (%) n (%) n (%) Yes 20 (25.3) 13 (17.3) 6 (7.7) No 59 (74.7) 62 (82.7) 72 (92.3) P-Valuea 0.001 0.041 Investigator Global Assessment (IGA) scores are 0-4 (Clear to Severe) aFrom a CMH test stratified by pooled site. Only treatment groups being compared included in the analysis. TABLE 82C Summary of Investigator Global Assessment (IGA) 2-Level Improvement from Baseline Visits 2, 4 and 8 and Treatment in the Intent-to-Treat Population (Multiple Imputation Method) Minocycline 1.5% Minocycline 3% Vehicle Visit (N = 79) (N = 75) (N = 78) Parameter n (%) n (%) n (%) Baseline Clear 0 0 0 Almost Clear 0 0 0 Mild 0 0 0 Moderate 34 (43.0) 29 (38.7) 40 (51.3) Severe 45 (57.0) 46 (61.3) 38 (48.7) Week 2 Clear 1 (1.3) 0 0 Almost Clear 1 (1.3) 2 (2.7) 2 (2.6) Mild 19 (24.1) 15 (20.0) 12 (15.4) Moderate 23 (29.1) 27 (36.0) 32 (41.0) Severe 35 (44.3) 31 (41.3) 32 (41.0) Week 2 Change from Baseline Improved by 4 Levels 0 0 0 Improved by 3 Levels 1 (1.3) 0 0 Improved by 2 Levels 4 (5.1) 4 (5.3) 2 (2.6) Improved by 1 Level 25 (31.6) 28 (37.3) 19 (24.4) No Improvement 47 (59.5) 41 (54.7) 56 (71.8) Worsened by 1 Level 2 (2.5) 2 (2.7) 1 (1.3) Worsened by 2 Levels 0 0 0 Improved at Least 2 Levels 5 (6.3) 4 (5.3) 2 (2.6) Did Not Improve at Least 2 Levels 74 (93.7) 71 (94.7) 76 (97.4) P-Valuea 0.239 0.363 Week 4 Clear 1 (1.3) 0 1 (1.3) Almost Clear 6 (7.6) 5 (6.7) 1 (1.3) Mild 25 (31.6) 22 (29.3) 16 (20.5) Moderate 21 (26.6) 23 (30.7) 27 (34.6) Severe 26 (32.9) 25 (33.3) 33 (42.3) Week 4 Change from Baseline Improved by 4 Levels 0 0 0 Improved by 3 Levels 2 (2.5) 0 1 (1.3) Improved by 2 Levels 14 (17.7) 14 (18.7) 1 (1.3) Improved by 1 Level 26 (32.9) 27 (36.0) 23 (29.5) No Improvement 36 (45.6) 33 (44.0) 51 (65.4) Worsened by 1 Level 1 (1.3) 1 (1.3) 2 (2.6) Worsened by 2 Levels 0 0 0 Improved at Least 2 Levels 16 (20.3) 14 (18.7) 2 (2.6) Did Not Improve at Least 2 Levels 63 (79.7) 61 (81.3) 76 (97.4) P-Valuea <0.001 0.001 Week 8 Clear 3 (3.8) 4 (5.3) 1 (1.3) Almost Clear 10 (12.7) 7 (9.3) 2 (2.6) Mild 29 (36.7) 29 (38.7) 23 (29.5) Moderate 15 (19.0) 16 (21.3) 21 (26.9) Severe 22 (27.8) 19 (25.3) 31 (39.7) Week 8 Change from Baseline Improved by 4 Levels 0 1 (1.3) 0 Improved by 3 Levels 6 (7.6) 5 (6.7) 1 (1.3) Improved by 2 Levels 16 (20.3) 20 (26.7) 7 (9.0) Improved by 1 Level 32 (40.5) 26 (34.7) 24 (30.8) No Improvement 24 (30.4) 22 (29.3) 42 (53.8) Worsened by 1 Level 1 (1.3) 1 (1.3) 4 (5.1) Worsened by 2 Levels 0 0 0 Improved at Least 2 Levels 22 (27.8) 26 (34.7) 8 (10.3) Did Not Improve at Least 2 Levels 57 (72.2) 49 (65.3) 70 (89.7) P-Valuea 0.004 <0.001 aFrom a CMH test stratified by pooled site. Only treatment groups being compared are included in the analysis. Source: Listing 16.2.10.1 TABLE 82D Summary of Investigator Global Assessment (IGA) 2-Level Improvement from Baseline that Results in Clear or Almost Clear Visits 2, 4 and 8 and Treatment in the Intent-to-Treat Population (Multiple Imputation Method) Visit Clear or Almost Clear Minocycline 1.5% Minocycline 3% Vehicle and Improved at (N = 79) (N = 75) (N = 78) Least 2 Levels n (%) n (%) n (%) Week 2 Yes 2 (2.5) 2 (2.7) 2 (2.6) No 77 (97.5) 73 (97.3) 76 (97.4) P-Valuea >0.999 0.933 Week 4 Yes 7 (8.9) 5 (6.7) 2 (2.6) No 72 (91.1) 70 (93.3) 76 (97.4) P-Valuea 0.055 0.155 Week 8 Yes 13 (16.5) 11 (14.7) 3 (3.8) No 66 (83.5) 64 (85.3) 75 (96.2) P-Valuea 0.009 0.014 aFrom a CMH test stratified by pooled site. Only treatment groups being compared are included in the analysis. Safety and Tolerability: Both doses of FMX103 appeared to be generally safe and well-tolerated. There were no serious treatment-related systemic adverse events, and there were only a few subjects overall who reported any treatment-related AEs (2, 4, and 5 in the 1.5%, 3%, and vehicle groups, respectively). Overall, 47% (109/232) of subjects reported ≥1 treatment-emergent AE (TEAE) (Table 83). The most common TEAEs (≥2% of subjects) included nasopharyngitis, urinary tract infection, cystitis, bronchitis (Table 84). 11 (4.7%) subjects reported treatment-related TEAEs, 9 had treatment-related dermal reactions (Tables 83 and Table 85). These reactions resolved before the end of the study. Serious TEAEs were reported in 4 subjects (3 in FMX-103 group and 1 in vehicle group) (Tables 83, and Table 85), however there were no treatment-related systemic TEAEs reported. In the FMX103 1.5% group, two subjects reported serious TEAEs (one had a contusion and one had a cerebral hemorrhage, hemiparesis, and a pulmonary embolism), and in the FMX103 3% group, one subject reported a serious TEAE (hemorrhoids). In the vehicle group, one subject reported a serious TEAE (gastroenteritis). None of these was considered to be treatment-related. A total of 4 subjects discontinued the study due to an adverse event (3 in the 3% group and 1 in the vehicle group (Table 83 and Table 85). All of these discontinued due to dermal-related TEAE skin (one subject in the vehicle group had pruritus and skin burning sensation; three subjects in the FMX103 3% group each had eczema, burning sensation, or worsening of rosacea), and all resolved by the end of the study (Table 83 and Table 85). Treatment appeared to be well tolerated; the severity of local signs and symptoms appeared to be similar between treatment groups. TABLE 83 Summary of Safety Profile Minocycline 1.5% Minocycline 3% Vehicle Overall Overall Summary of TEAEs, n (N = 79) (N = 75) (N = 78) (N = 232) (%) n (%) n (%) n (%) n (%) Subjects with 1 or more TEAE 46 (58.2) 32 (42.7) 31 (39.7) 109 (47.0) Subjects with 1 or more treatment- 2 (2.5) 4 (5.3) 5 (6.4) 11 (4.7) related TEAEab Treatment-Related Dermal 1 (1.3) 4(5.3) 5 (6.4) 10 (4.3) TEAEsc Subjects with 1 or more severe 3 (3.8) 2 (2.7) 4 (5.1) 9 (3.9) TEAE Subjects with 1 or more TEAE 0 3 (4.0) 1 (1.3) 4 (1.7) leading to study discontinuationb Subjects with 1 or more serious 2 (2.5) 1 (1.3) 1 (1.3) 4 (1.7) TEAEb Safety population includes all randomized subjects who applied at least one dose of study drug aIncludes unassessable, possible, probable, and certainly related adverse events bIncludes skin and subcutaneous tissue disorders, and general disorders and administration-site conditions (i.e, application-site erythema). cSubjects experiencing ≥1 AEs are counted only once for each AE term. TABLE 84 Profile of Commmon Treatment-Emergent Adverse Events That Occured in ≥2% of Subjects and Treatmet Related Dermal TEAES Minocycline 1.5% (N = 79) Minocycline 3% (N = 75) Vehicle (N = 78) System Organ Class Subjectsa Events Subjectsa Events Subjectsa Events Preferred Term n (%) n n (%) n n (%) n Any Adverse Event Overall 26 (32.9) 32 13 (17.3) 19 16 (20.5) 19 Infections and infestations Nasopharyngitis 11 (13.9) 11 3 (4.0) 3 9 (11.5) 9 Urinaiy tract infection 3 (3.8) 3 2 (2.7) 2 3 (3.8) 3 Cystitis 2 (2.5) 3 2 (2.7) 2 0 0 Bronchitis 3 (3.8) 3 0 0 0 0 Urinaiy tract infection bacterial 2 (2.5) 2 0 0 0 0 Influenza 0 0 0 0 2 (2.6) 3 Skin and subcutaneous tissue disorders Worsening of rosacea as 2 (2.5) 2 3 (4.0) 4 0 0 compared to baseline Eczema 2 (2.5) 2 2 (2.7) 2 2 (2.6) 2 Vascular disorders Hypertension 2 (2.5) 2 2 (2.7) 2 2 (2.6) 2 Eye disorders Eczema eyelids 2 (2.5) 2 0 0 0 0 Gastrointestinal disorders Toothache 2 (2.5) 2 0 0 0 0 Nervous system disorders Headache 0 0 2 (2.7) 4 0 0 aSubjects experiencing one or more adverse events are counted only once for each adverse event term. TABLE 85 Summary of treatment-related dermal reactions, serious TEAEs, and TEAE leading to study discontinuation FMX- FMX- 103 1.5% 103 3% Vehicle (n = 79) (n = 75) (n = 78) Subjects with treatment-related 1 (1.3) 3 (4.0) 5 (6.4) TEAEsa, n (%) Skin and subcutaneous tissue disorders Worsening of rosacea as 0 2 (2.7) 0 compared to baseline Eczema 0 1 (1.3) 1 (1.3) Skin exfoliation 0 1 (1.3) 0 Erythema 0 0 1 (1.3) Pruritus 0 0 1 (1.3) Scab 0 0 1 (1.3) Skin burning sensation 0 0 1 (1.3) Spotted redness in treatment area 1 (1.3) 0 0 Redness after medication application 0 0 1 (1.3) Face-burning or stinging 0 1 (1.3) 0 Eye disorders Eye discharge 1 (1.3) 0 0 Subjects with ≥1 serious 2 (2.5) 1 (1.3) 1 (1.3) TEAEa, n (1%) Haemorrhoids 0 1 (1.3) 0 Contusion 1 (1.3) 0 0 Cerebral haemorrhage 1 (1.3) 0 0 Hemiparesis 1 (1.3) 0 0 Pulmonary embolism 1 (1.3) 0 0 Gastroenteritis 0 0 1 (1.3) Subjects with ≥1 TEAE leading 0 3 (4.0) 1 (1.3) to study discontinuation n (%)a,b Eczema 0 1 (1.3) 0 Worsening of rosacea as 0 1 (1.3) 0 compared to baseline Pruritus 0 0 1 (1.3) Skin burning sensation 0 0 1 (1.3) Face burning or stinging 0 1 (1.3) 0 Safety population includes all randomized subjects who applied at least one dose of study drug. aSubjects experiencing ≥1 AEs are counted only once for each AE term. bEczema, rosacea, pruritus, face burning or stinging, and skin burning sensation were classed as skin and subcutaneous tissue disorders (TEAE dermal related). TABLE 86 Summary of Post-Baseline Local Safety Assessments by Treatment Safety Population Minocycline 1.5% Minocycline 3% Vehicle Scale (N = 79) (N = 75) (N = 78) Visit n (%) n (%) n (%) Telangiectasis Week 2 None 21 (26.6) 8 (10.7) 10 (12.8) Mild 39 (49.4) 42 (56.0) 41 (52.6) Moderate 19 (24.1) 20 (26.7) 22 (28.2) Severe 0 1 (1.3) 2 (2.6) None or Mild 60 (75.9) 50 (66.7) 51 (65.4) Week 4 None 20 (25.3) 11 (14.7) 9 (11.5) Mild 39 (49.4) 42 (56.0) 39 (50.0) Moderate 20 (25.3) 14 (18.7) 24 (30.8) Severe 0 1 (1.3) 2 (2.6) None or Mild 59 (74.7) 53 (70.7) 48 (61.5) Week 8 None 20 (25.3) 13 (17.3) 11 (14.1) Mild 38 (48.1) 37 (49.3) 32 (41.0) Moderate 19 (24.1) 15 (20.0) 26 (33.3) Severe 0 0 2 (2.6) None or Mild 58 (73.4) 50 (66.7) 43 (55.1) Week 12 None 22 (27.8) 14 (18.7) 11 (14.1) Mild 42 (53.2) 42 (56.0) 33 (42.3) Moderate 14 (17.7) 16 (21.3) 31 (39.7) Severe 0 1 (1.3) 2 (2.6) None or Mild 64 (81.0) 56 (74.7) 44 (56.4) Burning/Stinging Week 2 None 53 (67.1) 37 (49.3) 38 (48.7) Mild 17 (21.5) 24 (32.0) 24 (30.8) Moderate 8 (10.1) 8 (10.7) 11 (14.1) Severe 1. (1.3) 2 (2.7) 2 (2.6) None or Mild 70 (88.6) 61 (81.3) 62 (79.5) Week 4 None 50 (63.3) 47 (62.7) 42 (53.8) Mild 20 (25.3) 14 (18.7) 23 (29.5) Moderate 7 (8.9) 7 (9.3) 9 (11.5) Severe 2 (2.5) 0 0 None or Mild 70 (88.6) 61 (81.3) 65 (83.3) Week 8 None 58 (73.4) 50 (66.7) 40 (51.3) Mild 14 (17.7) 13 (17.3) 22 (28.2) Moderate 5 (6.3) 1 (1.3) 8 (10.3) Severe 0 1 (1.3) 1 (1.3) None or Mild 72 (91.1) 63 (84.0) 62 (79.5) Week 12 None 55 (69.6) 54 (72.0) 45 (57.7) Mild 19 (24.1) 13 (17.3) 27 (34.6) Moderate 4 (5.1) 5 (6.7) 5 (6.4) Severe 0 1 (1.3) 0 None or Mild 74 (93.7) 67 (89.3) 72 (92.3) Flushing/Blushing Week 2 None 42 (53.2) 35 (46.7) 27 (34.6) Mild 22 (27.8) 23 (30.7) 25 (32.1) Moderate 13 (16.5) 10 (13.3) 18 (23.1) Severe 2 (2.5) 3 (4.0) 5 (6.4) None or Mild 64 (81.0) 58 (77.3) 52 (66.7) Week 4 None 45 (57.0) 40 (53.3) 23 (29.5) Mild 22 (27.8) 18 (24.0) 31 (39.7) Moderate 7 (8.9) 8 (10.7) 18 (23.1) Severe 5 (6.3) 2 (2.7) 2 (2.6) None or Mild 67 (84.8) 58 (77.3) 54 (69.2) Week 8 None 47 (59.5) 39 (52.0) 32 (41.0) Mild 22 (27.8) 20 (26.7) 24 (30.8) Moderate 6 (7.6) 5 (6.7) 13 (16.7) Severe 2 (2.5) 1 (1.3) 2 (2.6) None or Mild 69 (87.3) 59 (78.7) 56 (71.8) Week 12 None 51 (64.6) 39 (52.0) 33 (42.3) Mild 16 (20.3) 22 (29.3) 30 (38.5) Moderate 10 (12.7) 11 (14.7) 12 (15.4) Severe 1 (1.3) 1 (1.3) 2 (2.6) None or Mild 67 (84.8) 61 (81.3) 63 (80.8) Clinical Erythema Assessment: Both FMX103 doses appeared to reduce erythema (Table 87). Following treatment, a decrease in erythema was observed. At 12 weeks, the 1.5% and 3% doses of FMX103 were effective in reducing erythema, compared to the vehicle-treated group (Table 87 and FIG. 3) as opposed to oral Orecea which had no effect on erythema. In particular, the majority of subjects in each treatment group (approximately 53% to 55% in each group) had a clinical erythema assessment of moderate or severe. At Week 12, a larger majority of subjects in the 1.5% and 3% FMX-103 groups (approximately 76% to 85%, respectively) had a clinical erythema assessment of clear to mild vs. approximately 68% of subjects in the vehicle group. Thus, FMX103 advantageously reduced erythema in moderate to severe cases, as well as avoided systemic side effects. TABLE 87 Summary of Changes from Baseline in Clinical Erythema Assessment by Visit and Treatment Intent-to-Treat Population (Multiple Imputation Method) Minocycline 1.5% Minocycline 3% Vehicle Visit (N = 79) (N = 75) (N = 78) Parameter n (%) n (%) n (%) Week 2 Baseline Clear 1 (1.3) 0 0 Almost Clear 12 (15.2) 7 (9.3) 7 (9.0) Mild 24 (30.4) 28 (37.3) 28 (35.9) Moderate 33 (41.8) 31 (41.3) 36 (46.2) Severe 9 (11.4) 9 (12.0) 7 (9.0) Post-Baseline Clear 0 2 (2.7) 0 Almost Clear 21 (26.6) 12 (16.0) 10 (12.8) Mild 30 (38.0) 34 (45.3) 28 (35.9) Moderate 19 (24.1) 21 (28.0) 34 (43.6) Severe 9 (11.4) 6 (8.0) 6 (7.7) Change in Moderate or Severe Erythema Cases* −33% (42 to 28) −33% (40 to 27) −7% (43 to 40) Improved at Least 2 Levels 1 (1.3) 5 (6.7) 0 Did Not Improve at Least 2 Levels 78 (98.7) 70 (93.3) 78 (100.0) Week 4 Baseline Clear 1 (1.3) 0 0 Almost Clear 12 (15.2) 7 (9.3) 7 (9.0) Mild 24 (30.4) 28 (37.3) 28 (35.9) Moderate 33 (41.8) 31 (41.3) 36 (46.2) Severe 9 (11.4) 9 (12.0) 7 (9.0) Post-Baseline Clear 3 (3.8) 2 (2.7) 1 (1.3) Almost Clear 22 (27.8) 18 (24.0) 12 (15.4) Mild 25 (31.6) 39 (52.0) 29 (37.2) Moderate 20 (25.3) 12 (16.0) 28 (35.9) Severe 9 (11.4) 4 (5.3) 8 (10.3) Change in Moderate or Severe Erythema Cases* −31% (42 to 29) −60% (40 to 16) −16.3% (43 to 36) Improved at Least 2 Levels 4 (5.1) 7 (9.3) 1 (1.3) Did Not Improve at Least 2 Levels 75 (94.9) 68 (90.7) 77 (98.7) Week 8 Baseline Clear 1 (1.3) 0 0 Almost Clear 12 (15.2) 7 (15.2) 7 (9.0) Mild 24 (30.4) 28 (30.4) 28 (35.9) Moderate 33 (41.8) 31 (41.8) 36 (46.2) Severe 9 (11.4) 9 (11.4) 7 (9.0) Post-Baseline Clear 5 (6.3) 1 (1.3) 4 (5.1) Almost Clear 23 (29.1) 21 (28.0) 10 (12.8) Mild 29 (36.7) 39 (52.0) 33 (42.3) Moderate 17 (21.5) 12 (16.0) 26 (33.3) Severe 5 (6.3) 2 (2.7) 5 (6.4) Change in Moderate or Severe Erythema Cases* −48% (42 to 22) −65% (40 to 14) −28% (43 to 31) Change in Severe Erythema Cases** −44% (9 to 5) −78% (9 to 2) −28.6% (7 to 5) Improved at Least 2 Levels 12 (15.2) 12 (16.0) 6 (7.7) Did Not Improve at Least 2 Levels 67 (84.8) 63 (84.0) 72 (92.3) Week 12 Baseline Clear 1 (1.3) 0 0 Almost Clear 12 (15.2) 7 (9.3) 7 (9.0) Mild 24 (30.4) 28 (37.3) 28 (35.9) Moderate 33 (41.8) 31 (41.3) 36 (46.2) Severe 9 (11.4) 9 (12.0) 7 (9.0) Post-Baseline Clear 4 (5.1) 5 (6.7) 3 (3.8) Almost Clear 23 (29.1) 17 (22.7) 15 (19.2) Mild 33 (41.8) 42 (56.0) 35 (44.9) Moderate 18 (22.8) 9 (12.0) 20 (25.6) Severe 1 (1.3) 2 (2.7) 5 (6.4) Change in Moderate or Severe Erythema Cases* −55% (42 to 19) −73% (40 to 11) −42% (43 to 25) Change in Severe Erythema Cases** −89% (9 to 1) −78% (9 to 2) −28.6% (7 to 5) Improved at Least 2 Levels 10 (12.7) 11 (14.7) 7 (9.0) Did Not Improve at Least 2 Levels 69 (87.3) 64 (85.3) 71 (91.0) *% reduction of moderate to severe cases out of number moderate to severe cases **% reduction of severe cases out of number severe cases FMX103 vs. Oracea® (Oral Doxycycline 40 mg)2 Currently, Oracea® is the drug of choice for treatment of papulopustular rosacea. However, the current Phase 2 trial showed that FMX103 had surprising advantages, since it achieved greater effect despite a shorter treatment period (12 weeks vs. 16 weeks) and despite a higher baseline severity of rosacea (both mean lesion count and IGA severity, see Table 88), while avoiding systemic adverse events associated with oral doxycyline. As shown in Table 88, the results for reduction of absolute mean lesion count of FMX103 (a 21 point reduction for the 1.5% group) and percent change of lesion count (61.4% for the 1.5% group) were all higher than the results observed with Oracea®. TABLE 88 Summary of clinical trial results for FMX103 and Oracea (literature comparison) FMX103 1.5% Oracea ® Oral Doxycycline1, 2 Topical Minocycline (Week 16) (Week 12) Study 1 Study 2 Active Vehicle Active Vehicle Active Vehicle Inflammatory Lesions Baseline No. of lesions 34.5 30.6 19.5 20.3 20.5 21.2 Mean Absolute Reduction −21.1 −7.8 −11.8 −5.9 −9.5 −4.3 Mean Percent Reduction 61.4% −29.7% — — — — IGA Baseline Moderate 43% 51.3% 52.8% 52.4% 54.2% 55.6% IGA Severe 57% 48.7% 40.9% 39.5% 33.8% 39.6% ≥2 IGA Grade Reduction 41.8% 17.9% 45.7% 25.8% 22.5% 16.0% IGA = Clear/Almost Clear 25.3% 7.7% 30.7% 19.4% 14.8% 6.3% 1Source: (1) Oracea Prescribing Information, December 2014; (2) Del Rosso et al, JAAD 56 (2007) 791-802 2Literature Comparison: clinical trials are conducted under widely varying conditions, efficacy rates observed in the clinical trials of one drug cannot be directly compared to rates in the clinical trials of another drug. Head-to-head trials with FMX103 were not conducted. Example 9 Pharmacokinetic Comparison of Once-Daily Topical Minocycline Foam 4% vs Oral Minocycline for Moderate-to-Severe Acne Objective: To characterize minocycline pharmacokinetics and relative bioavailability following multiple-dose topical administration of minocycline hydrochloride (HCl) foam 4% (FMX-101 4%) as compared with single-dose oral of minocycline HCl extended-release tablets (Solodyn®) in in both adult and pediatric ubjects with moderate-to-severe acne. Methods: Two Phase I, single-center, nonrandomized, open-label, active-controlled, 2-period, 2-treatment crossover clinical studies were conducted. One study included 30 healthy adults (mean age, 22.6 years; 90% white, and 60% females) and the other included 20 pediatric subjects (mean age, 13.2 years; 65% black or African American, and 55% females) who had moderate-to-severe acne. Subjects were initially assigned to receive a single oral dose of a minocycline HCl extended-release tablet (approximately 1 mg/kg) after an overnight fast of at least 10 hours (Period 1). At 10 days after the oral minocycline dose, topical minocycline foam 4% was applied, once daily for 21 days (Period 2). Each application was approximately 4 g (a maximal-use dose). Serial blood samples were obtained before and after administration of oral minocycline and each topical application of minocycline foam 4% on days 1, 12, and 21. On the day of initial dosing (Day 1), subjects checked into the clinic where they were confined until 1 hour after study drug was administered. Predose clinical assessments were performed and a 1 mL blood sample for PK analysis was obtained before study drug was administered. Pediatric subjects received a 4 g, once-daily topical application of FMX101 4% for 7 days. Blood samples were collected at 3, 12, 16, and 24 hours after application on day 7. Subjects: Adults were eligible for this study if they were 18 to 35 years of age; children were eligible for the pediatric study if they were 9 to 16 years and 11 months of age and in good health, as judged on the basis of their medical history and the screening procedures. They were required to have moderate-to-severe facial acne vulgaris as well as acne affecting at least two additional regions of the body (neck, upper chest, upper back, or arms). Body mass index of the subjects was specified to range from 18.5 to 29.9 kg/m2. Use of tobacco and/or nicotine during the 30 days prior to the screening visit was prohibited, and all subjects were required to have a negative test for drug abuse and to be able to fully comply with the study requirements. All subjects provided written, informed consent. Subjects were excluded if they met any one of the following criteria: female who was pregnant or lactating, or planning a pregnancy; use of medicated cleansers or topical acne treatment within 1 week prior to enrollment, or use of topical retinoids, anti-inflammatories, corticosteroids, or systemic antibiotics or other systemic acne treatments within 4 weeks prior to enrollment, or use of systemic retinoids or corticosteroids within 12 weeks prior to enrollment; any abnormal laboratory values at baseline; any dermatologic condition of the face or facial hair, or any other conditions that, in the opinion of the investigator, could have interfered with the clinical evaluations or the course of the study, or exposed the subject to undue risk. Sampling: During Period 1, subjects received a single oral dose of minocycline; blood samples were obtained before dosing and through 96 hours (at 30 minutes and at 1, 1.5, 2, 3, 4, 6, 9, 12, 16, 24, 48, 72, and 96 hours) after administration of oral minocycline. During Period 2, topical minocycline foam 4% was applied daily for 21 days. Blood samples were obtained before dosing and at 2, 4, 8, 12, 16, and 24 hours after the first topical application of minocycline foam 4% (Period 2, day 1). On days 6, 9, 10, 11, and 16, blood samples were obtained at approximately 30 minutes before the scheduled application. On days 12 and 21, blood samples were obtained at 30 minutes before and at 2, 4, 8, 12, 16, and 24 hours after topical application of minocycline foam 4%. Day 21 was the last day of application, at which time all assessments and safety procedures were performed. After the final application, subjects were asked to return for additional blood sampling on days 23, 24, and 25. Bioanalytical Methods: Blood samples were collected and centrifuged, and the separated plasma was stored at approximately −70° C. Plasma minocycline concentrations were determined using validated liquid chromatography with a tandem mass spectrometry detection method (Nuvisan GmbH); the limit of detection was 0.270 ng/mL. Pharmacokinetic Analyses: Noncompartmental pharmacokinetic parameters for minocycline were calculated for all subjects for each day during Period 1 and on days 1, 12, and 21 for Period 2. Pharmacokinetic parameters included the following: Cmax (maximum plasma concentration); tmax (time of maximum measured plasma concentration); AUC0-inf (area under the plasma concentration vs time curve [AUC] from time 0 to infinity); AUC0-tldc (AUC from time 0 to the time of last detectable concentration); t1/2 (terminal phase half-life); C24 (minocycline concentration 24 hours after topical application of minocycline foam 4%); and AUC0-tau (AUC during the 24-hour dosing interval for topical minocycline foam 4%). AUC0-tldc was calculated by the linear trapezoidal method, and AUC0-inf was calculated as the sum of AUC0-tldc plus the ratio of the last measurable plasma concentration to the terminal-phase rate constant; both of these assessments were performed for the oral minocycline dose only. Accumulation ratio was calculated by dividing the AUC0-tau of day 12 or day 21 by the AUC0-tau of day 1 for day 12 and day 21, respectively, where tau is 1 day (24 hours). Safety Evaluation: Safety was assessed by the evaluation of reported and observed adverse events (AEs), vital signs (blood pressure, heart rate), clinical laboratory assessments (hematology, chemistry, and urinalysis), and electrocardiograms (ECGs). The number and percentage of subjects were documented for (1) any treatment-emergent AE (TEAE); (2) any treatment-related TEAE (probable, possible); (3) any serious TEAE; (4) any severe TEAE; and (5) any TEAE leading to drug withdrawal. The intensity, duration, and causal relationship to the investigational products were rated for all AEs. Statistical Analyses: Descriptive statistics were reported for minocycline concentration data at each sample time and were also calculated for all pharmacokinetic parameters. Actual sample collection times were used for the purpose of calculating pharmacokinetic parameters. All deviations from the scheduled sampling time were reported in the final report as “Sample Time Deviations.” No values of kel, AUC0-inf, or t1/2 were reported for cases that did not exhibit a terminal log-linear phase in the concentration vs time profile. Geometric mean was calculated for Cmax, AUC0-tldc, AUC0-inf, and AUC0-tau, and the harmonic mean was calculated for t1/2. Analysis of multiple-dose accumulation, determination of steady state, and other pertinent comparisons of pharmacokinetic parameters across or between doses were performed using the appropriate statistical methods. The 90% confidence intervals (CIs) for the difference between treatment least squares means (LSMs) were calculated for the parameters AUC (AUC0-inf, AUC0-tau) and Cmax using log-transformed data. Topical minocycline foam 4% (test treatment) was compared against oral minocycline (reference). The CIs were expressed as a percentage relative to the LSM of the reference treatment. Results: In total, 30 subjects were enrolled, and all completed the study as planned. The mean age of the subjects was 22.6 years (range, 18 to 30 years). They were mostly white (90%) and female (60%). All subjects had moderate-to-severe acne at baseline evaluation. Treatment adherence rate was high: only 2 subjects missed a single topical minocycline foam 4% application (on day 3) and only 1 subject missed multiple topical minocycline foam 4% applications (on days 9, 10, and 11). After a single oral dose of minocycline, plasma minocycline concentration increased until 3 hours (median tmax value), followed by a log-linear decrease over the remainder of the 96-hour sampling period (FIG. 4A). The geometric mean Cmax was 850.04 ng/mL (Table 89). TABLE 89 Summary of PK Parameters (Pharmacokinetic Concentration Population) Following Single Dose Oral Administration of Solodyn (~1 mg/kg minocycline) and Topical Application of FMX-101, 4% for 21 days to Acne Patients, Study FX2014-03 CV Geometric Harmonic PK Parameter N Mean (SD) Median Min, Max (%) Mean Mean Period 1, Solodyn (~1 mg/kg minocycline) Day 1-5 Cmax (ng/mL) 30 873.367 (220.046) 801.00 603.00, 1620.00 25.20 850.049 — Tmax (h) 30 2.7 (0.81) 3.0 1.5, 4.0 30.01 — — AUC 0-ddc (ng h/mL) 30 15227.30 (3624.298) 15363.00 9317.00, 25420.00 23.80 14823.41 — kel (1/h) 30 0.044 (0.005) 0.04 0.03, 0.05 11.52 — — AUC0-inf (ng h/mL) 30 15474.57 (3690.744) 15553.50 9387.00, 25697.00 23.85 15060.29 — T1/2 (h) 30 16.0 (1.85) 15.9 12.8, 20.1 11.59 — 15.8 Period 2, FMX-101, 4% (4 g) Day 1-2 Cmax (ng/mL) 30 1.706 (0.823) 1.50 0.68, 3.88 48.26 1.539 — Tmax (h) 30 11.5 (4.01) 12.0 4.0, 23.8 35.00 — — C24 (ng/mL) 30 1.336 (0.667) 1.13 0.53, 3.09 49.91 1.192 — AUC0-tau (ng h/mL)1 30 31.75 (14.950) 28.81 10.87, 72.56 47.09 28.70 — Day 12-13 Cmax (ng/mL) 29 1.325 (0.787) 1.33 0.14, 3.27 59.40 1.063 — Tmax (h) 29 9.4 (5.13) 8.0 0.0, 23.8 54.33 — — C24 (ng/mL) 29 0.919 (0.531) 0.86 0.00, 2.01 57.76 0.869 — AUC0-tau (ng h/mL)1 29 24.62 (14.100) 22.31 3.24, 55.69 57.26 20.06 — Accumulation Ratio R2 29 0.85 (0.552) 0.76 0.00, 2.56 — — — Day 21-25 Cmax (ng/mL) 30 1.253 (0.645) 1.02 0.41, 2.73 51.52 1.109 — Tmax (h) 30 12.3 (4.79) 14.0 4.0, 23.8 39.05 — — kel (1/h) 14 0.018 (0.006) 0.02 0.01, 0.03 32.59 — — T1/2 (h) 14 44.3 (25.39) 37.8 26.7, 125.3 57.30 — 37.6 C24 (ng/mL) 30 0.901 (0.406) 0.77 0.30, 1.89 45.11 0.821 — AUC0-tau (ng h/mL)1 30 23.02 (10.798) 20.45 6.28, 46.85 46.91 20.70 — Accumulation Ratio R2 30 0.79 (0.368) 0.62 0.39, 1.66 — — — SD = standard deviation. CV = coefficient of variation. Concentrations below the limit of quantitation (LOQ) were reported as zero for the purpose of calculating PK parameters. 1AUC0-tau = AUC during the 24-hour dosing interval. 2On Day 12, R = AUC 0-tau Day 12/AUC 0-tau Day 1; On Day 21, R = AUC 0-tau Day 21/AUC 0-tau Day 1. Source: Table 14.2.2.1. Following topical application of a 4-g maximal-use dose of minocycline foam 4%, plasma minocycline concentration increased until 8 to 14 hours (median tmax value) on days 1, 12, and 21. The change in mean plasma minocycline concentration with time following topical application of minocycline foam 4% is shown in FIG. 4B. The plasma concentration at 24 hours after topical application of minocycline foam 4% was low; geometric mean C24 values on days 1, 12, and day 21 were 1.192, 0.869, and 0.821 ng/mL, respectively (Table 89). A comparison of the plasma minocycline concentration vs time profiles over the first 24 hours after oral minocycline or topical minocycline foam 4% administration is shown in FIG. 4C. Overall, the plasma minocycline concentration following topical application of minocycline foam 4% was very low; the geometric mean Cmax values ranged from 1.1 ng/mL to 1.5 ng/mL (Table 89). Steady state for topical application of minocycline foam 4% was achieved by day 6 (FIG. 5). Relative bioavailability of minocycline after topical minocycline foam 4% administration, as compared with oral minocycline, for day 12 and day 21 was 0.126% and 0.131%, respectively, based on Cmax, and it was 0.134% and 0.137%, respectively, based on AUC values (Table 90). Minocycline exposure following daily topical application of minocycline foam 4% was 730 to 765 times lower than that following a single oral dose of −1 mg/kg minocycline. The daily dosing of topical minocycline foam 4% was associated with a mean (range) accumulation ratio of 0.85 (0.00, 2.56) and 0.79 (0.39, 1.66) at day 12 and day 21, respectively (Table 89). There was no evidence that minocycline had accumulated during the 21 days of topical application of minocycline foam 4%. In pediatric subjects, following topical application of FMX101 4% for 7 days, the overall average plasma concentration of minocycline across all ages was 2.5 ng/mL (relatively constant over the entire sampling interval). See Table 92. Concentrations tend to be higher for younger age groups (9-11 years: 3.5 ng/mL; 12-14 years: 2.5 ng/mL) than for the older age group (15-16 years, 11 months: 1.7 ng/mL). The mean overall maximum observed plasma concentration (Cmax) plasma minocycline concentration 24 hours after FMX101 application (C24), and area under the concentration-time curve from time zero (predose) through 24 hours (AUC0-tau) were approximately 3.1 ng/mL, 2.5 ng/mL, and 61 ng*h/mL, respectively. See Table 93. Cmax, C24, and AUC0-tau tended to be higher in the subjects aged 9 to 11 years and subjects aged 12 to 14 years than the subjects aged 15 years to 16 years 11 months, however the small sample size precludes making any conclusions regarding the effect of age on these PK parameters. In both studies, FMX101 4% was safe and well-tolerated. There were no drug-related treatment-emergent adverse events (TEAEs), no TEAEs that led to treatment discontinuation, and no serious adverse events. Overall, there was a high rate of subject satisfaction with the use of FMX101, 4%. A majority of subjects reported they were “satisfied” or “very satisfied” with the treatment compared with topical acne therapies used previously. Additionally, the subjects were satisfied with the feel of the foam on the skin. TABLE 90 Summary of minocycline relative bioavailability with oral minocycline administration and topical application of minocycline foam 4% at days 12 and 21. Topical minocycline foam 4% (FMX-101) vs oral Geometric LSM Ratio (%) minocycline (Solodyn N (GMR),a % (90% CI) Day 12 Cmax 29 0.126 (0.100, 0.159) Day 12 AUCb 29 0.134 (0.110, 0.163) Day 21 Cmax 30 0.131 (0.113, 0.151) Day 21 AUCc 30 0.137 (0.121, 0.156) Notes aThe 90% confidence intervals for the difference between Test (topical minocycline foam 4%) and Reference (oral minocycline (Solodyn) treatment least squares mean values were calculated using natural logarithm-transformed Cmax and AUC values. Geometric LSM ratio (GMR) and the associated 90% CI are back transformed point estimate and the associated 90% CI. bDay 12 AUC0-tau for topical minocycline foam 4% (FMX-101) vs AUC0-inf for oral minocycline (Solodyn). cDay 21 AUC0-tau for topical minocycline foam 4% vs AUC0-inf (FMX-101) for oral minocycline (Solodyn). Abbreviations: AUC, area under the curve; Cmax, maximum plasma concentration; CI, confidence interval; AUC0-inf, AUC from time 0 to infinity; AUC0-tau, AUC during the 24-hour dosing interval for topical minocycline foam 4%. SAFETY EVALUATION IN ADULTS: Once-daily application of topical minocycline foam 4% for 21 days was well tolerated. There was minimal systemic absorption and accumulation of minocycline over the 21 days of topical application of minocycline foam 4% as compared with oral minocycline. The most common TEAEs observerd were dysmenorrhea, nasal congestion, and rhinorrhea, all occurring in the topical minocycline foam treatment period (Table 91). In the oral minocycline treatment period, 2 subjects (6.7%) reported a total of 2 TEAEs, while 9 subjects (30%) in the topical minocycline foam 4% treatment period reported a total of 14 TEAEs. There were no TEAEs considered to be related to the study medication. There were also no serious TEAEs, severe TEAEs, or TEAEs that resulted in study medication being withdrawn, as well as no clinically significant laboratory findings in any subjects. SAFETY EVALUATION IN PEDIATRICS: Once-daily application of topical minocycline foam 4% for 7 days was safe and well tolerated. There were no TEAEs considered related to study drug. There were no clinically significant laboratory findings in any subject. Adverse events are summarized in Table 94. One subject (5.0%) reported a total of 2 TEAEs (nausea and vomiting). There were no serious TEAEs, no severe TEAEs, and no TEAEs that resulted in study medication being withdrawn. No TEAEs associated with laboratory abnormalities or vital signs were reported. No clinically significant abnormal physical examination findings were reported for any subject. TABLE 91 Overall summary of AEs following administration of oral minocycline and topical application of minocycline foam 4% daily for 21 days. Topical Oral minocycline minocycline foam (N = 30) 4% (N = 30) Subjects with treatment-relateda TEAE, 0 0 n (%) Subjects with serious TEAE, n (%) 0 0 Subjects with TEAE leading to study 0 0 discontinuation, n (%) Subjects with any TEAEa, n (%) 2 (6.7) 9 (30.0) Dysmenorrhea 0 2 (6.7) Nasal congestion 0 2 (6.7) Rhinorrhea 0 2 (6.7) Asthma 0 1 (3.3) Bronchitis 0 1 (3.3) Cough 1 (3.3) 0 Dermatitis contact 0 1 (3.3) Headache 1 (3.3) 0 Oropharyngeal pain 0 1 (3.3) Pharyngitis streptococcal 0 1 (3.3) Respiratory tract congestion 0 1 (3.3) Tonsillitis 0 1 (3.3) Notes aSubjects with one or more TEAEs that were considered possibly or probably related. bSubjects with one or more TEAEs are only counted once. Abbreviations: TEAE, treatment-emergent adverse event. TABLE 92 Plasma Concentrations of Minocycline in Pediatric Acne Patients Treated with FMX101 Mean (SD) Concentrations of Minocycline in Plasma (ng/mL) Cohort 1 Cohort 2 Cohort 3 Day and Time (9 to 11 years) (12 to 14 years) (15 to 16 years 11 months) Overall of Sample1 (N = 6) (N = 8) (N = 6) (N = 20) Day 1, Predose 0.000 (0.0000) 0.000 (0.0000) 0.000 (0.0000) 0.000 (0.0000) Day 7, Predose 3.700 (4.3614) 2.111 (2.3463) 1.870 (1.2783) 2.515 (2.8473) Day 7, 3 hours 3.693 (3.9303) 2.164 (2.0046) 1.803 (1.1810) 2.514 (2.5618) Day 8, 12 hours 3.972 (3.8346) 2.233 (1.8408) 1.775 (0.9688) 2.617 (2.4961) Day 8, 16 hours 3.780 (3.7667) 2.263 (1.9884) 1.620 (0.9149) 2.525 (2.4891) Day 8, 24 hours 3.663 (3.2094) 2.446 (1.8781) 1.479 (0.8684) 2.521 (2.2284) Source: Table 14.2.1 Abbreviations: SD = standard deviation 1As the Day 7 dose was applied in the evening, some samples were collected on calendar Day 8, but PK parameters calculated from data obtained within approximately 24 hours of the Day 7 dose are referred to as Day 7 parameters in this clinical study report. TABLE 93 Summary of Pharmacokinetic Parameters of Minocycline in Pediatric Acne Patients Treated with FMX101 Mean (SD) Pharmacokinetic Parameters1 of Minocycline in Plasma Cmax Tmax C24 AUC0-tau Cohort and Age (ng/mL) (h)2 (ng/mL) (ng * h/mL) Cohort 1 (9 to 11 years) 4.447 (3.9687) 12 (0, 24) 3.663 (3.2094) 90.861 (90.1626) (N = 6) Cohort 2 (12 to 14 years) 2.783 (2.1505) 20 (0, 24) 2.446 (1.8781) 54.015 (46.2250) (N = 8) Cohort 3 2.036 (1.1676) 6 (0, 24) 1.479 (0.8684) 40.797 (23.7635) (15 to 16 years 11 months) (N = 6) Overall 3.058 (2.6792) 12.1 (0, 24) 2.521 (2.2284) 61.104 (59.2125) (N = 20) Source: Table 14.2.2 Abbreviations: AUC0-tau = area under the concentration-time curve (ng/mL * hours) from time zero (predose) through 24 hours; C24 = plasma minocycline concentration 24 hours after FMX101 application; Cmax = maximum observed plasma concentration; SD = standard deviation; Tmax = time to maximum measured plasma concentration. 1Terminal phase rate constant (kel) and apparent terminal phase half-life (T1/2) were not estimable because either there were fewer than 3 values in the terminal phase, the slope was positive, or the T1/2 estimate was more than half the range of the terminal phase. 2Median (minimum, maximum) shown for Tmax. TABLE 94 Overall Summary of Adverse Events (Safety Population) Following Topical Application of FMX101, 4% for 7 Days to Pediatric Acne Patients, Study FX2016-21 All Subjects (N = 20) Subjects with Any TEAE, N (%) 1 (5.0) Number of TEAEs 2 Subjects with Any Treatment-Related TEAE, N (%)1 0 Number of Treatment-Related TEAEs 0 Subjects with Any Serious TEAE, N (%) 0 Number of Serious TEAEs 0 Subjects with Any Severe TEAE, N (%) 0 Number of Severe TEAEs 0 Subjects with Any TEAE Leading to 0 Drug Withdrawn, N (%) Number of TEAEs Leading to Drug Withdrawn 0 Source: Table 14.3.1.1 Abbreviations: N = number of subjects; TEAE = treatment-emergent adverse event. Note: TEAEs were defined as AEs with an onset date on or after the date of the first dose of study drug or existing events that worsened after the first study drug application during the study. 1Treatment-related AEs included possibly and probably related. This Phase 1 study in adults evaluated the pharmacokinetics and bioavailability of minocycline in multiple-dose, once-daily topical application of minocycline foam 4%, as compared with oral administration of minocycline HCl. The pharmacokinetic results demonstrated minimal systemic absorption and accumulation of minocycline following the maximal-use dose of topical minocycline foam 4% for 21 days, as compared with oral minocycline. Topical minocycline foam 4% was well tolerated in once-daily application in subjects with AV, with no serious or severe AEs or AEs related to study medication or resulting in treatment discontinuation. Systemic exposure to minocycline with daily topical application of the 4-g dose of minocycline foam 4% for 21 days was 730 to 765 times lower than that following a single, oral, ˜1 mg/kg dose of minocycline. There was no evidence of accumulation of minocycline over the 21 days of once-daily topical application of a 4-g maximal-use dose of minocycline foam 4%. The observation of slightly higher mean minocycline values (Cmax) on day 1 than on day 12 or day 21 was probably due to residual minocycline from the oral minocycline dose that had been administered 10 days prior to the start of topical minocycline foam 4% application. Plasma minocycline values were measurable for the majority of subjects before topical minocycline foam 4% application; however, this observation was considered to have no impact on the interpretation of the results. In this study, all AEs were reported, and vital signs and clinical laboratory assessments, including hematology, chemistry and urinalysis, were monitored. Overall, topical minocycline foam 4% was well tolerated following multiple-dose administration for up to 21 days. The most common TEAEs were dysmenorrhea, nasal congestion, and rhinorrhea. There were no treatment-related AEs, no serious or severe TEAEs, and no serious TEAEs that led to withdrawal from the study. Common systemic adverse reactions reported in clinical trials with oral minocycline have included headache, fatigue, dizziness, and itch, which were not seen in this study. There were also no reported cases of autoimmune conditions, such as drug-induced lupus-like syndrome, nor of skin and hypersensitivity reactions that have been associated with oral minocycline. There were no findings of clinically significant abnormalities of laboratory values or vital signs, or abnormalities in ECGs or physical examinations in any subjects. Acne severity did not worsen in subjects after 21 days of using topical minocycline foam 4%. CONCLUSION: In both adult and pediatric subjects, the plasma concentration of minocycline was low after topical application of FMX101 4%. No significant systemic exposure to minocycline was observed with once-daily topical application of FMX101 4% for 21 days in adults and 7 days in pedatirc subjects. FMX101 4% appears to be a well-tolerated treatment option for both pediatric and adult subjects with moderate-to-severe acne. Without being bound by any theory, the improved patient satisfaction with the use of FMX101, 4%, may correlate at least in part with the lower blood exposure of the minocycline after application of the FMX101, 4% formulation versus oral administration of SOLODYN®. Additionally, the lower blood exposure of the minocycline in patients treated with FMX101, 4% may correlate with a lower incidence of treatment-related adverse events. Example 10 Changes in RosaQoL Index Score at Week 12 from Baseline RosaQoL (Rosacea Quality of Life) index scores, measuring the impact of rosacea treatment on health-related quality of life, indicated that both doses of FMX103 were significantly better than the vehicle foam in improving the RosaQoL overall score from baseline at Week 12 (p=0.003 and p=0.036, respectively) (FIG. 6). Significant improvement at Week 12 was demonstrated in the symptom subscale scores for both doses of FMX103 and in the emotional subscale scores for FMX103 1.5%, as compared to vehicle foam. Post hoc analyses of global questions to assess patient-reported outcomes showed a similar trend. For the question, “How do you rate your rosacea over the past 4 weeks?”, approximately 52 percent and 54 percent of the FMX103 1.5% and 3% groups, respectively, answered “good” to “excellent,” as compared to approximately 20 percent of subjects in the vehicle foam group at Week 12 (both p<0.001). Approximately 75 percent in both treatment groups also reported “better” to the comparative question, “How is your rosacea compared to the last time you filled out this survey?”, while approximately 42 percent of subjects in the vehicle group at Week 12 answered “better” to the same question (both p<0.001). Compliance with study drug dosing was high, with rates of 97.5, 94.7, and 98.7 percent in the FMX103 1.5%, FMX103 3%, and vehicle foam groups, respectively. The number of grams of study drug used per day was also similar among treatment groups: 0.36, 0.38, and 0.39 g for FMX103 1.5%, FMX103 3%, and vehicle, respectively. Having described preferred embodiments of the compositions and methods with reference to the accompanying drawings, it is to be understood that the compositions and methods provided herein are not limited to the precise embodiments, and that various changes and modifications can be effected therein by those skilled in the art without departing from the scope or spirit of the disclosure as defined in the appended claims.
<SOH> BACKGROUND <EOH>Rosacea is a chronic acneiform disorder affecting skin and potentially the eye. It is a syndrome of undetermined etiology characterized by both vascular and papulopustular components involving the face and occasionally the neck, scalp, ears and upper trunk. Clinical findings include mid facial erythema, telangiectasis, papules and pustules, and sebaceous gland hypertrophy. Rosacea is characterized by episodic flushing of affected areas, which can be triggered by various factors, such as consumption of alcohol, hot drinks, spicy foods or physical exercise. Facial rosacea is classified/graded in multiple clinical forms: (1) erythematotelangiectatic rosacea which is characterized by (semi-) permanent erythema and/or flushing; (2) papulopustular rosacea, characterized by presence of inflammatory lesions such as papules and pustules; (3) phymatous rosacea characterized by circumscribed permanent swelling/thickening of skin areas, typically the nose; and (4) ocular rosacea characterized by the appearance of redness in eyes and eyelids due to telangiectasias and inflammation, feeling of dryness, irritation, or gritty, foreign body sensations, itching, burning, stinging, and sensitivity to light, eyes being susceptible to infection, or blurry vision. Rosacea occurs most commonly in adult life, between the ages of 30 and 60 years. It is very common in skin types I-II (according Fitzpatrick) and more common in Caucasians, with a prevalence of up to 5% in the U.S. and in Europe. It is estimated that from 10 to 20 million Americans have the condition. Topical treatments for rosacea include metronidazole, azelaic acid and brimonidine tartrate. However, approved topical therapies rarely show sufficient clinical efficacy or provide only cosmetic relief for several hours. Mainstays of treatment for rosacea are the oral tetracyclines: doxycycline and minocycline. Low-dose systemic doxycycline (Oracea® resp. Oraycea®) is approved for rosacea whereas systemic minocycline is used in many cases for rosacea off-label. Minocycline is generally regarded as having less photosensitivity than doxycycline. The long-term use of systemic antibiotics is limited by potential liver toxicity, phototoxicity, drug-drug interactions and development of antibacterial resistance. Hence, an efficacious topical tetracycline formulation is highly warranted to close this medical gap. “Acne” is a general term that describes another very common skin disorder, which afflicts many people. The prevalence of adult acne is about 3% in men and between about 11% and 12% in women. Moderate to severe acne is observed in 14% of acne patients. There are various types of acne recognized in the field, including, for example: acne vulgaris and acne conglobata. Acne vulgaris (cystic acne or simply acne) is generally characterized by areas of skin with seborrhea (scaly red skin), comedones (blackheads and whiteheads), papules (pinheads), pustules (pimples), nodules (large papules) and/or possibly scarring. Acne vulgaris may affect the face, the upper part of the chest, and the back. Severe acne vulgaris is inflammatory, but acne vulgaris can also manifest in non-inflammatory forms. Acne conglobata is a severe form of acne, and may involve many inflamed nodules that are connected under the skin to other nodules. Acne conglobata often affects the neck, chest, arms, and buttocks. There are typically three levels of acne vulgaris: mild, moderate, and severe. Mild acne vulgaris is characterized by the presence of few to several papules and pustules, but no nodules. Patients with moderate acne typically have several to many papules and pustules, along with a few to several nodules. With severe acne vulgaris, patients typically have numerous or extensive papules and pustules, as well as many nodules. Acne may also be classified by the type of lesion: comedonal, papulopustular, and nodulocystic. Pustules and cysts are considered inflammatory acne. Mild to moderate acne is often treated topically, using, e.g., retinoids, benzoyl peroxide and some antibiotics. Topical retinoids are comedolytic and anti-inflammatory. Antibiotics such as tetracycline antibiotics are generally only available orally or by injection. Topical antibiotics are mainly used for their role against P. acnes . Benzoyl peroxide products are also effective against P. acnes . Unfortunately, these medications can lack satisfactory safety and efficacy profiles. In one or more embodiments, there are provided herein new and better topical anti-acne treatments and formulations. Diagnosis of acne vulgaris may begin with a visual inspection to determine the presence and amount of comedones, papules, pustules, nodules, and other inflammatory lesions. A diagnosis of acne vulgaris may also be confirmed via clinical laboratory tests, for example, measurement of testosterone levels and performing skin lesion cultures. Systemic antibiotics are generally indicated for moderate or severe acne. The most commonly used systemic antibiotics are tetracycline and their derivatives (e.g., minocycline). These agents have anti-inflammatory properties and they are effective against P. acnes . The more lipophilic antibiotics, such as minocycline and doxycycline, are generally more effective than tetracycline. Greater efficacy may also be due to less P. acnes resistance to minocycline. Oral tetracycline antibiotics are generally not recommended in the treatment of minor mild acne, primarily because they cause hyper-pigmentation, erythema and dryness. Oral tetracycline therapy may induce hyperpigmentation in many organs, including nails, bone, skin, eyes, thyroid, visceral tissue, oral cavity (teeth, mucosa, alveolar bone), sclerae and heart valves. Skin and oral pigmentation have been reported to occur independently of time or amount of drug administration, whereas other tissue pigmentation has been reported to occur upon prolonged administration. Skin pigmentation includes diffuse pigmentation as well as over sites of scars or injury. Oral tetracyclines should not be used for pregnant women or nursing mothers due to teratogenic effects. Accordingly, there exists a need for topical formulations with tetracyclines which can avoid the side effects observed with oral applications. For example, SOLODYN®, a commercially available product, is indicated to treat only inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 12 years of age or older. Adverse side effects from the use of SOLODYN® include, inter alia, diarrhea, dizziness, lightheadedness, and nausea, in addition to allergic reactions, bloody stool, blurred vision, rectal or genital irritation, and red, swollen, blistered, or peeling skin. Because of these side effects, the Food and Drug Administration added oral minocycline to its Adverse Event Reporting System (AERS), a list of medications under investigation by the FDA for potential safety issues. Thus, a product that requires a shorter treatment period, has no or fewer adverse effects, does not cause or causes less skin irritation, and treats both inflammatory and non-inflammatory lesions would be advantageous and could improve patient compliance. There also exists a need for improved compositions and methods for treating rosacea, as well as acne. Provided herein are compositions and methods to address those needs.
<SOH> SUMMARY <EOH>In one aspect, provided is a method for treating rosacea or acne in a subject in need thereof, the method comprising: administering to said subject a topical composition comprising an effective amount of a tetracycline antibiotic. In another aspect, provided is a hydrophobic gel or foam composition comprising: a tetracycline antibiotic, wherein said tetracycline antibiotic is present in said gel or foam composition in an amount effective to treat rosacea or acne in a subject. In an exemplary embodiment, the gel or foam composition provided herein further comprises at least one hydrophobic solvent, at least one viscosity-modifying agent, or a combination thereof. In some embodiments, the composition comprises silicon dioxide (SiO 2 ). In a particular embodiment, the tetracycline antibiotic is minocycline hydrochloride or doxycycline hyclate, or a combination thereof. In yet another aspect, provided is a method of manufacturing a gel or foam composition having a tetracycline antibiotic, the method comprising: providing a composition having one or more hydrophobic solvents; heating said composition; adding fatty alcohols, fatty acids, and waxes; cooling said composition; adding SiO 2 ; and adding tetracycline antibiotic. In a further aspect, provided is a method for treating rosacea or acne in a subject in need thereof, the method comprising: administering to said subject a topical composition comprising an effective amount of a tetracycline antibiotic, wherein said tetracycline antibiotic is minocycline. In a yet further aspect, provided is a hydrophobic foam or gel composition comprising: about 50% by weight of soybean oil; about 23.6% by weight of coconut oil; about 5% by weight of cyclomethicone; about 2.8 to 4.3% by weight of light mineral oil; about 3.5% by weight of cetostearyl alcohol; about 3% by weight of stearic acid; about 2.5% by weight of myristyl alcohol; about 2% by weight of hydrogenated castor oil; about 2% by weight of beeswax; about 1.5% by weight of stearyl alcohol; about 1.1% by weight of behenyl alcohol; and about 1.5 to 3% by weight of minocycline. In an additional aspect, provided is a method for treating a rosacea in a subject in need thereof, the method comprising: administering to said subject a hydrophobic foam or gel composition comprising about 50% by weight of soybean oil; about 23.6% by weight of coconut oil; about 5% by weight of cyclomethicone; about 2.8 to 4.3% by weight of light mineral oil; about 3.5% by weight of cetostearyl alcohol; about 3% by weight of stearic acid; about 2.5% by weight of myristyl alcohol; about 2% by weight of hydrogenated castor oil; about 2% by weight of beeswax; about 1.5% by weight of stearyl alcohol; about 1.1% by weight of behenyl alcohol; and about 1.5 to 3% by weight of minocycline. In an additional aspect, provided is a method for reducing papules and pustules in a subject in need thereof, the method comprising: administering to said subject a topical composition comprising an effective amount of a tetracycline antibiotic to treat, ameliorate, reduce, or cure acne or rosacea. In an additional aspect, provided is a method for reducing skin lesion in a subject in need thereof, the method comprising: administering to said subject a topical composition comprising an effective amount of a tetracycline antibiotic. In an additional aspect, provided is a method for reducing skin redness in a subject in need thereof, the method comprising: administering to said subject a topical composition comprising an effective amount of a tetracycline antibiotic. In an additional aspect, provided is a method for treating erythema in a subject in need thereof, the method comprising: administering to said subject a topical composition comprising an effective amount of a tetracycline antibiotic. In an additional aspect, provided is a method for treating a rosacea in a subject in need thereof, the method comprising: administering to said subject a placebo topical composition, wherein said composition is free of a tetracycline antibiotic. In an additional aspect, provided is a method for reducing papules and pustules in a subject in need thereof, the method comprising: administering to said subject a placebo topical composition, wherein said composition is free of a tetracycline antibiotic. In an additional aspect, provided is a method for reducing skin lesions in a subject in need thereof, the method comprising: administering to said subject a placebo topical composition, wherein said composition is free of a tetracycline antibiotic. In an additional aspect, provided is a method for reducing skin redness in a subject in need thereof, the method comprising: administering to said subject a placebo topical composition, wherein said composition is free of a tetracycline antibiotic. In an additional aspect, provided is a method for treating erythema in a subject in need thereof, the method comprising: administering to said subject a placebo topical composition, wherein said composition is free of a tetracycline antibiotic. Other features and advantages of the compositions and methods will become apparent from the following detailed description examples and figures. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.
A61K90014
20170908
20180308
91396.0
A61K900
1
RAMACHANDRAN, UMAMAHESWARI
COMPOSITIONS AND METHODS FOR TREATING ROSACEA AND ACNE
SMALL
0
ACCEPTED
A61K
2,017
15,700,258
PENDING
LEVOTHYROXINE LIQUID FORMULATIONS
The present invention is directed to a liquid formulation comprising levothyroxine or a pharmaceutically acceptable salt thereof. The formulation of the present invention includes tromethamine, sodium iodide, and water and has a pH of about 9.0 to about 11.5. The liquid formulation according to the invention is stable and ready-to-use.
1. A liquid formulation comprising levothyroxine or a pharmaceutically acceptable salt thereof; a stabilizing agent; not more than 2% liothyronine (T3); and water; wherein the formulation is stable for at least 12 months at 25±2° C. 2. The formulation of claim 1, wherein levothyroxine or a pharmaceutically acceptable salt thereof is levothyroxine sodium. 3. The formulation of claim 2, wherein levothyroxine sodium is present at a concentration of from about 5 mcg/mL to about 500 mcg/mL. 4. The formulation of claim 1, wherein the stabilizing agent comprises an amine. 5. The formulation of claim 4, wherein the amine is selected from the group consisting of tromethamine, bis(2-hydroxyethyl)-imino-tris(hydroxymethyl)methane, monoethanolamine, diethanolamine, triethanolamine, 2-amino-2-methyl-1,3-propanediol, 2-dimethylamino-2-methyl-1-propanediol, 2-amino-2-ethylpropanol, 2-amino-1-butanol, and 2-amino-2-methyl-1-propanol. 6. The formulation of claim 5, wherein the amine is tromethamine which is present at a concentration of about 1 mg/mL to about 50 mg/mL. 7. The formulation of claim 1, wherein the stabilizing agent comprises a salt of iodine. 8. The formulation of claim 7, wherein the salt of iodine is sodium iodide or potassium iodide. 9. The formulation of claim 8, wherein the salt of iodine is sodium iodide which is present at a concentration of about 10 mcg/mL to about 500 mcg/mL. 10. The formulation of claim 1, wherein the formulation has a pH of from about 9.0 to about 11.5. 11. The formulation of claim 10, wherein the formulation has a pH of from about 9.8 to about 10.8. 12. The formulation of claim 1, wherein the formulation contains not more than 1.5% (T3). 13. The formulation of claim 1, wherein the formulation contains not more than 1.0% liothyronine (T3). 14. The formulation of claim 1, wherein the formulation contains not more than 5.0% total impurities. 15. The formulation of claim 1, wherein the formulation contains not more than 2.5% total impurities. 16. The formulation of claim 1, wherein the formulation is stable for at least 18 months at 25±2° C. 17. The formulation of claim 1, wherein the formulation retains at least about 90% of the initial amount of levothyroxine or pharmaceutically acceptable salt thereof after storage for at least 12 months at 25±2° C. 18. The formulation of claim 1, wherein the formulation retains at least about 95% of the initial amount of levothyroxine or pharmaceutically acceptable salt thereof after storage for at least 12 months at 25±2° C. 19. The formulation of claim 1, wherein the formulation does not contain a buffer. 20. The formulation of claim 1, wherein the formulation is a ready-to-use formulation contained within a vial, ampoule, cartridge, syringe, or bag.
CROSS-REFERENCE TO RELATED APPLICATIONS This patent application is a continuation of co-pending U.S. patent application Ser. No. 15/366,864, filed Dec. 1, 2016, the disclosure of which is incorporated herein by reference in its entirety for all purposes. BACKGROUND OF THE INVENTION Levothyroxine sodium for injection is a sterile lyophilized product for parenteral administration of levothyroxine sodium for thyroid replacement therapy. Levothyroxine sodium for injection is particularly useful when thyroid replacement is needed on an urgent basis, for short term thyroid replacement, and/or when oral administration is not possible, such as for a patient in a state of myxedema coma. Full chemical names for levothyroxine sodium include 4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodo-L-phenylalanine sodium, and L-tyrosine-O-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-monosodium salt. Levothyroxine sodium has a molecular weight of approximately 798.85 and the following chemical structure: Conventional formulations of levothyroxine sodium for injection are preservative-free lyophilized powders containing levothyroxine sodium and the excipients mannitol, sodium phosphate buffer, and sodium hydroxide. Administration of the conventional formulations involve reconstitution of the lyophilized powder in 0.9% sodium chloride injection (USP) to provide an injectable solution. However, use of the conventional lyophilized formulations requires reconstitution or dilution by healthcare practitioners prior to use. Once reconstituted, the levothyroxine sodium solutions have a limited stability, and must be used within a few hours of reconstitution. In addition, contaminants may be introduced into the solutions during the reconstitution process, thereby compromising patient safety. It has been shown that levothyroxine in oral tablets and in aqueous solutions undergoes degradation. Major degradation products of levothyroxine are known to include 3,3′,5-triiodothyronine (T3) 3,5-diiodothyronine (T2) 3,3′,5,5′-tetraiodothyroacetic acid (TTAA4) 3,3′,5-triiodothyroacetic acid (TTAA3) and 3,5-diiodothyroacetic acid (TTAA2) (Kannamkumarath et al., J. Anal. At. Spectrom., 2004, 19: 107-113 and Patel et al., Int. J. Pharm., 2003, 264: 35-43)). 3,3′,5-triiodothyronine, known as liothyronine or T3, is a major degradant. Aqueous solutions of levothyroxine sodium have been shown to be more stable at basic pH than at acidic pH, but significant degradation of levothyroxine sodium also has been shown to occur at basic pH (Patel et al., Int. J. Pharm., 2003, 264: 35-43). Thus, there remains a need in the art for a ready-to-use injectable formulation of levothyroxine sodium that exhibits storage stability. BRIEF SUMMARY OF THE INVENTION The invention provides a liquid formulation comprising levothyroxine or a pharmaceutically acceptable salt thereof, tromethamine, sodium iodide, and water, wherein the formulation has a pH of about 9.0 to about 11.5. The invention also provides a liquid formulation comprising (a) levothyroxine or a pharmaceutically acceptable salt thereof in a concentration of about 20 mcg/mL to about 100 mcg/mL, (b) tromethamine in a concentration of about 5 mg/mL to about 20 mg/mL, (c) sodium iodide in a concentration of about 100 mcg/mL to about 300 mcg/mL, (d) sodium chloride, and (e) water, wherein the formulation has a pH of about 9.8 to about 10.8. DETAILED DESCRIPTION OF THE INVENTION The invention provides a liquid formulation comprising levothyroxine or a pharmaceutically acceptable salt thereof, tromethamine, sodium iodide, and water, wherein the formulation has a pH of about 9.0 to about 11.5. The liquid formulation according to the invention is stable and ready-to-use. As used herein, a “ready-to-use” formulation is a sterile, injectable formulation that is not reconstituted from a solid by a healthcare provider prior to use. Rather, a ready-to-use formulation is supplied by a pharmaceutical manufacturer in a suitable container (e.g., vial, syringe, bag, container) in liquid form. In some embodiments, a ready-to-use formulation is an injectable formulation that is administered to a subject without dilution. In other embodiments, a ready-to-use formulation is a concentrated, liquid solution that must be diluted prior to administration to a subject. Thus, in some embodiments, the formulation of the present invention can be further diluted in an appropriate diluent such as, for example, WFI (water for injection), 0.9% sodium chloride, or 5% dextrose to a lower levothyroxine concentration. The formulation according to the present invention is stable. As used herein, the terms “stable” and “stability” encompass any characteristic of the formulation which may be affected by storage conditions including, without limitation, potency, total impurities, levothyroxine degradation products, specific optical rotation, optical purity, water content, appearance, viscosity, sterility, and color and clarity. The storage conditions which may affect stability include, for example, duration of storage, temperature, humidity, and/or light exposure. In certain embodiments, a stable levothyroxine formulation refers to a formulation that retains at least about 90%, or about least about 95%, or at least about 96%, or at least about 98%, of the labeled concentration of levothyroxine or pharmaceutically acceptable salt thereof after storage under typical and/or accelerated conditions. In further embodiments, a stable levothyroxine formulation refers to less than about 15% (area percent), or less than about 10% (area percent), or less than about 7% (area percent), or less than about 5% (area percent), or less than about 2% (area percent) of levothyroxine-related impurities are present after storage under typical and/or accelerated conditions. In some embodiments, the liquid formulation of the invention is stable for at least 12 months, at least 18 months, at least 24 months, or at least 36 months at refrigerated temperature (e.g., at 5±2° C.). In other embodiments, the liquid formulation of the invention is stable for at least 12 months, at least 18 months, at least 24 months, or at least 36 months at room temperature (e.g., at 25±2° C.). Methods for determining the stability of a formulation of the invention with respect to a given parameter are well-known to those of skill in the art. For example, individual impurities and total impurities can be assessed by high-performance liquid chromatography (HPLC) or thin layer chromatography (TLC). Unless otherwise indicated to the contrary, a percentage amount of liothyronine, other individual impurities, or total impurities reported herein in the formulation is determined by a peak area percent method using HPLC. The formulation comprises levothyroxine or any pharmaceutically acceptable salt thereof. Preferably, the formulation comprises levothyroxine sodium. In an embodiment, the levothyroxine sodium is levothyroxine sodium pentahydrate, which is the sodium salt of the levo-isomer of thyroxine, an active physiological substance found in the thyroid gland. When the formulation comprises levothyroxine sodium, the levothyroxine sodium can be present in the formulation in any suitable concentration. Typically, levothyroxine sodium can be present in the formulation at a concentration of about 5 mcg/mL (micrograms/milliliter) or more, for example, about 10 mcg/mL or more, about 15 mcg/mL or more, about 20 mcg/mL or more, about 25 mcg/mL or more, about 30 mcg/mL or more, about 35 mcg/mL or more, about 40 mcg/mL or more, or about 45 mcg/mL or more. Alternatively, levothyroxine sodium can be present in the formulation at a concentration of about 500 mcg/mL or less, for example, about 450 mcg/mL or less, about 400 mcg/mL or less, about 350 mcg/mL or less, about 300 mcg/mL or less, about 250 mcg/mL or less, about 200 mcg/mL or less, or about 150 mcg/mL or less. Levothyroxine sodium can be present in the formulation in a concentration bounded by any two of the aforementioned endpoints. For example, levothyroxine sodium can be present in the formulation in a concentration of about 5 mcg/mL to about 500 mcg/mL, for example, about 10 mcg/mL to about 450 mcg/mL, about 15 mcg/mL to about 400 mcg/mL, about 20 mcg/mL to about 350 mcg/mL, about 25 mcg/mL to about 300 mcg/mL, about 30 mcg/mL to about 300 mcg/mL, about 35 mcg/mL to about 300 mcg/mL, about 40 mcg/mL to about 300 mcg/mL, about 45 mcg/mL to about 300 mcg/mL, or about 50 mcg/mL to about 250 mcg/mL, or about 20 mcg/mL to about 100 mcg/mL. In a preferred embodiment, levothyroxine sodium is present at a concentration of about 20 mcg/mL. In another preferred embodiment, levothyroxine sodium is present at a concentration of about 40 mcg/mL. In yet another preferred embodiment, levothyroxine sodium is present at a concentration of about 100 mcg/mL. The formulation can be provided in any suitable volume. In some embodiments, the volume of the formulation is about 0.5 mL or more, e.g., about 1 mL or more, about 3 mL or more, about 5 mL or more, about 8 mL or more, about 10 mL or more, about 20 mL or more, or about 50 mL or more. In other embodiments, the volume of the formulation is about 200 mL or less, e.g., about 150 mL or less, about 100 mL or less, about 50 mL or less, about 30 mL or less, about 15 mL or less, about 10 mL or less, or about 5 mL or less. The formulation can be provided in a volume bounded by any two of the aforementioned endpoints. For example, the formulation can be provided in a volume of about 1 mL to about 200 mL, about 1 mL to about 50 mL, about 3 mL to about 30 mL, about 5 mL to about 100 mL, or about 3 mL to about 10 mL. In certain preferred embodiments, the volume of the formulation is about 5 mL. One of ordinary skill in the art can readily select an appropriate container based upon the volume of the formulation. The formulation comprises at least one stabilizing agent. The stabilizing agent serves to stabilize levothyroxine or a pharmaceutically acceptable salt thereof in the liquid formulation. In some embodiments, the stabilizing agent is an amine. Non-limiting examples of suitable amines include tromethamine (i.e., 2-amino-2-hydroxymethyl-propane-1,3-diol or Tris), bis(2-hydroxyethyl)-imino-tris(hydroxymethyl)methane (Bis-tris or Bis-tris methane), monoethanolamine, diethanolamine, triethanolamine, 2-amino-2-methyl-1,3-propanediol, 2-dimethylamino-2-methyl-1-propanediol, 2-amino-2-ethylpropanol, 2-amino-1-butanol, and 2-amino-2-methyl-1-propanol. Preferably, the amine is tromethamine. The amine can be present in the formulation in any suitable concentration. Typically, the amine can be present in the formulation at a concentration of about 1 mg/mL (milligram/milliliter) or more, for example, about 5 mg/mL or more, about 10 mg/mL or more, about 15 mg/mL or more, or about 20 mg/mL or more. Alternatively, the amine can be present in the formulation at a concentration of about 50 mg/mL or less, for example, about 45 mg/mL or less, about 40 mg/mL or less, about 35 mg/mL or less, about 30 mg/mL or less, about 25 mg/mL or less, or about 20 mg/mL or less. Thus, the amine can be present in the formulation in a concentration bounded by any two of the aforementioned endpoints. For example, the amine can be present in the formulation in a concentration of about 1 mg/mL to about 50 mg/mL, for example, about 1 mg/mL to about 50 mg/mL, about 5 mg/mL to about 45 mg/mL, about 5 mg/mL to about 40 mg/mL, about 5 mg/mL to about 35 mg/mL, about 5 mg/mL to about 30 mg/mL, about 5 mg/mL to about 25 mg/mL, or about 5 mg/mL to about 20 mg/mL. In a preferred embodiment, the amine is tromethamine present at a concentration of about 20 mg/mL. In another preferred embodiment, the amine is tromethamine present at a concentration of about 10 mg/mL. In some embodiments, the stabilizing agent is a salt of iodine, such as sodium iodide or potassium iodide. In some embodiments, the formulation comprises sodium iodide at a concentration of about 10 mcg/mL or more, e.g., 25 mcg/mL or more, 50 mcg/mL or more, 75 mcg/mL or more, 100 mcg/mL or more, 125 mcg/mL or more, 150 mcg/mL or more, 175 mcg/mL or more, or 200 mcg/mL or more. In other embodiments, the formulation comprises sodium iodide at a concentration of about 500 mcg/mL or less, e.g., 450 mcg/mL or less, 400 mcg/mL or less, 350 mcg/mL or less, 300 mcg/mL or less, 250 mcg/mL or less, 200 mcg/mL or less, 175 mcg/mL or less, or 150 mcg/mL or less. Thus, the sodium iodide can be present in the formulation in a concentration bounded by any two of the aforementioned endpoints. For example, the sodium iodide can be present in the formulation in a concentration of about 10 mcg/mL to about 500 mcg/mL, for example, about 50 mcg/mL to about 400 mcg/mL, about 100 mcg/mL to about 300 mcg/mL, about 125 mcg/mL to about 300 mcg/mL, about 125 mcg/mL to about 250 mcg/mL, about 125 mcg/mL to about 200 mcg/mL, about 125 mcg/mL to about 175 mcg/mL, or about 125 mcg/mL to about 150 mcg/mL. In a preferred embodiment, the sodium iodide is present at a concentration of about 140 mcg/mL. The formulation can comprise one, two, or three or more stabilizing agents. In certain embodiments, the formulation comprises an amine and a salt of iodine, preferably tromethamine and sodium iodide. In some embodiments, the formulation comprises about 10 mg/mL tromethamine and about 140 mcg/mL sodium iodide. The formulation comprises an isotonicity adjuster. Non-limiting examples of suitable isotonicity adjusters include sodium chloride, potassium chloride, dextrose, glycerin, and mannitol. In a preferred embodiment, the isotonicity adjuster is sodium chloride. The isotonicity adjuster can be present at any suitable concentration. In some embodiments, the isotonicity adjuster is present at a concentration that renders the formulation isotonic or approximately isotonic with cells (e.g., red blood cells) and/or isotonic or approximately isotonic to blood plasma. The formulation optionally comprises a pH adjuster. The pH adjuster can be any suitable pH adjuster, for example, the pH adjuster can be sodium hydroxide, potassium hydroxide, hydrochloric acid, or combinations thereof. In a preferred embodiment, the pH adjuster is sodium hydroxide, hydrochloric acid, or a combination thereof. The formulation can have any suitable pH. Typically, the formulation can have a pH of about 9.0 or more including, for example, about 9.0 or more, about 9.2 or more, about 9.4 or more, about 9.6 or more, about 9.8 or more, about 10.0 or more, or about 10.2 or more. Alternatively, the formulation can have a pH of about 11.5 or less including, for example, about 11.3 or less, about 11.1 or less, about 11.0 or less, about 10.9 or less, about 10.8 or less, about 10.7 or less, about 10.6 or less, or about 10.5 or less. The formulation can have a pH bounded by any two of the above endpoints recited for the formulation. For example the formulation can have a pH of about 9.0 to about 11.5 including, for example, about 9.0 to about 11.0, about 9.2 to about 10.8, about 9.2 to about 10.8, about 9.4 to about 10.8, about 9.6 to about 10.8, about 9.8 to about 10.8, about 10.0 to about 10.8, about 10.0 to about 10.7, about 10.0 to about 10.5, or about 10.2 to about 10.6. Tromethamine has a buffering range of about 7 to about 9. In a preferred embodiment, the pH of the formulation is about 9.8 to about 10.8, which is above the buffering range of tromethamine. While not wishing to be bound by any particular theory, it is believed that tromethamine exerts a stabilizing effect on levothyroxine by a mechanism unrelated to buffering of the formulation. In a preferred embodiment, the formulation comprises (a) levothyroxine or a pharmaceutically acceptable salt thereof in a concentration of about 20 mcg/mL to about 100 mcg/mL, (b) tromethamine in a concentration of about 5 mg/mL to about 20 mg/mL, (c) sodium iodide in a concentration of about 100 mcg/mL to about 300 mcg/mL, (d) sodium chloride, and (e) water, wherein the formulation has a pH of about 9.8 to about 10.8. The formulation that comprises levothyroxine or a pharmaceutically acceptable salt thereof, tromethamine, sodium iodide, sodium chloride, and water may further include one or more other substances. Non-limiting examples of other substances include diluents, salts, buffers, stabilizers, solubilizers, and preservatives. In certain embodiments, the other substance is a cyclodextrin, such as hydroxypropyl-β-cyclodextrin or sulfobutylether β-cyclodextrin. A formulation comprising levothyroxine or a pharmaceutically acceptable salt thereof, tromethamine, sodium iodide, sodium chloride, and water can be prepared by using any suitable technique, many of which are known to those skilled in the art. The formulation can be prepared in a batch or continuous process. Generally, the formulation can be prepared by combining the components thereof in any order. The term “component” as used herein includes individual ingredients (e.g., levothyroxine sodium, tromethamine, sodium iodide, sodium chloride, optional pH adjuster, etc.) as well as any combination of ingredients (e.g., levothyroxine sodium, tromethamine, sodium iodide, sodium chloride, optional pH adjuster, etc.). In some embodiments, the formulation is formed by combining the components together in a vessel. The components can be combined in any order. In some embodiments, the water is added to a suitable vessel, then the tromethamine, sodium iodide, and sodium chloride are added, either sequentially or together, and the mixture is stirred. Next, the pH is adjusted to the desired value. Subsequently, the levothyroxine sodium is added, and the mixture is stirred until the levothyroxine sodium is dissolved. In some embodiments, the water and sodium chloride are combined and stirred until the sodium chloride is dissolved to provide an aqueous solution of sodium chloride. Subsequently, the levothyroxine sodium, tromethamine, and sodium iodide are added, either sequentially or together, and the mixture is stirred. Next, the pH is adjusted to the desired value. Optional ingredients, such as diluents, salts, buffers, stabilizers, solubilizers, and preservatives, can be provided to the formulation at any stage in its preparation. In some embodiments, the formulation is filtered through one or more filters prior to filling the composition into one or more suitable containers, such as a vial, an ampoule, a cartridge, a syringe, or a bag. Preferably, one or more of the filtration steps and the filling step are performed under aseptic conditions in order to provide a sterile container comprising a sterile formulation. A sterile formulation of the invention is preferably one in which substantially all forms of microbial life have been destroyed by an appreciable amount to meet the sterilization criteria set forth in the U.S. Pharmacopeia. See U.S. Pharmacopeia 32, NF 27, 1 (2009) 80-86. The invention also provides a container comprising a formulation comprising levothyroxine sodium, tromethamine, sodium iodide, sodium chloride, optional pH adjustor, and any other optional components. In certain embodiments, the container is a vial, an ampoule, a bag, a bottle, a cartridge, or a syringe. In some embodiments, the container, the composition, or both the container and the composition are sterile. Preferably, the container is sealed by way of a closure, such as a stopper, plunger, and/or tip-cap. The container and closure can be made of glass, plastic, and/or rubber. One or more surfaces of the container and/or closure can be treated with a compound to limit reactivity with one or more components of the formulation. In some embodiments, the container and/or closure are treated with silicon. In other embodiments, the container is treated with ammonium sulfate ((NH4)2SO4). The container can be clear or opaque, and can be any color. In some embodiments, the container is flint colored. In other embodiments, the container is amber colored. In certain embodiments, the invention provides a pre-filled syringe containing a formulation of the invention described herein. In certain embodiments, a syringe according to the invention is a component of an autoinjector. In some embodiments, the liquid formulation of the invention contains not more than 1.5% liothyronine (T3). In other embodiments, the liquid formulation contains not more than 1.25% liothyronine, e.g., not more than 1.0% liothyronine, not more than 0.9% liothyronine, not more than 0.8% liothyronine, not more than 0.7% liothyronine, not more than 0.6% liothyronine, not more than 0.5% liothyronine, not more than 0.4% liothyronine, not more than 0.35% liothyronine, not more than 0.30% liothyronine, not more than 0.25% liothyronine, not more than 0.2% liothyronine, or any range therein. For example, in certain embodiments, the liquid formulation contains 0.2%-1.5% liothyronine, 0.25%-1.25% liothyronine, 0.25%-1.0% liothyronine, 0.3%-0.9% liothyronine, 0.2%-0.4% liothyronine, 0.25%-0.4% liothyronine, or 0.25%-0.35% liothyronine. In some embodiments, the liquid formulation contains not more than a specified amount of liothyronine as measured after storage of the formulation at a predetermined temperature for a predetermined time period. In certain embodiments, the liquid formulation contains not more than 1.0% liothyronine, e.g., not more than 0.8% liothyronine, not more than 0.6% liothyronine, not more than 0.5% liothyronine, not more than 0.4% liothyronine, not more than 0.30% liothyronine, not more than 0.2% liothyronine, or any range therein as measured after storage of the formulation at 25±2° C. for a period of four months. In other embodiments, the liquid formulation contains not more than 1.5% liothyronine, e.g., not more than 1.25%, not more than 1.0%, not more than 0.8%, not more than 0.6%, not more than 0.5%, not more than 0.4%, or any range therein as measured after storage of the formulation at 40±2° C. for a period of four months. In some embodiments, the liquid formulation of the invention contains not more than 5.0% total impurities. In other embodiments, the liquid formulation contains not more than 4.0% total impurities, e.g., not more than 3.5% total impurities, not more than 3.0% total impurities, not more than 2.5% total impurities, not more than 2.0% total impurities, not more than 1.5% total impurities, not more than 1.25% total impurities, not more than 1.0% total impurities, not more than 0.9% total impurities, not more than 0.8% total impurities, not more than 0.7% total impurities, or any range therein. For example, in certain embodiments, the liquid formulation contains 1.0%-5.0% total impurities, 1.5%-3.5% total impurities, 0.8%-3.0% total impurities, 0.7%-2.0% total impurities, 1.25%-4.0% total impurities, 0.8%-1.5% total impurities, or 0.9%-1.25% total impurities. In some embodiments, the liquid formulation contains not more than a specified amount of total impurities as measured after storage of the formulation at a predetermined temperature for a predetermined time period. In certain embodiments, the liquid formulation contains not more than 2.0% total impurities, e.g., not more than 1.5% total impurities, not more than 1.25% total impurities, not more than 1.0% total impurities, not more than 0.9% total impurities, not more than 0.8% total impurities, not more than 0.7% total impurities, or any range therein as measured after storage of the formulation at 25±2° C. for a period of four months. In other embodiments, the liquid formulation contains not more than 5.0% total impurities, e.g., not more than 4.0% total impurities, not more than 3.5% total impurities, not more than 3.0% total impurities, not more than 2.5% total impurities, not more than 2.0% total impurities, not more than 1.5% total impurities, or any range therein as measured after storage of the formulation at 40±2° C. for a period of four months. The invention also provides a method of stabilizing a levothyroxine formulation by forming a mixture comprising levothyroxine or a pharmaceutically acceptable salt thereof, tromethamine, sodium iodide, sodium chloride, and water, thereby stabilizing the formulation. The identity and amounts of levothyroxine or pharmaceutically acceptable salt thereof, tromethamine, sodium iodide, and sodium chloride present in the mixture as well as the pH can be the same as the identity and amounts of these components and the pH described herein with respect to a formulation of the invention. The formulation formed by the method of stabilizing a levothyroxine formulation can have the same stability characteristics as the stability characteristics described herein with respect to a formulation of the invention, particularly with regard to total impurities and liothyronine. The formulation according to the invention is suitable for administration to a subject to treat or prevent a disease or condition. Preferably, the subject is a mammal. More preferably, the mammal is a human. Preferably, the disease or condition is a disease or condition that is treatable by the administration of levothyroxine or a pharmaceutically acceptable salt thereof, such as hypothyroidism. In some embodiments, the condition is myxedema coma. The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. Example 1 This example demonstrates the stability of exemplary formulations comprising levothyroxine sodium, tromethamine, and water as a function of the pH of the formulation. Separate samples containing levothyroxine sodium at a concentration of 20 mcg/mL, tromethamine at a concentration of 10 mg/mL in normal saline (0.9% NaCl in water) were adjusted to various pH levels. One sample additionally contained hydroxypropyl (HP) β-cyclodextrin at a concentration of 10 mg/mL. 5 mL of each sample was filled into 10 cc amber tubing vials, and the vials were stoppered with 20 mm stoppers under nitrogen. The samples were stored at temperatures of 25° C., 40° C. and 55° C. The samples stored at 55° C. were analyzed by HPLC at 1 and 4 weeks (W) of storage. The samples stored at 40° C. were analyzed by HPLC at 4 W and 3 months (M) of storage. The samples stored at 25° C. were analyzed by HPLC at 3M of storage. The HPLC conditions were as follows: Column: Waters SYMMETRY™ C8 (5 μm, 4.6×150 mm) HPLC column Mobile Phase A: Sodium heptanesulfonate/Acetonitrile/Water/Methanol/H3PO4 (4.023 g/800 mL/1600 mL/1600 mL/4 mL) Mobile Phase B: Sodium heptanesulfonate/Acetonitrile/Water/Methanol/H3PO4 (2.013 g/1000 mL/100 mL/900 mL/2 mL) Diluent: 0.01 N NaOH Column temperature: 25° C. Flow rate: 1.5 mL/min Injection volume: 40-200 Autosampler temperature: 5° C. Detection: UV at 225 nm Separation mode: Gradient Gradient program: Time % Mobile Phase (minutes) A B 25 100 0 40 10 90 50 10 90 51 100 0 60 100 0 The relative response time (RRT) for liothyronine to levothyroxine was approximately 0.73. The results for liothyronine, largest unknown impurity, and total impurities as determined by peak area percent are set forth in Table 1. TABLE 1 Levothyroxine Na (mcg/mL) 20 Tromethamine (mg/mL) 10 HP-β-cyclodextrin (mg/mL) — — — — 10 Solvent Normal saline pH 8 9 9.5 10 9 55° C., 1 W % Liothyronine 15.2 2.7 1.2 0.6 2.7 % largest unknown impurity 1.59 0.67 0.50 0.27 0.86 % total impurities 17.5 3.6 2.2 1.5 4.0 55° C., 4 W % Liothyronine nt nt 1.7 3.1 nt % largest unknown impurity nt nt 0.09 0.55 nt % total impurities nt nt 2.1 4.2 nt 40° C., 4 W % Liothyronine nt nt 0.9 0.4 nt % largest unknown impurity nt nt 0.12 0.12 nt % total impurities nt nt 1.7 0.6 nt 25° C., 3 M % Liothyronine nt nt 0.6 0.35 nt % largest unknown impurity nt nt 0.46 0.11 nt % total impurities nt nt 1.51 0.71 nt 40° C., 3 M % Liothyronine nt nt 1.56 0.87 nt % largest unknown impurity nt nt 0.48 0.16 nt % total impurities nt nt 2.66 1.35 nt nt = not tested The results described in Table 1 demonstrate reduced liothyronine and total impurities were detected in levothyroxine formulations having a pH of 9-10 as compared to pH 8. The effect of pH on levothyroxine stability was further tested in samples having a pH 9.5-11.5. Separate samples containing levothyroxine sodium at a concentration of 20 mcg/mL or 100 mcg/mL, tromethamine at a concentration of 10 mg/mL in normal saline were adjusted to various pH levels. 5 mL of each sample was filled into 10 cc amber tubing vials, and the vials were stoppered with 20 mm stoppers under nitrogen. The samples were stored at temperatures of 25° C., 40° C., and 55° C. The samples stored at 55° C. were analyzed by HPLC at 1 W and 2 W of storage. The samples stored at 25° C. and 40° C. were analyzed by HPLC at 2M of storage using the HPLC conditions described hereinabove. The results for liothyronine, largest unknown impurity, and total impurities as determined by peak area percent are set forth in Table 2. TABLE 2 Levothyroxine Na (mcg/mL) 20 20 100 20 Tromethamine (mg/mL) 10 Solvent Normal saline pH 9.5 10.4 10.4 11.5 55° C., 1 W % Liothyronine 0.9 0.2 0.3 0.1 % largest unknown 0.09 0.09 0.11 0.08 impurity % total impurities 1.2 0.5 0.7 0.4 55° C., 2 W % Liothyronine 1.9 0.4 0.8 0.2 % largest unknown 0.1 0.1 0.11 0.1 impurity % total impurities 2.0 0.9 1.1 0.4 25° C., 2 M % Liothyronine 0.34 0.17 0.23 0.34 % largest unknown 0.11 0.20 0.11 15.4 impurity % total impurities 0.7 0.6 0.6 19.6 40° C., 2 M % Liothyronine 1.00 0.38 0.49 0.31 % largest unknown 0.14 0.22 0.10 9.2 impurity % total impurities 1.44 0.88 0.8 12.1 The results described in Table 2 demonstrate that reduced liothyronine and/or total impurities were detected in levothyroxine formulations having a pH of 10.4 as compared to pH 9.5 or 11.5 following storage at 25° C. or 40° C. for 2M. Example 2 This example demonstrates the stability of exemplary formulations comprising levothyroxine sodium, sodium iodide, and tromethamine as a function of sodium iodide concentration and pH of the formulation. Separate samples containing 20 mcg/mL levothyroxine sodium, 10 mg/mL tromethamine, 5.4 mg/mL sodium chloride, and sodium iodide at a concentration of 280 mcg/mL, 140 mcg/mL, or 6 mcg/mL in water were adjusted to various pH levels. 5 mL of each sample was filled into 10 cc flint molded vials, and the vials were stoppered with 20 mm stoppers under nitrogen. The samples were stored at temperatures of 25° C. or 55° C. for 4 W prior to analysis by HPLC. The HPLC conditions were as follows: Column: ACE Excel 3 C18-PFP, 4.6×150 mm HPLC column Mobile Phase A: Sodium heptanesulfonate/Acetonitrile/Water/Methanol/H3PO4 (4.0 g/800 mL/1600 mL/1600 mL/4.0 mL) Mobile Phase B: Sodium heptanesulfonate/Acetonitrile/Water/Methanol/H3PO4 (4.0 g/2000 mL/200 mL/1800 mL/4.0 mL) Diluent: 0.01 N NaOH Column temperature: 25° C. Flow rate: 1.5 mL/min Injection volume: 80 Autosampler temperature: 5° C. Detection: UV at 225 nm Separation mode: Gradient Gradient program: Time % Mobile Phase (minutes) A B 0 100 0 25 100 0 40 10 90 50 10 90 51 100 0 60 100 0 The relative response time (RRT) for liothyronine to levothyroxine was approximately 0.71. The results for liothyronine, largest any other individual impurity (AOII), and total impurities as determined by peak area percent are set forth in Table 3. TABLE 3 Levothyroxine Na (mcg/mL) 20 Tromethamine (mg/mL) 10 Solvent 5.4 mg/mL sodium chloride in water NaI (mcg/mL) 280 140 6 pH 9.5 10 10.5 9.5 10 10.5 10.5 25° C., 4 W % Liothyronine 0.28 0.26 0.26 0.28 0.27 0.26 0.25 % AOII 0.56 0.55 0.57 0.52 0.55 0.6 0.33 % total impurities 1.58 1.61 1.66 1.51 1.64 1.75 1.9 55° C., 4 W % Liothyronine 1.63 1.06 0.71 1.74 1.06 0.74 0.87 % AOII 0.53 0.54 0.53 0.59 0.61 0.53 0.99 % total impurities 3.24 2.76 2.43 3.6 2.86 2.49 3.5 The samples also were stored at temperatures of 25° C. or 40° C. for 2M or 4M prior to analysis by HPLC. The HPLC conditions were as follows: Column: Phenomenex Kinetex 2.6 μm C18, 4.6×150 mm HPLC column Mobile Phase A: 0.05 M Sulfamic Acid, pH 2.0 Mobile Phase B: Acetonitrile Diluent: 10% Mobile Phase A in Methanol:Acetonitrile:Mobile Phase A (1000 mL:300 mL:700 mL) Column temperature: 27° C. Flow rate: 1.2 mL/min Injection volume: 50 Autosampler temperature: 25° C. Detection: UV at 225 nm Separation mode: Gradient Gradient program: Time % Mobile Phase (minutes) A B 0 70 30 5 70 30 33 32 68 35 32 68 36 70 30 50 70 30 The relative response time (RRT) for liothyronine to levothyroxine was approximately 0.62. The results for liothyronine, largest any other individual impurity (AOII), and total impurities as determined by peak area percent are set forth in Table 4. TABLE 4 Levothyroxine Na (mcg/mL) 20 Tromethamine (mg/mL) 10 Solvent 5.4 mg/mL sodium chloride in water NaI (mcg/mL) 280 140 6 pH 9.5 10 10.5 9.5 10 10.5 10.5 25° C., 2 M % Liothyronine 0.28 0.24 0.23 0.29 0.25 0.24 0.26 % AOII 0.11 0.12 0.11 0.09 0.10 0.12 0.46 % total impurities 0.81 0.8 0.85 0.76 0.77 0.88 1.85 40° C., 2 M % Liothyronine 0.9 0.55 0.39 0.88 0.55 0.41 0.43 % AOII 0.13 0.13 0.17 0.14 0.14 0.15 0.91 % total impurities 1.56 1.2 1.07 1.42 1.18 1.09 2.5 25° C., 4 M % Liothyronine 0.35 0.28 0.25 0.35 0.28 0.26 0.25 % AOII 2.14 0.17 0.11 0.18 0.17 0.17 1.21 % total impurities 3.26 0.93 1.04 1.00 0.93 0.94 2.81 40° C., 4 M % Liothyronine 1.23 0.84 0.58 1.3 0.86 0.59 0.6 % AOII 0.52 1.38 1.07 0.72 0.92 0.69 1.45 % total impurities 2.76 3.23 2.72 2.84 2.73 2.14 3.51 The results described in Tables 3 and 4 demonstrate that levels of liothyronine in formulations comprising 140 mcg/mL or 280 mcg/mL sodium iodide were decreased as the pH was increased from 9.5 to 10 and from 10 to 10.5 following storage at 55° C. for 4 W or at 40° C. for 2M or 4M. The levels of total impurities in formulations comprising 140 mcg/mL sodium iodide also were decreased as the pH was increased from 9.5 to 10 and from 10 to 10.5 following storage at 55° C. for 4 W or at 40° C. for 2M or 4M. Lower levels of AOII and total impurities were detected in formulations comprising 140 mcg/mL or 280 mcg/mL sodium iodide at pH 10.5 as compared to formulations comprising 6 mcg/mL sodium iodide at pH 10.5 following storage at 55° C.° for 4 W or at 40° C. for 2M or 4M. Example 4 This example demonstrates the stability of exemplary formulations comprising levothyroxine sodium, sodium iodide, and tromethamine as a function of vial type. An aqueous solution containing 20 mcg/mL levothyroxine sodium, 10 mg/mL tromethamine, 5.4 mg/mL sodium chloride, and 6 mcg/mL sodium iodide was adjusted to pH 10.5. 5 mL of the solution was filled into each of the vials described in Table 5, and the vials were stoppered under nitrogen. TABLE 5 Inner Glass vial surface Type Size Color preparation treatment Vial 1 Glass 10 cc Flint Molded No Vial 2 Glass 10 cc Amber Molded (NH4)2SO4 Vial 3 Glass 5 cc Amber Tubing (NH4)2SO4 Vial 4 Glass 6 cc Flint Molded No Vial 5 Plastic1 10 cc Opaque N/A N/A Vial 6 Plastic2 10 cc Opaque N/A N/A Vial 7 Plastic3 10 cc Clear N/A N/A Vial 8 Plastic3 10 cc Amber N/A N/A Vial 9 Plastic4 10 cc Clear N/A Silicon Vial 10 Plastic4 10 cc Amber N/A Silicon 1polypropylene copolymer - ExxonMobil PP9122 2polypropylene copolymer - Flint Hills Resources 23M2A 3cyclic olefin polymer - Daikyo CRYSTAL ZENITH ™ 4cyclic olefin polymer - SiO2 Medical Products The vials were stored at a temperature of 25° C. or 55° C. for 4 W prior to analysis by HPLC. The HPLC conditions were the same as described hereinabove for the data of Table 3. The results for liothyronine (T3), largest any other individual impurity (AOII), and total impurities as determined by peak area percent are set forth in Table 6. TABLE 6 Storage Temp 25° C. 55° C. Impurity T3 AOII Tot T3 AOII Tot Vial 1 0.25 0.33 1.9 0.87 0.99 3.5 Vial 2 0.28 0.39 2 1.59 4.97 14.6 Vial 3 0.25 2.54 4.4 0.91 2.31 4.9 Vial 4 0.22 0.52 2.5 1.11 4.02 7.9 Vial 5 0.25 0.7 3.4 0.85 8.76 20.3 Vial 6 0.25 0.89 3.7 0.73 10.51 29.9 Vial 7 0.24 0.75 2.6 0.78 7.29 10.7 Vial 8 0.24 0.81 2.7 0.75 7.09 10.6 Vial 9 0.25 0.48 1.9 0.78 2.79 5.4 Vial 10 NT NT NT 0.76 3 5.7 The results described in Table 6 demonstrate that vial material, size, color, and/or treatment can affect the stability of formulations comprising levothyroxine sodium, sodium iodide, and tromethamine. Example 5 This example demonstrates the stability of comparative formulations comprising levothyroxine sodium, glycerol, sodium chloride, and water as a function of the pH of the formulation. Separate samples containing levothyroxine sodium at a concentration of 20 mcg/mL and glycerol at a concentration of 100 mg/mL in normal saline were adjusted to pH levels of 7, 8, and 9. 5 mL of each sample was filled into 10 cc amber tubing vials, and the vials were stoppered with 20 mm stoppers under nitrogen. The samples were stored at a temperature of 55° C. The samples were analyzed by HPLC at 1 week of storage using the HPLC conditions described in Example 1. The results for liothyronine, largest unknown impurity, and total impurities as determined by peak area percent are set forth in Table 7. TABLE 7 Levothyroxine Na (mcg/mL) 20 Glycerol (mg/mL) 100 Solvent Normal saline pH 7 8 9 55° C., 1 W % Liothyronine 3.6 3.4 2.4 % largest unknown 1.16 1.30 0.82 impurity % total impurities 5.3 5.4 3.8 The results described in Table 7 demonstrate that high levels of impurities are formed in levothyroxine formulations containing glycerol over the pH range 7-9 following storage at 55° C. for one week. Example 6 This example demonstrates a method for preparing an exemplary formulation of the invention. The composition of an exemplary formulation containing 100 mcg levothyroxine in 5 mL volume is as described in Table 8. TABLE 8 Component Quantity per mL Levothyroxine sodium, USP 20 mcg Sodium chloride 6.48 mg Sodium iodide 0.14 mg Tromethamine, USP 10 mg Sodium hydroxide (1N) As needed to adjust pH to 10-10.5 Hydrochloric acid (1N) (target 10.3) Purified water q.s. The compositions for exemplary formulations containing 200 mcg or 500 mcg levothyroxine in 5 mL volume are the same as described in Table 8, except that the concentrations of levothyroxine sodium are 40 mcg/mL and 100 mcg/mL, respectively. An exemplary formulation is prepared by filling purified water in an amount of approximately 80% of a predetermined final batch volume into a suitable container. The entire amounts of sodium chloride, sodium iodide, and tromethamine are added in succession, with mixing until dissolution of each ingredient prior to addition of the next ingredient. The pH is determined, and then adjusted to pH 10.3 (range of 10.0 to 10.5) with sodium hydroxide and/or hydrochloric acid. The entire amount of levothyroxine sodium is added to the container, and the solution is mixed until dissolution. The pH is determined, and then adjusted to pH 10.3 (range of 10.0 to 10.5) with sodium hydroxide and/or hydrochloric acid. Purified water is added in an amount sufficient to reach the predetermined batch volume with continued mixing to ensure complete dissolution of all ingredients. The formulation can be bubbled with nitrogen or other suitable gas throughout the compounding to limit the dissolved oxygen in the formulation. Under aseptic conditions, the solution is filtered through a 0.22 μm filter, and then 5 mL of the filtered solution is filled into containers (e.g. vials) under nitrogen. The containers are then sealed (e.g., stoppered) under nitrogen. All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein. The use of the terms “a” and “an” and “the” and “at least one” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term “at least one” followed by a list of one or more items (for example, “at least one of A and B”) is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
<SOH> BACKGROUND OF THE INVENTION <EOH>Levothyroxine sodium for injection is a sterile lyophilized product for parenteral administration of levothyroxine sodium for thyroid replacement therapy. Levothyroxine sodium for injection is particularly useful when thyroid replacement is needed on an urgent basis, for short term thyroid replacement, and/or when oral administration is not possible, such as for a patient in a state of myxedema coma. Full chemical names for levothyroxine sodium include 4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodo-L-phenylalanine sodium, and L-tyrosine-O-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-monosodium salt. Levothyroxine sodium has a molecular weight of approximately 798.85 and the following chemical structure: Conventional formulations of levothyroxine sodium for injection are preservative-free lyophilized powders containing levothyroxine sodium and the excipients mannitol, sodium phosphate buffer, and sodium hydroxide. Administration of the conventional formulations involve reconstitution of the lyophilized powder in 0.9% sodium chloride injection (USP) to provide an injectable solution. However, use of the conventional lyophilized formulations requires reconstitution or dilution by healthcare practitioners prior to use. Once reconstituted, the levothyroxine sodium solutions have a limited stability, and must be used within a few hours of reconstitution. In addition, contaminants may be introduced into the solutions during the reconstitution process, thereby compromising patient safety. It has been shown that levothyroxine in oral tablets and in aqueous solutions undergoes degradation. Major degradation products of levothyroxine are known to include 3,3′,5-triiodothyronine (T3) 3,5-diiodothyronine (T2) 3,3′,5,5′-tetraiodothyroacetic acid (TTAA4) 3,3′,5-triiodothyroacetic acid (TTAA3) and 3,5-diiodothyroacetic acid (TTAA2) (Kannamkumarath et al., J. Anal. At. Spectrom., 2004, 19: 107-113 and Patel et al., Int. J. Pharm., 2003, 264: 35-43)). 3,3′,5-triiodothyronine, known as liothyronine or T3, is a major degradant. Aqueous solutions of levothyroxine sodium have been shown to be more stable at basic pH than at acidic pH, but significant degradation of levothyroxine sodium also has been shown to occur at basic pH (Patel et al., Int. J. Pharm., 2003, 264: 35-43). Thus, there remains a need in the art for a ready-to-use injectable formulation of levothyroxine sodium that exhibits storage stability.
<SOH> BRIEF SUMMARY OF THE INVENTION <EOH>The invention provides a liquid formulation comprising levothyroxine or a pharmaceutically acceptable salt thereof, tromethamine, sodium iodide, and water, wherein the formulation has a pH of about 9.0 to about 11.5. The invention also provides a liquid formulation comprising (a) levothyroxine or a pharmaceutically acceptable salt thereof in a concentration of about 20 mcg/mL to about 100 mcg/mL, (b) tromethamine in a concentration of about 5 mg/mL to about 20 mg/mL, (c) sodium iodide in a concentration of about 100 mcg/mL to about 300 mcg/mL, (d) sodium chloride, and (e) water, wherein the formulation has a pH of about 9.8 to about 10.8. detailed-description description="Detailed Description" end="lead"?
A61K31198
20170911
20180607
66080.0
A61K31198
6
HUI, SAN MING R
LEVOTHYROXINE LIQUID FORMULATIONS
UNDISCOUNTED
1
CONT-ACCEPTED
A61K
2,017
15,702,435
PENDING
EZETIMIBE-ASSOCIATED APOA-I MIMETIC PEPTIDES SHOWING ENHANCED SYNERGISM
In various embodiments, ezetimibe-associated apoA-I mimetic peptide are provided that show improved synergistic activity between ezetimibe and the apoA-I peptide in vivo. In certain embodiments the peptide component is a transgenic 6F and the ezetimibe-associated apoA-I mimetic peptide is an Ez-T6F peptide. Methods of making the Ez-apoA-I peptides are also provided. In certain embodiments the methods involve incubating ezetimibe and an apoAI mimetic peptide (e.g., T6F) in a solution comprising ethyl acetate and acetic acid or in a solution comprising ethyl lactate and lactic acid; and drying the solution to provide a dry ezetimibe-associated apoA-I mimetic peptide.
1: A method of preparing an ezetimibe-associated apoA-I mimetic peptide, said method comprising: incubating ezetimibe and said apoAI mimetic peptide in a solution comprising ethyl acetate and acetic acid or in a solution comprising ethyl lactate and lactic acid; and drying said solution to provide a dry ezetimibe-associated apoA-I mimetic peptide. 2. (canceled) 3: The method of claim 1, wherein said incubating comprises incubating 1:10 ezetimibe:Tg6F by weight. 4: The method of claim 1, wherein said drying comprises: drying said solution to produce a dry residue; resuspending said residue in water to provide a resuspended mixture; and drying the resuspended mixture to provide a dry powder extract comprising ezetimibe-associated apoA-I mimetic peptide. 5-7. (canceled) 8: The method of claim 4, wherein said drying the resuspended mixture comprises lyophilizing said mixture to provide said dry powder extract. 9: The method of claim 1, wherein the incubating peptide with ezetimibe is for at least about 10 minutes, or at least about 15 minutes, or at least about 30 minutes, or at least about 45 minutes, or at least about 1 hr, or at least about 1.5 hour, or at least about 2 hrs, or at least about 3 hrs, or at least about 4 hrs, or at least about 5 hours, or at least about 6 hrs, or at least about 12 hours, or at least about 1 day. 10-11. (canceled) 12: The method of claim 1, wherein said incubating comprises incubating said ezetimibe and said apoAI mimetic peptide in a solution comprising ethyl acetate and acetic acid. 13. (canceled) 14: The method of claim 12, wherein said solution comprises about 5% acetic acid. 15: The method of claim 1, wherein said incubating comprises incubating said ezetimibe and said apoAI mimetic peptide in a solution comprising ethyl lactate and lactic acid. 16. (canceled) 17: The method of claim 15, wherein said solution comprises about 5% lactic acid. 18: The method of claim 1, wherein: said apoA-I mimetic peptide is a chemically synthesized peptide; or said apoA-I mimetic peptide is a peptide recombinantly expressed in a plant cell. 19. (canceled) 20: The method of claim 18, wherein said apoA-I mimetic peptide is provided as a tissue of a transgenic plant wherein said tissue contains a heterologous ApoA-I mimetic peptide expressed by said plant. 21: The method of claim 20, wherein: said tissue is provided as a substantially dry powder; said powder is mixed with said solution comprising ethyl acetate and acetic acid or with said solution comprising ethyl lactate and lactic acid, to form an extraction mixture; and said extraction mixture is incubated before addition of said ezetimibe. 22: The method of claim 21, wherein said extraction mixture is incubated for at least about 15 minutes, or at least about ½ hour, or at least about 1 hour, or at least about 2 hours, or at least about 3 hours, or at least about 4 hours, or at least about 5 hours, or at least about 6 hours, or at least about 7 hours, or at least about 12 hours, or at least about 18 hours, or at least about 24 hours, or at least about 48 hours, or at least about 72 hours, or at least about 96 hours. 23. (canceled) 24: The method of claim 20, wherein said providing tissue comprises providing said tissue as a freeze-dried powder. 25: The method of claim 20, wherein said tissue of a transgenic plant comprises tissue of a tomato plant. 26-28. (canceled) 29: The method of claim 20, wherein: said ApoA-I mimetic peptide comprises the amino acid sequence DWLKAFYDKFFEKFKEFF (6F) (SEQ ID NO:1); and/or said ApoA-I mimetic peptide comprises the amino acid sequence FFEKFKEFFKDYFAKLWD (rev6F) (SEQ ID NO:15); and/or said ApoA-I mimetic peptide comprises the amino acid sequence DWFKAFYDKVAEKFKEAF (4F) (SEQ ID NO:6); and/or said ApoA-I mimetic peptide comprises the amino acid sequence FAEKFKEAVKDYFAKFWD (rev4F) (SEQ ID NO:13); and/or said heterologous ApoA-I mimetic peptide comprises the amino acid sequence, LLEQLNEQFNWVSRLANL; and/or said heterologous ApoA-I mimetic peptide comprises the amino acid sequence LVGRQLEEFL. 30. (canceled) 31: The method of claim 1, wherein said ezetimibe-associated apoA-I mimetic pepide is effective to decrease plasma total cholesterol in said mammal, and/or to decrease plasma plasma triglyceride in said mammal, and/or to decrease plasma 5-HETE in said mammal, and/or to decrease plasma 12-HETE in said mammal, and/or to decrease plasma 15-HETE in said mammal, and/or to decrease SAA levels in said mammal, and/or to increase plasma paraoxonase activity in said mammal, and/or to decrease plasma levels of lyophosphatidic acid (LPA) in a mammal when fed to said mammal alone or as a component of a food or diet. 32: The method of claim 1, wherein: said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma total cholesterol to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide; and/or said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma triglyceride, and/or raises plasma HDL cholesterol to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide; and/or said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma 5-HETE to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide; and/or said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma 12-HETE to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide; and/or said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma 15-HETE to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide; and/or said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma SAA to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide. 33: An ezetimibe-associated apoA-I mimetic peptide, wherein said ezetimibe associated apoA-I mimetic has greater biological activity than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide. 34: The ezetimibe-associated apoA-I mimetic peptide of claim 33, wherein said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma total cholesterol to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide; and/or said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma triglyceride, and/or raises plasma HDL cholesterol to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide; and/or said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma 5-HETE to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide; and/or said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma 12-HETE to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide; and/or said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma 15-HETE to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide; and/or said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma SAA to a greater amount tjhuyhan a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide. 35-37. (canceled) 38: The ezetimibe-associated apoA-I mimetic peptide of claim 33, wherein: said ApoA-I mimetic peptide comprises the amino acid sequence DWLKAFYDKFFEKFKEFF (6F) (SEQ ID NO:1); and/or said ApoA-I mimetic peptide comprises the amino acid sequence FFEKFKEFFKDYFAKLWD (rev6F) (SEQ ID NO:15); and/or said ApoA-I mimetic peptide comprises the amino acid sequence DWFKAFYDKVAEKFKEAF (4F) (SEQ ID NO:6); and/or said ApoA-I mimetic peptide comprises the amino acid sequence FAEKFKEAVKDYFAKFWD (rev4F) (SEQ ID NO:13); and/or said ApoA-I mimetic peptide comprises the amino acid sequence, LLEQLNEQFNWVSRLANL; and/or said ApoA-I mimetic peptide comprises the amino acid sequence LVGRQLEEFL. 39-41. (canceled) 42: A pharmaceutical formulation comprising: an ezetimibe-associated apoA-I mimetic peptide of claim 33; and a pharmaceutically acceptable carrier or diluent. 43-45. (canceled) 46: A method for the treatment or prophylaxis of a pathology characterized by an inflammatory response, said method comprising administering to a mammal in need thereof an effective amount of an ezetimibe-associated peptide of claim 33. 47-50. (canceled) 51: The method of claim 46, wherein: said pathology is atherosclerosis; and/or said pathology is macular degeneration; or said pathology is dyslipidemia; or said pathology is Alzheimer's disease; or said pathology is Crohn's disease; or said pathology is ulcerative colitis; or said pathology is cancer. 52-57. (canceled) 58: A method of preventing or reducing the uptake of one or more dietary pro-inflammatory micro-lipid components in a mammal, said method comprising administering to the mammal an effective amount of an ezetimibe-associated peptide of claim 33. 59-64. (canceled)
CROSS-REFERENCE TO RELATED APPLICATIONS This application claims benefit of and priority to U.S. Ser. No. 62/401,102, filed on Sep. 28, 2016, which is incorporated herein by reference in its entirety for all purposes. STATEMENT OF GOVERNMENTAL SUPPORT This invention was made with Government support under HL030568, awarded by the National Institutes of Health. The Government has certain rights in the invention. BACKGROUND Mimetics of apolipoprotein A-I (apoA-I) containing only 18 amino acids showed promise in animal models of disease (Getz and Reardon (2011) J Inflamm. Res. 4: 83-92; Navab et al. (2012) Arterioscler. Thromb. Vasc. Biol. 32: 2553-2560), and improved HDL function in humans when given orally at high doses despite achieving low plasma peptide levels (Bloedon (2008) J. Lipid Res. 49: 1344-1352). However, when high plasma levels were achieved with low doses of peptide given intravenously or by subcutaneous (SQ) injection, no improvement in HDL function was seen (Watson et al. (2011) J. Lipid Res. 52: 361-373). Studies in mice indicated that the major site of action for these peptides is in the intestine and that a high dose of peptide is required for efficacy (Navab et al. (2011) J. Lipid Res. 52: 1200-1210; Navab et al. (2012) J. Lipid Res. 53: 437-445). The high dose requirement provides a barrier to use in humans because of the cost of chemically synthesizing these peptides. To overcome this barrier an 18 amino acid peptide (6F peptide, DWLKAFYDKFFEKFKEFF (SEQ ID NO:1) was transgenically expressed in tomatoes (Chattopadhyay et al. (2013) J. Lipid Res. 54: 995-1010). Feeding LDL receptor-null (LDLR−/−) mice a Western diet (WD) for 13 weeks containing 2.2% by weight of freeze dried tomato powder made from transgenic tomatoes expressing the apoA-I mimetic peptide 6F (Tg6F) reduced plasma serum amyloid A (SAA) levels, reduced plasma total cholesterol levels, reduced plasma triglyceride levels, reduced plasma unsaturated (but not saturated) lysophosphatidic acid (LPA) levels, increased plasma paraoxonase-1 activity, increased plasma HDL-cholesterol levels, and decreased the extent of aortic atherosclerosis by about 50% (Chattopadhyay et al. (2013) J. Lipid Res. 54: 995-1010; Getz and Reardon (2013) J. Lipid Res. 54: 878-880). Two hours after LDLR−/− mice finished eating WD containing Tg6F, intact 6F peptide was found in the small intestine but not in the plasma (Chattopadhyay et al. (2013) J. Lipid Res. 54: 995-1010). Plasma levels of unsaturated (but not saturated) LPA correlated with the extent of aortic atherosclerosis. The content of LPA in the tissue of the small intestine was found to decrease after feeding Tg6F and the level of LPA (but not cholesterol) in the tissue of the small intestine correlated with the extent of aortic atherosclerosis (Id.). Without any purification steps, when the transgenic tomatoes expressing 6F peptide were freeze-dried, ground into powder and fed to a mouse model of dyslipidemia and atherosclerosis at only 2.2% of a high-fat high-cholesterol diet by weight, the transgenic tomatoes significantly reduced dyslipidemia, inflammation and atherosclerosis in the mice. This provided a daily dose of approximately 40 mg/kg/day. SUMMARY In various embodiments, novel ezetimibe-associated apoA-I mimetic peptides are provided as well as uses thereof. It was surprising discovery that an ezetimibe-associated ApoA-I mimetic peptide (Ez-ApoA-I pepide) could be produced by incubating ezeimibe and Tg6F peptide together in a solution comprising ethyl acetate with 5% acetic acid followed by removal of the ethyl acetate. Suprisingly, this resulted in a significantly more effective preparation. In particular the ezetimibe-associated ApoA-I mimetic peptide showed greater biological activity than equivalent amounts of ezetimibe and ApoA-I peptide when administered in a combined formulation. Various embodiments contemplated herein may include, but need not be limited to, one or more of the following: Embodiment 1 A method of preparing an ezetimibe-associated apoA-I mimetic peptide, said method comprising: incubating ezetimibe and said apoAI mimetic peptide in a solution comprising ethyl acetate and acetic acid or in a solution comprising ethyl lactate and lactic acid; and drying said solution to provide a dry ezetimibe-associated apoA-I mimetic peptide. Embodiment 2 The method of embodiment 1, wherein said incubating comprising incubating 0.1:10 or 0.5:10 or 1:10, or 2:10 or 4:10 or 5:10, or 6:10, or 7:10, or 8:10, or 9:10, or 1:1 ezetimibe:Tg6F by weight. Embodiment 3 The method of embodiment 1, wherein said incubating comprising incubating 1:10 ezetimibe:Tg6F by weight. Embodiment 4 The method according to any one of embodiments 1-3, wherein said drying comprises: drying said solution to produce a dry residue; resuspending said residue in water to provide a resuspended mixture; and drying the resuspended mixture to provide a dry powder extract comprising ezetimibe-associated apoA-I mimetic peptide. Embodiment 5 The method of embodiment 4, wherein said resuspending comprises re-suspending said residue in distilled water. Embodiment 6 The method of embodiment 4, wherein said resuspending comprises re-suspending said residue in de-ionized water. Embodiment 7 The method of embodiment 4, wherein said resuspending comprises re-suspending said residue in food-grade water. Embodiment 8 The method according to any one of embodiments 4-7, wherein said drying the resuspended mixture comprises lyophilizing said mixture to provide said dry powder extract. Embodiment 9 The method according to any one of embodiments 1-8, wherein the incubating peptide with ezetimibe is for at least about 10 minutes, or at least about 15 minutes, or at least about 30 minutes, or at least about 45 minutes, or at least about 1 hr, or at least about 1.5 hour, or at least about 2 hrs, or at least about 3 hrs, or at least about 4 hrs, or at least about 5 hours, or at least about 6 hrs, or at least about 12 hours, or at least about 1 day. Embodiment 10 The method according to any one of embodiments 1-8, wherein said incubating is for about 2 hrs. Embodiment 11 The method according to any one of embodiments 1-10, wherein said incubating is at room temperature. Embodiment 12 The method according to any one of embodiments 1-11, wherein said incubating comprises incubating said ezetimibe and said apoAI mimetic peptide in a solution comprising ethyl acetate and acetic acid. Embodiment 13 The method of embodiment 12, wherein said solution comprises about 1% to about 25% acetic acid, or about 2% to about 20% acetic acid, or about 3% to about 15% acetic acid, or about 4% to about 10% acetic acid, or about 4% to about 8% acetic acid, or from about 4% to about 6% acetic acid. Embodiment 14 The method of embodiment 13, wherein said solution comprises about 5% acetic acid. Embodiment 15 The method according to any one of embodiments 1-11, wherein said incubating comprises incubating said ezetimibe and said apoAI mimetic peptide in a solution comprising ethyl lactate and lactic acid. Embodiment 16 The method of embodiment 15, wherein said solution comprises about 1% to about 25% lactic acid, or about 2% to about 20% lactic acid, or about 3% to about 15% lactic acid, or about 4% to about 10% lactic acid, or about 4% to about 8% lactic acid, or from about 4% to about 6% lactic acid. Embodiment 17 The method of embodiment 15, wherein said solution comprises about 5% lactic acid. Embodiment 18 The method according to any one of embodiments 1-17, wherein said apoA-I mimetic peptide is a chemically synthesized peptide. Embodiment 19 The method according to any one of embodiments 1-17, wherein said apoA-I mimetic peptide is a peptide recombinantly expressed in a plant cell. Embodiment 20 The method of embodiment 19, wherein said apoA-I mimetic peptide is provided as a tissue of a transgenic plant wherein said tissue contains a heterologous ApoA-I mimetic peptide expressed by said plant. Embodiment 21 The method of embodiment 20, wherein: said tissue is provided as a substantially dry powder; said powder is mixed with said solution comprising ethyl acetate and acetic acid or with said solution comprising ethyl lactate and lactic acid, to form an extraction mixture; and said extraction mixture is incubated before addition of said ezetimibe. Embodiment 22 The method of embodiment 21, wherein said extraction mixture is incubated for at least about 15 minutes, or at least about ½ hour, or at least about 1 hour, or at least about 2 hours, or at least about 3 hours, or at least about 4 hours, or at least about 5 hours, or at least about 6 hours, or at least about 7 hours, or at least about 12 hours, or at least about 18 hours, or at least about 24 hours, or at least about 48 hours, or at least about 72 hours, or at least about 96 hours. Embodiment 23 The method of embodiment 21, wherein said extraction mixture is incubated overnight. Embodiment 24 The method according to any one of embodiments 20-23, wherein, wherein said providing tissue comprises providing said tissue as a freeze-dried powder. Embodiment 25 The method according to any one of embodiments 20-24, wherein said tissue of a transgenic plant comprises tissue of a tomato plant. Embodiment 26 The method of embodiment 25, wherein said tissue of transgenic plant comprises a tomato fruit. Embodiment 27 The method according to any one of embodiments 20-24, wherein said tissue of a transgenic plant comprises tissue of a plant selected from the group consisting of tomatoes, carrots, potatoes, apples, pears, plums, peaches, oranges, kiwis, papayas, pineapples, guava, lilikoi, starfruit, lychee, mango, grape, pomegranate, mustard greens, kale, chard, lettuce, soybean, rice, corn and other grains (e.g., wheat, rice, barley, bulgur, faro, kamut, kaniwa, millet, oats, quinoa, rice, rye, sorghum, spelt, teff, triticale, and the like), berries such as strawberries, blueberries, blackberries, goji berries, and raspberries, banana, rice, turnip, maize, grape, fig, plum, potato, safflower seeds, nuts (e.g., almond, walnut, pecan, peanut, cashew, macademia, hazelnut, etc.), legumes (e.g., alfalfa, clover, peas, beans (including black beans), lentils, lupins, mesquite, carob, soybeans, and the like). Embodiment 28 The method according to any one of embodiments 20-27, wherein said peptide is expressed under the control of a CaMV promoter, or under the control of an E8 promoter, or under the control of an E4/E8 hybrid promoter. Embodiment 29 The method according to any one of embodiments 20-28, wherein said ApoA-I mimetic peptide comprises the amino acid sequence (6F) (SEQ ID NO: 1) DWLKAFYDKFFEKFKEFF. Embodiment 30 The method according to any one of embodiments 20-28, wherein said ApoA-I mimetic peptide comprises the amino acid sequence (rev6F) (SEQ ID NO: 15) FFEKFKEFFKDYFAKLWD. Embodiment 31 The method according to any one of embodiments 20-28, wherein said ApoA-I mimetic peptide comprises the amino acid sequence (4F) (SEQ ID NO: 6) DWFKAFYDKVAEKFKEAF. Embodiment 32 The method according to any one of embodiments 20-28, wherein said ApoA-I mimetic peptide comprises the amino acid sequence (rev4F) (SEQ ID NO: 13) FAEKFKEAVKDYFAKFWD. Embodiment 33 The method according to any one of embodiments 20-28, wherein said heterologous ApoA-I mimetic peptide comprises the amino acid sequence, LLEQLNEQFNWVSRLANL. Embodiment 34 The method according to any one of embodiments 20-28, wherein said heterologous ApoA-I mimetic peptide comprises the amino acid sequence LVGRQLEEFL. Embodiment 35 The method according to any one of embodiments 20-28, wherein said ApoA-I mimetic peptide comprises an amino acid sequence selected from the group consisting of (SEQ ID NO: 1) DWLKAFYDKFFEKFKEFF, (SEQ ID NO: 2) DWLKAFYDKVAEKLKEAF, (SEQ ID NO: 3) DWLKAFYDKVAEKLKEAF, (SEQ ID NO: 4) DWFKAFYDKVAEKLKEAF, (SEQ ID NO: 5) DWLKAFYDKVAEKFKEAF, (SEQ ID NO: 6) DWFKAFYDKVAEKFKEAF, (SEQ ID NO: 7) DWLKAFYDKVFEKFKEFF, (SEQ ID NO: 1) DWLKAFYDKFFEKFKEFF, (SEQ ID NO: 8) DWFKAFYDKFFEKFKEFF, (SEQ ID NO: 9) DWLKAFYDKVAEKLKEFF, (SEQ ID NO: 10) FAEKLKEAVKDYFAKLWD, (SEQ ID NO: 11) FAEKLKEAVKDYFAKLWD, (SEQ ID NO: 12) FAEKLKEAVKDYFAKFWD, (SEQ ID NO: 13) FAEKFKEAVKDYFAKFWD, (SEQ ID NO: 14) FFEKFKEFVKDYFAKLWD, (SEQ ID NO: 15) FFEKFKEFFKDYFAKLWD, (SEQ ID NO: 16) FFEKFKEFFKDYFAKFWD, (SEQ ID NO: 17) DWLKAFYDKVFEKFKEAF, (SEQ ID NO: 18) DWLKAFYDKVFEKLKEFF, (SEQ ID NO: 19) DWLKAFYDKVAEKFKEFF, (SEQ ID NO: 20) DWLKAFYDKVFEKFKEFF, (SEQ ID NO: 21) EWLKLFYEKVLEKFKEAF, (SEQ ID NO: 22) EWLKAFYDKVAEKFKEAF, (SEQ ID NO: 23) EWLKAFYDKVAEKLKEFF, (SEQ ID NO: 24) EWLKAFYDKVFEKFKEAF, (SEQ ID NO: 25) EWLKAFYDKVFEKLKEFF, (SEQ ID NO: 26) EWLKAFYDKVAEKFKEFF, (SEQ ID NO: 27) EWLKAFYDKVFEKFKEFF, (SEQ ID NO: 28) AFYDKVAEKLKEAF, (SEQ ID NO: 29) AFYDKVAEKFKEAF, (SEQ ID NO: 30) AFYDKVAEKFKEAF, (SEQ ID NO: 31) AFYDKFFEKFKEFF, (SEQ ID NO: 32) AFYDKFFEKFKEFF, (SEQ ID NO: 33) AFYDKVAEKFKEAF, (SEQ ID NO: 34) AFYDKVAEKLKEFF, (SEQ ID NO: 35) AFYDKVFEKFKEAF, (SEQ ID NO: 36) AFYDKVFEKLKEFF, (SEQ ID NO: 37) AFYDKVAEKFKEFF, (SEQ ID NO: 38) KAFYDKVFEKFKEF, (SEQ ID NO: 39) LFYEKVLEKFKEAF, (SEQ ID NO: 40) AFYDKVAEKFKEAF, (SEQ ID NO: 41) AFYDKVAEKLKEFF, (SEQ ID NO: 42) AFYDKVFEKFKEAF, (SEQ ID NO: 43) AFYDKVFEKLKEFF, (SEQ ID NO: 44) AFYDKVAEKFKEFF, (SEQ ID NO: 45) AFYDKVFEKFKEFF, (SEQ ID NO: 46) DWLKALYDKVAEKLKEAL, (SEQ ID NO: 47) DWFKAFYEKVAEKLKEFF, (SEQ ID NO: 48) DWFKAFYEKFFEKFKEFF, (SEQ ID NO: 49) EWLKALYEKVAEKLKEAL, (SEQ ID NO: 50) EWLKAFYEKVAEKLKEAF, (SEQ ID NO: 51) EWFKAFYEKVAEKLKEFF, (SEQ ID NO: 52) EWLKAFYEKVFEKFKEFF, (SEQ ID NO: 53) EWLKAFYEKFFEKFKEFF, (SEQ ID NO: 54) EWFKAFYEKFFEKFKEFF, (SEQ ID NO: 55) DFLKAWYDKVAEKLKEAW, (SEQ ID NO: 56) EFLKAWYEKVAEKLKEAW, (SEQ ID NO: 57) DFWKAWYDKVAEKLKEWW, (SEQ ID NO: 58) EFWKAWYEKVAEKLKEWW, (SEQ ID NO: 59) DKLKAFYDKVFEWAKEAF, (SEQ ID NO: 60) DKWKAVYDKFAEAFKEFL, (SEQ ID NO: 61) EKLKAFYEKVFEWAKEAF, (SEQ ID NO: 62) EKWKAVYEKFAEAFKEFL, (SEQ ID NO: 63) DWLKAFVDKFAEKFKEAY, (SEQ ID NO: 64) EKWKAVYEKFAEAFKEFL, (SEQ ID NO: 65) DWLKAFVYDKVFKLKEFF, (SEQ ID NO: 66) EWLKAFVYEKVFKLKEFF, (SEQ ID NO: 67) DWLRAFYDKVAEKLKEAF, (SEQ ID NO: 68) EWLRAFYEKVAEKLKEAF, (SEQ ID NO: 69) DWLKAFYDRVAEKLKEAF, (SEQ ID NO: 70) EWLKAFYERVAEKLKEAF, (SEQ ID NO: 71) DWLKAFYDKVAERLKEAF, (SEQ ID NO: 72) EWLKAFYEKVAERLKEAF, (SEQ ID NO: 73) DWLKAFYDKVAEKLREAF, (SEQ ID NO: 74) EWLKAFYEKVAEKLREAF, (SEQ ID NO: 75) DWLKAFYDRVAERLKEAF, (SEQ ID NO: 76) EWLKAFYERVAERLKEAF, (SEQ ID NO: 77) DWLRAFYDKVAEKLREAF, (SEQ ID NO: 78) EWLRAFYEKVAEKLREAF, (SEQ ID NO: 79) DWLRAFYDRVAEKLKEAF, (SEQ ID NO: 80) EWLRAFYERVAEKLKEAF, (SEQ ID NO: 81) DWLKAFYDKVAERLREAF, (SEQ ID NO: 82) EWLKAFYEKVAERLREAF, (SEQ ID NO: 83) DWLRAFYDKVAERLKEAF, (SEQ ID NO: 84) EWLRAFYEKVAERLKEAF, (SEQ ID NO: 85) DWLKAFYDKVAEKLKEAFPDWLKAFYDKVAEKLKEAF, (SEQ ID NO: 86) DWLKAFYDKVAEKLKEFFPDWLKAFYDKVAEKLKEFF, (SEQ ID NO: 87) DWFKAFYDKVAEKLKEAFPDWFKAFYDKVAEKLKEAF, (SEQ ID NO: 88) DKLKAFYDKVFEWAKEAFPDKLKAFYDKVFEWLKEAF, (SEQ ID NO: 89) DKWKAVYDKFAEAFKEFLPDKWKAVYDKFAEAFKEFL, (SEQ ID NO: 90) DWFKAFYDKVAEKFKEAFPDWFKAFYDKVAEKFKEAF, (SEQ ID NO: 91) DWLKAFVYDKVFKLKEFFPDWLKAFVYDKVFKLKEFF, (SEQ ID NO: 92) DWLKAFYDKFAEKFKEFFPDWLKAFYDKFAEKFKEFF, (SEQ ID NO: 93) EWFKAFYEKVAEKFKEAF, (SEQ ID NO: 94) DWFKAFYDKVAEKF, (SEQ ID NO: 95) FKAFYDKVAEKFKE, (SEQ ID NO: 96) FKAFYEKVAEKFKE, (SEQ ID NO: 97) FKAFYDKVAEKFKE, (SEQ ID NO: 98) FKAFYEKVAEKFKE, (SEQ ID NO: 99) DWFKAFYDKVAEKFKEAF, (SEQ ID NO: 100) EWFKAFYEKVAEKFKEAF, (SEQ ID NO: 101) AFYDKVAEKFKEAF, (SEQ ID NO: 102) DWFKAFYDKVAEKF, (SEQ ID NO: 103) DWLKAFYDKVFEKFKEFF, (SEQ ID NO: 104) EWLKAFYEKVFEKFKEFF, (SEQ ID NO: 105) AFYDKVFEKFKEFF, (SEQ ID NO: 106) AFYEKVFEKFKEFF, (SEQ ID NO: 107) DWLKAFYDKVFEKF, (SEQ ID NO: 108) EWLKAFYEKVFEKF, (SEQ ID NO: 109) LKAFYDKVFEKFKE, (SEQ ID NO: 110) LKAFYEKVFEKFKE, (SEQ ID NO: 111) EWFKAFYEKVADKFKDAF, (SEQ ID NO: 112) EWFKAFYDKVADKFKEAF, (SEQ ID NO: 113) DWFKAFYEKVADKFKEAF, (SEQ ID NO: 114) DWFKAFYEKVAEKFKDAF, (SEQ ID NO: 115) DFWKAFYDKVAEKFKEAF, (SEQ ID NO: 116) EFWKAFYEKVADKFKDAF, (SEQ ID NO: 117) EFWKAFYDKVADKFKEAF, (SEQ ID NO: 118) DFWKAFYEKVADKFKEAF, (SEQ ID NO: 119) DFWKAFYEKVAEKFKDAF, (SEQ ID NO: 120) DWFKAYFDKVAEKFKEAF, (SEQ ID NO: 121) EWFKAYFEKVADKFKDAF, (SEQ ID NO: 122) EWFKAYFDKVADKFKEAF, (SEQ ID NO: 123) DWFKAYFEKVADKFKEAF, (SEQ ID NO: 124) DWFKAYFEKVAEKFKDAF, (SEQ ID NO: 125) DWFKAFVDKYAEKFKEAF, (SEQ ID NO: 126) EWFKAFVEKYADKFKDAF, (SEQ ID NO: 127) EWFKAFVDKYADKFKEAF, (SEQ ID NO: 128) DWFKAFVEKYADKFKEAF, (SEQ ID NO: 129) DWFKAFVEKYAEKFKDAF, (SEQ ID NO: 130) DWFKAFYDKAVEKFKEAF, (SEQ ID NO: 131) EWFKAFYEKAVDKFKDAF, (SEQ ID NO: 132) EWFKAFYDKAVDKFKEAF, (SEQ ID NO: 133) DWFKAFYEKAVDKFKEAF, (SEQ ID NO: 134) DWFKAFYEKAVEKFKDAF, (SEQ ID NO: 135) DWFKAFYDKVFEKAKEAF, (SEQ ID NO: 136) EWFKAFYEKVFDKAKDAF, (SEQ ID NO: 137) EWFKAFYDKVFDKAKEAF, (SEQ ID NO: 138) DWFKAFYEKVFDKAKEAF, (SEQ ID NO: 139) DWFKAFYEKVFEKAKDAF, (SEQ ID NO: 140) DWFKAFYDKVAEKAKEFF, (SEQ ID NO: 141) EWFKAFYEKVADKAKDFF, (SEQ ID NO: 142) EWFKAFYDKVADKAKEFF, (SEQ ID NO: 143) DWFKAFYEKVADKAKEFF, (SEQ ID NO: 144) DWFKAFYEKVAEKAKDFF, (SEQ ID NO: 145) DWFKAFYDKVAEKFKEFA, (SEQ ID NO: 146) EWFKAFYEKVADKFKDFA, (SEQ ID NO: 147) EWFKAFYDKVADKFKEFA, (SEQ ID NO: 148) DWFKAFYEKVADKFKEFA, (SEQ ID NO: 149) DWFKAFYEKVAEKFKDFA, (SEQ ID NO: 150) DAFKAFYDKVAEKFKEWF, (SEQ ID NO: 151) EAFKAFYEKVADKFKDWF, (SEQ ID NO: 152) EAFKAFYDKVADKFKEWF, (SEQ ID NO: 153) DAFKAFYEKVADKFKEWF, (SEQ ID NO: 154) DAFKAFYEKVAEKFKDWF, (SEQ ID NO: 155) DAFKAFYDKVWEKFKEAF, (SEQ ID NO: 156) EAFKAFYEKVWDKFKDAF, (SEQ ID NO: 157) EAFKAFYDKVWDKFKEAF, (SEQ ID NO: 158) DAFKAFYEKVWDKFKEAF, (SEQ ID NO: 159) DAFKAFYEKVWEKFKDAF, (SEQ ID NO: 160) DYFKAFWDKVAEKFKEAF, (SEQ ID NO: 161) EYFKAFWEKVADKFKDAF, (SEQ ID NO: 162) EYFKAFWDKVADKFKEAF, (SEQ ID NO: 163) DYFKAFWEKVADKFKEAF, (SEQ ID NO: 164) DYFKAFWEKVAEKFKDAF, (SEQ ID NO: 165) DWAKAFYDKVAEKFKEFF, (SEQ ID NO: 166) EWAKAFYEKVADKFKDFF, (SEQ ID NO: 167) EWAKAFYDKVADKFKEFF, (SEQ ID NO: 168) DWAKAFYEKVADKFKEFF, (SEQ ID NO: 169) DWAKAFYEKVAEKFKDFF, (SEQ ID NO: 170) DWFKAAYDKVAEKFKEFF, (SEQ ID NO: 171) EWFKAAYEKVADKFKDFF, (SEQ ID NO: 172) EWFKAAYDKVADKFKEFF, (SEQ ID NO: 173) DWFKAAYEKVADKFKEFF, (SEQ ID NO: 174) DWFKAAYEKVAEKFKDFF, (SEQ ID NO: 175) DWFKAFADKVAEKFKEYF, (SEQ ID NO: 176) EWFKAFAEKVADKFKDYF, (SEQ ID NO: 177) EWFKAFADKVADKFKEYF, (SEQ ID NO: 178) DWFKAFAEKVADKFKEYF, (SEQ ID NO: 179) DWFKAFAEKVAEKFKDYF, (SEQ ID NO: 180) DWFKAFYDKAAEKFKEVF, (SEQ ID NO: 181) EWFKAFYEKAADKFKDVF, (SEQ ID NO: 182) EWFKAFYDKAADKFKEVF, (SEQ ID NO: 183) DWFKAFYEKAADKFKEVF, (SEQ ID NO: 184) DWFKAFYEKAAEKFKDVF, (SEQ ID NO: 185) DWYKAFFDKVAEKFKEAF, (SEQ ID NO: 186) EWYKAFFEKVADKFKDAF, (SEQ ID NO: 187) EWYKAFFDKVADKFKEAF, (SEQ ID NO: 188) DWYKAFFEKVADKFKEAF, (SEQ ID NO: 189) DWYKAFFEKVAEKFKDAF, (SEQ ID NO: 190) DWVKAFYDKFAEKFKEAF, (SEQ ID NO: 191) EWVKAFYEKFADKFKDAF, (SEQ ID NO: 192) EWVKAFYDKFADKFKEAF, (SEQ ID NO: 193) DWVKAFYEKFADKFKEAF, (SEQ ID NO: 194) DWVKAFYEKFAEKFKDAF, (SEQ ID NO: 195) DWFKAFFDKVAEKYKEAF, (SEQ ID NO: 196) EWFKAFFEKVADKYKDAF, (SEQ ID NO: 197) EWFKAFFDKVADKYKEAF, (SEQ ID NO: 198) DWFKAFFEKVADKYKEAF, (SEQ ID NO: 199) DWFKAFFEKVADKYKEAF, (SEQ ID NO: 200) DWFKAFFDKVAEKFKEAY, (SEQ ID NO: 201) EWFKAFFEKVADKFKDAY, (SEQ ID NO: 202) EWFKAFFDKVADKFKEAY, (SEQ ID NO: 203) DWFKAFFEKVADKFKEAY, (SEQ ID NO: 204) DWFKAFFEKVAEKFKDAY, (SEQ ID NO: 205) DWFKAFYDKFAEKFKEAV, (SEQ ID NO: 206) EWFKAFYEKFADKFKDAV, (SEQ ID NO: 207) EWFKAFYDKFADKFKEAV, (SEQ ID NO: 208) DWFKAFYEKFADKFKEAV, (SEQ ID NO: 209) DWFKAFYEKFAEKFKDAV, (SEQ ID NO: 210) DKFKAFYDKVAEKFWEAF, (SEQ ID NO: 211) EKFKAFYEKVADKFWDAF, (SEQ ID NO: 212) EKFKAFYDKVADKFWEAF, (SEQ ID NO: 213) DKFKAFYEKVADKFWEAF, (SEQ ID NO: 214) DKFKAFYEKVAEKFWDAF, (SEQ ID NO: 215) DKWKAFYDKVAEKFFEAF, (SEQ ID NO: 216) EKWKAFYEKVADKFFDAF, (SEQ ID NO: 217) EKWKAFYDKVADKFFEAF, (SEQ ID NO: 218) DKWKAFYEKVADKFFEAF, (SEQ ID NO: 219) DKWKAFYEKVAEKFFDAF, (SEQ ID NO: 220) DKFKAFYDKWAEVFKEAF, (SEQ ID NO: 221) EKFKAFYEKWADVFKDAF, (SEQ ID NO: 222) EKFKAFYDKWADVFKEAF, (SEQ ID NO: 223) DKFKAFYEKWADVFKEAF, (SEQ ID NO: 224) DKFKAFYEKWAEVFKDAF, (SEQ ID NO: 225) DKFKAFYDKVAEFWKEAF, (SEQ ID NO: 226) EKFKAFYEKVADFWKDAF, (SEQ ID NO: 227) EKFKAFYDKVADFWKEAF, (SEQ ID NO: 228) DKFKAFYEKVADFWKEAF, (SEQ ID NO: 229) DKFKAFYEKVAEFWKDAF, (SEQ ID NO: 230) FAEKFKEAVKDYFAKFWD, (SEQ ID NO: 231) FADKFKDAVKEYFAKFWE, (SEQ ID NO: 232) FADKFKEAVKDYFAKFWE, (SEQ ID NO: 233) FAEKFKDAVKEYFAKFWD, (SEQ ID NO: 234) FAEKFKDAVKDYFAKFWE, (SEQ ID NO: 235) FWEKFKEAVKDYFAKFAD, (SEQ ID NO: 236) FWDKFKDAVKEYFAKFAE, (SEQ ID NO: 237) FADKFKEAVKDYFAKFWE, (SEQ ID NO: 238) FAEKFKDAVKEYFAKFWD, (SEQ ID NO: 239) FAEKFKDAVKDYFAKFWE, (SEQ ID NO: 240) FFEKFKEAVKDYFAKAWD, (SEQ ID NO: 241) FFDKFKDAVKEYFAKAWE, (SEQ ID NO: 242) FFDKFKEAVKDYFAKAWE, (SEQ ID NO: 243) FFEKFKDAVKEYFAKAWD, (SEQ ID NO: 244) FFEKFKDAVKDYFAKAWE, (SEQ ID NO: 245) FAEKAKEFVKDYFAKFWD, (SEQ ID NO: 246) FADKAKDFVKEYFAKFWE, (SEQ ID NO: 247) FADKAKEFVKDYFAKFWE, (SEQ ID NO: 248) FAEKAKDFVKEYFAKFWD, (SEQ ID NO: 249) FAEKAKDFVKDYFAKFWE, (SEQ ID NO: 250) FAEKFKEVAKDYFAKFWD, (SEQ ID NO: 251) FADKFKDVAKEYFAKFWE, (SEQ ID NO: 252) FADKFKEVAKDYFAKFWE, (SEQ ID NO: 253) FAEKFKDVAKEYFAKFWD, (SEQ ID NO: 254) FAEKFKDVAKDYFAKFWE, (SEQ ID NO: 255) FAEKFKEAYKDVFAKFWD, (SEQ ID NO: 256) FADKFKDAYKEVFAKFWE, (SEQ ID NO: 257) FADKFKEAYKDVFAKFWE, (SEQ ID NO: 258) FAEKFKDAYKEVFAKFWD, (SEQ ID NO: 259) FAEKFKDAYKDVFAKFWE, (SEQ ID NO: 260) FAEKFKEAVKDFYAKFWD, (SEQ ID NO: 261) FADKFKDAVKEFYAKFWE, (SEQ ID NO: 262) FADKFKEAVKDFYAKFWE, (SEQ ID NO: 263) FAEKFKDAVKEFYAKFWD, (SEQ ID NO: 264) FAEKFKDAVKDFYAKFWE, (SEQ ID NO: 265) FAEKFWEAVKDYFAKFKD, (SEQ ID NO: 266) FADKFWDAVKEYFAKFKE, (SEQ ID NO: 267) FADKFWEAVKDYFAKFKE, (SEQ ID NO: 268) FAEKFWDAVKEYFAKFKD, (SEQ ID NO: 269) FAEKFWDAVKDYFAKFKE, (SEQ ID NO: 270) AFEKFKEAVKDYFAKFWD, (SEQ ID NO: 271) AFDKFKDAVKEYFAKFWE, (SEQ ID NO: 272) AFDKFKEAVKDYFAKFWE, (SEQ ID NO: 273) AFEKFKDAVKEYFAKFWD, (SEQ ID NO: 274) AFEKFKDAVKDYFAKFWE, (SEQ ID NO: 275) VAEKFKEAFKDYFAKFWD, (SEQ ID NO: 276) VADKFKDAFKEYFAKFWE, (SEQ ID NO: 277) VADKFKEAFKDYFAKFWE, (SEQ ID NO: 278) VAEKFKDAFKEYFAKFWD, (SEQ ID NO: 279) VAEKFKDAFKDYFAKFWE, (SEQ ID NO: 280) YAEKFKEAVKDFFAKFWD, (SEQ ID NO: 281) YADKFKDAVKEFFAKFWE, (SEQ ID NO: 282) YADKFKEAVKDFFAKFWE, (SEQ ID NO: 283) YAEKFKDAVKEFFAKFWD, (SEQ ID NO: 284) YAEKFKDAVKDFFAKFWE, (SEQ ID NO: 285) AAEKFKEFVKDYFAKFWD, (SEQ ID NO: 286) AADKFKDFVKEYFAKFWE, (SEQ ID NO: 287) AADKFKEFVKDYFAKFWE, (SEQ ID NO: 288) AAEKFKDFVKEYFAKFWD, (SEQ ID NO: 289) AAEKFKDFVKDYFAKFWE, (SEQ ID NO: 290) FFEKAKEAVKDYFAKFWD, (SEQ ID NO: 291) FFDKAKDAVKEYFAKFWE, (SEQ ID NO: 292) FFDKAKEAVKDYFAKFWE, (SEQ ID NO: 293) FFEKAKDAVKEYFAKFWD, (SEQ ID NO: 294) FFEKAKDAVKDYFAKFWE, (SEQ ID NO: 295) FYEKFKEAVKDAFAKFWD, (SEQ ID NO: 296) FYDKFKDAVKEAFAKFWE, (SEQ ID NO: 297) FYDKFKEAVKDAFAKFWE, (SEQ ID NO: 298) FYEKFKDAVKEAFAKFWD, (SEQ ID NO: 299) FYEKFKDAVKDAFAKFWE, (SEQ ID NO: 300) FVEKFKEAAKDYFAKFWD, (SEQ ID NO: 301) FVDKFKDAAKEYFAKFWE, (SEQ ID NO: 302) FVDKFKEAAKDYFAKFWE, (SEQ ID NO: 303) FVEKFKDAAKEYFAKFWD, (SEQ ID NO: 304) FVEKFKDAAKDYFAKFWE, (SEQ ID NO: 305) FAEKYKEAVKDFFAKFWD, (SEQ ID NO: 306) FADKYKDAVKEFFAKFWE, (SEQ ID NO: 307) FADKYKEAVKDFFAKFWE, (SEQ ID NO: 308) FAEKYKDAVKEFFAKFWD, (SEQ ID NO: 309) FAEKYKDAVKDFFAKFWE, (SEQ ID NO: 310) FAEKVKEAFKDYFAKFWD, (SEQ ID NO: 311) FADKVKDAFKEYFAKFWE, (SEQ ID NO: 312) FADKVKEAFKDYFAKFWE, (SEQ ID NO: 313) FAEKVKDAFKEYFAKFWD, (SEQ ID NO: 314) FAEKVKDAFKDYFAKFWE, (SEQ ID NO: 315) FAEKFKEYVKDAFAKFWD, (SEQ ID NO: 316) FADKFKDYVKEAFAKFWE, (SEQ ID NO: 317) FADKFKEYVKDAFAKFWE, (SEQ ID NO: 318) FAEKFKDYVKEAFAKFWD, (SEQ ID NO: 319) FAEKFKDYVKDAFAKFWE, (SEQ ID NO: 320) FAEKFKEAFKDYVAKFWD, (SEQ ID NO: 321) FADKFKDAFKEYVAKFWE, (SEQ ID NO: 322) FADKFKEAFKDYVAKFWE, (SEQ ID NO: 323) FAEKFKDAFKEYVAKFWD, (SEQ ID NO: 324) FAEKFKDAFKDYVAKFWE, (SEQ ID NO: 325) FAEKFKEAFKDYFAKVWD, (SEQ ID NO: 326) FADKFKDAFKEYFAKVWE, (SEQ ID NO: 327) FADKFKEAFKDYFAKVWE, (SEQ ID NO: 328) FAEKFKDAFKEYFAKVWD, (SEQ ID NO: 329) FAEKFKDAFKDYFAKVWE, (SEQ ID NO: 330) FAEKFKEAVKDFFAKYWD, (SEQ ID NO: 331) FADKFKDAVKEFFAKYWE, (SEQ ID NO: 332) FADKFKEAVKDFFAKYWE, (SEQ ID NO: 333) FAEKFKDAVKEFFAKYWD, (SEQ ID NO: 334) FAEKFKDAVKDFFAKYWE, (SEQ ID NO: 335) WAEKFFEAVKDYFAKFKD, (SEQ ID NO: 336) WADKFFDAVKEYFAKFKE, (SEQ ID NO: 337) WADKFFEAVKDYFAKFKE, (SEQ ID NO: 338) WAEKFFDAVKEYFAKFKD, (SEQ ID NO: 339) WAEKFFDAVKDYFAKFKE, (SEQ ID NO: 340) FAEKWFEAVKDYFAKFKD, (SEQ ID NO: 341) FADKWFDAVKEYFAKFKE, (SEQ ID NO: 342) FADKWFEAVKDYFAKFKE, (SEQ ID NO: 343) FAEKWFDAVKEYFAKFKD, (SEQ ID NO: 344) FAEKWFDAVKDYFAKFKE, (SEQ ID NO: 345) FAEKFVEAWKDYFAKFKD, (SEQ ID NO: 346) FADKFVDAWKEYFAKFKE, (SEQ ID NO: 347) FADKFVEAWKDYFAKFKE, (SEQ ID NO: 348) FAEKFVDAWKEYFAKFKD, (SEQ ID NO: 349) FAEKFVDAWKDYFAKFKE, (SEQ ID NO: 350) FYEKFAEAVKDWFAKFKD, (SEQ ID NO: 351) FYDKFADAVKEWFAKFKE, (SEQ ID NO: 352) FYDKFAEAVKDWFAKFKE, (SEQ ID NO: 353) FYEKFADAVKEWFAKFKD, (SEQ ID NO: 354) FYEKFADAVKDWFAKFKE, (SEQ ID NO: 355) DWFKHFYDKVAEKFKEAF, (SEQ ID NO: 356) EWFKHFYEKVADKFKDAF, (SEQ ID NO: 357) EWFKHFYDKVAEKFKEAF, (SEQ ID NO: 358) DWFKHFYEKVAEKFKEAF, (SEQ ID NO: 359) DWFKHFYDKVADKFKEAF, (SEQ ID NO: 360) DWFKHFYDKVAEKFKDAF, (SEQ ID NO: 361) DWHKFFYDKVAEKFKEAF, (SEQ ID NO: 362) EWHKFFYEKVADKFKDAF, (SEQ ID NO: 363) EWHKFFYDKVAEKFKEAF, (SEQ ID NO: 364) DWHKFFYEKVAEKFKEAF, (SEQ ID NO: 365) DWHKFFYDKVADKFKEAF, (SEQ ID NO: 366) DWHKFFYDKVAEKFKDAF, (SEQ ID NO: 367) DWFKFHYDKVAEKFKEAF, (SEQ ID NO: 368) EWFKFHYEKVADKFKDAF, (SEQ ID NO: 369) EWFKFHYDKVAEKFKEAF, (SEQ ID NO: 370) DWFKFHYEKVAEKFKEAF, (SEQ ID NO: 371) DWFKFHYDKVADKFKEAF, (SEQ ID NO: 372) DWFKFHYDKVAEKFKDAF, (SEQ ID NO: 373) DWFKVFYDKHAEKFKEAF, (SEQ ID NO: 374) EWFKVFYEKHADKFKDAF, (SEQ ID NO: 375) EWFKVFYDKHAEKFKEAF, (SEQ ID NO: 376) DWFKVFYEKHAEKFKEAF, (SEQ ID NO: 377) DWFKVFYDKHADKFKEAF, (SEQ ID NO: 378) DWFKVFYDKHAEKFKDAF, (SEQ ID NO: 379) DWFKAFYDKVAEKFKEHF, (SEQ ID NO: 380) EWFKAFYEKVADKFKDHF, (SEQ ID NO: 381) EWFKAFYDKVAEKFKEHF, (SEQ ID NO: 382) DWFKAFYEKVAEKFKEHF, (SEQ ID NO: 383) DWFKAFYDKVADKFKEHF, (SEQ ID NO: 384) DWFKAFYDKVAEKFKDHF, (SEQ ID NO: 385) DWFKAFYDKVAEKFKEFH, (SEQ ID NO: 386) EWFKAFYEKVADKFKDFH, (SEQ ID NO: 387) EWFKAFYDKVAEKFKEFH, (SEQ ID NO: 388) DWFKAFYDKVAEKFKEFH, (SEQ ID NO: 389) DWFKAFYEKVAEKFKEFH, (SEQ ID NO: 390) DWFKAFYDKVAEKFKEFH, (SEQ ID NO: 391) DWFKAFYDKVAEKFKDFH, (SEQ ID NO: 392) FAEKFKEAVKDYFAKFWD, (SEQ ID NO: 393) FHEKFKEAVKDYFAKFWD, (SEQ ID NO: 394) FHEKFKEAVKEYFAKFWE, (SEQ ID NO: 395) FHDKFKDAVKDYFAKFWD, (SEQ ID NO: 396) FHDKFKDAVKEYFAKFWE, (SEQ ID NO: 397) FHDKFKEAVKDYFAKFWD, (SEQ ID NO: 398) FHEKFKDAVKDYFAKFWD, (SEQ ID NO: 399) FHEKFKEAVKEYFAKFWD, (SEQ ID NO: 400) FHEKFKEAVKDYFAKFWE, (SEQ ID NO: 401) HFEKFKEAVKDYFAKFWD, (SEQ ID NO: 402) HFDKFKDAVKEYFAKFWE, (SEQ ID NO: 403) HFEKFKEAVKEYFAKFWE, (SEQ ID NO: 404) HFDKFKEAVKDYFAKFWD, (SEQ ID NO: 405) HFEKFKDAVKDYFAKFWD, (SEQ ID NO: 406) HFEKFKEAVKEYFAKFWD, (SEQ ID NO: 407) HFEKFKEAVKDYFAKFWE, (SEQ ID NO: 408) FFEKHKEAVKDYFAKFWD, (SEQ ID NO: 409) FFDKHKDAVKEYFAKFWE, (SEQ ID NO: 410) FFEKHKEAVKEYFAKFWE, (SEQ ID NO: 411) FFDKHKDAVKDYFAKFWD, (SEQ ID NO: 412) FFDKHKEAVKDYFAKFWD, (SEQ ID NO: 413) FFEKHKEAVKEYFAKFWD, (SEQ ID NO: 414) FFEKHKEAVKDYFAKFWE, (SEQ ID NO: 415) FVEKFKEAHKDYFAKFWD, (SEQ ID NO: 416) FVDKFKDAHKEYFAKFWE, (SEQ ID NO: 417) FVEKFKEAHKEYFAKFWE, (SEQ ID NO: 418) FVDKFKDAHKDYFAKFWD, (SEQ ID NO: 419) FVDKFKEAHKDYFAKFWD, (SEQ ID NO: 420) FVEKFKDAHKDYFAKFWD, (SEQ ID NO: 421) FVEKFKEAHKEYFAKFWD, (SEQ ID NO: 422) FVEKFKEAHKDYFAKFWE, (SEQ ID NO: 423) FAEKFKEHVKDYFAKFWD, (SEQ ID NO: 424) FADKFKDHVKEYFAKFWE, (SEQ ID NO: 425) FAEKFKEHVKEYFAKFWE, (SEQ ID NO: 426) FADKFKDHVKDYFAKFWD, (SEQ ID NO: 427) FADKFKEHVKDYFAKFWD, (SEQ ID NO: 428) FAEKFKDHVKDYFAKFWD, (SEQ ID NO: 429) FAEKFKEHVKEYFAKFWD, (SEQ ID NO: 430) FAEKFKEHVKDYFAKFWE, (SEQ ID NO: 431) FAEKFKEFVKDYHAKFWD, (SEQ ID NO: 432) FADKFKDFVKEYHAKFWE, (SEQ ID NO: 433) FADKFKEFVKDYHAKFWD, (SEQ ID NO: 434) FAEKFKDFVKDYHAKFWD, (SEQ ID NO: 435) FADKFKDFVKDYHAKFWD, (SEQ ID NO: 436) FAEKFKEFVKEYHAKFWE, (SEQ ID NO: 437) FAEKFKEFVKEYHAKFWD, (SEQ ID NO: 438) FAEKFKEFVKDYHAKFWE, (SEQ ID NO: 439) FAEKFKEFVKDYFAKHWD, (SEQ ID NO: 440) FADKFKDFVKEYFAKHWE, (SEQ ID NO: 441) FAEKFKEFVKEYFAKHWE, (SEQ ID NO: 442) FADKFKDFVKDYFAKHWD, (SEQ ID NO: 443) FADKFKEFVKDYFAKHWD, (SEQ ID NO: 444) FAEKFKDFVKDYFAKHWD, (SEQ ID NO: 445) FAEKFKEFVKEYFAKHWD, (SEQ ID NO: 446) FAEKFKEFVKDYFAKHWE, (SEQ ID NO: 447) FAEKFKEAVKEYFAKFWE, (SEQ ID NO: 448) FADKFKDAVKDYFAKFWD, (SEQ ID NO: 449) FAERFREAVKDYFAKFWD, (SEQ ID NO: 450) FAEKFREAVKDYFAKFWD, (SEQ ID NO: 451) FAEKFKEAVRDYFAKFWD, (SEQ ID NO: 452) FAEKFKEAVKDYFARFWD, (SEQ ID NO: 453) FAEKFKEAVKEYFAKFWE, (SEQ ID NO: 454) FADKFKDAVKDYFAKFWD, (SEQ ID NO: 455) FAERFREAVKDYFAKFWD, (SEQ ID NO: 456) FAEKFREAVKDYFAKFWD, (SEQ ID NO: 457) FAEKFKEAVRDYFAKFWD, (SEQ ID NO: 458) FAEKFKEAVKDYFARFWD, (SEQ ID NO: 459) FAEKFKEAVKEYFAKFWE, (SEQ ID NO: 460) FADKFKDAVKDYFAKFWD, (SEQ ID NO: 461) FAERFREAVKDYFAKFWD, (SEQ ID NO: 462) FAEKFREAVKDYFAKFWD, (SEQ ID NO: 463) FAEKFKEAVRDYFAKFWD, (SEQ ID NO: 464) FAEKFKEAVKDYFARFWD, (SEQ ID NO: 465) FAERFREAVKDYFAKFWD, (SEQ ID NO: 466) FAEKFREAVKDYFAKFWD, (SEQ ID NO: 467) FAEKFKEAVRDYFAKFWD, (SEQ ID NO: 468) FAEKFKEAVKDYFARFWD, (SEQ ID NO: 469) FAEKFKEAVKEYFAKFWE, (SEQ ID NO: 470) FADKFKDAVKDYFAKFWD, (SEQ ID NO: 471) FAERFREAVKDYFAKFWD, (SEQ ID NO: 472) FAEKFREAVKDYFAKFWD, (SEQ ID NO: 473) FAEKFKEAVRDYFAKFWD, (SEQ ID NO: 474) FAEKFKEAVKDYFARFWD, (SEQ ID NO: 475) LFEKFAEAFKDYVAKWKD, (SEQ ID NO: 476) LFERFAEAFKDYVAKWKD, (SEQ ID NO: 477) LFEKFAEAFRDYVAKWKD, (SEQ ID NO: 478) LFEKFAEAFKDYVARWKD, (SEQ ID NO: 479) LFEKFAEAFKDYVAKWRD, (SEQ ID NO: 480) LFEKFAEAFKEYVAKWKE, (SEQ ID NO: 481) LFDKFADAFKDYVAKWKD, (SEQ ID NO: 482) LFDKFAEAFKDYVAKWKD, (SEQ ID NO: 483) LFEKFADAFKDYVAKWKD, (SEQ ID NO: 484) LFEKFAEAFKEYVAKWKD, (SEQ ID NO: 485) LFEKFAEAFKDYVAKWKE, (SEQ ID NO: 486) FAEKAWEFVKDYFAKLKD, (SEQ ID NO: 487) FAERAWEFVKDYFAKLKD, (SEQ ID NO: 488) FAEKAWEFVKDYFAKLKD, (SEQ ID NO: 489) FAEKAWEFVKDYFAKLKD, (SEQ ID NO: 490) FAEKAWEFVKDYFAKLRD, (SEQ ID NO: 491) FAEKAWEFVKEYFAKLKE, (SEQ ID NO: 492) FADKAWDFVKDYFAKLKD, (SEQ ID NO: 493) FADKAWEFVKDYFAKLKD, (SEQ ID NO: 494) FAEKAWDFVKDYFAKLKD, (SEQ ID NO: 495) FAEKAWEFVKEYFAKLKD, (SEQ ID NO: 496) FAEKAWEFVKDYFAKLKE, (SEQ ID NO: 497) FFEKFKEFVKDYFAKLWD, (SEQ ID NO: 498) FFEKFKEFVKEYFAKLWE, (SEQ ID NO: 499) FFDKFKDFVKDYFAKLWD, (SEQ ID NO: 500) FFERFKEFVKDYFAKLWD, (SEQ ID NO: 501) FFEKFREFVKDYFAKLWD, (SEQ ID NO: 502) FFEKFKEFVRDYFAKLWD, (SEQ ID NO: 503) FFEKFKEFVKDYFARLWD, (SEQ ID NO: 504) FFDKFKEFVKDYFAKLWD, (SEQ ID NO: 505) FFEKFKDFVKDYFAKLWD, (SEQ ID NO: 506) FFEKFKEFVKEYFAKLWD, (SEQ ID NO: 507) FFEKFKEFVKDYFAKLWE, (SEQ ID NO: 508) FLEKFKEFVKDYFAKFWD, (SEQ ID NO: 509) FLEKFKEFVKEYFAKFWE, (SEQ ID NO: 510) FLDKFKEFVKDYFAKFWD, (SEQ ID NO: 511) FLDKFKEFVKDYFAKFWD, (SEQ ID NO: 512) FLEKFKDFVKDYFAKFWD, (SEQ ID NO: 513) FLEKFKEFVKEYFAKFWD, (SEQ ID NO: 514) FLEKFKEFVKDYFAKFWE, (SEQ ID NO: 515) FLERFKEFVKDYFAKFWD, (SEQ ID NO: 516) FLEKFREFVKDYFAKFWD, (SEQ ID NO: 517) FLEKFKEFVRDYFAKFWD, (SEQ ID NO: 518) FLEKFKEFVKDYFARFWD, (SEQ ID NO: 519) FFEKFKEFFKDYFAKLWD, (SEQ ID NO: 520) FFEKFKEFFKEYFAKLWE, (SEQ ID NO: 521) FFDKFKDFFKDYFAKLWD, (SEQ ID NO: 522) FFERFKEFFKDYFAKLWD, (SEQ ID NO: 523) FFEKFREFFKDYFAKLWD, (SEQ ID NO: 524) FFEKFKEFFRDYFAKLWD, (SEQ ID NO: 525) FFERFKEFFKDYFARLWD, (SEQ ID NO: 526) FFDKFKEFFKDYFAKLWD, (SEQ ID NO: 527) FFEKFKDFFKDYFAKLWD, (SEQ ID NO: 528) FFEKFKEFFKEYFAKLWD, (SEQ ID NO: 529) FFEKFKEFFKDYFAKLWE, (SEQ ID NO: 530) FAEKFKEAVKDYFAKFWD, (SEQ ID NO: 531) FAEKFKEAVKEYFAKFWE, (SEQ ID NO: 532) FADKFKDAVKDYFAKFWD, (SEQ ID NO: 533) FAERFREAVKDYFAKFWD, (SEQ ID NO: 534) FAEKFREAVKDYFAKFWD, (SEQ ID NO: 535) FAEKFKEAVRDYFAKFWD, (SEQ ID NO: 536) FAEKFKEAVKDYFARFWD, (SEQ ID NO: 537) DKWKAVYDKFAEAFKEFF, (SEQ ID NO: 538) EKWKAVYEKFAEAFKEFF, (SEQ ID NO: 539) DKWKAVYDKFADAFKDFF, (SEQ ID NO: 540) DRWKAVYDKFAEAFKEFF, (SEQ ID NO: 541) DKWRAVYDKFAEAFKEFF, (SEQ ID NO: 542) DKWKAVYDRFAEAFKEFF, (SEQ ID NO: 543) DKWKAVYDKFAEAFREFF, (SEQ ID NO: 544) FFEKFAEAFKDYVAKWKD, (SEQ ID NO: 545) FFEKFAEAFKEYVAKWKE, (SEQ ID NO: 546) FFDKFADAFKDYVAKWKD, (SEQ ID NO: 547) FFERFAEAFKDYVAKWKD, (SEQ ID NO: 548) FFERFAEAFRDYVAKWKD, (SEQ ID NO: 549) FFEKFAEAFKDYVARWKD, (SEQ ID NO: 550) FFERFAEAFKDYVAKWRD, (SEQ ID NO: 551) FFDKFAEAFKDYVAKWKD, (SEQ ID NO: 552) FFEKFADAFKDYVAKWKD, (SEQ ID NO: 553) FFERFAEAFKEYVAKWKD, (SEQ ID NO: 554) FFERFAEAFKDYVAKWKE, (SEQ ID NO: 555) FFEKFKEFFKDYFAKFWD, (SEQ ID NO: 556) FFDKFKDFFKDYFAKFWD, (SEQ ID NO: 557) FFEKFKEFFKEYFAKFWE, (SEQ ID NO: 558) FFERFKEFFKDYFAKFWD, (SEQ ID NO: 559) FFEKFREFFKDYFAKFWD, (SEQ ID NO: 560) FFEKFKEFFRDYFAKFWD, (SEQ ID NO: 561) FFEKFKEFFKDYFARFWD, (SEQ ID NO: 562) FFDKFKEFFKDYFAKFWD, (SEQ ID NO: 563) FFEKFKDFFKDYFAKFWD, (SEQ ID NO: 564) FFEKFKEFFKEYFAKFWD, (SEQ ID NO: 565) FFEKFKEFFKDYFAKFWE, (SEQ ID NO: 566) EVRAKLEEQAQQIRLQAEAFQARLKSWFEPLVE, (SEQ ID NO: 567) EVRAKLEEQAQQIRLQAEAFQARLKSWFE, (SEQ ID NO: 568) EVRSKLEEWFAAFREFAEEFLARLKS, (SEQ ID NO: 569) PVLDLFRELLNELLEALKQKLK, (SEQ ID NO: 570) DWLKAFYDKVAEKLKEAFPDWAKAAYDKAAEKAKEAA, (SEQ ID NO: 571) EELKEKLEELKEKLEEKLPEELKEKLEELKEKLEEKL, (SEQ ID NO: 572) EELKAKLEELKAKLEEKLPEELKAKLEELKAKLEEKL, (SEQ ID NO: 573) EKLKALLEKLLAKLKELLPEKLKALLEKLLAKLKELL, (SEQ ID NO: 574) EWLKELLEKLLEKLKELLPEWLKELLEKLLEKLKELL, (SEQ ID NO: 575) EKFKELLEKFLEKFKELLPEKFKELLEKFLEKFKELL, (SEQ ID NO: 576) EKLKELLEKLLELLKKLLPEKLKELLEKLLELLKKLL, (SEQ ID NO: 577) EKLKELLEKLKAKLEELLPEKLKELLEKLKAKLEELL, (SEQ ID NO: 578) EKLKELLEKLLAKLKELLPEKLKELLEKLLAKLKELL, (SEQ ID NO: 579) EKFKELLEKLLEKLKELLPEKFKELLEKLLEKLKELL, (SEQ ID NO: 580) EKLKAKLEELKAKLEELLPEKLKAKLEELKAKLEELL, (SEQ ID NO: 581) EELKELLKELLKKLEKLLPELKELLKELLKKLEKLL, (SEQ ID NO: 582) EELKKLLEELLKKLKELLPEELKKLLEELLKKLKELL, (SEQ ID NO: 583) EKLKELLEKLLEKLKELLAEKLKELLEKLLEKLKELL, (SEQ ID NO: 584) EKLKELLEKLLEKLKELLAAEKLKELLEKLLEKLKELL, (SEQ ID NO: 585) EKLKAKLEELKAKLEELLPEKAKAALEEAKAKAEELA, (SEQ ID NO: 586) EKLKAKLEELKAKLEELLPEHAKAALEEAKCKAEELA, (SEQ ID NO: 587) DHLKAFYDKVACKLKEAFPDWAKAAYDKAAEKAKEAA, (SEQ ID NO: 588) DWLKAFYDKVAEKLKEAFPDHAKAAYDKAACKAKEAA, (SEQ ID NO: 589) DWLKAFYDKVACKLKEAFPDWAKAAYNKAAEKAKEAA, (SEQ ID NO: 590) DHLKAFYDKVAEKLKEAFPDWAKAAYDKAAEKAKEAA, (SEQ ID NO: 591) VLESFKVSFLSALEEYTKKLNTQ, (SEQ ID NO: 592) DKWKAVYDKFAEAFKEFL, (SEQ ID NO: 593) DKLKAFYDKVFEWAKEAF, (SEQ ID NO: 595) DQYYLRVTTVA, (SEQ ID NO: 596) ECKPCLKQTCMKFYARVCR, (SEQ ID NO: 597) FSRASSIIDELFQD, (SEQ ID NO: 598) IQNAVNGVKQIKTLIEKTNEE, (SEQ ID NO: 599) LLEQLNEQFNWVSRLANL, (SEQ ID NO: 600) LLEQLNEQFNWVSRLANLTEGE, (SEQ ID NO: 601) LLEQLNEQFNWVSRLANLTQGE, (SEQ ID NO: 602) LVGRQLEEFL, (SEQ ID NO: 603) MNGDRIDSLLEN, (SEQ ID NO: 604) NELQEMSNQGSKYVNKEIQNAVNGV, (SEQ ID NO: 605) PCLKQTCMKFYARVCR, (SEQ ID NO: 606) PFLEMIHEAQQAMDI, (SEQ ID NO: 607) PGVCNETMMALWEECK, (SEQ ID NO: 608) PKFMETVAEKALQEYRKKHRE, (SEQ ID NO: 609) PSGVTEVVVKLFDS, (SEQ ID NO: 610) PSQAKLRRELDESLQVAERLTRKYNELLKSYQ, (SEQ ID NO: 611) PTEFIREGDDD, (SEQ ID NO: 612) QQTHMLDVMQD, (SEQ ID NO: 613) RKTLLSNLEEAKKKKEDALNETRESETKLKEL, (SEQ ID NO: 614) RMKDQCDKCREILSV, (SEQ ID NO: 615) GVFAKIFKWISGLFKKIG, (SEQ ID NO: 616) GIKKFLGSIWKFIKAFVG, (SEQ ID NO: 617) GFKKFLGSWAKIYKAFVG, (SEQ ID NO: 618) GFRRFLGSWARIYRAFVG, (SEQ ID NO: 619) TEELRVRLASHLRKLRKRLL, (SEQ ID NO: 620) TEELRVRLASHLRKLRK, (SEQ ID NO: 621) LRVRLASHLRKLRKRLL, (SEQ ID NO: 622) RLASHLRKLRKRLL, (SEQ ID NO: 623) SHLRKLRKRLL, (SEQ ID NO: 624) LRKLRKRLL, (SEQ ID NO: 625) LRKLRKRLLLRKLRKRLL, (SEQ ID NO: 626) LRKLRKRLLLRKLRKRLLLRKLRKRLL, (SEQ ID NO: 627) RQIKIWFQNRRMKWKKCLRVRLASHLRKLRKRLL, (SEQ ID NO: 628) LRVRLASHLRKLRKRLL, (SEQ ID NO: 629) EELRVRLASHLRKLRKRLLRDADDLQKRLAVYEEQAQQIRLQAEAFQA RLKSWFEPLVEDM, (SEQ ID NO: 630) CEELRVRLASHLRKLRKRLLRDADDLQKRLAVY, (SEQ ID NO: 631) LRKLRKRLLRDADDLLRKLRKRLLRDADDL, (SEQ ID NO: 632) TEELRVRLASHLRKLRKRLL, (SEQ ID NO: 633) TEELRVRLASHLEKLRKRLL, (SEQ ID NO: 634) TEELRVRLASHLRELRKRLL, (SEQ ID NO: 635) LREKKLRVSALRTHRLELRL, (SEQ ID NO: 636) LRKLRKRLLRDWLKAFYDKVAEKLKEAF, (SEQ ID NO: 637) LRRLRRRLLRDWLKAFYDKVAEKLKEAF, and (SEQ ID NO: 638) RRRRRRRRRRDWLKAFYDKVAEKLKEAF. Embodiment 36 The method according to any one of embodiments 1-35, wherein said ezetimibe-associated apoA-I mimetic pepide is effective to decrease plasma total cholesterol in said mammal, and/or to decrease plasma plasma triglyceride in said mammal, and/or to decrease plasma 5-HETE in said mammal, and/or to decrease plasma 12-HETE in said mammal, and/or to decrease plasma 15-HETE in said mammal, and/or to decrease SAA levels in said mammal, and/or to increase plasma paraoxonase activity in said mammal, and/or to decrease plasma levels of lyophosphatidic acid (LPA) in a mammal when fed to said mammal alone or as a component of a food or diet. Embodiment 37 The method according to any one of embodiments 1-36, wherein said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma total cholesterol to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide. Embodiment 38 The method according to any one of embodiments 1-37, wherein said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma triglyceride, and/or raises plasma HDL cholesterol to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide. Embodiment 39 The method according to any one of embodiments 1-38, wherein said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma 5-HETE to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide. Embodiment 40 The method according to any one of embodiments 1-39, wherein said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma 12-HETE to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide. Embodiment 41 The method according to any one of embodiments 1-40, wherein said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma 15-HETE to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide. Embodiment 42 The method according to any one of embodiments 1-41, wherein said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma SAA to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide. Embodiment 43 An ezetimibe-associated apoA-I mimetic peptide, wherein said ezetimibe associated apoA-I mimetic has greater biological activity than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide. Embodiment 44 The ezetimibe-associated apoA-I mimetic peptide of embodiment 43, wherein said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma total cholesterol to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide. Embodiment 45 The ezetimibe-associated apoA-I mimetic peptide according to any one of embodiments 43-44, wherein said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma triglyceride, and/or raises plasma HDL cholesterol to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide. Embodiment 46 The ezetimibe-associated apoA-I mimetic peptide according to any one of embodiments 43-45, wherein said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma 5-HETE to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide. Embodiment 47 The ezetimibe-associated apoA-I mimetic peptide according to any one of embodiments 43-46, wherein said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma 12-HETE to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide. Embodiment 48 The ezetimibe-associated apoA-I mimetic peptide according to any one of embodiments 43-47, wherein said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma 15-HETE to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide. Embodiment 49 The ezetimibe-associated apoA-I mimetic peptide according to any one of embodiments 43-48, wherein said ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma SAA to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide. Embodiment 50 The ezetimibe-associated apoA-I mimetic peptide according to any one of embodiments 43-49, wherein said apoA-I mimetic peptide is a chemically synthesized peptide. Embodiment 51 The ezetimibe-associated apoA-I mimetic peptide according to any one of embodiments 43-49 is a peptide recombinantly expressed in a plant cell. Embodiment 52 The ezetimibe-associated apoA-I mimetic peptide of embodiment 51, wherein said apoA-I mimetic peptide is derived from a tissue of a transgenic plant wherein said tissue contains a heterologous ApoA-I mimetic peptide expressed by said plant. Embodiment 53 The ezetimibe-associated apoA-I mimetic peptide according to any one of embodiments 43-52, wherein said ApoA-I mimetic peptide comprises the amino acid sequence DWLKAFYDKFFEKFKEFF (6F) (SEQ ID NO:1). Embodiment 54 The ezetimibe-associated apoA-I mimetic peptide according to any one of embodiments 43-52, wherein said ApoA-I mimetic peptide comprises the amino acid sequence FFEKFKEFFKDYFAKLWD (rev6F) (SEQ ID NO:15). Embodiment 55 The ezetimibe-associated apoA-I mimetic peptide according to any one of embodiments 43-52, wherein said ApoA-I mimetic peptide comprises the amino acid sequence DWFKAFYDKVAEKFKEAF (4F) (SEQ ID NO:6). Embodiment 56 The ezetimibe-associated apoA-I mimetic peptide according to any one of embodiments 43-52, wherein said ApoA-I mimetic peptide comprises the amino acid sequence FAEKFKEAVKDYFAKFWD (rev4F) (SEQ ID NO:13). Embodiment 57 The ezetimibe-associated apoA-I mimetic peptide according to any one of embodiments 43-52, wherein said ApoA-I mimetic peptide comprises the amino acid sequence, LLEQLNEQFNWVSRLANL. Embodiment 58 The ezetimibe-associated apoA-I mimetic peptide according to any one of embodiments 43-52, wherein said ApoA-I mimetic peptide comprises the amino acid sequence LVGRQLEEFL. Embodiment 59 The ezetimibe-associated apoA-I mimetic peptide according to any one of embodiments 43-52, wherein said ApoA-I mimetic peptide comprises an amino acid sequence selected from the group consisting of (SEQ ID NO: 1) DWLKAFYDKFFEKFKEFF, (SEQ ID NO: 2) DWLKAFYDKVAEKLKEAF, (SEQ ID NO: 3) DWLKAFYDKVAEKLKEAF, (SEQ ID NO: 4) DWFKAFYDKVAEKLKEAF, (SEQ ID NO: 5) DWLKAFYDKVAEKFKEAF, (SEQ ID NO: 6) DWFKAFYDKVAEKFKEAF, (SEQ ID NO: 7) DWLKAFYDKVFEKFKEFF, (SEQ ID NO: 1) DWLKAFYDKFFEKFKEFF, (SEQ ID NO: 8) DWFKAFYDKFFEKFKEFF, (SEQ ID NO: 9) DWLKAFYDKVAEKLKEFF, (SEQ ID NO: 10) FAEKLKEAVKDYFAKLWD, (SEQ ID NO: 11) FAEKLKEAVKDYFAKLWD, (SEQ ID NO: 12) FAEKLKEAVKDYFAKFWD, (SEQ ID NO: 13) FAEKFKEAVKDYFAKFWD, (SEQ ID NO: 14) FFEKFKEFVKDYFAKLWD, (SEQ ID NO: 15) FFEKFKEFFKDYFAKLWD, (SEQ ID NO: 16) FFEKFKEFFKDYFAKFWD, (SEQ ID NO: 17) DWLKAFYDKVFEKFKEAF, (SEQ ID NO: 18) DWLKAFYDKVFEKLKEFF, (SEQ ID NO: 19) DWLKAFYDKVAEKFKEFF, (SEQ ID NO: 20) DWLKAFYDKVFEKFKEFF, (SEQ ID NO: 21) EWLKLFYEKVLEKFKEAF, (SEQ ID NO: 22) EWLKAFYDKVAEKFKEAF, (SEQ ID NO: 23) EWLKAFYDKVAEKLKEFF, (SEQ ID NO: 24) EWLKAFYDKVFEKFKEAF, (SEQ ID NO: 25) EWLKAFYDKVFEKLKEFF, (SEQ ID NO: 26) EWLKAFYDKVAEKFKEFF, (SEQ ID NO: 27) EWLKAFYDKVFEKFKEFF, (SEQ ID NO: 28) AFYDKVAEKLKEAF, (SEQ ID NO: 29) AFYDKVAEKFKEAF, (SEQ ID NO: 30) AFYDKVAEKFKEAF, (SEQ ID NO: 31) AFYDKFFEKFKEFF, (SEQ ID NO: 32) AFYDKFFEKFKEFF, (SEQ ID NO: 33) AFYDKVAEKFKEAF, (SEQ ID NO: 34) AFYDKVAEKLKEFF, (SEQ ID NO: 35) AFYDKVFEKFKEAF, (SEQ ID NO: 36) AFYDKVFEKLKEFF, (SEQ ID NO: 37) AFYDKVAEKFKEFF, (SEQ ID NO: 38) KAFYDKVFEKFKEF, (SEQ ID NO: 39) LFYEKVLEKFKEAF, (SEQ ID NO: 40) AFYDKVAEKFKEAF, (SEQ ID NO: 41) AFYDKVAEKLKEFF, (SEQ ID NO: 42) AFYDKVFEKFKEAF, (SEQ ID NO: 43) AFYDKVFEKLKEFF, (SEQ ID NO: 44) AFYDKVAEKFKEFF, (SEQ ID NO: 45) AFYDKVFEKFKEFF, (SEQ ID NO: 46) DWLKALYDKVAEKLKEAL, (SEQ ID NO: 47) DWFKAFYEKVAEKLKEFF, (SEQ ID NO: 48) DWFKAFYEKFFEKFKEFF, (SEQ ID NO: 49) EWLKALYEKVAEKLKEAL, (SEQ ID NO: 50) EWLKAFYEKVAEKLKEAF, (SEQ ID NO: 51) EWFKAFYEKVAEKLKEFF, (SEQ ID NO: 52) EWLKAFYEKVFEKFKEFF, (SEQ ID NO: 53) EWLKAFYEKFFEKFKEFF, (SEQ ID NO: 54) EWFKAFYEKFFEKFKEFF, (SEQ ID NO: 55) DFLKAWYDKVAEKLKEAW, (SEQ ID NO: 56) EFLKAWYEKVAEKLKEAW, (SEQ ID NO: 57) DFWKAWYDKVAEKLKEWW, (SEQ ID NO: 58) EFWKAWYEKVAEKLKEWW, (SEQ ID NO: 59) DKLKAFYDKVFEWAKEAF, (SEQ ID NO: 60) DKWKAVYDKFAEAFKEFL, (SEQ ID NO: 61) EKLKAFYEKVFEWAKEAF, (SEQ ID NO: 62) EKWKAVYEKFAEAFKEFL, (SEQ ID NO: 63) DWLKAFVDKFAEKFKEAY, (SEQ ID NO: 64) EKWKAVYEKFAEAFKEFL, (SEQ ID NO: 65) DWLKAFVYDKVFKLKEFF, (SEQ ID NO: 66) EWLKAFVYEKVFKLKEFF, (SEQ ID NO: 67) DWLRAFYDKVAEKLKEAF, (SEQ ID NO: 68) EWLRAFYEKVAEKLKEAF, (SEQ ID NO: 69) DWLKAFYDRVAEKLKEAF, (SEQ ID NO: 70) EWLKAFYERVAEKLKEAF, (SEQ ID NO: 71) DWLKAFYDKVAERLKEAF, (SEQ ID NO: 72) EWLKAFYEKVAERLKEAF, (SEQ ID NO: 73) DWLKAFYDKVAEKLREAF, (SEQ ID NO: 74) EWLKAFYEKVAEKLREAF, (SEQ ID NO: 75) DWLKAFYDRVAERLKEAF, (SEQ ID NO: 76) EWLKAFYERVAERLKEAF, (SEQ ID NO: 77) DWLRAFYDKVAEKLREAF, (SEQ ID NO: 78) EWLRAFYEKVAEKLREAF, (SEQ ID NO: 79) DWLRAFYDRVAEKLKEAF, (SEQ ID NO: 80) EWLRAFYERVAEKLKEAF, (SEQ ID NO: 81) DWLKAFYDKVAERLREAF, (SEQ ID NO: 82) EWLKAFYEKVAERLREAF, (SEQ ID NO: 83) DWLRAFYDKVAERLKEAF, (SEQ ID NO: 84) EWLRAFYEKVAERLKEAF, (SEQ ID NO: 85) DWLKAFYDKVAEKLKEAFPDWLKAFYDKVAEKLKEAF, (SEQ ID NO: 86) DWLKAFYDKVAEKLKEFFPDWLKAFYDKVAEKLKEFF, (SEQ ID NO: 87) DWFKAFYDKVAEKLKEAFPDWFKAFYDKVAEKLKEAF, (SEQ ID NO: 88) DKLKAFYDKVFEWAKEAFPDKLKAFYDKVFEWLKEAF, (SEQ ID NO: 89) DKWKAVYDKFAEAFKEFLPDKWKAVYDKFAEAFKEFL, (SEQ ID NO: 90) DWFKAFYDKVAEKFKEAFPDWFKAFYDKVAEKFKEAF, (SEQ ID NO: 91) DWLKAFVYDKVFKLKEFFPDWLKAFVYDKVFKLKEFF, (SEQ ID NO: 92) DWLKAFYDKFAEKFKEFFPDWLKAFYDKFAEKFKEFF, (SEQ ID NO: 93) EWFKAFYEKVAEKFKEAF, (SEQ ID NO: 94) DWFKAFYDKVAEKF, (SEQ ID NO: 95) FKAFYDKVAEKFKE, (SEQ ID NO: 96) FKAFYEKVAEKFKE, (SEQ ID NO: 97) FKAFYDKVAEKFKE, (SEQ ID NO: 98) FKAFYEKVAEKFKE, (SEQ ID NO: 99) DWFKAFYDKVAEKFKEAF, (SEQ ID NO: 100) EWFKAFYEKVAEKFKEAF, (SEQ ID NO: 101) AFYDKVAEKFKEAF, (SEQ ID NO: 102) DWFKAFYDKVAEKF, (SEQ ID NO: 103) DWLKAFYDKVFEKFKEFF, (SEQ ID NO: 104) EWLKAFYEKVFEKFKEFF, (SEQ ID NO: 105) AFYDKVFEKFKEFF, (SEQ ID NO: 106) AFYEKVFEKFKEFF, (SEQ ID NO: 107) DWLKAFYDKVFEKF, (SEQ ID NO: 108) EWLKAFYEKVFEKF, (SEQ ID NO: 109) LKAFYDKVFEKFKE, (SEQ ID NO: 110) LKAFYEKVFEKFKE, (SEQ ID NO: 111) EWFKAFYEKVADKFKDAF, (SEQ ID NO: 112) EWFKAFYDKVADKFKEAF, (SEQ ID NO: 113) DWFKAFYEKVADKFKEAF, (SEQ ID NO: 114) DWFKAFYEKVAEKFKDAF, (SEQ ID NO: 115) DFWKAFYDKVAEKFKEAF, (SEQ ID NO: 116) EFWKAFYEKVADKFKDAF, (SEQ ID NO: 117) EFWKAFYDKVADKFKEAF, (SEQ ID NO: 118) DFWKAFYEKVADKFKEAF, (SEQ ID NO: 119) DFWKAFYEKVAEKFKDAF, (SEQ ID NO: 120) DWFKAYFDKVAEKFKEAF, (SEQ ID NO: 121) EWFKAYFEKVADKFKDAF, (SEQ ID NO: 122) EWFKAYFDKVADKFKEAF, (SEQ ID NO: 123) DWFKAYFEKVADKFKEAF, (SEQ ID NO: 124) DWFKAYFEKVAEKFKDAF, (SEQ ID NO: 125) DWFKAFVDKYAEKFKEAF, (SEQ ID NO: 126) EWFKAFVEKYADKFKDAF, (SEQ ID NO: 127) EWFKAFVDKYADKFKEAF, (SEQ ID NO: 128) DWFKAFVEKYADKFKEAF, (SEQ ID NO: 129) DWFKAFVEKYAEKFKDAF, (SEQ ID NO: 130) DWFKAFYDKAVEKFKEAF, (SEQ ID NO: 131) EWFKAFYEKAVDKFKDAF, (SEQ ID NO: 132) EWFKAFYDKAVDKFKEAF, (SEQ ID NO: 133) DWFKAFYEKAVDKFKEAF, (SEQ ID NO: 134) DWFKAFYEKAVEKFKDAF, (SEQ ID NO: 135) DWFKAFYDKVFEKAKEAF, (SEQ ID NO: 136) EWFKAFYEKVFDKAKDAF, (SEQ ID NO: 137) EWFKAFYDKVFDKAKEAF, (SEQ ID NO: 138) DWFKAFYEKVFDKAKEAF, (SEQ ID NO: 139) DWFKAFYEKVFEKAKDAF, (SEQ ID NO: 140) DWFKAFYDKVAEKAKEFF, (SEQ ID NO: 141) EWFKAFYEKVADKAKDFF, (SEQ ID NO: 142) EWFKAFYDKVADKAKEFF, (SEQ ID NO: 143) DWFKAFYEKVADKAKEFF, (SEQ ID NO: 144) DWFKAFYEKVAEKAKDFF, (SEQ ID NO: 145) DWFKAFYDKVAEKFKEFA, (SEQ ID NO: 146) EWFKAFYEKVADKFKDFA, (SEQ ID NO: 147) EWFKAFYDKVADKFKEFA, (SEQ ID NO: 148) DWFKAFYEKVADKFKEFA, (SEQ ID NO: 149) DWFKAFYEKVAEKFKDFA, (SEQ ID NO: 150) DAFKAFYDKVAEKFKEWF, (SEQ ID NO: 151) EAFKAFYEKVADKFKDWF, (SEQ ID NO: 152) EAFKAFYDKVADKFKEWF, (SEQ ID NO: 153) DAFKAFYEKVADKFKEWF, (SEQ ID NO: 154) DAFKAFYEKVAEKFKDWF, (SEQ ID NO: 155) DAFKAFYDKVWEKFKEAF, (SEQ ID NO: 156) EAFKAFYEKVWDKFKDAF, (SEQ ID NO: 157) EAFKAFYDKVWDKFKEAF, (SEQ ID NO: 158) DAFKAFYEKVWDKFKEAF, (SEQ ID NO: 159) DAFKAFYEKVWEKFKDAF, (SEQ ID NO: 160) DYFKAFWDKVAEKFKEAF, (SEQ ID NO: 161) EYFKAFWEKVADKFKDAF, (SEQ ID NO: 162) EYFKAFWDKVADKFKEAF, (SEQ ID NO: 163) DYFKAFWEKVADKFKEAF, (SEQ ID NO: 164) DYFKAFWEKVAEKFKDAF, (SEQ ID NO: 165) DWAKAFYDKVAEKFKEFF, (SEQ ID NO: 166) EWAKAFYEKVADKFKDFF, (SEQ ID NO: 167) EWAKAFYDKVADKFKEFF, (SEQ ID NO: 168) DWAKAFYEKVADKFKEFF, (SEQ ID NO: 169) DWAKAFYEKVAEKFKDFF, (SEQ ID NO: 170) DWFKAAYDKVAEKFKEFF, (SEQ ID NO: 171) EWFKAAYEKVADKFKDFF, (SEQ ID NO: 172) EWFKAAYDKVADKFKEFF, (SEQ ID NO: 173) DWFKAAYEKVADKFKEFF, (SEQ ID NO: 174) DWFKAAYEKVAEKFKDFF, (SEQ ID NO: 175) DWFKAFADKVAEKFKEYF, (SEQ ID NO: 176) EWFKAFAEKVADKFKDYF, (SEQ ID NO: 177) EWFKAFADKVADKFKEYF, (SEQ ID NO: 178) DWFKAFAEKVADKFKEYF, (SEQ ID NO: 179) DWFKAFAEKVAEKFKDYF, (SEQ ID NO: 180) DWFKAFYDKAAEKFKEVF, (SEQ ID NO: 181) EWFKAFYEKAADKFKDVF, (SEQ ID NO: 182) EWFKAFYDKAADKFKEVF, (SEQ ID NO: 183) DWFKAFYEKAADKFKEVF, (SEQ ID NO: 184) DWFKAFYEKAAEKFKDVF, (SEQ ID NO: 185) DWYKAFFDKVAEKFKEAF, (SEQ ID NO: 186) EWYKAFFEKVADKFKDAF, (SEQ ID NO: 187) EWYKAFFDKVADKFKEAF, (SEQ ID NO: 188) DWYKAFFEKVADKFKEAF, (SEQ ID NO: 189) DWYKAFFEKVAEKFKDAF, (SEQ ID NO: 190) DWVKAFYDKFAEKFKEAF, (SEQ ID NO: 191) EWVKAFYEKFADKFKDAF, (SEQ ID NO: 192) EWVKAFYDKFADKFKEAF, (SEQ ID NO: 193) DWVKAFYEKFADKFKEAF, (SEQ ID NO: 194) DWVKAFYEKFAEKFKDAF, (SEQ ID NO: 195) DWFKAFFDKVAEKYKEAF, (SEQ ID NO: 196) EWFKAFFEKVADKYKDAF, (SEQ ID NO: 197) EWFKAFFDKVADKYKEAF, (SEQ ID NO: 198) DWFKAFFEKVADKYKEAF, (SEQ ID NO: 199) DWFKAFFEKVADKYKEAF, (SEQ ID NO: 200) DWFKAFFDKVAEKFKEAY, (SEQ ID NO: 201) EWFKAFFEKVADKFKDAY, (SEQ ID NO: 202) EWFKAFFDKVADKFKEAY, (SEQ ID NO: 203) DWFKAFFEKVADKFKEAY, (SEQ ID NO: 204) DWFKAFFEKVAEKFKDAY, (SEQ ID NO: 205) DWFKAFYDKFAEKFKEAV, (SEQ ID NO: 206) EWFKAFYEKFADKFKDAV, (SEQ ID NO: 207) EWFKAFYDKFADKFKEAV, (SEQ ID NO: 208) DWFKAFYEKFADKFKEAV, (SEQ ID NO: 209) DWFKAFYEKFAEKFKDAV, (SEQ ID NO: 210) DKFKAFYDKVAEKFWEAF, (SEQ ID NO: 211) EKFKAFYEKVADKFWDAF, (SEQ ID NO: 212) EKFKAFYDKVADKFWEAF, (SEQ ID NO: 213) DKFKAFYEKVADKFWEAF, (SEQ ID NO: 214) DKFKAFYEKVAEKFWDAF, (SEQ ID NO: 215) DKWKAFYDKVAEKFFEAF, (SEQ ID NO: 216) EKWKAFYEKVADKFFDAF, (SEQ ID NO: 217) EKWKAFYDKVADKFFEAF, (SEQ ID NO: 218) DKWKAFYEKVADKFFEAF, (SEQ ID NO: 219) DKWKAFYEKVAEKFFDAF, (SEQ ID NO: 220) DKFKAFYDKWAEVFKEAF, (SEQ ID NO: 221) EKFKAFYEKWADVFKDAF, (SEQ ID NO: 222) EKFKAFYDKWADVFKEAF, (SEQ ID NO: 223) DKFKAFYEKWADVFKEAF, (SEQ ID NO: 224) DKFKAFYEKWAEVFKDAF, (SEQ ID NO: 225) DKFKAFYDKVAEFWKEAF, (SEQ ID NO: 226) EKFKAFYEKVADFWKDAF, (SEQ ID NO: 227) EKFKAFYDKVADFWKEAF, (SEQ ID NO: 228) DKFKAFYEKVADFWKEAF, (SEQ ID NO: 229) DKFKAFYEKVAEFWKDAF, (SEQ ID NO: 230) FAEKFKEAVKDYFAKFWD, (SEQ ID NO: 231) FADKFKDAVKEYFAKFWE, (SEQ ID NO: 232) FADKFKEAVKDYFAKFWE, (SEQ ID NO: 233) FAEKFKDAVKEYFAKFWD, (SEQ ID NO: 234) FAEKFKDAVKDYFAKFWE, (SEQ ID NO: 235) FWEKFKEAVKDYFAKFAD, (SEQ ID NO: 236) FWDKFKDAVKEYFAKFAE, (SEQ ID NO: 237) FADKFKEAVKDYFAKFWE, (SEQ ID NO: 238) FAEKFKDAVKEYFAKFWD, (SEQ ID NO: 239) FAEKFKDAVKDYFAKFWE, (SEQ ID NO: 240) FFEKFKEAVKDYFAKAWD, (SEQ ID NO: 241) FFDKFKDAVKEYFAKAWE, (SEQ ID NO: 242) FFDKFKEAVKDYFAKAWE, (SEQ ID NO: 243) FFEKFKDAVKEYFAKAWD, (SEQ ID NO: 244) FFEKFKDAVKDYFAKAWE, (SEQ ID NO: 245) FAEKAKEFVKDYFAKFWD, (SEQ ID NO: 246) FADKAKDFVKEYFAKFWE, (SEQ ID NO: 247) FADKAKEFVKDYFAKFWE, (SEQ ID NO: 248) FAEKAKDFVKEYFAKFWD, (SEQ ID NO: 249) FAEKAKDFVKDYFAKFWE, (SEQ ID NO: 250) FAEKFKEVAKDYFAKFWD, (SEQ ID NO: 251) FADKFKDVAKEYFAKFWE, (SEQ ID NO: 252) FADKFKEVAKDYFAKFWE, (SEQ ID NO: 253) FAEKFKDVAKEYFAKFWD, (SEQ ID NO: 254) FAEKFKDVAKDYFAKFWE, (SEQ ID NO: 255) FAEKFKEAYKDVFAKFWD, (SEQ ID NO: 256) FADKFKDAYKEVFAKFWE, (SEQ ID NO: 257) FADKFKEAYKDVFAKFWE, (SEQ ID NO: 258) FAEKFKDAYKEVFAKFWD, (SEQ ID NO: 259) FAEKFKDAYKDVFAKFWE, (SEQ ID NO: 260) FAEKFKEAVKDFYAKFWD, (SEQ ID NO: 261) FADKFKDAVKEFYAKFWE, (SEQ ID NO: 262) FADKFKEAVKDFYAKFWE, (SEQ ID NO: 263) FAEKFKDAVKEFYAKFWD, (SEQ ID NO: 264) FAEKFKDAVKDFYAKFWE, (SEQ ID NO: 265) FAEKFWEAVKDYFAKFKD, (SEQ ID NO: 266) FADKFWDAVKEYFAKFKE, (SEQ ID NO: 267) FADKFWEAVKDYFAKFKE, (SEQ ID NO: 268) FAEKFWDAVKEYFAKFKD, (SEQ ID NO: 269) FAEKFWDAVKDYFAKFKE, (SEQ ID NO: 270) AFEKFKEAVKDYFAKFWD, (SEQ ID NO: 271) AFDKFKDAVKEYFAKFWE, (SEQ ID NO: 272) AFDKFKEAVKDYFAKFWE, (SEQ ID NO: 273) AFEKFKDAVKEYFAKFWD, (SEQ ID NO: 274) AFEKFKDAVKDYFAKFWE, (SEQ ID NO: 275) VAEKFKEAFKDYFAKFWD, (SEQ ID NO: 276) VADKFKDAFKEYFAKFWE, (SEQ ID NO: 277) VADKFKEAFKDYFAKFWE, (SEQ ID NO: 278) VAEKFKDAFKEYFAKFWD, (SEQ ID NO: 279) VAEKFKDAFKDYFAKFWE, (SEQ ID NO: 280) YAEKFKEAVKDFFAKFWD, (SEQ ID NO: 281) YADKFKDAVKEFFAKFWE, (SEQ ID NO: 282) YADKFKEAVKDFFAKFWE, (SEQ ID NO: 283) YAEKFKDAVKEFFAKFWD, (SEQ ID NO: 284) YAEKFKDAVKDFFAKFWE, (SEQ ID NO: 285) AAEKFKEFVKDYFAKFWD, (SEQ ID NO: 286) AADKFKDFVKEYFAKFWE, (SEQ ID NO: 287) AADKFKEFVKDYFAKFWE, (SEQ ID NO: 288) AAEKFKDFVKEYFAKFWD, (SEQ ID NO: 289) AAEKFKDFVKDYFAKFWE, (SEQ ID NO: 290) FFEKAKEAVKDYFAKFWD, (SEQ ID NO: 291) FFDKAKDAVKEYFAKFWE, (SEQ ID NO: 292) FFDKAKEAVKDYFAKFWE, (SEQ ID NO: 293) FFEKAKDAVKEYFAKFWD, (SEQ ID NO: 294) FFEKAKDAVKDYFAKFWE, (SEQ ID NO: 295) FYEKFKEAVKDAFAKFWD, (SEQ ID NO: 296) FYDKFKDAVKEAFAKFWE, (SEQ ID NO: 297) FYDKFKEAVKDAFAKFWE, (SEQ ID NO: 298) FYEKFKDAVKEAFAKFWD, (SEQ ID NO: 299) FYEKFKDAVKDAFAKFWE, (SEQ ID NO: 300) FVEKFKEAAKDYFAKFWD, (SEQ ID NO: 301) FVDKFKDAAKEYFAKFWE, (SEQ ID NO: 302) FVDKFKEAAKDYFAKFWE, (SEQ ID NO: 303) FVEKFKDAAKEYFAKFWD, (SEQ ID NO: 304) FVEKFKDAAKDYFAKFWE, (SEQ ID NO: 305) FAEKYKEAVKDFFAKFWD, (SEQ ID NO: 306) FADKYKDAVKEFFAKFWE, (SEQ ID NO: 307) FADKYKEAVKDFFAKFWE, (SEQ ID NO: 308) FAEKYKDAVKEFFAKFWD, (SEQ ID NO: 309) FAEKYKDAVKDFFAKFWE, (SEQ ID NO: 310) FAEKVKEAFKDYFAKFWD, (SEQ ID NO: 311) FADKVKDAFKEYFAKFWE, (SEQ ID NO: 312) FADKVKEAFKDYFAKFWE, (SEQ ID NO: 313) FAEKVKDAFKEYFAKFWD, (SEQ ID NO: 314) FAEKVKDAFKDYFAKFWE, (SEQ ID NO: 315) FAEKFKEYVKDAFAKFWD, (SEQ ID NO: 316) FADKFKDYVKEAFAKFWE, (SEQ ID NO: 317) FADKFKEYVKDAFAKFWE, (SEQ ID NO: 318) FAEKFKDYVKEAFAKFWD, (SEQ ID NO: 319) FAEKFKDYVKDAFAKFWE, (SEQ ID NO: 320) FAEKFKEAFKDYVAKFWD, (SEQ ID NO: 321) FADKFKDAFKEYVAKFWE, (SEQ ID NO: 322) FADKFKEAFKDYVAKFWE, (SEQ ID NO: 323) FAEKFKDAFKEYVAKFWD, (SEQ ID NO: 324) FAEKFKDAFKDYVAKFWE, (SEQ ID NO: 325) FAEKFKEAFKDYFAKVWD, (SEQ ID NO: 326) FADKFKDAFKEYFAKVWE, (SEQ ID NO: 327) FADKFKEAFKDYFAKVWE, (SEQ ID NO: 328) FAEKFKDAFKEYFAKVWD, (SEQ ID NO: 329) FAEKFKDAFKDYFAKVWE, (SEQ ID NO: 330) FAEKFKEAVKDFFAKYWD, (SEQ ID NO: 331) FADKFKDAVKEFFAKYWE, (SEQ ID NO: 332) FADKFKEAVKDFFAKYWE, (SEQ ID NO: 333) FAEKFKDAVKEFFAKYWD, (SEQ ID NO: 334) FAEKFKDAVKDFFAKYWE, (SEQ ID NO: 335) WAEKFFEAVKDYFAKFKD, (SEQ ID NO: 336) WADKFFDAVKEYFAKFKE, (SEQ ID NO: 337) WADKFFEAVKDYFAKFKE, (SEQ ID NO: 338) WAEKFFDAVKEYFAKFKD, (SEQ ID NO: 339) WAEKFFDAVKDYFAKFKE, (SEQ ID NO: 340) FAEKWFEAVKDYFAKFKD, (SEQ ID NO: 341) FADKWFDAVKEYFAKFKE, (SEQ ID NO: 342) FADKWFEAVKDYFAKFKE, (SEQ ID NO: 343) FAEKWFDAVKEYFAKFKD, (SEQ ID NO: 344) FAEKWFDAVKDYFAKFKE, (SEQ ID NO: 345) FAEKFVEAWKDYFAKFKD, (SEQ ID NO: 346) FADKFVDAWKEYFAKFKE, (SEQ ID NO: 347) FADKFVEAWKDYFAKFKE, (SEQ ID NO: 348) FAEKFVDAWKEYFAKFKD, (SEQ ID NO: 349) FAEKFVDAWKDYFAKFKE, (SEQ ID NO: 350) FYEKFAEAVKDWFAKFKD, (SEQ ID NO: 351) FYDKFADAVKEWFAKFKE, (SEQ ID NO: 352) FYDKFAEAVKDWFAKFKE, (SEQ ID NO: 353) FYEKFADAVKEWFAKFKD, (SEQ ID NO: 354) FYEKFADAVKDWFAKFKE, (SEQ ID NO: 355) DWFKHFYDKVAEKFKEAF, (SEQ ID NO: 356) EWFKHFYEKVADKFKDAF, (SEQ ID NO: 357) EWFKHFYDKVAEKFKEAF, (SEQ ID NO: 358) DWFKHFYEKVAEKFKEAF, (SEQ ID NO: 359) DWFKHFYDKVADKFKEAF, (SEQ ID NO: 360) DWFKHFYDKVAEKFKDAF, (SEQ ID NO: 361) DWHKFFYDKVAEKFKEAF, (SEQ ID NO: 362) EWHKFFYEKVADKFKDAF, (SEQ ID NO: 363) EWHKFFYDKVAEKFKEAF, (SEQ ID NO: 364) DWHKFFYEKVAEKFKEAF, (SEQ ID NO: 365) DWHKFFYDKVADKFKEAF, (SEQ ID NO: 366) DWHKFFYDKVAEKFKDAF, (SEQ ID NO: 367) DWFKFHYDKVAEKFKEAF, (SEQ ID NO: 368) EWFKFHYEKVADKFKDAF, (SEQ ID NO: 369) EWFKFHYDKVAEKFKEAF, (SEQ ID NO: 370) DWFKFHYEKVAEKFKEAF, (SEQ ID NO: 371) DWFKFHYDKVADKFKEAF, (SEQ ID NO: 372) DWFKFHYDKVAEKFKDAF, (SEQ ID NO: 373) DWFKVFYDKHAEKFKEAF, (SEQ ID NO: 374) EWFKVFYEKHADKFKDAF, (SEQ ID NO: 375) EWFKVFYDKHAEKFKEAF, (SEQ ID NO: 376) DWFKVFYEKHAEKFKEAF, (SEQ ID NO: 377) DWFKVFYDKHADKFKEAF, (SEQ ID NO: 378) DWFKVFYDKHAEKFKDAF, (SEQ ID NO: 379) DWFKAFYDKVAEKFKEHF, (SEQ ID NO: 380) EWFKAFYEKVADKFKDHF, (SEQ ID NO: 381) EWFKAFYDKVAEKFKEHF, (SEQ ID NO: 382) DWFKAFYEKVAEKFKEHF, (SEQ ID NO: 383) DWFKAFYDKVADKFKEHF, (SEQ ID NO: 384) DWFKAFYDKVAEKFKDHF, (SEQ ID NO: 385) DWFKAFYDKVAEKFKEFH, (SEQ ID NO: 386) EWFKAFYEKVADKFKDFH, (SEQ ID NO: 387) EWFKAFYDKVAEKFKEFH, (SEQ ID NO: 388) DWFKAFYDKVAEKFKEFH, (SEQ ID NO: 389) DWFKAFYEKVAEKFKEFH, (SEQ ID NO: 390) DWFKAFYDKVAEKFKEFH, (SEQ ID NO: 391) DWFKAFYDKVAEKFKDFH, (SEQ ID NO: 392) FAEKFKEAVKDYFAKFWD, (SEQ ID NO: 393) FHEKFKEAVKDYFAKFWD, (SEQ ID NO: 394) FHEKFKEAVKEYFAKFWE, (SEQ ID NO: 395) FHDKFKDAVKDYFAKFWD, (SEQ ID NO: 396) FHDKFKDAVKEYFAKFWE, (SEQ ID NO: 397) FHDKFKEAVKDYFAKFWD, (SEQ ID NO: 398) FHEKFKDAVKDYFAKFWD, (SEQ ID NO: 399) FHEKFKEAVKEYFAKFWD, (SEQ ID NO: 400) FHEKFKEAVKDYFAKFWE, (SEQ ID NO: 401) HFEKFKEAVKDYFAKFWD, (SEQ ID NO: 402) HFDKFKDAVKEYFAKFWE, (SEQ ID NO: 403) HFEKFKEAVKEYFAKFWE, (SEQ ID NO: 404) HFDKFKEAVKDYFAKFWD, (SEQ ID NO: 405) HFEKFKDAVKDYFAKFWD, (SEQ ID NO: 406) HFEKFKEAVKEYFAKFWD, (SEQ ID NO: 407) HFEKFKEAVKDYFAKFWE, (SEQ ID NO: 408) FFEKHKEAVKDYFAKFWD, (SEQ ID NO: 409) FFDKHKDAVKEYFAKFWE, (SEQ ID NO: 410) FFEKHKEAVKEYFAKFWE, (SEQ ID NO: 411) FFDKHKDAVKDYFAKFWD, (SEQ ID NO: 412) FFDKHKEAVKDYFAKFWD, (SEQ ID NO: 413) FFEKHKEAVKEYFAKFWD, (SEQ ID NO: 414) FFEKHKEAVKDYFAKFWE, (SEQ ID NO: 415) FVEKFKEAHKDYFAKFWD, (SEQ ID NO: 416) FVDKFKDAHKEYFAKFWE, (SEQ ID NO: 417) FVEKFKEAHKEYFAKFWE, (SEQ ID NO: 418) FVDKFKDAHKDYFAKFWD, (SEQ ID NO: 419) FVDKFKEAHKDYFAKFWD, (SEQ ID NO: 420) FVEKFKDAHKDYFAKFWD, (SEQ ID NO: 421) FVEKFKEAHKEYFAKFWD, (SEQ ID NO: 422) FVEKFKEAHKDYFAKFWE, (SEQ ID NO: 423) FAEKFKEHVKDYFAKFWD, (SEQ ID NO: 424) FADKFKDHVKEYFAKFWE, (SEQ ID NO: 425) FAEKFKEHVKEYFAKFWE, (SEQ ID NO: 426) FADKFKDHVKDYFAKFWD, (SEQ ID NO: 427) FADKFKEHVKDYFAKFWD, (SEQ ID NO: 428) FAEKFKDHVKDYFAKFWD, (SEQ ID NO: 429) FAEKFKEHVKEYFAKFWD, (SEQ ID NO: 430) FAEKFKEHVKDYFAKFWE, (SEQ ID NO: 431) FAEKFKEFVKDYHAKFWD, (SEQ ID NO: 432) FADKFKDFVKEYHAKFWE, (SEQ ID NO: 433) FADKFKEFVKDYHAKFWD, (SEQ ID NO: 434) FAEKFKDFVKDYHAKFWD, (SEQ ID NO: 435) FADKFKDFVKDYHAKFWD, (SEQ ID NO: 436) FAEKFKEFVKEYHAKFWE, (SEQ ID NO: 437) FAEKFKEFVKEYHAKFWD, (SEQ ID NO: 438) FAEKFKEFVKDYHAKFWE, (SEQ ID NO: 439) FAEKFKEFVKDYFAKHWD, (SEQ ID NO: 440) FADKFKDFVKEYFAKHWE, (SEQ ID NO: 441) FAEKFKEFVKEYFAKHWE, (SEQ ID NO: 442) FADKFKDFVKDYFAKHWD, (SEQ ID NO: 443) FADKFKEFVKDYFAKHWD, (SEQ ID NO: 444) FAEKFKDFVKDYFAKHWD, (SEQ ID NO: 445) FAEKFKEFVKEYFAKHWD, (SEQ ID NO: 446) FAEKFKEFVKDYFAKHWE, (SEQ ID NO: 447) FAEKFKEAVKEYFAKFWE, (SEQ ID NO: 448) FADKFKDAVKDYFAKFWD, (SEQ ID NO: 449) FAERFREAVKDYFAKFWD, (SEQ ID NO: 450) FAEKFREAVKDYFAKFWD, (SEQ ID NO: 451) FAEKFKEAVRDYFAKFWD, (SEQ ID NO: 452) FAEKFKEAVKDYFARFWD, (SEQ ID NO: 453) FAEKFKEAVKEYFAKFWE, (SEQ ID NO: 454) FADKFKDAVKDYFAKFWD, (SEQ ID NO: 455) FAERFREAVKDYFAKFWD, (SEQ ID NO: 456) FAEKFREAVKDYFAKFWD, (SEQ ID NO: 457) FAEKFKEAVRDYFAKFWD, (SEQ ID NO: 458) FAEKFKEAVKDYFARFWD, (SEQ ID NO: 459) FAEKFKEAVKEYFAKFWE, (SEQ ID NO: 460) FADKFKDAVKDYFAKFWD, (SEQ ID NO: 461) FAERFREAVKDYFAKFWD, (SEQ ID NO: 462) FAEKFREAVKDYFAKFWD, (SEQ ID NO: 463) FAEKFKEAVRDYFAKFWD, (SEQ ID NO: 464) FAEKFKEAVKDYFARFWD, (SEQ ID NO: 465) FAERFREAVKDYFAKFWD, (SEQ ID NO: 466) FAEKFREAVKDYFAKFWD, (SEQ ID NO: 467) FAEKFKEAVRDYFAKFWD, (SEQ ID NO: 468) FAEKFKEAVKDYFARFWD, (SEQ ID NO: 469) FAEKFKEAVKEYFAKFWE, (SEQ ID NO: 470) FADKFKDAVKDYFAKFWD, (SEQ ID NO: 471) FAERFREAVKDYFAKFWD, (SEQ ID NO: 472) FAEKFREAVKDYFAKFWD, (SEQ ID NO: 473) FAEKFKEAVRDYFAKFWD, (SEQ ID NO: 474) FAEKFKEAVKDYFARFWD, (SEQ ID NO: 475) LFEKFAEAFKDYVAKWKD, (SEQ ID NO: 476) LFERFAEAFKDYVAKWKD, (SEQ ID NO: 477) LFEKFAEAFRDYVAKWKD, (SEQ ID NO: 478) LFEKFAEAFKDYVARWKD, (SEQ ID NO: 479) LFEKFAEAFKDYVAKWRD, (SEQ ID NO: 480) LFEKFAEAFKEYVAKWKE, (SEQ ID NO: 481) LFDKFADAFKDYVAKWKD, (SEQ ID NO: 482) LFDKFAEAFKDYVAKWKD, (SEQ ID NO: 483) LFEKFADAFKDYVAKWKD, (SEQ ID NO: 484) LFEKFAEAFKEYVAKWKD, (SEQ ID NO: 485) LFEKFAEAFKDYVAKWKE, (SEQ ID NO: 486) FAEKAWEFVKDYFAKLKD, (SEQ ID NO: 487) FAERAWEFVKDYFAKLKD, (SEQ ID NO: 488) FAEKAWEFVKDYFAKLKD, (SEQ ID NO: 489) FAEKAWEFVKDYFAKLKD, (SEQ ID NO: 490) FAEKAWEFVKDYFAKLRD, (SEQ ID NO: 491) FAEKAWEFVKEYFAKLKE, (SEQ ID NO: 492) FADKAWDFVKDYFAKLKD, (SEQ ID NO: 493) FADKAWEFVKDYFAKLKD, (SEQ ID NO: 494) FAEKAWDFVKDYFAKLKD, (SEQ ID NO: 495) FAEKAWEFVKEYFAKLKD, (SEQ ID NO: 496) FAEKAWEFVKDYFAKLKE, (SEQ ID NO: 497) FFEKFKEFVKDYFAKLWD, (SEQ ID NO: 498) FFEKFKEFVKEYFAKLWE, (SEQ ID NO: 499) FFDKFKDFVKDYFAKLWD, (SEQ ID NO: 500) FFERFKEFVKDYFAKLWD, (SEQ ID NO: 501) FFEKFREFVKDYFAKLWD, (SEQ ID NO: 502) FFEKFKEFVRDYFAKLWD, (SEQ ID NO: 503) FFEKFKEFVKDYFARLWD, (SEQ ID NO: 504) FFDKFKEFVKDYFAKLWD, (SEQ ID NO: 505) FFEKFKDFVKDYFAKLWD, (SEQ ID NO: 506) FFEKFKEFVKEYFAKLWD, (SEQ ID NO: 507) FFEKFKEFVKDYFAKLWE, (SEQ ID NO: 508) FLEKFKEFVKDYFAKFWD, (SEQ ID NO: 509) FLEKFKEFVKEYFAKFWE, (SEQ ID NO: 510) FLDKFKEFVKDYFAKFWD, (SEQ ID NO: 511) FLDKFKEFVKDYFAKFWD, (SEQ ID NO: 512) FLEKFKDFVKDYFAKFWD, (SEQ ID NO: 513) FLEKFKEFVKEYFAKFWD, (SEQ ID NO: 514) FLEKFKEFVKDYFAKFWE, (SEQ ID NO: 515) FLERFKEFVKDYFAKFWD, (SEQ ID NO: 516) FLEKFREFVKDYFAKFWD, (SEQ ID NO: 517) FLEKFKEFVRDYFAKFWD, (SEQ ID NO: 518) FLEKFKEFVKDYFARFWD, (SEQ ID NO: 519) FFEKFKEFFKDYFAKLWD, (SEQ ID NO: 520) FFEKFKEFFKEYFAKLWE, (SEQ ID NO: 521) FFDKFKDFFKDYFAKLWD, (SEQ ID NO: 522) FFERFKEFFKDYFAKLWD, (SEQ ID NO: 523) FFEKFREFFKDYFAKLWD, (SEQ ID NO: 524) FFEKFKEFFRDYFAKLWD, (SEQ ID NO: 525) FFERFKEFFKDYFARLWD, (SEQ ID NO: 526) FFDKFKEFFKDYFAKLWD, (SEQ ID NO: 527) FFEKFKDFFKDYFAKLWD, (SEQ ID NO: 528) FFEKFKEFFKEYFAKLWD, (SEQ ID NO: 529) FFEKFKEFFKDYFAKLWE, (SEQ ID NO: 530) FAEKFKEAVKDYFAKFWD, (SEQ ID NO: 531) FAEKFKEAVKEYFAKFWE, (SEQ ID NO: 532) FADKFKDAVKDYFAKFWD, (SEQ ID NO: 533) FAERFREAVKDYFAKFWD, (SEQ ID NO: 534) FAEKFREAVKDYFAKFWD, (SEQ ID NO: 535) FAEKFKEAVRDYFAKFWD, (SEQ ID NO: 536) FAEKFKEAVKDYFARFWD, (SEQ ID NO: 537) DKWKAVYDKFAEAFKEFF, (SEQ ID NO: 538) EKWKAVYEKFAEAFKEFF, (SEQ ID NO: 539) DKWKAVYDKFADAFKDFF, (SEQ ID NO: 540) DRWKAVYDKFAEAFKEFF, (SEQ ID NO: 541) DKWRAVYDKFAEAFKEFF, (SEQ ID NO: 542) DKWKAVYDRFAEAFKEFF, (SEQ ID NO: 543) DKWKAVYDKFAEAFREFF, (SEQ ID NO: 544) FFEKFAEAFKDYVAKWKD, (SEQ ID NO: 545) FFEKFAEAFKEYVAKWKE, (SEQ ID NO: 546) FFDKFADAFKDYVAKWKD, (SEQ ID NO: 547) FFERFAEAFKDYVAKWKD, (SEQ ID NO: 548) FFERFAEAFRDYVAKWKD, (SEQ ID NO: 549) FFEKFAEAFKDYVARWKD, (SEQ ID NO: 550) FFERFAEAFKDYVAKWRD, (SEQ ID NO: 551) FFDKFAEAFKDYVAKWKD, (SEQ ID NO: 552) FFEKFADAFKDYVAKWKD, (SEQ ID NO: 553) FFERFAEAFKEYVAKWKD, (SEQ ID NO: 554) FFERFAEAFKDYVAKWKE, (SEQ ID NO: 555) FFEKFKEFFKDYFAKFWD, (SEQ ID NO: 556) FFDKFKDFFKDYFAKFWD, (SEQ ID NO: 557) FFEKFKEFFKEYFAKFWE, (SEQ ID NO: 558) FFERFKEFFKDYFAKFWD, (SEQ ID NO: 559) FFEKFREFFKDYFAKFWD, (SEQ ID NO: 560) FFEKFKEFFRDYFAKFWD, (SEQ ID NO: 561) FFEKFKEFFKDYFARFWD, (SEQ ID NO: 562) FFDKFKEFFKDYFAKFWD, (SEQ ID NO: 563) FFEKFKDFFKDYFAKFWD, (SEQ ID NO: 564) FFEKFKEFFKEYFAKFWD, (SEQ ID NO: 565) FFEKFKEFFKDYFAKFWE, (SEQ ID NO: 566) EVRAKLEEQAQQIRLQAEAFQARLKSWFEPLVE, (SEQ ID NO: 567) EVRAKLEEQAQQIRLQAEAFQARLKSWFE, (SEQ ID NO: 568) EVRSKLEEWFAAFREFAEEFLARLKS, (SEQ ID NO: 569) PVLDLFRELLNELLEALKQKLK, (SEQ ID NO: 570) DWLKAFYDKVAEKLKEAFPDWAKAAYDKAAEKAKEAA, (SEQ ID NO: 571) EELKEKLEELKEKLEEKLPEELKEKLEELKEKLEEKL, (SEQ ID NO: 572) EELKAKLEELKAKLEEKLPEELKAKLEELKAKLEEKL, (SEQ ID NO: 573) EKLKALLEKLLAKLKELLPEKLKALLEKLLAKLKELL, (SEQ ID NO: 574) EWLKELLEKLLEKLKELLPEWLKELLEKLLEKLKELL, (SEQ ID NO: 575) EKFKELLEKFLEKFKELLPEKFKELLEKFLEKFKELL, (SEQ ID NO: 576) EKLKELLEKLLELLKKLLPEKLKELLEKLLELLKKLL, (SEQ ID NO: 577) EKLKELLEKLKAKLEELLPEKLKELLEKLKAKLEELL, (SEQ ID NO: 578) EKLKELLEKLLAKLKELLPEKLKELLEKLLAKLKELL, (SEQ ID NO: 579) EKFKELLEKLLEKLKELLPEKFKELLEKLLEKLKELL, (SEQ ID NO: 580) EKLKAKLEELKAKLEELLPEKLKAKLEELKAKLEELL, (SEQ ID NO: 581) EELKELLKELLKKLEKLLPELKELLKELLKKLEKLL, (SEQ ID NO: 582) EELKKLLEELLKKLKELLPEELKKLLEELLKKLKELL, (SEQ ID NO: 583) EKLKELLEKLLEKLKELLAEKLKELLEKLLEKLKELL, (SEQ ID NO: 584) EKLKELLEKLLEKLKELLAAEKLKELLEKLLEKLKELL, (SEQ ID NO: 585) EKLKAKLEELKAKLEELLPEKAKAALEEAKAKAEELA, (SEQ ID NO: 586) EKLKAKLEELKAKLEELLPEHAKAALEEAKCKAEELA, (SEQ ID NO: 587) DHLKAFYDKVACKLKEAFPDWAKAAYDKAAEKAKEAA, (SEQ ID NO: 588) DWLKAFYDKVAEKLKEAFPDHAKAAYDKAACKAKEAA, (SEQ ID NO: 589) DWLKAFYDKVACKLKEAFPDWAKAAYNKAAEKAKEAA, (SEQ ID NO: 590) DHLKAFYDKVAEKLKEAFPDWAKAAYDKAAEKAKEAA, (SEQ ID NO: 591) VLESFKVSFLSALEEYTKKLNTQ, (SEQ ID NO: 592) DKWKAVYDKFAEAFKEFL, (SEQ ID NO: 593) DKLKAFYDKVFEWAKEAF, (SEQ ID NO: 595) DQYYLRVTTVA, (SEQ ID NO: 596) ECKPCLKQTCMKFYARVCR, (SEQ ID NO: 597) FSRASSIIDELFQD, (SEQ ID NO: 598) IQNAVNGVKQIKTLIEKTNEE, (SEQ ID NO: 599) LLEQLNEQFNWVSRLANL, (SEQ ID NO: 600) LLEQLNEQFNWVSRLANLTEGE, (SEQ ID NO: 601) LLEQLNEQFNWVSRLANLTQGE, (SEQ ID NO: 602) LVGRQLEEFL, (SEQ ID NO: 603) MNGDRIDSLLEN, (SEQ ID NO: 604) NELQEMSNQGSKYVNKEIQNAVNGV, (SEQ ID NO: 605) PCLKQTCMKFYARVCR, (SEQ ID NO: 606) PFLEMIHEAQQAMDI, (SEQ ID NO: 607) PGVCNETMMALWEECK, (SEQ ID NO: 608) PKFMETVAEKALQEYRKKHRE, (SEQ ID NO: 609) PSGVTEVVVKLFDS, (SEQ ID NO: 610) PSQAKLRRELDESLQVAERLTRKYNELLKSYQ, (SEQ ID NO: 611) PTEFIREGDDD, (SEQ ID NO: 612) QQTHMLDVMQD, (SEQ ID NO: 613) RKTLLSNLEEAKKKKEDALNETRESETKLKEL, (SEQ ID NO: 614) RMKDQCDKCREILSV, (SEQ ID NO: 615) GVFAKIFKWISGLFKKIG, (SEQ ID NO: 616) GIKKFLGSIWKFIKAFVG, (SEQ ID NO: 617) GFKKFLGSWAKIYKAFVG, (SEQ ID NO: 618) GFRRFLGSWARIYRAFVG, (SEQ ID NO: 619) TEELRVRLASHLRKLRKRLL, (SEQ ID NO: 620) TEELRVRLASHLRKLRK, (SEQ ID NO: 621) LRVRLASHLRKLRKRLL, (SEQ ID NO: 622) RLASHLRKLRKRLL, (SEQ ID NO: 623) SHLRKLRKRLL, (SEQ ID NO: 624) LRKLRKRLL, (SEQ ID NO: 625) LRKLRKRLLLRKLRKRLL, (SEQ ID NO: 626) LRKLRKRLLLRKLRKRLLLRKLRKRLL, (SEQ ID NO: 627) RQIKIWFQNRRMKWKKCLRVRLASHLRKLRKRLL, (SEQ ID NO: 628) LRVRLASHLRKLRKRLL, (SEQ ID NO: 629) EELRVRLASHLRKLRKRLLRDADDLQKRLAVYEEQAQQIRLQAEAFQA RLKSWFEPLVEDM, (SEQ ID NO: 630) CEELRVRLASHLRKLRKRLLRDADDLQKRLAVY, (SEQ ID NO: 631) LRKLRKRLLRDADDLLRKLRKRLLRDADDL, (SEQ ID NO: 632) TEELRVRLASHLRKLRKRLL, (SEQ ID NO: 633) TEELRVRLASHLEKLRKRLL, (SEQ ID NO: 634) TEELRVRLASHLRELRKRLL, (SEQ ID NO: 635) LREKKLRVSALRTHRLELRL, (SEQ ID NO: 636) LRKLRKRLLRDWLKAFYDKVAEKLKEAF, (SEQ ID NO: 637) LRRLRRRLLRDWLKAFYDKVAEKLKEAF, and (SEQ ID NO: 638) RRRRRRRRRRDWLKAFYDKVAEKLKEAF. Embodiment 60 The ezetimibe-associated apoA-I mimetic peptide according to any one of embodiments 43-59, wherein said peptide is obtainable using a method according to any one of embodiments 1-23. Embodiment 61 The ezetimibe-associated apoA-I mimetic peptide according to any one of embodiments 43-59, wherein said peptide is prepared using a method according to any one of embodiments 1-23. Embodiment 62 A pharmaceutical formulation comprising: an ezetimibe-associated apoA-I mimetic peptide according to any one of embodiments 43-61; and a pharmaceutically acceptable carrier or diluent. Embodiment 63 The formulation of embodiment 62, wherein said ezetimibe-associated peptide is in a pharmaceutically acceptable excipient suitable for oral administration. Embodiment 64 The formulation according to any one of embodiments 62-63, wherein said ezetimibe-associated peptide is provided as a unit dosage formulation. Embodiment 65 The formulation according to any one of embodiments 62-34, wherein said ezetimibe-associated peptide is formulated for administration by a route selected from the group consisting of oral administration, nasal administration, rectal administration, intraperitoneal injection, intravascular injection, subcutaneous injection, transcutaneous administration, and intramuscular injection. Embodiment 66 A method for the treatment or prophylaxis of a pathology characterized by an inflammatory response, said method comprising administering to a mammal in need thereof an effective amount of an ezetimibe-associated peptide according to any one of embodiments 43-61 and/or a pharmaceutical formulation according to any one of embodiments 62-65. Embodiment 67 The method of embodiment 66, wherein said pathology is atherosclerosis. Embodiment 68 The method of embodiment 67, wherein said mammal is diagnosed with atherosclerosis and said administering comprises administering a sufficient amount of said ezetimibe-associated peptide and/or a pharmaceutical formulation to ameliorate one or more symptoms of atherosclerosis and/or to reduce one or more markers of an atherosclerotic pathology. Embodiment 69 The method of embodiment 67, wherein said mammal is at risk for atherosclerosis and said administering comprises administering a sufficient amount of extract, and/or protein powder, and/or nutritional supplement to reduce the risk for atherosclerosis, and/or to improve a risk marker for atherosclerosis, and/or to slow the progression of atherosclerosis. Embodiment 70 The method of embodiment 69, wherein said risk marker is HDL/LDL, CRP, triglycerides, SAA, paraoxonase activity, Lp(a), oxidized LDL or antibodies to oxidized LDL, or sPLA2. Embodiment 71 The method according to any one of embodiments 66-70, wherein said pathology is macular degeneration. Embodiment 72 The method according to any one of embodiments 66-70, wherein said pathology is dyslipidemia. Embodiment 73 The method according to any one of embodiments 66-70, wherein said pathology is Alzheimer's disease. Embodiment 74 The method according to any one of embodiments 66-70, wherein said pathology is Crohn's disease. Embodiment 75 The method according to any one of embodiments 66-70, wherein said pathology is ulcerative colitis. Embodiment 76 The method according to any one of embodiments 66-70, wherein said pathology is cancer. Embodiment 77 The method of embodiment 76, wherein said cancer is a cancer selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Adrenocortical carcinoma, AIDS-related cancers (e.g., Kaposi sarcoma, lymphoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, bile duct cancer, extrahepatic cancer, bladder cancer, bone cancer (e.g., Ewing sarcoma, osteosarcoma, malignant fibrous histiocytoma), brain stem glioma, brain tumors (e.g., astrocytomas, brain and spinal cord tumors, brain stem glioma, central nervous system atypical teratoid/rhabdoid tumor, central nervous system embryonal tumors, central nervous system germ cell tumors, craniopharyngioma, ependymoma, breast cancer, bronchial tumors, burkitt lymphoma, carcinoid tumors (e.g., childhood, gastrointestinal), cardiac tumors, cervical cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CIVIL), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous t-cell lymphoma, duct cancers e.g. (bile, extrahepatic), ductal carcinoma in situ (DCIS), embryonal tumors, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer (e.g., intraocular melanoma, retinoblastoma), fibrous histiocytoma of bone, malignant, and osteosarcoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumors (e.g., ovarian cancer, testicular cancer, extracranial cancers, extragonadal cancers, central nervous system), gestational trophoblastic tumor, brain stem cancer, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular (liver) cancer, histiocytosis, langerhans cell cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kaposi sarcoma, kidney cancer (e.g., renal cell, Wilm's tumor, and other kidney tumors), langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphoblastic (ALL), acute myeloid (AML), chronic lymphocytic (CLL), chronic myelogenous (CML), hairy cell, lip and oral cavity cancer, liver cancer (primary), lobular carcinoma in situ (LCIS), lung cancer (e.g., childhood, non-small cell, small cell), lymphoma (e.g., AIDS-related, Burkitt (e.g., non-Hodgkin lymphoma), cutaneous T-Cell (e.g., mycosis fungoides, Sézary syndrome), Hodgkin, non-Hodgkin, primary central nervous system (CNS)), macroglobulinemia, Waldenström, male breast cancer, malignant fibrous histiocytoma of bone and osteosarcoma, melanoma (e.g., childhood, intraocular (eye)), merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, midline tract carcinoma, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, Myelogenous Leukemia, Chronic (CIVIL), multiple myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oral cavity cancer, lip and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors (islet cell tumors), papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, plasma cell neoplasm, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, renal pelvis and ureter, transitional cell cancer, rhabdomyosarcoma, salivary gland cancer, sarcoma (e.g., Ewing, Kaposi, osteosarcoma, rhadomyosarcoma, soft tissue, uterine), Sézary syndrome, skin cancer (e.g., melanoma, merkel cell carcinoma, basal cell carcinoma, nonmelanoma), small intestine cancer, squamous cell carcinoma, squamous neck cancer with occult primary, stomach (gastric) cancer, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, trophoblastic tumor, ureter and renal pelvis cancer, urethral cancer, uterine cancer, endometrial cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, and Wilm's tumor. Embodiment 78 The method of embodiment 76, wherein said cancer is a cancer selected from the group consisting of ovarian cancer, endometrial cancer, colon cancer, and familial adenomatous polyposis. Embodiment 79 The method of embodiment 76, wherein said cancer is a cancer selected from the group consisting of ovarian cancer, breast cancer, and colon cancer. Embodiment 80 The method according to any one of embodiments 76-79, wherein said method produces one or more effects selected from the group consisting of decreasing tumor burden, extending 1 survival, a decrease in or suppression of tumor growth and/or metastasis, a decrease in tumor angiogenesis, and a decrease in tumor invasiveness. Embodiment 81 The method of embodiment 80, wherein said method decreases tumor burden. Embodiment 82 The method of embodiment 80, wherein said method decreases and/or suppresses tumor growth and/or metastasis. Embodiment 83 The method of embodiment 80, wherein said method decreases tumor angiogenesis. Embodiment 84 The method of embodiment 80, wherein said method decreases tumor invasiveness. Embodiment 85 The method according to any one of embodiments 66-84, wherein said ezetimibe-associated peptide and/or a pharmaceutical formulation is administered in an amount sufficient to reduce lyophosphatidic acid (LPA) levels in said mammal. Embodiment 86 The method according to any one of embodiments 66-85, wherein said mammal is a human. Embodiment 87 The method according to any one of embodiments 66-85, wherein said mammal is a non-human mammal. Embodiment 88 The method of embodiment 87, wherein said non-human mammal is a non-human mammal selected from the group consisting of a canine, a feline, an equine, a porcine, a bovine, and a largomorph. Embodiment 89 A method of preventing or reducing the uptake of one or more dietary pro-inflammatory micro-lipid components in a mammal, said method comprising administering to the mammal an effective amount of an ezetimibe-associated peptide according to any one of embodiments 43-61 and/or a pharmaceutical formulation according to any one of embodiments 62-65. Embodiment 90 The method of embodiment 89, wherein said one or more dietary pro-inflammatory micro-lipid components comprises lysophosphatidic acid. Embodiment 91 The method according to any one of embodiments 89-90, wherein said one or more dietary pro-inflammatory micro-lipid components comprises phosphatidic acid. Embodiment 92 The method according to any one of embodiments 89-91, wherein said mammal has or is at risk for atherosclerosis. Embodiment 93 The method of embodiment 92, wherein said mammal is diagnosed with atherosclerosis. Embodiment 94 The method of embodiment 92, wherein said mammal is determined to be at risk for atherosclerosis. Embodiment 95 The method of embodiment 94, wherein said mammal is determined to be at risk said risk by measurement of a marker selected from the group consisting of HDL/LDL, CRP, triglycerides, SAA, paraoxonase activity, Lp(a), oxidized LDL or antibodies to oxidized LDL, or sPLA2. Embodiment 96 The method according to any one of embodiments 89-95, wherein said ezetimibe-associated peptide and/or a pharmaceutical formulation is administered in an amount sufficient to reduce lyophosphatidic acid (LPA) levels in said mammal. Embodiment 97 The method according to any one of embodiments 89-96, wherein said mammal is a human. Embodiment 98 The method according to any one of embodiments 89-96, wherein said mammal is a non-human mammal. Embodiment 99 The method of embodiment 98, wherein said non-human mammal is a non-human mammal selected from the group consisting of a canine, a feline, an equine, a porcine, a bovine, and a lagomorph. Definitions The HDL inflammatory index refers to the ability of HDL to inhibit LDL-induced monocyte chemotactic activity. In certain embodiments the HDL-inflammatory index is calculated by comparing the monocyte chemotactic activity generated by a standard control LDL in the absence and presence of the test HDL. In the absence of the test HDL the monocyte chemotactic activity is normalized to 1.0. If the monocyte chemotactic activity increases upon addition of the test HDL, the HDL-inflammatory index is >1.0 and the test HDL is classified as pro-inflammatory. If the monocyte chemotactic activity decreases upon addition of the test HDL, the HDL-inflammatory index is <1.0 and the HDL is classified as anti-inflammatory. A reduction in HDL inflammatory index is considered an improvement in HDL inflammatory index. The terms “polypeptide”, “peptide” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues. The terms apply to amino acid polymers in which one or more amino acid residues is an artificial chemical analogue of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers, however a recombinantly expressed peptide typically consists of amino acids that are all found in the host organism (e.g., naturally occurring amino acids). The term “an amphipathic helical peptide” refers to a peptide comprising at least one amphipathic helix (amphipathic helical domain). Certain amphipathic helical peptides contemplated herein can comprise two or more (e.g., 3, 4, 5, etc.) amphipathic helices. The term “class A amphipathic helix” refers to a protein structure that forms an α-helix producing a segregation of a polar and nonpolar faces with the positively charged residues residing at the polar-nonpolar interface and the negatively charged residues residing at the center of the polar face (see, e.g., Segrest et al. (1990) Proteins: Structure, Function, and Genetics 8: 103-117). “Apolipoprotein J” (apo J) is known by a variety of names including clusterin, TRPM2, GP80, and SP 40 (see, e.g., Fritz (1995) Pp 112 In: Clusterin: Role in Vertebrate Development, Function, and Adaptation (Harmony JAK Ed.), R.G. Landes, Georgetown, Tex.,). It was first described as a heterodimeric glycoprotein and a component of the secreted proteins of cultured rat Sertoli cells (see, e.g., Kissinger et al. (1982) Biol. Reprod.; 27: 233240). The translated product is a single-chain precursor protein that undergoes intracellular cleavage into a disulfide-linked 34 kDa α subunit and a 47 kDa β subunit (see, e.g., Collard and Griswold (1987) Biochem., 26: 3297-3303). It has been associated with cellular injury, lipid transport, apoptosis and it may be involved in clearance of cellular debris caused by cell injury or death. Clusterin has been shown to bind to a variety of molecules with high affinity including lipids, peptides, and proteins and the hydrophobic probe 1-anilino-8-naphthalenesulfonate (Bailey et al. (2001) Biochem., 40: 11828-11840). The class G amphipathic helix is found in globular proteins, and thus, the name class G. The feature of this class of amphipathic helix is that it possesses a random distribution of positively charged and negatively charged residues on the polar face with a narrow nonpolar face. Because of the narrow nonpolar face this class does not readily associate with phospholipid (see, e.g., Segrest et al. (1990) Proteins: Structure, Function, and Genetics. 8: 103-117; Erratum (1991) Proteins: Structure, Function and Genetics, 9: 79). Several exchangeable apolipoproteins possess similar but not identical characteristics to the G amphipathic helix. Similar to the class G amphipathic helix, this other class possesses a random distribution of positively and negatively charged residues on the polar face. However, in contrast to the class G amphipathic helix which has a narrow nonpolar face, this class has a wide nonpolar face that allows this class to readily bind phospholipid and the class is termed G* to differentiate it from the G class of amphipathic helix (see, e.g., Segrest et al. (1992) J. Lipid Res., 33: 141-166; Anantharamaiah et al. (1993) Pp. 109-142 In: The Amphipathic Helix, Epand, R. M. Ed CRC Press, Boca Raton, Fla.). Computer programs to identify and classify amphipathic helical domains have been described by Jones et al. (1992) J. Lipid Res. 33: 287-296) and include, but are not limited to the helical wheel program (WHEEL or WHEEL/SNORKEL), helical net program (HELNET, HELNET/SNORKEL, HELNET/Angle), program for addition of helical wheels (COMBO or COMBO/SNORKEL), program for addition of helical nets (COMNET, COMNET/SNORKEL, COMBO/SELECT, COMBO/NET), consensus wheel program (CONSENSUS, CONSENSUS/SNORKEL), and the like. The term “treat” when used with reference to treating, e.g. a pathology or disease refers to the mitigation and/or elimination of one or more symptoms of that pathology or disease, and/or a reduction in the rate of onset or severity of one or more symptoms of that pathology or disease, and/or the prevention of that pathology or disease. The term “ameliorating” when used with respect to “ameliorating one or more symptoms of atherosclerosis” refers to a reduction, prevention, or elimination of one or more symptoms characteristic of atherosclerosis and/or associated pathologies. Such a reduction includes, but is not limited to a reduction or elimination of oxidized phospholipids, a reduction in atherosclerotic plaque formation and rupture, a reduction in clinical events such as heart attack, angina, or stroke, a decrease in hypertension, a decrease in inflammatory protein biosynthesis, reduction in plasma cholesterol, and the like. A “transgenic plant” is a plant that expresses in at least some of the cells of the plant a heterologous peptide. In certain embodiments the heterologous peptide consists of, or comprises the amino acid sequence of one or more apolipoprotein(s) or apolipoprotein mimetics, e.g., an apoA-I mimetic, and/or a G* peptide, and/or an apoE peptide, e.g., as described herein. In certain embodiments the transgenic plant is a plant that at least a portion of which is edible by a human and/or by a non-human mammal. The term “biological activity” when used with respect to an apolipoprotein peptide, an apolipoprotein peptide mimetic, a peptide/protein comprising one or more apolipoprotein and/or apolipoprotein mimetic domains indicates that the peptide, when fed to a mammal lowers plasma SAA levels, and/or increases paraoxonase activity, and/or reduces levels of lysophosphatidic acid, and/or reduces levels of metabolites of arachidonic and linoleic acids. A transgenic plant or portion thereof having biological activity indicates that the plant or portion thereof when fed to a mammal lowers plasma SAA levels, and/or increases paraoxonase activity, and/or reduces levels of lysophosphatidic acid, and/or reduces levels of metabolites of arachidonic and linoleic acids. The term “recombinant nucleic acid” as used herein refers to nucleic acid, originally formed in vitro, in general, in a form not normally found in nature. A “heterologous” DNA coding sequence is a structural coding sequence that is not native to the plant being transformed, or a coding sequence that has been engineered for improved characteristics of its protein product. Heterologous, with respect to the promoter, refers to a coding sequence that does not exist in nature in the same gene with the promoter to which it is currently attached. By “promoter” or “promoter segment” (e.g., a tomato E8 promoter or E4 promoter or hybrid E4/E8 promoter) is meant a sequence of DNA that functions alone as a promoter or as a component of a promoter herein to direct transcription of a downstream gene, and can include promoter or promoter segments derived by means of ligation with operator regions, random or controlled mutagenesis, addition or duplication of enhancer sequences, addition or modification with synthetic linkers, and the like. By an E8 or an E4 gene promoter is meant a promoter obtained from an E8 or E4 gene considered to share sequence identity with the tomato E8 or E4 gene sequences (e.g., as described in U.S. Pat. No. 6,118,049), or a particular region or regions thereof, or from a gene having at least about 70%, preferably at least about 80%, more preferably at least about 85%, even more preferably at least about 90% sequence identify, or at least about 95% sequence identity, or at least about 98% sequence identity over a length of polynucleotide sequence corresponding to the tomato E8 or tomato E4 gene sequences. The term “conservative substitution” is used in reference to proteins or peptides to reflect amino acid substitutions that do not substantially alter the activity (e.g., ability to reduce SAA, and/or ability to increase paroxonase in a mammal. Typically conservative amino acid substitutions involve substitution one amino acid for another amino acid with similar chemical properties (e.g. charge or hydrophobicity). The following six groups each contain amino acids that are typical conservative substitutions for one another: 1) Alanine (A), Serine (S), Threonine (T); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); and 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W). A “macro-lipid component of the diet” refers to a lipid component of a mammal's diet that is typically present in milligram amounts per gram of diet. In a Western diet such macro-lipid components typically include, but are not limited to phospholipids such as phosphatidylcholine and sterols such as cholesterol. Even lysophosphatidylcholine is likely to be present in milligram quantities after phosphatidylcholine is acted upon in the Duodenum by PLA2 and hence, in various embodiments, can be regarded as a macro-lipid component. A “micro-lipid component of the diet” refers to a lipid component of a mammal's diet that is typically present in microgram (or lower) amounts per gram of diet. Illustrative microlipid components typically include, but are not limited to lysophosphatidic acid, phosphatidic acid, and the like. The term “ezetimibe” refers to (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one, the pharmaceutical also known as ZETIA® or EZETROL® which is typically used as a drug to lower plasma cholesterol levels. Without being bound by a particular theory, it is believed that ezetimibe acts by decreasing cholesterol absorption in the small intestine. The phrase “a mixed ezetimibe apoA-I peptide formulation” or “combined (ezetimibe/apoA-I) formulation”) refers to a formulation in which ezetimibe and an apoA-I peptide are provided as separate components that are simply combined, e.g., by mixing the dry powders. The phrase “ezetimibe-associated apoA-I mimetic peptide” or “Ez-peptide” (e.g., Ez-T6F) refers to an apoA-I mimetic peptide that has been reacted with ezetimibe (e.g., by incubating ezetimibe with the peptide in a solution comprising ethyl acetate and acetic acid or in a solution comprising ethyl lactate and lactic acid) as described herein. The ezetimibe-associated apoA-I mimetic peptide may be designated Ez-peptide. Thus, for example, an ezetimibe associated transgenic 6F peptice (Tg6F) may be designated Ez-Tg6F. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows total plasma cholesterol for female LDLR null mice age 5-8 months (n=20 per group) fed standard mouse chow (Chow) or a Western diet high in cholesterol and fat (WD) or fed WD+0.06% by weight of a freeze-dried concentrate of transgenic tomatoes expressing the apoA-I mimetic peptide 6F, or fed WD with ezetimibe added to give a daily dose of 10 mg/kg body weight/day (WD+Ezetimibe), or the mice were fed WD with Tg6F added at 0.06% by weight plus Ezetimibe (each added separately to the diet by mixing the dried powders into the diet) to give a daily dose of Ezetimibe of 10 mg/kg body weight, or the mice were fed WD to which was added 0.06% ezetimibe-associated Tg6F (Ez-Tg6F) by weight containing sufficient Ezetimibe to give a daily dose of 10 mg/kg body weight/day that was prepared as described herein. NS=Not Significant. FIG. 2 shows the decrease in plasma total cholesterol compared to WD. The data in FIG. 1 were calculated to show the decrease in plasma total cholesterol compared to WD. FIG. 3 shows plasma triglycerides. The plasma from the mice in FIG. 1 was analyzed for triglycerides as described (see, e.g., Chattopadhyay et al. (2015) Pharma. Res. Per. 3: e00154; Chattopadhyay et al. (2016) J. Lipid. Res. 57: 832-847). FIG. 4 shows the decrease in plasma triglycerides. The data in FIG. 3 were calculated to show the decrease in plasma triglycerides compared to WD. FIG. 5 shows plasma HDL cholesterol. The plasma from the mice in FIG. 1 was analyzed for HDL-cholesterol as described (see, e.g., Chattopadhyay et al. (2015) Pharma. Res. Per. 3: e00154; Chattopadhyay et al. (2016) J. Lipid. Res. 57: 832-847). FIG. 6 shows the increase in plasma HDL-cholesterol compared to WD. The data in FIG. 5 were calculated to show the increase in plasma HDL-cholesterol compared to WD. FIG. 7 shows plasma 5-HETE levels. The plasma from the mice in FIG. 1 was analyzed for 5-HETE as described (see, e.g., Navab et al. (2012) J. Lipid Res., 53: 437-445). FIG. 8 shows the decrease in plasma 5-HETE levels compared to WD. The data in FIG. 7 were calculated to show the decrease in plasma 5-HETE levels compared to WD. FIG. 9 shows plasma 12-HETE levels. The plasma from the mice in FIG. 1 was analyzed for 12-HETE as described (see, e.g., Navab et al. (2012) J. Lipid Res., 53: 437-445). FIG. 10 shows the decrease in plasma 12-HETE compared to WD. The data in FIG. 9 were calculated to show the decrease in plasma 12-HETE compared to WD. FIG. 11 shows plasma 15-HETE levels. The plasma from the mice in FIG. 1 was analyzed for 15-HETE as described (see, e.g., Navab et al. (2012) J. Lipid Res., 53: 437-445). FIG. 12 shows the decrease in plasma 15-HETE compared to WD. The data in FIG. 11 were calculated to show the decrease in plasma 15-HETE compared to WD. FIG. 13 shows plasma SAA levels. The plasma from the mice in FIG. 1 was analyzed for SAA as described as described (see, e.g., Chattopadhyay et al. (2015) Pharma. Res. Per. 3: e00154; Chattopadhyay et al. (2016) J. Lipid. Res. 57: 832-847). FIG. 14 shows the decrease in plasma SAA compared to WD. The data in FIG. 13 were calculated to show the decrease in plasma 15-HETE compared to WD. FIG. 15, panels A-F, shows that addition of either Ezetimibe or Tg6F to WD ameliorated dyslipidemia in LDLR null mice and addition of both to WD (Combined Formulation) was significantly better than addition of either agent alone. Female LDLR null mice age 3-6 months (n=20-28 per group) were fed standard mouse chow (Chow) or a Western diet (WD) or the mice were fed WD+0.06% by weight of Tg6F concentrate, which was prepared as described in Methods, or the mice were fed WD with Ezetimibe added to give a daily dose of 10 mg/kg body weight (WD+Ezetimibe) or the mice were fed WD with Tg6F added at 0.06% by weight plus Ezetimibe (each added separately to the diet) to give a daily dose of Ezetimibe of 10 mg/kg body weight as described in Methods for the Combined Formulation. After feeding the diets for two weeks the mice were bled and plasma lipid levels were determined as described in Methods. Panel A) Plasma total cholesterol levels. Panel B) The decrease in plasma cholesterol compared to WD for each treatment. Panel C) Plasma triglyceride levels. Panel D) The decrease in plasma triglycerides compared to WD for each treatment. Panel E) Plasma HDL-Cholesterol levels. Panel F) The Increase in plasma HDL-Cholesterol compared to WD for each treatment. The data shown are Mean±SEM. NS=Not significant. FIG. 16, panels A-N, shows that the enhanced effectiveness of the Combined Formulation depends on the presence of the 6F peptide in Tg6F. Female LDLR null mice age 4-7 months (n=20 per group) were fed standard mouse chow (Chow) or a Western diet (WD) or the mice were fed WD+0.06% by weight of a control transgenic tomato concentrate that does not contain the 6F peptide (EV) as described in Methods, or the mice were fed WD with Ezetimibe added to give a daily dose of 10 mg/kg body weight (WD+Ezetimibe) or the mice were fed WD+Ezetimibe+0.06% by weight of EV (WD+Ezetimibe+EV), or the mice were fed WD with Tg6F added at 0.06% by weight (WD+Tg6F), or the mice were fed Tg6F added at 0.06% by weight plus Ezetimibe (each added separately to the diet) to give a daily dose of Ezetimibe of 10 mg/kg body weight (WD+Combined Formulation) as described in Methods. After feeding the diets for two weeks the mice were bled and plasma lipid levels, plasma levels of lysophosphatidylcholine (LysoPC), and plasma levels of Serum Amyloid A (SAA) were determined as described in Example 3 Methods. Panel A) Plasma total cholesterol levels. Panel B) The decrease in plasma cholesterol compared to WD for each treatment. Panel C) Plasma triglyceride levels. Panel D) The decrease in plasma triglycerides compared to WD for each treatment. Panel E) Plasma HDL-Cholesterol levels. Panel F) The Increase in plasma HDL-Cholesterol compared to WD for each treatment. Panel G) Plasma LysoPC 18:0 levels. Panel H) The decrease in plasma LysoPC 18:0 levels compared to WD for each treatment. Panel I) Plasma LysoPC 18:1 levels. Panel J) The decrease in plasma LysoPC 18:1 levels compared to WD for each treatment. Panel K) Plasma LysoPC 20:4 levels. Panel L) The decrease in plasma LysoPC 20:4 levels compared to WD for each treatment. Panel M) Plasma SAA levels. Panel N) The decrease in plasma SAA levels compared to WD for each treatment. The data shown are Mean±SEM. NS=Not significant. FIG. 17, panels A-N, shows a novel method for administering Tg6F and Ezetimibe together is significantly more effective compared to adding them separately to WD as in the Combined Formulation. Female LDLR null mice age 5-8 months (n=20 per group) were fed standard mouse chow (Chow), or a Western diet (WD), or the mice were fed WD with Ezetimibe added to give a daily dose of 10 mg/kg body weight (WD+Ezetimibe), or the mice were fed WD with Tg6F added at 0.06% by weight of diet (WD+Tg6F), or the mice were fed Tg6F added at 0.06% by weight of diet plus Ezetimibe (each added separately to the diet) to give a daily dose of Ezetimibe of 10 mg/kg body weight (WD+Combined Formulation), or using the Novel Method described in Methods the mice were fed WD containing Tg6F at 0.06% by weight of diet and Ezetimibe sufficient to provide the mice with 10 mg/kg/day (WD+Novel Method). After feeding the diets for two weeks, the mice were bled and plasma lipid levels, plasma levels of hydroxyeicosatetraenoic acid (HETE), and plasma levels of Serum Amyloid A (SAA) were determined as described in Methods. Panel A) Plasma total cholesterol levels. Panel B) The decrease in plasma cholesterol compared to WD for each treatment. Panel C) Plasma triglyceride levels. Panel D) The decrease in plasma triglycerides compared to WD for each treatment. Panel E) Plasma HDL-Cholesterol levels. Panel F) The Increase in plasma HDL-Cholesterol compared to WD for each treatment. Panel G) Plasma 5-HETE levels. Panel H) The decrease in plasma 5-HETE levels compared to WD for each treatment. Panel I) Plasma 12-HETE levels. Panel J) The decrease in plasma 12-HETE levels compared to WD for each treatment. Panel K) Plasma 15-HETE levels. Panel L) The decrease in plasma 15-HETE levels compared to WD for each treatment. Panel M) Plasma SAA levels. Panel N) The decrease in plasma SAA levels compared to WD for each treatment. The data shown are Mean±SEM. NS=Not significant. FIG. 18, panels A-F, shows that incubating Ezetimibe in the ethyl acetate with 5% acetic acid Tg6F supernatant for 2 hours or overnight gave similar results. Female LDLR null mice age 8-10 months (n=20 per group) were fed standard mouse chow (Chow), or a Western diet (WD), or the mice were fed WD with Ezetimibe added to give a daily dose of 10 mg/kg body weight (WD+Ezetimibe), or the mice were fed WD with Tg6F added at 0.06% by weight of diet (WD+Tg6F), or the mice were fed Tg6F added at 0.06% by weight of diet plus Ezetimibe (each added separately to the diet) to give a daily dose of Ezetimibe of 10 mg/kg body weight (WD+Combined Formulation), or the mice were fed WD containing Tg6F at 0.06% by weight of diet and Ezetimibe sufficient to provide the mice with 10 mg/kg/day that had been prepared by the Novel Method with Ezetimibe incubated in the ethyl acetate with 5% acetic acid supernatant for 2 hours (WD+Novel Method-2h) or the Ezetimibe was incubated in the ethyl acetate with 5% acetic acid supernatant overnight (WD+Novel Method-ON) as described in Methods. After feeding the diets for two weeks, the mice were bled and plasma lipid levels and plasma levels of Serum Amyloid A (SAA) were determined as described in Methods. Panel A) Plasma total cholesterol levels. Panel B) The decrease in plasma cholesterol compared to WD for each treatment. Panel C) Plasma triglyceride levels. Panel D) The decrease in plasma triglycerides compared to WD for each treatment. Panel E) Plasma SAA levels. Panel F) The decrease in plasma SAA levels compared to WD for each treatment. The data shown are Mean±SEM. NS=Not significant. FIG. 19, panels A-H, shows that the novel method for administering Tg6F and Ezetimibe together is significantly more effective compared to adding them separately to WD (Combined Formulation) in old mice. Female LDLR null mice age 9-12 months (n=25 per group) were fed standard mouse chow (Chow), or a Western diet (WD), or the mice were fed WD with Ezetimibe added to give a daily dose of 10 mg/kg body weight (WD+Ezetimibe), or the mice were fed WD with Tg6F added at 0.06% by weight of diet (WD+Tg6F), or the mice were fed Tg6F added at 0.06% by weight of diet plus Ezetimibe (each added separately to the diet) to give a daily dose of Ezetimibe of 10 mg/kg body weight (WD+Combined Formulation), or using the Novel Method described in Methods (2 hour incubation of Ezetimibe in the ethyl acetate with 5% acetic acid supernatant) the mice were fed WD containing Tg6F at 0.06% by weight of diet and Ezetimibe sufficient to provide the mice with 10 mg/kg/day (WD+Novel Method). After feeding the diets for two weeks, the mice were bled and plasma lipid levels and plasma levels of Serum Amyloid A (SAA) were determined as described in Methods. Panel A) Plasma total cholesterol levels. Panel B) The decrease in plasma cholesterol compared to WD for each treatment. Panel C) Plasma triglyceride levels. Panel D) The decrease in plasma triglycerides compared to WD for each treatment. Panel E) Plasma HDL-Cholesterol levels. Panel F) The Increase in plasma HDL-Cholesterol compared to WD for each treatment. Panel G) Plasma SAA levels. Panel H) The decrease in plasma SAA levels compared to WD for each treatment. The data shown are Mean±SEM. NS=Not significant. DETAILED DESCRIPTION Methods of transgenically expressing apoA-I memetic peptides (e.g., the 6F peptide) in various plants including tomatoes were previously described (see, e.g., PCT Publication No: WO 2013/148214 A1). Without any purification steps, when the transgenic tomatoes were freeze-dried, ground into powder and fed to a mouse model of dyslipidemia and atherosclerosis at only 2.2% of a high-fat high-cholesterol diet by weight, the transgenic tomatoes significantly reduced dyslipidemia, inflammation and atherosclerosis in the mice. This amount of plant matter provided a daily dose to mice of approximately 40 mg/kg/day. Delivery of an equivalent dosage to a human would require the human to eat approximately 150 grams of freeze-dried tomato powder three times daily. Accordingly, concentration methods were developed to reduces the volume of plant matter (e.g., tomato powder) required to only 3%-4% of that volume (see, e.g., PCT/US2015/031134). The methods typically involved expresses one or more peptides that have ApoA-I activity in a plant tissue. The tissue comprising heterologous ApoA-I peptide was provided as a substantially dry powder that was mixed with a solution comprising ethyl acetate and acetic acid or with a solution comprising ethyl lactate and lactic acid, to form an extraction mixture. In various embodiments, the mixture is incubated (e.g., at room temperature, or at an elevated temperature (e.g., up to about 30° C., or up to about 35° C., or up to about 37° C. or 38° C., or up to about 40° C.) to extract/concentrate the ApoA-I peptide activity. The supernatant was then dried down to provide a concentrate. While simply coadministation of the transgenic 6F peptide in combination with ezetimibe (a cholesterol uptake inhibitor) may be contemplated, it was a surprising discovery that an ezetimibe-associated ApoA-I mimetic peptide could be produced by adding the same dose of ezetimibe to the to the supernatant of Tg6F that had been incubated overnight in ethyl acetate with 5% acetic acid followed by an additional two hour incubation at room temperature and removal of the ethyl acetate. Suprisingly, this resulted in a significantly more effective preparation. More specifically, it was suprirsingly observed that if instead of adding the same doses of Tg6F and Ezetimibe separately to the diet and feeding the diet as a combined formulation to a subject (e.g., mice in the Examples herein), addition of an ezetimibe-associated peptide (e.g., Ez-Tg6F) providing the same dosage of ezetimibe and peptide would produce a significantly better result. FIG. 1 shows the case for plasma Total Cholesterol. In the example shown, the separate addition of Tg6F and Ezetimibe to the diet which was fed to the mice as a combined formulation did not significantly reduce plasma Total Cholesterol beyond the addition of either agent alone, but the addition to the diet of the same doses of Tg6F and Ezetimibe as ezetimibe-associated Tg6F (Ez-Tg6F) prepared by the novel method described above, was significantly more effective in reducing plasma Total Cholesterol than either agent added alone. In view of these discoveries and the additional data shown in the Examples herein, it is believed that ezetimibe-associated ApoA-I peptides prepared as described herein, e.g., by incubating ezetimibe and the apoAI mimetic peptide in a solution comprising ethyl acetate and acetic acid or in a solution comprising ethyl lactate and lactic acid, and drying the solution to provide a dry ezetimibe-associated apoA-I mimetic peptide can provide superior biological activity and efficacy than separate administration of ezetimibe and the apoA-I mimetic peptide or than combined formulations comprising ezetimibe and the apoA-I mimetic peptide. In certain embodiments the apoA-I peptide is a chemically synthesized peptide. However, in other embodiments the ApoA-I peptide is a recombinant peptide expressed in a tissue (e.g., in a plant tissue). In the latter case, the association with ezetimibe can readily be incorporated into the concentration protocol to provide an ezetimibe-associated peptide. In either case, in certain embodiments, the ezetimibe-associated apoA-I mimetic peptide is prepared by incubating ezetimibe and one or more apoAI mimetic peptide(s) in a solution comprising ethyl acetate and acetic acid or in a solution comprising ethyl lactate and lactic acid, and then drying the solution to provide a dry ezetimibe-associated apoA-I mimetic peptide. In certain embodiments the drying comprises drying said solution to produce a dry residue; resuspending said residue in water to provide a resuspended mixture; and drying (e.g., lyophilizing) the resuspended mixture to provide a dry powder extract comprising ezetimibe-associated apoA-I mimetic peptide. In certain embodiments the incubation of ezetimibe with peptide is for at least about 10 minutes, or at least about 15 minutes, or at least about 30 minutes, or at least about 45 minutes, or at least about 1 hr, or at least about 1.5 hour, or at least about 2 hrs, or at least about 3 hrs, or at least about 4 hrs, or at least about 5 hours, or at least about 6 hrs, or at least about 12 hours, or at least about 1 day. In certain embodiments the incubating is for about 2 hrs. In certain embodiments the incubating is at room temperature. Where the apoA-I mimetic peptide is provided as a heterologous peptide expressed in a plant, the plant tissue may be extracted in a solution comprising ethyl acetate and acetic acid or in a solution comprising ethyl lactate and lactic acid prior to combination with ezetimibe. In certain embodiments this extraction mixture is incubated for at least about 15 minutes, or at least about ½ hour, or at least about 1 hour, or at least about 2 hours, or at least about 3 hours, or at least about 4 hours, or at least about 5 hours, or at least about 6 hours, or at least about 7 hours, or at least about 12 hours, or at least about 18 hours, or at least about 24 hours, or at least about 48 hours, or at least about 72 hours, or at least about 96 hours. In certain embodiments the extraction from plant tissue and the reaction with ezetimibe may occur simultaneously. Thus, both components (peptide and ezetimibe) can be added to a solution comprising ethyl acetate and acetic acid or in a solution comprising ethyl lactate and lactic acid and incubated (e.g. for at least about 15 minutes, or at least about ½ hour, or at least about 1 hour, or at least about 2 hours, or at least about 3 hours, or at least about 4 hours, or at least about 5 hours, or at least about 6 hours, or at least about 7 hours, or at least about 12 hours, or at least about 18 hours, or at least about 24 hours, or at least about 48 hours, or at least about 72 hours, or at least about 96 hours). In certain embodiments any of these reactions are carried out at room temperature, or at an elevated temperature (e.g., up to about 30° C., or up to about 35° C., or up to about 37° C. or 38° C., or up to about 40° C. In certain embodiments the solution comprising ethyl acetate and acetic acid comprises about 1% to about 25% acetic acid, or about 2% to about 20% acetic acid, or about 3% to about 15% acetic acid, or about 4% to about 10% acetic acid, or about 4% to about 8% acetic acid, or from about 4% to about 6% acetic acid. In certain embodiments the solution comprising ethyl lactate and lactic acid comprises about 1% to about 25% lactic acid, or about 2% to about 20% lactic acid, or about 3% to about 15% lactic acid, or about 4% to about 10% lactic acid, or about 4% to about 8% lactic acid, or from about 4% to about 6% lactic acid. In certain embodiments the ratio of ezetimibe and apoA-I peptide incubated together ranges from about 1:10 (ezetimibe:Tg6F by weight) or in some cases 0.1:10 or 0.5:10 or 2:10 or 4:10 or 1:1. In view of the foregoing, it is believed the synergistic activity of ezetimibe and apoA-I peptide is significantly improved when formulated as an ezetimibe-associated ApoA-I peptide. In certain embodiments the ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma total cholesterol to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide. In certain embodiments the ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma triglyceride to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide. In certain embodiments the ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma 5-HETE to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide. In certain embodiments the ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma 12-HETE to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide. In certain embodiments the ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma 15-HETE to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide. In certain embodiments the ezetimibe-associated apoA-I mimetic pepide, when fed to a mammal, lowers plasma SAA to a greater amount than a mixed ezetimibe apoA-I peptide formulation containing the same amounts of ezetimibe and apoA-I peptide. As noted above, after incubation, the liquid phase of the mixture can be collected and dried to provide a concentrated dry powder extract that displays the biological activity of the ezetimibe-associated apoA-I mimetic peptide. In certain embodiments this collecting and drying can comprise drying the liquid phase to produce a dry residue and optionally, resuspending said residue in water (e.g. distilled water, de-ionized water, food-grade water) or a buffer to provide a resuspended mixture; and optionally drying the resuspended mixture to provide the dry powder extract. In various embodiments the drying operations can be performed using any conventional drying procedure including, but not limited to lyophilization, drying at room temperature (e.g., under a dry gas such as argon), drying at elevated temperature, drying at low pressure, and the like. The resulting extract can optionally be compounded with any edible components for administration to a subject. While the concentration protocol is illustrated with respect to a transgenic tomato plant expressing a heterologous 6F peptide, it is believe the same protocols can be effectively utilized with any of a number of other plants/plant tissues expressing any one or more peptides having ApoA-I activity. Thus, in various embodiments the transgenic plant tissue comprises a tissue from a transgenic plant such as tomatoes, carrots, potatoes, apples, pears, plums, peaches, oranges, kiwis, papayas, pineapples, guava, lilikoi, starfruit, lychee, mango, grape, pomegranate, mustard greens, kale, chard, lettuce, soybean, rice, corn and other grains (e.g., wheat, rice, barley, bulgur, faro, kamut, kaniwa, millet, oats, quinoa, rice, rye, sorghum, spelt, teff, triticale, and the like), berries such as strawberries, blueberries, blackberries, goji berries, and raspberries, banana, rice, turnip, maize, grape, fig, plum, potato, safflower seeds, nuts (e.g., almond, walnut, pecan, peanut, cashew, macademia, hazelnut, etc.), legumes (e.g., alfalfa, clover, peas, beans (including black beans), lentils, lupins, mesquite, carob, soybeans, and the like). In certain embodiments the plant is selected from the group consisting of tomato, rice, tobacco, turnip, maize, corn, soybean, grape, fig, plum, potato, carrot, pomegranate, mustard greens, chard, kale, lettuce, broccoli, and safflower seeds. In certain embodiments the tissue of the transgenic plant comprises a fruit (e.g. a tomato). In certain embodiments the tissue of the transgenic plant comprises a seed, a leaf, a root, a tuber, a flower, and the like. ApoA-I Mimetics and Other Peptides for Use in Ez-Peptides. Having demonstrated that the 6F peptide when expressed in a plant (e.g., a tomato) shows significant biological activity when the peptide is processed with ezetimibe as described herein to provide an ezetimibe-associated peptide, it is believed that similar results can be obtained with any of a number of other therapeutic peptides comprising or consisting of domains that are therapeutic peptide sequences and these results can be obtained by chemically synthesized peptides and/or by expression of the peptide(s) in tomato or other plants, e.g., as described herein and in PCT Publication No: WO 2013/148214 A1 and in Chattopadhyay et al. (2013) J. Lipid Res., 54: 995-10101, and Navab et al. (2013) J. Lipid Res., 54: 3403-3418. In certain embodiments these peptides include, but are not limited to class A amphipathic helical peptides, class A amphipathic helical peptide mimetics of apoA-I having aromatic or aliphatic residues in the non-polar face, Apo-J (G* peptides), apoE peptides, and the like, and peptide mimetics, e.g., as described below. ApoA-I Mimetic Peptides. In certain embodiments the peptides used there to prepare ezetimibe-modified peptides comprise or consist of apoA-I mimetic peptides. In certain embodiments such peptides include, but are not limited to, class A amphipathic helical peptides, e.g. as described in U.S. Pat. No. 6,664,230, and PCT Publications WO 02/15923 and WO 2004/034977, which are incorporated herein by reference for the peptide sequences disclosed therein. It was discovered that peptides comprising a class A amphipathic helix (“class A peptides”), in addition to being capable of mitigating one or more symptoms of atherosclerosis are also useful in the treatment of one or more of the other indications described herein. Class A peptides are characterized by formation of an α-helix that produces a segregation of polar and non-polar residues thereby forming a polar and a nonpolar face with the positively charged residues residing at the polar-nonpolar interface and the negatively charged residues residing at the center of the polar face (see, e.g., Anantharamaiah (1986) Meth. Enzymol, 128: 626-668). It is noted that the fourth exon of apo A-I, when folded into 3.667 residues/turn produces a class A amphipathic helical structure. Significant biological activity has been demonstrated for various apoA-I mimetic peptides including, but not limited to the peptides designated 4F, retro (reverse 4F), 5F, 6F, and the like. Various class A peptides inhibited lesion development in atherosclerosis-susceptible mice. In addition, the peptides show varying, but significant degrees of efficacy in mitigating one or more symptoms of the various pathologies described herein. A number of such peptides described in PCT patent application Nos: PCT/US2001/026497 (WO 2002/015923), PCT/US2003/032442 (WO 2004/034977), PCT/US2008/085409, and in Bielicki et al. (2010) J. Lipid Res. 51: 1496-1503, Zheng et al. (2011) Biochemistry, 50: 4068-4076, Di Bartolo et al. (2011) Lipids in Health and Disease 10: 224. In certain embodiments the peptides used for the preparation of ezetimibe associated peptides (Ez-peptides) described herein comprise one or more domains that have an amino acid sequence shown in Table 1 or the reverse sequence. TABLE 1 Certain ApoA-I mimetic peptides that can be used for the preparation of ezetimibe associated peptides (Ez-peptides), e.g., as described herein. The table includes various class A and/or class Y peptide analogs. For each sequence listed in this table, the retro form of the sequence is also comtemplated. Thus, for example where the 6F peptide sequence DWLKAFYDKFFEKFKEFF (SEQ ID NO: 1) is shown, the retro amino acid sequence FFEKFKEFFKDYFAKLWD (SEQ ID NO: 15) is also contemplated. Peptide Name Amino Acid Sequence SEQ ID NO. 18A DWLKAFYDKVAEKLKEAF 2 2F DWLKAFYDKVAEKLKEAF 3 3F DWFKAFYDKVAEKLKEAF 4 3F14 DWLKAFYDKVAEKFKEAF 5 4F DWFKAFYDKVAEKFKEAF 6 5F DWLKAFYDKVFEKFKEFF 7 6F DWLKAFYDKFFEKFKEFF 1 7F DWFKAFYDKFFEKFKEFF 8 DWLKAFYDKVAEKLKEFF 9 Rev18A FAEKLKEAVKDYFAKLWD 10 Rev2F FAEKLKEAVKDYFAKLWD 11 Ref3F FAEKLKEAVKDYFAKFWD 12 Rev4F FAEKFKEAVKDYFAKFWD 13 Rev5F FFEKFKEFVKDYFAKLWD 14 Rev6F FFEKFKEFFKDYFAKLWD 15 Rev7F FFEKFKEFFKDYFAKFWD 16 DWLKAFYDKVFEKFKEAF 17 DWLKAFYDKVFEKLKEFF 18 DWLKAFYDKVAEKFKEFF 19 DWLKAFYDKVFEKFKEFF 20 EWLKLFYEKVLEKFKEAF 21 EWLKAFYDKVAEKFKEAF 22 EWLKAFYDKVAEKLKEFF 23 EWLKAFYDKVFEKFKEAF 24 EWLKAFYDKVFEKLKEFF 25 EWLKAFYDKVAEKFKEFF 26 EWLKAFYDKVFEKFKEFF 27 AFYDKVAEKLKEAF 28 AFYDKVAEKFKEAF 29 AFYDKVAEKFKEAF 30 AFYDKFFEKFKEFF 31 AFYDKFFEKFKEFF 32 AFYDKVAEKFKEAF 33 AFYDKVAEKLKEFF 34 AFYDKVFEKFKEAF 35 AFYDKVFEKLKEFF 36 AFYDKVAEKFKEFF 37 KAFYDKVFEKFKEF 38 LFYEKVLEKFKEAF 39 AFYDKVAEKFKEAF 40 AFYDKVAEKLKEFF 41 AFYDKVFEKFKEAF 42 AFYDKVFEKLKEFF 43 AFYDKVAEKFKEFF 44 AFYDKVFEKFKEFF 45 DWLKALYDKVAEKLKEAL 46 DWFKAFYEKVAEKLKEFF 47 DWFKAFYEKFFEKFKEFF 48 EWLKALYEKVAEKLKEAL 49 EWLKAFYEKVAEKLKEAF 50 EWFKAFYEKVAEKLKEFF 51 EWLKAFYEKVFEKFKEFF 52 EWLKAFYEKFFEKFKEFF 53 EWFKAFYEKFFEKFKEFF 54 DFLKAWYDKVAEKLKEAW 55 EFLKAWYEKVAEKLKEAW 56 DFWKAWYDKVAEKLKEWW 57 EFWKAWYEKVAEKLKEWW 58 DKLKAFYDKVFEWAKEAF 59 DKWKAVYDKFAEAFKEFL 60 EKLKAFYEKVFEWAKEAF 61 EKWKAVYEKFAEAFKEFL 62 DWLKAFVDKFAEKFKEAY 63 EKWKAVYEKFAEAFKEFL 64 DWLKAFVYDKVFKLKEFF 65 EWLKAFVYEKVFKLKEFF 66 DWLRAFYDKVAEKLKEAF 67 EWLRAFYEKVAEKLKEAF 68 DWLKAFYDRVAEKLKEAF 69 EWLKAFYERVAEKLKEAF 70 DWLKAFYDKVAERLKEAF 71 EWLKAFYEKVAERLKEAF 72 DWLKAFYDKVAEKLREAF 73 EWLKAFYEKVAEKLREAF 74 DWLKAFYDRVAERLKEAF 75 EWLKAFYERVAERLKEAF 76 DWLRAFYDKVAEKLREAF 77 EWLRAFYEKVAEKLREAF 78 DWLRAFYDRVAEKLKEAF 79 EWLRAFYERVAEKLKEAF 80 DWLKAFYDKVAERLREAF 81 EWLKAFYEKVAERLREAF 82 DWLRAFYDKVAERLKEAF 83 EWLRAFYEKVAERLKEAF 84 DWLKAFYDKVAEKLKEAFPDWLKAFYD 85 KVAEKLKEAF DWLKAFYDKVAEKLKEFFPDWLKAFYD 86 KVAEKLKEFF DWFKAFYDKVAEKLKEAFPDWFKAFYD 87 KVAEKLKEAF DKLKAFYDKVFEWAKEAFPDKLKAFYD 88 KVFEWLKEAF DKWKAVYDKFAEAFKEFLPDKWKAVYD 89 KFAEAFKEFL DWFKAFYDKVAEKFKEAFPDWFKAFYD 90 KVAEKFKEAF DWLKAFVYDKVFKLKEFFPDWLKAFVY 91 DKVFKLKEFF DWLKAFYDKFAEKFKEFFPDWLKAFYD 92 KFAEKFKEFF EWFKAFYEKVAEKFKEAF 93 DWFKAFYDKVAEKF 94 FKAFYDKVAEKFKE 95 FKAFYEKVAEKFKE 96 FKAFYDKVAEKFKE 97 FKAFYEKVAEKFKE 98 DWFKAFYDKVAEKFKEAF 99 EWFKAFYEKVAEKFKEAF 100 AFYDKVAEKFKEAF 101 DWFKAFYDKVAEKF 102 DWLKAFYDKVFEKFKEFF 103 EWLKAFYEKVFEKFKEFF 104 AFYDKVFEKFKEFF 105 AFYEKVFEKFKEFF 106 DWLKAFYDKVFEKF 107 EWLKAFYEKVFEKF 108 LKAFYDKVFEKFKE 109 LKAFYEKVFEKFKE 110 [Switch D-E]-1-4F EWFKAFYEKVADKFKDAF 111 [Switch D-E]-2-4F EWFKAFYDKVADKFKEAF 112 [Switch D-E]-3-4F DWFKAFYEKVADKFKEAF 113 [Switch D-E]-4-4F DWFKAFYEKVAEKFKDAF 114 4F-2 DFWKAFYDKVAEKFKEAF 115 [Switch D-E]-1-4F-2 EFWKAFYEKVADKFKDAF 116 [Switch D-E]-2-4F-2 EFWKAFYDKVADKFKEAF 117 [Switch D-E]-3-4F-2 DFWKAFYEKVADKFKEAF 118 [Switch D-E]-4-4F-2 DFWKAFYEKVAEKFKDAF 119 4F-3 DWFKAYFDKVAEKFKEAF 120 [Switch D-E]-1-4F-5 EWFKAYFEKVADKFKDAF 121 [Switch D-E]-2-4F-5 EWFKAYFDKVADKFKEAF 122 [Switch D-E]-3-4F-5 DWFKAYFEKVADKFKEAF 123 [Switch D-E]-4-4F-5 DWFKAYFEKVAEKFKDAF 124 4F-4 DWFKAFVDKYAEKFKEAF 125 [Switch D-E]-1-4F-4 EWFKAFVEKYADKFKDAF 126 [Switch D-E]-2-4F-4 EWFKAFVDKYADKFKEAF 127 [Switch D-E]-3-4F-4 DWFKAFVEKYADKFKEAF 128 [Switch D-E]-4-4F DWFKAFVEKYAEKFKDAF 129 4-F-5 DWFKAFYDKAVEKFKEAF 130 [Switch D-E]-1-4F-5 EWFKAFYEKAVDKFKDAF 131 [Switch D-E]-2-4F-5 EWFKAFYDKAVDKFKEAF 132 [Switch D-E]-3-4F-5 DWFKAFYEKAVDKFKEAF 133 [Switch D-E]-4-4F-5 DWFKAFYEKAVEKFKDAF 134 4F-6 DWFKAFYDKVFEKAKEAF 135 [Switch D-E]-1-4F-6 EWFKAFYEKVFDKAKDAF 136 [Switch D-E]-2-4F-6 EWFKAFYDKVFDKAKEAF 137 [Switch D-E]-3-4F-6 DWFKAFYEKVFDKAKEAF 138 [Switch D-E]-4-4F-6 DWFKAFYEKVFEKAKDAF 139 4F-7 DWFKAFYDKVAEKAKEFF 140 [Switch D-E]-1-4F-7 EWFKAFYEKVADKAKDFF 141 [Switch D-E]-2-4F-7 EWFKAFYDKVADKAKEFF 142 [Switch D-E]-3-4F-7 DWFKAFYEKVADKAKEFF 143 [Switch D-E]-4-4F-7 DWFKAFYEKVAEKAKEFF 144 4F-8 DWFKAFYDKVAEKFKEFA 145 [Switch D-E]-1-4F-8 EWFKAFYEKVADKFKDFA 146 [Switch D-E]-2-4F-8 EWFKAFYDKVADKFKEFA 147 [Switch D-E]-3-4F-8 DWFKAFYEKVADKFKEFA 148 [Switch D-E]-4-4F-8 DWFKAFYEKVAEKFKDFA 149 4F-9 DAFKAFYDKVAEKFKEWF 150 [Switch D-E]-1-4F-9 EAFKAFYEKVADKFKDWF 151 [Switch D-E]-2-4F-9 EAFKAFYDKVADKFKEWF 152 [Switch D-E]-3-4F-9 DAFKAFYEKVADKFKE 153 [Switch D-E]-4-4F-9 DAFKAFYEKVAEKFKDWF 154 4F-10 DAFKAFYDKVWEKFKEAF 155 [Switch D-E]-1-4F-10 EAFKAFYEKVWDKFKDAF 156 [Switch D-E]-2-4F-10 EAFKAFYDKVWDKFKEAF 157 [Switch D-E]-3-4F-10 DAFKAFYEKVWDKFKEAF 158 [Switch D-E]-4-4F-10 DAFKAFYEKVWEKFKDAF 159 4F-11 DYFKAFWDKVAEKFKEAF 160 [Switch D-E]-1-4F-11 EYFKAFWEKVADKFKDAF 161 [Switch D-E]-2-4F-11 EYFKAFWDKVADKFKEAF 162 [Switch D-E]-3-4F-11 DYFKAFWEKVADKFKEAF 163 [Switch D-E]-4-4F-11 DYFKAFWEKVAEKFKDAF 164 4F-12 DWAKAFYDKVAEKFKEFF 165 [Switch D-E]-1-4F-12 EWAKAFYEKVADKFKDFF 166 [Switch D-E]-2-4F-12 EWAKAFYDKVADKFKEFF 167 [Switch D-E]-3-4F-12 DWAKAFYEKVADKFKEFF 168 [Switch D-E]-4-4F-12 DWAKAFYEKVAEKFKDFF 169 4F-13 DWFKAAYDKVAEKFKEFF 170 [Switch D-E]-1-4F-13 EWFKAAYEKVADKFKDFF 171 [Switch D-E]-2-4F-13 EWFKAAYDKVADKFKEFF 172 [Switch D-E]-3-4F-13 DWFKAAYEKVADKFKEFF 173 [Switch D-E]-4-4F-13 DWFKAAYEKVAEKFKDFF 174 4F-14 DWFKAFADKVAEKFKEYF 175 [Switch D-E]-1-4F-14 EWFKAFAEKVADKFKDYF 176 [Switch D-E]-2-4F-14 EWFKAFADKVADKFKEYF 177 [Switch D-E]-3-4F-14 DWFKAFAEKVADKFKEYF 178 [Switch D-E]-4-4F DWFKAFAEKVAEKFKDYF 179 4F-15 DWFKAFYDKAAEKFKEVF 180 [Switch D-E]-1-4F-15 EWFKAFYEKAADKFKDVF 181 [Switch D-E]-2-4F-15 EWFKAFYDKAADKFKEVF 182 [Switch D-E]-3-4F-15 DWFKAFYEKAADKFKEVF 183 [Switch D-E]-4-4F-15 DWFKAFYEKAAEKFKDVF 184 4F-16 DWYKAFFDKVAEKFKEAF 185 [Switch D-E]-1-4F-16 EWYKAFFEKVADKFKDAF 186 [Switch D-E]-2-4F-16 EWYKAFFDKVADKFKEAF 187 [Switch D-E]-3-4F-16 DWYKAFFEKVADKFKEAF 188 [Switch D-E]-4-4F-16 DWYKAFFEKVAEKFKDAF 189 4F-17 DWVKAFYDKFAEKFKEAF 190 [Switch D-E]-1-4F-17 EWVKAFYEKFADKFKDAF 191 [Switch D-E]-2-4F-17 EWVKAFYDKFADKFKEAF 192 [Switch D-E]-3-4F-17 DWVKAFYEKFADKFKEAF 193 [Switch D-E]-4-4F-17 DWVKAFYEKFAEKFKDAF 194 4F-18 DWFKAFFDKVAEKYKEAF 195 [Switch D-E]-1-4F-18 EWFKAFFEKVADKYKDAF 196 [Switch D-E]-2-4F-18 EWFKAFFDKVADKYKEAF 197 [Switch D-E]-3-4F-18 DWFKAFFEKVADKYKEAF 198 [Switch D-E]-3-4F-18 DWFKAFFEKVADKYKEAF 199 4F-19 DWFKAFFDKVAEKFKEAY 200 [Switch D-E]-1-4F-19 EWFKAFFEKVADKFKDAY 201 [Switch D-E]-2-4F-19 EWFKAFFDKVADKFKEAY 202 [Switch D-E]-3-4F-19 DWFKAFFEKVADKFKEAY 203 [Switch D-E]-4-4F-19 DWFKAFFEKVAEKFKDAY 204 4F-20 DWFKAFYDKFAEKFKEAV 205 [Switch D-E]-1-4F-20 EWFKAFYEKFADKFKDAV 206 [Switch D-E]-2-4F-20 EWFKAFYDKFADKFKEAV 207 [Switch D-E]-3-4F-20 DWFKAFYEKFADKFKEAV 208 [Switch D-E]-4-4F-20 DWFKAFYEKFAEKFKDAV 209 4F-21 DKFKAFYDKVAEKFWEAF 210 [Switch D-E]-1-4F-21 EKFKAFYEKVADKFWDAF 211 [Switch D-E]-2-4F-21 EKFKAFYDKVADKFWEAF 212 [Switch D-E]-3-4F-21 DKFKAFYEKVADKFWEAF 213 [Switch D-E]-4-4F-21 DKFKAFYEKVAEKFWDAF 214 4F-22 DKWKAFYDKVAEKFFEAF 215 [Switch D-E]-1-4F-22 EKWKAFYEKVADKFFDAF 216 [Switch D-E]-2-4F-22 EKWKAFYDKVADKFFEAF 217 [Switch D-E]-3-4F-22 DKWKAFYEKVADKFFEAF 218 [Switch D-E]-4-4F-22 DKWKAFYEKVAEKFFDAF 219 4F-23 DKFKAFYDKWAEVFKEAF 220 [Switch D-E]-1-4F-23 EKFKAFYEKWADVFKDAF 221 [Switch D-E]-2-4F-23 EKFKAFYDKWADVFKEAF 222 [Switch D-E]-3-4F-23 DKFKAFYEKWADVFKEAF 223 [Switch D-E]-4-4F-23 DKFKAFYEKWAEVFKDAF 224 4F-24 DKFKAFYDKVAEFWKEAF 225 [Switch D-E]-1-4F-24 EKFKAFYEKVADFWKDAF 226 [Switch D-E]-2-4F-24 EKFKAFYDKVADFWKEAF 227 [Switch D-E]-3-4F-24 DKFKAFYEKVADFWKEAF 228 [Switch D-E]-4-4F-24 DKFKAFYEKVAEFWKDAF 229 Rev-4F FAEKFKEAVKDYFAKFWD 230 [Switch D-E]-1-Rev-4F FADKFKDAVKEYFAKFWE 231 [Switch D-E]-2-Rev-4F FADKFKEAVKDYFAKFWE 232 [Switch D-E]-3-Rev-4F FAEKFKDAVKEYFAKFWD 233 [Switch D-E]-4-Rev-4F FAEKFKDAVKDYFAKFWE 234 Rev-4F-1 FWEKFKEAVKDYFAKFAD 235 [Switch D-E]-1-Rev-4F-1 FWDKFKDAVKEYFAKFAE 236 [Switch D-E]-2-Rev-4F-1 FADKFKEAVKDYFAKFWE 237 [Switch D-E]-3-Rev-4F-1 FAEKFKDAVKEYFAKFWD 238 [Switch D-E]-4-Rev-4F-1 FAEKFKDAVKDYFAKFWE 239 Rev-4F-2 FFEKFKEAVKDYFAKAWD 240 [Switch D-E]-1-Rev-4F-2 FFDKFKDAVKEYFAKAWE 241 [Switch D-E]-2-Rev-4F-2 FFDKFKEAVKDYFAKAWE 242 [Switch D-E]-3-Rev-4F-2 FFEKFKDAVKEYFAKAWD 243 [Switch D-E]-4-Rev-4F-2 FFEKFKDAVKDYFAKAWE 244 Rev-4F-3 FAEKAKEFVKDYFAKFWD 245 [Switch D-E]-1-Rev-4F-3 FADKAKDFVKEYFAKFWE 246 [Switch D-E]-2-Rev-4F-3 FADKAKEFVKDYFAKFWE 247 [Switch D-E]-3-Rev-4F-3 FAEKAKDFVKEYFAKFWD 248 [Switch D-E]-4-Rev-4F-3 FAEKAKDFVKDYFAKFWE 249 Rev-4F-4 FAEKFKEVAKDYFAKFWD 250 [Switch D-E]-1-Rev-4F-4 FADKFKDVAKEYFAKFWE 251 [Switch D-E]-2-Rev-4F-4 FADKFKEVAKDYFAKFWE 252 [Switch D-E]-3-Rev-4F-4 FAEKFKDVAKEYFAKFWD 253 [Switch D-E]-4-Rev-4F-4 FAEKFKDVAKDYFAKFWE 254 Rev-4F-5 FAEKFKEAYKDVFAKFWD 255 [Switch D-E]-1-Rev-4F-5 FADKFKDAYKEVFAKFWE 256 [Switch D-E]-2-Rev-4F-5 FADKFKEAYKDVFAKFWE 257 [Switch D-E]-3-Rev-4F-5 FAEKFKDAYKEVFAKFWD 258 [Switch D-E]-4-Rev-4F-5 FAEKFKDAYKDVFAKFWE 259 Rev-4F-6 FAEKFKEAVKDFYAKFWD 260 [Switch D-E]-1-Rev-4F-6 FADKFKDAVKEFYAKFWE 261 [Switch D-E]-2-Rev-4F-6 FADKFKEAVKDFYAKFWE 262 [Switch D-E]-3-Rev-4F-6 FAEKFKDAVKEFYAKFWD 263 [Switch D-E]-4-Rev-4F-6 FAEKFKDAVKDFYAKFWE 264 Rev-4F-7 FAEKFWEAVKDYFAKFKD 265 [Switch D-E]-1-Rev-4F-7 FADKFWDAVKEYFAKFKE 266 [Switch D-E]-2-Rev-4F-7 FADKFWEAVKDYFAKFKE 267 [Switch D-E]-3-Rev-4F-7 FAEKFWDAVKEYFAKFKD 268 [Switch D-E]-4-Rev-4F-7 FAEKFWDAVKDYFAKFKE 269 Rev-4F-8 AFEKFKEAVKDYFAKFWD 270 [Switch D-E]-1-Rev-4F-8 AFDKFKDAVKEYFAKFWE 271 [Switch D-E]-2-Rev-4F-8 AFDKFKEAVKDYFAKFWE 272 [Switch D-E]-3-Rev-4F-8 AFEKFKDAVKEYFAKFWD 273 [Switch D-E]-4-Rev-4F-8 AFEKFKDAVKDYFAKFWE 274 Rev-F-9 VAEKFKEAFKDYFAKFWD 275 [Switch D-E]-1-Rev-4F-9 VADKFKDAFKEYFAKFWE 276 [Switch D-E]-2-Rev-4F-9 VADKFKEAFKDYFAKFWE 277 [Switch D-E]-3-Rev-4F-9 VAEKFKDAFKEYFAKFWD 278 [Switch D-E]-4-Rev-4F-9 VAEKFKDAFKDYFAKFWE 279 Rev-4F-10 YAEKFKEAVKDFFAKFWD 280 [Switch D-E]-1-Rev-4F-10 YADKFKDAVKEFFAKFWE 281 [Switch D-E]-2-Rev-4F-10 YADKFKEAVKDFFAKFWE 282 [Switch D-E]-3-Rev-4F-10 YAEKFKDAVKEFFAKFWD 283 [Switch D-E]-4-Rev-4F-10 YAEKFKDAVKDFFAKFWE 284 Rev-4F-11 AAEKFKEFVKDYFAKFWD 285 [Switch D-E]-1-Rev-4F-11 AADKFKDFVKEYFAKFWE 286 [Switch D-E]-2-Rev-4F-11 AADKFKEFVKDYFAKFWE 287 [Switch D-E]-3-Rev-4F-11 AAEKFKDFVKEYFAKFWD 288 Switch D-E]-4-Rev-4F-11 AAEKFKDFVKDYFAKFWE 289 Rev-4F-12 FFEKAKEAVKDYFAKFWD 290 [Switch D-E]-1-Rev-4F-12 FFDKAKDAVKEYFAKFWE 291 [Switch D-E]-2-Rev-4F-12 FFDKAKEAVKDYFAKFWE 292 [Switch D-E]-3-Rev-4F-12 FFEKAKDAVKEYFAKFWD 293 [Switch D-E]-4-Rev-4F-12 FFEKAKDAVKDYFAKFWE 294 Rev-4F-13 FYEKFKEAVKDAFAKFWD 295 [Switch D-E]-1-Rev-4F-13 FYDKFKDAVKEAFAKFWE 296 [Switch D-E]-2-Rev-4F-13 FYDKFKEAVKDAFAKFWE 297 [Switch D-E]-3-Rev-4F-13 FYEKFKDAVKEAFAKFWD 298 [Switch D-E]-4-Rev-4F-13 FYEKFKDAVKDAFAKFWE 299 Rev-4F-14 FVEKFKEAAKDYFAKFWD 300 [Switch D-E]-1-Rev-4F-14 FVDKFKDAAKEYFAKFWE 301 [Switch D-E]-2-Rev-4F-14 FVDKFKEAAKDYFAKFWE 302 [Switch D-E]-3-Rev-4F-14 FVEKFKDAAKEYFAKFWD 303 [Switch D-E]-4-Rev-4F-14 FVEKFKDAAKDYFAKFWE 304 Rev-4F-15 FAEKYKEAVKDFFAKFWD 305 [Switch D-E]-1-Rev-4F-15 FADKYKDAVKEFFAKFWE 306 [Switch D-E]-2-Rev-4F-15 FADKYKEAVKDFFAKFWE 307 [Switch D-E]-3-Rev-4F-15 FAEKYKDAVKEFFAKFWD 308 [Switch D-E]-4-Rev-4F-15 FAEKYKDAVKDFFAKFWE 309 Rev-4F-16 FAEKVKEAFKDYFAKFWD 310 [Switch D-E]-1-Rev-4F-16 FADKVKDAFKEYFAKFWE 311 [Switch D-E]-2-Rev-4F-16 FADKVKEAFKDYFAKFWE 312 [Switch D-E]-3-Rev-4F-16 FAEKVKDAFKEYFAKFWD 313 [Switch D-E]-4-Rev-4F-16 FAEKVKDAFKDYFAKFWE 314 Rev-4F-17 FAEKFKEYVKDAFAKFWD 315 [Switch D-E]-1-Rev-4F-17 FADKFKDYVKEAFAKFWE 316 [Switch D-E]-2-Rev-4F-17 FADKFKEYVKDAFAKFWE 317 [Switch D-E]-3-Rev-4F-17 FAEKFKDYVKEAFAKFWD 318 [Switch D-E]-4-Rev-4F-17 FAEKFKDYVKDAFAKFWE 319 Rev-4F-18 FAEKFKEAFKDYVAKFWD 320 [Switch D-E]-1-Rev-4F-18 FADKFKDAFKEYVAKFWE 321 [Switch D-E]-2-Rev-4F-18 FADKFKEAFKDYVAKFWE 322 [Switch D-E]-3-Rev-4F-18 FAEKFKDAFKEYVAKFWD 323 [Switch D-E]-4-Rev-4F-18 FAEKFKDAFKDYVAKFWE 324 Rev-4F-19 FAEKFKEAFKDYFAKVWD 325 [Switch D-E]-1-Rev-4F-19 FADKFKDAFKEYFAKVWE 326 [Switch D-E]-2-Rev-4F-19 FADKFKEAFKDYFAKVWE 327 [Switch D-E]-3-Rev-4F-19 FAEKFKDAFKEYFAKVWD 328 Switch D-E]-4-Rev-4F-19 FAEKFKDAFKDYFAKVWE 329 Rev-4F-20 FAEKFKEAVKDFFAKYWD 330 [Switch D-E]-1-Rev-4F-20 FADKFKDAVKEFFAKYWE 331 [Switch D-E]-2-Rev-4F-20 FADKFKEAVKDFFAKYWE 332 [Switch D-E]-3-Rev-4F-20 FAEKFKDAVKEFFAKYWD 333 [Switch D-E]-4-Rev-4F-20 FAEKFKDAVKDFFAKYWE 334 Rev-4F-21 WAEKFFEAVKDYFAKFKD 335 [Switch D-E]-1-Rev-4F-7 WADKFFDAVKEYFAKFKE 336 [Switch D-E]-2-Rev-4F-7 WADKFFEAVKDYFAKFKE 337 [Switch D-E]-3-Rev-4F-7 WAEKFFDAVKEYFAKFKD 338 Switch D-E]-4-Rev-4F-7 WAEKFFDAVKDYFAKFKE 339 Rev-4F-22 FAEKWFEAVKDYFAKFKD 340 [Switch D-E]-1-Rev-4F-22 FADKWFDAVKEYFAKFKE 341 [Switch D-E]-2-Rev-4F-22 FADKWFEAVKDYFAKFKE 342 [Switch D-E]-3-Rev-4F-22 FAEKWFDAVKEYFAKFKD 343 [Switch D-E]-4-Rev-4F-22 FAEKWFDAVKDYFAKFKE 344 Rev-4F-23 FAEKFVEAWKDYFAKFKD 345 [Switch D-E]-1-Rev-4F-23 FADKFVDAWKEYFAKFKE 346 [Switch D-E]-2-Rev-4F-23 FADKFVEAWKDYFAKFKE 347 [Switch D-E]-3-Rev-4F-23 FAEKFVDAWKEYFAKFKD 348 [Switch D-E]-4-Rev-4F-23 FAEKFVDAWKDYFAKFKE 349 Rev-4F-24 FYEKFAEAVKDWFAKFKD 350 [Switch D-E]-1-Rev-4F-24 FYDKFADAVKEWFAKFKE 351 [Switch D-E]-2-Rev-4F-24 FYDKFAEAVKDWFAKFKE 352 [Switch D-E]-3-Rev-4F-24 FYEKFADAVKEWFAKFKD 353 [Switch D-E]-4-Rev-4F-24 FYEKFADAVKDWFAKFKE 354 [A-5 > H] 4F DWFKHFYDKVAEKFKEAF 355 [A-5 > H, D-E switched]4F EWFKHFYEKVADKFKDAF 356 [A-5 > H, D-1 > E]4F EWFKHFYDKVAEKFKEAF 357 [A-5 > H, D-8 > E]4-F DWFKHFYEKVAEKFKEAF 358 [A-5 > H, E-12 > D] 4F DWFKHFYDKVADKFKEAF 359 [A-5 > H, E-16 > D] 4F DWFKHFYDKVAEKFKDAF 360 [F-3 > H, A-5 > F]-4F DWHKFFYDKVAEKFKEAF 361 [F-3 > H, A-5 > F, D-E switched]-4F EWHKFFYEKVADKFKDAF 362 [F-3 > H, A-5 > F, D-1 > E]-4F EWHKFFYDKVAEKFKEAF 363 [F-3 > H, A-5 > F, D-8 > E]-4F DWHKFFYEKVAEKFKEAF 364 [F-3 > H, A-5 > F, E-12 > D]-4F DWHKFFYDKVADKFKEAF 365 [F-3 > H, A-5 > F, E-16 > D]-4F DWHKFFYDKVAEKFKDAF 366 [A-5 > F, F-6 > H]4F DWFKFHYDKVAEKFKEAF 367 [A-5 > F, F-6 > H, D-E switched]4F EWFKFHYEKVADKFKDAF 368 [[A-5 > F, F-6 > H, D-1 > E]4F EWFKFHYDKVAEKFKEAF 369 [A-5 > F, F-6 > H, D-8 > E]4F DWFKFHYEKVAEKFKEAF 370 [A-5 > F, F-6 > H, E-12 > D]4F DWFKFHYDKVADKFKEAF 371 [A-5 > F, F-6 > H, E-16 > D]4F DWFKFHYDKVAEKFKDAF 372 [A-5 > V, V-10 > H]4F DWFKVFYDKHAEKFKEAF 373 [A-5 > V, V-10 > H, D-E switched]4F EWFKVFYEKHADKFKDAF 374 [A-5 > V, V-10 > H, D-1 > E]4F EWFKVFYDKHAEKFKEAF 375 [A-5 > V, V-10 > H, D-8 > E] 4F DWFKVFYEKHAEKFKEAF 376 [A-5 > V, V-10 > H, E-12 > D] 4F DWFKVFYDKHADKFKEAF 377 [A-5 > V, V-10 > H, E16 > D] 4F DWFKVFYDKHAEKFKDAF 378 [[A-17 > H]4F DWFKAFYDKVAEKFKEHF 379 [A-17 > H, D-E switched] 4F EWFKAFYEKVADKFKDHF 380 [[A-17 > H, D-1 > E]4F EWFKAFYDKVAEKFKEHF 381 [[A-17 > H, D-8 > E]4F DWFKAFYEKVAEKFKEHF 382 [[A-17 > H, E-12 > D]4F DWFKAFYDKVADKFKEHF 383 [[A-17 > H, E16 > D]4F DWFKAFYDKVAEKFKDHF 384 [A-17 > F, F-18 > H] 4F DWFKAFYDKVAEKFKEFH 385 [A-17 > F, F-18 > H, D-E switched] 4F EWFKAFYEKVADKFKDFH 386 [A-17 > F, F-18 > H, D-1 > E]-4F EWFKAFYDKVAEKFKEFH 387 [A-17 > F, F-18 > H] 4F DWFKAFYDKVAEKFKEFH 388 [A-17 > F, F-18 > H, D-8 > E]-4F DWFKAFYEKVAEKFKEFH 389 [A-17 > F, F-18 > H, E-12 > D] 4F DWFKAFYDKVAEKFKEFH 390 [A-17 > F, F-18 > H], E-16 > D]-4F DWFKAFYDKVAEKFKDFH 391 Rev-4F FAEKFKEAVKDYFAKFWD 392 [A-2 > H]Rev4F FHEKFKEAVKDYFAKFWD 393 Rev-[A-2 > H, D > E]-4F FHEKFKEAVKEYFAKFWE 394 Rev-[A-2 > H, E > D]4F FHDKFKDAVKDYFAKFWD 395 [A-2 > H, D-E switched] Rev-4F FHDKFKDAVKEYFAKFWE 396 [A-2 > H, E-3 > D]Rev-4F FHDKFKEAVKDYFAKFWD 397 [A-2 > H, E-7 > D]Rev-4F FHEKFKDAVKDYFAKFWD 398 [A-2 > H, D-11 > E]Rev-4F FHEKFKEAVKEYFAKFWD 399 [A-2 > H, D-18 > E]Rev-4F FHEKFKEAVKDYFAKFWE 400 [F-1 > H, A-2 > F]Rev-4F HFEKFKEAVKDYFAKFWD 401 [F-1 > H, A-2 > F, D-E switched]Rev-4F HFDKFKDAVKEYFAKFWE 402 [F-1 > H, A-2 > F, D > E]Rev-4F HFEKFKEAVKEYFAKFWE 403 [F-1 > H, A-2 > F, E-3 > D]Rev-4F HFDKFKEAVKDYFAKFWD 404 [F-1 > H, A-2 > F, E-7 > D]Rev-4F HFEKFKDAVKDYFAKFWD 405 [F-1 > H, A-2 > F, D-11 > E]Rev-4F HFEKFKEAVKEYFAKFWD 406 [F-1 > H, A-2 > F, D-18 > E]Rev-4F HFEKFKEAVKDYFAKFWE 407 [A-2 > F, F-5 > H] Rev D-4F FFEKHKEAVKDYFAKFWD 408 [A-2 > F, F-5 > H, D-E switched] Rev D-4F FFDKHKDAVKEYFAKFWE 409 [A-2 > F, F-5 > H, D > E] Rev D-4F FFEKHKEAVKEYFAKFWE 410 [A-2 > F, F-5 > H, E > D] Rev D-4F FFDKHKDAVKDYFAKFWD 411 [A-2 > F, F-5 > H, E-3 > D] Rev D-4F FFDKHKEAVKDYFAKFWD 412 [A-2 > F, F-5 > H, D-11 > E] Rev D-4F FFEKHKEAVKEYFAKFWD 413 [A-2 > F, F-5 > H, D-18 > E] Rev D-4F FFEKHKEAVKDYFAKFWE 414 [A-2 > V, V-9 > H] Rev D-4F FVEKFKEAHKDYFAKFWD 415 [A-2 > V, V-9 > H, D-E switched] Rev D-4F FVDKFKDAHKEYFAKFWE 416 [A-2 > V, V-9 > H, D > E] Rev D-4F FVEKFKEAHKEYFAKFWE 417 [A-2 > V, V-9 > H, E > D] Rev D-4F FVDKFKDAHKDYFAKFWD 418 [A-2 > V, V-9 > H, E-3 > D] Rev D-4F FVDKFKEAHKDYFAKFWD 419 [A-2 > V, V-9 > H, E-7 > D] Rev D-4F FVEKFKDAHKDYFAKFWD 420 [A-2 > V, V-9 > H, D-11 > E] Rev D-4F FVEKFKEAHKEYFAKFWD 421 [A-2 > V, V-9 > H, D-18 > E] Rev D-4F FVEKFKEAHKDYFAKFWE 422 [A-8 > H]Rev-4F FAEKFKEHVKDYFAKFWD 423 [A-8 > H, D-E switched]Rev-4F FADKFKDHVKEYFAKFWE 424 [A-8 > H, D > E]Rev-4F FAEKFKEHVKEYFAKFWE 425 [A-8 > H, E > D]Rev-4F FADKFKDHVKDYFAKFWD 426 [A-8 > H, E-3 > D]Rev-4F FADKFKEHVKDYFAKFWD 427 [A-8 > H, E-7 > D]Rev-4F FAEKFKDHVKDYFAKFWD 428 [A-8 > H, D-11 > E]Rev-4F FAEKFKEHVKEYFAKFWD 429 [A-8 > H, D-18 > E]Rev-4F FAEKFKEHVKDYFAKFWE 430 [A-8 > F, F-13 > H]Rev-4F FAEKFKEFVKDYHAKFWD 431 [A-8 > F, F-13 > H, D-E switched]Rev-4F FADKFKDFVKEYHAKFWE 432 [A-8 > F, F-13 > H, E-3 > D]Rev-4F FADKFKEFVKDYHAKFWD 433 [A-8 > F, F-13 > H, E-7 > D]Rev-4F FAEKFKDFVKDYHAKFWD 434 [A-8 > F, F-13 > H, E > D]Rev-4F FADKFKDFVKDYHAKFWD 435 [A-8 > F, F-13 > H, D > E]Rev-4F FAEKFKEFVKEYHAKFWE 436 [A-8 > F, F-13 > H, D-11 > E]Rev-4F FAEKFKEFVKEYHAKFWD 437 [A-8 > F, F-13 > H, D-18 > E]Rev-4F FAEKFKEFVKDYHAKFWE 438 [A-8 > F, F16 > H]Rev.-4F FAEKFKEFVKDYFAKHWD 439 [A-8 > F, F16 > H, D-E switched]Rev.-4F FADKFKDFVKEYFAKHWE 440 [A-8 > F, F16 > H, D > E]Rev.-4F FAEKFKEFVKEYFAKHWE 441 [A-8 > F, F16 > H, E > D]Rev.-4F FADKFKDFVKDYFAKHWD 442 [A-8 > F, F16 > H, E-3 > D]Rev.-4F FADKFKEFVKDYFAKHWD 443 [A-8 > F, F16 > H, E-7 > D]Rev.-4F FAEKFKDFVKDYFAKHWD 444 [A-8 > F, F16 > H, D-11 > E]Rev.-4F FAEKFKEFVKEYFAKHWD 445 [A-8 > F, F16 > H, D-18 > E]Rev.-4F FAEKFKEFVKDYFAKHWE 446 Rev-[D > E]-4F FAEKFKEAVKEYFAKFWE 447 Rev-[E > D]4F FADKFKDAVKDYFAKFWD 448 Rev-R4-4F FAERFREAVKDYFAKFWD 449 Rev-R6-4F FAEKFREAVKDYFAKFWD 450 Rev-R10-4F FAEKFKEAVRDYFAKFWD 451 Rev-R14-4F FAEKFKEAVKDYFARFWD 452 Rev-[D > E]-4F FAEKFKEAVKEYFAKFWE 453 Rev-[E > D]4F FADKFKDAVKDYFAKFWD 454 Rev-R4-4F FAERFREAVKDYFAKFWD 455 Rev-R6-4F FAEKFREAVKDYFAKFWD 456 Rev-R10-4F FAEKFKEAVRDYFAKFWD 457 Rev-R14-4F FAEKFKEAVKDYFARFWD 458 Rev-[D > E]-4F FAEKFKEAVKEYFAKFWE 459 Rev-[E > D]4F FADKFKDAVKDYFAKFWD 460 Rev-R4-4F FAERFREAVKDYFAKFWD 461 Rev-R6-4F FAEKFREAVKDYFAKFWD 462 Rev-R10-4F FAEKFKEAVRDYFAKFWD 463 Rev-R14-4F FAEKFKEAVKDYFARFWD 464 Rev-R4-4F FAERFREAVKDYFAKFWD 465 Rev-R6-4F FAEKFREAVKDYFAKFWD 466 Rev-R10-4F FAEKFKEAVRDYFAKFWD 467 Rev-R14-4F FAEKFKEAVKDYFARFWD 468 Rev-[D > E]-4F FAEKFKEAVKEYFAKFWE 469 Rev-[E > D]4F FADKFKDAVKDYFAKFWD 470 Rev-R4-4F FAERFREAVKDYFAKFWD 471 Rev-R6-4F FAEKFREAVKDYFAKFWD 472 Rev-R10-4F FAEKFKEAVRDYFAKFWD 473 Rev-R14-4F FAEKFKEAVKDYFARFWD 474 Rev3F-2 LFEKFAEAFKDYVAKWKD 475 RevR4-3F-2 LFERFAEAFKDYVAKWKD 476 RevR10-3F2 LFEKFAEAFRDYVAKWKD 477 RevR15-3F-2 LFEKFAEAFKDYVARWKD 478 Rev R17-3F-2 LFEKFAEAFKDYVAKWRD 479 Rev[D > E]3F2 LFEKFAEAFKEYVAKWKE 480 Rev [E > D]3F-2 LFDKFADAFKDYVAKWKD 481 Rev-[E3 > D]-3F-2 LFDKFAEAFKDYVAKWKD 482 Rev-[E7 > D]-3F-2 LFEKFADAFKDYVAKWKD 483 Rev[D11 > E]3F-2 LFEKFAEAFKEYVAKWKD 484 Rev-[D18 > E]3F-2 LFEKFAEAFKDYVAKWKE 485 Rev3F-1 FAEKAWEFVKDYFAKLKD 486 RevR4-3F-1 FAERAWEFVKDYFAKLKD 487 RevR10-3F-1 FAEKAWEFVKDYFAKLKD 488 RevR15-3F-1 FAEKAWEFVKDYFAKLKD 489 RevR17-3F-1 FAEKAWEFVKDYFAKLRD 490 Rev[D > E]3F-1 FAEKAWEFVKEYFAKLKE 491 Rev [E > D}3F-1 FADKAWDFVKDYFAKLKD 492 Rev [E3 > D]-3F-1 FADKAWEFVKDYFAKLKD 493 Rev[E7 > D]3F-1 FAEKAWDFVKDYFAKLKD 494 Rev4-[D11 > E]3F-1 FAEKAWEFVKEYFAKLKD 495 Rev-[D18 > E]3F-1 FAEKAWEFVKDYFAKLKE 496 Rev-5F FFEKFKEFVKDYFAKLWD 497 Rev-[D > E]5F FFEKFKEFVKEYFAKLWE 498 Rev-[E > D]5F FFDKFKDFVKDYFAKLWD 499 Rev-R4-5F FFERFKEFVKDYFAKLWD 500 Rev-R6-5F FFEKFREFVKDYFAKLWD 501 Rev-R10-5F FFEKFKEFVRDYFAKLWD 502 Rev-R15-5F FFEKFKEFVKDYFARLWD 503 Rev-[E3 > D]-5F FFDKFKEFVKDYFAKLWD 504 Rev-[E7 > D]5F FFEKFKDFVKDYFAKLWD 505 Rev-[D11 > E]-5F FFEKFKEFVKEYFAKLWD 506 Rev-[D18 > E]-5F FFEKFKEFVKDYFAKLWE 507 Rev-5F-2 FLEKFKEFVKDYFAKFWD 508 Rev-[D > E]-5F-2 FLEKFKEFVKEYFAKFWE 509 Rev-[E > D]-5F-2 FLDKFKEFVKDYFAKFWD 510 Rev-[E3 > D]-5F-2 FLDKFKEFVKDYFAKFWD 511 Rev-[E7 > D]-5F-2 FLEKFKDFVKDYFAKFWD 512 Rev4-[D11 > E]-5F-2 FLEKFKEFVKEYFAKFWD 513 Rev-[D18 > E]-5F-2 FLEKFKEFVKDYFAKFWE 514 Rev-R4-5F-2 FLERFKEFVKDYFAKFWD 515 Rev-R6-5F-2 FLEKFREFVKDYFAKFWD 516 RevR10-5F-2 FLEKFKEFVRDYFAKFWD 517 Rev-R16-5F-2 FLEKFKEFVKDYFARFWD 518 Rev-6F FFEKFKEFFKDYFAKLWD 519 Rev-[D > E]-6F FFEKFKEFFKEYFAKLWE 520 Rev-[E > D]-6F FFDKFKDFFKDYFAKLWD 521 Rev-R4-6F FFERFKEFFKDYFAKLWD 522 Rev-R6-6F FFEKFREFFKDYFAKLWD 523 Rev-R10-6F FFEKFKEFFRDYFAKLWD 524 Rev-R14-6F FFERFKEFFKDYFARLWD 525 Rev-[E3 > D]-6F FFDKFKEFFKDYFAKLWD 526 Rev-[E7 > D]-6F FFEKFKDFFKDYFAKLWD 527 Rev-[D11 > E]-6F FFEKFKEFFKEYFAKLWD 528 Rev-[D18 > E]-6F FFEKFKEFFKDYFAKLWE 529 Rev-4F FAEKFKEAVKDYFAKFWD 530 Rev-[D > E]-4F FAEKFKEAVKEYFAKFWE 531 Rev-[E > D]4F FADKFKDAVKDYFAKFWD 532 Rev-R4-4F FAERFREAVKDYFAKFWD 533 Rev-R6-4F FAEKFREAVKDYFAKFWD 534 Rev-R10-4F FAEKFKEAVRDYFAKFWD 535 Rev-R14-4F FAEKFKEAVKDYFARFWD 536 4F-2 DKWKAVYDKFAEAFKEFF 537 [D > E]-4F-2 EKWKAVYEKFAEAFKEFF 538 [E > D]-4F-2 DKWKAVYDKFADAFKDFF 539 R2-4F-2 DRWKAVYDKFAEAFKEFF 540 R4-4F-2 DKWRAVYDKFAEAFKEFF 541 R9-4F-2 DKWKAVYDRFAEAFKEFF 542 R14-4F-2 DKWKAVYDKFAEAFREFF 543 Rev4F-2 FFEKFAEAFKDYVAKWKD 544 Rev-[D > E]-4F-2 FFEKFAEAFKEYVAKWKE 545 Rev-[E > D]-3F-2 FFDKFADAFKDYVAKWKD 546 Rev-R4-4F-2 FFERFAEAFKDYVAKWKD 547 Rev-R10-4F-2 FFERFAEAFRDYVAKWKD 548 Rev-R15-4F-2 FFEKFAEAFKDYVARWKD 549 Rev-R17-4F-2 FFERFAEAFKDYVAKWRD 550 Rev-[E3 > D]-4F-2 FFDKFAEAFKDYVAKWKD 551 Rev-[E7 > D]-4F-2 FFEKFADAFKDYVAKWKD 552 Rev-[D11 > E]-4F-2 FFERFAEAFKEYVAKWKD 553 Rev-[D18 > E]-4F-2 FFERFAEAFKDYVAKWKE 554 Rev-7F FFEKFKEFFKDYFAKFWD 555 Rev-[E > D]-7F FFDKFKDFFKDYFAKFWD 556 Rev-[D > E]-7F FFEKFKEFFKEYFAKFWE 557 Rev-R4-7F FFERFKEFFKDYFAKFWD 558 Rev-R6-7F FFEKFREFFKDYFAKFWD 559 Rev-R10-7F FFEKFKEFFRDYFAKFWD 560 Rev-R14-7F FFEKFKEFFKDYFARFWD 561 Rev-[E3 > D]-7F FFDKFKEFFKDYFAKFWD 562 Rev-[E7 > D]7F FFEKFKDFFKDYFAKFWD 563 Rev-[D11 > E]-7F FFEKFKEFFKEYFAKFWD 564 Rev-[D18 > E]-7F FFEKFKEFFKDYFAKFWE 565 EVRAKLEEQAQQIRLQAEAFQARLKSWFEPLVE 566 EVRAKLEEQAQQIRLQAEAFQARLKSWFE 567 EVRSKLEEAAFREFAEEFLARLKS 568 PVLDLFRELLNELLEALKQKLK 569 DWLKAFYDKVAEKLKEAF- P- 570 DWAKAAYDKAAEKAKEAA EELKEKLEELKEKLEEKL-P- 571 EELKEKLEELKEKLEEKL EELKAKLEELKAKLEEKL-P- 572 EELKAKLEELKAKLEEKL EKLKALLEKLLAKLKELL P- 573 EKLKALLEKLLAKLKELL EWLKELLEKLLEKLKELL-P- 574 EWLKELLEKLLEKLKELL EKFKELLEKFLEKFKELL-P- 575 EKFKELLEKFLEKFKELL EKLKELLEKLLELLKKLL-P- 576 EKLKELLEKLLELLKKLL EKLKELLEKLKAKLEELL-P- 577 EKLKELLEKLKAKLEELL EKLKELLEKLLAKLKELL-P- 578 EKLKELLEKLLAKLKELL EKFKELLEKLLEKLKELL-P- 579 EKFKELLEKLLEKLKELL EKLKAKLEELKAKLEELL-P- 580 EKLKAKLEELKAKLEELL EELKELLKELLKKLEKLL-P- 581 ELKELLKELLKKLEKLL EELKKLLEELLKKLKELL-P- 582 EELKKLLEELLKKLKELL EKLKELLEKLLEKLKELL-A- 583 EKLKELLEKLLEKLKELL EKLKELLEKLLEKLKELL-AA- 584 EKLKELLEKLLEKLKELL EKLKAKLEELKAKLEELL-P- 585 EKAKAALEEAKAKAEELA EKLKAKLEELKAKLEELL-P- 586 EHAKAALEEAKCKAEELA DHLKAFYDKVACKLKEAF-P- 587 DWAKAAYDKAAEKAKEAA DWLKAFYDKVAEKLKEAF-P- 588 DHAKAAYDKAACKAKEAA DWLKAFYDKVACKLKEAF-P- 589 DWAKAAYNKAAEKAKEAA DHLKAFYDKVAEKLKEAF-P- 590 DWAKAAYDKAAEKAKEAA VLESFKVSFLSALEEYTKKLNTQ 591 (3FCπ) DKWKAVYDKFAEAFKEFL 592 (3FIπ) DKLKAFYDKVFEWAKEAF 593 Apo-J (G* Peptides). It was also discovered that peptides that mimic the amphipathic helical domains of apoJ are also capable of mitigating one or more symptoms of atherosclerosis and/or other pathologies described herein. Apolipoprotein J possesses a wide nonpolar face termed globular protein-like, or G* amphipathic helical domains. The class G amphipathic helix is found in globular proteins, and thus, the name class G. This class of amphipathic helix is characterized by a random distribution of positively charged and negatively charged residues on the polar face with a narrow nonpolar face. Because of the narrow nonpolar face this class does not readily associate with phospholipids. The G* of amphipathic helix possesses similar, but not identical, characteristics to the G amphipathic helix. Similar to the class G amphipathic helix, the G* class peptides possesses a random distribution of positively and negatively charged residues on the polar face. However, in contrast to the class G amphipathic helix which has a narrow nonpolar face, this class has a wide nonpolar face that allows this class to readily bind phospholipid and the class is termed G* to differentiate it from the G class of amphipathic helix. A number of suitable G* amphipathic peptides are described U.S. Pat. Nos. 6,930,085, and 7,638,494, and in PCT Publication No: PCT/US03/09988 (WO 2003/086326) which are incorporated herein by reference for the peptides described therein. In certain embodiments the G* (apoJ) peptides used for the preparation of ezetimibe associated peptides (Ez-peptides) comprise one or more domains that have an amino acid sequence shown in Table 2 or the reverse sequence. TABLE 2 Certain peptides related to G* amphipathic helical domains of app J that can be used for the preparation of ezetimibe associated peptides (Ez-peptides), e.g., as described herein. For each sequence listed in this table, the retro form of the sequence is also contemplated. Thus, for example where the sequence DQYYLRVTTVA (SEQ ID NO: 595) is shown, the amino acid sequence AVTTVRLYYQD (SEQ ID NO: 594) is also contemplated. Amino Acid Sequence SEQ ID NO DQYYLRVTTVA 595 ECKPCLKQTCMKFYARVCR 596 FSRASSIIDELFQD 597 IQNAVNGVKQIKTLIEKTNEE 598 LLEQLNEQFNWVSRLANL 599 LLEQLNEQFNWVSRLANLTEGE 600 LLEQLNEQFNWVSRLANLTQGE 601 LVGRQLEEFL 602 MNGDRIDSLLEN 603 NELQEMSNQGSKYVNKEIQNAVNGV 604 PCLKQTCMKFYARVCR 605 PFLEMIHEAQQAMDI 606 PGVCNETMMALWEECK 607 PKFMETVAEKALQEYRKKHRE 608 PSGVTEVVVKLFDS 609 PSQAKLRRELDESLQVAERLTRKYNELLKSYQ 610 PTEFIREGDDD 611 QQTHMLDVMQD 612 RKTLLSNLEEAKKKKEDALNETRESETKLKEL 613 RMKDQCDKCREILSV 614 ApoE Mimetic Peptides ApoE mimetic peptides have also been demonstrated to have activities similar to those described above for ApoA-I mimetic peptides, particularly with respect to neurological and/or ocular dysfunction (see, e.g., Handattu et al. (2010) J. Lipid Res. 51: 3491-3499; Laskowitz et al. (2001) Experimental Neurology 167: 74-85; Minami et al. (2010) Molecular Neurodegeneration, 5:16; Bhattacharj ee et al. (2008) Invest Ophthalmol Vis Sci. 49: 4263-4268; Li et al. 92010) J. Pharmacol. and Experimental Therapeutics 334: 106-115; Klein and Yakel (2004) Neurosci., 127: 563-567; Laskowitz et al. (2007) J. of Neurotrauma 24: 1093-1107; Christensen et al. (2011) J. Immunol., 186: 2535-2542; Croy et al. 92004) Biochemistry 43: 7328-7335). In certain embodiments the peptides used for the preparation of ezetimibe associated peptides (Ez-peptides) comprise one or more domains that have an apoE amino acid sequence or a dual ApoE/ApoA-I sequence shown in Table 3 or the reverse sequence. TABLE 3 Certain ApoE peptides that can be used for the preparation of ezetimibe associated peptides (Ez-peptides), e.g., as described herein. For each sequence listed in this table, the retro form of the sequence is also contemplated. Thus, for example where the sequence GIKKFLGSIWKFIKAFVG (SEQ ID NO: 616) is shown, the amino acid sequence GVFAKIFKWISGLFKKIG (SEQ ID NO: 615) is also contemplated. Amino Acid Sequence SEQ ID NO ApoE peptides: GIKKFLGSIWKFIKAFVG 616 GFKKFLGSWAKIYKAFVG 617 GFRRFLGSWARIYRAFVG 618 TEELRVRLASHLRKLRKRLL 619 TEELRVRLASHLRKLRK 620 LRVRLASHLRKLRKRLL 621 RLASHLRKLRKRLL 622 SHLRKLRKRLL 623 LRKLRKRLL 624 LRKLRKRLLLRKLRKRLL 625 LRKLRKRLLLRKLRKRLLLRKLRKRLL 626 RQIKIWFQNRRMKWKKCLRVRLASHLRKLRKRLL 627 LRVRLASHLRKLRKRLL 628 EELRVRLASHLRKLRKRLLRDADDLQKRLAVYEEQAQQ 629 IRLQAEAFQARLKSWFEPLVEDM CEELRVRLASHLRKLRKRLLRDADDLQKRLAVY 630 LRKLRKRLLRDADDLLRKLRKRLLRDADDL 631 TEELRVRLASHLRKLRKRLL 632 TEELRVRLASHLEKLRKRLL 633 TEELRVRLASHLRELRKRLL 634 LREKKLRVSALRTHRLELRL 635 Dual ApoE and ApoA-I mimetic peptides: LRKLRKRLLRDWLKAFYDKVAEKLKEAF 636 LRRLRRRLLRDWLKAFYDKVAEKLKEAF 637 RRRRRRRRRRDWLKAFYDKVAEKLKEAF 638 It has been demonstrated that in certain embodiments, linking the receptor binding domain of apolipoprotein E (apoE) to a class A amphipathic helix can enhance internalization and degradation of LDL by fibroblasts and can lower plasma cholesterol and restore endothelial function (see, e.g., Datta et al. (2000) Biochemistry 39: 213-220; Gupta et al. (2005) Circulation 111: 3112-3118). Accordingly in certain embodiments, any of the peptides described herein, can be provided as a peptide also comprising an apoE receptor binding domain (see, e.g., SEQ ID NOs:636-638 for illustrative examples). In various embodiments, peptides comprising an oxpholipin domain such as Arg-Glu-Dpa-Thr-Gly-Leu-Ala-Trp-Glu-Trp-Trp-Arg-Thr-Val (SEQ ID NO:639), where Dpa (3,3′-diphenyl alanine) is substituted with Trp, Phe, or Ala) are also contemplated. Oxpholipin peptides are described by Ruchala et al. (2010) PLoS ONE 5(4): e10181) and in PCT Publication No: PCT/US2010/046534 (WO/2011/031460), which are incorporated herein by reference for the peptides described therein and where such peptides incorporate 3,3′-diphenylalanine, this residue is substituted with Trp, Phe, or Ala. In addition to the sequences listed in Tables 1, 2, and 3 amino acid sequences comprising 1 conservative substitution, 2 conservative substitutions, 3 conservative substitutions, 4 conservative substitutions, 5 conservative substitutions, 6 conservative substitutions, 7 conservative substitutions, 8 conservative substitutions, 9 conservative substitutions, or 10 conservative substitutions are contemplated. The foregoing peptides are intended to be illustrative and not limiting. In view of the surprising discovery that ApoA-I mimetic peptides and other related peptides described herein can be used for the preparation of ezetimibe associated peptides (Ez-peptides), one of skill in the art will recognized that numerous other such peptides can also also be used for the preparation of ezetimibe associated peptides (Ez-peptides), e.g., to afford a similar utility. Chemical Synthesis of apoA-I Mimetic Peptides. In various embodiments the peptides use for the ezetimibe-associated apoA-I peptide is synthesized by any of a number of fluid or solid phase peptide synthesis techniques known to those of skill in the art. In certain embodiments the peptide is syntheized using solid phase synthesis in which the C-terminal amino acid of the sequence is attached to an insoluble support followed by sequential addition of the remaining amino acids in the sequence. Techniques for solid phase synthesis are well known to those of skill in the art and are described, for example, by Barany and Merrifield (1963) Solid-Phase Peptide Synthesis; pp. 3-284 in The Peptides: Analysis, Synthesis, Biology. Vol. 2: Special Methods in Peptide Synthesis, Part A; Merrifield et al. (1963) J. Am. Chem. Soc., 85: 2149-2156, and Stewart et al. (1984) Solid Phase Peptide Synthesis, 2nd ed. Pierce Chem. Co., Rockford, Ill. In one embodiment, the peptides are synthesized by the solid phase peptide synthesis procedure using a benzhyderylamine resin (Beckman Bioproducts, 0.59 mmol of NH2/g of resin) as the solid support. The COOH terminal amino acid (e.g., t-butylcarbonyl-Phe) is attached to the solid support through a 4-(oxymethyl)phenacetyl group. This is a more stable linkage than the conventional benzyl ester linkage, yet the finished peptide can still be cleaved by hydrogenation. Transfer hydrogenation using formic acid as the hydrogen donor is used for this purpose. Detailed protocols used for peptide synthesis and analysis of synthesized peptides are describe in a miniprint supplement accompanying Anantharamaiah et al. (1985) J. Biol. Chem., 260(16): 10248-10255. It is noted that in the chemical synthesis of peptides, particularly peptides comprising D amino *acids, the synthesis usually produces a number of truncated peptides in addition to the desired full-length product. The purification process (e.g. HPLC) typically results in the loss of a significant amount of the full-length product. Construction and Propagation of Transgenic Plants. In various embodiments the ezetimibe-associated apoA-I peptide is prepared using an apoA-I mimetic pepide that is recombinantly expressed, e.g., in a plant, yeast, or animal tissue. In certain embodiments the ezetimibe-associated apoA-I peptide is prepared using the tissue of a plant (e.g., a tomato) that where said tissue contains a heterologous ApoA-I mimetic peptide expressed by the plant. The construction and propagation of transgenic plants expressing ApoA-I peptides or mimetics thereof and suitable for the preparation of ezetimibe-associated ApoA-I peptides as described herein is detailed, inter alia, in PCT Publication No: WO 2013/148214 A1 and in Chattopadhyay et al. (2013) J. Lipid Res., 54: 995-10101, and Navab et al. (2013) J. Lipid Res., 54: 3403-3418. The methods typically involve constructing a vector (e.g., a plasmid vector) or a DNA fragment by operably linking a DNA sequence encoding the peptide(s) of interest (e.g., peptides comprising ApoA-I, and/or G*, and/or ApoE domain(s)) to a plant-functional promoter capable of directing the expression of the peptide in the plant and then transforming a plant cell with the plasmid vector or DNA fragment. Where preferred, the method may be extended to produce transgenic plants from the transformed cells by including a step of regenerating a transgenic plant from the transgenic plant cell. The resulting plants provide tissues, extracts of which having ApoA-I activity can be produced using the methods described herein. Illustrative, but non-limiting methods of producing such transgenic plants are also described below. Nucleic Acids and Vectors Expressing the Peptide(s) of Interest. Typically, the codon usage of the nucleic acid that is to express the desired amino acid sequence(s) is selected to reflect the optimal codon usage in that plant. Methods of optimizing codon usage for expression of a nucleic acid in a particular host organism are known to those of skill in the art, and numerous software tools are available for such optimization. For example, codon tables are available from the Codon Usage Database, maintained by the Department of Plant Gene Research in Kazusa, Japan (see, e.g., www.kazusa.or.jp/codon/). In certain embodiments the codon optimized nucleic acid sequence is incorporated into an expression vector (e.g., a plasmid). Typically the nucleic acid sequence is operably linked (put under control of) a promoter capable of directing expression of the nucleic acid sequence in the host plant. Promoters Promoters that are known or found to cause transcription of a foreign gene in plant cells are well known to those of skill in the art. Such promoters include, for example, promoters of viral origin and promoters of plant origin. The promoters can be constitutive or inducible, and in various embodiments, are tissue-specific promoters. In various embodiments any of these promoters are contemplated for the expression of a peptide described herein in a plant/plant tissue. The most common promoters used for constitutive overexpression in plants are derived from plant virus sources, such as the cauliflower mosaic (CaMV) 35S promoter (Odell et al. (1985) Nature, 313: 810-812). This promoter, like similar virally derived promoters used in plant systems, is harvested from double-stranded DNA viral genomes, which use host nuclear RNA polymerase and do not appear to depend on any trans-acting viral gene products. The CaMV 35S promoter delivers high expression in virtually all regions of the transgenic plant, is readily obtainable in research and academic settings, and available in plant transformation vector cassettes that allow for easy subcloning of the transgene of interest. The CaMV 35S promoter can drive high levels of transgene expression in both dicots and monocots (Battraw and Hall (1990) Plant Mol. Biol. 15: 527-538; Benfey et al. (1990) EMBO J. 9: 1677-1684). In various embodiments the full-sized 35S promoter (−941 to +9 bp) (Odell et al. (1985) Nature, 313: 810-812) or various fragments such as a 2343 bp fragment can be used. Other viral promoters are also well known to those of skill in the art. These include, but are not limited to the cassava vein mosaic virus (CsVMV) promoter (see, e.g., Verdaguer et al. (1996) Plant Mol. Biol. 31: 1129-1139; Verdaguer et al. (1998) Plant Mol. Biol. 37: 1055-1067; Li et al. (2001) Plant Sci. 160: 877-887), Australian banana streak virus (BSV) promoters (see, e.g., Schenk et al. (2001) Plant Mol. Biol. 47: 399-412), mirabilis mosaic virus (MMV) promoter (see, e.g., Dey and Maiti (1999) Plant Mol. Biol. 40: 771-782), the figwort mosaic virus (FMV) promoter (see, e.g., Sanger et al. (1990) Plant Mol. Biol. 14: 433-443; Maiti et al. (1997) Transgenic Res. 6: 143-156) and the like. Endogenous plant promoters are also used regularly to drive high constitutive levels of transgene expression (Gupta et al. (2001) Plant Biotechnol. 18: 275-282; Dhankher et al. (2002) Nature Biotechnol. 20: 1-6). A number of these strong constitutive promoters are derived from actin and ubiquitin genes. For example, the Act2 promoter was developed from the actin gene family in Arabidopsis (An et al. (1996) Plant J. 10: 107-121). The rice actin 1 gene promoter has also been developed for use in cereal systems (McElroy et al. (1991; Zhang et al. (1991) Plant Cell 3: 1155-1165) and drives expression in virtually all tissues except xylem when transformed back into rice. Ubiquitin promoters, for example the maize ubiquitin 1 promoter (pUbi) has provided high expression in of heterologous genes in maize protoplasts. The maize Ubi1 promoter: GUS fusion has been used in rice (Cornejo et al. (1993) Plant Mol. Biol. 23: 567-581). The Ubi.U4 gene promoter has also been shown to drive high expression activity (Garbarino et al. (1995) Plant Physiol. 109: 1371-1378). A number of tissue-specific (e.g., specific to fruit, seed/grain, tubers/root storage systems, florets/flowers, Leaves/green tissue, anthers/pollen, and the like) are known. Illustrative, but non-limiting fruit-specific promoters include, for example promoters from the 1-aminocyclopropane-1-carboxylate (ACC) oxidase gene, the E8 gene, and polygalacturonase (PG) genes have been characterized in apple (Atkinson et al. (1998) Plant Mol. Biol. 38: 449-460) and tomato (Montgomery et al. (1993) Plant Cell 5: 1049-1062; Nicholass et al. (1995) Plant Mol. Biol. 28: 423-435; Deikman and Fischer (1988) EMBO J. 7: 3315-3320). The promoter of the tomato E8 gene has been used successfully in a number of instances to target transgene expression to fruit. The promoter of the tomato polygalacturonase gene (PG gene product accumulates during ripening and is associated with fruit softening) has been used to drive expression of heterologous genes (Fraser et al. (2002) Eur. J. Biochem. 270: 1365-1380). In tomato, a single gene encodes PG, and analysis of a 1.4 kb promoter fragment shows that it also directs ripening-specific expression (Montgomery et al. (1993) Plant Cell 5: 1049-1062). Phytoene desaturase (Pds) is the second dedicated enzyme in carotenoid biosynthesis and is also encoded by a single gene in tomato (Giuliano et al. (1993) Plant Cell 5: 379-387). Because carotenoids accumulate in the chloroplasts and chromoplasts, the tomato Pds promoter (2.0 kb from start of translation) drives high levels of expression in organs and developing tissues where chromoplasts are found (fruits, petals, anthers) (Corona et al. (1996) Plant J. 9: 505-512). Seed-specific transgene expression has been used for a number of genetic engineering applications. Illustrative seed specific promoters include, but are not limited to the promoters of various seed storage proteins. Other seed specific promoters include for example, those from the soybean β-conglycinin (Chen et al. (1989) Dev. Genet. 10: 112-122; Chamberland et al. (1992) Plant Mol. Biol. 19: 937-949; Lessard et al. (1993) Plant Mol. Biol. 5: 873-885), the sunflower helianthinin genes (Nunberg et al. (1994) Plant Cell 6: 473-486), and the like. One of the best-characterized and most commonly used seed-specific promoters is the French bean β-phaseolin gene (see, e.g., Bustos et al. (1989) Plant Cell 1: 839-853; van der Geest and Hall (1997) Plant J. 6: 413-423). Another useful seed specific promoter is the cotton α-globulin promoter (Sunilkumar et al. (2002) Transgenic Res. 11: 347-359) and has been characterized in cotton, Arabidopsis, and tobacco. In monocots, several promoters of storage proteins include, but are not limited to the endosperm-specific hordein promoters in barley (Forde et al. (1985) Nucleic Acids Res. 13: 7327-7339), glutenin promoters from wheat (Lamacchia et al. (2001) J. Exp. Bot. 52: 243-250), the zein promoters in maize (Marzabal et al. (1998) Plant J. 16: 41-52), and the granule-bound starch synthase 1 (gbss1) gene in wheat (Kluth et al. (2002) Plant Mol. Biol. 49: 669-682). Tubers/root storage specific promoters include, but are not limited to the potato class I patatin family members, B33 and PAT 21 (Jefferson et al. (1990; Liu et al. (1991), the potato granule-bound starch synthase (GBSS) promoter, sweet potato, sporamin and β-amylase promoters (Maeo et al. (2001) Plant Mol. Biol. 46: 627-637), e.g., the gSPO-A1 promoter (Ohta et al. (1991) Mol. Gen. Genet. 225: 369-378). Promoters specific to legume-rhizobium-associated root nodules include promoters of genes expressed early in nodule organogenesis (ENOD genes) (see, e.g., Lauridsen et al. (1993) Plant J. 3: 484-492; Vijn et al. (1995) Plant Mol. Biol. 28: 1103-1110; Fang and Hirsch (1998) Plant Physiol. 116: 53-68; Hohnjec et al. (2000) Mol. Gen. Genet. 264: 241-250), late nodulin promoters (see, e.g., Sandal et al. (1987) Nucleic Acids Res. 15: 1507-1519; Stougaard et al. (1987) EMBO J. 6: 3565-3569), leghemoglobin promoters, the Sesbania rostrata leghemoglobin glb3 promoter (see, e.g., Szabados et al. (1990) Plant Cell 2: 973-986; Szczyglowski et al. (1996) Plant Mol. Biol. 31: 931-935), and the like. Root specific promoters are described, for example, by Yamamoto et al. (1991) Plant Cell 3: 371-382. Non-plant root-specific promoters include the promoters of the rooting loci (rol) genes found in the Ri (root-inducing) plasmid of A. rhizogenes (e.g., the rolD promoter), Domain A of the CaMV 35S promoter (Benfey and Chua (1989) Plant Cell 2: 849-856), the TobRB7 promoter from tobacco (Yamamoto et al. (1991) Plant Cell 3: 371-382), and the like. Promoters specific to leaves/green tissues include, but are not limited to, promoters from the rbcS multigene family encoding the small subunit of ribulose-1,5-bisphosphate carboxylase such as the pea rbcS-3A promoter the alfalfa rbcS promoter the Rubisco promoter, promoters from the chlorophyll a/b-binding (Cab) protein genes (e.g., CAB2 promoter) (Piechulla et al. (1998) Plant Mol. Biol. 38: 655-662), the alfalfa 1532 bp RAc promoter, and the like. Illustrative, but non-limiting examples of tissue specific promoters are shown in Table 4. Table 4 shows illustrative, but non-limiting examples of tissue specific promoters. Tissue Illustrative Promoters Fruit specific Apple ACC oxidase Tomato polygalactouronidase Tomato E8 Tomato PDS Green tissue specific Pea rbcs-3A Arabidopsis CAB2 Alfalfa RAc Nodule specific Vicia faba VfEnod12 Bean NVP30 S. rostrata leghemoglobin Root specific A. rhizogenes rolD Domain A, CaMV 35S Tobacco TobRB7 Tuber/storage organ specific Potato patatin B33 Potato patatin PAT21 Potato GBSS Seed specific Bean beta-phaseolin Cotton alpha-globulin Wheat gbssl Zma10 Kz or Zmag12 (maize zein gene) Zmag12 (maize glutelin gene) Seed coat specific Pea GsGNS2 Floral specific Chrysanthemum UEP1 Bean CHS15 Petunia EPSPS Pollen specific Maize ZMC5 Tomato lat52 Pistil specific Pear PsTL1 Potato SK2 In certain embodiments, the peptide(s) described are expressed under the control of the CaMV promoter. As used herein, the phrase “CaMV 35S” promoter includes variations of CaMV 35S promoter, e.g. promoters derived by means of ligations with operator regions, random or controlled mutagenesis, etc.). In certain embodiments, the peptide(s) described herein are expressed under the control of the E8 promoter. In certain embodiments, the peptide(s) described herein are expressed under the control of the hybrid tomato E4/E8 plant promoter (see, e.g., U.S. Pat. No. 6,118,049). Vectors As indicated above, the nucleic acid encoding the peptide(s) described herein is placed in a vector (e.g., a plasmid vector) under control of the desired promoter. In certain embodiments the vector (e.g., plasmid vector) can further encode one or more selectable markers (e.g., an antibiotic resistance marker such as the npt II gene for kanamycin resistance) and markers that confer selection by hygromycin, streptomycin, spectinomycin, or phosphinotricin. Illustrative selectable markers for use in plants include, but are not limited to neomycin phosphotransferase, hygromycin phosphotransferase, dihydrofolate reductase, chloramphenicol acetyl transferase, gentamycin acetyl transferase, nopaline synthase, octopine synthase, p-galactosidase, p-glucuronidase, streptomycin phosphotransferase, bleomycin resistance, firefly luciferase, bacterial luciferase, threonine dehydratase, metallothionein il, epsp synthase, phosphinothricin acetyl transferase, acetolactate synthase, bromoxynil nitrilase, and the like. In certain embodiments the vector can encode a signal peptide (e.g., ALPAH-Al1-Phaseolus vulgaris). Sequences that can be provided include, for example, a leader sequence (e.g., to allow secretion or vacuolar targeting), and translation termination signals. More generally a number of vectors for plant cell transformation and heterologous gene expression are known to those of skill in the art. For example, the structures of a wide array of plasmids that have proven effective in (a) plant transformation and expression of heterologous genes including constructs that confer resistance to kanamycin, hygromycin, streptomycin, spectinomycin and phosphinotricin, or that confer β-glucuronidase (GUS) gene expression are described by Jones et al. (1992) Transgenic Res., 1: 285-297. Binary vector constructs that carry polylinkers of the pUC and Bluescript types, plasmids that permit the expression of any heterologous reading frame from either nopaline synthase (nos) or octopine synthase (ocs) promoters, as well as the cauliflower mosaic virus 35S promoter, using either the nopaline synthase or octopine synthase 3′ polyadenylation sequences, are also presented in this reference. These constructs permit a choice of orientation of the resulting transgene of interest, relative to the orientation of the selection marker gene. Most of the plasmids described by Jones et al. (supra.) are publicly/commercially available. Illustrative and non-limiting examples of vectors include the pRL200 vector that has been used to stably transform lettuce (see, e.g., Kanamoto et al. (2006) Transgenic Res., 15: 205-217), the pCAMBI1381-GUS plasmid has been used to target specific tissues in tomatoes (see, e.g., Lim et al. (2012) Molecules and Cells 34: 53-59), the pSB S4642 vector, the chloroplast transformation vector pLD, and the like. Means of constructing the heterologous “gene” and incorporating it into a plasmid are well known to those of skill in the art. For example the heterologous “gene” can be chemically synthesized using a DNA synthesizer. Commercial services can also provide nucleic acid sequences synthesized to order. The construct can then be cloned into the vector using, for example, PCR cloning procedures. Methods of making the nucleic acid constructs described herein are well known to those of skill in the art, and specific methods are illustrated in the examples. Cloning and transformation methods, DNA vectors and the use of regulatory sequences are well known to the skilled artisan and may for instance be found in Current Protocols in Molecular Biology, F. M. Ausubel et al, Wiley Interscience, 2004, incorporated herein by reference. In certain embodiments the marker genes (e.g., selectable markers) are removed from the transgenic plant. Methods of removing selectable markers are well known to those of skill in the art. In one illustrative, but non-limiting approach the marker genes are eliminated using MAT vector systems. MAT (Multi-Auto-Transformation) vectors are designed to use the oncogenes (ipt, iaaM/H, rol) of Agrobacterium, which control the endogenous levels of plant hormones and the cell responses to plant growth regulators, to differentiate transgenic cells, and to select marker-free transgenic plants. The oncogenes are combined with the site-specific recombination system (R/RS). At transformation, the oncogenes regenerate transgenic plants and then are removed by the R/RS system to generate marker-free transgenic plants. Protocols for the choice of a promoter for the oncogenes and the recombinase (R) gene, the state of plant materials and the tissue culture conditions are described, for example, by Ebinuman et al. (2005) Meth. Mol. Biol., 286: 237-254. Host Plant Selection A wide variety of plant species have been genetically transformed with foreign DNA, using several different techniques to insert genes (see, e.g., Wu (1989) Pp. 35-15 In: Plant Biotechnology, Kung, S. and Arntzen, eds., Butterworth Publishers, Boston, Mass.; Deak et al. (1986) Plant Cell Rep. 5, 97-100; McCormick et al. (1986) Plant Cell Rep., 5: 81-84; Shahin and Simpson (1986) Hort. Sci. 21: 1199-1201; Umbeck et al. (1987) Bio/Technology 5: 263-266; Christon et al. (1990) Trends Biotechnol. 8: 145-151; Datta et al. (1990) Bio/Technology 8: 736-740; Hinchee et al. (1988) Bio/Technology 6: 915-922; Raineri et al. (1990) Bio/Technology, 8: 33-38; Fromm et al. (1990) Bio/Technology 8: 833-839; and the like). Since many edible plants used by humans for food or as components of animal feed are dicotyledenous plants, in certain embodiments, it is preferred to employ dicotyledons for expression of the peptide(s) described herein, although monocotyledon transformation is also applicable especially in the production of certain grains useful for animal feed. In certain embodiments the host plant selected for genetic transformation has edible tissue in which the peptide(s) of interest can be expressed. Thus, in various embodiments, the peptide(s) can be expressed in a part of the plant, such as the fruit, leaves, stems, seeds, or roots, which may be consumed by a human or an animal for which the peptide(s) are intended. Various other considerations can inform selection of the host plant. It is sometimes preferred that the edible tissue of the host plant not require heating prior to consumption since the heating may reduce the effectiveness of apolipoprotein or mimetic for animal or human use. Also, it is sometimes preferred that the host plant express the peptide(s) in the form of a drinkable liquid. In certain embodiments plants that are suitable for expression of the peptide(s) described herein include any dicotyledon or monocotyledon that is edible in part or in whole by a human or an animal. Illustrative plants include, for example, tomatoes, carrots, potatoes, apples, pears, plums, peaches, oranges, kiwis, papayas, pineapples, guava, lilikoi, starfruit, lychee, mango, grape, pomegranate, mustard greens, kale, chard, lettuce, soybean, rice, corn and other grains (e.g., wheat, rice, barley, bulgur, faro, kamut, millet, oats, quinoa, rice, rye, sorghum, spelt, teff, triticale, and the like), berries such as strawberries, blueberries, blackberries, goji berries, and raspberries, banana, rice, turnip, maize, grape, fig, plum, potato, safflower seeds, nuts (e.g., almond, walnut, pecan, peanut, cashew, macademia, hazelnut, etc.), legumes (e.g., alfalfa, clover, peas, beans (including black beans), lentils, lupins, mesquite, carob, soybeans, and the like), and the like. In certain embodiments expression in plants such as tobacco and the like, is also contemplated. Methods of Gene Transfer into Plants Any of a number of transformation protocols can be used to transform the plant cells and plants described herein. While certain preferred embodiments described below utilize particular transformation protocols, it will be understood by those of skill in the art that any transformation method may be utilized within the definitions and scope of the invention. There are a number of methods for introducing foreign genes into both monocotyledenous and dicotyledenous plants (see, e.g., Potrykus (1991) Annu. Rev. Plant Physiol, Plant Mol. Biol. 42: 205-225; Shimamoto et al. (1989) Nature 338: 274-27, and the like. Methods for stable integration of exogenous DNA into plant genomic DNA include for example agrobacterium-mediated gene transfer, direct DNA uptake including methods for direct uptake DNA into protoplasts, DNA uptake induced by brief electric shock of plant cells, DNA injection into plant cells or tissues by particle bombardment, or by the use of micropipette systems, or by the direct incubation of DNA with germinating pollen; and the use of plant virus as gene vectors. Plant transformation and regeneration in dicotyledons by Agrobacterium tumefaciens (A. tumefaciens) is well documented. The application of the Agrobacterium tumefaciens system with, for example, the leaf disc transformation method (see, e.g., Horsch et al. (1988) Pp. 1-9 In: Plant Molecular Biology Manual AS, Kluwer Academic Publishers, Dordrecht) permits efficient gene transfer, selection and regeneration. Monocotyledons have also been found to be capable of genetic transformation by Agrobacterium tumefaciens as well as by other methods such as direct DNA uptake mediated by PEG (polyethylene glycol), or electroporation. Successful transfer of foreign genes into corn (see, e.g., Rhodes et al. (1989) Science 240: 204-207) and rice (see, e.g., Toriyama et al. (1988) Bio/Technology 6: 1072-1074; Zhang and Wu (1988) Theor. Appl. Genet. 76: 835-840), tomato (see, e.g., Frary and Earl (1996) Plant Cell Rept. 15: 235-240), as well as wheat and sorghum protoplasts, and numerous other species has been demonstrated. The Agrobacterium system includes the use of plasmid vectors that contain defined DNA segments that integrate into the plant genomic DNA. Methods of inoculation of the plant tissue vary depending upon the plant species and the Agrobacterium delivery system. One illustrative approach is the leaf disc procedure which can be performed with any tissue explant that provides a good source for initiation of whole plant differentiation. The Agrobacterium system is especially viable in the creation of transgenic dicotyledenous plants. As indicated above there are various methods of direct DNA transfer into plant cells. In electroporation, the protoplasts are briefly exposed to a strong electric field. In microinjection, the DNA is mechanically injected directly into the cells using very small micropipettes. In microparticle bombardment, the DNA is adsorbed on microprojectiles such as magnesium sulfate crystals or tungsten particles, and the microprojectiles are physically accelerated into cells or plant tissues. Another method of vector transfer is the transmission of genetic material using modified plant viruses. DNA of interest is integrated into DNA viruses, and these viruses are used to infect plants at wound sites. One method of transfection utilizing Agrobacterium tumafaciens is illustrated herein in the Examples. Using these teachings, numerous other plants can be similarly transformed. Those skilled in the art should recognize that there are multiple choices of Agrobacterium strains and plasmid construction strategies that can be used to optimize genetic transformation of plants. They will also recognize that A. tumefaciens may not be the only Agrobacterium strain used. Other Agrobacterium strains such as A. rhizogenes might be more suitable in some applications. Methods of inoculation of the plant tissue vary depending upon the plant species and the Agrobacterium delivery system. A very convenient approach is the leaf disc procedure which can be performed with any tissue explant that provides a good source for initiation of whole plant differentiation. The addition of nurse tissue may be desirable under certain conditions. Other procedures such as the in vitro transformation of regenerating protoplasts with A. tumefaciens may be followed to obtain transformed plant cells as well. It is noted that heterologous genes have been expressed in a wide variety of plants, particular edible plants. Thus, for example, a minimal peach chlorophyll a/b-binding protein gene (Lhcb2*Pp/) promoter (Cab19) and an enhanced mas35S CaMV promoter has been used to express heterologous genes in tomatoes (see, e.g., Bassett et al. (2007) BMC Biotechnology 7: 47). A 35S::PtFT1 promoter (35S CaMV promoter) has been used successfully in plums (see, e.g., Srinivasan PLoS ONE 7(7):e40715) and in apples (see, e.g., Trankener et al. (2010) Planta 232: 1309-1324). Suc2 promoter sequence of the A. Thaliana SUC2 gene (sucrose-H+symporter) has also been used (Id.). Another promoter used in apples was the Pgst1 promoter from potato (see, e.g., Malnoy et al. (2006) Transgenic Res., 15: 83-93). The 35S CaMV promoter has been used in apples for many years (see, e.g., Gleave (1992) Plant Mol Biol. 20: 1203-1207). Other promoters that are derivatives of the 35S CaMV promoter have been used in apples such as the potato proteinase inhibitor II (Pint) promoter (see, e.g., Ko et al. (2002) J. Amer. Soc. Hort. Sci. 127: 515-519). Butelli et al. used a binary vector (pDEL.ROS) containing both Delila and Rosea1 cDNAs from snapdragon under the control of the E8 promoter from tomato to produce tomatoes enriched in anthocyanins (see e.g., Butelli et al. (2008) Nature Biotechnology 26: 1301-1308). Kesanakurti et al. (2012) Physiologia Plantarum 146: 136-148) used the E8 promoter to produce tomato plants to transgenically produce tomato anionic peroxidase (tap1). Yang et al. (2012) Transgenic Res. 21: 1043-1056) demonstrated that the Gentiana lutea zeaxanthin epoxidase (GlZEP) promoter was highly expressed in transgenic tomato plants. In view of the foregoing, one of skill will recognize that using the teachings and examples provided herein, any of peptides (e.g., apoA-I mimetic peptides) described herein can be expressed in an effective amount in a plant tissue with at most routine experimentation. The resulting plant tissue that contains one or more peptides having the desired ApoA-I activity can then be concentrated suite the method described herein to produce a biologically active (ApoA-I active) plant extract. Method of Administering Ezetimibe-Associated apoA-I Peptide Mimetics for Therapeutic and/or Prophylactic Use. In various embodiments methods for the prophylaxis and/or treatment of various pathologies, especially pathologies characterized by an inflammatory response (see, e.g., Table 5) are provided. In certain embodiments the methods involve administering to a mammal in need thereof (e.g., a human, a non-human mammal) an ezetimibe-associated ApoA-I peptide described herein (e.g., Ez-Tg6F). In certain embodiments the ezetimibe-associated ApoA-I peptide is simply orally administered to the mammal. In certain embodiments the ezetimibe-associated ApoA-I peptide is administered in combination with a food, and/or a protein powder, and/or a nutritional supplement, and/or a “power bar”, and/or a “defined diet”. In various embodiments the ezetimibe-associated ApoA-I peptides described herein are used in the prophylaxis and/or treatment of pathologies that include, but are not limited to atherosclerosis, arthritis, cancer, diabetes, hepatic fibrosis, macular degeneration, kidney disease, obesity, osteoporosis, scleroderma, systemic lupus erythematosus, transplant vasculopathy, and vascular dementia. In certain embodiments the pathology is atherosclerosis and the administration is for the treatment of disease or is a prophylactic administration. In certain embodiments, the prophylactic administration is to a subject (e.g., a human or non-human mammal) showing one or more risk factors for atherosclerosis (e.g., obesity, family history, elevated cholesterol, hypertension, diabetes, metabolic syndrome, low levels of HDL-cholesterol, elevated levels of triglycerides, or levels of high sensitivity CRP that are in the upper half of normal or are frankly elevated, and the like). In certain embodiments the pathology is a cancer and the administration is as a therapeutic method in its own right and/or to augment therapeutic methods and/or to reduce adverse side effects to therapeutic methods (e.g., chemotherapy, radiotherapy, etc.). Various cancers for which the administration is believed to be suitable include, but are not limited to ovarian cancer, colon cancer, myeloma or multiple myeloma, breast cancer, bone cancer, cervical cancer, brain cancer, lung cancer, skin cancer including malignant melanoma, and prostate cancer. In certain embodiments the administration of the extract is to prevent the onset, slow the onset and/or slow the progression of Alzheimer's disease and/or other dementias. Administration of Ez-ApoA-I Mimetic Peptides. In certain embodiments the mammal is administered the ezetimibe-associated ApoA-I peptide (e.g., Ez-Tg6F, etc.). In certain embodiments the mammal is simply fed the ezetimibe-associated ApoA-I peptide as a powder, or in a solution or suspension, or formulated into a gel or pill. In certain embodiments the ezetimibe-associated ApoA-I peptide is combined with other dietary components (e.g., as a food ingredient) for administration to the subject. Pills Capsules and Lozenges. In certain embodiments the ezetimibe-associated ApoA-I peptide(s) can be formulated for direct administration to a subject. Such formulations include, for example a simple powder that can be directly administered or combined with, e.g., a drink for administration. Suitable unit dosage forms, include, but are not limited to powders, tablets, pills, capsules, lozenges, bars, and the like. Such compositions can be manufactured by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. For oral administration, the formulations can involve combining the ezetimibe-associated ApoA-I peptide(s) with carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. For oral solid formulations such as, for example, powders, capsules and tablets, suitable excipients include fillers such as sugars, such as lactose, sucrose, mannitol and sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulating agents; and binding agents. If desired, disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. If desired, solid dosage forms may be sugar-coated or enteric-coated using standard techniques. For oral liquid preparations such as, for example, suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, glycols, oils, alcohols, etc. Additionally, flavoring agents, preservatives, coloring agents and the like can be added. For buccal administration, the compositions may take the form of tablets, lozenges, etc. formulated in conventional manner. Protein Powder In certain embodiments the mammal is administered a “protein powder comprising a ezetimibe-associated ApoA-I peptide as described herein. In certain embodiments the protein powder further comprises an additional protein. Illustrative proteins include, but are not limited to whey protein (e.g., whey concentrate, whey isolate, and whey hydrolysate), casein protein (or milk protein), soy protein, egg-white protein, hemp seed protein, rice protein, pea protein, and the like. Methods of isolating/producing protein powder are well known to those of skill in the art. Typical methods involve a crude isolation step (e.g., filtering processes to separate lactose from milk in the preparation of whey protein) followed by a concentration step, e.g., an ion exchange purification to purify the protein without denaturing it. In certain embodiments the ezetimibe-associated ApoA-I peptide(s) described herein are simply added to a commercially available protein powder. Food or Food Ingredient Comprising a Plant or Plant Part. In certain embodiments the mammal is administered a food or a food ingredient that is eaten before or after or in combination with the ezetimibe-associated ApoA-I peptide (s) described herein. In certain embodiments, the food is a food product that naturally comprises all or a part of the same type of plant in which the peptide is transgenically expressed. Thus, where ezetimibe-associated ApoA-I peptide comprises a transgenic tomato extract, the food may also comprise a tomato, tomato paste or sauce, and the like. Nutritional Supplement. In certain embodiments the ezetimibe-associated ApoA-I peptide (s) described herein are provided as a component of a nutritional supplement (e.g., a vitamin supplement, a protein supplement, etc.). Illustrative vitamin supplements include, for example, vitamin A supplements, vitamin B supplements, vitamin D supplements, vitamin C supplements, fatty acid supplements (e.g., omega 3 fatty acids), mineral supplements such as calcium, zinc, and iron, and various combinations thereof. In certain embodiments the ezetimibe-associated ApoA-I peptide (s) described herein are provided as a component of a multivitamin formulation or combined in a multi-component package with other vitamin/FA/mineral supplements. In certain embodiments where the extract is used in such a supplement the extract, e.g., provided as a fine powder is then incorporated into a multivitamin, or tableted or encapsulated by itself. In certain embodiments the vitamin supplement comprises vitamin A, and/or vitamin B1, and/or B2, and/or B6 and/or B12, and/or vitamin C, and/or vitamin E, and/or a fatty acid. Defined Diet/Meal Replacement Product. In certain embodiments the ezetimibe-associated ApoA-I peptide(s) described herein are provided as a component of a “defined diet” and/or meal replacement products (MRPs). A defined diet is a diet, optionally pre-packaged, that is intended to meet all the dietary requirements of a particular subject. For example, for humans a defined diet can be a pre-determined diet designed to facilitate a particular dietary goal (e.g., weight reduction, reduction of allergens, lactose, weight gain, protein elevation, etc.). In the case of non-human mammals (e.g., canines, felines, porcines, equines, bovines, etc.) the “defined diet” can be provided in the form an animal food product. The animal food product can be designed to meet particular dietary goals, e.g., as described above for a human. In certain embodiments, the animal food product can be provided as the component of a treatment regimen (e.g., for a farm animal, pet, etc.) afflicted with, or at risk for, a particular pathology, e.g., cancer, atherosclerosis, kidney disease, etc. Meal replacement products are a form of defined diet, either pre-packaged powdered drink mixes or edible bars designed to replace prepared meals. MRPs are generally high in protein, low in fat, have a low to moderate amount of carbohydrates, and contain a wide array of vitamins and minerals. The majority of MRPs use whey protein, casein (often listed as calcium caseinate or micellar casein), soy protein, and/or egg albumin as protein sources. Carbohydrates are typically derived from maltodextrin, oat fiber, brown rice, and/or wheat flour. Some MRPs also contain flax oil powder as a source of essential fatty acids. MRPs can also contain other ingredients. These can include, but are not limited to creatine monohydrate, glutamine peptides, L-glutamine, calcium alpha-ketoglutarate, additional amino acids, lactoferrin, conjugated linoleic acid, and medium chain triglycerides. In certain embodiments the “defined diet” comprises one or more food items. Each food item may be individually prepackaged. In addition, one or more of the food items may be nutritionally enhanced by fortification of vitamins and minerals and/or by incorporation of ezetimibe-associated ApoA-I peptide(s) described herein, The individual food items may be prepared by processing, e.g., mixing, precooking, cooking, freezing, dehydrating or freeze-drying, such that the meal may be maintained in a frozen or dry condition for an extended period. Additionally, an individual food item may be packaged in such a way that, before consumption, the food item must be mixed by hand or blender, cooked by placing the food component on a stove top, in an oven or microwave, or prepared by adding cool, hot or boiling water or by submerging the food item into boiling water. One or more of the food items may be shelf-stable. Preferably, a food item has a sufficiently long storage or shelf-life such that defined diet may be stored in advance of consumption. In certain embodiments a storage or shelf-life under retail conditions in a range of about six to twelve months is desirable. In certain embodiments individual food items may be in the form of solids, semi-solids or liquids and may include, but are not limited to, soup products, protein supplements, grain foods, starch foods, fruit or vegetables foods, nutritional drinks and beverages. In certain embodiments the ezetimibe-associated ApoA-I peptide (s) described herein are simply combined with/incorporated into the defined diet and/or meal replacement product (MRP). For example, in certain embodiments, the ezetimibe-associated ApoA-I peptide powder is added to one or more of the food components comprising the defined diet or MRP. Power Bars. In certain embodiments the ezetimibe-associated ApoA-I peptide (s) described herein are provided as a component of a “power bar”/energy bar. Energy bars are supplemental bars that typically contain cereals and/or dried fruit(s), and/or other high energy foods and/or fiber targeted at people that require quick energy or that are on certain weight loss regimens, but do not have time for a meal. They are different from energy drinks, which contain caffeine, whereas bars provide food energy. Numerous power bar formulations are known to those of skill in the art. In certain embodiments the peptide comprising or consisting of one or more apolipoprotein domains is incorporated into the power bar as a protein (amino acid) component. In certain embodiments the transgenic plant or at least a portion thereof is provided as a component of the power bar. In various embodiments the plant can be provided as all or a portion of a fruit and/or fiber component of the power bar formulation. Animal Uses. As indicated above, in various embodiments, the ezetimibe-associated ApoA-I peptide (s) described herein are is provided as a component of an animal diet. The diet can be provided to simply maintain a healthy animal or in certain embodiments, the diet is optimized to facilitate a prophylactic or therapeutic effect. Illustrative animal diets include, but are not limited to diets for juvenile animals, diets for normal adult animals, diets for old animals, weight loss diets, dental health diets, thyroid health diets, gastrointestinal health diets, hypoallergenic diets, kidney health diets, bladder health diets, aging diets, and the like. In certain embodiments the diet is a diet optimized for treatment of an animal with kidney disease and/or with cancer. In certain embodiments the diet is designed for administration to an animal receiving chemotherapy and/or radiotherapy. In certain embodiments the ezetimibe-associated ApoA-I peptide(s) described herein are simply added to the diet as an additional food (e.g., amino acid) source. The extract can be incorporated into a wet animal food or a dried (e.g., pellet) animal food. In certain embodiments the extract can provides a fiber component of the diet. Therapeutic/Prophylactic Applications of Ezetimibe-Associated ApoA-I Peptide(a). It has been demonstrated that ezetimibe-associated ApoA-I peptide(s) described herein (e.g., Ez-Tg6F) are therapeutically and/or prophylactically effective in a number of indications characterized by an inflammatory response. Such indications include, for example atherosclerosis as described for example, in U.S. Pat. Nos. 6,664,230, 6,933,279, 7,144,862, 7,166,578, 7,199,102 and PCT Publication Nos: PCT/US2001/026497 (WO 2002/015923), and PCT/US2008/085409, which are incorporated herein by reference for the peptides and indications described herein. Accordingly, it is believed that ezetimibe-associated ApoA-I peptide as described herein comprising the peptides or portions thereof are similarly effective in such indications. Thus, in certain embodiments, methods for the treatment or prophylaxis of a pathology characterized by an inflammatory response are provided where the method comprises administering to a mammal in need thereof an effective amount of a ezetimibe-associated ApoA-I peptide comprising one or more peptides from Tables 1, 2, and/or 3. In certain embodiments the ezetimibe-associated ApoA-I peptide comprises a peptide having an amino acid sequence selected from the group consisting of (6F, SEQ ID NO: 1) DWLKAFYDKFFEKFKEFF, (rev6F, SEQ ID NO: 15) FFEKFKEFFKDYFAKLWD, (4F, SEQ ID NO: 6) DWFKAFYDKVAEKFKEAF, (rev4F, SEQ ID NO: 13) FAEKFKEAVKDYFAKFWD, (SEQ ID NO: 599) LLEQLNEQFNWVSRLANL, and (SEQ ID NO: 602) LVGRQLEEFL. An illustrative, but non-limiting list of indications/conditions for which the peptides described herein have been shown to be effective and/or are believed to be effective is shown in Table 5. TABLE 5 Illustrative conditions in which the ezetimibe-associated peptides described herein (e.g., 4F, Ez-6F, Ez-t6F, etc.) have been shown to be or are believed to be effective. It is believed the transgenic plant extracts described herein will be similarly effective. atherosclerosis/symptoms/consequences thereof plaque formation lesion formation myocardial infarction stroke congestive heart failure vascular function: arteriole function arteriolar disease associated with aging associated with Alzheimer's disease associated with chronic kidney disease associated with hypertension associated with multi-infarct dementia associated with subarachnoid hemorrhage peripheral vascular disease pulmonary disease: chronic obstructive pulmonary disease (COPD), emphysema asthma idiopathic pulmonary fibrosis pulmonary fibrosis adult respiratory distress syndrome osteoporosis Paget's disease coronary calcification autoimmune: rheumatoid arthritis polyarteritis nodosa polymyalgia rheumatica lupus erythematosus multiple sclerosis Wegener's granulomatosis central nervous system vasculitis (CNSV) Sjögren's syndrome Scleroderma polymyositis AIDS inflammatory response infections: bacterial fungal viral parasitic influenza (including avian flu) viral pneumonia endotoxic shock syndrome sepsis sepsis syndrome (clinical syndrome where it appears that the patient is septic but no organisms are recovered from the blood) trauma/wound: organ transplant transplant atherosclerosis transplant rejection corneal ulcer chronic/non-healing wound ulcerative colitis reperfusion injury (prevent and/or treat) ischemic reperfusion injury (prevent and/or treat) spinal cord injuries (mitigating effects) cancers lung myeloma/multiple myeloma ovarian cancer breast cancer colon cancer bone cancer cervical cancer prostate cancer osteoarthritis inflammatory bowel disease allergic rhinitis cachexia diabetes Alzheimer's disease implanted prosthesis biofilm formation Crohns' disease Ulcerative colitis Inflammatory bowel disease renal failure (acute renal failure, chronic renal failure) sickle cell disease, sickle cell crisis amelioration of adriamycin toxicity amelioration of anthracylin toxicity to improve insulin sensitivity to treat the metabolic syndrome to increase adiponectin to reduce abdominal fat dermatitis, acute and chronic eczema psoriasis contact dermatitis scleroderma diabetes and related conditions Type I Diabetes Type II Diabetes Juvenile Onset Diabetes Prevention of the onset of diabetes Diabetic Nephropathy Diabetic Neuropathy Diabetic Retinopathy erectile dysfunction macular degeneration multiple sclerosis nephropathy neuropathy Parkinson's Disease peripheral vascular disease meningitis Specific biological activities: increase Heme Oxygenase 1 increase extracellular superoxide dismutase prevent endothelial sloughing prevent the association of myeloperoxidase with ApoA-I prevent the nitrosylation of tyrosine in ApoA-I render HDL anti-inflammatory improve vasoreactivity increase the formation of pre-beta HDL promote reverse cholesterol transport promote reverse cholesterol transport from macrophages synergize the action of statins It is noted that the conditions listed in Table 5 are intended to be illustrative and not limiting. Additional Pharmacologically Active Agents. In various embodiments pharmacologically active agents may be delivered along with the primary active agents, e.g., the ezetimibe-associated ampA-I mimetic peptides described herein. In one embodiment, such agents include, but are not limited to agents that reduce the risk of atherosclerotic events and/or complications thereof. Such agents include, but are not limited to beta blockers, beta blockers and thiazide diuretic combinations, statins, aspirin, ace inhibitors, ace receptor inhibitors (ARBs), and the like. Statins. It is believed that administration of one or more the ezetimibe-associated ampA-I mimetic peptides described herein with one or more statins can synergistically enhance the effect of the statin(s). That is, the statins can achieve a similar efficacy at lower dosage thereby obviating potential adverse side effects (e.g. muscle wasting) associated with these drugs and/or cause the statins to be significantly more anti-inflammatory at any given dose. The major effect of the statins is to lower LDL-cholesterol levels, and they lower LDL-cholesterol more than many other types of drugs. Statins generally inhibit an enzyme, HMG-CoA reductase, that controls the rate of cholesterol production in the body. These drugs typically lower cholesterol by slowing down the production of cholesterol and by increasing the liver's ability to remove the LDL-cholesterol already in the blood. The large reductions in total and LDL-cholesterol produced by these drugs appears to result in large reductions in heart attacks and heart disease deaths. Thanks to their track record in these studies and their ability to lower LDL-cholesterol, statins have become the drugs most often prescribed when a person needs a cholesterol-lowering medicine. Studies using statins have reported 20 to 60 percent lower LDL-cholesterol levels in patients on these drugs. Statins also reduce elevated triglyceride levels and produce a modest increase in HDL-cholesterol. Recently it has been appreciated that statins have anti-inflammatory properties that may not be directly related to the degree of lipid lowering achieved. For example it has been found that statins decrease the plasma levels of the inflammatory marker CRP relatively independent of changes in plasma lipid levels. This anti-inflammatory activity of statins has been found to be as or more important in predicting the reduction in clinical events induced by statins than is the degree of LDL lowering. The statins are usually given in a single dose at the evening meal or at bedtime. These medications are often given in the evening to take advantage of the fact that the body makes more cholesterol at night than during the day. In certain embodiments when combined with the ezetimibe-associated ampA-I mimetic peptides described herein the combined peptide/statin treatment regimen will also typically be given in the evening. Suitable statins are well known to those of skill in the art. Such statins include, but are not limited to atorvastatin (Lipitor®, Pfizer), simvastatin (Zocor®, Merck0, pravastatin (Pravachol®, Bristol-Myers Squibb0, fluvastatin (Lescol®, Novartis), lovastatin (Mevacor®, Merck), rosuvastatin (Crestor®, Astra Zeneca), and Pitavastatin (Sankyo), and the like. The combined statin/ezetimibe-associated peptide dosage can be routinely optimized for each patient. Typically statins show results after several weeks, with a maximum effect in 4 to 6 weeks. Prior to combined treatment with a statin and one of the peptides described herein, the physician would obtain routine tests for starting a statin including LDL-cholesterol and HDL-cholesterol levels. Additionally, the physician would also measure the anti-inflammatory properties of the patient's HDL and determine CRP levels with a high sensitivity assay. After about 4 to 6 weeks of combined treatment, the physician would typically repeat these tests and adjust the dosage of the medications to achieve maximum lipid lowering and maximum anti-inflammatory activity. Beta Blockers. In certain embodiments the ezetimibe-associated ampA-I mimetic peptides described herein can be administered in conjunction with one or more beta blockers. Suitable beta blockers include, but are not limited to cardioselective (selective beta 1 blockers), e.g., acebutolol (Sectral®), atenolol (Tenormin®), betaxolol (KERLONE®), bisoprolol (ZEBETA®), metoprolol (LOPRESSOR®), and the like. Suitable non-selective blockers (block beta 1 and beta 2 equally) include, but are not limited to carteolol (CARTROL®), nadolol (CORGARD®), penbutolol (LEVATOL®), pindolol (VISKEN®), propranolol (INDERAL®), timolol (BLOCKADREN®), labetalol (NORMODYNE®, TRANDATE®), and the like. Suitable beta blocker thiazide diuretic combinations include, but are not limited to Lopressor HCT, ZIAC, Tenoretic, Corzide, Timolide, Inderal LA 40/25, Inderide, Normozide, and the like. ACE Inhibitors. In certain embodiments the ezetimibe-associated ampA-I mimetic peptides described herein can be administerd in conjunction with one or more ACE inhibitors. Suitable ACE inhibitors include, but are not limited to captopril (e.g. CAPOTEN® by Squibb), benazepril (e.g., LOTENSIN® by Novartis), enalapril (e.g., VASOTEC® by Merck), fosinopril (e.g., MONOPRIL® by Bristol-Myers), lisinopril (e.g. PRINIVIL® by Merck or ZESTRIL® by Astra-Zeneca), quinapril (e.g. ACCUPRIL® by Parke-Davis), ramipril (e.g., ALTACE® by Hoechst Marion Roussel, King Pharmaceuticals), imidapril, perindopril erbumine (e.g., ACEON® by Rhone-Polenc Rorer), trandolapril (e.g., MAVIK® by Knoll Pharmaceutical), and the like. Suitable ARES (Ace Receptor Blockers) include but are not limited to losartan (e.g. COZAAR® by Merck), irbesartan (e.g., AVAPRO® by Sanofi), candesartan (e.g., ATACAND® by Astra Merck), valsartan (e.g., DIOVAN® by Novartis), and the like. XII. Kits. In another embodiment this invention provides kits for amelioration of one or more symptoms of atherosclerosis and/or for the prophylactic treatment of a subject (human or animal) at risk for atherosclerosis and/or for reducing the uptake of cholesterol, and/or for ameliorating dyslipidemia, cancer, and/or a number of illnesses associated with chronic inflammation including, but not limited to, Alzheimer's disease, Crohn's disease and ulcerative colitis among others. In various embodiments the kits will typically comprise a container containing one or more of the ezetimibe-associated peptides and/or pharmaceutical formulations thereof described herein. In certain embodiments the kits can, optionally, further comprise one or more other agents used in the treatment of heart disease and/or atherosclerosis. Such agents include, but are not limited to, beta blockers, vasodilators, aspirin, statins, ace inhibitors or ace receptor inhibitors (ARBs) and the like, e.g. as described above. In certain embodiments, the kits additionally include a statin (e.g. cerivastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, lovastatin. rosuvastatin, pitavastatin, etc.) either formulated separately or in a combined formulation with the ezetimibe-associated peptide(s). Typically, the dosage of a statin in such a formulation can be lower than the dosage of a statin typically prescribed without the synergistic peptide. In addition, the kits optionally include labeling and/or instructional materials providing directions (i.e., protocols) for the practice of the methods or use of the “therapeutics” or “prophylactics” of this invention. Preferred instructional materials describe the use of one or more ezetimibe-associated polypeptides described herein to mitigate one or more symptoms of atherosclerosis and/or to prevent the onset or increase of one or more of such symptoms in an individual at risk for atherosclerosis, or for reducing the uptake of cholesterol, and/or for ameliorating dyslipidemia, cancer, and/or a number of illnesses associated with chronic inflammation including, but not limited to, Alzheimer's disease, Crohn's disease and ulcerative colitis among others. The instructional materials may also, optionally, teach preferred dosages/therapeutic regiment, counter indications and the like. While the instructional materials typically comprise written or printed materials they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this invention. Such media include, but are not limited to electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. Such media may include addresses to internet sites that provide such instructional materials. Examples The following examples are offered to illustrate, but not to limit the claimed invention. Example 1 Concentration of 6F Peptide Activity in Tomato Plant Extract Transgenic tomatoes were constructed with the vector pBI121 containing the GUS gene (empty vector control tomatoes; EV) or transgenic tomatoes were constructed with the vector pBI121 in which the GUS gene was replaced with a sequence designed to express the apoA-I mimetic peptide 6F (D-W-L-K-A-F-Y-D-K-F-F-E-K-F-K-E-F-F, Seq ID NO:1) (Tg6F) and grown, freeze-dried and ground into powder as previously described (Chattopadhyay et al. (2013) J. Lipid Res., 54: 995-10101). Ten grams of freeze-dried tomato powder from EV and ten grams of freeze-dried tomato powder from Tg6F tomatoes were thoroughly mixed an incubated for 24 hours in 250 mL of ethyl acetate (HPLC grade from Fisher Scientific, catalogue number E195-4) containing 5% glacial acetic acid (HPLC grade from Fisher Scientific, catalogue number (A35-500). The liquid phase was collected and dried under argon gas. The remaining solids were dissolved in 20 mL of distilled water and then lyophilized. The final extracts were weighed and stored at −20° C. until use. The weight of the final extract from EV was 300 mg and the weight of the final Tg6F extract was 310 mg. Example 2 Preparation of Ezetimibe-Associated 6F Peptide and Use Thereof to Reduce Plasma Total Cholesterol Female LDLR null mice age 5-8 months (n=20 per group) were fed standard mouse chow (Chow) or a Western diet high in cholesterol and fat (WD) or were fed WD+0.06% by weight of a freeze-dried concentrate of transgenic tomatoes expressing the apoA-I mimetic peptide 6F, which was prepared as previously described (see, e.g., Chattopadhyay et al. (2015) Pharma. Res. Per. 3: e00154; Chattopadhyay et al. (2016) J. Lipid Res. 57: 832-847; PCT Pub. Nos: WO 2013/148214 (PCT/US2013/031037), WO 2015/175968 (PCT/US2015/031134)) (Tg6F), or the mice were fed WD with Ezetimibe added to give a daily dose of 10 mg/kg body weight/day (WD+Ezetimibe), or the mice were fed WD with Tg6F added at 0.06% by weight plus Ezetimibe (each added separately to the diet) to give a daily dose of Ezetimibe of 10 mg/kg body weight; the Tg6F and Ezetimibe were mixed into WD as described previously (Chattopadhyay et al. (2016) J. Lipid. Res. 57: 832-847) (Combined Formulation), or the mice were fed WD to which was added ezetimibe-associated transgenic 6F peptide (Ez-tg6F) at 0.06% Tg6F by weight containing sufficient Ezetimibe to give a daily dose of 10 mg/kg body weight/day that was prepared as described herein. Specifically, the ezetimibe-associated Tg6F peptide (Ez-Tg6F) was made by adding the ezetimibe directly to a solution of ethyl acetate 5% acetic acid that had been incubated overnight at room temperature with freeze-dried tomato powder obtained from transgenic tomatoes expressing the 6F peptide, and which had been removed to a separate vessel as described previously (see, e.g., Chattopadhyay et al. (2015) Pharma. Res. Per. 3: e00154; Chattopadhyay et al. (2016) J. Lipid. Res. 57: 832-847) prior to addition of the ezetimibe. After the addition of the ezetimibe, the solution was incubated at room temperature with gentle mixing for two hours prior to processing and addition of the resulting freeze-dried powder to WD as previously described (Chattopadhyay et al. (2016) J. Lipid. Res. 57: 832-847). After feeding the diets for two weeks, the mice were bled and total plasma cholesterol levels were determined as described (Id.). NS=Not Significant. The total cholesterol for each treatment is shown in FIG. 1. FIG. 2 shows the decrease in plasma total cholesterol for each condition in FIG. 1 compared to WD. FIG. 3 shows plasma triglyceride levels in the mice. in the example shown there was a significant reduction in plasma triglyceride levels when Tg6F and ezetimibe were fed to the mice as a combined formulation, but there was an even greater decrease in plasma triglyceride levels when the same doses of Tg6F and ezetimibe were administered as Ez-Tg6F after preparation by the methods described herein. FIG. 4 shows the decrease in plasma triglycerides for each condition in FIG. 3 compared to WD. FIG. 5 shows the plasma HDL-cholesterol levels for the mice. In the example shown there was a significant increase in plasma HDL-cholesterol levels when Tg6F and ezetimibe were fed to the mice as a combined formulation, but there was an even greater increase in plasma HDL-cholesterol levels when the same doses of Tg6F and Ezetimibe were administered as Ez-Tg6F prepared as described herein. FIG. 6 shows the increase in plasma HDL-cholesterol for each condition in FIG. 5 compared to WD. FIG. 7 shows plasma 5-HETE levels for the mice described in FIG. 1. In the example shown, the separate addition of Tg6F and Ezetimibe to the diet which was fed to the mice as a combined formulation did not significantly reduce plasma 5-HETE levels beyond the addition of either agent alone, but the addition to the diet of the same doses of Tg6F and Ezetimibe as Ez-Tg6F prepared as described herein, was significantly more effective in reducing plasma 5-HETE levels than either agent added alone. FIG. 8 shows the decrease in plasma 5-HETE levels for each condition in FIG. 7 compared to WD. FIG. 9 shows plasma 12-HETE levels for the mice described in FIG. 1. In the example shown, the addition of Ezetimibe as a single agent was without effect but the addition of Tg6F as a single agent significantly reduced plasma 12-HETE levels. The separate addition of Tg6F and Ezetimibe to the diet which was fed to the mice as a combined formulation did not significantly reduce plasma 12-HETE levels beyond the addition of Tg6F alone, but the addition to the diet of the same doses of Ez-Tg6F prepared as described herein, was significantly more effective in reducing plasma 12-HETE levels than either Ezetimibe or Tg6F added as a single agent. FIG. 10 shows the decrease in plasma 12-HETE levels for each condition in FIG. 9 compared to WD. FIG. 11 shows plasma 15-HETE levels for the mice described in FIG. 1. In the example shown, the addition of Ezetimibe as a single agent was without effect but the addition of Tg6F as a single agent significantly reduced plasma 15-HETE levels. The separate addition of Tg6F and Ezetimibe to the diet which was fed to the mice as a combined formulation did not significantly reduce plasma 15-HETE levels beyond the addition of Tg6F alone, but the addition to the diet of the same doses of Tg6F and Ezetimibe as Ez-Tg6F, prepared as described herein, was significantly more effective in reducing plasma 15-HETE levels than either Ezetimibe or Tg6F added as a single agent. FIG. 12 shows the decrease in plasma 15-HETE levels for each condition in FIG. 11 compared to WD. FIG. 13 shows plasma SAA levels for the mice described in FIG. 1. In the example shown, the separate addition of both Tg6F and Ezetimibe to the diet, which was fed to the mice as a combined formulation did not significantly reduce plasma SAA levels. In contrast, the reduction in plasma SAA levels achieved by addition to the diet of the same doses of Tg6F and Ezetimibe as Ez-Tg6F, prepared as described herein, was highly significant. FIG. 14 shows the decrease in plasma SAA levels for each condition in FIG. 13 compared to WD. The data in FIGS. 1-14 demonstrate a significant improvement in efficacy by using ezetimibe-associated apoA-I peptides as described herein (e.g., Ez-Tg6F) compared to using a combined formulation of the same doses of Tg6F and Ezetimibe. Example 3 Ezetimibe Enhances ApoA-I Mimetic Tg6F Amelioration of Dyslipidemia and Systemic Inflammation Abbreviations in Example 3 The following abbreviations are used in this example: 4F: the peptide Ac-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH2; 6F: the peptide D-W-L-K-A-F-Y-D-K-F-F-E-K-F-K-E-F-F without end blocking groups; ABC: ATP-binding cassette; EV: transgenic tomatoes expressing a control marker protein: β-glucuronidase; HETE: hydroxyeicosatetraenoic acid; LDLR: Low density lipoprotein receptor; LysoPC: lysophosphatidylcholine; LysoPC 18:0: LysoPC with stearic acid at sn-1 and a hydroxyl group at sn-2; LysoPC 18:1: LysoPC with oleic acid at sn-1 and a hydroxyl group at sn-2; LysoPC 20:4: LysoPC with arachidonic acid at sn-1 and a hydroxyl group at sn-2; NPC1L1: Niemann-Pick C1-like 1; PC: phosphatidylcholine; SAA: serum amyloid A; TICE: transintestinal cholesterol efflux; Tg6F: transgenic tomatoes expressing the 6F peptide; and WD: Western diet. Summary of Example 3 As described in this Example, Ezetimibe or a concentrate of transgenic tomatoes expressing the 6F peptide (Tg6F) were added as single agents to a Western diet (WD) and fed to LDLR null mice providing Ezetimibe at 10 mg/kg/day or Tg6F at 0.06% by weight of diet. After two weeks, plasma lipid levels and serum amyloid A (SAA) were determined. As single agents, Ezetimibe and Tg6F were equally effective in reducing plasma levels of total cholesterol, triglycerides, 5-HETE, and SAA and were equally effective in increasing plasma HDL-cholesterol levels. When both were added to WD at the same doses (Combined Formulation), in general, the resulting values were significantly better compared to adding them as single agents. Surprisingly, when Ezetimibe was added during the preparation of the Tg6F concentrate and the resulting concentrate containing both Ezetimibe and Tg6F was added to WD (Novel Method), the decrease in plasma total cholesterol, triglycerides, 5-HETE, 12-HETE, 15-HETE, and SAA was significantly greater as was the increase in plasma HDL-cholesterol levels compared to administering the same doses as single agents or in the Combined Formulation. We conclude that Ezetimibe and Tg6F prepared by the Novel Method likely results in an Ezetimibe-Tg6F associated peptide that may have significant therapeutic potential. Background of Example 3 We previously reported that an oral apoA-I mimetic peptide (4F) when synthesized from all D-amino acids (D-4F) improved HDL anti-inflammatory properties and reduced aortic atherosclerosis in mouse models without significantly altering plasma cholesterol concentrations (Navab et al. (2002) Circ. 105:290-292.). In a subsequent publication we reported that the D-4F peptide synergized with statins to render HDL anti-inflammatory and cause lesion regression in old apoE null mice (Navab et al. (2005) Arterioscler. Thromb. Vasc. Biol. 25: 1426-1432). In these studies, total plasma cholesterol levels were not significantly altered, but HDL-cholesterol levels, plasma apoA-I levels and paraoxonase-1 (PON) activity were significantly increased (Id). In humans, at high doses (but not at low doses), oral D-4F improved HDL anti-inflammatory properties without altering plasma cholesterol levels (Bloedon et al. (2008) J. Lipid Res. 49: 1344-1352). Thus, the 4F peptide did not significantly alter plasma cholesterol levels, but improved HDL anti-inflammatory properties and aortic atherosclerosis. In contrast to the 4F peptide, a related peptide with two additional phenylalanine residues on the hydrophobic face of the class A amphipathic helix (6F) when expressed as a transgene in tomatoes and fed as freeze-dried tomato powder (Tg6F) significantly reduced plasma cholesterol and triglycerides and serum amyloid A (SAA) levels, increased plasma HDL-cholesterol levels and PON activity and decreased aortic atherosclerosis in mice (Chattopadhyay et al. (2013) J. Lipid Res. 54: 995-1010). When the 4F peptide was synthesized from all D-amino acids and administered orally, low levels of peptide were found in the plasma of mice and humans (Navab et al. (2002) Circ. 105:290-292; Bloedon et al. (2008) J. Lipid Res. 49: 1344-1352; Navab et al. (2004) Circ. 109:3215-3220). When the 4F peptide was synthesized from all L-amino acids and administered orally to mice, little to none of the peptide was detected in plasma (Navab et al. (2002) Circ. 105:290-292). Nonetheless when the 4F peptide synthesized from all L-amino acids was incorporated into mouse chow at high doses, the peptide was efficacious in a mouse model of ovarian cancer (Su et al. (2010) Proc. Natl. Acad. Sci. USA, 107: 19997-20002). Directly comparing the 4F peptide synthesized from all D-amino acids with 4F peptide synthesized from all L-amino acids when both were administered by injection at the same dose in cholesterol-fed rabbits, revealed no difference in efficacy (Van Lenten et al. (2007) J Lipid Res. 48: 2344-2353). Administration of low doses of 4F peptide synthesized from all L-amino acids when administered by injection yielded high plasma levels of peptide, but did not improve HDL function (Watson et al. (2011) J. Lipid Res. 52: 361-373). As a result of the discrepancy between the study in humans in which the 4F peptide was administered orally and was found to be efficacious at high doses despite extremely low levels of peptide in the plasma (Bloedon et al. (2008) J. Lipid Res. 49: 1344-1352), and the study in humans in which the 4F peptide was administered at low doses by injection and was not found to be efficacious despite very high levels of peptide in the plasma (Watson et al. (2011) J. Lipid Res. 52: 361-373), additional studies were performed in mice. These studies demonstrated that the dose of peptide administered, and not the peptide plasma level determined efficacy regardless of the route of administration (Navab et al. (2011) J Lipid Res. 52: 1200-1210; Navab et al. (2012) J. Lipid Res. 53: 437-446). These studies (Id.) also demonstrated that the dose required for efficacy was far above the highest dose tested in the human clinical trials that did not demonstrate efficacy (Watson et al. (2011) J. Lipid Res. 52: 361-373). Subsequently, our laboratory reported that intravenous administration of either D-4F or L-4F results in a remarkable targeting of the peptide to the proximal small intestine where it is transported into the intestinal lumen by the process of transintestinal cholesterol efflux (TICE) (Meriwether et al. (2016) J Lipid Res. 57: 1175-1193). Based on our data, we concluded that the 4F peptide functions as a modulator of the TICE pathway and suggests that the anti-inflammatory functions of 4F may be a partial consequence of the codependent intestinal transport of both 4F and cholesterol (Id.). Nakano et al. (Nakano et al. (2016) PLoS ONE 11: e0152207) reported that Ezetimibe promotes TICE by targeting the Niemann-Pick C1-like 1 (NPC1L1) protein, which blocks internalization of cholesterol from the brush border membrane causing cholesterol in the brush border membrane to exit by diffusion into the lumen of the small intestine or be pumped out into the lumen of the small intestine by ATP-binding cassette (ABC) protein complex ABC5/G8 (Chang and Chang (2008) Cell Metabolism. 7: 469-471). Since both the 4F apoA-I mimetic peptide and Ezetimibe have been reported to promote TICE (Meriwether et al. (2016) J Lipid Res. 57: 1175-1193; Nakano et al. (2016) PLoS ONE 11: e0152207), and both Ezetimibe and Tg6F lower plasma cholesterol levels, it seemed reasonable to determine if Ezetimibe would enhance the amelioration of dyslipidemia and systemic inflammation by Tg6F. We report here that is indeed the case. Additionally, we report a novel method for preparing Tg6F and Ezetimibe for oral administration that is significantly better than adding them separately to a Western diet (WD) and feeding them as a combined formulation to LDLR null mice. Materials and Methods Materials Transgenic tomatoes expressing the 6F peptide (Tg6F) and control transgenic tomatoes (EV) that express a marker protein (β-glucuronidase) instead of the 6F peptid were grown and processed as described previously (Chattopadhyay et al. (2016) J. Lipid Res. 57: 832-847). Ezetimibe was purchased from Cayman Chemical Company, Ann Arbor, Mich. (Catalogue No. 16331). All other materials were purchased from sources previously described (Id.). Mice and Diets LDLR-null mice originally purchased from Jackson Laboratories on a C57BL/6J background were obtained from the breeding colony of the Department of Laboratory and Animal Medicine at the David Geffen School of Medicine at UCLA. The gender and age of the mice are stated in the legend to each figure. The mice were maintained on standard mouse chow (Ralston Purina) before being switched to a Western diet WD (Teklad, Harlan, catalog #TD88137). Single Agents and the Combined Formulation In experiments in which Tg6F or EV or Ezetimibe were administered as single agents, the EV or Tg6F concentrate was added to WD at 0.06% by weight or Ezetimibe was added to WD to give a final dose of 10 mg/kg body weight/day. The EV or Tg6F concentrate or Ezetimibe was mixed into the diets as described (Chattopadhyay et al. (2015) Pharma. Res. Per. 3: e00154). In experiments in which the EV or Tg6F concentrates and Ezetimibe were both added to WD, each was added separately to WD at the same dose as used for the single agents, and each was mixed into the diet as described (Id.). Hereafter, the separate addition of the Tg6F concentrate and Ezetimibe to WD is referred to as the “Combined Formulation” to distinguish it from the “Novel Method” described below. A Novel Method In some experiments in which Tg6 and Ezetimibe were both administered, instead of adding Tg6F and Ezetimibe separately to WD as described above for the “Combined Formulation”, Ezetimibe was added to the supernatant of ethyl acetate with 5% acetic acid that had been incubated overnight with the freeze-dried transgenic 6F tomato powder as previously described (Chattopadhyay et al. (2016) J. Lipid Res. 57: 832-847; Chattopadhyay et al. (2015) Pharma. Res. Per. 3: e00154). The amount of Ezetimibe added to the supernatant provided 10 mg/kg body weight per day of Ezetimibe in the final preparation. After addition of Ezetimibe to the supernatant, the mixture was incubated at room temperature with gentle mixing for periods ranging from 2-hours to overnight as indicated in the Figure legends. Subsequently, the ethyl acetate was removed as described (Id.), the resulting powder was re-suspended in water and freeze-dried (Chattopadhyay et al. (2016) J. Lipid Res. 57: 832-847). The final freeze-dried tomato powder containing the 6F peptide together with Ezetimibe is hereafter referred to as “Novel Method” to distinguish it from the “Combined Formulation”. The final Novel Method freeze-dried tomato powder was mixed into to the diet as described (Chattopadhyay et al. (2016) J. Lipid Res. 57: 832-847; Chattopadhyay et al. (2015) Pharma. Res. Per. 3: e00154), and fed to the mice to give them the same dose each day of Tg6F (0.06% of diet by weight) and Ezetimibe (10 mg/kg body weight) as was the case when the agents were administered singly or as the Combined Formulation. Each day the mice ate all of the food administered for each condition; there was no difference in food consumption between groups. At the end of the treatment periods, the mice were fasted overnight in clean cages with new bedding, and following blood collection for plasma determinations, and prior to harvesting of organs, the mice were perfused under anesthesia to remove all blood (Chattopadhyay et al. (2013) J. Lipid Res. 54: 995-1010; Navab et al. (2013) J. Lipid Res. 54: 3403-3418), and organs were harvested and washed as described previously (Id.). All mouse studies were approved by the Animal Research Committee at UCLA. Assays Plasma lipids, and serum amyloid A (SAA) levels were determined and LC-MS/MS was performed as described (Navab et al. (2012) J. Lipid Res. 53: 437-446; Chattopadhyay et al. (2016) J. Lipid Res. 57: 832-847; Chattopadhyay et al. (2015) Pharma. Res. Per. 3: e00154). Determination of neutral sterols in the feces was performed as described (Meriwether et al. (2016) J Lipid Res. 57: 1175-1193). Statistical Analysis Statistical analyses were performed initially by ANOVA. After determining that statistically significant differences were present by ANOVA, further comparisons were made by unpaired two-tailed t-test. All statistical analyses were performed using Graph-Pad Prism version 5.03 (GraphPad Software, San Diego, Calif.). Statistical significance was considered achieved if P<0.05. Results Addition of Either Ezetimibe or Tg6F to WD Ameliorated Dyslipidemia in LDLR Null Mice and Addition of Both to WD (Combined Formulation) was Significantly Better than Addition of Either Agent Alone We previously reported that a dose of Tg6F of 0.06% by weight of diet was near maximal for ameliorating dyslipidemia in LDLR null mice on WD (Chattopadhyay et al. (2015) Pharma. Res. Per. 3: e00154). Therefore, we tested Tg6F at 0.06% by weight added to WD. In cholesterol-fed monkeys the ED50 value (the median effective dose) of Ezetimibe for inhibiting the rise in plasma cholesterol levels was 0.5 μg/kg/day (17). In mice the ED50 value for Ezetimibe was reported to be 700 μg/kg/day (Publication 29480958T REV 14 by Merck/Schering-Plough Pharmaceuticals. 2007. Zetia (Ezetimibe) tablets. www.accessdata.fda.gov/drugsatfda_docs/label/2008/021445s019lbl.pdf). The recommended dose for a human is 10 mg daily (0.14 mg/kg/day for a 70 Kg human) (Id.). We tested Ezetimibe at a dose of 10 mg/kg/day, a dose equal to or greater than the highest dose used in mice that we found in the literature (Nakano et al. (2016) PLoS ONE 11: e0152207; Publication 29480958T REV 14 by Merck/Schering-Plough Pharmaceuticals. 2007. Zetia (Ezetimibe) tablets. www.accessdata.fda.gov/drugsatfda_docs/label/2008/021445s019lbl.pdf; Davis et al. (2001) Arterioscle.r Thromb. Vasc. Biol. 21:2032-2038; Altmann et al. (2014) Sic. Transl. Med. 303:1201-1204). As shown in the experiment described in FIG. 15, adding either Tg6F or Ezetimibe to WD significantly ameliorated dyslipidemia, and adding both to WD at the same dose (Combined Formulation) further significantly ameliorated dyslipidemia. FIG. 15, panel A shows the results for total plasma cholesterol levels, and FIG. 15, panel B presents the data plotted to show the decrease in plasma cholesterol compared to WD for each treatment. FIG. 15, panel C shows the results for plasma triglyceride levels, and FIG. 15, panel D presents the data plotted to show the decrease in plasma triglycerides compared to WD for each treatment. FIG. 15, panel D shows the results for plasma HDL-Cholesterol levels, and FIG. 15, panel E presents the data plotted to show the increase in plasma HDL-Cholesterol compared to WD for each treatment. In this experiment Tg6F and Ezetimibe were not different as single agents except for HDL-Cholesterol where Tg6F was superior to Ezetimibe as a single agent. In each case the Combined Formulation was significantly better than the single agents. Adding both Tg6F and Ezetimibe to WD (Combined Formulation) ameliorated dyslipidemia, reduced plasma levels of lysophosphatidylcholine (LysoPC), and reduced Serum Amyloid A (SAA) levels in LDLR null mice significantly more than adding the single agents. In contrast, adding the same dose of Ezetimibe and a control transgenic tomato concentrate (EV) that does not contain the 6F peptide to WD was no more effective than Ezetimibe as a single agent— As shown in FIG. 16, panels A-F, the Combined Formulation was significantly more effective in ameliorating dyslipidemia compared to adding Tg6F or Ezetimibe to WD as single agents. However, adding a control transgenic tomato concentrate (EV) that does not contain the 6F peptide to WD together with the same dose of Ezetimibe as contained in the Combined Formulation did not significantly ameliorate dyslipidemia beyond that achieved by adding Ezetimibe to WD as a single agent. Similar results were seen for changes in LysoPC 18:0 (FIG. 16, panels G and H), LysoPC 18:1 (FIG. 16, panels I and J), LysoPC 20:4 (FIG. 16, panels K and L), and plasma SAA levels (FIG. 16, panels M and N). We conclude that the enhanced effectiveness of adding both Tg6F and Ezetimibe to WD (Combined Formulation) compared to the single agents is due to the presence of the 6F peptide in Tg6F. A Novel Method for Administering Tg6F and Ezetimibe Together that is Significantly More Effective Compared to Adding them Separately to WD as in the Combined Formulation Instead of adding Tg6F and Ezetimibe separately to WD as in the Combined Formulation, we added Ezetimibe during the preparation of the Tg6F concentrate. In making the Tg6F concentrate, freeze-dried tomato powder from transgenic 6F tomatoes are incubated at room temperature in ethyl acetate with 5% acetic acid (Chattopadhyay et al. (2015) Pharma. Res. Per. 3: e00154). After an overnight incubation the supernatant contains the 6F peptide, which is recovered by removing the ethyl acetate. The resulting solids are re-suspended in water and subjected to a final freeze drying that results in a uniform fluffy tomato powder that by weight is 37-fold more active than the starting material (Id.). Surprisingly, we found that after the overnight incubation, if we added Ezetimibe to the supernatant and incubated it for 2 hours prior to removing the ethyl acetate with 5% acetic acid, the final resulting lyophilized tomato powder containing Ezetimibe and the 6F peptide was significantly more effective when added to WD than the same dose of Tg6F and Ezetimibe added in the Combined Formulation (i.e., both added separately to WD). In the experiment described in FIG. 17, the Combined Formulation demonstrated a non-significant trend for improving some measurements compared to the results obtained with Tg6F and Ezetimibe added as single agents. However, using the Novel Method for administering Tg6F and Ezetimibe together in WD was significantly more effective than adding Tg6F or Ezetimibe as single agents to WD or adding both separately to WD (Combined Formulation). FIG. 17, panels A-F, shows the results for the effect of each treatment on dyslipidemia in the LDLR null mice. FIG. 17, panels G-L show the results of each treatment on plasma hydroxyeicosatetraenoic acid levels. FIG. 17, panels M and N show the results of each treatment on plasma SAA levels. FIG. 18 demonstrates that incubating Ezetimibe in the ethyl acetate with 5% acetic acid supernatant for 2 hours or incubating overnight gave similar results. FIGS. 4 and 5 demonstrate that the Novel Method was superior to the Combined Formulation in old mice (up to one year of age). Discussion Adding Ezetimibe or Tg6F as Single Agents to WD— Each parameter measured was significantly improved by Tg6F added to WD as a single agent. In five out of five experiments adding either Ezetimibe or Tg6F to WD improved plasma total cholesterol and triglyceride levels. In four out of four experiments in which plasma HDL-cholesterol was measured, adding either Ezetimibe or Tg6F as a single agent to WD significantly increased the levels. In four out of four experiments in which SAA was measured, adding Ezetimibe or Tg6F as a single agent to WD significantly decreased the levels. In the experiment in which plasma HETE levels were measured adding either Ezetimibe or Tg6F as a single agent to WD significantly decreased plasma levels of 5-HETE (FIG. 17, panels G and H). In this experiment, adding Tg6F as a single agent to WD also significantly decreased plasma levels of 12-HETE and 15-HETE, but adding Ezetimibe as a single agent to WD failed to significantly decrease plasma 12-HETE and 15-HETE levels (FIG. 17, panels I-L). The levels of 12-HETE and 15-HETE in the mouse are determined primarily by 12/15-lipoxygenase activity while the levels of 5-HETE are determined by the activity of 5-lipoxygenase. From our studies, we cannot determine why Ezetimibe effectively reduced the levels of 5-HETE, while not significantly altering 12-HETE or 15-HETE levels. In the experiment in which plasma LysoPC levels were measured, adding Ezetimibe or Tg6F as single agents to WD failed to significantly alter plasma levels of LysoPC 18:0 (FIG. 16, panels G and H). We previously reported that when LDLR null mice were fed WD, Tg6F failed to decrease plasma LysoPC 18:0 levels, but did reduce plasma LysoPC 18:1 levels (Chattopadhyay et al. (2016) J. Lipid Res. 57: 832-847). Consistent with this previous report (Id.) adding either Tg6F or Ezetimibe to WD as single agents significantly decreased plasma levels of LysoPC 18:1 (FIG. 16, panels I and J) and also significantly reduced plasma levels of LysoPC 20:4 (FIG. 16, panels K and L). Thus, with the exception of the case for plasma 12-HETE and 15-HETE levels, adding Ezetimibe or Tg6F to WD as single agents gave comparable results at near maximal doses for each. Adding Both Ezetimibe and Tg6F Separately to WD (Combined Formulation) While Ezetimibe and Tg6F were effective when added as single agents at near maximal doses to WD, adding both of them to WD separately at the same doses (Combined Formulation), in general, resulted in significantly greater effectiveness. In four out of five experiments the Combined Formulation was significantly better than either agent alone in reducing plasma total cholesterol levels. In one experiment the mice receiving the Combined Formulation showed a trend for a decrease in plasma total cholesterol compared to the mice receiving the single agents, but the difference did not reach statistical significance (FIG. 17, panels A and B). In five out of five experiments, the Combined Formulation was significantly better than either agent alone in reducing plasma triglyceride levels. In four out of four experiments, the Combined Formulation was significantly better than either agent alone in increasing plasma HDL-cholesterol levels. In three out four experiments, the Combined Formulation was significantly better than either agent alone in decreasing plasma SAA levels. In one experiment the values for plasma SAA for the mice receiving the Combined Formulation were slightly but significantly higher than the case for the single agents (FIG. 17, panels M and N). While neither Ezetimibe or Tg6F as single agents significantly altered plasma LysoPC 18:0 levels, the Combined Formulation significantly reduced plasma LysoPC 18:0 levels (FIGS. 16G and 16H). The Combined Formulation was also significantly better than either agent alone in further reducing plasma levels of LysoPC 18:1 (FIGS. 16I and 16J) and plasma levels of LysoPC 20:4 (FIG. 16, panels K and L). While showing a trend toward lower levels of plasma 5-HETE the values for the Combined formulation were not significantly different from those obtained with the single agents (FIG. 17, panels G and H). Similarly, the values for the Combined Formulation were not significantly different from that obtained by adding Tg6F as a single agent for plasma 12-HETE (FIG. 17, panels I and J) and plasma 15-HETE (FIG. 17, panels K and L); as noted above, Ezetimibe as a single agent did not significantly alter plasma 12-HETE or 15-HETE levels. We previously reported (Chattopadhyay et al. (2015) Pharma. Res. Per. 3: e00154) that adding to WD concentrate from control transgenic tomatoes (EV) that expressed a marker protein instead of the 6F peptide was significantly less effective compared to adding concentrate from transgenic tomatoes expressing the 6F peptide (Tg6F) to WD. As shown in FIG. 16, separately adding Ezetimibe and the control EV concentrate to WD was no more effective than adding Ezetimibe as a single agent. In contrast, as noted above, separately adding Ezetimibe and Tg6F to WD (Combined Formulation) was significantly more effective in lowering plasma levels of total cholesterol, triglycerides, LysoPC 18:0, LysoPC 18:1, LysoPC 20:4, and SAA and increasing plasma HDL-cholesterol levels (FIG. 16). Thus, we conclude that the 6F peptide is responsible for the enhanced effectiveness of the combined formulation. A Novel Method for Increasing the Effectiveness of Adding Ezetimibe and Tg6F to WD Adding Ezetimibe and Tg6F separately to WD was in general (but not always) significantly more effective than adding the single agents to WD as discussed above. It was a surprising finding that adding Ezetimibe to the ethyl acetate with 5% acetic acid supernatant during the preparation of the Tg6F concentrate resulted in a final preparation that when added to WD was significantly more effective compared to the single agents or the Combined Formulation. In three out three experiments, despite the diet containing the same amount of Ezetimibe and Tg6F, plasma total cholesterol, plasma triglyceride and plasma SAA levels were significantly lower with the Novel Method compared to the administration of the single agents or the Combined Formulation. In two out of two experiments in which HDL-cholesterol was measured, plasma HDL-cholesterol levels were significantly higher with the Novel Method compared to the administration of the single agents or the Combined Formulation. Plasma 5-HETE, 12-HETE and 15-HETE levels were significantly lower with the Novel Method compared to the administration of the single agents or the Combined Formulation. What explains the increased effectiveness of the Novel Method? There are several possibilities. During the preparation of the final concentrate there might be the formation of a covalent or non-covalent new molecule that is more effective. Another possibility is that during the preparation of the concentrate the tomato polyphenols together with the 6F peptide form micelles, which the Ezetimibe inserts into resulting in better targeting of Ezetimibe and Tg6F in the small intestine. While not being bound to a particular mechanism, the the data are clear that the Novel Method described herein results in a significantly more active preparation that likely is due to the formation of an Ezetimibe-T6F associated peptide. Based on the data presented here, we believe that the Ezetimibe-T6F associated peptide may have therapeutic potential for treating dyslipidemia and systemic inflammation. Based on our previous work (Id.) we believe that the Ezetimibe-T6F associated peptide also may have therapeutic potential for treating cancer. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.
<SOH> BACKGROUND <EOH>Mimetics of apolipoprotein A-I (apoA-I) containing only 18 amino acids showed promise in animal models of disease (Getz and Reardon (2011) J Inflamm. Res. 4: 83-92; Navab et al. (2012) Arterioscler. Thromb. Vasc. Biol. 32: 2553-2560), and improved HDL function in humans when given orally at high doses despite achieving low plasma peptide levels (Bloedon (2008) J. Lipid Res. 49: 1344-1352). However, when high plasma levels were achieved with low doses of peptide given intravenously or by subcutaneous (SQ) injection, no improvement in HDL function was seen (Watson et al. (2011) J. Lipid Res. 52: 361-373). Studies in mice indicated that the major site of action for these peptides is in the intestine and that a high dose of peptide is required for efficacy (Navab et al. (2011) J. Lipid Res. 52: 1200-1210; Navab et al. (2012) J. Lipid Res. 53: 437-445). The high dose requirement provides a barrier to use in humans because of the cost of chemically synthesizing these peptides. To overcome this barrier an 18 amino acid peptide (6F peptide, DWLKAFYDKFFEKFKEFF (SEQ ID NO:1) was transgenically expressed in tomatoes (Chattopadhyay et al. (2013) J. Lipid Res. 54: 995-1010). Feeding LDL receptor-null (LDLR −/− ) mice a Western diet (WD) for 13 weeks containing 2.2% by weight of freeze dried tomato powder made from transgenic tomatoes expressing the apoA-I mimetic peptide 6F (Tg6F) reduced plasma serum amyloid A (SAA) levels, reduced plasma total cholesterol levels, reduced plasma triglyceride levels, reduced plasma unsaturated (but not saturated) lysophosphatidic acid (LPA) levels, increased plasma paraoxonase-1 activity, increased plasma HDL-cholesterol levels, and decreased the extent of aortic atherosclerosis by about 50% (Chattopadhyay et al. (2013) J. Lipid Res. 54: 995-1010; Getz and Reardon (2013) J. Lipid Res. 54: 878-880). Two hours after LDLR −/− mice finished eating WD containing Tg6F, intact 6F peptide was found in the small intestine but not in the plasma (Chattopadhyay et al. (2013) J. Lipid Res. 54: 995-1010). Plasma levels of unsaturated (but not saturated) LPA correlated with the extent of aortic atherosclerosis. The content of LPA in the tissue of the small intestine was found to decrease after feeding Tg6F and the level of LPA (but not cholesterol) in the tissue of the small intestine correlated with the extent of aortic atherosclerosis (Id.). Without any purification steps, when the transgenic tomatoes expressing 6F peptide were freeze-dried, ground into powder and fed to a mouse model of dyslipidemia and atherosclerosis at only 2.2% of a high-fat high-cholesterol diet by weight, the transgenic tomatoes significantly reduced dyslipidemia, inflammation and atherosclerosis in the mice. This provided a daily dose of approximately 40 mg/kg/day.
<SOH> SUMMARY <EOH>In various embodiments, novel ezetimibe-associated apoA-I mimetic peptides are provided as well as uses thereof. It was surprising discovery that an ezetimibe-associated ApoA-I mimetic peptide (Ez-ApoA-I pepide) could be produced by incubating ezeimibe and Tg6F peptide together in a solution comprising ethyl acetate with 5% acetic acid followed by removal of the ethyl acetate. Suprisingly, this resulted in a significantly more effective preparation. In particular the ezetimibe-associated ApoA-I mimetic peptide showed greater biological activity than equivalent amounts of ezetimibe and ApoA-I peptide when administered in a combined formulation. Various embodiments contemplated herein may include, but need not be limited to, one or more of the following:
A61K3804
20170912
20180329
64641.0
A61K3804
0
DABKOWSKI, ERINNE R
EZETIMIBE-ASSOCIATED APOA-I MIMETIC PEPTIDES SHOWING ENHANCED SYNERGISM
SMALL
0
ACCEPTED
A61K
2,017
15,702,442
PENDING
POLYAXIAL BONE SCREW WITH SHANK ARTICULATION PRESSURE INSERT AND METHOD
A polyaxial bone screw assembly includes a threaded shank body having an upper portion, a receiver member or head, a retaining and articulating structure, and a pressure insert disposed between the shank upper portion and a rod. The receiver has a U-shaped cradle defining a channel for receiving a spinal fixation rod and a receiver cavity. The retaining and articulating structure attaches to the shank and rotates with the shank in the cavity during positioning. The pressure insert presses upon the shank upper portion and not the retaining and articulating structure.
1. A pivotal bone anchor assembly for securing an elongate rod to a bone, the pivotal bone anchor assembly comprising: a receiver having a longitudinal axis, a first pair of opposed upstanding arms extending upwardly from a lower body to define an upwardly open channel configured to receive the elongate rod, and a cavity within the lower body communicating with the open channel and with a downward facing bottom surface of the receiver through a distal opening in the lower body, the cavity having a substantially spherical inner seating surface adjacent to the distal opening, the upstanding arms having spaced apart and opposed interior surfaces with a discontinuous guide and advancement structure formed into upper portions thereof, and a pair of opposed upper recesses and at least one pair of opposed lower insert engaging recesses formed therein between the guide and advancement structure and the cavity, the upper and lower opposed recesses separated by opposed inwardly facing interior edges having a width less than a width for both the upper and lower opposed recesses; a bone anchor disposed within the receiver, the bone anchor having a proximal end portion and an anchor portion extending distally from the proximal end portion and through the distal opening for fixation to the bone, the proximal end portion having a partial spherically shaped outer upper surface above a hemisphere thereof; and a pressure insert positioned within the receiver channel above the bone anchor partial spherically shaped outer upper surface, the pressure insert comprising a base with a second pair of opposed upstanding arms extending upward from the base to define a curvate rod-engaging seating surface therebetween, the second pair of opposed upstanding arms having laterally facing outer surfaces extending down to the base to define substantially continuous lateral side surfaces devoid of any inwardly extending groove, aperture or slot, each of the lateral side surfaces having an upper section with a receiver engagement structure protruding laterally outward and extending upward to an upwardly-facing top surface thereon, wherein the pressure insert is directly engageable and downwardly displaceable using a removable first tool within the receiver channel after the bone anchor proximal end portion is disposed within the receiver cavity to apply pressure to the bone anchor upper surface, with the top surface of the laterally protruding receiver engagement structure being received in biased and at least partially overlapped engagement with a downwardly-facing top surface on the at least one pair of opposed lower insert engage recesses so as to prevent the insert from moving upwardly thereafter within the receiver prior to insertion of the elongate rod and a closure into the receiver channel. 2. The pivotal bone anchor assembly of claim 1, wherein the bone anchor proximal end portion further comprises a capture structure configured to secure a retaining and articulating structure to the bone anchor. 3. The pivotal bone anchor assembly of claim 2, wherein the retaining and articulating structure is secured to the capture structure of the bone anchor with a threaded connection. 4. The pivotal bone anchor assembly of claim 2, wherein the retaining and articulating structure is pre-positioned within the receiver cavity and then secured to the capture structure of the bone anchor when the capture structure of the bone anchor is inserted upwardly into the receiver cavity through the distal opening. 5. The pivotal bone anchor assembly of claim 1, wherein the at least one pair of opposed lower insert engaging recesses further includes a plurality of paired opposed lower insert engaging recesses formed into the receiver interior surfaces before the pressure insert is disposed within the receiver. 6. The pivotal bone anchor assembly of claim 1, wherein the at least one pair of opposed lower insert engaging recesses further comprises a plurality of downwardly-facing ridges formed into the receiver interior surfaces before the pressure insert is disposed within the receiver. 7. The pivotal bone anchor assembly of claim 1, wherein the at least one pair of opposed lower insert engaging recesses extends only partially into the receiver interior surfaces in the laterally outward direction so as to not extend entirely through the upstanding arms of the receiver to an exterior surface thereof. 8. The pivotal bone anchor assembly of claim 1, wherein the receiver upstanding arms further include at least one exterior horizontally radiused tool engagement groove formed into an exterior surface thereof proximate a top surface of each upstanding arm, and extending at least partially circumferentially about a periphery of each arm. 9. The pivotal bone anchor assembly of claim 8, wherein each horizontally radiused tool engagement groove includes a downward-facing upper surface spaced below the top surface of the upstanding arm and an upward-facing lower surface spaced above the elongate rod when the elongate rod is secured within the open channel. 10. The pivotal bone anchor assembly of claim 1, wherein the closure is a break-off closure. 11. The pivotal bone anchor assembly of claim 1, wherein the bone anchor is cannulated. 12. The pivotal bone anchor assembly of claim 1 wherein the closure has a receiver-mating structure formed on an outer sidewall surface thereof and engageable with the receiver guide and advancement structure. 13. The pivotal bone anchor assembly of claim 12, wherein the closure receiver-mating structure and the receiver guide and advancement structure each further comprise complimentary helically wound threads formed on the outer sidewall surface of the closure and the interior surfaces of the receiver upstanding arms, respectively. 14. The pivotal bone anchor assembly of claim 13, wherein the helically wound threads are reverse angle threads. 15. The pivotal bone anchor assembly of claim 1, wherein the receiver has a laterally facing radiused outer surface located around the receiver longitudinal axis. 16. The pivotal bone anchor assembly of claim 1, wherein the base of the pressure insert includes a bottom surface with a central opening extending through the base. 17. The bone anchor assembly of claim 1, wherein the insert can be pulled back up with a second tool. 18. A bone anchor assembly for securing an elongate rod to a bone, the bone anchor assembly comprising: a shank having a proximal capture portion with a top surface and an anchor portion extending distally from the proximal capture portion for fixation to the bone; a receiver having a longitudinal axis, an upper portion defining a upwardly open channel with inner sidewall surfaces configured to receive the elongate rod, and a lower portion defining a cavity having an interior surface communicating with the open channel and a receiver bottom opening, the shank positionable within the receiver with the shank anchor portion extending through the bottom opening, the inner sidewall surfaces including a closure mating structure formed therein, the receiver having an internal structure with a downwardly-facing surface located between the closure mating structure and the receiver bottom opening; a closure positionable within the receiver open channel; and a pressure insert sized and shaped to be initially disposed adjacent the receiver internal structure downwardly-facing surface and engaged by a tool so as to be downwardly displaceable within the receiver, after the shank has been positioned within the receiver cavity, the pressure insert having an outer surface configured to engage the receiver internal structure downwardly-facing surface in an overlapping relationship, the receiver internal structure downwardly-facing surface being formed in the receiver before the pressure insert is disposed within the receiver open channel, wherein the insert outer surface and the receiver internal structure downwardly-facing surface have a frictionally-biased overlapping engagement therebetween to frictionally hold and prevent the insert from moving back up within the receiver prior to the elongate rod and the closure being received within the receiver open channel, and wherein when the bone anchor assembly is in a locked position, with the elongate rod and closure within the receiver open channel, the closure remains spaced from the pressure insert. 19. The bone anchor assembly of claim 18, further comprising a retainer sized and shaped for loading into the receiver cavity prior to the shank to capture and hold the shank proximal capture portion within the cavity while an outer surface of the retainer engages the interior surface of the cavity to allow for pivoting motion between the receiver and the shank so as to provide for changes in the pivotal orientation therebetween. 20. The bone anchor assembly of claim 18, wherein the pressure insert has a frictional engagement with the shank top surface. 21. The bone anchor assembly of claim 18, wherein the receiver internal structure downwardly-facing surface further comprises a discontinuous recessed upper shoulder machined into the inner sidewall surfaces between the closure mating structure and the receiver bottom opening. 22. The bone anchor assembly of claim 18, wherein the outer surface of the pressure insert that comes into frictionally-biased overlapping engagement with the receiver internal structure downwardly-facing surface is at least partially sloped. 23. The bone anchor assembly of claim 18, wherein the frictional biased overlapping engagement between the receiver internal structure downwardly-facing surface and the insert outer surface is sufficient to retain the shank in a selected angle of pivotal orientation with respect to the receiver without continuously applied compression by the closure through the elongate rod. 24. The bone anchor assembly of claim 18, wherein the pressure insert is pushed downwardly so as to be displaced along the longitudinal axis of the receiver from a first position to a second position with the tool. 25. The bone anchor assembly of claim 18, wherein a portion of the pressure insert has a non-round shape with a width that is less than a length thereof. 26. The bone anchor assembly of claim 18, wherein an upper surface of the pressure insert includes at least one tool engagement structure complimentary with an engagement portion of the tool. 27. The bone anchor assembly of claim 26, wherein the at least one tool engagement structure further comprises a plurality of such tool engagement structures formed into the upper surface of the pressure insert. 28. A pivotal bone anchor assembly for securing an elongate rod to a bone, the pivotal bone anchor assembly comprising: a closure; a receiver defining an internal cavity in communication with an upper open channel and with a bottom surface of the receiver through a lower opening, the open channel being configured to receive the elongate rod and the closure above the elongate rod to secure the elongate rod to the receiver; a shank having an upper portion and a body for fixation to the bone, the upper portion being pivotably positioned within a lower portion of the receiver internal cavity with the shank body extending downward through the lower opening; and a pressure insert at least partially positionable within the open channel and operably engageable by a tool after the shank is disposed within the internal cavity to move an outer engagement surface of the pressure insert into at least partially overlapped contact with a receiver internal structure mating surface formed in the receiver before the insert is positioned therein, so as to bias the shank upper portion into a frictional articulatable relationship with the receiver prior to the assembly being locked with the closure and to prevent the insert from moving back up within the upper open channel, wherein the pressure insert is spaced from the closure when the closure and rod are positioned within the open channel. 29. The pivotal bone anchor assembly of claim 28, wherein the pressure insert is downwardly displaceable by the tool to move the insert outer engagement surface into the at least partially overlapped contact with the receiver internal structure mating surface. 30. The pivotal bone anchor assembly of claim 28, wherein the pressure insert is rotatable by the tool to move the insert outer engagement surface into the at least partially overlapped contact with the receiver internal structure mating surface, the contact being biased between the pressure insert and the receiver internal structure mating surface and between the pressure insert and the shank upper portion. 31. The pivotal bone anchor assembly of claim 28, further comprising a retaining structure positioned within the receiver internal cavity prior to the shank and engageable with the shank upper portion to prevent the shank from exiting the receiver through the lower opening. 32. The pivotal bone anchor assembly of claim 31, wherein the retaining structure remains spaced from the pressure insert through all articulations of the shank body relative to the receiver. 33. The pivotal bone anchor assembly of claim 31, wherein the retaining structure is configured to space the upper portion of the shank from an interior surface of the receiver cavity. 34. The pivotal bone anchor assembly of claim 28, wherein the shank upper portion further comprises a spherical enlargement engageable by a retaining structure. 35. The pivotal bone anchor assembly of claim 28, wherein the pressure insert has a rod-engaging surface. 36. The pivotal bone anchor assembly of claim 28, wherein the shank upper portion includes a convex, partial spherically shaped upper surface, and the pressure insert includes a bottom surface having a concave, partial spherically shaped recess configured to receive the shank partially spherically shaped upper surface, the spherically shaped recess having a continuous lower edge around a circumference thereof. 37. The pivotal bone anchor assembly of claim 28, wherein the pressure insert outer engagement surface further comprises an upper surface of at least one structure protruding laterally from an external side of the pressure insert. 38. The pivotal bone anchor assembly of claim 37, wherein the at least one laterally producing structure further comprises a plurality of upwardly facing ridges protruding from the external side of the pressure insert.
CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 12/802,668 filed Jun. 11, 2010, which is a continuation of U.S. application Ser. No. 11/140,343 filed May 27, 2005, all of which are incorporated by reference herein. BACKGROUND OF THE INVENTION The present invention is directed to polyaxial bone screws for use in bone surgery, particularly spinal surgery, and particularly to inserts for such screws. Bone screws are utilized in many types of spinal surgery, such as for osteosynthesis, in order to secure various implants to vertebrae along the spinal column for the purpose of stabilizing and/or adjusting spinal alignment. Although both closed-ended and open-ended bone screws are known, open-ended screws are particularly well suited for connections to rods and connector arms, because such rods or arms do not need to be passed through a closed bore, but rather can be laid or urged into an open channel within a receiver or head of such a screw. Typical open-ended bone screws include a threaded shank with a pair of parallel projecting branches or arms which form a yoke with a U-shaped slot or channel to receive a rod. Hooks and other types of connectors, as are used in spinal fixation techniques, may also include open ends for receiving rods or portions of other structure. A common mechanism for providing vertebral support is to implant bone screws into certain bones which then in turn support a longitudinal structure such as a rod, or are supported by such a rod. Bone screws of this type may have a fixed head or receiver relative to a shank thereof. In the fixed bone screws, the rod receiver head cannot be moved relative to the shank and the rod must be favorably positioned in order for it to be placed within the receiver head. This is sometimes very difficult or impossible to do. Therefore, polyaxial bone screws are commonly preferred. Open-ended polyaxial bone screws allow rotation of the head or receiver about the shank until a desired rotational position of the head is achieved relative to the shank. Thereafter, a rod can be inserted into the head or receiver and eventually the head is locked or fixed in a particular position relative to the shank. However, in certain instances, a surgeon may desire to set and fix the angular position of the head or receiver relative to the shank independently of rod insertion or rod locking. Additionally, it may be desirable to reset and fix the angle of orientation of the head or receiver during the surgical procedure. SUMMARY OF THE INVENTION A polyaxial bone screw assembly according to the invention includes a shank having an upper portion and a body for fixation to a bone; a head or receiver defining an open channel; and at least one compression or pressure insert. The shank is connected to the head or receiver at the upper portion and the shank body is swivelable with respect to the head or receiver. The pressure insert is receivable in the head open channel. The pressure insert includes a base and a head engagement structure. The pressure insert base is frictionally engageable with the shank upper portion and the head engagement structure is engageable with the receiver head. The pressure insert has an articulation position wherein the insert head engagement structure is engaged with the head and the base frictionally engages a projecting end of the shank upper portion with the pressure insert exerting an independent force or pressure on the shank upper portion sufficient to retain the shank body in a selected angle with respect to the head without continuously applied compression by a closure top through the rod. Pressure inserts according to the invention include a side loading insert having a ratcheted outer surface for engagement with a ratcheted inner surface on the bone screw receiver head. Another embodiment includes a cam insert, side loaded or down loaded into the bone screw receiver head, having sloped upper surfaces for engagement with an upper shoulder of a recess formed in the bone screw receiver head. OBJECTS AND ADVANTAGES OF THE INVENTION Therefore, objects of the present invention include: providing an improved spinal implant assembly for implantation into vertebrae of a patient; providing such an assembly that includes an open-headed implant, a shank pivotally connected to the implant head, a rod or other structural element, and a pressure insert disposed between the shank and the rod; providing a pressure insert that may be utilized independently to set an angle of articulation of the shank with respect to the head prior to or after insertion of the rod; providing such an assembly that has a low profile after final installation; providing such an assembly in which the pressure insert may be assembled into a bone screw head prior or subsequent to installing the bone screw into bone; providing such an assembly in which the bone screw includes a retaining structure that includes a non-slip feature for driving the shank into bone; and providing such an assembly that is easy to use, especially adapted for the intended use thereof and wherein the implant assembly components are comparatively inexpensive to produce. Other objects and advantages of this invention will become apparent from the following description taken in conjunction with the accompanying drawings wherein are set forth, by way of illustration and example, certain embodiments of this invention. The drawings constitute a part of this specification and include exemplary embodiments of the present invention and illustrate various objects and features thereof. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an exploded perspective view of an assembly according to the invention including a shank with a capture structure at one end thereof, a head or receiver, a retaining and articulating structure and a side-loading pressure insert. FIG. 2 is a perspective view of the assembly of FIG. 1 shown assembled. FIG. 3 is an enlarged, perspective view of the insert of FIG. 1. FIG. 4 is a front elevational view of the insert of FIG. 3. FIG. 5 is a side elevational view of the insert of FIG. 3. FIG. 6 is a top plan view of the insert of FIG. 3. FIG. 7 is a bottom plan view of the insert of FIG. 3. FIG. 8 is a cross-sectional view of the insert taken along the line 8-8 of FIG. 6. FIG. 9 is an enlarged and partial front elevational view of the assembled shank, bone screw head and retaining and articulating structure of FIG. 2 shown prior to insertion of the side-loading insert. FIG. 10 is an enlarged and partial front elevational view of the assembly of FIG. 2. FIG. 11 is an enlarged and partial side elevational view of the assembly of FIG. 2 shown with the side-loading insert in engagement with the bone screw shank, setting the shank in an angle of articulation with respect to the head. FIG. 12 is a partial front elevational view of a bone screw driving tool according to the invention. FIG. 13 is a partial side elevational view of the bone screw driving tool of FIG. 12. FIG. 14 is an enlarged and partial cross-sectional view of the head and insert taken along the line 14-14 of FIG. 2, shown with the shank and retaining and articulating structure in front elevation and further shown with the driving tool of FIG. 12. FIG. 15 is a cross-sectional view taken along the line 15-15 of FIG. 14. FIG. 16 is an enlarged and partial cross-sectional view of the head, retaining and articulating structure and insert taken along the line 16-16 of FIG. 2, shown with the shank in front elevation and further shown with the driving tool of FIG. 12 shown in the side elevational view of FIG. 13. FIG. 17 is a reduced view of the bone screw and driving tool of FIG. 14 further shown in exploded view with a guide wire and vertebra. FIG. 18 is an enlarged view of the bone screw, driving tool, guide wire and vertebra of FIG. 17 shown in cooperation during a process of bone screw installation. FIG. 19 is an exploded perspective view of a nested bone screw fastener assembly including a fastener base integral with a break-off head and an inner set screw. FIG. 20 is an enlarged cross-sectional view taken along the line 20-20 of FIG. 19 and shown with a set screw tool. FIG. 21 is a cross-sectional view similar to FIG. 20, showing the set screw inserted in the fastener base. FIG. 22 is a partial cross-sectional view of the bone screw and insert assembly of FIG. 14 shown with a rod, also in cross-section and in a process of mating with the nested bone screw fastener assembly of FIG. 21. FIG. 23 is a partial cross-sectional view, similar to FIG. 22 shown with a manipulation tool in a process of moving the side-loaded insert upwardly and away from the bone screw shank to allow for pivoting of the bone screw shank with respect to the head. FIG. 24 is a partial cross-sectional view, similar to FIGS. 22 and 23, shown with the shank fixed at a selected angle with respect to the head by frictional contact with the insert prior to frictional contact between the rod and the nested fastener assembly. FIG. 25 is a reduced partial and cross-sectional view similar to FIG. 24, showing the break-off head of the nested closure assembly being removed with a torquing tool. FIG. 26 is a partial cross-sectional view similar to FIG. 25 shown with a set screw tool engaged with the inner set screw in a process of tightening the set screw against the rod. FIG. 27 is a cross-sectional view similar to FIG. 26 showing a fully installed nested fastener in front elevation. FIG. 28 is a partial cross-sectional view similar to FIG. 26, showing engagement and removal of the nested fastener from the bone screw head with a set screw tool. FIG. 29 is an exploded perspective view of a second embodiment of an assembly according to the invention including a shank with a capture structure at one end thereof, a head, a retaining and articulating structure and an insert. FIG. 30 is an enlarged cross-sectional view of the bone screw head and retaining and articulating structure taken along the line 30-30 of FIG. 29, shown with the retaining and articulating structure turned on a side thereof for insertion into the head. FIG. 31 is a cross-sectional view similar to FIG. 30 showing the retaining and articulating structure turned back into the orientation shown in FIG. 29 but within the head in preparation for engagement with the capture structure of the shank. FIG. 32 is an enlarged front elevational view of the insert of FIG. 29. FIG. 33 is an enlarged side elevational view of the insert of FIG. 29. FIG. 34 is an enlarged top plan view of the insert of FIG. 29. FIG. 35 is an enlarged bottom plan view of the insert of FIG. 29. FIG. 36 is an enlarged partial cross-sectional view of the head similar to FIG. 31 showing the shank and capture structure in front elevation in a process of engagement with the retaining and articulating structure, also shown in front elevation. FIG. 37 is a partial cross-sectional view of the head similar to FIG. 36 showing the shank capture structure engaged with the retaining and articulating structure and showing a process of insertion of the insert into the head. FIG. 38 is a cross-sectional view taken along the line 38-38 of FIG. 37. FIG. 39 is a cross-sectional view taken along the line 39-39 of FIG. 37. FIG. 40 is a reduced partial cross-sectional view of the head and front elevational view of the shank, retaining and articulating structure and insert similar to FIG. 37, showing the insert rotated to a shank setting position and the assembly in a process of being driven into bone with a driving tool. FIG. 41 is an enlarged cross-sectional view taken along the line 41-41 of FIG. 40. FIG. 42 is an enlarged and partial cross-sectional view of the head similar to FIG. 40, shown with the shank, retaining and articulating structure and insert in front elevation and further showing a rod in cross-section and an engaged closure top in front elevation. FIG. 43 is an exploded perspective view of a third embodiment of an assembly according to the invention including a shank with a capture structure at one end thereof, a head, a retaining and articulating structure and an insert. FIG. 44 is an enlarged cross-sectional view of the bone screw head and retaining and articulating structure taken along the line 44-44 of FIG. 43, shown with the retaining and articulating structure turned on a side thereof for insertion into the head. FIG. 45 is a cross-sectional view similar to FIG. 44 showing the retaining and articulating structure turned back into the orientation shown in FIG. 43 but within the head in preparation for engagement with the capture structure of the shank. FIG. 46 is a partial cross-sectional view of the head similar to FIG. 45 showing the shank and capture structure in front elevation in a process of engagement with the retaining and articulating structure, also shown in front elevation. FIG. 47 is a partial cross-sectional view of the head similar to FIG. 46 showing the shank capture structure engaged with the retaining and articulating structure and showing a process of insertion of the insert into the head. FIG. 48 is a cross-sectional view taken along the line 48-48 of FIG. 47. FIG. 49 is a cross-sectional view taken along the line 49-49 of FIG. 47. FIG. 50 is an enlarged front elevational view of the insert of FIG. 43. FIG. 51 is an enlarged side elevational view of the insert of FIG. 43. FIG. 52 is a reduced partial cross-sectional view of the head and front elevational view of the shank, retaining and articulating structure and insert similar to FIG. 47, showing the insert rotated to a shank setting position and the assembly in a process of being driven into bone with a driving tool. FIG. 53 is an enlarged cross-sectional view taken along the line 53-53 of FIG. 52. FIG. 54 an enlarged and partial cross-sectional view of the head similar to FIG. 52, shown with the shank, retaining and articulating structure and insert in front elevation and further showing a rod in cross-section and an engaged closure top in front elevation. DETAILED DESCRIPTION OF THE INVENTION As required, detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention, which may be embodied in various forms. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention in virtually any appropriately detailed structure. With reference to FIGS. 1-28, the reference numeral 1 generally designates a polyaxial bone screw assembly according to the present invention. The assembly 1 includes a shank 4 that further includes a body 6 integral with an upwardly extending capture structure 8; a head or receiver 10; a retaining and articulating structure or ring 12; and a side-loading pressure insert 14. The shank 4, head or receiver 10, retaining and articulating structure 12 and insert 14 are preferably assembled prior to implantation of the shank body 6 into a vertebra 15, which procedure is shown in FIGS. 17 and 18. FIGS. 19-28 further show a closure structure or nested fastener, generally 18, of the invention for capturing a longitudinal member such as a rod 21 within the head or receiver 10. The insert 14 allows for setting an angle of articulation between the shank body 6 and the head or receiver 10 prior to insertion of the rod 21, if desired. Upon installation, which will be described in detail below, the nested fastener 18 presses against the rod 21 that in turn presses against the insert 14 that presses against the capture structure 8 which biases the retaining and articulating structure 12 into fixed frictional contact with the head or receiver 10, so as to fix the rod 21 relative to the vertebra 15. The head or receiver 10 and shank 4 cooperate in such a manner that the head 10 and shank 4 can be secured at any of a plurality of angles, articulations or rotational alignments relative to one another and within a selected range of angles both from side to side and from front to rear, to enable flexible or articulated engagement of the head 10 with the shank 4 until both are locked or fixed relative to each other. The shank 4, best illustrated in FIGS. 1 and 2, is elongate, with the shank body 6 having a helically wound bone implantable thread 24 extending from near a neck 26 located adjacent to the capture structure 8 to a tip 28 of the body 6 and extending radially outward therefrom. During use, the body 6 utilizing the thread 24 for gripping and advancement is implanted into the vertebra 15 leading with the tip 28 and driven down into the vertebra 15 with an installation or driving tool 31 so as to be implanted in the vertebra 15 to near the neck 26, as shown in FIG. 24, and as is described more fully in the paragraphs below. The shank 4 has an elongate axis of rotation generally identified by the reference letter A. It is noted that any reference to the words top, bottom, up and down, and the like, in this application refers to the alignment shown in the various drawings, as well as the normal connotations applied to such devices, and is not intended to restrict positioning of the assembly 1 in actual use. The neck 26 extends axially outward and upward from the shank body 6. The neck 26 may be of reduced radius as compared to an adjacent top 32 of the body 6. Further extending axially and outwardly from the neck 26 is the capture structure 8 that provides a connective or capture structure disposed at a distance from the body top 32 and thus at a distance from the vertebra 15 when the body 6 is implanted in the vertebra 15. The capture structure 8 is configured for connecting the shank 4 to the head or receiver 10 and capturing the shank 4 in the head 10. The capture structure 8 has an outer substantially cylindrical surface 34 having a helically wound guide and advancement structure thereon which in the illustrated embodiment is a V-shaped thread 36 extending from near the neck 26 to adjacent to an annular upper surface 38. Although a simple thread 36 is shown in the drawings, it is foreseen that other structures including other types of threads, such as buttress and reverse angle threads, and non threads, such as helically wound flanges with interlocking surfaces, may be alternatively used in alternative embodiments of the present invention. Projecting along the axis A upwardly and outwardly from the annular surface 38 of the capture structure 8 is a curved or dome-shaped top 42. The illustrated top 42 is radially extending, convex, substantially hemispherical or dome-shaped, preferably having a substantially uniform radius of generation to provide for positive engagement with the insert 14 at almost any orientation of the shank 4, as will be described more fully below. It is foreseen that in certain embodiments the radius may vary depending upon the needs and desires of the particular structure and the domed top 42 may have a shape that is only partly spherical or some other shape. For example, the domed top could be radiused at the location of greatest projection along the axis A and otherwise feathered along a periphery thereof so as to not have a continuous uniform radius of generation throughout but rather a continually changing radius of generation along at least the length thereof. The shank 4 shown in some of the drawings is cannulated, having a small central bore 44 extending an entire length of the shank 4 along the axis A. The bore 44 has a first circular opening 46 at the shank tip 28 and a second circular opening 48 at the top surface 42. The bore 44 is coaxial with the threaded body 6 and the capture structure outer surface 34. The bore 44 provides a passage through the shank 4 interior for a length of wire or pin 49 as shown in FIGS. 17 and 18, inserted into the vertebra 15 prior to the insertion of the shank body 6, the pin 49 providing a guide for insertion of the shank body 6 into the vertebra 15. Referring to FIGS. 1, 2, 9-11 and 14, the head or receiver 10 has a generally cylindrical outer profile with a substantially cylindrical base 50 integral with a pair of opposed upstanding arms 52 that extend from the base 50 to a top surface 54. The arms 52 form a U-shaped cradle and define a U-shaped channel 56 between the arms 52 and include an upper opening 57 and a lower seat 58 having substantially the same radius as the rod 21 for operably snugly receiving the rod 21. Each of the arms 52 has an interior surface 60 that defines the inner cylindrical profile and includes a partial helically wound guide and advancement structure 62. In the illustrated embodiment, the guide and advancement structure 62 is a partial helically wound flangeform configured to mate under rotation with a similar structure on the nested fastener 18, as described more fully below. However, it is foreseen that the guide and advancement structure 62 could alternatively be a V-shaped thread, a buttress thread, a square thread, a reverse angle thread or other thread like or non-thread like helically wound advancement structures for operably guiding under rotation and advancing the fastener 18 downward between the arms 52. Tool engaging grooves 64 are formed on outer substantially cylindrical surfaces 65 of the arms 52 which may be used for holding the head 10 during assembly with the shank 4 and the retaining and articulating structure 12 and also during the implantation of the shank body 6 into vertebra 15. The illustrated grooves 64 are disposed near the top 54 of the head 10 and each extend partially circumferentially about a periphery of each arm 52 and may include an undercut or dovetail feature for engagement with a holding tool. A holding tool (not shown) is equipped with structure sized and shaped to be received in the grooves 64. The holding tool and respective grooves 64 may be configured for either a twist on/twist off engagement with the head, or a flexible snap on/snap off engagement wherein the holding tool has legs which splay outwardly to position the tool for engagement in the grooves 64 or a combination thereof. It is foreseen that the grooves 64 and the cooperating holding tool may be configured to be of a variety of sizes and locations along the cylindrical surfaces 65. Also disposed centrally on each arm 52 is an oval through-bore 68 that allows for manipulation of the insert 14 as will be described more fully below. Communicating with the U-shaped channel 56 and located within the base 50 of the head or receiver 10 is a chamber or cavity 78 substantially defined by an inner surface 80 of the base 50, the cavity 78 opening upwardly into the U-shaped channel 56. The inner surface 80 is substantially spherical, with at least a portion thereof forming a partial internal spherical seating surface 82 having a first radius. The surface 82 is sized and shaped for mating with the retaining and articulating structure 12, as described more fully below. The base 50 further includes a restrictive neck 83 defining a bore 84 communicating with the cavity 78 and a lower exterior 86 of the base 50. The bore 84 is coaxially aligned with respect to a rotational axis B of the head 10. The bore 84 may be conically counterbored or beveled in a region 85 to widen the angular range of the shank 4. The neck 83 and associated bore 84 are sized and shaped to be smaller than a radial dimension of the retaining and articulating structure 12, as will be discussed further below, so as to form a restriction at the location of the neck 83 relative to the retaining and articulating structure 12, to prevent the retaining and articulating structure 12 from passing from the cavity 78 and out into the lower exterior 86 of the head 10 when the retaining and articulating structure 12 is seated. However, it is foreseen that the retaining and articulating structure could be compressible (such as where such structure has a missing section) and that the retaining structure could be loaded up through the neck 83 and then allowed to expand and fully seat in the spherical seating surface. It is foreseen that the inner surface 80 may further include an elongate upper loading recess (not shown) for accommodating and loading the retaining and articulating structure 12 into the cavity 78. Such a loading recess would be generally vertically disposed in the head 10, extending between and communicating with both the channel 56 and the cavity 78, allowing for ease in top loading the retaining and articulating structure 12 into the cavity through the upper opening 57 and otherwise allowing for the spherical wall 80 of the head 10 to have a radius allowing for substantial thickness and strength of the head base 50. On each arm 52, disposed adjacent to and directly below the guide and advancement structure 62 is an inner, inset surface 87 having a width or diameter greater than a distance between the interior surfaces 60 of the arms 52. An inner insert receiving surface 88 is located between the surface 87 and the inner substantially spherical surface 80. The insert receiving surface 88 includes a band of ridges or teeth 89 extending across each arm 52 and running parallel to the head top surface 54. The ridges or teeth 89 each incline in a downward direction toward the base 50 and are sized and shaped to cooperate with ratchet teeth disposed on the insert 14 as will be described more fully below. The inner surface 87 provides space for insertion of the insert 14 into the head 10 with no initial engagement of the teeth 89 with the head 10 as illustrated in FIG. 10. The retaining and articulating structure or ring 12 is used to retain the capture structure 8 of the shank 4 within the head 10. The retaining and articulating structure 12, best illustrated by FIGS. 1, 14, 16 and 18, has an operational central axis that is the same as the elongate axis A associated with the shank 4, but when the retaining and articulating structure 12 is separated from the shank 4, the axis of rotation is identified as an axis C. The retaining and articulating structure 12 has a central bore 90 that passes entirely through the retaining and articulating structure 12 from a top surface 92 to a bottom surface 94 thereof. A first inner cylindrical surface 96 defines a substantial portion of the bore 90, the surface 96 having a helically wound guide and advancement structure thereon as shown by a helical rib or thread 98 extending from adjacent the top surface 92 to adjacent the bottom surface 94. Although a simple helical rib 98 is shown in the drawings, it is foreseen that other helical structures including other types of threads, such as buttress and reverse angle threads, and non threads, such as helically wound flanges with interlocking surfaces, may be alternatively used in an alternative embodiment of the present invention. The inner cylindrical surface 96 with helical rib 98 are configured to mate under rotation with the capture structure outer surface 34 and helical advancement structure or thread 36, as described more fully below. The retaining and articulating structure 12 has a radially outer partially spherically shaped surface 104 sized and shaped to mate with the partial spherically shaped seating surface 82 of the head and having a radius approximately equal to the radius associated with the surface 82. The retaining and articulating structure radius is larger than the radius of the neck 83 of the head 10. Although not required, it is foreseen that the outer partially spherically shaped surfaced 104 may be a high friction surface such as a knurled surface or the like. The retaining and articulating structure top surface 92 extends from the central bore 90 to the outer surface 104. The top surface 92 is disposed at an angle with respect to the bottom surface 94, with the top surface 92 sloping in a downward direction toward the bottom surface 94 as the top surface 92 extends toward the outer surface 104. As illustrated in FIG. 11 and discussed more fully below, the angle of inclination of the top surface 92 is configured for contact and frictional engagement with a bottom surface of the insert 14. The retaining and articulating structure 12 further includes a tool engagement structure in the form of a transverse slot 106 formed in the top surface 92 for engagement with the driving tool 31 shown in FIGS. 17 and 18. As will be described more fully below, the tool 31 is configured to fit within the transverse slot 106 on either side of the domed top 42 of the shank 4 and utilized for driving the shank body 6 into the vertebra 15. The elongate rod or longitudinal member 21 that is utilized with the assembly 1 can be any of a variety of implants utilized in reconstructive spinal surgery, but is normally a cylindrical elongate structure having a smooth, outer cylindrical surface 108 of uniform diameter. The rod 21 is preferably sized and shaped to snugly seat near the bottom of the U-shaped channel 56 of the head 10 and, during normal operation, is positioned slightly above the bottom of the channel 56 at the lower seat 58. In the illustrated embodiment, the domed top 42 of the shank 4 does not come into direct contact with the rod 21, but rather, the side-loading insert 44 is received within the bone screw head 10 prior to rod insertion, and ultimately is positioned between the rod 21 and the top 42. The insert 14 is best illustrated in FIGS. 3-7. The insert 14 includes a base 110 integral with a pair of upstanding arms 112. The base 110 and arms 112 form a generally U-shaped, open, through-channel 114 having a substantially cylindrical bottom seating surface 116 configured to operably snugly engage the rod 21. Each arm 112 has a faceted outer profile with a lower facet or face 120 extending from the base 110 and integral with a side facet or face 122 that includes a bar or rack of inclined teeth 124 for ratcheting the insert 14 down by degrees into the head 10 in cooperation with the ridges or teeth 89 disposed on the insert receiving surface 88, as will be described more fully below. Each side facet or face 122 extends between one of the lower facets 120 and a top surface 126. The ratchet teeth 124 are disposed near the top surface 126 and each tooth 124 runs in a direction parallel to the top surface 126. Furthermore, each tooth 124 includes a surface 130 inclined in an outward and upward direction toward the top surface 126. The teeth 124 are thus readily movable or ratcheted downwardly toward the cavity 78 of the bone screw head 10 when desired, after side insertion of the insert 14 into the head 10 as illustrated in FIGS. 1 and 2. Once the teeth 124 are pressed downwardly into engagement with the teeth 89, the insert 14 resists upward movement toward the opening 57 of the bone screw head channel 56. Disposed on either side of each side facet 122 are lateral facets 128 that terminate at planar outer edge surfaces 132. Also extending between the edge surfaces 132 and the base 110 are lower facets 134. A pair of opposing, squared-off notches 136 are formed on each lower facet 134 in a central location where the facet 134 contacts the edge surfaces 132. The notches 136 are sized and shaped to correspond and cooperate with the transverse slot 106 of the retaining and articulating structure 12 to allow for insertion of the driving tool 31 through the notches 136 and into the slot 106 for engagement with the retaining and articulating structure during installation of the shank body 6 into bone. Disposed centrally on a bottom surface 138 of the base 110, opposite the seating surface 116 is a concave, substantially spherical formation 140. A cannulation bore 142 extends through a central portion of the formation 140. The formation 140 is sized and shaped to snugly frictionally fit about the domed top 42 of the capture structure 8. As will be described in greater detail below, as the insert 14 is ratcheted downwardly into contact with the domed top 42 and the retaining and articulating structure 12, the insert 14 may be used to set the articulation of the shank body 6 with respect to the bone screw head 10 prior to insertion and locking of the rod 21 into the head 10, or by inserting and compressing the rod 21 with the closure top 18 and then releasing the closure top 18. As illustrated in FIG. 23 and discussed more fully below, the side bores or apertures 68 formed in the head 10 allow for manipulation of the insert 14 with respect to the dome shaped top 42 by a tool 146 that has opposed pinchers or prongs 147 for extending through the bores 68 and pressing against the arms 112 of the insert 14 to loosen the insert 14 from the head 10. Eventually, the rod 21 is placed in the U-shaped channel 56 and/or the rod 21 which has been placed in the channel directly, abutingly engages or re-engages the insert 14 that in turn engages the shank capture structure domed top 42, as shown, for example, in FIGS. 11 and 22, consequently biasing the shank 4 downwardly in a direction toward the base 50 of the head 10 when the assembly 1 is fully assembled. The shank 4 and retaining and articulating structure 12 are thereby locked in position relative to the head 10 by the rod 21 firmly pushing downward on the insert 14 and the shank domed top surface 42. With reference to FIGS. 12-18, the driving tool 31 according to the invention includes a handle 150, an elongate cylindrical stem or shaft 154 and an engagement structure 156. The engagement structure 156 is configured to operably mate with both the insert 14 and the retaining and articulating structure 12 at the transverse slot 106 thereof. The shaft 154 with attached engagement structure 156 is receivable in and passes through the interior of the bone screw head 10. The stem or shaft 154 is rigidly attached to the handle 150 and coaxial therewith. The handle 150 includes outer grooves 158 disposed about an outer cylindrical surface 160 thereof to aid in gripping and rotating the respective components. The engagement structure 156 includes an oblong support 162 with two opposed arms 164 extending downwardly from the support 162 and away from the shaft 154 at either end of the support 162. The oblong support 162 has a substantially cylindrical lower surface 166 sized and shaped to fit within the U-shaped channel 114 of the insert 14 and operably mate with the bottom seating surface 116 during turning rotation and driving the of the bone screw shank 4 into bone. Each arm 164 further includes an extension 168 sized and shaped to fit within the transverse slot 106 of the retaining and articulating structure 12. As illustrated in FIG. 16, each extension 168 has a thickness such that the extension 168 fits snugly between the threaded cylindrical surface 34 of the capture structure 8 and the inner surface 80 of the head 10, while a bottom surface 170 of the extension 168 seats evenly on a base surface 171 of the transverse slot 106. Each arm 164 also includes an inner seating surface 174 disposed parallel to the base surface 171. Each inner seating surface 174 is sized and shape to seat upon and engage the annular top surface 38 of the capture structure 8 when the extensions 168 are seated within the transverse slot 106. Thus, the engagement structure 156 of the driving tool 31 engages the bone screw assembly 1 at the lower cylindrical surface 166, the extensions 168 and the inner seating surface 174 when driving the shank body 6 into the vertebra 15, as will be described more fully below. The driving tool 31 also includes a centrally located cannulation bore 176 extending along a length thereof, sized shaped and located to cooperate with the cannulation bore 44 of the bone screw shank 4 and the cannulation bore 142 of the insert 14. With particular reference to FIGS. 19-21, the closure structure or nested fastener 18 can be any of a variety of different types of closure structures for use in conjunction with the present invention with suitable mating structure on the upstanding arms 52 of the head 10. The fastener 18 screws between the spaced arms 52. The illustrated fastener 18 includes an outer fastener 204 and an uploaded set screw 206. The fastener 204 includes a base 208 integral or otherwise attached to a break-off head 210. The base 208 cooperates with the head 10 of the bone screw assembly 1, as illustrated in FIGS. 22-28, to close the head U-shaped channel 56 and to clamp the spinal fixation rod 21 within the bone screw head 10. The break-off installation head 210 includes a faceted outer surface 220 sized and shaped for engagement with a tool 221 for installing the fastener 204 to the bone screw head or receiver 10 and thereafter separating the break-off head 210 from a respective base 208 when installation torque exceeds selected levels. The base 208 of the fastener 204 is substantially cylindrical, having an axis of rotation D and an external surface 250 having a guide and advancement structure 252 disposed thereon. The guide and advancement structure 252 is matingly attachable to the guide and advancement structure 62 of the bone screw head 10. As with the guide and advancement structure 62, the guide and advancement structure 252 can be of any type, including V-type threads, buttress threads, reverse angle threads, or square threads. Preferably the guide and advancement structure 252 is a helically wound flange form that interlocks with the reciprocal flange form as part of the guide and advancement structure 62 on the interior of the bone screw arms 52. The guide and advancement structures 62 and 252 are preferably of a type that do not exert radially outward forces on the arms 52 and thereby avoid tendencies toward splaying of the arms 52 of the bone screw head 10, when the fastener 204 is tightly torqued into the head 10. The fastener 204 includes an internal, centrally located through-bore 254. At the base 208, the bore 254 is substantially defined by a guide and advancement structure, shown in FIGS. 20 and 21 as an internal V-shaped thread 256. The thread 256 is sized and shaped to receive the threaded set screw 206 therein as will be discussed in more detail below. Although a traditional V-shaped thread 256 is shown, it is foreseen that other types of helical guide and advancement structures may be used. Near a substantially annular planar top surface 258 of the base 208, an abutment shoulder 260, extends uniformly radially inwardly. The abutment shoulder 260 is spaced from the V-shaped thread 256 and sized and shaped to be a stop for the set screw 206, prohibiting the set screw 206 from advancing out of the top 258 of the base 208. It is foreseen that alternatively, the set screw 206 may be equipped with an outwardly extending abutment feature near a base thereof, with complimentary alterations made in the base 208, such that the set screw 206 would be prohibited from advancing out of the top 258 of the base 208 due to abutment of such outwardly extending feature against a surface of the base 208. An inner cylindrical wall 262 separates the abutment shoulder 260 from the thread 256. The cylindrical wall 262 has a diameter slightly greater than a root or major diameter of the internal thread 256. The wall 262 partially defines a cylindrical space or passage 264 for axial adjustable placement of the screw 206 with respect to the rod 21 as will be discussed in more detail below. The fastener 204 further includes the break-off head 210 that is integral or otherwise attached to the fastener 204 at a neck or weakened region 266. The neck 266 is dimensioned in thickness to control the torque at which the break-off head 210 separates from the fastener 204. The preselected separation torque of the neck 266 is designed to provide secure clamping of the rod 21 by the fastener 204 before the head 210 separates. For example, 120 inch pounds of force may be a selected break-off torque. The illustrated, hexagonal faceted surfaces 220 of the break-off head 210 enables positive, non-slip engagement of the head 210 by the installation and torquing tool 221 illustrated in FIG. 25. Separation of the break-off head 210 leaves only the more compact base 208 of the fastener 204 installed in the bone screw head or receiver 10, so that the installed fastener 204 has a low profile. The base 208 of the fastener 204 may include structure to provide clamping engagement between the base 208 and the rod 21. In the embodiment disclosed in FIGS. 19-28, a bottom surface 268 of the base 208 has an interference structure in the form of a “cup point” or V-shaped ridge or ring 270. The V-ring 270 operably cuts into the outer surface 108 of the rod 21 during assembly, when the fastener 204 is threaded into the screw head 10, so that the fastener more positively secures the rod 21 against rotational and translational movement of the rod 21 relative to the bone screw head 10. As the rod 21 may be bent or skewed with respect to the head 10 at a location of engagement between the rod 21 and the fastener 204, only a portion or a side of the V-ring 270 may engage with and cut into the rod 21. It is also foreseen that in some embodiments, clamp enhancing structure on the fastener 204, such as the V-ring 270, or surface finish such as knurling, may or may not be necessary or desirable. The uploadable set screw 206 has a substantially planar top 276 and a bottom 277. The set screw 206 is substantially cylindrical in shape, having an axis of rotation E, and includes an outer cylindrical surface 278 with a V-shaped thread 280 extending from the top 276 to the bottom 277 thereof. The surface 278 and thread 280 are sized and shaped to be received by and mated with the inner thread 256 of the fastener base 208 in a nested relationship. Thus, in operation, the axis of rotation E is the same as the axis of rotation D of the fastener 204. The embodiment of the set screw 206 best illustrated in FIGS. 19-21 includes interference structure for enhancing clamping or setting engagement with the surface 108 of the rod 21. The bottom 277 of the illustrated set screw 206 has a centrally located set point 282 and a peripherally located cup point or V-shaped set ring 284 projecting therefrom. The set point 282 and the set ring 284 are designed to cut into the surface 108 of the rod 21 when the set screw 206 is tightly fastened into the fastener base 208. The set point 282 projects outwardly from the bottom 277 to a location beyond the outermost surface of the set ring 284. Thus, the set point 282 is an initial and primary source of engagement with the rod 21, directly pressing against the rod 18 along the central axis of rotation D of the set screw 206. As with the V-ring 270 of the fastener 204, the V-ring 284 may contact and press against the rod 21 only along a portion thereof if the rod 21 is bent or otherwise disposed in a skewed relationship with the bone screw head 10. It is foreseen that a domed shape projection (not shown) may be utilized in lieu of the set point 282. Such a projection may be a radially extending convex, curved, partially spherical or dome-shaped interference or compressive structure, having a substantially uniform radius to provide for positive engagement with the rod 21 at the surface 108. Such a domed structure may extend a greatest distance along the central axis E. It is also foreseen that other structures for enhancing clamping, such as knurling or the like may be used in some embodiments or none in others. The set screw 206 includes a central aperture 286 formed in the top 276 and defined by faceted side walls 288 and a hexagonal bottom seating surface 289, forming a hex-shaped internal drive for positive, non-slip engagement by a set screw installment and removal tool such as an Allen-type wrench 290 as depicted in FIGS. 20, 26 and 28. With reference to FIG. 20, the central aperture 286 cooperates with the central internal bore 254 of the fastener 204 for accessing and uploading the set screw 206 into the fastener 204 prior to engagement with the bone screw head 10. After the nested fastener 18 engages the bone screw head 10, and the break-off head 210 is broken off, the tool 290 is used to set and lock the set screw 206 against the rod 21 as illustrated in FIG. 26. There are circumstances under which it is desirable or necessary to release the rod 21 from the bone screw head 10. For example, it might be necessary for a surgeon to re-adjust components of a spinal fixation system, including the rod 21, during an implant procedure, following an injury to a person with such a system implanted. In such circumstances, the tool 290 may be used to remove both the set screw 206 and attached fastener base 208 as a single unit, with the set screw 206 contacting and contained within the base 208 by the abutment shoulder 260. Thus, as illustrated in FIG. 28, rotation of the tool 290 engaged with the set screw 206 backs both the set screw 206 and the fastener base 208 out of the guide and advancement structure 252 in the arms 52 of the bone screw head 10, thereby releasing the rod 21 for removal from the bone screw head 10 or repositioning of the rod 21. It is foreseen that other removal structures such as side slots or other screw receiving and engagement structures may be used to engage the set screw 206 that is nested in the fastener base 208. With reference to FIGS. 1 and 2, prior to the polyaxial bone screw assembly 1 being implanted in the vertebra 15, the retaining and articulating structure 12 is typically first inserted or top-loaded, into the head U-shaped channel 56, and then into the cavity 78 to dispose the structure 12 within the inner surface 80 of the head 10. The structure 12 is typically turned or rotated such that the axis C is perpendicular to the axis B of the head 10 during insertion of the structure 12 into the head 10. Then, after the retaining and articulating structure 12 is within the cavity 78, the retaining and articulating structure 12 is rotated approximately 90 degrees such that the axis C is coaxial with the axis B of the head 10, and then the structure 12 is seated in sliding engagement with the seating surface 82 of the head 10. The shank capture structure 8 is preloaded, inserted or bottom-loaded into the head 10 through the bore 84 defined by the neck 83. In other embodiments according to the invention (not shown), the shank 4 may be sized and configured to be top-loaded, if desired in which case it must be inserted prior to the retaining and articulating structure 12. The retaining and articulating structure 12, now disposed in the head 10 is coaxially aligned with the shank capture structure 8 so that the helical v-shaped thread 36 rotatingly mates with the thread 98 of the retaining and articulating structure 12. The shank 4 and/or the retaining and articulating structure 12 are rotated to fully mate the structures 36 and 98 along the respective cylindrical surfaces 34 and 96, fixing the capture structure 8 to the retaining and articulating structure 12, until the annular top surface 38 of the capture structure 8 and the retaining and articulating structure top surface 92 are contiguous. Permanent, rigid engagement of the capture structure 8 to the retaining and articulating structure 12 may be further ensured and supported by the use of adhesive, a spot weld, a one-way thread or deforming one or both of the threads 36 and 98 with a punch or the like. With reference to FIG. 9, at this time the shank 4 is in slidable and rotatable engagement with respect to the head 10, while the capture structure 8 and the lower aperture or neck 83 of the head 10 cooperate to maintain the shank body 6 in rotational relation with the head 10. According to the embodiment of the invention shown in FIGS. 1-28, only the retaining and articulating structure 12 is in slidable engagement with the head spherical seating surface 82. Both the capture structure 8 and threaded portion of the shank body 6 are in spaced relation with the head 10. The shank body 6 can be rotated through a substantial angular rotation relative to the head 10, both from side to side and from front to rear so as to substantially provide a universal or ball joint wherein the angle of rotation is only restricted by engagement of the neck 26 of the shank body 6 with the neck or lower aperture 83 of the head 10. It is foreseen that in some embodiments that the retaining structure could simply keep the shank upper portion in the receiver and not articulate with the shank upper portion. In such embodiments, the shank upper portion could have a spherical enlargement that articulates with the head spherical seating surface, the insert and the retaining structure itself. The insert 14 is then loaded into the head 10 as illustrated in FIGS. 1 and 2 and further operationally shown in FIGS. 9-11. With particular reference to FIG. 10, the insert U-shaped channel 114 is aligned with the head 10 U-shaped channel 56 and the insert 14 is initially side-loaded into the head 10 with the ratchet teeth 124 disposed adjacent to the surfaces 87 and directly above the ratchet teeth 89 of the insert receiving surface 88. Such placement allows for unrestricted angular rotation of the shank body 6 with respect to the head 10. As illustrated in FIG. 11, the insert 14 may be pushed downward into contact with the domed top 42, frictionally engaging the top 42 with the insert 14 and thus setting the angle of orientation of the shank body 6 with respect to the head 10 at any desired angle. Because of the orientation of the insert ratchet teeth 124 and the bone screw head ratchet teeth 89, the insert 14 is readily and easily pushed downward into the head and toward the domed top 42, setting or fixing the desired angle of orientation between the shank body 6 and the head 10. Again, this can be done directly with a tool or by compression through the rod 21. Furthermore, the cooperating ratchet teeth 124 and 89 resist any upward, loosening forces, as will be described more fully below. As shown in FIG. 11, a full range of articulation is possible utilizing the insert 14, also due to the cooperation of the sloped, faceted surfaces 120, 134, of the insert 14 and also the inclined top surface 92 of the retaining and articulating structure 12. With reference to FIG. 10, and also FIGS. 12-18, the assembly 1 is typically screwed into a bone, such as the vertebra 15, by rotation of the shank 4 using the driving tool 31 that operably drives and rotates the shank 4 by engagement thereof with the insert 14 and the transverse slot 106 of the retaining and articulating structure 12. Specifically with reference to FIGS. 14-16, the tool 31 shown in FIGS. 12 and 13 is inserted into the head 10 of the bone screw fitted with an insert that has been loosely placed in the head 10 as shown in FIG. 10. The surface 166 of the driving tool 31 comes into contact with the bottom seating surface 116 of the insert 14 and the tool arms 164 extend through the insert notches 136, pushing the insert down into the head 10 until the tool extensions 168 seat within the transverse slot 106 with the tool bottom surface 170 frictionally engaging the base 171 defining the transverse slot 106. As illustrated in FIG. 16, some frictional engagement between the tool surface 174 and the top surface 38 of the capture structure 8 may also be achievable during rotation of the driving tool 31. It is foreseen that in other embodiments according to the invention, the transverse slot 106 may be replaced by other types of tool engaging recesses. Preferably prior to implantation of the bone screw assembly 1 into the vertebra 15, the set screw 206 is assembled with the fastener 204. With particular reference to FIGS. 19-21, the Allen-type tool 290 is inserted through the bore 254 of the fastener 204 and into the aperture 286 of the set screw 206 until seated on the bottom surface 289, with faceted outer surfaces 292 of the tool 290 engaging the inner faceted walls 288 of the set screw 206. The set screw 206 is then uploaded into the fastener 204 by rotation of the set screw 206 with respect to the fastener 204 to mate the set screw thread 280 with the fastener inner thread 256 until the set screw top surface 276 abuts the abutment shoulder 260, resulting in the nested arrangement of the fastener 18 shown in FIG. 21, with the set screw 206 completely enveloped in the fastener base 208. The nested assembly 18 shown in FIG. 21 is now pre-assembled and ready for use with a bone screw head 10 and cooperating rod 21. As illustrated in FIG. 21, in such a pre-assembly arrangement, the V-ring 270 preferably projects beyond the point 282 and the V-ring 284 of the set screw 206, such that the base 208 will seat fully within the bone screw arms 52 prior to engagement of the set screw 206 with the rod 21. Typically at least two and up to a plurality of bone screw assemblies 1 are implanted into vertebrae for use with the rod 21. With reference to FIGS. 17 and 18, each vertebra 15 may be pre-drilled to minimize stressing the bone and have the guide wire or pin 49 inserted therein that is shaped for the cannula 44 of the bone screw shank 6 and provides a guide for the placement and angle of the shank 4 with respect to the vertebra 15. A further tap hole may be made using a tap with the guide wire 49 as a guide. Then, the assembly 1 and the driving tool 31 are threaded onto the guide wire by first threading the wire into the bottom opening 46 of the shank body 6. The wire 49 is then threaded out of the top opening 48 and through the bore 142 of the insert 14 and then into the bore 176 of the driving tool 31. The shank body 6 is then driven into the vertebra 15, by rotation of the driving tool 31, using the wire 49 as a placement guide. With reference to FIG. 22, the rod 21 is eventually positioned within the head U-shaped channel 56, and the nested fastener 18 is then inserted into and advanced between the arms 52. With reference to FIG. 23, before or after rod insertion, it may be desirable to move the insert 14 to a position disengaged from the shank domed top 42 to allow for rotation of the shank body 6 with respect to the head 10 to a desired angle of articulation. As illustrated in FIG. 23, the manipulation tool 146 may be utilized for such purpose by inserting the prongs 147 of the tool 146 into the opposing bores 68 and pinching or squeezing the insert arms 112 toward one another to release the insert ratchet teeth 124 from the ratchet teeth 89 disposed on the head 10, and then move the insert 14 up and away from the domed top 42. The tool 146 may also be used to lower the insert 14 into position against the domed top 42. The bores 68 are preferably configured with an oblong orientation such that the insert 14 may be accessed for upward and downward positioning. Thus, utilizing the insert 14, a bone screw assembly 1 may be set and fixed at a desired angle of articulation prior to implantation of the rod 21, or after the rod 21 is placed in the head 10. Furthermore, if it is desired for the bone screw shank to remain rotatable with respect to the head 10 during part or all of a procedure until the rod 21 and bone screw assembly 1 are clamped into final position with the fastener 18, the insert 14 may be manipulated as shown in FIG. 23 to provide for such freedom of articulation. With reference to FIG. 24, the insert 14 is pressed downwardly into engagement with the shank domed top surface 42 to set the angle of articulation of the shank body 6 with respect to the head 10 at the position shown. The rod 21 is seated on the insert 14 and the fastener 18 is initially placed between the arms 52 and rotated using the installation tool 221 engaged with the surfaces 220 of the break-off head 210 until the fastener guide and advancement structure 252 is fully mated with the head guide and advancement structure 62, but with the set screw 206 in position within the fastener base 208 such that the point 282 and the ring 284 are not engaged with the rod 21. With reference to FIG. 25, the break-off head 210 is then twisted to a preselected torque, for example 90 to 120 inch pounds, also utilizing the tool 221 in engagement with the faceted outer surface 220 of the break-off head 210, with or without bending of the rod 21 in order to achieve and maintain a desired alignment of the spine. With reference to FIGS. 26 and 27, thereafter, the set screws 206 are tightened, preferably in a selected order, by inserting the Allen-type tool 290 into the aperture 286 and rotating the tool 290 to thread the set screw 206 downwardly toward the rod 21. As each set screw 206 is torqued tightly using the tool 290, first the point 282 and then portions of the V-ring 284 preferably come into contact and abrade or dig into the rod surface 108. As previously discussed herein, because the rod 21 may be bent, not all projected portions of the fastener base 208 and the set screw 206 may come into contact with the rod 21. The availability of multiple locations of engagement of the fastener base 208 and the set screw 206 with the rod 21 increases the probability that the rod 21 will be engaged securely by the nested fastener assembly 18. It is noted that the fastener base 208 may only seat at the bottom of the bone screw head opening 57 so as to close the opening 57 and capture the rod 21 therein without the V-ring 270 or the base 268 contacting the rod surface 108. The set screw 206 is then turned and tightened against the rod 21, the point 284 engaging the rod surface 108 and thereby securing the rod 21 in place. FIG. 27 illustrates the polyaxial bone screw assembly 1 and including the rod 21 and the nested fastener 18 positioned in a vertebra 15. The axis A of the bone shank 4 is illustrated as not being coaxial with the axis B of the head 10 and the shank 4 is fixed in this angular locked configuration. Other angular configurations can be achieved, as required during installation surgery due to positioning of the rod 21 or the like. It is noted that in the illustrated embodiment, the shank domed top 42 is rounded to approximately equally extend upward into the channel 56 approximately the same amount no matter what degree of rotation exists between the shank 4 and head 10 and the surface 42 is sized to extend slightly upwardly into the U-shaped channel 56. Thus, the surface 42 is engaged by the insert 14 that is in turn engaged by the rod 21 and pushed downwardly toward the base 50 of the head 10 when the nested fastener 18 biases downwardly toward and onto the rod 21. However, it is foreseen that the thickness of the insert 14 may be increased to allow for a shank top that does not extend into the U-shaped channel 56. The downward pressure on the shank 4 pressed upon by the insert 14 in turn urges the retaining and articulating structure 12 downward toward the head seating surface 82, with the retaining and articulating structure outer surface 104 in frictional engagement with the head seating surface 82. As the nested fastener 18 presses against the rod 21, the rod 21 presses against the shank and the retaining and articulating structure 12 that is now rigidly attached to the shank 4 which in turn becomes frictionally and rigidly attached to the head 10, fixing the shank body 6 in a desired angular configuration with respect to the head 10 and the rod 21. With reference to FIG. 28, if removal of the assembly 1 is necessary, or if it is desired to release the rod 21 at a particular location, disassembly is accomplished by using the Allen-type driving tool 290, mated with the set screw 206 at the aperture 286 and turned in a direction to rotate the set screw 206 up and out of the base 208. The set screw top 276 then backs into and abuts the abutment shoulder 260, transferring rotational torque exerted from the tool 290 from the set screw 206 to the fastener base 208. The base 208 then rotates with the guide and advancement structure 252 threading out of the guide and advancement structure 62 of the head 10. Thus, both the set screw 206 and the fastener base 208 are removed from the bone screw head 10 at the same time. If desired, the manipulation tool 146 may be used as shown in FIG. 23 and previously described herein to disengage the insert 14 from the shank domed top 42. Finally, disassembly of the assembly 1 is accomplished in reverse order to the procedure described previously herein for assembly. With reference to FIGS. 29-42, the reference number 301 generally represents a second or alternative embodiment of an assembly according to the present invention. The assembly 301 includes a bone screw shank 304, having a capture structure 306 and a shank body 308 with a thread 310 for threadably implanting into a bone, such as a vertebra 313, and a head or receiver 314 which connects with the shank 304 to engage and secure a structural member, such as a spinal fixation rod 316, relative to the vertebra 313. The assembly 301 also includes a retaining and articulating structure or ring 320 operably positioned within the head or receiver 314 and engaging the capture structure 306 on the upper portion of the shank 304. The capture structure 306 is retained within the head or receiver 314 by the retaining and articulating structure 320 as will be described more fully below. The assembly 301 further includes a pressure insert 324, engageable with the upper portion of the capture structure 306 and the rod 316 as will be described more fully below. The shank 304, head or receiver 314, retaining and articulating structure 320 and the insert 324 are preferably assembled prior to implantation of the shank body 308 into the vertebra 313. With reference to FIG. 42, the assembly 301 further includes a closure top 326 for fixing the rod 316 within the head or receiver 314. The insert 324 allows for setting an angle of articulation between the shank body 308 and the head or receiver 314 prior to insertion of the rod 316, if desired. Upon installation, which will be described in detail below, the closure top 326 presses against the rod 316 that in turn presses against the insert 324 that presses against the upper end of the capture structure 306 which biases the retaining and articulating structure 320 into fixed frictional contact with the head or receiver 314, so as to fix the rod 316 relative to the vertebra 313. The head or receiver 314 and shank 304 cooperate in such a manner that the head or receiver 314 and shank 304 can be secured at any of a plurality of angles, articulations or rotational alignments relative to one another and within a selected range of angles both from side to side and from front to rear, to enable flexible or articulated engagement of the head or receiver 314 with the shank 304 until both are locked or fixed relative to each other. Referring to FIGS. 29, 36-38 and 40, the shank 304 is elongated and sized and shaped to be screwed into one of the vertebra 313. The shank body 308 includes the external helically wound thread 310 that extends from an outer tip 330 to a neck 332 disposed adjacent the capture structure 306. On the illustrated shank 304, the capture structure 306 includes a region 334 that is frusto-conical in shape, diverging in diameter in a direction away from the outer tip 330 and that is coaxially aligned with an axis of rotation of the shank body 308. The region 334 terminates at an annular seating surface 335. The illustrated capture structure 306 has a maximum radius that is less than a radius associated with the shank thread 310 and further, preferably less than the radius of the shank body 308 whereupon the thread 8 is located. The capture structure 306 has a plurality of tool engageable grooves, apertures or the like 336 to enable positive engagement by an appropriately shaped installation tool 338 to thread and drive the shank body 308 into the vertebra 313 as will be discussed in greater detail below. The illustrated shank capture structure 306 includes four evenly spaced tool engageable grooves 336, but it is foreseen that the driving structure may include fewer grooves, an alternative configuration of grooves or other driver receiving structure. An upper end surface 340 of the capture structure 306 opposite the tip 330 is provided with a formation or dome 342 to be positively and interferingly engaged by the insert 324, which in turn is positively engaged by the rod 316 when the assembly 301 is assembled into place. The illustrated dome 342 is radiused, knurled and centered on the upper end surface 340 so as to be coaxial with the remainder of the shank 304. The scoring or knurling of the dome 342 operably frictionally abuts against the insert 324 when the insert 324 is rotated into engagement with the head or receiver 314, as described more fully below, to provide for a selected setting of a desired angle of articulation between the shank body 308 and the head 314 prior to insertion and locking down of the rod 315. It is foreseen that in certain embodiments, the purpose of the dome 342 is simply to be engaged by the insert 324 that is in turn engaged by the rod 316, pushing the shank 304 in such a manner as to frictionally engage the retaining and articulating structure 320 with the head 314 as described below. Preferably, the dome 342 is radiused so that the dome 342 engages the insert 324 at approximately the same location regardless of the angle of articulation of the shank body 308 with respect to the head 314. However, it is foreseen that in certain embodiments shapes other than the dome 342 could be utilized. Referring to FIGS. 29-31, and 36-42, the head or receiver 314 is generally cylindrical in external profile and has a central and axially aligned shank receiving bore 346 ending at an inner and lower neck 347. The neck 347 is radiused to receive the shank capture structure 306 and preferably smaller than a radius of the shank body 308 and thread 310. The bore 346 is also preferably sized larger than the capture structure 306 of the shank 304 to enable the shank 394 to be oriented through a range of angular dispositions relative to the head or receiver 314. The bore 346 may be conically counterbored or beveled in a region 348 to widen the angular range of the shank 304. The head or receiver 314 is provided with a U-shaped rod cradle 350 sized to receive the rod 316 therethrough. The illustrated cradle 350 is rounded and radiused at an inner or lower portion or seat 352 to snugly mate with a cylindrical outer surface 354 of the rod 316 and open at an outer end or top 356, with spaced apart side surfaces 358 so as to form upstanding and spaced apart arms 360. The side surfaces 358 have guide and advancement structures 362 formed thereon that are complementary to guide and advancement structures 364 of the closure top 326 (FIG. 42). The illustrated structures 362 and 364 are helically wound flanges or threads that advance the closure top 326 into the head 314, as the closure top 326 is rotated about a central axis thereof. It is foreseen that the structures 362 and 364 may be interlocking helical flange forms similar to the structures 62 and 252 previously described herein with respect to the assembly 1, V-shaped threads, buttress threads, square threads, reverse angle threads, or other types of threads or flange forms. Preferably, the structures 362 and 364 are of such a nature as to resist splaying of the arms 360 when the closure top 326 is advanced into the U-shaped cradle 350. Furthermore the head or receiver 314 includes an assembly cavity 366 formed therein that opens into the cradle 350. A partially spherical socket or seat 368 defines the assembly cavity 366. The seat 368 is disposed between the arm inner surfaces 358 and the neck 347 defining the shank bore 346 and as illustrated has a radius that is slightly less than a radius of the assembly cavity 366. The seat 368 has a substantially spherical shape and extends upward coaxially through the head 314 from the neck 347 to the cavity 366. The cavity 366 and the seat 368 will be detailed further below. Each arm inner surface 358 further includes a recessed portion 370 disposed between the guide and advancement structure 362 and the seat 368. The portion 370 is defined by an upper shoulder 372, a lower shoulder 374 and a wall 376 disposed between the upper and lower shoulders 372, 374. The wall 376 is parallel to an axis of rotation of the head 314 that is operably coaxial with the shank 304. As will be described in greater detail below, the insert 324 may be operably disposed in the recessed portion 370 and include a setting position wherein the insert 324 abuts against the upper shoulder 372 and presses against the shank capture structure dome 342, allowing for the setting of a desired angle of articulation of the bone screw shank body 308 with respect to the head 314 during surgery, prior to lock down of the rod 316 by the closure top 326. The head or receiver 314 may further include external, closed end grip bores 378 for positive engagement by a holding tool (not shown) to facilitate secure gripping of the head 314 during assembly, installation and/or manipulation of the assembly 301. The retaining and articulating structure 320, best illustrated in FIGS. 29-31 and 36 is used to retain the capture structure 306 within the head or receiver 314. The retaining and articulating structure 320 is in the form of a discontinuous ring that resiliently expands and contracts to enable the structure 320 to be snapped over and seated on the capture structure 306. The retaining and articulating structure 320, similar to a remainder of the assembly 301, is preferably formed of a material such as a spring stainless steel, tantalum, titanium or other resilient implantable material. The illustrated retaining and articulating structure 320 forms a gap or radial split 380 extending from a top surface 382 to a bottom surface 384 thereof, that allows the structure 320 to expand in circumference to fit over the capture structure 306. The retaining and articulating structure 320 includes an inner surface 382 formed by a through-bore sized and shaped to be compatible with the conical shape of the capture structure 306. The retaining and articulating structure 320 has an outer surface that is frusto-spherical, partially spherical, or a segment of a sphere, with a spherical radius approximately equivalent to the spherical radius of the spherical seat 368 within the head 314 and smaller than a radius of the cavity 366. As will be described more fully below, the bottom surface 384 seats upon the annular seating surface 335 of the shank capture structure 306 when the retaining and articulating structure 320 is fully installed on the capture structure 306. The closure top 326 is generally cylindrical in shape and is provided with a break-off head 390 that is connected to the closure top 326 by a weakened area or neck 392 such that the break-off head 390 separates from the closure top 326 at a predetermined torque applied to the break-off head 390 during assembly. The illustrated break-off head 390 has a hexagonal cross section for engagement by a tool (not shown) of a complementary shape. The closure top 326 further includes a central point 394 for abrading and/or penetrating the rod 316 when fully installed on the head 314. Furthermore, the closure top 326 includes a driving formation, such as a hex aperture (not shown) for removal of the closure top, if desired, after the break-off head 390 is broken off. The insert 324 is best illustrated in FIGS. 32-35. The insert 324 includes a substantially conical base portion 401 integral with a body portion 404. The base portion 401 extends outwardly from an annular, flat bottom surface 402 to the body portion 404. The body portion 404 is oblong, having a width W that is smaller than a length L thereof. The width W is bounded by two substantially flat surfaces 405. The width W is slightly smaller than a distance between the inner surfaces of the arms 358 of the head 314. The length L, taken along a center line 406 is slightly smaller than a diameter of the recessed portion 370 measured between the surfaces 376. A U-shaped cradle or channel 407 running parallel to the width W extends through the body portion 404, and is sized and shaped to receive the rod 316 thereon as will be described more fully below. Arms 408 disposed on either side of the cradle 406 each included a top surface 410 that is parallel to the bottom surface 402 and a sloped surface 412, starting at the top surface 410 and sloping downwardly toward the base portion 401. The arms 408 also include rounded, substantially cylindrical side surfaces 414, each having a radius slightly smaller than a radius of the wall 376 that partially defines the recessed portion 370 of the head 314. The sloped surfaces 412 are disposed opposite one another and the top surfaces 410 are disposed opposite one another. The sloped surfaces 412 also slope in opposite directions, each starting at the center line or axis 406 and running outwardly and downwardly away therefrom to provide for a cam action when the insert 324 is placed in the head 314 as shown in FIG. 37, and then rotated, the sloped surfaces 412 engaging the upper shoulder 372 of the recessed portion 370 of the head 314 and thus transforming the circular motion of rotating the insert 324 in the recessed portion 370 of the head 314 into linear motion, pressing the insert 324 against the shank dome 342 as will be described more fully below. Each arm 408 of the body portion 404 includes a substantially flat bottom surface 416 extending from the conical base portion 401 to the cylindrical surface 414. The base portion 401 further includes a centrally located concave, substantially spherical bottom formation 418 contiguous to the annular bottom surface 402. The spherical bottom formation 418 is sized and shaped to cooperate and engage with the dome 342 of the shank capture structure 306, providing a snug, frictional fit. Apertures 420 extend through the U-shaped cradle 407 and are sized and shaped to cooperate and align with the apertures 336 of the capture structure 306. Thus, in the illustrated embodiment, four evenly spaced apertures 420 extend through the insert 324 and axially align with the apertures 336 as illustrated in FIGS. 39 and 40, both when the insert 324 is initially placed in the head 314 and when the insert 324 is rotated within the head 314 such that the top surfaces 410 are adjacent the upper shoulder 371. Alignment of the apertures 420 and the apertures 336 allow for engagement between the capture structure 306, the insert 324 and the driving tool 338 as will be described more fully below. The driver 338 illustrated at FIG. 40 includes a handle (not shown), a drive shaft 426 and an engagement portion 428. The engagement portion 426 includes an oblong support 430 sized and shaped to fit within the U-shaped cradle 407 of the insert 324. Four prongs 432 extending from the oblong support 430 are sized and shaped to extend through the apertures 420 of the insert 324 and into the apertures 336 in the capture structure 306, thus operably engaging both the bone screw shank 304 and the insert 324 when rotating and driving the shank body 308 into the vertebra 313. FIGS. 30, 31 and 36 illustrate the assembly of the bone screw head 314, shank 304 and retaining and articulating structure 320. In FIG. 30, the retaining and articulating structure 320 is inserted into the head 314 through an interior of the U-shaped cradle 350. The retaining and articulating structure 320 is first oriented with a central axis thereof at a right angle to a central axis of the bore 346. Then, the retaining and articulating structure is oriented as illustrated in FIG. 31 with the central axis of the retaining and articulating structure 320 being parallel or coincident with the axis of the bore 346 and the neck 347, by rotating the retaining and articulating structure 320 within the assembly cavity 366. With reference to FIG. 36, the capture structure 306 of the shank 304 is then inserted through the head bore 346 and then adjacent to the retaining and articulating structure inner surface 386 by expanding the retaining and articulating structure 320 at the radial split 380 so as to snap the retaining and articulating structure 320 over and around the capture structure 306 at the frusto-conical surface 334. The relative resistance encountered by the retaining and articulating structure 320 allows the capture structure 306 to expand the circumference of the retaining and articulating structure 320, by expansion of the split 380, so that the capture structure 306 enters the retaining and articulating structure 320. As illustrated in FIG. 37, when fully seated, the surface 334 frictionally engages the retaining and articulating structure inner surface 386 and the bottom surface 384 of the retaining and articulating structure 320 abuts against the annular seating surface 335 of the capture structure 306 thereby limiting penetration of the capture structure 306 into the retaining and articulating ring structure 320. FIG. 37 shows the assembly 301 with the retaining and articulating structure 320 lowered from the assembly position and positioned in the spherical seat 368 with the central axis of the shank 304 coaxial with the central axis of the head 314. However, similar to the assembly 1, the relevant discussion of which is incorporated by reference herein, the curved or spherical seat 368 and the curved or spherical outer surface 388 of the retaining and articulating structure 320, allows universal angular positioning of the shank 304 relative to the head 314. The retaining and articulating structure 320, thus performs the functions of preventing the capture structure 306 of the shank 304 from slipping through the neck 347 and, in conjunction with the seat 368, forms a ball joint for relative orientation of the shank 304 and the head 314. The insert 324 is then loaded into the head 314 as illustrated in FIGS. 37 and 39, with the width dimension W being oriented as shown with respect to the arms 360 to allow top loading of the insert 324. The insert 324 is lowered into the head 314 until the concave bottom formation 418 is seated on the dome 342. For driving the bone screw shank body 308 into bone, such as the vertebra 313, the insert 324 is first rotated axially as illustrated in FIGS. 40 and 41, with the sloping surfaces 412 of the insert 324 contacting the upper shoulder 372 defining the head recessed portion 370, thereby pushing the capture structure 306 and attached retaining and articulating structure 320 downwardly against the seat 368. As the insert is rotated approximately 90 degrees until the flat surfaces 410 fully engage the upper shoulder 372, the insert 324 functions as a cam, providing a mechanical linkage that converts rotary motion to linear motion. Frictional engagement between the retaining and articulating structure 320 and the seat 368 sets the bone shank 304 in an angular position with respect to the head 314, but does not lock such into position. Thus, the insert 324 may be used at any time during a procedure to set the shank body 308 at a desired angle with respect to the head 314, but that position is not rigidly fixed until the rod 316 presses down upon the insert 324. When the insert flat surfaces 410 engage the upper shoulder 372, the apertures 420 of the insert 324 are aligned with the apertures 336 of the capture structure 306 and the insert cradle 407 is oriented in a position to receive the oblong support 430 of the driving tool engagement portion 428. With particular reference to FIG. 40, the assembly 301 is typically screwed into a bone, such as the vertebra 313, by rotation of the shank 304 using the driving tool 338 that operably drives and rotates the shank 304 by engagement thereof with the insert 324 and the apertures 336 of the capture structure 306. The driving tool 338 is inserted into the head 314 of the bone screw with the prongs 432 first inserted into the apertures 420 and then the apertures 336 until the oblong support 430 is seated on the insert cradle 407. Typically at least two and up to a plurality of bone screw assemblies 301 are implanted into vertebrae for use with the rod 316. As described with respect to the assembly 1, and incorporated by reference herein, each vertebra 313 may be pre-drilled to minimize stressing the bone. Although not shown, the assembly 301 may be cannulated in a manner as described with respect to the assembly 1 so that a guide wire or pin may be used as a guide for the placement and angle of the assembly 301. The shank body 308 is then driven into the vertebra 313, by rotation of the driving tool 338. With reference to FIG. 42, the rod 316 is eventually positioned within the head U-shaped rod cradle 350, and the closure top 326 is then inserted into and advanced between the arms 360. Before rod insertion, it may be desirable to rotate the insert 324 to a position disengaged from the shank domed top 342 as shown in FIG. 37, to allow for a loose angular connection of the shank body 308 with respect to the head 314 until a desired angle of articulation is decided upon. The driving tool 338 may be utilized to rotate the insert 324 by inserting the prongs 432 in the apertures 420. Then, the insert 324 may be rotated to the position shown in FIG. 41, setting, but not locking such desired angular orientation between the shank body 308 and the head 314. In other words, when the insert 324 is in contact with the upper shoulder 372, the insert 324 presses down on the shank 304, providing sufficient frictional engagement between the retaining and articulating structure 320 and the head seat 368 that the shank 304 resists angular movement. However, it may not be desirable to rotate the insert 324 in order to change the angular orientation of the shank 304 with respect to the head 314. The shank 304 may simply be moved, using some force, to a desired position, which will then be the set position. With reference to FIG. 24, the rod 316 is seated on the insert 324 and the closure top 326 is initially placed between the arms 360 and rotated using an installation tool (not shown) engaged with surfaces of the break-off head 390 until the guide and advancement structure 364 is fully mated with the head guide and advancement structure 262, with the point 394 penetrating the rod 316. The break-off head 390 is then twisted to a preselected torque, for example 90 to 120 inch pounds, until broken off. If removal of the assembly 301 is necessary, or if it is desired to release the rod 316 at a particular location, disassembly is accomplished by using a tool (not shown) with a driving formation (not shown) located on the closure top 326 to rotate and remove the closure top 326 from the head 314. Disassembly of the assembly 301 is accomplished in reverse order to the procedure described previously herein for assembly. With reference to FIGS. 43-54, the reference number 501 generally represents a third embodiment of an assembly according to the present invention. The assembly 401 includes a bone screw shank 504, having a capture structure 506 and a shank body 508 with a thread 510 for threadably implanting into a bone, such as a vertebra 513, and a head or receiver 514 which connects with the shank 504 to engage and secure a structural member, such as a spinal fixation rod 516, relative to the vertebra 513. The assembly 501 also includes a retaining and articulating structure or ring 520 operably positioned within the head or receiver 514 and engaging the capture structure 506 of the shank 504. The capture structure 506 is retained within the head or receiver 514 by the retaining and articulating structure 520 as will be described more fully below. The assembly 501 further includes a pressure insert 524, engageable with the capture structure 506 and the rod 516 as will be described more fully below. The shank 504, head or receiver 514, retaining and articulating structure 520 and the insert 524 are preferably assembled prior to implantation of the shank body 508 into the vertebra 513. With reference to FIG. 54, the assembly 501 further includes a closure top 526 for fixing the rod 516 within the head or receiver 514. The insert 524 allows for setting an angle of articulation between the shank body 508 and the head or receiver 514 prior to insertion of the rod 516, if desired. Upon installation, which will be described in detail below, the closure top 526 presses against the rod 516 that in turn presses against the insert 524 that presses against the capture structure 506 which biases the retaining and articulating structure 520 into fixed frictional contact with the head or receiver 514, so as to fix the rod 516 relative to the vertebra 513. The head or receiver 514 and shank 504 cooperate in such a manner that the head or receiver 514 and shank 504 can be secured at any of a plurality of angles, articulations or rotational alignments relative to one another and within a selected range of angles both from side to side and from front to rear, to enable flexible or articulated engagement of the head or receiver 514 with the shank 504 until both are locked or fixed relative to each other. Referring to FIGS. 43, 46-48 and 52, the shank 504 is elongated and sized and shaped to be screwed into one of the vertebra 513. The shank body 508 includes the external helically wound thread 510 that extends from an outer tip 530 to a neck 532 disposed adjacent the capture structure 506. On the illustrated shank 504, the capture structure 506 includes a substantially cylindrical threaded region 534 that is coaxially aligned with an axis of rotation of the shank body 508. The region 534 terminates at an annular seating surface 535. The illustrated capture structure 506 has a maximum radius that is less than a radius associated with the shank thread 510. The capture structure 506 has a plurality of tool engageable grooves, apertures or the like 536 to enable positive engagement by an appropriately shaped installation tool 538 to thread and drive the shank body 508 into the vertebra 513 as will be discussed in greater detail below. The illustrated shank capture structure 506 includes four evenly spaced tool engageable grooves 536, but it is foreseen that the driving structure may include fewer grooves, an alternative configuration of grooves or other driver receiving structure. An upper end surface 540 of the capture structure 506 opposite the tip 530 is provided with a formation or dome 542 to be positively and interferingly engaged by the insert 524, which in turn is positively engaged by the rod 516 when the assembly 501 is assembled into place. The illustrated dome 542 is radiused, knurled and centered on the upper end surface 540 so as to be coaxial with the remainder of the shank 504. The scoring or knurling of the dome 542 operably frictionally abuts against the insert 524 when the insert 524 is rotated into engagement with the head or receiver 514, as described more fully below, to provide for a selected setting of a desired angle of articulation between the shank body 508 and the head or receiver 514 prior to insertion and locking down of the rod 515. It is foreseen that in certain embodiments, the purpose of the dome 542 is simply to be engaged by the insert 524 that is in turn engaged by the rod 516, pushing the shank 504 in such a manner as to frictionally engage the retaining and articulating structure 520 with the head or receiver 514 as described below. Preferably, the dome 542 is radiused so that the dome 542 engages the insert 524 at approximately the same location regardless of the angle of articulation of the shank body 508 with respect to the head or receiver 514. However, it is foreseen that in certain embodiments shapes other than the dome 542 could be utilized. In the embodiment shown in FIGS. 43-54, the upper end 540 supporting the dome 542 has a hex-shaped profile with side surfaces 543 configured to mate with an assembly or driving tool (not shown). Referring to FIGS. 43-48, the head or receiver 514 is generally cylindrical in external profile and has a central and axially aligned shank receiving bore 546 ending at an inner and lower neck 547. The neck 547 is radiused to receive the shank capture structure 506 and preferably smaller than a radius of the shank body 508 and thread 510. The bore 546 is also preferably sized larger than the capture structure 506 of the shank 504 to enable the shank 594 to be oriented through a range of angular dispositions relative to the head or receiver 514. The bore 546 may be conically counterbored or beveled in a region 548 to widen the angular range of the shank 504. The head or receiver 514 is provided with a U-shaped rod cradle 550 sized to receive the rod 516 therethrough. The illustrated cradle 550 is rounded and radiused at an inner or lower portion or seat 552 to snugly mate with a cylindrical outer surface 554 of the rod 516 and open at an outer end or top 556, with spaced apart side surfaces 558 so as to form upstanding and spaced apart arms 560. The side surfaces 558 have guide and advancement structures 562 formed thereon that are complementary to guide and advancement structures 564 of the closure top 526 (FIG. 54). The illustrated structures 562 and 564 are helically wound flanges or threads that advance the closure top 526 into the head or receiver 514, as the closure top 526 is rotated about a central axis thereof. It is foreseen that the structures 562 and 564 may be interlocking helical flange forms similar to the structures 62 and 252 previously described herein with respect to the assembly 1, V-shaped threads, buttress threads, reverse angle threads, or other types of threads or flange forms. Preferably, the structures 562 and 564 are of such a nature as to resist splaying of the arms 560 when the closure top 526 is advanced into the U-shaped cradle 550. Furthermore the head or receiver 514 includes an assembly cavity 566 formed therein that opens into the cradle 550. A partially spherical socket or seat 568 defines the assembly cavity 566. The seat 568 is disposed between the arm inner surfaces 558 and the neck 547 defining the shank bore 546 and as illustrated has a radius that is slightly less than a radius of the assembly cavity 566. The seat 568 has a substantially spherical shape and extends upward coaxially through the head or receiver 514 from the neck 547 to the cavity 566. The cavity 566 and the seat 568 will be detailed further below. Each arm inner surface 558 further includes a recessed portion 570 disposed between the guide and advancement structure 562 and the seat 568. The portion 570 is defined by an upper shoulder 572, a lower shoulder 574 and a wall 576 disposed between the upper and lower shoulders 572, 574. The wall 576 is parallel to an axis of rotation of the head or receiver 514 that is operably coaxial with the shank 504. As will be described in greater detail below, the insert 524 may be operably disposed in the recessed portion 570 and include a setting position wherein the insert 524 abuts against the upper shoulder 572 and presses against the shank capture structure dome 542, allowing for the setting of a desired angle of articulation of the bone screw shank body 508 with respect to the head 514 during surgery, prior to lock down of the rod 516 by the closure top 526. The head or receiver 514 may further include external, closed end grip bores 578 for positive engagement by a holding tool (not shown) to facilitate secure gripping of the head 514 during assembly, installation and/or manipulation of the assembly 501. The retaining and articulating structure 520, best illustrated in FIGS. 43-48 and 54 is used to retain the capture structure 506 within the head or receiver 514. The retaining and articulating structure 520 is in the form of a ring. The retaining and articulating structure 520 includes a top surface 582, a bottom surface 584, an inner surface 586 having a thread 587 and an outer surface 588. The thread 587 is sized and shaped to mate with the threaded region 534 of the capture structure 506. The retaining and articulating structure 520, similar to a remainder of the assembly 501, is preferably formed of a material such as a spring stainless steel, tantalum, titanium or other resilient implantable material. The retaining and articulating structure outer surface 588 is frusto-spherical, partially spherical, or a segment of a sphere, with a spherical radius approximately equivalent to the spherical radius of the spherical seat 568 within the head or receiver 514 and smaller than a radius of the cavity 566. As will be described more fully below, the bottom surface 584 seats upon the annular seating surface 535 of the shank capture structure 506 when the retaining and articulating structure 520 is fully installed on the capture structure 506. The closure top 526 is generally cylindrical in shape and is provided with a break-off head 590 that is connected to the closure top 526 by a weakened area or neck 592 such that the break-off head 590 separates from the closure top 526 at a predetermined torque applied to the break-off head 590 during assembly. The illustrated break-off head 590 has a hexagonal cross section for engagement by a tool (not shown) of a complementary shape. The closure top 526 further includes a central point 594 for abrading and/or penetrating the rod 516 when fully installed on the head 514. Furthermore, the closure top 526 includes a driving formation, such as a hex aperture (not shown) for removal of the closure top, if desired, after the break-off head 590 is broken off. The insert 524 is best illustrated in FIGS. 43, 47 and 49-54. The insert 524 includes a substantially conical base portion 601 integral with a body portion 604. The base portion 601 extends outwardly from an annular, flat bottom surface 602 to the body portion 604. The body portion 604 is oblong, having a width W′ that is smaller than a length L′ thereof. The width W′ is bounded by two substantially flat surfaces 605. The width W′ is slightly smaller than a distance between the inner surfaces of the arms 558 of the head 514. The length L′, taken along a center line 606 is slightly smaller than a diameter of the recessed portion 570 measured between the surfaces 576. A U-shaped cradle or channel 607 running parallel to the width W extends through the body portion 604, and is sized and shaped to receive the rod 516 thereon as will be described more fully below. Arms 608 disposed on either side of the cradle 606 each included a top surface 610 that is parallel to the bottom surface 602 and a sloped surface 612, starting at the top surface 610 and sloping downwardly toward the base portion 601. The arms 608 also include rounded, substantially cylindrical side surfaces 614, each having a radius slightly smaller than a radius of the wall 576 that partially defines the recessed portion 570 of the head 514. The sloped surfaces 612 are disposed opposite one another and the top surfaces 610 are disposed opposite one another. The sloped surfaces 612 also slope in opposite directions, each starting at the center line or axis 606 and running outwardly and downwardly away therefrom to provide for a cam action when the insert 524 is placed in the head 514 as shown in FIG. 49, and then rotated, the sloped surfaces 612 engaging the upper shoulder 572 of the recessed portion 570 of the head 514 and thus transforming the circular motion of rotating the insert 524 in the recessed portion 570 of the head 514 into linear motion, pressing the insert 524 against the shank dome 542 as will be described more fully below. Each arm 608 of the body portion 604 includes a substantially flat bottom surface 616 extending from the conical base portion 601 to the cylindrical surface 614. The base portion 601 further includes a centrally located concave, substantially spherical bottom formation 618 contiguous to the annular bottom surface 602. The spherical bottom formation 618 is sized and shaped to cooperate and engage with the dome 642 of the shank capture structure 606, providing a snug, frictional fit. Apertures 620 extend through the U-shaped cradle 607 and are sized and shaped to cooperate and align with the apertures 536 of the capture structure 506. Thus, in the illustrated embodiment, four evenly spaced apertures 620 extend through the insert 524 and axially align with the apertures 536 as illustrated in FIGS. 49 and 53, both when the insert 524 is initially placed in the head 514 and when the insert 524 is rotated within the head 514 such that the top surfaces 610 are adjacent the upper shoulder 571. The alignment of the apertures 620 and the apertures 536 as shown in FIG. 53 allow for engagement between the capture structure 506, the insert 524 and the driving tool 538 as will be described more fully below. A pair of points 622 are disposed in the U-shaped cradle 607 and project therefrom. The points 622 are disposed along the center line 606 and near the surfaces 610 and 612, but could be placed in other areas. The points 622 are sized and shaped to abrade and penetrate the rod 516 as will be described more fully below. One to six or more points could be utilized. The driver 538 illustrated at FIG. 52 includes a handle (not shown), a drive shaft 626 and an engagement portion 628. The engagement portion 626 includes four prongs 632 extending therefrom sized and shaped to extend through the apertures 620 of the insert 524 and into the apertures 536 in the capture structure 506, thus operably engaging both the bone screw shank 504 and the insert 524 when rotating and driving the shank body 508 into the vertebra 513. FIGS. 43-47 illustrate the assembly of the bone screw head 514, shank 504 and retaining and articulating structure 520. In FIG. 44, the retaining and articulating structure 520 is inserted into the head 514 through an interior of the U-shaped cradle 550. The retaining and articulating structure 520 is first oriented with a central axis thereof at a right angle to a central axis of the bore 546. Then, the retaining and articulating structure is oriented as illustrated in FIG. 45 with the central axis of the retaining and articulating structure 520 being parallel or coincident with the axis of the bore 546 and the neck 547, by rotating the retaining and articulating structure 520 within the assembly cavity 566. With reference to FIG. 56, the capture structure 506 of the shank 504 is then inserted through the head bore 546 and then rotated with respect to the retaining and articulating structure 520, mating the threaded region 534 with thread 587 disposed on the inner surface 586 of the retaining and articulating structure 520. As illustrated in FIG. 47, when fully seated, the bottom surface 584 of the retaining and articulating structure 520 abuts against the annular seating surface 535 of the capture structure 506. FIGS. 47 and 48 show the assembly 501 with the retaining and articulating structure 520 lowered from the assembly position and positioned in the spherical seat 568 with the central axis of the shank 504 coaxial with the central axis of the head 514. However, similar to the assembly 1, the relevant discussion of which is incorporated by reference herein, the curved or spherical seat 568 and the curved or spherical outer surface 588 of the retaining and articulating structure 520, allows universal angular positioning of the shank 504 relative to the head 514. The retaining and articulating structure 520, thus performs the functions of preventing the capture structure 506 of the shank 504 from slipping through the neck 547 and, in conjunction with the seat 568, forms a ball joint for relative orientation of the shank 504 and the head 514. The insert 524 is then loaded into the head 514 as illustrated in FIGS. 47 and 49, with the width dimension W′ being oriented as shown with respect to the arms 560 to allow top loading of the insert 524. The insert 524 is lowered into the head 514 until the concave bottom formation 618 is seated on the dome 542. For driving the bone screw shank body 508 into bone, such as the vertebra 513, the insert 524 is first rotated axially as illustrated in FIGS. 52 and 53, with the sloping surfaces 612 of the insert 524 contacting the upper shoulder 572 defining the head recessed portion 570, thereby pushing the capture structure 506 and attached retaining and articulating structure 520 downwardly against the seat 568. As the insert is rotated approximately 90 degrees until the flat surfaces 610 fully engage the upper shoulder 572, the insert 524 functions as a cam, providing a mechanical linkage that converts rotary motion to linear motion. Frictional engagement between the retaining and articulating structure 520 and the seat 568 sets the bone shank 504 in an angular position with respect to the head 514, but does not lock such into position. Thus, the insert 524 may be used at any time during a procedure to set the shank body 508 at a desired angle with respect to the head 514, but that position is not rigidly fixed until the rod 516 presses down upon the insert 524. When the insert flat surfaces 610 engage the upper shoulder 572, the apertures 620 of the insert 524 are aligned with the apertures 536 of the capture structure 506 and the insert cradle 607 is oriented in a position to receive the oblong support 630 of the driving tool engagement portion 628. With particular reference to FIG. 52, the assembly 501 is screwed into a bone, such as the vertebra 513, by rotation of the shank 504 using the driving tool 538 that operably drives and rotates the shank 504 by engagement thereof with the apertures 620 of the insert 524 and the apertures 536 of the capture structure 506. The driving tool 538 is inserted into the head 514 of the bone screw with the prongs 632 first inserted into the apertures 620 and then the apertures 536, and then driven and rotated into bone. Alternatively, the assembly 501 may be driven into bone prior to placement of the insert 524 in the head 514. A hex driving tool (not shown) sized and shaped to mate with the surfaces 543 of the capture structure 506 may be used to rotate and drive the shank body 508 into the vertebra 513. Thereafter, the insert 524 may be placed in the bone screw head 514 as shown in FIG. 47. Typically at least two and up to a plurality of bone screw assemblies 501 are implanted into vertebrae for use with the rod 516. As described with respect to the assembly 1, and incorporated by reference herein, each vertebra 513 may be pre-drilled to minimize stressing the bone. Although not shown, the assembly 501 may be cannulated in a manner as described with respect to the assembly 1 so that a guide wire or pin may be used as a guide for the placement and angle of the assembly 501. The shank body 508 is then driven into the vertebra 513, by rotation of the driving tool 538. With reference to FIG. 54, the rod 516 is eventually positioned within the head U-shaped rod cradle 550, and the closure top 526 is then inserted into and advanced between the arms 560. Before rod insertion, it may be desirable to rotate the insert 524 to a position disengaged from the shank domed top 542 as shown in FIG. 47, to allow for a loose angular connection of the shank body 508 with respect to the head 514 until a desired angle of articulation is decided upon. The driving tool 538 may be utilized to rotate the insert 524 by inserting the prongs 632 in the apertures 620. Then, the insert 524 may be rotated to the position shown in FIG. 53, setting, but not locking such desired angular orientation between the shank body 508 and the head 514. In other words, when the insert 5324 is in contact with the upper shoulder 572, the insert 524 presses down on the shank 504, providing sufficient frictional engagement between the retaining and articulating structure 520 and the head seat 568 that the shank 504 resists angular movement. However, it may not be desirable to rotate the insert 524 in order to change the angular orientation of the shank 504 with respect to the head 514. The shank 504 may simply be moved, using some force, to a desired position, which will then be the set position. With reference to FIG. 54, the rod 516 is seated on the insert 524 and the closure top 526 is initially placed between the arms 560 and rotated using an installation tool (not shown) engaged with surfaces of the break-off head 590 until the guide and advancement structure 564 is fully mated with the head guide and advancement structure 562, with the point 594 penetrating the rod 516 and also the points 622 penetrating the rod 516. The break-off head 590 is then twisted to a preselected torque, for example 90 to 120 inch pounds, until broken off. If removal of the assembly 501 is necessary, or if it is desired to release the rod 516 at a particular location, disassembly is accomplished by using a tool (not shown) with a driving formation (not shown) located on or in the closure top 526 to rotate and remove the closure top 526 from the head 514. Disassembly of the assembly 501 is accomplished in reverse order to the procedure described previously herein for assembly. It is to be understood that while certain forms of the present invention have been illustrated and described herein, it is not to be limited to the specific forms or arrangement of parts described and shown.
<SOH> BACKGROUND OF THE INVENTION <EOH>The present invention is directed to polyaxial bone screws for use in bone surgery, particularly spinal surgery, and particularly to inserts for such screws. Bone screws are utilized in many types of spinal surgery, such as for osteosynthesis, in order to secure various implants to vertebrae along the spinal column for the purpose of stabilizing and/or adjusting spinal alignment. Although both closed-ended and open-ended bone screws are known, open-ended screws are particularly well suited for connections to rods and connector arms, because such rods or arms do not need to be passed through a closed bore, but rather can be laid or urged into an open channel within a receiver or head of such a screw. Typical open-ended bone screws include a threaded shank with a pair of parallel projecting branches or arms which form a yoke with a U-shaped slot or channel to receive a rod. Hooks and other types of connectors, as are used in spinal fixation techniques, may also include open ends for receiving rods or portions of other structure. A common mechanism for providing vertebral support is to implant bone screws into certain bones which then in turn support a longitudinal structure such as a rod, or are supported by such a rod. Bone screws of this type may have a fixed head or receiver relative to a shank thereof. In the fixed bone screws, the rod receiver head cannot be moved relative to the shank and the rod must be favorably positioned in order for it to be placed within the receiver head. This is sometimes very difficult or impossible to do. Therefore, polyaxial bone screws are commonly preferred. Open-ended polyaxial bone screws allow rotation of the head or receiver about the shank until a desired rotational position of the head is achieved relative to the shank. Thereafter, a rod can be inserted into the head or receiver and eventually the head is locked or fixed in a particular position relative to the shank. However, in certain instances, a surgeon may desire to set and fix the angular position of the head or receiver relative to the shank independently of rod insertion or rod locking. Additionally, it may be desirable to reset and fix the angle of orientation of the head or receiver during the surgical procedure.
<SOH> SUMMARY OF THE INVENTION <EOH>A polyaxial bone screw assembly according to the invention includes a shank having an upper portion and a body for fixation to a bone; a head or receiver defining an open channel; and at least one compression or pressure insert. The shank is connected to the head or receiver at the upper portion and the shank body is swivelable with respect to the head or receiver. The pressure insert is receivable in the head open channel. The pressure insert includes a base and a head engagement structure. The pressure insert base is frictionally engageable with the shank upper portion and the head engagement structure is engageable with the receiver head. The pressure insert has an articulation position wherein the insert head engagement structure is engaged with the head and the base frictionally engages a projecting end of the shank upper portion with the pressure insert exerting an independent force or pressure on the shank upper portion sufficient to retain the shank body in a selected angle with respect to the head without continuously applied compression by a closure top through the rod. Pressure inserts according to the invention include a side loading insert having a ratcheted outer surface for engagement with a ratcheted inner surface on the bone screw receiver head. Another embodiment includes a cam insert, side loaded or down loaded into the bone screw receiver head, having sloped upper surfaces for engagement with an upper shoulder of a recess formed in the bone screw receiver head.
A61B177037
20170912
20180104
96981.0
A61B1770
2
YANG, ANDREW
PIVOTAL BONE ANCHOR ASSEMBLY WITH INTERFERENCE FIT INSERT
SMALL
1
CONT-ACCEPTED
A61B
2,017
15,702,837
PENDING
MICROCONTROLLER-BASED MULTIFUNCTIONAL ELECTRONIC SWITCH AND LIGHTING APPARATUS HAVING THE SAME
A microcontroller-based multifunctional electronic switch for lighting control uses a detection design to sense and convert external control signals into message carrying sensing signals interpretable to a microcontroller. Based on signal format of message carrying sensing signal received, the microcontroller recognizes working mode chosen by the external control signal and thereby executes an appropriate process. The system and method of the present invention may be equally applicable to detection design, such as touch less and direct touch interface implemented by infrared ray sensor, push button or wireless control device in conjunction with APP preloaded, for performing multiple working modes including on/off mode, dimming mode, color temperature tuning mode, dim to warm mode, commanding mode for controlling a lighting family comprising a plurality of member lamps remotely located or delay shut off mode.
1. A microcontroller based electronic switch for controlling lighting performance of an LED lamp configured with a plurality of LED lighting loads comprising: a first controllable switching element, electrically connectable between a power source and a first LED lighting load for emitting light with a first color temperature; a second controllable switching element, electrically connectable between the power source and a second LED lighting load for emitting light with a second color temperature; at least a detection device, for detecting an external control signal and converting said external control signal into a message carrying sensing signal; and a microcontroller to receive and interpret said message carrying sensing signal generated by said detection device, wherein said microcontroller through a first control pin is electrically coupled to said first controllable switching element, and through a second control pin is electrically coupled to said second controllable switching element, wherein said microcontroller through a third control pin receives said message carrying sensing signal from said detection device, wherein said microcontroller controls a conduction state or a cutoff state of said first controllable switching element through said first control pin and said microcontroller controls the conduction state or the cutoff state of said second controllable switching element through said second control pin to control electric power transmissions from the power source respectively to said first LED lighting load and to said second LED lighting load according to said message carrying sensing signal generated by said detection device; wherein the first color temperature is higher than the second color temperature; wherein said message carrying sensing signal is characterized with a signal format of a short voltage signal, a long voltage signal, a plurality of short voltage signals, a plurality of long voltage signals or a combination of the short voltage signal and the long voltage signal generated in a preset time interval; wherein the short voltage signal and the long voltage signal are respectively defined either by a time length of a voltage signal or by the time length of a series of pulse signals consecutively generated; wherein when the microcontroller receives said message carrying sensing signal, said microcontroller manages to activate a corresponding process according to said signal format of said message carrying sensing signal to perform at least one of various working modes including at least an on/off switch control mode, a dimming control mode, a color temperature tuning control mode, a color temperature switching mode, a dimming and color temperature tuning control mode, and a delay shutoff control mode; wherein when said first controllable switching element and said second controllable switching element are in the conduction state, said microcontroller further controls electric power transmission levels from the power source respectively to said first LED lighting load and to said second LED lighting load according to said signal format of said message carrying sensing signal received, wherein said microcontroller through said first control pin outputs a first control signal to control a conduction rate of said first controllable switching element, said microcontroller through said second control pin outputs a second control signal to control the conduction rate of said second controllable switching element; wherein said microcontroller is an integrated circuit programmable for generating said first control signal and said second control signal, or an application specific integrated circuit (ASIC) custom made for generating said first control signal and said second control signal. 2. The microcontroller based electronic switch according to claim 1, wherein said detection device is configured with a touch less interface for detecting said external control signal and converting said external control signal into said message carrying sensing signal interpretable to said microcontroller. 3. The microcontroller based electronic switch according to claim 2, wherein the touch less interface is an infrared ray sensor having a structure wherein a means emits infrared light into an area to form a defined detection zone, and a means for detecting a motion of an object entering and leaving said defined detection zone is a means for detecting infrared light reflected from said object moving into said defined detection zone, wherein when an object enters and leaves said defined detection zone, a circuitry responsively generates a first voltage sensing signal with a time length corresponding to a time interval of the object entering and staying in said defined detection zone; wherein when the object leaves said defined detection zone, said circuitry delivers a second voltage signal, said first voltage sensing signal with the time length is a basic format for configuring said message carrying sensing signal to be delivered to said microcontroller. 4. The microcontroller based electronic switch according to claim 2, wherein the touch less interface is a wireless remote control device electrically coupled to said microcontroller to receive and convert an external control signal into said message carrying sensing signal with said signal format interpretable to said microcontroller. 5. The microcontroller based electronic switch according to claim 4, wherein the wireless remote control device is a Wi-Fi wireless signal receiver, a Bluetooth wireless signal receiver, a Zigbee wireless signal receiver or a radio frequency wireless signal receiver. 6. The microcontroller based electronic switch according to claim 1, wherein a wireless signal transmitter is further electrically coupled with said microcontroller to convert said message carrying sensing signal into a wireless control signal to control a lighting performance of at least one remote lighting apparatus. 7. The microcontroller based electronic switch according to claim 6, wherein the wireless signal transmitter is a Wi-Fi wireless signal transmitter, a Bluetooth wireless signal transmitter, a Zigbee wielded signal transmitter, or a radio frequency wireless signal transmitter. 8. The microcontroller based electronic switch according to claim 1, wherein said detection device is configured with a direct touch interface for detecting and converting said external control signal into said message carrying sensing signal interpretable to said microcontroller. 9. The microcontroller based electronic switch according to claim 8, wherein the direct touch interface is a push button or a touch sensor, wherein when an user contacts the direct touch interface for a time interval, a circuitry responsively generates a first voltage sensing signal with a time length corresponding to the time interval of said direct touch interface being contacted; when the user withdraws from the direct touch interface, the circuitry delivers a second voltage signal; the first voltage sensing signal with the time length is a basic format for configuring said message carrying sensing signal to be delivered to said microcontroller. 10. The microcontroller based electronic switch according to claim 8, wherein the direct touch interface is a power interruption detection circuitry electrically coupled with said microcontroller to detect a signal of a short power interruption and convert said short power interruption signal into said message carrying sensing signal with said signal format interpretable to said microcontroller, wherein said microcontroller accordingly activates a corresponding process to perform a relevant working mode. 11. The microcontroller based electronic switch according to claim 8, wherein the direct touch interface is a circuitry to detect a voltage level generated by a voltage divider and to convert said voltage level into said message carrying sensing signal with said signal format corresponding to said voltage level generated for setting the conduction rates of said first controllable switching element and said second controllable switching element respectively according to microcontroller design. 12. The microcontroller based electronic switch according to claim 1, wherein when said microcontroller receives said message carrying sensing signal, said microcontroller operates at least one working mode in response to said signal format of said message carrying sensing signal. 13. The microcontroller based electronic switch according to claim 12, wherein the working mode is the on/off switch control mode, wherein when said microcontroller receives said message carrying sensing signal, said microcontroller checks the states of said first controllable switching element and second controllable switching element, wherein if at least one of said first controllable switching element and said second controllable switching element is in conduction state, said microcontroller accordingly operates to cutoff both said first controllable switching element and said second controllable switching element, wherein if both said first controllable switching element and said second controllable switching element are in cutoff state, said microcontroller accordingly manages to conduct at least one of said first controllable switching element and said second controllable switching element. 14. The microcontroller based electronic switch according to claim 12, wherein the working mode is the delay shutoff control mode; wherein when said microcontroller receives said message carrying sensing signal, said microcontroller checks the states of said first controllable switching element and said second controllable switching element, wherein if at least one of said first controllable switching element and said second controllable switching element is in conduction state, said microcontroller accordingly activates a process of delay shutoff to cutoff both said first controllable switching element and said second controllable switching element after a preset delay time; wherein the LED lamp is instantly turned off after the preset delay time or the LED lamp is gradually turned off during the preset delay time or the LED lamp is first reduced to a lower level illumination for a shorter time interval followed by a gradual turn off through the end of the preset delay time; wherein if both said first controllable switching element and said second controllable switching element are in cutoff state, said microcontroller instantly and accordingly manages to conduct at least one of said first controllable switching element and said second controllable switching element. 15. The microcontroller based electronic switch according to claim 12, wherein the working mode is the dimming control mode, wherein said first control signal and said second control signal are designed to operate with an arrangement that the conduction rate of said first controllable switching element and the conduction rate of said second controllable switching element are unidirectionally and proportionally adjusted with the same pace such that a mingled color temperature of said first LED lighting load and said second LED lighting load through a light diffuser is maintained at a constant level while the light intensity is being proportionally adjusted according to the time length of said message carrying sensing signal. 16. The microcontroller based electronic switch according to claim 12, wherein the working mode is the color temperature tuning control mode; wherein said first control signal and said second control signal are designed to operate with an arrangement that the conduction rate of said first controllable switching element and the conduction rate of said second controllable switching element are reversely adjusted with the same pace such that the total light intensity of said first LED lighting load and said second LED lighting load is maintained at a constant level while a mingled color temperature of said first LED lighting load and said second LED lighting load thru a light diffuser is proportionately adjusted according to the time length of said message carrying sensing signal. 17. The microcontroller based electronic switch according to claim 12, wherein the working mode is a color temperature switching mode; wherein when said microcontroller receives said message carrying sensing signal, said microcontroller operates to change the conduction rates of said first controllable switching element and said second controllable switching element according to a designed combination of conduction rates between said first controllable switching element and said second controllable switching element to render a mingled color temperature of said first LED lighting load and said second LED lighting load thru a light diffuser to be alternately changed in such a way from a first mingled color temperature into a second mingled color temperature, and vice versa, in response to said message carrying sensing signal, wherein the total conduction rate of said first controllable switching element and said second controllable switching element is operated at a constant level. 18. The microcontroller based electronic switch according to claim 12, wherein the working mode is the dimming and color temperature tuning control mode; wherein said first control signal and said second control signal are designed to operate with an arrangement that the conduction rate of said first controllable switching element is reduced at a faster pace than the conduction rate of said second controllable switching element being reduced such that the mingled color temperature of said first LED lighting load and said second LED lighting load thru a light diffuser continues to change to a warmer illumination along with a continuous reduction of light intensity, wherein during a cycle of the dimming and color temperature tuning control mode, the light intensity and the mingled color temperature of said first LED lighting load and said second LED lighting load are determined by the time length of said message carrying sensing signal received from said detection device. 19. The microcontroller based electronic switch according to claim 12, wherein the working mode is the dimming and color temperature tuning control mode, wherein said first control signal and said second control signal are designed with an arrangement that the conduction rate of said first controllable switching element is proportionately decreased according to the time length of said message carrying sensing signal while the conduction rate of said second controllable switching element is maintained at a low but constant level till being turned off to create a dim to warm effect, wherein during a cycle of the dimming and color temperature tuning control mode, the light intensity and the mingled color temperature of said first LED load and said second LED load thru a light diffuser are determined by the time length of said message carrying sensing signal received from said detection device. 20. The microcontroller based electronic switch according to claim 12, wherein the working mode is the color temperature tuning control mode, wherein when said microcontroller receives a first said message carrying sensing signal, said microcontroller operates to activate a free running process to perform an automatic color temperature tuning cycle, wherein said first control signal and said second control signal are designed to operate with an arrangement that the conduction rate of said first controllable switching element and the conduction rate of said second controllable switching element are continuously and reversely changed with the same pace such that the total light intensity of said first LED lighting load and said second LED lighting load is maintained at a constant level while a mingled color temperature of said first LED lighting load and said second LED lighting load thru a light diffuser is continuously and proportionately changed from a higher color temperature to a lower color temperature or from a lower color temperature to a higher temperature, wherein when said microcontroller receives a second said message carrying sensing signal during the automatic color temperature tuning cycle, said microcontroller operates to terminate the free running process with the mingled color temperature of said first LED lighting load and said second LED lighting load thru the light diffuser being thereby determined and memorized for repetitive performance. 21. The microcontroller based electronic switch according to claim 12, wherein the working mode is the dimming and color temperature tuning control mode, wherein when said microcontroller receives said message carrying sensing signal with a relevant said signal format, said microcontroller operates to activate a relevant process to successively and respectively change conduction rates of said first switching element and said second switching element from maximum conduction rates to minimum conduction rates, and continuously from the minimum conduction rates to the maximum conduction rates to complete a dimming and color temperature tuning cycle, wherein a moment at which the message carrying sensing signal ceases during the dimming and color temperature tuning cycle, the illumination levels and color temperatures of said first LED lighting load and said second LED lighting load are thereby determined and memorized for repetitive performance. 22. The microcontroller based electronic switch according to claim 21, wherein during a first half cycle period of the dimming and color temperature tuning cycle said first control signal and said second control signal are designed to operate with an arrangement that the conduction rate of said first controllable switching element is decreased at a faster pace than the conduction rate of said second controllable switching element being decreased such that said first controllable switching element leads said second controllable switching element in both decreasing the conduction rate and reaching a cutoff state during a first half cycle period of the dimming and color temperature tuning cycle to create a dim to warm effect; wherein during a second half cycle period of the dimming and color temperature cycle the conduction rate of the first controllable switching element is increased at a faster pace than the conduction rate of said second controllable switching element being increased with a time phase delay such that both said first controllable switching element and said second controllable switching element simultaneously reach the full conduction state at the end of the full cycle period of the dimming and color temperature tuning cycle to create a brighten to cold effect, wherein at any time during a full cycle of the dimming and color temperature tuning mode, the light intensity and the mingled color temperature of the lighting apparatus are determined by the time length of said message carrying sensing signal received from said detection device. 23. A microcontroller based electronic switch for controlling lighting performance of an LED lamp configured with a plurality of LED lighting loads comprising: a first controllable switching element, electrically connectable between a first LED lighting load for emitting light with a first color temperature and a power source; a second controllable switching element, electrically connectable between a second LED lighting load for emitting light with a second color temperature and the power source; a first detection device for detecting a first external control signal and converting said first external control signal into a first message carrying sensing signal; a second detection device for detecting a second external control signal and converting said second external control signal into a second message carrying sensing signal; and a microcontroller through a first control pin receives said first message carrying sensing signal generated by said first detection device, said microcontroller through a second control pin receives said second message carrying sensing signal generated by said second detection device, wherein said microcontroller through a third control pin is electrically coupled to said first controllable switching element, wherein said microcontroller through a fourth control pin is electrically coupled to said second controllable switching element, wherein said microcontroller respectively controls conduction state or cutoff state of said first controllable switching element and said second controllable switching element to control electric power transmissions from the power source respectively to said first LED lighting load and to said second LED lighting load according to said first message carrying sensing signal and said second message carrying sensing signal generated respectively by said first detection device and said second detection device; wherein the first color temperature is higher than the second color temperature; wherein said first detection device is a touch less interface to receive and convert the first external control signal into said first message carrying sensing signal interpretable to said microcontroller; wherein said second detection device is a direct touch interface to receive and convert the second external control signal into said second message carrying sending signal interpretable to said microcontroller; wherein said first message carrying sensing signal and said second message carrying sensing signal are characterized with a signal format of, a short voltage signal, a long voltage signal, a plurality of short voltage signals, a plurality of voltage signals or a combination of the short voltage signal and the long voltage signal generated in a preset time interval; wherein the short voltage signal and the long voltage signal are respectively defined either by a time length of a voltage signal or by the time length of a series of pulse signals consecutively generated; wherein when said microcontroller receives said first message carrying sensing signal or said second message carrying sensing signal, said microcontroller manages to activate a corresponding process according to said signal format of said first message carrying sensing signal or said second message carrying sensing signal to perform at least one of various working modes including at least an on/off switch control mode, a dimming control mode, a color temperature tuning control mode, a dimming and color temperature tuning control mode, and a delay shutoff control mode; wherein when said first controllable switching element and said second controllable switching element are in the conduction state, said microcontroller further controls electric power transmission levels from the power source respectively to said first LED lighting load and to said second LED lighting load according to a time length of the long voltage signal of said first message carrying sensing signal or said second message carrying sensing signal received, wherein said microcontroller through said third control pin outputs a first control signal to control a conduction rate of said first controllable switching element, said microcontroller through said fourth control pin outputs a second control signal to control the conduction rate of said second controllable switching element; wherein said microcontroller is an integrated circuit programmable for generating said first control signal and said second control signal, or an application specific integrated circuit (ASIC) custom made for generating said first control signal and said second control signal. 24. The microcontroller based electronic switch according to claim 23, wherein the touch less interface of said first detection device is an infrared ray sensor having a structure wherein a means for emitting infrared light into an area to form a defined detection zone, and a means for detecting a motion of an object entering and leaving said defined detection zone is a means for detecting infrared light reflected from the object moving into said defined detection zone, wherein when an object enters and leaves said defined detection zone, a circuitry responsively generates a first voltage signal with a time length corresponding to the time interval of the object entering and staying in said defined detection zone; wherein when the object leaves said defined detection zone, said circuitry delivers a second voltage signal, said first voltage signal with the time length is a basic format for configuring said first message carrying sensing signal to be delivered to said microcontroller. 25. The microcontroller based electronic switch according to claim 23, wherein the touch less interface of said first detection device is a wireless remote control device electrically coupled to said microcontroller to receive and convert a wireless external control signal into said first message carrying sensing signal with said signal format interpretable to said microcontroller. 26. The microcontroller based electronic switch according to claim 25, wherein the wireless remote control device is a Wi-Fi wireless signal receiver, a Bluetooth wireless signal receiver, a Zigbee wireless signal receiver or a radio frequency wireless signal receiver. 27. The microcontroller based electronic switch according to claim 23, wherein the direct touch interface of said second detection device is a push button or a touch sensor, wherein when an user contacts the direct touch interface for a time interval, a circuitry responsively generates a first voltage signal with a time length corresponding to the time interval of said direct touch interface being contacted wherein when the user withdraws from the direct touch interface, said second detection device delivers a second voltage signal; the first voltage signal with the time length is a basic format for configuring said second message carrying sensing signal to be delivered to said microcontroller. 28. The microcontroller based electronic switch according to claim 23, wherein the direct touch interface of said second detection device is a power interruption detection circuitry electrically coupled with said microcontroller to detect a signal of a short power interruption and convert said short power interruption signal into said message carrying sensing signal with said signal format interpretable to said microcontroller for performing various working modes. 29. The microcontroller based electronic switch according to claim 23, wherein the direct touch interface of said second detection device is a circuitry to detect a voltage level generated by a voltage divider and to convert said voltage level into said message carrying sensing signal with said signal format corresponding to said voltage level for controlling and setting the conduction rates of said first controllable switching element and said second controllable switching element respectively according to microcontroller design. 30. The microcontroller based electronic switch according to claim 23, wherein a wireless signal transmitter is further electrically coupled with said microcontroller to convert said first message carrying sensing signal or said second message carrying sensing signal into a wireless control signal to control a lighting performance of at least one remote lighting apparatus. 31. The microcontroller based electronic switch according to claim 30, wherein the wireless signal transmitter is a Wi-Fi wireless signal transmitter, a Bluetooth wireless signal transmitter, a Zigbee wireless signal transmitter, or a radio frequency wireless signal transmitter. 32. A lighting apparatus comprising: a first LED lighting load for emitting light with a first color temperature; a second LED lighting load for emitting light with a second color temperature; a diffuser, covering said first LED lighting load and said second LED lighting load to create a diffused light with a mingled color temperature; and a microcontroller based electronic switch electrically connected to said first LED lighting load and to said second LED lighting load, said microcontroller based electronic switch further comprising: a first switching element, electrically connected between said first LED lighting load and a power source; a second switching element, electrically connected between said second LED lighting load and the power source; at least a detection device, for detecting an external control signal and converting said external control signal into said message carrying sensing signal; a microcontroller to receive and interpret said message carrying sensing signal generated by said detection device, wherein said microcontroller through a first control pin is electrically coupled to said first switching element, and through a second control pin is electrically coupled to said second switching element, wherein said microcontroller through a third control pin receives said message carrying sensing signal from said detection device, wherein said microcontroller controls a conduction state or a cutoff state of said first switching element through said first control pin and said microcontroller controls the conduction state or the cutoff state of said second switching element through said second control pin to control electric power transmissions from the power source respectively to said first LED lighting load and to said second LED lighting load according to said message carrying sensing signal generated by said detection device; wherein the first color temperature is higher than the second color temperature; wherein said message carrying sensing signal is characterized with a signal format of a short voltage signal, a long voltage signal, a plurality of the short voltage signals, a plurality of the long voltage signals or a combination of the short voltage signal and the long voltage signal generated in a preset time interval; wherein the short voltage signal and the long voltage signal are respectively defined either by a time length of a voltage signal or by the time length of a series of pulse signals consecutively generated; wherein when the microcontroller receives said message carrying sensing signal, said microcontroller operates to activate a corresponding process according to said signal format of said message carrying sensing signal to perform at least one of various working modes including at least an on/off switch control mode, a dimming control mode, a color temperature tuning control mode, a color temperature switching mode, a dimming and color temperature tuning control mode, and a delay shutoff control mode; wherein when said first switching element and said second switching element are in the conduction state, said microcontroller further controls electric power transmission levels from the power source respectively to said first LED lighting load and to said second LED lighting load according to said signal format of said message carrying sensing signal received, wherein said microcontroller through said first control pin outputs a first control signal to change a conduction rate of said first switching element, said microcontroller through said second control pin outputs a second control signal to change the conduction rate of said second switching element; wherein said microcontroller is an integrated circuit programmable for generating said first control signal and said second control signal, or an application specific integrated circuit (ASIC) custom made for generating said first control signal and said second control signal. 33. The lighting apparatus according to claim 32, wherein both said first switching element and said second switching element are controllable switching element, wherein when said microcontroller receives said message carrying sensing signal, said microcontroller operates to output said first control signal and said second control signal with an arrangement that the conduction rate of said first switching element and the conduction rate of said second switching element are reversely adjusted with the same pace such that the total power level transmitted to said first LED lighting load and said second LED lighting load is maintained at a constant level while the color temperature of the lighting apparatus is proportionately adjusted according to the time length of said message carrying sensing signal to perform the color temperature tuning control mode. 34. The lighting apparatus according to claim 32, wherein both said first switching element and said second switching element are controllable switching element, wherein said first control signal and said second control signal are designed to operate with an arrangement that the conduction rate of said first switching element and the conduction rate of said second switching element are unidirectionally and proportionally adjusted with the same pace such that the color temperature of the lighting apparatus is maintained at a constant level while the light intensity of the lighting apparatus is being proportionately adjusted according to the time length of said message carrying sensing signal to perform the dimming control mode. 35. The lighting apparatus according to claim 32, wherein at least said first switching element is a controllable switching element, wherein when said dimming and color temperature tuning control mode is performed, said microcontroller manages to output said first control signal to proportionately reduce the conduction rate of said first switching element such that said first LED lighting load with said first color temperature is dimmed according to the time length of said message carrying sensing signal, wherein said microcontroller manages to output said second control signal to control the conduction state of said second switching element such that said second LED lighting load with said second color temperature operates at a constant power level before being turned off to create a dim to warm effect, wherein during a cycle of the dimming and color temperature tuning control mode, the light intensity and the mingled color temperature of the lighting apparatus are determined by the time length of said message carrying sensing signal received from said detection device. 36. The lighting apparatus according to claim 32, wherein said first switching element and said second switching element are controllable switching elements, wherein when said dimming and color temperature tuning control mode is performed, said microcontroller outputs said first control signal to control a conduction rate of said first switching element, said microcontroller outputs said second control signal to control the conduction rate of said second switching element, wherein said first control signal and said second control signal are designed to operate with an arrangement that said first LED lighting load and said second LED lighting load are respectively dimmed in such a way that said first LED lighting load leads said second LED lighting load in reaching a turnoff state in performing said dimming and color temperature tuning control mode such that said mingled color temperature of said lighting apparatus continues to change to a warmer illumination along with a continuous reduction of light intensity according to the time length of said message carrying sensing signal, wherein during a cycle of the dimming and color temperature tuning control mode, the light intensity and the mingled color temperature of the lighting apparatus are determined by the time length of said message carrying sensing signal received from said detection device. 37. The lighting apparatus according to claim 32, wherein said first LED lighting load is configured with M light emitting diodes and said second LED lighting load is configured with N light emitting diodes, wherein said first switching element comprises a plurality of transistors with each transistor electrically coupled to at least one of said M light emitting diodes, wherein the conduction rate of said first switching element is adjustable by reducing number of conducted light emitting diodes of said M light emitting diodes through outputting control signal(s) to respectively control conduction or cutoff of said transistor(s) selected, wherein when said dimming and color temperature tuning control mode is performed, said microcontroller successively outputs said first control signal to decreasingly change the conduction rate of said first switching element such that said first LED lighting load with said first color temperature is turned off gradually, wherein said microcontroller successively outputs said second control signal to manage the conduction state or the cutoff state of said second switching element such that said second LED lighting load with said second color temperature operates at a constant power level before being turned off to create a dim to warm effect, wherein during a cycle of the dimming and color temperature tuning mode, the light intensity and the mingled color temperature of the lighting apparatus are determined by the time length of said message carrying sensing signal received from said detection device. 38. The lighting apparatus according to claim 32, wherein said detection device is a touch less interface for detecting said external control signal and converting said external control signal into said message carrying sensing signal interpretable to said microcontroller. 39. The lighting apparatus according to claim 38, wherein the touch less interface of said detection device is an infrared ray sensor with a structure wherein a means for emitting infrared light into an area to form a defined detection zone, and a means for detecting a motion of an object entering and leaving said defined detection zone is a means for detecting infrared light reflected from the object moving into said defined detection zone, wherein when the object enters and leaves said defined detection zone, a circuitry responsively generates a first voltage sensing signal with a time length corresponding to the time interval of the object entering and staying in said defined detection zone; wherein when the object leaves said defined detection zone, said circuitry delivers a second voltage signal, said first voltage sensing signal with the time length is a basic format for configuring said message carrying sensing signal to be delivered to said microcontroller. 40. The lighting apparatus according to claim 39, wherein the lighting apparatus is a LED light bulb constructed with said microcontroller based electronic switch, and said detection device is said infrared ray sensor being mounted in or on the LED bulb housing for detecting said external control signal. 41. The lighting apparatus according to claim 38, wherein the touch less interface is a wireless remote control device electrically coupled to said microcontroller to receive and convert an external control signal into said message carrying sensing signal with said signal format interpretable to said microcontroller. 42. The lighting apparatus according to claim 41, wherein the wireless remote control device is a Wi-Fi wireless signal receiver, a Bluetooth wireless signal receiver, a Zigbee wireless signal receiver or a radio frequency wireless signal receiver. 43. The lighting apparatus according to claim 32, wherein a wireless signal transmitter is further electrically coupled with said microcontroller to convert said message carrying sensing signal into a wireless control signal to control a lighting performance of at least one remote lighting apparatus. 44. The lighting apparatus according to claim 43, wherein the wireless signal transmitter is a Wi-Fi wireless signal transmitter, a Bluetooth wireless signal transmitter, a Zigbee wireless signal transmitter, or a radio frequency wireless signal transmitter. 45. The lighting apparatus according to claim 32, wherein said detection device is a direct touch interface for detecting said external control signal and converting said external control signal into said message carrying sensing signal interpretable to said microcontroller. 46. The lighting apparatus according to claim 45, wherein said direct touch interface is configured with a push button or a touch sensor, wherein when an user contacts said direct touch interface for a time interval, a circuitry responsively generates a first voltage signal with a time length corresponding to the time interval of said direct touch interface being contacted; wherein when the user withdraws from the direct touch interface, said circuitry delivers a second voltage signal; the first voltage signal with the time length is a basic format for configuring said message carrying sensing signal to be delivered to said microcontroller. 47. The lighting apparatus according to claim 45, wherein said direct touch interface is a power interruption detection circuitry electrically coupled with said microcontroller to detect a signal of a short power interruption and convert said short power interruption signal into said message carrying sensing signal interpretable to said microcontroller for performing various working modes. 48. The lighting apparatus according to claim 45, wherein said direct touch interface is a circuitry to detect a voltage level generated by a voltage divider and convert said voltage level into said message carrying sensing signal with said signal format corresponding to said voltage level generated for setting conduction rates of said first switching element and said second switching element respectively according to microcontroller design. 49. A lighting apparatus comprising: a first LED lighting load for emitting light with a first color temperature; a second LED lighting load for emitting light with a second color temperature; a third LED lighting load for emitting light with a third color temperature; a diffuser, covering said first LED lighting load, said second LED lighting load and said third LED lighting load to create a diffused light with a mingled color temperature; a microcontroller based electronic switch electrically connected to said first LED lighting load, said second LED lighting load and said third LED lighting load, said microcontroller based electronic switch further comprising: a first controllable switching element, electrically connected between said first LED lighting load and a power source; a second controllable switching element, electrically connected between said second LED lighting load and the power source; a third controllable switching element, electrically connected between said third LED lighting load and the power source; at least a detection device, for detecting an external control signal and converting said external control signal into a message carrying sensing signal; and a microcontroller to receive and interpret said message carrying sensing signal generated by said detection device, wherein said microcontroller through a first control pin is electrically coupled to said first controllable switching element, said microcontroller through a second control pin is electrically coupled to said second controllable switching element, and said microcontroller through a third control pin is electrically coupled to said third controllable switching element; wherein said microcontroller through a fourth control pin receives said message carrying sensing signal from said detection device, wherein said microcontroller controls a conduction state or a cutoff state of said first controllable switching element through said first control pin, said microcontroller controls the conduction state or the cutoff state of said second controllable switching element through said second control pin, and said microcontroller controls the conduction state or the cutoff state of said third controllable switching element through said third control pin to control electric power transmissions from the power source respectively to said first LED lighting load, to said second LED lighting load and to said third LED lighting load according to said message carrying sensing signal generated by said detection device; wherein the first color temperature is higher than the second color temperature and the second color temperature is higher than the third color temperature; wherein said message carrying sensing signal is characterized with a signal format of a short voltage signal, a long voltage signal, a plurality of short voltage signals, a plurality of long signals or a combination of the short voltage signal and the long voltage signal generated in a preset time interval; wherein the short voltage signal and the long voltage signal are respectively defined either by a time length of a voltage signal or by the time length of a voltage signal comprising a series of pulse signals consecutively generated; wherein when the microcontroller receives said message carrying sensing signal, said microcontroller operates to activate a corresponding process according to said signal format of said message carrying sensing signal to perform at least one of various working modes including at least an on/off switch control mode, a dimming control mode, a color temperature tuning control mode, a dimming and color temperature tuning control mode and a delay shutoff control mode; wherein when said first controllable switching element, said second controllable switching element and said third controllable switching element are in the conduction state, said microcontroller further controls electric power transmission levels from the power source respectively to said first LED lighting load, to said second LED lighting load and to said third LED lighting load according to said signal format of said message carrying sensing signal received, wherein said microcontroller through said first control pin outputs a first control signal to change conduction rate of said first controllable switching element, said microcontroller through said second control pin outputs a second control signal to change conduction rate of said second controllable switching element and said microcontroller through said third control pin outputs a third control signal to change conduction rate of said third controllable switching element; wherein when said microcontroller receives said message carrying sensing signal with a relevant said signal format for performing said dimming and color temperature tuning control mode, said microcontroller manages to output different control signals to said first controllable switching element, to said second controllable switching element and to said third controllable switching element with an arrangement that said first LED lighting load leads said second LED lighting load and said second LED lighting load leads said third LED lighting load in reaching a turnoff state such that the mingled color temperature of said lighting apparatus continues to change to a warmer illumination along with a continuous reduction of light intensity according to the time length of said message carrying sensing signal, wherein during a cycle of the dimming and color temperature tuning control mode, the light intensity and the mingled color temperatures of the lighting apparatus are determined by the time length of said message carrying sensing signal received from said detection device; wherein said microcontroller is an integrated circuit programmable for generating said first control signal, said second control signal and said third control signal, or an application specific integrated circuit (ASIC) custom made for generating said first control signal, said second control signal and said third control signal. 50. The lighting apparatus according to claim 49, wherein said detection device is configured with a touch less interface for detecting said external control signal and converting said external control signal into said message carrying sensing signal interpretable to said microcontroller. 51. The lighting apparatus according to claim 50, wherein said touch less interface is an infrared ray sensor with a structure wherein a means for emitting infrared light into an area to form a defined detection zone, and a means for detecting a motion of an object entering and leaving said defined detection zone is a means for detecting infrared light reflected from the object moving into said defined detection zone, wherein when the object enters and leaves said defined detection zone, a circuitry responsively generates a first voltage sensing signal with a time length corresponding to the time interval of the object entering and staying in said defined detection zone; wherein when the object leaves said defined detection zone, said circuitry delivers a second voltage signal, said first voltage sensing signal with the time length is a basic format for configuring said message carrying sensing signal to be delivered to said microcontroller. 52. The lighting apparatus according to claim 51, wherein the lighting apparatus is a LED light bulb constructed with said microcontroller based electronic switch, and said detection device is said infrared ray sensor being mounted in or on the LED bulb housing for detecting said external control signal. 53. The lighting apparatus according to claim 50, wherein said touch less interface is a wireless remote control device electrically coupled to said microcontroller to receive and convert an external control signal into said message carrying sensing signal with said signal format interpretable to said microcontroller. 54. The lighting apparatus according to claim 53, wherein the wireless remote control device is a Wi-Fi wireless signal receiver, a Bluetooth wireless signal receiver, a Zigbee wireless signal receiver or a radio frequency wireless signal receiver. 55. The lighting apparatus according to claim 49, wherein a wireless signal transmitter is further electrically coupled with said microcontroller to convert said message carrying sensing signal into a wireless control signal to control a lighting performance of at least one remote lighting apparatus. 56. The lighting apparatus according to claim 55, wherein the wireless signal transmitter is a Wi-Fi wireless signal transmitter, a Bluetooth wireless signal transmitter, a Zigbee wireless signal transmitter, or a radio frequency wireless signal transmitter. 57. The lighting apparatus according to claim 49, wherein said detection device is configured with a direct touch interface for detecting said external control signal and converting said external control signal into said message carrying sensing signal interpretable to said microcontroller. 58. The lighting apparatus according to claim 57, wherein said direct touch interface is a push button or a touch sensor, wherein when an user contacts the direct touch interface for a time interval, a circuitry responsively generates a first voltage signal with a time length corresponding to the time interval of said direct touch interface being contacted; wherein when the user withdraws from the direct touch interface, said circuitry delivers a second voltage signal; the first voltage signal with the time length is a basic format for configuring said message carrying sensing signal to be delivered to said microcontroller. 59. The lighting apparatus according to claim 57, wherein said direct touch interface is a power interruption detection circuitry electrically coupled with said microcontroller to detect a signal of a short power interruption and convert said short power interruption signal into said message carrying sensing signal interpretable to said microcontroller for performing various working modes. 60. The lighting apparatus according to claim 57, wherein said direct touch interface is a circuitry to detect a voltage level generated by a voltage divider and to convert said voltage level into said message carrying sensing signal with said signal format corresponding to said voltage level generated for setting conduction rates of said first switching element and said second switching element respectively according to microcontroller design. 61. A method of creating a dim to warm effect for controlling lighting performance of an LED lamp comprising: using at least a first LED lighting load with a high color temperature and a second LED lighting load with a low color temperature to form a lighting unit of said LED lamp; electrically coupling a switching circuitry to said first LED lighting load and to said second LED lighting load to respectively deliver different average electric powers to said first LED lighting load and to said second LED lighting load for generating different illuminations respectively; using a detection device to detect an external control signal and to convert said external control signal into a message carrying sensing signal with a time length; using a microcontroller to output at least a control signal to control conduction rate of said switching circuitry electrically coupled to said first LED lighting load and to said second LED load according to the time length of said message carrying sensing signal received from said detection device; and using a diffuser to cover at least said first LED lighting load with the high color temperature and said second LED lighting load with the low color temperature to create a diffused light with a mingled color temperature; wherein said switching circuitry comprises at least one semiconductor switching element; wherein when a dimming cycle is performed, said microcontroller receives said message carrying sensing signal and responsively outputs said control signal(s) to continuously reduce conduction rate of said switching circuitry coupled to said first LED lighting load and to said second LED lighting load with an arrangement that said first LED lighting load with the high color temperature leads said second LED lighting load with the low color temperature in reaching a turnoff state during said dimming cycle such that the mingled color temperature of said LED lamp continues to change to a warmer illumination along with a continuous reduction of light intensity according to the time length of said message carrying sensing signal to create a dim to warm effect; wherein at any time during said dimming cycle the light intensity and the mingled color temperature of the lighting apparatus are determined by the time length of said message carrying sensing signal received from said detection device, wherein said microcontroller is an integrated circuit programmable for generating at least said first control signal, or an application specific integrated circuit (ASIC) custom made for generating at least said first control signal. 62. The method of creating a dim to warm effect for controlling lighting performance of an LED lamp according to claim 61, wherein during said dimming cycle said switching circuitry manages to continually reduce the average electrical power delivered to said first LED lighting load and said switching circuitry simultaneously manages to deliver a constant average electric power to said second LED lighting load till being turned off at the end of the dimming cycle, wherein said first LED lighting load leads said second LED lighting load in reaching a turnoff state before the end of the dimming cycle. 63. The method of creating a dim to warm effect for controlling lighting performance of an LED lamp according to claim 61, during said dimming cycle said switching circuitry manages to continuously reduce the average electric power delivered to said first LED lighting load at a faster pace than reducing the average electric power delivered to said second LED lighting load such that said first LED lighting load leads said second LED lighting load in reaching a turnoff state in performing said dimming cycle to create a dim to warm effect through a light diffuser according to the time length of said message carrying sensing signal, wherein at any time during said dimming cycle, the light intensity and the mingled color temperature of said LED lamp are determined by the time length of said message carrying sensing signal received from said detection device. 64. The method of creating a dim to warm effect for controlling lighting performance of an LED lamp according to claim 61, wherein during said dimming cycle, said switching circuitry manages to continuously reduce the average electric power delivered to said first LED lighting load at a faster pace such that said first LED lighting load leads said second LED lighting load in reaching the turnoff state during said dimming cycle, wherein in order to accelerate the color temperature tuning pace along with a continuous reduction of light intensity of said LED lamp, said switching circuitry initially manages to increase the average electric power delivered to said second LED lighting load with a pace slower than the reduction pace of the average electric power delivered to said first LED lighting load such that the total average electric powers delivered to said first LED lighting load and said second LED lighting load continues to decline while the color temperature of said LED lamp continues to change to a warmer illumination at a faster pace to perform a faster dim to warm process, wherein when a dim to warm process ceases at a time point when the first LED lighting load reaches the turnoff state is an inflection time point for said switching circuitry to reversely manage to decrease the average electric power delivered to said second LED lighting load till reaching the turnoff state at the ending point of said dimming cycle, such that the dimming of the LED lamp continues to perform with the low color temperature of said second LED lighting load thru the end of said dimming cycle to complete a full cycle of said dim to warm process, wherein at any time during said dimming cycle, the light intensity and the mingled color temperature of said LED lamp are determined by the time length of said message carrying sensing signal received from said detection device. 65. A lighting apparatus comprising: a first LED lighting load for emitting light with a first color temperature; a second LED lighting load for emitting light with a second color temperature; a diffuser, covering said first LED lighting load and said second LED lighting load to create a diffused light with a mingled color temperature; and a microcontroller based electronic switch, electrically coupled to said first LED lighting load and said second LED lighting load, wherein said microcontroller based electronic switch further comprising: a first controllable switching element, electrically coupled between said first LED lighting load and a power source; a second controllable switching element, electrically coupled between said second LED lighting load and the power source; a first detection device for detecting a first external control signal and converting said first external control signal into a first message carrying sensing signal; a second detection device for detecting a second external control signal and converting said second external control signal into a second message carrying sensing signal; and a microcontroller to receive and interpret said first message carrying sensing signal and said second message carrying sensing signal to respectively activate a corresponding process for controlling and setting a light intensity level and a color temperature level of the lighting apparatus; wherein said microcontroller through a first control pin is electrically coupled to said first controllable switching element and through a second control pin is electrically coupled to said second controllable switching element, wherein said microcontroller through a third control pin receives said first message carrying sensing signal from said first detection device, wherein said microcontroller through a fourth control pin receives said second message carrying sensing signal from said second detection device; wherein the color temperature of said first LED lighting load is higher than the color temperature of said second LED lighting load; wherein said first message carrying sensing signal and said second message carrying sensing signal are characterized with a signal format of a short voltage signal, a long voltage signal or a plurality of short voltage signals generated in a preset time interval; wherein the short voltage signal and the long voltage signal are respectively defined either by a time length of a voltage signal or by the time length of a voltage signal comprising a series of pulse signals consecutively generated; wherein said first detection device is a first direct touch interface designed to detect said first external control signal and convert said first external control signal into said first message carrying sensing signal interpretable to said microcontroller for controlling and setting the color temperature of the lighting apparatus; wherein when said microcontroller receives said first message carrying sensing signal from said first detection device, said microcontroller manages to activate a first process to output a first control signal to reduce the conduction rate of said first controllable switching element and meantime to output a second control signal to increase the conduction rate of said second controllable switching element, or vice versa, according to the time length of said first message carrying sensing signal with an arrangement that the total power delivered to said first LED lighting load and said second LED lighting load remains unchanged; wherein said second detection device is a second direct touch interface designed to detect a second external control signal and convert said second external control signal into said second message carrying sensing signal interpretable to said microcontroller for controlling and setting the light intensity level of the lighting apparatus; wherein when said microcontroller receives said second message carrying sensing signal from said second detection device, said microcontroller manages to activate a second process to determine a total power level transmitted to said first LED lighting load and said second LED lighting load according to the time length of said second message carrying sensing signal with an arrangement that the ratio between the power delivered to said first LED lighting load and the power delivered to said second LED lighting load remains at a constant level; wherein said microcontroller outputs a third control signal to reduce the conduction rate of said first controllable switching element and meantime to output a fourth control signal to reduce the conduction rate of said second controllable switching element with the same pace, or vice versa, such that the mingled color temperature through the diffuser remains unchanged. 66. The lighting apparatus according to claim 65, wherein a power switch is used to control on state and off state of the lighting apparatus; wherein when the power switch is turned on the lighting apparatus responsively perform an illumination and wherein when the power switch is turned off the illumination of the lighting apparatus is immediately shutoff. 67. The lighting apparatus according to claim 65, wherein a third detection device is further installed and coupled to a control pin of the microcontroller to detect a voltage signal generated by a third direct touch interface and convert said voltage signal into a third message carrying sensing signal for controlling an on/off performance of the lighting apparatus; wherein when said microcontroller receives said third message carrying sensing signal, said microcontroller operates to turn on or turn off the lighting apparatus alternatively, wherein the direct touch interface is a push button or a touch pad. 68. The lighting apparatus according to claim 65, wherein the first direct touch interface of said first detection device comprises a circuitry to detect a voltage level generated by a voltage divider and convert said voltage level into said first message carrying sensing signal. 69. The lighting apparatus according to claim 65, wherein the second direct touch interface of said second detection device comprises a circuitry to detect a voltage level generated by a voltage divider and convert said voltage level into said second message carrying sensing signal. 70. The lighting apparatus according to claim 65, wherein the first direct touch interface of said first detection device comprise a circuitry to detect a voltage signal generated by a push button interface or a touch pad interface, and convert said voltage signal into said first message carrying sensing signal with a time length corresponding to the time length of the push button interface or the touch pad interface being continuously contacted by an user for controlling and setting the color temperature level of the lighting apparatus. 71. The lighting apparatus according to claim 65, wherein the second direct touch interface of said second detection device comprises a circuitry to detect a voltage signal generated by a push button interface or a touch pad interface and convert said voltage signal into said second message carrying sensing signal with a time length corresponding to the time length of the push button interface or touch pad interface being continuously contacted by an user for controlling and setting the light intensity level of the lighting apparatus. 72. The lighting apparatus according to claim 65, wherein a wireless signal transmitter is further electrically coupled with said microcontroller to convert said first message carrying sensing signal or said second message carrying sensing signal into a wireless signal to control a lighting performance of at least one lighting apparatus. 73. The lighting apparatus according to claim 72, wherein the wireless signal transmitter is a Wi-Fi wireless signal transmitter, a Bluetooth wireless signal transmitter or a radio frequency wireless signal transmitter. 74. A lighting apparatus comprising: a first LED lighting load for emitting light with a first color temperature; a second LED lighting load for emitting light with a second color temperature; a diffuser, covering the first lighting load and the second lighting load to create a diffused light with a mingled color temperature; a clock, providing clock time information to the microcontroller for managing variation of color temperature of the lighting apparatus according to a programmed pattern of color temperature schedule; and a microcontroller based electronic switch electrically connected to the first LED lighting load and the second LED lighting load; wherein the microcontroller based electronic switch comprising: a first controllable switching element, electrically connected between the first LED lighting load and a power source for controlling a first electrical power level transmitted to the first LED lighting load; a second controllable switching element, electrically connected between the second LED lighting load and the power source for controlling a second electrical power level transmitted to the second LED lighting load; a detection device, for detecting an external control signal and converting said external control signal into a messaging carrying sensing signal; and a microcontroller to receive and interpret the message carrying sensing signal generated by the detection device, wherein said microcontroller is electrically connected between said first controllable switching element and said detection device, said microcontroller is also electrically connected between said second controllable switching element and said detection device, said microcontroller is designed to execute a task of managing the illumination characteristics of the lighting apparatus including light intensity and light color temperature; wherein said microcontroller controls a conduction state, a cutoff state or conduction rates of said first controllable switching element and said second controllable switching element to control electric power transmissions from the power source respectively to said first LED lighting load and said second LED lighting load according to a process designed for automatic tuning of the color temperature of the lighting apparatus based on the time information provided by said clock and according to a signal format of said message carrying sensing signal generated by the detection device; wherein the first color temperature is higher than the second color temperature; wherein the clock time information is either received from a clock electrically connected to said microcontroller or received from a mobile device configured with a clock time capacity through a wireless signal receiver electrically connected with said microcontroller; wherein the signal format is a voltage signal with a short time length, a voltage signal with a long time length or a plurality of voltage signals generated in a preset time interval; wherein the short voltage signal and the long voltage signal are respectively defined either by a time length of a voltage signal or by the time length of a voltage signal comprising a series of pulse signals consecutively generated; wherein when said microcontroller receives said message carrying sensing signal, said microcontroller manages to activate a corresponding process according to the signal format of said message carrying sensing signal to perform one of various working modes including an on/off switch control mode, a dimming control model, a color temperature tuning control mode and a delay shutoff mode. 75. The lighting apparatus according to claim 74, wherein said detection device is configured with a touch less interface for detecting said external control signal and converting said external control signal into said message carrying sensing signal interpretable to said microcontroller. 76. The lighting apparatus according to claim 75, wherein said touch less interface is an infrared ray sensor having a structure wherein a means for emitting infrared light into an area to form a defined detection zone, and a means for detecting a motion of an object entering and leaving said defined detection zone is a means for detecting infrared light reflected from said object moving into said defined detection zone, wherein when an object enters and leaves said defined detection zone, a circuitry responsively generates a first voltage sensing signal with a time length corresponding to the time interval of the object entering and staying in said defined detection zone; wherein when the object leaves said defined detection zone, said circuitry delivers a second voltage signal, said first voltage sensing signal with the time length is a basic format for configuring said message carrying sensing signal to be delivered to said microcontroller. 77. The lighting apparatus according to claim 75, wherein said touch less interface is a wireless remote control device electrically coupled to said microcontroller to receive and to convert a wireless external control signal into said message carrying sensing signal with said signal format interpretable to said microcontroller. 78. The lighting apparatus according to claim 77, wherein the wireless remote control device is a Wi-Fi wireless signal receiver, a Bluetooth wireless signal receiver or a RF (radio frequency) wireless signal receiver, wherein the wireless external control signal, the clock and the time information are received from a mobile device. 79. The lighting apparatus according to claim 74, wherein a wireless signal transmitter is further electrically coupled with said microcontroller to convert said message carrying sensing signal into a wireless control signal to control a lighting performance of at least one remote lighting apparatus. 80. The lighting apparatus according to claim 79, wherein the wireless signal transmitter is a Wi-Fi wireless signal transmitter, a Bluetooth wireless signal transmitter, a Zigbee wireless signal transmitter, or a radio frequency wireless signal transmitter. 81. The lighting apparatus according to claim 74, wherein said detection device is configured with a direct touch interface for detecting said external control signal and converting said external control signal into said message carrying sensing signal interpretable to said microcontroller. 82. The lighting apparatus according to claim 81, wherein said direct touch interface is a push button or a touch sensor, wherein when an user contacts the direct touch interface for a time interval, a circuitry responsively generates a first voltage sensing signal with a time length corresponding to the time interval of said direct touch interface being contacted; when the user withdraws from the direct touch interface, the circuitry delivers a second voltage signal; the first voltage sensing signal with the time length is a basic format for configuring said message carrying sensing signal to be delivered to said microcontroller. 83. The lighting apparatus according to claim 81, wherein said direct touch interface is a circuitry to detect a voltage level generated by a voltage divider and convert said voltage level into said message carrying sensing signal with said signal format corresponding to said voltage level for setting a total conduction rate of said first controllable switching element and said second controllable switching element according to microcontroller design. 84. The lighting apparatus according to claim 74, wherein when the first controllable switching element and second controllable switching element are in the conduction state, said microcontroller further controls a first electrical power level transmitted to the first LED lighting load and a second electrical power level transmitted to the second LED lighting load from the power source according to the signal format of said message carrying sensing signal received from said detection device, wherein the first electric power level transmitted to the first LED lighting load ranges from X wattage to Y wattage, the second electric power level transmitted to the second LED lighting load ranges from Y wattage to X wattage, and vice versa, wherein the sum of X and Y is maintained at a constant value to perform the color temperature tuning control mode according to a designed pattern of color temperature schedule. 85. The lighting apparatus according to claim 74, wherein when the first controllable switching element and the second controllable switching element are in the conduction state, said microcontroller further controls a first electrical power level transmitted from the power source to the first LED lighting load and a second electrical power level transmitted from the power source to the second LED lighting load according to the signal format of said message carrying sensing signal received from said detection device, wherein the first electrical power level transmitted to the first LED lighting load and the second electrical power level transmitted to the second LED lighting load are designed to be increased or decreased with the same pace such that the ratio of the first electrical power level to the second electrical power level is maintained at a constant level to perform the dimming control mode. 86. A lighting apparatus comprising: a first LED lighting load for emitting light with a first color temperature; a second LED lighting load for emitting light with a second color temperature; a diffuser, covering the first LED lighting load and the second LED lighting load to create a diffused light with a mingled color temperature; and a microcontroller based electronic switch electrically connected to the first LED lighting load and the second LED lighting load, comprising: a first controllable switching element, electrically connected between the first LED lighting load and a power source; a second controllable switching element, electrically connected between the second LED lighting load and the power source; a detection device, for detecting and converting an external control signal into a message carrying sensing signal; a wireless signal transmitter, for transmitting a coded wireless control signal converted from said message carrying sensing signal; and a microcontroller to receive and interpret said message carrying sensing signal generated by said detection device, wherein said microcontroller is electrically connected between the first controllable switching element and said detection device, said microcontroller is also electrically connected between said second controllable switching element and said detection device, said microcontroller is also electrically coupled to said wireless signal transmitter for controlling a lighting performance of at least a second lighting apparatus located in a different location; wherein said microcontroller controls a conduction state, a cutoff state or conduction rates of said first controllable switching element and said second controllable switching element to control electric power transmissions from the power source respectively to said first LED lighting load and said second LED lighting load according to said message carrying sensing signal generated by said detection device; wherein the first color temperature is higher than the second color temperature; wherein the detection device is a wireless remote control device electrically coupled to a pin of said microcontroller to receive and convert a wireless external control signal into said message carrying sensing with a signal format interpretable to said microcontroller, wherein the signal format of said message carrying sensing signal is a voltage signal with a short time length, a voltage signal with a long time length or a plurality of voltage signals generated in a preset time interval; wherein the short voltage signal and the long voltage signal are respectively defined either by a time length of a voltage signal or by the time length of a voltage signal comprising a series of pulse signals consecutively generated; wherein when said microcontroller receives said message carrying sensing signal, said microcontroller manages to activate a corresponding process according to the signal format of said message carrying sensing signal to perform at least one of various working modes including at least an on/off switch control mode, a dimming control mode for selecting light intensity, a color temperature tuning mode for selecting light color, a color temperature switching mode and a delay timer control mode for managing delay shutoff before switching off the light. 87. The lighting apparatus according to claim 86, wherein the wireless remote control device is a Wi-Fi wireless control signal receiver, a Bluetooth wireless control signal receiver or a RF (radio frequency) wireless control signal receiver. 88. The lighting apparatus according to claim 86 wherein the lighting apparatus is configured as a commanding lamp in a lighting family comprising a plurality of member lamps installed in different locations in a living space for providing illumination; wherein the commanding lamp is designed with a capacity to control lighting performances of all member lamps respectively or collectively, wherein the commanding lamp is the only lamp installed with both said wireless control signal receiver and said wireless signal transmitter in the lighting family of member lamps, wherein the commanding lamp receives the wireless external control signal and converts the wireless external control signal into said message carrying sensing signal interpretable to said microcontroller to control lighting performances of the commanding lamp or any of other member lamps, wherein for controlling any of other member lamps, said microcontroller manages to convert said message carrying sensing signal into a coded wireless control signal for transmitting to the member lamp, wherein upon receiving said coded wireless control signal the wireless control signal receiver of the member lamp manages to convert said coded wireless control signal into a message carrying sensing signal interpretable to the microcontroller of the member lamp for controlling lighting performance of the member lamp. 89. The lighting apparatus according to claim 86, wherein the wireless signal transmitter is a Wi-Fi wireless signal transmitter, a Bluetooth wireless signal transmitter, a Zigbee wireless signal transmitter or a radio frequency wireless signal transmitter. 90. The lighting apparatus according to claim 86, wherein said microcontroller comprises a memory for saving or installing an application program (APP) or a software program, wherein the application program (APP) from an internet or a cloud server is downloaded for updating the memory of said microcontroller. 91. A lighting apparatus comprising; a first LED lighting load for emitting light with a first color temperature; a second LED lighting load for emitting light with a second color temperature; a diffuser, covering the first lighting load and the second lighting load to create a diffused light with a mingled color temperature; and a microcontroller based electronic switch electrically connected to the first LED lighting load and the second LED lighting load, comprising: a first controllable switching element, electrically connected between the first LED lighting load and a power source; a second controllable switching element, electrically connected between the second LED lighting load and the power source; a detection device, for detecting an external control signal and converting said external control signal into a message carrying sensing signal; and a microcontroller to receive and interpret the message carrying sensing signal generated by said detection device, wherein said microcontroller is electrically connected between said first controllable switching element and said detection device, said microcontroller is electrically connected between said second controllable switching element and said detection device, said microcontroller controls a conduction state, a cutoff state or conduction rates of said first controllable switching element and said second controllable switching element to control electric power transmissions from the power source respectively to said first LED lighting load with the first color temperature and said second LED lighting load with the second color temperature according to said message carrying sensing signal generated by said detection device; wherein the first color temperature is higher than the second color temperature; wherein said detection device is a power interruption detection circuit electrically coupled with said microcontroller to detect a signal of a short power interruption and convert said short power interruption signal into said message carrying sensing signal interpretable to said microcontroller, wherein when said microcontroller receives said message carrying sensing signal, said microcontroller operates to change the conduction rates of said first controllable switching element and said second controllable switching element according to combinations of conduction rates between said first controllable switching element and said second controllable switching element to alternately perform a different mingled color temperature, wherein the total conduction rate of said first controllable switching element and said second controllable switching element is operated at a constant level. 92. The lighting apparatus according to claim 91, wherein the combinations of conduction rates between said first controllable switching element and said second controllable comprises at least a first combination and a second combination, wherein the first combination is with an arrangement that said first controllable switching element is in a full conduction state while said second controllable switching element is in a complete cutoff state, wherein the second combination is with an arrangement that said first controllable switching element is in the complete cutoff state while said second controllable switching element is in the full conduction state, the lighting apparatus thereby alternatively performs between a first color temperature illumination and a second color temperature illumination according to said message carrying sensing signal received by said microcontroller. 93. A microcontroller based electronic switch for controlling a lighting performance of an LED lamp configured with a plurality of LED lighting loads comprising a first controllable switching element, electrically connectable between a first LED lighting load for emitting light with a first color temperature and a power source; a second controllable switching element, electrically connectable between a second LED lighting load for emitting light with a second color temperature and the power source; a first detection device for detecting a first external control signal and converting said first external control signal into a first message carrying sensing signal; a second detection device for detecting a second external control signal and converting said second external control signal into a second message carrying sensing signal; and a microcontroller through a first control pin receives said first message carrying sensing signal generated by said first detection device, said microcontroller through a second control pin receives said second message carrying sensing signal generated by said second detection device, wherein said microcontroller through a third control pin is electrically coupled to said first controllable switching element, wherein said microcontroller through a fourth control pin is electrically coupled to said second controllable switching element; wherein the first color temperature is higher than the second color temperature; wherein said first detection device and said second detection device are direct touch interface; wherein when said first controllable switching element and said second controllable switching element are in the conduction state, said microcontroller further controls electric power transmission levels from the power source respectively to said first LED lighting load and to said second LED lighting load according to said first message carrying sensing signal or said second message carrying sensing signal received, wherein said microcontroller through said third control pin outputs a first control signal to control conduction rate of said first controllable switching element, said microcontroller through said fourth control pin outputs a second control signal to control conduction rate of said second controllable switching element; wherein said first message carrying sensing signal and said second message carrying sensing signal are characterized with a signal format with a time length, wherein the time length of the signal format is defined either by the time duration of a voltage signal or by the time duration of a series of pulse signals consecutively generated; wherein when said microcontroller receives said first message carrying sensing signal, said microcontroller manages to activate a first process to control a lighting characteristic of light intensity or color temperature of the LED lamp through a light diffuser according to the time length of said first message carrying sensing signal, wherein when said microcontroller receives said second message carrying sensing signal, said microcontroller manages to activate a second process to reversely control the lighting characteristic of the LED lamp through the light diffuser according to the time length of said second message carrying sensing signal, wherein the first process and the second process are designed to operate a reverse function to each other for adjusting the lighting characteristic of the LED lamp; wherein said microcontroller is an integrated circuit programmable for generating said first control signal and said second control signal, or an application specific integrated circuit (ASIC) custom made for generating said first control signal and said second control signal. 94. The microcontroller based electronic switch according to claim 93, wherein the lighting characteristic is the light intensity, wherein when said first detection device and said second detection device are used for controlling the light intensity of the LED lamp, the first process operates to increase and set a light intensity of the LED lamp by proportionately increasing the conduction rates of said first controllable switching element and said second controllable switching element according to the time length of said first message carrying sensing signal, wherein the second process operates to decrease and set the light intensity of the LED lamp by proportionately decreasing the conduction rates of said first controllable switching element and said second controllable switching element according to the time length of said second message carrying sensing signal. 95. The microcontroller based electronic switch according to claim 93, wherein the lighting characteristic is the light color temperature, wherein when said first detection device and said second detection device are used for tuning the light color temperature of the LED lamp, the first process operates to decrease conduction rate of said first controllable switching element and at the same time to increase conduction rate of said second controllable switching element with an arrangement that the total of electric powers transmitted to said first LED lighting load and said second LED lighting load is maintained at a constant level for decreasing and setting the color temperature of the LED lamp according to the time length of said first message carrying sensing signal, wherein the second process operates to increase conduction rate of said first controllable switching element and at the same time to decrease conduction rate of said second controllable switching element with the arrangement that the total of electric powers transmitted to said first LED lighting load and said second LED lighting load is maintained at the constant level for increasing and setting the color temperature of the LED lamp. 96. The microcontroller based electronic switch according to claim 93, wherein said first detection device and said second detection device are integrated into a seesaw device, wherein one end of the seesaw device performs the function of said first detection device while the other end of the seesaw device performs the function of said second detection device for adjusting and setting the lighting characteristic of either the light intensity or the light color temperature. 97. The microcontroller based electronic switch according to claim 93, wherein a third detection device is furthered installed and coupled to a control pin of the microcontroller for controlling an on/off performance of the LED lamp, wherein the third detection device is a direct touch interface electrically coupled to said microcontroller for detecting a third external control signal and converting said third external control signal into a third message carrying sensing signal with a signal format of a short voltage signal, wherein when said microcontroller receives said third message carrying sensing signal, said microcontroller operate to alternatively turn on or tun off the LED lamp. 98. The microcontroller based electronic switch according to claim 93, wherein a power switch is further installed to turn on or turn off the LED lamp.
CROSS-REFERENCE TO RELATED APPLICATIONS This Application is a continuation application of prior application Ser. No. 15/292,395 filed on Oct. 13, 2016, currently pending. The application Ser. No. 15/292,395 is a continuation application of prior application Ser. No. 15/095,540 filed on Apr. 11, 2016, now U.S. Pat. No. 9,497,834. The application Ser. No. 15/095,540 is a continuation application of prior application Ser. No. 14/579,248 filed on Dec. 22, 2014, now U.S. Pat. No. 9,345,112 B2. The U.S. Pat. No. 9,345,112 B2 is a continuation-in-part of Non-provisional application Ser. No. 13/792,002 filed on Mar. 9, 2013, now U.S. Pat. No. 8,947,000 B2. BACKGROUND 1. Technical Field The present disclosure relates to a technology using a microcontroller with program codes designed to provide a user friendly solution for performing on/off switch control, diming control, and timer management for a lighting apparatus or an electrical appliance. 2. Description of Related Art A mechanical-type electric switch is a manually operated electromechanical device. Its function is based on attaching or detaching two metal conductors to produce a short or open circuit, respectively. This mechanical-type switch is not suitable for installing in a space where has the concern of gas explosion, because an instantaneous surge current, produced by suddenly engaging or releasing the metallic contact of the switch, may generate electric sparks to ignite fire. A controllable semiconductor switching element, such as a triac, has nearly zero voltage between two output-electrodes in conduction mode and nearly zero current through two output-electrodes in cut-off mode. Solid state electronic switch utilizing the above unique features of triac for circuit on/off switch control can avoid generating electric arc, since the main current pathway of the solid-state switch is not formed by engaging the two metal conductors. It becomes a much better choice than mechanical-type electric switch from the stand point of safety consideration. Solid-state electronic switches are constructed with various methods to trigger controllable switching element, like triac or thyristor, into conduction or cutoff for desired electric power transmission. For example, U.S. Pat. No. 4,322,637 disclosed a technique using optical coupling element to control bi-directional thyristor or triac in conduction or off state; or another U.S. Pat. No. 6,285,140B1 disclosed a technique using microcontroller incorporated with zero-crossing-point detector to generate AC-synchronized time-delay pulse to control triac in on or cut-off state so as to transmit variable electric power to a light-emitting diode load. Mostly a mechanical toggle or spring button of similar setup is usually applied on the electronic switch to facilitate manual on/off switch operation. The operation of electronic switch with mechanical toggle means an inevitable contact by hand which is not appropriate in working places such as kitchens or hospitals. To relieve concerns of contagion or contamination resulted through hand contacts, touchless switches are developed. For example, U.S. Pat. No. 5,637,863 disclosed a technique utilized infrared sensor to activate electronic switch to operate on/off switch control, and even dimming control presumably by modifying its circuit design. In retrospect, the above mentioned prior arts have however still some drawbacks. For instance, U.S. Pat. No. 5,637,863 used a complicated infrared sensor construction and circuit design; or U.S. Pat. No. 6,285,140B1 did not resort to an efficient control of electric power transmission from power source to various electric impedances which is required in lighting apparatus. SUMMARY An exemplary embodiment of the present disclosure provides a microcontroller based electronic switch for detecting an external motion signal. The microcontroller based electronic switch comprises a first controllable switching element, a second controllable switching element, a detection device and a microcontroller. The first controllable switching element is electrically connected between a power source and a first lighting load for emitting light with a first color temperature. The second controllable switching element is electrically connected between the power source and a second lighting load for emitting light with a second color temperature. The detection device is for detecting an external motion signal played by a user and converting said external motion signal into a message carrying sensing signal. The microcontroller with program codes is written and designed to read and interpret the message carrying sensing signal generated by said detection device, wherein said microcontroller is electrically connected between said first controllable switching element and said detection device, said microcontroller is electrically connected between said second controllable switching element and said detection device. Said microcontroller controls a conduction state or cutoff state of said first controllable switching element and said second controllable switching element according to said message carrying sensing signal generated by said detection device. When the first controllable switching element and the second controllable switching element are in the conduction state, said microcontroller further controls electric power transmission levels from the power source to the first lighting load and the second lighting load according to specific format of said message carrying sensing signal received from said detection device. In one exemplary embodiment, the detection device is an infrared ray sensor comprising a means for emitting infrared light to form a defined infrared ray detecting zone and a means for detecting infrared light reflected from an object moving into said infrared ray detecting zone. A circuitry responsively generates a message carrying sensing signal having a first voltage with a time length corresponding to the time interval the object entering and staying in said infrared ray detecting zone. When the object leaves the infrared ray detecting zone, the infrared ray sensor delivers a second voltage signal. In one exemplary embodiment, the detection device is an electrostatic induction sensor comprising a copper sheet sensing unit with adequately designed shape and size to form an electrostatic detecting zone. A circuitry responsively generates a message carrying sensing signal having a first voltage with a time length corresponding to the time interval an inductive object enters and stays in said electrostatic detecting zone. When said object leaves said electrostatic detecting zone, said electrostatic sensor delivers a second voltage signal. In one exemplary embodiment, the detection device is a direct touch interface (such as a push button or a touch sensor) connecting with a pin of the microcontroller. When the user contacts the direct touch interface (for example, presses the push button) for a time interval, a first voltage signal is detected by the microcontroller which is a message carrying sensing signal having the first voltage with a time length corresponding to the time interval the touch interface being contacted. When the user leaves the direct touch interface (for example, releases the button), the direct touch interface delivers a second voltage signal. An exemplary embodiment of the present disclosure provides a lighting apparatus comprising a first lighting load, a second lighting load, a diffuser and a microcontroller based electronic switch. The first lighting load is for emitting light with a first color temperature. The second lighting load is for emitting light with a second color temperature. The diffuser covers the first lighting load and the second lighting load. The microcontroller based electronic switch comprises a first controllable switching element, a second controllable switching element, a detection device and a microcontroller. The first controllable switching element is electrically connected between the first lighting load and a power source. The second controllable switching element is electrically connected between the second lighting load and the power source. The detection device is for detecting an external motion signal played by a user and converting said external motion signal into a message carrying sensing signal. The microcontroller with program codes is written and designed to read and interpret the message carrying sensing signal generated by said detection device, wherein said microcontroller is electrically connected between said first controllable switching element and said detection device, said microcontroller is electrically connected between said second controllable switching element and said detection device. Said microcontroller controls a conduction state or cutoff state of said first controllable switching element and said second controllable switching element according to said message carrying sensing signal generated by said detection device. When the first controllable switching element and second controllable switching element are in the conduction state, said microcontroller further controls electric power transmission levels from the power source to the first lighting load and the second lighting load according to specific format of said message carrying sensing signal received from said detection device. With the microcontroller based electronic switch to control the lighting power levels, the color temperature of the diffused light (also called the blended or mingled light) of the first lighting load and the second lighting load can be controlled. In one exemplary embodiment, the detection device is an infrared ray sensor comprising a means for emitting infrared light to form a defined infrared ray detecting zone and a means for detecting infrared light reflected from an object moving into said infrared ray detecting zone. A circuitry responsively generates a message carrying sensing signal having a first voltage with a time length corresponding to the time interval the object entering and staying in said infrared ray detecting zone. When the object leaves the infrared ray detecting zone, the infrared ray sensor delivers a second voltage signal. In one exemplary embodiment, the detection device is an electrostatic induction sensor comprising a copper sheet sensing unit with adequately designed shape and size to form an electrostatic detecting zone. A circuitry responsively generates a message carrying sensing signal having a first voltage with a time length corresponding to the time interval an inductive object enters and stays in said electrostatic detecting zone. When said object leaves said electrostatic detecting zone, said electrostatic sensor delivers a second voltage signal. In one exemplary embodiment, the detection device is a direct touch interface (such as a push button or a touch sensor) connecting with a pin of the microcontroller. When the user contacts the direct touch interface (for example, presses the push button) for a time interval, a first voltage signal is detected by the microcontroller which is a message carrying sensing signal having the first voltage with a time length corresponding to the time interval the touch interface being contacted. When the user leaves the direct touch interface (for example, releases the button), the direct touch interface delivers a second voltage signal. To sum up, the present disclosure is characteristic in, a contactless interface between the user and the multifunctional electronic switch is created to implement at least two operation modes of the electronic switch by using software codes written in OTPROM (one-time programmable read only memory) of microcontroller to analyze the message carrying sensing signals. In order to further understand the techniques, means and effects of the present disclosure, the following detailed descriptions and appended drawings are hereby referred, such that, through which, the purposes, features and aspects of the present disclosure can be thoroughly and concretely appreciated; however, the appended drawings are merely provided for reference and illustration, without any intention to be used for limiting the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings are included to provide a further understanding of the present disclosure, and are incorporated in and constitute a part of this specification. The drawings illustrate exemplary embodiments of the present disclosure and, together with the description, serve to explain the principles of the present disclosure. FIG. 1 is a block diagram of a microcontroller based electronic switch using an infrared ray sensor as a detection device applied for two AC lighting loads with different color temperatures powered by an AC power source according to an exemplary embodiment of the present disclosure. FIG. 2 is a circuit diagram of a microcontroller based electronic switch using an infrared ray sensor applied for two AC lighting loads with different color temperatures powered by an AC power source according to an exemplary embodiment of the present disclosure. FIG. 3A is a schematic diagram showing a practical operation of an infrared ray sensor associated with a microcontroller based electronic switch according to an exemplary embodiment of the present disclosure. FIG. 3B is a waveform diagram showing a low voltage sensing signal according to an exemplary embodiment of the present disclosure. FIG. 4 is a flow chart of a program executed in a microcontroller based electronic switch according to an exemplary embodiment of the present disclosure. FIG. 5 is a voltage waveform diagram of a microcontroller based electronic switch when the electronic switch operating in the on/off switch control mode is in cut-off state according to an exemplary embodiment of the present disclosure. FIG. 6 is a voltage waveform diagram of a microcontroller based electronic switch when the electronic switch operating in the on/off switch control mode is in conduction state according to an exemplary embodiment of the present disclosure. FIG. 7 is a voltage waveform diagram of a microcontroller based electronic switch operating in the dimming control mode according to an exemplary embodiment of the present disclosure. FIG. 8A is a block diagram of a microcontroller based electronic switch for a DC power source according to an exemplary embodiment of the present disclosure. FIG. 8B is a voltage waveform diagram of the pulse width modulation voltage signals associated with FIG. 8A according to an exemplary embodiment of the present disclosure. FIG. 9A is an application diagram of an exemplary embodiment of the present disclosure for a lighting apparatus. FIG. 9B is an application diagram of an exemplary embodiment of the present disclosure for a lighting apparatus. FIG. 10A is an application diagram of a traditional popular piece of under cabinet light with LED as light source. FIG. 10B is an application diagram of an exemplary embodiment of the present disclosure for a LED under cabinet light featured with a touch-less interface between the user and the under cabinet light. FIG. 10C is an application diagram of an exemplary embodiment of the present disclosure for a wall switch construction electrically connected to a ceiling light for the performance of three working modes. FIG. 10D is another application diagram of an exemplary embodiment of the present disclosure for a lighting apparatus with a diffuser of hollow body accommodating the lighting loads and the microcontroller based electronic switch. FIG. 10E is another application diagram of an exemplary embodiment of the present disclosure for a lighting apparatus with a diffuser of hollow body accommodating the lighting loads and the microcontroller based electronic switch. FIG. 11A is another application diagram of an exemplary embodiment of the present disclosure for the direction of motion path detected by an infrared ray sensor. FIG. 11B is another application diagram of an exemplary embodiment of the present disclosure for the direction of motion path detected by an infrared ray sensor. FIG. 11C is another application diagram of an exemplary embodiment of the present disclosure for the direction of motion path detected by an infrared ray sensor. FIG. 11D is another application diagram of an exemplary embodiment of the present disclosure for the direction of motion path detected by an infrared ray sensor. DESCRIPTION OF THE EXEMPLARY EMBODIMENTS Reference will now be made in detail to the exemplary embodiments of the present disclosure, examples of which are illustrated in the accompanying drawings. Wherever possible, the same reference numbers are used in the drawings and the description to refer to the same or like parts. Referring to FIG. 1, FIG. 1 is a block diagram of a microcontroller based electronic switch using an infrared ray sensor as a detection device applied for two AC lighting loads with different color temperatures powered by an AC power source according to an exemplary embodiment of the present disclosure. A microcontroller based electronic switch 1 is connected in series to an AC power source 3, and is further connected to a first lighting load 2a (also indicated by “load a” shown in FIG. 1) and a second lighting load 2b (also indicated by “load b” shown in FIG. 1), so as to control AC power delivered to the first lighting load 2a and the second lighting load 2b. The microcontroller based electronic switch 1 comprises at least an infrared ray sensor 11, a microcontroller 12, a zero-crossing-point detector 13, and two bi-directional controllable semiconductor switching elements 14a, 14b. The bi-directional controllable semiconductor switching element 14a is a first controllable switching element. The bi-directional controllable semiconductor switching element 14b is a second controllable switching element. The infrared ray sensor 11 is connected to one pin of microcontroller 12 to transmit a low voltage sensing signal to the microcontroller 12, wherein the low voltage sensing signal represents a message carrying sensing signal of the infrared ray sensor 11. The zero-crossing-point detector 13 is connected to another pin of microcontroller 12 and is also electrically coupled to the AC power source 3 to produce AC power synchronized signals which are fed to the microcontroller 12. The microcontroller 12 through its one designated pin is electrically connected to the control electrode of the bi-directional controllable semiconductor switching element 14a so as using appropriate conduction phase (characterized by tD_a) to control the electrical conduction state of the bi-directional controllable semiconductor switching element 14a. Also, the microcontroller 12 through its another one designated pin is electrically connected to the control electrode of the bi-directional controllable semiconductor switching element 14b so as using appropriate conduction phase (characterized by tD_b) to control the electrical conduction state of the bi-directional controllable semiconductor switching element 14b. The first lighting load 2a is for emitting light with low color temperature (first color temperature), and the second lighting load 2b is for emitting light with high color temperature (second color temperature). When the bi-directional controllable semiconductor switching elements 14a, 14b are in the conduction state, said microcontroller 12 further controls electric power transmission levels from the AC power source 3 to the first lighting load 2a and the second lighting load 2b according to the signal format of the message carrying sensing signal received from the infrared ray sensor 11. In this embodiment, the electric power transmission level for the first lighting load 2a can range from X-watt to Y-watt, and the electric power transmission level for the second lighting load 2b can range from Y-watt to X-watt, wherein X+Y is a constant value, but the present disclosure is not so restricted. An apparent color temperature generated by blending the lights emitted from the two lighting loads 2a,2b may be controlled by the power levels X and Y according to CTapp=CT2a·X/(X+Y)+CT2b·Y/(X+Y), where CTapp is said apparent color temperature, CT2a and CT2b are respectively the color temperatures of the first and the second lighting load 2a, 2b. For example, X-watt can be three watts and Y-watt can be nine watts, such that the power of the first lighting load 2a ranges from three watts to nine watts, and the power of the second lighting load 2b ranges from nine watts to three watts, wherein the total power of the first lighting load 2a and the second lighting load 2b can be fixed to twelve watts. When the color temperatures of the first lighting load 2a and the second lighting load 2b are respectively 3000K (CT2a) and 5700K (CT2b), the apparent color temperature (CTapp) of the blended or diffused light of the first lighting load 2a and the second lighting load 2b can range nearly from 3700K (nine watts of the first lighting load 2a and three watts of the second lighting load 2b) to 5000K (three watts of the first lighting load 2a and nine watts of the second lighting load 2b) depending on the electric power transmission levels fed to the first lighting load 2a and the second lighting load 2b controlled by the microcontroller 12. In another example, X-watt can be zero watts and Y-watt can be twelve watts, such that the power of the first lighting load 2a ranges from zero watts to twelve watts, and the power of the second lighting load 2b ranges from twelve watts to zero watts, wherein X+Y watt can be fixed to twelve watts. When the color temperatures of the first lighting load 2a and the second lighting load 2b are respectively 3000K and 5700K, the apparent color temperature of the diffused light of the first lighting load 2a and the second lighting load 2b can range from 3000K (twelve watts of the first lighting load 2a and no power of the second lighting load 2b) to 5700K (twelve watts of the second lighting load 2b and no power of the first lighting load 2a) depending on the electric power transmission levels fed to the first lighting load 2a and the second lighting load 2b. Thus, a desired color temperature may be generated by controlling the power levels of the first lighting load 2a and the second lighting load 2b to create proper color blending effect under a fixed total lighting power level with this type of microcontroller based electronic switch. In still another embodiment, the electric power transmission level for the first lighting load 2a can range from X-watt to Y-watt, and the electric power transmission level for the second lighting load 2b can range from Z-watt to W-watt, wherein X, Y, Z and W can be referred to different power levels. However, the present disclosure does not restrict the variation ranges of the power levels of the two loads 2a, 2b. The infrared ray sensor 11 detects object motions coming from the user and converts the detected result into message carrying low voltage sensing signals readable to the microcontroller 12. The microcontroller 12 decodes the low voltage sensing signals (message carrying low voltage sensing signals) according to the program designed and written in its OTPROM (one-time programmable read only memory) memory. The microcontroller 12 is with program codes written and designed to read and interpret the message carrying sensing signal generated by the infrared ray sensor 11. The infrared ray sensor 11 is an exemplary embodiment for a detection device to detect the external motion signal played by the user and convert the external motion signal into a message carrying sensing signal. The microcontroller 12 recognizes the working mode that the user has chosen and proceeds to execute the corresponding loop of subroutine for performing the selected working mode. In view of implementing versatile controls of color temperature and illumination level of a lighting apparatus, at least two working modes are provided and defined in the software codes with corresponding loops of subroutine for execution. One working mode is on/off switch control mode. In this working mode, according to the low voltage sensing signal from the infrared ray sensor 11, the microcontroller 12 operates the bi-directional controllable semiconductor switching element 14 in conduction state or cut-off state alternatively. More specifically, in this working mode, together with the zero-crossing-point detector 13, the microcontroller 12 generates phase delay voltage pulses synchronized with the AC power source 3 in each AC-half cycle to trigger the bi-directional controllable semiconductor switching elements 14a, 14b to be in proper conduction states to respectively transmit X-watt and Y-watt electric power to the first lighting load 2a and the second lighting load 2b, such that a fixed amount of total electric power (X+Y watts) is sent to the two lighting loads 2a, 2b; or the microcontroller 12 generates a zero voltage to set the bi-directional controllable semiconductor switching elements 14a, 14b to be in cut-off state, and thereby ceases to transmit the fixed electric power to the two lighting loads 2a, 2b. Another working mode is switching between low color temperature and high color temperature. When the first switching element is in a full conduction state and the second switching element is in a full cutoff state, the light consequently demonstrates the low color temperature of illumination characteristic. When the first switching element is in the full cutoff state and the second switching element is in the full conduction state, the lighting apparatus consequently demonstrates the high color temperature of illumination characteristic. Still another working mode is color temperature tuning mode about controlling different levels of electric power transmission to the two lighting loads 2a, 2b by controlling the conduction rate of the bi-directional controllable semiconductor switching elements 14a and 14b. Using the synchronized signals produced by the zero-crossing-point detector 13 as a reference, the microcontroller 12 generates phase delay voltage pulses synchronized with the AC power source 3 in each AC half-cycle to trigger the conduction of the bi-directional controllable semiconductor switching elements 14 to respectively transmit X-watt and Y-watt electric power to the first lighting load 2a and the second lighting load 2b. Responding to the low voltage sensing signals of specific format from the infrared ray sensor 11, the microcontroller 12 execute the corresponding loop of subroutine for performing the color temperature tuning mode, such that the phase delays of the triggering pulses are continuously changed during each half cycle period of the AC power source 3, to render the conduction rate of the bi-directional controllable semiconductor switching elements 14a gradually increasing and, at the same time, the conduction rate of the bi-directional controllable semiconductor switching elements 14b gradually decreasing, or vice versa. Consequently, the power level X of the lighting loads 2a is gradually increasing and the power level Y of the lighting loads 2b is gradually decreasing, or vice versa. The color temperature of the blended or diffused light of the two lighting load 2a, 2b may thus be adjusted in the color temperature tuning mode through controlling the conduction rate of the switching elements 14a, 14b to change the power levels of the two lighting loads 2a, 2b. At the end of the color temperature tuning mode, a desired apparent color temperature diffused from the two lighting loads 2a, 2b can be set and managed by the message carrying sensing signal from the infrared ray sensor 11 which is generated according to the user's intention. For the color temperature tuning mode, additional sub-modes can be performed in detail. When the detection device generates the first voltage sensing signal, said microcontroller manages to output the control signal to the first controllable switching element and the second controllable switching element to alternately perform one of programmed combinations of conduction states between the first controllable switching element and the second controllable switching element, wherein the combinations include at least three combination modes; wherein the first combination mode is where the first controllable switching element is in a complete conduction state while the second controllable switching element is in a cutoff state with the lighting apparatus performing the low color temperature, wherein the second combination mode is where the first controllable switching element is in a cutoff state while the second controllable switching element is in a complete conduction state with the lighting apparatus performing the high color temperature, wherein the third combination mode is where both the first controllable switching element and the second controllable switching element are in cutoff state with the lighting apparatus being turned off. Referring to FIG. 1 and FIG. 2, FIG. 2 is a circuit diagram of a microcontroller based electronic switch applied for an AC power source according to an exemplary embodiment of the present disclosure. As FIG. 2 shows, the microcontroller based electronic switch 1 comprises an infrared ray sensor 11, a microcontroller 12, a zero-crossing-point detector 13, and two bi-directional controllable semiconductor switching elements 14a, 14b. The microcontroller based electronic switch 1 is connected respectively through the bi-directional controllable semiconductor switching elements 14a, 14b with the first lighting load 2a and the second lighting load 2b, both have different color temperatures, and then connected to the AC power source 3 in a serial fashion. A DC voltage VDD for the circuit system is derived by conventional voltage reduction and rectification from the AC power 3. The infrared ray sensor 11 is composed of a transmitting circuit 110 and a receiving circuit 112, wherein the message carrying sensing signal is sent out by a transistor stage M2. The drain of the transistor M2 is connected to a pin pin_3 of the microcontroller 12 to deliver the message carrying sensing signals to the microcontroller 12. The zero-crossing-point detector 13 is composed of a transistor Q1 and a diode D3. The collector of the transistor Q1 is connected to a pin pin_10 of the microcontroller 12, the base of the transistor Q1 is connected to a conducting wire of the AC power source 3 through the diode D3 and a resistor R3. In the positive half-cycle for AC power source 3, the transistor Q1 is saturated conducting, and the voltage at the collector of the transistor Q1 is close to zero. In the negative half-cycle for AC power source 3, the transistor Q1 is cut-off, and the voltage at the collector of the transistor Q1 is a high voltage of VDD. Corresponding to the sine wave of the AC power source 3, the zero-crossing-point detector 13 generates therefore signals of square wave alternatively with a low voltage and a high voltage through the collector of the transistor Q1. The square wave is synchronized with the AC power source 3 and sent to a pin pin_10 of the microcontroller 12 for the purpose of controlling conduction phase, and the details thereof are described later. In practice, the bi-directional controllable semiconductor switching element 14a can be a triac T1a, the pin pin_1 of the microcontroller 12 is connected to the gate of the triac T1a to control the conduction or cut-off state of the triac T1a, or to control the conduction rate of the triac T1a. Also, the bi-directional controllable semiconductor switching element 14b can be a triac T1b, the pin pin_2 of the microcontroller 12 is connected to the gate of the triac T1b to control the conduction or cut-off state of the triac T1b, or to control the conduction rate of the triac T1b. Thus, the first lighting load 2a and the second lighting load 2b are respectively driven by triac T1a and triac T1b with phase delay pulses characterized by time delays tD_a and tD_b with respect to the zero crossing point of AC power voltage in each AC half-cycle to respectively display X-watt (or Y-watt) lighting from the first lighting load 2a and Y-watt (or X-watt) power lighting from the second lighting load 2b controlled by infrared ray sensor 11. Thus, the color temperature of the diffused light of the two lighting load 2a, 2b may be adjusted by properly selecting tD_a and tD_b, such that the summation of tD_a and tD_b is a constant, and the total lighting power of the first lighting load 2a (X) and the second lighting load 2b (Y), X+Y, is a fixed value. Still referring to FIG. 2, the infrared ray sensor 11 comprises a transmitting circuit and a receiving circuit. In the transmitting circuit, an infrared light-emitting diode IR_LED is connected to the drain of the transistor M1 in a serial fashion, and the gate of the transistor M1 is connected to an output of the timer 110. In practice, the timer 110 can be a 555 timer IC. The 555 timer IC generates a square-wave with a frequency of about 3 kHz to modulate the drain current of the transistor M1, such that the infrared light-emitting diode IR_LED provides an infrared light signal with a square wave form which is severed as the light source of the infrared ray sensor. The receiving circuit is an infrared light detection circuit and comprises a photosensitive diode PD, two serially connected amplifiers 112, 114, and a transistor M2. The drain of the transistor M2 is connected to a pin pin_3 of the microcontroller 12. In practice, the amplifiers 112 and 114 can be LM324 operational amplifier. The combination of the amplifier 114 and resistors R7 through R10 is a Schmitt trigger circuit having a threshold voltage, and the threshold voltage is produced by the voltage divider composed by resistors R8 and R9. The Schmitt trigger circuit makes possible a high discrimination of a true detection to a false one. The photosensitive diode PD is used to receive the infrared light signal from the transmitting circuit. If the output voltage of the amplifier 112 exceeds the threshold voltage, the amplifier 114 produces a high voltage applied to the gate of the transistor M2, such that the transistor M2 is turned on. Therefore, the drain of the transistor M2 provides a low voltage sensing signal which is close to zero voltage, and the time length of the low voltage sensing signal is related to the time period the infrared ray is detected. In addition, if the photosensitive diode PD does not receive the infrared light signal, the output voltage of the amplifier 112 is lower than the threshold voltage, and then the amplifier 114 provides a low voltage to the gate of the transistor M2, such that the transistor M2 is turned off. Therefore, the drain of the transistor M2 provides a high voltage of VDD. In other words, the pin pin_3 of the microcontroller 12 receives either a low voltage sensing signal or a high voltage depending on whether the infrared ray sensor 11 detects the infrared light or not, wherein the time length of the low voltage sensing signal is about the time period within which the infrared light is detected. In other words, the infrared ray sensor 11 generates a sensing signal which is characterized by a low voltage within a time length. The sensing signal with a specific time length of low voltage can be considered as a sensing signal format which carries message to make the microcontroller 12 to operate in one of at least two working modes accordingly, wherein one working mode is on/off switch control mode and the another one is color temperature tuning mode to control the conduction rate of the bi-directional controllable semiconductor switching elements 14a and 14b. Further, still another mode is dimming control mode. The color temperature tuning mode can give a color temperature tuning cycle to change the color temperature of the blended light, wherein the total power of the blended light is unchanged (X+Y watts is unchanged during the cycle). The dimming control mode provides dimming cycles to set the total power of the blended light (X+Y watts is changed during the cycle), wherein the color temperature of the blended light is unchanged during the dimming cycle. Referring to FIG. 2, FIG. 3A and FIG. 3B, FIG. 3A is a schematic diagram showing a practical operation of an infrared ray sensor associated with a microcontroller based electronic switch according to an exemplary embodiment of the present disclosure, and FIG. 3B is a waveform diagram showing a low voltage sensing signal according to an exemplary embodiment of the present disclosure. In FIG. 3A, the infrared light-emitting diode IR_LED is parallel arranged to the photosensitive diode PD without accurate alignment. When an object, here is a human hand, moves in front of the infrared light-emitting diode IR_LED, the infrared light emitted from the infrared light-emitting diode IR_LED scatters from the object surface onto the photo sensing surface of the photosensitive diode PD. FIG. 3B shows a waveform of the low voltage sensing signal provided from the infrared ray sensor 11. If the photosensitive diode PD does not receive the infrared light scattered from the target object surface, or the intensity of the infrared light received by the photosensitive diode PD is insufficient, the drain of the transistor M2 provides a high voltage H of VDD. Within an appropriate distance, the photosensitive diode PD receives the infrared light scattered from the object surface, and the intensity of the received infrared light is enough to cause the output voltage of the amplifier 112 exceeding the threshold voltage, the amplifier 114 produces a high voltage, such that the transistor M2 is turned on, and the drain of the transistor M2 provides a signal with a low voltage L of about zero volt. In other words, when the infrared ray sensor 11 detects an object, most commonly user's hand, purposefully entering the infrared ray detecting zone, the infrared ray sensor 11 generates a low voltage sensing signal, by contrast when an object is not within the infrared ray detecting zone, the infrared ray sensor 11 generates a high voltage. In brief, the infrared ray sensor 11 comprises a means for emitting infrared light to form the defined infrared ray detecting zone, and a means for detecting infrared light reflected from the object moving into the infrared ray detecting zone. The appropriate distance or the infrared ray detecting zone is defined as an effective sensing range or area of the infrared ray sensor 11. In FIG. 3B, the time length Ts of the low voltage L is approximately equal to the time period that an object stays within the infrared ray detecting zone, wherein the time period is about a few tenths through a few seconds. When the object leaves the infrared ray detecting zone, the signal delivered from the infrared ray sensor 11 changes from a low voltage L to a high voltage H, as shown in FIG. 3B. Hence the sensing signal generated from the infrared ray sensor 11 is a binary signal readable to the program written in the OTPROM memory of the microcontroller 12. The microcontroller based electronic switch 1 utilizes specific sensing signal format characterized by the time length Ts of the low voltage sensing signal to implement at least two functions, namely, on/off switch control and dimming control. By introducing a preset time To, the microcontroller 12 can execute subroutine corresponding to the functions of the on/off switch control, the color temperature tuning control and the illumination power dimming control determined by a comparison scheme of the time length Ts with the preset time To. The user can therefore operates the microcontroller-based electronic switch 1 in a convenient manner simply by moving his hand into or out of the infrared ray detecting zone of the infrared ray sensor 11, and staying his hand there for a time period to select desired performance function. Referring to FIG. 2, FIG. 3 and FIG. 4, FIG. 4 is a flow chart of a program executed in a microcontroller of a microcontroller based electronic switch according to an exemplary embodiment of the present disclosure. The program written in the OTPROM memory of the microcontroller 12 includes several subroutine loops. These loops are started from the loop of steps S1 through S6 of the on/off switch control mode, and may jump into the loop of steps S8 through S10 of the color temperature tuning mode (or the dimming control mode) according to the time length Ts of the low voltage sensing signal. The pin pin_3 of the microcontroller 12 receives a high voltage H or a low voltage L from the infrared ray sensor 11, wherein the time length Ts of the low voltage sensing signal is about the time length which the user's hand stays within the infrared ray detecting zone. The program of the microcontroller 12 starts its execution from the loop of steps S1 and S2 in which the microcontroller based electronic switch 1 is off. The program of the microcontroller 12 scans the voltage at the pin pin_3 of the microcontroller 12. If the voltage at the pin pin_3 of the microcontroller 12 is high (bit 1), the program of the microcontroller 12 stays in the loop of steps S1 and S2 that the microcontroller based electronic switch 1 is off. On the contrary, if the voltage at the pin pin_3 is low (bit 0), the program of the microcontroller 12 jumps into the loop of steps S3 through S6 in which the microcontroller based electronic switch 1 is on. At step S4 when the microcontroller based electronic switch 1 is on, the program of the microcontroller 12 scans the voltage at the pin pin_3 of the microcontroller 12. If the voltage at the pin pin_3 of the microcontroller 12 is low (bit 0), the program of the microcontroller 12 jumps to step S5 to compare the time length Ts with a preset time To. In practice, the preset time To is between 1 through 3 seconds, but the present disclosure is not limited thereto. At step S5, the program of the microcontroller 12 check the time length Ts, if Ts is shorter than the preset time To, step S5 proceeds to step S6 to detect whether the voltage at the pin pin_3 is momentary a high voltage H (bit 1). At step S6, if the voltage at the pin pin_3 is the voltage H, the program goes back to the loop of steps S1 and S2 in which the microcontroller based electronic switch 1 is off. At step S6, if the voltage at the pin pin_3 is low, the program remains in the loop of steps S3 through S6 in which the microcontroller based electronic switch 1 is on. To sum up, the on/off switch control mode is described by the loops consisting of steps S1 through S6 that the microcontroller based electronic switch 1 is operated in off- and on-state rotationally. The microcontroller based electronic switch 1 is on or off according to whether the user moves his hand into and then pulls out the infrared ray detecting zone of the infrared ray sensor 11 within the preset time To. At step S5, the program of the microcontroller 12 check the time length Ts, if the time length Ts is longer than the preset time To, the program jumps to step S7 to detect whether the time length Ts is longer than n times the preset time To (n≧2). At step S7, if the time length Ts is not longer than n times the preset time To, the program goes back to the loop of steps S3 through S6 that the microcontroller based electronic switch 1 remains on. At step S7, if the time length Ts is longer than n times the preset time To, the program jumps into a loop consisting of steps S8 through S10 to execute a subroutine for the color temperature tuning mode (or the dimming control mode) of microcontroller based electronic switch 1. FIG. 4 does not show the details of subroutine associated with the color temperature tuning mode (or the dimming control mode), but the process is described in short as follows. At step 9, the program of the microcontroller 12 scans the voltage at the pin pin_3 of the microcontroller 12. The program proceeds to step 10 from Step 9, if the voltage at the pin pin_3 is low. At step 10, the subroutine of the microcontroller 12 checks if Ts>nTo. If the voltage at the pin pin_3 is low for several times, and the time lengths denoted by Ts or Ts′ are shorter than n times the preset time To, the subroutine remains in the rotation loop defined by step 8 through S10, and microcontroller 12 continuously increases or decreases the electric power transmission to the lighting loads 2a, 2b by controlling the conduction rates. If the electric power of the lighting load reaches the maximum or minimum electric power, the program of the microcontroller 12 responds no more to the low voltage sensing signal. At step 10, if the time length Ts is longer than n times the preset time To, the program of the microcontroller 12 jumps back to the loop of steps S1 and S2 in which the microcontroller based electronic switch 1 is off. Then, the program of the microcontroller 12 resumes itself from steps S1 and S2 in a rotational manner to execute the subroutines represented by the steps shown in FIG. 4. In the exemplary embodiment of FIG. 2, the preset time To and the number n can be set 2 seconds and 2, respectively. Referring to the steps executed by the microcontroller 12 in FIG. 4, if the detected time length Ts of the low voltage sensing signal at the pin pin_3 is less than 2 seconds, that means the time period which the hand stays within the infrared ray detecting zone is less than 2 seconds, the microcontroller 12 remains in the current function mode. If the detected time length Ts at the pin pin_3 is longer than 4 seconds, that means the time length which the hand stays within the infrared ray detecting zone is longer than 4 seconds, the microcontroller 12 changes the current function mode to another one function mode. In other words, if the time length Ts of the low voltage sensing signal is shorter than the preset time To, the microcontroller 12 operates either in on/off switch control mode or in color temperature tuning mode (or dimming control mode). If the detected time length Ts of the low voltage sensing signal is longer than n times the preset time To, the microcontroller 12 changes its program execution from the on/off switch control mode into the color temperature tuning mode (or the dimming control mode) and vice versa. In another embodiment, the concept of the present disclosure can be further extended to implement a multifunctional electronic switch having at least three functions built in one, which are on/off switch control, illumination dimming control and color temperature management. The program written in the OTPROM memory of the microcontroller can be modified in such a manner that the microcontroller responds not only to the low voltage sensing signal of the infrared ray sensor, but also to a specific sequence of the sensing signals. The microcontroller executes subroutines of working modes corresponding to the said three functions according to the detected time length Ts and special sequence of the low voltage sensing signals. The first working mode is on/off switch control mode used to control the conduction or cut-off state of the controllable semiconductor switching elements. The second working mode is dimming control mode used to control the conduction rates of the controllable semiconductor switching elements. The third working mode is color temperature management mode used to change alternatively from a high color temperature to a low one, or vice versa, or to tune the color temperature of the diffused light from two lighting loads. When the infrared ray sensor generates a low voltage sensing signal within the preset time To, the microcontroller operates in the on/off switch control mode by controlling the conduction or cut-off state of both the controllable semiconductor switching elements alternately. If the time length Ts of the low voltage sensing signal is longer than n times the preset time To, the microcontroller changes its operation from the on/off switch control mode to the color temperature tuning or dimming control mode. Once in the dimming (tuning) control mode, the microcontroller executes subroutine to gradually change the conduction rates of the controllable semiconductor switching elements from the maximum conduction rate to the minimum conduction rate, and then to gradually change the conduction rate from the minimum conduction rate to the maximum conduction rate for completing a dimming cycle wherein the process is a free run. In the dimming cycle with free run, the moment when the infrared ray sensor provides a high voltage is a dimming end point. According to the dimming control mode design, the microcontroller locks the conduction rates of the controllable semiconductor switching elements at the dimming end point. Thereafter, if the infrared ray sensor generates a plurality of low voltage sensing signals, for instance, a plural signal of two consecutive sensing signals, each within the preset time To, the microcontroller operates in the color temperature management mode by executing a subroutine to select a color temperature of the diffused light from two lighting loads through controlling different power levels delivered to the two lighting loads of different color temperatures. It is clear to see the advantage of the present disclosure to integrate various switch control functions in one without changing the hardware circuit design. All are simply done by defining the format of sensing signals and by modifying the program written in the OTPROM memory in the microcontroller. As mentioned above, various switch control functions can be integrated in one without changing the hardware circuit design of the microcontroller and the two loads. There may be variations of detection device in using electronic switch of the present disclosure for touch and touch less applications. For example, (1) Dual detection device technology in which two detection device are integrated in one electronic switch, for instance, by connecting two infrared ray sensors respectively with two pins of the microcontroller 12 in FIG. 1, to control a lighting apparatus: one first detection device sending message carrying sensing signal to control the color temperature of illumination characteristic, one second detection device sending message carrying sensing signal to control the light intensity of illumination characteristic; (2) Single detection device technology in which one detection device is built in an electronic switch to generate message carrying sensing signal to control a lighting apparatus by using different types of signal formats: a first type sensing signal (for instance, a low voltage within a short preset time To) to control the on/off performance, a second type sensing signal (for instance, a low voltage with a long time length Ts) to control the switching between low color temperature mode and high color temperature mode, and a third type sensing signal (for instance, a plural signals of two consecutive low voltages) for dimming the light intensity of illumination characteristic; (3) Single detection device technology using free running technique in response to a specific format sensing signal to offer selection of color temperature. The free running subroutine can be designed to apply to an electronic switch installed on wall for managing the illumination characteristics of a remotely located lighting apparatus such as a ceiling light installed on the ceiling. Unless a wireless communication unit is employed, a typical wall switch is constrained by a single circuit to only perform one illumination characteristic, being either controlling the light intensity or controlling the color temperature. If both the color temperature and light intensity are required to manage, the only way is to use the free running technology to execute one of the two illumination characteristics. The free running subroutine can be so deigned such that whenever a power supply is on, the microcontroller with software subroutine will check the memory unit to see if a preset color temperature or light intensity is established to decide if the free running subroutine needs to be activated, in the absence of preset datum, a free running action will be activated to gradually change the lighting intensity from maximum intensity to minimum intensity and continuously from minimum intensity to maximum intensity for completing a tuning/dimming cycle on an automatic basis and at any moment during a tuning/dimming cycle the user can determine the light intensity by acting a motion signal to lock in the level of the light intensity. The automatic tuning/dimming only continues for a short duration and in the absence of selection by the user, the microcontroller with program codes will execute a predetermined lighting intensity. Similarly, the same mechanism can be applied for tuning the color temperature to allow the user to select the desired color temperature during a free tuning cycle by acting a motion signal with the detection device to lock in the desired level of color temperature. With the help of free running technology, the wall control unit can therefore be used solely for operating the remaining illumination characteristic. The concept of free running technology can be further applied to develop a life style LED lighting solution where the color temperature is gradually changed according to time schedule programmed for performing different color temperature catering to the living style of human beings that people are more used to low color temperature with a warm atmosphere during the night time from 7 PM through 5 PM while during the day time people are more used to the high color temperature for working hours. A clock can be employed to provide the time information necessary for working with a program of scheduled color temperature pattern. The conduction rate r1 of the first controllable switching element can be varied in a reverse direction with respect to the conduction rate r2 of the second controllable switching element, the microcontroller with program codes executes to vary the conduction rate of the first controllable switching element according to a programmed pattern of color temperature changes in a subroutine; when r1 is equal to zero, the first controllable switching element is in a cutoff state while the second controllable switching element is in a full conduction state, the lighting apparatus performs a low color temperature, 3000K for instance, which may be the desired color temperature for the night time from 7 PM to 5 PM, when r1 is maximum, the first controllable switching element is in a full conduction state while the second controllable switching element is in a cut off state, the lighting apparatus performs a high color temperature, 5000K for instance, which may be the desired color temperature for noon time at 12 PM. A single color temperature may be assigned for night period from 7 PM through 5 AM for the sleeping time. For day time it can be programmed to gradually change the values of r1 and r2 from maximum to 0 between 5 AM to 12 PM and from 0 to maximum between 12 PM to 7 PM. With such arrangement at any time when the power is turned on the lighting apparatus automatically performs a desired color temperature according to the programmed pattern of color temperature at scheduled time frame. Refer to FIG. 5, FIG. 6 and FIG. 7 in accompanying FIG. 2 and FIG. 4. According to an exemplary embodiment of the present disclosure, FIG. 5 is a voltage waveform diagram of a microcontroller based electronic switch in cut-off state when operating in on/off switch control mode, FIG. 6 is a voltage waveform diagram of a microcontroller based electronic switch in conduction state when operating in on/off switch control mode, and FIG. 7 is a voltage waveform diagram of a microcontroller based electronic switch when operating in dimming control mode. In FIG. 5, FIG. 6, and FIG. 7, the voltage waveforms as shown from the top are, respectively, a sine wave output from the AC power source 3, an output signal of the zero-crossing-point detector 13 that is fed to pin pin_10 of the microcontroller 12, an output signal from the pin pin_1 of the microcontroller 12, and a voltage waveform between the two ends of the load 2a. The voltage waveforms are used to describe the interactions related to the program of the microcontroller 12 and the microcontroller based electronic switch 1 in the above mentioned two working modes. As already described above, the voltage signal generated by the zero-crossing-point detector 13 is a square wave with a low and a high voltage, which is fed to the pin pin_10 of the microcontroller 12 and, to be explained later, served as an external interrupt trigger signal. The voltage signal from the pin pin_1 of the microcontroller 12 is sent to the gate of the triac T1a to control the conduction state of the triac T1a. In the same way, the similar voltage signal from the pin pin_2 of the microcontroller 12 is sent to the gate of the triac T1b to control the conduction state of the triac T1b. In the program loops corresponding to the on/off switch control mode and the dimming control mode, the microcontroller 12 utilizes the external interrupt control technique to generate voltage pulses synchronized with AC power. To accomplish it, the program of the microcontroller 12 has a setup with the voltage level variations at the pin pin_10 as external interrupt trigger signals. Since the time point of high or low voltage level variation in the signal generated by the zero-crossing-point detector 13 is the zero crossing point of AC sine wave, the external interrupt process is automatically triggered at the zero crossing point of the AC power source 3, and the related meaning of the details are further described in FIG. 6 and FIG. 7. Referring to FIG. 5 in accompanying FIG. 2 and FIG. 4, the program of the microcontroller 12 starts from the loop of steps S1 and S2 of on/off switch control mode, wherein the microcontroller based electronic switch 1 is off. The program of the microcontroller 12 scans the voltage at the pin pin_3. If the voltage at the pin pin_3 is a high voltage, the microcontroller 12 generates a zero voltage at the pin pin_1, which is fed to the gate of the triac T1a to turn it off. For no current flowing through the triac T1a, the voltage between the two ends of the load 2a is zero in each AC cycle. In the same way, if the voltage at the pin pin_3 is a high voltage, the microcontroller 12 generates a zero voltage at the pin pin_2, which is fed to the gate of the triac T1b to turn it off. Refer to FIG. 6 in accompanying FIG. 2 and FIG. 4. If the program of the microcontroller 12 detects a low voltage at the pin pin_3, the program of microcontroller 12 jumps to steps S3 and S4 of on/off switch control mode, wherein the microcontroller based electronic switch 1 is on. The microcontroller 12 scans within a few microseconds the voltage at the pin pin_10. The external interrupt happens in each AC half cycle (of some milliseconds) at the time point of voltage level variation in the square wave signal. In the external interrupt process, no other program is executed, instead the program is commanded to go back to the main program instantly. The program of the microcontroller 12 is designed based on the time point when the external interrupt occurs, which is also the zero crossing point of the AC power source 3. After some delay times with respected to the time point of the external interrupt, the program of the microcontroller 12 generates a pulse signal at the pin pin_1 and a pulse signal at the pin pin_2. The signal provided from the pin pin_1 is a zero-crossing-point time-delay pulse having a delay time tD_a after the zero crossing point of AC power. The signal provided from the pin pin_2 is a zero-crossing-point time-delay pulse tD_b having a delay time tD_b after the zero crossing point of AC power. The zero-crossing-point time-delay pulse tD_a (or tD_b) is generated both in the positive and negative half-cycle of the AC power source 3, and used to trigger in synchronization with AC power source 3 the triac T1a (or triac T1b) into conduction, such that the AC power source 3 delivers in each half AC cycle electric power to the first lighting load 2a (or the second lighting load 2b) which is in proportion to a conduction time ton_a of the triac T1a (or ton_b of triac T1b). In contrast with the AC power source 3 and the zero crossing point delay pulses, the voltage waveform on the first lighting load 2a is depicted in FIG. 6, and the conduction time ton_a is designated. The voltage waveform on the second lighting load 2b can be similar to the voltage waveform on the first lighting load 2a, wherein the conduction time ton_b of triac T1b can be different from the conduction time ton_a of the triac T1a which are respectively resulted from different delay time tD_b and delay time tD_a of the zero-crossing-point time-delay pulses. In the loop of steps S3 and S4 of the microcontroller based electronic switch 1 being on, the delay times tD_a and tD_b of the zero-crossing delay voltage pulses are both predetermined values to make a constant average electric power delivered to the loads 2a, 2b. The color temperature of the diffused light of the two lighting load 2a, 2b may be controlled by properly selecting tD_a and tD_b, such that the summation of tD_a and tD_b is a constant, and the total lighting power of the first lighting load 2a (X) and the second lighting load 2b (Y), X+Y, is a fixed value. However, it is not to limit thereto in the present disclosure. By designing a minimum time delay, summation of the conduction time ton_a and ton_b of the triac T1a and the triac T1b can reach the maximum to make the maximum electric power transmission to the loads 2a, 2b. In practice, the loads 2a, 2b can be fluorescent lamps, AC LEDs (light emitting diode) screwed-in LED bulbs or incandescent bulbs, wherein said light-emitting diode module comprises a full-wave rectifier bridge and a plurality of light-emitting diodes in series connected between the two terminals of the rectifier bridge output port. Alternatively, the two loads 2a, 2b can be DC LED modules power by a DC source. Refer to FIG. 7 in accompanying FIG. 2 and FIG. 4. In the loop of steps S3 through S6, the microcontroller based electronic switch 1 is on, the program of the microcontroller 12 scans the voltage at the pin pin_3. If the sensing signal fed to the pin pin_3 is a low voltage with the time length Ts longer than nTo (n≧2), the program of the microcontroller 12 jumps to the loop of steps S8 through S10 for executing the color temperature tuning mode. When the microcontroller based electronic switch 1 is in the color temperature tuning mode, the program of the microcontroller 12 scans the voltage at the pin pin_10, so as to generate a zero-crossing-point time-delay pulse with a delay time tD_a at the pin pin_1 and to generate a zero-crossing-point time-delay pulse with a delay time tD_b at the pin pin_2. Simultaneously, the program of the microcontroller 12 scans the voltage at the pin pin_3. If the detected sensing voltage at the pin pin_3 is a low voltage with different time length Ts, the program continuously increases the delay time tD_a and decreases the delay time tD_b, or vice versa, of the zero-crossing-point time-delay pulses generated respectively at the pin pin_1 and pin pin_2, wherein the varying time length tD_a and tD_b are in proportion to the time length Ts. It should be noted that both delay times tD_a and tD_b vary in an appropriate range from “to” to “1/(2f)−to”, wherein to=(1/2πf)sin−1(Vt/Vm), f is the AC frequency, Vt is the threshold voltage or cut-in voltage of the lighting loads 2a, 2b and Vm is the voltage amplitude of the AC power source 3. This constraint on tD_a and tD_b is required to ensure in each AC half-cycle to stably trigger the triac T1a and triac T1b into conduction when the threshold voltage Vm of the lighting loads 2a, 2b are taken into consideration. FIG. 7 shows for one case the waveforms in the color temperature tuning mode wherein the delay time tD_a of the time delay pulse at the pin pin_1 is gradually increased along the time axis. The delay time tD_a decides the time length of the conduction time ton_a of triac T1a. The average electric power delivered to the first lighting load 2a, which is in proportion to the time length ton_a, is accordingly decreased. At the same time for the same case, not shown in FIG. 7, the delay time tD_b of the time delay pulse at the pin pin_2 is gradually decreased in the reverse direction, the conduction time ton_b of triac T1b and the average electric power delivered to the second lighting load 2b are thus accordingly increased. Consequently, the color temperature of the diffused light of the two lighting load 2a, 2b may vary gradually from a high temperature to a low one, or vice versa, due to alternatively changing the power levels of the two lighting load 2a, 2b controlled by the trigger pulses with delay times tD_a and tD_b. When the voltage at the pin pin_3 becomes high to terminate the color temperature tuning mode, the final values of the delay times tD_a and tD_b are then stored in the memory of the microcontroller 12 as new predetermined values to perform illumination with a desired color temperature and power level. In addition, the concept of the present disclosure can also be applied to the DC power source, wherein the controllable semiconductor switching element and the program of the microcontroller 12 should be modified slightly, and the zero-crossing-point detector should be removed. Referring to FIG. 8A, FIG. 8A is a block diagram of a microcontroller based electronic switch 1′ using an infrared ray sensor as a detection device for a DC power source according to an exemplary embodiment of the present disclosure. The microcontroller based electronic switch 1′ is connected to a DC power source 3′ and a first lighting load 2′a in a serial fashion, so as to control the electric power of the DC power source 3′ delivered to the first lighting load 2′a. Also, the microcontroller based electronic switch 1′ is connected to the DC power source 3′ and a second lighting load 2′b in a serial fashion, so as to control the electric power of the DC power source 3′ delivered to the second lighting load 2′b. Compared to FIG. 1, the microcontroller based electronic switch 1′ in FIG. 8A comprises an infrared ray sensor 11′, a microcontroller 12′, and uni-directional controllable semiconductor switching elements 14′a, 14′b. In practice, the uni-directional controllable semiconductor switching elements 14′a, 14′b can be bipolar junction transistors (BJTs) or metal-oxide-semiconductor field-effect transistors (MOSFETs). The loads 2′a and 2′b can respectively emit low color temperature light and high color temperature light. The load 2′a and 2′b can be light-emitting diodes or incandescent bulbs, but present disclosure is not limited thereto. Referring to FIG. 3 and FIG. 8B, the infrared ray sensor 11′ detects a user's hand, for instance, and converts the outcome into message carrying low voltage sensing signals readable to the microcontroller 12′. The microcontroller 12′ decodes the low voltage sensing signal according to the program designed and written in its OTPROM, so as to make the microcontroller based electronic switch 1′ operate in on/off switch control mode and color temperature tuning mode (or dimming control mode) accordingly. In the on/off switch control mode when the microcontroller based electronic switch 1′ is off, the program of the microcontroller 12′ generates a zero voltage fed to the gate of the uni-directional controllable semiconductor switching element 14′a (or 14′b) so as to turn off the switching element 14′a (or 14′b). In the on/off switch control mode when the microcontroller based electronic switch 1′ is on, the program of the microcontroller 12′ generates PWM_a (pulse-width-modulation) (or PWM_b) signal fed to the gate of the uni-directional controllable semiconductor switching element 14′a (or 14′b) so as to turn on the switching element 14′a (or 14′b) such that a fixed electric power is transmitted from the DC power source 3′ to the load 2′a (or 2′b). FIG. 8B is a voltage waveform diagram of the PWM signals according to an exemplary embodiment of the present disclosure. The PWM voltage signal is a square wave signal comprising a zero voltage (or low-voltage) and a high voltage, wherein the high voltage drives the uni-directional controllable semiconductor switching element 14′a (or 14′b) into conduction. If the time length of the high voltage is T2a (or T2b) and the period of the PWM voltage signal is T1, the average electric power delivered to the load 2′a (or 2′b) through the uni-directional controllable semiconductor switching element 14′a (or 14′b) is proportional to the ratio T2a/T1 (or T2b/T1), which is by definition the duty cycle of the PWM voltage signal and is denoted as δ=T2a/T1 (or δ=T2b/T1). More specifically, the electronic switch 1′ controls on/off and dimming of the first lighting load 2′a and the second lighting load 2′b in response to the operation of the infrared ray sensor 11′. When the switch 1′ is turned on, the microcontroller 12′ sends PWM voltage signals PWM_a and PWM_b for FIG. 8A controlled by the infrared ray sensor 11′: as shown, it is always to generates voltage signals PWM_a and PWM_b with two predetermined time lengths of T2a and T2b, wherein T2a+T2b=T1 for respectively controlling the load 2a to generate X watts power illumination and the load 2b to generate Y watts power illumination, where the summation X+Y is a fixed value. It may be T2a<T2b or T2a>T2b in response to the control signal generated by infrared ray sensor 11′. In a free running mode for color temperature tuning in response to the control signal generated by infrared ray sensor 11′, T2a may be varied gradually from a large value to a small one while T2b varied gradually from a small value to a large one, and vice versa, wherein T2a+T2b=T1. A color temperature generated by blending the lights emitted from the lighting load 2′a and 2′b can thus be selected when the free running mode for color temperature tuning is terminated by moving object (for example, the user's hand) out of the detecting zone of the infrared ray sensor 11′, and then the final values of T2a and T2b would be stored in the memory of the microcontroller 11′. The present disclosure is not limited by the PWM waveforms as depicted in FIG. 8B. In a practical design scheme, the parameters T2a and T2b of the PWM voltage signals can have a relation T2a+T2b=A, wherein “A” is a predetermined constant. Since the average electric powers delivered to the lighting loads 2′a and 2′b are respectively proportional to the duty cycles T2a/T1 and T2b/T1, both are smaller than one, the total average lighting power is in proportion to the summation of T2a/T1 and T2b/T1. When the voltage signals PWM_a and PWM_b are designed with A>T1, the color temperature of the diffused light of the two lighting load 2a, 2b can be generated under a total average lighting power larger than the one when A=T1. With A<T1, the total average lighting power is smaller than the one when A=T1. Thus, besides the color temperature tuning, the illumination power level may be controlled through varying the parameter A in a predetermined range by the microcontroller based electronic switch 1′ of the present disclosure. The aforementioned microcontroller-based electronic switch can have many functions, such as on/off switch control, dimming control and color temperature tuning or management control, that are integrated in one without additional hardware complexity. This multifunctional electronic switch can be applied to a lighting apparatus. Please refer to FIG. 9A, a lighting apparatus having the microcontroller-based multifunctional electronic switch is provided. The lighting apparatus comprises a base 91a, a first lighting load 92a, a second lighting load 93a, a diffuser 94a and a microcontroller based electronic switch (not shown in the figure). The base 91a is for disposing the first lighting load 92a, the second lighting load 93a and the microcontroller based electronic switch which has been described in previous embodiments. The operation of the microcontroller based electronic switch related to lighting characteristic control of the first lighting load 92a and the second lighting load 93a can be referred to previous embodiments, thus the redundant information is not repeated. For diffusing or spreading out or scattering the different color temperature light emitted by the first lighting load 91a and the second lighting load 92a, a diffuser 94a is provided to cover the first lighting load 92a and the second lighting load 93a. Further, the first lighting load 92a and the second lighting load 93a can be alternatively disposed on the base 91a. As shown in FIG. 9B, the first lighting load 92a comprises a plurality of lighting elements, and the second lighting load 93a comprises a plurality of lighting elements, wherein a lighting element of the second lighting load 93a is inserted between the two adjacent lighting elements of the first lighting load 92a for obtaining uniform color temperature of the diffused light, but present disclosure is not limited thereto. Another embodiment of the lighting apparatus can be referred to FIG. 9B. Due to the difference for the appearance of the lighting apparatus, the arrangement of the lighting elements of the first lighting load 92a and the lighting elements of the second lighting load 93a shown in FIG. 9B is different from that shown in FIG. 9A. As shown in FIG. 9B, the lighting elements of the first lighting load 92a and the lighting elements of the second lighting load 93a are both disposed in a circular arrangement. The lighting elements of the first lighting load 92a and the lighting elements of the second lighting load 93a constitute a plurality of concentric circles. The concentric circles of the first lighting load 92a and the concentric circles of the second lighting load 93a are interlaced for obtaining uniform color temperature of the diffused or blended light. However, the present disclosure is not restricted thereto. An artisan of ordinary skill in the art will appreciate how to arrange the first lighting load and the second lighting load covered by the diffuser to obtain the result of uniform color temperature of light. Furthermore, although the above description of the exemplary embodiments takes infrared ray sensor as a means for detecting user's motion and generating sensing signal, the technology of the present disclosure has no restriction on the types of detection method used. There are quite a few detection methods including touch or touchless means that can be applied to the present invention of the multifunctional electronic switch such as an infrared ray sensor (touchless interface), an electrostatic induction sensor (also touchless interface), a conduction based touch sensor (direct touch interface), or a push button sensor (direct touch interface). Each detection method may require different motion signals to be played by the user but the core technology remains using the time length and format of the binary sensing signals as the message carrier for transmitting the user's choice of working mode. The microcontroller thereby decodes or interprets the received message carrying sensing signals according to the software program written in the OTPROM, recognizes the working mode selected by the user and activates the corresponding loop of subroutine for performance execution. Similar to the infrared ray sensor, the electrostatic induction sensor can also create a touchless interface. The electrostatic induction sensor generally comprises a copper sheet sensing unit with adequately design shape and packaged with non-conductive material. Such copper sheet sensing unit is further electrically connected to a signal generating circuit similar to the infrared detection sensor unit. The copper sensing unit serves as an anode pole and the human body (normally refers to finger or hand) serves as a cathode pole to form a configuration of a capacitor. When the user's hand is approaching the copper sensing unit, the electric charges are being gradually induced and built up on the surface of the copper sensing unit with increasing density. Consequently, the copper sensing unit changes its electric state from zero voltage state to a growing voltage state. Such voltage level will continue to grow as the user's hand moving closer and closer to the copper sensing unit till reaching a designed threshold point which will trigger the detection circuit to generate a low voltage sensing signal. The distance between the copper sensing unit and the space point where the threshold voltage incurs is defined as the effective detecting zone. Similarly but reversely when the user's hand is moving out from an operative point of the detecting zone of the copper sensing unit, the voltage level will continue to decline till passing the designed threshold point which will trigger the cutoff of the low voltage sensing signal. The time length of the low voltage sensing signal so generated or in other words the time period between moving in and moving out the effective detecting zone can be designed to represent the selection of different working modes. If the time length is shorter than a preset time interval, it means the user's selection is to perform the on/off switch control mode; if the time length is longer than a preset time interval, it means the user's selection is to perform the diming or power level control mode; if two or more low voltage sensing signals are consecutively generated within a preset time interval, in other words the user's hand moving in and out the detecting zone twice or swing across the detecting zone back and forth, it means the user's selection is to perform the color temperature management mode. For direct touch detection sensors, such as a touch sensor (for example a touch pad) or a push button detection sensor, one touch on the conductive base or one instant press on the control button within a preset time interval will trigger the generation of a single sensing signal which will cause the microcontroller to execute the subroutine of the on/off switch control mode; a long touch on a conductive base or a long press on a control button longer than the preset time interval will trigger the generation of a single sensing signal with time length longer than the preset time interval and the microcontroller responsively will execute the subprogram of dimming control mode. Double instant touches on the conductive base or double instant press on the control button within a preset time interval will trigger the generation of two consecutive sensing signals which will cause the microcontroller to execute the subroutine of color temperature management mode. FIG. 10A and FIG. 10B together provide a good show case to prove the value of the user friendly concept of the present invention. Picture shown in FIG. 10A is a popular piece of under cabinet light with LED as light source. A manual on/off control switch is built on the right hand side of the rectangular housing and a dimming knob is built on the front panel facing downward. Under cabinet lights are always installed underneath the kitchen cabinets to provide sufficient indirect illumination to the user to do the kitchen work. The under cabinet lights and the kitchen cabinet are always installed at approximately the breast level of the users for the convenience of doing kitchen work so that the users can comfortably do the kitchen work without bending their body and having to work in a glaring environments. The current market piece as shown in FIG. 10A is not an user friendly device; the user has to either use his or her hand to blindly search the locations of the on/off switch and the dimming knob or to bend his or her body to find the exact locations of the two control units for operation. Additionally, the direct touch to control the on/off switch and dimmer also brings up concerns of contagion and contamination in preparing food in kitchen area and the housewives may have to wash their hands more frequently than necessary. FIG. 10B is an application of the present invention for a LED under cabinet light featured with a touchless interface between the user and the under cabinet light. A motion of single swing of user's hand across the detecting zone of the microcontroller based electronic switch 1b will activate the on/off switch mode alternately turning on and turning off the under cabinet light 2b. A motion of placing user's hand in the detecting zone exceeding a preset time interval will activate the dimming mode to allow selection of brightness or power level. And a motion of double swings of user's hand across the detecting zone within a preset time interval will activate the color temperature tuning mode to provide the user a possibility to select a desired illumination color temperature. The three basic working modes can be easily managed with simple motions played by the user without the hassles of having to blindly search the control switch and dimming knob, or to bend body to find the location of the control elements or to frequently wash hands to avoid concerns of contagion and contamination in preparing food. This is truly a very user friendly exemplary embodiment of the present disclosure compared with what are currently being sold in the market as shown in FIG. 10A. FIG. 10C is another application of the present invention for a wall switch construction electrically connected to a ceiling light for the performance of three working modes. A motion of single swing across the detecting zone in front of the wall switch 1c by user's hand within a preset time interval will activate the on/off switch control mode alternately turning on and turning off the ceiling light 2c. A motion of placing user's hand in front of the wall switch 1c and stay in the detecting zone for a time period longer than a preset time interval will activate the dimming mode to allow the user to select the desired brightness. And a motion of double swings across the detecting zone within a preset time interval will activate the performance of the color temperature management mode to provide the user a convenient way to select a desired illumination color temperature. This new wall switch when compared with conventional switch represents a very user friendly innovation from the easy operation point of view. The conventional touch based wall switch is also a virus gathering spot because of use by many users and the issue of contagion and contamination is always a valid concern even outside the surgical space. FIG. 10D is another application of the present invention for a lighting apparatus with a diffuser of hollow body accommodating the lighting loads and the microcontroller based electronic switch. The diffuser is furthered bonded with a metallic threaded cap with bipolar construction for connecting with a power socket. FIG. 10E is a similar art with a flat diffuser bonded with a metal shade to accommodate the lighting loads and the microcontroller based electronic switch. Both have an infrared ray sensor 310 positioned at the bottom of the diffuser to form a short detection zone for an user to play motion signals for performing the multi functions of controlling on/off mode, dimming mode, color temperature tuning mode or delay shutoff mode. FIGS. 11A-D are another exemplary embodiments of the present invention using the aforementioned dual detection device technology for generating message carrying sensing signal to control a lighting apparatus. The dual detection device technology is based on two detection device which are respectively connected with two pins of a microcontroller in an electronic switch to control a lighting apparatus, such as, one first detection device generating message carrying sensing signal to control the color temperature of illumination and one second detection device generating message carrying sensing signal to control the light intensity of illumination. The dual detection device technology can be constructed in two arrangements: the first arrangement is to install the first detection device on one side (left side for instance) of the lighting apparatus and install the second detection device on the other side (right side) of the lighting apparatus. For instance, in FIG. 10B, the detection device 1b being an infrared ray sensor in the center can be relocated to the left side near the end cap as the first detection device to operate the light intensity control subroutine of microcontroller, a second infrared ray sensor as the second detection device is added and installed on the other end of the light apparatus to operate the color temperature control subroutine. The second arrangement is to have two detection device, here, two infrared ray sensors 310, aligned next to each other along the direction of motion path as shown in FIG. 11A and FIG. 11B, or in FIG. 11C and FIG. 11D. A hand swing from left side to enter the detecting zones formed by the two infrared ray sensors 310, as shown in FIG. 11A and FIG. 11C, will cause the first infrared ray sensor of the electronic switch to first detect the motion signal before the second infrared ray sensor can detect the same motion signal, the first infrared ray sensor will thereby generate a voltage sensing signal, the microcontroller with a pin connected with the first infrared ray sensor accordingly interprets such voltage sensing signal to activate a subroutine to operate the light intensity control mode. Thus, a first hand-swing from the left side to swing across the detecting zones will turn on the light, a second left side started hand swing will alternately change the light to perform a different state of light intensity including off mode, a left side started hand swing to enter the detecting zones and stay for a time length longer than a preset time interval will activate a free running dimming cycle for the user to select the desired light intensity. Similarly but contrarily in terms of direction for playing motion signal, a right side started hand swing to swing across the detecting zones formed by the two infrared ray sensors, as shown in FIG. 11B and FIG. 11D, will cause the second infrared ray sensor to first detect the motion signal before the first infrared ray sensor can detect such motion signal, the second infrared ray sensor thereby will generate another voltage sensing signal sending to the microcontroller of the electronic switch, the microcontroller with another pin connected to the second infrared ray sensor accordingly operates to activate a different subroutine of the microcontroller to operate the color temperature tuning mode. Thus, a right side started motion signal to swing across the detecting zones formed by the two infrared ray sensors will turn on the light to perform the highest color temperature mode, a second right side started motion signal to swing across the detecting zones will alternately change the light to perform a different state of programmed color temperatures including the lowest color temperature mode, a right hand started motion signal to enter and stay in the detecting zone for a time length longer than a preset time interval will activate a free running color temperature tuning cycle for the user to select a desired color temperature for the light. Also, when the hand (or an object) leaves the infrared ray detecting zones, the infrared ray sensors deliver a second voltage sensing signal to terminate the corresponding subroutine. The present invention of the microcontroller based electronic switch can be extensively used in the control of lighting performance for many I applications can be simply grouped into three main categories of application based on the installation location of the present invention in relation with the lighting devices used as follows: 1) The microcontroller based electronic switch is installed inside a wall electric outlet for controlling a remotely located lighting apparatus which users are unable to reach to play motion control. FIG. 10C is a representative example. 2) The microcontroller based electronic switch is installed inside the housing of a lighting apparatus which users are able to reach and play motion control. FIG. 10B of a under cabinet light is a representative example. 3) The microcontroller based electronic switch is directly installed inside a light emitting device with a detecting sensor hiding behind a diffuser and a detecting zone is formed outside nearby the diffuser. FIG. 10D is a light bulb application with a microcontroller electronic switch built inside the bulb and an infrared ray detecting sensor installed at bottom of the bulb to form a infrared detecting zone near by the bottom of the light bulb. FIG. 10E is a pendant application with an infrared ray detection sensor built inside and an infrared ray detecting sensor installed at the bottom of a flat diffuser. Both are representative examples classified as detecting sensor installed at bottom of diffuser to form a detecting zone near by the diffuser. As a summary of the present disclosure the key technology of the present invention involves an electronic switch using a microcontroller with program codes to receive, interpret and execute a message carrying sensing signal converted from an external control signal to control performances of lighting characteristics including light intensity and light color temperature of an LED lamp. The LED lamp comprises a first LED lighting load featured with a high color temperature electrically connected to a first controllable switching element and a second LED lighting load featured with a low color temperature electrically connected to a second controllable switching element. The first controllable switching element and the second controllable switching element are respectively coupled with the microcontroller. The microcontroller upon receiving the message carrying sensing signal accordingly activates a corresponding subroutine to output a first control signal and a second control signal to respectively control a conduction rate of the first controllable switching device and a conduction rate of the second controllable switching element to respectively transmit electric powers to the first LED lighting load and the second LED lighting load such that a mingled color temperature thru a light diffuser and the light intensity of the LED lamp are thereby determined according to a programmed combination of conduction rates of the first controllable switching device and the second controllable switching device. A detection device serves as an interface between human and the electronic switch to convert the external control signal into the message carrying sensing signal readable and interpretable to the micro controller. The detection device is may be configured as touch less interface and direct touch interface. The touch less interface may be implemented by a wireless method to receive wireless external control signal and convert the wireless external control signal into the message carrying sensing signal readable and interpretable to the microcontroller. The wireless external control signal can be transformed from a motion signal generated with an infrared ray motion sensor, or it can be an electromagnetic wireless signal generated with a wireless receiver or transceiver, or it can be transformed from a voice signal generated with an A.I. (artificial intelligence) based device. The direct touch interface on the other hand uses a wired method to receive the external control signal set by an user, wherein the external control signal can be generated from a push button, a touch pad, a voltage divider, or a power interruption switch or button operated by the user, or a conduction rate of a phase controller set by the user, wherein, if the external control signal is an analogue signal, a conversion circuitry may be included in the detection device or as a virtual circuitry programmable embedded in the microcontroller to convert the analogue signal into the message carrying sensing signal readable and interpretable to the microcontroller. The above-mentioned descriptions represent merely the exemplary embodiment of the present disclosure, without any intention to limit the scope of the present disclosure thereto. Various equivalent changes, alterations or modifications based on the claims of present disclosure are all consequently viewed as being embraced by the scope of the present disclosure.
<SOH> BACKGROUND <EOH>
<SOH> SUMMARY <EOH>An exemplary embodiment of the present disclosure provides a microcontroller based electronic switch for detecting an external motion signal. The microcontroller based electronic switch comprises a first controllable switching element, a second controllable switching element, a detection device and a microcontroller. The first controllable switching element is electrically connected between a power source and a first lighting load for emitting light with a first color temperature. The second controllable switching element is electrically connected between the power source and a second lighting load for emitting light with a second color temperature. The detection device is for detecting an external motion signal played by a user and converting said external motion signal into a message carrying sensing signal. The microcontroller with program codes is written and designed to read and interpret the message carrying sensing signal generated by said detection device, wherein said microcontroller is electrically connected between said first controllable switching element and said detection device, said microcontroller is electrically connected between said second controllable switching element and said detection device. Said microcontroller controls a conduction state or cutoff state of said first controllable switching element and said second controllable switching element according to said message carrying sensing signal generated by said detection device. When the first controllable switching element and the second controllable switching element are in the conduction state, said microcontroller further controls electric power transmission levels from the power source to the first lighting load and the second lighting load according to specific format of said message carrying sensing signal received from said detection device. In one exemplary embodiment, the detection device is an infrared ray sensor comprising a means for emitting infrared light to form a defined infrared ray detecting zone and a means for detecting infrared light reflected from an object moving into said infrared ray detecting zone. A circuitry responsively generates a message carrying sensing signal having a first voltage with a time length corresponding to the time interval the object entering and staying in said infrared ray detecting zone. When the object leaves the infrared ray detecting zone, the infrared ray sensor delivers a second voltage signal. In one exemplary embodiment, the detection device is an electrostatic induction sensor comprising a copper sheet sensing unit with adequately designed shape and size to form an electrostatic detecting zone. A circuitry responsively generates a message carrying sensing signal having a first voltage with a time length corresponding to the time interval an inductive object enters and stays in said electrostatic detecting zone. When said object leaves said electrostatic detecting zone, said electrostatic sensor delivers a second voltage signal. In one exemplary embodiment, the detection device is a direct touch interface (such as a push button or a touch sensor) connecting with a pin of the microcontroller. When the user contacts the direct touch interface (for example, presses the push button) for a time interval, a first voltage signal is detected by the microcontroller which is a message carrying sensing signal having the first voltage with a time length corresponding to the time interval the touch interface being contacted. When the user leaves the direct touch interface (for example, releases the button), the direct touch interface delivers a second voltage signal. An exemplary embodiment of the present disclosure provides a lighting apparatus comprising a first lighting load, a second lighting load, a diffuser and a microcontroller based electronic switch. The first lighting load is for emitting light with a first color temperature. The second lighting load is for emitting light with a second color temperature. The diffuser covers the first lighting load and the second lighting load. The microcontroller based electronic switch comprises a first controllable switching element, a second controllable switching element, a detection device and a microcontroller. The first controllable switching element is electrically connected between the first lighting load and a power source. The second controllable switching element is electrically connected between the second lighting load and the power source. The detection device is for detecting an external motion signal played by a user and converting said external motion signal into a message carrying sensing signal. The microcontroller with program codes is written and designed to read and interpret the message carrying sensing signal generated by said detection device, wherein said microcontroller is electrically connected between said first controllable switching element and said detection device, said microcontroller is electrically connected between said second controllable switching element and said detection device. Said microcontroller controls a conduction state or cutoff state of said first controllable switching element and said second controllable switching element according to said message carrying sensing signal generated by said detection device. When the first controllable switching element and second controllable switching element are in the conduction state, said microcontroller further controls electric power transmission levels from the power source to the first lighting load and the second lighting load according to specific format of said message carrying sensing signal received from said detection device. With the microcontroller based electronic switch to control the lighting power levels, the color temperature of the diffused light (also called the blended or mingled light) of the first lighting load and the second lighting load can be controlled. In one exemplary embodiment, the detection device is an infrared ray sensor comprising a means for emitting infrared light to form a defined infrared ray detecting zone and a means for detecting infrared light reflected from an object moving into said infrared ray detecting zone. A circuitry responsively generates a message carrying sensing signal having a first voltage with a time length corresponding to the time interval the object entering and staying in said infrared ray detecting zone. When the object leaves the infrared ray detecting zone, the infrared ray sensor delivers a second voltage signal. In one exemplary embodiment, the detection device is an electrostatic induction sensor comprising a copper sheet sensing unit with adequately designed shape and size to form an electrostatic detecting zone. A circuitry responsively generates a message carrying sensing signal having a first voltage with a time length corresponding to the time interval an inductive object enters and stays in said electrostatic detecting zone. When said object leaves said electrostatic detecting zone, said electrostatic sensor delivers a second voltage signal. In one exemplary embodiment, the detection device is a direct touch interface (such as a push button or a touch sensor) connecting with a pin of the microcontroller. When the user contacts the direct touch interface (for example, presses the push button) for a time interval, a first voltage signal is detected by the microcontroller which is a message carrying sensing signal having the first voltage with a time length corresponding to the time interval the touch interface being contacted. When the user leaves the direct touch interface (for example, releases the button), the direct touch interface delivers a second voltage signal. To sum up, the present disclosure is characteristic in, a contactless interface between the user and the multifunctional electronic switch is created to implement at least two operation modes of the electronic switch by using software codes written in OTPROM (one-time programmable read only memory) of microcontroller to analyze the message carrying sensing signals. In order to further understand the techniques, means and effects of the present disclosure, the following detailed descriptions and appended drawings are hereby referred, such that, through which, the purposes, features and aspects of the present disclosure can be thoroughly and concretely appreciated; however, the appended drawings are merely provided for reference and illustration, without any intention to be used for limiting the present disclosure.
H05B370227
20170913
20180308
72646.0
H05B3702
2
TRAN, THUY V
MICROCONTROLLER-BASED MULTIFUNCTIONAL ELECTRONIC SWITCH AND LIGHTING APPARATUS HAVING THE SAME
SMALL
1
CONT-ACCEPTED
H05B
2,017
15,703,285
PENDING
MOBILE DISTRIBUTION STATION WITH FAIL-SAFES
A distribution station includes a mobile trailer, a pump on the mobile trailer, a manifold on the mobile trailer and connected with the pump, a plurality of hoses in communication with the manifold, and a plurality of valves on the mobile trailer. Each of the valves is situated between the manifold and a respective different one of the hoses. Each of a plurality of fluid level sensors is associated with a respective different one of the hoses. The fluid level sensors are operable to detect respective different fluid levels. A controller is configured to operate the valves responsive to signals from the fluid level sensors, activate and deactivate the pump, identify whether there is a risk condition based upon at least one variable operating parameter, and deactivate the pump responsive to the risk condition.
1. A fuel distribution station comprising: a mobile trailer; a pump on the mobile trailer; a manifold on the mobile trailer and connected with the pump; a plurality of hoses in fluid communication with the manifold; a plurality of valves on the mobile trailer, each of the valves situated between the manifold and a respective different one of the hoses; a plurality of fluid level sensors, each of the fluid level sensors associated with a respective different one of the hoses, and the fluid level sensors operable to detect respective different fluid levels; and a controller configured to operate the valves responsive to signals from the fluid level sensors, activate and deactivate the pump, and identify whether there is a risk condition based upon at least one variable operating parameter and deactivate the pump responsive to the risk condition. 2. The fuel distribution station as recited in claim 1, wherein the variable operating parameter includes fluid pressure, and the controller identifies whether there is the risk condition based upon the fluid pressure exceeding a preset fluid pressure threshold. 3. The fuel distribution station as recited in claim 1, wherein the variable operating parameter includes fluid pressure, and the controller identifies whether there is the risk condition based upon change of the fluid pressure within a preset time period. 4. The fuel distribution station as recited in claim 1, wherein the variable operating parameter includes one of the fluid levels, and the controller identifies whether there is the risk condition based upon a change in the one of the fluid levels. 5. The fuel distribution station as recited in claim 1, wherein the variable operating parameter includes fluid temperature, and the controller identifies whether there is the risk condition based upon the fluid temperature exceeding a preset fluid temperature threshold. 6. The fuel distribution station as recited in claim 5, wherein the fluid temperature is taken at a point between the pump and the manifold. 7. The fuel distribution station as recited in claim 5, wherein the fluid temperature is taken at a point proximate the pump. 8. The fuel distribution station as recited in claim 1, wherein the controller is configured to limit the number of valves that are open based upon a minimum threshold fluid pressure. 9. The fuel distribution station as recited in claim 8, wherein the controller is configured to delay an opening of one of the valves until closing of another one of the valves. 10. The fuel distribution station as recited in claim 1, further comprising an electronic register on the mobile trailer and connected with the pump. 11. The fuel distribution station as recited in claim 10, further comprising an air eliminator between the pump and the electronic register. 12. A fuel distribution station comprising: a mobile trailer; a pump on the mobile trailer; a manifold on the mobile trailer and connected with the pump; a plurality of hoses in fluid communication with the manifold; a plurality of valves on the mobile trailer, each of the valves situated between the manifold and a respective different one of the hoses; a plurality of fluid level sensors, each of the fluid level sensors associated with a respective different one of the hoses, and the fluid level sensors operable to detect respective different fluid levels; and a controller configured to activate and deactivate the pump, open and close the valves responsive to signals from the fluid level sensors, and limit the number of the valves that are open at one time with respect to a fluid pressure. 13. The fuel distribution station as recited in claim 12, wherein the controller is configured to identify whether there is a risk condition based upon at least one variable operating parameter and deactivate the pump responsive to the risk condition. 14. The fuel distribution station as recited in claim 13, wherein the variable operating parameter includes fluid pressure, and the controller identifies whether there is the risk condition based upon the fluid pressure exceeding a preset fluid pressure threshold. 15. The fuel distribution station as recited in claim 13, wherein the variable operating parameter includes fluid pressure, and the controller identifies whether there is the risk condition based upon change of the fluid pressure within a preset time period. 16. The fuel distribution station as recited in claim 13, wherein the variable operating parameter includes one of the fluid levels, and the controller identifies whether there is the risk condition based upon a change in the one of the fluid levels. 17. The fuel distribution station as recited in claim 13, wherein the variable operating parameter includes fluid temperature, and the controller identifies whether there is the risk condition based upon the fluid temperature exceeding a preset fluid temperature threshold. 18. The fuel distribution station as recited in claim 7, wherein the fluid temperature is taken at a point proximate the pump. 19. A fuel distribution station comprising: a mobile trailer; a pump on the mobile trailer; a manifold on the mobile trailer and connected with the pump; a plurality of hoses in fluid communication with the manifold; a plurality of valves on the mobile trailer, each of the valves situated between the manifold and a respective different one of the hoses; a plurality of fluid level sensors, each of the fluid level sensors associated with a respective different one of the hoses, and the fluid level sensors operable to detect respective different fluid levels; and a controller configured to activate and deactivate the pump, open and close the valves responsive to signals from the fluid level sensors, and identify whether there is a risk condition based upon at least one variable operating parameter and deactivate the pump responsive to the risk condition, wherein the at least one variable operating parameter includes fill level of a tank such that the risk condition exists if the controller identifies that one of the valves is opened to begin filling that tank but there is no change in the fluid level associated with that tank within a preset time period.
CROSS-REFERENCE TO RELATED APPLICATION The present disclosure is a continuation of U.S. patent application Ser. No. 15/290,400 filed Oct. 11, 2016. BACKGROUND Hydraulic fracturing (also known as fracking) is a well-stimulation process that utilizes pressurized liquids to fracture rock formations. Pumps and other equipment used for hydraulic fracturing typically operate at the surface of the well site. The equipment may operate semi-continuously, until refueling is needed, at which time the equipment may be shut-down for refueling. Shut-downs are costly and reduce efficiency. More preferably, to avoid shut-downs fuel is replenished in a hot-refueling operation while the equipment continues to run. This permits fracking operations to proceed fully continuously; however, hot-refueling can be difficult to reliably sustain for the duration of the fracking operation. SUMMARY A fuel distribution station according to an example of the present disclosure includes a mobile trailer, a pump on the mobile trailer, a manifold on the mobile trailer connected with the pump, a plurality of hoses in fluid communication with the manifold, and a plurality of valves on the mobile trailer. Each of the valves is situated between the manifold and a respective different one of the hoses. Fluid level sensors are associated with respective different ones of the hoses, and the fluid level sensors are operable to detect respective different fluid levels. A controller is configured to operate the valves responsive to signals from the fluid level sensors, activate and deactivate the pump, and identify whether there is a risk condition based upon at least one variable operating parameter and deactivate the pump responsive to the risk condition. In a further embodiment of any of the foregoing embodiments, the variable operating parameter includes fluid pressure, and the controller identifies whether there is the risk condition based upon the fluid pressure exceeding a preset fluid pressure threshold. In a further embodiment of any of the foregoing embodiments, the variable operating parameter includes fluid pressure, and the controller identifies whether there is the risk condition based upon change of the fluid pressure within a preset time period. In a further embodiment of any of the foregoing embodiments, the variable operating parameter includes one of the fluid levels, and the controller identifies whether there is the risk condition based upon a change in the one of the fluid levels. In a further embodiment of any of the foregoing embodiments, the variable operating parameter includes fluid temperature, and the controller identifies whether there is the risk condition based upon the fluid temperature exceeding a preset fluid temperature threshold. In a further embodiment of any of the foregoing embodiments, the fluid temperature is taken at a point between the pump and the manifold. In a further embodiment of any of the foregoing embodiments, the fluid temperature is taken at a point proximate the pump. In a further embodiment of any of the foregoing embodiments, the controller is configured to limit the number of valves that are open based upon a minimum threshold fluid pressure. In a further embodiment of any of the foregoing embodiments, the controller is configured to delay an opening of one of the valves until closing of another one of the valves. A further embodiment of any of the foregoing embodiments includes an electronic register on the mobile trailer and connected with the pump. A further embodiment of any of the foregoing embodiments includes an air eliminator between the pump and the electronic register. A method for a distribution station according to an example of the present disclosure includes selectively opening the valves responsive to signals from the fluid level sensors. In correspondence with opening the valves, the method includes activating the pump to convey a fluid through any open ones of the valves and identifying whether there is a risk condition based upon at least one variable operating parameter. The pump is deactivated responsive to the risk condition. In a further embodiment of any of the foregoing embodiments, the variable operating parameter includes fluid pressure, and identifying whether there is the risk condition based upon the fluid pressure exceeding a preset fluid pressure threshold. In a further embodiment of any of the foregoing embodiments, the variable operating parameter includes fluid pressure, and identifying whether there is the risk condition based upon change of the fluid pressure within a preset time period. In a further embodiment of any of the foregoing embodiments, the variable operating parameter includes one of the fluid levels, and identifying whether there is the risk condition based upon a change in the one of the fluid levels. In a further embodiment of any of the foregoing embodiments, the variable operating parameter includes fluid temperature, and identifying whether there is the risk condition based upon the fluid temperature exceeding a preset fluid temperature threshold. A further embodiment of any of the foregoing embodiments includes taking the fluid temperature at a point between the pump and the manifold. A further embodiment of any of the foregoing embodiments includes taking the fluid temperature at a point proximate the pump. A further embodiment of any of the foregoing embodiments includes limiting the number of valves that are open based upon a minimum threshold fluid pressure by delaying the opening of one of the valves until closing of another one of the valves. BRIEF DESCRIPTION OF THE DRAWINGS The various features and advantages of the present disclosure will become apparent to those skilled in the art from the following detailed description. The drawings that accompany the detailed description can be briefly described as follows. FIG. 1 illustrates an example mobile fuel distribution station. FIG. 2 illustrates an internal layout of a mobile fuel distribution station. FIG. 3 illustrates an isolated view of hose reels on a support rack used in a mobile fuel distribution station. FIG. 4 illustrates an example of a connection between a manifold, a control valve, and a reel. FIG. 5 illustrates a sectioned view of an example hose for a mobile fuel distribution station. FIG. 6 illustrates an example of an integrated fuel cap sensor for a mobile fuel distribution station. FIG. 7 illustrates an example of the routing of a sensor communication line through a reel in a mobile fuel distribution station. FIG. 8 illustrates another example mobile fuel distribution station that is capable of delivering and tracking two different types of fluids. FIG. 9 illustrates a system that can be used to remotely monitor and manage one or more mobile distribution stations. FIG. 10 is a workflow logic diagram that represents an example of a method for managing one or more mobile distribution stations. The size of the diagram exceeds what can be shown on a page. Therefore, FIG. 10 is divided into sub-sections, indicated as FIG. 10A, FIG. 10B, FIG. 10C, FIG. 10D, FIG. 10E, and FIG. 10F. The sub-sections show the details of the workflow logic diagram and, where appropriate, linking arrows to adjacent sub-sections. The relative location of the sub-sections to each other is also shown. FIG. 11 is another workflow logic diagram that represents an example of a method for managing one or more mobile distribution stations. The size of the diagram exceeds what can be shown on a page. Therefore, FIG. 11 is divided into sub-sections, indicated as FIG. 11A, FIG. 11B, FIG. 11C, FIG. 11D, FIG. 11E, FIG. 11F, FIG. 11G, and FIG. 11H. The sub-sections show the details of the workflow logic diagram and, where appropriate, linking arrows to adjacent sub-sections. The relative location of the sub-sections to each other is also shown. DETAILED DESCRIPTION FIG. 1 illustrates a mobile distribution station 20 and FIG. 2 illustrates an internal layout of the station 20. As will be described, the station 20 may serve in a “hot-refueling” capacity to distribute fuel to multiple pieces of equipment while the equipment is running, such as fracking equipment at a well site. As will be appreciated, the station 20 is not limited to applications for fracking or for delivering fuel. The examples herein may be presented with respect to fuel delivery, but the station 20 may be used in mobile delivery of other fluids, in other gas/petroleum recovery operations, or in other operations where mobile refueling or fluid delivery will be of benefit. In this example, the station 20 includes a mobile trailer 22. Generally, the mobile trailer 22 is elongated and has first and second opposed trailer side walls W1 and W2 that join first and second opposed trailer end walls E1 and E2. Most typically, the trailer 22 will also have a closed top (not shown). The mobile trailer 22 may have wheels that permit the mobile trailer 22 to be moved by a vehicle from site to site to service different hot-refueling operations. In this example, the mobile trailer 22 has two compartments. A first compartment 24 includes the physical components for distributing fuel, such as diesel fuel, and a second compartment 26 serves as an isolated control room for managing and monitoring fuel distribution. The compartments 24/26 are separated by an inside wall 28a that has an inside door 28b. The first compartment 24 includes one or more pumps 30. Fuel may be provided to the one or more pumps 30 from an external fuel source, such as a tanker truck on the site. On the trailer 22, the one or more pumps 30 are fluidly connected via a fuel line 32 with a high precision register 34 for metering fuel. The fuel line 32 may include, but is not limited to, hard piping. In this example, the fuel line 32 includes a filtration and air eliminator system 36a and one or more sensors 36b. Although optional, the system 36a is beneficial in many implementations, to remove foreign particles and air from the fuel prior to delivery to the equipment. The one or more sensors 36b may include a temperature sensor, a pressure sensor, or a combination thereof, which assist in fuel distribution management. The fuel line 32 is connected with one or more manifolds 38. In the illustrated example, the station 20 includes two manifolds 38 that arranged on opposed sides of the compartment 24. As an example, the manifolds 38 are elongated tubes that are generally larger in diameter than the fuel line 32 and that have at least one inlet and multiple outlets. Each hose 40 is wound, at least initially, on a reel 42 that is rotatable to extend or retract the hose 40 externally through one or more windows of the trailer 22. Each reel 42 may have an associated motor to mechanically extend and retract the hose 40. As shown in an isolated view in FIG. 3, the reels 42 are mounted on a support rack 42a. In this example, the support rack 42a is configured with upper and lower rows of reels 42. Each row has five reels 42 such that each support rack 42a provides ten reels 42 and thus ten hoses 40. There are two support racks 42a (FIG. 2) arranged on opposed sides of the first compartment 24, with an aisle (A) that runs between the support racks 42a from an outside door E to the inside door 28b. The station 20 therefore provides twenty hoses 40 in the illustrated arrangement, with ten hoses 40 provided on each side of the station 20. As will be appreciated, fewer or additional reels and hoses may be used in alternative examples. As shown in a representative example in FIG. 4, each hose 40 is connected to a respective one of the reels 42 and a respective one of a plurality of control valves 44. For example, a secondary fuel line 46 leads from the manifold 38 to the reel 42. The control valve 44 is in the secondary fuel line 46. The control valve 44 is moveable between open and closed positions to selectively permit fuel flow from the manifold 38 to the reel 42 and the hose 40. For example, the control valve 44 is a powered valve, such as a solenoid valve. In the illustrated example, the first compartment 24 also includes a sensor support rack 48. The sensor support rack 48 holds integrated fuel cap sensors 50 (when not in use), or at least portions thereof. When in use, each integrated fuel cap sensor 50 is temporarily affixed to a piece of equipment (i.e., the fuel tank of the equipment) that is subject to the hot-refueling operation. Each hose 40 may include a connector end 40a and each integrated fuel cap sensor 50 may have a corresponding mating connector to facilitate rapid connection and disconnection of the hose 40 with the integrated fuel cap sensor 50. For example, the connector end 40a and mating connector on the integrated fuel cap sensor 50 form a hydraulic quick-connect. At least the control valves 44, pump or pumps 30, sensor or sensors 36b, and register 34 are in communication with a controller 52 located in the second compartment 26. As an example, the controller 52 includes software, hardware, or both that is configured to carry out any of the functions described herein. In one further example, the controller 52 includes a programmable logic controller with a touch-screen for user input and display of status data. For example, the screen may simultaneously show multiple fluid levels of the equipment that is being serviced. When in operation, the integrated fuel cap sensors 50 are mounted on respective fuel tanks of the pieces of equipment that are subject to the hot-refueling operation. The hoses 40 are connected to the respective integrated fuel cap sensors 50. Each integrated fuel cap sensor 50 generates signals that are indicative of the fuel level in the fuel tank of the piece of equipment on which the integrated fuel cap sensor 50 is mounted. The signals are communicated to the controller 52. The controller 52 interprets the signals and determines the fuel level for each fuel tank of each piece of equipment. In response to a fuel level that falls below a lower threshold, the controller 52 opens the control valve 44 associated with the hose 40 to that fuel tank and activates the pump or pumps 30. The pump or pumps 30 provide fuel flow into the manifolds 38 and through the open control valve 44 and reel 42 such that fuel is provided through the respective hose 40 and integrated fuel cap sensor 50 into the fuel tank. The lower threshold may correspond to an empty fuel level of the fuel tank, but more typically the lower threshold will be a level above the empty level to reduce the potential that the equipment completely runs out of fuel and shuts down. The controller 52 also determines when the fuel level in the fuel tank reaches an upper threshold. The upper threshold may correspond to a full fuel level of the fuel tank, but more typically the upper threshold will be a level below the full level to reduce the potential for overflow. In response to reaching the upper threshold, the controller 52 closes the respective control valve 44 and ceases the pump or pumps 30. If other control valves 44 are open or are to be opened, the pump or pumps 30 may remain on. The controller 52 can also be programmed with an electronic stop failsafe measure to prevent over-filling. As an example, once an upper threshold is reached on a first tank and the control valve 44 is closed, but the pump 30 is otherwise to remain on to fill other tanks, if the fuel level continues to rise in the first tank, the controller 52 shuts the pump 30 off. Multiple control valves 44 may be open at one time, to provide fuel to multiple pieces of equipment at one time. If there is demand for fuel from two or more fuel tanks, the controller 52 may manage which of the valves 44 open and when they open. For instance, the controller 52 is configured to limit the number of valves 44 that are open at one time based upon a minimum threshold fluid pressure. In one example, the controller 52 limits the number of valves 44 that are open at one time to four in order to ensure that there is adequate fuel pressure in the system to fill the equipment in a short time. In contrast, if a high number of valves were open at once, the fuel pressure may fall to a low level such that it takes a longer time to fill the fuel tanks of the equipment. The controller 52 may perform the functions above while in an automated operating mode. Additionally, the controller 52 may have a manual mode in which a user can control at least some functions through the PLC, such as starting and stopped the pump 30 and opening and closing control valves 44. For example, manual mode may be used at the beginning of a job when initially filling tanks to levels at which the fuel cap sensors 50 can detect fuel and/or during a job if a fuel cap sensor 50 becomes inoperable. Of course, operating in manual mode may deactivate some automated functions, such as filling at the low threshold or stopping at the high threshold. In one example, the controller 52 sequentially opens the control valves 44 using a delay. In this example the limit of the number of valves 44 that can be open at one time is four. If five fuel tanks require filling, rather than having the five corresponding valves 44 all open at once, the controller 52 opens four of the valves 44 and delays opening the fifth of the valves 44. Upon completion of filling of one of the fuel tanks, the controller 52 closes the corresponding valve 44 and opens the fifth valve 44. Thus, the delay involves a demand for fuel that would result in the opening of the valve 44 but that is instead displaced in time until a condition is met. In the example above, the condition is that the number of open valves 44 must be less than four before opening the fifth valve 44. In addition to the use of the sensor signals to determine fuel level, or even as an alternative to use of the sensor signals, the refueling may be time-based. For instance, the fuel consumption of a given piece of equipment may be known such that the fuel tank reaches the lower threshold at known time intervals. The controller 52 is operable to refuel the fuel tank at the time intervals rather than on the basis of the sensor signals, although sensor signals may also be used to verify fuel level. The controller 52 also tracks the amount of fuel provided to the fuel tanks. For instance, the register 34 precisely measures the amount of fuel provided from the pump or pumps 30. As an example, the register 34 is an electronic register and has a resolution of about 0.1 gallons. The register 34 communicates measurement data to the controller 52. The controller 52 can thus determine the total amount of fuel used to very precise levels. The controller 52 may also be configured to provide outputs of the total amount of fuel consumed. For instance, a user may program the controller 52 to provide outputs at desired intervals, such as by worker shifts or daily, weekly, or monthly periods. The outputs may also be used to generate invoices for the amount of fuel used. As an example, the controller 52 may provide a daily output of fuel use and trigger the generation of an invoice that corresponds to the daily fuel use, thereby enabling almost instantaneous invoicing. The controller 52 is also configured with one or more fail-safes. A-safe ensures that the station 20 shuts down in response to an undesired circumstance or threat of an undesired circumstance, i.e. a risk condition. In this regard, during regular operation when there is no risk condition, the controller 52 selectively activates and deactivates the pump, and selectively opens and closes the valves 44 to provide fuel. The controller 52 identifies whether there is a risk condition based upon at least one variable operating parameter. An operating parameter may originate from the sensor or sensors 36b, fuel cap sensors 50, or other particular locations in the system. Thus, a sensor may be implemented at a particular point of interest and connected for communication with the controller 52, such as by a transmitter or wired connection. Moreover, one or more sensor may be incorporated into the fuel cap sensors 50 to provide diagnostics at a fuel tank, such as tank temperature, pressure, etc. As will be discussed below, the operating parameters may relate to pressure, temperature, fluid level or other parameter indicative of an undesired circumstance. If the controller 52 identifies the risk condition, the controller 52 deactivates the pump 30 responsive to the risk condition and closes any valves 44 that are open. The deactivation of the pump 30 stops or slows the flow of fluid. For instance, a fluid leak may cause a divergence in an operating parameter and trigger the controller 52 to deactivate the pump 30, thereby slowing or stopping flow of leaking fuel. In one further example, the variable operating parameter includes fluid pressure. For instance, the sensor or sensors 36b may include pressure sensors that provide fluid pressure feedback to the controller 52. The controller 52 identifies whether the risk condition is present based upon comparison of the fluid pressure to a preset fluid pressure threshold. If the fluid pressure exceeds the threshold, the controller 52 determines that the risk condition is present and deactivates the pump 30. As an example, if one of the valves 44 was supposed to open but did not open, there may be a pressure build-up to a level in excess of the threshold. In a further example, the risk condition is additionally or alternatively based upon a change of the fluid pressure within a preset time period. If an expected change in pressure does not occur within the time period, the controller 52 determines that the risk condition is present and deactivates the pump 30. For instance, within a preset time period of the pump 30 being activated or one of the valves 44 being opened, if there is a decrease in pressure, the controller 52 determines that the risk condition is present and deactivates the pump 30. The decrease may need to exceed a preset threshold decrease for the controller 52 to determine that the risk condition is present. In one further example, the variable operating parameter additionally or alternatively includes the fluid levels. If one or more of the valves 44 are opened to begin filling the corresponding tanks, the levels in those tanks are expected to change. However, if there is no change or substantially no change in a level within a preset time period, which is otherwise expected to increase, the controller 52 determines that the risk condition is present and deactivates the pump 30. Thus, if a hose 40 were to rupture, spillage of fuel is limited to the volume of fuel in the hose 40. For instance, the preset time period may be three seconds, six seconds, ten seconds, or fifteen seconds, which may limit spillage to approximately fifteen gallons for a given size of hose. In one further example, the variable operating parameter additionally or alternatively includes fluid temperature. For instance, the sensor or sensors 36b may include a temperature sensor that provides fluid temperature feedback to the controller 52. The controller 52 identifies whether the risk condition is present based upon comparison of the fluid temperature to a preset fluid temperature threshold. If the fluid temperature exceeds the threshold, the controller 52 determines that the risk condition is present and deactivates the pump 30 and closes any valves 44 that are open. As an example, if the pump 30 overheats, the fluid may heat to a temperature above the threshold. In this regard, the temperature can be taken from a location proximate the pump 30, such as at a point between the pump 30 and the manifold 38. The controller 52 may also represent a method for use with the station 20. For example, the method may include selectively opening the valves 44 responsive to signals from the integrated fuel cap sensors 50 and, in correspondence with opening the valves 44, activating the pump 30 to convey a fluid through any open ones of the valves 44. The method then involves identifying whether there is a risk condition based upon at least one variable operating parameter and deactivating the pump 30 responsive to the risk condition. In a further example, the integrated fuel cap sensors 50 are each hard-wired to the controller 52. The term “hard-wired” or variations thereof refers to a wired connection between two components that serves for electronic communication there between, which here a sensor and a controller. The hard-wiring may facilitate providing more reliable signals from the integrated fuel cap sensors 50. For instance, the many pieces of equipment, vehicles, workers, etc. at a site may communicate using wireless devices. The wireless signals may interfere with each other and, therefore, degrade communication reliability. Hard-wiring the integrated fuel cap sensors 50 to the controller 52 facilitates reduction in interference and thus enhances reliability. In general, hard-wiring in a hot-refueling environment presents several challenges. For example, a site has many workers walking about and typically is located on rough terrain. Thus, as will be described below, each integrated fuel cap sensor 50 is hard-wired through the associated hose 40 to the controller 52. FIG. 5 illustrates a representative portion of one of the hoses 40 and, specifically, the end of the hose 40 that will be located at the fuel tank of the equipment being refueled. In this example, the hose 40 includes a connector 60 at the end for detachably connecting the hose 40 to the integrated fuel cap sensors 50. The hose 40 is formed of a tube 62 and a sleeve 64 that circumscribes the tube 62. As an example, the tube 62 may be a flexible elastomeric tube and the sleeve 64 may be a flexible fabric sleeve. The sleeve 64 is generally loosely arranged around the tube 62, although the sleeve 64 may closely fit on the tube 62 to prevent substantial slipping of the sleeve 64 relative to the tube 62 during use and handling. Optionally, to further prevent slipping and/or to secure the sleeve 64, bands may be tightened around the hose 40. As an example, one or more steel or stainless steel bands can be provided at least near the ends of the hose 40. A plurality of sensor communication lines 66 (one shown) are routed with or in the respective hoses 40. For instance, each line 66 may include a wire, a wire bundle, and/or multiple wires or wire bundles. In one further example, the line 66 is a low milli-amp intrinsic safety wiring, which serves as a protection feature for reducing the concern for operating electrical equipment in the presence of fuel by limiting the amount of thermal and electrical energy available for ignition. In this example, the line 66 is routed through the hose 40 between (radially) the tube 62 and the sleeve 64. The sleeve 64 thus serves to secure and protect the line 66, and the sleeve 64 may limit spill and spewing if there is a hose 40 rupture. In particular, since the line 66 is secured in the hose 40, the line 66 does not present a tripping concern for workers. Moreover, in rough terrain environments where there are stones, sand, and other objects that could damage the line 66 if it were free, the sleeve 64 shields the line 66 from direct contact with such objects. In further examples, the line 66 may be embedded or partially embedded in the tube 62 or the sleeve 64. In this example, the line 66 extends out from the end of the hose 40 and includes a connector 68 that is detachably connectable with a respective one of the integrated fuel cap sensors 50. For example, FIG. 6 illustrates a representative example of one of the integrated fuel cap sensors 50. The integrated fuel cap sensor 50 includes a cap portion 50a and a fluid level sensor portion 50b. The cap portion 50a is detachably connectable with a port of a fuel tank. The cap portion 50a includes a connector port 50c, which is detachably connectable with the connector 60 of the hose 40. The sensor portion 50b includes a sensor 50d and a sensor port 50e that is detachably connectable with the connector 68 of the line 66. The fuel cap sensor 50 may also include a vent port that attaches to a drain hose, to drain any overflow into a containment bucket and/or reduce air pressure build-up in a fuel tank. Thus, a user may first mount the cap portion 50a on the fuel tank of the equipment, followed by connecting the hose 40 to the port 50c and connecting the line 66 to the port 50e. The sensor 50d may be any type of sensor that is capable of detecting fluid or fuel level in a tank. In one example, the sensor 50d is a guided wave radar sensor. A guided wave radar sensor may include a transmitter/sensor that emits radar waves, most typically radio frequency waves, down a probe. A sheath may be provided around the probe. For example, the sheath may be a metal alloy (e.g., stainless steel or aluminum) or polymer tube that surrounds the probe. One or more bushings may be provided between the probe and the sheth, to separate the probe from the sheath. The sheath shields the probe from contact by external objects, the walls of a fuel tank, or other components in a fuel tank, which might otherwise increase the potential for faulty sensor readings. The probe serves as a guide for the radar waves. The radar waves reflect off of the surface of the fuel and the reflected radar waves are received into the transmitter/sensor. A sensor controller determines the “time of flight” of the radar waves, i.e., how long it takes from emission of the radar waves for the radar waves to reflect back to the transmitter/sensor. Based on the time, the sensor controller, or the controller 52 if the sensor controller does not have the capability, determines the distance that the radar waves travel. A longer distance thus indicates a lower fuel level (farther away) and a shorter distance indicates a higher fuel level (closer). The line 66 routes through the hose 40 and back to the reel 42 in the trailer 22. For example, the line 66 is also routed or hard-wired through the reel 42 to the controller 52. FIG. 7 illustrates a representative example of the routing in the reel 42. In this example, the reel 42 includes a spindle 42b about which the reel is rotatable. The spindle 42b may be hollow, and the line 66 may be routed through the spindle 42b. The reel 42 may also include a connector 42c mounted thereon. The connector 42c receives the line 66 and serves as a port for connection with another line 66a to the controller 52. The lines 66a may converge to one or more communication junction blocks or “bricks” prior to the controller 52. The communication junction blocks may serve to facilitate the relay of the signals back to the controller 52. The communication junction blocks may alternatively or additionally serve to facilitate identification of the lines 66, and thus the signals, with respect to which of the hoses a particular line 66 is associated with. For instance, a group of communication junction blocks may have unique identifiers and the lines 66 into a particular communication junction block may be associated with identifiers. A signal relayed into the controller 52 may thus be associated with the identifier of the communication junction blocks and a particular line 66 of that communication junction block in order to identify which hose the signal is to be associated with. The valves 44 may also communicate with the controller 52 in a similar manner through the communication junction blocks. As can be appreciated from the examples herein, the station 20 permits continuous hot-refueling with enhanced reliability. While there might generally be a tendency to choose wireless sensor communication for convenience, a hard-wired approach mitigates the potential for signal interference that can arise with wireless. Moreover, by hard-wiring the sensors through the hoses to the controller, wired communication lines are protected from exposure and do not pose additional concerns for workers on a site. FIG. 8 illustrates another example of a mobile fuel distribution station 120. In this disclosure, like reference numerals designate like elements where appropriate and reference numerals with the addition of one-hundred or multiples thereof designate modified elements that are understood to incorporate the same features and benefits of the corresponding elements. In this example, the station 120 is similar to station 20 but is configured to deliver, and track, at least two different fluid products. The first compartment 24 includes two pumps 130a/130b. Two different fluids, such as two different fuels, may be provided to the pumps 130a/130b from external fuel sources, such as tanker trucks on the site. On the trailer 22, the pumps 130a/130b are fluidly connected via respective fuel lines 132a/132b with respective high precision registers 134a/134b for metering fuel. The fuel lines 132a/132b may include, but are not limited to, hard piping. In this example, the fuel lines 132a/132b each include a respective filtration and air eliminator system 136a-1/136a-2 and one or more respective sensors 136b-1/136b-2. The sensors 136b-1/136b-2 may include a temperature sensor, a pressure sensor, or a combination thereof, which assist in fuel distribution management. The pump 130a and fuel line 132a are connected with the one or more manifolds 38 as described above. The pump 130b and fuel line 132b are connected with the reel 142 and hose 140. The pump 130a serves to provide fuel to the manifolds 38 and then to the reels 42 and hoses 40. The pump 130b serves to separately provide fuel to the reel 142 and hose 140. Thus, a first type of fuel can be delivered and tracked via the pump 130a and hoses 40, and a second type of fuel can be delivered and tracked via the pump 130b and hose 140. For example, in the station 120, nineteen hoses 40 may be configured to deliver and track the first type of fuel and one hose 140 may be configured to deliver and track the second type of fuel. As can be appreciated, the station 120 can be modified to have greater or fewer of the hoses 40 that provide the first fuel and a greater number of the hoses 142 that provide the second fuel. In this example, the hoses 40 are adapted for hot-refueling as discussed above with respect to the station 20. The hose 142 (or hoses 142 if there are more) may be adapted for a different purpose, such as to fuel on-road vehicles. In this regard, the hoses 40 include the connector ends 40a for connecting with the integrated fuel cap sensors 50. The hose or hoses 142 include or are configured to connect with a different type of end, such as a nozzle dispenser end 140a. The nozzle dispenser end 140a may include a handle that is configured to dispense fuel when manually depressed by a user. Thus, the hoses 40 and the hoses 142 have different ends that are adapted for different delivery functions. One example implementation of the station 120 is to deliver and track different fuels, such as a clear diesel fuel and a dyed diesel fuel. Clear diesel fuel is typically used for road vehicles and is subject to government taxes; dyed diesel fuel is typically used for off-road vehicles and is not taxed. The dyed fuel can thus be delivered to off-road equipment at a site using the pump 130a and hoses 40, while clear fuel can be delivered to on-road vehicles at a site using the pump 130b and hose 142. Because the dyed diesel fuel and the clear diesel fuel are dispensed through different pumps and different registers 134a/134b, the consumption of these fuels can be separately tracked. In particular, the tax implications of the use of the two fuels can be more easily managed, to ensure with greater reliability that the proper fuels are used for the proper purposes. FIG. 9 illustrates a system 69 for remotely monitoring and/or managing at least one mobile distribution station 20 (A). It is to be appreciated that the system 69 may include additional mobile distribution stations, shown in phantom at 20 (B), 20 (C), and 20 (D) (collectively mobile distribution stations 20), for example. The mobile distribution stations 20 may be located at a single work site or located across several different work sites S1 and S2. Each mobile distribution station 20 is in communication with one or more servers 71 that are remotely located from the mobile distribution stations 20 and work sites S1/S2. In most implementations, the communication will be wireless. The server 71 may include hardware, software, or both that is configured to perform the functions described herein. The server 71 may also be in communication with one or more electronic devices 73. The electronic device 73 is external of or remote from the mobile fuel distribution stations 20. For example, the electronic device 73 may be, but is not limited to, a computer, such as a desktop or laptop computer, a cellular device, or tablet device. The electronic device 73 may communicate and interact in the system 69 via data connectivity, which may involve internet connectivity, cellular connectivity, software, mobile application, or combinations of these. The electronic device 73 may include a display 73a, such as an electronic screen, that is configured to display the fuel operating parameter data of each of the mobile distribution stations 20. As an example, the electronic device 73 may display in real-time the operating parameter data of each of the mobile distribution stations 20 in the system 69 to permit remote monitoring and management control of the mobile distribution stations 20. For instance, the operating parameter data may include fuel temperature, fuel pressure, fuel flow, total amount of fuel distributed, operational settings (e.g., low and high fuel level thresholds), or other parameters. The server 71 may also be in communication with one or more cloud-based devices 75. The cloud-based device 75 may include one or more servers and a memory for communicating with and storing information from the server 71. The server 71 is configured to communicate with the mobile distribution stations 20. Most typically, the server 71 will communicate with the controller 52 of the mobile distribution station 20. In this regard, the controller 52 of each mobile distribution station 20 may be include hardware, software, or both that is configured for external communication with the server 71. For example, each controller 52 may communicate and interact in the system 69 via data connectivity, which may involve internet connectivity, cellular connectivity, software, mobile application, or combinations of these. The server 71 is configured to receive operating parameter data from the mobile distribution stations 20. The operating parameter data may include or represent physical measurements of operating conditions of the mobile distribution station 20, status information of the mobile distribution station 20, setting information of the mobile distribution station 20, or other information associated with control or management of the operation of the mobile distribution station 20. For example, the server 71 utilizes the information to monitor and auto-manage the mobile distribution station 20. The monitoring and auto-management may be for purposes of identifying potential risk conditions that may require shutdown or alert, purposes of intelligently enhancing operation, or purposes of reading fuel or fluid levels in real-time via the sensors 50. As an example, the server 71 may utilize the information to monitor or display fuel or fluid levels, or determine whether the fuel operating parameter data is within a preset limit and send a control action in response to the operating parameter data being outside the preset limit. As will described in further detail below, the control action may be a shutdown instruction to the mobile fuel distribution stations 20, an adjustment instruction to the mobile fuel distribution stations 20, or an alert to the electronic device 73. FIG. 10 illustrates a workflow logic diagram of an example control method 77 which can be implemented with the system 69 or with other configurations of one or more mobile distribution stations 20 and one or more servers. In general, the illustrated method 77 can be used to provide a shutdown instruction or an alert if operating parameter data of one or more mobile distribution stations 20 is outside of a preset limit. For instance, if fuel pressure or fuel temperature in one of the mobile distribution stations 20 exceeds one or more limits, the method 77 shuts down the mobile distribution station 20 and/or sends an alert so that appropriate action can, if needed, be taken in response to the situation. In particular, in hot-refueling implementations, the ability to automatically shut down or to provide a remote alert may facilitate enhancement of reliable and safe operation. Referring to FIG. 10, one or more current or instantaneous operating parameters are read (i.e., by the controller 52). An operating parameter may include, but is not limited to, fuel temperature and fuel pressure. Other parameters may additionally or alternatively be used, such as pump speed or power and fuel flow. Parameters may be first order parameters based on first order readings from sensor signals, or second order parameters that are derived or calculated from first order parameters or first order sensor signals. For instance, temperature is a first order parameter and direct detection of temperature to produce signals representative of temperature constitute first order sensor signals. The product of temperature and pressure, for example, is a second order parameter that is based on first order sensor signals of each of temperature and pressure. As will be appreciated, there may be additional types of second order parameters based on temperature, pressure, power, flow, etc., which may or may not be weighted in a calculation of a second order parameter. In this example, the current operating parameter is compared with a prior operating parameter stored in memory in the controller 52. A difference in the current operating parameter and the prior operating parameter is calculated to produce a change (delta) value in the operating parameter. The change value is used as the operating parameter data for control purposes in the method 77. The operating parameter data thus represents the change in the operating parameter from the prior reading to the current reading. Use of the change value as the operating parameter data serves to reduce the amount of data that is to be sent in connection with the method 77. For example, the actual operating parameter values may be larger than the change values and may thus require more memory and bandwidth to send than the change values. The change values are sampled and calculated at a predesignated interval rate. In this example, the interval rate is once per second. Each operating parameter is stored in memory for use as the next “prior” operating parameter for comparison with a subsequent “new” operating parameter reading. The controller 52 may be programmed to perform the above steps. As will be appreciated, the steps above achieve data efficiency, and actual values could alternatively or additionally be used if memory and bandwidth permit. Each operating parameter data reading (i.e., change value) is published or sent via IoT (Internet of Things) Gateway to an IoT Platform, which may be implemented fully or partially on the server 71 and cloud device 75. The operating parameter data may also contain additional information, such as but not limited to, metadata with time stamp information and identification of the individual mobile distribution station 20. In this example, the operating parameter data of interest is associated with fuel pressure and fuel temperature. In the method 77, the operating parameter data for fuel temperature and fuel pressure are compared to, respectively, a preset fuel temperature shutdown limit and a preset fuel pressure shutdown limit. The shutdown limits may be temperature and pressure limits corresponding to rated limits of the pump 30, fuel line 32, and manifold 38, for example. If the temperature or pressure are outside of the preset fuel temperature or pressure shutdown limits, the method 77 initiates a shutdown event. In this example, the shutdown event includes identifying the particular mobile distribution station 20 associated with the temperature or pressure that is outside of the preset limit, forming a shutdown instruction message, and publishing or sending the shutdown instruction message via the IoT Gateway to the corresponding identified mobile distribution station 20. Upon receiving the shutdown instruction message, the controller 52 of the identified mobile distribution station 20 validates and executes the shutdown instruction. For instance, shutdown may include shutting off the pump 30 and closing all of the control valves 44. In this example, the method 77 includes a timing feature that waits for confirmation of shutdown. Confirmation may be generated by the controller 52 performing an electronic check of whether the pump 30 is off and the control valves 44 are closed. Confirmation may additionally or alternatively involve manual feedback via input into the controller 52 by a worker at the identified mobile distribution station 20. Once shutdown is confirmed by the controller 52, confirmation of shutdown is published or sent via the Iot Gateway to the IoT Platform for subsequent issuance of an alert. If there is no confirmation of shutdown by a maximum preset time threshold, a non-confirmation of shutdown is published or sent for subsequent issuance of an alert. If the temperature and/or pressure is not outside of the preset fuel temperature or pressure shutdown limits, the method 77 in this example continues to determine whether the fuel temperature and fuel pressure with are, respectively, outside of a preset fuel temperature threshold limit and a preset fuel pressure threshold limit. The threshold limits will typically be preset at levels which indicate a potential for shutdown conditions. For example, the threshold limits may be intermediate temperature or pressure levels which, if exceeded, may indicate an upward trend in temperature or pressure toward the shutdown limits. In one example, the threshold limits are rate of change thresholds. For instance, a change value in temperature and/or pressure that exceeds a corresponding threshold change limit may be indicative that temperature and/or pressure is rapidly elevating toward the shutdown condition. In response to the temperature and/or pressure being outside of the preset fuel temperature or pressure threshold limits, the method 77 initiates an alert event. In this example, the alert event includes initiating an event notification. In the event notification, the method 77 conducts a lookup of notification channels and then issues an alert via one or more selected notification channels, such as an alert on the display 73a. As an example, the notification channels may be selected by user preferences and may include alerts by email, SMS (short message service), and/or mobile device app notification (e.g., banners, badges, home screen alerts, etc.). The event notification is also used for alerts of confirmation and non-confirmation of shutdown. The method 77 thus provides capability to nearly instantaneously issue an alert that can be immediately and readily viewed in real-time on the electronic device 73 so that appropriate action, if needed, can be taken. In one example, such actions may include adjustment of operation settings of the mobile distribution station 20, which may be communicated and implemented via the system 69 from the electronic device 73 to the mobile distribution station 20. FIG. 11 illustrates a workflow logic diagram of an example control management method 79 which can be implemented with the method 77 and with the system 69 or with other configurations of one or more mobile distribution stations 20 and one or more servers. For example, the method 79 is used to identify shutdown conditions and/or remotely intelligently auto-manage operation of one or more mobile distribution stations 20. The initial portion of the method 79 with respect to generating operating parameters data may be similar to the method 77; however, the method 79 uses the operating parameter data to calculate an efficiency score and identify shutdown conditions or other actions to be taken in response to the efficiency score. For example, the efficiency score is a second order parameter and is a calculation based on multiple fuel operating parameters selected from fuel temperature, fuel pressure, fuel flow, and time. The efficiency score is then compared to an efficiency score shutdown limit. If the calculated efficiency score exceeds the limit, the method 79 initiates the shutdown event as described above. As an example, the efficiency score is the product of a safety score multiplied by one or more of a temperature score, a pressure score, a flow rate score, a tank level score, or the sum of two or more of these scores. For instance, the efficiency score is as shown in Equation I below. Efficiency Score=Safety Score×(Temperature Score+Pressure Score+Flow Rate Score+Tank Level Score). Equation I In one example, the safety score is a product of a safety factor and logic values of one or zero for each of the temperature score, the pressure score, the flow rate score, and the tank level score. Thus, if any of the temperature score, the pressure score, the flow rate score, or the tank level score fails, resulting in a logic value of zero, the efficiency score will be zero. In response to an efficiency score of zero, the method 79 initiates the shutdown event as described above. The logic values are assigned according to whether the given parameter is within a predetermined minimum/maximum range. If the parameter is within the range, the logic value is one and if the parameter is outside of the range, the value is zero. As an example, the safety score may be determined by: Safety Score=(Safety Check Positive Response/Total Safety Checks)*(IF(Temperature Reading between MIN LIMIT and MAX LIMIT)THEN 1 ELSE 0))*(IF(Pressure Reading between MIN LIMIT and MAX LIMIT)THEN 1 ELSE 0))*(IF(Flow Rate Reading between MIN LIMIT and MAX LIMIT)THEN 1 ELSE 0))*(IF(Tank Inventory Reading between MIN LIMIT and MAX LIMIT)THEN 1 ELSE 0)), wherein Temperature Score=(((Temperature Reading−Min Limit)/Temperature Reading)+((Max Limit+Temperature Reading)/Temperature Reading)))/2, Pressure Score=(((Pressure Reading−Min Limit)/Pressure Reading)+((Max Limit+Pressure Reading)/Pressure Reading)))/2, Flow Rate Score=(((Flow Rate Reading−Min Limit)/Flow Rate Reading)+((Max Limit+Flow Rate Reading)/Flow Rate Reading)))/2, and Tank Level Score=(((Tank Level Reading−Min Limit)/Tank Level Reading)+((Max Limit+Tank Level Reading)/Tank Level Reading)))/2. In one example, the safety factor includes a calculation based on safety checks of a mobile distribution station 20. For instance, the safety factor is the quotient of positive or passing safety checks divided by the total number of safety check made. A safety check may involve periodic validation of multiple parameters or conditions on the site of a station 20 and/or in the station 20. As examples, the safety check may include validation that electrical power supply is fully functional (e.g., a generator), validation of oil levels (e.g., in a generator), validation of whether there are any work obstructions at the site, etc. Thus, each safety check may involve validation of a set of parameters and conditions. If validation passes, the safety check is positive and if validation does not pass the safety check is negative. As an example, if 5 safety checks are conducted for a station 20 and four of the checks pass and one does not pass, the safety factor is equal to four divided by five, or 0.8. The method 79 also uses the efficiency score to actively intelligently auto-manage operation of one or more of the mobile distribution stations 20. For example, the efficiency score is compared in the method 79 with an efficiency score threshold limit or efficiency score range. If the efficiency score is outside of the limit or range, the method 79 initiates an adjustment event to adjust settings of the operating parameters of the mobile distribution station 20. For example, pumping rate or power may be changed to increase or decrease fuel pressure. In further examples in the table below, preset actions are taken in response to efficiency scores within preset ranges. Efficiency Score Action <=1 SHUTDOWN >1 AND <=2 ALERT >2 AND <=3 ADJUST SETTINGS >3 AND <=4 NO ACTION The adjustment event may include forming an adjustment instruction message and publishing or sending the adjustment instruction message to the mobile distribution station 20 via the IoT Gateway. Upon receiving the adjustment instruction message the controller 52 of the mobile distribution station 20 validates and executes the message. The message constitutes a control action to change one or more of the operating parameters to move the efficiency score within the limit or range. As an example, pumping rate is changed to change fuel pressure. Other parameters may additionally or alternatively be adjusted to change the fuel efficiency score, such as but not limited to, fuel tank upper and lower thresholds, sequence of opening/closing control valves 44, and number of control valves 44 that may be open at one time. Thus, once implemented, the method 79 can serve to auto-adjust operation of one or more of the mobile distribution stations 20, without human intervention, to achieve enhanced or optimize fuel distribution. In one example, a rate of fuel consumption of one or more pieces of the equipment may be calculated, and the upper and/or lower fuel level threshold settings are changed in response to the calculated rate of fuel consumption. For instance, if consumption is lower or higher than a given fuel level threshold setting warrants, the fuel level threshold setting is responsively auto-adjusted up or down for more efficient operation. For a low consumption rate, there may be a downward adjustment of the lower fuel level threshold, since there is lower likelihood that the low consumption rate will lead to a fully empty condition in the equipment. Similarly, for a high consumption rate, there may be an upward adjustment of the lower fuel level threshold, since there is higher likelihood that the high consumption rate will lead to a fully empty condition in the equipment. Thus, the mobile distribution station 20 can be operated more efficiently and safely by distributing fuel at proper times to ensure filling the equipment with desired safety margins. Similar to the shutdown instruction message described above, the method 79 may include a timing feature that waits for confirmation of adjustment. Once adjustment is confirmed by the controller 52, confirmation of adjustment is published or sent via the Iot Gateway to the IoT Platform for subsequent issuance of an alert. If there is no confirmation of adjustment by a maximum preset time threshold, a non-confirmation of adjustment is published or sent for subsequent issuance of an alert. In further examples, the method 79 may exclude use of the efficiency score for purposes of shutdown or for purposes of intelligent auto-management. That is, the method 79 may employ the efficiency score for only one or the other of shutdown or intelligent auto-management. Additionally or alternatively, the system 69 with one or more mobile distribution stations 20 and one or more servers may be used for centralized, intelligent auto-filling. For example, fuel levels may be tracked in real-time or near real-time. When a fuel level associated with one of the stations 20 reaches the lower threshold, described above, an instruction may be sent via the system 69 to active the pump 30 and open the appropriate control valve 44. Moreover, the system 69 can ensure that there is minimal or zero delay time from the time of identifying the low threshold to the time that filling begins. Thus, at least a portion of the functionality of the controllers 52 may be remotely and centrally based in the server of the system 69. Although a combination of features is shown in the illustrated examples, not all of them need to be combined to realize the benefits of various embodiments of this disclosure. In other words, a system designed according to an embodiment of this disclosure will not necessarily include all of the features shown in any one of the Figures or all of the portions schematically shown in the Figures. Moreover, selected features of one example embodiment may be combined with selected features of other example embodiments. The preceding description is exemplary rather than limiting in nature. Variations and modifications to the disclosed examples may become apparent to those skilled in the art that do not necessarily depart from this disclosure. The scope of legal protection given to this disclosure can only be determined by studying the following claims.
<SOH> BACKGROUND <EOH>Hydraulic fracturing (also known as fracking) is a well-stimulation process that utilizes pressurized liquids to fracture rock formations. Pumps and other equipment used for hydraulic fracturing typically operate at the surface of the well site. The equipment may operate semi-continuously, until refueling is needed, at which time the equipment may be shut-down for refueling. Shut-downs are costly and reduce efficiency. More preferably, to avoid shut-downs fuel is replenished in a hot-refueling operation while the equipment continues to run. This permits fracking operations to proceed fully continuously; however, hot-refueling can be difficult to reliably sustain for the duration of the fracking operation.
<SOH> SUMMARY <EOH>A fuel distribution station according to an example of the present disclosure includes a mobile trailer, a pump on the mobile trailer, a manifold on the mobile trailer connected with the pump, a plurality of hoses in fluid communication with the manifold, and a plurality of valves on the mobile trailer. Each of the valves is situated between the manifold and a respective different one of the hoses. Fluid level sensors are associated with respective different ones of the hoses, and the fluid level sensors are operable to detect respective different fluid levels. A controller is configured to operate the valves responsive to signals from the fluid level sensors, activate and deactivate the pump, and identify whether there is a risk condition based upon at least one variable operating parameter and deactivate the pump responsive to the risk condition. In a further embodiment of any of the foregoing embodiments, the variable operating parameter includes fluid pressure, and the controller identifies whether there is the risk condition based upon the fluid pressure exceeding a preset fluid pressure threshold. In a further embodiment of any of the foregoing embodiments, the variable operating parameter includes fluid pressure, and the controller identifies whether there is the risk condition based upon change of the fluid pressure within a preset time period. In a further embodiment of any of the foregoing embodiments, the variable operating parameter includes one of the fluid levels, and the controller identifies whether there is the risk condition based upon a change in the one of the fluid levels. In a further embodiment of any of the foregoing embodiments, the variable operating parameter includes fluid temperature, and the controller identifies whether there is the risk condition based upon the fluid temperature exceeding a preset fluid temperature threshold. In a further embodiment of any of the foregoing embodiments, the fluid temperature is taken at a point between the pump and the manifold. In a further embodiment of any of the foregoing embodiments, the fluid temperature is taken at a point proximate the pump. In a further embodiment of any of the foregoing embodiments, the controller is configured to limit the number of valves that are open based upon a minimum threshold fluid pressure. In a further embodiment of any of the foregoing embodiments, the controller is configured to delay an opening of one of the valves until closing of another one of the valves. A further embodiment of any of the foregoing embodiments includes an electronic register on the mobile trailer and connected with the pump. A further embodiment of any of the foregoing embodiments includes an air eliminator between the pump and the electronic register. A method for a distribution station according to an example of the present disclosure includes selectively opening the valves responsive to signals from the fluid level sensors. In correspondence with opening the valves, the method includes activating the pump to convey a fluid through any open ones of the valves and identifying whether there is a risk condition based upon at least one variable operating parameter. The pump is deactivated responsive to the risk condition. In a further embodiment of any of the foregoing embodiments, the variable operating parameter includes fluid pressure, and identifying whether there is the risk condition based upon the fluid pressure exceeding a preset fluid pressure threshold. In a further embodiment of any of the foregoing embodiments, the variable operating parameter includes fluid pressure, and identifying whether there is the risk condition based upon change of the fluid pressure within a preset time period. In a further embodiment of any of the foregoing embodiments, the variable operating parameter includes one of the fluid levels, and identifying whether there is the risk condition based upon a change in the one of the fluid levels. In a further embodiment of any of the foregoing embodiments, the variable operating parameter includes fluid temperature, and identifying whether there is the risk condition based upon the fluid temperature exceeding a preset fluid temperature threshold. A further embodiment of any of the foregoing embodiments includes taking the fluid temperature at a point between the pump and the manifold. A further embodiment of any of the foregoing embodiments includes taking the fluid temperature at a point proximate the pump. A further embodiment of any of the foregoing embodiments includes limiting the number of valves that are open based upon a minimum threshold fluid pressure by delaying the opening of one of the valves until closing of another one of the valves.
B67D73218
20170913
20180412
70409.0
B67D732
1
GRAY, PAUL J
MOBILE DISTRIBUTION STATION WITH FAIL-SAFES
UNDISCOUNTED
1
CONT-ACCEPTED
B67D
2,017
15,703,827
PENDING
PNEUMATIC TIRE
A tire 2 includes a tie gum 24 between a carcass 12 and each chafer 22. In the tire 2, an inner liner 20 is formed from a thermoplastic elastomer composition including a styrene-isobutylene-styrene block copolymer. The inner liner 20 has a thickness of not greater than 1.5 mm. The tie gum 24 joins the inner liner 20 and the chafer 22 and has a volume resistivity of not greater than 108 Ω·cm.
1. A pneumatic tire comprising a pair of beads, a carcass, an inner liner, a pair of chafers, and a pair of tie gums, wherein the carcass extends on and between one of the beads and the other of the beads, the inner liner is joined to an inner surface of the carcass, each chafer is turned up around the bead, each tie gum is located between the carcass and the chafer, the inner liner is formed from a thermoplastic elastomer composition including a styrene-isobutylene-styrene block copolymer and has a thickness of not greater than 1.5 mm, and the tie gum joins the inner liner and the chafer and has a volume resistivity of not greater than 108 Ω·cm. 2. The pneumatic tire according to claim 1, wherein the inner liner has a thickness of not less than 0.5 mm. 3. The pneumatic tire according to claim 1, wherein a joint width of the inner liner and the tie gum is not less than 5 mm and not greater than 10 mm. 4. The pneumatic tire according to claim 1, wherein the tie gum is a processed product of a tie gum sheet, and the tie gum sheet has a width of not less than 25 mm and not greater than 40 mm. 5. The pneumatic tire according to claim 4, wherein the tie gum sheet has a thickness of not less than 0.5 mm and not greater than 1.3 mm.
This application claims priority on Patent Application No. 2016-211160 filed in JAPAN on Oct. 28, 2016. The entire contents of this Japanese Patent Application are hereby incorporated by reference. BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to pneumatic tires. Description of the Related Art A tire includes an inner liner. The inner liner is joined to the inner surface of a carcass. The inner liner is formed from a crosslinked rubber having an excellent air blocking property. The inner liner maintains the internal pressure of the tire. The inner liner is normally composed of two layers. These layers are each formed from a rubber composition. In the rubber composition for one of the layers (hereinafter, first layer), the principal component of the base rubber is a butyl rubber such as isobutylene-isoprene-rubber and halogenated isobutylene-isoprene-rubber. In the rubber composition for the other layer (hereinafter, second layer), the principal component of the base rubber is a diene rubber such as natural rubber. The first layer serves to maintain the internal pressure of the tire, and the second layer serves to join the first layer to the carcass. Regarding the inner liner of the tire, various studies have been made in order to achieve weight reduction, improvement of adhesiveness, improvement of uniformity, and the like. One example of the studies is disclosed in JP2012-158166 (US2013/0230697). Each of the first layer and the second layer described above has a thickness of about 1 mm. The conventional inner liner composed of the first layer and the second layer has a thickness of about 2 mm. The inner liner is provided so as to cover the entirety of the inner surface of the tire. The influence of the inner liner on the weight of the tire is great. According to the technique disclosed in the above publication, an inner liner having a small thickness can be obtained. This inner liner is expected to contribute to weight reduction. However, in the case where this thin inner liner is used for a tire, in manufacture of the tire, when the inner liner is processed into a film shape and sent to the next step by a roller, the inner liner excessively sticks to the roller due to static electricity and cannot be sent to the next step in some cases. Each bead portion of a tire is fitted to a rim. The bead portion is brought into contact with the rim. In the tire, a chafer is provided for protecting the bead portion. In manufacture of the tire, an intermediate component obtained by combining an inner liner and chafers is prepared and assembled to other components to prepare a raw cover. The above-described thin inner liner has inferior adhesiveness to a chafer. Thus, when the thin inner liner is left in a state of a raw cover, the inner liner may peel from the chafer. Points to be improved remain regarding use of a thin inner liner for achieving weight reduction without deterioration of the internal pressure maintaining performance of a tire. An object of the present invention is to provide a pneumatic tire in which weight reduction is achieved without deterioration of the internal pressure maintaining performance of the tire. SUMMARY OF THE INVENTION A pneumatic tire according to the present invention includes a pair of beads, a carcass, an inner liner, a pair of chafers, and a pair of tie gums. The carcass extends on and between one of the beads and the other of the beads. The inner liner is joined to an inner surface of the carcass. Each chafer is turned up around the bead. Each tie gum is located between the carcass and the chafer. The inner liner is formed from a thermoplastic elastomer composition including a styrene-isobutylene-styrene block copolymer and has a thickness of not greater than 1.5 mm. The tie gum joins the inner liner and the chafer and has a volume resistivity of not greater than 108 Ω·cm. In the pneumatic tire according to the present invention, the inner liner is thin. Since the inner liner is formed from the thermoplastic elastomer composition including the styrene-isobutylene-styrene block copolymer, the inner liner sufficiently maintains the internal pressure of the tire although the inner liner is thin. In addition, it is not necessary to use a layer formed from a rubber composition including a diene rubber as a base rubber as in a conventional inner liner, in order to join the inner liner to the inner surface of the carcass. The inner liner contributes to weight reduction. In the tire, weight reduction is achieved without deterioration of the internal pressure maintaining performance of the tire. Furthermore, in the tire, the inner liner and the chafers are joined to each other by the tie gums provided between the carcass and the chafers. In the tire, since the tie gums have electrical conductivity, when the inner liner processed into a film shape is sent to the next step by a roller in manufacture of the tire, static electricity generated in the inner liner is discharged through the tie gums. Thus, the inner liner is sent to the next step without excessively sticking to the roller. Moreover, since the tie gums are interposed between the inner liner and the chafers, the inner liner is prevented from peeling from the chafers in a state of a raw cover prior to vulcanization. Regarding the tire, stable manufacture of the tire is possible with a conventional manufacturing facility. According to the present invention, a pneumatic tire in which weight reduction is achieved without deterioration of the internal pressure maintaining performance of the tire is obtained. Preferably, in the pneumatic tire, the inner liner has a thickness of not less than 0.5 mm. Preferably, in the pneumatic tire, a joint width of the inner liner and the tie gum is not less than 5 mm and not greater than 10 mm. Preferably, in the pneumatic tire, the tie gum is a processed product of a tie gum sheet. The tie gum sheet has a width of not less than 25 mm and not greater than 40 mm. Preferably, in the pneumatic tire, the tie gum sheet has a thickness of not less than 0.5 mm and not greater than 1.3 mm. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a cross-sectional view showing a portion of a pneumatic tire according to an embodiment of the present invention; FIG. 2 is a cross-sectional view of the tire taken along the line II-II in FIG. 1; and FIG. 3 is a conceptual diagram showing an intermediate component prepared for forming an inner liner, tie gums, and chafers of the tire in FIG. 1. DESCRIPTION OF THE PREFERRED EMBODIMENTS The following will describe in detail the present invention based on preferred embodiments with appropriate reference to the drawings. FIG. 1 shows a pneumatic tire 2. In FIG. 1, the up-down direction is the radial direction of the tire 2, the right-left direction is the axial direction of the tire 2, and the direction perpendicular to the surface of the sheet is the circumferential direction of the tire 2. In FIG. 1, an alternate long and short dash line CL represents the equator plane of the tire 2. The shape of the tire 2 is symmetrical about the equator plane except for a tread pattern. In FIG. 1, reference character PW indicates an axially outer end of the tire 2. The tire 2 has a maximum cross-sectional width at the outer end PW. In FIG. 1, the tire 2 is mounted on a rim R. The rim R is a normal rim. The tire 2 is inflated with air. Accordingly, the internal pressure of the tire 2 is adjusted to a normal internal pressure. In the present invention, unless otherwise specified, the dimensions and the angles of each component of the tire 2 are measured in this state. That is, in the present invention, the dimensions and the angles of each component of the tire 2 are measured in a state where the tire 2 is mounted on the normal rim and inflated with air to the normal internal pressure. During the measurement, no load is applied to the tire 2. In the case where the tire 2 is designed for a passenger car, the dimensions and angles are measured in a state where the internal pressure is 180 kPa, unless otherwise specified. In the present specification, the normal rim means a rim specified in a standard on which the tire 2 is based. The “Standard Rim” in the JATMA standard, the “Design Rim” in the TRA standard, and the “Measuring Rim” in the ETRTO standard are normal rims. In the present specification, the normal internal pressure means an internal pressure specified in the standard on which the tire 2 is based. The “highest air pressure” in the JATMA standard, the “maximum value” recited in “TIRE LOAD LIMITS AT VARIOUS COLD INFLATION PRESSURES” in the TRA standard, and the “INFLATION PRESSURE” in the ETRTO standard are normal internal pressures. The tire 2 includes a tread 4, a pair of sidewalls 6, a pair of clinches 8, a pair of beads 10, a carcass 12, a belt 14, a band 16, a pair of cushion layers 18, an inner liner 20, a pair of chafers 22, and a pair of tie gums 24. The tire 2 is of a tubeless type. The tire 2 is mounted to a passenger car. The tread 4 has a shape that is convex outward in the radial direction. The tread 4 forms a tread surface 26 that is brought into contact with a road surface. Grooves 28 are formed on the tread 4. The tread pattern is formed by the grooves 28. The tread 4 is formed from a crosslinked rubber. Particularly, a crosslinked rubber for which wear resistance, heat resistance, and grip performance are taken into consideration is used for a portion of the tread 4 that includes the tread surface 26. Each sidewall 6 extends from the edge of the tread 4 substantially inward in the radial direction. A radially outer portion of the sidewall 6 is joined to the tread 4. A radially inner portion of the sidewall 6 is joined to the clinch 8. The sidewall 6 is formed from a crosslinked rubber that has excellent cut resistance and weather resistance. The sidewall 6 prevents the carcass 12 from being damaged. Each clinch 8 is located substantially inward of the sidewall 6 in the radial direction. The clinch 8 is located outward of the bead 10 and the carcass 12 in the axial direction. The clinch 8 is formed from a crosslinked rubber that has excellent wear resistance. The clinch 8 comes into contact with a flange F of the rim R. Each bead 10 is located inward of the clinch 8 in the axial direction. The bead 10 includes a core 30 and an apex 32 extending from the core 30 outward in the radial direction. The core 30 has a ring shape and includes a non-stretchable wound wire. A typical material of the wire is steel. The apex 32 is tapered outward in the radial direction. The apex 32 is formed from a crosslinked rubber having high hardness. The carcass 12 includes a carcass ply 34. The carcass 12 of the tire 2 is composed of a single carcass ply 34. The carcass 12 may be composed of two or more carcass plies 34. The carcass ply 34 extends on and between the beads 10 at both sides and along the tread 4 and each sidewall 6. The carcass ply 34 is turned up around each core 30 from the inner side toward the outer side in the axial direction. Because of this turning-up, a main portion 36 and a pair of turned-up portions 38 are formed in the carcass ply 34. The carcass ply 34 includes the main portion 36 and the pair of turned-up portions 38. The main portion 36 extends on and between one of the cores 30 and the other of the cores 30. Each turned-up portion 38 extends outward in the radial direction from the core 30. The carcass ply 34 includes a large number of cords aligned with each other, and a topping rubber, which are not shown. The absolute value of the angle of each cord relative to the equator plane is 75° to 90°. In other words, the carcass 12 has a radial structure. The cords are formed from an organic fiber. Examples of preferable organic fibers include polyester fibers, nylon fibers, rayon fibers, polyethylene naphthalate fibers, and aramid fibers. The belt 14 is located inward of the tread 4 in the radial direction. The belt 14 is laminated on the carcass 12. The belt 14 reinforces the carcass 12. The belt 14 includes an inner layer 40 and an outer layer 42. As is obvious from FIG. 1, the width of the inner layer 40 is slightly larger than the width of the outer layer 42 in the axial direction. Each of the inner layer 40 and the outer layer 42 includes a large number of cords aligned with each other, and a topping rubber, which are not shown. Each cord is tilted relative to the equator plane. The absolute value of the tilt angle is generally not less than 10° and not greater than 35°. The direction in which each cord of the inner layer 40 is tilted relative to the equator plane is opposite to the direction in which each cord of the outer layer 42 is tilted relative to the equator plane. The material of the cords is preferably steel. An organic fiber may be used for the cords. The width, in the axial direction, of the belt 14 is preferably equal to or greater than 0.7 times of the maximum width of the tire 2. The belt 14 may include three or more layers. The band 16 is located outward of the belt 14 in the radial direction. The width of the band 16 is larger than the width of the belt 14 in the axial direction. The band 16 includes a cord and a topping rubber, which are not shown. The cord is helically wound. The band 16 has a so-called jointless structure. The cord extends substantially in the circumferential direction. The angle of the cord relative to the circumferential direction is not greater than 5° and further not greater than 2°. The belt 14 is held by the cord, so that lifting of the belt 14 is suppressed. The cord is formed from an organic fiber. Examples of preferable organic fibers include nylon fibers, polyester fibers, rayon fibers, polyethylene naphthalate fibers, and aramid fibers. Each cushion layer 18 is laminated on the carcass 12 in the vicinity of the edge of the belt 14. The cushion layer 18 is formed from a flexible crosslinked rubber. The cushion layer 18 absorbs stress on the edge of the belt 14. The inner liner 20 is located inward of the carcass 12. The inner liner 20 extends on and between one of the beads 10 and the other of the beads 10. In the tire 2, an edge 44 of the inner liner 20 is located inward of the apex 32 in the radial direction. Although described later, the inner liner 20 has an excellent air blocking property. The inner liner 20 maintains the internal pressure of the tire 2. FIG. 2 shows a portion of a cross-section of the tire 2 taken along the line II-II in FIG. 1. In FIG. 2, the right-left direction is the axial direction of tire 2, the up-down direction is the circumferential direction of the tire 2, and the direction perpendicular to the surface of the sheet is the radial direction of the tire 2. The line II-II is a straight line that passes through the outer end PW shown in FIG. 1 and extends in the axial direction. As shown in FIG. 2, the inner liner 20 of the tire 2 includes a first layer 46 and a second layer 48. Specifically, the inner liner 20 is composed of the first layer 46 and the second layer 48. The first layer 46 forms an inner portion of the inner liner 20, and the second layer 48 forms an outer portion of the inner liner 20. A plurality of other layers may be provided between the first layer 46 and the second layer 48. In the tire 2, the inner liner 20 is joined to the inner surface of the carcass 12 without another member being interposed therebetween. In the tire 2, the second layer 48 is joined to the inner surface of the carcass 12, and the first layer 46 is joined to the carcass 12 via the second layer 48. In the tire 2, each of the first layer 46 and the second layer 48 is formed from a thermoplastic elastomer composition. As described above, the inner liner 20 is composed of the first layer 46 and the second layer 48. The inner liner 20 is formed from a thermoplastic elastomer composition. The thermoplastic elastomer composition for the first layer 46 includes a styrene-isobutylene-styrene block copolymer (also referred to as styrene-isobutylene-styrene triblock copolymer (SIBS)) as a base polymer. In other words, the thermoplastic elastomer composition for the inner liner 20 includes the styrene-isobutylene-styrene block copolymer. The styrene-isobutylene-styrene block copolymer includes an isobutylene block. The isobutylene block contributes to an air blocking property. Thus, the first layer 46 including the styrene-isobutylene-styrene block copolymer is less likely to allow air to pass therethrough. The first layer 46 contributes to the air blocking property of the tire 2. In the tire 2, in light of air blocking property, the proportion of the styrene-isobutylene-styrene block copolymer to the entire base polymer is preferably not less than 5% by weight and more preferably not less than 10% by weight. In light of air blocking property, this proportion is particularly preferably 100% by weight, but this proportion is preferably not greater than 80% by weight in consideration of processability. In the tire 2, the molecular weight of the styrene-isobutylene-styrene block copolymer is not particularly limited. However, in light of fluidity, forming processability, rubber elasticity, and the like, the weight average molecular weight of the styrene-isobutylene-styrene block copolymer that is obtained by GPC (gel permeation chromatography) in terms of polystyrene is preferably not less than 50000 and preferably not greater than 400000. In light of air blocking property and durability, the weight proportion of the styrene component included in the styrene-isobutylene-styrene block copolymer is preferably not less than 10% by weight and preferably not greater than 30% by weight. The base polymer for the first layer 46 can include a rubber component in addition to the above-described styrene-isobutylene-styrene block copolymer. Examples of the rubber component include isobutylene-isoprene-rubber, natural rubber, and isoprene rubber. In the case where the base polymer includes a rubber component, the proportion of the rubber component to the entire base polymer is preferably not less than 60% by weight in light of processability. In light of air blocking property, this proportion is preferably not greater than 95% by weight. In the tire 2, the composition for the first layer 46 can include a tackifier. Examples of the tackifier include C9 petroleum resins and C5 petroleum resins. Examples of C9 petroleum resins include trade names “ARKON P70, P90, P100, P125, P140, M90, M100, M115, and M135”, manufactured by Arakawa Chemical Industries, Ltd. Examples of C5 petroleum resins include trade names “Hi-Rez G100” manufactured by Mitsui Chemicals, Inc., and trade name “Marukarez T100AS” manufactured by Maruzen Petrochemical Co., Ltd. In the case where the composition includes a tackifier, the amount of the tackifier with respect to 100 parts by weight of the base polymer is preferably not less than 5 parts by weight from the standpoint that favorable stickiness is obtained. In light of processability, this amount is preferably not greater than 20 parts by weight. In the tire 2, the composition for the first layer 46 can include chemicals, such as a filler such as carbon black, a lubricant such as stearic acid, an antioxidant, and the like, in addition to the above-described tackifier. In consideration of processability and performance of the tire 2, optimum chemicals are blended into the composition in optimum amounts. The thermoplastic elastomer composition for the second layer 48 includes a base polymer. Examples of the base polymer used for the composition include a styrene-isoprene-styrene block copolymer (also referred to as styrene-isoprene-styrene triblock copolymer (SIS)) and a styrene-isobutylene copolymer (also referred to as styrene-isobutylene diblock copolymer (SIB)). In the tire 2, the second layer 48 may be composed of a layer formed from a composition including the styrene-isoprene-styrene block copolymer as a base polymer, or may be composed of a layer formed from a composition including the styrene-isobutylene copolymer as a base polymer. The second layer 48 may be composed of a combination of one layer formed from a composition including the styrene-isoprene-styrene block copolymer as a base polymer and another layer formed from a composition including the styrene-isobutylene copolymer as a base polymer. In the styrene-isoprene-styrene block copolymer, an isoprene block is a soft segment. The styrene-isoprene-styrene block copolymer contributes to the adhesiveness and the stickiness of the second layer 48. In the styrene-isobutylene copolymer, an isobutylene block is a soft segment. The styrene-isobutylene copolymer also contributes to the adhesiveness and the stickiness of the second layer 48. In the tire 2, in the case where the base polymer includes the styrene-isoprene-styrene block copolymer, in light of adhesiveness and stickiness, the proportion of the styrene-isoprene-styrene block copolymer to the entire base polymer is preferably not less than 5% by weight and more preferably not less than 10% by weight. In light of adhesiveness and stickiness, this weight proportion is particularly preferably 100% by weight, but this proportion is preferably not greater than 80% by weight in consideration of processability. In the tire 2, in the case where the base polymer includes the styrene-isobutylene copolymer, in light of adhesiveness and stickiness, the proportion of the styrene-isobutylene copolymer to the entire base polymer is preferably not less than 5% by weight and more preferably not less than 10% by weight. In light of adhesiveness and stickiness, this weight proportion is particularly preferably 100% by weight, but this proportion is preferably not greater than 80% by weight in consideration of processability. In the tire 2, the molecular weight of the styrene-isoprene-styrene block copolymer is not particularly limited. However, in light of forming processability, rubber elasticity, and the like, the weight average molecular weight of the styrene-isoprene-styrene block copolymer that is obtained by GPC (gel permeation chromatography) in terms of polystyrene is preferably not less than 100000 and preferably not greater than 290000. In light of stickiness, adhesiveness, and rubber elasticity, the weight proportion of the styrene component included in the styrene-isoprene-styrene block copolymer is preferably not less than 10% by weight and preferably not greater than 30% by weight. In the tire 2, the molecular weight of the styrene-isobutylene copolymer is not particularly limited. However, in light of forming processability, rubber elasticity, and the like, the weight average molecular weight of the styrene-isobutylene copolymer that is obtained by GPC (gel permeation chromatography) in terms of polystyrene is preferably not less than 40000 and preferably not greater than 120000. In light of stickiness, adhesiveness, and rubber elasticity, the weight proportion of the styrene component included in the styrene-isobutylene copolymer is preferably not less than 10% by weight and preferably not greater than 35% by weight. In the tire 2, the composition for the second layer 48 can include chemicals, such as a rubber component such as natural rubber, a filler such as carbon black, a lubricant such as stearic acid, an antioxidant, and the like, in addition to the above-described base polymer. In consideration of processability and performance of the tire 2, optimum chemicals are blended into the composition in optimum amounts. As described above, in the tire 2, the inner liner 20 is composed of the first layer 46 and the second layer 48. In light of productivity, the inner liner 20 may be composed of only the first layer 46. Whether, for example, the inner liner 20 is composed of the first layer 46 and the second layer 48 or the inner liner 20 is composed of only the first layer 46, is determined as appropriate according to the specifications of the tire 2. As shown in FIG. 1, in the tire 2, each chafer 22 is located in the vicinity of the bead 10. The chafer 22 is turned up around the bead 10 from the inner side toward the outer side in the axial direction. An edge 50 (hereinafter, first edge) portion of the chafer 22 is located inward of the main portion 36 of the carcass 12 in the axial direction. The first edge 50 portion is located inward of the inner liner 20 in the axial direction. As shown, the first edge 50 of the chafer 22 is located outward of the edge 44 of the inner liner 20 in the radial direction. The first edge 50 of the chafer 22 is located outward of the core 30 in the radial direction. In the tire 2, the chafer 22 and the inner liner 20 overlap each other in the axial direction. Another edge 52 (hereinafter, second edge) portion of the chafer 22 is located outward of the turned-up portion 38 of the carcass 12 in the axial direction. The second edge 52 is interposed between the turned-up portion 38 and the clinch 8. When the tire 2 is mounted onto the rim R, the chafer 22 comes into contact with the rim R. Because of this contact, the vicinity of the bead 10 is protected. The chafer 22 includes a fabric and a rubber with which the fabric is impregnated. In the tire 2, a chafer 22 formed from a crosslinked rubber may be used. Each tie gum 24 is located between the carcass 12 and the chafer 22. In the tire 2, the tie gum 24 is located between the first edge 50 portion of the chafer 22 and an edge 44 portion of the inner liner 20. The position of an edge 54 (hereinafter, first edge) of the tie gum 24 coincides with the position of the first edge 50 of the chafer 22 in the radial direction. The tie gum 24 is formed from a crosslinked rubber having excellent adhesiveness. The tie gum 24 firmly joins to the carcass 12 and the inner liner 20 and also firmly joins to the chafer 22. Another edge 56 (hereinafter, second edge) of the tie gum 24 is located near the position of a heel (reference character H in FIG. 1) of the tire 2. In the tire 2, at a radially outer portion with respect to the position H, the tie gum 24 is not provided between the turned-up portion 38 and the chafer 22. A rubber composition for each tie gum 24 includes a base rubber. In the tire 2, the principal component of the base rubber is preferably a diene rubber. The diene rubber contributes to adhesiveness. Examples of the diene rubber include natural rubber, isoprene rubber, butadiene rubber, styrene-butadiene rubber, chloroprene rubber, and acrylonitrile butadiene rubber. In light of adhesiveness, natural rubber is preferable as the diene rubber. Two or more types of diene rubbers may be used in combination. In the tire 2, in light of processability, the base rubber can include another rubber other than the diene rubber. Examples of the other rubber include ethylene-propylene rubber, urethane rubber, and acrylic rubber. As described above, the principal component of the base rubber is preferably the diene rubber. In the case where the base rubber includes another rubber other than the diene rubber, the proportion of the diene rubber to the entire base rubber is not less than 60% by weight and particularly preferably not less than 80% by weight. The rubber composition includes a reinforcing agent. The reinforcing agent is typically carbon black. FEF, GPF, HAF, ISAF, SAF, and the like can be used. The rubber composition can also include chemicals such as a filler, a softener, a tackifier, a crosslinking agent such as sulfur or the like, a vulcanization accelerator, a crosslinking activator, an antioxidant, and the like, in addition to the reinforcing agent. In consideration of processability and performance of the tire 2, optimum chemicals are blended into the rubber composition in optimum amounts. In FIG. 2, a double-headed arrow TI represents the thickness of the inner liner 20. In the tire 2, the thickness TI of the inner liner 20 is not greater than 1.5 mm. In the tire 2, the inner liner 20 is thin. Since the inner liner 20 is formed from the thermoplastic elastomer composition including the styrene-isobutylene-styrene block copolymer, the inner liner 20 sufficiently maintains the internal pressure of the tire 2 although the inner liner 20 is thin. In addition, it is not necessary to use a layer formed from a rubber composition including a diene rubber as abase rubber as in a conventional inner liner, in order to join the inner liner 20 to the inner surface of the carcass 12. The inner liner 20 contributes to weight reduction. In the tire 2, weight reduction is achieved without deterioration of the internal pressure maintaining performance of the tire 2. When the inner liner 20 is excessively thin, the inner liner 20 may not be able to sufficiently maintain the internal pressure of the tire 2. From the standpoint that the inner liner 20 can sufficiently perform its function to maintain the internal pressure of the tire 2, the thickness TI of the inner liner 20 is preferably not less than 0.5 mm. The tire 2 described above is manufactured as follows. In manufacture of the tire 2, a plurality of rubber components are assembled to obtain a raw cover (unvulcanized tire 2). The raw cover is put into a mold. The outer surface of the raw cover comes into contact with the cavity surface of the mold. The inner surface of the raw cover comes into contact with a bladder or a rigid core. The raw cover is pressurized and heated in the mold. A rubber composition of the raw cover flows due to the pressurization and the heating. Crosslinking reaction is caused in the rubber due to the heating, to obtain the tire 2 shown in FIG. 1. By using a mold having a rugged pattern on the cavity surface thereof, a rugged pattern is formed on the tire 2. In manufacture of the tire 2, for forming the inner liner 20, the pair of tie gums 24, and the pair of chafers 22, an intermediate component obtained by combining these components is prepared. In manufacture of the tire 2, an intermediate component 58 shown in FIG. 3 is supplied to a former (not shown) and combined with other components to obtain a raw cover. In manufacture of the tire 2, in a preparation step of preparing the intermediate component 58, fabrics are impregnated with a rubber, and sheet-shaped chafers 22 are prepared. In manufacture of the tire 2, the chafers 22 of the tire 2 shown in FIG. 1 are obtained by adjusting the shapes of the sheet-shaped chafers 22 and pressurizing and heating the sheet-shaped chafers 22 in a mold. The chafers 22 in the tire 2 are processed products of the sheet-shaped chafers 22. In the present invention, when the sheet-shaped chafers 22 are represented in distinction from the chafers 22 in the tire 2, the sheet-shaped chafers 22 are referred to as chafer sheets 60. The chafers 22 in the tire 2 are processed products of the chafer sheets 60. The length of each chafer sheet 60 is determined in consideration of the length, in the circumferential direction, of the chafer 22 in the tire 2. The width of each chafer sheet 60 is determined in consideration of the length of the chafer 22 in the cross-section of the tire 2 shown in FIG. 1. In the preparation step, sheet-shaped tie gums 24 are prepared by extruding the rubber composition for the tie gums 24. In manufacture of the tire 2, the tie gums 24 of the tire 2 shown in FIG. 1 are obtained by adjusting the shapes of the sheet-shaped tie gums 24 and pressurizing and heating the sheet-shaped tie gums 24 in a mold. The tie gums 24 in the tire 2 are processed products of the sheet-shaped tie gums 24. In the present invention, when the sheet-shaped tie gums 24 are represented in distinction from the tie gums 24 in the tire 2, the sheet-shaped tie gums 24 are referred to as tie gum sheets 62. The tie gums 24 in the tire 2 are processed products of the tie gum sheets 62. The length of each tie gum sheet 62 is determined in consideration of the length, in the circumferential direction, of the tie gum 24 in the tire 2. In the preparation step, a film-shaped inner liner 20 is prepared by co-extruding the thermoplastic elastomer composition for the first layer 46 and the thermoplastic elastomer composition for the second layer 48. In manufacture of the tire 2, the inner liner 20 of the tire 2 shown in FIG. 1 is obtained by adjusting the shape of the film-shaped inner liner 20 and pressurizing and heating the film-shaped inner liner 20 in a mold. The inner liner 20 in the tire 2 is a processed product of the film-shaped inner liner 20. In the present invention, when the film-shaped inner liner 20 is represented in distinction from the inner liner 20 in the tire 2, the film-shaped inner liner 20 is referred to as inner film 64. The inner liner 20 in the tire 2 is a processed product of the inner film 64. The inner film 64 is composed of a film-shaped first layer 46 and a film-shaped second layer 48. In the present invention, when the film-shaped first layer 46 is represented in distinction from the first layer 46 in the tire 2, the film-shaped first layer 46 is referred to as first film 66. When the film-shaped second layer 48 is represented in distinction from the second layer 48 in the tire 2, the film-shaped second layer 48 is referred to as second film 68. The length of the inner film 64 is determined in consideration of the length, in the circumferential direction, of the inner liner 20 in the tire 2. The width of the inner film 64 is determined in consideration of the length of the inner liner 20 in the cross-section of the tire 2 shown in FIG. 1. In manufacture of the tire 2, after the chafer sheets 60, the tie gum sheets 62, and the inner film 64 are prepared, these components are combined as shown in FIG. 3. Accordingly, the intermediate component 58 is obtained. The intermediate component 58 is composed of a pair of the chafer sheets 60, a pair of the tie gum sheets 62, and the inner film 64. In other words, the intermediate component 58 is composed of a pair of the chafers 22 processed into a sheet shape, a pair of the tie gums 24 processed into a sheet shape, and the inner liner 20 processed into a film shape. In the intermediate component 58, the tie gum sheets 62 are laminated on the right and left chafer sheets 60, respectively. As shown in FIG. 3, the widths of the tie gum sheets 62 are set such that the tie gum sheets 62 are narrower than the chafer sheets 60. Thus, the entireties of the tie gum sheets 62 are laminated on the chafer sheets 60. Then, edge 70 portions of the inner film 64 are laminated on the right and left tie gum sheets 62, respectively. In this lamination, the first film 66 forming a part of the inner film 64 is laminated on the tie gum sheets 62. In the intermediate component 58, the edge 70 portions of the inner film 64 are joined to the tie gum sheets 62, and the tie gum sheets 62 are joined to the chafer sheets 60. As described above, the rubber composition for the tie gums 24 includes carbon black as a reinforcing agent. Carbon black has a property of conducting electricity. Thus, the tie gums 24 have electrical conductivity. Specifically, the volume resistivity of each tie gum 24 is not greater than 108 Ω·cm. The tie gum sheets 62 are formed from the rubber composition for the tie gums 24. Thus, the tie gum sheets 62 also have electrical conductivity. In the tire 2, the inner liner 20 and the chafers 22 are joined to each other by the tie gums 24 provided between the carcass 12 and the chafers 22. In the tire 2, since the tie gums 24 have electrical conductivity, when the intermediate component 58 including the inner liner 20 processed into a film shape is sent to the next step by a roller in manufacture of the tire 2, static electricity generated in the inner liner 20 is discharged through the tie gums 24 processed into a sheet shape. Thus, the intermediate component 58 is sent to the next step without excessively sticking to the roller. Moreover, since the tie gums 24 are interposed between the inner liner 20 and the chafers 22, the inner liner 20 is prevented from peeling from the chafers 22 in a state of the raw cover prior to vulcanization. Regarding the tire 2, stable manufacture of the tire 2 is possible with a conventional manufacturing facility. As described above, in the tire 2, weight reduction is achieved without deterioration of the internal pressure maintaining performance of the tire 2. That is, according to the present invention, the pneumatic tire 2 in which weight reduction is achieved without deterioration of the internal pressure maintaining performance of the tire 2 is obtained. In FIG. 3, a double-headed arrow WL represents a joint width of the inner liner 20 and the tie gum 24. The joint width WL is obtained by measuring the length from the edge 70 of the inner film 64 to an edge 72 of the tie gum sheet 62. The joint width WL agrees with the length from the edge 44 of the inner liner 20 to the first edge 50 of the tie gum 24 in the tire 2 shown in FIG. 1. In manufacture of the tire 2, the joint width WL is preferably not less than 5 mm and not greater than 10 mm. By the joint width WL being set to be not less than 5 mm, the inner liner 20 is sufficiently joined to each tie gum 24, so that the inner liner 20 is prevented from peeling from the tie gum 24. Since a sufficient joint width is obtained, favorable internal pressure maintaining performance is achieved in the tire 2. By the joint width WL being set to be not greater than 10 mm, the tie gum 24 having a sufficient volume is formed between the carcass 12 and each chafer 22, particularly, at a radially inner side portion with respect to the core 30 of the bead 10, in the tire 2. The tire 2 is less likely to be displaced relative to the rim R. In FIG. 3, a double-headed arrow WT represents the width of the tie gum sheet 62. A double-headed arrow TT represents the thickness of the tie gum sheet 62. In manufacture of the tire 2, the width WT of each tie gum sheet 62 is preferably not less than 25 mm and not greater than 40 mm. By the width WT being set to be not less than 25 mm, the tie gum 24 having a sufficient volume is formed between the carcass 12 and each chafer 22, particularly, at the radially inner side portion with respect to the core 30 of the bead 10, in the tire 2. The tire 2 is less likely to be displaced relative to the rim R. By the width WT being set to be not greater than 40 mm, the volume of the tie gum 24 at the radially inner side portion with respect to the core 30 of the bead 10 is appropriately maintained in the tire 2. In the tire 2, an increase in fitting pressure and influence of the tie gum 24 on the weight are suppressed. In manufacture of the tire 2, the thickness TT of each tie gum sheet 62 is preferably not less than 0.5 mm and not greater than 1.3 mm. By the thickness TT being set to be not less than 0.5 mm, the tie gum 24 having a sufficient volume is formed between the carcass 12 and each chafer 22, particularly, at the radially inner side portion with respect to the core 30 of the bead 10, in the tire 2. The tire 2 is less likely to be displaced relative to the rim R. By the thickness TT being set to be not greater than 1.3 mm, the volume of the tie gum 24 at the radially inner side portion with respect to the core 30 of the bead 10 is appropriately maintained in the tire 2. In the tire 2, an increase in fitting pressure and influence of the tie gum 24 on the weight are suppressed. In FIG. 3, a double-headed arrow T1 represents the thickness of the first film 66. A double-headed arrow T2 represents the thickness of the second film 68. In the case where the inner liner 20 is composed of the first layer 46 and the second layer 48, in manufacture of the tire 2, the thickness T1 of the first film 66 is preferably not less than 0.2 mm and not greater than 0.8 mm. By the thickness T1 being set to be not less than 0.2 mm, the first layer 46 effectively contributes to the internal pressure maintaining performance of the tire 2 in cooperation with the second layer 48. By the thickness T1 being set to be not greater than 0.8 mm, influence of the first layer 46 on the weight is suppressed in the tire 2. In the case where the inner liner 20 is composed of the first layer 46, the thickness T1 of the first film 66 is preferably not less than 0.5 mm in light of internal pressure maintaining performance, and is preferably not greater than 1.5 mm in light of influence on the weight of the tire 2. In manufacture of the tire 2, the thickness T2 of the second film 68 is preferably not less than 0.2 mm and not greater than 0.8 mm. By the thickness T2 being set to be not less than 0.2 mm, the second film 68 contributes to the stickiness and the adhesiveness of the inner liner 20. The second layer 48, which is the processed product of the second film 68, contributes to the internal pressure maintaining performance of the tire 2 in cooperation with the first layer 46. By the thickness T2 being set to be not greater than 0.8 mm, influence of the second layer 48 on the weight is suppressed in the tire 2. EXAMPLES Example 1 The intermediate component shown in FIG. 3 was prepared, and the tire shown in FIGS. 1 and 2 was produced. The size of the tire is 195/65R15. The thickness TI of the inner liner was set to 1.0 mm. The width WT of each tie gum sheet was set to 25 mm. The thickness TT of each tie gum sheet was set to 0.7 mm. “8” is shown in the row of “logR” in Table 1 below and indicates that the volume resistivity of each tie gum was set to 108 Ω·cm. The joint width WL of the inner film and each tie gum sheet was set to 10 mm. In Example 1 (abbreviated as “Ex. 1” in table 1), the inner liner is composed of a first layer and a second layer. In the inner liner, the first layer and the second layer were formed so as to have the same thickness. In Example 1, an inner film was prepared by co-extruding a thermoplastic elastomer composition for the first layer and a thermoplastic elastomer composition for the second layer. For the first layer, a thermoplastic elastomer composition having the following components was used. Base polymer (SIBS) (*1) 100 parts by weight Tackifier (*2) 10 parts by weight For the second layer, a thermoplastic elastomer composition having the following components was used. Base polymer 100 parts by weight SIS (*3) (50 parts by weight) SIBS (*1) (50 parts by weight) (*1) Styrene-isobutylene-styrene block copolymer (trade name “SIBSTAR 102T (Shore A hardness=25, styrene component content=25% by weight, weight average molecular weight=100000)” manufactured by Kaneka Corporation). (*2) Trade name “ARKON P140 (C9 petroleum resin, softening point=140° C., weight average molecular weight =70000)” manufactured by Arakawa Chemical Industries, Ltd. (*3) Styrene-isoprene-styrene block copolymer (trade name “D1161JP (styrene component content=15% by weight, weight average molecular weight=150000)” manufactured by Kraton Corporation). Comparative Example 1 In Comparative Example 1 (abbreviated as “Comp. 1” in table 1), a conventional tire was manufactured. As the inner liner of Comparative Example 1, a conventional inner liner is used. The inner liner is composed of two layers each formed from a rubber composition. In the rubber composition for one of the layers (hereinafter, butyl layer), the principal component of the base rubber is isobutylene-isoprene-rubber. In the rubber composition for the other layer (tie gum layer), the principal component of the base rubber is natural rubber. The thickness of the butyl layer was 1.0 mm, and the thickness of the tie gum layer was 1.0 mm (the thickness of the inner liner=2.0 mm) . Comparative Example 2 A tire of Comparative Example 2 was manufactured in the same manner as Example 1, except the tie gums were not used. In Comparative Example 2, the joint width of each chafer and the inner liner was set to 10 mm. This is shown as “10” in the row of the joint width WL in Table 1 below. Comparative Example 3 A tire of Comparative Example 3 was manufactured in the same manner as Example 1, except the width WT of each tie gum sheet and the volume resistivity of each tie gum were as shown in Table 1 below. Examples 2 to 4 and Comparative Example 4 Tires of Examples 2 to 4 and Comparative Example 4 were manufactured in the same manner as Example 1, except the thickness TI of the inner liner was as shown in Table 2 below. Examples 5 to 7 Tires of Examples 5 to 7 were manufactured in the same manner as Example 1, except the joint width WL was as shown in Table 3 below. Examples 8 to 10 Tires of Examples 8 to 10 were manufactured in the same manner as Example 1, except the width WT of each tie gum sheet was as shown in Table 3 below. Examples 11 to 14 Tires of Examples 11 to 14 were manufactured in the same manner as Example 1, except the width WT and the thickness TT of each tie gum sheet were as shown in Table 4 below. [Manufacturability] In manufacture of each tire, whether the intermediate component excessively stuck to a roll and whether the inner liner peeled from the chafer in a state of a raw cover were confirmed. The results are shown in Tables 1 to 4 below. In Tables 1 to 4, the results are shown as “GOOD” when a tire was able to be manufactured without occurrence of excessive sticking and peeling, and are shown as “BAD” when excessive sticking or peeling occurred and a tire was not able to be manufactured. [Weight] The weight of each tire was measured. The results are shown in Tables 1 to 4 below as indexes with the value of Comparative Example 1 being defined as 100. The lower the value is, the lighter the tire is. [Internal Pressure Maintaining Performance] Each tire was mounted onto a normal rim and inflated with air to an internal pressure of 230 kPa. In the air-inflated state, the tire was stored at room temperature (20° C. to 30° C.). At the time when 2 months elapsed, the internal pressure of the tire was measured, and the reduction ratio of the internal pressure was obtained. The results are shown in Tables 1 to 4 below as indexes with the value of Comparative Example 1 being defined as 100. The lower the value is, the more the internal pressure is maintained. 80 or lower as an index value was set as a target. [Detachment from Rim] Each tire was mounted onto a normal rim and inflated with air to an internal pressure of 230 kPa. Lateral force was applied to the bead portion of the tire in compliance with the test conditions specified in FMVSS139, and the lateral force applied when the bead portion became detached from a seat surface of the rim was measured. The results are shown in Tables 1 to 4 below as indexes with the value of Comparative Example 1 being defined as 100. The higher the value is, the more the tire is unlikely to be detached from the rim. 75 or higher as an index value was set as a target. [Hofmann] The tightening force of each test tire was measured with a Hofmann compression tester. The results are shown in Tables 1 to 4 below as indexes with the value of Comparative Example 1 being defined as 100. The higher the value is, the greater the tightening force is, and the more the tire is unlikely to be displaced relative to the rim. Being in a range of 65 to 135 as an index value was set as a target. [Fittability] Each tire was fitted to a normal rim, was filled with air (supply pressure=600 kPa), and was mounted onto the rim. At the moment when the bead portion of the tire climbed over a hump of the rim, the filling with air was stopped once, and the pressure (fitting pressure) was measured. The results are shown in Tables 1 to 4 below as indexes with the value of Comparative Example 1 being defined as 100. The higher the value is, the higher the fitting pressure is. 250 or lower as an index value was set as an acceptable level, and 125 or lower was set as a target. TABLE 1 Results of Evaluation Comp. Comp. Comp. Ex. 1 2 3 1 Inner liner Thickness TI — 1.0 1.0 1.0 [mm] Tie gum Width WT — — 15 25 [mm] Thickness TT — — 0.7 0.7 [mm] logR [Ω · cm] — — 9 8 Joint width — 10 10 10 WL [mm] Manufacturability GOOD BAD BAD GOOD Weight 100 — — 96 Internal 100 — — 64 pressure maintaining performance Detachment 100 — — 96 from rim Hofmann 100 — — 96 Fittability 100 — — 96 TABLE 2 Results of Evaluation Ex. Ex. Ex. Comp. 2 3 4 4 Inner liner Thickness TI 0.3 0.5 1.5 1.8 [mm] Tie gum Width WT 25 25 25 25 [mm] Thickness TT 0.7 0.7 0.7 0.7 [mm] logR [Ω · cm] 8 8 8 8 Joint width 10 10 10 10 WL [mm] Manufacturability GOOD GOOD GOOD GOOD Weight 92 94 99 101 Internal 83 68 57 53 pressure maintaining performance Detachment 96 96 96 96 from rim Hofmann 92 97 92 89 Fittability 83 83 83 75 TABLE 3 Results of Evaluation Ex. Ex. 5 Ex. 6 Ex. 7 Ex. 8 Ex. 9 10 Inner liner Thickness TI 1.0 1.0 1.0 1.0 1.0 1.0 [mm] Tie gum Width WT 25 25 25 15 35 40 [mm] Thickness TT 0.7 0.7 0.7 0.7 0.7 0.7 [mm] logR [Ω · cm] 8 8 8 8 8 8 Joint width 3 5 15 10 10 10 WL [mm] Manufacturability GOOD GOOD GOOD GOOD GOOD GOOD Weight 96 96 96 95 97 97 Internal 83 64 64 64 64 64 pressure maintaining performance Detachment 99 96 92 71 96 96 from rim Hofmann 92 96 72 61 95 92 Fittability 92 96 79 67 92 92 TABLE 4 Results of Evaluation Ex. Ex. Ex. Ex. 11 12 13 14 Inner liner Thickness TI 1.0 1.0 1.0 1.0 [mm] Tie gum Width WT 25 25 40 40 [mm] Thickness TT 0.3 0.5 1.3 1.6 [mm] logR [Ω · cm] 8 8 8 8 Joint width 10 10 10 10 WL [mm] Manufacturability GOOD GOOD GOOD GOOD Weight 95 96 98 98 Internal 64 64 64 64 pressure maintaining performance Detachment 75 93 100 113 from rim Hofmann 79 90 111 145 Fittability 75 88 200 267 As shown in Tables 1 to 4, the evaluation for the tires of the examples is higher than that for the tires of the comparative examples. From the results of evaluation, advantages of the present invention are clear. The above-described technique regarding the inner liner is also applicable to various types of tires. The above descriptions are merely illustrative examples, and various modifications can be made without departing from the principles of the present invention.
<SOH> BACKGROUND OF THE INVENTION <EOH>
<SOH> SUMMARY OF THE INVENTION <EOH>A pneumatic tire according to the present invention includes a pair of beads, a carcass, an inner liner, a pair of chafers, and a pair of tie gums. The carcass extends on and between one of the beads and the other of the beads. The inner liner is joined to an inner surface of the carcass. Each chafer is turned up around the bead. Each tie gum is located between the carcass and the chafer. The inner liner is formed from a thermoplastic elastomer composition including a styrene-isobutylene-styrene block copolymer and has a thickness of not greater than 1.5 mm. The tie gum joins the inner liner and the chafer and has a volume resistivity of not greater than 10 8 Ω·cm. In the pneumatic tire according to the present invention, the inner liner is thin. Since the inner liner is formed from the thermoplastic elastomer composition including the styrene-isobutylene-styrene block copolymer, the inner liner sufficiently maintains the internal pressure of the tire although the inner liner is thin. In addition, it is not necessary to use a layer formed from a rubber composition including a diene rubber as a base rubber as in a conventional inner liner, in order to join the inner liner to the inner surface of the carcass. The inner liner contributes to weight reduction. In the tire, weight reduction is achieved without deterioration of the internal pressure maintaining performance of the tire. Furthermore, in the tire, the inner liner and the chafers are joined to each other by the tie gums provided between the carcass and the chafers. In the tire, since the tie gums have electrical conductivity, when the inner liner processed into a film shape is sent to the next step by a roller in manufacture of the tire, static electricity generated in the inner liner is discharged through the tie gums. Thus, the inner liner is sent to the next step without excessively sticking to the roller. Moreover, since the tie gums are interposed between the inner liner and the chafers, the inner liner is prevented from peeling from the chafers in a state of a raw cover prior to vulcanization. Regarding the tire, stable manufacture of the tire is possible with a conventional manufacturing facility. According to the present invention, a pneumatic tire in which weight reduction is achieved without deterioration of the internal pressure maintaining performance of the tire is obtained. Preferably, in the pneumatic tire, the inner liner has a thickness of not less than 0.5 mm. Preferably, in the pneumatic tire, a joint width of the inner liner and the tie gum is not less than 5 mm and not greater than 10 mm. Preferably, in the pneumatic tire, the tie gum is a processed product of a tie gum sheet. The tie gum sheet has a width of not less than 25 mm and not greater than 40 mm. Preferably, in the pneumatic tire, the tie gum sheet has a thickness of not less than 0.5 mm and not greater than 1.3 mm.
B60C150635
20170913
20180503
60315.0
B60C1506
0
BRADY, GEORGE WALKER
PNEUMATIC TIRE
UNDISCOUNTED
0
PENDING
B60C
2,017
15,703,964
ACCEPTED
METHOD AND SYSTEM FOR DATA DEMULTIPLEXING
A method and system for demultiplexing packets of a message is provided. The demultiplexing system receives packets of a message, identifies a sequence of message handlers for processing the message, identifies state information associated with the message for each message handler, and invokes the message handlers passing the message and the associated state information. The system identifies the message handlers based on the initial data type of the message and a target data type. The identified message handlers effect the conversion of the data to the target data type through various intermediate data types.
1-25. (canceled) 26. A method, comprising: receiving, at a computing device having a processing circuit, a packet of a message; determining, by the computing device, a key value for packet, wherein the key value is determined based on one or more headers in the packet; using, by the computing device, the key value to determine whether the computing device is currently storing a previously created path for the key value; in response to determining that no path is currently stored for the key value, the computing device: identifying, using the key value, one or more routines for processing the packet, including a routine that is used to execute a Transmission Control Protocol (TCP) to convert packets having a TCP format into a different format; creating a path using the identified one or more routines; and processing the packet using the created path. 27. The method of claim 26, wherein the created path stores state information for at least one of the identified one or more routines. 28. The method of claim 26, wherein the created path stores state information for each of the identified one or more routines. 29. The method of claim 26, wherein the created path specifies an ordering in which the identified one or more routines are to be performed to process the packet. 30. The method of claim 29, wherein the ordering specifies that an application layer protocol is to be performed subsequent to the TCP. 31. The method of claim 30, wherein the application layer protocol is HTTP, and wherein the different format is HTTP. 32. The method of claim 29, wherein the ordering specifies that a first execution of the TCP is to be followed by execution of an application layer protocol, which is to be followed by a second execution of the TCP. 33. The method of claim 32, wherein the first execution of the TCP receives information from a network and the second execution of the TCP sends information via the network. 34. The method of claim 29, wherein the ordering specifies that the TCP is an initial one of the one or more routines. 35. The method of claim 29, wherein the ordering specifies that the TCP is to be performed after performing an Ethernet protocol. 36. The method of claim 26, further comprising: receiving, at the computing device, a subsequent packet of the message; determining, by the computing device based on the subsequent packet, the key value; using, by the computing device, the key value to identify the created path for the message; and processing, by the computing device, the subsequent packet using the path. 37. The method of claim 36, wherein processing the subsequent packet includes: queuing the subsequent packet for one or more routines specified in the path; and performing the one or more routines according to an ordering specified by the path, wherein performing at least one of the routines includes accessing state information stored in the path. 38. The method of claim 36, wherein packets of the message are all associated with a single TCP session. 39. The method of claim 26, wherein the key value includes an IP address and one or more port addresses. 40. A method, comprising: receiving, at a computing device having a processing circuit, a packet of a message; determining, by the computing device, a key value for the packet, wherein the key value is determined based on one or more headers in the packet; using, by the computing device, the key value to determine whether the computing device is currently storing a previously created path for the key value; in response to determining that no path is currently stored for the key value, the computing device: identifying, using the key value, one or more routines for processing the packet, including a routine that is used to execute a User Datagram Protocol (UDP) to convert packets having a UDP format into a different format; creating a path using the identified one or more routines; and processing the packet using the created path. 41. An apparatus, comprising: a network interface; a processor circuit; a memory storing program instructions executable by the processor circuit to: receiving, via the network interface, a packet of a message; determine a key value for the packet, wherein the key value is determined based on one or more headers in the packet; use the key value to determine whether the apparatus is currently storing a path for the key value, wherein one or more routines are specified in the path for processing packets of the message; in response to determining that no path is currently stored for the key value: identify, using the key value, one or more routines for processing the packet, including a particular routine that is used to execute a Transmission Control Protocol (TCP) to convert packets having a TCP format into a different format; create a path using the identified one or more routines; process the packet using the created path; and store the path for use in processing subsequent packets in the message; and in response to determining that a path is currently stored for the key value; process the packet using the stored path. 42. The apparatus of claim 41, wherein the apparatus is configured to process the packet by queuing the packet for the one or more routines identified in the path. 43. The apparatus of claim 41, wherein the different format is an application layer format. 44. The apparatus of claim 41, wherein the particular routine is executable to utilize state information stored within the path. 45. The apparatus of claim 41, wherein the path stores state information for at least some of the one or more routines.
CROSS REFERENCES TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 10/636,314, filed Aug. 6, 2003, titled Method and System for Data Demultiplexing, for all purposes including but not limited to the right of priority and benefit of earlier filing date, and expressly incorporates by reference the entire content of patent application Ser. No. 10/636,314 for all purposes. U.S. patent application Ser. No. 10/636,314 is a continuation of U.S. patent application Ser. No. 09/474,664 (now U.S. Pat. No. 6,629,163), filed Dec. 29, 1999, titled Method and System for Demultiplexing a First Sequence of Packet Components to Identify Specific Components Wherein Subsequent Components Are Processed Without Re-Identifying Components. This application claims the benefit of the following applications for all purposes including but not limited to the right of priority and benefit of earlier filing date, and expressly incorporates by reference the entire content of the following applications for all purposes: U.S. patent application Ser. No. 10/636,314; and U.S. patent application Ser. No. 09/474,664. TECHNICAL FIELD The present invention relates generally to a computer system for data demultiplexing. BACKGROUND Computer systems, which are becoming increasingly pervasive, generate data in a wide variety of formats. The Internet is an example of interconnected computer systems that generate data in many different formats. Indeed, when data is generated on one computer system and is transmitted to another computer system to be displayed, the data may be converted in many different intermediate formats before it is eventually displayed. For example, the generating computer system may initially store the data in a bitmap format. To send the data to another computer system, the computer system may first compress the bitmap data and then encrypt the compressed data. The computer system may then convert that compressed data into a TCP format and then into an IP format. The IP formatted data may be converted into a transmission format, such as an ethernet format. The data in the transmission format is then sent to a receiving computer system. The receiving computer system would need to perform each of these conversions in reverse order to convert the data in the bitmap format. In addition, the receiving computer system may need to convert the bitmap data into a format that is appropriate for rendering on output device. In order to process data in such a wide variety of formats, both sending and receiving computer systems need to have many conversion routines available to support the various formats. These computer systems typically use predefined configuration information to load the correct combination of conversion routines for processing data. These computer systems also use a process-oriented approach when processing data with these conversion routines. When using a process-oriented approach, a computer system may create a separate process for each conversion that needs to take place. A computer system in certain situations, however, can be expected to receive data and to provide data in many different formats that may not be known until the data is received. The overhead of statically providing each possible series of conversion routines is very high. For example, a computer system that serves as a central controller for data received within a home would be expected to process data received via telephone lines, cable TV lines, and satellite connections in many different formats. The central controller would be expected to output the data to computer displays, television displays, entertainment centers, speakers, recording devices, and so on in many different formats. Moreover, since the various conversion routines may be developed by different organizations, it may not be easy to identify that the output format of one conversion routine is compatible with the input format of another conversion routine. It would be desirable to have a technique for dynamically identifying a series of conversion routines for processing data. In addition, it would be desirable to have a technique in which the output format of one conversion routine can be identified as being compatible with the input format of another conversion routine. It would also be desirable to store the identification of a series of conversion routines so that the series can be quickly identified when data is received. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a block diagram illustrating example processing of a message by the conversion system. FIG. 2 is a block diagram illustrating a sequence of edges. FIG. 3 is a block diagram illustrating components of the conversion system in one embodiment. FIG. 4 is a block diagram illustrating example path data structures in one embodiment. FIG. 5 is a block diagram that illustrates the interrelationship of the data structures of a path. FIG. 6 is a block diagram that illustrates the interrelationship of the data structures associated with a session. FIGS. 7 A, 7B, and 7C comprise a flow diagram illustrating the processing of the message send routine. FIG. 8 is a flow diagram of the demux routine. FIG. 9 is a flow diagram of the initialize demux routine. FIG. 10 is a flow diagram of the init end routine. FIG. 11 is a flow diagram of a routine to get the next binding. FIG. 12 is a flow diagram of the get key routine. FIG. 13 is a flow diagram of the get session routine. FIG. 14 is a flow diagram of the nail binding routine. FIG. 15 is a flow diagram of the find path routine. FIG. 16 is a flow diagram of the process of path hopping routine. DETAILED DESCRIPTION A method and system for converting a message that may contain multiple packets from an source format into a target format. When a packet of a message is received, the conversion system in one embodiment searches for and identifies a sequence of conversion routines (or more generally message handlers) for processing the packets of the message by comparing the input and output formats of the conversion routines. (A message is a collection of data that is related in some way, such as stream of video or audio data or an email message.) The identified sequence of conversion routines is used to convert the message from the source format to the target format using various intermediate formats. The conversion system then queues the packet for processing by the identified sequence of conversion routines. The conversion system stores the identified sequence so that the sequence can be quickly found (without searching) when the next packet in the message is received. When subsequent packets of the message are received, the conversion system identifies the sequence and queues the packets for pressing by the sequence. Because the conversion system receives multiple messages with different source and target formats and identifies a sequence of conversion routines for each message, the conversion systems effectively “demultiplexes” the messages. That is, the conversion system demultiplexes the messages by receiving the message, identifying the sequence of conversion routines, and controlling the processing of each message by the identified sequence. Moreover, since the conversion routines may need to retain state information between the receipt of one packet of a message and the next packet of that message, the conversion system maintains state information as an instance or session of the conversion routine. The conversion system routes all packets for a message through the same session of each conversion routine so that the same state or instance information can be used by all packets of the message. A sequence of sessions of conversion routines is referred to as a “path.” In one embodiment, each path has a path thread associated with it for processing of each packet destined for that path. In one embodiment, the packets of the messages are initially received by “drivers,” such as an Ethernet driver. When a driver receives a packet, it forwards the packet to a forwarding component of the conversion system. The forwarding component is responsible for identifying the session of the conversion routine that should next process the packet and invoking that conversion routine. When invoked by a driver, the forwarding component may use a demultiplexing (“demux”) component to identify the session of the first conversion routine of the path that is to process the packet and then queues the packet for processing by the path. A path thread is associated with each path. Each path thread is responsible for retrieving packets from the queue of its path and forwarding the packets to the forwarding component. When the forwarding component is invoked by a path thread, it initially invokes the first conversion routine in the path. That conversion routine processes the packet and forwards the processed packet to the forwarding component, which then invokes the second conversion routine in the path. The process of invoking the conversion routines and forwarding the processed packet to the next conversion routine continues until the last conversion routine in the path is invoked. A conversion routine may defer invocation of the forwarding component until it aggregates multiple packets or may invoke the forwarding component multiple times for a packet once for each sub-packet. The forwarding component identifies the next conversion routine in the path using the demux component and stores that identification so that the forwarding component can quickly identify the conversion routine when subsequent packets of the same message are received. The demux component, searches for the conversion routine and session that is to next process a packet. The demux component then stores the identification of the session and conversion routine as part of a path data structure so that the conversion system does not need to search for the session and conversion routine when requested to demultiplex subsequent packets of the same message. When searching for the next conversion routine, the demux component invokes a label map get component that identifies the next conversion routine. Once the conversion routine is found, the demux component identifies the session associated with that message by, in one embodiment, invoking code associated with the conversion routine. In general, the code of the conversion routine determines what session should be associated with a message. In certain situations, multiple messages may share the same session. The demux component then extends the path for processing that packet to include that session and conversion routine. The sessions are identified so that each packet is associated with the appropriate state information. The dynamic identification of conversion routines is described in U.S. patent application Ser. No. 11/933,093, filed on Oct. 31, 2007 (now U.S. Pat. No. 7,730,211), entitled “Method and System for Generating a Mapping Between Types of Data,” which is hereby incorporated by reference. FIG. 1 is a block diagram illustrating example processing of a message by the conversion system. The driver 101 receives the packets of the message from a network. The driver performs any appropriate processing of the packet and invokes a message send routine passing the processed packet along with a reference path entry 150. The message send routine is an embodiment of the forwarding component. A path is represented by a series of path entries, which are represented by triangles. Each member path entry represents a session and conversion routine of the path, and a reference path entry represents the overall path. The passed reference path entry 150 indicates to the message send routine that it is being invoked by a driver. The message send routine invokes the demux routine 102 to search for and identify the path of sessions that is to process the packet. The demux routine may in turn invoke the label map get routine 104 to identify a sequence of conversion routines for processing the packet. In this example, the label map get routine identifies the first three conversion routines, and the demux routine creates the member path entries 151, 152, 153 of the path for these conversion routines. Each path entry identifies a session for a conversion routine, and the sequence of path entries 151-155 identifies a path. The message send routine then queues the packet on the queue 149 for the path that is to process the packets of the message. The path thread 105 for the path retrieves the packet from the queue and invokes the message send routine 106 passing the packet and an indication of the path. The message send routine determines that the next session and conversion routine as indicated by path entry 151 has already been found. The message send routine then invokes the instance of the conversion routine for the session. The conversion routine processes the packet and then invokes the message send routine 107. This processing continues until the message send routine invokes the demux routine 110 after the packet is processed by the conversion routine represented by path entry 153. The demux routine examines the path and determines that it has no more path entries. The demux routine then invokes the label map get routine 111 to identify the conversion routines for further processing of the packet. When the conversion routines are identified, the demux routine adds path entries 154, 155 to the path. The messages send routine invokes the conversion routine associated with path entry 154. Eventually, the conversion routine associated with path entry 155 performs the final processing for the path. The label map get routine identifies a sequence of “edges” for converting data in one format into another format. Each edge corresponds to a conversion routine for converting data from one format to another. Each edge is part of a “protocol” (or more generally a component) that may include multiple related edges. For example, a protocol may have edges that each convert data in one format into several different formats. Each edge has an input format and an output format. The label map get routine identifies a sequence of edges such that the output format of each edge is compatible with the input format of another edge in the sequence, except for the input format of the first edge in the sequence and the output format of the last edge in the sequence. FIG. 2 is a block diagram illustrating a sequence of edges. Protocol PI includes an edge for converting format D1 to format D2 and an edge for converting format D1 to format D3; protocol P2 includes an edge for converting format D2 to format D5, and so on. A 30 sequence for converting format D1 to format D15 is shown by the curved lines and is defined by the address “P1:I, P2:1, P3:2, P4:7.” When a packet of data in format D I is processed by this sequence, it is converted to format DIS. During the process, the packet of data is sequentially converted to format D2, D5, and D13. The output format of protocol P2, edge 1 (i.e., P2:1) is format D5, but the input format of P3:2 is format D10. The label map get routine uses an aliasing mechanism by which two formats, such as D5 and D10 are identified as being compatible. The use of aliasing allows different names of the same format or compatible formats to be correlated. FIG. 3 is a block diagram illustrating components of the conversion system in one embodiment. The conversion system 300 can operate on a computer system with a central processing unit 301, I/O devices 302, and memory 303. The 110 devices may include an Internet connection, a connection to various output devices such as a television, and a connection to various input devices such as a television receiver. The media mapping system may be stored as instructions on a computer-readable medium, such as a disk drive, memory, or data transmission medium. The data structures of the media mapping system may also be stored on a computer-readable medium. The conversion system includes drivers 304, a•forwarding component 305, a demux component 306, a label map get component 307, path data structures 308, conversion routines 309, and instance data 310. Each driver receives data in a source format and forwards the data to the forwarding component. The forwarding component identifies the next conversion routine in the path and invokes that conversion routine to process a packet. The forwarding component may invoke the demux component to search for the next conversion routine and add that conversion routine to the path. The demux component may invoke the label map get component to identify the next conversion routine to process the packet. The demux component stores information defining the paths in the path structures. The conversion routines store their state information in the instance data. FIG. 4 is a block diagram illustrating example path data structures in one embodiment. The demux component identifies a sequence of “edges” for converting data in one format into another format by invoking the label map get component. Each edge corresponds to a conversion routine for converting data from one format to another. As discussed above, each edge is part of a “protocol” that may include multiple related edges. For example, a protocol may have edges that each convert data in one format into several different formats. Each edge has as an input format (“input label”) and an output format (“output label”). Each rectangle represents a session 410, 420, 430, 440, 450 for a protocol. A session corresponds to an instance of a protocol. That is, the session includes the protocol and state information associated with that instance of the protocol. Session 410 corresponds to a session for an Ethernet protocol; session 420 corresponds to a session for an IP protocol; and sessions 430, 440, 450 correspond to sessions for a TCP protocol. FIG. 4 illustrates three paths 461, 462, 463. Each path includes edges 411, 421, 431. The paths share the same Ethernet session 410 and IP session 420, but each path has a unique TCP session 430, 440, 450. Thus, path 461 includes sessions 410, 420, and 430; path 462 includes sessions 410, 420, and 440; and path 463 includes sessions 410, 420, and 450. The conversion system represents each path by a sequence of path entry structures. Each path entry structure is represented by a triangle. Thus, path 461 is represented by path entries 415, 425, and 433. The conversion system represents the path entries of a path by a stack list. Each path also has a queue 471, 472, 473 associated with it. Each queue stores the messages that are to be processed by the conversion routines of the edges of the path. Each session includes a binding 412, 422, 432, 442, 452 that is represented by an oblong shape adjacent to the corresponding edge. A binding for an edge of a session represents those paths that include the edge. The binding 412 indicates that three paths are bound (or “nailed”) to edge 411 of the Ethernet session 410. The conversion system uses a path list to track the paths that are bound to a binding. The path list of binding 412 identifies path entries 413, 414, and 415. FIG. 5 is a block diagram that illustrates the interrelationship of the data structures of a path. Each path has a corresponding path structure 501 that contains status information and pointers to a message queue structure 502, a stack list structure 503, and a path address structure 504. The status of a path can be extend, continue, or end. Each message handler returns a status for the path. The status of extend means that additional path entries should be added to the path. The status of end means that this path should end at this point and subsequent processing should continue at a new path. The status of continue means that the protocol does not care how the path is handled. In one embodiment, when a path has a status of continue, the system creates a copy of the path and extends the copy. The message queue structure identifies the messages (or packets of a message) that are queued up for processing by the path and identifies the path entry at where the processing should start. The stack list structure contains a list of pointers to the path entry structures 505 that comprise the path. Each path entry structure contains a pointer to the corresponding path data structure, a pointer to a map structure 507, a pointer to a multiplex list 508, a pointer to the corresponding path address structure, and a pointer to a member structure 509. A map structure identifies the output label of the edge of the path entry and optionally a target label and a target key. A target key identifies the session associated with the protocol that converts the packet to the target label. (The terms “media,” “label,” and “format” are used interchangeably to refer to the output of a protocol.) The multiplex list is used during the demux process to track possible next edges when a path is being identified as having more than one next edge. The member structure indicates that the path entry represents an edge of a path and contains a pointer to a binding structure to which the path entry is associated (or “nailed”), a stack list entry is the position of the path entry within the associated stack list, a path list entry is the position of the path entry within the associated path list of a binding and an address entry is the position of the binding within the associated path address. A path address of a path identifies the bindings to which the path entries are bound. The path address structure contains a URL for the path, the name of the path identified by the address, a pointer to a binding list structure 506, and the identification of the current binding within the binding list. The URL (e.g., “protocol://tcp(0)/ip(0)/eth(0)”) identifies conversion routines (e.g., protocols and edges) of a path in a human-readable format. The URL (universal resource locator) includes a type field (e.g., “protocol”) followed by a sequence of items (e.g., “tcp(0)”). The type field specifies the format of the following information in the URL, that specifies that the type field is followed by a sequence of items. Each item identifies a protocol and an edge (e.g., the protocol is “tcp” and the edge is “0”). In one embodiment, the items of a URL may also contain an identifier of state information that is to be used when processing a message. These URLs can be used to illustrate to a user various paths that are available for processing a message. The current binding is the last binding in the path as the path is being built. The binding list structure contains a list of pointers to the binding structures associated with the path. Each binding structure 510 contains a pointer to a session structure, a pointer to an edge structure, a key, a path list structure, and a list of active paths through the binding. The key identifies the state information for a session of a protocol. A path list structure contains pointers to the path entry structures associated with the binding. FIG. 6 is a block diagram that illustrates the interrelationship of the data structures associated with a session. A session structure 601 contains the context for the session, a pointer to a protocol structure for the session, a pointer to a binding table structure 602 for the bindings associated with the session, and the key. The binding table structure contains a list of pointers to the binding structures 510 for the session. The binding structure is described above with reference to FIG. 5. The path list structure 603 of the binding structure contains a list of pointers to path entry structures 505. The path entry structures are described with reference to FIG. 5. FIGS. 7 A, 7B, and 7C comprise a flow diagram illustrating the processing of the message send routine. The message send routine is passed a message along with the path entry associated with the session that last processed the message. The message send routine invokes the message handler of the next edge in the path or queues the message for processing by a path. The message handler invokes the demux routine to identify the next path entry of the path. When a driver receives a message, it invokes the message send routine passing a reference path entry. The message send routine examines the passed path entry to determine (1) whether multiple paths branch from the path of the passed path entry, (2) whether the passed path entry is a reference with an associated path, or (3) whether the passed path entry is a member with a next path entry. If multiple paths branch from the path of the passed path entry, then the routine recursively invokes the message send routine for each path. If the path entry is a reference with an associated path, then the driver previously invoked the message send routine, which associated a path with the reference path entry, and the routine places the message on the queue for the path. If the passed path entry is a member with a next path entry, then the routine invokes the message handler (i.e., conversion routine of the edge) associated with the next path entry. If the passed path entry is a reference without an associated path or is a member without a next path entry, then the routine invokes the demux routine to identify the next path entry. The routine then recursively invokes the messages send routine passing that next path entry. In decision block 701, if the passed path entry has a multiplex list, then the path branches off into multiple paths and the routine continues at block 709, else the routine continues at block 702. A packet may be processed by several different paths. For example, if a certain message is directed to two different output devices, then the message is processed by two different paths. Also, a message may need to be processed by multiple partial paths when searching for a complete path. In decision block 702, if the passed path entry is a member, then either the next path entry indicates a nailed binding or the path needs to be extended and the routine continues at block 704, else the routine continues at block 703. A nailed binding is a binding (e.g., edge and protocol) is associated with a session. In decision block 703, the passed path entry is a reference and if the passed path entry has an associated path, then the routine can queue the message for the associated path and the routine continues at block 703A, else the routine needs to identify a path and the routine continues at block 707. In block 703A, the routine sets the entry to the first path entry in the path and continues at block 717. In block 704, the routine sets the variable position to the stack list entry of the passed path entry. In decision block 705, the routine sets the variable next entry to the next path entry in the path. If there is a next entry in the path, then the next session and edge of the protocol have been identified and the routine continues at block 706, else the routine continues at block 707. In block 706, the routine passes the message to the message handler of the edge associated with the next entry and then returns. In block 706, the routine invokes the demux routine passing the passed message, the address of the passed path entry, and the passed path entry. The demux routine returns a list of candidate paths for processing of the message. In decision block 708, if at least one candidate path is returned, then the routine continues at block 709, else the routine returns. Blocks 709-716 illustrate the processing of a list of candidate paths that extend from the passed path entry. In blocks 710-716, the routine loops selecting each candidate path and sending the message to be process by each candidate path. In block 710, the routine sets the next entry to the first path entry of the next candidate path. In decision block 711, if all the candidate paths have not yet been processed, then the routine continues at block 712, else the routine returns. In decision block 712, if the next entry is equal to the passed path entry, then the path is to be extended and the routine continues at block 705, else the routine continues at block 713. The candidate paths include a first path entry that is a reference path entry for new paths or that is the last path entry of a path being extended. In decision block 713, if the number of candidate paths is greater than one, then the routine continues at block 714, else the routine continues at block 718. In decision block 714, if the passed path entry has a multiplex list associated with it, then the routine continues at block 716, else the routine continues at block 715. In block 715, 11 the routine associates the list of candidate path with the multiplex list of the passed path entry and continues at block 716. In block 716, the routine sends the message to the next entry by recursively invoking the message send routine. The routine then loops to block 710 to select the next entry associated with the next candidate path. Blocks 717-718 are performed when the passed path entry is a reference path entry that has a path associated with it. In block 717, if there is a path associated with the next entry, then the routine continues at block 718, else the routine returns. In block 718, the routine queues the message for the path of the next entry and then returns. FIG. 8 is a flow diagram of the demux routine. This routine is passed the packet (message) that is received, an address structure, and a path entry structure. The demux routine extends a path, creating one if necessary. The routine loops identifying the next binding (edge and protocol) that is to process the message and “nailing” the binding to a session for the message, if not already nailed. After identifying the nailed binding, the routine searches for the shortest path through the nailed binding, creating a path if none exists. In block 801, the routine invokes the initialize demux routine. In blocks 802-810, the routine loops identifying a path or portion of a path for processing the passed message. In decision block 802, if there is a current status, which was returned by the demux key routine that was last invoked (e.g., continue, extend, end, or postpone), then the routine continues at block 803, else the routine continues at block 811. In block 803, the routine invokes the get next binding routine. The get next binding routine returns the next binding in the path. The binding is the edge of a protocol. That routine extends the path as appropriate to include the binding. The routine returns a return status of break, binding, or multiple. The return status of binding indicates that the next binding in the path was found by extending the path as appropriate and the routine continues to “nail” the binding to a session as appropriate. The return status of multiple means that multiple trails (e.g., candidate paths) were identified as possible extensions of the path. In a decision block 804, if the return status is break, then the routine continues at block 811. If the return status is multiple, then the routine returns. If the return status is binding, then the routine continues at block 805. In decision block 805, if the retrieved binding is nailed as indicated by being assigned to a session, then the routine loops to block 802, else the routine continues at block 806. In block 806, the routine invokes the get key routine of the edge associated with the binding. The get key routine creates the key for the session associated with the message. If a key cannot be created until subsequent bindings are processed or because the current binding is to be removed, then the get key routine returns a next binding status, else it returns a continue status. In decision block 807, if the return status of the get key routine is next binding, then the routine loops to block 802 to get the next binding, else the routine continues at block 808. In block 808, the routine invokes the routine get session. The routine get session returns the session associated with the key, creating a new session if necessary. In block 809, the routine invokes the routine nail binding. The routine nail binding retrieves the binding if one is already nailed to the session. Otherwise, that routine nails the binding to the session. In decision block 810, if the nail binding routine returns a status of simplex, then the routine continues at block 811 because only one path can use the session, else the routine loops to block 802. Immediately upon return from the nail binding routine, the routine may invoke a set map routine of the edge passing the session and a map to allow the edge to set its map. In block 811, the routine invokes the find path routine, which finds the shortest path through the binding list and creates a path if necessary. In block 812, the routine invokes the process path hopping routine, which determines whether the identified path is part of a different path. Path hopping occurs when, for example, IP fragments are built up along separate paths, but once the fragments are built up they can be processed by the same subsequent path. FIG. 9 is a flow diagram of the initialize demux routine. This routine is invoked to initialize the local data structures that are used in the demux process and to identify the initial binding. The demux routine finds the shortest path from the initial binding to the final binding. If the current status is demux extend, then the routine is to extend the path of the passed path entry by adding additional path entries. If the current status is demux end, then the demux routine is ending the current path. If the current status is demux continue, then the demux routine is in the process of continuing to extend or in the process of starting a path identified by the passed address. In block 901, the routine sets the local map structure to the map structure in the passed path entry structure. The map structure identifies the output label, the target label, and the target key. In the block 902, the routine initializes the local message structure to the passed message structure and initializes the pointers path and address element to null. In block 903, the routine sets of the variable saved status to 0 and the variable status to demux continue. The variable saved status is used to track the status of the demux process when backtracking to nail a binding whose nail was postponed. In decision block 904, if the passed path entry is associated with a path, then the routine continues at block 905, else the routine continues at block 906. In block 905, the routine sets the variable status to the status of that path. In block 906, if the variable status is demux continue, then the routine continues at block 907. If the variable status is demux end, then the routine continues at block 908. If the variable status is demux extend, then the routine continues at block 909. In block 907, the status is demux continue, and the routine sets the local pointer path address to the passed address and continues at block 911. In block 908, the status is demux end, and the routine invokes the init end routine and continues at block 911. In block 909, the status is demux extend, and the routine sets the local path address to the address of the path that contains the passed path entry. In block 910, the routine sets the address element and the current binding of the path address pointed to by the local pointer path address to the address entry of the member structure of the passed path entry. In the block 911, the routine sets the local variable status to demux continue and sets the local binding list structure to the binding list structure from the local path address structure. In block 912, the routine sets the local pointer current binding to the address of the current binding pointed to by local pointer path address and sets the local variable postpone to 0. In block 913, the routine sets the function traverse to the function that retrieves the next data in a list and sets the local pointer session to null. The routine then returns. FIG. 10 is a flow diagram of the init end routine. If the path is simplex, then the routine creates a new path from where the other one ended, else the routine creates a copy of the path. In block 1001, if the binding of the passed path entry is simplex (i.e., only one path can be bound to this binding), then the routine continues at block 1002, else the routine continues at block 1003. In block 1002, the routine sets the local pointer path address to point to an address structure that is a copy of the address structure associated with the passed path entry structure with its current binding to the address entry associated with the passed path entry structure, and then returns. In block 1003, the routine sets the local pointer path address to point to an address structure that contains the URL of the path that contains the passed path entry. In block 1004, the routine sets the local pointer element to null to initialize the selection of the bindings. In blocks 1005 through 1007, the routine loops adding all the bindings for the address of the passed path entry that include and are before the passed path entry to the address pointed to by the local path address. In block 1005, the routine retrieves the next binding from the binding list starting with the first. If there is no such binding, then the routine returns, else the routine continues at block 1006. In block 1006, the routine adds the binding to the binding list of the local path address structure and sets the current binding of the local variable path address. In the block 1007, if the local pointer element is equal to the address entry of the passed path entry, then the routine returns, else the routine loops to block 1005 to select the next binding. FIG. 11 is a flow diagram of a routine to get the next binding. This routine returns the next binding from the local binding list. If there is no next binding, then the routine invokes the routine label map get to identify the list of edges (“trails”) that will map the output label to the target label. If only one trail is identified, then the binding list of path address is extended by the edges of the trail. If multiple trails are identified, then a path is created for each trail and the routine returns so that the demux process can be invoked for each created path. In block 1101, the routine sets the local pointer binding to point to the next or previous (as indicated by the traverse function) binding in the local binding list. In block 1102, if a binding was found, then the routine returns an indication that a binding was found, else the routine continues at block 1103. In block 1103, the routine invokes the label map get function passing the output label and target label of the local map structure. The label map get function returns a trail list. A trail is a list of edges from the output label to the target label. In decision block 1104, if the size of the trail list is one, then the routine continues at block 1105, else the routine continues at block 1112. In blocks 1105-1111, the routine extends the binding list by adding a binding data structure for each edge in the trail. The routine then sets the local binding to the last binding in the binding list. In block 1108, the routine sets the local pointer current binding to point to the last binding in the local binding list. In block 1106, the routine sets the local variable temp trail to the trail in the trail list. In block 1107, the routine extends the binding list by temp trail by adding a binding for each edge in the trail. These bindings are not yet nailed. In block 1108, the routine sets the local binding to point to the last binding in the local binding list. In decision block 1109, if the local binding does not have a key for a session and the local map has a target key for a session, then the routine sets the key for the binding to the target key of the local map and continues at block 1110, else the routine loops to block 1101 to retrieve the next binding in path. In block 1110, the routine sets the key of the local binding to the target key of the local map. In block 1111, the routine sets the target key of the local map to null and then loop to block 1101 to return the next binding. In decision block 1112, if the local session is set, then the demultiplexing is already in progress and the routine returns a break status. In block 1113, the routine invokes a prepare multicast paths routine to prepare a path entry for each trail in the trail list. The routine then returns a multiple status. FIG. 12 is a flow diagram of the get key routine. The get key routine invokes an edge's demux key routine to retrieve a key for the session associated with the message. The key identifies the session of a protocol. The demux key routine creates the appropriate key for the message. The demux key routine returns a status of remove, postpone, or other. The status of remove indicates that the current binding should be removed from the path. The status of postpone indicates that the demux key routine cannot create the key because it needs information provided by subsequent protocols in the path. For example, a TCP session is defined by a combination of a remote and local port address and an IP address. Thus, the TCP protocol postpones the creating of a key until the IP protocol identifies the IP address. The get key routine returns a next binding status to continue at the next binding in the path. Otherwise, the routine returns a continue status. In block 1201, the routine sets the local edge to the edge of the local binding (current binding) and sets the local protocol to the protocol of the local edge. In block 1202, the routine invokes the demux key routine of the local edge passing the local message, local path address, and local map. The demux key routine sets the key in the local binding. In decision block 1203, if the demux key routine returns a status of remove, then the routine continues at block 1204. If the demux key routine returns a status of postpone, then the routine continues at block 1205, else the routine continues at block 1206. In block 1204, the routine sets the flag of the local binding to indicate that the binding is to be removed and continues at block 1206. In block 1205, the routine sets the variable traverse to the function to list the next data, increments the variable postpone, and then returns a next binding status. In blocks 1206-1214, the routine processes the postponing of the creating of a key. In blocks 1207-1210, if the creating of a key has been postponed, then the routine indicates to backtrack on the path, save the demux status, and set the demux status to demux continue. In blocks 1211-1213, if the creating of a key has not been postponed, then the routine indicates to continue forward in the path and to restore any saved demux status. The save demux status is the status associated by the binding where the backtrack started. In decision block 1206, if the variable postpone is set, then the routine continues at block 1207, else the routine continues at block 1211. In block 1207, the routine decrements the variable postpone and sets the variable traverse to the list previous data function. In decision block 1208, if the variable saved status is set, then the routine continues at block 1210, else the routine continues at block 1209. The variable saved status contains the status of the demux process when the demux process started to backtrack. In block 1209, the routine sets the variable saved status to the variable status. In block 1210, the routine sets the variable status to demux continue and continues at block 1214. In block 1211, the routine sets the variable traverse to the list next data function. In decision block 1212, if the variable saved status in set, then the routine continues at block 1213, else the routine continues at block 1214. In block 1213, the routine sets the variable status to the variable saved status and sets the variable saved status to 0. In decision block 1214, if the local binding indicates that it is to be removed, then the routine returns a next binding status, else the routine returns a continue status. FIG. 13 is a flow diagram of the get session routine. This routine retrieves the session data structure, creating a data structure session if necessary, for the key indicated by the binding. In block 1301, the routine retrieves the session from the session table of the local protocol indicated by the key of the local binding. Each protocol maintains a mapping from each key to the session associated with the key. In decision block 1302, if there is no session, then the routine continues at block 1303, else the routine returns. In block 1303, the routine creates a session for the local protocol. In block 1304, the routine initializes the key for the local session based on the key of the local binding. In block 1305, the routine puts the session into the session table of the local protocol. In block 1306, the routine invokes the create session function of the protocol to allow the protocol to initialize its context and then returns. FIG. 14 is a flow diagram of the nail binding routine. This routine determines whether a binding is already associated with (“nailed to”) the session. If so, the routine returns that binding. If not, the routine associates the binding with the session. The routine returns a status of simplex to indicate that only one path can extend through the nailed binding. In decision block 1401, if the binding table of the session contains an entry for the edge, then the routine continues at block 1402, else the routine continues at block 1405. In block 1402, the routine sets the binding to the entry from the binding table of the local session for the edge. In block 1403, the routine sets the current binding to point to the binding from the session. In block 1404, if the binding is simplex, then the routine returns a simplex status, else the routine returns. Blocks 1405 through 1410 are performed when there is no binding in the session for the edge. In block 1405, the routine sets the session of the binding to the variable session. In block 1406, the routine sets the key of the binding to the key from the session. In block 1407, the routine sets the entry for the edge in the binding table of the local session to the binding. In block 1408, the routine invokes the create binding function of the edge of the binding passing the binding so the edge can initialize the binding. If that function returns a status of remove, the routine continues at block 1409. In block 1409, the routine sets the binding to be removed and then returns. FIG. 15 is a flow diagram of the find path routine. The find path routine identifies the shortest path through the binding list. If no such path exists, then the routine extends a path to include the binding list. In decision block 1501, if the binding is simplex and a path already goes through this binding (returned as an entry), then the routine continues at block 1502, else the routine continues at block 1503. In block 1502, the routine sets the path to the path of the entry and returns. In block 1503, the routine initializes the pointers element and short entry to null. In block 1504, the routine sets the path to the path of the passed path entry. If the local path is not null and its status is demux extend, then the routine continues at block 1509, else the routine continues at block 1505. In blocks 1505-1508, the routine loops identifying the shortest path through the bindings in the binding list. The routine loops selecting each path through the binding. The selected path is eligible if it starts at the first binding in the binding list and the path ends at the binding. The routine loops setting the short entry to the shortest eligible path found so far. In block 1505, the routine sets the variable first binding to the first binding in the binding list of the path address. In block 1506, the routine selects the next path (entry) in the path list of the binding starting with the first. If a path is selected (indicating that there are more paths in the binding), then the routine continues at block 1507, else the routine continues at block 1509. In block 1507, the routine determines whether the selected path starts at the first binding in the binding list, whether the selected path ends at the last binding in the binding list, and whether the number of path entries in the selected path is less than the number of path entries in the shortest path selected so far. If these conditions are all satisfied, then the routine continues at block 1508, else the routine loops to block 1506 to select the next path (entry). In block 1508, the routine sets the shortest path (short entry) to the selected path and loops to block 1506 to select the next path through the binding. In block 1509, the routine sets the selected path (entry) to the shortest path. In decision block 1510, if a path has been found, then the routine continues at block 1511, else the routine continues at block 1512. In block 1511, the routine sets the path to the path of the selected path entry and returns. Blocks 1512-1516 are performed when no paths have been found. In block 1512, the routine sets the path to the path of the passed path entry. If the passed path entry has a path and its status is demux extend, then the routine continues at block 1515, else the routine continues at block 1513. In block 1513, the routine creates a path for the path address. In block 1514, the routine sets the variable element to null and sets the path entry to the first element in the stack list of the path. In block 1515, the routine sets the variable element to be address entry of the member of the passed path entry and sets the path entry to the passed path entry. In block 1516, the routine invokes the extend path routine to extend the path and then returns. The extend path routine creates a path through the bindings of the binding list and sets the path status to the current demux status. FIG. 16 is a flow diagram of the process of path hopping routine. Path hopping occurs when the path through the binding list is not the same path as that of the passed path entry. In decision block 1601, if the path of the passed path entry is set, then the routine continues at block 1602, else the routine continues at block 1609. In decision block 1602, if the path of the passed path entry is equal to the local path, then the routine continues at 1612, else path hopping is occurring and the routine continues at block 1603. In blocks 1603-1607, the routine loops positioning pointers at the first path entries of the paths that are not at the same binding. In block 1603, the routine sets the variable old stack to the stack list of the path of the passed path entry. In block 1604, the routine sets the variable new stack to the stack list of the local path. In block 1605, the routine sets the variable old element to the next element in the old stack. In block 1606, the routine sets the variable element to the next element in the new stack. In decision block 1607, the routine loops until the path entry that is not in the same binding is located. In decision block 1608, if the variable old entry is set, then the routine is not at the end of the hopped from path and the routine continues at block 1609, else routine continues at block 1612. In block 1609, the routine sets the variable entry to the previous entry in the hopped-to path. In block 1610, the routine sets the path of the passed path entry to the local path. In block 1611, the routine sets the local entry to the first path entry of the stack list of the local path. In block 1612, the routine inserts an entry into return list and then returns. Although the conversion system has been described in terms of various embodiments, the invention is not limited to these embodiments. Modification within the spirit of the invention will be apparent to those skilled in the art. For example, a conversion routine may be used for routing a message and may perform no conversion of the message. Also, a reference to a single copy of the message can be passed to each conversion routine or demux key routine. These routines can advance the reference past the header information for the protocol so that the reference is positioned at the next header. After the demux process, the reference can be reset to point to the first header for processing by the conversion routines in sequence. The scope of the invention is defined by the claims that follow.
<SOH> BACKGROUND <EOH>Computer systems, which are becoming increasingly pervasive, generate data in a wide variety of formats. The Internet is an example of interconnected computer systems that generate data in many different formats. Indeed, when data is generated on one computer system and is transmitted to another computer system to be displayed, the data may be converted in many different intermediate formats before it is eventually displayed. For example, the generating computer system may initially store the data in a bitmap format. To send the data to another computer system, the computer system may first compress the bitmap data and then encrypt the compressed data. The computer system may then convert that compressed data into a TCP format and then into an IP format. The IP formatted data may be converted into a transmission format, such as an ethernet format. The data in the transmission format is then sent to a receiving computer system. The receiving computer system would need to perform each of these conversions in reverse order to convert the data in the bitmap format. In addition, the receiving computer system may need to convert the bitmap data into a format that is appropriate for rendering on output device. In order to process data in such a wide variety of formats, both sending and receiving computer systems need to have many conversion routines available to support the various formats. These computer systems typically use predefined configuration information to load the correct combination of conversion routines for processing data. These computer systems also use a process-oriented approach when processing data with these conversion routines. When using a process-oriented approach, a computer system may create a separate process for each conversion that needs to take place. A computer system in certain situations, however, can be expected to receive data and to provide data in many different formats that may not be known until the data is received. The overhead of statically providing each possible series of conversion routines is very high. For example, a computer system that serves as a central controller for data received within a home would be expected to process data received via telephone lines, cable TV lines, and satellite connections in many different formats. The central controller would be expected to output the data to computer displays, television displays, entertainment centers, speakers, recording devices, and so on in many different formats. Moreover, since the various conversion routines may be developed by different organizations, it may not be easy to identify that the output format of one conversion routine is compatible with the input format of another conversion routine. It would be desirable to have a technique for dynamically identifying a series of conversion routines for processing data. In addition, it would be desirable to have a technique in which the output format of one conversion routine can be identified as being compatible with the input format of another conversion routine. It would also be desirable to store the identification of a series of conversion routines so that the series can be quickly identified when data is received.
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a block diagram illustrating example processing of a message by the conversion system. FIG. 2 is a block diagram illustrating a sequence of edges. FIG. 3 is a block diagram illustrating components of the conversion system in one embodiment. FIG. 4 is a block diagram illustrating example path data structures in one embodiment. FIG. 5 is a block diagram that illustrates the interrelationship of the data structures of a path. FIG. 6 is a block diagram that illustrates the interrelationship of the data structures associated with a session. FIGS. 7 A, 7 B, and 7 C comprise a flow diagram illustrating the processing of the message send routine. FIG. 8 is a flow diagram of the demux routine. FIG. 9 is a flow diagram of the initialize demux routine. FIG. 10 is a flow diagram of the init end routine. FIG. 11 is a flow diagram of a routine to get the next binding. FIG. 12 is a flow diagram of the get key routine. FIG. 13 is a flow diagram of the get session routine. FIG. 14 is a flow diagram of the nail binding routine. FIG. 15 is a flow diagram of the find path routine. FIG. 16 is a flow diagram of the process of path hopping routine. detailed-description description="Detailed Description" end="lead"?
H04L6908
20170913
20180717
20180111
70259.0
H04L2906
6
DUONG, DUC T
METHOD AND SYSTEM FOR DATA DEMULTIPLEXING
UNDISCOUNTED
1
CONT-ACCEPTED
H04L
2,017
15,704,274
PENDING
Crystalline Inhibitor of 4-Hydroxyphenylpyruvate Dioxygenase
The present invention relates to an improved synthesis and crystallization process of the 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, also known as nitisinone or NTBC.
1-11. (canceled) 12. A method of inhibiting 4-hydroxyphenylpyruvate dioxygenase enzyme in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of crystalline 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione having a X-ray powder diffraction pattern with at least five specific peaks at about 2-theta=7.4, 14.7, 15.7, 22.9, and 29.7, wherein said peaks may be plus or minus 0.2° 2-theta and have an intensity of at least 30%. 13. The method of claim 12, wherein the patient is suffering from a disease selected from the group consisting of oculocutaneous/ocular albinism, microbial infections, restless leg syndrome, alkaptonuria, and hereditary tyrosinemia type 1. 14. The method of claim 13, wherein the disease to be treated is hereditary tyrosinemia type 1. 15. The method of claim 12, wherein the therapeutically effective amount of the crystalline 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione is from about 0.1 to about 2 mg/kg/day. 16. The method of claim 15, wherein the therapeutically effective amount of crystalline 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione is from about 1 to about 2 mg/kg/day. 17. A method of treating oculocutaneous/ocular albinism, microbial infections, restless leg syndrome, alkaptonuria, or hereditary tyrosinemia type 1, the method comprising administering to a patient in need thereof a therapeutically effective amount of crystalline 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione having X-ray powder diffraction pattern with at least five specific peaks at about 2-theta=7.4, 14.7, 15.7, 22.9, and 29.7, wherein said values may be plus or minus 0.2° 2-theta and have an intensity of at least 30%. 18. The method of claim 17, wherein the disease to be treated is hereditary tyrosinemia type 1. 19. The method of claim 17, wherein the therapeutically effective amount of crystalline 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione is from about 0.1 to about 2 mg/kg/day. 20. The method of claim 19, wherein the therapeutically effective amount of crystalline 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione is from about 1 to about 2 mg/kg/day. 21. A method of treating oculocutaneous/ocular albinism, microbial infections, restless leg syndrome, alkaptonuria, or hereditary tyrosinemia type 1, the method comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising crystalline 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione having X-ray powder diffraction pattern with at least five specific peaks at about 2-theta=7.4, 14.7, 15,7, 22.9, and 29.7, wherein said values may be plus or minus 0.2° 2-theta and have an intensity of at least 30%, 22. The method of claim 21, wherein the disease to be treated is hereditary tyrosinemia type 1. 23. The method of claim 21, wherein the therapeutically effective amount of crystalline 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione is from about 0.1 to about 2 mg/kg/day. 24. The method of claim 23, wherein the therapeutically effective amount of crystalline 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione is from about 1 to about 2 mg/kg/day.
FIELD OF THE INVENTION The present invention relates to an improved synthesis and crystallization process of 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, also known as nitisinone or NTBC. This new process of synthesis and crystallization gives rise to an extremely pure and stable 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione. BACKGROUND OF THE INVENTION NTBC is a drug marketed by Swedish Orphan Biovitrum International AB under the brand name Orfadin® and it is used to slow the effects of hereditary tyrosinemia type 1 (HT-1) in adult and pediatric patients. It has been approved by FDA and EMA in January 2002 and February 2005 respectively. HT-1 disease is due to a deficiency of the final enzyme of the tyrosine catabolic pathway fumarylacetoacetate hydrolase. NTBC is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD), an enzyme which precedes film arylacetoacetate hydrolase. By inhibiting the normal catabolism of tyrosine in patients with HT-1, NTBC prevents the accumulation of the toxic intermediates maleylacetoacetate and fumarylacetoacetate, that in patients with HT-1 are converted to the toxic as succinylacetone and succinylacetoacetate, the former inhibiting the porphyrin synthesis pathway leading to the accumulation of 5-aminolevulinate. Usefulness of NTBC in the treatment of further diseases has also been documented. A non-comprehensive list is reported hereinafter. Effectiveness of Orfadin® in the treatment of diseases where the products of the action of HPPD are involved (e.g., HT-1) has been described notably in EP0591275131 corresponding to U.S. Pat. No. 5,550,165B1. Synthesis of NTBC is also described in this patent. WO2011106655 reports a method for increasing tyrosine plasma concentrations in a subject suffering from oculocutaneous/ocular albinism, the method comprising administering to the subject a pharmaceutically acceptable composition comprising NTBC in the range of between about 0.1 mg/kg/day to about 10 mg/kg/day. U.S. Pat. No. 8,354,451B2 reports new methods of combating microbial infections due to fungi or bacteria by means of administration to a subject of a therapeutically active amount of NTBC. WO2010054273 discloses NTBC-containing compositions and methods for the treatment and/or prevention of restless leg syndrome (RLS). EP1853241B1 claims the use of NTBC in the treatment of a neurodegenerative disease, notably Parkinson disease. Introne W. J., et al., disclosed usefulness of nitisinone in the treatment of alkaptonuria (Introne W. J., et al., Molec. Genet. Metab., 2011, 103, 4, 307), The key step of the synthesis reported in EP0591275B1 (now propriety of Swedish Orphan Biovitrum International AB, SE), involves the reaction of 2-nitro-4-trifluoromethylbenzoyl chloride and cyclohexane-1,3-dione in the presence of triethylamine and then use of acetone cyanohydrin in order to promote the rearrangement of the key intermediate enol ester. After washing and extraction from CH2Cl2, the crude product is recrystallized from ethyl acetate to get the desired 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione as a solid having a melting point of 88-94° C. Another patent (U.S. Pat. No. 4,695,673) filed in name of Stauffer Chemical Company disclosed a process of synthesis of acylated 1,3-dicarbonyl compounds in which the intermediate enol ester is isolated prior to its rearrangement into the final product, said rearrangement making use of a cyanohydrin compound derived from alkali metal, methyl alkyl ketone, benzaldehyde, cyclohexanone, C2-C5 aliphatic aldehyde, lower alkyl 341 or directly by using hydrogen cyanide. Yet another patent (U.S. Pat. No. 5,006,158) filed in name of ICI Americas Inc. disclosed a process similar to the one disclosed in U.S. Pat. No. 4,695,673 wherein the intermediate enol ester was isolated prior to its rearrangement into the final product by use of potassium cyanide. Said reaction can optionally be done by concomitant use of a phase transfer catalyst such as Crown ethers. The preferred solvent for conducting such a reaction is 1,2-dichloroethane. Still a further patent (EP0803791) filed in name of Zeneca Ltd disclosed an alternative synthesis of nitisinone involving the reaction of 1,3-cyclohexanedione and variously substituted benzoyl chloride in the presence of sodium or potassium carbonate in CH3CN or DMF. Best yields were obtained using CH3CN as solvent and sodium carbonate as the base. Reaction was performed at 55-57° C. in 17 hours. It is well known that one of the problems of the actual drug formulation (i.e., Orfadin® capsules) is its chemical instability. Indeed, even if Orfadin® has to be stored in a refrigerator at a temperature ranging from 2° C. to 8° C., its shelf life is of only 18 months. After first opening, the in-use stability is a single period of 2 months at a temperature not above 25° C., after which it must be discarded. It will be evident that such storage conditions have an impact in the distribution chain of the medicine, in terms of costs and also in terms of logistics for the patient. Therefore, there is an urgent need of more stable formulations, both from a logistic supply chain point of view, and from the patient compliance point of view. Since the formulation of Orfadin® contains only the active ingredient and starch as excipient, relative instability may be attributed to the active pharmaceutical ingredient itself; in other words it can derive from the way it is synthesized and/or the way it is extracted from the reaction mixture, and/or the way it is finally crystallized. Furthermore, some impurities may contribute to render the final product less stable overtime. Consequently, it is of major importance to identify a process of synthesis and/or a crystallization method that enable the reliable production of a highly pure and stable product. Impurities as herein-above mentioned can derive either from the final product itself (through chemical degradation) or directly from the starting materials/solvents used in the process of synthesis. Regarding the latter option, it is therefore primordial to ascertain that at each step, impurities are completely removed in order not to get them at the final stage, also considering that some of them could potentially be cyto/genotoxic. The impurities correlated to nitisinone can be either derived from the starting materials themselves (i.e., impurities 1 and 2) or obtained as side products during the process of synthesis major under storage conditions (i.e., impurities 3 to 5) and are the following: 2-nitro-4-(trifluoromethyl) benzoic acid (Impurity n° 1), 1,3-cyclohexanedione (CHD) (Impurity n° 2), 4-(trifluoromethyl)salicylic acid (Impurity n° 3), 2-[3-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione (Impurity n° 4), and 6-trifluoromethyl-3,4-dihydro-2H-xanthene-1,9-dione (Impurity n° 5). Impurity-2, impurity-3, and impurity-5 have been previously reported in WO2015101794. Strangely, impurity-4 has never been reported, even if it is an obvious side-product which can easily be formed during the coupling reaction between 1,3-cyclohexanedione and 2-nitro-4-(trifluoromethyl) benzoic acid, the latter being not 100% pure but Wining some amount of regioisomer 3-nitro-4-(trifluoromethyl) benzoic acid. Potential genotoxicity of impurity n° 4 which possesses an aromatic nitro moiety was assessed using in-silica techniques and resulted to be a potential genotoxic impurity. According to the FDA ICH M7 guidelines, daily intake of a mutagenic impurity (Threshold of Toxicological Concern, TTC) in an amount not greater than 1.5 μg per person is considered to be associated with a negligible risk to develop cancer over a lifetime of exposure. Consequently, assuming a daily dose of 2 mg/kg, for a person weighing 70 kg, the maximum tolerated impurity content of such a compound would be of about 11 ppm, as calculated according to the equation underneath. concentration   limit   ( ppm ) = TTC   ( µ   g  /  day ) Dose   ( g  /  day ) It is therefore of paramount importance to ensure that the process of synthesis of nitisinone and the purification steps of the same give rise to an API devoid of such impurity n° 4, or at least far below the threshold of 11 ppm as indicated above. The skilled person will understand that total absence of said impurity is highly desirable. It is well known in the pharmaceutical field that investigation of potential polymorphism of a solid API is of crucial importance and is also recommended by major regulatory authorities such as FDA. Notwithstanding the fact that nitisinone has been used for years to treat HT-1 patients, it appears that no NTBC formulation fully satisfies the requisites of stability and/or compliance standard for the patients. Therefore, there is an unmet medical need of long-term pure and stable formulations. DESCRIPTION OF THE INVENTION It has been surprisingly found that nitisinone obtained through the process, object of a first embodiment of the instant invention is not only highly pure, but also extremely stable. This process of synthesis encompasses a crystallization step of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione by means of toluene and traces amount of acetonitrile. While not intending to be bound in any way by any theory, it is believed that the improved chemical stability of nitisinone is attributable to its crystalline purity obtainable through the presently claimed invention. The expressions “extremely stable” and/or “long term stable” and/or “highly stable” shall be understood for purposes of the present invention to mean that the chemical integrity of nitisinone is of at least 95% after one month of storage of nitisinone at 25° C. and 60% RH. When referring to purity determined by HPLC techniques, said chromatograms are gathered at a wavelength of 235 nm. When referring to temperatures and/or pH, the term “about” shall be understood for purposes of the present invention to mean plus or minus 10% of the temperature and/or pH values mentioned, preferably plus r minus 5% and even more preferably plus or minus 1%. In one embodiment, said chemical integrity is of at least 96% after six mouths of storage of nitisinone at 25° C. and 60% RH. In another embodiment, said chemical integrity is of at least 97% after six months of storage of nitisinone at 25° C. and 60% RH. In a preferred embodiment, said chemical integrity is of at least 98% after six months of storage of nitisinone at 25° C. and 60% RH. In a still preferred embodiment, said chemical integrity is of at least 99% after six months of storage of nitisinone at 25° C. and 60% RH. Another embodiment of the invention contemplates chemical integrity of nitisinone after nine months of storage at 25° C. and 60% RH. In said embodiment, the chemical integrity of nitisinone is of at least 95% after nine months of storage of nitisinone at 25° C. and 60% RH. In a preferred embodiment, the chemical integrity of nitisinone is of at least 96% after nine months of storage of nitisinone at 25° C. and 60% RH. In another preferred embodiment, the chemical integrity of nitisinone is of at least 97% after nine months of storage of nitisinone at 25° C. and 60% RH. In a still preferred embodiment, the chemical integrity of nitisinone is of at feast 98% after nine months of storage of nitisinone at 25° C. and 60% RH. In a still more preferred embodiment, the chemical integrity of nitisinone is of at least 99% after nine months of storage of nitisinone at 25° C. and 60% RH. Another embodiment of the invention contemplates chemical integrity of nitisinone after six months of storage at 40° C. and 75% RH. In said embodiment, the chemical integrity of nitisinone is of at least 95% after six months of storage of nitisinone at 40° C. and 75% RH. In a preferred embodiment, the chemical integrity of nitisinone is of at least 96% after six months of storage of nitisinone at 40° C. and 75% RH. In another preferred embodiment, the chemical integrity of nitisinone is of at least 97% after six months of storage of nitisinone at 40° C. and 75% RH. In a still preferred embodiment, the chemical integrity of nitisinone is of at least 98% after six months of storage of nitisinone at 40° C. and 75% RH. In a still more preferred embodiment, the chemical integrity of nitisinone is of at least 99% after six months of storage of nitisinone at 40° C. and 75% RH. In an even more preferred embodiment, nitisinone is in crystalline form and contains less than 10 ppm of 2-[3-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione and less than 0.05% of any single impurities chosen from the group consisting of 2-nitro-4-(trifluoromethyl) benzoic acid, 1,3-cyclohexanedione, 4-(trifluoromethyl)salicylic acid, and 6-trifluoromethyl-3,4-dihydro-2H-xanthene-1,9-dione, after storage for six months at a temperature of 40° C. and 75% relative humidity. It is submitted that testing at 40° C. and 75% RH for a short time such as six months, is considered indicative of stability at 25° C. (i.e., room temperature) for a longer period of time (fifteen to eighteen months). An embodiment of this invention consists of a process to synthesize nitisinone, by reacting 2-nitro-4-(trifluoromethyl) benzoyl chloride and 1,3-cyclohexanedione in acetonitrile solution in the presence of potassium carbonate. In a more preferred embodiment, nitisinone is obtained highly pure by subsequent crystallization. In a still more preferred embodiment, the crystallization is obtained by means of toluene. In an even more preferred embodiment, the crystallization process encompasses the following steps: a) adding crude nitisinone to an approximately 3/1 binary acetonitrile/toluene mixture, wherein the ratio nitisinone/binary mixture is around 1/4 (w/v) and heating at a temperature of about 55° C. until complete dissolution; b) concentrating the solution from step a) to a final volume roughly twice the initial volume of toluene added in step a) at a temperature below 50° C. in order to obtain a solution of nitisinone in toluene containing approximatively 0.5-0.6 g of nitisinone per ml of solvent; c) adding toluene to the mixture obtained in step b) in order to double the final volume obtained from step b); d) repeating step b); e) heating to about 55° C. for 1 h; f) cooling slowly to about 10° C. in 10 to 12 h; g) filtering off the solid thus obtained in step f) and rinsing it with pre-cooled toluene; and h) drying the crystals under vacuum at a temperature of about 60° C. for 4 h. In another embodiment, the present invention provides nitisinone Form A, having an impurity 2-nitro-4-(trifluoromethyl) benzoic acid (Impurity n° 1) in an amount less than about 0.10 area percent and more preferably less than 0.05%, as measured by HPLC/MS. In yet another embodiment, the present invention provides nitisinone Form A, having an impurity 1,3-cyclohexanedione (CHD) (Impurity n° 2) in an amount less than about 0.10 area percent and more preferably less than 0.05%, as measured by HPLC/MS. In a still further embodiment, the present invention provides nitisinone Form A, having an impurity 4-(trifluoromethyl)salicylic acid (Impurity n° 3) in an amount less than about 0.10 area percent and more preferably less than 0.05%, as measured by HPLC/MS. In a yet still further embodiment, the present invention provides nitisinone Form A, having an impurity 2-[3-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione (Impurity n° 4) in an amount less than about 10 ppm and more preferably less than 5 ppm, as measured by HPLC/MS. In another embodiment, the present invention provides nitisinone Form A, having an impurity 6-trifluoromethyl-3,4-dihydro-2H-xanthene-1,9-dione (Impurity n° 5) in an amount less than about 0.10 area percent and more preferably less than 0.05%, as ineasured by HPLC/MS. In another preferred embodiment, the present invention provides nitisinone Form A, having a total amount of impurities 1 to 5 less than about 0.50 area percent and more preferably less than 0.25%, as measured by HPLC/MS. In a still even more preferred embodiment, the present invention contemplates nitisinone crystalline Form A having a purity of at least 99.94%. In a still further even more preferred embodiment, the present invention contemplates nitisinone crystalline Form A having a purity of at least 99.94% and containing less than 10 ppm of impurity n° 4, preferably less than 5 ppm, ideally less than 1 ppm. In a further preferred embodiment, nitisinone crystals have a PSD (d90) between 310 to 350 μm. Another embodiment of the present invention consists of a crystalline pure nitisinone Form A, which has a X-ray powder diffraction pattern with at least five specific peaks at about 2-theta=7.4, 14.7, 15.7, 22.9, and 29.7, wherein said values may be plus or minus 0.2° 2-theta and have an intensity of at least 30%. In a further embodiment of the present invention, the crystalline pure nitisinone Form A has a X-ray powder diffraction pattern with at least ten specific peaks at about 2-theta=7.4, 14.7, 15.7, 22.9, 23.5, 23.8. 25.7, 29.7, 30.3, and 31.9 wherein said values may be plus or minus 0.2° 2-theta. Another aspect of the instant invention regards usefulness of the thus obtained crystalline Form A nitisinone active ingredient in a pharmaceutical formulation as a medicament due to its 4-hydroxyphenylpyruvate dioxygenase inhibiting properties for the treatment of disorders where such inhibition results in improving the health of the patient. In particular, patients suffering from. HT-1, or from oculocutaneous/ocular albinism, or from microbial infections due to fungi or bacteria, or from restless leg syndrome, or from neurodegenerative disease, notably Parkinson disease can be treated. In a preferred embodiment of the present invention, the pharmaceutical formulation is for treating patients suffering from HT-1. In accordance with the foregoing, there are provided methods of inhibiting 4-hydroxyphenylpyruvate dioxygenase enzyme in a patient. The methods include administering an effective amount of the crystalline 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione described herein to a patient in need thereof. Within this aspect of the invention, patients requiring inhibition of the 4-hydroxyphenylpyruvate dioxygenase enzyme will be those suffering from diseases such as oculocutaneous/ocular albinism, microbial infections, restless leg syndrome, alkaptonuria, and hereditary tyrosinemia type 1. Preferred aspects of this embodiment include treating hereditary tyrosinemia type 1. Generally, the pharmaceutical formulation of the present invention is administered in a “therapeutically effective amount”. The amount of the pharmaceutical formulation actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, any other potential drug the patient is currently taking, the age, the sex, body weight, and response of the individual patient, the severity of the patient's symptoms, and the Like. Generally, however, the crystalline Form A nitisinone is administered in amounts ranging from between about 0.1 mg/kg/day to about 2 mg/kg/day, with amounts of from about 1-2 mg/kg/day being preferred. A further embodiment of the present invention consists of a pharmaceutical formulation comprising nitisinone obtained by the process described in example 2. It is submitted that testing at 40° C. and 75% RH for a short time such as six months, is considered indicative of stability at 25° C. room temperature) for a longer period of time (fifteen to eighteen months). DESCRIPTION OF THE DRAWING FIG. 1: represents the X-ray spectra of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione Form A polymorph. EXAMPLES Abbreviations: CH3CN: acetonitrile HCl: hydrochloric acid HPLC: high-performance liquid chromatography HPLC/MS: high-performance liquid chromatography-mass spectrometry General Remarks: Crystalline form has been characterised by Broker D8 Advance X-ray powder diffraction (XRPD). Bragg-Brentano geometry, CuKα radiation with wavelength λ=1.54; scanning with 2θ angle range of 3° to 40°, step size of 0.02° for 0.5 seconds per step. Linear solid-state detector (Lynx Eye). Micronization has been performed with a laboratory scale micronizer FLUID JET MILL J-20 (Tecnologia Meccanica Srl) using the following milling conditions: Grind air: dry nitrogen gas Ring pressure: 3.9 bar Venturi pressure: 4.1 bar Feed rate: 0.30 g/min Particle size and d(90) has been determined using laser light scattering technique using a Malvern Mastersizer 3000 and water as dispersant. Example 1 Thionyl chloride (162 g, 1.36 mol) was added dropwise into a suspension of 2-nitro-4-trifluoromethylbenzoic acid (228 g, 0.97 mol) in toluene (630 g) at 80° C. The thus obtained solution was kept under stirring at 80° C. for 20 hours, and then cooled to 50° C. The volatiles were removed under reduced pressure in order to get the expected 2-nitro-4-trifluoromethylbenzoyl chloride as an oil. The latter, cooled to 25° C. was added dropwise to a suspension of 1,3-cyclohexanedione (109 g, 0.97 mol) and potassium carbonate (323 g, 2.33 mol) in CH3CN (607 g). After 18 h the mixture was diluted with water (500 ml) and slowly acidified to about pH=1 with HCl 37%. The mixture was then warmed. to about 55° C. and the phases were separated. The organic layer was washed with a 10% aqueous solution of sodium chloride and then, concentrated under reduced pressure at a temperature below 55° C. to reach a volume of 380 ml. The thus obtained mixture was stirred at 55° C. for 1 h and then cooled to 0° C. in 16 to 18 h. The resulting solid was filtered and rinsed several times with pre-cooled (0° C.) toluene. The wet solid was dried at 60° C. under vacuum for 6 h to provide nitisinone. (164 g) as a white to yellowish solid with a purity of 98.4% as measured by HPLC and a content of potentially genotoxic impurity n° 4 of 6.1 ppm measured by HPLC/MS. Example 2 Nitisinone as obtained from example 1 (164 g) was added to a 3/1 (w/w) mixture of CH3CN/toluene (volume of solvent: 038 ml). The mixture was warmed gently to about 55° C. under stirring until solids were completely dissolved. The solution was then concentrated under reduced pressure maintaining the internal temperature below 50° C. to reach a volume of 290 ml. Then, more toluene (255 g) was added and the solution was concentrated again under reduced pressure until the residual volume reached 290 ml. The solution was heated to about 55° C. for 1 h and successively cooled slowly in 10 to 12 h to 10° C. The resulting solid was filtered and rinsed several times with pre-cooled (0° C.) toluene. The wet solid was dried at about 60° C. under vacuum for 4 h to provide nitisinone (136 g) as a white to yellowish solid, with a purity of 99.94% and a 99.8% assay measured by HPLC and a d(90) particle size between 310 and 350 μm. The content of potential genotoxic impurity n° 4 resulted below 1 ppm. Stability Studies As evidenced in Table 1, nitisinone obtained through the process of the invention resulted extremely stable even in accelerated conditions for a period of at least six months. Importantly, the potentially genotoxic impurity-4 resulted below the limit of quantification, independently from the storage conditions. The presence of impurity-4 was checked by reverse HPLC/MS using the method described in the table underneath. Column Ascentis Express C18 5 μm, 50 × 4.6 mm Flow 1 ml/minute Injection volume 10 μl Wavelength 235 nm Column temperature 30° C. Detector MS Polarity: positive; SIM Mode; m/z = 330 Gas temp: 300° C. Gas flow: 13.1 l/min Nebulizer: 20 psi Capillary: 4500 nA Step 0 to SIM > to MS Step 1 to SIM > to waste Mobile phase A CH3CN Mobile phase B H2O/0.1% TFA HPLC Gradient Time % A % B 0 50 50 10 70 30 12 70 30 13 50 50 23 50 50 Retention time 5.8 minutes TABLE 1 25° C./60% RH 30° C./65% RH 40° C./75% RH Tests Specifications 6 months 9 months 6 months 9 months 6 months Appearance White to yellowish C C C C C (Visual) crystalline powder Water content (KF) NMT 0.5% w/w 0.0% 0.0% 0.2% 0.0% 0.2% Assay - on anhydrous 98.0-102.0% 98.8% 98.8% 99.4% 101.4% 100.4% basis (HPLC) Impurity-1 NMT 0.15% <0.01% <0.01% <0.01% <0.01% <0.01% Impurity-2 NMT 0.15% <0.01% <0.01% <0.01% <0.01% <0.01% Impurity-3 NMT 0.15% <0.01% <0.01% <0.01% <0.01% <0.01% Impurity 4 NMT 10 ppm <5 ppm <5 ppm <5 ppm <5 ppm <5 ppm Impurity 5 NMT 0.15% 0.01% <0.01% 0.01% <0.01% 0.01% Any unspecified NMT 0.10% <0.01% <0.01% <0.01% <0.01% <0.01% impurities Total impurities NMT 0.50% 0.01% <0.01% 0.01% <0.01% 0.01% C = Conform; NMT = No more than
<SOH> BACKGROUND OF THE INVENTION <EOH>NTBC is a drug marketed by Swedish Orphan Biovitrum International AB under the brand name Orfadin® and it is used to slow the effects of hereditary tyrosinemia type 1 (HT-1) in adult and pediatric patients. It has been approved by FDA and EMA in January 2002 and February 2005 respectively. HT-1 disease is due to a deficiency of the final enzyme of the tyrosine catabolic pathway fumarylacetoacetate hydrolase. NTBC is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD), an enzyme which precedes film arylacetoacetate hydrolase. By inhibiting the normal catabolism of tyrosine in patients with HT-1, NTBC prevents the accumulation of the toxic intermediates maleylacetoacetate and fumarylacetoacetate, that in patients with HT-1 are converted to the toxic as succinylacetone and succinylacetoacetate, the former inhibiting the porphyrin synthesis pathway leading to the accumulation of 5-aminolevulinate. Usefulness of NTBC in the treatment of further diseases has also been documented. A non-comprehensive list is reported hereinafter. Effectiveness of Orfadin® in the treatment of diseases where the products of the action of HPPD are involved (e.g., HT-1) has been described notably in EP0591275131 corresponding to U.S. Pat. No. 5,550,165B1. Synthesis of NTBC is also described in this patent. WO2011106655 reports a method for increasing tyrosine plasma concentrations in a subject suffering from oculocutaneous/ocular albinism, the method comprising administering to the subject a pharmaceutically acceptable composition comprising NTBC in the range of between about 0.1 mg/kg/day to about 10 mg/kg/day. U.S. Pat. No. 8,354,451B2 reports new methods of combating microbial infections due to fungi or bacteria by means of administration to a subject of a therapeutically active amount of NTBC. WO2010054273 discloses NTBC-containing compositions and methods for the treatment and/or prevention of restless leg syndrome (RLS). EP1853241B1 claims the use of NTBC in the treatment of a neurodegenerative disease, notably Parkinson disease. Introne W. J., et al., disclosed usefulness of nitisinone in the treatment of alkaptonuria (Introne W. J., et al., Molec. Genet. Metab., 2011, 103, 4, 307), The key step of the synthesis reported in EP0591275B1 (now propriety of Swedish Orphan Biovitrum International AB, SE), involves the reaction of 2-nitro-4-trifluoromethylbenzoyl chloride and cyclohexane-1,3-dione in the presence of triethylamine and then use of acetone cyanohydrin in order to promote the rearrangement of the key intermediate enol ester. After washing and extraction from CH 2 Cl 2 , the crude product is recrystallized from ethyl acetate to get the desired 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione as a solid having a melting point of 88-94° C. Another patent (U.S. Pat. No. 4,695,673) filed in name of Stauffer Chemical Company disclosed a process of synthesis of acylated 1,3-dicarbonyl compounds in which the intermediate enol ester is isolated prior to its rearrangement into the final product, said rearrangement making use of a cyanohydrin compound derived from alkali metal, methyl alkyl ketone, benzaldehyde, cyclohexanone, C 2 -C 5 aliphatic aldehyde, lower alkyl 341 or directly by using hydrogen cyanide. Yet another patent (U.S. Pat. No. 5,006,158) filed in name of ICI Americas Inc. disclosed a process similar to the one disclosed in U.S. Pat. No. 4,695,673 wherein the intermediate enol ester was isolated prior to its rearrangement into the final product by use of potassium cyanide. Said reaction can optionally be done by concomitant use of a phase transfer catalyst such as Crown ethers. The preferred solvent for conducting such a reaction is 1,2-dichloroethane. Still a further patent (EP0803791) filed in name of Zeneca Ltd disclosed an alternative synthesis of nitisinone involving the reaction of 1,3-cyclohexanedione and variously substituted benzoyl chloride in the presence of sodium or potassium carbonate in CH 3 CN or DMF. Best yields were obtained using CH 3 CN as solvent and sodium carbonate as the base. Reaction was performed at 55-57° C. in 17 hours. It is well known that one of the problems of the actual drug formulation (i.e., Orfadin® capsules) is its chemical instability. Indeed, even if Orfadin® has to be stored in a refrigerator at a temperature ranging from 2° C. to 8° C., its shelf life is of only 18 months. After first opening, the in-use stability is a single period of 2 months at a temperature not above 25° C., after which it must be discarded. It will be evident that such storage conditions have an impact in the distribution chain of the medicine, in terms of costs and also in terms of logistics for the patient. Therefore, there is an urgent need of more stable formulations, both from a logistic supply chain point of view, and from the patient compliance point of view. Since the formulation of Orfadin® contains only the active ingredient and starch as excipient, relative instability may be attributed to the active pharmaceutical ingredient itself; in other words it can derive from the way it is synthesized and/or the way it is extracted from the reaction mixture, and/or the way it is finally crystallized. Furthermore, some impurities may contribute to render the final product less stable overtime. Consequently, it is of major importance to identify a process of synthesis and/or a crystallization method that enable the reliable production of a highly pure and stable product. Impurities as herein-above mentioned can derive either from the final product itself (through chemical degradation) or directly from the starting materials/solvents used in the process of synthesis. Regarding the latter option, it is therefore primordial to ascertain that at each step, impurities are completely removed in order not to get them at the final stage, also considering that some of them could potentially be cyto/genotoxic. The impurities correlated to nitisinone can be either derived from the starting materials themselves (i.e., impurities 1 and 2) or obtained as side products during the process of synthesis major under storage conditions (i.e., impurities 3 to 5) and are the following: 2-nitro-4-(trifluoromethyl) benzoic acid (Impurity n° 1), 1,3-cyclohexanedione (CHD) (Impurity n° 2), 4-(trifluoromethyl)salicylic acid (Impurity n° 3), 2-[3-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione (Impurity n° 4), and 6-trifluoromethyl-3,4-dihydro-2H-xanthene-1,9-dione (Impurity n° 5). Impurity-2, impurity-3, and impurity-5 have been previously reported in WO2015101794. Strangely, impurity-4 has never been reported, even if it is an obvious side-product which can easily be formed during the coupling reaction between 1,3-cyclohexanedione and 2-nitro-4-(trifluoromethyl) benzoic acid, the latter being not 100% pure but Wining some amount of regioisomer 3-nitro-4-(trifluoromethyl) benzoic acid. Potential genotoxicity of impurity n° 4 which possesses an aromatic nitro moiety was assessed using in-silica techniques and resulted to be a potential genotoxic impurity. According to the FDA ICH M7 guidelines, daily intake of a mutagenic impurity (Threshold of Toxicological Concern, TTC) in an amount not greater than 1.5 μg per person is considered to be associated with a negligible risk to develop cancer over a lifetime of exposure. Consequently, assuming a daily dose of 2 mg/kg, for a person weighing 70 kg, the maximum tolerated impurity content of such a compound would be of about 11 ppm, as calculated according to the equation underneath. concentration   limit   ( ppm ) = TTC   ( µ   g  /  day ) Dose   ( g  /  day ) It is therefore of paramount importance to ensure that the process of synthesis of nitisinone and the purification steps of the same give rise to an API devoid of such impurity n° 4, or at least far below the threshold of 11 ppm as indicated above. The skilled person will understand that total absence of said impurity is highly desirable. It is well known in the pharmaceutical field that investigation of potential polymorphism of a solid API is of crucial importance and is also recommended by major regulatory authorities such as FDA. Notwithstanding the fact that nitisinone has been used for years to treat HT-1 patients, it appears that no NTBC formulation fully satisfies the requisites of stability and/or compliance standard for the patients. Therefore, there is an unmet medical need of long-term pure and stable formulations.
C07C20546
20170914
20180531
65066.0
C07C20546
1
KATAKAM, SUDHAKAR
Crystalline Inhibitor of 4-Hydroxyphenylpyruvate Dioxygenase
UNDISCOUNTED
1
CONT-ACCEPTED
C07C
2,017
15,704,922
PENDING
Heat Dissipating Structures and Mobility Apparatus for Electronic Headset Frames
A heat sink for electronic devices, such as wearable displays, dissipates heat away from and electrical component, such as a microprocessor. An adjustable support assembly permits adjustment of a visual display relative to a user's field of view.
1 A wearable display including a headset configured to be worn by a user, a visual display assembly including a support body supported by the headset and a visual display supported by the support body to be positioned forward of a user's eye wearing the headset, an electrical component in communication with the visual display, and a heat sink in thermal communication with the electrical component, the heat sink including a base positioned to receive heat from the electrical component and a plurality of heat fins in thermal communication with the base to dissipate heat from the electrical component into the environment. 2. The wearable display of claim 1, wherein heat sink further includes a lip coupled to the base. 3. The wearable display of claim 2, wherein the lip has first and second ends, the lip has a first width at the first end, and a second width at the second end that is greater than the first width. 4. The wearable display of claim 1, wherein the heat sink further includes an extension coupled to the base and positioned inside the support body of the visual display. 5. The wearable display of claim 4, wherein the electrical component is a microprocessor and the extension is coupled to the microprocessor. 6. The wearable display of claim 4, wherein the base is positioned outside of the visual display. 7. The wearable display of claim 1, wherein the plurality of heat fins are arranged side-by-side from a first end of a second end, a first heat fin has a first length, a second heat fin has a second length, and a third heat fin positioned between the first and second heat fins has a third length that is greater than first and second lengths. 8. The wearable display of claim 1, wherein the heatsink includes a tab that cradles the support body. 9. The wearable display of claim 8, wherein the tab of the heatsink includes a micro USB port. 10. The wearable display of claim 8, wherein the heat sink further includes a lip positioned on a first side of the support body of the visual display and the tab is positioned on a second side of the support body of the visual display that is opposite the first side of the support body of the visual display. 11. A wearable display including a headset configured to be worn by a user, a visual display assembly including a support body supported by the headset and a visual display supported by the support body to be positioned forward of a user's eye wearing the headset, and an adjustable support assembly coupling the support body to the headset in one of a plurality of positions. 12. The wearable display of claim 11, therein the adjustable support assembly includes a clamp coupled to the visual display. 13. The wearable display of claim 12, wherein the clamp is rotatable about a horizontal axis of rotation when a user is wearing the wearable display. 14. The wearable display of claim 12, wherein the clamp includes a screw that is loosened to release the visual display and tightened to secure the visual display to the clamp. 15. The wearable display of claim 11, wherein the adjustable support assembly includes a headset base coupled to the headset and a visual display base rotatably coupled to the headset base. 16. The wearable display of claim 15, wherein the adjustable support, assembly further includes an O-ring positioned between the headset base and the visual display base.
CROSS REFERENCE TO RELATED APPLICATION The present application is a continuation of U.S. application Ser. No. 15/479,026, filed Apr. 4, 2017, and claims the benefit of U.S. Provisional Application No. 62/318,141, filed Apr. 4, 2016 and U.S. Provisional Application No. 62/318,554, filed Apr. 5, 2016, the disclosures of which are hereby incorporated by reference in their entireties. FIELD OF THE DISCLOSURE The present disclosure relates to electronic devices including a frame configured to be worn on the head of a user. BACKGROUND OF THE DISCLOSURE Electronic headset frames, such as Google® Glass Enterprise Edition visual display, serve as an optical display designed as a pair of glasses to be mounted to the head of a user. These electronic headset frames are capable of not only displaying images, but also recording the visuals of a user. These electronic headset frames may include an arm or “pod” which houses components such as the microprocessor, which are subject to overheating after a period of time due to the heat generated by electronic chips in the microprocessor which cause the device to either malfunction or shut off. Additionally, these electronic headset frames are currently provided via immobile eyeglasses which restrict the user's vertical field of view. BRIEF SUMMARY OF THE DISCLOSURE According to one aspect of the present disclosure, a wearable display is provided. The wearable display includes a headset configured to be worn by a user and a visual display assembly including a support body supported by the headset and a visual display supported by the support body to be positioned forward of a user's eye wearing the headset. The wearable display further includes an electrical component in communication with the visual display and a heat sink in thermal communication with the electrical component. The heat sink includes a base positioned to receive heat from the electrical component and a plurality of heat fins in thermal communication with the base to dissipate heat from the electrical component into the environment. According to another aspect of the present disclosure, a wearable display is provided that includes a headset configured to be worn by a user and a visual display assembly including a support body supported by the headset and a visual display supported by the support body to be positioned forward of a user's eye wearing the headset. The wearable display further includes an adjustable support assembly coupling the support body to the headset in one of a plurality of positions. Additional features of the present disclosure will become apparent to those skilled in the art upon consideration of the following detailed description of the illustrative embodiment exemplifying the best mode of carrying out the disclosure as presently perceived. BRIEF DESCRIPTION OF THE DRAWINGS The aforementioned aspects and many of the intended features of this disclosure will grow to be appreciated at a greater level once references to the following accompanying illustrations are expounded upon. FIG. 1 is an overall view of wearable display including a headset and a visual display positionable in a user's field of vision; FIG. 2 is a perspective view of the visual display showing a heat sink coupled to the visual display; FIG. 3 is a perspective view of the heatsink of FIG. 2 showing the heatsink including a plurality of heat fins and tab that provides a cradle; FIG. 4 is an end view of the heat sink of FIG. 2 showing the cradle; FIG. 5 is a top plan view of the heat sink showing the heat sink including a plurality of connections in the tab to communicate with electrical components of the visual display; FIG. 6 is a bottom view of the heat sink of FIG. 2 showing the tab including a micro USB port; FIG. 7 is an elevation view of the heat sink of FIG. 2; FIG. 8 is a top view of the clamping structure of the mobility apparatus includinga view of the square hole; FIG. 9 is a perspective view of an adjustable support assembly that couples the visual display to the headset; FIG. 10 is another perspective view of the adjustable support assembly; FIG. 11 is an exploded view of the adjustable support assembly; FIG. 12 is a side elevation view of a base of the adjustable support assembly and a screw that clamps the visual display to the headset; FIG. 13 is a bottom view of the base of FIG. 12; FIG. 14 is a perspective view of the base of FIG. 12; and FIG. 15 is another perspective view of the base of FIG. 12. Equivalent reference components point to corresponding parts throughout the several views. Unless otherwise indicated, the components shown in the drawings are proportional to each other. Wherein, the illustrations depicted are manifestations of the disclosure, and such illustrations shall in no way be interpreted as limiting the scope of the disclosure. For the purposes of promoting an understanding of the principals of the disclosure, reference will now be made to the embodiments illustrated in the drawings, which are described below. The embodiments disclosed below are not intended to be exhaustive or limit the disclosure to the precise form disclosed in the following detailed description. Rather, the embodiments are chosen and described so that others skilled in the art may utilize their teachings. It will be understood that no limitation of the scope of the disclosure is thereby intended. The disclosure includes any alterations and further modifications in the illustrative devices and described methods and further applications of the principles of the disclosure which would normally occur to one skilled in the art to which the disclosure relates. DETAILED DESCRIPTION OF THE DRAWINGS According to the present disclosure, a wearable display 10 is provided that includes a headset 12 positionable on a user's head (not shown) and visual display assembly 14, also referred to as a glass pod 14. Glass pod 14 includes a support body 16 coupled to headset 12 that wraps around the side of a user's head to a position in front of the user's field of view. Glass pod 14 further includes a visual display 18 supported by support body 16 positioned in the users field of view. Visual display 18 is preferably transparent and configured to display images, data, etc. in the user's field of view, Glass pod 14 is preferably a Google® Enterprise Edition visual display. Additional details of suitable visual display assemblies are provided in U.S. Pat. No. 8,493,204 and U.S. Patent Publication Nos 2013/0069850; 2013/0258270, and 2013/0235331, the entire disclosures of which are incorporated by reference herein. According to alternative embodiments, other headset configurations may be provided such as glasses and other headset configurations known to those of ordinary skill in the art. Glass pod 14 is connected to headset 12 with an adjustable support assembly 20. Support assembly 20 allows a user to adjust the position of visual display 18. In one embodiment, glass pod 14 can be rotated to be within the user's field of view; however, in other embodiments, glass pod 14 can be rotated to be inside and outside of the user's field of view or a multitude of other angles relative to the user's range of head motions, preferably within a 360 degree radius. Glass pod 14 includes several electrical components that provide power, communications, processing, and otherwise support the features of glass pod 14. For example, glass pod 14 includes a battery 22 positioned inside support body 16, a microprocessor/CPU 24, a camera 19 (shown extended from its normal position in FIG. 1), a touchpad (not shown), a speaker (not shown), and a microphone (not shown). Often, such electrical components generate heat. On occasion, if such heat is not dissipated away from the electrical component at a sufficient rate, the electrical component may heat up too much. To avoid component failure and/or other issues, the electronic components may be partially or fully disabled to eliminate and/or reduce the heat generation. When disabled, a particular feature(s) of glass pod 14 may be disabled. To facilitate dissipation of heat away from one or more of the electrical components and to maintain functionality, glass pod 14 is provide with a heat sink 26 as shown in FIG. 1. As shown in FIGS. 1 and 2, heat sink 26 is coupled to an outer side of glass pod 14, forward of a user's ear when worn by a user. Heat sink 26 is positioned to receive heat from microprocessor 24 and to dissipate the heat away from microprocessor 24 and preferably away from the user. According to the preferred embodiment, heat sink 24 is made of aluminum. According to other embodiments, heat sink 24 may be made of other metals and other materials having high thermal conductivity. As shown in FIG. 3, heat sink 26 includes a base 28, a plurality of heat fins 30, a communications tab 32, an upper lip 34, and a heat transfer extension 36. As shown in FIGS. 3 and 4, base 28 is contoured to match an outer profile of support assembly 20. During assembly, base 28 is adhered to support assembly 20 with a thermally conductive adhesive. Upper lip 34 is positioned on top of support assembly 20 and transitions from wider to narrower to match a thickness of support assembly 20. Upper lip 34 may also be adhered to support structure with thermally conductive adhesive. Preferably, the thermally conductive adhesive has a thermal conductivity greater than the thermal conductive of the material of support assembly 20. As shown in FIGS. 3 and 4, heat transfer extension 36 is substantially cylindrical and positioned in contact, preferably direct contact, with CPU 24 to facilitate the transfer of heat from CPU 24 to base 28. In the embodiment, plastic support assembly 20 of pod 14 that protects CPU 24 is drilled to include a small hole (not shown) that receives extension 26 to contact CPU 24. Upon such contact and use of CPU 24, the heat that comes from CPU 24 is then transferred to extension 22 and into base 28, and then released through base 28 and primarily through heat fins 30. CPU 24 may also be connected to extension 22 by using a thermal adhesive. As shown in FIGS. 5 and 6, heat fins 30 have approximately the same width. As shown in FIG. 7, heat fins 30 have a length that varies with the counter of the lower edge of base 28, which matches the counter of the underside of support assembly 20. As shown in FIGS. 3-7, heat sink 26 may also include tab/extension 32 that cradles and underside of support assembly 20. In addition to cradling support assembly 20, tab 32 includes a micro USB port 35. Micro USB 35 provides power and data connection points to pod 14 to external sources. As shown in FIG. 5, tab 32 includes a plurality of contacts/connections (female) 36 that align with electrical connection points (male) on support assembly 20. Tab 32 converts the existing power and data connection points of pod 14 to micro USB port 35. Micro USB 35 is connected to pod 14 by soldering the existing data connection points of pod 14 to data and power connection points 36 of tab 32. With micro USB port 35, pod 14 can be charged and communicate/transmit data simultaneously. According to alternative embodiments of the present disclosure, one or more features of heat sink 26 is not provided. For example, according to one embodiment, heat transfer extension 36 is not provided and/or tab 32 is not provided. As shown in FIG. 1, wearable display 10 includes adjustable support assembly 20. Support assembly 20 includes a headset base 38, a fastener 40 (see FIG. 11), a pod/visual display base 42, a rubber O-ring 44 positioned between headset base 38 and pod base 42, a clamp 46, partially defined by pod base 42, a screw 48, and knob 50. Other than a portion of fastener 40, most of adjustable support assembly 20 is positioned externally of a headband 52 of headset 12. Fastener 40 includes a head 54 positioned on the interior of headband 52 and a shaft 56 that extends through headband 52 through a hole 58 in headband 52. As shown in FIG. 11, headset base 38 includes a cylindrical bore 60 that receives a cylindrical portion 62 of shaft 56. O-ring 44 is positioned over shaft 56. Pod base 42 includes a square bore 64 that receives a square portion 66 of shaft 56. Knob 50 includes a threaded bore 68 that receives a threaded end 70 of shaft 56. Clamp 46 defines an opening 72 sized to receive support assembly 20 as shown in FIGS. 14 and 15. Screw 48 extending through clamp 46 into opening 72 and is tightened to secure pod 14 to pod base 42 and therefore headset 12. To adjust the position of pod 14 relative to headset 12 or remove pod 14 from headset 12, screw 48 may be loosened. When repositioned, screw 48 is again tightened. Also during this movement, the direction of camera 19 can be adjusted so that camera 19 can be pointed at a locus of activity, such as a surgical site. The images captured by camera 19 can be transmitted to others for viewing and commentary, if necessary. During or after use, it may be desirable to move visual display 18 out of the user's field of view or to reposition visual display 18 within the user's field of view. According to the present disclosure, pod 14 with visual display 18 may be rotated about a horizontal axis of rotation relative to headset 12. To rotate pod 14, a user at least partially unscrews knob 50, which relieve compression placed on O-ring 44 and friction provided between headset base 38 and pod base 42 by O-ring 44. By reducing this friction, it is easier/possible to rotate pod 12 relative to headset 12. When pod 14 is in the desired location, knob 50 is tightened so that O-ring is compressed, creating friction to hold pod 14 in place. If O-ring 44 is decompressed enough, it is possible to apply enough force/torque to pod 14 to overcome the friction created by O-ring 44 without having to loosen knob 50. While this disclosure has been described as having an exemplary design, the present disclosure may be further modified within the spirit and scope of this disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the disclosure using its general principles. Further, this application is intended to cover such departures from the present disclosure as come within known or customary practices in the art to which this disclosure pertains.
<SOH> BACKGROUND OF THE DISCLOSURE <EOH>Electronic headset frames, such as Google® Glass Enterprise Edition visual display, serve as an optical display designed as a pair of glasses to be mounted to the head of a user. These electronic headset frames are capable of not only displaying images, but also recording the visuals of a user. These electronic headset frames may include an arm or “pod” which houses components such as the microprocessor, which are subject to overheating after a period of time due to the heat generated by electronic chips in the microprocessor which cause the device to either malfunction or shut off. Additionally, these electronic headset frames are currently provided via immobile eyeglasses which restrict the user's vertical field of view.
<SOH> BRIEF SUMMARY OF THE DISCLOSURE <EOH>According to one aspect of the present disclosure, a wearable display is provided. The wearable display includes a headset configured to be worn by a user and a visual display assembly including a support body supported by the headset and a visual display supported by the support body to be positioned forward of a user's eye wearing the headset. The wearable display further includes an electrical component in communication with the visual display and a heat sink in thermal communication with the electrical component. The heat sink includes a base positioned to receive heat from the electrical component and a plurality of heat fins in thermal communication with the base to dissipate heat from the electrical component into the environment. According to another aspect of the present disclosure, a wearable display is provided that includes a headset configured to be worn by a user and a visual display assembly including a support body supported by the headset and a visual display supported by the support body to be positioned forward of a user's eye wearing the headset. The wearable display further includes an adjustable support assembly coupling the support body to the headset in one of a plurality of positions. Additional features of the present disclosure will become apparent to those skilled in the art upon consideration of the following detailed description of the illustrative embodiment exemplifying the best mode of carrying out the disclosure as presently perceived.
G06F1163
20170914
20180104
72063.0
G06F116
1
AUGUSTIN, CHRISTOPHER L
Heat Dissipating Structures and Mobility Apparatus for Electronic Headset Frames
UNDISCOUNTED
1
CONT-ACCEPTED
G06F
2,017
15,705,208
ACCEPTED
EMULSION FORMULATIONS OF APREPITANT
Disclosed herein are novel pharmaceutical formulations of aprepitant suitable for parenteral administration including intravenous administration. Also included are formulations including both aprepitant and dexamethasone sodium phosphate. The pharmaceutical formulations are stable oil-in-water emulsions for non-oral treatment of emesis and are particularly useful for treatment of subjects undergoing highly emetogenic cancer chemotherapy.
1. A physically stable pharmaceutical composition comprising: 0.4 wt/wt % to 1.0 wt/wt % aprepitant; 13 wt/wt % to 15 wt/wt % egg yolk lecithin; 9 wt/wt % to 10 wt/wt % soybean oil; and a pH modifier, wherein the pH modifier is sodium oleate; wherein the pH of the composition ranges from 7.5 to 9.0, wherein the ratio of egg yolk lecithin to aprepitant (wt %:wt %) ranges from about 18:1 to 22:1. 2. The composition according to claim 1, wherein the composition comprises 0.7 wt/wt % aprepitant. 3. The composition according to claim 1, wherein the composition comprises 14 wt/wt % egg yolk lecithin. 4. The composition according to claim 1, wherein the composition further comprises 3 wt/wt % to 8 wt/wt % sucrose. 5. The composition according to claim 1, wherein the composition further comprises 5 wt/wt % sucrose. 6. The composition according to claim 1, wherein the composition further comprises 2 wt/wt % to 6 wt/wt % ethanol. 7. The composition according to claim 1, wherein the composition further comprises less than 6 wt/wt % ethanol. 8. A physically stable pharmaceutical composition suitable for intravenous administration comprising: 0.7 wt/wt % aprepitant; 14 wt/wt % egg yolk lecithin; 9 wt/wt % to 10 wt/wt % soybean oil; and a pH modifier, wherein the pH modifier is sodium oleate; wherein the pH of the composition ranges from 7.5 to 9.0, wherein the ratio of egg yolk lecithin to aprepitant (wt %:wt %) ranges from about 18:1 to 22:1. 9. The composition according to claim 8, wherein the composition further comprises 5 wt/wt % sucrose. 10. The composition according to claim 8, wherein the composition further comprises 2 wt/wt % to 6 wt/wt % ethanol. 11. The composition according to claim 8, wherein the composition further comprises less than 4 wt/wt % ethanol. 12. A method for treating nausea and vomiting in a subject in need thereof comprising administering to the subject the pharmaceutical composition according to claim 1. 13. The method according to claim 12, wherein the nausea and vomiting is chemotherapy induced nausea and vomiting. 14. The method according to claim 13, wherein the chemotherapy induced nausea and vomiting is in response to highly emetic chemotherapy. 15. The method according to claim 13, wherein the chemotherapy induced nausea and vomiting is in response to moderately emetic chemotherapy. 16. The method according to claim 12, wherein the administering is intravenous. 17. A method for treating nausea and vomiting in a subject in need thereof comprising administering to the subject the pharmaceutical composition according to claim 8. 18. The method according to claim 17, wherein the nausea and vomiting is chemotherapy induced nausea and vomiting. 19. The method according to claim 18, wherein the chemotherapy induced nausea and vomiting is in response to highly emetic chemotherapy. 20. The method according to claim 18, wherein the chemotherapy induced nausea and vomiting is in response to moderately emetic chemotherapy. 21. The method according to claim 17, wherein the administering is intravenous.
CROSS-REFERENCE TO RELATED APPLICATIONS This application in a continuation of U.S. application Ser. No. 14/859,013, filed Sep. 18, 2015, which claims the benefit of U.S. Provisional Application No. 62/052,948 filed on Sep. 19, 2014, the disclosures of which are fully incorporated by reference in their entirety. TECHNICAL FIELD The disclosure relates generally to emulsion formulations and systems for the intravenous or parenteral administration of aprepitant for treatment of emesis. The emulsion formulations are stable for prolonged periods of time. Also described are methods for preparing the stable aprepitant emulsions and pharmaceutical formulations. BACKGROUND Aprepitant, having the chemical name 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one, has the structure: Aprepitant is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Aprepitant is currently available in the United States as an oral capsule, however due to the nausea and vomiting experienced by patients, it is desirable to formulate aprepitant as a liquid suitable for parenteral or intravenous administration. Liquid formulations containing aprepitant are very challenging to make as aprepitant is a molecule having poor solubility and poor permeability characteristics. One means of addressing this challenge is to prepare an emulsion which may both allow preparation of an injectable formulation as well as enhance bioavailability of the aprepitant once administered. Intravenous emulsions should have a very small droplet size to circulate in the bloodstream without causing capillary blockage and embolization. These size limits are typified by USP33-NF28 General Chapter <729> for Globule Size Distribution in Lipid Injectable Emulsions, hereinafter referred to as USP <729>, which defines universal limits for (1) mean droplet size not exceeding 500 nm or 0.5 μm and (2) the population of large-diameter fat globules, expressed as the volume-weighted percentage of fat greater than 5 μm (PFAT5) not exceeding 0.05%, irrespective of the final lipid concentration. Emulsion formulations must be physically stable. The droplet size limits defined in USP <729> apply throughout the assigned shelf life. All true emulsions are thermodynamically unstable and may over time undergo a range of processes which tend to increase the droplet size. These include direct droplet coalescence, when two droplets collide and form a single new droplet, and aggregation, in which droplets adhere together to form larger masses. Aggregation may in some cases be a precursor of further coalescence into larger droplets. These processes may result in large aggregates rising to the surface of the container, a phenomenon known as ‘creaming’, and ultimately to free oil being visible on the emulsion surface, known as ‘cracking’. Emulsion formulations must also be chemically stable. The drug substance may degrade; for example, lipophilic drugs will partition into the oil phase, which will confer some degree of protection, but hydrolytic degradation may still occur at the oil-water interface. Possible chemical degradation within parenteral fat emulsions includes oxidation of unsaturated fatty acid residues present in triglyceride and lecithin, and hydrolysis of phospholipids leading to the formation of free fatty acids (FFA) and lysophospholipids. Such degradants lower pH, which may then promote further degradation. Thus, pH should be controlled during manufacture and parenteral emulsion formulations may include a buffering agent to provide additional control. Any decrease in pH over the assigned shelf-life may be indicative of chemical degradation. In the present application, emulsion formulations were prepared and characterized to identify a formulation and process that will allow aprepitant to be incorporated into an emulsion for intravenous injection and remain stable during the shelf life of the formulation. BRIEF SUMMARY The following aspects and embodiments thereof described and illustrated below are meant to be exemplary and illustrative, not limiting in scope. In one aspect, a pharmaceutical composition suitable for intravenous administration is provided which comprises a stable emulsion comprising an oil phase, wherein the oil phase comprises aprepitant, a surfactant and a co-surfactant; and an aqueous phase, wherein the aqueous phase comprises water, a tonicity agent and a pH-adjusting agent. In some embodiments, the pH-adjusting agent is a buffer. In one embodiment, the composition is an oil-in-water emulsion comprising an oil selected from the group consisting of structurally modified or hydrolyzed coconut oil, olive oil, soybean oil, safflower oil, triglycerides, octyl and decyl glycerate, ethyl oleate, glyceryl linoleate, ethyl linoleate, glyceryl oleate, cholesteryl oleate/linoleate or a mixture thereof. In one embodiment, the composition comprises about 5 wt/wt % (weight/weight %) to 15 wt/wt %, 5 wt/wt % to 10 wt/wt %, 7 wt/wt % to 10 wt/wt % or 8 wt/wt % to 9 wt/wt % oil. In another embodiment, the oil is soybean oil. In one embodiment, the composition comprises about 10 wt/wt % to 20 wt/wt %, 12 wt/wt % to 17 wt/wt %, 13 wt/wt % to 16 wt/wt %, 13 wt/wt % to 15 wt/wt %, or 13 wt/wt % to 14 wt/wt % emulsifier. In another embodiment, the composition comprises about 13 wt/wt %, 13.5 wt/wt %, 14 wt/wt %, 14.5 wt/wt %, 15 wt/wt %, 16 wt/wt %, 17 wt/wt %, 18 wt/wt %, 19 wt/wt % or 20 wt/wt % emulsifier. In another embodiment the emulsifier is a lecithin. In another embodiment the lecithin is an egg yolk lecithin. In one embodiment, the composition comprises about 20 wt/wt % to 50 wt/wt %, 30 wt/wt % to 50 wt/wt %, 35 wt/wt % to 45 wt/wt %, 30 wt/wt % to 45 wt/wt %, 37 wt/wt % to 42 wt/wt %, 38 wt/wt % to 40 wt/wt %, 30 wt/wt %, 31 wt/wt %, 32 wt/wt %, 33 wt/wt %, 34 wt/wt %, 35 wt/wt %, 36 wt/wt %, 37 wt/wt %, 38 wt/wt %, 39 wt/wt %, 40 wt/wt %, 41 wt/wt %, 42 wt/wt %, 43 wt/wt %, 44 wt/wt %, 45 wt/wt %, 46 wt/wt %, 47 wt/wt %, 48 wt/wt %, 49 wt/wt %, 50 wt/wt % of oil expressed as a percentage of the weight of the oil per the sum of weight of oil, emulsifier and oleate in a unit of the composition. In another embodiment, the oil is soybean oil. In one embodiment, the composition comprises about 40 wt/wt % to 80 wt/wt %, 50 wt/wt % to 70 wt/wt %, 55 wt/wt % to 65 wt/wt %, 57 wt/wt % to 63 wt/wt %, 58 to 60 wt/wt %, 35 wt/wt % to 40 wt/wt %, 30 wt/wt % to 40 wt/wt %, 50 wt/wt %, 51 wt/wt %, 52 wt/wt %, 53 wt/wt %, 54 wt/wt %, 55 wt/wt %, 56 wt/wt %, 57 wt/wt %, 58 wt/wt %, 59 wt/wt %, 60 wt/wt %, 61 wt/wt %, 62 wt/wt %, 63 wt/wt %, 64 wt/wt %, 65 wt/wt %, 66 wt/wt %, 67 wt/wt %, 68 wt/wt %, 69 wt/wt %, 70 wt/wt % of emulsifier expressed as a percentage of the weight of emulsifier per the sum of weight of oil, emulsifier and oleate in a unit of the composition. In another embodiment the emulsifier is a lecithin. In another embodiment the lecithin is an egg yolk lecithin. In one embodiment, the ratio of oil to aprepitant (wt %:wt %) in the composition ranges from about 11:1 to 20:1, 11:1 to 15:1, 12:1 to 16:1, 12:1 to 14:1, 11:1 to 15:1, 12:1 to 14:1, 12.5:1 to 13.5:1, 13:1 to 14:1, or 12:1 to 15:1. In another embodiment, the ratio of oil to aprepitant (wt %:wt %) in the composition is about 11:1 to 20:1, 11:1 to 15:1, 12:1 to 16:1, 12:1 to 14:1, 11:1, 11.5:1, 12:1, 12.5:1, 13:1, 13.5:1, 14:1, 14.5:1 or 15:1, 15.5:1, 16:1. In one embodiment, the ratio of emulsifier to aprepitant (wt %:wt %) in the composition ranges from about 15:1 to 30:1, 20:1 to 25:1, 18:1 to 22:1 or 10:1 to 30:1. In another embodiment, the ratio of emulsifier:aprepitant (wt %:wt %) in the composition is about 15:1, 18:1, 19:1, 20:1, 21:1, 22:1 23:1, 24:1, or 25:1. In one embodiment, the ratio of (emulsifier plus oil) to aprepitant (wt %:wt %) in the composition ranges from about 20:1 to 40:1, 25:1 to 35:1, 30:1 to 35:1. In another embodiment, the ratio of oil:aprepitant is about 25:1, 26:1, 27:1, 28:1, 29:1 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1 or 40:1. In one embodiment, the ratio of emulsifier to oil (wt %:wt %) in the composition ranges from about 0.5:1 to 4:1, 1:1 to 2:1, or 1.25:1 to 1.75:1. In another embodiment, the ratio of emulsifier to oil (wt %:wt %) in the composition is about 0.5:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 1.05:1, 1.15:1, 1.25:1, 1.35:1, 1.45:1, 1.55:1, 1.65:1, 1.75:1, 1.85:1, or 1.95:1. In one embodiment, a therapeutic dose comprises about 1 to 4 g, 1.5 to 3 g, 1.8 to 2.8 g, 2.3 to 2.8 g, 1.8 to 2.3 g, 1 g, 1.1 g, 1.2 g, 1.3 g, 1.4 g, 1.5 g, 1.6 g, 1.7 g, 1.8 g. 1.9 g, 2 g, 2.1 g, 2.2 g, 2.3 g, 2.4 g, 2.5 g, 2.6 g, 2.7 g, 2.8 g. 2.9 g, 3 g, 3.1 g, 3.2 g, 3.3 g, 3.4 g, 3.5 g, 3.6 g, 3.7 g, 3.8 g. 3.9 g, 4 g emulsifier. In another embodiment, the emulsifier is a lecithin. In another embodiment the emulsifier is egg yolk lecithin. In one embodiment, a therapeutic dose comprises about 0.5 to 3 g, 1 to 2.5 g, 1 to 2 g, 1 to 1.5 g, 1.5 g to 2 g, 0.5 g 0.6 g, 0.7 g, 0.8 g, 0.9 g, 1 g, 1.1 g, 1.2 g, 1.3 g, 1.4 g, 1.5 g, 1.6 g, 1.7 g, 1.8 g. 1.9 g, 2 g, 2.1 g, 2.2 g, 2.3 g, 2.4 g, 2.5 g oil. In another embodiment, the oil is soybean oil. In one embodiment, the emulsifier is a phospholipid. In another embodiment, the emulsifier is selected from the group consisting of egg phospholipids, soy phospholipids, phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, phosphatidylglycerols, phosphatidylinositols, phosphatidic acids, mixed chain phospholipids, lysophospholipids, hydrogenated phospholipids, partially hydrogenated phospholipids, and mixtures thereof. In one embodiment, the composition comprises a co-surfactant. In another embodiment, the co-surfactant is ethanol. In one embodiment, the composition comprises about 0 wt/wt % to 10 wt/wt %, 1 wt/wt % to 9 wt/wt %, or 2 wt/wt % to 6 wt/wt % co-surfactant. In another embodiment, the composition comprises less than 10 wt/wt %, less than 9 wt/wt %, less than 8 wt/wt %, less than 7, less than 6 wt/wt %, less than 5 wt/wt %, less than 4 wt/wt %, less than 3 wt/wt %, less than 2 wt/wt % or less than 1 wt/wt % co-surfactant. In one embodiment, the composition comprises about 0 wt/wt % to 10 wt/wt %, 1 wt/wt % to 9 wt/wt %, or 2 wt/wt % to 6 wt/wt % ethanol. In another embodiment, the composition comprises less than 10 wt/wt %, less than 9 wt/wt %, less than 8 wt/wt %, less than 7, less than 6 wt/wt %, less than 5 wt/wt %, less than 4 wt/wt %, less than 3 wt/wt %, less than 2 wt/wt % or less than 1 wt/wt % ethanol. In one embodiment, the emulsion comprises an aqueous phase which comprises a tonicity agent, a pH-adjusting agent, and water. In one embodiment, the emulsion comprises an aqueous phase which comprises an osmotic agent, a pH-adjusting agent, and water. In one embodiment, the emulsion comprises an aqueous phase which comprises a tonicity agent, an osmotic agent, a pH-adjusting agent, and water. In one embodiment, the aqueous phase further comprises a buffer. In one embodiment, the aqueous phase comprises a buffer but does not comprise a pH-adjusting agent which is different than the buffer. In another embodiment, the buffer functions as both a pH-adjusting agent and a buffer. In another embodiment, when the aqueous phase comprises a buffer, the composition contains no tonicity agent. In one another embodiment, the buffer is selected from the group consisting of phosphate buffer, citrate buffer, Tris buffer, carbonate buffer, succinate buffer, maleate buffer and borate buffer. In another embodiment, the buffer is selected from the group, phosphate buffered saline (PBS), modified PBS (PBS-mod) and citrate buffer. In one embodiment, the aqueous phase comprises a buffer, that when mixed with the oil phase will provide a substantially isotonic oil in water emulsion. In one embodiment, the osmotic agent is selected from the group consisting of glycerol, sorbitol, xylitol, mannitol, glucose, trehalose, maltose, sucrose, raffinose, lactose, dextran, polyethylene glycol, or propylene glycol. In another embodiment, the osmotic agent is an inorganic salt such as sodium chloride and mixtures thereof. In one embodiment, the pH adjusting agent is selected from the group consisting of sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium carbonate, Tris, sodium linoleate, sodium oleate, potassium carbonate, potassium linoleate, potassium oleate, and mixtures thereof. In one embodiment, the composition has a pH of about 6 to 9, 7 to 9, 7.5 to 9, 7.5 to 8.5, 8 to 9, 6 to 8, 7 to 8, or 6, 7, 8 or 9. In one embodiment, the composition comprises about 0 wt/wt % to 25 wt/wt %, 2 wt/wt % to 20 wt/wt %, 3 wt/wt % to 15 wt/wt %, or 3 wt/wt % to 8 wt/wt % tonicity agent. In another embodiment, the composition comprises about 1 wt/wt %, 2 wt/wt %, 3 wt/wt %, 4 wt/wt %, 5 wt/wt %, 6 wt/wt %, 7 wt/wt %, 8 wt/wt %, 9 wt/wt %, or 10 wt/wt %, 11 wt/wt %, 12 wt/wt %, 13 wt/wt %, 14 wt/wt %, 15 wt/wt %, 16 wt/wt %, 17 wt/wt %, 18 wt/wt %, 19 wt/wt %, or 20 wt/wt %, 21 wt/wt %, 22 wt/wt %, 23 wt/wt %, 24 wt/wt %, 25 wt/wt % tonicity agent. In still another embodiment, the composition comprises no tonicity agent. In one embodiment, the composition comprises about 0 wt/wt % to 25 wt/wt %, 2 wt/wt % to 20 wt/wt %, 3 wt/wt % to 15 wt/wt %, or 3 wt/wt % to 8 wt/wt % osmotic agent. In another embodiment, the composition comprises about 1 wt/wt %, 2 wt/wt %, 3 wt/wt %, 4 wt/wt %, 5 wt/wt %, 6 wt/wt %, 7 wt/wt %, 8 wt/wt %, 9 wt/wt %, or 10 wt/wt %, 11 wt/wt %, 12 wt/wt %, 13 wt/wt %, 14 wt/wt %, 15 wt/wt %, 16 wt/wt %, 17 wt/wt %, 18 wt/wt %, 19 wt/wt %, or 20 wt/wt %, 21 wt/wt %, 22 wt/wt %, 23 wt/wt %, 24 wt/wt %, 25 wt/wt % osmotic agent. In still another embodiment, the composition comprises no osmotic agent. In one embodiment, the aqueous phase comprises a dose of dexamethasone sodium phosphate in a dose of the composition. In another embodiment, the dose of dexamethasone sodium phosphate ranges from about 0.5 mg to 30 mg, 0.5 mg to 25 mg, 1 mg to 20 mg, 10 mg to 20 mg, or 3 mg to 16 mg. In another embodiment, the dose of dexamethasone sodium phosphate is about 9 mg or 16 mg in a dose of the composition. In one embodiment, the oil phase comprises a dose of dexamethasone in a dose of the composition. In another embodiment, the dose of dexamethasone ranges from about 0.5 mg to 30 mg, 0.5 mg to 20 mg, 1 mg to 18 mg, 10 mg to 20 mg, or 3 mg to 16 mg. In another embodiment, the dose of dexamethasone is about 8 mg or 12 mg in a dose of the composition. In one embodiment, the emulsion comprises about 0.002 wt/wt % to 0.2 wt/wt %, 0.003 wt/wt % to 0.16 wt/wt %, 0.02 wt/wt % to 0.1 wt/wt % dexamethasone sodium phosphate. In one embodiment, the composition is a stable system maintaining an intensity-weighted mean particle size as determined by dynamic light scattering (DLS) of about 50 nm to 1000 nm, 50 to 500 nm, 50 nm to 400 nm, 50 nm to 300 nm, 50 nm to 200 nm or 50 nm to 100 nm. In another embodiment, the average droplet size is maintained below 500 nm for a period of at least 1 month, 3 months, 6 months, 9 months, 12 months, 2 years or 3 years at room temperature. In another embodiment, the average droplet size is maintained below 500 nm for a period of at least 1 month, 3 months, 6 months, 9 months, 12 months, 2 years or 3 years at 5° C. In another aspect, a method for preparing an emulsion comprising aprepitant and suitable for parenteral administration is provided. In one embodiment, the administration is intravenous administration. In one embodiment, the method comprises: a) preparing an oil phase by dissolving aprepitant and an emulsifier in ethanol, then adding in oil to generate an oil-based mixture; b) preparing an aqueous phase by mixing water, optionally with a tonicity agent, optionally with an osmotic agent and optionally with a pH modifier and optionally with a buffer to generate an aqueous mixture; c) combining the oil-based mixture and the aqueous mixture and subjecting this to high speed homogenization to generate a crude emulsion; and d) subjecting the crude emulsion to high pressure homogenization to generate a fine emulsion. In one embodiment, preparing the oil phase further comprises dissolving dexamethasone with the aprepitant and the emulsifier in the ethanol. In one embodiment, the method comprises: a) preparing an oil phase by dissolving aprepitant and an emulsifier in ethanol and oil to generate an oil-based mixture; b) preparing an aqueous phase by mixing water, optionally with a tonicity agent, optionally with an osmotic agent and optionally with a pH modifier and optionally with a buffer to generate an aqueous mixture; c) combining the oil-based mixture and the aqueous mixture and subjecting this to high speed homogenization to generate a crude emulsion; and d) subjecting the crude emulsion to high pressure homogenization to generate a fine emulsion. In one embodiment, preparing the oil phase further comprises dissolving dexamethasone with the aprepitant and the emulsifier in the ethanol and oil. In one embodiment, preparing the aqueous phase further comprises mixing dexamethasone with the water, tonicity agent, pH modifier, and a buffer. In another embodiment, the dexamethasone is a salt of dexamethasone. In still another embodiment, the dexamethasone is dexamethasone sodium phosphate. In one embodiment, the method further comprises sterilizing the fine emulsion to generate the final emulsion, wherein the final emulsion is suitable for injection into a subject. In one embodiment, the dissolution in ethanol is performed at a temperature of about 25° C. to 80° C., 40° C. to 75° C., 60° C. to 70° C., or at about 25° C., 35° C., 45° C., 60° C., 65° C., 70° C. or 75° C. In one embodiment, the high-speed homogenization is performed at a speed of about 2,000 rpm (revolutions per minute) to 25,000 rpm. In another embodiment, the high-speed homogenization is performed at a speed of about 20,000 rpm. In yet another embodiment, the high-speed homogenization is performed at a speed of about 3600 rpm. In one embodiment, the high-speed homogenization is performed for a time period of about 0.5 min to 1 hour, 1 min to 45 min, or 1 min to 30 min. In another embodiment, the high-speed homogenization is performed for a time period of about 20 to 40 min or for about 30 min. In one embodiment, the high-speed homogenization is performed at about 10° C. to about 60° C., 20° C. to about 60° C., about 30° C. to about 50° C., or about 35° C. to about 45° C. In another embodiment, the high-speed homogenization is performed at about 25° C., 30° C., 35° C., 40° C., 45° C. or 50° C. In one embodiment, the high-pressure homogenization is performed at a pressure of about 10,000 psi (pounds per square inch) to 30,000 psi. In another embodiment, the high-pressure homogenization is performed at a pressure of about 20,000 psi. In one embodiment, the high-pressure homogenization is performed with cooling. In another embodiment, the high-pressure homogenization is performed with cooling which is sufficient to bring the temperature of the emulsion at the outlet of the process to about 0° C. to about 60° C., about 10° C. to about 40° C., about 20° C. to about 30° C., or to about 20° C., 25° C. or 30° C. within the time period. In one embodiment, the sterilizing the fine emulsion comprises filtering the fine emulsion through a nylon filter. In another embodiment, the nylon filter is a Posidyne® filter. In yet another embodiment, the filter has a pore size of about 0.2 μm (micrometers). Additional embodiments of the present compositions and methods and the like, will be apparent from the following description, drawings, examples, and claims. As can be appreciated from the foregoing and following description, each and every feature described herein, and each and every combination of two or more of such features, is included within the scope of the present disclosure provided that the features included in such a combination are not mutually inconsistent. In addition, any feature or combination of features may be specifically excluded from any embodiment of the present invention. Additional aspects and advantages of the present invention are set forth in the following description and claims, particularly when considered in conjunction with the accompanying examples and drawings. BRIEF DESCRIPTION OF DRAWINGS FIGS. 1A-D provide microscope images of samples from Examples 1, 2, 3 and 6 after a freeze-thaw cycle. FIG. 1A: Example 1, FIG. 1B: Example 2, FIG. 1C: Example 3, FIG. 1D: Example 6. FIG. 2 shows plasma levels of aprepitant after injection of a fosaprepitant solution () or an aprepitant emulsion prepared as described herein (▴). FIG. 3 shows plasma levels of aprepitant after injection of a solution of fosaprepitant (▴) or after injection of an emulsion containing aprepitant and dexamethasone prepared as described herein (). FIG. 4 shows plasma levels of dexamethasone after injection of a solution of dexamethasone sodium phosphate () or after injection of an emulsion containing aprepitant and dexamethasone prepared as described herein (▴). DETAILED DESCRIPTION Various aspects now will be described more fully hereinafter. Such aspects may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey its scope to those skilled in the art. I. DEFINITIONS As used in this specification, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a “polymer” includes a single polymer as well as two or more of the same or different polymers, reference to an “excipient” includes a single excipient as well as two or more of the same or different excipients, and the like. Where a range of values is provided, it is intended that each intervening value between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. For example, if a range of 1 μm to 8 μm is stated, it is intended that 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μm are also explicitly disclosed, as well as the range of values greater than or equal to 1 μm and the range of values less than or equal to 8 μm. As used herein, the term “about” means±5%, ±10%, or ±20% of the value being modified. The term “emulsion” or “emulsion formulation” means a colloidal dispersion of two immiscible liquids in the form of droplets, whose diameter, in general, is between 10 nanometers and 100 microns. An emulsion is denoted by the symbol O/W (oil-in-water) if the continuous phase is an aqueous solution and by W/O (water-in-oil) if the continuous phase is an oil. Other examples of emulsions such as O/W/O (oil-in-water-oil) include oil droplets contained within aqueous droplets dispersed in a continuous oil phase. “Physically stable” emulsions will meet the criteria under USP <729>, which defines universal limits for (1) mean droplet size not exceeding 500 nm or 0.5 μm and (2) the population of large-diameter fat globules, expressed as the volume-weighted percentage of fat greater than 5 μm (PFAT5) not exceeding 0.05%, at 5° C. or room temperature for a designated storage time period. In addition, physically stable emulsions will have no visible aprepitant crystals upon storage at 5° C. or room temperature for a designated time period. Crystals are considered visible when viewed at magnification of 4× to 10×. An emulsion is physically stable if it meets the criteria under USP <729> and aprepitant crystals are not visible upon storage at 5° C. or room temperature for a time period equal to or at least 1 week, 2 weeks, 4 weeks, 1 month, 2 months, 6 months, 1 year or 2 years. “Chemically stable” emulsions of the disclosure are ones in which the concentration of the active component (i.e., the drug being delivered) does not change by more than about 20% under appropriate storage conditions for at least 1 month. In certain embodiments, the aprepitant concentration in an emulsion of the present disclosure does not change by more than about 5%, 10%, 15% or 20% under appropriate storage conditions for at least 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, or 24 months. In one example, the stable emulsion compositions of the disclosure are stable over a wide range of temperatures, e.g., −20° C. to 40° C. The compositions of the disclosure may be stored at about 5° C. to about 25° C. “Oil phase” in a water-in-oil emulsion refers to all components in the formulation that individually exceed their solubility limit in the water phase; these are materials that generally have solubilities of less than 1% in distilled water, however, water phase components such as salts may decrease the solubility of certain oils resulting in their partitioning into the oil phase. The oil phase refers to the non-aqueous portion of a water-in-oil emulsion. “Aqueous phase” or “water phase” in a water-in-oil emulsion refers to the water present and any components that are water soluble, i.e., have not exceeded their solubility limit in water. “Aqueous phase”, as used herein, includes a water-containing liquid which can contain pharmaceutically acceptable additives such as acidifying, alkalizing, buffering, chelating, complexing and solubilizing agents, antioxidants and antimicrobial preservatives, humectants, suspending and/or viscosity modifying agents, tonicity and wetting or other biocompatible materials. The aqueous phase refers to the non-oil portion of a water-in-oil emulsion. An “emulsifier” refers to a compound that deters the separation of the injectable emulsion into individual oil and aqueous phases. Emulsifiers useful in the present disclosure generally are (1) compatible with the other ingredients of the stable emulsions of the present disclosure, (2) do not interfere with the stability or efficacy of the drugs contained in the emulsions, (3) are stable and do not deteriorate in the preparation, and (4) are non-toxic. Suitable emulsifiers include, but are not limited to, propylene glycol mono- and di-fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene-polyoxypropylene co-polymers and block co-polymers, salts of fatty alcohol sulphates, sorbitan fatty acid esters, esters of polyethylene-glycol glycerol ethers, oil and wax based emulsifiers, glycerol monostearate, glycerine sorbitan fatty acid esters and phospholipids. A “phospholipid” refers to a triester of glycerol with two fatty acids and one phosphate ion. Exemplary phospholipids useful in the present invention include, but are not limited to, phosphatidyl chlorine, lecithin (a mixture of choline ester of phosphorylated diacylglyceride), phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid with about 4 to about 22 carbon atoms, and more generally from about 10 to about 18 carbon atoms and varying degrees of saturation. The phospholipids can have any combination of fatty acid as its fatty acyl side chain, for example, the phospholipids can have a saturated fatty acid such as a decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, icosanoic acid, (a C20 saturated fatty acid); sodium behenic acid, or an unsaturated fatty acid such as myristoleic acid, palmitoleic acid, oleic acid, sodium linoleic acid, alpha linolenic acid, sodium arachidonic acid, eicosapentanoic acid, and the like. The two fatty acyl residues on the phospholipids may be the same or they may be different fatty acids. The phospholipid component of the drug delivery composition can be either a single phospholipid or a mixture of several phospholipids. The phospholipids should be acceptable for the chosen route of administration. In one aspect, the phospholipids used as emulsifiers in the present invention are naturally occurring phospholipids from a natural origin. For example, naturally occurring lecithin is a mixture of the diglycerides of stearic, palmitic, and oleic acids, linked to the choline ester of phosphoric acid, commonly called phosphatidylcholine, and can be obtained from a variety of sources such as eggs and soya beans. Soy lecithin and egg lecithin (including hydrogenated versions of these compounds) have been characterized in various compositions and are generally recognized to be safe, have combined emulsification and solubilization properties, and tend to be broken down into innocuous substances more rapidly than most synthetic surfactants. The term “lecithin” includes a complex mixture of acetone-insoluble phosphatides, of which phosphatidylcholine is a significant component. The term lecithin is also used as a synonym for phosphatidylcholine. Useful lecithins include, but are not limited to, eggyolk-, egg-, soybean-, and corn-derived lecithin. In one embodiment, the emulsifier is lecithin, such as egg yolk-derived lecithin. The terms egg lecithin and egg yolk derived lecithin are used interchangeable throughout. The compositions described herein preferably comprise lecithin as an emulsifier. The amount of phospholipids, by weight, in the emulsions of the present disclosure may be within a range of about 10 wt/wt % to about 20 wt/wt %, 11 wt/wt % to 19 wt/wt %, 11 wt/wt % to 15 wt/wt %, 12 wt/wt % to 13 wt/wt %, 13 wt/wt % to 14 wt/wt %, 13 wt/wt % to 20 wt/wt %, or 12 wt/wt % to 18 wt/wt %. In certain embodiments, the phospholipids in the emulsions are at a concentration, by weight, about 11 wt/wt %, 12 wt/wt %, 12.5 wt/wt %, 13 wt/wt %, 13.5 wt/wt %, 14 wt/wt %, 14.5 wt/wt %, or 15 wt/wt %. “Oil” refers to an organic liquid of mineral, vegetable, animal, essential or synthetic origin, including, for example, aliphatic or wax-based hydrocarbons, aromatic hydrocarbons or mixed aliphatic and aromatic hydrocarbons. The term “buffer” or “buffered” as used herein means a solution containing both a weak acid and its conjugate base, whose pH changes only slightly upon addition of acid or base. As used herein, the phrase “buffering agent” means a species whose inclusion in a solution provides a buffered solution. The term “therapeutic agent” describes any natural or synthetic compound which has a biological activity. II. APREPITANT EMULSION AND METHODS OF MAKING The present disclosure is directed to stable pharmaceutical compositions including aprepitant, a surfactant or mixtures of surfactants, a co-surfactant, an oil, with an aqueous phase. The composition is in the form of an oil-in-water emulsion which remains stable over an extended period of time and which is suitable for dilution and intravenous administration. The active agent, e.g., aprepitant, is present in the oil phase with an emulsifier, a co-emulsifier and an oil. The oil phase is then combined with an aqueous phase comprising water and a tonicity agent as described below to generate the stable emulsion. Prior to combining the oil phase with the aqueous phase, the oil phase will have an oil:aprepitant ratio of about 13:1. Use of this ratio was surprisingly found to produce, when mixed with the water phase, an emulsion which is more stable as compared to an emulsion in which the oil phase contains an oil:aprepitant ratio of less than about 12:1 or 11:1, and/or greater than about 15:1, 20:1, or 30:1. Moreover, the present compositions also possess favorable stability properties when the amount of emulsifier in the oil phase is greater than the amount of oil. For example, the oil phase contains an emulsifier:oil ratio of about 5:1 to 1:1, 3:1 to 1:1 or a ratio of about 1.5:1. Such ratios of emulsifier:oil have surprisingly been found to impart greater stability on the final emulsion which is suitable for injection into a patient. For example, an aprepitant emulsion having a phospholipid:oil ratio within the oil phase of about 1.5:1 was found to have greater stability than a similar aprepitant emulsion, wherein the oil phase comprises a phospholipid:oil ratio of about 0.01:1, 0.1:1, 0.5:1 or 0.9:1. 1. Oil Phase The oil (hydrophobic) phase comprises an oil. Triglycerides are exemplary oils for use in the compositions described herein. In certain embodiments the oil is or comprises a vegetable oil. “Vegetable oil” refers to oil derived from plant seeds or nuts. Vegetable oils are typically “long-chain triglycerides” (LCTs), formed when three fatty acids (usually 14 to 22 carbons in length, with unsaturated bonds in varying numbers and locations, depending on the source of the oil) form ester bonds with the three hydroxyl groups on glycerol. In certain embodiments, vegetable oils of highly purified grade (also called “super refined”) are used to ensure safety and stability of the oil-in-water emulsions. In certain embodiments hydrogenated vegetable oils, which are produced by controlled hydrogenation of the vegetable oil, may be used. Exemplary vegetable oils include but are not limited to almond oil, babassu oil, black currant seed oil, borage oil, canola oil, castor oil, coconut oil, corn oil, cottonseed oil, olive oil, peanut oil, palm oil, palm kernel oil, rapeseed oil, safflower oil, soybean oil, sunflower oil and sesame oil. Hydrogenated and/or or partially hydrogenated forms of these oils may also be used. In specific embodiments, the oil is or comprises safflower oil, sesame oil, corn oil, olive oil and/or soybean oil. In more specific embodiments, the oil is or comprises safflower oil, and/or soybean oil. The oil is present in the emulsion at about 9 wt/wt %, though this may vary between about 5 wt/wt % to 12 wt/wt % or 9 wt/wt % to 10 wt/wt %. The aprepitant is first mixed with an emulsifier such as a phospholipid emulsifier. Examples 1, 2, 3 and 6 below describe emulsions made using an egg lecithin. The phospholipid emulsifier is added to a concentration of greater than 10 wt/wt %, 11 wt/wt %, 12 wt/wt % or 13 wt/wt % of the emulsion but less than 15 wt/wt %, 17 wt/wt % or 20 wt/wt % of the emulsion. The mixture of aprepitant and emulsifier is dissolved in a co-emulsifier such as a short chain alcohol (1 to 6 carbons). In Examples 1, 2, 3 and 6 below, the co-emulsifier is ethanol. The mixture is mixed at an elevated temperature, such as at about 60° C. or 70° C. or at an elevated temperature within the range of about 50° C. or 70° C., until the aprepitant and emulsifier are dissolved. This mixture is then combined with the oil, such as soybean oil, by mixing again at an elevated temperature such as at about 60° C. to produce the oil phase containing the aprepitant. Excess co-emulsifier can be removed by standard evaporation methods including heating, or pressure reduction, or a combination thereof such employed in a rotary evaporator. In this process, about 10% to 100%, 20% to 95%, 80% to 100%, 90% to 100%, or 95% to 100% of the ethanol evaporates depending on preparation scale, any pressure reduction, and heating time. In one embodiment, the aprepitant and the emulsifier are dissolved in a co-emulsifier and an oil. In Examples 1, 2, 3 and 6 below, the co-emulsifier is ethanol, the oil is soybean oil, however, the methods can be used with any one or more of the co-emulsifiers and oils described herein. The mixture is mixed at an elevated temperature, such as at about 60° C. or 70° C. or at an elevated temperature within the range of about 50° C. or 70° C., at least until the aprepitant and emulsifier are dissolved to produce the oil phase containing aprepitant. The mixture of aprepitant, emulsifier, co-emulsifier and oil are mixed at the elevated temperature for about 15 min to 120 min, about 15 min to 45 min, about 30 min to 90 min, or for about 15 min, 30 min or 50 min. Excess co-emulsifier can be removed by standard evaporation methods including heating, or pressure reduction, or a combination thereof in a rotary evaporator. During this process, about 10% to 100%, 20% to 95%, 80% to 100%, 90% to 100%, or 95% to 100% of the ethanol evaporates depending on preparation scale, any pressure reduction, and heating time. In one embodiment, dexamethasone is added to the oil phase comprising the aprepitant, emulsifier and oil to generate an oil phase comprising both aprepitant and dexamethasone prior to mixing with the aqueous phase to generate the pharmaceutical emulsion for injection. Dexamethasone is added to the oil phase to provide a dose of about 12 mg dexamethasone. 2. Aqueous Phase The aqueous phase of the aprepitant emulsion can be a mixture of water and a tonicity agent, including those such as but not limited to sucrose, mannitol, glycerin or dextrose or a mixture thereof. Also included in the aqueous phase is a pH-modifying agent. Sodium oleate is used in Examples 1, 2 and 3 below to adjust the pH of the emulsion to about 6 to 9, depending on the desired emulsion formulation. The aqueous phase is produced by mixing water with the tonicity agent and sodium oleate as the pH modifying agent. Other pH modifiers that may be used include but are not limited to sodium hydroxide, potassium hydroxide, magnesium hydroxide, Tris, sodium carbonate and sodium linoleate. The pH modifier used is effective for adjusting the pH of the emulsion to a preferred pH of about 6 to 9, 7 to 8, or about 6, 7, 8 or 9. The aqueous phase can readily form by mixing at room temperature. The aqueous phase may further contain a buffering agent to promote stability of the emulsion formulation. The drug substance may degrade; for example, lipophilic drugs will partition into the oil phase, which will confer some degree of protection, but hydrolytic degradation may still occur at the oil-water interface. Possible chemical degradation within parenteral fat emulsions includes oxidation of unsaturated fatty acid residues present in triglyceride and lecithin, and hydrolysis of phospholipids leading to the formation of free fatty acids (FFA) and lysophospholipids. Such degradants lower pH, which may then promote further degradation. Thus, pH should be controlled during manufacture and emulsion formulations may include a buffering agent to provide additional control. Any decrease in pH over the assigned shelf-life may be indicative of chemical degradation. Suitable buffers are well known to the person skilled in the art and include but are not limited to a phosphate buffer, citrate buffer, Tris buffer, carbonate buffer, succinate buffer, maleate buffer or borate buffer. Tris buffer is used in Example 11 below to adjust the pH of the emulsion to about 8 to 9. In a particular embodiment, the buffer is selected from the group, phosphate buffered saline (PBS), modified PBS (PBS-mod) and citrate buffer. In a particular embodiment, the aqueous phase comprises a buffer, that when mixed with the oil phase will provide a substantially isotonic oil in water emulsion. Buffering agents useful for the presently described compositions include, but are not limited to, a phosphate buffer, citrate buffer, Tris buffer, carbonate buffer, succinate buffer, maleate buffer or borate buffer. In a particular embodiment, the buffer is selected from the group, phosphate buffered saline (PBS), modified PBS (PBS-mod) and citrate buffer. In a particular embodiment, the aqueous phase comprises a buffer, that when mixed with the oil phase will provide a substantially isotonic oil in water emulsion. In some embodiments, when the aqueous phase contains a buffering agent, the aqueous phase does not include a tonicity agent. Also, when a buffer is added to the aqueous phase, a pH-adjusting agent may not be added to the aqueous phase. It is understood that a buffer can be added to the aqueous phase or the buffer can be added to the emulsion. In some embodiments, the aqueous phase contains a tonicity agent such as sucrose. The tonicity agent is added to an aqueous phase having about 0% to 30%, 0% to 25% or about 20% of the tonicity agent (wt/wt). It was surprisingly found that a composition containing about 20% sucrose wt/wt in the aqueous phase produced an emulsion that was particularly stable as determined by freeze-thaw testing. Accordingly, preferred embodiments include an emulsion in which the aqueous phase comprises a tonicity agent which imparts greater chemical and/or physical stability as compared to an emulsion wherein the aqueous phase contains less than about 10%, 15% or 20% wt/wt tonicity agent or more than about 30%, 40% or 50% wt/wt tonicity agent. In one embodiment, the aqueous phase further comprises dexamethasone sodium phosphate (also referred to as “dexamethasone phosphate”). Dexamethasone sodium phosphate is a corticosteroid which is freely soluble in water. Daily dosages for dexamethasone sodium phosphate range from about 0.5 mg to 20 mg, more preferably from about 14 mg to 18 mg or 16 mg, depending on the severity of the disease or disorder. Accordingly, an aprepitant emulsion further comprising dexamethasone may contain dexamethasone sodium phosphate in the aqueous phase. Accordingly, the aqueous phase of an emulsion suitable for intravenous administration may contain about 0.5 mg to 20 mg, 14 mg to 18 mg or about 16 mg dexamethasone sodium phosphate. In another embodiment, a solution of dexamethasone sodium phosphate can be mixed into the fine emulsion prior to sterile filtration to prepare an emulsion containing dexamethasone sodium phosphate in the aqueous phase, 3. Aprepitant Emulsion The pharmaceutical aprepitant compositions of the present disclosure are sterile oil-in-water emulsions comprising the aqueous and oil phases described above. Also encompassed by the disclosure are methods for preparing stable emulsions comprising aprepitant which are suitable for intravenous administration and which can be prepared according to the conventional manufacturing procedures using aseptic techniques. The aqueous phase is combined with the oil phase, under high-speed homogenization to produce a coarse emulsion. As described in Examples 1, 2, 3, 4, 5 and 6, the combined aqueous and oil phases is homogenized using an IKA Ultra-Turrax T25 dispersing instrument at a speed of 20,000 rpm for 1 min. The speed used in this first homogenization step may vary, for example, from 2000 rpm to 25,000 rpm, or from 15,000 rpm to 22,000 rpm. The time of the homogenization step can also vary, for example, from 0.5 min to 1 hour, or from 1 min to 45 min. This crude emulsion is then homogenized into a fine emulsion by a high-pressure homogenizer, which may be a microfluidizer. The interaction chamber and the cooling coil portions of the microfluidizer are cooled by water, such as by an ice bath. The temperature of the ice bath may be between 0 to 10° C., or 2 to 6° C. The temperature of the emulsion coming out of the high-pressure homogenization may be between 0 to 60° C., 15° C., to 60° C., 20° C. to 40° C., or at about 25° C. The microfluidizer is first primed with water, then the crude emulsion is introduced. The output from the homogenizer is initially run to waste to remove priming water, and priming water and emulsion mixtures, and then collected in a clean vessel when the stream becomes consistent in appearance. The high-pressure homogenizer cycle may be repeated to sufficiently reduce oil droplet size. The pressure used for the homogenization may vary. The pressures may be between 5000 and 30,000 psi. The number of passes through the microfluidizer may vary in order to achieve the desired droplet size. The number of passes may be from about 2 to 20, 2 to 15, 4 to 15, 4 to 12 or 7 to 8. The pharmaceutical formulation may then be passed through a filter system at room temperature, and/or autoclaved, to achieve sterilization. The filters used to achieve sterilization may be chosen by the skilled artisan and may have a nominal pore size of 0.2 μm. The filter material used may vary. In one embodiment, the filter is nylon. In another embodiment, the filter is a Posidyne® filter (covalent charge-modified Nylon 6,6 membrane which exhibits a net positively-charged zeta potential in aqueous solutions). For large scale production the method above may need to be modified. A skilled practitioner could combine these materials in a different order and using different processing equipment to achieve the desired end result. In one embodiment of the disclosure, the homogenization can be done in repeated cycles to achieve an emulsion in which the oil particle/globule size is less than 2 microns (μm) with intermediate cooling of the homogenized product to a temperature less than about 25° C. The final emulsion comprises an oil portion (oil phase) dispersed in an aqueous portion (aqueous phase). The ratio of components to the aprepitant within the oil phase is an important characteristic of the emulsion which may affect stability of the formulation prepared for injection. As described above, the oil phase comprises aprepitant, an oil and an emulsifier, examples of which are provided herein. The final aprepitant emulsion contains 0.7 wt/wt % aprepitant, but may range from about 0.2 wt/wt % to 1.5 wt/wt %, 0.4 wt/wt % to 1.0 wt/wt % or 0.6 wt/wt % to 0.7 wt/wt %. An emulsion is prepared which contains about 130 mg aprepitant, however, preparations may also be prepared according to the present disclosure which contain about 100 mg to 1000 mg, 100 mg to 500 mg, 250 mg to 750 mg or 100 mg to 200 mg aprepitant. In one embodiment, the ratio of oil:aprepitant (wt %:wt %) within the oil phase ranges from about 11:1 to 15:1, 12:1 to 14:1, 13:1 to 13.5:1, 13:1 to 14:1, or 12:1 to 15:1. In another embodiment, the ratio of oil:aprepitant is about 11:1, 11.5:1, 12:1, 12.5:1, 13:1, 13.5:1, 14:1, 14.5:1 or 15:1. The ratio of emulsifier to aprepitant may also vary. For example, the ratio of emulsifier:aprepitant (wt %:wt %) within the oil portion ranges from about 15:1 to 30:1, 20:1 to 25:1, 18:1 to 22:1 or 10:1 to 30:1. In one embodiment, the emulsifier:aprepitant (wt %:wt %) is about 15:1, 18:1, 19:1, 20:1, 21:1, 22:1 or 23:1. The ratio of components within the oil phase may alternatively be expressed in the ratio of (emulsifier plus oil):aprepitant (wt %:wt %). Ratios envisioned in the present disclosure may range from about 20:1 to 40:1, 25:1 to 35:1, 30:1 to 35:1 or 33:1 to 37:1, or may be, for example, about 30:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1 or 40:1. The composition of the present disclosure has a significant advantage in terms of reduced toxicity as compared to injectable formulations which may contain less desirable excipients such as detergents, e.g., Tween-20 or Tween-80. The present formulations take advantage of the ability to solubilize therapeutically effective amounts of aprepitant in an oil phase which can then be used to generate an emulsion suitable for injection. Accordingly, described herein are pharmaceutical emulsion compositions containing aprepitant and optionally dexamethasone or dexamethasone sodium phosphate, wherein the emulsion does not comprise a detergent. The composition of the present disclosure gives a product suitable for parenteral use because of low particle size. The composition of the present disclosure is easy to use as the product can be diluted with an agent such as an aqueous solution of sucrose, an aqueous solution of maltose or dextrose 5% injection or normal saline to achieve the required concentration for parenteral administration. The composition of the present disclosure also has a prolonged shelf life and hence is suitable for a readily marketable product. The compositions of the disclosure are both chemically and physically stable. A physically stable emulsion of the invention is one which can be stored under appropriate conditions for at least 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 24 or 36 months, without an increase in average droplet size above that allowed as stated in USP <729>. As well, the population of large-diameter fat globules should be within the limits stated in USP <729>. Droplet size limits defined in USP <729> apply throughout the assigned shelf life, which for a commercial pharmaceutical formulation may extend to 2-3 years or longer. All true emulsions are thermodynamically unstable and may over time undergo a range of processes which tend to increase the droplet size. These include direct droplet coalescence, when two droplets collide and form a single new droplet, and aggregation, in which droplets adhere together to form larger masses. Aggregation may in some cases be a precursor of further coalescence into larger droplets. These processes may result in large aggregates rising to the surface of the container, a phenomenon known as ‘creaming’, and ultimately to free oil being visible on the emulsion surface, known as ‘cracking’. Droplet size measurements such as those defined in USP<729> can measure the initial increases in size, and hence are predictive of emulsion physical stability, at early times, long before the formulation shows macroscopic visible changes. Accordingly, the emulsions as described herein are stable compositions having an intensity-weighted mean droplet diameter less than about 500 nm, 400 nm, 300 nm, 200 nm or 100 nm. The oil or particle droplet size, i.e. diameter, according to the present disclosure is measured using a dynamic light scattering (DLS) instrument, such as the Malvern Zetasizer 4000, Malvern Zetasize Nano S90 or preferably the Malvern Zetasizer Nano ZS. Intensity-weighted particles sizes were recorded, since they do not require the knowledge of the refractive index of the particle. In Malvern Zetasizer instruments, there are two fits for determining the intensity-weighted diameter of the oil droplet size. The first is a cumulant fit that is used to determine the Z-average diameter; this fit can additionally give the polydispersity index (PDI). This cumulant fit is recommended for monodisperse samples possessing a PDI of lower than 0.2. The second is a non-negative least squares (NNLS) fit. This gives the Peak 1 diameter, Peak 2 diameter and Peak 3 diameter. This is more suitable for polydisperse samples having a PDI of greater than 0.2. The emulsion preparations as described herein may further comprise a preservative in quantities that preserve the composition. Suitable preservatives used in some of the embodiments of present disclosure include, but are not limited to, disodium edetate, tocopherol, benzalkonium chloride, methyl, ethyl, propyl or butylparaben, benzyl alcohol, phenylethyl alcohol, benzethonium, chlorobutanol, potassium sorbate or combination thereof. III. MEDICAL USE The pharmaceutical compositions of the present disclosure can be used for the prevention or treatment of emesis and provide a non-oral option for patients undergoing highly or moderately emetogenic chemotherapy. The disclosure thus encompasses a method of treatment comprising intravenously administering an aprepitant emulsion as described herein to a subject undergoing highly or moderately emetogenic chemotherapy. Another embodiment relates to the use of the pharmaceutical formulations of the disclosure in the manufacture of a medicament for use preventing or treating emesis in a subject in need thereof. The amount of the aprepitant and optionally dexamethasone required for use in the methods of the disclosure may vary with the method of administration and condition of the patient, and the degree of therapy required, and will be ultimately at the discretion of the attendant physician or clinician. IV. EXAMPLES The following examples are illustrative in nature and are in no way intended to be limiting. Example 1 Preparing of Aprepitant Emulsions for Intravenous Injection To prepare the aprepitant emulsion, an oil phase was first prepared by combining 750 mg of aprepitant and 15.0 g of egg lecithin (LIPOID E 80) with 12.0 ml of ethanol. This mixture was dissolved by heating and stirring at 60° C. and 200 rpm for 15 min. To the resultant solution was added in 10.0 g of soybean oil. Heating at 60° C. and stirring at 200 rpm was continued for another 15 min. The aqueous phase was prepared by dissolving 5.60 g of sucrose and 0.500 g of sodium oleate in 70.0 ml of water for injection. This mixture was stirred at 300 rpm at room temperature for 30 min. The aqueous phase was then added to the oil phase and subsequently subjected to high-speed homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 min to produce the crude emulsion. This crude emulsion was then passed 8 times through an ice-cooled high-pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi. The resultant fine emulsion was sterilized by passing it through a 0.2 μm nylon syringe filter (Corning). The details of the emulsion composition are provided in Table 1 below and a microscope image of the sample is provided in FIG. 1A. By dynamic light scattering (Malvern® Zetasizer Nano ZS), the intensity-weighted particle size analyzed using non-negative least squares (NNLS) fit gave a Peak 1 diameter of 99 nm. The intensity-weighted mean particle size determined using cumulant fit provided a Z-average diameter of 87 nm. The zeta potential was measured to be −43 mV by laser Doppler micro-electrophoresis (Malvern® Zetasizer Nano ZS). The pH of the injectable emulsion was 8.74. This aprepitant-containing emulsion can be injected as is, or diluted for infusion with 5% dextrose or 0.9% saline. TABLE 1 Ratio to Component Amount (g) Concentration (w/w %) Aprepitant Aprepitant 0.750 0.679 1 Lipoid E 80 15.0 13.6 20 Soybean Oil 10.0 9.05 13.3 Ethanol1 8.59 7.78 11.5 Sucrose 5.60 5.07 7.5 Sodium Oleate 0.500 0.453 0.667 Water for Injection 70.0 63.4 93.3 Total 110 100 — 1Final amount after taking into account the ethanol that was evaporated during processing. Example 2 To prepare the aprepitant emulsion, an oil phase was first prepared by combining 450 mg of aprepitant and 9.00 g of egg lecithin (LIPOID E 80) with 4.0 ml of ethanol. This mixture was dissolved by heating and stirring at 60° C. and 200 rpm for 15 min. To the resultant solution was added 6.00 g of soybean oil. Heating at 60° C. and stirring at 200 rpm was continued for another 15 min. The aqueous phase was prepared by dissolving 3.36 g of sucrose and 0.300 g of sodium oleate in 42.0 ml of water for injection. This mixture was stirred at 300 rpm at room temperature for 30 min. The aqueous phase was then added to the oil phase and subsequently subjected to high-speed homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 min to produce the crude emulsion. This crude emulsion was then passed 8 times through an ice-cooled high-pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi. The resultant fine emulsion was sterilized by passing it through a 0.2 μm nylon syringe filter (Corning). The details of the emulsion composition are provided in Table 2 below and a microscope image of the sample is provided in FIG. 1B. By dynamic light scattering (Malvern® Zetasizer Nano ZS), the intensity-weighted particle size analyzed using NNLS fit gave a Peak 1 diameter of 127 nm. The intensity-weighted mean particle sized determined using cumulant fit provided a Z-average diameter of 101 nm. The zeta potential was measured to be −47 mV by laser Doppler micro-electrophoresis (Malvern® Zetasizer Nano ZS). The pH of the injectable emulsion was 8.77. This aprepitant-containing emulsion can be injected as is, or diluted for infusion with 5% dextrose or 0.9% saline. TABLE 2 Ratio to Component Amount (g) Concentration (w/w %) Aprepitant Aprepitant 0.450 0.714 1 Lipoid E 80 9.00 14.3 20 Soybean Oil 6.00 9.52 13.3 Ethanol1 1.89 3.00 4.20 Sucrose 3.36 5.33 7.47 Sodium Oleate 0.300 0.476 0.667 Water for Injection 42.0 66.7 93.3 Total 63.0 100 — 1Final amount after taking into account the ethanol that was evaporated during processing. Example 3 To prepare the aprepitant emulsion, an oil phase was first prepared by combining 450 mg of aprepitant and 9.00 g of egg lecithin (LIPOID E 80) with 6.0 ml of ethanol. This mixture was dissolved by heating and stirring at 60° C. and 200 rpm for 15 min. To the resultant solution was added in 6.00 g of soybean oil. Heating at 60° C. and stirring at 200 rpm was continued for another 15 min. The aqueous phase was prepared by dissolving 15.62 g of sucrose and 0.300 g of sodium oleate in 42.0 ml of water for injection. This mixture was stirred at 300 rpm at room temperature for 30 min. The aqueous phase was then added to the oil phase and subsequently subjected to high-speed homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 min to produce the crude emulsion. This crude emulsion was then passed 8 times through an ice-cooled high-pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi. The resultant fine emulsion was sterilized by passing it through a 0.2 μm nylon syringe filter (Corning). The details of the emulsion composition are provided in Table 3 below and a microscope image of the sample is provided in FIG. 1C. By dynamic light scattering (Malvern® Zetasizer Nano ZS), the intensity-weighted particle size analyzed using NNLS fit gave a Peak 1 diameter of 88 nm. The intensity-weighted mean particle sized determined using cumulant fit provided a Z-average diameter of 68 nm. The zeta potential was measured to be −42 mV by laser Doppler micro-electrophoresis (Malvern® Zetasizer Nano ZS). The pH of the injectable emulsion was 8.80. This aprepitant-containing emulsion is to be diluted with water for injection by 4-fold prior to injection. TABLE 3 Ratio to Component Amount (g) Concentration (w/w %) Aprepitant Aprepitant 0.450 0.587 1 Lipoid E 80 9.00 11.7 20 Soybean Oil 6.00 7.83 13.3 Ethanol1 3.27 4.26 7.26 Sucrose 15.6 20.4 34.7 Sodium Oleate 0.300 0.391 0.667 Water for Injection 42.0 54.8 93.3 Total 76.6 100 — 1Final amount after taking into account the ethanol that was evaporated during processing. Example 4 Alternate Aprepitant Emulsion Formulation for Intravenous Injection An aprepitant emulsion was prepared which has less than 10% wt/wt of the phospholipid emulsifier and which was adjusted to a pH of less than 8.0. To prepare the aprepitant emulsion, an oil phase was first prepared by combining 450 mg of aprepitant and 6.67 g of egg lecithin (LIPOID E 80) with 7.2 ml of ethanol. This mixture was dissolved by heating and stirring at 60° C. and 200 rpm. Heating and stirring was carried out until the ethanol was evaporated and a thick residue was observed. To the resultant solution was added in 6.00 g of soybean oil and an appropriate amount of ethanol to obtain a clear oil phase upon heating at 60° C. The aqueous phase was prepared by dissolving 3.36 g of sucrose in 50.5 ml of water for injection at 60° C. The aqueous phase was then added to the oil phase and subsequently subjected to high-speed homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 min to produce the crude emulsion. The pH of this crude emulsion was adjusted to 7.0 and then passed 8 times through an ice-cooled high-pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi. The resultant fine emulsion was sterilized by passing it through a 0.2 μm nylon syringe filter (Corning). The details of the emulsion composition are provided in Table 4 below. Within 4 days post preparation at room temperature, crystals were observed in the product by microscopy. TABLE 4 Ratio to Component Amount (g) Concentration (w/w %) Aprepitant Aprepitant 0.450 0.672 1 Lipoid E 80 6.67 9.95 14.8 Soybean Oil 6.00 8.96 13.3 Sucrose 3.36 5.02 7.47 Water for Injection 50.5 75.4 112 Total 67.0 100 — Example 5 An aprepitant emulsion was prepared which contains oleic acid. To prepare the aprepitant emulsion, an oil phase was first prepared by combining 250 mg of aprepitant, 2.50 g of egg lecithin (LIPOID E 80), 15.0 g of soybean oil and 125 mg of oleic acid. Ten ml of ethanol was added to dissolve the mixture at 70° C. The ethanol was removed by pressure reduction in a 70° C. water bath to yield a clear oil phase. A preheated aqueous phase containing 82.1 ml of water for injection at 70° C. was added to the oil phase and subsequently subjected to high-speed homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 min to produce the crude emulsion. This crude emulsion was passed 8 times through an ice-cooled high-pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi. The resultant fine emulsion was sterilized by passing it through a 0.2 μm nylon syringe filter (Corning). The details of the emulsion composition are provided in Table 5 below. Within 4 days post-preparation at room temperature, crystals were observed in the product by microscopy. TABLE 5 Ratio to Component Amount (g) Concentration (w/w %) aprepitant Aprepitant 0.250 0.250 1 Lipoid E 80 2.50 2.50 10 Soybean Oil 15.0 15.0 60 Oleic Acid 0.125 0.125 0.5 Water for Injection 82.1 82.1 328 Total 100 100 — Example 6 Preparing of Emulsions Containing Aprepitant and Dexamethasone Sodium Phosphate for Intravenous Injection To prepare an injectable emulsion containing aprepitant and dexamethasone sodium phosphate, an oil phase was first prepared by combining 773 mg of aprepitant and 15.5 g of egg lecithin (LIPOID E 80) with 10.3 ml of ethanol. This mixture was dissolved by heating and stirring at 60° C. and 200 rpm for 15 min. To the resultant solution was added in 10.3 g of soybean oil. Heating at 60° C. and stirring at 200 rpm was continued for another 15 min. The aqueous phase was prepared by dissolving 5.77 g of sucrose and 0.515 g of sodium oleate in 71.1 ml of water for injection. This mixture was stirred at 300 rpm at room temperature for 30 min. The aqueous phase was then added to the oil phase and subsequently subjected to high-speed homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 min to produce the crude emulsion. This crude emulsion was then passed 8 times through an ice-cooled high-pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi. Dexamethasone sodium phosphate (93.5 mg) dissolved in 1 ml of water for injection was mixed into the fine emulsion. This resultant fine emulsion containing both aprepitant and dexamethasone sodium phosphate was sterilized by passing it through a 0.2 μm nylon syringe filter (Corning). The details of the emulsion composition are provided in Table 6 below and a microscope image of the sample is provided in FIG. 1D. By dynamic light scattering (Malvern® Zetasizer Nano ZS), the intensity-weighted particle size analyzed using NNLS fit gave a Peak 1 diameter of 95 nm. The intensity-weighted mean particle size determined using cumulant fit provided a Z-average diameter of 70 nm. The zeta potential was measured to be −43 mV by laser Doppler micro-electrophoresis (Malvern® Zetasizer Nano ZS). The pH of the injectable emulsion was 8.92. This aprepitant and dexamethasone sodium phosphate containing emulsion can be injected as is, or diluted for infusion with 5% dextrose or 0.9% saline. TABLE 6 Ratio to Component Amount (g) Concentration (w/w %) aprepitant Aprepitant 0.773 0.688 1 Dexamethasone 0.0935 0.0832 0.121 Sodium Phosphate Lipoid E 80 15.5 13.8 20 Soybean Oil 10.3 9.17 13.3 Ethanol1 7.31 6.51 9.47 Sucrose 5.77 5.14 7.47 Sodium Oleate 0.515 0.459 0.667 Water for Injection 72.1 64.2 93.3 Total 112 100 — 1Final amount after taking into account the ethanol that was evaporated during processing. Example 7 Stability of the Aprepitant Emulsion at Room Temperature and 5° C. Stability of the aprepitant emulsions prepared as described in Examples 1, 2 3 and 6 was measured by incubating each emulsion preparation at room temperature (about 25° C.) or at 5° C. Mean particle size and percentage of fat globules above 5 μm were measured using DLS and light obscuration respectively to determine if they satisfy USP <729>. The emulsions were also inspected by microscopy for aprepitant crystals. Example 1 was stable at room temperature for 2 months, that is, the mean particle size and percentage of fat globules above 5 μm satisfied USP <729>. Additionally, no aprepitant crystals were visible by microscopy. After 2 months storage at room temperature, creaming was observed in Examples 1 and 6. This corresponded with the observation of aprepitant crystals. Examples 2 and 3 were stable at room temperature for 3 and 2 months respectively. After these time points, aprepitant crystals were observed in these formulations. Storage at 5° C. resulted in longer emulsion stability for Examples 1, 2, 3 and 6. Table 7 shows the characterizations of Examples 1, 2, 3 and 6 and their respective stabilities at room temperature and at 5° C. TABLE 7 Particle Particle Size as Size as Z- Stability at Peak 1 Average Zeta 25° C. per Stability at 5° C. Diameter Diameter Potential USP <729> per USP Sample PDI (nm) (nm) (mV) pH (months) <729> Example 1 0.122 99 87 −43 8.74 2 >10 months Example 2 0.200 127 101 −47 8.77 3 >10 months Example 3 0.219 88 68 −42 8.80 2 >10 months Example 6 0.244 95 70 −43 8.92 2 >10 months Example 8 Stability of the Aprepitant Emulsion to Freeze-Thaw Cycle The aprepitant emulsions prepared according to Examples 1, 2, 3 and 6 were tested for stability upon exposure to a freeze-thaw cycle. Samples from the Examples 1, 2, 3 and 6 were stored at −20° C. overnight. They were thawed to room temperature the next day and visualized by microscopy. Prior to freezing, all samples did not present any visible particles under the microscope. FIG. 1 shows microscope images, at 10×, of emulsions after the freeze-thaw cycle (Examples 1, 2, 3 and 6 are shown as FIGS. 1 A, B, C, and D, respectively). Emulsions prepared as described in examples 1, 2 and 6 showed visible particles after exposure to freezing. Only Example 3 was stable after freezing. As FIG. 1C shows, no visible particles were observed for the formulation of Example 3. This enhanced stability was conferred by the presence of a large concentration of sucrose (20 w/w % in Example 3 compared to 5 w/wt % in Examples 1, 2 and 6). Example 9 The pharmacokinetics of an aprepitant emulsion prepared according to Example 1 was determined. Two groups of six male Sprague-Dawley rats each were injected intravenously with, respectively, fosaprepitant in solution or aprepitant emulsion prepared according to Example 1. All drugs were administered at an effective concentration equivalent to 14 mg/kg aprepitant. Blood from all rats was collected at the appropriate time intervals and processed to plasma by centrifugation. Plasma samples were analyzed by LC-MS/MS for aprepitant and fosaprepitant, as appropriate. A plasma concentration versus time curve of aprepitant for the emulsion described in Example 1 and for fosaprepitant is presented in FIG. 2 (fosaprepitant in solution, ; aprepitant emulsion, ▴). The curves indicate the initial aprepitant level reached immediately after injection of the aprepitant emulsion was almost 3 times higher than the initial aprepitant level reached immediately after injection of the fosaprepitant solution. Plasma levels of aprepitant resulting from each injection, however, were essentially the same by the 3-hour time point indicating the formulations were bioequivalent except for a delay in the conversion of fosaprepitant to aprepitant. Example 10 The pharmacokinetics of an aprepitant and dexamethasone sodium phosphate combination emulsion prepared according to Example 6 was determined. Male Sprague-Dawley rats each were injected intravenously with fosaprepitant solution (group 1), dexamethasone sodium phosphate solution (group 2), or an emulsion containing aprepitant and dexamethasone sodium phosphate prepared according to Example 6 (group 3). Groups 1 and 2 consisted of six rats each; for group 3, twelve rats were injected with the aprepitant and dexamethasone sodium phosphate combination emulsion to allow for the collection of sufficient samples for the measurement of both active ingredients. In groups 1 and 3, a dose was administered at an effective drug concentration equivalent to 2 mg/kg aprepitant. In groups 2 and 3, a dose was administered at an effective drug concentration equivalent to 0.24 mg/kg dexamethasone sodium phosphate. Blood from all rats was collected at the appropriate time intervals and processed to plasma by centrifugation. Plasma samples were analyzed by LC-MS/MS for dexamethasone, aprepitant, and fosaprepitant, as appropriate. FIGS. 3 and 4 present the plasma concentration versus time curve of aprepitant and dexamethasone, respectively. FIG. 3 compares the aprepitant plasma concentration versus time curve resulting from injection of the emulsion described in Example 6 (FIG. 3, ) vs. injection of a solution of fosaprepitant (FIG. 3, ▴). FIG. 4 compares the dexamethasone plasma concentration versus time curve resulting from injection of a dexamethasone sodium phosphate solution (FIG. 4, ) vs. injection of the emulsion described in Example 6. The curves indicate that the aprepitant in the emulsion is released approximately simultaneously with the dexamethasone sodium phosphate. The presence of dexamethasone sodium phosphate in the emulsion does not affect the pharmacokinetics of aprepitant. Example 11 To prepare the aprepitant emulsion comprising a buffering agent, an oil phase is first prepared by combining 750 mg of aprepitant, 15.0 g of egg lecithin (LIPOID E 80), 10.0 g of soybean oil and 3.75 ml of ethanol. This mixture is dissolved by heating and stirring at 70° C. and 200 rpm for 30 min. The aqueous phase is prepared by dissolving 2.17 g of sucrose and 0.500 g of sodium oleate in a mixture of 4.1 ml of 1M Tris buffer (pH 8.4) and 65.9 ml of water for injection. This mixture is stirred at 300 rpm at room temperature for 30 min. The aqueous phase is then added to the oil phase and subsequently subjected to high-speed homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 min to produce the crude emulsion. This crude emulsion is then passed 8 times through an ice-cooled high-pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi. The resultant fine emulsion is sterilized by passing it through a 0.2 μm nylon syringe filter (Corning). Dynamic light scattering is used to determine the intensity-weighted particle size using NNLS fit to give the Peak 1 diameter, the intensity-weighted mean particle sized is determined using cumulant fit to provide the Z-average diameter. The zeta potential is measured by laser Doppler micro-electrophoresis (Malvern® Zetasizer Nano ZS). This aprepitant-containing emulsion can be injected as is, or diluted for infusion with 5% dextrose or 0.9% saline. While a number of exemplary aspects and embodiments have been discussed above, those of skill in the art will recognize certain modifications, permutations, additions and sub-combinations thereof. It is therefore intended that the following appended claims and claims hereafter introduced are interpreted to include all such modifications, permutations, additions and sub-combinations as are within their true spirit and scope.
<SOH> BACKGROUND <EOH>Aprepitant, having the chemical name 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one, has the structure: Aprepitant is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Aprepitant is currently available in the United States as an oral capsule, however due to the nausea and vomiting experienced by patients, it is desirable to formulate aprepitant as a liquid suitable for parenteral or intravenous administration. Liquid formulations containing aprepitant are very challenging to make as aprepitant is a molecule having poor solubility and poor permeability characteristics. One means of addressing this challenge is to prepare an emulsion which may both allow preparation of an injectable formulation as well as enhance bioavailability of the aprepitant once administered. Intravenous emulsions should have a very small droplet size to circulate in the bloodstream without causing capillary blockage and embolization. These size limits are typified by USP33-NF28 General Chapter <729> for Globule Size Distribution in Lipid Injectable Emulsions, hereinafter referred to as USP <729>, which defines universal limits for (1) mean droplet size not exceeding 500 nm or 0.5 μm and (2) the population of large-diameter fat globules, expressed as the volume-weighted percentage of fat greater than 5 μm (PFAT5) not exceeding 0.05%, irrespective of the final lipid concentration. Emulsion formulations must be physically stable. The droplet size limits defined in USP <729> apply throughout the assigned shelf life. All true emulsions are thermodynamically unstable and may over time undergo a range of processes which tend to increase the droplet size. These include direct droplet coalescence, when two droplets collide and form a single new droplet, and aggregation, in which droplets adhere together to form larger masses. Aggregation may in some cases be a precursor of further coalescence into larger droplets. These processes may result in large aggregates rising to the surface of the container, a phenomenon known as ‘creaming’, and ultimately to free oil being visible on the emulsion surface, known as ‘cracking’. Emulsion formulations must also be chemically stable. The drug substance may degrade; for example, lipophilic drugs will partition into the oil phase, which will confer some degree of protection, but hydrolytic degradation may still occur at the oil-water interface. Possible chemical degradation within parenteral fat emulsions includes oxidation of unsaturated fatty acid residues present in triglyceride and lecithin, and hydrolysis of phospholipids leading to the formation of free fatty acids (FFA) and lysophospholipids. Such degradants lower pH, which may then promote further degradation. Thus, pH should be controlled during manufacture and parenteral emulsion formulations may include a buffering agent to provide additional control. Any decrease in pH over the assigned shelf-life may be indicative of chemical degradation. In the present application, emulsion formulations were prepared and characterized to identify a formulation and process that will allow aprepitant to be incorporated into an emulsion for intravenous injection and remain stable during the shelf life of the formulation.
<SOH> BRIEF SUMMARY <EOH>The following aspects and embodiments thereof described and illustrated below are meant to be exemplary and illustrative, not limiting in scope. In one aspect, a pharmaceutical composition suitable for intravenous administration is provided which comprises a stable emulsion comprising an oil phase, wherein the oil phase comprises aprepitant, a surfactant and a co-surfactant; and an aqueous phase, wherein the aqueous phase comprises water, a tonicity agent and a pH-adjusting agent. In some embodiments, the pH-adjusting agent is a buffer. In one embodiment, the composition is an oil-in-water emulsion comprising an oil selected from the group consisting of structurally modified or hydrolyzed coconut oil, olive oil, soybean oil, safflower oil, triglycerides, octyl and decyl glycerate, ethyl oleate, glyceryl linoleate, ethyl linoleate, glyceryl oleate, cholesteryl oleate/linoleate or a mixture thereof. In one embodiment, the composition comprises about 5 wt/wt % (weight/weight %) to 15 wt/wt %, 5 wt/wt % to 10 wt/wt %, 7 wt/wt % to 10 wt/wt % or 8 wt/wt % to 9 wt/wt % oil. In another embodiment, the oil is soybean oil. In one embodiment, the composition comprises about 10 wt/wt % to 20 wt/wt %, 12 wt/wt % to 17 wt/wt %, 13 wt/wt % to 16 wt/wt %, 13 wt/wt % to 15 wt/wt %, or 13 wt/wt % to 14 wt/wt % emulsifier. In another embodiment, the composition comprises about 13 wt/wt %, 13.5 wt/wt %, 14 wt/wt %, 14.5 wt/wt %, 15 wt/wt %, 16 wt/wt %, 17 wt/wt %, 18 wt/wt %, 19 wt/wt % or 20 wt/wt % emulsifier. In another embodiment the emulsifier is a lecithin. In another embodiment the lecithin is an egg yolk lecithin. In one embodiment, the composition comprises about 20 wt/wt % to 50 wt/wt %, 30 wt/wt % to 50 wt/wt %, 35 wt/wt % to 45 wt/wt %, 30 wt/wt % to 45 wt/wt %, 37 wt/wt % to 42 wt/wt %, 38 wt/wt % to 40 wt/wt %, 30 wt/wt %, 31 wt/wt %, 32 wt/wt %, 33 wt/wt %, 34 wt/wt %, 35 wt/wt %, 36 wt/wt %, 37 wt/wt %, 38 wt/wt %, 39 wt/wt %, 40 wt/wt %, 41 wt/wt %, 42 wt/wt %, 43 wt/wt %, 44 wt/wt %, 45 wt/wt %, 46 wt/wt %, 47 wt/wt %, 48 wt/wt %, 49 wt/wt %, 50 wt/wt % of oil expressed as a percentage of the weight of the oil per the sum of weight of oil, emulsifier and oleate in a unit of the composition. In another embodiment, the oil is soybean oil. In one embodiment, the composition comprises about 40 wt/wt % to 80 wt/wt %, 50 wt/wt % to 70 wt/wt %, 55 wt/wt % to 65 wt/wt %, 57 wt/wt % to 63 wt/wt %, 58 to 60 wt/wt %, 35 wt/wt % to 40 wt/wt %, 30 wt/wt % to 40 wt/wt %, 50 wt/wt %, 51 wt/wt %, 52 wt/wt %, 53 wt/wt %, 54 wt/wt %, 55 wt/wt %, 56 wt/wt %, 57 wt/wt %, 58 wt/wt %, 59 wt/wt %, 60 wt/wt %, 61 wt/wt %, 62 wt/wt %, 63 wt/wt %, 64 wt/wt %, 65 wt/wt %, 66 wt/wt %, 67 wt/wt %, 68 wt/wt %, 69 wt/wt %, 70 wt/wt % of emulsifier expressed as a percentage of the weight of emulsifier per the sum of weight of oil, emulsifier and oleate in a unit of the composition. In another embodiment the emulsifier is a lecithin. In another embodiment the lecithin is an egg yolk lecithin. In one embodiment, the ratio of oil to aprepitant (wt %:wt %) in the composition ranges from about 11:1 to 20:1, 11:1 to 15:1, 12:1 to 16:1, 12:1 to 14:1, 11:1 to 15:1, 12:1 to 14:1, 12.5:1 to 13.5:1, 13:1 to 14:1, or 12:1 to 15:1. In another embodiment, the ratio of oil to aprepitant (wt %:wt %) in the composition is about 11:1 to 20:1, 11:1 to 15:1, 12:1 to 16:1, 12:1 to 14:1, 11:1, 11.5:1, 12:1, 12.5:1, 13:1, 13.5:1, 14:1, 14.5:1 or 15:1, 15.5:1, 16:1. In one embodiment, the ratio of emulsifier to aprepitant (wt %:wt %) in the composition ranges from about 15:1 to 30:1, 20:1 to 25:1, 18:1 to 22:1 or 10:1 to 30:1. In another embodiment, the ratio of emulsifier:aprepitant (wt %:wt %) in the composition is about 15:1, 18:1, 19:1, 20:1, 21:1, 22:1 23:1, 24:1, or 25:1. In one embodiment, the ratio of (emulsifier plus oil) to aprepitant (wt %:wt %) in the composition ranges from about 20:1 to 40:1, 25:1 to 35:1, 30:1 to 35:1. In another embodiment, the ratio of oil:aprepitant is about 25:1, 26:1, 27:1, 28:1, 29:1 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1 or 40:1. In one embodiment, the ratio of emulsifier to oil (wt %:wt %) in the composition ranges from about 0.5:1 to 4:1, 1:1 to 2:1, or 1.25:1 to 1.75:1. In another embodiment, the ratio of emulsifier to oil (wt %:wt %) in the composition is about 0.5:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 1.05:1, 1.15:1, 1.25:1, 1.35:1, 1.45:1, 1.55:1, 1.65:1, 1.75:1, 1.85:1, or 1.95:1. In one embodiment, a therapeutic dose comprises about 1 to 4 g, 1.5 to 3 g, 1.8 to 2.8 g, 2.3 to 2.8 g, 1.8 to 2.3 g, 1 g, 1.1 g, 1.2 g, 1.3 g, 1.4 g, 1.5 g, 1.6 g, 1.7 g, 1.8 g. 1.9 g, 2 g, 2.1 g, 2.2 g, 2.3 g, 2.4 g, 2.5 g, 2.6 g, 2.7 g, 2.8 g. 2.9 g, 3 g, 3.1 g, 3.2 g, 3.3 g, 3.4 g, 3.5 g, 3.6 g, 3.7 g, 3.8 g. 3.9 g, 4 g emulsifier. In another embodiment, the emulsifier is a lecithin. In another embodiment the emulsifier is egg yolk lecithin. In one embodiment, a therapeutic dose comprises about 0.5 to 3 g, 1 to 2.5 g, 1 to 2 g, 1 to 1.5 g, 1.5 g to 2 g, 0.5 g 0.6 g, 0.7 g, 0.8 g, 0.9 g, 1 g, 1.1 g, 1.2 g, 1.3 g, 1.4 g, 1.5 g, 1.6 g, 1.7 g, 1.8 g. 1.9 g, 2 g, 2.1 g, 2.2 g, 2.3 g, 2.4 g, 2.5 g oil. In another embodiment, the oil is soybean oil. In one embodiment, the emulsifier is a phospholipid. In another embodiment, the emulsifier is selected from the group consisting of egg phospholipids, soy phospholipids, phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, phosphatidylglycerols, phosphatidylinositols, phosphatidic acids, mixed chain phospholipids, lysophospholipids, hydrogenated phospholipids, partially hydrogenated phospholipids, and mixtures thereof. In one embodiment, the composition comprises a co-surfactant. In another embodiment, the co-surfactant is ethanol. In one embodiment, the composition comprises about 0 wt/wt % to 10 wt/wt %, 1 wt/wt % to 9 wt/wt %, or 2 wt/wt % to 6 wt/wt % co-surfactant. In another embodiment, the composition comprises less than 10 wt/wt %, less than 9 wt/wt %, less than 8 wt/wt %, less than 7, less than 6 wt/wt %, less than 5 wt/wt %, less than 4 wt/wt %, less than 3 wt/wt %, less than 2 wt/wt % or less than 1 wt/wt % co-surfactant. In one embodiment, the composition comprises about 0 wt/wt % to 10 wt/wt %, 1 wt/wt % to 9 wt/wt %, or 2 wt/wt % to 6 wt/wt % ethanol. In another embodiment, the composition comprises less than 10 wt/wt %, less than 9 wt/wt %, less than 8 wt/wt %, less than 7, less than 6 wt/wt %, less than 5 wt/wt %, less than 4 wt/wt %, less than 3 wt/wt %, less than 2 wt/wt % or less than 1 wt/wt % ethanol. In one embodiment, the emulsion comprises an aqueous phase which comprises a tonicity agent, a pH-adjusting agent, and water. In one embodiment, the emulsion comprises an aqueous phase which comprises an osmotic agent, a pH-adjusting agent, and water. In one embodiment, the emulsion comprises an aqueous phase which comprises a tonicity agent, an osmotic agent, a pH-adjusting agent, and water. In one embodiment, the aqueous phase further comprises a buffer. In one embodiment, the aqueous phase comprises a buffer but does not comprise a pH-adjusting agent which is different than the buffer. In another embodiment, the buffer functions as both a pH-adjusting agent and a buffer. In another embodiment, when the aqueous phase comprises a buffer, the composition contains no tonicity agent. In one another embodiment, the buffer is selected from the group consisting of phosphate buffer, citrate buffer, Tris buffer, carbonate buffer, succinate buffer, maleate buffer and borate buffer. In another embodiment, the buffer is selected from the group, phosphate buffered saline (PBS), modified PBS (PBS-mod) and citrate buffer. In one embodiment, the aqueous phase comprises a buffer, that when mixed with the oil phase will provide a substantially isotonic oil in water emulsion. In one embodiment, the osmotic agent is selected from the group consisting of glycerol, sorbitol, xylitol, mannitol, glucose, trehalose, maltose, sucrose, raffinose, lactose, dextran, polyethylene glycol, or propylene glycol. In another embodiment, the osmotic agent is an inorganic salt such as sodium chloride and mixtures thereof. In one embodiment, the pH adjusting agent is selected from the group consisting of sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium carbonate, Tris, sodium linoleate, sodium oleate, potassium carbonate, potassium linoleate, potassium oleate, and mixtures thereof. In one embodiment, the composition has a pH of about 6 to 9, 7 to 9, 7.5 to 9, 7.5 to 8.5, 8 to 9, 6 to 8, 7 to 8, or 6, 7, 8 or 9. In one embodiment, the composition comprises about 0 wt/wt % to 25 wt/wt %, 2 wt/wt % to 20 wt/wt %, 3 wt/wt % to 15 wt/wt %, or 3 wt/wt % to 8 wt/wt % tonicity agent. In another embodiment, the composition comprises about 1 wt/wt %, 2 wt/wt %, 3 wt/wt %, 4 wt/wt %, 5 wt/wt %, 6 wt/wt %, 7 wt/wt %, 8 wt/wt %, 9 wt/wt %, or 10 wt/wt %, 11 wt/wt %, 12 wt/wt %, 13 wt/wt %, 14 wt/wt %, 15 wt/wt %, 16 wt/wt %, 17 wt/wt %, 18 wt/wt %, 19 wt/wt %, or 20 wt/wt %, 21 wt/wt %, 22 wt/wt %, 23 wt/wt %, 24 wt/wt %, 25 wt/wt % tonicity agent. In still another embodiment, the composition comprises no tonicity agent. In one embodiment, the composition comprises about 0 wt/wt % to 25 wt/wt %, 2 wt/wt % to 20 wt/wt %, 3 wt/wt % to 15 wt/wt %, or 3 wt/wt % to 8 wt/wt % osmotic agent. In another embodiment, the composition comprises about 1 wt/wt %, 2 wt/wt %, 3 wt/wt %, 4 wt/wt %, 5 wt/wt %, 6 wt/wt %, 7 wt/wt %, 8 wt/wt %, 9 wt/wt %, or 10 wt/wt %, 11 wt/wt %, 12 wt/wt %, 13 wt/wt %, 14 wt/wt %, 15 wt/wt %, 16 wt/wt %, 17 wt/wt %, 18 wt/wt %, 19 wt/wt %, or 20 wt/wt %, 21 wt/wt %, 22 wt/wt %, 23 wt/wt %, 24 wt/wt %, 25 wt/wt % osmotic agent. In still another embodiment, the composition comprises no osmotic agent. In one embodiment, the aqueous phase comprises a dose of dexamethasone sodium phosphate in a dose of the composition. In another embodiment, the dose of dexamethasone sodium phosphate ranges from about 0.5 mg to 30 mg, 0.5 mg to 25 mg, 1 mg to 20 mg, 10 mg to 20 mg, or 3 mg to 16 mg. In another embodiment, the dose of dexamethasone sodium phosphate is about 9 mg or 16 mg in a dose of the composition. In one embodiment, the oil phase comprises a dose of dexamethasone in a dose of the composition. In another embodiment, the dose of dexamethasone ranges from about 0.5 mg to 30 mg, 0.5 mg to 20 mg, 1 mg to 18 mg, 10 mg to 20 mg, or 3 mg to 16 mg. In another embodiment, the dose of dexamethasone is about 8 mg or 12 mg in a dose of the composition. In one embodiment, the emulsion comprises about 0.002 wt/wt % to 0.2 wt/wt %, 0.003 wt/wt % to 0.16 wt/wt %, 0.02 wt/wt % to 0.1 wt/wt % dexamethasone sodium phosphate. In one embodiment, the composition is a stable system maintaining an intensity-weighted mean particle size as determined by dynamic light scattering (DLS) of about 50 nm to 1000 nm, 50 to 500 nm, 50 nm to 400 nm, 50 nm to 300 nm, 50 nm to 200 nm or 50 nm to 100 nm. In another embodiment, the average droplet size is maintained below 500 nm for a period of at least 1 month, 3 months, 6 months, 9 months, 12 months, 2 years or 3 years at room temperature. In another embodiment, the average droplet size is maintained below 500 nm for a period of at least 1 month, 3 months, 6 months, 9 months, 12 months, 2 years or 3 years at 5° C. In another aspect, a method for preparing an emulsion comprising aprepitant and suitable for parenteral administration is provided. In one embodiment, the administration is intravenous administration. In one embodiment, the method comprises: a) preparing an oil phase by dissolving aprepitant and an emulsifier in ethanol, then adding in oil to generate an oil-based mixture; b) preparing an aqueous phase by mixing water, optionally with a tonicity agent, optionally with an osmotic agent and optionally with a pH modifier and optionally with a buffer to generate an aqueous mixture; c) combining the oil-based mixture and the aqueous mixture and subjecting this to high speed homogenization to generate a crude emulsion; and d) subjecting the crude emulsion to high pressure homogenization to generate a fine emulsion. In one embodiment, preparing the oil phase further comprises dissolving dexamethasone with the aprepitant and the emulsifier in the ethanol. In one embodiment, the method comprises: a) preparing an oil phase by dissolving aprepitant and an emulsifier in ethanol and oil to generate an oil-based mixture; b) preparing an aqueous phase by mixing water, optionally with a tonicity agent, optionally with an osmotic agent and optionally with a pH modifier and optionally with a buffer to generate an aqueous mixture; c) combining the oil-based mixture and the aqueous mixture and subjecting this to high speed homogenization to generate a crude emulsion; and d) subjecting the crude emulsion to high pressure homogenization to generate a fine emulsion. In one embodiment, preparing the oil phase further comprises dissolving dexamethasone with the aprepitant and the emulsifier in the ethanol and oil. In one embodiment, preparing the aqueous phase further comprises mixing dexamethasone with the water, tonicity agent, pH modifier, and a buffer. In another embodiment, the dexamethasone is a salt of dexamethasone. In still another embodiment, the dexamethasone is dexamethasone sodium phosphate. In one embodiment, the method further comprises sterilizing the fine emulsion to generate the final emulsion, wherein the final emulsion is suitable for injection into a subject. In one embodiment, the dissolution in ethanol is performed at a temperature of about 25° C. to 80° C., 40° C. to 75° C., 60° C. to 70° C., or at about 25° C., 35° C., 45° C., 60° C., 65° C., 70° C. or 75° C. In one embodiment, the high-speed homogenization is performed at a speed of about 2,000 rpm (revolutions per minute) to 25,000 rpm. In another embodiment, the high-speed homogenization is performed at a speed of about 20,000 rpm. In yet another embodiment, the high-speed homogenization is performed at a speed of about 3600 rpm. In one embodiment, the high-speed homogenization is performed for a time period of about 0.5 min to 1 hour, 1 min to 45 min, or 1 min to 30 min. In another embodiment, the high-speed homogenization is performed for a time period of about 20 to 40 min or for about 30 min. In one embodiment, the high-speed homogenization is performed at about 10° C. to about 60° C., 20° C. to about 60° C., about 30° C. to about 50° C., or about 35° C. to about 45° C. In another embodiment, the high-speed homogenization is performed at about 25° C., 30° C., 35° C., 40° C., 45° C. or 50° C. In one embodiment, the high-pressure homogenization is performed at a pressure of about 10,000 psi (pounds per square inch) to 30,000 psi. In another embodiment, the high-pressure homogenization is performed at a pressure of about 20,000 psi. In one embodiment, the high-pressure homogenization is performed with cooling. In another embodiment, the high-pressure homogenization is performed with cooling which is sufficient to bring the temperature of the emulsion at the outlet of the process to about 0° C. to about 60° C., about 10° C. to about 40° C., about 20° C. to about 30° C., or to about 20° C., 25° C. or 30° C. within the time period. In one embodiment, the sterilizing the fine emulsion comprises filtering the fine emulsion through a nylon filter. In another embodiment, the nylon filter is a Posidyne® filter. In yet another embodiment, the filter has a pore size of about 0.2 μm (micrometers). Additional embodiments of the present compositions and methods and the like, will be apparent from the following description, drawings, examples, and claims. As can be appreciated from the foregoing and following description, each and every feature described herein, and each and every combination of two or more of such features, is included within the scope of the present disclosure provided that the features included in such a combination are not mutually inconsistent. In addition, any feature or combination of features may be specifically excluded from any embodiment of the present invention. Additional aspects and advantages of the present invention are set forth in the following description and claims, particularly when considered in conjunction with the accompanying examples and drawings.
A61K315377
20170914
20180522
20180104
58642.0
A61K315377
1
LEVIN, MIRIAM A
EMULSION FORMULATIONS OF APREPITANT
SMALL
1
CONT-ACCEPTED
A61K
2,017
15,705,390
PENDING
COVERING FOR A MEDICAL SCOPING DEVICE
The present invention relates to a cover having a plurality of moveable, external, angled projecting elements for use with flexible medical scoping devices such as endoscopes or enteroscopes. The invention includes the cover with an over cuff and use of the disposable removable covering in methods of medical scoping procedures or examinations. The invention also includes an applicator for assisting in placing the covering about or over a medical device and a kit of parts.
1. (canceled) 2. A cover for a medical scoping device shaft, the cover comprising an elongate tubular member and being arranged for application over the medical scoping device with the cover extending along at least a part of a length of a distal end of the medical scoping device shaft, the tubular member comprising an inner surface at least a part of which grips the shaft and holds the cover in place and a plurality of spaced apart projecting elements having a tip and a base connected to the cover, wherein the projecting elements are flexible and resiliently deformable along their entire length, wherein the projecting elements are sufficiently flexible to be movable between a resting position to a first position wherein the tips of the projecting elements are substantially parallel to a longitudinal axis of the tubular member and the medical scoping device shaft whereby the tips point toward a proximal end of the cover and to a second position wherein the tips of the projecting elements are at an angle approximately perpendicular to the longitudinal axis of the tubular member and the medical scoping device shaft so that the projecting elements fan out to thereby contact with, provide support for and to dilate a lumen wall of a body passage into which the medical scoping device shaft with the cover has been inserted, wherein at least some of the projecting elements are positioned in one or more rings extending circumferentially about the cover, and wherein the projecting elements in a distal ring of the one or more rings are moveable to a third position to have a curvilinear configuration extending outward from the tubular member whereby one or more of the tips of the projecting elements of the distal ring point towards a distal end of the cover. 3. The cover of claim 2 wherein the projecting elements are in the form of bristles, spikes, spines, fins, wedges, paddles or cones and are arranged to extend outwardly and away from the outer surface of the elongate tubular member, and wherein in the third position, when the one or more tips of the projecting elements point toward a distal end of the cover, those one or more tips are spaced apart from a respective base and reside further away from the respective base relative to at least the first position. 4. The cover of claim 2 wherein the projecting elements are cylindrical, conical or tapered. 5. The cover of claim 2 wherein the projecting elements are formed integrally with the outer surface of the elongate tubular member or are attached or moulded thereto or are moulded to cross members. 6. The cover of claim 2 wherein the at least a part of the inner surface of the tubular member which grips the shaft and holds the cover in place is either or both proximal or distal end regions of the tubular member or the entire inner surface of the tubular member. 7. The cover of claim 2, wherein the elongate tubular member is a contiguous tubular member. 8. The cover of claim 2, wherein the elongate tubular member comprises a wall with slits, ridges or gaps running in a longitudinal direction, parallel with a longitudinal axis of the cover. 9. The cover of claim 8, wherein the number of slits or gaps is directly proportional to the number of projecting elements, and wherein the projecting elements are positioned in the slits or gaps between solid parts of the tubular member. 10. The cover of claim 2, wherein the projecting elements are between 2 to 20 mm in length from the base to the tip. 11. The cover of claim 2, wherein the projecting elements are between 4 to 14 mm in length from the base to the tip. 12. The cover of claim 2, wherein the length of the projecting elements are shorter at either or both a distal end and the proximal end of the cover. 13. The cover of claim 2, wherein the projecting elements comprise some that have a longer length than others, and wherein the projecting elements that are of the longer length are more flexible and are constructed of a softer material than the projecting elements of a shorter length. 14. The cover of claim 2 wherein the projecting elements are in the form of hairs or bristles and a diameter of the projecting elements is between 0.5 to 3.0 mm. 15. The cover of claim 2, wherein the elongate tubular member and/or the projecting elements are constructed of a biocompatible flexible material selected from the group comprising polymers, plastics, elastomers, silicon and silicon elastomeric materials and rubbers. 16. The cover of claim 2 wherein the projecting elements in the resting position are acutely angled with respect to a central longitudinal axis of the elongate tubular member at an angle of between 35° to 85°. 17. The cover of claim 2, wherein the one or more rings are between 1 to 20 rings. 18. The cover of claim 2, wherein the one or more rings is a single ring comprising only the distal ring. 19. The cover of claim 2, wherein the one or more rings is a plurality of longitudinally spaced apart rings. 20. The cover of claim 2 wherein each ring of the cover comprises between 4 to 16 of the projecting elements. 21. The cover of claim 2, wherein the one or more rings is a plurality of rings, wherein the rings are longitudinally spaced apart by a distance of between 2.5 cm to 0.5 cm. 22. The cover of claim 2, wherein the distal ring of the projecting elements is positioned between 1 mm to 20 mm from a distal end tip of the cover. 23. The cover of claim 2, wherein the one or more rings comprises a proximal ring of the projecting elements, wherein the proximal ring is positioned between 1 cm and 5 cm from the proximal end of the cover. 24. The cover of claim 2, wherein the projecting elements are all of equal diameter, length, number in a respective ring, and wherein the one or more rings comprises a plurality of rings that are evenly longitudinally spaced apart, and wherein at least one ring has different size and/or different numbers of the projecting elements from other rings. 25. The cover of claim 2, wherein the projecting elements are either straight or curved. 26. The cover of claim 2 further comprising an over cuff. 27. The cover of claim 23 wherein the over cuff is placed over the cover and is provided with slits or gaps of approximately the same dimensions as that of the cover so that the projecting elements are able to protrude through the aligned slits or gaps. 28. The cover of claim 26, wherein the over cuff is of the same or approximately same length as the cover. 29. The cover of claim 26, wherein the over cuff is constructed of a polycarbonate or a plastics material. 30. The cover of claim 26, wherein the projecting elements, on insertion into a body orifice, fall below an outer surface of the over cuff. 31. The cover of claim 2, wherein the cover is provided with one or more apertures positioned at a proximal end of the cover. 32. The cover of claim 2, further comprising a visually transmissive viewing surface at a distal end which is optionally in the form of an open ended transparent plastic or Perspex® cap. 33. The cover of claim 2, wherein an outer surface of the cover comprises a lubricating agent selected from the group comprising a hydrogel polymer, poly(2-hydroxyethyl methacrylate) (PHEMA), ComfortCoat®, silicone, glycerine, olive oil, castor oil, chlorotrifluoroethylene (CTFE oil) and polyphenyl ethers or a mixture thereof, optionally wherein the cover is coated only at its distal most part and on an outer surface of the projecting elements of the distal most part. 34. The cover of claim 2 wherein the cover is removable or detachable from the medical scoping device. 35. The cover of claim 2, wherein the projecting elements are moveable beyond the second position and can flick over at a critical point of maximum inflexion so that the tips point towards a distal end of the cover and the medical scoping device. 36. The cover of claim 2 further including a projecting elements closure device which can be drawn from a distal to a proximal end to enclose and flatten the projecting elements from the second position that is approximately perpendicular to the longitudinal axis of the medical scoping device shaft to the first position wherein the projecting elements are approximately parallel to the said axis. 37. The cover of claim 2 in which the projecting elements are hinged at their base onto the outer surface of the elongate tubular member. 38. A medical scoping device having attached thereto a cover according to claim 2. 39. The medical scoping device of claim 38 wherein the cover is releasably attached thereto. 40. A medical scoping device according to claim 38 wherein the device is an endoscope or an enteroscope. 41. A medical scoping device comprising: a medical scoping device shaft having an air suction conduit for removing air from a body passage into an orifice of an individual under investigation; and a cover releasably attached to the medical scoping device shaft and covering at least a part of the shaft at its distal end, wherein the cover grips the shaft and holds the cover in place, and wherein the cover comprises a plurality of spaced apart projecting elements that extend outwardly therefrom, the medical scoping device configured so that when advancing the medical scoping device into a patient's body passage, the projecting elements deflect to a first radially inward position to facilitate advancing the medical scoping device, the medical scoping device being configured so that, when partially withdrawing the medical scoping device toward its proximal end, such withdrawal causes the projecting elements to deflect to a second radially outward position at which at least some tips of the projecting elements extend distally further than a distal end of the cover and the distal end of the medical scoping device in response to contact with a lumen wall to dilate the lumen while holding the medical scoping device in position for visualization of the lumen and to evert and engage folds in the wall of the body passage that are more distal than the distal end of the cover and the medical scoping device whereby visualization is allowed as the folds in the wall of the body passage revert to their normal anatomical position permitting a light from the medical scoping device to emit across a mucosa of the lumen providing visualization of at least a portion of a surface of the mucosa, and the medical scoping device being configured so that when withdrawing the medical scoping device, the projecting elements deflect so that at least some of the tips of the projecting elements extend distally further than the distal end of the cover and the distal end of the medical scoping device to facilitate withdrawal of the medical scoping device. 42. The medical scoping device of claim 41 wherein, in response to when the projecting elements dilate the lumen and evert, at least some of the projecting elements that extend beyond the distal end of the cover and the medical scoping device are configured to flatten folds in the wall of the body passage. 43. A medical scoping device comprising: a medical scoping device shaft having an air suction conduit for removing air from a body passage of a subject; and an elongate tubular member releasably attached to the medical scoping device shaft and covering at least a part of a distal end of the medical scoping device shaft, wherein the elongate tubular member comprises a plurality of circumferentially spaced apart outwardly projecting elements, wherein the projecting elements have a length with a free end comprising a tip, wherein the projecting elements are sufficiently flexible and sufficiently long to be moveable to have different curvilinear configurations relative to the tubular member, wherein the projecting elements are flexible and resiliently deformable along their entire length, wherein, in at least one of the different curvilinear configurations, at least one of the tips of the projecting elements resides longitudinally distally further than a distal end of the tubular member. 44. The device of claim 43, wherein the at least one of the tips of the projecting elements that resides longitudinally distally further than the distal end of the tubular member also resides distally further than a tip of the distal end of the medical scoping device shaft. 45. The device of claim 43, wherein, in at least one of the different curvilinear configurations, the at least one of the tips of the projecting elements that resides longitudinally distally further than a distal end of the tubular member also extends laterally outward with the tip further away from the tubular member relative to at least a resting configuration thereof. 46. A cover for a medical scoping device, comprising: a tubular member releasably attachable to a medical scoping device shaft and covering at least a part of a distal end of the medical scoping device shaft, wherein the tubular member comprises a plurality of circumferentially spaced apart projecting elements, wherein the projecting elements have a respective base and an opposing free end comprising a tip, wherein the projecting elements are flexible and resiliently deformable along their entire length, wherein the projecting elements are sufficiently flexible and long to be moveable to have a curvilinear configuration extending outward from the tubular member whereby one or more of the tips of the projecting elements extend distally further than the tubular member, thereby, on withdrawal from the body passage, the cover can keep a tip of the medical scoping device shaft in a central part of the body passage as the medical scoping device shaft moves backwards and/or can evert folds in a wall of the body passage allowing proximal surfaces to be viewed. 47. The cover of claim 46, wherein when the one or more tips of the projecting elements extend distally further than the tubular member those one or more tips are spaced apart from a respective base and reside further away from the respective base and tubular member relative to at least a resting configuration thereof.
The present invention relates to a covering or sheath or sleeve or cuff having external projections for use with a medical device and in particular for use with flexible medical scoping devices such as endoscopes or enteroscopes. The invention includes inter alia use of the disposable removable covering in methods of medical scoping procedures or examinations, particularly but not exclusively, where the site is the colon or small intestine. The invention also includes a kit including an applicator for assisting in placing the covering about or over a medical scoping device. BACKGROUND In endoscopic examinations/procedures, flexible instruments designed to view the gastro-intestinal tract are inserted along a body cavity to an internal part such as the stomach, duodenum, small intestine or large intestine. The instruments are provided with fibre-optic or charge-couple device (CCD) cameras which enable images to be transmitted around bends and images to be produced to displays on a television screen. Accordingly, it is possible to view the inside surfaces of the oesophagus, stomach and duodenum using a gastroscope, the small intestine with an enteroscope, part of the colon using a flexible sigmoidoscope and the whole of the large intestine (the bowel) with a colonoscope. Enteroscopy is the endoscopic examination of the small intestine whereas colonoscopy is the endoscopic examination of the colon and the distal part of the small bowel and flexible sigmoidoscopy is the examination of the rectum and lower part of the bowel. Each scoping procedure may provide a visual diagnosis (e.g. ulceration, polyps) and grants the opportunity for biopsy or removal of suspected lesions. Whilst colonoscopic and enteroscopic examinations are the most effective techniques to assess the state of health of the bowel, they are inconvenient, uncomfortable, expensive procedures that are associated with significant risks of potentially serious complications. The most common complications are: failure to achieve a complete examination (5-10%); failure to detect a polyp (up to 20%); reaction to intravenous drugs; over-sedation leading to hypoxia and cardio-vascular collapse; splenic injury (rare); bowel perforation, (1 in 500-1500); full thickness burn (uncommon) and; bleeding following polypectomy. A further disadvantage of colonoscopic and enteroscopic procedures is that they are time consuming for patients and medical personnel alike, the procedure can take anywhere from 20 minutes to 2 hours depending on how difficult it is to advance a scope through the colon or small intestine. The colonoscopy itself takes around thirty minutes to perform but in some cases may require up to an hour, and for the patient, there is a recovery period of up to two hours in hospital whilst sedation passes off and over that time clinical observation is needed. Typically, the number of clinically competent personnel required to conduct a colonoscopic procedure are an endoscopist specialist and three assistants including the person responsible for reprocessing the equipment. In addition, staffing is required for the recovery area. Two yet further additional significant difficulties associated with colonoscopy and scoping procedures more generally are as follows: Firstly, the anatomy of the colon is such that the lining is thrown into folds. As the tip of the endoscope passes along the lumen of the colon, these folds hamper the endoscopist's ability to visualise the entire surface of the mucosa and in particular, detect pre-malignant and malignant lesions tucked away on the proximal face of these folds during extubation. Secondly, the position of the tip of may be difficult to maintain from the moment at which a lesion or polyp is detected to the completion of any therapeutic procedure. As the colonoscope is withdrawn the tip does not travel back at a constant speed but rather with jerks and slippages particularly when traversing a bend or length of colon where the bowel has been concertinaed over the endoscope shaft during intubation. The tip of the device may, at any moment, slip backwards thereby causing the clinician to lose position. If tip position is lost, the clinician is required to relocate the lesion or polyp for the therapeutic procedure to be continued. The colonoscopic procedure is not simple because the bowel is long and convoluted. In places it is tethered by peritoneal bands and in others it lies relatively free. When the tip of the endoscope encounters a tight bend the free part of the colon “loops” as more of the endoscope is introduced and so looping occurs in the free part of the colon before the bend when there is difficulty negotiating the bend. This leads to stretching of the mesentery of the loop (the tissue that carries the nerves and blood vessels to the bowel). If the stretching is continued or severe while the endoscopist pushes round the bend, the patient experiences pain the blood pressure falls and the pulse slows. Loop formation is the main cause of failure or delay in completing an examination. It is responsible for the pain experienced by the patient and the need for heavy sedation that in turn leads to cardio-respiratory complications. It is also the major cause of perforation in patients not undergoing a therapeutic procedure. Attempts have been made to try to overcome the problems associated with colonoscopic procedures, for example, it is known in the prior art to provide endoscope sheaths having differential frictional resistance provided by very small external protrusions such as wedge-shaped profiles or scales so there is low frictional resistance during forward movement of the covered endoscope shaft through a body cavity and a greater frictional resistance during its rearward movement. In practice however little improvement is achieved in overcoming looping. It is also known from the prior art to use a double balloon enteroscope or an Aer-O-Scope™. The double balloon enteroscope requires a substantial amount of additional kit, a high level of operator skill in timing the sequential inflation and deflation of the balloons and moreover it is a lengthy procedure sometimes taking hours. The Aer-O-Scope™ provides low pressure colon insufflations with CO2 to propel the balloon along “slippery” colon walls without forceful manoeuvring but cannot be used for biopsy or therapy. Despite the forgoing drawbacks, for the foreseeable future colonoscopy will remain the procedure of choice for the examination of the large bowel. Newer methods for the detection of polyps and cancer using non-invasive technology may be identified but to obtain biopsies, remove polyps and to treat intra-colonic lesions no alternatives have appeared to date. An improved medical scoping device that could reduce the time taken for the colonoscopist or enteroscopist to perform the procedure would offer immediate advantages to patients and clinicians alike. An improved medical scoping device that could reduce the risk of complications during a procedure would offer immediate advantages to patients and clinicians alike. A medical scoping device that could improve endoscopic intubation, extubation and visualisation of the large bowel would offer immediate advantages to both patients and clinicians alike. A medical scoping device that could reduce loss of tip position during a medical procedure would offer immediate advantages to both patients and clinicians alike. An improved medical scoping device that could reduce the requirement or level of sedation for a patient would offer immediate advantages to both patients and clinicians alike. An improved medical scoping device that could overcome the problems associated with looping and so reduce discomfort to the person on whom the procedure was being performed, would offer immediate advantages to patients and clinicians alike. BRIEF SUMMARY OF THE DISCLOSURE According to a first aspect of the present invention there is provided a cover for a medical scoping device shaft, the cover comprising an elongate tubular member and being arranged for application over the medical scoping device shaft with the cover extending along at least a part of the length of a distal end of the shaft, the tubular member comprising an inner surface at least a part of which grips the shaft and acts to hold the cover in place and an outer surface comprising a plurality of spaced projecting elements having a tip and a base that are moveable between a resting position to a position wherein the tip of the projecting element is substantially parallel to a longitudinal axis of the medical scoping device and to a position that is at an angle that is approximately perpendicular to the longitudinal axis of the medical scoping device shaft so that the said projecting elements are fanned out to contact with and provide support for and to dilate a lumen wall of a body passage into which the medical scoping device has been inserted. According to a second aspect of the invention there is provided a medical scoping device comprising an air suction means for removing air from a body passage, an elongate flexible shaft having a proximal end associated with a viewing means and a distal end, the medical scoping device further comprising the cover of the first aspect of the invention releasably attached thereto and covering at least a part of the shaft at its distal end. According to a third aspect of the invention there is provided a cover according to a first aspect of the invention or a medical scoping device of the second aspect of the invention for use in a scoping procedure. According to a fourth aspect of the invention there is provided an applicator for attaching a cover to a shaft of a medical scoping device, the applicator comprising a pair of complimentarily mated casings each sized and shaped so as to accommodate a cover for a medical scoping device therein, each casing further comprising an engaging means for releasably engaging the casings to one another and each casing comprising at least one securing means for securing a proximal end of the said cover thereto. According to a fifth aspect of the invention there is provided a kit comprising at least one cover according to the first aspect of the invention and an applicator according to the fourth aspect of the invention, optionally the kit further includes a medical scoping device and/or a cutting means and/or a distal end cap. According to a sixth aspect of the invention there is provided a method of avoiding looping in a medical scoping procedure, the method comprising inserting a medical scoping device shaft having an air suction means for removing air from a body passage into an orifice of an individual under investigation, the medical scoping device further comprising a cover releasably attached to the medical scoping device shaft and covering at least a part of the shaft at its distal end, wherein the cover comprises an elongate tubular member having an inner surface at least a part of which grips the shaft and acts to hold the cover in place and an outer surface comprising a plurality of spaced projecting elements, and wherein when advancing the medical scoping device into the patient's bowel or small intestine and the distal end encounters a bend or loop in the patient's bowel or small intestine, the medical scoping device is withdrawn towards its proximal end causing the projecting elements to splay or fan out and to dilate the lumen of the bowel or small intestine whilst holding the medical scoping device in position, if necessary air is then drawn out causing the body passage walls to collapse around and about the projecting elements thereby drawing the body passage wall into spaces between the projecting elements so said projecting elements engage with and grip the body passage wall, the medical scoping device is then further withdrawn towards the proximal end causing it to straighten and the body passage wall to concertina along the shaft of the scope proximal to the bend or loop whilst the lumen ahead of the distal end opens up, the medical scoping device is then advanced towards its distal end and the bend or loop is navigated. According to a seventh aspect of the invention there is provided a method of improving endoscopic visualisation, the method essentially comprising the steps of the sixth aspect of the invention wherein the projecting elements open a lumen and evert thereby flattening colonic folds for inspection during withdrawal whereby visualisation is further enhanced as colonic folds revert to their normal anatomical position permitting light from the medical scoping device to play across the mucosa, thus enabling careful visualisation of the surface of the mucosa that was hitherto hidden or difficult to view. According to an eighth aspect of the invention there is provided a method of maintaining tip position and improving tip control during an examination, the method essentially comprising the steps of the sixth aspect of the invention wherein the projecting elements maintain the medical scoping device tip in a central part of the bowel lumen as the device moves in a proximal direction thereby holding the mucosa to prevent the tip from flipping backwards so as to maintain position during therapy. BRIEF DESCRIPTION OF THE DRAWINGS Embodiments of the invention are further described hereinafter with reference to the accompanying drawings, in which: FIG. 1 shows one embodiment of the cover according to the present invention. FIG. 2 shows a transverse section through the cover of FIG. 1. FIG. 3 shows in detail a longitudinal section of the distal end of the cover of FIG. 1. FIG. 4 shows a disassembled applicator and cover. FIG. 5 shows an assembled applicator and cover. FIG. 6A shows a top view of an applicator, FIG. 6B shows a side view, FIG. 6C shows a top view of a disassembled applicator and cover, FIG. 6D shows a proximal end view and FIG. 6E shows a distal end view. FIG. 7 shows a side view of a viewing means attachment. FIGS. 8A-8E show different embodiments of the projecting elements. FIG. 9A shows the cover of the present invention having one embodiment of the projecting elements closing means and FIG. 9B shows a cover having flattened projecting elements. FIGS. 10A-10B show an alternative embodiment of the cover of the invention; FIG. 10A shows a top plan view and FIG. 10B shows an underside plan view. FIGS. 11A-11E show a series of different views of an alternative embodiment of the cover of present invention including an over cuff; FIG. 11A shows a transverse through section; FIG. 11B shows a front view and FIGS. 11C and 11D show bottom and top side angled views; and FIG. 11E shows the cover including the over cuff placed over the distal end of a medical scoping device. FIGS. 12A-12D show a series of schematic anatomical through sections of a medical scoping device with a cover of the present invention including the over cuff, in the course of a medical scoping procedure. FIG. 12A shows insertion of the scoping device and cover via the anus into the colon of an individual undergoing an endoscopic procedure; FIG. 12B shows forward passage along the colon; FIG. 12C shows controlled withdrawal, flattening of the colonic wall and improved visualisation and; FIG. 12D shows air suction causing the colon wall to collapse or wrap around the device and to grip the cover and device. DETAILED DESCRIPTION Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise. Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed. The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference. Reference herein to a “medical scoping device” is intended to refer to endoscopes, enteroscopes, sigmiodoscopes, gastroscopes, colonoscopes and panendoscopes and is used interchangeably and is intended to include all scoping instruments whether passed directly or through a cannula into a body/organ/tissue cavity. Endoscopy involves the inspection of the inside of the body or body cavity and includes arthroscopy, cystoscopy, gastroscopy, uteroscopy and colonoscopy whereas enteroscopy is the examination of the small intestine including the duodenum, jejunum, and ileum. In all instances the scopes are elongate flexible probes and it is intended that the covers of the present invention may be used in conjunction with all of the aforementioned scopes. Accordingly a “medical scoping procedure” is intended to include any medical procedure or examination that involves use of a medical scoping device as hereinbefore described. The distal end the cover is the end which is commensurate with the distal end of the medical scoping device shaft which comprises lenses, channels such as air suction conduits and light guides. It is the end which is furthest from the endoscopist/colonoscopist and as such is the end of the instrument which is deepest within the patient's body and therefore it is the end which will first come into contact with a looped segment of the bowel. Accordingly, a distal movement of the endoscope is a forward movement i.e. further into a patient's bowel. Conversely, the proximal end of the sheath is the end which is commensurate with the proximal end of the endoscope and which is the end situated nearest the operator and therefore a proximal movement of the endoscope is a backward movement towards the operator. In one aspect of the present invention provides the medical scoping device cover provides an improved means of conducting probing procedures, avoiding the problems associated with looping and generally improving the speed and comfort of the procedure for the patient. The cover is arranged for application over the medical scoping device shaft so as to surround it and to extend along at least a distal part or tip region of the shaft. The cover comprises an inner surface at least a part of which grips the shaft of the medical device and holds the cover in place against movement longitudinally of the shaft during displacement of the shaft through a body passage into which the shaft is inserted in use, and the outer surface of the sleeve is provided with protrusions configured to cover the endoscope shaft onto which the cover is applied whereby the protrusions when fanned out or extended from the shaft body provide a means for gently holding on to or gripping the inner surface of the body passage and opening up the lumen. The gripping of the body passage by the projecting elements is enhanced by removal of any air in the body passage so that the wall of the body passage into which the medical device has been inserted collapses on to the projecting elements and is drawn into the spaces between the projecting elements thus the body passage walls are held against the cover and a rearward or proximal movement of the device causes the body passage to concertina behind the gripped portion of the body passage, the scope to straighten and the lumen ahead of the distal end to straighten and open up. Preferably, the at least a part of an inner surface of the cover that is in contact with the distal end of the medical scoping device shaft may either be upper and lower end regions of the cover or the entire inner surface. Preferably, the elongate tubular member may comprise a contiguous tubular member or alternatively it may be provided with slits or gaps or ridges running in a longitudinal direction commensurate with the longitudinal axis of the medical scoping device. In this embodiment of the invention the number of slits is directly proportional to the number of projecting elements, the projecting elements being positioned in the slits or gaps between the solid parts of the cover. Preferably, the projecting elements are in the form of bristles, spikes, spines, fins, wedges, paddles or cones and are arranged to extend outwardly and away from the outer surface of the elongate tubular member. The projecting elements may be cylindrical, conical or tapered and the tips of the projecting elements may either be rounded or blunted. Preferably, the projecting elements may be formed integrally with the outer surface of the elongate tubular member or alternatively they may be attached or moulded thereto. In the instance that the cover is provided with longitudinal slits or gaps then the projecting elements may be provided attached to or moulded in between adjacent slits or gaps. In the instance of the projecting elements being attached or moulded to the outer surface of the cover, the bases of the projecting elements may be hinged onto the outer surface of the elongate tubular member. In this way the projecting elements are hinged and capable of moving between a resting position, where the tips extend away from the scoping device shaft at a selected angle, to a position wherein the tips of the projecting elements are substantially parallel to a longitudinal axis of the enteroscope/endoscope shaft and also to a position wherein the projecting elements project outwards from the enteroscope/endoscope shaft at an angle of less than or equal to perpendicular to the longitudinal axis of the medical scoping device shaft. In this position the projecting elements can be said to be fanned out. In the alternative embodiment, the projecting elements are attached at their base to circumferentially positioned cross members situated below the level of the outer surface of the casing to form a hinge. In this way the projecting elements are hinged and capable of moving between a resting position, where the tips extend away from the scoping device shaft at a selected angle, to a position wherein the tips of the projecting elements are substantially parallel to a longitudinal axis of the enteroscope/endoscope shaft an fall below the level of the outer surface of the casing and also to a position wherein the projecting elements project outwards from the enteroscope/endoscope shaft at an angle of less than or equal to perpendicular to the longitudinal axis of the medical scoping device shaft. In this position the projecting elements can be said to be fanned out. Preferably, the tips of the projecting elements when in a position of being substantially parallel to the longitudinal axis of the medical scoping device may either be directed towards a distal or proximal end of the covered medical scoping device. It will be appreciated that the projecting elements can be said to be moveable between at least three, and in some embodiments, four positions. In a first position the projecting elements project at a selected acute angle away from the longitudinal axis of the medical scoping device, this is the “resting position”. In a second position when the covered medical scoping device is pushed in a distal direction into a patient's lumen forces act upon the projecting elements to push them towards the shaft of the scoping medical device so that they are substantially parallel to the longitudinal axis of the medical scoping device and so that the tips point towards a proximal end of the scope. In a third position, when the covered scoping device is withdrawn in a proximal direction the projecting elements are caused to fan out and are substantially perpendicular to the longitudinal axis of the shaft of the scoping medical device. In some embodiments of the invention the projecting elements are moveable beyond the third position and flick over at a critical point so that the tips point towards the distal end of the scoping medical device, this is the fourth position, and is the position in which the medical scoping device can be withdrawn through the orifice into which it was initially inserted. Alternatively, the cover may be provided with a projecting elements closure means optionally in the form of a sleeve which can be drawn from a distal to a proximal end and which flattens the projecting elements from the third or resting position to the second position described above. Accordingly in some embodiments of the invention where the projecting elements do not flick over at a critical point the covers of the present invention are preferably provided with a projecting element closure means that moves the projecting elements from a fanned out position to a position where they are substantially parallel to the longitudinal axis of the shaft of the medical scoping device. Preferably, the projecting elements closure means is in the form of a sleeve that is capable of being drawn over the projecting elements. Preferably, the projecting elements closure means is provided with a draw string or the like which allows the sleeve to unfurl in a proximal direction. Preferably, the bases of the moulded projecting elements are raised so that they form a bump or bulge on the outer surface of the elongate tubular member under which is an air pocket. The projecting elements are hinged or moveable about their bases to enable them to be moveable and in one embodiment to flick over beyond a critical point of maximum flexion so that the tips point distally to allow for a smooth removal of the medical device from the body passage and orifice into which the device has been inserted. Preferably, the bases of the moulded elements are attached at their base to circumferentially positioned cross members. The projecting elements are hinged or moveable about their bases to flick over beyond a critical point of maximum flexion so that the tips point distally to allow for a smooth removal of the medical device from the body passage and orifice into which the device has been inserted. Preferably, the hinges at the bases of the projecting elements facilitate movement of the projecting elements between a resting position at an acute angle, preferably between 85 to 35° and more preferably about 55 to 75° in addition to a tendency to collapse to the second position i.e. one that is substantially parallel to the horizontal access. The hinges also facilitate a tendency to resist flexion to a point substantially perpendicular to the longitudinal axis (90°) and a tendency to flatten to an obtuse angle i.e. flipping over to about 170-180° upon extubation after a critical angle is exceeded. Preferably, the hinges may be of variable stiffness. Preferably, the bristles are between 2 to 20 mm in length from base to tip and more preferably they are between 4 to 15 mm in length and more preferably still are between 4 to 10 mm in length. In embodiments of the invention where multiple rings of projecting elements are provided then preferably, the length of the bristles is marginally shorter at either or both the distal and proximal ends of the cover. Thus the central region of the cover comprises bristles of a longer length so that the bristles of the cover when seen in side view are elliptical. Preferably, the projecting elements that are of a longer length are more flexible and are constructed of a softer material than projecting elements of a shorter length and more preferably still the longer projecting elements are everted. Preferably, in the embodiments where the projecting elements are in the form of bristles or hairs the diameter of the projecting element is between 0.5 to 3.0 mm and more preferably still is about 1.5 mm. Preferably, the projecting elements may be either straight or curved. Projecting elements with a slight curve offer the advantage of when they abut or contact the colonic wall there is a tendency to deform, so that the tip of the projecting element bends out rather than pressing into or impinging onto the colonic wall causing trauma. The slight curve reveals the under surface of the projecting elements into the colonic wall, pushing it away and flattening folds as they pass by. It will be appreciated that the elongate tubular member and the projecting elements are constructed of a suitable biocompatible material so that they are flexible and resiliently deformable, suitable materials include but are not limited to a material selected from the group comprising polymers, plastics, elastomers and rubbers. Suitable examples include polyurethane, polychlorpropene, natural rubber, silicon and silicon elastomeric materials a particularly preferred material is a thermoplastic elastomer for example and without limitation Pebax®. Preferably, the elongate tubular member and projecting elements are constructed from the same or differing materials, from a manufacturing perspective a cover comprising the same construction material is preferred however it is within the scope of the invention to construct the projecting elements from a different material to the elongate tubular member's main body. Preferably, the projecting elements in a resting position are acutely angled with respect to the central longitudinal axis of the cover and more preferably the projecting elements are positioned at an angle of between 35° to 85° with respect to a central longitudinal axis of a central line of the cover, more preferably they are angled at about 55° to 75° from the cover's central longitudinal axis. Preferably, the projecting elements are positioned in rings running circumferentially around the cover and along the length of the cover. Ideally, there is at least one or more rings and more ideally two rings and in other embodiments up to 20 rings. It will be appreciated that the projecting elements may, in some embodiments, be provided as a single ring. Preferably, each ring comprises between 4 to 16 projecting elements and more preferably between 5 to 10 projecting elements. The rings of projecting elements may be aligned uniformly in parallel descending the length of the cover or they may be off set against one another. Preferably, the rings of the projecting elements are spaced apart by a distance of between 2.5 cm to 0.5 cm and more preferably still by about 1.5 cm to 0.5 cm. It will be appreciated that the cover of the present invention may be constructed uniformly, that is to say that the projecting elements may all be of equal diameter, length, number in ring and evenly spaced apart rows of rings in a uniform manner. Alternatively, it is included within the scope of the invention that any one or more of these parameters may comprise a mixture of different parameters, that is to say that the cover may comprise projecting elements of differing diameters, lengths, numbers in rings and the rows of rings may be differentially spaced apart in a non-uniform manner. Preferably, the cover further comprises an over cuff. The over cuff is placed over the cover of the present invention. In the embodiments of the invention where the cover comprises slits or gaps, the over cuff is also provided with slits or gaps of the same dimensions as that of the cover so that the projecting elements are able to protrude through the aligned slits or gaps. Preferably, the over cuff is of the same or approximately same length as the cover. Preferably, the over cuff is constructed of a polycarbonate or the like. Preferably, the first ring of projecting elements, i.e. the most distal ring, is positioned between 1 to 20 mm from the distal end of the cover and more preferably it is positioned between 5 to 15 mm from the distal end. Preferably, in the instance of multiple rings the last ring of projecting elements, i.e. the most proximal ring, is positioned between 1.0 cm and 10.0 cm from the proximal end of the cover and more preferably it is positioned between 1.0 cm and 3.0 cm from the proximal end. Preferably, the cover is provided with one or more apertures positioned at the proximal end of the cover. The apertures are provided so that they may slot over the securing means of an applicator casing thereby holding the cover in position for receiving an enteroscope or endoscope into the hollow body of the elongate tubular member. More preferably, the cover comprises at least four apertures evenly spaced apart for securing the cover to the applicator casing prior to insertion of the scope into the cover. Preferably, the cover further comprises a viewing means mounted at its distal end. The viewing means is preferably a disposable transparent tubular open ended cap and may be in the form of a plastic or Perspex® cap attachment which can facilitate maintaining image focus and correct depth of field. The addition of a transparent plastic open ended cap can advantageously permit entry into the ileum. Preferably, the outer surface of the cover (i.e. the surface of the cover that is, in use, in contact with the patient's body cavity) is coated with a lubricating agent that may be a hydrophobic or hydrophilic agent. Suitable hydrophilic agents include, but are not limited to, hydrogel polymers such as poly(2-hydoxyethyl methacrylate) (PHEMA) and ComfortCoat®, suitable hydrophobic agents include, but are not limited to, silicone, glycerine, olive oil, castor oil, chlorotrifluoroethylene (CTFE oil) and polyphenyl ethers or a mixture thereof. Preferably, the lubricating agent is sprayed or brushed onto the outer surface of the cover and more preferably still, is coated only onto the distal end of the cover so that only the outer surface of distal end of the cover is coated leaving the proximal surface and under surface of projecting elements free of the lubricating agent thereby providing greater purchase on the surface of the body passage during extubation facing aspects e Preferably, the cover is detachable or removable from the endoscope/enteroscope. In use, the cover of the present invention is placed about the medical device shortly before insertion into the patient under investigation and is removed from the medical device once the examination/procedure has been completed. The cover of the present invention may then be disposed of. Preferably, the cover of the present invention is provided with the projecting elements along its length and especially when in position on a medical scoping device at its distal end. The main difficulty with performing colonoscopy is the anatomy. Some lengths of bowel are attached to loose mesentery rendering them mobile and subject to looping whilst other parts are fixed, often causing a sharp change of direction which leads to greater friction when trying to advance around the bend. Furthermore, depending upon the tightness of the bend, the tip of the colonoscope (or the flexed knuckle that has been induced at the end of the instrument to steer round the bend) abuts the side wall of the bend so that forward momentum induced by the endoscopist is directed in the opposite direction to the one desired preventing any advance and leading to trauma at the point of contact and increased looping in the mobile segment. Because there is an angle to be negotiated at these fixed points, forward vision may be lost as well. Until the acute bend has been negotiated pushing the colonoscope forward leads to the development of a loop in the mobile segment. This in turn creates tension on the mesentery causing pain, slowing the heart rate and lowering the blood pressure. Further attempts to “push round the loop” can lead to damage of the bowel both in the looped segment and at the tip of the colonoscope if its end is hard against the wall of the bowel. Advantageously, the projecting elements of the cover of the present invention provide an ease of movement around the relevant regions thereby reducing tension between the bowel surface and the instrument and allowing for the colon to be concertinaed behind the distal end. In the present invention the projecting elements are designed to open out when the scope is withdrawn from a patient and this creates a fan or spread of projecting elements that gently support the wall of the body passage and especially the colon. When the colon is tortuous, withdrawing the colonoscope draws the colon back, opening up the path ahead. Forward motion simply causes the hairs to collapse against the side of the sleeve so that they are in the so called second position and are substantially parallel to the longitudinal central axis of the scope accordingly the scope can be advanced without hindrance. In practice the technique of forward advancement and drawing back allows for rapid concertinaing of the colon behind the cover and also advantageously opens the way ahead so reducing loss of vision in the procedure especially when looping. Furthermore, it enables rapid advancement through a tortuous colon without losing position. As regards the suctioning effect or “wrap around” which is an entirely new concept in the field, suction of air draws the colonic wall into close apposition to the colonoscope wall, wrapping it around the cover and in between the projecting elements into the spaces therebetween. This in turn increases the backward friction and allows the colonoscope to be withdrawn, shortening and telescoping the proximal colon over the shaft whilst not allowing the distal end or tip to slip backwards. Yet further advantages of the cover of the present invention include close approximation of the colonic wall to the projecting elements or hairs enhancing tip grip, maintenance of distal tip position when reducing a proximal loop, straightening out the distal bowel tortuosity. It will be appreciated that the cover of the present invention may be used in conjunction with existing scopes and that no special modifications to scopes currently used in practise is required. In one aspect of the invention the applicator comprises two complimentary casings that engage together to form a hollow shell, the engaging means may be in the form of snap-fit male-female elements, clips or locks or the like the specifics of which are not intended to limit the scope of the invention. Preferably, the securing means of the applicator comprise rod like projections that engage with apertures provided at the proximal end of the cover, the apertures in the cover are sized and shaped so as to accommodate the rods therein. Thus, the apertures of the cover are placed over the rods to secure the cover within the casing or shell and then the medical device scope is inserted into the hollow space of the elongate tubular member. Preferably, the number of securing means (rods and apertures) are commensurate on the applicator and cover. Preferably, the applicator may further include an end cap that is slotted into position and held secure so that when the medical scoping device is inserted into the application its distal end abuts and engages with the end cap. Also included within the scope of the invention is a kit of parts comprising at least one cover having all the features as herein before described, a medical scoping device that includes an air suction means, an applicator for placing the cover about the scope and optionally a transparent open-ended cap held either within the applicator or attached to the cover itself. It will be appreciated that the cover of the present invention can be constructed with various diameters so that it may be used to fit over the shaft of existing medical scoping devices. For example, paediatric scoping devices comprise shaft diameters of around 11 mm whereas an adult scoping device shaft diameter is in the region of 12 mm, the cover of the present invention may be constructed with suitable diameters according to a user's requirements. The invention will now be described with reference to the Figures. FIG. 1 shows a cover (1) according to the present invention, the cover comprises a number of projecting elements (2) in the form of bristles, moulded at an acute angle with respect to the longitudinal axis of the cover to the outer surface (3) of the elongate tubular member. FIG. 1 shows the projecting elements in their resting position and the tips pointing towards the proximal end (6). The projecting elements (2) are moulded at their base to form a raised portion or bump (4). A small air pocket is formed beneath the raised portion or bump (4) on the inner surface (7) of the cover which allows for flexibility of the projecting elements about their base in use and especially when negotiating the confines of a body passage. As described herein before the projecting elements are angled, at rest in the so called first position, to around 45° to 65° towards the proximal end (6) of the cover and with respect to a central longitudinal axis of the cover and, in a forward or distal movement within a body passage once the endoscope or enteroscope has been inserted into the hollow (8) of the cover, the projecting elements are flattened so as to be approximately parallel to the said longitudinal axis with the projecting elements tips pointing towards the proximal end (6). This is the second position. The projecting elements are fanned out or expanded into a third position when the covered scope is withdrawn in a proximal movement. During this reverse movement the endoscopist can apply the air suction means to withdraw air from the body passage causing the body passage wall to partially collapse about the projecting elements (2) and be drawn into the spaces (3) between the individual projecting elements and the spaces between rings and rows of rings of projecting elements. In this way the wall of the body passage is gripped and wrapped around the cover, if further forward or distal movement is applied the body passage wall remains gripped by the projecting elements and effectively bunches up or concertinas in the proximal area thereby allowing the distal end to move forward and overcome the looping or bend obstacle. In some embodiments of the invention the projecting elements (2) are capable of flicking or flipping over past the critical point of maximum inflexion at 90° so that the tips point towards the distal end (5) in a so called fourth position, making withdrawal of the device through the relevant orifice more comfortable for the patient. Alternatively they may be flattened against the cover main body as depicted in FIG. 9B as described herein after. In use, in preliminary trials endoscopists have reported that the cover of the invention remains in position on the flexible medical scoping device shaft and that the projecting elements do not impede the periphery of the visual field. The projecting elements may be in form of bristles (FIG. 8A), fins or paddles (FIG. 8B), cones (FIG. 8C), bulbs, stalks or buds (FIG. 8D) or any other flexible projection (FIG. 8E). The projecting elements are provided in rings, typically of about 1 to 10 rings and more typically of two rings in uniform circumferential formation and evenly spaced apart with projecting elements being of a marginally shorter length in the first (distal end (5)) and last (proximal end (6)) rows. At the proximal end (6) the cover is provided with several apertures (16) which are capable of fitting over rods provided on the applicator. FIG. 2 shows a transverse section through the cover that has bristle type projecting elements. With regard to FIG. 3, the distal end (5) of the cover is seen in greater detail. The distal end comprises a head (14) and a profiled end region (9, 10) over which a transparent cap (13) may be placed and held in position by clips (11, 12) or the like. This distal region is the end that is furthest in the patient and provides the light and lens through which the endoscopist can observe the body passage. In some-embodiments of the invention the cap (13) is provided with the cover or may be placed in the applicator and the scope is inserted through the cover and caused to engage with the cap in situ. The end cap is an optional additional feature which can be provided if desired with either the cover or the applicator. In order to place the cover about an enteroscope or endoscope the cover is held in place within an applicator comprising a pair of casings (17, 18). FIG. 4 shows a disassembled applicator and the securing means (19) of the casings (17, 18) in the form of rods which are inserted into apertures (16) of the proximal end of the cover. Although not shown in FIG. 4 an end cap can be held in place at the distal end. In FIG. 5, the casings are fitted together by any suitable means and the cover held in position within the shell or casing. In order to fit the cover about a scope, the scope is inserted into the hollow (8) and pushed up into the casing towards the distal end (5) whilst the cover is secured about its proximal end (5) by means (16, 19). FIG. 6A shows a top view of an assembled casing and FIG. 6B shows a side view with the cover in place inside, FIG. 6C shows a top view of a disassembled applicator and cover, FIG. 6D shows a proximal end view with the apertures of the cover over the rods stretching the cover to form an interior space 20 through which the scope is inserted and FIG. 6E shows a distal end view with the viewing hole which may also include the end cap. In one aspect of the invention there is provided a kit of parts which may optionally include a viewing means attachment (20) optionally provided with a portal (21) for removing under suction any excess fluid (FIG. 7). As mentioned herein before, in some embodiments of the invention the projecting elements are not configured to adopt the fourth position where the tip ends are pointed in a distal direction following a flip over past the critical point at maximum inflexion. In such embodiments, the cover is provided with a projecting element closure means (23) typically in the form of a sleeve (FIGS. 9A and 9B). To close the projecting elements, in order that the scoping medical device can be comfortably withdrawn out of the orifice into which it was inserted, the projecting elements closure means is pulled over the projecting elements by a cord or line or string (24) so that sleeve (23) unfurls in a proximal direction over the projecting elements (2) thereby flattening them against the scope shaft (E). Once flattened (FIG. 9B) the scope can be withdrawn from the patient. In an alternative embodiment of the invention the cover is provided with slits or gaps (28) running in a longitudinal direction and between the distal (A) and proximal (B) regions of the cover, in this embodiment the cover is also provided with an over cuff (25). The over cuff itself is also provided with slits or gaps (30) between its proximal and distal ends that are of approximately commensurate dimensions as the slits or gaps in the cover so that, when the over cuff is placed over the cover, the slits or gaps in both the cover and over cuff are aligned, providing continuous spaces (29) through both items whilst at each of the distal (A) and proximal (B) ends the cover and over-cuff have continuous rings (31 and 32). The slits or gaps through which projecting elements can protrude are spaces (29) defined by adjacent strips of the cover (28) and over cuff (30) between the proximal and distal ends. FIG. 10A shows a plan view of a cover and over cuff (25). The over cuff has a snug fit over the cover and is typically constructed of a polycarbonate or other plastics material, projecting elements (2) protrude outwardly between strips (26) of the over cuff and at the distal tip the over cuff it marginally overlaps the cover providing a rim (27) around hollow (8). At the proximal end of the cover and over cuff (FIG. 10B), the differential lengths of projecting elements can be seen, the longer elements (2A) at the distal end project beyond the shorter elements (2B) at the proximal end by between 2-4 mm. Each projecting element protrudes between the slits or gaps (29) defined by the strips (26 and 28) of the over cuff and cover respectively. FIGS. 11A through to 11D show various views of the cover and over-cuff of the present invention and FIG. 11E shows the cover and over cuff arrangement when placed over the distal end shaft (33) of a medical scoping device. In use, as depicted in the series of FIGS. 12A to 12D, the medical scoping device distal tip with the cover and over cuff (3, 25) is inserted via the anus (34) into the colon of an individual under investigation. On inserting the medical scoping device, cover and over cuff into the patient the projecting elements are moved from an at rest position, referred herein before as the first position to a second position where they are flattened towards the medical scoping device shaft the so called second position (FIG. 12A). The distal end tip of the medical scoping comprises a channel (37) through which a light source, image relaying mean and air suction is supplied. During intubation, the projecting elements are designed to collapse into the device during insertion through the anus. This exposes the smooth low friction surface of the cover and over cuff to the mucosa to aid intubation. Negotiating the sigmoid loop is improved by at least one or two rows of projecting elements that offer different functions depending on the requirement of the endoscopist. The longer distal hairs are soft and slightly everted so that they gently grip the mucosa to maintain tip position when the endoscope is straightened “soft grip”. When complex loops form and there is a need for stronger grip at the tip to enable their reduction, conventional suction draws the colon close to the surface of the cover creating “wrap around”. The colonic mucosa envelopes the proximal shorter projecting elements providing a tight hold while the colonoscope is shortened to enable the bowel to concertina over the shaft of the endoscope without tip slide-back. “Wrap around” avoids the use of acute tip deflection to maintain tip position and reduces the need to torque. Endoscopists report that both techniques are intuitive and simple to perform. Straightening a looped endoscope without losing tip position or vision advantageously potentially reduces time to caecum and patient discomfort. In the course of preliminary trials with the device of the present invention, endoscopists have reported no impediment to intubation and a greater amount of exposure of mucosa in the sigmoid area during withdrawal. The flexible shaft (33) of the medical scoping device is advanced in a distal direction through the colon towards the bend or loop region (36) of the of the colon (FIG. 12B) whilst insufflatting the colon immediately forwards of the distal tip. The projecting elements once passed the anus revert to their resting first position. As the scope passes further up the colon and encounters the loop region the projecting elements engage with the colon wall in a soft grip (third position where the projecting elements fan out and the endoscopist can perform a controlled proximal withdrawal flattening the colonic folds for good visualisation (FIG. 12C). As regards improved visualisation, the distal row of longer projecting elements is designed to open the colonic lumen for close inspection. Viewing the proximal surface of the colonic folds is difficult and time consuming. The projecting elements of the cover of the present invention act to gently open and flatten the colonic folds for inspection during withdrawal, endoscopists report that the cover of the present invention provides distinct improvements. Improved visualisation is important for identifying small pre-malignant and malignant lesions that might be tucked out of sight when performing conventional endoscopy. Visualisation is further enhanced when using the cover of the present invention, especially with wide vision endoscopes. As mentioned herein before two of the significant disadvantages associated with colonoscopy and scoping procedures is firstly that the natural folds of the colon wall hamper the colonoscopist's ability to visualise the entire surface of the mucosa and secondly in maintaining and controlling position of the distal tip during the procedure. These two difficulties are resolved as follows: For improved visualisation, the projecting elements gently open the lumen and evert thereby flattening the colonic folds for inspection during withdrawal. Visualisation is further enhanced as the colonic folds slowly revert to their normal anatomical position permitting light to play across the mucosa, thus enabling careful visualisation of the surface of the mucosa that was hitherto hidden or difficult to view. As regards, tip position control, the projecting elements of the device gently stabilise the tip of the scoping device within the lumen of the colon or small intestine immediately prior to and during therapeutic procedures. This has the advantage of permitting the endoscopist the reassurance that the tip will remain in position from the stage of visualising a lesion or polyp until completion of the therapeutic procedure. In use, the distal row of the projecting elements are designed to flare outwards on withdrawal. They keep the instrument tip in the central part of the bowel lumen as the instrument moves backwards, gently holding the mucosa to prevent the tip from flipping backwards, they maintain position during therapy and improve all-round visualisation. During extubation they evert the folds enabling their proximal surface to be viewed. In order to negotiate the loop or bend the endoscopist can apply air suction so that the colon wall (38) collapses onto the shaft (3) and into the spaces between adjacent rings of projecting elements (39), the projecting elements still being in the third position (FIG. 12D). The colon wall concertinas about the shaft (3) and the endoscopist can then cease suction so that the colon wall straightens and the scope can be further advanced. On withdrawing the scope especially through the anus the projecting elements can flip over to the fourth position so that the scope can be comfortably withdrawn. During controlled tip withdrawal, the cover of the present invention is designed to provide controlled extubation. During conventional withdrawal there is a tendency for the colonoscope tip suddenly to slip backwards. This happens especially when passing a bend or flexure and the “missed” area then has to be re-intubated, sometimes with the creation of a painful loop. The long, soft, distal projecting elements of the present invention prevent sudden tip slippage and hold the tip in the centre of the colonic lumen providing both control and good visualisation as the endoscope is withdrawn.
<SOH> BACKGROUND <EOH>In endoscopic examinations/procedures, flexible instruments designed to view the gastro-intestinal tract are inserted along a body cavity to an internal part such as the stomach, duodenum, small intestine or large intestine. The instruments are provided with fibre-optic or charge-couple device (CCD) cameras which enable images to be transmitted around bends and images to be produced to displays on a television screen. Accordingly, it is possible to view the inside surfaces of the oesophagus, stomach and duodenum using a gastroscope, the small intestine with an enteroscope, part of the colon using a flexible sigmoidoscope and the whole of the large intestine (the bowel) with a colonoscope. Enteroscopy is the endoscopic examination of the small intestine whereas colonoscopy is the endoscopic examination of the colon and the distal part of the small bowel and flexible sigmoidoscopy is the examination of the rectum and lower part of the bowel. Each scoping procedure may provide a visual diagnosis (e.g. ulceration, polyps) and grants the opportunity for biopsy or removal of suspected lesions. Whilst colonoscopic and enteroscopic examinations are the most effective techniques to assess the state of health of the bowel, they are inconvenient, uncomfortable, expensive procedures that are associated with significant risks of potentially serious complications. The most common complications are: failure to achieve a complete examination (5-10%); failure to detect a polyp (up to 20%); reaction to intravenous drugs; over-sedation leading to hypoxia and cardio-vascular collapse; splenic injury (rare); bowel perforation, (1 in 500-1500); full thickness burn (uncommon) and; bleeding following polypectomy. A further disadvantage of colonoscopic and enteroscopic procedures is that they are time consuming for patients and medical personnel alike, the procedure can take anywhere from 20 minutes to 2 hours depending on how difficult it is to advance a scope through the colon or small intestine. The colonoscopy itself takes around thirty minutes to perform but in some cases may require up to an hour, and for the patient, there is a recovery period of up to two hours in hospital whilst sedation passes off and over that time clinical observation is needed. Typically, the number of clinically competent personnel required to conduct a colonoscopic procedure are an endoscopist specialist and three assistants including the person responsible for reprocessing the equipment. In addition, staffing is required for the recovery area. Two yet further additional significant difficulties associated with colonoscopy and scoping procedures more generally are as follows: Firstly, the anatomy of the colon is such that the lining is thrown into folds. As the tip of the endoscope passes along the lumen of the colon, these folds hamper the endoscopist's ability to visualise the entire surface of the mucosa and in particular, detect pre-malignant and malignant lesions tucked away on the proximal face of these folds during extubation. Secondly, the position of the tip of may be difficult to maintain from the moment at which a lesion or polyp is detected to the completion of any therapeutic procedure. As the colonoscope is withdrawn the tip does not travel back at a constant speed but rather with jerks and slippages particularly when traversing a bend or length of colon where the bowel has been concertinaed over the endoscope shaft during intubation. The tip of the device may, at any moment, slip backwards thereby causing the clinician to lose position. If tip position is lost, the clinician is required to relocate the lesion or polyp for the therapeutic procedure to be continued. The colonoscopic procedure is not simple because the bowel is long and convoluted. In places it is tethered by peritoneal bands and in others it lies relatively free. When the tip of the endoscope encounters a tight bend the free part of the colon “loops” as more of the endoscope is introduced and so looping occurs in the free part of the colon before the bend when there is difficulty negotiating the bend. This leads to stretching of the mesentery of the loop (the tissue that carries the nerves and blood vessels to the bowel). If the stretching is continued or severe while the endoscopist pushes round the bend, the patient experiences pain the blood pressure falls and the pulse slows. Loop formation is the main cause of failure or delay in completing an examination. It is responsible for the pain experienced by the patient and the need for heavy sedation that in turn leads to cardio-respiratory complications. It is also the major cause of perforation in patients not undergoing a therapeutic procedure. Attempts have been made to try to overcome the problems associated with colonoscopic procedures, for example, it is known in the prior art to provide endoscope sheaths having differential frictional resistance provided by very small external protrusions such as wedge-shaped profiles or scales so there is low frictional resistance during forward movement of the covered endoscope shaft through a body cavity and a greater frictional resistance during its rearward movement. In practice however little improvement is achieved in overcoming looping. It is also known from the prior art to use a double balloon enteroscope or an Aer-O-Scope™. The double balloon enteroscope requires a substantial amount of additional kit, a high level of operator skill in timing the sequential inflation and deflation of the balloons and moreover it is a lengthy procedure sometimes taking hours. The Aer-O-Scope™ provides low pressure colon insufflations with CO 2 to propel the balloon along “slippery” colon walls without forceful manoeuvring but cannot be used for biopsy or therapy. Despite the forgoing drawbacks, for the foreseeable future colonoscopy will remain the procedure of choice for the examination of the large bowel. Newer methods for the detection of polyps and cancer using non-invasive technology may be identified but to obtain biopsies, remove polyps and to treat intra-colonic lesions no alternatives have appeared to date. An improved medical scoping device that could reduce the time taken for the colonoscopist or enteroscopist to perform the procedure would offer immediate advantages to patients and clinicians alike. An improved medical scoping device that could reduce the risk of complications during a procedure would offer immediate advantages to patients and clinicians alike. A medical scoping device that could improve endoscopic intubation, extubation and visualisation of the large bowel would offer immediate advantages to both patients and clinicians alike. A medical scoping device that could reduce loss of tip position during a medical procedure would offer immediate advantages to both patients and clinicians alike. An improved medical scoping device that could reduce the requirement or level of sedation for a patient would offer immediate advantages to both patients and clinicians alike. An improved medical scoping device that could overcome the problems associated with looping and so reduce discomfort to the person on whom the procedure was being performed, would offer immediate advantages to patients and clinicians alike.
<SOH> BRIEF SUMMARY OF THE DISCLOSURE <EOH>According to a first aspect of the present invention there is provided a cover for a medical scoping device shaft, the cover comprising an elongate tubular member and being arranged for application over the medical scoping device shaft with the cover extending along at least a part of the length of a distal end of the shaft, the tubular member comprising an inner surface at least a part of which grips the shaft and acts to hold the cover in place and an outer surface comprising a plurality of spaced projecting elements having a tip and a base that are moveable between a resting position to a position wherein the tip of the projecting element is substantially parallel to a longitudinal axis of the medical scoping device and to a position that is at an angle that is approximately perpendicular to the longitudinal axis of the medical scoping device shaft so that the said projecting elements are fanned out to contact with and provide support for and to dilate a lumen wall of a body passage into which the medical scoping device has been inserted. According to a second aspect of the invention there is provided a medical scoping device comprising an air suction means for removing air from a body passage, an elongate flexible shaft having a proximal end associated with a viewing means and a distal end, the medical scoping device further comprising the cover of the first aspect of the invention releasably attached thereto and covering at least a part of the shaft at its distal end. According to a third aspect of the invention there is provided a cover according to a first aspect of the invention or a medical scoping device of the second aspect of the invention for use in a scoping procedure. According to a fourth aspect of the invention there is provided an applicator for attaching a cover to a shaft of a medical scoping device, the applicator comprising a pair of complimentarily mated casings each sized and shaped so as to accommodate a cover for a medical scoping device therein, each casing further comprising an engaging means for releasably engaging the casings to one another and each casing comprising at least one securing means for securing a proximal end of the said cover thereto. According to a fifth aspect of the invention there is provided a kit comprising at least one cover according to the first aspect of the invention and an applicator according to the fourth aspect of the invention, optionally the kit further includes a medical scoping device and/or a cutting means and/or a distal end cap. According to a sixth aspect of the invention there is provided a method of avoiding looping in a medical scoping procedure, the method comprising inserting a medical scoping device shaft having an air suction means for removing air from a body passage into an orifice of an individual under investigation, the medical scoping device further comprising a cover releasably attached to the medical scoping device shaft and covering at least a part of the shaft at its distal end, wherein the cover comprises an elongate tubular member having an inner surface at least a part of which grips the shaft and acts to hold the cover in place and an outer surface comprising a plurality of spaced projecting elements, and wherein when advancing the medical scoping device into the patient's bowel or small intestine and the distal end encounters a bend or loop in the patient's bowel or small intestine, the medical scoping device is withdrawn towards its proximal end causing the projecting elements to splay or fan out and to dilate the lumen of the bowel or small intestine whilst holding the medical scoping device in position, if necessary air is then drawn out causing the body passage walls to collapse around and about the projecting elements thereby drawing the body passage wall into spaces between the projecting elements so said projecting elements engage with and grip the body passage wall, the medical scoping device is then further withdrawn towards the proximal end causing it to straighten and the body passage wall to concertina along the shaft of the scope proximal to the bend or loop whilst the lumen ahead of the distal end opens up, the medical scoping device is then advanced towards its distal end and the bend or loop is navigated. According to a seventh aspect of the invention there is provided a method of improving endoscopic visualisation, the method essentially comprising the steps of the sixth aspect of the invention wherein the projecting elements open a lumen and evert thereby flattening colonic folds for inspection during withdrawal whereby visualisation is further enhanced as colonic folds revert to their normal anatomical position permitting light from the medical scoping device to play across the mucosa, thus enabling careful visualisation of the surface of the mucosa that was hitherto hidden or difficult to view. According to an eighth aspect of the invention there is provided a method of maintaining tip position and improving tip control during an examination, the method essentially comprising the steps of the sixth aspect of the invention wherein the projecting elements maintain the medical scoping device tip in a central part of the bowel lumen as the device moves in a proximal direction thereby holding the mucosa to prevent the tip from flipping backwards so as to maintain position during therapy.
A61B100135
20170915
20180111
92216.0
A61B100
1
FAIRCHILD, AARON BENJAMIN
COVERING FOR A MEDICAL SCOPING DEVICE
UNDISCOUNTED
1
CONT-ACCEPTED
A61B
2,017
15,705,703
PENDING
EMBEDDING DIGITAL CONTENT WITHIN A DIGITAL PHOTOGRAPH DURING CAPTURE OF THE DIGITAL PHOTOGRAPH
A wireless communication device comprises position determining system, a digital imaging system and a photograph customization system coupled to the position locating system and the digital imaging system. The position determining system is configured to provide information indicating a current position of the wireless communication device. The digital imaging system is configured to create digitally rendered images of visual content acquired thereby. The visual content is displayed on an image viewing structure of the digital imaging device while being acquired. The photograph customization system is configured to use the current location of the digital imaging device for providing one or more embeddable content images and to display information from at least one of the one or more embeddable content images on an image viewing structure of the digital imaging device while the visual content being acquired by the digital imaging system is being displayed on the image viewing structure.
1. (canceled) 2. (canceled) 3. (canceled) 4. (canceled) 5. (canceled) 6. (canceled) 7. (canceled) 8. (canceled) 9. (canceled) 10. (canceled) 11. (canceled) 12. (canceled) 13. (canceled) 14. (canceled) 15. (canceled) 16. (canceled) 17. A computer-implemented method performed by a wireless communication device, comprising: receiving a request to embed system-provided content into a photograph to be taken at a current location of the wireless communication device using a digital imaging device of the wireless communication device; receiving one or more embeddable content images responsive to the receipt of the request to embed; selecting one of the one or more of the one or more embeddable content images; displaying the selected one or more embeddable content images on an image viewing structure of the wireless communication device; displaying visual content captured in real-time by the digital imaging device on the image viewing structure in combination with the selected one or more embeddable content images, wherein displaying the selected one or more embeddable content images comprises maintaining the selected embeddable content image within an area of the image viewing structure independent of the visual content that is being captured in real-time by the digital imaging device such that the selected one or more embeddable content images remains displayed on the image viewing structure irrespective of the visual content being captured by the digital imaging device, and wherein the selected one or more embeddable content images are displayed as a mask over the visual content that is being captured in real-time by the digital imaging device; and outputting from the wireless communication device a visual image data structure comprising a photograph, wherein the photograph comprises the selected one or more embeddable content images and portions of said captured real-time visual content that are visible on the image viewing structure through the mask. 18. A computer-implemented method performed by a wireless communication device, said wireless communication device including a digital imaging device and image viewing structure, said method comprising: receiving a request to embed a system-provided embeddable content image with an image to be captured by said digital imaging device at a location of said wireless communication device; receiving an embeddable content image responsive to said receiving a request to embed; displaying in an area of said image viewing structure said embeddable content image; maintaining said embeddable content image in a static position in said area of said image viewing structure; and displaying in combination in said image viewing structure a combined visual image comprising: a captured image provided from said digital imaging device in real time at the location; said embeddable content image displayed as a mask over said captured image. 19. The computer implemented of claim 18, further comprising: in said displaying, selectively positioning said captured image relative to said embeddable content image. 20. The computer implemented of claim 19, further comprising: in said displaying, said captured image selectively positioned relative to said embeddable content image by said digital imaging device framing said captured image when said captured image is taken. 21. The computer implemented of claim 18, further comprising: in said displaying, said embeddable content image maintained in said static position without reference to visual content of said captured image. 22. The computer implemented of claim 18, further comprising: generating a digital file comprising said combined visual image. 23. The computer implemented of claim 22, further comprising: said combined visual image comprising said embeddable content image and a portion of said captured image visible in the image viewing structure through the mask. 24. The computer implemented of claim 18, further comprising: selecting the embeddable content image from a plurality of embeddable content images received responsive to said receiving a request to embed. 25. (canceled) 26. (canceled) 27. A computer-implemented method performed by a wireless communication device having a digital imaging device and image viewing structure, said method comprising: displaying in combination in said image viewing structure a combined visual image comprising: a captured image provided from said digital imaging device in real time at a location of taking a photograph; an embeddable content image provided by said wireless communication device, said embeddable content image displayed as a mask over said captured image, said embeddable content image maintained in a static position in said image viewing structure during the taking of the photograph. 28. A computer-implemented method performed by a wireless communication device, having a digital imaging device and image viewing structure, said method comprising: receiving, by said wireless communication device, an embeddable content image; maintaining said embeddable content image in a static position in said image viewing structure when taking a captured image by the digital imaging device; and displaying in combination in said image viewing structure a combined visual image comprising: said embeddable content image in said static position displayed as a mask over said captured image; said captured image provided from said digital imaging device in real time when taken by the digital imaging device, the captured image selectively positioned relative to said embeddable content image. 29. The computer-implemented method of claim 28, further comprising: in said displaying, said embeddable content image maintained in said static position in said image viewing structure without reference to visual content of said captured image. 30. The computer-implemented method of claim 28, further comprising: generating a digital file comprising said combined visual image. 31. The computer-implemented method of claim 30, further comprising: said digital file further comprising said combined visual image including said embeddable content image in combination with said captured image as displayed in said image viewing structure. 32. The computer-implemented method of claim 28, further comprising: said embeddable content image provided by said wireless communication device in relation to a location of said wireless communication device where the captured image is to be taken by said digital imaging device. 33. The computer-implemented method of claim 28, further comprising: said embeddable content image received by said wireless communication device in relation to the location of said wireless communication device when the captured image is taken by said digital imaging device. 34. The computer-implemented method of claim 28, further comprising: said embedded content image selected from a plurality of embedded content images provided by said wireless communication device. 35. The computer-implemented method of claim 28, further comprising: said embeddable content image selected from a plurality of embeddable content images received by said wireless communication device in relation to the location of said wireless communication device when taking the captured image. 36. The computer-implemented method of claim 28, further comprising: the embeddable content image displayed as a mask over said captured image filtering a portion of said captured image visible in said combined visual image. 37. (canceled) 38. (canceled)
CROSS REFERENCE TO RELATED APPLICATIONS This continuation patent application claims priority from co-pending United States Non-provisional Patent Application having Ser. No. 14/251,707, filed 14, Apr. 2014, entitled “Embedding digital content within a digital photograph during capture of the digital photograph”, which have a common applicant herewith and is being incorporated herein in its entirety by reference. United States Non-provisional Patent Application having Ser. No. 14/251,707, filed 14, Apr. 2014, entitled “Embedding digital content within a digital photograph during capture of the digital photograph” claims priority from Provisional Patent Application having Ser. No. 61/966,161, filed 15, Feb. 2014, entitled “Viewfinder watermark technique is a new WYSIWYG (What You See Is What You Get) method for embedding an electronic digital watermark/image within a users live camera lens/window viewer whether the lens is a digital screen or eyepiece. This method occurs prior to the user taking a photo. In addition, this method would be internal to the device process whether it was on a camera or smart phone or hand held device. When user snaps/takes photo, what was seen in the live viewer with embedded image becomes the same image in a digital photo's output file; therefore, when comparing what was seen in the camera viewer with the digital photo file or printed photo, the result is WYSIWYG (What You See Is What You Get)”, both of which have a common applicant herewith and are being incorporated herein in their entirety by reference. FIELD OF THE DISCLOSURE The disclosures made herein relate generally to digital photography solutions and, more particularly, to embedding digital content within a digital photograph during capture of the digital photograph. BACKGROUND Digital photography, like traditional film photography, is widely used for memorializing events and moments. With the advent of social media and wireless communication, it has become common place for people to use digital photographs as an integral part of their social networking endeavors such as through posting of pictures on their on-line social network page. This is due in no small part to the inclusion of digital cameras in wireless communication devices (e.g., smartphones, tablets, etc) and the affordability of digital cameras. As such, ever increasing numbers of people are now taking photographs as a routine part of their daily lives whether it be for personal enjoyment and entertainment, to share with friends and family, or both. Unlike traditional film photography, digital photography offers the ability to immediately view, edit and share photographs. This being the case, people have an expectation that their digital imaging solution offer them various approaches for enhancing their digital photographs though contextualization (e.g., editing a label into the photograph after it is taken) and/or customization (e.g., editing a border, special effect, etc into the photograph after it is taken). However, these post-capture approaches for enhancing their digital photographs often contribute to photos not being shared or added to an album because one or more separate process must performed after taking the photograph to achieve such contextualization and/or customization. Therefore, enabling such contextualization and/or customization to be performed in combination with taking a photograph is advantageous, desirable and useful. SUMMARY OF THE DISCLOSURE Embodiments of the present invention are directed to a system-implemented solution (e.g., an internal process of a digital imaging device) for enabling personalization (e.g., via contextualization and/or customization) to be performed in combination with taking a photograph with a digital imaging device. A digital camera, a smartphone camera, and a tablet are examples of a digital imaging device that can be configured in accordance with an embodiment of the present invention. More specifically, embodiments of the present invention are directed to displaying an embedded digital image (e.g., an electronic digital icon (e.g., watermark), picture, text, or the like) within an image viewing structure (e.g., eyepiece, visual display, or the like) of a digital imaging device prior to and during a photograph being taken using the digital imaging device. Accordingly, when a user of such a digital imaging device takes the photograph, as-viewed visual content seen within the image viewing structure (i.e., the embedded digital image overlaid on to-be-photographed visual content) is the same as what would be a corresponding outputted digital file of the imaging device. In this regard, the corresponding outputted digital file is a ‘What You See Is What You Get (WYSIWYG)’ representation of the as-viewed visual content within the image viewing structure of the imaging device when the to-be-photographed visual content is captured by the digital imaging device. Advantageously, the embedded digital image can be selected based on an actual location of the digital imaging device at the time when the to-be-photographed visual content is captured using the digital imaging device (i.e., the current location of the digital imaging device). In one embodiment of the present invention, a computer-implemented method comprises a plurality of operations. An operation is performed for receiving a request to embed system-provided content into a photograph to be taken using a digital imaging device. An operation is performed for providing, dependent upon a current location of the digital imaging device when the request is received, one or more embeddable images. An operation is performed for displaying, on an image viewing structure of the digital imaging device, the one or more embeddable content images in combination with visual content being viewed by the digital imaging device. In another embodiment of the present invention, a wireless communication device comprises position determining system, a digital imaging system and a photograph customization system coupled to the position locating system and the digital imaging system. The position determining system is configured to provide information indicating a current position of the wireless communication device. The digital imaging system is configured to create digitally rendered images of visual content acquired thereby. The visual content is displayed on an image viewing structure of the digital imaging device while being acquired. The photograph customization system is configured to use the current location of the digital imaging device for providing one or more embeddable content images and to display information from at least one of the one or more embeddable content images on an image viewing structure of the digital imaging device while the visual content being acquired by the digital imaging system is being displayed on the image viewing structure. In another embodiment of the present invention, a non-transitory computer-readable medium has tangibly embodied thereon and accessible therefrom processor-executable instructions that, when executed by at least one data processing device of at least one computer, causes the at least one data processing device to perform a method for generating a photo. Generating the photo comprises a plurality of operations. An operation of receiving a request to embed system-provided content into a photograph to be taken using a digital imaging device is performed. An operation of providing one or more embeddable images dependent upon a current location of the digital imaging device when the request is received is performed. An operation of displaying the one or more embeddable content images on an image viewing structure of the digital imaging device in combination with visual content being viewed by the digital imaging device is performed. These and other objects, embodiments, advantages and/or distinctions of the present invention will become readily apparent upon further review of the following specification, associated drawings and appended claims. BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1A and 1B are a flow diagram showing a system-implemented method configured in accordance with an embodiment of the present invention. FIGS. 2A-2H are diagrammatic views showing various aspects of a smartphone application configured in accordance with an embodiment of the present invention. FIG. 3 is a diagrammatic view showing a watermark image configured in accordance with an embodiment of the present invention. FIG. 4 is a diagrammatic view showing a watermark registration form configured in accordance with an embodiment of the present invention. FIG. 5 is a diagrammatic view of a computer system configured in accordance with an embodiment of the present invention. DETAILED DESCRIPTION FIGS. 1A and 1B are a flow diagram showing an embodiment of a system-implemented method (i.e., method 100) for embedding digital content within a digital photograph during capture of the digital photograph. It is disclosed herein that the embedded digital content can be that in the form of an icon, a logo, a string of text/numerals, a picture, a photograph, and/or the like (i.e., generally refereed to herein as a watermark). In this regard, embodiments of the present invention are not limited to any particular type of embedding digital content. Furthermore, although the method steps described herein are discussed in a particular order, one of skill in the art will recognize that many method steps can be carried out in a different order and overlap in time without departing from the spirit of this disclosure. The method 100 of FIG. 1 provides for customization of a photograph through embedding supplemental content (i.e., embedded digital content) into a photograph being taken using the digital imaging device. Advantageously, the embedded digital content is displayed within an image viewing structure (e.g., eyepiece, visual display, or the like) of the digital imaging device prior to and during the photograph being taken thereby ensuring desired framing of the photographed visual content with respect to the embedded digital content. To this end, the embedded digital content is maintained at a static position within an area of the image viewing structure. Accordingly, when the photograph is taken, as-viewed visual content seen within the image viewing structure includes the embedded digital content merged (e.g., overlaid onto) to-be-photographed visual content such that what is seen is the same as what would be a corresponding outputted digital file of the imaging device (i.e. the outputted photograph). Furthermore, the embedded digital content is advantageously selected based on an actual location of the digital imaging device at the time when the to-be-photographed visual content is captured using the digital imaging device. The method 100 is preferably implemented via an application (or operating system) of a digital imaging device such as, for example, the smartphone 200 shown in FIGS. 2A-2G. A smartphone and similarly capable types of tablets, notepads and cameras are each an example of a data processing system in the context of embodiments of the present invention. An Apple iPhone brand cellular telephone and a cellular phone with an Android brand operating system are examples of smart phones. It is disclosed herein that embodiments of the present invention are not limited to any particular brand, form or configuration of data processing system. The method 100 begins with an operation 102 for activating a camera (e.g., a digital camera, a camera or a smartphone, a camera of a tablet or the like), followed by an operation 104 for receiving a request for the addition of a watermark (i.e., embedded digital content) to a photo to be taken. As shown in FIG. 2A, the visual content that is being viewed by the camera of the smartphone 200 is displayed within a respective area 202 of a visual display 204 (i.e., image viewing structure) of the smartphone 200. The request for the addition of the watermark to the photograph to be taken can be implemented through the pressing of an ‘Add Watermark’ button 206. After receiving the request for the addition of the watermark, an operation 106 is performed for determining if a default watermark source has been selected. For example, if not previously selected such as upon an initial implementation of the method 100 on the smartphone 200, the default watermark source may need to be selected from a plurality of available watermark sources. If it is determined that the default watermark source has not been selected, an operation 108 is performed for displaying available watermark sources, followed by an operation 110 being performed for receiving a selected default watermark source. After receiving the default watermark source, or if the default watermark source has already been selected, an operation 111 is performed for determining the source of watermarks (i.e., the default watermark source). As shown in FIG. 2B, selection of a preferred watermark source can include be implemented via the visual display 204 of the smartphone 200 through selection of a button 208 for choosing location-based watermarks (e.g., as determined through use of a global positioning system to determine a current location of the smartphone 200) as the default watermark source, through selection of a button 210 for choosing user-provided textual watermarks (e.g., provided though manual entry of text by a user) as the default watermark source, or through selection of a button 212 for choosing user-imported watermarks as the default watermark source. If it is determined that the source of watermarks is manually entered watermark information (e.g., user-provided textual watermarks, user-imported watermark, or the like), an operation 112 is performed for requesting the watermark information (e.g., text or imported watermark file), followed by an operation 113 being preformed for receiving the requested watermark information. Thereafter, an operation 114 is performed for creating the selected watermark image using the received watermark information. For example, if the manually entered watermark information specifies a text string (e.g., All Season Nursery Mandeville, La.), a watermark image is created by instantiating a watermark image template 300 with the watermark information, as shown in FIG. 3. As can be seen, in preferred embodiments, the watermark image template 300 includes an watermark content portion 302 (i.e., an optically opaque portion of the watermark image) in which watermark information is located and a captured image portion 304 (i.e., an optically transparent portion of the watermark image) in which visual content captured by a digital imaging device is located. As discussed below in greater detail, the optically transparent portion of the watermark image allows a portion of an image in a background layer to be visible through the optically transparent portion of the watermark image. In preferred embodiments of the present invention, the watermark image (e.g., a captured visual content portion thereof) is in exact proportion to exterior dimensions (e.g., aspect ratio) of display area size for visual content being viewed using the digital imaging device. The watermark image is displayed as a foreground image and the visual content being viewed using the digital imaging device is displayed as a background image. The matching proportions of the watermark image to the exterior dimensions of the visual content display area ensure that the watermark image is aligned with a resulting image captured by the digital imaging device (i.e., as-viewed visual content is framed within the optically transparent portion of the watermark image in the same manner as viewed on the visual display when the photo is taken). If it is determined that the source of watermarks is a location-based watermarks (i.e., not manually entered), an operation 116 is performed for determining available location-based watermark selections. In the context of the present invention, a location-based watermark refers to a watermark associated with a location that is within a prescribed distance from a current location of a digital imaging device performing the method 100. For example, such location can be determined through use of a location service of the digital imaging device. For example, a current location of the phone can be determined by a global positioning functionality of a smartphone, a tablet, a digital camera, or the like). Location-based watermarks can be registered or unregistered. In the case of registered watermarks, determining the available location-based watermarks includes determining a current location of the digital imaging device and using such location to retrieve available registered watermarks from a database of registered watermarks (e.g., those that are within a prescribed distance from the current location of the digital imaging device). In the case of unregistered watermarks, determining the available location-based watermarks includes determining a current location of the digital imaging device and using such location to retrieve entries from a database of entries (e.g., places/destinations) searchable by their global positioning system coordinates (e.g., those having global positioning system coordinates that are within a prescribed distance from the current location of the digital imaging device). After determining the available location-based watermark selections, an operation 118 is performed for displaying the available location-based watermark selections. As shown in FIGS. 2C and 2D, for example, a list of available registered watermarks 216 can be provided on a first location-based watermark page displayed in response to selection of a registered watermarks display button 217 and a list of available unregistered watermarks 218 can be provided on a second location-based watermark page displayed in response to selection of an unregistered watermarks display button 219. It is disclosed herein that additional information can be garnished by each one of the watermark selections. In one example, hovering over a particular one of the watermark selections causes supplemental information about it to be displayed and the particular one of the watermarks is chosen by clicking/tapping on it. In another example, clicking on a particular one of the watermark selections causes supplemental information to be displayed and the particular one of the watermark is chosen by clicking/tapping on a choose this watermark selection′ button that is displayed in conjunction with the supplemental information. In preferred embodiments of the present invention, registered watermarks are maintained in a database of registered watermarks that have respective location defining information associated therewith. For example, as shown in FIG. 4, a watermark registration form 400 enables watermark registration information to be provided to a system that manages registered watermarks (e.g., embedded image management server). Examples of the watermark registration information includes, but is not limited to, a watermark title 402, a watermark image file 404, one or more social media content identifiers 406 (e.g., a hash tag, a handle identifier, or the like), global positioning coordinates 408, and a physical street address 410. As shown in FIG. 1A, after the available location-based watermark selections are displayed, an operation 120 is performed for receiving a chosen one of the available location-based watermark selections. The chosen one of the available location-based watermark selections can correspond to a registered watermark or to an unregistered watermark. If the chosen one of the available location-based watermark selections corresponds to a registered watermark, an operation 122 is performed for downloading a watermark image (e.g., in the form of a file of digital information) corresponding to the chosen one of the available location-based watermark selections. Otherwise, the chosen one of the available location-based watermark selections corresponds to an unregistered watermark, which results in an operation 124 being performed for creating a watermark image using information associated with the unregistered watermark selection (e.g., name of establishment at associated location, address of location, etc), as discussed above in reference to FIGS. 2D and 3. In preferred embodiments, the watermark image created using the information associated with the unregistered watermark selection can be created in the same manner as discussed above in reference to FIG. 3. In view of the disclosures made herein, a skilled person will appreciate that the watermark selection process discussed above can be implemented a plurality of times for embedding more than one watermark into a photograph (e.g., at different locations of the photograph). After downloading or creating the watermark image, an operation 126 is performed for capturing viewed visual content (i.e., the captured visual content). Capturing the viewed visual content refers to causing visual content that is currently being viewed by the digital imaging device at a particular instant to be captured as a digital record (e.g., file). For example, capture of visual content being viewed by a camera of the smartphone 200 is performed in response to depressing a shutter button 220. In response to capturing the viewed visual content, a photographic image becomes displayed on the visual display 204 of the smartphone 200. The photographic image comprises the watermark image 224 corresponding to the chosen watermark in combination with the captured visual content 226. For example, the captured visual content becomes displayed within a captured visual content portion (e.g., as shown by the dotted line in FIG. 2E) of a watermark image 224. Advantageously, the watermark image is maintained at a static position within an area of the visual display 204 while the visual content is being viewed and captured (i.e., the visual content being viewed is displayed within the captured visual content portion of the watermark image 224. In the case of a watermark image in a PNG (portable network graphics) file format, once a user selects the chosen one of the watermark image selections, the watermark image is placed as a layer into an active image viewing structure (e.g., camera viewer window) of the digital imaging device. The watermark image is sized to the same dimensions (e.g., aspect ratio) of the as-displayed visual content being viewed by the digital imaging device (e.g., full size of the image viewing structure). Because the watermark image is displayed on the image viewing structure in a foreground layer and the viewed image content is displayed on the image viewing structure in a background layer, it allows a user to see as-viewed visual content in a background layer through the transparent portion of the watermark image. Non-transparent portions of the watermark image (e.g., border area and area having logo(s) text, etc) stay in foreground of the image viewing structure thereby blocking underlying portions of the viewed visual content. This gives user the ability to line up visual content in the image viewing structure with respect to the watermark image. Accordingly, when the photograph is taken, viewed visual content seen within the visual display 204 includes the watermark image 224 merged (e.g., overlaid onto) the to-be-photographed visual content such that what is seen on the visual display 204 at the instant the shutter button 220 is depressed is the same as the resulting outputted photograph. After capturing viewed visual content, an operation 128 can be performed for offering an option of applying a filter to the photographic image. As shown in FIG. 2F, such offering of the application of a filter can include displaying a plurality of as-filtered image examples 228 on the visual display 204 of the smartphone 200. Each one of the as-filtered image examples 228 depicts a respective filter effect as applied to the photographic image. A particular one of the as-filtered image examples 228 can be clicked on for causing the corresponding filter effect to be applied to the photographic image. In response to selection of the particular one of the as-filtered image examples 228, an operation 130 is performed applying the selected filter to the photographic image. As shown in FIG. 2G, the photographic image displayed on the visual display 204 of the smartphone 200 is updated to depict the effect of the filter. As can be seen in FIG. 2G, in preferred embodiments of the present invention, the filter effect is applied to only the captured visual content portion of the photographic image such that the watermark image remains in an unfiltered state. For example, the watermark is in a PNG file format and is displayed in a foreground layer of photographic image and the captured visual content appears in a background layer of photographic image in a JPEG (joint photo experts group) file format. As the user views both layers, the user then can select different electronic camera filters that only change the background layer. In this regard the captured visual content remains the same (i.e., unfiltered). After applying the filter, or when it is requested that the photographic image remain unfiltered, an operation 132 is performed for saving the photographic image. For example, saving the photographic image can include merging an imaging layer having the watermark image with an imaging layer having the captured visual content. In response to or in combination with saving the photographic image, an operation 134 is performed for offering an ability to share the photographic image. In response to the offer to share the photographic image being declined, the method 100 ends. Otherwise, an operation 136 is performed for displaying options for sharing the photographic image. For example, as shown in FIG. 2H, displayed options for sharing the photo can include a selection 230 for printing the photographic image, a selection 232 for emailing the photographic image, a selection 234 for copying the photographic image, and one or more selections 236 for providing the photographic image to a social media account. In response to an operation 138 being performed for receiving a selected sharing option, an operation 140 is performed for implementing sharing of the photographic image in accordance with the selected sharing option. In the case of selected sharing option being providing the photographic image to a social media account, sharing of the photographic image can also include sharing a social media content identifier associated with the watermark in the photographic image. For example, in the case of a registered watermark, the social media content identifier associated with the watermark in the photographic image can be downloaded along with the registered watermark. Sharing of the social media content identifier includes transmitting the photograph and the social media content identifier for reception by a social media system, which provides a convenient means for allowing the photographic image to be subsequently utilized by the social media system (e.g., shared and/or tracked using the social media system). Turning now to a discussion of approaches for implementing embodiments of the present invention, systems and methods (e.g., the method 100 disclosed above in reference to FIGS. 1a and 1B) in accordance with embodiments of the present invention can be implemented in any number of different types of data processing systems (e.g., a computer system) in addition to the specific physical implementation of a data processing system in the form of a smart phone. To this end, FIG. 5 shows a diagrammatic representation of one embodiment of a computer system 500 within which a set of instructions can execute for causing a device to perform or execute any one or more of the aspects and/or methodologies of the present disclosure. The components in FIG. 5 are examples only and do not limit the scope of use or functionality of any hardware, software, embedded logic component, or a combination of two or more such components implementing particular embodiments. The computer system 500 can include a processor 501, a memory 503, and a storage 508 that communicate with each other, and with other components, via a bus 540. The bus 540 can also link a display 532, one or more input devices 533 (which can, for example, include a keypad, a keyboard, a mouse, a stylus, etc.), one or more output devices 534, one or more storage devices 535, and various tangible storage media 536. All of these elements can interface directly or via one or more interfaces or adaptors to the bus 540. For instance, the various tangible storage media 536 can interface with the bus 540 via storage medium interface 526. Computer system 500 can have any suitable physical form, including but not limited to one or more integrated circuits (ICs), printed circuit boards (PCBs), mobile handheld devices (such as mobile telephones or PDAs), laptop or notebook computers, distributed computer systems, computing grids, or servers. All or a portion of the elements 501-536 can be housed in a single unit (e.g., a cell phone housing, a tablet housing, or the like). Processor(s) 501 (or central processing unit(s) (CPU(s))) optionally contains a cache memory unit 502 for temporary local storage of instructions, data, or computer addresses. Processor(s) 501 are configured to assist in execution of computer readable instructions. Computer system 500 can provide functionality as a result of the processor(s) 501 executing software embodied in one or more tangible computer-readable storage media, such as memory 503, storage 508, storage devices 535, and/or storage medium 536. The computer-readable media can store software that implements particular embodiments, and processor(s) 501 can execute the software. Memory 503 can read the software from one or more other computer-readable media (such as mass storage device(s) 535, 536) or from one or more other sources through a suitable interface, such as network interface 520. The software can cause processor(s) 501 to carry out one or more processes or one or more steps of one or more processes described or illustrated herein. Carrying out such processes or steps can include defining data structures stored in memory 503 and modifying the data structures as directed by the software. The memory 503 can include various components (e.g., machine readable media) including, but not limited to, a random access memory component (e.g., RAM 504) (e.g., a static RAM “SRAM”, a dynamic RAM “DRAM, etc.), a read-only component (e.g., ROM 505), and any combinations thereof. ROM 505 can act to communicate data and instructions unidirectionally to processor(s) 501, and RAM 504 can act to communicate data and instructions bidirectionally with processor(s) 501. ROM 505 and RAM 504 can include any suitable tangible computer-readable media described below. In one example, a basic input/output system 506 (BIOS), including basic routines that help to transfer information between elements within computer system 500, such as during start-up, can be stored in the memory 503. Fixed storage 508 is connected bidirectionally to processor(s) 501, optionally through storage control unit 507. Fixed storage 508 provides additional data storage capacity and can also include any suitable tangible computer-readable media described herein. Storage 508 can be used to store operating system 509, EXECs 510 (executables), data 511, APV applications 512 (application programs), and the like. Often, although not always, storage 508 is a secondary storage medium (such as a hard disk) that is slower than primary storage (e.g., memory 503). Storage 508 can also include an optical disk drive, a solid-state memory device (e.g., flash-based systems), or a combination of any of the above. Information in storage 508 can, in appropriate cases, be incorporated as virtual memory in memory 503. In one example, storage device(s) 535 can be removably interfaced with computer system 500 (e.g., via an external port connector (not shown)) via a storage device interface 525. Particularly, storage device(s) 535 and an associated machine-readable medium can provide nonvolatile and/or volatile storage of machine-readable instructions, data structures, program modules, and/or other data for the computer system 500. In one example, software can reside, completely or partially, within a machine-readable medium on storage device(s) 535. In another example, software can reside, completely or partially, within processor(s) 501. Bus 540 connects a wide variety of subsystems. Herein, reference to a bus can encompass one or more digital signal lines serving a common function, where appropriate. Bus 540 can be any of several types of bus structures including, but not limited to, a memory bus, a memory controller, a peripheral bus, a local bus, and any combinations thereof, using any of a variety of bus architectures. As an example and not by way of limitation, such architectures include an Industry Standard Architecture (ISA) bus, an Enhanced ISA (EISA) bus, a Micro Channel Architecture (MCA) bus, a Video Electronics Standards Association local bus (VLB), a Peripheral Component Interconnect (PCI) bus, a PCI-Express (PCI-X) bus, an Accelerated Graphics Port (AGP) bus, HyperTransport (HTX) bus, serial advanced technology attachment (SATA) bus, and any combinations thereof. Computer system 500 can also include an input device 533. In one example, a user of computer system 500 can enter commands and/or other information into computer system 500 via input device(s) 533. Examples of an input device(s) 533 include, but are not limited to, an alpha-numeric input device (e.g., a keyboard), a pointing device (e.g., a mouse or touchpad), a touchpad, a joystick, a gamepad, an audio input device (e.g., a microphone, a voice response system, etc.), an optical scanner, a video or still image capture device (e.g., a camera), and any combinations thereof. Input device(s) 533 can be interfaced to bus 540 via any of a variety of input interfaces 523 (e.g., input interface 523) including, but not limited to, serial, parallel, game port, USB, FIREWIRE, THUNDERBOLT, or any combination of the above. In particular embodiments, when computer system 500 is connected to network 530, computer system 500 can communicate with other devices, specifically mobile devices and enterprise systems, connected to network 530. Communications to and from computer system 500 can be sent through network interface 520. For example, network interface 520 can receive incoming communications (such as requests or responses from other devices) in the form of one or more packets (such as Internet Protocol (IP) packets) from network 530, and computer system 500 can store the incoming communications in memory 503 for processing. Computer system 500 can similarly store outgoing communications (such as requests or responses to other devices) in the form of one or more packets in memory 503 and communicated to network 530 from network interface 520. Processor(s) 501 can access these communication packets stored in memory 503 for processing. Examples of the network interface 520 include, but are not limited to, a network interface card, a modem, and any combination thereof. Examples of a network 530 or network segment 530 include, but are not limited to, a wide area network (WAN) (e.g., the Internet, an enterprise network), a local area network (LAN) (e.g., a network associated with an office, a building, a campus or other relatively small geographic space), a telephone network, a direct connection between two computing devices, and any combinations thereof. A network, such as network 530, can employ a wired and/or a wireless mode of communication. In general, any network topology can be used. Information and data can be displayed through a display 532. Examples of a display 532 include, but are not limited to, a liquid crystal display (LCD), an organic liquid crystal display (OLED), a cathode ray tube (CRT), a plasma display, and any combinations thereof. The display 532 can interface to the processor(s) 501, memory 503, and fixed storage 508, as well as other devices, such as input device(s) 533, via the bus 540. The display 532 is linked to the bus 540 via a video interface 522, and transport of data between the display 532 and the bus 540 can be controlled via the graphics control 521. In addition to a display 532, computer system 500 can include one or more other peripheral output devices 534 including, but not limited to, an audio speaker, a printer, and any combinations thereof. Such peripheral output devices can be connected to the bus 540 via an output interface 524. Examples of an output interface 524 include, but are not limited to, a serial port, a parallel connection, a USB port, a FIREWIRE port, a THUNDERBOLT port, and any combinations thereof. In addition or as an alternative, computer system 500 can provide functionality as a result of logic hardwired or otherwise embodied in a circuit, which can operate in place of or together with software to execute one or more processes or one or more steps of one or more processes described or illustrated herein. Reference to software in this disclosure can encompass logic, and reference to logic can encompass software. Moreover, reference to a computer-readable medium (also sometimes referred to as machine-readable medium” can encompass a circuit (such as an IC) storing software for execution, a circuit embodying logic for execution, or both, where appropriate. The present disclosure encompasses any suitable combination of hardware, software, or both. The term “computer-readable medium” should be understood to include any structure that participates in providing data that can be read by an element of a computer system. Such a medium can take many forms, including but not limited to, non-volatile media, volatile media, and transmission media. Non-volatile media include, for example, optical or magnetic disks and other persistent memory. Volatile media include dynamic random access memory (DRAM) and/or static random access memory (SRAM). Transmission media include cables, wires, and fibers, including the wires that comprise a system bus coupled to processor. Common forms of machine-readable media include, for example, a floppy disk, a flexible disk, a hard disk, a magnetic tape, any other magnetic medium, a CD-ROM, a DVD, any other optical medium. Those of skill in the art would understand that information and signals can be represented using any of a variety of different technologies and techniques. For example, data, instructions, commands, information, signals, bits, symbols, and chips that can be referenced throughout the above description can be represented by voltages, currents, electromagnetic waves, magnetic fields or particles, optical fields or particles, or any combination thereof. Those of skill would further appreciate that the various illustrative logical blocks, modules, circuits, and algorithm steps described in connection with the embodiments disclosed herein can be implemented as electronic hardware, computer software, or combinations of both. To clearly illustrate this interchangeability of hardware and software, various illustrative components, blocks, modules, circuits, and steps have been described above generally in terms of their functionality. Whether such functionality is implemented as hardware or software depends upon the particular application and design constraints imposed on the overall system. Skilled artisans can implement the described functionality in varying ways for each particular application, but such implementation decisions should not be interpreted as causing a departure from the scope of the present invention. The various illustrative logical blocks, modules, and circuits described in connection with the embodiments disclosed herein can be implemented or performed with a general purpose processor, a digital signal processor (DSP), an application specific integrated circuit (ASIC), a field programmable gate array (FPGA) or other programmable logic device, discrete gate or transistor logic, discrete hardware components, or any combination thereof designed to perform the functions described herein. A general purpose processor can be a microprocessor, but in the alternative, the processor can be any conventional processor, controller, microcontroller, or state machine. A processor can also be implemented as a combination of computing devices, e.g., a combination of a DSP and a microprocessor, a plurality of microprocessors, one or more microprocessors in conjunction with a DSP core, or any other such configuration. The steps of a method or algorithm described in connection with the embodiments disclosed herein can be embodied directly in hardware, in a software module executed by a processor, or in a combination of the two. A software module can reside in RAM memory, flash memory, ROM memory, EPROM memory, EEPROM memory, registers, hard disk, a removable disk, a CD-ROM, or any other form of storage medium known in the art. An exemplary storage medium is coupled to the processor such the processor can read information from, and write information to, the storage medium. In the alternative, the storage medium can be integral to the processor. The processor and the storage medium can reside in an ASIC. The ASIC can reside in a user terminal. In the alternative, the processor and the storage medium can reside as discrete components in a user terminal. The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein can be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein. Although the present invention has been described with reference to several exemplary embodiments, it is understood that the words that have been used are words of description and illustration, rather than words of limitation. Changes can be made within the purview of the appended claims, as presently stated and as amended, without departing from the scope and spirit of the present invention in all its aspects. Although the present invention has been described with reference to particular means, materials and embodiments, the present invention is not intended to be limited to the particulars disclosed; rather, the present invention extends to all functionally equivalent technologies, structures, methods and uses such as are within the scope of the appended claims.
<SOH> BACKGROUND <EOH>Digital photography, like traditional film photography, is widely used for memorializing events and moments. With the advent of social media and wireless communication, it has become common place for people to use digital photographs as an integral part of their social networking endeavors such as through posting of pictures on their on-line social network page. This is due in no small part to the inclusion of digital cameras in wireless communication devices (e.g., smartphones, tablets, etc) and the affordability of digital cameras. As such, ever increasing numbers of people are now taking photographs as a routine part of their daily lives whether it be for personal enjoyment and entertainment, to share with friends and family, or both. Unlike traditional film photography, digital photography offers the ability to immediately view, edit and share photographs. This being the case, people have an expectation that their digital imaging solution offer them various approaches for enhancing their digital photographs though contextualization (e.g., editing a label into the photograph after it is taken) and/or customization (e.g., editing a border, special effect, etc into the photograph after it is taken). However, these post-capture approaches for enhancing their digital photographs often contribute to photos not being shared or added to an album because one or more separate process must performed after taking the photograph to achieve such contextualization and/or customization. Therefore, enabling such contextualization and/or customization to be performed in combination with taking a photograph is advantageous, desirable and useful.
<SOH> SUMMARY OF THE DISCLOSURE <EOH>Embodiments of the present invention are directed to a system-implemented solution (e.g., an internal process of a digital imaging device) for enabling personalization (e.g., via contextualization and/or customization) to be performed in combination with taking a photograph with a digital imaging device. A digital camera, a smartphone camera, and a tablet are examples of a digital imaging device that can be configured in accordance with an embodiment of the present invention. More specifically, embodiments of the present invention are directed to displaying an embedded digital image (e.g., an electronic digital icon (e.g., watermark), picture, text, or the like) within an image viewing structure (e.g., eyepiece, visual display, or the like) of a digital imaging device prior to and during a photograph being taken using the digital imaging device. Accordingly, when a user of such a digital imaging device takes the photograph, as-viewed visual content seen within the image viewing structure (i.e., the embedded digital image overlaid on to-be-photographed visual content) is the same as what would be a corresponding outputted digital file of the imaging device. In this regard, the corresponding outputted digital file is a ‘What You See Is What You Get (WYSIWYG)’ representation of the as-viewed visual content within the image viewing structure of the imaging device when the to-be-photographed visual content is captured by the digital imaging device. Advantageously, the embedded digital image can be selected based on an actual location of the digital imaging device at the time when the to-be-photographed visual content is captured using the digital imaging device (i.e., the current location of the digital imaging device). In one embodiment of the present invention, a computer-implemented method comprises a plurality of operations. An operation is performed for receiving a request to embed system-provided content into a photograph to be taken using a digital imaging device. An operation is performed for providing, dependent upon a current location of the digital imaging device when the request is received, one or more embeddable images. An operation is performed for displaying, on an image viewing structure of the digital imaging device, the one or more embeddable content images in combination with visual content being viewed by the digital imaging device. In another embodiment of the present invention, a wireless communication device comprises position determining system, a digital imaging system and a photograph customization system coupled to the position locating system and the digital imaging system. The position determining system is configured to provide information indicating a current position of the wireless communication device. The digital imaging system is configured to create digitally rendered images of visual content acquired thereby. The visual content is displayed on an image viewing structure of the digital imaging device while being acquired. The photograph customization system is configured to use the current location of the digital imaging device for providing one or more embeddable content images and to display information from at least one of the one or more embeddable content images on an image viewing structure of the digital imaging device while the visual content being acquired by the digital imaging system is being displayed on the image viewing structure. In another embodiment of the present invention, a non-transitory computer-readable medium has tangibly embodied thereon and accessible therefrom processor-executable instructions that, when executed by at least one data processing device of at least one computer, causes the at least one data processing device to perform a method for generating a photo. Generating the photo comprises a plurality of operations. An operation of receiving a request to embed system-provided content into a photograph to be taken using a digital imaging device is performed. An operation of providing one or more embeddable images dependent upon a current location of the digital imaging device when the request is received is performed. An operation of displaying the one or more embeddable content images on an image viewing structure of the digital imaging device in combination with visual content being viewed by the digital imaging device is performed. These and other objects, embodiments, advantages and/or distinctions of the present invention will become readily apparent upon further review of the following specification, associated drawings and appended claims.
G06T10021
20170915
20180308
83039.0
G06T100
2
YANG, WEI WEN
EMBEDDING DIGITAL CONTENT WITHIN A DIGITAL PHOTOGRAPH DURING CAPTURE OF THE DIGITAL PHOTOGRAPH
MICRO
1
CONT-ACCEPTED
G06T
2,017
15,706,139
PENDING
Accessory Cart
In the specification and drawings an accessory cart is described and shown with a base, a housing element that is connected to the base and extends upward from the base, and a platform, which is connected to the housing element with the height of the platform being automatically adjustable.
1. An accessory cart, comprising: a base; an adjustable housing element connected to the base, the housing element extending upward from the base; a work platform connected to the housing element, the cart further comprising an input device, the input device configured to receive a user identifier, the user identifier being associated with a predetermined height of the housing element; said accessory cart having stored thereon a series of predetermined heights, each of the stored predetermined heights being associated with at least one user identifier, whereby said accessory cart is further configured to receive a user identifier from the input device and to adjust the housing element, using automatic non-manual means, to position the work platform at the predetermined height associated with the user identifier. 2. The accessory cart of claim 1 where the predetermined height is a position for a standing user. 3. The accessory cart of claim 1 where the predetermined height is a position for a sitting user. 4. The accessory cart of claim 1 further comprising a series of casters attached to the base, and a tracking wheel attached near the center of the base. 5. The accessory cart of claim 1 where the input device comprises a wireless communication device adapted to wirelessly receive the user identifier. 6. The accessory cart of claim 1 wherein the user identifier is a biometric identifier. 7. The accessory cart of claim 1 wherein the user identifier is a user login identifier. 8. The accessory cart of claim 1 wherein the user identifier is an access identifier. 9. A method of adjusting a height of a platform of an accessory cart, said accessory cart comprising a base, an adjustable housing element connected to the base, and a work platform connected to the housing element, the accessory cart further comprising an input device, a computer processor and computer memory; said computer memory having stored thereon a series of predetermined positions and user identifiers, each of said series of predetermined positions being associated with at least one user identifier, said method comprising the steps of: said processor receiving a specified user identifier from the input device, where the user identifier is associated with a predetermined position; said processor receiving, from the computer memory, the specific predetermined position associated with the user identifier; and using the specific predetermined position to move the adjustable housing element by automatic non-manual means to thereby move the work surface to a specific predetermined position. 10. The method of claim 9 where the predetermined position of the work platform is a position for a standing user. 11. The method of claim 9 where the predetermined position of the work platform is a position for a sitting user. 12. The method of claim 9 wherein the accessory cart further comprises a monitor positioned above the worksurface. 13. The method of claim 9 where the input device comprises a wireless communication device adapted to wirelessly receive the user identifier. 14. The method of claim 9 wherein the user identifier is a biometric identifier. 15. The method of claim 9 wherein the user identifier is a user login identifier. 16. The method of claim 9 wherein the identifier is an access identifier.
CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 14/714,994, filed on May 18, 2015, which application was a continuation of U.S. application Ser. No. 13/763,395, filed on Feb. 8, 2013, which claims the benefit of U.S. Provisional Application No. 61/596,635, filed Feb. 8, 2012, all of which are hereby incorporated by reference. BACKGROUND OF THE INVENTION Mobile accessory carts that carry computers are commonly used in healthcare and other industries to provide portable workstations. Similar to a computer workstation in an ordinary office setting, ergonomic features are important for mobile accessory carts as well. For example, the height of the work surface, keyboard, and monitor all play a major role in ergonomics because posture is determined by sight and reach. Adjustability of the height of the work surface, keyboard, and/or monitor is very important as users come in all shapes and sizes. While current mobile accessory carts allow users to adjust the height of the work surface, keyboard, and/or monitor, the adjustability mechanisms are often cumbersome and complicated and require many steps. As a result, users are not making the necessary adjustments to mobile accessory carts. This is especially true in the healthcare industry, where healthcare professionals typically use multiple mobile accessory carts throughout the day, for an average of only approximately three to four minutes at a time. Further, many healthcare professionals do not receive the proper training regarding optimal ergonomic positioning of the work surface, keyboard, and monitor of a mobile accessory cart. Therefore, in rare situations in which users do make adjustments to a mobile accessory cart, they are often not ergonomically correct for the particular user. By not making the proper ergonomic adjustments, continuous work in a poor ergonomic position leads to repetitive strain injuries, which are increasingly being reported by healthcare professionals. SUMMARY OF THE INVENTION An embodiment of the present invention is directed to an accessory cart that comprises a base, a housing element, which is connected to the base, extending upward from the base and a work platform that is connected to the housing element with the height of the work platform being automatically adjustable. An embodiment of an accessory cart where the work platform is automatically adjustable to a plurality of predetermined heights and each of the plurality of predetermined heights corresponds to a measurable aspect of a potential user. An embodiment of an accessory cart where the measurable aspect of the potential user is a height of the potential user. An embodiment of an accessory cart where the height of the work platform is automatically adjustable without a need for a user to manually make a selection on the accessory cart. An embodiment of an accessory cart, which comprises a sensor, and the height of the work platform is automatically adjustable based on information obtained by the sensor about the user. An embodiment of an accessory cart, which comprises a deployable tracking wheel, which is located at about a center of gravity of the accessory cart, connected to the base. An embodiment of an accessory cart, which comprises a release switch with the tracking wheel being deployable in a first state by continuous engagement of the release switch by a potential user and the tracking wheel being retractable in a second state by disengagement of the release switch by the potential user. An embodiment of an accessory cart where the work platform has a first groove formed in a first surface of the work platform and a second groove formed in a second surface of the work platform, which opposes the first surface and the computer input device platform is slideable along the first groove and the second groove at most to a first lateral edge or a second lateral edge of the work platform. An embodiment of an accessory cart where the accessory cart comprises a computer input device platform that is removably connected to the work platform. An embodiment of an accessory cart, which comprises a power supply located on the accessory cart with the power supply capable of being wirelessly charged. An embodiment of an accessory cart, which comprises a keyboard platform that is fixed at an ergonomically negative angle. An embodiment of an accessory cart, which comprises a keyboard support surface and the keyboard support surface is fixed at an ergonomically negative angle. An embodiment of an accessory cart, which comprises a computer input device platform that is magnetically connectable to the keyboard support surface. An embodiment of a method of adjusting a height of a platform of an accessory cart, that comprises the steps of equipping the accessory cart with a plurality of predetermined platform heights, and automatically adjusting the platform to at least one of the plurality of predetermined platform heights. An embodiment of a method of adjusting a height of a platform of an accessory cart where the method comprises the step of corresponding a measurable aspect of a potential user to at least one of the plurality of predetermined platform heights. An embodiment of a method of adjusting a height of a platform of an accessory cart where the method comprises the step of corresponding a height of a potential user to at least one of the plurality of predetermined platform heights. An embodiment of a method of adjusting a height of a platform of an accessory cart where the method comprises the step of wirelessly charging a power supply located on the accessory cart. An embodiment of a method of adjusting a height of a platform of an accessory cart where the method comprises the step of deploying a tracking wheel from a base of the accessory cart. An embodiment of an accessory cart that comprises a base, a housing element, which is connected to the base, extending upward from the base, a platform, which is connected to the housing element and a means for automatically adjusting a height of the platform. BRIEF DESCRIPTION OF THE DRAWINGS The accompanying figures, where like reference numerals refer to identical or functionally similar elements throughout the separate views, which are not true to scale, and which, together with the detailed description below, are incorporated in and form part of the specification, serve to illustrate further various embodiments and to explain various principles and advantages all in accordance with the present invention. Advantages of embodiments of the present invention will be apparent from the following detailed description of the exemplary embodiments thereof, which should be considered in conjunction with the accompanying drawings in which: FIG. 1 is a side perspective view of an exemplary mobile accessory cart; FIG. 2 is a front view of the accessory cart of FIG. 1; FIG. 3 is a rear perspective view of the accessory cart of FIG. 1; FIG. 4 is a partial rear perspective view of the accessory cart of FIG. 1; FIG. 5 is another front view of the accessory cart of FIG. 1, shown with a monitor rotated to the side; FIG. 6 is a diagram of multiple side views of the accessory cart of FIG. 1, illustrating various configurations of a monitor mount; FIGS. 7A to 7C depict ergonomic challenges associated with mounted monitors; FIG. 8 is a partial perspective view of the accessory cart of FIG. 1; FIG. 9A is a perspective view of an upper portion of the accessory cart of FIG. 1; FIG. 9B is a partial side view of the accessory cart of FIG. 1, illustrating the ergonomic range for positioning of a user's forearm relative to the accessory cart; FIG. 10A is a perspective view of the upper portion of the accessory cart of FIG. 1, shown with an exemplary computer input device platform attached thereto; FIG. 10B is a partial side view of the accessory cart of FIG. 1, illustrating the ergonomic range for positioning of a user's forearm relative to the accessory cart; FIG. 11A is a diagram of the ergonomic range for a user's sight and vertical reach relative to the accessory cart of FIG. 1; FIG. 11B is a diagram of the ergonomic range for a user's horizontal reach relative to the accessory cart of FIG. 1; FIG. 12 is a diagram depicting the accessory cart of FIG. 1 in both a sit configuration and a stand configuration; FIG. 13 is a diagram of typical steps required to adjust existing accessory carts; FIG. 14 is a diagram of steps of FIG. 13 for adjusting an accessory cart in accordance with the present invention; FIGS. 15A and 15B are illustrations of a user pushing an existing accessory cart and the track of an existing accessory cart taken when pushed by a user; FIG. 16A is a partial, bottom side perspective view of the accessory cart of FIG. 1; FIG. 16B is a partial, cross-sectional, side perspective view of a lower portion of the accessory cart of FIG. 1; FIGS. 16C and 16D are partial, transparent views of the accessory cart of FIG. 1; FIG. 16E is a diagram illustrating a path of motion for the accessory cart of FIG. 1; FIGS. 17A to 17D illustrate perspective views of the accessory cart of FIG. 1, shown with various computer solutions; FIG. 18A is a rear perspective, partially transparent, view of the accessory cart of FIG. 1; FIG. 18B is a partial, rear perspective view of a top portion of the accessory cart of FIG. 1; FIG. 18C is a partial, rear perspective view of a lower portion of the accessory cart of FIG. 1; FIG. 19A is a partial, cross-sectional, rear side perspective view of the accessory cart of FIG. 1; FIG. 19B is a partial, cross-sectional side view of the accessory cart of FIG. 1; FIGS. 20A and 20B are partial, side perspective views of the accessory cart of FIG. 1, shown with an extended work surface; FIG. 21A is a front perspective view of the accessory cart of FIG. 1, shown with additional storage options; FIG. 21B is a partial, front side perspective view of the accessory cart of FIG. 1, shown with alternative storage options and accessories; FIG. 21C is a partial, rear side perspective view of the accessory cart of FIG. 1, shown with yet further alternative storage options and accessories; FIGS. 22 and 23 are perspective views of the accessory cart of FIG. 1, shown with wireless battery recharging solutions; FIG. 24 is a front view of another exemplary accessory cart; FIG. 25 is front side perspective view of the accessory cart of FIG. 24; FIG. 26 is a side view of the accessory cart of FIG. 24; FIG. 27 is a perspective view of an exemplary accessory cart in accordance with a further embodiment; FIGS. 28A and 28B are perspective views of an exemplary accessory cart in accordance with yet an additional embodiment; FIGS. 29A to 29C are partial, side views of the accessory cart of FIG. 24, shown with various storage configurations; FIGS. 30A to 30D are side perspective views of embodiments of an yet a further exemplary accessory cart shown with various additional storage configurations; FIG. 31 is a perspective view of a storage option for use with an accessory cart; FIG. 32 is a partial, bottom perspective view of the accessory cart of FIGS. 30A to 30D; FIGS. 33A to 33E are perspective views of storage options and components thereof for use with an accessory cart; FIG. 34 is a partial, perspective view of an upper portion of the accessory cart of FIGS. 30A to 30D; FIG. 35 is a side perspective view of the accessory cart of FIGS. 30A to 30D; FIG. 36 is a cross-sectional view of a computer input device platform assembled with an accessory cart; FIG. 37 is a perspective view of an embodiment of a computer input device platform; and FIG. 38 is a cross-sectional view of the computer input device platform of FIG. 37. DETAILED DESCRIPTION OF THE INVENTION As required, detailed embodiments of the present invention are disclosed herein. However, it is to be understood that the disclosed embodiments are merely exemplary of the invention, which can be embodied in various forms. As such, any feature(s) used in one embodiment can be used in another embodiment. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention in virtually any appropriately detailed structure. Further, the terms and phrases used herein are not intended to be limiting, but rather, to provide an understandable description of the invention. While the specification concludes with claims defining the features of the invention that are regarded as novel, it is believed that the invention will be better understood from a consideration of the following description in conjunction with the drawing figures, in which like reference numerals are carried forward. Alternate embodiments may be devised without departing from the spirit or the scope of the invention. Additionally, well-known elements of exemplary embodiments of the invention will not be described in detail or will be omitted so as not to obscure the relevant details of the invention. Before the present invention is disclosed and described, it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. The terms “a” or “an,” as used herein, are defined as one or more than one. The term “plurality,” as used herein, is defined as two or more than two. The term “another,” as used herein, is defined as at least a second or more. The terms “including” and/or “having,” as used herein, are defined as comprising (i.e., open language). The terms “connected” and/or “coupled,” as used herein, are defined as connected, although not necessarily directly, and not necessarily mechanically. Relational terms such as first and second, top and bottom, and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. The terms “comprises,” “comprising,” or any other variation thereof are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. An element proceeded by “comprises . . . a” does not, without more constraints, preclude the existence of additional identical elements in the process, method, article, or apparatus that comprises the element. As used herein, the term “about” or “approximately” applies to all numeric values, whether or not explicitly indicated. These terms generally refer to a range of numbers that one of skill in the art would consider equivalent to the recited values (i.e., having the same function or result). In many instances these terms may include numbers that are rounded to the nearest significant figure. The terms “program,” “software application,” and the like as used herein, are defined as a sequence of instructions designed for execution on a computer system. A “program,” “computer program,” or “software application” may include a subroutine, a function, a procedure, an object method, an object implementation, an executable application, an applet, a servlet, a source code, an object code, a shared library/dynamic load library and/or other sequence of instructions designed for execution on a computer system. Herein various embodiments of the present invention are described. In many of the different embodiments, features are similar. Therefore, to avoid redundancy, repetitive description of these similar features may not be made in some circumstances. It shall be understood, however, that description of a first-appearing feature applies to the later described similar feature and each respective description, therefore, is to be incorporated therein without such repetition. Described now are exemplary embodiments of the present invention. Referring now to the drawings, beginning with FIGS. 1 to 4, an exemplary embodiment of a mobile accessory cart 100 is shown that can include features such as ergonomic positioning of a keyboard and a mouse, automatic height adjustment of a work surface to an ergonomically correct position, and advanced control and mobility. The accessory cart 100 includes a work platform 106 supported by a height-adjustable housing element 104 extending upward from a base 102. A monitor mount 121 extends upward from the work platform 106 to support a monitor 124 above the work platform 106 such that the monitor 124 can be both rotatable and height-adjustable. A keyboard platform 110 is fitted to extend from the underside of the work platform 106 to support a keyboard 117 thereon at an ergonomic fixed angle relative to the work platform 106. As shown in FIGS. 1 and 4, the monitor mount 121 includes a gantry or monitor support frame 122, which has two side portions 123a and a middle portion 123b extending therebetween. Each side portion 123a is attached to an opposing side of the work platform 106 and extends upward from the work platform 106 to the middle portion 123b, thereby providing an increased work surface 108 and better viewing access through a viewing window 105 created between the work surface 108 and the raised middle portion 123b of the monitor support frame 122 while guiding the cart 100. Moreover, the monitor mount 121 can further function as a handle for pulling the accessory cart 100 from behind, can be used as an attachment point for accessories, and allows for integrated cable management of cables that extend from within the work platform 106 through an opening 152 at the back side of the accessory cart 100 (see FIGS. 18A, 18B, and 21C). The monitor mount 121 further includes an exemplary monitor arm 125 that attaches at a first end to and extends upward from the middle portion 123b of the monitor support frame 122 with the monitor 124 attached at a second end of the monitor arm 125. The monitor arm 125 can be pivotally mounted to the monitor support frame 122 at a pivot point 126. The pivot point 126 defines an axis substantially parallel to the middle portion 123b of the monitor support frame 122 and about which the monitor arm 125 is operable to pivot to adjust the vertical position of the monitor 124 relative to the work platform 106. In a further exemplary embodiment, a mounting bracket 128, which is affixable to the back of the monitor 124, can be pivotally mounted to the monitor arm 125 at pivot points 127a and 127b. The pivot point 127a defines an axis that is substantially perpendicular to the middle portion 123b of the monitor support frame 122 and about which the monitor 124 is operable to pivot to allow rotation of the monitor 124, for example, to share information with a patient (see FIG. 5). The pivot point 127b defines an axis that is substantially parallel to the middle portion 123b of the monitor support frame 122 and about which the monitor 124 is operable to pivot such that the monitor 124 is rotatable at an angle relative to the work platform 106, for bi-focal use, transporting the accessory cart 100, or touch screen use (if using a touch-screen monitor), for example (see FIG. 6). Additionally, the monitor mount 121, in combination with the monitor arm 125 and the pivot points 126, 127a, and 127b aid to ensure that the height of a monitor is adjustable within a proper ergonomic range (e.g., 19 inches-23 inches for 5% females to 95% males). It should be noted that the pivot points 126, 127a, and 127b can include any suitable connection mechanism for pivotally connecting monitors to monitor arms. Moreover, the exemplary monitor mount 121 can be configured to hold different sized monitors using industry-standard VESA mounts and brackets. Accordingly, the exemplary monitor mount 121 addresses the challenges faced by users of mobile accessory carts that comprise a computer monitor, including those depicted in FIGS. 7A to 7C, (the adjustment of a monitor to ensure that it is positioned within a proper ergonomic range for a user, allowing the monitor to be rotatable, and having the ability to move a monitor out of view when a user is moving the accessory cart) among others. FIG. 8 depicts an embodiment of the keyboard platform 110, which includes a keyboard support frame 112 and a keyboard support surface 116, mounted on the keyboard support frame 112. The keyboard support frame 112 includes a substantially U-shaped support bar 114 and a pair of arms 111 with each arm 111 extending at a fixed angle from an end of the U-shaped support bar 114. The arms 111 attach the keyboard support frame 112 to the underside or the sides of the work platform 106 so that the U-shaped support bar 114 (and the keyboard support surface 116 and keyboard 117 mounted thereon) is fixed at an ergonomic negative angle, which will be described in further detail below with respect to FIGS. 9B, 10B, and 11A. In the embodiment depicted in FIG. 8, the keyboard support surface 116 is slidably mounted on the fixed keyboard support frame 112 and is movable between a first position and a second position. FIGS. 9A and 10A illustrate the keyboard support surface 116 in the first or front-most position, in which the keyboard support surface 116 abuts the U-shaped support bar 114 so that the user has full access to type on a keyboard 117 supported on the keyboard support surface 116. FIGS. 8 and 16A illustrate the keyboard support surface 116 in the second position or rear-most position, in which the keyboard support surface 116 is moved in a direction toward the work platform 106 (as indicated by the arrow 132 in FIG. 8) to create a gap 120 between the keyboard support surface 116 and the support bar 114. In this position, the support bar 114 can serve as a handle that can be grasped by a user who inserts his/her fingers within the gap 120 to maneuver the mobile accessory cart 100. Thus, the only working position in which the keyboard 117 can be placed to provide access to the keys is limited to ergonomically safe positions. In other words, the keyboard platform 110 locks out non-ergonomic work positions. As shown in FIG. 8, an exemplary palm support 126 is provided across the front end of the U-shaped support bar 114 for added comfort during typing and transporting the accessory cart 100. The palm support 126 can be comprised of a deformable material, such as Technogel® or any other suitable material and can be attached to the U-shaped support bar 114 by any suitable attachment means, including but not limited to an overmolding, adhesives or any suitable mechanical mechanism. In an embodiment depicted in FIG. 16A, the keyboard support surface 116 includes an upwardly curved lip 115 and/or alternative stop mechanisms (e.g., notches or posts) at its rear end to prevent the keyboard 117 from sliding out the back of the keyboard platform 110, due to the ergonomic negative tilt of the keyboard support surface 116. In the embodiment where the keyboard support surface 116 is slidably mounted, the contact between the keyboard support surface 116 and the U-shaped support bar 114 is frictionally enhanced such that the keyboard support surface 116 does not readily slide with respect to the U-shaped support bar 114. Rather, force (i.e., either pushing or pulling on the keyboard support surface 116) is required to overcome the frictional engagement between the keyboard support surface 116 and the U-shaped support bar 114. As a result, the keyboard support surface 116 can be relatively fixed with respect to the work platform 106 at any location between the front-most and the rear-most positions. The keyboard support surface 116 may slide relative to the U-shaped support bar 114 by any suitable means, including but not limited to, channels formed in either the U-shaped support bar 114 or the underside of the keyboard support surface 116 that engage ribs on the other one of the U-shaped support bar 114 and the underside of the keyboard support surface 116. Moreover, as shown in steps 4 through 6 of FIG. 13, existing accessory carts typically have a separate platform that swivels or slides out from the work platform for supporting a computer input device, such as a mouse. However, the separate platform not only enlarges the footprint of the accessory cart, but also forces the user into a poor ergonomic position since the user's hand must reach away from the work platform 106 and the user's body. Additionally, if left extended from the work platform after use, it is subject to being hit, knocked, and broken either when the accessory cart is being moved or when another person passes by the accessory cart. As shown in an embodiment depicted, for example, in FIG. 9A, the keyboard support surface 116 is sized to fit the keyboard 117 and a mouse 118 side-by-side, thereby functioning as both a keyboard platform and a mouse platform. Alternatively, in another embodiment, as depicted in FIG. 10A and in more detail in FIGS. 37 and 38, a computer input device platform 150 is slidably attached to the work platform 106 so that it can be adjusted for right-hand or left-hand use. Rather than extend from a side of the work platform 106, the computer input device platform 119 attaches near the front the work platform 106, in a groove 550 formed in the top and/or a groove 552 formed in the bottom surface of the work platform 106, and is slidable along the front edge of the work surface 108 at most to the right and left edges of the work platform 106 to maintain a small footprint, ensure that a user maintains proper ergonomic positioning by operating the mouse 118 within the user's shoulder width, avoid damage to the computer input device platform 119, and to eliminate a user having to store the mouse 118 after each use (See FIGS. 30A to 30D, 32, 34 and 36). As best seen in FIGS. 37 and 38, the computer input device platform 150 includes a clamping means that includes a first protrusion 159 that extends in a first direction, which is substantially opposite that of a platform surface 154 on which the mouse 118 rests, a substantially C-shaped extension 156, which protrudes from the underside of the platform surface 154, and a second protrusion 158 that extend from the C-shaped extension 156 toward the first protrusion 159. The computer input device platform 119 is comprised of a transparent and/or semi-transparent material, such as plastic or glass that is clear or at least partially clear, to allow to the user to view the keyboard 117 and the control panel 130 at the front of the work platform 106. Additionally, the computer input device platform 150 can include a textured, semi-transparent surface to create friction and ensure the mouse 118 does not slide off of the platform 119. In a further embodiment, as shown in FIGS. 35 and 36, an alternative computer input device platform 119 can be removably secured to the keyboard support surface 516 by magnets, or any other known securing means, which secure the computer input device platform 119 to the keyboard support surface 516, but which also allows the computer input device platform 119 to be removed from the keyboard support surface 516 if sufficient force is applied. Thus, the computer input device platform 119 can be moved from one desired location on the keyboard support surface 516 to another desired location on the keyboard support surface 516 and secured once again to the keyboard support surface 516. In the embodiment, magnets can be located on or in the computer input device platform 119 and/or the work platform or the keyboard support surface 516. Both of the computer input device platforms 119, 150 can be installed at the same time to allow a user to place the mouse 118 on either desired platform 119, 150 or, if desired, one of the platforms 119 or 150 can be removed. Thus, the exemplary accessory cart 100 provides improved ergonomic positioning of the keyboard 117 and the mouse 118 with either embodiment shown in FIGS. 9A and 10A. As best shown in FIG. 11B, both the keyboard 117 and the mouse 118 are positioned within the shoulder width of the user. Additionally, as shown in FIGS. 9B, 10B, 30A-30D, 33 and 34C, the keyboard platform 110, 510 is fixed at a negative angle so as to ensure the user's forearm remains within the ergonomic region 76 (as described in further detail below) while typing. The keyboard work platform can be orientated between 0 degrees and −45 degrees. Preferably, however, the exemplary keyboard platform 110 is positioned at about a 10° decline from the horizontal position (i.e., negative 10 degrees) and about 3 inches below the work platform 106 so that the handle 114 is as far as possible (laterally) from the base 102 to provide ample room for the user's toe clearance while walking. In a further embodiment, the accessory cart 100 includes an automatic height adjustment mechanism that automatically adjusts the height of the work platform 106 and/or the monitor 124 to a predetermined ergonomic positioned associated with an input height. As used in the specification and claims, “automatically adjustable” is defined as being moveable by a non-manual force to a predetermined position, the predetermined position being based on information obtained by or contained within a device such as a controller, processor, computer, or database. As used in the specification and claims, “automatically adjusting” is defined as moving by a non-manual force to a predetermined position, the predetermined position being based on information obtained by or contained within a device such as a controller, processor, computer, or database. The predetermined ergonomic position of the height adjustment mechanism is based upon the average distance between the eyes and elbows of a person having the input height. Referring to FIG. 11A, an ergonomic position is one in which the user does not have to strain his/her neck to view the monitor 124 and maintains his/her forearm at the illustrated horizontal position or within the region 72 for mousing and at the illustrated horizontal position or within the region 74 for typing. As depicted in FIG. 11A, the “horizontal position” of the forearm is when the forearm is at approximately a 90° angle from the upper arm. Thus, the optimal position of the monitor 124 is at or slightly below eye level, as indicated by the region 70. The mouse 118 or other computer input device should be positioned so that the user's forearm can be maintained in the horizontal position or slightly inclined within about 20° relative to the horizontal position. The keyboard 117 should be positioned so that the user's forearm can be maintained in the horizontal position or declined within the 45° decline relative to the horizontal position. The “ergonomic negative angle” referenced above is derived from this 45° decline. To maintain the user's forearm within the region 74, the keyboard 117 should be tilted at a negative angle relative to the user, i.e., the end of the keyboard 117 closest to the work platform 106, and thus furthest from the user, should be lower (i.e., closer to the ground) than the end of the keyboard 117 closest to the user. Thus, the keyboard platform 110 is configured to support the keyboard 117 at an ergonomic negative angle. The keyboard platform 110 and the keyboard support surface 116 are fixed at a negative angle relative to the work platform 108. As shown in FIGS. 9B and 10B, for example, the user's elbows are aligned with the work platform 108. Therefore, if the keyboard platform 110 is fixed at a pre-determined ergonomic angle relative to the work platform 106, it is only necessary to adjust the height of the work platform 106 to fit each particular user to ensure the correct ergonomic positioning in terms of user reach. In another exemplary embodiment, the automatic height adjustment mechanism can electronically adjust both the height of the work platform 106 and the height of the monitor 124. As the height of the work platform 106 is adjusted, the monitor 124 moves with the work platform 106 since it is attached to the work platform 106 by the monitor mount 121. Additionally, as described above, the monitor arm 125 allows for height adjustment of the monitor 124 relative to the work platform 106. Thus, the height of the monitor 124 can also be adjusted independent from the adjustment of the work platform 106. However, the monitor mount 121 for the accessory cart 100 is specially designed to support the monitor 124 at a predetermined neutral position, which is about midway between the ergonomically recommended position for the tallest users (95 percentile male) and the shortest users (5 percentile female). This position is considered safe for all users because it eliminates the possibility of extreme mal-adjustment, although it is not optimized for each user. Therefore, if the work platform 106 is positioned at a correct ergonomic height, the monitor 124 is more likely to also be positioned at safe (or at least less poorly adjusted) height. Thus, the accessory cart 100 reduces the need for independent adjustment of the monitor 124 relative to the work platform 106. As shown in FIG. 8, the work platform 106 can include a control panel 130 that is in communication with a processor (not shown) and the processor in turn is in communication with a database that contains a list of possible user heights and the predetermined ergonomic positions associated with each of the possible heights. The processor and the database can be located within the base 102, the housing element 104, or the work platform 106 of the accessory cart 100. Alternatively, the processor and/or the database can be located remote from the accessory cart 100, in wireless communication with each other and/or the control panel 130. The processor is also in communication with a motorized lift mechanism located within the base 102 and/or the housing element 104 of the accessory cart 100. The control panel 130 can include a touch screen with a series of number scrolls, a slide bar, a number pad, buttons, knobs or other suitable means accessible to the user for the input of the user's height. Alternatively, the control panel 130 can include a number of pre-set height options selectable via a touch screen, buttons, or knobs. The pre-set height options could include specific heights (e.g., 5′1″, 5′2″, 5′3″, etc.) or height ranges (e.g., a button for heights in the range of 4′8″ to 5′0″, a button for heights in the range of 5′1″ to 5′3″, a button for heights in the range of 5′4″ to 5′6″ and so forth). In another alternative embodiment, each user has an access ID, with his/her height information associated therewith, identifiable by the control panel 130 through, for example, swiping an access ID card or inputting an access ID code. This could also be tied to the login or other security feature (e.g., a biometric ID) which identifies the user and allows access to the computer to which the monitor 124 is connected. Near field communication technology, such as embedded within a user's cellular phone, can also allow the accessory cart to recognize the identity of a user and obtain the height information associated with that user. In yet another alternative embodiment, the height of the work surface 108 can be communicated to the user as the height of the work platform 106 changed, through, for example, a display screen showing numbers scrolling, an icon indicating height increase, a slide bar, or a display of changing numbers indicating the height change. In a further embodiment, the control panel 130 can further include a “sit” height adjustment option the user can select through, for example, a button, scroll feature, slide or other interface, to adjust the work platform 106 to a typical desk level (see FIG. 12). In an even further alternative embodiments, the accessory cart 100 can be equipped with a sensor (e.g., retinal, sonar, laser, IR, motion, position, and heat detecting sensor, a camera, or other measuring devices) operable to detect a measurable aspect of a user, such as the height of a user, and communicate the detected information to the processor. The sensor(s) can be coupled to the work platform 106, monitor mount 121, or the monitor 124. As an example of a use of the accessory cart 100, when a user approaches the accessory cart 100, the user inputs his/her height at the control panel 130. The height information is communicated to and received by the processor, which communicates with the database to obtain the predetermined ergonomic position information associated with the user's input height. Based upon the received predetermined ergonomic position information, the processor communicates an instruction to the motorized lift mechanism to adjust the work platform 106 to the predetermined ergonomic position. Accordingly, the work platform 106 (and the monitor 124 movable therewith) automatically adjusts to a height that is ergonomic for the user. In a further exemplary embodiment, the height of the monitor 124 relative to the work platform 106 can also be adjusted using a motorized height adjustment mechanism that monitors specific motion to account for differences between the eyes and elbows of people with varying height (taller people tend to have longer torsos). Thus, like the motorized lift mechanism for adjustment of the work platform 106, the motorized monitor lift mechanism can be in communication with the processor and operable to further control the movement of the monitor 124 relative to the work platform 106 upon receipt of instructions from the processor (based on the predetermined ergonomic position information). Anthropometric data could be used in determining the amount of monitor height specific adjustment. This data could be stored separately in the database from height adjustment data for the work platform 106. Any automated or default positioning could include the possibility for the user to position the monitor out of the recommended ergonomic range to accommodate the use of bi-focals, as shown in FIG. 6. If the monitor 124 is out of the recommended ergonomic position, the cart 100 automatically adjusts the monitor 124 back to the neutral position the next time the cart 100 is adjusted. This ensures that poor ergonomic positioning is not the default for the cart 100. In another embodiment, the accessory cart 100 can allow a user to make adjustments to the predetermined platform height or the predetermined monitor height in order to suit the user's personal preferences. These adjustments to the predetermined heights can then be stored in a database for future selection by that user. Accordingly, the exemplary accessory cart 100 eliminates many of the steps required to adjust a typical existing accessory cart 50 to an ergonomic position. For example, referring to FIG. 13, the height of the work platform of the exemplary existing accessory cart 50 is manually adjusted at step 1; the height of the monitor is further adjusted manually at step 2; the keyboard platform is adjusted at step 3; the mouse platform is laterally extended at step 4; and the mouse positioned onto the mouse platform at steps 5 and 6. However, as shown in FIG. 14, a significant number of these steps are either eliminated or simplified with the accessory cart 100. Instead of manually adjusting the height of the work platform 106, or pressing a button until an estimated ergonomic position is reached, the accessory cart 100 automatically moves to an ergonomic position based on the user's height, which can be input or detected at step 1. Since the monitor mount 121 is specially designed to support the monitor 124 at the predetermined neutral position, further adjustment of the monitor 124 relative to the work platform 106 (at step 2) is no longer required, although still an option with the accessory cart 100. Further, with the keyboard platform 110 (and computer input device platform 119), the keyboard 117 and mouse 118 are positioned in a desired ergonomic range without the need for the additional adjustment in steps 4 through 6. In addition to the ergonomic advantages discussed above, the exemplary accessory cart 100 also has advanced control and mobility. Referring to FIGS. 15A and 15B, existing mobile accessory carts 55 are typically equipped with only four free-rotating swivel casters 56, which permit the user to maneuver the cart around corners, or push it out of the way if necessary, but makes the cart difficult to steer. In particular, the momentum of the cart may be a problem if the cart is moved quickly, as the cart may become difficult to stop or turn. In addition, the carts 55 are difficult to push in a straight line, as the four swivel casters may cause the cart to move slightly from side to side as it is pushed, especially if the floors are uneven. As shown in FIGS. 16B to 16E, an exemplary base 102 includes four swivel casters 140 and a tracking wheel 144 deployable to support the base 102 as close to its center as possible to balance the weight of the cart 100 and control the movement of the cart 100 from the center of gravity. Thus, the cart 100, which rotates about the wheel 144 (when deployed), turns almost about its own center of gravity, providing better control and maneuverability. Additionally, the majority of the weight of the cart 100 is located low, close to the wheel 144, for increased control. Referring to FIG. 16C, the tracking wheel 144 is biased in a first position, in which the wheel 144 is retracted within a cavity 146 in the underside of the base 102 and does not engage a floor surface. Through a wheel release mechanism, the wheel 144 is deployed to second tracking position, in which the wheel 144 engages a floor surface, as show in FIG. 16D. As depicted in FIG. 16A, a wheel release switch 148 is disposed along the underside of the keyboard support bar 114 so that when the keyboard support bar 114 functions as the cart handle, the user's hands (inserted through the gap 120) engage the wheel release switch 148 as the user grasps the handle 114 to maneuver the accessory cart 100. When the switch 148 is engaged, by the user maintaining a grip in the switch 148, the wheel 144 is driven down to the floor surface by an electric motor housed within the base 102 and the wheel 144 is held against the floor via a primary torsion spring that allows the wheel 144 to passively travel approximately 8 mm below the nominal floor and back within the cavity 146 (approximately 25 mm about the nominal floor), while applying full contact force. This allows the wheel 144 to work across troughs and over bumps. The wheel motor applies the downward motion to the wheel 144 via a control wire that operates a lever that rotates a shaft, which lowers the wheel 144. A secondary torsion spring lifts the wheel back within the cavity 146 when the motor is reversed. The secondary spring maintains tension in the control wire. Additionally, in an embodiment, the motor can operate the wire via a pulley that is shaped to initially operate at high speed and low force to quickly take the wheel 144 to the floor and then operate at low speed and high force to compress (wind up) the primary spring. This optimizes the speed of operation and wheel contact force for a given motor size. When the switch 148 is released by the user, the wheel retracts back within the cavity 146. Thus, as shown in FIG. 16E, greater control and mobility are achieved, almost automatically, through the deployment of the tracking wheel 144 by merely grasping the cart handle 114 to maneuver the cart 100, which in turn allows the cart 100 to be easily moved out of the way when desired. As illustrated in FIG. 8, the control panel 130 can include, in addition to the height input display, a battery life indicator and a wheel tracking indicator, which informs the user as to whether or not the wheel release switch 148 is engaged and the wheel is “tracking” along the floor. As best shown in FIGS. 16C-D, the base 102 can include a front inclined surface 103, which functions as a footrest for the user while in a standing position and also provides additional toe/stride clearance. Referring to FIGS. 17A to 17D, the exemplary accessory cart 100 is designed to be used with a variety of wired or wireless computing solutions, including but not limited to a laptop housed within the work platform 106 (see FIG. 17A) or within a holder 151 at the back of the cart 100, a CPU housed within a CPU holder 153, (e.g., at the base 102 of the cart 100), or a thin client solution (see FIG. 17D). The monitor 124, keyboard 117, and mouse 118 can be connected to the computer solution through any suitable means known in the art and the computer solution can be connected to a power supply housed within the cart 100, (e.g., within the base 102), by any suitable means. As shown in FIG. 18A, the housing element 104 can be at least partially hollow to provide a cable management channel for cables connecting from a hub 134 in the base 102 (see FIG. 18C). An additional hub 138 and/or a power cord reel 136 can be housed within the work platform 106 (see FIG. 18B) or within other locations on the accessory cart, (e.g., within the base 102). This helps with infection control issues (cords are difficult to clean), and is an aesthetic improvement. Another feature aiding with infection control is the fit between the outer surface of the height adjustable housing element 104 within the cavity 146 of the housing element 104, as shown in FIGS. 19A-B. As shown in FIGS. 20A-B, the exemplary accessory cart 100 can further include a work surface 160 that extends laterally for additional workspace and storage. The work surface 160 can be stored within the work platform 106 during nonuse. FIGS. 21A-C illustrate various embodiments of additional storage drawers (FIGS. 21A and 21C), ledges (FIGS. 21B and 21C) and other accessories 162A to 162C, such as removable side bins, scanners, cup-holders, etc. The mobile accessory cart 100 can include any suitable power supply, including a rechargeable battery. Keeping the battery on mobile accessory carts charged is a challenge. Healthcare professionals are very busy, sometimes with life-threatening situations, and do not have the time to focus on keeping the accessory carts plugged in. Since the healthcare professionals usually use any cart available, and do not have one cart assigned to each person, there is no sense of ownership for any particular cart. When the battery runs low, often another cart is used and the cart that is out of power is abandoned. Without power, the carts cannot function and merely take up space. Further, running the battery down too far can also damage the battery life, which means the battery life will depreciate faster in the future and will need to be replaced more often. Referring to FIGS. 22 and 23, the exemplary accessory cart 100 is depicted as being charged wirelessly, alleviating the problems indicated above with respect to the failure to recharge accessory carts. In FIG. 22, the accessory cart 100 is charged using magnetic induction technology with a receiver 170, which is electrically coupled with a rechargeable battery, for example, within the base 102, on the base 102 communicating with transmitters 172 located within a baseboard 174 or a wallpaper along a wall 175. The positioning of the transmitters 172 allows for re-charging of the battery through induction even if the receiver 170 is not perfectly aligned with the transmitters 172, although the cart 100 should be placed as close to the baseboard 174 as possible for optimal battery charging. In FIG. 23, the accessory cart 100 is charged using resonant inductive coupling technology. Here, the receiver 176 is electrically coupled with the rechargeable battery within the base 102 and is located on the bottom of the base 102 so that the receiver 176 can communicate with daisy-chained transmitters 178 in the floor 180. Alignment of the cart 100 is even less important in this situation in view of the dispersion of the transmitters 178 throughout the flooring 180. As a result, wireless charging solutions, in which transmitters are positioned along the walls and/or flooring of the medical facility, alleviate the problems associated with having to rely on a busy healthcare professional to plug the cart 100 into a wall outlet for recharging of the battery. Moreover, a motion sensor can be included in the exemplary accessory cart 100 that is operable to detect the presence of a user at the front of the accessory cart 100 and turn on a light positioned on the front underside of the work platform 106 to light the keyboard platform 110. Furthermore, the exemplary accessory cart 100 can provide ergonomic training to the user, through a presentation device (e.g., a display on the control panel 130, a monitor such as monitor 124, and/or a speaker), on general ergonomic principles, and specific instructions for cart use. In an embodiment, the ergonomic training can be in the form of a presentation such as interactive software, a video and/or audio file, a slide show, or any other suitable medium. The ergonomic training presentation can be stored in the accessory cart 100 (for example, the ergonomic training presentation could be stored in an on-board computer), or the ergonomic training presentation could be stored in a location that is remote from the accessory cart 100, but that is in wireless communication with the accessory cart. In another embodiment, the ergonomic training could be initiated at the request of the user, such as by the user pressing a button or making a selection on the control panel 130, or, in yet another embodiment, the ergonomic training could be initiated automatically upon the accessory cart detecting the approach or arrival of a user. Automatic initiation of the ergonomic training could be particularly desirable in the event that the accessory cart 100 detects that the approaching user is a new user who has not used the accessory cart 100 previously. In yet an even further embodiment, the accessory cart 100 can have an on-board computer, which is housed within the base 102, housing element 104, or the work platform 106, and used to track information about battery use, battery life, user patterns, use positioning (sit or stand), duration of use, frequency of use, distance traveled, or other relevant information for use by the medical facility IT personnel or facility planners for understanding the use of the accessory cart 100 and future needs, or for future product development. The on-board computer can comprise a micro-controller or the processor described above or can be separate therefrom. The on-board computer can also include a collision detection feature. When adjusting the height of the work platform 106, the monitor 124, or other component of the accessory cart 100, the work platform 106, monitor 124, or other component could collide with an external object, such as a desk or shelf. Upon such a collision, the on-board computer can detect the collision (e.g., such as by detecting changes in electrical current drawn by the motor as the motor strains against the external object), stop the height adjustment movement, and then reverse the height adjustment movement for a short distance, such as a distance of one inch. The on-board computer can be capable of other functions as well, such as facilitating wired or wireless communication between components or other desirable functions. FIGS. 24 to 26 illustrate another exemplary accessory cart 200, wherein parts common with the accessory cart 100 are denoted by like reference numerals increased by 100. In this embodiment, the monitor mount 221, which aids in the monitor 224 being able to be raised above the work platform 206, has a different structure as compared to the monitor mount 121 depicted, for example, in FIG. 1. FIGS. 24-26 should not be construed as limiting the monitor mount 221 structurally as the monitor mount 221 and can take many different forms. As shown in FIGS. 24 to 26, the monitor mount 221 includes an adjustment mechanism 250 (e.g., a Universal Front-End Adjuster manufactured by Humanscale®) attached to the monitor arm 225, which allows for height adjustment of the monitor 224. Exemplary adjustment mechanisms are described in U.S. application Ser. No. 11/150,870, and U.S. application Ser. No. 12/102,312, each of which is hereby incorporated herein by reference in its entirety. The adjustment mechanism 250 allows for additional height adjustment of the monitor 224 independently of the work platform 206 to account for differences between the eyes and elbows of users with varying height. The monitor 225 can be adjusted manually via the adjustment mechanism 250 or automatically via a motorized lift mechanism specific to monitor adjustment and coupled to the adjustment mechanism 250 (as similarly disclosed above with respect to the accessory cart 100). Additionally, in the exemplary embodiment, the monitor arm 225 is rotatably attached to the support frame 222 such that it is operable to rotate about an axis substantially parallel with the housing element 204 to turn the monitor 224 around to allow for patient viewing. In this embodiment, the telescoping aspect of the housing element 204 is reversed such that the larger housing element 204 is connected to the base 202 and the narrow housing element 204 is located closer to the work platform 206. Although the keyboard platform 210 is slightly different in structure from the keyboard platform 110 of the accessory cart 100, the keyboard platform 210 can take many forms, can be fixed at an ergonomic negative angle, and can function as a handle through. FIGS. 27 and 28 illustrate additional embodiments of accessory carts 300 and 400, respectively, similar to the previously disclosed accessory carts 100 and 200, but with different work platform options. As shown in FIG. 27, the work platform 306 includes a slot within which a monitor rests. The work platform 406 in FIG. 28 extends vertically, in place of a monitor mount, and includes a recess within which the keyboard portion of a laptop is positioned. The laptop monitor extends above the work platform 406 and is supported by a monitor support 425 attached to the work platform 406. The work platform 406 thus elevates the laptop to a predetermined ergonomic position. FIGS. 29A-C illustrate additional configurations of storage options 600, 602, 604 (e.g., side drawers, ledges, and cable management) that can be incorporated into any of the accessory cart embodiments. Alternatively, FIGS. 30A through 30D, 32 and 34 through 36, depict yet another embodiment of an accessory cart 500. As shown, the accessory cart 500 includes a keyboard platform 510 with arms 511 that extend from a work platform 506, a keyboard support surface 516, and a u-shaped support bar 514a that is spaced from the keyboard support surface 516. The keyboard support surface 516, which is located in the keyboard platform 510, is permanently fixed at a negative angle and is not slidable. Instead, the keyboard support surface 516 is fixed at an unadjustable position on the keyboard platform 510 such that a permanent gap 520 is created between the keyboard support surface 516 and the support bar 514. The cart 500 further includes a first groove 550, which is formed in the work surface 508 and a second groove, which is formed in a bottom surface of the work platform 506. The grooves 550, 552 allow the computer input device platform 150 to be slideable laterally about the work surface 506 of the cart 500. Additionally, FIGS. 30A to 34E include yet additional drawer configurations and storage options 606, 608, 610 and 612 that can be incorporated into any accessory cart embodiment. The accessory carts can be configured with drawers of different sizes and shapes to accommodate various storage needs. As shown in FIG. 30A, a single drawer 610 is incorporated into the cart 500. Alternatively, FIGS. 30B through 30D illustrate the cart 500 configured with multiple drawers 608, 610, 612 of different sizes and shapes. Each drawer can be equipped with a latch mechanism, which secures the drawer in place or locks the drawer to prevent unauthorized access. FIG. 31 illustrates a perspective view of one drawer 606 configuration that can be incorporated in any of the described accessory carts. FIGS. 33A through 33E show various additional accessories 614 and 616 that can be attached or installed on any accessory cart described herein. FIG. 36 illustrates a cross-sectional view of the computer input device platform 150 assembled with the accessory cart 500. However, it should be noted again that the computer input device platform 150 can be used with any accessory cart embodiment described herein. As depicted, the computer input device platform 150 extends from the work surface 508 around the front of the cart 500 and terminates at an underside of the work platform 506. To secure the computer input device platform 150 to the cart 500, the first protrusion 159 is arranged in the first groove 550 and the second protrusion 158 is arranged in a second groove 552. The computer input device platform 150 can be arranged in the grooves 550, 552 by any known means, including, but not limited to, a snap-fit. Finally, FIGS. 37 and 38 illustrate various views the computer input device platform 150 described in detail above. The foregoing description and accompanying drawings illustrate the principles, exemplary embodiments, and modes of operation of the invention. However, the invention should not be construed as being limited to the particular embodiments discussed above. Additional variations of the embodiments discussed above will be appreciated by those skilled in the art and the above-described embodiments should be regarded as illustrative rather than restrictive. Accordingly, it should be appreciated that variations to those embodiments can be made by those skilled in the art without departing from the scope of the invention.
<SOH> BACKGROUND OF THE INVENTION <EOH>Mobile accessory carts that carry computers are commonly used in healthcare and other industries to provide portable workstations. Similar to a computer workstation in an ordinary office setting, ergonomic features are important for mobile accessory carts as well. For example, the height of the work surface, keyboard, and monitor all play a major role in ergonomics because posture is determined by sight and reach. Adjustability of the height of the work surface, keyboard, and/or monitor is very important as users come in all shapes and sizes. While current mobile accessory carts allow users to adjust the height of the work surface, keyboard, and/or monitor, the adjustability mechanisms are often cumbersome and complicated and require many steps. As a result, users are not making the necessary adjustments to mobile accessory carts. This is especially true in the healthcare industry, where healthcare professionals typically use multiple mobile accessory carts throughout the day, for an average of only approximately three to four minutes at a time. Further, many healthcare professionals do not receive the proper training regarding optimal ergonomic positioning of the work surface, keyboard, and monitor of a mobile accessory cart. Therefore, in rare situations in which users do make adjustments to a mobile accessory cart, they are often not ergonomically correct for the particular user. By not making the proper ergonomic adjustments, continuous work in a poor ergonomic position leads to repetitive strain injuries, which are increasingly being reported by healthcare professionals.
<SOH> SUMMARY OF THE INVENTION <EOH>An embodiment of the present invention is directed to an accessory cart that comprises a base, a housing element, which is connected to the base, extending upward from the base and a work platform that is connected to the housing element with the height of the work platform being automatically adjustable. An embodiment of an accessory cart where the work platform is automatically adjustable to a plurality of predetermined heights and each of the plurality of predetermined heights corresponds to a measurable aspect of a potential user. An embodiment of an accessory cart where the measurable aspect of the potential user is a height of the potential user. An embodiment of an accessory cart where the height of the work platform is automatically adjustable without a need for a user to manually make a selection on the accessory cart. An embodiment of an accessory cart, which comprises a sensor, and the height of the work platform is automatically adjustable based on information obtained by the sensor about the user. An embodiment of an accessory cart, which comprises a deployable tracking wheel, which is located at about a center of gravity of the accessory cart, connected to the base. An embodiment of an accessory cart, which comprises a release switch with the tracking wheel being deployable in a first state by continuous engagement of the release switch by a potential user and the tracking wheel being retractable in a second state by disengagement of the release switch by the potential user. An embodiment of an accessory cart where the work platform has a first groove formed in a first surface of the work platform and a second groove formed in a second surface of the work platform, which opposes the first surface and the computer input device platform is slideable along the first groove and the second groove at most to a first lateral edge or a second lateral edge of the work platform. An embodiment of an accessory cart where the accessory cart comprises a computer input device platform that is removably connected to the work platform. An embodiment of an accessory cart, which comprises a power supply located on the accessory cart with the power supply capable of being wirelessly charged. An embodiment of an accessory cart, which comprises a keyboard platform that is fixed at an ergonomically negative angle. An embodiment of an accessory cart, which comprises a keyboard support surface and the keyboard support surface is fixed at an ergonomically negative angle. An embodiment of an accessory cart, which comprises a computer input device platform that is magnetically connectable to the keyboard support surface. An embodiment of a method of adjusting a height of a platform of an accessory cart, that comprises the steps of equipping the accessory cart with a plurality of predetermined platform heights, and automatically adjusting the platform to at least one of the plurality of predetermined platform heights. An embodiment of a method of adjusting a height of a platform of an accessory cart where the method comprises the step of corresponding a measurable aspect of a potential user to at least one of the plurality of predetermined platform heights. An embodiment of a method of adjusting a height of a platform of an accessory cart where the method comprises the step of corresponding a height of a potential user to at least one of the plurality of predetermined platform heights. An embodiment of a method of adjusting a height of a platform of an accessory cart where the method comprises the step of wirelessly charging a power supply located on the accessory cart. An embodiment of a method of adjusting a height of a platform of an accessory cart where the method comprises the step of deploying a tracking wheel from a base of the accessory cart. An embodiment of an accessory cart that comprises a base, a housing element, which is connected to the base, extending upward from the base, a platform, which is connected to the housing element and a means for automatically adjusting a height of the platform.
A47B2104
20170915
20180125
96764.0
A47B2104
1
TO, TOAN C
Accessory Cart
UNDISCOUNTED
1
CONT-ACCEPTED
A47B
2,017
15,707,891
PENDING
BONE PLATE WITH A TRANSFIXATION SCREW HOLE
A system for securing bones together across a joint includes a transfixation screw and a plate. The plate includes an elongate spine having a transfixation screw hole disposed along the spine. The transfixation screw hole includes an inner surface configured to direct the transfixation screw through the transfixation screw hole such that the transfixation screw extends alongside the bridge portion at a trajectory configured to pass through a first position on the first bone and a second position on the second bone once the plate is placed across the joint. The transfixation screw includes a head configured to abut the inner surface of the transfixation screw hole and a shaft configured to contiguously extend through the first bone, across the joint, and into the second bone.
1. A system for securing bones together across a joint, comprising a transfixation screw and a plate wherein: the plate comprises: an elongate spine having a first end comprising at least one attachment point for attaching the first end to a first bone on a first side of a joint, a second end comprising at least one attachment point for attaching the second end to a second bone on a second side of the joint, and a bridge portion disposed between the first end and the second end, the bridge portion configured to span across the joint; and a transfixation screw hole disposed along the spine, the transfixation screw hole comprising an inner surface configured to direct the transfixation screw through the transfixation screw hole such that the transfixation screw extends alongside the bridge portion at a trajectory configured to pass through a first position on the first bone and a second position on the second bone once the plate is placed across the joint; and the transfixation screw comprises a head configured to abut the inner surface of the transfixation screw hole and a shaft configured to contiguously extend through the first bone, across the joint, and into the second bone.
CROSS-REFERENCE TO RELATED APPLICATIONS The present application is a continuation of co-pending, commonly assigned, patent application Ser. No. 15/147,828 entitled “BONE PLATE WITH A TRANSFIXATION SCREW HOLE,” filed May 5, 2016, which is a continuation of patent application Ser. No. 14/015,900 entitled “BONE PLATE WITH A TRANSFIXATION SCREW HOLE,” filed Aug. 30, 2013, which is a continuation of patent application Ser. No. 12/431,017 entitled “BONE PLATE WITH A TRANSFIXATION SCREW HOLE,” filed Apr. 28, 2009, U.S. Pat. No. 8,529,608, issued Sep. 10, 2013, the disclosures of which are hereby incorporated herein by reference in their entirety. TECHNICAL FIELD The present disclosure relates to a device for securing bones together, and more particularly, to a bone plate with a transfixation screw hole. BACKGROUND OF THE INVENTION When performing certain medical procedures, such as reconstructing a joint that has been damaged due to bone or soft tissue trauma, a surgeon may need to fuse the bones of the joint together in a configuration that approximates the natural geometry of the joint. One way to achieve this objective is to attach the bones of the joint to a plate that holds the bones in alignment with one another while they fuse together. BRIEF SUMMARY OF THE INVENTION The present disclosure relates generally to orthopedic devices. More specifically, the present disclosure relates to a bone plate with a transfixation screw hole for securing the bones of a joint together and a method for using the same. In particular embodiments, a system for securing bones together across a joint includes a transfixation screw and a plate. The plate includes an elongate spine having a first end that includes at least one attachment point for attaching the first end to a first bone on a first side of a joint, a second end that includes at least one attachment point for attaching the second end to a second bone on a second side of the joint, and a bridge portion disposed between the first end and the second end configured to span across the joint. The plate further includes a transfixation screw hole disposed along the spine. The transfixation screw hole includes an inner surface configured to direct the transfixation screw through the transfixation screw hole such that the transfixation screw extends alongside the bridge portion at a trajectory configured to pass through a first position on the first bone and a second position on the second bone once the plate is placed across the joint. The transfixation screw comprises a head configured to abut the inner surface of the transfixation screw hole and a shaft configured to contiguously extend through the first bone, across the joint, and into the second bone. Depending upon design, a central axis of the inner surface of the transfixation screw hole may define the trajectory, and the trajectory may be configured to cross a neutral bending axis of the joint once the plate is placed across the joint. in particular embodiments, a plate for securing bones together may include an elongate spine having a first end that includes at least one attachment point for attaching the first end to a first bone on a first side of a joint, a second end that includes at least one attachment point for attaching the second end to a second bone on a second side of the joint, and a bridge portion disposed between the first end and the second end configured to span across the joint. The plate may further include a transfixation screw hole disposed along the spine. The transfixation screw hole includes an inner surface configured to direct a transfixation screw through the transfixation screw hole such that the transfixation screw extends alongside the bridge portion at a trajectory configured to pass through a first position on the first bone and a second position on the second bone once the plate is placed across the joint. In particular embodiments, a method for securing bones together across a joint includes placing a plate over a first bone on a first side of a joint and a second bone on a second side of the joint. The plate may include an elongate spine having a first end that includes at least one attachment point for attaching the first end to the first bone, a second end that includes at least one attachment point for attaching the second end to the second bone, and a bridge portion disposed between the first end and the second end configured to span across the joint. The plate may further include a transfixation screw hole disposed along the spine. The transfixation screw hole includes an inner surface configured to direct the transfixation screw through the transfixation screw hole such that the transfixation screw extends alongside the bridge portion at a trajectory configured to pass through a first position on the first bone and a second position on the second bone once the plate is placed across the joint. The method may further include attaching the plate to the first bone and the second bone, and inserting a transfixation screw into the first bone and the second bone through the transfixation screw hole. The transfixation screw may include a head configured to abut the inner surface of the transfixation screw hole and a shaft configured to contiguously extend through the first bone, across the joint, and into the second bone. Particular embodiments of the present disclosure may provide a number of technical advantages, including for example, the ability to tightly couple the bones of a joint together by inserting a transfixation screw across the joint through a bone plate. In particular embodiments, the transfixation screw may have a “lag effect” that enables the bones of the joint to be approximated with one another by rotation of the transfixation screw. For example, the transfixation screw may include an unthreaded portion configured to rotate freely within the first bone and a threaded portion configured to threadably engage the second bone. When the transfixation screw is rotated, the unthreaded portion of the transfixation screw may rotate freely within the first bone while the threaded portion of the transfixation screw advances into the second bone, drawing the second bone toward the first bone and compressing the joint. These technical advantages (e.g., the presence of the transfixation screw across the joint, and the lag effect of the transfixation screw) may increase the contact pressure on the bony interface of the joint, increasing the probability of a positive fusion. Depending upon design, the inner surface of the transfixation screw hole in the plate may direct the transfixation screw along a trajectory that crosses a neutral bending axis of the joint as the transfixation screw passes from the first bone to the second bone. This technical advantage may create a “tension band” construct that enables the transfixation screw to absorb a portion of the mechanical stress that would otherwise be imposed upon the plate above the joint when a load is applied to the joint. This technical advantage may enhance the integrity and reliability of the plate and increase the load that the plate may support without increasing plate thickness. Other technical advantages of the present disclosure will be readily apparent to one skilled in the art from the following figures, descriptions, and claims. Moreover, while specific advantages have been enumerated above, various embodiments may include all, some, or none of the enumerated advantages. BRIEF DESCRIPTION OF THE DRAWINGS For a more complete understanding of the present disclosure and its advantages, reference is now made to the following descriptions, taken in conjunction with the accompanying drawings, in which: FIG. 1 illustrates a failed metatarso-phalangeal joint in the big toe of a human foot; FIG. 2 illustrates a bone plate being used in conjunction with a transfixation screw to repair the failed metatarso-phalangeal joint of FIG. 1 according to an example embodiment of the present disclosure; FIG. 3 illustrates a more detailed isometric view of the bone plate of FIG. 2; and FIG. 4 illustrates a bone plate adapted for use on a tarso-metatarsal joint according to an example embodiment of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION The metatarso-phalangeal joint is a joint between a metatarsal bone of the foot and the proximal phalanx of a toe. It is common, particularly in sports, for the first metatarsophalangeal joint (e.g., the metatarso-phalangeal joint of the big toe) to be injured as a result of trauma to or hyper extension of the big toe. In other scenarios, degradation of the metatarsophalangeal joint may be caused by arthritis. Minor injuries to the metatarso-phalangeal joint, such as a sprain, may often be treated using conservative measures such as immobilization and icing of the toe, accompanied by rest and anti-inflammatory medication. These measures may be followed by taping or splinting of the injured joint to help prevent recurrent hyperextensions of the toe. In more severe cases involving major trauma to the bone or soft tissue of the metatarso-phalangeal joint, as illustrated in FIG. 1, conservative measures may be ineffective, and surgery may be required. One procedure for reconstructing a severely damaged metatarso-phalangeal joint involves fusing the bones of the joint together using plates and/or screws. More particularly, a fusion procedure may involve reducing the opposing faces of the bones of the joint to a bleeding bone bed, approximating the bones with one another, and screwing the bones together to promote fusion. In some cases, the bones may be screwed together without the use of a plate. However, this option may not provide adequate lateral support for the bones, possibly allowing them to shift out of alignment, resulting in a malunion or a nonunion of the joint. Another option for surgically repairing a severely damaged metatarso-phalangeal joint involves securing the bones of the joint together using a plate. In this procedure, after the bones of the joint have been approximated next to one another, the plate may be laid across the joint. The plate may then be screwed to the bones of the joint to hold them in alignment next to one another, enabling the joint fuse. However, when a load is placed upon the joint (e.g., when weight is placed upon the foot) it is possible for the plate to bend or break above the joint. This may cause the bones of the joint to fall out of approximation, resulting in a non-union (e.g., a failed fusion of the joint). Consequently, the ability to rigidly hold the bones of a joint in tight approximation without bending or breaking is one metric for judging the effectiveness of a joint-fixation plate. One way to increase the durability and reliability of a joint-fixation plate is to include a transfixation screw hole in the plate that enables a transfixation screw to transfix the joint through the plate. As explained in more detail below, once the transfixation screw is screwed across the joint, it may absorb some of the stress that would otherwise be exerted on the plate when a load is placed upon the joint. This may reduce the strain on the plate, increasing its reliability and durability. Additionally, while the plate may provide lateral support for the joint, the transfixation screw may hold the bones of the joint in tight approximation, increasing the likelihood of a positive fusion of the joint. This may be particularly important on the plantar side of the joint due to tensile stresses exerted on that side of the joint when loaded. FIGS. 2-3 illustrate an example embodiment of a bone plate 100 that includes a transfixation screw hole 102 in accordance with the present disclosure. More particularly, FIG. 2 illustrates bone plate 100 being used in conjunction with a transfixation screw 150 to repair the failed metatarso-phalangeal joint of FIG. 1. FIG. 3 illustrates a more detailed isometric view of bone plate 100. For reference purposes, bone plate 100 and its various features may be referred to as having a top surface intended to face away from the bones of joint 106 and a bottom surface intended to face toward the bones of joint 106 (e.g., to be placed upon the bones of joint 106). Though particular features of bone plate 100 may be explained using such intended placement as a point of reference, this method of explanation is not meant to limit the scope of the present disclosure to any particular configuration or orientation of bone plate 100. As shown in FIG. 2, bone plate 100 is being used to reconstruct a failed joint 106 of a human foot. In particular, FIG. 2 illustrates transfixation screw 150 being inserted through bone plate 100 into a first bone 104a and a second bone 104b (collectively, bones 104) in order to fuse joint 106 (show collapsed in FIG. 1). Bone 104a refers to the bone positioned directly beneath transfixation screw hole 102 (e.g., touching the bottom surface of transfixation screw hole 102) while bone 104b refers to the bone positioned on the opposite side of joint 106. Although bone 104a is illustrated and described as the first metatarsal, bone 104b is illustrated and described as the first proximal phalanx, and joint 106 is illustrated and described as the metatarso-phalangeal joint 106 of the big toe, one of ordinary skill in the art will appreciate those specific examples are presented for the sake of explanatory clarification and will further appreciate that bones 104 and joint 106 may generically refer to any suitable set of bones forming any suitable joint in the body. In a typical procedure, a surgeon may use bone plate 100 to fuse joint 106 according to the following example surgical procedure. To begin the procedure, the surgeon may create an incision over joint 106 to expose bones 104. After exposing bones 104, the surgeon may perform any pre-fusion steps such as removing cartilage from joint 106 and reducing the opposing faces of bones 104 to a bleeding bone bed. Following the pre-fusion steps, the surgeon may approximate bones 104 by positioning them next to one in a desired configuration for fusion. The surgeon may then secure bones 104 together by placing bone plate 100 across joint 106 such that transfixation screw hole 102 overlies bone 104a. The surgeon may screw bone plate 100 to bones 104, for example by inserting one or more bone screws 134 into one or more screw holes located on either end of bone plate 100, after which, the surgeon may create a path for transfixation screw 150. To create a path for transfixation screw 150, the surgeon may drill a pilot hole into bones 104 through transfixation screw hole 102. In particular embodiments, the surgeon may use the central axis 116 of transfixation screw hole 102 as a guide to establish the trajectory for the pilot hole. Once the pilot hole has been created, transfixation screw 150 may be inserted into the pilot hole through transfixation screw hole 102 and screwed into bones 104 until the head of transfixation screw 150 abuts the inner surface of transfixation screw hole 102. After bones 104 have been secured together using transfixation screw 150, the surgeon may close the incision, leaving bones 104 to fuse together. To facilitate the process of aligning bones 104, bone plate 100 may include one or more joint-specific characteristics that may conform to the natural geometry of joint 106 or bones 104. For example, in the case of the metatarso-phalangeal joint, bone plate 100 may include a rise (similar to rise 210 in FIG. 4) that fits over the head on the dorsal section of metatarsal 104a. This may enable bone plate 100 to be seated firmly against the head of metatarsal 104a and provide a natural footing for bone plate 100 against metatarsal 104a. In other embodiments, the rise may be eliminated from bone plate 100 and the dorsal head of metatarsal 104a may be ground down to enable bone plate 100 to be laid flush against bones 104. Depending upon design, bone plate 100 may further include a dorsiflexion angle (of approximately 10 degrees) between the first end 126b of the plate and the second end 126a of the plate that mimics the natural elevation of the first metatarsal 104a relative to the first proximal phalanx 104b. The inclusion of a dorsiflexion angle between first end 126b and second end 126a may reduce the force on bone plate 100 during activities such as walking. Furthermore, bone plate 100 may include a valgus angle (of approximately 10 degrees) between the first end 126b of the plate and the second end 126a of the plate that mimics the natural lateral alignment of the first metatarsal 104a relative to the first proximal phalanx 104b. The inclusion of a valgus angle in bone plate 100 may further help to reduce the force on bone plate 100 during activities such as walking. In particular embodiments, to provide lateral support for joint 106, the ends of plate 100 may be may be curved around the medial side of bones 104. One of ordinary skill in the art will appreciate that above-described characteristics of bone plate 100 were described with respect to the metatarso-phalangeal joint for the sake of explanatory simplicity and will further appreciate that particular embodiments of bone plate 100 may be adapted equally as well to approximate the natural geometry of virtually any joint 106 in the body without departing from the scope of the present disclosure. As mentioned above, transfixation screw 150, once inserted across joint 106, may absorb a portion of the stress that would otherwise be exerted on the portion of bone plate 100 spanning across joint 106 when a load is placed upon joint 106. For example, in the case of the metatarso-phalangeal joint 106, activities that place weight on the foot, such as walking or standing, may cause metatarso-phalangeal joint 106 to flex. Due to the biomechanics of the foot, when the metatarso-phalangeal joint 106 flexes, the upper or “dorsal” side of joint 106 will compress together, while the bottom or “plantar” side of joint 106 will draw apart under tension. This is generally true for any hinge-type joint. The line about which the force on joint 106 transitions from tension to compression may be referred to as the neutral bending axis 118 of the joint 106. In other words, neutral bending axis 118 defines the boundary line that separates the tension side of joint 106 from the compression side of joint 106. When transfixation screw 150 is screwed into joint 106 along a trajectory that crosses neutral bending axis 118 (as show in FIG. 2), a “tension band” construct is created that puts transfixation screw 150 under tension when joint 106 flexes. Normally, the plantar side of bone 104a (e.g., the portion of bone 104a on the tension side of joint 106) will draw away from the plantar side of bone 104b when a load is applied to joint 106. However, when transfixation screw 150 is screwed across joint 106 such that the head 152 of transfixation screw 150 abuts the inner surface of transfixation screw hole 102, the portion of transfixation screw 150 engaged with bone 104b will pull against the head 152 of transfixation screw 150 when a load is applied to joint 106. Since the head of transfixation screw 150 is braced against the inner surface of transfixation screw hole 102, it will absorb the tension forces transmitted up the shaft of transfixation screw 150, preventing the plantar side of bone 104b from drawing away from the plantar side of bone 104a. In particular embodiments, the interface between bone 104a and transfixation screw 150 may provide another mechanism for absorbing the tension forces transmitted up the shaft of transfixation screw 150. For example, if transfixation screw 150 is threadably engaged with bone 104a, the threading on transfixation screw 150 may provide a footing against bone 104a which may also absorb a portion of the tension forces transmitted up the shaft of transfixation screw 150 from bone 104b when a load is applied to joint 106. In either case, once transfixation screw 150 has been screwed into joint 106 along a trajectory that crosses the neutral bending axis 118 of joint 106, a tension band construct may be created that enables transfixation screw 150 to absorb the tension forces that would otherwise draw the tension side of joint 106 apart when a load is placed on joint 106. In particular embodiments, transfixation screw hole 102 may be used to establish the trajectory for transfixation screw 150. For example, bone plate 100 may be configured such that, once bones 104 have been approximated and bone plate 100 has been placed across joint 106, the central axis 116 of transfixation screw hole 102 may align along a trajectory that crosses the neutral bending axis 118 of joint 106. For example, the central axis 116 of transfixation screw hole 102 may be configured to pass through joint 106 at a transfixation angle 114 of about 30 degrees to about 70 degrees relative to neutral bending axis 118 to achieve the desired tension band construct once bone plate 100 is secured across joint 106. In one example embodiment, central axis 116 may be configured to pass through joint 106 at a transfixation angle 114 of about 50 degrees. Consequently, by drilling a pilot hole along central axis 116, a surgeon may create a path for transfixation screw 150 that spans from a first position 120 on bone 104a located on the compression side of joint 106 to a second position 122 on bone 104b located on the tension side of joint 106, creating the desired tension band construct for transfixation screw 150. Alternatively, a surgeon may forgo drilling a pilot hole and may instead use a transfixation screw 150 having a self drilling feature. In that case, the surgeon could achieve a tension band construct by screwing the transfixation screw 150 directly into joint 106 along the trajectory of central axis 116. Transfixation screw 150 may be any component of hardware having a head 152 configured to abut the surface of bone plate 100 and a shaft 154 operable to secure bones 104 together in a fixed configuration. For example, transfixation screw 150 may be a nut and bolt assembly, a pin assembly, or a bone screw. As another example and not by way of limitation, transfixation screw 150 may be a lag screw that includes a head 152 coupled to a shaft 154 having an unthreaded portion 156 and a threaded portion 158 that ends at a tip 156. Once transfixation screw 150 is screwed into bones 104 through transfixation screw hole 102, this configuration of transfixation screw 150 may result in a lag effect that may tighten the interface between bones 104 when transfixation 150 is rotated. In particular embodiments, the length of shaft 154 may be less than the length of the portion of central axis 116 that passes through bones 104 in order to keep tip 156 from protruding out of bone 104b (e.g., out of the plantar aspect of first proximal phalanx 104b) when transfixation screw 150 screwed into bones 104. To achieve a lag effect, a surgeon, after affixing bone plate 100 across joint 106 and drilling a pilot hole for transfixation screw 150 as described above, may screw transfixation screw 150 into joint 106 until unthreaded portion 156 extends completely through bone 104a and threaded portion 158 threadably engages bone 104b. At this point, further rotation of transfixation screw 150 may cause threaded portion 158 to advance further into bone 104b, causing bone 104b to ride up further onto shaft 154 and press against bone 104a while unthreaded portion 156 spins freely within bone 104a. Transfixation screw 150 may be further rotated under these conditions until head 152 conies to bear on the inner surface of transfixation screw hole 102, cinching bone 104a between the bottom surface of bone plate 100 and bone 104b. This may create a tight interface between bones 104, increasing the chance of a positive fusion. In another example procedure, a lag effect may be achieved by drilling a pilot hole in bone 104a that is larger in diameter than shaft 154. This may enable transfixation screw 150 to spin freely within bone 104a to achieve the desired lag effect, even if the entirety of shaft 154 is threaded. FIG. 3 illustrates an external view of the top surface of bone plate 100. In particular embodiments, bone plate 100 may be characterized by a substantially thin construction that generally includes an elongate spine 124 having a first end 126a that includes at least one attachment point 128 for attaching first end 126a to bone 104a, a second end 126b comprising at least one attachment point 128 for attaching second end 126b to bone 104b, and a bridge portion 130 disposed between ends 126 configured to span across joint 106. Bone plate 100 may further include a transfixation screw hole 102, and a compression hole 132 which may be used to cinch bones 104 together using a bone screw 134. Each attachment point 128 may be any mechanism or fixture operable to serve as a rigid point of attachment between bone plate 100 and a bone 104. As one example and not by way of limitation, an attachment point 128 may be an unthreaded screw hole in bone plate 100 configured to accept a bone screw 134. As another example and not by way of limitation, an attachment point 128 may be a threaded screw hole that provides a locking interface between bone screw 134 and bone plate 100. To accomplish this locking interface, the underside of the head of screw 134 may include threads that interfere with the threading on the inside of the threaded screw hole to lock bone screw 134 into bone plate 100. Consequently, once bone screw 134 is screwed into bone 104 through the threaded screw hole, bone screw 134 may be prevented from loosening or backing out of bone 104. An example system for providing a locking interface between a screw hole and a screw is presented in U.S. Provisional Application No. 61/106,511, entitled, “Angulated Locking Plate/Screw Interface.” In particular embodiments, the inner surface of transfixation screw hole 102 may also be threaded to provide a locking interface between transfixation screw 150 and bone plate 100. In this case, the head of transfixation screw 150 may also be threaded. As another example and not by way of limitation, an attachment point 128 may be any type of clip or clamp included on bone plate 100 operable to rigidly affix bone plate 100 to a bone. One of ordinary skill in the art will appreciate that the above-described embodiments of attachment points 128 were presented for the sake of explanatory clarification and will further appreciate that the present disclosure contemplates each attachment point 128 being any suitable mechanism or fixture operable to serve as a rigid point of attachment between bone plate 100 and bone 104. Spine 124 may generally define the central portion of bone plate 100 spanning along the length of bone plate 100. As an example and not by way of limitation, spine 124 may include a contiguous linear or curvilinear section of bone plate 100 spanning from the tip of first end 126a to the tip of second end 126b. As mentioned above, spine 124 includes a bridge portion 130 configured to span across joint 106. Since bridge portion 130 is configured to span across joint 106, it is typically defined by an unbroken section of spine 124 that is free of voids such as positioning holes or screw holes that could potentially reduce the bending strength of bridge portion 130. Depending upon design, bridge portion 130 may include a thickened section 136 of bone plate 100 to increase the bending strength of bridge portion 130. This may lessen the risk of bridge portion 130 bending or breaking above joint 106 when a load is applied to joint 106. In particular embodiments, thickened section 136 may be defined by a thickened ridge of material in hone plate 100 having its greatest thickness along bridge portion 130 and gradually decreasing in thickness as one moves away from bridge portion 130 along the length of bone plate 100 toward ends 126. The increased material thickness may provide central section 130 with a higher section modulus than the proximal and distal areas of the plate located at ends 126. In a typical design, thickened section 136 may be about 100% to 200% thicker than the adjacent portions of bone plate 100. Including thickened section 136 in bone plate 100 may confer a number of advantages over plates of uniform thickness, one of which is the ability to efficiently increase the section modulus (and strength) of bridge portion 130 without adding material thickness to the entirety of bone plate 100. Transfixation screw hole 102 may be defined by an inner surface of bone plate 100 surrounding a generally circular opening in bone plate 100, As an example and not by way of limitation, transfixation screw hole 102 may be disposed along the center line 138 of spine 124, immediately adjacent to bridge portion 130. In the case of a bone plate 100 designed for use on the first metatarso-phalangeal joint, the placement of transfixation screw hole 102 adjacent to bridge portion 130 may enable transfixation screw 102 to penetrate the first metatarsal 104a on the dorsal aspect of the metatarsal head and pass into the plantar cortex of the first medial phalanx 104b, transfixing the metatarso-phalangeal joint 106. In particular embodiments, the portion of bone plate 100 that includes transfixation screw hole 102 may be thicker than other portions of hone plate 100. For example, transfixation screw hole 102 may be included in thickened section 136, adjacent to bridge portion 130. This may enable a countersink to be created around transfixation screw hole 102 so that the head 152 of transfixation screw 150 may rest flush with the top surface of bone plate 100 once transfixation screw 150 is screwed into transfixation screw hole 102. The increased plate thickness around transfixation screw hole 102 may also enable transfixation screw hole 102 to be machined into bone plate 100 at an angle relative to the top surface of bone plate 100 (e.g., other than perpendicular to the top surface of bone plate 100). As mentioned above, in particular embodiments, bone plate 100 may include a compression hole 132 for tightening bones 104 together using a bone screw 134. Compression hole 132 may be defined by an inner surface of bone plate 100 surrounding a generally oblong opening in bone plate 100. More particularly, the inner surface of compression hole 132 may have a narrow end 131a, and a wide end 131b that includes a horse-shoe-shaped countersink 133. To compress bones 104 together using compression hole 132, a surgeon may use the following example procedure. The surgeon may begin by attaching the second end 126b of bone plate 100 to bone 104b using the attachment points 128 located on end 126b. The surgeon may then manually approximate bone 104a against bone 104b, placing bone 104a under compression hole 132. While holding bone 104a against the bottom surface of compression hole 132, either by hand or using a clamp, the surgeon may drill a pilot hole for bone screw 134 into bone 104a. The trajectory of the pilot hole may be generally perpendicular to the top surface of bone plate 100 and be located approximately in the center of narrow end 131a (e.g., located at the focus of narrow end 131a). After creating the pilot hole, the surgeon may then screw bone screw 134 into the pilot hole until the head of bone screw 134 comes into contact with countersink 133 near the tips 135 of countersink 133. To facilitate the compression feature, the underside of the head of bone screw 134 may be generally conical, having a taper angle approximately equal to the taper angle of countersink 133. Once the head of bone screw 135 is in contact with counter sink 133 near tips 135, further rotation of bone screw 135 may cause the head of bone screw 134 to ride down into countersink 133, drawing bone plate 100 further up onto bone 104a and causing bones 104 to press together at the interface of joint 106. After approximating bones 104 by screwing bone screw 134 into compression hole 132 as just described, the surgeon may use other attachment points 128 to further secure bone plate 100 to bone 104a. The surgeon may also screw transfixation screw 150 into joint 106 through transfixation screw hole 102 after tightening bones 104 together using compression hole 132. Depending upon design, compression hole 132 may be threaded to provide a locking interface for bone screw 134. In particular embodiments, bone plate 100 may comprise one or more positioning holes 140 that may be used to position bone plate 100 relative to the bones 104 of joint 106. To position bone plate 100 using a positioning hole 140, a surgeon may insert a K-wire into one of the bones 104, after which the surgeon may position bone plate 100 on bone 104 by inserting the K-wire through positioning hole 140 and sliding bone plate 100 down onto bone 104. Additionally, the surgeon may rotate bone plate 100 about the K-wire using positioning hole 140 to achieve a desired orientation of bone plate 100 relative to bone 104. To ensure that bone plate 100 may be precisely positioned on bone 104 using a K-wire, the diameter of positioning hole 140 may be approximately equal to the diameter of the K-wire. Once bone plate 100 has been properly positioned, the surgeon may secure bone plate 100 to bone 104, temporarily for example, by inserting another K-wire into another one of positioning holes 140, or more permanently, using attachment points 128. In particular embodiments, the bottom surface of bone plate 100 may include one or more contact reduction features 146 which may reduce the amount of surface area of bone plate 100 that contacts bones 104 when bone plate 100 is secured across joint 106. As an example and not by way of limitation, the bottom surface of bone plate 100 may include one or more channels, notches, or other recessions which may reduce (e.g., minimize) the amount of bone plate 100 that contacts bones 104. This may lessen the amount of vascular impingement caused by bone plate 100, promoting blood flow to bones 104 and bone growth. In particular embodiments, each of the screw holes in bone plate 100 (e.g., attachment points 128, compression hole 132, or transfixation screw hole 102) may include a countersink capable of seating the head of a screw flush with the top surface of bone plate 100. This feature may provide several benefits such as lessening the chance of uncomfortable impingement on the surrounding soft tissue, and reducing patient palpation and visualization of bone plate 100. In particular embodiments, bone plate 100 may further include flared hips 148 adjacent to transfixation screw hole 102. Flared hips may generally be defined by a widened section of bone plate 100. As an example and not by way of limitation, flared hips 148 may include two generally parabolic wings extending laterally from spine 124, symmetrically opposed to one another about transfixation screw hole 102. As will be appreciated by one of skill in the art, the entry point for transfixation screw 150 into bone 104a may be generally be located at the center of the bottom side of transfixation screw hole 102 when transfixation screw is inserted into transfixation screw hole 102 along central axis 116. Consequently, in embodiments where transfixation screw hole 102 is formed into bone plate 100 at an angle, the entry point for transfixation screw 150 may be out of sight (e.g., covered up by the top of transfixation screw hole 102) when bone plate 100 is viewed from above. Therefore, to help a surgeon precisely position the entry point for transfixation screw 150 onto a desired location on bone 104a, the entry point for transfixation screw 150 (e.g., the center of the bottom side of transfixation screw hole 102) may reside directly in between the widest portion of flared hips 148. Accordingly, by positioning the widest portion of hips 148 directly adjacent to the desired location for transfixation screw 150 on bone 104a, the surgeon may confidently position the entry point for transfixation screw 150 at the desired location, even when the entry point is out of sight. Flared hips 148 may also increase the strength of bone plate 100 around transfixation screw hole 102, lessening the chance of plate deformation or breakage. Depending upon design, bone plate 100 may be formed from any material or combination of materials suitable for forming medical implants. Such materials may have high strength-to-weight ratios and may be inert to human body fluids. As an example and not by way of limitation, bone plate 100 may be formed from a forged titanium alloy. Titanium may provide several benefits as a material for bone plate 100 such as being relatively lightweight, providing adequate strength for withstanding forces typically experienced by a bone plate, and being visible in radiographs of the implant region. FIG. 4 illustrates an example embodiment of a bone plate 200 adapted for use in a Lapidus procedure where bone plate 200 may be secured across the first tarso-metatarsal (TMT) joint 206, located between the first metatarsal 204a and the first cuneiform 204b. Though bone plate 200 is adapted for placement over the TMT joint, particular embodiments of bone plate 200 may include some or all of the features of bone plate 100 described above, appropriately adapted to conform to the TMT joint 206. For example, when used on TMT joint 206, transfixation screw hole 202 may be configured to guide a transfixation screw 250 from the dorsal aspect of metatarsal 204a to the plantar aspect of first cuneiform 204b in order to transfix TMT joint 206. Likewise, bone plate 100 may include some or all of the features described with respect to bone plate 200, appropriately adapted to conform to the MPJ joint 106. For reference purposes, like numbers may be used to refer to like features between bone plate 100 and bone plate 200. Bone plate 200 may generally be “H-shaped”, and include an elongate spine 224 having a plurality of flanges 242 extending laterally therefrom. Each flange 242 may further include one or more attachment points 228 (similar or identical to attachment points 128 described above) for attaching bone plate 200 to a bone 204. Flanges 242 may serve as a primary mechanism for attaching bone plate 200 to bones 204, although particular embodiments of bone plate 200 may further include one or more additional attachment points 228 disposed along spine 224 for attaching bone plate 200 to bones 204. Each flange 242 may be any type of rigid lateral extension from spine 224. As an example and not by way of limitation, each flange 242 may be a rigid rounded tab extending laterally from the side of spine 224. Depending upon design, each flange 242 may be separated from the next by a gap 244, which may enable a surgeon to independently contour each flange 242 to a desired position (e.g., to conform flanges 242 to match the geometry of bones 204). Furthermore, each flange 242 may be relatively thinner than spine 224 to reduce the mechanical force needed to contour flanges 242 up or down relative to spine 224. This thinning of flanges 242 may confer a number of advantages over plates having uniform thickness, such as for example, providing a surgeon with the ability to easily contour flanges 242 to a desired position. In particular embodiments, flanges 242 may enable a surgeon to contour bone plate 200 such that attachments points 242 are located on both the medial and dorsal aspects of bones 204. Once a flange 242 has been contoured to a desired position, it may be affixed to bone 204 using an attachment point 228. To facilitate the process of aligning bones 204, bone plate 200 may include one or more features which mimic the natural geometry of the TMT joint 206. For example, bone plate 200 may include a rise 210 of approximately 0 mm to 5 mm (e.g., 2 mm) that mimics the natural elevation of the first metatarsal 204a relative to the first cuneiform 204b. As another example and not by way of limitation, bone plate 200 may include a varus angle of about 0 degrees to about 30 degrees (e.g., 15 degrees) between the first end 226a of the plate and the second end 226b of the plate that mimics the natural elevation of first metatarsal 204a relative to first cuneiform 204b. in particular embodiments, bone plate 200 may be symmetric about center line 238 to enable bone plate 200 to be applied to either the left foot or the right foot, without substantial modification. The particular embodiments disclosed above are illustrative only, as particular embodiments of the present disclosure may be modified and practiced in different but equivalent manners apparent to those skilled in the art having the benefit of the teachings herein. Furthermore, no limitations are intended to the details of construction or design herein shown, other than as described in the claims below. It is therefore evident that the particular illustrative embodiments disclosed above may be altered or modified and all such variations are considered within the scope and spirit of the present disclosure. In particular, every range of values (e.g., “from about a to about b,” or, equivalently, “from approximately a to b,” or, equivalently, “from approximately a-b”) disclosed herein is to be understood as referring to the power set (the set of all subsets) of the respective range of values. The terms in the claims have their plain, ordinary meaning unless otherwise explicitly and clearly defined by the patentee. Although the present disclosure has been described in several embodiments, a myriad of changes, substitutions, and modifications may be suggested to one skilled in the art, and it is intended that the present disclosure encompass such changes, substitutions, and modifications as fall within the scope of the present appended claims.
<SOH> BACKGROUND OF THE INVENTION <EOH>When performing certain medical procedures, such as reconstructing a joint that has been damaged due to bone or soft tissue trauma, a surgeon may need to fuse the bones of the joint together in a configuration that approximates the natural geometry of the joint. One way to achieve this objective is to attach the bones of the joint to a plate that holds the bones in alignment with one another while they fuse together.
<SOH> BRIEF SUMMARY OF THE INVENTION <EOH>The present disclosure relates generally to orthopedic devices. More specifically, the present disclosure relates to a bone plate with a transfixation screw hole for securing the bones of a joint together and a method for using the same. In particular embodiments, a system for securing bones together across a joint includes a transfixation screw and a plate. The plate includes an elongate spine having a first end that includes at least one attachment point for attaching the first end to a first bone on a first side of a joint, a second end that includes at least one attachment point for attaching the second end to a second bone on a second side of the joint, and a bridge portion disposed between the first end and the second end configured to span across the joint. The plate further includes a transfixation screw hole disposed along the spine. The transfixation screw hole includes an inner surface configured to direct the transfixation screw through the transfixation screw hole such that the transfixation screw extends alongside the bridge portion at a trajectory configured to pass through a first position on the first bone and a second position on the second bone once the plate is placed across the joint. The transfixation screw comprises a head configured to abut the inner surface of the transfixation screw hole and a shaft configured to contiguously extend through the first bone, across the joint, and into the second bone. Depending upon design, a central axis of the inner surface of the transfixation screw hole may define the trajectory, and the trajectory may be configured to cross a neutral bending axis of the joint once the plate is placed across the joint. in particular embodiments, a plate for securing bones together may include an elongate spine having a first end that includes at least one attachment point for attaching the first end to a first bone on a first side of a joint, a second end that includes at least one attachment point for attaching the second end to a second bone on a second side of the joint, and a bridge portion disposed between the first end and the second end configured to span across the joint. The plate may further include a transfixation screw hole disposed along the spine. The transfixation screw hole includes an inner surface configured to direct a transfixation screw through the transfixation screw hole such that the transfixation screw extends alongside the bridge portion at a trajectory configured to pass through a first position on the first bone and a second position on the second bone once the plate is placed across the joint. In particular embodiments, a method for securing bones together across a joint includes placing a plate over a first bone on a first side of a joint and a second bone on a second side of the joint. The plate may include an elongate spine having a first end that includes at least one attachment point for attaching the first end to the first bone, a second end that includes at least one attachment point for attaching the second end to the second bone, and a bridge portion disposed between the first end and the second end configured to span across the joint. The plate may further include a transfixation screw hole disposed along the spine. The transfixation screw hole includes an inner surface configured to direct the transfixation screw through the transfixation screw hole such that the transfixation screw extends alongside the bridge portion at a trajectory configured to pass through a first position on the first bone and a second position on the second bone once the plate is placed across the joint. The method may further include attaching the plate to the first bone and the second bone, and inserting a transfixation screw into the first bone and the second bone through the transfixation screw hole. The transfixation screw may include a head configured to abut the inner surface of the transfixation screw hole and a shaft configured to contiguously extend through the first bone, across the joint, and into the second bone. Particular embodiments of the present disclosure may provide a number of technical advantages, including for example, the ability to tightly couple the bones of a joint together by inserting a transfixation screw across the joint through a bone plate. In particular embodiments, the transfixation screw may have a “lag effect” that enables the bones of the joint to be approximated with one another by rotation of the transfixation screw. For example, the transfixation screw may include an unthreaded portion configured to rotate freely within the first bone and a threaded portion configured to threadably engage the second bone. When the transfixation screw is rotated, the unthreaded portion of the transfixation screw may rotate freely within the first bone while the threaded portion of the transfixation screw advances into the second bone, drawing the second bone toward the first bone and compressing the joint. These technical advantages (e.g., the presence of the transfixation screw across the joint, and the lag effect of the transfixation screw) may increase the contact pressure on the bony interface of the joint, increasing the probability of a positive fusion. Depending upon design, the inner surface of the transfixation screw hole in the plate may direct the transfixation screw along a trajectory that crosses a neutral bending axis of the joint as the transfixation screw passes from the first bone to the second bone. This technical advantage may create a “tension band” construct that enables the transfixation screw to absorb a portion of the mechanical stress that would otherwise be imposed upon the plate above the joint when a load is applied to the joint. This technical advantage may enhance the integrity and reliability of the plate and increase the load that the plate may support without increasing plate thickness. Other technical advantages of the present disclosure will be readily apparent to one skilled in the art from the following figures, descriptions, and claims. Moreover, while specific advantages have been enumerated above, various embodiments may include all, some, or none of the enumerated advantages.
A61B178057
20170918
20180104
58291.0
A61B1780
2
WOODALL, NICHOLAS W
BONE PLATE WITH A TRANSFIXATION SCREW HOLE
UNDISCOUNTED
1
CONT-ACCEPTED
A61B
2,017
15,710,604
PENDING
COMBINED ORTHODONTIC MOVEMENT OF TEETH WITH AIRWAY DEVELOPMENT THERAPY
Systems, devices and methods are disclosed for reshaping airways concurrently with dental and/or orthodontic treatment. The systems can have a series of two or more oral appliances configured to progressively reposition the maxillary and mandibular teeth in two or more successive steps. Each oral appliance in the series can have one or more maxillary blocks, one or more mandibular blocks, a maxillary oral tray, and a mandibular oral tray. One or more maxillary blocks can be attached to or integrated with the maxillary oral tray. One or more mandibular blocks can be attached to or integrated with the mandibular oral tray. The maxillary and mandibular oral trays can be configured to move one or more teeth from a tooth first position to a tooth second position. The maxillary and mandibular blocks can be configured to interact with one another to treat sleep breathing disorders.
1. An oral appliance for the treatment of sleep breathing disorders, comprising: one or more maxillary blocks; one or more mandibular blocks; a maxillary oral tray, wherein the one or more maxillary blocks are attached to or integrated with the maxillary oral tray; and a mandibular oral tray, wherein the one or more mandibular blocks are attached to or integrated with the mandibular oral tray, wherein the maxillary and mandibular oral trays are configured to move one or more teeth from a tooth first position to a tooth second position, wherein each maxillary block has as a maxillary block guide surface, wherein each mandibular block has as a mandibular block guide surface, and wherein each maxillary block guide surface is opposed to and configured to interact with at least one mandibular block guide surface to at least one of move one or more teeth, advance a mandible, increase an interocclusal separation between a maxillary dentition and a mandibular dentition, and expand a palate. 2. The oral appliance of claim 1, wherein the maxillary block guide surfaces and the mandibular block guide surfaces are configured to interact to reshape an airway into a more open configuration from a less open configuration. 3. The oral appliance of claim 1, wherein the maxillary block guide surfaces and the mandibular block guide surfaces are configured to interact to inhibit an airway from partially or completely closing from an open configuration. 4. The oral appliance of claim 1, wherein each maxillary guide surface and each mandibular guide surface extends about 30% or more along a length of each respective block. 5. The oral appliance of claim 1, wherein each maxillary block guide surface can be at a maxillary guide surface angle relative to a portion of an occlusal surface of the maxillary dentition of about 15 degrees to about 75 degrees. 6. The oral appliance of claim 1, wherein each mandibular block guide surface can be at a mandibular guide surface angle relative to a portion of an occlusal surface of the mandibular dentition of about 15 degrees to about 75 degrees. 7. The oral appliance of claim 1, wherein each maxillary and mandibular block guide surface defines at least one of a longitudinal slope relative to a longitudinal axis of its respective block and/or a transverse slope relative to a transverse axis of its respective block. 8. A system for the treatment of sleep breathing disorders, comprising: a series of two or more oral appliances configured to progressively reposition the maxillary and mandibular teeth in two or more successive steps, wherein each oral appliance in the series comprises: one or more maxillary blocks; one or more mandibular blocks; a maxillary oral tray, wherein the one or more maxillary blocks are attached to or integrated with the maxillary oral tray; and a mandibular oral tray, wherein the one or more mandibular blocks are attached to or integrated with the mandibular oral tray, wherein the maxillary and mandibular oral trays are configured to move one or more teeth from a tooth first position to a tooth second position, wherein each maxillary block has as a maxillary block guide surface, wherein each mandibular block has as a mandibular block guide surface, and wherein each maxillary block guide surface is opposed to and configured to interact with at least one mandibular block guide surface to at least one of move one or more teeth, advance a mandible, increase an interocclusal separation between a maxillary dentition and a mandibular dentition, and expand a palate. 9. The system of claim 8, wherein the maxillary block guide surfaces and the mandibular block guide surfaces of each oral appliance in the series are configured to interact to inhibit an airway from partially or completely closing from an open configuration. 10. The system of claim 8, wherein at least one maxillary guide surface and at least one mandibular guide surface of at least one of the oral appliances in the series extends about 30% or more along a length of its associated block. 11. The system of claim 8, wherein at least one of the maxillary block guide surfaces in the series can be at a maxillary guide surface angle relative to a portion of an occlusal surface of the maxillary dentition of about 15 degrees to about 75 degrees. 12. The system of claim 8, wherein at least one of the mandibular block guide surfaces in the series can be at a mandibular guide surface angle relative to a portion of an occlusal surface of the mandibular dentition of about 15 degrees to about 75 degrees. 13. The system of claim 8, wherein each maxillary and mandibular block guide surface in the series defines at least one of a longitudinal slope relative to a longitudinal axis of its respective block and/or a transverse slope relative to a transverse axis of its respective block. 14. The system of claim 8, wherein the series of two or more oral appliances comprises a first oral appliance having first oral appliance dimensions and a second oral appliance having second oral appliance dimensions, wherein one or more of the second oral appliance dimensions are greater than or less than one or more of the first oral appliance dimensions. 15. The system of claim 14, wherein the one or more second oral appliance dimensions greater than or less than the one or more first oral appliance dimensions comprises at least one of a maxillary or mandibular block length, height, or width and/or a maxillary or mandibular block guide surface angle. 16. The system of claim 15, wherein one or more of the second oral appliance dimensions are greater than or less than one or more of the first oral appliance dimensions by about 1% to about 500%. 17. A method of treating sleep breathing disorders, comprising: providing a series of two or more oral appliances configured to progressively reposition the maxillary and mandibular teeth in two or more successive steps, wherein each oral appliance in the series comprises: one or more maxillary blocks; one or more mandibular blocks; a maxillary oral tray, wherein the one or more maxillary blocks are attached to or integrated with the maxillary oral tray; and a mandibular oral tray, wherein the one or more mandibular blocks are attached to or integrated with the mandibular oral tray, wherein the maxillary and mandibular oral trays are configured to move one or more teeth from a tooth first position to a tooth second position, wherein each maxillary block has as a maxillary block guide surface, wherein each mandibular block has as a mandibular block guide surface, and wherein each maxillary block guide surface is opposed to and configured to interact with at least one mandibular block guide surface to at least one of move one or more teeth, advance a mandible, increase an interocclusal separation between a maxillary dentition and a mandibular dentition, and expand a palate. 18. The method of claim 17, wherein the series of two or more oral appliances comprises a first oral appliance having first oral appliance dimensions and a second oral appliance having second oral appliance dimensions, wherein one or more of the second oral appliance dimensions are greater than or less than one or more of the first oral appliance dimensions. 19. The method of claim 18, wherein the one or more second oral appliance dimensions greater than or less than the one or more first oral appliance dimensions comprises at least one of a maxillary or mandibular block length, height, or width and/or a maxillary or mandibular block guide surface angle. 20. The method of claim 19, wherein one or more of the second oral appliance dimensions are greater than or less than one or more of the first oral appliance dimensions by about 1% to about 500%.
CROSS-REFERENCE TO RELATED APPLICATION This application claims priority to U.S. Provisional Application No. 62/397,749 filed Sep. 21, 2016, which is herein incorporated by reference in its entirety for all purposes. BACKGROUND 1. Technical Field Systems, devices and methods for reshaping airways are disclosed. More specifically, systems, devices and methods are disclosed for reshaping airways concurrently with dental and/or orthodontic treatment. 2. Background of the Art Airway disorders affect a large portion of the population and are regarded as multifactorial conditions with a multitude of etiologies and treatment modalities. Orthodontic treatment can aid in the development of the airway a treatment modality for airway disorders, the current invention allows for the combined use of orthodontic and airway treatment modalities. Airway disorders affect a significant population with estimates of the 3% of pediatric population and 10% of the adult population. Morbidity from airway disorders ranges from mental and physical deterioration to disabling illnesses or even death. In children, physical and cognitive development can be delayed or stunted. Adult manifestations can include tiredness, somnolence, memory loss and sleep disorders. The airway is shaped by various craniofacial structures. Evaluation of craniofacial structures is therefore of paramount importance in treating airway disorders. Orthodontic treatment can manipulate craniofacial structures to reshape and open the airway of both pediatric and adult patients. Combining oral airway devices with orthodontic treatment can help not only orthodontic issues but the overall health of the patient. Results of this combined therapy by manipulating not only the dental arches but also the drape of the soft tissue that establishes airway size, shape and volume. Obstructive sleep apnea (OSA) is a major health risk that various oral and dental appliances have been addressing for years. However, these appliances merely address the symptoms associated with OSA—they are not therapeutic in nature. The present disclosure addresses these deficiencies by combining orthodontic and OSA treatments. Treating OSA concurrently with orthodontic treatment can advantageously ease symptoms associated with OSA while attaining a therapeutic result of the airway condition by enlarging or otherwise reshaping the airway. Comprehensive dental treatments should include consideration of the structures involved, including the airway. The present invention allows the dental provider to combine airway development therapy, obstructive sleep apnea and orthodontic treatment to end with a result that considers a beautiful smile with a patent airway day and night. The invention allows for numerous different treatment philosophies for OSA and airway development to be treated with orthodontic aligners simultaneously. This includes but is not limited to mandibular advancement style appliances, palatal and mandibular expanders using the orthodontic aligners. By manipulating the 3D models the aligners can act both as orthodontic movers of teeth along with ideal positioning of the jaws to open the airway. A need exists to combine orthodontic and/or dental treatment with OSA appliances. The advantages of combining these modalities include: (1) opening the airway due to orthodontic advancing and/or widening of the arches to potentially cure the disease or at least lessen the symptoms, (2) OSA appliances worn exclusively at night can cause temporomandibular joint dysfunction or myofascial pain dysfunction, which can be advantageously addressed by the daytime and nighttime appliances disclosed herein, (3) existing OSA devices can cause morning malalignment of the teeth and/or with prolong use cause orthodontic problems which by design can be prevented or otherwise mitigated with the oral appliances disclosed herein, (4) the oral appliances disclosed herein can be titrated over a series of two or more steps for ideal mandibular advancement and/or opening with the software and/or different ramp designs which can encourage true hinge rotation as well as translation of the temporomandibular joint, and/or (5) the oral appliances disclosed herein can allow free mandibular motion while having the ability to hold the joint in a fixed position if necessary for the desired treatment or comfort of the patient. BRIEF SUMMARY OF THE INVENTION This disclosure relates generally to the combined orthodontic movement and/or dental treatment of teeth, airway development and treatment of sleep breathing disorders. More specifically, orthodontic and/or dental airway development systems, apparatuses and methods of using the same are disclosed. The airway development systems and apparatuses disclosed can concurrently move teeth and reshape the airway. The airway development systems and apparatuses disclosed can concurrently advance the mandible and reshape the airway. The airway development systems apparatuses disclosed can concurrently expand the hard and/or soft palate and reshape the airway. The airway development systems and apparatuses disclosed can concurrently whiten teeth and reshape the airway. The airway development systems and apparatuses disclosed can concurrently clean teeth and reshape the airway. The airway development systems and apparatuses disclosed can concurrently move teeth, advance the mandible, expand the hard and/or soft palate, whiten teeth, apply hygienic treatment, reshape the airway, or any combination thereof. The airway development systems and apparatuses can have dental trays and/or orthodontic aligner trays. The airway development systems and apparatuses can have airway development blocks. The airway development blocks can be attached to or integrated with one or more trays. Oral appliances for the treatment of sleep breathing disorders are disclosed. For example, an oral appliance is disclosed that can have one or more maxillary blocks. The oral appliance can have one or more mandibular blocks. The oral appliance can have a maxillary oral tray. One or more maxillary blocks can be attached to or integrated with the maxillary oral tray. The oral appliance can have a mandibular oral tray. One or more mandibular blocks can be attached to or integrated with the mandibular oral tray. The maxillary and mandibular oral trays configured to move one or more teeth from a tooth first position to a tooth second position. Each maxillary block can have a maxillary block guide surface. Each mandibular block can have a mandibular block guide surface. Each maxillary block guide surface can be opposed to and configured to interact with at least one mandibular block guide surface to at least one of move one or more teeth, advance a mandible, increase an interocclusal separation between a maxillary dentition and a mandibular dentition, and expand a palate. Systems for the treatment of sleep breathing disorders are disclosed. For example a system is disclosed that can have a series of two or more oral appliances configured to progressively reposition the maxillary and mandibular teeth in two or more successive steps. Each oral appliance in the series can have one or more maxillary blocks. Each oral appliance in the series can have one or more mandibular blocks. Each oral appliance in the series can have a maxillary oral tray. One or more maxillary blocks can be attached to or integrated with the maxillary oral tray. Each oral appliance in the series can have a mandibular oral tray. One or more mandibular blocks can be attached to or integrated with the mandibular oral tray. The maxillary and mandibular oral trays can be configured to move one or more teeth from a tooth first position to a tooth second position. Each maxillary block can have a maxillary block guide surface. Each mandibular block can have a mandibular block guide surface. Each maxillary block guide surface can be opposed to and configured to interact with at least one mandibular block guide surface to at least one of move one or more teeth, advance a mandible, increase an interocclusal separation between a maxillary dentition and a mandibular dentition, and expand a palate. Methods of treating sleep breathing disorders are disclosed. For example, a method is disclosed that can include providing a series of two or more oral appliances configured to progressively reposition the maxillary and mandibular teeth in two or more successive steps. Each oral appliance in the series can have one or more maxillary blocks. Each oral appliance in the series can have one or more mandibular blocks. Each oral appliance in the series can have a maxillary oral tray. One or more maxillary blocks can be attached to or integrated with the maxillary oral tray. Each oral appliance in the series can have a mandibular oral tray. One or more mandibular blocks can be attached to or integrated with the mandibular oral tray. The maxillary and mandibular oral trays can be configured to move one or more teeth from a tooth first position to a tooth second position. Each maxillary block can have a maxillary block guide surface. Each mandibular block can have a mandibular block guide surface. Each maxillary block guide surface can opposed to and configured to interact with at least one mandibular block guide surface to at least one of move one or more teeth, advance a mandible, increase an interocclusal separation between a maxillary dentition and a mandibular dentition, and expand a palate. BRIEF DESCRIPTION OF THE DRAWINGS The drawings shown and described are exemplary embodiments and non-limiting. Like reference numerals indicate identical or functionally equivalent features throughout. FIG. 1 illustrates isometric views of a variation of airway development blocks of an oral appliance. FIG. 2 illustrates a top elevational view of the oral appliance of FIG. 1. FIG. 3 illustrates a side isometric view of the oral appliance of FIG. 1 in an assembled configuration under compression. FIG. 4 illustrates a schematic of a variation of an aligner on teeth. FIG. 5 illustrates a schematic of a variation of a maxillary aligner on teeth that has a variation of an airway development block. FIG. 6 illustrates a schematic of a variation of maxillary and mandibular aligners on teeth with each having a variation of an airway development block. FIG. 7 illustrates a schematic of a variation of a series of oral appliances. FIG. 8 illustrates a variation of a process for making a variation of an oral appliance. DETAILED DESCRIPTION Systems, devices and methods are disclosed that can concurrently reshape and/or maintain the airway, apply orthodontic treatment, apply dental treatment, or any combination thereof. The systems, devices and methods disclosed can apply orthodontic treatment to any craniofacial structure, including the dentition, the palate, the maxilla, the mandible, or any combination thereof. The systems, devices and methods disclosed can apply any dental treatment to the teeth, including whitening treatments, cleaning treatments, gingival recession treatments, or any combination thereof. For example, systems, devices and methods are disclosed that can concurrently move one or more teeth, advance the mandible, retrude the mandible, expand the hard and/or soft palate, whiten teeth, clean teeth, treat gum line recession, reshape the airway, maintain the airway, or any combination thereof. The disclosed systems, devices and methods can orthodontically reshape the airway by manipulating one or more craniofacial structures. The airway can be reshaped into a more open configuration by widening the dental arches, by increasing the interocclusal distance between the upper and lower teeth and/or by advancing the lower jaw. The airway can be reshaped concurrently with the orthodontic treatment of, for example, misaligned teeth, malocclusions, and/or narrow arches. Additionally or alternatively, the airway can be reshaped concurrently with a teeth whitening, cleaning and/or gingival recession treatment. More particularly, oral appliances are disclosed that can reshape and/or maintain the airway to treat sleep breathing disorders (SBD) such as obstructive sleep apnea (OSA) and snoring. The oral appliances disclosed can reshape the airway by simultaneously manipulating one or more craniofacial structures and moving teeth, cleaning teeth, whitening teeth, or any combination thereof. The oral appliances disclosed can treat SBD and snoring with various orthodontic treatment modalities, for example, mandibular advancement, palatal expansion and/or mandibular expansion. The oral appliances disclosed can simultaneously provide both orthodontic and SBD treatment and result in more properly aligned teeth and a more open airway. The oral appliances disclosed can simultaneously provide dental whitening, dental cleaning and/or gingival recession treatments in combination with SBD treatment and result in whiter teeth, cleaner teeth, healthier gums, fresher breath, and a more open airway. System and Apparatus SBD appliance therapy can be combined with the orthodontic movement of teeth, for example, with orthodontic aligner treatment. The SBD appliances disclosed can simultaneously reposition the jaw and orthodontically move teeth, for example, by virtue of their combination with aligner treatment. The systems disclosed however, not only simply allow for their combination, the systems also advantageously allow for their treatments to be coordinated with one another. FIG. 1 illustrates a variation of a customizable oral appliance 10 for reshaping and/or maintaining the airway. The appliance 10 can have one or more maxillary blocks 12 and one or more mandibular blocks 14. For example, the appliance 10 can have 1 to 6 maxillary blocks 12 and 1 to 6 mandibular blocks 14. The number of maxillary blocks 12 can be less than, equal to, or greater than the number of mandibular blocks 14. For example, FIG. 1 illustrates that the appliance 10 can have two maxillary blocks 12 and two mandibular blocks 14. As another example, the appliance 10 can have one maxillary block 12 and two mandibular blocks 14 or vice versa. The appliance 10 can have one, two, three, four, or five more maxillary blocks 12 than mandibular blocks 14 or vice versa. The appliance 10 can have one or more maxillary blocks 12 and no mandibular blocks 14 or one or more mandibular blocks 14 and no maxillary blocks 12. The blocks 12, 14 can be placed in a person's oral cavity. FIG. 1 illustrates that the appliance 10 can have a first maxillary block 12a and a second maxillary block 12b. Anatomically, the maxillary first block 12a can be a left block and the maxillary second block 12b can be a right block, or vice versa. The maxillary first and second blocks 12a, 12b can be configured to be placed on a lateral left and right side, respectively, of a maxillary dental arch. The appliance 10 can have a first mandibular block 14a and a second mandibular block 14b. Anatomically, the mandibular first block 14a can be a left block and the mandibular second block 14b can be a right block, or vice versa. The mandibular first and second blocks 14a, 14b can be configured to be placed on a lateral left and right side, respectively, of a mandibular dental arch. FIG. 1 illustrates that the blocks 12, 14 can each have a buccal side 16, a lingual side 18, an anterior portion 20, a posterior portion 22 and teeth surfaces 24. Each maxillary block 12 can have a maxillary tooth surface 24a and/or a mandibular tooth surface 24b. Each mandibular block 14 can have a maxillary tooth surface 24a and/or a mandibular tooth surface 24b. The surfaces 24 can conform to surfaces of the teeth and/or can have a geometry to orthodontically move one or more teeth from one position to another. One or more of the surfaces 24 of maxillary and mandibular blocks can be configured to have a friction fit over a portion of one or more teeth. The maxillary tooth surfaces 24a of the maxillary blocks 12 can have a surface geometry configured to move one or more maxillary teeth from a first position to a second position. The mandibular tooth surfaces 24b of the maxillary blocks 12 can be flat (e.g., as shown in FIG. 1) or can have a surface geometry configured to move one or more mandibular teeth from a first position to a second position. The mandibular tooth surfaces 24b of the mandibular blocks 14 can have a surface geometry configured to move one or more mandibular teeth from a first position to a second position. The maxillary tooth surfaces 24a of the mandibular blocks 14 can be flat (e.g., as shown in FIG. 1) or can have a surface geometry configured to move one or more maxillary teeth from a first position to a second position. A series of blocks 12, 14 can be designed to progressively reposition the maxillary and/or mandibular teeth in two or more successive steps, for example, as disclosed in PCT Publication WO 2016/004415 and U.S. application Ser. No. 15/386,280 (published as US 2017/0100214) in relation to orthodontic trays, both of which are herein incorporated by reference in their entireties for all purposes. Each block 12, 14 in a series can have a surface 24 that has a geometry that corresponds to an intermediate or end tooth arrangement intended for the block 12, 14 in the series. The blocks 12, 14 can be sufficiently resilient to accommodate or conform to misaligned teeth, but apply sufficient force against the misaligned teeth to reposition the teeth to the intermediate or end arrangement as desired for the particular treatment step. A series of blocks 12, 14 can have geometries selected to progressively reposition teeth from a first arrangement through one or more successive intermediate arrangements to a final arrangement. Each block in the series can have the same or different dimensions than one or more other blocks in the series, as described below. A series of blocks 12, 14 can have 1 to 100 maxillary blocks 12 and 1 to 100 mandibular blocks 14, for example, 1 to 55 maxillary blocks 12 and 1 to 55 mandibular blocks 14, 1 to 50 maxillary blocks 12 and 1 to 50 mandibular blocks 14, 1 to 45 maxillary blocks 12 and 1 to 45 mandibular blocks 14, 1 to 40 maxillary blocks 12 and 1 to 40 mandibular blocks 14, less than 40 maxillary blocks 12 and less than 40 mandibular blocks, or any combination thereof. For example, a series of blocks can have 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 maxillary blocks 12 and 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 mandibular blocks 14. The number of maxillary blocks 12 can be the same or different as the number mandibular blocks 14 in a series. FIG. 1 illustrates that the maxillary blocks 12 can each have one or more maxillary block guide surfaces 26 (e.g., 1 to 6 or more maxillary guide surfaces 26) and that the mandibular blocks 14 can each have one or more mandibular block guide surfaces 28 (e.g., 1 to 6 or more mandibular guide surfaces 28). The guide surfaces 26, 28 are variously referred to throughout as ramps, stops, disclusion surfaces, expansion surfaces, resting surfaces and/or other similar terms. The guide surfaces 26 can be on any part or define any surface of the blocks 12, 14, for example, the anterior and/or posterior portions 20, 22 of the maxillary and mandibular blocks 12, 14. FIG. 1 illustrates that the anterior portion 20 of the maxillary blocks 12 can have one maxillary guide surface 26 and that the posterior portion 22 of the mandibular blocks 14 can have one mandibular guide surface 28. For example, FIG. 1 illustrates that the maxillary first and second blocks 12a, 12b can have maxillary first and second guide surfaces 26a, 26b, respectively, and that the mandibular first and second blocks 14a, 14b can have mandibular first and second guide surfaces 28a, 28b, respectively. The exact number and orientation of the guide surfaces 26, 28 can be customizable and depend on a person's tolerance for the blocks 12, 14, craniofacial structure, teeth alignment, orthodontic treatments being applied, dental treatment being applied or any combination thereof, each factor being critical to the design of the blocks 12, 14. Each block in a series can have the same or different number and/or orientation of guide surfaces 28a, 28b as one or more other blocks in the series. While FIG. 1 illustrates that the anterior portions 20 of the maxillary blocks 12 and the posterior portions 22 of the mandibular blocks 14 have the guide surfaces 26, 28 (e.g., guide surfaces 26a, 26b, 28a, 28b), the anterior and/or posterior portion 20, 22 of each of the maxillary and mandibular blocks can have one or more guide surfaces in addition to or in lieu of the guide surfaces 26, 28 shown in FIG. 1. For example, the posterior portions 22 of the maxillary blocks 12 can have guide surfaces and/or the anterior portions 20 of the mandibular blocks 14 can have guide surfaces. However, the anterior and/or posterior portions 20, 22 of the maxillary and/or mandibular blocks 12 need not have a guide surface. For example, FIG. 1 illustrates that the posterior portions 22 of the maxillary blocks 12 and the anterior portions 20 of the mandibular blocks 14 can have ends that do not have a guide surface. FIG. 1 illustrates that the ends of the posterior portions 22 of the maxillary blocks 12 and the anterior portions 20 of the mandibular blocks 14 can have a flat or curved surface with a portion that is perpendicular or nearly perpendicular to an occlusal plane. Each guide surface (e.g., guide surfaces 26, 28) can be paired with an opposing (also referred to as cooperating, interacting, engaging, contacting, or interfering) guide surface. For example, the blocks 12, 14 can be paired such that their corresponding guide surfaces 26, 28 form one or more corresponding guide surfaces pairs 26-28. Each guide surface in a guide surface pair can be configured to interact with its opposing guide surface. For example, the opposing guide surfaces of a guide surface pair 26-28 can be configured to slidably engage or otherwise move relative to one another and/or be configured to rest against each other or otherwise inhibit or prevent movement relative to one another. At least a portion of each guide surface, including the entire guide surface, can be configured to contact at least a portion of its opposing guide surface, including the entire opposing guide surface, such that any portion 100% or less is appreciated. FIG. 1 illustrates that the two left blocks 12a, 14a can form a left guide surface pair 26a-28a and that the two right blocks 12b, 14b can form a right guide surface pair 26b-28b. The maxillary and mandibular guide surfaces 26a, 28a of the left pair 26a-28a can be designed to interact with each other and the maxillary and mandibular guide surfaces 26b, 28b of the right pair 26b-28b can be designed to interact with each other. Each guide surface 26, 28 can interact with its opposing guide surface in a self-guided manner. The guide surfaces 26, 28 can position the mandible in the anatomically correct joint position while the teeth are moving orthodontically. Each guide surface 26, 28 can be or have one or more planar surfaces (e.g., 1 to 50 planar surfaces). For example, FIG. 1 illustrates that each guide surface 26, 28 can have one planar surface. However, the guide surfaces 26, 28 can have any surface geometry, including planar, curved (e.g., one or more concave and/or convex portions), polygonal (e.g., any combination of two or more planes), irregular, or any combination thereof. Thus, although the guide surfaces 26, 28 can function as guide planes and may be planar in general characteristics, strict conformity with flatness associated with a plane is not required. The guide surfaces 26, 28 can be angled such that they define one or more inclined, horizontal, and/or declined planar surfaces. The guide surfaces 26, 28 can be at one or more angles relative to, for example, a reference plane, reference surface, or reference axis. FIG. 1 illustrates that the maxillary guide surfaces 26 (e.g., the maxillary first and second guide surfaces 26a, 26b) can each be at maxillary guide surface angle 30. The maxillary guide surface angle 30 can be the angle formed between the maxillary guide surfaces 26 and a reference plane, reference surface, or reference axis such as the maxillary tooth surface 24a (or an occlusal plane), maxillary orthodontic aligner (not shown), or any combination thereof. The maxillary guide surface angle 30 can be from about 0 degrees to about 90 degrees or more broadly from about 0 degrees to about 150 degrees. For angles greater than 90 degrees, the maxillary guide surface 26 can face toward as opposed to away from the maxillary dentition. For example, the maxillary guide surface angle 30 can be from about 15 degrees to about 75 degrees, from about 40 degrees to about 50 degrees, from about 30 degrees to about 60 degrees, from about 20 degrees to about 70 degrees, or from about 10 degrees to about 80 degrees, including every 1 degree increment within these ranges; for example, the maxillary guide surface angle 30 can be about 0 degrees, about 5 degrees, about 10 degrees, about 15 degrees, about 20 degrees, about 25 degrees, about 30 degrees, about 35 degrees, about 40 degrees, about 45 degrees, about 50 degrees, about 55 degrees, about 60 degrees, about 65 degrees, about 70 degrees, about 75 degrees, about 80 degrees, about 85 degrees, about 90 degrees, about 130 degrees, about 135 degrees, about 140 degrees, about 145 degrees, or about 150 degrees. Angles within these ranges and/or having these values can advantageously allow the maxillary and mandibular blocks 12, 14 to slidably engage or otherwise move relative to one another and/or rest against each other or otherwise inhibit or prevent movement relative to one another. Angles within these ranges and/or having these values can advantageously allow the maxillary and mandibular blocks 12, 14 to contact (e.g., slidably contact) each other to move and/or maintain the mandible into a forward position and/or to increase and/or maintain the interocclusal separation between the maxillary and mandibular dental arches. Angles within these ranges and/or having these values can therefore advantageously facilitate the reshaping of the airway into a more open configuration (e.g., from a less open first configuration to a more open second configuration). Each maxillary block 12 in a series can have the same or different maxillary guide surface angle 30 as one or more other maxillary blocks 12 in the series. FIG. 1 illustrates that the mandibular guide surfaces 28 (e.g., the mandibular first and second guide surfaces 28a, 28b) can each be at a mandibular guide surface angle 32. The mandibular guide surface angle 32 can be the angle formed between the mandibular guide surfaces 28 and a reference plane, reference surface, or reference axis such as the mandibular tooth surface 24b (or an occlusal plane), mandibular orthodontic aligner (not shown), or any combination thereof. The mandibular guide surface angle 32 can be from about 0 degrees to about 90 degrees or more broadly from about 0 degrees to about 150 degrees. For angles greater than 90 degrees, the mandibular guide surface 28 can face toward as opposed to away from the mandibular dentition. For example, the mandibular guide surface angle 32 can be from about 15 degrees to about 75 degrees, from about 40 degrees to about 50 degrees, from about 30 degrees to about 60 degrees, from about 20 degrees to about 70 degrees, or from about 10 degrees to about 80 degrees, including every 1 degree increment within these ranges; for example, the mandibular guide surface angle 32 can be about 0 degrees, about 5 degrees, about 10 degrees, about 15 degrees, about 20 degrees, about 25 degrees, about 30 degrees, about 35 degrees, about 40 degrees, about 45 degrees, about 50 degrees, about 55 degrees, about 60 degrees, about 65 degrees, about 70 degrees, about 75 degrees, about 80 degrees, about 85 degrees, about 90 degrees, about 130 degrees, about 135 degrees, about 140 degrees, about 145 degrees, or about 150 degrees. Angles within these ranges and/or having these values can advantageously allow the maxillary and mandibular blocks 12, 14 to slidably engage or otherwise move relative to one another and/or rest against each other or otherwise inhibit or prevent movement relative to one another. Angles within these ranges and/or having these values can advantageously allow the maxillary and mandibular blocks 12, 14 to contact (e.g., slidably contact) each other to move and/or maintain the mandible into a forward position and/or to increase and/or maintain the interocclusal separation between the maxillary and mandibular dental arches. Angles within these ranges and/or having these values can therefore advantageously facilitate the reshaping of the airway into a more open configuration (e.g., from a less open first configuration to a more open second configuration). Each mandibular block 14 in a series can have the same or different maxillary guide surface angle 32 as one or more other mandibular blocks in the series. FIG. 1 illustrates that the maxillary and mandibular guide surface angles 30, 32 of a maxillary and mandibular block pair (e.g., pair 12a-14a, pair 12b-14b) can be any two complementary or nearly complementary angles. For example, the first and second block pairs 12a-14a and 12b-14b can have angle pairs (listed as angle-angle, in degrees) of about 45-45, 40-50, 35-55, 30-60, 25-65, 20-70, 15-75, 10-80, 5-85, or vice versa—about 45-45, 50-40, 55-35, 60-30, 65-25, 70-20, 75-15, 80-10, 85-5. The maxillary blocks 12 can have the first listed complementary angle and the mandibular blocks 14 can have the second listed complementary angle in each of the angle-angle pairs. The mandibular blocks 14 can have the first listed complementary angle and the maxillary blocks 12 can have the second listed complementary angle in each of the angle-angle pairs. In this way, the maxillary and mandibular blocks 12, 14 can form cooperating pairs of blocks 12-14 and guide surfaces 26-28 as described above. However, the maxillary and mandibular guide surface angles 30, 32 can be non-complementary and still enable one or more portions of each of the guide surfaces 26, 28 to cooperate with one another. Moreover, the guide surfaces 26, 28 need not form surface angles 30, 32—which can occur where, for example, the guide surfaces are irregular, curved, polygonal, or any combination thereof, yet still advantageously be configured to interact and function as guide surfaces. FIG. 1 illustrates that the maxillary first and second blocks 12a, 12b can have maxillary first and second guide surface angles 30a, 30b, respectively. The maxillary first and second guide surface angles 30a, 30b can be the same or different from one another. For example, the maxillary first guide surface angle 30a can be less than, equal to, or greater than the maxillary second guide surface angle 30b. The maxillary first guide surface angle 30a can be from about 1 degree to about 90 degrees greater or less than the maxillary second guide surface angle 30b, more narrowly from about 1 degree to about 45 degrees greater or less than the maxillary second guide surface angle 30b, more narrowly yet from about 1 degree to about 30 degrees greater or less than the maxillary second guide surface angle 30b, still more narrowly from about 1 degree to about 15 degrees greater or less than the maxillary second guide surface angle 30b, yet still more narrowly from about 1 degree to about 5 degrees greater or less than the maxillary second guide surface angle 30b, or vice versa. FIG. 1 illustrates that the mandibular first and second blocks 14a, 14b can have mandibular first and second guide surface angles 32a, 32b, respectively. The mandibular first and second guide surface angles 32a, 32b can be the same or different from one another. For example, the mandibular first guide surface angle 32a can be less than, equal to, or greater than the mandibular second guide surface angle 32b. The mandibular first guide surface angle 32a can be from about 1 degree to about 90 degrees greater or less than the mandibular second guide surface angle 32b, more narrowly from about 1 degree to about 45 degrees greater or less than the mandibular second guide surface angle 32b, more narrowly yet from about 1 degree to about 30 degrees greater or less than the mandibular second guide surface angle 30b, still more narrowly from about 1 degree to about 15 degrees greater or less than the mandibular second guide surface angle 32b, yet still more narrowly from about 1 degree to about 5 degrees greater or less than the mandibular second guide surface angle 32b, or vice versa. FIG. 1 illustrates that the maxillary guide surfaces 26 can extend away from an occlusal surface of the maxillary dentition and/or from a maxillary oral tray (not shown, e.g., a maxillary orthodontic tray), for example, toward the mandible. The mandibular guide surfaces 28 can extend away from an occlusal surface of the mandibular dentition and/or a mandibular oral tray (not shown, e.g., a mandibular orthodontic tray), for example, toward the maxilla. Each guide surface (e.g., guide surfaces 26, 28) can have a first end and a second end. The first and second ends can be the base of the guide surface and the second end can be the top of the guide surface. The base of the maxillary guide surface 26 can be closer to a surface of a maxillary tooth and/or maxillary oral tray than the top of the maxillary guide surface 26 and the base of the mandibular guide surface 28 can be closer to a surface of a mandibular tooth and/or mandibular oral tray than the top of the mandibular guide surface 28. For example, FIG. 1 illustrates that the bases of the maxillary and mandibular guide surfaces 26, 28 can be proximate to and extend from maxillary and mandibular occlusal surfaces, respectively, toward the opposing dentition; however, one or more of the bases can be offset from the occlusal surface or oral tray such that the offset base(s) are separated from the dentition or a surface of a maxillary or mandibular oral tray by about 0.5 mm to about 50 mm. The tops can be proximate to or separated from (e.g., by about 0.5 mm to about 50 mm) the opposing dentition. FIG. 1 illustrates that the tops of the mandibular guide surfaces 28 can be configured to be proximate the maxillary detention and/or oral tray and that the tops of the maxillary guide surfaces 26 can be configured to be separated from the mandibular dentition and/or oral tray. The guide surfaces 26, 28 can extend along any portion of a length of a block, for example, 100% or less, 75% or less, 50% or less, 25% or less. For example, FIG. 1 illustrates that each guide surface 26, 28 can extend about 33% along a length of its respective block, thereby advantageously providing a large guide surface. Guide surfaces 26, 28 that extend along greater than about 10% of a length of a block can advantageously enable each block 12, 14 in a treatment series to be used for greater treatment period before a user graduates to the next block. Guide surfaces greater than this 10% threshold can reduce the number of blocks 12, 14 required in a treatment series. Guide surfaces greater than this 10% threshold can increase user comfort and tolerance for user error. Although not illustrated, each maxillary ramp 26 can extend about 100% along the length of a maxillary block 12, for example, from a maxillary block first end to a maxillary block second end such that the maxillary blocks 12 have a shape of a triangular wedge when viewed from the side. Similarly, each mandibular ramp 28 can extend about 100% along the length of a mandibular block 14, for example, from a mandibular block first end to a mandibular block second end such that the mandibular blocks 14 have a shape of a triangular wedge when viewed from the side. FIG. 1 illustrates that the maxillary and mandibular guide surfaces 26, 28 can be sloped longitudinally such that the angles 30, 32 are the angles that are formed as the guide surfaces 26, 28 extend longitudinally across the blocks 12, 14, for example, from the anterior portion 20 to the posterior portion 22 of the blocks 12, 14. As a result, the guide surfaces 26, 28 can form one or more longitudinal slopes. Additionally or alternatively, the maxillary and mandibular guide surfaces 26, 28 can be sloped transversely such that the angles 30, 32 can be the angles that are formed as the maxillary guide surfaces 26 extend laterally across the block, for example, from a first lateral side to a second lateral side (e.g., left to right and/or right to left) of the blocks 12, 14, or from a longitudinal center to a first and/or second lateral side of the blocks 12, 14. As a result, the guide surfaces 26, 28 can form one or more transverse slopes. Each guide surface 26, 28 can have a longitudinal and/or transverse slope. The longitudinal and transverse guide surfaces can have the same or different slope from one another. For example, one or more guide surfaces can have a longitudinal slope of about 35 degrees and a transverse slope of about 20 degrees. The one or more longitudinal slopes can reshape the airway by advancing the mandible. The one or more transverse slopes can reshape the airway by causing palatal expansion, for example, by exerting an outward force on the dentition. Each block in a series can have the same or different longitudinal and/or transverse slope(s) as one or more other blocks in the series. FIG. 1 illustrates the relative positions of the maxillary and mandibular blocks 12, 14 relative to the maxillary and mandibular dental arches, respectively. The maxillary blocks 12 (e.g., maxillary first and second blocks 12a, 12b) can be configured to overlay one or more posterior teeth and/or one or more anterior teeth. The maxillary blocks 12 can be configured to overlay a central incisor, a lateral incisor, a canine, one or more premolars, one or more molars, or any combination thereof. FIG. 1 illustrates that the maxillary first and second blocks 12a, 12b can overlay a portion of the posterior ends of the maxillary dental arch, for example, the second and third molars. The mandibular blocks 14 (e.g., mandibular first and second blocks 14a, 14b) can be configured to overlay one or more posterior teeth and/or one or more anterior teeth. The mandibular blocks 14 (e.g., mandibular first and second blocks 14a, 14b) can be configured to overlay a central incisor, a lateral incisor, a canine, one or more premolars, one or more molars, or any combination thereof. FIG. 1 illustrates that the mandibular first and second blocks 14a, 14b can overlay the posterior ends and an anterior portion of the mandibular dental arch, for example, the second premolar and the first, second and third molars. Each block in a series can have the same or different relative position as one or more other blocks in the series. The location of the maxillary and/or mandibular blocks 12, 14 relative to a dentition and/or to each other can be determined by a dentist, orthodontist, one or more computer algorithms, or a combination thereof. For example, a computer program can be used to retrieve data from oral data acquisition devices (e.g., scanners, x-ray devices, cameras) to record and measure orthodontic malocclusions and teeth misalignments. A computer program can be used to retrieve data from oral data acquisition devices to record and measure the orthodontic correction of malocclusions and misalignments during treatment. FIGS. 2 and 3 illustrate that the maxillary blocks 12 (e.g., maxillary first and second blocks 12a, 12b) can each have a length 12L, a width 12W and a height 12H. The length 12L can be from about 1 mm to about 50 mm, including every 0.5 mm increment between about 1 mm and about 50 mm, for example, about 15.0 mm. The width 12W can be from about 1 mm to about 30 mm, including every 0.5 mm increment between about 1 mm and about 30 mm, for example, 8.0 mm. The height 12H can be from about 1 mm to about 50 mm, including every 0.5 mm increment between about 1 mm and about 50 mm, for example, 18 mm. Each maxillary block 12 in a series can have the same or different length 12L, width 12W, and/or height 12H as one or more other maxillary blocks 12 in the series. The lengths 12L of multiple or successive maxillary blocks 12 can each have the same length or one or more different lengths 12L. For example, the lengths 12L of multiple or successive maxillary blocks 12 can become progressively longer, progressively shorter, follow another progressive pattern (e.g., increase and/or decrease), or remain constant. For example, the lengths 12L of the maxillary blocks 12 in a series can increase from about 15.0 mm to about 20.0 mm, vice versa (e.g., decrease from about 15.0 mm to about 10.0 mm), increase from about 15.0 to about 18.0 mm and then decrease to about 16.5 mm, or remain constant at about 15.0 mm. The widths 12W of multiple or successive maxillary blocks 12 can each have the same width or one or more different widths 12W. For example, the widths 12W of multiple or successive maxillary blocks 12 can become progressively longer, progressively shorter, follow another progressive pattern (e.g., increase and/or decrease), or remain constant. For example, the widths 12W of the maxillary blocks 12 in a series can increase from about 8.0 mm to about 13.0 mm, vice versa (e.g., decrease from about 8.0 mm to about 3.0 mm), increase from about 8.0 to about 11.0 mm and then decrease to about 10.0 mm, or remain constant at about 8.0 mm. The heights 12H of multiple or successive maxillary blocks 12 can each have the same height or one or more different heights 12H. The height 12H can be a maximum height. For example, the heights 12H of multiple or successive maxillary blocks 12 can become progressively longer, progressively shorter, follow another progressive pattern (e.g., increase and/or decrease), or remain constant. For example, the heights 12H of the maxillary blocks 12 in a series can increase from about 10.0 mm to about 15.0 mm, vice versa (e.g., decrease from about 15.0 mm to about 10.0 mm), increase from about 8.0 to about 11.0 mm and then decrease to about 10.0 mm, or remain constant at about 10.0 mm. FIGS. 2 and 3 illustrate that the mandibular blocks 14 (e.g., mandibular first and second blocks 14a, 14b) can each have a length 14L, a width 14W and a height 14H. The length 14L can be from about 1 mm to about 50 mm, including every 0.5 mm increment between about 1 mm and about 50 mm, for example, about 35.0 mm. The width 14W can be from about 1 mm to about 30 mm, including every 0.5 mm increment between about 1 mm and about 30 mm, for example, 8.0 mm. The height 12H can be from about 1 mm to about 50 mm, including every 0.5 mm increment between about 1 mm and about 50 mm, for example, 9 mm. Each mandibular block 14 in a series can have the same or different length 14L, width 14W, and/or height 14H as one or more other mandibular blocks 14 in the series. The lengths 14L of multiple or successive mandibular blocks 14 can each have the same length or one or more different lengths 14L. For example, the lengths 14L of multiple or successive mandibular blocks 14 can become progressively longer, progressively shorter, follow another progressive pattern (e.g., increase and/or decrease), or remain constant. For example, the lengths 14L of the mandibular blocks 14 in a series can increase from about 35.0 mm to about 40.0 mm, vice versa (e.g., decrease from about 35.0 mm to about 30.0 mm), increase from about 35.0 to about 38.0 mm and then decrease to about 36.5 mm, or remain constant at about 35.0 mm. The widths 14W of multiple or successive mandibular blocks 14 can each have the same width or one or more different widths 14W. For example, the widths 14W of multiple or successive mandibular blocks 14 can become progressively longer, progressively shorter, follow another progressive pattern (e.g., increase and/or decrease), or remain constant. For example, the widths 14W of the mandibular blocks 14 in a series can increase from about 8.0 mm to about 13.0 mm, vice versa (e.g., decrease from about 8.0 mm to about 3.0 mm), increase from about 8.0 mm to about 11.0 mm and then decrease to about 10.0 mm, or remain constant at about 8.0 mm. The heights 14H of multiple or successive mandibular blocks 14 can each have the same height or one or more different heights 14H. The height 14H can be a maximum height. For example, the heights 14H of multiple or successive mandibular blocks 14 can become progressively longer, progressively shorter, follow another progressive pattern (e.g., increase and/or decrease), or remain constant. For example, the heights 14H of the mandibular blocks 14 in a series can increase from about 3.0 mm to about 8.0 mm, vice versa (e.g., decrease from about 3.0 mm to about 0.5 mm), increase from about 3.0 mm to about 6.0 mm and then decrease to about 4.5.0 mm, or remain constant at about 3.0 mm. The length 12L can be greater than, equal to, or less than the length 14L. For example, FIG. 2 illustrates that the length 12L can be less than the length 14L. The width 12W can be greater than, equal to, or less than the width 14W. For example, FIG. 2 illustrates that the width 12W can be about equal to the width 14W. The height 12H can be greater than, equal to, or less than the height 14H. For example, FIG. 2 illustrates that the height 12H can be less than the height 14H. Each block 12, 14 can have one or more lengths, widths, heights, or any combination thereof. FIG. 3 illustrates that the guide surfaces 26 (e.g., guide surface 26b) can have a guide surface length 26L and that the guide surfaces 28 (e.g., guide surface 28b) can have a guide surface length 28L. The surface length 26L can be from about 1 mm to about 50 mm, including every 0.5 mm increment between about 1 mm and about 50 mm, for example, about 5 mm, about 6 mm, about 7 mm, about 8 mm, about 9 mm, about 10 mm, about 11 mm, about 12 mm, about 13 mm, about 14 mm, about 15 mm, about 16 mm, about 17 mm, about 18 mm, about 19 mm, about 20 mm. The surface length 28L can be from about 1 mm to about 50 mm, including every 0.5 mm increment between about 1 mm and about 50 mm, for example, about 5 mm, about 6 mm, about 7 mm, about 8 mm, about 9 mm, about 10 mm, about 11 mm, about 12 mm, about 13 mm, about 14 mm, about 15 mm, about 16 mm, about 17 mm, about 18 mm, about 19 mm, about 20 mm. Each block in a series can have the same or different guide surface length 26L as one or more other blocks in the series. The guide surface lengths 26L of multiple or successive maxillary blocks 12 can each have the same length or one or more different lengths 26L. For example, the guide surface lengths 26L of multiple or successive maxillary blocks 12 can become progressively longer, progressively shorter, follow another progressive pattern (e.g., increase and/or decrease), or remain constant. For example, the guide surface lengths 26L of the maxillary blocks 12 in a series can increase from about 10.0 mm to about 20.0 mm, vice versa (e.g., decrease from about 10.0 mm to about 5.0 mm), increase from about 10.0 to about 13.0 mm and then decrease to about 5.0 mm, or remain constant at about 10.0 mm. The guide surface lengths 28L of multiple or successive mandibular blocks 14 can each have the same length or one or more different lengths 28L. For example, the guide surface lengths 28L of multiple or successive mandibular blocks 12 can become progressively longer, progressively shorter, follow another progressive pattern (e.g., increase and/or decrease), or remain constant. For example, the guide surface lengths 26L of the mandibular blocks 12 in a series can increase from about 10.0 mm to about 20.0 mm, vice versa (e.g., decrease from about 10.0 mm to about 5.0 mm), increase from about 10.0 to about 13.0 mm and then decrease to about 5.0 mm, or remain constant at about 10.0 mm. FIG. 3 illustrates that one or more of the maxillary and mandibular blocks 12, 14 can have a free surface 25 (also referred to as a hanging surface) positioned opposite a tooth surface 24 (e.g., tooth surface 24a and/or 24b) that is configured to not contact an opposing block (e.g., any surface of the opposing block), an opposing dental or orthodontic tray, an opposing dentition, or any combination thereof. For example, FIG. 1 illustrates that one or more maxillary blocks 12 can have a free surface 25. The maxillary first block 12a can have a maxillary first block hanging surface 25a and/or the maxillary second block 12b can have a maxillary second block hanging surface 25b. A hanging surface 25 can advantageously provide more space for the tongue in the oral cavity, increase the size of the airway and help keep open the airway. Additionally or alternatively, a hanging surface can advantageously inhibit or prevent the blocks 12, 14 from triggering a person's gag reflex, for example, by reducing the size of the oral appliance 10 positioned in the back of the oral cavity. FIG. 3 illustrates that a gap can form between a free hanging surface 25 (e.g., the maxillary second block hanging surface 25b) and an opposing dentition (e.g., the mandibular dentition). The gap can be from about 0 mm to about 50 mm, more narrowly from about 1 mm to about 20 mm, yet more narrowly from about 1 mm to about 15 mm, yet still more narrowly from about 1 mm to about 10 mm, including every 0.5 mm increment within these ranges, for example, about 5 mm, about 6 mm, about 7 mm, about 8 mm, about 9 mm, about 10 mm. The gap can be the shortest distance between the free surface 25 and the opposing dental tray, orthodontic tray, or teeth. The gap can be the greatest distance between the free surface 25 and the opposing dental tray, orthodontic tray, or teeth. The gap can be measured between any point on an opposing dental tray, orthodontic tray, or teeth to any point on the hanging surface 25. The point on the hanging surface may or may not correspond with a point that is closest to or farthest from the opposing dental tray, orthodontic tray, or teeth. FIG. 3 illustrates a variation of the relative positions of the maxillary and mandibular blocks 12, 14 to one another when the jaw is in a closed position. FIG. 3 illustrates that when the jaw is fully closed at least a portion of a posterior portion 22 of the maxillary blocks 12 (e.g., the maxillary first and second blocks 12a, 12b) can be posterior to at least a portion of a posterior portion 22 of the mandibular blocks 14 (e.g., the mandibular first and second blocks 14a, 14b), or vice versa (if, for example, the positions of the blocks 12, 14 are reversed such that the maxillary blocks 12 are placed in their same relative positions on the mandibular dental arch and the mandibular blocks 14 are place in their same relative positions on the maxillary dental arch). For example, FIG. 3 illustrates that the maxillary blocks 12 do not extend anterior to the top of the ramp of the mandibular blocks 14, and are accordingly posterior to the remaining portion of the mandibular blocks 14. The dimensions and relative positions of the blocks 12, 14 disclosed herein will depend on, and can be customized to accommodate, for example, a person's airway, dental and/or orthodontic needs, their anatomy, the number of blocks in a series, the number oral trays in a series, or any combination thereof; thus, although various positions, ranges and values are disclosed, each permutation of the disclosed positions, ranges and values and equivalents thereof is considered critical to the overall design of the oral appliance 10, as each combination of dimensions and positions, when used together to reposition the jaw, adjust the bite, and/or reshape and/or maintain a person's airway, is critical to providing the treatment desired. Additionally, each block in a series can have any combination of the dimensions and positions disclosed, as the design of each block in a series will depend on a person's unique dentition and other craniofacial structures as well as the implemented orthodontic and/or SBD treatment plan. If the foregoing disclosure yet lacks clarity, every permutation of block dimensions and positions within the ranges and values disclosed is hereby explicitly disclosed, for example, in 0.1 mm increments, such that any combination of block dimensions and/or relative positions is claimable. The first and second maxillary blocks 12a, 12b can be connected via one or more maxillary connectors. The maxillary connector(s) can be a wire, resilient wire, polymer strand, resilient polymer strand, dental tray, orthodontic tray, or any combination thereof that conform to, extend along, or wrap around a buccal side, a lingual side, and/or an occlusal surface of at least a portion of the maxillary dental arch. A first end of the maxillary connector(s) can be attached to or integrated with any portion of the maxillary first or second block 12a, 12b and a second end of the maxillary connector(s) can be attached to or integrated with any portion of the other of the maxillary first or second block 12a, 12b. The maxillary connector(s) can be used to stabilize the first and second maxillary blocks 12a, 12b. The maxillary connector(s) can be designed and/or manipulated (e.g., progressively manipulated over a series of treatments) to orthodontically move maxillary teeth. The first and second mandibular blocks 14a, 14b can be connected via one or more mandibular connectors. The mandibular connector(s) can be a wire, resilient wire, polymer strand, resilient polymer strand, dental tray, orthodontic tray, or any combination thereof that conform to, extend along, or wrap around a buccal side, a lingual side and/or an occlusal surface of at least a portion of the mandibular dental arch. A first end of the mandibular connector(s) can be attached to or integrated with any portion of the mandibular first or second block 14a, 14b and a second end of the mandibular connector(s) can be attached to or integrated with any portion of the other of the mandibular first or second block 14a, 14b. The mandibular connector(s) can be used to stabilize the first and second mandibular blocks 14a, 14b. The mandibular connector(s) can be designed and/or manipulated (e.g., progressively manipulated over a series of treatments) to orthodontically move mandibular teeth. Orthodontic and dental trays are individually and collectively referred to throughout as oral trays such that an oral tray can be an orthodontic and/or a dental tray, for example, an aligner (also referred to as an orthodontic tray), a whitening tray, or an orthodontic teeth whitening aligner that is configured to move and whiten at least one tooth. Oral trays are also referred to as aligners and aligner components throughout. The blocks 12, 14 can be attached to or integrated with a maxillary and/or mandibular oral tray. For example, the maxillary blocks 12 can be integrated with a maxillary and/or mandibular oral tray and/or the mandibular blocks 14 can be integrated with a maxillary and/or mandibular oral tray. A series of oral trays can be designed to progressively reposition the maxillary and/or mandibular teeth in two or more successive steps, for example, as disclosed in PCT Publication WO 2016/004415 and U.S. application Ser. No. 15/386,280 (published as US 2017/0100214), both of which have been incorporated herein by reference in their entireties for all purposes. Each oral tray in a series can have a tooth surface that has a geometry that corresponds to an intermediate or end tooth arrangement intended for the oral tray in the series. The oral trays can be sufficiently resilient to accommodate or conform to misaligned teeth, but apply sufficient force against the misaligned teeth to reposition the teeth to the intermediate or end arrangement as desired for the particular treatment step. A series of oral trays can have geometries selected to progressively reposition teeth from a first arrangement through one or more successive intermediate arrangements to a final arrangement. A series of trays can have 1 to 100 maxillary trays and 1 to 100 mandibular trays, for example, 1 to 55 maxillary trays and 1 to 55 mandibular trays, 1 to 50 maxillary trays and 1 to 50 mandibular trays, 1 to 45 maxillary trays and 1 to 45 mandibular trays, 1 to 40 maxillary trays and 1 to 40 mandibular trays, less than 40 maxillary trays 12 and less than 40 mandibular trays, including every 1 tray increment within these ranges, or any combination thereof. For example, a series of trays can have 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 maxillary trays and 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 mandibular trays. The number of maxillary trays can be the same or different as the number mandibular trays in a series. The trays can orthodontically move the teeth into one or more correct physiological positions. For example, the trays can orthodontically move the teeth into one or more positions that physiologically allows for a more open airway. Each tray in a series can be configured to move one or more teeth, or one or more trays in a series can be configured to not move any teeth. For example, where the mandibular teeth are in a desired alignment but the position of the maxillary teeth are still in need of an adjustment, the mandibular tray can be configured to maintain the position of the mandibular teeth and the maxillary tray can be configured to move one or more maxillary teeth. The blocks 12, 14 can be modular such that they can be removably attached to a maxillary and/or mandibular oral tray, for example, to an orthodontic tray and/or to a dental tray (i.e., any tray without an orthodontic function). The blocks 12, 14 can be attached to one or multiple oral trays with one or multiple attachment mechanisms (also referred to as anchors), such as clasps, clips, hooks, elastic hooks, barbs, spurs, fasteners, or any combination thereof. Additionally or alternatively, the blocks 12, 14 can fit over a portion of an oral tray with a friction fit and/or a snap fit. For example, the oral tray can have a ridge over which the blocks 12, 14 can be snapped. The ridge can extend at least partially along a surface of the oral tray. A first end (e.g., a base) of each maxillary block 12 can be anchored to a maxillary oral tray. A second end (e.g., a top portion) of each maxillary block 12 can be anchored to a mandibular oral tray. A first end (e.g., a base) of each mandibular block 14 can be anchored to a mandibular oral tray. A second end (e.g., a top portion) of each mandibular block 14 can be anchored to a maxillary oral tray. A modular block design can be especially advantageous where a series of orthodontic trays are designed as disclosed in WO 2016/004415, as the modular design can allow the reuse and/or repositioning of the blocks 12, 14 along the arch of the maxillary and/or mandibular dentition on a single aligner or on multiple successive aligners. The modular design can advantageously allow the repositioning of one or more blocks 12, 14 from a first position on an oral tray to one or more other positions on the oral tray different from the first position. For example, the modular design can allow the repositioning each block (e.g., blocks 12 and/or 14) in a series 1 to 100 times on one or multiple oral trays, including every increment of 1 between 1 and 100. A modular design can also advantageously allow a series of blocks to be mixed and matched with each oral tray in an oral tray series. One or both guide surfaces of a guide surfaces pair 26-28 (e.g., pair 26a-28a and/or pair 26b-28b) can have a coating or otherwise comprise a material which permits relative motion between two opposed guide surfaces in a first direction and resists relative motion between two opposed guide surfaces in a second direction opposite the first direction. For example, the mandibular blocks 14 can be configured to engage the maxillary blocks 12 and slide forward along the guide surfaces 26 of the maxillary blocks 12 upon the application of a compressive force between two opposing maxillary and mandibular blocks 12, 14 (e.g., upon closing the jaw from an open position or by otherwise “biting down” on the blocks 12, 14). As another example, the mandibular blocks 14 can be configured to engage the maxillary blocks 12 and slide forward along the guide surfaces 26 of the maxillary blocks 12 in a first direction when the jaw relaxes or is voluntarily opened and then relaxed and be prevented or inhibited from sliding along the guide surfaces 26 in a second direction opposite the first direction. The guide surfaces (e.g., guide surfaces 26 and/or 28) can have a first coefficient of friction associated with movement of the mandibular blocks 12 in a first direction and a second coefficient of friction associated with movement of the mandibular blocks 12 in a second direction opposite the first direction. The second coefficient of friction can be greater than the first coefficient of friction. The first and second coefficients of friction can be static coefficients of friction μs. The first and second coefficients of friction can be kinetic coefficients of friction μk. One or both guide surfaces of a guide surface pair 26-28 (e.g., pair 26a-28a and/or pair 26b-28b) can have a coating or otherwise comprise a material (e.g., an adhesive or a ferromagnetic material) which inhibits relative motion between two opposed guide surfaces when they interact. Additionally or alternatively, one or more magnets can be placed in the blocks 12, 13 such that the maxillary blocks 12 magnetically attract the mandibular blocks 14 and vice versa. The maxillary and mandibular blocks 12, 14 can comprise a thermoplastic material. The maxillary and mandibular blocks 12, 14 can be thermoformed with the aid of a computer algorithm. The maxillary and mandibular aligners can comprise a thermoplastic material. The maxillary and mandibular aligners can be thermoformed with the aid of a computer program. The maxillary blocks 12 and the maxillary aligners can be attached to, integrated with, or monolithically formed with one another. The mandibular blocks 14 and the mandibular aligners can be attached to, integrated with, or monolithically formed with one another. The maxillary and mandibular blocks 12, 14 can be rigid such that they resist deformation under pressure or semi-rigid such that they permit deformation and/or are compliant under pressure. Semi-rigid and/or compliant materials can advantageously increase user comfort and prevent, inhibit, or limit sleep bruxism. The blocks 12, 14 can be solid or hollow. For example, the blocks 12, 14 can have one or more airway channels (e.g., 1 to 10 or more airway channels). The airway channels can extend at least partially laterally and/or at least partially longitudinally through the blocks 12, 14. The airway channels can extend through the blocks 12, 14 from the buccal side 16 to the lingual side 18. The airway channels can extend through the blocks 12, 14 from an anterior side to a posterior side. One or more of the airway channels of a maxillary block 12 can be at least partially aligned (e.g., partially or completely collinear) with one or more channels of a mandibular block 14. Each channel can have an anterior end and a posterior end. A posterior end of the channel of an anterior block (e.g., the mandibular blocks 14 in FIG. 1) can overlap completely or partially with an anterior end of the channel of a posterior block (e.g., the maxillary blocks 12 in FIG. 1). The posterior ends of the airway channels of the posterior blocks (e.g., the maxillary blocks 12 in FIG. 1) can be directed toward the pharynx to facilitate inhalation and exhalation. A posterior portion of the airway channels in the posterior blocks (e.g., the maxillary blocks 12 in FIG. 1) can be curved such that the posterior ends of the posterior blocks are directed toward the pharynx or the base of the tongue. The airway channels can be straight, curved, tapered, or any combination thereof. A cooperating pair of blocks 12-14 can have 1 to 10 or more airway channels. For example, the cooperating pair of blocks 12a-14a and 12b-14b can each have one maxillary airway channel and two mandibular airway channels extending at least partially longitudinally and/or laterally through the blocks 12a, 12b, 14a, 14b. One of the mandibular airway channels can be at least partially aligned with the maxillary airway channel. The three airway channels (the one maxillary and two mandibular channels) can thereby advantageously form two airway channels from an anterior portion of the oral appliance 10 to a posterior portion of the oral appliance 10. The one or more airway channels in the oral appliance 10 can decrease the amount of dead space in the oral cavity by increasing the size of the oral cavity available for airflow through the oral cavity by allowing air to flow through the blocks 12, 14. By increasing the volume in the oral cavity available for airflow, the one or more airway channels can advantageously reduce the amount of respiratory effort required for inhalation and exhalation and/or decrease the velocity of the air passing through oral cavity, and can therefore, in turn, prevent, inhibit, and/or reduce the likelihood of an SBD event and/or the occurrence of snoring. The one or more airway channels can and/or can help prevent, inhibit, and/or reduce SBD and/or snoring. The airway channels can be substantially the same size as the block or any lesser size, collectively or individually. For example, a transverse and/or longitudinal cross-sectional area of the airway channels can be about 1% to about 100% of a transverse and/or longitudinal cross-sectional area of the blocks 12, 14, more narrowly from about 1% to about 95%, more narrowly still from about 1% to about 90%, including every 1% increment within these ranges, for example, about 25%, 50%, 75%, 90%, or 95%. A length of the airway channels can be about 1% to about 100% of a length of the blocks 12, 14, more narrowly from about 1% to about 90%, more narrowly still from about 1% to about 80%, including every 1% increment within these ranges, for example, about 25%, 50%, 75%, or 95%. The airway channels can extend laterally across the blocks 12, 14 such that the airway channels extend across about 1% to about 100% the width of a block, more narrowly from about 1% to about 90%, more narrowly still from about 1% to about 80%, including every 1% increment within these ranges, for example, about 25%, 50%, 75%, or 95%. One or more sensors can be positioned in one or multiple airway channels, integrated into a wall of one or multiple airway channels, integrated or positioned on an outer surface of one or multiple blocks 12, 14, integrated in one or multiple blocks 12, 14, integrated or positioned on one or more oral trays, or any combination thereof. The one or more sensors can be flow sensors, pressure sensors, temperature sensors, or any combination thereof. The sensor(s) can be in communication with a controller configured to activate an alarm when an obstruction is detected, for example, when a flow sensor detects a stoppage or reduction in flow that exceeds a time interval threshold, when a pressure sensor detects a drop in pressure that exceeds a pressure drop threshold, when a temperature sensor detects a temperature increase of exhaled or oral cavity air that exceeds a temperature threshold, or any combination thereof. The alarm can be auditory and/or tactile (e.g., vibration), and can be emitted from an alarm mechanism, including, for example, the controller. The controller can be integrated with the oral device 10 or be in wireless communication therewith. The controller can be configured to communicate an alarm signal to a smartphone or other computing device which can process the signal and emit an auditory and/or tactile alarm. The alarm can be configured to wake a person up from a potentially dangerous SBD event. One or more sensors (e.g., one or more pressure sensors) can be in communication with the controller to detect whether the oral appliance 10 is properly or improperly positioned. The controller can be configured to activate an alarm if the oral appliance 10 is improperly positioned, for example, if it becomes dislodged when a person is sleeping (e.g., if one or more pressure sensors detect a pressure drop that exceeds a pressure drop threshold). Method of Use The oral appliance 10, or a series of oral appliances 10, can be placed in an oral cavity as shown in FIG. 3. The blocks 12, 14 can facilitate or otherwise encourage a person to open their mouth and/or move their mandible forward, for example, due to the size and/or shape of the blocks 12, 14 and/or due the interaction between the blocks 12, 14 when a person opens their mouth and/or bites down on the blocks after the oral appliance is placed in the oral cavity. The size of the blocks 12, 14 can cause a person to open their mouth at least as wide as the smallest thickness of the blocks 12, 14 (e.g., the length, width, and/or height of the blocks) to accommodate placement of the blocks 12, 14 in the oral cavity. The size and/or shape of the blocks 12, 14 can be configured to encourage a person to move their mandible forward with or without biting down on the blocks 12, 14. For example, the blocks 12, 14 can interact to move the mandible forward when a person bites down on the blocks 12, 14. However, a person can use the blocks 12, 14 with or without moving their mandible forward. The size and/or shape of the blocks 12, 14 can be configured to advance a person's mandible. The size and/or shape of the blocks 12, 14 can be configured to not advance a person's mandible. The size and/or shape of the blocks 12, 14 can cause a mandible to advance from a retruded position, neutral position, or advanced position. The size and/or shape of the blocks 12, 14 can prevent, inhibit, or limit mandibular retrusion relative to a retruded position, neutral position, or advanced position of the mandible, whether such a position is a natural position of a person, or whether it is caused by the blocks 12, 14. In this way, the blocks 12, 14 can be configured to interact with one another to reshape and/or maintain the airway and prevent, inhibit, or limit the airway from partially and/or entirely closing to treat SBD, for example, from a partially or entirely open configuration. Such an arrangement can advantageously provide SBD treatment by repositioning the jaw and/or by opening up the airway. As described above, one or more maxillary blocks 12 can cooperate with one or more mandibular blocks 14 to reposition the jaw, adjust the bite, and/or reshape and/or maintain the airway. FIG. 3 illustrates that the blocks 12, 14 can cooperate with one another to move the mandible forward. FIG. 3 also illustrates that the blocks 12, 14 can cooperate with one another to reshape the airway into one or more open configurations, for example, by increasing the interocclusal separation between maxillary and mandibular dentitions. The blocks 12, 14 can be designed to maintain the mandible in one or more forward positions when the blocks 12, 14 are engaged with one another. The blocks 12, 14 can also be designed to maintain the airway in one or more open configurations, including one or more reshaped configurations caused at least partially by the interaction of the blocks 12, 14. The blocks 12, 14 can interact with one another to reshape the airway by repositioning (also referred to as displacing) the mandible relative to the maxilla. For example, the blocks 12, 14 can be configured to move the mandible forward and/or increase the interocclusal separation between the maxillary and mandibular dental arches when the blocks 12, 14 interact with one another. Such displacement can advantageously reposition the jaw, adjust the bite, and/or reshape the airway and cause the airway to become more open—thus providing SBD treatment. The blocks 12, 14 can interact with one another to adjust the bite by maintaining a neutral position (e.g., non-advanced position) or a displaced position (e.g., advanced position) of the mandible relative to the maxilla. The blocks 12, 14 can also interact with one another to maintain an open airway by maintaining a neutral position (e.g., non-advanced) or a displaced position (e.g., advanced position) of the mandible relative to the maxilla. For example, the blocks 12, 14 can prevent, inhibit, or limit posterior movement of the mandible and/or a reduction of the interocclusal distance when the mandible is in a neutral and/or displaced position. Such mandibular support can advantageously treat SBD by training the jaw to return to a new, or modified, neutral position. Such mandibular support can also advantageously prevent, inhibit, or limit the tongue from falling back and collapsing the airway. A neutral position is considered any natural occlusal position. A displaced position is considered any non-displaced position, for example, any advanced and/or retruded position, natural or imposed. The blocks 12, 14 can cause a displaced mandibular position to become a new natural occlusal position, for example, by orthodontically manipulating (e.g., progressively manipulating with a series of trays and/or blocks) craniofacial structures over time such that the mandible and associated structures acquire a new equilibrium (e.g., neutral) position. The blocks 12, 14 can interact with one another to widen the maxillary (also referred to as superior or upper) dental arch and/or the mandibular (also referred to as inferior or lower) dental arch. For example, the blocks 12, 14 can have one or more transverse slopes that can interact with one another to widen the hard and/or soft palates. Such widening can advantageously reshape the airway and cause it to become more open. Widening the mandibular dental arch can increase the size of the sublingual space and decrease the amount of obstruction the tongue causes in the oral cavity. Widening the maxillary dental arch can cause palatal expansion and thereby increase the size of the oral cavity. The blocks 12, 14 can interact to move the mandible forward, temporarily or permanently. The blocks 12, 14 can also interact to cause the airway to develop a more open configuration, temporarily or permanently. The blocks 12, 14 can be configured to temporarily or permanently manipulate craniofacial structures. The one or more guide surface pairs 26-28 of the oral appliance 10 (e.g., pair 26a-28a and/or pair 26b-28b) can interact in such a manner to prevent, inhibit, or limit posterior movement of the mandible and associated structures (e.g., the tongue), for example, to SBD. The maxillary and mandibular guide surfaces 26, 28 can be configured to interact with one another or to otherwise contact each other throughout treatment or only during a portion thereof. As described above, the blocks 12, 14 can be configured to interact in a self-guided manner. FIG. 3 illustrates that a cooperating pair of guide surfaces 26b, 28b can interact to advance the mandible into a forward position (also referred to as advanced). FIG. 3 also illustrates that such advancement can increase the interocclusal distance between the dental arches, but the SBD appliance 10 can advance the mandible without increasing the interocclusal distance as well. Where there is an increase in the interocclusal distance, the resultant interocclusal distance can be greater than the natural interocclusal distance that would otherwise result between the arches if the jaw were simply advanced without the use of guide surfaces 26, 28. For example, the resultant interocclusal distance can be greater than the natural interocclusal separation that the alignment of the anterior teeth causes when the mandible is advanced when clenched. Where the anterior teeth do not produce natural disclusion upon the advancement of the mandible, the resultant interocclusal distance that results can be due solely to one or more cooperating pairs of guide surfaces 26, 28 when the mandible is advanced. FIG. 3 illustrates that the closing of the jaws with a cooperating pair of guide surfaces 26, 28 can advance the mandible forward an advancement distance 34. The advancement distance 34 can be from about 0 mm to about 30 mm, more narrowly from about 0 mm to about 20 mm, yet more narrowly from about 0 mm to about 10 mm, yet still more narrowly from about 5 mm to about 10 mm, including every 0.25 mm increment within these ranges, for example, about 5 mm, about 6 mm, about 7 mm, about 8 mm, about 9 mm, about 10 mm, about 11 mm, about 12 mm, about 13 mm, about 14 mm, about 15 mm, about 16 mm, about 17 mm, about 18 mm, about 19 mm, about 20 mm. FIG. 3 illustrates that the cooperating pair of guide surfaces 26, 28 can advance the mandible forward a sufficient advancement distance 34 to artificially create an underbite (also referred to as a Class III malocclusion). For example, the cooperating pair of guide surfaces 26, 28 can advance the mandible forward such that the maxillary incisors are within the anterior perimeter (as opposed to posterior where the molars are) of the mandibular incisors by, for example, from about 0.5 mm to about 5.0 mm, including every 0.25 mm increment within this range. The closing of the jaws with a cooperating pair of guide surfaces 26, 28 can increase the interocclusal distance 36 between the dental arches from about 0 mm to about 60 mm, more narrowly from about 0 mm to about 50 mm, more narrowly from about 0 mm to about 40 mm, yet more narrowly from about 0 mm to about 30 mm, yet still more narrowly from about 0 mm to about 20 mm, yet more narrowly still from about 0 mm to about 10 mm, including every 0.25 mm increment within these ranges, for example, about 30 mm, about 31 mm, about 32 mm, about 33 mm, about 34 mm, about 35 mm, about 36 mm, about 37 mm, about 38 mm, about 39 mm, about 40 mm. The range of natural disclusion can range from 0 mm to about 10 mm, including every 0.25 mm increment within this range. The interocclusal distance 36 can be the height 12H of a maxillary block 12, the height 14H of a mandibular block 14, or a combination thereof. At least a portion of each pair of cooperating guide surfaces 26, 28 (e.g., guide surfaces 26b, 28b) can contact each other when the jaw is being closed, for example from an open configuration to a closed (or less open) configuration. At least a portion of each pair of opposing guide surfaces 26, 28 can slidably contact each other such that at least a portion of the guide surfaces 26, 28 slide past one another to advance the mandible and increase the interocclusal distance when the jaw is closed, for example, from an open configuration to a less open configuration. The cooperating guide surfaces can have a contact length that ranges from 0 mm when not in contact to about 1 mm to about 30 mm when in contact, including every 0.5 mm increment within this range. The contact length can increase from 0 mm to a maximum contact length as the mandible is closed against the maxilla, or equivalently, as the mandibular dentition is closed against the maxillary dentition. FIG. 3 illustrates that the cooperating guide surfaces 26, 28 can have a maximum contact length of about 3 mm to about 15 mm, including every 0.5 mm increment within this range, for example, 12 mm. The maximum contact length can be the entire length or only part of the length of one or both of the cooperating guide surfaces 26, 28. FIG. 3 illustrates that the maximum contact length can be the length of the maxillary guide surfaces 26. Alternatively or additionally, at least a portion of each pair of opposing guide surface 26, 28 can be configured to not slidably contact each other, but rather merely rest against each another when the jaw is open to prevent, inhibit, or limit retrusion of the mandible. For example, when the jaws are partially or fully closed, at least a portion of each pair of cooperating guide surfaces 26, 28 (e.g., guide surfaces 26b, 28b) can contact its opposing guide surface such that at least one of the guide surfaces 26, 28 prevents, inhibits, or limits posterior movement of the mandible. For example, FIG. 3 illustrates that the maxillary second guide surface 26b can interfere with (e.g., prevent, inhibit, or limit) any posterior movement of the mandibular second guide surface 28b, thereby interfering with any posterior movement of the mandibular second block 14b and the mandible. The maxillary and mandibular blocks 12, 14 can cooperate to allow the mandible to move in multiple directions when the jaws are in a fully closed position, for example, side-to-side, front-to-back, and/or up-and-down (or in any three mutually orthogonal reference planes). For example, the blocks 12, 14 can have a movement tolerance of about 1 mm to about 5 mm (e.g., including every 0.25 mm increment within this range) along three or fewer reference planes/axes to advantageously maximize comfort, reduce the likelihood of the SBD device 10 from causing new SBD issues, minimize sleep bruxism, and/or inhibit the blocks 12, 14 from becoming dislodged while concurrently treating SBD and/or snoring. The posterior guide surface of a posterior-anterior guide surface pair can, for example, resist but allow posterior movement of the anterior guide surface. The posterior and anterior guide surfaces can be any two opposing surfaces, for example, the maxillary second guide surface 26b and the mandibular second guide surface 28b pair, with the maxillary second guide surface 26b being posterior to the mandibular second guide surface 28b. Alternatively or additionally, the posterior guide surface can freely allow posterior movement of the anterior guide surface over the tolerance range and then begin to resist further posterior movement. For example, the posterior and anterior guide surfaces (e.g., posterior guide surfaces 26 and anterior guide surfaces 28) can be partially or entirely coated with the coating described above. The maxillary and mandibular guide surface angles 30, 32 can have angles that self-guide the mandible to return to a more forward position when the mandible moves posteriorly. The maxillary and mandibular blocks 12, 14 can cooperate to allow the mandible to have six degrees of freedom when the jaw is being opened and closed. The maxillary and mandibular blocks 12, 14 can be locked together when the mandible is in an advanced position, and allow movement within the tolerance range within one, two, three, four, five, and/or six degrees of freedom. Alternatively or additionally, the oral appliances 10 disclosed herein can allow free mandibular motion except for the retrusion prevented, inhibited, or limited by two opposed guide surface pairs 26, 28 when they are in a position to interact with one another. As described above, a series of blocks 12, 14 can be designed and applied or used over time to move one or more teeth, advance and/or maintain a position of the mandible, increase the interocclusal distance 36 and/or widen the hard and/or soft palates in two or more successive steps in a series. Exemplary dimensional variations are disclosed below, but these are in no way limiting, as every permutation of the dimensions and relative positions herein disclosed is appreciated, for example, including every 0.25 mm increment or 0.5% increment within the dimensional ranges disclosed herein. Successive dimensional changes can advantageously achieve the desired treatment in each step in a series. Each block 12, 14 in a series can have guide surface angles 30, 32 that correspond to an intermediate or end mandible advancement position or interocclusal distance intended for the block 12, 14 in the series. Each block 12, 14 in a series can have block lengths, widths and heights 12L, 14L, 12W, 14W, 12H, 14H that correspond to an intermediate or end mandible advancement position or interocclusal distance intended for the block 12, 14 in the series. Each block 12, 14 in a series can have guide surface lengths 26L, 28L that correspond to an intermediate or end mandible advancement position or interocclusal distance intended for the block 12, 14 in the series. Each block 12, 14 in a series can be configured to contact a different portion or a length of a guide surface of an opposing block. Each block 12, 14 in a series can have a longitudinal and/or transverse slope that corresponds to an intermediate or end mandible advancement position or interocclusal distance intended for the block 12, 14 in the series. One or more of the dimensions disclosed can be increased, decreased, or remain unchanged from one treatment step to the next treatment step (i.e., one or more dimensions can remain unchanged between two treatment steps). For example, one or more dimensions can be increased and/or decreased from a first dimension to a second dimension between two treatment steps (e.g., between a first treatment step and a second treatment step with no treatment step between the first and second treatment steps, or between any two treatment steps) such that the second dimension is about 0.5 mm to about 40 mm greater than or less than the value of the first dimension in the first treatment step than in the second (e.g., subsequent) treatment step, for example, every 0.25 mm increment between 0.5 mm and 40 mm (e.g., 0.5 mm, 1.0 mm, 1.5 mm, 2.0 mm, 2.5 mm, 3.0 mm, 3.5 mm, 4.0 mm, 4.5 mm, 5.0 mm and so on). For example, one or more dimensions can be increased and/or decreased from a first dimension to a second dimension between two treatment steps (e.g., between a first treatment step and a second treatment step with no treatment step between the first and second treatment steps, or between any two treatment steps) such that the second dimension is about 1% to about 500% greater than or less than the value of the first dimension in the first treatment step than in the second (e.g., subsequent) treatment step, for example, every 1% increment between 1% and 500% (e.g., 1%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, 175% and so on). In a treatment series, the blocks 12, 14 can move one or more teeth, reposition the mandible, adjust the bite, adjust the interocclusal distance, and/or widen the hard and/or soft palates to an intermediate or end arrangement as desired in one or more treatment steps in a series. The blocks 12, 14 can progressively move teeth, increase and/or decrease the advancement distance 34, increase and/or decrease the interocclusal distance 36, widen the hard and/or soft palates, adjust the bite, or any combination thereof. For example, the blocks 12, 14 in a series can progressively increase the advancement distance 34 from a first distance to a second distance greater than the second distance. The blocks 12, 14 in a series can progressively decrease the advancement distance 34 from the second distance to a third distance less than the second distance and greater than the first distance. As another example, the blocks 12, 14 in a series can progressively increase the interocclusal distance 36 from a first distance to a second distance greater than the first distance. The blocks 12, 14 in a series can progressively decrease the interocclusal distance 36 from the second distance to a third distance less than the second distance and greater than the first distance. As another example, the blocks 12, 14 in a series can progressively increase the width of a palate from a first width to a second width greater than the first width. The design of a series of blocks can advantageously reduce the initial shock of treatment to the affected craniofacial (e.g., mandible, dental arches, airway, palate) structures potentially caused by the blocks 12, 14 and therefore make the treatment more comfortable. Exemplary dimensional variations are disclosed below, but these are in no way limiting, as every permutation of the dimensions and relative positions herein disclosed is appreciated, for example, including every 0.25 mm increment or 0.5% increment within the dimensional ranges disclosed herein. One or more of the dimensions disclosed can be increased, decreased, or remain unchanged from one treatment step to the next treatment step (i.e., one or more dimensions can remain unchanged between two treatment steps). Such craniofacial dimensions (e.g., dimensions 34 and 36) can be increased and/or decreased from a first dimension to a second dimension between two treatment steps (e.g., between a first treatment step and a second treatment step with no treatment step between the first and second treatment steps, or between any two treatment steps) such that the second dimension is about 0.5 mm to about 40 mm greater than or less than the value of the first dimension in the first treatment step than in the second (e.g., subsequent) treatment step, for example, every 0.5 mm increment between 0.5 mm and 40 mm (e.g., 0.5 mm, 1.0 mm, 1.5 mm, 2.0 mm, 2.5 mm, 3.0 mm, 3.5 mm, 4.0 mm, 4.5 mm, 5.0 mm and so on). Such craniofacial dimensions (e.g., dimensions 34 and 36) can be increased and/or decreased from a first dimension to a second dimension between two treatment steps (e.g., between a first treatment step and a second treatment step with no treatment step between the first and second treatment steps, or between any two treatment steps) such that the second dimension is about 1% to about 500% greater than or less than the value of the first dimension in the first treatment step than in the second (e.g., subsequent) treatment step, for example, every 1% increment between 1% and 500% (e.g., 1%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, 175% and so on). FIG. 4 illustrates a variation of an aligner 38 on teeth. The aligner 38 can have the properties of the oral trays described herein. For example, the aligner 38 can be a maxillary dentition aligner 38a or a mandibular dentition aligner 38b. The aligner 38 can have an inner surface and an outer surface. The inner surface can define a tooth-receiving cavity. The inner surface can be configured to contact one or more teeth. The inner surface can have a geometry configured to move one or more maxillary or mandibular teeth from a first position to a second position, for example, by exerting a force on one or more teeth (e.g., from an interference fit configured to move one or more teeth). The aligner 38 can fit over all or a subset of teeth in the maxillary and/or mandibular dentition. A series of aligners 38 (e.g., maxillary and/or mandibular aligners 38a, 38b) can be designed and applied or used over time in order to reposition one or more maxillary and/or mandibular teeth in two or more successive steps, for example, as disclosed in PCT Publication WO 2016/004415 and U.S. application Ser. No. 15/386,280 (published as US 2017/0100214), both of which have been incorporated herein by reference in their entireties for all purposes. As described above, each aligner 38 in a series can have an inner surface that has a geometry that corresponds to an intermediate or end tooth arrangement intended for each aligner 38 in the series. The aligners 38 can be sufficiently resilient to accommodate or conform to misaligned teeth, but apply sufficient force against the misaligned teeth to reposition the teeth to the intermediate or end arrangement as desired for the particular treatment step. A series of aligners 38 can have geometries selected to progressively reposition teeth from a first arrangement through one or more successive intermediate arrangements to a final arrangement. SBD appliance therapy can be combined with orthodontic aligner treatment as described above, for example, with an aligner 38 (e.g., a maxillary and/or mandibular aligner 38a, 38b). As further described above, one or more airway development blocks 12 and/or 14 (also referred to as guides) can be directly or indirectly attached to or integrated with an aligner 38 (e.g., a maxillary and/or mandibular aligner 38a, 38b). The one or more maxillary blocks 12 can be monolithically formed with a maxillary aligner 38a. The one or more mandibular blocks 14 can be monolithically formed with a mandibular aligner 38a. FIG. 5 illustrates that a maxillary aligner 38a can have a maxillary guide 12 that has a guide surface 26. The guide 12 can be on an anterior or posterior portion of the maxillary aligner 38a. For example, FIG. 5 illustrates that the guide 12 can be on an anterior portion of the aligner 38a. The guide 12 can be one of the block 12, 14 described above with reference to FIGS. 1-3, and can be integrated with the aligner 38a as shown in FIG. 5. FIG. 6 illustrates that the guide 12 can be on a posterior portion of the aligner 38a. The aligner 38a can advantageously orthodontically move teeth concurrently with treating SBD, for example, by interacting with a mandibular aligner 38b. For example, FIG. 6 illustrates a jaw in a closed position having a maxillary aligner 38a and a mandibular aligner 38b with posterior guides 12, 14, where the posterior guides 12, 14 are interacting to keep the jaw in a closed position with more space between the upper and lower dentition than would otherwise occur without the posterior guides 12, 14. The guides 12, 14 can be the blocks 12, 14 described above with reference to FIGS. 1-3, and can be integrated with the aligners 38a, 38b, respectively, as shown in FIG. 6. FIGS. 1-3, 5 and 6 each illustrate device components comprising angled surfaces and disclusion ramps such as airway development blocks 12, 14 that can be combined with the aligner 38 in FIG. 4 to concurrently provide SBD treatment along with the orthodontic movement of teeth. However, all types of SBD appliance therapy can be combined with orthodontic aligner treatment shown in FIG. 4, including other mandibular advancement appliances (e.g., Herbst appliances, elastic mandibular advancement (EMA) appliances), as well as, for example, stabilization splints (e.g., nightguards, day guards), deprogrammers (e.g., anterior deprogrammers), flat planes, and full contact splints with anterior guidance. For example, the aligner 38 can be combined with, attached to, removably attached to, or integrated with these other types of devices. The aligner 38 can replace the teeth (e.g., occlusal) engagement portions of these other types of SBD devices/components so that each appliance 10 can provide orthodontic treatment (e.g., orthodontically move teeth) in addition to providing SBD treatment. Such orthodontic/SBD appliances can advantageously orthodontically move the teeth into a position that is physiologically correct for the craniofacial musculature during SBD treatment with an SBD appliance. The maxillary and mandibular aligner components and/or the SBD components of these oral appliances 10 can comprise a thermoplastic material that can, for example, be thermoformed with the aid of a computer program. A maxillary component (e.g., maxillary block 12a and/or maxillary aligner 38a) can be attached to a mandibular component (e.g., mandibular block 12b and/or mandibular aligner 38b), for example, via an attachment mechanism. The attachment mechanism can be an interference fit (also referred to as a friction fit), snap fit, tether, band, elastic band, hook, elastic hook, or any combination thereof. For example, the maxillary blocks 12 and/or the maxillary aligners 38a can have a male component (e.g., a protrusion) and the mandibular blocks 14 and/or the mandibular aligners 38b can have a female component (e.g., a recess or a hole) configured to receive the protrusion via an interference fit or a snap fit, or vice versa. The male component can have a form factor that is slightly larger than the female component to generate an interference fit. For example, the protrusion can have a form factor that is slightly larger than the recess or hole such that an interference fit is produced when the protrusion is inserted into the recess or hole. The male component can have a form factor that is slightly smaller than the female component to generate an interference fit. For example, the protrusion can have a form factor that is slightly smaller than the recess or hole such that an interference fit is produced when the protrusion is inserted into the recess or hole. A maxillary block 12a can be attached to a mandibular block 12b and/or to a mandibular aligner 38b via the attachment mechanism. A maxillary aligner 38a can be attached to a mandibular block 12b and/or to a mandibular aligner 38b via the attachment mechanism. The device 10 can have one or more attachment mechanisms, for example a first attachment mechanism for the left maxillary and mandibular components and/or a second attachment mechanism for the right maxillary and mandibular components. The attachment mechanism can have one, two, three, four, five, and/or six degrees of freedom. The attachment mechanism can partially or completely restrict movement of the jaw in one or more degrees of freedom. The attachment mechanism can help keep the jaw in a desired arrangement, for example, a desired open and/or closed position to treat SBD. The freedom of movement allowed by the attachment mechanism desirably enables the device 10 to treat SBD and simultaneously prevent or inhibit the onset of temporomandibular joint dysfunction (TMD). TMD can be caused by locking the jaw into a position or otherwise restricting movement of the jaw. The jaw movement permitted by the attachment between the maxillary component (e.g., maxillary block 12 and/or maxillary aligner 38a) and the mandibular component (e.g., mandibular block 14 and/or mandibular aligner 38b) via the attachment mechanism when the device 10 is in use can help prevent or otherwise inhibit the user from developing problems with their temporomandibular joint. Alternatively or additionally, the attachment mechanism can have zero degrees of freedom and completely restrict motion of the lower jaw. Different blocks 12 and/or aligners 38 in a series can have different degrees of freedom when in an attached configuration. Changing the motion permitted by the jaw during treatment with different appliances 10 in the series can desirably prevent or inhibit the user from developing TMD. The appliances 10 in the series can restrict movement of the lower jaw differently than one or more preceding appliances 10 and/or differently than one or more subsequent appliances 10. The amount of movement or the degrees of freedom can be changed for every appliance 10 in the series, or every 2-50 appliances 10 in the series, including every 1 appliance increment within this range, for example, every 5 appliances 10. When the maxillary and mandibular components are in an attached configuration, the attachment mechanism can prevent the jaw from moving (e.g., opening or closing vertically or moving from side to side) and/or can limit the amount by which the lower jaw is able to move, for example, by preventing or limiting the amount of relative movement between the aligners 38 and/or between one or more aspects of the SBD devices or components of the appliance 10. When the maxillary and mandibular components are attached to one another, the attachment mechanism can prevent all movement of the lower jaw (e.g., by preventing all relative movement between the aligners 38). When the maxillary and mandibular components are attached to one another, the attachment mechanism can allow the lower jaw to have one, two, three, four, five, or six degrees of freedom such that the lower jaw is translatable along and/or rotatable about one, two, and/or three axes (e.g., along and/or about one, two, and/or three mutually perpendicular axes such as x, y, and/or z Cartesian axes). To permit the lower jaw to move, the attachment mechanism can permit relative movement between the aligners 38 and/or between one or more aspects of the SBD devices or components of the appliance 10. For example, when the maxillary and mandibular components are in an attached configuration, the attachment mechanism can permit the lower jaw to translate from about 0.5 mm to about 5 mm, including every 0.5 mm increment within this range, for example, about 2.0 mm, along one, two, or three axes. For example, when the maxillary and mandibular components are in an attached configuration, the attachment mechanism can permit the lower jaw to rotate from about 1 degree to about 30 degrees, including every 1 degree increment within this range, for example, about 10 degrees, about one, two, or three axes. The attachment mechanism can impart a restorative force to the lower jaw to return to a neutral position (e.g., the desired position) once displaced (e.g., translated and/or rotated) away from the neutral position. Additionally or alternatively, the attachment mechanism can include one or more elastic bands and/or guide surfaces apart from the attachment mechanism to impart a restorative force or otherwise encourage a return to the neutral position. The aligners described herein can form a friction fit with the dentition. The friction fit can be non-uniformly spread across the aligners to apply different forces to different teeth, thereby enabling different teeth to be orthodontically moved by different amounts, with the amounts being proportionate to the various (e.g., different) forces applied across the dentition. Two sets of oral appliances 10 can be made for every stage of treatment: one for daytime use and one for nighttime use. The daytime oral appliances 10 can orthodontically move teeth with or without SBD treatment. For example, the daytime oral appliances 10 can have an SBD component that is smaller than the nighttime oral appliances 10, or the daytime oral appliances 10 can omit the SBD component altogether. The nighttime oral appliances 10 can concurrently treat SBD and orthodontically move teeth. The nighttime oral appliances can have an SBD component. Each daytime oral appliance 10 in a series can be designed to open and/or advance the lower jaw less than the corresponding nighttime oral appliance 10 in the series, or not at all. The daytime and nighttime appliances can have the same corresponding stage of orthodontic treatment. The daytime stage of orthodontic treatment can be less aggressive (e.g., apply less force to the teeth) than the nighttime stage of orthodontic treatment. Alternatively or additionally, only one series of oral appliances 10 can be made for every step of treatment (as opposed to two parallel series of appliances—one for day use and one for night use). For example, one or more of the locked configurations of the appliance 10 in each step of a series can be for daytime use and one or more of the locked configurations of the appliance 10 in each step of a series can be for nighttime use. FIG. 7 illustrates a schematic of a variation of a series 200 of oral appliances 10. The oral appliance series 200 can have ND daywear oral appliances 10 in a daytime series 200D and/or can have NN nightwear oral appliances 10 in a nighttime series 200N, where ND and NN can each be between 1 and 100, including every increment of 1 within this range. ND can be the same or different from NN. The dimensions of the daytime and nighttime oral appliances 10 in each step of the series 200 can be the same or different than one another. The daytime and nighttime oral appliances 10 in each step of the series 200 can advance the jaw as described above, for example, by the same amount. For example, FIG. 7 illustrates that steps 1-4 of the series 200 can each progressively move the jaw forward by about 1.0 mm, by about 0.5 mm, by about 0.5 mm, and by about 1.0 mm, respectively, which is represented in FIG. 7 by arrows 201, 202, 203, and 204, respectively. FIG. 7 illustrates the relative positions of the maxillary aligner and SBD components (e.g., aligner 38a and SBD components 12) relative to the mandibular aligner and SBD components (e.g., aligner 38b and SBD components 14). Method of Making FIG. 8 illustrates a variation of a process 100 of making the oral appliance 10. A computer program can be used to retrieve data from data acquisition devices (e.g., oral scanners, x-ray devices, cameras) to record and measure orthodontic malocclusions and teeth misalignments. Step 102 illustrates that after a digital model of the dentition is obtained, the digital models for the lower and upper arches can be loaded, e.g., into a computer. Step 104 illustrates that the bite registration can be set and a model of the appliance 10 can be created. The desired treatment can be simulated in step 106, including, for example, mandibular advancement, palatal expansion, teeth movement, or any combination thereof. The TMJ temporal bone, disc and mandibular head relationship can be checked in step 108, for example, when mandibular advancement is simulated in step 106. If the check is satisfactory, the process can move on to step 110, otherwise the process can return to step 106 and run one or more additional simulations. Based at least partly on the simulation(s) and check(s) in steps 106 and 108, an algorithm can be configured to design one or more aspects of the SBD components (e.g., guide surfaces 26, 28) in step 110 to effect the desired mandibular advancement. Step 112 illustrates that the blocks 12, 14 and/or oral trays can be designed that have the guide surfaces 26, 28 designed in step 110. Step 112 also illustrates that an optional elastic hook can be designed to prevent the jaw from opening and moving away from the maxillary blocks 12 when a person is sleeping. Step 114 illustrates that the blocks 12, 14 and/or oral trays designed in step 112 can move one or more teeth to a new arch occlusion based on a new arch relationship at least partly determined by the algorithm. The process 100 can be used to create one oral appliance 10 or a series of oral appliances 10. Software can be used to manipulate digital impressions (scans) of the dental arches to incrementally move the teeth as well as designing the functional applications for daytime and/or nighttime use on a 3D printed model for appliance fabrication utilizing traditional vacu-form technique or direct to print appliances. Using the process 100 in FIG. 8, an oral appliance 10 and/or a series of oral appliances 10 can be designed by the computer algorithm based on data the algorithm receives and processes from one or multiple data acquisition devices (e.g., scanners, x-ray devices, cameras) that can individually or collectively form a digital impression of an oral cavity and the dentition therein. For example, the dimensions of the oral appliance 10 in each step, including the SBD components (e.g., maxillary and mandibular blocks 12, 14, or one or more aspects thereof, including the oral trays) and/or the aligner components (e.g., maxillary and mandibular aligners 38a, 38b) can be determined from data received from the data acquisition devices. The algorithm in process 100 can combine orthodontic aligners with multiple different discipline SBD treatments, for example, to adjust the bite, restore some or all of the teeth, and move the teeth into a more desirable position. For example, the data retrieved from the data acquisition devices can be used to measure orthodontic malocclusions, determine orthodontic corrections for the malocclusions while simultaneously treating SBD, for example, by designing a series of oral appliances 10 that can progressively treat SBD (or SBD symptoms) concurrently with a progressive orthodontic movement of teeth. Computer software can be used to determine the orthodontic movements of the teeth in one or more steps of a series. Computer software can be used to design the appliances 10. Computer software can be used to manufacture 3D models or directly print appliances 10. Models of the appliances 10 can be created by using computer software to incrementally move the teeth digitally and then print a 3D model from which an orthodontic aligner can be fabricated. Alternatively or additionally, the aligners can be fabricated directly with a 3D printer using computer software. The orthodontic aligner can be altered or otherwise modified on the occlusal surface to create the desired SBD treatment appliance 10 while the orthodontic movement is concurrently occurring. Giving the dentist or orthodontist the ability to treat SBD simultaneously with the orthodontic movement of teeth via a computer program that converts data received from one or more data acquisition devices into a series of successive orthodontic/SBD appliances 10 can advantageously open up many new treatment protocols for dentists and orthodontists to use to serve their patients. The claims are not limited to the exemplary embodiments shown in the drawings, but instead may claim any feature disclosed or contemplated in the disclosure as a whole. Any elements described herein as singular can be pluralized (i.e., anything described as “one” can be more than one). Any species element of a genus element can have the characteristics or elements of any other species element of that genus. Some elements may be absent from individual figures for reasons of illustrative clarity. The above-described configurations, elements or complete assemblies and methods and their elements for carrying out the disclosure, and variations of aspects of the disclosure can be combined and modified with each other in any combination. All devices, apparatuses, systems, and methods described herein can be used for medical (e.g., diagnostic, therapeutic or rehabilitative) or non-medical purposes.
<SOH> BACKGROUND <EOH>
<SOH> BRIEF SUMMARY OF THE INVENTION <EOH>This disclosure relates generally to the combined orthodontic movement and/or dental treatment of teeth, airway development and treatment of sleep breathing disorders. More specifically, orthodontic and/or dental airway development systems, apparatuses and methods of using the same are disclosed. The airway development systems and apparatuses disclosed can concurrently move teeth and reshape the airway. The airway development systems and apparatuses disclosed can concurrently advance the mandible and reshape the airway. The airway development systems apparatuses disclosed can concurrently expand the hard and/or soft palate and reshape the airway. The airway development systems and apparatuses disclosed can concurrently whiten teeth and reshape the airway. The airway development systems and apparatuses disclosed can concurrently clean teeth and reshape the airway. The airway development systems and apparatuses disclosed can concurrently move teeth, advance the mandible, expand the hard and/or soft palate, whiten teeth, apply hygienic treatment, reshape the airway, or any combination thereof. The airway development systems and apparatuses can have dental trays and/or orthodontic aligner trays. The airway development systems and apparatuses can have airway development blocks. The airway development blocks can be attached to or integrated with one or more trays. Oral appliances for the treatment of sleep breathing disorders are disclosed. For example, an oral appliance is disclosed that can have one or more maxillary blocks. The oral appliance can have one or more mandibular blocks. The oral appliance can have a maxillary oral tray. One or more maxillary blocks can be attached to or integrated with the maxillary oral tray. The oral appliance can have a mandibular oral tray. One or more mandibular blocks can be attached to or integrated with the mandibular oral tray. The maxillary and mandibular oral trays configured to move one or more teeth from a tooth first position to a tooth second position. Each maxillary block can have a maxillary block guide surface. Each mandibular block can have a mandibular block guide surface. Each maxillary block guide surface can be opposed to and configured to interact with at least one mandibular block guide surface to at least one of move one or more teeth, advance a mandible, increase an interocclusal separation between a maxillary dentition and a mandibular dentition, and expand a palate. Systems for the treatment of sleep breathing disorders are disclosed. For example a system is disclosed that can have a series of two or more oral appliances configured to progressively reposition the maxillary and mandibular teeth in two or more successive steps. Each oral appliance in the series can have one or more maxillary blocks. Each oral appliance in the series can have one or more mandibular blocks. Each oral appliance in the series can have a maxillary oral tray. One or more maxillary blocks can be attached to or integrated with the maxillary oral tray. Each oral appliance in the series can have a mandibular oral tray. One or more mandibular blocks can be attached to or integrated with the mandibular oral tray. The maxillary and mandibular oral trays can be configured to move one or more teeth from a tooth first position to a tooth second position. Each maxillary block can have a maxillary block guide surface. Each mandibular block can have a mandibular block guide surface. Each maxillary block guide surface can be opposed to and configured to interact with at least one mandibular block guide surface to at least one of move one or more teeth, advance a mandible, increase an interocclusal separation between a maxillary dentition and a mandibular dentition, and expand a palate. Methods of treating sleep breathing disorders are disclosed. For example, a method is disclosed that can include providing a series of two or more oral appliances configured to progressively reposition the maxillary and mandibular teeth in two or more successive steps. Each oral appliance in the series can have one or more maxillary blocks. Each oral appliance in the series can have one or more mandibular blocks. Each oral appliance in the series can have a maxillary oral tray. One or more maxillary blocks can be attached to or integrated with the maxillary oral tray. Each oral appliance in the series can have a mandibular oral tray. One or more mandibular blocks can be attached to or integrated with the mandibular oral tray. The maxillary and mandibular oral trays can be configured to move one or more teeth from a tooth first position to a tooth second position. Each maxillary block can have a maxillary block guide surface. Each mandibular block can have a mandibular block guide surface. Each maxillary block guide surface can opposed to and configured to interact with at least one mandibular block guide surface to at least one of move one or more teeth, advance a mandible, increase an interocclusal separation between a maxillary dentition and a mandibular dentition, and expand a palate.
A61C736
20170920
20180322
67703.0
A61C736
0
CARREIRO, CAITLIN ANN
COMBINED ORTHODONTIC MOVEMENT OF TEETH WITH AIRWAY DEVELOPMENT THERAPY
SMALL
0
PENDING
A61C
2,017
15,710,711
PENDING
INFORMATION APPARATUS AND SOFTWARE APPLICATIONS SUPPORTING PRINTING OF DIGITAL CONTENT OVER A NETWORK TO A REGISTERED PRINTER
Software applications and information apparatus supporting output of digital content over a network (e.g., Internet) to an output device (e.g., printer) are herein disclosed and enabled. To output digital content, an application for accessing a service provided over the network is installed, the information apparatus is connected to the local area network of the output device, the output device in the local area network (e.g., IEEE 802.11) is discovered, output device information is received from the discovered output device, and the output device information is transmitted to the service for registering the output device. Subsequent to registration, the information apparatus using an application (e.g., Internet browser, email, document) and having appropriate security or authentication information may transmit digital content to the service to output digital content at the registered output device. The output of digital content does not require a device specific driver that is installed in the information apparatus.
1. A method for outputting digital content from an information apparatus to an output device by using one or more application software executable at the information apparatus, the information apparatus includes: one or more processors; a user interface for interacting with a user; wireless communication circuitry for wireless communication; a memory or storage component; and one or more application software stored, at least partly, in the memory or storage component, the one or more application software includes at least one of an Internet browsing application, an email application, a document creation application, or a digital imaging application, individually or in any combination; wherein the one or more application software is executable by the one or more processors to facilitate output of digital content from the information apparatus; and wherein the method comprises: (1) wirelessly establishing, using the wireless communication circuitry of the information apparatus, a wireless local area network connection to a wireless local area network; (2) wirelessly discovering, via the communication interface, an output device that is in the wireless local area network; (3) wirelessly receiving, by the one or more application software and via the wireless communication circuitry, output device information from the output device discovered in (2), the output device information includes at least one of identification information, capability information, address information, status information, or attribute information, individually or in any combination, related to the output device; (4) obtaining, by the one or more application software, security information or authentication information for accessing one or more servers operated, at least in part, by a service provided over a network; (5) accessing, by the one or more application software, the one or more servers based, at least in part, on the security or authentication information obtained in (4); (6) registering, using the one or more application software, the output device discovered in (2) with the service, by transmitting at least part of the output device information received in (3) to the one or more servers in (5); and (7) transmitting, using the one or more application software and from the information apparatus to the one or more servers, a digital content object that includes at least part of the digital content for outputting at the registered output device in (6). 2. The method of claim 1, wherein the wireless communication circuitry includes one or more chips or chipsets, the one or more chips or chipsets are compatible, at least in part, with at least part of a protocol within IEEE 802.11 standards for establishing the wireless local area network communication. 3. The method of claim 2, wherein output device is a printer, and the discovered output device is a discovered printer, and the registered output device is a registered printer, and the method is a printing method; and wherein outputting or printing at least part of the digital content at the registered printer does not require a printer driver that is specific to the printer to be installed in the information apparatus. 4. The method of claim 3, wherein the printing method further comprises: (8) receiving, by the one or more application software at the information apparatus, output data from the one or more servers, the output data related to the digital content and is device specific for outputting at the registered output device in (6), and the receiving of the output data is based on having transmitted the digital content object in (7); and (9) wirelessly delivering, over the wireless local area network, at least part of the output data received in (8) to the registered output device in (6). 5. The method of claim 3, wherein the transmitting of the output device information in (6) is for storing the at least part of the output device information at the one or more servers operated, at least in part, by the service, the storing of the output device information at the one or more servers is for sharing with one or more mobile devices having appropriate security information or authentication information for accessing the service, the one or more mobile devices including a client application software installed in the one or more mobile device; and wherein, subsequent to having registered the output device with the service, the method further comprises transmitting, using the client application software at the one or more mobile devices and to the one or more servers, a digital content object that includes at least part of a selected digital content for output at the registered output device in (6). 6. A method for outputting digital content from an information apparatus to an output device by using one or more application software executable at the information apparatus, the information apparatus includes: one or more processors; a user interface for interacting with a user; wireless communication circuitry for wireless communication; a memory or storage component; and one or more application software stored, at least partly, in the memory or storage component, the one or more application software is executable by the one or more processors to facilitate output of digital content from the information apparatus; and wherein the method comprises: (1) establishing, using the wireless communication circuitry of the information apparatus, a wireless local area network connection to a wireless local area network; (2) obtaining, by the one or more application software, output device information related to an output device that is available in the wireless local area network in (1), the output device information includes at least one of identification information, capability information, address information, status information, or attribute information, individually or in any combination; (3) obtaining, by the one or more application software, security information or authentication information for accessing one or more servers operated, at least in part, by a service provided over a network; (4) accessing, by the one or more application software, the one or more servers based, at least in part, on the security or authentication information obtained in (3); (5) registering, using the one or more application software, the output device in (2) with the service, by transmitting at least part of the output device information obtained in (2) to the one or more servers in (4); (6) providing, by the one or more application software, a list of one or more registered output devices that are registered with the service for user selection via the user interface of the information apparatus, the list of one or more registered output devices include the output device registered in (5); (7) receiving, by the one or more application software, an indication of a selected output device from among the list of one or more registered output devices in (6) provided for user selection; and (8) obtaining, by the one or more application software, selected digital content for outputting at least part of the selected digital content at the selected output device in (7). 7. The method of claim 6, further comprises: (9) providing, by the one or more application software, an output item or output function control over the user interface of the information apparatus for user selection, the output item or the output function control is for outputting the selected digital content in (8); and (10) receiving, by the one or more application software and via the user interface of the information apparatus, selection of the output item or the output function control in (9) for outputting at least part of the selected digital content at the selected output device in (7). 8. The method of claim 7, wherein subsequent to having received the selection of the output item or output function control in (10), the output method further comprises: (11) transmitting, by the one or more application software, a digital content object from the information apparatus to the one or more servers over the network, the digital content object includes at least part of the selected digital content or at least a reference or a pointer to the selected digital content, individually or in any combination; (12) receiving, by the one or more application software at the information apparatus, output data from the one or more servers, the output data related to the selected digital content for outputting at the registered output device in (5), and the output data corresponding to the digital content object transmitted in (11); and (13) delivering, over the wireless local area network, at least part of the output data received in (12) to the output device in the wireless local area network registered in (5). 9. The method of claim 8, wherein the output device information in (2) is received from the output device, and the output device information includes identification information related to the output device, the identification information includes one or more of a name, a model, a brand, an identifier, a registration, a URL, a security key, a PIN, or an IP address, individually or in any combination. 10. The method of claim 9, wherein the wireless communication circuitry includes one or more chips or chipsets that are compatible, at least in part, with at least part of a protocol within IEEE 802.11 standards or Bluetooth specifications for wireless communication; and wherein the method further comprises: wirelessly discovering, via the wireless communication circuitry of the information apparatus, the output device in the wireless local area network; and wirelessly receiving the output device information from the output device. 11. The method of claim 10, wherein output device is a printer, and wherein the discovered output device is a discovered printer, and wherein the registered output device is a registered printer, and wherein the method is a printing method; and wherein outputting or printing at least part of the selected digital content at the registered printer does not require a printer driver that is device specific to the printer to be installed in the information apparatus. 12. The method of claim 11, wherein the one or more application software is at least one of an Internet browsing application, an email application, a document creation application, an output manager software, or a digital imaging application, individually or in any combination; and wherein the information apparatus is at least one of a smart phone, an information pad, an Internet appliance, an e-book, or a digital camera, individually or in any combination. 13. The method of claim 10, wherein obtaining output device information includes an input from the user of the information apparatus. 14. A non-transitory computer readable recording medium having recorded therein software program executable, at least partly, by one or more processors of an information apparatus to perform an output method, the information apparatus includes: the one or more processors; a user interface for interacting with a user; a communication interface for establishing a local area network connection to a local area network; and wherein the output method, comprises: (1) accessing, by the software program, one or more servers operated, at least in part, by a service provided over a network, the accessing of the one or more servers is based, at least in part, on having obtained, by the software program, appropriate security or authentication information for accessing the service; (2) discovering, via the communication interface, an output device that is in the local area network; (3) receiving, by the software program and via the communication interface, output device information from the output device discovered in (2), the output device information includes at least one of identification information, capability information, address information, status information, or attribute information, individually or in any combination, related to the output device; (4) transmitting, using the software program, at least part of the output device information received from the output device in (3) to the one or more servers accessed in (1); and subsequent to having transmitted the output device information to the one or more servers, the method further comprises: (5) obtaining, by the software program, at least a pointer or reference to selected digital content for output at the output device in (2); (6) providing, by the software program, an output item or output function control over the user interface of the information apparatus for user selection, the output item or output function control for outputting the selected digital content in (5); and (7) receiving, by the software program and via the user interface of the information apparatus, selection of the output item or output function control in (6) for outputting at least part of the selected digital content at the output device. 15. The medium of claim 14, wherein the output method further comprises: (8) transmitting, by the software program, a content object from the information apparatus to the one or more servers over the network, the content object includes at least part of the selected digital content or at least a reference or a pointer to the selected digital content, individually or in any combination; (9) receiving, by the software program at the information apparatus, output data from the one or more servers, the output data related to the selected digital content included in the content object transmitted in (8); and (10) transmitting, via the communication interface and over the local area network, at least part of the output data received from the one or more servers in (9) to the output device for outputting at least part of the selected digital content at the output device. 16. The medium of claim 15, wherein the communication interface is a wireless communication interface, and wherein the wireless communication interface includes one or more chips or chipsets that are compatible, at least in part, with at least part of a protocol within IEEE 802.11 standards for establishing a wireless local area network connection, and wherein the local area network in (2) is a wireless local area network; and wherein discovering the output device in the local area network in (2) includes wirelessly discovering, via the wireless communication interface of the information apparatus, the output device in the wireless local area network. 17. The medium of claim 16, wherein the output data received from the one or more servers is device specific for rendering at the output device; and wherein the output data is related, at least in part, to the output device information transmitted to the one or more servers in (4); and wherein the output device is a printer and the output method is a printing method; and wherein outputting or printing at least part of the selected digital content at the printer does not require a device specific printer driver that is specific to the printer to be installed in the information apparatus. 18. The medium of claim 17, wherein the output data received from the one or more servers includes an encryption scheme for ensuring the security of the output data that is device specific for rendering at the output device. 19. The medium of claim 16, wherein the output device is at least one of a printer, an audio output device, a display device, a television, or a controller connectable to a television, individually or in any combination; and wherein the output device information received from the output device in (3) includes identification information related to the output device, the identification information includes one or more of a name, a model, a brand, an identifier, a registration, an URL, a PIN, a security key, or an IP address, individually or in any combination; and wherein the identification information of the output device is to facilitate one or more client devices to select the output device for service; and wherein, subsequent to transmitting the output device information from the information apparatus to the one or more servers in (4), the output device information is further accessible by the one or more client devices that has subscribed to the service for outputting digital content, the accessing of the output device information by the one or more client devices is based, at least in part, on the one or more client devices having appropriate security or authentication information for accessing the service provided over the network, the one or more client devices includes the information apparatus. 20. The medium of claim 19, wherein the software program is at least part of application software that is at least one of an Internet browsing application, an email application, a document creation application, an output manager application, an operating system software component, or a digital imaging application, individually or in any combination; and wherein the output method further comprises: (a) providing, by the software program, a list of one or more registered output devices registered with the service, the list of one or more registered output devices for user selection on the user interface of the information apparatus, and the list of one or registered output devices includes the output device discovered in (2), and the providing of the list is based on having transmitted the output device information in (4); and (b) receiving, by the software program, an indication of a selected output device from among the list of one or more registered output devices in (a) as the selected output device for outputting at least part of the selected digital content in (10).
CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 10/053,765 filed Jan. 18, 2002, which claims priority to U.S. Provisional Patent Application Ser. No. 60/262,764, filed Jan. 19, 2001. Additionally, this application is a continuation-in-part of U.S. patent application Ser. No. 09/992,413 filed Nov. 18, 2001, which claims benefit of U.S. Provisional Patent Application Ser. No. 60/252,682 filed Nov. 20, 2000. Moreover, this application is a continuation-in-part of U.S. patent application Ser. No. 13/710,299 filed Dec. 10, 2012, which is a continuation of U.S. patent application Ser. 12/903,048 filed Oct. 12, 2010 and now issued as U.S. Pat. No. 8,332,521, which is a continuation of U.S. patent application Ser. No. 10/016,223 filed Nov. 1, 2001 and now issued as U.S. Pat. No. 7,941,541, and which claims benefit of U.S. Provisional Patent Application Ser. No. 60/245,101, filed Nov. 1, 2000. The complete disclosures of the above patent applications are hereby incorporated by reference for all purposes. TECHNICAL FIELD OF THE INVENTION Present invention relates to providing content to an output device and, in particular, to providing universal output in which an information apparatus can pervasively output content to an output device without the need to install a dedicated device dependent driver or applications for each output device. BACKGROUND OF THE DISCLOSURE The present invention relates to universal data output and, in particular, to providing a new data output method and a new raster image process for information apparatuses and output devices. As described herein, information apparatuses refer generally to computing devices, which include both stationary computers and mobile computing devices (pervasive devices). Examples of such information apparatuses include, without limitation, desktop computers, laptop computers, networked computers, palmtop computers (hand-held computers), personal digital assistants (PDAs), Internet enabled mobile phones, smart phones, pagers, digital capturing devices (e.g., digital cameras and video cameras), Internet appliances, e-books, information pads, and digital or web pads. Output devices may include, without limitation, fax machines, printers, copiers, image and/or video display devices (e.g., televisions, monitors and projectors), and audio output devices. For simplicity and convenience, hereafter, the following descriptions may refer to an output device as a printer and an output process as printing. However, it should be understood that the term printer and printing used in the discussion of present invention refer to one embodiment used as a specific example to simplify the description of the invention. The references to printer and printing used here are intended to be applied or extended to the larger scope and definition of output devices and should not be construed as restricting the scope and practice of present invention. Fueled by an ever-increasing bandwidth, processing power, wireless mobile devices, and wireless software applications, millions of users are or will be creating, downloading, and transmitting content and information using their pervasive or mobile computing devices. As a result, there is a need to allow users to conveniently output content and information from their pervasive computing devices to any output device. As an example, people need to directly and conveniently output from their pervasive information apparatus, without depending on synchronizing with a stationary computer (e.g., desktop personal computer) for printing. To illustrate, a mobile worker at an airport receiving e-mail in his hand-held computer may want to walk up to a nearby printer or fax machine to have his e-mail printed. In addition, the mobile worker may also want to print a copy of his to-do list, appointment book, business card, and his flight schedule from his mobile device. As another example, a user visiting an e-commerce site using his mobile device may want to print out transaction confirmation. In still another example, a user who takes a picture with a digital camera may want to easily print it out to a nearby printer. In any of the above cases, the mobile user may want to simply walk up to a printer and conveniently print a file (word processing document, PDF, HTML etc.) that is stored on the mobile device or downloaded from a network (e.g., Internet, corporate network). Conventionally, an output device (e.g., a printer) is connected to an information apparatus via a wired connection such as a cable line. A wireless connection is also possible by using, for example, radio communication or infrared communication. Regardless of wired or wireless connection, a user must first install in the information apparatus an output device driver (e.g., printer driver in the case the output device is a printer) corresponding to a particular output device model and make. Using a device-dependent or specific driver, the information apparatus may process output content or digital document into a specific output device's input requirements (e.g., printer input requirements). The output device's input requirements correspond to the type of input that the output device (e.g., a printer) understands. For example, a printer's input requirement may include printer specific input format (e.g., one or more of an image, graphics or text format or language). Therefore, an output data (or print data in the case the output device is a printer) herein refers to data that is acceptable for input to an associated output device. Examples of input requirements may include, without limitation, audio format, video format, file format, data format, encoding, language (e.g., page description language, markup language etc), instructions, protocols or data that can be understood or used by a particular output device make and model. Input requirements may be based on proprietary or published standards or a combination of the two. An output device's input requirements are, therefore, in general, device dependent. Different output device models may have their own input requirements specified, designed or adopted by the output device manufacturer (e.g., the printer manufacturer) according to a specification for optimal operation. Consequently, different output devices usually require use of specific output device drivers (e.g., printer drivers) for accurate output (e.g., printing). Sometimes, instead of using a device driver (e.g., printer driver), the device driving feature may be included as part of an application software. Installation of a device driver (e.g., printer driver) or application may be accomplished by, for example, manual installation using a CD or floppy disk supplied by the printer manufacturer. Or alternatively, a user may be able to download a particular driver or application from a network. For a home or office user, this installation process may take anywhere from several minutes to several hours depending on the type of driver and user's sophistication level with computing devices and networks. Even with plug-and-play driver installation, the user is still required to execute a multi-step process for each printer or output device. This installation and configuration process adds a degree of complexity and work to end-users who may otherwise spend their time doing other productive or enjoyable work. Moreover, many unsophisticated users may be discouraged from adding new peripherals (e.g., printers, scanners, etc.) to their home computers or networks to avoid the inconvenience of installation and configuration. It is therefore desirable that an information apparatus can output to more than one output device without the inconvenience of installing multiple dedicated device dependent drivers. In addition, conventional output or printing methods may pose significantly higher challenges and difficulties for mobile device users than for home and office users. The requirement for pre-installation of a device-dependent driver diminishes the benefit and concept of mobile (pervasive) computing and output. For example, a mobile user may want to print or output e-mail, PowerPoint® presentation documents, web pages, or other documents at an airport, gas station, convenience store, kiosk, hotel, conference room, office, home, etc. It is highly unlikely that the user would find at any of these locations a printer of the same make and model as is at the user's base station. As a consequence, under the conventional printing method, the user would have to install and configure a printer driver each time at each such remote location before printing. It is usually not a viable option given the hundreds, or even thousands of printer models in use, and the limited storage, memory space, and processing power of the information apparatus. Moreover, the user may not want to be bothered with looking for a driver or downloading it and installing it just to print out or display one page of email at the airport. This is certainly an undesirable and discouraging process to promote pervasive or mobile computing. Therefore, a more convenient printing method is needed in support of the pervasive computing paradigm where a user can simply walk up to an output device (e.g., printer or display device) and easily output a digital document without having to install or pre-install a particular output device driver (e.g., printer driver). Another challenge for mobile users is that many mobile information apparatuses have limited memory space, processing capacity and power. These limitations are more apparent for small and low-cost mobile devices including, for example, PDAs, mobile phones, screen phones, pagers, e-books, Internet Pads, Internet appliances etc. Limited memory space poses difficulties in installing and running large or complex printer or device drivers, not to mention multiple drivers for a variety of printers and output devices. Slow processing speed and limited power supply create difficulties driving an output device. For example, processing or converting a digital document into output data by a small mobile information apparatus may be so slow that it is not suitable for productive output. Intensive processing may also drain or consume power or battery resources. Therefore, a method is needed so that a small mobile device, with limited processing capabilities, can still reasonably output content to various output devices. To output or render content (e.g. digital document) to an output device, a raster image processing (RIP) operation on the content is usually required. RIP operation can be computationally intensive and may include (1) a rasterization operation, (2) a color space conversion, and (3) a halftoning operation. RIP may also include other operations such as scaling, segmentation, color matching, color correction, GCR (Grey component replacement), Black generation, image enhancement compression/decompression, encoding/decoding, encryption/decryption GCR, image enhancement among others. Rasterization operation in RIP involves converting objects and descriptions (e.g. graphics, text etc) included in the content into an image form suitable for output. Rasterization may include additional operations such as scaling and interpolation operations for matching a specific output size and resolution. Color space conversion in RIP includes converting an input color space description into a suitable color space required for rendering at an output device (e.g. RGB to CMYK conversion). Digital halftoning is an imaging technique for rendering continuous tone images using fewer luminance and chrominance levels. Halftoning operations such as error diffusion can be computationally intensive and are included when the output device's bit depth (e.g. bits per pixel) is smaller than the input raster image bit depth. Conventionally, RIP operations are included either in an information apparatus, or as part of an output device or output system (e.g. in a printer controller). FIG. 1A illustrates a flow diagram of a conventional data output method 102 in which RIP 110 is implemented in the information apparatus. Output devices that do not include a printer controller to perform complex RIP operations, such as a lower-cost, lower speed inkjet printer, normally employ data output method 102. In data output method 102, an information apparatus obtains content (e.g. a digital document) in step 100 for rendering or output at an output device. The information apparatus may includes an application (e.g. device driver), which implements RIP operation 110. The information apparatus generates an output data in step 120 and transmits the output data to the output device in step 130 for rendering. The output data relating to the content is in an acceptable form (e.g. in an appropriate output size and resolution) to the output engine (e.g. display engine, printer engine etc.) included in the output device. The output data in a conventional output method 102 is usually device dependent. One drawback for the data output method 102 of FIG. 1A is that the information apparatus performs most if not the entire raster image processing operations 110 required for output. The RIP operations may require intensive computation. Many information apparatus such as mobile information device might have insufficient computing power and/or memory to carry out at an acceptable speed the RIP operations 110 required in an output process. Another drawback for the conventional data output method 102 of FIG. 1A is that the generated output data is device dependent and therefore is typically not very portable to other output devices. As a result, the information apparatus may need to install multiple applications or device drivers for multiple output devices, which may further complicate its feasibility for use in information apparatuses with limited memory, storage and processing power. FIG. 1B illustrates a flow diagram of another conventional data output method 104 in which the RIP is implemented in an output device. An example of an output device that implements process 104 is a high-speed laser printer which includes a printer controller for performing RIP operations and an output engine (e.g. printer engine) for rendering content. Printer controller may be internally installed or externally connected to an output device (printer in this example). In data output method 104, an information apparatus obtains content for output in step 100 and generates in step 160 an output data or print data for transmitting to the output device in step 170. Print data includes information related to the content and is usually encoded in a page description language (PDL) such as PostScript and PCL etc. In step 180, the printer receives the output data or print data (in a PDL). In step 190, a printer controller included in the printer interprets the PDL, performs RIP operations, and generates a printer-engine print data that is in a form acceptable to the printer engine (e.g. a raster image in an appropriate output size, bit depth, color space and resolution). In step 150 the printer engine renders the content with the printer-engine print data. It will be understood that a reference to print data or output data including a language, such as PDL, should be interpreted as meaning that the print data or output data is encoded using that language. Correspondingly, a reference to a data output process generating a language, such as PDL, should be interpreted as meaning that the data output process encodes data using that language. There are many drawbacks in the conventional data output method 104 shown in FIG. 1B. These drawbacks are especially apparent for mobile computing devices with limited processing power and memory. One such drawback is that the output data or print data, which include a page description language (PDL) such as PostScript or PCL, can be very complex. Generating complex PDL may increase memory and processing requirements for an information apparatus. Furthermore, interpreting, decoding and then raster image processing complex PDL can increase computation, decrease printing speed, and increase the cost of the output device or its printer controller. Another drawback is that the output data that includes PDL can creates a very large file size that would increase memory and storage requirements for the information apparatus, the output device and/or the printer controller etc. Large file size may also increase the bandwidth required in the communication link between the information apparatus and the output device. Finally, to rasterize text in an output device, a printer controller may need to include multiple fonts. When a special font or international characters is not included or missing in the printer controller, the rendering or output can potentially become inaccurate or inconsistent. SUMMARY OF THE INVENTION Accordingly, this invention provides a convenient universal data output method in which an information apparatus and an output device or system share the raster image processing operations. Moreover, the new data output method eliminates the need to install a plurality of device-dependent dedicated drivers or applications in the information apparatus in order to output to a plurality of output devices. In accordance with present invention, an electronic system and method of pervasive and universal output allow an information apparatus to output content conveniently to virtually any output device. The information apparatus may be equipped with a central processing unit, input/output control unit, storage unit, memory unit, and wired or wireless communication unit or adapters. The information apparatus preferably includes a client application that may be implemented as a software application, a helper application, or a device driver (a printer driver in case of a printer). The client application may include management and control capabilities with hardware and software components including, for example, one or more communication chipsets residing in its host information apparatus. The client application in the information apparatus may be capable of communicating with, managing and synchronizing data or software components with an output device equipped with an output controller of present invention. Rendering content in an output device refers to printing an image of the content onto an substrate in the case of a printing device; displaying an image of the content in the case of a displaying device; playing an audio representation of the content in a voice or sound output device or system. An output controller may be a circuit board, card or software components residing in an output device. Alternatively, the output controller may be connected externally to an output device as an external component or “box.” The output controller may be implemented with one or more combinations of embedded processor, software, firmware, ASIC, DSP, FPGA, system on a chip, special chipsets, among others. In another embodiment, the functionality of the output controller may be provided by application software running on a PC, workstation or server connected externally to an output device. In conventional data output method 102 as described with reference to FIG. 1A, an information apparatus transmits output data to an output device for rendering. Output data corresponds to content intended for output and is mostly raster image processed (RIPed) and therefore is device dependent because raster image processing is a typical device dependent operation. Output data may be encoded or compressed with one or more compression or encoding techniques. In present invention, an information apparatus generates an intermediate output data for transmitting to an output device. The intermediate output data includes a rasterized image corresponding to the content; however, device dependent image processing operations of a RIP (e.g. color matching and halftoning) have not been performed. As a result, an intermediate output data is more device independent and is more portable than the output data generated by output method with reference to FIG. 1A. In one implementation of this invention, the intermediate output data includes MRC (Mixed raster content) format, encoding and compression techniques, which further provides improved image quality and compression ratio compared to conventional image encoding and compression techniques. In an example of raster image process and data output method of the present invention, a client application such as a printer driver is included in an information apparatus and performs part of raster image processing operation such as rasterization on the content. The information apparatus generates an intermediate output data that includes an output image corresponding to the content and sends the intermediate output data to an output device or an output system for rendering. An output controller application or component included in the output device or output system implements the remaining part of the raster image processing operations such as digital halftoning, color correction among others. Unlike conventional raster image processing methods, this invention provides a more balanced distribution of the raster image processing computational load between the Information apparatus and the output device or the output system. Computational intensive image processing operations such as digital halftoning and color space conversions can be implemented in the output device or output system. Consequently, this new raster image processing method reduces the processing and memory requirements for the information apparatus when compared to conventional data output methods described with reference to FIG. 1A in which the entire raster image process is implemented in the information apparatus. Additionally, in this invention, a client application or device driver included in the information apparatus, which performs part of the raster image processing operation, can have a smaller size compared to a conventional output application included in the information apparatus, which performs raster image processing operation. In another implementation, the present invention provides an information apparatus with output capability that is more universally accepted by a plurality of output devices. The information apparatus, which includes a client application, generates an intermediate output data that may include device independent attributes. An output controller includes components to interpret and process the intermediate output data. The information apparatus can output content to different output devices or output systems that include the output controller even when those output devices are of different brand, make, model and with different output engine and input data requirements. Unlike conventional output methods, a user does not need to preinstall in the information apparatus multiple dedicated device dependent drivers or applications for each output device. The combination of a smaller-sized client application, a reduced computational requirement in the information apparatus, and a more universal data output method acceptable for rendering at a plurality of output devices enable mobile devices with less memory space and processing capabilities to implement data output functions which otherwise would be difficulty to implement with conventional output methods. In addition, this invention can reduce the cost of an output device or an output system compared to conventional output methods 104 that include a page description language (PDL) printer controller. In the present invention, an information apparatus generates and sends an intermediate output data to an output device or system. The intermediate output data in one preferred embodiment includes a rasterized output image corresponding to the content intended for output. An output controller included in an output device or an output system decodes and processes the intermediate output data for output, without performing complex interpretation and rasterization compared to conventional methods described in process 104. In comparison, the conventional data output process 104 generates complex PDL and sends this PDL from an information apparatus to an output device that includes a printer controller (e.g. a PostScript controller or a PCL5 controller among others). Interpretation and raster image processing of a PDL have much higher computational requirements compared to decoding and processing the intermediate output data of this invention that include rasterized output image or images. Implementing a conventional printer controller with, for example, PDL increases component cost (e.g. memories, storages, ICs, software and processors etc.) when compared to using the output controller included in the data output method of this present invention. Furthermore, an output data that includes PDL can create a large file size compared to an intermediate output data that includes rasterized output image. The data output method for this invention comparatively transmits a smaller output data from an information apparatus to an output device. Smaller output data size can speed up transmission, lower communication bandwidth, and reduce memory requirements. Finally, this invention can provide a convenient method to render content at an output device with or without connection to a static network. In conventional network printing, both information apparatus and output device must be connected to a static network. In this invention, through local communication and synchronization between an information apparatus and an output device, installation of hardware and software to maintain static network connectivity may not be necessary to enable the rendering of content to an output device. According to the several aspects of the present invention there is provided the subject matter defined in the appended independent claims. Additional objects and advantages of the present invention will be apparent from the detailed description of the preferred embodiment thereof, which proceeds with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1A is a flow diagram of a conventional data output method and its corresponding raster image process in accordance with prior art. FIG. 1B is a flow diagram of a second conventional data output method and its corresponding raster image process for an output device that includes a conventional printer controller in accordance with prior art. FIGS. 2A and 2B are block diagrams illustrating components of an operating environment that can implement the process and apparatus of the present invention. FIG. 3A is a schematic block diagram illustrating hardware/software components of an information apparatus implementation in accordance with the present invention. The information apparatus includes an operating system. FIG. 3B is a second schematic block diagram illustrating hardware/software components of an information apparatus implementation in accordance with the present invention. FIG. 4A is a block diagram of a conventional printing system or printer with a conventional printer controller. FIG. 4B is a block diagram of a second conventional output system or output device. FIG. 5A is a schematic block diagram of a printing system or printer with a conventional printer controller and an output controller in accordance with present invention. FIG. 5B is a schematic block diagram of a second output system or output device that includes an output controller in accordance with present invention. FIG. 6A is a schematic block diagram illustrating hardware/software components of an output controller in accordance with present invention. The output controller includes an operating system. FIG. 6B is a second schematic block diagram illustrating hardware/software components of an output controller in accordance with present invention. The output controller does not include an operating system. FIG. 6C is a third schematic block diagram illustrating hardware/software components of an output controller in accordance with present invention. The output controller combines the functionality of a printer controller and an output controller of present invention. FIGS. 7A-7F illustrate various configurations and implementations of output controller with respect to an output device such as a printer. FIG. 8A is a block diagram illustrating an exemplary implementation of hardware/software components of wireless communication unit. FIG. 8B is block diagram illustrating a second exemplary implementation of hardware/software components of wireless communication unit. FIG. 9 is a flow diagram of a universal data output method and its corresponding raster imaging process of the present invention. FIG. 10 is a block diagram of a universal data output method of the present invention with respect to the components, system and apparatus described with reference to FIG. 2. FIG. 11 is a flow diagram illustrating one way of implementing a discovery process optionally included in the output process of FIG. 10. FIGS. 12A and 12B are flow diagrams of exemplary client application process included in the output process of FIG. 10. FIGS. 13A and 13B are flow diagrams of exemplary output device or output system process included in the output process of FIG. 10. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Sets forth below are definitions of terms that are used in describing implementations of the present invention. These definitions are provided to facilitate understanding and illustration of implementations of the present invention and should in no way be construed as limiting the scope of the invention to a particular example, class, or category. Output Device Profile (Or Object) An output device profile (or object) includes software and data entity, which encapsulates within itself both data and attributes describing an output device and instructions for operating that data and attributes. An output device profile may reside in different hardware environments or platforms or applications, and may be transported in the form of a file, a message, a software object or component among other forms and techniques. For simplicity of discussion, a profile or object may also include, for example, the concept of software components that may have varying granularity and can consist of one class, a composite of classes, or an entire application. The term profile or object used herein is not limited to software or data as its media. Any entity containing information, descriptions, attributes, data, instructions etc. in any computer-readable form or medium such as hardware, software, files based on or including voice, text, graphics, image, or video information, etc., are all valid forms of profile and object definition. A profile or object may also contain in one of its fields or attributes a reference or pointer to another profile or object, or a reference or pointer to data and or content. A reference to a profile or object may include one or more, or a combination of pointers, identifiers, names, paths, addresses or any descriptions relating to a location where an object, profile, data, or content can be found. An output device profile may contain one or more attributes that may identify and describe, for example, the capabilities and functionalities of a particular output device such as a printer. An output device profile may be stored in the memory component of an output device, an information apparatus or in a network node. A network node includes any device, server or storage location that is connected to the network. As described below in greater detail, an information apparatus requesting output service may communicate with an output device. During such local service negotiation, at least a partial output device profile may be uploaded to the information apparatus from the output device. By obtaining the output device profile (or printer profile in the case of a printer), the information apparatus may learn about the capability, compatibility, identification, and service provided by the output device. As an example, an output device profile may contain one or more of the following fields and or attribute descriptions. Each of following fields may be optional, and furthermore, each of the following fields or attributes may or may not exist in a particular implementation (e.g., may be empty or NULL): Identification of an output device (e.g., brand, model, registration, IP address etc.) Services and feature sets provided by an output device (e.g., color or grayscale output, laser or inkjet, duplex, output quality, price per page, quality of service, etc.) Type of input languages, formats, output data and/or input requirements (e.g., PostScript, PCL, XML, RTL, etc.) supported by an output device. Device specific or dependent parameters and information (e.g., communication protocols, color space, color management methods and rendering intents, resolution, halftoning methods, dpi (dots-per-inch), bit depth, page size, printing speed, number of independent colors channels or ink etc.) Data and tables needed for image processing such as color table, halftone table, scale factor, encoding/decoding parameters and methods, compression and decompression parameters and method etc. Another profile which contain parameters and information about the output device and its service (e.g. color profiles, halftoning profiles, communication profiles, rasterization profiles, quality of service etc.). Payment information on a plurality of services provided by an output device. Information or security requirements and type of authentication an output device supports. Date and version of the output device profile, history of its modification and updates. Software components containing algorithms or instructions or data, which may be uploaded to run in an information apparatus. For example, a graphical user interface (GUI) software component may be uploaded to an information apparatus. The software component may be incorporated into or launched in the information apparatus by a client application of present invention to capture a user's preferences (e.g., print quality, page layout, number of copies, number of cards per page, etc.). In another example, software components may include methods, instructions or executables for compression/decompression, encoding/decoding, color matching or correction, segmentation, scaling, halftoning, encryption/decryption among others. Pointer or reference to one or more output device parameters, including one or more of the above described output device profile or object fields and or attribute descriptions. For example, a more up-to-date or original version of output device parameters may sometimes be stored in a network node (any device, server or storage location that is connected to the network), or within the information apparatus where it can be obtained by the client application. An output device profile may include pointer or pointers to these output device parameters. Content (Or Data Content, Digital Content, Output Content) Content (or data content, digital content, output content) is the data intended for output, which may include texts, graphics, images, forms, videos, audio among other content types. Content may include the data itself or a reference to that data. Content may be in any format, language, encoding or combination, and it can be in a format, language or encoding that is partially or totally proprietary. A digital document is an example of content that may include attributes and fields that describe the digital document itself and or reference or references to the digital document or documents. Examples of a digital document may be any one or combination of file types: HTML, VHTML, PostScript, PCL, XML, PDF, MS Word, PowerPoint, JPEG, MPEG, GIF, PNG, WML, VWML, CHTML, HDML, ASCII, 2-byte international coded characters, etc. Content may be used interchangeably with the term data content, output content or digital content in the descriptions of present invention. Intermediate Output Data Output data (or print data in case of a printer) is the electronic data sent from an information apparatus to an output device. Output data is related to the content intended for output and may be encoded in a variety of formats and languages (e.g. postscript, PCL, XML), which may include compressed or encrypted data. Some output device manufacturers may also include in the output data (or print data) a combination of proprietary or non-proprietary languages, formats, encoding, compression, encryption etc. Intermediate output data is the output data of the present invention, and it includes the broader definition of an output file or data generated by an information apparatus, or a client application or device driver included in the information apparatus. An intermediate output data may contain text, vector graphics, images, video, audio, symbols, forms or combination and can be encoded with one or more of a page description language, a markup language, a graphics format, an imaging format, a metafile among others. An intermediate output data may also contain instructions (e.g. output preferences) and descriptions (e.g. data layout) among others. Part or all of an intermediate output data may be compressed, encrypted or tagged. In a preferred embodiment of this invention, intermediate output data contains rasterized image data. For example, vector graphics and text information or objects that are not in image form included in content can be rasterized or conformed into image data in an information apparatus and included in an intermediate output data. Device dependent image processing operations of a RIP such as digital halftoning and color space conversions can be implemented at an output device or an output system. The intermediate output data can be device dependent or device independent. In one implementation, the rasterized output image is device dependent if the rasterization parameters used, such as resolution, scale factor, bit depth, output size and or color space are device dependent. In another implementation of this invention, the rasterized image may be device independent if the rasterization parameters used are device independent. Rasterization parameter can become device independent when those parameters include a set of predetermined or predefined rasterization parameters based on a standard or a specification. With predefined or device independent rasterization parameters, a client application of present invention can rasterize at least a portion of the content and generate a device independent image or images included in the intermediate output data. By doing so, the intermediate output data may become device independent and therefore, become universally acceptable with output devices that have been pre-configured to accept the intermediate output data. One advantage of rasterizing or converting text and graphics information into image data at the information apparatus is that the output device or printer controller no longer needs to perform complex rasterization operation nor do they need to include multiple fonts. Therefore, employing the intermediate output data and the data output method described herein could potentially reduce the cost and complexity of an output controller, printer controller and or output device. One form of image data encoding is known as mixed raster content, or MRC. Typically, an image stored in MRC includes more than one image or bitmap layers. In MRC, an image can be segmented in different layers based on segmentation criteria such as background and foreground, luminance and chrominance among others. For example, an MRC may include three layers with a background layer, a foreground layer and a toggle or selector layer. The three layers are coextensive and may include different resolution, encoding and compression. The foreground and background layers may each contain additional layers, depending on the manner in which the respective part of the image is segmented based on the segmentation criteria, component or channels of a color model, image encoding representation (HLS, RGB, CMYK, YCC, LAB etc) among others. The toggle layer may designate, for each point, whether the foreground or background layer is effective. Each layer in a MRC can have different bit depths, resolution, color space, which allow, for example, the foreground layer to be compressed differently from the background layer. The MRC form of image data has previously been used to minimize storage requirements. Further, an MRC format has been proposed for use in color image fax transmission. In one embodiment of present invention, the intermediate output data includes one or more rasterized output images that employ MRC format, encoding and or related compression method. In this implementation, different layers in the output image can have different resolutions and may include different compression techniques. Different information such as chrominance and luminance and or foreground and background information in the original content (e.g. digital document) can be segmented and compressed with different compression or encoding techniques. Segmented elements or object information in the original content can also be stored in different image layers and with different resolution. Therefore, with MRC, there is opportunity to reduce output data file size, retain greater image information, increase compression ratio, and improve image quality when compared to other conventional image encoding and compression techniques. Implementations of rasterization, raster image processing and intermediate output data that include MRC encoding in the present invention are described in more detail below. Rasterization Rasterization is an operation by which graphics and text in a digital document are converted to image data. For image data included in the digital document, rasterization may include scaling and interpolation. The rasterization operation is characterized by rasterization parameters including, among others bit depth and resolution. A given rasterization operation may be characterized by several more rasterization parameters, including output size, color space, color channels etc. Values of one or more of the rasterization parameters employed in a rasterization operation may be specified by default; values of one or more of the rasterization parameters may be supplied to the information apparatus as components of a rasterization vector. In a given application, the rasterization vector may specify a value of only one rasterization parameter, default values being employed for other rasterization parameters used in the rasterization operation. In another application the rasterization vector may specify values of more than one, but less than all, rasterization parameters, default values being employed for at least one other rasterization parameter used in the rasterization operation. And in yet another application the rasterization vector may specify values of all the rasterization parameters used in the rasterization operation. FIGS. 2A and 2B are block diagrams illustrating components of an operating environment that can implement the process and apparatus of present invention. FIG. 2A shows an electronic system which includes an information apparatus 200 and an output device 220. The output device 220 includes an output controller 230. FIG. 2B illustrates a second implementation of an electronic system that includes an information apparatus 200 and an output system 250. The output system 250 includes an output device 220 and an output controller 230 which may be externally connected to, or otherwise associated with, the output device 220 in the output system 250. Information apparatus 200 is a computing device with processing capability. In one embodiment, information apparatus 200 may be a mobile computing device such as palmtop computer, handheld device, laptop computer, personal digital assistant (PDA), smart phone, screen phone, e-book, Internet pad, communication pad, Internet appliance, pager, digital camera, etc. It is possible that information apparatus 200 may also include a static computing device such as a desktop computer, workstation, server, etc. FIGS. 3A and 3B are block diagrams illustrating examples of hardware/software components included in an information apparatus 200 of present invention. Information apparatus 200 may contain components such as a processing unit 380, a memory unit 370, an optional storage unit 360 and an input/output control unit (e.g. communication manager 330). Information apparatus 200 may include an interface (not shown) for interaction with users. The interface may be implemented with software or hardware or a combination. Examples of such interfaces include, without limitation, one or more of a mouse, a keyboard, a touch-sensitive or non-touch-sensitive screen, push buttons, soft keys, a stylus, a speaker, a microphone, etc. Information apparatus 200 typically contains one or more network communication unit 350 that interfaces with other electronic devices such as network node (not shown), output device 220, and output system 230. The network communication unit may be implemented with hardware (e.g., silicon chipsets, antenna), software (e.g., protocol stacks, applications) or a combination. In one embodiment of the present invention, communication interface 240 between information apparatus 200 and output device 220 or output system 250 is a wireless communication interface such as a short-range radio interface including those implemented according to the Bluetooth or IEEE 802.11 standard. The communication interface may also be realized by other standards and/or means of wireless communication that may include radio, infrared, cellular, ultrasonic, hydrophonic among others for accessing one or more network node and/or devices. Wired line connections such as serial or parallel interface, USB interface and fire wire (IEEE 1394) interface, among others, may also be included. Connection to a local network such as an Ethernet or a token Ring network, among others, may also be implemented in the present invention for local communication between information apparatus 200 and output device 220. Examples of hardware/software components of communication units 350 that may be used to implement wireless interface between the information apparatus 200 and the output device 220 are described in more detail with reference to FIGS. 8A and 8B below. For simplicity, FIG. 3 illustrates one implementation where an information apparatus 200 includes one communication unit 350. However, it should be noted that an information apparatus 200 may contain more than one communication unit 350 in order to support different interfaces, protocols, and/or communication standards with different devices and/or network nodes. For example, information apparatus 200 may communicate with one output device 220 through a Bluetooth standard interface or through an IEEE 802.11 standard interface while communicating with another output device 220 through a parallel cable interface. The information apparatus 200 may also be coupled to a wired or wireless network (e.g. the Internet or corporate network) to send, receive and/or download information. Information apparatus 200 may be a dedicated device (e.g., email terminal, web terminal, digital camera, e-book, web pads, Internet appliances etc.) with functionalities that are pre-configured by manufacturers. Alternatively, information apparatus 200 may allow users to install additional hardware components and or application software 205 to expand its functionality. Information apparatus 200 may contain a plurality of applications 205 to implement its feature sets and functionalities. As an example, a document browsing or editing application may be implemented to help user view and perhaps edit, partially or entirely, digital documents written in certain format or language (e.g., page description language, markup language, etc.). Digital documents may be stored locally in the information apparatus 200 or in a network node (e.g., in content server). An example of a document browsing application is an Internet browser such as Internet Explorer, Netscape Navigator, or a WAP browser. Such browsers may retrieve and display content (e.g. digital content) written in mark-up languages such as HTML, WML, XML, CHTML, HDML, among others. Other examples of software applications in the information apparatus 200 may include a document editing software such as Microsoft Word™ which also allows users to view and or edit digital documents that have various file extensions (e.g., doc, rtf, html, XML etc.) whether stored locally in the information apparatus 200 or in a network node. Still, other example of software applications 205 may include image acquisition and editing software. As illustrated previously with reference to FIG. 1, there are many difficulties in providing output capability to an information apparatus 200 that has limited memory and processing capability. To address theses difficulties, information apparatus 200 includes a client application 210 that helps provide the universal data output capability of the present invention. Client application 210 may include software and data that can be executed by the processing unit 380 of information apparatus 200. Client application 210 may be implemented as a stand-alone software application or as a part of or feature of another software application, or in the form of a device driver, which may be invoked, shared and used by other application software 205 in the information apparatus 200. Client application 210 may also include components to invoke other applications 205 (e.g., a document browsing application, editing application, data and/or image acquisition application, a communication manager, a output manager etc.) to provide certain feature sets, as described below. FIG. 3 illustrates a configuration where the client application 210 is a separate application from the other application 205 such as the case when the client application is a device driver; however, it should be noted that the client application 210 can be combined or being part of the other application not shown in FIG. 3. Client application 210 may be variously implemented in an information apparatus 200 and may run on different operating systems or platforms. The client application 210 may also run in an environment with no operating system. For example, FIG. 3A illustrates an implementation where the information apparatus 200A includes an operating system 340A; while FIG. 3B illustrates an implementation where the information apparatus 200B does not include an operating system. Client application 210 includes a rasterization component 310 to conform content into one or more raster output images according to one or more rasterization parameters; an intermediate output data generator component 320 that generates and/or encodes intermediate output data that includes the one or more output images; and a communications manager 330 that manages the communication and interaction with an output device 220 or system 250 or output controller 230. Communications manager can be implemented as part of the client application 210 (shown in FIG. 3) or as a separate application (not shown). Components in a client application can be implemented in software, hardware or combination. As an example, client application 210 may include or utilize one or more of the following: Components or operations to obtain content (e.g. digital document) for output. The client application 210 may obtain a digital document from other applications 205 (e.g. document browsing application, content creation and editing application, etc.), or the client application 210 may provide its own capability for user to browse, edit and or select a digital document. Components or operations to rasterize content that includes text, graphics and images among others objects or elements into one or more raster images according to a set of rasterization parameters such as scale factor, output size, bit depth, color space and resolution. The rasterization parameters may be obtained in various ways, for example, from an output device profile uploaded from an output device 220, or stored locally in information apparatus 200, or manually inputted by a user. Alternatively, rasterization parameters may be based on a predefined standard or specification stored in the information apparatus 200 as a set of defaults, or hard-coded in the client application 210, or calculated by the client application 210 after communicating with an output device 220, output controller 230, and/or a user. Components or operations to generate intermediate output data that includes at least one rasterized output image corresponding to the content (e.g. digital document). This process may further include one or combination of compression, encoding, encryption and color correction among others. The intermediate output data may include, for example, images, instructions, documents and or format descriptions, color profiles among others. Components or operations to transmit the intermediate output data to an output device 220 or system 250 through wired or wireless communication link 240. The client application 210 may also optionally include or utilize one or more of the following components or operations: Components or operations to communicate with one or more output devices 220 to upload an output device profile. Components or operations to communicate directly or indirectly (such as through an operating system or component or object model, messages, file transfer etc.) with other applications 205 residing in the same information apparatus 200 to obtain objects, data, and or content needed, or related to the pervasive output process of present invention (e.g. obtain a digital document for printing). Components or operations to manage and utilize directly or indirectly functionalities provided by hardware components (e.g. communication unit 350) residing in its host information apparatus 200. Components or operations to provide a graphical user interface (GUI) in host information apparatus to interact with user. Components or operations to obtain user preferences. For example, a user may directly input his or her preferences through a GUI. A set of default values may also be employed. Default values may be pre-set or may be obtained by information apparatus 200 as result of communicating and negotiating with an output device 220 or output controller 230. The above functionalities and process of client application 210 of present invention are described in further detail in the client application process with reference to FIG. 12. Output device 220 is an electronic system capable of outputting digital content regardless of whether the output medium is substrate (e.g., paper), display, projection, or sound. A typical example of output device 220 is a printer, which outputs digital documents containing text, graphics, image or any combination onto a substrate. Output device 220 may also be a display device capable of displaying still images or video, such as, without limitation, televisions, monitors, and projectors. Output device 220 can also be a device capable of outputting sound. Any device capable of playing or reading digital content in audio (e.g., music) or data (e.g., text or document) formats is also a possible output device 220. A printer is frequently referred to herein as an example of an output device to simplify discussion or as the primary output device 220 in a particular implementation. However, it should be recognized that present invention applies also to other output devices 220 such as fax machines, digital copiers, display screens, monitors, televisions, projectors, voice output devices, among others. Rendering content with an output device 220 refers to outputting the content on a specific output medium (e.g., papers, display screens etc). For example, rendering content with a printer generates an image on a substrate; rendering content with a display device generates an image on a screen; and rendering content with an audio output device generates sound. A conventional printing system in general includes a raster image processor and a printer engine. A printer engine includes memory buffer, marking engine among other components. The raster image processor converts content into an image form suitable for printing; the memory buffer holds the rasterized image ready for printing; and the marking engine transfers colorant to substrate (e.g., paper). The raster image processor may be located within an output device (e.g. included in a printer controller 410) or externally implemented (in an information apparatus 200, external controller, servers etc). Raster image processor can be implemented as hardware, software, or a combination (not shown). As an example, raster image processor may be implemented in a software application or device driver in the information apparatus 200. Examples of raster image processing operations include image and graphics interpretation, rasterization, scaling, segmentation, color space transformation, image enhancement, color correction, halftoning, compression etc. FIG. 4A illustrates a block diagram of one conventional printing system or printer 400A that includes a printer controller 410 and a printer engine 420A. The printer controller 410 includes an interpreter 402 and a raster image processor 406, and the printer engine 420 includes memory buffer 424A and a marking engine 426A. Marking engine may use any of a variety of different technologies to transfer a rasterized image to paper or other media or, in other words, to transfer colorant to a substrate. The different marking or printing technologies that may be used include both impact and non-impact printing. Examples of impact printing may include dot matrix, teletype, daisywheel, etc. Non-impact printing technologies may include inkjet, laser, electrostatic, thermal, dye sublimation, etc. The marking engine 426 and memory buffer 424 of a printer form its printer engine 420, which may also include additional circuitry and components, such as firmware, software or chips or chipsets for decoding and signal conversion, etc. Input to a printer engine 420 is usually a final rasterized printer-engine print data generated by a raster image processor 406. Such input is usually device dependent and printer or printer engine specific. The printer engine 420 may take this device dependent input and generate or render output pages (e.g. with ink on a substrate). When a raster image processor is located inside an output device 220, it is usually included in a printer controller 410 (as shown in FIG. 4A). A printer controller 410 may interpret, rasterize, and convert input print data in the form of a page description language (e.g., PostScript, PCL), markup language (e.g., XML, HTML) or other special document format or language (e.g. PDF, EMF) into printer-engine print data which is a final format, language or instruction that printer engine 420A can understand. Print data sent to a printer with printer controller 410 is usually in a form (e.g. postscript) that requires further interpretation, processing or conversion. A printer controller 410 receives the print data, interprets, process, and converts the print data into a form that can be understood by the printer engine 420A. Regardless of the type of print data, conventionally, a user may need a device-specific driver in his or her information apparatus 200 in order to output the proper language, format, or file that can be accepted by a specific printer or output device 220. FIG. 4B illustrates another conventional output device 400B. Output device 400B may be a printing device, a display device, a projection device, or a sound device. In the case that the output device is a printing device or a printer, the printer with reference to FIG. 4B does not include a printer controller 410. As an example, printer 400B may be a low-cost printer such as a desktop inkjet printer. RIP operations in this example may be implemented in a software application or in a device driver included in an information apparatus 200. The information apparatus 200 generates device dependent output data (or print data in case of a printer) by rasterizing and converting a digital document into output data (e.g. into a compressed CMKY data with one or more bits per pixel) that can be understood by an output engine (or printer engine in case of a printer) 420B. Regardless of type or sophistication level, different output device 220 conventionally needs different printer drivers or output management applications in an information apparatus 200 to provide output capability. Some mobile devices with limited memory and processing power may have difficulty storing multiple device drivers or perform computational intensive RIP operations. It may also be infeasible to install a new device dependent or specific printer driver each time there is a need to print to a new printer. To overcome these difficulties, present invention provides several improvements to output device 220 or output system 250 as described in detail next. In present invention, output device 220 may include an output controller 230 to help managing communication and negotiation processes with an information apparatus 200 and to process output data. Output controller 230 may include dedicated hardware or software or combination of both for at least one output device 220. Output controller 230 may be internally installed, or externally connected to one or more output devices 220. The output controller 230 is sometimes referred to as a print server or output server. FIGS. 5A and 5B illustrate two exemplary internal implementations of the output controller 230 of present invention. FIG. 5A illustrates the implementation of an output controller 230 inside a conventional printer with reference to FIG. 4A, which includes a conventional printer controller 410(5A). The output controller 230(5A) includes an interpreter 510A component for decoding the intermediate output data of present invention; and a converter component 530A for converting one or more decoded output images into a printer-controller print data that is suitable for input to the printer controller 410(5A). An optional image processing component 520A may be included in the output controller 230(5A). FIG. 5B illustrates the implementation of an output controller 230 included internally in a conventional output device 220 with reference to FIG. 4B, which does not include a printer controller. The output controller 230(5B) includes an interpreter 510B component for decoding the intermediate output data of present invention; an image processor 520B component for performing one or more image processing operations such as color space conversion, color matching and digital halftoning; and an optional encoder 530B component to conform the processed output images into an output-engine output data that is suitable for input to the output engine 420B if the result of the image processing is not already in required form suitable for the output engine 420B. In one implementation, output device 220 may include a communication unit 550 or adapter to interface with information apparatus 200. Output device 220 may sometimes include more than one communication unit 550 in order to support different interfaces, protocols, or communication standards with different devices. For example, output device 220 may communicate with a first information apparatus 200 through a Bluetooth interface while communicating with a second information apparatus 200 through a parallel interface. Examples of hardware components of a wireless communication unit are described in greater detail below with reference to FIGS. 8A and 8B. In one embodiment, output controller 230 does not include a communication unit, but rather utilizes or manages a communication unit residing in the associated output device 220 such as the illustration in FIG. 5. In another embodiment, output controller 230 may include or provide a communication unit to output device 220 as shown in FIG. 6. For example, an output controller 230 with a wireless communication unit may be installed internally or connected externally to a legacy printer to provide it with wireless communication capability that was previously lacking. FIG. 6 includes three functional block diagrams illustrating the hardware/software components of output controller 230 in three different implementations. Each components of an output controller 230 may include software, hardware, or combination. For example, an output controller 230 may include components using one or more or combinations of an application-specific integrated circuit (ASIC), a digital signal processor (DSP), a field programmable gate array (FPGA), firmware, system on a chip, and various communication chip sets. Output controller 230 may also contain embedded processors 670 A with software components or embedded application software to implement its feature sets and functionalities. Output controller 230 may contain an embedded operating system 680. With an operating system, some or all functionalities and feature sets of the output controller 230 may be provided by application software managed by the operating system. Additional application software may be installed or upgraded to newer versions in order to, for example, provide additional functionalities or bug fixes. FIG. 6A and FIG. 6C illustrates examples of implementation with an operating system 680 while FIG. 6B illustrates an example without the operating system 680 or the optional embedded processor 670. Output controller 230 typically includes a memory unit 640, or may share a memory unit with, for example, printer controller 410. The memory unit and storage unit, such as ROM, RAM, flash memory and disk drive among others, may provide persistent or volatile storage. The memory unit or storage unit may store output device profiles, objects, codes, instructions or data (collectively referred to as software components) that implement the functionalities of the output controller 230. Part of the software components (e.g., output device profile) may be uploaded to information apparatus 200 during or before a data output operation. An output controller 230 may include a processor component 670A and 670C, a memory component 650, an optional storage component 640, and an optional operating system component 680. FIG. 6 shows one architecture or implementation where the memory 650, storage 640, processor 670, and operating system 680 components, if exist, can be share or accessed by other operational components in the output controller 230 such as the interpreter 610 and image processor 650. FIG. 6 shows two communication units 660A and 660B included in the output controller 230; however, the output controller 230 of present invention may include any number of communication units 660. It is also possible that the output controller does not contain any communication unit but rather utilizes the communication unit of an output device. The output controller 230 may be connected externally to an output device 220 or integrated internally into the output device 220. FIGS. 5A and 5B illustrate implementations of output controller 230 inside an output device 220. The output controller 230, however, may also be implemented as an external box or station that is wired or wirelessly connected to an output device 220. An output controller 230 implemented as an external box or station to an output device 220 may contain its own user interface. One example of such an implementation is a print server connected to an output device 220 in an output system 250. Another configuration and implementation is to integrate or combine the functionalities of an output controller 230 with an existing printer controller 410 (referred to as “combined controller”) if the output device 220 is a printer as shown with reference to FIG. 7C or 7F. A combined controller can also be internally integrated or externally connected to output device 220, and include functionalities of both printer controller 410 (e.g., input interpretation and or raster image processing) and output controller 230 of present invention. One advantage of this configuration is that the functionalities or components of output controller 230 and printer controller 410 may share the same resources, such as processing unit, memory unit, etc. FIG. 6C illustrates an example of a combined controller implementation or output controller 230 where the printer controller 410C, interpreter 610C and converter 630C shares the use of the processor 670C, memory 650C and storage 640C, managed by an operating system 680C. Various exemplary implementations and configurations of an output controller 230 with respect to an output device 220 or output system 250 are illustrated in further detail with reference to FIG. 7. Other possible implementations of output controller 230 may include, for example, a conventional personal computer (PC), a workstation, and an output server or print server. In these cases, the functionalities of output controller 230 may be implemented using application software installed in a computer (e.g., PC, server, or workstation), with the computer connected with a wired or wireless connection to an output device 220. Using a PC, server, workstation, or other computer to implement the feature sets of output controller 230 with application software is just another possible embodiment of the output controller 230 and in no way departs from the spirit, scope and process of the present invention. The difference between output controller 230 and printer controller 410 should be noted. Printer controller 410 and output controller 230 are both controllers and are both dedicated hardware and or software for at least one output device 220. Output controller 230 refers to a controller with feature sets, capabilities, and functionalities of the present invention. A printer controller 410 may contain functions such as interpreting an input page description language, raster image processing, and queuing, among others. An output controller 230 may include part or all of the features of a printer controller 410 in addition to the feature sets, functionalities, capabilities, and processes of present invention. Functionalities and components of output controller 230 for the purpose of providing universal data output may include or utilize: Components and operations to receive output data from a plurality of information apparatus 200; the output data may include an intermediate output data containing at least one rasterized image related to the data content intended for output. Components and operations to interpret and/or decode the intermediate output data. Components and operations to process the intermediate output data. Such components and operations may include image processing functions such as scaling, segmentation, color correction, color management, GCR, image enhancement, decompression, decryption, and or halftoning among others. Components and operations to generate an output-engine output data, the output-engine output data being in an output data format acceptable for input to an output engine. Components and operations to send the output-engine output data to the output engine. When associated with an output device 220 that includes a printer controller 410, the output controller of present invention may further include or utilize: Components and operations to convert the intermediate output data into a printer-controller print data (e.g. a PDL such as PostScript and PCL), the printer-controller print data being in a format acceptable to a printer controller. Components and operations to send printer-controller print data to one or more printer controllers. In addition to the above components and functionalities, output controller 230 may further include one or more of the following: Components and operations to communicate with one or more information apparatus 200 through a wired or wireless interface. Components and operations to communicate and or manage a communication unit included in the output controller 230 or output device 220. Components and operations to store at least part of an output device profile (a printer profile in case of a printer) in a memory component. Components and operations to respond to service request from an information apparatus 200 by transmitting at least part of an output device profile to the information apparatus requesting service. The output controller 230 may transmit the output device profiles or object in one or multiple sessions. Components and operations to broadcast or advertise the services provided by a host output device 220 to one or more information apparatus 200 that may request such services. Components and operations to implement payment processing and management functions by, for example, calculating and processing payments according to the services requested or rendered to a client (information apparatus 200). Components and operations to provide a user interface such as display screen, touch button, soft key, etc. Components and operations to implement job management functions such as queuing and spooling among others. Components and operations to implement security or authentication procedures. For example, the output controller 230 may store in its memory component (or shared memory component) an access control list, which specifies what device or user may obtain service from its host (or connected) output device 220. Therefore, an authorized information apparatus 200 may gain access after confirming with the control list. When output controller 230 is implemented as firmware, or an embedded application, the configuration and management of the functionalities of output controller 230 may be optionally accomplished by, for example, using controller management software in a host computer. A host computer may be a desktop personal computer (PC), workstation, or server. The host computer may be connected locally or through a network to the output device 220 or the controller 230. Communication between the host computer and the output controller 230 can be accomplished through wired or wireless communication. The management application software in the host computer can manage the settings, configurations, and feature sets of the output controller 230. Furthermore, host computer's configuration application may download and or install application software, software components and or data to the output controller 230 for the purpose of upgrading, updating, and or modifying the features and capabilities of the output controller 230. Output device 220 in one implementation includes or is connected to output controller 230 described above. Therefore, functionalities and feature sets provided by output controller 230 are automatically included in the functionalities of output device 220. The output device 220 may, however, implement or include other controllers and/or applications that provide at least partially the features and functionalities of the output controller 230. Therefore, the output device 220 may include some or all of the following functionalities: Components and operations to receive multiple service requests or queries (e.g., a service request, a data query, an object or component query etc.) from a plurality of information apparatus 200 and properly respond to them by returning components, which may contain data, software, instructions and/or objects. Components and operations to receive output data from a plurality of information apparatus 200; the output data may include an intermediate output data containing one or more rasterized image related to the content intended for output. Components and operations to interpret and/or decoding the intermediate output data. Components and operations to process and/or convert the intermediate output data into a form (e.g. output-engine print data) suitable for rendering at an output engine associated with the output device. Components and operations to render a representation or an image related to the content onto an output medium (e.g. substrate or a display screen). An output device 220 may further comprise optionally one or more of the following functionalities: Components and operations for establishing and managing a communication link with an information apparatus 200 requesting service; the communication link may include wired or wireless communication. Components and operations for storing at least part of an output device profile (e.g. printer profile) in a memory component. Components and operations to provide at least part of an output device profile (e.g., printer profile in case of a printer) to one or more information apparatus 200 requesting service. The output device 220 may transmit the output device profile in one or multiple sessions. Components and operations to advertise or broadcast services provided or available to one or more information apparatus 200. Components and operations to implement payment processing and management functions by, for example, calculating and processing payments according to the services requested by or rendered to a client (information apparatus 200). Components and operations to implement job management functionalities such as queuing and spooling among others. Components and operations to provide a user interface such as display screen touch button, soft key, power switch, etc. Components and operations to implement security or authentication procedures. For example, the output device 220 may store in its memory component (or a shared memory component) an access control list, which specifies what device or user may obtain service from it. Therefore, an authorized information apparatus 200 may gain access after confirming with the control list. FIGS. 7A-7F illustrate various alternative configurations and implementations of output controller 230 with respect to an output device 230. Printer is sometimes used as an exemplary output device 230 to demonstrate the various configurations. It should be understood, however, the output device 230 of present invention is not limited to printers. As described with reference to FIG. 4., a printer may or may not contain a printer controller 410. Printer 400A that includes a printer controller 410 typically has higher speed and is more expensive than printer 400B which does not include a printer controller 410. FIG. 7A shows that output controller 230 may be cascaded externally to one or more printers (only one shown). Information apparatus 200 communicates with output controller 230A, which then communicates with output device 220 such as a printer 220A. The communication link between the output controller 230A and the printer 220A may be a wired link or a wireless link, as described above. FIGS. 6A and 6B illustrates two examples of functional component design of the output controller that can implement the configuration illustrated in FIG. 7A. The Image processor 620 in this implementation is optional. FIG. 7B shows another implementation in which output controller 230B is installed as one or more circuit boards or cards internally inside printer 220B. The output controller 230B may co-exist with printer controller 410 and other components of the printer 220B. One example of this implementation is to connect output controller 230B sequentially with the printer controller 310. FIG. 5A shows as an example of an implementation. FIG. 7C shows another implementation in which the functionalities of output controller 230 and printer controller 410 are combined into a single controller (referred to as “combined controller”) 230C. In this implementation, it is possible to reduce the cost of material when compared to implementing two separate controllers as shown in FIG. 7B. As an example, the combined controller 230C may share the same processors, memories, and storages to run the applications and functionalities of the two types of controllers and therefore, may have lower component costs when compared to providing two separate controllers. FIG. 6C illustrates an example of a combined controller functional component implementation. Some printers do not include a raster image processor or printer controller 410, as illustrated in FIG. 4B. An example of this type of printer is a lower cost desktop inkjet printer. Input to an inkjet printer may consist of a compressed CMYK data (proprietary or published) with one or more bits per pixel input. To output to a printer that does not include a printer controller, a device specific software application or a printer driver is typically required in an information apparatus 200 to perform raster image processing operations. Accordingly, output controller 230 can be implemented into a variety of output devices 220 and/or output systems 250 including printers that do not have printer controllers for performing raster image processing operations. FIG. 7D and FIG. 7E illustrate two implementations of output controller 230 in an output device 220 or system 250. The output device 230 or system 250 may include a display device, a projection device, an audio output device or a printing device. In the case when the output device 220D or 220E is a printer, it does not include a printer controller. FIG. 7D illustrates an implementation of an output controller 230D installed as an external component or “box” to output device 220D. For example, the output controller 230 may be implemented as an application in a print server or as a standalone box or station. In this configuration, some or all of raster image processing operations may be implemented in the output controller 230D. Output controller 230D receives intermediate output data from an information apparatus 200 and generates output-engine output data that is acceptable to the output engine included in the output device 220D. The output controller 230D may send the output data to the output device 220D through a wired or wireless communication link or connection. FIGS. 6A and 6B illustrates two example of functional component design of the output controller that can implement the configurations for both FIGS. 7D and 7E. FIG. 7E shows a fifth implementation of output controller 230E in which the output controller 230E is incorporated within output device 220E as one or more circuit boards or cards and may contain software and applications running on an embedded processor. As with output device 220D (FIG. 7D), output device 220E does not include a printer controller 410. Accordingly, the output controller 230E implements the functionalities and capabilities of present invention that may include part of or complete raster imaging processing operation. FIG. 7F shows a sixth implementation, an external combined controller 230F that integrates the functionalities of a printer controller 310 and an output controller into a single external combined controller component or “box” 230F. The two controller functions may share a common processor as well as a common memory space to run applications of the two types of controllers. Under this configuration, either information apparatus 200 or the combined controller 230F could perform or share at least part of raster image processing functionality. FIG. 6C shows an example of functional components of a combined controller 230F. Another implementation of the combined controller 230F shown in FIG. 7F is to use an external computing device (PC, workstation, or server) running one or more applications that include the functionality of output controller 230 and printer controller 410. The above are examples of different implementations and configurations of output controller 230. Other implementations are also possible. For example, partial functionalities of output controller 230 may be implemented in an external box or station while the remaining functionalities may reside inside an output device 220 as a separate board or integrated with a printer controller 410. As another example, the functionalities of output controller 230 may be implemented into a plurality of external boxes or stations connected to the same output device 220. As a further example, the same output controller 230 may be connected to service a plurality of output devices 220 FIGS. 8A and 8B are block diagrams illustrating two possible configurations of hardware/software components of wireless communication units. These wireless communication units can be implemented and included in information apparatus 200, in output controller 230 and in output device 220. Referring to FIG. 8A, a radio adapter 800 may be implemented to enable data/voice transmission among devices (e.g., information apparatus 200 and output device 220) through radio links. An RF transceiver 814 coupled with antenna 816 is used to receive and transmit radio frequency signals. The RF transceiver 814 also converts radio signals into and from electronic signals. The RF transceiver 814 is connected to an RF link controller 810 by an interface 812. The interface 812 may perform functions such as analog-to-digital conversion, digital-to-analog conversion, modulation, demodulation, compression, decompression, encoding, decoding, and other data or format conversion functions. RF link controller 810 implements real-time lower layer (e.g., physical layer) protocol processing that enables the hosts (e.g., information apparatus 200, output controller 230, output device 220, etc.) to communicate over a radio link. Functions performed by the link controller 810 may include, without limitation, error detection/correction, power control, data packet processing, data encryption/decryption and other data processing functions. A variety of radio links may be utilized. A group of competing technologies operating in the 2.4 GHz unlicensed frequency band is of particular interest. This group currently includes Bluetooth, Home radio frequency (Home RF) and implementations based on IEEE 802.11 standard. Each of these technologies has a different set of protocols and they all provide solutions for wireless local area networks (LANs). Interference among these technologies could limit deployment of these protocols simultaneously. It is anticipated that new local area wireless technologies may emerge or that the existing ones may converge. Nevertheless, all these existing and future wireless technologies may be implemented in the present invention without limitation, and therefore, in no way depart from the scope of present invention. Among the currently available wireless technologies, Bluetooth may be advantageous because it requires relatively lower power consumption and Bluetooth-enabled devices operate in piconets, in which several devices are connected in a point-to-multipoint system. Referring to FIG. 8B, one or more infrared (IR) adapters 820 may be implemented to enable data transmission among devices through infrared transmission. The IR adapters 820 may be conveniently implemented in accordance with the Infrared Data Association (IrDA) standards and specifications. In general, the IrDA standard is used to provide wireless connectivity technologies for devices that would normally use cables for connection. The IrDA standard is a point-to-point (vs. point-to-multipoint as in Bluetooth), narrow angle, ad-hoc data transmission standard. Configuration of infrared adapters 820 may vary depending on the intended rate of data transfer. FIG. 8B illustrates one embodiment of infrared adapter 820. Transceiver 826 receives/emits IR signals and converts IR signals to/from electrical signals. A UART (universal asynchronous receiver/transmitter) 822 performs the function of serialization/deserialization, converting serial data stream to/from data bytes. The UART 822 is connected to the IR transceiver 826 by encoder/decoder (ENDEC) 824. This configuration is generally suitable for transferring data at relatively low rate. Other components (e.g., packet framer, phase-locked loop) may be needed for higher data transfer rates. FIGS. 8A and 8B illustrate exemplary hardware configurations of wireless communication units. Such hardware components may be included in devices (e.g., information apparatus 200, output controller 230, output device 220, etc.) to support various wireless communications standards. Wired links, however, such as parallel interface, USB, Firewire interface, Ethernet and token ring networks may also be implemented in the present invention by using appropriate adapters and configurations. FIG. 9 is a logic flow diagram of an exemplary raster imaging process (RIP) 902 that can implement the universal output method of present invention. Content (e.g. digital document) 900 may be obtained and/or generated by an application running in an information apparatus 200. For example, a document browsing application may allow a user to download and or open digital document 900 stored locally or in a network node. As another example, a document creating or editing application may allow a user to create or edit digital documents in his/her information apparatus 200. A client application 210 in the information apparatus may be in the form of a device driver, invoked by other applications residing in the information apparatus 200 to provide output service. Alternatively, the client application 210 of present invention may be an application that includes data output and management component, in addition of other functionalities such as content acquisitions, viewing, browsing, and or editing etc. For example, a client application 210 in an information apparatus 200 may itself include components and functions for a user to download, view and or edit digital document 900 in addition of the output management function described herein. Raster image process method 902 allows an information apparatus 200 such as a mobile device to pervasively and conveniently output content (e.g. a digital document) to an output device 220 or system 250 that includes an output controller 230. A client application 210 in an information apparatus 200 may perform part of raster image processing operations (e.g. rasterization operation). Other operations of raster image processing such as halftoning can be completed by the output device 220 or by the output controller 230. In conventional data output methods, raster image processing is either implemented entirely in an information apparatus (e.g. a printer that does not include a printer controller with reference to FIG. 1A) or in an output device (e.g. a printer that includes a printer controller with reference to FIG. 1B). Present invention provides a more balanced approach where raster image process operations are shared between an information apparatus 200 and an output device 220 or system 250. For example, content 600 may be processed (e.g. raster image processed) by different components or parts of an overall output system from a client application 210 to an output controller 230 before being sent to an output engine or a printer engine for final output in step 960. Because the raster image processing operations are not completely implemented in the information apparatus 200, there is less processing demand on the information apparatus 200. Therefore, present RIP process may enable additional mobile devices with less memory and processing capability to have data output capability. In step 910, rasterization operation, a content (e.g. digital document), which may include text, graphics, and image objects, is conformed or rasterized to image form according to one or more rasterization parameters such as output size, bit depth, color space, resolution, number of color channels etc. During the rasterization operation, text and vector graphics information in the content are rasterized or converted into image or bitmap information according to a given set of rasterization parameters. Image information in the content or digital document may be scaled and or interpolated to fit a particular output size, resolution and bit depth etc. The rasterization parameters are in general device dependent, and therefore may vary according to different requirements and attributes of an output device 220 and its output engine. There are many ways to obtain device dependent rasterization parameters, as described in more detail below with reference to FIG. 12A. Device dependent rasterization parameters, in one example, may be obtained from an output device profile stored in an information apparatus 200, an output device 220 or an output controller 230. In an alternative implementation, rasterization parameters may be predetermined by a standard or specification. In this implementation, in step 910 the content 900 is rasterized to fit or match this predefined or standard rasterization parameters. Therefore, the rasterized output image becomes device independent. One advantage of being device independent is that the rasterized output image is acceptable with controllers, devices and/or output devices implemented or created with the knowledge of such standard or specification. A rasterized image with predefined or standardized attributes is usually more portable. For example, both the client application 210 and output device 220 or its output controller 230 may be preprogrammed to receive, interpret, and or output raster images based on a predefined standard and/or specification. Occasionally, a predefined standard or specification for rasterization parameters may require change or update. One possible implementation for providing an easy update or upgrade is to store information and related rasterization parameters in a file or a profile instead of hard coding these parameters into programs, components or applications. Client application 210, output controller 230, and/or the output device 220 can read a file or a profile to obtain information related to rasterization parameters. To upgrade or update the standard specification or defaults requires only replacing or editing the file or the profile instead of replacing a software application or component such as the client application 210. In step 920 the rasterized content in image form is encoded into an intermediate output data. The intermediate output data, which describes the output content, may include image information, instructions, descriptions, and data (e.g. color profile). The rasterized output image may require further processing including one or more of compression, encoding, encryption, smoothing, image enhancement, segmentation, color correction among others before being stored into the intermediate output data. The output image in the intermediate output data may be encoded in any image format and with any compression technique such as JPEG, BMP, TIFF, JBIG etc. In one preferred embodiment, a mixed raster content (MRC) format and its related encoding and/or compression methods are used to generate the output image. The advantages of using MRC over other image formats and techniques may include, for example, better compression ratio, better data information retention, smaller file size, and or relatively better image quality among others. In step 930, the intermediate output data is transmitted to the output device 220 or output system 250 for further processing and final output. The transmission of the intermediate output data may be accomplished through wireless or wired communication links between the information apparatus 200 and the output device 220 and can be accomplished through one or multiple sessions. In step 940, the output device 220 or output system 250 receives the transmitted intermediate output data. The output device 220 or output system 250 may include an output controller 230 to assist communicating with the information apparatus 200 and/or processing the intermediate output data. Output controller 230 may have a variety of configurations and implementations with respect to output device 220 as shown in FIG. 7A-7F. Interpretation process 940 may include one or more of parsing, decoding, decompression, decryption, image space conversion among other operations if the received intermediate output data requires such processing. An output image is decoded or retrieved from the intermediate output data and may be temporarily stored in a buffer or memory included in the output device/output system (220/250) or output controller 230 for further processing. If the intermediate output data includes components with MRC format or encoding techniques, it may contain additional segmented information (e.g. foreground and background), which can be used to enhance image quality. For example, different techniques or algorithms in scaling, color correction, color matching, image enhancement, anti-aliasing and or digital halftoning among others may be applied to different segments or layers of the image information to improve output quality or maximize retention or recovery of image information. Multiple layers may later be combined or mapped into a single layer. These image processing and conversion components and/or operations can be included in the output controller 230 of present invention. In step 950, the decoded or retrieved output image from the intermediate output data may require further processing or conversion. This may include one or more of scaling, segmentation, interpolation, color correction, GCR, black generation, color matching, color space transformation, anti-aliasing, image enhancement, image smoothing and or digital halftoning operations among others. In an embodiment where the output device 220 does not include a printer controller, an output controller 230 or an output device 220 that includes output controller, after performing the remaining portion of RIP operations (e.g. color space conversion and halftoning) on the output image, may further convert the output data in step 950 into a form that is acceptable for input to a printer engine for rendering. In an alternative embodiment where the output device 220 or the output system 250 includes a conventional printer controller, the output controller may simply decodes and or converts the intermediate output data (print data in this example) into format or language acceptable to the printer controller. For example, a printer controller may require as input a page description language (e.g. PostScript, PCL, PDF, etc.), a markup language (HTML, XML etc) or other graphics or document format. In these cases, the output controller 230 may interpret, decompress and convert the intermediate print data into an output image that has optimal output resolution, bit depth, color space, and output size related to the printer controller input requirements. The output image is then encoded or embedded into a printer-controller print data (e.g. a page description language) and sent to the printer controller. A printer-controller print data is a print data that is acceptable or compatible for input to the printer controller. After the printer controller receives the printer-controller print data, the printer controller may further perform operations such as parsing, rasterization, scaling, color correction, image enhancement, halftoning etc on the output image and generate an appropriate printer-engine print data suitable for input to the printer engine. In step 960, the output-engine output data or printer-engine print data generated by the output controller 230 or the printer controller in step 950 is sent to the output engine or printer engine of the output device for final output. FIG. 10 illustrates a flow diagram of a universal data output process of the present invention that includes the raster image processing illustrated with reference to FIG. 9. A universal data output process allows an information apparatus 200 to pervasively output content or digital document to an output device. The data output process may include or utilize: A user interface component and operation where a user initiates an output process and provides an indication of the selected output content (e.g. digital document) for output. A client application component or operation that processes the content indicated for output, and generates an intermediate output data. The intermediate output data may include at least partly a raster output image description related to the content. An information apparatus component or operation that transmits the intermediate output data to one or more selected output device 220. An output device component (e.g. output controller) or operation that interprets the intermediate output data and may further process or convert the output data into a form more acceptable to an output engine for rendering of the content. With reference to FIG. 10, a user in step 1000 may initiate the universal output method or process 1002. Typically, a user initiates the output process by invoking a client application 210 in his/her information apparatus 200. The client application 210 may be launched as an independent application or it may be launched from other applications 205 (such as from a document browsing, creating or editing application) or as part of or component of or a feature of another application 205 residing in the same information apparatus 200. When launched from another application 205, such as the case when the client application is a device driver or helper application, the client application 210 may obtain information, such as the content (e.g. digital document) from that other application 205. This can be accomplished, for example, by one or combinations of messages or facilitated through an operating system or a particular object or component model etc. During output process 1002, a user may need to select one or more output devices 220 for output service. An optional discovery process step 1020 may be implemented to help the user select an output device 220. During the discovery process step 1020, a user's information apparatus 200 may (1) search for available output devices 220; (2) provide the user with a list of available output devices 220; and (3) provide means for the user to choose one or more output devices 220 to take the output job. An example of a discovery process 1020 is described below in greater detail with reference to FIG. 11. The optional discovery process 1020 may sometimes be unnecessary. For example, a user may skip the discovery process 1020 if he or she already knows the output device (e.g., printer) 220 to which the output is to be directed. In this case, the user may simply connect the information apparatus 200 to that output device 220 by wired connections or directly point to that output device 220 in a close proximity such as in the case of infrared connectivity. As another example, a user may pre-select or set the output device or devices 220 that are used frequently as preferred defaults. As a result, the discovery process 1020 may be partially or completely skipped if the default output device 220 or printer is found to be available. In stage 1030, the client application may interact with output device 220, the user, and/or other applications 205 residing in the same information apparatus 200 to (1) obtain necessary output device profile and/or user preferences, (2) perform functions or part of raster image processing operations such as rasterization, scaling and color correction, and/or (3) convert or encode at least partially the rasterized content (e.g. digital document) into an intermediate output data. The processing and generation of the intermediate output data may reflect in part a relationship to an output device profile and/or user preferences obtained, if any. The intermediate output data generated by the client application 210 is then transmitted through wired or wireless local communication link(s) 240 to the output controller 230 included or associated with the selected output device 220 or output system 250. An exemplary client application process is described in greater detail with reference to FIG. 12. In step 1040, the output controller 230 of present invention receives the intermediate output data. In the case where the selected output device 230 does not include a printer controller, the output controller 230 of present invention may further perform processing functions such as parsing, interpreting, decompressing, decoding, color correction, image enhancement, GCR, black generation and halftoning among others. In addition, the output controller 230 may further convert or conform the intermediate output data into a form or format suitable for the output engine (e.g. printer engine in the case of a printer). The generated output-engine output data from the output controller is therefore, in general, device dependent and acceptable for final output with the output engine (or the printer engine in case of a printer) included in the selected output device 220 or output system 250. In the case where the selected output device 220 is a printer, and when the printer includes or is connected to a printer controller, the output controller 230 may generate the proper language or input format required to interface with the printer controller (referred to as printer-controller print data). The printer controller may for example require a specific input such as a page description language (PDL), markup language, or a special image or graphics format. In these cases, the output controller 230 in step 1040 may interpret and decode the intermediate output data, and then convert the intermediate output data into the required printer-controller print data (e.g. PDL such as PostScript or PCL). The printer-controller print data generated by the output controller is then sent to the printer controller for further processing. The printer controller may perform interpretation and raster image processing operations among other operations. After processing, the printer controller generates a printer-engine print data suitable for rendering at the printer engine. In either case, the output controller 230 or printer controller generates an output-engine output data that is suitable for sending to or interfacing with the output engine or the printer engine included in the output device for rendering. The output data may be temporarily buffered in components of the output device 220. An implementation of the output device process 1040 is described in greater detail with reference to FIG. 13. The steps included in the universal pervasive output process 1002 may proceed automatically when a user requests output service. Alternatively, a user may be provided with options to proceed, cancel, or input information at each and every step. For example, a user may cancel the output service at any time by, for example, indicating a cancellation signal or command or by terminating the client application 210 or by shutting down the information apparatus 200 etc FIG. 11 is a flow diagram of an example of a discovery process 720, which may be an optional step to help a user locate one or more output devices 220 for an output job. The discovery process 1020 may, however, be skipped partially or entirely. Implementation of discovery process 1020 may require compatible hardware and software components residing in both the information apparatus 200 and the output device 220. The information apparatus 200 may utilize the client application 210 or other application 205 in this process. The discovery process 1020 may include: An information apparatus 200 communicating with available output devices 220 to obtain information and attributes relating to the output device 220 and or its services such as output device capability, feature sets, service availability, quality of service, condition. An Information apparatus 200 provides the user information on each available and or compatible output devices 220. A user selects or the client application 210 (automatically or not) selects one or more output devices 220 for the output service from the available or compatible output devices 220. Various protocols and or standards may be used during discovery process 1020. Wireless communication protocols are preferred. Wired communication, on the other hand, may also be implemented. Examples of applicable protocols or standards may include, without limitation, Bluetooth, HAVi, Jini, Salutation, Service Location Protocol, and Universal Plug-and-play among others. Both standard and proprietary protocols or combination may be implemented in the discovery process 1020. However, these different protocols, standards, or combination shall not depart from the spirit and scope of present invention. In one implementation an application (referred here for simplicity of discussion as a “communication manager,” not shown) residing in the information apparatus 200 helps communicate with output device 220 and manages service requests and the discovery process 1020. The communication manager may be a part of or a feature of the client application 210. Alternatively or in combination, the communication manager may also be a separate application. When the communication manager is a separate application, the client application 210 may have the ability to communicate, manage or access functionalities of the communication manager. The discovery process 1020 may be initiated manually by a user or automatically by a communication manager when the user requests an output service with information apparatus 200. In the optional step 1100, a user may specify searching or matching criteria. For example, a user may indicate to search for color printers and or printers that provide free service. The user may manually specify such criteria each time for the discovery process 1020. Alternatively or in combination, a user may set default preferences that can be applied to a plurality of discovery processes 1020. Sometimes, however, no searching criteria are required: the information apparatus 200 may simply search for all available output devices 220 that can provide output service. In step 1101, information apparatus 200 searches for available output devices 220. The searching process may be implemented by, for example, an information apparatus 200 (e.g. with the assistance of a communication manager) multi-casting or broadcasting or advertising its service requests and waiting for available output devices 220 to respond. Alternatively or in combination, an information apparatus 200 may “listen to” service broadcasts from one or more output devices 220 and then identify the one or more output devices 220 that are needed or acceptable. It is also possible that multiple output devices 220 of the same network (e.g., LAN) register their services with a control point (not shown). A control point is a computing system (e.g., a server) that maintains records on all service devices within the same network. An information apparatus 200 may contact the control point and search or query for the needed service In step 1102, if no available output device 220 is found, the communication manager or the client application 210 may provide the user with alternatives 1104. Such alternatives may include, for example, aborting the discovery process 1020, trying discovery process 1020 again, temporarily halting the discovery process 1020, or being notified when an available output device 220 is found. As an example, the discovery process 1020 may not detect any available output device 220 in the current wired/wireless network. The specified searching criteria (if any) are then saved or registered in the communication manager. When the user enters a new network having available output devices 220, or when new compatible output devices 220 are added to the current network, or when an output device 220 becomes available for any reason, the communication manager may notify the user of such availability. In step 1106, if available output devices 220 are discovered, the communication manager may obtain some basic information, or part of or the entire output device profile, from each discovered output device 220. Examples of such information may include, but not limited to, device identity, service charge, subscription, service feature, device capability, operating instructions, etc. Such information is preferably provided to the user through the user interface (e.g., display screen, speaker, etc.) of information apparatus 200. In step 1108, the user may select one or more output devices 220 based on information provided, if any, to take the output job. If the user is not satisfied with any of the available output device 220, the user may decline the service. In this case, the user may be provided with alternatives such as to try again in step 1110 with some changes made to the searching criteria. The user may choose to terminate the service request at any time. In step 1112, with one or more output devices 220 selected or determined, the communication link between information apparatus 200 and the selected output device or devices 220 may be “locked”. Other output devices 220 that are not selected may be dropped. The output process 1020 may then proceed to the client application process of step 1030 of FIG. 10. FIG. 12A is a flow diagram of an exemplary client application process with reference to step 1030 of FIG. 10. A client application process 1202 for universal output may include or utilize: A client application 210 that obtains content (e.g. digital document) intended for output. A client application 210 that obtains output device parameters (e.g. rasterization parameters, output job parameters). One example of implementation is to obtain the output device parameters from an output device profile (e.g. printer profile), which includes device dependent parameters. Such profile may be stored in an output controller 230, output device 220 or information apparatus 200. A client application 210 that may optionally obtain user preferences through (1) user's input (automatic or manual) or selections or (2) based on preset preference or pre-defined defaults or (3) combination of the above. A client application 210 that rasterizes at least part of the content intended for output (e.g. a digital document) according to one or more rasterization parameters obtained from previous steps such as through output device profile, user selection, predefined user preferences, predefined default or standard etc. A client application 210 that generates an intermediate output data containing at least part of the rasterized image related at least partly to the content intended for output. A client application that transmits the intermediate output data to an output device 220 or output controller 230 for further processing and or final output. A client application 210 may obtain content (e.g. digital document) 900 or a pointer or reference to the content in many ways. In a preferred embodiment, the client application 210 is in the form of a device driver or an independent application, and the content or its reference can be obtained by the client application 210 from other applications 205 in the same information apparatus 200. To illustrate an example, a user may first view or download or create a digital document by using a document browsing, viewing and or editing application 205 in his/her information apparatus 200, and then request output service by launching the client application 210 as a device driver or helper application. The client application 210 communicates with the document browsing or editing application to obtain the digital document or reference to the digital document. As another example, the client application 210 is an independent application and it launches another application to help locate and obtain the digital document for output. In this case, a user may first launch the client application 210, and then invoke another application 205(e.g. document editing and or browsing application) residing in the same information apparatus 200 to view or download a digital document. The client application 210 then communicates with the document browsing or editing application to obtain the digital document for output. In another embodiment, the client application 210 itself provides multiple functionalities or feature sets including the ability for a user to select the content (e.g. digital document) for output. For example, the client application 210 of present invention may provide a GUI where a user can directly input or select the reference or path of a digital document that the user wants to output. In order to perform rasterization operation on content (e.g. digital document) 900, the client application 210 in step 1210 needs to obtain device dependent parameters of an output device 220 such as the rasterization parameters. Device dependent parameters may be included in an output device profile. A client application 210 may obtain an output device profile or rasterization parameters in various ways. As an example, an output device profile or rasterization parameters can be obtained with one or combination of the following: The client application communicates with an output device 220 to upload output device profile or information related to one or more rasterization parameters. The client application 210 obtains the output device profile from a network node (e.g. server). A user selects an output device profile stored in the user's information apparatus 200. The client application 210 automatically retrieves or uses a default profile, predefined standard values or default values among others. The client application 210 obtains output device parameters by calculating, which may include approximation, based at least partly on the information it has obtained from one or combination of an output device 220, a user, default values, and a network node. It is important to note that step 1210 is an optional step. In some instance, part of or the entire output device profile or related device dependent information may have been already obtained by the client application 210 during the prior optional discovery process (step 1020 in FIG. 10). In this case, step 1210 may be partially or entirely skipped. In one implementation, the client application 210 communicates with one or more output devices 220 to upload output device profiles stored in the memory or storage components of those one or more output devices 220 or their associated one or more output controllers 230. In some instance, the uploaded output device profile may contain partially or entirely references or pointers to device parameters instead of the device parameters themselves. The actual output device parameters may be stored in a network node or in the information apparatus 200, where they can be retrieved by the client application 210 or by other applications 205 using the references or pointers. It should be noted that a plurality of information apparatuses 200 may request to obtain output device profile or profiles from the same output device 220 at the same time or at least during overlapping periods. The output device 220 or its associated output controller 230 may have components or systems to manage multiple communication links and provide the output device profile or profiles concurrently or in an alternating manner to multiple information apparatuses 200. Alternatively, an output device 220 may provide components or systems to queue the requests from different information apparatuses 200 and serve them in a sequential fashion according to a scheme such as first come first served, quality of service, etc. Multi-user communication and service management capability with or without queuing or spooling functions may be implemented by, for example, the output controller 230 as optional feature sets. In another implementation, one or more output device profiles may be stored locally in the information apparatus 200. The client application 210 may provide a GUI where a user can select a profile from a list of pre-stored profiles. As an example, the GUI may provide the user with a list of output device names (e.g. makes and models), each corresponding to an output device profile stored locally. When the user selects an output device 220, the client application 210 can then retrieve the output device profile corresponding to the name selected by the user. In certain cases, during a discovery or communication process described earlier, the client application 210 may have already obtained the output device ID, name, or reference or other information in a variety of ways described previously. In this case, the client application 210 may automatically activate or retrieve an output device profile stored in the information apparatus 200 based on the output device ID, name, or reference obtained without user intervention. In yet another implementation, the client application 210 may use a set of pre-defined default values stored locally in a user's information apparatus 200. Such defaults can be stored in one or more files or tables. The client application 210 may access a file or table to obtain these default values. The client application 210 may also create or calculate certain default values based on the information it has obtained during previous steps (e.g. in optional discovery process, based on partial or incomplete printer profile information obtained, etc). A user may or may not have an opportunity to change or overwrite some or all defaults. Finally, if, for any reason, no device dependent information is available, the client application 210 may use standard output and rasterization parameters or pre-defined default parameters. The above illustrates many examples and variations of implementation, these and other possible variations in implementation do not depart from the scope of the present invention. In step 1220, the client application 210 may optionally obtain user preferences. In one exemplary implementation, the client application 210 may obtain user preferences with a GUI (graphical user interface). For simplicity, a standard GUI form can be presented to the user independent of the make and model of the output device 220 involved in the output process. Through such an interface, the user may specify some device independent output parameters such as page range, number of cards per page, number of copies, etc. Alternatively or in combination, the client application 210 may also incorporate output device-dependent features and preferences into the GUI presented to the user. The device-dependent portion of the GUI may be supported partly or entirely by information contained in the output device profile obtained through components and processes described in previous steps. To illustrate, device dependent features and capabilities may include print quality, color or grayscale, duplex or single sided, output page size among others. It is preferred that some or all components, attributes or fields of user preferences have default values. Part or all default values may be hard-coded in software program in client application 210 or in hardware components. Alternatively, the client application 210 may also access a file to obtain default values, or it may calculate certain default values based on the information it has obtained during previous steps or components (e.g. from an output device profile). A user may or may not have the ability to pre-configure, or change or overwrite some or all defaults. The client application 210 may obtain and use some or all defaults with or without user intervention or knowledge. In step 1230, the client application 210 of present invention performs rasterization operation to conform a content (e.g. a digital document), which may includes objects and information in vector graphics, text, and images, into one or more output images in accordance with the rasterization parameters obtained in previous steps. During rasterization process, text and vector graphics object or information in the content is rasterized or converted into image or bitmap form according to the given set of rasterization parameters. Image information in the content may require scaling and interpolation operations to conform the rasterization parameters. Rasterization process may further include operations such as scaling, interpolation, segmentation, image transformation, image encoding, color space transformation etc. to fit or conform the one or more output images to the given set of rasterization parameters such as target output size, resolution, bit depth, color space and image format etc. In step 1240, the client application 210 generates an intermediate output data that includes the rasterized one or more output images. The intermediate output data of the present invention may contain image information, instructions, descriptions, and data such as color profile among others. Creating and generating intermediate output data may further include operations such as compression, encoding, encryption, smoothing, segmentation, scaling and or color correction, among others. The image or images contained in an intermediate output data may be variously encoded and/or implemented with different image formats and/or compression methods (e.g. JPEG, BMP, TIFF, JBIG etc or combination). One preferred implementation is to generate or encode the output image in the intermediate output data with mixed raster content (MRC) description. The use of MRC in the data output process of present invention provides opportunities to improve the compression ratio by applying different compression techniques to segmented elements in the content. In addition, MRC provides opportunities to maintain more original content information during the encoding process of the output image and, therefore, potentially improve output quality. In step 1250, the client application 210 transmits intermediate output data to an output device 220 through local communication link 240. The communication link may be implemented with wired or wireless technologies and the transmission may include one or multiple sessions. It should be recognized that FIG. 12A illustrates one example of a client application process 1030 in the data output method 1002 of present invention. Other implementations with more or less steps are possible, and several additional optional processes not shown in FIG. 12 may also be included in the client application process 1030. Use of these different variations, however, does not result in a departure from the scope of the present invention. As an example, an optional authentication step may be included when the selected output device 220 provides service to a restricted group of users. Various authentication procedures may be added in step 1210 when client application 210 obtains output device profile by communicating with an output device or an output controller. As another example, authentication procedures may also be implemented in step 1250 when the client application transmits intermediate output data to one or more output devices 220 or output controllers 230. A simple authentication may be implemented by, for example, comparing the identity of an information apparatus 200 with an approved control list of identities stored in the output device 220 or output controller 230. Other more complex authentication and encryption schemes may also be used. Information such as user name, password, ID number, signatures, security keys (physical or digital), biometrics, fingerprints, voice among others, may be used separately or in combination as authentication means. Such identification and or authentication information may be manually provided by user or automatically detected by the selected output device or devices 220 or output controller 230. With successful authentication, a user may gain access to all or part of the services provided by the output device 220. The output device profile that the client application 210 obtains may vary according to the type or quality of service requested or determined. If authentication fails, it is possible that a user may be denied partially or completely access to the service. In this case, the user may be provided with alternatives such as selecting another output device 220 or alternative services. Another optional process is that a user may be asked to provide payment or deposit or escrow before, during or after output service such as step 1210 or 1250 with reference to FIG. 12. Examples of payment or deposit may include cash, credit card, bankcard, charge card, smart card, electronic cash, among others. The output controller 220 may provide payment calculation or transaction processing as optional feature sets of present invention. FIG. 12B illustrates another exemplary client application output process 1030 with which an information apparatus 200 can pervasively and universally output content to one or more output devices 220 associated with or equipped with an output controller 230 of present invention. The process illustrated in FIG. 12B is similar to the process described in FIG. 12A except that step 1210, obtaining output device profile, is skipped. In this embodiment, the client application 210 utilizes a set of hard-coded, standard or predefined output device parameters including rasterization parameters with which the client application 210 can perform rasterization operation and other required image processing functions. Users may be provided with the option of changing these parameters or inputting alternative parameters. Rasterization parameters include output size, output resolution, bit depth, color space, color channels, scale factors etc. These pre-defined parameters typically comply with a specification or a standard. The same specification and standard may also defined or describe at least partly the intermediate output data. Predefined standard parameters can be stored in a file or profile in an information apparatus 200, an output controller 230, and/or in an output device 220 for easy update or upgrade. In client output process 1204, since the rasterization parameters are predefined, the client application 210 may not need to upload printer profiles from the selected output device 230. Consequently, no two-way communication between the information apparatus 200 and the output device or devices 220 is necessary in this process 1204 when compared with process 1202 illustrated in FIG. 12A. The client application 210 performs rasterization operation 1225 based on standard and/or predefined parameters and generates a rasterized output image with predefined or standard properties of those rasterization parameters. The resulting intermediate output data, which includes at least one rasterized output image, is transmitted from the information apparatus 200 to an output device 220 in step 1250 or to its associated output controller 230 for rendering or output. The intermediate output data generated in process 1202 in general is less device dependent compared to the intermediate output data generated in the process 1202 shown in FIG. 12A. The output controller 230 included or associated with the output device 220 may be preprogrammed to interpret the raster output image, which includes properties or attributes that correspond to those standard or predefined parameters. The standard or predefined rasterization parameters may be hard coded or programmed into the client application 210 and/or the output controller 230. However, instead of hard coding those parameters, one technique to facilitate updates or changes is to store those standard parameters in a default file or profile. The standard or predefined parameters contained in the file or profile can be retrieved and utilized by applications in an information apparatus 200 (e.g. client application 210) and/or by applications or components in an output device 220 or the output controller 230. In this way, any necessary updates, upgrades or required changes to those predefined or standard parameters can be easily accomplished by replacing or modifying the file or profile instead of modifying or updating the program, application or components in the information apparatus 200, output device 220 and/or output controller 230. A client application process 1204 providing universal output capability to information apparatus 200 may include or utilize: A client application 210 that obtains content (e.g. digital document) intended for output. A client application 210 that optionally obtains user preferences (in step 1220) through (1) user's input (automatic or manual) or selections or (2) based on preset preference or predefined defaults or (3) combination of the above. A client application 210 that rasterizes content (in step 1230 or 1225) according to pre-defined or standard rasterization parameters. A client application 210 that generates intermediate output data (in step 1240) for rendering or output at an output device 220; the intermediate output data containing at least partially a rasterized image related to the content intended for output. A client application 210 that transmits the intermediate output data to an output device 220 (in step 1250) for further processing and final output. One advantage of the client output process 1204 of FIG. 12B compared to the process 1202 illustrated in FIG. 12A is that the generated intermediate output data is in general less device dependent. The device independent attribute allows the intermediate output data to be more portable and acceptable to more output devices equipped or associated with output controllers. Both data output processes (1202 and 1204) enable universal output; allowing a user to install a single client application 210 or components in an information apparatus 200 to provide output capability to more than one output device 220. FIG. 13A illustrates one example of an output device process 1302 and its associated raster imaging method of present invention. In this output device process 1302, an output device 220 is capable of receiving an intermediate output data from an information apparatus 200. The output device process 1302 and its operations may include or utilize: An output device/system or output controller that receives intermediate output data (in step 1300). The intermediate output data includes at least partially a raster output image describing at least part of the content for rendering at the output device 220 or system 250. An output device/system or output controller that interprets (in step 1310) the intermediate output data; in one preferred embodiment, the intermediate output data includes an output image utilizing one or more MRC formats or components. An output device/system or output controller that performs image processing operation (in step 1320) on the raster image. The image processing operation may include but not limited to image decompression, scaling, halftoning, color matching, among others. An output device/system or output controller that converts and or generates (in step 1330) output-engine output data that is in a format or description suitable for input to an output engine (e.g. printer engine in case of a printer) included in an output device 220. An output engine in an output device 220 that renders or generates a final output (e.g. the output-engine output data) in step 1370. The output device 220 or output system 250 may include an output controller 230 internally or externally to assist the management and operation of the output process 1302. As shown in FIG. 7, there are many possible configurations and implementations of an output controller 230 associated to an output device 220 Herein and after, output controller 230 is regarded as an integral part of the output device to which it is attached. Hence, the following described output device operations may be partially or completely performed by the output controller associated with it. In step 1300, output device process 1302 is initiated by client application 210 transmitting an intermediate output data to output device 220 or output system 250. In step 1310, the output device 220 reads and interprets the intermediate output data, containing at least one raster output image relating to the content intended for output. During the reading and interpretation process 1310, the output device 220 may include components that parse the intermediate output data and perform operations such as decompression, decoding, and decryption among others. The output image may be variously encoded and may include one or more compression methods. In the event that the method of image encoding includes MRC format, then, in one example implementation, during decoding and mapping of the output image in step 1310, the lower resolution layer and information in an image that includes MRC may be mapped, scaled or interpolated to a higher-resolution output image to produce a better image quality. Therefore, step 1310, in the event that the intermediate output data includes MRC component, each layer in an MRC image can be decompressed, processed, mapped and combined into a single combined output image layer. Step 1310 may also include scaling, color space transformation, and/or interpolation among others. In addition to the possibility of mapping methods using different scaling and interpolation ratio with different layers, another advantage of using MRC is that segmentation information contained in MRC can be utilized to apply different image processing and enhancement techniques to data in different layers of an MRC image in step 1320. In step 1320, the output device 220 may further perform image processing operations on the decoded output image. These image processing operations may include, for example, color correction, color matching, image segmentation, image enhancement, anti-aliasing, image smoothing, digital watermarking, scaling, interpolation, and halftoning among others. The image processing operations 1320 may be combined or operated concurrently with step 1310. For example, while each row, pixel, or portion of the image is being decoded and or decompressed, image processing operations 1320 is applied. In another implementation, the image processing 1320 may occur after the entire output image or a large portion of the image has been decoded or decompressed. If the intermediate output data includes MRC component, then in step 1320, there are additional opportunities to improve image quality. An image encoded in MRC contains segmented information that a traditional single layer image format does not usually have. As an example, foreground can be in one layer, and background in another. As another example, chrominance information may be in one layer and luminance may be in another. This segmented information in MRC may be used to apply different or selective image processing methods and algorithms to different layers or segments to enhance image quality or retain or recover image information. Different image processing techniques or algorithms may include color matching, color correction, black generation, halftoning, scaling, interpolation, anti-aliasing, smoothing, digital watermarking etc. For example, one can apply calorimetric color matching to foreground information and perceptual color matching to background information or vice versa. As another example, error diffusion halftoning can be applied to foreground and stochastic halftoning can be applied to background or vice versa. As yet another example, bi-cubic interpolation can be applied to a layer and bi-linear or minimum distance interpolation can be applied to a different layer. In step 1330, the output device 220 or the output controller 230 may convert the processed image (e.g. halftoned) into a form acceptable to the output engine of output device 220. This conversion step is optional, depending on the type, format and input requirement of a particular output device engine (e.g. printer engine in case of a printer). Different output engines may have different input raster image input requirements. As an example different output engines may require different input image formats, number of bits or bytes per pixel, compression or uncompressed form, or different color spaces (e.g. such as RGB, CMY, CMYK, or any combination of Hi-Fi color such as green, orange, purple, red etc). Incoming raster image data can be encoded in a row, in a column, in multiple rows, in multiple columns, in a chunk, in a segment, or a combination at a time for sending the raster data to the output engine. In some cases, step 1330 may be skipped if the result of step 1320 is already in a form acceptable to the output device engine. In other cases, however, further conversion and or processing may be required to satisfy the specific input requirement of a particular output device engine. It is important to note that the above described processing from step 1310 to step 1330 may require one or more memory buffers to temporarily store processed results. The memory buffer can store or hold a row, a column, a portion, or a chunk, of the output image in any of the steps described above. Storing and retrieving information into and from the memory buffer may be done sequentially, in an alternating fashion, or in an interlaced or interleaved fashion among other possible combinations. Step 1310 to step 1330 operations can be partially or completely implemented with the output controller 230. In step 1370, the output device engine included in the output device 220 or output system 250 receives the output-engine output data generated in step 1330 or step 1320. The output-engine output data is in a form that satisfies the input requirements and attributes of the output engine, such as color space, color channel, bit depth, output size, resolution, etc. The output engine then takes this output-engine output data and outputs or renders the data content through its marking engine or display engine. One advantage of data output method 1002 that includes output device process 1302 is that it has less processing requirements on an information apparatus 200 compared to conventional process with reference to FIG. 1A, and therefore, enables more information apparatus 200 with relatively lower processing power and memory space to have output capability. For example, some image processing functions, such as halftoning (e.g. error diffusion) may require substantial processing and computing power. In data output process 1002 that includes output device process 1302, halftoning is performed in step 1320 by an output device component (e.g. the output controller 230) included in the output device 220 or the output system 250, not in the information apparatus 200; therefore reducing the computational requirements for the information apparatus 200. Another advantage of data output 1302 is that the intermediate output data is less device dependent than the output data generated by conventional output method 102 with reference to FIG. 1A. The device independence provides opportunity to allow a single driver or application in an information apparatus 200 to output intermediate output data to a plurality of output devices 220 that include output controllers 230. Some output devices 220 may contain a printer controller 410. An example of this type of output device or printer is a PostScript printer or PCL printer among others. FIG. 13B illustrates an example of an output device process 1304 with a printer that includes a printer controller 410. As discussed in FIG. 1, a printer with a printer controller requires input such as page description language (e.g. PostScript, PCL etc.), markup language (HTML, XML etc), special image format, special graphics format, or a combination, depending on the type of the printer controller. There are many printing system configurations for providing the data output capability and process to a printer or a printing system that includes a printer controller. In one example, the existing printer controller in the output device 220 may incorporate the feature sets provided by the output controller to form a “combined controller” as described previously with reference to FIGS. 7C and 7F. In another example, the output controller 230 of present invention may be connected sequentially or cascaded to an existing printer controller; the output controller 230 can be internally installed (with reference to FIG. 7B) or externally connected (with reference to FIG. 7A) to the output device 220. For output device 220 that includes a printer controller, the output controller 230 may simply decode the intermediate output data in step 1310 and then convert it into a form acceptable for input to the printer controller in step 1350. An output device process 1304 and operations for an output device 220 or system 250 that includes a printer controller 410 may include or utilize: An output controller 230 or components in an output device 220 or system 250 that receives an intermediate print data or output data (with reference to step 1300), the intermediate print data includes at least a raster image related at least in part to the content for rendering at the output device 220. An output controller 230 or components in an output device 220 or system 250 that interprets the intermediate output data (with reference to step 1310); in one preferred embodiment, the intermediate output data includes an output image utilizing one or more MRC format or components. An output controller 230 or components in an output device 220 or system 250 that converts the intermediate output data into a printer-controller print data (with reference to step 1350); the printer-controller print data includes a format or language (e.g. PDL, PDF, HTML, XML etc.) that is acceptable or compatible to the input requirement of a printer controller. A printer controller or components in an output device 220 or system 250 that receives a printer controller print data; the printer controller may parse, interpret and further process (e.g. rasterization, scaling, image enhancement, color correction, color matching, halftoning etc.) and convert the printer-controller print data into a printer-engine print data (with reference to step 1360); the printer-engine print data comprising of a format or description acceptable for input to a printer engine in the output device 220 or the output system 250. A printer engine or components in an output device 220 or system 250 that renders or generates a final output (with reference to step 1370) with the input printer engine print data. In output device process 1304, step 1300 (receiving intermediate output data) and step 1310 (interpret intermediate output data) are identical to step 1300 and step 1310 in output device process 1302, which have been described in previous sections with reference to FIG. 13A. In step 1350, the output controller 230 converts the intermediate print data into a printer-controller print data that is in a form compatible or acceptable for input to a printer controller. For example, a printer controller may require as input a specific page description language (PDL) such as PostScript. The output controller 230 then creates a PostScript file and embeds the output image generated or retrieved in step 1310 into the PostScript file. The output controller 230 can also create and embed the output image from step 1310 into other printer controller print data formats, instructions or languages. In step 1360, the printer controller receives printer-controller print data generated in step 1350 that includes an acceptable input language or format to the printer controller. The printer controller may parse, interpret, and decode the input printer-controller print data. The printer controller may further perform raster image processing operations such as rasterization, color correction, black generation, GCR, anti-aliasing, scaling, image enhancement, and halftoning among others on the output image. The printer controller may then generate a printer-engine print data that is suitable for input to the printer engine. The type and or format of printer-engine print data may vary according to the requirement of a particular printer engine. It is important to note that the above described process from step 1310 to step 1360 may require one or more memory buffer to temporarily store processed results. The memory buffer can store or hold a row, a column, a portion, or a chunk, of the output image in any of the steps described above. Storing and retrieving information into and from the memory buffer may be done sequentially, alternated, or in an interlaced or interleaved fashion among other possible combinations. Process and operations of step 1310 to step 1360 can be implemented with output controller 230. In step 1370, the printer engine included in the output device 220 or output system 250 generates or renders the final output based on the printer-engine print data generated in step 1360. For example, the printer-engine print data may be in CMY, CMYK, and RGB etc, and this may be in one or more bits per pixel format, satisfying the size and resolution requirement of the printer engine. The printer engine included the output device 220 may take this print data and generate or render an output page through its marking engine. Having described and illustrated the principles of our invention with reference to an illustrated embodiment, it will be recognized that the illustrated embodiment can be modified in arrangement and detail without departing from such principles. In view of the many possible embodiments to which the principles of our invention may be applied, it should be recognized that the detailed embodiments are illustrative only and should not be taken as limiting the scope of our invention. Rather, I claim as my invention all such embodiments as may come within the scope of the following claims and equivalents thereto. Unless the context indicates otherwise, a reference in a claim to the number of instances of an element, be it a reference to one instance or more than one instance, requires at least the stated number of instances of the element but is not intended to exclude from the scope of the claim a structure or method having more instances of that element than stated. Specifically, but without limitation, a reference in a claim to an or one output device or system, to an or one image, or to a or one rasterization parameter is not intended to exclude from the scope of the claim a structure or method having, including, employing or supplying two or more output devices or system, images or rasterization parameters.
<SOH> BACKGROUND OF THE DISCLOSURE <EOH>The present invention relates to universal data output and, in particular, to providing a new data output method and a new raster image process for information apparatuses and output devices. As described herein, information apparatuses refer generally to computing devices, which include both stationary computers and mobile computing devices (pervasive devices). Examples of such information apparatuses include, without limitation, desktop computers, laptop computers, networked computers, palmtop computers (hand-held computers), personal digital assistants (PDAs), Internet enabled mobile phones, smart phones, pagers, digital capturing devices (e.g., digital cameras and video cameras), Internet appliances, e-books, information pads, and digital or web pads. Output devices may include, without limitation, fax machines, printers, copiers, image and/or video display devices (e.g., televisions, monitors and projectors), and audio output devices. For simplicity and convenience, hereafter, the following descriptions may refer to an output device as a printer and an output process as printing. However, it should be understood that the term printer and printing used in the discussion of present invention refer to one embodiment used as a specific example to simplify the description of the invention. The references to printer and printing used here are intended to be applied or extended to the larger scope and definition of output devices and should not be construed as restricting the scope and practice of present invention. Fueled by an ever-increasing bandwidth, processing power, wireless mobile devices, and wireless software applications, millions of users are or will be creating, downloading, and transmitting content and information using their pervasive or mobile computing devices. As a result, there is a need to allow users to conveniently output content and information from their pervasive computing devices to any output device. As an example, people need to directly and conveniently output from their pervasive information apparatus, without depending on synchronizing with a stationary computer (e.g., desktop personal computer) for printing. To illustrate, a mobile worker at an airport receiving e-mail in his hand-held computer may want to walk up to a nearby printer or fax machine to have his e-mail printed. In addition, the mobile worker may also want to print a copy of his to-do list, appointment book, business card, and his flight schedule from his mobile device. As another example, a user visiting an e-commerce site using his mobile device may want to print out transaction confirmation. In still another example, a user who takes a picture with a digital camera may want to easily print it out to a nearby printer. In any of the above cases, the mobile user may want to simply walk up to a printer and conveniently print a file (word processing document, PDF, HTML etc.) that is stored on the mobile device or downloaded from a network (e.g., Internet, corporate network). Conventionally, an output device (e.g., a printer) is connected to an information apparatus via a wired connection such as a cable line. A wireless connection is also possible by using, for example, radio communication or infrared communication. Regardless of wired or wireless connection, a user must first install in the information apparatus an output device driver (e.g., printer driver in the case the output device is a printer) corresponding to a particular output device model and make. Using a device-dependent or specific driver, the information apparatus may process output content or digital document into a specific output device's input requirements (e.g., printer input requirements). The output device's input requirements correspond to the type of input that the output device (e.g., a printer) understands. For example, a printer's input requirement may include printer specific input format (e.g., one or more of an image, graphics or text format or language). Therefore, an output data (or print data in the case the output device is a printer) herein refers to data that is acceptable for input to an associated output device. Examples of input requirements may include, without limitation, audio format, video format, file format, data format, encoding, language (e.g., page description language, markup language etc), instructions, protocols or data that can be understood or used by a particular output device make and model. Input requirements may be based on proprietary or published standards or a combination of the two. An output device's input requirements are, therefore, in general, device dependent. Different output device models may have their own input requirements specified, designed or adopted by the output device manufacturer (e.g., the printer manufacturer) according to a specification for optimal operation. Consequently, different output devices usually require use of specific output device drivers (e.g., printer drivers) for accurate output (e.g., printing). Sometimes, instead of using a device driver (e.g., printer driver), the device driving feature may be included as part of an application software. Installation of a device driver (e.g., printer driver) or application may be accomplished by, for example, manual installation using a CD or floppy disk supplied by the printer manufacturer. Or alternatively, a user may be able to download a particular driver or application from a network. For a home or office user, this installation process may take anywhere from several minutes to several hours depending on the type of driver and user's sophistication level with computing devices and networks. Even with plug-and-play driver installation, the user is still required to execute a multi-step process for each printer or output device. This installation and configuration process adds a degree of complexity and work to end-users who may otherwise spend their time doing other productive or enjoyable work. Moreover, many unsophisticated users may be discouraged from adding new peripherals (e.g., printers, scanners, etc.) to their home computers or networks to avoid the inconvenience of installation and configuration. It is therefore desirable that an information apparatus can output to more than one output device without the inconvenience of installing multiple dedicated device dependent drivers. In addition, conventional output or printing methods may pose significantly higher challenges and difficulties for mobile device users than for home and office users. The requirement for pre-installation of a device-dependent driver diminishes the benefit and concept of mobile (pervasive) computing and output. For example, a mobile user may want to print or output e-mail, PowerPoint® presentation documents, web pages, or other documents at an airport, gas station, convenience store, kiosk, hotel, conference room, office, home, etc. It is highly unlikely that the user would find at any of these locations a printer of the same make and model as is at the user's base station. As a consequence, under the conventional printing method, the user would have to install and configure a printer driver each time at each such remote location before printing. It is usually not a viable option given the hundreds, or even thousands of printer models in use, and the limited storage, memory space, and processing power of the information apparatus. Moreover, the user may not want to be bothered with looking for a driver or downloading it and installing it just to print out or display one page of email at the airport. This is certainly an undesirable and discouraging process to promote pervasive or mobile computing. Therefore, a more convenient printing method is needed in support of the pervasive computing paradigm where a user can simply walk up to an output device (e.g., printer or display device) and easily output a digital document without having to install or pre-install a particular output device driver (e.g., printer driver). Another challenge for mobile users is that many mobile information apparatuses have limited memory space, processing capacity and power. These limitations are more apparent for small and low-cost mobile devices including, for example, PDAs, mobile phones, screen phones, pagers, e-books, Internet Pads, Internet appliances etc. Limited memory space poses difficulties in installing and running large or complex printer or device drivers, not to mention multiple drivers for a variety of printers and output devices. Slow processing speed and limited power supply create difficulties driving an output device. For example, processing or converting a digital document into output data by a small mobile information apparatus may be so slow that it is not suitable for productive output. Intensive processing may also drain or consume power or battery resources. Therefore, a method is needed so that a small mobile device, with limited processing capabilities, can still reasonably output content to various output devices. To output or render content (e.g. digital document) to an output device, a raster image processing (RIP) operation on the content is usually required. RIP operation can be computationally intensive and may include (1) a rasterization operation, (2) a color space conversion, and (3) a halftoning operation. RIP may also include other operations such as scaling, segmentation, color matching, color correction, GCR (Grey component replacement), Black generation, image enhancement compression/decompression, encoding/decoding, encryption/decryption GCR, image enhancement among others. Rasterization operation in RIP involves converting objects and descriptions (e.g. graphics, text etc) included in the content into an image form suitable for output. Rasterization may include additional operations such as scaling and interpolation operations for matching a specific output size and resolution. Color space conversion in RIP includes converting an input color space description into a suitable color space required for rendering at an output device (e.g. RGB to CMYK conversion). Digital halftoning is an imaging technique for rendering continuous tone images using fewer luminance and chrominance levels. Halftoning operations such as error diffusion can be computationally intensive and are included when the output device's bit depth (e.g. bits per pixel) is smaller than the input raster image bit depth. Conventionally, RIP operations are included either in an information apparatus, or as part of an output device or output system (e.g. in a printer controller). FIG. 1A illustrates a flow diagram of a conventional data output method 102 in which RIP 110 is implemented in the information apparatus. Output devices that do not include a printer controller to perform complex RIP operations, such as a lower-cost, lower speed inkjet printer, normally employ data output method 102 . In data output method 102 , an information apparatus obtains content (e.g. a digital document) in step 100 for rendering or output at an output device. The information apparatus may includes an application (e.g. device driver), which implements RIP operation 110 . The information apparatus generates an output data in step 120 and transmits the output data to the output device in step 130 for rendering. The output data relating to the content is in an acceptable form (e.g. in an appropriate output size and resolution) to the output engine (e.g. display engine, printer engine etc.) included in the output device. The output data in a conventional output method 102 is usually device dependent. One drawback for the data output method 102 of FIG. 1A is that the information apparatus performs most if not the entire raster image processing operations 110 required for output. The RIP operations may require intensive computation. Many information apparatus such as mobile information device might have insufficient computing power and/or memory to carry out at an acceptable speed the RIP operations 110 required in an output process. Another drawback for the conventional data output method 102 of FIG. 1A is that the generated output data is device dependent and therefore is typically not very portable to other output devices. As a result, the information apparatus may need to install multiple applications or device drivers for multiple output devices, which may further complicate its feasibility for use in information apparatuses with limited memory, storage and processing power. FIG. 1B illustrates a flow diagram of another conventional data output method 104 in which the RIP is implemented in an output device. An example of an output device that implements process 104 is a high-speed laser printer which includes a printer controller for performing RIP operations and an output engine (e.g. printer engine) for rendering content. Printer controller may be internally installed or externally connected to an output device (printer in this example). In data output method 104 , an information apparatus obtains content for output in step 100 and generates in step 160 an output data or print data for transmitting to the output device in step 170 . Print data includes information related to the content and is usually encoded in a page description language (PDL) such as PostScript and PCL etc. In step 180 , the printer receives the output data or print data (in a PDL). In step 190 , a printer controller included in the printer interprets the PDL, performs RIP operations, and generates a printer-engine print data that is in a form acceptable to the printer engine (e.g. a raster image in an appropriate output size, bit depth, color space and resolution). In step 150 the printer engine renders the content with the printer-engine print data. It will be understood that a reference to print data or output data including a language, such as PDL, should be interpreted as meaning that the print data or output data is encoded using that language. Correspondingly, a reference to a data output process generating a language, such as PDL, should be interpreted as meaning that the data output process encodes data using that language. There are many drawbacks in the conventional data output method 104 shown in FIG. 1B . These drawbacks are especially apparent for mobile computing devices with limited processing power and memory. One such drawback is that the output data or print data, which include a page description language (PDL) such as PostScript or PCL, can be very complex. Generating complex PDL may increase memory and processing requirements for an information apparatus. Furthermore, interpreting, decoding and then raster image processing complex PDL can increase computation, decrease printing speed, and increase the cost of the output device or its printer controller. Another drawback is that the output data that includes PDL can creates a very large file size that would increase memory and storage requirements for the information apparatus, the output device and/or the printer controller etc. Large file size may also increase the bandwidth required in the communication link between the information apparatus and the output device. Finally, to rasterize text in an output device, a printer controller may need to include multiple fonts. When a special font or international characters is not included or missing in the printer controller, the rendering or output can potentially become inaccurate or inconsistent.
<SOH> SUMMARY OF THE INVENTION <EOH>Accordingly, this invention provides a convenient universal data output method in which an information apparatus and an output device or system share the raster image processing operations. Moreover, the new data output method eliminates the need to install a plurality of device-dependent dedicated drivers or applications in the information apparatus in order to output to a plurality of output devices. In accordance with present invention, an electronic system and method of pervasive and universal output allow an information apparatus to output content conveniently to virtually any output device. The information apparatus may be equipped with a central processing unit, input/output control unit, storage unit, memory unit, and wired or wireless communication unit or adapters. The information apparatus preferably includes a client application that may be implemented as a software application, a helper application, or a device driver (a printer driver in case of a printer). The client application may include management and control capabilities with hardware and software components including, for example, one or more communication chipsets residing in its host information apparatus. The client application in the information apparatus may be capable of communicating with, managing and synchronizing data or software components with an output device equipped with an output controller of present invention. Rendering content in an output device refers to printing an image of the content onto an substrate in the case of a printing device; displaying an image of the content in the case of a displaying device; playing an audio representation of the content in a voice or sound output device or system. An output controller may be a circuit board, card or software components residing in an output device. Alternatively, the output controller may be connected externally to an output device as an external component or “box.” The output controller may be implemented with one or more combinations of embedded processor, software, firmware, ASIC, DSP, FPGA, system on a chip, special chipsets, among others. In another embodiment, the functionality of the output controller may be provided by application software running on a PC, workstation or server connected externally to an output device. In conventional data output method 102 as described with reference to FIG. 1A , an information apparatus transmits output data to an output device for rendering. Output data corresponds to content intended for output and is mostly raster image processed (RIPed) and therefore is device dependent because raster image processing is a typical device dependent operation. Output data may be encoded or compressed with one or more compression or encoding techniques. In present invention, an information apparatus generates an intermediate output data for transmitting to an output device. The intermediate output data includes a rasterized image corresponding to the content; however, device dependent image processing operations of a RIP (e.g. color matching and halftoning) have not been performed. As a result, an intermediate output data is more device independent and is more portable than the output data generated by output method with reference to FIG. 1A . In one implementation of this invention, the intermediate output data includes MRC (Mixed raster content) format, encoding and compression techniques, which further provides improved image quality and compression ratio compared to conventional image encoding and compression techniques. In an example of raster image process and data output method of the present invention, a client application such as a printer driver is included in an information apparatus and performs part of raster image processing operation such as rasterization on the content. The information apparatus generates an intermediate output data that includes an output image corresponding to the content and sends the intermediate output data to an output device or an output system for rendering. An output controller application or component included in the output device or output system implements the remaining part of the raster image processing operations such as digital halftoning, color correction among others. Unlike conventional raster image processing methods, this invention provides a more balanced distribution of the raster image processing computational load between the Information apparatus and the output device or the output system. Computational intensive image processing operations such as digital halftoning and color space conversions can be implemented in the output device or output system. Consequently, this new raster image processing method reduces the processing and memory requirements for the information apparatus when compared to conventional data output methods described with reference to FIG. 1A in which the entire raster image process is implemented in the information apparatus. Additionally, in this invention, a client application or device driver included in the information apparatus, which performs part of the raster image processing operation, can have a smaller size compared to a conventional output application included in the information apparatus, which performs raster image processing operation. In another implementation, the present invention provides an information apparatus with output capability that is more universally accepted by a plurality of output devices. The information apparatus, which includes a client application, generates an intermediate output data that may include device independent attributes. An output controller includes components to interpret and process the intermediate output data. The information apparatus can output content to different output devices or output systems that include the output controller even when those output devices are of different brand, make, model and with different output engine and input data requirements. Unlike conventional output methods, a user does not need to preinstall in the information apparatus multiple dedicated device dependent drivers or applications for each output device. The combination of a smaller-sized client application, a reduced computational requirement in the information apparatus, and a more universal data output method acceptable for rendering at a plurality of output devices enable mobile devices with less memory space and processing capabilities to implement data output functions which otherwise would be difficulty to implement with conventional output methods. In addition, this invention can reduce the cost of an output device or an output system compared to conventional output methods 104 that include a page description language (PDL) printer controller. In the present invention, an information apparatus generates and sends an intermediate output data to an output device or system. The intermediate output data in one preferred embodiment includes a rasterized output image corresponding to the content intended for output. An output controller included in an output device or an output system decodes and processes the intermediate output data for output, without performing complex interpretation and rasterization compared to conventional methods described in process 104 . In comparison, the conventional data output process 104 generates complex PDL and sends this PDL from an information apparatus to an output device that includes a printer controller (e.g. a PostScript controller or a PCL5 controller among others). Interpretation and raster image processing of a PDL have much higher computational requirements compared to decoding and processing the intermediate output data of this invention that include rasterized output image or images. Implementing a conventional printer controller with, for example, PDL increases component cost (e.g. memories, storages, ICs, software and processors etc.) when compared to using the output controller included in the data output method of this present invention. Furthermore, an output data that includes PDL can create a large file size compared to an intermediate output data that includes rasterized output image. The data output method for this invention comparatively transmits a smaller output data from an information apparatus to an output device. Smaller output data size can speed up transmission, lower communication bandwidth, and reduce memory requirements. Finally, this invention can provide a convenient method to render content at an output device with or without connection to a static network. In conventional network printing, both information apparatus and output device must be connected to a static network. In this invention, through local communication and synchronization between an information apparatus and an output device, installation of hardware and software to maintain static network connectivity may not be necessary to enable the rendering of content to an output device. According to the several aspects of the present invention there is provided the subject matter defined in the appended independent claims. Additional objects and advantages of the present invention will be apparent from the detailed description of the preferred embodiment thereof, which proceeds with reference to the accompanying drawings.
G06F31236
20170920
20180125
66411.0
G06F312
1
RILEY, MARCUS T
INFORMATION APPARATUS AND SOFTWARE APPLICATIONS SUPPORTING OUTPUT OF DIGITAL CONTENT OVER A NETWORK TO A REGISTERED OUTPUT DEVICE
UNDISCOUNTED
1
CONT-ACCEPTED
G06F
2,017
15,710,804
ACCEPTED
SYSTEM AND METHOD FOR VOICE CONTROL OF MEASUREMENT APPARATUS
Measurement apparatus includes sensors configured to generate signals associated with physiological parameters and adapted to be coupled to tissue comprising blood and to communicate signals associated with the parameters to feedback control circuitry capable of generating physiological information from the signals. A software application is configured to operate on a control system capable of receiving the physiological information and configured to receive voice input signals and manually entered input signals. The control system includes a touch-screen, a proximity sensor, circuitry for obtaining movement information from a positioning sensor, a mechanical system having actuators, and a wireless transmitter to transmit the physiological information over a wireless link to a host. The host is configured to generate status information from the data and includes a memory storage device for recording the status information and a communication device communicating the status information to display output devices that may be located remotely.
1. A measurement apparatus comprising: one or more sensors configured to generate signals associated with one or more physiological parameters, wherein at least one of the one or more sensors is adapted to be coupled to tissue comprising blood and to communicate to feedback control circuitry at least a portion of the signals associated with one or more physiological parameters, the feedback control circuitry capable of generating physiological information from the at least a portion of the signals associated with one or more physiological parameters, a software application configured to operate on a control system that is capable of receiving at least some of the physiological information, the control system configured to receive voice input signals and manually entered input signals and comprising a touch-screen, a proximity sensor, circuitry for obtaining movement information from a positioning sensor, a mechanical system comprising one or more actuators, and a wireless transmitter to transmit data, including at least some of the physiological information, over a wireless link to a host, wherein the host is configured to generate status information from the data and comprises: a memory storage device for recording the status information; and a communication device for communicating at least a portion of the status information over a communication link to one or more display output devices, wherein the one or more display output devices are located remotely from the host. 2. The measurement apparatus of claim 1, wherein at least one of the one or more sensors is capable of measuring heart rate and blood oxygen level. 3. The measurement apparatus of claim 1, wherein at least one of the one or more sensors is adapted to be inserted into a user's body, and the measurement apparatus further comprises a flexible portion. 4. The measurement apparatus of claim 1, further comprising one or more semiconductor diodes generating an input light beam, and a lens system configured to receive at least a portion of the input light beam and configured to communicate at least the portion of the input light beam onto the tissue comprising blood. 5. The measurement apparatus of claim 1, wherein alarms or alerts are generated based on the signals from the one or more sensors. 6. A measurement apparatus comprising: a flexible portion, adapted to be inserted into a user's body, including one or more sensors configured to generate a plurality of different signals associated with one or more physiological parameters, wherein at least one of the one or more sensors is adapted to be coupled to a tissue comprising blood, the measurement apparatus configured to communicate with a software application configured to operate on a control system adapted to receive and process physiological information, the control system comprising a touch-screen, a proximity sensor, circuitry for obtaining movement information from a positioning sensor, a mechanical system comprising one or more actuators, and a wireless transmitter to transmit data over a wireless link to a host, the software application operable to generate the physiological information based at least in part on the different signals from the one or more sensors, at least some of the physiological information comprising at least a part of the data, wherein the control system is further configured to receive voice input signals and manually entered input signals, and wherein alarms or alerts are capable of being generated based on the different signals from the one or more sensors; and wherein the control system improves a signal-to-noise ratio of the different signals with a differential measurement based on the different signals. 7. The measurement apparatus of claim 6, wherein the host is configured to generate status information from the data and comprises: a memory storage device for recording the status information; and a communication device for communicating at least a portion of the status information over a communication link to one or more display output devices, wherein the one or more display output devices are located remotely from the host. 8. The measurement apparatus of claim 6, wherein the control system further comprises knobs and buttons. 9. The measurement apparatus of claim 8, wherein the control system is further coupled to one or more semiconductor diodes configured to generate an input light beam, and a lens system configured to receive at least a portion of the input light beam and configured to communicate at least the portion of the input light beam onto the user's body. 10. The measurement apparatus of claim 9, wherein at least the portion of the input light beam is adapted for use in diagnostics, wherein the diagnostics comprise a spectroscopic procedure, and wherein the spectroscopic procedure is based at least in part on a comparison of amplitudes at a plurality of associated wavelengths transmitted or reflected from the user's body. 11. The measurement apparatus of claim 6, wherein the measurement apparatus is further coupled to feedback control circuitry, the feedback control circuitry capable of receiving at least a portion of the signals associated with one or more physiological parameters. 12. The measurement apparatus of claim 6, wherein the measurement apparatus communicates to the control system through a base device, the base device capable of receiving at least a portion of the signals associated with one or more physiological parameters. 13. A measurement apparatus comprising: one or more sensors configured to generate signals associated with one or more physiological parameters, the physiological parameters including at least one of blood pressure, heart rate and blood oxygen level, wherein at least one of the one or more sensors is adapted to be coupled to tissue comprising blood and is adapted to be inserted into an orifice associated with a user, and wherein at least one of the one or more sensors is capable of generating data associated with proximity to the tissue comprising blood; the measurement apparatus configured to communicate with a software application configured to operate on a control system adapted to receive and process physiological information, the control system comprising a touch-screen, a mechanical system comprising one or more actuators, and a wireless transmitter to transmit data over a wireless link to a host, the software application operable to generate the physiological information based at least in part on the signals from the one or more sensors, at least some of the physiological information comprising at least a part of the data, wherein the control system is further configured to receive voice input signals and manually entered input signals. 14. The measurement apparatus of claim 13, wherein the host is configured to generate status information from the data and comprises: a memory storage device for recording the status information; and a communication device for communicating at least a portion of the status information over a communication link to one or more display output devices, wherein the one or more display output devices are located remotely from the host. 15. The measurement apparatus of claim 13, wherein at least one of the one or more sensors is adapted to provide positioning information. 16. The measurement apparatus of claim 13, wherein the control system further comprises knobs and buttons. 17. The measurement apparatus of claim 16, wherein the control system is further coupled to one or more semiconductor diodes configured to generate an input light beam, and a lens system configured to receive at least a portion of the input light beam and configured to communicate at least the portion of the input light beam onto the user. 18. The measurement apparatus of claim 17, wherein at least the portion of the input light beam is adapted for use in diagnostics, wherein the diagnostics comprise a spectroscopic procedure, and wherein the spectroscopic procedure is based at least in part on a comparison of amplitudes at a plurality of associated wavelengths transmitted or reflected from the user. 19. The measurement apparatus of claim 13, further coupled to a speaker and a microphone and arranged to minimize background noise. 20. The measurement apparatus of claim 13, wherein at least one of a host or the control system includes voice recognition software to process at least a portion of the voice input signals. 21. A measurement apparatus comprising: at least one sensor having a flexible portion adapted to be inserted into a user's body and coupled to a tissue comprising blood, the at least one sensor configured to generate a plurality of different signals associated with one or more physiological parameters, the measurement apparatus configured to communicate through a base device to a software application configured to operate on a control system adapted to receive and process physiological information, the control system comprising a touch-screen, a proximity sensor, circuitry for obtaining movement information from a positioning sensor, a mechanical system comprising one or more actuators, and a wireless transmitter to transmit data over a wireless link to a host, and wherein the control system improves a signal-to-noise ratio of the different signals with a differential measurement based on the different signals; wherein the software application is operable to generate the physiological information based at least in part on the different signals from the one or more sensors, at least some of the physiological information comprising at least a part of the data, wherein the control system is further configured to receive voice input signals and manually entered input signals, and wherein alarms or alerts are capable of being generated based on the different signals from the one or more sensors; and wherein the host is configured to generate status information from the data and comprises: a memory storage device for recording the status information; and a communication device for communicating at least a portion of the status information over a communication link to one or more display output devices, wherein the one or more display output devices are located remotely from the host.
CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 15/258,133 filed Sep. 7, 2016, which is a continuation of U.S. patent application Ser. No. 14/734,069 filed Jun. 9, 2015, now U.S. Pat. No. 9,456,751, issued Oct. 4, 2016, which is a continuation of U.S. patent application Ser. No. 14/476,082, filed Sep. 3, 2014, now U.S. Pat. No. 9,055,868, issued Jun. 16, 2015, which is a continuation of U.S. patent application Ser. No. 14/186,814 filed Feb. 21, 2014, which is a continuation of U.S. patent application Ser. No. 13/913,678 filed Jun. 10, 2013, now U.S. Pat. No. 8,848,282, issued Sep. 30, 2014, which is a continuation of U.S. patent application Ser. No. 13/531,853 filed Jun. 25, 2012, now U.S. Pat. No. 8,679,011, issued Mar. 25, 2014, which is a continuation of U.S. patent application Ser. No. 13/349,244 filed Jan. 12, 2012, now U.S. Pat. No. 8,472,108, issued Jun. 25, 2013, which is a continuation of U.S. application Ser. No. 13/078,547 filed Apr. 1, 2011, abandoned, which is a divisional of U.S. patent application Ser. No. 12/625,253 filed Nov. 24, 2009, now U.S. Pat. No. 8,098,423, issued Jan. 17, 2012, which is a divisional of U.S. patent application Ser. No. 12/206,432, filed Sep. 8, 2008, now U.S. Pat. No. 7,633,673, issued Dec. 15, 2009, which is a divisional of U.S. patent application Ser. No. 10/812,608, filed Mar. 30, 2004, now U.S. Pat. No. 7,433,116, issued Oct. 7, 2008, which is a continuation of U.S. patent application Ser. No. 10/757,341, filed Jan. 13, 2004, now U.S. Pat. No. 7,259,906, issued Aug. 21, 2007, which is a continuation of U.S. patent application Ser. No. 10/652,276 filed Aug. 29, 2003, abandoned. application Ser. No. 10/652,276 claims the benefit of U.S. Provisional Patent Application No. 60/408,025 filed Sep. 3, 2002. The disclosures of all of the above are incorporated in their entirety by reference herein. TECHNICAL FIELD This disclosure relates generally to medical diagnostic systems. SUMMARY OF EXAMPLE EMBODIMENTS In one embodiment, a measurement apparatus comprises one or more sensors configured to generate signals associated with one or more physiological parameters, wherein at least one of the one or more sensors is adapted to be coupled to tissue comprising blood and to communicate to feedback control circuitry at least a portion of the signals associated with one or more physiological parameters. The feedback control circuitry may be capable of generating physiological information from the at least a portion of the signals associated with one or more physiological parameters. A software application is configured to operate on a control system that is capable of receiving at least some of the physiological information, the control system configured to receive voice input signals and manually entered input signals and comprising a touch-screen, a proximity sensor, circuitry for obtaining movement information from a positioning sensor, a mechanical system comprising one or more actuators, and a wireless transmitter to transmit data, including at least some of the physiological information, over a wireless link to a host. The host is configured to generate status information from the data and comprises a memory storage device for recording the status information and a communication device for communicating at least a portion of the status information over a communication link to one or more display output devices, wherein the one or more display output devices are located remotely from the host. In one embodiment, a measurement apparatus comprises a flexible portion, adapted to be inserted into a user's body, including one or more sensors configured to generate signals associated with one or more physiological parameters. At least one of the one or more sensors is adapted to be coupled to tissue comprising blood. The measurement apparatus is configured to communicate with a software application configured to operate on a control system adapted to receive and process physiological information. The control system comprises a touch-screen, a proximity sensor, circuitry for obtaining movement information from a positioning sensor, a mechanical system comprising one or more actuators, and a wireless transmitter to transmit data over a wireless link to a host. The software application is operable to generate the physiological information based at least in part on the signals from the one or more sensors. At least some of the physiological information comprises at least a part of the data, wherein the control system is further configured to receive voice input signals and manually entered input signals, and wherein alarms or alerts are capable of being generated based on the signals from the one or more sensors. In one embodiment, a measurement apparatus comprises one or more sensors configured to generate signals associated with one or more physiological parameters. The physiological parameters include at least one of blood pressure, heart rate and blood oxygen level. At least one of the one or more sensors is adapted to be coupled to tissue comprising blood and is adapted to be inserted into an orifice associated with a user. At least one of the one or more sensors is capable of generating data associated with proximity to the tissue comprising blood. The measurement apparatus is configured to communicate with a software application configured to operate on a control system adapted to receive and process physiological information. The control system comprises a touch-screen, a mechanical system comprising one or more actuators, and a wireless transmitter to transmit data over a wireless link to a host. The software application is operable to generate the physiological information based at least in part on the signals from the one or more sensors. At least some of the physiological information comprises at least a part of the data. The control system is further configured to receive voice input signals and manually entered input signals. In one embodiment, a measurement apparatus includes one or more sensors configured to generate signals associated with one or more physiological parameters, wherein at least one of the one or more sensors is adapted to be coupled to a tissue comprising blood. The measurement apparatus is configured to communicate through a base device to a software application configured to operate on a control system adapted to receive and process physiological information, wherein the base device is capable of receiving at least a portion of the signals associated with one or more physiological parameters. The control system comprises a touch-screen, a proximity sensor, circuitry for obtaining movement information from a positioning sensor, a mechanical system comprising one or more actuators, and a wireless transmitter to transmit data over a wireless link to a host. The software application is operable to generate the physiological information based at least in part on the signals from the one or more sensors, at least some of the physiological information comprising at least a part of the data, wherein the control system is further configured to receive voice input signals and manually entered input signals. The host is configured to generate status information from the data and comprises a memory storage device for recording the status information and a communication device for communicating at least a portion of the status information over a communication link to one or more display output devices, wherein the one or more display output devices are located remotely from the host. In another embodiment, a measurement apparatus includes one or more sensors configured to generate signals associated with one or more physiological parameters, wherein at least one of the one or more sensors is adapted to be coupled to a tissue comprising blood. The measurement apparatus is configured to communicate with a software application configured to operate on a control system adapted to receive and process physiological information. The control system comprises a touch-screen, a proximity sensor, circuitry for obtaining movement information from a positioning sensor, a mechanical system comprising one or more actuators, and a wireless transmitter to transmit data over a wireless link to a host. The software application is operable to generate the physiological information based at least in part on the signals from the one or more sensors, at least some of the physiological information comprising at least a part of the data. The control system is further configured to receive voice input signals and manually entered input signals. The host is configured to generate status information from the data and comprises a memory storage device for recording the status information and a communication device for communicating at least a portion of the status information over a communication link to one or more display output devices, wherein the one or more display output devices are located remotely from the host. In one embodiment, a measurement apparatus includes one or more sensors configured to generate signals associated with one or more physiological parameters, the physiological parameters including at least one of blood pressure, heart rate and blood oxygen level, wherein at least one of the one or more sensors is adapted to be coupled to a tissue comprising blood. The measurement apparatus is configured to communicate with a software application configured to operate on a control system adapted to receive and process physiological information. The control system includes a touch-screen, a proximity sensor, circuitry for obtaining movement information from a positioning sensor, a mechanical system comprising one or more actuators, and a wireless transmitter to transmit data over a wireless link to a host. The software application is operable to generate the physiological information based at least in part on the signals from the one or more sensors, at least some of the physiological information comprising at least a part of the data. The control system is further configured to receive voice input signals and manually entered input signals. The host is configured to generate status information from the data and comprises a memory storage device for recording the status information and a communication device for communicating at least a portion of the status information over a communication link to one or more display output devices, wherein the one or more display output devices are located remotely from the host. In one embodiment, a light-based medical diagnostic system includes a pump source comprising a plurality of semiconductor diodes with pump beams, a multiplexer capable of combining the plurality of semiconductor diode pump beams and generating at least a multiplexed pump beam comprising one or more wavelengths, a first waveguide structure configured to receive at least a portion of the one or more wavelengths, wherein the first waveguide structure comprises at least in part a gain fiber and outputs a first optical beam, and a second waveguide structure configured to receive at least a portion of the first optical beam and to communicate at least the portion of the first optical beam to an output end of the second waveguide structure to form an output beam, wherein at least a portion of the output beam comprises at least one wavelength in the range of 1.7 microns or more. A lens system is configured to receive at least the portion of the output beam and to communicate at least the portion of the output beam through a patient's mouth onto a part of a patient's body comprising a patient's blood. In various embodiments, at least the portion of the output beam is adapted for use in medical diagnostics to measure a property of the patient's blood, wherein the medical diagnostics comprise a spectroscopic procedure comprising a differential measurement, wherein the differential measurement is based at least in part on a comparison of amplitudes at a plurality of associated wavelengths transmitted or reflected from the patient's blood. In another embodiment, a light-based diagnostic system includes a pump source comprising a plurality of semiconductor diodes with pump beams, a multiplexer capable of combining the plurality of semiconductor diode pump beams and generating at least a multiplexed pump beam comprising one or more wavelength, first and second waveguide structures, and a lens system. The first waveguide structure is configured to receive at least a portion of the one or more wavelengths, wherein the first waveguide structure comprises at least in part a fused silica fiber, and outputs a first optical beam. The second waveguide structure is configured to receive at least a portion of the first optical beam and to communicate at least the portion of the first optical beam to an output end of the second waveguide structure to form an output beam. The lens system is configured to receive at least a portion of the output beam and to communicate at least the portion of the output beam through an orifice in a patient's body. In various embodiments, at least the portion of the output beam is adapted for use in multi-wavelength diagnostics to measure a property of a part of the patient's body, wherein the multi-wavelength diagnostics comprise a spectroscopic procedure comprising a differential measurement, wherein the differential measurement is based at least in part on a comparison of amplitudes at a plurality of associated wavelengths transmitted or reflected from the part of the patient's body. In yet another embodiment, a light-based medical diagnostic system includes a pump source comprising a plurality of semiconductor diodes with pump beams and a multiplexer capable of combining the plurality of semiconductor diode pump beams and generating at least a multiplexed pump beam comprising one or more wavelengths. A first waveguide structure is configured to receive at least a portion of the one or more wavelengths, wherein the first waveguide structure comprises at least in part a fused silica fiber, and outputs a first optical beam. A second waveguide structure is configured to receive at least a portion of the first optical beam and to communicate at least the portion of the first optical beam to an output end of the second waveguide structure to form an output beam. A lens system is configured to receive at least a portion of the output beam and to communicate at least the portion of the output beam onto a part of a patient's body comprising a patient's blood. In one embodiment, a measurement apparatus comprises an insertable portion capable of being inserted into an orifice associated with a body of a patient. The insertable portion comprising an automated head unit capable of being manipulated in at least two axes of motion based at least in part on one or more control signals. The measurement apparatus further comprises one or more controllers coupled to the automated head unit. In one particular embodiment, the one or more controllers generate the one or more control signals based at least in part on an input signal. In another embodiment, a measurement apparatus capable of minimizing tissue damage comprises an insertable portion capable of being inserted into an orifice associated with a body of a patient. The measurement apparatus further comprises one or more sensors coupled to the insertable portion. The one or more sensors capable of generating a feedback signal capable of being used to substantially minimize damage to tissue associated with the patient. In yet another embodiment, a measurement apparatus capable of being used in a medical procedure comprises a pump laser capable of generating a pump signal. The measurement apparatus further comprises a Raman wavelength shifter coupled to the pump laser, at least a portion of the wavelength shifter comprising a waveguide structure. In one particular embodiment, the Raman wavelength shifter generates an output optical signal comprising a wavelength of approximately 1.7 microns or more. In still another embodiment, a measurement apparatus capable of being used in a medical procedure comprises a Raman wavelength shifter operable to generate an optical signal comprising a mid-infrared wavelength. At least a portion of the Raman wavelength shifter comprises a chalcogenide waveguide. In another embodiment, a system for controlling a measurement apparatus includes a monitor capable of communicating medical information associated with a patient and a communication device capable of receiving one or more input signals from a user. In one particular embodiment, the one or more input signals are based at least in part on the medical information displayed on the monitor. The system further includes one or more processors coupled to the communicated device and operable to convert the one or more input signals into one or more control signals capable of being used to manipulate a measurement apparatus. Depending on the specific features implemented, particular embodiments may exhibit some, none, or all of the following technical advantages. Various embodiments may be capable of reducing medical professional fatigue through the implementation of a control system capable of manipulating a measurement apparatus through voice commands. Some embodiments may be capable of controlling a measurement apparatus from a remote location. Other embodiments may be capable of reducing the level of dexterity required of a medical professional when performing a medical procedure. Other technical advantages will be readily apparent to one skilled in the art from the following figures, description, and claims. Moreover, while specific advantages have been enumerated, various embodiments may include all, some, or none of the enumerated advantages. BRIEF DESCRIPTION OF THE DRAWINGS To provide a more complete understanding of the present invention and certain features and advantages, thereof, reference is made to the following description taken in conjunction with the accompanying drawings, in which: FIG. 1 illustrates one example embodiment of a measurement apparatus control system; FIG. 2 illustrates another example embodiment of a measurement apparatus control system; FIG. 3 illustrates an example measurement apparatus capable of being inserted into a patient's body during a medical procedure; FIG. 4 is a block diagram illustrating a flow of command signals from a medical professional to a measurement apparatus in a measurement apparatus control system; FIG. 5 is a flow chart illustrating an exemplary method for processing a voice control signal and/or a command signal received by a measurement apparatus control system; FIG. 6A compares a surgical incision made using a 2.94 micron optical signal wavelength to a surgical incision made using a 6.45 micron optical signal wavelength; FIG. 6B illustrates example evanescent spectra in different cell-type regions; FIG. 7 illustrates example attenuation characteristics of several optical fibers based on wavelength; FIGS. 8A through 8D are block diagrams illustrating example embodiments of Raman wavelength shifters and/or Raman oscillators capable of shifting a pump signal to an output signal wavelength of 1.7 microns or more; and FIGS. 9A through 9C are block diagrams illustrating example embodiments of pump sources that are capable of generating a pump signal for use in a Raman wavelength shifter. DESCRIPTION OF EXAMPLE EMBODIMENTS As required, detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention that may be embodied in various and alternative forms. The figures are not necessarily to scale; some features may be exaggerated or minimized to show details of particular components. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a representative basis for teaching one skilled in the art to variously employ the present invention. FIG. 1 illustrates one example embodiment of a measurement apparatus control system 100. In this example, system 100 includes a measurement apparatus 10, a manipulator 40, a microphone 50, a display device 60, and a host 70. In various embodiments, system 100 may be capable of receiving voice commands associated with the manipulation of measurement apparatus 10 from a medical professional, such as a nurse, a medical assistant, a medical technician, and/or a doctor. In some cases, system 100 is capable of assisting a medical professional during a medical procedure by processing data signals associated with one or more voice commands and manipulating measurement apparatus 10 in response to those commands. Measurement apparatus 10 may comprise any device or instrument that a medical professional needs to perform a medical procedure. Measurement apparatus 10 can comprise, for example, a surgical scalpel, a scope, a laser, an imaging device, a microscope, or a combination of these or any other suitable device. As used throughout this document, the term “scope” refers to any measurement apparatus capable of entering a patient's body, such as endoscopes, colonoscopes, gastroscopes, enteroscopes, bronchoscopes, laryngoscopes, choledochoscopes, sigmoidoscopes, duodenoscopes, arthoroscopes, cystoscopes, hyteroscopes, laparoscopes, or a combination of these or any other suitable device. In one particular embodiment, measurement apparatus 10 comprises an endoscope. In those cases, the endoscope may comprise an insertable portion capable of being inserted through an orifice associated with a patient. In other embodiments, the insertable portion may be capable of being guided through the patient's orifice, and capable of collecting biological samples from the patient for investigation. The orifice associated with the patient may comprise, for example, a throat, a mouth, a nasal passage, an orifice created by the medical professional, and/or any other suitable orifice. In some embodiments, measurement apparatus 10 may include a fiber-optic cable with a lens system at the end that is capable of sending images to a camera and/or a display device, such as display device 60. In other embodiments, measurement apparatus 10 may comprise one or more sensors coupled to feedback control circuitry that is capable of minimizing collateral tissue damage during a medical procedure. In various embodiments, the one or more sensors and the control circuitry may be capable of providing positioning information to a medical professional and/or a controller, such as system controller 90. In other embodiments, the one or more sensors and the control circuitry may be capable of providing data associated with one or more physiological parameters associated with the patent to a medical professional and/or a controller. In some cases, the one or more sensors may be capable of detecting and/or alerting a medical professional or a controller when measurement apparatus 10 is in close proximity to and/or in contact with tissue. In other cases, the one or more sensors and the control circuitry may be capable of detecting when measurement apparatus 10 is in contact with tissue and capable of overriding control signals received by measurement apparatus 10. In this example, manipulator 40 includes an actuation unit 20 and a supporting structure 30. Actuation unit 20 may house one or more control systems capable of receiving control signals and manipulating measurement apparatus 10 in response to those control signals. The one or more control systems may comprise, for example, a mechanical control system, an electrical control system, or a combination of these or any other control system. As used throughout this document, the phrase “mechanical control system” refers to a control system that at least partially includes mechanical components. In various embodiments, actuation unit 20 can implement a mechanical control system, such as a hydraulic system, pneumatic system, or a pulley guidewire system. Supporting structure 30 may comprise a robotic arm, one or more pivoted links, multiple links connected together to move in a “scissor-like” manner, or any other structure capable of supporting and manipulating measurement apparatus 10. Although this example depicts manipulator 40 and measurement apparatus 10 as separate devices, manipulator 40 and measurement apparatus 10 can comprise a unitary medical apparatus capable of performing the desired functionalities without departing from the scope of the present disclosure. For example, manipulator 40 and measurement apparatus 10 can be combined to form a unitary medical apparatus, such as an endoscope, have an automated portion. In some embodiments, a freedom of motion associated with manipulator 40 can have a resolution that substantially replicates the manual dexterity of a medical professional and/or a manual measurement apparatus used by the medical professional. In some cases, manipulator 40 may have a step size and/or angle of rotation step size that is substantially similar to the manual dexterity of a medical professional and/or a manual measurement apparatus used by the medical professional. For example, the number of degrees of manipulation freedom associated with measurement apparatus 10 can match the number of degrees of manipulation freedom currently available on manual devices. That is, if a conventional manual device that has four degrees of freedom in the x-y plane, then the range of motion associated with manipulator 40 can include at least four degrees of freedom in the x-y plane. In some embodiments, manipulator 40 may include manual override controls that allow a medical professional to exercise manual control of measurement apparatus 10. Manipulator 40 is coupled to host 70 through a first communication link 45. As used throughout this document, the term “couple” and or “coupled” refers to any direct or indirect communication between two or more elements, whether or not those elements are in physical contact with one another. In this example, first communication link 45 is operable to facilitate the communication of command/data signals 47 between manipulator 40 and host 70. Command/data signals 47 may comprise, for example, video signals from a video device coupled to measurement apparatus 10, data obtained by sensors coupled to measurement apparatus 10, or manipulation commands generated in response to voice commands, auxiliary input commands, and/or automated commands. In this example, host 70 is capable of performing a desired communicating and/or computing functionality. For example, host 70 may be capable of at least partially contributing to the manipulation of measurement apparatus 10. In other embodiments, host 70 may be capable of collecting, entering, processing, storing, retrieving, amending, and/or dispatching medical data during a medical procedure. In operation, host 70 may execute with any of the well-known MS-DOS, PC-DOS, 0S-2, MAC-OS, WINDOWS, UNIX, or other appropriate operating systems. In some embodiments, host 70 may include a graphical user interface (GUI) 72 that enables a medical professional to display medical data and/or medical video associated with measurement apparatus 10. Host 70 may comprise, for example, a desktop computer, a laptop computer, a server computer, a personal digital assistant, and/or any other computing or communicating device or combination of devices. In this example, host 70 includes system controller 90 capable of processing, collecting, storing, retrieving, and/or amending medical data and/or video during a medical procedure. System controller 90 may comprise one or more computers, an embedded microprocessor, or any other appropriate device or combination of devices capable of processing and/or generating voice command signals 47 and/or 57. In operation, system controller 90 may execute with any of the well-known MS-DOS, PC-DOS, 0S-2, MAC-OS, WINDOWS, UNIX, or other appropriate operating systems. In this embodiment, system controller 90 may implement voice recognition software operable to process voice command signals 57. For example, system controller 90 may implement one or more voice recognition software programs, such as ViaVoice or Dragon Speech Recognition software, or any appropriate proprietary or nonproprietary voice recognition software. In certain embodiments, the voice recognition software may be programmed to recognize the medical professional's voice and commands may be customized to the medical professional's preferences. In addition, the voice recognition software may be capable of filtering out background noise. System controller 90 is operable to process voice command signals 57, generate command/data signals 47 in response to the voice command, and communicate the command/data signals 47 to manipulator 40. System controller 90 may also be used to collect and record data using a memory storage device. System controller 90 may be operable to provide data associated with a patient's medical status during a medical procedure to the medical professional using display device 60 and/or GUI 72, or any other appropriate devices. In this embodiment, host 70 also includes an auxiliary input device 80 coupled to system controller 90. Although a keyboard is depicted in this example, any other device capable of inputting commands and/or data may be used without departing from the scope of this disclosure. In this example, auxiliary device 80 is operable to facilitate manual entry of manipulation commands to supplement and/or replace voice commands. In addition, the medical professional may use auxiliary device 80 to input data into system controller 90, such as the patient's physiological parameters, for example, blood pressure, heart rate, blood oxygen level, or to retrieve data stored in a memory device associated with host 70. In this example, system 100 also includes display device 60 and a graphical user interface (GIU) 72, each capable of displaying medical information, such as medical data and/or medical video. Display device 60 and GUI 72 may comprise, for example, a monitor, a LED, a heads-up display, virtual reality goggles, a closed circuit television, a CAVE environment, or any other device or combination of devices capable of displaying. In some cases, display device 60 and GUI 72 may display a live video image from a video device associated with measurement apparatus 10, information about a patient's medical status, such as the current state of any number of the patient's physiological parameters, information about the particular measurement apparatus 10 being used, or any other information that may assist a medical professional during a medical procedure. In this example, display device 60 is coupled to host 70 through a third communication link 65, which is operable to facilitate the communication of data signals 67 to and/or from host 70. In this example, system 100 also includes communication device 50 that enables a medical professional to communicate with host 70. Communication device 50 can comprise any device that enables a medical professional to communicate with host 70. Communication device 50 may comprise, for example, a telephone, a wireless device, a voice-over-IP device, a unidirectional microphone attached to a headset worn by a medical professional, a bi-directional microphone, or any other suitable communicating device or combination of devices. Communication device 50 may be selectively attached to and/or placed near the medical professional for ease of use. Attaching communication device 50 to the medical professional can, in some cases, advantageously minimize background noise. Although system 100 includes one communication device 50 in this example, any other number of communication devices may be used without departing from the scope of the present disclosure. Communication device 50 is coupled to host 70 through a second communication link 55, which is operable to facilitate the communication of voice command signals 57 between communication device 50 and host 70. In the illustrated embodiment, system 100 includes at least a first communications link 45, a second communications link 55, and a third communications link 65 each operable to facilitate the communication of data to and/or from host 70. Communications links 45, 55, and 65 may include any hardware, software, firmware, or combination thereof. In various embodiments, communications link 45, 55, and 65 may comprise any communications medium capable of assisting in the communication of analog and/or digital signals. Communications links 45, 55, and 65 may, for example, comprise a twisted-pair copper telephone line, a fiber optic line, a Digital Subscriber Line (DSL), a wireless link, a USB bus, a PCI bus, an Ethernet interface, or any other suitable interface operable to assist in the communication of information to and/or from network 104. In conventional medical procedures involving a scope, a medical professional manually manipulates the measurement apparatus based on feedback from the measurement apparatus. The medical professional typically uses one hand to hold the measurement apparatus and guide it into and through a patient's body. The medical professional's other hand is used to manipulate the manual controls of the measurement apparatus. Thus, conventional systems typically require significant manual dexterity, which can result in a significant amount of strain on the medical professional. Unlike conventional procedures, system 100 comprises a communication device 50 that enables a medical professional to manipulate measurement apparatus 10 using voice commands, auxiliary input commands, and/or automated commands. Allowing a medical professional to use voice commands and/or automated commands can significantly reduce the manual dexterity, and the resulting strain, imposed on the medical professional during a medical procedure. In operation, a medical professional can speak voice commands into communication device 50 for communication to host 70. Host 70 receives voice command signals 57 from communication device 50 and processes those signals using a voice recognition module associated with host 70. Host 70 converts the voice command signals into command/data signals 47 and communicates signals 47 to manipulator 40. Manipulator 40 responds by causing measurement apparatus 10 to perform its desired function. Voice commands may comprise, for example, a voice to take a photograph of a portion of the patient's body, a voice command to change an image size by zooming in or out, or any other suitable voice command capable of causing measurement apparatus 10 to perform its functionality. In other embodiments, host 70 is capable of automatically generating command/data signals 47 based at least in part on data received from measurement apparatus 10 through communication link 47. FIG. 2 illustrates another example embodiment of a measurement apparatus control system 300. System 300 includes system 150 for remote manipulation of a measurement apparatus 210 and system 200 for voice control of measurement apparatus 210. In this example, system 150 is capable of controlling at least a portion of system 200 from a remote location. For example, a medical professional may use system 150 to remotely control system 200 in the case where the medical professional is not located near system 200. The remote location may comprise, for example, a different location in the hospital that includes system 200, a location in a different hospital, or any other location. System 150 can include a communication device 155, a display device 160, a first auxiliary input device 165, and a second auxiliary input device 180. The structure and function of communication device 155, display device 160, and second auxiliary input device 180 can be substantially similar to the structure and function of communication device 50, display device 60, and auxiliary input device 80, respectively, of FIG. I. First auxiliary input device 165 may comprise, for example, a joystick, a computer mouse, a rollerball, knobs, levers, buttons, touchpads, touchscreens, or any other appropriate control device capable of being used to control manipulator 240. In this example, a medical professional can use first auxiliary input device 165 to control manipulator 240 from the remote location. In this embodiment, system 200 includes a measurement apparatus 210, a manipulator 240, a communication device 250, and a display device 260. System 200 also includes a host 270 comprising GUI 272, a third auxiliary input device 280, and a system controller 290. Although host 270 resides within system 200 in this example, host 270 could reside within system 150 or could reside in any location accessible to system 300 without departing from the scope of the present disclosure. The structure and function of measurement apparatus 210, manipulator 240, communication device 250, display device 260, host 270, GUI 272, third auxiliary input device 280, and system controller 290 can be substantially similar to the structure and function of measurement apparatus 10, manipulator 40, communication device 50, display device 60, host 70, GUI 72, auxiliary input device 80, and system controller 90, respectively, of FIG. 1. System 150 communicates with system 200 over communication link 305. Although communication link 305 comprises a single communication link in this example, any other number of communication links may be used without departing from the scope of the present disclosure. Communications link 305 may include any hardware, software, firmware, or combination thereof. In various embodiments, communications link 305 may comprise a communications medium capable of assisting in the communication of analog and/or digital signals. Communications link 305 may, for example, comprise a twisted-pair copper telephone line, a fiber optic line, a Digital Subscriber Line (DSL), a wireless link, a USB bus, a PCI bus, an Ethernet interface, or a combination of these or other elements. In some embodiments, a first medical professional can manually insert measurement apparatus 210 into a patient. In those cases, system 200 can communicate data to a second medical professional using remote system 150 through communication link 305. The second medical professional, while monitoring display device 160, can remotely manipulate measurement apparatus 210 using voice instructions communicated through communication device 155 coupled to communication link 305 to host 270. In this manner, the medical professional using system 150 can substantially emulate a medical professional's manual control of measurement apparatus 210. In other embodiments, the medical professional can remotely manipulate measurement apparatus 210 using auxiliary devices 165 and/or 180. In an alternative embodiment, a medical professional can insert medical device 210 into a patient using system 200 locally or using system 150 remotely. In addition to voice command control and/or auxiliary input device control, other methods of measurement apparatus control may be implemented. In some cases, system 150 and/or system 200 can implement a heads-up-display (HUD) capable of controlling and/or manipulating measurement apparatus 210 and/or manipulator 240. The HUD may be capable of projecting images onto or near the eyes of a medical professional and capable of sending command signals using a virtual control device attached to the medical professional. In another example, the medical professional may wear a helmet capable of manipulating measurement apparatus 210 and/or manipulator 240 based at least in part on command signals generated in response to a motion associated with the head of the medical professional. For example, rotation of the head to the right may indicate that the operator wants the measurement apparatus to move to the right. FIG. 3 illustrates an example measurement apparatus 400. In various embodiments, at least a portion of measurement apparatus 400 may be inserted into a patient's body through an orifice during a medical procedure. The orifice may comprise, for example, the patient's throat or mouth, the patient's nasal passages, an incision made during surgery, or any other suitable orifice. In this particular example, measurement apparatus 400 comprises a scope. The scope may comprise, for example, an endoscope, a colonoscope, a gastroscope, a enteroscope, a bronchoscope, a laryngoscope, a choledochoscope, a sigmoidoscope, a duodenoscope, a arthoroscope, a cystoscope, a hyteroscope, a laparoscope, or a combination of these or any other suitable device. In various embodiments, measurement apparatus 400 can be controlled through, for example, voice commands, auxiliary input command, automated commands, and/or manual commands. In some cases, measurement apparatus 400 can be coupled to a measurement apparatus control system, such as system 100 or system 300 of FIG. 1 and FIG. 2, respectively. Measurement apparatus 400 includes a base portion 410 capable of controlling and/or at least partially contributing to the manipulation of an insertable portion 420. In this example, base portion 410 includes control system 435 capable of at least partially contributing to the control and/or the manipulation of insertable portion 420. Control system 435 may be capable of receiving, processing, executing, and/or communicating one or more signals associated with the manipulation of insertable portion 420. In various embodiments, these signals received by base portion 410 may comprise, for example, voice commands, auxiliary input commands, automated commands, physiological parameters, video data, positioning data, or a combination of these or other signal types. In various embodiments, control system 435 may reside in a location outside of base portion 410 and/or may be partially or wholly included within base portion 410. Control systems 435 may comprise, for example, a mechanical control system, an electrical control system, an electro-mechanical control system, or a combination of these or any other suitable control system. The phrase “mechanical control system” refers to a control system that at least partially includes mechanical components. Mechanical control systems can include, for example, hydraulic components, pneumatic components, pulleys, guidewires, gears, actuators, pushrods, sprocket/chain mechanisms, feedback control circuitry, or any other suitable components. In this particular embodiment, control system 435 includes a manual override control module 411, an x-axis control module 412, a y-axis control module 414, and a z-axis control module 416. Control modules 411, 412, 414, and 416 may include any hardware, software, firmware, or combination thereof. In some embodiments, control modules 411, 412, 414, and 416 may comprise buttons, knobs, dials, control circuitry, or any other suitable control input device. In this particular embodiment, control modules 412, 414, and 416 operate to receive and process input signals from a medical professional. In addition, control modules 412, 414, and 416 operate to at least partially contribute to the manipulation of insertable portion 420. The input signals may comprise, for example, voice commands, auxiliary input commands, and/or manual input commands. In other embodiments, control modules 412, 414, and 416 operate to receive and process input signals from a host and/or system controller. For example, a medical professional can use control modules 412, 414, and 416 to individually control measurement apparatus 400 in the x-, y-, and z-axes, respectively. In various embodiments, override control module 411 may be capable of enabling the medical professional to override the automatic operation of measurement apparatus 400 as necessary during a medical procedure. Control system 435 may also include touch-screen 417 and controller 418. Controller 418 operates to combine the individual control functions of control modules 412, 414, and 416 into a single controller. For example, a medical professional can use controller 418 and/or touchscreen 417 to manually control measurement apparatus 400 in the x-, y-, and z-axes, respectively. Controller 418 can comprise any device capable of controlling the manipulation of insertable portion 420. Controller can comprise, for example, a joystick, a rollerball, knobs, levers, buttons, or any other appropriate control device. Control system 435 further includes motors 436, pulleys 432, and guidewires 434. Although motors, pulleys, and guidewires are used in this example, control system 435 can include any other components capable of contributing to the manipulation of insertable portion 420 without departing from the scope of the present disclosure. In this example, motors 436 operate to control the positioning of insertable portion 420 based at least in part on control signals received from modules 411, 412, 414, and 416, and/or controller 418. Motors 436 operate to manipulate guidewires 434 coupled to one end of insertable portion 420. In other embodiments, base unit 410 includes actuators, pushrods, sprocket/chain mechanisms, feedback control circuitry, or any other control mechanism appropriate to control insertable portion 420. In this example, pulleys 432 and motors 436 operate to control the tension in guidewires 434. In some embodiments, each guidewire 434 may comprise two or more segments, each segment comprising a different radial stiffness. For example, a first segment of guidewire 434 may be coupled to pulley 432, and a second segment of guidewire 434 may be coupled to an end of insertable portion 420. In that example, the second segment of guidewire segment may have a radial stiffness that is less than a radial stiffness associated with the first segment guidewire. In various embodiments, the force exerted by guidewires 434 can cause insertable portion 430 to move in a corresponding manner. Measurement apparatus 400 may also include insertable portion 420 connected to base portion 410 and capable of being inserted into an orifice or incision in a patient's body during a medical procedure. In this particular embodiment, a medical professional can, using base portion 410, manipulate insertable portion 420 in the patient's body to perform a medical procedure. In various embodiments, a medical professional can control insertable portion 420 using voice commands, auxiliary input commands, automated commands, and/or manually. In this example, insertable portion 420 includes a flexible portion 430 and an automated head unit 440. In this particular embodiment, one end of each guidewire 434 is connected to one end of automated head unit 440, while the other end of each guidewire 434 is connected to one of pulleys 432. Although pulleys and guidewires are used to manipulate automated head unit 440, any other appropriate control mechanism may be used without departing from the scope of the present disclosure. In this example, control system 435 operates to create tension in guidewires 434. The tension in guidewires 434 operates to exert a force on automated head unit 440, which causes automated head unit 440 to move in a corresponding manner. For example, control system 435 may operate to apply tension to one or more guidewires 434 creating a force in the x-plane, which causes automated head unit 440 to move in the x-plane. Any suitable movement of automated head unit 440 in the x-y plane tends to impart a corresponding movement to flexible portion 430 in the x-y plane. In this example, four guidewires 434 are used to manipulate automated head unit 440 with two guidewires 434 connected along the x-axis and two guidewires 434 connected along the y-axis. In an alternative embodiment, six or more guidewires 434 may be positioned around the periphery of the insertable portion 420, which can allow a medical professional more precise control of measurement apparatus 400. In some cases, the movement of automated head unit 440 may be controlled independently of the movement of flexible portion 430. In some embodiments, flexible portion 430 and automated head unit 440 may operate as “telescoping” tubes, where automated head unit 440 may retract into and extend from flexible portion 430 to adjust a length (L) of insertable portion 420. Such a telescoping motion may be controlled through the positioning of pulleys 432 and guidewires 434. In this particular embodiment, control modules 412, 414, and/or 416 receive and process command signals corresponding to a desired manipulation of insertable portion 420. Control module 412 and control module 414 are operable to control the motion of automated head unit 440 and the entire insertable portion 420 in the x-axis and y-axis, respectively. In some embodiments, control module 416 is operable to adjust the distance that automated head unit 440 moves relative to flexible portion 430. In those cases, control module 416 is operable to cause motor 436 to position the pulleys 432 and guidewires 434 so as to extend and retract automated head unit 440 relative to flexible portion 430. Control module 412 and control module 414 are operable to independently control the motion of automated head unit 440 regardless of length L, enabling insertable portion 420 to have independent motion in the x-, y-, and z-axes. Insertable portion 420 may also include sensors 442 and a camera 444. Although this example depicts sensors 442 as being connected to automated head unit 440, sensors may be connected to any portion of measurement apparatus 400 without departing from the scope of the present disclosure. Injury may occur when a medical professional accidentally or mistakenly causes insertable portion 420 to contact tissue associated with the patient, which can cause bruising or damage to the tissue. Sensors 442 can comprise any device capable of providing data and/or a signal to a medical professional. Sensors 442 may be capable of generating and transmitting, for example, positioning information associated with insertable portion 420, physiological information associated with the patient, control signals, a signal indicating the presence or absence of blood, or any other data. In one particular embodiment, sensors 442 are capable of generating and transmitting data associated with proximity to tissue of the patient of insertable portion 420. In other embodiments, sensors 442 may be capable of detecting a collision with tissue. In those cases, sensors 442 are capable of generating and transmitting a feedback signal to control modules 412, 414, 416, a host coupled to measurement apparatus 400, or a system controller coupled to measurement apparatus 400. For example, sensors 442 may communicate data indicating that wall tissue of a patient's orifice has been encountered and that device 400 may need to be directed away from that wall to prevent injury to the patient's tissue. In some embodiments, sensors 442 operate to generate alarms associated with measurement apparatus 400. For example, one or more sensors 442 may monitor the presence of blood in the orifice, so that the medical professional may be alerted to unexpected or excessive bleeding. In operation, measurement apparatus 400 may be inserted into the patient by inserting insertable portion 420 into the appropriate orifice or incision. In some embodiments, a medical professional can insert measurement apparatus 400 into the patient. In other embodiments, the insertion of measurement apparatus 400 into the patient may be performed using a measurement apparatus control system implementing a manipulator, such as system 100 and manipulator 40 of FIG. 1 or system 300 and manipulator 240 of FIG. 2. In this particular embodiment, measurement apparatus 400 is capable of being manipulated in at least three axes of motion. That is, measurement apparatus 400 is capable of being manipulated in the x-axis, y-axis, and z-axis. In other embodiments, measurement apparatus 400 is capable of being manipulated in at least two axes of motion. In some embodiments, measurement apparatus 400 may be capable of manipulating insertable portion 420 one axis at a time. In other embodiments, measurement apparatus 400 may be capable of manipulating insertable portion 420 one axis at a time and manipulating insertable portion 420 along multiple axes substantially simultaneously. In this example, measurement apparatus 400 is capable of manipulating insertable portion 420 along multiple axes substantially simultaneously. As used throughout this document, the phrase, “substantially simultaneously” refers to the manipulation of insertable portion 420 and/or automated head unit 440 in multiple axes in response to an input command before responding to a subsequent input command. For example, measurement apparatus 400 can manipulate insertable portion 420 along the z-axis and, during that manipulation, measurement apparatus 400 can also manipulate insertable portion 420 along the x-axis. In various embodiments, measurement apparatus 400 can manipulate automated head unit 440 independently of the movement of flexible portion 430. FIG. 4 is a block diagram illustrating a flow of command signals from a medical professional to a measurement apparatus in a measurement apparatus control system 500. In various embodiments, measurement apparatus control system 500 can be substantially similar to control system 100 of FIG. 1 or control system 300 of FIG. 2. In this example, a communication device 550 receives a voice command 502 from a medical professional. In various embodiments, the structure and function of communication device 550 can be substantially similar to the structure and function of communication device 50 of FIG. 1. Communication device 550 operates to convert voice command 502 into an electrical voice command signal 504 and to communicate electrical voice command signal 504 to a system controller 590. In various embodiments, the structure and function of system controller 590 can be substantially similar to the structure and function of system controller 90 of FIG. I. In this particular embodiment, system controller 590 comprises a voice recognition module 592 capable of at least partially contributing to one or more functions of system controller 590. That is, voice control module 592 is not required to be capable of performing the desired functionality of system controller 590 alone, but may contribute to the performance of the function as part of a larger routine. In this example, voice recognition module 592 at least partially contributes to the conversion of voice command signal 504 to a control signal 506. Voice recognition module 592 may include any hardware, software, firmware, or any combination thereof that is capable of converting voice command signal 504 into control signal 506. System controller 590 also includes a command generator module 594 capable of at least partially contributing to one or more functions of system controller 590. In this example, command generator module 594 operates to receive control signal 506 communicated from voice recognition module 592 and at least partially contributes to the conversion of control signal 506 into a command signal 508. Command generator 594 may comprise any hardware, software, firmware, or any combination thereof that is capable of converting control signal 506 into command signal 508. In this example, command generator module 594 communicates command signal 508 to a signal generator module 596 capable of at least partially contributing to one or more functions of system controller 590. In this example, signal generator module 596 at least partially contributes to the conversion of command signal 508 into an actuation signal 510. Signal generator 596 may comprise any hardware, software, firmware, or any combination thereof that is capable of converting command signal 508 into actuation signal 510. In this example, system controller 590 communicates actuation signal 510 to a device control module 560 capable of manipulating a measurement apparatus 570. In various embodiments, the structure and function of device control module 560 can be substantially similar to the structure and function of actuation unit 20 of FIG. 1 or base portion 410 of FIG. 3. In various embodiments, the structure and function of measurement apparatus 570 can also be substantially similar to the structure and function of measurement apparatus 10 of FIG. 1 or measurement apparatus 400 of FIG. 3. In various embodiments, device control module 560 may be capable of generating a feedback signal 512 and communicating feedback signal 512 to system controller 590. Feedback signal 512 may comprise, for example, positioning data associated with measurement apparatus 570, a video feed, a physiological parameter associated with a patient, or any other information associated with measurement apparatus 570, device control module 560, and/or a patient undergoing a medical procedure. In some embodiments, measurement apparatus 570 can communicate data 514 to system controller 590. Data 514 may comprise, for example, positioning data, one or more physiological parameters associated with a patient, a live video feed associated with a camera coupled to measurement apparatus 570, or any other data capable of being collected by measurement apparatus 570. In various embodiments, system controller 590 may be capable of generating commands on its own based at least in part on data 514 and/or feedback signal 512 communicated from measurement apparatus 570 and/or device control module 560. For example, if measurement apparatus 570 comprises a scope with blood sensors, system controller 590 may stop the movement of the scope within a patient's body if data 514 is received from measurement apparatus 570 indicating that the patient is bleeding excessively. In this example, system 500 also includes a display device 580 capable of displaying data associated with measurement apparatus 570 and/or a patient. The structure and functional of display device 580 can be substantially similar to the structure and function of display device 60 or GUI 72 of FIG. 1. Although system 500 includes a single display device in this example, any other number of display devices may be used without departing from the scope of the present disclosure. In some embodiments, system controller 590 can communicate an output signal 516 containing data associated with measurement apparatus 570 and/or a patient to display device 580. In some embodiments, system 500 may also include an audio output device 587 capable of communicating data associated with measurement apparatus 570 and/or a patient. Audio output device 587 can comprise any device capable of providing an audio output signal, such as a speaker, headphones, an audio alarm device, or any other suitable audio output device. Although system 500 includes a single audio output device in this example, any other number of audio output devices may be used without departing from the scope of the present disclosure. In some embodiments, system controller 590 may communicate an audio output signal 516 to output device 587 so that the medical professional may receive the data associated with output signal 516 in audio format. Although, in most cases, voice command 502 represents the primary control input into system 500, system 500 also includes an auxiliary input device 585 capable of generating a control signal 518. Control signal 518 can comprise data that is substantially similar to data contained within control signal 506. In various embodiments, the structure and function of auxiliary input device 585 can be substantially similar to the structure and function of auxiliary input devices 165 or 180 of FIG. 2. Although system 500 includes a single auxiliary input device in this example, any other number of auxiliary input devices may be used without departing from the scope of the present disclosure. In this particular embodiment, auxiliary input device 585 is coupled directly to command generator 594. In some embodiments, auxiliary input device 585 may also receive data signals 520 from system controller 590. For example, in a case where auxiliary input device 585 comprises a “force-feedback” joystick, signals 520 may comprise the feedback signal representing the force being exerted on measurement apparatus 570 by the patient's body. FIG. 5 is a flow chart illustrating an exemplary method 600 for processing a voice control signal and/or a command signal received by a measurement apparatus control system. In one particular embodiment, voice control signals and/or command signals are received from system 100 of FIG. I. Although system 100 is used in this example, any other system, such as systems 300 and 500 of FIGS. 2 and 4, respectively, may be used without departing from the scope of the present disclosure. In this example, method 600 begins at step 602 where communication device 50 receives a voice command from a medical professional. Communication device 50 operates to convert the voice command into voice command signal 57 and communicates voice command signal 57 to host 70. In this particular example, host 70 includes a voice recognition module that processes voice command signal 57 at step 604 by converting voice command signal 57 into a control signal. In various embodiments, the structure and function of the voice recognition module can be substantially similar to voice recognition module 592 of FIG. 4. In this example, the voice recognition module further operates to identify the specific voice command represented by the control signal at step 606. In some embodiments, identifying the specific voice command may be accomplished by comparing the received control signal with a list of pre-programmed commands stored in a memory device associated with host 70. The voice recognition module validates the control signal at step 608. If the voice command is not recognized as a pre-programmed command, the invalid voice command is ignored and the method loops back to step 602. If the voice command is valid, the voice recognition module communicates the control signal to a command generator. In this example, the command generator operates to convert the control signal into a command signal representing the voice command at step 610. In various embodiments, the structure and function of the command generator can be substantially similar to the structure and function of command generator module 594 of FIG. 4. In an alternate embodiment, auxiliary control signals capable of manipulating a measurement apparatus may be generated by an auxiliary input device at step 616. In various embodiments, the auxiliary input device may comprise, for example, auxiliary input devices 165 and/or 180 of FIG. 2. The auxiliary input device communicates the auxiliary control signal to the command generator, which converts the auxiliary control signal into a command signal at step 610. The command generator also operates to communicate the command signal to a signal generator. In this example, the signal generator operates to convert the command signal into an actuation signal 47 representing the voice command of the medical professional at step 612. In various embodiments, the structure and function of the signal generator can be substantially similar to the structure and function of signal generator module 596 of FIG. 4. In this example, manipulator 40 and/or measurement apparatus 10 operates to receive and execute actuation signal 47 at step 614. Measurement apparatuss, such as a scope, that are adapted to be inserted into the patient's body typically permit the introduction of a waveguide structure or other wired device through the patient's orifice. The waveguide structure can comprise, for example, an optical fiber, a hollow tube waveguide, an air core waveguide, a planar waveguide, or a combination of these or other devices. Examples of such additional devices include, for example, surgical knives, sample collectors, and/or cauterizing heads. In some cases, inserting a waveguide structure may enable, for example, the early detection of cancerous cells and may contribute to the removal of the cancerous cells. In various embodiments, the waveguide structure may communicate an optical signal wavelength of 1.7 microns or more. In some embodiments, a waveguide structure may be implemented in a measurement apparatus that uses an optical signal wavelength in the mid-infrared (mid-IR) wavelength range to perform surgery and/or spectroscopy on a patient. In various embodiments, a wavelength in the mid-IR range comprises a wavelength between approximately two (2) microns and approximately ten (10) microns. In other embodiments, a wavelength in the mid-IR range comprises a wavelength between approximately five (5) and seven (7) microns. For light-based surgery and spectroscopy, it can be particularly advantageous to use an optical signal wavelength in the range between approximately 5 microns to approximately 7 microns to minimize tissue damage or collateral damage. In a particular embodiment, an optical signal having a wavelength of approximately 6.45 microns may be advantageously used for light-based surgery and/or spectroscopy. In some embodiments, a Raman wavelength shifter coupled to a pump laser is capable of generating an optical signal wavelength in the mid-IR range. As used in this document, the phrase “Raman wavelength shifter” refers to any device that uses the Raman effect to shift a shorter optical signal wavelength to a longer optical signal wavelength. The Raman wavelength shifters may comprise, for example, one or more reflectors, one or more gratings, an optical fiber, or a combination of these or other elements. In various embodiments, the Raman wavelength shifter may comprise, for example, a chalcogenide glass fiber that is capable of shifting the shorter pump laser wavelength to a longer wavelength, such as a wavelength in the mid-IR region. The chalcogenide fiber may comprise, for example, a ZBLAN fiber, a sulphide fiber, a selenides fiber, or a telluride fiber, or a combination of these or other fiber types. In other embodiments, a first wavelength shifter coupled to a pump laser may be capable of shifting an optical signal wavelength to approximately 2 microns. The first wavelength shifter may comprise, for example, a fused silica optical fiber capable of shifting the shorter pump laser wavelength to approximately two (2) microns. In that example, a second Raman wavelength shifter is coupled to the first Raman wavelength shifter and is capable of shifting the two (2) micron signal to a wavelength in the five (5) to seven (7) micron range. In that example, the second Raman wavelength shifter comprises a chalcogenide glass fiber. FIG. 6A compares a surgical incision made using a 2.94 micron optical signal wavelength to a surgical incision made using a 6.45 micron optical signal wavelength. This figure illustrates that tissue damage, such as denatured tissue, can result when a measurement apparatus implements a 2.94 micron optical signal wavelength. This tissue damage tends to result from the protein temperatures in the tissue do not uniformly exceed the water temperature in the aqueous components of the tissue. Compared to the incision performed using the 2.94 micron optical signal wavelength, the incision made using the 6.45 micron optical signal has little or no denatured tissue. This reduction in collateral tissue damage is based at least in part on the tissue's ability to absorb differential energy. For example, when using an optical signal wavelength at approximately 6.45 microns to create an incision, the protein temperatures in the tissue uniformly exceed the water temperature in the tissue and the protein begins to transform into brittle denatured protein. The brittle fracture of the proteins at the onset of explosive vaporization leads to the confinement of collateral damage. Therefore, the use of a 6.45 micron optical signal wavelength as a tissue cutting implement may minimize collateral tissue damage during laser-based surgery. By using an optical signal wavelength of 6.45 microns with a medical scope-type device, “clean” surgery may be performed for many medical procedures, such as removing cancerous polyps. Similar results can be obtained using an optical signal wavelength in the five (5) to seven (7) micron range. FIG. 6B illustrates example evanescent spectra in different cell-type regions (using a mouse as the biological sample). This figure illustrates that cancerous cells tend to show a distinct reduction 700 in transmission at an optical signal wavelength of approximately 6.1 microns. Medical professionals can exploit this spectral signature in various medical procedures, such as a procedure for the early detection of cancer. Thus, an optical signal wavelength in the mid-IR range may be used to perform a medical procedure for the early detection of tissue abnormalities such as cancer cells. In other embodiments, an optical signal wavelength in the mid-IR range can be used in a diagnostic procedure, such as spectroscopy. Diagnostic techniques capable of using the mid-IR optical signal wavelength include, for example, transmission, reflection, fluorescence, and near field microscopy. Although specific examples of spectroscopy are discussed, any other appropriate form of spectroscopy may be used without departing from the scope of this disclosure. To improve the signal-to-noise ratio of a spectroscopic measurement such as in FIG. 6B, several methodologies may be used. First, a differential measurement may be taken between a known cancer-free area and the suspect area, for example, differential spectroscopy rather than absolute spectroscopy. In addition, measurements may be taken at several wavelengths and compared to each other. For example, measuring the differential transmission of the tissue at two or more wavelengths, such as 5 microns and 6.1 microns, may: improve the signal-to-noise ratio of the cancer cell signature. FIG. 7 illustrates example attenuation characteristics of several optical fibers based on wavelength. This example shows that fused silica (Si02) fibers become lossy above approximately 2 microns in wavelength, while mid-IR optical fibers remain relatively loss-less above 2 microns. A mid-IR fiber may comprise any optical fiber capable of at least partially transmitting for at least a portion of the mid-IR range. For example, a mid-IR fiber may comprise a chalcogenide fiber, such as a sulfide fiber, a selenides fiber, or a telluride fiber. Therefore, in some cases, a pump source coupled to a measurement apparatus, such as measurement apparatus 400 of FIG. 3, may comprise a high powered pump source coupled to a Raman wavelength shifter comprising a mid-IR fiber. In a particular embodiment, such a pump source may operate in a pulsed mode or in a continuous wave mode. The power levels required depend on the particular application. For example, spectroscopy may require a relatively low power level, while surgery may require a relatively high power level. Conventional surgical devices capable of using a 5.0 to 6.5 micron optical signal wavelength typically implement a Free Electron Laser (FEL) pump source. However, a FEL pump source is a large and very expensive facility that tends to be impractical for surgical applications. Unlike conventional surgical devices, a measurement apparatus, such as device 400 of FIG. 3, can include a pump laser coupled to one or more Raman wavelength shifters capable of shifting a shorter signal wavelength to a longer signal wavelength. In that example, at least a portion of the Raman wavelength shifter can be implemented in a waveguide structure. In various embodiments, the longer signal wavelength can comprise, for example, an optical signal wavelength in the mid-IR wavelength range. Coupling a pump laser to one or more Raman wavelength shifters can result in a commercially and economically viable optical cutting implement for use in a measurement apparatus. In addition, coupling a pump laser to one or more Raman wavelength shifters can result in a significantly smaller footprint area than a FEL pump source and can significantly reduce the cost. Conventional wavelength shifters or oscillators are typically implemented in fused silica fiber. The loss associated with fused silica fiber tends to increase rapidly for optical signal wavelengths greater than about 2 or 2.3 microns. Unlike conventional wavelength shifters, a measurement apparatus, such as device 400 of FIG. 3, can include a Raman wavelength shifter or oscillator that is capable of transmitting in the mid-IR wavelength range, such as chalcogenide optical fibers. FIGS. 8A through 8D are block diagrams illustrating example embodiments of Raman wavelength shifters and/or Raman oscillators capable of shifting a shorter pump signal wavelength to a longer output signal wavelength. Although particular examples of wavelength shifters are described in FIGS. 8A through 8D, any other Raman wavelength shifter can be implemented without departing from the scope of the present disclosure. FIG. 8A is a block diagram illustrating one example of a Raman wavelength shifter 800 capable of shifting a shorter pump signal 810 wavelength to a longer output signal wavelength 812. In this example, Raman wavelength shifter 800 operates to generate an optical signal wavelength 812 of 1.7 microns or more. In various embodiments, Raman wavelength shifter 800 can operate to generate an optical signal wavelength 812 in the mid-IR wavelength range. In other embodiments, Raman wavelength shifter 800 can operate to generate an optical signal wavelength 812 a wavelength in the five (5) to seven (7) micron range. In various embodiments, pump signal 810 can comprise, for example, a 1310 nanometer (nm) wavelength, 1390 nm wavelength, 1510 nm wavelength, or other optical signal wavelength. Raman wavelength shifter includes a gain fiber 804 operable to facilitate shifting pump signal 810 to a desired wavelength. Gain fiber 804 may comprise any waveguide structure capable of wavelength shifting pump signal 810 to a longer wavelength or a different Raman cascade order. In this particular embodiment, gain fiber 804 comprises an optical fiber. The optical fiber used as gain fiber 804 may comprise, for example, a dispersion compensating fiber, a dispersion shifter fiber, a single mode fiber, a chalcogenide fiber, a fused silica optical fiber, or a combination of these or other fiber types. Raman wavelength shifter 800 also includes a broadband reflector 802 operable to substantially reflect all optical signal wavelengths contained within Raman wavelength shifter 800 and a pump signal coupler 806. Reflector 802 may comprise any device capable of reflecting a wide range of wavelength signals, such as a mirror. Pump signal coupler 806 may comprise any device capable of coupling pump signal 810 to Raman wavelength shifter 800, such as a wavelength division multiplexer or a power coupler. In this example, Raman wavelength shifter 800 further includes a wavelength separator 808 capable of transmitting at least a portion of the desired wavelength from Raman wavelength shifter 800. In addition, wavelength separator 808 operates to at least partially reflect a desired wavelength to gain medium 804 to continue lasing at the desired wavelength or wavelengths. In this particular embodiment, a cavity is formed between reflector 802 and wavelength separator 808. Separator 808 could comprise, for example, a demultiplexer, one or more partially transmissive gratings, one or more partially transmitting mirrors, one or more Fabry Perot filters, one or more dielectric gratings, or any combination of these or other devices. FIG. 8B is a block diagram illustrating one example of a Raman wavelength shifter 820 capable of shifting a shorter pump signal 830 wavelength to a longer output signal wavelength 832. In this example, Raman wavelength shifter 820 operates to generate an optical signal wavelength 832 of 1.7 microns or more. In various embodiments, Raman wavelength shifter 820 operates to generate an optical signal wavelength 832 in the mid-IR wavelength range. In other embodiments, Raman wavelength shifter 820 operates to generate an optical signal wavelength 832 a wavelength in the five (5) to seven (7) micron range. In various embodiments, pump signal 830 can comprise, for example, a 1310 nanometer (nm) wavelength, 1390 nm wavelength, 1510 nm wavelength, or other optical signal wavelength. In this example, Raman wavelength shifter 820 includes a reflector 822, a gain fiber 824, a pump input coupler 826, and a wavelength separator 828. In various embodiments, the structure and function of reflector 822, gain fiber 824, coupler 826, and separator 828 can be substantially similar to reflector 802, gain fiber 804, coupler 806, and separator 808 of FIG. 8A, respectively. In this particular embodiment, at least a portion of gain fiber 824 can comprise a chalcogenide fiber. Raman wavelength shifter 820 may also include at least a first selecting element 825a and a second selecting element 825b. Although this example may also include two selecting elements 825a and 825b, any number of selecting elements can be used without departing from the scope of the present disclosure. Selecting elements 825a and 825b can comprise any device, such as a dielectric grating or one or more Fabry Perot filters. Each selecting element operates to transmit a portion of a desired wavelength to be output from Raman wavelength shifter 820. In addition, each selecting element 825a and 825b operates to at least partially reflect a desired wavelength to gain medium 824 to allow wavelength shifter 820 to continue lasing at the desired wavelength or wavelengths. In this particular embodiment, an optical cavity is formed between reflector 822 and selecting element 825a and/or selecting element 825b. FIG. 8C is a block diagram illustrating one example of a Raman wavelength shifter 840 capable of shifting a shorter pump signal 850 wavelength to a longer output signal wavelength 852. In this example, Raman wavelength shifter 840 operates to generate an optical signal wavelength 852 of 1.7 microns or more. In various embodiments, Raman wavelength shifter 840 operates to generate an optical signal wavelength 852 in the mid-IR wavelength range. In other embodiments, Raman wavelength shifter 840 operates to generate an optical signal wavelength 852 a wavelength in the five (5) to seven (7) micron range. In various embodiments, pump signal 850 can comprise, for example, a 980 nanometer (nm) wavelength, a 1060 nm wavelength, a 1310 nm wavelength, a 1390 nm wavelength, a 1510 nm wavelength, or other optical signal wavelength. In this example, Raman wavelength shifter 840 includes a gain fiber 844, a pump input coupler 846, and selecting elements 845. In various embodiments, the structure and function of gain fiber 844, coupler 826, selecting elements 845, and output coupler 848 can be substantially similar to gain fiber 824, coupler 826, selecting elements 825, and coupler 828 of FIG. 8B, respectively. In this particular embodiment, at least a portion of gain fiber 824 can comprise a chalcogenide fiber. The example illustrated in FIG. 8C differs from the example illustrated in FIG. 8B in that wavelength shifter 840 implements a plurality of reflective gratings 847a-847n each centered on a different wavelength of a reflection band. Although this example includes three gratings, any number of gratings can be used without departing from the scope of the present disclosure. Gratings 847a-847n can comprise any device, such as a high-reflectivity dielectric grating. In this particular example, each grating 847a-847n comprises a grating with a reflectivity between ninety-five (95) to one hundred (100) percent at the center wavelength. Gratings 847a-847n operate to facilitate cascading of pump signal 850 to a desired output wavelength. In this particular embodiment, an optical cavity is formed between selecting elements 845 and gratings 847. FIG. 8D is a block diagram illustrating one example of a Raman wavelength shifter 860 capable of shifting a shorter pump signal 870 wavelength to a longer output signal wavelength 832. In this example, Raman wavelength shifter 860 operates to generate an optical signal wavelength 872 of 1.7 microns or more. In various embodiments, Raman wavelength shifter 860 operates to generate an optical signal wavelength 872 in the mid-IR wavelength range. In other embodiments, Raman wavelength shifter 860 operates to generate an optical signal wavelength 872 a wavelength in the five (5) to seven (7) micron range. In various embodiments, pump signal 870 can comprise, for example, a 980 nm wavelength, a 1060 nm wavelength, a 1310 nm wavelength, a 1390 nm wavelength, a 1510 nm wavelength, or other optical signal wavelength. In this example, Raman wavelength shifter 860 includes a gain fiber 864, a pump input coupler 866, electing elements 864, reflective gratings 867, and an output coupler 868. In various embodiments, the structure and function of gain fiber 864, input coupler 866, elements 864, gratings 867, and output coupler 868 can be substantially similar to gain fiber 844, coupler 846, elements 845, gratings 847, and coupler 848 of FIG. 8C, respectively. Although example elements are illustrated, Raman wavelength shifter 860 may include some, none, or all of these elements. For example, in some embodiments, pump input coupler 866 and/or output coupler 868 may be optional. The example illustrated in FIG. 8D differs from the example illustrated in FIG. 8C in that wavelength shifter 860 implements a Q-switcher 863 capable of transitioning from a reflective state to a transmissive state. Q-switcher 863 can comprise a device or combination of devices having a variable loss. For example, Q-switcher may comprise one or more moving mirrors, electro-optic switches, saturable absorbers, or a combination of these or other optical devices. In some cases, Q-switcher 863 can initially operate as a reflective mirror so that optical signal energy may build-up within the laser cavity. After the laser cavity contains a sufficient amount of optical energy, Qswitcher 863 can operate to substantially transmit the desired optical signal wavelength in the form of a relatively large pulse or burst. In various embodiments, Q-switcher 863 may be capable of providing an output signal having a pulse width in the range of two (2) nanoseconds to one hundred (100) milliseconds. In other embodiments, Q-switcher 863 may be capable of providing an output signal having a pulse repetition rate in the range of two (2) hertz to one hundred (100) megahertz. FIGS. 9A through 9C are block diagrams illustrating example embodiments of pump sources that are capable of generating a pump signal for use in a Raman wavelength shifter. Although particular examples of pump sources are described in FIGS. 9A through 9C, any other pump source can be implemented without departing from the scope of the present disclosure. FIG. 9A is a block diagram illustrating one example embodiment of a pump source 900 capable of being coupled to a Raman wavelength shifter and/or a Raman oscillator. Pump source 900 can comprise any device capable of generating an optical signal at a desired wavelength and power. For example, pump source 900 can comprise a solid state laser, such a Nd:YAG or Nd:YLF laser, a semiconductor laser, a laser diode, a cladding pump fiber laser, or any combination of these or other light sources. In this example, pump source 900 comprises a high powered laser 902 coupled to a Raman oscillator or a Raman wavelength shifter, such as Raman wavelength shifters 800, 820, 840, or 860 of FIGS. 8A through 8D. FIG. 9B is a block diagram illustrating one example embodiment of a pump source 920 capable of being coupled to a Raman wavelength shifter and/or a Raman oscillator. In this example, pump source 920 includes a pump laser 922 and an intermediate stage 924 capable of shifting the optical signal wavelength generated by pump laser 922 to a longer wavelength. The structure and function of laser 922 may be substantially similar to the structure and function of pump source 900 of FIG. 9A. In this particular example, intermediate state 924 comprises a first Raman wavelength shifter 924. In some embodiments, intermediate wavelength shifter 924 may advantageously be implemented using fused silica optical fiber. In some embodiments, pump sources 900 and 920 may comprise a cladding-pumped fiber laser, capable of emitting a pump signal wavelength of approximately 1 micron. In those examples, pump sources 900 and 920 can be coupled to a first or auxiliary cascaded Raman oscillator or Raman wavelength shifter. In some cases, the auxiliary Raman oscillator or Raman wavelength shifter may comprise, for example, Raman wavelength shifters 800, 820, 840, or 860 of FIGS. 8A through 8D implementing a fused silica optical fiber. Such an arrangement may be used to shift the 1 micron optical signal to approximately 2 to 2.3 microns. The 2-2.3 micron signal output from the auxiliary Raman wavelength shifter can then be shifted to a mid-IR wavelength by another cascaded Raman oscillator or Raman wavelength shifter that implements in mid-IR fiber. FIG. 9C is a block diagram illustrating one example embodiment of a pump source 940 capable of being coupled to a Raman wavelength shifter and/or a Raman oscillator. In this example, pump source 940 includes a pump laser 942 and a multiplexer 944 capable of combining a plurality of pump signals into a pump output signal. In this particular example, pump source 900 comprises a first laser diode 942a and a second laser diode 942b each centered at a desired wavelength and capable of generating pump signals 943a and 943b. Although this example includes two laser diodes, any number of laser diodes may be used without departing from the scope of the present disclosure. In various embodiments, laser diodes 942a and 942b can be centered on substantially the same wavelength, such as 980 nm, 1310 nm, 1390 nm, 14xx nm, or 1510 nm. In this particular embodiment, pump signals 943a and 943b are combined by multiplexer 944. Multiplexer 944 can comprise any device capable of combining pump signals 943, such as a wavelength division multiplexer. In various embodiments, multiplexer 944 can be capable of polarization and/or wavelength multiplexing pump signals 943a and 943b to form a pump output signal. In some embodiments, a Raman wavelength shifter, such as those illustrated in FIGS. 8A through 8D, may be used to deliver an optical signal wavelength directly to the patient. In other embodiments, a second mid-IR waveguide structure, that at least partially transmits in at least a portion of the mid-IR wavelength range, may be coupled to the output of the Raman wavelength shifter to deliver the optical signal wavelength to the patient. Coupling a second mid-IR waveguide structure to the Raman wavelength shifter can advantageously allow the delivery waveguide structure to be disposed after use within the patient. In addition, coupling a second mid-IR waveguide structure can substantially reduce the chance of breaking a fiber associated with a Raman wavelength shifter. Furthermore, it may be desirable to couple a tapered end or lens on the delivery fiber for improved focusing of optical signal on the patient. In various embodiments, an optical signal wavelength is capable of being delivered to a measurement apparatus inserted into a patient using a waveguide structure having a relatively low coupling loss. In some cases, the waveguide structure maintain the coupling loss to, for example, 5 dB or less, 3 dB or less, or even less than 1 dB. Although the present invention has been described with several embodiments, a multitude of changes, substitutions, variations, alterations, and modifications may be suggested to one skilled in the art, and it is intended that the invention encompass all such changes, substitutions, variations, alterations, and modifications as fall within the spirit and scope of the appended claims.
<SOH> TECHNICAL FIELD <EOH>This disclosure relates generally to medical diagnostic systems.
<SOH> SUMMARY OF EXAMPLE EMBODIMENTS <EOH>In one embodiment, a measurement apparatus comprises one or more sensors configured to generate signals associated with one or more physiological parameters, wherein at least one of the one or more sensors is adapted to be coupled to tissue comprising blood and to communicate to feedback control circuitry at least a portion of the signals associated with one or more physiological parameters. The feedback control circuitry may be capable of generating physiological information from the at least a portion of the signals associated with one or more physiological parameters. A software application is configured to operate on a control system that is capable of receiving at least some of the physiological information, the control system configured to receive voice input signals and manually entered input signals and comprising a touch-screen, a proximity sensor, circuitry for obtaining movement information from a positioning sensor, a mechanical system comprising one or more actuators, and a wireless transmitter to transmit data, including at least some of the physiological information, over a wireless link to a host. The host is configured to generate status information from the data and comprises a memory storage device for recording the status information and a communication device for communicating at least a portion of the status information over a communication link to one or more display output devices, wherein the one or more display output devices are located remotely from the host. In one embodiment, a measurement apparatus comprises a flexible portion, adapted to be inserted into a user's body, including one or more sensors configured to generate signals associated with one or more physiological parameters. At least one of the one or more sensors is adapted to be coupled to tissue comprising blood. The measurement apparatus is configured to communicate with a software application configured to operate on a control system adapted to receive and process physiological information. The control system comprises a touch-screen, a proximity sensor, circuitry for obtaining movement information from a positioning sensor, a mechanical system comprising one or more actuators, and a wireless transmitter to transmit data over a wireless link to a host. The software application is operable to generate the physiological information based at least in part on the signals from the one or more sensors. At least some of the physiological information comprises at least a part of the data, wherein the control system is further configured to receive voice input signals and manually entered input signals, and wherein alarms or alerts are capable of being generated based on the signals from the one or more sensors. In one embodiment, a measurement apparatus comprises one or more sensors configured to generate signals associated with one or more physiological parameters. The physiological parameters include at least one of blood pressure, heart rate and blood oxygen level. At least one of the one or more sensors is adapted to be coupled to tissue comprising blood and is adapted to be inserted into an orifice associated with a user. At least one of the one or more sensors is capable of generating data associated with proximity to the tissue comprising blood. The measurement apparatus is configured to communicate with a software application configured to operate on a control system adapted to receive and process physiological information. The control system comprises a touch-screen, a mechanical system comprising one or more actuators, and a wireless transmitter to transmit data over a wireless link to a host. The software application is operable to generate the physiological information based at least in part on the signals from the one or more sensors. At least some of the physiological information comprises at least a part of the data. The control system is further configured to receive voice input signals and manually entered input signals. In one embodiment, a measurement apparatus includes one or more sensors configured to generate signals associated with one or more physiological parameters, wherein at least one of the one or more sensors is adapted to be coupled to a tissue comprising blood. The measurement apparatus is configured to communicate through a base device to a software application configured to operate on a control system adapted to receive and process physiological information, wherein the base device is capable of receiving at least a portion of the signals associated with one or more physiological parameters. The control system comprises a touch-screen, a proximity sensor, circuitry for obtaining movement information from a positioning sensor, a mechanical system comprising one or more actuators, and a wireless transmitter to transmit data over a wireless link to a host. The software application is operable to generate the physiological information based at least in part on the signals from the one or more sensors, at least some of the physiological information comprising at least a part of the data, wherein the control system is further configured to receive voice input signals and manually entered input signals. The host is configured to generate status information from the data and comprises a memory storage device for recording the status information and a communication device for communicating at least a portion of the status information over a communication link to one or more display output devices, wherein the one or more display output devices are located remotely from the host. In another embodiment, a measurement apparatus includes one or more sensors configured to generate signals associated with one or more physiological parameters, wherein at least one of the one or more sensors is adapted to be coupled to a tissue comprising blood. The measurement apparatus is configured to communicate with a software application configured to operate on a control system adapted to receive and process physiological information. The control system comprises a touch-screen, a proximity sensor, circuitry for obtaining movement information from a positioning sensor, a mechanical system comprising one or more actuators, and a wireless transmitter to transmit data over a wireless link to a host. The software application is operable to generate the physiological information based at least in part on the signals from the one or more sensors, at least some of the physiological information comprising at least a part of the data. The control system is further configured to receive voice input signals and manually entered input signals. The host is configured to generate status information from the data and comprises a memory storage device for recording the status information and a communication device for communicating at least a portion of the status information over a communication link to one or more display output devices, wherein the one or more display output devices are located remotely from the host. In one embodiment, a measurement apparatus includes one or more sensors configured to generate signals associated with one or more physiological parameters, the physiological parameters including at least one of blood pressure, heart rate and blood oxygen level, wherein at least one of the one or more sensors is adapted to be coupled to a tissue comprising blood. The measurement apparatus is configured to communicate with a software application configured to operate on a control system adapted to receive and process physiological information. The control system includes a touch-screen, a proximity sensor, circuitry for obtaining movement information from a positioning sensor, a mechanical system comprising one or more actuators, and a wireless transmitter to transmit data over a wireless link to a host. The software application is operable to generate the physiological information based at least in part on the signals from the one or more sensors, at least some of the physiological information comprising at least a part of the data. The control system is further configured to receive voice input signals and manually entered input signals. The host is configured to generate status information from the data and comprises a memory storage device for recording the status information and a communication device for communicating at least a portion of the status information over a communication link to one or more display output devices, wherein the one or more display output devices are located remotely from the host. In one embodiment, a light-based medical diagnostic system includes a pump source comprising a plurality of semiconductor diodes with pump beams, a multiplexer capable of combining the plurality of semiconductor diode pump beams and generating at least a multiplexed pump beam comprising one or more wavelengths, a first waveguide structure configured to receive at least a portion of the one or more wavelengths, wherein the first waveguide structure comprises at least in part a gain fiber and outputs a first optical beam, and a second waveguide structure configured to receive at least a portion of the first optical beam and to communicate at least the portion of the first optical beam to an output end of the second waveguide structure to form an output beam, wherein at least a portion of the output beam comprises at least one wavelength in the range of 1.7 microns or more. A lens system is configured to receive at least the portion of the output beam and to communicate at least the portion of the output beam through a patient's mouth onto a part of a patient's body comprising a patient's blood. In various embodiments, at least the portion of the output beam is adapted for use in medical diagnostics to measure a property of the patient's blood, wherein the medical diagnostics comprise a spectroscopic procedure comprising a differential measurement, wherein the differential measurement is based at least in part on a comparison of amplitudes at a plurality of associated wavelengths transmitted or reflected from the patient's blood. In another embodiment, a light-based diagnostic system includes a pump source comprising a plurality of semiconductor diodes with pump beams, a multiplexer capable of combining the plurality of semiconductor diode pump beams and generating at least a multiplexed pump beam comprising one or more wavelength, first and second waveguide structures, and a lens system. The first waveguide structure is configured to receive at least a portion of the one or more wavelengths, wherein the first waveguide structure comprises at least in part a fused silica fiber, and outputs a first optical beam. The second waveguide structure is configured to receive at least a portion of the first optical beam and to communicate at least the portion of the first optical beam to an output end of the second waveguide structure to form an output beam. The lens system is configured to receive at least a portion of the output beam and to communicate at least the portion of the output beam through an orifice in a patient's body. In various embodiments, at least the portion of the output beam is adapted for use in multi-wavelength diagnostics to measure a property of a part of the patient's body, wherein the multi-wavelength diagnostics comprise a spectroscopic procedure comprising a differential measurement, wherein the differential measurement is based at least in part on a comparison of amplitudes at a plurality of associated wavelengths transmitted or reflected from the part of the patient's body. In yet another embodiment, a light-based medical diagnostic system includes a pump source comprising a plurality of semiconductor diodes with pump beams and a multiplexer capable of combining the plurality of semiconductor diode pump beams and generating at least a multiplexed pump beam comprising one or more wavelengths. A first waveguide structure is configured to receive at least a portion of the one or more wavelengths, wherein the first waveguide structure comprises at least in part a fused silica fiber, and outputs a first optical beam. A second waveguide structure is configured to receive at least a portion of the first optical beam and to communicate at least the portion of the first optical beam to an output end of the second waveguide structure to form an output beam. A lens system is configured to receive at least a portion of the output beam and to communicate at least the portion of the output beam onto a part of a patient's body comprising a patient's blood. In one embodiment, a measurement apparatus comprises an insertable portion capable of being inserted into an orifice associated with a body of a patient. The insertable portion comprising an automated head unit capable of being manipulated in at least two axes of motion based at least in part on one or more control signals. The measurement apparatus further comprises one or more controllers coupled to the automated head unit. In one particular embodiment, the one or more controllers generate the one or more control signals based at least in part on an input signal. In another embodiment, a measurement apparatus capable of minimizing tissue damage comprises an insertable portion capable of being inserted into an orifice associated with a body of a patient. The measurement apparatus further comprises one or more sensors coupled to the insertable portion. The one or more sensors capable of generating a feedback signal capable of being used to substantially minimize damage to tissue associated with the patient. In yet another embodiment, a measurement apparatus capable of being used in a medical procedure comprises a pump laser capable of generating a pump signal. The measurement apparatus further comprises a Raman wavelength shifter coupled to the pump laser, at least a portion of the wavelength shifter comprising a waveguide structure. In one particular embodiment, the Raman wavelength shifter generates an output optical signal comprising a wavelength of approximately 1.7 microns or more. In still another embodiment, a measurement apparatus capable of being used in a medical procedure comprises a Raman wavelength shifter operable to generate an optical signal comprising a mid-infrared wavelength. At least a portion of the Raman wavelength shifter comprises a chalcogenide waveguide. In another embodiment, a system for controlling a measurement apparatus includes a monitor capable of communicating medical information associated with a patient and a communication device capable of receiving one or more input signals from a user. In one particular embodiment, the one or more input signals are based at least in part on the medical information displayed on the monitor. The system further includes one or more processors coupled to the communicated device and operable to convert the one or more input signals into one or more control signals capable of being used to manipulate a measurement apparatus. Depending on the specific features implemented, particular embodiments may exhibit some, none, or all of the following technical advantages. Various embodiments may be capable of reducing medical professional fatigue through the implementation of a control system capable of manipulating a measurement apparatus through voice commands. Some embodiments may be capable of controlling a measurement apparatus from a remote location. Other embodiments may be capable of reducing the level of dexterity required of a medical professional when performing a medical procedure. Other technical advantages will be readily apparent to one skilled in the art from the following figures, description, and claims. Moreover, while specific advantages have been enumerated, various embodiments may include all, some, or none of the enumerated advantages.
A61B50075
20170920
20180626
20180201
61148.0
A61B500
1
HELLNER, MARK
MEASUREMENT APPARATUS FOR PHYSIOLOGICAL PARAMETERS
UNDISCOUNTED
1
CONT-ACCEPTED
A61B
2,017
15,712,074
ACCEPTED
Biosynthesis Of Human Milk Oligosaccharides In Engineered Bacteria
The invention provides compositions and methods for engineering bacteria to produce fucosylated oligosaccharides, and the use thereof in the prevention or treatment of infection.
1. A method for producing a fucosylated oligosaccharide in a bacterium, comprising providing a bacterium, said bacterium comprising a functional β-galactosidase gene, an exogenous fucosyltransferase gene, a GDP-fucose synthesis pathway, a functional lactose permease gene; culturing said bacterium in the presence of lactose; and retrieving a fucosylated oligosaccharide from said bacterium or from a culture supernatant of said bacterium. 2. The method of claim 1, wherein said β-galactosidase gene comprises an E. coli lacZ gene. 3. The method of claim 1, wherein said β-galactosidase gene is an endogenous β-galactosidase gene or an exogenous β-galactosidase gene. 4. The method of claim 1, wherein said bacterium accumulates an increased intracellular lactose pool, and produces a low level of β-galactosidase. 5. The method of claim 1, wherein said exogenous fucosyltransferase gene encodes α(1,2) fucosyltransferase or α(1,3) fucosyltransferase. 6. The method of claim 5, wherein said α(1,2) fucosyltransferase gene comprises a Bacteroides fragilis wcfW gene. 7. The method of claim 5, wherein said α(1,3) fucosyltransferase gene comprises a Helicobacter pylori 26695 futA gene. 8. The method of claim 5, wherein said bacterium comprises both an exogenous fucosyltransferase gene encoding α(1,2) fucosyltransferase and an exogenous fucosyltransferase gene encoding α(1,3) fucosyltransferase. 9. The method of claim 1, wherein said GDP-fucose synthesis pathway comprises endogenous enzymes or exogenous enzymes. 10. The method of claim 1, wherein said lactose permease gene is an endogenous lactose permease gene or an exogenous lactose permease gene. 11. A method for producing a fucosylated oligosaccharide in a bacterium, comprising providing an enteric bacterium, said bacterium comprising a functional β-galactosidase gene, an exogenous fucosyltransferase gene, a mutation in a colanic acid synthesis gene, and a functional lactose permease gene; culturing said bacterium in the presence of lactose; and retrieving a fucosylated oligosaccharide from said bacterium or from a culture supernatant of said bacterium. 12. The method of claim 11, wherein said β-galactosidase gene comprises an E. coli lacZ gene. 13. The method of claim 11, wherein said exogenous fucosyltransferase gene encodes α(1,2) fucosyltransferase or α(1,3) fucosyltransferase. 14. The method of claim 11, wherein said enteric bacterium comprises E. coli. 15. The method of claim 14, wherein said colanic acid synthesis gene comprises a wcaJ gene 16. The method of claim 14, wherein said bacterium further comprises a mutation in a lon gene. 17. The method of claim 14, wherein said bacterium comprises a functional, wild-type E. coli lacZ+ gene inserted into an endogenous lon gene. 18. The method of claim 14, wherein an endogenous lacZ gene of said E. coli is deleted. 19. The method of claim 14, wherein said bacterium further comprises an exogenous rcsA or rcsB gene. 20. The method of claim 14, wherein said bacterium further comprises a mutation in a lacA gene. 21. A method for producing a 3′-sialyl-3-fucosyllactose (3′-S3FL) in a bacterium, said bacterium comprising a functional β-galactosidase gene, an exogenous sialyl-transferase gene, an exogenous fucosyltransferase gene, a GDP-fucose synthesis pathway, a deficient sialic acid catabolic pathway, a sialic acid synthetic capability, and a functional lactose permease gene; culturing said bacterium in the presence of lactose; and retrieving said 3′-S3FL from said bacterium or from a culture supernatant of said bacterium. 22. The method of claim 21, wherein said exogenous sialyl-transferase gene encodes α(2,3)sialyl-transferase. 23. The method of claim 21, wherein said exogenous fucosyltransferase gene encodes α(1,3) fucosyltransferase. 24. The method of claim 21, wherein said deficient sialic acid catabolic pathway comprises a null mutation in endogenous N-acetylneuraminate lyase or N-acetylmannosamine kinase genes. 25. The method of claim 21, wherein said sialic acid synthetic capability comprises an exogenous UDP-GlcNAc 2-epimerase gene, an exogenous Neu5Ac synthase gene, or an exogenous CMP-Neu5Ac synthetase gene. 26. A method for producing a 3′-sialyl-3-fucosyllactose (3′-S3FL) in an enteric bacterium, said enteric bacterium comprising a functional lacZ gene, an exogenous fucosyltransferase gene, an exogenous sialyltransferase gene, a mutation in an endogenous colanic acid synthesis gene, a functional lactose permease gene, a deficient sialic acid catabolic pathway, and sialic acid synthetic capability; culturing said bacterium in the presence of lactose; and retrieving said 3′-S3FL from said bacterium or from a culture supernatant of said bacterium. 27. The method of claim 26, wherein said exogenous fucosyltransferase gene encodes α(1,3) fucosyltransferase. 28. The method of claim 26, wherein said exogenous sialyltransferase gene encodes an α(2,3)sialyl transferase. 29. The method of claim 26, wherein said deficient sialic acid catabolic pathway comprises a null mutation in endogenous N-acetylneuraminate lyase or N-acetylmannosamine kinase genes. 30. The method of claim 26, wherein said sialic acid synthetic capability comprises an exogenous UDP-GlcNAc 2-epimerase gene, an exogenous Neu5Ac synthase gene, or an exogenous CMP-Neu5Ac synthetase gene.
RELATED APPLICATIONS This application is a continuation of U.S. Ser. No. 15/442,131, filed Feb. 24, 2017, which is a continuation of U.S. Ser. No. 14/033,664 filed Sep. 23, 2013, now U.S. Pat. No. 9,587,241 issued Feb. 15, 2017, which is a divisional of U.S. Ser. No. 13/398,526 filed Feb. 16, 2012, now U.S. Pat. No. 9,453,230 issued Sep. 27, 2016, and claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 61/443,470, filed Feb. 16, 2011, the entire contents of each of which are incorporated herein by reference. INCORPORATED-BY-REFERENCE OF SEQUENCE LISTING The contents of the text file named “37847-505C03US_Sequence_Listing.txt”, which was created on Sep. 21, 2017 and is 94 KB in size, are hereby incorporated by reference in their entirety. FIELD OF THE INVENTION The invention provides compositions and methods for producing purified oligosaccharides, in particular certain fucosylated and/or sialylated oligosaccharides that are typically found in human milk. BACKGROUND OF THE INVENTION Human milk contains a diverse and abundant set of neutral and acidic oligosaccharides (human milk oligosaccharides, HMOS). Many of these molecules are not utilized directly by infants for nutrition, but they nevertheless serve critical roles in the establishment of a healthy gut microbiome, in the prevention of disease, and in immune function. Prior to the invention described herein, the ability to produce HMOS inexpensively at large scale was problematic. For example, HMOS production through chemical synthesis was limited by stereo-specificity issues, precursor availability, product impurities, and high overall cost. As such, there is a pressing need for new strategies to inexpensively manufacture large quantities of HMOS for a variety of commercial applications. SUMMARY OF THE INVENTION The invention described herein features efficient and economical methods for producing fucosylated and sialylated oligosaccharides. The method for producing a fucosylated oligosaccharide in a bacterium comprises the following steps: providing a bacterium that comprises a functional β-galactosidase gene, an exogenous fucosyltransferase gene, a GDP-fucose synthesis pathway, and a functional lactose permease gene; culturing the bacterium in the presence of lactose; and retrieving a fucosylated oligosaccharide from the bacterium or from a culture supernatant of the bacterium. To produce a fucosylated oligosaccharide by biosynthesis, the bacterium utilizes an endogenous or exogenous guanosine diphosphate (GDP)-fucose synthesis pathway. By “GDP-fucose synthesis pathway” is meant a sequence of reactions, usually controlled and catalyzed by enzymes, which results in the synthesis of GDP-fucose. An exemplary GDP-fucose synthesis pathway in Escherichia coli is set forth below. In the GDP-fucose synthesis pathway set forth below, the enzymes for GDP-fucose synthesis include: 1) manA=phosphomannose isomerase (PMI), 2) manB=phosphomannomutase (PMM), 3) manC=mannose-1-phosphate guanylyltransferase (GMP), 4) gmd=GDP-mannose-4,6-dehydratase (GMD), 5) fcl=GDP-fucose synthase (GFS), and 6) ΔwcaJ=mutated UDP-glucose lipid carrier transferase. Glucose→Glc-6-P→Fru-6-P→1 Man-6-P→2 Man-1-P→3 GDP-Man→4,5 GDP-Fuc 6 Colanic acid. The synthetic pathway from fructose-6-phosphate, a common metabolic intermediate of all organisms, to GDP-fucose consists of 5 enzymatic steps: 1) PMI (phosphomannose isomerase), 2) PMM (phosphomannomutase), 3) GMP (mannose-1-phosphate guanylyltransferase), 4) GMD (GDP-mannose-4,6-dehydratase), and 5) GFS (GDP-fucose synthase). Individual bacterial species possess different inherent capabilities with respect to GDP-fucose synthesis. Escherichia coli, for example, contains enzymes competent to perform all five steps, whereas Bacillus licheniformis is missing enzymes capable of performing steps 4 and 5 (i.e., GMD and GFS). Any enzymes in the GDP-synthesis pathway that are inherently missing in any particular bacterial species are provided as genes on recombinant DNA constructs, supplied either on a plasmid expression vector or as exogenous genes integrated into the host chromosome. The invention described herein details the manipulation of genes and pathways within bacteria such as the enterobacterium Escherichia coli K12 (E. coli) or probiotic bacteria leading to high level synthesis of HMOS. A variety of bacterial species may be used in the oligosaccharide biosynthesis methods, for example Erwinia herbicola (Pantoea agglomerans), Citrobacter freundii, Pantoea citrea, Pectobacterium carotovorum, or Xanthomonas campestris. Bacteria of the genus Bacillus may also be used, including Bacillus subtilis, Bacillus licheniformis, Bacillus coagulans, Bacillus thermophilus, Bacillus laterosporus, Bacillus megaterium, Bacillus mycoides, Bacillus pumilus, Bacillus lentus, Bacillus cereus, and Bacillus circulans. Similarly, bacteria of the genera Lactobacillus and Lactococcus may be modified using the methods of this invention, including but not limited to Lactobacillus acidophilus, Lactobacillus salivarius, Lactobacillus plantarum, Lactobacillus helveticus, Lactobacillus delbrueckii, Lactobacillus rhamnosus, Lactobacillus bulgaricus, Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus casei, Lactobacillus reuteri, Lactobacillus jensenii, and Lactococcus lactis. Streptococcus thermophiles and Proprionibacterium freudenreichii are also suitable bacterial species for the invention described herein. Also included as part of this invention are strains, modified as described here, from the genera Enterococcus (e.g., Enterococcus faecium and Enterococcus thermophiles), Bifidobacterium (e.g., Bifidobacterium longum, Bifidobacterium infantis, and Bifidobacterium bifidum), Sporolactobacillus spp., Micromomospora spp., Micrococcus spp., Rhodococcus spp., and Pseudomonas (e.g., Pseudomonas fluorescens and Pseudomonas aeruginosa). Bacteria comprising the characteristics described herein are cultured in the presence of lactose, and a fucosylated oligosaccharide is retrieved, either from the bacterium itself or from a culture supernatant of the bacterium. The fucosylated oligosaccharide is purified for use in therapeutic or nutritional products, or the bacteria are used directly in such products. The bacterium also comprises a functional β-galactosidase gene. The β-galactosidase gene is an endogenous β-galactosidase gene or an exogenous β-galactosidase gene. For example, the β-galactosidase gene comprises an E. coli lacZ gene (e.g., GenBank Accession Number V00296 (GI:41901), incorporated herein by reference). The bacterium accumulates an increased intracellular lactose pool, and produces a low level of β-galactosidase. A functional lactose permease gene is also present in the bacterium. The lactose permease gene is an endogenous lactose permease gene or an exogenous lactose permease gene. For example, the lactose permease gene comprises an E. coli lacY gene (e.g., GenBank Accession Number V00295 (GI:41897), incorporated herein by reference). Many bacteria possess the inherent ability to transport lactose from the growth medium into the cell, by utilizing a transport protein that is either a homolog of the E. coli lactose permease (e.g., as found in Bacillus licheniformis), or a transporter that is a member of the ubiquitous PTS sugar transport family (e.g., as found in Lactobacillus casei and Lactobacillus rhamnosus). For bacteria lacking an inherent ability to transport extracellular lactose into the cell cytoplasm, this ability is conferred by an exogenous lactose transporter gene (e.g., E. coli lacy) provided on recombinant DNA constructs, and supplied either on a plasmid expression vector or as exogenous genes integrated into the host chromosome. The bacterium comprises an exogenous fucosyltransferase gene. For example, the exogenous fucosyltransferase gene encodes α(1,2) fucosyltransferase and/or α(1,3) fucosyltransferase. An exemplary α(1,2) fucosyltransferase gene is the wcfW gene from Bacteroides fragilis NCTC 9343 (SEQ ID NO: 4). An exemplary α(1,3) fucosyltransferase gene is the Helicobacter pylori 26695 futA gene. One example of the Helicobacter pylori futA gene is presented in GenBank Accession Number HV532291 (GI:365791177), incorporated herein by reference. Alternatively, a method for producing a fucosylated oligosaccharide by biosynthesis comprises the following steps: providing an enteric bacterium that comprises a functional β-galactosidase gene, an exogenous fucosyltransferase gene, a mutation in a colanic acid synthesis gene, and a functional lactose permease gene; culturing the bacterium in the presence of lactose; and retrieving a fucosylated oligosaccharide from the bacterium or from a culture supernatant of the bacterium. To produce a fucosylated oligosaccharide by biosynthesis, the bacterium comprises a mutation in an endogenous colanic acid (a fucose-containing exopolysaccharide) synthesis gene. By “colanic acid synthesis gene” is meant a gene involved in a sequence of reactions, usually controlled and catalyzed by enzymes that result in the synthesis of colanic acid. Exemplary colanic acid synthesis genes include an rcsA gene (e.g., GenBank Accession Number M58003 (GI:1103316), incorporated herein by reference), an rcsB gene, (e.g., GenBank Accession Number E04821 (GI:2173017), incorporated herein by reference), a weal gene, (e.g., GenBank Accession Number (amino acid) BAA15900 (GI:1736749), incorporated herein by reference), a wzxC gene, (e.g., GenBank Accession Number (amino acid) BAA15899 (GI:1736748), incorporated herein by reference), a wcaD gene, (e.g., GenBank Accession Number (amino acid) BAE76573 (GI:85675202), incorporated herein by reference), a wza gene, (e.g., GenBank Accession Number (amino acid) BAE76576 (GI:85675205), incorporated herein by reference), a wzb gene, and (e.g., GenBank Accession Number (amino acid) BAE76575 (GI:85675204), incorporated herein by reference), and a wzc gene (e.g., GenBank Accession Number (amino acid) BAA15913 (GI:1736763), incorporated herein by reference). This is achieved through a number of genetic modifications of endogenous E. coli genes involved either directly in colanic acid precursor biosynthesis, or in overall control of the colanic acid synthetic regulon. Specifically, the ability of the host E. coli strain to synthesize colanic acid, an extracellular capsular polysaccharide, is eliminated by the deletion of the wcaJ gene, encoding the UDP-glucose lipid carrier transferase. In a wcaJ null background, GDP-fucose accumulates in the E. coli cytoplasm. Over-expression of a positive regulator protein, RcsA, in the colanic acid synthesis pathway results in an increase in intracellular GDP-fucose levels. Over-expression of an additional positive regulator of colanic acid biosynthesis, namely RcsB, is also utilized, either instead of or in addition to over-expression of RcsA, to increase intracellular GDP-fucose levels. Alternatively, colanic acid biosynthesis is increased following the introduction of a null mutation into the E. coli lon gene (e.g., GenBank Accession Number L20572 (GI:304907), incorporated herein by reference). Lon is an adenosine-5′-triphosphate (ATP)-dependant intracellular protease that is responsible for degrading RcsA, mentioned above as a positive transcriptional regulator of colanic acid biosynthesis in E. coli. In a lon null background, RcsA is stabilized, RcsA levels increase, the genes responsible for GDP-fucose synthesis in E. coli are up-regulated, and intracellular GDP-fucose concentrations are enhanced. For example, the bacterium further comprises a functional, wild-type E. coli lacZ+ gene inserted into an endogenous gene, for example the lon gene in E. coli. In this manner, the bacterium may comprise a mutation in a lon gene. The bacterium also comprises a functional β-galactosidase gene. The β-galactosidase gene is an endogenous β-galactosidase gene or an exogenous β-galactosidase gene. For example, the β-galactosidase gene comprises an E. coli lacZ gene. The endogenous lacZ gene of the E. coli is deleted or functionally inactivated, but in such a way that expression of the downstream lactose permease (lacY) gene remains intact. The bacterium comprises an exogenous fucosyltransferase gene. For example, the exogenous fucosyltransferase gene encodes α(1,2) fucosyltransferase and/or α(1,3) fucosyltransferase. An exemplary α(1,2) fucosyltransferase gene is the wcfW gene from Bacteroides fragilis NCTC 9343 (SEQ ID NO: 4). An exemplary α(1,3) fucosyltransferase gene is the Helicobacter pylori 26695 futA gene. One example of the Helicobacter pylori futA gene is presented in GenBank Accession Number HV532291 (GI:365791177), incorporated herein by reference. A functional lactose permease gene is also present in the bacterium. The lactose permease gene is an endogenous lactose permease gene or an exogenous lactose permease gene. For example, the lactose permease gene comprises an E. coli lacY gene. The bacterium may further comprise an exogenous rcsA and/or rcsB gene (e.g., in an ectopic nucleic acid construct such as a plasmid), and the bacterium optionally further comprises a mutation in a lacA gene (e.g., GenBank Accession Number X51872 (GI:41891), incorporated herein by reference). Bacteria comprising the characteristics described herein are cultured in the presence of lactose, and a fucosylated oligosaccharide is retrieved, either from the bacterium itself or from a culture supernatant of the bacterium. The fucosylated oligosaccharide is purified for use in therapeutic or nutritional products, or the bacteria are used directly in such products. The bacteria used herein to produce HMOS are genetically engineered to comprise an increased intracellular guanosine diphosphate (GDP)-fucose pool, an increased intracellular lactose pool (as compared to wild type) and to comprise fucosyl transferase activity. Accordingly, the bacterium contains a mutation in a colanic acid (a fucose-containing exopolysaccharide) synthesis pathway gene, such as a wcaJ gene, resulting in an enhanced intracellular GDP-fucose pool. The bacterium further comprises a functional, wild-type E. coli lacZ+ gene inserted into an endogenous gene, for example the lon gene in E. coli. In this manner, the bacterium may further comprise a mutation in a lon gene. The endogenous lacZ gene of the E. coli is deleted or functionally inactivated, but in such a way that expression of the downstream lactose permease (lacY) gene remains intact. The organism so manipulated maintains the ability to transport lactose from the growth medium, and to develop an intracellular lactose pool for use as an acceptor sugar in oligosaccharide synthesis, while also maintaining a low level of intracellular beta-galactosidase activity useful for a variety of additional purposes. The bacterium may further comprise an exogenous rcsA and/or rcsB gene (e.g., in an ectopic nucleic acid construct such as a plasmid), and the bacterium optionally further comprises a mutation in a lacA gene. Preferably, the bacterium accumulates an increased intracellular lactose pool, and produces a low level of beta-galactosidase. The bacterium possesses fucosyl transferase activity. For example, the bacterium comprises one or both of an exogenous fucosyltransferase gene encoding an α(1,2) fucosyltransferase and an exogenous fucosyltransferase gene encoding an α(1,3) fucosyltransferase. An exemplary α(1,2) fucosyltransferase gene is the wcfW gene from Bacteroides fragilis NCTC 9343 (SEQ ID NO: 4). Prior to the present invention, this wcfW gene was not known to encode a protein with an α(1,2) fucosyltransferase activity, and further was not suspected to possess the ability to utilize lactose as an acceptor sugar. Other α(1,2) fucosyltransferase genes that use lactose as an acceptor sugar (e.g., the Helicobacter pylori 26695 futC gene or the E. coli O128:B12 wbsJ gene) may readily be substituted for Bacteroides fragilis wcjW. One example of the Helicobacter pylori futC gene is presented in GenBank Accession Number EF452503 (GI:134142866), incorporated herein by reference. An exemplary α(1,3) fucosyltransferase gene is the Helicobacter pylori 26695 futA gene, although other α(1,3) fucosyltransferase genes known in the art may be substituted (e.g., α(1,3) fucosyltransferase genes from Helicobacter hepaticus Hh0072, Helicobacter bilis, Campylobacter jejuni, or from Bacteroides species). The invention includes a nucleic acid construct comprising one, two, three or more of the genes described above. For example, the invention includes a nucleic acid construct expressing an exogenous fucosyltransferase gene (encoding α(1,2) fucosyltransferase or α(1,3) fucosyltransferase) transformed into a bacterial host strain comprising a deleted endogenous β-galactosidase (e.g., lacZ) gene, a replacement functional β-galactosidase gene of low activity, a GDP-fucose synthesis pathway, a functional lactose permease gene, and a deleted lactose acetyltransferase gene. Also within the invention is an isolated E. coli bacterium as described above and characterized as comprising a defective colanic acid synthesis pathway, a reduced level of β-galactosidase (LacZ) activity, and an exogenous fucosyl transferase gene. The invention also includes: a) methods for phenotypic marking of a gene locus in a β-galactosidase negative host cell by utilizing a β-galactosidase (e.g., lacZ) gene insert engineered to produce a low but readily detectable level of β-galactosidase activity, b) methods for readily detecting lytic bacteriophage contamination in fermentation runs through release and detection of cytoplasmic β-galactosidase in the cell culture medium, and c) methods for depleting a bacterial culture of residual lactose at the end of production runs. a), b) and c) are each achieved by utilizing a functional β-galactosidase (e.g., lacZ) gene insert carefully engineered to direct the expression of a low, but detectable level of β-galactosidase activity in an otherwise β-galactosidase negative host cell. A purified fucosylated oligosaccharide produced by the methods described above is also within the invention. A purified oligosaccharide, e.g., 2′-FL, 3FL, LDFT, is one that is at least 90%, 95%, 98%, 99%, or 100% (w/w) of the desired oligosaccharide by weight. Purity is assessed by any known method, e.g., thin layer chromatography or other electrophoretic or chromatographic techniques known in the art. The invention includes a method of purifying a fucosylated oligosaccharide produced by the genetically engineered bacterium described above, which method comprises separating the desired fucosylated oligosaccharide (e.g., 2′-FL) from contaminants in a bacterial cell extract or lysate, or bacterial cell culture supernatant. Contaminants include bacterial DNA, protein and cell wall components, and yellow/brown sugar caramels sometimes formed in spontaneous chemical reactions in the culture medium. The oligosaccharides are purified and used in a number of products for consumption by humans as well as animals, such as companion animals (dogs, cats) as well as livestock (bovine, equine, ovine, caprine, or porcine animals, as well as poultry). For example, a pharmaceutical composition comprising purified 2′-fucosyllactose (2′-FL), 3-fucosyllactose (3FL), lactodifucotetraose (LDFT), or 3′-sialyl-3-fucosyllactose (3′-S3FL) and an excipient is suitable for oral administration. Large quantities of 2′-FL, 3FL, LDFT, or 3′-S3FL are produced in bacterial hosts, e.g., an E. coli bacterium comprising a heterologous α(1,2)fucosyltransferase, a heterologous α(1,3) fucosyltransferase, or a heterologous sialyltransferase, or a combination thereof. An E. coli bacterium comprising an enhanced cytoplasmic pool of each of the following: lactose, GDP-fucose, and CMP-Neu5Ac, is useful in such production systems. In the case of lactose and GDP-fucose, endogenous E. coli metabolic pathways and genes are manipulated in ways that result in the generation of increased cytoplasmic concentrations of lactose and/or GDP-fucose, as compared to levels found in wild type E. coli. For example, the bacteria contain at least 10%, 20%, 50%, 2×, 5×, 10× or more of the levels in a corresponding wild type bacteria that lacks the genetic modifications described above. In the case of CMP-Neu5Ac, endogenous Neu5Ac catabolism genes are inactivated and exogenous CMP-Neu5Ac biosynthesis genes introduced into E. coli resulting in the generation of a cytoplasmic pool of CMP-Neu5Ac not found in the wild type bacterium. A method of producing a pharmaceutical composition comprising a purified HMOS is carried out by culturing the bacterium described above, purifying the HMOS produced by the bacterium, and combining the HMOS with an excipient or carrier to yield a dietary supplement for oral administration. These compositions are useful in methods of preventing or treating enteric and/or respiratory diseases in infants and adults. Accordingly, the compositions are administered to a subject suffering from or at risk of developing such a disease. The invention therefore provides methods for increasing intracellular levels of GDP-fucose in Escherichia coli by manipulating the organism's endogenous colanic acid biosynthesis pathway. This is achieved through a number of genetic modifications of endogenous E. coli genes involved either directly in colanic acid precursor biosynthesis, or in overall control of the colanic acid synthetic regulon. The invention also provides for increasing the intracellular concentration of lactose in E. coli, for cells grown in the presence of lactose, by using manipulations of endogenous E. coli genes involved in lactose import, export, and catabolism. In particular, described herein are methods of increasing intracellular lactose levels in E. coli genetically engineered to produce a human milk oligosaccharide by incorporating a lacA mutation into the genetically modified E. coli. The lacA mutation prevents the formation of intracellular acetyl-lactose, which not only removes this molecule as a contaminant from subsequent purifications, but also eliminates E. coli's ability to export excess lactose from its cytoplasm, thus greatly facilitating purposeful manipulations of the E. coli intracellular lactose pool. Also described herein are bacterial host cells with the ability to accumulate a intracellular lactose pool while simultaneously possessing low, functional levels of cytoplasmic β-galactosidase activity, for example as provided by the introduction of a functional recombinant E. coli lacZ gene, or by a β-galactosidase gene from any of a number of other organisms (e.g., the lac4 gene of Kluyveromyces lactis (e.g., GenBank Accession Number M84410 (GI:173304), incorporated herein by reference). Low, functional levels of cytoplasmic β-galactosidase include β-galactosidase activity levels, of between 0.05 and 200 units, e.g., between 0.05 and 5 units, between 0.05 and 4 units, between 0.05 and 3 units, or between 0.05 and 2 units (for unit definition see: Miller J H, Laboratory CSH. Experiments in molecular genetics. Cold Spring Harbor Laboratory Cold Spring Harbor, N.Y.; 1972; incorporated herein by reference). This low level of cytoplasmic β-galactosidase activity, while not high enough to significantly diminish the intracellular lactose pool, is nevertheless very useful for tasks such as phenotypic marking of desirable genetic loci during construction of host cell backgrounds, for detection of cell lysis due to undesired bacteriophage contaminations in fermentation processes, or for the facile removal of undesired residual lactose at the end of fermentations. In one aspect, the human milk oligosaccharide produced by engineered bacteria comprising an exogenous nucleic acid molecule encoding an α(1,2) fucosyltransferase, is 2′-FL (2′-fucosyllactose). Preferably, the α(1,2)fucosyltransferase utilized is the previously completely uncharacterized wcfW gene from Bacteroides fragilis NCTC 9343 of the present invention, alternatively the futC gene of Helicobacter pylori 26695 or the wbsJ gene of E. coli strain O128:B12, or any other α(1,2) fucosyltransferase capable of using lactose as the sugar acceptor substrate may be utilized for 2′-FL synthesis. In another aspect the human milk oligosaccharide produced by engineered bacteria comprising an exogenous nucleic acid molecule encoding an α(1,3) fucosyltransferase, is 3FL (3-fucosyllactose), wherein the bacterial cell comprises an exogenous nucleic acid molecule encoding an exogenous α(1,3) fucosyltransferase. Preferably, the bacterial cell is E. coli. The exogenous α(1,3) fucosyltransferase is isolated from, e.g., Helicobacter pylori, H. hepaticus, H bilis, C. jejuni, or a species of Bacteroides. In one aspect, the exogenous α(1,3) fucosyltransferase comprises H. hepaticus Hh0072, H. pylori 11639 FucTa, or H. pylori UA948 FucTa (e.g., GenBank Accession Number AF194963 (GI:28436396), incorporated herein by reference). The invention also provides compositions comprising E. coli genetically engineered to produce the human milk tetrasaccharide lactodifucotetraose (LDFT). The E. coli in this instance comprise an exogenous nucleic acid molecule encoding an α(1,2) fucosyltransferase and an exogenous nucleic acid molecule encoding an α(1,3) fucosyltransferase. In one aspect, the E. coli is transformed with a plasmid expressing an α(1,2) fucosyltransferase and/or a plasmid expressing an α(1,3) fucosyltransferase. In another aspect, the E. coli is transformed with a plasmid that expresses both an α(1,2) fucosyltransferase and an α(1,3) fucosyltransferase. Alternatively, the E. coli is transformed with a chromosomal integrant expressing an α(1,2) fucosyltransferase and a chromosomal integrant expressing an α(1,3) fucosyltransferase. Optionally, the E. coli is transformed with plasmid pG177. Also described herein are compositions comprising a bacterial cell that produces the human milk oligosaccharide 3′-S3FL (3′-sialyl-3-fucosyllactose), wherein the bacterial cell comprises an exogenous sialyl-transferase gene encoding α(2,3)sialyl-transferase and an exogenous fucosyltransferase gene encoding α(1,3) fucosyltransferase. Preferably, the bacterial cell is E. coli. The exogenous fucosyltransferase gene is isolated from, e.g., Helicobacter pylori, H hepaticus, H bilis, C. jejuni, or a species of Bacteroides. For example, the exogenous fucosyltransferase gene comprises H. hepaticus Hh0072, H. pylori 11639 FucTa, or H. pylori UA948 FucTa. The exogenous sialyltransferase gene utilized for 3′-S3FL production may be obtained from any one of a number of sources, e.g., those described from N. meningitidis and N. gonorrhoeae. Preferably, the bacterium comprises a GDP-fucose synthesis pathway. Additionally, the bacterium contains a deficient sialic acid catabolic pathway. By “sialic acid catabolic pathway” is meant a sequence of reactions, usually controlled and catalyzed by enzymes, which results in the degradation of sialic acid. An exemplary sialic acid catabolic pathway in Escherichia coli is described herein. In the sialic acid catabolic pathway described herein, sialic acid (Neu5Ac; N-acetylneuraminic acid) is degraded by the enzymes NanA (N-acetylneuraminic acid lyase) and NanK (N-acetylmannosamine kinase). For example, a deficient sialic acid catabolic pathway is engineered in Escherichia coli by way of a null mutation in endogenous nanA (N-acetylneuraminate lyase) (e.g., GenBank Accession Number D00067 (GI:216588), incorporated herein by reference) and/or nanK (N-acetylmannosamine kinase) genes (e.g., GenBank Accession Number (amino acid) BAE77265 (GI:85676015), incorporated herein by reference). Other components of sialic acid metabolism include: (nanT) sialic acid transporter; (ManNAc-6-P) N-acetylmannosamine-6-phosphate; (GlcNAc-6-P) N-acetylglucosamine-6-phosphate; (GlcN-6-P) Glucosamine-6-phosphate; and (Fruc-6-P) Fructose-6-phosphate. Moreover, the bacterium (e.g., E. coli) also comprises a sialic acid synthetic capability. For example, the bacterium comprises a sialic acid synthetic capability through provision of an exogenous UDP-GlcNAc 2-epimerase (e.g., neuC of Campylobacter jejuni or equivalent (e.g., GenBank Accession Number (amino acid) AAG29921 (GI:11095585), incorporated herein by reference)), a Neu5Ac synthase (e.g., neuB of C. jejuni or equivalent, e.g., GenBank Accession Number (amino acid) AAG29920 (GI:11095584), incorporated herein by reference)), and/or a CMP-Neu5Ac synthetase (e.g., neuA of C. jejuni or equivalent, e.g., GenBank Accession Number (amino acid) ADN91474 (GI:307748204), incorporated herein by reference). Additionally, the bacterium also comprises a functional β-galactosidase gene and a functional lactose permease gene. Bacteria comprising the characteristics described herein are cultured in the presence of lactose, and a 3′-sialyl-3-fucosyllactose is retrieved, either from the bacterium itself or from a culture supernatant of the bacterium. Also provided are methods for producing a 3′-sialyl-3-fucosyllactose (3′-S3FL) in an enteric bacterium, wherein the enteric bacterium comprises a mutation in an endogenous colanic acid synthesis gene, a functional lacZ gene, a functional lactose permease gene, an exogenous fucosyltransferase gene encoding α(1,3) fucosyltransferase, and an exogenous sialyltransferase gene encoding an α(2,3)sialyl transferase. Additionally, the bacterium contains a deficient sialic acid catabolic pathway. For example, the bacterium comprises a deficient sialic acid catabolic pathway by way of a null mutation in endogenous nanA (N-acetylneuraminate lyase) and/or nanK (N-acetylmannosamine kinase) genes. The bacterium also comprises a sialic acid synthetic capability. For example, the bacterium comprises a sialic acid synthetic capability through provision of an exogenous UDP-GlcNAc 2-epimerase (e.g., neuC of C. jejuni or equivalent), a Neu5Ac synthase (e.g., neuB of C. jejuni or equivalent), and/or a CMP-Neu5Ac synthetase (e.g., neuA of C. jejuni or equivalent). Bacteria comprising the characteristics described herein are cultured in the presence of lactose, and a 3′-sialyl-3-fucosyllactose is retrieved, either from the bacterium itself or from a culture supernatant of the bacterium. Also provided is a method for phenotypic marking of a gene locus in a host cell, whose native β-galactosidase gene is deleted or inactivated, by utilizing an inserted recombinant β-galactosidase (e.g., lacZ) gene engineered to produce a low, but detectable level of β-galactosidase activity. Similarly, the invention also provides methods for depleting a bacterial culture of residual lactose in a β-galactosidase negative host cell, whose native β-galactosidase gene is deleted or inactivated, by utilizing an inserted recombinant β-galactosidase (e.g., lacZ) gene engineered to produce a low but detectable level of β-galactosidase activity. Finally, also provided is a method for detecting bacterial cell lysis in a culture of a β-galactosidase negative host cell, whose native β-galactosidase gene is deleted or inactivated, by utilizing an inserted recombinant β-galactosidase. (e.g., lacZ) gene engineered to produce a low but detectable level of β-galactosidase activity. Methods of purifying a fucosylated oligosaccharide produced by the methods described herein are carried out by binding the fucosylated oligosaccharide from a bacterial cell lysate or bacterial cell culture supernatant of the bacterium to a carbon column, and eluting the fucosylated oligosaccharide from the column. Purified fucosylated oligosaccharide are produced by the methods described herein. Optionally, the invention features a vector, e.g., a vector containing a nucleic acid. The vector can further include one or more regulatory elements, e.g., a heterologous promoter. The regulatory elements can be operably linked to a protein gene, fusion protein gene, or a series of genes linked in an operon in order to express the fusion protein. In yet another aspect, the invention comprises an isolated recombinant cell, e.g., a bacterial cell containing an aforementioned nucleic acid molecule or vector. The nucleic acid sequence can be optionally integrated into the genome. The term “substantially pure” in reference to a given polypeptide, polynucleotide or oligosaccharide means that the polypeptide, polynucleotide or oligosaccharide is substantially free from other biological macromolecules. The substantially pure polypeptide, polynucleotide or oligosaccharide is at least 75% (e.g., at least 80, 85, 95, or 99%) pure by dry weight. Purity can be measured by any appropriate calibrated standard method, for example, by column chromatography, polyacrylamide gel electrophoresis, thin layer chromatography (TLC) or HPLC analysis. Polynucleotides, polypeptides, and oligosaccharides of the invention are purified and/or isolated. Purified defines a degree of sterility that is safe for administration to a human subject, e.g., lacking infectious or toxic agents. Specifically, as used herein, an “isolated” or “purified” nucleic acid molecule, polynucleotide, polypeptide, protein or oligosaccharide, is substantially free of other cellular material, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized. For example, Purified HMOS compositions are at least 60% by weight (dry weight) the compound of interest. Preferably, the preparation is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight the compound of interest. Purity is measured by any appropriate calibrated standard method, for example, by column chromatography, polyacrylamide gel electrophoresis, thin layer chromatography (TLC) or HPLC analysis. For example, a “purified protein” refers to a protein that has been separated from other proteins, lipids, and nucleic acids with which it is naturally associated. Preferably, the protein constitutes at least 10, 20, 50 70, 80, 90, 95, 99-100% by dry weight of the purified preparation. By “isolated nucleic acid” is meant a nucleic acid that is free of the genes which flank it in the naturally-occurring genome of the organism from which the nucleic acid is derived. The term covers, for example: (a) a DNA which is part of a naturally occurring genomic DNA molecule, but is not flanked by both of the nucleic acid sequences that flank that part of the molecule in the genome of the organism in which it naturally occurs; (b) a nucleic acid incorporated into a vector or into the genomic DNA of a prokaryote or eukaryote in a manner, such that the resulting molecule is not identical to any naturally occurring vector or genomic DNA; (c) a separate molecule such as a cDNA, a genomic fragment, a fragment produced by polymerase chain reaction (PCR), or a restriction fragment; and (d) a recombinant nucleotide sequence that is part of a hybrid gene, i.e., a gene encoding a fusion protein. Isolated nucleic acid molecules according to the present invention further include molecules produced synthetically, as well as any nucleic acids that have been altered chemically and/or that have modified backbones. For example, the isolated nucleic acid is a purified cDNA or RNA polynucleotide. A “heterologous promoter”, when operably linked to a nucleic acid sequence, refers to a promoter which is not naturally associated with the nucleic acid sequence. The terms “express” and “over-express” are used to denote the fact that, in some cases, a cell useful in the method herein may inherently express some of the factor that it is to be genetically altered to produce, in which case the addition of the polynucleotide sequence results in over-expression of the factor. That is, more factor is expressed by the altered cell than would be, under the same conditions, by a wild type cell. Similarly, if the cell does not inherently express the factor that it is genetically altered to produce, the term used would be to merely “express” the factor since the wild type cell did not express the factor at all. The terms “treating” and “treatment” as used herein refer to the administration of an agent or formulation to a clinically symptomatic individual afflicted with an adverse condition, disorder, or disease, so as to effect a reduction in severity and/or frequency of symptoms, eliminate the symptoms and/or their underlying cause, and/or facilitate improvement or remediation of damage. The terms “preventing” and “prevention” refer to the administration of an agent or composition to a clinically asymptomatic individual who is susceptible to a particular adverse condition, disorder, or disease, and thus relates to the prevention of the occurrence of symptoms and/or their underlying cause. The invention provides a method of treating, preventing, or reducing the risk of infection in a subject comprising administering to said subject a composition comprising a human milk oligosaccharide, purified from a culture of a recombinant strain of the current invention, wherein the HMOS binds to a pathogen and wherein the subject is infected with or at risk of infection with the pathogen. In one aspect, the infection is caused by a Norwalk-like virus or Campylobacter jejuni. The subject is preferably a mammal in need of such treatment. The mammal is, e.g., any mammal, e.g., a human, a primate, a mouse, a rat, a dog, a cat, a cow, a horse, or a pig. In a preferred embodiment, the mammal is a human. For example, the compositions are formulated into animal feed (e.g., pellets, kibble, mash) or animal food supplements for companion animals, e.g., dogs or cats, as well as livestock or animals grown for food consumption, e.g., cattle, sheep, pigs, chickens, and goats. Preferably, the purified HMOS is formulated into a powder (e.g., infant formula powder or adult nutritional supplement powder, each of which is mixed with a liquid such as water or juice prior to consumption) or in the form of tablets, capsules or pastes or is incorporated as a component in dairy products such as milk, cream, cheese, yogurt or kefir, or as a component in any beverage, or combined in a preparation containing live microbial cultures intended to serve as probiotics, or in prebiotic preparations intended to enhance the growth of beneficial microorganisms either in vitro or in vivo. For example, the purified sugar (e.g., 2′-FL) can be mixed with a Bifidobacterium or Lactobacillus in a probiotic nutritional composition. (i.e. Bifidobacteria are beneficial components of a normal human gut flora and are also known to utilize HMOS for growth. By the terms “effective amount” and “therapeutically effective amount” of a formulation or formulation component is meant a nontoxic but sufficient amount of the formulation or component to provide the desired effect. The transitional term “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. By contrast, the transitional phrase “consisting of” excludes any element, step, or ingredient not specified in the claim. The transitional phrase “consisting essentially of” limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention. Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All published foreign patents and patent applications cited herein are incorporated herein by reference. Genbank and NCBI submissions indicated by accession number cited herein are incorporated herein by reference. All other published references, documents, manuscripts and scientific literature cited herein are incorporated herein by reference. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic illustration showing the synthetic pathway of the major neutral fucosyl-oligosaccharides found in human milk. FIG. 2 is a schematic illustration showing the synthetic pathway of the major sialyloligosaccharides found in human milk. FIG. 3 is a schematic demonstrating metabolic pathways and the changes introduced into them to engineer 2′-fucosyllactose (2′-FL) synthesis in Escherichia coli (E. coli). Specifically, the lactose synthesis pathway and the GDP-fucose synthesis pathway are illustrated. In the GDP-fucose synthesis pathway: manA=phosphomannose isomerase (PMI), manB=phosphomannomutase (PMM), manC=mannose-1-phosphate guanylyltransferase (GMP), gmd=GDP-mannose-4,6-dehydratase, fcl=GDP-fucose synthase (GFS), and ΔwcaJ=mutated UDP-glucose lipid carrier transferase. FIG. 4 is a photograph of a thin layer chromatogram of purified 2′-FL produced in E. coli. FIG. 5 is a schematic demonstrating metabolic pathways and the changes introduced into them to engineer 3′-sialyllactose (3′-SL) synthesis in E. coli. Abbreviations include: (Neu5Ac) N-acetylneuraminic acid, sialic acid; (nanT) sialic acid transporter; (ΔnanA) mutated N-acetylneuraminic acid lyase; (ManNAc) N-acetylmannosamine; (ΔnanK) mutated N-acetylmannosamine kinase; (ManNAc-6-P) N-acetylmannosamine-6-phosphate; (GlcNAc-6-P) N-acetylglucosamine-6-phosphate; (GlcN-6-P) Glucosamine-6-phosphate; (Fruc-6-P) Fructose-6-phosphate; (neuA), CMP-N-acetylneuraminic acid synthetase; (CMP-Neu5Ac) CMP-N-acetylneuraminic acid; and (neuB), N-acetylneuraminic acid synthase. FIG. 6 is a schematic demonstrating metabolic pathways and the changes introduced into them to engineer 3-fucosyllactose (3-FL) synthesis in E. coli. FIG. 7 is a plasmid map of pG175, which expresses the E. coli α(1,2)fucosyltransferase gene wbsJ. FIG. 8 is a photograph of a western blot of lysates of E. coli containing pG175 and expressing wbsJ, and of cells containing pG171, a pG175 derivative plasmid carrying the H. pylori 26695 futC gene in place of wbsJ and which expresses futC. FIG. 9 is a photograph of a thin layer chromatogram of 3FL produced in E. coli containing the plasmid pG176 and induced for expression of the H. pylori 26695 α(1,3)fucosyltransferase gene futA by tryptophan addition. FIG. 10 is a plasmid map of pG177, which contains both the H. pylori 26695 α(1,2)fucosyltransferase gene futC and the H. pylori 26695 α(1,3)fucosyltransferase gene futA, configured as an operon. FIG. 11 is a photograph of a thin layer chromatogram of 2′-FL, 3FL, and LDFT (lactodifucotetraose) produced in E. coli, directed by plasmids pG171, pG175 (2′-FL), pG176 (3FL), and pG177 (LDFT, 2′-FL and 3FL). FIG. 12 is a diagram showing the replacement of the lon gene in E. coli strain E390 by a DNA fragment carrying both a kanamycin resistance gene (derived from transposon Tn5) and a wild-type E. coli lacZ+ coding sequence. FIG. 13A-E is a DNA sequence with annotations (in GenBank format) of the DNA insertion into the lon region diagrammed in FIG. 12 (SEQ ID NOs 9-15). FIG. 14 is a table containing the genotypes of several E. coli strains of the current invention. FIG. 15 is a plasmid map of pG186, which expresses the α(1,2)fucosyltransferase gene futC in an operon with the colanic acid pathway transcription activator gene rcsB. FIG. 16 is a photograph of a western blot of lysates of E. coli containing pG180, a pG175 derivative plasmid carrying the B. fragilis wcfW gene in place of wbsJ and which expresses wcfW, and of cells containing pG171, a pG175 derivative plasmid carrying the H. pylori 26695 futC gene in place of wbsJ and which expresses futC. FIG. 17 is a photograph of a thin layer chromatogram of 2′-FL produced in E. coli by cells carrying plasmids pG180 or pG171 and induced for expression of wcfW or futC respectively. FIG. 18 is a photograph of a thin layer chromatogram showing the kinetics and extent of 2′-FL production in a 10 L bioreactor of E. coli host strain E403 transformed with plasmid pG171. FIG. 19 is a column chromatogram and a TLC analysis of the resolution on a carbon column of a sample of 2′-FL made in E. coli from a lactose impurity. FIG. 20 is a photograph of a thin layer chromatogram showing 3′-SL in culture medium produced by E. coli strain E547, containing plasmids expressing a bacterial α(2,3)sialyltransferase and neuA, neuB and neuC. DETAILED DESCRIPTION OF THE INVENTION Human milk glycans, which comprise both oligosaccharides (HMOS) and their glycoconjugates, play significant roles in the protection and development of human infants, and in particular the infant gastrointestinal (GI) tract. Milk oligosaccharides found in various mammals differ greatly, and their composition in humans is unique (Hamosh M., 2001 Pediatr Clin North Am, 48:69-86; Newburg D. S., 2001 Adv Exp Med Biol, 501:3-10). Moreover, glycan levels in human milk change throughout lactation and also vary widely among individuals (Morrow A. L. et al., 2004 J Pediatr, 145:297-303; Chaturvedi P et al., 2001 Glycobiology, 11:365-372). Previously, a full exploration of the roles of HMOS was limited by the inability to adequately characterize and measure these compounds. In recent years sensitive and reproducible quantitative methods for the analysis of both neutral and acidic HMOS have been developed (Erney, R., Hilty, M., Pickering, L., Ruiz-Palacios, G., and Prieto, P. (2001) Adv Exp Med Biol 501, 285-297. Bao, Y., and Newburg, D. S. (2008) Electrophoresis 29, 2508-2515). Approximately 200 distinct oligosaccharides have been identified in human milk, and combinations of a small number of simple epitopes are responsible for this diversity (Newburg D. S., 1999 Curr_Med Chem, 6:117-127; Ninonuevo M. et al., 2006 J Agric Food Chem, 54:7471-74801). HMOS are composed of 5 monosaccharides: D-glucose (Glc), D-galactose (Gal), N-acetylglucosamine (GlcNAc), L-fucose (Fuc), and sialic acid (N-acetyl neuraminic acid, Neu5Ac, NANA). HMOS are usually divided into two groups according to their chemical structures: neutral compounds containing Glc, Gal, GlcNAc, and Fuc, linked to a lactose (Galβ1-4Glc) core, and acidic compounds including the same sugars, and often the same core structures, plus NANA (Charlwood J. et al., 1999 Anal_Biochem, 273:261-277; Martin-Sosa et al., 2003 J Dairy Sci, 86:52-59; Parkkinen J. and Finne J., 1987 Methods Enzymol, 138:289-300; Shen Z. et al., 2001 J Chromatogr A, 921:315-321). Approximately 70-80% of oligosaccharides in human milk are fucosylated, and their synthetic pathways are believed to proceed in a manner similar to those pathways shown in FIG. 1 (with the Type I and Type II subgroups beginning with different precursor molecules). A smaller proportion of the oligosaccharides in human milk are sialylated, or are both fucosylated and sialylated. FIG. 2 outlines possible biosynthetic routes for sialylated (acidic) HMOS, although their actual synthetic pathways in humans are not yet completely defined. Interestingly, HMOS as a class, survive transit through the intestine of infants very efficiently, a function of their being poorly transported across the gut wall and of their resistance to digestion by human gut enzymes (Chaturvedi, P., Warren, C. D., Buescher, C. R., Pickering, L. K. & Newburg, D. S. Adv Exp Med Biol 501, 315-323 (2001)). One consequence of this survival in the gut is that HMOS are able to function as prebiotics, i.e. they are available to serve as an abundant carbon source for the growth of resident gut commensal microorganisms (Ward, R. E., Niñonuevo, M., Mills, D. A., Lebrilla, C. B., and German, J. B. (2007) Mol Nutr Food Res 51, 1398-1405). Recently, there is burgeoning interest in the role of diet and dietary prebiotic agents in determining the composition of the gut microflora, and in understanding the linkage between the gut microflora and human health (Roberfroid, M., Gibson, G. R., Hoyles, L., McCartney, A. L., Rastall, R., Rowland, I., Wolvers, D., Watzl, B., Szajewska, H., Stahl, B., Guarner, F., Respondek, F., Whelan, K., Coxam, V., Davicco, M. J., Léotoing, L., Wittrant, Y., Delzenne, N. M., Cani, P. D., Neyrinck, A. M., and Meheust, A. (2010) Br J Nutr 104 Suppl 2, S1-63). A number of human milk glycans possess structural homology to cell receptors for enteropathogens, and serve roles in pathogen defense by acting as molecular receptor “decoys”. For example, pathogenic strains of Campylobacter bind specifically to glycans in human milk containing the H-2 epitope, i.e., 2′-fucosyl-N-acetyllactosamine or 2′-fucosyllactose (2′-FL); Campylobacter binding and infectivity are inhibited by 2′-FL and other glycans containing this H-2 epitope (Ruiz-Palacios, G. M., Cervantes, L. E., Ramos, P., Chavez-Munguia, B., and Newburg, D. S. (2003) J Biol Chem 278, 14112-14120). Similarly, some diarrheagenic E. coli pathogens are strongly inhibited in vivo by HMOS containing 2′-linked fucose moieties. Several major strains of human caliciviruses, especially the noroviruses, also bind to 2′-linked fucosylated glycans, and this binding is inhibited by human milk 2′-linked fucosylated glycans. Consumption of human milk that has high levels of these 2′-linked fucosyloligosaccharides has been associated with lower risk of norovirus, Campylobacter, ST of E. coli-associated diarrhea, and moderate-to-severe diarrhea of all causes in a Mexican cohort of breastfeeding children (Newburg D. S. et al., 2004 Glycobiology, 14:253-263; Newburg D. S. et al., 1998 Lancet, 351:1160-1164). Several pathogens are also known to utilize sialylated glycans as their host receptors, such as influenza (Couceiro, J. N., Paulson, J. C. & Baum, L. G. Virus Res 29, 155-165 (1993)), parainfluenza (Amonsen, M., Smith, D. F., Cummings, R. D. & Air, G. M. J Virol 81, 8341-8345 (2007), and rotoviruses (Kuhlenschmidt, T. B., Hanafin, W. P., Gelberg, H. B. & Kuhlenschmidt, M. S. Adv Exp Med Biol 473, 309-317 (1999)). The sialyl-Lewis X epitope is used by Helicobacter pylori (Mandavi, J., Sondén, B., Hurtig, M., Olfat, F. O., et al. Science 297, 573-578 (2002)), Pseudomonas aeruginosa (Scharfman, A., Delmotte, P., Beau, J., Lamblin, G., et al. Glycoconj J 17, 735-740 (2000)), and some strains of noroviruses (Rydell, G. E., Nilsson, J., Rodriguez-Diaz, J., Ruvën-Clouet, N., et al. Glycobiology 19, 309-320 (2009)). While studies suggest that human milk glycans could be used as prebiotics and as antimicrobial anti-adhesion agents, the difficulty and expense of producing adequate quantities of these agents of a quality suitable for human consumption has limited their full-scale testing and perceived utility. What has been needed is a suitable method for producing the appropriate glycans in sufficient quantities at reasonable cost. Prior to the invention described herein, there were attempts to use several distinct synthetic approaches for glycan synthesis. Novel chemical approaches can synthesize oligosaccharides (Flowers, H. M. Methods Enzymol 50, 93-121 (1978); Seeberger, P. H. Chem Commun (Camb) 1115-1121 (2003)), but reactants for these methods are expensive and potentially toxic (Koeller, K. M. & Wong, C. H. Chem Rev 100, 4465-4494 (2000)). Enzymes expressed from engineered organisms (Albermann, C., Piepersberg, W. & Wehmeier, U. F. Carbohydr Res 334, 97-103 (2001); Bettler, E., Samain, E., Chazalet, V., Bosso, C., et al. Glycoconj J 16, 205-212 (1999); Johnson, K. F. Glycoconj J 16, 141-146 (1999); Palcic, M. M. Curr Opin Biotechnol 10, 616-624 (1999); Wymer, N. & Toone, E. J. Curr Opin Chem Biol 4, 110-119 (2000)) provide a precise and efficient synthesis (Palcic, M. M. Curr Opin Biotechnol 10, 616-624 (1999)); Crout, D. H. & Vic, G. Curr Opin Chem Biol 2, 98-111 (1998)), but the high cost of the reactants, especially the sugar nucleotides, limits their utility for low-cost, large-scale production. Microbes have been genetically engineered to express the glycosyltransferases needed to synthesize oligosaccharides from the bacteria's innate pool of nucleotide sugars (Endo, T., Koizumi, S., Tabata, K., Kakita, S. & Ozaki, A. Carbohydr Res 330, 439-443 (2001); Endo, T., Koizumi, S., Tabata, K. & Ozaki, A. Appl Microbiol Biotechnol 53, 257-261 (2000); Endo, T. & Koizumi, S. Curr Opin Struct Biol 10, 536-541 (2000); Endo, T., Koizumi, S., Tabata, K., Kakita, S. & Ozaki, A. Carbohydr Res 316, 179-183 (1999); Koizumi, S., Endo, T., Tabata, K. & Ozaki, A. Nat Biotechnol 16, 847-850 (1998)). However, low overall product yields and high process complexity have limited the commercial utility of these approaches. Prior to the invention described herein, which enables the inexpensive production of large quantities of neutral and acidic HMOS, it had not been possible to fully investigate the ability of this class of molecule to inhibit pathogen binding, or indeed to explore their full range of potential additional functions. Prior to the invention described herein, chemical syntheses of HMOS were possible, but were limited by stereo-specificity issues, precursor availability, product impurities, and high overall cost (Flowers, H. M. Methods Enzymol 50, 93-121 (1978); Seeberger, P. H. Chem Commun (Camb) 1115-1121 (2003); Koeller, K. M. & Wong, C. H. Chem Rev 100, 4465-4494 (2000)). Also, prior to the invention described herein, in vitro enzymatic syntheses were also possible, but were limited by a requirement for expensive nucleotide-sugar precursors. The invention overcomes the shortcomings of these previous attempts by providing new strategies to inexpensively manufacture large quantities of human milk oligosaccharides for use as dietary supplements. The invention described herein makes use of an engineered bacterium E. coli (or other bacteria) engineered to produce 2′-FL, 3FL, LDFT, or sialylated fucosyl-oligosaccharides in commercially viable levels, for example the methods described herein enable the production of 2′-fucosylactose at >50 g/L in bioreactors. Example 1. Engineering of E. coli to Generate Host Strains for the Production of Fucosylated Human Milk Oligosaccharides The E. coli K12 prototroph W3110 was chosen as the parent background for fucosylated HMOS biosynthesis. This strain had previously been modified at the ampC locus by the introduction of a tryptophan-inducible PtrpB-cI+ repressor construct (McCoy, J. & Lavallie, E. Current protocols in molecular biology/edited by Frederick M. Ausubel . . . [et al.] (2001)), enabling economical production of recombinant proteins from the phage λ PL promoter (Sanger, F., Coulson, A. R., Hong, G. F., Hill, D. F. & Petersen, G. B. J Mol Biol 162, 729-773 (1982)) through induction with millimolar concentrations of tryptophan (Mieschendahl, M., Petri, T. & Hänggi, U. Nature Biotechnology 4, 802-808 (1986)). The strain GI724, an E. coli W3110 derivative containing the tryptophan-inducible PtrpB-cI+ repressor construct in ampC, was used at the basis for further E. coli strain manipulations (FIG. 14). Biosynthesis of fucosylated HMOS requires the generation of an enhanced cellular pool of both lactose and GDP-fucose (FIG. 3). This enhancement was achieved in strain GI724 through several manipulations of the chromosome using λ Red recombineering (Court, D. L., Sawitzke, J. A. & Thomason, L. C. Annu Rev Genet 36, 361-388 (2002)) and generalized P1 phage transduction (Thomason, L. C., Costantino, N. & Court, D. L. Mol Biol Chapter 1, Unit 1.17 (2007)). FIG. 14 is a table presenting the genotypes of several E. coli strains constructed for this invention. The ability of the E. coli host strain to accumulate intracellular lactose was first engineered in strain E183 (FIG. 14) by simultaneous deletion of the endogenous β-galactosidase gene (lacZ) and the lactose operon repressor gene (lacI). During construction of this deletion in GI724 to produce E183, the lacIq promoter was placed immediately upstream of the lactose permease gene, lacY. The modified strain thus maintains its ability to transport lactose from the culture medium (via LacY), but is deleted for the wild-type copy of the lacZ (β-galactosidase) gene responsible for lactose catabolism. An intracellular lactose pool is therefore created when the modified strain is cultured in the presence of exogenous lactose. Subsequently, the ability of the host E. coli strain to synthesize colanic acid, an extracellular capsular polysaccharide, was eliminated in strain E205 (FIG. 14) by the deletion of the wcaJ gene, encoding the UDP-glucose lipid carrier transferase (Stevenson, G., Andrianopoulos, K., Hobbs, M. & Reeves, P. R. J Bacteriol 178, 4885-4893 (1996)) in strain E183. In a wcaJ null background, GDP-fucose accumulates in the E. coli cytoplasm (Dumon, C., Priem, B., Martin, S. L., Heyraud, A., et al. Glycoconj J 18, 465-474 (2001)). A thyA (thymidylate synthase) mutation was introduced into strain E205 to produce strain E214 (FIG. 14) by P1 transduction. In the absence of exogenous thymidine, thyA strains are unable to make DNA, and die. The defect can be complemented in trans by supplying a wild-type thyA gene on a multicopy plasmid (Belfort, M., Maley, G. F. & Maley, F. Proceedings of the National Academy of Sciences 80, 1858 (1983)). This complementation is used herein as a means of plasmid maintenance (eliminating the need for a more conventional antibiotic selection scheme to maintain plasmid copy number). One strategy for GDP-fucose production is to enhance the bacterial cell's natural synthesis capacity. For example, this is enhancement is accomplished by inactivating enzymes involved in GDP-fucose consumption, and/or by overexpressing a positive regulator protein, RcsA, in the colanic acid (a fucose-containing exopolysaccharide) synthesis pathway. Collectively, this metabolic engineering strategy re-directs the flux of GDP-fucose destined for colanic acid synthesis to oligosaccharide synthesis (FIG. 3). By “GDP-fucose synthesis pathway” is meant a sequence of reactions, usually controlled and catalyzed by enzymes, which results in the synthesis of GDP-fucose. An exemplary GDP-fucose synthesis pathway in Escherichia coli as described in FIG. 3 is set forth below. In the GDP-fucose synthesis pathway set forth below, the enzymes for GDP-fucose synthesis include: 1) manA=phosphomannose isomerase (PMI), 2) manB=phosphomannomutase (PMM), 3) manC=mannose-1-phosphate guanylyltransferase (GMP), 4) gmd=GDP-mannose-4,6-dehydratase (GMD), 5) fcl=GDP-fucose synthase (GFS), and 6) ΔwcaJ=mutated UDP-glucose lipid carrier transferase. Glucose→Glc-6-P→Fru-6-P→1 Man-6-P→2 Man-1-P→3 GDP-Man→4,5 GDP-Fuc 6 Colanic acid. Specifically, the magnitude of the cytoplasmic GDP-fucose pool in strain E214 is enhanced by over-expressing the E. coli positive transcriptional regulator of colanic acid biosynthesis, RscA (Gottesman, S. & Stout, V. Mol Microbiol 5, 1599-1606 (1991)). This over-expression of RcsA is achieved by incorporating a wild-type rcsA gene, including its promoter region, onto a multicopy plasmid vector and transforming the vector into the E. coli host, e.g. into E214. This vector typically also carries additional genes, in particular one or two fucosyltransferase genes under the control of the pL promoter, and thyA and beta-lactamase genes for plasmid selection and maintenance. pG175 (SEQ ID NO: 1 and FIG. 7), pG176 (SEQ ID NO: 2), pG177 (SEQ ID NO: 3 and FIG. 10), pG171 (SEQ ID NO: 5) and pG180 (SEQ ID NO: 6) are all examples of fucosyltransferase-expressing vectors that each also carry a copy of the rcsA gene, for the purpose of increasing the intracellular GDP-fucose pool of the E. coli hosts transformed with these plasmids. Over-expression of an additional positive regulator of colanic acid biosynthesis, namely RcsB (Gupte G, Woodward C, Stout V. Isolation and characterization of rcsb mutations that affect colanic acid capsule synthesis in Escherichia coli K-12. J Bacteriol 1997, July; 179(13):4328-35.), can also be utilized, either instead of or in addition to over-expression of RcsA, to increase intracellular GDP-fucose levels. Over-expression of rcsB is also achieved by including the gene on a multi-copy expression vector. pG186 is such a vector (SEQ ID NO: 8 and FIG. 15). pG186 expresses rcsB in an operon with futC under pL promoter control. The plasmid also expresses rcsA, driven off its own promoter. pG186 is a derivative of pG175 in which the α(1,2) FT (wbsJ) sequence is replaced by the H. pylori futC gene (FutC is MYC-tagged at its C-terminus). In addition, at the XhoI restriction site immediately 3′ of the futC CDS, the E. coli rcsB gene is inserted, complete with a ribosome binding site at the 5′end of the rcsB CDS, and such that futC and rcsB form an operon. A third means to increase the intracellular GDP-fucose pool may also be employed. Colanic acid biosynthesis is increased following the introduction of a null mutation into the E. coli lon gene. Lon is an ATP-dependant intracellular protease that is responsible for degrading RcsA, mentioned above as a positive transcriptional regulator of colanic acid biosynthesis in E. coli (Gottesman, S. & Stout, V. Mol Microbiol 5, 1599-1606 (1991)). In a ion null background, RcsA is stabilized, RcsA levels increase, the genes responsible for GDP-fucose synthesis in E. coli are up-regulated, and intracellular GDP-fucose concentrations are enhanced. The lon gene was almost entirely deleted and replaced by an inserted functional, wild-type, but promoter-less E. coli lacZ+ gene (Δlon::(kan, lacZ+) in strain E214 to produce strain E390. λ Red recombineering was used to perform the construction. FIG. 12 illustrates the new configuration of genes engineered at the lon locus in E390. FIG. 13A-E presents the complete DNA sequence of the region, with annotations in GenBank format. Genomic DNA sequence surrounding the lacZ+ insertion into the lon region in E. coli strain E390 is set forth below (SEQ ID NO: 7) The lon mutation in E390 increases intracellular levels of RcsA, and enhances the intracellular GDP-fucose pool. The inserted lacZ+ cassette not only knocks out lon, but also converts the lacZ− host back to both a lacZ+ genotype and phenotype. The modified strain produces a minimal (albeit still readily detectable) level of β-galactosidase activity (1-2 units), which has very little impact on lactose consumption during production runs, but which is useful in removing residual lactose at the end of runs, is an easily scorable phenotypic marker for moving the lon mutation into other lacZ− E. coli strains by P1 transduction, and can be used as a convenient test for cell lysis (e.g. caused by unwanted bacteriophage contamination) during production runs in the bioreactor. The production host strain, E390 incorporates all the above genetic modifications and has the following genotype: ampC::(PtrpB λcI+), PlacIq(ΔlacI-lacZ)158lacY+, ΔwcaJ, thyA748::Tn10, Δlon::(kan, lacZ+) An additional modification of E390 that is useful for increasing the cytoplasmic pool of free lactose (and hence the final yield of 2′-FL) is the incorporation of a lacA mutation. LacA is a lactose acetyltransferase that is only active when high levels of lactose accumulate in the E. coli cytoplasm. High intracellular osmolarity (e.g., caused by a high intracellular lactose pool) can inhibit bacterial growth, and E. coli has evolved a mechanism for protecting itself from high intra cellular osmolarity caused by lactose by “tagging” excess intracellular lactose with an acetyl group using LacA, and then actively expelling the acetyl-lactose from the cell (Danchin, A. Bioessays 31, 769-773 (2009)). Production of acetyl-lactose in E. coli engineered to produce 2′-FL or other human milk oligosaccharides is therefore undesirable: it reduces overall yield. Moreover, acetyl-lactose is a side product that complicates oligosaccharide purification schemes. The incorporation of a lacA mutation resolves these problems. Strain E403 (FIG. 14) is a derivative of E390 that carries a deletion of the lacA gene and thus is incapable of synthesizing acetyl-lactose. The production host strain, E403 incorporates all the above genetic modifications and has the following genotype: ampC::(PtrpBλcI+), PlacIq(ΔlacI-lacZ)158lacY+, ΔwcaJ, thyA748::Tn10, Δlon::(kan, lacZ+)ΔlacA Example 2. 2′-FL Production at Small Scale Various alternative α(1,2) fucosyltransferases are able to utilize lactose as a sugar acceptor and are available for the purpose of 2′-FL synthesis when expressed under appropriate culture conditions in E. coli E214, E390 or E403. For example the plasmid pG175 (ColE1, thyA+, bla+, PL2-wbsJ, rcsA+) (SEQ ID NO: 1, FIG. 7) carries the wbsJ α(1,2)fucosyltransferase gene of E. coli strain O128:B12 and can direct the production of 2′-FL in. E. coli strain E403. In another example plasmid pG171 (ColE1, thyA+, bla+, PL2-futC, rcsA+) (SEQ ID NO: 5), carries the H. pylori 26695 futC α(1,2)fucosyltransferase gene (Wang, G., Rasko, D. A., Sherburne, R. & Taylor, D. E. Mol Microbiol 31, 1265-1274 (1999)) and will also direct the production of 2′-FL in strain E403. In a preferred example, the plasmid pG180 (ColE1, thyA+, bla+, PL2-wcfW, rcsA+) (SEQ ID NO: 6) carries the previously uncharacterized Bacteroides fragilis NCTC 9343 wcfW α(1,2)fucosyltransferase gene of the current invention and directs the production of 2′-FL in E. coli strain E403. The addition of tryptophan to the lactose-containing growth medium of cultures of any one of the strains E214, E390 or E403, when transformed with any one of the plasmids pG171, pG175 or pG180 leads, for each particular strain/plasmid combination, to activation of the host E. coli tryptophan utilization repressor TrpR, subsequent repression of PtrpB, and a consequent decrease in cytoplasmic cI levels, which results in a de-repression of PL, expression of futC, wbsJ or wcfW, respectively, and production of 2′-FL. FIG. 8 is a coomassie blue-stained SDS PAGE gel of lysates of E. coli containing pG175 and expressing wbsJ, and of cells containing pG171 and expressing futC. Prominent stained protein bands running at a molecular weight of approximately 35 kDa are seen for both WbsJ and FutC at 4 and 6 h following PL induction (i.e., after addition of tryptophan). FIG. 16 is a coomassie blue-stained SDS PAGE gel of lysates of E. coli containing pG180 and expressing wcfW, and of cells containing pG171 and expressing H. pylori futC. Prominent stained bands for both WcfW and FutC are seen at a molecular weight of approximately 40 kDa at 4 and 6 h following PL induction (i.e., after addition of tryptophan to the growth medium). For 2′-FL production in small scale laboratory cultures (<100 ml) strains were grown at 30 C in a selective medium lacking both thymidine and tryptophan to early exponential phase (e.g. M9 salts, 0.5% glucose, 0.4% casaminoacids). Lactose was then added to a final concentration of 0.5 or 1%, along with tryptophan (200 μM final) to induce expression of the α(1,2) fucosyltransferase, driven from the PL promoter. At the end of the induction period (˜24 h) TLC analysis was performed on aliquots of cell-free culture medium, or of heat extracts of cells (treatments at 98 C for 10 min, to release sugars contained within the cell). FIG. 11 shows a TLC analysis of cytoplasmic extracts of engineered E. coli cells transformed with pG175 or pG171. Cells were induced to express wbsJ or futC, respectively, and grown in the presence of lactose. The production of 2′-FL can clearly be seen in heat extracts of cells carrying either plasmid. FIG. 17 shows a TLC analysis of cytoplasmic extracts of engineered E. coli cells transformed with pG180 or pG171. Cells were induced to express wcfW or futC, respectively, and grown in the presence of lactose. The production of 2′-FL can clearly be seen with both plasmids. Prior to the present invention the wcfW gene had never been shown to encode a protein with demonstrated α(1,2) fucosyltransferase activity, or to utilize lactose as a sugar acceptor substrate. The DNA sequence of the Bacteroides fragilis strain NCTC 9343 wcfW gene (protein coding sequence) is set forth below (SEQ ID NO: 4). Example 3. 2′-FL Production in the Bioreactor 2′-FL can be produced in the bioreactor by any one of the host E. coli strains E214, E390 or E403, when transformed with any one of the plasmids pG171, pG175 or pG180. Growth of the transformed strain is performed in a minimal medium in a bioreactor, 10 L working volume, with control of dissolved oxygen, pH, lactose substrate, antifoam and nutrient levels. Minimal “FERM” medium is used in the bioreactor, which is detailed below. Ferm (10 liters): Minimal medium comprising: 40 g (NH4)2HPO4 100 g KH2PO4 10 g MgSO4.7H2O 40 g NaOH Trace elements: 1.3 g NTA 0.5 g FeSO4.7H2O 0.09 g MnCl2.4H2O 0.09 g ZnSO4.7H2O 0.01 g CoCl2.6H2O 0.01 g CuCl2.2H2O 0.02 g H3BO3 0.01 g Na2MoO4.2H2O (pH 6.8) Water to 10 liters DF204 antifoam (0.1 ml/L) 150 g glycerol (initial batch growth), followed by fed batch mode with a 90% glycerol-1% MgSO4-1× trace elements feed, at various rates for various times. Production cell densities of A600>100 are routinely achieved in these bioreactor runs. Briefly, a small bacterial culture is grown overnight in “FERM”—in the absence of either antibiotic or exogenous thymidine. The overnight culture (@˜2 A600) is used to inoculate a bioreactor (10 L working volume, containing “FERM”) to an initial cell density of ˜0.2 A600. Biomass is built up in batch mode at 30° C. until the glycerol is exhausted (A600˜20), and then a fed batch phase is initiated utilizing glycerol as the limiting carbon source. At A600˜30, 0.2 g/L tryptophan is added to induce α(1,2) fucosyltransferase synthesis. An initial bolus of lactose is also added at this time. 5 hr later, a continuous slow feed of lactose is started in parallel to the glycerol feed. These conditions are continued for 48 hr (2′-FL production phase). At the end of this period, both the lactose and glycerol feeds are terminated, and the residual glycerol and lactose are consumed over a final fermentation period, prior to harvest. 2′-FL accumulates in the spent fermentation medium at concentrations as much as 30 times higher than in the cytoplasm. The specific yield in the spent medium varies between 10 and 50 g/L, depending on precise growth and induction conditions. FIG. 18 is a TLC of culture medium samples removed from a bioreactor at various times during a 2′-FL production run utilizing plasmid pG171 transformed into strain E403. All of the input lactose was converted to product by the end of the run, and product yield was approximately 25 g/L 2′-FL. Example 4. 2′-Fucosyllactose Purification 2′-FL purification from E. coli fermentation broth is accomplished though five steps: 1. Clarification Fermentation broth is harvested and cells removed by sedimentation in a preparative centrifuge at 6000×g for 30 min. Each bioreactor run yields about 5-7 L of partially clarified supernatant. Clarified supernatants have a brown/orange coloration attributed to a fraction of caramelized sugars produced during the course of the fermentation, particularly by side-reactions promoted by the ammonium ions present in the fermentation medium. 2. Product Capture on Coarse Carbon A column packed with coarse carbon (Calgon 12×40 TR) of ˜1000 ml volume (dimension 5 cm diameter×60 cm length) is equilibrated with 1 column volume (CV) of water and loaded with clarified culture supernatant at a flow rate of 40 ml/min. This column has a total capacity of about 120 g of sugar (lactose). Following loading and sugar capture, the column is washed with 1.5 CV of water, then eluted with 2.5 CV of 50% ethanol or 25% isopropanol (lower concentrations of ethanol at this step (25-30%) may be sufficient for product elution). This solvent elution step releases about 95% of the total bound sugars on the column and a small portion of the color bodies (caramels). In this first step capture of the maximal amount of sugar is the primary objective. Resolution of contaminants is not an objective. The column can be regenerated with a 5 CV wash with water. 3. Evaporation A volume of 2.5 L of ethanol or isopropanol eluate from the capture column is rotary-evaporated at 56 C and a sugar syrup in water is generated (this typically is a yellow-brown color). Alternative methods that could be used for this step include lyophilization or spray-drying. 4. Flash Chromatography on Fine Carbon and Ion Exchange Media A column (GE Healthcare HiScale50/40, 5×40 cm, max pressure 20 bar) connected to a Biotage Isolera One FLASH Chromatography System is packed with 750 ml of a Darco Activated Carbon G60 (100-mesh): Celite 535 (coarse) 1:1 mixture (both column packings obtained from Sigma). The column is equilibrated with 5 CV of water and loaded with sugar from step 3 (10-50 g, depending on the ratio of 2′-FL to contaminating lactose), using either a celite loading cartridge or direct injection. The column is connected to an evaporative light scattering (ELSD) detector to detect peaks of eluting sugars during the chromatography. A four-step gradient of isopropanol, ethanol or methanol is run in order to separate 2′-FL from monosaccharides (if present), lactose and color bodies. e.g., for B=ethanol: Step 1, 2.5 CV 0% B; Step 2, 4 CV 10% B (elutes monosaccharides and lactose contaminants); step 3, 4 CV 25% B (Elutes 2′-FL); step 4, 5 CV 50% B (elutes some of the color bodies and partially regenerates the column). Additional column regeneration is achieved using methanol @ 50% and isopropanol @ 50%. Fractions corresponding to sugar peaks are collected automatically in 120-ml bottles, pooled and directed to step 5. In certain purification runs from longer-than-normal fermentations, passage of the 2′-FL-containing fraction through anion-exchange and cation exchange columns can remove excess protein/DNA/caramel body contaminants. Resins tested successfully for this purpose are Dowex 22 and Toyopearl Mono-Q, for the anion exchanger, and Dowex 88 for the cation exchanger. Mixed bed Dowex resins have proved unsuitable as they tend to adsorb sugars at high affinity via hydrophobic interactions. FIG. 19 illustrates the performance of Darco G60:celite 1:1 in separating lactose from 2′-fucosyllactose when used in Flash chromatography mode. 5. Evaporation/Lyophilization 3.0 L of 25% B solvent fractions is rotary-evaporated at 56 C until dry. Clumps of solid sugar are re-dissolved in a minimum amount of water, the solution frozen, and then lyophilized. A white, crystalline, sweet powder (2′-FL) is obtained at the end of the process. 2′-FL purity obtained lies between 95 and 99%. Sugars are routinely analyzed for purity by spotting 1 μl aliquots on aluminum-backed silica G60 Thin Layer Chromatography plates (10×20 cm; Macherey-Nagel). A mixture of LDFT (Rf=0.18), 2′-FL (Rf=0.24), lactose (Rf=0.30), trehalose (Rf=0.32), acetyl-lactose (Rf=0.39) and fucose (Rf=0.48) (5 g/L concentration for each sugar) is run alongside as standards. The plates are developed in a 50% butanol:25% acetic acid:25% water solvent until the front is within 1 cm from the top. Improved sugar resolution can be obtained by performing two sequential runs, drying the plate between runs. Sugar spots are visualized by spraying with α-naphthol in a sulfuric acid-ethanol solution (2.4 g α-naphthol in 83% (v/v) ethanol, 10.5% (v/v) sulfuric acid) and heating at 120 C for a few minutes. High molecular weight contaminants (DNA, protein, caramels) remain at the origin, or form smears with Rfs lower than LDFT. Example 5. 3FL Production Any one of E. coli host strains E214, E390 or E403, when transformed with a plasmid expressing an α(1,3)fucosyltransferase capable of using lactose as the sugar acceptor substrate, will produce the human milk oligosaccharide product, 3-fucosyllactose (3FL). FIG. 9 illustrates the pathways utilized in engineered strains of E. coli of this invention to achieve production of 3FL. For example, the plasmid pG176 (ColE1, thyA+, bla+, PL2-futA, rcsA+) (SEQ ID NO: 2), is a derivative of pG175 in which the α(1,2) FT (wbsJ) sequence is replaced by the Helicobacter pylori futA gene (Dumon, C., Bosso, C., Utille, J. P., Heyraud, A. & Samain, E. Chembiochem 7, 359-365 (2006)). pG176 will direct the production of 3FL when transformed into any one of the host E. coli strains E214, E390 or E403. FIG. 11 shows a TLC analysis of 3FL production from E403 transformed with pG176. Additionally there are several other related bacterial-type α(1,3)-fucosyltransferases identified in Helicobacter pylori which could be used to direct synthesis of 3FL, e.g., “11639 FucTa” (Ge, Z., Chan, N. W., Palcic, M. M. & Taylor, D. E. J Biol Chem 272, 21357-21363 (1997); Martin, S. L., Edbrooke, M. R., Hodgman, T. C., van den Eijnden, D. H. & Bird, M. I. J Biol Chem 272, 21349-21356 (1997)) and “UA948 FucTa” (Rasko, D. A., Wang, G., Palcic, M. M. & Taylor, D. E. J Biol Chem 275, 4988-4994 (2000)). In addition to α(1,3)-fucosyltransferases from H. pylori, an α(1,3)fucosyltransferase (Hh0072, sequence accession AAP76669) isolated from Helicobacter hepaticus exhibits activity towards both non-sialylated and sialylated Type 2 oligosaccharide acceptor substrates (Zhang, L., Lau, K., Cheng, J., Yu, H., et al. Glycobiology (2010)). Furthermore, there are several additional bacterial α(1,3)-fucosyltransferases that may be used to make 3FL according to the methods of this invention. For example, close homologs of Hh0072 are found in H. H. bilis (HRAG_01092 gene, sequence accession EEO24035), and in C. jejuni (C1336_000250319 gene, sequence accession EFC31050). 3FL biosynthesis is performed as described above for 2′-FL, either at small scale in culture tubes and culture flasks, or in a bioreactor (10 L working volume) utilizing control of dissolved oxygen, pH, lactose substrate, antifoam and carbon:nitrogen balance. Cell densities of A600˜100 are reached in the bioreacter, and specific 3FL yields of up to 3 g/L have been achieved. Approximately half of the 3FL produced is found in the culture supernatant, and half inside the cells. Purification of 3FL from E. coli culture supernatants is achieved using an almost identical procedure to that described above for 2′-FL. The only substantive difference being that 3FL elutes from carbon columns at lower alcohol concentrations than does 2′-FL. Example 6. The Simultaneous Production of Human Milk Oligosaccharides 2′-Fucosyllactose (2′-FL), 3-Fucosyllactose (3FL), and Lactodifucohexaose (LDFT) in E. coli E. coli strains E214, E390 and E403 accumulate cytoplasmic pools of both lactose and GDP-fucose, as discussed above, and when transformed with plasmids expressing either an α(1,2) fucosyltransferase or an α(1,3) fucosyltransferase can synthesize the human milk oligosaccharides 2′-FL or 3FL respectively. The tetrasaccharide lactodifucotetraose (LDFT) is another major fucosylated oligosaccharide found in human milk, and contains both α(1,2)- and α(1,3)-linked fucose residues. pG177 (FIG. 10, SEQ ID NO: 3) is a derivative of pG175 in which the wbsJ gene is replaced by a two gene operon comprising the Helicobacter pylori futA gene and the Helicobacter pylori futC gene (i.e., an operon containing both an α(1,3)- and α(1,2)-fucosyltransferase). E. coli strains E214, E390 and E403 produce LDFT when transformed with plasmid pG177 and grown, either in small scale or in the bioreactor, as described above. In FIG. 11 (lanes pG177), LDFT made in E. coli, directed by pG177, was observed on analysis of cell extracts by thin layer chromatography. Example 7. 3′-SL Synthesis in the E. coli Cytoplasm The first step in the production of 3′-sialyllactose (3′-SL) in E. coli is generation of a host background strain that accumulates cytoplasmic pools of both lactose and CMP-Neu5Ac (CMP-sialic acid). Accumulation of cytoplasmic lactose is achieved through growth on lactose and inactivation of the endogenous E. coli β-galactosidase gene (lacZ), being careful to minimize polarity effects on lacY, the lac permease. This accumulation of a lactose pool has already been accomplished and is described above in E. coli hosts engineered for 2′-FL, 3FL and LDFT production. Specifically, a scheme to generate a cytoplasmic CMP-Neu5Ac pool, modified from methods known in the art, (e.g., Ringenberg, M., Lichtensteiger, C. & Vimr, E. Glycobiology 11, 533-539 (2001); Fierfort, N. & Samain, E. J Biotechnol 134, 261-265 (2008)), is shown in FIG. 5. Under this scheme, the E. coli K12 sialic acid catabolic pathway is first ablated through introduction of null mutations in endogenous nanA (N-acetylneuraminate lyase) and nanK (N-acetylmannosamine kinase) genes. By “sialic acid catabolic pathway” is meant a sequence of reactions, usually controlled and catalyzed by enzymes, which results in the degradation of sialic acid. An exemplary sialic acid catabolic pathway in Escherichia coli is set forth in FIG. 5. In the sialic acid catabolic pathway in FIG. 5, sialic acid (Neu5Ac; N-acetylneuraminic acid) is degraded by the enzymes NanA (N-acetylneuraminic acid lyase) and NanK (N-acetylmannosamine kinase). Other abbreviations for the sialic acid catabolic pathway in FIG. 5 include: (nanT) sialic acid transporter; (ΔnanA) mutated N-acetylneuraminic acid lyase; (ΔnanK) mutated N-acetylmannosamine kinase; (ManNAc-6-P) N-acetylmannosamine-6-phosphate; (GlcNAc-6-P) N-acetylglucosamine-6-phosphate; (GlcN-6-P) Glucosamine-6-phosphate; (Fruc-6-P) Fructose-6-phosphate; (neuA), CMP-N-acetylneuraminic acid synthetase; (CMP-Neu5Ac) CMP-N-acetylneuraminic acid; and (neuB), N-acetylneuraminic acid synthase. Next, since E. coli K12 lacks a de novo sialic acid synthesis pathway, sialic acid synthetic capability is introduced through the provision of three recombinant enzymes; a UDP-GlcNAc 2-epimerase (e.g., neuC), a Neu5Ac synthase (e.g., neuB) and a CMP-Neu5Ac synthetase (e.g., neuA). Equivalent genes from C. jejuni, E. coli K1, H. influenzae or from N. meningitides can be utilized (interchangeably) for this purpose. The addition of sialic acid to the 3′ position of lactose to generate 3′-sialyllactose is then achieved utilizing a bacterial-type α(2,3)sialyltransferase, and numerous candidate genes have been described, including those from N. meningitidis and N. gonorrhoeae (Gilbert, M., Watson, D. C., Cunningham, A. M., Jennings, M. P., et al. J Biol Chem 271, 28271-28276 (1996); Gilbert, M., Cunningham, A. M., Watson, D. C., Martin, A., et al. Eur J Biochem 249, 187-194 (1997)). The Neisseria enzymes are already known to use lactose as an acceptor sugar. The recombinant N. meningitidis enzyme generates 3′-sialyllactose in engineered E. coli (Fierfort, N. & Samain, E. J Biotechnol 134, 261-265 (2008)). FIG. 20 shows a TLC analysis of culture media taken from a culture of E. coli strain E547 (ampC::(PtrpBλcI+), PlacIq(ΔlacI-lacZ)158lacY+, ΔlacA, Δnan) and carrying plasmids expressing neuA,B,C and a bacterial-type α(2,3)sialyltransferase. The presence of 3′-sialylactose (3′-SL) in the culture media is clearly seen. Example 8. The Production of Human Milk Oligosaccharide 3′-Sialyl-3-Fucosyllactose (3′-S3FL) in E. coli Prior to the invention described herein, it was unpredictable that a combination of any particular fucosyltransferase gene and any particular sialyl-transferase gene in the same bacterial strain could produce 3′-S3FL. Described below are results demonstrating that the combination of a fucosyltransferase gene and a sialyl-transferase gene in the same LacZ+ E. coli strain resulted in the production of 3′-S3FL. These unexpected results are likely due to the surprisingly relaxed substrate specificity of the particular fucosyltransferase and sialyl-transferase enzymes utilized. Humans synthesize the sialyl-Lewis X epitope utilizing different combinations of six α(1,3)fucosyl- and six α(2,3)sialyl-transferases encoded in the human genome (de Vries, T., Knegtel, R. M., Holmes, E. H. & Macher, B. A. Glycobiology 11, 119R-128R (2001); Taniguchi, A. Curr Drug Targets 9, 310-316 (2008)). These sugar transferases differ not only in their tissue expression patterns, but also in their acceptor specificities. For example, human myeloid-type α(1,3) fucosyltransferase (FUT IV) will fucosylate Type 2 (Galβ1->4Glc/GlcNAc) chain-based acceptors, but only if they are non-sialylated. In contrast “plasma-type” α(1,3) fucosyltransferase (FUT VI) will utilize Type 2 acceptors whether or not they are sialylated, and the promiscuous “Lewis” α(1,3/4) fucosyltransferase (FUT III), found in breast and kidney, will act on sialylated and non-sialylated Type 1 (Galβ1->3GlcNAc) and Type 2 acceptors (Easton, E. W., Schiphorst, W. E., van Drunen, E., van der Schoot, C. E. & van den Eijnden, D. H. Blood 81, 2978-2986 (1993)). A similar situation exists for the family of human□ α(2,3)sialyl-transferases, with different enzymes exhibiting major differences in acceptor specificity (Legaigneur, P., Breton, C., El Battari, A., Guillemot, J. C., et al. J Biol Chem 276, 21608-21617 (2001); Jeanneau, C., Chazalet, V., Augé, C., Soumpasis, D. M., et al. J Biol Chem 279, 13461-13468 (2004)). This diversity in acceptor specificity highlights a key issue in the synthesis of 3′-sialyl-3-fucosyllactose (3′-S3FL) in E. coli, i.e., to identify a suitable combination of fucosyl- and sialyl-transferases capable of acting cooperatively to synthesize 3′-S3FL (utilizing lactose as the initial acceptor sugar). However, since human and all other eukaryotic fucosyl- and sialyl-transferases are secreted proteins located in the lumen of the golgi, they are poorly suited for the task of 3′-S3FL biosynthesis in the bacterial cytoplasm. Several bacterial pathogens are known to incorporate fucosylated and/or sialylated sugars into their cell envelopes, typically for reasons of host mimicry and immune evasion. For example; both Neisseria meningitides and Campylobacter jejuni are able to incorporate sialic acid through 2,3-linkages to galactose moieties in their capsular lipooligosaccharide (LOS) (Tsai, C. M., Kao, G. & Zhu, P. I Infection and Immunity 70, 407 (2002); Gilbert, M., Brisson, J. R., Karwaski, M. F., Michniewicz, J., et al. J Biol Chem 275, 3896-3906 (2000)), and some strains of E. coli incorporate α(1,2) fucose groups into lipopolysaccharide (LPS) (Li, M., Liu, X. W., Shao, J., Shen, J., et al. Biochemistry 47, 378-387 (2008); Li, M., Shen, J., Liu, X., Shao, J., et al. Biochemistry 47, 11590-11597 (2008)). Certain strains of Helicobacter pylori are able not only to incorporate α(2,3)-sialyl-groups, but also α(1,2)-, α(1,3)-, and α(1,4)-fucosyl-groups into LPS, and thus can display a broad range of human Lewis-type epitopes on their cell surface (Moran, A. P. Carbohydr Res 343, 1952-1965 (2008)). Most bacterial sialyl- and fucosyl-transferases operate in the cytoplasm, i.e., they are better suited to the methods described herein than are eukaryotic golgi-localized sugar transferases. Strains of E. coli engineered to express the transferases described above accumulate a cytoplasmic pool of lactose, as well as an additional pool of either the nucleotide sugar GDP-fucose, or the nucleotide sugar CMP-Neu5Ac (CMP-sialic acid). Addition of these sugars to the lactose acceptor is performed in these engineered hosts using candidate recombinant α(1,3)-fucosyl- or α(2,3)-sialyl-transferases, generating 3-fucosyllactose and 3′-sialyllactose respectively. Finally, the two synthetic capabilities are combined into a single E. coli strain to produce 3′-S3FL. An E. coli strain that accumulates cytoplasmic pools of both lactose and GDP-fucose has been developed. This strain, when transformed with a plasmid over-expressing an α(1,2)fucosyltransferase, produces 2′-fucosyllactose (2′-FL) at levels of ˜10-50 g/L of bacterial culture medium. A substitution of the α(1,2) fucosyltransferase in this host with an appropriate α(1,3) fucosyltransferase leads to the production of 3-fucosyllactose (3FL). The bacterial α(1,3) fucosyltransferase then works in conjunction with a bacterial α(2,3)sialyltransferase to make the desired product, 3′-S3FL. An α(1,3)fucosyltransferase (Hh0072) isolated from Helicobacter hepaticus exhibits activity towards both non-sialylated and sialylated Type 2 oligosaccharide acceptor substrates (Zhang, L., Lau, K., Cheng, J., Yu, H., et al. Glycobiology (2010)). This enzyme is cloned, expressed, and evaluated to measure utilization of a lactose acceptor and to evaluate production of 3FL in the context of the current GDP-fucose-producing E. coli host. Hh0072 is also tested in concert with various bacterial α(2,3)sialyltransferases for its competence in 3′-S3FL synthesis. As alternatives to Hh0072, there are two characterized homologous bacterial-type 3-fucosyltransferases identified in Helicobacter pylori, “11639 FucTa” (Ge, Z., Chan, N. W., Palcic, M. M. & Taylor, D. E. J Biol Chem 272, 21357-21363 (1997); Martin, S. L., Edbrooke, M. R., Hodgman, T. C., van den Eijnden, D. H. & Bird, M. I. J Biol Chem 272, 21349-21356 (1997)) and “UA948 FucTa” (Rasko, D. A., Wang, G., Palcic, M. M. & Taylor, D. E. J Biol Chem 275, 4988-4994 (2000)). These two paralogs exhibit differing acceptor specificities, “11639 FucTa” utilizes only Type 2 acceptors and is a strict α(1,3)-fucosyltransferase, whereas “UA948 FucTa” has relaxed acceptor specificity (utilizing both Type1 and Type 2 acceptors) and is able to generate both α(1,3)- and α(1,4)-fucosyl linkages. The precise molecular basis of this difference in specificity was determined (Ma, B., Lau, L. H., Palcic, M. M., Hazes, B. & Taylor, D. E. J Biol Chem 280, 36848-36856 (2005)), and characterization of several additional α(1,3)-fucosyltransferase paralogs from a variety of additional H. pylori strains revealed significant strain-to-strain acceptor specificity diversity. In addition to the enzymes from H. pylori and H. hepaticus, other bacterial α(1,3)-fucosyltransferases are optionally used. For example, close homologs of Hh0072 are found in H. bilis (HRAG_01092 gene, sequence accession EEO24035), and in C. jejuni (C1336_000250319 gene, sequence accession EFC31050). Described below is 3′-S3FL synthesis in E. coli. The first step towards this is to combine into a single E. coli strain the 3-fucosyllactose synthetic ability, outlined above, with the ability to make 3′-sialyllactose, also outlined above. All of the chromosomal genetic modifications discussed above are introduced into a new host strain, which will then simultaneously accumulate cytoplasmic pools of the 3 specific precursors; lactose, GDP-fucose and CMP-Neu5Ac. This “combined” strain background is then used to host simultaneous production of an α(1,3)fucosyltransferase with an α(2,3)sialyltransferase, with gene expression driven either off two compatible multicopy plasmids or with both enzyme genes positioned on the same plasmid as an artificial operon. Acceptor specificities for some of the bacterial α(1,3)fucosyltransferases and α(2,3)sialyltransferases, particularly with respect to fucosylation of 3′-sialyllactose and sialylation of 3-fucosyllactose and different combinations of α(1,3)fucosyltransferase and α(2,3)sialyltransferase enzymes are evaluated. Production levels and ratios of 3′-SL, 3FL and 3′-S3FL are monitored, e.g., by TLC, with confirmation of identity by NMR and accurate quantitation either by calibrated mass spectrometry utilizing specific ion monitoring, or by capillary electrophoresis (Bao, Y., Zhu, L. & Newburg, D. S. Simultaneous quantification of sialyloligosaccharides from human milk by capillary electrophoresis. Anal Biochem 370, 206-214 (2007)). The sequences corresponding to the SEQ ID NOs described herein are provided below. The sequence of PG175 is set forth below (SEQ ID NO: 1): TCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCG GAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGCAGACAAGCCCG TCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAACTATG CGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATATGCGGTGTGAAA TACCGCACAGATGCGTAAGGAGAAAATACCGCATCAGGCGCCTCCTCAAC CTGTATATTCGTAAACCACGCCCAATGGGAGCTGTCTCAGGTTTGTTCCT GATTGGTTACGGCGCGTTTCGCATCATTGTTGAGTTTTTCCGCCAGCCCG ACGCGCAGTTTACCGGTGCCTGGGTGCAGTACATCAGCATGGGGCAAATT CTTTCCATCCCGATGATTGTCGCGGGTGTGATCATGATGGTCTGGGCATA TCGTCGCAGCCCACAGCAACACGTTTCCTGAGGAACCATGAAACAGTATT TAGAACTGATGCAAAAAGTGCTCGACGAAGGCACACAGAAAAACGACCGT ACCGGAACCGGAACGCTTTCCATTTTTGGTCATCAGATGCGTTTTAACCT GCAAGATGGATTCCCGCTGGTGACAACTAAACGTTGCCACCTGCGTTCCA TCATCCATGAACTGCTGTGGTTTCTGCAGGGCGACACTAACATTGCTTAT CTACACGAAAACAATGTCACCATCTGGGACGAATGGGCCGATGAAAACGG CGACCTCGGGCCAGTGTATGGTAAACAGTGGCGCGCCTGGCCAACGCCAG ATGGTCGTCATATTGACCAGATCACTACGGTACTGAACCAGCTGAAAAAC GACCCGGATTCGCGCCGCATTATTGTTTCAGCGTGGAACGTAGGCGAACT GGATAAAATGGCGCTGGCACCGTGCCATGCATTCTTCCAGTTCTATGTGG CAGACGGCAAACTCTCTTGCCAGCTTTATCAGCGCTCCTGTGACGTCTTC CTCGGCCTGCCGTTCAACATTGCCAGCTACGCGTTATTGGTGCATATGAT GGCGCAGCAGTGCGATCTGGAAGTGGGTGATTTTGTCTGGACCGGTGGCG ACACGCATCTGTACAGCAACCATATGGATCAAACTCATCTGCAATTAAGC CGCGAACCGCGTCCGCTGCCGAAGTTGATTATCAAACGTAAACCCGAATC CATCTTCGACTACCGTTTCGAAGACTTTGAGATTGAAGGCTACGATCCGC ATCCGGGCATTAAAGCGCCGGTGGCTATCTAATTACGAAACATCCTGCCA GAGCCGACGCCAGTGTGCGTCGGTTTTTTTACCCTCCGTTAAATTCTTCG AGACGCCTTCCCGAAGGCGCCATTCGCCATTCAGGCTGCGCAACTGTTGG GAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGG GGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGT CACGACGTTGTAAAACGACGGCCAGTGCCAAGCTTTCTTTAATGAAGCAG GGCATCAGGACGGTATCTTTGTGGAGAAAGCAGAGTAATCTTATTCAGCC TGACTGGTGGGAAACCACCAGTCAGAATGTGTTAGCGCATGTTGACAAAA ATACCATTAGTCACATTATCCGTCAGTCGGACGACATGGTAGATAACCTG TTTATTATGCGTTTTGATCTTACGTTTAATATTACCTTTATGCGATGAAA CGGTCTTGGCTTTGATATTCATTTGGTCAGAGATTTGAATGGTTCCCTGA CCTGCCATCCACATTCGCAACATACTCGATTCGGTTCGGCTCAATGATAA CGTCGGCATATTTAAAAACGAGGTTATCGTTGTCTCTTTTTTCAGAATAT CGCCAAGGATATCGTCGAGAGATTCCGGTTTAATCGATTTAGAACTGATC AATAAATTTTTTCTGACCAATAGATATTCATCAAAATGAACATTGGCAAT TGCCATAAAAACGATAAATAACGTATTGGGATGTTGATTAATGATGAGCT TGATACGCTGACTGTTAGAAGCATCGTGGATGAAACAGTCCTCATTAATA AACACCACTGAAGGGCGCTGTGAATCACAAGCTATGGCAAGGTCATCAAC GGTTTCAATGTCGTTGATTTCTCTTTTTTTAACCCCTCTACTCAACAGAT ACCCGGTTAAACCTAGTCGGGTGTAACTACATAAATCCATAATAATCGTT GACATGGCATACCCTCACTCAATGCGTAACGATAATTCCCCTTACCTGAA TATTTCATCATGACTAAACGGAACAACATGGGTCACCTAATGCGCCACTC TCGCGATTTTTCAGGCGGACTTACTATCCCGTAAAGTGTTGTATAATTTG CCTGGAATTGTCTTAAAGTAAAGTAAATGTTGCGATATGTGAGTGAGCTT AAAACAAATATTTCGCTGCAGGAGTATCCTGGAAGATGTTCGTAGAAGCT TACTGCTCACAAGAAAAAAGGCACGTCATCTGACGTGCCTTTTTTATTTG TACTACCCTGTACGATTACTGCAGCTCGAGTTATTATAATTTTACCCACG ATTCGGGAATAATATCATGTTTAATATCTTTCTTAAACCATTTACTCGGA GCAATTACTGTTTTATTTTTATTTTCATTTAACCAAGCAGCCCACCAACT GAAAGAACTATTTGAAATTATATTATTTTTACATTTACTCATAAGCAGCA TATCTAATTCAACATGATAAGCATCACCTTGAACAAAACATATTTGATTA TTAAAAAATATATTTTCCCTGCACCACTTTATATCATCAGAAAAAATGAA GAGAAGGGTTTTTTTATTAATAACACCTTTATTCATCAAATAATCAATGG CACGTTCAAAATATTTTTCACTACATGTGCCATGAGTTTCATTTGCTATT TTACTGGAAACATAATCACCTCTTCTAATATGTAATGAACAAGTATCATT TTCTTTAATTAAATTAAGCAATTCATTTTGATAACTATTAAACTTGGTTT TAGGTTGAAATTCCTTTATCAACTCATGCCTAAATTCCTTAAAATATTTT TCAGTTTGAAAATAACCGACGATTTTTTTATTTATACTTTTGGTATCAAT ATCTGGATCATACTCTAAACTTTTCTCAACGTAATGCTTTCTGAACATTC CTTTTTTCATGAAATGTGGGATTTTTTCGGAAAATAAGTATTTTTCAAAT GGCCATGCTTTTTTTACAAATTCTGAACTACAAGATAATTCAACTAATCT TAATGGATGAGTTTTATATTTTACTGCATCAGATATATCAACAGTCAAAT TTTGATGAGTTCTTTTTGCAATAGCAAATGCAGTTGCATACTGAAACATT TGATTACCAAGACCACCAATAATTTTAACTTCCATATGTATATCTCCTTC TTCTAGAATTCTAAAAATTGATTGAATGTATGCAAATAAATGCATACACC ATAGGTGTGGTTTAATTTGATGCCCTTTTTCAGGGCTGGAATGTGTAAGA GCGGGGTTATTTATGCTGTTGTTTTTTTGTTACTCGGGAAGGGCTTTACC TCTTCCGCATAAACGCTTCCATCAGCGTTTATAGTTAAAAAAATCTTTCG GAACTGGTTTTGCGCTTACCCCAACCAACAGGGGATTTGCTGCTTTCCAT TGAGCCTGTTTCTCTGCGCGACGTTCGCGGCGGCGTGTTTGTGCATCCAT CTGGATTCTCCTGTCAGTTAGCTTTGGTGGTGTGTGGCAGTTGTAGTCCT GAACGAAAACCCCCCGCGATTGGCACATTGGCAGCTAATCCGGAATCGCA CTTACGGCCAATGCTTCGTTTCGTATCACACACCCCAAAGCCTTCTGCTT TGAATGCTGCCCTTCTTCAGGGCTTAATTTTTAAGAGCGTCACCTTCATG GTGGTCAGTGCGTCCTGCTGATGTGCTCAGTATCACCGCCAGTGGTATTT ATGTCAACACCGCCAGAGATAATTTATCACCGCAGATGGTTATCTGTATG TTTTTTATATGAATTTATTTTTTGCAGGGGGGCATTGTTTGGTAGGTGAG AGATCAATTCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTT GCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGG TCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGG TTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGG CCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCC ATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAG AGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGG AAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACC TGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGC TGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGT GCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATC GTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCC ACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTT CTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGGACAGTATTTGGTA TCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCT TGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAA GCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCT TTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATT TTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTA AAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTG ACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTA TTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGAT ACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACC CACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGG GCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTAT TAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGC GCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTT GGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATG ATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCG TTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCA CTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGAC TGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGA GTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGA ACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTC AAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCAC CCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCA AAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAA ATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATC AGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAAT AAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTGACGT CTAAGAAACCATTATTATCATGACATTAACCTATAAAAATAGGCGTATCA CGAGGCCCTTTCGTC The sequence of pG176 is set forth below (SEQ ID NO: 2): TCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCG GAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGCAGACAAGCCCG TCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAACTATG CGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATATGCGGTGTGAAA TACCGCACAGATGCGTAAGGAGAAAATACCGCATCAGGCGCCATGAAACA GTATTTAGAACTGATGCAAAAAGTGCTCGACGAAGGCACACAGAAAAACG ACCGTACCGGAACCGGAACGCTTTCCATTTTTGGTCATCAGATGCGTTTT AACCTGCAAGATGGATTCCCGCTGGTGACAACTAAACGTTGCCACCTGCG TTCCATCATCCATGAACTGCTGTGGTTTCTGCAGGGCGACACTAACATTG CTTATCTACACGAAAACAATGTCACCATCTGGGACGAATGGGCCGATGAA AACGGCGACCTCGGGCCAGTGTATGGTAAACAGTGGCGCGCCTGGCCAAC GCCAGATGGTCGTCATATTGACCAGATCACTACGGTACTGAACCAGCTGA AAAACGACCCGGATTCGCGCCGCATTATTGTTTCAGCGTGGAACGTAGGC GAACTGGATAAAATGGCGCTGGCACCGTGCCATGCATTCTTCCAGTTCTA TGTGGCAGACGGCAAACTCTCTTGCCAGCTTTATCAGCGCTCCTGTGACG TCTTCCTCGGCCTGCCGTTCAACATTGCCAGCTACGCGTTATTGGTGCAT ATGATGGCGCAGCAGTGCGATCTGGAAGTGGGTGATTTTGTCTGGACCGG TGGCGACACGCATCTGTACAGCAACCATATGGATCAAACTCATCTGCAAT TAAGCCGCGAACCGCGTCCGCTGCCGAAGTTGATTATCAAACGTAAACCC GAATCCATCTTCGACTACCGTTTCGAAGACTTTGAGATTGAAGGCTACGA TCCGCATCCGGGCATTAAAGCGCCGGTGGCTATCTAAGGCGCCATTCGCC ATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGC TATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGG GTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGC CAAGCTTTCTTTAATGAAGCAGGGCATCAGGACGGTATCTTTGTGGAGAA AGCAGAGTAATCTTATTCAGCCTGACTGGTGGGAAACCACCAGTCAGAAT GTGTTAGCGCATGTTGACAAAAATACCATTAGTCACATTATCCGTCAGTC GGACGACATGGTAGATAACCTGTTTATTATGCGTTTTGATCTTACGTTTA ATATTACCTTTATGCGATGAAACGGTCTTGGCTTTGATATTCATTTGGTC AGAGATTTGAATGGTTCCCTGACCTGCCATCCACATTCGCAACATACTCG ATTCGGTTCGGCTCAATGATAACGTCGGCATATTTAAAAACGAGGTTATC GTTGTCTCTTTTTTCAGAATATCGCCAAGGATATCGTCGAGAGATTCCGG TTTAATCGATTTAGAACTGATCAATAAATTTTTTCTGACCAATAGATATT CATCAAAATGAACATTGGCAATTGCCATAAAAACGATAAATAACGTATTG GGATGTTGATTAATGATGAGCTTGATACGCTGACTGTTAGAAGCATCGTG GATGAAACAGTCCTCATTAATAAACACCACTGAAGGGCGCTGTGAATCAC AAGCTATGGCAAGGTCATCAACGGTTTCAATGTCGTTGATTTCTCTTTTT TTAACCCCTCTACTCAACAGATACCCGGTTAAACCTAGTCGGGTGTAACT ACATAAATCCATAATAATCGTTGACATGGCATACCCTCACTCAATGCGTA ACGATAATTCCCCTTACCTGAATATTTCATCATGACTAAACGGAACAACA TGGGTCACCTAATGCGCCACTCTCGCGATTTTTCAGGCGGACTTACTATC CCGTAAAGTGTTGTATAATTTGCCTGGAATTGTCTTAAAGTAAAGTAAAT GTTGCGATATGTGAGTGAGCTTAAAACAAATATTTCGCTGCAGGAGTATC CTGGAAGATGTTCGTAGAAGCTTACTGCTCACAAGAAAAAAGGCACGTCA TCTGACGTGCCTTTTTTATTTGTACTACCCTGTACGATTACTGCAGCTCG AGTTAATTCAAATCTTCTTCAGAAATCAATTTTTGTTCCAAACCCAATTT TTTAACCAACTTTCTCACCGCGCGCAACAAAGGCAAGGATTTTTGATAAG CTTTGCGATAGATTTTAAAAGTGGTGTTTTGAGAGAGTTCTAATAAAGGC GAAGCGTTTTGTAAAAGCCGGTCATAATTAACCCTCAAATCATCATAATT AACCCTCAAATCATCAATGGATACTAACGGCTTATGCAGATCGTACTCCC ACATGAAAGATGTTGAGAATTTGTGATAAATCGTATCGTTTTCTAAAATC GTTTTAAAAAAATCTAGGATTTTTTTAAAACTCAAATCTTGGTAAAAGTA AGCTTTCCCATCAAGGGTGTTTAAAGGGTTTTCATAGAGCATGTCTAAAT AAGCGTTTGGGTGCGTGTGCAGGTATTTGATATAATCAATCGCTTCATCA AAGTTGTTGAAATCATGCACATTCACAAAACTTTTAGGGTTAAAATCTTT CGCCACGCTGGGACTCCCCCAATAAATAGGAATGGTATGGCTAAAATACG CATCAAGGATTTTTTCGGTTACATAGCCATAACCTTGCGAGTTTTCAAAA CAGAGATTGAACTTGTATTGGCTTAAAAACTCGCTTTTGTTTCCAACCTT ATAGCCTAAAGTGTTTCTCACACTTCCTCCCCCAGTAACTGGCTCTATGG AATTTAGAGCGTCATAAAAAGCGTTCCTCATAGGAGCGTTAGCGTTGCTC GCTACAAAACTGGCAAACCCTCTTTTTAAAAGATCGCTCTCATCATTCAC TACTGCGCACAAATTAGGGTGGTTTTCTTTAAAATGATGAGAGGGTTTTT TTAAAGCATAAAGGCTGTTGTCTTTGAGTTTGTAGGGCGCAGTGGTGTCA TTAACAAGCTCGGCTTTATAGTGCAAATGGGCATAATACAAAGGCATTCT CAAATAACGATCATTAAAATCCAATTCATCAAAGCCTATGGCGTAATCAA AGAGGTTGAAATTAGGTGATTCGTTTTCACCGGTGTAAAACACTCGTTTA GTGTTTTGATAAGATAAAATCTTTCTAGCCGCTCCAAGAGGATTGCTAAA AACTAGATCTGAAAATTCATTGGGGTTTTGGTGGAGGGTGATTGCGTAGC GTTGGCTTAGGATAAAATAAAGAACGCTCTTTTTAAATTCTTTAATTTCT TCATCTCCCCACCAATTCGCCACAGCGATTTTTAGGGGGGGGGGGGGAGA TTTAGAGGCCATTTTTTCAATGGAAGCGCTTTCTATAAAGGCGTCTAATA GGGGTTGGAACATATGTATATCTCCTTCTTGAATTCTAAAAATTGATTGA ATGTATGCAAATAAATGCATACACCATAGGTGTGGTTTAATTTGATGCCC TTTTTCAGGGCTGGAATGTGTAAGAGCGGGGTTATTTATGCTGTTGTTTT TTTGTTACTCGGGAAGGGCTTTACCTCTTCCGCATAAACGCTTCCATCAG CGTTTATAGTTAAAAAAATCTTTCGGAACTGGTTTTGCGCTTACCCCAAC CAACAGGGGATTTGCTGCTTTCCATTGAGCCTGTTTCTCTGCGCGACGTT CGCGGCGGCGTGTTTGTGCATCCATCTGGATTCTCCTGTCAGTTAGCTTT GGTGGTGTGTGGCAGTTGTAGTCCTGAACGAAAACCCCCCGCGATTGGCA CATTGGCAGCTAATCCGGAATCGCACTTACGGCCAATGCTTCGTTTCGTA TCACACACCCCAAAGCCTTCTGCTTTGAATGCTGCCCTTCTTCAGGGCTT AATTTTTAAGAGCGTCACCTTCATGGTGGTCAGTGCGTCCTGCTGATGTG CTCAGTATCACCGCCAGTGGTATTTATGTCAACACCGCCAGAGATAATTT ATCACCGCAGATGGTTATCTGTATGTTTTTTATATGAATTTATTTTTTGC AGGGGGGCATTGTTTGGTAGGTGAGAGATCAATTCTGCATTAATGAATCG GCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCC TCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATC AGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACG CAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAA AAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCA TCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTAT AAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTT CCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAG CGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGG TCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGAC CGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACA CGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGA GGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGC TACACTAGAAGGACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTAC CTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTG GTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAA GGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTG GAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGA TCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAA AGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGA GGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGAC TCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCC AGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATC AGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAA CTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTA AGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGG CATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTT CCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCG GTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGT GTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGC CATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTC TGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACG GGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAA AACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCC AGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTAC TTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAA AAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTT TTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATA CATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACAT TTCCCCGAAAAGTGCCACCTGACGTCTAAGAAACCATTATTATCATGACA TTAACCTATAAAAATAGGCGTATCACGAGGCCCTTTCGTC The sequence of pG177 is set forth below (SEQ ID NO: 3): TCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCG GAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGCAGACAAGCCCG TCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAACTATG CGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATATGCGGTGTGAAA TACCGCACAGATGCGTAAGGAGAAAATACCGCATCAGGCGCCATGAAACA GTATTTAGAACTGATGCAAAAAGTGCTCGACGAAGGCACACAGAAAAACG ACCGTACCGGAACCGGAACGCTTTCCATTTTTGGTCATCAGATGCGTTTT AACCTGCAAGATGGATTCCCGCTGGTGACAACTAAACGTTGCCACCTGCG TTCCATCATCCATGAACTGCTGTGGTTTCTGCAGGGCGACACTAACATTG CTTATCTACACGAAAACAATGTCACCATCTGGGACGAATGGGCCGATGAA AACGGCGACCTCGGGCCAGTGTATGGTAAACAGTGGCGCGCCTGGCCAAC GCCAGATGGTCGTCATATTGACCAGATCACTACGGTACTGAACCAGCTGA AAAACGACCCGGATTCGCGCCGCATTATTGTTTCAGCGTGGAACGTAGGC GAACTGGATAAAATGGCGCTGGCACCGTGCCATGCATTCTTCCAGTTCTA TGTGGCAGACGGCAAACTCTCTTGCCAGCTTTATCAGCGCTCCTGTGACG TCTTCCTCGGCCTGCCGTTCAACATTGCCAGCTACGCGTTATTGGTGCAT ATGATGGCGCAGCAGTGCGATCTGGAAGTGGGTGATTTTGTCTGGACCGG TGGCGACACGCATCTGTACAGCAACCATATGGATCAAACTCATCTGCAAT TAAGCCGCGAACCGCGTCCGCTGCCGAAGTTGATTATCAAACGTAAACCC GAATCCATCTTCGACTACCGTTTCGAAGACTTTGAGATTGAAGGCTACGA TCCGCATCCGGGCATTAAAGCGCCGGTGGCTATCTAAGGCGCCATTCGCC ATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGC TATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGG GTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGC CAAGCTTTCTTTAATGAAGCAGGGCATCAGGACGGTATCTTTGTGGAGAA AGCAGAGTAATCTTATTCAGCCTGACTGGTGGGAAACCACCAGTCAGAAT GTGTTAGCGCATGTTGACAAAAATACCATTAGTCACATTATCCGTCAGTC GGACGACATGGTAGATAACCTGTTTATTATGCGTTTTGATCTTACGTTTA ATATTACCTTTATGCGATGAAACGGTCTTGGCTTTGATATTCATTTGGTC AGAGATTTGAATGGTTCCCTGACCTGCCATCCACATTCGCAACATACTCG ATTCGGTTCGGCTCAATGATAACGTCGGCATATTTAAAAACGAGGTTATC GTTGTCTCTTTTTTCAGAATATCGCCAAGGATATCGTCGAGAGATTCCGG TTTAATCGATTTAGAACTGATCAATAAATTTTTTCTGACCAATAGATATT CATCAAAATGAACATTGGCAATTGCCATAAAAACGATAAATAACGTATTG GGATGTTGATTAATGATGAGCTTGATACGCTGACTGTTAGAAGCATCGTG GATGAAACAGTCCTCATTAATAAACACCACTGAAGGGCGCTGTGAATCAC AAGCTATGGCAAGGTCATCAACGGTTTCAATGTCGTTGATTTCTCTTTTT TTAACCCCTCTACTCAACAGATACCCGGTTAAACCTAGTCGGGTGTAACT ACATAAATCCATAATAATCGTTGACATGGCATACCCTCACTCAATGCGTA ACGATAATTCCCCTTACCTGAATATTTCATCATGACTAAACGGAACAACA TGGGTCACCTAATGCGCCACTCTCGCGATTTTTCAGGCGGACTTACTATC CCGTAAAGTGTTGTATAATTTGCCTGGAATTGTCTTAAAGTAAAGTAAAT GTTGCGATATGTGAGTGAGCTTAAAACAAATATTTCGCTGCAGGAGTATC CTGGAAGATGTTCGTAGAAGCTTACTGCTCACAAGAAAAAAGGCACGTCA TCTGACGTGCCTTTTTTATTTGTACTACCCTGTACGATTACTGCAGCTCG AGTTAATTCAAATCTTCTTCAGAAATCAATTTTTGTTCAGCGTTATACTT TTGGGATTTTACCTCAAAATGGGATTCTATTTTCACCCACTCCTTACAAA GGATATTCTCATGCCCAAAAAGCCAGTGTTTGGGGCCAATAATGATTTTT TCTGGATTTTCTATCAAATAGGCCGCCCACCAGCTATAAGTGCTATTAGC GATAATGCCATGCTGACAAGATTGCATGAGCAGCATGTCCCAATACGCCT CTTCTTCTTTATCCCTAGTGGTCATGTCCATAAAAGGGTAGCCAAGATCA AGATTTTGCGTGAATTCTAAGTCTTCGCAAAACACAAAAAGCTCCATGTT TGGCACGCGCTTTGCCATATACTCAAGCGCCTTTTTTTGATAGTCAATAC CAAGCTGACAGCCAATCCCCACATAATCCCCTCTTCTTATATGCACAAAC ACGCTGTTTTTAGCGGCTAAAATCAAAGAAAGCTTGCACTGATATTCTTC CTCTTTTTTATTATTATTCTTATTATTTTCGGGTGGTGGTGGTAGAGTGA AGGTTTGCTTGATTAAAGGGGATATAGCATCAAAGTATCGTGGATCTTGG AAATAGCCAAAAAAATAAGTCAAGCGGCTTGGCTTTAGCAATTTAGGCTC GTATTCAAAAACGATTTCTTGACTCACCCTATCAAATCCCATGCATTTGA GCGCGTCTCTTACTAGCTTGGGGAGGTGTTGCATTTTAGCTATAGCGATT TCTTTCGCGCTCGCATAGGGCAAATCAATAGGGAAAAGTTCTAATTGCAT TTTCCTATCGCTCCAATCAAAAGAAGTGATATCTAACAGCACAGGCGTAT TAGAGTGTTTTTGCAAACTTTTAGCGAAAGCGTATTGAAACATTTGATTC CCAAGCCCTCCGCAAATTTGCACCACCTTAAAAGCCATATGTATATCTCC TTCTTGCTCGAGTTAATTCAAATCTTCTTCAGAAATCAATTTTTGTTCCA AACCCAATTTTTTAACCAACTTTCTCACCGCGCGCAACAAAGGCAAGGAT TTTTGATAAGCTTTGCGATAGATTTTAAAAGTGGTGTTTTGAGAGAGTTC TAATAAAGGCGAAGCGTTTTGTAAAAGCCGGTCATAATTAACCCTCAAAT CATCATAATTAACCCTCAAATCATCAATGGATACTAACGGCTTATGCAGA TCGTACTCCCACATGAAAGATGTTGAGAATTTGTGATAAATCGTATCGTT TTCTAAAATCGTTTTAAAAAAATCTAGGATTTTTTTAAAACTCAAATCTT GGTAAAAGTAAGCTTTCCCATCAAGGGTGTTTAAAGGGTTTTCATAGAGC ATGTCTAAATAAGCGTTTGGGTGCGTGTGCAGGTATTTGATATAATCAAT CGCTTCATCAAAGTTGTTGAAATCATGCACATTCACAAAACTTTTAGGGT TAAAATCTTTCGCCACGCTGGGACTCCCCCAATAAATAGGAATGGTATGG CTAAAATACGCATCAAGGATTTTTTCGGTTACATAGCCATAACCTTGCGA GTTTTCAAAACAGAGATTGAACTTGTATTGGCTTAAAAACTCGCTTTTGT TTCCAACCTTATAGCCTAAAGTGTTTCTCACACTTCCTCCCCCAGTAACT GGCTCTATGGAATTTAGAGCGTCATAAAAAGCGTTCCTCATAGGAGCGTT AGCGTTGCTCGCTACAAAACTGGCAAACCCTCTTTTTAAAAGATCGCTCT CATCATTCACTACTGCGCACAAATTAGGGTGGTTTTCTTTAAAATGATGA GAGGGTTTTTTTAAAGCATAAAGGCTGTTGTCTTTGAGTTTGTAGGGCGC AGTGGTGTCATTAACAAGCTCGGCTTTATAGTGCAAATGGGCATAATACA AAGGCATTCTCAAATAACGATCATTAAAATCCAATTCATCAAAGCCTATG GCGTAATCAAAGAGGTTGAAATTAGGTGATTCGTTTTCACCGGTGTAAAA CACTCGTTTAGTGTTTTGATAAGATAAAATCTTTCTAGCCGCTCCAAGAG GATTGCTAAAAACTAGATCTGAAAATTCATTGGGGTTTTGGTGGAGGGTG ATTGCGTAGCGTTGGCTTAGGATAAAATAAAGAACGCTCTTTTTAAATTC TTTAATTTCTTCATCTCCCCACCAATTCGCCACAGCGATTTTTAGGGGGG GGGGGGGAGATTTAGAGGCCATTTTTTCAATGGAAGCGCTTTCTATAAAG GCGTCTAATAGGGGTTGGAACATATGTATATCTCCTTCTTGAATTCTAAA AATTGATTGAATGTATGCAAATAAATGCATACACCATAGGTGTGGTTTAA TTTGATGCCCTTTTTCAGGGCTGGAATGTGTAAGAGCGGGGTTATTTATG CTGTTGTTTTTTTGTTACTCGGGAAGGGCTTTACCTCTTCCGCATAAACG CTTCCATCAGCGTTTATAGTTAAAAAAATCTTTCGGAACTGGTTTTGCGC TTACCCCAACCAACAGGGGATTTGCTGCTTTCCATTGAGCCTGTTTCTCT GCGCGACGTTCGCGGCGGCGTGTTTGTGCATCCATCTGGATTCTCCTGTC AGTTAGCTTTGGTGGTGTGTGGCAGTTGTAGTCCTGAACGAAAACCCCCC GCGATTGGCACATTGGCAGCTAATCCGGAATCGCACTTACGGCCAATGCT TCGTTTCGTATCACACACCCCAAAGCCTTCTGCTTTGAATGCTGCCCTTC TTCAGGGCTTAATTTTTAAGAGCGTCACCTTCATGGTGGTCAGTGCGTCC TGCTGATGTGCTCAGTATCACCGCCAGTGGTATTTATGTCAACACCGCCA GAGATAATTTATCACCGCAGATGGTTATCTGTATGTTTTTTATATGAATT TATTTTTTGCAGGGGGGCATTGTTTGGTAGGTGAGAGATCAATTCTGCAT TAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTC TTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGC GAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCA GGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAG GAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCC CTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCG ACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCG CTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCC CTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGT TCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGT TCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACC CGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATT AGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCC TAACTACGGCTACACTAGAAGGACAGTATTTGGTATCTGCGCTCTGCTGA AGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAA ACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCG CAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTG ACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTA TCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAA ATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCT TAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATA GTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACC ATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTC CAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGT GGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGA AGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCA TTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTC AGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTG CAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGT TGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTT ACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAAC CAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGG CGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTC ATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCT GTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAG CATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAA AATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCAT ACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCA TGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTT CCGCGCACATTTCCCCGAAAAGTGCCACCTGACGTCTAAGAAACCATTAT TATCATGACATTAACCTATAAAAATAGGCGTATCACGAGGCCCTTTCGTC The sequence of Bacteroides fragilis NCTC 9343 wcfW CDS DNA is set for the below (SEQ ID NO: 4): ATGATTGTATCATCTTTGCGAGGAGGATTGGGGAATCAAATGTTTATTTA CGCTATGGTGAAGGCCATGGCATTAAGAAACAATGTACCATTCGCTTTTA ATTTGACTACTGATTTTGCAAATGATGAAGTTTATAAAAGGAAACTTTTA TTATCATATTTTGCATTAGACTTGCCTGAAAATAAAAAATTAACATTTGA TTTTTCATATGGGAATTATTATAGAAGGCTAAGTCGTAATTTAGGTTGTC ATATACTTCATCCATCATATCGTTATATTTGCGAAGAGCGCCCTCCCCAC TTTGAATCAAGGTTAATTAGTTCTAAGATTACAAATGCTTTTCTGGAAGG ATATTGGCAGTCAGAAAAATATTTTCTTGATTATAAACAAGAGATAAAAG AGGACTTTGTAATACAAAAAAAATTAGAATACACATCGTATTTGGAATTG GAAGAAATAAAATTGCTAGATAAGAATGCCATAATGATTGGGGTTAGACG GTATCAGGAAAGTGATGTAGCTCCTGGTGGAGTGTTAGAAGATGATTACT ATAAATGTGCTATGGATATTATGGCATCAAAAGTTACTTCTCCTGTTTTC TTTTGTTTTTCACAAGATTTAGAATGGGTTGAAAAACATCTAGCGGGAAA ATATCCTGTTCGTTTGATAAGTAAAAAGGAGGATGATAGTGGTACTATAG ATGATATGTTTCTAATGATGCATTTTCGTAATTATATAATATCGAATAGC TCTTTTTACTGGTGGGGAGCATGGCTTTCGAAATATGATGATAAGCTGGT GATTGCTCCAGGTAATTTTATAAATAAGGATTCTGTACCAGAATCTTGGT TTAAATTGAATGTAAGATAA The sequence of pG171 is set forth below (SEQ ID NO: 5): TCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCG GAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGCAGACAAGCCCG TCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAACTATG CGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATATGCGGTGTGAAA TACCGCACAGATGCGTAAGGAGAAAATACCGCATCAGGCGCCTCCTCAAC CTGTATATTCGTAAACCACGCCCAATGGGAGCTGTCTCAGGTTTGTTCCT GATTGGTTACGGCGCGTTTCGCATCATTGTTGAGTTTTTCCGCCAGCCCG ACGCGCAGTTTACCGGTGCCTGGGTGCAGTACATCAGCATGGGGCAAATT CTTTCCATCCCGATGATTGTCGCGGGTGTGATCATGATGGTCTGGGCATA TCGTCGCAGCCCACAGCAACACGTTTCCTGAGGAACCATGAAACAGTATT TAGAACTGATGCAAAAAGTGCTCGACGAAGGCACACAGAAAAACGACCGT ACCGGAACCGGAACGCTTTCCATTTTTGGTCATCAGATGCGTTTTAACCT GCAAGATGGATTCCCGCTGGTGACAACTAAACGTTGCCACCTGCGTTCCA TCATCCATGAACTGCTGTGGTTTCTGCAGGGCGACACTAACATTGCTTAT CTACACGAAAACAATGTCACCATCTGGGACGAATGGGCCGATGAAAACGG CGACCTCGGGCCAGTGTATGGTAAACAGTGGCGCGCCTGGCCAACGCCAG ATGGTCGTCATATTGACCAGATCACTACGGTACTGAACCAGCTGAAAAAC GACCCGGATTCGCGCCGCATTATTGTTTCAGCGTGGAACGTAGGCGAACT GGATAAAATGGCGCTGGCACCGTGCCATGCATTCTTCCAGTTCTATGTGG CAGACGGCAAACTCTCTTGCCAGCTTTATCAGCGCTCCTGTGACGTCTTC CTCGGCCTGCCGTTCAACATTGCCAGCTACGCGTTATTGGTGCATATGAT GGCGCAGCAGTGCGATCTGGAAGTGGGTGATTTTGTCTGGACCGGTGGCG ACACGCATCTGTACAGCAACCATATGGATCAAACTCATCTGCAATTAAGC CGCGAACCGCGTCCGCTGCCGAAGTTGATTATCAAACGTAAACCCGAATC CATCTTCGACTACCGTTTCGAAGACTTTGAGATTGAAGGCTACGATCCGC ATCCGGGCATTAAAGCGCCGGTGGCTATCTAATTACGAAACATCCTGCCA GAGCCGACGCCAGTGTGCGTCGGTTTTTTTACCCTCCGTTAAATTCTTCG AGACGCCTTCCCGAAGGCGCCATTCGCCATTCAGGCTGCGCAACTGTTGG GAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGG GGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGT CACGACGTTGTAAAACGACGGCCAGTGCCAAGCTTTCTTTAATGAAGCAG GGCATCAGGACGGTATCTTTGTGGAGAAAGCAGAGTAATCTTATTCAGCC TGACTGGTGGGAAACCACCAGTCAGAATGTGTTAGCGCATGTTGACAAAA ATACCATTAGTCACATTATCCGTCAGTCGGACGACATGGTAGATAACCTG TTTATTATGCGTTTTGATCTTACGTTTAATATTACCTTTATGCGATGAAA CGGTCTTGGCTTTGATATTCATTTGGTCAGAGATTTGAATGGTTCCCTGA CCTGCCATCCACATTCGCAACATACTCGATTCGGTTCGGCTCAATGATAA CGTCGGCATATTTAAAAACGAGGTTATCGTTGTCTCTTTTTTCAGAATAT CGCCAAGGATATCGTCGAGAGATTCCGGTTTAATCGATTTAGAACTGATC AATAAATTTTTTCTGACCAATAGATATTCATCAAAATGAACATTGGCAAT TGCCATAAAAACGATAAATAACGTATTGGGATGTTGATTAATGATGAGCT TGATACGCTGACTGTTAGAAGCATCGTGGATGAAACAGTCCTCATTAATA AACACCACTGAAGGGCGCTGTGAATCACAAGCTATGGCAAGGTCATCAAC GGTTTCAATGTCGTTGATTTCTCTTTTTTTAACCCCTCTACTCAACAGAT ACCCGGTTAAACCTAGTCGGGTGTAACTACATAAATCCATAATAATCGTT GACATGGCATACCCTCACTCAATGCGTAACGATAATTCCCCTTACCTGAA TATTTCATCATGACTAAACGGAACAACATGGGTCACCTAATGCGCCACTC TCGCGATTTTTCAGGCGGACTTACTATCCCGTAAAGTGTTGTATAATTTG CCTGGAATTGTCTTAAAGTAAAGTAAATGTTGCGATATGTGAGTGAGCTT AAAACAAATATTTCGCTGCAGGAGTATCCTGGAAGATGTTCGTAGAAGCT TACTGCTCACAAGAAAAAAGGCACGTCATCTGACGTGCCTTTTTTATTTG TACTACCCTGTACGATTACTGCAGCTCGAGTTTAATTCAAATCTTCTTCA GAAATCAATTTTTGTTCAGCGTTATACTTTTGGGATTTTACCTCAAAATG GGATTCTATTTTCACCCACTCCTTACAAAGGATATTCTCATGCCCAAAAA GCCAGTGTTTGGGGCCAATAATGATTTTTTCTGGATTTTCTATCAAATAG GCCGCCCACCAGCTATAAGTGCTATTAGCGATAATGCCATGCTGACAAGA TTGCATGAGCAGCATGTCCCAATACGCCTCTTCTTCTTTATCCCTAGTGG TCATGTCCATAAAAGGGTAGCCAAGATCAAGATTTTGCGTGAATTCTAAG TCTTCGCAAAACACAAAAAGCTCCATGTTTGGCACGCGCTTTGCCATATA CTCAAGCGCCTTTTTTTGATAGTCAATACCAAGCTGACAGCCAATCCCCA CATAATCCCCTCTTCTTATATGCACAAACACGCTGTTTTTAGCGGCTAAA ATCAAAGAAAGCTTGCACTGATATTCTTCCTCTTTTTTATTATTATTCTT ATTATTTTCGGGTGGTGGTGGTAGAGTGAAGGTTTGCTTGATTAAAGGGG ATATAGCATCAAAGTATCGTGGATCTTGGAAATAGCCAAAAAAATAAGTC AAGCGGCTTGGCTTTAGCAATTTAGGCTCGTATTCAAAAACGATTTCTTG ACTCACCCTATCAAATCCCATGCATTTGAGCGCGTCTCTTACTAGCTTGG GGAGGTGTTGCATTTTAGCTATAGCGATTTCTTTCGCGCTCGCATAGGGC AAATCAATAGGGAAAAGTTCTAATTGCATTTTCCTATCGCTCCAATCAAA AGAAGTGATATCTAACAGCACAGGCGTATTAGAGTGTTTTTGCAAACTTT TAGCGAAAGCGTATTGAAACATTTGATTCCCAAGCCCTCCGCAAATTTGC ACCACCTTAAAAGCCATATGTATATCTCCTTCTTGAATTCTAAAAATTGA TTGAATGTATGCAAATAAATGCATACACCATAGGTGTGGTTTAATTTGAT GCCCTTTTTCAGGGCTGGAATGTGTAAGAGCGGGGTTATTTATGCTGTTG TTTTTTTGTTACTCGGGAAGGGCTTTACCTCTTCCGCATAAACGCTTCCA TCAGCGTTTATAGTTAAAAAAATCTTTCGGAACTGGTTTTGCGCTTACCC CAACCAACAGGGGATTTGCTGCTTTCCATTGAGCCTGTTTCTCTGCGCGA CGTTCGCGGCGGCGTGTTTGTGCATCCATCTGGATTCTCCTGTCAGTTAG CTTTGGTGGTGTGTGGCAGTTGTAGTCCTGAACGAAAACCCCCCGCGATT GGCACATTGGCAGCTAATCCGGAATCGCACTTACGGCCAATGCTTCGTTT CGTATCACACACCCCAAAGCCTTCTGCTTTGAATGCTGCCCTTCTTCAGG GCTTAATTTTTAAGAGCGTCACCTTCATGGTGGTCAGTGCGTCCTGCTGA TGTGCTCAGTATCACCGCCAGTGGTATTTATGTCAACACCGCCAGAGATA ATTTATCACCGCAGATGGTTATCTGTATGTTTTTTATATGAATTTATTTT TTGCAGGGGGGCATTGTTTGGTAGGTGAGAGATCAATTCTGCATTAATGA ATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGC TTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGG TATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGAT AACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCG TAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACG AGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGA CTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCC TGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGG GAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTG TAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCC CGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAA GACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGA GCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTA CGGCTACACTAGAAGGACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAG TTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACC GCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAA AAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTC AGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAA AGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAAT CTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCA GTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCC TGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGG CCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATT TATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCT GCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAG AGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTA CAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCC GGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAA AGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCG CAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTC ATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTC ATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAA TACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATT GGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAG ATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTT TTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCC GCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTT CCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCG GATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGC ACATTTCCCCGAAAAGTGCCACCTGACGTCTAAGAAACCATTATTATCAT GACATTAACCTATAAAAATAGGCGTATCACGAGGCCCTTTCGTC The sequence of pG180 is set forth below (SEQ ID NO: 6): TCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCG GAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGCAGACAAGCCCG TCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAACTATG CGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATATGCGGTGTGAAA TACCGCACAGATGCGTAAGGAGAAAATACCGCATCAGGCGCCTCCTCAAC CTGTATATTCGTAAACCACGCCCAATGGGAGCTGTCTCAGGTTTGTTCCT GATTGGTTACGGCGCGTTTCGCATCATTGTTGAGTTTTTCCGCCAGCCCG ACGCGCAGTTTACCGGTGCCTGGGTGCAGTACATCAGCATGGGGCAAATT CTTTCCATCCCGATGATTGTCGCGGGTGTGATCATGATGGTCTGGGCATA TCGTCGCAGCCCACAGCAACACGTTTCCTGAGGAACCATGAAACAGTATT TAGAACTGATGCAAAAAGTGCTCGACGAAGGCACACAGAAAAACGACCGT ACCGGAACCGGAACGCTTTCCATTTTTGGTCATCAGATGCGTTTTAACCT GCAAGATGGATTCCCGCTGGTGACAACTAAACGTTGCCACCTGCGTTCCA TCATCCATGAACTGCTGTGGTTTCTGCAGGGCGACACTAACATTGCTTAT CTACACGAAAACAATGTCACCATCTGGGACGAATGGGCCGATGAAAACGG CGACCTCGGGCCAGTGTATGGTAAACAGTGGCGCGCCTGGCCAACGCCAG ATGGTCGTCATATTGACCAGATCACTACGGTACTGAACCAGCTGAAAAAC GACCCGGATTCGCGCCGCATTATTGTTTCAGCGTGGAACGTAGGCGAACT GGATAAAATGGCGCTGGCACCGTGCCATGCATTCTTCCAGTTCTATGTGG CAGACGGCAAACTCTCTTGCCAGCTTTATCAGCGCTCCTGTGACGTCTTC CTCGGCCTGCCGTTCAACATTGCCAGCTACGCGTTATTGGTGCATATGAT GGCGCAGCAGTGCGATCTGGAAGTGGGTGATTTTGTCTGGACCGGTGGCG ACACGCATCTGTACAGCAACCATATGGATCAAACTCATCTGCAATTAAGC CGCGAACCGCGTCCGCTGCCGAAGTTGATTATCAAACGTAAACCCGAATC CATCTTCGACTACCGTTTCGAAGACTTTGAGATTGAAGGCTACGATCCGC ATCCGGGCATTAAAGCGCCGGTGGCTATCTAATTACGAAACATCCTGCCA GAGCCGACGCCAGTGTGCGTCGGTTTTTTTACCCTCCGTTAAATTCTTCG AGACGCCTTCCCGAAGGCGCCATTCGCCATTCAGGCTGCGCAACTGTTGG GAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGG GGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGT CACGACGTTGTAAAACGACGGCCAGTGCCAAGCTTTCTTTAATGAAGCAG GGCATCAGGACGGTATCTTTGTGGAGAAAGCAGAGTAATCTTATTCAGCC TGACTGGTGGGAAACCACCAGTCAGAATGTGTTAGCGCATGTTGACAAAA ATACCATTAGTCACATTATCCGTCAGTCGGACGACATGGTAGATAACCTG TTTATTATGCGTTTTGATCTTACGTTTAATATTACCTTTATGCGATGAAA CGGTCTTGGCTTTGATATTCATTTGGTCAGAGATTTGAATGGTTCCCTGA CCTGCCATCCACATTCGCAACATACTCGATTCGGTTCGGCTCAATGATAA CGTCGGCATATTTAAAAACGAGGTTATCGTTGTCTCTTTTTTCAGAATAT CGCCAAGGATATCGTCGAGAGATTCCGGTTTAATCGATTTAGAACTGATC AATAAATTTTTTCTGACCAATAGATATTCATCAAAATGAACATTGGCAAT TGCCATAAAAACGATAAATAACGTATTGGGATGTTGATTAATGATGAGCT TGATACGCTGACTGTTAGAAGCATCGTGGATGAAACAGTCCTCATTAATA AACACCACTGAAGGGCGCTGTGAATCACAAGCTATGGCAAGGTCATCAAC GGTTTCAATGTCGTTGATTTCTCTTTTTTTAACCCCTCTACTCAACAGAT ACCCGGTTAAACCTAGTCGGGTGTAACTACATAAATCCATAATAATCGTT GACATGGCATACCCTCACTCAATGCGTAACGATAATTCCCCTTACCTGAA TATTTCATCATGACTAAACGGAACAACATGGGTCACCTAATGCGCCACTC TCGCGATTTTTCAGGCGGACTTACTATCCCGTAAAGTGTTGTATAATTTG CCTGGAATTGTCTTAAAGTAAAGTAAATGTTGCGATATGTGAGTGAGCTT AAAACAAATATTTCGCTGCAGGAGTATCCTGGAAGATGTTCGTAGAAGCT TACTGCTCACAAGAAAAAAGGCACGTCATCTGACGTGCCTTTTTTATTTG TACTACCCTGTACGATTACTGCAGCTCGAGTTTAATTCAAATCTTCTTCA GAAATCAATTTTTGTTCTCTTACATTCAATTTAAACCAAGATTCTGGTAC AGAATCCTTATTTATAAAATTACCTGGAGCAATCACCAGCTTATCATCAT ATTTCGAAAGCCATGCTCCCCACCAGTAAAAAGAGCTATTCGATATTATA TAATTACGAAAATGCATCATTAGAAACATATCATCTATAGTACCACTATC ATCCTCCTTTTTACTTATCAAACGAACAGGATATTTTCCCGCTAGATGTT TTTCAACCCATTCTAAATCTTGTGAAAAACAAAAGAAAACAGGAGAAGTA ACTTTTGATGCCATAATATCCATAGCACATTTATAGTAATCATCTTCTAA CACTCCACCAGGAGCTACATCACTTTCCTGATACCGTCTAACCCCAATCA TTATGGCATTCTTATCTAGCAATTTTATTTCTTCCAATTCCAAATACGAT GTGTATTCTAATTTTTTTTGTATTACAAAGTCCTCTTTTATCTCTTGTTT ATAATCAAGAAAATATTTTTCTGACTGCCAATATCCTTCCAGAAAAGCAT TTGTAATCTTAGAACTAATTAACCTTGATTCAAAGTGGGGAGGGCGCTCT TCGCAAATATAACGATATGATGGATGAAGTATATGACAACCTAAATTACG ACTTAGCCTTCTATAATAATTCCCATATGAAAAATCAAATGTTAATTTTT TATTTTCAGGCAAGTCTAATGCAAAATATGATAATAAAAGTTTCCTTTTA TAAACTTCATCATTTGCAAAATCAGTAGTCAAATTAAAAGCGAATGGTAC ATTGTTTCTTAATGCCATGGCCTTCACCATAGCGTAAATAAACATTTGAT TCCCCAATCCTCCTCGCAAAGATGATACAATCATATGTATATCTCCTTCT TGTCTAGAATTCTAAAAATTGATTGAATGTATGCAAATAAATGCATACAC CATAGGTGTGGTTTAATTTGATGCCCTTTTTCAGGGCTGGAATGTGTAAG AGCGGGGTTATTTATGCTGTTGTTTTTTTGTTACTCGGGAAGGGCTTTAC CTCTTCCGCATAAACGCTTCCATCAGCGTTTATAGTTAAAAAAATCTTTC GGAACTGGTTTTGCGCTTACCCCAACCAACAGGGGATTTGCTGCTTTCCA TTGAGCCTGTTTCTCTGCGCGACGTTCGCGGCGGCGTGTTTGTGCATCCA TCTGGATTCTCCTGTCAGTTAGCTTTGGTGGTGTGTGGCAGTTGTAGTCC TGAACGAAAACCCCCCGCGATTGGCACATTGGCAGCTAATCCGGAATCGC ACTTACGGCCAATGCTTCGTTTCGTATCACACACCCCAAAGCCTTCTGCT TTGAATGCTGCCCTTCTTCAGGGCTTAATTTTTAAGAGCGTCACCTTCAT GGTGGTCAGTGCGTCCTGCTGATGTGCTCAGTATCACCGCCAGTGGTATT TATGTCAACACCGCCAGAGATAATTTATCACCGCAGATGGTTATCTGTAT GTTTTTTATATGAATTTATTTTTTGCAGGGGGGCATTGTTTGGTAGGTGA GAGATCAATTCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTT TGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCG GTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACG GTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAG GCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTC CATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCA GAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTG GAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATAC CTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACG CTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTG TGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTAT CGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGC CACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGT TCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGGACAGTATTTGGT ATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTC TTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCA AGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATC TTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGAT TTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATT AAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCT GACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCT ATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGA TACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGAC CCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAG GGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTA TTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTG CGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTT TGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACAT GATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATC GTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGC ACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGA CTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCG AGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAG AACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCT CAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCA CCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGC AAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGA AATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTAT CAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAA TAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTGACG TCTAAGAAACCATTATTATCATGACATTAACCTATAAAAATAGGCGTATC ACGAGGCCCTTTCGTC The sequence of W3110 deltalon::Kan::lacZ with RBS Escherichia coli str. K-12 substr. W3110 is set forth below (SEQ ID NO: 7): GTCCATGGAAGACGTCGAAAAAGTGGTTATCGACGAGTCGGTAATTGATG GTCAAAGCAAACCGTTGCTGATTTATGGCAAGCCGGAAGCGCAACAGGCA TCTGGTGAATAATTAACCATTCCCATACAATTAGTTAACCAAAAAGGGGG GATTTTATCTCCCCTTTAATTTTTCCTCTATTCTCGGCGTTGAATGTGGG GGAAACATCCCCATATACTGACGTACATGTTAATAGATGGCGTGAAGCAC AGTCGTGTCATCTGATTACCTGGCGGAAATTAAACTAAGAGAGAGCTCTA TGATTCCGGGGATCCGTCGACCTGCAGTTCGAAGTTCCTATTCTCTAGAA AGTATAGGAACTTCAGAGCGCTTTTGAAGCTCACGCTGCCGCAAGCACTC AGGGCGCAAGGGCTGCTAAAGGAAGCGGAACACGTAGAAAGCCAGTCCGC AGAAACGGTGCTGACCCCGGATGAATGTCAGCTACTGGGCTATCTGGACA AGGGAAAACGCAAGCGCAAAGAGAAAGCAGGTAGCTTGCAGTGGGCTTAC ATGGCGATAGCTAGACTGGGCGGTTTTATGGACAGCAAGCGAACCGGAAT TGCCAGCTGGGGCGCCCTCTGGTAAGGTTGGGAAGCCCTGCAAAGTAAAC TGGATGGCTTTCTTGCCGCCAAGGATCTGATGGCGCAGGGGATCAAGATC TGATCAAGAGACAGGATGAGGATCGTTTCGCATGATTGAACAAGATGGAT TGCACGCAGGTTCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGAC TGGGCACAACAGACAATCGGCTGCTCTGATGCCGCCGTGTTCCGGCTGTC AGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGTGCCC TGAATGAACTGCAGGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACG GGCGTTCCTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGA CTGGCTGCTATTGGGCGAAGTGCCGGGGCAGGATCTCCTGTCATCTCACC TTGCTCCTGCCGAGAAAGTATCCATCATGGCTGATGCAATGCGGCGGCTG CATACGCTTGATCCGGCTACCTGCCCATTCGACCACCAAGCGAAACATCG CATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGATG ATCTGGACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGG CTCAAGGCGCGCATGCCCGACGGCGAGGATCTCGTCGTGACCCATGGCGA TGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTCTGGATTCA TCGACTGTGGCCGGCTGGGTGTGGCGGACCGCTATCAGGACATAGCGTTG GCTACCCGTGATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCGCTT CCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCT ATCGCCTTCTTGACGAGTTCTTCTAATAAGGGGATCTTGAAGTTCCTATT CCGAAGTTCCTATTCTCTAGAAAGTATAGGAACTTCGAAGCAGCTCCAGC CTACATAAAGCGGCCGCTTATTTTTGACACCAGACCAACTGGTAATGGTA GCGACCGGCGCTCAGCTGGAATTCCGCCGATACTGACGGGCTCCAGGAGT CGTCGCCACCAATCCCCATATGGAAACCGTCGATATTCAGCCATGTGCCT TCTTCCGCGTGCAGCAGATGGCGATGGCTGGTTTCCATCAGTTGCTGTTG ACTGTAGCGGCTGATGTTGAACTGGAAGTCGCCGCGCCACTGGTGTGGGC CATAATTCAATTCGCGCGTCCCGCAGCGCAGACCGTTTTCGCTCGGGAAG ACGTACGGGGTATACATGTCTGACAATGGCAGATCCCAGCGGTCAAAACA GGCGGCAGTAAGGCGGTCGGGATAGTTTTCTTGCGGCCCTAATCCGAGCC AGTTTACCCGCTCTGCTACCTGCGCCAGCTGGCAGTTCAGGCCAATCCGC GCCGGATGCGGTGTATCGCTCGCCACTTCAACATCAACGGTAATCGCCAT TTGACCACTACCATCAATCCGGTAGGTTTTCCGGCTGATAAATAAGGTTT TCCCCTGATGCTGCCACGCGTGAGCGGTCGTAATCAGCACCGCATCAGCA AGTGTATCTGCCGTGCACTGCAACAACGCTGCTTCGGCCTGGTAATGGCC CGCCGCCTTCCAGCGTTCGACCCAGGCGTTAGGGTCAATGCGGGTCGCTT CACTTACGCCAATGTCGTTATCCAGCGGTGCACGGGTGAACTGATCGCGC AGCGGCGTCAGCAGTTGTTTTTTATCGCCAATCCACATCTGTGAAAGAAA GCCTGACTGGCGGTTAAATTGCCAACGCTTATTACCCAGCTCGATGCAAA AATCCATTTCGCTGGTGGTCAGATGCGGGATGGCGTGGGACGCGGCGGGG AGCGTCACACTGAGGTTTTCCGCCAGACGCCACTGCTGCCAGGCGCTGAT GTGCCCGGCTTCTGACCATGCGGTCGCGTTCGGTTGCACTACGCGTACTG TGAGCCAGAGTTGCCCGGCGCTCTCCGGCTGCGGTAGTTCAGGCAGTTCA ATCAACTGTTTACCTTGTGGAGCGACATCCAGAGGCACTTCACCGCTTGC CAGCGGCTTACCATCCAGCGCCACCATCCAGTGCAGGAGCTCGTTATCGC TATGACGGAACAGGTATTCGCTGGTCACTTCGATGGTTTGCCCGGATAAA CGGAACTGGAAAAACTGCTGCTGGTGTTTTGCTTCCGTCAGCGCTGGATG CGGCGTGCGGTCGGCAAAGACCAGACCGTTCATACAGAACTGGCGATCGT TCGGCGTATCGCCAAAATCACCGCCGTAAGCCGACCACGGGTTGCCGTTT TCATCATATTTAATCAGCGACTGATCCACCCAGTCCCAGACGAAGCCGCC CTGTAAACGGGGATACTGACGAAACGCCTGCCAGTATTTAGCGAAACCGC CAAGACTGTTACCCATCGCGTGGGCGTATTCGCAAAGGATCAGCGGGCGC GTCTCTCCAGGTAGCGAAAGCCATTTTTTGATGGACCATTTCGGCACAGC CGGGAAGGGCTGGTCTTCATCCACGCGCGCGTACATCGGGCAAATAATAT CGGTGGCCGTGGTGTCGGCTCCGCCGCCTTCATACTGCACCGGGCGGGAA GGATCGACAGATTTGATCCAGCGATACAGCGCGTCGTGATTAGCGCCGTG GCCTGATTCATTCCCCAGCGACCAGATGATCACACTCGGGTGATTACGAT CGCGCTGCACCATTCGCGTTACGCGTTCGCTCATCGCCGGTAGCCAGCGC GGATCATCGGTCAGACGATTCATTGGCACCATGCCGTGGGTTTCAATATT GGCTTCATCCACCACATACAGGCCGTAGCGGTCGCACAGCGTGTACCACA GCGGATGGTTCGGATAATGCGAACAGCGCACGGCGTTAAAGTTGTTCTGC TTCATCAGCAGGATATCCTGCACCATCGTCTGCTCATCCATGACCTGACC ATGCAGAGGATGATGCTCGTGACGGTTAACGCCTCGAATCAGCAACGGCT TGCCGTTCAGCAGCAGCAGACCATTTTCAATCCGCACCTCGCGGAAACCG ACATCGCAGGCTTCTGCTTCAATCAGCGTGCCGTCGGCGGTGTGCAGTTC AACCACCGCACGATAGAGATTCGGGATTTCGGCGCTCCACAGTTTCGGGT TTTCGACGTTCAGACGTAGTGTGACGCGATCGGCATAACCACCACGCTCA TCGATAATTTCACCGCCGAAAGGCGCGGTGCCGCTGGCGACCTGCGTTTC ACCCTGCCATAAAGAAACTGTTACCCGTAGGTAGTCACGCAACTCGCCGC ACATCTGAACTTCAGCCTCCAGTACAGCGCGGCTGAAATCATCATTAAAG CGAGTGGCAACATGGAAATCGCTGATTTGTGTAGTCGGTTTATGCAGCAA CGAGACGTCACGGAAAATGCCGCTCATCCGCCACATATCCTGATCTTCCA GATAACTGCCGTCACTCCAGCGCAGCACCATCACCGCGAGGCGGTTTTCT CCGGCGCGTAAAAATGCGCTCAGGTCAAATTCAGACGGCAAACGACTGTC CTGGCCGTAACCGACCCAGCGCCCGTTGCACCACAGATGAAACGCCGAGT TAACGCCATCAAAAATAATTCGCGTCTGGCCTTCCTGTAGCCAGCTTTCA TCAACATTAAATGTGAGCGAGTAACAACCCGTCGGATTCTCCGTGGGAAC AAACGGCGGATTGACCGTAATGGGATAGGTCACGTTGGTGTAGATGGGCG CATCGTAACCGTGCATCTGCCAGTTTGAGGGGACGACGACAGTATCGGCC TCAGGAAGATCGCACTCCAGCCAGCTTTCCGGCACCGCTTCTGGTGCCGG AAACCAGGCAAAGCGCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAG GGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGA TGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACG ACGTTGTAAAACGACGGCCAGTGAATCCGTAATCATGGTCATAGTAGGTT TCCTCAGGTTGTGACTGCAAAATAGTGACCTCGCGCAAAATGCACTAATA AAAACAGGGCTGGCAGGCTAATTCGGGCTTGCCAGCCTTTTTTTGTCTCG CTAAGTTAGATGGCGGATCGGGCTTGCCCTTATTAAGGGGTGTTGTAAGG GGATGGCTGGCCTGATATAACTGCTGCGCGTTCGTACCTTGAAGGATTCA AGTGCGATATAAATTATAAAGAGGAAGAGAAGAGTGAATAAATCTCAATT GATCGACAAGATTGCTGCAGGGGCTGATATCTCTAAAGCTGCGGCTGGCC GTGCGTTAGATGCTATTATTGCTTCCGTAACTGAATCTCTGAAAGAAGG The sequence of pG186 is set forth below (SEQ ID NO: 8): TCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCG GAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGCAGACAAGCCCG TCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAACTATG CGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATATGCGGTGTGAAA TACCGCACAGATGCGTAAGGAGAAAATACCGCATCAGGCGCCTCCTCAAC CTGTATATTCGTAAACCACGCCCAATGGGAGCTGTCTCAGGTTTGTTCCT GATTGGTTACGGCGCGTTTCGCATCATTGTTGAGTTTTTCCGCCAGCCCG ACGCGCAGTTTACCGGTGCCTGGGTGCAGTACATCAGCATGGGGCAAATT CTTTCCATCCCGATGATTGTCGCGGGTGTGATCATGATGGTCTGGGCATA TCGTCGCAGCCCACAGCAACACGTTTCCTGAGGAACCATGAAACAGTATT TAGAACTGATGCAAAAAGTGCTCGACGAAGGCACACAGAAAAACGACCGT ACCGGAACCGGAACGCTTTCCATTTTTGGTCATCAGATGCGTTTTAACCT GCAAGATGGATTCCCGCTGGTGACAACTAAACGTTGCCACCTGCGTTCCA TCATCCATGAACTGCTGTGGTTTCTGCAGGGCGACACTAACATTGCTTAT CTACACGAAAACAATGTCACCATCTGGGACGAATGGGCCGATGAAAACGG CGACCTCGGGCCAGTGTATGGTAAACAGTGGCGCGCCTGGCCAACGCCAG ATGGTCGTCATATTGACCAGATCACTACGGTACTGAACCAGCTGAAAAAC GACCCGGATTCGCGCCGCATTATTGTTTCAGCGTGGAACGTAGGCGAACT GGATAAAATGGCGCTGGCACCGTGCCATGCATTCTTCCAGTTCTATGTGG CAGACGGCAAACTCTCTTGCCAGCTTTATCAGCGCTCCTGTGACGTCTTC CTCGGCCTGCCGTTCAACATTGCCAGCTACGCGTTATTGGTGCATATGAT GGCGCAGCAGTGCGATCTGGAAGTGGGTGATTTTGTCTGGACCGGTGGCG ACACGCATCTGTACAGCAACCATATGGATCAAACTCATCTGCAATTAAGC CGCGAACCGCGTCCGCTGCCGAAGTTGATTATCAAACGTAAACCCGAATC CATCTTCGACTACCGTTTCGAAGACTTTGAGATTGAAGGCTACGATCCGC ATCCGGGCATTAAAGCGCCGGTGGCTATCTAATTACGAAACATCCTGCCA GAGCCGACGCCAGTGTGCGTCGGTTTTTTTACCCTCCGTTAAATTCTTCG AGACGCCTTCCCGAAGGCGCCATTCGCCATTCAGGCTGCGCAACTGTTGG GAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGG GGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGT CACGACGTTGTAAAACGACGGCCAGTGCCAAGCTTTCTTTAATGAAGCAG GGCATCAGGACGGTATCTTTGTGGAGAAAGCAGAGTAATCTTATTCAGCC TGACTGGTGGGAAACCACCAGTCAGAATGTGTTAGCGCATGTTGACAAAA ATACCATTAGTCACATTATCCGTCAGTCGGACGACATGGTAGATAACCTG TTTATTATGCGTTTTGATCTTACGTTTAATATTACCTTTATGCGATGAAA CGGTCTTGGCTTTGATATTCATTTGGTCAGAGATTTGAATGGTTCCCTGA CCTGCCATCCACATTCGCAACATACTCGATTCGGTTCGGCTCAATGATAA CGTCGGCATATTTAAAAACGAGGTTATCGTTGTCTCTTTTTTCAGAATAT CGCCAAGGATATCGTCGAGAGATTCCGGTTTAATCGATTTAGAACTGATC AATAAATTTTTTCTGACCAATAGATATTCATCAAAATGAACATTGGCAAT TGCCATAAAAACGATAAATAACGTATTGGGATGTTGATTAATGATGAGCT TGATACGCTGACTGTTAGAAGCATCGTGGATGAAACAGTCCTCATTAATA AACACCACTGAAGGGCGCTGTGAATCACAAGCTATGGCAAGGTCATCAAC GGTTTCAATGTCGTTGATTTCTCTTTTTTTAACCCCTCTACTCAACAGAT ACCCGGTTAAACCTAGTCGGGTGTAACTACATAAATCCATAATAATCGTT GACATGGCATACCCTCACTCAATGCGTAACGATAATTCCCCTTACCTGAA TATTTCATCATGACTAAACGGAACAACATGGGTCACCTAATGCGCCACTC TCGCGATTTTTCAGGCGGACTTACTATCCCGTAAAGTGTTGTATAATTTG CCTGGAATTGTCTTAAAGTAAAGTAAATGTTGCGATATGTGAGTGAGCTT AAAACAAATATTTCGCTGCAGGAGTATCCTGGAAGATGTTCGTAGAAGCT TACTGCTCACAAGAAAAAAGGCACGTCATCTGACGTGCCTTTTTTATTTG TACTACCCTGTACGATTACTGCAGCTCGAGTTAGTCTTTATCTGCCGGAC TTAAGGTCACTGAAGAGAGATAATTCAGCAGGGCGATATCGTTCTCGACA CCCAGCTTCATCATCGCAGATTTCTTCTGGCTACTGATGGTTTTAATACT GCGGTTCAGCTTTTTAGCGATCTCGGTCACCAGGAAGCCTTCCGCAAACA GGCGCAGAACTTCACTCTCTTTTGGCGAGAGACGCTTGTCACCGTAACCA CCAGCACTGATTTTTTCCAACAGGCGAGAAACGCTTTCCGGGGTAAATTT CTTCCCTTTCTGCAGCGCGGCGAGAGCTTTCGGCAGATCGGTCGGTGCAC CTTGTTTCAGCACGATCCCTTCGATATCCAGATCCAATACCGCACTAAGA ATCGCCGGGTTGTTGTTCATAGTCAGAACAATGATCGACAGGCTTGGGAA ATGGCGCTTGATGTACTTGATTAAGGTAATGCCATCGCCGTACTTATCGC CAGGCATGGAGAGATCGGTAATCAACACATGCGCATCCAGTTTCGGCAGG TTGTTGATCAGTGCTGTAGAGTCTTCAAATTCGCCGACAACATTCACCCA CTCAATTTGCTCAAGTGATTTGCGAATACCGAACAAGACTATCGGATGGT CATCGGCAATAATTACGTTCATATTGTTCATTGTATATCTCCTTCTTCTC GAGTTTAATTCAAATCTTCTTCAGAAATCAATTTTTGTTCAGCGTTATAC TTTTGGGATTTTACCTCAAAATGGGATTCTATTTTCACCCACTCCTTACA AAGGATATTCTCATGCCCAAAAAGCCAGTGTTTGGGGCCAATAATGATTT TTTCTGGATTTTCTATCAAATAGGCCGCCCACCAGCTATAAGTGCTATTA GCGATAATGCCATGCTGACAAGATTGCATGAGCAGCATGTCCCAATACGC CTCTTCTTCTTTATCCCTAGTGGTCATGTCCATAAAAGGGTAGCCAAGAT CAAGATTTTGCGTGAATTCTAAGTCTTCGCAAAACACAAAAAGCTCCATG TTTGGCACGCGCTTTGCCATATACTCAAGCGCCTTTTTTTGATAGTCAAT ACCAAGCTGACAGCCAATCCCCACATAATCCCCTCTTCTTATATGCACAA ACACGCTGTTTTTAGCGGCTAAAATCAAAGAAAGCTTGCACTGATATTCT TCCTCTTTTTTATTATTATTCTTATTATTTTCGGGTGGTGGTGGTAGAGT GAAGGTTTGCTTGATTAAAGGGGATATAGCATCAAAGTATCGTGGATCTT GGAAATAGCCAAAAAAATAAGTCAAGCGGCTTGGCTTTAGCAATTTAGGC TCGTATTCAAAAACGATTTCTTGACTCACCCTATCAAATCCCATGCATTT GAGCGCGTCTCTTACTAGCTTGGGGAGGTGTTGCATTTTAGCTATAGCGA TTTCTTTCGCGCTCGCATAGGGCAAATCAATAGGGAAAAGTTCTAATTGC ATTTTCCTATCGCTCCAATCAAAAGAAGTGATATCTAACAGCACAGGCGT ATTAGAGTGTTTTTGCAAACTTTTAGCGAAAGCGTATTGAAACATTTGAT TCCCAAGCCCTCCGCAAATTTGCACCACCTTAAAAGCCATATGTATATCT CCTTCTTGAATTCTAAAAATTGATTGAATGTATGCAAATAAATGCATACA CCATAGGTGTGGTTTAATTTGATGCCCTTTTTCAGGGCTGGAATGTGTAA GAGCGGGGTTATTTATGCTGTTGTTTTTTTGTTACTCGGGAAGGGCTTTA CCTCTTCCGCATAAACGCTTCCATCAGCGTTTATAGTTAAAAAAATCTTT CGGAACTGGTTTTGCGCTTACCCCAACCAACAGGGGATTTGCTGCTTTCC ATTGAGCCTGTTTCTCTGCGCGACGTTCGCGGCGGCGTGTTTGTGCATCC ATCTGGATTCTCCTGTCAGTTAGCTTTGGTGGTGTGTGGCAGTTGTAGTC CTGAACGAAAACCCCCCGCGATTGGCACATTGGCAGCTAATCCGGAATCG CACTTACGGCCAATGCTTCGTTTCGTATCACACACCCCAAAGCCTTCTGC TTTGAATGCTGCCCTTCTTCAGGGCTTAATTTTTAAGAGCGTCACCTTCA TGGTGGTCAGTGCGTCCTGCTGATGTGCTCAGTATCACCGCCAGTGGTAT TTATGTCAACACCGCCAGAGATAATTTATCACCGCAGATGGTTATCTGTA TGTTTTTTATATGAATTTATTTTTTGCAGGGGGGCATTGTTTGGTAGGTG AGAGATCAATTCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGT TTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTC GGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATAC GGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAA GGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTT CCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTC AGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCT GGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATA CCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCAC GCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGT GTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTA TCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAG CCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAG TTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGGACAGTATTTGG TATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCT CTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGC AAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGAT CTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGA TTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAAT TAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTC TGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTC TATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACG ATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGA CCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAA GGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCT ATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTT GCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGT TTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACA TGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGAT CGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAG CACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTG ACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACC GAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCA GAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTC TCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGC ACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAG CAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGG AAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTA TCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAA ATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTGAC GTCTAAGAAACCATTATTATCATGACATTAACCTATAAAAATAGGCGTAT CACGAGGCCCTTTCGTC Other Embodiments While the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. The patent and scientific literature referred to herein establishes the knowledge that is available to those with skill in the art. All United States patents and published or unpublished United States patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are hereby incorporated by reference. Genbank and NCBI submissions indicated by accession number cited herein are hereby incorporated by reference. All other published references, documents, manuscripts and scientific literature cited herein are hereby incorporated by reference. While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.
<SOH> BACKGROUND OF THE INVENTION <EOH>Human milk contains a diverse and abundant set of neutral and acidic oligosaccharides (human milk oligosaccharides, HMOS). Many of these molecules are not utilized directly by infants for nutrition, but they nevertheless serve critical roles in the establishment of a healthy gut microbiome, in the prevention of disease, and in immune function. Prior to the invention described herein, the ability to produce HMOS inexpensively at large scale was problematic. For example, HMOS production through chemical synthesis was limited by stereo-specificity issues, precursor availability, product impurities, and high overall cost. As such, there is a pressing need for new strategies to inexpensively manufacture large quantities of HMOS for a variety of commercial applications.
<SOH> SUMMARY OF THE INVENTION <EOH>The invention described herein features efficient and economical methods for producing fucosylated and sialylated oligosaccharides. The method for producing a fucosylated oligosaccharide in a bacterium comprises the following steps: providing a bacterium that comprises a functional β-galactosidase gene, an exogenous fucosyltransferase gene, a GDP-fucose synthesis pathway, and a functional lactose permease gene; culturing the bacterium in the presence of lactose; and retrieving a fucosylated oligosaccharide from the bacterium or from a culture supernatant of the bacterium. To produce a fucosylated oligosaccharide by biosynthesis, the bacterium utilizes an endogenous or exogenous guanosine diphosphate (GDP)-fucose synthesis pathway. By “GDP-fucose synthesis pathway” is meant a sequence of reactions, usually controlled and catalyzed by enzymes, which results in the synthesis of GDP-fucose. An exemplary GDP-fucose synthesis pathway in Escherichia coli is set forth below. In the GDP-fucose synthesis pathway set forth below, the enzymes for GDP-fucose synthesis include: 1) manA=phosphomannose isomerase (PMI), 2) manB=phosphomannomutase (PMM), 3) manC=mannose-1-phosphate guanylyltransferase (GMP), 4) gmd=GDP-mannose-4,6-dehydratase (GMD), 5) fcl=GDP-fucose synthase (GFS), and 6) ΔwcaJ=mutated UDP-glucose lipid carrier transferase. Glucose→Glc-6-P→Fru-6-P→ 1 Man-6-P→ 2 Man-1-P→ 3 GDP-Man→ 4,5 GDP-Fuc 6 Colanic acid. The synthetic pathway from fructose-6-phosphate, a common metabolic intermediate of all organisms, to GDP-fucose consists of 5 enzymatic steps: 1) PMI (phosphomannose isomerase), 2) PMM (phosphomannomutase), 3) GMP (mannose-1-phosphate guanylyltransferase), 4) GMD (GDP-mannose-4,6-dehydratase), and 5) GFS (GDP-fucose synthase). Individual bacterial species possess different inherent capabilities with respect to GDP-fucose synthesis. Escherichia coli , for example, contains enzymes competent to perform all five steps, whereas Bacillus licheniformis is missing enzymes capable of performing steps 4 and 5 (i.e., GMD and GFS). Any enzymes in the GDP-synthesis pathway that are inherently missing in any particular bacterial species are provided as genes on recombinant DNA constructs, supplied either on a plasmid expression vector or as exogenous genes integrated into the host chromosome. The invention described herein details the manipulation of genes and pathways within bacteria such as the enterobacterium Escherichia coli K12 ( E. coli ) or probiotic bacteria leading to high level synthesis of HMOS. A variety of bacterial species may be used in the oligosaccharide biosynthesis methods, for example Erwinia herbicola ( Pantoea agglomerans ), Citrobacter freundii, Pantoea citrea, Pectobacterium carotovorum , or Xanthomonas campestris . Bacteria of the genus Bacillus may also be used, including Bacillus subtilis, Bacillus licheniformis, Bacillus coagulans, Bacillus thermophilus, Bacillus laterosporus, Bacillus megaterium, Bacillus mycoides, Bacillus pumilus, Bacillus lentus, Bacillus cereus , and Bacillus circulans . Similarly, bacteria of the genera Lactobacillus and Lactococcus may be modified using the methods of this invention, including but not limited to Lactobacillus acidophilus, Lactobacillus salivarius, Lactobacillus plantarum, Lactobacillus helveticus, Lactobacillus delbrueckii, Lactobacillus rhamnosus, Lactobacillus bulgaricus, Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus casei, Lactobacillus reuteri, Lactobacillus jensenii , and Lactococcus lactis. Streptococcus thermophiles and Proprionibacterium freudenreichii are also suitable bacterial species for the invention described herein. Also included as part of this invention are strains, modified as described here, from the genera Enterococcus (e.g., Enterococcus faecium and Enterococcus thermophiles ), Bifidobacterium (e.g., Bifidobacterium longum, Bifidobacterium infantis , and Bifidobacterium bifidum ), Sporolactobacillus spp., Micromomospora spp., Micrococcus spp., Rhodococcus spp., and Pseudomonas (e.g., Pseudomonas fluorescens and Pseudomonas aeruginosa ). Bacteria comprising the characteristics described herein are cultured in the presence of lactose, and a fucosylated oligosaccharide is retrieved, either from the bacterium itself or from a culture supernatant of the bacterium. The fucosylated oligosaccharide is purified for use in therapeutic or nutritional products, or the bacteria are used directly in such products. The bacterium also comprises a functional β-galactosidase gene. The β-galactosidase gene is an endogenous β-galactosidase gene or an exogenous β-galactosidase gene. For example, the β-galactosidase gene comprises an E. coli lacZ gene (e.g., GenBank Accession Number V00296 (GI:41901), incorporated herein by reference). The bacterium accumulates an increased intracellular lactose pool, and produces a low level of β-galactosidase. A functional lactose permease gene is also present in the bacterium. The lactose permease gene is an endogenous lactose permease gene or an exogenous lactose permease gene. For example, the lactose permease gene comprises an E. coli lacY gene (e.g., GenBank Accession Number V00295 (GI:41897), incorporated herein by reference). Many bacteria possess the inherent ability to transport lactose from the growth medium into the cell, by utilizing a transport protein that is either a homolog of the E. coli lactose permease (e.g., as found in Bacillus licheniformis ), or a transporter that is a member of the ubiquitous PTS sugar transport family (e.g., as found in Lactobacillus casei and Lactobacillus rhamnosus ). For bacteria lacking an inherent ability to transport extracellular lactose into the cell cytoplasm, this ability is conferred by an exogenous lactose transporter gene (e.g., E. coli lacy) provided on recombinant DNA constructs, and supplied either on a plasmid expression vector or as exogenous genes integrated into the host chromosome. The bacterium comprises an exogenous fucosyltransferase gene. For example, the exogenous fucosyltransferase gene encodes α(1,2) fucosyltransferase and/or α(1,3) fucosyltransferase. An exemplary α(1,2) fucosyltransferase gene is the wcfW gene from Bacteroides fragilis NCTC 9343 (SEQ ID NO: 4). An exemplary α(1,3) fucosyltransferase gene is the Helicobacter pylori 26695 futA gene. One example of the Helicobacter pylori futA gene is presented in GenBank Accession Number HV532291 (GI:365791177), incorporated herein by reference. Alternatively, a method for producing a fucosylated oligosaccharide by biosynthesis comprises the following steps: providing an enteric bacterium that comprises a functional β-galactosidase gene, an exogenous fucosyltransferase gene, a mutation in a colanic acid synthesis gene, and a functional lactose permease gene; culturing the bacterium in the presence of lactose; and retrieving a fucosylated oligosaccharide from the bacterium or from a culture supernatant of the bacterium. To produce a fucosylated oligosaccharide by biosynthesis, the bacterium comprises a mutation in an endogenous colanic acid (a fucose-containing exopolysaccharide) synthesis gene. By “colanic acid synthesis gene” is meant a gene involved in a sequence of reactions, usually controlled and catalyzed by enzymes that result in the synthesis of colanic acid. Exemplary colanic acid synthesis genes include an rcsA gene (e.g., GenBank Accession Number M58003 (GI:1103316), incorporated herein by reference), an rcsB gene, (e.g., GenBank Accession Number E04821 (GI:2173017), incorporated herein by reference), a weal gene, (e.g., GenBank Accession Number (amino acid) BAA15900 (GI:1736749), incorporated herein by reference), a wzxC gene, (e.g., GenBank Accession Number (amino acid) BAA15899 (GI:1736748), incorporated herein by reference), a wcaD gene, (e.g., GenBank Accession Number (amino acid) BAE76573 (GI:85675202), incorporated herein by reference), a wza gene, (e.g., GenBank Accession Number (amino acid) BAE76576 (GI:85675205), incorporated herein by reference), a wzb gene, and (e.g., GenBank Accession Number (amino acid) BAE76575 (GI:85675204), incorporated herein by reference), and a wzc gene (e.g., GenBank Accession Number (amino acid) BAA15913 (GI:1736763), incorporated herein by reference). This is achieved through a number of genetic modifications of endogenous E. coli genes involved either directly in colanic acid precursor biosynthesis, or in overall control of the colanic acid synthetic regulon. Specifically, the ability of the host E. coli strain to synthesize colanic acid, an extracellular capsular polysaccharide, is eliminated by the deletion of the wcaJ gene, encoding the UDP-glucose lipid carrier transferase. In a wcaJ null background, GDP-fucose accumulates in the E. coli cytoplasm. Over-expression of a positive regulator protein, RcsA, in the colanic acid synthesis pathway results in an increase in intracellular GDP-fucose levels. Over-expression of an additional positive regulator of colanic acid biosynthesis, namely RcsB, is also utilized, either instead of or in addition to over-expression of RcsA, to increase intracellular GDP-fucose levels. Alternatively, colanic acid biosynthesis is increased following the introduction of a null mutation into the E. coli lon gene (e.g., GenBank Accession Number L20572 (GI:304907), incorporated herein by reference). Lon is an adenosine-5′-triphosphate (ATP)-dependant intracellular protease that is responsible for degrading RcsA, mentioned above as a positive transcriptional regulator of colanic acid biosynthesis in E. coli . In a lon null background, RcsA is stabilized, RcsA levels increase, the genes responsible for GDP-fucose synthesis in E. coli are up-regulated, and intracellular GDP-fucose concentrations are enhanced. For example, the bacterium further comprises a functional, wild-type E. coli lacZ + gene inserted into an endogenous gene, for example the lon gene in E. coli . In this manner, the bacterium may comprise a mutation in a lon gene. The bacterium also comprises a functional β-galactosidase gene. The β-galactosidase gene is an endogenous β-galactosidase gene or an exogenous β-galactosidase gene. For example, the β-galactosidase gene comprises an E. coli lacZ gene. The endogenous lacZ gene of the E. coli is deleted or functionally inactivated, but in such a way that expression of the downstream lactose permease (lacY) gene remains intact. The bacterium comprises an exogenous fucosyltransferase gene. For example, the exogenous fucosyltransferase gene encodes α(1,2) fucosyltransferase and/or α(1,3) fucosyltransferase. An exemplary α(1,2) fucosyltransferase gene is the wcfW gene from Bacteroides fragilis NCTC 9343 (SEQ ID NO: 4). An exemplary α(1,3) fucosyltransferase gene is the Helicobacter pylori 26695 futA gene. One example of the Helicobacter pylori futA gene is presented in GenBank Accession Number HV532291 (GI:365791177), incorporated herein by reference. A functional lactose permease gene is also present in the bacterium. The lactose permease gene is an endogenous lactose permease gene or an exogenous lactose permease gene. For example, the lactose permease gene comprises an E. coli lacY gene. The bacterium may further comprise an exogenous rcsA and/or rcsB gene (e.g., in an ectopic nucleic acid construct such as a plasmid), and the bacterium optionally further comprises a mutation in a lacA gene (e.g., GenBank Accession Number X51872 (GI:41891), incorporated herein by reference). Bacteria comprising the characteristics described herein are cultured in the presence of lactose, and a fucosylated oligosaccharide is retrieved, either from the bacterium itself or from a culture supernatant of the bacterium. The fucosylated oligosaccharide is purified for use in therapeutic or nutritional products, or the bacteria are used directly in such products. The bacteria used herein to produce HMOS are genetically engineered to comprise an increased intracellular guanosine diphosphate (GDP)-fucose pool, an increased intracellular lactose pool (as compared to wild type) and to comprise fucosyl transferase activity. Accordingly, the bacterium contains a mutation in a colanic acid (a fucose-containing exopolysaccharide) synthesis pathway gene, such as a wcaJ gene, resulting in an enhanced intracellular GDP-fucose pool. The bacterium further comprises a functional, wild-type E. coli lacZ + gene inserted into an endogenous gene, for example the lon gene in E. coli . In this manner, the bacterium may further comprise a mutation in a lon gene. The endogenous lacZ gene of the E. coli is deleted or functionally inactivated, but in such a way that expression of the downstream lactose permease (lacY) gene remains intact. The organism so manipulated maintains the ability to transport lactose from the growth medium, and to develop an intracellular lactose pool for use as an acceptor sugar in oligosaccharide synthesis, while also maintaining a low level of intracellular beta-galactosidase activity useful for a variety of additional purposes. The bacterium may further comprise an exogenous rcsA and/or rcsB gene (e.g., in an ectopic nucleic acid construct such as a plasmid), and the bacterium optionally further comprises a mutation in a lacA gene. Preferably, the bacterium accumulates an increased intracellular lactose pool, and produces a low level of beta-galactosidase. The bacterium possesses fucosyl transferase activity. For example, the bacterium comprises one or both of an exogenous fucosyltransferase gene encoding an α(1,2) fucosyltransferase and an exogenous fucosyltransferase gene encoding an α(1,3) fucosyltransferase. An exemplary α(1,2) fucosyltransferase gene is the wcfW gene from Bacteroides fragilis NCTC 9343 (SEQ ID NO: 4). Prior to the present invention, this wcfW gene was not known to encode a protein with an α(1,2) fucosyltransferase activity, and further was not suspected to possess the ability to utilize lactose as an acceptor sugar. Other α(1,2) fucosyltransferase genes that use lactose as an acceptor sugar (e.g., the Helicobacter pylori 26695 futC gene or the E. coli O128:B12 wbsJ gene) may readily be substituted for Bacteroides fragilis wcjW. One example of the Helicobacter pylori futC gene is presented in GenBank Accession Number EF452503 (GI:134142866), incorporated herein by reference. An exemplary α(1,3) fucosyltransferase gene is the Helicobacter pylori 26695 futA gene, although other α(1,3) fucosyltransferase genes known in the art may be substituted (e.g., α(1,3) fucosyltransferase genes from Helicobacter hepaticus Hh0072, Helicobacter bilis, Campylobacter jejuni , or from Bacteroides species). The invention includes a nucleic acid construct comprising one, two, three or more of the genes described above. For example, the invention includes a nucleic acid construct expressing an exogenous fucosyltransferase gene (encoding α(1,2) fucosyltransferase or α(1,3) fucosyltransferase) transformed into a bacterial host strain comprising a deleted endogenous β-galactosidase (e.g., lacZ) gene, a replacement functional β-galactosidase gene of low activity, a GDP-fucose synthesis pathway, a functional lactose permease gene, and a deleted lactose acetyltransferase gene. Also within the invention is an isolated E. coli bacterium as described above and characterized as comprising a defective colanic acid synthesis pathway, a reduced level of β-galactosidase (LacZ) activity, and an exogenous fucosyl transferase gene. The invention also includes: a) methods for phenotypic marking of a gene locus in a β-galactosidase negative host cell by utilizing a β-galactosidase (e.g., lacZ) gene insert engineered to produce a low but readily detectable level of β-galactosidase activity, b) methods for readily detecting lytic bacteriophage contamination in fermentation runs through release and detection of cytoplasmic β-galactosidase in the cell culture medium, and c) methods for depleting a bacterial culture of residual lactose at the end of production runs. a), b) and c) are each achieved by utilizing a functional β-galactosidase (e.g., lacZ) gene insert carefully engineered to direct the expression of a low, but detectable level of β-galactosidase activity in an otherwise β-galactosidase negative host cell. A purified fucosylated oligosaccharide produced by the methods described above is also within the invention. A purified oligosaccharide, e.g., 2′-FL, 3FL, LDFT, is one that is at least 90%, 95%, 98%, 99%, or 100% (w/w) of the desired oligosaccharide by weight. Purity is assessed by any known method, e.g., thin layer chromatography or other electrophoretic or chromatographic techniques known in the art. The invention includes a method of purifying a fucosylated oligosaccharide produced by the genetically engineered bacterium described above, which method comprises separating the desired fucosylated oligosaccharide (e.g., 2′-FL) from contaminants in a bacterial cell extract or lysate, or bacterial cell culture supernatant. Contaminants include bacterial DNA, protein and cell wall components, and yellow/brown sugar caramels sometimes formed in spontaneous chemical reactions in the culture medium. The oligosaccharides are purified and used in a number of products for consumption by humans as well as animals, such as companion animals (dogs, cats) as well as livestock (bovine, equine, ovine, caprine, or porcine animals, as well as poultry). For example, a pharmaceutical composition comprising purified 2′-fucosyllactose (2′-FL), 3-fucosyllactose (3FL), lactodifucotetraose (LDFT), or 3′-sialyl-3-fucosyllactose (3′-S3FL) and an excipient is suitable for oral administration. Large quantities of 2′-FL, 3FL, LDFT, or 3′-S3FL are produced in bacterial hosts, e.g., an E. coli bacterium comprising a heterologous α(1,2)fucosyltransferase, a heterologous α(1,3) fucosyltransferase, or a heterologous sialyltransferase, or a combination thereof. An E. coli bacterium comprising an enhanced cytoplasmic pool of each of the following: lactose, GDP-fucose, and CMP-Neu5Ac, is useful in such production systems. In the case of lactose and GDP-fucose, endogenous E. coli metabolic pathways and genes are manipulated in ways that result in the generation of increased cytoplasmic concentrations of lactose and/or GDP-fucose, as compared to levels found in wild type E. coli . For example, the bacteria contain at least 10%, 20%, 50%, 2×, 5×, 10× or more of the levels in a corresponding wild type bacteria that lacks the genetic modifications described above. In the case of CMP-Neu5Ac, endogenous Neu5Ac catabolism genes are inactivated and exogenous CMP-Neu5Ac biosynthesis genes introduced into E. coli resulting in the generation of a cytoplasmic pool of CMP-Neu5Ac not found in the wild type bacterium. A method of producing a pharmaceutical composition comprising a purified HMOS is carried out by culturing the bacterium described above, purifying the HMOS produced by the bacterium, and combining the HMOS with an excipient or carrier to yield a dietary supplement for oral administration. These compositions are useful in methods of preventing or treating enteric and/or respiratory diseases in infants and adults. Accordingly, the compositions are administered to a subject suffering from or at risk of developing such a disease. The invention therefore provides methods for increasing intracellular levels of GDP-fucose in Escherichia coli by manipulating the organism's endogenous colanic acid biosynthesis pathway. This is achieved through a number of genetic modifications of endogenous E. coli genes involved either directly in colanic acid precursor biosynthesis, or in overall control of the colanic acid synthetic regulon. The invention also provides for increasing the intracellular concentration of lactose in E. coli , for cells grown in the presence of lactose, by using manipulations of endogenous E. coli genes involved in lactose import, export, and catabolism. In particular, described herein are methods of increasing intracellular lactose levels in E. coli genetically engineered to produce a human milk oligosaccharide by incorporating a lacA mutation into the genetically modified E. coli . The lacA mutation prevents the formation of intracellular acetyl-lactose, which not only removes this molecule as a contaminant from subsequent purifications, but also eliminates E. coli 's ability to export excess lactose from its cytoplasm, thus greatly facilitating purposeful manipulations of the E. coli intracellular lactose pool. Also described herein are bacterial host cells with the ability to accumulate a intracellular lactose pool while simultaneously possessing low, functional levels of cytoplasmic β-galactosidase activity, for example as provided by the introduction of a functional recombinant E. coli lacZ gene, or by a β-galactosidase gene from any of a number of other organisms (e.g., the lac4 gene of Kluyveromyces lactis (e.g., GenBank Accession Number M84410 (GI:173304), incorporated herein by reference). Low, functional levels of cytoplasmic β-galactosidase include β-galactosidase activity levels, of between 0.05 and 200 units, e.g., between 0.05 and 5 units, between 0.05 and 4 units, between 0.05 and 3 units, or between 0.05 and 2 units (for unit definition see: Miller J H, Laboratory CSH. Experiments in molecular genetics. Cold Spring Harbor Laboratory Cold Spring Harbor, N.Y.; 1972; incorporated herein by reference). This low level of cytoplasmic β-galactosidase activity, while not high enough to significantly diminish the intracellular lactose pool, is nevertheless very useful for tasks such as phenotypic marking of desirable genetic loci during construction of host cell backgrounds, for detection of cell lysis due to undesired bacteriophage contaminations in fermentation processes, or for the facile removal of undesired residual lactose at the end of fermentations. In one aspect, the human milk oligosaccharide produced by engineered bacteria comprising an exogenous nucleic acid molecule encoding an α(1,2) fucosyltransferase, is 2′-FL (2′-fucosyllactose). Preferably, the α(1,2)fucosyltransferase utilized is the previously completely uncharacterized wcfW gene from Bacteroides fragilis NCTC 9343 of the present invention, alternatively the futC gene of Helicobacter pylori 26695 or the wbsJ gene of E. coli strain O128:B12, or any other α(1,2) fucosyltransferase capable of using lactose as the sugar acceptor substrate may be utilized for 2′-FL synthesis. In another aspect the human milk oligosaccharide produced by engineered bacteria comprising an exogenous nucleic acid molecule encoding an α(1,3) fucosyltransferase, is 3FL (3-fucosyllactose), wherein the bacterial cell comprises an exogenous nucleic acid molecule encoding an exogenous α(1,3) fucosyltransferase. Preferably, the bacterial cell is E. coli . The exogenous α(1,3) fucosyltransferase is isolated from, e.g., Helicobacter pylori, H. hepaticus, H bilis, C. jejuni , or a species of Bacteroides . In one aspect, the exogenous α(1,3) fucosyltransferase comprises H. hepaticus Hh0072 , H. pylori 11639 FucTa, or H. pylori UA948 FucTa (e.g., GenBank Accession Number AF194963 (GI:28436396), incorporated herein by reference). The invention also provides compositions comprising E. coli genetically engineered to produce the human milk tetrasaccharide lactodifucotetraose (LDFT). The E. coli in this instance comprise an exogenous nucleic acid molecule encoding an α(1,2) fucosyltransferase and an exogenous nucleic acid molecule encoding an α(1,3) fucosyltransferase. In one aspect, the E. coli is transformed with a plasmid expressing an α(1,2) fucosyltransferase and/or a plasmid expressing an α(1,3) fucosyltransferase. In another aspect, the E. coli is transformed with a plasmid that expresses both an α(1,2) fucosyltransferase and an α(1,3) fucosyltransferase. Alternatively, the E. coli is transformed with a chromosomal integrant expressing an α(1,2) fucosyltransferase and a chromosomal integrant expressing an α(1,3) fucosyltransferase. Optionally, the E. coli is transformed with plasmid pG177. Also described herein are compositions comprising a bacterial cell that produces the human milk oligosaccharide 3′-S3FL (3′-sialyl-3-fucosyllactose), wherein the bacterial cell comprises an exogenous sialyl-transferase gene encoding α(2,3)sialyl-transferase and an exogenous fucosyltransferase gene encoding α(1,3) fucosyltransferase. Preferably, the bacterial cell is E. coli . The exogenous fucosyltransferase gene is isolated from, e.g., Helicobacter pylori, H hepaticus, H bilis, C. jejuni , or a species of Bacteroides . For example, the exogenous fucosyltransferase gene comprises H. hepaticus Hh0072, H. pylori 11639 FucTa, or H. pylori UA948 FucTa. The exogenous sialyltransferase gene utilized for 3′-S3FL production may be obtained from any one of a number of sources, e.g., those described from N. meningitidis and N. gonorrhoeae . Preferably, the bacterium comprises a GDP-fucose synthesis pathway. Additionally, the bacterium contains a deficient sialic acid catabolic pathway. By “sialic acid catabolic pathway” is meant a sequence of reactions, usually controlled and catalyzed by enzymes, which results in the degradation of sialic acid. An exemplary sialic acid catabolic pathway in Escherichia coli is described herein. In the sialic acid catabolic pathway described herein, sialic acid (Neu5Ac; N-acetylneuraminic acid) is degraded by the enzymes NanA (N-acetylneuraminic acid lyase) and NanK (N-acetylmannosamine kinase). For example, a deficient sialic acid catabolic pathway is engineered in Escherichia coli by way of a null mutation in endogenous nanA (N-acetylneuraminate lyase) (e.g., GenBank Accession Number D00067 (GI:216588), incorporated herein by reference) and/or nanK (N-acetylmannosamine kinase) genes (e.g., GenBank Accession Number (amino acid) BAE77265 (GI:85676015), incorporated herein by reference). Other components of sialic acid metabolism include: (nanT) sialic acid transporter; (ManNAc-6-P) N-acetylmannosamine-6-phosphate; (GlcNAc-6-P) N-acetylglucosamine-6-phosphate; (GlcN-6-P) Glucosamine-6-phosphate; and (Fruc-6-P) Fructose-6-phosphate. Moreover, the bacterium (e.g., E. coli ) also comprises a sialic acid synthetic capability. For example, the bacterium comprises a sialic acid synthetic capability through provision of an exogenous UDP-GlcNAc 2-epimerase (e.g., neuC of Campylobacter jejuni or equivalent (e.g., GenBank Accession Number (amino acid) AAG29921 (GI:11095585), incorporated herein by reference)), a Neu5Ac synthase (e.g., neuB of C. jejuni or equivalent, e.g., GenBank Accession Number (amino acid) AAG29920 (GI:11095584), incorporated herein by reference)), and/or a CMP-Neu5Ac synthetase (e.g., neuA of C. jejuni or equivalent, e.g., GenBank Accession Number (amino acid) ADN91474 (GI:307748204), incorporated herein by reference). Additionally, the bacterium also comprises a functional β-galactosidase gene and a functional lactose permease gene. Bacteria comprising the characteristics described herein are cultured in the presence of lactose, and a 3′-sialyl-3-fucosyllactose is retrieved, either from the bacterium itself or from a culture supernatant of the bacterium. Also provided are methods for producing a 3′-sialyl-3-fucosyllactose (3′-S3FL) in an enteric bacterium, wherein the enteric bacterium comprises a mutation in an endogenous colanic acid synthesis gene, a functional lacZ gene, a functional lactose permease gene, an exogenous fucosyltransferase gene encoding α(1,3) fucosyltransferase, and an exogenous sialyltransferase gene encoding an α(2,3)sialyl transferase. Additionally, the bacterium contains a deficient sialic acid catabolic pathway. For example, the bacterium comprises a deficient sialic acid catabolic pathway by way of a null mutation in endogenous nanA (N-acetylneuraminate lyase) and/or nanK (N-acetylmannosamine kinase) genes. The bacterium also comprises a sialic acid synthetic capability. For example, the bacterium comprises a sialic acid synthetic capability through provision of an exogenous UDP-GlcNAc 2-epimerase (e.g., neuC of C. jejuni or equivalent), a Neu5Ac synthase (e.g., neuB of C. jejuni or equivalent), and/or a CMP-Neu5Ac synthetase (e.g., neuA of C. jejuni or equivalent). Bacteria comprising the characteristics described herein are cultured in the presence of lactose, and a 3′-sialyl-3-fucosyllactose is retrieved, either from the bacterium itself or from a culture supernatant of the bacterium. Also provided is a method for phenotypic marking of a gene locus in a host cell, whose native β-galactosidase gene is deleted or inactivated, by utilizing an inserted recombinant β-galactosidase (e.g., lacZ) gene engineered to produce a low, but detectable level of β-galactosidase activity. Similarly, the invention also provides methods for depleting a bacterial culture of residual lactose in a β-galactosidase negative host cell, whose native β-galactosidase gene is deleted or inactivated, by utilizing an inserted recombinant β-galactosidase (e.g., lacZ) gene engineered to produce a low but detectable level of β-galactosidase activity. Finally, also provided is a method for detecting bacterial cell lysis in a culture of a β-galactosidase negative host cell, whose native β-galactosidase gene is deleted or inactivated, by utilizing an inserted recombinant β-galactosidase. (e.g., lacZ) gene engineered to produce a low but detectable level of β-galactosidase activity. Methods of purifying a fucosylated oligosaccharide produced by the methods described herein are carried out by binding the fucosylated oligosaccharide from a bacterial cell lysate or bacterial cell culture supernatant of the bacterium to a carbon column, and eluting the fucosylated oligosaccharide from the column. Purified fucosylated oligosaccharide are produced by the methods described herein. Optionally, the invention features a vector, e.g., a vector containing a nucleic acid. The vector can further include one or more regulatory elements, e.g., a heterologous promoter. The regulatory elements can be operably linked to a protein gene, fusion protein gene, or a series of genes linked in an operon in order to express the fusion protein. In yet another aspect, the invention comprises an isolated recombinant cell, e.g., a bacterial cell containing an aforementioned nucleic acid molecule or vector. The nucleic acid sequence can be optionally integrated into the genome. The term “substantially pure” in reference to a given polypeptide, polynucleotide or oligosaccharide means that the polypeptide, polynucleotide or oligosaccharide is substantially free from other biological macromolecules. The substantially pure polypeptide, polynucleotide or oligosaccharide is at least 75% (e.g., at least 80, 85, 95, or 99%) pure by dry weight. Purity can be measured by any appropriate calibrated standard method, for example, by column chromatography, polyacrylamide gel electrophoresis, thin layer chromatography (TLC) or HPLC analysis. Polynucleotides, polypeptides, and oligosaccharides of the invention are purified and/or isolated. Purified defines a degree of sterility that is safe for administration to a human subject, e.g., lacking infectious or toxic agents. Specifically, as used herein, an “isolated” or “purified” nucleic acid molecule, polynucleotide, polypeptide, protein or oligosaccharide, is substantially free of other cellular material, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized. For example, Purified HMOS compositions are at least 60% by weight (dry weight) the compound of interest. Preferably, the preparation is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight the compound of interest. Purity is measured by any appropriate calibrated standard method, for example, by column chromatography, polyacrylamide gel electrophoresis, thin layer chromatography (TLC) or HPLC analysis. For example, a “purified protein” refers to a protein that has been separated from other proteins, lipids, and nucleic acids with which it is naturally associated. Preferably, the protein constitutes at least 10, 20, 50 70, 80, 90, 95, 99-100% by dry weight of the purified preparation. By “isolated nucleic acid” is meant a nucleic acid that is free of the genes which flank it in the naturally-occurring genome of the organism from which the nucleic acid is derived. The term covers, for example: (a) a DNA which is part of a naturally occurring genomic DNA molecule, but is not flanked by both of the nucleic acid sequences that flank that part of the molecule in the genome of the organism in which it naturally occurs; (b) a nucleic acid incorporated into a vector or into the genomic DNA of a prokaryote or eukaryote in a manner, such that the resulting molecule is not identical to any naturally occurring vector or genomic DNA; (c) a separate molecule such as a cDNA, a genomic fragment, a fragment produced by polymerase chain reaction (PCR), or a restriction fragment; and (d) a recombinant nucleotide sequence that is part of a hybrid gene, i.e., a gene encoding a fusion protein. Isolated nucleic acid molecules according to the present invention further include molecules produced synthetically, as well as any nucleic acids that have been altered chemically and/or that have modified backbones. For example, the isolated nucleic acid is a purified cDNA or RNA polynucleotide. A “heterologous promoter”, when operably linked to a nucleic acid sequence, refers to a promoter which is not naturally associated with the nucleic acid sequence. The terms “express” and “over-express” are used to denote the fact that, in some cases, a cell useful in the method herein may inherently express some of the factor that it is to be genetically altered to produce, in which case the addition of the polynucleotide sequence results in over-expression of the factor. That is, more factor is expressed by the altered cell than would be, under the same conditions, by a wild type cell. Similarly, if the cell does not inherently express the factor that it is genetically altered to produce, the term used would be to merely “express” the factor since the wild type cell did not express the factor at all. The terms “treating” and “treatment” as used herein refer to the administration of an agent or formulation to a clinically symptomatic individual afflicted with an adverse condition, disorder, or disease, so as to effect a reduction in severity and/or frequency of symptoms, eliminate the symptoms and/or their underlying cause, and/or facilitate improvement or remediation of damage. The terms “preventing” and “prevention” refer to the administration of an agent or composition to a clinically asymptomatic individual who is susceptible to a particular adverse condition, disorder, or disease, and thus relates to the prevention of the occurrence of symptoms and/or their underlying cause. The invention provides a method of treating, preventing, or reducing the risk of infection in a subject comprising administering to said subject a composition comprising a human milk oligosaccharide, purified from a culture of a recombinant strain of the current invention, wherein the HMOS binds to a pathogen and wherein the subject is infected with or at risk of infection with the pathogen. In one aspect, the infection is caused by a Norwalk-like virus or Campylobacter jejuni . The subject is preferably a mammal in need of such treatment. The mammal is, e.g., any mammal, e.g., a human, a primate, a mouse, a rat, a dog, a cat, a cow, a horse, or a pig. In a preferred embodiment, the mammal is a human. For example, the compositions are formulated into animal feed (e.g., pellets, kibble, mash) or animal food supplements for companion animals, e.g., dogs or cats, as well as livestock or animals grown for food consumption, e.g., cattle, sheep, pigs, chickens, and goats. Preferably, the purified HMOS is formulated into a powder (e.g., infant formula powder or adult nutritional supplement powder, each of which is mixed with a liquid such as water or juice prior to consumption) or in the form of tablets, capsules or pastes or is incorporated as a component in dairy products such as milk, cream, cheese, yogurt or kefir, or as a component in any beverage, or combined in a preparation containing live microbial cultures intended to serve as probiotics, or in prebiotic preparations intended to enhance the growth of beneficial microorganisms either in vitro or in vivo. For example, the purified sugar (e.g., 2′-FL) can be mixed with a Bifidobacterium or Lactobacillus in a probiotic nutritional composition. (i.e. Bifidobacteria are beneficial components of a normal human gut flora and are also known to utilize HMOS for growth. By the terms “effective amount” and “therapeutically effective amount” of a formulation or formulation component is meant a nontoxic but sufficient amount of the formulation or component to provide the desired effect. The transitional term “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. By contrast, the transitional phrase “consisting of” excludes any element, step, or ingredient not specified in the claim. The transitional phrase “consisting essentially of” limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention. Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All published foreign patents and patent applications cited herein are incorporated herein by reference. Genbank and NCBI submissions indicated by accession number cited herein are incorporated herein by reference. All other published references, documents, manuscripts and scientific literature cited herein are incorporated herein by reference. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
C12N1570
20170921
20180515
20180322
69611.0
C12N1570
2
PROUTY, REBECCA E
Biosynthesis Of Human Milk Oligosaccharides In Engineered Bacteria
UNDISCOUNTED
1
CONT-ACCEPTED
C12N
2,017
15,712,780
PENDING
APPARATUS, METHOD AND SYSTEM FOR A TUNNELING CLIENT ACCESS POINT
The disclosure details the implementation of an apparatus, method, and system comprising a portable device configured to communicate with a terminal and a network server, and execute stored program code in response to user interaction with an interactive user interface. The portable device contains stored program code configured to render an interactive user interface on a terminal output component to enable the user the control processing activity on the portable device and access data and programs from the portable device and a network server.
1. A portable device configured to communicate with a communications network, the communication network comprising (i) a communications network node, and (ii) a terminal, the terminal comprising a processor, an output component, and a memory configured to store executable program code, including first program code which, when executed by the terminal processor, is configured to affect the presentation of an interactive user interface by the terminal output component, and second program code which, when executed by the terminal processor, is configured to facilitate communications between the terminal and the portable device, the portable device comprising: (a) at least one communication interface configured to enable the transmission of communications between the portable device and the communications network; (b) a processor; and (c) a memory having executable program code stored thereon, including: (1) third program code which, when executed by the portable device processor, is configured to facilitate communications between the portable device and the communications network; (2) fourth program code which, when executed by the portable device processor in response to user interaction with the interactive user interface presented by the terminal output component, is configured to cause a communication to be transmitted to the communications network node; and (3) fifth program code which, when executed, is configured to affect the presentation of the interactive user interface by the terminal output component. 2. The portable device according to claim 1, wherein the terminal comprises a network interface configured to enable the transmission of communications between the terminal and the communications network node, and wherein the fourth program code, when executed by the portable device processor, is configured to cause the communication to be transmitted through the terminal network interface to the communications network node. 3. The portable device according to claim 2, wherein the fourth program code, when executed by the portable device processor, is configured to cause the terminal to transmit the communication through the terminal network interface to the communications network node. 4. The portable device according to claim 3, wherein the fourth program code, when executed by the portable device processor, is configured to provide the terminal with data stored on the portable device memory to cause the terminal to transmit the communication through the terminal network interface to the communications network node. 5. The portable device according to claim 4, wherein the data stored on the portable device memory comprises user authorization data. 6. The portable device according to claim 5, wherein the user authorization data comprises biometric data. 7. The portable device according to claim 4, wherein the data stored on the portable device memory comprises a digital certificate. 8. The portable device according to claim 4, wherein the data stored on the portable device memory comprises portable device identification information. 9. The portable device according to claim 3, wherein the fourth program code, when executed by the portable device processor, is configured to affect the execution of sixth program code to cause the terminal to transmit the communication through the terminal network interface to the communications network node. 10. The portable device according to claim 9, wherein the sixth program code is stored on the terminal memory and, when executed by the terminal processor, is configured to cause the terminal to transmit the communication through the terminal network interface to the communications network node. 11. The portable device according to claim 1, wherein the at least one communication interface comprises a network interface configured to enable the transmission of communications between the portable device and the communications network node, and wherein the fourth program code, when executed by the portable device processor, is configured to cause the communication to be transmitted through the portable device network interface to the communications network node. 12. The portable device according to claim 1, wherein the fifth program code is configured to be executed by the portable device processor. 13. The portable device according to claim 12, wherein the fifth program code is configured to be executed by the portable device processor in response to the execution of the fourth program code. 14. The portable device according to claim 12, wherein the fifth program code is configured to be executed by the portable device processor in response to user interaction with the interactive user interface presented by the terminal output component. 15. The portable device according to claim 12, wherein the fifth program code, when executed by the portable device processor, is configured to cause a communication to be transmitted to the terminal to affect the presentation of the interactive user interface by the terminal output component. 16. The portable device according to claim 12, wherein the fifth program code, when executed by the portable device processor, is configured to cause a communication to be transmitted to the terminal to cause the terminal processor to execute fifth program code to affect the presentation of the interactive user interface by the terminal output component. 17. The portable device according to claim 1, wherein the fifth program code is configured to be executed by the terminal processor. 18. The portable device according to claim 1, wherein the at least one communication interface comprises a wireless network interface configured to enable the transmission of communications between the portable device and the terminal and between the portable device and the communications network node. 19. The portable device according to claim 18, wherein the wireless network interface is configured to employ a WiFi connectivity protocol. 20. The portable device according to claim 18, wherein the wireless network interface is configured to employ a Bluetooth connectivity protocol. 21. The portable device according to claim 1, wherein the at least one communication interface comprises a first communication interface configured to enable the transmission of communications between the portable device and the terminal and a second communication interface configured to enable the transmission of communications between the portable device and the communications network node. 22. The portable device according to claim 21, wherein the first communication interface comprises a wireless communication interface configured to employ a WiFi connectivity protocol. 23. The portable device according to claim 21, wherein the first communication interface comprises a wireless communication interface configured to employ a Bluetooth connectivity protocol. 24. The portable device according to claim 21, wherein the first communication interface is configured to employ a serial communication protocol. 25. The portable device according to claim 24, wherein the first communication interface comprises a universal serial bus interface. 26. The portable device according to claim 21, wherein the second communication interface comprises a wireless communication interface configured to employ a WiFi connectivity protocol. 27. The portable device according to claim 21, wherein the second communication interface comprises a wireless communication interface configured to employ a Bluetooth connectivity protocol. 28. The portable device according to claim 1, wherein the communications network node comprises a server. 29. The portable device according to claim 1, wherein the communications network node comprises a data storage system. 30. The portable device according to claim 1, wherein the fourth program code, when executed by the portable device processor, is configured to cause the communication to be transmitted to the communications network node to facilitate verification of the portable device. 31. The portable device according to claim 1, wherein the fourth program code, when executed by the portable device processor, is configured to cause the communication to be transmitted to the communications network node to facilitate the download of data to the portable device. 32. The portable device according to claim 1, wherein the fourth program code, when executed by the portable device processor, is configured to cause the communication to be transmitted to the communications network node to facilitate access to data stored on a communications network node. 33. The portable device according to claim 1, wherein the fourth program code, when executed by the portable device processor, is configured to cause the communication to be transmitted to the communications network node to facilitate the transmission of data to the portable device. 34. The portable device according to claim 33, wherein the data comprises video data content. 35. The portable device according to claim 33, wherein the data comprises audio data content. 36. The portable device according to claim 33, wherein the data comprises a live data feed. 37. The portable device according to claim 34, wherein the terminal output component comprises a video monitor and the portable device is configured to transmit video data content to the terminal for presentation by the terminal video monitor. 38. The portable device according to claim 35, wherein the terminal output component comprises a speaker and the portable device is configured to transmit audio data content to the terminal for presentation by the terminal speaker. 39. The portable device according to claim 36, wherein the portable device is configured to transmit to the terminal the live data feed received from the communications network node. 40. The portable device according to claim 1, wherein the executable program code stored on the portable device memory comprises an operating system configured to be executed by the portable device processor. 41. The portable device according to claim 1, wherein the fourth program code, when executed by the portable device processor, is configured to cause the communication to be transmitted to the communications network node to facilitate the transmission of program code to the portable device. 42. The portable device according to claim 41, wherein the program code transmitted to the portable device comprises the fifth program code. 43. The portable device according to claim 42, wherein the fifth program code, when executed, is configured to affect the presentation of advertisement information by the terminal output component. 44. The portable device according to claim 1, wherein the fourth program code, when executed by the portable device processor, is configured to cause the communication to be transmitted to the communications network node to facilitate the transmission of encrypted data to a communications network node. 45. The portable device according to claim 1, wherein the fourth program code, when executed by the portable device processor, is configured to cause the communication to be transmitted to the communications network node to facilitate the transmission of encrypted data to the portable device. 46. The portable device according to claim 1, wherein the fourth program code, when executed by the portable device processor, is configured to cause the communication to be transmitted to the communications network node to facilitate synchronizing data stored on the portable device memory with data stored on a communications network node. 47. The portable device according to claim 1, wherein the fourth program code, when executed by the portable device processor, is configured to cause the communication to be transmitted to the communications network node to facilitate synchronizing program code stored on the portable device with program code stored on a communications network node. 48. The portable device according to claim 1, wherein the interactive user interface comprises a graphic user interface. 49. A portable device configured to communicate with a communications network, the communication network comprising (i) a communications network node, and (ii) a terminal, the terminal comprising a processor, an output component, and a memory configured to store executable program code, including first program code which, when executed by the terminal processor, is configured to affect the presentation of an interactive user interface by the terminal output component, and second program code which, when executed by the terminal processor, is configured to facilitate communications between the terminal and the portable device, the portable device comprising: (a) at least one communication interface configured to enable the transmission of communications between the portable device and the communications network; (b) a processor; and (c) a memory having executable program code stored thereon, including: (1) third program code which, when executed by the portable device processor, is configured to facilitate communications between the portable device and the communications network; (2) fourth program code which, when executed by the portable device processor in response to user interaction with the interactive user interface presented by the terminal output component, is configured to cause a communication to be transmitted to the communications network node and affect the presentation of the interactive user interface by the terminal output component. 50. The portable device according to claim 49, wherein the terminal comprises a network interface configured to enable the transmission of communications between the terminal and the communications network node, and wherein the fourth program code, when executed by the portable device processor, is configured to cause the communication to be transmitted through the terminal network interface to the communications network node. 51. The portable device according to claim 50, wherein the fourth program code, when executed by the portable device processor, is configured to cause the terminal to transmit the communication through the terminal network interface to the communications network node. 52. The portable device according to claim 51, wherein the fourth program code, when executed by the portable device processor, is configured to provide the terminal with data stored on the portable device memory to cause the terminal to transmit the communication through the terminal network interface to the communications network node. 53. The portable device according to claim 52, wherein the data stored on the portable device memory comprises user authorization data. 54. The portable device according to claim 53, wherein the user authorization data comprises biometric data. 55. The portable device according to claim 52, wherein the data stored on the portable device memory comprises a digital certificate. 56. The portable device according to claim 52, wherein the data stored on the portable device memory comprises portable device identification information. 57. The portable device according to claim 51, wherein the fourth program code, when executed by the portable device processor, is configured to affect the execution of fifth program code to cause the terminal to transmit the communication through the terminal network interface to the communications network node. 58. The portable device according to claim 57, wherein the fifth program code is stored on the terminal memory and, when executed by the terminal processor, is configured to cause the terminal to transmit the communication through the terminal network interface to the communications network node. 59. The portable device according to claim 49, wherein the at least one communication interface comprises a network interface configured to enable the transmission of communications between the portable device and the communications network node, and wherein the fourth program code, when executed by the portable device processor, is configured to cause the communication to be transmitted through the portable device network interface to the communications network node. 60. The portable device according to claim 49, wherein the fourth program code, when executed by the portable device processor, is configured to cause a communication to be transmitted to the terminal to affect the presentation of the interactive user interface by the terminal output component. 61. The portable device according to claim 49, wherein the fourth program code, when executed by the portable device processor, is configured to cause a communication to be transmitted to the terminal to cause the terminal processor to execute fifth program code to affect the presentation of the interactive user interface by the terminal output component. 62. The portable device according to claim 49, wherein the at least one communication interface comprises a wireless network interface configured to enable the transmission of communications between the portable device and the terminal and between the portable device and the communications network node. 63. The portable device according to claim 62, wherein the wireless network interface is configured to employ a WiFi connectivity protocol. 64. The portable device according to claim 62, wherein the wireless network interface is configured to employ a Bluetooth connectivity protocol. 65. The portable device according to claim 49, wherein the at least one communication interface comprises a first communication interface configured to enable the transmission of communications between the portable device and the terminal and a second communication interface configured to enable the transmission of communications between the portable device and the communications network node. 66. The portable device according to claim 65, wherein the first communication interface comprises a wireless communication interface configured to employ a WiFi connectivity protocol. 67. The portable device according to claim 65, wherein the first communication interface comprises a wireless communication interface configured to employ a Bluetooth connectivity protocol. 68. The portable device according to claim 65, wherein the first communication interface is configured to employ a serial communication protocol. 69. The portable device according to claim 68, wherein the first communication interface comprises a universal serial bus interface. 70. The portable device according to claim 65, wherein the second communication interface comprises a wireless communication interface configured to employ a WiFi connectivity protocol. 71. The portable device according to claim 65, wherein the second communication interface comprises a wireless communication interface configured to employ a Bluetooth connectivity protocol. 72. The portable device according to claim 49, wherein the communications network node comprises a server. 73. The portable device according to claim 49, wherein the communications network node comprises a data storage system. 74. The portable device according to claim 49, wherein the fourth program code, when executed by the portable device processor, is configured to cause the communication to be transmitted to the communications network node to facilitate verification of the portable device. 75. The portable device according to claim 49, wherein the fourth program code, when executed by the portable device processor, is configured to cause the communication to be transmitted to the communications network node to facilitate the download of data to the portable device. 76. The portable device according to claim 49, wherein the fourth program code, when executed by the portable device processor, is configured to cause the communication to be transmitted to the communications network node to facilitate access to data stored on a communications network node. 77. The portable device according to claim 49, wherein the fourth program code, when executed by the portable device processor, is configured to cause the communication to be transmitted to the communications network node to facilitate the transmission of data to the portable device. 78. The portable device according to claim 77, wherein the data comprises video data content. 79. The portable device according to claim 77, wherein the data comprises audio data content. 80. The portable device according to claim 77, wherein the data comprises a live data feed. 81. The portable device according to claim 78, wherein the terminal output component comprises a video monitor and the portable device is configured to transmit video data content to the terminal for presentation by the terminal video monitor. 82. The portable device according to claim 79, wherein the terminal output component comprises a speaker and the portable device is configured to transmit audio data content to the terminal for presentation by the terminal speaker. 83. The portable device according to claim 80, wherein the portable device is configured to transmit to the terminal the live data feed received from the communications network node. 84. The portable device according to claim 49, wherein the executable program code stored on the portable device memory comprises an operating system configured to be executed by the portable device processor. 85. The portable device according to claim 49, wherein the fourth program code, when executed by the portable device processor, is configured to cause the communication to be transmitted to the communications network node to facilitate the transmission of program code to the portable device. 86. The portable device according to claim 85, wherein the program code transmitted to the portable device comprises the fourth program code. 87. The portable device according to claim 86, wherein the fourth program code, when executed by the portable device processor, is configured to affect the presentation of advertisement information by the terminal output component. 88. The portable device according to claim 49, wherein the fourth program code, when executed by the portable device processor, is configured to cause the communication to be transmitted to the communications network node to facilitate the transmission of encrypted data to a communications network node. 89. The portable device according to claim 49, wherein the fourth program code, when executed by the portable device processor, is configured to cause the communication to be transmitted to the communications network node to facilitate the transmission of encrypted data to the portable device. 90. The portable device according to claim 49, wherein the fourth program code, when executed by the portable device processor, is configured to cause the communication to be transmitted to the communications network node to facilitate synchronizing data stored on the portable device memory with data stored on a communications network node. 91. The portable device according to claim 49, wherein the fourth program code, when executed by the portable device processor, is configured to cause the communication to be transmitted to the communications network node to facilitate synchronizing program code stored on the portable device with program code stored on a communications network node. 92. A method implemented on a portable device comprising a processor, a memory having executable program code stored thereon, and at least one communication interface configured to enable the transmission of communications between the portable device and a communications network, the communications network comprising (i) a communications network node, (ii) and a terminal, the terminal comprising a processor, an output component, and a memory configured to store executable program code, including first program code which, when executed by the terminal processor, is configured to affect the presentation of an interactive user interface by the terminal output component, and second program code which, when executed by the terminal processor, is configured to facilitate communications between the terminal and the portable device, the method comprising: (a) executing third program code stored on the portable device memory to facilitate communications between the portable device and the communications network; (b) executing, in response to a communication received by the portable device resulting from user interaction with the interactive user interface presented by the terminal output component, fourth program code stored on the portable device memory to cause a communication to be transmitted to the communications network node; and (e) affecting the presentation of the interactive user interface by the terminal output component. 93. The method according to claim 92, wherein the terminal comprises a network interface and the step of executing the fourth program code to cause a communication to be transmitted to the communications network node comprises causing a communication to be transmitted through the terminal network interface to the communications network node. 94. The method according to claim 93, wherein the step of executing the fourth program code to cause a communication to be transmitted to the communications network node comprises causing a communication to be transmitted to the terminal to facilitate a communication to be transmitted through the terminal network interface to the communications network node. 95. The method according to claim 93, wherein the step of executing the fourth program code to cause a communication to be transmitted to the communications network node comprises providing the terminal with data stored on the portable device memory to facilitate the terminal to transmit a communication through the terminal network interface to the communications network node. 96. The method according to claim 95, wherein the data stored on the portable device memory comprises user authorization data. 97. The method according to claim 96, wherein the user authorization data comprises biometric data. 98. The method according to claim 95, wherein the data stored on the portable device memory comprises a digital certificate. 99. The method according to claim 95, wherein the data stored on the portable device memory comprises portable device identification information. 100. The method according to claim 92, wherein the terminal comprises a network interface and the step of executing the fourth program code to cause a communication to be transmitted to the communication network node comprises affecting the execution of fifth program code to cause a communication to be transmitted through the terminal network interface to the communications network node. 101. The method according to claim 100, wherein the fifth program code is stored on the terminal memory and, when executed by the terminal processor, is configured to cause a communication to be transmitted through the terminal network interface to the communications network node. 102. The method according to claim 92, wherein the at least one communication interface comprises a network interface configured to enable the transmission of communications between the portable device and the communications network node and the step of executing the fourth program code to cause a communication to be transmitted to the communications network node comprises causing a communication to be transmitted through the portable device network interface to the communications network node. 103. The method according to claim 102, wherein the step of executing the fourth program code to cause a communication to be transmitted to the communications network node comprises retrieving data stored on the portable device memory to facilitate a communication to be transmitted through the portable device network interface to the communications network node. 104. The method according to claim 103, wherein the data stored on the portable device memory comprises user authorization data. 105. The method according to claim 104, wherein the user authorization data comprises biometric data. 106. The method according to claim 103, wherein the data stored on the portable device memory comprises a digital certificate. 107. The method according to claim 103, wherein the data stored on the portable device memory comprises portable device identification information. 108. The method according to claim 92, wherein the at least one communication interface comprises a wireless network interface configured to enable the transmission of communications between the portable device and the terminal and between the portable device and the communications network node. 109. The method according to claim 108, wherein the wireless network interface is configured to employ a WiFi connectivity protocol. 110. The method according to claim 108, wherein the wireless network interface is configured to employ a Bluetooth connectivity protocol. 111. The method according to claim 92, wherein the at least one communication interface comprises a first communication interface configured to enable the transmission of communications between the portable device and the terminal and a second communication interface configured to enable the transmission of communications between the portable device and the communications network node. 112. The method according to claim 111, wherein the first communication interface comprises a wireless communication interface configured to employ a WiFi connectivity protocol. 113. The method according to claim 111, wherein the first communication interface comprises a wireless network interface configured to employ a Bluetooth connectivity protocol. 114. The method according to claim 111, wherein the first communication interface is configured to employ a serial communication protocol. 115. The method according to claim 114, wherein the first communication interface comprises a universal serial bus interface. 116. The method according to claim 111, wherein the second communication interface comprises a wireless communication interface configured to employ a WiFi connectivity protocol. 117. The method according to claim 111, wherein the second communication interface comprises a wireless network interface configured to employ a Bluetooth connectivity protocol. 118. The method according to claim 92, wherein the step of executing the fourth program code to cause a communication to be transmitted to the communications network node facilitates verification of the portable device. 119. The method according to claim 92, wherein the step of executing the fourth program code to cause a communication to be transmitted to the communications network node facilitates access to data stored on a communications network node. 120. The method according to claim 92, wherein the step of executing the fourth program code to cause a communication to be transmitted to the communications network node facilitates the transmission of data to the portable device. 121. The method according to claim 120, wherein the data comprises encrypted data. 122. The method according to claim 120, wherein the data comprises video data content. 123. The method according to claim 120, wherein the data comprises audio data content. 124. The method according to claim 120, wherein the data comprises a live data feed. 125. The method according to claim 122, further comprising transmitting the video data content to the terminal for presentation by the terminal output component. 126. The method according to claim 123, further comprising transmitting the audio data content to the terminal for presentation by the terminal output component. 127. The method according to claim 124, further comprising transmitting the live data feed to the terminal for presentation by the terminal output component. 128. The method according to claim 92, wherein the step of executing the fourth program code to cause a communication to be transmitted to the communications network node facilitates the transmission of encrypted data to a communications network node. 129. The method according to claim 92, wherein the step of executing the fourth program code to cause a communication to be transmitted to the communications network node facilitates synchronizing data stored on the portable device memory with data stored on a communications network node. 130. The method according to claim 92, wherein the step of executing the fourth program code to cause a communication to be transmitted to the communications network node facilitates synchronizing program code stored on the portable device memory with program code stored on a communications network node. 131. The method according to claim 92, wherein the step of affecting the presentation of the interactive user interface by the terminal output component comprises providing the terminal processor with access to fifth program code stored on the portable device memory which, when executed by the terminal processor, is configured to affect the presentation of the interactive user interface by the terminal output component. 132. The method according to claim 131, wherein the step of providing the terminal processor with access to the fifth program code comprises storing the fifth program code on the terminal memory. 133. The method according to claim 92, wherein the step of affecting the presentation of the interactive user interface by the terminal output component comprises executing fifth program code stored on the portable device memory to affect the presentation of the interactive user interface by the terminal output component. 134. The method according to claim 92, wherein the step of affecting the presentation of the interactive user interface by the terminal output component comprises transmitting a communication to cause the terminal processor to execute fifth program code stored on the terminal memory to affect the presentation of an interactive user interface by the terminal output component. 135. The method according to claim 92, wherein the step of affecting the presentation of the interactive user interface by the terminal output component comprises executing sixth program code stored on the portable device memory to cause a communication to be transmitted to the terminal to cause the terminal processor to execute fifth program code stored on the terminal memory to affect the presentation of an interactive user interface by the terminal output component. 136. The method according to claim 135, wherein the step of affecting the presentation of the interactive user interface by the terminal output component comprises executing the sixth program code in response to a communication received by the portable device resulting from user interaction with an interactive user interface presented by the terminal output component. 137. The method according to claim 92, wherein the step of affecting the presentation of the interactive user interface by the terminal output component results from executing the fourth program code. 138. A system implementing a communications network, the communications network comprising (i) a communications network node, and (ii) a terminal, the terminal comprising a processor, an output component, and a memory configured to store executable program code, including first program code which, when executed by the terminal processor, is configured to affect the presentation of an interactive user interface by the terminal output component, and second program code which, when executed by the terminal processor, is configured to facilitate communications to and from the terminal, the system comprising: (a) a portable device comprising at least one communication interface configured to enable the transmission of communications between the portable device and the communications network, a processor, and a memory having executable program code stored thereon, the portable device configured to: (1) execute third program code stored on the portable device memory to facilitate communications between the portable device and the communications network; (2) execute, in response to a communication received by the portable device resulting from user interaction with the interactive user interface presented by the terminal output component, fourth program code stored on the portable device memory to cause a communication to be transmitted to the communications network node; and (3) affect the presentation of the interactive user interface by the terminal output component. 139. The system according to claim 138, wherein the terminal comprises a network interface and the portable device processor is configured to execute the fourth program code to cause the communication to be transmitted through the terminal network interface to the communications network node. 140. The system according to claim 139, wherein the portable device processor is configured to execute the fourth program code to cause a communication to be transmitted to the terminal to facilitate the communication to be transmitted through the terminal network interface to the communications network node. 141. The system according to claim 138, wherein the portable device processor is configured to execute the fourth program code to provide the terminal with data stored on the portable device memory to facilitate the terminal to transmit the communication through the terminal network interface to the communications network node. 142. The system according to claim 141, wherein the data stored on the portable device memory comprises user authorization data. 143. The system according to claim 142, wherein the user authorization data comprises biometric data. 144. The system according to claim 141, wherein the data stored on the portable device memory comprises a digital certificate. 145. The system according to claim 141, wherein the data stored on the portable device memory comprises portable device identification information. 146. The system according to claim 138, wherein the terminal comprises a network interface and the portable device processor is configured to execute the fourth program code to affect the execution of fifth program code to cause the communication to be transmitted through the terminal network interface to the communications network node. 147. The system according to claim 146, wherein the fifth program code is stored on the terminal memory and, when executed by the terminal processor, is configured to cause the communication to be transmitted through the terminal network interface to the communications network node. 148. The system according to claim 138, wherein the at least one communication interface comprises a network interface configured to enable the transmission of communications between the portable device and the communications network node and the portable device processor is configured to execute the fourth program code to cause the communication to be transmitted through the portable device network interface to the communications network node. 149. The system according to claim 148, wherein the portable device processor is configured to execute the fourth program code to retrieve data stored on the portable device memory to facilitate the communication to be transmitted through the portable device network interface to the communications network node. 150. The system according to claim 149, wherein the data stored on the portable device memory comprises user authorization data. 151. The system according to claim 150, wherein the user authorization data comprises biometric data. 152. The system according to claim 149, wherein the data stored on the portable device memory comprises a digital certificate. 153. The system according to claim 149, wherein the data stored on the portable device memory comprises portable device identification information. 154. The system according to claim 138, wherein the at least one communication interface comprises a wireless network interface configured to enable the transmission of communications between the portable device and the terminal and between the portable device and the communications network node. 155. The system according to claim 154, wherein the wireless network interface is configured to employ a WiFi connectivity protocol. 156. The system according to claim 154, wherein the wireless network interface is configured to employ a Bluetooth connectivity protocol. 157. The system according to claim 138, wherein the at least one communication interface comprises a first communication interface configured to enable the transmission of communications between the portable device and the terminal and a second communication interface configured to enable the transmission of communications between the portable device and the communications network node. 158. The system according to claim 157, wherein the first communication interface comprises a wireless communication interface configured to employ a WiFi connectivity protocol. 159. The system according to claim 157, wherein the first communication interface comprises a wireless network interface configured to employ a Bluetooth connectivity protocol. 160. The system according to claim 157, wherein the first communication interface is configured to employ a serial communication protocol. 161. The system according to claim 160, wherein the first communication interface comprises a universal serial bus interface. 162. The system according to claim 157, wherein the second communication interface comprises a wireless communication interface configured to employ a WiFi connectivity protocol. 163. The system according to claim 157, wherein the second communication interface comprises a wireless network interface configured to employ a Bluetooth connectivity protocol. 164. The system according to claim 138, wherein the portable device processor is configured to execute the fourth program code to cause the communication to be transmitted to the communications network node to facilitate verification of the portable device. 165. The system according to claim 138, wherein the portable device processor is configured to execute the fourth program code to cause the communication to be transmitted to the communications network node to facilitate access to data stored on a communications network node. 166. The system according to claim 138, wherein the portable device processor is configured to execute the fourth program code to cause the communication to be transmitted to the communications network node to facilitate the transmission of data to the portable device. 167. The system according to claim 166, wherein the data comprises encrypted data. 168. The system according to claim 166, wherein the data comprises video data content. 169. The system according to claim 166, wherein the data comprises audio data content. 170. The system according to claim 166, wherein the data comprises a live data feed. 171. The system according to claim 168, wherein the portable device is configured to transmit the video data content to the terminal for presentation by the terminal output component. 172. The system according to claim 169, wherein the portable device is configured to transmit the audio data content to the terminal for presentation by the terminal output component. 173. The system according to claim 170, wherein the portable device is configured to transmit the live data feed to the terminal for presentation by the terminal output component. 174. The system according to claim 138, wherein the portable device processor is configured to execute the fourth program code to cause the communication to be transmitted to the communications network node to facilitate the transmission of encrypted data to a communications network node. 175. The system according to claim 138, wherein the portable device processor is configured to execute the fourth program code to cause the communication to be transmitted to the communications network node to facilitate synchronizing data stored on the portable device memory with data stored on a communications network node. 176. The system according to claim 138, wherein the portable device processor is configured to execute the fourth program code to cause the communication to be transmitted to the communications network node to facilitate synchronizing program code stored on the portable device memory with program code stored on a communications network node. 177. The system according to claim 138, wherein the portable device is configured to affect the presentation of the interactive user interface by the terminal output component by providing the terminal processor with access to fifth program code stored on the portable device memory which, when executed by the terminal processor, is configured to affect the presentation of the interactive user interface by the terminal output component. 178. The system according to claim 177, wherein the portable device is configured to provide the terminal processor with access to the fifth program code by storing the fifth program code on the terminal memory. 179. The system according to claim 138, wherein the portable device is configured to affect the presentation of the interactive user interface by the terminal output component by executing fifth program code stored on the portable device memory to affect the presentation of the interactive user interface by the terminal output component. 180. The system according to claim 138, wherein the portable device is configured to affect the presentation of the interactive user interface by the terminal output component by causing a communication to be transmitted to the terminal to cause the terminal processor to execute fifth program code stored on the terminal memory to affect the presentation of an interactive user interface by the terminal output component. 181. The system according to claim 138, wherein the portable device is configured to affect the presentation of the interactive user interface by the terminal output component by executing sixth program code stored on the portable device memory to cause a communication to be transmitted to the terminal to cause the terminal processor to execute fifth program code stored on the terminal memory to affect the presentation of an interactive user interface by the terminal output component. 182. The system according to claim 181, wherein the portable device is configured to affect the presentation of the interactive user interface by the terminal output component by executing the sixth program code in response to a communication received by the portable device resulting from user interaction with an interactive user interface presented by the terminal output component. 183. The system according to claim 138, wherein the portable device is configured to affect the presentation of the interactive user interface by the terminal output component as a result of executing the fourth program code.
This application is a continuation of U.S. application Ser. No. 14/721,540, filed May 26, 2015, which is a continuation of U.S. application Ser. No. 13/960,514, filed Aug. 6, 2013, now U.S. Pat. No. 9,059,969, which is a continuation of U.S. application Ser. No. 12/950,321, filed Nov. 19, 2010, now U.S. Pat. No. 8,539,047, which is a continuation of U.S. application Ser. No. 10/807,731, filed on Mar. 23, 2003, now U.S. Pat. No. 7,861,006. FIELD The present invention is directed generally to an apparatus, method, and system of accessing data, and more particularly, to an apparatus, method and system to transmit and process data comprising a portable device in communication with a terminal and a communications network comprising a plurality of communications network nodes. BACKGROUND Portable Computing and Storage Computing devices have been becoming smaller over time. Currently, some of the smallest computing devices are in the form of personal digital assistants (PDAs). Such devices usually come with a touch screen, an input stylus and/or mini keyboard, and battery source. These devices, typically, have storage capacities around 64 MB. Examples of these devices include Palm's Palm Pilot. Information Technology Systems Typically, users, which may be people and/or other systems, engage information technology systems (e.g., commonly computers) to facilitate information processing. In turn, computers employ processors to process information; such processors are often referred to as central processing units (CPU). A common form of processor is referred to as a microprocessor. A computer operating system, which, typically, is software executed by CPU on a computer, enables and facilitates users to access and operate computer information technology and resources. Common resources employed in information technology systems include: input and output mechanisms through which data may pass into and out of a computer; memory storage into which data may be saved; and processors by which information may be processed. Often information technology systems are used to collect data for later retrieval, analysis, and manipulation, commonly, which is facilitated through database software. Information technology systems provide interfaces that allow users to access and operate various system components. User Interface The function of computer interfaces in some respects is similar to automobile operation interfaces. Automobile operation interface elements such as steering wheels, gearshifts, and speedometers facilitate the access, operation, and display of automobile resources, functionality, and status. Computer interaction interface elements such as check boxes, cursors, menus, scrollers, and windows (collectively and commonly referred to as widgets) similarly facilitate the access, operation, and display of data and computer hardware and operating system resources, functionality, and status. Operation interfaces are commonly called user interfaces. Graphical user interfaces (GUIs) such as the Apple Macintosh Operating System's Aqua, Microsoft's Windows XP, or Unix's X-Windows provide a baseline and means of accessing and displaying information, graphically, to users. Networks Networks are commonly thought to comprise of the interconnection and interoperation of clients, servers, and intermediary nodes in a graph topology. It should be noted that the term “server” as used herein refers generally to a computer, other device, software, or combination thereof that processes and responds to the requests of remote users across a communications network. Servers serve their information to requesting “clients.” The term “client” as used herein refers generally to a computer, other device, software, or combination thereof that is capable of processing and making requests and obtaining and processing any responses from servers across a communications network. A computer, other device, software, or combination thereof that facilitates, processes information and requests, and/or furthers the passage of information from a source user to a destination user is commonly referred to as a “node.” Networks are generally thought to facilitate the transfer of information from source points to destinations. A node specifically tasked with furthering the passage of information from a source to a destination is commonly called a “router.” There are many forms of networks such as Local Area Networks (LANs), Pico networks, Wide Area Networks (WANs), Wireless Networks (WLANs), etc. For example, the Internet is generally accepted as being an interconnection of a multitude of networks whereby remote clients and servers may access and interoperate with one another. SUMMARY Although all of the aforementioned portable computing systems exist, no effective solution to securely access, execute, and process data is available in an extremely compact form. Currently, PDAs, which are considered among the smallest portable computing solution, are bulky, provide uncomfortably small user interfaces, and require too much power to maintain their data. Current PDA designs are complicated and cost a lot because they require great processing resources to provide custom user interfaces and operating systems. Further, current PDAs are generally limited in the amount of data they can store or access. No solution exists that allows users to employ traditional large user interfaces they are already comfortable with, provides greater portability, provides greater memory footprints, draws less power, and provides security for data on the device. As such, the disclosed tunneling client access point (TCAP) is very easy to use; at most it requires the user to simply plug the device into any existing and available desktop or laptop computer, through which, the TCAP can make use of a traditional user interface and input/output (I/O) peripherals, while the TCAP itself, otherwise, provides storage, execution, and/or processing resources. Thus, the TCAP requires no power source to maintain its data and allows for a highly portable “thumb” footprint. Also, by providing the equivalent of a plug-n-play virtual private network (VPN), the TCAP provides certain kinds of accessing of remote data in an easy and secure manner that was unavailable in the prior art. In accordance with certain aspects of the disclosure, the above-identified problems of limited computing devices are overcome and a technical advance is achieved in the art of portable computing and data access. An exemplary tunneling client access point (TCAP) includes a method to dispose a portable storage device in communication with a terminal. The method includes providing the memory for access on the terminal, executing processing instructions from the memory on the terminal to access the terminal, communicating through a conduit, and processing the processing instructions. In accordance with another embodiment, a portable tunneling storage processor is disclosed. The apparatus has a memory and a processor disposed in communication with the memory, and configured to issue a plurality of processing instructions stored in the memory. Also, the apparatus has a conduit for external communications disposed in communication with the processor, configured to issue a plurality of communication instructions as provided by the processor, configured to issue the communication instructions as signals to engage in communications with other devices having compatible conduits, and configured to receive signals issued from the compatible conduits. BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings illustrate various non-limiting, example, inventive aspects in accordance with the present disclosure: FIG. 1 is of a flow diagram illustrating embodiments of a tunneling client access point (TCAP); FIG. 2 is of a flow diagram illustrating embodiments of a system of tunneling client access point and access terminal interaction; FIG. 3 is of a flow diagram illustrating embodiments of engaging the tunneling client access point to an access terminal interaction; FIG. 4 is of a flow diagram illustrating embodiments of accessing the tunneling client access point and server through an access terminal; FIGS. 5-8 is of a flow diagram illustrating embodiments of facilities, programs, and/or services that the tunneling client access point and server may provide to the user as accessed through an access terminal; FIG. 9 is of a block diagram illustrating embodiments of a tunneling client access point server controller; FIG. 10 is of a block diagram illustrating embodiments of a tunneling client access point controller; The leading number of each reference number within the drawings indicates the first figure in which that reference number is introduced. As such, reference number 101 is first introduced in FIG. 1. Reference number 201 is first introduced in FIG. 2, etc. DETAILED DESCRIPTION Topology FIG. 1 illustrates embodiments for a topology between a tunneling client access point (TCAP) (see FIG. 10 for more details on the TCAP) and TCAP server (TCAPS) (see FIG. 9 for more details on the TCAPS). In this embodiment, a user 133a may plug-in a TCAP into any number of access terminals 127 located anywhere. Access terminals (ATs) may be any number of computing devices such as servers, workstations, desktop computers, laptops, portable digital assistants (PDAs), and/or the like. The type of AT used is not important other than the device should provide a compatible mechanism of engagement to the TCAP 130 and provide an operating environment for the user to engage the TCAP through the AT. In one embodiment, the TCAP provides a universal serial bus (USB) connector through which it may plug into an AT. In other embodiment, the TCAP may employ Bluetooth, WiFi and/or other wireless connectivity protocols to connect with ATs that are also so equipped. In one embodiment, the AT provides Java and/or Windows runtime environments, which allows the TCAP to interact with the input/output mechanisms of the AT. See FIG. 9 for more details and embodiments on the types of connections that may be employed by the TCAP. Once the TCAP has engaged with an AT, it can provide the user with access to its storage and processing facilities. If the AT is connected to a communication network 113, the TCAP may then communicate beyond the AT. In one embodiment, the TCAP can provide extended storage and/or processing resources by engaging servers 110, 115, 120, which have access to and can provide extended storage 105 to the TCAP through the AT. In one embodiment, a single server and storage device may provide such TCAP server support. In another embodiment, server support is provided over a communications network, e.g., the Internet, by an array of front-end load-balancing servers 120. These servers can provide access to storage facilities within the servers or to remote storage 105 across a communications network 113b, c (e.g., a local area network (LAN)). In such an embodiment, a backend server 110 may offload the front-end server with regard to data access to provide greater throughput. For purposes of load balancing and/or redundancy, a backup server 115 may be similarly situated to provide for access and backup in an efficient manner. In such an embodiment, the back-end servers may be connected to the front-end servers through a communications network 113b (e.g., wide area network (WAN)). The backend servers 110, 115 may be connected to the remote storage 105 through a communications network 113c as well (e.g., a high speed LAN, fiber-channel, and/or the like). Thus, to the user 133a, the contents of the TCAP 130 appear on the AT as being contained on the TCAP 125 even though much of the contents may actually reside on the servers 115, 120 and/or the servers' storage facilities 105. In these ways, the TCAP “tunnels” data through an AT. The data may be provided through the AT's I/O for the user to observe without it actually residing on the AT. Also, the TCAP may tunnel data through an AT across a communications network to access remote servers without requiring its own more complicated set of peripherals and I/O. TCAP and AT Interaction FIG. 2 illustrates embodiments for a system of tunneling client access point (TCAP) (see FIG. 10 for more details on the TCAP) and access terminal interaction. FIG. 2 provides an overview for TCAP and AT interaction and subsequent figures will provide greater detail on elements of the interaction. In this embodiment, a user engages the TCAP 201. For example, the user may plug the TCAP into an AT via the AT's USB port. Thereafter the user is presented with a login prompt 205 on the AT's display mechanism, e.g., on a video monitor. After a user successfully logs in (for example by providing a user name and password) 204, the TCAP can then accept user inputs from the AT and its peripherals (the TCAP can then also provide output to the user via the AT's peripherals). The user may employ the AT's input peripherals as user input devices that control actions on the TCAP. Depending on the user's actions 215, the TCAP can be used by the AT as a storage device from which it can access and store data and programs 225. For example, if the user takes the action of opening a file from the TCAP's memory, e.g., by double clicking on an icon when the TCAP is mounted as a USB drive on the AT, then the AT may treat the TCAP as a memory device and retrieve information from the TCAP 225. If the user's action 215 is one that is directed at executing on the TCAP 215, then the AT will not be involved in any execution. For example, if the user drops an icon representing a graphics file onto a drag-and-drop location visually representing the TCAP, then the file may be copied to the TCAP where it will process and spool the file for sending the graphics file to be printed at a remote location. In such a case, all of the requirements to process and spool the file are handled by the TCAP's processor and the AT would only be used as a mechanism for user input and output and as a conduit through which the TCAP may send files. Regardless of if there is an action 215 to execute on the TCAP 220 or to access or store data on the TCAP 225, the AT is used to display the status of any actions 230. At any time the user may select to terminate TCAP related facilities executing either on the AT, a backend server, on the TCAP itself, and/or the like 235. In one embodiment, the user may select a quit option that is displayed on the AT's screen. In another embodiment, the user may simply disengage the TCAP from the AT by severing the connection (e.g., turning power off, physically pulling the device off the AT, turning off wireless transmissions, and/or the like). It should be noted that such abrupt severing may result in the loss of data, file corruption, etc. if the TCAP has not saved data that is on the AT or on some remote server, however, if the TCAP is employing flash like memory, its contents should remain intact. If there is no instruction signal to terminate the TCAP 235, execution will continue and the TCAP will continue to take and look for input from the user. Of course if the TCAP has been set to perform certain actions, those actions will continue to execute, and the TCAP may respond to remote servers when it is communicating with them through the AT. When the user issues a terminate signal 235, then the TCAP will shut down by saving any data to the TCAP that is in the AT's memory and then terminating any programs executing on both the AT and TCAP that were executed by and/or from the TCAP 240. If no activities are taking place on the TCAP and all the data is written back to the TCAP 240, then the TCAP may optionally unmount itself from the AT's file-system 245. At this point, if there is a TCAP I/O driver executing on the AT, that driver may be terminated as triggered by the absence of the TCAP at a mount point 250. After the TCAP is unmounted and/or the TCAP I/O driver is terminated, it is safe to disengage the TCAP from the AT. TCAP and AT Interaction FIG. 3 illustrates embodiments engaging the tunneling client access point to an access terminal interaction. Examples of engaging the TCAP 301 with an AT were discussed above in FIG. 1 127, 130, 133a and FIG. 2 201. In one embodiment, the TCAP 130 is engaged with an access terminal 327, 305. As mentioned in FIG. 1, the TCAP is capable of engaging with ATs using a number of mechanisms. In one embodiment, the TCAP has a USB connector for plugging into an AT, which acts as a conduit for power and data transfer. In another embodiment, the TCAP may use Bluetooth to establish a wireless connection with a number of ATs. In another embodiment, the TCAP may employ WiFi. In yet another embodiment, the TCAP may employ multiple communications mechanisms. It should be noted, with some wireless mechanisms like Bluetooth and WiFi, simply coming into proximity with an AT that is configured for such wireless communication may result in the TCAP engaging with and establish a communications link with the AT. In one embodiment, the TCAP has a “connect” button that will allow such otherwise automatically engaging interactions take place only if the “connect” button is engaged by a user. Such an implementation may provide greater security for users (see FIG. 10 for more details on the TCAP). After being engaged 305, the TCAP will then power on. In an embodiment requiring a direct connection, e.g., USB, simply plugging the TCAP into the AT provides power. In a wireless embodiment, the TCAP may be on in a lower powered state or otherwise turned on by engaging the connect button as discussed above. In such an embodiment, the TCAP can employ various on-board power sources (see FIG. 10 for more details on the TCAP). The TCAP then may load its own operating system 315. The operating system can provide for interaction with the AT. In one embodiment, a Java runtime is executed on the TCAP, and Java applets communicate with the AT through Java APIs. In another embodiment, a driver is loaded onto the AT, and the on-TCAP Java operating system applets communicate to and through the AT via the driver running on the AT, wherein the driver provides an API through and to which messages may be sent. After engaging with the AT, the TCAP can provide its memory space to the AT 320. In one embodiment, the TCAP's memory is mapped and mounted as a virtual disk drive 125 storage 325. In this manner, the TCAP may be accessed and manipulated as a standard storage device through the AT's operating system. Further, the TCAP and in some cases the AT can determine if the AT is capable of accessing program instructions stored in the TCAP's memory 330. In one embodiment, the AT's operating system looks to auto-run a specified file from any drive as it mounts. In such an embodiment, the TCAP's primary interface may be specified in such a boot sequence. For example, under windows, an autorun.inf file can specify the opening of a program from the TCAP by the AT; e.g., OPEN=TCAP.EXE. Many operating systems are capable of at least accessing the TCAP as a USB memory drive 330 and mounting its contents as a drive, which usually becomes accessible in file browsing window 125. If the TCAP does not mount, the AT's operating system will usually generate an error informing the user of a mounting problem. If the AT is not capable of executing instruction from the TCAP, a determination is made if an appropriate driver is loaded on the AT to access the TCAP 335. In one embodiment, the TCAP can check to see if an API is running on the AT. For example, the TCAP provide an executable to be launched, e.g., as specified through autorun.inf, and can establish communications through its connection to the AT, e.g., employing TCP/IP communications over the USB port. In such an embodiment, the TCAP can ping the AT for the program, and if an acknowledgement is received, the TCAP has determined that proper drivers and APIs exist. If no such API exists, the TCAP may launch a driver installation program for the AT as through an autorun.inf. In an alternative embodiment, if nothing happens, a user may double click onto an installer program that is stored on the mounted TCAP 342, 340. It should be noted, that although the TCAP's memory space may be mounted, certain areas of the TCAP may be inaccessible until there is an authorization. For example, certain areas and content on the TCAP may be encrypted. It should be noted that any such access terminal modules that drive AT and TCAP interaction may be saved onto the TCAP by copying the module to a mounted TCAP. Nevertheless, if the AT is capable of accessing program instructions in TCAP memory 330, a TCAP driver is loaded on the AT 335, and/or the user engages a program in the TCAP memory 340, then the AT can execute program instructions from the TCAP's memory, which allows the TCAP to use the AT's I/O and allowing the user to interface with TCAP facilities 345. It should be noted that some ATs may not be able to mount the TCAP at all. In such an instance, the user may have to install the TCAP drivers by downloading them from a server on the Internet, loading them from a diskette or CD, and/or the like. Once the TCAP is engaged to the AT 301, execution may continue 398. TCAP and AT Interaction FIG. 4 illustrates embodiments accessing the tunneling client access point and server through an access terminal. Upon engaging the TCAP to the AT as described in FIG. 3 301, 398, the user may then go on to access the TCAP and its services 498. It should be noted that users may access certain unprotected areas of the TCAP once it has been mounted, as described in FIG. 3. However, to more fully access the TCAP's facilities, the user may be prompted to either login and/or registration window 205a to access the TCAP and its services, which may be displayed on the AT 405. It is important to note that in one embodiment, the execution of the login and/or registration routines are handled by the TCAP's processor. In such an embodiment, the TCAP may run a small Web server providing login facilities, and connect to other Web based services through the AT's connection to the Internet. Further, the TCAP may employ a basic Web browsing core engine by which it may connect to Web services through the AT's connection to a communications network like the Internet. For purposes of security, in one embodiment, the TCAP may connect to a remote server by employing a secure connection, e.g., HTTPS, VPN, and/or the like. Upon displaying a login window 405, e.g., 205a, the user may select to register to access the TCAP and its services, or they may simply log in by providing security verification. In one example, security authorization may be granted by simply providing a user and password as provided through a registration process. In another embodiment, authorization may be granted through biometric data. For example, the TCAP may integrate a fingerprint and/or heat sensor IC into its housing. Employing such a device, and simply by providing one's finger print by laying your finger to the TCAP's surface, would provide the login facility with authorization if the user's finger print matches one that was stored during the registration process. If the user does not attempt to login 415, i.e., if the user wishes to register to use the TCAP and its services, then the TCAP can determine if the AT is online 420. This may be accomplished in a number of ways. In one embodiment, the TCAP itself may simply ping a given server and if acknowledgement of receipt is received, the TCAP is online. In another embodiment, the TCAP can query for online status by engaging the AT through the installed APIs. If the AT is not online, then the user may be presented with an error message 425. Thus, if a user does not have a login, and does not have the ability to register, then restricted areas of the TCAP will remain unavailable. Thereafter, flow can continue 498 and the user may have another opportunity to login and/or register. In one embodiment as a login integrity check, the TCAP keeps track of the number of failed attempts to login and/or register and may lock-out all further access if a specified number of failed attempts occurs. In one embodiment, the lockdown may be permanent by erasing all data on the TCAP. In another embodiment, the TCAP will disallow further attempts for a specified period of time. If the user is attempting to register 415, and the AT is online 420, then the user map provide registration information 440 into a screen form 440a. Registration information fields may require a user's name, address, email address, credit card information, biometric information (e.g., requiring the user to touch a biometric fingerprint IC on the TCAP), and/or the like. The TCAP may determine if all the information was provided as required for registration and may query backend servers to determine if the user information is unique 445. If the user did not properly fill out the registration information or if another user is already registered, the TCAP can provided an error message to such effect. Also, both the TCAP and its back-end servers may make log entries tracking such failed attempts for purposes of defending against fraud and/or security breaches. The user may then modify the registration information 440 and again attempt to register. Similarly to the login integrity checks, the TCAP can lockout registration attempts if the user fails to register more than some specified number of times. Upon providing proper registration information 445 or proper login authentication 415, the TCAP can query backend servers to see if the user is registered. In one embodiment, such verification may be achieved by sending a query to the servers to check its database for the authorization information and/or for duplicate registrations. The servers would then respond providing an acknowledgment of proper registration and authorization to access data on the backend servers. If the users are not registered on the backend servers 430, then the TCAP can provide an error message to the user for display on the AT to such effect 435. In an alternative embodiment, the registration information may be stored on the TCAP itself. In one embodiment, the registration would be maintained in encrypted form. Thus, the user's login information may be checked relative to the information the TCAP itself, and if there is a match, access may be granted, otherwise an error message will be displayed 435. The TCAP may then continue 498 to operate as if it were just engaged to the AT. If the user is confirmed to be registered 430, then the TCAP may provide options for display 453, 453a. Depending on the context and purpose of a particular TCAP, the options may vary. For example, the a screen 453a may provide the user with the options to access data either online or offline. The user might simply click on a button and gain secure access to such data that may be decrypted by the TCAP. In one embodiment, the TCAP will determine if the AT is online 455. If this was already determined 420, this check 455 may be skipped. If the AT is online 455, optionally, the TCAP determines if the user wishes to synchronize the contents of the TCAP with storage facilities at the backend server 470. In one embodiment, the user may designate that such synchronization is to always take place. If synchronization is specified 470, then the TCAP will provide and receive updated data to and from the backend servers, overwriting older data with updated versions of the data 475. If the AT is online 455 and/or after any synchronization 475, the TCAP may provide the user with all of its service options as authorized by the account and programs available on the TCAP and at the backend server 480. Once again, these facilities, programs, and/or services may vary greatly depending on the context and deployment requirements of the user. The options to be presented to the user from the TCAP or the TCAP services from the backend server, as displayed through the TCAP onto the AT's display 480, are myriad and some example embodiments are provided in FIGS. 5-8. Upon presenting the user with the options, the user is then able to access, execute, store data and programs on the TCAP and on the remote server 485. All areas of the TCAP and services are then open, including any encrypted data areas. If the AT is not online 455, the TCAP may provide options for the user not including online services 460. In one embodiment, the online options that may be presented on the AT display will be dimmed and/or omitted to reflect the lack of accessibility. However, the user will be able to access, execute, store data and programs on the TCAP, including any encrypted data areas 465. TCAP Facilities and Services FIGS. 5-8 illustrate embodiments of facilities, programs, and/or services that the tunneling client access point and server may provide to the user as accessed through an AT. Any particular set of facilities may have a myriad of options. The options and the general nature of the facilities provided on any particular TCAP are dependant upon the requirements of a given set of users. For example, certain groups and/or agencies may require TCAPS to be targeted towards consumer photographs, and may employ TCAPs to further that end. Other groups may require high security facilities, and tailor the TCAPs accordingly. In various environments, an organization may wish to provide a secure infrastructure to all of its agents for securely accessing the organization's data from anywhere and such an organization could tailor the TCAPs contents to reflect and respond to its needs. By providing a generalized infrastructure on the TCAP backend servers and within the TCAP by using a generalized processor, the TCAPs may be deployed in numerous environments. In one particular embodiment as in FIG. 5, the TCAP provides facilities to access, process, and store email, files, music, photos and videos through the TCAP. Upon engaging 101 of FIG. 1 the TCAP 130 to an AT 307, the TCAP will mount and display through the AT's file browser window 125 of FIG. 1. As has already described, in the case where the AT has no TCAP driver software, the user may double click on the installer software stored on the TCAP 507. Doing so will launch the installer software from the TCAP's memory to execute on the AT, and the user may be presented with a window to confirm the desire to install the TCAP software onto the AT 507. Upon confirming the install 507, the software will install on the AT and the user will be asked to wait as they are apprised of the install progress 509. Upon installation, the TCAP front-end software may execute and present the user with various options in various and fanciful interface formats 511, 460, 480 of FIG. 4. In one embodiment, these user interfaces and programs are Java applications that may execute on the AT and a present Java runtime. In an alternative embodiment, a small applet may run on the AT, but all other activities may execute on the TCAP's processor, which would use the AT display only as a display terminal. In the embodiment where the TCAP executes program instructions, the TCAP may be engaged to receive commands and execute by receiving a signal from the access terminal driver instructing it to execute certain program files or, alternatively, looking to default location and executing program instructions. In yet another embodiment, the TCAP may obtain updated interfaces and programs from a backend server for execution either on the TCAP itself and/or the AT; this may be done by synchronization with the backend server and checking for updates of specified files at the backend server. By engaging the user interface, perhaps by clicking on a button to open the TCAP facilities and services 511, the interface may further unfurl to present options to access said facilities and services 513. Here, the interface may reflect ownership of the TCAP by providing a welcome screen and showing some resources available to the user; for example, a button entitled “My Stuff” may serve as a mechanism to advance the user to a screen where they may access their personal data store. At this point the user may attempt to login to access their data by engaging an appropriate button, which will take them to a screen that will accept login information 519. Alternatively, the user may also register if it is their first time using the TCAP by selecting an appropriate button, which will advance the user to a registration screen 515 wherein the user may enter their name, address, credit card information, etc. Upon successfully providing registration information, the user may be prompted for response to further solicitations on a follow-up screen 517. For example, depending on the services offered for a particular TCAP, the user may be provided certain perks like 5 MB of free online storage on a backend server, free photographic prints, free email access, and/or the like 517. After the user is prompted to login 518 and successfully provides proper login information 519, or after successfully registering 515 and having responded to any solicitations 517, the user may be provided with general options 521 to access data stored on the TCAP itself 522 or in their online account 520 maintained on a backend server. For example, if the user selects the option to access their online storage 520, they may be presented with more options to interact with email, files, music, photos and videos that are available online 523. Perhaps if the user wished to check their email, the user might select to interact with their email, and a screen allowing them to navigate through their email account(s) would be presented 525. Such online access to data may be facilitated through http protocols whereby the TCAP applications send and receive data through http commands across a communications network interacting with the backend servers and/or other servers. Any received results may be parsed and imbedded in a GUI representation of a Java application. For example, the email facility may run as a Java applet 525 and may employ a POP mail protocol to pull data from a specified mail server to present to the user. Similarly, many other facilities may be engaged by the user through the TCAP. In one embodiment, the user may drag 508 a file 506 onto a drag-and-drop zone 505 that is presented on the TCAP interface. Upon so doing, various drag-and-drop options may unfurl and present themselves to the user 550. It should be noted that the file may come from anywhere, i.e., from the AT, the TCAP, and/or otherwise. For example, upon dragging and dropping a graphics file, a user may be prompted with options to order prints, upload the file to an online storage space, save the file to the TCAP's memory space, cancel the action, and/or the like 550. If the user sends the file for storage, or otherwise wishes to see and manage their data, an interface allowing for such management may be presented 555. The interface may organize and allow access to general data, picture, and music formats 554, provide usage statistics (e.g., free space, capacity, used space, etc.) 553, provide actions to manipulate and organize the data 552, provide status on storage usage on the TCAP 551 and online 549, and/or the like. Should the user engage a user interface element indicating the wish to manipulate their picture data 548, the TCAP interface will update to allow more specific interaction with the user's photos 557. In such a screen, the user may select various stored pictures and then indicate a desire to order photo prints by engaging the appropriate user interface element 558. Should the user indicate their desire for prints 558, they will be presented with an updated interface allowing the specification of what graphics files they wish to have printed 559. In one embodiment, the users may drag-and-drop files into a drop zone, or otherwise engage file browsing mechanisms 560 that allow for the selection of desired files. Upon having identified the files for prints 559, a user may be presented with an interface allowing for the selection of print sizes and quantities 561. After making such specifications, the user may be required to provide shipping information 563 and information for payments 565. After providing the billing information to a backend server for processing and approval, the user may be presented with a confirmation interface allowing for editing of the order, providing confirmation of costs, and allowing for submission of a final order for the selected prints 567. Upon submitting the order, the TCAP will process the files for spooling to a backend server that will accept the order and files, which will be developed as prints and the user's account will be charged accordingly. In one embodiment, all of the above order and image processing operations occur and execute on the TCAP CPU. For example, the TCAP may employ various rendering technologies, e.g., ghostscript, to allow it to read and save PDFs and other media formats. FIG. 6 goes on to illustrate embodiments and facets of the facilities of FIG. 5. The TCAP interface allows the user to perform various actions at any given moment. As has already been discussed in FIG. 5, the user may drag 508 a file 506 onto a drag and drop zone 505 so as to provide the file to the TCAP for further manipulation. As in 550 of FIG. 5, the user may be presented with various options subsequent to a drag-and-drop operation. Also, the TCAP interface may provide visual feedback that files have been dropped in the drop zone by highlighting the drop zone 505b. Should the user wish, they may close the TCAP interface by engaging a close option 633. Also, the ability to change and/or update their personal information may be accessed through the TCAP interface 616, which would provide a form allowing the user to update their registration information 630. In one embodiment, should the user forget their login information, they may request login help 635 and the TCAP will send their authorization information to the last known email address and inform the user of same 640. Also, the TCAP interface may provide help facilities that may be accessed at any time by simply engaging a help facility user interface element 617. So doing will provide the user with help screen information as to how to interact with the TCAP's facilities 625. Upon providing proper login information 619 and logging-in 619, the user may be presented with a welcome screen with various options to access their data 621 as has already been discussed in FIG. 5, 521. By engaging a user interface element to access online storage 620, the user may be presented with various options to interact with online storage 623, 523 of FIG. 5. Should the user wish to interact with data on the TCAP itself, the user may indicate so by engaging the appropriate user interface option 622. So doing will provide the user with further options related to data stored on the TCAP 655. The user may engage an option to view the storage contents 658 and the TCAP interface will provide a listing of the contents 662, which may be manipulated through selection and drag-and-drop operations with the files. In one embodiment, the user may order prints of photos 657 from files that are on the TCAP itself. As discussed in FIG. 5, the user may select files for which they desire prints 660. Here, the selected files will first be processed by the TCAP in preparation for sending to backend servers and file manipulations 670. The user may specify various attributes regarding the prints they desire, e.g., the size, number, cropping, red-eye correction, visual effects, and/or the like 661. In one embodiment, such processing occurs on the TCAP processor, while in other embodiments such processing can take place on the AT or backend server. Once again, the user may provide a shipping address 663, and make a final review to place the order 667. Upon committing to the order 667, the processed files are uploaded to the backend servers that will use the files to generate prints 690. A confirmation screen may then be provided to the user with an order number and other relevant information 695. FIG. 7 goes on to illustrate embodiments and facets of the facilities of FIGS. 5-6 as may apply in different environments. As is demonstrated, the look and feel of the TCAP interface is highly malleable and can serve in many environments. FIG. 7 illustrates that even within a single organization, various environments might benefit from TCAPs and services tailored to serve such environments 733b-d. In this case TCAPs can serve in consumer 733b, industry trade 733c, corporate 733d, and/or the like environments. As has already been discussed, initially in any of the environments, after engaging the TCAP to an AT, the user may be prompted to install the TCAP interface 705 and informed of the installation procedure 710. The user may then be presented with the installed TCAP interface 715, which may be activated by engaging an interface element to unfurl the interface, e.g., in this case by opening the top to a can of soda 717. Opening the interface will present the user with various options as 720, as has already been discussed in FIGS. 5-6. Similarly the user may login 725 or make a selection to register for various TCAP services and provide the requisite information in the provided form 730. Upon registering and/or logging-in 725, various options may be presented based upon the configuration of the TCAP. For example, if the TCAP was configured and tailored for consumers, then upon logging in 725 the consumer user might be presented 733a-b with various consumer related options 740. Similarly, if the TCAP were tailored for 733a, c the trade industry or 733a, d the corporate environment, options specific to the trade industry 770 and corporate environment 760 may be presented. In one embodiment, an organization wishing to provide TCAPs to consumers might provide options 740 for free music downloads 743, free Internet radio streaming 748, free news (e.g., provided through an RSS feed from a server) 766, free photo printing 750, free email 740, free coupons 742, free online storage 741, and/or the like. Users could further engage such services (e.g., clicking free music file links for downloading to the TCAP, by ordering prints 750, etc. For example, the user may select files on the TCAP 750, select the types of photos they would like to receive 752, specify a delivery address 754, confirm the order 756 all of which will result in the TCAP processing the files and uploading them to the backend servers for generation of prints (as has already been discussed in FIGS. 5-6). In another embodiment, an organization wishing to provide TCAPs to a trade industry might provide options 770 for advertising 780, events 775, promotions 772, and/or the like. It is important to note that information regarding such options may be stored either on the TCAP or at a backend server. In one embodiment, such information may be constantly synchronized from the backend servers to the TCAPs. This would allow an organization to provide updates to the trade industry to all authorized TCAP “key holders.” In such an embodiment, the user may be presented with various advertising related materials for the organization, e.g., print, television, outdoor, radio, web, and/or the like 780. With regard to events, the user may be presented with various related materials for the organization, e.g., trade shows, music regional, sponsorship, Web, and/or the like 775. With regard to promotions, the user may be presented with various related materials for the organization, e.g., rebates, coupons, premiums, and/or the like 772. In another embodiment, an organization wishing to provide TCAPs to those in the corporate environment and might provide options relating to various corporate entities 760. Selecting any of the corporate entities 760 may provide the user with options to view various reports, presentations, and/or the like, e.g., annual reports, 10K reports, and/or the like 765. Similarly, the reports may reside on the TCAP and/or the corporate TCAP can act as a security key allowing the user to see the latest corporate related materials from a remote backend server. FIG. 8 goes on to illustrate embodiments and facets of the facilities of FIGS. 5-7 as may apply in different environments. FIG. 8 illustrates that TCAPs may serve to provide heightened security to any environment. As has been discussed in previous figures, users may engage the TCAP interface 805 to access various options 810. The TCAP interface is highly adaptable and various services may be presented within it. For example, a stock ticker may be provided as part of the interface in a financial setting 810. Any number of live data feeds may dynamically update on the face of the interface. Upon logging-in 815 or registering a new account 820, the user may be informed that communications that are taking place are secured 825. In one embodiment, various encryption formats may be used by the TCAP to send information securely to the backend servers. It is important to note that in such an embodiment, even if data moving out of the TCAP and across the AT were captured at the AT, such data would not be readable because the data was encrypted by the TCAP's processor. As such, the TCAP acts as a “key” and provides a plug-and-play VPN to users. Such functionality, heretofore, has been very difficult to set up and/or maintain. In this way, all communications, options presented and views of user data are made available only to the TCAP with the proper decryption key. In heightened security environments, display of TCAP data is provided on the screen only in bitmapped format straight to the video memory of the AT and, therefore, is not stored anywhere else on the AT. This decreases the likelihood of capturing sensitive data. As such, the user may access their data on the TCAP and/or online 830 in a secure form whereby the user may navigate and interact with his/her data and various services 835 in a secure manner. Tunneling Client Access Point Server Controller FIG. 9 illustrates one embodiment incorporated into a tunneling client access point server (TCAPS) controller 901. In this embodiment, the TCAP controller 901 may serve to process, store, search, serve, identify, instruct, generate, match, and/or update data in conjunction with a TCAP (see FIG. 10 for more details on the TCAP). TCAPS act as backend servers to TCAPs, wherein TCAPS provide storage and/or processing resources to great and/or complex for the TCAP to service itself. In effect, the TCAPS transparently extend the capacity of a TCAP. In one embodiment, the TCAPS controller 901 may be connected to and/or communicate with entities such as, but not limited to: one or more users from user input devices 911; peripheral devices 912; and/or a communications network 913. The TCAPS controller may even be connected to and/or communicate with a cryptographic processor device 928. A TCAPS controller 901 may be based on common computer systems that may comprise, but are not limited to, components such as: a computer systemization 902 connected to memory 929. Computer Systemization A computer systemization 902 may comprise a clock 930, central processing unit (CPU) 903, a read only memory (ROM) 906, a random access memory (RAM) 905, and/or an interface bus 907, and most frequently, although not necessarily, are all interconnected and/or communicating through a system bus 904. Optionally, a cryptographic processor 926 may be connected to the system bus. The system clock typically has a crystal oscillator and provides a base signal. The clock is typically coupled to the system bus and various clock multipliers that will increase or decrease the base operating frequency for other components interconnected in the computer systemization. The clock and various components in a computer systemization drive signals embodying information throughout the system. Such transmission and reception of signals embodying information throughout a computer systemization may be commonly referred to as communications. These communicative signals may further be transmitted, received, and the cause of return and/or reply signal communications beyond the instant computer systemization to: communications networks, input devices, other computer systemizations, peripheral devices, and/or the like. Of course, any of the above components may be connected directly to one another, connected to the CPU, and/or organized in numerous variations employed as exemplified by various computer systems. The CPU comprises at least one high-speed data processor adequate to execute program modules for executing user and/or system-generated requests. The CPU may be a microprocessor such as AMD's Athlon, Duron and/or Opteron; IBM and/or Motorola's PowerPC; Intel's Celeron, Itanium, Pentium and/or Xeon; and/or the like processor(s). The CPU interacts with memory through signal passing through conductive conduits to execute stored program code according to conventional data processing techniques. Such signal passing facilitates communication within the TCAPS controller and beyond through various interfaces. Should processing requirements dictate a greater amount speed, mainframe and super computer architectures may similarly be employed. Interface Adapters Interface bus(ses) 907 may accept, connect, and/or communicate to a number of interface adapters, conventionally although not necessarily in the form of adapter cards, such as but not limited to: input output interfaces (I/O) 908, storage interfaces 909, network interfaces 910, and/or the like. Optionally, cryptographic processor interfaces 927 similarly may be connected to the interface bus. The interface bus provides for the communications of interface adapters with one another as well as with other components of the computer systemization. Interface adapters are adapted for a compatible interface bus. Interface adapters conventionally connect to the interface bus via a slot architecture. Conventional slot architectures may be employed, such as, but not limited to: Accelerated Graphics Port (AGP), Card Bus, (Extended) Industry Standard Architecture ((E)ISA), Micro Channel Architecture (MCA), NuBus, Peripheral Component Interconnect (Extended) (PCI(X)), Personal Computer Memory Card International Association (PCMCIA), and/or the like. Storage interfaces 909 may accept, communicate, and/or connect to a number of storage devices such as, but not limited to: storage devices 914, removable disc devices, and/or the like. Storage interfaces may employ connection protocols such as, but not limited to: (Ultra) (Serial) Advanced Technology Attachment (Packet Interface) ((Ultra) (Serial) ATA(PI)), (Enhanced) Integrated Drive Electronics ((E)IDE), Institute of Electrical and Electronics Engineers (IEEE) 1394, fiber channel, Small Computer Systems Interface (SCSI), Universal Serial Bus (USB), and/or the like. Network interfaces 910 may accept, communicate, and/or connect to a communications network 913. Network interfaces may employ connection protocols such as, but not limited to: direct connect, Ethernet (thick, thin, twisted pair 10/100/1000 Base T, and/or the like), Token Ring, wireless connection such as IEEE 802.11a-x, and/or the like. A communications network may be any one and/or the combination of the following: a direct interconnection; the Internet; a Local Area Network (LAN); a Metropolitan Area Network (MAN); an Operating Missions as Nodes on the Internet (OMNI); a secured custom connection; a Wide Area Network (WAN); a wireless network (e.g., employing protocols such as, but not limited to a Wireless Application Protocol (WAP), I-mode, and/or the like); and/or the like. A network interface may be regarded as a specialized form of an input output interface. Further, multiple network interfaces 910 may be used to engage with various communications network types 913. For example, multiple network interfaces may be employed to allow for the communication over broadcast, multicast, and/or unicast networks. Input Output interfaces (I/O) 908 may accept, communicate, and/or connect to user input devices 911, peripheral devices 912, cryptographic processor devices 928, and/or the like. I/O may employ connection protocols such as, but not limited to: Apple Desktop Bus (ADB); Apple Desktop Connector (ADC); audio: analog, digital, monaural, RCA, stereo, and/or the like; IEEE 1394a-b; infrared; joystick; keyboard; midi; optical; PC AT; PS/2; parallel; radio; serial; USB; video interface: BNC, composite, digital, Digital Visual Interface (DVI), RCA, S-Video, VGA, and/or the like; wireless; and/or the like. A common output device is a video display, which typically comprises a Cathode Ray Tube (CRT) or Liquid Crystal Display (LCD) based monitor with an interface (e.g., DVI circuitry and cable) that accepts signals from a video interface. The video interface composites information generated by a computer systemization and generates video signals based on the composited information in a video memory frame. Typically, the video interface provides the composited video information through a video connection interface that accepts a video display interface (e.g., a DVI connector accepting a DVI display cable). User input devices 911 may be card readers, dongles, finger print readers, gloves, graphics tablets, joysticks, keyboards, mouse (mice), trackballs, trackpads, retina readers, and/or the like. Peripheral devices 912 may be connected and/or communicate to I/O and/or other facilities of the like such as network interfaces, storage interfaces, and/or the like. Peripheral devices may be audio devices, cameras, dongles (e.g., for copy protection, ensuring secure transactions with a digital signature, and/or the like), external processors (for added functionality), goggles, microphones, monitors, network interfaces, printers, scanners, storage devices, video devices, visors, and/or the like. It should be noted that although user input devices and peripheral devices may be employed, the TCAPS controller may be embodied as an embedded, dedicated, and/or headless device, wherein access would be provided over a network interface connection. Cryptographic units such as, but not limited to, microcontrollers, processors 926, interfaces 927, and/or devices 928 may be attached, and/or communicate with the TCAPS controller. A MC68HC16 microcontroller, commonly manufactured by Motorola Inc., may be used for and/or within cryptographic units. Equivalent microcontrollers and/or processors may also be used. The MC68HC16 microcontroller utilizes a 16-bit multiply-and-accumulate instruction in the 16 MHz configuration and requires less than one second to perform a 512-bit RSA private key operation. Cryptographic units support the authentication of communications from interacting agents, as well as allowing for anonymous transactions. Cryptographic units may also be configured as part of CPU. Other commercially available specialized cryptographic processors include VLSI Technology's 33 MHz 6868 or Semaphore Communications' 40 MHz Roadrunner 184. Memory Generally, any mechanization and/or embodiment allowing a processor to affect the storage and/or retrieval of information is regarded as memory 929. However, memory is a fungible technology and resource, thus, any number of memory embodiments may be employed in lieu of or in concert with one another. It is to be understood that a TCAPS controller and/or a computer systemization may employ various forms of memory 929. For example, a computer systemization may be configured wherein the functionality of on-chip CPU memory (e.g., registers), RAM, ROM, and any other storage devices are provided by a paper punch tape or paper punch card mechanism; of course such an embodiment would result in an extremely slow rate of operation. In a typical configuration, memory 929 will include ROM 906, RAM 905, and a storage device 914. A storage device 914 may be any conventional computer system storage. Storage devices may include a drum; a (fixed and/or removable) magnetic disk drive; a magneto-optical drive; an optical drive (i.e., CD ROM/RAM/Recordable (R), ReWritable (RW), DVD R/RW, etc.); and/or other devices of the like. Thus, a computer systemization generally requires and makes use of memory. Module Collection The memory 929 may contain a collection of program and/or database modules and/or data such as, but not limited to: operating system module(s) 915 (operating system); information server module(s) 916 (information server); user interface module(s) 917 (user interface); Web browser module(s) 918 (Web browser); database(s) 919; cryptographic server module(s) 920 (cryptographic server); TCAPS module(s) 935; and/or the like (i.e., collectively a module collection). These modules may be stored and accessed from the storage devices and/or from storage devices accessible through an interface bus. Although non-conventional software modules such as those in the module collection, typically, are stored in a local storage device 914, they may also be loaded and/or stored in memory such as: peripheral devices, RAM, remote storage facilities through a communications network, ROM, various forms of memory, and/or the like. Operating System The operating system module 915 is executable program code facilitating the operation of a TCAPS controller. Typically, the operating system facilitates access of I/O, network interfaces, peripheral devices, storage devices, and/or the like. The operating system may be a highly fault tolerant, scalable, and secure system such as Apple Macintosh OS X (Server), AT&T Plan 9, Be OS, Linux, Unix, and/or the like operating systems. However, more limited and/or less secure operating systems also may be employed such as Apple Macintosh OS, Microsoft DOS, Palm OS, Windows 2000/2003/3.1/95/98/CE/Millenium/NT/XP (Server), and/or the like. An operating system may communicate to and/or with other modules in a module collection, including itself, and/or the like. Most frequently, the operating system communicates with other program modules, user interfaces, and/or the like. For example, the operating system may contain, communicate, generate, obtain, and/or provide program module, system, user, and/or data communications, requests, and/or responses. The operating system, once executed by the CPU, may enable the interaction with communications networks, data, I/O, peripheral devices, program modules, memory, user input devices, and/or the like. The operating system may provide communications protocols that allow the TCAPS controller to communicate with other entities through a communications network 913. Various communication protocols may be used by the TCAPS controller as a subcarrier transport mechanism for interaction, such as, but not limited to: multicast, TCP/IP, UDP, unicast, and/or the like. Information Server An information server module 916 is stored program code that is executed by the CPU. The information server may be a conventional Internet information server such as, but not limited to Apache Software Foundation's Apache, Microsoft's Internet Information Server, and/or the. The information server may allow for the execution of program modules through facilities such as Active Server Page (ASP), ActiveX, (ANSI) (Objective-) C (++), Common Gateway Interface (CGI) scripts, Java, JavaScript, Practical Extraction Report Language (PERL), Python, WebObjects, and/or the like. The information server may support secure communications protocols such as, but not limited to, File Transfer Protocol (FTP); HyperText Transfer Protocol (HTTP); Secure Hypertext Transfer Protocol (HTTPS), Secure Socket Layer (SSL), and/or the like. The information server provides results in the form of Web pages to Web browsers, and allows for the manipulated generation of the Web pages through interaction with other program modules. After a Domain Name System (DNS) resolution portion of an HTTP request is resolved to a particular information server, the information server resolves requests for information at specified locations on a TCAPS controller based on the remainder of the HTTP request. For example, a request such as http://123.124.125.126/myInformation.html might have the IP portion of the request “123.124.125.126” resolved by a DNS server to an information server at that IP address; that information server might in turn further parse the http request for the “/myInformation.html” portion of the request and resolve it to a location in memory containing the information “myInformation.html.” Additionally, other information serving protocols may be employed across various ports, e.g., FTP communications across port 21, and/or the like. An information server may communicate to and/or with other modules in a module collection, including itself, and/or facilities of the like. Most frequently, the information server communicates with the TCAPS database 919, operating systems, other program modules, user interfaces, Web browsers, and/or the like. Access to TCAPS database may be achieved through a number of database bridge mechanisms such as through scripting languages as enumerated below (e.g., CGI) and through inter-application communication channels as enumerated below (e.g., C ORB A, WebObjects, etc.). Any data requests through a Web browser are parsed through the bridge mechanism into appropriate grammars as required by the TCAP. In one embodiment, the information server would provide a Web form accessible by a Web browser. Entries made into supplied fields in the Web form are tagged as having been entered into the particular fields, and parsed as such. The entered terms are then passed along with the field tags, which act to instruct the parser to generate queries directed to appropriate tables and/or fields. In one embodiment, the parser may generate queries in standard SQL by instantiating a search string with the proper join/select commands based on the tagged text entries, wherein the resulting command is provided over the bridge mechanism to the TCAPS as a query. Upon generating query results from the query, the results are passed over the bridge mechanism, and may be parsed for formatting and generation of a new results Web page by the bridge mechanism. Such a new results Web page is then provided to the information server, which may supply it to the requesting Web browser. Also, an information server may contain, communicate, generate, obtain, and/or provide program module, system, user, and/or data communications, requests, and/or responses. User Interface A user interface module 917 is stored program code that is executed by the CPU. The user interface may be a conventional graphic user interface as provided by, with, and/or atop operating systems and/or operating environments such as Apple Macintosh OS, e.g., Aqua, Microsoft Windows (NT/XP), Unix X Windows (KDE, Gnome, and/or the like), and/or the like. The user interface may allow for the display, execution, interaction, manipulation, and/or operation of program modules and/or system facilities through textual and/or graphical facilities. The user interface provides a facility through which users may affect, interact, and/or operate a computer system. A user interface may communicate to and/or with other modules in a module collection, including itself, and/or facilities of the like. Most frequently, the user interface communicates with operating systems, other program modules, and/or the like. The user interface may contain, communicate, generate, obtain, and/or provide program module, system, user, and/or data communications, requests, and/or responses. Web Browser A Web browser module 918 is stored program code that is executed by the CPU. The Web browser may be a conventional hypertext viewing application such as Microsoft Internet Explorer or Netscape Navigator. Secure Web browsing may be supplied with 128 bit (or greater) encryption by way of HTTPS, SSL, and/or the like. Some Web browsers allow for the execution of program modules through facilities such as Java, JavaScript, ActiveX, and/or the like. Web browsers and like information access tools may be integrated into PDAs, cellular telephones, and/or other mobile devices. A Web browser may communicate to and/or with other modules in a module collection, including itself, and/or facilities of the like. Most frequently, the Web browser communicates with information servers, operating systems, integrated program modules (e.g., plug-ins), and/or the like; e.g., it may contain, communicate, generate, obtain, and/or provide program module, system, user, and/or data communications, requests, and/or responses. Of course, in place of a Web browser and information server, a combined application may be developed to perform similar functions of both. The combined application would similarly affect the obtaining and the provision of information to users, user agents, and/or the like from TCAPS enabled nodes. The combined application may be nugatory on systems employing standard Web browsers. TCAPS Database A TCAPS database module 919 may be embodied in a database and its stored data. The database is stored program code, which is executed by the CPU; the stored program code portion configuring the CPU to process the stored data. The database may be a conventional, fault tolerant, relational, scalable, secure database such as Oracle or Sybase. Relational databases are an extension of a flat file. Relational databases consist of a series of related tables. The tables are interconnected via a key field. Use of the key field allows the combination of the tables by indexing against the key field; i.e., the key fields act as dimensional pivot points for combining information from various tables. Relationships generally identify links maintained between tables by matching primary keys. Primary keys represent fields that uniquely identify the rows of a table in a relational database. More precisely, they uniquely identify rows of a table on the “one” side of a one-to-many relationship. Alternatively, the TCAPS database may be implemented using various standard data-structures, such as an array, hash, (linked) list, struct, structured text file (e.g., XML), table, and/or the like. Such data-structures may be stored in memory and/or in (structured) files. In another alternative, an object-oriented database may be used, such as Frontier, ObjectStore, Poet, Zope, and/or the like. Object databases can include a number of object collections that are grouped and/or linked together by common attributes; they may be related to other object collections by some common attributes. Object-oriented databases perform similarly to relational databases with the exception that objects are not just pieces of data but may have other types of functionality encapsulated within a given object. If the TCAPS database is implemented as a data-structure, the use of the TCAPS database may be integrated into another module such as the TCAPS module. Also, the database may be implemented as a mix of data structures, objects, and relational structures. Databases may be consolidated and/or distributed in countless variations through standard data processing techniques. Portions of databases, e.g., tables, may be exported and/or imported and thus decentralized and/or integrated. In one embodiment, the database module 919 includes three tables 919a-c. A user accounts table 919a includes fields such as, but not limited to: a user name, user address, user authorization information (e.g., user name, password, biometric data, etc.), user credit card, organization, organization account, TCAP unique identifier, account creation data, account expiration date; and/or the like. In one embodiment, user accounts may be activated only for set amounts of time and will then expire once a specified date has been reached. An user data table 919b includes fields such as, but not limited to: a TCAP unique identifier, backup image, data store, organization account, and/or the like. A user programs table 919c includes fields such as, but not limited to: system programs, organization programs, programs to be synchronized, and/or the like. In one embodiment, user programs may contain various user interface primitives, which may serve to update TCAPs. Also, various accounts may require custom database tables depending upon the environments and the types of TCAPs a TCAPS may need to serve. It should be noted that any unique fields may be designated as a key field throughout. In an alternative embodiment, these tables have been decentralized into their own databases and their respective database controllers (i.e., individual database controllers for each of the above tables). Employing standard data processing techniques, one may further distribute the databases over several computer systemizations and/or storage devices. Similarly, configurations of the decentralized database controllers may be varied by consolidating and/or distributing the various database modules 919a-c. The TCAPS may be configured to keep track of various settings, inputs, and parameters via database controllers. A TCAPS database may communicate to and/or with other modules in a module collection, including itself, and/or facilities of the like. Most frequently, the TCAPS database communicates with a TCAPS module, other program modules, and/or the like. The database may contain, retain, and provide information regarding other nodes and data. Cryptographic Server A cryptographic server module 920 is stored program code that is executed by the CPU 903, cryptographic processor 926, cryptographic processor interface 927, cryptographic processor device 928, and/or the like. Cryptographic processor interfaces will allow for expedition of encryption and/or decryption requests by the cryptographic module; however, the cryptographic module, alternatively, may run on a conventional CPU. The cryptographic module allows for the encryption and/or decryption of provided data. The cryptographic module allows for both symmetric and asymmetric (e.g., Pretty Good Protection (PGP)) encryption and/or decryption. The cryptographic module may employ cryptographic techniques such as, but not limited to: digital certificates (e.g., X.509 authentication framework), digital signatures, dual signatures, enveloping, password access protection, public key management, and/or the like. The cryptographic module will facilitate numerous (encryption and/or decryption) security protocols such as, but not limited to: checksum, Data Encryption Standard (DES), Elliptical Curve Encryption (ECC), International Data Encryption Algorithm (IDEA), Message Digest 5 (MD5, which is a one way hash function), passwords, Rivest Cipher (RCS), Rijndael, RSA (which is an Internet encryption and authentication system that uses an algorithm developed in 1977 by Ron Rivest, Adi Shamir, and Leonard Adleman), Secure Hash Algorithm (SHA), Secure Socket Layer (SSL), Secure Hypertext Transfer Protocol (HTTPS), and/or the like. Employing such encryption security protocols, the TCAPS may encrypt all incoming and/or outgoing communications and may serve as node within a virtual private network (VPN) with a wider communications network. The cryptographic module facilitates the process of “security authorization” whereby access to a resource is inhibited by a security protocol wherein the cryptographic module effects authorized access to the secured resource. In addition, the cryptographic module may provide unique identifiers of content, e.g., employing and MD5 hash to obtain a unique signature for an digital audio file. A cryptographic module may communicate to and/or with other modules in a module collection, including itself, and/or facilities of the like. The cryptographic module supports encryption schemes allowing for the secure transmission of information across a communications network to enable a TCAPS module to engage in secure transactions if so desired. The cryptographic module facilitates the secure accessing of resources on TCAPS and facilitates the access of secured resources on remote systems; i.e., it may act as a client and/or server of secured resources. Most frequently, the cryptographic module communicates with information servers, operating systems, other program modules, and/or the like. The cryptographic module may contain, communicate, generate, obtain, and/or provide program module, system, user, and/or data communications, requests, and/or responses. TCAPS A TCAPS module 935 is stored program code that is executed by the CPU. The TCAPS affects accessing, obtaining and the provision of information, services, transactions, and/or the like across various communications networks. The TCAPS enables TCAP users to simply access data and/or services across a communications network in a secure manner. The TCAPS extends the storage and processing capacities and capabilities of TCAPs. The TCAPS coordinates with the TCAPS database to identify interassociated items in the generation of entries regarding any related information. A TCAPS module enabling access of information between nodes may be developed by employing standard development tools such as, but not limited to: (ANSI) (Objective-) C (++), Apache modules, binary executables, Java, Javascript, mapping tools, procedural and object oriented development tools, PERL, Python, shell scripts, SQL commands, web application server extensions, WebObjects, and/or the like. In one embodiment, the TCAPS server employs a cryptographic server to encrypt and decrypt communications. A TCAPS module may communicate to and/or with other modules in a module collection, including itself, and/or facilities of the like. Most frequently, the TCAPS module communicates with a TCAPS database, operating systems, other program modules, and/or the like. The TCAPS may contain, communicate, generate, obtain, and/or provide program module, system, user, and/or data communications, requests, and/or responses. Distributed TCAP The structure and/or operation of any of the TCAPS node controller components may be combined, consolidated, and/or distributed in any number of ways to facilitate development and/or deployment. Similarly, the module collection may be combined in any number of ways to facilitate deployment and/or development. To accomplish this, one may integrate the components into a common code base or in a facility that can dynamically load the components on demand in an integrated fashion. The module collection may be consolidated and/or distributed in countless variations through standard data processing and/or development techniques. Multiple instances of any one of the program modules in the program module collection may be instantiated on a single node, and/or across numerous nodes to improve performance through load-balancing and/or data-processing techniques. Furthermore, single instances may also be distributed across multiple controllers and/or storage devices; e.g., databases. All program module instances and controllers working in concert may do so through standard data processing communication techniques. The configuration of the TCAPS controller will depend on the context of system deployment. Factors such as, but not limited to, the budget, capacity, location, and/or use of the underlying hardware resources may affect deployment requirements and configuration. Regardless of if the configuration results in more consolidated and/or integrated program modules, results in a more distributed series of program modules, and/or results in some combination between a consolidated and distributed configuration, data may be communicated, obtained, and/or provided. Instances of modules consolidated into a common code base from the program module collection may communicate, obtain, and/or provide data. This may be accomplished through intra-application data processing communication techniques such as, but not limited to: data referencing (e.g., pointers), internal messaging, object instance variable communication, shared memory space, variable passing, and/or the like. If module collection components are discrete, separate, and/or external to one another, then communicating, obtaining, and/or providing data with and/or to other module components may be accomplished through inter-application data processing communication techniques such as, but not limited to: Application Program Interfaces (API) information passage; (distributed) Component Object Model ((D)COM), (Distributed) Object Linking and Embedding ((D)OLE), and/or the like), Common Object Request Broker Architecture (CORBA), process pipes, shared files, and/or the like. Messages sent between discrete module components for inter-application communication or within memory spaces of a singular module for intra-application communication may be facilitated through the creation and parsing of a grammar. A grammar may be developed by using standard development tools such as lex, yacc, and/or the like, which allow for grammar generation and parsing functionality, which in turn may form the basis of communication messages within and between modules. Again, the configuration will depend upon the context of system deployment. Tunneling Client Access Point Controller FIG. 10 illustrates one embodiment incorporated into a tunneling client access point (TCAP) controller 1001. Much of the description of the TCAPS of FIG. 9 applies to the TCAP, and as such, the disclosure focuses more upon the variances exhibited in the TCAP. In this embodiment, the TCAP controller 1001 may serve to process, store, search, identify, instruct, generate, match, and/or update data within itself, at a TCAPS, and/or through an AT. The first and foremost difference between the TCAP and the TCAPS is that the TCAP is very small as was shown 130 of FIG. 1. The TCAP may be packaged in plugin sticks, often, smaller than the size of a human thumb. In one embodiment, a TCAP may be hardened for military use. In such an embodiment, the shell 1001 may be composed of metal, and/or other durable composites. Also, components within may be shielded from radiation. In one embodiment, the TCAP controller 1001 may be connected to and/or communicate with entities such as, but not limited to: one or more users from an access terminal 1011b. The access terminal itself may be connected to peripherals such as user input devices (e.g., keyboard 1012a, mouse 1012b, etc.); and/or a communications network 1013 in manner similar to that described in FIG. 9. A TCAP controller 1001 may be based on common computer systems components that may comprise, but are not limited to, components such as: a computer systemization 1002 connected to memory 1029. Optionally, the TCAP controller 1001 may convey information 1058, produce output through an output device 1048, and obtain input from control device 1018. Control Device The control device 1018 may be optionally provided to accept user input to control access to the TCAP controller. In one embodiment, the control device may provide a keypad 1028. Such a keypad would allow the user to enter passwords, personal identification numbers (PIN), and/or the like. In an alternative embodiment, the control device may include a security device 1038. In one embodiment, the security device is a fingerprint integrated circuit (fingerprint IC) that provides biometric fingerprint information such as, but not limited to AuthenTec Inc.'s FingerLoc™ AF-S2™. Either a fingerprint IC and/or other biometric device will provide biometric validation information that may be used to confirm the identity of a TCAP user and ensure that transactions are legitimate. In alternative embodiments, a simple button, heat sensor, and/or other type of user input functionality may be provided solely and/or in concert with other types of control device types. The control device may be connected to the I/O interface, the system bus, or the CPU directly. The output device 1048 is used to provide status information to the user. In one alternative embodiment, the output device is an LCD panel capable of providing alpha numeric and/or graphic displays. In an alternative embodiment, the output device may be a speaker providing audible signals indicating errors and/or actually streaming information that is audible to the user, such as voice alerts. The output device may be connected to the I/O interface, the system bus, or the CPU directly. The conveyance information 1058 component of the TCAP controller may include any number of indicia representing the TCAP's source on the cover 1001. Source conveying indicia may include, but is not limited to: an owner name 1059 for readily verifying a TCAP user; a photo of the owner 1060 for readily verifying a TCAP controller owner; mark designating the source that issued the TCAP 1061, 1001 such as a corporate logo, and/or the like; fanciful design information 1062 for enhancing the visual appearance of the TCAP; and/or the like. It should be noted that the conveyance information 11421 may be positioned anywhere on the cover 1189. Computer Systemization A computer systemization 1002 may comprise a clock 1030, central processing unit (CPU) 1003, a read only memory (ROM) 1006, a random access memory (RAM) 1005, and/or an interface bus 1007, and most frequently, although not necessarily, are all interconnected and/or communicating through a system bus 1004. Optionally the computer systemization may be connected to an internal power source 1086. Optionally, a cryptographic processor 1026 may be connected to the system bus. The system clock typically has a crystal oscillator and provides a base signal. Of course, any of the above components may be connected directly to one another, connected to the CPU, and/or organized in numerous variations employed as exemplified by various computer systems. The CPU comprises at least one low-power data processor adequate to execute program modules for executing user and/or system-generated requests. The CPU may be a microprocessor such as ARM' s Application Cores, Embedded Cores, Secure Cores; Motorola's DragonBall; and/or the like processor(s). Power Source The power source 1086 may be of any standard form for powering small electronic circuit board devices such as but not limited to: alkaline, lithium hydride, lithium ion, nickel cadmium, solar cells, and/or the like. In the case of solar cells, the case provides an aperture through which the solar cell protrudes are to receive photonic energy. The power cell 1086 is connected to at least one of the interconnected subsequent components of the TCAP thereby providing an electric current to all subsequent components. In one example, the power cell 1086 is connected to the system bus component 1004. In an alternative embodiment, an outside power source 1086 is provided through a connection across the I/O 1008 interface. For example, a USB and/or IEEE 1394 connection carries both data and power across the connection and is therefore a suitable source of power. Interface Adapters Interface bus(ses) 1007 may accept, connect, and/or communicate to a number of interface adapters, conventionally although not necessarily in the form of adapter cards, such as but not limited to: input output interfaces (I/O) 1008, storage interfaces 1009, network interfaces 1010, and/or the like. Optionally, cryptographic processor interfaces 1027 similarly may be connected to the interface bus. The interface bus provides for the communications of interface adapters with one another as well as with other components of the computer systemization. Interface adapters are adapted for a compatible interface bus. In one embodiment, the interface bus provides I/O 1008 via a USB port. In an alternative embodiment, the interface bus provides I/O via an IEEE 1394 port. In an alternative embodiment, wireless transmitters are employed by interfacing wireless protocol integrated circuits (ICs) for I/O via the interface bus 1007. Storage interfaces 1009 may accept, communicate, and/or connect to a number of storage devices such as, but not limited to: storage devices 1014, removable disc devices, and/or the like. Storage interfaces may employ connection protocols such as, but not limited to a flash memory connector, and/or the like. In one embodiment, an optional network interface may be provide 1010. Input Output interfaces (I/O) 1008 may accept, communicate, and/or connect to an access terminal 1011b. I/O may employ connection protocols such as, but not limited to: Apple Desktop Bus (ADB); Apple Desktop Connector (ADC); IEEE 1394a-b; infrared; PC AT; PS/2; parallel; radio; serial; USB, and/or the like; wireless component; and/or the like. Wireless Component In one embodiment a wireless component may comprise a Bluetooth chip disposed in communication with a transceiver 1043 and a memory 1029 through the interface bus 1007 and/or system bus 1004. The transceiver may be either external to the Bluetooth chip, or integrated within the Bluetooth chip itself. The transceiver is a radio frequency (RF) transceiver operating in the range as required for Bluetooth transmissions. Further, the Bluetooth chip 1044 may integrate an input/output interface (PO) 1066. The Bluetooth chip and its I/O may be configured to interface with the TCAP controller through the interface bus, the system buss, and/or directly with the CPU. The I/O may be used to interface with other components such as an access terminal 1011b equipped with similar wireless capabilities. In one embodiment, the TCAP may optionally interconnect wirelessly with a peripheral device 912 and/or a control device 911 of FIG. 9. In one example embodiment, the I/O may be based on serial line technologies, a universal serial bus (USB) protocol, and/or the like. In an alternative embodiment, the I/O may be based on the ISO 7816-3 standard. It should be noted that the Bluetooth chip in an alternative embodiment may be replaced with an IEEE 802.11b wireless chip. In another embodiment, both a Bluetooth chip and an IEEE 802.11b wireless chip may be used to communicate and or bridge communications with respectively enabled devices. It should further be noted that the transceiver 1043 may be used to wirelessly communicate with other devices powered by Bluetooth chips and/or IEEE 802.11b chips and/or the like. The ROM can provide a basic instruction set enabling the Bluetooth chip to use its I/O to communicate with other components. A number of Bluetooth chips are commercially available, and may be used as a Bluetooth chip in the wireless component, such as, but not limited to, CSR's BlueCore line of chips. If IEEE 802.11b functionality is required, a number of chips are commercially available for the wireless component as well. Cryptographic units such as, but not limited to, microcontrollers, processors 1026, and/or interfaces 1027 may be attached, and/or communicate with the TCAP controller. A Secure Core component commonly manufactured by ARM, Inc. and may be used for and/or within cryptographic units. Memory Generally, any mechanization and/or embodiment allowing a processor to affect the storage and/or retrieval of information is regarded as memory 1029. However, memory is a fungible technology and resource, thus, any number of memory embodiments may be employed in lieu of or in concert with one another. It is to be understood that a TCAP controller and/or a computer systemization may employ various forms of memory 1029. In a typical configuration, memory 1029 will include ROM 1006, RAM 1005, and a storage device 1014. A storage device 1014 may be any conventional computer system storage. Storage devices may include flash memory, micro hard drives, and/or the like. Module Collection The memory 1029 may contain a collection of program and/or database modules and/or data such as, but not limited to: operating system module(s) 1015 (operating system); information server module(s) 1016 (information server); user interface module(s) 1017 (user interface); Web browser module(s) 1018 (Web browser); database(s) 1019; cryptographic server module(s) 1020 (cryptographic server); access terminal module 1021; TCAP module(s) 1035; and/or the like (i.e., collectively a module collection). These modules may be stored and accessed from the storage devices and/or from storage devices accessible through an interface bus. Although non-conventional software modules such as those in the module collection, typically, are stored in a local storage device 1014, they may also be loaded and/or stored in memory such as: peripheral devices, RAM, remote storage facilities through an access terminal, communications network, ROM, various forms of memory, and/or the like. In one embodiment, all data stored in memory is encrypted by employing the cryptographic server 1020 as described in further detail below. In one embodiment, the ROM contains a unique TCAP identifier. For example, the TCAP may contain a unique digital certificate, number, and/or the like, which may be used for purposes of verification and encryption across a network and/or in conjunction with a TCAPS. Operating System The operating system module 1015 is executable program code facilitating the operation of a TCAP controller. Typically, the operating system facilitates access of I/O, network interfaces, peripheral devices, storage devices, and/or the like. The operating system may be a highly fault tolerant, scalable, and secure system such as Linux, and/or the like operating systems. However, more limited and/or less secure operating systems also may be employed such as Java runtime OS, and/or the like. An operating system may communicate to and/or with other modules in a module collection, including itself, and/or the like. Most frequently, the operating system communicates with other program modules, user interfaces, and/or the like. For example, the operating system may contain, communicate, generate, obtain, and/or provide program module, system, user, and/or data communications, requests, and/or responses. The operating system, once executed by the CPU, may enable the interaction with an access terminal, communications networks, data, I/O, peripheral devices, program modules, memory, user input devices, and/or the like. The operating system may provide communications protocols that allow the TCAP controller to communicate with other entities through an access terminal. Various communication protocols may be used by the TCAP controller as a subcarrier transport mechanism for interaction, such as, but not limited to: TCP/IP, USB, and/or the like. Information Server An information server module 1016 is stored program code that is executed by the CPU. The information server may be a conventional Internet information server such as, but not limited to Apache Software Foundation's Apache, and/or the like. The information server may allow for the execution of program modules through facilities such as Active Server Page (ASP), ActiveX, (ANSI) (Objective-) C (++), Common Gateway Interface (CGI) scripts, Java, JavaScript, Practical Extraction Report Language (PERL), Python, WebObjects, and/or the like. The information server may support secure communications protocols such as, but not limited to, File Transfer Protocol (FTP); HyperText Transfer Protocol (HTTP); Secure Hypertext Transfer Protocol (HTTPS), Secure Socket Layer (SSL), and/or the like. The information server provides results in the form of Web pages to Web browsers, and allows for the manipulated generation of the Web pages through interaction with other program modules. An information server may communicate to and/or with other modules in a module collection, including itself, and/or facilities of the like. Most frequently, the information server communicates with the TCAP database 1019, operating systems, other program modules, user interfaces, Web browsers, and/or the like. Access to TCAP database may be achieved through a number of database bridge mechanisms such as through scripting languages as enumerated below (e.g., CGI) and through inter-application communication channels as enumerated below (e.g., CORBA, WebObjects, etc.). Any data requests through a Web browser are parsed through the bridge mechanism into appropriate grammars as required by the TCAP. In one embodiment, the information server would provide a Web form accessible by a Web browser. Entries made into supplied fields in the Web form are tagged as having been entered into the particular fields, and parsed as such. The entered terms are then passed along with the field tags, which act to instruct the parser to generate queries directed to appropriate tables and/or fields. In one embodiment, the parser may generate queries in standard SQL by instantiating a search string with the proper join/select commands based on the tagged text entries, wherein the resulting command is provided over the bridge mechanism to the TCAP as a query. Upon generating query results from the query, the results are passed over the bridge mechanism, and may be parsed for formatting and generation of a new results Web page by the bridge mechanism. Such a new results Web page is then provided to the information server, which may supply it to the requesting Web browser. Also, an information server may contain, communicate, generate, obtain, and/or provide program module, system, user, and/or data communications, requests, and/or responses. User Interface A user interface module 1017 is stored program code that is executed by the CPU. The user interface may be a conventional graphic user interface as provided by, with, and/or atop operating systems and/or operating environments such as Apple Macintosh OS, e.g., Aqua, Microsoft Windows (NT/XP), Unix X Windows (KDE, Gnome, and/or the like), and/or the like. The TCAP may employ code natively compiled for various operating systems, or code compiled using Java. The user interface may allow for the display, execution, interaction, manipulation, and/or operation of program modules and/or system facilities through textual and/or graphical facilities. The user interface provides a facility through which users may affect, interact, and/or operate a computer system. A user interface may communicate to and/or with other modules in a module collection, including itself, and/or facilities of the like. Most frequently, the user interface communicates with operating systems, other program modules, and/or the like. The user interface may contain, communicate, generate, obtain, and/or provide program module, system, user, and/or data communications, requests, and/or responses. Web Browser A Web browser module 1018 is stored program code that is executed by the CPU. A small-scale embedded Web browser may allow the TCAP to access and communicate with an attached access terminal, and beyond across a communications network. An example browser is Blazer, Opera, FireFox, etc. A browsing module may contain, communicate, generate, obtain, and/or provide program module, system, user, and/or data communications, requests, and/or responses. Of course, in place of a Web browser and information server, a combined application may be developed to perform similar functions of both. The combined application would similarly affect the obtaining and the provision of information to users, user agents, and/or the like from TCAP enabled nodes. The combined application may be nugatory on systems employing standard Web browsers. TCAP Database A TCAP database module 1019 may be embodied in a database and its stored data. The database is stored program code, which is executed by the CPU; the stored program code portion configuring the CPU to process the stored data. In one embodiment, the TCAP database may be implemented using various standard data-structures, such as an array, hash, (linked) list, struct, structured text file (e.g., XML), table, and/or the like. Such data-structures may be stored in memory and/or in (structured) files. If the TCAP database is implemented as a data-structure, the use of the TCAP database may be integrated into another module such as the TCAP module. Databases may be consolidated and/or distributed in countless variations through standard data processing techniques. Portions of databases, e.g., tables, may be exported and/or imported and thus decentralized and/or integrated. In one embodiment, the database module 1019 includes three tables 1019a-c. A user accounts table 1019a includes fields such as, but not limited to: a user name, user address, user authorization information (e.g., user name, password, biometric data, etc.), user credit card, organization, organization account, TCAP unique identifier, account creation data, account expiration date; and/or the like. In one embodiment, user accounts may be activated only for set amounts of time and will then expire once a specified date has been reached. An user data table 1019b includes fields such as, but not limited to: a TCAP unique identifier, backup image, data store, organization account, and/or the like. In one embodiment, the entire TCAP memory 1029 is processes into an image and spooled to a TCAPS for backup storage. A user programs table 1019c includes fields such as, but not limited to: system programs, organization programs, programs to be synchronized, and/or the like. It should be noted that any unique fields may be designated as a key field throughout. In an alternative embodiment, these tables have been decentralized into their own databases and their respective database controllers (i.e., individual database controllers for each of the above tables). Employing standard data processing techniques, one may further distribute the databases over several computer systemizations and/or storage devices. Similarly, configurations of the decentralized database controllers may be varied by consolidating and/or distributing the various database modules 1019a-c. The TCAP may be configured to keep track of various settings, inputs, and parameters via database controllers. A TCAP database may communicate to and/or with other modules in a module collection, including itself, and/or facilities of the like. Most frequently, the TCAP database communicates with a TCAP module, other program modules, and/or the like. The database may contain, retain, and provide information regarding other nodes and data. Cryptographic Server A cryptographic server module 1020 is stored program code that is executed by the CPU 1003, cryptographic processor 1026, cryptographic processor interface 1027, and/or the like. Cryptographic processor interfaces will allow for expedition of encryption and/or decryption requests by the cryptographic module; however, the cryptographic module, alternatively, may run on a conventional CPU. The cryptographic module allows for the encryption and/or decryption of provided data. The cryptographic module allows for both symmetric and asymmetric (e.g., Pretty Good Protection (PGP)) encryption and/or decryption. The cryptographic module may employ cryptographic techniques such as, but not limited to: digital certificates (e.g., X.509 authentication framework), digital signatures, dual signatures, enveloping, password access protection, public key management, and/or the like. The cryptographic module will facilitate numerous (encryption and/or decryption) security protocols such as, but not limited to: checksum, Data Encryption Standard (DES), Elliptical Curve Encryption (ECC), International Data Encryption Algorithm (IDEA), Message Digest 5 (MD5, which is a one way hash function), passwords, Rivest Cipher (RC5), Rijndael, RSA (which is an Internet encryption and authentication system that uses an algorithm developed in 1977 by Ron Rivest, Adi Shamir, and Leonard Adleman), Secure Hash Algorithm (SHA), Secure Socket Layer (SSL), Secure Hypertext Transfer Protocol (HTTPS), and/or the like. The cryptographic module facilitates the process of “security authorization” whereby access to a resource is inhibited by a security protocol wherein the cryptographic module effects authorized access to the secured resource. In addition, the cryptographic module may provide unique identifiers of content, e.g., employing and MD5 hash to obtain a unique signature for an digital audio file. A cryptographic module may communicate to and/or with other modules in a module collection, including itself, and/or facilities of the like. The cryptographic module supports encryption schemes allowing for the secure transmission of information across a communications network to enable a TCAP module to engage in secure transactions if so desired. The cryptographic module facilitates the secure accessing of resources on TCAP and facilitates the access of secured resources on remote systems; i.e., it may act as a client and/or server of secured resources. Most frequently, the cryptographic module communicates with information servers, operating systems, other program modules, and/or the like. The cryptographic module may contain, communicate, generate, obtain, and/or provide program module, system, user, and/or data communications, requests, and/or responses. In one embodiment, the TCAP employs the cryptographic server to encrypt all data stored in memory 1029 based on the TCAP's unique ID and user's authorization information. In another embodiment, the TCAP employs the cryptographic server to encrypt all data sent through the access terminal based in the TCAP's unique ID and user's authorization information. TCAP A TCAP module 1035 is stored program code that is executed by the CPU. The TCAP affects accessing, obtaining and the provision of information, services, storage, transactions, and/or the like within its memory and/or across various communications networks. The TCAP enables users to simply access data and/or services from any location where an access terminal is available. It provides secure, extremely low powerful and ultra portable access to data and services that were heretofore impossible. The TCAP coordinates with the TCAP database to identify interassociated items in the generation of entries regarding any related information. A TCAP module enabling access of information between nodes may be developed by employing standard development tools such as, but not limited to: (ANSI) (Objective-) C (++), Apache modules, binary executables, Java, Javascript, mapping tools, procedural and object oriented development tools, PERL, Python, shell scripts, SQL commands, web application server extensions, WebObjects, and/or the like. In one embodiment, the TCAP server employs a cryptographic server to encrypt and decrypt communications. A TCAP module may communicate to and/or with other modules in a module collection, including itself, and/or facilities of the like. Most frequently, the TCAP module communicates with a TCAP database, a TCAP access terminal module 1021 running on an access terminal 1011b, operating systems, other program modules, and/or the like. The TCAP may contain, communicate, generate, obtain, and/or provide program module, system, user, and/or data communications, requests, and/or responses. Access Terminal Module An access terminal module 1021 is stored program code that is executed by a CPU. In one embodiment, the TCAP allows the access terminal 1011b to access its memory 1029 across its I/O 1008 and the access terminal executes the module. The access terminal module affects accessing, obtaining and the provision of information, services, storage, transactions, and/or the like within the TCAP's and access terminal's memory and/or across various communications networks. The access terminal module 1021 acts as a bridge through which the TCAP can communicate with communications network, and through which users may interact with the TCAP by using the I/O of the access terminal. The access terminal module coordinates with the TCAP module 1035 to send data and communications back and forth. A access terminal module enabling access of information between the TCAP and access terminal may be developed by employing standard development tools such as, but not limited to: (ANSI) (Objective-) C (++), Apache modules, binary executables, Java, Javascript, mapping tools, procedural and object oriented development tools, PERL, Python, shell scripts, SQL commands, web application server extensions, WebObjects, and/or the like. In one embodiment, the access terminal module is compiled for target access terminal platform, e.g., for Windows. In an alternative embodiment, a processor independent approach is taken, e.g., Java is used, so that the access terminal module will run on multiple platforms. In another embodiment, the TCAP server employs a cryptographic server to encrypt and decrypt communications as between it, the TCAP, and outside servers. A access terminal module may communicate to and/or with other modules in a module collection, including itself, and/or facilities of the like. Most frequently, the access terminal module communicates with a TCAP, other program modules, and/or the like. The access terminal module may contain, communicate, generate, obtain, and/or provide program module, system, user, and/or data communications, requests, and/or responses. Distributed TCAP The structure and/or operation of any of the TCAP node controller components may be combined, consolidated, and/or distributed in any number of ways to facilitate development and/or deployment. Similarly, the module collection may be combined in any number of ways to facilitate deployment and/or development. To accomplish this, one may integrate the components into a common code base or in a facility that can dynamically load the components on demand in an integrated fashion. The module collection may be consolidated and/or distributed in countless variations through standard data processing and/or development techniques. Multiple instances of any one of the program modules in the program module collection may be instantiated on a single node, and/or across numerous nodes to improve performance through load-balancing and/or data-processing techniques. Furthermore, single instances may also be distributed across multiple controllers and/or storage devices; e.g., databases. All program module instances and controllers working in concert may do so through standard data processing communication techniques. The configuration of the TCAP controller will depend on the context of system deployment. Factors such as, but not limited to, the budget, capacity, location, and/or use of the underlying hardware resources may affect deployment requirements and configuration. Regardless of if the configuration results in more consolidated and/or integrated program modules, results in a more distributed series of program modules, and/or results in some combination between a consolidated and distributed configuration, data may be communicated, obtained, and/or provided. Instances of modules consolidated into a common code base from the program module collection may communicate, obtain, and/or provide data. This may be accomplished through intra-application data processing communication techniques such as, but not limited to: data referencing (e.g., pointers), internal messaging, object instance variable communication, shared memory space, variable passing, and/or the like. If module collection components are discrete, separate, and/or external to one another, then communicating, obtaining, and/or providing data with and/or to other module components may be accomplished through inter-application data processing communication techniques such as, but not limited to: Application Program Interfaces (API) information passage; (distributed) Component Object Model ((D)COM), (Distributed) Object Linking and Embedding ((D)OLE), and/or the like), Common Object Request Broker Architecture (CORBA), process pipes, shared files, and/or the like. Messages sent between discrete module components for inter-application communication or within memory spaces of a singular module for intra-application communication may be facilitated through the creation and parsing of a grammar. A grammar may be developed by using standard development tools such as lex, yacc, and/or the like, which allow for grammar generation and parsing functionality, which in turn may form the basis of communication messages within and between modules. Again, the configuration will depend upon the context of system deployment. The entirety of this disclosure (including the Cover Page, Title, Headings, Field, Background, Summary, Brief Description of the Drawings, Detailed Description, Claims, Abstract, Figures, and otherwise) shows by way of illustration various embodiments in which the claimed inventions may be practiced. The advantages and features of the disclosure are of a representative sample of embodiments only, and are not exhaustive and/or exclusive. They are presented only to assist in understanding and teach the claimed principles. It should be understood that they are not representative of all claimed inventions. As such, certain aspects of the disclosure have not been discussed herein. That alternate embodiments may not have been presented for a specific portion of the invention or that further undescribed alternate embodiments may be available for a portion is not to be considered a disclaimer of those alternate embodiments. It will be appreciated that many of those undescribed embodiments incorporate the same principles of the invention and others are equivalent. Thus, it is to be understood that other embodiments may be utilized and functional, logical, organizational, structural and/or topological modifications may be made without departing from the scope and/or spirit of the disclosure. As such, all examples and/or embodiments are deemed to be non-limiting throughout this disclosure. Also, no inference should be drawn regarding those embodiments discussed herein relative to those not discussed herein other than for purposes of space and reducing repetition. For instance, it is to be understood that the logical and/or topological structure of any combination of any program modules (a module collection), other components and/or any present feature sets as described in the figures and/or throughout are not limited to a fixed operating order and/or arrangement, but rather, any disclosed order is exemplary and all equivalents, regardless of order, are contemplated by the disclosure. Furthermore, it is to be understood that such features are not limited to serial execution, but rather, any number of threads, processes, services, servers, and/or the like that may execute asynchronously, simultaneously, synchronously, and/or the like are contemplated by the disclosure. As such, some of these features may be mutually contradictory, in that they cannot be simultaneously present in a single embodiment. Similarly, some features are applicable to one aspect of the invention, and inapplicable to others. In addition, the disclosure includes other inventions not presently claimed. Applicant reserves all rights in those presently unclaimed inventions including the right to claim such inventions, file additional applications, continuations, continuations in part, divisions, and/or the like thereof. As such, it should be understood that advantages, embodiments, examples, functional, features, logical, organizational, structural, topological, and/or other aspects of the disclosure are not to be considered limitations on the disclosure as defined by the claims or limitations on equivalents to the claims.
<SOH> BACKGROUND <EOH>
<SOH> SUMMARY <EOH>Although all of the aforementioned portable computing systems exist, no effective solution to securely access, execute, and process data is available in an extremely compact form. Currently, PDAs, which are considered among the smallest portable computing solution, are bulky, provide uncomfortably small user interfaces, and require too much power to maintain their data. Current PDA designs are complicated and cost a lot because they require great processing resources to provide custom user interfaces and operating systems. Further, current PDAs are generally limited in the amount of data they can store or access. No solution exists that allows users to employ traditional large user interfaces they are already comfortable with, provides greater portability, provides greater memory footprints, draws less power, and provides security for data on the device. As such, the disclosed tunneling client access point (TCAP) is very easy to use; at most it requires the user to simply plug the device into any existing and available desktop or laptop computer, through which, the TCAP can make use of a traditional user interface and input/output (I/O) peripherals, while the TCAP itself, otherwise, provides storage, execution, and/or processing resources. Thus, the TCAP requires no power source to maintain its data and allows for a highly portable “thumb” footprint. Also, by providing the equivalent of a plug-n-play virtual private network (VPN), the TCAP provides certain kinds of accessing of remote data in an easy and secure manner that was unavailable in the prior art. In accordance with certain aspects of the disclosure, the above-identified problems of limited computing devices are overcome and a technical advance is achieved in the art of portable computing and data access. An exemplary tunneling client access point (TCAP) includes a method to dispose a portable storage device in communication with a terminal. The method includes providing the memory for access on the terminal, executing processing instructions from the memory on the terminal to access the terminal, communicating through a conduit, and processing the processing instructions. In accordance with another embodiment, a portable tunneling storage processor is disclosed. The apparatus has a memory and a processor disposed in communication with the memory, and configured to issue a plurality of processing instructions stored in the memory. Also, the apparatus has a conduit for external communications disposed in communication with the processor, configured to issue a plurality of communication instructions as provided by the processor, configured to issue the communication instructions as signals to engage in communications with other devices having compatible conduits, and configured to receive signals issued from the compatible conduits.
H04L6742
20170922
20180111
57313.0
H04L2906
1
BOUTAH, ALINA A
APPARATUS, METHOD AND SYSTEM FOR A TUNNELING CLIENT ACCESS POINT
SMALL
1
CONT-ACCEPTED
H04L
2,017
15,713,324
PENDING
FLUORESCENT COMPOUND COMPRISING A FLUOROPHORE CONJUGATED TO A pH-TRIGGERED POLYPEPTIDE
The present subject matter provides compounds, compositions, and methods for identifying, monitoring, treating, and removing diseased tissue. Compounds, compositions, and methods for identifying, monitoring, and detecting circulating fluids such as blood are also provided.
1. A pHLIP-fluorophore compound comprising (a) a pH-triggered polypeptide (pHLIP peptide); and (b) a fluorophore, wherein the fluorophore is a near-infrared (NIR) fluorophore, a cyanine fluorophore, or an optoacoustic contrast imaging agent. 2. The compound of claim 1, having the structure: 3. The compound of claim 1, wherein the pHLIP peptide comprises amino acids in the sequence LFPTXTLL (SEQ ID NO: 1), wherein X is a protonatable amino acid, and wherein the fluorophore comprises a NIR fluorophore. 4. The compound of claim 3, wherein X is D. 5. The compound of claim 1, wherein the fluorophore comprises indocyanine green (ICG). 6. The compound of claim 1, wherein the pHLIP peptide comprises the sequence: XnYm; YmXn; XnYmXj; YmXnYi; YmXnYiXj; XnYmXjYi; YmXnYiXjYi; XnYmXjYiXl; YmXnYiXjYlXh; XnYmXjYiXhYg; YmXnYiXjYiXhYg; XnYmXjYiXhYgXf; (XY)n; (YX)n; (XY)nYm; (YX)nYm; (XY)nXm; (YX)nXm; Ym(XY)n; Ym(YX)n; Xn(XY)m; Xn(YX)m; (XY)nYm(XY)i; (YX)nYm(YX)i; (XY)nXm(XY)i; (YX)nXm(YX)i; Ym(XY)n; Ym(YX)n; Xn(XY)m; Xn(YX)m, wherein, i) Y is a non-polar amino acid with solvation energy, ΔGXcor>+0.50, or Gly, ii) X is a protonatable amino acid, and iii) n, m, I, j, l, h, g, f are integers from 1 to 8. 7. The compound of claim 1, wherein the pHLIP peptide has a net negative charge at a pH of about 7.5 or 7.75 in water. 8. The compound of claim 1, wherein the pHLIP peptide has an acid dissociation constant at logarithmic scale (pKa) of less than about 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, or 7. 9. The compound of claim 1, wherein the pHLIP peptide comprises at least 1 artificial protonatable amino acid. 10. The compound of claim 1, wherein the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 40 genetically coded amino acids. 11. The compound of claim 1, wherein the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 40 non-genetically coded amino acids. 12. The compound of claim 1, wherein the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 40 D-amino acids. 13. The compound of claim 1, wherein the pHLIP peptide comprises at least 8 amino acids, wherein, at least 2, 3, or 4 of the 8 amino acids of the pHLIP peptide are non-polar, and at least 1, 2, 3, or 4 of the at least 8 amino acids of the pHLIP peptide are protonatable. 14. The compound of claim 1, wherein the fluorophore a cyanine fluorophore. 15. The compound of claim 1, wherein the fluorophore is a NIR fluorophore. 16. The compound of claim 1, wherein the fluorophore comprises an optoacoustic contrast imaging agent. 17. The compound of claim 1, comprising (a) a pHLIP peptide comprising amino acids in the sequence LFPTXTLL (SEQ ID NO: 1), wherein X is a protonatable amino acid, wherein the pHLIP peptide has a higher affinity to a membrane lipid bilayer at pH 5.0 compared to at pH 8.0; and (b) indocyanine green (ICG), wherein said ICG is covalently attached to the first or the second amino acid counted from the N-terminus of the pHLIP peptide. 18. The compound of claim 17, wherein X is D. 19. The compound of claim 17, wherein said pHLIP peptide comprises amino acids in the sequence ACDDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 4) or ACDDQNPWRAYLDLLFPTDTLLLDLLWG (SEQ ID NO: 9), and wherein said ICG is covalently attached to the cysteine thereof. 20. The compound of claim 19, comprising the following structure: 21. The compound of claim 17, wherein said pHLIP peptide comprises amino acids in the sequence ADDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 5) or ADDQNPWRAYLDLLFPTDTLLLDLLWG (SEQ ID NO: 2), and wherein said ICG is covalently attached to the N-terminal alanine thereof. 22. The compound of claim 21, comprising the following structure: 23. The compound of claim 17, wherein said pHLIP peptide comprises amino acids in the sequence AKDDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 8) or AKDDQNPWRAYLDLLFPTDTLLLDLLWG (SEQ ID NO: 3), and wherein said ICG is covalently attached to the lysine thereof. 24. The compound of claim 23, comprising the following structure: 25. The compound of claim 17, wherein said pHLIP peptide comprises amino acids in the sequence ACDDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 4), and wherein said ICG is covalently attached to the cysteine thereof. 26. The compound of claim 25, comprising the following structure: 27. The compound of claim 17, wherein the pHLIP peptide comprises an artificial protonatable amino acid. 28. The compound of claim 27, wherein the artificial protonatable amino acid comprises at least 1, 2, 3, 4 or 5 carboxyl groups. 29. The compound of claim 17, wherein the protonatable amino acid comprises aspartic acid or gamma-carboxyglutamic acid. 30. The compound of claim 17, wherein said pHLIP peptide comprises amino acids in the sequence LLFPTDTLLL (SEQ ID NO: 25). 31. The compound of claim 30, wherein said pHLIP peptide comprises amino acids in the sequence LDLLFPTDTLLLD (SEQ ID NO: 26). 32. The compound of claim 31, wherein said pHLIP peptide comprises amino acids in the sequence AYLDLLFPTDTLLLDLL (SEQ ID NO: 27). 33. The compound of claim 32, wherein said pHLIP peptide comprises amino acids in the sequence DDQNPWRAYLDLLFPTDTLLLDLLW (SEQ ID NO: 28). 34. The compound of claim 33, wherein said pHLIP peptide comprises amino acids in the sequence: (SEQ ID NO: 4) ACDDQNPWRAYLDLLFPTDTLLLDLLWA, (SEQ ID NO: 2) ADDQNPWRAYLDLLFPTDTLLLDLLWG, (SEQ ID NO: 3) AKDDQNPWRAYLDLLFPTDTLLLDLLWG, (SEQ ID NO: 5) ADDQNPWRAYLDLLFPTDTLLLDLLWA, (SEQ ID NO: 6) ADDQNPWRAYLDLLFPTDTLLLDLLWCA, (SEQ ID NO: 7) ADDQNPWRAYLDLLFPTDTLLLDLLWKA, (SEQ ID NO: 8) AKDDQNPWRAYLDLLFPTDTLLLDLLWA, (SEQ ID NO: 9) ACDDQNPWRAYLDLLFPTDTLLLDLLWG, (SEQ ID NO: 10) ADDQNPWRAYLDLLFPTDTLLLDLLWCG, (SEQ ID NO: 11) ADDQNPWRAYLDLLFPTDTLLLDLLWKG, (SEQ ID NO: 12) ACDDQNPWRAYLDLLFPTDTLLLDLLWKG, (SEQ ID NO: 13) AKDDQNPWRAYLDLLFPTDTLLLDLLWCG, or (SEQ ID NO: 14) ACKDDQNPWRAYLDLLFPTDTLLLDLLWG. 35. The compound of claim 17, wherein the amino acid sequence of said pHLIP peptide is less than 100%, 99%, or 95% identical to each of the amino acid sequences set forth as SEQ ID NOS: 15-24. 36. The compound of claim 17, wherein said pHLIP peptide comprises 20-30 amino acids. 37. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. 38. The composition of claim 37, further comprising D-glucose. 39. The composition of claim 38, wherein said composition comprises a mouthwash. 40. A method for detecting diseased or damaged tissue in subject, comprising (a) administering the compound of claim 1 to the subject; (b) contacting the subject with electromagnetic radiation comprising an excitation wavelength of the fluorophore; and (c) detecting electromagnetic radiation emitted from the compound, wherein detection of the radiation indicates the presence of the diseased tissue. 41. The method of claim 40, wherein the diseased or damaged tissue is cancer tissue, precancerous tissue, inflamed tissue, ischemic tissue, arthritic tissue, cystic fibrotic tissue, tissue infected with a microorganism, or atherosclerotic tissue. 42. The method of claim 41, wherein the diseased tissue is cancer tissue, and the cancer tissue is in the bladder, the upper urinary tract, a kidney, the prostate, a breast, the head, the neck, the oral cavity, the pancreas, a lung, the liver, the cervix, an ovary, or the brain of the subject. 43. The method of claim 40, wherein the level of radiation emitted from precancerous tissue or cancer tissue is at least 20% greater than a level of radiation emitted from normal non-cancerous tissue. 44. The method of claim 40, wherein said bodily organ comprises a kidney or a urinary bladder. 45. A method for detecting movement of a bodily fluid in subject, comprising (a) administering the compound of claim 1 to the subject; (b) contacting the subject with electromagnetic radiation comprising an excitation wavelength of the fluorophore; and (c) detecting electromagnetic radiation emitted from the compound, wherein detection of the radiation indicates the presence of the bodily fluid. 46. The method of claim 45, wherein the bodily fluid comprises blood. 47. The method of claim 46, wherein the blood is in circulation, within a bodily lumen, within a vessel lumen, within a capillary lumen, within a vein lumen, within an artery lumen, or within a solid tissue. 48. The method of claim 45, wherein the bodily fluid comprises lymph. 49. The method of claim 40, wherein the compound is administered to the subject via intravessical instillation, intravenous administration, intraperitoneal administration, topical administration, mucosal administration, oral administration, intraarterial administration, intracerebral administration, intracerebroventricular administration, intrathecal administration, intracardiac administration, intracavernous administration, intraosseous administration, intraocular administration, intravitreal administration, intramuscular administration, intradermal administration, transdermal administration, transmucosal administration, intralesional administration, subcutaneous administration, epicutaneous administration, extra-amniotic administration, intravaginal administration, intravesical administration, or nasal administration. 50. The method of claim 40, wherein said compound is administered by applying a liquid, powder, or spray comprising said compound to a surface of said subject. 51. The method of claim 50, wherein said surface comprises a site within the body of said subject that is accessed via surgery. 52. The method of claim 40, wherein electromagnetic radiation emitted from said compound is detected in vivo. 53. The method of claim 40, wherein electromagnetic radiation emitted from said compound is detected ex vivo. 54. The method of claim 40, further comprising surgically removing a cancer or a precancerous cell or tissue identified by step (c). 55. The method of claim 47, wherein the method comprises fluorescence angiography. 56. The method of claim 47, which is performed during an ophthalmologic procedure, cardiothoracic surgery, bypass coronary surgery, neurosurgery, hepatobilliary surgery, reconstructive surgery, cholecystectomy, colorectal resection, brain surgery, muscle perfusion, wound or trauma surgery, or laparoscopic surgery. 57. A method for detecting a fluorophore in a biological sample ex vivo, (a) contacting a biological sample from a subject with the compound of claim 1; (b) contacting the biological sample with electromagnetic radiation comprising an excitation wavelength of the fluorophore; and (c) detecting electromagnetic radiation emitted from the fluorophore. 58. The method of claim 58, wherein the biological sample comprises a tissue biopsy specimen, a liquid biopsy specimen, surgically removed tissue, a surgically removed liquid, or blood.
RELATED APPLICATION This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62/398,448, filed Sep. 22, 2016, the entire content of which is incorporated herein by reference. STATEMENT AS TO FEDERALLY SPONSORED RESEARCH This invention was made with government support under R01 GM073857 awarded by the National Institutes of Health. The government has certain rights in the invention. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Oct. 31, 2017, is named 40984-508001US_SL.txt and is 455,778 bytes in size. FIELD OF THE INVENTION The present invention relates to cancer therapy and diagnostics, including, e.g., fluorescence-image guided procedures. BACKGROUND Bladder cancer is the fifth most common cancer, constituting 4.5% of all new cancer cases in the United States. 76,960 new cases were estimated in 2016 and the death rate currently expected from bladder cancer is 21% (16,390). Approximately 2.4 percent of men and women will be diagnosed with bladder cancer at some point during their lifetime. In 2012, there were an estimated 577,403 individuals living with bladder cancer in the United States. Almost all of these patients require continuous surveillance, and, occasionally, treatments. For all stages combined, the 5-year relative survival rate is 77%. Survival declines to 70% at 10 years and 65% at 15 years after diagnosis. Bladder cancer can be non-muscle or muscle invasive. Half of all bladder cancer patients are diagnosed while the tumor is non-muscle invasive, for which the 5-year survival is 96%. Most (up to 98%) of malignant bladder tumors arise in the epithelium, 90-92% of these bladder cancers are urothelial carcinomas (Siegel et al. (2012) CA Cancer J Clin 62(1):10-29, Pasin et al. (2008) Rev Urol 10(1):31-43). Less common bladder cancers are squamous cell or adenocarcinomas. Approximately 20-25% of patients have muscle invasive disease, and of non-muscle invasive disease patients will progress to muscle invasive disease at 5 years follow up depending on intermediate or high risk of the progression (Anastasiadis & de Reijke (2012) Ther Adv Urol 4(1):13-32, Kamat et al. (2014) J Urol 192(2):305-315). SUMMARY OF THE INVENTION The present subject matter provides, inter alia, fluorescent compounds comprising, consisting essentially of, or consisting of a pH-triggered polypeptide (a “pHLIP peptide”) and a fluorophore. Such compounds may be referred to herein as “pHLIP-fluorophore compounds.” Methods and compositions comprising such fluorescent compounds are also provided. For example, non-limiting implementations relate to fluorescence-image guided medical procedures, such as fluorescence and optoacoustic imaging. In various embodiments, the pHLIP peptide has the sequence: XnYm; YmXn; XnYmXj; YmXnYi; YmXnYiXj; XnYmXjYi; YmXnYiXjYl; XnYmXjYiX; YmXnYiXjYlXh; XnYmXjYiXhYg; YmXnYiXjYlXhYg; XnYmXjYiXhYgXf; (XY)n; (YX)n; (XY)nYm; (YX)nYm; (XY)nXm; (YX)nXm; Ym(XY)n; Ym(YX)n; Xn(XY)m; Xn(YX)m; (XY)nYm(XY)i; (YX)nYm(YX)i; (XY)nXm(XY)i; (YX)nXm(YX)i; Ym(XY)n; Ym(YX)n; Xn(XY)m; Xn(YX)m, wherein, i) Y is a non-polar amino acid with solvation energy, ΔGXcor>+0.50, or Gly (see, e.g., Table 1), ii) X is a protonatable amino acid, and iii) n, m, I, j, l, h, g, f are integers from 1 to 8. In some embodiments, the pHLIP peptide has the following sequence: NH2-ACDDQNPWRAYLDLLFPTDTLLLDLLWA-COOH (SEQ ID NO: 4), where “NH2—” is the amino-terminal end of the peptide (and is part of the N-terminal alanine) and the “—COOH” is the carboxy-terminal end of the peptide (and is part of the C-terminal alanine). In amino acid sequences disclosed herein (e.g., in text, tables, structures, lists, or otherwise), the “NH2—” and/or the “—COOH” of a peptide may optionally be omitted or not shown. In certain embodiments, the fluorophore is covalently attached to the cysteine of a pHLIP peptide having the sequence: NH2-ACDDQNPWRAYLDLLFPTDTLLLDLLWA-COOH (SEQ ID NO: 4). In various embodiments, the pHLIP-fluorophore compound has the following structure (SEQ ID NO: 4 is disclosed below): In the sequence above, the pHLIP peptide sequence is NH2-ACDDQNPWRAYLDLLFPTDTLLLDLLWA-COOH (SEQ ID NO: 4), however the structures of the alanine and the cysteine at the N-terminal end of the peptide are shown. In some embodiments, the pHLIP peptide has a net negative charge at a pH of about 7.5 or 7.75 in water. In certain embodiments, the pHLIP peptide has an acid dissociation constant at logarithmic scale (pKa) of less than about 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, or 7. In various embodiments, the pHLIP peptide comprising at least 1 artificial protonatable amino acid. As used herein, an “artificial” amino acid is an amino acid that is not genetically encoded. In some embodiments, the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 40 genetically coded amino acids. In certain embodiments, the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 40 non-genetically coded amino acids. In various embodiments, the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 40 D-amino acids. In some embodiments, the pHLIP peptide comprises at least 8 amino acids, wherein, at least 2, 3, or 4 of the 8 amino acids of said peptide are non-polar, and at least 1, 2, 3, or 4 of the at least 8 amino acids of said pHLIP peptide are protonatable. In certain embodiments, the pHLIP peptide comprises a functional group to which a fluorophore may be attached. For example, the pHLIP peptide comprised a functional group before it was part of the pHLIP-fluorophore compound, and the fluorophore was attached covalently to the pHLIP peptide via a chemical interaction involving the functional group. In some embodiments, the pHLIP peptide comprises a functional group, and the fluorophore is non-covalently attached (e.g., via non-covalent binding such as an electrostatic interaction) to the functional group. In the context of attachment of a pHLIP peptide to a fluorophore, a “functional group” is a portion of a compound (such as a pHLIP peptide) that is used to attach the compound to another compound (such as a pHLIP peptide to a fluorophore). A “functional group” may optionally be referred to as an “attachment group.” In various embodiments, a functional group is chemically reactive. In some embodiments, a functional group on a pHLIP peptide reacts with a functional group on a fluorophore to leave a covalent bond that connects the pHLIP peptide to the fluorophore, resulting in a pHLIP-fluorophore compound. Non-limiting examples of functional groups include amino acid side chains (such as the —SH side chain of cysteine or a —NH2 side chain of lysine); thiols (e.g., moieties comprising, consisting essentially of, or consisting of —SH); esters such as maleimide esters; moieties comprising -she; and moieties that may be involved in click reactions (such as azides, alkynes, strained difluorooctynes, diaryl-strained-cyclooctynes, 1,3-nitrones, cyclooctenes, trans-cycloalkenes, oxanorbornadienes, tetrazines, tetrazoles, activated alkenes, and oxanorbomadienes. As used herein, the term “fluorophore” includes any compound that emits energy. The energy may be in the form of, e.g., acoustic energy (such as sound waves), heat, or electromagnetic radiation. In various embodiments, the electromagnetic radiation may be visible or non-visible to the human eye. In some embodiments, the electromagnetic radiation is infrared or near-infrared. Non-limiting examples of fluorophores include luminescent compounds, fluorescent compounds, phosphorescent compounds, chemiluminescent compounds, optoacoustic compounds, and quencher compounds (e.g., fluorescent quencher compounds). Fluorophores may comprise, e.g., small molecule compounds (e.g., organic compounds having a molecular weight of less than about 2000, 1000, or 500 daltons), proteins, or chelated metals (e.g., a chelator attached to a metal via covalent or non-covalent coordination bonds, wherein the combination of the chelator and the metal is fluorescent). In some embodiments, a chelated metal is within a “cage” formed by a chelator, and the combination of the chelator and the metal is fluorescent. In certain embodiments, the emission of energy (e.g., electromagnetic radiation such as luminescence, acoustic energy such as sound waves, or heat) does not involve the absorption and then emission of energy. In some embodiments, the emission of energy involves the absorbance and then the emission of energy. As used herein, a compound that transfers greater than 50% the energy of absorbed light into the heat is called a “quencher.” In some embodiments, a quencher transfers all of the energy of absorbed light into heat. In various embodiments, a quencher can emit some amount of light, but most of the absorbed energy (e.g., at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% of the absorbed energy) is transferred into the heat. Non-limiting examples of quenchers include: i) Dabsyl (dimethylaminoazobenzenesulfonic acid); ii) Black Hole Quenchers (which can quench in wide range of practically the entire visible spectrum); and iii) IRDye QC-1 [which can quench in the range for visible to NIR (500-900 nm)]. A main principle of optoacoustic imaging is the following: Absorption of light by a fluorophore or quencher, and the transfer of energy into heat, which leads to thermal expansion and the generation of acoustic waves, which are detected. In general, fluorophores transfer some, e.g., a minimal amount, of energy to heat; however most of the energy of a fluorophore is emitted in a form of light. In certain preferred embodiments relating to luminescent fluorophores (e.g., fluorophores that emit electromagnetic radiation such as light), a fluorophore emits more energy in the form of electromagnetic radiation (e.g., light), and less energy is transferred to heat. In certain preferred embodiments relating to quenchers, a quencher emits less energy in the form of electromagnetic radiation (e.g., light), and more energy is transferred to heat. Therefore, ICG can be used as a fluorophore in fluorescent imaging, as well as in optoacoustic imaging, due its property of transferring some energy to the heat. In various embodiments, 1, 2, 3, 4, 5 or more fluorophores are attached to the pHLIP peptide. In some embodiments, the functional group of the pHLIP peptide to which a fluorophore may be (or has been) attached comprises an amino acid, azido modified amino acid, or alkynyl modified amino acid. In certain embodiments, the pHLIP peptide is covalently attached to the fluorophore via an amide bond. In certain embodiments, the functional group of the pHLIP peptide comprises (or comprised) a free sulfhydryl (SH), or a primary amine. In embodiments, the pHLIP peptide is attached to one or more fluorophores (e.g., a fluorophore, a quencher such as a fluorophore quencher, or a combination comprising a fluorophore-quencher pair) to form a pHLIP-fluorophore compound that is used as a diagnostic, imaging, ex vivo imaging agent, or as a research tool. In various embodiments, the pHLIP peptide comprises one or more fluorophores attached to a functional group used as a diagnostic, imaging, ex vivo imaging agent, or as a research tool. In some embodiments, the fluorophore comprises a fluorescent dye, or a fluorescent quencher, or a combination of both. In some embodiments, a fluorophore-quencher system used in fluorescence-guided imaging. For non-limiting descriptions of such systems, see, e.g., www.bachem.com/service-support/newsletter/peptide-trends-july-2016/. A non-limiting example of the use of a fluorophore-quencher system is described in Karabadzhak et al. (2014) ACS Chem Biol. 9(11):2545-53, the entire content of which is incorporated herein by reference. In certain embodiments, when the distance between a fluorophore and a quencher increases [e.g., because of a conformational change or due to the breakage of a bond (such as a peptide or other bond) connecting the fluorophore and the quencher], then the intensity of emission of fluorophore increases. In certain embodiments, the efficiency of fluorescence increases when the distance between the fluorophore and the quencher increases, which results in increased of fluorescent intensity. In some embodiments, a pHLIP compound comprising a fluorophore or a quencher (e.g., a pHLIP-quencher) is used for optoacoustic imaging. In various embodiments, optoacoustic imaging comprises a compound or moiety that absorbs light and transfers it to heat (e.g., with a optoacoustic imaging agent), which is measured by ultrasound, as opposed to fluorescence. In embodiments, fluorescence comprises a compound of moiety that absorbs light and emits it in the form of fluorescence or phosphorescence. In some embodiments, a fluorophore (e.g., a fluorophore that emits more energy in the form of light than heat) is used for optoacoustic imaging. In certain embodiments, an ICG-pHLIP peptide is used for optoacoustic imaging. A non-limiting example of the use of a compound comprising a pHLIP peptide and a fluorescent dye as a multispectral optoacoustic tomography (MSOT) imaging agent is described in Kimbrough et al. (2015) Clin Cancer Res. 21(20):4576-85, the entire content of which is incorporated herein by reference. In certain embodiments, the fluorophore comprises a near-infrared (NIR) fluorescent dye, e.g., indocyanine green (ICG), which operates in (e.g., has a peak emission wavelength within) NIR wavelengths. Infrared radiation extends from the nominal red edge of the visible spectrum at 700 nanometers (nm) to 1 mm. NIR radiation comprises a wavelength of 750 nm to 1.4 m. In some embodiments, the ICG has a peak emission wavelength between 810 nm and 880 nm (e.g., in the context of a pHLIP-fluorophore compound). In certain embodiments, the ICG has a peak emission wavelength between 810 nm and 860 nm. In various embodiments, the ICG has a peak emission wavelength of about 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, or 880 nm. In some embodiments, a 805 nm laser is used for ICG excitation. In certain embodiments, a 801, 802, 803, 804, 804, 805, 806, 807, 808, 809, 810, 800-805, 804-806, or 802-807 nm laser is used for ICG excitation. Non-limiting examples of NIR imaging systems (which may be useful in, e.g., clinical and diagnostic applications) include INFRARED 800™, available from Carl Zeiss Meditec AG; Artemis®, available from Quest Medical Imaging BV; HyperEye Medical System®, available from Mizuho Medical Co. Ltd.; Near infrared fluorescence imager PDE® C9830, available from Hamamatsu Photonics K.K.; SPECTROPATH® Image-Guided Surgery System, available from Spectropath Inc.; the following from NOVADAQ Technologies Inc.: SPY Elite® (imaging for open surgery), PINPOINT® (endoscopic fluorescence imaging), LUNA® (Fluorescence Angiography for Wound Care); Firefly® Fluorescence imaging for the da Vinci Si System, available from Intuitive Surgical Inc.; NIR Leica® FL800, available from Leica Microsystems; Fluobeam®, available from Fluoptics Minatec-BHT; KG, Storz Karl Storz-Endoskope® (Near-Infrared/Indocyanine Green), available from Karl Storz GmbH & Co.; and InfraVision™ Imaging System, available from Stryker Corporation. In various embodiments, the fluorophore comprises an agent that operates at a wavelength (e.g., has a peak emission wavelength within) of from about 670 nm to about 750 nm, e.g., methylene blue. In certain embodiments, the fluorophore comprises a cyanine dye. In embodiments, a cyanine dye operates at a wavelength (e.g., has a peak emission wavelength within) of 550-620 nm, 590-700 nm, 650-730 nm, 680-770 nm, 750-820 nm, or 770-850 nm. Non-limiting examples of cyanine dyes include Cy2, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, Cy7, and Cy7.5. In some embodiments, the cyanine dye is Cy3, Cy3.5, Cy5, Cy5.5, Cy7, or Cy7.5. In certain embodiments, the Cy3 has a peak emission wavelength between 550 and 620 nm (e.g., in the context of a pHLIP-fluorophore compound). In various embodiments, the Cy3.5 has a peak emission wavelength between 590 and 700 nm (e.g., in the context of a pHLIP-fluorophore compound). In some embodiments, the Cy5 has a peak emission wavelength between 650 and 730 nm (e.g., in the context of a pHLIP-fluorophore compound). In certain embodiments, the Cy5.5 has a peak emission wavelength between 680 and 770 nm (e.g., in the context of a pHLIP-fluorophore compound). In various embodiments, the Cy7 has a peak emission wavelength between 750 and 820 nm (e.g., in the context of a pHLIP-fluorophore compound). In certain embodiments, the Cy7.5 has a peak emission wavelength between 770 and 850 nm (e.g., in the context of a pHLIP-fluorophore compound). In some embodiments, the peak emission wavelength of a fluoroophore may vary (e.g., by about 5, 6, 7, 8, 9, or 10%) based on the environment and/or solvent around the fluorophore. In some embodiments, the fluorophore comprises a fluorescent, or an optoacoustic contrast imaging agent. In certain embodiments, an optoacoustic imaging agent is fluorescent. In various embodiments, an optoacoustic imaging agent is not fluorescent. In certain embodiments, an optoacoustic imaging agent absorbs light, and transfers most of the light's energy (e.g., at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% of the light's energy) into heat. In various embodiments, the heat is detected by ultrasound. In some embodiments, a quencher is be a fluorophore with a very low quantum yield, such that most of the energy absorbed by the quencher is transferred to heat rather than electromagnetic radiation (such as light). Non-limiting examples of optoacoustic contrast imaging agents include ICG (which can be used for fluorescent imaging as well as for optoacoustic imaging), Alexa Fluor 750, Evans blue, BHQ3 (Black Hole Quencher®-3; commercially available from, e.g., Biosearch Technologies, California, United States), QXL®680 (commercially available from, e.g., Cambridge Bioscience, Cambridge, United Kingdom), IRDye®800CW (commercially available from, e.g., LI-COR, Nebraska, United States), MMPSense™ 750 FAST (commercially available from, e.g., PerkinElmer Inc., Texas, United States), diketopyrrolopyrrole cyanine, cypate-C18, Au nanoparticles (such as Au nanospheres, Au nanoshells, Au nanorods, Au nanocages, Au nanoclusters, Au nanostars, and Au nanobeacons), nanoparticles comprising a gold core covered with the Raman molecular tag trans-1,2-bis(4-pyridyl)-ethylene, Ag nanoplates, Ag nanosystems, quantum dots, nanodiamonds, polypyrrole nanoparticles, copper sulfide, graphene nanosheets, iron oxide-gold core-shells, Gd2O3, single-walled carbon nanotubules, dye-loaded perfluorocarbon-based nanoparticles, AuMBs, triggered nanodroplets, cobalt nanowontons, nanoroses, goldsilica core shell nanorods, superparamagnetic iron oxide, and methylene blue. Non-limiting examples and descriptions of optoacoustic contrast imaging agents are described in Wu et al. (2014) Int. J. Mol. Sci., 15, 23616-23639 (see, e.g., Table 1), the entire contents of which are incorporated herein by reference. In various embodiments, a pHLIP-fluorophore compound provided herein is for use as an agent in preoperative, intraoperative and postoperative settings. In some embodiments, a pHLIP-fluorophore compound provided herein is for use as an agent for ex vivo imaging, and ex vivo diagnostics. In various embodiments, a pHLIP-fluorophore compound provided herein is used to detect or image diseased tissue. Non-limiting examples of diseased tissue include cancerous tissue, inflamed tissue, ischemic tissue, arthritic tissue, cystic fibrotic tissue, tissue infected with a microorganism, and atherosclerotic tissue. In some embodiments, a pHLIP-fluorophore compound provided herein is for use as an agent in fluorescence angiography. Fluorescence angiography is a procedure in which a fluorescent compound (such as a pHLIP-fluorophore compound disclosed herein) is injected into the bloodstream. The fluorescent compound highlights the blood vessels. In various embodiments, the vessels are in the back of the eye. In some embodiments the vessels are imaged or photographed. In non-limiting examples, fluorescence angiography is used to identify, detect image, or manage an eye disorder. In certain embodiments relating to ophthalmology, fluorescence angiography may be used to look at blood flow in, e.g., the retina and choroid. In various embodiments, fluorescence angiography provides real-time imaging of blood vessels to follow changes during surgical procedures. Some non-limiting examples include the use of fluorescence in ophthalmology to evaluate the chorioretinal vasculature; in cardiothoracic surgery to assess the effectiveness of a coronary artery bypass; in neurovascular surgery to assess the effect of a superficial temporal artery-middle cerebral artery bypass graft in cerebral revascularization procedure; in hepatobilliary surgery to identify the haptic segment and subsegment for anatomical hepatic resection; in reconstructive surgeries; and in cholecystectomy and colorectal resection. In non-limiting examples of diagnostic applications, fluorescence angiography is used for imaging of hemodynamics in the brain; circulatory features of rheumatoid arthritis; muscle perfusion; burns and to assess various other effects of trauma. In certain embodiments, a pHLIP-fluorophore compound provided herein is for visualization of blood circulation in ophthalmology, cardiothoracic surgery, bypass coronary surgery, neurosurgery, hepatobilliary surgery, reconstructive surgery, cholecystectomy, colorectal resection, brain surgery, muscle perfusion, wound and trauma surgery, and laparoscopic surgery. In various embodiments, a pHLIP-fluorophore compound provided herein is for visualization of lymph nodes. In some embodiments, a pHLIP-fluorophore compound provided herein is for visualization or detection of pre-cancerous tissue or cancerous lesions. In certain embodiments, a pHLIP-fluorophore compound provided herein is for visualization or detection of pre-cancerous tissue or cancerous lesions in bladder, upper urinary tract, kidney, prostate, breast, head and neck, oral, pancreatic, lungs, liver, cervical, ovarian, or brain tumors. In various embodiments, a pHLIP-fluorophore compound provided herein for real-time assessment of blood flow and tissue perfusion during intraoperative procedures. In an aspect, provided herein is a composition for parenteral, local, or systemic administration comprising a pHLIP-fluorophore compound. In an aspect, included herein is a composition for intravenous, intraarterial, intraperitoneal, intracerebral, intracerebroventricular, intrathecal, intracardiac, intracavemous, intraosseous, intraocular, intravitreal administration of a pHLIP-fluorophore compound. In an aspect, provided herein is composition for intramuscular, intradermal, transdermal, transmucosal, intralesional, subcutaneous, topical, epicutaneous, extra-amniotic, intravaginal, intravesical, nasal, or oral administration of a pHLIP-fluorophore compound. In an aspect, included herein is a composition for an ex vivo treatment of biopsy specimens, liquid biopsy specimens, surgically removed tissue, surgically removed liquids, or blood comprising a pHLIP-fluorophore compound. In an aspect, a subject's blood is contacted with the pHLIP-fluorophore compound (e.g., in vivo or ex vivo). In various embodiments, a lower dose of a fluorophore (such as ICG) is effective when the fluorophore is part of a pHLIP fluorophore composition, e.g., conjugate, compared to the effective dose (e.g., for imaging or detection) of the free fluorophore, e.g., the non-conjugated fluorophore. In some embodiments, administration of a lower effective dose of the fluorophore as part of a pHLIP fluorophore compound results in lower side effects. In certain embodiments, a fluorophore may make a subject more sensitive to solar radiation after administration such that the subject develops a greater degree of sunburn following exposure to solar radiation compared to a subject to which a fluorophore such as ICG has not been administered. In various embodiments, a fluorophore is delivered as part of a pHLIP fluorophore compound to subject in a lower dose than would be necessary if the fluorophore was administered in free form, thereby reducing or minimizing phototoxicity (e.g., toxicity to the skin/sunburn) from exposure to solar radiation than if the free form of the fluorophore was administered. In some embodiments, the pHLIP-fluorophore compound comprises a pHLIP and ICG (e.g., an ICG-pHLIP peptide such as ICG-Var3). In certain embodiments, the pHLIP-fluorophore compound is administered at a dose of about 0.01-0.5 mg/kg of a subject. In various embodiments, the pHLIP-fluorophore compound is administered at a dose of about 0.02-0.2 mg/kg of a subject. In some embodiments, the pHLIP-fluorophore compound is administered at a dose of about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.125, 0.15, 0.175, 0.2, 0.25, or 0.5 mg/kg of a subject. In certain embodiments, the pHLIP-fluorophore compound is administered at a dose of at least about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.125, 0.15, 0.175, or 0.2 mg/kg, but less than about 0.25, 0.5, 1, 2, 3, 4, or 5 mg/kg. In various embodiments, 1-10 mg of the pHLIP-fluorophore compound is administered to a subject. In some embodiments, about 0.5 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 15 mg of the pHLIP-fluorophore compound is administered to a subject. In certain embodiments, at least 0.5, 1, 2, or 3 mg, but less than 10 or 1 mg, of the pHLIP-fluorophore compound is administered to the subject. In various embodiments, about 0.3-3 μmol of the pHLIP-fluorophore compound is administered to the subject. In some embodiments, about 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 μmol of the pHLIP-fluorophore compound is administered to the subject. In certain embodiments, at least about 0.1, 0.5, or 1 μmol, but less than 3, 4, or 5 μmol, of the pHLIP-fluorophore compound is administered to the subject. In various embodiments, the pHLIP-fluorophore compound is administered by intravenous injection for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-10, 1-15, 5-10, 5-15, 5-20, 10-15, 10-20, or 15-20 minutes. In certain embodiments, about 0.5 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 15 mg of the pHLIP-fluorophore compound is instilled into an organ or tissue (e.g. a bladder). In certain embodiments, at least 0.5, 1, 2, or 3 mg, but less than 10 or 1 mg, of the pHLIP-fluorophore compound is instilled into an organ or tissue (e.g. a bladder). In various embodiments, about 0.3-3 μmol of the pHLIP-fluorophore compound is instilled into an organ or tissue (e.g. a bladder). In some embodiments, about 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 μmol of the pHLIP-fluorophore compound is instilled into an organ or tissue (e.g. a bladder). In certain embodiments, at least about 0.1, 0.5, or 1 μmol, but less than 3, 4, or 5 μmol, of the pHLIP-fluorophore compound is instilled into an organ or tissue (e.g. a bladder). In various embodiments, the pHLIP-fluorophore compound is instilled into an organ or tissue (e.g. a bladder) for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-10, 1-15, 5-10, 5-15, 5-20, 10-15, 10-20, or 15-20 minutes. In certain embodiments, the pHLIP-fluorophore compound further comprises polyethylene glycol. In some embodiments, the pHLIP-fluorophore compound further comprises one or more polyethylene glycol subunits (e.g., 3, 4, 5, 6, 7, 8, 9, 0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 3-10, 10-20, or 3-20 subunits). Included herein is a method for detecting (e.g., imaging) blood flow in a subject, comprising (a) administering a pHLIP-fluorophore compound comprising a fluorophore (such as ICG) disclosed herein to the subject; (b) contacting the subject (e.g., an area, cell, tissue, or organ of the subject, such as an area or tissue that may comprise a portion of the administered pHLIP-fluorophore compound) with electromagnetic radiation comprising an excitation wavelength of the fluorophore; and (c) detecting electromagnetic radiation emitted from the pHLIP-fluorophore compound in the subject. In embodiments, detection of the radiation indicates the presence (e.g., the location or amount at a location) of blood in the subject. In embodiments, an image of the blood in the subject is produced. Also provided is a method for detecting (e.g., imaging) a pHLIP-fluorophore compound in a subject, comprising (a) administering a pHLIP-fluorophore compound comprising a fluorophore (such as ICG) disclosed herein to the subject; (b) contacting the subject (e.g., an area or tissue of the subject, such as an area, cell, tissue, or organ that may comprise a portion of the administered pHLIP-fluorophore compound) with electromagnetic radiation comprising an excitation wavelength of the fluorophore; and (c) detecting electromagnetic radiation emitted from the pHLIP-fluorophore compound in the subject. In embodiments, detection of the radiation indicates the presence (e.g., the location or amount at a location) of a bodily fluid such as blood in the subject. In embodiments, an image of the blood in the subject is produced. Included herein is a method for optoacoustic detection or imaging of blood flow in a subject, comprising (a) administering a pHLIP-fluorophore compound, wherein the fluorophore is an optoacoustic imaging agents such as a luminescent fluorophore or a quencher; (b) contacting the subject (e.g., an area, cell, tissue, or organ of the subject, such as an area or tissue that may comprise a portion of the administered pHLIP-fluorophore compound) with electromagnetic radiation comprising an excitation wavelength of the fluorophore; and (c) detecting energy such as acoustic energy (e.g., sound waves). In embodiments, detection of the energy indicates the presence (e.g., the location or amount at a location) of blood in the subject. In various embodiments, an image of the blood in the subject is produced. In some embodiments, the presence of acoustic energy is detected by ultrasound (e.g., heat is released and creates expansion, generating sound waves, which is detected). The present subject matter also provides a method for detecting (e.g., imaging) a pHLIP-fluorophore compound in a subject, wherein the fluorophore is an optoacoustic imaging agents such as a luminescent fluorophore or a quencher, the method comprising (a) administering the pHLIP-fluorophore compound to the subject; (b) contacting the subject (e.g., an area or tissue of the subject, such as an area, cell, tissue, or organ that may comprise a portion of the administered pHLIP-fluorophore compound) with electromagnetic radiation comprising an excitation wavelength of the fluorophore; and (c) detecting energy such as acoustic energy (e.g., sound waves). In embodiments, detection of the energy indicates the presence (e.g., the location or amount at a location) of a bodily fluid such as blood in the subject. In embodiments, an image of the blood in the subject is produced. In embodiments, the presence of acoustic energy is detected by ultrasound. Depending on context, “excitation wavelength” may be used synonymously with “absorption wavelength.” In various embodiments, the method comprises a fluorescence-guided imaging procedure performed during surgery or during a doctor's visit. In some embodiments, the method comprises fluorescence angiography. In certain embodiments, the method comprises the assessment of the perfusion of tissues and organs. In various embodiments, the method comprises the assessment of hepatic function. In some embodiments, the fluorescence-guided imaging procedure comprises targeting, marking, detecting, or visualization of pre-cancerous tissue, cancerous tissue, inflamed tissue, ischemic tissue, arthritic tissue, tissue infected with a microorganism, and/or atherosclerotic tissue. In certain embodiments, the method comprises assessing patency of a coronary artery bypass during cardiothoracic surgery. In some embodiments, the method comprises assessing the effect of a superficial temporal artery-middle cerebral artery bypass graft during or after neurovascular surgery, e.g., in a cerebral revascularization procedure. In certain embodiments, the method comprises identify the haptic segment and subsegment for anatomical hepatic resection during hepatobilliary surgery. In some embodiments, the method comprises imaging tissue or blood during a reconstructive surgery. In certain embodiments, the method comprises imaging tissue or blood during cholecystectomy or colorectal resection. In some embodiments, the method comprises intraoperatively identifying brain tumors such as malignant gliomas. In various embodiments, the method comprises a diagnostic imaging procedure. In some embodiments, the method comprises retinal angiography. In certain embodiments, the method comprises detecting or imaging chorioretinal vasculature. In some embodiments, the method comprises mapping and visualization of lymph nodes. In certain embodiments, the method comprises targeting and marking (e.g., visualizing or detecting) pre-cancerous tissue, cancerous lesions and/or assessment of tumor margins. In various embodiments, the pHLIP-fluorophore compound is administered by parenteral, local, or systemic administration. In certain embodiments, a pHLIP-fluorophore compound is administered by intravenous, intraarterial, intraperitoneal, intracerebral, intracerebroventricular, intrathecal, intracardiac, intracavemous, intraosseous, intraocular, or intravitreal administration. In various embodiments, pHLIP-fluorophore compound is administered by intramuscular, intradermal, transdermal, transmucosal, intralesional, subcutaneous, topical, epicutaneous, extra-amniotic, intravaginal, intravesical, nasal, or oral administration. In an aspect, provided herein is a method for the ex vivo staining of human specimens and ex vivo diagnostics, comprising (a) contacting a biological sample from a subject with a pHLIP-fluorophore compound comprising a fluorophore (such as ICG) disclosed herein; (b) contacting the biological sample with electromagnetic radiation comprising an excitation wavelength of the fluorophore; and (c) detecting electromagnetic radiation emitted from the pHLIP-fluorophore compound. In embodiments, the biological sample comprises a biopsy specimen, a liquid biopsy specimen, surgically removed tissue, a surgically removed liquid, or blood. In some embodiments, the pHLIP peptide comprises a sequence of at least 8 to 25 consecutive amino acids (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 consecutive amino acids) that is present in any one of the following sequences: (SEQ ID NO: 36) WARYADWLFTTPLLLLDLALL, (SEQ ID NO: 37) YARYADWLFTTPLLLLDLALL, (SEQ ID NO: 38) WARYSDWLFTTPLLLYDLGLL, (SEQ ID NO: 39) WARYTDWFTTPLLLYDLALLA, (SEQ ID NO: 40) WARYTDWLFTTPLLLYDLGLL, (SEQ ID NO: 41) WARYADWLFTTPLLLLDLSLL, (SEQ ID NO: 42) LLALDLLLLPTTFLWDAYRAW, (SEQ ID NO: 43) LLALDLLLLPTTFLWDAYRAY, (SEQ ID NO: 44) LLGLDYLLLPTTFLWDSYRAW, (SEQ ID NO: 45) ALLALDYLLLPTTFWDTYRAW, (SEQ ID NO: 46) LLGLDYLLLPTTFLWDTYRAW, (SEQ ID NO: 47) LLSLDLLLLPTTFLWDAYRAW, (SEQ ID NO: 48) GLAGLLGLEGLLGLPLGLLEGLWLGL, (SEQ ID NO: 49) LGLWLGELLGLPLGLLGELGLLGALG, (SEQ ID NO: 50) WRAYLDLLFPTDTLLLDLLW, (SEQ ID NO: 51) WLLDLLLTDTPFLLDLYARW, (SEQ ID NO: 52) WARYLEWLFPTETLLLEL, (SEQ ID NO: 53) WAQYLELLFPTETLLLEW, (SEQ ID NO: 54) LELLLTETPFLWELYRAW, (SEQ ID NO: 55) WELLLTETPFLLELYQAW, (SEQ ID NO: 56) WLFTTPLLLLNGALLVE, (SEQ ID NO: 57) WLFTTPLLLLPGALLVE, (SEQ ID NO: 58) WARYADLLFPTTLAW, (SEQ ID NO: 59) EVLLAGNLLLLPTTFLW, (SEQ ID NO: 60) EVLLAGPLLLLPTTFLW, (SEQ ID NO: 61) WALTTPFLLDAYRAW, (SEQ ID NO: 62) NLEGFFATLGGEIALWSLVVLAIE, (SEQ ID NO: 63) EGFFATLGGEIALWSDVVLAIE, (SEQ ID NO: 64) EGFFATLGGEIPLWSDVVLAIE, (SEQ ID NO: 65) EIALVVLSWLAIEGGLTAFFGELN, (SEQ ID NO: 66) EIALVVDSWLAIEGGLTAFFGE, (SEQ ID NO: 67) EIALVVDSWLPIEGGLTAFFGE, (SEQ ID NO: 68) ILDLVFGLLFAVTSVDFLVQW, and (SEQ ID NO: 69) WQVLFDVSTVAFLLGFVLDLI. In embodiments, the pHLIP peptide comprises the amino acid sequence WRAYLDLLFPTDTLLLDLLW (SEQ ID NO: 50) with additional amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids) optionally added to either side. In certain embodiments, the pHLIP peptide has the sequence: (SEQ ID NO: 70) WARYADWLFTTPLLLLDLALL, (SEQ ID NO: 71) YARYADWLFTTPLLLLDLALL, (SEQ ID NO: 72) WARYSDWLFTTPLLLYDLGLL, (SEQ ID NO: 73) WARYTDWFTTPLLLYDLALLA, (SEQ ID NO: 74) WARYTDWLFTTPLLLYDLGLL, (SEQ ID NO: 75) WARYADWLFTTPLLLLDLSLL, (SEQ ID NO: 76) LLALDLLLLPTTFLWDAYRAW, (SEQ ID NO: 77) LLALDLLLLPTTFLWDAYRAY, (SEQ ID NO: 78) LLGLDYLLLPTTFLWDSYRAW, (SEQ ID NO: 79) ALLALDYLLLPTTFWDTYRAW, (SEQ ID NO: 80) LLGLDYLLLPTTFLWDTYRAW, (SEQ ID NO: 81) LLSLDLLLLPTTFLWDAYRAW, (SEQ ID NO: 82) GLAGLLGLEGLLGLPLGLLEGLWLGL, (SEQ ID NO: 83) LGLWLGELLGLPLGLLGELGLLGALG, (SEQ ID NO: 84) WRAYLDLLFPTDTLLLDLLW, (SEQ ID NO: 85) WLLDLLLTDTPFLLDLYARW, (SEQ ID NO: 86) WARYLEWLFPTETLLLEL, (SEQ ID NO: 87) WAQYLELLFPTETLLLEW, (SEQ ID NO: 88) LELLLTETPFLWELYRAW, (SEQ ID NO: 89) WELLLTETPFLLELYQAW, (SEQ ID NO: 90) WLFTTPLLLLNGALLVE, (SEQ ID NO: 91) WLFTTPLLLLPGALLVE, (SEQ ID NO: 92) WARYADLLFPTTLAW, (SEQ ID NO: 93) EVLLAGNLLLLPTTFLW, (SEQ ID NO: 94) EVLLAGPLLLLPTTFLW, (SEQ ID NO: 95) WALTTPFLLDAYRAW, (SEQ ID NO: 96) NLEGFFATLGGEIALWSLVVLAIE, (SEQ ID NO: 97) EGFFATLGGEIALWSDVVLAIE, (SEQ ID NO: 98) EGFFATLGGEIPLWSDVVLAIE, (SEQ ID NO: 99) EIALVVLSWLAIEGGLTAFFGELN, (SEQ ID NO: 100) EIALVVDSWLAIEGGLTAFFGE, (SEQ ID NO: 101) EIALVVDSWLPIEGGLTAFFGE, (SEQ ID NO: 102) ILDLVFGLLFAVTSVDFLVQW, or (SEQ ID NO: 103) WQVLFDVSTVAFLLGFVLDLI. In various embodiments, the pHLIP peptide comprises the sequence of at least 8 to 25 consecutive amino acids (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 consecutive amino acids) that is present in any one of the following sequences: (SEQ ID NO: 104) WARYAXWLFTTPLLLLXLALL, (SEQ ID NO: 105) YARYAXWLFTTPLLLLXLALL, (SEQ ID NO: 106) WARYSXWLFTTPLLLYXLGLL, (SEQ ID NO: 107) WARYTXWFTTPLLLYXLALLA, (SEQ ID NO: 108) WARYTXWLFTTPLLLYXLGLL, (SEQ ID NO: 109) WARYAXWLFTTPLLLLXLSLL, (SEQ ID NO: 110) LLALXLLLLPTTFLWXAYRAW, (SEQ ID NO: 111) LLALXLLLLPTTFLWXAYRAY, (SEQ ID NO: 112) LLGLXYLLLPTTFLWXSYRAW, (SEQ ID NO: 113) ALLALXYLLLPTTFWXTYRAW, (SEQ ID NO: 114) LLGLXYLLLPTTFLWXTYRAW, (SEQ ID NO: 115) LLSLXLLLLPTTFLWXAYRAW, (SEQ ID NO: 116) GLAGLLGLXGLLGLPLGLLXGLWLGL, (SEQ ID NO: 117) LGLWLGXLLGLPLGLLGXLGLLGALG, (SEQ ID NO: 118) WRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 119) WLLXLLLTXTPFLLXLYARW, (SEQ ID NO: 120) WARYLXWLFPTXTLLLXL, (SEQ ID NO: 121) WAQYLXLLFPTXTLLLXW, (SEQ ID NO: 122) LXLLLTXTPFLWXLYRAW, (SEQ ID NO: 123) WXLLLTXTPFLLXLYQAW, (SEQ ID NO: 124) WLFTTPLLLLNGALLVX, (SEQ ID NO: 125) WLFTTPLLLLPGALLVX, (SEQ ID NO: 126) WARYAXLLFPTTLAW, (SEQ ID NO: 127) XVLLAGNLLLLPTTFLW, (SEQ ID NO: 128) XVLLAGPLLLLPTTFLW, (SEQ ID NO: 129) WALTTPFLLXAYRAW, (SEQ ID NO: 130) NLXGFFATLGGXIALWSLVVLAIX, (SEQ ID NO: 131) XGFFATLGGXIALWSXVVLAIX, (SEQ ID NO: 132) XGFFATLGGXIPLWSXVVLAIX, (SEQ ID NO: 133) XIALVVLSWLAIXGGLTAFFGXLN, (SEQ ID NO: 134) XIALVVXSWLAIXGGLTAFFGX, (SEQ ID NO: 135) XIALVVXSWLPIXGGLTAFFGX, (SEQ ID NO: 136) ILXLVFGLLFAVTSVXFLVQW, and (SEQ ID NO: 137) WQVLFXVSTVAFLLGFVLXLI, wherein each X is, individually, D, E, Gla, or Aad. In some embodiments, the pHLIP peptide comprises the sequence: (SEQ ID NO: 138) WARYAXWLFTTPLLLLXLALL, (SEQ ID NO: 139) YARYAXWLFTTPLLLLXLALL, (SEQ ID NO: 140) WARYSXWLFTTPLLLYXLGLL, (SEQ ID NO: 141) WARYTXWFTTPLLLYXLALLA, (SEQ ID NO: 142) WARYTXWLFTTPLLLYXLGLL, (SEQ ID NO: 143) WARYAXWLFTTPLLLLXLSLL, (SEQ ID NO: 144) LLALXLLLLPTTFLWXAYRAW, (SEQ ID NO: 145) LLALXLLLLPTTFLWXAYRAY, (SEQ ID NO: 146) LLGLXYLLLPTTFLWXSYRAW, (SEQ ID NO: 147) ALLALXYLLLPTTFWXTYRAW, (SEQ ID NO: 148) LLGLXYLLLPTTFLWXTYRAW, (SEQ ID NO: 149) LLSLXLLLLPTTFLWXAYRAW, (SEQ ID NO: 150) GLAGLLGLXGLLGLPLGLLXGLWLGL, (SEQ ID NO: 151) LGLWLGXLLGLPLGLLGXLGLLGALG, (SEQ ID NO: 152) WRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 153) WLLXLLLTXTPFLLXLYARW, (SEQ ID NO: 154) WARYLXWLFPTXTLLLXL, (SEQ ID NO: 155) WAQYLXLLFPTXTLLLXW, (SEQ ID NO: 156) LXLLLTXTPFLWXLYRAW, (SEQ ID NO: 157) WXLLLTXTPFLLXLYQAW, (SEQ ID NO: 158) WLFTTPLLLLNGALLVX, (SEQ ID NO: 159) WLFTTPLLLLPGALLVX, (SEQ ID NO: 160) WARYAXLLFPTTLAW, (SEQ ID NO: 161) XVLLAGNLLLLPTTFLW, (SEQ ID NO: 162) XVLLAGPLLLLPTTFLW, (SEQ ID NO: 163) WALTTPFLLXAYRAW, (SEQ ID NO: 164) NLXGFFATLGGXIALWSLVVLAIX, (SEQ ID NO: 165) XGFFATLGGXIALWSXVVLAIX, (SEQ ID NO: 166) XGFFATLGGXIPLWSXVVLAIX, (SEQ ID NO: 167) XIALVVLSWLAIXGGLTAFFGXLN, (SEQ ID NO: 168) XIALVVXSWLAIXGGLTAFFGX, (SEQ ID NO: 169) XIALVVXSWLPIXGGLTAFFGX, (SEQ ID NO: 170) ILXLVFGLLFAVTSVXFLVQW, or (SEQ ID NO: 171) WQVLFXVSTVAFLLGFVLXLI, wherein each X is, individually, D, E, Gla, or Aad. In certain embodiments, the pHLIP peptide comprises the sequence of at least 8 to 25 consecutive amino acids (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 consecutive amino acids) that is present in any one of the following sequences: (SEQ ID NO: 447) X2X2RX2X2X1X2X2X2X3X3X2X2X2X2X2X1X2X2X2X2, (SEQ ID NO: 448) X2X2RX2X3X1X2X2X2X3X3X2X2X2X2X2X1X2GX2X2, (SEQ ID NO: 449) X2X2RX2X3X1X2X2X3X3X2X2X2X2X2X1X2X2X2X2X2, (SEQ ID NO: 450) X2X2RX2X2X1X2X2X2X3X3X2X2X2X2X2X1X2X3X2X2, (SEQ ID NO: 451) X2X2X2X2X1X2X2X2X2X2X3X3X2X2X2X1X2X2RX2X2, (SEQ ID NO: 452) X2X2GX2X1X2X2X2X2X2X3X3X2X2X2X1X3X2RX2X2, (SEQ ID NO: 453) X2X2X2X2X2X1X2X2X2X2X2X3X3X2X2X1X3X2RX2X2, (SEQ ID NO: 454) X2X2X3X2X1X2X2X2X2X2X3X3X2X2X2X1X2X2RX2X2, (SEQ ID NO: 455) GX2X2GX2X2GX2X1GX2X2GX2X2X2GX2X2X1GX2X2X2GX2, (SEQ ID NO: 456) X2GX2X2X2GX1X2X2GX2X2X2GX2X2GX1X2GX2X2GX2X2G, (SEQ ID NO: 457) X2RX2X2X2X1X2X2X2X2X3X1X3X2X2X2X1X2X2X2, (SEQ ID NO: 458) X2X2X2X1X2X2X2X3X1X3X2X2X2X2X1X2X2X2RX2, (SEQ ID NO: 459) X2X2RX2X2X1X2X2X2X2X3X1X3X2X2X2XX2, (SEQ ID NO: 460) X2X2QX2X2X1X2X2X2X2X3X1X3X2X2X2X1X2, (SEQ ID NO: 461) X2X1X2X2X2X3X1X3X2X2X2X2X1X2X2RX2X2, (SEQ ID NO: 462) X2X1X2X2X2X3X1X3X2X2X2X2X1X2X2QX2X2, (SEQ ID NO: 463) X2X2X2X3X3X2X2X2X2X2NGX2X2X2X2X1, (SEQ ID NO: 464) X2X2X2X3X3X2X2X2X2X2X2GX2X2X2X2X1, (SEQ ID NO: 465) X2X2RX2X2X1X2X2X2X2X3X3X2X2X2, (SEQ ID NO: 466) X1X2X2X2X2GNX2X2X2X2X2X3X3X2X2X2, (SEQ ID NO: 467) X1X2X2X2X2GX2X2X2X2X2X2X3X3X2X2X2, (SEQ ID NO: 468) X2X2X2X3X3X2X2X2X2X1X2X2RX2X2, (SEQ ID NO: 469) GNX2X1GX2X2X2X3X2GGX1X2X2X2X2X3X2X2X2X2X2X2X1, (SEQ ID NO: 470) X1GX2X2X2X3X2GGX1X2X2X2X2X3X1X2X2X2X2X2X1, (SEQ ID NO: 471) X1GX2X2X2X3X2GGX1X2X2X2X2X3X1X2X2X2X2X2X1, (SEQ ID NO: 472) X1X2X2X2X2X2X2X3X2X2X2X2X1GGX2X3X2X2X2GX1X2NG, (SEQ ID NO: 473) X1X2X2X2X2X2X1X3X2X2X2X2X1GGX2X3X2X2X2GX1, (SEQ ID NO: 474) X1X2X2X2X2X2X1X3X2X2X2X2X1GGX2X3X2X2X2GX1, (SEQ ID NO: 475) X2X2X1X2X2X2GX2X2X2X2X2X3X3X2X1X2X2X2QX2, and (SEQ ID NO: 476) X2QX2X2X2X1X2X3X3X2X2X2X2X2GX2X2X2X1X2X2, wherein each X1 is, individually, D, E, Gla, or Aad, each X2 is, individually, A, I, L, M, F, P, W, Y, V, or G and each X3 is, individually, S, T, or G. In various embodiments, the pHLIP peptide comprises the sequence: (SEQ ID NO: 477) X2X2RX2X2X1X2X2X2X3X3X2X2X2X2X2X1X2X2X2X2, (SEQ ID NO: 478) X2X2RX2X3X1X2X2X2X3X3X2X2X2X2X2X1X2GX2X2, (SEQ ID NO: 479) X2X2RX2X3X1X2X2X3X3X2X2X2X2X2X1X2X2X2X2X2, (SEQ ID NO: 480) X2X2RX2X2X1X2X2X2X3X3X2X2X2X2X2X1X2X3X2X2, (SEQ ID NO: 481) X2X2X2X2X1X2X2X2X2X2X3X3X2X2X2X1X2X2RX2X2, (SEQ ID NO: 482) X2X2GX2X1X2X2X2X2X2X3X3X2X2X2X1X3X2RX2X2, (SEQ ID NO: 483) X2X2X2X2X2X1X2X2X2X2X2X3X3X2X2X1X3X2RX2X2, (SEQ ID NO: 484) X2X2X3X2X1X2X2X2X2X2X3X3X2X2X2X1X2X2RX2X2, (SEQ ID NO: 485) GX2X2GX2X2GX2X1GX2X2GX2X2X2GX2X2X1GX2X2X2GX2, (SEQ ID NO: 486) X2GX2X2X2GX1X2X2GX2X2X2GX2X2GX1X2GX2X2GX2X2G, (SEQ ID NO: 487) X2RX2X2X2X1X2X2X2X2X3X1X3X2X2X2X1X2X2X2, (SEQ ID NO: 488) X2X2X2X1X2X2X2X3X1X3X2X2X2X2X1X2X2X2RX2, (SEQ ID NO: 489) X2X2RX2X2X1X2X2X2X2X3X1X3X2X2X2XX2, (SEQ ID NO: 490) X2X2QX2X2X1X2X2X2X2X3X1X3X2X2X2X1X2, (SEQ ID NO: 491) X2X1X2X2X2X3X1X3X2X2X2X2X1X2X2RX2X2, (SEQ ID NO: 492) X2X1X2X2X2X3X1X3X2X2X2X2X1X2X2QX2X2, (SEQ ID NO: 493) X2X2X2X3X3X2X2X2X2X2NGX2X2X2X2X1, (SEQ ID NO: 494) X2X2X2X3X3X2X2X2X2X2X2GX2X2X2X2X1, (SEQ ID NO: 495) X2X2RX2X2X1X2X2X2X2X3X3X2X2X2, (SEQ ID NO: 496) X1X2X2X2X2GNX2X2X2X2X2X3X3X2X2X2, (SEQ ID NO: 497) X1X2X2X2X2GX2X2X2X2X2X2X3X3X2X2X2, (SEQ ID NO: 498) X2X2X2X3X3X2X2X2X2X1X2X2RX2X2, (SEQ ID NO: 499) GNX2X1GX2X2X2X3X2GGX1X2X2X2X2X3X2X2X2X2X2X2X1, (SEQ ID NO: 500) X1GX2X2X2X3X2GGX1X2X2X2X2X3X1X2X2X2X2X2X1, (SEQ ID NO: 501) X1GX2X2X2X3X2GGX1X2X2X2X2X3X1X2X2X2X2X2X1, (SEQ ID NO: 502) X1X2X2X2X2X2X2X3X2X2X2X2X1GGX2X3X2X2X2GX1X2NG, (SEQ ID NO: 503) X1X2X2X2X2X2X1X3X2X2X2X2X1GGX2X3X2X2X2GX1, (SEQ ID NO: 504) X1X2X2X2X2X2X1X3X2X2X2X2X1GGX2X3X2X2X2GX1, (SEQ ID NO: 505) X2X2X1X2X2X2GX2X2X2X2X2X3X3X2X1X2X2X2QX2, and (SEQ ID NO: 506) X2QX2X2X2X1X2X3X3X2X2X2X2X2GX2X2X2X1X2X2, wherein each X1 is, individually, D, E, Gla, or Aad, each X2 is, individually, A, I, L, M, F, P, W, Y, V, or G, and each X3 is, individually, S, T, or G. In some embodiments, the pHLIP peptide comprises a sequence of at least 8 to 25 consecutive amino acids (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 consecutive amino acids) that is present in any one of the following sequences: (SEQ ID NO: 172) AEQNPIYWARYAEWLFTTPLLLLELALLVEAEET, (SEQ ID NO: 173) ADDQNPWRAYLDLLFPDTTDLLLLDLLWDADET, (SEQ ID NO: 174) AEEQNPWRAYLELLFPETTELLLLELLWEAEET, (SEQ ID NO: 175) AEQNPIYWARYAGlaWLFTTPLLLLGlaLALLVDADET, (SEQ ID NO: 176) AEQNPIYWARYAAadWLFTTPLLLLAadLALLVDADET, (SEQ ID NO: 177) AEQNPIYWARYAAadWLFTTPLLLLGlaLALLVDADET, (SEQ ID NO: 178) CEQNPIYWARYADWHFTTPLLLLDLALLVDADE, (SEQ ID NO: 179) ADNNPWIYARYADLTTFPLLLLDLALLVDFDD, (SEQ ID NO: 180) ADNNPFIYARYADLTTWPLLLLDLALLVDFDD, (SEQ ID NO: 181) ADNNPFIYARYADLTTFPLLLLDLALLVDWDD, (SEQ ID NO: 182) ADNNPFPYARYADLTTWILLLLDLALLVDFDD, (SEQ ID NO: 183) ADNNPFIYAYRADLTTFPLLLLDLALLVDWDD, (SEQ ID NO: 184) ADNNPFIYATYADLRTFPLLLLDLALLVDWDD, (SEQ ID NO: 185) ADDQNPWRAYLDLLFPTDTLLLDLLWDADE, (SEQ ID NO: 186) ADDQNPWRAYLGlaLLFPTDTLLLDLLW, (SEQ ID NO: 187) ADDQNPWRAYLDLLFPTGlaTLLLDLLW, (SEQ ID NO: 188) ADDQNPWRAYLDLLFPTDTLLLGlaLLW, (SEQ ID NO: 189) ADDQNPWRAYLGlaLLFPTGlaTLLLDLLW, (SEQ ID NO: 190) ADDQNPWRAYLGlaLLFPTDTLLLGlaLLW, (SEQ ID NO: 191) ADDQNPWRAYLDLLFPTGlaTLLLGlaLLW, (SEQ ID NO: 192) ADDQNPWRAYLGlaLLFPTGlaTLLLGlaLLW, (SEQ ID NO: 193) ADDQNPWRAYLAadLLFPTDTLLLDLLW, (SEQ ID NO: 194) ADDQNPWRAYLDLLFPTAadTLLLDLLW, (SEQ ID NO: 195) ADDQNPWRAYLDLLFPTDTLLLAadLLW, (SEQ ID NO: 196) ADDQNPWRAYLAadLLFPTAadTLLLDLLW, (SEQ ID NO: 197) ADDQNPWRAYLAadLLFPTDTLLLAadLLW, (SEQ ID NO: 198) ADDQNPWRAYLDLLFPTAadTLLLAadLLW, (SEQ ID NO: 199) ADDQNPWRAYLAadLLFPTAadTLLLAadLLW, (SEQ ID NO: 200) ADDQNPWRAYLGlaLLFPTAadTLLLDLLW, (SEQ ID NO: 201) ADDQNPWRAYLGlaLLFPTDTLLLAadLLW, (SEQ ID NO: 202) ADDQNPWRAYLGlaLLFPTGlaTLLLAadLLW, (SEQ ID NO: 203) ADDQNPWRAYLAadLLFPTGlaTLLLDLLW, (SEQ ID NO: 204) ADDQNPWRAYLAadLLFPTDTLLLGlaLLW, (SEQ ID NO: 205) ADDQNPWRAYLGlaLLFPTAadTLLLGlaLLW, (SEQ ID NO: 206) GEEQNPWLGAYLDLLFPLELLGLLELGLW, (SEQ ID NO: 207) EQNPIYILDLVFGLLFAVTSVDFLVQWDDAGD, (SEQ ID NO: 208) NNEGFFATLGGEIALWSDVVLAIE, and (SEQ ID NO: 209) DNNEGFFATLGGEIPLWSDVVLAIE. In certain embodiments, the pHLIP peptide comprises the sequence: (SEQ ID NO: 210) AEQNPIYWARYAEWLFTTPLLLLELALLVEAEET, (SEQ ID NO: 211) ADDQNPWRAYLDLLFPDTTDLLLLDLLWDADET, (SEQ ID NO: 212) AEEQNPWRAYLELLFPETTELLLLELLWEAEET, (SEQ ID NO: 213) AEQNPIYWARYAGlaWLFTTPLLLLGlaLALLVDADET, (SEQ ID NO: 214) AEQNPIYWARYAAadWLFTTPLLLLAadLALLVDADET, (SEQ ID NO: 215) AEQNPIYWARYAAadWLFTTPLLLLGlaLALLVDADET, (SEQ ID NO: 216) CEQNPIYWARYADWHFTTPLLLLDLALLVDADE, (SEQ ID NO: 217) ADNNPWIYARYADLTTFPLLLLDLALLVDFDD, (SEQ ID NO: 218) ADNNPFIYARYADLTTWPLLLLDLALLVDFDD, (SEQ ID NO: 219) ADNNPFIYARYADLTTFPLLLLDLALLVDWDD, (SEQ ID NO: 220) ADNNPFPYARYADLTTWILLLLDLALLVDFDD, (SEQ ID NO: 221) ADNNPFIYAYRADLTTFPLLLLDLALLVDWDD, (SEQ ID NO: 222) ADNNPFIYATYADLRTFPLLLLDLALLVDWDD, (SEQ ID NO: 223) ADDQNPWRAYLDLLFPTDTLLLDLLWDADE, (SEQ ID NO: 224) ADDQNPWRAYLGlaLLFPTDTLLLDLLW, (SEQ ID NO: 225) ADDQNPWRAYLDLLFPTGlaTLLLDLLW, (SEQ ID NO: 226) ADDQNPWRAYLDLLFPTDTLLLGlaLLW, (SEQ ID NO: 227) ADDQNPWRAYLGlaLLFPTGlaTLLLDLLW, (SEQ ID NO: 228) ADDQNPWRAYLGlaLLFPTDTLLLGlaLLW, (SEQ ID NO: 229) ADDQNPWRAYLDLLFPTGlaTLLLGlaLLW, (SEQ ID NO: 230) ADDQNPWRAYLGlaLLFPTGlaTLLLGlaLLW, (SEQ ID NO: 231) ADDQNPWRAYLAadLLFPTDTLLLDLLW, (SEQ ID NO: 232) ADDQNPWRAYLDLLFPTAadTLLLDLLW, (SEQ ID NO: 233) ADDQNPWRAYLDLLFPTDTLLLAadLLW, (SEQ ID NO: 234) ADDQNPWRAYLAadLLFPTAadTLLLDLLW, (SEQ ID NO: 235) ADDQNPWRAYLAadLLFPTDTLLLAadLLW, (SEQ ID NO: 236) ADDQNPWRAYLDLLFPTAadTLLLAadLLW, (SEQ ID NO: 237) ADDQNPWRAYLAadLLFPTAadTLLLAadLLW, (SEQ ID NO: 238) ADDQNPWRAYLGlaLLFPTAadTLLLDLLW, (SEQ ID NO: 239) ADDQNPWRAYLGlaLLFPTDTLLLAadLLW, (SEQ ID NO: 240) ADDQNPWRAYLGlaLLFPTGlaTLLLAadLLW, (SEQ ID NO: 241) ADDQNPWRAYLAadLLFPTGlaTLLLDLLW, (SEQ ID NO: 242) ADDQNPWRAYLAadLLFPTDTLLLGlaLLW, (SEQ ID NO: 243) ADDQNPWRAYLGlaLLFPTAadTLLLGlaLLW, (SEQ ID NO: 244) GEEQNPWLGAYLDLLFPLELLGLLELGLW, (SEQ ID NO: 245) EQNPIYILDLVFGLLFAVTSVDFLVQWDDAGD, (SEQ ID NO: 246) NNEGFFATLGGEIALWSDVVLAIE, or (SEQ ID NO: 247) DNNEGFFATLGGEIPLWSDVVLAIE. In various embodiments, the pHLIP peptide comprises the sequence of at least 8 to 25 consecutive amino acids (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 consecutive amino acids) that is present in any one of the following sequences: (SEQ ID NO: 248) AXQNPIYWARYAXWLFTTPLLLLXLALLVXAXXT (SEQ ID NO: 249) AXXQNPWRAYLXLLFPXTTXLLLLXLLWXAXXT, (SEQ ID NO: 250) AXXQNPWRAYLXLLFPXTTXLLLLXLLWXAXXT, (SEQ ID NO: 251) AXQNPIYWARYAXWLFTTPLLLLXLALLVXAXXT, (SEQ ID NO: 252) AXQNPIYWARYAXWLFTTPLLLLXLALLVXAXXT, (SEQ ID NO: 253) AXQNPIYWARYAXWLFTTPLLLLXLALLVXAXXT, (SEQ ID NO: 254) CXQNPIYWARYAXWHFTTPLLLLXLALLVXAXX, (SEQ ID NO: 255) AXNNPWIYARYAXLTTFPLLLLXLALLVXFXX, (SEQ ID NO: 256) AXNNPFIYARYAXLTTWPLLLLXLALLVXFXX, (SEQ ID NO: 257) AXNNPFIYARYAXLTTFPLLLLXLALLVXWXX, (SEQ ID NO: 258) AXNNPFPYARYAXLTTWILLLLXLALLVXFXX, (SEQ ID NO: 259) AXNNPFIYAYRAXLTTFPLLLLXLALLVXWXX, (SEQ ID NO: 260) AXNNPFIYATYAXLRTFPLLLLXLALLVXWXX, (SEQ ID NO: 261) AXXQNPWRAYLXLLFPTXTLLLXLLWXAXX, (SEQ ID NO: 262) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 263) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 264) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 265) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 266) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 267) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 268) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 269) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 270) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 271) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 272) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 273) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 274) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 275) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 276) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 277) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 278) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 279) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 280) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 281) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 282) GXXQNPWLGAYLXLLFPLXLLGLLXLGLW, (SEQ ID NO: 283) XQNPIYILXLVFGLLFAVTSVXFLVQWXXAGX, (SEQ ID NO: 284) NNXGFFATLGGXIALWSXVVLAIX, and (SEQ ID NO: 285) XNNXGFFATLGGXIPLWSXVVLAIX, wherein each X is, individually, D, E, Gla, or Aad. In some embodiments, the pHLIP peptide comprises the sequence: (SEQ ID NO: 286) AXQNPIYWARYAXWLFTTPLLLLXLALLVXAXXT, (SEQ ID NO: 287) AXXQNPWRAYLXLLFPXTTXLLLLXLLWXAXXT, (SEQ ID NO: 288) AXXQNPWRAYLXLLFPXTTXLLLLXLLWXAXXT, (SEQ ID NO: 289) AXQNPIYWARYAXWLFTTPLLLLXLALLVXAXXT, (SEQ ID NO: 290) AXQNPIYWARYAXWLFTTPLLLLXLALLVXAXXT, (SEQ ID NO: 291) AXQNPIYWARYAXWLFTTPLLLLXLALLVXAXXT, (SEQ ID NO: 292) CXQNPIYWARYAXWHFTTPLLLLXLALLVXAXX, (SEQ ID NO: 293) AXNNPWIYARYAXLTTFPLLLLXLALLVXFXX, (SEQ ID NO: 294) AXNNPFIYARYAXLTTWPLLLLXLALLVXFXX, (SEQ ID NO: 295) AXNNPFIYARYAXLTTFPLLLLXLALLVXWXX, (SEQ ID NO: 296) AXNNPFPYARYAXLTTWILLLLXLALLVXFXX, (SEQ ID NO: 297) AXNNPFIYAYRAXLTTFPLLLLXLALLVXWXX, (SEQ ID NO: 298) AXNNPFIYATYAXLRTFPLLLLXLALLVXWXX, (SEQ ID NO: 299) AXXQNPWRAYLXLLFPTXTLLLXLLWXAXX, (SEQ ID NO: 300) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 301) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 302) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 303) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 304) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 305) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 306) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 307) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 308) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 309) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 310) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 311) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 312) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 313) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 314) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 315) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 316) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 317) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 318) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 319) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 320) GXXQNPWLGAYLXLLFPLXLLGLLXLGLW, (SEQ ID NO: 321) XQNPIYILXLVFGLLFAVTSVXFLVQWXXAGX, (SEQ ID NO: 322) NNXGFFATLGGXIALWSXVVLAIX, or (SEQ ID NO: 323) XNNXGFFATLGGXIPLWSXVVLAIX, wherein each X is, individually, D, E, Gla, or Aad. In certain embodiments, the pHLIP peptide comprises the sequence of at least 8 to 25 consecutive amino acids (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 consecutive amino acids) that is present in any one of the following sequences: (SEQ ID NO: 507) X2X1QNX2X2X2X2X2RX2X2X1X2X2X2X3X3X2X2X2X2X2X1X2X2X2X2X2 X1X2 X1X1X3, (SEQ ID NO: 508) X2X1X1QNX2X2RX2X2X2X1X2X2X2X2X1X3X3X1X2X2X2X2X1X2X2X2X1X2X1X1X3, (SEQ ID NO: 509) CX1QNX2X2X2X2X2RX2X2X1X2HX2X3X3X2X2X2X2X2X1X2X2X2X2X2X1X2X1X1, (SEQ ID NO: 510) X2X1NNX2X2X2X2X2RX2X2X1X2X3X3X2X2X2X2X2X2X1X2X2X2X2X2X1X2X1X1, (SEQ ID NO: 511) X2X1NNX2X2X2X2X2X2RX2X1X2X3X3X2X2X2X2X2X2X1X2X2X2X2X2X1X2X1X1, (SEQ ID NO: 512) X2X1NNX2X2X2X2X2X3X2X2X1X2RX3X2X2X2X2X2X2X1X2X2X2X2X2X1X2X1X1, (SEQ ID NO: 513) X2X1X1QNX2X2RX2X2X2X1X2X2X2X2X3X1X3X2X2X2X1X2X2X2X1X2X1X1, (SEQ ID NO: 514) X2X1X1QNX2X2RX2X2X2X1X2X2X2X2X3X1X3X2X2X2X1X2X2X2, (SEQ ID NO: 515) X2X1X1QNX2X2X2X2X2X2X2X1X2X2X2X2X2X1X2X2X2X2X2X1X2X2X2X2, (SEQ ID NO: 516) X1QNX2X2X2X2X2X1X2X2X2X2X2X2X2X2X2X3X3X2X1X2X2X2QX2X1X1X2X2, (SEQ ID NO: 517) NNX1X2X2X2X2X3X2X2X2X1X2X2X2X2X3X1X2X2X2X2X2X1, and (SEQ ID NO: 518) X1NNX1X2X2X2X2X3X2X2X2X1X2X2X2X2X3X1X2X2X2X2X2X1, wherein each X1 is, individually, D, E, Gla, or Aad, each X2 is, individually, A, I, L, M, F, P, W, Y, V, or G and each X3 is, individually, S, T, or G. In various embodiments, the pHLIP peptide comprises the sequence: (SEQ ID NO: 519) X2X1QNX2X2X2X2X2RX2X2X1X2X2X2X3X3X2X2X2X2X2X1X2X2X2X2X2X1X2 X1X1X3, (SEQ ID NO: 520) X2X1X1QNX2X2RX2X2X2X1X2X2X2X2X1X3X3X1X2X2X2X2X1X2X2X2X1X2X1X1X3, (SEQ ID NO: 521) CX1QNX2X2X2X2X2RX2X2X1X2HX2X3X3X2X2X2X2X2X1X2X2X2X2X2X1X2X1X1, (SEQ ID NO: 522) X2X1NNX2X2X2X2X2RX2X2X1X2X3X3X2X2X2X2X2X2X1X2X2X2X2X2X1X2X1X1, (SEQ ID NO: 523) X2X1NNX2X2X2X2X2X2RX2X1X2X3X3X2X2X2X2X2X2X1X2X2X2X2X2X1X2X1X1, (SEQ ID NO: 524) X2X1NNX2X2X2X2X2X3X2X2X1X2RX3X2X2X2X2X2X2X1X2X2X2X2X2X1X2X1X1, (SEQ ID NO: 525) X2X1X1QNX2X2RX2X2X2X1X2X2X2X2X3X1X3X2X2X2X1X2X2X2X1X2X1X1, (SEQ ID NO: 526) X2X1X1QNX2X2RX2X2X2X1X2X2X2X2X3X1X3X2X2X2X1X2X2X2, (SEQ ID NO: 527) X2X1X1QNX2X2X2X2X2X2X2X1X2X2X2X2X2X1X2X2X2X2X2X1X2X2X2X2, (SEQ ID NO: 528) X1QNX2X2X2X2X2X1X2X2X2X2X2X2X2X2X2X3X3X2X1X2X2X2QX2X1X1X2X2, (SEQ ID NO: 529) NNX1X2X2X2X2X3X2X2X2X1X2X2X2X2X3X1X2X2X2X2X2X1, and (SEQ ID NO: 530) X1NNX1X2X2X2X2X3X2X2X2X1X2X2X2X2X3X1X2X2X2X2X2X1, wherein each X1 is, individually, D, E, Gla, or Aad, each X2 is, individually, A, I, L, M, F, P, W, Y, V, or G and each X3 is, individually, S, T, or G. In some embodiments, a pHLIP peptide comprises at least 8 consecutive amino acids, wherein (i) at least 4 of the 8 consecutive amino acids are non-polar amino acids, (ii) at least 1 of the at least 8 consecutive amino acids is protonatable, and (iii) the at least 8 consecutive amino acids comprise 8 consecutive amino acids in a sequence that is identical to a sequence of 8 consecutive amino acids that occurs in a naturally occurring human protein. In certain embodiments, the pHLIP peptide has higher affinity for a membrane lipid bilayer at pH 5.0, 5.5, 6, 6.0, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0 compared to the affinity at pH 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0. In various embodiments, the at least 8 consecutive amino acids comprise a sequence that is at least 85%, 90%, or 95% identical to (e.g., is 100% identical to) (i) a sequence of at least 8 consecutive amino acids that occurs in a naturally occurring human protein; or (ii) the reverse of a sequence of at least 8 consecutive amino acids that occurs in a naturally occurring human protein. In some embodiments, the naturally occurring human protein is a human rhodopsin protein. In certain embodiments, the of 8 consecutive amino acids that occurs in the human rhodopsin protein are within the following sequence: NLEGFFATLGGEIALWSLVVLAIE (SEQ ID NO: 531). The reverse of this sequence is EIALVVLSWLAIEGGLTAFFGELN (SEQ ID NO: 532). In various embodiments, the sequence of the pHLIP peptide comprises 8-20 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 8-15, 8-20, 10-15, 10-20, or 15-20) consecutive amino acids that have a sequence that is at least 85%, 90%, or 95% identical to a sequence of 8-20 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 8-15, 8-20, 10-15, 10-20, or 15-20) consecutive amino acids that occurs in a human rhodopsin protein, wherein the sequence of the 8-20 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 8-15, 8-20, 10-15, 10-20, or 15-20) consecutive amino acids of the pHLIP peptide has 1, 2, or 3 amino acid substitutions compared to the sequence of the 8-20 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 8-15, 8-20, 10-15, 10-20, or 15-20) consecutive amino acids that occurs in a human rhodopsin protein. In some embodiments, the sequence has a L to D, L to E, A to P, or C to G substitution compared to the 8-20 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 8-15, 8-20, 10-15, 10-20, or 15-20) consecutive amino acids that occur in the human rhodopsin protein. In certain embodiments, the sequence of the pHLIP peptide comprises 20 consecutive amino acids that have a sequence that is 85%, 90%, or 95% identical to the reverse of a sequence of 8-20 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 8-15, 8-20, 10-15, 10-20, or 15-20) consecutive amino acids that occurs in a human rhodopsin protein, wherein the sequence of the 20 consecutive amino acids has 1, 2, or 3 amino acid substitutions compared to the reverse of the sequence of the 8-20 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 8-15, 8-20, 10-15, 10-20, or 15-20) consecutive amino acids that occurs in a human rhodopsin protein. In some embodiments, the sequence has a L to D, L to E, A to P, or C to G substitution compared to the reverse of the 8-20 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 8-15, 8-20, 10-15, 10-20, or 15-20) consecutive amino acids that occur in the human rhodopsin protein. A non-limiting example of a genomic nucleotide sequence that encodes human rhodopsin is available under National Center for Biotechnology Information (NCBI) Reference Sequence No: NC_000003.12, all information available under NCBI Reference Sequence No: NC_000003.12 is incorporated herein by reference. The nucleotide sequence that is available from NCBI Reference Sequence No: NC_000003.12 is as follows: (SEQ ID NO: 31) AGAGTCATCCAGCTGGAGCCCTGAGTGGCTGAGCTCAGGCCTTCGCAGCA TTCTTGGGTGGGAGCAGCCACGGGTCAGCCACAAGGGCCACAGCCATGAA TGGCACAGAAGGCCCTAACTTCTACGTGCCCTTCTCCAATGCGACGGGTG TGGTACGCAGCCCCTTCGAGTACCCACAGTACTACCTGGCTGAGCCATGG CAGTTCTCCATGCTGGCCGCCTACATGTTTCTGCTGATCGTGCTGGGCTT CCCCATCAACTTCCTCACGCTCTACGTCACCGTCCAGCACAAGAAGCTGC GCACGCCTCTCAACTACATCCTGCTCAACCTAGCCGTGGCTGACCTCTTC ATGGTCCTAGGTGGCTTCACCAGCACCCTCTACACCTCTCTGCATGGATA CTTCGTCTTCGGGCCCACAGGATGCAATTTGGAGGGCTTCTTTGCCACCC TGGGCGGTATGAGCCGGGTGTGGGTGGGGTGTGCAGGAGCCCGGGAGCAT GGAGGGGTCTGGGAGAGTCCCGGGCTTGGCGGTGGTGGCTGAGAGGCCTT CTCCCTTCTCCTGTCCTGTCAATGTTATCCAAAGCCCTCATATATTCAGT CAACAAACACCATTCATGGTGATAGCCGGGCTGCTGTTTGTGCAGGGCTG GCACTGAACACTGCCTTGATCTTATTTGGAGCAATATGCGCTTGTCTAAT TTCACAGCAAGAAAACTGAGCTGAGGCTCAAAGAAGTCAAGCGCCCTGCT GGGGCGTCACACAGGGACGGGTGCAGAGTTGAGTTGGAAGCCCGCATCTA TCTCGGGCCATGTTTGCAGCACCAAGCCTCTGTTTCCCTTGGAGCAGCTG TGCTGAGTCAGACCCAGGCTGGGCACTGAGGGAGAGCTGGGCAAGCCAGA CCCCTCCTCTCTGGGGGCCCAAGCTCAGGGTGGGAAGTGGATTTTCCATT CTCCAGTCATTGGGTCTTCCCTGTGCTGGGCAATGGGCTCGGTCCCCTCT GGCATCCTCTGCCTCCCCTCTCAGCCCCTGTCCTCAGGTGCCCCTCCAGC CTCCCTGCCGCGTTCCAAGTCTCCTGGTGTTGAGAACCGCAAGCAGCCGC TCTGAAGCAGTTCCTTTTTGCTTTAGAATAATGTCTTGCATTTAACAGGA AAACAGATGGGGTGCTGCAGGGATAACAGATCCCACTTAACAGAGAGGAA AACTGAGGCAGGGAGAGGGGAAGAGACTCATTTAGGGATGTGGCCAGGCA GCAACAAGAGCCTAGGTCTCCTGGCTGTGATCCAGGAATATCTCTGCTGA GATGCAGGAGGAGACGCTAGAAGCAGCCATTGCAAAGCTGGGTGACGGGG AGAGCTTACCGCCAGCCACAAGCGTCTCTCTGCCAGCCTTGCCCTGTCTC CCCCATGTCCAGGCTGCTGCCTCGGTCCCATTCTCAGGGAATCTCTGGCC ATTGTTGGGTGTTTGTTGCATTCAATAATCACAGATCACTCAGTTCTGGC CAGAAGGTGGGTGTGCCACTTACGGGTGGTTGTTCTCTGCAGGGTCAGTC CCAGTTTACAAATATTGTCCCTTTCACTGTTAGGAATGTCCCAGTTTGGT TGATTAACTATATGGCCACTCTCCCTATGGAACTTCATGGGGTGGTGAGC AGGACAGATGTCTGAATTCCATCATTTCCTTCTTCTTCCTCTGGGCAAAA CATTGCACATTGCTTCATGGCTCCTAGGAGAGGCCCCCACATGTCCGGGT TATTTCATTTCCCGAGAAGGGAGAGGGAGGAAGGACTGCCAATTCTGGGT TTCCACCACCTCTGCATTCCTTCCCAACAAGGAACTCTGCCCCACATTAG GATGCATTCTTCTGCTAAACACACACACACACACACACACACACAACACA CACACACACACACACACACACACACACACAAAACTCCCTACCGGGTTCCC AGTTCAATCCTGACCCCCTGATCTGATTCGTGTCCCTTATGGGCCCAGAG CGCTAAGCAAATAACTTCCCCCATTCCCTGGAATTTCTTTGCCCAGCTCT CCTCAGCGTGTGGTCCCTCTGCCCCTTCCCCCTCCTCCCAGCACCAAGCT CTCTCCTTCCCCAAGGCCTCCTCAAATCCCTCTCCCACTCCTGGTTGCCT TCCTAGCTACCCTCTCCCTGTCTAGGGGGGAGTGCACCCTCCTTAGGCAG TGGGGTCTGTGCTGACCGCCTGCTGACTGCCTTGCAGGTGAAATTGCCCT GTGGTCCTTGGTGGTCCTGGCCATCGAGCGGTACGTGGTGGTGTGTAAGC CCATGAGCAACTTCCGCTTCGGGGAGAACCATGCCATCATGGGCGTTGCC TTCACCTGGGTCATGGCGCTGGCCTGCGCCGCACCCCCACTCGCCGGCTG GTCCAGGTAATGGCACTGAGCAGAAGGGAAGAAGCTCCGGGGGCTCTTTG TAGGGTCCTCCAGTCAGGACTCAAACCCAGTAGTGTCTGGTTCCAGGCAC TGACCTTGTATGTCTCCTGGCCCAAATGCCCACTCAGGGTAGGGGTGTAG GGCAGAAGAAGAAACAGACTCTAATGTTGCTACAAGGGCTGGTCCCATCT CCTGAGCCCCATGTCAAACAGAATCCAAGACATCCCAACCCTTCACCTTG GCTGTGCCCCTAATCCTCAACTAAGCTAGGCGCAAATTCCAATCCTCTTT GGTCTAGTACCCCGGGGGCAGCCCCCTCTAACCTTGGGCCTCAGCAGCAG GGGAGGCCACACCTTCCTAGTGCAGGTGGCCATATTGTGGCCCCTTGGAA CTGGGTCCCACTCAGCCTCTAGGCGATTGTCTCCTAATGGGGCTGAGATG AGACACAGTGGGGACAGTGGTTTGGACAATAGGACTGGTGACTCTGGTCC CCAGAGGCCTCATGTCCCTCTGTCTCCAGAAAATTCCCACTCTCACTTCC CTTTCCTCCTCAGTCTTGCTAGGGTCCATTTCTTACCCCTTGCTGAATTT GAGCCCACCCCCTGGACTTTTTCCCCATCTTCTCCAATCTGGCCTAGTTC TATCCTCTGGAAGCAGAGCCGCTGGACGCTCTGGGTTTCCTGAGGCCCGT CCACTGTCACCAATATCAGGAACCATTGCCACGTCCTAATGACGTGCGCT GGAAGCCTCTAGTTTCCAGAAGCTGCACAAAGATCCCTTAGATACTCTGT GTGTCCATCTTTGGCCTGGAAAATACTCTCACCCTGGGGCTAGGAAGACC TCGGTTTGTACAAACTTCCTCAAATGCAGAGCCTGAGGGCTCTCCCCACC TCCTCACCAACCCTCTGCGTGGCATAGCCCTAGCCTCAGCGGGCAGTGGA TGCTGGGGCTGGGCATGCAGGGAGAGGCTGGGTGGTGTCATCTGGTAACG CAGCCACCAAACAATGAAGCGACACTGATTCCACAAGGTGCATCTGCATC CCCATCTGATCCATTCCATCCTGTCACCCAGCCATGCAGACGTTTATGAT CCCCTTTTCCAGGGAGGGAATGTGAAGCCCCAGAAAGGGCCAGCGCTCGG CAGCCACCTTGGCTGTTCCCAAGTCCCTCACAGGCAGGGTCTCCCTACCT GCCTGTCCTCAGGTACATCCCCGAGGGCCTGCAGTGCTCGTGTGGAATCG ACTACTACACGCTCAAGCCGGAGGTCAACAACGAGTCTTTTGTCATCTAC ATGTTCGTGGTCCACTTCACCATCCCCATGATTATCATCTTTTTCTGCTA TGGGCAGCTCGTCTTCACCGTCAAGGAGGTACGGGCCGGGGGGTGGGCGG CCTCACGGCTCTGAGGGTCCAGCCCCCAGCATGCATCTGCGGCTCCTGCT CCCTGGAGGAGCCATGGTCTGGACCCGGGTCCCGTGTCCTGCAGGCCGCT GCCCAGCAGCAGGAGTCAGCCACCACACAGAAGGCAGAGAAGGAGGTCAC CCGCATGGTCATCATCATGGTCATCGCTTTCCTGATCTGCTGGGTGCCCT ACGCCAGCGTGGCATTCTACATCTTCACCCACCAGGGCTCCAACTTCGGT CCCATCTTCATGACCATCCCAGCGTTCTTTGCCAAGAGCGCCGCCATCTA CAACCCTGTCATCTATATCATGATGAACAAGCAGGTGCCTACTGCGGGTG GGAGGGCCCCAGTGCCCCAGGCCACAGGCGCTGCCTGCCAAGGACAAGCT ACTTCCCAGGGCAGGGGAGGGGGCTCCATCAGGGTTACTGGCAGCAGTCT TGGGTCAGCAGTCCCAATGGGGAGTGTGTGAGAAATGCAGATTCCTGGCC CCACTCAGAACTGCTGAATCTCAGGGTGGGCCCAGGAACCTGCATTTCCA GCAAGCCCTCCACAGGTGGCTCAGATGCTCACTCAGGTGGGAGAAGCTCC AGTCAGCTAGTTCTGGAAGCCCAATGTCAAAGTCAGAAGGACCCAAGTCG GGAATGGGATGGGCCAGTCTCCATAAAGCTGAATAAGGAGCTAAAAAGTC TTATTCTGAGGGGTAAAGGGGTAAAGGGTTCCTCGGAGAGGTACCTCCGA GGGGTAAACAGTTGGGTAAACAGTCTCTGAAGTCAGCTCTGCCATTTTCT AGCTGTATGGCCCTGGGCAAGTCAATTTCCTTCTCTGTGCTTTGGTTTCC TCATCCATAGAAAGGTAGAAAGGGCAAAACACCAAACTCTTGGATTACAA GAGATAATTTACAGAACACCCTTGGCACACAGAGGGCACCATGAAATGTC ACGGGTGACACAGCCCCCTTGTGCTCAGTCCCTGGCATCTCTAGGGGTGA GGAGCGTCTGCCTAGCAGGTTCCCTCCAGGAAGCTGGATTTGAGTGGATG GGGCGCTGGAATCGTGAGGGGCAGAAGCAGGCAAAGGGTCGGGGCGAACC TCACTAACGTGCCAGTTCCAAGCACACTGTGGGCAGCCCTGGCCCTGACT CAAGCCTCTTGCCTTCCAGTTCCGGAACTGCATGCTCACCACCATCTGCT GCGGCAAGAACCCACTGGGTGACGATGAGGCCTCTGCTACCGTGTCCAAG ACGGAGACGAGCCAGGTGGCCCCGGCCTAAGACCTGCCTAGGACTCTGTG GCCGACTATAGGCGTCTCCCATCCCCTACACCTTCCCCCAGCCACAGCCA TCCCACCAGGAGCAGCGCCTGTGCAGAATGAACGAAGTCACATAGGCTCC TTAATTTTTTTTTTTTTTTTAAGAAATAATTAATGAGGCTCCTCACTCAC CTGGGACAGCCTGAGAAGGGACATCCACCAAGACCTACTGATCTGGAGTC CCACGTTCCCCAAGGCCAGCGGGATGTGTGCCCCTCCTCCTCCCAACTCA TCTTTCAGGAACACGAGGATTCTTGCTTTCTGGAAAAGTGTCCCAGCTTA GGGATAAGTGTCTAGCACAGAATGGGGCACACAGTAGGTGCTTAATAAAT GCTGGATGGATGCAGGAAGGAATGGAGGAATGAATGGGAAGGGAGAACAT ATCTATCCTCTCAGACCCTCGCAGCAGCAGCAACTCATACTTGGCTAATG ATATGGAGCAGTTGTTTTTCCCTCCCTGGGCCTCACTTTCTTCTCCTATA AAATGGAAATCCCAGATCCCTGGTCCTGCCGACACGCAGCTACTGAGAAG ACCAAAAGAGGTGTGTGTGTGTCTATGTGTGTGTTTCAGCACTTTGTAAA TAGCAAGAAGCTGTACAGATTCTAGTTAATGTTGTGAATAACATCAATTA ATGTAACTAGTTAATTACTATGATTATCACCTCCTGATAGTGAACATTTT GAGATTGGGCATTCAGATGATGGGGTTTCACCCAACCTTGGGGCAGGTTT TTAAAAATTAGCTAGGCATCAAGGCCAGACCAGGGCTGGGGGTTGGGCTG TAGGCAGGGACAGTCACAGGAATGCAGAATGCAGTCATCAGACCTGAAAA AACAACACTGGGGGAGGGGGACGGTGAAGGCCAAGTTCCCAATGAGGGTG AGATTGGGCCTGGGGTCTCACCCCTAGTGTGGGGCCCCAGGTCCCGTGCC TCCCCTTCCCAATGTGGCCTATGGAGAGACAGGCCTTTCTCTCAGCCTCT GGAAGCCACCTGCTCTTTTGCTCTAGCACCTGGGTCCCAGCATCTAGAGC ATGGAGCCTCTAGAAGCCATGCTCACCCGCCCACATTTAATTAACAGCTG AGTCCCTGATGTCATCCTTATCTCGAAGAGCTTAGAAACAAAGAGTGGGA AATTCCACTGGGCCTACCTTCCTTGGGGATGTTCATGGGCCCCAGTTTCC AGTTTCCCTTGCCAGACAAGCCCATCTTCAGCAGTTGCTAGTCCATTCTC CATTCTGGAGAATCTGCTCCAAAAAGCTGGCCACATCTCTGAGGTGTCAG AATTAAGCTGCCTCAGTAACTGCTCCCCCTTCTCCATATAAGCAAAGCCA GAAGCTCTAGCTTTACCCAGCTCTGCCTGGAGACTAAGGCAAATTGGGCC ATTAAAAGCTCAGCTCCTATGTTGGTATTAACGGTGGTGGGTTTTGTTGC TTTCACACTCTATCCACAGGATAGATTGAAACTGCCAGCTTCCACCTGAT CCCTGACCCTGGGATGGCTGGATTGAGCAATGAGCAGAGCCAAGCAGCAC AGAGTCCCCTGGGGCTAGAGGTGGAGGAGGCAGTCCTGGGAATGGGAAAA ACCCCA A non-limiting example of a human rhodopsin amino acid sequence is available under UniProt Accession No: P08100. All information available under UniProt Accession No: P08100 is incorporated herein by reference. An amino acid sequence that is available from UniProt Accession No: P08100 is as follows (the underlined amino acids relate may be used in non-limiting examples of pHLIPs, and especially as a starting point to design pHLIP peptides): (SEQ ID NO: 32) MNGTEGPNFYVPFSNATGVVRSPFEYPQYYLAEPWQFSMLAAYMFLLIVL GFPINFLTLYVTVQHKKLRTPLNYILLNLAVADLFMVLGGFTSTLYTSLH GYFVFGPTGCNLEGFFATLGGEIALWSLVVLAIERYVVVCKPMSNFRFGE NHAIMGVAFTWVMALACAAPPLAGWSRYIPEGLQCSCGIDYYTLKPEVNN ESFVIYMFVVHFTIPMIIIFFCYGQLVFTVKEAAAQQQESATTQKAEKEV TRMVIIMVIAFLICWVPYASVAFYIFTHQGSNFGPIFMTIPAFFAKSAAI YNPVIYIMMNKQFRNCMLTTICCGKNPLGDDEASATVSKTETSQVAPA For example, a pHLIP peptide comprising the sequence DNNEGFFATLGGEIPLWSDVVLAIE (SEQ ID NO: 209) is a useful pHLIP peptide that comprises 3 substitution mutations (underlined) and one added amino acid (the N-terminal D) compared to NLEGFFATLGGEIALWSLVVLAIE (SEQ ID NO: 62). See also, e.g., Hum pHLIP in Table 11, as well as sequences in Tables 5 and 6. A non-limiting example of a cDNA sequence that encodes human rhodopsin is available under NCBI Reference Sequence No: NM_000539.3, all information available under NCBI Reference Sequence No: NM_000539.3 is incorporated herein by reference. The nucleotide sequence that is available from NCBI Reference Sequence No: NM_000539.3 is as follows: (SEQ ID NO: 33) AGAGTCATCCAGCTGGAGCCCTGAGTGGCTGAGCTCAGGCCTTCGCAGCA TTCTTGGGTGGGAGCAGCCACGGGTCAGCCACAAGGGCCACAGCCATGAA TGGCACAGAAGGCCCTAACTTCTACGTGCCCTTCTCCAATGCGACGGGTG TGGTACGCAGCCCCTTCGAGTACCCACAGTACTACCTGGCTGAGCCATGG CAGTTCTCCATGCTGGCCGCCTACATGTTTCTGCTGATCGTGCTGGGCTT CCCCATCAACTTCCTCACGCTCTACGTCACCGTCCAGCACAAGAAGCTGC GCACGCCTCTCAACTACATCCTGCTCAACCTAGCCGTGGCTGACCTCTTC ATGGTCCTAGGTGGCTTCACCAGCACCCTCTACACCTCTCTGCATGGATA CTTCGTCTTCGGGCCCACAGGATGCAATTTGGAGGGCTTCTTTGCCACCC TGGGCGGTGAAATTGCCCTGTGGTCCTTGGTGGTCCTGGCCATCGAGCGG TACGTGGTGGTGTGTAAGCCCATGAGCAACTTCCGCTTCGGGGAGAACCA TGCCATCATGGGCGTTGCCTTCACCTGGGTCATGGCGCTGGCCTGCGCCG CACCCCCACTCGCCGGCTGGTCCAGGTACATCCCCGAGGGCCTGCAGTGC TCGTGTGGAATCGACTACTACACGCTCAAGCCGGAGGTCAACAACGAGTC TTTTGTCATCTACATGTTCGTGGTCCACTTCACCATCCCCATGATTATCA TCTTTTTCTGCTATGGGCAGCTCGTCTTCACCGTCAAGGAGGCCGCTGCC CAGCAGCAGGAGTCAGCCACCACACAGAAGGCAGAGAAGGAGGTCACCCG CATGGTCATCATCATGGTCATCGCTTTCCTGATCTGCTGGGTGCCCTACG CCAGCGTGGCATTCTACATCTTCACCCACCAGGGCTCCAACTTCGGTCCC ATCTTCATGACCATCCCAGCGTTCTTTGCCAAGAGCGCCGCCATCTACAA CCCTGTCATCTATATCATGATGAACAAGCAGTTCCGGAACTGCATGCTCA CCACCATCTGCTGCGGCAAGAACCCACTGGGTGACGATGAGGCCTCTGCT ACCGTGTCCAAGACGGAGACGAGCCAGGTGGCCCCGGCCTAAGACCTGCC TAGGACTCTGTGGCCGACTATAGGCGTCTCCCATCCCCTACACCTTCCCC CAGCCACAGCCATCCCACCAGGAGCAGCGCCTGTGCAGAATGAACGAAGT CACATAGGCTCCTTAATTTTTTTTTTTTTTTTAAGAAATAATTAATGAGG CTCCTCACTCACCTGGGACAGCCTGAGAAGGGACATCCACCAAGACCTAC TGATCTGGAGTCCCACGTTCCCCAAGGCCAGCGGGATGTGTGCCCCTCCT CCTCCCAACTCATCTTTCAGGAACACGAGGATTCTTGCTTTCTGGAAAAG TGTCCCAGCTTAGGGATAAGTGTCTAGCACAGAATGGGGCACACAGTAGG TGCTTAATAAATGCTGGATGGATGCAGGAAGGAATGGAGGAATGAATGGG AAGGGAGAACATATCTATCCTCTCAGACCCTCGCAGCAGCAGCAACTCAT ACTTGGCTAATGATATGGAGCAGTTGTTTTTCCCTCCCTGGGCCTCACTT TCTTCTCCTATAAAATGGAAATCCCAGATCCCTGGTCCTGCCGACACGCA GCTACTGAGAAGACCAAAAGAGGTGTGTGTGTGTCTATGTGTGTGTTTCA GCACTTTGTAAATAGCAAGAAGCTGTACAGATTCTAGTTAATGTTGTGAA TAACATCAATTAATGTAACTAGTTAATTACTATGATTATCACCTCCTGAT AGTGAACATTTTGAGATTGGGCATTCAGATGATGGGGTTTCACCCAACCT TGGGGCAGGTTTTTAAAAATTAGCTAGGCATCAAGGCCAGACCAGGGCTG GGGGTTGGGCTGTAGGCAGGGACAGTCACAGGAATGCAGAATGCAGTCAT CAGACCTGAAAAAACAACACTGGGGGAGGGGGACGGTGAAGGCCAAGTTC CCAATGAGGGTGAGATTGGGCCTGGGGTCTCACCCCTAGTGTGGGGCCCC AGGTCCCGTGCCTCCCCTTCCCAATGTGGCCTATGGAGAGACAGGCCTTT CTCTCAGCCTCTGGAAGCCACCTGCTCTTTTGCTCTAGCACCTGGGTCCC AGCATCTAGAGCATGGAGCCTCTAGAAGCCATGCTCACCCGCCCACATTT AATTAACAGCTGAGTCCCTGATGTCATCCTTATCTCGAAGAGCTTAGAAA CAAAGAGTGGGAAATTCCACTGGGCCTACCTTCCTTGGGGATGTTCATGG GCCCCAGTTTCCAGTTTCCCTTGCCAGACAAGCCCATCTTCAGCAGTTGC TAGTCCATTCTCCATTCTGGAGAATCTGCTCCAAAAAGCTGGCCACATCT CTGAGGTGTCAGAATTAAGCTGCCTCAGTAACTGCTCCCCCTTCTCCATA TAAGCAAAGCCAGAAGCTCTAGCTTTACCCAGCTCTGCCTGGAGACTAAG GCAAATTGGGCCATTAAAAGCTCAGCTCCTATGTTGGTATTAACGGTGGT GGGTTTTGTTGCTTTCACACTCTATCCACAGGATAGATTGAAACTGCCAG CTTCCACCTGATCCCTGACCCTGGGATGGCTGGATTGAGCAATGAGCAGA GCCAAGCAGCACAGAGTCCCCTGGGGCTAGAGGTGGAGGAGGCAGTCCTG GGAATGGGAAAAACCCCA In some embodiments, the pHLIP peptide comprises the sequence: XnYm; YmXn; Xn-YmXj; YmXnYi; YmXnYiXj; XnYmXjYi; YmXnYiXjYl; XnYmXjYiXl; YmXnYiXjYlXh; XnYmXjYiXhYg; YmXnYiXjYlXhYg; XnYmXjYiXhYgXf; (XY)n; (YX)n; (XY)nYm; (YX)nYm; (XY)nXm; (YX)nXm; Ym(XY)n; Ym(YX)n; Xn(XY)m; Xn(YX)m; (XY)nYm(XY)i; (YX)Ym(YX)i; (XY)nXm(XY)i; (YX)nXm(YX)i; Ym(XY)1; Ym(YX)1; X1(XY)m; or X1(YX)m, wherein, (i) each Y is, individually, a non-polar amino acid with solvation energy, ΔGXcor>+0.50, or Gly; (ii) each X is, individually, a protonatable amino acid, (iii) n, m, i, j, l, h, g, f are each, individually, an integer from 1 to 8. In certain embodiments, the pHLIP peptide has a net negative charge at a pH of about 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, or 7.5 in water. In various embodiments, the pHLIP peptide has an acid dissociation constant on a base 10 logarithmic scale (pKa) of less than about 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, or 7.0. In certain embodiments, the pHLIP peptide has a pKa of at least about 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0. In some embodiments, the pHLIP peptide has a pKa between about 6.5 and about 7.0, e.g., about 6.6 and about 7.0, about 6.7 and about 7.0, about 6.8 and about 7.0, or about 6.9 and about 7.0. In certain embodiments, the pHLIP peptide has a pKa of about 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0. In some embodiments, the pHLIP peptide comprises (a) 1 protonatable amino acid which is aspartic acid, glutamic acid, alpha-aminoadipic acid, or gamma-carboxyglutamic acid; or (b) at least 2, 3, or 4 protonatable amino acids, wherein the protonatable amino acids comprise aspartic acid, glutamic acid, alpha-aminoadipic acid, gamma-carboxyglutamic acid, or any combination thereof. In certain embodiments, the pHLIP peptide comprises at least 1 non-native protonatable amino acid. In various embodiments, the non-native protonatable amino acid comprises at least 1, 2, 3, or 4 carboxyl groups. In some embodiments, the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 carboxyl groups. In certain embodiments, the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 40 genetically coded amino acids. In various embodiments, the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 40 non-genetically coded amino acids. In some embodiments, the amino acids of the pHLIP peptide are non-native amino acids. In certain embodiments, the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 40 D-amino acids. In various embodiments, the pHLIP peptide comprises at least 1 non-genetically coded amino acid, wherein the non-genetically coded amino acid is an aspartic acid derivative, or a glutamic acid derivative. In some embodiments, the pHLIP peptide comprises at least 8 consecutive amino acids, wherein, at least 2, 3, or 4 of the at least 8 consecutive amino acids are non-polar, and at least 1, 2, 3, or 4 of the at least 8 consecutive amino acids is protonatable. In various embodiments, the pHLIP peptide is directly covalently attached via a bond, or covalently attached via a linker, to a fluorophore. In some embodiments, a pHLIP peptide is attached to a fluorophore by a covalent bond, wherein the covalent bond is an ester bond, a disulfide bond, a bond between two selenium atoms, a bond between a sulfur and a selenium atom, or an acid-labile bond. In some embodiments, the pHLIP peptide is attached to a fluorophore by a covalent bond, wherein the covalent bond is a bond that has been formed by a click chemistry reaction. In certain embodiments, the covalent bond is a bond that has been formed by a reaction between (i) an azide and an alkyne; (ii) an alkyne and a strained difluorooctyne; (iii) a diaryl-strained-cyclooctyne and a 1,3-nitrone; (iv) a cyclooctene, trans-cycloalkene, or oxanorbomadiene and an azide, tetrazine, or tetrazole; (v) an activated alkene or oxanorbomadiene and an azide; (vi) a strained cyclooctene or other activated alkene and a tetrazine; or (vii) a tetrazole that has been activated by ultraviolet light and an alkene. In certain embodiments, the covalent bond is a peptide bond. In various embodiments, the covalent bond is not a peptide bond. In various embodiments, a pHLIP-fluorophore compound comprises a pHLIP peptide that is attached to the linker by a covalent bond. In some embodiments, the covalent bond is a peptide bond. In certain embodiments, the covalent bond is a disulfide bond, a bond between two selenium atoms, or a bond between a sulfur and a selenium atom. In various embodiments, the covalent bond is a bond that has been formed by a click chemistry reaction. In some embodiments, the covalent bond is a bond that has been formed by a reaction between (i) an azide and an alkyne; (ii) an alkyne and a strained difluorooctyne; (iii) a diaryl-strained-cyclooctyne and a 1,3-nitrone; (vi) a cyclooctene, trans-cycloalkene, or oxanorbomadiene and an azide, tetrazine, or tetrazole; (v) an activated alkene or oxanorbomadiene and an azide; (vi) a strained cyclooctene or other activated alkene and a tetrazine; or (vii) a tetrazole that has been activated by ultraviolet light and an alkene. In certain embodiments, the covalent bond is a peptide bond. In various embodiments, the covalent bond is not a peptide bond. In some embodiments, the linker comprises an artificial polymer or a synthetically produced polymer that has the structure of a polymer that exists in nature. In certain embodiments, the linker comprises a polypeptide, a polylysine, a polyarginine, a polyglutanmic acid, a polyaspartic acid, a polycysteine, or a polynucleic acid. In various embodiments, the linker does not comprise an amino acid. In some embodiments, the linker comprises a polysaccharide, a chitosan, or an alginate. In certain embodiments, the linker comprises a poly(ethylene glycol), a poly(lactic acid), a poly(glycolic acid), a poly(lactic-co-glycolic acid), a poly(malic acid), a polyorthoester, a poly(vinylalcohol), a poly(vinylpyrrolidone), a poly(methyl methacrylate), a poly(acrylic acid), a poly(acrylanide), a poly(methacrylic acid), a poly(amidoamine), a polyanhydrides, or a polycyanoacrylate. In various embodiments, the linker comprises poly(ethylene glycol). In certain embodiments, the poly(ethylene glycol) has a molecular weight of 60 to 100000 Daltons, e.g., at least about 60, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 5000, 10000, 15000, 20000, 25000 Daltons, but less than about 100000, 90000, 70000, 60000, 50000, 40000, or 30000 Daltons. In various embodiments, the linker comprises a linear polymer or a branched polymer. In some embodiments, the linker comprises an organic compound structure. In certain embodiments, the organic compound structure has a molecular weight less than about 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0.5 kDa. In some embodiments, the linker is attached to a fluorophore (e.g., a luminescent fluorophore or a quencher) via a covalent bond. In certain embodiments, the covalent bond is an ester bond, a disulfide bond, a bond between two selenium atoms, a bond between a sulfur and a selenium atom, or an acid-labile bond. In various embodiments, the covalent bond is a bond that has been formed by a click chemistry reaction. In some embodiments, the covalent bond is a bond that has been formed by a reaction between (i) an azide and an alkyne; (ii) an alkyne and a strained difluorooctyne; (iii) a diaryl-strained-cyclooctyne and a 1,3-nitrone; (vi) a cyclooctene, trans-cycloalkene, or oxanorbomadiene and an azide, tetrazine, or tetrazole; (v) an activated alkene or oxanorbomadiene and an azide; (vi) a strained cyclooctene or other activated alkene and a tetrazine; or (vii) a tetrazole that has been activated by ultraviolet light and an alkene. In certain embodiments, the covalent bond is a peptide bond. In various embodiments, the covalent bond is not a peptide bond. In some embodiments, the fluorophore is a fluorescent dye or a fluorescent protein. Non-limiting examples of fluorophores include fluorescent dyes, phosphorescent dyes, quantum dots, xanthene derivatives, cyanine derivatives, naphthalene derivatives, coumarin derivatives, oxadiaxol derivatives, pyrene derivatives, acridine derivatives, arylmethine derivatives, or tetrapyrrole derivatives. Xanthene derivatives include but are not limited to fluorescein, rhodamine, Oregon green, eosin, Texas red, and Cal Fluor dyes. Cyanine derivatives include but are not limited to cyanine, indocarbocyanine, indocyanine green (ICG), oxacarbocyanine, thiacarbocyanine, merocyanine, and Quasar dyes. Naphthalene derivatives include but are not limited to dansyl and prodan derivatives. Oxadiazole derivatives include but are not limited to pyridyloxazol, nitrobenzoxadiazole and benzoxadiazole. A non-limiting example of a pyrene derivative is cascade blue. Oxadine derivatives include but are not limited to Nile red, Nile blue, cresyl violet, and oxazine 170. Acridine derivatives include but are not limited to proflavin, acridine orange, and acridine yellow. Arylmethine derivatives include but are not limited to auramine, crystal violet, and malachite green. Tetrapyrrole derivatives include but are not limited to porphin, phtalocyanine, and bilirubin. In various embodiments, a pHLIP-fluorophore compound included herein is used as a diagnostic agent, an imaging agent. In some embodiments, a pHLIP-fluorophore compound provided herein is used as an agent for in vivo imaging or in an in vivo diagnostic method. In certain embodiments, a pHLIP-fluorophore compound provided herein is used as an agent for ex vivo imaging or in an ex vivo diagnostic method. Certain implementations comprise a formulation for a parenteral, a local, or a systemic administration comprising a pHLIP-fluorophore compound as disclosed herein. Formulations comprising a pHLIP-fluorophore compound for intravenous, intraarterial, intraperitoneal, intracerebral, intracerebroventricular, intrathecal, intracardiac, intracavemous, intraosseous, intraocular, or intravitreal administration are also provided. The present subject matter also includes a formulation for intravesical instillation comprising a pHLIP-fluorophore compound as disclosed herein. In various embodiments, the fluorophore is covalently attached to the membrane insertion peptide via a linkage such as a thiol linkage or ester linkage or acid-labile linkage. Other types of linkages, chemical bonds, or binding associations are also used. Exemplary linkages or associations are mediated by disulfide, and/or a peptide with a protein binding motif, and/or a protein kinase consensus sequence, and/or a protein phosphatase consensus sequence, and/or a protease-reactive sequence, and/or a peptidase-reactive sequence, and/or a transferase-reactive sequence, and/or a hydrolase-reactive sequence, and/or an isomerase-reactive sequence, and/or a ligase-reactive sequence, and/or an extracellular metalloprotease-reactive sequence, and/or a lysosomal protease-reactive sequence, and/or a beta-lactamase-reactive sequence, and/or an oxidoreductase-reactive sequence, and/or an esterase-reactive sequence, and/or a glycosidase-reactive sequence, and/or a nuclease-reactive sequence. In certain embodiments, the fluorophore is covalently attached to the membrane insertion peptide via a non-cleavable linkage. In various embodiments, a non-cleavable linkage is a covalent bond that is not cleaved by an enzyme expressed by a mammalian cell, and/or not cleaved by glutathione and/or not cleaved at conditions of low pH. Non-limiting examples of non-cleavable linkages include maleimide linkages, linkages resulting from the reaction of a N-hydroxysuccinimide ester with a primary amine (e.g., a primary amine of a lysine side-chain), linkages resulting from a click reaction, thioether linkages, or linkages resulting from the reaction of a primary amine (—NH2) or thio (—SH) functional group with succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC). Exemplary non-cleavable linkages include linkages comprising a maleimide alkane linker, and linkages comprising a maleimide cyclohexane linker, As is described above, the compositions may be used in, e.g., a clinical setting for diagnostic and therapeutic applications in humans as well as animals (e.g., companion animals such as dogs and cats as well as livestock such as horses, cattle, goats, sheep, llamas). Membrane-inserting compounds comprising such moieties may be used in a variety of clinical diagnostic methods, including real-time image-guided therapeutic interventions. Included herein are compositions that are administered to the body for diagnostic use, e.g., using methods known in the art. For example, the methods are carried out by infusing into a vascular lumen, e.g., intravenously (such as via a jugular vein, peripheral vein or the perivascular space). In some embodiments, the composition is infused into the lungs of a mammal, e.g., as an aerosol or lavage. In various embodiments, the composition is administered by intravesical instillation into a human or animal bladder, oral cavity, intestinal cavity, esophagus, or trachea. In some embodiments, the injection can be into the peritoneal cavity of the mammal, subdermally, or subcutaneously. Included herein are pharmaceutical compositions comprising a pH-triggered compound and a pharmaceutically acceptable carrier. In some embodiments, a subject is a mammal. In certain embodiments, the mammal is a rodent (e.g., a mouse or a rat), a primate (e.g., a chimpanzee, a gorilla, a monkey, a gibbon, a baboon), a cow, a camel, a dog, a cat, a horse, a llama, a sheep, a goat, a chicken, a turkey, or a duck. In certain embodiments, the subject is a human. The present subject matter provides compounds and compositions for detecting diseased tissue. For example, aspects of the present subject matter relate to the detection of cancerous tissue (e.g., of a tumor or a metastatic lesion) and/or precancerous tissue (e.g., dysplastic tissue). The compound includes a pHLIP peptide covalently linked to indocyanine green (ICG). The pHLIP peptide comprises amino acids in the sequence LFPTXTLL (SEQ ID NO: 1), wherein X is a protonatable amino acid. In preferred embodiments, X is a protonatable amino acid other than glutamic acid, such as aspartic acid. Additionally, the pH-triggered peptide has a higher affinity to a membrane lipid bilayer at pH 5.0 compared to at pH 8.0. In various implementations, the ICG is covalently attached to the first or the second amino acid counted from the N-terminus of the pHLIP peptide. Aspects of the present disclosure provide pHLIP peptides linked to an ICG compound. In various implementations, the pHLIP peptide is directly linked to a ICG by a covalent bond. In some non-limiting examples, the covalent bond is an ester bond, a thioester bond, a disulfide bond, a bond between two selenium atoms, a bond between a sulfur and a selenium atom, or an acid-labile bond. In some embodiments, the covalent bond between the pHLIP peptide and the ICG is a bond that has been formed by a click reaction. Non-limiting examples of click reactions include reactions between an azide and an alkyne; an alkyne and a strained difluorooctyne; a diaryl-strained-cyclooctyne and a 1,3-nitrone; a cyclooctene, trans-cycloalkene, or oxanorbornadiene and an azide, tetrazine, or tetrazole; an activated alkene or oxanorbornadiene and an azide; a strained cyclooctene or other activated alkene and a tetrazine; or a tetrazole that has been activated by ultraviolet light and an alkene. Some implementations provide a pHLIP peptide that is attached to a linker compound by a covalent bond, wherein the linker compound is attached to the IGC by a covalent bond. In non-limiting examples, the covalent bond between the pHLIP peptide and the linker compound and/or the covalent bond between the linker compound and the ICG is a disulfide bond, a bond between two selenium atoms, a bond between a sulfur and a selenium atom, or a bond that has been formed by a click reaction. In various embodiments, the ICG is covalently attached to the pHLIP peptide via a linkage such as a thiol linkage or thioester linkage or ester linkage or acid-labile linkage. Other types of linkages, chemical bonds, or binding associations may also be used. Exemplary linkages or associations are mediated by disulfide, and/or a peptide with a protein binding motif, and/or a protein kinase consensus sequence, and/or a protein phosphatase consensus sequence, and/or a protease-reactive sequence, and/or a peptidase-reactive sequence, and/or a transferase-reactive sequence, and/or a hydrolase-reactive sequence, and/or an isomerase-reactive sequence, and/or a ligase-reactive sequence, and/or an extracellular metalloprotease-reactive sequence, and/or a lysosomal protease-reactive sequence, and/or a beta-lactamase-reactive sequence, and/or an oxidoreductase-reactive sequence, and/or an esterase-reactive sequence, and/or a glycosidase-reactive sequence, and/or a nuclease-reactive sequence. In certain embodiments, the fluorophore is covalently attached to the pHLIP peptide via a non-cleavable linkage. In various embodiments a non-cleavable linkage is a covalent bond that is not cleaved by an enzyme expressed by a mammalian cell, and/or not cleaved by glutathione and/or not cleaved at conditions of low pH. Non-limiting examples of non-cleavable linkages include maleimide linkages [e.g., linkages resulting from the reaction of a maleimide ester with a thiol (e.g., at the thiol of a cysteine side-chain)], N-hydroxysuccinimide (NHS) linkages [e.g., linkages resulting from the reaction of a NHS ester with a primary amine (e.g., at the N-terminus of a polypeptide chain or a primary amine of a lysine side-chain)], linkages resulting from a click reaction, thioester linkages, thioether linkages, or linkages resulting from the reaction of a primary amine (—NH2) or thio (—SH) functional group with succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC). Exemplary non-cleavable linkages include a maleimide alkane linker, e.g. and a maleimide cyclohexane linker, e.g. In various embodiments, the pHLIP peptide comprises amino acids in the sequence ACDDQNPWRAYLDLLFPTDTLLLDLLWG (SEQ ID NO: 9), and wherein said ICG is covalently attached to the cysteine thereof. In certain embodiments, ICG is covalently bound to the cysteine. In some embodiments, the N-terminus and/or the C-terminus is not bound to any compound. In a non-limiting example, the compound comprises the following structure (SEQ ID NO: 4 is disclosed below): In some embodiments, the pHLIP peptide comprises amino acids in the sequence ADDQNPWRAYLDLLFPTDTLLLDLLWG (SEQ ID NO: 2), and the ICG is covalently attached to the N-terminal alanine of the pHLIP peptide. In a non-limiting example, the compound comprises the following structure (SEQ ID NO: 2 is disclosed below): In some embodiments, the pHLIP peptide comprises amino acids in the sequence AKDDQNPWRAYLDLLFPTDTLLLDLLWG (SEQ ID NO: 3), and the ICG is covalently attached to the lysine of the pHLIP peptide. A non-limiting example of such a compound comprises the structure (SEQ ID NO: 3 is disclosed below): In certain embodiments, the pHLIP peptide comprises amino acids in the sequence ACDDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 4), and the ICG is covalently attached to the cysteine of the pHLIP peptide. In a non-limiting example, the compound comprises the structure (SEQ ID NO: 4 is disclosed below): In various embodiments, the pHLIP peptide comprises amino acids in the sequence ACDDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 4), and wherein said ICG is covalently attached to the cysteine thereof. In certain embodiments, ICG is covalently bound to the cysteine. In some embodiments, the N-terminus and/or the C-terminus is not bound to any compound. In a non-limiting example, the compound comprises the following structure (SEQ ID NO: 4 is disclosed below): This structure may optionally be drawn as follows (SEQ ID NO: 4 is disclosed below): In some embodiments, the pHLIP peptide comprises amino acids in the sequence ADDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 5), and the ICG is covalently attached to the N-terminal alanine of the pHLIP peptide. In a non-limiting example, the compound comprises the following structure: In some embodiments, the pHLIP peptide comprises amino acids in the sequence AKDDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 8), and the ICG is covalently attached to the lysine of the pHLIP peptide. A non-limiting example of such a compound comprises the structure: Protonatable amino acids include amino acids with acidic side chains (e.g., side chains comprising one or more carboxyl groups). For example, a protonatable amino acid may have a side-chain with a pKa at 25° C. of less than about 7.0, 6.75, 6.5, 6.25, 6, 5.75, 5.5, 5.25, 5.0, 4.75, 4.5, 4.25, 4.0, 3.75, 3.5, 3.25, or 3.0. Non-limiting examples of protonatable amino acids include aspartic acid, glutamic acid, and gamma-carboxyglutamic acid. In various embodiments, the pHLIP peptide comprises an artificial protonatable amino acid. In some embodiments, the artificial protonatable amino acid comprises at least 1, 2, 3, 4 or 5 carboxyl groups. Of the standard α-amino acids, all but glycine can exist in either of two optical isomers, called L or D amino acids, which are mirror images of each other. While L-amino acids represent all of the amino acids found in proteins during translation in the ribosome, D-amino acids are found in some proteins produced by enzyme posttranslational modifications after translation and translocation to the endoplasmic reticulum. D-amino acids are abundant components of the peptidoglycan cell walls of bacteria, and D-serine acts as a neurotransmitter in the brain. The L and D convention for amino acid configuration refers not to the optical activity of the amino acid itself, but rather to the optical activity of the isomer of glyceraldehyde from which that amino acid can be synthesized (D-glyceraldehyde is dextrorotary; L-glyceraldehyde is levorotary). In some embodiments, all or some of the amino acids in a pHLIP peptide are D-amino acids. For example, pHLIP peptide may comprise solely L-amino acids or solely D-amino acids, or a combination of both D-amino acids and L-amino acids. Various embodiments include a pHLIP peptide comprising amino acids in the sequence LLFPTDTLLL (SEQ ID NO: 25). In some embodiments, the pHLIP peptide comprises amino acids in the sequence LDLLFPTDTLLLD (SEQ ID NO: 26). In certain embodiments, the pHLIP peptide comprises amino acids in the sequence AYLDLLFPTDTLLLDLL (SEQ ID NO: 27). In various embodiments, the pHLIP peptide comprises amino acids in the sequence DDQNPWRAYLDLLFPTDTLLLDLLW (SEQ ID NO: 28). In some embodiments, the pHLIP peptide comprises amino acids in the sequence WRAYLDLLFPTDTLLLDLLWG (SEQ ID NO: 29) or WRAYLDLLFPTDTLLLDLLW (SEQ ID NO: 30). Optionally, the pHLIP peptide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more amino acids at the N-terminus and/or C-terminus of an amino acid sequence disclosed herein. In various embodiments, the pHLIP peptide comprises amino acids in the sequence: (SEQ ID NO: 2) ADDQNPWRAYLDLLFPTDTLLLDLLWG, (SEQ ID NO: 3) AKDDQNPWRAYLDLLFPTDTLLLDLLWG, (SEQ ID NO: 4) ACDDQNPWRAYLDLLFPTDTLLLDLLWA, (SEQ ID NO: 5) ADDQNPWRAYLDLLFPTDTLLLDLLWA, (SEQ ID NO: 6) ADDQNPWRAYLDLLFPTDTLLLDLLWCA, (SEQ ID NO: 7) ADDQNPWRAYLDLLFPTDTLLLDLLWKA, (SEQ ID NO: 8) AKDDQNPWRAYLDLLFPTDTLLLDLLWA, (SEQ ID NO: 9) ACDDQNPWRAYLDLLFPTDTLLLDLLWG, (SEQ ID NO: 10) ADDQNPWRAYLDLLFPTDTLLLDLLWCG, (SEQ ID NO: 11) ADDQNPWRAYLDLLFPTDTLLLDLLWKG, (SEQ ID NO: 12) ACDDQNPWRAYLDLLFPTDTLLLDLLWKG, (SEQ ID NO: 13) AKDDQNPWRAYLDLLFPTDTLLLDLLWCG, (SEQ ID NO: 14) ACKDDQNPWRAYLDLLFPTDTLLLDLLWG, (SEQ ID NO: 15) ACDDQNPWRAYLDLLFPTDTLLLDLLW, (SEQ ID NO: 16) AKDDQNPWRAYLDLLFPTDTLLLDLLWC, (SEQ ID NO: 17) ACDDQNPWARYLDWLFPTDTLLLDL, (SEQ ID NO: 18) CDNNNPWRAYLDLLFPTDTLLLDW, (SEQ ID NO: 19) ACEEQNPWARYLEWLFPTETLLLEL, (SEQ ID NO: 20) ACEEQNPWRAYLELLFPTETLLLELLW, (SEQ ID NO: 21) CEEQQPWAQYLELLFPTETLLLEW, (SEQ ID NO: 22) CEEQQPWRAYLELLFPTETLLLEW, (SEQ ID NO: 23) AAEEQNPWARYLEWLFPTETLLLEL, or (SEQ ID NO: 24) AKEEQNPWARYLEWLFPTETLLLEL. In some embodiments, the amino acid sequence of the pHLIP peptide is less than 100%, 99%, or 95% identical to the amino acid sequence set forth as SEQ ID NOS: 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24. In some embodiments, the amino acid sequence of the pHLIP peptide is less than 100%, 99%, or 95% identical to each of the amino acid sequences set forth as SEQ ID NOS: 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24. In certain embodiments, the amino acid sequence of the pHLIP peptide is 95-100%, 95-99%, or 90-95% identical to one or more of the amino acid sequences set forth as SEQ ID NOS: 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24. In some embodiments, the amino acid sequence of the pHLIP peptide is identical to SEQ ID NO: 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24. In certain embodiments, the pHLIP peptide comprises 20-30 amino acids. For example, the pHLIP peptide comprises about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acids. In some embodiments, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or 1-3, 1-5, or 5-10 N-terminal amino acids of the pHLIP peptide are outside the cell (i.e., not within the lipid bilayer of the cell membrane) when the pHLIP peptide is inserted into the cell membrane. In various embodiments, when the compound is inserted into a cell membrane, then the ICG portion thereof is at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-5, 5-10, 5-15, or 10-15 angstroms (Å) from the lipid bilayer of the cell membrane. Aspects of the present subject matter provide a composition comprising a compound disclosed herein and a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises D-glucose, e.g., about 5-25 mM D-glucose, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 25 mM D-glucose. In some embodiments, the composition comprises a buffer, e.g., the composition is buffered such that it comprises pH of about 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.8, 7.9, or 8.0. In certain embodiments, the composition comprises phosphate buffered saline (PBS). Aspects of the present subject matter relate to the detection of oral cavity cancer, e.g., by spraying or administering a composition comprising a compound disclosed herein to the oral cavity. For example, the composition may comprise a mouthwash or a mouth spray. Also provided is a method for detecting cancer tissue or precancerous tissue in a bodily organ or tissue, comprising (a) contacting the bodily organ or tissue with a compound disclosed herein; (b) contacting the compound with electromagnetic radiation comprising an excitation wavelength of ICG; and (c) detecting electromagnetic radiation emitted from the compound, wherein detection of the radiation indicates the presence of the cancerous tissue or the precancerous tissue. In various embodiments, the level of radiation emitted from a precancerous tissue and/or a cancer tissue is at least 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or 20-fold, 25-fold, or more greater than a level of radiation emitted from normal non-cancerous tissue (e.g., corresponding normal-noncancerous tissue in a corresponding bodily organ or tissue). The compounds, compositions, and methods provided herein are useful for detecting cancerous or precancerous tissue in many bodily organs and tissues. In some embodiments, the bodily organ is a kidney or a urinary bladder. Non-limiting examples of tissues in which cancerous or precancerous tissue may be detected include bone, joint, ligament, muscle, tendon, salivary gland, tooth, gum, parotid gland, submandibular gland, sublingual gland, pharynx, esophagus, stomach, small intestine (e.g., duodenum, jejunum, and/or ileum), large intestine, liver, gallbladder, pancreas, nasal cavity, pharynx, larynx, trachea, bronchi, lung, diaphragm, kidney, ureter, bladder, urethra, ovary, uterus, fallopian tube, uterus, cervix, vagina, teste, epididymis, vas deferens, seminal vesicle, prostate, bulbourethral gland, pituitary gland, pineal gland, thyroid gland, parathyroid gland, adrenal gland, heart, artery, vein, capillary, lymphatic, lymph node, bone marrow, thymus, spleen, brain, cerebral hemisphere, diencephalon, brainstem, midbrain, pons, medulla oblongata, cerebellum, spinal cord, ventricular, choroid plexus, nerve, eye, ear, olfactory, breast, and skin tissue. In some embodiments, the diseased cancer tissue detected is sarcoma or carcinoma tissue. Non-limiting types of cancer that may be detected using compounds, compositions, and methods disclosed herein include bladder cancer, lung cancer, brain cancer, melanoma, breast cancer, cervical cancer, ovarian cancer, adrenal cancer, esophageal cancer, upper gastrointestinal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, Castleman Disease, colon/rectum cancer, endometrial cancer, esophagus cancer, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GISTs), gestational trophoblastic disease, Kaposi sarcoma, kidney cancer, laryngeal cancer, hypopharyngeal cancer, liver cancer, malignant mesothelioma, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oral cavity cancer, oropharyngeal cancer, osteosarcoma, pancreatic cancer, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, small intestine cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulbar cancer, and Wilms tumors. In various embodiments, the cancer comprises a solid tumor. In some embodiments, the cancerous or precancerous tissue is in the bladder, the upper urinary tract, a lymph node, a breast, a prostate, a head, a neck, a brain, a pancreas, a lung, a liver, or a kidney. The compounds, compositions, and methods provided herein are also useful for detecting cancer cells (such as metastatic cancer cells) in tissue such as a lymph node. In some embodiments, the lymph node is in a subject who has cancer. In various embodiments, the lymph node is in a subject with bladder cancer, upper urinary tract cancer, breast cancer, prostate cancer, head and neck cancer, bran cancer, pancreatic cancer, lung cancer, liver cancer, or kidney cancer. Diseased tissue (e.g., precancerous or cancer tissue) may be detected in tissue samples or biopsies obtained, removed, or provided from a subject. In various embodiments, the tissue comprises a tissue biopsy. Alternatively or in addition, the presence of diseased tissue is detected on a biological surface in vivo or in situ, e.g., the skin surface, the surface of a mucosal membrane, or an internal site (e.g., the internal surface of a bladder, the surface of a colon, the surface of an esophagus, or the surface of a surgical site within the subject). For example, the tissue to be interrogated comprises a lumen, e.g., a duct (such as a kidney duct), a ureter, an intestinal tissue (large or small intestine), an esophagus, or an airway lumen such as a tracheobronchial tube or alveolar tube. In some embodiments, a compound provided herein is used to detect the presence of melanoma tissue. In some embodiments, the bodily organ or tissue is present in a subject. Optionally, methods disclosed herein may include steps such as washing steps to remove excess unbound or unattached compound, i.e. compound that is not attached to a low pH tissue via insertion of a pHLIP peptide construct into a cell membrane. For example, an organ sample or tissue biopsy may be washed or perfused before ICG fluorescence is detected (e.g., imaged). In non-limiting examples in which a body cavity or surface has been contacted with a compound (e.g., in liquid or spray form), the cavity or surface may be flushed or washed to remove excess ICG before detection/imaging. In some embodiments, flushing/washing is performed using, e.g., an aqueous solution such as saline or water. In some embodiments, flushing/washing is performed with the carrier that was used to deliver the ICG-pHLIP peptide. In some embodiments, contacting a bodily organ, tissue, or fluid (such as blood) with a compound provided herein comprises administering the compound to a subject. For example, the compound is detected in vivo. In certain embodiments, the compound is administered to the subject via intravessical instillation, intravenous injection, intraperitoneal injection, topical administration, mucosal administration, or oral administration. For example, the compound may be administered to a site within the subject (e.g., sprayed, applied onto, delivered as a liquid) via tube that is inserted into the subject. The site may be, e.g., an existing, former, or suspected tumor site, and/or normal tissue that is being assessed for the presence of cancerous or precancerous tissue. In some embodiments, a tube or other device (e.g., a catheter, needle, aspirator, inhaler, endoscope, cystoscope, atomizer, spray nozzle, probe, syringe, pipette, or nebulizer) is used to deliver the compound to, e.g., the esophagus, bladder, or colon. In certain embodiments, fluorescence of the compound is detected (e.g., imaged) using an endoscope or a cystoscope. For example, the endoscope or cystoscope may be configured to (i) emit electromagnetic radiation comprising an excitation wavelength of ICG and/or (ii) detect electromagnetic radiation emitted from the compound (i.e., the ICG component of the compound). In some embodiments, the compound is administered by applying a liquid, powder, or spray comprising the compound to a surface of the subject. In some embodiments, the surface comprises a site within the body of the subject that is accessed and/or exposed via surgery. In some embodiments, the surgery comprises endoscopic surgery or cystoscopic surgery. In certain embodiments, the compound is administered to an oral cavity of the subject. In various embodiments, electromagnetic radiation emitted from the compound is detected ex vivo. In some embodiments, a tissue sample (e.g., a biopsy or an organ) from a subject is perfused, soaked, sprayed, incubated, and/or injected with a composition comprising a compound herein, followed by washing, and then imaging for ICG fluorescence. Aspects of the present subject matter relate to methods comprising surgically removing cancerous tissue or precancerous tissue, e.g., cancer tissue or precancerous tissue detected with a compound, composition, or method disclosed herein. For example, the fluorescence of the compounds provided herein may be used to guide surgery such that all cancerous and/or precancerous tissue is removed, i.e., clean (non-cancer containing) margins of the surgical site are achieved. The present subject matter provides methods for identifying precancerous and cancer/tumor tissue faster than existing pathological methods. For example, tissue removed during surgery can be contacted with ICG-pHLIP peptides, washed, and then rapidly imaged to determine, e.g., whether all of the tissue removed was precancerous or cancerous and/or whether precancerous or cancerous tissue remains in a subject. Alternatively or in addition, the surgical site may be contacted with a compound (e.g., by local or systemic administration) to determine whether any diseased tissue remains at the site. The methods provided herein do not require, e.g., time consuming immunohistological staining or evaluation by a trained pathologist. The speed (e.g., 30 minutes or less) at which the methods provided herein may be performed enable clinicians to test for the presence or absence of precancerous or cancerous tissue (e.g., within a subject or a sample from the subject) during ongoing surgery, e.g., to determine whether and where surgery should continue (e.g., to remove more tissue). The development, reoccurrence, and treatment of cancer can also be detected and monitored. For example, a subject who has had cancer surgically removed or treated (e.g., with chemotherapy or radiation) may be tested for cancer using compounds and methods disclosed herein. For example, the inside of a bladder, colon, esophagus, or oral cavity, and/or a mucosal membrane/skin surface may be contacted with a compound provided herein and then detected to determine whether precancerous and/or cancerous tissue is developing or has developed. In instances where, e.g., chemotherapy or radiation therapy efficacy is assessed, the amount of cancer tissue may be monitored. Thus, ICG-pH-triggered compounds provided herein can be used to assist decisions regarding whether cancer treatment should be initiated or continued, and/or whether a different treatment regimen should be attempted (e.g., if a previously administered dose/regimen has not reduced the amount of cancer tissue as desired). Many different types of subjects with various stages of cancer can be assessed and/or treated using the compounds, compositions, and methods provided herein. However, various embodiments relate to the detection and treatment of cancer before the removal of a large amount of tissue (e.g., an organ such as a bladder or kidney, or, e.g. a portion of an organ such as a colon) is warranted or advisable. In various embodiments, the subject does not comprise invasive or metastatic cancer. In certain embodiments, relating to subjects with urothelial carcinoma, the subject does not comprise high grade urothelial carcinoma. In some embodiments, the subject does not comprise invasive high grade urothelial carcinoma. Each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. Thus, all combinations of the various elements described herein are within the scope of the invention. Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. DESCRIPTION OF THE DRAWINGS The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. As used herein with respect to the data provided in the drawings and Examples 1-3, the terms “ICG-Var3” “ICG-Var3 peptide” “ICG-Var3 compound” and “ICG-Var3 construct” refer to a pHLIP-fluorophore compound comprising a pHLIP peptide with the amino acid sequence NH2-ACDDQNPWRAYLDLLFPTDTLLLDLLWA-COOH (SEQ ID NO: 4) with ICG covalently bound to the cysteine thereof [A-Cys(ICG)-DDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO:4)], having the following structure (SEQ ID NO: 4 is disclosed below): The term “ICG-pHLIP peptide” is a more general term than “ICG-Var3” and includes any pHLIP-fluorophore compound comprising ICG and a pHLIP peptide. FIGS. 1A-B are graphs showing normalized absorbance (A) and fluorescence (B) spectra of an ICG-Var3 compound measured in phosphate buffered saline (PBS) pH 7.4 containing 10 mM D-glucose. The fluorescence (with an excitation wavelength of 790 nm) of ICG-Var3 compound is increased about 25 fold in the presence of 1-palnitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) liposomes compared to the emission in buffer. FIGS. 2A-L are images showing representative white light (A, D, G, J), NIR fluorescence (B, E, H, K) ex vivo imaging of bladder specimens and hemolysin and eosin (HE) stained tumor sections (C, F, I, L) are shown, demonstrating targeting of invasive high grade urothelial carcinoma (A, B, C), non-invasive high grade urothelial carcinoma (D, E, F), carcinoma in situ (G, H, I) and dysplasia (J, K, L) by ICG-Var3 imaging agent. The diagnosis was confirmed by pathological analysis. The fluorescent lesions were marked in case #11 to identify locations for pathology analysis. FIGS. 3A-B are cartoons showing non-limiting examples of (A) pHLIP tethering of a cargo molecule to the surface of a cell in diseased tissue and (B) pHLIP delivery of cargo into a cell in diseased tissue. FIGS. 4A-F are a series of images showing the targeting of cancerous lesions in bladder tissue with a ICG-Var3 compound; white light (A, D), NIR fluorescence (B, E) and overlay of white light and fluorescent images (C, F) are shown. FIGS. 5A-I are a series of images showing the targeting of cancerous lesions in bladder tissue with a ICG-Var3 compound; white light (A, D, G), NIR fluorescence (B, E, H) and overlay of white light and fluorescent images (C, F, G) are shown. FIGS. 6A-F are a series of images showing the targeting of cancerous lesions in bladder tissue with a ICG-Var3 compound; white light (A, D), NIR fluorescence (B, E) and overlay of white light and fluorescent images (C, F) are shown. FIGS. 7A-C are a series of images showing the targeting of cancerous lesions in bladder tissue with a ICG-Var3 compound; white light (A), NIR fluorescence (B) and overlay of white light and fluorescent images (C) are shown. FIGS. 8A-G are a series of images showing the targeting of cancerous lesions in bladder tissue with a ICG-Var3 compound; white light (A, D, F), NIR fluorescence (B, E, G) and overlay of white light and fluorescent images (C) are shown. The on the figure F and G the case of normal tissue is shown not targeted by ICG-Var3 compound. FIGS. 9A-C are a series of images showing the targeting of cancerous lesions in bladder tissue with a ICG-Var3 compound; white light (A), NIR fluorescence (B) and overlay of white light and fluorescent images (C) are shown. FIG. 10 is a set of images showing the targeting of cancerous lesions in kidney tissue with a ICG-Var3 compound, on the left NIR fluorescence image of kidney is shown and on the right the white light image is shown. Kidney collected after radical nephrectomy was perfused with ICG-Var3 compound for 30 min through the artery to mimic IV administration of the compound, followed by washing with saline and ex vivo imaging. FIG. 11 is an image showing the targeting of 4T1 murine mammary carcinoma with an ICG-Var3 compound. The ICG-Var3 compound was administered by intravenous (IV) injection (40 μM, 100 μL) and imaged 16 hours (h) after injection. The highly invasive 4T1 mammary carcinoma model mimics stage IV of human breast cancer. FIG. 12 is an image showing the targeting of AY27 rat bladder cancer in nude mice with an ICG-Var3 compound. The ICG-Var3 compound was administered by IV injection (40 μM, 100 μL) and imaged 16 h after injection. FIG. 13 is an image showing the targeting of 4T1 tumors with an ICG-Var3 compound. The ICG-Var3 compound was administered by IV injection (20, 10 and 5 μM, as indicated) and imaged 16 h after injection. The fluorescent signal decreased with the decrease of the injected ICG-Var3 compound dose. FIG. 14 is a graph showing the targeting of 4T1 tumors with an ICG-Var3 compound (at 20, 10 and 5 μM concentrations, intravenous injection, imaged at 16 h). With decrease of concentration of ICG-Var3 compound, the fluorescence intensity in tumor, liver and kidney decreases. The fluorescence values were obtained from the images recorded using a standard endoscopic light source/imaging system at the laser power 2 and gain 3. FIG. 15 is an image showing the targeting of 4T1 tumors with 10 μM of ICG-Var3 compound with IV and intraperitoneal (IP) injection. Imaging was performed 16 h after injection. FIG. 16 is an image showing targeting of 4T1 tumors with 20 μM of ICG-Var3 compound compared to 20 μM of IR800-pHLIP compound. The compounds were administered by IV injection and imaging was performed 16 h after injection. The fluorescent signal in tumor detected with an endoscope (e.g., a standard endoscopic light source/imaging system) is higher for the ICG-Var3 compound compared to the IR800-pHLIP compound. FIG. 17 is a chart comparing the targeting of 4T1 tumors with 20 μM of ICG-Var3 compound versus 20 μM of IR800-pHLIP compound. The compounds were administered by IV injection and imaging was performed 16 h after injection. The fluorescent signal in a tumor detected by the endoscope was higher for the ICG-Var3 compound compared to the IR800-pHLIP compound. The ICG-Var3 compound was cleared by the liver and the IR800-pHLIP compound was cleared by the kidney. FIG. 18 is a set of images showing the visualization of tumor margins with a ICG-Var3 compound. The tumor margins are defined very well by the ICG-Var3 compound. Additionally, muscle tissue is not targeted by the ICG-Var3 compound. FIG. 19 shows the BLOSUM62 matrix. FIG. 20 is a set of NIR fluorescent pictures of mouse leg obtained at 5 and 30 min after IV administration of ICG-Cys (ICG maleimide was conjugated with Cys residue). FIG. 21 is a set of NIR fluorescent pictures of a mouse leg obtained at 5, 30, 60, 90 and 120 min after IV administration of ICG-Var3 pHLIP (ICG-Var3 pHLIP is an ICG-Var3 compound with a Var3 pHLIP peptide; see Table 11 for pHLIP peptide amino acid sequence). FIG. 22 is a set of NIR fluorescent pictures of a mouse leg obtained at 5, 30, 60, 90 and 120 min after IV administration of ICG-WT pHLIP (ICG-WT pHLIP is an ICG-Var3 compound with a WT pHLIP peptide; see Table 11 for pHLIP peptide amino acid sequence). FIG. 23 is a set of NIR fluorescent pictures of a mouse leg obtained at 5, 30, 60, 90 and 120 min after IV administration of ICG-Hum pHLIP (ICG-Hum pHLIP is an ICG-Var3 compound with a Hum pHLIP peptide; see Table 11 for pHLIP peptide amino acid sequence). FIG. 24 is a set of NIR fluorescent pictures of a mouse leg obtained at 5, 30, 60, 90 and 120 min after IV administration of ICG-NpHLIP (ICG-NpHLIP is an ICG-Var3 compound with a NpHLIP peptide; see Table 11 for pHLIP peptide sequence). FIG. 25 is a set of NIR fluorescent pictures of a mouse ear obtained at 5 and 30 min after IV administration of ICG-Cys (ICG maleimide was conjugated with Cys residue). FIG. 26 is a set of NIR fluorescent pictures of a mouse ear obtained at 5, 30, 60, 90 and 120 min after IV administration of ICG-Var3 pHLIP. FIG. 27 is a set of NIR fluorescent pictures of a mouse ear obtained at 5, 30, 60, 90 and 120 min after IV administration of ICG-WT pHLIP. FIG. 28 is a set of NIR fluorescent pictures of a mouse ear obtained at 5, 30, 60, 90 and 120 min after IV administration of ICG-Hum pHLIP. FIG. 29 is a set of NIR fluorescent pictures of a mouse ear obtained at 5, 30, 60, 90 and 120 min after IV administration of ICG-NpHLIP. FIG. 30 is a set of NIR fluorescent pictures of a mouse blood collected at 5, 30, 60, 90 and 120 min after IV administration of ICG-Cys, ICG-WT pHLIP, ICG-Var3 pHLIP, ICG-NpHLIP and ICG-Hum pHLIP. FIG. 31 is a set of NIR fluorescent pictures of a mouse leg obtained at 5 and 30 min after IV administration of IR800-Cys (IR800 maleimide was conjugated with Cys residue). FIG. 32 is a set of NIR fluorescent pictures of a mouse leg obtained at 5, 30, 60, 90 and 120 min after IV administration of IR800-Var3 pHLIP (see Table 11 for pHLIP peptide amino acid sequence). FIG. 33 is a set of NIR fluorescent pictures of a mouse leg obtained at 5, 30, 60, 90 and 120 min after IV administration of IR800-WT pHLIP (see Table 11 for pHLIP peptide amino acid sequence). FIG. 34 is a set of NIR fluorescent pictures of a mouse ear obtained at 5 and 30 min after IV administration of IR800-Cys (IR800 maleimide was conjugated with Cys residue). FIG. 35 is a set of NIR fluorescent pictures of a mouse ear obtained at 5, 30, 60, 90 and 120 min after IV administration of IR800-Var3 pHLIP (see Table 11 for pHLIP peptide amino acid sequence). FIG. 36 is a set of NIR fluorescent pictures of a mouse ear obtained at 5, 30, 60, 90 and 120 min after IV administration of IR800-WT pHLIP (see Table 11 for pHLIP peptide amino acid sequence). FIG. 37 is a set of NIR fluorescent pictures of a mouse blood collected at 5, 30, 60, 90 and 120 min after IV administration of IR800-Cys, IR800-WT pHLIP and IR800-Var3 pHLIP (see Table 11 for pHLIP peptide amino acid sequences). FIGS. 38A-C are a series of images showing the targeting of cancerous lesions in human bladder tissue with ICG-Var3 compound (A) color image of bladder, (B) fluorescent image of bladder), (C) color image of bladder with contour identifying tumor margins are shown [outline/contour shows invasive high grade transitional cell cancer (TCC)]. Diagnosis was confirmed by pathological investigation. 4 μM of 80 mL (1.34 mg) of ICG-Var3 was instilled in PBS with glucose into human bladder obtained after cystectomy surgery for 15 min followed by washing with saline, cutting and imaging with NIR endoscope (see Table 11 for pHLIP peptide amino acid sequences). Standard pathological analysis (hemolysin and eosin staining) was performed on fluorescent and non-fluorescent tissue samples. FIGS. 39A-C are a series of images showing the targeting of cancerous lesions in human bladder tissue with ICG-Var3 compound (A) color image of bladder, (B) fluorescent image of bladder), (C) color image of bladder with contour identifying tumor margins are shown (outline/contour shows carcinoma in situ). Diagnosis was confirmed by pathological investigation. 4 μM of 80 mL (1.34 mg) of ICG-Var3 was instilled in PBS with glucose into human bladder obtained after cystectomy surgery for 15 min followed by washing with saline, cutting and imaging with NIR endoscope (see Table 11 for pHLIP peptide amino acid sequences). Standard pathological analysis (hemolysin and eosin staining) was performed on fluorescent and non-fluorescent tissue samples. FIGS. 40A-C are a series of images showing the targeting of cancerous lesions in human bladder tissue with ICG-Var3 compound (A) color image of bladder, (B) fluorescent image of bladder), (C) color image of bladder with contour identifying tumor margins are shown. Diagnosis was confirmed by pathological investigation (outline/contour shows invasive high grade TCC). 4 μM of 80 mL (1.34 mg) of ICG-Var3 was instilled in PBS with glucose into human bladder obtained after cystectomy surgery for 15 min followed by washing with saline, cutting and imaging with NIR endoscope (see Table 11 for pHLIP peptide amino acid sequences). Standard pathological analysis (hemolysin and eosin staining) was performed on fluorescent and non-fluorescent tissue samples. FIGS. 41A-D are a series of images showing the targeting of cancerous lesions in human bladder tissue with ICG-Var3 compound (4 μM of 80 mL or 1.34 mg) (A) color image of bladder, (B) overlay of color and fluorescent images of bladder), (C and D) fluorescent images of bladder obtained with different excitation laser power are shown. FIGS. 42A and B are series of images showing the targeting of cancerous lesions in human bladder tissue with ICG-Var3 compound (A) color image of bladder, (B) fluorescent image obtained in bladder full with saline, the way as cystoscopy is done. 4 μM of 80 mL (1.34 mg) of ICG-Var3 was instilled in PBS with glucose into human bladder obtained after cystectomy surgery for 15 min followed by washing with saline and imaging bladder full with saline using 5 mm tip of NIR endoscope (see Table 11 for pHLIP peptide amino acid sequences). FIGS. 43A-C are a series of images showing the targeting of cancerous lesions in human bladder tissue with IR800-pHLIP compound (A) color image of bladder, (B) fluorescent image of bladder), (C) color image of bladder with contour identifying tumor margins are shown (outline/contour shows necrosis and treatment effect). Diagnosis was confirmed by pathological investigation. 4 μM of 80 mL (1.34 mg) of IR800-Var3 was instilled in PBS with glucose into human bladder obtained after cystectomy surgery for 15 min followed by washing with saline, cutting and imaging with NIR endoscope (see Table 11 for pHLIP peptide amino acid sequences). Standard pathological analysis (hemolysin and eosin staining) was performed on fluorescent and non-fluorescent tissue samples. FIGS. 44A-C are a series of images showing the targeting of cancerous lesions in human bladder tissue with IR800-pHLIP compound (A) color image of bladder, (B) fluorescent image of bladder), (C) color image of bladder with contour identifying tumor margins are shown [outline/contour shows high grade TCC with squamous cell carcinoma (SCC)]. Diagnosis was confirmed by pathological investigation. 4 μM of 80 mL (1.34 mg) of IR800-Var3 was instilled in PBS with glucose into human bladder obtained after cystectomy surgery for 15 min followed by washing with saline, cutting and imaging with NIR endoscope (see Table 11 for pHLIP peptide amino acid sequences). Standard pathological analysis (hemolysin and eosin staining) was performed on fluorescent and non-fluorescent tissue samples. FIG. 45 is an overlay of color and fluorescent images showing the targeting of cancerous lesions in upper urinary tract with ICG-Var3 compound (4 μM of 80 mL or 1.34 mg) (see Table 11 for pHLIP peptide amino acid sequences). FIG. 46 is an overlay of color and fluorescent images showing the targeting of cancerous lesions in upper urinary tract with ICG-Var3 compound (4 μM of 80 mL or 1.34 mg) (see Table 11 for pHLIP peptide amino acid sequences). FIGS. 47A-C is a series of images showing the targeting of cancerous lesions in human upper urinary tract tissue with ICG-Var3 compound (4 μM of 80 mL or 1.34 mg) (A) color image, (B) fluorescent image, (C) color image with contour identifying tumor margins are shown (outline/contour shows invasive high grade TCC). Diagnosis was confirmed by pathological investigation. DETAILED DESCRIPTION Fluorescence imaging has applications in medicine for many image-guided procedures. A long-standing example is fluorescence angiography for the assessment of blood flow and tissue perfusion in preoperative, intraoperative, and postoperative settings. Fluorescence angiography can provide real-time imaging of blood vessels to follow changes during surgical procedures. Some examples include the use of fluorescence in ophthalmology to evaluate the chorioretinal vasculature (Jia et al. 2015 Proc Natl Acad Sci USA 112(18): E2395-2402; Campagnoli et al. 2016 Retin Cases Brief Rep 10(2):175-182); cardiothoracic surgery to assess the patency of the coronary artery bypass (Desai et al. 2005 J Am Coll Cardiol 46(8): 1521-1525; Unno et al. 2008 Eur J Vasc Endovasc Surg 35(2): 205-207; Handa et al. 2009 Interact Cardiovasc Thorac Surg 9(2): 150-154); in neurovascular surgery to assess the effect of a superficial temporal artery-middle cerebral artery bypass graft in cerebral revascularization procedure (Woitzik et al. 2005 J Neurosurg 102(4): 692-698); in hepatobilliary surgery to identify the haptic segment and subsegment for anatomical hepatic resection (Aoki et al. 2008 World J Surg 32(8): 1763-1767; Ishizawa et al. 2009 J Am Coll Surg 208(1): el-4); in reconstructive surgeries (Azuma et al. 2008 Plast Reconstr Surg 122(4): 1062-1067; Lee et al. 2010 Plast Reconstr Surg 126(5): 1472-1481; Lee et al. 2010 J Reconstr Microsurg 26(1): 59-65; Murray et al. 2010 Plast Reconstr Surg 126(1): 33e-34e); and in cholecystectomy and colorectal resection (Boni et al. 2015 Surg Endosc 29(7): 2046-2055). In diagnostic applications, fluorescence angiography is used for imaging of hemodynamics in the brain (Kohl-Bareis et al. 2002 J Biomed Opt 7(3): 464-470; Leung et al. 2007 Appl Opt 46(10): 1604-1614); circulatory features of rheumatoid arthritis (Fischer et al. 2010 Acad Radiol 17(3): 375-381; Gompels et al. 2010 Rheumatology (Oxford) 49(8): 1436-1446); muscle perfusion (Habazettl et al. 2010 J Appl Physiol (1985) 108(4): 962-967); burns (Griffiths et al. 2016 Gland Surg 5(2): 133-149) to assess various other effects of trauma (Schomacker et al. 1997 J Trauma 43(5): 813-819). Further, fluorescence image-guided procedures are employed for mapping and visualization of lymph nodes, targeting and marking (e.g., visualizing or detecting) cancerous lesions and assessment of tumor margins by in vivo and ex vivo imaging (Jacobs 2008 Ann Surg Oncol 15(5): 1271-1272; Ankersmit et al. 2011 Colorectal Dis 13 Suppl 7: 70-73; Ferroli et al. 2011 Acta Neurochir Suppl 109: 251-257; Cahill et al. 2012 Surg Endosc 26(1): 197-204; Mondal et al. 2014 Adv Cancer Res 124: 171-211; Burggraaf et al. 2015 Nat Med 21(8): 955-961). A number of U.S. Food and Drug Administration (FDA) approved fluorescent dyes have been used in the clinic: fluorescein, which emits light at 500-600 nm wavelengths visible by naked eye, is traditionally used in retinal angiography, and NIR fluorescent dyes including ICG and IR800 (a proprietary Li-COR Biosciences fluorescent dye). NIR dyes work in the so-called tissue optical window, from 650-1350 nm, where light has its greatest tissue penetration. Penetrating NIR light is selected for excitation (750-805 nm) and fluorescence is observed at longer emission wavelengths within the window, allowing deepest tissue imaging. ICG is the most widely used NIR fluorescent dye (Desai et al. 2005 J Am Coll Cardiol 46(8): 1521-1525; Woitzik et al. 2005 J Neurosurg 102(4): 692-698; Unno et al. 2008 Eur J Vasc Endovasc Surg 35(2): 205-207; Marshall et al. 2010 Open Surg Oncol J 2(2): 12-25; Polom et al. 2011 Cancer 117(21): 4812-4822; Alander et al. 2012 Int J Biomed Imaging 2012: 940585; Zelken and Tufaro 2015 Ann Surg Oncol 22 Suppl 3: S1271-1283; Griffith et al. 2016 Gland Surg 5(2): 133-149). ICG was developed for photography by the Kodak Research Laboratories in 1955 and was already approved for clinical use in 1956 (Bjornsson et al. 1982 Experientia 38(12): 1441-1442; Bjomsson et al. 1983 J Clin Chem Clin Biochem 21(7): 453-458). ICG angiography was the first clinical application of ICG (Choromokos et al. 1969 J Biol Photogr Assoc 37(2): 100-104; Kogure and Choromokos 1969 J Appl Physiol 26(1): 154-157; Kogure et al. 1970 Arch Ophthalmol 83(2): 209-214). From the early 1970's ICG was used in ophthalmology for imaging retinal blood vessels, retinal angiography (Flower 1973 Invest Ophthalmol 12(12): 881-895). Following intravenous injection, ICG is rapidly bound to plasma proteins, with minimal leakage into the interstitium. The half-life time is 2.5 min (Benson and Kues 1978 Phys Med Biol 23(1): 159-163; Desmettre et al. 2000 Surv Ophthalmol 45(1): 15-27). There are no known metabolites. ICG is rapidly extracted by the liver without modifications and nearly exclusively excreted by the liver appearing unconjugated in the bile about 8 min after injection, depending on liver vascularization and function (Alander et al. 2012 Int J Biomed Imaging 2012: 940585). When injected outside blood vessels, ICG binds to proteins and is found in the lymph, reaching the nearest draining lymph node usually within 15 min, and after 1-2 h, it binds to the regional lymph nodes, deposited into macrophages (Tajima et al. 2010 Ann Surg Oncol 17(7): 1787-1793; Korn et al. 2014 Plast Reconstr Surg 133(4): 914-922). The intravenous injection dose of ICG typically varies in the range of 0.5 mg/ml/kg to 2.0 mg/ml/kg of body weight. No significant toxic effects have been observed in humans with the high dose of 5 mg/kg of body weight (Alander et al. 2012 Int J Biomed Imaging 2012: 940585), and chronic toxicity must be modest given the many years of unremarkable clinical experience. In addition to FDA approved fluorescein and NIR dyes, there are few other FDA approved fluorescent molecules used in specific applications, such as methylene blue (Winer et al. 2010 Ann Surg Oncol 17(4): 1094-1100; van der Vorst et al. 2012 World J Gastrointest Surg 4(7): 180-184; Verbeek et al. 2013 J Urol 190(2): 574-579), and 5-aminolevulinic acid (5-ALA) and its derivatives. 5-ALA and hexaminolevulinate hydrochloride, called Cysview in the United States, are heme precursors that induce production and intracellular accumulation of the fluorescent protoporphyrin, PpIX. 5-ALA is applied in the field of neurosurgery, mostly to intraoperatively identify brain tumors such as malignant gliomas (Stummer et al. 2006 Lancet Oncol 7(5): 392-401; Roberts et al. 2011 J Neurosurg 114(3): 595-603). Cysview is used for fluorescent visualization of cancerous lesions in the bladder using blue light cystoscopy, where 100 mg of Cysview agent dissolved in 50 ml (400 μmol) is applied topically, by intravesical instillation, for about 1 hour. It has been shown that blue light cystoscopy improves visualization of cancerous lesions and recurrence-free survival in patients compared to white light cystoscopy (Jocham et al. 2008 Eur Urol 53(6): 1138-1148; Santos Cortes et al. 2011 Arch Esp Urol 64(1): 18-31; Lerner et al. 2012 Urol Oncol 30(3): 285-289; Burger et al. 2013 Eur Urol 64(5): 846-854; Rink et al. 2013 Eur Urol 64(4): 624-638). Provided herein, inter alia, are pHLIP-fluorophore compounds comprising a membrane insertion peptide and a fluorophore (e.g., ICG), i.e., wherein the fluorophore is covalently attached to the membrane insertion peptide. pHLIP-fluorophore compounds comprising ICG may alternatively be referred to as “ICG-pHLIP peptides.” In various embodiments, a pHLIP-fluorophore compound inserts into circulating cells and/or cells that line a body lumen (such as a blood vessel, artery, vein, capillary, urinary tract, urethra, renal tube, airway, or alveoli). In some embodiments, a pHLIP-fluorophore compound has increased fluorescence intensity upon insertion into a cell membrane. Non-limiting aspects of the present subject matter relate to the use of membrane insertion peptides that insert into cell membranes at neutral pH (e.g., pH 7.0) or the pH of a bodily fluid such as blood (e.g., normal blood having a pH between 7.35 and 7.45). Included herein are ICG-pHLIP peptides, i.e., compounds comprising ICG and a pHLIP peptide, wherein the ICG is covalently attached to the pHLIP peptide. Aspects of the present subject matter relate to the unexpected properties of ICG-pHLIP peptide compounds. Surprisingly, (i) ICG-pHLIP peptides selectively target and mark diseased (e.g., tumor) tissue, and (ii) have increased fluorescence intensity upon insertion into cell membranes. In some embodiments, the fluorophore is ICG. Though free ICG (i.e., ICG that is not conjugated to another molecule) may have an affinity for the hydrophobic lipid bilayer of cell membranes, it is rapidly cleared when injected into the blood of a subject. Thus, high and/or repeated doses of free ICG are needed for diagnostic imaging techniques. However, when conjugated to a membrane insertion peptide, ICG persists much longer in circulation. In various embodiments, the amount of ICG that is administered as part of a pHLIP-fluorophore compound is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% less than would be administered if the ICG was administered as free ICG (in terms of moles of free ICG). In some embodiments, ICG that is part of a pHLIP-fluorophore compound is detectable in the blood for at least 25%, 50%, 75%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000% longer than free ICG, when administered in the same amount (in terms of moles of free ICG) under corresponding conditions. Without being bound by any scientific theory, membrane-inserting compounds comprising ICG reduce the rate at which ICG that is removed from circulation (e.g., by the kidneys and/or liver) by tethering the ICG to the cell membranes of circulating cells such as red blood cells and/or cells that line circulatory system. The tethering of ICG to the cell membranes is non-covalent and reversible. Moreover, as discussed below, the fluorescence of ICG increases when it is in close proximity to a lipid bilayer (such as a cell membrane), enabling more fluorescence to be achieved with less ICG. Thus, lower doses of membrane insertion peptide-conjugated ICG can be used (e.g., for diagnostic approaches) compared to the doses of free ICG that are typically used. The membrane-inserting compounds provided herein may also provide higher signal-to-noise than free ICG. With respect to embodiments relating to blood and the cardiovasculature, membrane insertion peptides that insert into cell membranes at or near neutral pH may be used. Thus, pH-triggered compounds that may insert at a minimally acidic, neutral, or slightly basic pH, and which may not be suitable for detecting acidic tissues, are useful in various embodiments disclosed herein. In some embodiments, a membrane-inserting compound comprising ICG has at least about 5, 10, 20, 25, 50, or 100 times the half-life of free ICG (e.g., in blood). The disadvantages of using ICG alone for diagnostic methods includes rapid binding to proteins (such as albumins) and circulating phospholipids in blood, low tissue permeability, and the inability to target cancerous tissue. However, ICG-pHLIP peptides readily penetrate cancerous tissue to specifically and effectively label tumor tissue for, e.g., surgical removal. Surprisingly, the presence of ICG in an ICG-pHLIP peptide construct does not disrupt the ability of pHLIP peptides to accumulate in tumor tissue and specifically insert into the membranes of tumor cells. When an ICG-pHLIP peptide is inserted into a cell (e.g., a cell in a tumor or acidic tissue, or a circulating cell such as a red blood cell), the ICG component thereof is held at a distance from the surface of the cell membrane (i.e., outside the lipid bilayer of the cell membrane), where fluorescence of the ICG may be used to detect the cancer cell in contrast to ICG alone, which associates directly with the membrane. Since the ICG component is attached to the pHLIP peptide component of the ICG-pHLIP peptide, the ICG component is not free interact with the cell membrane directly or surrounding molecules as it otherwise would. Thus, both the location and the orientation of the ICG with respect to, e.g., the cell membrane, are artificial and indirect. Surprisingly, the ICG component of an ICG-pHLIP peptide exhibits dramatically increased fluorescence when tethered to the surface of a cancer cell (e.g., in a tumor or metastatic lesion). For example, the fluorescence intensity increases by at least about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 50%, 75%, 100%, 2-fold, 10-fold, 12-fold, 15-fold, 20-fold, 25-fold, or more is achieved compared to untethered ICG. In certain embodiments, the increased fluorescence of an ICG-pHLIP peptides upon binding to cell membranes increases the tumor/background signal significantly. Though ICG may have an affinity for the hydrophobic lipid bilayer of cell membranes, this affinity is not pH specific. Surprisingly, the non-specific affinity of ICG for cell membranes (e.g., along vessels and in normal tissues) does not prevent pHLIP peptides from infiltrating and specifically and selectively tagging precancerous and cancerous tissue. The connection between ICG and the cell membrane, being via its attachment to a pH-triggered peptide, is both unnatural and indirect. In various embodiments, the pH-triggered peptide may separate ICG from the cell membrane, e.g. via a stretch of amino acids. For example, the non-limiting ICG-pHLIP peptides used in Example 1 (ICG-Var3 compounds) comprise pHLIP peptides with N-terminal amino acids that separate ICG from the cell membrane. The separation may comprise a polypeptide tether of, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids. SEQ ID NO: 3 comprises about seven N-terminal amino acids separate ICG from the cell membrane by about 11 Å. The underlined portion of the following sequence corresponds to the potential transmembrane portion, and the italicized amino acids indicate the seven N-terminal amino acids: (SEQ ID NO: 3) AKDDQNPWRAYLDLLFPTDTLLLDLLWG Assuming a random coil configuration of the seven N-terminal amino acids outside of the lipid bilayer, and taking the contour length per residue to be is 4.3 Å (Dietz, H. Rief, M. Proc Natl Acad Sci USA 2006, 103, 1244-1247; Carrion-Vazquez et al., Nat Struct Biol 2003, 10, 738-743; Oesterhelt et al., Science 2000, 288, 143-146), then the average end-to-end length of the coil can be estimated to be 11 Å. Thus, when ICG is attached to amino acids in the sequence of SEQ ID NO: 3, then the ICG is at the end of a flexible linker of amino acids that is about 11 Å long. Surprisingly, the fluorescence of ICG conjugated to the N-terminus of a pHLIP peptide was found to increase about 25-fold upon insertion into a cell membrane. Separation of ICG from the cell membrane is not required, however. In some embodiments, the pHLIP peptide does not separate ICG from the cell membrane. In certain embodiments, the N-terminal amino acid sequence of the pHLIP peptide has a length or structure such that the conjugated ICG is less than about 10 Å, 9 Å, 8 Å, 7 Å, 6 Å, 5 Å, 4 Å, 3 Å, 2 Å, 1 Å, 1-5 Å, 1-10 Å, or 5-10 Å from the cell membrane, or is in contact with the cell membrane. Alternatively, the N-terminal amino acid sequence of the pHLIP peptide has a length or structure such that the conjugated ICG is at least about 1 Å, 2 Å, 3 Å, 4 Å, 5 Å, 6 Å, 7 Å, 8 Å, 9 Å, 10 Å, 11 Å, 12 Å, 13 Å, 14 Å, 15 Å, or 20 Å from the cell membrane. Increased fluorescence upon the indirect association of ICG with a cell membrane (regardless of the distance of IGC from the cell membrane) is surprising. Bladder cancer is the fifth most common cancer. Timely diagnosis and appropriate early management protocols are of paramount significance for improving patient outcomes. Aspects of the present subject matter relate to the non-limiting data presented herein, which were generated in the first study to show efficient pH dependent near infrared imaging of bladder malignant tumors without targeting of normal tissue. The data presented herein show that conjugates comprising ICG and pHLIP peptides (which are pHLIP peptides) bind to and identify cancerous and precancerous tissues. The pH Low Insertion Peptide (pHLIP-peptide) conjugated with a near infrared fluorescent dye (ICG) (a ICG-pHLIP peptide such as ICG-Var3) construct is suitable for use as a predictive clinical marker, specifically staining human bladder tumors after intravesical administration ex vivo. The targeting allows delivery of various imaging probes, which may offer early diagnosis and improve the outcomes of endoscopic and radical surgical resection of urothelial carcinomas. In addition, delivery of therapeutic molecules to cancer tissue by pHLIP peptides such as pHLIP might open an opportunity for novel targeted treatment of bladder cancers. An important medical objective is the identification of early stage lesions, such as pre-cancerous tissue or carcinoma in situ, since it is expected that diagnosis at this stage will decrease the frequency of treatments, increasing patient health and reducing expense. Each type and stage of bladder cancer requires a different type of treatment. High recurrence frequency, procedural costs, and the requirement for prolonged active monitoring, make bladder cancer one of the most expensive cancers in the United States, placing a heavy economic burden on the healthcare system from lifetime endoscopic follow ups and treatments. Patients suffer from high morbidity and the complications associated with chemotherapy, radiation and radical surgery (Mariotto et al. (2011) J Natl Cancer Inst 103(2):117-128). Therefore, as noted, timely diagnosis of the tumor and appropriate management protocols are of great significance for decreasing treatment cost and improving a patient's life style. Advances in the early detection of bladder cancer lesions are likely to increase the chances of timely successful treatment, the prevention of recurrences, and bladder function preservation. Cancers, including urothelial carcinoma, are associated with multiple alterations in the genome, including changes in epigenetic regulation, point mutations, gene deletions, duplications and chromosomal rearrangements. These changes are heterogeneous, leading to heterogeneity of the overexpression of particular biomarkers at the surfaces of cancer cells within a tumor and between tumors. Heterogeneity significantly limits success in the use of cell surface biomarkers for the targeted delivery of therapeutics. On other hand, multiple studies have revealed that neoplastic cells produce an acidic environment due to increased metabolic activity (Damaghi et al. (2013) Front Physiol 4:370). Adaptations to the highly acidic microenvironment are critical steps in the transition from an avascular pre-invasive tumor to a malignant invasive carcinoma (Gillies et al. (2012) Nat Rev Cancer 12(7):487-493; Estrella et al. (2013) Cancer Res 73(5):1524-1535; Gatenby et al. (2006) Cancer Res 66(10):5216-5223). Thus, acidity may provide a universal biomarker for tumor targeting that is not subject to the selection of resistant cell lines (Bailey et al. (2012) Adv Pharmacol 65:63-107). pHLIP peptides (such as pHLIP peptides) are a class of membrane-binding peptides that specifically target acidic cells in vitro and in vivo (Andreev et al. (2014) Front Physiol 5:97) by inserting across cellular membranes when the extracellular pH is low (Weerakkody et al. (2013) Proc Natl Acad Sci USA 110(15):5834-5839). pHLIP peptides (such as pHLIP peptides) conjugated with fluorescent dyes have been used to differentiate normal from neoplastic tissue in various animal tumor models ((Weerakkody et al. (2013) Proc Natl Acad Sci USA 110(15):5834-5839; Reshetnyak et al. (2011) Mol Imaging Biol 13(6):1146-1156; Adochite et al. (2014) Mol Pharm 11(8):2896-2905; Cruz-Monserrate et al. (2014) Sci Rep 4:4410), and in human biopsy head and neck samples (Luo et al. (2014) Cancer Prev Res (Phila) 7(10):1035-1044; Luo et al. (2012) J Biomed Opt 17(10):106006). In various implementations, an ICG-pHLIP peptide (such as ICG-Var3 or an ICG-pHLIP) targets low extracellular pH allowing visualization of malignant lesions in human bladder carcinoma ex vivo. In the non-limiting examples below, cystectomy specimens obtained after radical surgery were immediately irrigated with non-buffered saline and instilled with a solution of the ICG-Var3 construct, incubated, and rinsed. Bladders were subsequently opened and imaged, the fluorescent spots were marked, and a standard pathological analysis was carried out to establish the correlation between ICG-Var3 imaging and white light pathological assessment. Accurate targeting of bladder lesions was achieved with a sensitivity of 97%. Specificity is 100%, but reduced to 80%, if targeting of necrotic tissue from previous transurethral resections or chemotherapy are considered as false positives. ICG-Var3 imaging agent marked high grade urothelial carcinomas, both muscle invasive and non-muscle invasive. Carcinoma in situ (CIS) was accurately diagnosed in 11 cases, whereas only 4 cases were seen using white light, so imaging with the ICG-Var3 compound offers improved early diagnosis of bladder cancers, and may also enable new treatment alternatives. The ICG-Var3 compound is a promising tool for the early detection of urothelial carcinoma, regardless of subtype, with high sensitivity and specificity. The detection might be used for monitoring the state of disease and/or for marking lesions for surgical removal. Monitoring and/or diagnosing cancer in a subject can be performed for a variety of cancers, e.g., by assessing whether ICG-pHLIP peptides specifically bind to a tissue being tested for a neoplasm. In some embodiments, the tissue is in a subject and the compound is applied directly to the tissues or injected systemically (or, e.g., subcutaneously or intraperitoneally). In non-limiting examples, tubes such as catheters are used to deliver compounds disclosed herein to bladder, esophagus, stomach, and colon tissues. The compounds may be administered in, e.g., spray, mist, droplet, liquid, or powder form. In some embodiments, a compound is administered orally and then detected with, e.g., an endoscope or a cystoscope. Mouthwashes and sprays comprising a compound of the present subject matter may be used to detect cancers or precancerous lesions in the oral cavity. The compounds disclosed herein may also be applied directly to a cervix to detect, e.g., cervical cancer tissue. With respect to, e.g., skin cancers, the compounds may be applied to the skin surface. In certain embodiments, the tissue is a sample such as a biopsy and/or an organ or a portion thereof that has been surgically removed. ICG-pHLIP peptides such as the ICG-Var3 imaging agent improve diagnosis and resection of cancerous lesions in the bladder. The methods, compounds, compositions, systems, and kits provided herein, will reduce recurrence rates, improve patient outcomes, and lower the cost of medical care for bladder cancer. In addition, success with targeted imaging leads to pHLIP peptide (such as pHLIP) delivery of therapeutic molecules to bladder tumor cells, creating an opportunity for targeted treatment of bladder cancers. In various embodiments, an ICG-pHLIP peptide construct (such as the ICG-Var3construct) is a generally applicable imaging agent, since it targets a general property of the tumor microenvironment, tumor acidity. Targeting of primary tumors and metastatic lesions by fluorescent pHLIP peptides has been shown in more than 15 varieties of human, murine and rat tumors, including lymphoma, melanoma, pancreatic, breast and prostate transgenic mouse models and human tissue (bladder, kidney, breast and head/neck stained ex vivo). ICG, which is known to have poor tissue penetration and to bind to proteins in blood, has not been attempted. Surprisingly, conjugates comprising ICG and a pHLIP peptide (e.g., a pHLIP peptide) are able to specifically target cancer tissues. Moreover, conjugates comprising ICG and pHLIP peptides have unexpected properties, especially compared to conjugates comprising other fluorophores. For example, ICG fluorescence is enhanced about 25 times when a pHLIP peptide tethers it to a membrane. This facilitates not only the detection of tumors, but also the identification of boundaries between cancerous and non-cancerous tissue. Increased fluorescence intensity upon tethering to cell membranes has not been observed with other dyes/fluorophores that have been attached to pHLIP peptides, and allows an enhanced tumor/normal tissue fluorescence ratio. The data presented in the non-limiting Examples herein show that ICG-Var3 and ICG-WT (ACEQNPIYWARYADWLFTTPLLLLDLALLVDADEGT) (SEQ ID NO: 444) are useful for fluorescence angiography in numerous clinical procedures. The advantages compared to free ICG are significant. In various embodiments, the imaging time is extended from 2-5 min, used now for free ICG to 2-3 hours, with ICG-Var3 (or ICG-WT). Currently, during some procedures free ICG is injected 10 or more times. In some embodiments, an ICG-pHLIP (such as ICG-Var3) is injected just once and can be imaged throughout a procedure without creating any disturbance of clinical flow (which occurs, e.g., when free ICG is reinjected). Thus, the flow or sequence of steps or actions in a clinical procedure is disrupted less with an ICG-pHLIP than with free ICG. ICG-pHLIPs have significant advantages and provides improvements compared to the use of free-ICG in fluorescence angiography and other of clinical procedures. Three non-limiting examples of potential ICG-pHLIP (such as ICG-Var3) use are as follows: 1. Fluorescent Angiography after intravenous administration of an ICG-pHLIP (such as ICG-Var3): Imaging is performed within 5 min up to 2-3 hours after intravenous injection of an ICG-pHLIP for visualization of blood vessels and blood perfusion. ICG-Var3 can be used in numerous clinical procedures. 2. Targeting (e.g., identification for subsequent surgical resection) of acidic diseased tissue after intravenous administration of an ICG-pHLIP (such ICG-Var3): Imaging is performed at later time points, such as >4 hours or next day after intravenous injection of an ICG-pHLIP for visualization of targeting of acidic diseased tissue, such as precancerous lesions, tumors, cancer cells in lymph nodes, ischemic myocardium, atherosclerotic plaques, site of infection and others. In embodiments, there is more time to blood clearance and clearance of adjacent non-diseased tissue from an ICG-pHLIP to observe the best contrast (e.g., at an optimal time point) between diseased and non-diseased tissue. 3. Targeting (e.g., identification for subsequent surgical resection) of acidic diseased tissue after topical administration of an ICG-pHLIP (such as ICG-Var3): Imaging will be performed after topical administration of an ICG-pHLIP, such as instillation into a urinary bladder to detect bladder cancer, rinsing of mouth to detect oral cancer, spray on skin to detect skin cancer, spray on the cervix to detect cervical cancer, spray into the colon to detect colon cancer, and spray or inhalation into lung airway passages to detect lung cancer. The agent can also be used for non-cancerous applications, such as visualization of wounds or site of infections (which tissues are also acidic). For example, the agents are used in visualization of infection sites related to implanting of various devices, e.g., orthopedic, prosthetic, patches for slow drug release, implants, and cardiovascular devices such as stents in the body. In certain embodiments comprising the topical application of an ICG-pHLIP, imaging is performed with 10-60 min after topical application of an ICG-pHLIP. pH-Triggered Polypeptides A pH-triggered polypeptide (pHLIP peptides, also known as “pH-triggered pH (Low) Insertion Peptides”) is a water-soluble membrane peptide that interacts weakly with a cell membrane at neutral pH, without insertion into the lipid bilayer, but inserts into the cell membrane and forms a stable transmembrane alpha-helix at acidic pH (e.g., at a pH of less than about 7.0, 6.75, 6.5, 6.25, 6, 5.75, 5.5, 5.25, 5.0, 4.75, 4.5, 4.25, 4.0, 3.75, 3.5, 3.25, or 3.0). In some embodiments, the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 genetically coded amino acids. Alternatively or in addition the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 non-genetically coded amino acids. In some embodiments, the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 D-amino acids. In certain embodiments, the pHLIP peptide comprised a functional group to which the fluorophore was attached. In various embodiments, the functional group of the pHLIP peptide comprised an amino acid, azido modified amino acid, or alkynyl modified amino acid. In some embodiments, the functional group of the pHLIP peptide comprised a free sulfhydryl (SH), or a primary amine. In certain embodiments, one or more fluorophores were attached to the functional group. In various embodiments, a pHLIP peptide (e.g. a pHLIP peptide that is within a compound that comprises the pHLIP peptide and a fluorophore) has a net neutral charge at a low pH and a net negative charge at a neutral or high pH. In some embodiments, a pHLIP peptide has a net neutral charge at a pH of less than about 7, 6.9, 6.8, 6.7, 6.6, 6.5, 6.0, 5.5, 5.0, 4.5, or 4.0 and a net negative charge at a pH of about 7, 7.1, 7.2, 7.3, 7.4, 7.5, or 7.75 in water, e.g., distilled water. In certain embodiments, a pHLIP peptide has a net neutral charge at a pH of less than about 7 and a net negative charge at a pH of about 7 in water. In some embodiments, a pHLIP peptide has a net neutral charge at a pH of less than about 6.9 and a net negative charge at a pH of about 7 in water. In some embodiments, a pHLIP peptide has a net neutral charge at a pH of less than about 6.8 and a net negative charge at a pH of about 7 in water. In some embodiments, a pHLIP peptide has a net neutral charge at a pH of less than about 6.7 and a net negative charge at a pH of about 7 in water. In some embodiments, a pHLIP peptide has a net neutral charge at a pH of less than about 6.6 and a net negative charge at a pH of about 7 in water. In some embodiments, a pHLIP peptide has a net neutral charge at a pH of less than about 6.5 and a net negative charge at a pH of about 7 in water. In various embodiments, a pHLIP peptide has a net neutral charge at a pH of less than about 6.0 and a net negative charge at a pH of about 7. In some embodiments, a pHLIP peptide has a net neutral charge at a pH of less than about 5.5 and a net negative charge at a pH of about 7 in water. In certain embodiments, a pHLIP peptide has a net neutral charge at a pH of less than about 5.0 and a net negative charge at a pH of about 7 in water. In various embodiments, a pHLIP peptide has a net neutral charge at a pH of less than about 4.5 and a net negative charge at a pH of about 7 in water. In some embodiments, a pHLIP peptide has a net neutral charge at a pH of less than about 4.0 and a net negative charge at a pH of about 7 in water. In some embodiments, a pHLIP peptide (e.g., a pHLIP peptide that is within a compound that comprises the pHLIP peptide and a fluorophore) has a net negative charge at a pH of about 7, 7.25, 7.5, or 7.75 in water. Alternatively or in addition, the pHLIP peptide may have an acid dissociation constant at logarithmic scale (pKa) of less than about 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 6.6, 6.7, 6.8, 6.9, or 7. In various embodiments, a protonatable amino acid is an amino acid with a pKa of less than about 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, or 7. In certain embodiments, a protonatable amino acid is an amino acid with a pKa of less than about 6.5. In some embodiments, a protonatable amino acid is an amino acid with a pKa of less than about 5.5. In certain embodiments, a protonatable amino acid is an amino acid with a pKa of less than about 4.5. In various embodiments, a protonatable amino acid is an amino acid with a pKa of less than about 4.0. In some embodiments, a protonatable amino acid comprises a carboxyl group. pHLIP-fluorophore compounds may comprise pHLIP peptides of various sizes. For example, a pHLIP peptide may have 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 45, 46, 47, 48, 49, 50 or more amino acids; 8 to 15 amino acids; 8 to 50 amino acids; 8 to 40 amino acids; 8 to 30 amino acids; 8 to 20 amino acids; 8 to 10 amino acids; less than about 20 amino acids; less than 9, 10, 11, 12, 13, 14, or 15 amino acids; 10 amino acids; 9 amino acids, or 8 amino acids. In some embodiments, less than 1, 2, 3, 4, or 5 of the amino acids in the pHLIP peptide have a net positive charge at a pH of 7, 7.25, 7.5, or 7.75 in water. In certain embodiments, the pHLIP peptide comprises 0 amino acids having a net positive charge at a pH of about 7, 7.25, 7.5, or 7.75 in water. In certain embodiments, pHLIP peptide has about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more aromatic amino acids. For example, the aromatic amino acids may be one or more of a tryptophan, a tyrosine, a phenylalanine, and an artificial aromatic amino acid. In various embodiments, pHLIP peptides of the present subject matter have at least 1 protonatable amino acid. For example, a pHLIP peptide may comprise 1 protonatable amino acid which is aspartic acid, glutamic acid, or gamma-carboxyglutamic acid; or at least 2, 3, 4, 5, 6, 7, 8, 9, 10 or more protonatable amino acids, wherein the protonatable amino acids comprise one or more of aspartic acid, glutamic acid, and gamma-carboxyglutamic acid. In some embodiments, the protonatable amino acid is an artificial amino acid. In a non-limiting example, a pHLIP peptide has at least 2, 3, 4, 5, 6, 7, 8, 9, 10 or more protonatable amino acids, wherein the protonatable amino acids comprise aspartic acid, glutamic acid, gamma-carboxyglutamic acid, or any combination thereof. The present subject matter provides pHLIP peptides having artificial amino acids, such as at least 1 artificial protonatable amino acid. In various embodiments, the artificial protonatable amino acid comprises at least 1, 2, 3, 4 or 5 carboxyl groups and/or the pHLIP peptide may have at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 carboxyl groups. In some embodiments, a pHLIP peptide has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 artificial amino acids. In a non-limiting example, every amino acid of the pHLIP peptide is an artificial amino acid. In certain embodiments, a pHLIP peptide may include at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 D-amino acids. Various implementations of the present subject matter relate to pHLIP peptides having at least one artificial amino acid which is a cysteine derivative, an aspartic acid derivative, a glutamic acid derivative, a phenylalanine derivative, a tyrosine derivative, or a tryptophan derivative. For example, a pHLIP peptide may contain a cysteine derivative selected from the group consisting of D-Ethionine, Seleno-L-cystine, S-(2-Thiazolyl)-L-cysteine, and S-(4-Tolyl)-L-cysteine; an aspartic acid derivative which is a N-phenyl(benzyl)amino derivative of aspartic acid; a glutamic acid derivative selected from the group consisting of γ-Carboxy-DL-glutamic acid, 4-Fluoro-DL-glutamic acid, and (4S)-4-(4-Trifluoromethyl-benzyl)-L-glutamic acid; a phenylalanine derivative selected from the group consisting of (S)—N-acetyl-4-bromophenylalanine, N-Acetyl-2-fluoro-DL-phenylalanine, N-Acetyl-4-fluoro-DL-phenylalanine, 4-Chloro-L-phenylalanine, DL-2,3-Difluorophenylalanine, DL-3,5-Difluorophenylalanine, 3,4-Dihydroxy-L-phenylalanine, 3-(3,4-Dimethoxyphenyl)-L-alanine, 4-(Hydroxymethyl)-D-phenylalanine, N-(3-Indolylacetyl)-L-phenylalanine, p-Iodo-D-phenylalanine, α-Methyl-DL-phenylalanine, 4-Nitro-DL-phenylalanine, and 4-(Trifluoromethyl)-D-phenylalanine; a tyrosine derivative selected from the group consisting of α-Methyl-DL-tyrosine, 3-Chloro-L-tyrosine, 3-Nitro-L-tyrosine, and DL-o-Tyrosine; and/or a tryptophan derivative selected from the group consisting of 5-Fluoro-L-tryptophan, 5-Fluoro-DL-tryptophan, 5-Hydroxy-L-tryptophan, 5-Methoxy-DL-tryptophan, or 5-Methyl-DL-tryptophan. In various embodiments, a pHLIP peptide has at least 8 consecutive amino acids, wherein, at least 2, 3, 4, 5, or 6 of the 8 consecutive amino acids of the pHLIP peptide are non-polar, and at least 1 or 2 of the at least 8 consecutive amino acids of the pHLIP peptide is protonatable. For example, the pHLIP peptide may have 8-10 consecutive amino acids, including at least 2, 3, 4, 5, or 6 of the 8-10 consecutive amino acids that are non-polar, and at least 1 or 2 amino acids that are protonatable. Aspects of the present disclosure provide a pHLIP peptide that is linked to a fluorophore. In various implementations, the pHLIP peptide is directly linked to a linker moiety and/or a fluorophore by a covalent bond. In some non-limiting examples, the covalent bond is an ester bond, a disulfide bond, a bond between two selenium atoms, a bond between a sulfur and a selenium atom, or an acid-labile bond. In some embodiments, the covalent bond between the pHLIP peptide a linker moiety and/or a fluorophore is a bond that has been formed by a click reaction. Non-limiting examples of click reactions include reactions between an azide and an alkyne; an alkyne and a strained difluorooctyne; a diaryl-strained-cyclooctyne and a 1,3-nitrone; a cyclooctene, trans-cycloalkene, or oxanorbornadiene and an azide, tetrazine, or tetrazole; an activated alkene or oxanorbornadiene and an azide; a strained cyclooctene or other activated alkene and a tetrazine; or a tetrazole that has been activated by ultraviolet light and an alkene. Some implementations provide a pHLIP peptide that is attached to a linker compound by a covalent bond, wherein the linker compound is attached to the fluorophore or by a covalent bond. In non-limiting examples, the covalent bond between a pHLIP peptide and a linker compound and/or the covalent bond between a linker compound and a fluorophore is a disulfide bond, a bond between two selenium atoms, a bond between a sulfur and a selenium atom, or a bond that has been formed by a click reaction. In various embodiments, the fluorophore has a weight of (a) at least about 0.5, 1, 1.5, 2, 2.5, 5, 6, 7, 8, 9, or 10 kilodaltons (kDa); or (b) less than about 0.5, 1, 1.5, 2, 2.5, 5, 6, 7, 8, 9, or 10 kDa. In a non-limiting example, a pHLIP peptide is linked to a fluorophore having a weight of at least about 15 kDa. The fluorophore may be, e.g., polar or nonpolar. In various non-limiting examples, the fluorophore comprises a fluorescent dye or a fluorescent protein. In various embodiments, pHLIP-fluorophore compound (or a pHLIP peptide within a pHLIP-fluorophore compound) has a higher affinity for a membrane lipid bilayer at low pH compared to that at normal pH. For example, the affinity is at least 5 times higher at pH 5.0 than at pH 8.0. In some embodiments, the affinity is at least 10 times higher at pH 5.0 than at pH 8.0. In some embodiments, the binding/association/partitioning of a pH triggered compound with a membrane lipid bilayer is stronger at low pH (e.g., pH<6.5 or 7.0) compared to a higher pH (e.g., pH≥6.5 or 7.0). In some embodiments, a non-polar amino acid or amino acids comprise alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, or tryptophan. In some embodiments, a polar amino acid or amino acids comprise serine, threonine, asparagine, or glutamine. In some embodiments, the non-polar amino acid is an artificial amino acid such as 1-methyl-tryptophan. In various embodiments, a non-polar amino acid is defined as one having a side-chain solvation energy ≥0.5 kcal/mol. The values of solvation energy (ΔGXcorr) for the 20 common natural amino acids are known, e.g., as determined by Wimley W C, Creamer T P & White S H (1996) Biochemistry 35, 5109-5124 (hereinafter Wimley et al. 1996) or by Moon and Fleming, (2011) Proc. Nat. Acad. Sci. USA 101:10174-10177, the entire content of which is incorporated herein by reference. The table below provides exemplary side chain solvation energies for naturally occurring amino acids. TABLE 1 Solvation Free Energies of the Side Chains (X) of the 20 Natural Amino Acids in AcWL-X-LL (SEQ ID NO: 534). Non-polar residues are shown in bold and defined as residues with ΔGXcor > +0.50. Residue Charge ΔGXcor Ala 0 +0.65 Arg +1 −0.66 Asn 0 +0.30 Asp −1 −2.49 Cys 0 +1.17 Gln 0 +0.38 Glu −1 −2.48 GLY* 0 0 His +1 −1.18 Ile 0 +2.27 Leu 0 +2.40 Lys +1 −1.65 Met 0 +1.82 Phe 0 +2.86 Pro 0 +1.01 Ser 0 +0.69 Thr 0 +0.90 Trp 0 +3.24 Tyr 0 +1.86 Val 0 +1.61 Residue solvation free energies of the 20 natural amino acids relative to glycine calculated from the data in Table 1 of Wimley et al. 1996, page 5116. Free energies were corrected for the occlusion of neighboring residue areas and for the anomalous properties of glycine. Residue solvation free energies calculated with mole-fraction units. Residue solvation free energies for the X residue in the context of a AcWL-X-LL peptide (SEQ ID NO: 534) calculated from the free energies in Table 1 or Wimley et al. 1996, page 5116 using the virtual glycine (GLY*) as the reference (see text of Wimley et al. 1996) (SEQ ID NOS 534, 535, 534 and 534 are disclosed below, respectively, in order of appearance). ΔGXcor=ΔGWLXLL−ΔGWLG*LL+ΔσnpΔAhost, Ahost(X)=ATnp(WLXLL)−AXnp(WLXLL) These “corrected” values account for X-dependent changes in the nonpolar ASA of the host peptide. Values for Arg and Lys were calculated from experimental free energies measured at pH 1 where the ionic interaction between the side chain and carboxyl group does not occur. ΔGXcor is the best estimate of the solvation energy of residues occluded by neighboring residues of moderate size. Genetically coded amino acids and exemplary non-genetically coded amino acids are listed below in Table 2. In some embodiments, a pHLIP peptide comprises one or more cysteine residues. The cysteine residue(s) serves as a point of conjugation of cargo, e.g., using thiol linkage. Other means of linking cargo to a pHLIP peptide include esters and/or acid-labile linkages. Non cleavable covalent chemical linkages may also be made to secure a fluorophore permanently to a membrane insertion peptide (such as a pHLIP peptide). Membrane-inserting compounds provided herein are useful for diagnostic and imaging, or as research reagents/tools (e.g., to evaluate vascular or renal tissue structure or function). Various implementations of the present subject matter relate to a diagnostic conjugate comprising a pH triggered compound and a pharmaceutically acceptable detectable marker linked thereto. Exemplary detectable markers include imaging agents, dyes, nanoparticles, or other detectable labels. In various embodiments, the membrane-inserting compound itself is non-toxic, especially when an effective amount of the membrane-inserting compound is used. Acting as a monomer, a pHLIP peptide inserts across a cell membrane without forming a pore. The pHLIP peptide-nanotechnology platform can be used for, e.g. pH-selective targeting of therapeutic or imaging agents to solid tumors, where they are tethered to the surfaces of tumor cells, and/or pH-selective targeting of tumor cells with cytoplasmic delivery of cargo molecules attached to the pHLIP peptide's C-terminus via a cleavable bond. In a non-limiting example, a cargo molecule attached to the pHLIP peptide's C-terminus via an S—S bond that is cleaved in the cytoplasm. Among the successfully injected molecules are the organic dyes, phalloidin (a polar, cyclic peptide of more than 1 kDa), and 12-mer and 18-mer peptide nucleic acids (PNAs). If a cargo molecule is attached to the pHLIP peptide's N-terminus via a non-cleavable bond, a pHLIP peptide can tether the cargo molecule to the surface of a cell in acidic tissue. The pH-selective insertion and folding of pHLIP peptides into membranes has been used to target acidic tissue in vivo, including tumors and sites of inflammation. The pathway of pHLIP peptide entry into the membrane and the translocation of molecules into cells is not mediated by endocytosis, but by interactions with cell receptors or by formation of pores in the cell membrane. In some embodiments, pHLIP peptide insertion is associated with the protonation of a residue such as an Asp residue, which leads to an increase in pHLIP peptide hydrophobicity that immediately (within seconds) triggers the insertion of the peptide into a cell membrane. The insertion is accompanied by the release of energy, which may be used to move cell-impermeable cargo molecules through the lipid bilayer of membrane into the cell. Peptide interactions with proteins, especially plasma proteins, and membranes influence the pharmacokinetics of the peptide at neutral pH. pHLIP peptides demonstrate prolonged circulation in the blood, which is consistent with their ability to bind weakly to membrane surfaces at neutral and high pH, preventing the rapid clearance by the kidney expected for a small peptide. Aspects of the present subject matter relate to “Variant 3” or “Var3” pHLIP peptides. Var3 pHLIP peptides include a stretch of amino acids in the sequence LFPTXTLL (SEQ ID NO: 533), wherein X is aspartic acid. Non-limiting examples of Var3 pHLIP peptide sequences include ADDQNPWRAYLDLLFPTDTLLLDLLWG (SEQ ID NO: 2), AKDDQNPWRAYLDLLFPTDTLLLDLLWG (SEQ ID NO: 3), ACDDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 4), ADDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 5), ADDQNPWRAYLDLLFPTDTLLLDLLWCA (SEQ ID NO: 6), ADDQNPWRAYLDLLFPTDTLLLDLLWKA (SEQ ID NO: 7), AKDDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 8), ACDDQNPWRAYLDLLFPTDTLLLDLLWG (SEQ ID NO: 9), ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO: 10), ADDQNPWRAYLDLLFPTDTLLLDLLWKG (SEQ ID NO: 11), ACDDQNPWRAYLDLLFPTDTLLLDLLWKG (SEQ ID NO: 12), AKDDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO: 13), and ACKDDQNPWRAYLDLLFPTDTLLLDLLWG (SEQ ID NO: 14). Variants of the pHLIP peptides exemplified or otherwise disclosed herein may be designed using substitution techniques that are well understood in the art. Neither the pHLIP peptides exemplified herein nor the variants discussed below limit the full scope of the subject matter disclosed herein. Non-Limiting Variants of Non-Limiting Exemplified Peptides Membrane-inserting compounds provided herein may include a membrane insertion peptide (such as pHLIP peptide or a peptide that is not pH-triggered), e.g. any one of the non-limiting examples pHLIP peptides provided herein or a variant thereof. Variants of the membrane insertion peptides exemplified or otherwise disclosed herein may be designed using substitution techniques that are well understood in the art. Neither the membrane insertion peptides exemplified herein nor the variants discussed below limit the full scope of the subject matter disclosed herein. Non-limiting examples of variants of the specific membrane insertion disclosed herein include peptides having the reverse amino acid sequence of the specific membrane insertion peptides disclosed. For example, a disclosure of a membrane insertion peptide comprising the sequence WARYADWL (SEQ ID NO: 34) also provides the disclosure of a membrane insertion peptide comprising the sequence LWDAYRAW (SEQ ID NO: 35). Aspects of the present subject matter relate to membrane insertion peptides that result from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more conservative amino acid substitutions. A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, a residue in a pH-triggered peptide sequence (e.g., corresponding to a location relative to a SEQ ID NO disclosed herein) may be replaced with another amino acid residue from the same side chain family. In certain embodiments, conservative amino acid substitutions may be made using a natural amino acid or a non-natural amino acid. TABLE 2 Genetically coded and exemplary non-genetically coded amino acids including L-isomes, D-isomers, alpha-isomers, beta-isomers, glycol-, and methyl-modifications. No. Abbrev Name 1 Ala Alanine 2 Arg Arginine 3 Asn Asparagine 4 Asp Aspartic acid 5 Cys Cysteine 6 Gln Glutamine 7 Glu Glutamic acid 8 Gly Glycine 9 His Histidine 10 Ile Isoleucine 11 Leu Leucine 12 Lys Lysine 13 Met Methionine 14 Phe Phenylalanine 15 Pro Proline 16 Ser Serine 17 Thr Threonine 18 Trp Tryptophan 19 Tyr Tyrosine 20 Val Valine 21 Sec Selenocysteine 22 Sem Selenomethionine 23 Pyl Pyrrolysine 24 Aad Alpha-aminoadipic acid 25 Acpa Amino-caprylic acid 26 Aecys Aminoethyl cysteine 27 Afa Aminophenyl acetate 28 Gaba Gamma-aminobutyric acid 29 Aiba Aminoisobutyric acid 30 Aile Alloisoleucine 31 AIg Allylglycine 32 Aba Amino-butyric acid 33 Aphe Amino-phenylalanine 34 Brphe Bromo-phenylalanine 35 Cha Cyclo-hexylalanine 36 Cit Citrulline 37 Clala Chloroalanine 38 Cie Cycloleucine 39 Clphe Fenclonine (or chlorophenylalanine) 40 Cya Cysteic acid 41 Dab Diaminobutyric acid 42 Dap Diaminopropionic acid 43 Dap Diaminopimelic acid 44 Dhp Dehydro-proline 45 Dhphe DOPA (or 3,4-dihydroxyphenylalanine) 46 Fphe Fluorophenylalanine 47 Gaa Glucosaminic acid 48 Gla Gamma-carboxyglutamic acid 49 Hag Homoarginine 50 Hlys Hydroxylysine 51 Hnvl Hydroxynorvaline 52 Hog Homoglutamine 53 Hoph Homophenylalanine 54 Has Homoserine 55 Hse Homocysteine 56 Hpr Hydroxyproline 57 Iphe Iodo-phenylalanine 58 Ise Isoserine 59 Mle Methyl-leucine 60 Msmet Methionine-methylsulfonium chloride 61 Nala Naphthyl-alanine 62 Nle Norleucine (or 2-aminohexanoic acid) 63 Nmala N-methyl-alanine 64 Nva Norvaline (or 2-aminopentanoic acid) 65 Obser O-benzyl-serine 66 Obtyr O-benzyl-tyrosine 67 Oetyr O-ethyl-tyrosine 68 Omser O-methyl-serine 69 Omthr O-methy-threonine 70 Omtyr O-methyl-tyrosine 71 Orn Ornithine 72 Pen Penicillamine 73 Pga Pyroglutamic acid 74 Pip Pipecolic acid 75 Sar Sarcosine 76 Tfa Trifluoro-alanine 77 Thphe Hydroxy-Dopa 78 Vig Vinylglycine 79 Aaspa Amino-aminoethylsulfanylpropanoic acid 80 Ahdna Amino-hydroxy-dioxanonanolic acid 81 Ahoha Amino-hydroxy-oxahexanoic acid 82 Ahsopa Amino-hydroxyethylsulfanylpropanoic acid 83 Tyr(Me) Methoxyphenyl-methylpropanyl oxycarbonylamino propanoic acid 84 MTrp Methyl-tryptophan 85 pTyr Phosphorylated Tyr 86 pSer Phosphorylated Ser 87 pThr Phosphorylated Thr 88 BLys BiotinLys 89 Hyp Hydroproline 90 Phg Phenylglycine 91 Cha Cyclohexyl-alanine 92 Chg Cyclohexylglycine 93 Nal Naphthylalanine 94 Pal Pyridyl-alanine 95 Pra Propargylglycine 96 Gly(allyl) Pentenoic acid 97 Pen Penicillamine 98 MetO Methionine sulfoxide 99 Pca Pyroglutamic acid 100 Ac-Lys Acetylation of Lys TABLE 3 Non-limiting examples of protonatable residues and their substitutions including L-isomes, D-isomers, alpha-isomers, and beta-isomers. Original Residue Exemplary amino acids substitution Asp (D) Glu (E); Gla (Gla); Aad (Aad) Glu (E) Asp (D); Gla (Gla); Aad (Aad) TABLE 4 Examples of genetically coded amino acid substitutions Original Residue Substitution Ala (A) Gly; Ile; Leu; Met; Phe; Pro; Trp; Tyr; Val Arg (R) Lys Asn (N) Gln; His Asp (D) Glu Cys (C) Ser; Met Gln (Q) Asn; His Glu (E) Asp Gly (G) Ala; Ile; Leu; Met; Phe; Pro; Trp; Tyr; Val His (H) Asn; Gln Ile (I) Ala; Gly; Leu; Met; Phe; Pro; Trp; Tyr; Val Leu (L) Ala; Gly; Ile; Met; Phe; Pro; Trp; Tyr; Val Lys (K) Arg Met (M) Ala; Gly; Leu; Ile; Phe; Pro; Trp; Tyr; Val Phe (F) Ala; Gly; Leu; Ile; Met; Pro; Trp; Tyr; Val Pro (P) Ala; Gly; Leu; Ile; Met; Phe; Trp; Tyr; Val Ser (S) Thr Thr (T) Ser Trp (W) Ala; Gly; Leu; Ile; Met; Pro; Phe; Tyr; Val Tyr (Y) Ala; Gly; Leu; Ile; Met; Pro; Phe; Trp; Val Val (V) Ala; Gly; Leu; Ile; Met; Pro; Phe; Trp; Tyr TABLE 5 Non-limiting examples of putative membrane-inserting sequences belonging to different groups of pHLIP peptides. Each protonatable residue (shown in underline) could be replaced by its substitution from Table 3. Each non-polar residue could be replaced by its genetically coded amino acid substitution from Table 4, and/or non-genetically coded amino acid substitutions from Table 2. Groups Sequences Var3 WRAYLDLLFPTDTLLLDLLW (SEQ ID NO: 325) Var3 Reverse WLLDLLLTDTPFLLDLYARW (SEQ ID NO: 326) WT WARYADWLFTTPLLLLDLALLVDADE (SEQ ID NO: 327) WT Reverse EDADVLLALDLLLLPTTFLWDAYRAW (SEQ ID NO: 328) ATRAM GLAGLLGLEGLLGLPLGLLEGLWLGL (SEQ ID NO: 329) Var7 WARYLEWLFPTETLLLEL (SEQ ID NO: 330) WAQYLELLFPTETLLLEW (SEQ ID NO: 331) Single D/E WLFTTPLLLLNGALLVE (SEQ ID NO: 332) WLFTTPLLLLPGALLVE (SEQ ID NO: 333) WARYADLLFPTTLAW (SEQ ID NO: 334) pHLIP-Rho GNLEGFFATLGGEIALWSLVVLAIE (SEQ ID NO: 335) EGFFATLGGEIALWSDVVLAIE (SEQ ID NO: 336) EGFFATLGGEIPLWSDVVLAIE (SEQ ID NO: 337) pHLIP-Rho EIALVVLSWLAIEGGLTAFFGELNG (SEQ ID NO: 338) Reverse EIALVVDSWLAIEGGLTAFFGE (SEQ ID NO: 339) EIALVVDSWLPIEGGLTAFFGE (SEQ ID NO: 340) pHLIP-CA9 ILDLVFGLLFAVTSVDFLVQW (SEQ ID NO: 341) pHLIP-CA9 WQVLFDVSTVAFLLGFVLDLI (SEQ ID NO: 342) Reverse TABLE 6 Non-limiting examples of pHLIP sequences. A cysteine, a lysine, an azido-modified amino acid, or an alkynyl modified amino acid can be incorporated at the N-terminal (first 6 residues) or C-terminal (last 6 residues) parts of the peptides for conjugation with a cargo, and a linker. Seq ID Name Sequence SEQ ID NO: 343 WT-2D AEQNPIYWARYADWLFTTPLLLLDLALLVDADET SEQ ID NO: 344 WT-6E AEQNPIYWARYAEWLFTTPLLLLELALLVEAEET SEQ ID NO: 345 WT-3D ADDQNPWRAYLDLLFPDTTDLLLLDLLWDADET SEQ ID NO: 346 WT-9E AEEQNPWRAYLELLFPETTELLLLELLWEAEET SEQ ID NO: 347 WT-GlaD AEQNPIYWARYAGlaWLFTTPLLLLDLALLVDADET SEQ ID NO: 348 WT-DGla AEQNPIYWARYADWLFTTPLLLLGlaLALLVDADET SEQ ID NO: 349 WT-2Gla AEQNPIYWARYAGlaWLFTTPLLLLGlaLALLVDADET SEQ ID NO: 350 WT-AadD AEQNPIYWARYAAadWLFTTPLLLLDLALLVDADET SEQ ID NO: 351 WT-DAad AEQNPIYWARYADWLFTTPLLLLAadLALLVDADET SEQ ID NO: 352 WT-2Aad AEQNPIYWARYAAadWLFTTPLLLLAadLALLVDADET SEQ ID NO: 353 WT-GlaAad AEQNPIYWARYAGlaWLFTTPLLLLAadLALLVDADET SEQ ID NO: 354 WT-AadGla AEQNPIYWARYAAadWLFTTPLLLLGlaLALLVDADET SEQ ID NO: 355 WT-1 GGEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTG SEQ ID NO: 356 WT-2 GGEQNPIYWARYADWLFTTPLLLLDLALLVDADEGT SEQ ID NO: 357 WT-3 AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTG SEQ ID NO: 358 WT-4 AEQNPIYWARYADWLFTTPLLLLDLALLVDADEGT SEQ ID NO: 359 WT-2N AEQNPIYWARYANWLFTTPLLLLNLALLVDADEGTG SEQ ID NO: 360 WT-2K AEQNPIYWARYAKWLFTTPLLLLKLALLVDADEGTG SEQ ID NO: 361 WT-2DNNQ GGEQNPIYWARYADWLFTTPLLLLDLALLVNANQGT SEQ ID NO: 362 WT-D25A AAEQNPIYWARYADWLFTTPLLLLALALLVDADEGT SEQ ID NO: 363 WT-D14A AAEQNPIYWARYAAWLFTTPLLLLDLALLVDADEGT SEQ ID NO: 364 WT-P20A AAEQNPIYWARYADWLFTTALLLLDLALLVDADEGT SEQ ID NO: 365 WT-D25E AAEQNPIYWARYADWLFTTPLLLLELALLVDADEGT SEQ ID NO: 366 WT-D14E AAEQNPIYWARYAEWLFTTPLLLLDLALLVDADEGT SEQ ID NO: 367 WT-3D-2 AAEQNPIIYWARYADWLFTDLPLLLLDLLALLVDADEGT SEQ ID NO: 368 WT-R11Q GEQNPIYWAQYADWLFTTPLLLLDLALLVDADEGCG SEQ ID NO: 369 WT-D25Up GGEQNPIYWARYADWLFTTPLLLDLLALLVDADEGCG SEQ ID NO: 370 WT-D25Down GGEQNPIYWARYADWLFTTPLLLLLDALLVDADEGCG SEQ ID NO: 371 WT-D14Up GGEQNPIYWARYDAWLFTTPLLLLDLALLVDADEGTG SEQ ID NO: 372 WT-D14Down GGEQNPIYWARYAWDLFTTPLLLLDLALLVDADEGCG SEQ ID NO: 373 WT-P20G AAEQNPIYWARYADWLFTTGLLLLDLALLVDADEGT SEQ ID NO: 374 WT-DH DDDEDNPIYWARYADWLFTTPLLLLHGALLVDADCT SEQ ID NO: 375 WT-2H DDDEDNPIYWARYAHWLFTTPLLLLHGALLVDADECT SEQ ID NO: 376 WT-L16H CEQNPIYWARYADWHFTTPLLLLDLALLVDADEGT SEQ ID NO: 377 WT-1Wa AEQNPIYWARYADFLFTTPLLLLDLALLVDADET SEQ ID NO: 378 WT-1Wb AEQNPIYFARYADWLFTTPLLLLDLALLVDADEGT SEQ ID NO: 379 WT-1Wc AEQNPIYFARYADFLFTTPLLLLDLALLWDADET SEQ ID NO: 380 WT-W6 ADNNPWIYARYADLTTFPLLLLDLALLVDFDD SEQ ID NO: 381 WT-W17 ADNNPFIYARYADLTTWPLLLLDLALLVDFDD SEQ ID NO: 382 WT-W30 ADNNPFIYARYADLTTFPLLLLDLALLVDWDD SEQ ID NO: 383 WT-W17-P7 ADNNPFPYARYADLTTVVILLLLDLALLVDFDD SEQ ID NO: 384 WT-W39-R11 ADNNPFIYAYRADLTTFPLLLLDLALLVDWDD SEQ ID NO: 385 WT-W30-R15 ADNNPFIYATYADLRTFPLLLLDLALLVDWDD SEQ ID NO: 386 WT-Rev Ac-TEDADVLLALDLLLLPTTFLWDAYRAWYPNQEA-Am SEQ ID NO: 387 Var1-3D AEDQNPYWARYADWLFTTPLLLLDLALLVDG SEQ ID NO: 388 Var1-1D2E AEDQNPYWARYADWLFTTPLLLLELALLVEG SEQ ID NO: 389 Var2-3D AEDQNPYWRAYADLFTPLTLLDLLALWDG SEQ ID NO: 390 Var3-3D ADDQNPWRAYLDLLFPTDTLLLDLLWG SEQ ID NO: 391 Var3-WT ADDQNPWRAYLDLLFPTDTLLLDLLWDADEG SEQ ID NO: 392 Var3-Gla2D ADDQNPWRAYLGlaLLFPTDTLLLDLLWG SEQ ID NO: 393 Var3-DGlaD ADDQNPWRAYLDLLFPTGlaTLLLDLLWG SEQ ID NO: 394 Var3-2DGla ADDQNPWRAYLDLLFPTDTLLLGlaLLWG SEQ ID NO: 395 Var3-2GlaD ADDQNPWRAYLGlaLLFPTGlaTLLLDLLWG SEQ ID NO: 396 Var3-GlaDGla ADDQNPWRAYLGlaLLFPTDTLLLGlaLLWG SEQ ID NO: 397 Var3-D2Gla ADDQNPWRAYLDLLFPTGlaTLLLGlaLLWG SEQ ID NO: 398 Var3-3Gla ADDQNPWRAYLGlaLLFPTGlaTLLLGlaLLWG SEQ ID NO: 399 Var3-Aad2D ADDQNPWRAYLAadLLFPTDTLLLDLLWG SEQ ID NO: 400 Var3-DAadD ADDQNPWRAYLDLLFPTAadTLLLDLLWG SEQ ID NO: 401 Var3-2DAad ADDQNPWRAYLDLLFPTDTLLLAadLLWG SEQ ID NO: 402 Var3-2AadD ADDQNPWRAYLAadLLFPTAadTLLLDLLWG SEQ ID NO: 403 Var3-AadDAad ADDQNPWRAYLAadLLFPTDTLLLAadLLWG SEQ ID NO: 408 Var3-D2Aad ADDQNPWRAYLDLLFPTAadTLLLAadLLWG SEQ ID NO: 409 Var3-3Aad ADDQNPWRAYLAadLLFPTAadTLLLAadLLWG SEQ ID NO: 410 Var3-GlaAadD ADDQNPWRAYLGlaLLFPTAadTLLLDLLWG SEQ ID NO: 411 Var3-GlaDAad ADDQNPWRAYLGlaLLFPTDTLLLAadLLWG SEQ ID NO: 412 Var3-2GlaAad ADDQNPWRAYLGlaLLFPTGlaTLLLAadLLWG SEQ ID NO: 413 Var3-AadGlaD ADDQNPWRAYLAadLLFPTGlaTLLLDLLWG SEQ ID NO: 414 Var3-AadDGla ADDQNPWRAYLAadLLFPTDTLLLGlaLLWG SEQ ID NO: 415 Var3-GlaAadGla ADDQNPWRAYLGlaLLFPTAadTLLLGlaLLWG SEQ ID NO: 416 Var3-GLL GEEQNPWLGAYLDLLFPLELLGLLELGLWG SEQ ID NO: 417 Var3-M ADDDDDDPWQAYLDLLFPTDTLLLDLLW SEQ ID NO: 418 Var4-3E AEEQNPWRAYLELLFPTETLLLELLW SEQ ID NO: 419 Var5-3Da ADDQNPWARYLDWLFPTDTLLLDL SEQ ID NO: 420 Var6-3Db DNNNPWRAYLDLLFPTDTLLLDW SEQ ID NO: 421 Var7-3E AEEQNPWARYLEWLFPTETLLLEL SEQ ID NO: 422 Var7-M DDDDDDPWQAYLDLFPTDTLALDLW SEQ ID NO: 423 Var8-3E EEQQPWAQYLELLFPTETLLLEW SEQ ID NO: 424 Var9-3E EEQQPWRAYLELLFPTETLLLEW SEQ ID NO: 425 Var10-2D AEDQNPWARYADWLFPTTLLLLD SEQ ID NO: 426 Var11-2E AEEQNPWARYAEWLFPTTLLLLE SEQ ID NO: 427 Var12-1D AEDQNPWARYADLLFPTTLAW SEQ ID NO: 428 Var13-1E AEEQNPWARYAELLFPTTLAW SEQ ID NO: 429 Var15-2N DDDDDNPNYWARYANWLFTTPLLLLNGALLVEAEET SEQ ID NO: 430 Var16-2P DDDDDNPNYWARYAPWLFTTPLLLLPGALLVEAEET SEQ ID NO: 431 Var17 AEQNPIYFARYADFLFTTPLLLLDLALLWDADET SEQ ID NO: 432 Var18 AEQNPIYWARYADFLFTTPLLLLDLALLVDADET SEQ ID NO: 433 Var19a AEQNPIYWARYADWLFTTPL SEQ ID NO: 434 Var20 AEQNPIYFARYADLLFPTTLAW SEQ ID NO: 435 Var21 AEQNPIYWARYADLLFPTTLAF SEQ ID NO: 436 Var22 AEQNPIYWARYADLLFPTTLAW SEQ ID NO: 437 Var23 AEQNPIYFARYADWLFTTPL SEQ ID NO: 438 Var24 EDQNPWARYADLLFPTTLAW SEQ ID NO: 439 ATRAM GLAGLAGLLGLEGLLGLPLGLLEGLWLGLELEGNA SEQ ID NO: 440 pHLIP-CA9 EQNPIYILDLVFGLLFAVTSVDFLVQWDDAGD SEQ ID NO: 441 pHLIP-Rho GNLEGFFATLGGEIALWSLVVLAIE SEQ ID NO: 442 pHLIP-RhoM1 GNNEGFFATLGGEIALWSDVVLAIEG SEQ ID NO: 443 pHLIP-RhoM2 GDNNEGFFATLGGEIPLWSDVVLAIEG In the table above, “Am” means C-terminal amidation, which is a protected C-terminus, i.e., there is no free COOH group at the C-terminus and there is no charge at the C-terminus. “Ac”means N-terminal acylation, which is a protected N-terminus, i.e., there is no free NH2 group at the N-terminus and there is no charge at the N-terminus. TABLE 7 Non-limiting examples of linkers and components thereof ID Name 1 Peptide bond, (—CO—NH—) 2 Polypeptide 3 Polylysine 4 Polyarginine 5 Polyglutamic acid 6 Polyaspartic acid 7 Polycysteine 8 Collagen 9 Fibrinogen 10 Avidin 11 Streptavidin 12 Albumin 13 Antibody 14 Protein with 1 or more Lys, Arg, Cys, 15 Asp, Glu 16 Polynucleotide 17 Polysaccharide 18 Alginate 19 Chitosan 20 Poly(ethylene glycol) (PEG) 21 Poly(lactic acid) (PLA) 22 Poly(glycolic acid) (PGA) 23 Poly(lactic-co-glycolic acid) (PLGA) 24 Poly(malic acid) (PMA) 25 Polyorthoesters (POE) 26 Poly(vinylalcohol) (PVOH, PVA, 27 or PVAl) 28 Poly(vinylpyrrolidone) (PVP) 29 Poly(methyl methacrylate) (PMMA) 30 Poly(acrylic acid) (PAA) 31 Poly(acrylamide) (PAM) 32 Poly(methacrylic acid) (PMAA) 33 Poly(amidoamine) (PAMAM) 34 Polyanhydrides 35 Polycyanoacrylate 36 Particle 37 Metallic particle 38 Polymeric particle 39 Virus-like particle 40 Nanoparticle 41 Metallic nanoparticle 42 Lipid-based nanoparticle 43 Surfactant-based nanoparticle 44 Polymeric nanoparticle 45 Peptide-based nanoparticle Substitutions with natural amino acids may alternatively or additionally be characterized using a BLOcks SUbstitution Matrix (a BLOSUM matrix). An example of a BLOSUM matrix is the BLOSUM62 matrix, which is described in Styczynski et al. (2008) “BLOSUM62 miscalculations improve search performance” Nat Biotech 26 (3): 274-275, the entire content of which is incorporated herein by reference. The BLOSUM62 matrix is shown in FIG. 19. Substitutions scoring at least 4 on the BLOSUM62 matrix are referred to herein as “Class I substitutions”; substitutions scoring 3 on the BLOSUM62 matrix are referred to herein as “Class II substitutions”; substitutions scoring 2 or 1 on the BLOSUM62 matrix are referred to herein as “Class III substitutions”; substitutions scoring 0 or −1 on the BLOSUM62 matrix are referred to herein as “Class IV substitutions”; substitutions scoring −2, −3, or −4 on the BLOSUM62 matrix are referred to herein as “Class V substitutions.” Various embodiments of the subject application include membrane insertion peptides (e.g., pHLIP peptides) that have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more Class I, II, III, IV, or V substitutions compared to a membrane insertion peptides exemplified herein, or any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more of any combination of Class I, II, III, IV, and/or V substitutions compared to a membrane insertion peptide exemplified herein. Aspects of the present subject matter also relate to membrane insertion peptides having 1, 2, 3, 4, 5, or more amino acid insertions or deletions compared to membrane insertion peptides exemplified herein. D-Amino Acids Of the standard α-amino acids, all but glycine can exist in either of two optical isomers, called L or D amino acids, which are mirror images of each other. While L-amino acids represent all of the amino acids found in proteins during translation in the ribosome, D-amino acids are found in some proteins produced by enzyme posttranslational modifications after translation and translocation to the endoplasmic reticulum. D amino acids are abundant components of the peptidoglycan cell walls of bacteria, and D-serine acts as a neurotransmitter in the brain. The L and D convention for amino acid configuration refers not to the optical activity of the amino acid itself, but rather to the optical activity of the isomer of glyceraldehyde from which that amino acid can be synthesized (D-glyceraldehyde is dextrorotary; L-glyceraldehyde is levorotary). Membrane insertion peptides either fully or partially built of D-amino acids possess advantages over L-membrane insertion peptides. For example, D-membrane insertion peptides are biodegraded slower than their levorotary counterparts leading to enhanced activity and longer biological half-lives (Sela and Zisman, 1997 FASEB J, 11: 449-456, incorporated herein by reference). Thus, D-membrane insertion peptides may be used in the methods disclosed herein. Included herein are membrane insertion peptides that comprise solely L-amino acids or solely D-amino acids, or a combination of both D-amino acids and L-amino acids. Indocyanine Green The non-invasive near-infrared (NIR) fluorescence imaging dye ICG is approved by the United States Food and Drug administration (FDA) for ophthalmologic angiography to determine cardiac output and liver blood flow and function. This dye is also used in cancer patients for the detection of solid tumors, localization of lymphnodes, and for angiography during reconstructive surgery, visualization of retinal and choroidal vasculature, and photodynamic therapy. In cancer diagnostics and therapeutics, ICG could be used as both an imaging dye and a hyperthermia agent. ICG is a tricarbocyanine-type dye with NIR-absorbing properties (peak absorption around 800 nm) and little absorption in the visible range thus exhibit low autofluorescence, tissue absorbance, and scatter at NIR wavelengths (700-900 nm). Unconjugated ICG may comprise the following structure: A CAS Registry Number for ICG is 3599-32-4. ICG may be modified to, e.g., facilitate attachment the attachment thereof to peptides, such as pHLIPs disclosed herein. Non-limiting examples of commercially available (e.g., from Intrace Medical SA, Lausanne, Switzerland) modified ICG compounds include ICG N-succinimidyl ester (ICG-NHS ester), ICG-CBT, ICG-maleimide, ICG-azide, ICG-alkyne, and ICG-PEG-NHS ester. The succinimidyl esters (NHS) of the ICG dye offer the opportunity to develop optimal conjugates. Succinimidyl ester active groups provide an efficient and convenient way to selectively link ICG dyes to primary amines (R—NH2) on various substrates (antibodies, peptides, proteins, nucleic-acid, small molecule drugs, etc.). Succinimidyl esters have very low reactivity with aromatic amines, alcohols, and phenols, including tyrosine and histidine. An example of ICG-NHS ester comprises the following features: Excitation Class: Near infrared, NIR Excitation/Emission maximum (nm): 790/830 Molecular Weight: 828.04 g·mol−1 Formula: C49H53N3O7S Structure: The circled portion of the structure above indicates the linker moiety. A maleimide active group provides an efficient and convenient way to selectively link ICG dye to sulfhydryl groups (free thiol, R—SH) on various substrates (antibodies, peptides, proteins, oligonucleotides, small molecule drugs, etc.) at neutral (physiological) pH without any activation. Maleimides have very low reactivity with amines, alcohols, and phenols (such as tyrosine and histidine) and do not react with histidine and methionine, providing a very high labeling selectivity. An example of ICG-maleimide comprises the following features: Excitation Class: Near infrared, NIR Excitation/Emission maximum (nm): 790/830 Molecular Weight: 853.09 g·mol−1 Formula: C51H56N4O6S Structure: The circled portion of the structure above indicates the linker moiety. The 2-cyanobenzothiazole labeling procedure is based on the biocompatible click-reaction between 2-cyanobenzothiazole moiety and any 1, 2- or 1, 3-aminothiols (e.g. free or N-terminal cysteine). This click reaction is 3 orders of magnitude faster than commonly used Staudinger ligation and can provide useful conjugates. Cyanobenzothiazole (CBT) active groups provide an efficient and convenient way to site-selectively link ICG dyes to 1,2- or 1,3-aminothiols on various substrates (antibodies, peptides, proteins, nucleic-acid, small molecule drugs, etc.) without any additional activation. The labeling reaction with aminothiols is selective over reaction with simple thiols. The CBT click chemistry can be used together with all other biocompatible click reactions (like azide, alkyne, triphenylphosphine, tetrazine etc.), as it is very selective. In addition in ICG-CBT labeling procedure no side product is formed as here is no leaving group (unlike NHS esters). An example of an ICG-CBT comprises the following features: Excitation Class: Near infrared, NIR Excitation/Emission maximum (nm): 790/830 Molecular Weight: 931.38 g·mol−1 Formula: C55H57N5O5S2 Structure: The circled portion of the structure above indicates the linker moiety. ICG-azide can be used to label alkyne-tagged biomolecules (like proteins, lipids, nucleic acids, sugars) chemoselectively via click-chemistry. An example of ICG-azide comprises the following features: Excitation Class: Near infrared, NIR Excitation/Emission maximum (nm): 790/830 Molecular Weight: 931.21 g·mol−1 Formula: C53H66N6O7S The circled portion of the structure above indicates the linker moiety. ICG-alkyne can be used to label azide-tagged molecules via Cu(II)-catalyzed click reaction. The reaction is chemoselective and biocompatible. An example of ICG-alkyne comprises the following features: Excitation Class: Near infrared, NIR Excitation/Emission maximum (nm): 790/830 Solubility: DMSO, DMF, Acetonitrile, Methanol Molecular Weight: 767.38 g·mol−1 Formula: C48H53N3O4S Cyanine Fluorophores Cyanine fluorophores may optionally be referred to herein as “cyanine dyes.” Cyanine dyes are molecules containing polymethine bridge between two nitrogen atoms with a delocalized charge: Due to their structure, cyanines have outstandingly high extinction coefficients often exceeding 100,000 Lmol−1 cm−1. Different substituents allow to control properties of the chromophore, such as absorbance wavelength, photostability, and fluorescence. For example, absorbance and fluorescence wavelength can be controlled by a choice of polymethine bridge length: longer cyanines possess higher absorbance and emission wavelengths up to near infrared region. Non-limiting examples of cyanine dyes include non-sulfonated cyanines, and sulfonated cyanines. Available non-sulfonated dyes include, e.g., Cy3, Cy3.5, Cy5, Cy5.5, Cy7, and Cy7.5. Cy® stands for ‘cyanine’, and the first digit identifies the number of carbon atoms between the indolenine groups. Cy2 which is an oxazole derivative rather than indolenin, is an exception from this rule. The suffix 0.5 is added for benzo-fused cyanines. In certain embodiments, variation of the structures allows to change fluorescence properties of the molecules, and to cover most important part of visible and NIR spectrum with several fluorophores. The structures of Cy3, Cy3.5, Cy5, Cy5.5, Cy7, and Cy7.5 are as follows: Sulfonated cyanines include additional sulfo-groups which, in some embodiments, facilitate dissolution of dye molecules in aqueous phase. In various embodiments, charged sulfonate groups decrease aggregation of dye molecules and heavily labeled conjugates. Non-limiting examples of sulfonated cyanines include sulfo-Cy3, sulfo-Cy5, and sulfo-Cy7. IR800 The structure of IR800 maleimide is as follows: IR800 is also known as IRDye® 800CW Infrared Dye, and is available from LI-COR Biosciences (Nebraska, United States). Click Reactions Compounds described herein (e.g., pHLIP peptides and compounds comprising multiple pHLIP peptides) can include a covalent bond between the compound and a cargo compound, between a linker and a cargo compound, between a pHLIP peptide and a linker, and between two pHLIP peptides. In embodiments, a covalent bond has been formed by a bio-orthogonal reaction such as a cycloaddition reaction (e.g., a “click” reaction). Exemplary bio-orthogonal reactions suitable for the preparation for such compounds are described in, e.g., Zheng et al., “Development of Bioorthogonal Reactions and Their Applications in Bioconjugation,” Molecules, 2015, 20, 3190-3205. The diversity and commercial availability of peptide precursors are attractive for constructing the multifunctional entities described herein. Described herein are exemplary, non-limiting click reactions suitable for, e.g., the preparation of pH-triggered peptide compounds that include a covalent bond between the peptide and a cargo compound. Huisgen Cycloadditions A category of click reactions includes Huisgen 1,3-dipolar additions of acetylenes to azides. See, e.g., Scheme 1. In embodiments, CARGO corresponds to any cargo compound (such as a fluorophore) described herein. In embodiments, L1 is independently a bond, —NRA—, O, S, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, or L1 combines with R1 to form a substituted or unsubstituted 8-membered cycloalkynylene ring, or L1 comprises one or more amino acids as described herein. In embodiments, R1 is hydrogen, substituted or unsubstituted alkyl, or R1 combines with L1 to form a substituted or unsubstituted 8-membered cycloalkynylene ring, or L1 comprises one or more amino acids as described herein. In embodiments, L1 combines with R1 to form a substituted or unsubstituted 8-membered cycloalkynylene ring. In embodiments, the 8-membered cycloalkynylene ring is unsubstituted. In embodiments, the 8-membered cycloalkynylene ring comprises two fluoro substitutents (e.g., α to the alkynyl). In embodiments, L2 is independently a bond, —NRB—, O, S, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, or L2 comprises one or more amino acids as described herein. In embodiments, each RA and RB is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, the Huisgen cycloaddition is that described in Scheme 2 and Scheme 3. In embodiments, CARGO corresponds to any cargo compound (such as a fluorophore) described herein. In embodiments, L1 is independently a bond, —NRA—, O, S, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, or L1 comprises one or more amino acids as described herein. In embodiments, L2 is independently a bond, —NRB—, O, S, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, or L2 comprises one or more amino acids as described herein. In embodiments, CARGO corresponds to any cargo compound (such as a fluorophore) described herein. In embodiments, L1 is independently a bond, —NRA—, O, S, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, or L1 comprises one or more amino acids as described herein. In embodiments, one of R3, R4, and R5 is a cargo compound, and the other two variables are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, one of R3′, R4′, and R5′ is a pH-triggered peptide compound, the other two variables are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Cycloadditions with Alkenes In embodiments, certain activated alkenes (e.g., a strained alkene such as cis- or trans-cyclooctene or oxanorbomadiene), which may be represented as compound F or compound F′, can undergo cycloaddition reactions with, e.g., an azide (Scheme 4), a tetrazine (Scheme 5), or a tetrazole (Scheme 6). In embodiments, CARGO corresponds to any cargo compound (such as a fluorophore) described herein. In embodiments, L1 is independently a bond, —NRA—, O, S, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, or L1 comprises one or more amino acids as described herein. In embodiments, L2 is independently a bond, —NRB—, O, S, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, or L2 comprises one or more amino acids as described herein. In embodiments, CARGO corresponds to any cargo compound (such as a fluorophore) described herein. In embodiments, L1 is independently a bond, —NRA—, O, S, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, or L1 comprises one or more amino acids as described herein. In embodiments, L2 is independently a bond, —NRB—, O, S, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, or L2 comprises one or more amino acids as described herein. In embodiments, CARGO corresponds to any cargo compound (such as a fluorophore) described herein. In embodiments, L1 is independently a bond, —NRA—, O, S, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, or L1 comprises one or more amino acids as described herein. In embodiments, L2 is independently a bond, —NRB—, O, S, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, or L2 comprises one or more amino acids as described herein. In embodiments, R6 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, the invention features any of the compounds described herein (e.g., any of Compounds A, A′, B, B′; C, C′, D, D′, E, E′, F, F′, G, G′H, or H′; a compound according to any one of formulas (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-C), (II-D), (III-A), (III-B), (IV-A), (IV-B), (IV-C), (IV-C′), (IV-D), (IV-D′), (IV-E), or (IV-F); a compound according to Formula (A) such as any one of Formulas (A4)-(A20); or a compound according to any of SEQ ID NOS: 1-4); or a pharmaceutically acceptable salt thereof. In embodiments, the invention features a composition (e.g., a pharmaceutical composition) comprising any of the compounds described herein (e.g., any of Compounds A, A′, B, B′; C, C′, D, D′, E, E′, F, F′, G, G′H, or H′; a compound according to any one of formulas (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-C), (II-D), (III-A), (III-B), (IV-A), (IV-B), (IV-C), (IV-C′), (IV-D), (IV-D′), (IV-E), or (IV-F); a compound according to Formula (A) such as any one of Formulas (A4)-(A20); or a compound according to any of SEQ ID NOS: 1-4); or a pharmaceutically acceptable salt thereof. The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a non-cyclic straight (i.e., unbranched) or branched chain, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (—O—). The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, —CH2CH2CH2CH2—. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom (e.g. selected from the group consisting of O, N, P, S, Se and Si, and wherein the nitrogen, selenium, and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized). The heteroatom(s) O, N, P, S, Se, and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to: —CH2—CH2—O—CH3, —CH2—CH2—NH—CH3, —CH2—CH2—N(CH3)—CH3, —CH2—S—CH2—CH3, —CH2—CH2, —S(O)—CH3, —CH2—CH2—S(O)2—CH3, —CH═CH—O—CH3, —Si(CH3)3, —CH2—CH═N—OCH3, —CH═CH—N(CH3)—CH3, —O—CH3, —O—CH2—CH3, and —CN. Up to two heteroatoms may be consecutive, such as, for example, —CH2—NH—OCH3. Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, —CH2—CH2—S—CH2—CH2— and —CH2—S—CH2—CH2—NH—CH2—. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula —C(O)2R′-represents both —C(O)2R′— and —R′C(O)2—. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as —C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SeR′, —SR′, and/or —SO2R′. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as —NR′R″ or the like, it will be understood that the terms heteroalkyl and —NR′R″ are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as —NR′R″ or the like. The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term “heteroaryl” refers to aryl groups (or rings) that contain from one to four heteroatoms (e.g. selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized). Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A fused ring heterocyloalkyl-aryl is an aryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl, fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl-cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substituents described herein. Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different. Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g., substituents for cycloalkyl or heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g. all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different. Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl,” and “heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below. Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R″′, —OC(O)R′, —C(O)R′, —CO2R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R″′, —NR″C(O)2R′, —NR—C(NR′R″R″′)═NR″″, —NR—C(NR′R″)═NR″′, —S(O)R′, —S(O)2R′, —S(O)2NR′R″, —NRSO2R′, —CN, and —NO2 in a number ranging from zero to (2m′+1), where m′ is the total number of carbon atoms in such radical. R′, R″, R″′, and R″″ each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R″′, and R″″ group when more than one of these groups is present. When R′ and R″ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, —NR′R″ includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., —CF3 and —CH2CF3) and acyl (e.g., —C(O)CH3, —C(O)CF3, —C(O)CH2OCH3, and the like). Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R″′, —OC(O)R′, —C(O)R′, —CO2R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)2R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)2R′, —S(O)2NR′R″, —NRSO2R′, —CN, —NO2, —R′, —N3, —CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R′, R″, R′″, and R″″ are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R′″, and R″″ groups when more than one of these groups is present. Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one or more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency. As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si). Examples are provided below to facilitate a more complete understanding of the invention. The following examples illustrate the exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only, since alternative methods can be utilized to obtain similar results. General Definitions Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (e.g., in medicine, cell culture, molecular genetics, and biochemistry). As used herein, the term “about” in the context of a numerical value or range means±10% of the numerical value or range recited or claimed, unless the context requires a more limited range. In the descriptions above and in the claims, phrases such as “at least one of” or “one or more of” may occur followed by a conjunctive list of elements or features. The term “and/or” may also occur in a list of two or more elements or features. Unless otherwise implicitly or explicitly contradicted by the context in which it is used, such a phrase is intended to mean any of the listed elements or features individually or any of the recited elements or features in combination with any of the other recited elements or features. For example, the phrases “at least one of A and B;” “one or more of A and B;” and “A and/or B” are each intended to mean “A alone, B alone, or A and B together.” A similar interpretation is also intended for lists including three or more items. For example, the phrases “at least one of A, B, and C;” “one or more of A, B, and C;” and “A, B, and/or C” are each intended to mean “A alone, B alone, C alone, A and B together, A and C together, B and C together, or A and B and C together.” In addition, use of the term “based on,” above and in the claims is intended to mean, “based at least in part on,” such that an unrecited feature or element is also permissible. It is understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also provided by the invention. For example, “0.2-5 mg” is a disclosure of 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg etc. up to and including 5.0 mg. A small molecule is a compound that is less than 2000 daltons in mass. The molecular mass of the small molecule is preferably less than 1000 daltons, more preferably less than 600 daltons, e.g., the compound is less than 500 daltons, 400 daltons, 300 daltons, 200 daltons, or 100 daltons. As used herein, an “isolated” or “purified” compound, nucleic acid molecule, polynucleotide, polypeptide, or protein, is substantially free of other cellular material, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized. Purified compounds are at least 60% by weight (dry weight) the compound of interest. Preferably, the preparation is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight the compound of interest. For example, a purified compound is one that is at least 90%, 91%, 92%, 93%, 94%, 95%, 98%, 99%, or 100% (w/w) of the desired compound by weight. Purity is measured by any appropriate standard method, for example, by column chromatography, thin layer chromatography, or high-performance liquid chromatography (HPLC) analysis. A purified or isolated polynucleotide (ribonucleic acid (RNA) or deoxyribonucleic acid (DNA)) is free of the genes or sequences that flank it in its naturally-occurring state. Purified also defines a degree of sterility that is safe for administration to a human subject, e.g., lacking infectious or toxic agents. Similarly, by “substantially pure compound” is meant a compound that has been separated from the components that naturally accompany it. Typically, a compound is substantially pure when it is at least 60%, 70%, 80%, 90%, 95%, or even 99%, by weight, free from the proteins and naturally-occurring organic molecules with which the compound is naturally associated. The transitional term “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. By contrast, the transitional phrase “consisting of” excludes any element, step, or ingredient not specified in the claim. The transitional phrase “consisting essentially of” limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention. Typically and depending on context, the terms “subject,” “patient,” “individual,” and the like as used herein can be generally interchanged. That is, an individual described as a “patient” does not necessarily have a given disease, but may be merely seeking medical advice. The term “subject” as used herein includes any animal including a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. In some embodiments, the subject is a mammal. In certain embodiments, the subject is a human. As used herein, the singular forms “a,” “an,” and “the” include the plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to “a disease,” “a disease state”, or “a nucleic acid” is a reference to one or more such embodiments, and includes equivalents thereof known to those skilled in the art and so forth. As used herein, “treating” encompasses, e.g., inhibition, regression, or stasis of the progression of a disorder. Treating also encompasses the prevention or amelioration of any symptom or symptoms of the disorder. As used herein, “inhibition” of disease progression or a disease complication in a subject means preventing or reducing the disease progression and/or disease complication in the subject. As used herein, a “symptom” associated with a disorder includes any clinical or laboratory manifestation associated with the disorder, and is not limited to what the subject can feel or observe. As used herein, “effective” when referring to an amount of a therapeutic or imaging compound refers to the quantity of the compound that is sufficient to yield a desired result (e.g., therapeutic outcome or imaging signal strength) without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this disclosure. As used herein, “pharmaceutically acceptable” carrier or excipient refers to a carrier or excipient that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio. It can be, e.g., a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the subject. Various embodiments of the invention relate to pHLIP-fluorophore compounds comprising a pHLIP that is attached to a “cargo” such as a “fluorophore.” Depending on context, the cargo may be referred to by a name or characteristic of an unconjugated form of the cargo regardless of whether the cargo is conjugated to a pHLIP peptide. For example, a fluorophore known as “Fluorophore X” when in an unconjugated form may also be referred to herein as “Fluorophore X” when in a form that is bound to a pHLIP peptide. Examples and embodiments are provided below to facilitate a more complete understanding of the invention. The following examples and embodiments illustrate the exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific examples and embodiments disclosed, which are for purposes of illustration only, since alternative methods can be utilized to obtain similar results. EMBODIMENTS Embodiments include the following embodiments P1 to P35. Embodiment P1 A compound comprising (a) a pH-triggered polypeptide comprising amino acids in the sequence LFPTXTLL (SEQ ID NO: 1), wherein X is a protonatable amino acid, wherein the pH-triggered polypeptide has a higher affinity to a membrane lipid bilayer at pH 5.0 compared to at pH 8.0; and (b) indocyanine green (ICG), wherein said ICG is covalently attached to the first or the second amino acid counted from the N-terminus of the pH-triggered polypeptide. Embodiment P2 The compound of embodiment P1, wherein said pH-triggered polypeptide comprises amino acids in the sequence ADDQNPWRAYLDLLFPTDTLLLDLLWG (SEQ ID NO: 2), and wherein said ICG is covalently attached to the N-terminal alanine thereof. Embodiment P3 The compound of embodiment P2, comprising the following structure (SEQ ID NO: 2 is disclosed below): Embodiment P4 The compound of embodiment P1, wherein said pH-triggered polypeptide comprises amino acids in the sequence AKDDQNPWRAYLDLLFPTDTLLLDLLWG (SEQ ID NO: 3), and wherein said ICG is covalently attached to the lysine thereof. Embodiment P5 The compound of embodiment P4, comprising the following structure (SEQ ID NO: 3 is disclosed below): Embodiment P6 The compound of embodiment P1, wherein said pH-triggered polypeptide comprises amino acids in the sequence ACDDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 4), and wherein said ICG is covalently attached to the cysteine thereof. Embodiment P7 The compound of embodiment P6, comprising the following structure (SEQ ID NO: 4 is disclosed below): Embodiment P8 The compound of embodiment P1, wherein the pH-triggered polypeptide comprises an artificial protonatable amino acid. Embodiment P9 The compound of embodiment P8, wherein the artificial protonatable amino acid comprises at least 1, 2, 3, 4 or 5 carboxyl groups. Embodiment P10 The compound of any one of embodiments P1, P8, or P9, wherein the protonatable amino acid comprises aspartic acid or gamma-carboxyglutamic acid. Embodiment P11 The compound of embodiment any one of embodiments P1-P10, wherein said pH-triggered polypeptide comprises amino acids in the sequence LLFPTDTLLL (SEQ ID NO: 25). Embodiment P12 The compound of embodiment 11, wherein said pH-triggered polypeptide comprises amino acids in the sequence LDLLFPTDTLLLD (SEQ ID NO: 26). Embodiment P13 The compound of embodiment 12, wherein said pH-triggered polypeptide comprises amino acids in the sequence AYLDLLFPTDTLLLDLL (SEQ ID NO: 27). Embodiment P14 The compound of embodiment 13, wherein said pH-triggered polypeptide comprises amino acids in the sequence DDQNPWRAYLDLLFPTDTLLLDLLW (SEQ ID NO: 28). Embodiment P15 The compound of embodiment 14, wherein said pH-triggered polypeptide comprises amino acids in the sequence: (SEQ ID NO: 2) ADDQNPWRAYLDLLFPTDTLLLDLLWG, (SEQ ID NO: 3) AKDDQNPWRAYLDLLFPTDTLLLDLLWG, (SEQ ID NO: 4) ACDDQNPWRAYLDLLFPTDTLLLDLLWA, (SEQ ID NO: 5) ADDQNPWRAYLDLLFPTDTLLLDLLWA, (SEQ ID NO: 6) ADDQNPWRAYLDLLFPTDTLLLDLLWCA, (SEQ ID NO: 7) ADDQNPWRAYLDLLFPTDTLLLDLLWKA, (SEQ ID NO: 8) AKDDQNPWRAYLDLLFPTDTLLLDLLWA, (SEQ ID NO: 9) ACDDQNPWRAYLDLLFPTDTLLLDLLWG, (SEQ ID NO: 10) ADDQNPWRAYLDLLFPTDTLLLDLLWCG, (SEQ ID NO: 11) ADDQNPWRAYLDLLFPTDTLLLDLLWKG, (SEQ ID NO: 12) ACDDQNPWRAYLDLLFPTDTLLLDLLWKG, (SEQ ID NO: 13) AKDDQNPWRAYLDLLFPTDTLLLDLLWCG, or (SEQ ID NO: 14) ACKDDQNPWRAYLDLLFPTDTLLLDLLWG. Embodiment P16 The compound of any one of embodiments P1 or P8-P11, wherein the amino acid sequence of said pH-triggered polypeptide is less than 100%, 99%, or 95% identical to each of the amino acid sequences set forth as SEQ ID NOS: 15-24. Embodiment P17 The compound of any one of embodiments P1-P16, wherein said pH-triggered polypeptide comprises 20-30 amino acids. Embodiment P18 A composition comprising the compound of any one of embodiments P1-P17 and a pharmaceutically acceptable carrier. Embodiment P19 The composition of embodiment 18, further comprising D-glucose. Embodiment P20 The composition of embodiment P18 or P19, wherein said composition comprises a mouthwash. Embodiment P21 A method for detecting cancer tissue or precancerous tissue in a bodily organ or tissue, comprising (a) contacting the bodily organ or tissue with the compound of any one of embodiments P1-P17; (b) contacting said compound with electromagnetic radiation comprising an excitation wavelength of ICG; and (c) detecting electromagnetic radiation emitted from said compound, wherein detection of said radiation indicates the presence of said cancerous tissue or said precancerous tissue. Embodiment P22 The method of embodiment P21, wherein the level of radiation emitted from precancerous tissue or cancer tissue is at least 20% greater than a level of radiation emitted from normal non-cancerous tissue. Embodiment P23 The method of embodiment P21 or P22, wherein said bodily organ comprises a kidney or a urinary bladder. Embodiment P24 The method of any one of embodiments P21-P23, further comprising surgically removing said cancerous tissue or said precancerous tissue. Embodiment P25 The method of embodiment 21, wherein said tissue has been obtained, removed, or provided from a subject. Embodiment P26 The method of embodiment P21 or P25, wherein said tissue comprises a tissue biopsy. Embodiment P27 The method of any one of embodiments P21-P24, wherein said bodily organ or tissue is present in a subject. Embodiment P28 The method of any one of embodiments P21-P24, wherein contacting the bodily organ or tissue with the compound of any one of embodiments P1-P17 comprises administering the compound to a subject. Embodiment P29 The method of embodiment P28, wherein the compound is administered to the subject via intravessical instillation, intravenous injection, intraperitoneal injection, topical administration, mucosal administration, or oral administration. Embodiment P30 The method of embodiment P28 or P29, wherein said compound is administered by applying a liquid, powder, or spray comprising said compound to a surface of said subject. Embodiment P31 The method of embodiment P30, wherein said surface comprises a site within the body of said subject that is accessed via surgery. Embodiment P32 The method of embodiment P28 or P29, wherein said compound is administered to an oral cavity of said subject. Embodiment P33 The method of any one of embodiments P21-P32, wherein electromagnetic radiation emitted from said compound is detected in vivo. Embodiment P34 The method of any one of embodiments P21-P32, wherein electromagnetic radiation emitted from said compound is detected ex vivo. Embodiment P35 A method for removing cancer tissue or precancerous tissue from a bodily organ or tissue, comprising surgically removing a cancer cell or a precancerous cell detected according to the method of any one of embodiments P21-P24 or P27-P34. Further embodiments include the following embodiments 1 to 55. Embodiment 1 A pHLIP-fluorophore compound comprising (a) a pH-triggered polypeptide (pHLIP peptide); and (b) a fluorophore, wherein the fluorophore is a near-infrared (NIR) fluorophore, a cyanine fluorophore, or an optoacoustic contrast imaging agent. Embodiment 2 The compound of embodiment 1, having the structure (SEQ ID NO: 4 is disclosed below): Embodiment 3 The compound of embodiment 1 or 2, wherein the pHLIP peptide comprises amino acids in the sequence LFPTXTLL (SEQ ID NO: 1), wherein X is a protonatable amino acid, and wherein the fluorophore comprises a NIR fluorophore. Embodiment 4 The compound of any one of embodiments 1-3, wherein X is D. Embodiment 5 The compound of any one of any one of embodiments 1-4, wherein the fluorophore comprises indocyanine green (ICG). Embodiment 6 The compound of any one of embodiments 1-5, wherein the pHLIP peptide comprises the sequence: XnYm; YmXn; XnYmXj; YmXnYi; YmXnYiXj; XnYmXjYi; YmXnYiXjYl; XnYmXjYiXl; YmXnYiXjYlXh; XnYmXjYiXhYg; YmXnYiXjYlXhYg; XnYmXjYiXhYgXf; (XY)n; (YX)n; (XY)nYm; (YX)nYm; (XY)nXm; (YX)nXm; Ym(XY)n; Ym(YX)n; Xn(XY)m; Xn(YX)m; (XY)nYm(XY)i; (YX)nYm(YX)i; (XY)nXm(XY)i; (YX)nXm(YX)i; Ym(XY)n; Ym(YX)n; Xn(XY)m; Xn(YX)m, wherein, i) Y is a non-polar amino acid with solvation energy, ΔGXcor>+0.50, or Gly, ii) X is a protonatable amino acid, and iii) n, m, I, j, l, h, g, f are integers from 1 to 8. Embodiment 7 The compound of any one of embodiments 1-6, wherein the pHLIP peptide has a net negative charge at a pH of about 7.5 or 7.75 in water. Embodiment 8 The compound of any one of embodiments 1-7, wherein the pHLIP peptide has an acid dissociation constant at logarithmic scale (pKa) of less than about 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, or 7. Embodiment 9 The compound of any one of embodiments 1-8, wherein the pHLIP peptide comprises at least 1 artificial protonatable amino acid. Embodiment 10 The compound of any one of embodiments 1-9, wherein the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 40 genetically coded amino acids. Embodiment 11 The compound of any one of embodiments 1 or 3-10, wherein the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 40 non-genetically coded amino acids. Embodiment 12 The compound of any one of embodiments 1 or 3-11, wherein the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 40 D-amino acids. Embodiment 13 The compound of any one of embodiments 1-12, wherein the pHLIP peptide comprises at least 8 amino acids, wherein, at least 2, 3, or 4 of the 8 amino acids of the pHLIP peptide are non-polar, and at least 1, 2, 3, or 4 of the at least 8 amino acids of the pHLIP peptide are protonatable. Embodiment 14 The compound of any one of embodiments 1, 3, 4, or 6-13, wherein the fluorophore a cyanine fluorophore. Embodiment 15 The compound of any one of embodiments 1-14, wherein the fluorophore is a NIR fluorophore. Embodiment 16 The compound of any one of embodiments 1-15, wherein the fluorophore comprises an optoacoustic contrast imaging agent. Embodiment 17 The compound of any one of embodiments 1-16, comprising (a) a pHLIP peptide comprising amino acids in the sequence LFPTXTLL (SEQ ID NO: 1), wherein X is a protonatable amino acid, wherein the pHLIP peptide has a higher affinity to a membrane lipid bilayer at pH 5.0 compared to at pH 8.0; and (b) indocyanine green (ICG), wherein said ICG is covalently attached to the first or the second amino acid counted from the N-terminus of the pHLIP peptide. Embodiment 18 The compound of embodiment 17, wherein X is D. Embodiment 19 The compound of embodiment 17 or 18, wherein said pHLIP peptide comprises amino acids in the sequence ACDDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 4) or ACDDQNPWRAYLDLLFPTDTLLLDLLWG (SEQ ID NO: 9), and wherein said ICG is covalently attached to the cysteine thereof. Embodiment 20 The compound of embodiment 19, comprising the following structure (SEQ ID NO: 9 is disclosed below): (SEQ ID NO: 4 is disclosed below) or Embodiment 21 The compound of embodiment 17 or 18, wherein said pHLIP peptide comprises amino acids in the sequence ADDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 5) or ADDQNPWRAYLDLLFPTDTLLLDLLWG (SEQ ID NO: 2), and wherein said ICG is covalently attached to the N-terminal alanine thereof. Embodiment 22 The compound of embodiment 21, comprising the following structure (SEQ ID NO: 2 is disclosed below): Embodiment 23 The compound of embodiment 17 or 18, wherein said pHLIP peptide comprises amino acids in the sequence AKDDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 8) or AKDDQNPWRAYLDLLFPTDTLLLDLLWG (SEQ ID NO: 3), and wherein said ICG is covalently attached to the lysine thereof. Embodiment 24 The compound of embodiment 23, comprising the following structure (SEQ ID NO: 3 is disclosed below): Embodiment 25 The compound of embodiment 17 or 18, wherein said pHLIP peptide comprises amino acids in the sequence ACDDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 4), and wherein said ICG is covalently attached to the cysteine thereof. Embodiment 26 The compound of embodiment 25, comprising the following structure (SEQ ID NO: 4 is disclosed below): Embodiment 27 The compound of embodiment 17 or 18, wherein said pHLIP peptide comprises an artificial protonatable amino acid. Embodiment 28 The compound of embodiment 27, wherein the artificial protonatable amino acid comprises at least 1, 2, 3, 4 or 5 carboxyl groups. Embodiment 29 The compound of embodiment 17, wherein the protonatable amino acid comprises aspartic acid or gamma-carboxyglutamic acid. Embodiment 30 The compound of any one of embodiments 17-29, wherein said pHLIP peptide comprises amino acids in the sequence LLFPTDTLLL (SEQ ID NO: 25). Embodiment 31 The compound of embodiment 30, wherein said pHLIP peptide comprises amino acids in the sequence LDLLFPTDTLLLD (SEQ ID NO: 26). Embodiment 32 The compound of embodiment 31, wherein said pHLIP peptide comprises amino acids in the sequence AYLDLLFPTDTLLLDLL (SEQ ID NO: 27). Embodiment 33 The compound of embodiment 32, wherein said pHLIP peptide comprises amino acids in the sequence DDQNPWRAYLDLLFPTDTLLLDLLW (SEQ ID NO: 28). Embodiment 34 The compound of embodiment 33, wherein said pHLIP peptide comprises amino acids in the sequence: (SEQ ID NO: 4) ACDDQNPWRAYLDLLFPTDTLLLDLLWA, (SEQ ID NO: 2) ADDQNPWRAYLDLLFPTDTLLLDLLWG, (SEQ ID NO: 3) AKDDQNPWRAYLDLLFPTDTLLLDLLWG, (SEQ ID NO: 5) ADDQNPWRAYLDLLFPTDTLLLDLLWA, (SEQ ID NO: 6) ADDQNPWRAYLDLLFPTDTLLLDLLWCA, (SEQ ID NO: 7) ADDQNPWRAYLDLLFPTDTLLLDLLWKA, (SEQ ID NO: 8) AKDDQNPWRAYLDLLFPTDTLLLDLLWA, (SEQ ID NO: 9) ACDDQNPWRAYLDLLFPTDTLLLDLLWG, (SEQ ID NO: 10) ADDQNPWRAYLDLLFPTDTLLLDLLWCG, (SEQ ID NO: 11) ADDQNPWRAYLDLLFPTDTLLLDLLWKG, (SEQ ID NO: 12) ACDDQNPWRAYLDLLFPTDTLLLDLLWKG, (SEQ ID NO: 13) AKDDQNPWRAYLDLLFPTDTLLLDLLWCG, or (SEQ ID NO: 14) ACKDDQNPWRAYLDLLFPTDTLLLDLLWG. Embodiment 35 The compound of any one of embodiments 17-34, wherein the amino acid sequence of said pHLIP peptide is less than 100%, 99%, or 95% identical to each of the amino acid sequences set forth as SEQ ID NOS: 15-24. Embodiment 36 The compound of any one of embodiments 17-35, wherein said pHLIP peptide comprises 20-30 amino acids. Embodiment 37 A composition comprising the compound of any one of embodiments 1-36 and a pharmaceutically acceptable carrier. Embodiment 38 The composition of embodiment 37, further comprising D-glucose. Embodiment 39 The composition of embodiment 37 or 38, wherein said composition comprises a mouthwash. Embodiment 40 A method for detecting diseased or damaged tissue in subject, comprising (a) administering the compound of any one of embodiments 1-36 to the subject; (b) contacting the subject with electromagnetic radiation comprising an excitation wavelength of the fluorophore; and (c) detecting electromagnetic radiation emitted from the compound, wherein detection of the radiation indicates the presence of the diseased tissue. Embodiment 41 The method of embodiment 40, wherein the diseased or damaged tissue is cancer tissue, precancerous tissue, inflamed tissue, ischemic tissue, arthritic tissue, cystic fibrotic tissue, tissue infected with a microorganism, or atherosclerotic tissue. Embodiment 42 The method of embodiment 41 or 41, wherein the diseased tissue is cancer tissue, and the cancer tissue is in the bladder, the upper urinary tract, a kidney, the prostate, a breast, the head, the neck, the oral cavity, the pancreas, a lung, the liver, the cervix, an ovary, or the brain of the subject. Embodiment 43 The method of any one of embodiments 40-42, wherein the level of radiation emitted from precancerous tissue or cancer tissue is at least 20% greater than a level of radiation emitted from normal non-cancerous tissue. Embodiment 44 The method of any one of embodiments 40-43, wherein said bodily organ comprises a kidney or a urinary bladder. Embodiment 45 A method for detecting movement of a bodily fluid in subject, comprising (a) administering the compound of any one of embodiments 1-36 to the subject; (b) contacting the subject with electromagnetic radiation comprising an excitation wavelength of the fluorophore; and (c) detecting electromagnetic radiation emitted from the compound, wherein detection of the radiation indicates the presence of the bodily fluid. Embodiment 46 The method of embodiment 45, wherein the bodily fluid comprises blood. Embodiment 47 The method of embodiment 46, wherein the blood is in circulation, within a bodily lumen, within a vessel lumen, within a capillary lumen, within a vein lumen, within an artery lumen, or within a solid tissue. Embodiment 48 The method of embodiment 45, wherein the bodily fluid comprises lymph. Embodiment 49 The method of any one of embodiments 40-48, wherein the compound is administered to the subject via intravessical instillation, intravenous administration, intraperitoneal administration, topical administration, mucosal administration, oral administration, intraarterial administration, intracerebral administration, intracerebroventricular administration, intrathecal administration, intracardiac administration, intracavemous administration, intraosseous administration, intraocular administration, intravitreal administration, intramuscular administration, intradermal administration, transdermal administration, transmucosal administration, intralesional administration, subcutaneous administration, epicutaneous administration, extra-amniotic administration, intravaginal administration, intravesical administration, or nasal administration. Embodiment 50 The method of any one of embodiments 40-49, wherein said compound is administered by applying a liquid, powder, or spray comprising said compound to a surface of said subject. Embodiment 51 The method of embodiment 50, wherein said surface comprises a site within the body of said subject that is accessed via surgery. Embodiment 52 The method of any one of embodiments 40-51, wherein electromagnetic radiation emitted from said compound is detected in vivo. Embodiment 53 The method of any one of embodiments 40-51, wherein electromagnetic radiation emitted from said compound is detected ex vivo. Embodiment 54 The method of any one of embodiments 40-53, further comprising surgically removing a cancer or a precancerous cell or tissue identified by step (c). Embodiment 55 The method of any one of embodiments 40-54, wherein the method comprises fluorescence angiography. Embodiment 56 The method of any one of embodiments 40-55, which is performed during an ophthalmologic procedure, cardiothoracic surgery, bypass coronary surgery, neurosurgery, hepatobilliary surgery, reconstructive surgery, cholecystectomy, colorectal resection, brain surgery, muscle perfusion, wound or trauma surgery, or laparoscopic surgery. Embodiment 57 A method for detecting a fluorophore in a biological sample ex vivo, (a) contacting a biological sample from a subject with the compound of any one of embodiments 1-36; (b) contacting the biological sample with electromagnetic radiation comprising an excitation wavelength of the fluorophore; and (c) detecting electromagnetic radiation emitted from the fluorophore. Embodiment 58 The method of embodiment 57, wherein the biological sample comprises a tissue biopsy specimen, a liquid biopsy specimen, surgically removed tissue, a surgically removed liquid, or blood. EXAMPLES Example 1: Targeted Imaging of Urothelium Carcinoma in Human Bladders by an ICG-pHLIP Peptide (ICG-Var3) Ex Vivo Bladder cancer is the fifth most common in incidence and one of the most expensive cancers to treat. Early detection greatly improves the chances of survival and bladder preservation. This report is the first study using an ICG-Var3 conjugate for the diagnosis of urothelial carcinoma and precancerous lesions in fresh human radical cystectomy samples ex vivo, and points the way toward a wide range of diagnostic and therapeutic alternatives. A pHLIP peptide labeled with a near-infrared fluorescence dye, ICG, was used to monitor the targeting of tumors in human bladders. The absorption spectrum of ICG-Var3 is shown in FIG. 1A. The fluorescence of ICG-Var3 increases about 25-fold in the presence of POPC liposomes (FIG. 1B). Thus, binding of ICG-Var3 to the lipid bilayers of cancerous cell membranes significantly enhances the emission of ICG. Twenty two radical cystectomy patients were included in the study. Patient ages ranged from 51 to 84 (mean age 67.7 years), and the gender ratio: M/F was 19/3. Table 8 contains patient demographics, preoperative diagnosis, clinical stage of the disease and the results of imaging studies. The specimens did not show any adverse morphological findings after incubation with ICG-Var3, and there was no evidence of damage or degenerative effect in the non-tumoral tissue. The use of ICG-Var3 did not alter the pathological assessment of the radical cystectomy tissues. Overall, 29 malignant lesions were identified by pathology assessment of the 22 bladder specimens stained with ICG-Var3 (3 radical cystectomy cases were incubated ex vivo with ICG-Cys as negative controls). The frequencies of different pathologies in 29 lesions were as follows (FIG. 2A-L): high grade muscle invasive urothelial carcinoma (HGI) in 12; high grade non-muscle invasive urothelial carcinoma (HGN) in 5; carcinoma in situ (CIS) in 11, and high grade dysplasia in 1. In 7 cases near-infrared fluorescence imaging guided the pathologist to CIS not observed by white light inspection. In case #2 necrotic tissue inside a diverticulum was near-infrared fluorescence positive. For the negative control cases (cases #13, 19 and 20) only the ICG-Cys dye alone was used for instillation (at concentrations from 8 to 40 μM in an 80 ml volume), and no specific tumor targeting was observed. The tabular results of the sensitivity/specificity tests are shown in Tables 9-10. The test was performed for cancerous versus normal tissue excluding targeting of necrotic and previously treated tissue (Tables 9A and 9B). The sensitivity and specificity of targeting of cancerous tissue versus normal were found to be 97% and 100%, respectively. If targeting of necrotic tissue from prior post trans-urethral removal of bladder tumors and previously treated (chemotherapy) necrotic tumors by ICG-Var3 is considered as a false positive, the specificity is reduced from 100% to 80% (Tables 10a and 10b). ICG-Var3 Constructs Distinguish Cancer Cells from Normal Cells with High Sensitivity and Specificity An ICG-Var3 construct was used to target urothelial carcinoma in human bladder specimens immediately after surgical removal. ICG is an FDA approved near-infrared fluorescence dye that does not show any independent propensity for targeting neoplastic tissue as seen in renal cell carcinoma, mostly by perfusion and diffusion differences or neoplastic and normal tissue (washout). ICG is in clinical use to visualize vasculature or lymphatics (Tobis et al. (2012) J Endourol 26(7):797-802; Alander et al. (2012) Int J Biomed Imaging 2012:940585; Desmettre et al. (2000) Surv Ophthalmol 45(1):15-27). ICG has a low level of fluorescence in aqueous solution, while its emission increases upon binding to hydrophobic pockets of proteins (such as albumin) or cellular membranes. Targeting by the pHLIP peptide is based on low pH-triggered insertion into the lipid bilayers of cancer cell membranes. Thus, the pHLIP peptide tethers the ICG to the membrane, enhancing ICG fluorescence by about 25 fold. To avoid/minimize targeting of normal cells by the ICG-Var3 peptide, the construct was instilled in pH 7.4 PBS supplemented with 10 mM of D-glucose to promote the uptake of the ICG-Var3 peptide by cancer cells. Glycolytic cancer cells exhibit high glucose uptake, which enhances acidification of the extracellular space in vitro and in vivo (Kozin et al. (2001) Cancer Res 61(12):4740-4743). Thus, our goal was to selectively promote increased acidity at cancer cell surfaces to enhance pHLIP peptide insertion and targeting, while not affecting normal cells with normal metabolism. A mixture of different subtypes of urothelial carcinoma was used, given that the disease had advanced to the point where the bladder had to be removed. These cases included typical high grade urothelial carcinoma but also had different variants with prominent squamous cell differentiation, micropapillary urothelial carcinoma, adenocarcinoma and plasmacytoid morphology. The sensitivity (97%) and specificity (100%) of tumor targeting by ICG-Var3 peptide was found to be irrelevant to the subtype of tumor. Half of the cystectomy specimens examined revealed evidence of necrosis and effects from prior treatments, and all revealed evidence of residual tumor (invasive or in-situ) adjacent and associated with necrosis, which was targeted by ICG-Var3 peptide, possibly from entrapment or uptake of ICG by necrotic areas. Previous studies did not show targeting of necrotic tissue by pHLIP peptides in animal tumor models (Adochite et al. (2014) Mol Pharm 11(8):2896-2905). If targeting of necrotic and previously treated tissues are considered as false positives, the specificity is decreased to 80%, but no false positives were seen for unperturbed lesions. One lesion gave a positive near-infrared fluorescence imaging signal in the presence of dysplasia, revealed by subsequent pathology analysis. Urothelial dysplasia is an incidental microscopic finding where urothelial cells show mild atypical features short of the diagnosis of carcinoma in situ. It is considered a pre-cancerous process and studies have shown that up to 19% of urothelial dysplasia cases develop urothelial carcinoma (Althausen et al. (1976) J Urol 116(5):575-580; Smith et al. (1983) Br J Urol 55(6):665-669; Zuk et al. (1988) J Clin Pathol 41(12):1277-1280). Although precancerous, it is recommended that patients with dysplasia receive proper clinical follow up for early detection of an imminent carcinoma. Dysplasia has not been clinically detectable, so the ICG-Var3 peptide may be a useful marker for detection of high grade dysplasia in urothelium, allowing early detection of precancerous lesions. Bladder tissues are prone to inflammation and infection. Long standing inflammation and severe infections can cause transformations in the mucosa like cystitis cystica and cystitis glandularis that, due to high frequency, are considered normal findings in the urothelium. In one case, an area with marked uptake of ICG-Var3 peptide showed cystitis cystica et glandularis with chronic inflammation without any evidence of dysplasia or malignancy. It is noteworthy that almost all 22 cystectomy specimens revealed some degree of cystitis cystica et glandularis somewhere in the specimen. Only two lesions revealed cystitis cystica without any other pathology: one lesion (case #9) showed positive signal with ICG-Var3 peptide. When the instilled concentration of ICG-Var3 peptide was reduced to 4 μM, the cystitis cystica in the second case (case #18) was not stained. Reducing the concentration of ICG-Var3 peptide did not affect targeting of high grade invasive carcinoma and CIS (case #17). Optimizing the concentration and shortening the time of the ICG-Var3 instillation allows a clear signal differentiation among inflamed, necrotic and cancerous tissue. The ICG-Var3 peptide is a useful tool for the early detection of urothelial carcinoma, regardless of subtype, with high sensitivity and specificity. In various embodiments, the detection is used for monitoring the state of disease and/or for marking lesions for surgical removal. In some embodiments, the ICG-Var3 imaging agent improves diagnosis and resection of cancerous lesions in the bladder. In certain embodiments, the recurrence rate is reduced, patient outcomes are improved, and the cost of medical care for bladder cancer is lowered. In various embodiments, success with targeted imaging facilitates pHLIP delivery of therapeutic molecules to bladder tumor cells, enabling the targeted treatment (e.g., the specific delivery of chemotherapeutic agents) of bladder cancers. Without being bound by any theory, the ICG-Var3 construct is a generally applicable imaging agent, because it targets a general property of the tumor microenvironment, tumor acidity. Fluorescent pHLIPs have been shown to target primary tumors and metastatic lesions by in more than 15 varieties of human, murine, and rat tumors, including lymphoma, melanoma, pancreatic, breast, and prostate transgenic mouse models and human tissue (bladder, kidney, upper urinary tract, breast, liver, oral and head/neck stained ex vivo). TABLE 8 Demographic information, pathological stage and diagnosis, lesions seen by white light and fluorescence imaging. Case Sex Pathological Lesion White light # Age stage Pathological diagnosis Grade number diagnosis Fluor. 1 M/63 pT3aN1 Infiltrating high grade urothelial carcinoma, CIS & HGI 1 + + necrosis 2 M/61 pT0N0 Diverticulum with urothelial atypia & treatment — — + + effects 3 F/84 ypT3bN0 Invasive high grade urothelial carcinoma HGI 2 + + Invasive high grade urothelial carcinoma & necrosis HGI 3 + + 4 M/51 pT2aN1 Residual infiltrative high grade urothelial carcinoma HGI 4 + + micropapillary features, dysplasia & necrosis 5 M/69 pTaN0 Non-invasive high grade papillary carcinoma HGN 5 + + 6 M/65 pT1N0 Residual invasive high grade urothelial carcinoma, CIS HGI 6 + + & necrosis CIS CIS 7 + + CIS CIS 8 + + 7 M/61 pT1N0 Focally invasive high grade urothelial carcinoma, HGI 9 + + necrosis 8 M/79 pT1N0 Dysplasia DIS 10 − + Treatment effect & CCCG — — − + 9 M/74 pT0N0 CCCG — — − + 10 F/82 pT1N0 Non-invasive high grade urothelial carcinoma HGN 11 + + Invasive high grade urothelial carcinoma HGI 12 + − CIS CIS 13 − + CIS & CCCG CIS 14 − + 11 M/68 pTisN0 CIS & CCCG CIS 15 + + CIS CIS 16 − + 12 M/71 pTisN0 Non-invasive high grade urothelial carcinoma HGN 17 + + Non-invasive high grade urothelial carcinoma HGN 18 + + CIS CIS 19 − + CIS CIS 20 − + 13* M/66 pT3N1 Invasive high grade urothelial carcinoma + ICG-Cys Ulceration, necrosis, CCCG + 14 M/66 pT1N0 Non-invasive high grade urothelial carcinoma HGN 21 + + 15 M/57 pT1N0 Invasive high grade urothelial carcinoma HGI 22 + + 16 F/77 pTisN0 CIS with early invasion CIS 23 + + CIS with early invasion CIS 24 − + 17** M/57 pT1bN0 Invasive high grade urothelial carcinoma HGI 25 + + CIS with early invasion CIS 26 + + Necrosis & treatment effect — — + + 18** M/72 pT3aN0 Invasive high grade urothelial carcinoma, CIS HGI 27 + + Necrosis & treatment effect in diverticulum — — + − 19 M/64 pT2aN0 Invasive high grade urothelial carcinoma, CIS, Necrosis + ICG-Cys & treatment effect 20 M/63 ypT0N0 CCCG and reactive changes in scar + ICG-Cys 21 M/74 pT3aN0 Invasive high grade urothelial carcinoma in scar HGI 28 + + Necrosis — — + + 22** M/66 ypT3aN0 Invasive high grade urothelial carcinoma with HGI 29 + + neuroendocrine features *40 μM of 80 mL of the construct was used for instillation **4 μM of 80 mL of the construct was used for instillation TABLE 9A Tabular results of the sensitivity/specificity test of ICG-Var3 peptide targeting of cancerous lesions in the human bladder specimens: Carcinoma versus Normal excluding necrotic tissue and treatment effects. Receiver operator characteristics carcinoma vs normal TP + FN FP + TN Sum TP + FP TP, 28 FP, 0 28 FN + TN FN, 1 TN, 19 20 Sum 29 19 TP is the true positive; TN is the true negative; FP is the false positive; FN is the false negative TABLE 9B Descriptive parameters Measure Results Sensitivity, TRP 0.966 Specificity, SPC 1.000 Positive predictive value, PPV 1.000 Negative predictive values, NPV 0.950 False positive rate, FPR 0.000 False negative rate, FNR 0.034 False discovery rate, FDR 0.000 False omission rate, FOR 0.053 TABLE 10A Tabular results of the sensitivity/specificity test of ICG-Var3 peptide targeting of cancerous lesions in the human bladder specimens: Carcinoma versus Normal including necrotic tissue and treatment effects. Receiver operator characteristics carcinoma vs normal + necrosis TP + FN FP + TN Sum TP + FP TP, 28 FP, 5 33 FN + TN FN, 1 TN, 20 21 Sum 29 25 TP is the true positive; TN is the true negative; FP is the false positive; FN is the false negative TABLE 10B Descriptive parameters Measure Results Sensitivity, TRP 0.966 Specificity, SPC 0.800 Positive predictive value, PPV 0.848 Negative predictive values, NPV 0.952 False positive rate, FPR 0.020 False negative rate, FNR 0.034 False discovery rate, FDR 0.152 False omission rate, FOR 0.040 Materials and Methods Conjugation of ICG with the pHLIP Peptide A pHLIP variant 3 (Var3) peptide with a single Cys residue at the N-terminus, ACDDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 4), was synthesized and purified by reversed phase chromatography by CS Bio, Inc (Menlo Park, Calif., USA). The near infrared fluorescent dye, indocyanine green (ICG) maleimide (Intrace Medical, Lausanne, Switzerland), was conjugated to the pHLIP peptide at a ratio of 1:1 in DMF (dimethylformamide). The reaction progress was monitored by the reversed phase (Zorbax SB-C18 columns, 9.4×250 mm 5 μm, Agilent Technology) high-performance liquid chromatography (HPLC) using a gradient from 5-70% acetonitrile in water containing 0.05% trifluoroacetic acid. Also, for the negative control, ICG-maleimide was conjugated with the free amino acid, L-cysteine (Sigma). The concentration of labeled peptide in buffer was determined by ICG absorption at 800 nm, ε800=137,000 M−1 cm−1. The purity of the constructs was performed by analytical HPLC and SELDI-TOF mass spectrometry, the amount of free dye in the solution was less than 1%. Liposome Preparation Large unilamellar vesicles were prepared by extrusion. 2.5 mg POPC (Avanti Polar Lipids, Inc.; Alabaster, Ala.) lipids were dissolved in 0.5 ml chloroform, desolvated on a rotary evaporator and dried under high vacuum for 3 hours. The phospholipid film was then rehydrated in pH 7.4 PBS containing 10 mM D-glucose, vortexed for 5 minutes, and repeatedly extruded at least 15 times through a membrane with a 100 nm pore size. Absorption and Fluorescence Measurements Absorbance and fluorescence measurements were carried out on a Genesys 10S UV-Vis spectrophotometer (Thermo Scientific) and a SpectraMax M2 spectrofluorometer (Molecular Devices), respectively. The absorption spectra were measured in PBS pH 7.4 containing 10 mM D-glucose from 600 to 850 nm. The fluorescence spectra of 10 μM of ICG-Var3 peptide were measured from 810 to 850 nm at 790 nm excitation wavelength in PBS pH 7.4 containing 10 mM D-glucose, with or without 2 mM of POPC liposomes. Ex Vivo Imaging of Bladder Specimens 22 urothelial carcinoma patients that were scheduled for radical cystectomy were selected over a twelve month period. After radical cystectomy, bladder specimens were immediately removed and irrigated 3 times for 5 min via catheter with non-buffered saline and instilled and incubated with 80 ml of 8 μM or 32.8 μg/ml (unless otherwise is stated, see notes to Table 8) of ICG-Var3 construct or ICG-Cys in PBS pH 7.4 containing 10 mM D-glucose for 60 minutes. Then, the unbound constructs were removed by rinsing with 80 ml of saline solution 3-5 times, the bladder was irrigated thoroughly with buffered saline and opened using a Y incision on the anterior wall. Using a da Vinci Si near-infrared fluorescence imaging system (Firefly®), ex vivo fluorescent and white light imaging of the entire bladder and its parts was performed. The fluorescent spots were marked and standard pathological analysis was carried out to explore the correlation between appearance of fluorescent signal and cancer lesions. Pathological Analysis The specimen was sectioned and submitted after 24 hour fixation in 10% phosphate-buffered formalin according to the standard institutional grossing manual, with emphasis on the marked areas of the bladder. The sections were processed for routine histology into paraffin-embedded blocks. Five micrometer thick tissue sections were obtained and stained for hematoxylin and eosin (H&E). Evaluation of pathology was performed by a genitourinary (GU) pathologist, and a standard report was prepared based on the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 7th edition, 2010. Statistical Analysis Statistical parameters were calculated according to the following equations: TRP = TP TP + FN ; SPC = TN TN + FP PPV = TP TP + FP ; NPV = TN FN + TN ; FPR = FP FP + TN ; FNR = FN TP + FN ; FDR = FP TP + FP ; FOR = FN FP + TN Where TP is the true positive; TN is the true negative; FP is the false positive; FN is the false negative; TRP is the true positive rate or sensitivity; SPC is the true negative rate or specificity; PPV is the positive predictive value or precision; NPV is the negative predictive values; FPR is the false positive rate; FNR is the false negative rate; FDR is the false discovery rate; FOR is the false omission rate. Example 2: Visualization and Detection of Cancerous Lesions Visualization and detection of cancerous lesions in human body by systemic administration of a fluorescent or an optoacoustic imaging agents is very important and could be used to guide resection of tumors and detection/resection of lymph nodes with metastasized cancer cells. The main goal of the following study was investigation of ability of fluorescent ICG-Var3 and IR800-Var3 constructs to target various tumors in mice model after intravenous or intraperitoneal administration of fluorescent constructs. A Var3 peptide (ACDDQNPWRAYLDLLFPTDTLLLDLLWA; SEQ ID NO: 4) was purchased from CS Bio Co. Peptide was characterized by reversed phase high-performance liquid chromatography (RP-HPLC) using Zorbax SB-C18 and Zorbax SB-C8, 4.6×250 mm 5 μm columns (Agilent Technology). Peptide concentration was calculated by absorbance at 280 nm. Maleimide derivatives of ICG (indocyanine green, Intrace Medical) and IRDye®800CW (IR800, Li-Cor Biosciences) were conjugated with a single Cys residue at the N-terminal end of the Var3 peptide. The conjugation reactions were performed in DMF (dimethylformamide) at a ratio of about 1:1 dye:peptide and incubated at room temperature for about 8 hours and then at 4° C. until the conjugation was completed. The reaction progress and purity was monitored by reverse phase RT-HPLC to ensure absence of free dyes in the final solution. The products were lyophilized and characterized by SELDI-TOF mass spectrometry. The concentration of conjugates was determined in methanol by absorbance using the following molar extinction coefficients: ε778=300,000 M−1·cm−1 (for IR800-pHLIP) and ε800=137,000 M−1·cm−1 (for ICG-pHLIP). Adult female nude mice and female BALB/cAnNHsd mice (Envigo), 20-25 g in body mass were used in the study. Mouse mammary cancer 4T1 cells were subcutaneously implanted in the right flank (8×105 cells/0.1 mL/flank) of adult female BALB/cAnNHsd mice. Rat bladder cancer AY27 cells were subcutaneously implanted in the right flank (8×105 cells/0.1 mL/flank) of adult female nude mice. When tumors reached approximately 5-6 mm in diameter, single tail vein injection or single intraperitoneal injection of fluorophore-pHLIP solutions in PBS were performed. Fluorescent constructs were used in amounts of 100 L of 40 μM, or 100 μL of 20 μM, or 100 μL of 10 μM, or 100 μL of 5 μM. Imaging of mouse was performed at 16 hours after constructs administration. Skin was removed from the tumor site just before imaging while animal was under gas anesthesia, and mice were euthanized immediately after imaging. Tumor, kidney and liver were harvested, imaged and used for histopathological analysis. Imaging was performed using Stryker clinical imaging instrument. Autofluorescence was established by imaging mouse with no injection of fluorescent constructs (the level of autofluorescence signal was insignificant compared to the signal after the constructs administration). The murine 4T1 xenograft model closely mimics stage IV of human breast cancer (Yang et al. (2004) Cell 117(7): 927-939; Eckhardt et al. (2005) Mol Cancer Res 3(1): 1-13; Tao et al. (2008) BMC Cancer 8: 228). It is also known that 4T1 mammary tumor generate significant level of lactate and serve as a good model of an aggressive, acidic tumor (Serganova et al. (2011) Cancer Res 17(19): 6250-6261). 4T1 is triple negative breast tumor, which is difficult to target. An excellent targeting of 4T1 tumor by ICG-Var3 (FIG. 11). In FIG. 12 it is shown targeting of rat bladder tumor in nude mice. The fluorescent signal of ICG-Var3 in tumors (as well as kidney and liver) showed concentration dependence (FIGS. 13 and 14). It is important to note that signal in tumor was higher than in kidney and similar or slightly less than in liver (FIG. 14). Both intravenous and intraperitoneal administration of ICG-Var3 led to the excellent tumor targeting and visualization of tumors at 16 hours after construct administration (FIG. 15). Tumor visualization by NIR signal after intravenous administration of ICG-Var3 and IR800-Var3 was compared (FIG. 16). Despite on the fact that both fluorescent constructs target tumor with high precision visualization of tumors using ICG-Var3 was much better compared to the visualization of tumors using IR800-Var3. Without being bound by any theory, better tumor visualization using ICG-Var3 might be due to the amplification (enhancement) of ICG fluorescence near the surface of cancer cells membrane and/or use of clinical imaging instrument (e.g., using a Stryker endoscope or many other clinical instruments), which are much better optimized for excitation and imaging of ICG dye rather than IR800 dye. The quantification of tumor uptake is provided in FIG. 17. The fluorescent signal in liver and kidney was also different for ICG-Var3 and IR800-Var3. In embodiments, the fluorescent compound allows for visualization of tumor mass to establish clearly margin for tumor resection during fluorescent-guided surgical applications. In FIG. 18 it is shown 2 different tumor masses with surrounding muscle tissue removed from the mice. The obtained images demonstrate that fluorescent signal is useful for identifying tumor margins, which was confirmed by standard hemolysin and eosin (H&E) histopathological analysis. Example 3: Fluorescence Imaging of Blood Flow in Mice by ICG-Var3 and IR800-pHLIP Fluorescence angiography (FA) is widely used in various procedures to visualize blood vessels and monitor blood flow. ICG is employed in FA, however due to the fast blood clearance (half lifetime is just few minutes), the useful imaging window is restricted to few min after administration of ICG. In a course of some clinical procedures ICG is injected up to 10 times during a single procedure. There is obvious need to extend imaging window by using longer circulating imaging agents. Previous data clearly indicate that pHLIPs have long circulation in blood compared to the peptides of similar sizes (Reshetnyak et al. (2011) Mol Imaging Biol 13(6): 1146-1156; Daumar et al. (2012) Bioconjug Chem 23(8): 1557-1566; Macholl et al. (2012) Mol Imaging Biol 14(6): 725-734; Adochite et al. (2014) Mol Pharm 11(8): 2896-2905; Cruz-Monserrate et al. (2014) Sci Rep 4: 4410; Viola-Villegas et al. (2014) Proc Natl Acad Sci USA 111(20): 7254-7259; Adochite et al. (2016) Mol Imaging Biol 18(5): 686-696; Demoin et al. (2016) Bioconjug Chem 27(9): 2014-2023). Therefore the possibility of imaging blood in mice was explored using near infrared ICG and IR800 conjugated pHLIP peptides in comparison with ICG and IR800 dyes alone. All peptides were purchased from CS Bio Co. A list of peptides used in the study is given in Table 11. Peptides were characterized by reversed phase high-performance liquid chromatography (RP-HPLC) using Zorbax SB-C18 and Zorbax SB-C8, 4.6×250 mm 5 m columns (Agilent Technology). Peptide concentration was calculated by absorbance at 280 nm. TABLE 11 List of pHLIP sequences used in the study. Peptide Sequence WT pHLIP ACEQNPIYWARYADWLFTTPLLLLDLALLVDADEGT (SEQ ID NO: 444) Var3 pHLIP ACDDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 4) NpHLIP ACEQNPIYWARYANWLFTTPLLLLNLALLVDADEGT (SEQ ID NO: 445) Hum pHLIP GCDNNEGFFATLGGEIPLWSDVVLAIEG (SEQ ID NO: 446) Maleimide derivatives of ICG (indocyanine green, Intrace Medical) and IRDye®800CW (IR800, Li-COR Biosciences) were conjugated with free Cys residue or pHLIP peptides with a single Cys residue at the N-terminal end of the peptides. The conjugation reactions were performed in DMF (dimethylformamide) at a ratio of about 1:1 dye:peptide and incubated at room temperature for about 8 hours and then at 4° C. until the conjugation was completed. The reaction progress and purity was monitored by reverse phase RT-HPLC to ensure absence of free dyes in the final solution. The products were lyophilized and characterized by SELDI-TOF mass spectrometry. The concentration of conjugates was determined in methanol by absorbance using the following molar extinction coefficients: 6778=300,000 M−1·cm−1 (for IR800-conjugates) and ε800=137,000 M−1·cm−1 (for ICG-conjugates). Adult female nude mice (Envigo), 20 g in body mass were used in the study. Fluorescent constructs were given as a single tail vein injection in amounts of 100 μL of 40 μM in PBS. Imaging of mouse ear and leg was performed at 5, 30, 60, 90 and 120 min after construct administration. At 5, 30, 60, 90 and 120 min after construct administration 5 μL of blood was withdrawn from tail (and mixed with 5 μL of anticoagulating solution to preserve blood) while animal was under anesthesia. Mice were euthanized immediately after last imaging point (120 min). Blood collected from all animals was deposited on the glass slide, dried and imaged. Imaging was performed using Novadaq clinical imaging instrument. Autofluorescence was established by imaging mouse with no injection of fluorescent constructs (the level of autofluorescence signal was insignificant compared to the signal after the constructs administration). NIR fluorescence images of animal's ears and legs obtained at different time points after the constructs administration are shown in FIGS. 20-37. All images are presented with adjusted contrast/brightness ratios to best present imaging of blood vessels. The first set of images was obtained with ICG conjugated with pHLIPs and ICG-Cys. The imaging of dye alone (ICG-Cys) clearly demonstrates fast blood clearance of the dye. At 5 min after ICG-Cys injection it was already problematic to observe blood vessels. At the same time ICG-WT pHLIP and ICG-Var3 pHLIP exhibited an excellent persistent imaging of blood vessels within 2 hours. ICG-Hum pHLIP was slow in reaching the best imagibility condition and was fast in decaying. ICG-NpHLIP did not show good performance: the overall signal was low and imaging of blood flow was not well evident. The analysis of blood samples confirmed persistence of strong fluorescent signal within 2 hours for ICG-WT pHLIP and ICG-Var3 pHLIP, and significantly reduced signal of ICG-NpHLIP in blood samples. The best performed peptides, WT and Var3 pHLIPs, were tested also with another NIR fluorescent dye, IR800, to establish role of fluorescent dye. First, IR800-Cys alone did not allow to record good signal from the blood vessels. IR800-WT and IR800-Var3 pHLIPs were better in imaging of blood vessels, however not nearly as good as ICG-WT and ICG-Var3 pHLIPs. It was evident from images of ears and legs, as well as blood samples, that IR800 versions of pHLIP constructs were leaking from blood and start to be distributed in tissue within 2 hours time period. It is clear that property of dye affects biodistribution and blood clearance. The results indicate that the use of ICG-Var3 pHLIP and ICG-WT pHLIP leads to a significant improvement of imagibility of blood vessels and blood flow in numerous clinical procedures, since it can prolong time of imaging from 2-5 min to 2-3 hours. Other Embodiments While the invention has been described in conjunction with the description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. The patent and scientific literature referred to herein establishes the knowledge that is available to those with skill in the art. All United States patents and published or unpublished United States patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are hereby incorporated by reference. Genbank and NCBI submissions indicated by accession number cited herein are hereby incorporated by reference. All other published references, documents, manuscripts and scientific literature cited herein are hereby incorporated by reference. While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.
<SOH> BACKGROUND <EOH>Bladder cancer is the fifth most common cancer, constituting 4.5% of all new cancer cases in the United States. 76,960 new cases were estimated in 2016 and the death rate currently expected from bladder cancer is 21% (16,390). Approximately 2.4 percent of men and women will be diagnosed with bladder cancer at some point during their lifetime. In 2012, there were an estimated 577,403 individuals living with bladder cancer in the United States. Almost all of these patients require continuous surveillance, and, occasionally, treatments. For all stages combined, the 5-year relative survival rate is 77%. Survival declines to 70% at 10 years and 65% at 15 years after diagnosis. Bladder cancer can be non-muscle or muscle invasive. Half of all bladder cancer patients are diagnosed while the tumor is non-muscle invasive, for which the 5-year survival is 96%. Most (up to 98%) of malignant bladder tumors arise in the epithelium, 90-92% of these bladder cancers are urothelial carcinomas (Siegel et al. (2012) CA Cancer J Clin 62(1):10-29, Pasin et al. (2008) Rev Urol 10(1):31-43). Less common bladder cancers are squamous cell or adenocarcinomas. Approximately 20-25% of patients have muscle invasive disease, and of non-muscle invasive disease patients will progress to muscle invasive disease at 5 years follow up depending on intermediate or high risk of the progression (Anastasiadis & de Reijke (2012) Ther Adv Urol 4(1):13-32, Kamat et al. (2014) J Urol 192(2):305-315).
<SOH> SUMMARY OF THE INVENTION <EOH>The present subject matter provides, inter alia, fluorescent compounds comprising, consisting essentially of, or consisting of a pH-triggered polypeptide (a “pHLIP peptide”) and a fluorophore. Such compounds may be referred to herein as “pHLIP-fluorophore compounds.” Methods and compositions comprising such fluorescent compounds are also provided. For example, non-limiting implementations relate to fluorescence-image guided medical procedures, such as fluorescence and optoacoustic imaging. In various embodiments, the pHLIP peptide has the sequence: X n Y m ; Y m X n ; X n Y m X j ; Y m X n Y i ; Y m X n Y i X j ; X n Y m X j Y i ; Y m X n Y i X j Y l ; X n Y m X j Y i X; Y m X n Y i X j Y l X h ; X n Y m X j Y i X h Y g ; Y m X n Y i X j Y l X h Y g ; X n Y m X j Y i X h Y g X f ; (XY) n ; (YX) n ; (XY) n Y m ; (YX) n Y m ; (XY) n X m ; (YX) n X m ; Y m (XY) n ; Y m (YX) n ; X n (XY) m ; X n (YX) m ; (XY) n Y m (XY) i ; (YX) n Y m (YX) i ; (XY) n X m (XY) i ; (YX) n X m (YX) i ; Y m (XY) n ; Y m (YX) n ; X n (XY) m ; X n (YX) m , wherein, i) Y is a non-polar amino acid with solvation energy, ΔG X cor >+0.50, or Gly (see, e.g., Table 1), ii) X is a protonatable amino acid, and iii) n, m, I, j, l, h, g, f are integers from 1 to 8. In some embodiments, the pHLIP peptide has the following sequence: NH 2 -ACDDQNPWRAYLDLLFPTDTLLLDLLWA-COOH (SEQ ID NO: 4), where “NH 2 —” is the amino-terminal end of the peptide (and is part of the N-terminal alanine) and the “—COOH” is the carboxy-terminal end of the peptide (and is part of the C-terminal alanine). In amino acid sequences disclosed herein (e.g., in text, tables, structures, lists, or otherwise), the “NH 2 —” and/or the “—COOH” of a peptide may optionally be omitted or not shown. In certain embodiments, the fluorophore is covalently attached to the cysteine of a pHLIP peptide having the sequence: NH 2 -ACDDQNPWRAYLDLLFPTDTLLLDLLWA-COOH (SEQ ID NO: 4). In various embodiments, the pHLIP-fluorophore compound has the following structure (SEQ ID NO: 4 is disclosed below): In the sequence above, the pHLIP peptide sequence is NH 2 -ACDDQNPWRAYLDLLFPTDTLLLDLLWA-COOH (SEQ ID NO: 4), however the structures of the alanine and the cysteine at the N-terminal end of the peptide are shown. In some embodiments, the pHLIP peptide has a net negative charge at a pH of about 7.5 or 7.75 in water. In certain embodiments, the pHLIP peptide has an acid dissociation constant at logarithmic scale (pKa) of less than about 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, or 7. In various embodiments, the pHLIP peptide comprising at least 1 artificial protonatable amino acid. As used herein, an “artificial” amino acid is an amino acid that is not genetically encoded. In some embodiments, the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 40 genetically coded amino acids. In certain embodiments, the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 40 non-genetically coded amino acids. In various embodiments, the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 40 D-amino acids. In some embodiments, the pHLIP peptide comprises at least 8 amino acids, wherein, at least 2, 3, or 4 of the 8 amino acids of said peptide are non-polar, and at least 1, 2, 3, or 4 of the at least 8 amino acids of said pHLIP peptide are protonatable. In certain embodiments, the pHLIP peptide comprises a functional group to which a fluorophore may be attached. For example, the pHLIP peptide comprised a functional group before it was part of the pHLIP-fluorophore compound, and the fluorophore was attached covalently to the pHLIP peptide via a chemical interaction involving the functional group. In some embodiments, the pHLIP peptide comprises a functional group, and the fluorophore is non-covalently attached (e.g., via non-covalent binding such as an electrostatic interaction) to the functional group. In the context of attachment of a pHLIP peptide to a fluorophore, a “functional group” is a portion of a compound (such as a pHLIP peptide) that is used to attach the compound to another compound (such as a pHLIP peptide to a fluorophore). A “functional group” may optionally be referred to as an “attachment group.” In various embodiments, a functional group is chemically reactive. In some embodiments, a functional group on a pHLIP peptide reacts with a functional group on a fluorophore to leave a covalent bond that connects the pHLIP peptide to the fluorophore, resulting in a pHLIP-fluorophore compound. Non-limiting examples of functional groups include amino acid side chains (such as the —SH side chain of cysteine or a —NH 2 side chain of lysine); thiols (e.g., moieties comprising, consisting essentially of, or consisting of —SH); esters such as maleimide esters; moieties comprising -she; and moieties that may be involved in click reactions (such as azides, alkynes, strained difluorooctynes, diaryl-strained-cyclooctynes, 1,3-nitrones, cyclooctenes, trans-cycloalkenes, oxanorbornadienes, tetrazines, tetrazoles, activated alkenes, and oxanorbomadienes. As used herein, the term “fluorophore” includes any compound that emits energy. The energy may be in the form of, e.g., acoustic energy (such as sound waves), heat, or electromagnetic radiation. In various embodiments, the electromagnetic radiation may be visible or non-visible to the human eye. In some embodiments, the electromagnetic radiation is infrared or near-infrared. Non-limiting examples of fluorophores include luminescent compounds, fluorescent compounds, phosphorescent compounds, chemiluminescent compounds, optoacoustic compounds, and quencher compounds (e.g., fluorescent quencher compounds). Fluorophores may comprise, e.g., small molecule compounds (e.g., organic compounds having a molecular weight of less than about 2000, 1000, or 500 daltons), proteins, or chelated metals (e.g., a chelator attached to a metal via covalent or non-covalent coordination bonds, wherein the combination of the chelator and the metal is fluorescent). In some embodiments, a chelated metal is within a “cage” formed by a chelator, and the combination of the chelator and the metal is fluorescent. In certain embodiments, the emission of energy (e.g., electromagnetic radiation such as luminescence, acoustic energy such as sound waves, or heat) does not involve the absorption and then emission of energy. In some embodiments, the emission of energy involves the absorbance and then the emission of energy. As used herein, a compound that transfers greater than 50% the energy of absorbed light into the heat is called a “quencher.” In some embodiments, a quencher transfers all of the energy of absorbed light into heat. In various embodiments, a quencher can emit some amount of light, but most of the absorbed energy (e.g., at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% of the absorbed energy) is transferred into the heat. Non-limiting examples of quenchers include: i) Dabsyl (dimethylaminoazobenzenesulfonic acid); ii) Black Hole Quenchers (which can quench in wide range of practically the entire visible spectrum); and iii) IRDye QC-1 [which can quench in the range for visible to NIR (500-900 nm)]. A main principle of optoacoustic imaging is the following: Absorption of light by a fluorophore or quencher, and the transfer of energy into heat, which leads to thermal expansion and the generation of acoustic waves, which are detected. In general, fluorophores transfer some, e.g., a minimal amount, of energy to heat; however most of the energy of a fluorophore is emitted in a form of light. In certain preferred embodiments relating to luminescent fluorophores (e.g., fluorophores that emit electromagnetic radiation such as light), a fluorophore emits more energy in the form of electromagnetic radiation (e.g., light), and less energy is transferred to heat. In certain preferred embodiments relating to quenchers, a quencher emits less energy in the form of electromagnetic radiation (e.g., light), and more energy is transferred to heat. Therefore, ICG can be used as a fluorophore in fluorescent imaging, as well as in optoacoustic imaging, due its property of transferring some energy to the heat. In various embodiments, 1, 2, 3, 4, 5 or more fluorophores are attached to the pHLIP peptide. In some embodiments, the functional group of the pHLIP peptide to which a fluorophore may be (or has been) attached comprises an amino acid, azido modified amino acid, or alkynyl modified amino acid. In certain embodiments, the pHLIP peptide is covalently attached to the fluorophore via an amide bond. In certain embodiments, the functional group of the pHLIP peptide comprises (or comprised) a free sulfhydryl (SH), or a primary amine. In embodiments, the pHLIP peptide is attached to one or more fluorophores (e.g., a fluorophore, a quencher such as a fluorophore quencher, or a combination comprising a fluorophore-quencher pair) to form a pHLIP-fluorophore compound that is used as a diagnostic, imaging, ex vivo imaging agent, or as a research tool. In various embodiments, the pHLIP peptide comprises one or more fluorophores attached to a functional group used as a diagnostic, imaging, ex vivo imaging agent, or as a research tool. In some embodiments, the fluorophore comprises a fluorescent dye, or a fluorescent quencher, or a combination of both. In some embodiments, a fluorophore-quencher system used in fluorescence-guided imaging. For non-limiting descriptions of such systems, see, e.g., www.bachem.com/service-support/newsletter/peptide-trends-july-2016/. A non-limiting example of the use of a fluorophore-quencher system is described in Karabadzhak et al. (2014) ACS Chem Biol. 9(11):2545-53, the entire content of which is incorporated herein by reference. In certain embodiments, when the distance between a fluorophore and a quencher increases [e.g., because of a conformational change or due to the breakage of a bond (such as a peptide or other bond) connecting the fluorophore and the quencher], then the intensity of emission of fluorophore increases. In certain embodiments, the efficiency of fluorescence increases when the distance between the fluorophore and the quencher increases, which results in increased of fluorescent intensity. In some embodiments, a pHLIP compound comprising a fluorophore or a quencher (e.g., a pHLIP-quencher) is used for optoacoustic imaging. In various embodiments, optoacoustic imaging comprises a compound or moiety that absorbs light and transfers it to heat (e.g., with a optoacoustic imaging agent), which is measured by ultrasound, as opposed to fluorescence. In embodiments, fluorescence comprises a compound of moiety that absorbs light and emits it in the form of fluorescence or phosphorescence. In some embodiments, a fluorophore (e.g., a fluorophore that emits more energy in the form of light than heat) is used for optoacoustic imaging. In certain embodiments, an ICG-pHLIP peptide is used for optoacoustic imaging. A non-limiting example of the use of a compound comprising a pHLIP peptide and a fluorescent dye as a multispectral optoacoustic tomography (MSOT) imaging agent is described in Kimbrough et al. (2015) Clin Cancer Res. 21(20):4576-85, the entire content of which is incorporated herein by reference. In certain embodiments, the fluorophore comprises a near-infrared (NIR) fluorescent dye, e.g., indocyanine green (ICG), which operates in (e.g., has a peak emission wavelength within) NIR wavelengths. Infrared radiation extends from the nominal red edge of the visible spectrum at 700 nanometers (nm) to 1 mm. NIR radiation comprises a wavelength of 750 nm to 1.4 m. In some embodiments, the ICG has a peak emission wavelength between 810 nm and 880 nm (e.g., in the context of a pHLIP-fluorophore compound). In certain embodiments, the ICG has a peak emission wavelength between 810 nm and 860 nm. In various embodiments, the ICG has a peak emission wavelength of about 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, or 880 nm. In some embodiments, a 805 nm laser is used for ICG excitation. In certain embodiments, a 801, 802, 803, 804, 804, 805, 806, 807, 808, 809, 810, 800-805, 804-806, or 802-807 nm laser is used for ICG excitation. Non-limiting examples of NIR imaging systems (which may be useful in, e.g., clinical and diagnostic applications) include INFRARED 800™, available from Carl Zeiss Meditec AG; Artemis®, available from Quest Medical Imaging BV; HyperEye Medical System®, available from Mizuho Medical Co. Ltd.; Near infrared fluorescence imager PDE® C9830, available from Hamamatsu Photonics K.K.; SPECTROPATH® Image-Guided Surgery System, available from Spectropath Inc.; the following from NOVADAQ Technologies Inc.: SPY Elite® (imaging for open surgery), PINPOINT® (endoscopic fluorescence imaging), LUNA® (Fluorescence Angiography for Wound Care); Firefly® Fluorescence imaging for the da Vinci Si System, available from Intuitive Surgical Inc.; NIR Leica® FL800, available from Leica Microsystems; Fluobeam®, available from Fluoptics Minatec-BHT; KG, Storz Karl Storz-Endoskope® (Near-Infrared/Indocyanine Green), available from Karl Storz GmbH & Co.; and InfraVision™ Imaging System, available from Stryker Corporation. In various embodiments, the fluorophore comprises an agent that operates at a wavelength (e.g., has a peak emission wavelength within) of from about 670 nm to about 750 nm, e.g., methylene blue. In certain embodiments, the fluorophore comprises a cyanine dye. In embodiments, a cyanine dye operates at a wavelength (e.g., has a peak emission wavelength within) of 550-620 nm, 590-700 nm, 650-730 nm, 680-770 nm, 750-820 nm, or 770-850 nm. Non-limiting examples of cyanine dyes include Cy2, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, Cy7, and Cy7.5. In some embodiments, the cyanine dye is Cy3, Cy3.5, Cy5, Cy5.5, Cy7, or Cy7.5. In certain embodiments, the Cy3 has a peak emission wavelength between 550 and 620 nm (e.g., in the context of a pHLIP-fluorophore compound). In various embodiments, the Cy3.5 has a peak emission wavelength between 590 and 700 nm (e.g., in the context of a pHLIP-fluorophore compound). In some embodiments, the Cy5 has a peak emission wavelength between 650 and 730 nm (e.g., in the context of a pHLIP-fluorophore compound). In certain embodiments, the Cy5.5 has a peak emission wavelength between 680 and 770 nm (e.g., in the context of a pHLIP-fluorophore compound). In various embodiments, the Cy7 has a peak emission wavelength between 750 and 820 nm (e.g., in the context of a pHLIP-fluorophore compound). In certain embodiments, the Cy7.5 has a peak emission wavelength between 770 and 850 nm (e.g., in the context of a pHLIP-fluorophore compound). In some embodiments, the peak emission wavelength of a fluoroophore may vary (e.g., by about 5, 6, 7, 8, 9, or 10%) based on the environment and/or solvent around the fluorophore. In some embodiments, the fluorophore comprises a fluorescent, or an optoacoustic contrast imaging agent. In certain embodiments, an optoacoustic imaging agent is fluorescent. In various embodiments, an optoacoustic imaging agent is not fluorescent. In certain embodiments, an optoacoustic imaging agent absorbs light, and transfers most of the light's energy (e.g., at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% of the light's energy) into heat. In various embodiments, the heat is detected by ultrasound. In some embodiments, a quencher is be a fluorophore with a very low quantum yield, such that most of the energy absorbed by the quencher is transferred to heat rather than electromagnetic radiation (such as light). Non-limiting examples of optoacoustic contrast imaging agents include ICG (which can be used for fluorescent imaging as well as for optoacoustic imaging), Alexa Fluor 750, Evans blue, BHQ3 (Black Hole Quencher®-3; commercially available from, e.g., Biosearch Technologies, California, United States), QXL®680 (commercially available from, e.g., Cambridge Bioscience, Cambridge, United Kingdom), IRDye®800CW (commercially available from, e.g., LI-COR, Nebraska, United States), MMPSense™ 750 FAST (commercially available from, e.g., PerkinElmer Inc., Texas, United States), diketopyrrolopyrrole cyanine, cypate-C18, Au nanoparticles (such as Au nanospheres, Au nanoshells, Au nanorods, Au nanocages, Au nanoclusters, Au nanostars, and Au nanobeacons), nanoparticles comprising a gold core covered with the Raman molecular tag trans-1,2-bis(4-pyridyl)-ethylene, Ag nanoplates, Ag nanosystems, quantum dots, nanodiamonds, polypyrrole nanoparticles, copper sulfide, graphene nanosheets, iron oxide-gold core-shells, Gd 2 O 3 , single-walled carbon nanotubules, dye-loaded perfluorocarbon-based nanoparticles, AuMBs, triggered nanodroplets, cobalt nanowontons, nanoroses, goldsilica core shell nanorods, superparamagnetic iron oxide, and methylene blue. Non-limiting examples and descriptions of optoacoustic contrast imaging agents are described in Wu et al. (2014) Int. J. Mol. Sci., 15, 23616-23639 (see, e.g., Table 1), the entire contents of which are incorporated herein by reference. In various embodiments, a pHLIP-fluorophore compound provided herein is for use as an agent in preoperative, intraoperative and postoperative settings. In some embodiments, a pHLIP-fluorophore compound provided herein is for use as an agent for ex vivo imaging, and ex vivo diagnostics. In various embodiments, a pHLIP-fluorophore compound provided herein is used to detect or image diseased tissue. Non-limiting examples of diseased tissue include cancerous tissue, inflamed tissue, ischemic tissue, arthritic tissue, cystic fibrotic tissue, tissue infected with a microorganism, and atherosclerotic tissue. In some embodiments, a pHLIP-fluorophore compound provided herein is for use as an agent in fluorescence angiography. Fluorescence angiography is a procedure in which a fluorescent compound (such as a pHLIP-fluorophore compound disclosed herein) is injected into the bloodstream. The fluorescent compound highlights the blood vessels. In various embodiments, the vessels are in the back of the eye. In some embodiments the vessels are imaged or photographed. In non-limiting examples, fluorescence angiography is used to identify, detect image, or manage an eye disorder. In certain embodiments relating to ophthalmology, fluorescence angiography may be used to look at blood flow in, e.g., the retina and choroid. In various embodiments, fluorescence angiography provides real-time imaging of blood vessels to follow changes during surgical procedures. Some non-limiting examples include the use of fluorescence in ophthalmology to evaluate the chorioretinal vasculature; in cardiothoracic surgery to assess the effectiveness of a coronary artery bypass; in neurovascular surgery to assess the effect of a superficial temporal artery-middle cerebral artery bypass graft in cerebral revascularization procedure; in hepatobilliary surgery to identify the haptic segment and subsegment for anatomical hepatic resection; in reconstructive surgeries; and in cholecystectomy and colorectal resection. In non-limiting examples of diagnostic applications, fluorescence angiography is used for imaging of hemodynamics in the brain; circulatory features of rheumatoid arthritis; muscle perfusion; burns and to assess various other effects of trauma. In certain embodiments, a pHLIP-fluorophore compound provided herein is for visualization of blood circulation in ophthalmology, cardiothoracic surgery, bypass coronary surgery, neurosurgery, hepatobilliary surgery, reconstructive surgery, cholecystectomy, colorectal resection, brain surgery, muscle perfusion, wound and trauma surgery, and laparoscopic surgery. In various embodiments, a pHLIP-fluorophore compound provided herein is for visualization of lymph nodes. In some embodiments, a pHLIP-fluorophore compound provided herein is for visualization or detection of pre-cancerous tissue or cancerous lesions. In certain embodiments, a pHLIP-fluorophore compound provided herein is for visualization or detection of pre-cancerous tissue or cancerous lesions in bladder, upper urinary tract, kidney, prostate, breast, head and neck, oral, pancreatic, lungs, liver, cervical, ovarian, or brain tumors. In various embodiments, a pHLIP-fluorophore compound provided herein for real-time assessment of blood flow and tissue perfusion during intraoperative procedures. In an aspect, provided herein is a composition for parenteral, local, or systemic administration comprising a pHLIP-fluorophore compound. In an aspect, included herein is a composition for intravenous, intraarterial, intraperitoneal, intracerebral, intracerebroventricular, intrathecal, intracardiac, intracavemous, intraosseous, intraocular, intravitreal administration of a pHLIP-fluorophore compound. In an aspect, provided herein is composition for intramuscular, intradermal, transdermal, transmucosal, intralesional, subcutaneous, topical, epicutaneous, extra-amniotic, intravaginal, intravesical, nasal, or oral administration of a pHLIP-fluorophore compound. In an aspect, included herein is a composition for an ex vivo treatment of biopsy specimens, liquid biopsy specimens, surgically removed tissue, surgically removed liquids, or blood comprising a pHLIP-fluorophore compound. In an aspect, a subject's blood is contacted with the pHLIP-fluorophore compound (e.g., in vivo or ex vivo). In various embodiments, a lower dose of a fluorophore (such as ICG) is effective when the fluorophore is part of a pHLIP fluorophore composition, e.g., conjugate, compared to the effective dose (e.g., for imaging or detection) of the free fluorophore, e.g., the non-conjugated fluorophore. In some embodiments, administration of a lower effective dose of the fluorophore as part of a pHLIP fluorophore compound results in lower side effects. In certain embodiments, a fluorophore may make a subject more sensitive to solar radiation after administration such that the subject develops a greater degree of sunburn following exposure to solar radiation compared to a subject to which a fluorophore such as ICG has not been administered. In various embodiments, a fluorophore is delivered as part of a pHLIP fluorophore compound to subject in a lower dose than would be necessary if the fluorophore was administered in free form, thereby reducing or minimizing phototoxicity (e.g., toxicity to the skin/sunburn) from exposure to solar radiation than if the free form of the fluorophore was administered. In some embodiments, the pHLIP-fluorophore compound comprises a pHLIP and ICG (e.g., an ICG-pHLIP peptide such as ICG-Var3). In certain embodiments, the pHLIP-fluorophore compound is administered at a dose of about 0.01-0.5 mg/kg of a subject. In various embodiments, the pHLIP-fluorophore compound is administered at a dose of about 0.02-0.2 mg/kg of a subject. In some embodiments, the pHLIP-fluorophore compound is administered at a dose of about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.125, 0.15, 0.175, 0.2, 0.25, or 0.5 mg/kg of a subject. In certain embodiments, the pHLIP-fluorophore compound is administered at a dose of at least about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.125, 0.15, 0.175, or 0.2 mg/kg, but less than about 0.25, 0.5, 1, 2, 3, 4, or 5 mg/kg. In various embodiments, 1-10 mg of the pHLIP-fluorophore compound is administered to a subject. In some embodiments, about 0.5 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 15 mg of the pHLIP-fluorophore compound is administered to a subject. In certain embodiments, at least 0.5, 1, 2, or 3 mg, but less than 10 or 1 mg, of the pHLIP-fluorophore compound is administered to the subject. In various embodiments, about 0.3-3 μmol of the pHLIP-fluorophore compound is administered to the subject. In some embodiments, about 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 μmol of the pHLIP-fluorophore compound is administered to the subject. In certain embodiments, at least about 0.1, 0.5, or 1 μmol, but less than 3, 4, or 5 μmol, of the pHLIP-fluorophore compound is administered to the subject. In various embodiments, the pHLIP-fluorophore compound is administered by intravenous injection for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-10, 1-15, 5-10, 5-15, 5-20, 10-15, 10-20, or 15-20 minutes. In certain embodiments, about 0.5 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 15 mg of the pHLIP-fluorophore compound is instilled into an organ or tissue (e.g. a bladder). In certain embodiments, at least 0.5, 1, 2, or 3 mg, but less than 10 or 1 mg, of the pHLIP-fluorophore compound is instilled into an organ or tissue (e.g. a bladder). In various embodiments, about 0.3-3 μmol of the pHLIP-fluorophore compound is instilled into an organ or tissue (e.g. a bladder). In some embodiments, about 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 μmol of the pHLIP-fluorophore compound is instilled into an organ or tissue (e.g. a bladder). In certain embodiments, at least about 0.1, 0.5, or 1 μmol, but less than 3, 4, or 5 μmol, of the pHLIP-fluorophore compound is instilled into an organ or tissue (e.g. a bladder). In various embodiments, the pHLIP-fluorophore compound is instilled into an organ or tissue (e.g. a bladder) for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-10, 1-15, 5-10, 5-15, 5-20, 10-15, 10-20, or 15-20 minutes. In certain embodiments, the pHLIP-fluorophore compound further comprises polyethylene glycol. In some embodiments, the pHLIP-fluorophore compound further comprises one or more polyethylene glycol subunits (e.g., 3, 4, 5, 6, 7, 8, 9, 0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 3-10, 10-20, or 3-20 subunits). Included herein is a method for detecting (e.g., imaging) blood flow in a subject, comprising (a) administering a pHLIP-fluorophore compound comprising a fluorophore (such as ICG) disclosed herein to the subject; (b) contacting the subject (e.g., an area, cell, tissue, or organ of the subject, such as an area or tissue that may comprise a portion of the administered pHLIP-fluorophore compound) with electromagnetic radiation comprising an excitation wavelength of the fluorophore; and (c) detecting electromagnetic radiation emitted from the pHLIP-fluorophore compound in the subject. In embodiments, detection of the radiation indicates the presence (e.g., the location or amount at a location) of blood in the subject. In embodiments, an image of the blood in the subject is produced. Also provided is a method for detecting (e.g., imaging) a pHLIP-fluorophore compound in a subject, comprising (a) administering a pHLIP-fluorophore compound comprising a fluorophore (such as ICG) disclosed herein to the subject; (b) contacting the subject (e.g., an area or tissue of the subject, such as an area, cell, tissue, or organ that may comprise a portion of the administered pHLIP-fluorophore compound) with electromagnetic radiation comprising an excitation wavelength of the fluorophore; and (c) detecting electromagnetic radiation emitted from the pHLIP-fluorophore compound in the subject. In embodiments, detection of the radiation indicates the presence (e.g., the location or amount at a location) of a bodily fluid such as blood in the subject. In embodiments, an image of the blood in the subject is produced. Included herein is a method for optoacoustic detection or imaging of blood flow in a subject, comprising (a) administering a pHLIP-fluorophore compound, wherein the fluorophore is an optoacoustic imaging agents such as a luminescent fluorophore or a quencher; (b) contacting the subject (e.g., an area, cell, tissue, or organ of the subject, such as an area or tissue that may comprise a portion of the administered pHLIP-fluorophore compound) with electromagnetic radiation comprising an excitation wavelength of the fluorophore; and (c) detecting energy such as acoustic energy (e.g., sound waves). In embodiments, detection of the energy indicates the presence (e.g., the location or amount at a location) of blood in the subject. In various embodiments, an image of the blood in the subject is produced. In some embodiments, the presence of acoustic energy is detected by ultrasound (e.g., heat is released and creates expansion, generating sound waves, which is detected). The present subject matter also provides a method for detecting (e.g., imaging) a pHLIP-fluorophore compound in a subject, wherein the fluorophore is an optoacoustic imaging agents such as a luminescent fluorophore or a quencher, the method comprising (a) administering the pHLIP-fluorophore compound to the subject; (b) contacting the subject (e.g., an area or tissue of the subject, such as an area, cell, tissue, or organ that may comprise a portion of the administered pHLIP-fluorophore compound) with electromagnetic radiation comprising an excitation wavelength of the fluorophore; and (c) detecting energy such as acoustic energy (e.g., sound waves). In embodiments, detection of the energy indicates the presence (e.g., the location or amount at a location) of a bodily fluid such as blood in the subject. In embodiments, an image of the blood in the subject is produced. In embodiments, the presence of acoustic energy is detected by ultrasound. Depending on context, “excitation wavelength” may be used synonymously with “absorption wavelength.” In various embodiments, the method comprises a fluorescence-guided imaging procedure performed during surgery or during a doctor's visit. In some embodiments, the method comprises fluorescence angiography. In certain embodiments, the method comprises the assessment of the perfusion of tissues and organs. In various embodiments, the method comprises the assessment of hepatic function. In some embodiments, the fluorescence-guided imaging procedure comprises targeting, marking, detecting, or visualization of pre-cancerous tissue, cancerous tissue, inflamed tissue, ischemic tissue, arthritic tissue, tissue infected with a microorganism, and/or atherosclerotic tissue. In certain embodiments, the method comprises assessing patency of a coronary artery bypass during cardiothoracic surgery. In some embodiments, the method comprises assessing the effect of a superficial temporal artery-middle cerebral artery bypass graft during or after neurovascular surgery, e.g., in a cerebral revascularization procedure. In certain embodiments, the method comprises identify the haptic segment and subsegment for anatomical hepatic resection during hepatobilliary surgery. In some embodiments, the method comprises imaging tissue or blood during a reconstructive surgery. In certain embodiments, the method comprises imaging tissue or blood during cholecystectomy or colorectal resection. In some embodiments, the method comprises intraoperatively identifying brain tumors such as malignant gliomas. In various embodiments, the method comprises a diagnostic imaging procedure. In some embodiments, the method comprises retinal angiography. In certain embodiments, the method comprises detecting or imaging chorioretinal vasculature. In some embodiments, the method comprises mapping and visualization of lymph nodes. In certain embodiments, the method comprises targeting and marking (e.g., visualizing or detecting) pre-cancerous tissue, cancerous lesions and/or assessment of tumor margins. In various embodiments, the pHLIP-fluorophore compound is administered by parenteral, local, or systemic administration. In certain embodiments, a pHLIP-fluorophore compound is administered by intravenous, intraarterial, intraperitoneal, intracerebral, intracerebroventricular, intrathecal, intracardiac, intracavemous, intraosseous, intraocular, or intravitreal administration. In various embodiments, pHLIP-fluorophore compound is administered by intramuscular, intradermal, transdermal, transmucosal, intralesional, subcutaneous, topical, epicutaneous, extra-amniotic, intravaginal, intravesical, nasal, or oral administration. In an aspect, provided herein is a method for the ex vivo staining of human specimens and ex vivo diagnostics, comprising (a) contacting a biological sample from a subject with a pHLIP-fluorophore compound comprising a fluorophore (such as ICG) disclosed herein; (b) contacting the biological sample with electromagnetic radiation comprising an excitation wavelength of the fluorophore; and (c) detecting electromagnetic radiation emitted from the pHLIP-fluorophore compound. In embodiments, the biological sample comprises a biopsy specimen, a liquid biopsy specimen, surgically removed tissue, a surgically removed liquid, or blood. In some embodiments, the pHLIP peptide comprises a sequence of at least 8 to 25 consecutive amino acids (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 consecutive amino acids) that is present in any one of the following sequences: (SEQ ID NO: 36) WARYADWLFTTPLLLLDLALL, (SEQ ID NO: 37) YARYADWLFTTPLLLLDLALL, (SEQ ID NO: 38) WARYSDWLFTTPLLLYDLGLL, (SEQ ID NO: 39) WARYTDWFTTPLLLYDLALLA, (SEQ ID NO: 40) WARYTDWLFTTPLLLYDLGLL, (SEQ ID NO: 41) WARYADWLFTTPLLLLDLSLL, (SEQ ID NO: 42) LLALDLLLLPTTFLWDAYRAW, (SEQ ID NO: 43) LLALDLLLLPTTFLWDAYRAY, (SEQ ID NO: 44) LLGLDYLLLPTTFLWDSYRAW, (SEQ ID NO: 45) ALLALDYLLLPTTFWDTYRAW, (SEQ ID NO: 46) LLGLDYLLLPTTFLWDTYRAW, (SEQ ID NO: 47) LLSLDLLLLPTTFLWDAYRAW, (SEQ ID NO: 48) GLAGLLGLEGLLGLPLGLLEGLWLGL, (SEQ ID NO: 49) LGLWLGELLGLPLGLLGELGLLGALG, (SEQ ID NO: 50) WRAYLDLLFPTDTLLLDLLW, (SEQ ID NO: 51) WLLDLLLTDTPFLLDLYARW, (SEQ ID NO: 52) WARYLEWLFPTETLLLEL, (SEQ ID NO: 53) WAQYLELLFPTETLLLEW, (SEQ ID NO: 54) LELLLTETPFLWELYRAW, (SEQ ID NO: 55) WELLLTETPFLLELYQAW, (SEQ ID NO: 56) WLFTTPLLLLNGALLVE, (SEQ ID NO: 57) WLFTTPLLLLPGALLVE, (SEQ ID NO: 58) WARYADLLFPTTLAW, (SEQ ID NO: 59) EVLLAGNLLLLPTTFLW, (SEQ ID NO: 60) EVLLAGPLLLLPTTFLW, (SEQ ID NO: 61) WALTTPFLLDAYRAW, (SEQ ID NO: 62) NLEGFFATLGGEIALWSLVVLAIE, (SEQ ID NO: 63) EGFFATLGGEIALWSDVVLAIE, (SEQ ID NO: 64) EGFFATLGGEIPLWSDVVLAIE, (SEQ ID NO: 65) EIALVVLSWLAIEGGLTAFFGELN, (SEQ ID NO: 66) EIALVVDSWLAIEGGLTAFFGE, (SEQ ID NO: 67) EIALVVDSWLPIEGGLTAFFGE, (SEQ ID NO: 68) ILDLVFGLLFAVTSVDFLVQW, and (SEQ ID NO: 69) WQVLFDVSTVAFLLGFVLDLI. In embodiments, the pHLIP peptide comprises the amino acid sequence WRAYLDLLFPTDTLLLDLLW (SEQ ID NO: 50) with additional amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids) optionally added to either side. In certain embodiments, the pHLIP peptide has the sequence: (SEQ ID NO: 70) WARYADWLFTTPLLLLDLALL, (SEQ ID NO: 71) YARYADWLFTTPLLLLDLALL, (SEQ ID NO: 72) WARYSDWLFTTPLLLYDLGLL, (SEQ ID NO: 73) WARYTDWFTTPLLLYDLALLA, (SEQ ID NO: 74) WARYTDWLFTTPLLLYDLGLL, (SEQ ID NO: 75) WARYADWLFTTPLLLLDLSLL, (SEQ ID NO: 76) LLALDLLLLPTTFLWDAYRAW, (SEQ ID NO: 77) LLALDLLLLPTTFLWDAYRAY, (SEQ ID NO: 78) LLGLDYLLLPTTFLWDSYRAW, (SEQ ID NO: 79) ALLALDYLLLPTTFWDTYRAW, (SEQ ID NO: 80) LLGLDYLLLPTTFLWDTYRAW, (SEQ ID NO: 81) LLSLDLLLLPTTFLWDAYRAW, (SEQ ID NO: 82) GLAGLLGLEGLLGLPLGLLEGLWLGL, (SEQ ID NO: 83) LGLWLGELLGLPLGLLGELGLLGALG, (SEQ ID NO: 84) WRAYLDLLFPTDTLLLDLLW, (SEQ ID NO: 85) WLLDLLLTDTPFLLDLYARW, (SEQ ID NO: 86) WARYLEWLFPTETLLLEL, (SEQ ID NO: 87) WAQYLELLFPTETLLLEW, (SEQ ID NO: 88) LELLLTETPFLWELYRAW, (SEQ ID NO: 89) WELLLTETPFLLELYQAW, (SEQ ID NO: 90) WLFTTPLLLLNGALLVE, (SEQ ID NO: 91) WLFTTPLLLLPGALLVE, (SEQ ID NO: 92) WARYADLLFPTTLAW, (SEQ ID NO: 93) EVLLAGNLLLLPTTFLW, (SEQ ID NO: 94) EVLLAGPLLLLPTTFLW, (SEQ ID NO: 95) WALTTPFLLDAYRAW, (SEQ ID NO: 96) NLEGFFATLGGEIALWSLVVLAIE, (SEQ ID NO: 97) EGFFATLGGEIALWSDVVLAIE, (SEQ ID NO: 98) EGFFATLGGEIPLWSDVVLAIE, (SEQ ID NO: 99) EIALVVLSWLAIEGGLTAFFGELN, (SEQ ID NO: 100) EIALVVDSWLAIEGGLTAFFGE, (SEQ ID NO: 101) EIALVVDSWLPIEGGLTAFFGE, (SEQ ID NO: 102) ILDLVFGLLFAVTSVDFLVQW, or (SEQ ID NO: 103) WQVLFDVSTVAFLLGFVLDLI. In various embodiments, the pHLIP peptide comprises the sequence of at least 8 to 25 consecutive amino acids (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 consecutive amino acids) that is present in any one of the following sequences: (SEQ ID NO: 104) WARYAXWLFTTPLLLLXLALL, (SEQ ID NO: 105) YARYAXWLFTTPLLLLXLALL, (SEQ ID NO: 106) WARYSXWLFTTPLLLYXLGLL, (SEQ ID NO: 107) WARYTXWFTTPLLLYXLALLA, (SEQ ID NO: 108) WARYTXWLFTTPLLLYXLGLL, (SEQ ID NO: 109) WARYAXWLFTTPLLLLXLSLL, (SEQ ID NO: 110) LLALXLLLLPTTFLWXAYRAW, (SEQ ID NO: 111) LLALXLLLLPTTFLWXAYRAY, (SEQ ID NO: 112) LLGLXYLLLPTTFLWXSYRAW, (SEQ ID NO: 113) ALLALXYLLLPTTFWXTYRAW, (SEQ ID NO: 114) LLGLXYLLLPTTFLWXTYRAW, (SEQ ID NO: 115) LLSLXLLLLPTTFLWXAYRAW, (SEQ ID NO: 116) GLAGLLGLXGLLGLPLGLLXGLWLGL, (SEQ ID NO: 117) LGLWLGXLLGLPLGLLGXLGLLGALG, (SEQ ID NO: 118) WRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 119) WLLXLLLTXTPFLLXLYARW, (SEQ ID NO: 120) WARYLXWLFPTXTLLLXL, (SEQ ID NO: 121) WAQYLXLLFPTXTLLLXW, (SEQ ID NO: 122) LXLLLTXTPFLWXLYRAW, (SEQ ID NO: 123) WXLLLTXTPFLLXLYQAW, (SEQ ID NO: 124) WLFTTPLLLLNGALLVX, (SEQ ID NO: 125) WLFTTPLLLLPGALLVX, (SEQ ID NO: 126) WARYAXLLFPTTLAW, (SEQ ID NO: 127) XVLLAGNLLLLPTTFLW, (SEQ ID NO: 128) XVLLAGPLLLLPTTFLW, (SEQ ID NO: 129) WALTTPFLLXAYRAW, (SEQ ID NO: 130) NLXGFFATLGGXIALWSLVVLAIX, (SEQ ID NO: 131) XGFFATLGGXIALWSXVVLAIX, (SEQ ID NO: 132) XGFFATLGGXIPLWSXVVLAIX, (SEQ ID NO: 133) XIALVVLSWLAIXGGLTAFFGXLN, (SEQ ID NO: 134) XIALVVXSWLAIXGGLTAFFGX, (SEQ ID NO: 135) XIALVVXSWLPIXGGLTAFFGX, (SEQ ID NO: 136) ILXLVFGLLFAVTSVXFLVQW, and (SEQ ID NO: 137) WQVLFXVSTVAFLLGFVLXLI, wherein each X is, individually, D, E, Gla, or Aad. In some embodiments, the pHLIP peptide comprises the sequence: (SEQ ID NO: 138) WARYAXWLFTTPLLLLXLALL, (SEQ ID NO: 139) YARYAXWLFTTPLLLLXLALL, (SEQ ID NO: 140) WARYSXWLFTTPLLLYXLGLL, (SEQ ID NO: 141) WARYTXWFTTPLLLYXLALLA, (SEQ ID NO: 142) WARYTXWLFTTPLLLYXLGLL, (SEQ ID NO: 143) WARYAXWLFTTPLLLLXLSLL, (SEQ ID NO: 144) LLALXLLLLPTTFLWXAYRAW, (SEQ ID NO: 145) LLALXLLLLPTTFLWXAYRAY, (SEQ ID NO: 146) LLGLXYLLLPTTFLWXSYRAW, (SEQ ID NO: 147) ALLALXYLLLPTTFWXTYRAW, (SEQ ID NO: 148) LLGLXYLLLPTTFLWXTYRAW, (SEQ ID NO: 149) LLSLXLLLLPTTFLWXAYRAW, (SEQ ID NO: 150) GLAGLLGLXGLLGLPLGLLXGLWLGL, (SEQ ID NO: 151) LGLWLGXLLGLPLGLLGXLGLLGALG, (SEQ ID NO: 152) WRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 153) WLLXLLLTXTPFLLXLYARW, (SEQ ID NO: 154) WARYLXWLFPTXTLLLXL, (SEQ ID NO: 155) WAQYLXLLFPTXTLLLXW, (SEQ ID NO: 156) LXLLLTXTPFLWXLYRAW, (SEQ ID NO: 157) WXLLLTXTPFLLXLYQAW, (SEQ ID NO: 158) WLFTTPLLLLNGALLVX, (SEQ ID NO: 159) WLFTTPLLLLPGALLVX, (SEQ ID NO: 160) WARYAXLLFPTTLAW, (SEQ ID NO: 161) XVLLAGNLLLLPTTFLW, (SEQ ID NO: 162) XVLLAGPLLLLPTTFLW, (SEQ ID NO: 163) WALTTPFLLXAYRAW, (SEQ ID NO: 164) NLXGFFATLGGXIALWSLVVLAIX, (SEQ ID NO: 165) XGFFATLGGXIALWSXVVLAIX, (SEQ ID NO: 166) XGFFATLGGXIPLWSXVVLAIX, (SEQ ID NO: 167) XIALVVLSWLAIXGGLTAFFGXLN, (SEQ ID NO: 168) XIALVVXSWLAIXGGLTAFFGX, (SEQ ID NO: 169) XIALVVXSWLPIXGGLTAFFGX, (SEQ ID NO: 170) ILXLVFGLLFAVTSVXFLVQW, or (SEQ ID NO: 171) WQVLFXVSTVAFLLGFVLXLI, wherein each X is, individually, D, E, Gla, or Aad. In certain embodiments, the pHLIP peptide comprises the sequence of at least 8 to 25 consecutive amino acids (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 consecutive amino acids) that is present in any one of the following sequences: (SEQ ID NO: 447) X 2 X 2 RX 2 X 2 X 1 X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 , (SEQ ID NO: 448) X 2 X 2 RX 2 X 3 X 1 X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 X 2 X 2 X 1 X 2 GX 2 X 2 , (SEQ ID NO: 449) X 2 X 2 RX 2 X 3 X 1 X 2 X 2 X 3 X 3 X 2 X 2 X 2 X 2 X2X 1 X 2 X 2 X 2 X 2 X 2 , (SEQ ID NO: 450) X 2 X 2 RX 2 X 2 X 1 X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 3 X 2 X 2 , (SEQ ID NO: 451) X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 X 1 X 2 X 2 RX 2 X 2 , (SEQ ID NO: 452) X 2 X 2 GX 2 X 1 X 2 X 2 X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 X 1 X 3 X 2 RX 2 X 2 , (SEQ ID NO: 453) X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 1 X 3 X 2 RX 2 X 2 , (SEQ ID NO: 454) X 2 X 2 X 3 X 2 X 1 X 2 X 2 X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 X 1 X 2 X 2 RX 2 X 2 , (SEQ ID NO: 455) GX 2 X 2 GX 2 X 2 GX 2 X 1 GX 2 X 2 GX 2 X 2 X 2 GX 2 X 2 X 1 GX 2 X 2 X 2 GX 2 , (SEQ ID NO: 456) X 2 GX 2 X 2 X 2 GX 1 X 2 X 2 GX 2 X 2 X 2 GX 2 X 2 GX 1 X 2 GX 2 X 2 GX 2 X 2 G, (SEQ ID NO: 457) X 2 RX 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 3 X 1 X 3 X 2 X 2 X 2 X 1 X 2 X 2 X 2 , (SEQ ID NO: 458) X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 3 X 1 X 3 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 RX 2 , (SEQ ID NO: 459) X 2 X 2 RX 2 X 2 X 1 X 2 X 2 X 2 X 2 X 3 X 1 X 3 X 2 X 2 X 2 XX 2 , (SEQ ID NO: 460) X 2 X 2 QX 2 X 2 X 1 X 2 X 2 X 2 X 2 X 3 X 1 X 3 X 2 X 2 X 2 X 1 X 2 , (SEQ ID NO: 461) X 2 X 1 X 2 X 2 X 2 X 3 X 1 X 3 X 2 X 2 X 2 X 2 X 1 X 2 X 2 RX 2 X 2 , (SEQ ID NO: 462) X 2 X 1 X 2 X 2 X 2 X 3 X 1 X 3 X 2 X 2 X 2 X 2 X 1 X 2 X 2 QX 2 X 2 , (SEQ ID NO: 463) X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 X 2 X 2 NGX 2 X 2 X 2 X 2 X 1 , (SEQ ID NO: 464) X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 X 2 X 2 X 2 GX 2 X 2 X 2 X 2 X 1 , (SEQ ID NO: 465) X 2 X 2 RX 2 X 2 X 1 X 2 X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 , (SEQ ID NO: 466) X 1 X 2 X 2 X 2 X 2 GNX 2 X 2 X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 , (SEQ ID NO: 467) X 1 X 2 X 2 X 2 X 2 GX 2 X 2 X 2 X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 , (SEQ ID NO: 468) X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 X 2 X 1 X 2 X 2 RX 2 X 2 , (SEQ ID NO: 469) GNX 2 X 1 GX 2 X 2 X 2 X 3 X 2 GGX 1 X 2 X 2 X 2 X 2 X 3 X 2 X 2 X 2 X 2 X 2 X 2 X 1 , (SEQ ID NO: 470) X 1 GX 2 X 2 X 2 X 3 X 2 GGX 1 X 2 X 2 X 2 X 2 X 3 X 1 X 2 X 2 X 2 X 2 X 2 X 1 , (SEQ ID NO: 471) X 1 GX 2 X 2 X 2 X 3 X 2 GGX 1 X 2 X 2 X 2 X 2 X 3 X 1 X 2 X 2 X 2 X 2 X 2 X 1 , (SEQ ID NO: 472) X 1 X 2 X 2 X 2 X 2 X 2 X 2 X 3 X 2 X 2 X 2 X 2 X 1 GGX 2 X 3 X 2 X 2 X 2 GX 1 X 2 NG, (SEQ ID NO: 473) X 1 X 2 X 2 X 2 X 2 X 2 X 1 X 3 X 2 X 2 X 2 X 2 X 1 GGX 2 X 3 X 2 X 2 X 2 GX 1 , (SEQ ID NO: 474) X 1 X 2 X 2 X 2 X 2 X 2 X 1 X 3 X 2 X 2 X 2 X 2 X 1 GGX 2 X 3 X 2 X 2 X 2 GX 1 , (SEQ ID NO: 475) X 2 X 2 X 1 X 2 X 2 X 2 GX 2 X 2 X 2 X 2 X 2 X 3 X 3 X 2 X 1 X 2 X 2 X 2 QX 2 , and (SEQ ID NO: 476) X 2 QX 2 X 2 X 2 X 1 X 2 X 3 X 3 X 2 X 2 X 2 X 2 X 2 GX 2 X 2 X 2 X 1 X 2 X 2 , wherein each X 1 is, individually, D, E, Gla, or Aad, each X 2 is, individually, A, I, L, M, F, P, W, Y, V, or G and each X 3 is, individually, S, T, or G. In various embodiments, the pHLIP peptide comprises the sequence: (SEQ ID NO: 477) X 2 X 2 RX 2 X 2 X 1 X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 , (SEQ ID NO: 478) X 2 X 2 RX 2 X 3 X 1 X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 X 2 X2X 1 X 2 GX 2 X 2 , (SEQ ID NO: 479) X 2 X 2 RX 2 X 3 X 1 X 2 X 2 X 3 X 3 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 2 , (SEQ ID NO: 480) X 2 X 2 RX 2 X 2 X 1 X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 3 X 2 X 2 , (SEQ ID NO: 481) X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 X 1 X 2 X 2 RX 2 X 2 , (SEQ ID NO: 482) X 2 X 2 GX 2 X 1 X 2 X 2 X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 X 1 X 3 X 2 RX 2 X 2 , (SEQ ID NO: 483) X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 1 X 3 X 2 RX 2 X 2 , (SEQ ID NO: 484) X 2 X 2 X 3 X 2 X 1 X 2 X 2 X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 X 1 X 2 X 2 RX 2 X 2 , (SEQ ID NO: 485) GX 2 X 2 GX 2 X 2 GX 2 X 1 GX 2 X 2 GX 2 X 2 X 2 GX 2 X 2 X 1 GX 2 X 2 X 2 GX 2 , (SEQ ID NO: 486) X 2 GX 2 X 2 X 2 GX 1 X 2 X 2 GX 2 X 2 X 2 GX 2 X 2 GX 1 X 2 GX 2 X 2 GX 2 X 2 G, (SEQ ID NO: 487) X 2 RX 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 3 X 1 X 3 X 2 X 2 X 2 X 1 X 2 X 2 X 2 , (SEQ ID NO: 488) X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 3 X 1 X 3 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 RX 2 , (SEQ ID NO: 489) X 2 X 2 RX 2 X 2 X 1 X 2 X 2 X 2 X 2 X 3 X 1 X 3 X 2 X 2 X 2 XX 2 , (SEQ ID NO: 490) X 2 X 2 QX 2 X 2 X 1 X 2 X 2 X 2 X 2 X 3 X 1 X 3 X 2 X 2 X 2 X 1 X 2 , (SEQ ID NO: 491) X 2 X 1 X 2 X 2 X 2 X 3 X 1 X 3 X 2 X 2 X 2 X 2 X 1 X 2 X 2 RX 2 X 2 , (SEQ ID NO: 492) X 2 X 1 X 2 X 2 X 2 X 3 X 1 X 3 X 2 X 2 X 2 X 2 X 1 X 2 X 2 QX 2 X 2 , (SEQ ID NO: 493) X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 X 2 X 2 NGX 2 X 2 X 2 X 2 X 1 , (SEQ ID NO: 494) X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 X 2 X 2 X 2 GX 2 X 2 X 2 X 2 X 1 , (SEQ ID NO: 495) X 2 X 2 RX 2 X 2 X 1 X 2 X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 , (SEQ ID NO: 496) X 1 X 2 X 2 X 2 X 2 GNX 2 X 2 X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 , (SEQ ID NO: 497) X 1 X 2 X 2 X 2 X 2 GX 2 X 2 X 2 X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 , (SEQ ID NO: 498) X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 X 2 X 1 X 2 X 2 RX 2 X 2 , (SEQ ID NO: 499) GNX 2 X 1 GX 2 X 2 X 2 X 3 X 2 GGX 1 X 2 X 2 X 2 X 2 X 3 X 2 X 2 X 2 X 2 X 2 X 2 X 1 , (SEQ ID NO: 500) X 1 GX 2 X 2 X 2 X 3 X 2 GGX 1 X 2 X 2 X 2 X 2 X 3 X 1 X 2 X 2 X 2 X 2 X 2 X 1 , (SEQ ID NO: 501) X 1 GX 2 X 2 X 2 X 3 X 2 GGX 1 X 2 X 2 X 2 X 2 X 3 X 1 X 2 X 2 X 2 X 2 X 2 X 1 , (SEQ ID NO: 502) X 1 X 2 X 2 X 2 X 2 X 2 X 2 X 3 X 2 X 2 X 2 X 2 X 1 GGX 2 X 3 X 2 X 2 X 2 GX 1 X 2 NG, (SEQ ID NO: 503) X 1 X 2 X 2 X 2 X 2 X 2 X 1 X 3 X 2 X 2 X 2 X 2 X 1 GGX 2 X 3 X 2 X 2 X 2 GX 1 , (SEQ ID NO: 504) X 1 X 2 X 2 X 2 X 2 X 2 X 1 X 3 X 2 X 2 X 2 X 2 X 1 GGX 2 X 3 X 2 X 2 X 2 GX 1 , (SEQ ID NO: 505) X 2 X 2 X 1 X 2 X 2 X 2 GX 2 X 2 X 2 X 2 X 2 X 3 X 3 X 2 X 1 X 2 X 2 X 2 QX 2 , and (SEQ ID NO: 506) X 2 QX 2 X 2 X 2 X 1 X 2 X 3 X 3 X 2 X 2 X 2 X 2 X 2 GX 2 X 2 X 2 X 1 X 2 X 2 , wherein each X 1 is, individually, D, E, Gla, or Aad, each X 2 is, individually, A, I, L, M, F, P, W, Y, V, or G, and each X 3 is, individually, S, T, or G. In some embodiments, the pHLIP peptide comprises a sequence of at least 8 to 25 consecutive amino acids (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 consecutive amino acids) that is present in any one of the following sequences: (SEQ ID NO: 172) AEQNPIYWARYAEWLFTTPLLLLELALLVEAEET, (SEQ ID NO: 173) ADDQNPWRAYLDLLFPDTTDLLLLDLLWDADET, (SEQ ID NO: 174) AEEQNPWRAYLELLFPETTELLLLELLWEAEET, (SEQ ID NO: 175) AEQNPIYWARYA Gla WLFTTPLLLL Gla LALLVDADET, (SEQ ID NO: 176) AEQNPIYWARYA Aad WLFTTPLLLL Aad LALLVDADET, (SEQ ID NO: 177) AEQNPIYWARYA Aad WLFTTPLLLL Gla LALLVDADET, (SEQ ID NO: 178) CEQNPIYWARYADWHFTTPLLLLDLALLVDADE, (SEQ ID NO: 179) ADNNPWIYARYADLTTFPLLLLDLALLVDFDD, (SEQ ID NO: 180) ADNNPFIYARYADLTTWPLLLLDLALLVDFDD, (SEQ ID NO: 181) ADNNPFIYARYADLTTFPLLLLDLALLVDWDD, (SEQ ID NO: 182) ADNNPFPYARYADLTTWILLLLDLALLVDFDD, (SEQ ID NO: 183) ADNNPFIYAYRADLTTFPLLLLDLALLVDWDD, (SEQ ID NO: 184) ADNNPFIYATYADLRTFPLLLLDLALLVDWDD, (SEQ ID NO: 185) ADDQNPWRAYLDLLFPTDTLLLDLLWDADE, (SEQ ID NO: 186) ADDQNPWRAYL Gla LLFPTDTLLLDLLW, (SEQ ID NO: 187) ADDQNPWRAYLDLLFPT Gla TLLLDLLW, (SEQ ID NO: 188) ADDQNPWRAYLDLLFPTDTLLL Gla LLW, (SEQ ID NO: 189) ADDQNPWRAYL Gla LLFPT Gla TLLLDLLW, (SEQ ID NO: 190) ADDQNPWRAYL Gla LLFPTDTLLL Gla LLW, (SEQ ID NO: 191) ADDQNPWRAYLDLLFPT Gla TLLL Gla LLW, (SEQ ID NO: 192) ADDQNPWRAYL Gla LLFPT Gla TLLL Gla LLW, (SEQ ID NO: 193) ADDQNPWRAYL Aad LLFPTDTLLLDLLW, (SEQ ID NO: 194) ADDQNPWRAYLDLLFPT Aad TLLLDLLW, (SEQ ID NO: 195) ADDQNPWRAYLDLLFPTDTLLL Aad LLW, (SEQ ID NO: 196) ADDQNPWRAYL Aad LLFPT Aad TLLLDLLW, (SEQ ID NO: 197) ADDQNPWRAYL Aad LLFPTDTLLL Aad LLW, (SEQ ID NO: 198) ADDQNPWRAYLDLLFPT Aad TLLL Aad LLW, (SEQ ID NO: 199) ADDQNPWRAYL Aad LLFPT Aad TLLL Aad LLW, (SEQ ID NO: 200) ADDQNPWRAYL Gla LLFPT Aad TLLLDLLW, (SEQ ID NO: 201) ADDQNPWRAYL Gla LLFPTDTLLL Aad LLW, (SEQ ID NO: 202) ADDQNPWRAYL Gla LLFPT Gla TLLL Aad LLW, (SEQ ID NO: 203) ADDQNPWRAYL Aad LLFPT Gla TLLLDLLW, (SEQ ID NO: 204) ADDQNPWRAYL Aad LLFPTDTLLL Gla LLW, (SEQ ID NO: 205) ADDQNPWRAYL Gla LLFPT Aad TLLL Gla LLW, (SEQ ID NO: 206) GEEQNPWLGAYLDLLFPLELLGLLELGLW, (SEQ ID NO: 207) EQNPIYILDLVFGLLFAVTSVDFLVQWDDAGD, (SEQ ID NO: 208) NNEGFFATLGGEIALWSDVVLAIE, and (SEQ ID NO: 209) DNNEGFFATLGGEIPLWSDVVLAIE. In certain embodiments, the pHLIP peptide comprises the sequence: (SEQ ID NO: 210) AEQNPIYWARYAEWLFTTPLLLLELALLVEAEET, (SEQ ID NO: 211) ADDQNPWRAYLDLLFPDTTDLLLLDLLWDADET, (SEQ ID NO: 212) AEEQNPWRAYLELLFPETTELLLLELLWEAEET, (SEQ ID NO: 213) AEQNPIYWARYA Gla WLFTTPLLLL Gla LALLVDADET, (SEQ ID NO: 214) AEQNPIYWARYA Aad WLFTTPLLLL Aad LALLVDADET, (SEQ ID NO: 215) AEQNPIYWARYA Aad WLFTTPLLLL Gla LALLVDADET, (SEQ ID NO: 216) CEQNPIYWARYADWHFTTPLLLLDLALLVDADE, (SEQ ID NO: 217) ADNNPWIYARYADLTTFPLLLLDLALLVDFDD, (SEQ ID NO: 218) ADNNPFIYARYADLTTWPLLLLDLALLVDFDD, (SEQ ID NO: 219) ADNNPFIYARYADLTTFPLLLLDLALLVDWDD, (SEQ ID NO: 220) ADNNPFPYARYADLTTWILLLLDLALLVDFDD, (SEQ ID NO: 221) ADNNPFIYAYRADLTTFPLLLLDLALLVDWDD, (SEQ ID NO: 222) ADNNPFIYATYADLRTFPLLLLDLALLVDWDD, (SEQ ID NO: 223) ADDQNPWRAYLDLLFPTDTLLLDLLWDADE, (SEQ ID NO: 224) ADDQNPWRAYL Gla LLFPTDTLLLDLLW, (SEQ ID NO: 225) ADDQNPWRAYLDLLFPT Gla TLLLDLLW, (SEQ ID NO: 226) ADDQNPWRAYLDLLFPTDTLLL Gla LLW, (SEQ ID NO: 227) ADDQNPWRAYL Gla LLFPT Gla TLLLDLLW, (SEQ ID NO: 228) ADDQNPWRAYL Gla LLFPTDTLLL Gla LLW, (SEQ ID NO: 229) ADDQNPWRAYLDLLFPT Gla TLLL Gla LLW, (SEQ ID NO: 230) ADDQNPWRAYL Gla LLFPT Gla TLLL Gla LLW, (SEQ ID NO: 231) ADDQNPWRAYL Aad LLFPTDTLLLDLLW, (SEQ ID NO: 232) ADDQNPWRAYLDLLFPT Aad TLLLDLLW, (SEQ ID NO: 233) ADDQNPWRAYLDLLFPTDTLLL Aad LLW, (SEQ ID NO: 234) ADDQNPWRAYL Aad LLFPT Aad TLLLDLLW, (SEQ ID NO: 235) ADDQNPWRAYL Aad LLFPTDTLLL Aad LLW, (SEQ ID NO: 236) ADDQNPWRAYLDLLFPT Aad TLLL Aad LLW, (SEQ ID NO: 237) ADDQNPWRAYL Aad LLFPT Aad TLLL Aad LLW, (SEQ ID NO: 238) ADDQNPWRAYL Gla LLFPT Aad TLLLDLLW, (SEQ ID NO: 239) ADDQNPWRAYL Gla LLFPTDTLLL Aad LLW, (SEQ ID NO: 240) ADDQNPWRAYL Gla LLFPT Gla TLLL Aad LLW, (SEQ ID NO: 241) ADDQNPWRAYL Aad LLFPT Gla TLLLDLLW, (SEQ ID NO: 242) ADDQNPWRAYL Aad LLFPTDTLLL Gla LLW, (SEQ ID NO: 243) ADDQNPWRAYL Gla LLFPT Aad TLLL Gla LLW, (SEQ ID NO: 244) GEEQNPWLGAYLDLLFPLELLGLLELGLW, (SEQ ID NO: 245) EQNPIYILDLVFGLLFAVTSVDFLVQWDDAGD, (SEQ ID NO: 246) NNEGFFATLGGEIALWSDVVLAIE, or (SEQ ID NO: 247) DNNEGFFATLGGEIPLWSDVVLAIE. In various embodiments, the pHLIP peptide comprises the sequence of at least 8 to 25 consecutive amino acids (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 consecutive amino acids) that is present in any one of the following sequences: (SEQ ID NO: 248) AXQNPIYWARYAXWLFTTPLLLLXLALLVXAXXT (SEQ ID NO: 249) AXXQNPWRAYLXLLFPXTTXLLLLXLLWXAXXT, (SEQ ID NO: 250) AXXQNPWRAYLXLLFPXTTXLLLLXLLWXAXXT, (SEQ ID NO: 251) AXQNPIYWARYAXWLFTTPLLLLXLALLVXAXXT, (SEQ ID NO: 252) AXQNPIYWARYAXWLFTTPLLLLXLALLVXAXXT, (SEQ ID NO: 253) AXQNPIYWARYAXWLFTTPLLLLXLALLVXAXXT, (SEQ ID NO: 254) CXQNPIYWARYAXWHFTTPLLLLXLALLVXAXX, (SEQ ID NO: 255) AXNNPWIYARYAXLTTFPLLLLXLALLVXFXX, (SEQ ID NO: 256) AXNNPFIYARYAXLTTWPLLLLXLALLVXFXX, (SEQ ID NO: 257) AXNNPFIYARYAXLTTFPLLLLXLALLVXWXX, (SEQ ID NO: 258) AXNNPFPYARYAXLTTWILLLLXLALLVXFXX, (SEQ ID NO: 259) AXNNPFIYAYRAXLTTFPLLLLXLALLVXWXX, (SEQ ID NO: 260) AXNNPFIYATYAXLRTFPLLLLXLALLVXWXX, (SEQ ID NO: 261) AXXQNPWRAYLXLLFPTXTLLLXLLWXAXX, (SEQ ID NO: 262) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 263) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 264) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 265) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 266) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 267) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 268) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 269) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 270) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 271) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 272) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 273) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 274) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 275) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 276) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 277) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 278) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 279) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 280) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 281) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 282) GXXQNPWLGAYLXLLFPLXLLGLLXLGLW, (SEQ ID NO: 283) XQNPIYILXLVFGLLFAVTSVXFLVQWXXAGX, (SEQ ID NO: 284) NNXGFFATLGGXIALWSXVVLAIX, and (SEQ ID NO: 285) XNNXGFFATLGGXIPLWSXVVLAIX, wherein each X is, individually, D, E, Gla, or Aad. In some embodiments, the pHLIP peptide comprises the sequence: (SEQ ID NO: 286) AXQNPIYWARYAXWLFTTPLLLLXLALLVXAXXT, (SEQ ID NO: 287) AXXQNPWRAYLXLLFPXTTXLLLLXLLWXAXXT, (SEQ ID NO: 288) AXXQNPWRAYLXLLFPXTTXLLLLXLLWXAXXT, (SEQ ID NO: 289) AXQNPIYWARYAXWLFTTPLLLLXLALLVXAXXT, (SEQ ID NO: 290) AXQNPIYWARYAXWLFTTPLLLLXLALLVXAXXT, (SEQ ID NO: 291) AXQNPIYWARYAXWLFTTPLLLLXLALLVXAXXT, (SEQ ID NO: 292) CXQNPIYWARYAXWHFTTPLLLLXLALLVXAXX, (SEQ ID NO: 293) AXNNPWIYARYAXLTTFPLLLLXLALLVXFXX, (SEQ ID NO: 294) AXNNPFIYARYAXLTTWPLLLLXLALLVXFXX, (SEQ ID NO: 295) AXNNPFIYARYAXLTTFPLLLLXLALLVXWXX, (SEQ ID NO: 296) AXNNPFPYARYAXLTTWILLLLXLALLVXFXX, (SEQ ID NO: 297) AXNNPFIYAYRAXLTTFPLLLLXLALLVXWXX, (SEQ ID NO: 298) AXNNPFIYATYAXLRTFPLLLLXLALLVXWXX, (SEQ ID NO: 299) AXXQNPWRAYLXLLFPTXTLLLXLLWXAXX, (SEQ ID NO: 300) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 301) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 302) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 303) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 304) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 305) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 306) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 307) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 308) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 309) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 310) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 311) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 312) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 313) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 314) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 315) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 316) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 317) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 318) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 319) AXXQNPWRAYLXLLFPTXTLLLXLLW, (SEQ ID NO: 320) GXXQNPWLGAYLXLLFPLXLLGLLXLGLW, (SEQ ID NO: 321) XQNPIYILXLVFGLLFAVTSVXFLVQWXXAGX, (SEQ ID NO: 322) NNXGFFATLGGXIALWSXVVLAIX, or (SEQ ID NO: 323) XNNXGFFATLGGXIPLWSXVVLAIX, wherein each X is, individually, D, E, Gla, or Aad. In certain embodiments, the pHLIP peptide comprises the sequence of at least 8 to 25 consecutive amino acids (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 consecutive amino acids) that is present in any one of the following sequences: (SEQ ID NO: 507) X 2 X 1 QNX 2 X 2 X 2 X 2 X 2 RX 2 X 2 X 1 X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 1 X 1 X 3 , (SEQ ID NO: 508) X 2 X 1 X 1 QNX 2 X 2 RX 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 1 X 3 X 3 X 1 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 1 X 2 X 1 X 1 X 3 , (SEQ ID NO: 509) CX 1 QNX 2 X 2 X 2 X 2 X 2 RX 2 X 2 X 1 X 2 HX 2 X 3 X 3 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 1 X 1 , (SEQ ID NO: 510) X 2 X 1 NNX 2 X 2 X 2 X 2 X 2 RX 2 X 2 X 1 X 2 X 3 X 3 X 2 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 1 X 1 , (SEQ ID NO: 511) X 2 X 1 NNX 2 X 2 X 2 X 2 X 2 X 2 RX 2 X 1 X 2 X 3 X 3 X 2 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 1 X 1 , (SEQ ID NO: 512) X 2 X 1 NNX 2 X 2 X 2 X 2 X 2 X 3 X 2 X 2 X 1 X 2 RX 3 X 2 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 1 X 1 , (SEQ ID NO: 513) X 2 X 1 X 1 QNX 2 X 2 RX 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 3 X 1 X 3 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 1 X 2 X 1 X 1 , (SEQ ID NO: 514) X 2 X 1 X 1 QNX 2 X 2 RX 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 3 X 1 X 3 X 2 X 2 X 2 X 1 X 2 X 2 X 2 , (SEQ ID NO: 515) X 2 X 1 X 1 QNX 2 X 2 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 , (SEQ ID NO: 516) X 1 QNX 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 2 X 2 X 2 X 2 X 2 X 3 X 3 X 2 X 1 X 2 X 2 X 2 QX 2 X 1 X 1 X 2 X 2 , (SEQ ID NO: 517) NNX 1 X 2 X 2 X 2 X 2 X 3 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 3 X 1 X 2 X 2 X 2 X 2 X 2 X 1 , and (SEQ ID NO: 518) X 1 NNX 1 X 2 X 2 X 2 X 2 X 3 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 3 X 1 X 2 X 2 X 2 X 2 X 2 X 1 , wherein each X 1 is, individually, D, E, Gla, or Aad, each X 2 is, individually, A, I, L, M, F, P, W, Y, V, or G and each X 3 is, individually, S, T, or G. In various embodiments, the pHLIP peptide comprises the sequence: (SEQ ID NO: 519) X 2 X 1 QNX 2 X 2 X 2 X 2 X 2 RX 2 X 2 X 1 X 2 X 2 X 2 X 3 X 3 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 1 X 1 X 3 , (SEQ ID NO: 520) X 2 X 1 X 1 QNX 2 X 2 RX 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 1 X 3 X 3 X 1 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 1 X 2 X 1 X 1 X 3 , (SEQ ID NO: 521) CX 1 QNX 2 X 2 X 2 X 2 X 2 RX 2 X 2 X 1 X 2 HX 2 X 3 X 3 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 1 X 1 , (SEQ ID NO: 522) X 2 X 1 NNX 2 X 2 X 2 X 2 X 2 RX 2 X 2 X 1 X 2 X 3 X 3 X 2 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 1 X 1 , (SEQ ID NO: 523) X 2 X 1 NNX 2 X 2 X 2 X 2 X 2 X 2 RX 2 X 1 X 2 X 3 X 3 X 2 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 1 X 1 , (SEQ ID NO: 524) X 2 X 1 NNX 2 X 2 X 2 X 2 X 2 X 3 X 2 X 2 X 1 X 2 RX 3 X 2 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 1 X 1 , (SEQ ID NO: 525) X 2 X 1 X 1 QNX 2 X 2 RX 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 3 X 1 X 3 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 1 X 2 X 1 X 1 , (SEQ ID NO: 526) X 2 X 1 X 1 QNX 2 X 2 RX 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 3 X 1 X 3 X 2 X 2 X 2 X 1 X 2 X 2 X 2 , (SEQ ID NO: 527) X 2 X 1 X 1 QNX 2 X 2 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 , (SEQ ID NO: 528) X 1 QNX 2 X 2 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 2 X 2 X 2 X 2 X 2 X 3 X 3 X 2 X 1 X 2 X 2 X 2 QX 2 X 1 X 1 X 2 X 2 , (SEQ ID NO: 529) NNX 1 X 2 X 2 X 2 X 2 X 3 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 3 X 1 X 2 X 2 X 2 X 2 X 2 X 1 , and (SEQ ID NO: 530) X 1 NNX 1 X 2 X 2 X 2 X 2 X 3 X 2 X 2 X 2 X 1 X 2 X 2 X 2 X 2 X 3 X 1 X 2 X 2 X 2 X 2 X 2 X 1 , wherein each X 1 is, individually, D, E, Gla, or Aad, each X 2 is, individually, A, I, L, M, F, P, W, Y, V, or G and each X 3 is, individually, S, T, or G. In some embodiments, a pHLIP peptide comprises at least 8 consecutive amino acids, wherein (i) at least 4 of the 8 consecutive amino acids are non-polar amino acids, (ii) at least 1 of the at least 8 consecutive amino acids is protonatable, and (iii) the at least 8 consecutive amino acids comprise 8 consecutive amino acids in a sequence that is identical to a sequence of 8 consecutive amino acids that occurs in a naturally occurring human protein. In certain embodiments, the pHLIP peptide has higher affinity for a membrane lipid bilayer at pH 5.0, 5.5, 6, 6.0, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0 compared to the affinity at pH 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0. In various embodiments, the at least 8 consecutive amino acids comprise a sequence that is at least 85%, 90%, or 95% identical to (e.g., is 100% identical to) (i) a sequence of at least 8 consecutive amino acids that occurs in a naturally occurring human protein; or (ii) the reverse of a sequence of at least 8 consecutive amino acids that occurs in a naturally occurring human protein. In some embodiments, the naturally occurring human protein is a human rhodopsin protein. In certain embodiments, the of 8 consecutive amino acids that occurs in the human rhodopsin protein are within the following sequence: NLEGFFATLGGEIALWSLVVLAIE (SEQ ID NO: 531). The reverse of this sequence is EIALVVLSWLAIEGGLTAFFGELN (SEQ ID NO: 532). In various embodiments, the sequence of the pHLIP peptide comprises 8-20 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 8-15, 8-20, 10-15, 10-20, or 15-20) consecutive amino acids that have a sequence that is at least 85%, 90%, or 95% identical to a sequence of 8-20 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 8-15, 8-20, 10-15, 10-20, or 15-20) consecutive amino acids that occurs in a human rhodopsin protein, wherein the sequence of the 8-20 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 8-15, 8-20, 10-15, 10-20, or 15-20) consecutive amino acids of the pHLIP peptide has 1, 2, or 3 amino acid substitutions compared to the sequence of the 8-20 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 8-15, 8-20, 10-15, 10-20, or 15-20) consecutive amino acids that occurs in a human rhodopsin protein. In some embodiments, the sequence has a L to D, L to E, A to P, or C to G substitution compared to the 8-20 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 8-15, 8-20, 10-15, 10-20, or 15-20) consecutive amino acids that occur in the human rhodopsin protein. In certain embodiments, the sequence of the pHLIP peptide comprises 20 consecutive amino acids that have a sequence that is 85%, 90%, or 95% identical to the reverse of a sequence of 8-20 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 8-15, 8-20, 10-15, 10-20, or 15-20) consecutive amino acids that occurs in a human rhodopsin protein, wherein the sequence of the 20 consecutive amino acids has 1, 2, or 3 amino acid substitutions compared to the reverse of the sequence of the 8-20 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 8-15, 8-20, 10-15, 10-20, or 15-20) consecutive amino acids that occurs in a human rhodopsin protein. In some embodiments, the sequence has a L to D, L to E, A to P, or C to G substitution compared to the reverse of the 8-20 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 8-15, 8-20, 10-15, 10-20, or 15-20) consecutive amino acids that occur in the human rhodopsin protein. A non-limiting example of a genomic nucleotide sequence that encodes human rhodopsin is available under National Center for Biotechnology Information (NCBI) Reference Sequence No: NC_000003.12, all information available under NCBI Reference Sequence No: NC_000003.12 is incorporated herein by reference. The nucleotide sequence that is available from NCBI Reference Sequence No: NC_000003.12 is as follows: (SEQ ID NO: 31) AGAGTCATCCAGCTGGAGCCCTGAGTGGCTGAGCTCAGGCCTTCGCAGCA TTCTTGGGTGGGAGCAGCCACGGGTCAGCCACAAGGGCCACAGCCATGAA TGGCACAGAAGGCCCTAACTTCTACGTGCCCTTCTCCAATGCGACGGGTG TGGTACGCAGCCCCTTCGAGTACCCACAGTACTACCTGGCTGAGCCATGG CAGTTCTCCATGCTGGCCGCCTACATGTTTCTGCTGATCGTGCTGGGCTT CCCCATCAACTTCCTCACGCTCTACGTCACCGTCCAGCACAAGAAGCTGC GCACGCCTCTCAACTACATCCTGCTCAACCTAGCCGTGGCTGACCTCTTC ATGGTCCTAGGTGGCTTCACCAGCACCCTCTACACCTCTCTGCATGGATA CTTCGTCTTCGGGCCCACAGGATGCAATTTGGAGGGCTTCTTTGCCACCC TGGGCGGTATGAGCCGGGTGTGGGTGGGGTGTGCAGGAGCCCGGGAGCAT GGAGGGGTCTGGGAGAGTCCCGGGCTTGGCGGTGGTGGCTGAGAGGCCTT CTCCCTTCTCCTGTCCTGTCAATGTTATCCAAAGCCCTCATATATTCAGT CAACAAACACCATTCATGGTGATAGCCGGGCTGCTGTTTGTGCAGGGCTG GCACTGAACACTGCCTTGATCTTATTTGGAGCAATATGCGCTTGTCTAAT TTCACAGCAAGAAAACTGAGCTGAGGCTCAAAGAAGTCAAGCGCCCTGCT GGGGCGTCACACAGGGACGGGTGCAGAGTTGAGTTGGAAGCCCGCATCTA TCTCGGGCCATGTTTGCAGCACCAAGCCTCTGTTTCCCTTGGAGCAGCTG TGCTGAGTCAGACCCAGGCTGGGCACTGAGGGAGAGCTGGGCAAGCCAGA CCCCTCCTCTCTGGGGGCCCAAGCTCAGGGTGGGAAGTGGATTTTCCATT CTCCAGTCATTGGGTCTTCCCTGTGCTGGGCAATGGGCTCGGTCCCCTCT GGCATCCTCTGCCTCCCCTCTCAGCCCCTGTCCTCAGGTGCCCCTCCAGC CTCCCTGCCGCGTTCCAAGTCTCCTGGTGTTGAGAACCGCAAGCAGCCGC TCTGAAGCAGTTCCTTTTTGCTTTAGAATAATGTCTTGCATTTAACAGGA AAACAGATGGGGTGCTGCAGGGATAACAGATCCCACTTAACAGAGAGGAA AACTGAGGCAGGGAGAGGGGAAGAGACTCATTTAGGGATGTGGCCAGGCA GCAACAAGAGCCTAGGTCTCCTGGCTGTGATCCAGGAATATCTCTGCTGA GATGCAGGAGGAGACGCTAGAAGCAGCCATTGCAAAGCTGGGTGACGGGG AGAGCTTACCGCCAGCCACAAGCGTCTCTCTGCCAGCCTTGCCCTGTCTC CCCCATGTCCAGGCTGCTGCCTCGGTCCCATTCTCAGGGAATCTCTGGCC ATTGTTGGGTGTTTGTTGCATTCAATAATCACAGATCACTCAGTTCTGGC CAGAAGGTGGGTGTGCCACTTACGGGTGGTTGTTCTCTGCAGGGTCAGTC CCAGTTTACAAATATTGTCCCTTTCACTGTTAGGAATGTCCCAGTTTGGT TGATTAACTATATGGCCACTCTCCCTATGGAACTTCATGGGGTGGTGAGC AGGACAGATGTCTGAATTCCATCATTTCCTTCTTCTTCCTCTGGGCAAAA CATTGCACATTGCTTCATGGCTCCTAGGAGAGGCCCCCACATGTCCGGGT TATTTCATTTCCCGAGAAGGGAGAGGGAGGAAGGACTGCCAATTCTGGGT TTCCACCACCTCTGCATTCCTTCCCAACAAGGAACTCTGCCCCACATTAG GATGCATTCTTCTGCTAAACACACACACACACACACACACACACAACACA CACACACACACACACACACACACACACACAAAACTCCCTACCGGGTTCCC AGTTCAATCCTGACCCCCTGATCTGATTCGTGTCCCTTATGGGCCCAGAG CGCTAAGCAAATAACTTCCCCCATTCCCTGGAATTTCTTTGCCCAGCTCT CCTCAGCGTGTGGTCCCTCTGCCCCTTCCCCCTCCTCCCAGCACCAAGCT CTCTCCTTCCCCAAGGCCTCCTCAAATCCCTCTCCCACTCCTGGTTGCCT TCCTAGCTACCCTCTCCCTGTCTAGGGGGGAGTGCACCCTCCTTAGGCAG TGGGGTCTGTGCTGACCGCCTGCTGACTGCCTTGCAGGTGAAATTGCCCT GTGGTCCTTGGTGGTCCTGGCCATCGAGCGGTACGTGGTGGTGTGTAAGC CCATGAGCAACTTCCGCTTCGGGGAGAACCATGCCATCATGGGCGTTGCC TTCACCTGGGTCATGGCGCTGGCCTGCGCCGCACCCCCACTCGCCGGCTG GTCCAGGTAATGGCACTGAGCAGAAGGGAAGAAGCTCCGGGGGCTCTTTG TAGGGTCCTCCAGTCAGGACTCAAACCCAGTAGTGTCTGGTTCCAGGCAC TGACCTTGTATGTCTCCTGGCCCAAATGCCCACTCAGGGTAGGGGTGTAG GGCAGAAGAAGAAACAGACTCTAATGTTGCTACAAGGGCTGGTCCCATCT CCTGAGCCCCATGTCAAACAGAATCCAAGACATCCCAACCCTTCACCTTG GCTGTGCCCCTAATCCTCAACTAAGCTAGGCGCAAATTCCAATCCTCTTT GGTCTAGTACCCCGGGGGCAGCCCCCTCTAACCTTGGGCCTCAGCAGCAG GGGAGGCCACACCTTCCTAGTGCAGGTGGCCATATTGTGGCCCCTTGGAA CTGGGTCCCACTCAGCCTCTAGGCGATTGTCTCCTAATGGGGCTGAGATG AGACACAGTGGGGACAGTGGTTTGGACAATAGGACTGGTGACTCTGGTCC CCAGAGGCCTCATGTCCCTCTGTCTCCAGAAAATTCCCACTCTCACTTCC CTTTCCTCCTCAGTCTTGCTAGGGTCCATTTCTTACCCCTTGCTGAATTT GAGCCCACCCCCTGGACTTTTTCCCCATCTTCTCCAATCTGGCCTAGTTC TATCCTCTGGAAGCAGAGCCGCTGGACGCTCTGGGTTTCCTGAGGCCCGT CCACTGTCACCAATATCAGGAACCATTGCCACGTCCTAATGACGTGCGCT GGAAGCCTCTAGTTTCCAGAAGCTGCACAAAGATCCCTTAGATACTCTGT GTGTCCATCTTTGGCCTGGAAAATACTCTCACCCTGGGGCTAGGAAGACC TCGGTTTGTACAAACTTCCTCAAATGCAGAGCCTGAGGGCTCTCCCCACC TCCTCACCAACCCTCTGCGTGGCATAGCCCTAGCCTCAGCGGGCAGTGGA TGCTGGGGCTGGGCATGCAGGGAGAGGCTGGGTGGTGTCATCTGGTAACG CAGCCACCAAACAATGAAGCGACACTGATTCCACAAGGTGCATCTGCATC CCCATCTGATCCATTCCATCCTGTCACCCAGCCATGCAGACGTTTATGAT CCCCTTTTCCAGGGAGGGAATGTGAAGCCCCAGAAAGGGCCAGCGCTCGG CAGCCACCTTGGCTGTTCCCAAGTCCCTCACAGGCAGGGTCTCCCTACCT GCCTGTCCTCAGGTACATCCCCGAGGGCCTGCAGTGCTCGTGTGGAATCG ACTACTACACGCTCAAGCCGGAGGTCAACAACGAGTCTTTTGTCATCTAC ATGTTCGTGGTCCACTTCACCATCCCCATGATTATCATCTTTTTCTGCTA TGGGCAGCTCGTCTTCACCGTCAAGGAGGTACGGGCCGGGGGGTGGGCGG CCTCACGGCTCTGAGGGTCCAGCCCCCAGCATGCATCTGCGGCTCCTGCT CCCTGGAGGAGCCATGGTCTGGACCCGGGTCCCGTGTCCTGCAGGCCGCT GCCCAGCAGCAGGAGTCAGCCACCACACAGAAGGCAGAGAAGGAGGTCAC CCGCATGGTCATCATCATGGTCATCGCTTTCCTGATCTGCTGGGTGCCCT ACGCCAGCGTGGCATTCTACATCTTCACCCACCAGGGCTCCAACTTCGGT CCCATCTTCATGACCATCCCAGCGTTCTTTGCCAAGAGCGCCGCCATCTA CAACCCTGTCATCTATATCATGATGAACAAGCAGGTGCCTACTGCGGGTG GGAGGGCCCCAGTGCCCCAGGCCACAGGCGCTGCCTGCCAAGGACAAGCT ACTTCCCAGGGCAGGGGAGGGGGCTCCATCAGGGTTACTGGCAGCAGTCT TGGGTCAGCAGTCCCAATGGGGAGTGTGTGAGAAATGCAGATTCCTGGCC CCACTCAGAACTGCTGAATCTCAGGGTGGGCCCAGGAACCTGCATTTCCA GCAAGCCCTCCACAGGTGGCTCAGATGCTCACTCAGGTGGGAGAAGCTCC AGTCAGCTAGTTCTGGAAGCCCAATGTCAAAGTCAGAAGGACCCAAGTCG GGAATGGGATGGGCCAGTCTCCATAAAGCTGAATAAGGAGCTAAAAAGTC TTATTCTGAGGGGTAAAGGGGTAAAGGGTTCCTCGGAGAGGTACCTCCGA GGGGTAAACAGTTGGGTAAACAGTCTCTGAAGTCAGCTCTGCCATTTTCT AGCTGTATGGCCCTGGGCAAGTCAATTTCCTTCTCTGTGCTTTGGTTTCC TCATCCATAGAAAGGTAGAAAGGGCAAAACACCAAACTCTTGGATTACAA GAGATAATTTACAGAACACCCTTGGCACACAGAGGGCACCATGAAATGTC ACGGGTGACACAGCCCCCTTGTGCTCAGTCCCTGGCATCTCTAGGGGTGA GGAGCGTCTGCCTAGCAGGTTCCCTCCAGGAAGCTGGATTTGAGTGGATG GGGCGCTGGAATCGTGAGGGGCAGAAGCAGGCAAAGGGTCGGGGCGAACC TCACTAACGTGCCAGTTCCAAGCACACTGTGGGCAGCCCTGGCCCTGACT CAAGCCTCTTGCCTTCCAGTTCCGGAACTGCATGCTCACCACCATCTGCT GCGGCAAGAACCCACTGGGTGACGATGAGGCCTCTGCTACCGTGTCCAAG ACGGAGACGAGCCAGGTGGCCCCGGCCTAAGACCTGCCTAGGACTCTGTG GCCGACTATAGGCGTCTCCCATCCCCTACACCTTCCCCCAGCCACAGCCA TCCCACCAGGAGCAGCGCCTGTGCAGAATGAACGAAGTCACATAGGCTCC TTAATTTTTTTTTTTTTTTTAAGAAATAATTAATGAGGCTCCTCACTCAC CTGGGACAGCCTGAGAAGGGACATCCACCAAGACCTACTGATCTGGAGTC CCACGTTCCCCAAGGCCAGCGGGATGTGTGCCCCTCCTCCTCCCAACTCA TCTTTCAGGAACACGAGGATTCTTGCTTTCTGGAAAAGTGTCCCAGCTTA GGGATAAGTGTCTAGCACAGAATGGGGCACACAGTAGGTGCTTAATAAAT GCTGGATGGATGCAGGAAGGAATGGAGGAATGAATGGGAAGGGAGAACAT ATCTATCCTCTCAGACCCTCGCAGCAGCAGCAACTCATACTTGGCTAATG ATATGGAGCAGTTGTTTTTCCCTCCCTGGGCCTCACTTTCTTCTCCTATA AAATGGAAATCCCAGATCCCTGGTCCTGCCGACACGCAGCTACTGAGAAG ACCAAAAGAGGTGTGTGTGTGTCTATGTGTGTGTTTCAGCACTTTGTAAA TAGCAAGAAGCTGTACAGATTCTAGTTAATGTTGTGAATAACATCAATTA ATGTAACTAGTTAATTACTATGATTATCACCTCCTGATAGTGAACATTTT GAGATTGGGCATTCAGATGATGGGGTTTCACCCAACCTTGGGGCAGGTTT TTAAAAATTAGCTAGGCATCAAGGCCAGACCAGGGCTGGGGGTTGGGCTG TAGGCAGGGACAGTCACAGGAATGCAGAATGCAGTCATCAGACCTGAAAA AACAACACTGGGGGAGGGGGACGGTGAAGGCCAAGTTCCCAATGAGGGTG AGATTGGGCCTGGGGTCTCACCCCTAGTGTGGGGCCCCAGGTCCCGTGCC TCCCCTTCCCAATGTGGCCTATGGAGAGACAGGCCTTTCTCTCAGCCTCT GGAAGCCACCTGCTCTTTTGCTCTAGCACCTGGGTCCCAGCATCTAGAGC ATGGAGCCTCTAGAAGCCATGCTCACCCGCCCACATTTAATTAACAGCTG AGTCCCTGATGTCATCCTTATCTCGAAGAGCTTAGAAACAAAGAGTGGGA AATTCCACTGGGCCTACCTTCCTTGGGGATGTTCATGGGCCCCAGTTTCC AGTTTCCCTTGCCAGACAAGCCCATCTTCAGCAGTTGCTAGTCCATTCTC CATTCTGGAGAATCTGCTCCAAAAAGCTGGCCACATCTCTGAGGTGTCAG AATTAAGCTGCCTCAGTAACTGCTCCCCCTTCTCCATATAAGCAAAGCCA GAAGCTCTAGCTTTACCCAGCTCTGCCTGGAGACTAAGGCAAATTGGGCC ATTAAAAGCTCAGCTCCTATGTTGGTATTAACGGTGGTGGGTTTTGTTGC TTTCACACTCTATCCACAGGATAGATTGAAACTGCCAGCTTCCACCTGAT CCCTGACCCTGGGATGGCTGGATTGAGCAATGAGCAGAGCCAAGCAGCAC AGAGTCCCCTGGGGCTAGAGGTGGAGGAGGCAGTCCTGGGAATGGGAAAA ACCCCA A non-limiting example of a human rhodopsin amino acid sequence is available under UniProt Accession No: P08100. All information available under UniProt Accession No: P08100 is incorporated herein by reference. An amino acid sequence that is available from UniProt Accession No: P08100 is as follows (the underlined amino acids relate may be used in non-limiting examples of pHLIPs, and especially as a starting point to design pHLIP peptides): (SEQ ID NO: 32) MNGTEGPNFYVPFSNATGVVRSPFEYPQYYLAEPWQFSMLAAYMFLLIVL GFPINFLTLYVTVQHKKLRTPLNYILLNLAVADLFMVLGGFTSTLYTSLH GYFVFGPTGC NLEGFFATLGGEIALWSLVVLAIE RYVVVCKPMSNFRFGE NHAIMGVAFTWVMALACAAPPLAGWSRYIPEGLQCSCGIDYYTLKPEVNN ESFVIYMFVVHFTIPMIIIFFCYGQLVFTVKEAAAQQQESATTQKAEKEV TRMVIIMVIAFLICWVPYASVAFYIFTHQGSNFGPIFMTIPAFFAKSAAI YNPVIYIMMNKQFRNCMLTTICCGKNPLGDDEASATVSKTETSQVAPA For example, a pHLIP peptide comprising the sequence DN N EGFFATLGGEI P LWS D VVLAIE (SEQ ID NO: 209) is a useful pHLIP peptide that comprises 3 substitution mutations (underlined) and one added amino acid (the N-terminal D) compared to NLEGFFATLGGEIALWSLVVLAIE (SEQ ID NO: 62). See also, e.g., Hum pHLIP in Table 11, as well as sequences in Tables 5 and 6. A non-limiting example of a cDNA sequence that encodes human rhodopsin is available under NCBI Reference Sequence No: NM_000539.3, all information available under NCBI Reference Sequence No: NM_000539.3 is incorporated herein by reference. The nucleotide sequence that is available from NCBI Reference Sequence No: NM_000539.3 is as follows: (SEQ ID NO: 33) AGAGTCATCCAGCTGGAGCCCTGAGTGGCTGAGCTCAGGCCTTCGCAGCA TTCTTGGGTGGGAGCAGCCACGGGTCAGCCACAAGGGCCACAGCCATGAA TGGCACAGAAGGCCCTAACTTCTACGTGCCCTTCTCCAATGCGACGGGTG TGGTACGCAGCCCCTTCGAGTACCCACAGTACTACCTGGCTGAGCCATGG CAGTTCTCCATGCTGGCCGCCTACATGTTTCTGCTGATCGTGCTGGGCTT CCCCATCAACTTCCTCACGCTCTACGTCACCGTCCAGCACAAGAAGCTGC GCACGCCTCTCAACTACATCCTGCTCAACCTAGCCGTGGCTGACCTCTTC ATGGTCCTAGGTGGCTTCACCAGCACCCTCTACACCTCTCTGCATGGATA CTTCGTCTTCGGGCCCACAGGATGCAATTTGGAGGGCTTCTTTGCCACCC TGGGCGGTGAAATTGCCCTGTGGTCCTTGGTGGTCCTGGCCATCGAGCGG TACGTGGTGGTGTGTAAGCCCATGAGCAACTTCCGCTTCGGGGAGAACCA TGCCATCATGGGCGTTGCCTTCACCTGGGTCATGGCGCTGGCCTGCGCCG CACCCCCACTCGCCGGCTGGTCCAGGTACATCCCCGAGGGCCTGCAGTGC TCGTGTGGAATCGACTACTACACGCTCAAGCCGGAGGTCAACAACGAGTC TTTTGTCATCTACATGTTCGTGGTCCACTTCACCATCCCCATGATTATCA TCTTTTTCTGCTATGGGCAGCTCGTCTTCACCGTCAAGGAGGCCGCTGCC CAGCAGCAGGAGTCAGCCACCACACAGAAGGCAGAGAAGGAGGTCACCCG CATGGTCATCATCATGGTCATCGCTTTCCTGATCTGCTGGGTGCCCTACG CCAGCGTGGCATTCTACATCTTCACCCACCAGGGCTCCAACTTCGGTCCC ATCTTCATGACCATCCCAGCGTTCTTTGCCAAGAGCGCCGCCATCTACAA CCCTGTCATCTATATCATGATGAACAAGCAGTTCCGGAACTGCATGCTCA CCACCATCTGCTGCGGCAAGAACCCACTGGGTGACGATGAGGCCTCTGCT ACCGTGTCCAAGACGGAGACGAGCCAGGTGGCCCCGGCCTAAGACCTGCC TAGGACTCTGTGGCCGACTATAGGCGTCTCCCATCCCCTACACCTTCCCC CAGCCACAGCCATCCCACCAGGAGCAGCGCCTGTGCAGAATGAACGAAGT CACATAGGCTCCTTAATTTTTTTTTTTTTTTTAAGAAATAATTAATGAGG CTCCTCACTCACCTGGGACAGCCTGAGAAGGGACATCCACCAAGACCTAC TGATCTGGAGTCCCACGTTCCCCAAGGCCAGCGGGATGTGTGCCCCTCCT CCTCCCAACTCATCTTTCAGGAACACGAGGATTCTTGCTTTCTGGAAAAG TGTCCCAGCTTAGGGATAAGTGTCTAGCACAGAATGGGGCACACAGTAGG TGCTTAATAAATGCTGGATGGATGCAGGAAGGAATGGAGGAATGAATGGG AAGGGAGAACATATCTATCCTCTCAGACCCTCGCAGCAGCAGCAACTCAT ACTTGGCTAATGATATGGAGCAGTTGTTTTTCCCTCCCTGGGCCTCACTT TCTTCTCCTATAAAATGGAAATCCCAGATCCCTGGTCCTGCCGACACGCA GCTACTGAGAAGACCAAAAGAGGTGTGTGTGTGTCTATGTGTGTGTTTCA GCACTTTGTAAATAGCAAGAAGCTGTACAGATTCTAGTTAATGTTGTGAA TAACATCAATTAATGTAACTAGTTAATTACTATGATTATCACCTCCTGAT AGTGAACATTTTGAGATTGGGCATTCAGATGATGGGGTTTCACCCAACCT TGGGGCAGGTTTTTAAAAATTAGCTAGGCATCAAGGCCAGACCAGGGCTG GGGGTTGGGCTGTAGGCAGGGACAGTCACAGGAATGCAGAATGCAGTCAT CAGACCTGAAAAAACAACACTGGGGGAGGGGGACGGTGAAGGCCAAGTTC CCAATGAGGGTGAGATTGGGCCTGGGGTCTCACCCCTAGTGTGGGGCCCC AGGTCCCGTGCCTCCCCTTCCCAATGTGGCCTATGGAGAGACAGGCCTTT CTCTCAGCCTCTGGAAGCCACCTGCTCTTTTGCTCTAGCACCTGGGTCCC AGCATCTAGAGCATGGAGCCTCTAGAAGCCATGCTCACCCGCCCACATTT AATTAACAGCTGAGTCCCTGATGTCATCCTTATCTCGAAGAGCTTAGAAA CAAAGAGTGGGAAATTCCACTGGGCCTACCTTCCTTGGGGATGTTCATGG GCCCCAGTTTCCAGTTTCCCTTGCCAGACAAGCCCATCTTCAGCAGTTGC TAGTCCATTCTCCATTCTGGAGAATCTGCTCCAAAAAGCTGGCCACATCT CTGAGGTGTCAGAATTAAGCTGCCTCAGTAACTGCTCCCCCTTCTCCATA TAAGCAAAGCCAGAAGCTCTAGCTTTACCCAGCTCTGCCTGGAGACTAAG GCAAATTGGGCCATTAAAAGCTCAGCTCCTATGTTGGTATTAACGGTGGT GGGTTTTGTTGCTTTCACACTCTATCCACAGGATAGATTGAAACTGCCAG CTTCCACCTGATCCCTGACCCTGGGATGGCTGGATTGAGCAATGAGCAGA GCCAAGCAGCACAGAGTCCCCTGGGGCTAGAGGTGGAGGAGGCAGTCCTG GGAATGGGAAAAACCCCA In some embodiments, the pHLIP peptide comprises the sequence: X n Y m ; Y m X n ; X n -Y m X j ; Y m X n Y i ; Y m X n Y i X j ; X n Y m X j Y i ; Y m X n Y i X j Y l ; X n Y m X j Y i X l ; Y m X n Y i X j Y l X h ; X n Y m X j Y i X h Y g ; Y m X n Y i X j Y l X h Y g ; X n Y m X j Y i X h Y g X f ; (XY) n ; (YX) n ; (XY) n Y m ; (YX) n Y m ; (XY) n X m ; (YX) n X m ; Y m (XY) n ; Y m (YX) n ; X n (XY) m ; X n (YX) m ; (XY) n Y m (XY) i ; (YX)Y m (YX) i ; (XY) n X m (XY) i ; (YX) n X m (YX) i ; Y m (XY) 1 ; Y m (YX) 1 ; X 1 (XY) m ; or X 1 (YX) m , wherein, (i) each Y is, individually, a non-polar amino acid with solvation energy, ΔG X cor >+0.50, or Gly; (ii) each X is, individually, a protonatable amino acid, (iii) n, m, i, j, l, h, g, f are each, individually, an integer from 1 to 8. In certain embodiments, the pHLIP peptide has a net negative charge at a pH of about 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, or 7.5 in water. In various embodiments, the pHLIP peptide has an acid dissociation constant on a base 10 logarithmic scale (pKa) of less than about 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, or 7.0. In certain embodiments, the pHLIP peptide has a pKa of at least about 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0. In some embodiments, the pHLIP peptide has a pKa between about 6.5 and about 7.0, e.g., about 6.6 and about 7.0, about 6.7 and about 7.0, about 6.8 and about 7.0, or about 6.9 and about 7.0. In certain embodiments, the pHLIP peptide has a pKa of about 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0. In some embodiments, the pHLIP peptide comprises (a) 1 protonatable amino acid which is aspartic acid, glutamic acid, alpha-aminoadipic acid, or gamma-carboxyglutamic acid; or (b) at least 2, 3, or 4 protonatable amino acids, wherein the protonatable amino acids comprise aspartic acid, glutamic acid, alpha-aminoadipic acid, gamma-carboxyglutamic acid, or any combination thereof. In certain embodiments, the pHLIP peptide comprises at least 1 non-native protonatable amino acid. In various embodiments, the non-native protonatable amino acid comprises at least 1, 2, 3, or 4 carboxyl groups. In some embodiments, the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 carboxyl groups. In certain embodiments, the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 40 genetically coded amino acids. In various embodiments, the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 40 non-genetically coded amino acids. In some embodiments, the amino acids of the pHLIP peptide are non-native amino acids. In certain embodiments, the pHLIP peptide comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 40 D-amino acids. In various embodiments, the pHLIP peptide comprises at least 1 non-genetically coded amino acid, wherein the non-genetically coded amino acid is an aspartic acid derivative, or a glutamic acid derivative. In some embodiments, the pHLIP peptide comprises at least 8 consecutive amino acids, wherein, at least 2, 3, or 4 of the at least 8 consecutive amino acids are non-polar, and at least 1, 2, 3, or 4 of the at least 8 consecutive amino acids is protonatable. In various embodiments, the pHLIP peptide is directly covalently attached via a bond, or covalently attached via a linker, to a fluorophore. In some embodiments, a pHLIP peptide is attached to a fluorophore by a covalent bond, wherein the covalent bond is an ester bond, a disulfide bond, a bond between two selenium atoms, a bond between a sulfur and a selenium atom, or an acid-labile bond. In some embodiments, the pHLIP peptide is attached to a fluorophore by a covalent bond, wherein the covalent bond is a bond that has been formed by a click chemistry reaction. In certain embodiments, the covalent bond is a bond that has been formed by a reaction between (i) an azide and an alkyne; (ii) an alkyne and a strained difluorooctyne; (iii) a diaryl-strained-cyclooctyne and a 1,3-nitrone; (iv) a cyclooctene, trans-cycloalkene, or oxanorbomadiene and an azide, tetrazine, or tetrazole; (v) an activated alkene or oxanorbomadiene and an azide; (vi) a strained cyclooctene or other activated alkene and a tetrazine; or (vii) a tetrazole that has been activated by ultraviolet light and an alkene. In certain embodiments, the covalent bond is a peptide bond. In various embodiments, the covalent bond is not a peptide bond. In various embodiments, a pHLIP-fluorophore compound comprises a pHLIP peptide that is attached to the linker by a covalent bond. In some embodiments, the covalent bond is a peptide bond. In certain embodiments, the covalent bond is a disulfide bond, a bond between two selenium atoms, or a bond between a sulfur and a selenium atom. In various embodiments, the covalent bond is a bond that has been formed by a click chemistry reaction. In some embodiments, the covalent bond is a bond that has been formed by a reaction between (i) an azide and an alkyne; (ii) an alkyne and a strained difluorooctyne; (iii) a diaryl-strained-cyclooctyne and a 1,3-nitrone; (vi) a cyclooctene, trans-cycloalkene, or oxanorbomadiene and an azide, tetrazine, or tetrazole; (v) an activated alkene or oxanorbomadiene and an azide; (vi) a strained cyclooctene or other activated alkene and a tetrazine; or (vii) a tetrazole that has been activated by ultraviolet light and an alkene. In certain embodiments, the covalent bond is a peptide bond. In various embodiments, the covalent bond is not a peptide bond. In some embodiments, the linker comprises an artificial polymer or a synthetically produced polymer that has the structure of a polymer that exists in nature. In certain embodiments, the linker comprises a polypeptide, a polylysine, a polyarginine, a polyglutanmic acid, a polyaspartic acid, a polycysteine, or a polynucleic acid. In various embodiments, the linker does not comprise an amino acid. In some embodiments, the linker comprises a polysaccharide, a chitosan, or an alginate. In certain embodiments, the linker comprises a poly(ethylene glycol), a poly(lactic acid), a poly(glycolic acid), a poly(lactic-co-glycolic acid), a poly(malic acid), a polyorthoester, a poly(vinylalcohol), a poly(vinylpyrrolidone), a poly(methyl methacrylate), a poly(acrylic acid), a poly(acrylanide), a poly(methacrylic acid), a poly(amidoamine), a polyanhydrides, or a polycyanoacrylate. In various embodiments, the linker comprises poly(ethylene glycol). In certain embodiments, the poly(ethylene glycol) has a molecular weight of 60 to 100000 Daltons, e.g., at least about 60, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 5000, 10000, 15000, 20000, 25000 Daltons, but less than about 100000, 90000, 70000, 60000, 50000, 40000, or 30000 Daltons. In various embodiments, the linker comprises a linear polymer or a branched polymer. In some embodiments, the linker comprises an organic compound structure. In certain embodiments, the organic compound structure has a molecular weight less than about 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0.5 kDa. In some embodiments, the linker is attached to a fluorophore (e.g., a luminescent fluorophore or a quencher) via a covalent bond. In certain embodiments, the covalent bond is an ester bond, a disulfide bond, a bond between two selenium atoms, a bond between a sulfur and a selenium atom, or an acid-labile bond. In various embodiments, the covalent bond is a bond that has been formed by a click chemistry reaction. In some embodiments, the covalent bond is a bond that has been formed by a reaction between (i) an azide and an alkyne; (ii) an alkyne and a strained difluorooctyne; (iii) a diaryl-strained-cyclooctyne and a 1,3-nitrone; (vi) a cyclooctene, trans-cycloalkene, or oxanorbomadiene and an azide, tetrazine, or tetrazole; (v) an activated alkene or oxanorbomadiene and an azide; (vi) a strained cyclooctene or other activated alkene and a tetrazine; or (vii) a tetrazole that has been activated by ultraviolet light and an alkene. In certain embodiments, the covalent bond is a peptide bond. In various embodiments, the covalent bond is not a peptide bond. In some embodiments, the fluorophore is a fluorescent dye or a fluorescent protein. Non-limiting examples of fluorophores include fluorescent dyes, phosphorescent dyes, quantum dots, xanthene derivatives, cyanine derivatives, naphthalene derivatives, coumarin derivatives, oxadiaxol derivatives, pyrene derivatives, acridine derivatives, arylmethine derivatives, or tetrapyrrole derivatives. Xanthene derivatives include but are not limited to fluorescein, rhodamine, Oregon green, eosin, Texas red, and Cal Fluor dyes. Cyanine derivatives include but are not limited to cyanine, indocarbocyanine, indocyanine green (ICG), oxacarbocyanine, thiacarbocyanine, merocyanine, and Quasar dyes. Naphthalene derivatives include but are not limited to dansyl and prodan derivatives. Oxadiazole derivatives include but are not limited to pyridyloxazol, nitrobenzoxadiazole and benzoxadiazole. A non-limiting example of a pyrene derivative is cascade blue. Oxadine derivatives include but are not limited to Nile red, Nile blue, cresyl violet, and oxazine 170. Acridine derivatives include but are not limited to proflavin, acridine orange, and acridine yellow. Arylmethine derivatives include but are not limited to auramine, crystal violet, and malachite green. Tetrapyrrole derivatives include but are not limited to porphin, phtalocyanine, and bilirubin. In various embodiments, a pHLIP-fluorophore compound included herein is used as a diagnostic agent, an imaging agent. In some embodiments, a pHLIP-fluorophore compound provided herein is used as an agent for in vivo imaging or in an in vivo diagnostic method. In certain embodiments, a pHLIP-fluorophore compound provided herein is used as an agent for ex vivo imaging or in an ex vivo diagnostic method. Certain implementations comprise a formulation for a parenteral, a local, or a systemic administration comprising a pHLIP-fluorophore compound as disclosed herein. Formulations comprising a pHLIP-fluorophore compound for intravenous, intraarterial, intraperitoneal, intracerebral, intracerebroventricular, intrathecal, intracardiac, intracavemous, intraosseous, intraocular, or intravitreal administration are also provided. The present subject matter also includes a formulation for intravesical instillation comprising a pHLIP-fluorophore compound as disclosed herein. In various embodiments, the fluorophore is covalently attached to the membrane insertion peptide via a linkage such as a thiol linkage or ester linkage or acid-labile linkage. Other types of linkages, chemical bonds, or binding associations are also used. Exemplary linkages or associations are mediated by disulfide, and/or a peptide with a protein binding motif, and/or a protein kinase consensus sequence, and/or a protein phosphatase consensus sequence, and/or a protease-reactive sequence, and/or a peptidase-reactive sequence, and/or a transferase-reactive sequence, and/or a hydrolase-reactive sequence, and/or an isomerase-reactive sequence, and/or a ligase-reactive sequence, and/or an extracellular metalloprotease-reactive sequence, and/or a lysosomal protease-reactive sequence, and/or a beta-lactamase-reactive sequence, and/or an oxidoreductase-reactive sequence, and/or an esterase-reactive sequence, and/or a glycosidase-reactive sequence, and/or a nuclease-reactive sequence. In certain embodiments, the fluorophore is covalently attached to the membrane insertion peptide via a non-cleavable linkage. In various embodiments, a non-cleavable linkage is a covalent bond that is not cleaved by an enzyme expressed by a mammalian cell, and/or not cleaved by glutathione and/or not cleaved at conditions of low pH. Non-limiting examples of non-cleavable linkages include maleimide linkages, linkages resulting from the reaction of a N-hydroxysuccinimide ester with a primary amine (e.g., a primary amine of a lysine side-chain), linkages resulting from a click reaction, thioether linkages, or linkages resulting from the reaction of a primary amine (—NH 2 ) or thio (—SH) functional group with succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC). Exemplary non-cleavable linkages include linkages comprising a maleimide alkane linker, and linkages comprising a maleimide cyclohexane linker, As is described above, the compositions may be used in, e.g., a clinical setting for diagnostic and therapeutic applications in humans as well as animals (e.g., companion animals such as dogs and cats as well as livestock such as horses, cattle, goats, sheep, llamas). Membrane-inserting compounds comprising such moieties may be used in a variety of clinical diagnostic methods, including real-time image-guided therapeutic interventions. Included herein are compositions that are administered to the body for diagnostic use, e.g., using methods known in the art. For example, the methods are carried out by infusing into a vascular lumen, e.g., intravenously (such as via a jugular vein, peripheral vein or the perivascular space). In some embodiments, the composition is infused into the lungs of a mammal, e.g., as an aerosol or lavage. In various embodiments, the composition is administered by intravesical instillation into a human or animal bladder, oral cavity, intestinal cavity, esophagus, or trachea. In some embodiments, the injection can be into the peritoneal cavity of the mammal, subdermally, or subcutaneously. Included herein are pharmaceutical compositions comprising a pH-triggered compound and a pharmaceutically acceptable carrier. In some embodiments, a subject is a mammal. In certain embodiments, the mammal is a rodent (e.g., a mouse or a rat), a primate (e.g., a chimpanzee, a gorilla, a monkey, a gibbon, a baboon), a cow, a camel, a dog, a cat, a horse, a llama, a sheep, a goat, a chicken, a turkey, or a duck. In certain embodiments, the subject is a human. The present subject matter provides compounds and compositions for detecting diseased tissue. For example, aspects of the present subject matter relate to the detection of cancerous tissue (e.g., of a tumor or a metastatic lesion) and/or precancerous tissue (e.g., dysplastic tissue). The compound includes a pHLIP peptide covalently linked to indocyanine green (ICG). The pHLIP peptide comprises amino acids in the sequence LFPTXTLL (SEQ ID NO: 1), wherein X is a protonatable amino acid. In preferred embodiments, X is a protonatable amino acid other than glutamic acid, such as aspartic acid. Additionally, the pH-triggered peptide has a higher affinity to a membrane lipid bilayer at pH 5.0 compared to at pH 8.0. In various implementations, the ICG is covalently attached to the first or the second amino acid counted from the N-terminus of the pHLIP peptide. Aspects of the present disclosure provide pHLIP peptides linked to an ICG compound. In various implementations, the pHLIP peptide is directly linked to a ICG by a covalent bond. In some non-limiting examples, the covalent bond is an ester bond, a thioester bond, a disulfide bond, a bond between two selenium atoms, a bond between a sulfur and a selenium atom, or an acid-labile bond. In some embodiments, the covalent bond between the pHLIP peptide and the ICG is a bond that has been formed by a click reaction. Non-limiting examples of click reactions include reactions between an azide and an alkyne; an alkyne and a strained difluorooctyne; a diaryl-strained-cyclooctyne and a 1,3-nitrone; a cyclooctene, trans-cycloalkene, or oxanorbornadiene and an azide, tetrazine, or tetrazole; an activated alkene or oxanorbornadiene and an azide; a strained cyclooctene or other activated alkene and a tetrazine; or a tetrazole that has been activated by ultraviolet light and an alkene. Some implementations provide a pHLIP peptide that is attached to a linker compound by a covalent bond, wherein the linker compound is attached to the IGC by a covalent bond. In non-limiting examples, the covalent bond between the pHLIP peptide and the linker compound and/or the covalent bond between the linker compound and the ICG is a disulfide bond, a bond between two selenium atoms, a bond between a sulfur and a selenium atom, or a bond that has been formed by a click reaction. In various embodiments, the ICG is covalently attached to the pHLIP peptide via a linkage such as a thiol linkage or thioester linkage or ester linkage or acid-labile linkage. Other types of linkages, chemical bonds, or binding associations may also be used. Exemplary linkages or associations are mediated by disulfide, and/or a peptide with a protein binding motif, and/or a protein kinase consensus sequence, and/or a protein phosphatase consensus sequence, and/or a protease-reactive sequence, and/or a peptidase-reactive sequence, and/or a transferase-reactive sequence, and/or a hydrolase-reactive sequence, and/or an isomerase-reactive sequence, and/or a ligase-reactive sequence, and/or an extracellular metalloprotease-reactive sequence, and/or a lysosomal protease-reactive sequence, and/or a beta-lactamase-reactive sequence, and/or an oxidoreductase-reactive sequence, and/or an esterase-reactive sequence, and/or a glycosidase-reactive sequence, and/or a nuclease-reactive sequence. In certain embodiments, the fluorophore is covalently attached to the pHLIP peptide via a non-cleavable linkage. In various embodiments a non-cleavable linkage is a covalent bond that is not cleaved by an enzyme expressed by a mammalian cell, and/or not cleaved by glutathione and/or not cleaved at conditions of low pH. Non-limiting examples of non-cleavable linkages include maleimide linkages [e.g., linkages resulting from the reaction of a maleimide ester with a thiol (e.g., at the thiol of a cysteine side-chain)], N-hydroxysuccinimide (NHS) linkages [e.g., linkages resulting from the reaction of a NHS ester with a primary amine (e.g., at the N-terminus of a polypeptide chain or a primary amine of a lysine side-chain)], linkages resulting from a click reaction, thioester linkages, thioether linkages, or linkages resulting from the reaction of a primary amine (—NH 2 ) or thio (—SH) functional group with succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC). Exemplary non-cleavable linkages include a maleimide alkane linker, e.g. and a maleimide cyclohexane linker, e.g. In various embodiments, the pHLIP peptide comprises amino acids in the sequence ACDDQNPWRAYLDLLFPTDTLLLDLLWG (SEQ ID NO: 9), and wherein said ICG is covalently attached to the cysteine thereof. In certain embodiments, ICG is covalently bound to the cysteine. In some embodiments, the N-terminus and/or the C-terminus is not bound to any compound. In a non-limiting example, the compound comprises the following structure (SEQ ID NO: 4 is disclosed below): In some embodiments, the pHLIP peptide comprises amino acids in the sequence ADDQNPWRAYLDLLFPTDTLLLDLLWG (SEQ ID NO: 2), and the ICG is covalently attached to the N-terminal alanine of the pHLIP peptide. In a non-limiting example, the compound comprises the following structure (SEQ ID NO: 2 is disclosed below): In some embodiments, the pHLIP peptide comprises amino acids in the sequence AKDDQNPWRAYLDLLFPTDTLLLDLLWG (SEQ ID NO: 3), and the ICG is covalently attached to the lysine of the pHLIP peptide. A non-limiting example of such a compound comprises the structure (SEQ ID NO: 3 is disclosed below): In certain embodiments, the pHLIP peptide comprises amino acids in the sequence ACDDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 4), and the ICG is covalently attached to the cysteine of the pHLIP peptide. In a non-limiting example, the compound comprises the structure (SEQ ID NO: 4 is disclosed below): In various embodiments, the pHLIP peptide comprises amino acids in the sequence ACDDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 4), and wherein said ICG is covalently attached to the cysteine thereof. In certain embodiments, ICG is covalently bound to the cysteine. In some embodiments, the N-terminus and/or the C-terminus is not bound to any compound. In a non-limiting example, the compound comprises the following structure (SEQ ID NO: 4 is disclosed below): This structure may optionally be drawn as follows (SEQ ID NO: 4 is disclosed below): In some embodiments, the pHLIP peptide comprises amino acids in the sequence ADDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 5), and the ICG is covalently attached to the N-terminal alanine of the pHLIP peptide. In a non-limiting example, the compound comprises the following structure: In some embodiments, the pHLIP peptide comprises amino acids in the sequence AKDDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 8), and the ICG is covalently attached to the lysine of the pHLIP peptide. A non-limiting example of such a compound comprises the structure: Protonatable amino acids include amino acids with acidic side chains (e.g., side chains comprising one or more carboxyl groups). For example, a protonatable amino acid may have a side-chain with a pKa at 25° C. of less than about 7.0, 6.75, 6.5, 6.25, 6, 5.75, 5.5, 5.25, 5.0, 4.75, 4.5, 4.25, 4.0, 3.75, 3.5, 3.25, or 3.0. Non-limiting examples of protonatable amino acids include aspartic acid, glutamic acid, and gamma-carboxyglutamic acid. In various embodiments, the pHLIP peptide comprises an artificial protonatable amino acid. In some embodiments, the artificial protonatable amino acid comprises at least 1, 2, 3, 4 or 5 carboxyl groups. Of the standard α-amino acids, all but glycine can exist in either of two optical isomers, called L or D amino acids, which are mirror images of each other. While L-amino acids represent all of the amino acids found in proteins during translation in the ribosome, D-amino acids are found in some proteins produced by enzyme posttranslational modifications after translation and translocation to the endoplasmic reticulum. D-amino acids are abundant components of the peptidoglycan cell walls of bacteria, and D-serine acts as a neurotransmitter in the brain. The L and D convention for amino acid configuration refers not to the optical activity of the amino acid itself, but rather to the optical activity of the isomer of glyceraldehyde from which that amino acid can be synthesized (D-glyceraldehyde is dextrorotary; L-glyceraldehyde is levorotary). In some embodiments, all or some of the amino acids in a pHLIP peptide are D-amino acids. For example, pHLIP peptide may comprise solely L-amino acids or solely D-amino acids, or a combination of both D-amino acids and L-amino acids. Various embodiments include a pHLIP peptide comprising amino acids in the sequence LLFPTDTLLL (SEQ ID NO: 25). In some embodiments, the pHLIP peptide comprises amino acids in the sequence LDLLFPTDTLLLD (SEQ ID NO: 26). In certain embodiments, the pHLIP peptide comprises amino acids in the sequence AYLDLLFPTDTLLLDLL (SEQ ID NO: 27). In various embodiments, the pHLIP peptide comprises amino acids in the sequence DDQNPWRAYLDLLFPTDTLLLDLLW (SEQ ID NO: 28). In some embodiments, the pHLIP peptide comprises amino acids in the sequence WRAYLDLLFPTDTLLLDLLWG (SEQ ID NO: 29) or WRAYLDLLFPTDTLLLDLLW (SEQ ID NO: 30). Optionally, the pHLIP peptide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more amino acids at the N-terminus and/or C-terminus of an amino acid sequence disclosed herein. In various embodiments, the pHLIP peptide comprises amino acids in the sequence: (SEQ ID NO: 2) ADDQNPWRAYLDLLFPTDTLLLDLLWG, (SEQ ID NO: 3) AKDDQNPWRAYLDLLFPTDTLLLDLLWG, (SEQ ID NO: 4) ACDDQNPWRAYLDLLFPTDTLLLDLLWA, (SEQ ID NO: 5) ADDQNPWRAYLDLLFPTDTLLLDLLWA, (SEQ ID NO: 6) ADDQNPWRAYLDLLFPTDTLLLDLLWCA, (SEQ ID NO: 7) ADDQNPWRAYLDLLFPTDTLLLDLLWKA, (SEQ ID NO: 8) AKDDQNPWRAYLDLLFPTDTLLLDLLWA, (SEQ ID NO: 9) ACDDQNPWRAYLDLLFPTDTLLLDLLWG, (SEQ ID NO: 10) ADDQNPWRAYLDLLFPTDTLLLDLLWCG, (SEQ ID NO: 11) ADDQNPWRAYLDLLFPTDTLLLDLLWKG, (SEQ ID NO: 12) ACDDQNPWRAYLDLLFPTDTLLLDLLWKG, (SEQ ID NO: 13) AKDDQNPWRAYLDLLFPTDTLLLDLLWCG, (SEQ ID NO: 14) ACKDDQNPWRAYLDLLFPTDTLLLDLLWG, (SEQ ID NO: 15) ACDDQNPWRAYLDLLFPTDTLLLDLLW, (SEQ ID NO: 16) AKDDQNPWRAYLDLLFPTDTLLLDLLWC, (SEQ ID NO: 17) ACDDQNPWARYLDWLFPTDTLLLDL, (SEQ ID NO: 18) CDNNNPWRAYLDLLFPTDTLLLDW, (SEQ ID NO: 19) ACEEQNPWARYLEWLFPTETLLLEL, (SEQ ID NO: 20) ACEEQNPWRAYLELLFPTETLLLELLW, (SEQ ID NO: 21) CEEQQPWAQYLELLFPTETLLLEW, (SEQ ID NO: 22) CEEQQPWRAYLELLFPTETLLLEW, (SEQ ID NO: 23) AAEEQNPWARYLEWLFPTETLLLEL, or (SEQ ID NO: 24) AKEEQNPWARYLEWLFPTETLLLEL. In some embodiments, the amino acid sequence of the pHLIP peptide is less than 100%, 99%, or 95% identical to the amino acid sequence set forth as SEQ ID NOS: 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24. In some embodiments, the amino acid sequence of the pHLIP peptide is less than 100%, 99%, or 95% identical to each of the amino acid sequences set forth as SEQ ID NOS: 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24. In certain embodiments, the amino acid sequence of the pHLIP peptide is 95-100%, 95-99%, or 90-95% identical to one or more of the amino acid sequences set forth as SEQ ID NOS: 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24. In some embodiments, the amino acid sequence of the pHLIP peptide is identical to SEQ ID NO: 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24. In certain embodiments, the pHLIP peptide comprises 20-30 amino acids. For example, the pHLIP peptide comprises about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acids. In some embodiments, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or 1-3, 1-5, or 5-10 N-terminal amino acids of the pHLIP peptide are outside the cell (i.e., not within the lipid bilayer of the cell membrane) when the pHLIP peptide is inserted into the cell membrane. In various embodiments, when the compound is inserted into a cell membrane, then the ICG portion thereof is at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-5, 5-10, 5-15, or 10-15 angstroms (Å) from the lipid bilayer of the cell membrane. Aspects of the present subject matter provide a composition comprising a compound disclosed herein and a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises D-glucose, e.g., about 5-25 mM D-glucose, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 25 mM D-glucose. In some embodiments, the composition comprises a buffer, e.g., the composition is buffered such that it comprises pH of about 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.8, 7.9, or 8.0. In certain embodiments, the composition comprises phosphate buffered saline (PBS). Aspects of the present subject matter relate to the detection of oral cavity cancer, e.g., by spraying or administering a composition comprising a compound disclosed herein to the oral cavity. For example, the composition may comprise a mouthwash or a mouth spray. Also provided is a method for detecting cancer tissue or precancerous tissue in a bodily organ or tissue, comprising (a) contacting the bodily organ or tissue with a compound disclosed herein; (b) contacting the compound with electromagnetic radiation comprising an excitation wavelength of ICG; and (c) detecting electromagnetic radiation emitted from the compound, wherein detection of the radiation indicates the presence of the cancerous tissue or the precancerous tissue. In various embodiments, the level of radiation emitted from a precancerous tissue and/or a cancer tissue is at least 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or 20-fold, 25-fold, or more greater than a level of radiation emitted from normal non-cancerous tissue (e.g., corresponding normal-noncancerous tissue in a corresponding bodily organ or tissue). The compounds, compositions, and methods provided herein are useful for detecting cancerous or precancerous tissue in many bodily organs and tissues. In some embodiments, the bodily organ is a kidney or a urinary bladder. Non-limiting examples of tissues in which cancerous or precancerous tissue may be detected include bone, joint, ligament, muscle, tendon, salivary gland, tooth, gum, parotid gland, submandibular gland, sublingual gland, pharynx, esophagus, stomach, small intestine (e.g., duodenum, jejunum, and/or ileum), large intestine, liver, gallbladder, pancreas, nasal cavity, pharynx, larynx, trachea, bronchi, lung, diaphragm, kidney, ureter, bladder, urethra, ovary, uterus, fallopian tube, uterus, cervix, vagina, teste, epididymis, vas deferens, seminal vesicle, prostate, bulbourethral gland, pituitary gland, pineal gland, thyroid gland, parathyroid gland, adrenal gland, heart, artery, vein, capillary, lymphatic, lymph node, bone marrow, thymus, spleen, brain, cerebral hemisphere, diencephalon, brainstem, midbrain, pons, medulla oblongata, cerebellum, spinal cord, ventricular, choroid plexus, nerve, eye, ear, olfactory, breast, and skin tissue. In some embodiments, the diseased cancer tissue detected is sarcoma or carcinoma tissue. Non-limiting types of cancer that may be detected using compounds, compositions, and methods disclosed herein include bladder cancer, lung cancer, brain cancer, melanoma, breast cancer, cervical cancer, ovarian cancer, adrenal cancer, esophageal cancer, upper gastrointestinal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, Castleman Disease, colon/rectum cancer, endometrial cancer, esophagus cancer, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GISTs), gestational trophoblastic disease, Kaposi sarcoma, kidney cancer, laryngeal cancer, hypopharyngeal cancer, liver cancer, malignant mesothelioma, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oral cavity cancer, oropharyngeal cancer, osteosarcoma, pancreatic cancer, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, small intestine cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulbar cancer, and Wilms tumors. In various embodiments, the cancer comprises a solid tumor. In some embodiments, the cancerous or precancerous tissue is in the bladder, the upper urinary tract, a lymph node, a breast, a prostate, a head, a neck, a brain, a pancreas, a lung, a liver, or a kidney. The compounds, compositions, and methods provided herein are also useful for detecting cancer cells (such as metastatic cancer cells) in tissue such as a lymph node. In some embodiments, the lymph node is in a subject who has cancer. In various embodiments, the lymph node is in a subject with bladder cancer, upper urinary tract cancer, breast cancer, prostate cancer, head and neck cancer, bran cancer, pancreatic cancer, lung cancer, liver cancer, or kidney cancer. Diseased tissue (e.g., precancerous or cancer tissue) may be detected in tissue samples or biopsies obtained, removed, or provided from a subject. In various embodiments, the tissue comprises a tissue biopsy. Alternatively or in addition, the presence of diseased tissue is detected on a biological surface in vivo or in situ, e.g., the skin surface, the surface of a mucosal membrane, or an internal site (e.g., the internal surface of a bladder, the surface of a colon, the surface of an esophagus, or the surface of a surgical site within the subject). For example, the tissue to be interrogated comprises a lumen, e.g., a duct (such as a kidney duct), a ureter, an intestinal tissue (large or small intestine), an esophagus, or an airway lumen such as a tracheobronchial tube or alveolar tube. In some embodiments, a compound provided herein is used to detect the presence of melanoma tissue. In some embodiments, the bodily organ or tissue is present in a subject. Optionally, methods disclosed herein may include steps such as washing steps to remove excess unbound or unattached compound, i.e. compound that is not attached to a low pH tissue via insertion of a pHLIP peptide construct into a cell membrane. For example, an organ sample or tissue biopsy may be washed or perfused before ICG fluorescence is detected (e.g., imaged). In non-limiting examples in which a body cavity or surface has been contacted with a compound (e.g., in liquid or spray form), the cavity or surface may be flushed or washed to remove excess ICG before detection/imaging. In some embodiments, flushing/washing is performed using, e.g., an aqueous solution such as saline or water. In some embodiments, flushing/washing is performed with the carrier that was used to deliver the ICG-pHLIP peptide. In some embodiments, contacting a bodily organ, tissue, or fluid (such as blood) with a compound provided herein comprises administering the compound to a subject. For example, the compound is detected in vivo. In certain embodiments, the compound is administered to the subject via intravessical instillation, intravenous injection, intraperitoneal injection, topical administration, mucosal administration, or oral administration. For example, the compound may be administered to a site within the subject (e.g., sprayed, applied onto, delivered as a liquid) via tube that is inserted into the subject. The site may be, e.g., an existing, former, or suspected tumor site, and/or normal tissue that is being assessed for the presence of cancerous or precancerous tissue. In some embodiments, a tube or other device (e.g., a catheter, needle, aspirator, inhaler, endoscope, cystoscope, atomizer, spray nozzle, probe, syringe, pipette, or nebulizer) is used to deliver the compound to, e.g., the esophagus, bladder, or colon. In certain embodiments, fluorescence of the compound is detected (e.g., imaged) using an endoscope or a cystoscope. For example, the endoscope or cystoscope may be configured to (i) emit electromagnetic radiation comprising an excitation wavelength of ICG and/or (ii) detect electromagnetic radiation emitted from the compound (i.e., the ICG component of the compound). In some embodiments, the compound is administered by applying a liquid, powder, or spray comprising the compound to a surface of the subject. In some embodiments, the surface comprises a site within the body of the subject that is accessed and/or exposed via surgery. In some embodiments, the surgery comprises endoscopic surgery or cystoscopic surgery. In certain embodiments, the compound is administered to an oral cavity of the subject. In various embodiments, electromagnetic radiation emitted from the compound is detected ex vivo. In some embodiments, a tissue sample (e.g., a biopsy or an organ) from a subject is perfused, soaked, sprayed, incubated, and/or injected with a composition comprising a compound herein, followed by washing, and then imaging for ICG fluorescence. Aspects of the present subject matter relate to methods comprising surgically removing cancerous tissue or precancerous tissue, e.g., cancer tissue or precancerous tissue detected with a compound, composition, or method disclosed herein. For example, the fluorescence of the compounds provided herein may be used to guide surgery such that all cancerous and/or precancerous tissue is removed, i.e., clean (non-cancer containing) margins of the surgical site are achieved. The present subject matter provides methods for identifying precancerous and cancer/tumor tissue faster than existing pathological methods. For example, tissue removed during surgery can be contacted with ICG-pHLIP peptides, washed, and then rapidly imaged to determine, e.g., whether all of the tissue removed was precancerous or cancerous and/or whether precancerous or cancerous tissue remains in a subject. Alternatively or in addition, the surgical site may be contacted with a compound (e.g., by local or systemic administration) to determine whether any diseased tissue remains at the site. The methods provided herein do not require, e.g., time consuming immunohistological staining or evaluation by a trained pathologist. The speed (e.g., 30 minutes or less) at which the methods provided herein may be performed enable clinicians to test for the presence or absence of precancerous or cancerous tissue (e.g., within a subject or a sample from the subject) during ongoing surgery, e.g., to determine whether and where surgery should continue (e.g., to remove more tissue). The development, reoccurrence, and treatment of cancer can also be detected and monitored. For example, a subject who has had cancer surgically removed or treated (e.g., with chemotherapy or radiation) may be tested for cancer using compounds and methods disclosed herein. For example, the inside of a bladder, colon, esophagus, or oral cavity, and/or a mucosal membrane/skin surface may be contacted with a compound provided herein and then detected to determine whether precancerous and/or cancerous tissue is developing or has developed. In instances where, e.g., chemotherapy or radiation therapy efficacy is assessed, the amount of cancer tissue may be monitored. Thus, ICG-pH-triggered compounds provided herein can be used to assist decisions regarding whether cancer treatment should be initiated or continued, and/or whether a different treatment regimen should be attempted (e.g., if a previously administered dose/regimen has not reduced the amount of cancer tissue as desired). Many different types of subjects with various stages of cancer can be assessed and/or treated using the compounds, compositions, and methods provided herein. However, various embodiments relate to the detection and treatment of cancer before the removal of a large amount of tissue (e.g., an organ such as a bladder or kidney, or, e.g. a portion of an organ such as a colon) is warranted or advisable. In various embodiments, the subject does not comprise invasive or metastatic cancer. In certain embodiments, relating to subjects with urothelial carcinoma, the subject does not comprise high grade urothelial carcinoma. In some embodiments, the subject does not comprise invasive high grade urothelial carcinoma. Each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. Thus, all combinations of the various elements described herein are within the scope of the invention. Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below.
A61K490056
20170922
20180503
63697.0
A61K4900
0
NIEBAUER, RONALD T
FLUORESCENT COMPOUND COMPRISING A FLUOROPHORE CONJUGATED TO A pH-TRIGGERED POLYPEPTIDE
SMALL
0
PENDING
A61K
2,017
15,713,546
PENDING
PRINTING DEVICES SUPPORTING PRINTING OVER AIR OR PRINTING OVER A WIRELESS NETWORK
Printing devices (including controllers) supporting printing in a wireless local area network, printing over air, or network printing by registering the printing device with a service over a network are herein disclosed and enabled. The printing device may include wireless communication circuitry that supports part of IEEE 802.11 standards for (1) connecting to a wireless local area network (LAN) to establish communication with an information apparatus that is in the wireless LAN; (2) transmitting device information related to the printing device from the printing device to the information apparatus; and (3) receiving print data from the information apparatus over the wireless LAN for printing at the printing device. The print data is based on the device information transmitted to the information apparatus. A printer driver specific to the printing device may or may not be necessary to be installed in the information apparatus for printing to the printing device.
1. A method for a printing device to wirelessly provide printing services, the printing device includes wireless communication circuitry for establishing a wireless local area network connection to a wireless local area network, the method comprises: (1) wirelessly connecting, using the wireless communication circuitry of the printing device, to the wireless local area network; (2) wirelessly establishing communication, using the wireless communication circuitry of the printing device, with an information apparatus that is in the wireless local area network in (1); (3) wirelessly transmitting, using the wireless communication circuitry and over the wireless local area network, device information from the printing device to the information apparatus in (2), the device information includes at least one of identification information, capability information, address information, status information, or attribute information, individually or in any combination, related to the printing device; (4) wirelessly receiving, via the wireless communication circuitry of the printing device, print data from the information apparatus for printing at the printing device, the print data is based, at least in part, on the device information transmitted to the information apparatus in (3). 2. The method of claim 1, wherein the printing device is operable to provide printing service to the information apparatus without requiring the information apparatus to install, or to have preinstalled, a printer specific printer driver associated with the printing device at the information apparatus. 3. The method of claim 2, wherein the device information transmitted from the printing device to the information apparatus in (3), includes identification information related to the printing device, the identification information includes one or more of a name, a model, a brand, an identifier, a registration, a URL, a security key, a PIN, or an IP address, individually or in any combination, and the identification information is to facilitate, at least in part, the information apparatus identifying the printing device for service. 4. The method of claim 3, wherein the device information transmitted from the printing device to the information apparatus in (3), further includes capability information related to one or more languages or formats supported by the printing device, and wherein the print data received at the printing device is in accordance, at least in part, to the one or more languages or formats supported by the printing device and specified in the device information. 5. The method of claim 4, wherein the wireless communication circuitry includes one or more chips or chipsets, the one or more chips or chipsets are compatible, at least in part, with at least part of a protocol within IEEE 802.11 standards for wirelessly connecting to the wireless local area network in (1). 6. The method of claim 5, wherein the printing device further includes an interface for interacting with a user, and prior to wirelessly connecting to the wireless local area network, the method further comprises: receiving, via the interface of the printing device, security information or authentication information for establishing the wireless local area network connection; and using the received security information or the authentication information to wirelessly connect to the wireless local area network in (1). 7. The method of claim 6, wherein the printing device further includes a wireless device discovery component, and wherein the establishing of wireless communication with the information apparatus in (2) includes the printing device using the wireless device discovery component for the information apparatus to wirelessly discover the printing device or for the printing device to wirelessly discover the information apparatus. 8. The method of claim 2, wherein the information apparatus includes software program executable at the information apparatus, and wherein the method further comprises: (a) accessing, by the software program, one or more servers operated, at least in part, by a service provided over a network, the accessing of the one or more servers is based, at least in part, on having obtained, by the software program, appropriate security or authentication information for accessing the service; (b) wirelessly receiving, by the software program at the information apparatus, the device information in (3) from the printing device over the wireless local area network in (1); (c) transmitting, using the software program, at least part of the device information received from the printing device in (3) to the one or more servers accessed in (a); (d) receiving, by the software program at the information apparatus, output data from the one or more servers, the output data is device specific for printing at the printing device and is based, at least in part, on the device information transmitted in (c); and (e) transmitting, by the software program and over the wireless local area network, the print data in (4) to the printing device, the print data is related, at least in part, to the output data received from the one or more servers in (d).
CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 10/053,765 filed Jan. 18, 2002, which claims priority to U.S. Provisional Patent Application Ser. No. 60/262,764, filed Jan. 19, 2001. Additionally, this application is a continuation-in-part of U.S. patent application Ser. No. 09/992,413 filed Nov. 18, 2001, which claims benefit of U.S. Provisional Patent Application Ser. No. 60/252,682 filed Nov. 20, 2000. Moreover, this application is a continuation-in-part of U.S. patent application Ser. No. 13/710,299 filed Dec. 10, 2012, which is a continuation of U.S. patent application Ser. No. 12/903,048 filed Oct. 12, 2010 and now issued as U.S. Pat. No. 8,332,521, which is a continuation of U.S. patent application Ser. No. 10/016,223 filed Nov. 1, 2001 and now issued as U.S. Pat. No. 7,941,541, and which claims benefit of U.S. Provisional Patent Application Ser. No. 60/245,101, filed Nov. 1, 2000. The complete disclosures of the above patent applications are hereby incorporated by reference for all purposes. TECHNICAL FIELD OF THE INVENTION Present invention relates to providing content to an output device and, in particular, to providing universal output in which an information apparatus can pervasively output content to an output device without the need to install a dedicated device dependent driver or applications for each output device. BACKGROUND OF THE DISCLOSURE The present invention relates to universal data output and, in particular, to providing a new data output method and a new raster image process for information apparatuses and output devices. As described herein, information apparatuses refer generally to computing devices, which include both stationary computers and mobile computing devices (pervasive devices). Examples of such information apparatuses include, without limitation, desktop computers, laptop computers, networked computers, palmtop computers (hand-held computers), personal digital assistants (PDAs), Internet enabled mobile phones, smart phones, pagers, digital capturing devices (e.g., digital cameras and video cameras), Internet appliances, e-books, information pads, and digital or web pads. Output devices may include, without limitation, fax machines, printers, copiers, image and/or video display devices (e.g., televisions, monitors and projectors), and audio output devices. For simplicity and convenience, hereafter, the following descriptions may refer to an output device as a printer and an output process as printing. However, it should be understood that the term printer and printing used in the discussion of present invention refer to one embodiment used as a specific example to simplify the description of the invention. The references to printer and printing used here are intended to be applied or extended to the larger scope and definition of output devices and should not be construed as restricting the scope and practice of present invention. Fueled by an ever-increasing bandwidth, processing power, wireless mobile devices, and wireless software applications, millions of users are or will be creating, downloading, and transmitting content and information using their pervasive or mobile computing devices. As a result, there is a need to allow users to conveniently output content and information from their pervasive computing devices to any output device. As an example, people need to directly and conveniently output from their pervasive information apparatus, without depending on synchronizing with a stationary computer (e.g., desktop personal computer) for printing. To illustrate, a mobile worker at an airport receiving e-mail in his hand-held computer may want to walk up to a nearby printer or fax machine to have his e-mail printed. In addition, the mobile worker may also want to print a copy of his to-do list, appointment book, business card, and his flight schedule from his mobile device. As another example, a user visiting an e-commerce site using his mobile device may want to print out transaction confirmation. In still another example, a user who takes a picture with a digital camera may want to easily print it out to a nearby printer. In any of the above cases, the mobile user may want to simply walk up to a printer and conveniently print a file (word processing document, PDF, HTML etc) that is stored on the mobile device or downloaded from a network (e.g., Internet, corporate network). Conventionally, an output device (e.g., a printer) is connected to an information apparatus via a wired connection such as a cable line. A wireless connection is also possible by using, for example, radio communication or infrared communication. Regardless of wired or wireless connection, a user must first install in the information apparatus an output device driver (e.g., printer driver in the case the output device is a printer) corresponding to a particular output device model and make. Using a device-dependent or specific driver, the information apparatus may process output content or digital document into a specific output device's input requirements (e.g., printer input requirements). The output device's input requirements correspond to the type of input that the output device (e.g., a printer) understands. For example, a printer's input requirement may include printer specific input format (e.g., one or more of an image, graphics or text format or language). Therefore, an output data (or print data in the case the output device is a printer) herein refers to data that is acceptable for input to an associated output device. Examples of input requirements may include, without limitation, audio format, video format, file format, data format, encoding, language (e.g., page description language, markup language etc), instructions, protocols or data that can be understood or used by a particular output device make and model. Input requirements may be based on proprietary or published standards or a combination of the two. An output device's input requirements are, therefore, in general, device dependent. Different output device models may have their own input requirements specified, designed or adopted by the output device manufacturer (e.g., the printer manufacturer) according to a specification for optimal operation. Consequently, different output devices usually require use of specific output device drivers (e.g., printer drivers) for accurate output (e.g., printing). Sometimes, instead of using a device driver (e.g., printer driver), the device driving feature may be included as part of an application software. Installation of a device driver (e.g., printer driver) or application may be accomplished by, for example, manual installation using a CD or floppy disk supplied by the printer manufacturer. Or alternatively, a user may be able to download a particular driver or application from a network. For a home or office user, this installation process may take anywhere from several minutes to several hours depending on the type of driver and user's sophistication level with computing devices and networks. Even with plug-and-play driver installation, the user is still required to execute a multi-step process for each printer or output device. This installation and configuration process adds a degree of complexity and work to end-users who may otherwise spend their time doing other productive or enjoyable work. Moreover, many unsophisticated users may be discouraged from adding new peripherals (e.g., printers, scanners, etc.) to their home computers or networks to avoid the inconvenience of installation and configuration. It is therefore desirable that an information apparatus can output to more than one output device without the inconvenience of installing multiple dedicated device dependent drivers. In addition, conventional output or printing methods may pose significantly higher challenges and difficulties for mobile device users than for home and office users. The requirement for pre-installation of a device-dependent driver diminishes the benefit and concept of mobile (pervasive) computing and output. For example, a mobile user may want to print or output e-mail, PowerPoint® presentation documents, web pages, or other documents at an airport, gas station, convenience store, kiosk, hotel, conference room, office, home, etc. It is highly unlikely that the user would find at any of these locations a printer of the same make and model as is at the user's base station. As a consequence, under the conventional printing method, the user would have to install and configure a printer driver each time at each such remote location before printing. It is usually not a viable option given the hundreds, or even thousands of printer models in use, and the limited storage, memory space, and processing power of the information apparatus. Moreover, the user may not want to be bothered with looking for a driver or downloading it and installing it just to print out or display one page of email at the airport. This is certainly an undesirable and discouraging process to promote pervasive or mobile computing. Therefore, a more convenient printing method is needed in support of the pervasive computing paradigm where a user can simply walk up to an output device (e.g., printer or display device) and easily output a digital document without having to install or pre-install a particular output device driver (e.g., printer driver). Another challenge for mobile users is that many mobile information apparatuses have limited memory space, processing capacity and power. These limitations are more apparent for small and low-cost mobile devices including, for example, PDAs, mobile phones, screen phones, pagers, e-books, Internet Pads, Internet appliances etc. Limited memory space poses difficulties in installing and running large or complex printer or device drivers, not to mention multiple drivers for a variety of printers and output devices. Slow processing speed and limited power supply create difficulties driving an output device. For example, processing or converting a digital document into output data by a small mobile information apparatus may be so slow that it is not suitable for productive output. Intensive processing may also drain or consume power or battery resources. Therefore, a method is needed so that a small mobile device, with limited processing capabilities, can still reasonably output content to various output devices. To output or render content (e.g. digital document) to an output device, a raster image processing (RIP) operation on the content is usually required. RIP operation can be computationally intensive and may include (1) a rasterization operation, (2) a color space conversion, and (3) a halftoning operation. RIP may also include other operations such as scaling, segmentation, color matching, color correction, GCR (Grey component replacement), Black generation, image enhancement compression/decompression, encoding/decoding, encryption/decryption GCR, image enhancement among others. Rasterization operation in RIP involves converting objects and descriptions (e.g. graphics, text etc) included in the content into an image form suitable for output. Rasterization may include additional operations such as scaling and interpolation operations for matching a specific output size and resolution. Color space conversion in RIP includes converting an input color space description into a suitable color space required for rendering at an output device (e.g. RGB to CMYK conversion). Digital halftoning is an imaging technique for rendering continuous tone images using fewer luminance and chrominance levels. Halftoning operations such as error diffusion can be computationally intensive and are included when the output device's bit depth (e.g. bits per pixel) is smaller than the input raster image bit depth. Conventionally, RIP operations are included either in an information apparatus, or as part of an output device or output system (e.g. in a printer controller). FIG. 1A illustrates a flow diagram of a conventional data output method 102 in which RIP 110 is implemented in the information apparatus. Output devices that do not include a printer controller to perform complex RIP operations, such as a lower-cost, lower speed inkjet printer, normally employ data output method 102. In data output method 102, an information apparatus obtains content (e.g. a digital document) in step 100 for rendering or output at an output device. The information apparatus may includes an application (e.g. device driver), which implements RIP operation 110. The information apparatus generates an output data in step 120 and transmits the output data to the output device in step 130 for rendering. The output data relating to the content is in an acceptable form (e.g. in an appropriate output size and resolution) to the output engine (e.g. display engine, printer engine etc.) included in the output device. The output data in a conventional output method 102 is usually device dependent. One drawback for the data output method 102 of FIG. 1A is that the information apparatus performs most if not the entire raster image processing operations 110 required for output. The RIP operations may require intensive computation. Many information apparatus such as mobile information device might have insufficient computing power and/or memory to carry out at an acceptable speed the RIP operations 110 required in an output process. Another drawback for the conventional data output method 102 of FIG. 1A is that the generated output data is device dependent and therefore is typically not very portable to other output devices. As a result, the information apparatus may need to install multiple applications or device drivers for multiple output devices, which may further complicate its feasibility for use in information apparatuses with limited memory, storage and processing power. FIG. 1B illustrates a flow diagram of another conventional data output method 104 in which the RIP is implemented in an output device. An example of an output device that implements process 104 is a high-speed laser printer which includes a printer controller for performing RIP operations and an output engine (e.g. printer engine) for rendering content. Printer controller may be internally installed or externally connected to an output device (printer in this example). In data output method 104, an information apparatus obtains content for output in step 100 and generates in step 160 an output data or print data for transmitting to the output device in step 170. Print data includes information related to the content and is usually encoded in a page description language (PDL) such as PostScript and PCL etc. In step 180, the printer receives the output data or print data (in a PDL). In step 190, a printer controller included in the printer interprets the PDL, performs RIP operations, and generates a printer-engine print data that is in a form acceptable to the printer engine (e.g. a raster image in an appropriate output size, bit depth, color space and resolution). In step 150 the printer engine renders the content with the printer-engine print data. It will be understood that a reference to print data or output data including a language, such as PDL, should be interpreted as meaning that the print data or output data is encoded using that language. Correspondingly, a reference to a data output process generating a language, such as PDL, should be interpreted as meaning that the data output process encodes data using that language. There are many drawbacks in the conventional data output method 104 shown in FIG. 1B. These drawbacks are especially apparent for mobile computing devices with limited processing power and memory. One such drawback is that the output data or print data, which include a page description language (PDL) such as PostScript or PCL, can be very complex. Generating complex PDL may increase memory and processing requirements for an information apparatus. Furthermore, interpreting, decoding and then raster image processing complex PDL can increase computation, decrease printing speed, and increase the cost of the output device or its printer controller. Another drawback is that the output data that includes PDL can creates a very large file size that would increase memory and storage requirements for the information apparatus, the output device and/or the printer controller etc. Large file size may also increase the bandwidth required in the communication link between the information apparatus and the output device. Finally, to rasterize text in an output device, a printer controller may need to include multiple fonts. When a special font or international characters is not included or missing in the printer controller, the rendering or output can potentially become inaccurate or inconsistent. SUMMARY OF THE INVENTION Accordingly, this invention provides a convenient universal data output method in which an information apparatus and an output device or system share the raster image processing operations. Moreover, the new data output method eliminates the need to install a plurality of device-dependent dedicated drivers or applications in the information apparatus in order to output to a plurality of output devices. In accordance with present invention, an electronic system and method of pervasive and universal output allow an information apparatus to output content conveniently to virtually any output device. The information apparatus may be equipped with a central processing unit, input/output control unit, storage unit, memory unit, and wired or wireless communication unit or adapters. The information apparatus preferably includes a client application that may be implemented as a software application, a helper application, or a device driver (a printer driver in case of a printer). The client application may include management and control capabilities with hardware and software components including, for example, one or more communication chipsets residing in its host information apparatus. The client application in the information apparatus may be capable of communicating with, managing and synchronizing data or software components with an output device equipped with an output controller of present invention. Rendering content in an output device refers to printing an image of the content onto an substrate in the case of a printing device; displaying an image of the content in the case of a displaying device; playing an audio representation of the content in a voice or sound output device or system. An output controller may be a circuit board, card or software components residing in an output device. Alternatively, the output controller may be connected externally to an output device as an external component or “box.” The output controller may be implemented with one or more combinations of embedded processor, software, firmware, ASIC, DSP, FPGA, system on a chip, special chipsets, among others. In another embodiment, the functionality of the output controller may be provided by application software running on a PC, workstation or server connected externally to an output device. In conventional data output method 102 as described with reference to FIG. 1A, an information apparatus transmits output data to an output device for rendering. Output data corresponds to content intended for output and is mostly raster image processed (RIPed) and therefore is device dependent because raster image processing is a typical device dependent operation. Output data may be encoded or compressed with one or more compression or encoding techniques. In present invention, an information apparatus generates an intermediate output data for transmitting to an output device. The intermediate output data includes a rasterized image corresponding to the content; however, device dependent image processing operations of a RIP (e.g. color matching and halftoning) have not been performed. As a result, an intermediate output data is more device independent and is more portable than the output data generated by output method with reference to FIG. 1A. In one implementation of this invention, the intermediate output data includes MRC (Mixed raster content) format, encoding and compression techniques, which further provides improved image quality and compression ratio compared to conventional image encoding and compression techniques. In an example of raster image process and data output method of the present invention, a client application such as a printer driver is included in an information apparatus and performs part of raster image processing operation such as rasterization on the content. The information apparatus generates an intermediate output data that includes an output image corresponding to the content and sends the intermediate output data to an output device or an output system for rendering. An output controller application or component included in the output device or output system implements the remaining part of the raster image processing operations such as digital halftoning, color correction among others. Unlike conventional raster image processing methods, this invention provides a more balanced distribution of the raster image processing computational load between the Information apparatus and the output device or the output system. Computational intensive image processing operations such as digital halftoning and color space conversions can be implemented in the output device or output system. Consequently, this new raster image processing method reduces the processing and memory requirements for the information apparatus when compared to conventional data output methods described with reference to FIG. 1A in which the entire raster image process is implemented in the information apparatus. Additionally, in this invention, a client application or device driver included in the information apparatus, which performs part of the raster image processing operation, can have a smaller size compared to a conventional output application included in the information apparatus, which performs raster image processing operation. In another implementation, the present invention provides an information apparatus with output capability that is more universally accepted by a plurality of output devices. The information apparatus, which includes a client application, generates an intermediate output data that may include device independent attributes. An output controller includes components to interpret and process the intermediate output data. The information apparatus can output content to different output devices or output systems that include the output controller even when those output devices are of different brand, make, model and with different output engine and input data requirements. Unlike conventional output methods, a user does not need to preinstall in the information apparatus multiple dedicated device dependent drivers or applications for each output device. The combination of a smaller-sized client application, a reduced computational requirement in the information apparatus, and a more universal data output method acceptable for rendering at a plurality of output devices enable mobile devices with less memory space and processing capabilities to implement data output functions which otherwise would be difficulty to implement with conventional output methods. In addition, this invention can reduce the cost of an output device or an output system compared to conventional output methods 104 that include a page description language (PDL) printer controller. In the present invention, an information apparatus generates and sends an intermediate output data to an output device or system. The intermediate output data in one preferred embodiment includes a rasterized output image corresponding to the content intended for output. An output controller included in an output device or an output system decodes and processes the intermediate output data for output, without performing complex interpretation and rasterization compared to conventional methods described in process 104. In comparison, the conventional data output process 104 generates complex PDL and sends this PDL from an information apparatus to an output device that includes a printer controller (e.g. a PostScript controller or a PCL5 controller among others). Interpretation and raster image processing of a PDL have much higher computational requirements compared to decoding and processing the intermediate output data of this invention that include rasterized output image or images. Implementing a conventional printer controller with, for example, PDL increases component cost (e.g. memories, storages, ICs, software and processors etc.) when compared to using the output controller included in the data output method of this present invention. Furthermore, an output data that includes PDL can create a large file size compared to an intermediate output data that includes rasterized output image. The data output method for this invention comparatively transmits a smaller output data from an information apparatus to an output device. Smaller output data size can speed up transmission, lower communication bandwidth, and reduce memory requirements. Finally, this invention can provide a convenient method to render content at an output device with or without connection to a static network. In conventional network printing, both information apparatus and output device must be connected to a static network. In this invention, through local communication and synchronization between an information apparatus and an output device, installation of hardware and software to maintain static network connectivity may not be necessary to enable the rendering of content to an output device. According to the several aspects of the present invention there is provided the subject matter defined in the appended independent claims. Additional objects and advantages of the present invention will be apparent from the detailed description of the preferred embodiment thereof, which proceeds with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1A is a flow diagram of a conventional data output method and its corresponding raster image process in accordance with prior art. FIG. 1B is a flow diagram of a second conventional data output method and its corresponding raster image process for an output device that includes a conventional printer controller in accordance with prior art. FIGS. 2A and 2B are block diagrams illustrating components of an operating environment that can implement the process and apparatus of the present invention. FIG. 3A is a schematic block diagram illustrating hardware/software components of an information apparatus implementation in accordance with the present invention. The information apparatus includes an operating system. FIG. 3B is a second schematic block diagram illustrating hardware/software components of an information apparatus implementation in accordance with the present invention. FIG. 4A is a block diagram of a conventional printing system or printer with a conventional printer controller. FIG. 4B is a block diagram of a second conventional output system or output device. FIG. 5A is a schematic block diagram of a printing system or printer with a conventional printer controller and an output controller in accordance with present invention. FIG. 5B is a schematic block diagram of a second output system or output device that includes an output controller in accordance with present invention. FIG. 6A is a schematic block diagram illustrating hardware/software components of an output controller in accordance with present invention. The output controller includes an operating system. FIG. 6B is a second schematic block diagram illustrating hardware/software components of an output controller in accordance with present invention. The output controller does not include an operating system. FIG. 6C is a third schematic block diagram illustrating hardware/software components of an output controller in accordance with present invention. The output controller combines the functionality of a printer controller and an output controller of present invention. FIGS. 7A-7F illustrate various configurations and implementations of output controller with respect to an output device such as a printer. FIG. 8A is a block diagram illustrating an exemplary implementation of hardware/software components of wireless communication unit. FIG. 8B is block diagram illustrating a second exemplary implementation of hardware/software components of wireless communication unit. FIG. 9 is a flow diagram of a universal data output method and its corresponding raster imaging process of the present invention. FIG. 10 is a block diagram of a universal data output method of the present invention with respect to the components, system and apparatus described with reference to FIG. 2. FIG. 11 is a flow diagram illustrating one way of implementing a discovery process optionally included in the output process of FIG. 10. FIGS. 12A and 12B are flow diagrams of exemplary client application process included in the output process of FIG. 10. FIGS. 13A and 13B are flow diagrams of exemplary output device or output system process included in the output process of FIG. 10. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Sets forth below are definitions of terms that are used in describing implementations of the present invention. These definitions are provided to facilitate understanding and illustration of implementations of the present invention and should in no way be construed as limiting the scope of the invention to a particular example, class, or category. Output Device Profile (or Object) An output device profile (or object) includes software and data entity, which encapsulates within itself both data and attributes describing an output device and instructions for operating that data and attributes. An output device profile may reside in different hardware environments or platforms or applications, and may be transported in the form of a file, a message, a software object or component among other forms and techniques. For simplicity of discussion, a profile or object may also include, for example, the concept of software components that may have varying granularity and can consist of one class, a composite of classes, or an entire application. The term profile or object used herein is not limited to software or data as its media. Any entity containing information, descriptions, attributes, data, instructions etc. in any computer-readable form or medium such as hardware, software, files based on or including voice, text, graphics, image, or video information, etc., are all valid forms of profile and object definition. A profile or object may also contain in one of its fields or attributes a reference or pointer to another profile or object, or a reference or pointer to data and or content. A reference to a profile or object may include one or more, or a combination of pointers, identifiers, names, paths, addresses or any descriptions relating to a location where an object, profile, data, or content can be found. An output device profile may contain one or more attributes that may identify and describe, for example, the capabilities and functionalities of a particular output device such as a printer. An output device profile may be stored in the memory component of an output device, an information apparatus or in a network node. A network node includes any device, server or storage location that is connected to the network. As described below in greater detail, an information apparatus requesting output service may communicate with an output device. During such local service negotiation, at least a partial output device profile may be uploaded to the information apparatus from the output device. By obtaining the output device profile (or printer profile in the case of a printer), the information apparatus may learn about the capability, compatibility, identification, and service provided by the output device. As an example, an output device profile may contain one or more of the following fields and or attribute descriptions. Each of following fields may be optional, and furthermore, each of the following fields or attributes may or may not exist in a particular implementation (e.g., may be empty or NULL): Identification of an output device (e.g., brand, model, registration, IP address etc.) Services and feature sets provided by an output device (e.g., color or grayscale output, laser or inkjet, duplex, output quality, price per page, quality of service, etc.) Type of input languages, formats, output data and/or input requirements (e.g., PostScript, PCL, XML, RTL, etc.) supported by an output device. Device specific or dependent parameters and information (e.g., communication protocols, color space, color management methods and rendering intents, resolution, halftoning methods, dpi (dots-per-inch), bit depth, page size, printing speed, number of independent colors channels or ink etc.) Data and tables needed for image processing such as color table, halftone table, scale factor, encoding/decoding parameters and methods, compression and decompression parameters and method etc. Another profile which contain parameters and information about the output device and its service (e.g. color profiles, halftoning profiles, communication profiles, rasterization profiles, quality of service etc.). Payment information on a plurality of services provided by an output device. Information or security requirements and type of authentication an output device supports. Date and version of the output device profile, history of its modification and updates. Software components containing algorithms or instructions or data, which may be uploaded to run in an information apparatus. For example, a graphical user interface (GUI) software component may be uploaded to an information apparatus. The software component may be incorporated into or launched in the information apparatus by a client application of present invention to capture a user's preferences (e.g., print quality, page layout, number of copies, number of cards per page, etc.). In another example, software components may include methods, instructions or executables for compression/decompression, encoding/decoding, color matching or correction, segmentation, scaling, halftoning, encryption/decryption among others. Pointer or reference to one or more output device parameters, including one or more of the above described output device profile or object fields and or attribute descriptions. For example, a more up-to-date or original version of output device parameters may sometimes be stored in a network node (any device, server or storage location that is connected to the network), or within the information apparatus where it can be obtained by the client application. An output device profile may include pointer or pointers to these output device parameters. Content (or Data Content, Digital Content, Output Content) Content (or data content, digital content, output content) is the data intended for output, which may include texts, graphics, images, forms, videos, audio among other content types. Content may include the data itself or a reference to that data. Content may be in any format, language, encoding or combination, and it can be in a format, language or encoding that is partially or totally proprietary. A digital document is an example of content that may include attributes and fields that describe the digital document itself and or reference or references to the digital document or documents. Examples of a digital document may be any one or combination of file types: HTML, VHTML, PostScript, PCL, XML, PDF, MS Word, PowerPoint, JPEG, MPEG, GIF, PNG, WML, VWML, CHTML, HDML, ASCII, 2-byte international coded characters, etc. Content may be used interchangeably with the term data content, output content or digital content in the descriptions of present invention. Intermediate Output Data Output data (or print data in case of a printer) is the electronic data sent from an information apparatus to an output device. Output data is related to the content intended for output and may be encoded in a variety of formats and languages (e.g. postscript, PCL, XML), which may include compressed or encrypted data. Some output device manufacturers may also include in the output data (or print data) a combination of proprietary or non-proprietary languages, formats, encoding, compression, encryption etc. Intermediate output data is the output data of the present invention, and it includes the broader definition of an output file or data generated by an information apparatus, or a client application or device driver included in the information apparatus. An intermediate output data may contain text, vector graphics, images, video, audio, symbols, forms or combination and can be encoded with one or more of a page description language, a markup language, a graphics format, an imaging format, a metafile among others. An intermediate output data may also contain instructions (e.g. output preferences) and descriptions (e.g. data layout) among others. Part or all of an intermediate output data may be compressed, encrypted or tagged. In a preferred embodiment of this invention, intermediate output data contains rasterized image data. For example, vector graphics and text information or objects that are not in image form included in content can be rasterized or conformed into image data in an information apparatus and included in an intermediate output data. Device dependent image processing operations of a RIP such as digital halftoning and color space conversions can be implemented at an output device or an output system. The intermediate output data can be device dependent or device independent. In one implementation, the rasterized output image is device dependent if the rasterization parameters used, such as resolution, scale factor, bit depth, output size and or color space are device dependent. In another implementation of this invention, the rasterized image may be device independent if the rasterization parameters used are device independent. Rasterization parameter can become device independent when those parameters include a set of predetermined or predefined rasterization parameters based on a standard or a specification. With predefined or device independent rasterization parameters, a client application of present invention can rasterize at least a portion of the content and generate a device independent image or images included in the intermediate output data. By doing so, the intermediate output data may become device independent and therefore, become universally acceptable with output devices that have been pre-configured to accept the intermediate output data. One advantage of rasterizing or converting text and graphics information into image data at the information apparatus is that the output device or printer controller no longer needs to perform complex rasterization operation nor do they need to include multiple fonts. Therefore, employing the intermediate output data and the data output method described herein could potentially reduce the cost and complexity of an output controller, printer controller and or output device. One form of image data encoding is known as mixed raster content, or MRC. Typically, an image stored in MRC includes more than one image or bitmap layers. In MRC, an image can be segmented in different layers based on segmentation criteria such as background and foreground, luminance and chrominance among others. For example, an MRC may include three layers with a background layer, a foreground layer and a toggle or selector layer. The three layers are coextensive and may include different resolution, encoding and compression. The foreground and background layers may each contain additional layers, depending on the manner in which the respective part of the image is segmented based on the segmentation criteria, component or channels of a color model, image encoding representation (HLS, RGB, CMYK, YCC, LAB etc) among others. The toggle layer may designate, for each point, whether the foreground or background layer is effective. Each layer in a MRC can have different bit depths, resolution, color space, which allow, for example, the foreground layer to be compressed differently from the background layer. The MRC form of image data has previously been used to minimize storage requirements. Further, an MRC format has been proposed for use in color image fax transmission. In one embodiment of present invention, the intermediate output data includes one or more rasterized output images that employ MRC format, encoding and or related compression method. In this implementation, different layers in the output image can have different resolutions and may include different compression techniques. Different information such as chrominance and luminance and or foreground and background information in the original content (e.g. digital document) can be segmented and compressed with different compression or encoding techniques. Segmented elements or object information in the original content can also be stored in different image layers and with different resolution. Therefore, with MRC, there is opportunity to reduce output data file size, retain greater image information, increase compression ratio, and improve image quality when compared to other conventional image encoding and compression techniques. Implementations of rasterization, raster image processing and intermediate output data that include MRC encoding in the present invention are described in more detail below. Rasterization Rasterization is an operation by which graphics and text in a digital document are converted to image data. For image data included in the digital document, rasterization may include scaling and interpolation. The rasterization operation is characterized by rasterization parameters including, among others bit depth and resolution. A given rasterization operation may be characterized by several more rasterization parameters, including output size, color space, color channels etc. Values of one or more of the rasterization parameters employed in a rasterization operation may be specified by default; values of one or more of the rasterization parameters may be supplied to the information apparatus as components of a rasterization vector. In a given application, the rasterization vector may specify a value of only one rasterization parameter, default values being employed for other rasterization parameters used in the rasterization operation. In another application the rasterization vector may specify values of more than one, but less than all, rasterization parameters, default values being employed for at least one other rasterization parameter used in the rasterization operation. And in yet another application the rasterization vector may specify values of all the rasterization parameters used in the rasterization operation. FIGS. 2A and 2B are block diagrams illustrating components of an operating environment that can implement the process and apparatus of present invention. FIG. 2A shows an electronic system which includes an information apparatus 200 and an output device 220. The output device 220 includes an output controller 230. FIG. 2B illustrates a second implementation of an electronic system that includes an information apparatus 200 and an output system 250. The output system 250 includes an output device 220 and an output controller 230 which may be externally connected to, or otherwise associated with, the output device 220 in the output system 250. Information apparatus 200 is a computing device with processing capability. In one embodiment, information apparatus 200 may be a mobile computing device such as palmtop computer, handheld device, laptop computer, personal digital assistant (PDA), smart phone, screen phone, e-book, Internet pad, communication pad, Internet appliance, pager, digital camera, etc. It is possible that information apparatus 200 may also include a static computing device such as a desktop computer, workstation, server, etc. FIGS. 3A and 3B are block diagrams illustrating examples of hardware/software components included in an information apparatus 200 of present invention. Information apparatus 200 may contain components such as a processing unit 380, a memory unit 370, an optional storage unit 360 and an input/output control unit (e.g. communication manager 330). Information apparatus 200 may include an interface (not shown) for interaction with users. The interface may be implemented with software or hardware or a combination. Examples of such interfaces include, without limitation, one or more of a mouse, a keyboard, a touch-sensitive or non-touch-sensitive screen, push buttons, soft keys, a stylus, a speaker, a microphone, etc. Information apparatus 200 typically contains one or more network communication unit 350 that interfaces with other electronic devices such as network node (not shown), output device 220, and output system 230. The network communication unit may be implemented with hardware (e.g., silicon chipsets, antenna), software (e.g., protocol stacks, applications) or a combination. In one embodiment of the present invention, communication interface 240 between information apparatus 200 and output device 220 or output system 250 is a wireless communication interface such as a short-range radio interface including those implemented according to the Bluetooth or IEEE 802.11 standard. The communication interface may also be realized by other standards and/or means of wireless communication that may include radio, infrared, cellular, ultrasonic, hydrophonic among others for accessing one or more network node and/or devices. Wired line connections such as serial or parallel interface, USB interface and fire wire (IEEE 1394) interface, among others, may also be included. Connection to a local network such as an Ethernet or a token Ring network, among others, may also be implemented in the present invention for local communication between information apparatus 200 and output device 220. Examples of hardware/software components of communication units 350 that may be used to implement wireless interface between the information apparatus 200 and the output device 220 are described in more detail with reference to FIGS. 8A and 8B below. For simplicity, FIG. 3 illustrates one implementation where an information apparatus 200 includes one communication unit 350. However, it should be noted that an information apparatus 200 may contain more than one communication unit 350 in order to support different interfaces, protocols, and/or communication standards with different devices and/or network nodes. For example, information apparatus 200 may communicate with one output device 220 through a Bluetooth standard interface or through an IEEE 802.11 standard interface while communicating with another output device 220 through a parallel cable interface. The information apparatus 200 may also be coupled to a wired or wireless network (e.g. the Internet or corporate network) to send, receive and/or download information. Information apparatus 200 may be a dedicated device (e.g., email terminal, web terminal, digital camera, e-book, web pads, Internet appliances etc.) with functionalities that are pre-configured by manufacturers. Alternatively, information apparatus 200 may allow users to install additional hardware components and or application software 205 to expand its functionality. Information apparatus 200 may contain a plurality of applications 205 to implement its feature sets and functionalities. As an example, a document browsing or editing application may be implemented to help user view and perhaps edit, partially or entirely, digital documents written in certain format or language (e.g., page description language, markup language, etc.). Digital documents may be stored locally in the information apparatus 200 or in a network node (e.g., in content server). An example of a document browsing application is an Internet browser such as Internet Explorer, Netscape Navigator, or a WAP browser. Such browsers may retrieve and display content (e.g. digital content) written in mark-up languages such as HTML, WML, XML, CHTML, HDML, among others. Other examples of software applications in the information apparatus 200 may include a document editing software such as Microsoft Word™ which also allows users to view and or edit digital documents that have various file extensions (e.g., doc, rtf, html, XML etc.) whether stored locally in the information apparatus 200 or in a network node. Still, other example of software applications 205 may include image acquisition and editing software. As illustrated previously with reference to FIG. 1, there are many difficulties in providing output capability to an information apparatus 200 that has limited memory and processing capability. To address theses difficulties, information apparatus 200 includes a client application 210 that helps provide the universal data output capability of the present invention. Client application 210 may include software and data that can be executed by the processing unit 380 of information apparatus 200. Client application 210 may be implemented as a stand-alone software application or as a part of or feature of another software application, or in the form of a device driver, which may be invoked, shared and used by other application software 205 in the information apparatus 200. Client application 210 may also include components to invoke other applications 205 (e.g., a document browsing application, editing application, data and/or image acquisition application, a communication manager, a output manager etc.) to provide certain feature sets, as described below. FIG. 3 illustrates a configuration where the client application 210 is a separate application from the other application 205 such as the case when the client application is a device driver; however, it should be noted that the client application 210 can be combined or being part of the other application not shown in FIG. 3. Client application 210 may be variously implemented in an information apparatus 200 and may run on different operating systems or platforms. The client application 210 may also run in an environment with no operating system. For example, FIG. 3A illustrates an implementation where the information apparatus 200A includes an operating system 340A; while FIG. 3B illustrates an implementation where the information apparatus 200B does not include an operating system. Client application 210 includes a rasterization component 310 to conform content into one or more raster output images according to one or more rasterization parameters; an intermediate output data generator component 320 that generates and/or encodes intermediate output data that includes the one or more output images; and a communications manager 330 that manages the communication and interaction with an output device 220 or system 250 or output controller 230. Communications manager can be implemented as part of the client application 210 (shown in FIG. 3) or as a separate application (not shown). Components in a client application can be implemented in software, hardware or combination. As an example, client application 210 may include or utilize one or more of the following: Components or operations to obtain content (e.g. digital document) for output. The client application 210 may obtain a digital document from other applications 205 (e.g. document browsing application, content creation and editing application, etc.), or the client application 210 may provide its own capability for user to browse, edit and or select a digital document. Components or operations to rasterize content that includes text, graphics and images among others objects or elements into one or more raster images according to a set of rasterization parameters such as scale factor, output size, bit depth, color space and resolution. The rasterization parameters may be obtained in various ways, for example, from an output device profile uploaded from an output device 220, or stored locally in information apparatus 200, or manually inputted by a user. Alternatively, rasterization parameters may be based on a predefined standard or specification stored in the information apparatus 200 as a set of defaults, or hard-coded in the client application 210, or calculated by the client application 210 after communicating with an output device 220, output controller 230, and/or a user. Components or operations to generate intermediate output data that includes at least one rasterized output image corresponding to the content (e.g. digital document). This process may further include one or combination of compression, encoding, encryption and color correction among others. The intermediate output data may include, for example, images, instructions, documents and or format descriptions, color profiles among others. Components or operations to transmit the intermediate output data to an output device 220 or system 250 through wired or wireless communication link 240. The client application 210 may also optionally include or utilize one or more of the following components or operations: Components or operations to communicate with one or more output devices 220 to upload an output device profile. Components or operations to communicate directly or indirectly (such as through an operating system or component or object model, messages, file transfer etc.) with other applications 205 residing in the same information apparatus 200 to obtain objects, data, and or content needed, or related to the pervasive output process of present invention (e.g. obtain a digital document for printing). Components or operations to manage and utilize directly or indirectly functionalities provided by hardware components (e.g. communication unit 350) residing in its host information apparatus 200. Components or operations to provide a graphical user interface (GUI) in host information apparatus to interact with user. Components or operations to obtain user preferences. For example, a user may directly input his or her preferences through a GUI. A set of default values may also be employed. Default values may be pre-set or may be obtained by information apparatus 200 as result of communicating and negotiating with an output device 220 or output controller 230. The above functionalities and process of client application 210 of present invention are described in further detail in the client application process with reference to FIG. 12. Output device 220 is an electronic system capable of outputting digital content regardless of whether the output medium is substrate (e.g., paper), display, projection, or sound. A typical example of output device 220 is a printer, which outputs digital documents containing text, graphics, image or any combination onto a substrate. Output device 220 may also be a display device capable of displaying still images or video, such as, without limitation, televisions, monitors, and projectors. Output device 220 can also be a device capable of outputting sound. Any device capable of playing or reading digital content in audio (e.g., music) or data (e.g., text or document) formats is also a possible output device 220. A printer is frequently referred to herein as an example of an output device to simplify discussion or as the primary output device 220 in a particular implementation. However, it should be recognized that present invention applies also to other output devices 220 such as fax machines, digital copiers, display screens, monitors, televisions, projectors, voice output devices, among others. Rendering content with an output device 220 refers to outputting the content on a specific output medium (e.g., papers, display screens etc). For example, rendering content with a printer generates an image on a substrate; rendering content with a display device generates an image on a screen; and rendering content with an audio output device generates sound. A conventional printing system in general includes a raster image processor and a printer engine. A printer engine includes memory buffer, marking engine among other components. The raster image processor converts content into an image form suitable for printing; the memory buffer holds the rasterized image ready for printing; and the marking engine transfers colorant to substrate (e.g., paper). The raster image processor may be located within an output device (e.g. included in a printer controller 410) or externally implemented (in an information apparatus 200, external controller, servers etc). Raster image processor can be implemented as hardware, software, or a combination (not shown). As an example, raster image processor may be implemented in a software application or device driver in the information apparatus 200. Examples of raster image processing operations include image and graphics interpretation, rasterization, scaling, segmentation, color space transformation, image enhancement, color correction, halftoning, compression etc. FIG. 4A illustrates a block diagram of one conventional printing system or printer 400A that includes a printer controller 410 and a printer engine 420A. The printer controller 410 includes an interpreter 402 and a raster image processor 406, and the printer engine 420 includes memory buffer 424A and a marking engine 426A. Marking engine may use any of a variety of different technologies to transfer a rasterized image to paper or other media or, in other words, to transfer colorant to a substrate. The different marking or printing technologies that may be used include both impact and non-impact printing. Examples of impact printing may include dot matrix, teletype, daisywheel, etc. Non-impact printing technologies may include inkjet, laser, electrostatic, thermal, dye sublimation, etc. The marking engine 426 and memory buffer 424 of a printer form its printer engine 420, which may also include additional circuitry and components, such as firmware, software or chips or chipsets for decoding and signal conversion, etc. Input to a printer engine 420 is usually a final rasterized printer-engine print data generated by a raster image processor 406. Such input is usually device dependent and printer or printer engine specific. The printer engine 420 may take this device dependent input and generate or render output pages (e.g. with ink on a substrate). When a raster image processor is located inside an output device 220, it is usually included in a printer controller 410 (as shown in FIG. 4A). A printer controller 410 may interpret, rasterize, and convert input print data in the form of a page description language (e.g., PostScript, PCL), markup language (e.g., XML, HTML) or other special document format or language (e.g. PDF, EMF) into printer-engine print data which is a final format, language or instruction that printer engine 420A can understand. Print data sent to a printer with printer controller 410 is usually in a form (e.g. postscript) that requires further interpretation, processing or conversion. A printer controller 410 receives the print data, interprets, process, and converts the print data into a form that can be understood by the printer engine 420A. Regardless of the type of print data, conventionally, a user may need a device-specific driver in his or her information apparatus 200 in order to output the proper language, format, or file that can be accepted by a specific printer or output device 220. FIG. 4B illustrates another conventional output device 400B. Output device 400B may be a printing device, a display device, a projection device, or a sound device. In the case that the output device is a printing device or a printer, the printer with reference to FIG. 4B does not include a printer controller 410. As an example, printer 400B may be a low-cost printer such as a desktop inkjet printer. RIP operations in this example may be implemented in a software application or in a device driver included in an information apparatus 200. The information apparatus 200 generates device dependent output data (or print data in case of a printer) by rasterizing and converting a digital document into output data (e.g. into a compressed CMKY data with one or more bits per pixel) that can be understood by an output engine (or printer engine in case of a printer) 420B. Regardless of type or sophistication level, different output device 220 conventionally needs different printer drivers or output management applications in an information apparatus 200 to provide output capability. Some mobile devices with limited memory and processing power may have difficulty storing multiple device drivers or perform computational intensive RIP operations. It may also be infeasible to install a new device dependent or specific printer driver each time there is a need to print to a new printer. To overcome these difficulties, present invention provides several improvements to output device 220 or output system 250 as described in detail next. In present invention, output device 220 may include an output controller 230 to help managing communication and negotiation processes with an information apparatus 200 and to process output data. Output controller 230 may include dedicated hardware or software or combination of both for at least one output device 220. Output controller 230 may be internally installed, or externally connected to one or more output devices 220. The output controller 230 is sometimes referred to as a print server or output server. FIGS. 5A and 5B illustrate two exemplary internal implementations of the output controller 230 of present invention. FIG. 5A illustrates the implementation of an output controller 230 inside a conventional printer with reference to FIG. 4A, which includes a conventional printer controller 410(5A). The output controller 230(5A) includes an interpreter 510A component for decoding the intermediate output data of present invention; and a converter component 530A for converting one or more decoded output images into a printer-controller print data that is suitable for input to the printer controller 410(5A). An optional image processing component 520A may be included in the output controller 230(5A). FIG. 5B illustrates the implementation of an output controller 230 included internally in a conventional output device 220 with reference to FIG. 4B, which does not include a printer controller. The output controller 230(5B) includes an interpreter 510B component for decoding the intermediate output data of present invention; an image processor 520B component for performing one or more image processing operations such as color space conversion, color matching and digital halftoning; and an optional encoder 530B component to conform the processed output images into an output-engine output data that is suitable for input to the output engine 420B if the result of the image processing is not already in required form suitable for the output engine 420B. In one implementation, output device 220 may include a communication unit 550 or adapter to interface with information apparatus 200. Output device 220 may sometimes include more than one communication unit 550 in order to support different interfaces, protocols, or communication standards with different devices. For example, output device 220 may communicate with a first information apparatus 200 through a Bluetooth interface while communicating with a second information apparatus 200 through a parallel interface. Examples of hardware components of a wireless communication unit are described in greater detail below with reference to FIGS. 8A and 8B. In one embodiment, output controller 230 does not include a communication unit, but rather utilizes or manages a communication unit residing in the associated output device 220 such as the illustration in FIG. 5. In another embodiment, output controller 230 may include or provide a communication unit to output device 220 as shown in FIG. 6. For example, an output controller 230 with a wireless communication unit may be installed internally or connected externally to a legacy printer to provide it with wireless communication capability that was previously lacking. FIG. 6 includes three functional block diagrams illustrating the hardware/software components of output controller 230 in three different implementations. Each components of an output controller 230 may include software, hardware, or combination. For example, an output controller 230 may include components using one or more or combinations of an application-specific integrated circuit (ASIC), a digital signal processor (DSP), a field programmable gate array (FPGA), firmware, system on a chip, and various communication chip sets. Output controller 230 may also contain embedded processors 670 A with software components or embedded application software to implement its feature sets and functionalities. Output controller 230 may contain an embedded operating system 680. With an operating system, some or all functionalities and feature sets of the output controller 230 may be provided by application software managed by the operating system. Additional application software may be installed or upgraded to newer versions in order to, for example, provide additional functionalities or bug fixes. FIG. 6A and FIG. 6C illustrates examples of implementation with an operating system 680 while FIG. 6B illustrates an example without the operating system 680 or the optional embedded processor 670. Output controller 230 typically includes a memory unit 640, or may share a memory unit with, for example, printer controller 410. The memory unit and storage unit, such as ROM, RAM, flash memory and disk drive among others, may provide persistent or volatile storage. The memory unit or storage unit may store output device profiles, objects, codes, instructions or data (collectively referred to as software components) that implement the functionalities of the output controller 230. Part of the software components (e.g., output device profile) may be uploaded to information apparatus 200 during or before a data output operation. An output controller 230 may include a processor component 670A and 670C, a memory component 650, an optional storage component 640, and an optional operating system component 680. FIG. 6 shows one architecture or implementation where the memory 650, storage 640, processor 670, and operating system 680 components, if exist, can be share or accessed by other operational components in the output controller 230 such as the interpreter 610 and image processor 650. FIG. 6 shows two communication units 660A and 660B included in the output controller 230; however, the output controller 230 of present invention may include any number of communication units 660. It is also possible that the output controller does not contain any communication unit but rather utilizes the communication unit of an output device. The output controller 230 may be connected externally to an output device 220 or integrated internally into the output device 220. FIGS. 5A and 5B illustrate implementations of output controller 230 inside an output device 220. The output controller 230, however, may also be implemented as an external box or station that is wired or wirelessly connected to an output device 220. An output controller 230 implemented as an external box or station to an output device 220 may contain its own user interface. One example of such an implementation is a print server connected to an output device 220 in an output system 250. Another configuration and implementation is to integrate or combine the functionalities of an output controller 230 with an existing printer controller 410 (referred to as “combined controller”) if the output device 220 is a printer as shown with reference to FIG. 7C or 7F. A combined controller can also be internally integrated or externally connected to output device 220, and include functionalities of both printer controller 410 (e.g., input interpretation and or raster image processing) and output controller 230 of present invention. One advantage of this configuration is that the functionalities or components of output controller 230 and printer controller 410 may share the same resources, such as processing unit, memory unit, etc. FIG. 6C illustrates an example of a combined controller implementation or output controller 230 where the printer controller 410C, interpreter 610C and converter 630C shares the use of the processor 670C, memory 650C and storage 640C, managed by an operating system 680C. Various exemplary implementations and configurations of an output controller 230 with respect to an output device 220 or output system 250 are illustrated in further detail with reference to FIG. 7. Other possible implementations of output controller 230 may include, for example, a conventional personal computer (PC), a workstation, and an output server or print server. In these cases, the functionalities of output controller 230 may be implemented using application software installed in a computer (e.g., PC, server, or workstation), with the computer connected with a wired or wireless connection to an output device 220. Using a PC, server, workstation, or other computer to implement the feature sets of output controller 230 with application software is just another possible embodiment of the output controller 230 and in no way departs from the spirit, scope and process of the present invention. The difference between output controller 230 and printer controller 410 should be noted. Printer controller 410 and output controller 230 are both controllers and are both dedicated hardware and or software for at least one output device 220. Output controller 230 refers to a controller with feature sets, capabilities, and functionalities of the present invention. A printer controller 410 may contain functions such as interpreting an input page description language, raster image processing, and queuing, among others. An output controller 230 may include part or all of the features of a printer controller 410 in addition to the feature sets, functionalities, capabilities, and processes of present invention. Functionalities and components of output controller 230 for the purpose of providing universal data output may include or utilize: Components and operations to receive output data from a plurality of information apparatus 200; the output data may include an intermediate output data containing at least one rasterized image related to the data content intended for output. Components and operations to interpret and/or decode the intermediate output data. Components and operations to process the intermediate output data. Such components and operations may include image processing functions such as scaling, segmentation, color correction, color management, GCR, image enhancement, decompression, decryption, and or halftoning among others. Components and operations to generate an output-engine output data, the output-engine output data being in an output data format acceptable for input to an output engine. Components and operations to send the output-engine output data to the output engine. When associated with an output device 220 that includes a printer controller 410, the output controller of present invention may further include or utilize: Components and operations to convert the intermediate output data into a printer-controller print data (e.g. a PDL such as PostScript and PCL), the printer-controller print data being in a format acceptable to a printer controller. Components and operations to send printer-controller print data to one or more printer controllers. In addition to the above components and functionalities, output controller 230 may further include one or more of the following: Components and operations to communicate with one or more information apparatus 200 through a wired or wireless interface. Components and operations to communicate and or manage a communication unit included in the output controller 230 or output device 220. Components and operations to store at least part of an output device profile (a printer profile in case of a printer) in a memory component. Components and operations to respond to service request from an information apparatus 200 by transmitting at least part of an output device profile to the information apparatus requesting service. The output controller 230 may transmit the output device profiles or object in one or multiple sessions. Components and operations to broadcast or advertise the services provided by a host output device 220 to one or more information apparatus 200 that may request such services. Components and operations to implement payment processing and management functions by, for example, calculating and processing payments according to the services requested or rendered to a client (information apparatus 200). Components and operations to provide a user interface such as display screen, touch button, soft key, etc. Components and operations to implement job management functions such as queuing and spooling among others. Components and operations to implement security or authentication procedures. For example, the output controller 230 may store in its memory component (or shared memory component) an access control list, which specifies what device or user may obtain service from its host (or connected) output device 220. Therefore, an authorized information apparatus 200 may gain access after confirming with the control list. When output controller 230 is implemented as firmware, or an embedded application, the configuration and management of the functionalities of output controller 230 may be optionally accomplished by, for example, using controller management software in a host computer. A host computer may be a desktop personal computer (PC), workstation, or server. The host computer may be connected locally or through a network to the output device 220 or the controller 230. Communication between the host computer and the output controller 230 can be accomplished through wired or wireless communication. The management application software in the host computer can manage the settings, configurations, and feature sets of the output controller 230. Furthermore, host computer's configuration application may download and or install application software, software components and or data to the output controller 230 for the purpose of upgrading, updating, and or modifying the features and capabilities of the output controller 230. Output device 220 in one implementation includes or is connected to output controller 230 described above. Therefore, functionalities and feature sets provided by output controller 230 are automatically included in the functionalities of output device 220. The output device 220 may, however, implement or include other controllers and/or applications that provide at least partially the features and functionalities of the output controller 230. Therefore, the output device 220 may include some or all of the following functionalities: Components and operations to receive multiple service requests or queries (e.g., a service request, a data query, an object or component query etc.) from a plurality of information apparatus 200 and properly respond to them by returning components, which may contain data, software, instructions and/or objects. Components and operations to receive output data from a plurality of information apparatus 200; the output data may include an intermediate output data containing one or more rasterized image related to the content intended for output. Components and operations to interpret and/or decoding the intermediate output data. Components and operations to process and/or convert the intermediate output data into a form (e.g. output-engine print data) suitable for rendering at an output engine associated with the output device. Components and operations to render a representation or an image related to the content onto an output medium (e.g. substrate or a display screen). An output device 220 may further comprise optionally one or more of the following functionalities: Components and operations for establishing and managing a communication link with an information apparatus 200 requesting service; the communication link may include wired or wireless communication. Components and operations for storing at least part of an output device profile (e.g. printer profile) in a memory component. Components and operations to provide at least part of an output device profile (e.g., printer profile in case of a printer) to one or more information apparatus 200 requesting service. The output device 220 may transmit the output device profile in one or multiple sessions. Components and operations to advertise or broadcast services provided or available to one or more information apparatus 200. Components and operations to implement payment processing and management functions by, for example, calculating and processing payments according to the services requested by or rendered to a client (information apparatus 200). Components and operations to implement job management functionalities such as queuing and spooling among others. Components and operations to provide a user interface such as display screen touch button, soft key, power switch, etc. Components and operations to implement security or authentication procedures. For example, the output device 220 may store in its memory component (or a shared memory component) an access control list, which specifies what device or user may obtain service from it. Therefore, an authorized information apparatus 200 may gain access after confirming with the control list. FIGS. 7A-7F illustrate various alternative configurations and implementations of output controller 230 with respect to an output device 230. Printer is sometimes used as an exemplary output device 230 to demonstrate the various configurations. It should be understood, however, the output device 230 of present invention is not limited to printers. As described with reference to FIG. 4, a printer may or may not contain a printer controller 410. Printer 400A that includes a printer controller 410 typically has higher speed and is more expensive than printer 400B which does not include a printer controller 410. FIG. 7A shows that output controller 230 may be cascaded externally to one or more printers (only one shown). Information apparatus 200 communicates with output controller 230A, which then communicates with output device 220 such as a printer 220A. The communication link between the output controller 230A and the printer 220A may be a wired link or a wireless link, as described above. FIGS. 6A and 6B illustrates two examples of functional component design of the output controller that can implement the configuration illustrated in FIG. 7A. The Image processor 620 in this implementation is optional. FIG. 7B shows another implementation in which output controller 230B is installed as one or more circuit boards or cards internally inside printer 220B. The output controller 230B may co-exist with printer controller 410 and other components of the printer 220B. One example of this implementation is to connect output controller 230B sequentially with the printer controller 310. FIG. 5A shows as an example of an implementation. FIG. 7C shows another implementation in which the functionalities of output controller 230 and printer controller 410 are combined into a single controller (referred to as “combined controller”) 230C. In this implementation, it is possible to reduce the cost of material when compared to implementing two separate controllers as shown in FIG. 7B. As an example, the combined controller 230C may share the same processors, memories, and storages to run the applications and functionalities of the two types of controllers and therefore, may have lower component costs when compared to providing two separate controllers. FIG. 6C illustrates an example of a combined controller functional component implementation. Some printers do not include a raster image processor or printer controller 410, as illustrated in FIG. 4B. An example of this type of printer is a lower cost desktop inkjet printer. Input to an inkjet printer may consist of a compressed CMYK data (proprietary or published) with one or more bits per pixel input. To output to a printer that does not include a printer controller, a device specific software application or a printer driver is typically required in an information apparatus 200 to perform raster image processing operations. Accordingly, output controller 230 can be implemented into a variety of output devices 220 and/or output systems 250 including printers that do not have printer controllers for performing raster image processing operations. FIG. 7D and FIG. 7E illustrate two implementations of output controller 230 in an output device 220 or system 250. The output device 230 or system 250 may include a display device, a projection device, an audio output device or a printing device. In the case when the output device 220D or 220E is a printer, it does not include a printer controller. FIG. 7D illustrates an implementation of an output controller 230D installed as an external component or “box” to output device 220D. For example, the output controller 230 may be implemented as an application in a print server or as a standalone box or station. In this configuration, some or all of raster image processing operations may be implemented in the output controller 230D. Output controller 230D receives intermediate output data from an information apparatus 200 and generates output-engine output data that is acceptable to the output engine included in the output device 220D. The output controller 230D may send the output data to the output device 220D through a wired or wireless communication link or connection. FIGS. 6A and 6B illustrates two example of functional component design of the output controller that can implement the configurations for both FIGS. 7D and 7E. FIG. 7E shows a fifth implementation of output controller 230E in which the output controller 230E is incorporated within output device 220E as one or more circuit boards or cards and may contain software and applications running on an embedded processor. As with output device 220D (FIG. 7D), output device 220E does not include a printer controller 410. Accordingly, the output controller 230E implements the functionalities and capabilities of present invention that may include part of or complete raster imaging processing operation. FIG. 7F shows a sixth implementation, an external combined controller 230F that integrates the functionalities of a printer controller 310 and an output controller into a single external combined controller component or “box” 230F. The two controller functions may share a common processor as well as a common memory space to run applications of the two types of controllers. Under this configuration, either information apparatus 200 or the combined controller 230F could perform or share at least part of raster image processing functionality. FIG. 6C shows an example of functional components of a combined controller 230F. Another implementation of the combined controller 230F shown in FIG. 7F is to use an external computing device (PC, workstation, or server) running one or more applications that include the functionality of output controller 230 and printer controller 410. The above are examples of different implementations and configurations of output controller 230. Other implementations are also possible. For example, partial functionalities of output controller 230 may be implemented in an external box or station while the remaining functionalities may reside inside an output device 220 as a separate board or integrated with a printer controller 410. As another example, the functionalities of output controller 230 may be implemented into a plurality of external boxes or stations connected to the same output device 220. As a further example, the same output controller 230 may be connected to service a plurality of output devices 220 FIGS. 8A and 8B are block diagrams illustrating two possible configurations of hardware/software components of wireless communication units. These wireless communication units can be implemented and included in information apparatus 200, in output controller 230 and in output device 220. Referring to FIG. 8A, a radio adapter 800 may be implemented to enable data/voice transmission among devices (e.g., information apparatus 200 and output device 220) through radio links. An RF transceiver 814 coupled with antenna 816 is used to receive and transmit radio frequency signals. The RF transceiver 814 also converts radio signals into and from electronic signals. The RF transceiver 814 is connected to an RF link controller 810 by an interface 812. The interface 812 may perform functions such as analog-to-digital conversion, digital-to-analog conversion, modulation, demodulation, compression, decompression, encoding, decoding, and other data or format conversion functions. RF link controller 810 implements real-time lower layer (e.g., physical layer) protocol processing that enables the hosts (e.g., information apparatus 200, output controller 230, output device 220, etc.) to communicate over a radio link. Functions performed by the link controller 810 may include, without limitation, error detection/correction, power control, data packet processing, data encryption/decryption and other data processing functions. A variety of radio links may be utilized. A group of competing technologies operating in the 2.4 GHz unlicensed frequency band is of particular interest. This group currently includes Bluetooth, Home radio frequency (Home RF) and implementations based on IEEE 802.11 standard. Each of these technologies has a different set of protocols and they all provide solutions for wireless local area networks (LANs). Interference among these technologies could limit deployment of these protocols simultaneously. It is anticipated that new local area wireless technologies may emerge or that the existing ones may converge. Nevertheless, all these existing and future wireless technologies may be implemented in the present invention without limitation, and therefore, in no way depart from the scope of present invention. Among the currently available wireless technologies, Bluetooth may be advantageous because it requires relatively lower power consumption and Bluetooth-enabled devices operate in piconets, in which several devices are connected in a point-to-multipoint system. Referring to FIG. 8B, one or more infrared (IR) adapters 820 may be implemented to enable data transmission among devices through infrared transmission. The IR adapters 820 may be conveniently implemented in accordance with the Infrared Data Association (IrDA) standards and specifications. In general, the IrDA standard is used to provide wireless connectivity technologies for devices that would normally use cables for connection. The IrDA standard is a point-to-point (vs. point-to-multipoint as in Bluetooth), narrow angle, ad-hoc data transmission standard. Configuration of infrared adapters 820 may vary depending on the intended rate of data transfer. FIG. 8B illustrates one embodiment of infrared adapter 820. Transceiver 826 receives/emits IR signals and converts IR signals to/from electrical signals. A UART (universal asynchronous receiver/transmitter) 822 performs the function of serialization/deserialization, converting serial data stream to/from data bytes. The UART 822 is connected to the IR transceiver 826 by encoder/decoder (ENDEC) 824. This configuration is generally suitable for transferring data at relatively low rate. Other components (e.g., packet framer, phase-locked loop) may be needed for higher data transfer rates. FIGS. 8A and 8B illustrate exemplary hardware configurations of wireless communication units. Such hardware components may be included in devices (e.g., information apparatus 200, output controller 230, output device 220, etc.) to support various wireless communications standards. Wired links, however, such as parallel interface, USB, Firewire interface, Ethernet and token ring networks may also be implemented in the present invention by using appropriate adapters and configurations. FIG. 9 is a logic flow diagram of an exemplary raster imaging process (RIP) 902 that can implement the universal output method of present invention. Content (e.g. digital document) 900 may be obtained and/or generated by an application running in an information apparatus 200. For example, a document browsing application may allow a user to download and or open digital document 900 stored locally or in a network node. As another example, a document creating or editing application may allow a user to create or edit digital documents in his/her information apparatus 200. A client application 210 in the information apparatus may be in the form of a device driver, invoked by other applications residing in the information apparatus 200 to provide output service. Alternatively, the client application 210 of present invention may be an application that includes data output and management component, in addition of other functionalities such as content acquisitions, viewing, browsing, and or editing etc. For example, a client application 210 in an information apparatus 200 may itself include components and functions for a user to download, view and or edit digital document 900 in addition of the output management function described herein. Raster image process method 902 allows an information apparatus 200 such as a mobile device to pervasively and conveniently output content (e.g. a digital document) to an output device 220 or system 250 that includes an output controller 230. A client application 210 in an information apparatus 200 may perform part of raster image processing operations (e.g. rasterization operation). Other operations of raster image processing such as halftoning can be completed by the output device 220 or by the output controller 230. In conventional data output methods, raster image processing is either implemented entirely in an information apparatus (e.g. a printer that does not include a printer controller with reference to FIG. 1A) or in an output device (e.g. a printer that includes a printer controller with reference to FIG. 1B). Present invention provides a more balanced approach where raster image process operations are shared between an information apparatus 200 and an output device 220 or system 250. For example, content 600 may be processed (e.g. raster image processed) by different components or parts of an overall output system from a client application 210 to an output controller 230 before being sent to an output engine or a printer engine for final output in step 960. Because the raster image processing operations are not completely implemented in the information apparatus 200, there is less processing demand on the information apparatus 200. Therefore, present RIP process may enable additional mobile devices with less memory and processing capability to have data output capability. In step 910, rasterization operation, a content (e.g. digital document), which may include text, graphics, and image objects, is conformed or rasterized to image form according to one or more rasterization parameters such as output size, bit depth, color space, resolution, number of color channels etc. During the rasterization operation, text and vector graphics information in the content are rasterized or converted into image or bitmap information according to a given set of rasterization parameters. Image information in the content or digital document may be scaled and or interpolated to fit a particular output size, resolution and bit depth etc. The rasterization parameters are in general device dependent, and therefore may vary according to different requirements and attributes of an output device 220 and its output engine. There are many ways to obtain device dependent rasterization parameters, as described in more detail below with reference to FIG. 12A. Device dependent rasterization parameters, in one example, may be obtained from an output device profile stored in an information apparatus 200, an output device 220 or an output controller 230. In an alternative implementation, rasterization parameters may be predetermined by a standard or specification. In this implementation, in step 910 the content 900 is rasterized to fit or match this predefined or standard rasterization parameters. Therefore, the rasterized output image becomes device independent. One advantage of being device independent is that the rasterized output image is acceptable with controllers, devices and/or output devices implemented or created with the knowledge of such standard or specification. A rasterized image with predefined or standardized attributes is usually more portable. For example, both the client application 210 and output device 220 or its output controller 230 may be preprogrammed to receive, interpret, and or output raster images based on a predefined standard and/or specification. Occasionally, a predefined standard or specification for rasterization parameters may require change or update. One possible implementation for providing an easy update or upgrade is to store information and related rasterization parameters in a file or a profile instead of hard coding these parameters into programs, components or applications. Client application 210, output controller 230, and/or the output device 220 can read a file or a profile to obtain information related to rasterization parameters. To upgrade or update the standard specification or defaults requires only replacing or editing the file or the profile instead of replacing a software application or component such as the client application 210. In step 920 the rasterized content in image form is encoded into an intermediate output data. The intermediate output data, which describes the output content, may include image information, instructions, descriptions, and data (e.g. color profile). The rasterized output image may require further processing including one or more of compression, encoding, encryption, smoothing, image enhancement, segmentation, color correction among others before being stored into the intermediate output data. The output image in the intermediate output data may be encoded in any image format and with any compression technique such as JPEG, BMP, TIFF, JBIG etc. In one preferred embodiment, a mixed raster content (MRC) format and its related encoding and/or compression methods are used to generate the output image. The advantages of using MRC over other image formats and techniques may include, for example, better compression ratio, better data information retention, smaller file size, and or relatively better image quality among others. In step 930, the intermediate output data is transmitted to the output device 220 or output system 250 for further processing and final output. The transmission of the intermediate output data may be accomplished through wireless or wired communication links between the information apparatus 200 and the output device 220 and can be accomplished through one or multiple sessions. In step 940, the output device 220 or output system 250 receives the transmitted intermediate output data. The output device 220 or output system 250 may include an output controller 230 to assist communicating with the information apparatus 200 and/or processing the intermediate output data. Output controller 230 may have a variety of configurations and implementations with respect to output device 220 as shown in FIG. 7A-7F. Interpretation process 940 may include one or more of parsing, decoding, decompression, decryption, image space conversion among other operations if the received intermediate output data requires such processing. An output image is decoded or retrieved from the intermediate output data and may be temporarily stored in a buffer or memory included in the output device/output system (220/250) or output controller 230 for further processing. If the intermediate output data includes components with MRC format or encoding techniques, it may contain additional segmented information (e.g. foreground and background), which can be used to enhance image quality. For example, different techniques or algorithms in scaling, color correction, color matching, image enhancement, anti-aliasing and or digital halftoning among others may be applied to different segments or layers of the image information to improve output quality or maximize retention or recovery of image information. Multiple layers may later be combined or mapped into a single layer. These image processing and conversion components and/or operations can be included in the output controller 230 of present invention. In step 950, the decoded or retrieved output image from the intermediate output data may require further processing or conversion. This may include one or more of scaling, segmentation, interpolation, color correction, GCR, black generation, color matching, color space transformation, anti-aliasing, image enhancement, image smoothing and or digital halftoning operations among others. In an embodiment where the output device 220 does not include a printer controller, an output controller 230 or an output device 220 that includes output controller, after performing the remaining portion of RIP operations (e.g. color space conversion and halftoning) on the output image, may further convert the output data in step 950 into a form that is acceptable for input to a printer engine for rendering. In an alternative embodiment where the output device 220 or the output system 250 includes a conventional printer controller, the output controller may simply decodes and or converts the intermediate output data (print data in this example) into format or language acceptable to the printer controller. For example, a printer controller may require as input a page description language (e.g. PostScript, PCL, PDF, etc.), a markup language (HTML, XML etc) or other graphics or document format. In these cases, the output controller 230 may interpret, decompress and convert the intermediate print data into an output image that has optimal output resolution, bit depth, color space, and output size related to the printer controller input requirements. The output image is then encoded or embedded into a printer-controller print data (e.g. a page description language) and sent to the printer controller. A printer-controller print data is a print data that is acceptable or compatible for input to the printer controller. After the printer controller receives the printer-controller print data, the printer controller may further perform operations such as parsing, rasterization, scaling, color correction, image enhancement, halftoning etc on the output image and generate an appropriate printer-engine print data suitable for input to the printer engine. In step 960, the output-engine output data or printer-engine print data generated by the output controller 230 or the printer controller in step 950 is sent to the output engine or printer engine of the output device for final output. FIG. 10 illustrates a flow diagram of a universal data output process of the present invention that includes the raster image processing illustrated with reference to FIG. 9. A universal data output process allows an information apparatus 200 to pervasively output content or digital document to an output device. The data output process may include or utilize: A user interface component and operation where a user initiates an output process and provides an indication of the selected output content (e.g. digital document) for output. A client application component or operation that processes the content indicated for output, and generates an intermediate output data. The intermediate output data may include at least partly a raster output image description related to the content. An information apparatus component or operation that transmits the intermediate output data to one or more selected output device 220. An output device component (e.g. output controller) or operation that interprets the intermediate output data and may further process or convert the output data into a form more acceptable to an output engine for rendering of the content. With reference to FIG. 10, a user in step 1000 may initiate the universal output method or process 1002. Typically, a user initiates the output process by invoking a client application 210 in his/her information apparatus 200. The client application 210 may be launched as an independent application or it may be launched from other applications 205 (such as from a document browsing, creating or editing application) or as part of or component of or a feature of another application 205 residing in the same information apparatus 200. When launched from another application 205, such as the case when the client application is a device driver or helper application, the client application 210 may obtain information, such as the content (e.g. digital document) from that other application 205. This can be accomplished, for example, by one or combinations of messages or facilitated through an operating system or a particular object or component model etc. During output process 1002, a user may need to select one or more output devices 220 for output service. An optional discovery process step 1020 may be implemented to help the user select an output device 220. During the discovery process step 1020, a user's information apparatus 200 may (1) search for available output devices 220; (2) provide the user with a list of available output devices 220; and (3) provide means for the user to choose one or more output devices 220 to take the output job. An example of a discovery process 1020 is described below in greater detail with reference to FIG. 11. The optional discovery process 1020 may sometimes be unnecessary. For example, a user may skip the discovery process 1020 if he or she already knows the output device (e.g., printer) 220 to which the output is to be directed. In this case, the user may simply connect the information apparatus 200 to that output device 220 by wired connections or directly point to that output device 220 in a close proximity such as in the case of infrared connectivity. As another example, a user may pre-select or set the output device or devices 220 that are used frequently as preferred defaults. As a result, the discovery process 1020 may be partially or completely skipped if the default output device 220 or printer is found to be available. In stage 1030, the client application may interact with output device 220, the user, and/or other applications 205 residing in the same information apparatus 200 to (1) obtain necessary output device profile and/or user preferences, (2) perform functions or part of raster image processing operations such as rasterization, scaling and color correction, and/or (3) convert or encode at least partially the rasterized content (e.g. digital document) into an intermediate output data. The processing and generation of the intermediate output data may reflect in part a relationship to an output device profile and/or user preferences obtained, if any. The intermediate output data generated by the client application 210 is then transmitted through wired or wireless local communication link(s) 240 to the output controller 230 included or associated with the selected output device 220 or output system 250. An exemplary client application process is described in greater detail with reference to FIG. 12. In step 1040, the output controller 230 of present invention receives the intermediate output data. In the case where the selected output device 230 does not include a printer controller, the output controller 230 of present invention may further perform processing functions such as parsing, interpreting, decompressing, decoding, color correction, image enhancement, GCR, black generation and halftoning among others. In addition, the output controller 230 may further convert or conform the intermediate output data into a form or format suitable for the output engine (e.g. printer engine in the case of a printer). The generated output-engine output data from the output controller is therefore, in general, device dependent and acceptable for final output with the output engine (or the printer engine in case of a printer) included in the selected output device 220 or output system 250. In the case where the selected output device 220 is a printer, and when the printer includes or is connected to a printer controller, the output controller 230 may generate the proper language or input format required to interface with the printer controller (referred to as printer-controller print data). The printer controller may for example require a specific input such as a page description language (PDL), markup language, or a special image or graphics format. In these cases, the output controller 230 in step 1040 may interpret and decode the intermediate output data, and then convert the intermediate output data into the required printer-controller print data (e.g. PDL such as PostScript or PCL). The printer-controller print data generated by the output controller is then sent to the printer controller for further processing. The printer controller may perform interpretation and raster image processing operations among other operations. After processing, the printer controller generates a printer-engine print data suitable for rendering at the printer engine. In either case, the output controller 230 or printer controller generates an output-engine output data that is suitable for sending to or interfacing with the output engine or the printer engine included in the output device for rendering. The output data may be temporarily buffered in components of the output device 220. An implementation of the output device process 1040 is described in greater detail with reference to FIG. 13. The steps included in the universal pervasive output process 1002 may proceed automatically when a user requests output service. Alternatively, a user may be provided with options to proceed, cancel, or input information at each and every step. For example, a user may cancel the output service at any time by, for example, indicating a cancellation signal or command or by terminating the client application 210 or by shutting down the information apparatus 200 etc FIG. 11 is a flow diagram of an example of a discovery process 720, which may be an optional step to help a user locate one or more output devices 220 for an output job. The discovery process 1020 may, however, be skipped partially or entirely. Implementation of discovery process 1020 may require compatible hardware and software components residing in both the information apparatus 200 and the output device 220. The information apparatus 200 may utilize the client application 210 or other application 205 in this process. The discovery process 1020 may include: An information apparatus 200 communicating with available output devices 220 to obtain information and attributes relating to the output device 220 and or its services such as output device capability, feature sets, service availability, quality of service, condition. An Information apparatus 200 provides the user information on each available and or compatible output devices 220. A user selects or the client application 210 (automatically or not) selects one or more output devices 220 for the output service from the available or compatible output devices 220. Various protocols and or standards may be used during discovery process 1020. Wireless communication protocols are preferred. Wired communication, on the other hand, may also be implemented. Examples of applicable protocols or standards may include, without limitation, Bluetooth, HAVi, Jini, Salutation, Service Location Protocol, and Universal Plug-and-play among others. Both standard and proprietary protocols or combination may be implemented in the discovery process 1020. However, these different protocols, standards, or combination shall not depart from the spirit and scope of present invention. In one implementation an application (referred here for simplicity of discussion as a “communication manager,” not shown) residing in the information apparatus 200 helps communicate with output device 220 and manages service requests and the discovery process 1020. The communication manager may be a part of or a feature of the client application 210. Alternatively or in combination, the communication manager may also be a separate application. When the communication manager is a separate application, the client application 210 may have the ability to communicate, manage or access functionalities of the communication manager. The discovery process 1020 may be initiated manually by a user or automatically by a communication manager when the user requests an output service with information apparatus 200. In the optional step 1100, a user may specify searching or matching criteria. For example, a user may indicate to search for color printers and or printers that provide free service. The user may manually specify such criteria each time for the discovery process 1020. Alternatively or in combination, a user may set default preferences that can be applied to a plurality of discovery processes 1020. Sometimes, however, no searching criteria are required: the information apparatus 200 may simply search for all available output devices 220 that can provide output service. In step 1101, information apparatus 200 searches for available output devices 220. The searching process may be implemented by, for example, an information apparatus 200 (e.g. with the assistance of a communication manager) multi-casting or broadcasting or advertising its service requests and waiting for available output devices 220 to respond. Alternatively or in combination, an information apparatus 200 may “listen to” service broadcasts from one or more output devices 220 and then identify the one or more output devices 220 that are needed or acceptable. It is also possible that multiple output devices 220 of the same network (e.g., LAN) register their services with a control point (not shown). A control point is a computing system (e.g., a server) that maintains records on all service devices within the same network. An information apparatus 200 may contact the control point and search or query for the needed service In step 1102, if no available output device 220 is found, the communication manager or the client application 210 may provide the user with alternatives 1104. Such alternatives may include, for example, aborting the discovery process 1020, trying discovery process 1020 again, temporarily halting the discovery process 1020, or being notified when an available output device 220 is found. As an example, the discovery process 1020 may not detect any available output device 220 in the current wired/wireless network. The specified searching criteria (if any) are then saved or registered in the communication manager. When the user enters a new network having available output devices 220, or when new compatible output devices 220 are added to the current network, or when an output device 220 becomes available for any reason, the communication manager may notify the user of such availability. In step 1106, if available output devices 220 are discovered, the communication manager may obtain some basic information, or part of or the entire output device profile, from each discovered output device 220. Examples of such information may include, but not limited to, device identity, service charge, subscription, service feature, device capability, operating instructions, etc. Such information is preferably provided to the user through the user interface (e.g., display screen, speaker, etc.) of information apparatus 200. In step 1108, the user may select one or more output devices 220 based on information provided, if any, to take the output job. If the user is not satisfied with any of the available output device 220, the user may decline the service. In this case, the user may be provided with alternatives such as to try again in step 1110 with some changes made to the searching criteria. The user may choose to terminate the service request at any time. In step 1112, with one or more output devices 220 selected or determined, the communication link between information apparatus 200 and the selected output device or devices 220 may be “locked”. Other output devices 220 that are not selected may be dropped. The output process 1020 may then proceed to the client application process of step 1030 of FIG. 10. FIG. 12A is a flow diagram of an exemplary client application process with reference to step 1030 of FIG. 10. A client application process 1202 for universal output may include or utilize: A client application 210 that obtains content (e.g. digital document) intended for output. A client application 210 that obtains output device parameters (e.g. rasterization parameters, output job parameters). One example of implementation is to obtain the output device parameters from an output device profile (e.g. printer profile), which includes device dependent parameters. Such profile may be stored in an output controller 230, output device 220 or information apparatus 200. A client application 210 that may optionally obtain user preferences through (1) user's input (automatic or manual) or selections or (2) based on preset preference or pre-defined defaults or (3) combination of the above. A client application 210 that rasterizes at least part of the content intended for output (e.g. a digital document) according to one or more rasterization parameters obtained from previous steps such as through output device profile, user selection, predefined user preferences, predefined default or standard etc. A client application 210 that generates an intermediate output data containing at least part of the rasterized image related at least partly to the content intended for output. A client application that transmits the intermediate output data to an output device 220 or output controller 230 for further processing and or final output. A client application 210 may obtain content (e.g. digital document) 900 or a pointer or reference to the content in many ways. In a preferred embodiment, the client application 210 is in the form of a device driver or an independent application, and the content or its reference can be obtained by the client application 210 from other applications 205 in the same information apparatus 200. To illustrate an example, a user may first view or download or create a digital document by using a document browsing, viewing and or editing application 205 in his/her information apparatus 200, and then request output service by launching the client application 210 as a device driver or helper application. The client application 210 communicates with the document browsing or editing application to obtain the digital document or reference to the digital document. As another example, the client application 210 is an independent application and it launches another application to help locate and obtain the digital document for output. In this case, a user may first launch the client application 210, and then invoke another application 205 (e.g. document editing and or browsing application) residing in the same information apparatus 200 to view or download a digital document. The client application 210 then communicates with the document browsing or editing application to obtain the digital document for output. In another embodiment, the client application 210 itself provides multiple functionalities or feature sets including the ability for a user to select the content (e.g. digital document) for output. For example, the client application 210 of present invention may provide a GUI where a user can directly input or select the reference or path of a digital document that the user wants to output. In order to perform rasterization operation on content (e.g. digital document) 900, the client application 210 in step 1210 needs to obtain device dependent parameters of an output device 220 such as the rasterization parameters. Device dependent parameters may be included in an output device profile. A client application 210 may obtain an output device profile or rasterization parameters in various ways. As an example, an output device profile or rasterization parameters can be obtained with one or combination of the following: The client application communicates with an output device 220 to upload output device profile or information related to one or more rasterization parameters. The client application 210 obtains the output device profile from a network node (e.g. server). A user selects an output device profile stored in the user's information apparatus 200. The client application 210 automatically retrieves or uses a default profile, predefined standard values or default values among others. The client application 210 obtains output device parameters by calculating, which may include approximation, based at least partly on the information it has obtained from one or combination of an output device 220, a user, default values, and a network node. It is important to note that step 1210 is an optional step. In some instance, part of or the entire output device profile or related device dependent information may have been already obtained by the client application 210 during the prior optional discovery process (step 1020 in FIG. 10). In this case, step 1210 may be partially or entirely skipped. In one implementation, the client application 210 communicates with one or more output devices 220 to upload output device profiles stored in the memory or storage components of those one or more output devices 220 or their associated one or more output controllers 230. In some instance, the uploaded output device profile may contain partially or entirely references or pointers to device parameters instead of the device parameters themselves. The actual output device parameters may be stored in a network node or in the information apparatus 200, where they can be retrieved by the client application 210 or by other applications 205 using the references or pointers. It should be noted that a plurality of information apparatuses 200 may request to obtain output device profile or profiles from the same output device 220 at the same time or at least during overlapping periods. The output device 220 or its associated output controller 230 may have components or systems to manage multiple communication links and provide the output device profile or profiles concurrently or in an alternating manner to multiple information apparatuses 200. Alternatively, an output device 220 may provide components or systems to queue the requests from different information apparatuses 200 and serve them in a sequential fashion according to a scheme such as first come first served, quality of service, etc. Multi-user communication and service management capability with or without queuing or spooling functions may be implemented by, for example, the output controller 230 as optional feature sets. In another implementation, one or more output device profiles may be stored locally in the information apparatus 200. The client application 210 may provide a GUI where a user can select a profile from a list of pre-stored profiles. As an example, the GUI may provide the user with a list of output device names (e.g. makes and models), each corresponding to an output device profile stored locally. When the user selects an output device 220, the client application 210 can then retrieve the output device profile corresponding to the name selected by the user. In certain cases, during a discovery or communication process described earlier, the client application 210 may have already obtained the output device ID, name, or reference or other information in a variety of ways described previously. In this case, the client application 210 may automatically activate or retrieve an output device profile stored in the information apparatus 200 based on the output device ID, name, or reference obtained without user intervention. In yet another implementation, the client application 210 may use a set of pre-defined default values stored locally in a user's information apparatus 200. Such defaults can be stored in one or more files or tables. The client application 210 may access a file or table to obtain these default values. The client application 210 may also create or calculate certain default values based on the information it has obtained during previous steps (e.g. in optional discovery process, based on partial or incomplete printer profile information obtained, etc). A user may or may not have an opportunity to change or overwrite some or all defaults. Finally, if, for any reason, no device dependent information is available, the client application 210 may use standard output and rasterization parameters or pre-defined default parameters. The above illustrates many examples and variations of implementation, these and other possible variations in implementation do not depart from the scope of the present invention. In step 1220, the client application 210 may optionally obtain user preferences. In one exemplary implementation, the client application 210 may obtain user preferences with a GUI (graphical user interface). For simplicity, a standard GUI form can be presented to the user independent of the make and model of the output device 220 involved in the output process. Through such an interface, the user may specify some device independent output parameters such as page range, number of cards per page, number of copies, etc. Alternatively or in combination, the client application 210 may also incorporate output device-dependent features and preferences into the GUI presented to the user. The device-dependent portion of the GUI may be supported partly or entirely by information contained in the output device profile obtained through components and processes described in previous steps. To illustrate, device dependent features and capabilities may include print quality, color or grayscale, duplex or single sided, output page size among others. It is preferred that some or all components, attributes or fields of user preferences have default values. Part or all default values may be hard-coded in software program in client application 210 or in hardware components. Alternatively, the client application 210 may also access a file to obtain default values, or it may calculate certain default values based on the information it has obtained during previous steps or components (e.g. from an output device profile). A user may or may not have the ability to pre-configure, or change or overwrite some or all defaults. The client application 210 may obtain and use some or all defaults with or without user intervention or knowledge. In step 1230, the client application 210 of present invention performs rasterization operation to conform a content (e.g. a digital document), which may includes objects and information in vector graphics, text, and images, into one or more output images in accordance with the rasterization parameters obtained in previous steps. During rasterization process, text and vector graphics object or information in the content is rasterized or converted into image or bitmap form according to the given set of rasterization parameters. Image information in the content may require scaling and interpolation operations to conform the rasterization parameters. Rasterization process may further include operations such as scaling, interpolation, segmentation, image transformation, image encoding, color space transformation etc. to fit or conform the one or more output images to the given set of rasterization parameters such as target output size, resolution, bit depth, color space and image format etc. In step 1240, the client application 210 generates an intermediate output data that includes the rasterized one or more output images. The intermediate output data of the present invention may contain image information, instructions, descriptions, and data such as color profile among others. Creating and generating intermediate output data may further include operations such as compression, encoding, encryption, smoothing, segmentation, scaling and or color correction, among others. The image or images contained in an intermediate output data may be variously encoded and/or implemented with different image formats and/or compression methods (e.g. JPEG, BMP, TIFF, JBIG etc or combination). One preferred implementation is to generate or encode the output image in the intermediate output data with mixed raster content (MRC) description. The use of MRC in the data output process of present invention provides opportunities to improve the compression ratio by applying different compression techniques to segmented elements in the content. In addition, MRC provides opportunities to maintain more original content information during the encoding process of the output image and, therefore, potentially improve output quality. In step 1250, the client application 210 transmits intermediate output data to an output device 220 through local communication link 240. The communication link may be implemented with wired or wireless technologies and the transmission may include one or multiple sessions. It should be recognized that FIG. 12A illustrates one example of a client application process 1030 in the data output method 1002 of present invention. Other implementations with more or less steps are possible, and several additional optional processes not shown in FIG. 12 may also be included in the client application process 1030. Use of these different variations, however, does not result in a departure from the scope of the present invention. As an example, an optional authentication step may be included when the selected output device 220 provides service to a restricted group of users. Various authentication procedures may be added in step 1210 when client application 210 obtains output device profile by communicating with an output device or an output controller. As another example, authentication procedures may also be implemented in step 1250 when the client application transmits intermediate output data to one or more output devices 220 or output controllers 230. A simple authentication may be implemented by, for example, comparing the identity of an information apparatus 200 with an approved control list of identities stored in the output device 220 or output controller 230. Other more complex authentication and encryption schemes may also be used. Information such as user name, password, ID number, signatures, security keys (physical or digital), biometrics, fingerprints, voice among others, may be used separately or in combination as authentication means. Such identification and or authentication information may be manually provided by user or automatically detected by the selected output device or devices 220 or output controller 230. With successful authentication, a user may gain access to all or part of the services provided by the output device 220. The output device profile that the client application 210 obtains may vary according to the type or quality of service requested or determined. If authentication fails, it is possible that a user may be denied partially or completely access to the service. In this case, the user may be provided with alternatives such as selecting another output device 220 or alternative services. Another optional process is that a user may be asked to provide payment or deposit or escrow before, during or after output service such as step 1210 or 1250 with reference to FIG. 12. Examples of payment or deposit may include cash, credit card, bankcard, charge card, smart card, electronic cash, among others. The output controller 220 may provide payment calculation or transaction processing as optional feature sets of present invention. FIG. 12B illustrates another exemplary client application output process 1030 with which an information apparatus 200 can pervasively and universally output content to one or more output devices 220 associated with or equipped with an output controller 230 of present invention. The process illustrated in FIG. 12B is similar to the process described in FIG. 12A except that step 1210, obtaining output device profile, is skipped. In this embodiment, the client application 210 utilizes a set of hard-coded, standard or predefined output device parameters including rasterization parameters with which the client application 210 can perform rasterization operation and other required image processing functions. Users may be provided with the option of changing these parameters or inputting alternative parameters. Rasterization parameters include output size, output resolution, bit depth, color space, color channels, scale factors etc. These pre-defined parameters typically comply with a specification or a standard. The same specification and standard may also defined or describe at least partly the intermediate output data. Predefined standard parameters can be stored in a file or profile in an information apparatus 200, an output controller 230, and/or in an output device 220 for easy update or upgrade. In client output process 1204, since the rasterization parameters are predefined, the client application 210 may not need to upload printer profiles from the selected output device 230. Consequently, no two-way communication between the information apparatus 200 and the output device or devices 220 is necessary in this process 1204 when compared with process 1202 illustrated in FIG. 12A. The client application 210 performs rasterization operation 1225 based on standard and/or predefined parameters and generates a rasterized output image with predefined or standard properties of those rasterization parameters. The resulting intermediate output data, which includes at least one rasterized output image, is transmitted from the information apparatus 200 to an output device 220 in step 1250 or to its associated output controller 230 for rendering or output. The intermediate output data generated in process 1202 in general is less device dependent compared to the intermediate output data generated in the process 1202 shown in FIG. 12A. The output controller 230 included or associated with the output device 220 may be preprogrammed to interpret the raster output image, which includes properties or attributes that correspond to those standard or predefined parameters. The standard or predefined rasterization parameters may be hard coded or programmed into the client application 210 and/or the output controller 230. However, instead of hard coding those parameters, one technique to facilitate updates or changes is to store those standard parameters in a default file or profile. The standard or predefined parameters contained in the file or profile can be retrieved and utilized by applications in an information apparatus 200 (e.g. client application 210) and/or by applications or components in an output device 220 or the output controller 230. In this way, any necessary updates, upgrades or required changes to those predefined or standard parameters can be easily accomplished by replacing or modifying the file or profile instead of modifying or updating the program, application or components in the information apparatus 200, output device 220 and/or output controller 230. A client application process 1204 providing universal output capability to information apparatus 200 may include or utilize: A client application 210 that obtains content (e.g. digital document) intended for output. A client application 210 that optionally obtains user preferences (in step 1220) through (1) user's input (automatic or manual) or selections or (2) based on preset preference or predefined defaults or (3) combination of the above. A client application 210 that rasterizes content (in step 1230 or 1225) according to pre-defined or standard rasterization parameters. A client application 210 that generates intermediate output data (in step 1240) for rendering or output at an output device 220; the intermediate output data containing at least partially a rasterized image related to the content intended for output. A client application 210 that transmits the intermediate output data to an output device 220 (in step 1250) for further processing and final output. One advantage of the client output process 1204 of FIG. 12B compared to the process 1202 illustrated in FIG. 12A is that the generated intermediate output data is in general less device dependent. The device independent attribute allows the intermediate output data to be more portable and acceptable to more output devices equipped or associated with output controllers. Both data output processes (1202 and 1204) enable universal output; allowing a user to install a single client application 210 or components in an information apparatus 200 to provide output capability to more than one output device 220. FIG. 13A illustrates one example of an output device process 1302 and its associated raster imaging method of present invention. In this output device process 1302, an output device 220 is capable of receiving an intermediate output data from an information apparatus 200. The output device process 1302 and its operations may include or utilize: An output device/system or output controller that receives intermediate output data (in step 1300). The intermediate output data includes at least partially a raster output image describing at least part of the content for rendering at the output device 220 or system 250. An output device/system or output controller that interprets (in step 1310) the intermediate output data; in one preferred embodiment, the intermediate output data includes an output image utilizing one or more MRC formats or components. An output device/system or output controller that performs image processing operation (in step 1320) on the raster image. The image processing operation may include but not limited to image decompression, scaling, halftoning, color matching, among others. An output device/system or output controller that converts and or generates (in step 1330) output-engine output data that is in a format or description suitable for input to an output engine (e.g. printer engine in case of a printer) included in an output device 220. An output engine in an output device 220 that renders or generates a final output (e.g. the output-engine output data) in step 1370. The output device 220 or output system 250 may include an output controller 230 internally or externally to assist the management and operation of the output process 1302. As shown in FIG. 7, there are many possible configurations and implementations of an output controller 230 associated to an output device 220 Herein and after, output controller 230 is regarded as an integral part of the output device to which it is attached. Hence, the following described output device operations may be partially or completely performed by the output controller associated with it. In step 1300, output device process 1302 is initiated by client application 210 transmitting an intermediate output data to output device 220 or output system 250. In step 1310, the output device 220 reads and interprets the intermediate output data, containing at least one raster output image relating to the content intended for output. During the reading and interpretation process 1310, the output device 220 may include components that parse the intermediate output data and perform operations such as decompression, decoding, and decryption among others. The output image may be variously encoded and may include one or more compression methods. In the event that the method of image encoding includes MRC format, then, in one example implementation, during decoding and mapping of the output image in step 1310, the lower resolution layer and information in an image that includes MRC may be mapped, scaled or interpolated to a higher-resolution output image to produce a better image quality. Therefore, step 1310, in the event that the intermediate output data includes MRC component, each layer in an MRC image can be decompressed, processed, mapped and combined into a single combined output image layer. Step 1310 may also include scaling, color space transformation, and/or interpolation among others. In addition to the possibility of mapping methods using different scaling and interpolation ratio with different layers, another advantage of using MRC is that segmentation information contained in MRC can be utilized to apply different image processing and enhancement techniques to data in different layers of an MRC image in step 1320. In step 1320, the output device 220 may further perform image processing operations on the decoded output image. These image processing operations may include, for example, color correction, color matching, image segmentation, image enhancement, anti-aliasing, image smoothing, digital watermarking, scaling, interpolation, and halftoning among others. The image processing operations 1320 may be combined or operated concurrently with step 1310. For example, while each row, pixel, or portion of the image is being decoded and or decompressed, image processing operations 1320 is applied. In another implementation, the image processing 1320 may occur after the entire output image or a large portion of the image has been decoded or decompressed. If the intermediate output data includes MRC component, then in step 1320, there are additional opportunities to improve image quality. An image encoded in MRC contains segmented information that a traditional single layer image format does not usually have. As an example, foreground can be in one layer, and background in another. As another example, chrominance information may be in one layer and luminance may be in another. This segmented information in MRC may be used to apply different or selective image processing methods and algorithms to different layers or segments to enhance image quality or retain or recover image information. Different image processing techniques or algorithms may include color matching, color correction, black generation, halftoning, scaling, interpolation, anti-aliasing, smoothing, digital watermarking etc. For example, one can apply calorimetric color matching to foreground information and perceptual color matching to background information or vice versa. As another example, error diffusion halftoning can be applied to foreground and stochastic halftoning can be applied to background or vice versa. As yet another example, bi-cubic interpolation can be applied to a layer and bi-linear or minimum distance interpolation can be applied to a different layer. In step 1330, the output device 220 or the output controller 230 may convert the processed image (e.g. halftoned) into a form acceptable to the output engine of output device 220. This conversion step is optional, depending on the type, format and input requirement of a particular output device engine (e.g. printer engine in case of a printer). Different output engines may have different input raster image input requirements. As an example different output engines may require different input image formats, number of bits or bytes per pixel, compression or uncompressed form, or different color spaces (e.g. such as RGB, CMY, CMYK, or any combination of Hi-Fi color such as green, orange, purple, red etc). Incoming raster image data can be encoded in a row, in a column, in multiple rows, in multiple columns, in a chunk, in a segment, or a combination at a time for sending the raster data to the output engine. In some cases, step 1330 may be skipped if the result of step 1320 is already in a form acceptable to the output device engine. In other cases, however, further conversion and or processing may be required to satisfy the specific input requirement of a particular output device engine. It is important to note that the above described processing from step 1310 to step 1330 may require one or more memory buffers to temporarily store processed results. The memory buffer can store or hold a row, a column, a portion, or a chunk, of the output image in any of the steps described above. Storing and retrieving information into and from the memory buffer may be done sequentially, in an alternating fashion, or in an interlaced or interleaved fashion among other possible combinations. Step 1310 to step 1330 operations can be partially or completely implemented with the output controller 230. In step 1370, the output device engine included in the output device 220 or output system 250 receives the output-engine output data generated in step 1330 or step 1320. The output-engine output data is in a form that satisfies the input requirements and attributes of the output engine, such as color space, color channel, bit depth, output size, resolution, etc. The output engine then takes this output-engine output data and outputs or renders the data content through its marking engine or display engine. One advantage of data output method 1002 that includes output device process 1302 is that it has less processing requirements on an information apparatus 200 compared to conventional process with reference to FIG. 1A, and therefore, enables more information apparatus 200 with relatively lower processing power and memory space to have output capability. For example, some image processing functions, such as halftoning (e.g. error diffusion) may require substantial processing and computing power. In data output process 1002 that includes output device process 1302, halftoning is performed in step 1320 by an output device component (e.g. the output controller 230) included in the output device 220 or the output system 250, not in the information apparatus 200; therefore reducing the computational requirements for the information apparatus 200. Another advantage of data output 1302 is that the intermediate output data is less device dependent than the output data generated by conventional output method 102 with reference to FIG. 1A. The device independence provides opportunity to allow a single driver or application in an information apparatus 200 to output intermediate output data to a plurality of output devices 220 that include output controllers 230. Some output devices 220 may contain a printer controller 410. An example of this type of output device or printer is a PostScript printer or PCL printer among others. FIG. 13B illustrates an example of an output device process 1304 with a printer that includes a printer controller 410. As discussed in FIG. 1, a printer with a printer controller requires input such as page description language (e.g. PostScript, PCL etc.), markup language (HTML, XML etc), special image format, special graphics format, or a combination, depending on the type of the printer controller. There are many printing system configurations for providing the data output capability and process to a printer or a printing system that includes a printer controller. In one example, the existing printer controller in the output device 220 may incorporate the feature sets provided by the output controller to form a “combined controller” as described previously with reference to FIGS. 7C and 7F. In another example, the output controller 230 of present invention may be connected sequentially or cascaded to an existing printer controller; the output controller 230 can be internally installed (with reference to FIG. 7B) or externally connected (with reference to FIG. 7A) to the output device 220. For output device 220 that includes a printer controller, the output controller 230 may simply decode the intermediate output data in step 1310 and then convert it into a form acceptable for input to the printer controller in step 1350. An output device process 1304 and operations for an output device 220 or system 250 that includes a printer controller 410 may include or utilize: An output controller 230 or components in an output device 220 or system 250 that receives an intermediate print data or output data (with reference to step 1300), the intermediate print data includes at least a raster image related at least in part to the content for rendering at the output device 220. An output controller 230 or components in an output device 220 or system 250 that interprets the intermediate output data (with reference to step 1310); in one preferred embodiment, the intermediate output data includes an output image utilizing one or more MRC format or components. An output controller 230 or components in an output device 220 or system 250 that converts the intermediate output data into a printer-controller print data (with reference to step 1350); the printer-controller print data includes a format or language (e.g. PDL, PDF, HTML, XML etc.) that is acceptable or compatible to the input requirement of a printer controller. A printer controller or components in an output device 220 or system 250 that receives a printer controller print data; the printer controller may parse, interpret and further process (e.g. rasterization, scaling, image enhancement, color correction, color matching, halftoning etc.) and convert the printer-controller print data into a printer-engine print data (with reference to step 1360); the printer-engine print data comprising of a format or description acceptable for input to a printer engine in the output device 220 or the output system 250. A printer engine or components in an output device 220 or system 250 that renders or generates a final output (with reference to step 1370) with the input printer engine print data. In output device process 1304, step 1300 (receiving intermediate output data) and step 1310 (interpret intermediate output data) are identical to step 1300 and step 1310 in output device process 1302, which have been described in previous sections with reference to FIG. 13A. In step 1350, the output controller 230 converts the intermediate print data into a printer-controller print data that is in a form compatible or acceptable for input to a printer controller. For example, a printer controller may require as input a specific page description language (PDL) such as PostScript. The output controller 230 then creates a PostScript file and embeds the output image generated or retrieved in step 1310 into the PostScript file. The output controller 230 can also create and embed the output image from step 1310 into other printer controller print data formats, instructions or languages. In step 1360, the printer controller receives printer-controller print data generated in step 1350 that includes an acceptable input language or format to the printer controller. The printer controller may parse, interpret, and decode the input printer-controller print data. The printer controller may further perform raster image processing operations such as rasterization, color correction, black generation, GCR, anti-aliasing, scaling, image enhancement, and halftoning among others on the output image. The printer controller may then generate a printer-engine print data that is suitable for input to the printer engine. The type and or format of printer-engine print data may vary according to the requirement of a particular printer engine. It is important to note that the above described process from step 1310 to step 1360 may require one or more memory buffer to temporarily store processed results. The memory buffer can store or hold a row, a column, a portion, or a chunk, of the output image in any of the steps described above. Storing and retrieving information into and from the memory buffer may be done sequentially, alternated, or in an interlaced or interleaved fashion among other possible combinations. Process and operations of step 1310 to step 1360 can be implemented with output controller 230. In step 1370, the printer engine included in the output device 220 or output system 250 generates or renders the final output based on the printer-engine print data generated in step 1360. For example, the printer-engine print data may be in CMY, CMYK, and RGB etc, and this may be in one or more bits per pixel format, satisfying the size and resolution requirement of the printer engine. The printer engine included the output device 220 may take this print data and generate or render an output page through its marking engine. Having described and illustrated the principles of our invention with reference to an illustrated embodiment, it will be recognized that the illustrated embodiment can be modified in arrangement and detail without departing from such principles. In view of the many possible embodiments to which the principles of our invention may be applied, it should be recognized that the detailed embodiments are illustrative only and should not be taken as limiting the scope of our invention. Rather, I claim as my invention all such embodiments as may come within the scope of the following claims and equivalents thereto. Unless the context indicates otherwise, a reference in a claim to the number of instances of an element, be it a reference to one instance or more than one instance, requires at least the stated number of instances of the element but is not intended to exclude from the scope of the claim a structure or method having more instances of that element than stated. Specifically, but without limitation, a reference in a claim to an or one output device or system, to an or one image, or to a or one rasterization parameter is not intended to exclude from the scope of the claim a structure or method having, including, employing or supplying two or more output devices or system, images or rasterization parameters.
<SOH> BACKGROUND OF THE DISCLOSURE <EOH>The present invention relates to universal data output and, in particular, to providing a new data output method and a new raster image process for information apparatuses and output devices. As described herein, information apparatuses refer generally to computing devices, which include both stationary computers and mobile computing devices (pervasive devices). Examples of such information apparatuses include, without limitation, desktop computers, laptop computers, networked computers, palmtop computers (hand-held computers), personal digital assistants (PDAs), Internet enabled mobile phones, smart phones, pagers, digital capturing devices (e.g., digital cameras and video cameras), Internet appliances, e-books, information pads, and digital or web pads. Output devices may include, without limitation, fax machines, printers, copiers, image and/or video display devices (e.g., televisions, monitors and projectors), and audio output devices. For simplicity and convenience, hereafter, the following descriptions may refer to an output device as a printer and an output process as printing. However, it should be understood that the term printer and printing used in the discussion of present invention refer to one embodiment used as a specific example to simplify the description of the invention. The references to printer and printing used here are intended to be applied or extended to the larger scope and definition of output devices and should not be construed as restricting the scope and practice of present invention. Fueled by an ever-increasing bandwidth, processing power, wireless mobile devices, and wireless software applications, millions of users are or will be creating, downloading, and transmitting content and information using their pervasive or mobile computing devices. As a result, there is a need to allow users to conveniently output content and information from their pervasive computing devices to any output device. As an example, people need to directly and conveniently output from their pervasive information apparatus, without depending on synchronizing with a stationary computer (e.g., desktop personal computer) for printing. To illustrate, a mobile worker at an airport receiving e-mail in his hand-held computer may want to walk up to a nearby printer or fax machine to have his e-mail printed. In addition, the mobile worker may also want to print a copy of his to-do list, appointment book, business card, and his flight schedule from his mobile device. As another example, a user visiting an e-commerce site using his mobile device may want to print out transaction confirmation. In still another example, a user who takes a picture with a digital camera may want to easily print it out to a nearby printer. In any of the above cases, the mobile user may want to simply walk up to a printer and conveniently print a file (word processing document, PDF, HTML etc) that is stored on the mobile device or downloaded from a network (e.g., Internet, corporate network). Conventionally, an output device (e.g., a printer) is connected to an information apparatus via a wired connection such as a cable line. A wireless connection is also possible by using, for example, radio communication or infrared communication. Regardless of wired or wireless connection, a user must first install in the information apparatus an output device driver (e.g., printer driver in the case the output device is a printer) corresponding to a particular output device model and make. Using a device-dependent or specific driver, the information apparatus may process output content or digital document into a specific output device's input requirements (e.g., printer input requirements). The output device's input requirements correspond to the type of input that the output device (e.g., a printer) understands. For example, a printer's input requirement may include printer specific input format (e.g., one or more of an image, graphics or text format or language). Therefore, an output data (or print data in the case the output device is a printer) herein refers to data that is acceptable for input to an associated output device. Examples of input requirements may include, without limitation, audio format, video format, file format, data format, encoding, language (e.g., page description language, markup language etc), instructions, protocols or data that can be understood or used by a particular output device make and model. Input requirements may be based on proprietary or published standards or a combination of the two. An output device's input requirements are, therefore, in general, device dependent. Different output device models may have their own input requirements specified, designed or adopted by the output device manufacturer (e.g., the printer manufacturer) according to a specification for optimal operation. Consequently, different output devices usually require use of specific output device drivers (e.g., printer drivers) for accurate output (e.g., printing). Sometimes, instead of using a device driver (e.g., printer driver), the device driving feature may be included as part of an application software. Installation of a device driver (e.g., printer driver) or application may be accomplished by, for example, manual installation using a CD or floppy disk supplied by the printer manufacturer. Or alternatively, a user may be able to download a particular driver or application from a network. For a home or office user, this installation process may take anywhere from several minutes to several hours depending on the type of driver and user's sophistication level with computing devices and networks. Even with plug-and-play driver installation, the user is still required to execute a multi-step process for each printer or output device. This installation and configuration process adds a degree of complexity and work to end-users who may otherwise spend their time doing other productive or enjoyable work. Moreover, many unsophisticated users may be discouraged from adding new peripherals (e.g., printers, scanners, etc.) to their home computers or networks to avoid the inconvenience of installation and configuration. It is therefore desirable that an information apparatus can output to more than one output device without the inconvenience of installing multiple dedicated device dependent drivers. In addition, conventional output or printing methods may pose significantly higher challenges and difficulties for mobile device users than for home and office users. The requirement for pre-installation of a device-dependent driver diminishes the benefit and concept of mobile (pervasive) computing and output. For example, a mobile user may want to print or output e-mail, PowerPoint® presentation documents, web pages, or other documents at an airport, gas station, convenience store, kiosk, hotel, conference room, office, home, etc. It is highly unlikely that the user would find at any of these locations a printer of the same make and model as is at the user's base station. As a consequence, under the conventional printing method, the user would have to install and configure a printer driver each time at each such remote location before printing. It is usually not a viable option given the hundreds, or even thousands of printer models in use, and the limited storage, memory space, and processing power of the information apparatus. Moreover, the user may not want to be bothered with looking for a driver or downloading it and installing it just to print out or display one page of email at the airport. This is certainly an undesirable and discouraging process to promote pervasive or mobile computing. Therefore, a more convenient printing method is needed in support of the pervasive computing paradigm where a user can simply walk up to an output device (e.g., printer or display device) and easily output a digital document without having to install or pre-install a particular output device driver (e.g., printer driver). Another challenge for mobile users is that many mobile information apparatuses have limited memory space, processing capacity and power. These limitations are more apparent for small and low-cost mobile devices including, for example, PDAs, mobile phones, screen phones, pagers, e-books, Internet Pads, Internet appliances etc. Limited memory space poses difficulties in installing and running large or complex printer or device drivers, not to mention multiple drivers for a variety of printers and output devices. Slow processing speed and limited power supply create difficulties driving an output device. For example, processing or converting a digital document into output data by a small mobile information apparatus may be so slow that it is not suitable for productive output. Intensive processing may also drain or consume power or battery resources. Therefore, a method is needed so that a small mobile device, with limited processing capabilities, can still reasonably output content to various output devices. To output or render content (e.g. digital document) to an output device, a raster image processing (RIP) operation on the content is usually required. RIP operation can be computationally intensive and may include (1) a rasterization operation, (2) a color space conversion, and (3) a halftoning operation. RIP may also include other operations such as scaling, segmentation, color matching, color correction, GCR (Grey component replacement), Black generation, image enhancement compression/decompression, encoding/decoding, encryption/decryption GCR, image enhancement among others. Rasterization operation in RIP involves converting objects and descriptions (e.g. graphics, text etc) included in the content into an image form suitable for output. Rasterization may include additional operations such as scaling and interpolation operations for matching a specific output size and resolution. Color space conversion in RIP includes converting an input color space description into a suitable color space required for rendering at an output device (e.g. RGB to CMYK conversion). Digital halftoning is an imaging technique for rendering continuous tone images using fewer luminance and chrominance levels. Halftoning operations such as error diffusion can be computationally intensive and are included when the output device's bit depth (e.g. bits per pixel) is smaller than the input raster image bit depth. Conventionally, RIP operations are included either in an information apparatus, or as part of an output device or output system (e.g. in a printer controller). FIG. 1A illustrates a flow diagram of a conventional data output method 102 in which RIP 110 is implemented in the information apparatus. Output devices that do not include a printer controller to perform complex RIP operations, such as a lower-cost, lower speed inkjet printer, normally employ data output method 102 . In data output method 102 , an information apparatus obtains content (e.g. a digital document) in step 100 for rendering or output at an output device. The information apparatus may includes an application (e.g. device driver), which implements RIP operation 110 . The information apparatus generates an output data in step 120 and transmits the output data to the output device in step 130 for rendering. The output data relating to the content is in an acceptable form (e.g. in an appropriate output size and resolution) to the output engine (e.g. display engine, printer engine etc.) included in the output device. The output data in a conventional output method 102 is usually device dependent. One drawback for the data output method 102 of FIG. 1A is that the information apparatus performs most if not the entire raster image processing operations 110 required for output. The RIP operations may require intensive computation. Many information apparatus such as mobile information device might have insufficient computing power and/or memory to carry out at an acceptable speed the RIP operations 110 required in an output process. Another drawback for the conventional data output method 102 of FIG. 1A is that the generated output data is device dependent and therefore is typically not very portable to other output devices. As a result, the information apparatus may need to install multiple applications or device drivers for multiple output devices, which may further complicate its feasibility for use in information apparatuses with limited memory, storage and processing power. FIG. 1B illustrates a flow diagram of another conventional data output method 104 in which the RIP is implemented in an output device. An example of an output device that implements process 104 is a high-speed laser printer which includes a printer controller for performing RIP operations and an output engine (e.g. printer engine) for rendering content. Printer controller may be internally installed or externally connected to an output device (printer in this example). In data output method 104 , an information apparatus obtains content for output in step 100 and generates in step 160 an output data or print data for transmitting to the output device in step 170 . Print data includes information related to the content and is usually encoded in a page description language (PDL) such as PostScript and PCL etc. In step 180 , the printer receives the output data or print data (in a PDL). In step 190 , a printer controller included in the printer interprets the PDL, performs RIP operations, and generates a printer-engine print data that is in a form acceptable to the printer engine (e.g. a raster image in an appropriate output size, bit depth, color space and resolution). In step 150 the printer engine renders the content with the printer-engine print data. It will be understood that a reference to print data or output data including a language, such as PDL, should be interpreted as meaning that the print data or output data is encoded using that language. Correspondingly, a reference to a data output process generating a language, such as PDL, should be interpreted as meaning that the data output process encodes data using that language. There are many drawbacks in the conventional data output method 104 shown in FIG. 1B . These drawbacks are especially apparent for mobile computing devices with limited processing power and memory. One such drawback is that the output data or print data, which include a page description language (PDL) such as PostScript or PCL, can be very complex. Generating complex PDL may increase memory and processing requirements for an information apparatus. Furthermore, interpreting, decoding and then raster image processing complex PDL can increase computation, decrease printing speed, and increase the cost of the output device or its printer controller. Another drawback is that the output data that includes PDL can creates a very large file size that would increase memory and storage requirements for the information apparatus, the output device and/or the printer controller etc. Large file size may also increase the bandwidth required in the communication link between the information apparatus and the output device. Finally, to rasterize text in an output device, a printer controller may need to include multiple fonts. When a special font or international characters is not included or missing in the printer controller, the rendering or output can potentially become inaccurate or inconsistent.
<SOH> SUMMARY OF THE INVENTION <EOH>Accordingly, this invention provides a convenient universal data output method in which an information apparatus and an output device or system share the raster image processing operations. Moreover, the new data output method eliminates the need to install a plurality of device-dependent dedicated drivers or applications in the information apparatus in order to output to a plurality of output devices. In accordance with present invention, an electronic system and method of pervasive and universal output allow an information apparatus to output content conveniently to virtually any output device. The information apparatus may be equipped with a central processing unit, input/output control unit, storage unit, memory unit, and wired or wireless communication unit or adapters. The information apparatus preferably includes a client application that may be implemented as a software application, a helper application, or a device driver (a printer driver in case of a printer). The client application may include management and control capabilities with hardware and software components including, for example, one or more communication chipsets residing in its host information apparatus. The client application in the information apparatus may be capable of communicating with, managing and synchronizing data or software components with an output device equipped with an output controller of present invention. Rendering content in an output device refers to printing an image of the content onto an substrate in the case of a printing device; displaying an image of the content in the case of a displaying device; playing an audio representation of the content in a voice or sound output device or system. An output controller may be a circuit board, card or software components residing in an output device. Alternatively, the output controller may be connected externally to an output device as an external component or “box.” The output controller may be implemented with one or more combinations of embedded processor, software, firmware, ASIC, DSP, FPGA, system on a chip, special chipsets, among others. In another embodiment, the functionality of the output controller may be provided by application software running on a PC, workstation or server connected externally to an output device. In conventional data output method 102 as described with reference to FIG. 1A , an information apparatus transmits output data to an output device for rendering. Output data corresponds to content intended for output and is mostly raster image processed (RIPed) and therefore is device dependent because raster image processing is a typical device dependent operation. Output data may be encoded or compressed with one or more compression or encoding techniques. In present invention, an information apparatus generates an intermediate output data for transmitting to an output device. The intermediate output data includes a rasterized image corresponding to the content; however, device dependent image processing operations of a RIP (e.g. color matching and halftoning) have not been performed. As a result, an intermediate output data is more device independent and is more portable than the output data generated by output method with reference to FIG. 1A . In one implementation of this invention, the intermediate output data includes MRC (Mixed raster content) format, encoding and compression techniques, which further provides improved image quality and compression ratio compared to conventional image encoding and compression techniques. In an example of raster image process and data output method of the present invention, a client application such as a printer driver is included in an information apparatus and performs part of raster image processing operation such as rasterization on the content. The information apparatus generates an intermediate output data that includes an output image corresponding to the content and sends the intermediate output data to an output device or an output system for rendering. An output controller application or component included in the output device or output system implements the remaining part of the raster image processing operations such as digital halftoning, color correction among others. Unlike conventional raster image processing methods, this invention provides a more balanced distribution of the raster image processing computational load between the Information apparatus and the output device or the output system. Computational intensive image processing operations such as digital halftoning and color space conversions can be implemented in the output device or output system. Consequently, this new raster image processing method reduces the processing and memory requirements for the information apparatus when compared to conventional data output methods described with reference to FIG. 1A in which the entire raster image process is implemented in the information apparatus. Additionally, in this invention, a client application or device driver included in the information apparatus, which performs part of the raster image processing operation, can have a smaller size compared to a conventional output application included in the information apparatus, which performs raster image processing operation. In another implementation, the present invention provides an information apparatus with output capability that is more universally accepted by a plurality of output devices. The information apparatus, which includes a client application, generates an intermediate output data that may include device independent attributes. An output controller includes components to interpret and process the intermediate output data. The information apparatus can output content to different output devices or output systems that include the output controller even when those output devices are of different brand, make, model and with different output engine and input data requirements. Unlike conventional output methods, a user does not need to preinstall in the information apparatus multiple dedicated device dependent drivers or applications for each output device. The combination of a smaller-sized client application, a reduced computational requirement in the information apparatus, and a more universal data output method acceptable for rendering at a plurality of output devices enable mobile devices with less memory space and processing capabilities to implement data output functions which otherwise would be difficulty to implement with conventional output methods. In addition, this invention can reduce the cost of an output device or an output system compared to conventional output methods 104 that include a page description language (PDL) printer controller. In the present invention, an information apparatus generates and sends an intermediate output data to an output device or system. The intermediate output data in one preferred embodiment includes a rasterized output image corresponding to the content intended for output. An output controller included in an output device or an output system decodes and processes the intermediate output data for output, without performing complex interpretation and rasterization compared to conventional methods described in process 104 . In comparison, the conventional data output process 104 generates complex PDL and sends this PDL from an information apparatus to an output device that includes a printer controller (e.g. a PostScript controller or a PCL5 controller among others). Interpretation and raster image processing of a PDL have much higher computational requirements compared to decoding and processing the intermediate output data of this invention that include rasterized output image or images. Implementing a conventional printer controller with, for example, PDL increases component cost (e.g. memories, storages, ICs, software and processors etc.) when compared to using the output controller included in the data output method of this present invention. Furthermore, an output data that includes PDL can create a large file size compared to an intermediate output data that includes rasterized output image. The data output method for this invention comparatively transmits a smaller output data from an information apparatus to an output device. Smaller output data size can speed up transmission, lower communication bandwidth, and reduce memory requirements. Finally, this invention can provide a convenient method to render content at an output device with or without connection to a static network. In conventional network printing, both information apparatus and output device must be connected to a static network. In this invention, through local communication and synchronization between an information apparatus and an output device, installation of hardware and software to maintain static network connectivity may not be necessary to enable the rendering of content to an output device. According to the several aspects of the present invention there is provided the subject matter defined in the appended independent claims. Additional objects and advantages of the present invention will be apparent from the detailed description of the preferred embodiment thereof, which proceeds with reference to the accompanying drawings.
G06F31236
20170922
20180125
66411.0
G06F312
3
RILEY, MARCUS T
PRINTING DEVICES SUPPORTING PRINTING OVER AIR OR PRINTING OVER A WIRELESS NETWORK
UNDISCOUNTED
1
CONT-ACCEPTED
G06F
2,017
15,713,743
PENDING
ELECTRONIC CIGARETTE
An electronic cigarette includes a housing, a sleeve, an atomizer, a latch assembly and a control assembly. The sleeve includes a first limiting position and a second limiting position. The atomizer includes a mouthpiece. The atomizer is capable of being inserted into the sleeve and telescoping relative to the sleeve along an axial direction of the sleeve, so as to expose the mouthpiece or take out the atomizer from the sleeve. The latch assembly is arranged on an end of the atomizer opposite to the mouthpiece and configured to latch the atomizer in the sleeve when the atomizer is retracted into the sleeve and is positioned at the first limiting position. The control assembly is arranged on the sleeve and configured to unlock the latch assembly to allow the end of the atomizer to move to the second limiting position along the axial direction of the sleeve.
1. An electronic cigarette, comprising: a housing; a sleeve received in the housing, the sleeve comprising a first limiting position and a second limiting position; an atomizer comprising a mouthpiece, the atomizer capable of being inserted into the sleeve and telescoping relative to the sleeve along an axial direction of the sleeve, so as to expose the mouthpiece or take out the atomizer from the sleeve; a latch assembly arranged on an end of the atomizer opposite to the mouthpiece, the latch assembly configured to latch the atomizer in the sleeve when the atomizer is retracted into the sleeve and is positioned at the first limiting position; and a control assembly arranged on the sleeve, the control assembly configured to unlock the latch assembly to allow the end of the atomizer to move to the second limiting position along the axial direction of the sleeve. 2. The electronic cigarette according to claim 1, further comprising a first elastic assembly, wherein an end of the first elastic assembly abuts against the end of the atomizer opposite to the mouthpiece, the other end of the first elastic assembly is connected to a bottom of the sleeve, and the first elastic assembly is capable of pushing the atomizer outwards along the axial direction of the sleeve when the atomizer is retracted in the sleeve. 3. The electronic cigarette according to claim 2, wherein the sleeve defines a positioning hole on an inner wall thereof, the positioning hole is arranged at the first limiting position, the latch assembly comprises a second elastic assembly and a limiting pin, and the second elastic assembly elastically offsets the limiting pin along a radial direction of the sleeve, such that when the end of the atomizer opposite to the mouthpiece is retracted in the first limiting position, the limiting pin is aligned with the positioning hole and is latched in the positioning hole. 4. The electronic cigarette according to claim 3, wherein the control assembly comprises a control button, the control button is arranged on the first limiting position and partially exposed on an outer side of the sleeve, such that the limiting pin is capable of being unlocked from the first limiting position by pressing the control button. 5. The electronic cigarette according to claim 4, wherein the second limiting position is arranged on the inner wall of the sleeve and is spaced apart from the first limiting position at a predetermined distance. 6. The electronic cigarette according to claim 4, wherein the sleeve defines an axial limiting groove in the inner wall thereof, the axial limiting groove is communicated with the positioning hole, and the axial limiting groove is configured to receive and guide the limiting pin when the atomizer telescopes relative to the sleeve along the axial direction of the sleeve. 7. The electronic cigarette according to claim 3, wherein both the first elastic assembly and the second elastic assembly are springs. 8. The electronic cigarette according to claim 1, further comprising an air pump; wherein the air pump is arranged on a bottom of the sleeve and capable of pushing the atomizer outwards along the axial direction of the sleeve when the atomizer is retracted in the sleeve. 9. The electronic cigarette according to claim 1, further comprising an outer thread arranged on the end of the atomizer opposite to the mouthpiece; wherein the sleeve defines an inner thread configured to engage with the outer thread, the inner thread is arranged at the second limiting position, such that the outer thread engages with the inner thread to fix the atomizer to the sleeve when the end of the atomizer opposite to the mouthpiece is pushed outwards to the second limiting position. 10. The electronic cigarette according to claim 1, wherein the latch assembly is configured to latch the atomizer in the sleeve when the atomizer is retracted at the first limiting position and an outer end portion of the mouthpiece is flushed with an outer end portion of the housing.
CROSS-REFERENCE TO RELATED APPLICATIONS The present disclosure claims priority to Chinese Patent Application No. 201621082925.6, filed with the Chinese Patent Office on Sep. 26, 2016, titled “ELECTRONIC CIGARETTE,” the entire contents of which are incorporated herein by reference. TECHNICAL FIELD The present disclosure relates to the technical field of electronic cigarettes, and in particular, relates to an electronic cigarette. BACKGROUND In current market, suction nozzles of atomizers of electronic cigarettes are fixed. The suction nozzles of the atomizers are always exposed outside, which is unsanitary in use. Protection for the suction nozzles of the atomizers depends on package boxes, and thus the atomizers are inconvenient to carry and use. SUMMARY An embodiment of the present disclosure provides an electronic cigarette. The electronic cigarette includes: a housing; a sleeve received in the housing, the sleeve including a first limiting position and a second limiting position; an atomizer including a mouthpiece, the atomizer capable of being inserted into the sleeve and telescoping relative to the sleeve along an axial direction of the sleeve, so as to expose the mouthpiece or take out the atomizer from the sleeve; a latch assembly arranged on an end of the atomizer opposite to the mouthpiece, the latch assembly configured to latch the atomizer in the sleeve when the atomizer is retracted into the sleeve and is positioned at the first limiting position; and a control assembly arranged on the sleeve, the control assembly configured to unlock the latch assembly to allow the end of the atomizer to move to the second limiting position along the axial direction of the sleeve. BRIEF DESCRIPTION OF THE DRAWINGS One or more embodiments are illustrated by way of example, and not by limitation, in the figures of the accompanying drawings, wherein elements having the same reference numeral designations represent like elements throughout. The drawings are not to scale, unless otherwise disclosed. FIG. 1 is a schematic partial cross-section view of an electronic cigarette in a first operation state according to a first embodiment of the present disclosure; FIG. 2 is a schematic partial cross-section view of the electronic cigarette of FIG. 1 in a second operation state; FIG. 3 is a schematic partial cross-section view of an electronic cigarette in a first operation state according to a second embodiment of the present disclosure; and FIG. 4 is a schematic partial cross-section view of an electronic cigarette in a first state according to a third embodiment of the present disclosure. DETAILED DESCRIPTION To make a person skilled in the art better understand the present disclosure, the technical solutions of this disclosure are further described with reference to the accompanying drawings and the specific embodiments of the present disclosure. FIG. 1 and FIG. 2 illustrate an electronic cigarette 100 according to a first embodiment of the present disclosure. The electronic cigarette 100 includes a housing 10, a sleeve 1 arranged in the housing 10, an atomizer 2 including a mouthpiece 21 (also referred to as a suction nozzle), a latch assembly 3 and a control assembly 4. The sleeve 1 has a first limiting position (not labeled) and a second limiting position (not labeled). The atomizer 2 is capable of being inserted into the sleeve 1, and capable of telescoping along an axial direction of the sleeve 1 relative to the sleeve 1 to expose the mouthpiece 21 or take out the atomizer 2. The latch assembly 3 is arranged on one end of the atomizer 2 opposite to the mouthpiece 21, and is configured to latch the atomizer 2 in the sleeve 1 when the atomizer 2 is retracted into the sleeve 1 and is defined to the first limiting position; and the control assembly 4 is arranged on the sleeve 1, and is configured to unlock the latch assembly 3 to allow the other end of the atomizer 2 to move to the second limiting position along the axial direction of the sleeve 1. In this illustrated embodiment, the atomizer 2 is movable relative to sleeve 1, such that the mouthpiece 21 arranged on the atomizer 2 is non-fixed. When being not smoked, the mouthpiece 21 arranged on the atomizer 2 may be retracted into the sleeve 1, and when being smoked, the mouthpiece 21 arranged on the atomizer 2 may stretch out of the sleeve 1, which is easy to carry, and is sanitary for use. It should be noted that, to implement the function of the electronic cigarette, an electronic core module is arranged in the housing 10, and connected to the atomizer 2. The specific connection line is not illustrated in the drawings, and is not defined in the present disclosure. The electronic core module includes a battery and a controller, wherein the battery may be arranged on a bottom of the sleeve 1, and the controller may be arranged on one side of the housing 10 opposite to the sleeve 1, and the controller is further provided with a simulated smoking butt on the side of the housing 10. In this case, a shape of the housing 10 may be variable, which is not defined. Since any electronic core module and simulated smoking butt and any combinations may be used in the present disclosure to implement the electronic cigarette of the present disclosure, the controller of the electronic core module and the simulated smoking butt are not defined in the present disclosure, and the implementation is not descried herein any further. In addition, a specific structure of the atomizer 2 is not defined in the present disclosure, the electronic cigarette of the present disclosure may be implemented in any manner, which includes an atomizing housing, a liquid guiding body received in the atomizing housing, and a heating wire wound on the liquid guiding body, wherein the heating wire is connected to the electrical core module to provide a heating source. The details are not given herein any further. Further, referring to FIG. 1 and FIG. 2, the electronic cigarette 100 includes a first elastic assembly 5, wherein one end of the first elastic assembly 5 abuts against the other end of the atomizer 2 opposite to the mouthpiece 21, the other end of the first elastic assembly 5 is connected to a bottom of the sleeve 1, and the first elastic assembly 5 provides a thrust to push the atomizer 2 outwards along the axial direction of the sleeve 1 when the atomizer 2 is retracted into the sleeve 1. When the atomizer 2 is retracted into the sleeve 1, the first elastic assembly 5 is in a compressed state, and the first elastic assembly 5 in the compressed state provides a thrust to push the atomizer 2 outwards along the axial direction of the sleeve 1 under the effect of an elastic force, which enables the atomizer 2 to eject outwards, and thereby enables the mouthpiece 21 arranged on the atomizer 2 to stretch out of the sleeve 1. In this illustrated embodiment, the first elastic assembly 5 is a spring, and in other embodiments, the first elastic assembly 5 may also be other elastic parts, for example, an elastic piece. In addition, in this illustrated embodiment, the latch assembly 4 is configured to latch the atomizer 2 into the sleeve 1 when the atomizer 2 is retracted into the first limiting position and when an outer end portion of the mouthpiece 21 is flushed with an outer end portion of the housing 10, such that when being not smoked, the appearance of the electronic cigarette 100 is beautiful. Specifically, in this illustrated embodiment, referring to FIG. 1 and FIG. 2, the sleeve 1 defines a positioning hole 11 on an inner wall thereof, the positioning hole 11 are arranged in the first limiting position, and the latch assembly 3 includes a second elastic assembly 32 and a limiting pin 31. The second elastic assembly 32 elastically offsets the limiting pin 31 along a radial direction of the sleeve 1, such that when the other end of the atomizer 2 opposite to the mouthpiece 21 is retracted into the first limiting position, the limiting pin 31 is aligned with the positioning hole 11 and is further latched into the positioning hole 11. In this illustrated embodiment, the second elastic assembly 32 is a spring, and in other embodiments, the second elastic assembly 32 may be other elastic parts, for example, an elastic piece. Further, in this illustrated embodiment, the other end of the atomizer 2 defines a receiving cabin 22, the second elastic assembly 32 and the limiting pin 31 are sequentially arranged in the receiving cabin 22 along the radial direction of the sleeve 1. In other embodiments, the other end of the atomizer 2 may define a circular hole, such that the second elastic assembly 32 and the limiting pin 31 are sequentially arranged in the circular hole along the radial direction of the sleeve 1. In this illustrated embodiment, referring to FIG. 1 and FIG. 2, the control assembly 4 includes a control button 40, the control button 40 is arranged on the first limiting position, and partially exposed on an outer side of the sleeve 1, such that the limiting pin 31 is unlocked from the first limiting position by pressing the control button 40. The control assembly 4 further includes other components. For example, the control button 40 is movably connected to a connection member 42 of the sleeve 1. Further, in this illustrated embodiment, an outer side portion of the control button 40 exposed to the sleeve 1 is flushed with an outer surface of the housing 10, such that an entire appearance of the electronic cigarette 100 is beautiful. Further, in this illustrated embodiment, the second limiting position is arranged on the inner wall of the sleeve 1, and is spaced apart from the first limiting position at a predetermined distance. In other embodiments, the second limiting position may be also arranged on an outer end of the sleeve 1. Further, the inner wall of the sleeve 1 defines an axial limiting groove 12, the axial limiting groove 12 is communicated with the positioning hole 11, and is configured to limit the limiting pin 31 when the atomizer 2 telescopes relative to the sleeve 1 along the axial direction of the sleeve 1. The axial limiting groove 12 prevents the limiting pin 31 from deviation when the atomizer 2 telescopes along the axial direction of the sleeve 1, thereby resulting in that the latch assembly 3 fails to well latch the atomizer 2 into the sleeve 1. FIG. 3 illustrates an electronic cigarette 200 according to a second embodiment of the present disclosure. The electronic cigarette 200 shown in FIG. 3 is similar to the electronic cigarette 100 shown in FIGS. 1 and 2, except that the electronic cigarette 200 further includes an air pump 6. The air pump 6 is arranged on a bottom of the sleeve 1, and configured to provide a thrust to push the atomizer 2 outwards along the axial direction of the sleeve 1 when the atomizer 2 is retracted into the sleeve 1. When the control assembly 4 unlocks the latch assembly 3, the air pump 6 is in an operation state and thus provides a thrust to push the atomizer 2 outwards, and pushes the other end of the atomizer 2 to the second limiting position. FIG. 4 illustrates an electronic cigarette 300 according to a third embodiment of the present disclosure. The electronic cigarette 300 shown in FIG. 4 is similar to the electronic cigarette 100 shown in FIGS. 1 and 2, except that the electronic cigarette 300 further includes an outer thread 7 arranged on the other end of the atomizer 2 opposite to the mouthpiece 21; an inner thread (not shown) is arranged in the sleeve 1 at the second limiting position and configured to engage with the outer thread 7, such that the outer thread 7 engages with the inner thread to fix the atomizer 2 to the sleeve 1 when the other end of the atomizer 2 opposite to the mouthpiece 21 is pushed outwards to the second limiting position by applying an external force. Described above are exemplary embodiments of the present disclosure, but are not intended to limit the scope of the present disclosure. Any equivalent structure or equivalent process variation made based on the specification and drawings of the present disclosure, which is directly or indirectly applied in other related technical fields, fall within the scope of the present disclosure.
<SOH> BACKGROUND <EOH>In current market, suction nozzles of atomizers of electronic cigarettes are fixed. The suction nozzles of the atomizers are always exposed outside, which is unsanitary in use. Protection for the suction nozzles of the atomizers depends on package boxes, and thus the atomizers are inconvenient to carry and use.
<SOH> SUMMARY <EOH>An embodiment of the present disclosure provides an electronic cigarette. The electronic cigarette includes: a housing; a sleeve received in the housing, the sleeve including a first limiting position and a second limiting position; an atomizer including a mouthpiece, the atomizer capable of being inserted into the sleeve and telescoping relative to the sleeve along an axial direction of the sleeve, so as to expose the mouthpiece or take out the atomizer from the sleeve; a latch assembly arranged on an end of the atomizer opposite to the mouthpiece, the latch assembly configured to latch the atomizer in the sleeve when the atomizer is retracted into the sleeve and is positioned at the first limiting position; and a control assembly arranged on the sleeve, the control assembly configured to unlock the latch assembly to allow the end of the atomizer to move to the second limiting position along the axial direction of the sleeve.
A24F47008
20170925
20180329
97260.0
A24F4700
0
HYEON, HAE M
ELECTRONIC CIGARETTE HAVING PROTECTION FOR A SUCTION NOZZLE
SMALL
0
ACCEPTED
A24F
2,017
15,714,103
PENDING
PROGRAM, CONTROL METHOD, AND INFORMATION PROCESSING APPARATUS
Provided are a program, a control method, and an information processing apparatus which may provide an improved user interface on which a user may easily and efficiently execute various processes on a game content. The information processing apparatus may be caused to execute a game content specifying step of specifying a selected game content on the basis of first input operation data from an operation unit, a step of retrieving information from a storage unit, a step of specifying a direction from a start point to an end point of a second input operation on the basis of second input operation data from an operation unit, and an execution step of executing one process associated with the direction from the start point to the end point of the second input operation in the information from the storage unit on the selected game content.
1. A non-transitory computer-readable storage medium comprising program code that, when executed, causes an information processing apparatus including: a display unit configured to display a game content; an operation unit configured to receive a first input operation of a user, the first input operation of the user comprising a selection of a game content, the operation unit being further configured to receive a second input operation of the user, the second input operation of the user comprising an instruction to perform a process on the game content selected by the first input operation, the operation unit being further configured to output first input operation data comprising coordinate information associated with the first input operation and second input operation data comprising coordinate information associated with the second input operation; and a storage unit configured to store information comprising an association of a process executable on the game content and a particular direction; to execute steps of: game content specifying, in a game content specifying step, with the information processing apparatus, the selected game content based on the first input operation data; retrieving, on the information processing apparatus, the information from the storage unit, the information retrieved from the storage unit comprising the process executable on the game content and the particular direction associated with the process; determining a direction, from a start point to an end point, of the second input operation, based on the second input operation data; and executing, in an execution step, with the information processing apparatus, on the game content, a process associated with the direction of the second input operation game content, based on the information retrieved from the storage unit. 2. The non-transitory computer-readable medium according to claim 1, wherein the operation unit is configured to receive a third input operation different from the first input operation and the second input operation, and wherein the operation unit is configured to output third input operation data comprising coordinate information associated with the third input operation, and wherein the non-transitory computer-readable medium causes the information processing apparatus to execute a help display step of displaying help information, the help information comprising at least one of an image and a sentence explaining correspondence between processes on the game content and directions on the display unit, based on the third input operation data. 3. The non-transitory computer-readable medium according to claim 2, wherein, in the help display step, when a time from a start to an end of the third input operation exceeds a predetermined time and a distance between a coordinate of a start point and a coordinate of an end point is equal to or smaller than a predetermined distance, displaying the help information on the display unit. 4. The non-transitory computer-readable medium according to claim 1, wherein, in the execution step, when a distance from a start point to an end point of the second input operation exceeds a threshold value, the process executable on the game content is executed on the selected game content. 5. The non-transitory computer-readable medium according to claim 1, wherein, in the execution step, in a case where a speed from a start point to an end point of the second input operation exceeds a threshold value, the process executable on the game content is executed on the selected game content. 6. The non-transitory computer-readable medium according to claim 4, wherein, in the execution step, the distance is compared against a plurality of threshold values, and each of the plurality of threshold values is used to determine whether one of a plurality of different processes should be executed. 7. The non-transitory computer-readable medium according to claim 5, wherein, in the execution step, the speed is compared against a plurality of threshold values, and each of the plurality of threshold values is used to determine whether one of a plurality of different processes should be executed. 8. The non-transitory computer-readable medium according to claim 1, wherein, when a start point of the second input operation is specified and an end point is not specified, the information processing apparatus executes a prediction display step of displaying, on the display unit, a prediction, wherein the prediction is displayed at the time that a process associated with a direction from the start point to a specific intermediate point of the second input operation is executed. 8. The non-transitory computer-readable medium according to claim 7, wherein, in the execution step, when the direction from the start point to the end point of the second input operation is substantially the same as the direction from the start point to the specific intermediate point of the second input operation in the prediction display step, the program causes the information processing apparatus to execute the process executable on the game content on the selected game content. 9. The non-transitory computer-readable medium according to claim 1, wherein the display unit is configured to display a full-select button, and wherein, in the game content specifying step, when it is determined, based on the first input operation data, that the user has pushed the full-select button, selecting all the game content displayed on the display unit. 10. A control method for a game configured to be executed by an information processing apparatus including: a display unit configured to display a game content; an operation unit configured to receive a first input operation of a user, the first input operation of the user comprising a selection of a game content, the operation unit being further configured to receive a second input operation of the user, the second input operation of the user comprising an instruction to perform a process on the game content selected by the first input operation, the operation unit being further configured to output first input operation data comprising coordinate information associated with the first input operation and second input operation data comprising coordinate information associated with the second input operation; and a storage unit configured to store information comprising an association of a process executable on the game content and a particular direction; wherein the control method comprises: specifying, with the information processing apparatus, the selected game content based on the first input operation data; retrieving, on the information processing apparatus, the information from the storage unit, the information retrieved from the storage unit comprising the process executable on the game content and the particular direction associated with the process; determining a direction, from a start point to an end point, of the second input operation, based on the second input operation data; and executing, with the information processing apparatus, on the game content, a process associated with the direction of the second input operation game content, based on the information retrieved from the storage unit. 11. An information processing apparatus, comprising: a display unit configured to display a game content; an operation unit configured to receive a first input operation of a user, the first input operation of the user comprising a selection of a game content, the operation unit being further configured to receive a second input operation of the user, the second input operation of the user comprising an instruction to perform a process on the game content selected by the first input operation, the operation unit being further configured to output first input operation data comprising coordinate information associated with the first input operation and second input operation data comprising coordinate information associated with the second input operation; a storage unit configured to store information comprising an association of a process executable on the game content and a particular direction; and a control unit, wherein the control unit is configured to perform the steps of: specifying the selected game content based on the first input operation data; retrieving the information from the storage unit, the information retrieved from the storage unit comprising the process executable on the game content and the particular direction associated with the process; determining a direction, from a start point to an end point, of the second input operation, based on the second input operation data, and executing, on the game content, a process associated with the direction of the second input operation game content, based on the information retrieved from the storage unit.
BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to a program, a control method, and an information processing apparatus. Description of the Related Art A user playing a role-playing game or the like may acquire a game content such as a card, an item, equipment, a character, or the like with the playing of the game. The user can execute various processes (for example, synthesis, reinforcement, trade, and the like) by using the game content in the game. In a case where the user executes one process (for example, synthesis), the following procedure is often followed. First, the user selects one process from a menu screen and displays a dedicated screen for executing the process. On the dedicated screen, the user selects a game content (for example, a synthesis-source character and a material character) to be processed. Then, the user pushes an execute button. In the above procedure, selection and execution of one process are performed in separate steps. When the selection and execution of one process is performed in one step, the process for the game content is more efficiently executed. For example, JP-A-2012-185838 discloses a drag-and-drop widely used in a personal computer (PC). By the drag-and-drop, a selected object (for example, a document file or the like) is moved to an icon of one application, so that the process associated with the application can be executed. In recent years, in many cases, games are played on mobile terminals such as smartphones. A display unit of the mobile terminal is smaller in size than a display unit of the PC. For this reason, when various processes are executed on a game content in a game played on a mobile terminal, it is not practical to directly apply drag-and-drop. For this reason, a new user interface capable of efficiently executing various processes on the game content has been demanded. SUMMARY OF THE INVENTION The invention is to provide a program, a control method, and an information processing apparatus that realize a user interface capable of easily and efficiently executing various processes on a game content. According to an exemplary embodiment, there may be provided a program causing an information processing apparatus including a display unit which displays a game content, an operation unit which receives a first input operation of a user selecting a game content and a second input operation of instructing a process on the game content selected by the first input operation and outputs first input operation data where the first input operation may be associated with coordinate information and second input operation data where the second input operation may be associated with the coordinate information, and a storage unit which may store information where a process on the game content and a direction are associated with each other to execute: a game content specifying step of specifying the selected game content on the basis of the first input operation data; a step of retrieving the information from the storage unit; a step of specifying a direction from a start point to an end point of the second input operation on the basis of the second input operation data; and an execution step of executing one process associated with the direction from the start point to the end point of the second input operation in the information on the selected game content. According to another exemplary embodiment, there may be provided a control method for a game executed by an information processing apparatus including a display unit which displays a game content, an operation unit which receives a first input operation of a user selecting a game content and a second input operation of instructing a process on the game content selected by the first input operation and outputs first input operation data where the first input operation is associated with coordinate information and second input operation data where the second input operation is associated with the coordinate information, and a storage unit which may store information where a process on the game content and a direction are associated with each other, the control method including: specifying the selected game content on the basis of the first input operation data; retrieving the information from the storage unit; specifying a direction from a start point to an end point of the second input operation on the basis of the second input operation data; and executing one process associated with the direction from the start point to the end point of the second input operation in the information on the selected game content. According to still another exemplary embodiment, there may be provided an information processing apparatus, including: a display unit which displays a game content; an operation unit which receives a first input operation of a user selecting a game content and a second input operation of instructing a process on the game content selected by the first input operation and outputs first input operation data where the first input operation may be associated with coordinate information and second input operation data where the second input operation may be associated with the coordinate information; a storage unit which may store information where a process on the game content and a direction are associated with each other; and a control unit, in which the control unit specifies the selected game content on the basis of the first input operation data, retrieves the information from the storage unit, specifies a direction from a start point to an end point of the second input operation on the basis of the second input operation data, and executes one process associated with the direction from the start point to the end point of the second input operation in the information on the selected game content. According to an exemplary embodiment, it may be possible to provide a program, a control method, and an information processing apparatus realizing a user interface capable of easily and efficiently executing various processes on a game content. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a block diagram of an information processing apparatus according to an exemplary embodiment; FIG. 2 is a diagram illustrating a display area for displaying a game content; FIG. 3A is a diagram illustrating an example of help information; FIG. 3B is a diagram illustrating an example of help information; FIG. 4 is a diagram illustrating an example of information (table) stored in a storage unit; FIG. 5A a is a diagram illustrating a manner where a user executes one process by a slide operation; FIG. 5B a is a diagram illustrating a manner where a user executes one process by a slide operation; FIG. 6A is a diagram illustrating an execution of a process; FIG. 6B is a diagram illustrating a process canceling method in a case where prediction is displayed; FIG. 7 is a flowchart illustrating a control method for executing a process corresponding to a slide operation by a user on a game content in a game executed by the information processing apparatus; FIG. 8A is a diagram illustrating an example of page switching; FIG. 8B is a diagram illustrating an example of a slider; FIG. 8C is a diagram illustrating an example of a full-select button; FIG. 9A is a diagram illustrating processes for a plurality of game content; FIG. 9B is a diagram illustrating processes for one game content; FIG. 10 is a diagram illustrating an example of a screen for selecting a character by a slide operation; FIG. 11 is a diagram illustrating an example of a screen for selecting parameters to be reinforced by a slide operation; and FIG. 12 is a diagram illustrating an example of a screen in a case where drag-and-drop may be applied to a smartphone. DETAILED DESCRIPTION OF THE INVENTION Hereinafter, embodiments of the invention will be described. (Configuration of Information Processing Apparatus) An information processing apparatus 1 according to an exemplary embodiment will be described with reference to FIG. 1. The information processing apparatus 1 may be, for example, a smartphone, a tablet, a game machine, or the like, and may execute a game application (program). The game application may be received from, for example, a predetermined application distribution server via the Internet. Alternatively, the game application may be stored in advance in a storage device provided in the information processing apparatus 1 or a storage medium such as a memory card that may be readable by the information processing apparatus 1. Herein, an overview of a game application executed by the information processing apparatus 1 according to the embodiment (hereinafter, referred to as a game according to the embodiment) will be described. The game according to the embodiment may be, for example, a role-playing game or the like. A user may operate a user character in a virtual space to play the game. The user acquires a game content with the playing of the game. In addition, the user can execute various processes on the acquired game content. The game content may be electronic data used for a game and may include any medium such as a card, an item, equipment, a character, and an object. In addition, the user can execute, for example, acquisition, holding, use, management, exchange, synthesis, reinforcement, trade, destruction, donation, or the like as a process on the game content in the game. Herein, the usage mode of the game content may not be limited to those disclosed in this specification. The game according to the embodiment may include the following contents as a schematic example. The user may operate the user character to play the game while searching for the field in the game. In the field, for example, a town, a battle stage, and the like may be provided. For example, the user character can have a conversation with a resident character in a town, fight a battle against an enemy character encountered in a battle stage, and the like. In the field in the game, various events corresponding to the area may occur. As the events are executed, the main story of the game may progress. For example, in a case where a user character wins the battle with an enemy character, the user can acquire the game content. Configuration components of the information processing apparatus 1 will be described. The information processing apparatus 1 may be configured to include an operation unit 10, a storage unit 11, a display unit 12, and a control unit 13. The operation unit 10 may receive a user's input operation and outputs input operation data where the input operation may be associated with coordinate information. As described above, in the game executed by the information processing apparatus 1, various processes can be executed on the game content. The user's input operation received by the operation unit 10 may include, for example, an operation of the user selecting a game content to be processed. In addition, the user's input operation received by the operation unit 10 may include, for example, an operation of instructing execution of a desired process on the game content selected by the user. In the information processing apparatus 1 according to the embodiment, the operation unit 10 may be a touch panel integrated with the display unit 12. For example, the information processing apparatus 1 has a configuration in which a transparent sensor layer detecting a change in electrostatic capacitance which may be the operation unit 10 may be overlapped on a liquid crystal display (LCD) layer which may be the display unit 12 (a configuration in which the LCD layer may be viewed through the sensor layer by a user). The operation unit 10 can detect the position touched by the user by detecting the change in electrostatic capacitance. A touch panel of a type other than the electrostatic capacitance type may be employed as the operation unit 10. The user performs an input operation by touching the operation unit 10 by using a finger or an instrument such as a stylus. In the embodiment, the user can select a game content and deselect (release) the selected game content by tapping. The tap may be an operation in which the user touches the operation unit 10 with his or her finger and then releases the finger without moving the finger. In the embodiment, the user can select and release consecutive game content and can execute a desired process on the game content by tapping and/or slide operation. The slide operation may be an operation of moving a finger with which the user touches the operation unit 10 on the operation unit 10. The slide operation may include, for example, flick, swipe, and the like. The flick may be an operation in which the user touches the operation unit 10 with the finger or the like and releases the finger while quickly moving the finger in the state where the finger may be in touch with the operation unit. The swipe may be an operation in which the user touches the operation unit 10 with the finger or the like and moves the finger in the state where the finger may be in touch with the operation unit. Herein, the point at which the user touches the operation unit 10 with the finger or the like and starts an input operation may be referred to as a start point. In addition, the point at which the user releases the finger or the like that has been touching the operation unit 10 at the time of ending the input operation may be referred to as an end point. In addition, a point on the route between where the user touches the operation unit 10 at the start of the input operation to where the user ceases touching the operation unit 10 at the end of the input operation may be referred to as an intermediate point. Herein, it may be preferable that the point at which the finger or the like may be temporarily separated during the input operation may not be treated as an end point, and in a case where the finger or the like may be in touch with the operation unit 10 again within a predetermined time (for example, 0.5 seconds), the point may not be treated as an end point. The operation unit 10 associates the tap position, the start and end points of the slide operation, the route of the slide operation, and the like with the coordinate information on the touch panel. The start point, the end point, the route, and the like associated with the coordinate information may be output as the input operation data. In the information processing apparatus 1 according to the embodiment, coordinates in a rectangular coordinate system in which the horizontal and vertical directions of the screen of the display unit 12 integrated with the operation unit 10 may be the X and Y axes, respectively, may be used. In addition, the input operation data also may include information on the elapsed time from the start of the input operation. The storage unit 11 may be, for example, a storage device and may store various types of information and programs (game applications) necessary for processing the game. The storage unit 11 may include, for example, a semiconductor memory, a magnetic memory, an optical memory, or the like. The storage unit 11 may store an image of a game content displayed in a virtual space (virtual game space). In addition, the storage unit 11 may store various parameters (for example, attribute, level, attack power, defense power, rareness value, and the like) of the game content. In addition, the storage unit 11 may store a table 111 (refer to FIG. 4) described later. In addition, the storage unit 11 may store various images (texture images) for projection onto various objects arranged in a virtual space (texture mapping). In addition, the storage unit 11 may store images of backgrounds (background images) such as sky and distant landscape and images of fields (field images) such as towns and battle stages. The storage unit 11 may be a memory (for example, a RAM or the like) for storing the data received from the server as a cache. The display unit 12 displays the virtual space in which the user character may be arranged. In the embodiment, the display unit 12 may be a liquid crystal display (LCD) layer of a touch panel, but the display unit may not be limited thereto. For example, the display unit 12 may be a display device such as an organic EL display. The control unit 13 may be a dedicated microprocessor or a CPU which realizes a specific function by reading a specific program. The control unit 13 controls the operation of the information processing apparatus 1. For example, the control unit 13 may execute a game application in accordance with a user's operation on the operation unit 10. In addition, the control unit 13 may execute various processes related to the game. The control unit 13 allows the display unit 12 to display a virtual space including, for example, a field and a user character. In addition, the control unit 13 allows the display unit 12 to display a game content such as a card or equipment. In addition, the control unit 13 identifies the game content selected by the user's input operation. The control unit 13 may execute a process according to the user's input operation on the selected game content. Hereinafter, an example of a screen displayed on the display unit 12 of the information processing apparatus 1 according to the embodiment and a process on the game content will be described with reference to FIGS. 2 to 8. (Selection of Game Content) As illustrated in FIG. 2, the information processing apparatus 1 may be configured to include an operation unit 10 and a display unit 12 which may be integrated to constitute a touch panel. The display unit 12 may be provided with a display area 121 for displaying game content 2a to 2i. Each of the game content 2a to 2i may be an individual game content. In the display area 121, a list of the game content 2a to 2i may be displayed. To display a list may be to arrange and display the game content in an easy-to-understand manner for the user so that the user can easily select the game content. In the example of FIG. 2, a list in which the game content 2a to 2i may be arranged in three rows and three columns in the vertical and horizontal directions may be displayed. In the embodiment, regardless of the process to be executed, the display area 121 may be used for selecting the game content 2a to 2i. Since the selection screen may be unified regardless of the process, the result may be more convenient for the user. The user can select the game content by tapping the game content 2a to 2i displayed on the display area 121. By tapping the already-selected game content 2a to 2i, it may be possible to deselect (cancel the selection). In addition, even in a case where the user touches the game content 2a to 2i by the slide operation, the touched game content 2a to 2i can be selected. In the example of FIG. 2, the user has selected the game content 2d, 2e, 2g, and 2i. Since the display color of the selected game content 2d, 2e, 2g, and 2i changes, the user can confirm the selection result. As another example, the selected game content 2d, 2e, 2g, and 2i may be blinking, the shape may be changed, the display mode may be changed, or an image indicating the selection may be added. Herein, the operation unit 10 may receive the user's input operation and outputs the input operation data where the input operation may be associated with the coordinate information. As illustrated in FIG. 2, the operation unit 10 uses coordinates in a rectangular coordinate system in which the horizontal direction of the screen may be set to the X axis and the vertical direction may be set to the Y axis. The coordinate information may be used as follows. For example, the operation unit 10 may receive the user's input operation of tapping the game content 2i and outputs the input operation data in association with the coordinates of the tap position. After that, the input operation data may be retrieved by the control unit 13, and the coordinates of the tap position may be grasped. Then, control for changing the display color of the game content 2i displayed at the coordinates of the tap position may be executed by the control unit 13. The information processing apparatus 1 according to the embodiment can execute various processes on the selected game content 2d, 2e, 2g, and 2i. As described above, the information processing apparatus 1 may be, for example, a smartphone, a tablet, a game machine, or the like. For this reason, it may not be practical to directly apply drag-and-drop to the information processing apparatus 1. FIG. 12 illustrates an example of a screen in a case where drag-and-drop may be directly applied to an information processing apparatus 1A which may be a smartphone. In the display unit 12 of the information processing apparatus 1A, process regions corresponding to application icons may be provided. In the example of FIG. 12, as the process regions, there may be provided a region 140A for evolution synthesis, a region 140B for reinforcement synthesis, a region 140C for special synthesis, a region 140D for team formation, a region 140E for trade, and a region 140F for warehouse. In the example of FIG. 12, the user can collectively process the selected game content by dragging the selected game content 2d and 2e to one of the process regions. However, the process regions may be provided in the display unit 12 of which size may be smaller than that of the PC, so that the display area 121 for displaying the game content 2a to 2f becomes small. The number of game content that can be selected at one time may be decreased, and as a result, the number of times of execution of the process may be increased, which may be inconvenient for the user. The information processing apparatus 1 according to the embodiment can execute various processes on the selected game content 2d, 2e, 2g, and 2i without providing the process regions on the display unit 12. Specifically, the information processing apparatus 1 may execute various processes by allowing the processes to correspond to the directions of the user's slide operation. In other words, the user can execute a desired process only by slide operation in a predetermined direction. (Display of Help Information) Herein, there may be a possibility that the user may be confused as to which direction of the slide operation a desired process corresponds to. When the user long-pushes (long-taps) the game content after selecting the game content 2a to 2i, the information processing apparatus 1 according to the embodiment displays help information 122 on the display unit 12. FIG. 3A may be a diagram illustrating an example of the help information 122. In the embodiment, the help information 122 may be information such as an image explaining the correspondence between the processes on the game content and the directions. Herein, the help information 122 may include text-based explanation, such as a sentence. In addition, the help information 122 may be only the text-based explanation. Namely, the help information 122 may be at least one of an image and a sentence explaining the correspondence between the processes on the game content and the directions. In the example of FIG. 3A, the game content 2a to 2i displayed on the display area 121 may be equipment (for example, weapon, helmet, armor, shield, and the like) to be worn by the character. For the equipment, the processes of synthesis, warehouse, special synthesis, and trade may be possible. The synthesis may be a process of combining material equipment with synthesis-source equipment to configure the synthesis-source equipment as another equipment. The warehouse may be a process of moving equipment not to be used to a virtual warehouse in the game space to store the equipment. The special synthesis may be synthesis that may be performed by consuming not only in-game currency but also special items. The special synthesis can further reinforce the parameters of the synthesis-source equipment as compared to simple synthesis. The trade may be a process of exchanging equipment with in-game currency. In the example of FIG. 3A, the help information 122 indicates that the upward slide operation may be synthesis. In addition, the help information 122 indicates that the downward slide operation may be warehouse. In addition, the help information 122 indicates that the rightward slide operation may be special synthesis. In addition, the help information 122 indicates that the leftward slide operation may be trade. FIG. 3B may be a diagram illustrating another example of the help information 122. In the example of FIG. 3B, the game content 2a to 2i displayed on the display area 121 may be characters. For the characters, processes of reinforcement synthesis, evolution synthesis and trade may be possible. Reinforcement synthesis may be a process of reinforcing parameters of a synthesis-source character by combining a material character with the synthesis-source character. Evolution synthesis may be a process of converting a synthesis-source character into another character by combining a material character with the synthesis-source character. Trade may be a process of exchanging characters with in-game currency. In the example of FIG. 3B, the help information 122 indicates that the upward slide operation may be reinforcement synthesis. In addition, the help information 122 indicates that the rightward slide operation may be evolution synthesis. In addition, the help information 122 indicates that the leftward slide operation may be trade. In the example of FIG. 3B, there may be no process corresponding to the downward slide operation. In the embodiment, as illustrated in FIGS. 3A and 3B, the process varies depending on the type (equipment, character) of the game content 2a to 2i displayed on the display area 121. Namely, the information processing apparatus 1 associates an appropriate process according to the type of the game content with the direction of the slide operation. Such association may be executed on the basis of the information stored in the storage unit 11 as the table 111. FIG. 4 may be a diagram illustrating an example of the table 111 stored in the storage unit 11. As described above, the table 111 associates the process on the game content with the direction of the slide operation. In the embodiment, the table 111 associates various processes on the game content with the directions of the slide operations for each type of game content. The directions of the slide operations are, for example, upward, downward, leftward, rightward, upper rightward, and the like. However, not all directions need to be associated with processes. In the example of FIG. 4, even though the type of the game content may be a character, equipment, or an item, the process may not be associated with the upper rightward direction. The correspondence between the processes in a case where the type of the game content may be a character and equipment in FIG. 4 and the directions of the slide operations may be the same as the help information 122 described in FIGS. 3A and 3B, respectively. In addition, in the example of FIG. 4, in a case where the type of the game content may be an item, the upward slide operation may be associated with reinforcement executed by consuming points. In addition, the downward slide operation may be associated with the warehouse. In addition, the leftward slide operation may be associated with the trade. Herein, as another example, in the table 111, the correspondence between the processes and the directions of the slide operations may be shared without dividing for each type of game content. However, in a case where there may be many processes on the game content (for example, more than eight types), it may be preferable that the processes corresponding to the types of game content 2a to 2i displayed on the display area 121 as in the embodiment may be associated with the directions of the slide operations. In addition, as still another example, the processes may be different depending on the types of the selected game content 2d, 2e, 2g, and 2i instead of the types of the game content 2a to 2i displayed on the display area 121. In addition, as in the example of FIG. 4, it may be preferable that the same process may be associated with the same direction regardless of the type of the game content 2a to 2i. For example, even though the game content 2a to 2i may be characters, equipment, or items, it may be possible to trade the characters, equipment, or items. Then, the trade may be associated with the leftward direction. In addition, even though the game content 2a to 2i may be equipment or items, it may be possible to store the equipment or items in a warehouse (or to take the equipment or items out from the warehouse). Then, the warehouse may be associated with the downward direction. As in this example, it may be preferable that processes common to two or more types of game content 2a to 2i may be associated with the same direction of the slide operation. At this time, since the user may store the specific process and the specific direction in association with each other, it may be possible to reduce the trouble of confirming the help information 122. (Execution of Process) As described above, the user has selected the game content 2d, 2e, 2g, and 2i from the game content 2a to 2i displayed on the display area 121 by tapping (refer to FIG. 2). Then, the user long-pushes the operation unit 10 integrated with the display unit 12 to display the help information 122 and confirms the correspondence between the processes and the directions (refer to FIGS. 3A and 3B). Then, by performing a slide operation (flicking as a specific example) in a direction corresponding to a desired process, it may be possible to collectively execute the desired process on the selected game content 2d, 2e, 2g, and 2i. FIGS. 5A and 5B illustrate the states where the user may execute one process by a slide operation. In the examples of FIGS. 5A and 5B, the game content 2a to 2i displayed on the display area 121 may be equipment. In the example of FIG. 5A, the user may execute synthesis on the selected game content 2d, 2e, 2g, and 2i. The synthesis may be associated with an upward slide operation. When the user performs an upward slide operation with the finger or the like, a prediction 123 may be popped up in the middle of the process (before execution of synthesis). The prediction 123 may be a result expected in a case where one process corresponding to the direction of the slide operation to a middle point determined by the table 111 may be executed on the selected game content. The prediction 123 may not be limited to deterministic contents. For example, in a case where one process may be executed according to a predetermined probability, the prediction 123 may include one or plural results with probabilities (for example, X with a probability of 70%, Y with a probability of 20%, Z with a probability of 10%, or the like). In the example of FIG. 5A, the prediction 123 indicates the prediction result of the synthesis. The prediction 123 informs the user that the synthesis result may be “ABC (rare)” with a probability of 80%. Furthermore, when the user performs an upward slide operation with the finger or the like, synthesis may be executed on the selected game content 2d, 2e, 2g, and 2i. Herein, in the synthesis, the first selected game content 2d may be treated as a synthesis source, or the last selected game content 2i may be treated as a synthesis source. In the example of FIG. 5B, the user collectively sells the selected game content 2d, 2e, 2g, and 2i. The trade may be associated with the leftward slide operation. When the user performs a leftward slide operation with the finger or the like, the prediction 123 may be popped up in the middle of the process (before the trade may be executed). In the example of FIG. 5B, the prediction 123 indicates the prediction result of the trade (predicted trade amount). The prediction 123 informs the user that the predicted trade amount (total) of the selected game content 2d, 2e, 2g, and 2i may be “2350 G”. Herein, G may be a unit of in-game currency. Furthermore, when the user performs a leftward slide operation with the finger or the like, the selected game content 2d, 2e, 2g, and 2i may be collectively traded. FIG. 6A may be a diagram exemplifying an execution of a process. In the embodiment, as illustrated in FIG. 6A, the process may be executed or canceled in accordance with the length of the slide operation. In the case of executing one process on the selected game content 2d, 2e, 2g, and 2i, the user may perform a slide operation in the direction corresponding to one process by using the finger or the like. In the embodiment, a threshold value Th may be provided for the distance from the start point 131 to the end point 132 of the slide operation. For example, the threshold value Th may be set to a distance corresponding to 200 to 400 pixels on the display unit 12. The threshold value Th may be used for determining execution of the process. For example, in a case where a distance L1 from the start point 131 to the end point 132 exceeds the threshold value Th as indicated by an arrow on the left side of FIG. 6A (representing a slide operation), the information processing apparatus 1 may execute the process. In addition, for example, in a case where a distance L2 from the start point 131 to the end point 132 may be equal to or smaller than the threshold value Th as indicated by an arrow on the right side of FIG. 6A (representing a slide operation), the information processing apparatus 1 treats the process as canceled. Herein, in a case where the prediction 123 may be displayed, in some cases, the user considers that the user may want to stop the process according to the contents. In the example of FIG. 5A, the user grasps that the probability that the result of synthesis being “ABC (rare)” may be high according to the prediction 123. In a case where the user considers “ABC (rare)” to be unnecessary, there may be a possibility that the user may want to cancel the synthesis. In addition, in the example of FIG. 5B, the user grasps that the predicted trade amount may be “2350 G” according to the prediction 123. In a case where the user considers “2350 G” to be little money, there may be a possibility that the user may want to cancel the trade. In the embodiment, the process may be canceled in a case where the prediction 123 may be displayed by the following determination. FIG. 6B may be a diagram exemplifying a process canceling method in a case where the prediction 123 may be displayed. In the example of FIG. 6B, the user first may perform a slide operation upward from the start point 131 as indicated by a solid arrow. Then, while touching the operation unit 10 with the finger or the like, the user changes the direction to the lower rightward direction on the way and may perform the slide operation to the end point 132. In the upward slide operation from the initial start point 131, when the finger may be separated from the start point 131 by a specific distance smaller than the threshold value Th, the prediction 123 may be displayed. In the embodiment, the specific distance may be 80% (0.8 Th in FIG. 6B) of the threshold value Th. In addition, when the prediction 123 may be displayed, the intermediate point on the route (solid arrow in FIG. 6B) may be set as the specific intermediate point 133. Namely, the specific intermediate point may be an intermediate point that may be separated from the start point by a specific distance (a distance for displaying the prediction 123 of the process associated with one direction) in one direction. Herein, a multiplier (80%) for the threshold value Th giving the specific distance may be an example, and as another example, 50% may be used. As in the example of FIG. 6B, in a case where the direction from the start point 131 to the end point 132 of the slide operation (the direction of the vector Ve in FIG. 6B) is not the same as the direction from the start point 131 to the specific intermediate point 133 (the direction of the vector Vm in FIG. 6B), the information processing apparatus 1 may cancel the process. Namely, when the final direction from the start point 131 to the end point 132 may be different from the direction from the start point 131 displaying the prediction 123 to the specific intermediate point 133, the information processing apparatus 1 may determine that the user has intentionally changed the direction of the slide operation. Then, the information processing apparatus 1 may cancel the process. In the embodiment, in a case where the directions may be not the same as each other as described above, regardless of the distance (the length of the vector Ve in FIG. 6B) from the start point 131 to the end point 132 of the slide operation, the information processing apparatus 1 may cancel the process. Herein, the situation where the direction from the start point 131 to the end point 132 of the slide operation may be the same as the direction from the start point 131 to the specific intermediate point 133 may not be limited to exact coincidence. Namely, when the direction from the start point 131 to the end point 132 and the direction from the start point 131 to the specific intermediate point 133 may be substantially the same as each other, it may be determined that the information processing apparatus 1 may be the same. Whether or not the directions may be substantially the same as each other may be determined as follows. In the embodiment, when the angle formed by a vector Ve and a vector Vm in FIG. 6B exceeds a predetermined value (predetermined angle), it may be determined that the directions may be different, and when the angle is equal to or smaller than the predetermined value (predetermined angle), it may be determined that the directions are the same as each other. Herein, the predetermined value (predetermined angle) may be set to, for example, 20° in consideration of the shake of the user's input operation or the like. At this time, in a case where a slide operation that returns the user's finger or the like to an original position on the way (for example, around the start point 131) may be detected, the control unit 13 may cancel the process. (Flowchart) FIG. 7 may be a flowchart illustrating a game control method executed by the control unit 13. As illustrated in the flowchart of FIG. 7, the control unit 13 may execute processes corresponding to the user's slide operations with respect to the selected game content. First, the user's input operations received by the operation unit 10 may be classified into three input operations. The first input operation may be an input operation for the user to select a game content. The second input operation may be an input operation instructing a process on the game content selected by the first input operation. Then, the third input operation may be a user's input operation (for example, long-push) different from both the first input operation and the second input operation. The operation unit 10 may receive the first input operation, the second input operation, and the third input operation, and may associate the first input operation, the second input operation, and the third input operation with the coordinate information, and outputs as first input operation data, second input operation data, and third input operation data. The first to third input operation data may also include information on the elapsed time from the start of the input operation. The control unit 13 may retrieve the first input operation data from the operation unit 10 (step S1). Then, the control unit 13 specifies the selected game content on the basis of the first input operation data (step S2). Step S2 may be a game content specification step. The control unit 13 may retrieve coordinate information such as a tap position, a route of a slide operation, or the like from the first input operation data. The control unit 13 specifies the selected game content by comparing the retrieved coordinate information with the coordinates of the game content displayed on the display unit 12. The control unit 13 may retrieve the third input operation data from the operation unit 10 (step S3). Then, the control unit 13 may determine whether or not the third input operation is long-push (step S4). The control unit 13 may retrieve, from the third input operation data, for example, coordinate information on the start point and the end point of the input operation, information on the time from the start to the end, and the like. Then, the control unit 13 may determine whether or not the time from the start to the end of the input operation exceeds a predetermined time (a first long-push threshold value). In addition, the control unit 13 may determine whether or not the distance between the coordinates of the start point of the input operation and the coordinates of the end point of the input operation is equal to or smaller than a predetermined distance (a second long-push threshold value). In a case where the time from the start to the end of the input operation exceeds the first long-push threshold value and the distance between the coordinates of the start point and the coordinates of the end point is equal to or smaller than the second long-push threshold value, it may be determined that the input operation is long-push. The first long-push threshold value may be set in a range of, for example, 1 to 3 seconds. In addition, the second long-push threshold value may be set to a distance corresponding to, for example, 1 to 10 pixels on the display unit 12. In a case where it is determined that the third input operation is long-push (Yes in step S4), the control unit 13 may allow the display unit 12 to display the help information 122 (step S5). Step S5 may be a help display step. In the embodiment, the help information 122 displayed on the display unit 12 may not be displayed when a predetermined time (for example, 2 seconds) elapses after the user stops the long-push. After executing the process of step S5 and in a case where it may be determined that the third input operation is not long-push (No in step S4), the control unit 13 proceeds to the process of step S6. The control unit 13 may retrieve the table 111 from the storage unit 11 (step S6). As described above, the table 111 may be information in which the process on the game content may be associated with the direction of the slide operation. The control unit 13 may retrieve the second input operation data from the operation unit 10 (step S7). Then, the control unit 13 may retrieve coordinate information such as the start point of the slide operation and the route of the slide operation from the second input operation data. The control unit 13 may determine whether the end point of the slide operation is specified (step S8). In a case where the second input operation data may include the coordinate information of the end point of the slide operation, the control unit 13 may determine that the end point of the slide operation is specified (the end point exists) (Yes in step S8), and the process proceeds to step S11. In a case where it is determined that the end point of the slide operation is not specified (the end point does not exist) (No in step S8), the control unit 13 may execute the following processes relating to the display of the prediction 123. The control unit 13 may determine whether or not a specific intermediate point is included in the route during the slide operation (step S9). The specific intermediate point may be an intermediate point that may be separated from the start point of the slide operation by a specific distance (distance corresponding to 80% of the threshold value Th in the example of FIG. 6B) toward one direction. In a case where it is determined that a specific intermediate point is included in the route of the slide operation (Yes in step S9), the control unit 13 may allow the display unit 12 to display the prediction 123 of the time when one process associated with the direction from the start point to the specific intermediate point in the table 111 may be executed on the selected game content (step S10). Step S10 may be a prediction display step. In the embodiment, the prediction 123 displayed on the display unit 12 may not be displayed when a predetermined time (for example, 5 seconds) elapses from the start of display. After executing the process of step S10 and in a case where it is determined that a specific intermediate point is not included (No in step S9), the control unit 13 returns to the process of step S7. Then, the control unit 13 may retrieve the updated second input operation data. In a case where the second input operation data includes the coordinate information of the end point, the control unit 13 may retrieve the distance from the start point to the end point. Then, the control unit 13 may determine whether the distance from the start point to the end point of the second input operation exceeds a threshold value Th (refer to FIG. 6B) (step S11). In a case where it is determined that the distance from the start point to the end point is equal to or smaller than the threshold value Th (No in step S11), the control unit 13 may cancel the process on the selected game content and ends the series of processing. In a case where it is determined that the distance from the start point to the end point exceeds the threshold value Th (Yes in step S11), the control unit 13 may specify the direction from the start point to the end point of the second input operation (slide operation) (step S12). The control unit 13 may determine whether or not the prediction 123 has been displayed (step S13). In a case where the prediction 123 is not displayed on the display unit 12 (No in step S13), the control unit 13 may proceed to the process of step S15. In a case where the control unit 13 has allowed the display unit 12 to display the prediction 123 (Yes in step S13), the control unit 13 may proceed to the process of step S14 for determining the cancellation of the process. The control unit 13 may determine whether or not the direction from the start point to the end point of the second input operation (slide operation) is the same as the direction from the start point to the specific intermediate point at the time of prediction 123 display, that is, in the prediction display step (Step S14). If the angle between a vector Ve connecting the start point and the end point and a vector Vm connecting the start point and the specific intermediate point is equal to or smaller than a predetermined value in the process of step S14, the control unit 13 may determine that the directions are the same as each other. In a case where the direction from the start point to the end point of the second input operation is not the same as the direction from the start point to the specific intermediate point (No in step S14), the control unit 13 may cancel the process on the selected game content and may end a series of processes. In a case where the direction from the start point to the end point of the second input operation is the same as the direction from the start point to the specific intermediate point (Yes in step S14), the control unit 13 may proceed to the process of step S15. The control unit 13 may execute one process associated with the direction from the start point to the end point of the second input operation in the table 111 on the selected game content (step S15) and ends a series of processes. Step S15 may be an execution step. As described above, the information processing apparatus 1 according to the embodiment may associate the processes on the game content with the directions and may execute one process according to the direction of the user's slide operation on the selected game content. The information processing apparatus 1 according to the embodiment realizes a user interface capable of easily and efficiently executing various processes on the game content. In addition, in the information processing apparatus 1 according to the embodiment, there may be no need to provide process regions (refer to FIG. 12) corresponding to drag-and-drop application icons on the display unit 12. For this reason, the information processing apparatus 1 may be appropriate for such a smartphone which has the display unit 12 having a size smaller than that of a PC. Although the invention has been described with reference to the drawings and the embodiments, it should be noted that the skilled in the art can easily make various modifications and changes on the basis of the disclosure. Therefore, it should be noted that the modifications and changes may be included within the scope of the invention. For example, functions and the like included in each means, each step, or the like can be rearranged so as not to be logically contradictory, and a plurality of means, steps, or the like can be combined into one or divided. (Modified Examples and the Like) In the above-described embodiment, the control unit 13 may receive the input operation data from the operation unit 10. However, the storage unit 11 may temporarily store the input operation data. Then, the control unit 13 may receive the input operation data from the storage unit 11. At this time, since the storage unit 11 functions as a buffer, the control unit 13 can more flexibly select the timing of retrieving the input operation data. In the above-described example of the embodiment, the number of game content 2a to 2i that can be displayed may be displayed in a list on the display area 121. Herein, in a case where the user owns a game content which cannot be displayed on the display area 121, the user may switch pages by using the display area 121 as a unit. For example, as illustrated in FIG. 8A, the game content 1a to 1i may be included in the first page, the game content 2a to 2i may be included in the second page, and the game content 3a to 3i may be included in the third page. Herein, in the page switching by using the display area 121 as a unit, in response to an input slide operation in the leftward or rightward direction, the control unit 13 may switch a page to an adjacent page and display the page. For example, as illustrated in FIG. 8A, in a case where the game content 2a to 2i are displayed on the display area 121, in response to an input operation in which the user slides the finger leftward on the display area 121, the game content 3a to 3i may be displayed on the display area 121. Similarly, as illustrated in FIG. 8A, in a case where the game content 2a to 2i are displayed on the display area 121, in response to an input operation in which the user slides the finger rightward on the display area 121, the game content 1a to 1i may be displayed on the display area 121. In addition, in a case where page switching may be executed in response to the input slide operation in this manner, for example, in response to the input slide operation in the upward or downward direction, the control unit 13 may switch to a predetermined non-adjacent page and display the page. For example, as illustrated in FIG. 8A, in a case where the game content 2a to 2i are displayed on the display area 121, in response to an input operation in which the user slides the finger upward on the display area 121, the game content 12a to 12i corresponding to the ten previous pages may be displayed on the display area 121. Similarly, in a case where the game content 12a to 12i may be displayed on the display area 121, in response to an input operation in which the user slides the finger downward on the display area 121, the game content 2a to 2i corresponding to the ten previous pages may be displayed on the display area 121. Furthermore, in a case where page switching is executed in response to the input slide operation, for example, in response to the input slide operation in an oblique direction, the control unit 13 may switch to a predetermined non-adjacent page and display the page. For example, as illustrated in FIG. 8A, in a case where the game content 2a to 2i are displayed on the display area 121, in response to an input operation in which the user slides the finger from the lower left to the upper right the display area 121, the game content 102a to 102i corresponding to the 100 previous pages may be displayed on the display area 121. Herein, the page displayed on the display area 121 may be switched by the tab 124. In the example of FIG. 8A, the user has selected the tab 124 in which the number “2” is written. Then, the game content 2a to 2i included in the second page may be displayed on the display area 121. The user can easily switch pages by the tab 124. Herein, for example, in a case where the user selects the tab 124 in which the number “1” is written, the game content 1a to 1i may be displayed on the display area 121. In addition, instead of the tab 124, the page may be switched by the slider 125 illustrated in FIG. 8B. The slider 125 can move the knob in increments of scales corresponding to each page. Furthermore, as illustrated in FIG. 8C, a full-select button 126 capable of selecting the game content 2a to 2i displayed on the display area 121 at one time may be provided. For example, in a case where it is determined that the user pushed the full-select button 126 on the basis of the first input operation data, the control unit 13 may determine that all the game content 2a to 2i displayed on the display area 121 of the display unit 12 have been selected. At this time, the game content 1a to 1i of the first page and the game content 3a to 3i of the third page which are not selected by the tab 124 may not be displayed on the display unit 12. For this reason, the control unit 13 treats the game content 1a to 1i and the game content 3a to 3i as not being selected. Then, the control unit 13 may control the display unit 12 so as to change the display colors of the selected game content 2a to 2i. After that, in a case where it is determined that the user has pushed the full-select button 126 again, the control unit 13 may cancel the selection of the game content 2a to 2i. Namely, the full-select button 126 may function as a toggle button for selecting all of the game content displayed on the display unit 12 or canceling the selection. Herein, the game content may be sorted under one or more conditions, preferably a plurality of conditions which may be designated by the user. The object of sorting may be limited to the game content (for example, the game content 2a to 2i) displayed on the display area 121, or the object of sorting may be all the game content including the game content not displayed on the display area 121 (for example, the game content 1a to 1i, 2a to 2i, and 3a to 3i). The plurality of conditions denotes, for example, that a degree of rareness can be designated as the first condition and attribute can be designated as the second condition. Then, the game content may be sorted in descending order of the degree of rareness with respect to each attribute. By such sorting under the plurality of conditions, the user can easily allocate the appropriate game content to each page. In the above-described embodiment, the table 111 may associate various processes on the game content with the directions of the slide operation for each type of game content displayed on the display area 121 (refer to FIG. 4). Herein, the table 111 may have divisions as to whether the number of game content to be selected or more may be one or plural. Furthermore, even though the types of the game content may be the same, the processes may be different depending on whether the number of game content may be one or plural. In the examples of FIGS. 9A and 9B, the game content 2a to 2i as characters may be displayed on the display area 121. In the example of FIG. 9A, a plurality (two) of game content 2a and 2b may be selected. At this time, the help information 122 indicates that the processes of reinforcement synthesis, evolution synthesis and trade may be possible for the selected character. On the other hand, in the example of FIG. 9B, a single (one) game content 2a may be selected. At this time, it may be indicated in the help information 122 that processes of leader setting, equipment change, and trade may be possible for the selected character. In the example of FIG. 9B, instead of the reinforcement synthesis and the evolution synthesis requiring a plurality of game content, it may be possible to execute leader setting and equipment change processes for one game content. In this manner, depending on whether the number of selected game content may be one or plural, the process on the game content may be configured to be different, so that only an executable process may be associated with the direction of the slide operation. Therefore, it possible to realize a user interface that may be easier for the user to use. In the above-described embodiment, one process may be executed among various processes on the game content according to the direction of the slide operation. Herein, in the situation where it may be decided to execute one process on the game content already, the selection item in one process may be determined according to at least one of the direction and length of the slide operation. For example, after the user selects one process corresponding to the direction of the slide operation, the screen may be transitioned to a dedicated screen for executing one process, and similarly, the user may determine the selection item (for example, parameters, characters, and the like) by a slide operation on the dedicated screen. FIG. 10 illustrates a screen for allowing a user to select a character by a slide operation in a situation where a process of equipping the character with an already selected game content is decided. In the center of the screen, the equipment i to be equipped on the character may be displayed. Then, four characters A to D may be allocated to the upward, downward, leftward, and rightward directions of the equipment i. In the example of FIG. 10, the user may perform a rightward slide operation on the screen and instructs to equip the character B with the equipment i. Herein, the prediction 123 may also be displayed on this screen. As the prediction 123, images, parameters, and the like in a case where the character may be equipped with the equipment i corresponding to the direction of the user's slide operation may be displayed. By confirming the prediction 123, the user can try on the equipment with each character before executing the equipping process. In addition, in the example of FIG. 10, although the equipment i may be one weapon, it may be possible to equip the character with a plurality of equipment (for example, a sword and a shield). In addition, FIG. 11 illustrates a screen used by the user to select the parameters for reinforcement by the slide operation in the situation where the process of reinforcing the user character by the reinforcing point (the point which the character can be reinforced by consuming) may be decided. Six parameters (attack power, HP, skill, defense power, MP, and speed) may be assigned to the six directions from the center of the screen. In the example of FIG. 11, the user may perform an upward slide operation V1 on the screen, so that the user can reinforce the attack power assigned upward. In addition, in the example of FIG. 11, the user also may perform a slide operation V2 on the screen to the lower leftward direction (intermediate direction between the MP and the defense power), so that the user can simultaneously reinforce the MP and the defense power. The degree of reinforcement increases according to the length of the slide operation, and thus, the consumption of the reinforcing points also increases. In the example of FIG. 11, since the slide operation V1 may be longer than the slide operation V2, the attack power may be greatly reinforced compared with the MP and the defensive force. Herein, in a case where the user long-pushes the center of the screen, all the parameters may be uniformly reinforced with a strength corresponding to the time of long-push. In the above-described embodiment, one threshold value may be provided, and execution or cancellation of the process may be performed according to whether or not the distance from the start point to the end point of the slide operation exceeds the threshold value (refer to FIG. 6B). Herein, there may be a plurality of threshold values. Different threshold values may be used for determination of when to execute different processes. For example, it may be assumed that two processes “synthesis” and “trade” may be associated with one direction. Then, it may be assumed that a first threshold value and a second threshold value larger than the first threshold value may be provided. In a case where the distance from the start point to the end point of the user's slide operation is equal to or smaller than the first threshold value, the control unit 13 may determine that both of the two processes may be canceled. In addition, in a case where the distance exceeds the first threshold value and is equal to or smaller than the second threshold value, the control unit 13 may execute “synthesis” on the selected game content. In addition, in a case where the distance exceeds the second threshold value, the control unit 13 may execute “trade” instead of “synthesis” on the selected game content. In this manner, a plurality of the threshold values corresponding to a plurality of the processes may be provided, so that it may be possible to associate a plurality of the processes in one direction. Since more processes can be associated without increasing the number of slide directions, it may be possible to realize a user interface that enables more efficient operation. At this time, a plurality of processes may be associated with the longitudinal directions (for example, the upward and downward directions) of the display unit 12. In other words, one process may be associated with the short-side direction (for example, the leftward and rightward directions) of the display unit 12. By adjusting the number of processes associated with one direction in accordance with the shape of the display unit 12, even in the information processing apparatus 1 including the display unit 12 with a relatively small size, it may be possible to realize a user interface that may be easier to operate. In the above-described embodiment, the user's slide operation may be executed on the touch panel. However, the slide operation may not be limited to the touch operation but may be executed in the space (in the air). For example, the operation unit 10 may include a sensor for detecting movement of a user's finger or the like. Then, the operation unit 10 may use the route drawn by the user's finger or the like in the space as an input operation. In addition, for example, the operation unit 10 may be an operation device (controller) operated by a user. Furthermore, the route of the operating device that has moved in the space may be an input operation during the period from the time when the user pushes the button of the operation device (controller) to the time when the user releases the button. The point at which the button may be pushed and the point at which the button may be released may correspond to the start point and the end point, respectively. In addition, the direction from the start point to the end point in the space may be determined to be not only the vertical and horizontal directions (the directions on one plane) but also the forward direction and the depth direction. In the above-described embodiment, when a slide operation satisfying a predetermined condition (for example, a length exceeding the threshold value and no intentional change of direction) may be performed, one process may be immediately executed. Herein, even though the slide operation satisfying the predetermined condition may be performed, the process may be executed in a case where the preparation may be performed for the first time and the user may perform the slide operation once again in the same direction. For example, it may be assumed that the process associated with the direction of the slide operation performed by the user may be a warehouse. At this time, in the first slide operation, storing in the warehouse may not be executed, and a preparation screen may be displayed. The preparation screen may include, for example, a selected game content and a confirmation message of “Would you save it?” In addition, instead of the slide operation in the same direction, a long-push operation, a stop of a slide operation for a predetermined time, or the like may be used for the operation to execute the process performed by the user after the first slide operation. In the above-described embodiment, a process executed on the game content may be associated with the direction of the slide operation game content. Herein, cancellation may be associated with one direction of the slide operation. For example, regardless of the type of the game content, cancellation may be associated with the lower leftward direction. At this time, for example, in a case where it is noticed that there may be excess or deficiency in the selection of the game content, the user can immediately cancel the process by performing the slide operation in the lower leftward direction. In addition, the display of the help information 122 may be associated with one direction of the slide operation. For example, regardless of the type of the game content, the display of the help information 122 may be associated with the upper leftward direction. At this time, the user can immediately confirm the help information 122 at any time. In addition, as described above, in a case where preparation for a process (for example, preparation of a warehouse, preparation for trade, and the like) may be performed, final execution may be associated with one direction of the slide operation. At this time, it may be possible to collectively execute the processes after preparing the plurality of processes. In the above-described embodiment, in response to one input operation (slide) by the user, one process may be executed on the selected game content. However, in response to the input operation of the slide at multiple stages by the user, a plurality of different processes corresponding to the directions of the input operations at the respective stages may be executed. For example, after selecting an item (game content), in response to an input operation of sliding the finger rightward by a predetermined distance, an icon of “item synthesis” (or the above-described prediction 123 or the like) may be displayed. After that, in response to an input operation of further sliding the finger rightward by a predetermined distance, the process of “normal item synthesis” may be executed. On the other hand, herein, in response to an input operation of sliding the finger downward by a predetermined distance instead of rightward, the process of “special item synthesis” may be executed. In addition, herein, in response to an input operation of sliding the finger leftward by a predetermined distance instead of rightward or downward, the icon of “item synthesis” may be deleted, so that the execution of the synthesis process may be canceled. In the above-described embodiment, when the user long-pushes the game content after selecting the game content, the help information 122 may be displayed on the display unit 12. Herein, the operation for displaying the help information 122 on the display unit 12 may not be limited to long-push. For example, when the user draws a specific figure or the like (for example, a circle, a triangle, or the like), the help information 122 may be displayed on the display unit 12. In addition, in a case where the operation unit 10 may be provided with a pressure sensor and may determine the depth (the input level in the depth direction viewed from the user) according to the pressure of the user's input operation, depth information (pressure value) may be included in the input operation data. Then, in a case where the depth of the input operation may be at a first level, the control unit 13 may treat the input operation as a tap or slide operation, and in a case where the depth of the input operation may be at a second level, the help information 122 may be displayed. In the above-described embodiment, the display area 121 for displaying the game content may be a portion of the display unit 12. Herein, the whole of the display unit 12 may be the display area 121. In addition, in this case, the user can execute various processes on the selected game content by performing the slide operation in the display area 121. In addition, the number of game content that can be displayed on the display area 121 can be maximized. In the above-described embodiment, if the end point of the slide operation may not be specified, one process may not be executed. However, even though the end point of the slide operation may not be specified, at the time when the length of the route of the slide operation reaches a predetermined length (for example, the length corresponding to the threshold value Th in FIG. 6A), one process may be executed. In the above-described embodiment, a threshold value which may be a predetermined length may be provided, and execution or cancellation of the process may be performed according to whether or not the distance from the start point to the end point of the slide operation exceeds the threshold value (refer to FIG. 6B). Herein, the speed may be used instead of the distance. At this time, the threshold value may also be set to be a predetermined speed. In addition, in the above-described embodiment, a configuration may be employed in which a server apparatus communicating with the information processing apparatus 1 may execute a portion or all of the operations and processes executed by the control unit 13 of the information processing apparatus 1. For example, display control or the like of a screen displayed on the display unit 12 of the information processing apparatus 1 may be executed by any one of the information processing apparatus 1 and the server apparatus or may be executed by the information processing apparatus 1 and the server apparatus cooperating with each other. In addition, in the above-described embodiment, web display may be performed in which a portion of the game screen may be displayed on the display unit 12 of the information processing apparatus 1 on the basis of the data generated by the server apparatus, or native display may be performed in which a portion of the game screen may be displayed by native application installed in the information processing apparatus 1. In this manner, the game according to the above-described embodiment may be a hybrid game in which each of the information processing apparatus 1 and the server apparatus may execute a portion of the process. In addition, in order to function as the information processing apparatus 1 or the server apparatus, for example, a computer, a mobile phone, or the like may be appropriately used. The information processing apparatus 1 or the server apparatus can be realized by storing a program describing process contents for realizing each of the above-described may function in an accessible storage unit and allowing a CPU to read and execute the program.
<SOH> BACKGROUND OF THE INVENTION <EOH>
<SOH> SUMMARY OF THE INVENTION <EOH>The invention is to provide a program, a control method, and an information processing apparatus that realize a user interface capable of easily and efficiently executing various processes on a game content. According to an exemplary embodiment, there may be provided a program causing an information processing apparatus including a display unit which displays a game content, an operation unit which receives a first input operation of a user selecting a game content and a second input operation of instructing a process on the game content selected by the first input operation and outputs first input operation data where the first input operation may be associated with coordinate information and second input operation data where the second input operation may be associated with the coordinate information, and a storage unit which may store information where a process on the game content and a direction are associated with each other to execute: a game content specifying step of specifying the selected game content on the basis of the first input operation data; a step of retrieving the information from the storage unit; a step of specifying a direction from a start point to an end point of the second input operation on the basis of the second input operation data; and an execution step of executing one process associated with the direction from the start point to the end point of the second input operation in the information on the selected game content. According to another exemplary embodiment, there may be provided a control method for a game executed by an information processing apparatus including a display unit which displays a game content, an operation unit which receives a first input operation of a user selecting a game content and a second input operation of instructing a process on the game content selected by the first input operation and outputs first input operation data where the first input operation is associated with coordinate information and second input operation data where the second input operation is associated with the coordinate information, and a storage unit which may store information where a process on the game content and a direction are associated with each other, the control method including: specifying the selected game content on the basis of the first input operation data; retrieving the information from the storage unit; specifying a direction from a start point to an end point of the second input operation on the basis of the second input operation data; and executing one process associated with the direction from the start point to the end point of the second input operation in the information on the selected game content. According to still another exemplary embodiment, there may be provided an information processing apparatus, including: a display unit which displays a game content; an operation unit which receives a first input operation of a user selecting a game content and a second input operation of instructing a process on the game content selected by the first input operation and outputs first input operation data where the first input operation may be associated with coordinate information and second input operation data where the second input operation may be associated with the coordinate information; a storage unit which may store information where a process on the game content and a direction are associated with each other; and a control unit, in which the control unit specifies the selected game content on the basis of the first input operation data, retrieves the information from the storage unit, specifies a direction from a start point to an end point of the second input operation on the basis of the second input operation data, and executes one process associated with the direction from the start point to the end point of the second input operation in the information on the selected game content. According to an exemplary embodiment, it may be possible to provide a program, a control method, and an information processing apparatus realizing a user interface capable of easily and efficiently executing various processes on a game content.
A63F1340
20170925
20180405
65883.0
A63F1340
0
ROWLAND, STEVE
PROGRAM, CONTROL METHOD, AND INFORMATION PROCESSING APPARATUS
UNDISCOUNTED
0
ACCEPTED
A63F
2,017
15,714,558
PENDING
METHOD AND APPARATUS TO CORRECT BLUR IN ALL OR PART OF A DIGITAL IMAGE BY COMBINING PLURALITY OF IMAGES
A method and apparatus for use in a digital imaging device for correcting image blur in digital images by combining plurality of images. The plurality of images that are combined include a main subject that can be selected by user input or automatically by the digital imaging device. Blur correction can be performed to make the main subject blur-free while the rest of the image is blurred. All of the image may be made blur-free or the main subject can be made blur-free at the expense of the rest of the image. Result is a blur corrected image that is recorded in a memory.
1. A method for use in an imaging device, the method comprising: displaying an image in a user interface of the device; receiving a user input in the user interface, wherein the user input designates a first subject in the image; capturing a plurality of images using an image sensor of the device, wherein the plurality of images include the first subject and a second subject; combining the plurality of images by a processor of the device to obtain a combined image, such that: the combined image includes the first subject and the second subject, the first subject in the combined image is substantially blur free, and the second subject in the combined image is blurred compared to the first image; and storing the combined image in a memory of the device.
CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 14/875,204, filed Oct. 5, 2015, which is a continuation of U.S. patent application Ser. No. 14/586,297, filed on Dec. 30, 2014, which issued as U.S. Pat. No. 9,154,699 on Oct. 6, 2015, which is a continuation of U.S. patent application Ser. No. 13/653,144, filed on Oct. 16, 2012, which issued as U.S. Pat. No. 9,001,221 on Apr. 7, 2015, which is a continuation of U.S. patent application Ser. No. 13/442,370, filed on Apr. 9, 2012, which issued as U.S. Pat. No. 8,922,663 on Dec. 30, 2014, which is a continuation of U.S. patent application Ser. No. 12/274,032, filed on Nov. 19, 2008, which issued as U.S. Pat. No. 8,154,607 on Apr. 10, 2012, which is a continuation of U.S. patent application Ser. No. 11/089,081, filed on Mar. 24, 2005, which issued as U.S. Pat. No. 8,331,723 on Dec. 11, 2012, which claims the benefit of U.S. Provisional Application Ser. No. 60/556,230, filed on Mar. 25, 2004, the contents of each of which are incorporated by reference herein. FIELD OF INVENTION The present invention generally relates to digital image processing. More specifically, this invention relates to processing of digitized image data in order to correct for image distortion caused by relative motion between the imaging device and the subject at the time of image capture, or by optical distortion from other sources. BACKGROUND When capturing images, as with a camera, it is desirable to capture images without unwanted distortion. In general, sources of unwanted distortion can be characterized as equipment errors and user errors. Examples of common equipment errors include inadequate or flawed optical equipment, and undesirable characteristics of the film or other recording media. Using equipment and media of a quality that is suitable for a particular photograph can help mitigate the problems associated with the equipment and the recording medium, but in spite of this, image distortion due to equipment errors can still appear. Another source of image distortion is user error. Examples of common user errors include poor image processing, and relative motion between the imaging device and the subject of the image. For example, one common problem that significantly degrades the quality of a photograph is the blur that results from camera movement (i.e. shaking) at the time the photograph is taken. This can be difficult to avoid, especially when a slow shutter speed is used, such as in low light conditions, or when a large depth of field is needed and the lens aperture is small. Similarly, if the subject being photographed is moving, use of a slow shutter speed can also result in image blur. There are currently many image processing techniques that are used to improve the quality, or “correctness,” of a photograph. These techniques are applied to the image either at the time it is captured by a camera, or later when it is post-processed. This is true for both traditional “hardcopy” photographs that are chemically recorded on film, and for digital photographs that are captured as digital data, for example using a charged couple device (CCD) or a CMOS sensor. Also, hardcopy photographs can be scanned and converted into digital data, and are thereby able to benefit from the same digital signal processing techniques as digital photographs. Commonly used post-processing techniques for digitally correcting blurred images typically involve techniques that seek to increase the sharpness or contrast of the image. This can give the mistaken impression that the blur is remedied. However, in reality, this process causes loss of data from the original image, and also alters the nature of the photograph. Thus, current techniques for increasing the sharpness of an image do not really “correct” the blur that results from relative motion between a camera and a subject being photographed. In fact, the data loss from increasing the sharpness can result in a less accurate image than the original. Therefore, a different method that actually corrects the blur is desirable. In the prior art, electro-mechanical devices for correcting image blur due to camera motion are built into some high quality lenses, variously called “image stabilization”, “vibration reduction”, or similar names by camera/lens manufacturers. These devices seek to compensate for the camera/lens movement by moving one or more of the lens elements; hence countering the effect of the motion. Adding such a device to a lens typically makes the lens much more expensive, heavier and less sturdy, and can also compromise image quality. Accordingly, it is desirable to have a technique that corrects for distortion in photographs without adding excessively to the price, robustness or weight of a camera or other imaging device, or adversely affecting image quality. SUMMARY The present invention processes image data in order to correct an image for distortion caused by imager movement or by movement of the subject being imaged. In another embodiment, the present invention can prevent image distortion due to motion of the imaging device or subject at relatively slow shutter speeds, resulting in a substantially undistorted image. In another embodiment, the present invention measures relative motion between the imaging device and the subject by using sensors that detect the motion. When an image is initially captured, the effect of relative motion between the imaging device and the subject is that it transforms the “true image” into a blurred image, according to a 2-dimensional transfer function defined by the motion. The invention determines a transfer function that represents the motion and corrects the blur. In yet another embodiment, the transfer function is estimated using blind detection techniques. The transfer function is then inverted, and the inverted function is implemented in an image correcting filter that essentially reverses the blurring effect of the motion on the image. The image is processed through the filter, wherein blur due to the motion is reversed, and the true image is recovered. In yet another embodiment, the invention uses the transfer function to combine consecutive images taken at a fast shutter speed to avoid blur due to motion between camera and subject that could result from using a slow shutter speed. In still another embodiment, the image sensor is moved to counter camera motion while the image is being captured. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a portion of memory having memory locations wherein elements of a recorded image are stored. FIG. 2 is a portion of memory having memory locations wherein elements of a deconvolution filter are stored. FIG. 3 is a portion of memory having memory locations wherein the recorded image is stored for calculating the next value of a corrected image. FIG. 4 is a functional block diagram of a system for correcting an image for distortion using a transfer function representing the distortion, wherein the transfer function is derived from measurements of the motion that caused the distortion. FIG. 5 is a functional block diagram of a system for correcting an image for distortion using a transfer function representing the distortion, wherein the transfer function is derived using blind estimation techniques. FIG. 6 shows a unit for iterative calculation of the corrective filter coefficients and estimation of the correct image data. FIG. 7 illustrates support regions of an image r(n,m) and of a transfer function h(n,m), and the transfer function h(n,m) being applied to different parts of the image r(n,m). FIG. 8 shows a unit for blind deconvolution to calculate the correct image data. FIG. 9 is an image of an object being captured on an image sensor wherein pixel values represent points of the image. FIG. 10 illustrates the effect of moving an imager while capturing an image, resulting in multiple copies of the image being recorded over each other, causing blur. FIG. 11 illustrates combining images taken at fast shutter speeds to result in the equivalent of a final image taken at a slower shutter speed, but with reduced blur. FIG. 12 illustrates image blur correction where an image sensor is moved to compensate for imager movement. FIG. 13 is an example of an image distorted by movement of the imager when the image was captured. FIG. 14 is represents the image of FIG. 13 corrected according to the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described with reference to the figures wherein like numerals represent like elements throughout. Although the invention is explained hereinafter as a method of correcting for image distortion due to the shaking of a camera when a picture is taken, similar distortions can also be caused by other types of imaging equipment and by imperfections in photo processing equipment, movement of the subject being photographed, and other sources. The present invention can be applied to correct for these types of distortions as well. Additionally, although reference is made throughout the specification to a camera as the exemplary imaging device, the present invention is not limited to such a device. As aforementioned, the teachings of the present invention may be applied to any type of imaging device, as well as image post-processing techniques. Capturing and recording a photograph, for example by a camera, involves gathering the light reflected or emanating from a subject, passing it through an optical system, such as a series of lenses, and directing it onto a light sensitive recording medium. A typical recording medium in traditional analog photography is a film that is coated with light sensitive material. During processing of the exposed film, the image is fixed and recorded. In digital cameras, the recording medium is typically a dense arrangement of light sensors, such as a Charge-Coupled Device (CCD) or a CMOS sensor. The recording medium continuously captures the impression of the light that falls upon it as long as the camera shutter is open. Therefore, if the camera and the subject are moving with respect to each other (such as in the case when the user is unsteady and is shaking the camera, or when the subject is moving), the recorded image becomes blurred. To reduce this effect, a fast shutter speed can be used, thereby reducing the amount of motion occurring while the shutter is open. However, this reduces the amount of light from the subject captured on the recording medium, which can adversely affect image quality. In addition, increasing the shutter speed beyond a certain point is not always practical. Therefore, undesired motion blur occurs in many pictures taken by both amateur and professional photographers. The nature of the blur is that the light reflected from a reference point on the subject does not fall on a single point on the recording medium, but rather it ‘travels’ across the recording medium. Thus a spread-out, or smudged, representation of the reference point is recorded. Generally, all points of the subject move together, and the optics of the camera and the recording medium also move together. For example, in the case of a photograph of a moving car, wherein an image of the car is blurred due to uniform motion of all parts of the car. In other words, the image falling on the recording medium ‘travels’ uniformly across the recording medium, and all points of the subject blur in the same manner. The nature of the blur resulting from uniform relative motion can be expressed mathematically. In a 2-dimensional space with discrete coordinate indices ‘n’ and ‘in’, the undistorted image of the subject can be represented by s(n,m), and a transfer function h(n,m) can be used to represent the blur. Note that h(n,m) describes the way the image ‘travels’ on the recording medium while it is captured. The resulting image that is recorded, r(n,m), is given by: r(n,m)=s(n,m)**h(n,m); Equation (1) where ** represents 2-dimensional convolution. The mathematical operation of convolution is well known to those skilled in the art and describes the operation: r  ( n , m ) = ∑ i = - ∞ ∞  ∑ j = - ∞ ∞  h  ( i , j )  s  ( n - i , m - j ) . Equation   ( 2 ) In the sum operations in Equation (2), the summation limits are infinite. In practice, the summations are not infinite, since the support region of the transfer function is finite. In other words, the region where the function is non-zero is limited by the time the camera shutter is open and the amount of motion. Therefore, the summation is calculated for only the indices of the transfer function where the function itself is non-zero, for example, from i=−N . . . N and j=−M . . . M. If the transfer function h(n,m) is known, or its estimate is available, the blur that it represents can be “undone” or compensated for in a processor or in a computer program, and a corrected image can be obtained, as follows. Represent the “reverse” of the transfer function h(n,m) as h−1 (n,m) such that: h(n,m)**h−1(n,m)=g(n,m); Equation (3) where δ(n,m) is the 2-dimensional Dirac delta function, which is: δ  ( n , m ) = { 1    if   n = m = 0 0   otherwise . Equation   ( 4 ) The delta function has the property that when convolved with another function, it does not change the nature of that function. Therefore, once h(n,m) and hence h−1(n,m) are known, an image r(n,m) can be put through a correcting filter, called a “deconvolution filter”, which implements the inverse transfer function w(n,m)=h−1(n,m) and undoes the effect of blur. Then: r  ( n , m ) ** w  ( n , m ) =  r  ( n , m ) ** h - 1  ( n , m ) =  s  ( n , m ) ** h  ( n , m ) ** h - 1  ( n , m ) =  s  ( n , m ) ** δ  ( n , m ) =  s  ( n , m ) ; Equation   ( 5 ) and the correct image data s(n,m) is recovered. The deconvolution filter in this example is such that: ∑ i = - N N  ∑ j = - M M  w  ( i , j )  h  ( n - i , m - j ) = { 1   if   n = m = 0 0   otherwise . Equation   ( 6 ) Because of the property that the deconvolution operation forces the output of the convolution to be zero for all but one index, this method is called the “zero-forcing algorithm”. The zero-forcing algorithm itself is but one method that can be used, but there are others possible also, such as the least mean-square algorithm described in more detail below. In order to define a deconvolution filter, the transfer function h(n,m) representing the relative motion between the imager and the subject must be derived from measuring the motion, or alternatively by using blind estimation techniques. The inverse function h−1(n,m) must then be calculated and incorporated in a filter to recover a corrected image s(n,m). It is possible to determine h(n,m) using sensors that detect motion, and record it at the time the image is captured. One embodiment of the present invention includes one or more motion sensors, attached to or included within the imager body, the lens, or otherwise configured to sense any motion of the imager while an image is being captured, and to record this information. Such sensors are currently commercially available which are able to capture movement in a single dimension, and progress is being made to improve their accuracy, cost, and characteristics. To capture motion in two dimensions, two sensors may be used, each capable of detecting motion in a single direction. Alternatively, a sensor able to detect motion in more than one dimension can be used. The convolution in Equation (5) can be performed using memory elements, by performing an element-by-element multiplication and summation over the support region of the transfer function. The recorded image is stored, at least temporarily, in memory elements forming a matrix of values such as shown in FIG. 1. Similarly, the deconvolution filter w(n,m) is stored in another memory location as shown in FIG. 2. The deconvolution operation is then performed by multiplying the values in the appropriate memory locations on an element-by-element basis, such as multiplying r(n,m) and w(0,0); r(n−1,m) and w(1,0), and so on, and summing them all up. Element-by-element multiplication and summing results in the convolution: y  ( n , m ) = ∑ i = - N N  ∑ j = - M M  w  ( i , j )  r  ( n - i , m - j ) . Equation   ( 7 ) To calculate the next element, y(n+1,m) for example, the deconvolution filter w(n,m) multiplies the shifted memory locations, such as shown in FIG. 3, followed by the summation. Note that the memory locations do not need to be shifted in practice; rather, the pointers indicating the memory locations would move. In FIG. 1 and FIG. 3 portions of r(n,m) are shown that would be included in the element-by-element multiplication and summation, and this portion is the same size as w(n,m). However, it should be understood that r(n,m), that is the whole image, is typically much larger than the support region of w(n,m). To determine value of the convolution for different points, an appropriate portion of r(n,m) would be included in the calculations. The filter defined by Equation (5) is ideal in the sense that it reconstructs the corrected image from the blurred image with no data loss. A first embodiment calculates the inverse of h(n,m) where h(n,m) is known. As explained above, by making use of motion detecting devices, such as accelerometers, the motion of the imager (such as a camera and/or the associated lens) can be recorded while the picture is being captured, and the motion defines the transfer function describing this motion. A functional block diagram of this embodiment in accordance with the present invention is illustrated in FIG. 4, wherein a method 40 for correcting image distortion is shown. An image r(n,m) from camera optics is captured by an imager (step 41) and recorded in memory (step 42). Simultaneously, motion sensors detect and record camera motion (step 43) that occurs while the shutter of the camera is open. The transfer function representing the motion h(n,m) is derived (step 44), and the inverse transfer function h−1(n,m) is determined (step 46). The inverse transfer function is applied in a corrective filter (step 48) to the image, which outputs a corrected image s(n,m) (step 49). In this and other embodiments that make use of motion sensors to represent the imager's movement, derivation of the transfer function from motion information (step 44) takes into account the configuration of the imager and the lens also. For an imager that is a digital camera, for example, the focal length of the lens factors into the way the motion of the imager affects the final image. Therefore the configuration of the imager is part of the derivation of h(n,m). This is important especially for imagers with varying configurations, such as digital cameras with interchangeable lenses. In this first embodiment of the invention, an iterative procedure is used to compute the inverse transfer function from h(n,m). The approximate inverse transfer function at iteration k is denoted as ĥk−1(n,m). At this iteration, output of the deconvolution filter is: y k  ( n , m ) =  h ^ k - 1  ( n , m ) ** r  ( n , m ) =  ∑ i  ∑ j  h ^ k - 1  ( i , j )  r  ( n - i , m - j ) . Equation   ( 8 ) The filter output can be written as the sum of the ideal term and the estimation noise as:  Equation   ( 9 ) y k  ( n , m ) =  h - 1  ( n , m ) ** r  ( n , m ) + ( h ^ k - 1  ( n , m ) - h - 1  ( n , m ) ) ** r  ( n , m ) =  s  ( n , m ) + v k  ( n , m ) ; where v(n,m) is the estimation noise which is desirable to eliminate. An initial estimate of the correct image can be written as: ŝk(n,m)=ĥk−1(n,m)**r(n,m) Equation (10) However, this estimate can in general be iteratively improved. There are a number of currently known techniques described in estimation theory to achieve this. A preferable option is the Least Mean-Square (LMS) algorithm. A block diagram of a calculation unit 60 which implements this method is shown in FIG. 6. As an initial state, ĥ−10(n,m) is set to equal μr(n,m). Then, the following steps are iteratively repeated: Step 1, an estimate of the correct image is calculated in a first 2-dimensional finite impulse response (2D FIR) filter 62: ŝk(n,m)=ĥk−1(n,m)**r(n,m) Step 2, a received signal based on the estimated correct image is calculated in a second 2D FIR filter 64: {tilde over (r)}k(n,m)=ŝk(n,m)**h(n,m); and the estimation error is calculated using an adder 66: ek(n,m)=rk(n,m)−{tilde over (r)}k(n,m). Step 3, the inverse transfer function coefficients are then updated in the LMS algorithm unit 68: ĥk+1−1(n,m)=ĥk−1(n,m)+μr(n,m)ek(n,m); where μ is the step-size parameter. These steps are repeated until the estimation error becomes small enough to be acceptable; which value can be predetermined or may be set by a user. As the iterative algorithm converges, the estimated inverse transfer function approaches the correct inverse transfer function h−1(n,m). The inverse transfer function coefficients are the coefficients of the deconvolution filter, and the estimate ŝ(n,m) converges to s(n,m), the correct image, at the same time. This process can be repeated for the entire image, but it is less complex, and therefore preferable, to find the inverse filter first over a single transfer function support region, then apply it to the entire image r(n,m). While the above Steps 1-3 are being repeated, a different portion of the recorded image r(n,m) can be used in each iteration. As in FIG. 7, it should be noted that the recorded image r(n,m) typically has a much larger support region than the transfer function h(n,m) that represents the camera motion. Therefore, the above steps are preferably performed over a support region of h(n,m), and not over the entire image r(n,m), for each iteration. Although the present invention has been explained with reference to the LMS algorithm, this is by way of example and not by way of limitation. It should be clear to those skilled in the art that there are other iterative algorithms beside the LMS algorithm that can be used to achieve acceptable results, and also that there are equivalent frequency domain derivations of these algorithms. For example, it is possible to write Equation (1) in frequency domain as: R(ω1,ω2)=S(ω1,ω2)H(ω1,ω2); Equation (11) where R(ω1,ω2), S(ω1,ω2), and H(ω1,ω2) are the frequency domain representations (Fourier Transforms) of the captured image, the correct image, and the transfer function, respectively, and therefore: S  ( ω 1 , ω 2 ) = R  ( ω 1 , ω 2 ) H  ( ω 1 , ω 2 ) . Equation   ( 12 ) To obtain s(n,m) one would calculate S(ω1,ω2) as above and take the Inverse Fourier Transform, which should be known to those skilled in the art. However, this method does not always lead to well behaved solutions, especially when numerical precision is limited. In a second embodiment of the present invention, h(n,m) is not known. This second embodiment uses so-called blind deconvolution, whereby the transfer function h(n,m) is estimated using signal processing techniques. A functional block diagram of this embodiment is illustrated in FIG. 5, wherein a method 50 for correcting image distortion according to this embodiment is shown. An image r(n,m) from the optics from a camera is captured (step 51) and recorded in memory (step 52). Unlike the first embodiment, there are no motion sensors to detect and record camera motion that occurs while the shutter of the camera is open. Instead, the transfer function representing the motion h(n,m) is derived using blind estimation techniques (step 54), and the inverse transfer function h−1(n,m) is determined (step 56). The inverse transfer function is applied in a corrective filter to the image (step 58), which outputs a corrected image s(n,m) (step 59). Blind equalization techniques are used to obtain the deconvolution filter coefficients. This is also an iterative LMS algorithm, similar to that used in the first embodiment. In this second embodiment, an iterative procedure is also used to compute an approximate deconvolution filter, and the approximation is improved at each iteration until it substantially converges to the ideal solution. As aforementioned with respect to the first embodiment, the level of convergence may be predetermined or may be set by a user. The approximate deconvolution filter is denoted at iteration k as ŵk(n,m). At this iteration, the output of the deconvolution filter is: y k  ( n , m ) =  w ^ k  ( n , m ) ** r  ( n , m ) =  ∑ ∑ w ^ k  ( i , j )  r  ( n - i , m - j ) ; Equation   ( 13 ) The filter output can be written as the sum of the ideal term and the estimation noise as:  Equation   ( 14 ) y k  ( n , m ) =  w  ( n , m ) ** r  ( n , m ) + [ w ^ k  ( n , m ) - w  ( n , m ) ] ** r  ( n , m ) =  s  ( n , m ) + v k  ( n , m ) ; where v(n,m) is the estimation noise, which is desirable to eliminate. An initial estimate of the correct image can be written as: ŝk(n,m)=ŵk(n,m)**r(n,m). Equation (15) However, this estimate can be iteratively improved. There are a number of currently known techniques described in estimation theory to achieve this. A preferable option is the LMS algorithm. A block diagram of a calculation unit 80 which implements this method is shown in FIG. 8. As an initial state, ĥ−10(n,m) is set equal to μr(n,m). Then, the following steps are iteratively repeated: Step 1, an estimate of the correct image is calculated in a first 2D FIR filter 82: ŝk(n,m)=ĥk−1(n,m)**r(n,m). Step 2, a received signal based on the estimated correct image is calculated in a non-linear estimator 84: {tilde over (r)}k(n,m)=g(ŝk(n,m)); and the estimation error is calculated using an adder 86: ek(n,m)=rk(n,m)−{tilde over (r)}k(n,m). Step 3, the inverse transfer function coefficients are then updated in the LMS algorithm unit 88: ĥk+1−1(n,m)=ĥk−1(n,m)+μr(n,m)ek(n,m), where μ is the step-size parameter. The function g(.) calculated in step 2 is a non-linear function chosen to yield a Bayes estimate of the image data. Since this function is not central to the present invention and is well known to those of skill in the art, it will not be described in detail hereinafter. There are known blind detection algorithms for calculating s(n,m) by looking at higher order statistics of the image data r(n,m). A group of algorithms under this category are called Bussgang algorithms. There are also variations called Sato algorithms, and Godard algorithms. Another class of blind estimation algorithms use spectral properties (polyspectra) of the image data to deduce information about h(n,m). Any appropriate blind estimation algorithm can be used to determine h(n,m), and to construct a correcting filter. The first two embodiments of the present invention described hereinbefore correct blur in an image based on determining a transfer function that represents the motion of an imager while an image is being captured, and then correcting for the blur by making use of the “inverse” transfer function. One method determines the transfer function at the time the photograph is being captured by using devices that can detect camera motion directly. The other method generates a transfer function after the image is captured by using blind estimation techniques. Both methods then post-process the digital image to correct for blur. In both cases, the captured image is originally blurred by motion, and the blur is then removed. In accordance with a third embodiment of the present invention the blurring of an image is prevented as it's being captured, as described below. When an imager is moved while an image is being captured, multiple copies of the same image are, in effect, recorded over each other. For example, when an image is captured digitally it is represented as pixel values in the sensor points of the image sensor. This is pictorially represented in FIG. 9, in which the imager (for example, a camera and its associated lens) are not shown in order to simplify the depiction. If the imager is shaken or moved while the image is being captured, the situation is equivalent to copies of the same image being captured multiple times in an overlapping fashion with an offset. The result is a blurred image. This is particularly true if the shutter speed is relatively slow compared to the motion of the camera. This is graphically illustrated in FIG. 10. When the shutter speed is sufficiently fast compared to the motion of the imager, blur does not occur or is very limited because the displacement of the imager is not large enough to cause the light reflected from a point on the image to fall onto more than one point on the image sensor. This third embodiment of the invention takes advantage of the ability of an imager to record multiple images using fast shutter speeds. When an image is being captured using a setting of a relatively slow shutter speed, the imager actually operates at a higher shutter speed (for instance at the fastest shutter speed at which the imager is designed to operate), and captures multiple images “back to back.” For example, if the photograph is being taken with a shutter speed setting of 1/125 sec and the fastest shutter speed of the camera is 1/1000 sec, the camera actually captures 8 consecutive images, each taken with a shutter speed setting of 1/1000 sec. Then, the camera combines the images into a single image by aligning them such that each pixel corresponding to the same image point in each image is combined pixel-by-pixel into one pixel value by adding pixel values, averaging them, or using any other appropriate operation to combine them. The multiple images can all be stored and aligned once all of them are captured, or alternatively, each image can be aligned and combined with the first image in “real time” without the need to store all images individually. The blur of the resulting image is substantially reduced, as depicted in FIG. 11. The quality of an image can be measured in terms of signal-to-noise power ratio (SNR). When a fast shutter speed is used, the SNR of the image is degraded because the image sensor operates less effectively when the amount of light falling on it is reduced. However, since multiple images are being added, this degradation is overcome. Indeed, an SNR improvement can be expected using this embodiment, because the image data is being added coherently while the noise is being added non-coherently. This phenomenon is the basis for such concepts as maximal ratio combining (MRC). To determine how to align the pixel values, a device that can detect motion, such as an accelerometer or other motion sensor, is attached to or incorporated within the imager, and it records the motion of the imager while the photograph is being taken. The detected motion indicates how much the imager moved while each of the series of images was captured, each image having been captured back-to-back with a high shutter speed as explained in the example above. The imager moves each of the images in the series by an amount which is preferably measured in pixels, in the direction opposite the motion of the imager that occurred during the interval between the capture of the first image and each respective image in the series. Thus, the shift of each image is compensated for, and the correct pixels are aligned in each of the images. This is illustrated in FIG. 11. The combined image will not be blurred since there is no spilling of image points into more than one pixel in the combined final image. As an alternative to the third embodiment, the reference point for aligning the higher speed images is not the imager location, but the subject itself. In other words, higher shutter speed images can be aligned and combined such that a designated subject in a field of view is clear and sharp whereas other parts of the image may be blurred. For example, a moving subject such as a car in motion can be the designated subject. If high shutter speed images are combined such that the points of the image of the moving car are aligned, the image of the car will be clear and sharp, while the background is blurred. As a way to align a designated subject, such as the car in this example, pattern recognition and segmentation algorithms may be used that are well known to those skilled in the art, and defined in current literature. Alternatively, a tracking signal that is transmitted from the subject can be used to convey its position. Alternatively, the user can indicate, such as by an indicator in a viewfinder, which object in the field of view is the designated subject to be kept blur-free. A fourth embodiment of the invention compensates for movement of the imager or the subject by adjusting the position of the image sensor during image capture, according to the inverse of the transfer function describing the imager or subject motion, or both. This embodiment is illustrated in FIG. 12. This embodiment is preferably used in digital cameras wherein the image sensor 108 is a relatively small component and can be moved independently of the camera, but can also be used with film. Accordingly, this embodiment makes use of motion sensors, and detects the movement of the camera and/or the subject while the image is being captured. The signals from the motion sensors are used to control devices that adjust the position of the image sensor. In FIG. 12, horizontal motion sensor 102 and vertical motion sensor 104 measure movement of the camera while its shutter (not shown) is open and an image is being captured. The motion information is conveyed to a controller 106, which determines and sends signals to devices 110a, 110b, 110c, and 110d, which adjust the position of the image sensor 108. The control mechanism is such that the devices 110a-d, for example electromagnets or servos, move the image sensor 108 in the opposite direction of the camera motion to prevent motion blur. Additional sensors (not shown) can be used to detect motion of the subject, and the control mechanism configured to correct for that motion as well. FIG. 13 shows an example of a photographic image that is blurred due to user movement of the imager while taking the picture. FIG. 14 shows the same image, corrected according to the present invention. The invention substantially recovers the correct image from the blurred image. Those skilled in the art will recognize that all embodiments of the invention are applicable to digitized images which are blurred by uniform motion, regardless of the source of the image or the source of the motion blur. It is applicable to digital images blurred due to motion of the imager, of the subject, or both. In some cases, it is also applicable to images captured on film and then scanned into digital files. In the latter case, however, motion sensor information typically may not be available, and therefore only the blind estimation embodiment can be used. Also, where appropriate, the different embodiments of the invention can be combined. For example, the superposition embodiment can be used to avoid most blur, and the correcting filter using blind estimation embodiment can then be applied to correct the combined image for any remaining blur. In describing the invention, no distinction has been made between an imager that captures images one at a time, such as a digital camera, and one that captures sequence of images, such as digital or analog video recorders. A digital video recorder or similar device operates substantially the same way as a digital camera, with the addition of video compression techniques to reduce the amount of image data being stored, and various filtering operations used to improve image quality. The invention is also applicable to digital and analog video capture and processing, being applied to each image in the sequence of images, and can be used in conjunction with compression and other filtering. The implementation of the apparatus that performs the restoration of the images to their correct form can be done as part of the imager capturing the image, or it can be done as a post-process. When done as part of the imager, the image correcting apparatus can be implemented in an integrated circuit, or in software to run on a processor, or a combination of the two. When done as a post process, a preferred embodiment is that the image data is input into a post processing device such as a computer, and the blind estimation algorithm is performed by a computer program. In this embodiment, the implementation could be a dedicated computer program, or an add-on function to an existing computer program. Where a computer program performs the image restoration, a blind estimation algorithm can be executed by the program to calculate the estimated transfer function h(n,m). Alternatively, motion information can be recorded by the camera at the time the image is captured, and can be downloaded into the program to be used as an input to calculate h(n,m). In either case, the program then derives the correcting filter and applies the filter to correct the image. It should also be noted that if there are multiple blurred objects in an image, and the blur is caused by the objects moving in different directions, the image of each object will be blurred differently, each blurred object having a different transfer function describing its motion. The present invention can allow the user to individually select independently blurred parts of the image and individually correct only the selected parts, or alternatively, to correct a selected part of the image at the expense of the rest of the image, resulting in a blur-corrected subject and a blurred background. When increased accuracy is needed in obtaining h(n,m), those skilled in the art will recognize that, in some cases, the motion information from sensors can be used to calculate h(n,m), and an estimate of h(n,m) can also be calculated by blind estimation and the two transfer functions can be advantageously combined for more accurate results. There are other signal processing algorithms and digital filters which can be applied to digital images in order to improve their color saturation, reduce noise, adjust contrast and sharpness, etc. These can be incorporated as part of an imager, such as a digital camera, or as part of a post-processing application, such as a photo editing software running on a computer. It should be clear to those skilled in the art that those techniques can be applied in addition to the distortion correction of this invention.
<SOH> BACKGROUND <EOH>When capturing images, as with a camera, it is desirable to capture images without unwanted distortion. In general, sources of unwanted distortion can be characterized as equipment errors and user errors. Examples of common equipment errors include inadequate or flawed optical equipment, and undesirable characteristics of the film or other recording media. Using equipment and media of a quality that is suitable for a particular photograph can help mitigate the problems associated with the equipment and the recording medium, but in spite of this, image distortion due to equipment errors can still appear. Another source of image distortion is user error. Examples of common user errors include poor image processing, and relative motion between the imaging device and the subject of the image. For example, one common problem that significantly degrades the quality of a photograph is the blur that results from camera movement (i.e. shaking) at the time the photograph is taken. This can be difficult to avoid, especially when a slow shutter speed is used, such as in low light conditions, or when a large depth of field is needed and the lens aperture is small. Similarly, if the subject being photographed is moving, use of a slow shutter speed can also result in image blur. There are currently many image processing techniques that are used to improve the quality, or “correctness,” of a photograph. These techniques are applied to the image either at the time it is captured by a camera, or later when it is post-processed. This is true for both traditional “hardcopy” photographs that are chemically recorded on film, and for digital photographs that are captured as digital data, for example using a charged couple device (CCD) or a CMOS sensor. Also, hardcopy photographs can be scanned and converted into digital data, and are thereby able to benefit from the same digital signal processing techniques as digital photographs. Commonly used post-processing techniques for digitally correcting blurred images typically involve techniques that seek to increase the sharpness or contrast of the image. This can give the mistaken impression that the blur is remedied. However, in reality, this process causes loss of data from the original image, and also alters the nature of the photograph. Thus, current techniques for increasing the sharpness of an image do not really “correct” the blur that results from relative motion between a camera and a subject being photographed. In fact, the data loss from increasing the sharpness can result in a less accurate image than the original. Therefore, a different method that actually corrects the blur is desirable. In the prior art, electro-mechanical devices for correcting image blur due to camera motion are built into some high quality lenses, variously called “image stabilization”, “vibration reduction”, or similar names by camera/lens manufacturers. These devices seek to compensate for the camera/lens movement by moving one or more of the lens elements; hence countering the effect of the motion. Adding such a device to a lens typically makes the lens much more expensive, heavier and less sturdy, and can also compromise image quality. Accordingly, it is desirable to have a technique that corrects for distortion in photographs without adding excessively to the price, robustness or weight of a camera or other imaging device, or adversely affecting image quality.
<SOH> SUMMARY <EOH>The present invention processes image data in order to correct an image for distortion caused by imager movement or by movement of the subject being imaged. In another embodiment, the present invention can prevent image distortion due to motion of the imaging device or subject at relatively slow shutter speeds, resulting in a substantially undistorted image. In another embodiment, the present invention measures relative motion between the imaging device and the subject by using sensors that detect the motion. When an image is initially captured, the effect of relative motion between the imaging device and the subject is that it transforms the “true image” into a blurred image, according to a 2-dimensional transfer function defined by the motion. The invention determines a transfer function that represents the motion and corrects the blur. In yet another embodiment, the transfer function is estimated using blind detection techniques. The transfer function is then inverted, and the inverted function is implemented in an image correcting filter that essentially reverses the blurring effect of the motion on the image. The image is processed through the filter, wherein blur due to the motion is reversed, and the true image is recovered. In yet another embodiment, the invention uses the transfer function to combine consecutive images taken at a fast shutter speed to avoid blur due to motion between camera and subject that could result from using a slow shutter speed. In still another embodiment, the image sensor is moved to counter camera motion while the image is being captured.
H04N523287
20170925
20180125
70224.0
H04N5232
1
MONK, MARK T
METHOD AND APPARATUS TO CORRECT BLUR IN ALL OR PART OF A DIGITAL IMAGE BY COMBINING PLURALITY OF IMAGES
SMALL
1
CONT-ACCEPTED
H04N
2,017
15,715,065
PENDING
ELECTRONIC PERCUSSION INSTRUMENT AND METHOD FOR CONTROLLING SOUND GENERATION
An electronic percussion instrument to control generated sound in accordance with operation to the striking surface includes: a first sensor configured to detect a slapping operation on the striking surface; a second sensor configured to detect a contact operation to the striking surface; and a processor configured to control sound generated in response to detection of a slapping operation by the first sensor in accordance with a place of a contact operation to the striking surface detected by the second sensor.
1. An electronic percussion instrument having a surface, comprising: a first sensor configured to detect a striking operation on the surface; a second sensor configured to detect a contact operation to the surface; and a processor configured to control sound generated in response to detection of a striking operation by the first sensor, in accordance with a place of a contact operation to the surface detected by the second sensor. 2. The electronic percussion instrument according to claim 1, wherein the processor is configured to control sound generated in response to detection of a striking operation on a first place of the surface by the first sensor in accordance with a place of a contact operation detected by the second sensor. 3. The electronic percussion instrument according to claim 1, wherein the processor is configured to control generated sound in accordance with combination of a place of a striking operation on the surface detected by the first sensor and a place of a contact operation to the surface detected by the second sensor. 4. The electronic percussion instrument according to claim 1, wherein the processor is configured to control generated sound based on whether a place of a striking operation on the surface detected by the first sensor and a place of a contact operation to the surface detected by the second sensor are within a same range or not. 5. The electronic percussion instrument according to claim 4, wherein the processor is configured to, when the place of the striking operation and the place of the contact operation are not within the same range, control so as to change generated sound in response to detection of the striking operation, and when the place of the striking operation and the place of the contact operation are within the same range, control so as not to change sound generated in response to the striking operation. 6. The electronic percussion instrument according to claim 1, comprising: the surface; and a sound output unit, wherein the first sensor detects strength of a striking operation on the surface and a place of the striking operation on the surface, the second sensor detects a place of a contact operation to the surface, and the processor is configured to change at least one of loudness and pitch of sound generated by the sound output unit based on a difference in strength or place of the striking operation detected by the first sensor and change the sound generated by the sound output unit based on the contact operation detected by the second sensor. 7. The electronic percussion instrument according to claim 1, wherein the processor is configured to cancel sound generated in response to detection of a striking operation on the surface by the first sensor in response to a contact operation detected by the second sensor. 8. The electronic percussion instrument according to claim 7, wherein the processor is configured to, when a contact operation is detected by the second sensor during generation of sound, cancel the sound being generated. 9. The electronic percussion instrument according to claim 1, wherein the processor is configured to, when an output value of a threshold or more is detected by the second sensor for a set time, determine that the contact operation is performed. 10. The electronic percussion instrument according to claim 1, wherein the surface includes a plate member that can be elastically deformed, the first sensor detects strength of a striking operation on the surface and a place of the striking operation on the surface based on a change in resistance that changes with a contacting state between conductive thin films opposed on a face of the plate member, and the second sensor detects a place of a contact operation to the surface based on a change in capacitance detected by a detection unit disposed at a face of the plate member so as to correspond to the first sensor. 11. The electronic percussion instrument according to claim 10, wherein the surface includes the plate member as a single member, the first sensor includes a plurality of sensors disposed at a plurality of corresponding places at a face of the plate member, and the second sensor includes a plurality of sensors disposed at a plurality of corresponding places at a face of the plate member. 12. The electronic percussion instrument according to claim 10, wherein the first sensor is disposed at a position closer to the plate member than the second sensor is. 13. A method for controlling generated sound executed by a processor, comprising: detecting a place of a contact operation to a surface, and controlling generated sound in response to detection of a striking operation on the surface in accordance with the detected place of the contact operation. 14. The method for controlling generated sound according to claim 13, wherein the processor is configured to control sound generated in response to detection of a striking operation on a first position of the surface in accordance with the place of the contact operation to the surface. 15. The method for controlling generated sound according to claim 13, wherein the processor is configured to control generated sound in accordance with combination of a place of a striking operation on the surface and the place of a contact operation to the surface. 16. The method for controlling generated sound according to claim 13, wherein the processor is configured to control generated sound based on whether a place of a striking operation on the surface and a place of a contact operation to the surface are within a same range or not. 17. The method for controlling generated sound according to claim 16, wherein the processor is configured to, when the place of the striking operation and the place of the contact operation are not within the same range, control so as to change sound generated in response to detection of the striking operation, and when the place of the striking operation and the place of the contact operation are within the same range, control so as not to change sound generated in response to the striking operation. 18. A non-transitory recording medium to record a program, the program making a computer execute the processing of: detecting a place of a contact operation to a surface, and controlling generated sound in response to detection of a striking operation on the surface in accordance with the detected place of the contact operation.
BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to electronic percussion instruments, such as an electronic cajon. 2. Description of the Related Art Conventionally known percussion instruments include an acoustic percussion instrument not having a function of amplifying the sound electrically and an electronic percussion instrument configured to detect a striking operation and electrically amplify the sound generated in accordance with the strength detected and the struck position for outputting. For instance, Patent Document 1 describes an electronic percussion instrument including four sensor units including a piezoelectric device on the rear face of the striking surface. This percussion instrument is configured to detect a sound by the sensor units about the strength or the position of striking and amplifies the sound electrically in accordance with the strength and the position for outputting. [Patent Document 1] Japanese Patent Application Laid-Open No. 2006-030476 SUMMARY OF THE INVENTION One aspect of the present invention relates to an electronic percussion instrument having a surface. The electronic percussion instrument includes: a first sensor configured to detect a striking operation on the surface; a second sensor configured to detect a contact operation to the surface; and a processor configured to control sound generated in response to detection of a striking operation by the first sensor in accordance with a place of a contact operation to the surface detected by the second sensor. Another aspect of the present invention relates to a method for controlling generated sound executed by a processor. The method includes: detecting a place of a contact operation to a surface, and controlling generated sound in response to detection of a striking operation on the surface in accordance with the detected place of the contact operation. Another aspect of the present invention relates to a non-transitory recording medium to record a program. The program makes a computer execute the processing of: detecting a place of a contact operation to a surface, and controlling generated sound in response to detection of a striking operation on the surface in accordance with the detected place of the contact operation. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING FIG. 1 is a perspective view of an electronic percussion instrument according to one embodiment of the present invention. FIG. 2 is a cross-sectional view of the configuration of a striking surface and a detection unit. FIG. 3 is a block diagram showing a control block of the electronic percussion instrument. FIGS. 4A-4C are exploded views showing the configuration of a strike detection unit. FIG. 5 is a flowchart showing the control flow (first half of the main routine) of the electronic percussion instrument. FIG. 6 is a flowchart showing the control flow (latter half of the main routine) of the electronic percussion instrument. FIG. 7 is a flowchart showing the control flow (contact detection processing) of the electronic percussion instrument. FIG. 8 is a flowchart showing the control flow (velocity detection processing) of the electronic percussion instrument. FIG. 9 is a flowchart showing the control flow (timer processing) of the electronic percussion instrument. DETAILED DESCRIPTION OF THE INVENTION The following describes an embodiment of the present invention in details, with reference to the drawings. In the drawings, like reference numerals indicate like parts throughout the description of the embodiment. <Configuration of Electronic Percussion Instrument> Referring to FIGS. 1 to 4, the following describes the configuration of an electronic percussion instrument according to one embodiment of the present invention. FIG. 1 is a perspective view of an electronic percussion instrument according to one embodiment of the present invention. FIG. 2 is a cross-sectional view of the configuration of a striking surface (a surface for a striking operation and a contact operation) and a detection unit. FIG. 3 is a block diagram showing a control block of the electronic percussion instrument. FIGS. 4A-4C are exploded views showing the configuration of a slapping detection unit. FIG. 4A shows a conductive sheet, FIG. 4B shows the surface of a board, and FIG. 4C shows the rear face of the board. As shown in FIG. 1, the electronic percussion instrument 1 according to one embodiment of the present invention is an electric cajon, and includes a cubic case 11 having hollow. The front face of the case 11 is a striking surface 12. When a player sits astride the case 11 and slaps the striking surface 12 with one hand or both hands, sound is generated in accordance with the strength and the place of the slapping (striking). The striking surface 12 is attached to the front face of a case body 13 via an elastic member 14, and the case body makes up the top face, the bottom face, the left and right lateral faces and the back face of the case 11. This allows the striking surface to be displaced entirely in response to a slapping operation as well as to be elastic-deformed partially in response to a slapping operation because the striking surface includes a plate member that can be elastically deformed (see FIG. 2). Such displacement or deformation of the striking surface 12 enables reliable transmission of the force of the slapping operation to a slapping detection unit 21 described later. This enables precise detection of the strength and the place of slapping on the striking surface 12. As shown in FIG. 3, this electronic percussion instrument 1 includes a detection unit 2, a sound control unit 3, a sound output unit 4, and an input unit 5, and these units are connected mutually via a bus 6. The following describes these units. (Detection Unit) The detection unit 2 includes a plurality of slapping detection units 21 to detect a slapping operation (the strength and the place of slapping) at the striking surface 12, a plurality of contact detection units 22 to detect a contact operation to the striking surface 12, and an A/D conversion unit 23 to convert a detection signal of the slapping detection units 21 and of the contact detection units 22 to a digital signal and output the signal to the bus 6. The slapping detection units 21 can be in any mode as long as it can detect slapping of the striking surface 12, and may be configured to output a voltage value corresponding to the strength of slapping on the striking surface 12. This may include a vibration sensor that generates voltage in accordance with the strength of vibration or a suppress-strength detection sensor to detect a suppress strength. The present embodiment describes the slapping detection units 21 that are configured to detect the strength of slapping on the striking surface 12 based on a change in resistance that changes with the contacting state between conductive thin films. The slapping detection units 21 are disposed in a matrix form on one of the faces (hereinafter called a “surface”) of a circuit board 72. In the present embodiment, the striking surface 12 is divided into sixteen blocks in total including four in length and four in width. Then sixteen slapping detection units 21 are disposed in a matrix form on the surface of the circuit board 72 so as to detect the slapping operation in their corresponding blocks. The number and the arrangement of the slapping detection units 21 can be changed freely, and the positions of the slapping detection units 21 on the striking surface 12 are stored in the sound control unit 3 or the like. For precise detection of the slapping place on the striking surface 12, the slapping detection units 21 is preferably disposed at at least two places of the striking surface 12, including the center and the upper part. Specifically as shown in FIG. 2, the slapping detection units 21 include a conductive sheet 74 that is stacked on the surface of the circuit board 72. The circuit board 72 has carbon printing 71 as a conductive thin film on the surface, and the conductive sheet 74 has carbon printing 73 as a conductive thin film thereon. The circuit board 72 and the conductive sheet 74 are stacked so that their carbon printing 71 and carbon printing 73 are opposed via space 75. In the present embodiment, the conductive thin films formed on the base materials are made of carbon, which may be other conductive materials, such as silver and copper. The carbon printing 71 is disposed at a position corresponding to each of the slapping detection units 21 on the surface of the circuit board 72 (see FIG. 4B), and includes two spirals to form a pair of electrodes, for example. The carbon printing 73 includes solid-printed carbon on the conductive sheet 74 in a range corresponding to the two spirals as the pair of electrodes formed by the carbon printing 71, for example (see FIG. 4A). When a player slaps the striking surface 12, the space 75 as a gap between the carbon printing 71 and the carbon printing 73 is crashed, so that the pair of electrodes formed with the carbon printing 71 on the circuit board 72 is coupled to the carbon printing 73 on the conductive sheet 74 and so the pair of electrodes of the carbon printing 71 has electrical continuity. At this time, the contacting area of the carbon printing 73 with the carbon printing 71 changes with the strength of slapping so that the contacting area increases (the resistance decreases) with an increase in the strength of slapping, and so the voltage value at the slapping detection unit 21 increases. The slapping detection unit 21 thus outputs the voltage value corresponding to the strength of slapping. This voltage value is A/D converted by the A/D conversion unit 23, and is output to the bus 6 as a digital signal corresponding to the strength of slapping. The sound control unit 3 detects the digital signal as velocity (slapping strength value). That is, loudness of the sound generated by the sound output unit 4 can be changed with the magnitude of this voltage value. The slapping detection units 21 can be configured so that the pitch of sound changes with the slapping place (the place where the slapping detection unit is disposed on the striking surface 12). For instance, lower-pitched sound is issued when the player slaps a place close to the center of the striking surface 12, while higher-pitched sound is issued when the player slaps a place closer to the upper part of the striking surface 12. The slapping detection unit 21 may change at least one of loudness of the sound and pitch of the sound with the strength and the place of slapping, or may change both of them. As shown in FIG. 2, the contact detection units 22 are formed in a matrix form on the other face of the circuit board 72 (hereinafter called a “rear face”). In the present embodiment, the striking surface 12 is divided into sixteen blocks in total including four in length and four in width. Sixteen contact detection units 22 are disposed in a matrix form on the rear face of the circuit board 72 so as to detect the contact operation in their corresponding blocks. The number and the arrangement of the contact detection units 22 can be changed freely, and the positions of the contact detection units 22 on the striking surface 12 are stored in the sound control unit 3 or the like. For precise detection of the contacting position with the right hand or the left hand on the striking surface 12, the contact detection unit 22 is preferably disposed at at least one place at an upper part of the striking surface 12. The present embodiment describes the contact detection units 22 of a capacitance type. The contact detection units 22 may be of other types, such as a pressure-sensitive type, as long as they can detect a contact. Specifically the plurality of contact detection units 22 and electric circuits such as antennas 81 (electrodes) are disposed (see FIG. 4C) to detect a contact operation to the striking surface 12 based on a change in capacitance at the striking surface 12. They are configured to detect the capacitance of a virtual capacitor formed between the hand in contact with the striking surface 12 and the antenna 81 and output the capacitance as a voltage value. When a hand of the player comes into contact with the striking surface 12, the capacitance of the virtual capacitor changes, and so the contact detection units 22 output a voltage value corresponding to contact or non-contact of the hand. This voltage value is A/D converted by the A/D conversion unit 23, and is then output to the bus 6 as a digital signal corresponding to the capacitance. The sound control unit 3 detects it as a capacitance value. The contact detection units 22 are configured so that sound generated changes between a contact and non-contact of the player's hand with the striking surface 12. For instance, the sound can be cancelled and be echoed when the hand comes into contact there and does not come into contact there, respectively. The sound may be changed in accordance with a contact position, such as at an upper part. The present embodiment includes the slapping detection units 21 and the contact detection units 22 in the same number so that their detection areas substantially coincide. The numbers of the slapping detection units 21 and the contact detection units 22 may be different, and their detection areas may be displaced. (Sound Control Unit) The sound control unit 3 includes a CPU 31, a ROM 32 and a RAM 33, which are mutually connected via the bus 6. The sound control unit is connected to the detection unit 2, the sound output unit 4 and the input unit 5, and functions as a musical-sound generation instruction device. The CPU 31 functions as a processor of the musical-sound generation instruction device, and controls the electronic percussion instrument 1 as a whole and executes various types of processing. This includes processing to generate sound in accordance with a slapping operation and a contact operation on the striking surface 12, processing to let the sound output unit 4 issue sounds, and processing to change the play mode, the tone and the volume of the sound in accordance with setting at the input unit 5. The ROM 32 stores a program describing the various types of processing executed by the CPU 31 as well as waveform data to generate various types of musical sound corresponding to the plurality of slapping detection units 21 and the plurality of contact detection units 22. The RAM 33 stores a program read from the ROM 32 and data created during the processing by the CPU 31. The sound control unit 3 determines whether the hand coming into contact with the striking surface 12 is to perform a slapping operation or a contact operation. To this end, the sound control unit determines that the player performs a contact operation to the striking surface 12 when the contact detection unit 22 detects and outputs a capacitance value (output value) more than a threshold for a set period of time. This set period of time may be a fixed value specific to the electronic percussion instrument 1 or may be a variable that can be changed with a song performed or the rhythm. (Sound Output Unit) The sound output unit 4 includes a speaker 41 to output sound, a digital signal processor 42, a D/A conversion unit 43, and a power amplifier 44. The speaker 41 is connected to the digital signal processor 42 via the power amplifier 44 and the D/A conversion unit 43, and the digital signal processor 42 is connected to the sound control unit 3 via the bus 6. The sound output unit 4 D/A converts generated sound data created by the sound control unit 3 into an analog waveform signal, and outputs the signal to the speaker 41 via the power amplifier 44. (Input Unit) The input unit 5 includes a setting operation unit 51 to allow a user to perform various types of setting operation, and an A/D conversion unit 52 to convert a setting signal at the setting operation unit 51 into a digital signal and output the signal to the bus 6. The setting operation unit 51 enables a selection of the play mode, a selection of the tone, a selection of the volume of sound and the like. The sound control unit 3 detects a setting signal at the input unit 5 via the bus 6 to change the play mode, the tone, the volume of sound and the like. <Control Procedure of Electronic Percussion Instrument> Referring now to FIGS. 5 to 9, the following describes control flow of the electronic percussion instrument 1 (sound control unit 3) in the present embodiment in details. FIG. 5 is a flowchart showing the control flow (the first half of the main routine) of the electronic percussion instrument. FIG. 6 is a flowchart showing the control flow (the latter half of the main routine) of the electronic percussion instrument. FIG. 7 is a flowchart showing the control flow (contact detection processing) of the electronic percussion instrument. FIG. 8 is a flowchart showing the control flow (velocity detection processing) of the electronic percussion instrument. FIG. 9 is a flowchart showing the control flow (timer processing) of the electronic percussion instrument. (Main Routine) As shown in FIGS. 5 and 6, when executing the main routine, the sound control unit 3 firstly initializes variables to be used(=0) (Step S11). The variables to be initialized here include a variable “Block” to designate a block of the slapping detection units 21 and the contact detection units 22, an array variable “DET_BLOCK[0,1,2, . . . ]” to determine whether the contact detection unit 22 at each block is in a contact detected state or not (non-contacted=0, contacted=1), and an array variable “Velocity_DET[0,1,2, . . . ]” to determine the velocity of the slapping detection unit 21 at each block. Next, in the loop processing from Step S12 to Step S15, the sound control unit 3 determines whether a contact operation is performed or not for all of the blocks of the contact detection units 22. This determination processing is performed by repeatedly executing a contact detection processing (see FIG. 7) as an external function while incrementing the value of the variable “Block” until the value of the variable “Block” exceeds the block upper limit “N_Block” of the contact detection units 22 (in this embodiment, “15”). In this determination, when the value of the array variable “DET_BLOCK[Block]” corresponding to the block of the contact detection unit 22 in which a contact operation has been detected becomes “1” or when the loop processing ends, the variable “Block” is initialized (Step S16). Then, from Step S17 to Step S19, the sound control unit 3 performs sound-cancellation processing in response to the contact operation to the striking surface 12. Firstly, the sound control unit 3 determines whether the number of the array variables “DET_BLOCK[Block]” having the value of “1” is more than 1 or not (Step S17). If this determination results in Yes, the sound control unit 3 determines whether sound is being generated in response to a slapping operation or not (Step S18). If this determination also results in Yes, the sound control unit 3 determines that the operation is to cancel the sound through a contact to the striking surface 12, and then starts a sound-cancellation processing to cancel the current sound (Step S19). That is, when the sound output unit 4 generates sound and the contact detection unit 22 detects a contact, the sound control unit 3 controls to cancel the sound being generated by the sound output unit 4. In the loop processing from Step S20 to Step S23, the sound control unit 3 performs velocity detection processing for all of the blocks of the slapping detection units 21. This detection processing is performed by repeatedly executing a velocity detection processing (see FIG. 8) as an external function while incrementing the value of the variable “Block” until the value of the variable “Block” exceeds the block upper limit “NV_Block” of the slapping detection units 21 (in this embodiment, “15”). In this detection processing, when the value of the array variable “Velocity_DET[Block]” corresponding to each block of the slapping detection units 21 is the detected velocity value or when the loop processing ends, the variable “Block” is initialized (Step S24). Next, in the loop processing from Step S25 to Step S27, the sound control unit 3 determines whether a slapping operation occurs or not. This determination is based on whether the velocity at each block of the slapping detection units 21 exceeds a predetermined threshold “Velocity_DET_THR” or not. Herein when the sound control unit 3 determines that the velocities at all of the blocks of the slapping detection units 21 do not exceed the threshold “Velocity_DET_THR”, one processing of the main routine ends. On the contrary, if the sound control unit 3 determines that the velocity at any block exceeds the predetermined threshold “Velocity_DET_THR”, the sound control unit 3 initializes the variable “Block” (Step S28). Then the sound control unit determines whether the number of the array variables having the value of “1” is more than 1 or not (Step S29). When this determination results in No, the sound control unit 3 starts the processing to generate sound corresponding to a slapping operation that is performed without a contact operation, i.e., starts to generate sound in accordance with the strength and the place of the slapping specified by the array variable “Velocity_DET[Block]” (Step S30). When the determination at Step S29 results in Yes, the sound control unit 3 determines whether an error of the contact detection has occurred or not in the loop processing from Step S31 to Step S33. That is, when a slapping operation and a contact operation are detected at the same time at the same block, the slapping operation is likely determined as a contact operation erroneously. Then the sound control unit 3 determines that an error has occurred (YES at Step S32), and cancels the contact detected at the error processing (Step S34). That is, if the slapped place on the striking surface 12 detected by the slapping detection units 21 and the contacted place on the striking surface 12 detected by the contact detection units 22 are within the same range, the sound control unit 3 controls so as not to change the sound generated by the sound output unit 4 based on the contact to the striking surface 12 or the contacted place on the striking surface 12 detected by the contact detection units 22. In other words, the sound control unit 3 controls to generate sound only in accordance with the strength and the place of slapping detected by the slapping detection units 21. Then when the error determination results in NO, the sound control unit 3 starts to processing to generate sound when a slapping operation is performed while keeping a contact operation. That is, the sound control unit 3 starts to generate sound while considering the strength and the place of the slapping specified by the array variable “Velocity_DET[Block]” as well as the place of contact specified by the array variable “DET_BLOCK[Block]” (Step S35). That is, when the place of slapping on the striking surface 12 detected by the slapping detection units 21 and the place of a contact on the striking surface 12 detected by the contact detection units 22 are different, the sound control unit 3 controls to change the sound generated by the sound output unit 4 based on the contact to the striking surface 12 and the contacted place on the striking surface 12 detected by the contact detection units 22. (Contact Detection Processing) As shown in FIG. 7, when executing the contact detection processing, the sound control unit 3 firstly initializes variables to be used(=0) (Step S41). The variables to be initialized here include a variable “VAD_CAP” to store a capacitance value (AD value) of the contact detection units 22, a variable “i” to designate the contact detection units 22, a variable “N_CAP” to determine the number of the contact detection units 22 in the contact detected state, a variable “CAP_DET” to determine whether the contact detection unit 22 at a target block is in the contact detected state or not (non-contacted=0, contacted=1), and a variable “TIME” to store a timer value. Next, in the loop processing from Step S42 to Step S54, the sound control unit 3 determines whether the contact detection unit 22 as a target block is in the contact detected state or not. This loop processing is repeatedly executed while incrementing the value of the variable “i” until the value of the variable “i” exceeds the upper limit “i_ANT” of the contact detection units 22. In this loop processing from Step S42 to Step S54, a variable “TIME” is firstly initialized(=0) (Step S43), and then the timer processing as an external function starts (Step S44). Next, in the loop processing from Step S45 to Step S50, the sound control unit 3 determines whether the contact detection unit 22 designated by the variable “i” is in the contact detected state or not. The loop processing from Step S45 to Step S50 is repeated until the timer value of the variable “TIME” exceeds a constant “TIME_CAP_DET”. In the loop, the sound control unit 3 firstly acquires a capacitance value of the contact detection unit 22 designated by the variable “BLOCK” and the variable “i” (Step S46), and stores the acquired capacitance value in the variable “VAD_CAP” (Step S47). Next, the sound control unit 3 determines whether the value of the variable “VAD_CAP” exceeds a predetermined threshold “VAD_CAP_THR” or not (Step S48). When this determination results in YES, the sound control unit 3 updates the variable “TIME” (Step S49) and waits for the elapse of a contact determination time specified by a constant “TIME_CAP_DET”. That is, when the state of the value of the variable “VAD_CAP” exceeding the predetermined threshold “VAD_CAP_THR” continues for the contact determination time specified by the constant “TIME_CAP_DET” or longer, the sound control unit 3 determines that the contact detection unit 22 as the target is in the contact detected state. Then when the sound control unit 3 determines that the contact detection unit 22 as the target is in the contact detected state, the procedure leaves the loop from Step S45 to Step S50. Then, the variable “N_CAP” indicating the number of the contact detection units 22 in the contact detected state is incremented (Step S51). Thereafter, the sound control unit 3 increments the variable “i” (Step S52), and ends the timer processing. Then the procedure returns to Step S42 to shift to determine the contact detection at the next contact detection unit 22. On the contrary, when the determination at Step S48 results in NO, the procedure leaves the loop from Step S45 to Step S50 without waiting for the elapse of the determination time. Then, Step S51 is skipped, and the sound control unit 3 increments the variable “i” (Step S52), and ends the timer processing. Then the procedure returns to Step S42 to shift to determine the contact detection at the next contact detection unit 22. When the sound control unit 3 determines that the contact detection unit 22 as the target block is in the contact detected state, the procedure leaves the loop from Step S42 to Step S54. Then, the sound control unit 3 determines whether the variable “N_CAP” indicating the number of the contact detection units 22 in the contact detected state exceeds a predetermined threshold “N_CAP_THR” or not (Step S55). That is, when the number of the contact detection units 22 determined as in the contact detected state exceeds a predetermined threshold at the contact detection unit 22 as the target block, the sound control unit 3 determines that the contact detection unit 22 as the target is in the contact detected state. Then the determination at Step S55 results in YES, the sound control unit 3 stores “1” at the variable “CAP_DET” (Step S56), and returns the value “1” of the variable “CAP_DET” to the main routine (Step S57). On the contrary, when the determination at Step S55 results in NO, Step S56 is skipped. Then the sound control unit 3 returns the value “0” of the variable “CAP_DET” to the main routine (Step S57). (Velocity Detection Processing) As shown in FIG. 8, in the velocity detection processing, the sound control unit 3 firstly initializes variables to be used(=0) (Step S61). The variables to be initialized here include a variable “VAD_VELO” to store a detected value (AD value) of the slapping detection units 21 and a variable “VAD_VELO_MAX” to store a maximum value of the detected values at the slapping detection units 21. Next, the sound control unit 3 starts the timer processing as an external function (Step S62) and executes loop processing from Step S63 to Step S69. This loop processing is to acquire a maximum detected value of the slapping detection unit 21 as the target block during the slapping determination time specified by a constant “TIME_VDEC”. Firstly, the sound control unit 3 acquires a detected value of the slapping detection unit 21 at the block specified by a variable “BLOCK” (Step S64) and stores this in the variable “VAD_VELO” (Step S65). Then the sound control unit 3 determines whether the value of the variable “VAD_VELO” is larger than a variable “VAD_VELO_MAX” or not (Step S66). When this determination results in YES, the sound control unit 3 stores the value of the variable “VAD_VELO” into the variable “VAD_VELO_MAX” (Step S67), and updates the variable “TIME” (Step S68). Then the procedure returns to Step S63. On the contrary, when the determination at Step S66 results in NO, Step S67 is skipped, and the sound control unit 3 updates the variable “TIME” (Step S68). Then the procedure returns to Step S63. When the slapping determination time specified by the constant “TIME_VDEC” has passed, the procedure leaves the loop from Step S63 to Step S69. Then the sound control unit 3 initializes the variable “TIME” (Step S70) and ends the timer processing (Step S71). Then the sound control unit 3 returns the value of the variable “VAD_VELO_MAX” to the main routine (Step S72). (Timer Processing) As shown in FIG. 9, the timer processing includes a timer-start waiting loop processing from Step S81 to Step S83, and a timer activated loop processing from Step S84 to Step S87. In the timer-start waiting loop processing from Step S81 to Step S83, the variable “Time_CNT” to store the count value is repeatedly initialized(=0) (Step S82). When the flag “flag” shows “1”, the procedure leaves the loop and shifts to the timer activated loop processing from Step S84 to Step S87. In the timer activated loop processing from Step S84 to Step S87, the increment processing of the variable “Time_CNT” (Step S85) and the return processing to return the value of the variable “Time_CNT” to a higher-rank routine (Step S86) are repeated. When “0” is designated in the flag “flag” (Step S86), the procedure leaves the loop and the timer processing ends. As stated above, the electronic percussion instrument 1 according to one embodiment of the present invention includes: the striking surface 12; the slapping detection units 21 configured to detect the strength and the place of slapping on the striking surface 12; the contact detection units 22 configured to detect a contact by a player on the striking surface 12; and a sound control unit 3 configured to change at least one of the loudness and the pitch of sound generated by the sound output unit 4 based on the strength or the place of slapping on the striking surface 12 detected by the slapping detection units 21 and to change the sound generated by the sound output unit 4 based on a contact to the striking surface 12 detected by the contact detection units 22. With this configuration, the electronic percussion instrument 1 simply can change the tone of sound based on the strength and the place of slapping, and can realize play by a slapping operation together with a contact operation. For instance, the tone of sound can be changed by performing a slapping operation with one hand while touching the striking surface 12 with the other hand, or the sound can be cancelled by touching the striking surface 12 after a slapping operation. That is the descriptions on the present invention by way of the specific embodiment, and the technical scope of the present invention is not limited to the above embodiment. It will be appreciated for a person skilled in the art that the above-stated specific embodiments can be modified or improved in various ways. It should be understood that we intend to cover by the appended claims such modified or improved embodiments falling within the technical scope of the present invention. In the present embodiment, the striking surface 12 is only one face at the front face of the cubic shape. Instead, the striking surface may be a left or right lateral face, or may be two faces including both lateral faces or three faces. In the present embodiment, the electric circuit of the contact detection units 22 is disposed on the rear face of the circuit board 72. Instead, the contact detection units 22 may be disposed at a blank space between the slapping detection units 21 on the surface of the circuit board 72, or may be formed in the circuit board 72, i.e., as one layer of the laminated board. Aside from the circuit board 72 to make up the slapping detection units 21, an electric circuit exclusively used for the contact detection units 22 may be disposed. The electronic percussion instrument 1 in the present embodiment is implemented as an electronic cajon, which may be other percussion instruments, such as a bongo. The speaker 41 of the sound output unit 4 may be disposed separately from the electronic percussion instrument 1. In the embodiment as stated above, the control unit to perform various types of control is implemented through execution of a program stored in the ROM (memory) by the CPU (general-purpose processor). Instead, each of the plurality of types of control may be performed by the processor for exclusive use. In this case, such a processor for exclusive use may include a general-purpose processor (electronic circuit) that can execute any program and a memory to store a control program dedicated to the control, or may include an electronic circuit for exclusive use dedicated to the control. For example, when a CPU (general-purpose processor) executes a program stored in a ROM (memory), examples of the processing and the program executed by the CPU are as follows. CONFIGURATION EXAMPLE 1 The CPU is configured to control sound generated in accordance with the place of a contact operation to the striking surface and in response to detection of a slapping operation to the striking surface. CONFIGURATION EXAMPLE 2 In the above configuration example, the CPU is configured to control sound generated in response to detection of a slapping operation on a first position of the striking surface in accordance with the place of a contact operation to the striking surface. CONFIGURATION EXAMPLE 3 In the above configuration example, the CPU is configured to control sound generated in accordance with combination of the place of a slapping operation on the striking surface and the place of a contact operation to the striking surface. CONFIGURATION EXAMPLE 4 In the above configuration example, the CPU is configured to control generated sound whether the place of a slapping operation on the striking surface and the place of a contact operation to the striking surface are within the same range or not. CONFIGURATION EXAMPLE 5 In the above configuration example, the CPU is configured to, when the place of the slapping operation and the place of the contact operation are not within the same range, change sound generated in response to detection of the slapping operation, and when the place of the slapping operation and the place of the contact operation are within the same range, control so as not to change sound generated in response to the slapping operation. CONFIGURATION EXAMPLE 6 An electronic percussion instrument includes: a first sensor to detect a slapping operation on the striking surface; a second sensor to detect a contact operation to the striking surface; and a processor to control sound generated in response to detection of a slapping operation by the first sensor in accordance with the place of a contact operation to the striking surface detected by the second sensor. CONFIGURATION EXAMPLE 7 In the above configuration example, the first sensor detects the strength of a slapping operation on the striking surface and the place of the slapping operation on the striking surface, the second sensor detects the place of a contact operation to the striking surface, and the processor is configured to change at least one of the loudness and the pitch of sound generated by the sound output unit based on a difference in the strength or the place of the slapping operation detected by the first sensor and change the sound generated by the sound output unit based on the contact operation detected by the second sensor. CONFIGURATION EXAMPLE 8 In the above configuration example, the processor is configured to cancel the sound generated in response to detection of a slapping operation on the striking surface by the first sensor in response to detection of a contact operation detected by the second sensor. CONFIGURATION EXAMPLE 9 In the above configuration example, the processor is configured to, when a contact operation is detected by the second sensor during generation of sound, cancel the sound being generated. CONFIGURATION EXAMPLE 10 In the above configuration example, the processor is configured to, when an output value of a threshold or more is detected by the second sensor for a set time, determine that the contact operation is performed. CONFIGURATION EXAMPLE 11 In the above configuration example, the striking surface includes a plate member that can be elastically deformed, the first sensor detects the strength of a slapping operation on the striking surface and the place of the slapping operation on the striking surface based on a change in resistance that changes with a contacting state between conductive thin films opposed on a face of the plate member, and the second sensor detects the place of the contact operation to the striking surface based on a change in capacitance detected by a detection unit disposed at a face of the plate member so as to correspond to the first sensor. CONFIGURATION EXAMPLE 12 In the above configuration example, the striking surface includes one plate member, the first sensor includes a plurality of sensors disposed at a plurality of corresponding places at a face of the plate member, and the second sensor includes a plurality of sensors disposed at a plurality of corresponding places at a face of the plate member. CONFIGURATION EXAMPLE 13 In the above configuration example, the first sensor is disposed at a position closer to the plate member than the second sensor is. When a plurality of processors for exclusive use is used, the number of the processors and how to assign the plurality of types of control to these processors for exclusive use may be determined freely.
<SOH> BACKGROUND OF THE INVENTION <EOH>
<SOH> SUMMARY OF THE INVENTION <EOH>One aspect of the present invention relates to an electronic percussion instrument having a surface. The electronic percussion instrument includes: a first sensor configured to detect a striking operation on the surface; a second sensor configured to detect a contact operation to the surface; and a processor configured to control sound generated in response to detection of a striking operation by the first sensor in accordance with a place of a contact operation to the surface detected by the second sensor. Another aspect of the present invention relates to a method for controlling generated sound executed by a processor. The method includes: detecting a place of a contact operation to a surface, and controlling generated sound in response to detection of a striking operation on the surface in accordance with the detected place of the contact operation. Another aspect of the present invention relates to a non-transitory recording medium to record a program. The program makes a computer execute the processing of: detecting a place of a contact operation to a surface, and controlling generated sound in response to detection of a striking operation on the surface in accordance with the detected place of the contact operation.
G10H322
20170925
20180329
84267.0
G10H322
0
DONELS, JEFFREY
ELECTRONIC PERCUSSION INSTRUMENT AND METHOD FOR CONTROLLING SOUND GENERATION
UNDISCOUNTED
0
ACCEPTED
G10H
2,017
15,715,351
PENDING
6-Alkynyl-pyridine Derivatives
6-Alkynyl-pyridine of general formula (I) their use as SMAC mimetics, pharmaceutical compositions containing them, and their use as a medicaments for the treatment and/or prevention of diseases characterized by excessive or abnormal cell proliferation and associated conditions such as cancer. An exemplary compound is
1. A compound of formula I wherein R1 is selected from the group consisting of hydrogen, —C1-3alkyl and halogen; R2 is selected from the group consisting of hydrogen, —C1-3alkyl and halogen; R3 is selected from the group consisting of phenyl or a 9- to 14-membered heteroaryl wherein each of these groups is optionally substituted with R5 or R3 is a phenyl moiety fused with a 5-6 membered heterocycloalkyl, wherein each of these groups is optionally and independently substituted with one or more R6; R4 is a 5- or 6-membered heteroaryl substituted with —C1-3 alkyl or —O—C1-3alkyl; R5 is —C1-3alkyl; R6 is ═O or —C1-3alkyl; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein R1 is selected from the group consisting of hydrogen, —CH3 and Cl. 3. A compound according to claim 1, wherein R2 is selected from the group consisting of hydrogen, —CH3 and Cl. 4. A compound according to claim 1, wherein R1 is hydrogen and R2 is selected from the group consisting of hydrogen, —CH3 and Cl. 5. A compound according to claim 1, wherein R4 is a 6-membered heteroaryl substituted with —C1-3 alkyl or —O—C1-3 alkyl. 6. A compound according to claim 1, wherein R4 is selected from the group consisting of pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, each of which is independently substituted with —C1-3 alkyl or —O—C1-3 alkyl. 7. A compound according to claim 1, wherein R4 is selected from the group consisting of pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, each of which is independently substituted with —CH3 or —O—CH3. 8. A compound according to claim 1, wherein R3 is selected from the group consisting of phenyl, 9. A compound according to claim 1, selected from the group consisting of # Structure 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 and, 16 or a pharmaceutically acceptable salt thereof. 10. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. 11. A method for the treatment of cancer, which comprises administering to a host suffering from a cancer a therapeutically effective amount of a compound according to claim 1. 12. A method for the treatment of carcinomas of the breast, prostate, brain or ovary, non-small-cell lung carcinomas (NSCLC), melanomas, acute myeloid leukaemia (AML) or chronic lymphatic leukaemias (CLL), which comprises administering to a host suffering from one of said conditions a therapeutically effective amount of a compound according to claim 1.
This invention relates to compounds of the general formula (I) wherein the groups R1 to R4 have the meanings given in the claims and in the specification. The compounds of the invention are suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation, pharmaceutical preparations containing such compounds and their uses as a medicament. The compounds of the invention modulate IAP activity. BACKGROUND OF THE INVENTION Apoptosis, a form of programmed cell death, typically occurs in the normal development and maintenance of healthy tissues in multicellular organisms. It is a complex process, which results in the removal of damaged, diseased or developmentally redundant cells, without signs of inflammation or necrosis. Apoptosis thus occurs as a normal part of development, the maintenance of normal cellular homeostasis, or as a consequence of stimuli such as chemotherapy and radiation. The intrinsic apoptotic pathway is known to be deregulated in cancer and lymphoproliferative syndromes, as well as autoimmune disorders such as multiple sclerosis and rheumatoid arthritis. Additionally, alterations in a host apoptotic response have been described in the development or maintenance of viral and bacterial infections. Cancer cells gain the ability to overcome or circumvent apoptosis and continue with inappropriate proliferation despite strong pro-apoptotic signals such as hypoxia, endogenous cytokines, radiation treatments and chemotherapy. In autoimmune disease, pathogenic effector cells can become resistant to normal apoptotic cues. Resistance can be caused by numerous mechanisms, including alterations in the apoptotic machinery due to increased activity of anti-apoptotic pathways or expression of anti-apoptotic genes. Thus, approaches that reduce the threshold of apoptotic induction in cancer cells by overcoming resistance mechanisms may be of significant clinical utility. Caspases serve as key effector molecules in apoptosis signaling. Caspases (cysteine containing aspartate specific proteases) are strong proteases and once activated, digest vital cell proteins from within the cell. Since caspases are highly active proteases, tight control of this family of proteins is necessary to prevent premature cell death. In general, caspases are synthesized as largely inactive zymogens that require proteolytic processing for activation. This proteolytic processing is only one of the ways in which caspases are regulated. The second mechanism of regulation is through a family of proteins that bind and inhibit caspases. One family of molecules that inhibit caspases are the Inhibitors of Apoptosis (IAP) (Deveraux et al., J Clin Immunol (1999), 19: 388-398). IAPs were originally discovered in baculovirus by their ability to substitute for P35 protein function, an anti-apoptotic gene (Crook et al. (1993) J Virology 67, 2168-2174). Human IAPs are characterized by the presence of one to three homologous structural domains known as baculovirus IAP repeat (BIR) domains. Some IAP family members also contain a RING zinc finger domain at the C-terminus, with the capability to ubiquitylate target proteins via their E3 ligase function. The human IAPs, XIAP, HIAP1 (also referred to as cIAP2), and HIAP2 (cIAP1) each have three BIR domains, and a carboxy terminal RING zinc finger. Another IAP, NAIP, has three BIR domains (BIR1 , BIR2 and BIR3), but no RING domain, whereas Livin, TsIAP and MLIAP have a single BIR domain and a RING domain. The X chromosome-linked inhibitor of apoptosis (XIAP) is an example of an IAP, which can inhibit the initiator caspase Caspase-9, and the effector caspases, Caspase-3 and Caspase-7, by direct binding. XIAP can also induce the degradation of caspases through the ubiquitylation-mediated proteasome pathway via the E3 ligase activity of a RING zinc finger domain. Inhibition of Caspase-9 is mediated by the BIR3 domains of XIAP, whereas effector caspases are inhibited by binding to the linker-BIR2 domain The BIR domains also mediate the interactions of IAPs with tumor necrosis factor-receptor associated factor (TRAFs)-I and −2, and with TAB1, adaptor proteins affecting survival signaling through NFkB activation. IAP proteins can thus function as direct brakes on the apoptosis cascade by inhibiting active caspases or by redirecting cellular signaling to a pro-survival mode. Survivin is another member of the IAP family of antiapoptotic proteins. It is shown to be conserved in function across evolution as homologues of the protein are found both in vertebrates and invertebrates. Cancer cells and cells involved in autoimmune disease may avoid apoptosis by the sustained over-expression of one or more members of the IAP family of proteins. For example, IAP overexpression has been demonstrated to be prognostic of poor clinical outcome in multiple cancers, and decreased IAP expression through RNAi strategies sensitizes tumor cells to a wide variety of apoptotic insults including chemotherapy, radiotherapy and death receptor ligands. For XIAP, this is shown in cancers as diverse as leukemia and ovarian cancer. Over expression of cIAP1 and cIAP2 resulting from the frequent chromosome amplification of the 11q21-q23 region, which encompasses both genes, has been observed in a variety of malignancies, including medulloblastomas, renal cell carcinomas, glioblastomas, and gastric carcinomas. The interaction between the baculoviral IAP repeat-3 (BIR3) domain of X-linked inhibitor of apoptosis (XIAP) and caspase-9 is of therapeutic interest because this interaction is inhibited by the NH2-terminal seven-amino-acid residues of the so-called “second mitochondrial-derived activator of caspase” (in short and hereinafter SMAC), a naturally occurring antagonist of IAPs. Small-molecule SMAC mimetics have been generated anticipating efficacy in cancer by reconstituting apoptotic signaling. Thus, there is the need to provide SMAC mimetics useful for the prevention and/or treatment of diseases characterized by excessive or abnormal cell proliferation, such as cancer. The aim of the present invention is to provide new compounds which can be used for the prevention and/or treatment of diseases characterized by excessive or abnormal cell proliferation, in particular in the treatment of cancer. The compounds according to the invention are characterized by a powerful inhibitory effect of IAP-SMAC protein-protein-interaction. In addition to powerful inhibition of the IAP-SMAC protein-protein-interaction, for the development of pharmaceutical products it is important that the active agent shows low inhibition of P450 as recommended in the Guidelines of the FDA. It is desirable to have compounds which show low inhibition of P450 isoenzymes ideally with IC50 values greater than 5 μM. 6-alkynyl-pyridine derivatives as SMAC mimetics or IAP inhibitors are also described in WO 2013/127729. Table 1 summarizes some examples of the prior art document WO 2013/127729 which are characterized by a 6-membered heteroaryl substituent attached to the imidazol1,2-alpyridine in position 5 of the central pyridine ring together with their IC50 values representing the inhibition of the five P450 isoenzymes and their solubility values. For the compounds of Table 1, it has been found that for 3-5 of five P450 isoenzymes the IC50 is lower than 5 μM. As mentioned above the desirable range of the inhibition of the P450 isoenzyme is an IC50 greater 5 μM. More preferably, for all of the five isoenzymes the IC50 is greater than 5 μM. Accordingly, there is the need to provide compounds characterized by a 6-membered heteroaryl substituent on an imidazol1,2-alpyridine in position 5 of the central pyridine ring which show lower inhibition of the P450 isoenzymes, represented by IC50 values greater than 5 μM. The compounds of the invention differ from the compounds of Table 1 in that the 5-6 membered heteroaryl is further substituted with an alkyl group or a oxyalkyl group. Surprisingly, the compounds of the invention show lower P450 inhibition meaning that no or at maximum 2 of 5 P450 isoenzymes show inhibitory values with IC50<5 μM. Accordingly, the compounds of the invention show a powerful inhibitory effect of IAP-SMAC protein-protein-interaction and low inhibition of the P450 isoenzymes. Preferred compounds of the invention are those which combine powerful inhibition of IAP-SMAC protein-protein interaction, low inhibition of the P450 isoenzymes and solubility greater than 10 μg/ml at pH 6.8. TABLE 1 Measured examples from WO 2013/127729 inhibit many P450 isoenzymes already at concentrations below 5 μM and predominately show low solubility at pH 6.8. Solubility P450 P450 P450 P450 P450 pH 6.8 Ex # Structure 2C19 2C8 2C9 2D6 3A4 [μg/ml] 27 5.3 0.3 0.4 9.3 3.7 3 64 4.3 0.5 0.4 5.2 2.1 N/A 81 2.8 1.2 0.9 3.4 4.0 8 82 4.8 0.3 0.4 2.2 2.3 N/A 94 2.9 4.9 0.7 3.3 >50 N/A 185 16 1.7 4.8 2.7 3.0 60 DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds of formula (I) wherein R1 to R4 are as defined in the description and in the claims. The compounds according to formula (I) act as SMAC mimetics. Thus, the compounds of the invention may be used for example for the treatment of diseases which are characterized by an increased apoptosis threshold due to overexpression of IAP protein. Preferably, the compounds of the invention can be used in the treatment of cancer. The present invention therefore relates to compounds of general formula (I) Wherein R1 is selected from the group consisting of hydrogen, —C1-3alkyl and halogen; R2 is selected from the group consisting of hydrogen, —C1-3alkyl and halogen; R3 is selected from phenyl or a 9- to 14-membered heteroaryl wherein each of these groups is optionally substituted with R5 or R3 is a phenyl moiety fused with a 5-6 membered heterocycloalkyl, wherein each of these groups is optionally and independently substituted with one or more R6; R4 is a 5- or 6-membered heteroaryl substituted with —C1-3alkyl or —O—C1-3alkyl; R5 is —C1-3alkyl; R6 is ═O or —C1-3alkyl; and wherein the compounds of formula (I) may optionally be present in the form of salts. In a preferred embodiment the invention relates to compounds of formula (I), wherein R1 is selected from hydrogen, —CH3, —Cl. In a preferred embodiment the invention relates to compounds of formula (I), wherein R2 is selected from —H, —CH3, —Cl. In a preferred embodiment the invention relates to compounds of formula (I), wherein R1 is hydrogen and R2 is selected from hydrogen, —CH3 and Cl. In a preferred embodiment the invention relates to compounds of formula (I), wherein R4 is a 6-membered heteroaryl substituted with —C1-3alkyl or —O—C1-3alkyl. In a preferred embodiment the invention relates to compounds of formula (I), wherein R4 is a 6-membered heteroaryl substituted with —CH3 or —O—CH3. In a preferred embodiment the invention relates to compounds of formula (I), wherein R4 is selected from pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, each of which is independently substituted with —C1-3alkyl or —O—C1-3alkyl. In a preferred embodiment the invention relates to compounds of formula (I), wherein R4 is selected from pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, each of which is independently substituted with —CH3 or —O—CH3. In a preferred embodiment the invention relates to compounds of formula (I), wherein R4 is pyridyl substituted with —CH3. In a preferred embodiment the invention relates to compounds of formula (I), wherein R4 is pyridyl substituted with —O—CH3. In a preferred embodiment the invention relates to compounds of formula (I), wherein R4 is pyrimidinyl substituted with —CH3. In a preferred embodiment the invention relates to compounds of formula (I), wherein R4 is pyrazolyl substituted with —CH3. In a preferred embodiment the invention relates to compounds of formula (I), wherein R4 is imidazolyl substituted with —CH3. In a preferred embodiment the invention relates to compounds of formula (I), wherein R3 is selected phenyl, In a preferred embodiment the invention relates to compounds of formula (I), wherein R3is In a preferred embodiment the invention relates to compounds of formula (I), wherein R3 is In another aspect the invention relates to compounds of general formula (I) or of anyone of the embodiments as disclosed above for use in the treatment of cancer. In another aspect the invention relates to compounds of general formula (I) or of anyone of the embodiments as disclosed above—or the pharmaceutically acceptable salts thereof—for use as medicaments. In another aspect the invention relates to compounds of general formula (I) or of anyone of the embodiments as disclosed above—or the pharmaceutically acceptable salts thereof—for use in the treatment and/or prevention of cancer, infections, inflammations and autoimmune diseases. In another aspect the invention relates to compounds of general formula (I) or of anyone of the embodiments as disclosed above—or the pharmaceutically acceptable salts thereof—for use in the treatment and/or prevention of cancer, preferably of carcinomas of the breast, in particular triple negative breast cancer (TNBC), prostate, brain or ovary, non-small-cell lung carcinomas (NSCLC), melanomas, acute myeloid leukaemia (AML) and chronic lymphatic leukaemias (CLL). In another aspect the invention relates to compounds of general formula (I) or of anyone of the embodiments as disclosed above—or the pharmaceutically acceptable salts thereof—for use in the treatment and/or prevention of carcinomas of the breast, in particular triple negative breast cancer (TNBC), prostate, brain or ovary, non-small-cell lung carcinomas (NSCLC), melanomas, acute myeloid leukaemia (AML) and chronic lymphatic leukaemias (CLL). In another aspect the invention relates to a method for the treatment and/or prevention of cancer comprising administering a therapeutically effective amount of a compound of general formula (I) or of anyone of the embodiments as disclosed above—or one of the pharmaceutically acceptable salts thereof—to a human being. In another aspect the invention relates to a method for the treatment and/or prevention of carcinoma of the breast, in particular triple negative breast cancer (TNBC), prostate, brain or ovary, non-small-cell lung carcinomas (NSCLC), melanomas acute myeloid leukaemia (AML) and chronic lymphatic leukemias (CLL) comprising administering a therapeutically effective amount of a compound of general formula (I) or of anyone of the embodiments as disclosed above—or one of the pharmaceutically acceptable salts thereof—to a human being. In another aspect the invention relates to a pharmaceutical preparation containing as active substance one or more compounds of general formula (I) or of anyone of the embodiments as disclosed above—or the pharmaceutically acceptable salts thereof—optionally in combination with conventional excipients and/or carriers. In another aspect the invention relates to a pharmaceutical preparation comprising a compound of general formula (I) or of anyone of the embodiments as disclosed above—or one of the pharmaceutically acceptable salts thereof—and at least one other cytostatic or cytotoxic active substance, different from formula (I). Definitions Terms that are not specifically defined here have the meanings that are apparent to the skilled man in the light of the overall disclosure and the context as a whole. As used herein, the following definitions apply, unless stated otherwise: In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, —C1-5alkyl means an alkyl group or radical having 1 to 5 carbon atoms. In general, for groups comprising two or more subgroups, the first named sub-group is the radical attachment point, for example the substitutent —C1-5alkyl-C3-10cylcoalkyl, means a C3-10cylcoalkyl group which is bound to a C1-5alkyl, the latter of which is bound to the core structure or to the group to which the substitutent is attached. The indication of the number of members in groups that contain one or more heteroatom(s) (heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocycylalkyl) relates to the total atomic number of all the ring members or chain members or the total of all the ring and chain members. The person skilled in the art will appreciate that substituent groups containing a nitrogen atom can also be indicated as amine or amino. Similarly, groups containing oxygen atom can also be indicated with -oxy, like for example alkoxy. Groups containing —C(O)— can also be indicated as carboxy; groups containing —NC(O)— can also be indicated as amide; groups containing —NC(O)N— can also be indicated as urea; groups containing —NS(O)2— can also be indicated as sulfonamide. Alkyl denotes monovalent, saturated hydrocarbon chains, which may be present in both linear and branched form. If an alkyl is substituted, the substitution may take place independently of one another, by mono- or polysubstitution in each case, on all the hydrogen-carrying carbon atoms. The term “C1-5-alkyl” includes for example methyl (Me; —CH3), ethyl (Et; —CH2CH3), 1-propyl (n-propyl; n-Pr; —CH2CH2CH3), 2-propyl (i-Pr; iso-propyl; —CH(CH3)2), 1-butyl (n-butyl; n-Bu; —CH2CH2CH2CH3), 2-methyl-1-propyl (iso-butyl; i-Bu; —CH2CH(CH3)2), 2-butyl (sec-butyl; sec-Bu; —CH(CH3)CH2CH3), 2-methyl-2-propyl (tent-butyl; t-Bu; —C(CH3)3), 1-pentyl (n-pentyl; —CH2CH2CH2CH2CH3), 2-pentyl (—CH(CH3)CH2CH2CH3), 3-pentyl (—CH(CH2CH3)2), 3-methyl-1-butyl (iso-pentyl; —CH2CH2CH(CH3)2), 2-methyl-2-butyl (—C(CH3)2CH2CH3), 3-methyl-2-butyl (—CH(CH3)CH(CH3)2), 2,2-dimethyl-1-propyl (neo-pentyl; —CH2C(CH3)3), 2-methyl-1-butyl (—CH2CH(CH3)CH2CH3). By the terms propyl, butyl, pentyl, etc. without any further definition are meant saturated hydrocarbon groups with the corresponding number of carbon atoms, wherein all isomeric forms are included. The above definition for alkyl also applies if alkyl is a part of another group such as for example Cx-y-alkylamino or Cx-y-alkyloxy or Cx-y-alkoxy, wherein Cx-y-alkyloxy and Cx-y-alkoxy indicate the same group. The term alkylene can also be derived from alkyl. Alkylene is bivalent, unlike alkyl, and requires two binding partners. Formally, the second valency is produced by removing a hydrogen atom in an alkyl. Corresponding groups are for example —CH3 and —CH2, —CH2CH3 and —CH2CH2 or >CHCH3 etc. The term “C1-4-alkylene” includes for example —(CH2)—, —(CH2—CH2)—, —(CH(CH3))—, —(CH2—CH2—CH2)—, —(C(CH3)2)—, —(CH(CH2CH3))—, —(CH(CH3)—CH2)—, —(CH2—CH(CH3))—, —(CH2—CH2—CH2—CH2)—, —(CH2—CH2—CH(CH3))—, —(CH(CH3)—CH2—CH2)—, —(CH2—CH(CH3)—CH2)—, —(CH2—C(CH3)2)—, —(C (CH3)2—CH2)—(CH(CH3)—CH(CH3))—, —(CH2—CH(CH2CH3))—, —(CH(CH2CH3)—CH2)—, —(CH(CH2CH2CH3))—, —(CHCH(CH3)2)— and —C(CH3)(CH2CH3)—. Other examples of alkylene are methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, etc. By the generic terms propylene, butylene, pentylene, hexylene etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propylene includes 1-methylethylene and butylene includes 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene. The above definition for alkylene also applies if alkylene is part of another group such as for example in HO—Cx-y-alkylenamino or H2N—Cx-y-alkylenoxy. Unlike alkyl, alkenvl consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C—C double bond. If in an alkyl as hereinbefore defined having at least two carbon atoms, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenyl is formed. Examples of alkenyl are vinyl (ethenyl), prop-1-enyl, allyl (prop-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl, 2-methyl-prop-2-enyl, 2-methyl-prop-1-enyl, 1-methyl-prop-2-enyl, 1-methyl-prop-1-enyl, 1-methylidenepropyl, pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, 3-methyl-but-3-enyl, 3-methyl-but-2-enyl, 3-methyl-but-1-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl, 2,3-dimethyl-but-3-enyl, 2,3-dimethyl-but-2-enyl, 2-methylidene-3-methylbutyl, 2,3 -dimethyl-but-1-enyl, hexa-1,3 -dienyl, hexa-1,4-dienyl, penta-1,4-dienyl, penta-1,3-dienyl, buta-1,3-dienyl, 2,3-dimethylbuta-1,3-diene etc. By the generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexa-dienyl, heptadienyl, octadienyl, nonadienyl, decadienyl etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propenyl includes prop-1-enyl and prop-2-enyl, butenyl includes but-1-enyl, but-2-enyl, but-3-enyl, 1-methyl-prop-1-enyl, 1-methyl-prop-2-enyl etc. Alkenyl may optionally be present in the cis or trans or E or Z orientation with regard to the double bond(s). The above definition for alkenyl also applies when alkenyl is part of another group such as for example in Cx-y-alkenylamino or Cx-y-alkenyloxy. Unlike alkylene, alkenvlene consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C—C double bond. If in an alkylene as hereinbefore defined having at least two carbon atoms, two hydrogen atoms at adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenylene is formed. Examples of alkenylene are ethenylene, propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1,3-dimethylpropenylene, hexenylene etc. By the generic terms propenylene, butenylene, pentenylene, hexenylene etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propenylene includes 1-methylethenylene and butenylene includes 1-methylpropenylene, 2-methylpropenylene, 1,1-dimethylethenylene and 1,2-dimethylethenylene. Alkenylene may optionally be present in the cis or trans or E or Z orientation with regard to the double bond(s). The above definition for alkenylene also applies when alkenylene is a part of another group as in for example HO-Cx-y-alkenylenamino or H2N-Cx-y-alkenylenoxy. Unlike alkyl, alkynyl consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C—C triple bond. If in an alkyl as hereinbefore defined having at least two carbon atoms, two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valencies are saturated to form two further bonds, the corresponding alkynyl is formed. Examples of alkynyl are ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl, pent-l-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 3-methyl-but-1-ynyl. By the generic terms propynyl, butynyl, pentynyl, etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propynyl includes prop-1-ynyl and prop-2-ynyl, butynyl includes but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-1-ynyl, 1-methyl-prop-2-ynyl. If a hydrocarbon chain carries both at least one double bond and also at least one triple bond, by definition it belongs to the alkynyl subgroup. The above definition for alkynyl also applies if alkynyl is part of another group, as in Cx-y-alkynylamino or Cx-y-alkynyloxy, for example. Unlike alkylene, alkynylene consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C—C triple bond. If in an alkylene as hereinbefore defined having at least two carbon atoms, two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valencies are saturated to form two further bonds, the corresponding alkynylene is formed. Examples of alkynylene are ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene, 1,2-dimethylpropynylene, 1,3-dimethylpropynylene, hexynylene etc. By the generic terms propynylene, butynylene, pentynylene, ect. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propynylene includes 1-methylethynylene and butynylene includes 1-methylpropynylene, 2-methylpropynylene, 1,1-dimethylethynylene and 1,2-dimethyl-ethynylene. The above definition for alkynylene also applies if alkynylene is part of another group, as in HO—Cx-y-alkynyleneamino or H2N—Cx-y-alkynyleneoxy, for example. By heteroatoms are meant oxygen, nitrogen and sulphur atoms. Haloalkyl (haloalkenyl, haloalkynyl) is derived from the previously defined alkyl (alkenyl, alkynyl) by replacing one or more hydrogen atoms of the hydrocarbon chain independently of one another by halogen atoms, which may be identical or different. If a haloalkyl (haloalkenyl, haloalkynyl) is to be further substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Examples of haloalkyl (haloalkenyl, haloalkynyl) are —CF3, —CHF2, —CH2F, —CF2CF3, —CHFCF3, —CH2CF3, —CF2CH3, —CHFCH3, —CF2CF2CF3, —CF2CH2CH3, —CF═CF2, —CCl═CH2, —CBr═CH2, —Cl═CH2, —CHFCH2CH3, —CHFCH2CF3 etc. From the previously defined haloalkyl (haloalkenyl, haloalkynyl) are also derived the terms haloalkylene (haloalkenylene, haloalkynylene). Haloalkylene (haloalkenyl, haloalkynyl), unlike haloalkyl, is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from a haloalkyl. Corresponding groups are for example —CH2F and —CHF—, —CHFCH2F and —CHFCHF— or >CFCH2F etc. The above definitions also apply if the corresponding halogen groups are part of another group. Halogen relates to fluorine, chlorine, bromine and/or iodine atoms. Cycloalkyl is made up of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. The systems are saturated. In bicyclic hydrocarbon rings two rings are joined together so that they have at least two carbon atoms together. In spiro-hydrocarbon rings a carbon atom (spiroatom) belongs to two rings together. If a cycloalkyl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Cycloalkyl itself may be linked as a substituent to the molecule via every suitable position of the ring system. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.2.1]loctyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl (octahydroindenyl), bicyclo[4.4.0]decyl (decahydronaphthalene), bicyclo[2.2.1]heptyl (norbornyl), bicyclo[4.1.0]heptyl (norcaranyl), bicyclo[3.1.1]heptyl (pinanyl), spiro[2.5]loctyl, spiro[3.3]heptyl etc. The above definition for cycloalkyl also applies if cycloalkyl is part of another group as in Cx-y-cycloalkylamino or Cx-y-cycloalkyloxy, for example. If the free valency of a cycloalkyl is saturated, then an alicyclic group is obtained. The term cycloalkylene can thus be derived from the previously defined cycloalkyl. Cycloalkylene, unlike cycloalkyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a cycloalkyl. Corresponding groups are for example cyclohexyl and (cyclohexylene). The above definition for cycloalkylene also applies if cycloalkylene is part of another group as in HO—Cx-y-cycloalkyleneamino or H2N—Cx-y-cycloalkyleneoxy, for example. Cycloalkenyl is also made up of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. However, the systems are unsaturated, i.e. there is at least one C—C double bond but no aromatic system. If in a cycloalkyl as hereinbefore defined two hydrogen atoms at adjacent cyclic carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding cycloalkenyl is obtained. If a cycloalkenyl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Cycloalkenyl itself may be linked as a substituent to the molecule via every suitable position of the ring system. Examples of cycloalkenyl are cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohex-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl, cyclohept-l-enyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclohept-4-enyl, cyclobuta-1,3-dienyl, cyclopenta-1,4-dienyl, cyclopenta-1,3-dienyl, cyclopenta-2,4-dienyl, cyclohexa-1,3-dienyl, cyclohexa-1,5-dienyl, cyclohexa-2,4-dienyl, cyclohexa-1,4-dienyl, cyclohexa-2,5-dienyl, bicyclo[2.2.1]hepta-2,5-dienyl (norborna-2,5-dienyl), bicyclo[2.2.1]hept-2-enyl (norbornenyl), spiro[4.5]dec-2-ene etc. The above definition for cycloalkenyl also applies when cycloalkenyl is part of another group as in Cx-y-cycloalkenylamino or Cx-y-cycloalkenyloxy, for example. If the free valency of a cycloalkenyl is saturated, then an unsaturated alicyclic group is obtained. The term cycloalkenylene can thus be derived from the previously defined cycloalkenyl. Cycloalkenylene, unlike cycloalkenyl, is bivalent and requires two binding partners. Formally the second valency is obtained by removing a hydrogen atom from a cycloalkenyl. Corresponding groups are for example cyclopentenyl and (cyclopentenylene) etc. The above definition for cycloalkenylene also applies when cycloalkenylene is part of another group as in HO—Cx-y-cycloalkenyleneamino or H2N—Cx-y-cycloalkenyleneoxy, for example. Aryl denotes a mono-, bi- or tricyclic group with at least one aromatic carbocycle. Preferably it denotes a a monocyclic group with six carbon atoms (phenyl) or a bicyclic group with nine or ten carbon atoms (two six-membered rings or one six-membered ring with a five-membered ring), wherein the second ring may also be aromatic or, however, may also be saturated or partially saturated. If an aryl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Aryl itself may be linked as a substituent to the molecule via every suitable position of the ring system. Examples of aryl are phenyl, naphthyl, indanyl (2,3-dihydroindenyl), indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl (1,2,3,4-tetrahydronaphthyl, tetralinyl), dihydronaphthyl (1,2- dihydronaphthyl), fluorenyl etc. The above definition of aryl also applies when aryl is part of another group as in arylamino or aryloxy, for example. If the free valency of an aryl is saturated, then an aromatic group is obtained. The term arylene can also be derived from the previously defined aryl. Arylene, unlike aryl, is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from an aryl. Corresponding groups are e.g. phenyl and (o, m, p-phenylene), naphthyl and etc. The above definition for arylene also applies when arylene is part of another group as in HO-aryleneamino or H2N-aryleneoxy for example. Heterocyclyl denotes ring systems, which are derived from the previously defined cycloalkyl, cycloalkenyl and aryl by replacing one or more of the groups —CH2-independently of one another in the hydrocarbon rings by the groups —O—, —S— or —NH— or by replacing one or more of the groups ═CH— by the group ═N—, wherein a total of not more than five heteroatoms may be present, at least one carbon atom may be present between two oxygen atoms and between two sulphur atoms or between one oxygen and one sulphur atom and the ring as a whole must have chemical stability. Heteroatoms may optionally be present in all the possible oxidation stages (sulphur→sulphoxide —SO, sulphone —SO2-; nitroge→N-oxide). A direct result of the derivation from cycloalkyl, cycloalkenyl and aryl is that heterocyclyl is made up of the subgroups monocyclic heterorings, bicyclic heterorings, tricyclic heterorings and spiro-heterorings, which may be present in saturated or unsaturated form. Saturated and unsaturated, non-aromatic, heterocyclyl are also defined as heterocycloalkyl. By unsaturated is meant that there is at least one double bond in the ring system in question, but no heteroaromatic system is formed. In bicyclic heterorings two rings are linked together so that they have at least two (hetero)atoms in common. In spiro-heterorings a carbon atom (spiroatom) belongs to two rings together. If a heterocyclyl is substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon and/or nitrogen atoms. Heterocyclyl itself may be linked as a substituent to the molecule via every suitable position of the ring system. When the heterocyclyl has a nitrogen atom, the preferred position to bind the heterocyclyl substituent to the molecule is the nitrogen atom. Examples of heterocyclyl are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, oxiranyl, aziridinyl, azetidinyl, 1,4-dioxanyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, 1,3-dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, [1.4]-oxazepanyl, tetrahydrothienyl, homothiomorpholinyl-S, S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydro-pyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-S-oxide, tetrahydrothienyl-S,S-dioxide, homothiomorpholinyl-S-oxide, 2,3-dihydroazet, 2H-pyrrolyl, 4H-pyranyl, 1,4-dihydropyridinyl, 8-azabicyclo[3.2.1]octyl, 8-azabicyclo[5.1.0l]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 3,8-diaza-bicyclo[3.2.1]octyl, 2,5-diaza-bicyclo[2.2.1]heptyl, 1-aza-bicyclo[2.2.2]octyl, 3,8-diaza-bicyclo[3.2.1]octyl, 3,9-diaza-bicyclo[4.2.1]nonyl, 2,6-diaza-bicyclo[3.2.2]-nonyl, 1,4-dioxa-spiro[4.5]decyl, 1-oxa-3.8-diaza-spiro[4.5]decyl, 2,6-diaza-spiro[3.3]-heptyl, 2,7-diaza-spiro[4.4]nonyl, 2,6-diaza-spiro[3.4]octyl, 3,9-diaza-spiro[5.5]undecyl, 2.8-diaza-spiro[4.5]decyl etc. Further examples are the structures illustrated below, which may be attached via each hydrogen-carrying atom (exchanged for hydrogen): The above definition of heterocyclyl also applies if heterocyclyl is part of another group as in heterocyclylamino or heterocyclyloxy for example. If the free valency of a heteroyclyl is saturated, then a heterocyclic group is obtained. The term heterocyclylene is also derived from the previously defined heterocyclyl. Heterocyclylene, unlike heterocyclyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a heterocyclyl. Corresponding groups are for example piperidinyl and 2,3-dihydro-1H-pyrrolyl and The above definition of heterocyclylene also applies if heterocyclylene is part of another group as in HO-heterocyclyleneamino or H2N-heterocyclyleneoxy for example Heteroaryl denotes monocyclic heteroaromatic rings or polycyclic rings with at least one heteroaromatic ring, which compared with the corresponding aryl or cycloalkyl (cycloalkenyl) contain, instead of one or more carbon atoms, one or more identical or different heteroatoms, selected independently of one another from among nitrogen, sulphur and oxygen, wherein the resulting group must be chemically stable. The prerequisite for the presence of heteroaryl is a heteroatom and a heteroaromatic system. If a heteroaryl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon and/or nitrogen atoms. Heteroaryl itself may be linked as a substituent to the molecule via every suitable position of the ring system, both carbon and nitrogen. Examples of heteroaryl are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyridyl-N-oxide, pyrrolyl-N-oxide, pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide, thiazolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide, triazolyl-N-oxide, tetrazolyl-N-oxide, indolyl, isoindolyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl, indolizinyl, oxazolopyridyl, imidazopyridyl, naphthyridinyl, benzoxazolyl, pyridopyridyl, purinyl, pteridinyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl, quinolinyl-N-oxide, indolyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide, phthalazinyl-N-oxide, indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide etc. Further examples are the structures illustrated below, which may be attached via each hydrogen-carrying atom (exchanged for hydrogen): The above definition of heteroaryl also applies when heteroaryl is part of another group as in heteroarylamino or heteroaryloxy, for example. If the free valency of a heteroaryl is saturated, a heteroaromatic group is obtained. The term heteroarylene can therefore be derived from the previously defined heteroaryl. Heteroarylene, unlike heteroaryl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a heteroaryl. Corresponding groups are for example pyrrolyl and The above definition of heteroarylene also applies when heteroarylene is part of another group as in HO-heteroaryleneamino or H2N-heteroaryleneoxy, for example. The bivalent groups mentioned above (alkylene, alkenylene, alkynylene etc.) may also be part of composite groups (e.g. H2N—C1-4alkylene- or HO—C1-4alkylene-). In this case one of the valencies is saturated by the attached group (here: —NH2, —OH), so that a composite group of this kind written in this way is only a monovalent substituent over all. By substituted is meant that a hydrogen atom which is bound directly to the atom under consideration, is replaced by another atom or another group of atoms (substituent). Depending on the starting conditions (number of hydrogen atoms) mono- or polysubstitution may take place on one atom. Substitution with a particular substituent is only possible if the permitted valencies of the substituent and of the atom that is to be substituted correspond to one another and the substitution leads to a stable compound (i.e. to a compound which is not converted spontaneously, e.g. by rearrangement, cyclisation or elimination). Bivalent substituents such as ═S, ═NR, ═NOR, ═NNRR, ═NN(R)C(O)NRR, ═N2 or the like, may only be substituted at carbon atoms, wherein the bivalent substituent ═O may also be a substituent at sulphur. Generally, substitution may be carried out by a bivalent substituent only at ring systems and requires replacement by two geminal hydrogen atoms, i.e. hydrogen atoms that are bound to the same carbon atom that is saturated prior to the substitution. Substitution by a bivalent substituent is therefore only possible at the group —CH2- or sulphur atoms of a ring system. Stereochemistry/Solvates/Hydrates: Unless stated otherwise a structural formula given in the description or in the claims or a chemical name refers to the corresponding compound itself, but also encompasses the tautomers, stereoisomers, optical and geometric isomers (e.g. enantiomers, diastereomers, E/Z isomers, etc.), racemates, mixtures of separate enantiomers in any desired combinations, mixtures of diastereomers, mixtures of the forms mentioned hereinbefore (if such forms exist) as well as salts, particularly pharmaceutically acceptable salts thereof. The compounds and salts according to the invention may be present in solvated form (e.g. with pharmaceutically acceptable solvents such as e.g. water, ethanol etc.) or in unsolvated form. Generally, for the purposes of the present invention the solvated forms, e.g. hydrates, are to be regarded as of equal value to the unsolvated forms. Salts: The term “pharmaceutically acceptable” is used herein to denote compounds, materials, compositions and/or formulations which are suitable, according to generally recognised medical opinion, for use in conjunction with human and/or animal tissue and do not have or give rise to any excessive toxicity, irritation or immune response or lead to other problems or complications, i.e. correspond overall to an acceptable risk/benefit ratio. The term “pharmaceutically acceptable salts” relates to derivatives of the chemical compounds disclosed in which the parent compound is modified by the addition of acid or base. Examples of pharmaceutically acceptable salts include (without being restricted thereto) salts of mineral or organic acids in relation to basic functional groups such as for example amines, alkali metal or organic salts of acid functional groups such as for example carboxylic acids, etc. These salts include in particular acetate, ascorbate, benzenesulphonate, benzoate, besylate, bicarbonate, bitartrate, bromide/hydrobromide, Ca-edetate/edetate, camsylate, carbonate, chloride/hydrochloride, citrate, edisylate, ethane disulphonate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollylarsnilate, hexylresorcinate, hydrabamine, hydroxymaleate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, malate, maleate, mandelate, methanesulphonate, mesylate, methylbromide, methylnitrate, methylsulphate, mucate, napsylate, nitrate, oxalate, pamoate, pantothenate, phenyl acetate, phosphate/diphosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulphamide, sulphate, tannate, tartrate, teoclate, toluenesulphonate, triethiodide, ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumin and procaine. Other pharmaceutically acceptable salts may be formed with cations of metals such as aluminium, calcium, lithium, magnesium, potassium, sodium, zinc, etc. (cf. also Pharmaceutical salts, Birge, S. M. et al., J. Pharm. Sci., (1977), 66, 1-19). The pharmaceutically acceptable salts of the present invention may be prepared starting from the parent compound, which carries a basic or acidic functionality, by conventional chemical methods. Generally, such salts may be synthesised by reacting the free acid or base form of these compounds with a sufficient amount of the corresponding base or acid in water or an organic solvent such as for example ether, ethyl acetate, ethanol, isopropanol, acetonitrile (or mixtures thereof). Salts of acids other than those mentioned above, which are useful for example for purifying or isolating the compounds from the reaction mixtures (e.g. trifluoroacetates), are also to be regarded as part of the invention. In a representation such as for example the letter A has the function of a ring designation in order to make it easier, for example, to indicate the attachment of the ring in question to other rings. For bivalent groups in which it is crucial to determine which adjacent groups they bind and with which valency, the corresponding binding partners are indicated in brackets, where necessary for clarification purposes, as in the following representations: or (R2)—C(O)NH— or (R2)—NHC(O)—; Groups or substituents are frequently selected from among a number of alternative groups/substituents with a corresponding group designation (e.g. Ra, Rb etc). If such a group is used repeatedly to define a compound according to the invention in different molecular parts, it must always be borne in mind that the various uses are to be regarded as totally independent of one another. By a therapeutically effective amount for the purposes of this invention is meant a quantity of substance that is capable of obviating symptoms of illness or of preventing or alleviating these symptoms, or which prolong the survival of a treated patient. List of abbreviations ACN acetonitrile Bu butyl conc. concentrated d day(s) DCM dichloromethane Et ethyl EtOAc Ethyl acetate h hour(s) HPLC high performance liquid chromatography iPr isopropyl M molar Me methyl min minute(s) mL millilitre MS mass spectrometry N normal NMP N-methylpyrrolindinone NMR nuclear resonance spectroscopy NP normal phase ppm part per million prep preparative Rf retention factor RP reversed phase RT room temperature tert tertiary TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography tR retention time Other features and advantages of the present invention will become apparent from the following more detailed examples which exemplarily illustrate the principles of the invention without restricting its scope. General Unless stated otherwise, all the reactions are carried out in commercially obtainable apparatuses using methods that are commonly used in chemical laboratories. Starting materials that are sensitive to air and/or moisture are stored under protective gas and corresponding reactions and manipulations therewith are carried out under protective gas (nitrogen or argon). The compounds according to the invention are named in accordance with IUPAC guidelines. If a compound is to be represented both by a structural formula and by its nomenclature, in the event of a conflict the structural formula is decisive. Chromatography Thin layer chromatography is carried out on ready-made TLC plates of silica gel 60 on glass (with fluorescence indicator F-254) made by Merck. A Biotage Isolera Four apparatus is used for automated preparative NP chromatography together with Interchim Puri Flash columns (50 μm, 12-300 g) or glass columns filled with silica gel made by Millipore (Granula Silica Si-60A 35-70 μm). Preparative RP HPLC is carried out with columns made by Waters (Sunfire C18, 10 μm, 30×100 mm Part. No. 186003971 or X-Bridge C18, 10 μm, 30×100 mm Part. No. 186003930). The compounds are eluted using either different gradients of H2O/acetonitrile or H2O/MeOH, where 0.2% HCOOH is added to the water, or with different gradients utilizing a basic aqueous buffer solution (1L water contains 5 mL of an ammonium hydrogencarbonate solution (158 g per 1 L H2O) and 2 mL ammonia (7 mol/1 solution in MeOH)) instead of the water-HCOOH-mixture. The analytical HPLC (reaction monitoring) of intermediate compounds is carried out with columns made by Agilent and Waters. The analytical equipment is also provided with a mass detector in each case. HPLC Mass Spectroscopy/UV Spectrometry The retention times/MS-ESI+ for characterising the example compounds according to the invention are determined using an HPLC-MS apparatus (high performance liquid chromatography with mass detector) made by Agilent. Compounds that elute at the injection peak are given the retention time tR=0. Analytical HPLC Methods (A.M.) Method_1 (M_1) HPLC: Agilent 1100 Series MS: Agilent LC/MSD SL Column: Waters, Xbridge C18, 2.5 μm, 2.1×20 mm, Part.No. 186003201 Solvent: A: 20 mM NH4HCO3/NH3 B: ACN HPLC grade Detection: MS: Positive and negative Mass range: 120-800 m/z Injection: 5 μL Flow: 1.00 mL/min Column temp.: 60° C. Gradient: 0.00-1.50 min 10%→95% B 1.50-2.00 min 95% B 2.00-2.10 min 95%→10% B Method_2 (M_2) HPLC: Agilent 1100/1200 Series MS: Agilent LC/MSD SL Column: Waters X-Bridge BEH C18, 2.5 μm, 2.1×30 mm Eluant: A: 5 mM NH4HCO3/19 mM NH3 in H2O; B: ACN (HPLC grade) Detection: MS: Positive and negative mode ESI Mass range: 100-800 m/z Flow: 1.4 ml/min Column temp.: 45° C. Gradient: 0.00-0.01 min→5% B 0.01-1.00 min: 5%→100% B 1.00-1.37 min: 100% B 1.37-1.40 min: 100%→5% B Method_3 (M_3) HPLC: Agilent 1100 Series MS: Agilent LC/MSD SL Column: WatersXBridge C18, 5.0 μm, 2.1×50 mm Eluant: A: 5 mM NH4HCO3/19 mM NH3 in H2O; B: ACN (HPLC grade) Detection: MS: Positive and negative mode ESI Mass range: 105-1200 m/z Flow: 1.20 ml/min Column temp.: 35° C. Gradient: 0.00-0.01 min: 5% B 0.01-1.25 min: 5%→95% B 1.25-2.00 min: 95% B 2.00-2.01 min: 95%→5% B Method_4 (M_4) HPLC: Agilent 1100/1200 Series MS: Agilent LC/MSD SL Column: Waters Sunfire, C18, 5.0 μm, 2.1×50 mm, Part. No. 186002539 Eluant: A: H2O+0.2% HCOOH; B: ACN Detection: MS: Positive and negative mode ESI Mass range: 105-1200 m/z Flow: 1.20 ml/min Column temp.: 35° C. Gradient: 0.00-0.01 min: 5% B 0.01-1.50 min: 5%→95% B 1.50-2.00 min: 100% B Preparation of the Compounds According to the Invention The compounds according to the invention are prepared by methods of synthesis described hereinafter, in which the substituents of the general formulae have the meanings given hereinbefore. These methods are intended as an illustration of the invention, without restricting its subject matter and the scope of the compounds claimed to these examples. Where the preparation of starting compounds is not described, they are commercially obtainable or may be prepared analogously to known compounds or methods described herein. Substances described in literature are prepared according to the published methods. One method for the preparation of compounds of formula (I) is exemplified in Scheme I: 5,6-dibromopyridin-2-amine A is coupled with a trialkylsilylacetylene to obtain an intermediate B which is converted into intermediate C via amidation. The boronic acid D can be obtained through a Miyaura borylation reaction. By utilizing Suzuki coupling reactions, the boronic acid D can then be either transformed directly into compound F or intermediate E is synthesized first and F can be obtained in a succeeding step in which the Ry-bromo moiety is transformed into the final Rx group. A desilylation reaction leads to intermediate G which is converted into H e.g. via Sonogashira coupling. Finally, compounds of the formula (I) are obtained via deprotection reaction. The products are isolated by conventional means and preferably purified by chromatography. Preparation of Compounds B B1) 5-bromo-6-[2-tri(propan-2-yl)silylethynyl]pyridin-2-amine Under argon atmosphere a mixture of 5,6-dibromopyridin-2-amine (60 g, 233 mmol), ethynyl-tri(propan-2-yl)silane (64 ml, 285 mmol), copper(I) iodide (1.5 g, 7.88 mmol), triethylamine (80 ml, 577 mmol), ACN (200 ml), THF (100 ml) and dichlorobis(triphenyl-phosphine)palladium(II) (4.0 g, 5.48 mmol) is stirred for 2 h at 50° C. The solids are filtered off, the mixture is concentrated in vacuo and the product purified by NP chromatography. Yield: 76 g (92%). HPLC-MS: M+H=353/355; tR=1.79 min (Method_1). Preparation of Compounds C C1) tert-butyl-N-[1-[[5-bromo-6-[2-tri(propan-2-yl)silylethynyl]pyridin-2-yl]-amino]-1-oxopropan-2-yl]-N-methylcarbamate N,N′-Dicyclohexylcarbodiimide is added portionwise to a mixture of (46.4 g, 225 mmol) 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid (72.9 g, 359 mmol) and DCM (200 ml) under stirring at 5° C. This mixture is warmed to RT and stirring continued for 30 minutes before a mixture of 5-bromo-6-[2-tri(propan-2-yl)silylethynyl]-pyridin-2-amine B1 (53 g, 150 mmol) in DCM (200 ml) is added slowly. After stirring for 10 days at RT the mixture is diluted with DCM and extracted with aqueous saturated NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by NP chromatography. Yield: 71 g (87%). HPLC-MS: M+H=538/540; tR=1.98 min (Method_1). In order to obtain (R)- or (S)-enantiomers of final examples (2R)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid or (2S)-2-[methyl-[(2-methyl-propan-2-yl)oxycarbonyl]amino]propanoic acid can be employed. E.g. with (2S)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid the intermediate tert-butyl N-[(1S)-1-[(5 -bromo-6-{2-[tris (propan-2-yl)silyl]ethynyl}pyridin-2-yl)carbamoyl]-ethyl]-N-methylcarbamate is obtained (S)-C1: Yield: 71 g (87%). HPLC-MS: M+H=538/540; tR=1.98 min (Method_1). Accordingly, all subsequent intermediates described below in the racemic form can also be obtained as R- or S-enantiomers. E.g. D1, E1 and F1 are obtained as S-enantiomers starting from (S)-C1 and following the described procedures. Preparation of Compounds D D1) [6-[2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoylamino]-2-[2-tri(propan-2-yl)silylethynyl]pyridin-3-yl]boronic acid A mixture of tert-butyl-N-[1-[[5-bromo-6-[2-tri(propan-2-yl)silylethynyl]pyridin-2-yl]-amino]-1-oxopropan-2-yl]-N-methylcarbamate C1 (53 g, 98 mmol), bis(neopentyl glycolato)diboron (44.5 g, 197 mmol), KOAc (29 g, 295 mmol), 1,1′-Bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) (2.16 g, 2.95 mmol) and dioxane (250 ml) is stirred under argon atmosphere for 7 h at 55° C. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by NP chromatography. Yield: 44 g (89%). HPLC-MS: M+H=504; tR=1.67 min (Method_1). Preparation of Compounds E E1) tert-butyl N-{1-[(5-{2-bromo-7-methylimidazo[1,2-a]pyridin-3-yl}-6-{2-[tris-(propan-2-yl)silyl]ethynyl}pyridin-2-yl)carbamoyl]ethyl}-N-methylcarbamate A mixture of [6-[2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoylamino]-2-[2-tri(propan-2-yl)silylethynyl]pyridin-3-yl]boronic acid D1 (14.7 g, 29.2 mmol), 2-bromo-3-iodo-7-methylimidazo[1,2-a]pyridine S2 (11.8 g, 35.1 mmol), Na2CO3 (9.3 g, 87.7 mmol), dioxane (150 ml), water (30 ml) and 1,1′-bis(diphenylphosphino)ferrocenel-dichloropalladium(II) (2.14 g, 2.92 mmol) is stirred under argon atmosphere for 4 h at 110° C. At RT water (100 ml) is added and the mixture extracted with EtOAc. The combined organic layers are dried over MgSO4, concentrated in vacuo and the product purified by RP HPLC. Yield: 6.9 g (36%). HPLC-MS: M+H=668; tR=1.82 min (Method_1). Preparation of Compounds F F1) tert-butyl N-[1-({5-[2-(2-methoxypyridin-3-yl)-7-methylimidazo[1,2-a]pyridin-3-yl]-6-{2-[tris(propan-2-yl)silyl]ethynyl}pyridin-2-yl}carbamoyl)ethyl]-N-methylcarbamate A mixture of tert-butyl N-{1-[(5-{2-bromo-7-methylimidazo[1,2-a]pyridin-3-yl}-6-{2-[tris(propan-2-yl)silyl]ethynyl}pyridin-2-yl)carbamoyl]ethyl}-N-methylcarbamate E1 (1.0 g, 1.50 mmol), (2-methoxypyridin-3-yl)boronic acid (1.0 g, 6.54 mmol), Na2CO3 (475 mg, 4.48 mmol), dioxane (10 ml), water (2 ml) and 1,1′-bis(diphenylphosphino)-ferroceneldichloropalladium(II) (218 mg, 298 μmol) is stirred under argon atmosphere for 3 h at 100° C. At RT water (50 ml) is added and the mixture extracted with EtOAc. The combined organic layers are dried over MgSO4, concentrated in vacuo and the product purified by RP HPLC. Yield: 990 mg (95%). HPLC-MS: M+H=697; tR=2.02 min (Method_4). The following intermediates are prepared analogously from El utilizing corresponding boronic acids (for F2 +F5-F9) or boronic acid pinacol esters (for F3-F4): tret # Structure Chemical Name [min] [M + H] A.M. F2 tert-butyl N-methyl-N-[1-({5- [7-methyl-2(2-methyl- pyridin-4-yl)imidazo[1,2- a]pyridin-3-yl]-6-{2- [tris(propan-2-yl)silyl]- ethynyl}pyridin-2- yl}carbamoyl)ethyl]carbamate 1.23 681 M_2 F3 tert-butyl N-methyl-N-[1-({5- [7-methyl-2-(1-methyl-1H- pyrazol-4-yl)imidazo[1,2- a]pyridin-3-yl]-6-{2- [tris(propan-2- yl)silyl]ethynyl}pyridin-2- yl}carbamoyl)ethyl]carbamate 1.19 670 M_2 F4 tert-butyl N-methyl-N-[1-({5- [7-methyl-2-(1-methyl-1H- imidazol-5-yl)imidazo[1,2- a]pyridin-3-yl]-6-{2- [tris(propan-2- yl)silyl]ethynyl}pyridin-2- yl}carbamoyl)ethyl]carbamate 1.19 670 M_2 F5 tert-butyl N-methyl-N-[1-({5- [7-methyl-2-(2- methylpyridin-3- yl)imidazo[1,2-a]pyridin-3- yl]-6-{2-[tris(propan-2- yl)silyl]ethynyl}pyridin-2- yl}carbamoyl)ethyl]carbamate 1.23 681 M_2 F6 tert-butyl N-methyl-N-[1-({5- [7-methyl-2-(6- methylpyridin-3- yl)imidazo[1,2-a]pyridin-3- yl]-6-{2-[tris(propan-2- yl)silyl]ethynyl}pyridin-2- yl}carbamoyl)ethyl]carbamate 1.75 681 M_1 F7 tert-butyl N-methyl-N-[1-({5- [7-methyl-2-(2- methylpyridin-5- yl)imidazo[1,2-a]pyridin-3- yl]-6-{2-[tris(propan-2- yl)silyl]ethynyl}pyridin-2- yl}carbamoyl)ethyl]carbamate 1.22 682 M_2 F8 tert-butyl N-[1-({5-[2-(2- methoxypyridin-4-yl)-7- methylimidazo[1,2-a]pyridin- 3-yl]-6-{2-[tris(propan-2- yl)silyl]ethynyl}pyridin-2- yl}carbamoyl)ethyl]-N- methylcarbamate 2.43 697 M_4 F9 tert-butyl N-[1-({5-[2-(6- methoxypyridin-3-yl)-7- methylimidazo[1,2-a]pyridin- 3-yl]-6-{2-[tris(propan-2- yl)silyl]ethynyl}pyridin-2- yl}carbamoyl)ethyl]-N- methylcarbamate 1.27 697 M_2 F10) tert-butyl N-[1-({5-[7-chloro-2-(2-methoxypyridin-3-yl)imidazo[1,2-a]pyridin-3-yl]-6-{2-[tris(propan-2-yl)silyl]ethynyl}pyridin-2-yl}carbamoyl)ethyl]-N-methylcarbamate A mixture of [6-[2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoylamino]-2-[2-tri(propan-2-yl)silylethynyl]pyridin-3-yl]boronic acid D1 (895 mg, 1.78 mmol), 3-{7-chloro-3-iodoimidazo[1,2-a]pyridin-2-yl}-2-methoxypyridine S4a (685 mg, 1.78 mmol), Na2CO3 (565 mg, 5.33 mmol), dioxane (8 ml), water (1.5 ml) and 1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) (130 mg, 0.18 mmol) is stirred under argon atmosphere for 3 h at 100° C. At RT water (100 ml) is added and the mixture extracted with EtOAc. The combined organic layers are dried over MgSO4, concentrated in vacuo and the product purified by RP HPLC. Yield: 480 mg (38%). HPLC-MS: M+H=717; tR=1.30 min (Method_2). The following intermediate is prepared analogously utilizing S4b: tret # Structure Chemical Name [min] [M + H] A.M. F11 tert-butyl N-[1-({5-[2- (2-methoxypyridin-3- yl)-imidazo[1,2- a]pyridin-3-yl]-6-{2- [tris(propan-2- yl)silyl]ethynyl}pyridin- 2-yl}carbamoyl)ethyl]- N-methylcarbamate 1.25 683 M_2 Preparation of compounds G and H G1) tert-butyl N-[1-({6-ethynyl-5-[2-(2-methoxypyridin-3-yl)-7-methylimidazo[1,2-a]pyridin-3-yl]pyridin-2-yl}carbamoyl)ethyl]-N- methylcarbamate A mixture of tert-butyl N-[1-({5-[2-(2-methoxypyridin-3 -yl)-7 -methylimidazo [1,2-a]-pyridin-3 -yl]-6-{2-[tris(propan-2-yl)silyl]ethynyl} pyridin-2-yl}carbamoyl)ethyl]-N-methylcarbamate F1 (1.1 g, 1.59 mmol), THF (20 ml) and tetrabutylammonium fluoride (1 mol/1 solution in THF, 1.8 ml, 1.8 mmol) is stirred at RT for 1 h. The mixture is diluted with EtOAc and extracted with a saturated aqueous solution of sodium hydrogencarbonate and brine. The combined organic layers are dried over MgSO4 and concentrated in vacuo to give crude G1 which is used in the next step without further purification. H1) tert-butyl N-[1-({5-[2-(2-methoxypyridin-3-yl)-7-methylimidazo[1,2-a]pyridin-3-yl]-6-[2-(1-methylisoquinolin-6-yl)ethynyl]pyridin-2-yl}carbamoyl)ethyl]-N-methylcarbamate Dichlorobis(triphenylphosphine)palladium(II) (114 mg, 162 μmol) is added to a mixture of tert-butyl N-[1-({6-ethynyl-5-[2-(2-methoxypyridin-3 -yl)-7-methylimidazo [1,2-a]pyridin-3 -yl]pyridin-2-yl}carbamoyl)ethyl]-N-methylcarbamate G1 (439 mg, 812 μmol), 6-iodo-1-methylisoquinoline S5 (437 mg, 1.62 mmol), copper(I) iodide (15 mg, 79 μmol), triethylamine (350 μl, 2 mmol) and NMP (2 ml) under argon atmosphere at RT and is stirred at 50° C. for 17 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 223 mg (40%). HPLC-MS: M+H=682; tR=1.00 min (METHOD_2). The following intermediates are prepared analogously utilizing 6-iodo-1-methyliso-quinoline S5, 6-iodo-1-methyl-1,2-dihydroquinolin-2-one or iodobenzene: tret # Structure Chemical Name [min] [M + H] A.M. H2 tert-butyl N-methyl- N-[1-({5-[7-methyl- 2-(2-methylpyridin- 4-yl)-imidazo[1,2- a]pyridin-3-yl]-6-[2- (1- methylisoquinolin-6- yl)ethynyl]pyridin-2- yl}carbamoyl)- ethyl]carbamate 0.98 666 M_2 H3 tert-butyl N-methyl- N-[1-({5-[7-methyl- 2-(1-methyl-1H- pyrazol-4- yl)imidazo[1,2-a]- pyridin-3-yl]-6-[2- (1- methylisoquinolin-6- yl)ethynyl]pyridin-2- yl}carbamoyl)- ethyl]carbamate 0.95 655 M_2 H4 tert-butyl N-methyl- N-[1-({5-[7-methyl- 2-(1-methyl-1H- imidazol-5- yl)imidazo[1,2-a]- pyridin-3-yl]-6-[2- (1- methylisoquinolin-6- yl)ethynyl]pyridin-2- yl}carbamoyl)- ethyl]carbamate 0.93 655 M_2 H5 tert-butyl N-methyl- N-[1-({5-[7-methyl- 2-(2-methylpyridin- 3-yl)-imidazo[1,2- a]pyridin-3-yl]-6-[2- (1- methylisoquinolin-6- yl)ethynyl]pyridin-2- yl}carbamoyl)- ethyl]carbamate 0.96 666 M_2 H6 tert-butyl N-methyl- N-[1-({5-[7-methyl- 2-(6-methylpyridin- 3-yl)-imidazo[1,2- a]pyridin-3-yl]-6-[2- (1- methylisoquinolin-6- yl)ethynyl]pyridin-2- yl}carbamoyl)- ethyl]carbamate 0.99 666 M_2 H7 tert-butyl N-methyl- N-[1-({5-[7-methyl- 2-(2- methylpyrimidin-5- yl)imidazo[1,2-a]- pyridin-3-yl]-6-[2- (1- methylisoquinolin-6- yl)ethynyl]pyridin-2- yl}carbamoyl)- ethyl]carbamate 0.96 667 M_2 H8 tert-butyl N-[1-({5- [2-(2- methoxypyridin-4- yl)-7- methylimidazo[1,2- a]-pyridin-3-yl]-6- [2-(1- methylisoquinolin-6- yl)ethynyl]pyridin-2- yl}carbamoyl)ethyl]- N-methylcarbamate 1.02 682 M_2 H9 tert-butyl N-[1-({5- [2-(6- methoxypyridin-3- yl)-7- methylimidazo[1,2- a]-pyridin-3-yl]-6- [2-(1- methylisoquinolin-6- yl)ethynyl]pyridin-2- yl}carbamoyl)ethyl]- N-methylcarbamate 1.03 682 M_2 H10 tert-butyl N-[1-({5- [2-(2- methoxypyridin-3- yl)-7-methyl- imidazo[1,2- a]pyridin-3-yl]-6-[2- (1-methyl-2-oxo-1,2- dihydroquinolin-6- yl)-ethynyl]pyridin- 2-yl}- carbamoyl)ethyl]-N- methylcarbamate 0.96 698 M_2 H11 tert-butyl N-methyl- N-[1-({5-[7-methyl- 2-(2-methylpyridin- 4-yl)-imidazo[1,2- a]pyridin-3-yl]-6-(2- phenyl- ethynyl)pyridin-2- yl}-carbamoyl)- ethyl]carbamate 1.02 601 M_2 H12 tert-butyl N-methyl- N-[1-({5-[7-methyl- 2-(2- methylpyrimidin-5- yl)imidazo[1,2-a]- pyridin-3-yl]-6-[2- (1-methyl-2-oxo-1,2- dihydroquinolin-6- yl)-ethynyl]pyridin- 2-yl}-carbamoyl)- ethyl]carbamate 0.92 683 M_2 H13 tert-butyl N-[1-({5- [2-(2- methoxypyridin-4- yl)-7- methylimidazo[1,2- a]-pyridin-3-yl]-6- [2-(1-methyl-2-oxo- 1,2-dihydroquinolin- 6-yl)- ethynyl]pyridin-2- yl}- carbamoyl)ethyl]-N- methylcarbamate 0.98 698 M_2 H14 tert-butyl N-[1-({5- [2-(6- methoxypyridin-3- methylimidazo[1,2- a]-pyridin-3-yl]-6- [2-(1-methyl-2-oxo- 1,2-dihydroquinolin- 6-yl)- ethynyl]pyridin-2- yl}- carbamoyl)ethyl]-N- methylcarbamate 0.99 698 M_2 H15 tert-butyl N-[1-({5- [7-chloro-2-(2- methoxypyridin-3- yl)-imidazo[1,2- a]pyridin-3-yl]-6-[2- (1- methylisoquinolin-6- yl)ethynyl]pyridin-2- yl}carbamoyl)ethyl]- N-methylcarbamate 1.04 702 M_2 H16 tert-butyl N-[1-({5- [2-(2- methoxypyridin-3- yl)imidazo[1,2-a]- pyridin-3-yl]-6-[2- (1- methylisoquinolin-6- yl)ethynyl]pyridin-2- yl}carbamoyl)ethyl]- N-methylcarbamate 0.98 668 M_2 Preparation of Examples (I): EXAMPLE 1 N-{5-[2-(2-methoxypyridin-3-yl)-7-methylimidazo[1,2-a]pyridin-3-yl]-6-[2-(1-methylisoquinolin-6-yl)ethynyl]pyridin-2-yl}-2- (methylamino)-propanamide A mixture of tert-butyl N-[1-({5-[2-(2-methoxypyridin-3-yl)-7-methylimidazo[1,2-a]-pyridin-3 -yl]-6-[2-(1-methylisoquinolin-6-yl)ethynyl]pyridin-2-yl} carbamoyl)ethyl]-N-methylcarbamate H1 (223 mg, 327 μmol), DCM (10 ml) and TFA (2 ml) is stirred for 1 h at RT. Toluene (50 ml) is added and the mixture concentrated in vacuo. The product is purified by RP HPLC. Yield: 88 mg (46%). HPLC-MS: M+H=582; tR=1.17 min (METHOD_1). The following examples are prepared analogously from H2-H16: tret # Structure Chemical Name [min] [M + H] A.M. 2 N-{5-[7-methyl-2- (2-methylpyridin-4- yl)-imidazo[1,2- a]pyridin-3-yl]-6- [2-(1-methyl- isoquinolin-6-yl)- ethynyl]pyridin-2- yl}-2- (methylamino)- propanamide 1.13 566 M_1 3 N-{5-[7-methyl-2- (1-methyl-1H- pyrazol-4- yl)imidazo[1,2-a]- pyridin-3-yl]-6-[2- (1- methylisoquinolin- 6- yl)ethynyl]pyridin- 2-yl}-2- (methylamino)- propanamide 1.10 555 M_1 4 N-{5-[7-methyl-2- (1-methyl-1H- imidazol-5- yl)imidazo[1,2-a]- pyridin-3-yl]-6-[2- (1- methylisoquinolin- 6- yl)ethynyl]pyridin- 2-yl}-2- (methylamino)- propanamide 1.09 555 M_1 5 N-{5-[7-methyl-2- (2-methylpyridin-3- yl)-imidazo[1,2- a]pyridin-3-yl]-6- [2-(1-methyl- isoquinolin-6-yl)- ethynyl]pyridin-2- yl}-2- (methylamino)- propanamide 1.12 566 M_1 6 N-{5-[7-methyl-2- (6-methylpyridin-3- yl)-imidazo[1,2- a]pyridin-3-yl]-6- [2-(1-methyl- isoquinolin-6-yl)- ethynyl]pyridin-2- yl}-2- (methylamino)- propanamide 1.14 566 M_1 7 N-{5-[7-methyl-2- (2- methylpyrimidin-5- yl)imidazo[1,2-a]- pyridin-3-yl]-6-[2- (1- methylisoquinolin- 6- yl)ethynyl]pyridin- 2-yl}-2- (methylamino)- propanamide 1.12 567 M_1 8 N-{5-[2-(2- methoxypyridin-4- yl)-7- methylimidazo[1,2- a]pyridin-3-yl]-6- [2-(1- methylisoquinolin- 6- yl)ethynyl]pyridin- 2-yl}-2-(methyl- amino)propanamide 1.21 582 M_1 9 N-{5-[2-(6- methoxypyridin-3- yl)-7- methylimidazo[1,2- a]pyridin-3-yl]-6- [2-(1- methylisoquinolin- 6- yl)ethynyl]pyridin- 2-yl}-2-(methyl- amino)propanamide 1.23 582 M_1 10 N-{5-[2-(2- methoxypyridin-3- yl)-7- methylimidazo[1,2- a]-pyridin-3-yl]-6- [2-(1-methyl-2-oxo- 1,2- dihydroquinolin-6- yl)-ethynyl]pyridin- 2-yl}-2- (methylamino)- propanamide 1.10 598 M_1 11 N-{5-[7-methyl-2- (2-methylpyridin-4- yl)-imidazo[1,2- a]pyridin-3-yl]-6- (2-phenyl- ethynyl)pyridin-2- yl}-2- (methylamino)- propanamide 1.19 501 M_1 12 N-{5-[7-methyl-2- (2- methylpyrimidin-5- yl)imidazo[1,2-a]- pyridin-3-yl]-6-[2- (1-methyl-2-oxo- 1,2- dihydroquinolin-6- yl)-ethynyl]pyridin- 2-yl}-2- (methylamino)- propanamide 1.04 583 M_1 13 N-{5-[2-(2- methoxypyridin-4- yl)-7- methylimidazo[1,2- a]-pyridin-3-yl]-6- [2-(1-methyl-2-oxo- 1,2- dihydroquinolin-6- yl)-ethynyl]pyridin- 2-yl}-2- (methylamino)- propanamide 1.13 598 M_1 14 N-{5-[2-(6- methoxypyridin-3- yl)-7- methylimidazo[1,2- a]-pyridin-3-yl]-6- [2-(1-methyl-2-oxo- 1,2- dihydroquinolin-6- yl)-ethynyl]pyridin- 2-yl}-2- (methylamino)- propanamide 1.15 598 M_1 15 N-{5-[7-chloro-2- (2-methoxypyridin- 3-yl)-imidazo[1,2- a]pyridin-3-yl]-6- [2-(1-methyl- isoquinolin-6-yl)- ethynyl]pyridin-2- yl}-2- (methylamino)- propanamide 1.22 602 M_1 16 N-{5-[2-(2- methoxypyridin-3- yl)imidazo-[1,2- a]pyridin-3-yl]-6- [2-(1-methyliso- quinolin-6- yl)ethynyl]-pyridin- 2-yl}-2- (methylamino)- propanamide 1.11 508 M_1 The (S)-enantiomers of examples are obtained by employing (S)-C1 instead of C1 in the synthetic route: tret # Structure Chemical Name [min] [M + H] A.M. (S)-1 (2S)-N-{5-[2-(2- methoxypyridin-3-yl)- 7-methylimidazo[1,2- a]pyridin-3-yl]-6-[2- (1-methylisoquinolin- 6-yl)ethynyl]pyridin- 2-yl}-2-(methyl- amino)propanamide 1.17 582 M_1 (S)-2 (2S)-N-{5-[7-methyl- 2-(2-methylpyridin-4- yl)imidazo[1,2-a]- pyridin-3-yl]-6-[2-(1- methylisoquinolin-6- yl)ethynyl]pyridin-2- yl}-2-(methylamino)- propanamide 1.13 566 M_1 (S)-3 (2S)-N-{5-[7-methyl- 2-(1-methyl-1H- pyrazol-4-yl)- imidazo[1,2-a]pyridin- 3-yl]-6-[2-(1-methyl- isoquinolin-6-yl)- ethynyl]pyridin-2-yl}- 2-(methylamino)- propanamide 1.10 555 M_1 (S)-4 (2S)-N-{5-[7-methyl- 2-(1-methyl-1H- imidazol-5-yl)- imidazo[1,2-a]pyridin- 3-yl]-6-[2-(1-methyl- isoquinolin-6-yl)- ethynyl]pyridin-2-yl}- 2-(methylamino)- propanamide 1.09 555 M_1 (S)-5 (2S)-N-{5-[7-methyl- 2-(2-methylpyridin-3- yl)imidazo[1,2-a]- pyridin-3-yl]-6-[2-(1- methylisoquinolin-6- yl)ethynyl]pyridin-2- yl}-2-(methylamino)- propanamide 1.12 566 M_1 (S)-6 (2S)-N-{5-[7-methyl- 2-(6-methylpyridin-3- yl)imidazo[1,2-a]- pyridin-3-yl]-6-[2-(1- methylisoquinolin-6- yl)ethynyl]pyridin-2- yl}-2-(methylamino)- propanamide 1.14 566 M_1 (S)-7 (2S)-N-{5-[7-methyl- 2-(2-methylpyrimidin- 5-yl)imidazo[1,2-a]- pyridin-3-yl]-6-[2-(1- methylisoquinolin-6- yl)ethynyl]pyridin-2- yl}-2-(methylamino)- propanamide 1.12 567 M_1 (S)-8 (2S)-N-{5-[2-(2- methoxypyridin-4-yl)- 7-methylimidazo[1,2- a]pyridin-3-yl]-6-[2- (1-methylisoquinolin- 6-yl)ethynyl]pyridin- 2-yl}-2-(methyl- amino)propanamide 1.21 582 M_1 (S)-9 (2S)-N-{5-[2-(6- methoxypyridin-3-yl)- 7-methylimidazo[1,2- a]pyridin-3-yl]-6-[2- (1-methylisoquinolin- 6-yl)ethynyl]pyridin- 2-yl}-2-(methyl- amino)propanamide 1.23 582 M_1 (S)-10 (2S)-N-{5-[2-(2- methoxypyridin-3-yl)- 7-methylimidazo[1,2- a]pyridin-3-yl]-6-[2- (1-methyl-2-oxo-1,2- dihydroquinolin-6-yl)- ethynyl]pyridin-2-yl}- 2-(methylamino)- propanamide 1.10 598 M_1 (S)-11 (2S)-N-{5-[7-methyl- 2-(2-methylpyridin-4- yl)imidazo[1,2-a]- pyridin-3-yl]-6-(2- phenylethynyl)pyridin- 2-yl]-2-(methyl- amino)propanamide 1.19 501 M_1 (S)-12 (2S)-N-{5-[7-methyl- 2-(2-methylpyrimidin- 5-yl)imidazo[1,2-a]- pyridin-3-yl]-6-[2-(1- methyl-2-oxo-1,2- dihydroquinolin-6-yl)- ethynyl]pyridin-2-yl}- 2-(methylamino)- propanamide 1.04 583 M_1 (S)-13 (2S)-N-{5-[2-(2- methoxypyridin-4-yl)- 7-methylimidazo[1,2- a]pyridin-3-yl]-6-[2- (1-methyl-2-oxo-1,2- dihydroquinolin-6-yl)- ethynyl]pyridin-2-yl}- 2-(methylamino)- propanamide 1.13 598 M_1 (S)-14 (2S)-N-{5-[5-(6- methoxypyridin-3-yl)- 7-methylimidazo[1,2- a]pyridin-3-yl]-6-[2- (1-methyl-2-oxo-1,2- dihydroquinolin-6-yl)- ethynyl]pyridin-2-yl}- 2-(methylamino)- propanamide 1.15 598 M_1 (S)-15 (2S)-N-{5-[7-chloro- 2-(2-methoxypyridin- 3-yl)imidazo[1,2-a]- pyridin-3-yl]-6-[2-(1- methylisoquinolin-6- yl)ethynyl]pyridin-2- yl}-2-(methylamino)- propanamide 1.22 602 M_1 (S)-16 (2S)-N-{5-[5-(2- methoxypyridin-3- yl)imidazo[1,2-a]- pyridin-3-yl]-6-[2-(1- methylisoquinolin-6- yl)ethynyl]pyridin-2- yl}-2-(methylamino)- propanamide 1.11 508 M_1 Preparation of Building Blocks S S1) 2-bromo-7-methylimidazo[1,2-a]pyridine K2CO3 (15.7 g, 114 mmol) is added portionwise to 2-chloroacetic acid (19.6 g, 207 mmol) in water (100 ml) at RT and the mixture stirred for 15 min 4-Methylpyridin-2-amine (22.5 g, 208 mmol) is added, the mixture heated to reflux for 16 h and cooled to RT. The mixture is concentrated in vacuo to less than half its volume and cold ethanol (200 ml) is added. The precipitate is collected, washed with cold ethanol, dried in vacuo and used directly in the next step. The crude intermediate and POBr3 (90 g, 341 mmol) are heated to 100° C. for 16 h. The mixture is cooled to RT and slowly added to a cooled stirred mixture of DCM (500 ml) and aqueous NaOH (1 mol/1, 1000 ml). After stirring for 1 h at RT the organic phase is collected and the aqueous layer extracted with DCM. The combined organic layers are dried over MgSO4, concentrated in vacuo and the product purified by NP chromatography. Yield: 8.6 g (20%). HPLC-MS: tR=0.79 min (Method_1). S2) 2-bromo-3-iodo-7-methylimidazo[1,2-a]pyridine A mixture of 2-bromo-7-methylimidazo[1,2-a]pyridine S1 (8.6 g, 40.8 mmol), N-iodosuccinimide (9.2 g, 40.8 mmol) and ACN (500 ml) is stirred at RT for 3 h. The precipitate is collected, washed with ACN and dried in vacuo. Yield: 11.8 g (86%). HPLC-MS: tR=1.09 min (Method_1) S3a) 2-chloro-3-{7-chloroimidazo[1,2-a]pyridin-2-yl}pyridine Tetra-N-butylammonium tribromide (3.18 g, 6.60 mmol) is added to 1-(2-chloropyridin-3-yl)ethan-1-one (1 g, 6.43 mmol) in THF (15 ml) at RT and the mixture stirred for 2 h. 4-Chloropyridin-2-amine (0.83 g, 6.43 mmol), NaHCO3 (0.56 g, 6.67 mmol) and ethanol (10 ml) is added and the mixture stirred at 50° C. for 16 h. At RT water is added and the mixture extracted with EtOAc. The combined organic layers are dried over MgSO4, concentrated in vacuo and the product purified by RP HPLC. Yield: 0.88 g (52%). HPLC-MS: tR=0.80 min (Method_2). The following intermediates are prepared analogously: tret # Structure Chemical Name [min] [M + H] A.M. S3b 2-chloro-3-{imidazo[1,2-a]- pyridin-2-yl}pyridine 0.84 230 M_1 53c 2-chloro-3-{7-methyl- imidazo[1,2-a]pyridin-2-yl}- pyridine 0.79 244 M_2 S4a) 3-{7-chloro-3-iodoimidazo[1,2-a]pyridin-2-yl}-2-methoxypyridine A mixture of 2-chloro-3-{7 -chloroimidazo [1,2-a]pyridin-2-yl}pyridine S3a (0.86 g, 3.26 mmol), sodium methoxide (5.4 mol/l in MeOH, 4 ml, 21.6 mmol) and methanol (6 ml) is stirred at 60° C. for 2 days then at 80° C. for 2 days. At RT water is added and the mixture extracted with EtOAc. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The crude intermediate desiodo-S4a (3-{7-chloroimidazo[1,2-a]-pyridin-2-yl}-2-methoxypyridine, HPLC-MS: M+H=260; tR=1.05 min (Method_1) is used directly without further purification). N-iodosuccinimide (0.73 g, 3.26 mmol) and ACN (15 ml) are added to the crude material and the mixture is stirred for 2 h at RT. The precipitate is collected, washed with ACN and dried in vacuo. The filtrate is concentrated in vacuo, EtOAc is added and the mixture washed with an aqueous solution containing 10% sodium thiosulfate. The combined organic layers are dried over MgSO4, concentrated in vacuo and pooled with the precipitate to give the title compound which is used in the next step without further purification. Yield: 0.69 g (55%). HPLC-MS: M+H=386; tR=1.13 min (Method_1) The following intermediates are prepared analogously from S3b and S3c: tret # Structure Chemical Name [min] [M + H] A.M. Desiodo- S4b 3-{imidazo[1,2-a]- pyridin-2-yl}-2- methoxypyridine 0.90 226 M_1 S4b 3-{3-iodoimidazo[1,2-a]- pyridin-2-yl}-2- methoxypyridine 1.00 352 M_1 Desiodo- S4c 2-methoxy-3-{7- methylimidazo[1,2- a]pyridin-2-yl}pyridine 0.81 240 M_2 S4c 3-{3-iodo-7- methylimidazo[1,2- a]pyridin-2-yl}-2- methoxypyridine 0.87 366 M_2 S5) 6-iodo-1-methylisoquinoline A mixture of 1-methylisoquinolin-6-amine (27 g, 171 mmol) in 2-methylpropan-2-ol (1.5 1) and hydrochloric acid (2 mol/1, 1.5 l) is cooled to 0° C. Sodium nitrite (12 g, 177 mmol) is added and stirring continued for 30 minutes. The mixture is warmed to RT and stirred for 5 minutes before it is cooled to 0° C. again. Sodium iodide (45 g, 302 mmol) is added and the mixture stirred at RT for 30 min. The mixture is diluted with water and extracted with EtOAc. The aqueous phase is made basic with sodium hydroxide and extracted with EtOAc. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 5.2 g (11%). HPLC-MS: M+H=270; tR=1.70 mM (METHOD_3). Assays and Data XIAP BIR3 and cIAP1 BIR3 Binding Assays (DELFIA) BIR3 domains of human XIAP (covering amino acids 241 to 356; XIAP BIR3) and cIAP1 (covering amino acids 256 to 363; cIAP1 BIR3) were expressed and purified from Ecoli as GST-fusion proteins. Peptide AVPIAQKSE-Lys(Biotin), representing the N-terminus of mature human SMAC (SMAC peptide), was used as interaction partner in the protein-peptide interaction assay. BIR3 domains (10 nM) were incubated with SMAC peptide (10 nM) in assay buffer (50 mM Tris, 120 mM NaCl, 0.1% BSA, 1 mM DTT, 0.05% TritonX100) for one hour at room temperature in the presence of inhibitiory compounds. The assay mixture was transferred to a strepatvidin coated plate and incubated for one hour at room temperature to allow binding of the biotinylated peptide and associated BIR3 domains to the plate. After several washing steps Eu labeled anti-GST antibody (e.g. Perkin Elmer DELFIA Eu-N1-antiGST AD0250) was added to detect BIR3 domain-SMAC peptide interactions according to Perkin Elmer's instructions. Briefly, the antibody was added (dilution 1:5000 in Perkin Elmer DELFIA Assay Buffer 2013-01) and incubated for one hour. After 3 washing steps using Delfia Washing Buffer (Perkin Elmer DELFIA Wash 2013-05), Enhancement Solution (Perkin Elmer Enhancement Asolution 2013-02) was added and incubation continued for 10 minutes. Time resolved Europium fluoresecence was measured in a Wallac Victor using Standard assay settings. IC50 values for inhibitory compounds were calculated from assay results obtained by incubating BIR3 domains with SMAC peptide in the presence of serially diluted compounds (e.g. 1:5). DELFIA assay results were plotted against compound concentrations and Software GraphPad Prizm was used to calculate half maximal inhibitory concentrations (IC50 values). The IC50 values representing the biological activity of the examples are listed in the table below. All IC50 values are reported in nM and represent the activity of the (S)-isomers: cIAP1 XIAP # BIR-3 BIR-3 (S)-1 1 207 (S)-2 1 N/A (S)-3 1 252 (S)-4 1 303 (S)-5 2 677 (S)-6 1 108 (S)-7 1 124 (S)-8 1 147 (S)-9 1 267 (S)-10 1 260 (S)-11 1 13 (S)-12 2 333 (S)-13 1 219 (S)-14 1 1269 (S)-15 2 175 (S)-16 2 304 Cytochrome P450 Isoenzyme Inhibition Assays The inhibition of the conversion of a specific substrate to its metabolite is assayed at 37° C. with human liver microsomes and used to determine the inhibition of cytochrome P450 isoenzymes. For the following cytochrome P450 isoenzymes these substrates and metabolic reactions are monitored: P450 2C9: hydroxylation of Diclofenac; P450 3A4: hydroxylation of Midazolam; P450 2D6: demethylation of Dextromethorphan; P450 2C19: hydroxylation of Mephenytoin; P450 2C8: deethylation of Amodiaquine. The final incubation volume contains TRIS buffer (0.1 M), MgCl2 (5 mM), a certain concentration of human liver microsomes dependent on the P450 isoenzyme measured (P450 2C9, P450 3A4: 0.1 mg/ml; P450 2D6: 0.2 mg/ml; P450 2C19: 0.5 mg/ml; P450 2C8: 0.05 mg/ml) and a certain concentration of the individual substrate for each isoenzyme (P450 2C9: Diclofenac 10 μM; P450 3A4: Midazolam 5 μM; P450 2D6: Dextromethorphan 5 μM; P450 2C19: S-Mephenytoin 70 μM; P450 2C8: Amodiaquine 1 μM). The effect of the test compound is determined at five different concentrations in duplicate (e.g. highest concentration 10-50 μM with subsequent serial 1:4 dilutions) or without test compound (high control). Following a short preincubation period, reactions are started with the cofactor (NADPH, 1 mM) and stopped by cooling the incubation down to 8° C. and subsequently by addition of one volume of acetonitrile. An internal standard solution—usually the stable isotope of the formed metabolite—is added after quenching of incubations. Peak area analyte (=metabolite formed) and internal standard is determined by LC-MS/MS. The resulting peak area ratio analyte to internal standard in these incubations is compared to a control activity containing no test compound. Within each of the assay runs, the IC50 of a positive control inhibitor dependent on the P450 isoenzyme measured (P450 2C9: sulfaphenazole; P450 3A4: ketoconazole; P450 2D6: quinidine; P450 2C19: tranylcypromine; P450 2C8: Montelukast) is determined. The assay results are plotted against compound concentrations to calculated IC50 values (half maximal inhibitory concentrations) for inhibitory compounds utilizing Software GraphPad Prizm The IC50 values representing the inhibitory activity of the examples on the individual cytochrome P450 isoenzymes are listed in the table below. All IC50 values are reported in μM and represent the inhibitory activity of the (S)-isomers: P450 P450 P450 P450 P450 # 2C19 2C8 2C9 2D6 3A4 (S)-1 >50 11 38 35 >50 (S)-2 1.9 0.9 >50 >50 >50 (S)-3 >50 14 >50 >50 >50 (S)-4 36 9.8 27 6.4 >50 (S)-5 >50 1.3 >50 >50 >50 (S)-6 >50 25 >50 >50 >50 (S)-7 >50 >50 >50 >50 >50 (S)-8 38 1.6 >50 >50 >50 (S)-9 >50 15 >50 >50 >50 (S)-10 >50 9.3 45 >50 >50 (S)-11 14 15 >50 32 46 (S)-12 >50 >50 >50 >50 >50 (S)-13 12 4.5 >50 >50 >50 (S)-14 >50 >50 >50 >50 >50 (S)-15 32 2.2 19 16 >50 (S)-16 >50 3.4 21 29 >50 Solubility Measurement (DMSO Solution Precipitation Method) A 10 mM DMSO stock solution of a compound is used to determine its aqueous solubility. The DMSO solution is diluted with an aqueous medium (Mcllvaine buffer with pH=6.8) to a final concentration of 250 μM. After 24 h of shaking at ambient temperature a potentially formed precipitate is removed by filtration. The concentration of the filtrate is determined by LC-UV methods by comparing the signal to the signal of a reference solution with known concentration. The solubility of the examples at pH 6.8 is listed in the table below. All values are reported in μg/ml representing the (S)-isomers: Sol[μg/ml] # pH 6.8 (S)-1 35 (S)-2 8 (S)-3 1 (S)-4 39 (S)-5 <1 (S)-6 1 (S)-7 <1 (S)-8 <1 (S)-9 2 (S)-10 35 (S)-11 N/A (S)-12 <1 (S)-13 <1 (S)-14 <1 (S)-15 20 (S)-16 17 On the basis of their biological properties the compounds of general formula (1) according to the invention, their tautomers, racemates, enantiomers, diastereomers, mixtures thereof and the salts of all the above-mentioned forms are suitable for treating diseases characterised by excessive or abnormal cell proliferation. For example, the following cancers may be treated with compounds according to the invention, without being restricted thereto: brain tumours such as for example acoustic neurinoma, astrocytomas such as pilocytic astrocytomas, fibrillary astrocytoma, protoplasmic astrocytoma, gemistocytary astrocytoma, anaplastic astrocytoma and glioblastoma, brain lymphomas, brain metastases, hypophyseal tumour such as prolactinoma, HGH (human growth hormone) producing tumour and ACTH producing tumour (adrenocorticotropic hormone), craniopharyngiomas, medulloblastomas, meningeomas and oligodendrogliomas; nerve tumours (neoplasms) such as for example tumours of the vegetative nervous system such as neuroblastoma sympathicum, ganglioneuroma, paraganglioma (pheochromocytoma, chromaffinoma) and glomus-caroticum tumour, tumours on the peripheral nervous system such as amputation neuroma, neurofibroma, neurinoma (neurilemmoma, Schwannoma) and malignant Schwannoma, as well as tumours of the central nervous system such as brain and bone marrow tumours; intestinal cancer such as for example carcinoma of the rectum, colon carcinoma, colorectal carcinoma, anal carcinoma, carcinoma of the large bowel, tumours of the small intestine and duodenum; eyelid tumours such as basalioma or basal cell carcinoma; pancreatic cancer or carcinoma of the pancreas; bladder cancer or carcinoma of the bladder; lung cancer (bronchial carcinoma) such as for example small-cell bronchial carcinomas (oat cell carcinomas) and non-small cell bronchial carcinomas (NSCLC) such as plate epithelial carcinomas, adenocarcinomas and large-cell bronchial carcinomas; breast cancer such as for example mammary carcinoma such as infiltrating ductal carcinoma, colloid carcinoma, lobular invasive carcinoma, tubular carcinoma, adenocystic carcinoma and papillary carcinoma; non-Hodgkin's lymphomas (NHL) such as for example Burkitt's lymphoma, low-malignancy non-Hodgkin's lymphomas (NHL) and mucosis fungoides; uterine cancer or endometrial carcinoma or corpus carcinoma; CUP syndrome (Cancer of Unknown Primary); ovarian cancer or ovarian carcinoma such as mucinous, endometrial or serous cancer; gall bladder cancer; bile duct cancer such as for example Klatskin tumour; testicular cancer such as for example seminomas and non-seminomas; lymphoma (lymphosarcoma) such as for example malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas (NHL) such as chronic lymphatic leukaemia, leukaemic reticuloendotheliosis, immunocytoma, plasmocytoma (multiple myeloma), immunoblastoma, Burkitt's lymphoma, T-zone mycosis fungoides, large-cell anaplastic lymphoblastoma and lymphoblastoma; laryngeal cancer such as for example tumours of the vocal cords, supraglottal, glottal and subglottal laryngeal tumours; bone cancer such as for example osteochondroma, chondroma, chondroblastoma, chondromyxoid fibroma, osteoma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, giant cell tumour, chondrosarcoma, osteosarcoma, Ewing's sarcoma, reticulo-sarcoma, plasmocytoma, fibrous dysplasia, juvenile bone cysts and aneurysmatic bone cysts; head and neck tumours such as for example tumours of the lips, tongue, floor of the mouth, oral cavity, gums, palate, salivary glands, throat, nasal cavity, paranasal sinuses, larynx and middle ear; liver cancer such as for example liver cell carcinoma or hepatocellular carcinoma (HCC); leukaemias, such as for example acute leukaemias such as acute lymphatic/lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML); chronic leukaemias such as chronic lymphatic leukaemia (CLL), chronic myeloid leukaemia (CML); stomach cancer or gastric carcinoma such as for example papillary, tubular and mucinous adenocarcinoma, signet ring cell carcinoma, adenosquamous carcinoma, small-cell carcinoma and undifferentiated carcinoma; melanomas such as for example superficially spreading, nodular, lentigo-maligna and acral-lentiginous melanoma; renal cancer such as for example kidney cell carcinoma or hypernephroma or Grawitz's tumour; oesophageal cancer or carcinoma of the oesophagus; penile cancer; prostate cancer; throat cancer or carcinomas of the pharynx such as for example nasopharynx carcinomas, oropharynx carcinomas and hypopharynx carcinomas; retinoblastoma such as for example vaginal cancer or vaginal carcinoma; plate epithelial carcinomas, adenocarcinomas, in situ carcinomas, malignant melanomas and sarcomas; thyroid carcinomas such as for example papillary, follicular and medullary thyroid carcinoma, as well as anaplastic carcinomas; spinalioma, epidormoid carcinoma and plate epithelial carcinoma of the skin; thymomas, cancer of the urethra and cancer of the vulva. Preferred cancers, which may be treated with compounds according to the invention, are lung, liver, colon, brain, breast, ovary, prostate cancer, pancreas, kidney, stomach, head, neck and urothelial cancer, as well as lymphoma and leukemia. The new compounds may be used for the prevention, short-term or long-term treatment of the above-mentioned diseases, optionally also in combination with radiotherapy or other “state-of-the-art” compounds, such as e.g. cytostatic or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids or antibodies. The compounds of general formula (1) may be used on their own or in combination with other active substances according to the invention, optionally also in combination with other pharmacologically active substances. Chemotherapeutic agents which may be administered in combination with the compounds according to the invention, include, without being restricted thereto, hormones, hormone analogues and antihormones (e.g. tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g. anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists (e.g. goserelin acetate, luprolide), inhibitors of growth factors (growth factors such as for example “platelet derived growth factor” and “hepatocyte growth factor”, inhibitors are for example “growth factor” antibodies, “growth factor receptor” antibodies and tyrosine kinase inhibitors, such as for example cetuximab, gefitinib, imatinib, lapatinib and trastuzumab); antimetabolites (e.g. antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5-fluorouracil, capecitabin and gemcitabin, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine, fludarabine); antitumour antibiotics (e.g. anthracyclins such as doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g. cisplatin, oxaliplatin, carboplatin); alkylation agents (e.g. estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as for example carmustin and lomustin, thiotepa); antimitotic agents (e.g. Vinca alkaloids such as for example vinblastine, vindesin, vinorelbin and vincristine; and taxanes such as paclitaxel, docetaxel); topoisomerase inhibitors (e.g. epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantron) and various chemotherapeutic agents such as amifostin, anagrelid, clodronat, filgrastin, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer. Other possible combination partners are 2-chlorodesoxyadenosine, 2-fluorodesoxycytidine, 2-methoxyoestradiol, 2C4, 3-alethine, 131-I-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B, A 105972, A 204197, aldesleukin, alitretinoin, altretamine, alvocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apaziquone, apomine, aranose, arglabin, arzoxifene, atamestane, atrasentan, auristatin PE, AVLB, AZ10992, ABX-EGF, ARRY-300, ARRY-142886/AZD-6244, ARRY-704/AZD-8330, AS-703026, azacytidine, azaepothilone B, azonafide, BAY-43-9006, BBR-3464, BBR-3576, bevacizumab, biricodar dicitrate, BCX-1777, bleocin, BLP-25, BMS-184476, BMS-247550, BMS-188797, BMS-275291, BNP-1350, BNP-7787, BIBW 2992, BIBF 1120, bleomycinic acid, bleomycin A, bleomycin B, bryostatin-1, bortezomib, brostallicin, busulphan, CA-4 prodrug, CA-4, CapCell, calcitriol, canertinib, canfosfamide, capecitabine, carboxyphthalatoplatin, CCI-779, CEP-701, CEP-751, CBT-1 cefixime, ceflatonin, ceftriaxone, celecoxib, celmoleukin, cemadotin, CH4987655/RO-4987655, chlorotrianisene, cilengitide, ciclosporin, CDA-II, CDC-394, CKD-602, clofarabin, colchicin, combretastatin A4, CHS-828, CLL-Thera, CMT-3 cryptophycin 52, CTP-37, CP-461, CV-247, cyanomorpholinodoxorubicin, cytarabine, D 24851, decitabine, deoxorubicin, deoxyrubicin, deoxycoformycin, depsipeptide, desoxyepothilone B, dexamethasone, dexrazoxanet, diethylstilbestrol, diflomotecan, didox, DMDC, dolastatin 10, doranidazole, E7010, E-6201, edatrexat, edotreotide, efaproxiral, eflornithine, EKB-569, EKB-509, elsamitrucin, epothilone B, epratuzumab, ER-86526, erlotinib, ET-18-OCH3, ethynylcytidine, ethynyloestradiol, exatecan, exatecan mesylate, exemestane, exisulind, fenretinide, floxuridine, folic acid, FOLFOX, FOLFIRI, formestane, galarubicin, gallium maltolate, gefinitib, gemtuzumab, gimatecan, glufosfamide, GCS-IOO, G17DT immunogen, GMK, GPX-100, GSK-5126766, GSK-1120212, GW2016, granisetron, hexamethylmelamine, histamine, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibritumomab, idatrexate, idenestrol, IDN-5109, IMC-1C11, immunol, indisulam, interferon alpha-2a, interferon alfa-2b, interleukin-2, ionafamib, iproplatin, irofulven, isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX-2, JSF-154, J-107088, conjugated oestrogens, kahalid F, ketoconazole, KW-2170, lobaplatin, leflunomide, lenograstim, leuprolide, leuporelin, lexidronam, LGD-1550, linezolid, lutetium texaphyrin, lometrexol, losoxantrone, LU 223651, lurtotecan, mafosfamide, marimastat, mechloroethamine, methyltestosteron, methylprednisolone, MEN-10755, MDX-H210, MDX-447, MGV, midostaurin, minodronic acid, mitomycin, mivobulin, MK-2206, MLN518, motexafin gadolinium, MS-209, MS-275, MX6, neridronate, neovastat, nimesulide, nitroglycerin, nolatrexed, norelin, N-acetylcysteine, 06-benzylguanine, omeprazole, oncophage, ormiplatin, ortataxel, oxantrazole, oestrogen, patupilone, pegfilgrastim, PCK-3145, pegfilgrastim, PBI-1402, PEG-paclitaxel, PEP-005, P-04, PKC412, P54, PI-88, pelitinib, pemetrexed, pentrix, perifosine, perillylalcohol, PG-TXL, PG2, PLX-4032/RO-5185426, PT-100, picoplatin, pivaloyloxymethylbutyrate, pixantrone, phenoxodiol O, PKI166, plevitrexed, plicamycin, polyprenic acid, porfiromycin, prednisone, prednisolone, quinamed, quinupristin, RAF-265, ramosetron, ranpirnase, RDEA-119/BAY 869766, rebeccamycin analogues, revimid, RG-7167, rhizoxin, rhu-MAb, risedronate, rituximab, rofecoxib, Ro-31-7453, RO-5126766, RPR 109881A, rubidazon, rubitecan, R-flurbiprofen, S-9788, sabarubicin, SAHA, sargramostim, satraplatin, SB 408075, SU5416, SU6668, SDX-101, semustin, seocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR-31747, SRL-172, sorafenib, spiroplatin, squalamine, suberanilohydroxamic acid, sutent, T 900607, T 138067, TAS-103, tacedinaline, talaporfin, tariquitar, taxotere, taxoprexin, tazarotene, tegafur, temozolamide, tesmilifene, testosterone, testosterone propionate, tesmilifene, tetraplatin, tetrodotoxin, tezacitabine, thalidomide, theralux, therarubicin, thymectacin, tiazofurin, tipifarnib, tirapazamine, tocladesine, tomudex, toremofin, trabectedin, TransMID-107, transretinic acid, traszutumab, tretinoin, triacetyluridine, triapine, trimetrexate, TLK-286TXD 258, urocidin, valrubicin, vatalanib, vincristine, vinflunine, virulizin, WX-UK1, vectibix, xeloda, XELOX, XL-281, XL-518/R-7420, YM-511, YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZDI839, zoledronat and zosuquidar. Suitable preparations include for example tablets, capsules, suppositories, solutions—particularly solutions for injection (s.c., i.v., i.m.) and infusion—elixirs, emulsions or dispersible powders. The content of the pharmaceutically active compound(s) should be in the range from 0.1 to 90 wt. %, preferably 0.5 to 50 wt. % of the composition as a whole, i.e. in amounts which are sufficient to achieve the dosage range specified below. The doses specified may, if necessary, be given several times a day. Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers. Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets. Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates. Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles. Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules. Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof. Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose) emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate). The preparations are administered by the usual methods, preferably by oral or transdermal route, most preferably by oral route. For oral administration the tablets may, of course contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above. For parenteral use, solutions of the active substances with suitable liquid carriers may be used. However, it may sometimes be necessary to depart from the amounts specified, depending on the body weight, the route of administration, the individual response to the drug, the nature of its formulation and the time or interval over which the drug is administered. Thus, in some cases it may be sufficient to use less than the minimum dose given above, whereas in other cases the upper limit may have to be exceeded. When administering large amounts it may be advisable to divide them up into a number of smaller doses spread over the day. The formulation examples which follow illustrate the present invention without restricting its scope: Examples of Pharmaceutical Formulations A) Tablets per tablet active substance according to formula (I) 100 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg 500 mg The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size. B) Tablets per tablet active substance according to formula (I) 80 mg lactose 55 mg corn starch 190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethy starch 23 mg magnesium stearate 2 mg 400 mg The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size. C) Ampoule solution active substance according to formula (I) 50 mg sodium chloride 50 mg water for inj. 5 mL The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.
<SOH> BACKGROUND OF THE INVENTION <EOH>Apoptosis, a form of programmed cell death, typically occurs in the normal development and maintenance of healthy tissues in multicellular organisms. It is a complex process, which results in the removal of damaged, diseased or developmentally redundant cells, without signs of inflammation or necrosis. Apoptosis thus occurs as a normal part of development, the maintenance of normal cellular homeostasis, or as a consequence of stimuli such as chemotherapy and radiation. The intrinsic apoptotic pathway is known to be deregulated in cancer and lymphoproliferative syndromes, as well as autoimmune disorders such as multiple sclerosis and rheumatoid arthritis. Additionally, alterations in a host apoptotic response have been described in the development or maintenance of viral and bacterial infections. Cancer cells gain the ability to overcome or circumvent apoptosis and continue with inappropriate proliferation despite strong pro-apoptotic signals such as hypoxia, endogenous cytokines, radiation treatments and chemotherapy. In autoimmune disease, pathogenic effector cells can become resistant to normal apoptotic cues. Resistance can be caused by numerous mechanisms, including alterations in the apoptotic machinery due to increased activity of anti-apoptotic pathways or expression of anti-apoptotic genes. Thus, approaches that reduce the threshold of apoptotic induction in cancer cells by overcoming resistance mechanisms may be of significant clinical utility. Caspases serve as key effector molecules in apoptosis signaling. Caspases (cysteine containing aspartate specific proteases) are strong proteases and once activated, digest vital cell proteins from within the cell. Since caspases are highly active proteases, tight control of this family of proteins is necessary to prevent premature cell death. In general, caspases are synthesized as largely inactive zymogens that require proteolytic processing for activation. This proteolytic processing is only one of the ways in which caspases are regulated. The second mechanism of regulation is through a family of proteins that bind and inhibit caspases. One family of molecules that inhibit caspases are the Inhibitors of Apoptosis (IAP) (Deveraux et al., J Clin Immunol (1999), 19: 388-398). IAPs were originally discovered in baculovirus by their ability to substitute for P35 protein function, an anti-apoptotic gene (Crook et al. (1993) J Virology 67, 2168-2174). Human IAPs are characterized by the presence of one to three homologous structural domains known as baculovirus IAP repeat (BIR) domains. Some IAP family members also contain a RING zinc finger domain at the C-terminus, with the capability to ubiquitylate target proteins via their E3 ligase function. The human IAPs, XIAP, HIAP1 (also referred to as cIAP2), and HIAP2 (cIAP1) each have three BIR domains, and a carboxy terminal RING zinc finger. Another IAP, NAIP, has three BIR domains (BIR1 , BIR2 and BIR3), but no RING domain, whereas Livin, TsIAP and MLIAP have a single BIR domain and a RING domain. The X chromosome-linked inhibitor of apoptosis (XIAP) is an example of an IAP, which can inhibit the initiator caspase Caspase-9, and the effector caspases, Caspase-3 and Caspase-7, by direct binding. XIAP can also induce the degradation of caspases through the ubiquitylation-mediated proteasome pathway via the E3 ligase activity of a RING zinc finger domain. Inhibition of Caspase-9 is mediated by the BIR3 domains of XIAP, whereas effector caspases are inhibited by binding to the linker-BIR2 domain The BIR domains also mediate the interactions of IAPs with tumor necrosis factor-receptor associated factor (TRAFs)-I and −2, and with TAB1, adaptor proteins affecting survival signaling through NFkB activation. IAP proteins can thus function as direct brakes on the apoptosis cascade by inhibiting active caspases or by redirecting cellular signaling to a pro-survival mode. Survivin is another member of the IAP family of antiapoptotic proteins. It is shown to be conserved in function across evolution as homologues of the protein are found both in vertebrates and invertebrates. Cancer cells and cells involved in autoimmune disease may avoid apoptosis by the sustained over-expression of one or more members of the IAP family of proteins. For example, IAP overexpression has been demonstrated to be prognostic of poor clinical outcome in multiple cancers, and decreased IAP expression through RNAi strategies sensitizes tumor cells to a wide variety of apoptotic insults including chemotherapy, radiotherapy and death receptor ligands. For XIAP, this is shown in cancers as diverse as leukemia and ovarian cancer. Over expression of cIAP1 and cIAP2 resulting from the frequent chromosome amplification of the 11q21-q23 region, which encompasses both genes, has been observed in a variety of malignancies, including medulloblastomas, renal cell carcinomas, glioblastomas, and gastric carcinomas. The interaction between the baculoviral IAP repeat-3 (BIR3) domain of X-linked inhibitor of apoptosis (XIAP) and caspase-9 is of therapeutic interest because this interaction is inhibited by the NH2-terminal seven-amino-acid residues of the so-called “second mitochondrial-derived activator of caspase” (in short and hereinafter SMAC), a naturally occurring antagonist of IAPs. Small-molecule SMAC mimetics have been generated anticipating efficacy in cancer by reconstituting apoptotic signaling. Thus, there is the need to provide SMAC mimetics useful for the prevention and/or treatment of diseases characterized by excessive or abnormal cell proliferation, such as cancer. The aim of the present invention is to provide new compounds which can be used for the prevention and/or treatment of diseases characterized by excessive or abnormal cell proliferation, in particular in the treatment of cancer. The compounds according to the invention are characterized by a powerful inhibitory effect of IAP-SMAC protein-protein-interaction. In addition to powerful inhibition of the IAP-SMAC protein-protein-interaction, for the development of pharmaceutical products it is important that the active agent shows low inhibition of P450 as recommended in the Guidelines of the FDA. It is desirable to have compounds which show low inhibition of P450 isoenzymes ideally with IC50 values greater than 5 μM. 6-alkynyl-pyridine derivatives as SMAC mimetics or IAP inhibitors are also described in WO 2013/127729. Table 1 summarizes some examples of the prior art document WO 2013/127729 which are characterized by a 6-membered heteroaryl substituent attached to the imidazol1,2-alpyridine in position 5 of the central pyridine ring together with their IC50 values representing the inhibition of the five P450 isoenzymes and their solubility values. For the compounds of Table 1, it has been found that for 3-5 of five P450 isoenzymes the IC50 is lower than 5 μM. As mentioned above the desirable range of the inhibition of the P450 isoenzyme is an IC50 greater 5 μM. More preferably, for all of the five isoenzymes the IC50 is greater than 5 μM. Accordingly, there is the need to provide compounds characterized by a 6-membered heteroaryl substituent on an imidazol1,2-alpyridine in position 5 of the central pyridine ring which show lower inhibition of the P450 isoenzymes, represented by IC50 values greater than 5 μM. The compounds of the invention differ from the compounds of Table 1 in that the 5-6 membered heteroaryl is further substituted with an alkyl group or a oxyalkyl group. Surprisingly, the compounds of the invention show lower P450 inhibition meaning that no or at maximum 2 of 5 P450 isoenzymes show inhibitory values with IC50<5 μM. Accordingly, the compounds of the invention show a powerful inhibitory effect of IAP-SMAC protein-protein-interaction and low inhibition of the P450 isoenzymes. Preferred compounds of the invention are those which combine powerful inhibition of IAP-SMAC protein-protein interaction, low inhibition of the P450 isoenzymes and solubility greater than 10 μg/ml at pH 6.8. TABLE 1 Measured examples from WO 2013/127729 inhibit many P450 isoenzymes already at concentrations below 5 μM and predominately show low solubility at pH 6.8. Solubility P450 P450 P450 P450 P450 pH 6.8 Ex # Structure 2C19 2C8 2C9 2D6 3A4 [μg/ml] 27 5.3 0.3 0.4 9.3 3.7 3 64 4.3 0.5 0.4 5.2 2.1 N/A 81 2.8 1.2 0.9 3.4 4.0 8 82 4.8 0.3 0.4 2.2 2.3 N/A 94 2.9 4.9 0.7 3.3 >50 N/A 185 16 1.7 4.8 2.7 3.0 60 detailed-description description="Detailed Description" end="lead"?
A61K314709
20170926
20180118
59270.0
A61K314709
0
NORTHINGTON DAVI, ZINNA
6-Alkynyl-pyridine Derivatives
UNDISCOUNTED
1
CONT-ACCEPTED
A61K
2,017
15,716,675
PENDING
FUEL MANAGEMENT SYSTEM FOR VARIABLE ETHANOL OCTANE ENHANCEMENT OF GASOLINE ENGINES
Fuel management system for efficient operation of a spark ignition gasoline engine. Injectors inject an anti-knock agent such as ethanol directly into a cylinder of the engine. A fuel management microprocessor system controls injection of the anti-knock agent so as to control knock and minimize that amount of the anti-knock agent that is used in a drive cycle. It is preferred that the anti-knock agent is ethanol. The use of ethanol can be further minimized by injection in a non-uniform manner within a cylinder. The ethanol injection suppresses knock so that higher compression ratio and/or engine downsizing from increased turbocharging or supercharging can be used to increase the efficiency or the engine.
1. A fuel management system for a spark ignition engine that has a first fueling system that uses direct injection and also has a second fueling system that uses port fuel injection; and where the fueling is such that there is a first torque range where both the first and second fueling system are used throughout the range; and where the fraction of fueling provided by the first fueling system is higher at the highest value of torque in the first torque range than in the lowest value of torque in the first torque range; and where there is a second torque range where only the second fueling system is used; where when the torque is higher than the highest value of torque in the second torque range the engine is operated in the first torque range; and where the second torque range extends from zero torque to the highest torque in the second torque range. 2. The fuel management system of claim 1 where the fraction of fueling that is provided by the first fueling system in the first torque range increases with increasing torque. 3. The fuel management system of claim 1 where the fraction of fueling that is provided by the first fueling system in the first torque range increases with increasing torque in such a way that knock is prevented. 4. The fuel management system of claim 1 where the fraction of fueling that is provided by the first fueling system in the first torque range increases with increasing torque such that it is substantially equal to the fraction needed to prevent knock. 5. The fuel management system of claim 1 where in at least part of the first torque range closed loop control using a knock detector is used to increase the fraction of fueling that is provided by the first fueling system in the first torque range with increasing torque such that it is substantially equal to the fraction needed to prevent knock. 6. The fuel management system of claim 1 where in at least part of the first torque range closed loop control using a knock detector is used to increase the fraction of fueling that is provided by the first fueling system in the first torque range with increasing torque such that it is substantially equal to the fraction needed to prevent knock and where open loop control using a look up table is also employed. 7. The fuel management system of claim 1 where throughout the entire first torque range closed loop control using a knock detector is used to increase the fraction of fueling that is provided by the first fueling system in the first torque range with increasing torque such that it is substantially equal to the fraction needed to prevent knock; 8. The fuel management system of claim 1 where throughout the entire first torque range closed loop control using a knock detector is used to increase the fraction of fueling that is provided by the first fueling system in the first torque range with increasing torque such that it is substantially equal to the fraction needed to prevent knock and where open loop control using a look up table is also employed. 9. The fuel management system of claim 1 where if torque were increased beyond the highest torque in the second torque range fueling by the first fueling system alone would be needed to prevent knock. 10. The fuel management system of claim 1 where fueling from the first fueling system throughout the first torque range is minimized. 11. The fuel management system of claim 1 the highest torque in the second torque range is the highest torque at which the engine can be operated without the need for fueling from the first fueling system to prevent knock. 12. A fuel management system for a spark ignition engine that has a first fueling system that uses direct injection and also has a second fueling system that uses port fuel injection; and where the fueling is such that there is a first torque range where both the first and second fueling system are used throughout the range; and where there is a second torque range where only the second fueling system is used; where when the torque is higher than the highest value of torque in the second torque range the engine is operated in the first torque range; and where the second torque range extends from zero torque to the highest torque in the second torque range. 13. The fuel management system of claim 12 where the fraction of fuel provided by the first fueling system increases with increasing torque in at least part of the first torque range. 14. The fuel management system of claim 12 where the fraction of fuel provided by the first fueling system increases with increasing torque in at least part of the first torque range; and where spark retard is used to reduce the fraction of fuel that is provided by the first fueling system. 15. The fuel management system of claim 12 where the fraction of fuel provided by the first fueling system increases with increasing torque in at least part of the first torque range; and where spark retard is used to reduce the fraction of fuel provided by the first fueling system to zero. 16. The fuel management system of claim 12 where spark retard is used to reduce the fraction of fuel that is provided by the first fueling system. 17. The fuel management system of claim 12 where spark retard is used to reduce the fraction of fuel that is provided by the first fueling system; and where the fuel management system uses information from a knock detector and a sensed parameter; 18. The fuel management system of claim 12 where spark retard is used to reduce the fraction of fuel that is provided by the first fueling system to zero. 19. The fuel management system of claim 12 where spark retard is used to reduce the fraction of fuel that is provided by the first fueling system to zero; and where the fuel management system uses information from a knock detector and a sensed parameter. 20. The fuel management system of claim 12 where the fraction of fuel provided by the first fueling system in the first torque range increases with increasing torque; and where spark retard is used to reduce the fraction of fuel that would otherwise be used. 21. A fuel management system for a spark ignition engine where a fuel is provided by a first fueling system using direct injection and by a second fueling system using port fuel injection; and where there is a torque range throughout which both fueling systems are used; and wherein as torque decreases the fraction of fueling provided by the first fueling system decreases; and where there is second torque range where only the second fueling system is used; 22. The fuel management system of claim 21 where when the torque is higher than the highest torque in the second torque range the engine is operated in the first torque range. 23. The fuel management system of claim 21 where when the torque is higher than the highest torque in the second torque range the engine is operated in the first torque range; and where the second torque range extends from zero torque to the highest torque in the first torque range. 24. The fuel management system of claim 21 where when the torque is higher than the highest torque in the second torque range the engine is operated in the first torque range; and where the second torque range extends from zero torque to the highest torque in the first torque range; and where in at least part of the first torque range as torque is increased, the fraction of fuel that is provided by the first fueling system is such that it is substantially equal to that needed to prevent knock as torque is increased. 25. The fuel management system of claim 21 where when the torque is higher than the highest torque in the second torque range the engine is operated in the first torque range; and where the second fueling system is used from zero torque to the highest torque in the first torque range. and where throughout the first torque range as torque is increased, the fraction of fuel that is provided by the first fueling system is such that it is substantially equal to that needed to prevent knock as torque is increased. 26. The fuel management system of claim 21 where when the torque is higher than the highest torque in the second torque range the engine is operated in the first torque range; and where the second fueling system is used from zero torque to the highest torque in the first torque range; and where the highest torque in the first torque range is the highest torque at which the engine is operated with the use of both the first and second fueling systems; and where in at least part of the first torque as torque is increased, the fraction of fuel that is provided by the first fueling system is such that it is substantially equal to that needed to prevent knock as torque is increased. 27. The fuel management system of claim 21 where when the torque is higher than the highest torque in the second torque range the engine is operated in the first torque range; and where the second fueling system is used from zero torque to the highest torque in the first torque range; and where the highest torque in the first torque range is the highest torque at which the engine is operated with the use of both the first and second fueling systems; and where throughout the first torque range as torque is increased, the fraction of fuel that is provided by the first fueling system is such that it is substantially equal to that needed to prevent knock as torque is increased. 28. The fuel management system of claim 21 where when the torque is higher than the highest torque in the second torque range the engine is operated in the first torque range; and where the second fueling system is used from zero torque to the highest torque in the first torque range; and where the highest torque in the first torque range is the highest torque at which the engine is operated with the use of both the first and second fueling systems; and where throughout the first torque range as torque is increased, the fraction of fuel that is provided by the first fueling system is such that it is substantially equal to that needed to prevent knock as torque is increased; and where the highest torque in the first torque range is the highest torque at which the engine can be operated without the necessity of operating with use of the first fueling system alone. 29. The fuel management system of claim 21 where spark retard is employed so as to reduce the fraction of fuel that is provided by first fueling system. 30. The fuel management system of claim 21 where spark retard is employed so as to enable operation with the second fueling system alone where it would not otherwise be employed. 31. A fuel management system for a spark ignition engine where a fuel is provided by a first fueling system using direct injection and by a second fueling system using port fuel injection; and where there is a first torque range through which both fueling systems are used; and wherein as torque decreases the fraction of fueling provided by the first fueling system decreases; and where there is second torque range where only the second fueling system is used; and where the second torque range extends from zero torque to the lowest torque in the first torque range; and where spark retard is employed so as to reduce the fraction of fuel is provided by the first fueling system. 32. The fuel management system of claim 31 where in at least part of the first torque range the fraction of fuel that is provided by the first fueling system is substantially equal to that needed to prevent knock; and where the fueling management system uses a knock sensor to control the fraction of fuel that is provided by the first fueling system; and where spark retard is used to reduce the fraction of fuel provided by the first fueling system to zero. 33. The fuel management system of claim 31 where throughout the first torque range the fraction of fuel that is provided by the first fueling system is substantially equal to that needed to prevent knock; and where the fueling management system uses a knock sensor and also open loop control using a lookup table to control the fraction of fuel that is provided by the first fueling system; and where spark retard is used to reduce the fraction of fuel provided by the first fueling system to zero; and where the fuel management system uses information from a knock detector and from a sensed parameter in the control of spark retard; and where the highest torque in the second torque range is the highest torque at which the engine can be operation with the second fueling system alone without producing knock.
This application is a continuation of U.S. patent application Ser. No. 15/463,425 filed on Mar. 20, 2017, which is a continuation of U.S. patent application Ser. No. 14/982,086 filed on Dec. 29, 2015, which is a continuation of U.S. patent application Ser. No. 14/478,069 filed on Sep. 5, 2014, which is a continuation of U.S. patent application Ser. No. 14/249,806 filed on Apr. 10, 2014, which is now issued as U.S. Pat. No. 8,857,410, which is a continuation of U.S. patent application Ser. No. 13/956,498 filed on Aug. 1, 2013, which is now issued as U.S. Pat. No. 8,733,321, which is a continuation of U.S. patent application Ser. No. 13/629,836 filed on Sep. 28, 2012, which is now issued as U.S. Pat. No. 8,522,746, which is a continuation of U.S. patent application Ser. No. 13/368,382 filed on Feb. 8, 2012, which is now issued as U.S. Pat. No. 8,302,580, which is a continuation of U.S. patent application Ser. No. 13/282,787 filed Oct. 27, 2011, which is now issued as U.S. Pat. No. 8,146,568, which is a continuation of U.S. patent application Ser. No. 13/117,448 filed May 27, 2011, which is now issued as U.S. Pat. No. 8,069,839, which is a continuation of U.S. patent application Ser. No. 12/815,842, filed Jun. 15, 2010, which is now issued as U.S. Pat. No. 7,971,572, which is a continuation of U.S. patent application Ser. No. 12/329,729 filed on Dec. 8, 2008, which is now issued as U.S. Pat. No. 7,762,233, which is a continuation of U.S. patent application Ser. No. 11/840,719 filed on Aug. 17, 2007, which is now issued as U.S. Pat. No. 7,740,004, which is a continuation of U.S. patent application Ser. No. 10/991,774, which is now issued as U.S. Pat. No. 7,314,033. BACKGROUND This invention relates to spark ignition gasoline engines utilizing an antiknock agent which is a liquid fuel with a higher octane number than gasoline such as ethanol to improve engine efficiency. It is known that the efficiency of spark ignition (SI) gasoline engines can be increased by high compression ratio operation and particularly by engine downsizing. The engine downsizing is made possible by the use of substantial pressure boosting from either turbocharging or supercharging. Such pressure boosting makes it possible to obtain the same performance in a significantly smaller engine. See, J. Stokes, et al., “A Gasoline Engine Concept For Improved Fuel Economy The Lean-Boost System,” SAE Paper 2001-01-2902. The use of these techniques to increase engine efficiency, however, is limited by the onset of engine knock. Knock is the undesired detonation of fuel and can severely damage an engine. If knock can be prevented, then high compression ratio operation and high pressure boosting can be used to increase engine efficiency by up to twenty-five percent. Octane number represents the resistance of a fuel to knocking but the use of higher octane gasoline only modestly alleviates the tendency to knock. For example, the difference between regular and premium gasoline is typically six octane numbers. That is significantly less than is needed to realize fully the efficiency benefits of high compression ratio or turbocharged operation. There is thus a need for a practical means for achieving a much higher level of octane enhancement so that engines can be operated much more efficiently. It is known to replace a portion of gasoline with small amounts of ethanol added at the refinery. Ethanol has a blending octane number (ON) of 110 (versus 95 for premium gasoline) (see J. B. Heywood, “Internal Combustion Engine Fundamentals,” McGraw Hill, 1988, p. 477) and is also attractive because it is a renewable energy, biomass-derived fuel, but the small amounts of ethanol that have heretofore been added to gasoline have had a relatively small impact on engine performance. Ethanol is much more expensive than gasoline and the amount of ethanol that is readily available is much smaller than that of gasoline because of the relatively limited amount of biomass that is available for its production. An object of the present invention is to minimize the amount of ethanol or other antiknock agent that is used to achieve a given level of engine efficiency increase. By restricting the use of ethanol to the relatively small fraction of time in an operating cycle when it is needed to prevent knock in a higher load regime and by minimizing its use at these times, the amount of ethanol that is required can be limited to a relatively small fraction of the fuel used by the spark ignition gasoline engine. SUMMARY In one aspect, the invention is a fuel management system for efficient operation of a spark ignition gasoline engine including a source of an antiknock agent such as ethanol. An injector directly injects the ethanol into a cylinder of the engine and a fuel management system controls injection of the antiknock agent into the cylinder to control knock with minimum use of the antiknock agent. A preferred antiknock agent is ethanol. Ethanol has a high heat of vaporization so that there is substantial cooling of the air-fuel charge to the cylinder when it is injected directly into the engine. This cooling effect reduces the octane requirement of the engine by a considerable amount in addition to the improvement in knock resistance from the relatively high octane number of ethanol. Methanol, tertiary butyl alcohol, MTBE, ETBE, and TAME may also be used. Wherever ethanol is used herein it is to be understood that other antiknock agents are contemplated. The fuel management system uses a fuel management control system that may use a microprocessor that operates in an open loop fashion on a predetermined correlation between octane number enhancement and fraction of fuel provided by the antiknock agent. To conserve the ethanol, it is preferred that it be added only during portions of a drive cycle requiring knock resistance and that its use be minimized during these times. Alternatively, the gasoline engine may include a knock sensor that provides a feedback signal to a fuel management microprocessor system to minimize the amount of the ethanol added to prevent knock in a closed loop fashion. In one embodiment the injectors stratify the ethanol to provide non-uniform deposition within a cylinder. For example, the ethanol may be injected proximate to the cylinder walls and swirl can create a ring of ethanol near the walls. In another embodiment of this aspect of the invention, the system includes a measure of the amount of the antiknock agent such as ethanol in the source containing the antiknock agent to control turbocharging, supercharging or spark retard when the amount of ethanol is low. The direct injection of ethanol provides substantially a 13° C. drop in temperature for every ten percent of fuel energy provided by ethanol. An instantaneous octane enhancement of at least 4 octane numbers may be obtained for every 20 percent of the engine's energy coming from the ethanol. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a block diagram of one embodiment of the invention disclosed herein. FIG. 2 is a graph of the drop in temperature within a cylinder as a function of the fraction of energy provided by ethanol. FIG. 3 is a schematic illustration of the stratification of cooler ethanol charge using direct injection and swirl motion for achieving thermal stratification. FIG. 4 is a schematic illustration showing ethanol stratified in an inlet manifold. FIG. 5 is a block diagram of an embodiment of the invention in which the fuel management microprocessor is used to control a turbocharger and spark retard based upon the amount of ethanol in a fuel tank. DETAILED DESCRIPTION With reference first to FIG. 1, a spark ignition gasoline engine 10 includes a knock sensor 12 and a fuel management microprocessor system 14. The fuel management microprocessor system 14 controls the direct injection of an antiknock agent such as ethanol from an ethanol tank 16. The fuel management microprocessor system 14 also controls the delivery of gasoline from a gasoline tank 18 into engine manifold 20. A turbocharger 22 is provided to improve the torque and power density of the engine 10. The amount of ethanol injection is dictated either by a predetermined correlation between octane number enhancement and fraction of fuel that is provided by ethanol in an open loop system or by a closed loop control system that uses a signal from the knock sensor 12 as an input to the fuel management microprocessor 14. In both situations, the fuel management processor 14 will minimize the amount of ethanol added to a cylinder while still preventing knock. It is also contemplated that the fuel management microprocessor system 14 could provide a combination of open and closed loop control. As show in FIG. 1 it is preferred that ethanol be directly injected into the engine 10. Direct injection substantially increases the benefits of ethanol addition and decreases the required amount of ethanol. Recent advances in fuel injector and electronic control technology allows fuel injection directly into a spark ignition engine rather than into the manifold 20. Because ethanol has a high heat of vaporization there will be substantial cooling when it is directly injected into the engine 10. This cooling effect further increases knock resistance by a considerable amount. In the embodiment of FIG. 1 port fuel injection of the gasoline in which the gasoline is injected into the manifold rather than directly injected into the cylinder is preferred because it is advantageous in obtaining good air/fuel mixing and combustion stability that are difficult to obtain with direct injection. Ethanol has a heat of vaporization of 840 kJ/kg, while the heat of vaporization of gasoline is about 350 kJ/kg. The attractiveness of ethanol increases when compared with gasoline on an energy basis, since the lower heating value of ethanol is 26.9 MJ/kg while for gasoline it is about 44 MJ/kg. Thus, the heat of vaporization per Joule of combustion energy is 0.031 for ethanol and 0.008 for gasoline. That is, for equal amounts of energy the required heat of vaporization of ethanol is about four times higher than that of gasoline. The ratio of the heat of vaporization per unit air required for stoichiometric combustion is about 94 kJ/kg of air for ethanol and 24 kJ/kg of air for gasoline, or a factor of four smaller. Thus, the net effect of cooling the air charge is about four times lower for gasoline than for ethanol (for stoichiometric mixtures wherein the amount of air contains oxygen that is just sufficient to combust all of the fuel). In the case of ethanol direct injection according to one aspect of the invention, the charge is directly cooled. The amount of cooling due to direct injection of ethanol is shown in FIG. 2. It is assumed that the air/fuel mixture is stoichiometric without exhaust gas recirculation (EGR), and that gasoline makes up the rest of the fuel. It is further assumed that only the ethanol contributes to charge cooling. Gasoline is vaporized in the inlet manifold and does not contribute to cylinder charge cooling. The direct ethanol injection provides about I3° C. of cooling for each 10% of the fuel energy provided by ethanol. (It is also possible to use direct injection of gasoline as well as direct injection of ethanol. However, under certain conditions there can be combustion stability issues. The temperature decrement because of the vaporization energy of the ethanol decreases with lean operation and with EGR, as the thermal capacity of the cylinder charge increases. If the engine operates at twice the stoichiometric air/fuel ratio, the numbers indicated in FIG. 2 decrease by about a factor of 2 (the contribution of the ethanol itself and the gasoline is relatively modest). Similarly, for a 20% EGR rate, the cooling effect of the ethanol decreases by about 25%. The octane enhancement effect can be estimated from the data in FIG. 2. Direct injection of gasoline results in approximately a five octane number decrease in the octane number required by the engine, as discussed by Stokes, et al. Thus the contribution is about five octane numbers per 30K drop in charge temperature. As ethanol can decrease the charge temperature by about 120K, then the decrease in octane number required by the engine due to the drop in temperature, for 100% ethanol, is twenty octane numbers. Thus, when 100% of the fuel is provided by ethanol, the octane number enhancement is approximately thirty-five octane numbers with a twenty octane number enhancement coming from direct injection cooling and a fifteen octane number enhancement coming from the octane number of ethanol. From the above considerations, it can be projected that even if the octane enhancement from direct cooling is significantly lower, a total octane number enhancement of at least 4 octane numbers should be achievable for every 20% of the total fuel energy that is provided by ethanol. Alternatively the ethanol and gasoline can be mixed together and then port injected through a single injector per cylinder, thereby decreasing the number of injectors that would be used. However, the air charge cooling benefit from ethanol would be lost. Alternatively the ethanol and gasoline can be mixed together and then port fuel injected using a single injector per cylinder, thereby decreasing the number of injectors that would be used. However, the substantial air charge cooling benefit from ethanol would be lost. The volume of fuel between the mixing point and the port fuel injector should be minimized in order to meet the demanding dynamic octane-enhancement requirements of the engine. Relatively precise determinations of the actual amount of octane enhancement from given amounts of direct ethanol injection can be obtained from laboratory and vehicle tests in addition to detailed calculations. These correlations can be used by the fuel management microprocessor system 14. An additional benefit of using ethanol for octane enhancement is the ability to use it in a mixture with water. Such a mixture can eliminate the need for the costly and energy consuming water removal step in producing pure ethanol that must be employed when ethanol is added to gasoline at a refinery. Moreover, the water provides an additional cooling (due to vaporization) that further increases engine knock resistance. In contrast the present use of ethanol as an additive to gasoline at the refinery requires that the water be removed from the ethanol. Since unlike gasoline, ethanol is not a good lubricant and the ethanol fuel injector can stick and not open, it is desirable to add a lubricant to the ethanol. The lubricant will also denature the ethanol and make it unattractive for human consumption. Further decreases in the required ethanol for a given amount of octane enhancement can be achieved with stratification (non-uniform deposition) of the ethanol addition. Direct injection can be used to place the ethanol near the walls of the cylinder where the need for knock reduction is greatest. The direct injection may be used in combination with swirl. This stratification of the ethanol in the engine further reduces the amount of ethanol needed to obtain a given amount of octane enhancement. Because only the ethanol is directly injected and because it is stratified both by the injection process and by thermal centrifugation, the ignition stability issues associated with gasoline direct injection (GDI) can be avoided. It is preferred that ethanol be added to those regions that make up the end-gas and are prone to auto-ignition. These regions arc near the walls of the cylinder. Since the end-gas contains on the order of 25% of the fuel, substantial decrements in the required amounts of ethanol can he achieved by stratifying the ethanol. In the case of the engine 10 having substantial organized motion (such as swirl), the cooling will result in forces that thermally stratify the discharge (centrifugal separation of the regions at different density due to different temperatures). The effect of ethanol addition is to increase gas density since the temperature is decreased. With swirl the ethanol mixture will automatically move to the zone where the end-gas is, and thus increase the anti-knock effectiveness of the injected ethanol. The swirl motion is not affected much by the compression stroke and thus survives better than tumble-like motion that drives turbulence towards top-dead-center (TDC) and then dissipates. It should be pointed out that relatively modest swirls result in large separating (centrifugal) forces. A 3 m/s swirl motion in a 5 cm radius cylinder generates accelerations of about 200 m/s2, or about 20 g's. FIG. 3 illustrates ethanol direct injection and swirl motion for achieving thermal stratification. Ethanol is predominantly on an outside region which is the end-gas region. FIG. 4 illustrates a possible stratification of the ethanol in an inlet manifold with swirl motion and thermal centrifugation maintaining stratification in the cylinder. In this case of port injection of ethanol, however, the advantage of substantial charge cooling may be lost. With reference again to FIG. 2, the effect of ethanol addition all the way up to 100% ethanol injection is shown. At the point that the engine is 100% direct ethanol injected, there may be issues of engine stability when operating with only stratified ethanol injection that need to be addressed. In the case of stratified operation it may also be advantageous to stratify the injection of gasoline in order to provide a relatively uniform equivalence ratio across the cylinder (and therefore lower concentrations of gasoline in the regions where the ethanol is injected). This situation can be achieved, as indicated in FIG. 4, by placing fuel in the region of the inlet manifold that is void of ethanol. The ethanol used in the invention can either be contained in a separate tank from the gasoline or may be separated from a gasoline/ethanol mixture stored in one tank. The instantaneous ethanol injection requirement and total ethanol consumption over a drive cycle can be estimated from information about the drive cycle and the increase in torque (and thus increase in compression ratio. engine power density, and capability for downsizing) that is desired. A plot of the amount of operating time spent at various values of torque and engine speed in FTP and US06 drive cycles can be used. It is necessary to enhance the octane number at each point in the drive cycle where the torque is greater than permitted for knock free operation with gasoline alone. The amount of octane enhancement that is required is determined by the torque level. A rough illustrative calculation shows that only a small amount of ethanol might be needed over the drive cycle. Assume that it is desired to increase the maximum torque level by a factor of two relative to what is possible without direct injection ethanol octane enhancement. Information about the operating time for the combined FTP and US06 cycles shows that approximately only 10 percent of the time is spent at torque levels above 0.5 maximum torque and less than 1 percent of the time is spent above 0.9 maximum torque. Conservatively assuming that 100% ethanol addition is needed at maximum torque and that the energy fraction of ethanol addition that is required to prevent knock decreases linearly to zero at 50 percent of maximum torque, the energy fraction provided by ethanol is about 30 percent. During a drive cycle about 20 percent of the total fuel energy is consumed at greater than 50 percent of maximum torque since during the 10 percent of the time that the engine is operated in this regime, the amount of fuel consumed is about twice that which is consumed below 50 percent of maximum torque. The amount of ethanol energy consumed during the drive cycle is thus roughly around 6 percent (30 percent×0.2) of the total fuel energy. In this case then, although 100% ethanol addition was needed at the highest value of torque, only 6% addition was needed averaged over the drive cycle. The ethanol is much more effectively used by varying the level of addition according to the needs of the drive cycle. Because of the lower heat of combustion of ethanol, the required amount of ethanol would be about 9% of the weight of the gasoline fuel or about 9% of the volume (since the densities of ethanol and gasoline are comparable). A separate tank with a capacity of about 1.8 gallons would then be required in automobiles with twenty gallon gasoline tanks. The stored ethanol content would be about 9% of that of gasoline by weight, a number not too different from present-day reformulated gasoline. Stratification of the ethanol addition could reduce this amount by more than a factor of two. An on-line ethanol distillation system might alternatively be employed but would entail elimination or reduction of the increase torque and power available from turbocharging. Because of the relatively small amount of ethanol and present lack of an ethanol fueling infrastructure, it is important that the ethanol vehicle be operable if there is no ethanol on the vehicle. The engine system can be designed such that although the torque and power benefits would be lower when ethanol is not available, the vehicle could still be operable by reducing or eliminating turbocharging capability and/or by increasing spark retard so as to avoid knock. As shown in FIG. 5, the fuel management microprocessor system 14 uses ethanol fuel level in the ethanol tank 16 as an input to control the turbocharger 22 (or supercharger or spark retard, not shown). As an example, with on-demand ethanol octane enhancement, a 4-cylinder engine can produce in the range of 280 horsepower with appropriate turbocharging or supercharging but could also be drivable with an engine power of 140 horsepower without the use of ethanol 300 according to the invention. The impact of a small amount of ethanol upon fuel efficiency through use in a higher efficiency engine can greatly increase the energy value of the ethanol. For example, gasoline consumption could be reduced by 20% due to higher efficiency engine operation from use of a high compression ratio, strongly turbocharged operation and substantial engine downsizing. The energy value of the ethanol, including its value in direct replacement of gasoline (5% of the energy of the gasoline), is thus roughly equal to 25% of the gasoline that would have been used in a less efficient engine without any ethanol. The 5% gasoline equivalent energy value of ethanol has thus been leveraged up to a 25% gasoline equivalent value. Thus, ethanol can cost roughly up to five times that of gasoline on an energy basis and still be economically attractive. The use of ethanol as disclosed herein can be a much greater value use than in other ethanol applications. Although the above discussion has featured ethanol as an exemplary anti-knock agent, the same approach can be applied to other high octane fuel and fuel additives with high vaporization energies such as methanol (with higher vaporization energy per unit fuel), and other anti-knock agents such as tertiary butyl alcohol, or ethers such as methyl tertiary butyl ether (MTBE), ethyl tertiary butyl ether (ETBE), or tertiary amyl methyl ether (TAME). it is recognized that modifications and variations of the invention disclosed herein will be apparent to those of ordinary skill in the art and it is intended that all such modifications and variations be included within the scope of the appended claims.
<SOH> BACKGROUND <EOH>This invention relates to spark ignition gasoline engines utilizing an antiknock agent which is a liquid fuel with a higher octane number than gasoline such as ethanol to improve engine efficiency. It is known that the efficiency of spark ignition (SI) gasoline engines can be increased by high compression ratio operation and particularly by engine downsizing. The engine downsizing is made possible by the use of substantial pressure boosting from either turbocharging or supercharging. Such pressure boosting makes it possible to obtain the same performance in a significantly smaller engine. See, J. Stokes, et al., “A Gasoline Engine Concept For Improved Fuel Economy The Lean-Boost System,” SAE Paper 2001-01-2902. The use of these techniques to increase engine efficiency, however, is limited by the onset of engine knock. Knock is the undesired detonation of fuel and can severely damage an engine. If knock can be prevented, then high compression ratio operation and high pressure boosting can be used to increase engine efficiency by up to twenty-five percent. Octane number represents the resistance of a fuel to knocking but the use of higher octane gasoline only modestly alleviates the tendency to knock. For example, the difference between regular and premium gasoline is typically six octane numbers. That is significantly less than is needed to realize fully the efficiency benefits of high compression ratio or turbocharged operation. There is thus a need for a practical means for achieving a much higher level of octane enhancement so that engines can be operated much more efficiently. It is known to replace a portion of gasoline with small amounts of ethanol added at the refinery. Ethanol has a blending octane number (ON) of 110 (versus 95 for premium gasoline) (see J. B. Heywood, “Internal Combustion Engine Fundamentals,” McGraw Hill, 1988, p. 477) and is also attractive because it is a renewable energy, biomass-derived fuel, but the small amounts of ethanol that have heretofore been added to gasoline have had a relatively small impact on engine performance. Ethanol is much more expensive than gasoline and the amount of ethanol that is readily available is much smaller than that of gasoline because of the relatively limited amount of biomass that is available for its production. An object of the present invention is to minimize the amount of ethanol or other antiknock agent that is used to achieve a given level of engine efficiency increase. By restricting the use of ethanol to the relatively small fraction of time in an operating cycle when it is needed to prevent knock in a higher load regime and by minimizing its use at these times, the amount of ethanol that is required can be limited to a relatively small fraction of the fuel used by the spark ignition gasoline engine.
<SOH> SUMMARY <EOH>In one aspect, the invention is a fuel management system for efficient operation of a spark ignition gasoline engine including a source of an antiknock agent such as ethanol. An injector directly injects the ethanol into a cylinder of the engine and a fuel management system controls injection of the antiknock agent into the cylinder to control knock with minimum use of the antiknock agent. A preferred antiknock agent is ethanol. Ethanol has a high heat of vaporization so that there is substantial cooling of the air-fuel charge to the cylinder when it is injected directly into the engine. This cooling effect reduces the octane requirement of the engine by a considerable amount in addition to the improvement in knock resistance from the relatively high octane number of ethanol. Methanol, tertiary butyl alcohol, MTBE, ETBE, and TAME may also be used. Wherever ethanol is used herein it is to be understood that other antiknock agents are contemplated. The fuel management system uses a fuel management control system that may use a microprocessor that operates in an open loop fashion on a predetermined correlation between octane number enhancement and fraction of fuel provided by the antiknock agent. To conserve the ethanol, it is preferred that it be added only during portions of a drive cycle requiring knock resistance and that its use be minimized during these times. Alternatively, the gasoline engine may include a knock sensor that provides a feedback signal to a fuel management microprocessor system to minimize the amount of the ethanol added to prevent knock in a closed loop fashion. In one embodiment the injectors stratify the ethanol to provide non-uniform deposition within a cylinder. For example, the ethanol may be injected proximate to the cylinder walls and swirl can create a ring of ethanol near the walls. In another embodiment of this aspect of the invention, the system includes a measure of the amount of the antiknock agent such as ethanol in the source containing the antiknock agent to control turbocharging, supercharging or spark retard when the amount of ethanol is low. The direct injection of ethanol provides substantially a 13° C. drop in temperature for every ten percent of fuel energy provided by ethanol. An instantaneous octane enhancement of at least 4 octane numbers may be obtained for every 20 percent of the engine's energy coming from the ethanol.
F02D410025
20170927
20180118
63491.0
F02D4100
1
HUYNH, HAI H
FUEL MANAGEMENT SYSTEM FOR VARIABLE ETHANOL OCTANE ENHANCEMENT OF GASOLINE ENGINES
UNDISCOUNTED
1
CONT-ACCEPTED
F02D
2,017
15,716,838
PENDING
STEROID COMPOUND FOR USE IN THE TREATMENT OF HEPATIC ENCEPHALOPATHY
The present invention provides the steroidal compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime, or a pharmaceutically acceptable salt thereof, for use in treatment of hepatic encephalopathy.
1. A method of treating hepatic encephalopathy, comprising administering a pharmaceutically effective amount of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein said hepatic encephalopathy is selected from the group consisting of minimal hepatic encephalopathy, overt hepatic encephalopathy, type A hepatic encephalopathy, type B hepatic encephalopathy and type C hepatic encephalopathy, and wherein the treatment comprises the co-administration of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime with an ammonia-lowering compound. 2. The method of claim 1, wherein said hepatic encephalopathy is minimal hepatic encephalopathy. 3. The method of claim 1, wherein said hepatic encephalopathy is overt hepatic encephalopathy. 4. The method of claim 1, wherein said hepatic encephalopathy is type A hepatic encephalopathy. 5. The method of claim 1, wherein said hepatic encephalopathy is type B hepatic encephalopathy. 6. The method of claim 1, wherein said hepatic encephalopathy is type C hepatic encephalopathy. 7. The method of any of claim 1, wherein said patient suffers from acute liver failure. 8. The method of claim 1, wherein said patient suffers from chronic liver disease with or without acute-on-chronic liver failure. 9. The method of claim 1, wherein said compound is provided before, during or after a liver transplantation. 10. The method according to any one of claims 1 to 9, wherein the ammonia-lowering compound is selected from the group consisting of rifaximin and lactulose. 11. A method of preventing hepatic encephalopathy, comprising administering a pharmaceutically effective amount of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein said hepatic encephalopathy is selected from the group consisting of minimal hepatic encephalopathy, overt hepatic encephalopathy, type A hepatic encephalopathy, type B hepatic encephalopathy and type C hepatic encephalopathy, and wherein the treatment comprises the co-administration of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime with an ammonia-lowering compound. 12. The method of claim 11, wherein said hepatic encephalopathy is minimal hepatic encephalopathy. 13. The method of claim 11, wherein said hepatic encephalopathy is overt hepatic encephalopathy. 14. The method of claim 11, wherein said hepatic encephalopathy is type A hepatic encephalopathy. 15. The method of claim 11, wherein said hepatic encephalopathy is type B hepatic encephalopathy. 16. The method of claim 11, wherein said hepatic encephalopathy is type C hepatic encephalopathy. 17. The method of any of claim 11, wherein said patient suffers from acute liver failure. 18. The method of claim 11, wherein said patient suffers from chronic liver disease with or without acute-on-chronic liver failure. 19. The method of claim 11, wherein said compound is provided before, during or after a liver transplantation. 20. The method according to any one of claims 11 to 19, wherein the ammonia-lowering compound is selected from the group consisting of rifaximin, lactulose, ornithine phenylacetate and glycerol phenyl butyrate.
RELATED APPLICATIONS This application is a continuation of U.S. Ser. No. 15/352,035, filed Nov. 15, 2016, which is a continuation of U.S. application Ser. No. 15/114,972, filed on Jul. 28, 2016. U.S. application Ser. No. 15/114,972 is the 35 U.S.C. §371 national stage filing of International Application No. PCT/GB2015/050060, filed Jan. 14, 2015, which claims priority to Swedish Application No. 1450089-6, filed Jan. 29, 2014. The entire contents of U.S. application Ser. No. 15/114,972 and U.S. application Ser. No. 15/114,972 are hereby incorporated by reference. FIELD OF THE INVENTION The present invention concerns a steroid compound for use in treatment of hepatic encephalopathy. BACKGROUND OF THE INVENTION Hepatic encephalopathy (HE) is a serious neuropsychiatric and neurocognitive complication in acute and chronic liver disease. HE is a significant and increasing health care problem due to the large and increasing prevalence of chronic liver disease. HE is characterized by impairments of the sleep-wake cycle, cognition, memory, learning, motor coordination, consciousness, decreased energy levels and personality change, ranging from minimal HE (MHE) to overt HE (OHE). MHE is manifested with cognitive impairment and has detrimental effects on health related quality of life and the ability to perform complex tasks such as driving. In addition, OHE is clinically manifested with mental and motor disorders and the symptoms ranges from disorientation through sedation and coma. Naturally occurring steroids are subject to intense metabolism and are typically not suitable for oral administration. The metabolites of the endogenous steroid hormones pregnenolone, progesterone, deoxycorticosterone, cortisone and cortisol, known as pregnanolones as well as the metabolites of testosterone, androstenedione and dehydroepiandrosterone, have all been the subject of various studies, at least partially elucidating their role in the neurological signal system in mammals. The steroid metabolites induce CNS symptoms and disorders and steroids act as positive modulators on the gamma-aminobutyric acid receptor-chloride ionophore (GABAA-R) complex and are therefore called GABAA receptor modulating steroids (GAMS). Certain steroids have been shown to be specific GABAA receptor enhancers. Examples of these steroids can inter alia be found in WO 2008/063128. Some of these steroids are potent and have e.g. been shown to have an ability to induce amnesia, sedation and anesthesia in pharmacological dose. WO 99/45931 and WO 03/059357 disclose antagonistic effects of steroids. Wang et al. 2000 (Acta Physiol Scand 169, 333-341) and Wang et al. 2002 (J Neurosci 22(9):3366-75) disclose antagonistic effects of 3β-OH-5α-pregnan-20-one and other 3β-OH-5α/β pregnan steroids. WO2006/056794 and WO2010/144498 discloses use of compounds for treatment of liver decompensation, hepatic encephalopathy and portal hypertension. There is a need to provide new and effective therapeutic treatments for hepatic encephalopathy and related disorders DESCRIPTION OF THE INVENTION The present invention provides the compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, for use in treatment of hepatic encephalopathy. 3α-Ethynyl-3β-hydroxyandrostan-17-one oxime belongs to a class of compounds known as GABAA receptor modulating steroid antagonists (GAMSAs). We have found that 3α-ethynyl-3β-hydroxyandrostan-17-one oxime is able to selectively inhibit the positive modulation of the GABAA receptor by endogenous steroids such as allopregnanolone and tetrahydrodeoxycorticosterone (THDOC). These steroids are known to induce sedation, cognitive impairment and motor disturbances, and their concentration in the brain is increased in patients with liver disease-induced hyperammonemia and HE. However, we have also found that 3α-ethynyl-3β-hydroxyandrostan-17-one oxime does not have an antagonistic effect towards the action of gamma-aminobutyric acid (GABA) at the GABAA receptors. This surprising selectivity is advantageous from a safety perspective as inhibition of GABA binding at the GABAA receptors can lead to side-effects, including convulsions. Furthermore, 3α-ethynyl-3β-hydroxyandrostan-17-one acts on both the α1 and α5 GABAA receptor sub-types and so is able to exert a positive effect on both the motor and cognitive impairment, and the sedative effects, that result from the over-activation of GABAA receptors. The positive effect of 3α-ethynyl-3β-hydroxyandrostan-17-one on motor and cognitive impairment has been illustrated in two animal models of HE (hyperammonemia and porta-caval anastomosis in rats vide infra). Unlike existing treatments for HE, 3α-ethynyl-3β-hydroxyandrostan-17-one does not affect ammonia levels in vivo. Therefore, there is clearly also potential for it's complementary use in therapy. Accordingly, there is good basis to believe that 3α-ethynyl-3β-hydroxyandrostan-17-one oxime is particularly well-suited to the treatment of HE and related disorders. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows that 3α-ethynyl-3β-hydroxyandrostan-17-one oxime does not affect blood ammonia levels. Values are the mean±SEM of 12 rats per group, values significantly different from controls are indicated by asterisks; ***, p<0.001. CV=control rats treated with vehicle; HAV=hyperammonemic rats treated with vehicle; HA+GAM=hyperammonemic rats treated with 3α-ethynyl-3β-hydroxyandrostan-17-one oxime. FIG. 2 shows that 3α-ethynyl-3β-hydroxyandrostan-17-one oxime restores spatial learning of hyperammonemic rats in the Radial maze. The figure shows working errors in the radial test. Working errors in block 1. Values are the mean±SEM of 8 rats per group. # p<0.05 versus HAV. CV=control rats treated with vehicle; HAV=hyperammonemic rats treated with vehicle; HA+GAM=hyperammonemic rats treated with 3α-ethynyl-3β-hydroxyandrostan-17-one oxime. FIG. 3 shows that 3α-ethynyl-3β-hydroxyandrostan-17-one oxime, in the Morris water maze test, restores special memory of hyperammonemic rats. The figure shows the time to find the platform on the first trial of day 3. Values are the mean±SEM of 8 rats per group. HAV versus CV p=0.052. CV=control rats treated with vehicle; HAV=hyperammonemic rats treated with vehicle; HA+GAM=hyperammonemic rats treated with 3α-ethynyl-3β-hydroxyandrostan-17-one oxime. FIG. 4 shows that 3α-ethynyl-3β-hydroxyandrostan-17-one oxime restores motor coordination of hyperammonemic rats. Values are the mean±SEM of 15 rats per group. Values significantly different from CV are indicated by *, p<0.05, values significantly different from HAV are indicated by ###, p<0.001. CV=control rats treated with vehicle; HAV=hyperammonemic rats treated with vehicle; HA+GAM=hyperammonemic rats treated with 3α-ethynyl-3β-hydroxyandrostan-17-one oxime. FIG. 5 shows total plasma 3α-ethynyl-3β-hydroxyandrostan-17-one oxime concentrations. Total plasma 3α-ethynyl-3β-hydroxyandrostan-17-one oxime concentrations in control and hyperammonemic rats 4 and 23 hours after the subcutaneous injection of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime on day five and during the last week of treatment with daily injections. HA=Hyper ammonia animals. FIG. 6 provides unbound* brain 3α-ethynyl-3β-hydroxyandrostan-17-one oxime concentrations in control and hyperammonemic rats 1-2 hours after the s.c. injection of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime after seven weeks with daily injections of 20 mg/kg. *Unbound brain concentration=fraction of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime in the brain that is not bound to carrier protein or brain tissue. FIG. 7 provides representative electrophysiological measurements showing tetrahydrodeoxycorticosterone (THDOC) enhanced activation of α1β2γ2L GABAA receptors. HEK-293 cells expressing human α1β2γ2L GABAA receptors were exposed to 30 μM GABA or 30 μM GABA plus 100 nM THDOC for 40 ms. With THDOC there was a 20 s pre-incubation before application of THDOC+GABA. FIG. 8 provides representative electrophysiological measurements showing 3α-ethynyl-3β-hydroxyandrostan-17-one (GAMSA) antagonism of the THDOC enhanced activation of α1β2γ2L and α5β3γ2L GABAA receptors and no inhibition of GABA. A) 1 μM 3α-ethynyl-3β-hydroxyandrostan-17-one antagonism of the 100 nM THDOC enhanced activation of 30 μM GABA with the α1β2γ2L GABAA receptor, B) 1 μM 3α-ethynyl-3β-hydroxyandrostan-17-one does not antagonize the 30 μM GABA activation of the α1β2γ2L GABAA receptor C) 1 μM 3α-ethynyl-3β-hydroxyandrostan-17-one antagonism of the 200 nM THDOC enhanced activation of 0.3 μM GABA with the α5β3γ2L GABAA receptor; indicating antagonism of THDOC's effect D) 1 μM 3α-ethynyl-3β-hydroxyandrostan-17-one does not antagonize the 0.3 μM GABA activation of the α5β3γ2L GABAA receptor. FIG. 9 illustrates the ability of 3α-ethynyl-3β-hydroxyandrostan-17-one to restore motor coordination in hyperammonemic and PCS rats. Motor coordination was assessed using the beam walking test. (A) shows the data for control (CV) or hyperammonemic (HAV) rats treated with vehicle and for hyperammonemic rats treated with 3 (HA3), 10 (HA10) or 20 (HA20) mg/kg of 3α-ethynyl-3β-hydroxyandrostan-17-one. (B) shows the data for sham-operated controls (SM) or PCS rats treated with vehicle and for PCS rats treated with 0.7 (PCS0.7) or 2.5 (PCS2.5) mg/kg of 3α-ethynyl-3β-hydroxyandrostan-17-one. Values are the mean±SEM of the number of rats indicated under each bar. Values significantly different from control or sham rats are indicated by asterisks. Values significantly different from hyperammonemic or PCS rats treated with vehicle are indicated by “a”. * p<0.05; a p<0.05; aa p<0.01; aaa p<0.001. FIG. 10 illustrates the ability of 3α-ethynyl-3β-hydroxyandrostan-17-one to restore spatial memory in the Morris water maze in hyperammonemic and PCS rats. Spatial learning memory in the Morris water maze was assessed in control (CV) or hyperammonemic (HAV) rats treated with vehicle and for hyperammonemic rats treated with 3 (HA3), 10 (HA10) or 20 (HA20) mg/kg of 3α-ethynyl-3β-hydroxyandrostan-17-one (A, B) and in sham-operated controls (SM) or PCS rats treated with vehicle and for PCS rats treated with 0.7 (PCS0.7) or 2.5 (PCS2.5) mg/kg of 3α-ethynyl-3β-hydroxyandrostan-17-one (C,D). (A,C) Escape latencies (in seconds) to reach the platform during the different sessions. (B,D) Time spent (%) in the correct quadrant during the memory test. Values are the mean±SEM of the number of rats indicated under each bar. Values significantly different from control or sham rats are indicated by asterisks. Values significantly different from hyperammonemic or PCS rats treated with vehicle are indicated by “a”. * p<0.05; a p<0.05. FIG. 11 illustrates the ability of 3α-ethynyl-3β-hydroxyandrostan-17-one to restore spatial learning in the radial maze in hyperammonemic and PCS rats. Spatial learning in the radial maze was assessed in control (CV) or hyperammonemic (HAV) rats treated with vehicle and for hyperammonemic rats treated with 3 (HA3), 10 (HA10) or 20 (HA20) mg/kg of 3α-ethynyl-3β-hydroxyandrostan-17-one (A, B) and in sham-operated controls (SM) or PCS rats treated with vehicle and for PCS rats treated with 0.7 (PCS0.7) or 2.5 (PCS2.5) mg/kg of 3α-ethynyl-3β-hydroxyandrostan-17-one (C,D). (A,C) Working errros during the different sessions. (B,D) Working errors during days 1-2. Values are the mean±SEM of the number of rats indicated under each bar. Values significantly different from control or sham rats are indicated by asterisks. Values significantly different from hyperammonemic or PCS rats treated with vehicle are indicated by “a”. * p<0.05; a p<0.05; aa p<0.01. FIG. 12 illustrates the ability of 3α-ethynyl-3β-hydroxyandrostan-17-one to increase spontaneous motor activity during the night and partially restore the circadian rhythm of PCS rats. Motor activity was assessed in sham-operated controls (SM) or PCS rats treated with vehicle or with 0.7 (PCS0.7) or 2.5 (PCS2.5) mg/kg of 3α-ethynyl-3β-hydroxyandrostan-17-one. Motor activity during each hour is shown in A; the ratio of activity during the night and during the day in B and the total activity during the day or the night in C. Lights are turned off at 7:00 pm. Values are the mean±SEM of 8 rats per group. Values significantly different from SM rats are indicated by asterisks; * p<0.05; ** p<0.01; *** p<0.001. Values significantly different from PCS rats are indicated by a; a p<0.05. FIG. 13 illustrates the ability of ethynyl-3β-hydroxyandrostan-17-one to normalize vertical activity during the day and to partially restore the circadian rhythm of PCS rats. The experiment was carried out as described for FIG. 12 but vertical counts are shown. Values are the mean±SEM of 8 rats per group. Values significantly different from SM rats are indicated by asterisks; * p<0.05; ** p<0.01; *** p<0.001. Values significantly different from PCS rats are indicated by a; a p<0.05; aa p<0.01. FIG. 14 shows ethynyl-3β-hydroxyandrostan-17-one exposure in the plasma and in the brain at time at behavioral testing, in hyperammonemic and PCS rats. In A) hyperammonemic rats and B) PCS rats, the total plasma concentrations of ethynyl-3β-hydroxyandrostan-17-one are shown in μM. In C) hyperammonemic rats and D) PCS rats, the unbound brain concentrations of ethynyl-3β-hydroxyandrostan-17-one are shown in nmol/kg. Note the similar exposures in the different rat models with the doses used, in hyperammonemic rats 3, 10 and 20 mg/kg/day and in rats with PCS 0.7 and 2.5 mg/kg/day. Data are from the end of the study, i.e. after nine weeks of daily treatments with ethynyl-3β-hydroxyandrostan-17-one in sesame oil given s.c. once daily. Before the present invention is described in detail, it is to be understood that the terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting. It is noted that, as used in this specification and the appended claims, the singular forms “a”, “an”, and “the” also include plural referents unless the context clearly dictates otherwise. The term “pharmaceutical composition” is used in its widest sense, encompassing all pharmaceutically applicable compositions containing at least one active substance and optional carriers, adjuvants, diluents, constituents etc. The terms “administration” and “mode of administration” as well as “route of administration” are also used in their widest sense. The compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime as used in accordance with the invention may be administered in a number of ways depending largely on whether a local, topical or systemic mode of administration is most appropriate for the hepatic encephalopathy condition to be treated. These different modes of administration are for example topical (e.g., on the skin), local (including ophthalmic and to various mucous membranes, for example vaginal and rectal delivery), oral, parenteral or pulmonary, including the upper and lower airways. The preparation of such compositions and formulations is generally known to those skilled in the pharmaceutical and formulation arts and may be applied to the formulation of the composition of the present invention. With the term “antagonist” is meant a substance that hinders another substance, an agonist, to induce its effect. In this application the terms antagonist and blocker are used interchangeably. With the term “Type A hepatic encephalopathy” is typically meant hepatic encephalopathy associated with acute liver failure, typically associated with cerebral oedema. With the term “Type B hepatic encephalopathy” is typically meant hepatic encephalopathy (bypass) caused by portal-systemic shunting without associated intrinsic liver disease. With the term “Type C hepatic encephalopathy” is typically meant hepatic encephalopathy occurring in patients with cirrhosis—this type is subdivided in episodic, persistent and minimal encephalopathy. With the term “minimal hepatic encephalopathy” is typically meant hepatic encephalopathy that does not lead to clinically overt cognitive dysfunction, but can be demonstrated with neuropsychological studies. With the term “overt hepatic encephalopathy” is typically meant clinically apparent hepatic encephalopathy manifested as neuropsychiatric syndrome with a large spectrum of mental and motor disorders. Overt hepatic encephalopathy may arise episodically, over a period of hours or days in patients previously stable or patients may present with persistent neuropsychiatric abnormalities. With the term “hyperammonemia” is typically meant a metabolic disturbance characterized by an excess of ammonia in the blood. With the term “liver transplantation” is typically meant a surgical procedure to remove a diseased liver as a consequence of e.g. acute liver failure or cirrhosis, and replace it with a healthy liver from a donor. Most liver transplant operations use livers from deceased donors but a liver may also come from a living donor (a portion of a healthy person's liver). Patients with e.g. cirrhosis commonly experience hepatic encephalopathy and preoperative hepatic encephalopathy is a significant predictor of post-transplant neurologic complications. With the term “acute-on-chronic liver failure” is typically meant acute decompensation of cirrhosis, at least one organ failure, or belongs to a subgroup with high short-term mortality rate. With the term “compensated cirrhosis” is typically meant liver cirrhosis without any clinical evidence but may include asymptotic esophageal or gastric varices and early symptoms such as fatigue and loss of energy, loss of appetite and weight loss, nausea or abdominal pain. With the term “decompensated cirrhosis” is typically meant advanced liver cirrhosis with a range of clinical evidence such as jaundice, ascites, oedema, hepatic encephalopathy, gastrointestinal haemorrhage, portal hypertension, bacterial infections, or any combination. With the term “portal hypertension” is typically meant a hepatic venous pressure gradient following liver cirrhosis, with or without associated transjugular intrahepatic portsystemic shunt (TIPS). With the term “prevention” within this disclosure, is typically meant prevention of disease or disorder hepatic encephalopathy to occur. With the term “alleviation” within this disclosure, is typically meant reduction of or freedom from the disease or disorder hepatic encephalopathy. Patients suffering from hepatic encephalopathy may show symptoms including, but not limited to, impairments of the sleep-wake cycle, cognition, memory, learning, motor coordination, consciousness, decreased energy levels and personality change, cognitive impairment, disorientation and coma. The present inventors have surprisingly shown that 3α-ethynyl-3β-hydroxyandrostan-17-one oxime may be useful for the treatment of hepatic encephalopathy. In a first aspect of the invention, there is provided the compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, for use in treatment of hepatic encephalopathy. In one embodiment of the invention, said hepatic encephalopathy is type A hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is type B hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is type C hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is minimal hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is overt hepatic encephalopathy. In another embodiment of the invention, said compound for use is where said hepatic encephalopathy is treated in a patient with acute liver failure. In another embodiment of the invention, said compound for use is where said hepatic encephalopathy is treated in a patient with chronic liver disease with or without acute-on-chronic liver failure. In another embodiment of the invention, said compound for use is for prevention or alleviation of hepatic encephalopathy, such as type A hepatic encephalopathy, type B hepatic encephalopathy, type C hepatic encephalopathy, minimal hepatic encephalopathy, overt hepatic encephalopathy, in a patient with acute liver failure, or in a patient with chronic liver disease with or without acute-on-chronic liver failure. In another embodiment of the invention, said compound for use is provided before, during or after a liver transplantation. In another embodiment of the invention, there is provided a pharmaceutical composition comprising 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, for use in treatment of hepatic encephalopathy, together with one or more pharmaceutically acceptable carriers, excipients and/or diluents. In another aspect of the invention, there is provided a method of treating hepatic encephalopathy, comprising administering a pharmaceutically effective amount of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, to a patient in need thereof. In one embodiment of the invention, said hepatic encephalopathy is type A hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is type B hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is type C hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is minimal hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is overt hepatic encephalopathy. In another embodiment of the invention, said patient suffers from acute liver failure. In another embodiment of the invention, said patient suffers from chronic liver disease with or without acute-on-chronic liver failure. In another embodiment of the invention, said compound is provided before, during or after a liver transplantation. In another embodiment of the invention, there is provided a method of preventing or alleviating hepatic encephalopathy, comprising administering a pharmaceutically effective amount of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, to a patient in need thereof. Said hepatic encephalopathy may be type A hepatic encephalopathy, type B hepatic encephalopathy, type C hepatic encephalopathy, minimal hepatic encephalopathy or overt hepatic encephalopathy. Further, said prevention may be in a patient with acute liver failure, or in a patient with chronic liver disease with or without acute-on-chronic liver failure. In a another aspect of the invention, there is provided the compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, for use in treatment of portal hypertension. Said use may also be prevention or alleviation of portal hypertension. The patient with portal hypertension typically suffers from a liver disease, such as a chronic liver disease, cirrhosis or acute liver failure. In another aspect of the invention, there is provided a method of treating portal hypertension, comprising administering a pharmaceutically effective amount of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, to a patient in need thereof. Said method may also be in prevention or alleviation of portal hypertension. The patient with portal hypertension typically suffers from a liver disease, such as a chronic liver disease, cirrhosis or acute liver failure. In a another aspect of the invention, there is provided the compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, for use in treatment of liver decompensation. Said use may also be prevention or alleviation of liver decompensation. The patient with liver decompensation typically suffers from a liver disease, such as a chronic liver disease or may be suspected of having a precipitating event, such as gastrointestinal bleeding, infection, portal vein thrombosis or dehydration. In another aspect of the invention, there is provided a method of treating liver decompensation, comprising administering a pharmaceutically effective amount of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, to a patient in need thereof. Said method may also be in prevention or alleviation of liver decompensation. The patient with liver decompensation typically suffers from a liver disease, such as a chronic liver disease or may be suspected of having a precipitating event, such as gastrointestinal bleeding, infection, portal vein thrombosis or dehydration. In a another aspect of the invention, there is provided use of the compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating hepatic encephalopathy. In one embodiment of the invention, said hepatic encephalopathy is type A hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is type B hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is type C hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is minimal hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is overt hepatic encephalopathy. In another embodiment of the invention, said use is where said hepatic encephalopathy is treated in a patient with acute liver failure. In another embodiment of the invention, said use is where said hepatic encephalopathy is treated in a patient with chronic liver disease with or without acute-on-chronic liver failure. In another embodiment of the invention, said use is provided before, during or after a liver transplantation. In another embodiment of the invention, said use of the compound 3α-ethynyl-3-β-hydroxyandrostan-17-one oxime, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament, may be for prevention or alleviation of hepatic encephalopathy, such as type A hepatic encephalopathy, type B hepatic encephalopathy, type C hepatic encephalopathy, minimal hepatic encephalopathy, overt hepatic encephalopathy, in a patient with acute liver failure, or in a patient with chronic liver disease with or without acute-on-chronic liver failure. In another embodiment of this aspect, there is provided a pharmaceutical composition comprising 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, for use in treatment of hepatic encephalopathy, together with pharmaceutically acceptable carriers, excipients and or diluents. Said use may also be in prevention or alleviation of hepatic encephalopathy. In further aspect of the invention, is the compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof for use in inhibiting or treating symptoms caused by hyperammonemia. A further embodiment of the invention is the compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime for use in the treatment or prevention of hepatic encephalopathy, such as type A hepatic encephalopathy, type B hepatic encephalopathy, type C hepatic encephalopathy, minimal hepatic encephalopathy, overt hepatic encephalopathy, in a patient with acute liver failure, or in a patient with chronic liver disease with or without acute-on-chronic liver failure; wherein said treatment or prevention comprises the co-administration of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime, or a pharmaceutically acceptable salt thereof, with an ammonia-lowering compound, such as rifaximin, lactulose, ornithine phenylacetate and glycerol phenylbutyrate, preferably the ammonia-lowering compound is rifaximin or lactulose, and most preferably the ammonia-lowering compound is rifaximin. A further embodiment of the invention is a method of treatment or prevention of hepatic encephalopathy, such as type A hepatic encephalopathy, type B hepatic encephalopathy, type C hepatic encephalopathy, minimal hepatic encephalopathy, overt hepatic encephalopathy, in a patient with acute liver failure, or in a patient with chronic liver disease with or without acute-on-chronic liver failure; wherein said treatment or prevention comprises the co-administration of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime, or a pharmaceutically acceptable salt thereof, with an ammonia-lowering compound, such as rifaximin, lactulose, ornithine phenylacetate and glycerol phenylbutyrate, preferably the ammonia-lowering compound is rifaximin or lactulose, and most preferably the ammonia-lowering compound is rifaximin. A further embodiment of the invention is the use of the compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime in the manufacture of a medicament for the treatment or prevention of hepatic encephalopathy, such as type A hepatic encephalopathy, type B hepatic encephalopathy, type C hepatic encephalopathy, minimal hepatic encephalopathy, overt hepatic encephalopathy, in a patient with acute liver failure, or in a patient with chronic liver disease with or without acute-on-chronic liver failure; wherein said treatment or prevention comprises the co-administration of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime, or a pharmaceutically acceptable salt thereof, with an ammonia-lowering compound, such as rifaximin, lactulose, ornithine phenylacetate and glycerol phenylbutyrate, preferably the ammonia-lowering compound is rifaximin or lactulose, and most preferably the ammonia-lowering compound is rifaximin. A further aspect of the invention is the compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime, wherein one or more hydrogen atom in each possible substituent position may be substituted for deuterium or tritium, for use in the treatment of hepatic encephalopathy such as minimal hepatic encephalopathy or overt hepatic encephalopathy. A further aspect of the invention is the compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime, wherein one or more hydrogen atom in each possible substituent position may be substituted for deuterium or tritium, for use assays that involve determining the concentration of the compound in tissue or fluids. According to the present invention, 3α-ethynyl-3β-hydroxyandrostan-17-one oxime may be administered through one of the following routes of administration: intravenously, nasally, per rectum, bucally, intravaginally, percutaneously, intramuscularly and orally. According to one embodiment, 3α-ethynyl-3β-hydroxyandrostan-17-one oxime is administered intravenously. According to another embodiment, 3α-ethynyl-3β-hydroxyandrostan-17-one oxime is administered nasally. Percutaneous administration, using 3α-ethynyl-3β-hydroxyandrostan-17-one oxime formulated as a cream, a gel, and an ointment or in the form of slow-release adhesive medicine patches, is another possible form of administration, similarly suitable for self-medication. The pharmaceutical composition may be adapted or adjusted according to normal pharmacological procedures, comprising the effective pharmaceutical in a chemical form, suitable for the chosen route, together with suitable adjuvants, carriers, diluents and vehicles, conventionally used and well-known to a person skilled in the art. Conventionally used adjuvants and vehicles for oral administration are for example fillers or suspending agents like titanium dioxide, lactose anhydride, silica, silica colloidalis, methylcellulose, magnesium stearate, microcrystalline cellulose and the like. Conventionally used adjuvants and vehicles for intravenous administration are for example sterile water for injections (WFI), sterile buffers (for example buffering the solution to pH 7,4) albumin solution, lipid solutions, cyclodextrins and the like. Conventionally used adjuvants and vehicles for transdermal administration are for example Vaseline, liquid paraffin, glycerol, water, MCT oil, sesame oil, vegetable oils and the like. The dose will naturally vary depending on the mode of administration, the particular condition to be treated or the effect desired, gender, age, weight and health of the patient, as well as possibly other factors, evaluated by the treating physician. The invention will now be described by a number of illustrative, non-limiting examples. Example 1 Synthesis of 3α-ethynyl-3β-hydroxyandrostan-17-one Oxime Step 1: Synthesis of 3α-ethynyl-3β-hydroxyandrostan-17-one 3,17-androstandione (5.0 mmol) was dissolved in 50 mL dry THF at room temperature (rt) under nitrogen. Ethynyl magnesium bromide (1.1 equiv) was added dropwise at rt under stirring and the solution was left stirring overnight at rt under nitrogen flow. The solution was then quenched with saturated NH4Cl(aq) and the aqueous phase extracted with dichloromethane (3×30 mL). The collected organic phases were evaporated under reduced pressure, the resulting yellow oil dissolved in dichloromethane, washed with brine and dried over MgSO4. The solution was reduced under vacuum, and the residue purified by silica flash column chromatography (1:4 diethylether:dichloromethane), typical yields 65%. Eventual traces of byproducts can be eliminated by further recrystallization from diethylether. 1H NMR (400 MHz, CDCl3-d6): δ 2.43 (s, 1H); 2.42 (m, 1H); 2.10-2.04 (m, 2H); 1.02 (m, 1H); 0.86 (s, 3H); 0.83 (s, 3H). Step 2: Synthesis of 3α-ethynyl-3β-hydroxyandrostan-17-one Oxime 3α-ethynyl-3β-hydroxyandrostan-17-one (10 mmol) was dissolved in dichloromethane 5 mL and ethanol 50 mL at room temperature and air atmosphere, in a 250 mL round bottom flask. 4 equiv. of NH2OH hydrochloride and 4 equiv. of sodium acetate were dissolved in 5 mL H2O and then added to the steroid solution. 20 mL of ethanol was added and the mixture put on reflux overnight. The mixture was then cooled and the solvent removed under reduced pressure. The white residue was treated with 50 mL H2O and 50 mL dichloromethane, the aqueous phase extracted with 3×30 mL dichloromethane. The collected organic phases were then dried over MgSO4, filtrated and the solvent removed under reduced pressure. The final residue was purified by silica flash column chromatography dichloromethane:diethyl ether 4:1, typical yields 95-100% (quantitative). 1H NMR (400 MHz, CDCl3-d6): δ 2.51-2.47 (m, 2H); 2.43 (s, 1H); 1.00 (m, 1H); 0.80 (m, 1H); 0.90 (s, 3H), 0.83 (s, 3H). Example 2 Therapeutic Effect of 3α-ethynyl-3β-hydroxyandrostan-17-one Oxime in Animal Model of Hepatic Encephalopathy Treatment and Testing Schedule In this study an animal model of chronic hyperammonemia was used that reproduces many of the cognitive and motor alterations present in hepatic encephalopathy. Rats were fed with ammonia in their food and after two weeks with ammonia enriched food they developed symptoms of hepatic encephalopathy. The beam walking test was made during the 3rd and 4th week of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime treatment while the Morris Water maze test was made during 4th-5th week of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime treatment and the Radial maze test was made during 6th-7th week of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime treatment. The study was divided into two series with animals (male Wistar rats), each series included the following groups; Controls treated with vehicle (CV, n=8 per series), Controls treated with 3α-ethynyl-3β-hydroxyandrostan-17-one oxime (C+GAM, n=8 per series), hyperammonemic rats treated with vehicle (HAV, n=8 per series), hyperammonemic rats treated with 3α-ethynyl-3β-hydroxyandrostan-17-one oxime (HA+GAM, n=8 per series). The once daily treatment with 3α-ethynyl-3β-hydroxyandrostan-17-one oxime at 20 mg/kg or with vehicle was performed with subcutaneous injections of 1 ml/kg around 9 a.m. Treatment started one week after starting with the ammonium containing diet and continued for the whole experimental period. Test article of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime was prepared as a suspension in sesame oil at 20 mg/kg. Spatial Learning in the Radial Maze The Radial maze was designed as a method to assess spatial learning. The apparatus is composed of a central area that gives access to eight equally-sized arms. The arms were 70 cm long and 10 cm wide and the central area was 30 cm in diameter. The maze was made of black Perspex and was elevated 80 cm above de floor. Each arm had lateral walls with a height higher in the side proximal to the central area (30 cm) than in the distal side (5 cm). In the distal extreme of each arm, a recessed cup was installed for positioning the food rewards (Hernandez-Rabaza V. et al 2010). To habituate rats to the maze, the rats were allowed to explore the maze for 10 minutes on two consecutive days in the presence of distal cues (posters and objects of different sizes), which remained in place throughout training. Training in the radial maze was composed of five blocks of three trials each, performed on ten consecutive days. The task involved locating four pellets, each placed at the end of a different arm according to a random configuration. Configurations were specific for each rat and were kept invariable throughout training. The number of spatial reference errors and working memory were calculated and expressed as number of reference and working errors per block. In addition, a learning index was used to evaluate the learning of the task and was defined as number of right choices-reference errors (Hernandez-Rabaza et al. 2010). Results 3α-ethynyl-3β-hydroxyandrostan-17-one oxime restored spatial learning of hyperammonemic rats in the Radial maze. Hyperammonemic rats show reduced spatial learning and perform more working errors in the Radial maze task. Spatial memory was completely restored by 3α-ethynyl-3β-hydroxyandrostan-17-one oxime (FIG. 2). Example 3 Therapeutic Effect of 3α-ethynyl-3β-hydroxyandrostan-17-one Oxime in Animal Model of Hepatic Encephalopathy Treatment and Testing Schedule The treatment and testing schedule was as set out in example 2. Spatial Memory in the Morris Water Maze The maze was designed as a method to assess spatial learning (Morris R. 1984). The test was carried out using a black circular pool (160 cm diameter, 40 cm height) arbitrarily divided into four quadrants. Water opacity was obtained by adding black paint. A transparent Plexiglas platform, 10 cm in diameter, was immersed 2 cm under the water surface at the centre of one quadrant during training sessions (Monfort et al., European Journal of Neuroscience, 2007, 25, 2103-211). The test was carried out as follows; the first day was the pre-training day, rats were put in the water two times for 30 s only to adapt to water. Then the rats were trained to learn the fixed location of the invisible platform during 3 days. Each training trial involved placing the rat into the pool facing the wall at one of the three quadrants lacking the platform. A different starting point was randomly used on each trial. Training consisted of five swims per day. Each animal was allowed a maximum of 120 s to find the platform and was left for 15 s on the platform, if a rat failed to locate the platform within 120 s it was manually guided to the platform by the experimenter. The aim of this test is that the rats learn where the invisible platform is placed and reach it in the shortest time possible. The time, speed and path needed to find the hidden platform was recorded by a video tracking system provided by Viewpoint Company (Viewpoint 2.5, Champagne au Mont D′ Or, France) and used as a measure of learning of the task. After 15 training trial, the platform was removed from the pool, the rats were allowed to swim for 90 s in the pool and the time spent in the quadrant where the platform was positioned during training was recorded. Results 3α-ethynyl-3β-hydroxyandrostan-17-one oxime completely restored spatial memory of hyperammonemic rats in the Morris water maze. Hyperammonemic rats showed reduced memory and needed more time than controls to find the platform (FIG. 3). Example 4 Therapeutic Effect of 3α-ethynyl-3β-hydroxyandrostan-17-one Oxime in Animal Model of Hepatic Encephalopathy Treatment and Testing Schedule The treatment and testing schedule was as set out in example 2. Motor Coordination in the Beam Walking In the beam-walking test rats are trained to traverse an elevated, narrow beam to reach an enclosed escape platform. The beam is made of smooth round wood (20 mm in diameter). The beam is elevated 1 m from the floor. The parameters of motor coordination measured are: footslips (or foot faults) and latency to traverse the beam. (Jover et al., 2006; Carter et al., 2010). To habituate the rat, the experimenter places the rat at the beginning of the beam and helps the rat to cross the beam three times. After that, the test consists of three consecutive trials. The number of times the left or right hind paw slip off the beam was recorded for each trial. Results 3α-ethynyl-3β-hydroxyandrostan-17-one oxime completely reversed motor in-coordination of hyperammonemic rats in the beam-walking test. Hyperammonemic rats showed motor in-coordination (increased number of slips=foot faults) (FIG. 4). Example 5 Concentrations of 3α-ethynyl-3β-hydroxyandrostan-17-one Oxime in Plasma and Brain Tissue after Exogenous Administration Obtaining Plasma Blood was obtained from the tail of the rats (from Example 2) in the end of second week of ammonia treatment and first week of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime treatment and also from the neck during the animal sacrifice. To obtain the plasma it was added EDTA 7.5 nM and centrifuged at 1500 r.p.m during 5 minutes. Ammonia Determination Ammonia concentration in blood samples was measured using the Pocket chem BA (Woodley Equipment Company Ltd, United Kingdom), an ammonia analyzer. The device enables immediate testing and delivers results in 3 minutes and 20 s. It also eliminates the need for pre-processes such as centrifugal separation. Sacrifice Rats were sacrificed by decapitation. One half of the brain including the cerebellum was collected and conserved at −80° C. for determination of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime. Different brain areas (cerebellum, cortex, hippocampus and striatum) were dissected and conserved at −80° C. for possible determination of GAMS. Analysis of 3α-ethynyl-3/3-hydroxyandrostan-17-one Oxime Concentration Collected brain and plasma samples were analyzed for 3α-ethynyl-3β-hydroxyandrostan-17-one oxime concentrations. Plasma and brain samples were thawed at room temperature. Plasma was protein-precipitated with a 3-fold volume with acetonitrile and brain tissue was homogenized with a 1:4 ratio of tissue:PBS (pH 7.4) and then extracted with a 2-fold volume of methanol:acetonitrile (1:1) for 20 min during sonication. Thereafter samples were shaken and centrifuged for 10 min at 10 000×g (Heraeus Pico 17 centrifuge). The supernatant was then diluted with an equal volume of PBS and analyzed. Some samples were reanalyzed as 10-fold dilutions due to too high concentration of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime. The dilutions were made with a solution of 37.5% acetonitrile in PBS buffer. Standards were prepared by spiking blank plasma/brain homogenate into the concentrations 0.5-5 000 ng/ml and otherwise treated as the samples. The determination was made with LC-MS. Results Ammonia determination: 3α-ethynyl-3β-hydroxyandrostan-17-one oxime did not affect blood ammonia levels. Ammonia levels in blood are increased in rats fed the ammonium diet (167±17 μM) compared to control rats (47±3 μM). 3α-ethynyl-3β-hydroxyandrostan-17-one oxime did not affect blood ammonia levels in control rats (55±7 μM) or in hyperammonemic rats (139±15 μM) (FIG. 1). These results are surprising as all earlier studies showing effect on hepatic encephalopathy symptoms have decreased ammonia levels. Determination of 3α-ethynyl-3β-hydroxyandrostan-17-one Oxime after Exposure In the present study the total concentration of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime in plasma was analysed on treatment day five and at the last week of treatment with 3α-ethynyl-3β-hydroxyandrostan-17-one oxime, four hours and 23 hours after injection, respectively. The concentrations of 3α-ethynyl-3β-hydroxy, androstan-17-one oxime in plasma are shown in FIG. 5 and the brain concentrations in FIG. 6. On treatment day five the concentrations of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime were lower 23 hours after injection than 4 hours after injection, while at the last week of treatment similar concentrations of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime were found at both 4 hours and 23 hours in both groups, respectively. In the brain, similar concentrations of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime were found in control (91±4.1 nmol/kg unbound* 3α-ethynyl-3β-hydroxyandrostan-17-one oxime) and in HA rats (106±15.4 nmol/kg unbound* 3α-ethynyl-3β-hydroxyandrostan-17-one oxime), 1-2 h after the last treatment (FIG. 6). The concentrations showed surprising high levels and stable concentrations throughout the 24 hours. *Unbound brain concentration=fraction of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime in the brain that is not bound to carrier protein or brain tissue. Example 6 Ability of 3α-ethynyl-3β-hydroxyandrostan-17-one Oxime to Antagonize the Effect of THDOC but not GABA at the GABAA Receptor. Whole-Cell Voltage-Clamp Electrophysiology with α1β2γ2L and α5β3γ2L GABAA Receptors For electrophysiology measurements the Dynaflow® system with the Resolve chip was used (Cellectricon, Göteborg, Sweden). HEK-293 cells were permanently transfected with vectors including the human CMV promoter for constitutive expression of the human α5, β3, and γ2L GABAA receptor subunits (α5β3γ2L) or the human α1, β2, and γ2L GABAA receptor subunits (α1β2γ2L). The cell lines used were selected for good reactivity to GABA and to THDOC. Before measurements cells were incubated for 15 min at 37° C. in 95% air+5% CO2 in extracellular solution (EC) containing the following: 137 mM NaCl, 5.0 mM KCl, 1.0 mM CaCl2, 1.2 mM MgCl2, 10 mM HEPES, and 10 mM glucose, 0.1% DMSO pH 7.4. Thereafter, detached cells were added to the EC solution in the Dynaflow chip bath. Whole-cell voltage-clamp recordings were made at room temperature (21-23° C., −17 mV with compensation for liquid junction potential as in Haage et al., 2002; Neher, 1992). Command pulses were generate and data collected by PClamp 9.0 software, DigiData 1322A converter, and AxonPatch 200B (Axon Instruments, Foster City, Calif.). Patch electrodes (2-6 MΩ) were filled with intracellular solution (IC) including: 140 mM Cs-gluconate, 3.0 mM NaCl, 1.2 mM MgCl2, 10 mM HEPES, 1.0 mM EGTA, 2 mM Mg-ATP, 0.1% DMSO, pH 7.2. THDOC and 3α-ethynyl-3β-hydroxyandrostan-17-one oxime were dissolved in dimethyl sulfoxide (DMSO) and thereafter diluted with EC solution to include 0.1% DMSO. Different protocols were used for different electrophysiology measurements. As α1β2γ2L-GABAA receptors in vivo are present within the synapse a condition resembling that situation, a short application (40 ms) of a high GABA concentration (30 μM), was used. Contrary, α5β3γ2L-GABAA receptors are present extrasynaptically, thus the conditions used were long exposures (6 s) to a low GABA concentration (0.3 μM). The EC75 concentration of THDOC was used, i.e. 100 nM with studies of α1β2γ2L and 200 nM when α5β3γ2L expressing cells were evaluated. With both cell types a pre-exposure with THDOC or THDOC plus 3α-ethynyl-3β-hydroxyandrostan-17-one was used before application of GABA. Steroid effects in presence of GABA were normalized to controls in order to avoid the effects of inter- and intracellular variation in the measured parameters, each cell was used as its own control and the area under the curve (AUC) was analyzed. Results The effects of 3α-ethynyl-3β-hydroxyandrostan-17-one at the GABAA receptor were studied with electrophysiological measurements on recombinant HEK293-cells expressing human variants of the receptor. The 100 nM THDOC-enhanced activation of the α1β2γ2L GABAA receptor in presence of GABA is shown in FIG. 7. 3α-Ethynyl-3β-hydroxyandrostan-17-one (1 μM) partly antagonises the effect of THDOC at both the α1β2γ2L and the α5β3γ2L subunit variants of the GABAA receptor (FIGS. 8 A and C). With α1β2γ2L receptors 3α-ethynyl-3β-hydroxyandrostan-17-one inhibits 29±4.7% of the THDOC enhancement of GABA (P<0.001) and with the α5β3γ2L receptor the inhibition is 49±4.7% (P<0.001, Table 1). Contrary, 3α-ethynyl-3β-hydroxyandrostan-17-one (1 μM) does not antagonize the GABA-activation of the GABAA receptor (FIGS. 8 B and D). There is no significant effect of 3α-ethynyl-3β-hydroxyandrostan-17-one at either the α1β2γ2L GABAA receptor (−3.1±1.7%, NS) or the α5β3γ2L GABAA receptor (−3.8±1.5%, NS) when GABA is the sole activator of the receptor (Table 1). TABLE 1 Ability of 3α-ethynyl-3β-hydroxyandrostan-17-one (GAMSA) to antagonize THDOC but not GABA at the GABAA receptor. GABAA [GAMSA] [GABA] [THDOC] GAMSA receptor μM μM nM effect P-value α1β2γ2L 1 30 100 −29 ± 4.7% <0.001 1 30 — −3.1 ± 1.7% >0.05, NS α5β3γ2L 1 0.3 200 −49 ± 4.7% <0.001 1 0.3 — −3.8 ± 1.5% >0.05, NS Example 7 Selectivity of 3α-ethynyl-3β-hydroxyandrostan-17-one Over Other Targets and Receptors. The binding of 3α-ethynyl-3β-hydroxyandrostan-17-one was determined for receptors, ion channels and enzymes, including all major classes of neurotransmitter receptors. In total 113 targets were tested in duplicate with 3α-ethynyl-3β-hydroxyandrostan-17-one at 10 μM (Perkin Elmer, Customized screen). Binding activity was defined as greater than or equal to 50% inhibition of ligand binding. Results At 10 μM 3α-ethynyl-3β-hydroxyandrostan-17-one did not show binding activity at any of the studied neurotransmitter related receptors, steroid receptors, or peptide receptors. Example 8 Therapeutic Effect of 3α-ethynyl-3β-hydroxyandrostan-17-one on the Motor Co-Ordination of Rats with HE and Porta-Caval Anastomosis. Treatment and Testing Schedule Chronic Hyperammonemia in Rats. Male Wistar rats (140-160 g) were made hyperammonemic by feeding them a diet containing ammonium acetate (30% by weight) (Felipo et al, European Journal of Biochemistry, 1988, 176, 567-571). Porta-Caval Anastomosis. Male Wistar rats (220-240 g) were anesthetized with isoflurane, and an end-to side porta-caval anastomosis was performed as described by Lee and Fisher (Surgery, 1961, 50, 668-672). Control rats were sham operated; they had the portal vein and inferior vena cava clamped for 10 min. Rats that were subjected to the porta-caval anastomosis procedure are herein referred to as “PCS rats”. Adequate measures were taken to minimize pain and discomfort to the animals. The experiments were approved by the Comite de Experimentación y Bienestar Animal (CEBA) of our Center and were performed in accordance with guidelines of the Directive of the European Commission (2010/63/EU) and Spanish legislation (R.D. 1201/2005 for care and management of experimental animals. Treatment with 3α-ethynyl-3β-hydroxyandrostan-17-one. 3α-ethynyl-3β-hydroxyandrostan-17-one in sesame oil was administered by subcutaneous injections in the back of the rats, once daily. Two different sets of experiments were performed in hyperammonemic rats. In the first set four groups of rats were used: 1) control rats injected with vehicle; 2) hyperammonemic rats injected with vehicle; 3) control rats injected with 20 mg/Kg of 3α-ethynyl-3β-hydroxyandrostan-17-one and 4) hyperammonemic rats injected with 20 mg/Kg of 3α-ethynyl-3β-hydroxyandrostan-17-one. Control rats injected with 3α-ethynyl-3β-hydroxyandrostan-17-one were not included thereafter because no relevant effect was found in these rats. In the second set of experiments five groups of rats were used: 1) control rats injected with vehicle; 2) hyperammonemiac rats injected with vehicle and 3-5) hyperammonemic rats injected with 3, 10 or 20 mg/Kg of 3α-ethynyl-3β-hydroxyandrostan-17-one. In each experiment 6-8 rats per group were used. For the experiments using PCS rats, the following groups of rats were used: 1) Sham rats injected with vehicle; 2) PCS rats injected with vehicle; 3-4) PCS rats injected with 0.7 or 2.5 mg/Kg of 3α-ethynyl-3β-hydroxyandrostan-17-one. The number of rats used in each experiment is either shown in the corresponding Figure or given in the description of the corresponding Figure. Statistical Analysis. The data shown are the mean±SEM of the number of rats indicated in each Figure. Statistical significance was estimated with two-way ANOVA and Bonferroni post-test and with Student's t-test when only one parameter was compared. The analyses were performed using GraphPad PRISM software for Windows (GraphPad software Inc., La Jolla, Calif., USA). Motor Coordination. Beam Walking Test. Motor coordination was tested as described by Gonzalez-Usano et al (ACS Chemical Neuroscience, 2014, 19, 5(2), 100-105) using a wooden beam (20 mm diameter). Rats were made to traverse a one-meter-long wooden beam located approximately one meter above the ground, and the number of foot faults (slips) was recorded by two observers. The rats were trained for the test by being made to traverse the beam up to five times before measurements were recorded. The number of foot faults (slips) is a measure of motor in-coordination. Results 3α-Ethynyl-3β-hydroxyandrostan-17-one was shown to restore motor coordination for both the hyperammonemic and PCS rats. Hyperammonemic rats show motor in-coordination in the beam walking test, with higher (p<0.05) number of slips (1.4±0.1) than control rats (1.0±0.1). Treatment with 3α-ethynyl-3β-hydroxyandrostan-17-one restores motor coordination in hyperammonemic rats (FIG. 9A). The effects were statistically significant for the doses of 3 mg/kg (0.8±0.1 slips, p<0.05) and 20 mg/kg (0.78±0.07 slips, p<0.05). PCS rats also show motor in-coordination in the beam walking test, with higher (p<0.01) number of slips (1.2±0.1) than sham-operated control rats (0.71±0.07). Treatment with 3α-ethynyl-3β-hydroxyandrostan-17-one also restores motor coordination in PCS rats (FIG. 9B). The number of slips for the dose of 0.7 mg/kg was 0.75±0.10 (p<0.05 vs PCS rats). At 2.5 mg/Kg 3α-ethynyl-3β-hydroxyandrostan-17-one also improved motor coordination, returning to values similar to sham rats (0.8±0.1 slips; p vs PCS rats=0.058) (FIG. 9B). Example 9 Therapeutic Effect of 3α-ethynyl-3β-hydroxyandrostan-17-one on the Spatial Memory and Spatial Learning of Rats with HE and Porta-Caval Anastomosis. Treatment and Testing Schedule The treatment and testing schedule were as set out in Example 8. Spatial Memory and Learning in the Morris Water Maze Test. The test was carried out as described by Monfort et al. (European Journal of Neuroscience, 2007, 25, 2103-2111) using a circular pool (160 cm diameter, 40 cm height) arbitrarily divided into four quadrants. After pre-training, the rats were trained to learn the fixed location of the invisible platform over 3 days. Training involved placing the rat into the pool facing the wall in one of the three quadrants lacking the platform. A different starting point was randomly used on each trial. Training consisted of three swims per day. Each animal was allowed a maximum of 120 seconds to find the platform and was left for 20 seconds on the platform. If a rat failed to locate the platform within 120 seconds it was manually guided to the platform by the experimenter. The time needed to find the hidden platform was recorded manually and used as a measure of learning of the task. Spatial memory was assessed 24 hours later by removing the platform and measuring the time spent by the rat in the quadrant where the platform was. Results. 3α-Ethynyl-3β-hydroxyandrostan-17-one was shown to restore spatial memory in the Morris water maze test in hyperammonemic and PCS rats. Hyperammonemic rats showed reduced spatial memory in the Morris water maze. All groups of rats learned to find the platform and the latency to reach it was reduced along the three training days (FIG. 10A). Learning ability was slightly reduced in hyperammonemic rats, which needed more time than control to reach the platform. Spatial memory was significantly reduced (p<0.05) in hyperammonemic rats. In the memory test hyperammonemic rats remained less time (30±2% of the time) in the right quadrant than control rats (39±2% of the time). Treatment with 3α-ethynyl-3β-hydroxyandrostan-17-one restored spatial memory in the Morris water maze in hyperammonemic rats. The percentages of time spent in the correct quadrant were 41±4, 42±5 and 38±3, for 3, 10 and 20 mg/kg doses, respectively (FIG. 10B). PCS rats also showed reduced spatial memory in the Morris water maze. All groups of rats learned to find the platform and the latency to reach it was reduced along the three training days (FIG. 10C). Spatial memory was significantly reduced (p<0.05) in PCS rats. In the memory test PCS rats remained less time (31±3% of the time) in the right quadrant than control rats (41±2% of the time). Treatment with 3α-ethynyl-3β-hydroxyandrostan-17-one restored spatial memory in the Morris water maze in PCS rats. The percentages of time spent in the correct quadrant were 34±4 and 39±3, for 0.7 and 2.5 mg/kg doses, respectively (FIG. 10D). Example 10 Therapeutic Effect of 3α-ethynyl-3β-hydroxyandrostan-17-one on the Spatial Learning of Rats with HE and Porta-Caval Anastomosis. Treatment and Testing Schedule The treatment and testing schedule were as set out in Example 8. Spatial Learning in the Radial Maze Test. The apparatus was composed of a central area that gave access to eight equally-sized arms. The arms were 70 cm long and 10 cm wide and the central area was 30 cm in diameter. The distal extreme of each arm had a cup containing food rewards. Rats were allowed to explore the maze for 10 minutes on two consecutive days in the presence of distal cues to adapt to the maze. Training in the radial maze was composed of three trials per day on six consecutive days. The task involved locating four pellets, each placed at the end of a different arm according to a random configuration as described by Hernandez-Rabaza et al. (Addiction Biology, 2010, 15, 413-423). The number of working memory errors (visits to arms already visited in the same trial) were recorded and expressed as working errors. Results 3α-Ethynyl-3β-hydroxyandrostan-17-one was found to restore spatial learning in the radial maze test. Hyperammonemic rats show reduced spatial learning in the radial maze. As shown in FIG. 11A, the number of working errors was higher in hyperammonemic than in control rats at days 1-3. All groups of rats learned along the training days and the difference between control and hyperammonemic rats was not significant after day 3. (FIG. 11A). The number of working errors in days 1-2 was higher (p<0.05) in hyperammonemic (18±3 errors) than in control rats (11±1.5 errors). Hyperammonemic rats treated with 3α-ethynyl-3β-hydroxyandrostan-17-one behaved as controls. The number of errors (not significantly different from controls) was 6.5±2.8, 8.8±1.9 and 12±2, for 3, 10 and 20 mg/kg doses, respectively (FIG. 11B-C). PCS rats also show reduced spatial learning in the radial maze. As shown in FIG. 11C, the number of working errors was higher in PCS rats than in sham rats at days 1 and 2. All groups of rats learned along the training days and the difference between sham and PCS rats was not significant after day 3. (FIG. 11C). The number of working errors in days 1-2 (FIG. 11D) was higher (p<0.01) in PCS rats (22±2 errors) than in sham rats (10±2 errors). Treatment of PCS rats with 0.7 mg/Kg of 3α-ethynyl-3β-hydroxyandrostan-17-one was not enough to improve performance in the radial maze (23±2 errors). Treatment with 2.5 mg/Kg completely normalized performance of PCS rats in the radial maze (11±1 errors, p<0.05 vs PCS). Example 11 Therapeutic Effect of 3α-ethynyl-3β-hydroxyandrostan-17-one on the Circadian Rhythms and Nocturnal Motor Activity in PCS Rats. Treatment and Testing Schedule The treatment and testing schedule were as set out in Example 8. Circadian Rhythms of Spontaneous Locomotor Activity. Motor activity was measured using an actimeter (Med Associates, S t. Albans, Vt.). Rats were placed individually in an open-field activity chamber (43×43×31 cm), and motor activity was recorded continuously for 14 days in conditions of light-dark (L:D), 12 h:12 h. Data were recorded at intervals of 5 minutes. Motor activity was detected by arrays of infrared motion detectors, placed in three directions, x, y and z. One ambulatory count is recorded by the apparatus when the rat interrupts three consecutive infrared detectors, in x or y position. A vertical count is recorded when rat interrupts infrared detectors in z position. The software allows measuring different parameter of motor activity, such as ambulatory counts or vertical counts (Ahabrach et al. Journal of Neuroscience Research, 2010, 88, 1605-14). Results. 3α-Ethynyl-3β-hydroxyandrostan-17-one was found to increase spontaneous motor activity during the night and to partially restore the circadian rhythm of PCS rats. PCS rats show reduced motor activity (ambulatory counts) during the night (the active phase of the rats) showing 1849±176 counts, which is significantly (p<0.05) lower than in control rats (4546±584 counts). 3α-ethynyl-3β-hydroxyandrostan-17-one at 0.7 mg/kg increased slightly (p<0.05) the activity in PCS rats to 2652±275 counts. 3α-ethynyl-3β-hydroxyandrostan-17-one at 2.5 mg/kg did not affect ambulatory counts (2235±170 counts 3α-ethynyl-3β-hydroxyandrostan-17-one) (FIGS. 12A and 12C). The ratio of ambulatory activity during the night vs activity during the day is reduced in PCS rats, indicating altered circadian rhythm (FIG. 12B). For the control rats this ratio was 3.3±0.4 and was reduced (p<0.001) in PCS rats to 0.8±0.16. PCS rats treated with 3α-ethynyl-3β-hydroxyandrostan-17-one showed a partial but significant improvement (p<0.05) in the night/day ratio of activity, reaching 1.7±0.2 and 1.6±0.3 for 0.7 and 2.5 mg/kg, respectively (FIG. 12B). This indicates partial restoration of circadian rhythm of activity. 3α-Ethynyl-3β-hydroxyandrostan-17-one was also found to normalize vertical activity during the day and to partially restore the circadian rhythm of PCS rats. PCS rats showed reduced vertical activity during the night (the active phase of the rats) showing 561±108 counts, which is significantly (p<0.05) lower than in control rats (1228±138 counts). 3α-Ethynyl-3β-hydroxyandrostan-17-one at 0.7 mg/kg or 2.5 mg/kg did not affect vertical activity during the night (664±121 and 695±185 counts, respectively) (FIGS. 12A and 12C). In contrast, PCS rats showed increased vertical activity during the day showing 682±114 counts, which is significantly (p<0.05) higher than in control rats (391±64 counts). 3α-ethynyl-3β-hydroxyandrostan-17-one at 0.7 mg/kg or 2.5 mg/kg completely normalized vertical activity during the day, reaching 339±47 and 424±44 counts, respectively. (FIGS. 12A and 12C). The ratio of vertical activity during the night vs activity during the day was also reduced in PCS rats, indicating altered circadian rhythm (FIG. 12B). For controls this ratio is 3.7±0.6 and is reduced (p<0.001) in PCS rats to 0.8±0.01. PCS rats treated with 3α-ethynyl-3β-hydroxyandrostan-17-one showed a partial but significant improvement (p<0.01) in the night/day ratio of activity, reaching 2.1±0.4 and 1.9±0.6 for 0.7 and 2.5 mg/kg, respectively (FIG. 12B). This indicates partial restoration of circadian rhythm of vertical activity. Example 12 Effect of 3α-ethynyl-3β-hydroxyandrostan-17-one Treatment on Blood Ammonia Concentration in Hyperammonemic and PCS Rats. Treatment and Testing Schedule The treatment and testing schedule were as set out in Example 8. Determination of Ammonia. Blood ammonia was measured using the kit II Ammonia Arkray test (PocketChem BA, Arkray) using 20 μL of fresh blood following manufacturer's specifications. Results 3α-Ethynyl-3β-hydroxyandrostan-17-one was found not to affect ammonia levels in hyperammonemic and PCS rats. Blood ammonia levels were increased (p<0.001) in hyperammonemic rats 167±16 μM compared to controls (47±3 μM). Treatment with 20 mg/Kg of 3α-ethynyl-3β-hydroxyandrostan-17-one did not affect ammonia levels in hyperammonemic rats (139±14 μM). Similar results were obtained in PCS rats. Blood ammonia levels were increased (p<0.001) in PCS rats (348±27 μM) compared with sham rats (125±31 μM). Treatment with 3α-ethynyl-3β-hydroxyandrostan-17-one did not affect blood ammonia, which remained at 302±30 and 294±37 μM in PCS rats treated with 0.7 and 2.5 mg/Kg of 3α-ethynyl-3β-hydroxyandrostan-17-one, respectively. Example 13 3α-Ethynyl-3β-hydroxyandrostan-17-one Concentration in Plasma and Brain Tissue in Hyperammonemic and PCS Rats after the Treatment Period. Treatment and Testing Schedule The treatment and testing schedule were as set out in Example 8. Analysis of 3α-ethynyl-3β-hydroxyandrostan-17-one Exposure. At the end of the treatment period plasma was collected from the tail vein, and after sacrifice by decapitation brains were collected and immediately frozen on dry ice. For analysis of 3α-ethynyl-3β-hydroxyandrostan-17-one exposure, brain tissue was homogenized with a 1:4 ratio of tissue:PBS (pH 7.4) and then extracted with a 2-fold volume of methanol:acetonitrile (1:1), while plasma was protein-precipitated with a 3-fold volume with acetonitrile. Analyses were performed by Waters ACQUITY UPLC+Waters XEVO-TQS triple quadrupole mass spectrometer (Admescope Oy, Oulu, Finland). For calculations of the amount of free 3α-ethynyl-3β-hydroxyandrostan-17-one exposure in the brain the fraction unbound (Fub) in brain homogenates were determined by dialysis, Fub in HA=0.70 and Fub in PCS=1.43% (Admescope Oy, Oulu, Finland). Results In hyperammonemic rats the once-daily administration of 3α-ethynyl-3β-hydroxyandrostan-17-one at 3, 10 and 20 mg/Kg resulted in a dose-dependent exposure in both plasma and in brain tissue. At the time for the behavioral testing the total concentrations of 3α-ethynyl-3β-hydroxyandrostan-17-one in plasma were 0.34±0.03, 1.08±0.11, 1.95±0.61 μM, respectively, and in the brain tissue the unbound concentrations of 3α-ethynyl-3β-hydroxyandrostan-17-one were 6.1±1.4, 11.6±1.4, 23±5 nmol/kg, respectively, (FIG. 14A). Also in PCS rats the exposures were dose-dependent and with the lower doses used in these rats, 0.7 and 2.5 mg/Kg, the exposures were very similar to those in the hyperammonemic rats. Total concentrations in plasma were 0.48±0.09, and 1.64±0.30 μM, at 0.7 and 2.5 mg/kg/day respectively, and unbound concentrations in the brain were 6.18±0.97, and 17±2 nmol/kg, respectively, at the time for the behavioral testing.
<SOH> BACKGROUND OF THE INVENTION <EOH>Hepatic encephalopathy (HE) is a serious neuropsychiatric and neurocognitive complication in acute and chronic liver disease. HE is a significant and increasing health care problem due to the large and increasing prevalence of chronic liver disease. HE is characterized by impairments of the sleep-wake cycle, cognition, memory, learning, motor coordination, consciousness, decreased energy levels and personality change, ranging from minimal HE (MHE) to overt HE (OHE). MHE is manifested with cognitive impairment and has detrimental effects on health related quality of life and the ability to perform complex tasks such as driving. In addition, OHE is clinically manifested with mental and motor disorders and the symptoms ranges from disorientation through sedation and coma. Naturally occurring steroids are subject to intense metabolism and are typically not suitable for oral administration. The metabolites of the endogenous steroid hormones pregnenolone, progesterone, deoxycorticosterone, cortisone and cortisol, known as pregnanolones as well as the metabolites of testosterone, androstenedione and dehydroepiandrosterone, have all been the subject of various studies, at least partially elucidating their role in the neurological signal system in mammals. The steroid metabolites induce CNS symptoms and disorders and steroids act as positive modulators on the gamma-aminobutyric acid receptor-chloride ionophore (GABA A -R) complex and are therefore called GABA A receptor modulating steroids (GAMS). Certain steroids have been shown to be specific GABA A receptor enhancers. Examples of these steroids can inter alia be found in WO 2008/063128. Some of these steroids are potent and have e.g. been shown to have an ability to induce amnesia, sedation and anesthesia in pharmacological dose. WO 99/45931 and WO 03/059357 disclose antagonistic effects of steroids. Wang et al. 2000 (Acta Physiol Scand 169, 333-341) and Wang et al. 2002 (J Neurosci 22(9):3366-75) disclose antagonistic effects of 3β-OH-5α-pregnan-20-one and other 3β-OH-5α/β pregnan steroids. WO2006/056794 and WO2010/144498 discloses use of compounds for treatment of liver decompensation, hepatic encephalopathy and portal hypertension. There is a need to provide new and effective therapeutic treatments for hepatic encephalopathy and related disorders
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 shows that 3α-ethynyl-3β-hydroxyandrostan-17-one oxime does not affect blood ammonia levels. Values are the mean±SEM of 12 rats per group, values significantly different from controls are indicated by asterisks; ***, p<0.001. CV=control rats treated with vehicle; HAV=hyperammonemic rats treated with vehicle; HA+GAM=hyperammonemic rats treated with 3α-ethynyl-3β-hydroxyandrostan-17-one oxime. FIG. 2 shows that 3α-ethynyl-3β-hydroxyandrostan-17-one oxime restores spatial learning of hyperammonemic rats in the Radial maze. The figure shows working errors in the radial test. Working errors in block 1. Values are the mean±SEM of 8 rats per group. # p<0.05 versus HAV. CV=control rats treated with vehicle; HAV=hyperammonemic rats treated with vehicle; HA+GAM=hyperammonemic rats treated with 3α-ethynyl-3β-hydroxyandrostan-17-one oxime. FIG. 3 shows that 3α-ethynyl-3β-hydroxyandrostan-17-one oxime, in the Morris water maze test, restores special memory of hyperammonemic rats. The figure shows the time to find the platform on the first trial of day 3. Values are the mean±SEM of 8 rats per group. HAV versus CV p=0.052. CV=control rats treated with vehicle; HAV=hyperammonemic rats treated with vehicle; HA+GAM=hyperammonemic rats treated with 3α-ethynyl-3β-hydroxyandrostan-17-one oxime. FIG. 4 shows that 3α-ethynyl-3β-hydroxyandrostan-17-one oxime restores motor coordination of hyperammonemic rats. Values are the mean±SEM of 15 rats per group. Values significantly different from CV are indicated by *, p<0.05, values significantly different from HAV are indicated by ###, p<0.001. CV=control rats treated with vehicle; HAV=hyperammonemic rats treated with vehicle; HA+GAM=hyperammonemic rats treated with 3α-ethynyl-3β-hydroxyandrostan-17-one oxime. FIG. 5 shows total plasma 3α-ethynyl-3β-hydroxyandrostan-17-one oxime concentrations. Total plasma 3α-ethynyl-3β-hydroxyandrostan-17-one oxime concentrations in control and hyperammonemic rats 4 and 23 hours after the subcutaneous injection of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime on day five and during the last week of treatment with daily injections. HA=Hyper ammonia animals. FIG. 6 provides unbound* brain 3α-ethynyl-3β-hydroxyandrostan-17-one oxime concentrations in control and hyperammonemic rats 1-2 hours after the s.c. injection of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime after seven weeks with daily injections of 20 mg/kg. *Unbound brain concentration=fraction of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime in the brain that is not bound to carrier protein or brain tissue. FIG. 7 provides representative electrophysiological measurements showing tetrahydrodeoxycorticosterone (THDOC) enhanced activation of α1β2γ2L GABA A receptors. HEK-293 cells expressing human α1β2γ2L GABA A receptors were exposed to 30 μM GABA or 30 μM GABA plus 100 nM THDOC for 40 ms. With THDOC there was a 20 s pre-incubation before application of THDOC+GABA. FIG. 8 provides representative electrophysiological measurements showing 3α-ethynyl-3β-hydroxyandrostan-17-one (GAMSA) antagonism of the THDOC enhanced activation of α1β2γ2L and α5β3γ2L GABA A receptors and no inhibition of GABA. A) 1 μM 3α-ethynyl-3β-hydroxyandrostan-17-one antagonism of the 100 nM THDOC enhanced activation of 30 μM GABA with the α1β2γ2L GABA A receptor, B) 1 μM 3α-ethynyl-3β-hydroxyandrostan-17-one does not antagonize the 30 μM GABA activation of the α1β2γ2L GABA A receptor C) 1 μM 3α-ethynyl-3β-hydroxyandrostan-17-one antagonism of the 200 nM THDOC enhanced activation of 0.3 μM GABA with the α5β3γ2L GABA A receptor; indicating antagonism of THDOC's effect D) 1 μM 3α-ethynyl-3β-hydroxyandrostan-17-one does not antagonize the 0.3 μM GABA activation of the α5β3γ2L GABA A receptor. FIG. 9 illustrates the ability of 3α-ethynyl-3β-hydroxyandrostan-17-one to restore motor coordination in hyperammonemic and PCS rats. Motor coordination was assessed using the beam walking test. (A) shows the data for control (CV) or hyperammonemic (HAV) rats treated with vehicle and for hyperammonemic rats treated with 3 (HA3), 10 (HA10) or 20 (HA20) mg/kg of 3α-ethynyl-3β-hydroxyandrostan-17-one. (B) shows the data for sham-operated controls (SM) or PCS rats treated with vehicle and for PCS rats treated with 0.7 (PCS0.7) or 2.5 (PCS2.5) mg/kg of 3α-ethynyl-3β-hydroxyandrostan-17-one. Values are the mean±SEM of the number of rats indicated under each bar. Values significantly different from control or sham rats are indicated by asterisks. Values significantly different from hyperammonemic or PCS rats treated with vehicle are indicated by “a”. * p<0.05; a p<0.05; aa p<0.01; aaa p<0.001. FIG. 10 illustrates the ability of 3α-ethynyl-3β-hydroxyandrostan-17-one to restore spatial memory in the Morris water maze in hyperammonemic and PCS rats. Spatial learning memory in the Morris water maze was assessed in control (CV) or hyperammonemic (HAV) rats treated with vehicle and for hyperammonemic rats treated with 3 (HA3), 10 (HA10) or 20 (HA20) mg/kg of 3α-ethynyl-3β-hydroxyandrostan-17-one (A, B) and in sham-operated controls (SM) or PCS rats treated with vehicle and for PCS rats treated with 0.7 (PCS0.7) or 2.5 (PCS2.5) mg/kg of 3α-ethynyl-3β-hydroxyandrostan-17-one (C,D). (A,C) Escape latencies (in seconds) to reach the platform during the different sessions. (B,D) Time spent (%) in the correct quadrant during the memory test. Values are the mean±SEM of the number of rats indicated under each bar. Values significantly different from control or sham rats are indicated by asterisks. Values significantly different from hyperammonemic or PCS rats treated with vehicle are indicated by “a”. * p<0.05; a p<0.05. FIG. 11 illustrates the ability of 3α-ethynyl-3β-hydroxyandrostan-17-one to restore spatial learning in the radial maze in hyperammonemic and PCS rats. Spatial learning in the radial maze was assessed in control (CV) or hyperammonemic (HAV) rats treated with vehicle and for hyperammonemic rats treated with 3 (HA3), 10 (HA10) or 20 (HA20) mg/kg of 3α-ethynyl-3β-hydroxyandrostan-17-one (A, B) and in sham-operated controls (SM) or PCS rats treated with vehicle and for PCS rats treated with 0.7 (PCS0.7) or 2.5 (PCS2.5) mg/kg of 3α-ethynyl-3β-hydroxyandrostan-17-one (C,D). (A,C) Working errros during the different sessions. (B,D) Working errors during days 1-2. Values are the mean±SEM of the number of rats indicated under each bar. Values significantly different from control or sham rats are indicated by asterisks. Values significantly different from hyperammonemic or PCS rats treated with vehicle are indicated by “a”. * p<0.05; a p<0.05; aa p<0.01. FIG. 12 illustrates the ability of 3α-ethynyl-3β-hydroxyandrostan-17-one to increase spontaneous motor activity during the night and partially restore the circadian rhythm of PCS rats. Motor activity was assessed in sham-operated controls (SM) or PCS rats treated with vehicle or with 0.7 (PCS0.7) or 2.5 (PCS2.5) mg/kg of 3α-ethynyl-3β-hydroxyandrostan-17-one. Motor activity during each hour is shown in A; the ratio of activity during the night and during the day in B and the total activity during the day or the night in C. Lights are turned off at 7:00 pm. Values are the mean±SEM of 8 rats per group. Values significantly different from SM rats are indicated by asterisks; * p<0.05; ** p<0.01; *** p<0.001. Values significantly different from PCS rats are indicated by a; a p<0.05. FIG. 13 illustrates the ability of ethynyl-3β-hydroxyandrostan-17-one to normalize vertical activity during the day and to partially restore the circadian rhythm of PCS rats. The experiment was carried out as described for FIG. 12 but vertical counts are shown. Values are the mean±SEM of 8 rats per group. Values significantly different from SM rats are indicated by asterisks; * p<0.05; ** p<0.01; *** p<0.001. Values significantly different from PCS rats are indicated by a; a p<0.05; aa p<0.01. FIG. 14 shows ethynyl-3β-hydroxyandrostan-17-one exposure in the plasma and in the brain at time at behavioral testing, in hyperammonemic and PCS rats. In A) hyperammonemic rats and B) PCS rats, the total plasma concentrations of ethynyl-3β-hydroxyandrostan-17-one are shown in μM. In C) hyperammonemic rats and D) PCS rats, the unbound brain concentrations of ethynyl-3β-hydroxyandrostan-17-one are shown in nmol/kg. Note the similar exposures in the different rat models with the doses used, in hyperammonemic rats 3, 10 and 20 mg/kg/day and in rats with PCS 0.7 and 2.5 mg/kg/day. Data are from the end of the study, i.e. after nine weeks of daily treatments with ethynyl-3β-hydroxyandrostan-17-one in sesame oil given s.c. once daily. detailed-description description="Detailed Description" end="lead"? Before the present invention is described in detail, it is to be understood that the terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting. It is noted that, as used in this specification and the appended claims, the singular forms “a”, “an”, and “the” also include plural referents unless the context clearly dictates otherwise. The term “pharmaceutical composition” is used in its widest sense, encompassing all pharmaceutically applicable compositions containing at least one active substance and optional carriers, adjuvants, diluents, constituents etc. The terms “administration” and “mode of administration” as well as “route of administration” are also used in their widest sense. The compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime as used in accordance with the invention may be administered in a number of ways depending largely on whether a local, topical or systemic mode of administration is most appropriate for the hepatic encephalopathy condition to be treated. These different modes of administration are for example topical (e.g., on the skin), local (including ophthalmic and to various mucous membranes, for example vaginal and rectal delivery), oral, parenteral or pulmonary, including the upper and lower airways. The preparation of such compositions and formulations is generally known to those skilled in the pharmaceutical and formulation arts and may be applied to the formulation of the composition of the present invention. With the term “antagonist” is meant a substance that hinders another substance, an agonist, to induce its effect. In this application the terms antagonist and blocker are used interchangeably. With the term “Type A hepatic encephalopathy” is typically meant hepatic encephalopathy associated with acute liver failure, typically associated with cerebral oedema. With the term “Type B hepatic encephalopathy” is typically meant hepatic encephalopathy (bypass) caused by portal-systemic shunting without associated intrinsic liver disease. With the term “Type C hepatic encephalopathy” is typically meant hepatic encephalopathy occurring in patients with cirrhosis—this type is subdivided in episodic, persistent and minimal encephalopathy. With the term “minimal hepatic encephalopathy” is typically meant hepatic encephalopathy that does not lead to clinically overt cognitive dysfunction, but can be demonstrated with neuropsychological studies. With the term “overt hepatic encephalopathy” is typically meant clinically apparent hepatic encephalopathy manifested as neuropsychiatric syndrome with a large spectrum of mental and motor disorders. Overt hepatic encephalopathy may arise episodically, over a period of hours or days in patients previously stable or patients may present with persistent neuropsychiatric abnormalities. With the term “hyperammonemia” is typically meant a metabolic disturbance characterized by an excess of ammonia in the blood. With the term “liver transplantation” is typically meant a surgical procedure to remove a diseased liver as a consequence of e.g. acute liver failure or cirrhosis, and replace it with a healthy liver from a donor. Most liver transplant operations use livers from deceased donors but a liver may also come from a living donor (a portion of a healthy person's liver). Patients with e.g. cirrhosis commonly experience hepatic encephalopathy and preoperative hepatic encephalopathy is a significant predictor of post-transplant neurologic complications. With the term “acute-on-chronic liver failure” is typically meant acute decompensation of cirrhosis, at least one organ failure, or belongs to a subgroup with high short-term mortality rate. With the term “compensated cirrhosis” is typically meant liver cirrhosis without any clinical evidence but may include asymptotic esophageal or gastric varices and early symptoms such as fatigue and loss of energy, loss of appetite and weight loss, nausea or abdominal pain. With the term “decompensated cirrhosis” is typically meant advanced liver cirrhosis with a range of clinical evidence such as jaundice, ascites, oedema, hepatic encephalopathy, gastrointestinal haemorrhage, portal hypertension, bacterial infections, or any combination. With the term “portal hypertension” is typically meant a hepatic venous pressure gradient following liver cirrhosis, with or without associated transjugular intrahepatic portsystemic shunt (TIPS). With the term “prevention” within this disclosure, is typically meant prevention of disease or disorder hepatic encephalopathy to occur. With the term “alleviation” within this disclosure, is typically meant reduction of or freedom from the disease or disorder hepatic encephalopathy. Patients suffering from hepatic encephalopathy may show symptoms including, but not limited to, impairments of the sleep-wake cycle, cognition, memory, learning, motor coordination, consciousness, decreased energy levels and personality change, cognitive impairment, disorientation and coma. The present inventors have surprisingly shown that 3α-ethynyl-3β-hydroxyandrostan-17-one oxime may be useful for the treatment of hepatic encephalopathy. In a first aspect of the invention, there is provided the compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, for use in treatment of hepatic encephalopathy. In one embodiment of the invention, said hepatic encephalopathy is type A hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is type B hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is type C hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is minimal hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is overt hepatic encephalopathy. In another embodiment of the invention, said compound for use is where said hepatic encephalopathy is treated in a patient with acute liver failure. In another embodiment of the invention, said compound for use is where said hepatic encephalopathy is treated in a patient with chronic liver disease with or without acute-on-chronic liver failure. In another embodiment of the invention, said compound for use is for prevention or alleviation of hepatic encephalopathy, such as type A hepatic encephalopathy, type B hepatic encephalopathy, type C hepatic encephalopathy, minimal hepatic encephalopathy, overt hepatic encephalopathy, in a patient with acute liver failure, or in a patient with chronic liver disease with or without acute-on-chronic liver failure. In another embodiment of the invention, said compound for use is provided before, during or after a liver transplantation. In another embodiment of the invention, there is provided a pharmaceutical composition comprising 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, for use in treatment of hepatic encephalopathy, together with one or more pharmaceutically acceptable carriers, excipients and/or diluents. In another aspect of the invention, there is provided a method of treating hepatic encephalopathy, comprising administering a pharmaceutically effective amount of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, to a patient in need thereof. In one embodiment of the invention, said hepatic encephalopathy is type A hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is type B hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is type C hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is minimal hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is overt hepatic encephalopathy. In another embodiment of the invention, said patient suffers from acute liver failure. In another embodiment of the invention, said patient suffers from chronic liver disease with or without acute-on-chronic liver failure. In another embodiment of the invention, said compound is provided before, during or after a liver transplantation. In another embodiment of the invention, there is provided a method of preventing or alleviating hepatic encephalopathy, comprising administering a pharmaceutically effective amount of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, to a patient in need thereof. Said hepatic encephalopathy may be type A hepatic encephalopathy, type B hepatic encephalopathy, type C hepatic encephalopathy, minimal hepatic encephalopathy or overt hepatic encephalopathy. Further, said prevention may be in a patient with acute liver failure, or in a patient with chronic liver disease with or without acute-on-chronic liver failure. In a another aspect of the invention, there is provided the compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, for use in treatment of portal hypertension. Said use may also be prevention or alleviation of portal hypertension. The patient with portal hypertension typically suffers from a liver disease, such as a chronic liver disease, cirrhosis or acute liver failure. In another aspect of the invention, there is provided a method of treating portal hypertension, comprising administering a pharmaceutically effective amount of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, to a patient in need thereof. Said method may also be in prevention or alleviation of portal hypertension. The patient with portal hypertension typically suffers from a liver disease, such as a chronic liver disease, cirrhosis or acute liver failure. In a another aspect of the invention, there is provided the compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, for use in treatment of liver decompensation. Said use may also be prevention or alleviation of liver decompensation. The patient with liver decompensation typically suffers from a liver disease, such as a chronic liver disease or may be suspected of having a precipitating event, such as gastrointestinal bleeding, infection, portal vein thrombosis or dehydration. In another aspect of the invention, there is provided a method of treating liver decompensation, comprising administering a pharmaceutically effective amount of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, to a patient in need thereof. Said method may also be in prevention or alleviation of liver decompensation. The patient with liver decompensation typically suffers from a liver disease, such as a chronic liver disease or may be suspected of having a precipitating event, such as gastrointestinal bleeding, infection, portal vein thrombosis or dehydration. In a another aspect of the invention, there is provided use of the compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating hepatic encephalopathy. In one embodiment of the invention, said hepatic encephalopathy is type A hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is type B hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is type C hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is minimal hepatic encephalopathy. In another embodiment of the invention, said hepatic encephalopathy is overt hepatic encephalopathy. In another embodiment of the invention, said use is where said hepatic encephalopathy is treated in a patient with acute liver failure. In another embodiment of the invention, said use is where said hepatic encephalopathy is treated in a patient with chronic liver disease with or without acute-on-chronic liver failure. In another embodiment of the invention, said use is provided before, during or after a liver transplantation. In another embodiment of the invention, said use of the compound 3α-ethynyl-3-β-hydroxyandrostan-17-one oxime, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament, may be for prevention or alleviation of hepatic encephalopathy, such as type A hepatic encephalopathy, type B hepatic encephalopathy, type C hepatic encephalopathy, minimal hepatic encephalopathy, overt hepatic encephalopathy, in a patient with acute liver failure, or in a patient with chronic liver disease with or without acute-on-chronic liver failure. In another embodiment of this aspect, there is provided a pharmaceutical composition comprising 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof, for use in treatment of hepatic encephalopathy, together with pharmaceutically acceptable carriers, excipients and or diluents. Said use may also be in prevention or alleviation of hepatic encephalopathy. In further aspect of the invention, is the compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof for use in inhibiting or treating symptoms caused by hyperammonemia. A further embodiment of the invention is the compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime for use in the treatment or prevention of hepatic encephalopathy, such as type A hepatic encephalopathy, type B hepatic encephalopathy, type C hepatic encephalopathy, minimal hepatic encephalopathy, overt hepatic encephalopathy, in a patient with acute liver failure, or in a patient with chronic liver disease with or without acute-on-chronic liver failure; wherein said treatment or prevention comprises the co-administration of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime, or a pharmaceutically acceptable salt thereof, with an ammonia-lowering compound, such as rifaximin, lactulose, ornithine phenylacetate and glycerol phenylbutyrate, preferably the ammonia-lowering compound is rifaximin or lactulose, and most preferably the ammonia-lowering compound is rifaximin. A further embodiment of the invention is a method of treatment or prevention of hepatic encephalopathy, such as type A hepatic encephalopathy, type B hepatic encephalopathy, type C hepatic encephalopathy, minimal hepatic encephalopathy, overt hepatic encephalopathy, in a patient with acute liver failure, or in a patient with chronic liver disease with or without acute-on-chronic liver failure; wherein said treatment or prevention comprises the co-administration of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime, or a pharmaceutically acceptable salt thereof, with an ammonia-lowering compound, such as rifaximin, lactulose, ornithine phenylacetate and glycerol phenylbutyrate, preferably the ammonia-lowering compound is rifaximin or lactulose, and most preferably the ammonia-lowering compound is rifaximin. A further embodiment of the invention is the use of the compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime in the manufacture of a medicament for the treatment or prevention of hepatic encephalopathy, such as type A hepatic encephalopathy, type B hepatic encephalopathy, type C hepatic encephalopathy, minimal hepatic encephalopathy, overt hepatic encephalopathy, in a patient with acute liver failure, or in a patient with chronic liver disease with or without acute-on-chronic liver failure; wherein said treatment or prevention comprises the co-administration of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime, or a pharmaceutically acceptable salt thereof, with an ammonia-lowering compound, such as rifaximin, lactulose, ornithine phenylacetate and glycerol phenylbutyrate, preferably the ammonia-lowering compound is rifaximin or lactulose, and most preferably the ammonia-lowering compound is rifaximin. A further aspect of the invention is the compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime, wherein one or more hydrogen atom in each possible substituent position may be substituted for deuterium or tritium, for use in the treatment of hepatic encephalopathy such as minimal hepatic encephalopathy or overt hepatic encephalopathy. A further aspect of the invention is the compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime, wherein one or more hydrogen atom in each possible substituent position may be substituted for deuterium or tritium, for use assays that involve determining the concentration of the compound in tissue or fluids. According to the present invention, 3α-ethynyl-3β-hydroxyandrostan-17-one oxime may be administered through one of the following routes of administration: intravenously, nasally, per rectum, bucally, intravaginally, percutaneously, intramuscularly and orally. According to one embodiment, 3α-ethynyl-3β-hydroxyandrostan-17-one oxime is administered intravenously. According to another embodiment, 3α-ethynyl-3β-hydroxyandrostan-17-one oxime is administered nasally. Percutaneous administration, using 3α-ethynyl-3β-hydroxyandrostan-17-one oxime formulated as a cream, a gel, and an ointment or in the form of slow-release adhesive medicine patches, is another possible form of administration, similarly suitable for self-medication. The pharmaceutical composition may be adapted or adjusted according to normal pharmacological procedures, comprising the effective pharmaceutical in a chemical form, suitable for the chosen route, together with suitable adjuvants, carriers, diluents and vehicles, conventionally used and well-known to a person skilled in the art. Conventionally used adjuvants and vehicles for oral administration are for example fillers or suspending agents like titanium dioxide, lactose anhydride, silica, silica colloidalis, methylcellulose, magnesium stearate, microcrystalline cellulose and the like. Conventionally used adjuvants and vehicles for intravenous administration are for example sterile water for injections (WFI), sterile buffers (for example buffering the solution to pH 7,4) albumin solution, lipid solutions, cyclodextrins and the like. Conventionally used adjuvants and vehicles for transdermal administration are for example Vaseline, liquid paraffin, glycerol, water, MCT oil, sesame oil, vegetable oils and the like. The dose will naturally vary depending on the mode of administration, the particular condition to be treated or the effect desired, gender, age, weight and health of the patient, as well as possibly other factors, evaluated by the treating physician. The invention will now be described by a number of illustrative, non-limiting examples.
A61K31568
20170927
20180118
96712.0
A61K31568
0
BERRY, LAYLA D
STEROID COMPOUND FOR USE IN THE TREATMENT OF HEPATIC ENCEPHALOPATHY
UNDISCOUNTED
1
CONT-ACCEPTED
A61K
2,017
15,716,893
PENDING
METASTATIC CANCER DECOY TRAP
A method of treating or preventing cancer metastasis in a subject is described. The method includes implanting a decoy trap within the subject, the decoy trap comprising an implantable trap device including a metastatic cancer attractant. Methods of diagnosing cancer metastasis in a subject using the decoy traps are also described. The methods include implanting the decoy trap in the subject and allowing the decoy trap to remain within the subject for a period of time, and then diagnosing the subject as having metastatic cancer if metastatic cancer cells are detected in the decoy trap.
1. A method of treating or preventing cancer metastasis in a subject, comprising implanting a decoy trap within the subject, the decoy trap comprising an implantable trap device including a metastatic cancer attractant. 2. The method of claim 1, wherein the cancer metastasis is bone metastasis, and the metastatic cancer attractant is a bone-seeking cancer attractant. 3. The method of claim 2, wherein the bone-seeking cancer attractant is pericytes. 4. The method of claim 3, wherein the subject is human and the pericytes are human pericytes. 5. The method of claim 2, wherein the implantable trap device comprises bone tissue. 6. The method of claim 2, wherein the implantable trap device comprises a porous calcium phosphate ceramic. 7. The method of claim 1, wherein the method is used to treat the metastasis originating from breast cancer, prostate cancer, or lung cancer primary tumors. 8. The method of claim 1, wherein the decoy trap comprises a composite vascular structure. 9. The method of claim 1, wherein the decoy trap further comprises a labeled probe that specifically binds to cancer cells. 10. The method of claim 1, wherein the decoy trap is implanted in contact with a blood vessel. 11. A method of diagnosing cancer metastasis in a subject, comprising implanting a decoy trap within the subject, the decoy trap comprising an implantable trap device including a metastatic cancer attractant, allowing the decoy trap to remain within the subject for a period of time, and diagnosing the subject as having metastatic cancer if metastatic cancer cells are detected in the decoy trap. 12. The method of claim 11, wherein the cancer metastasis is bone metastasis and the metastatic cancer attractant is a bone-seeking cancer attractant. 13. The method of claim 12, wherein the bone-seeking cancer attractant is pericytes. 14. The method of claim 13, wherein the pericytes are human pericytes. 15. The method of claim 12, wherein the implantable trap device comprises bone tissue. 16. The method of claim 12, wherein the implantable trap device comprises a porous calcium phosphate ceramic. 17. The method of claim 11, wherein the method is used to diagnose metastasis in a subject diagnosed with breast, prostate, or lung cancer. 18. The method of claim 11, wherein the decoy trap is removed from the subject before detecting bone-seeking cancer cells in the decoy trap. 19. The method of claim 11, wherein the decoy trap remains in vivo while detecting bone-seeking cancer cells in the decoy trap. 20. The method of claim 11, further comprising determining quantifying the amount of metastatic cancer cells that have entered the decoy trap. 21. The method of claim 11, wherein the decoy trap further comprises a labeled probe that specifically binds to metastatic cancer cells.
This application is a continuation-in-part of U.S. patent application Ser. No. 15/327,332, filed on Jan. 18, 2017, which was a national stage application claiming the benefit of International Patent Application No. PCT/US2015/041061, filed on Jul. 20, 2015, which claimed the benefit of the benefit of U.S. Provisional Application Ser. No. 62/026,081 filed Jul. 18, 2014, all of which are incorporated by reference herein. GOVERNMENT FUNDING This invention was made with government support under grant No. RO1 CA163562-01A1 awarded by the National Cancer Institute of the National Institutes of Health. The government has certain rights in this invention. BACKGROUND Mesenchymal Stem Cells (MSC) have long been described as cellular progenitors of mesenchymal lineages including bone, cartilage, fat, muscle and other connective tissues. In addition, a secretory capacity has been identified with both immunomodulatory and trophic activities, exerted at sites of injury where they interact with other local cellular components. The recent identification of the MSC niche in the perivascular space as pericytes has opened the possibility that MSC may have additional roles directly controlling tissue homeostasis from their cardinal abluminal location. Caplan, A. I., Cell Stem Cell 2008; 3(3), 229-230. Metastasis is a leading prognostic indicator for cancer survival and a major contributor to cancer mortality. The skeleton and liver are common organs for cancer dissemination in various malignancies including malignant melanoma. Although the preponderance of distant metastases implies a selective advantage for arriving disseminating cells, recent studies have determined that the rates of tumor growth, invasion, and metastasis are in fact independent pathological traits governed by different sets of genes. Nguyen D X, Massague J, Nat Rev Genet 2007; 8(5), 341-352. Nevertheless, they share a common feature, namely their dependence on the vasculature that provides access to oxygen and nutrients, as well as a route for cancer cell dissemination. Current cancer therapies are designed to alter not only specific biological functions in cancer cells, but also to target components of the tumor microenvironment (TME)/stroma, especially the vasculature. Pericytes are a specialized cell type that function abluminally covering and stabilizing blood vessels following their recruitment to forming vessels as progenitor cells via PDGF-B/PDGFRB signaling. Armulik et al., Circ Res 2005; 97(6), 512-523. Pericyte involvement in primary tumors growth constitutes a novel therapeutic target based on compelling evidence showing superior reduction in size when targeted in parallel with endothelial cells (ECs). Bergers et al., J Clin Invest 2003; 111(9),1287-1295. However, pericyte coverage of the vasculature seems to differentially regulate tumor growth and metastatic potential, as intravasation of cancer cells is increased in primary tumors grown in mice with a genetically-determined deficient pericyte coverage. Xian et al., J Clin Invest 2006; 116(3), 642-651. These findings have led to the appreciation, in some cases, of pericytes in primary tumors as gatekeepers for cancer dissemination. Gerhardt H, Semb H., J Mol Med 2008; 86(2),135-144. In parallel, in response to tumor signals, BM-derived progenitor cells of mesenchymal origin (as MSCs) are recruited to the tumor stroma localizing in perivascular sites and helping to assemble a supporting vascular network critical for tumor growth. Bergfeld S A, DeClerck Y A., Cancer metastasis reviews 2010; 29(2), 249-261. Taken together, BM-derived MSC (BM-MSC) appear to play a critical role during primary tumor formation, and growth. In contrast, the role of pericytes at the target organ microenvironment during cancer cell extravasation is not known. Recently, data suggest that cellular and molecular elements in the BM are related to the establishment and progression of skeletal metastasis. For example, blocking PDGFB with a multi-target tyrosine kinase inhibitor (Sunitinib) impairs bone invasion of circulating osteotropic lung cancer cell lines due to altered tumor cell-BM stroma interactions. Catena et al., Cancer Research 2011; 71(1), 164-174. In addition, it has been established that invading cancer cells physically associate with mesenchymal derived cells in the BM affecting various biological activities of engrafted cancer cells, including dormancy/quiescence, resistance to chemotherapy and metastatic growth. Corcoran et al., PLoS One 2008; 3(6), e2563. However, the specific identity of the cellular and molecular elements, as well as the precise location where the sequence of events occur during extravasation is still not well understood. The mechanisms governing skeletal metastasis involve comparable details to those used by hematopoietic stem cells (HSC) and their progeny entering the BM. The “homing” behavior of HSCs and exit of progeny relies on the existence of a specific physical niche within the BM where other cellular players, including MSC, favor the constant trafficking of such progenitors across the sinusoidal wall. Shiozawa et al showed that invading osteotropic prostate cancer cells enter the HSC niche competing with resident cells and thus establishing physical anchors for further growth inside the BM. Shiozawa et al., The Journal of clinical investigation, 2011; 121(4), 1298-1312. There remains a need for novel methods of diagnosing and treating metastatic cancer, such as bone metastasis. SUMMARY With the notion of BM-MSC as pericytes, the inventors propose taking advantage of the physical interaction of invading cancer cells and resident BM-MSC occurring at the abluminal space of BM sinusoids as a determinant step in the initiation and fate of skeletal metastasis. The inventors have shown that altering the physical interaction between vascular components of the target organ microenvironment (ECs and MSC/pericytes) via genetic manipulation of PDGF-B, dramatically impairs the engraftment of intraarterially-delivered cancer cells, thus reducing the frequency of osteolytic bone metastasis. Through in vitro and in vivo approaches, including a humanized assay in which fully functional extraskeletal bone is engineered with human MSC (hMSC), the essential molecular players and mechanisms involved in the extravasation of circulating MCC to the BM were established, that become disrupted in the absence of sinusoidal MSC/pericytes. In parallel, they observed that the situation in the BM is replicated in the liver exclusively, whereas no invasion by melanoma was seen in mutant mice. The inventors therefore propose that the presence of MSC as pericytes surrounding BM and liver sinusoids is required for extravasation of MCC, and that the effects of the EC/pericyte dissociation at the metastatic target organ do not mirror its effects during intravasation at the primary tumor. The inventors show that MSC/pericytes function as sentinels regulating cancer cell dissemination with a differential effect during intravasation at the primary tumor and extravasation at the target organ. The molecular mechanisms, cellular players and locations during the establishment of melanoma metastasis to BM and liver were defined. This can be used to trap metastatic cancer cells in order to treat and/or diagnose metastatic cancer. Accordingly, in one aspect, the invention provides a method of treating cancer metastasis in a subject, comprising implanting a decoy trap within the subject, the decoy trap comprising an implantable trap device including a metastatic cancer attractant. In some embodiments, the method is used to treat the metastasis originating from breast cancer, prostate cancer, or lung cancer primary tumors. In one embodiment, the cancer metastasis is bone metastasis, and the metastatic cancer attractant is a bone-seeking cancer attractant. In another embodiment, the bone-seeking cancer attractant is pericytes. In a further embodiment, the subject is human and the pericytes are human pericytes. In some embodiments, the implantable trap device comprises bone tissue. In further embodiments, the implantable trap device comprises a porous calcium phosphate ceramic. In other embodiments, the decoy trap comprises a composite vascular structure. In yet further embodiments, the decoy trap further comprises a labeled probe that specifically binds to cancer cells. In other embodiments, the decoy trap is implanted in contact with a blood vessel. Another aspect of the invention provides a method of diagnosing cancer metastasis in a subject, comprising implanting a decoy trap within the subject, the decoy trap comprising an implantable trap device including a metastatic cancer attractant, allowing the decoy trap to remain within the subject for a period of time, and diagnosing the subject as having metastatic cancer if metastatic cancer cells are detected in the decoy trap. In some embodiments, the method is used to diagnose metastasis in a subject diagnosed with breast, prostate, or lung cancer. In further embodiments, the decoy trap is removed from the subject before detecting bone-seeking cancer cells in the decoy trap. In other embodiments, the decoy trap remains in vivo while detecting bone-seeking cancer cells in the decoy trap. In some embodiments of the method of diagnosing metastatic cancer, the cancer metastasis is bone metastasis and the metastatic cancer attractant is a bone-seeking cancer attractant. In other embodiments, the bone-seeking cancer attractant is pericytes. In further embodiments, the pericytes are human pericytes. In some embodiments, the implantable trap device comprises bone tissue. In further embodiments, the implantable trap device comprises a porous calcium phosphate ceramic. In some embodiments of the method of diagnosing metastatic cancer, the decoy trap further comprises a labeled probe that specifically binds to metastatic cancer cells. In further embodiments, the method comprises determining quantifying the amount of metastatic cancer cells that have entered the decoy trap. BRIEF DESCRIPTIONS OF THE DRAWINGS FIG. 1 provides an exploded view of a decoy trap that has been implanted in a subject. FIGS. 2A and 2B provide images showing BM vascular appearance and micro computed tomography (μCT) assessment of invaded bones. (A) CD31 (Pecam) immunostaining of PDGF-B mutant and Het mice (control) BM, showing no signs of blood vessels gross abnormalities such as collapse and hemorrhages. (B) Gross appearance, two-dimensional CT scanning, and tri-dimensional renderings—volumetric and surface of Het (control) and PDGF-B mutant (Mut) mice humeri. Note the marked osteolysis area in the Het humerus (arrow). FIGS. 3A-3C provide graphs and images of BLI of injected PDGF-B mutant and control mice (Het and WT): (A) Imaging 15 minutes, 5 and 12 days post-injection, showing increased skeletal invasion (limbs and spine) in WT and Het mice compared to PDGF-B mutant mice and the disappearance of a metastatic signal at 12 days in PDGF-B mutant mice (grey circles). (B) Absence in PDGF-B mutant and persistence in Het mice of the spine signal (white circle) after adrenal gland removal (white arrows) confirming the non-spinal origin of the signal in PDGF5-B mutant spine (arrow in A). (C) Quantification of signal (photon flux and area covered by tumors) showing statistical difference between PDGF-B mutant and Het mice (*=p<0.01). Data are represented as mean±SEM. Representative mice of n=15 (5 per group). FIGS. 4A and 4B provide images of gross inspection of distant melanoma dissemination: (A) Craniofacial and appendicular invasion by MCC exhibiting a significant reduction in PDGF-B mutant mice. All skulls and scapulae in the mutants were clear of metastases or had only few/small foci, which contrasts sharply with the multiple major/multifocal invasion observed in Het mice. Spines in PDGF-B mutant mice were clear of metastasis in 2/5 mice, or harbored only 1-2 small foci restricted to one vertebral segment in the remaining 3 animals. WT and Het mice had multiple multi-segment metastases in all animals. Both distal femur and proximal tibia were compromised bilaterally in all WT and Het controls, while bilateral invasion was observed in only 1 of 5 PDGF-B mutant mice, with remaining 4 mice exhibiting only one compromised leg that was restricted to the proximal tibia. (B) Melanoma invasion to other target organs with comparable results in both genotypes except for liver (reduced in PDGF-B mutant mice). Arrows: adrenal glands. Circle: adrenal gland agenesis. Three representative mice shown of n=15 (5 per group). FIGS. 5A-5C provide images showing the histology of metastatic bone tumors. (A, B) Metastatic tumors (T) in distal femur (A) and liver (B) are smaller or absent in PDGF-B mutant mice. Bars=200 μm (low magnification) and 10 μm (high magnification). Melanin-producing B16F10 cells (arrows) localize in the abluminal side of BM sinusoids (Sin), extending to the tissue parenchyma (impaired in PDGF-B mutant mice). (C) CD146 immunohistochemistry (IHC) in BM sections from Het mice. Engrafted B16F10 cells (arrows) physically associate with CD146-positive BM-MSC/pericytes (signal) at the perivascular space and inside the parenchyma (circle). Dotted line=boundary between tumor-invaded and tumor-free BM. Bar=10 μm. FIGS. 6A-6C provide graphs and images showing induced gene silencing in B16F10 and hMSCs. Effective CD146 silencing (90%) in B16F10 (A) and hMSCs (75%) (B), assessed by immunocytochemistry (ICC) in cultured cells. (C) Sdf-1/CXCL12 effective gene silencing (55%) in hMSCs evidenced by qPCR from RNA obtained from cultured cells. * (p<0.05). Bars=200 μm. FIGS. 7A-7C provide graphs and images showing the invasion of engineered B16F10 MCC: Reduced invasion of CD146-silenced MCC to craniofacial, appendicular structures and liver (compared to NT-shRNA), evaluated by BLI (A) and gross examination (B & C). BLI signal reached statistical significance (*=p<0.01). Data are represented as mean±SEM. Representative mice of n=6 (3 per group). FIG. 8 provides a schematic representation of humanized extraskeletal ossicle conformation. The schematic representation of the ossicle showing theoretical cell dispositions within the tissue structure before and after silencing induction with IPTG administration in the drinking water. A timeline of the experiment is also shown. Adip=Adipocyte; Sin=Sinusoid; MK=Megakaryocyte. FIGS. 9A and 9B provide images showing the human origin of perivascular cells in ossicles and in vivo silencing of CD146. (A) Immunodetection (IHC) of the MSC marker CD271 (blue signal) with a human specific antibody evidences the donor (human) origin of perivascular cells in the engineered ossicles. (B) Immunodetection (IHC) of CD146 in ossicle sections revealing its presence in perivascular cells (arrows) in control structures, significantly reduced in ossicles made with CD146-silenced hMSCs. Bars=200 μm. FIGS. 10A-10C provide graphs and images showing the B16F10 MCC invasion to humanized extraskeletal ossicles. (A) MCC invasion of the skeleton (top row BLI) and specific implanted ossicles, evaluated by direct examination after harvesting (middle row) and by BLI (bottom row). The signal from the cubes BLI was quantified (photon flux) giving statistical difference of all groups compared to control (*=p<0.01). Data are represented as mean±SEM. Representative mice and cubes of n=8. (B) Histological analysis (H&E staining) of harvested ossicles shows significant melanoma invasion in structures made with control MSC while significantly reduced or absent with Sdf-1/CXCL12 and CD146-silenced cells. SD cubes exhibit no bone and vasculature formation. Bar=200 μm. (C) Immunolocalization (IHC) of CD146 (arrow) in sections from Control ossicles showing invading MCC physically associated with MSC/pericytes at the perivascular space surrounding sinusoids (Sin), and advancing towards the tissue parenchyma as a cell complex (red circle). Bar=10 μm. FIGS. 11A and 11B provide a cross-sectional representation and images showing the in vitro transendothelial migration (TEM) assay: (A) Schematic representation of the modified TEM. (B—top row) Fluorescence microscopy of DiI-labeled hMSC expressing either non-target (NT) or Sdf-1/CXCL12 silencing vectors (Sdf-1_shRNA) and papillary dermal Fibroblasts seeded at the bottom surface of an 8 μm pore diameter insert membrane. (B—bottom row) Merged bright field and fluorescence microscopy showing B16F10 melanoma cell invasion to the membrane and interaction with seeded cells (Bar=200 μm). Representative pictures from three independent experiments. FIGS. 12A and 12B provide a schematic representation and image showing the in vitro transendothelial migration assay and a result from the assay. (A) DiI-labeled hMSC (red) expressing either nontarget (NT) or Sdf-1/CXCL12 silencing vectors (Sdf-1_shRNA) seeded at the surface of the transwell at varying distances from the insert. (B) No invasion of MCC to the membrane was observed at all distances (one field shown), confirming the lack of migration by B16F10 cells. FIGS. 13A and 13B provide a schematic representation of the proposed model. (A) PDGFR-β-expressing MSCs are recruited as pericytes by endothelial cells (EC)-secreted PDGF-B retained in the heparan sulfate-rich pericellular matrix. In their perivascular location, they create an Sdf-1/CXCL12 gradient across the endothelium (black dots) attracting CXCR4-expressing melanoma cells. Sdf-1/CXCL12 is also expressed in smaller quantities by ECs. Cell-cell interactions mediated by homotypic CD146 binding generates that this cellular complex then enters the BM parenchyma. The absence of MSCs in their normal perivascular niche disrupts these mechanisms. FIGS. 14A and 14B provides image obtained using two-photon microscopy of the habitat (ossicle). (A) Three-dimensional reconstructions of the habitat made with eGFP-hMSCs reveals close proximity of hMSCs to vasculature (arrows). (B) Melanoma (B16F10) were intra-arterially injected and imaged 10 days after injection. Tumor cells can be observed near the vasculature of the habitat with hMSCs now detached from their perivascular locations. Intravital microscopy of the habitat was performed using a Leica SP5 fitted with a DM6000 stage, a 20× water immersion lens, and a 16 W Ti/Sapphire IR laser. Fluorescent dextran was injected into the circulation to illuminate blood vessel prior to imaging. FIGS. 15A and 15B provide images showing the differential effect of laminins 411 and 511 on cancer cell migration in the presence of hMSCs. Membrane inserts were coated with recombinant laminins 411 and 511 (10 ug/ml). Human MSCs were seeded on the opposite side of each membrane (w/o HUVEC and matrigel). After 24 h, cancer cell lines expressing dTomato fluorescent protein were seeded on the membrane inserts and allowed to migrate for 48 h. Non-migrating cells were scraped from the top of the membrane with a cotton swap. A higher migration rate was observed when laminin 411 was present. The same effect was observed using A375. MDA-231 migration showed no response to laminin 411 or 511. Interestingly, this correlates with the fact that B16F10, PC3 and A375 highly express CD146; however, MDA-231 had the lowest expression. FIGS. 16A-16D provide images and a graph showing the differential effect of laminins 411 and 511 on cancer cell migration in the presence of hMSCs. Transmigration of B16F10 cells increased in the presence of recombinant laminin 411 and was inhibited in the presence of laminin 511 (A, B). Membrane inserts were coated with recombinant laminins 411 or 511 (10 ug/ml). Human MSCs were seeded on the opposite side of the membrane. After 24 h, melanoma (A375) expressing dTomato were seeded and allowed to migrate for 48 h. Non-migrating cells were scraped from the top of the membrane with a cotton swap. Number of cells that migrated were quantified using Image-J software. (C) hMSC silenced for Lama4 (shLama4) do not support A375 transmigration and when Lama5 is silenced, A375 transmigration is enhanced. These results confirm the permissiveness of laminin 4 for the transmigration of melanoma. (D) provides a graphic representation of a side-view of the transendothelilal migration (TEM) assay. DETAILED DESCRIPTION The methods and techniques described herein are generally performed according to conventional methods well-known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. See, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual, 3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2001) and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates (1992), and Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1990). Definitions For clarification in understanding and ease in reference a list of terms used throughout the brief description section and the remainder of the application has been compiled here. Some of the terms are well known throughout the field and are defined here for clarity, while some of the terms are unique to this application and therefore have to be defined for proper understanding of the application. “A” or “an” means herein one or more than one; at least one. Where the plural form is used herein, it generally includes the singular. As used herein, the term “diagnosis” can encompass determining the likelihood that a subject will develop a disease, or the existence or nature of disease in a subject. The term diagnosis, as used herein also encompasses determining the severity and probable outcome of disease or episode of disease or prospect of recovery, which is generally referred to as prognosis). “Diagnosis” can also encompass diagnosis in the context of rational therapy, in which the diagnosis guides therapy, including initial selection of therapy, modification of therapy (e.g., adjustment of dose or dosage regimen), and the like. As used herein, the term “prognosis” refers to a prediction of the probable course and outcome of a disease, or the likelihood of recovery from a disease. Prognosis is distinguished from diagnosis in that it is generally already known that the subject has the disease, although prognosis and diagnosis can be carried out simultaneously. In the case of a prognosis for metastatic cancer, the prognosis categorizes the relative severity of the metastasis, which can be used to guide selection of appropriate therapy for the metastatic cancer. “Mesenchymal stem cells” or “MSCs” are derived from the embryonal mesoderm and can be isolated from many sources, including adult bone marrow, peripheral blood, fat, placenta, and umbilical blood, among others. MSCs can differentiate into many mesodermal tissues, including muscle, bone, cartilage, fat, and tendon. There is considerable literature on these cells. See, for example, U.S. Pat. Nos. 5,486,389; 5,827,735; 5,811,094; 5,736,396; 5,837,539; 5,837,670; and 5,827,740. See also Pittenger, M. et al, Science, 284:143-147 (1999). “Stem cell” means an undifferentiated cell that can undergo self-renewal (i.e., progeny with the same multi-differentiation potential) and also produce progeny cells that are committed to a particular differentiation lineage. Within the context of the invention, a stem cell would also encompass a more differentiated cell that has de-differentiated, for example, by nuclear transfer, by fusion with a more primitive stem cell, by introduction of specific transcription factors, or by culture under specific conditions. See, for example, Wilmut et al., Nature, 385:810-813 (1997); Ying et al., Nature, 416:545-548 (2002); Guan et al., Nature, 440:1199-1203 (2006); Takahashi et al., Cell, 126:663-676 (2006); Okita et al., Nature, 448:313-317 (2007); and Takahashi et al., Cell, 131:861-872 (2007). As used herein, the terms “treatment,” “treating,” and the like, refer to obtaining a desired pharmacologic or physiologic effect. The effect may be therapeutic in terms of a partial or complete cure for a disease or an adverse effect attributable to the disease. “Treatment,” as used herein, covers any treatment of a disease in a mammal, particularly in a human, and can include inhibiting the disease or condition, i.e., arresting its development; and relieving the disease, i.e., causing regression of the disease. Prevention or prophylaxis, as used herein, refers to preventing the disease or a symptom of a disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it (e.g., including diseases that may be associated with or caused by a primary disease). Prevention may include completely or partially preventing a disease or symptom. With regard to cancer metastasis, prevention refers to avoiding or decreasing the number of secondary cancer sites that form outside of the primary tumor. The terms “therapeutically effective” and “pharmacologically effective” are intended to qualify the amount of an agent which will achieve the goal of improvement in disease severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies. The effectiveness of treatment may be measured by evaluating a reduction in tumor load or decrease in tumor growth in a subject in response to the administration of anticancer agents. The reduction in tumor load may be represent a direct decrease in mass, or it may be measured in terms of tumor growth delay, which is calculated by subtracting the average time for control tumors to grow over to a certain volume from the time required for treated tumors to grow to the same volume. In the case of antimetastatic agents, the effectiveness of treatment may be measured by evaluating whether treatment has prevented or decreased the spread of the cancer from the original source to new tissues. The terms “individual,” “subject,” and “patient” can be used interchangeably herein irrespective of whether the subject has or is currently undergoing any form of treatment. As used herein, the term “subject” generally refers to any vertebrate, including, but not limited to a mammal. Examples of mammals including primates, including simians and humans, equines (e.g., horses), canines (e.g., dogs), felines, various domesticated livestock (e.g., ungulates, such as swine, pigs, goats, sheep, and the like), as well as domesticated pets (e.g., cats, hamsters, mice, and guinea pigs). Treatment or diagnosis of humans is of particular interest. Treating Cancer Metastasis In one aspect, the present invention provides a method of treating or preventing cancer metastasis in a subject, comprising implanting a decoy trap within the subject, the decoy trap comprising an implantable trap device including a metastatic cancer attractant. The decoy trap catches metastasizing cancer cells by drawing them into the decoy trap as a result of attraction of the metastasizing cancer cells to the implantable trap device and/or the metastatic cancer attractant, thereby preventing or decreasing the number of circulating cancer cancer cells that can become established as metastatic cancer in other tissue of the subject. Cancer is a disease of abnormal and excessive cell proliferation. Cancer is generally initiated by an environmental insult, certain gene mutations or gene deletions, or error in replication that allows a small fraction of cells to escape the normal controls on proliferation and increase their number. The damage or error generally affects the DNA encoding cell cycle checkpoint controls, or related aspects of cell growth control such as tumor suppressor genes. As this fraction of cells proliferates, additional genetic variants may be generated, and if they provide growth advantages, will be selected in an evolutionary fashion. Cells that have developed growth advantages but have not yet become fully cancerous are referred to as precancerous cells. Cancer results in an increased number of malignant cells in a subject. These cells may form an abnormal mass of cells called a tumor, the cells of which are referred to as tumor cells. The overall amount of tumor cells in the body of a subject is referred to as the tumor load. Tumors can be either benign or malignant. A benign tumor contains cells that are proliferating but remain at a specific site and are often encapsulated. The cells of a malignant tumor, on the other hand, can invade and destroy nearby tissue and spread to other parts of the body through a process referred to as metastasis. As used herein, “metastasis” refers to the ability of cells of a cancer (e.g. a primary tumor, or a metastatic tumor) to be transmitted to other locations in the subject (i.e., target organs) and to establish new tumors at such locations. The metastatic process involves a number of different steps. After creation of the initial tumor mass, the tumor is vascularized with a capillary network from the surrounding host tissue. Intravasation of the capillary network by tumor cells then occurs, resulting in the creation of circulating cancer cells. Thin-wall venule-like lymphatic channels offer very little resistance to penetration by tumor cells and provide the most common pathways for tumor cells entry into the circulation, although in some cases detachment and embolization of small tumor cell aggregates occur. Tumor cells that survive circulation may then arrest in the capillary beds of organs, after which extravasation occurs, through interaction of the circulating tumor cell with the endothelium, and facilitated by pericytes. Proliferation within the organ parenchyma completes the metastatic process. The invention is used to treat or prevent cancer metastasis. The most common places for the metastases to begin are referred to as the primary cancer, and include are the lung, breast, skin, colon, kidney, prostate, pancrease, liver, and cervix. There is a propensity for certain tumors to seed in particular organs. The propensity for a metastatic cell to spread to a particular organ is termed ‘organotropism’. For example, prostate cancer usually metastasizes to the bones. In a similar manner, colon cancer has a tendency to metastasize to the liver. Stomach cancer often metastasises to the ovary in women. In some embodiments, the method is used to treat the metastasis originating from breast cancer, prostate cancer, or lung cancer primary tumors. The cells capable of forming metastatic cancer are circulating cancer cells are those that move within the bloodstream, as opposed to cancer cells present at a fixed location, such as a solid tumor. The circulating cancer cells form metastatic cancer cites by transendothelial migration. A circulating tumor cell, as used herein, is a cell that can circulate through blood vessels but is capable of forming a new cancer site upon extravasation. A variety of types of circulating tumor cells can be used in a method of the invention, including cells from metastatic epithelial cancers, carcinomas, melanoma, leukemia, etc. The tumor cells may be, e.g., from cancers of breast, lung, colon, bladder, prostate, liver, gastrointestinal tract, endometrium, tracheal-bronchial tract, pancreas, liver, uterus, ovary, nasopharynges, prostate, bone or bone marrow, brain, skin or other suitable tissues or organs. In a preferred embodiment, the cancer cells are of human origin. Transendothelial migration refers to the migration of cells through the various layers making up the blood vessel, and in particular the endothelial layer. Transendothelial migration includes extravasation and intravasation. Extravasation refers to migration of a cell (e.g., a circulating tumor cell) from within the blood vessel to outside of the blood vessel (e.g, to an organ or tissue such as bone), while intravasation refers to migration of a cell from outside the blood vessel (e.g., at the site of a primary tumor) to within the blood vessel. Pericytes can play an active role in facilitating transendothelial migration through the endothelium of the blood vessel. Facilitation works via the creation of both cancer cell-attracting molecular gradients and docking points for cell-cell attachment (both exerted by the facilitators). These mechanisms attract cancer cells close to the endothelium capturing them with further migration outside the blood vessel. For example, carbohydrate-mediated cancer cell adhesion to the vascular endothelium is involved in the metastasis of a wide variety of cancers, including gastric, colorectal, pancreatic, liver, ovary, head and neck, and breast cancers, etc. In some embodiments, blood vessel transendothelial migration is facilitated extravasation, while in other embodiments blood vessel transendothelial migration is facilitated intravasation. In further embodiments, the blood vessel transendothelial migration is the facilitated extravasation of circulating cancer cells (e.g., melanoma cells) into the tissue model (e.g., bone tissue) of the invention. Pericytes are contractile cells that wrap around the endothelial cells of blood vessels throughout the body. Also known as Rouget cells or mural cells, pericytes are embedded in basement membrane where they communicate with endothelial cells of the blood vessels by means of both direct physical contact and paracrine signaling. Pericytes regulate capillary blood flow, the clearance and phagocytosis of cellular debris, and the permeability of the blood vessel to other cells, including circulating cancer cells. A variety of integrin molecules and other factors are involved in communication between pericytes and endothelial cells separated by the basement membrane. The decoy traps of the invention can be used to treat or diagnose the metastasis that is directed to various secondary tissues, based on the organotropism of the particular metastatic cancer and the ability of the decoy trap to retain circulating cancer cells that have contacted the decoy trap. In some embodiments, the method is used to treat or prevent the development of bone metastasis. Bone-originating primary tumors such as osteosarcoma, chondrosarcoma, and Ewing's sarcoma are rare, and bone cancer can occur as a result of metastasis to the bone. While many types of cancer are capable of forming metastatic tumors within bone, the microenvironment of the marrow tends to favor particular types of cancer, including prostate, breast, and lung cancers. Particularly in prostate cancer, bone metastases tend to be the only site of metastasis. The most common sites of bone metastases are the spine, pelvis, ribs, skull, and proximal femur. Although the prevalence of melanoma bone metastasis is lower than these cancers, the mortality rate of bone metastasis due to melanoma is the highest among these cancers. Symptoms of bone metastases severe pain, bone fractures, spinal cord compression, hypercalcemia, anemia, spinal instability, and decreased mobility. The presence of bone metastases can be confirmed using a CT scan. The present invention employs a decoy trap—also referred to as an implanted tissue mimicking model—for treating or diagnosing cancer metastasis. The decoy trap comprises an implantable trap device including a metastatic cancer attractant. The implantable trap device is a three-dimensional tissue model reflective of a biological tissue, particularly an organ such as bone or liver, to which cancer cells might be expected to metastasize based on its organotropic predilection. An organ or tissue, as used herein, refers to a differentiated part of an organism which has a specific function. In some embodiments, the implantable trap device is composed of normal animal tissue obtained from a suitable animal subject, or a different compatible subject. In other embodiments, the implantable trap device is an artificial tissue model such as an organoid, or that has been otherwise engineered using cell culture or inorganic materials. Tumor cells are retained within the implantable trap device by molecular specific attachment to the tissue. For example, in the case of bone tissue, the tumor cells are pulled into the stroma of bone marrow and become immobilized by their attachment to the bone stroma. The form of the implantable trap device is not limited, and may be, for example, an epithelial tissue device that can be constructed by culturing, for example, surface epithelial cells and glandular epithelial cells; a connective tissue device that can be constructed by culturing, for example, fibroblasts and fat cells; a muscle tissue device that can be constructed by culturing, for example, myoblasts, cardiac muscle cells, and smooth muscle cells; a nerve tissue device that can be constructed by culturing, for example, nerve cells and glial cells; and an organoid model that can be constructed from a combination of cells derived from two or more tissues. The cells used are not limited to normal mature differentiated cells, and may be undifferentiated cells such as embryonic stem cells, somatic stem cells, and induced pluripotent stem cells; focus-derived cells such as cancer cells; or transformants transfected by exogeneous genes. Preferably the implantable trap device is formed of tissue for which the target metastatic cancer has an organotropic affinity. One embodiment of the implantable trap device 10 is shown in FIG. 1. The implantable trap device 10 is positioned around a blood vessel 12. For example, the implantable trap device 10 can be implanted in a cancer patient in the same manner used to implant drug ports. The expanded view shows the process of removing cancer (e.g., melanoma) cells within the implantable trap device 10. Positioned within the implantable trap device 10 and around the blood vessel 12 are a plurality of metastatic cancer attractants 14 (e.g., pericytes). The implantable trap device 10 is made up of a decoy matrix material 16. Lining the blood vessel is the basement membrane 18, or in some cases basal lamina, which is made by both the vascular endothelium and perivascular cells. Metastatic cancer cells 20 (e.g., melanoma) enter the implantable trap device 10 through the blood vessel, and are attracted into the decoy matrix material 16 by the metastatic cancer attractant 14, after which they are trapped within the decoy matrix material 16 of the device. In some embodiments, the implantable test device is a bone tissue device. Bone tissue devices can be made of organic or inorganic scaffold material, and mimic bone tissue, typically for bone tissue engineering purposes. A variety of bone tissue models are known to those skilled in the art. See Sarkar, S, Lee, B, Korean J Intern Med. 2015, 30(3):279-293. For example, bone tissue devices can be constructed using bioceramics, glass and glass ceramics, biopolymers, and graphene. In particular, porous ceramic materials are useful as bone tissue models. Dennis J., Caplan A., J Oral Implantol. 1993; 19(2):106-15. In some embodiments, the implantable trap device comprises a porous calcium phosphate, such as a porous calcium phosphate ceramic cube. Samavedi et al., Acta Biomater. 2013 9(9):8037-45. In further embodiments, the porous calcium phosphate is embedded in a natural or extruded polymer. For example, in some embodiments, the porous calcium phosphate is embedded in the natural polymer collagen coated with hydroxylapatite. The decoy trap is implanted into the subject in a manner which allows or encourages acceptance by the subject. For example, in some embodiments, the decoy trap may be implanted within a subject using an implantation guide or guide wire configured to be visible using ultrasound, allowing the implantation procedure to be guided using ultrasound imaging. In some embodiments, a single decoy trap is implanted into the subject, while in other embodiments a plurality of decoy traps are implanted into the subject. Use of a plurality of decoy traps in a subject can be useful for the treatment or diagnosis of different types of metastatic cancer, to increase effectiveness by placement in various spatially discrete organs or tissue, or for other purposes. In some embodiments, the decoy trap is implanted in contact with a blood vessel. Blood vessels are generally cylindrical conduits that are part of the circulatory system that transports blood throughout the body. An arrangement of blood vessels is referred to as vasculature. Blood vessels include arteries, capillaries, and veins. The space within the blood vessel is referred to as the lumen, while the first layer adjacent to the lumen is the endothelium. The endothelium is a single layer of simple squamous endothelial cells glued by a polysaccharide intercellular matrix. Outside of the endothelium is the basement membrane, which is a thin, fibrous, non-cellular region of tissue that separates the endothelium from the surrounding smooth muscle and connective tissue. Capillaries have a significantly simpler structure, consisting of endothelium surrounded by a basement membrane. Capillaries can be fenestrated (i.e., equipped with diaphragms that regulate the size of the fenestration) or non-fenestrated (i.e., open pore capillaries or sinudoids). In addition to an implantable trap device, the decoy trap also includes a metastatic cancer attractant. The metastatic cancer attractant should serve to reinforce the ability of the implantable trap device to attract metastatic cancer having an organotropic affinity for the type of tissue being modeled by the implantable trap device, and maintain the cancer cells within the trap once they have been attracted. Examples of cancer attractants are the cellular components (e.g., MSC, pericytes) and other perivascular niche components and molecules such as CXCL12 (chemochine) and laminins 411 and 421, which are components of the vascular basement membrane. In some embodiments, the decoy trap is configured to attract metastatic bone cancer cells, and the metastatic cancer attractant is a bone-seeking cancer attractant. An example of a bone-seeking cancer attractant is a pericyte. Other cancer attractants include compounds known to encourage transendothelial migration. For example, the compound may be known to have an effect on the adhesion of cancer cells to blood vessels. In additional embodiments, the agent is known to have an affect on the activity of pericytes. Examples of agents that have an effect on the activity of a pericyte-affecting molecule can be selected from the group consisting of a platelet-derived growth factor (PDGF)-BB/PDGF receptor β, a membrane type 1-matrix metalloproteinase, heparin sulphate proteoglycans, N-cadherin, Ang1/Tie-2, transforming growth factor β, hepatocyte growth factor, ephrinB2, vascular cell adhesion molecule 1/α4-integrin, CD146, Sdf-1/CXCL12, fibronectin, and laminin (e.g., laminin 411 and laminin 421). Additional factors known to attract circulating cancer cells include various peptides and carbohydrates involved in cell signaling and adhesion, such as CD146. Factors that can be identified involve constitutive and induced molecules expressed in either the invading cancer cell or the local/resident pericyte. These include secreted growth factors and their cognate receptors, cell-cell adhesion molecules and cell-ECM interacting molecules. In some embodiments, the decoy trap initially comprises mesenchymal stem cells. Mesenchymal stem cells are characterized by their ability to produce and secrete structural molecules commonly found within the extra cellular matrix (ECM), though it is well established that mesenchymal stem cells also produces an array of different signaling molecules which can function in both the differentiation of cells (as in the case of the developing organ) as well as the maintenance of stemness, as seen in the mesenchymal components of the intestinal stem-cell niche. The expression patterns of mesenchymal stem cells have been shown to be vastly different dependent on the site of origin, though some general markers expressed in multiple mesenchymal lineages are vimentin, fibronectin and various forms of collagen. In contrast to the cells of the epithelial components of a developing organ mesenchyme is marked by a migrating capability. Mesenchymal stem cells reside as pericytes in the abluminal aspect of blood vessels (i.e., perivascular niche) in all vascularized tissues in the body. Mesenchymal stem cells have the capacity of recognizing sites of injury, where they reassemble as pericytes and exert immunomodulatory and trophic activities locally. In some embodiments, the subject is human and the pericytes are human pericytes. Upon implantation into the subject, a proportion of the loaded mesenchymal stem cells into the tissue implantable trap device differentiate into ECM-producing cells (e.g., osteoblasts in bone), while some migrate to the basement membrane of the nascent blood vessels that form around and inside the implanted tissue mimicking model, readopting their perivascular nature (i.e., as pericytes). Accordingly, in some embodiments, the decoy trap comprises a composite vascular structure. The system of blood vessels, including pericytes, that forms around and inside the decoy trap is referred to herein as a composite vascular structure, which serves to provide vascular support for the decoy trap. Note that while differentiation of the mesencymal cells typically occurs subsequent to implantation, that differentiation of the mesenchymal cells can also be carried out ex vivo in some embodiments of the invention, before implantation. The decoy traps can prevent the circulating cancer cells from forming metastatic cancer by trapping and isolating them, thereby inhibiting metastatic progression. For example, the decoy traps may result in the delayed appearance of secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of secondary tumors, slowed or decreased severity of secondary effects of disease, among others. In the extreme, complete inhibition is achieved, and is referred to herein as prevention (e.g., virtually complete inhibition, no metastasis if it had not occurred, no further metastasis if there had already been metastasis of a cancer, or virtually complete inhibition of the growth of a primary tumor caused by re-seeding of the tumor by a circulating cancer cell. In some embodiments, the decoy traps are removed from the subject after a period of time, or upon detection of metastatic cancer cells within the decoy traps, in order to permanently remove the metastatic cancer cells from the subject. In some embodiments, the decoy trap can be combined with other forms of treatment for cancer (e.g., metastatic cancer). Additional methods of anticancer therapy include one or more methods selected from the group consisting of surgery, cryoablation, thermal ablation, radiotherapy (e.g., external beam radiotherapy), chemotherapy, radiofrequency ablation, electroporation, alcohol ablation, high intensity focused ultrasound, photodynamic therapy, administration of monoclonal antibodies, and administration of immunotoxins. Examples of agents suitable for use in anticancer therapy include cyclophosphamide, dacarbazine, methotrexate, fluorouracil, gemcitabine, capecitabine, hydroxyurea, topotecan, irinotecan, azacytidine, vorinostat, ixabepilone, bortezomib, taxanes (paclitaxel, docetaxel), cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, vinorelbine, colchicin, anthracyclines (doxorubicin and epirubicin) daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, adriamycin, 1-dehydrotestosterone, glucocorticoid, procaine, tetracaine, lidocaine, propranolol, puromycin, ricin, and maytansinoids, Gefitinib, Erlotinib, Lapatinib, Sorafenib, Sunitinib, Imatinib, Dasatinib, Nilotinib, temsirolimus, everolimus, rapamycin, Trastuzumab, Cetuximab, Panitumumab, Bevacizumab, Rituximab, and Tositumomab. Methods of Diagnosing Cancer Metastasis in a Subject In another aspect, the invention provides a method of diagnosing cancer metastasis in a subject. The method includes implanting a decoy trap within the subject, the decoy trap comprising an implantable trap device including a metastatic cancer attractant, allowing the decoy trap to remain within the subject for a period of time, and diagnosing the subject as having metastatic cancer if metastatic cancer cells are detected in the decoy trap. In some embodiments, the decoy trap remains in vivo while detecting bone-seeking cancer cells in the decoy trap. In other embodiments, the decoy trap is removed from the subject before detecting bone-seeking cancer cells in the decoy trap (i.e., the metastatic cancer cells are detected ex vivo). The metastatic cancer being diagnosed can be any of the types of metastatic cancer described herein. In addition, the method can be used to diagnose metastasis in a subject who has already been diagnosed with cancer, and in particular cancers known to commonly lead to metastasis such as breast, prostate, or lung cancer. Likewise, the decoy trap used in the method of diagnosis can include any of the features described herein. For example, in some embodiments, the cancer metastasis is bone metastasis and the metastatic cancer attractant is a bone-seeking cancer attractant. In further embodiments, the bone-seeking cancer attractant is pericytes, such as human pericytes. In other embodiments, the implantable trap device comprises bone tissue. In further embodiments, the implantable trap device comprises a porous calcium phosphate ceramic. In some embodiments, the decoy trap further comprises a labeled probe that specifically binds to metastatic cancer cells. These probes can be used to detect the presence of metastatic cancer cells in the decoy trap either in methods of treatment or methods of diagnosis. Any of a variety of conventional labels can be used to label metastatic cancer cells. For example, suitable labels include green fluorescent protein (GFP), red fluorescent protein (RFP), and luciferase, whose use is described in the Examples. Other conventional labels include DsRed, EYFP, ECFP, EVFP and derivatives of EGFP. See also the markers listed at the web site of BD Biosciences (Clontech). When it is desirable to label two different cell populations at the same time (e.g., metastatic cancer cells and cells of a resident tumor, or metastatic cancer cells inoculated at two different (e.g. orthotopic and/or ectopic) sites in a subject), labels which can be easily distinguished can be used. For example, a first cell type can be labeled with a GFP and a second cell type with RPF; or a first cell type can be labeled with firefly luciferase and a second cell type with Renilla luciferase. Methods of detecting (e.g., quantitating) detectably labeled metastatic cancer cells in the decoy trap will be evident to the skilled worker. For example, when a metastatic cancer cell is labeled with a fluorescent marker, it can be detected by examining, with a fluorescent microscope, a tissue sample from the tumor of the subject. When a metastatic cancer cell is labeled with luciferase, the tumor can be examined in the living subject (e.g. in real time) by measuring light emission (bioluminescence) from the marker. Methods of detection can be readily quantified by non-invasive photon flux emission measurement of luminescence (luciferase), non-invasive imaging of fluorescence, ex-vivo imaging of luminescence, ex-vivo imaging of fluorescence, fluorescence-activated sorting of tumor cells after dissociation of the extracted tumors into a cell suspension, immunohistochemical analysis of marker proteins, to provide quatitative, reproducible assays. For example, in some embodiments, the method further comprises determining quantifying the amount of metastatic cancer cells that have entered the decoy trap. In some embodiments, the metastatic cancer cells trapped within the decoy trap are characterized to determine the type of metastatic cancer cells or to characterize the metastatic cancer cells in other ways. For example, the metastatic cancer cells can be genetically analyzed to determine their genetic characteristics using methods such as PCR analysis. In further embodiments, the metastatic cancer cells trapped within the decoy trap are removed and implanted in another setting, such as cell culture or an immunocompromized animal model, in order to further characterize the metastatic cancer cells or determine their susceptibility to differing types of chemotherapeutic agents. The following examples are included to demonstrate a preferred embodiment of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the example, which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute a preferred mode for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. Examples Example 1: Mesenchymal Stem Cells Regulate Melanoma Cancer Cells Extravasation to Bone and Liver at their Perivascular Niche Skeleton and liver are preferred organs for cancer dissemination in metastatic melanoma negatively impacting quality of life, therapeutic success and overall survival rates. At the target organ, the local microenvironment and cell-to-cell interactions between invading and resident stromal cells constitute critical components during the establishment and progression of metastasis. Mesenchymal Stem Cells (MSCs) possess, in addition to their cell progenitor function, a secretory capacity based on cooperativity with other cell types in injury sites including primary tumors (PT). However, their role at the target organ microenvironment during cancer dissemination is not known. We report that local MSCs, acting aspericytes, regulate the extravasation of melanoma cancer cells (MCC) specifically to murine bone marrow (BM) and liver. Intra-arterially injected wild-type MCC fail to invade those selective organs in a genetic model of perturbed pericyte coverage of the vasculature (PDGF-Bret/ret), similar to CD146-deficient MCC injected into wild type mice. Invading MCC interact with resident MSCs/pericytes at the perivascular space through co-expressed CD146 and Sdf-1/CXCL12-CXCR4 signaling. Implanted engineered bone structures with MSCs/pericytes deficient of either Sdf-1/CXCL12 or CD146 become resistant to invasion by circulating MCC. Collectively, the presence of MSCs/pericytes surrounding the target organ vasculature is required for efficient melanoma metastasis to BM and liver. Materials and Methods PDGF-Bret/ret mice: PDGF-Bret/ret transgenic mice (PDGF-B mutant) were kindly provided by Drs. Betsholtz and Genové (Karolinska Institute, Stockholm, Sweden). These transgenic mice (C57B1/6 background) express a mutant PDGF-B that lacks a C-terminal retention motif required to confine this growth factor to the EC compartment, necessary for the recruitment of pericyte progenitors expressing PDGFRB. Armulik et al., Circ Res 2005; 97(6), 512-523. The impaired PDGF-B binding results in defective pericyte recruitment and coverage of microvessels with fewer pericytes and their partial abluminal detachment from the vessel wall. Gerhardt H, Semb H., J Mol Med 2008; 86(2), 135-144. Given that the Pdgfbret allele is hypo-functional and PDGF-Bret/+ mice are indistinguishable from PDGF-B+/+ mice, adult (10 week old) Het, WT and PDGF-B mutant littermate mice (n=5 per group) were used in all experiments. Lindblom et al., Genes Dev 2003; 17(15), 1835-1840. Bioluminescence Imaging (BLI): BLI was performed after subcutaneous injection of 200 μl of 12.5 mg/ml of luciferin substrate (Biosynth, Cat# L-8220) using a Xenogen IVIS 200 series system. Fifteen minutes after B16F10 cell infusion, an early BLI was performed to evaluate cell distribution throughout the body. Later, images at days 3, 7 and 12 were obtained to evaluate cancer cells engraftment and their temporal progression as growing metastases. To quantify tumor invasion to target organs, BLI signal was analyzed (d12) in terms of photon flux (photons/second/cm2/steradian) and the area covered by signal (cm2e−1) taken at specific locations (extremities and spine after adrenal glands removal) using a pre-defined geometrical shape. Gene Silencing in B16F10 MCC and hMSC Cells: CD146 was silenced in B16F10 MCC using a validated shRNA murine sequence cloned in a regular pLKO.1-puro vector, bacterially amplified, sequence verified and delivered as lentiviral transduction particles ready to use (MISSION® RNAi clone ID: NM_023062.1-656s1c1, Sigma Aldrich, St Louis, Mo.). CD146 and Sdf-1/CXCL12 were silenced in BM-derived hMSC using validated human shRNA sequences cloned into an inducible pLKO-puro-IPTG-3xLacO vector [Isopropyl β-D-1-thiogalactopyranoside (IPTG)-dependent transcriptional induction], also delivered as viral particles (MISSION® RNAi clone IDs: CD146: NM_006500.1-1322s1c1; Sdf-1/CXCL12: NM_000609.4-157s21c1, Sigma Aldrich, St Louis, Mo.). The use of an inducible system is intended to avoid the effects of silencing CD146 and Sfd-1/CXCL12 during the formation of both bone and the sinusoidal network inside the ossicles. For the TEM assay, Sdf-1/CXCL12 gene silencing was induced 5 days before the assay. In Vitro Transendothelial Migration Assay (TEM): A modified Boyden chamber cell migration assay was used to quantitate the invasion potential of B16F10 cancer cells in 2 different conditions, relative to pre-labeled hMSCs with the cationic lipophilic dye Dil for their fluorescence detection: A) When the MSC/pericytes are in close contact with the membrane but silenced for Sdf-1/CXCL12; and B) When the distance between the membrane (acting as an endothelium) and the MSC/pericytes is increased, reminiscent of the PDGF-Bret/ret mutant mice “anatomic” phenotype (in vitro counterpart). Humanized Heterotopic Bone Formation Assay: A total of 4.5×106 non-transduced hMSC and hMSC expressing inducible vectors for non-target (NT), CD146 (CD146.shRNA) and Sdf-1/CXCL12 (Sdf-1.shRNA) were vacuum-loaded into sterile porous ceramic cube carriers (hydroxyapatite/tricalcium phosphate 40/60—Zimmer, Warsaw, Ind.) pre-coated with a 100 μg/ml solution of fibronectin. Dennis et al., Biomaterials 1998; 19(15), 1323-1328. The cubes were subcutaneously implanted into immunocompromised mice (CB17-Prkdc SCID) for 8 weeks to form extraskeletal bone structures (ossicles). Every animal (n=8) received 4 cubes, each representing one of the conditions tested. In order to minimize any potential anatomical effect, their relative positions were changed in each animal. After 8 weeks, gene silencing at the protein level in hMSC was accomplished by administering IPTG (12.5 mM) in the drinking water for 7 days. At this time, 1×106 murine B16F10 MCC were intra-arterially injected. BLI images at days 1, 3, 7 and 12 were taken to evaluate MCC engraftment and growth. Two weeks after cell injections, the animals were sacrificed, imaged and the implanted ossicles analyzed by histology. Modified B16F10 MCC: B16F10 cells typically colonize target organs within 2 weeks after systemic injection, at which time metastases can be macroscopically observed as black melanin deposits produced by the engrafted cells. B16F10 cells were lentiviral-transduced with a dual-fusion reporter (fluc-mrfp) encoding firefly luciferase and monomeric red fluorescent protein allowing tracking by Bioluminescence (BLI) and Fluorescence imaging respectively. Love et al., J Nucl Med 2007; 48(12), 2011-2020; Lin et al., Translational Medicine 2012; 1(12), 886-897. Stably transduced cells were sorted by FACS based on red fluorescence intensity, and cells with highest signal collected and serially expanded. Intra-Arterial Injections of Cancer Cells: All animal experiments were approved by the local IACUC (Case Western Reserve University) and conform to the U.S. Public Health Service Policy on Humane Care and Use of Laboratory Animals (NIH, Department of Health and Human Services). Five×105 B16F10 cells (in 200 μl of sterile PBS) were delivered intra-arterially under general inhaled anesthesia (2% isoflurane) via a carotid catheter advanced towards the aortic arch, thereby bypassing the lungs and avoiding the first passage effect. Lin et al., Molecular therapy 2013; 22 (1), 160-168. All animals were injected at the same rate (over 2 minutes), monitored for breathing rate and rectal temperature and followed until full recovery from anesthesia. Clinical Assessment: General evaluation of mice throughout the experiments includes: body weight, general aspect, degree of mobility and ambulation in an open space, and qualitative assessment of bone cancer-related pain by evaluating movement-evoked limb lifting during walking. Vermeirsch et al., Pharmacol Biochem Behav 2004; 79(2), 243-251. The limb lifting assessment, although subjective, can provide information regarding early functional consequences in colonized bones that can be correlated with the degree of cancer cells engraftment evaluated by BLI, as pain appears before any radiological evidence of bone colonization. Animal Dissections: A thorough body dissection was performed in order to directly assess invasion by cancer cells. Given that B16F10 melanoma cells actively produce melanin, the degree of tissue colonization can be initially estimated by the presence of deposited pigment. Micro-Computed Bone Scans (μCT) and Bone Morphometry: Bone osteolysis was assessed in paraffin fixed whole bone samples by μCT imaging using a GE Healthcare eXplore Locus machine. Multiple micro-tomographic slices obtained with a resolution of 20 μm were then reconstructed in 3D renderings for further analysis. Morphometric parameters [bone volume/total volume (BV/TV), trabecular number (TbN), trabecular thickness (TbTh), trabecular spacing (TbSp), bone mineral content (BMC) and bone mineral density (BMD)] were calculated in processed samples and used as indicators of an underlying bone phenotype. Histology and Immunohistochemistry: For histology (H&E staining) and IHC, harvested bones and ossicles were fixed in 4% Paraformaldehyde (PFA) for 48 h, decalcified in a solution of 12.5% EDTA/2.5% PFA-pH 7.5 for 10 days (4° C.), and then paraffin embedded and sectioned (10 μm). IHC in sections was performed after antigen retrieval (Proteinase K at 37° C.), endogenous peroxidase quenching (3% H2O2) and primary antibody incubation using the ImmPRESS™ polymerized reporter enzyme staining system (peroxidase micropolymers) with different enzyme substrates (chromogens) allowing multiple labeling (Vector Labs). The following optimized primary antibodies were used: Rabbit monoclonal anti-CD146 (Millipore, Billerica, Mass., Cat #04-1147); Mouse monoclonal anti-human CD271 (BD Pharmingen Cat #557194) to specifically identify MSC/pericytes of human origin; Rat monoclonal anti-CD31 (Abcam ab56299, Cambridge, Mass.) to identify endothelial cells. Gene Silencing in B16F10 MCC and hMSC Cells: Cultures of hMSC were established as previously described. Haynesworth et al., Bone 1992; 13(1), 81-88. The BM was collected using a procedure reviewed and approved by the University Hospitals of Cleveland Institutional Review Board. Cells were obtained from healthy de-identified adult volunteer donors after signing an informed consent. The use of an inducible system is based on the lactose operator-repressor system that efficiently suppresses target gene expression both in vitro and in vivo after 24 h of IPTG administration to mice in the drinking water (12.5 mM). Wu et al., DNA Cell Biol 1997; 16(1), 17-22. In all cases, 100,000 cells per well (6 well plate) were transduced in 1.5 ml total volume containing Protamine Sulfate (100 μg/mL) as coadjuvant, and viral particles at MOI 5. Selection was performed for 10 days with Puromycin (5 μg/ml) with non-transduced cells serving as selection control. Amplified transduced cells were tested for silencing efficiency by immunocytochemistry in coverslip-cultured cells (CD146) and qPCR in regular cultures (Sdf-1/CXCL12) using a non-target (NT) sequence as control. For the inducible silencing vectors, transgene activation was tested using two different concentrations (200 μM and 1 mM) of IPTG (Life technologies, Carlsbad, Calif.) for 6 days. For qPCR assessments, cells were collected by centrifugation for 5 mM at 1200 rpm (110×g) and RNA isolated with TRIzol (Invitrogen) followed by DNaseI digestion and purification with the RNeasy mini kit (Qiagen). One μg of high quality total RNA was retrotranscribed with SuperScript III (Invitrogen), and 10 ng of the resulting cDNA was amplified by qPCR in a StepOne Real-time thermocycler (Applied Biosystems) using SYBR-green. Results werenormalized to the endogenous expression of GAPDH and the fold expression calculated with the 2−ΔΔCT method. In Vitro Transendothelial Migration Assay (TEM): A) When the MSC/pericytes are silenced for Sdf-1/CXCL12: DiI-labeled hMSCs (5×105) expressing either NT_shRNA or Sdf-1/CXCL12_shRNA vectors were treated with IPTG (200 μM) for 5 days to induce gene silencing. They were then cultured at the bottom of an 8 μm pore size polyethylene therephthalate membrane pre-coated with Gelatin (1% for 1 h at 37° C.) and a thin layer of Matrigel (BD BioCoat™ Matrigel™) facing the upper chamber following manufacturer's instructions. As controls, no cells and human papillary dermal fibroblasts were cultured similarly. Forty-eight hours after culturing the coated membrane with the engineered hMSCs, 1×105 B16F10 melanoma cancer cells were seeded in the upper chamber and allowed to migrate through the membrane for additional 48 hours. The upper chamber was then scrapped with a cotton swab to remove unattached cells and the membrane removed from the insert with a scalpel, fixed in 10% Neutral Buffered Formalin and analyzed by bright field and fluorescence microscopy merging both images. B) When the distance between the endothelium and the MSC/pericytes is increased: The TEM was performed comparing the results obtained in A (distance of ˜50 μm) with different distances between the hMSCs and the coated membrane (<1 mm, 1 mm and >1 mm). The hMSCs were plated on the bottom surface of the receiving plate and the B16F10 cancer cells were seeded on the upper chamber coated with Matrigel and Gelatin in an insert with adjustable heights (carrier plate system—Nunc®, Thermo Scientific). Statistical Comparisons: BLI data from injected animals (photon flux and area covered by tumors) were pooled individually (extremities and spine of each mouse) and statistical difference between PDGF-B mutant and Het mice calculated using a paired T-test. BLI data from engineered cubes (photon flux) were compared and statistical difference calculated following a one-way ANOVA with Tukey's multiple comparison tests (contrasted to control cubes). Results Skeletal and Liver Melanoma Tumor Burden is Reduced in PDGF-Bret/ret Mice: In PDGF-B mutant mice no underlying bone and gross vascular phenotypes (FIG. 2A) were observed. Twelve days after B16F10 cell injection, both heterozygous (Het) and wild type (WT) mice exhibited marked clinical deterioration including severe cachexia (32±3% body weight reduction vs. 20±2% in PDGF-B mutant mice, P<0.05), restricted mobility/ambulation, hunched backs, increased movement-evoked limb lifting and respiratory distress, not observed in PDGF-B mutant mice. BLI assessment shows that WT and Het mice exhibit an increased skeletal tumor burden as compared with PDGF-B mutants, determined by the number of metastatic foci in the extremities, pelvis and spine, and by their signal quantification (FIG. 2). In PDGF-B mutant mice (n=3) some metastatic foci disappeared in time (FIG. 3A—circles). The extensive compromise of long bones seen in Het controls was linked with functional bone osteolysis, analyzed by two (2D)- and three (3D)-dimensional volumetric micro computed tomography (μCT) reconstruction (FIG. 2B). Animal dissections confirmed the overall significant reduction in skeletal invasion in PDGF-B mutant mice compared with Het controls (FIG. 4A), also evident in liver but not in other melanoma target organs including adrenal glands, lungs and brain (FIG. 4B). In addition to the significantly reduced overall macroscopic tumor burden, histological analysis revealed comparable reductions in tumor size in PDGF B mutant mice (FIG. 5A). Similarly, no metastatic foci were observed histologically in PDGF-B mutant livers compared with the multifocal invasion in WT and Het mice (FIG. 5B). MCC Establish a Perivascular Niche During Engraftment/Invasion in the Skeleton and Liver where they Interact with Resident Murine MSC/Pericytes: High power microscopy analysis of all histological specimens across genotypes revealed the absence of micrometastatic foci in regions where invasion was not visible macroscopically. Melanin producing cancer cells were observed abluminally with respect to BM and liver sinusoids, adopting a perivascular location. In WT and Het mice, the invaded MCC colonized the BM parenchyma where they appear to reside in physical association with CD146-expressing resident MSC/pericytes (FIG. 5C). This is in contrast to PDGF-B mutant-derived samples where no further advancement of invading cells was observed beyond the perivascular space (FIG. 5A, high magnification). This physical association and the constitutive expression of CD146 by both MCC and MSC/pericytes prompted us to evaluate CD146 as a potential mechanism for an intercellular adhesion between them at the perivascular space generated during extravasation. CD146 Silencing in MCC Impairs their Ability to Extravasate to Skeleton and Liver: We first assessed the role of CD146 from the invading cell perspective. A high CD146 silencing efficiency (˜90%) was obtained after lentiviral transduction of B16F10 cells with the constitutive CD146_shRNA vector as compared with the NT (non-targeting)_shRNA control (FIG. 6A). These engineered cells were then intra-arterially injected into WT mice (n=6). Animals that received control cells (NT_shRNA; n=3) exhibited a more rapid and dramatic clinical deterioration compared with animals that received cells with silenced CD146, including a more pronounced weight loss (34±3% vs. 18±2%, P<0.05), ambulation difficulties, restricted limb movements and hunched backs. Similar to PDGF-B mutant mice, invasion was compromised selectively to skeleton and liver in mice that received CD146-silenced B16F10 cells compared to control cells (FIG. 7). CD146 Silencing in BM-Derived hMSC/Pericytes Impairs MCC Invasion to Humanized Extraskeletal Bone Structures in Mice: As CD146 has been shown to exhibit homotypic interactions, we next evaluated the role of CD146 silencing now from the resident MSC/pericyte perspective. The two concentrations of IPTG tested resulted in a comparable silencing efficiency of CD146 in hMSC (˜75%) as assessed by immunolocalization of the protein in cultured cells (FIG. 6B). Engineered cells were used to create osteogenic ceramic cubes (depicted in FIG. 8), which after implantation in immunocompromised mice generated humanized extraskeletal bones (ossicles) that fully recapitulate the native bone structure including the formation of blood vessels (sinusoids) and sequentially functional hematopoietic tissue. Within these humanized osseous structures, donor-derived hMSC form the bone tissue and assemble as pericytes during the formation of vascular structures, as shown by Sacchetti et al, and confirmed by our observations with immunolocalization of the hMSC marker CD271 using a specific anti-human antibody (FIG. 9A). Sacchetti et al., Cell 2007; 131(2), 324-336. This humanized assay allowed us to circumvent the use of a CD146 KO mouse to monitor the effects of CD146 deficiency on the ability of resident perivascular cells to drive melanoma cell extravasation into the BM. As a control, untransduced WT hMSC (control) and a subset of hMSC with pathologically slow dividing activity after being transduced with the NT_shRNA vector and passaged several times (SD) were used. These two controls represent normal (control) and an aberrant (SD) formation of the ossicles and all their structural components of which the SD cells reflected the reduced osteogenic capacity of hMSC after serial passaging. Eight weeks after subcutaneous ossicle implantation, IPTG (12.5 mM for 7 days) was administered through the drinking water to induce the in vivo gene silencing within these bone structures, evidenced by immunolocalization of CD146 in sections (FIG. 9B), and consistent with the in vitro silencing. Intra-arterially injected MCC were found to invade the skeleton and the control hMSC-made ossicles as evidenced by the intense BLI signals that were observed in all structures (5/5) (FIG. 10A). In contrast, ossicles made with hMSC that lacked CD146 generated a dramatic reduction in the invasion of MCC, detected in only one structure (1/5) with a faint signal. As expected, ossicles made with slow dividing hMSC (SD) were not invaded by MCC, as these structures lacked substantial bone formation, vascular structures and hematopoietic tissue observed in a histological analysis (FIG. 10B). Finally, like the situation in the murine BM, invading MCC were found in humanized ossicles in close spatial relationship with resident hMSC/pericytes identified by immunolocalization of CD146 (FIG. 10C). Sdf-1/CXCL12 Silencing in BM-Derived hMSC/Pericytes is Required for MCC to Invade Humanized Extraskeletal Bone Structures and to Migrate In Vitro: Sdf-1/CXCL12 has been described as a potent attractant to CXCR4-expressing cells, including MCC. Bartolome et al., Cancer Res 2004; 64(7), 2534-2543. Its expression in the BM has been demonstrated to come primarily from perivascular cells (i.e., MSC/pericytes). Ding L, Morrison S J, Nature 2013; 495(7440), 231-235. Therefore, we assessed its potential contribution during extravasation of MCC into bone, through it silencing in resident MSC/pericytes using the humanized extraskeletal bone formation assay. The two concentrations of IPTG tested to induce Sdf-1/CCXCL12 gene silencing generated a comparable ˜55% reduction relative to untreated parental hMSC, or to NT_shRNA-transduced hMSC treated with IPTG (FIG. 6C). Sdf-1/CXCL12 silencing in hMSC/pericytes showed a significant reduction both in the number of ossicles invaded (2/5) and the intensity of the BLI signal obtained (FIG. 10A), as well as on the size of the secondary tumors where present (FIG. 10B). In an in vitro modified transendothelial migration (TEM) assay (FIG. 11A), fluorescence microscopy revealed DiI pre-labeled hMSC that were seeded at the bottom of an 8 μm pore membrane forming colony-like structures (FIG. 11B—top row). Bright-field microscopy showed the interaction of B16F10 cells (after migrating from the upper chamber) with parental hMSC (i.e., NT_shRNA control cells) in that same plane, an event that was noticeably absent in their Sdf-1/CXCL12-deficient counterparts and when skin fibroblasts and no cells were used as controls (FIG. 11B—bottom row). Similarly, an increased distance between the MCC and hMSC prevented their migration throughout the membrane regardless of whether the hMSC were silenced or not for Sdf-1/CXCL12 (FIG. 12). DISCUSSION Through the use of complementary in vitro and in vivo approaches, including a humanized assay of bone metastases in mice, we documented details of the function of MSC/pericytes in mediating the extravasation and the initial metastatic seeding of MCC at the BM and liver microvasculature. Mechanistically, we describe the participation of the cell surface molecule CD146 and the chemokine Sdf-1/CXCL12 as critical determinants of the molecular events occurring during the dissemination process resulting in the physical association between the invading cancer cell and the MSC/pericyte at the target organ microenvironment (i.e., perivascular space). Importantly, genetic ablation of abluminal positioning of pericytes alleviates these untoward events, and as such, we propose that circulating MCC follow an Sdf-1/CXCL12 gradient that facilitates their access to endothelial fenestrations and resident MSC/pericytes. These MSC/pericytes specifically associate with CD146-positive MCC and promote their extravasation into the target organ parenchyma (depicted in FIG. 13). The concept of a physical association between invading cancer cells and stromal cells in the BM has been previously reported as critical for the progression and fate of metastatic tumors. Yoneda T, Hiraga T., Biochem Biophys Res Commun 2005; 328(3), 679-687. In addition, the participation of MSC during the endothelial transmigration of low metastatic breast cancer cells has been suggested using in vitro models. Nevertheless, our study constitutes the first direct in vivo evidence of the participation of MSC as pericytes during the process of melanoma dissemination, as well as the description of the precise location (i.e., perivascular space) and the molecular players involved in the cell-to-cell association that lead to the establishment of distant metastases. We observed a close proximity between invading MCC and resident MSC/pericytes at both the sinusoidal perivascular space and the tissue parenchyma. See FIGS. 14A and 14B, which show the proximity of hMSCs to the vasculature. These observations further suggest the physical interaction between those two cell types during the extravasation of cancer cells at the target organ and establishes a previously underappreciated sentinel role of MSC (as pericytes) during the process of cancer cell invasion. MSC have been historically seen as the in vitro precursors of mesenchymal tissues including bone, cartilage, fat and muscle. Nevertheless, our data supports the recent proposition that MSC reside in vivo in a perivascular niche and that they arise from perivascular cells, while suggesting that they participate in parallel homeostatic functions exerted at their strategic abluminal location including cancer invasion to target organs. Indeed, the function of pericytes during cancer dissemination is not limited solely to their known effect on vascular stability (Armulik et al., Circ Res 2005; 97(6), 512-523), but instead indicates a more active role during the process of cancer cell extravasation. In fact, pericytes have been described as gatekeepers of tumor metastasis, since their absence promotes cancer cell dissemination to target tissues from primary tumors in mice. Xian et al., J Clin Invest 2006; 116(3), 642-651. Using the same genetic model of pericyte disturbed coverage reported by Xian et al (PDGF-Bret/ret mice), we now present evidence that invasion of circulating MCC is significantly and selectively reduced in the skeleton and liver, but remains surprisingly intact at other target organs (e.g., brain, adrenal glands and lungs). These apparent discrepancies may be explained by the following arguments. First, Xian et al focused on the process of cancer cells intravasation from a primary tumor (insulinoma) where an “abnormal” tumor forming vasculature is further destabilized in the mutant mice, thereby increasing the number of tumor cells capable of escaping into the vasculature. This increased number of circulating cancer cells might account for the distant colonization observed in a fraction of the animals. In stark contrast, we focused on the process of extravasation of a predetermined, fixed number of intra-arterially injected MCC from a vessel network at the target organ impacted only by the expression of the transgene. Second, Xian et al studied an insulinoma primary tumor, which makes comparisons of distal invasion difficult to assess because insulinoma cells typically do not invade the BM and liver as proficiently as MCC. Third, it has been proposed that primary tumors secrete factors that “prepare” the target organ for future invasion, a process known as pre-metastatic niche formation. Psaila B, Lyden D., Nat Rev Cancer 2009; 9(4), 285-293. In contrast to the model of Xian et al, our study bypassed the formation of a primary tumor, thus preventing this contributing phenomenon. Finally, Xian et al described both lymphatic and hematogenous pathways as contributors of distant dissemination. Our model does not involve a lymphatic-mediated mechanism as we inject the cancer cells intra-arterially. However, some MSCs could be occupying lymphatic sites. In addition, truly lymphatic-dependent bone metastases are still controversial. Edwards et al., Human pathology 2008; 39(1), 49-55. Taken together, the pivotal role of MSC/pericytes at their perivascular niche regulating the extravasation of circulating MCC to bone and liver further expands our knowledge about novel functions of these adult stem cells. In parallel, the identified molecular mechanisms involving intercellular adhesion molecules (i.e., CD146) and secreted chemokines (i.e., Sdf-1/CXCL12) strengthens the concept of cellular cooperativity reported at sites of injury and primary tumors and now expanded to target organs during cancer dissemination. Example 2—Laminins 411 and 511 as Metastatic Cancer Attractants Experiments were carried out to determine the effectiveness of laminins 411 and 511 as metastatic cancer attractants. The transendothelial migration (TEM) assay includes three layers; a layer of HMVEC or HUVEC cells over a layer of basement membrane (e.g., matrigel, laminins), which are in turn positioned over a lyer of BM-hMSCs. Cancer cells are positioned over the three layer system. FIGS. 15A and B and 16A-C show the differential effect of laminins 411 and 511 on cancer cell migration in the presence of hMSCs using the TEM assay. The results show that both laminin 411 and laminin 511 have an effect on cancer cell migration to the BM-HSCs, with laminin 411 showing about twice the effect of laminin 511. FIG. 16D shows the assay in which the ability of laminins 411 and 511 to function as metastatic cancer attractants was evaluated. While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims. All patents, publications and references cited in the foregoing specification are herein incorporated by reference in their entirety.
<SOH> BACKGROUND <EOH>Mesenchymal Stem Cells (MSC) have long been described as cellular progenitors of mesenchymal lineages including bone, cartilage, fat, muscle and other connective tissues. In addition, a secretory capacity has been identified with both immunomodulatory and trophic activities, exerted at sites of injury where they interact with other local cellular components. The recent identification of the MSC niche in the perivascular space as pericytes has opened the possibility that MSC may have additional roles directly controlling tissue homeostasis from their cardinal abluminal location. Caplan, A. I., Cell Stem Cell 2008; 3(3), 229-230. Metastasis is a leading prognostic indicator for cancer survival and a major contributor to cancer mortality. The skeleton and liver are common organs for cancer dissemination in various malignancies including malignant melanoma. Although the preponderance of distant metastases implies a selective advantage for arriving disseminating cells, recent studies have determined that the rates of tumor growth, invasion, and metastasis are in fact independent pathological traits governed by different sets of genes. Nguyen D X, Massague J, Nat Rev Genet 2007; 8(5), 341-352. Nevertheless, they share a common feature, namely their dependence on the vasculature that provides access to oxygen and nutrients, as well as a route for cancer cell dissemination. Current cancer therapies are designed to alter not only specific biological functions in cancer cells, but also to target components of the tumor microenvironment (TME)/stroma, especially the vasculature. Pericytes are a specialized cell type that function abluminally covering and stabilizing blood vessels following their recruitment to forming vessels as progenitor cells via PDGF-B/PDGFRB signaling. Armulik et al., Circ Res 2005; 97(6), 512-523. Pericyte involvement in primary tumors growth constitutes a novel therapeutic target based on compelling evidence showing superior reduction in size when targeted in parallel with endothelial cells (ECs). Bergers et al., J Clin Invest 2003; 111(9),1287-1295. However, pericyte coverage of the vasculature seems to differentially regulate tumor growth and metastatic potential, as intravasation of cancer cells is increased in primary tumors grown in mice with a genetically-determined deficient pericyte coverage. Xian et al., J Clin Invest 2006; 116(3), 642-651. These findings have led to the appreciation, in some cases, of pericytes in primary tumors as gatekeepers for cancer dissemination. Gerhardt H, Semb H., J Mol Med 2008; 86(2),135-144. In parallel, in response to tumor signals, BM-derived progenitor cells of mesenchymal origin (as MSCs) are recruited to the tumor stroma localizing in perivascular sites and helping to assemble a supporting vascular network critical for tumor growth. Bergfeld S A, DeClerck Y A., Cancer metastasis reviews 2010; 29(2), 249-261. Taken together, BM-derived MSC (BM-MSC) appear to play a critical role during primary tumor formation, and growth. In contrast, the role of pericytes at the target organ microenvironment during cancer cell extravasation is not known. Recently, data suggest that cellular and molecular elements in the BM are related to the establishment and progression of skeletal metastasis. For example, blocking PDGFB with a multi-target tyrosine kinase inhibitor (Sunitinib) impairs bone invasion of circulating osteotropic lung cancer cell lines due to altered tumor cell-BM stroma interactions. Catena et al., Cancer Research 2011; 71(1), 164-174. In addition, it has been established that invading cancer cells physically associate with mesenchymal derived cells in the BM affecting various biological activities of engrafted cancer cells, including dormancy/quiescence, resistance to chemotherapy and metastatic growth. Corcoran et al., PLoS One 2008; 3(6), e2563. However, the specific identity of the cellular and molecular elements, as well as the precise location where the sequence of events occur during extravasation is still not well understood. The mechanisms governing skeletal metastasis involve comparable details to those used by hematopoietic stem cells (HSC) and their progeny entering the BM. The “homing” behavior of HSCs and exit of progeny relies on the existence of a specific physical niche within the BM where other cellular players, including MSC, favor the constant trafficking of such progenitors across the sinusoidal wall. Shiozawa et al showed that invading osteotropic prostate cancer cells enter the HSC niche competing with resident cells and thus establishing physical anchors for further growth inside the BM. Shiozawa et al., The Journal of clinical investigation, 2011; 121(4), 1298-1312. There remains a need for novel methods of diagnosing and treating metastatic cancer, such as bone metastasis.
<SOH> SUMMARY <EOH>With the notion of BM-MSC as pericytes, the inventors propose taking advantage of the physical interaction of invading cancer cells and resident BM-MSC occurring at the abluminal space of BM sinusoids as a determinant step in the initiation and fate of skeletal metastasis. The inventors have shown that altering the physical interaction between vascular components of the target organ microenvironment (ECs and MSC/pericytes) via genetic manipulation of PDGF-B, dramatically impairs the engraftment of intraarterially-delivered cancer cells, thus reducing the frequency of osteolytic bone metastasis. Through in vitro and in vivo approaches, including a humanized assay in which fully functional extraskeletal bone is engineered with human MSC (hMSC), the essential molecular players and mechanisms involved in the extravasation of circulating MCC to the BM were established, that become disrupted in the absence of sinusoidal MSC/pericytes. In parallel, they observed that the situation in the BM is replicated in the liver exclusively, whereas no invasion by melanoma was seen in mutant mice. The inventors therefore propose that the presence of MSC as pericytes surrounding BM and liver sinusoids is required for extravasation of MCC, and that the effects of the EC/pericyte dissociation at the metastatic target organ do not mirror its effects during intravasation at the primary tumor. The inventors show that MSC/pericytes function as sentinels regulating cancer cell dissemination with a differential effect during intravasation at the primary tumor and extravasation at the target organ. The molecular mechanisms, cellular players and locations during the establishment of melanoma metastasis to BM and liver were defined. This can be used to trap metastatic cancer cells in order to treat and/or diagnose metastatic cancer. Accordingly, in one aspect, the invention provides a method of treating cancer metastasis in a subject, comprising implanting a decoy trap within the subject, the decoy trap comprising an implantable trap device including a metastatic cancer attractant. In some embodiments, the method is used to treat the metastasis originating from breast cancer, prostate cancer, or lung cancer primary tumors. In one embodiment, the cancer metastasis is bone metastasis, and the metastatic cancer attractant is a bone-seeking cancer attractant. In another embodiment, the bone-seeking cancer attractant is pericytes. In a further embodiment, the subject is human and the pericytes are human pericytes. In some embodiments, the implantable trap device comprises bone tissue. In further embodiments, the implantable trap device comprises a porous calcium phosphate ceramic. In other embodiments, the decoy trap comprises a composite vascular structure. In yet further embodiments, the decoy trap further comprises a labeled probe that specifically binds to cancer cells. In other embodiments, the decoy trap is implanted in contact with a blood vessel. Another aspect of the invention provides a method of diagnosing cancer metastasis in a subject, comprising implanting a decoy trap within the subject, the decoy trap comprising an implantable trap device including a metastatic cancer attractant, allowing the decoy trap to remain within the subject for a period of time, and diagnosing the subject as having metastatic cancer if metastatic cancer cells are detected in the decoy trap. In some embodiments, the method is used to diagnose metastasis in a subject diagnosed with breast, prostate, or lung cancer. In further embodiments, the decoy trap is removed from the subject before detecting bone-seeking cancer cells in the decoy trap. In other embodiments, the decoy trap remains in vivo while detecting bone-seeking cancer cells in the decoy trap. In some embodiments of the method of diagnosing metastatic cancer, the cancer metastasis is bone metastasis and the metastatic cancer attractant is a bone-seeking cancer attractant. In other embodiments, the bone-seeking cancer attractant is pericytes. In further embodiments, the pericytes are human pericytes. In some embodiments, the implantable trap device comprises bone tissue. In further embodiments, the implantable trap device comprises a porous calcium phosphate ceramic. In some embodiments of the method of diagnosing metastatic cancer, the decoy trap further comprises a labeled probe that specifically binds to metastatic cancer cells. In further embodiments, the method comprises determining quantifying the amount of metastatic cancer cells that have entered the decoy trap.
A61K3544
20170927
20180222
67892.0
A61K3544
0
SGAGIAS, MAGDALENE K
METASTATIC CANCER DECOY TRAP
SMALL
1
CONT-REJECTED
A61K
2,017
15,717,056
ACCEPTED
Elastomeric Coating Composition
An elastomeric coating composition to enhance or alter the aesthetic appearance of an automobile. The coating composition can be applied by spraying onto either a vehicle paint job or clear coat and is semi-permanent upon drying. The coating composition can be manually removed from the vehicle by peeling without damaging the underlying paint job or clear coat on the vehicle.
1. A coating composition, comprising: a composite film comprising: a polymer; a tackifier; a hydrocarbon resin; a solvent; and a UV stabilizer; and at least one pigment additive. 2. The coating composition according to claim 1, wherein the hydrocarbon resin has a softening point of at least 140 degrees Celsius. 3. The coating composition according to claim 1, wherein the hydrocarbon resin has a melting point of at least 140 degrees Celsius. 4. The coating composition according to claim 1, wherein the polymer is a Styrene/ethylene/butylene/styrene liner triblock copolymer. 5. The coating composition according to claim 4, wherein the solvent comprises a mixture of xylene, toluene and naphtha. 6. The coating composition according to claim 5, further comprising a silicon dioxide thixotrope. 7. The coating composition according to claim 6 that is manually peel-able when dried onto a surface. 8. The coating composition according to claim 7 having a viscosity configured for use in a high volume low pressure sprayer application 9. The coating composition according to claim 1, wherein the hydrocarbon resin is present in an amount between 5 percent by weight and 7 percent by weight. 10. The coating composition according to claim 9, wherein the hydrocarbon resin is present in an amount between 5.5 percent by weight and 6.75 percent by weight. 11. The coating composition according to claim 10, wherein the hydrocarbon resin is present in an amount of 5.7 percent by weight. 12. The coating composition according to claim 1 wherein the composite film further comprises a hindered amine light stabilizer. 13. The coating composition according to claim 1 wherein the composite film further comprises an antioxidant. 14. The coating composition according to claim 1 wherein the composite film further comprises a pigment additive. 15. The coating composition according to claim 1 further comprising a gloss coating on the coating composition. 16. A coating composition comprising: a composite film comprising: a styrene/ethylene/butylene/styrene liner triblock copolymer; a hydrocarbon resin; a tackifier; silicon dioxide thixotrope; a hindered amine light stabilizer; a UV stabilizer; an antioxidant; a solvent blend; and at least one pigment additive; and a gloss coating on the composite film. 17. The coating composition according to claim 16 wherein the styrene/ethylene/butylene/styrene liner triblock copolymer is present in an amount greater than 6 weight percent. 18. The coating composition according to claim 16 wherein the hydrocarbon resin is present in an amount greater than 5 weight percent. 19. The coating composition according to claim 16 wherein the tackifier is present in an amount greater than 1 weight percent. 20. The coating composition according to claim 16 wherein the hindered amine light stabilizer is present in an amount greater than or equal to 0.20 weight percent. 21. The coating composition according to claim 16 wherein the UV stabilizer is present in an amount greater than or equal to 0.20 weight percent. 22. The coating composition according to claim 16 wherein the antioxidant is present in an amount greater than or equal to 0.20 weight percent. 23. The coating composition according to claim 16 wherein the solvent blend comprises a mixture of 22/11/9 of Xylene, Toluene, and VM&P Naphtha in an amount greater than 80 weight percent.
CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of application No. 15/056,052 filed on Feb. 29, 2016 entitled “Elastomeric Coating Composition and Method of Applying Same” which claims priority to Provisional Application No. 62/126,587 filed on Feb. 28, 2015 and entitled “Elastomeric Coating Composition and Method of Applying Same.” The content of these applications are fully incorporated herein for all purposes. BACKGROUND OF THE INVENTION This invention relates to an elastomeric coating specifically engineered to enhance or alter the aesthetic appearance of an automobile. In traditional settings, automobile paint shops change the color and finish of trucks, cars, and other vehicles by applying permanent paint to the exterior of the vehicle. This process is extremely time consuming, expensive, and irreversible unless the owner starts over and re-paints the vehicle again. Other aesthetic enhancements to vehicles include pin stripe appliques or the like. These kinds of embellishments are often glued to the surf ace of the vehicle to provide a unique look to the exterior finish and are intended to be permanent. The main kinds of temporary exterior enhancements to a vehicle finish are often magnetized or attached with a removable glue, neither of which is durable. A need exists in the art of automobile finishing for a solution to the problem that individuals and businesses prefer to decorate their vehicles with finishes that are changeable without having to re-paint or re-apply a permanent finish again and again. SUMMARY OF THE INVENTION A coating composition for vehicles, comprises a polymer, a tackifier, a hydrocarbon resin; and a solvent. In another embodiment, the coating composition includes a styrene/ethylene/butylene/styrene liner triblock copolymer in an amount by weight of 6.51 percent; a hydrocarbon resin in an amount by weight of 5.70 percent; a tackifier in an amount by weight of 1.14 percent; silicon dioxide thixotrope in an amount by weight of 0.57 percent; a hindered amine light stabilizer (HALS) in an amount by weight of 0.20 percent; a UV stabilizer in an amount by weight of 0.20 percent; an antioxidant in an amount by weight of 0.20 percent; a solvent blend including a mixture of 22/11/9 of Xylene, Toluene, and VM&P Naphtha in an amount by weight of 85.47 percent. The foregoing has outlined rather broadly the more pertinent and important features of the present invention in order that the detailed description of the invention that follows may be better understood so that the present contribution to the art can be more fully appreciated. Additional features of the invention will be described hereinafter which form the subject of the claims of the invention. It should be appreciated by those skilled in the art that the conception and the specific embodiments disclosed may be readily utilized as a basis for modifying or designing other structures and methods for carrying out the same purposes of the present invention. It should also be realized by those skilled in the art that such equivalent constructions and methods do not depart from the spirit and scope of the invention as set forth in the appended claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT In one embodiment, the coating of this disclosure is an elastomeric coating composition that is useful in part to cover the exterior finish of a vehicle in a semi-permanent manner. As used herein, the term “vehicle” encompasses all of the usual embodiments of a device used for travel, including but not limited to, automobiles and trucks. Other kinds of vehicles may also fall within the scope of this invention, such as more specialized uses like race cars, motorcycles, golf carts, or even boats. None of these examples limits the kinds of “vehicles” for which the coating described herein may be used. The coating described in this disclosure is considered semi-permanent in that the coating, applied properly, does not wash off or fall off the vehicle after application, but stays in place on the vehicle until the user chooses to remove it. When the user or owner of a vehicle decides to remove the coating, the coating is amenable to being peeled off without harming the underlying original finish of the vehicle. The coating, however, does not detach from the original finish of the vehicle unless and until the user makes a concerted effort to peel the coating off of the vehicle. When the coating is removed, the coating does not damage the underlying finish to which it has been applied. In one embodiment, the coating is an adherent film, configured for spraying onto a vehicle and having a formulation including, at least in part: 1) Thermoplastic rubber 2) Hydrocarbon resin 3) Tackifier 4) Solvent system using Varnish Makers & Painters (VM&P) Naphtha, Xylene, and Toluene 5) Thixotropic Silica 6) Anti-oxidant/UV stabilizers. In one embodiment, the anti-oxidants and UV stabilizers are applied as a solution to the coating and allowed to air dry thereon. Subsequent layers provide for full coverage, where desired results can be achieved. The coating described herein, therefore, relates to an improved elastomeric coating composition used to alter the original appearance of a vehicle and a number of its exterior components, including but not limited to painted or clear coat surfaces, trim, wheels, rims, and badges, whereby future removal is allowed, returning the vehicle back to its originally equipped and manufactured state. One method of the present invention includes the utilization of the coating solution to coat the vehicle in stages, where the initial coat and each subsequent layer is allow to air dry thereby providing for a desired change or changes in appearance. The film is both adherent and of uniform composition, and forms a rugged composite shell which retains its elastomeric properties under prolonged UV exposure and other naturally occurring environmental elements. The composite film was engineered with an application-specific bond strength to achieve both adequate adhesion balanced with good removability characteristics, as well as superior tensile and peel strength properties. The quantity of tackifier used in the formulation is within a range and concentration so that the film is stable upon vehicle application and will stay on the outer surface of the vehicle so long as the owner desires, but with the tackifier used in proper quantities, the film peels off the surface of the vehicle without damaging the underlying original paint job or clear coat. In this way, the tackifier is used in the appropriate quantity and the film solution has a tackifier therein in a range of composition or concentration to ensure that the film is peel-able upon drying. The peeling force needed to remove the film after drying is within a range allowing for peeling by hand without damaging the original paint job and clear coat on the vehicle. Generally, the present invention is an adherent-coherent coating system where a base or primer coat is not required. The coating is sprayed directly onto an original equipment manufacturer vehicle finish. The coating described herein has made significant contributions to the development of a pigment carrier system and loading concentrations of the same in order to achieve the desired appearance after a specified number of coats. The application technique for the coating is by pressurized spraying via HVLP (high volume low pressure) spraying equipment. The pigment carrier system used with the film described herein is important, as the color of the film can be very important for marketing and commercial applications. The pigments used to color the film may be proprietary to the owner of the technology disclosed herein, such that pigments that are wetted into solution yield vibrant, deeper, or generally more aesthetically pleasing colors. The carriers used for the pigments may be based in polyol compounds or mineral oil mixtures. Typically composite coatings are measured by a number of desirable physical and chemical properties such as durability, adhesion, cohesion, and bond and peel strengths. As a rule, the inventor maximized each of these properties whenever possible; however, as often was the case a tradeoff occurred, where the increase of one component led to an adverse reaction in the overall composite system; therefore, the inventor employed a measured compromise approach with respect to the conflicting properties in order to achieve a collection of desired use characteristics. Research and trials of at least 100 attempts were employed using various types and ratios of styrene/ethylene/butylene elastomers, hydrocarbon resins, thixotropic silicas and solvents and respective ratios that best provided for adequate spray and finishing characteristics, strength and durability properties, coupled with desired bond and peel behaviors. A number of various hydrocarbon resins were incorporated to help enhance the overall durability and scratch resistance not yet achieved by earlier formulations. After rigorous research and development, certain hydrocarbon resins, for example but not limited to Eastman's Plastolyn™ 290, have been identified as being one useful ingredient to aid the enhancement of the coatings overall look, feel, finish texture and enhanced mar resistance, again not seen by earlier formulations. Other purified aromatic monomers having similarly high softening points are also options for this line of coatings. In one embodiment, other aromatic hydrocarbon resins having a softening point of at least 140 degrees Celsius (according to ASTM D6493-11(2015), Standard Test Methods for Softening Point of Hydrocarbon Resins and Rosin Based Resins) and a melt viscosity of about 1000 poise at 165 degrees Celsius could provide similar results. In another embodiment, the hydrocarbon resin exhibits a melt viscosity of 1,100 mPa·s (200° C.). The same is true with the solvent ratios. Each solvent tested had specific properties that among other reactions, i.e. chemical-solubility parameters, Kb values, and polar and/or non-polar reactions, must be incorporated into the composite system in specific orders and quantities to aid in the proper homogeneous solution and subsequent end use via the high volume low pressure spraying equipment. More rigorous testing identified both the candidates and ratios thereof for use in the end composite solution. As with all elastomeric films built to an adequate thickness, the subject coating shares similar properties in its imperviousness to acids, alkalis, salts, moisture, and capability of withstanding prolonged UV exposure while remaining flexible over a wide range of temperatures. Therefore, it is a primary objective of the subject invention to provide an improved coating used in aid of altering or enhancing the appearance of the exterior of automobiles and method of doing the same. The dried composite film possesses superior texture such that a satin or vinyl look is achieved and bond, peel and tensile strength characteristics are optimized for end user ease of use. Furthermore, the subject invention is to provide an improved technique for coating the exterior of automobiles such that a smooth vinyl and/or satin like appearance can be achieved not seen in earlier formulations. Furthermore, augmenting the subject invention using colorants, namely of organic and inorganic variety, but not limited to the use of automotive powders, flakes and pearls. Other and further objects of the present invention will become apparent to those skilled in the art upon a study of the following specification and appended claims. The thermoplastic rubber component consists of a styrene/ethylene/butylene/styrene linear triblock copolymer. The undusted hydrogenated version of these triblock copolymers is utilized. This material is sprayed on the substrate, i.e. clear-coat to be coated in multiple coats to ensure adequate coverage and uniform texture across the entire surface sprayed. After application, the film is allowed to dry, with the solvent becoming fugitive to the system; but in a specific order where the tail solvent, in this case xylene, provides for adequate leveling. The following paragraphs list examples of formulations used to form the film disclosed herein: EXAMPLE 1 Subject Coating/Film Formulation Percent Ingredient by Weight Styrene/ethylene/butylene/styrene liner triblock 6.51 copolymer, e.g., sold by Kraton Performance Polymers, Inc. under the designation “Kraton G-1652” Hydrocarbon resin-e.g., Plastolyn 290 sold by 5.7 Eastman Chemical Company Tackifier e.g., Eastotac H100 W sold by 1.14 Eastman Chemical Company Silicon dioxide Thixotrope sold by Cabot 0.57 Corp. e.g., Cabosil M-5 Hindered amine light stabilizer (HALS) 0.20 Chemstab LS-292 e.g., distributed by TMC Materials, Inc. UV stabilizer Chemsorb LS-328 e.g., 0.20 distributed by TMC Materials, Inc. Antioxidant Chemnox AN-1010 e.g., 0.20 distributed by TMC Materials, Inc. A solvent blend including a mixture of 22 I 11 85.47 I 9 of Xylene, Toluene, and VM&P Naphtha. EXAMPLE 2 Subject Coating/Film Formulation Ingredient Grams Percent by Weight Kraton 1652 32 6.50% Plastolyn 290 28 5.69% Eastotac H100 4.5 0.91% Cab-o Sil M5 3.7 0.75% Chemstab 1.8 0.37% Chemsorb 1.3 0.26% Chemnox 1 0.20% Xylene 220 44.69% Toluene 120 24.38% Naphtha 80 16.25% TOTAL 492.3 100.00% EXAMPLE 3 Pigmentation Ounces/gallon by Pigment weight in Ounces Covert Black 12808-A 3 Killa Red R-8174 3 Bright White W-4514-B 5.7 Primer Gray 12823 5.7 Glacier Blue B-7934 4.7 Lethal Blue B-6591-A 4.2 Venom Green G-7380-A 4.2 Incendiary Yellow Y-3922-A 5.7 Agent Orange O-1981-B 5.7 Purple P-1468-A 5.8 Pink R-8187-A 5.2 Mil Spec Tan T-6276 4.2 Mil Spec Green G-7384 3.2 Gangsta Black KSEB-2022 3 Another layer of gloss coating is also an option for the coating described herein. One example is a spray-able gloss coating having a slow activator, such as but not limited to, SEM 50501 EZ Clear Coat. Applying this kind of gloss coat to the peel-able coating formulation described above gives the shiny finish that users desire and still allows the resulting finish to be peeled off without damaging the paint and clear coat below. These and other aspects of the film composition and method of making the same are set forth in the claims below.
<SOH> BACKGROUND OF THE INVENTION <EOH>This invention relates to an elastomeric coating specifically engineered to enhance or alter the aesthetic appearance of an automobile. In traditional settings, automobile paint shops change the color and finish of trucks, cars, and other vehicles by applying permanent paint to the exterior of the vehicle. This process is extremely time consuming, expensive, and irreversible unless the owner starts over and re-paints the vehicle again. Other aesthetic enhancements to vehicles include pin stripe appliques or the like. These kinds of embellishments are often glued to the surf ace of the vehicle to provide a unique look to the exterior finish and are intended to be permanent. The main kinds of temporary exterior enhancements to a vehicle finish are often magnetized or attached with a removable glue, neither of which is durable. A need exists in the art of automobile finishing for a solution to the problem that individuals and businesses prefer to decorate their vehicles with finishes that are changeable without having to re-paint or re-apply a permanent finish again and again.
<SOH> SUMMARY OF THE INVENTION <EOH>A coating composition for vehicles, comprises a polymer, a tackifier, a hydrocarbon resin; and a solvent. In another embodiment, the coating composition includes a styrene/ethylene/butylene/styrene liner triblock copolymer in an amount by weight of 6.51 percent; a hydrocarbon resin in an amount by weight of 5.70 percent; a tackifier in an amount by weight of 1.14 percent; silicon dioxide thixotrope in an amount by weight of 0.57 percent; a hindered amine light stabilizer (HALS) in an amount by weight of 0.20 percent; a UV stabilizer in an amount by weight of 0.20 percent; an antioxidant in an amount by weight of 0.20 percent; a solvent blend including a mixture of 22/11/9 of Xylene, Toluene, and VM&P Naphtha in an amount by weight of 85.47 percent. The foregoing has outlined rather broadly the more pertinent and important features of the present invention in order that the detailed description of the invention that follows may be better understood so that the present contribution to the art can be more fully appreciated. Additional features of the invention will be described hereinafter which form the subject of the claims of the invention. It should be appreciated by those skilled in the art that the conception and the specific embodiments disclosed may be readily utilized as a basis for modifying or designing other structures and methods for carrying out the same purposes of the present invention. It should also be realized by those skilled in the art that such equivalent constructions and methods do not depart from the spirit and scope of the invention as set forth in the appended claims. detailed-description description="Detailed Description" end="lead"?
C09D520
20170927
20180306
20180118
75225.0
C09D520
2
HARLAN, ROBERT D
Elastomeric Coating Composition
SMALL
1
CONT-ACCEPTED
C09D
2,017
15,717,138
ACCEPTED
INTERNET QUERIED DIRECTIONAL NAVIGATION SYSTEM WITH MOBILE AND FIXED ORIGINATING LOCATION DETERMINATION
A mobile wireless network and a method of operation provide directional assistance in response to an Internet query. The directional assistance is provided from a location of the querying device to a destination that may be selectively prompted based on whether the destination is a nearby business, a type of business, a street address, or another mobile device or fixed telephone location. The location of the querying device is also selectively determined depending on whether the querying device is a wireless device such as a mobile telephone, or whether the device has a presumed fixed location, such as an ordinary telephone connected to a public-switched telephone network (PSTN).
1. A method of providing navigation assistance to a user of a communications device, the method comprising: receiving, by a directional assistance service, an Internet query initiated at the communications device and directed via the Internet to initiate a request for navigational assistance to a destination; responsive to receiving the Internet query, determining whether or not the communications device is a mobile wireless communications device; responsive to determining that the communications device is the mobile wireless communications device, the directional assistance service determining and using a present location of the mobile wireless communications device as a location of the communications device; responsive to determining that the communications device is not the mobile wireless communications device, obtaining a fixed location associated with the communications device to determine the location of the communications device; and the directional assistance service providing navigation information to the communications device in response to the Internet query, wherein the navigation provides directions for proceeding from the location of the communications device to a location of the destination. 2. The method of claim 1, wherein the determining and using the present location of the mobile wireless communications device comprises querying an external user location database of a network of the mobile wireless communications device to determine the location of the communications device. 3. The method of claim 1, wherein the determining and using the present location of the mobile wireless communications device comprises: the directional assistance service initiating locating the mobile wireless communications device by sending a query to a switch or base station controller of a wireless network; and building an internal database storing the present location of the mobile wireless communications device with results of the query and using the stored location as the location of the communications device. 4. The method of claim 1, wherein the obtaining the fixed location associated with the communications device comprises retrieving the fixed location from a database. 5. The method of claim 4, wherein the retrieving the fixed location from the database comprises querying a public service telephone network (PSTN). 6. The method of claim 1, further comprising receiving a user input of a destination telephone number at the communications device, wherein the received Internet query includes the destination phone number, and wherein the directional assistance service determines the location of the destination from the destination phone number. 7. The method of claim 1, further comprising receiving a user input of a destination address at the communications device, wherein the received Internet query includes the destination address, and wherein the directional assistance service determines the location of the destination from the destination address. 8. The method of claim 1, further comprising receiving a user input of a name of a business at the communications device, wherein the received Internet query includes the name of the business, and wherein the directional assistance service determines the location of the destination from the name of the business. 9. The method of claim 8, wherein the user input of the name of the business is a first user input, and wherein the method further comprises: the directional assistance service providing selection between the first user input of the name of the business or a second user input of a destination telephone number at the communications device; receiving a third user input specifying selection of either user input of the name of the business or the destination telephone number; and receiving either the first user input of the name of the business or the second user input of the destination telephone number as a destination descriptor, and wherein the received Internet query includes the destination descriptor, and wherein the directional assistance service determines the location of the destination from the destination descriptor. 10. The method of claim 1, further comprising: the directional assistance service prompting the user of the communications device to provide an option for selection of suggested nearby businesses as the destination; responsive to the user selecting the option for selection of the suggested nearby businesses, the directional assistance service suggesting one or more nearby businesses; and responsive to a user input selecting a selected one of the suggested nearby businesses, sending the Internet query including an identifier of the selected one of the suggested nearby businesses. 11. The method of claim 10, further comprising: the directional assistance service prompting the user of the communications device to provide an option for selection of a category of business for the suggested nearby businesses; responsive to the user selecting the option for selection of the category of business, sending a prompt for the user to specify the category of business; and responsive to the user specifying the category of business, the directional assistance service suggesting the one or more nearby businesses matching the category of business. 12. The method of claim 1, further comprising: the directional assistance service prompting the user of the communications device to provide an option for selection of tracking another communications device that is another mobile wireless communications device; and responsive to the user selecting the option for tracking the another mobile wireless communications device, the directional assistance service sending the Internet query with an identifier of the another mobile wireless communications device. 13. The method of claim 1, further comprising: the directional assistance service prompting the user of the communications device to provide an option for selection between providing one of a destination telephone number, a destination address, a destination business or a category of business; responsive to the user selecting the option for providing the destination telephone number, receiving a second user input of the destination telephone number, wherein the received Internet query includes the destination telephone number, and wherein the directional assistance service determines the location of the destination from the destination telephone number; responsive to the user selecting the option for providing the destination address, receiving a third user input of the destination address, wherein the received Internet query includes the destination address, and wherein the directional assistance service determines the location of the destination from the destination address; responsive to the user selecting the option for providing a category of business, receiving a fourth user input specifying the category of business; responsive to receiving the fourth user input, the directional assistance service suggesting one or more nearby businesses matching the category of business; and further responsive to receiving the fourth user input and further responsive to receiving a fifth user input selecting one of the suggested one or more nearby businesses matching the category of business, sending an identifier of the selected one of the suggested one or more nearby businesses in the Internet query, wherein the directional assistance service determines the location of the destination from the identifier of the selected one of the suggested one or more nearby businesses. 14. The method of claim 13, wherein the directional assistance service prompting the user of the communications device to provide the option for selection between providing one of the destination telephone number, the destination address, the destination business or the category of businesses further provides an option for locating another mobile wireless communications device, and responsive to the user selecting the option for locating the another mobile wireless communications device, receiving a sixth user input of a telephone number of the another mobile wireless communications device, wherein the received Internet query includes the telephone number of the another mobile wireless communications device, and wherein the directional assistance service determines the location of the destination from the telephone number of the another mobile wireless communications device. 15. A mobile wireless communications network, comprising: multiple radio-frequency transceivers and associated multiple antennas to which the associated radio-frequency transceivers are coupled, wherein the multiple radio-frequency transceivers are configured for radio-frequency communication with one or more mobile wireless communications devices; and a directional assistance network coupled to the multiple radio-frequency transceivers, wherein the directional assistance network receives an Internet query initiated at a communications device and directed via the Internet to initiate a request for navigational assistance to a destination and responsive to receiving the Internet query, determines whether or not the communications device is a one of the one or more mobile wireless communications devices, and responsive to determining that the communications device is a one of the one or more mobile wireless communications devices, determines and uses a present location of the communication device as a location of the communications device, wherein the directional assistance network, responsive to determining that the communications device is not one of the one or more mobile wireless communications devices, obtains a fixed location associated with the communications device to determine the location of the communications device, and wherein the directional assistance network provides navigation information to the communications device in response to the Internet query, and wherein the navigation information provides directions for proceeding from the location of the communications device to a location of the destination. 16. The mobile wireless communications network of claim 15, wherein the directional assistance network determines and uses the present location of the communications device by querying an external user location database of a wireless network to which of the one or more mobile wireless communications devices are connected to determine the location of the communications device. 17. The mobile wireless communications network of claim 15, wherein the directional assistance network determines and uses the present location of the communications device by initiating locating the communications device by sending a query to a switch or base station controller of a wireless network to which the one or more mobile wireless communications devices are connected, building an internal database storing the present location of the communications device with results of the query and using the stored location as the location of the communications device. 18. The mobile wireless communications network of claim 15, wherein the directional assistance network obtains the fixed location associated with the communications device by retrieving the fixed location from a database. 19. The mobile wireless communications network of claim 18, wherein the directional assistance network retrieves the fixed location from the database by querying a public service telephone network (PSTN). 20. The mobile wireless communications network of claim 15, wherein the communications device further receives a user input of a destination address and sends the Internet query to the directional assistance network including the destination address, and wherein the directional assistance network determines the location of the destination from the destination address. 21. The mobile wireless communications network of claim 15, wherein the communications device further receives a user input of a destination telephone number and sends the Internet query to the directional assistance network including the destination phone number, and wherein the directional assistance network determines the location of the destination from the destination phone number. 22. The mobile wireless communications network of claim 15, wherein the communications device further receives a user input of a name of a business, wherein the Internet query received by the directional assistance network includes the name of the business, and wherein the directional assistance network determines the location of the destination from the name of the business. 23. The mobile wireless communications network of claim 22, wherein the user input of the name of the business is a first user input, and wherein the directional assistance network provides selection between the first user input of the name of the business or a second user input of a destination telephone number via the communications device, wherein the communications device receives a third user input specifying selection of either user input of the name of the business or the destination telephone number and either the first user input of the name of the business or the second user input of the destination telephone number as a destination descriptor, and wherein the communications device sends the Internet query including the destination descriptor, and wherein the directional assistance network determines the location of the destination from the destination descriptor. 24. The mobile wireless communications network of claim 15, wherein the directional assistance network further prompts the user via the communications device to provide an option for selection of suggested nearby businesses as the destination, and responsive to the user selecting the option for selection of the suggested nearby businesses, the directional assistance network suggests one or more nearby businesses, and wherein responsive to a user input selecting a selected one of the suggested nearby businesses at the communications device, the communication device sends the Internet query including an identifier of the selected one of the suggested nearby businesses. 25. The mobile wireless communications of claim 24, wherein the directional assistance network further prompts the user of the communications device to provide an option for selection of a category of business for the suggested nearby businesses and responsive to the user selecting the option for selection of the category of business, sends a prompt for the user to specify the category of business, wherein the directional assistance network, responsive to the user specifying the category of business, the directional assistance network suggesting the one or more nearby businesses matching the category of business. 26. The mobile wireless communications network of claim 15, wherein the directional assistance network further prompts the user via the communications device to provide an option for selection of tracking another communications device that is another mobile wireless communications device, and wherein the communications device, responsive to the user selecting the option for tracking the another communications device, sends the Internet query with an identifier of the another communications device. 27. The mobile wireless network of claim 15, wherein the directional assistance network prompts the user of the communications device to provide an option for selection between providing one of a destination telephone number, a destination address, a destination business or a category of business, wherein the directional assistance network, responsive to the user selecting the option for providing the destination telephone number, receives a second user input of the destination telephone number in the Internet query, whereby the directional assistance network determines the location of the destination from the destination telephone number, wherein the directional assistance network, responsive to the user selecting the option for providing the destination address, receives a third user input of the destination address in the Internet query, whereby the directional assistance network determines the location of the destination from the destination address, and wherein the directional assistance network, responsive to the user selecting the option for providing a category of business, receives a fourth user input specifying the category of business from the communications device and responsive to receiving the fourth user input, the directional assistance network communicating a suggestion of one or more nearby businesses matching the category of business to the communications device, and receives a fifth user input selecting one of the suggested one or more nearby businesses and sends an identifier of the selected one of the suggested one or more nearby businesses in the Internet query, whereby the directional assistance network determines the location of the destination from the identifier. 28. The mobile wireless communications network of claim 27, wherein the directional assistance network further prompts the user of the communications device to provide an option for selection of locating another mobile wireless communications device, and responsive to the user selecting the option for locating the another mobile wireless communications device, receives a sixth user input of a telephone number of the another mobile wireless communications device in the Internet query, and wherein the directional assistance network determines the location of the destination from the telephone number of the another mobile wireless communications device. 29. A method of providing navigation assistance to a user of a communications device, the method comprising: a directional assistance network prompting the user of the communications device to provide an option for selection of suggested nearby businesses as a destination; responsive to the user selecting the option for selection of suggested nearby businesses, the directional assistance network suggesting one or more nearby businesses; responsive to a user input selecting a selected one of the suggested nearby businesses, the communications device sending an Internet query including an identifier of the selected one of the suggested nearby businesses. the directional assistance network receiving the Internet query, wherein the directional assistance network determines a location of the destination from the identifier of the selected one of the suggested nearby businesses; responsive to receiving the Internet query, determining whether or not the communications device is a mobile wireless communications device; responsive to determining that the communications device is a mobile wireless communications device, the directional assistance network determining and using a present location of the mobile wireless communications device as a location of the communications device; responsive to determining that the communications device is not the mobile wireless communications device, obtaining a fixed location associated with the communications device to determine the location of the communications device by querying a public service telephone network (PSTN) to retrieve the fixed location of the communications device from a database; the directional assistance network initiating locating the mobile wireless communications device by sending a query to a switch or base station controller of a wireless network; and building an internal database storing the present location of the mobile wireless communications device with results of the query and using the stored location as the location of the communications device; and the directional assistance network providing navigation information to the communications device in response to the query, wherein the navigation provides directions for proceeding from the location of the communications device to the location of the destination. 30. A mobile wireless communications network, comprising: multiple radio-frequency transceivers and associated multiple antennas to which the associated radio-frequency transceivers are coupled, wherein the multiple radio-frequency transceivers are configured for radio-frequency communication with one or more mobile wireless communications devices; and a directional assistance network coupled to the multiple radio-frequency transceivers, wherein the directional assistance network prompts a user of the communications device to provide an option for selection of suggested nearby businesses as a destination, and responsive to the user selecting the option for selection of suggested nearby businesses, the directional assistance network suggesting one or more nearby businesses, wherein the directional assistance network receives an Internet query initiated at the communications device and directed via the Internet to initiate a request for navigational assistance to a selected one of the one or more nearby businesses as the destination and responsive to receiving the Internet query, determines whether or not the communications device is one of the one or more mobile wireless communications devices, and responsive to determining that the communications device is one of the one or more mobile wireless communications devices determines and uses a present location of the one of the communications device as a location of the communications device by initiating locating the communications device by sending a query to a switch or base station controller of the wireless network, building an internal database storing the present location of the communications device with results of the query and using the stored location as the location of the communications device, and responsive to determining that the communications device is not one of the one or more mobile wireless communications devices, obtains a fixed location associated with the communications device retrieving the fixed location from a database by querying a public service telephone network (PSTN) to determine the location of the communications device, and wherein the directional assistance network provides navigation information to the communications device in response to the query, wherein the navigation information provides directions for proceeding from the location of the communications device to a location of the destination.
The present Application is a Continuation of U.S. patent application Ser. No. 15/468,265 filed on Mar. 24, 2017 and published as U.S. Patent Publication No. 20170195847 on Jul. 6, 2017, which is a Continuation of U.S. patent application Ser. No. 15/297,222, filed on Oct. 19, 2016, and issued as U.S. Pat. No. 9,642,024 on May 2, 2017, which is a Continuation of U.S. patent application Ser. No. 14/642,408, filed on Mar. 9, 2015 and issued as U.S. Pat. No. 9,510,320 on Nov. 29, 2016, which is a Continuation of U.S. patent application Ser. No. 11/505,578, filed on Aug. 17, 2006 and issued as U.S. Pat. No. 8,977,284 on Mar. 10, 2015, which is a Continuation-in-part of U.S. patent application Ser. No. 10/255,552, filed on Sep. 24, 2002 and published as U.S. Patent Publication No. 20030134648 on Jul. 17, 2003, and claims priority thereto under 35 U.S.C. § 120. U.S. patent application Ser. No. 10/255,552 claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application Ser. No. 60/327,327 filed on Oct. 4, 2001, U.S. Provisional Patent Application Ser. No. 60/383,528 filed on May 28, 2002, U.S. Provisional Patent Application Ser. No. 60/352,761 filed on Jan. 29, 2002, U.S. Provisional Patent Application Ser. No. 60/335,203 filed on Oct. 23, 2001, U.S. Provisional Patent Application Ser. No. 60/383,529 filed on May 28, 2002, U.S. Provisional Patent Application Ser. No. 60/391,469 filed on Jun. 26, 2002, U.S. Provisional Patent Application Ser. No. 60/353,379 filed on Jan. 30, 2002 and U.S. Provisional Patent Application Ser. No. 60/381,249 filed on May 16, 2002. The disclosures of all of the above-referenced U.S. Patent Applications are incorporated herein by reference. FIELD OF THE INVENTION The present invention is directed generally to a system and method for locating mobile wireless devices, and more specifically to a mobile wireless network using a hierarchical location determination scheme. BACKGROUND OF THE INVENTION Wireless networks 100 are becoming increasingly important worldwide. Wireless networks 100 are rapidly replacing conventional wire-based telecommunications systems in many applications. Cellular radio telephone networks (“CRT”), and specialized mobile radio and mobile data radio networks are examples. The general principles of wireless cellular telephony have been described variously, for example in U.S. Pat. No. 5,295, 180 to Vendetti, et al., which is incorporated herein by reference. There is great interest in using existing infrastructures of wireless networks 100 for locating people and/or objects in a cost effective manner. Such a capability would be invaluable in a variety of situations, especially in emergency or crime situations. Due to the substantial benefits of such a location system, several attempts have been made to design and implement such a system. Systems have been proposed that rely upon signal strength and triangulation techniques to permit location include those disclosed in U.S. Pat. Nos. 4,818,998 and 4,908,629 to Apsell et al. (“the Apsell patents”) and U.S. Pat. No. 4,891,650 to Sheffer (“the Sheffer patent”). However, these systems have drawbacks that include high expense in that special purpose electronics are required. Furthermore, the systems are generally only effective in line-of-sight conditions, such as rural settings. Radio wave multipath, refractions and ground clutter cause significant problems in determining the location of a signal source in most geographical areas that are more than sparsely populated. Moreover, these drawbacks are particularly exacerbated in dense urban canyon (city) areas, where errors and/or conflicts in location measurements can result in substantial inaccuracies. Another example of a location system using time difference of arrival (TDOA) and triangulation for location are satellite-based systems, such as the military and commercial versions of the global positioning satellite system (GPS). GPS can provide accurate position from a time-based signal received simultaneously from at least three satellites. A ground-based GPS receiver at or near the object to be located determines the difference between the time at which each satellite transmits a time signal and the time at which the signal is received and, based on the time differentials, determines the object's location. However, the GPS is impractical in many applications. The signal power levels from the satellites are low and the GPS receiver requires a clear, line-of-sight path to at least three satellites above a horizon greater than about 60 degrees for effective operation. Accordingly, inclement weather conditions, such as clouds_, terrain features, such as hills and trees, and buildings restrict the ability of the GPS receiver to determine its position. Furthermore, the initial GPS signal detection process for a GPS receiver can be relatively long (i.e., several minutes) for determining the receiver's position. Such delays are unacceptable in many applications such as, for example, emergency response and vehicle tracking. Additionally there exists no one place that this location information is stored such that a plurality of wireless devices 104 could be located on a geographic basis. Summary of Factors Affecting Rf Propagation The physical radio propagation channel perturbs signal strength, causing rate changes, phase delay, low signal to noise ratios (e.g., ell for the analog case, or Eb/no, RF energy per bit, over average noise density ratio for the digital case) and doppler-shift. Signal strength is usually characterized by: Free space path loss (Lp) Slow fading loss or margin (Lslow) Fast fading loss or margin (Lfast) Loss due to slow fading includes shadowing due to clutter blockage (sometimes included in 1.p). Fast fading is composed of multipath reflections which cause: 1) delay spread; 2) random phase shift or rayleigh fading, and 3) random frequency modulation due to different doppler shifts on different paths. Summing the path loss and the two fading margin loss components from the above yields a total path loss of: Ltotal=Lp±Lslow+Lfast Referring to FIG. 3, the figure illustrates key components of a typical cellular and PCS power budget design process. The cell designer increases the transmitted power PTX by the shadow fading margin Lslow which is usually chosen to be within the 1−2 percentile of the slow fading probability density function (PDF) to minimize the probability of unsatisfactorily low received power level PRX at the receiver. The PRX level must have enough signal to noise energy level (e.g., 10 dB) to overcome the receiver's internal noise level (e.g., −118 dBm in the case of cellular 0.9 GHz), for a minimum voice quality standard. Thus in the example PRx must never be below −108 dBm, in order to maintain the quality standard. Additionally the short term fast signal fading due to multipath propagation is taken into account by deploying fast fading margin Lfast, which is typically also chosen to be a few percentiles of the fast fading distribution. The 1 to 2 percentiles compliment other network blockage guidelines. For example the cell base station traffic loading capacity and network transport facilities are usually designed for a 1−2 percentile blockage factor as well. However, in the worst-case scenario both fading margins are simultaneously exceeded, thus causing a fading margin overload. Detailed Description of the Prior Art Turning to FIG. 1 is a typical second-generation wireless network 100 architecture designed for a code division multiple access (CDMA) and is similar for a time division multiple access (TOMA) or others such as GSM. These are all digital systems that may or may not have the ability to operate in an analog mode. A general overview of the operation of this system will begin when the wireless device user 102 initiates a call with the wireless device 104. A wireless device 104 may take the form of a wireless device 104, personal digital assistant (PDA), laptop computer, personal communications system, vehicle mounted system, etc. Radio frequency (RF) signal 106 is sent from the wireless device 104 to a radio tower and base-station transceiver subsystem (BTS) 300 (FIG. 3), having a global positioning system (GPS) receiver 110-A, 110•8, or 110-C as part of the BTS. The GPS receiver 302 (described in FIG. 3) receives a GPS satellite network signal 112 from the GPS satellite network 114, used by the radio tower with network BTS 108 for timing information. That information is used by the BTS to synchronize the communications signal and allow decoding of the digitized wireless device 104 radio frequency signal 106. The call is then carried from the radio tower and BTS with GPS receiver 110•A, 110-B, or 110-C through a wired link 116 via a T1, T3, microwave link, etc, to the base station controller (BSC) 118-A with vocording 120, CIS 122, and a backhaul 1/F 124, where the call is formatted and coded into data packets by the BSS manager 126 via an intersystem logical connection 128. The call is then sent to the switch 130 via intersystem logical connections 132, where the call is then forwarded through intersystem logical connections 150 to the PSTN 138. The call may also be directly routed to another wireless device 104 on the wireless network 100. From the PSTN 138, the call is forwarded through a connection from the PSTN 138 to communications link 140 and then to land lines 142. As the call proceeds, the words or data from the wireless device user 102 and the ultimate person or device at the receiving end of the call, are formatted, coded and decoded again and again, in the manor described above, throughout the conversation as the conversation or data volleys back and forth. Turning to FIG. 2 is a typical third generation (3G) wireless network 200. The only major difference between the second generation wireless network 100 and third generation wireless network's 200 architecture is the addition of a packet data service node (PDSN) 202 and in the inner system logical connection 204 which connects the PDSN 202 to the BSC 118-B. However, It should be noted that the expansions in architecture do not affect current implementation of this machine and/or process as described by this patent. The methodology is the same as in the second generation wireless network 100 (FIG. 1) and for completeness the periphery 3G 200 components and their logical locations have been shown. As other technologies in network design emerge, it is important to realize that modifications and improvements can be made to this design and patent while retaining the spirit in which it was written. FIG. 1 and FIG. 2 demonstrates the logical locations in which this patent applies to current technology. It is both obvious and required that some changes would have to be made to accommodate future technologies and again are understood to be within the spirit of this patent. Ability to Locate Wireless Device There are numerous methods for obtaining the location of a wireless device 104, which have been taught in the prior art. Most common are in wireless networks (CDMA, TOMA, GSM, etc). All of these wireless networks 100 currently use similar hardware, which these patented location methods take advantage of. Referring now to FIG. 3, details of a typical three sector radio tower 110-A. The BTS 300 with a GPS receiver 302 are shown. This radio tower 110•A exists in most current wireless networks 100 (FIGS. 1) and 200 (FIG. 2) and is used most commonly. Its inclusion is for completeness of this document. Still referring to FIG. 3, the typical three sector radio tower 110-A with BTS 300 setup includes a BSC 118-A, and 118-B which is connected to a BTS 300 through a T1 116 or a microwave link 304. The GPS has a receiver 302 that is used in its operation to establish timing information for communication synchronization. The radio tower 110-A has 3 sectors. Each sector comprises one primary receive antenna 306-A, 308-A, 310-A, and one diversity receive antenna 306-C, 308-C, 310-C. Each sector also has one transmit antenna 306-B, 308-B, 310-B. These receiver antennas and transmit antennas are elevated by the radio tower pole 312 and connected to the BTS by antenna leads 314. FIG. 4 illustrates the typical footprint characteristics (side view) of a typical three-sector radio tower antenna 110-A, such as described in FIG. 3. Each sector has a primary lobe 400 (which corresponds with its primary directivity), multiple side lobes 402-A and 402-B, and multiple rear lobes 404. FIG. 5 illustrates the typical footprint characteristics (top view) of a typical threesector radio tower antenna 110-A, such as described in FIG. 3. Each sector has a primary lobe 400 (which corresponds with its primary directivity), multiple side lobes 402-A, and 402-B, and multiple rear lobes 404. Location Determined As Follows As many other patents go into great depth on location-based methods, for completeness, a brief description of the methods preferred by this patent will be discussed. FIG. 6 shows general methods for triangulation with three radio towers; 110-A, 110-B, and 110-C. This method is covered in numerous other patents but the basic idea is included for completeness. Still referring to FIG. 6 round trip delay (RTD) from each radio tower and BTS 110-A, 110-B and 110-C is used to calculate distance from radio towers to the wireless device 104. To calculate distance 600-A, 600-B, and 600-C, take the RTD (unit in seconds) and multiply by the speed of light (or speed in relative medium of propagation) and divide by two. RTD*c/2·D, D=Distance in meters from tower (c=speed of light) Having done so, you can calculate the position, relative to the known geological position of the towers 110-A, 110-B, and 110-C, of the wireless device 104. To calculate position you find the intersection of three concentric spheres around each radio tower and BTS 110-A, 110-B, and 110-C with each radius equaling the distance 600-A, 600-B, and 600-C to the wireless device 104 from that radio tower and BTS. The wireless device 104 location is the intersection of the three spheres. FIG. 7 shows a two-tower location finding method as taught in the prior art. It is included for completeness of this document. It uses two towers 110-A, and 11 OB with a wireless device 104 at distances of 700-A, and 700-B. Because each tower has more than one sector, as the wireless device 104 approaches a radio tower 110-A or 11 O•B, it may be talking to more than one sector on a single radio tower as is illustrated in FIG. 4, FIG. 5, and FIG. 6. When this occurs, there is a critical distance below which the time it takes for two sectors on a single tower to reach the wireless device 104 is indistinguishable due to hardware calculation limitations. This would make the distance from both sectors (which are already very close, being located on the same tower) appear the same. In this case you should regard the tower as having only one sector, characterized by the distance (equal) from the two sectors. Now, using this as a base you can calculate the location at the wireless device 104 by examining the intersection on the two spheres (one from each tower) and the intersection of the vertical plane between the two towers 110-A and 110−8. This should result in a single point and hence the location of the wireless device 104. FIG. 8 shows a one-tower 110-A location method. It shows a tower (3 sectors) and three distances 800-A, 800−8, 800-C from a wireless device 104. In this case, the wireless device 104 has approached a radio tower 110-A so closely that is talking to three sectors on the site. Because, at this proximity, the distance 800-A, 800-B and 800-C between the three sectors (Sector 1, Sector 2, and Sector 3) on the radio tower 110-A is so negligible, the accuracy is reduced to predicting the wireless device's 104 location with one concentric sphere around the radio tower 110-A, with a radius equaling the distance 800-A, 800-8, or 800-C from any site as calculated above. Relative direction can be computed using the sector (Sector 1, Sector 2, or Sector 3) with the strongest receive power from the wireless device 104 as the likely direction to the wireless device 104 (assuming highly directive antennas are being used). The problem with these methods is that they do not disclose a means for formatting and structuring the decoded data from a plurality of wireless devices 104 into a database or other means of collaboration of data. This database could create a universal standard that could be accessed by other applications such as navigation apparatuses; wireless networks 100 for network tuning purposes; or many other applications. SUMMARY OF THE INVENTION The primary object of the invention is to provide a process and machine for transferring acquired geographical data, user information, date/time information and/or user controlled settings information for a plurality of wireless devices 104 to a database providing it as a resource for other software applications. Another object of the invention is to provide a user location database manager (ULDM) 904 (FIG. 9) comprising a machine and process for decoding and converting acquired geographical data, user information, date/time information and/or user controlled settings information into a universal standard which is a practical and usable format such as, for example, longitude/latitude for applications in other hardware and/or software. A further object of the invention is to provide a user location database (ULD) 900 (FIG. 9) comprising a means for storing geographical data, user information, date/time information, other defined data, and/or user controlled settings information for a plurality of wireless devices 104. Yet another object of the invention is to provide a user location database coordinator (ULDC) 908 (FIG. 9) comprising a means for interfacing a plurality of user location databases (ULD) 900 and allowing remote query of data of a herein created network of ULD's 1512 (FIG. 15) from individual or a plurality of attached ULD's 1512. A further object of the ULDC 908 is to provide a feature for redundancy and input/output capable ports for expansion. Yet another object of the invention is to provide a user location database coordinator network (ULDCN) 1600 (FIG. 16) comprising a means for querying a plurality of user ULD's 1512 and/or ULD's 1512 attached to any ULDC 908. Still yet another object of the invention is to provide a means for access by a plurality of “e-mobility” services 144 that could take advantage of the ULD 900. Another object of the invention is to provide a means for interfacing directly form a BSS manager 126 to the user location database manager (ULDM) 904 for maintenance and direct access of said features. Still yet another object of the invention is to provide a hierarchy process for query (HPQ) comprising a means for a user location database coordinator network (ULDCN) 1600 to query a plurality of user location databases coordinators (ULDC) 908 in a programmable order so as to optimize the query results. Another object of the invention is to provide a hierarchy of user location methods (HULM) comprising a means for the user location database manager(s) to select the most accurate location method, from a programmable plurality of location methods, for locating the plurality of wireless devices 104 according to variable conditions that exist within the wireless network or location information from the wireless device 104 including GPS and triangulation. Another object of the invention is to provide a user control setting comprising a means for a privacy flag in the ULD 900 database entry for a device to be activated/deactivated/semi-active for privacy reasons so that the user's location is not monitored or monitored anonymously. A further object of the invention is to provide for a machine/process ULDC 908 for transferring acquired geographical data, user information, date/time information and/or user controlled settings information for a plurality of wireless devices 104 that explicitly contain GPS equipment, to a database providing it as a resource for other applications. Still yet another object of the invention is to provide the ULD 900 as database resource for: Applications such as “911” emergency crew, police, etc., to track/find wireless devices though ULDC 908 queries. Applications such as wireless network tuning; in order to save engineers some of the time and expense required to gather field data, which may be used. Applications such as navigational mapping programs and/or apparatus that may be used, for example, to aid in mapping vehicle travel routes in order to avoid traffic jams and find faster moving routes of travel. Applications such as a vehicle traffic monitoring system, which for example, could be used by emergency vehicles, traffic engineers to monitor traffic, or by employers to monitor and track employee travels, locations and estimated times of arrival. Applications such as a resource for a telephone recording law database for recording of telephone conversations at or near the switch 130, or on the wireless device 104, to as to comply with recording laws of the city, county, state or country. Applications such as a geographic advertising system (GAS) resource for targeting advertising (coupons, sales, special offers, etc.) offers (solicitations) to users of wireless devices 102 based on the wireless device's 104 location or for users of wireless devices 102 to query advertising offers, prices for goods and services based on the location of the wireless device 104. Other objects and advantages of the present invention will become apparent from the following descriptions, taken in connection with the accompanying drawings, wherein, by way of illustration and example, an embodiment of the present invention is disclosed. A machine for transferring acquired data, user information, date/time information and/or user controlled settings information for a plurality of wireless devices 104 to a database providing it as a resource for other software applications that comprise of: ULDM 904 having a means for decoding and converting the acquired geographical data, user information, date/time information and/or user controlled settings information into a usable format ULD 900 comprising a means for storing the geographical data, user information, date/time information and/or user controlled settings information for the plurality of wireless devices ULDC 908 comprising a means for interfacing a plurality of ULD's 1512 and allowing remote query of ULD 900 database entries. A process for transferring the acquired geographical data, user information, date/time information and/or user controlled settings information for the plurality of wireless devices 104 to the dynamic database providing it as said resource for other applications comprising the steps of decoding and converting the acquired geographical data, user information, date/time information, other defined data, and/or user controlled settings information into a usable format for the ULDM 904. Additionally storing the decoded and converted geographical data, user information, date/time information, other defined data, and/or user controlled settings information for the plurality of wireless devices 104 into the ULD 900. Further, interfacing the plurality of ULD's 1512 into the ULDC 908 and any ULDC 908 network. The drawings constitute a part of this specification and include exemplary embodiments to the invention, which may be embodied in various forms. It is to be understood that in some instances various aspects of the invention may be shown exaggerated or enlarged to facilitate an understanding of the invention. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 TYPICAL SECOND GENERATION WIRELESS NETWORK ARCHITECTURE (PRIOR ART) FIG. 2 TYPICAL THIRD GENERATION WIRELESS NETWORK ARCHITECHTURE (PRIOR ART) FIG. 3 TYPICAL THREE SECTOR RADIO TOWER CONFIGURATION (PRIOR ART) FIG. 4 TYPICAL FOOTPRINT CHARACTERISTICS OF EACH SECTOR (SIDE VIEW) (PRIOR ART) FIG. 5 TYPICAL FOOTPRINT CHARACTERISTICS OF EACH SECTOR (TOP VIEW) (PRIOR ART) FIG. 6 THREE TOWER LOCATION METHOD (PRIOR ART) FIG. 7 TWO TOWER LOCATION METHOD (PRIOR ART) FIG. 8 SINGLE TOWER LOCATION METHOD (PRIOR ART) FIG. 9 TYPICAL SECOND GENERATION WIRELESS NETWORK ARCHITECTURE WITH EMBODIMENTS FIG.10 TYPICAL THIRD GENERATION WIRELESS NETWORK ARCHITECTURE WITH EMBODIMENTS FIG. 11 FLOWCHART OF TRACKING WIRELESS DEVICE'S LOCATION FIG. 12 INTERWORKING BETWEEN BSC, SWITCH, AND ULDM FIG. 13 USER LOCATION DATABASE COORDINATOR (MARKET LEVEL QUEERY) FIG. 14 USER LOCATION DATABASE COORDINATOR FLOWCHART FIG. 15 GENERIC USER LOCATION DATABASE COORDINATOR COMPONENTS FIG. 16 USER LOCATION DATABASE COORDINATOR (MARKET BASED SYSTEM) FIG. 17 USER LOCATION DATABASE COORDINATOR NETWORK (REGION BASED SYSTEM) FIG. 18 USER LOCATION DATABASE COORDINATOR NETWORK (DIRECT SYSTEM) FIG. 19 ULDC EXTERNAL QUERY CONNECTIVITY FIG. 20 HIERARCHY OF LOCATION METHODS FIG. 21 VALIDATION OF LOCATION METHODS FIG. 22 E-MOBILITY USER LOCATION DATABASE QUERIES FIG. 23 RF REMOTE LINK COMPONENTS FIG. 24 RF REMOTE LINK TO REMOTE MOBILE DEVICE FIG. 25 RF REMOTE LINK NETWORK FIG. 26 REMOTE MOBILE DEVICE CONTROL HARDWARE FIG. 27 COMPONENTS UTILIZED BY ULDM FIG. 28 INTER WORKING SYSTEM DIAGRAM FIG. 29 PHYSICAL REALIZATION OF PREFFERED EMBODIMENTS FIG. 30 STANDARDIZATION/CONVERSION SOFTWARE FIG. 31 BSC ACCESS CONTROL SOFTWARE FIG. 32 USER INTERFACE SOFTWARE FIG. 33 DEVICE LOCATION SOFTWARE FIG. 34 TRAGETING DEVICES TO TRACK FIG. 35A PRIMARY ANALYTIC SOFTWARE FIG. 35B PRIMARY ANALYTIC SOFTWARE (CONTINUED) FIG. 35C PRIMARY ANALYTIC SOFTWARE (CONTINUED) FIG. 36 MONITORING SOFTWARE FLOWCHART FIG. 37 CASE FILE GENERATION FIG. 38A FAULT DIAGNOSIS/CORRECTION SOFTWARE FIG. 38B FAULT DIAGNOSIS/CORRECTION SOFTWARE (CONTINUED) FIG. 38-C FAULT DIAGNOSIS/CORRECTION SOFTWARE (CONTINUED) FIG. 39 CORRELATED MAPPING SOFTWARE FLOWCHART FIG. 40 DISPLAY SOFTWARE FLOWCHART FIG. 41 FINAL DISPLAY OUTPUT FIG. 42 PRO-ACTIVE NETWORK TUNING SOFTWARE FIG. 43 ACTIVE WIRELESS UNIT DENSITY GEOGRAPHIC ZONING FIG. 44 ACTIVE WIRELESS UNIT DENSITY FIG. 45 TERRAIN INTEFERENCE NON-RADIAL ZONING FIG. 46 TERRAIN INTEFERENCE RADIAL DIVIDED ZONING FIG. 47 TERRAIN INTEFERENCE RADIAL DIVIDED BORDER ZONES FIG. 48 THERMAL PROCESS FLOWCHART FIG. 49 ACTIVE WIRELESS UNIT DENSITY PROCESS FIG. 50 TERRAIN TUNING PROCESS FIG. 51 NETWORK EQUIPMENT TUNING FLOWCHART FIG. 52 NTS PRO-ACTIVE SYSTEM MENU FIG. 53 USER LOGS INTO SYSTEM FIG. 54 ENTRY OF DESIRED TELEPHONE NUMBER FIG. 55 USER CHOICES MENU FIG. 56 USER SELECTS BUILDINGS TO DISPLAY FIG. 57 ADDING) DELEATING AND EDITING PHONEBOOK ENTRIES FIG. 58 USER SELECTION ON BUILDINGS TO DISPLAY FIG. 59 “BUILDING MEMORY” USER'S CHOICE MENU FIG. 60 “BUILDING MEMORY” CONTINUED FIG. 61 CATEGORIZING BUILDING MEMORY FIG. 62 “LISTING” ADDED TO “BUILDING MEMORY” FIG. 63 “NAME” ADDED TO “BUILDING MEMORY” FIG. 64 “CATEGORY” ADDED TO “BUILDING MEMORY” FIG. 65 “ADDRESS” ADDED TO “BUILDING MEMORY” FIG. 66 “PHONE NUMBER” ADDED TO “BUILDING MEMORY” FIG. 67 DISPLAY OF CALL HISTORY FIG. 68 PRINT CALL HISTORY FIG. 69 ADD CALL/LOCATION HISTORY TO PHONE BILL FIG. 70 FLOWCHART OF THE DIRECTIONAL ASSISTANCE NETWORK (DAN) QUERY PROCESS FIG. 71. FLOWCHART OF DAN USER INTERFACE TO RECEIVE DIRECTIONS BY A PHONE NUMBER FIG. 72 FLOWCHART OF DAN USER INTERFACE TO RECEIVE DIRECTIONS BY ANAME FIG. 73 FLOWCHART OF DAN USER INTERFACE TO RECEIVE DIRECTIONS BY A CATEGORY FIG. 74 FLOWCHART OF DAN USER INTERFACE TO RECEIVE DIRECTIONS BY AN ADDRESS FIG. 75 FLOWCHART OF DAN USER INTERFACE TO RECEIVE DIRECTIONS BY FASTEST TRAVEL TIME FIG. 76 FLOWCHART OF DAN USER INTERFACE TO RECEIVE DIRECTIONS BY SHORTEST DISTANCE FIG. 77 FLOWCHART OF DAN USER INTERFACE TO BE CONNECTED TO A SELECTED LISTING FIG. 78 FLOWCHART OF DAN USER INTERFACE TO LOCATE A WCD FIG. 79 FLOWCHART OF DAN USER INTERFACE TO RECEIVE A MAP AND TRAVEL PLANS FIG. 80 TRAFFIC MONITORING AND ROUTING SOFTWARE PROCESS FLOWCHART FIG. 81 DIRECTIONAL ASSISTANCE NETWORK STRUCTURE FIG. 82 PRIMARY EMBODIMENTS LOCATION ON A TYPICAL 2/3G CELLULAR NETWORK FIG. 83 PRIMARY EMBODIEMENT'S ALTERNATE LOCATION ON A TYPICAL 2/3G CELLULAR NETWORK FIG. 84 PRIMARY EMBODIMENT'S ALTERNATE LOCATION #2 ON A TYPICAL 2/3G CELLULAR NETWORK FIG. 85 DAN LINKING SOFTWARE FIG. 86 TRAFFIC TIME CALCULATION PERFORMANCE BASED ON VARIABLE A FIG. 87 TRAFFIC TIME CALCULATION PERFORMANCE BASED ON VARIABLE TRAFFIC DENSITY RATIO MASTER LIST OF COMPONENTS 100 SECOND GENERATION WIRELESS DEVICE NETWORK 102 WIRELESS DEVICE USER 104 WIRELESS DEVICE 104-A WIRELESS DEVICE 104-B WIRELESS DEVICE 104-C WIRELESS DEVICE 104-D WIRELESS DEVICE 106 WIRELESS DEVICE RF SIGNAL 108 RADIO TOWER AND BTS WITH GPS RECEIVER NETWORK 110-A RADIO TOWER AND BTS WITH GPS RECEIVER 110-B RADIO TOWER AND BTS WITH GPS RECEIVER. 110-C RADIO TOWER AND BTS WITH GPS RECEIVER 112 GPS SATELLITE NETWORK SIGNAL 114 GPS SATELLITE NETWORK 116 COMMUNICATION LINKS (T1, T3, MICROWAVE LINK, ETC.) 118-A BASE STATION CONTROLLER (BSC) WITH VOCORDING, CIS & BACKHUAL 1/F 118-B BASE STATION CONTROLLER (BSC) WITH VOCORDING AND ATMIC 120 VOCORDING 122 CDMA INTERCONNECTION SUBSYSTEM (CIS) 124 BACKHUAL 1/F 126 BSS MANAGER 128 INTERSYSTEM LOGICAL CONNECTIONS 130 SWITCH (MTX OR OTHER) 132 INTERSYSTEM LOGICAL CONNECTIONS 134 INTERSYSTEM LOGICAL CONNECTIONS 136 INTERSYSTEM LOGICAL CONNECTIONS 138 PUBLICLY SWITCHED TELEPHONE NETWORK (PSTN) 140 CONNECTION FROM PSTN TO LAND LINES p0 142 LAND LINES 144 E-MOBILITY SERVICES 148 INTERSYSTEM LOGICAL CONNECTIONS 150 INTERSYSTEM LOGICAL CONNECTIONS 152 SECOND GENERATION SWITCHING STATION 154 INTERWORKING FUNCTION 156 PACKET DATA NETWORK 200 THIRD GENERATION WIRELESS DEVICE NETWORK 202 PACKET DATA SERVICE NODE 204 INTERSYSTEM LOGICAL CONNECTIONS 210 INTERSYSTEM LOGICAL CONNECTION 212 ATMIC 300 BASE STATION TRANCEVER SUBSYSTEM (BTS) 302 GPS RECEIVER 304 MICROWAVE LINK 306-A SECTOR ONE PRIMARY RECEIVER ANTENNA 306-B SECTOR ONE TRANSMIT ANTENNA 306-C SECTOR ONE DIVERSITY RECEIVER ANTENNA 308-A SECTOR TWO PRIMARY RECEIVER ANTENNA 308-B SECTOR TWO TRANSMIT ANTENNA 308-C SECTOR TWO DIVERSITY RECEIVER ANTENNA 310-A SECTOR THREE PRIMARY RECEIVER ANTENNA 310-B SECTOR THREE TRANSMIT ANTENNA 310-C SECTOR THREE DIVERSITY RECEIVER ANTENNA 312 RADIO TOWER POLE 314 ANTENNA LEADS TO BTS 400 MAIN LOBE AND PRIMARY DIRECTIVITY 402-A SIDE LOBE 402-B SIDE LOBE 404 REAR LOBE 600-A DISTANCE FROM RADIO TOWER AND BTS WITH GPS RECEIVER 110-A, TO WIRELESS DEVICE 104 600-B DISTANCE FROM RADIO TOWER AND BTS WITH GPS RECEIVER 110-B, TO WIRELESS DEVICE 104 600-C DISTANCE FROM RADIO TOWER AND BTS WITH GPS RECEIVER 110-C TO WIRELESS DEVICE 104 700-A DISTANCE FROM RADIO TOWER AND BTS WITH GPS RECEIVER 110-A, TO WIRELESS DEVICE 104 700-B DISTANCE FROM RADIO TOWER AND BTS WITH GPS RECEIVER 110-B, TO WIRELESS DEVICE 104 800-A DISTANCE FROM RADIO TOWER AND BTS WITH GPS RECEIVER 110-A, SECTOR ONE, TO WIRELESS DEVIC.E 104 800-B DISTANCE FROM RADIO TOWER 110-A, SECTOR TWO TO WIRELESS DEVICE 104 800-C DISTANCE FROM RADIO TOWER 110-A, SECTOR THREE TO WIRELESS DEVICE 104 900 USER LOCATION DATABASE 902 DATABASE LOGIC CENTER 904 USER LOCATION DATABASE MANAGER 906 STANDARDIZATION CONVERSION (SOFTWARE/HARDWARE) 908 USER LOCATION DATABASE COORDINATOR (ULDC) 910-A COMMUNICATIONS LINKS (T1, T3,DEDICATED LINES, MICROWAVE LINK, ETC.) 910-B COMMUNICATIONS LINK (T1, T3, DEDICATED LINES, MICROWAVE LINK, ETC.) 910-C COMMUNICATIONS LINK (T1, T3, DEDICATED LINES, MICROWAVE LINK, ETC.) 910-D COMMUNICATIONS LINK (T1, T3, DEDICATED LINES, MICROWAVE LINK, ETC.) 912 INTERSYSTEM LOGICAL CONNECTIONS 922 INTERSYSTEM LOGICAL CONNECTIONS 924 INTERSYSTEM LOGICAL CONNECTIONS 926 INTERSYSTEM LOGICAL CONNECTIONS 928 INTERSYSTEM LOGICAL CONNECTIONS 1200 TIMING (TOA, RTD, ETC.) 1210 SIGNAL STRENGTH MEASURES 1220 CALL PROCESS INFORMATION 1230 RADIO TOWER AND BTS LATITUDE/LONGITUDE 1240 RADIO TOWER ALTITUDE 1250 RADIO TOWER DOWNTILT 1260 REGION TYPE OF TOWER (RURAL, URBAN, ETC.) 1270 CALL PROCESS IDENTIFICATION NUMBER 1280 HLR/VLR INFORMATION ON CALLER 1290 AZIMUTH ON SECTORS AND RADIO TOWERS 1300-A SECOND GENERA TIONWIRELESS NETWORK SERVICE PROVIDER 1300-B SECOND GENERATION WIRELESS NETWORK SERVICE PROVIDER 1302-A THIRD GENERATION WIRELESS NETWORK SERVICE PROVIDER 1302-B THIRD GENERATION WIRELESS NETWORK SERVICE PROVIDER 1304 EMERGENCY MEDICAL SERVICES APPLICATIONS 1306 COMMUNICATIONS LINK {T1, 13, DEDICATED LINES, SATELITE, MICROWAVE LINK, ETC.) 1500-A COMMUNICAITONS LINK (DEDICATED LINES, SATELLITE, T1, T3, ETC.) 1500-B COMMUNICATIONS LINK (DEDICATED LINES, SATELITE, T1, T3, ETC.) 1500-C COMMUNICATIONS LINK (DEDICATED LINES, .SATELLITE, T1, T3, ETC.) 1500-D COMMUNICATIONS LINK (DEDICATED LINES, SATELITE, T1, T3, ETC.) 1500-E COMMUNICATIONS LINK (DEDICATED LINES, SATELLITE, T1, T3, ETC.) 1502 PLURALITY OF ULDC'S 1506 UPLINK CONNECTION COMPONENT OF THE ULDC 1508 SINGLE ULDC HIGHER ON HIERARCHY 1510 ULD ACCESS CONTROL UNIT OF THE ULDC 1512 PLURALITY OF ULD'S 1516 REMOTE ACCESS CONTROL UNIT OF THE ULDC 1518-A RF REMOTE LINK 1518-B RF REMOTE LINK 1518-C RF REMOTE LINK 1522 DATA LOGGING UNIT OF THE ULDC 1524 ULDC CONTROL HARDWARE/SOFTWARE 1526 MAINTENANCE UNIT 1528 MASTER ULDM AND LOCATION VERIFICATION PROCESS 1530 MARKET OR GROUP ULD 1532 MIRROR DATABASE 1534 MULTIPLE DOWNLINK CONNECTIONS OF THE ULDC 1536 ULDC ACCESS CONTROL UNIT OF THE ULD 1538 UPLINK/DOWNLINK ATM REDUNDANT CONNECTION 1540 PLURALITY OF REMOTE ACCESS TERMINALS 1542 ULDC OR FUTURE EXPANSION REQUIRING ULDC INTERFACE 1600 USER LOCATION DATABASE COORDINATOR NETWORK (MARKET BASED SYSTEM) 1602 NATIONAL OR INTERNATIONAL ULDC 1604 MARKET “A” ULDC 1606 MARKET “B” ULDC 1608 MARKET “C” ULDC 1610 MARKET “D” ULDC 1612 MARKET “F” ULDC 1614 MARKET “G” ULDC 1616 MARKET “H” ULDC 1618 OPTIONAL COMMUNICATIONS LINK BETWEEN MARKET ULD'S 1620 MARKET “E” ULDC 1630-A COMMUNICATIONS LINK (DEDICATED LINES, SATELITE, T1, T3, ETC) 1630-B COMMUNICATIONS LINK (DEDICATED LINES, SATELITE, T1, T3, ETC) 1630-C COMMUNICATIONS LINK (DEDICATED LINES, SATELITE, T1, T3, ETC) 1630-D COMMUNICATIONS LINK (DEDICATED LINES, SATELITE, T1, T3, ETC) 1630-E COMMUNICATIONS LINK (DEDICATED LINES, SATELITE, T1, T3, ETC) 1630-F COMMUNICATIONS LINK (DEDICATED LINES, SATELITE, T1, T3, ETC) 1630-G COMMUNICATIONS LINK (DEDICATED LINES, SATELITE, T1, T3, ETC) 1630-H COMMUNICATIONS LINK (DEDICATED LINES, SATELITE, T1, T3, ETC) 1700 USER LOCATION DATABASE COORDINATOR NETWORK (REGION BASED SYSTEM) 1702 DISTRICT “A” ULDC 1704 DISTRICT “B” ULDC 1706 REGION “A” ULDC 1708 REGION “B” ULDC 1710 REGION “C” ULDC 1712 REGION “D” ULDC 1714-A OPTIONAL COMMUNICATIONS LINK (DEDICATED LINES, SATELLITE, T1, T3, ETC) 1714-B OPTIONAL COMMUNICATIONS LINK (DEDICATED LINES, SATELLITE, T1, T3, ETC) 1714-C OPTIONAL COMMUNICATIONS LINK (DEDICATED LINES, SATELLITE, T1, T3, ETC) 1714-D OPTIONAL COMMUNICATIONS LINK (DEDICATED LINES, SATELITE, T1, T3, ETC) 1716-A COMMUNICATIONS LINK (DEDICATED LINES, SATELLITE, T1, T3, ETC) 1716-B COMMUNICATIONS LINK (DEDICATED LINES, SATELLITE, T1, T3, ETC) 1716-C COMMUNICATIONS LINK (DEDICATED LINES, SATELLITE, T1, T3, ETC) 1716-D COMMUNICATIONS LINK (DEDICATED LINES, SATELLITE, T1, T3, ETC) 1716-E COMMUNICATIONS LINK (DEDICATED LINES, SATELLITE, T1, T3, ETC) 1716-F COMMUNICATIONS LINK (DEDICATED LINES, SATELLITE, T1, T3, ETC) 1716-G COMMUNICATIONS LINK (DEDICATED LINES, SATELLITE, T1, T3, ETC) 1716-H COMMUNICATIONS LINK (DEDICATED LINES, SATELLITE, T1, T3, ETC) 1716-I COMMUNICATIONS LINK(DEDICATED LINES, SATELLITE, T1, T3, ETC) 1716-J COMMUNICATIONS LINK(DEDICATED LINES, SATELLITE, T1, T3, ETC) 1716-K COMMUNICATIONS LINK(DEDICATED LINES, SATELLITE, T1, T3, ETC) 1716-L COMMUNICATIONS LINK(DEDICATED LINES, SATELLITE, T1, T3, ETC) 1716-M COMMUNICATIONS LINK(DEDICATED LINES, SATELLITE, T1, T3, ETC) 1716-N COMMUNICATIONS LINK(DEDICATED LINES, SATELLITE, T1, T3, ETC) 1800 USER LOCATION DATABASE COORDINATOR NETWORK (DIRECT SYSTEM) 1900 REMOTE WIRELESS DEVICE 1902 WIRELESS COMMUNICATIONS LINK (RADIO FREQUENCY LINK, ETC.) 1904 PLURALITY OF REMOTE WIRELESS DEVICES 1906 POLICE 1908 AUTHORIZED ACCOUNTS AND OTHERS 1910-A COMMUNICATIONS LINK (DEDICATED LINES, SATELITE, T1, T3, ETC. 1910-B COMMUNICATIONS LINK (DEDICATED LINES, SATELITE, T1, T3, ETC.) 2300 OMNIDIRECTIONAL TRANSMIT/RECEIVE ANTENNA 2302 ANTENNA LEADS 2304 TRANSMIT UNIT 2308 RECEIVE UNIT 2310 MAINTENANCE UNIT 2320 TRANSMIT CONTROL UNIT 2330 RECEIVER CONTROL UNIT 2340 ULDC INTERFACE CONTROL HARDWARE/SOFTWARE 2350 RF LINK MANAGEMENT HARDWARE/SOFTWARE 2360 POWER CONTROL UNIT 2380 CONNECTION TO EXTERNAL POWER SOURCE 2410 PCMICA INTERFACE CARD 2420 CONTROL HARDWARE 2430 ANTENNA 2440 DATA CABLE 2450 TOP COMPUTER 2460 ANTENNA LEADS 2470 CONNECTION TO EXTERNAL POWER SOURCE 1518-A RF REMOTE LINK 1902 RF REMOTE LINK 2500 RF REMOTE LINK NETWORK 2510 DENSE URBAN AREA 2520 URBAN AREA 2530 SUB-URBAN AREA 2605 TRANSMIT UNIT 2608 RECEIVE UNIT 2620 TRANSMIT CONTROL UNIT 2630 RECEIVE CONTROL UNIT 2640 RF INTERFACE CONTROL HARDWARE/SOFTWARE 2660 POWER CONTROL UNIT 2800 NETWORK TUNING SYSTEM/PRIMARY EMBODIMENT 2802 MONITORING SOFTWARE 2804 BSC ACCESS CONTROL SOFTWARE 2806 FAULT DIAGNOSIS/CORRECTION SOFTWARE 2808 DEVICE LOCATION SOFTWARE 2810 GEOGRAPHIC INFORMATION DATABASE 2812 CRISS-CROSS PHONEBOOK DATABASE WITH LAT/LONG CORRELATIONS 2814 PRIMARY ANALYTIC SOFTWARE 2816 INTERNAL CENTRAL PROCESSING UNIT AND COMPUTER 2818 INTERNAL MEMORY STORAGE 2820 CASE FILES WITH LAT/LONG 2822 SERVICING EFFECTING FACTORS WITH LAT/LONG CORRELATIONS 2824 RADIO TOWER WITH LAT/LONG CORRELATIONS 2826 USER INTERFACE SOFTWARE 2828 CORRELATING MAPPING SOFTWARE 2830 CORRELATING DATA FOR LAT/LONG INFORMATION 2832 DISPLAY SOFTWARE/HARDWARE 2834 E-MOBILE CONNECTION 2836 DISPLAY SCREEN 2838 LINK REQUIREMENTS FOR SCANNING MODE 2840-A PASSIVE LINKS 2840-B PASSIVE LINKS 2842-A PASSIVE LINK AND/OR ACTIVE LINKS 2842-B PASSIVE LINK AND/OR ACTIVE LINKS 2844-A PASSIVE LINK AND/OR ACTIVE LINKS 2844-B PASSIVE LINK AND/OR ACTIVE LINKS 2844-C PASSIVE LINK AND/OR ACTIVE LINKS 2844-D PASSIVE LINK AND/OR ACTIVE LINKS 2844-E PASSIVE LINK AND/OR ACTIVE LINKS 2844-F PASSIVE LINK AND/OR ACTIVE LINKS 2844-G PASSIVE LINK AND/OR ACTIVE LINKS 2844-H PASSIVE LINK AND/OR ACTIVE LINKS 2844-I PASSIVE LINK AND/OR ACTIVE LINKS 2846-A PASSIVE SCANNING MODE, ACTIVE LINKS 2846-B PASSIVE SCANNING MODE, ACTIVE LINKS 2846-C PASSIVE SCANNING MODE, ACTIVE LINKS 2848 USER 2900 MASTER SERVER 2902 EXTERNAL ACCESS POINT 2904 LOCAL ACCESS POINT 2906 HIGHSPEED INTERNET GATEWAY 2908 WORLD WIDE WEB 2910 INDIVIDUAL COMPUTERS 2912 CORPORATE EXTERNAL LAN (SECURE) 2914 BACK-UP SYSTEM SERVER 2916 DATA FLOW DIAGRAM 2918-A DATA FLOW CONNECTIONS 2918-B DATA FLOW CONNECTIONS 2918-C DATA FLOW CONNECTIONS 2918-D DATA FLOW CONNECTIONS 2918-E DATA FLOW CONNECTIONS 2918-F DATA FLOW CONNECTIONS 2918-G DATA FLOW CONNECTIONS 2918-H DATA FLOW CONNECTIONS 2920-A LAN CONNECTIONS 2920-B LAN CONNECTIONS 2920-C LAN CONNECTIONS 3000 START (GENERIC COMMAND) 3004 PROTOCOL DATABASE 3012 RECEIVE DEVICE PROTOCOL LIST 3110 COMMAND LIST 3200 INTERNET 3202 INTERNET 3206 LOCAL SERVER/WORK STATION 3216 USER DATABASE 3224 SYSTEM LOG 3700 LOCATION OF WIRELESS DEVICE BEING TRACKED 3704 FORWARD RECEIVE POWER 3706 FORWARD TRANSMIT POWER 3708 EC/LO 3710 NEIGHBOR LIST 3712 MESSAGING 3714 FER 3716 OTHER ERROR CODES 3718 OTHER USER DEFINED FACTORS 3720 ERROR CODE 3722 CASE FILE # 3724 WIRELESS DEVICE ID # 3726 OTHER USER DEFINED FACTORS 3816 LOCAL ERROR DATABASE 3828 TREND ANALYSIS DATA 3878 STORED ERROR DATA 3886 MESSAGE TABLE 3888 CORRECTION TABLE 3920 DATA LAYER 3926 MASTER DATA LAYER 3936 MASTER MAP LAYER 3940 FILTERED MASTER DATA LAYER 3942 FILTERED DATE LAYER 3944 FILTERED MASTER MAPPING LAYER 3946 FILTERED MAPPING LAYER 3950 PRIMARY DISPLAY LAYER DATA FILE 4002 PRIMARY DISPLAY LAYER 4004 SECONDARY DISPLAY LAYER 4100 RADIO TOWER LOCATIONS DISPLAY LAYER 4110 WIRELESS DEVICE LOCATIONS DISPLAY LAYER 4120 SERVICE AFFECTING FACTORS DISPLAY LAYER 4130 ERROR CODES DISPLAY LAYER 4140 CRISS-CROSS PHONEBOOK ENTRIES DISPLAY LAYER 4150 AUXILIARY OBJECT LOCATIONS DISPLAY LAYER 4160 GEOGRAPHIC/TOPOLOGICAL STREET MAP OVERLAY DISPLAY LAYER 4170 FINAL DISPLAY OUTPUT 5300 LOCATION TRACKING SYSTEM 5304 USER NAME AND PASSWORD 5306 INTERNAL STORAGE MEMORY 5312 USER RECORDS 5322 HELP MENU/SERVICE AGENT/OPERATOR 5326 MERCHANT CREDIT CARD SERVICES ACCOUNT 5400 MEMBERSHIP DATA 5420 FAX ON DEMAND 5422 POSTAL ADDRESS CONVERSION HARDWARE/SOFTWARE 5424 AUTOMATED ANSWERING HARDWARE/SOFTWARE 5426 VOICE TEXT READ-UP HARDWARE/SOFTWARE 5502 USER CHOICE MENU 8100 directional assistance network (DAN) 8101 primary logic software 8105 voice interface software 8110 voice mapping software 8115 device location software 8120 routing software 8125 traffic monitoring software 8130 data interface software 8135 external DAN query interface software 8140 external connections to query device 8145 PSTN phone location database 8150 criss-cross lat/long geographic database 8155 geographic database mapping software 8160 standardization and conversion software/hardware 8165 external network connection 8170 computer system 8202 wireless communication 8205 wireless communication device 8212 PSTN/PSTN location database communication interface 8220 telephone 8222 MTX/PSTN interface 8227 MTX/BSC interface 8232 BSC/BTS interface 8237 MTX/user location database interface 8242 MTX/e-mobility services interface 8247 MTX/PDN interface 8252 PON/internet gateway interface 8255 internet gateway 8257 internet gateway/internet interface 8260 internet 8262 a-mobility services/DAN interface 8267 MTX/WCD location software interface 8270 WCD location software 8300 DAN linking software 8310 DAN/internet interface 8320 a-mobility services/DAN linking software interface 8410 DAN/PSTN interface 8515 interim linking software 8517 interim linking software/packet routing software/hardware interface 8520 packet routing software/hardware 8522 interim linking software/DAN data query software interface 8525 DAN data query software DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Detailed descriptions of the preferred embodiment are provided herein. It is to be understood, however, that the present invention may be embodied in various forms. Therefore, specific details disclosed herein are not to be interpreted as limiting, but rather as a basis for the claims and as a representative basis for teaching one skilled in the art to employ the present invention in virtually any appropriately detailed system, structure or manner. Referring to FIG. 9, this invention of both a machine and process focuses directly on the ability to use dynamic location based information of a plurality of wireless devices 104 in the form of latitude and longitude, store that data to a dynamic software database user location database (ULD) 900, via the database logic center 902, and allow a means by which to share the software database ULD 900 with other entities (either software or hardware). The hardware shown in FIG. 9 (possibly logically integrated into existing hardware) consists of a ULD 900, a database logic center (DLC) 902, a user location database manager (ULDM) 904, standardization conversion hardware/software 906, and a user location database coordinator (ULDC) 908. These systems/machines and the software/processes defined within this invention add a unique and novel ability that in its entirety will benefit both business and public as a whole. This benefit will be financially profitable for businesses by allowing the creation of a universal standard that software applications can be developed off of, greatly reducing individual project cost by using this invention as resource. Additionally, as many new wireless software programs are increasingly using location based technology in the form of GPS, this invention would then increase the profitability of companies by using this technology for their software because it is based on existing infrastructure and would not require a consumer, who possesses a wireless device 104, to purchase any additional equipment. This would require less investment by a company using this invention, and increase immediate profit of any hardware/software/firmware applications developed using this invention. The fundamental machine is defined by the inclusion of the ULD 900, DLC 902, ULDM 904, standardization conversion hardware/software 906, and ULDC, 908. Basic functions as expanded on in subsequent sections of this invention are as follows: ULD 900: Software database for data that includes user entries consisting of a user identifier, latitude and longitude, and other aspects as described in subsequent sections. DLC 902 converts data into a storable format for the ULD 900 ULDM 904: Responsible for reading/writing/appending user entries in the ULD 900 and calculating the data that will be entered into those entries by gathering information from the BSC 118-A and the switch (MTX or other) 130. Standardization Conversion Hardware/Software 906 converts data into a standardized format for the ULDC 908. ULDC 908: Allows remote access of a singular or plurality of ULD's 1512 by a remote database query. The machine and process are compatible with existing 2nd generation wireless device network 100 and future 3rd generation wireless device networks 200. Current wireless networks such as in FIG. 1 are commonly referred to as 2G or second-generation networks 100. Still referring to FIG. 9, the components that have been added to the architecture of the second-generation wireless network 100 comprise of the primary embodiments of the machine and process. The ULDM 904 is used for acquiring geographic location data from the BSC 118-A (call processing information/TDOA/RSSI and other data such as predetermined location) and user identifying information (phone number) from the switch (MTX or other) 130. It then creates a database entry using the user information {phone number), date/time information and user controlled settings of a plurality of wireless devices 104 and puts it into the ULD 900 in its software database entry format via the DLC 902. The ULD 900 is a software database resource, containing user entries created by the ULDM 904, for other software/hardware applications such as the shown a-Mobility services 144. The ULDC 908 connects to the switch {MTX or other) 130 and allows remote access to the ULD 900. Logical and physical connections between these physical and logical bodies are illustrated as intersystem logical connections 922, 148, 924, 926, 928 and the wired link {T1, or other) 910-A between the switch {MTX or other) 130 and the ULDC 908. Still referring to FIG. 9, also within the scope of this invention, is the ability for location to be determined at the wireless device 104. This could be accomplished if the device contained a GPS unit itself, or a other means of determining location and could acquire its geographic location {latitude/longitude/altitude/time). In such a case, information would be transmitted back to the switch {MTX or other) 130 by the phone and reported to the ULDM 904. The location would then be transmitted directly into the DLC 902 (of the ULD 900), and stored in the ULD 900. In this case, the wireless device 104 is responsible for the determination of its location. Regardless of where the location at the wireless device 104 is computed, this invention's integrity remains the same. The ability to compute the location at the wireless device 104, or within the wireless device network 100 or 200 is covered by numerous previous patents. Still referring to FIG. 9, the data can be sent/received by the e-mobility services 144 or directly to the BSC 206 as data. Location information in this case would be sent continuously or limited by features on the wireless device 104. Implementation of this method with wireless device 104 having GPS equipment, requires the wireless device 104 to be in relative sight to the sky. The GPS unit would require integration and other procedures to integrate with the wireless device 104. Other methods (as taught in the prior art) of determining the location of the wireless device 104 at the wireless device 104 may not require the wireless device 104 to be in plain sight or relative to the sky. Regardless, the final results once the longitude/latitude data is sent from the wireless device 104 is the same if the data is calculated at the wireless device 104, or calculated at the ULDM 904. Still referring to FIG. 9, to utilize any calculations of locations at the wireless device 104, that data will need to be transmitted to the radio towers and BTS 110-A, 110-B, and 110-C, along with voice. Various systems exists to accommodate this including time divided multiple access (TOMA), code divided multiple access (CDMA) and others. Beyond the 2G wireless device networks 100 (FIG. 1) exists an emerging technology called 3G (FIG. 2), or third generation (networks) 200. These wireless networks offer greater features and bandwidth to wireless devices 104 on the network. Integration as shown in FIG. 2 is identical to FIG. 1, or to the 2G wireless device network 100. Additional Embodiments Additionally embodiments include a means for a plurality of “e-mobility” services 144 to access the ULD 900 through software (possibly SQL or other similar database query methods). Further included is a means for interfacing directly from the BSS manager 126 to the ULDM 904 for maintenance and direct access of said features. Further embodiments include adding to the ULDC 908 a means for redundancy in case of hardware/software failure, using optional input/output capable ports. Additionally, creating a user location database coordinator network (ULDCN) (FIG. 16) 1600, comprising a means for querying a plurality of user location database coordinators (ULDC's) 1502 and their respective ULD's 1512. A further additional embodiment details a process for querying a plurality of ULDC's 1502 in a programmable order so as to optimize the query results. A method also claimed is the hierarchy of user location methods (HOLM) that comprises a means for the ULDM 904 to select the most accurate location method from a plurality of location methods, for locating the plurality of wireless devices 104 according to variable conditions which exist within the wireless device network 100. To ensure consumer privacy, a user control setting comprising a means for a “full” privacy flag (meaning an electronic register indicating the user does not want their phones location information tracked) to be set by a wireless device user 102, alerts the ULDM 904 if it can record latitude and longitude location data to the ULD 900 for that given wireless device user 102. An “anonymous” privacy flag allows the location of a wireless device 104 to be monitored on a limited basis, by not reporting the identification information of the wireless device 104. An additional embodiment is the addition of a RF remote link 1518 and remote mobile device 1900, which can be added to the ULDC 908 in order to allow queries of the ULDC 908 from remote locations. Although the ULDC 908 can be queried by the wireless device 104, the use of the RF remote link 1518 and remote mobile device 1900 allow queries to be performed on a broader RF band than would be found on the wireless device 104. This broader RF band allows for more data to be transferred at a greater speed than is possible by a typical wireless device 104. Altertnative Embodiements Alternate embodiments to the invention include the ability for the hierarchy process for query (HPQ) to be programmed by a designated entity, person, or group in such a way as deemed appropriate by that party to ensure a desired search procedure. Additionally the hierarchy of user location method's used by the ULDM 904 could be modified, appended, reprioritized or otherwise changed to use a plurality of location methods as programmed by a person, group or other entity to obtain any desired level of detail regarding the accuracy of the latitude and longitude calculations. Other alternatives include the ability for the privacy flag to be locked in the inactive position by the owner of the wireless device 104, by remote access, if it is to be used for example, by an employee, a child, a thief or if the wireless device 104 is lost. Having the ability for the privacy flag to be automatically turned in the off position when the user of the wireless device 104 dials emergency services such as for example “911” is also an alternative embodiment. Additionally, the ability for the privacy flag to be turned off by the service provider in the case of, for example, court ordered surveillance. Alternative ways to access the privacy flag are having it be controlled and/or implemented from the wireless device 104 or the BSS manager 126. A further alternative embodiment is transferring acquired geographical data, user information, date/time information, other defined data, and/or user controlled settings information for a plurality of wireless devices 104 containing GPS equipment, or other location means, to the ULDM 904 (from the wireless device itself) and then to the ULD 900. This also includes the approach of having the means for the location of the wireless device 104 to be computed at the wireless device 104 and then transmitted to the radio tower and BTS 110-A, to the BSC 118-A or 118-B, and then into the ULDM 904 and finally to the ULD 900. Detailed Description of Drawings With Embodiments Referring to FIG. 9, is a typical second-generation (2G) wireless device network 100 architecture similar to that found in FIG. 1. However, in FIG. 9, some of the embodiments of this invention, which include a ULDM 904 a ULD 900 combined with the database logic center (DLC) 902, a standardization conversion software/hardware apparatus 906, and a ULDC 908 have been added. When the wireless device user 102 sends voice or data through the wireless device 104, the voice and data are sent via a radio frequency signal 106 to the radio tower network 108. The RF signal 106 from the wireless device 104 is then received by the radio tower and BTS (with GPS receiver network 108). For illustration purposes, the radio towers and BTS 110-A, 110-B, and 110-C receive the RF signal 106. The user's voice and data information, along with other information (described in greater detail in FIG. 12) is then sent through a dedicated line (T1, T3, microwave or other dedicated line) 910, to the base station controller (BSC) 118-A. Information, which has been gathered from the radio tower and BTS with GPS receiver network 108, is then dispensed from the BSC 118-A to the switch (MTX or other) 130 and the ULDM 904. The ULDM 904 then decodes the information that is gathered from the base station controller (SSC) 118-A and the switch (MTX or other) 130. It computes the location of a wireless device 104 in accordance with another embodiment of this invention, the hierarchy of user location methods (HULM). The hierarchy of user location methods is a series of changeable and programmable algorithms, which incorporates the appropriate location methods as taught in the prior art. The appropriate method for determining the location of the wireless device 104 would consist of many factors including rural or urban locations of radio towers and other BTS information. Many other factors are covered under the prior art. The ULDM 904 then communicates with the DLC 902 through an intersystem logical connection 150. The DLC 902 then stores the decoded data in the ULD 900 in the form of longitude and latitude information, date and time information, user identification information, user selected settings and other factors (as illustrated in FIG. 12). The switch (MTX or other) 130 is simply the place where the ULDC 908 communicates data. The ULDM 904 converts and sends the query via the intersystem logical connection 924, to the ULD 900 through the DLC 902. The ULD 900 then uses its DLC 902 to convert query into internally recognized code and then retrieves it from the entry from the ULD 900. The results are passed back to the DLC 902, which converts the entry back into a format used by the ULDM 904. The entry is passed back through the switch, (MTX or other) 130, to the ULDC 908. This decoded data can also be sent through an intersystem logical connection 922 toe-mobility services 144 where the decoded data can be accessed and used by a plurality of entities and applications. Still referring to FIG. 9, these e-mobility services 144 can be accessed by other applications within a single service provider's second-generation wireless device network 100. This networking of ULD's 1512 between service providers and other entities is accomplished through the use of two additional embodiments of this invention, a standardization conversion software/hardware 906 and a ULDC 908. The wireless device 104 can interface with a plurality of applications that are accessed through e-mobility services 144. The wireless device 104 can also query the ULD's 1512 and ULDC's 1502 and use this data for applications within the wireless device 104 or other equipment attached to the wireless device 104. These e-mobility service(s) 144, ULD's 1512 and ULDC's 1502 can also be interfaced via the Internet and the publicly switched telephone network (PSTN) 138. The standardization conversion software/hardware 906 is known in the prior arts, however its use in this application is considered to be a point of novelty. The purpose of this device is to facilitate a standardization of the software and hardware transmissions from the service providers second generation wireless device network 100, to device is comprising software and hardware outside of the second generation wireless device network 100. However the standardization conversion software/hardware 906, may not be needed within the second generation wireless device network 100 if it is already operating with a hardware and software system which is compatible with the interfacing of hardware and software outside of the second generation wireless device network 100. In an alternative embodiment the standardization conversion software/hardware 906 is comprised within, or as a peripheral of the device external to the second generation wireless device network 100 such as the ULDC 908. As previously stated the ULDC 908, which is referred to in FIG. 9, enables the networking of a plurality of ULD 900 which can be accessed through e-mobility services 144 so as to provide a resource, as an embodiment of this invention, for locating individual wireless devices 104 for such applications as (for example) emergency medical services locating a loss or injured wireless device user 102, or to assist a wireless device user 102 to locate a loss or stolen wireless device 104. The ULDC 908, can also be used, in an alternative embodiment of this invention, as a resource to view and monitor the location of a plurality of wireless devices 104 at the same time, which would be useful in such applications such as (for example) vehicle traffic monitoring so as to enable vehicle trip route planning for emergency medical service vehicles trying to find the fastest route of travel to a particular emergency by avoiding congested traffic areas, or for vehicle trip route planning by individual drivers. Yet another alternative embodiment of the user ULDC 908 is to provide a resource for monitoring the location of a plurality of selected wireless devices 104 so as to be useful in such applications (for example) as monitoring the location of wireless devices 104 operated by police 1906, so as to enable faster response time by the police 1906 in an emergency situation, or location of wireless devices 104 operated by taxi services or delivery services in order to improve efficiency, or for businesses to monitor the location of employs. Now referring to FIG. 10, the same embodiments of this invention, as illustrated in FIG. 9, are illustrated here in the third-generation wireless device network architecture 200. These embodiments operate the same as in FIG. 9. For a third generation wireless device network 200, the differences involved are minor. Primary operation of the embodiment does not change. However, additional embodiments do exist. The ability to send data at higher rates and to allow faster bi-directional communication between the wireless device 104 and the wireless device network 200 are key. These factors allow the realization of real-time applications to be run from the wireless device 104 that could access various E-mobility services 144 and consequently the ULD 900. Now referring to FIG. 11, is a flowchart of tracking wireless device's 104 location. The items of this flowchart, which are numbered from 1100 through 1196, are intended to demonstrate the current state-of-the-art regarding the processing of a call transmission from a wireless device 104 and are therefore prior art. The items of this flowchart, which are numbered 1100 through 1196, are unique to this convention and should be considered points of novelty. The call process begins 1100, when the user originates a call 1105, and the base-station transceiver subsystem (BTS) 300 receives the call 1105. Information is then sent from the base station transceivers subsystem to the base station controller (BSC) 1110, at which point the base station controller 206 establishes resources for the call 1120. The base station controller 206 checks the switch (MTX or other) 130 database for user information 1125. The switch {MTX or other) 130 authenticates user information and delivers it to the BSC 1130. From this point the BSC 206 establishes the call and routes the call to its destination 1135, through the switch (MTX or other) 130 and then to the publicly switched telephone network 138 or directly to other wireless devices 104 on the wireless network 1135. The call proceeds 1140, until the call is terminated 1145. The BSC 206 then acknowledges the end of the call and tears down the resources 1150 at which point the call process ends 1155. Still referring to FIG. 11, the location process runs in parallel with the call and begins when the switch (MTX or other) 130 authenticates user information and delivers the call to the BSC 1130. It is at this point that the switch (MTX or other) 130 passes the call process identification number 1165 to the ULDM 904. The ULDM 904, negotiates with the ULD 900 and sets up the entry 1160. It is at this point when the ULDM 904, checks to see if the user has activated the full privacy flag 1170. The full privacy flag 1170, is an embodiment of this invention. The privacy flag 1170, is intended to allow the user to choose whether or not his/her location can be monitored by the ULDM 904. If the user has chosen to turn his full privacy flag 1170, on the ULDM 904, then logs user inactive 1194 and the ULDM 904, stops tracking 1196. If the user has not turned their full privacy flag 1170 on, the BSC retrieves data on the call 1175. This also applies to when a user may opt to have an ‘Anonymous Privacy Flag’. In this case, the user's location can only be accessed by external applications as part of an anonymous location query. In such case, the location of a said user could not be associated with any user information. The difference between the “full privacy” flag and the “anonymous” flag is that the full privacy flag will not let any external program access any data, personal or location information. While, on the other hand, the anonymous flag when set, will allow location-based information to be released, but not personal identifying information. These are both electronic registers that exist in the database entry of the user. The querying software checks them first, to discover the access rights to the user's personal and location-based information. The ULDM 904, then computes the location and the location time and date information and other information 1180, which is acquired from the BSC 206 and the switch (MTX for other) 130. It then sends the updated data information 1185 to the ULD 900, via the database logic center 1180. As the call proceeds, user information is updated 1185. If the call is still active, the ULDM 904 computes the location and adds location time/date information 1180 and other desired information from the BSC 206 and the switch (MTX or other) 130 and then enters this information into the ULD 900, via the database logic center 1180. At this point the user information is updated again 1185. During this process the e-mobility service 144, applications have full access to the ULD 900, which can also be accessed directly by base station subsystem (BSS) 1190. When the user information is updated 1185 and it is determined that the call is not active 1192, the ULDM 904, logs the ULD 900, entry as inactive 1194 and the ULDM 904, stops tracking the wireless device 1196. Referring to FIG. 12, this diagram illustrates in greater detail, the inter-working communication between the base-station controller (BSC) 118-A or 118−8, the switch (MTX or other) 130 and the ULDM 904. The ULDM 904 and the BSC 118-A or 118-B are connected by an intersystem logical connection 154. The ULDM 904 and the switch (MTX or other) 130 are also connected by an inner system logical connection 152. The BSC 118-A or 118-B and the switch (MTX or other) 130 are connected by an inner system logical connection 132. A wide variety of information is available to be shared between the ULDM 904, the BSC 118-A or 118-B, and the switch (MTX or other) 130 and can be used in the algorithms of the hierarchy of user location methods. Of these, the items that are most important in determining location, include timing (time difference of arrival (TDOA) and round trip delay (RTD) 1200, signal strength measurements 1210, and call processing information 1220, which are obtained from the BSC 118-A or 118-B. In addition, the switch (MTX or other) 130 provides the following information which is used to determine the location, including, radio tower and BTS latitude/longitude 1230, radio tower altitude 1240, radio tower down tilt 1250, region type of tower (rural, urban, etc.) 1260, call process identification number 1270, HLRNLR information on caller 1280, and Azimuth on sectors and radio towers 1290. However, if a location algorithm of the HULM requires an additional item, they would be available to the ULDM 904, from the switch (MTX or other) 130, and BSC 118A or 118-B. In an alternative embodiment, location information from the wireless device 104 can also be obtained from the BSC, if the wireless device 104 is equipped with GPS or other location equipment. Now referring to FIG. 13, this diagram illustrates a market level query of the ULDC 908. This ULDC 908, is an embodiment of this invention and has been previously illustrated in FIG. 9 and FIG. 10. The ULDC 908, facilitates the interfacing of a plurality of wireless service providers 1300-A, 1300-B, 1302-A and 1302-B. In this example of a market level query, the ULDC 908, is queried by an emergency medical services application 1304, (for example) for the location of the individual wireless device 104. In this case a query is sent which is carried through a communications link 1306, to the ULDC 908. The ULDC 908, then evaluates the query using another embodiment of this invention, the hierarchy of process for query (HPQ). The hierarchy of process for query (HPQ) is a changeable and programmable method performing queries within a ULDC 908 or a user location database coordinator network 1600. It simply instructs the ULDC 908, on which devices to query for the results of the requested information (query). Now referring to FIG. 14, is a flowchart, which illustrates a query for information pertaining to a single wireless device 104. As illustrated, the ULDC 908, waits for a query 1400. Then, a remote system (for example, emergency medical services for a service provider) sends a query to the ULDC 908 in the form of a phone number and includes its assigned query ID number 1402. The ULDC 908, searches all of the ULD 900, connected to it, in accordance to the parameters set by the hierarchy process for query (HPQ), for the user entry 1404. The entry that was requested by the remote system would then be found in a ULD 1406. The entry information is then sent back to the querying remote system, via the query ID number assigned at the beginning of the process 1408. The remote system then acknowledges the received data from the ULDC 1410. Now referring to FIG. 15, is an illustration of components of the ULDC 908 that has an ATM/direct connection 1500-A with a plurality of a ULDC 908, in a hierarchy. 1500-B connects to the ULDC's 908, uplink connection 1506, to higher ULDC 908. The connection 1500-B should be dedicated in the sense that interruptions are only when planned for and are expected. Suitable connections are T1, T3, microwave or other similar methods. The ULD 900, access control unit 1510, allows interface with a plurality of ULD 's 1512, having bi-directional connections 1500-C to each. These connections 1500-C, are communications links (T1, T3, microwave or other dedicated lines) 1306. CRC checking and other error checking methods are recommended when implementing the software design in the ULDC 908, control unit interface. Still referring to FIG. 15, the remote access control unit (RACU) 1516, allows dial-up, permanent, or other connections/other external source access to the ULDC 908. The RACU 1516 has accommodations for a plurality of connection options so-called dial-up or regular phone line connections and will require an internal modem to allow external connections of this type. The speed of the modem should not need to exceed to a 1400 kbs per port, although a faster modem could be used. Also accommodations for permanent connections should exist. Data line connection adapters for T1, or other digital sources should be integrated. As specific on this integration prior art, simply their presence as a whole is claimed in this invention as unique. The RF mobile link 1518-A, could also be connected to the RACU 1516, via a communications link 1500-D. The data-logging unit 1522, is responsible for storing/logging queries. It records queries and results from the queries, as well as the user/ID number of the requesting entity to an internal software database. This database should be permanent (but replaceable). A hard drive with the storage capacity of 40 GB should suffice and if it reaches its storage threshold data entries are erased starting ((starting with the oldest first). This storage capacity should allow for up to 1-year worth of entries (if not more) to be reported before old entries are erased. Still referring to FIG. 15, other components comprised with the ULDC 908, include; ULDC 908 control hardware/software 1524, a maintenance unit 1526, a master ULDM 904 and location verification process 1528, a market or group ULD 1530, and a mirror database 1532. The mirror database 1532, would mirror connected ULD's 1512, for faster access to information. Still referring to FIG. 15, in an alternative embodiment, the ULDC 908, may comprise a DLC 902, e-mobility services 144 and standardization conversion hardware/software 906. This standardization conversion hardware/software 906 would enable the ULDC 908 to be more compatible with hardware/software which is external (for example, service provider, user applications, etc.) to the ULDC 908. Adding e-mobility services 144 to the ULDC 908 would add efficiency to the query process when the ULDC 908 is asked to query a plurality of locations of wireless devices 104, from a plurality of service providers comprising a plurality of ULD's 1512. FIG. 16 shows an illustration of an alternative architecture of a ULDCN 1600. This alternative architecture illustrates the operation of a market-based system. In this architecture, a remote query, (for example) may be sent by an application comprised within the service providers network, to the service provider's e-mobility services 144, for the location of a wireless device 104. If it is determined, by the search of the service providers ULD 900, that the wireless device 104, is not operating within the service providers wireless device network 100, the query would be forwarded from the market level ULDC 908, via a dedicated communications link 910-A, and then to a national/international user location database coordinator 1602, via a dedicated line 1630-A. This national/international ULDC 1602, will then query other market level ULDC's 1604, 1606, 1608, 1610, 1612, 1614, 1616, in the process specified by the hierarchy process for query (HPQ), for the location of the specified wireless device 104, which may be roaming outside of its home wireless network 100. This architecture offers the advantage of easily accessible viewing of market level ULDC's 1502, on the market level and also on a national/international level 1602. Still referring to FIG. 16, another notable embodiment which is illustrated in this architecture is the optional communications link 1618, between the various market level ULDC 1604, 1606, 1608, 1610, 1620, 1612, 1614, 1616. These optional communications links 1618, are notable because it offers two important features; the ability from one market to another without using the national/international level ULDC 1602, and also as an alternative communications link between the market level ULDCN 1600, and the national/international level ULDC 1602, in case there is a break in one or more of the communications links 1630-B, 1630-C, 1630-D, 1630-E, 1630-A, 1630-F, 1630-G, or 1630-H. Now referring to FIG. 17, is an illustration of the architecture of a regionally based ULDCN 1700. Underneath the national/international ULDC 1602, exists a plurality of district user location database coordinator's 1702 and 1704, with regional user location database coordinator's 1706, 1708, 1710, and 1712, and market user location database coordinator's 1604, 1606, 1608, 1610, 1620, 1612, 1614, and 1616, under them respectively. Service providers 1300-A, 1300-B, 1302-A, and 1302-B, are positioned below the market user location database coordinators 1620, mentioned above. Optional communications links 1714-A, 1714-B, 1714-C and 1714-D, exists between district and regional ULDC's 1502, in order to provide a more efficient means for routing queries, to provide alternative routing possibilities in case of a communications link break, or to compensate for hardware/software problems within the ULDCN 1700. Queries within the ULDCN 1700, are performed in accordance with the hierarchy process of query (HPQ). Queries are routed through communications links, which are permanent connections such as (for example) TI lines 13 lines or microwave links 1716-A, 1716-B, 1716-C, 1716-D, 1716-E, 1716-F, 1716-G, 1716-1-1; 1716-I, 1716-J, 1716-K, 1716-L, 1716-M, 1716-N. These communications links 1716-A through 1716-N, represent uplink (From ULD/ULDC) and downlinks (From ULD/ULDC). Now referring to FIG. 18, a direct system is illustrated for connecting to a user location database coordinator network 1800. This alternative embodiment illustrates the means for service providers a plurality of wireless network, to query a national/international user location database coordinator 1602 directly. These service providers 1300-A, 1300-B, 1302-A, and 1302-B are linked to the national/international user application database coordinator 1602 via communications links 910-A, 910-B, 910-C, and 910-0, which are permanent connections such as (for example) T1 lines T3 lines or microwave links. In an alternative embodiment, the service provider may use an optional communications link 1618 in order to provide an alternative method for routing queries. Now examining FIG. 19, illustrates the external connectivity for sending queries to the ULDC 908. A plurality of sources as defined in the embodiments can query the ULDC 908. Additionally, an RF remote link 1518-A could be set up that would allow queries from remotely enabled remote wireless devices 1900, such as laptop computers 2450, and other devices via a radio frequency (RF) link 1902. These devices would allow queries to come from a plurality of remote wireless devices 1904. Queries can also come from services such as police 1906, emergency medical services 1304 or authorized accounts and other entities 1908. The queries flow to the ULDC 908 and then to the ULD's 1512 and ULDC's 1502 connected. The ULDC 908 follows the HPQ to collect results from queries. Defining the external connectivity for queries of the ULDC 908 is a list of externally connected devices. These devices consist of a plurality of users/devices that can request data from the ULDC 908. They include: A single ULDC higher on the hierarchy 1508 A plurality of ULD's 1512 A plurality of ULDC's 1502 EMS Services 1304 RF remote link 1518-A, and indirectly remote wireless query devices 1904 Police 1906 Authorized accounts and others 1908 The ULDC 908 is able to multitask and process these connections simultaneously and can be controlled via software multitasking operations (common knowledge). This allows a large number and complexity of ULD 900 queries to occur simultaneously at the ULDC 908. These devices each connect to the ULDC 908 in different ways. The parallel or lower ULDC's 1502, and ULD's 1512 are attached connection with dedicated lines, satellite, Ti, T3, microwave, etc. 1500-C and 1500-A. The plurality ULDC's 1502 higher in the hierarchy 1508 are connected with a dedicated line, satellite, Ti, T3, microwave, etc. 1500-B through the uplink port (see FIG. 15) of the ULDC 908. The remaining devices connect individually through the dialup/fixed connections 1306, 1500-D, 1910-A and 1910-B to the ULDC 908. The services using this method are the EMS services 1304, Police 1906, RF remote link 1518-A, and other authorized accounts 1908. Each of the connected devices 1304, 1518-A, 1906, and 1908 using the dialup/fixed connection lines 1306, 1500-D, 1910-A, and 1910-B would need software to interface with the ULDC 908. This software is common knowledge by and software engineer to develop. It would consist of a program that would have database query abilities, a graphical user interface, and ways to display and organize queries of the ULDC 908. The RF remote link 1518-A connected to the ULDC 908 has special requirements. Itself, it cannot submit queries alone to the ULDC 908. Its primary function is to act as a bridge between the ULDC 908 and wireless device 104, specifically connected to the RF remote link 1518-A. It converts signals from land lines 142, (TI coaxial, other) into a RF spectrum to be sent to the remote mobile devices 1900 designed for the RF link 1910-C. Similarly the remote mobile devices 1900 that communicate with the ULDC 908 send SF links 1910-C back to the ULDC 908. The RF remote link 1518-A organizes these signals by users and then converts them to landlines 142, (Ti ,coax,other) and transmits the signal back to the ULDC 908. The functionality of this RF remote network 2500 (see FIG. 25) is to allow remote mobile devices 1900 in the field to be able to query the ULDC 908 on a secure wireless RF link 1902 connection. The SF spectrum for this FR link 1902 would most likely be between 200 MHz and 10 Ghz (or any desired frequency). This frequency would have to, however, be authorized by the FCC for use. The remote wireless devices 1900 could exist as laptop computers 2450. They would require an additional piece of hardware with a remote RF transmitter/receiver 1518-A and an attached antenna 2430. This hardware could exist as a PCMCIA card with a connection to control hardware and the antenna 2430. Software control would occur on the laptop computer 2450, itself. The laptop 2450, would simply have to have the following minimum requirements: Sufficient processor/memory and computing ability to run the query software At least one PCMCIA type 1 or 3 slot. Ability to function on battery power or other wireless power source Ability to power transmitting antenna sufficiently Computable software operating system (OS) for query software. The RF link 1902 would be sent using a secure method such as spread spectrum with frequency hopping. Its signal would be sent as RF signals. The receiving antenna at the RF remote link 1518-A would therefore have to be within the range of the remote wireless devices 1900 signal. It would require a transmit and receive antenna 2430 to send and receive signals from the remote wireless devices 1900. This antenna 2430 should be an omni directional antenna such as a quarter wave monopole. The range of signals it can send and detect would be a function of the receivers sensitivity and noise rejection ability. The rejection of noise should be greatly increased with the use of a spread spectrum signal. The benefits of the RF remote link 1518-A and its connected remote mobile devices 1900 it is a secure way to query the ULDC 908. The remote wireless devices 1900 could be carried by police 1906, EMS 1304, and authorized accounts and other entities 1908 that may need to locate wireless devices 104 and their users 102 for emergencies or for any lawful reason. FIG. 20 demonstrates the logic of the hierarchy of location methods. The hierarchy decision algorithm is polled 2000 and the decision process proceeds. First the hierarchy attempts to calculate the location (latitude/longitude) of the mobile wireless device 104, using the digital signature method 2010 as covered in prior art. Next it verifies the validity of the result by looking at the RSSI of surrounding towers 2020. If the guess is valid it allows the result to be saved to the ULD 2060. If the guess is invalid, the location is calculated based on triangulation and RSSI 2030. Location is compared to fore mentioned criteria (RSSI) 2040 and if the calculation is approved, the location is saved 2050 to the ULD 900. If the calculation was incorrect, the location is calculated based on RSSI 2040 only, and stored 2050 to the ULD 900 (least accurate method). In FIG. 20 the HOLM is described. It begins when data is sent from the BSC. The first method used is the digital signature method of U.S. Pat. No. 6,249,252 or similar. If the selection is validated (as shown in FIG. 21) the value is added to the ULD 900 entry. If not, combination method based on triangulation and signal strength is used. If that method is not valid the least accurate method based only on RSSI is used 2050. FIG. 27 provides examples of location methods. It should be noted that these location methods are only examples and can be changed or modified in order to accommodate new location techniques. FIG. 21 demonstrates the Compare (validation method in FIG. 20 (2020, 2040) method when validating location. First, the computed value 2100 is passed to the algorithm. It looks at whether all the towers in the range of the wireless device 104 are communicating with the wireless device 104 (and their RSSI) 2110. Then are test zone is established 2120 that is a large but definitive area based on the towers communicating with the wireless device 104 is computed. The computed (original location) is compared to the test zone 2130. If the computed value resides within this zone then the location is checked as valid 2160. If it is not, the next method for location 2150 as shown in FIG. 20 is requested. In FIG. 21 the error check method of the FIG. 20 is shown. After the value is computed for location, it is checked. All towers first report RSSI of the wireless device 104. Location zone is then determined in a rough sized area. If the measurement falls within this area then the location is accurate. If not a signal to use the next method is returned. Alternatively, wireless devices 104 comprising location equipment such as, for example, GPS, may also be considered as a source for location information, and evaluated on the accuracy of the location method utilized at the wireless device 104. FIG. 22 illustrates e-mobility ULD queries 2200. E-mobility applications 144 can directly query the local ULD 900 through its DLC 902. These e-mobility applications 144 can also query remote ULD's 1512 by sending queries through the switch (MTX or other) 130, through and standardization process 906, to the upper ULDC's 1502 and consequently to any attached ULD's 1512 or ULDC's 1502. When queries are returned they are passed based on the query ID back to the e-mobility applications 144 by passing the result to the ULDC 908, though any standardization processes 906, to the switch (MTX or other) 130, and then back to the original e-mobility application 144. In FIG. 22 the method in which e-mobility applications 144 query remote ULD's 1512 is shown. They first send a query to the ULDC 908 through the switch (MTX or other) 130 connection. The query is then sent to relative ULD's 1512 and ULDC's 1502 based on the HPQ. Results are then forwarded back to the ULDC 908 and to the switch (MTX or other) 130. At this point the result is then sent to the e-mobility applications 144. FIG. 23 shows an illustration of the RF remote link 1518-A components. The ULDC 908 connects to the ULDC interface control hardware/software 2340. Residing logically or physically in the unit is the RF link management hardware/software 2350 that controls decoding/coding of message queues sent between the wireless query devices 1940 and the ULDC 908. Next is the power control unit 2360 that powers the RF remote link 1518-A and it's transmit/receive hardware. The maintenance unit 2310 allows for external diagnostics and repair of the unit. The transmit control unit 2320 controls data conversion to RF signals. The receiver control unit 2330 controls conversion of received RF Signals. The transmit unit 2304 amplifies and sends signals to the attached antenna 2300 via coax antenna lead cable 2302. The receive unit 2308 connects to the antenna and detects and isolates the received signals from the antenna 2300 originating from the wireless query devices. Now referring to FIG. 24, the remote wireless devices can exist as laptop computer 2450 or any other mobile computing device. They would require an additional piece of control hardware 2420 to control RF coding and decoding as well as the ability to function as a RE transmitter/receiver 2420 for an attached antenna 2430. This hardware could exist as a PCMCIA card 2410 with a connection 2440 to control hardware and the antenna 2460. Software control would occur on the laptop 2450 itself. The laptop 2450 would simply have to have the following minimum requirements: Sufficient processor/memory and computing ability to run the query software At least one PCMCIA type 1 or 3 slot. Ability to function on battery power or other mobile power source Ability to power transmitting antenna sufficiently Computable Software operating system (OS) for query software. The transmitted RF signals 1902 would be sent/received from the RE remote Ink 1518-A that would process queries and send them to the ULDC 908 via a data line 1500-D (Ti/fixed/or other). FIG. 25 illustrates an RF remote link RF network 2500. To cover the desired land area, towers should be placed as to target, first, dense urban areas. Ideally one RF remote link tower 1518-A would have coverage for this are. Secondarily other antenna 1518-B and 1518-C could cover this area. Then coverage for less populated areas such as urban 2520 and the sub-urban 2530 would be covered subsequently. The frequency and separation of towers 1518-A, 1518-B, and 1518-C in areas such as sub-urban 2530 area need not be as dense because less call/queries from mobile query devices 1900 would occur here. The primary coverage is the dense populated 2510 areas. FIG. 26 illustrates the design of a remote mobile query device 2440. The primary unit is a laptop computing device 2450 that has the required software for its functionality to send/receive queries to the RF remote link 1518-A. It then connects via a control card (possibly PCMCIA card interface 2410) to the RF interface control hardware/software unit 2640. This unit includes transmit and receive control units 2620, 2630 RF front ends 2605, 2608 and an attached antenna 2430 to communicated via RF signals with the RF remote link 1518-A. Queries to the ULDC 908 originate from the wireless query device 1900 and are sent to the ULDC 908 via RF transmissions to the remote RF link 1518-A. FIG. 27 illustrates to hardware and data that is required by the four recommended methods of location. These methods each require different elements to work appropriately. When deciding which method to use, care should be taken that all elements are available (or substitutes). These elements include: switch (MTX), HLR, VLR, ULD, BSC, SIBS Shelves, BTS, wireless device, timing data, signal strength, call processing information, latitude/longitude of BTS's, radio tower, down tilt, region type, azimuth on sectors, HLRIVLR data. Other location methods may also be utilized. Alternatively, wireless devices 104 comprising location equipment such as, for example, GPS, may also be considered as a source for location information, and evaluated on the accuracy of the location method utilized at the wireless device 104. Operations Call Process—Interaction of Invention To make clear the interactions of this invention and how it actually functions, refer to FIG. 11. It illustrates what happens when a wireless device 104 makes a call and how it is tracked. The diagram shows each logical function in the process. Here is the process as described in the FIG. 11. Call Originates 1100 1. ULDM 904 gets user information from the switches user database 1165. 2. ULDM 904 checks ULD to see if the user already has a previous entry 1160. 3. If user exists in the ULD, then the records' “log status” flag is turned on 1160. 4. If user does not exist in ULD 900, then a new entry is made for the user and flagged (log status) to “on” 1160. 5. The ULDM 904 now checks the entry for the “private” status of the log 1170 (more specifically, existing entries that have been modified by customer request as private). 6. If the entry is private, then the ULDM flags the entry as ‘inactive” 1194 and stops monitoring 1196 phone. 7. If log is NOT private, the ULDM 904 accesses the BSC with the call number, processes the ID number and retrieves data on the call 1175. 8. ULDM 904 decodes data and calculates user's geographical location (latitude/longitude) 1180. 9. ULDM 904 updates user entry in ULD 900 with geographic information 1185. 10. ULDM 904 updates ULD 900 entry with the current time and date 1185. 11. ULDM 904 continues updating ULD 900 entry for user while BSC reports call as active 1185. 12. When call ends, ULDM 904 flags log as inactive 1194 and stops monitoring 1196 call process ID number in BSC. Still referring to FIG. 11, the user entry is created 1160. It first checks if the entry exists and then, if not, creates one using the format subsequently described. Now referring to FIG. 9, to make this process above work, the ULDM 904 has to gather timing information and other measurements, such as in U.S. Pat. No. 6,249,252, from the BSC 118-A to make its calculations. Additionally, it combines this with wireless device 104 and radio tower with BTS 110-A, 110-B, and 110-C information acquired from the switch (MIX or other) 130. Information gathered from the BSC 118-A includes: Timing (TDOA, RID) information from radio towers 110-A, 110-B, and 110-C talking to the wireless device 104. Signal strength measurements from radio towers 110-A, 110-B, and 110-C talking to wireless device 104. Call Processing information in the call control hardware/software of the BTS. Information gathered from the switch (MTX or other) 130 include: Directionality of each radio tower 110-A, 110-B, and 110-C talking to wireless, such as AZIMUTH, DOWTILT, etc. Telephone number and call processing ID#. Latitude/Longitude/Altitude of the BTS/Radio Towers 110-A, 110-B, and 110C talking to the wireless device 104. Specifically, the ULDM 904 uses multiple methods (covered in the forementioned patents) to determine latitude and longitude of a wireless device 104 that involves the gathering of the fore mentioned data. Many major methods as covered under numerous patents have described, in detail, individual methods for acquiring a target location. The most prominent and robust is covered in U.S. Pat. No. 6,249,252. As its methodology is quite complex, any individual seeking to understand it should read it in its entirety. However good U.S. Pat. No. 6,249,252 is, it is recommended that a single method not be relied upon solely. Whereas some methods are good for dense urban terrain (conquering, RF multi-path issues) as in the case of U.S. Pat. No. 6,249,252, others are better for suburban type terrain. The choice in methodology as programmed into the software in the ULDM 904 should be transparent to the effect that based on decision protocols one method or a series of methods should be used in various circumstances automatically. For dense urban areas with high multi-path, a method such as U.S. Pat. Nos. 6,249,252 or 6,249,680 should be used. These patents deal with high RF multi-path in a dense urban environment. As described in their disclosures, they use digital signatures for key ‘reference” locations, allowing a wireless device's geographic location to be acquired with reasonable accuracy. For suburban, rural or other relatively similar environments, simpler location determining methods should be used. Multi-path RF signals are less of an issue and the suburban methods above are far too complicated and would require a high cost to implement, due to tuning. The recommended method is a simpler TDOAJTOA method such as in U.S. Pat. No. 6,167,275. These methods often also use receive strength as a function. Often as the case may be, in practical purposes, one of the location determining methods may still not be enough. In this case a third method based mainly on receive strength could be used (as covered in other available patents). What is unique and should be a part of the location determining software portion of this method, is the decision making process on choosing which method to use is determined. As a wireless network is deployed, sectors/antennas are classified as rural, suburban, etc., the decision-making software should first reference this type’ and then choose which type of methods to use (U.S. Pat. No. 6,249,252 or like U.S. Pat. No. 6,167,275). A final check should be to use signal strength (RSSI) to verify/discount an erroneous locations. If the location determined does not correspond to a reasonable value (latitude and longitude plus some degree of error) relative to receive strength, the other primary location determining method should be used to calculate to location. The selective use of these two location-determining methods, with a validity check using RSSI of receiving antennas, should ensure a reasonable location. **Note: If both primary location-determining methods fail to give a reasonable location, a very inaccurate estimate on RSSI could be used. The selection of the location determining methodologies used to determine geographic location, and priorities on each, should be selected based on the geographic conditions (terrain, tree density, building density, and other) of the wireless communications network. Therefore, the preceding recommendations could be altered and still remain in the spirit of this invention. ULD User Entries All entries in the ULD 900 must have a coding standard. The ULDM 904 uses this to create entries in the ULD 900. It is recommended that the following standard coding technique be used for entries, as it is very efficient. Bits (ordered left to Data Type 0-39 User# 40-103 Location 104-151 Date + Time 152 Log 153 Private 154-167 Spare User ID# Format XXX-XXX-XX)(X (10 digit) phone number of user 4 bits per digit=40 bits Bits 0-39 Example: 813-513-8776 Binary—10000001001 10101000100111000011101110110 Location: Bit 40 1 = North, 0 = South Bits 41-48 degrees (0-179) Bits 49-54 minutes (0-59) Bits 55-60 seconds (0-59) Bits 61-64 hexiseconds (0-59) Bits 65 1 = West, 0-East Bits 66-73 degrees (0-179) Bits 74-79 minutes (0-59) Bits 80-85 seconds (0-59) Bits 86-89 hexiseconds (0-15) Bits 90-103 spare (possibly used to denote accuracy) Example: 39 degrees 13 minutes 12 seconds 8 hexiseconds North 8 degrees 25 minutes 18 seconds 5 hexiseconds West Binary: 100100111001101 0011001000100001000011001010010010100000000000000 HEX: 939A644219494000 Time & Date: Bits 104-108 hour (0-24) Bits 109-114 minute (0-59) Bits 115-120 second (0-59) Bits 121-124 hexiseconds (0-15) Bits 125-128 month (0-12) Bits 129-133 day (0-31) Bits 134-145 year (0-4095) Bits 146-151 extra Example: 2248:05 12 hexiseconds 7/18/2001 Binary: 10110110000000101110001111001001111101000100 HEX: B602E3C9F44 Log Status: 1 = logging Bit 152 0 = not logging Full Private: 1 = Full private mode Bit 153 0 = not full private Anonymous 1 = Anonymous Private Bit 154 Private O = Not Anonymous Private Spare Bits 154-153 extra for future development/expansion. This area may be designated for future registers for other programs which need to add data tot the users database configuration. Final data entry formatted value-using values in examples: HEX: 81351 38776939A64421 9494000B602E3C9F44000 Accessing the ULD Repeating this process for every user creates the database on the ULD 900. This database is now accessible via software three ways: The ULDM 9O4 ULDM 904 is controlled by the BSS Manager 126 The BSS Manager 126 can then have access to the ULD 900 through the ULDM 904. E-Mobility services 144 (having read only access to the ULD 900) The ULDC 908 connection that allows remote queries (Connects via switch (MTX or other) 130) The first and most direct way to access the ULD 900 is from the BSS manager 126. This device is allowed read, write, and append access to the ULD 900 via the DLC 902. It can perform maintenance (editing entries) and other system level events. Querying the ULD 900 can be developed on the software level by SQL or other database query techniques. This patent does not cover nor intend to limit the creative ability of a programmer in developing ways in which to design the software interfaces. These creative approaches would be within the spirit of the patent, as all software written for this invention would have to be written into existing hardware that has proprietary design. However, is should be noted that this does limit the scope of this patent in any way. It is easily achievable though common approach to a software engineer skilled in the area of database management, to write software that could make direct queries of entries by multiple criteria specified by a user at the BSS manager 126. The second method of accessing the ULD 900 is by e-mobility 144 software applications that have read only privileges. These software applications, by means of software SQL statements or other similar database query techniques, access user entries in the ULD 900: Software applications such as these can include features like direction finding software (accessible from the “wireless web”) where knowing the wireless devices 104 location is necessary. This type of e-mobility 144 software application is made possible by this unique invention—greatly simplifying the amount of time needed in development of the code because it can use the information in the ULD 900. The third method is by a connection to a remote ULDC 908. A ULDC 908 is an important element that should be (but is not required) available in conjunction with any ULD 900 or plurality of ULD's 1512. Its primary function is to allow a plurality of connected devices, which can include ULD's 1512 and additional ULDC's 1502, to be remotely queried (using SQL or any other similar method) by any entity, person or other system connected to the ULDC's 1502 access ports. Uses of this could be for emergency services (911, EMS, etc), government requested “taps” and other purposes where locating a wireless device 104 would be useful. ULDC Architecture FIG. 17 shows a generic representation of the ULDC network (ULDN) 1600. Design can very, but the general hierarchy is always the same, with ULDC's 1502 having only one parent (a ULDC 908) and having multiple children (either ULDC's 1502 or ULD's 1512) The connections 910-A, 910-B, 910-C, and 910-D are dedicated data lines (Ti or other). The internal diagram of a ULDC 908 is shown in FIG. 15. Its components are: Direct e-mobility services 144 Standardization control hardware/software 906 Database logic center 902 Uplink connection 1506 Multiple downlink connections 1534 ULD access control unit 1536 ULDC access control unit 845 Remote access control unit 1516 Data logging unit 1522 Uplink/downlink optional expansion port 1538 Maintenance unit 1526 ULDC control hardware/software 1524 Master ULDM and location process 1528 Mirror database 1532 Market or group ULD 1530 The uplink connection 1506 should only be established with a single ULDC 908 higher in the hierarchy of the ULDCN 1600. This connection 1500-B is a 2-way ATM connection carried on a Ti or other similar dedicated line, which allows queries from another ULDC 1508 higher on the network hierarchy. The downlink consists of ULD's 1512 and ULDC's 1502 with can be queried (by SQL or other database query means) directly by the ULDC 908. There are two access control mechanisms, the ULD access control unit 1510 and the ULDC access control unit 1536, which control access protocols for each type of query. These two devices negotiate and talk to ULD's 151 2 and ULDC's 1502 sending and receiving data between them (queries and responses). The connections should be dedicated lines (Ti or other similar) 1500-A or 1500-C. The remote access control unit 1516 is responsible for negotiating remote hosts 1540, either by dial-up or a dedicated means of connection, to the ULDC 908 for purposes of database query submission to obtain geographic location information on wireless devices 104. These connected devices connect through the remote access control unit 1516 and submit queries to it that then are sent to all connected devices for the search, finally returning the results to the logged on host. To facilitate the querying process, any connected device should be assigned an ID#. These numbers are so when a query is sent, its original “owner” can be passed with it so the results are passed back to the right entity. The data logging 1522 unit logs queries and the 1D# of the user who made the query, to an internal storage device (internal hard drive or other large data storage device). Lastly, the uplink/downlink optional port 1538 is for future expansions such as redundant connections to other ULDC's 1502 to allow querying laterally in the hierarchy of the ULDC network 1700, as in FIG. 17. Any alterations for specific needs or for compatibility issues to the ULDC's 1502 architecture are conceded to be within the scope of this invention. To expedite searches and to give a general flow, the following search method is recommended for the ULDC 908 architecture. Alterations for specific integration needs are within the spirit of the invention. Searching the ULDC Each ULDC 908 should contain data about itself in an internal register that is set when devices are attached to it. Such information includes the area code of all the “home’ user entries on its system. “Home” users are users that and listed in the HLR's (home location registrars) of the connected devices. This indicates that users with these area codes have a high probability of being found in certain databases. So, generally the area codes listed could include the area codes of users in the HLR of the swiltch (MIX's or others) 130 (connected to their respective ULD's 1512) that are connected to the ULDC 908. Each ULDC 908 contains a list (stored in data register) of all the area codes off all searchable devices attached. These devices could be ULD's 1512 or even other ULDC's 1502, where the list of the ULDC 908 (the ULD's 1512 attached to it) would be added to the other higher ULDC's 1 502 connected to their uplink ports. In this way any ULDC 908 would have all area codes of the database's HLR's below it in the hierarchy. Access ID#'s are assigned to any entity or connection to the ULDC 908 that can submit a query. For example, the uplink connection could be by default #1, the plurality of remote terminals could be #2 or higher. This ID is referenced to all queries so results can be associated with the original owner. When a search begins, the ULDC 908 query first searches the “chain” of connected devices FIG. 15 looking first at the ULD's 1512 that contains the area code of the queried entry. If no attached ULD 900 contains the area code, then the ULDC 908 then looks at the ULIJC's 1502 with the area code. Doing so causes a great decrease in search time. This continues on until the ULD 900 with the user entry is found. The general flow of a query is in FIG. 14. It begins by the ULDC 908 being in IDLE mode (not being queried) waiting for a query. A logged on device sends a query in the form of a phone number and includes it ID#. The query and ID# are logged to the internal logging database. The ULDC 908 searches all connected devices, then when the result is found, it is returned to the ID# included with the query. The logged on device, or host, then acknowledges the data. At this point the ULDC 908 goes back to idle mode. A pseudo-code for a search algorithm may look similar to this. Done in SQL or any similar database query language, this would access the ULDC 908 and search for entries. Input Query From Host //check attached devices for area code //descriptor m=(number of attached devices) Let n=0 Start n-n+1 If attached device n (list of area codes) includes query area code Then go to Find {directly query ULD 900) Else if n=m go to end Else if n<m go to start Find (repeat process for all layers of devices) *When this search gets to a ULD 900 it should directly query it. If no entry is found it should continue then by search all devices under the ULDC 908 (queried) in the hierarchy. Conclusions, Ramifications and Scope Possible issues that could arise involve privacy and the concern for misuse/abuse. These issues have been considered while developing this technology, and measures to eliminate these worries are implemented in the device. Marking user entries as private can reduce privacy worries. Customer service or any other entities connected to the ULD 900 control software would make the change. When the system is told to track a user (when the user communicates with the network on his/her wireless device the ULDM 904 automatically starts) a check by the ULDM 904 is immediately done to see if a “full privacy” flag 1170 has been set. If it is, tracking location of the wireless devices 104 by the ULDM 904 and any modification of the entry in the database does not occur. Using this technology, the system cannot inadvertently track users, and privacy is assured. If an “anonymous privacy” flag is set, location information for a user account can only be retrieved—but no user information will be sent. This can be used by external applications that only require the location of a plurality of devices, without regard to user information. Such an application like the Directional Assistance Network uses this to anonymously find devices on roadways. Additional concerns lie in who can access this information. Because all information is stored at the switch (MTX or other) 130 of the network, direct access (and append/write access) to the database can only occur there. This assures that no other wireless device 104 on the network can tamper with this information. Only authorized personnel at the switch (MTX or other) 130 or persons remotely accessing it through the ULDC 908 have access. Results of this database and control system are that a diverse range of software applications can be developed that could access and utilize the database. Emergency services could find users on wireless devices 104 on the network, increasing general public health in medical emergencies when users have a wireless device 104. Other “e-mobility” 144 software applications could also access the database giving the users of the wireless device 104 access to services such as direction finding software, location/mapping information and many other portals. The benefit is that this information is controlled and stored by a central entity (the ULD 900 on the network, creating a universal portal that is centrally manageable. This technology was previously only available to a limited extent by GPS software. GPS requires that a device have its antenna outdoors or in relatively plain view of the sky to work properly. Cost and bulky sizing are also problems with GPS equipment as compared to cellular mobile devices 104. Additionally, adding GPS to wireless devices 104 would integrate smoothly into this invention. It would simply make it not necessary for location calculations to be done at the ULDM 904. Currently, with an increasing amount of wireless devices 104 connected to wireless (CDMA, TDMA, GSM or other) networks 100, it only seems natural that expanding this technology would benefit the population as a whole. While the invention has been described in connection with a preferred embodiment, it is not intended to limit the scope of the invention to the particular form set forth, but on the contrary, it is intended to cover such alternatives, modifications, and equivalents as may be included within the spirit and scope of the invention as defined by the appended claims. Network Tuning System; Summary of the Invention The present invention is directed generally to a machine and process for calculating and displaying wireless device locations and wireless network service problems with reference to related wireless devices on the said wireless network. The present invention can be referred to as a display system and a wireless network tuning system (WNTS). This invention uses a method(s) for locating wireless devices and referencing their location and performance with wireless network known parameters. The invention allows more readily accessible representation of wireless device locations on a display screen and problems to be presented to wireless network engineers. More generally, the present invention is directed to a computational machine and process for displaying wireless device locations, and for detecting and referencing wireless network errors with specific geographical location information of the affected wireless devices. The present invention then can allow a detailed display of the wireless network's problems, and correct the network's problems with a fault diagnosis and correction system. In an additional embodiment, the present invention can provide a means to display other user selected objects including, locations of radio towers and BTS's, service effecting factors, criss-cross phonebook database entries, and a geographic/topographic map overlay. Other customized user-selected objects may be displayed as an auxiliary overlay to the display screen. In an alternative embodiment, this customized display criteria can be created and viewed by users within the wireless network and to users outside of the wireless network and can act as a resource for other hardware and software which have a need to display locations of wireless devices. In a second alternative embodiment, the present invention provides a means for generating “case files” which can be customized by a user to provide customized queries when a user has a need for information based on, or relating to, the location of a single wireless device or a plurality of wireless devices. This customized criteria is retrieved in the form of a “case file” that can be created and interfaced by users within the wireless network and to users outside of the wireless network. The abilities of this invention would be to offer a means of displaying the location of a plurality of wireless devices on a display screen, and to allow wireless network engineers to monitor and debug wireless network problems from the switch (MTX or other) with little or no actual field testing. Problems recorded in the field could be resolved without delay. The WNTS functions in a basic sense by monitoring the wireless network for problems that affect service to connected wireless devices. When these problems are detected the WNTS can then monitor and track all wireless devices in the problem area and record data on faults and problems these wireless device incur relevant to their latitude/longitude. The WNTS can then correct the problem automatically, or make suggestions to the wireless network engineers for the possible cause of the problem and corrective actions, which may fix the problem. The most common method to debug these problems is for engineers to go to the field and take limited “snaps shots” of the wireless network that only record data for brief periods of time on limited wireless devices. The process and machine as claimed within, allows a plurality of wireless devices to be monitored and recorded over a period of time, as well as wireless network parameters as they interact with the wireless devices, and additionally record faults these wireless devices incur at specific geographic locations. To be able to employ the embodiments of this method, process, and machine, you must have the ability to find and locate wireless devices on the wireless network. Also, an additional technology that would allow rapid access to this data would be a dynamic database or system designed to store and hold information including latitude and longitude of the said wireless devices. The ability to determine the user's geographic location in the form of latitude and longitude data is disclosed in an attached document entitled, “A machine for providing a dynamic database of geographic location information for a plurality of wireless communications devices and process for making same”. This document referenced above, is a United States Provisional Patent, U.S. Ser. No. 60/327,327, which was filed on Oct. 0′, 2001. This provisional patent application references the use of user location databases (ULD), user location database coordinators (ULDC), and other location means The use of ULD, ULDC, and other location means is disclosed (offered only as an example of location means) in the fore mentioned provisional patent application, but can also include other means of location including a wireless device comprising a global positioning system (GPS). The fore mentioned provisional patent provides a system that allows a plurality of wireless devices on a plurality of wireless networks to have their geographical location as well as other bit, of data stored to easily accessible databases continually. A system such as this allows a plurality of wireless devices to be tracked, and have their locations stored on a dynamic database for query from a plurality of sources. In an alternate embodiment, the dynamic database could be created and contained within the current invention, and could track and store in memory or a physical database, the geographic location and data of designated wireless devices. This current invention provides a machine and process with a primary goal to allow a new and novel way to correlate wireless network problems and the manner in which they affect wireless devices on the wireless network and also to provide a trouble shooting system to suggest corrective actions to correct wireless network problems. Such a WNTS would allow a fast and efficient way to optimize a wireless network, without the need for field-testing by wireless network engineers. In an alternative embodiment, the current invention also offers a means for displaying the geographic location of an individual wireless device or a plurality of wireless devices on a display screen. The ability to display the location of wireless devices on a display screen is a useful and novel feature which can be utilized by other applications which require the ability to view and monitor the location of wireless devices. This alternative embodiment also allows for overlays of a geographic street map display and a criss-cross phonebook display and other user selected displays. Detailed descriptions of the preferred embodiment are provided herein. It is to be understood, however, that the present invention may be embodied in various forms. Therefore, specific details disclosed herein are not to be interpreted as limiting, but rather as a basis for the claims and as a representative basis for teaching one skilled in the art to employ the present invention in virtually any appropriately detailed system, structure or manner. For example, the components contained within the current invention may reside within the same physical hardware, or the components may reside outside the physical hardware. Detailed Description of the Preferred Embodiment Referring to FIG. 28 the primary architecture of the embodiments 2800 are illustrated. The main divisions between an existing wireless network 100, and the primary embodiment 2800 are illustrated. The components in the primary embodiments are: Elements of the Machine and Process (2800) The primary elements of the machine and process include: Monitoring software 2802 BSC access control software 2804 Fault diagnosis and correction software 2806 Device location software 2808 User location database 900 User location database coordinator 908 Geographic information database 2810 Criss-cross phonebook database with lat/long correlations 2812 Standardization/conversion hardware/software 906 Primary analytic software 2814 Internal central processing unit and computer 2816 Internal memory storage 2818 Case files with lat/long correlations 2820 Service effecting factors with lat/long correlations 2822 Radio tower lat/long correlations 2824 User interface software 2826 Correlating mapping software 2828 Correlating data for lat/long information 2830 Display software 2832 These elements are considered to be the basic requirements for such a system. Additional software and or hardware could easily be added to customize or extend the abilities of this invention (FIG. 28, Box 2800) without escaping the limits of its intentions and the spirit of its novelty. Monitoring Software 2802: The monitoring software 2802 is designed to monitor a wireless network 100 for errors or problems that result in service disruption to wireless devices 104-A, 104-B, 104-C, 104-D within the radio tower network 105. These errors could result in degradation or even loss or service to the wireless devices 104-A, 104-B, 104-C, 104-D. The monitoring software 2802 interacts directly with the base station controller (BSC) 118-A and the primary analytic software 2814. The monitoring software 2802 intercepts and decodes error codes produced by the BSC 118-A and interprets their effects on the wireless device 104-A, 104-B, 104-C, 104-D. If the error is service affecting then the fault is send to the primary analytic software 2814. The fault monitoring software 2802 acts as an accessory to the primary analytic software 2814, which is where any interpretations of faults are made. Base Station Controller (BSC) Access Control Software 2804: The base station controller (BSC) access control software 2804 is responsible for interfacing the components and processes of the current invention 2800 with the BSC 2804 of a wireless network 100. The BSC 2804 contains all the call information as well as all the information on wireless network faults. It should be noted that some wireless network designs have the network fault information stored elsewhere, and that the BSC access control software 2804 could be used to access that information at any other location also. The BSC access control software 2804 interacts directly with the BSC 118-A and the primary analytic software 2814. The BSC access control software 2804 has the primary function of serving as an intermediary software package that can interlace the current invention 2800 and the BSC 118-A and switch (MTX or other) 130. Fault Diagnosis/Correction Software 2806: The fault diagnosis and correction software 2606 is activated when a service-affecting fault is sent from the monitoring software 2802 to the primary analytical software 2814. When the primary analytical software 2814 receives the fault, the primary analytical software 2814 generates a case file 2820. The fault diagnosis and correction software 2806 examines the factors of the case file 2820, the service effecting factors with lat/long 2822, the radio tower and BTS with lat/long 2824, and the geographic information database with lat/long 2910. The fault diagnosis and correction software 2806 comprises a programmable diagnosis and correction system, which can be serviced and updated through a user input device (BSS manager or other) 126. When a case file 2820 is generated by the primary analytic software 2814, the possible causes of the fault are determined by matching the data contained in the case file 2820 against a list of possible fault causing factors. Once a number of possible causes for the fault have been isolated, the fault diagnosis and correction software 2806 can then perform diagnostic testing within the wireless network 100 to eliminate false positives, and provide a list of possible causes and corrective actions which may by preformed by the wireless network engineers. The fault diagnosis and correction software 2806 can operate in three modes: Passive diagnosis mode Active diagnosis mode Automatic correction mode The passive diagnosis mode examines contents of the case file 2820, along with the service effecting factors with lat/long 2822, the radio tower and BTS with lat/long 2824, and the geographic information database with lat/long 2810. Once the circumstances of the fault has been matched against the list of possible fault causing factors, and a list of likely causes and corrective actions are determined and tested, the list possible causes and suggested corrective actions is added to the case file 2820. When wireless network engineers examine the case file 2820, they can view the list possible causes and suggested corrective actions generated by the fault diagnosis and correction software 2806. The active diagnosis mode allows network engineers to use the automated diagnostic features of the fault diagnosis and correction software 2806 to automate the diagnosis and correction process. The active diagnosis mode is a completely user definable mode. It allows the user to define certain radio towers with BTS's 110-A, 110-B, 110-C, 110-D, 110-E, wireless devices 104-A, 104-B, 104-C, 104-D, or other criteria to be monitored for faults. This mode requires actual input from the wireless network engineers and cannot start automatically. Benefits of this mode would be to monitor problems or areas that would not be triggered in the passive mode, or to monitor problems that are anticipated in advance. The automatic correction mode can be programmed by the wireless network engineers to operate both in the passive diagnosis mode and the active diagnosis mode. When the automatic correction mode is activated, the fault diagnosis I correction software 2806 is allowed to make adjustments to the wireless network 100 if the result of the fault diagnosis testing prove conclusively (or to a very high probability) that the cause of the fault has been determined and that a determined corrective action will fix the problem. When a corrective action is made in the automatic correction mode, the cause of the fault and corrective action taken are recorded in the case file 2820. Device Location Software 2808: The device location software 2808 is the package that when activated by the primary analytic software 2814 is able to retrieve information from a database such as a ULD 900, or a ULDC 908, that holds geographic information (as well as time, date of the acquired geographic information). Additionally, as an alternative embodiment this device location software 2808 can directly query the BSC 118-A and calculate the location of a wireless device 104-A, 104-B, 104-C, 104-D, as instructed by the primary analytic software 2814. The device location software 2808 interacts directly with the BSC 118-A, the primary analytic software 2814, the ULD 900 and/or ULDC 908. The device location software 2808 should be able to be passed queries to return the location of: A specific wireless device All wireless devices on specific BTS's All wireless devices on a plurality of BTS's The device location software 2808 would directly query a dynamic database as discussed above (ULD 900, ULDC 908) to retrieve individual locations for wireless devices 104-A, 104-B, 104-C or 104-D. Alternatively, if no ULD 900 or ULDC 908 were available, the device location software 2808 would directly access and decode the BSC 118-A in order to determine the individual location of the wireless device 104-A, 104-B, 104-C, 104-D. The device location software can also retrieve the location of wireless devices 104-A, 104-B, 104-C, 104−0, equipped with a GPS system, or other means of determining geographic location such as triangulation, round trip delay, or other means. If a plurality of individual wireless devices 104-A, 104-B, 104-C, and 104-D were queried, they would all be sequentially resolved by queries to the ULD 900, the ULDC 908, device location software 2808, by direct access and decoding of the BSC 118-A, or by querying the wireless device 104-A, 104-B, 104-C, 104-D. If a specific radio tower and BTS 110-A, 110-B, 110-C, 110-D, 110-E (and thus all wireless devices connected 104-A, 104-B, 104-C, 104-D) is requested. Then the device location software 2808 would first query, by means of the BSC access control software 2804, the BSC 206 and retrieve information on which wireless devices 104-A, 104-B, 104-C, 104-D where connected to a given radio tower and BTS 110-A, 110-B, 110-C, 110-D, 110-E. The results of this action would be to retrieve the ID#'s for all the wireless devices 104-A, 104-B, 104-C, 104-D connected to any radio tower and BTS 110-A, 110-B, 110-C, 110-D, 110-E. If plurality of radio tower and BTS's 110-A, 110-B, 110-C, 110-D, 110-E (and thus all wireless devices 104-A, 104-B, 104-C, 104-D connected to) are requested, then the device location software 2808 would first query, by means of the BSC access control software 2804, the BSC 118-A and retrieve information on what wireless devices 104-A, 104-B, 104-C, 104-D where connected to all given radio towers and BTS's 110-A, 110-B, 110-C, 110-D, 110-E. The results of this action would be to retrieve the ID#'s for all the wireless devices 104-A,104-B, 104-C, 104-0, connected to all requested radio towers and BTS's 110-A, 110-B, 110-C, 110-D, 110-E. User Location Database 900: A user location database (ULD) 900, is covered under United States Provisional Patent, U.S. Ser. No. 60/327,327, which was filed on Oct. 4′, 2001, is an important element of this invention, but is not required. A ULD 900 is a database comprising a means for obtaining and storing the geographical data, user information, date/time information and/or user controlled settings information for the plurality of wireless devices 104-A, 104-B, 104-C, 104-D. This information can be retrieved through e-mobility services 144 as well as though direct queries of either the BSS manager 126 or ULDC 908. As related to the current invention 2800, the ULD 900 is accessed through an e-mobility connection 2834 and can then supply location information about wireless devices 104-A, 104-B, 104-C, 104-D connected to the wireless network 100. The ULD 900 may physically reside within the current invention 2800 or as an alternative embodiment, may be physically located outside the current invention 2800, and accessed, for example through e-mobility services 144. Availability of the entries in the database of wireless devices 104-A, 104-B, 104C, 104-D depends on the implementation of the ULD 900 into the switch (MTX or other) 130 architecture, as not to be covered by this Patent. Noted, should be the ability of an e-mobility service 144 to be able to calculate location information by direct query of the BSC 118-A or using other hardware, and following similar methods in acquiring this data as done by the ULD 900. User Location Database Coordinator 908: A user location database coordinator (ULDC) 908, is covered under United States Provisional Patent, U.S. Ser. No. 60/327,327, which was filed on Oct. 4, 2001, is an important element that should be (but is not required) available in conjunction with any ULD 900 or plurality of ULD's 1512. Its primary function is to allow a plurality of connected devices, which can include ULD's 1512 and additional ULDCs 1502, to be remotely queried (using SQL or any other similar method) by any entity, person or other system connected to the ULDC's 1502 access ports. Uses of this could be for emergency services (911, EMS, etc), government requested “taps” and other purposes where locating a wireless device 104-A, 104-B, 104-C, 104-D would be useful. The current embodiment 2800 can use a ULDC 908 to access information on other switches (MTX or other) 130 or physical devices such to obtain location information not contained in its own database. This is especially important when there may be more than a single switch (MTX or other) 130 in a given geographic area. The usefulness is that a ULDC 908 will integrate a plurality of switch (MTX or other) 130 networks together and for a super network, in which a larger diagnostic area can be established. Geographic Information Database 2810: A geographic information database 2810 is a software database. The geographic information database 2810 can reside physically separate as in part of any other storage media connected to the primary analytic software 2814. It contains in part or in whOle database information on: Roadway locations (correlated to latitude/longitude) Landmark locations (correlated to latitude/longitude) Residential locations Commercial building locations Railway locations Other user defined objects Topological survey information Altitude referenced to latitude/longitude Ground slope Other topological data (user customizable) Location information of wireless network equipment BTS BTS repeaters Other equipment Ground clutter User defined class of objects The geographic information database 2810 is used to implement a layer of geographic information onto a display screen 2836, which is seen by a user of the current invention 2800. When the data from the geographic information database 2810 is combined with factors accumulated by the primary analytic software 2814, the primary display software 2832 can produce useful and convenient data analysis to a user. Criss-Cross Phonebook with Lat/Long Database 2812: The criss-cross phonebook with latitude and longitude database 2812 enables internal or external applications to request phonebook listings on a cross-referenced basis. The criss-cross phonebook database 2812 comprises the longitude and latitude of listings sorted by names, addresses and phone numbers of residences, businesses, wireless devices, and government agencies, as well as category of goods/services sold (for business listings) and the price and availability of said goods and services. The criss-cross phonebook database 2812 can be queried and cross referenced by name, telephone, street address, category of goods and/or services, availability of product and price of goods/services, latitude and longitude, These requested listings may be overlaid onto the display screen 2836 along with other requested display layers. This criss-cross phonebook database 2812 is a novel and useful embodiment to the current invention 2800, because it would allow a display screen 2836 to display, for example, the location of local area hospitals overlaid on the display screen 2836 with the location of a wireless device 104-A, 104-B, 104-C, 104-D, and a street map from the geographic information database 2810. This embodiment would enable a user of a wireless device 104-A, 104-B, 104-C, 104-D to easily determine their geographic position and the geographic location and direction to the closest hospital. Another example would be that it would enable a police department to monitor the locations of the wireless devices 104-A, 104-B, 104-C, 104-D used by police officers. When the police department receives a call for police response, the police department would be able to determine which police officer is best able to respond. May other examples exist regarding the usefulness of this embodiment for government, business and private users. Standardization/Conversion Hardware/Software 906; The standardization/conversion hardware/software 906 provides a means to standardize and convert protocols thereby providing standardized and converted protocols. These standardized and converted protocols provide a means for the elements of the present invention 2800 to interface with elements outside of the present invention 2800. See FIG. 30 for flowchart of this embodiment. Primary Analytic Software 2814: The primary analytic software 2814 is the actual processing center of the current invention 2800. The primary analytic software 2814 is where correlations between wireless network problems and the related wireless devices 104-A, 104-B, 104-C, 104-D occur. The primary analytic software 2814 controls all claimed embodiments as listed in FIG. 28, Box 2800. The primary analytic software 2814 connects to the monitoring software 2802, BSC access control software 2804, fault diagnosis/correction hardware/software 2806, device location software 2808, geographic information database 2810, criss-cross phonebook database 2812, standardization/conversion hardware/software 906, the user interface software 2826 and display software 2832. The primary analytic software 2814 can run in three ways Passive scanning mode Active scanning mode Inactive In the passive scanning mode of the primary analytic software 2814 is able to monitor and decode all the wireless network errors received from the monitoring software 2802. All the errors have been pre-filtered by the monitoring software 2802 and include only service affecting errors. A configurable element of the primary analytic software 2814 is the level or specific errors that would be considered for the passive mode. These level or specific errors are user defined by configuring them in the primary analytic software's 2814 configuration file. This method would allow specific errors to be monitored passively without supervision by a network engineer. When a valid error occurs, the primary analytic software 2814 begins logging the error to a case file 2820. Then the primary analytic software 2814 analyzes the case file 2820 and retrieves the wireless device's 104-A, 104-B, 104-C, 104-D 1D#and additionally retrieves the radio tower and BTS's 110-A, 110-B, 110-C, 110-D, 110-E involved in the error (or alternatively all the radio towers and BTS's 110-A, 110-B, 110-C, 110-D, 110-E talking to the wireless devices 104-A, 104-B, 104-C, 104-D. Using this information, the primary analytic software 2814 knows what area of the radio tower network 108 to monitor. Now, the device location acquisition software 2802 will be queried by the primary analytic software 2814 to retrieve the identity of the radio tower and BTS 110-A, 110-B, 110-C, 110-D, 110-E 1D#'s that were involved with the error codes in the open case file 2818. The result of the query will contain the latitude and longitude as well as the time of the error. The primary analytic software 2814 then continually queries the device locatiqn software 2808 with the given radio tower and BTS's 110-A, 110-B, 110-C, 110-D, 110-E thus monitoring all activity on them. The data recorded to the case file 2820 is: Latitude and longitude of wireless devices 104-A, 104-B, 104-C, 104-D on the radio tower and BTS's 110-A, 110-B, 110-C, 110-D, 110-E Errors codes on the radio tower and BTS's 110-A, 110-B, 110-C, 110-D, 110-E coded to the wireless devices 104-A, 104-B, 104-C, 104-D involved Service effecting factors for each wireless device 104-A, 104-B, 104-C, 104-D tracked on the radio tower and BTS's 110-A, 110-B, 110-C, 110-D, 110-E Forward receive power (FIG. 37, BOX 3704) Forward transmit power (FIG. 37, BOX 3706) Ec/lo (FIG. 37, BOX 3708) Neighbor lists (FIG. 37, BOX 3710) Other user definable factors (FIG. 37, BOX 3712) Fault diagnosis and correction software's diagnosis and corrective action recommended and/or taken. Radio tower and BTS latilong 2824 The primary analytic software 2814 continues to update the case file 2820 for a user definable time period. When the time is up the case file 2820 is closed and saved to a hard disk. A message is sent to the user input device 126 (BSS manager or other) 126 alerting that a case file 2820 has been created and giving the initial error that caused the case file 2820 to be started. The active scanning mode of the primary analytic software 2814 is a completely user definable mode. It allows the user to define certain radio towers and BTS's 110-A, 110-B, 110-C, 110−0, 110-E, wireless devices 104-A, 104-B, 104-C, 104-D, or other criteria to be monitored. This mode requires actual input from the network engineers and cannot start automatically. Benefits of this mode would be to monitor problems or areas that would not be triggered in the passive mode, or to monitor problems that are anticipated in advance. Internal CPU and Computer 2816: The internal CPU and computer 2816 are a user preference based on system demand. They could be part of or even exist as hardware currently in the wireless network 100. Alternately, new hardware could be supplied that can power and run the current invention's 2800 software. The memory bandwidth and CPU power would have to be server level. RAM should be of the ECC type, and a parallel process architecture would surely result in higher performance. Internal Storage 2818: Internal storage 2818 of the current invention's 2800 data can be contained in any hardware realizable data storage unit. This internal storage 2818 unit must have the ability to change its size dynamically or have sufficient size such that expansion or reduction in database size will not exceed the physical storage maximum. For redundancy a suggested method is to employ a RAID storage system where multiple physical storage units contain the same data. They operate simultaneously to protect the data. If one unit fails then another is still running and can provide the data. Speed is also an important factor. Additional RAID designs employ striping techniques to increase access time of stored data on the physical storage device. The physical storage devices can be hard-drives, magnetic storage media, or other storage methods commonly available. The RAID design would be particularly valuable with regards to the ULD 900 and ULDC 908. The RAID design offers a “mirror” database, thereby limiting the demands created by continues quires to the wireless network 100. Case Files 2820: Still referring to FIG. 28, this diagram also illustrates the translation of a case file 2820. The interaction from the user is initiated in the user interface software 2826. The primary analytic software 2814 then sends a queue to the primary display software 2832 for the requested case file 2820. Operating in parallel, the case file 2820 is accessed and data is interpreted by the display software 2832. The lat/long information is calculated and correlated with the recorded data. The correlating mapping software 2828 then brings this information together as shown in FIG. 41 and displays it to the display screen 2836 for the user 2848. Service Effecting Factors with Lat/Long 2822: Factors that can be elected to be contained as part of a case file or simply to be track can contain in part or in whole: RF signal parameters Forward receive power Forward transmit power Packet/frame loss (frame error rate) Signal/noise level Fading Other user defined objects Call success factors Dropped calls Blocked calls Access failures Handoff sequences Hard hand-offs Soft-hand-offs Inter-system hand-offs Call initiate Call end Other user defined objects Messaging BTS forward messaging Mobile acknowledgements BTS reverse messaging Error codes Call process messaging Hand-off messaging Call initialization messaging Call ending messaging Other user defined objects Mobile connection type Active—voice Active—data IDLE (paging) Other user defined objects Radio tower and BTS Information 2824: Radio tower and BTS 110-A, 110-B, 110-C, 110-D, 110-E location information should be located in the switch (MTX) 130 as part of current 2G/3G wireless network 100/ 200 information. The following information is copied into the geographic information database 2810 from the radio tower and BTS information 2824: Latitude Longitude Antenna height Azimuth Down-tilt Beam-width Other user defined objects User Interface Software 2826: The user interface software 2826 is a simple software package that simply defines the look and feel for interfacing with the said machine and process 2800. It allows setting to be adjusted, configuration files to be created, and a plurality of other factors to be interfaced with. It also allows a graphical user interface (GUI) to be presented to the user 2848. It connects to the user input devices (BSS manager or other) 126 and the primary analytic software 2814. As the step is purely and interface problem and is common knowledge to a software programmer, any method employed here is easily within the scope of this invention, Correlated Mapping Software 2828: The correlated mapping software 2828 is a realizable software package that the current invention 2800 uses to integrate information from the user location database 900, the user location database coordinator 908, the geographic information database 2810, the criss-cross phonebook database 2812, the device location software 2808, the case files 2820, the service effecting factors 2822, the radio tower and BTS's 110-A, 110-B, 110-C, 110-D, 110-E and other sources as directed by the display software 2832. This correlated mapping software 2828 takes all these factors and visually overlays them as to produce an output containing a complete output to the user. The correlated mapping software 2828 extrapolates locations of the case files 2820 contents over time. The physical display can be programmed by the end user for a plurality of display options. These options can include: Service affecting factors 2822 related to individual radio tower and BTS's 110-A, 110-B, 110-C, 110-D, 110-E Case files 2820 data at specific times Receive strength over entire case file 2820 plotted geographically Individual call messaging and indicated with symbols (ex: square for a drop call placed geographically where the drop occurred.) User location database 900 data User location database coordinator 908 data Geographic information database 2810 data Criss-cross phonebook database 2812 data Device location software 2808 data Other user defined objects 2848 See FIG. 39 for flowchart of this embodiment. Correlated Data for Lat/Long Information 2830: This information is simply the final form of the data before it is processed into the final display output for a user 2848. It has processed by the correlated mapping software 2828 already. Display Software 2832: The display software 2832 is where the visual output for a case file FIG. 41 is generated. When the user input device (BSS manager or other) 126 requests a case file 2820, the display software 2832 is activated to decode and display a meaningful representation to a person at the console. It connects to the display screen 2836 and the primary analytic software 2814. First the display software 2832 generates an error code list that that displays all the case files 2820 and which radio towers and BTS's 110-A, 110-B, 110-C, 110-D, 110-E, were involved. The display software 2832 then decodes the errors and correlates them to the specific wireless devices 104-A, 104-B, 104-C, 104-D involved and plots the errors on a map. This map would have to location of wireless devices 104-A, 104-B, 104-C, 104-D when the error occurred. It also superimposes the network factors it recorded for the wireless device 104-A, 104-B, 104-C, 104-D for a user defined time, before and after the error occurred. Alternately, the latitude and longitude coordinates could be translated. Current common knowledge software packages (example: Street Atlas software) allow latitude and longitude coordinates to be translated into addressing information relative to roads and specific postal addressing. Latitude and longitude coordinates obtained by GPS systems on the wireless device 104-A, 104-B, 104-C, 104-D or a location retrieved though a ULD 900 or ULDC 908 or similar device would be converted to standard addressing. Using this method, the engineer can see every wireless device 104-A, 104-B, 104-C, 104-D that had problems and generated errors, and look at what happened before the problem, and what the result of the error had on the wireless device 104-A, 104-B, 104-C, 104-D. The huge benefit is that the actual location that the error occurred can be seen without having to do field-testing. For example, a case file 2820 could show a dropped call for a wireless device 104-A, 104-B, 104-C, 104-D, and show that the ec/lo increased dramatically before the drop. It would also show exactly where it occurred and include the all the network factors at the time of the error. This is a very beneficial visual display because the engineer can see a plurality of wireless devices 104-A, 104-B, 104-C, 104-D that had the same problem and quickly find a solution to the problem. Interactions between components in FIG. 28 are indicated as communications links which are used as passive links 2840-A, 2840-B in the primary analytic software's 2814 passive scanning mode, active links 2846-A, 2846-B, 2846-C in the active scanning mode, and passive link and/or active links 2834, 2844-A, 2844-B, 2844-C, 2844-D, 2844-E, 2844-F, 2844-G, 2844-H, 2844-I and 2846-A in both the passive and active scanning modes. These passive and active links may by T-1 lines, T-3 lines, dedicated lines, intersystem logical connections 132 and/or other, depending on the actual physical configuration and geographic location of the components. Other links which are illustrated in FIG. 28, and which also act as passive and active links include the 1-1 lines 2844-A, 2844-B, 2844-C, 2844-D and 2844-E, which connect the radio towers and BTS's 110-A, 110-B, 110-C, 110-D 110-E in the radio tower and BTS network 108, to the BSC 118-A. The BSC 118-A is connected to the switch (MTX or other) 130 by an intersystem logical connection 132. The switch (MTX or other) 130 is connected to the publicly switched telephone network 138 with an intersystem logical connection 150. The switch (MTX or others) 130 is connected to the e-mobility services 144 by an intersystem logical connection 148. The intersystem logical connections 132, 150 and 148 can also act as passive and active links for the primary analytic software 2814. Now referring to FIG. 29 is a description of the physical realization of the preferred embodiment. It shows the way in which the embodiment of the said invention can be realized by the use of its supporting hardware. The software detailed by the said embodiment is contained in the hardware. The hardware is required though for a successful implementation of the embodiment, and should be seen as such. Shown also, is a network with a central master server 2900 that contains the preferred embodiment 2800 and all software. Access points to the master server 2900 are: External access point 2902 E-mobility applications 144 Local access points 2904 BSC 118-A In FIG. 29 the external access point 2902 are isolated from the master server 2900 by a hardware firewall. It then connects to a high speed Internet gateway 2906 and then to the worldwide wed (Internet) 2908. From this point, individual computers 2910 or devices are able to route commands to the master server 2900 using this said connectivity. Additional external connectivity is allowed by use of a corporate LAN 2912 being tied directly to the external access point 2902. This access is NOT via any Internet connection, and is thus a secure connection. E-mobility applications 144 may also access the system directly. The e-mobility applications 144 system is tied into the BSC 118-A and switch 130, and connects to the wireless devices 104 where the e-mobility applications 144 are interfaced by the user. Shown in FIG. 29 is the local access point 2904 connection, which constitutes any local connection to the network. Of these types (external access 2902, e-mobility applications 144, local access point 2904 and BSC 206) local access points 2904 this is the most secure. The local access point 2904 connection is used for configuration and other administrative activity. Any available command for the said embodiment can be executed here through a local connection. Still referring to FIG. 29 a back-up system server 2914 is also installed and attached to the master server 2900. All data/software/connections are mirrored using a redundant array of independent disks (RAID) or similar method to add redundancy to protect the operational ability of the said embodiment if the master server 2900 were to fail. The fourth type of connection, the BSC 118-A, is shown in its logical connection to the network. The BSC 118-A provides a means to access the master server 2900 through the switch 130 and the publicly switched telephone network (PSTN) 138. The ability to access the master server 215 through the BSC 118-A can allow for alternate connection means including access from internet 3200 and remote sources connected to the BSC 118-A. The uses could include data exchange or remote operational commands. Still referring to FIG. 29 is the data flow diagram 2916, which illustrates the type of connections between the components of the network. These connections include; data flow connections, local area network (LAN) connections, intersystem logical connections. Now referring to FIG. 30 is an illustration of the standardization and conversion hardware and software 906 that may be used to interface the said primary embodiments 2800 with hardware and software, which are external to the primary embodiments 2800. The standardization and conversion hardware and software 906 are an SISO (single input single output) type control structure, where a single input results in a single output. In this case, a command from one protocol is input, and the correct protocol for the receiving machine is sent (after being converted internally). The flow of this process begins by a start command 3000 being sent to the standardization and conversion hardware and software 906. The standardization and conversion hardware and software 906 checks the protocol against known types using its internal protocol database 3004. If there is a match, and the protocol is recognized 3006, then it checks device attached 3008 and determines (or is pre-configured) the appropriate protocol by checking receive devices protocol 3010 from the receive device protocol list 3012. it then determines if a conversion can be made 3014. If it can convert the command, then it is converted 3016. The command is then sent 3018 to the connected device 3020. The conversion would end” 3022 at this point, and wait for another command. If any of the decision boxes (3006, 3014) are ‘no” then a ‘protocol error” 3024 is recorded and the recorded “protocol error” 3024 is send back to the sending source. Still referring to FIG. 30 the standardization and conversion process operates the same in either direction, from the source to destination or the destination to the source. The standardization and conversion process is bidirectional. Now referring to FIG. 31 is an illustration of the BSC access control software 2804. The BSC access control software 2804 is responsible for negotiating a connection between the primary analytic software 2814 and the BSC 118-A. Still referring to FIG. 31, the execution of its internal operations begins when the primary analytic software 2814 sends a request 3100 to the BSC 118-A. The BSC access control software 2804 then interrupts the start-idle state 3102 that the BSC access control software 2804 functions in when in idle mode. The BSC access control software 2804 checks to see if there is a new request 3104 form the primary analytic software 2814. If there was a new request, then the BSC access control software 2804 sends a command to receive the message 3106 from the primary analytic software 2814. It then compares the command 3108 to a command list 3110 of convertible commands (converting to BSC 118-A native commands). The next step is to check if the command is convertible 3112. If the command is convertible 3112, then the command is converted 3114 to the BSC 118-A native code (or protocol). The message (code) is then sent 3116 to the BSC 118-A. The system then goes back into the start (idle-wait for response mode) 3102 waiting for a new command or a returned answer from the BSC 118A. If however, prior to step 3112 the command was not convertible, then a ‘command error” will be sent 3118 to the primary analytic software 2814, and the system will return to the start (idle-wait for response mode) 3102. In this case, steps 3114, 3226, 206, 3102 are skipped. Still referring to FIG. 32, if no new command from the primary analytic software 2814 is received 3104, but a result from the BSC 206 is returned 3118, then the reverse conversion process begins. The BSC 118-A native code is converted into primary analytic software 2814 native messaging 3120. The message is then sent 3122 to the primary analytic software 2814. If no result was received from the BSC 118-A, then the system would have returned to the start (idle-wait for response mode) 3102. If a message was sent back 3122 to the primary analytic software 2814. The system then also returns to the start (idle-wait for response mode) 3102. Now referring to FIG. 32, the user interface software 3200 is illustrated. The user interface software 3200 is responsible for interfacing the user with the primary analytical software 2814 and other subsystems. It allows a plurality of connections to be used as interfaces: Internet 3202 Intranet 3204 Other user defined objects 2848 Local server/workstation 3206 When these four types begin to negotiate 3210 with the user interface software 3200, all protocol and other pure connectivity issues are resolved by commonly known techniques, the standardization I conversion hardware I software 906, or through standard protocols. The first step is for the user interface software 3200 to obtain the login information 3212 from the user. The user interface software 3200 then compares the user's login information 3214 against an encrypted database containing the user list. The database containing this information is termed the “user database” 3216. If the user is not authenticated 3218, then the session is terminated 3220. If the user is authenticated 3218, then the user interface software 3200 begins to log the user's activities, including login information 3222 to the system log 3224. Still referring to FIG. 32, the user interface software 3200 now determines the access rights 3226 of the users and allows the user to access 3228 the primary analytics software's 2814 features that it is allowed to. The system monitors continually the user's activity 3230 for abnormal usage. If there is abnormal usage 3232 then a message is sent to the system administrator 3234 and the session is closed 3236. If there was normal usage 3232 then the user may continue to access the system 3228. Again referring to FIG. 32, the user interface software 3200 also monitors for the users activity duration and when the user has been idle for more than a set time 3238 then the session is closed 3236. When the user ends the session 3240 the system logs the normal closure of the connection 3242 to the system log 3224 and closes the connection 3236. Now referring to FIG. 33 is a description of the device location software 2808. This device location software 2808 package is used to determine the location of a wireless device 104 connected to a wireless network 100/200 or other similar network to which a wireless device 104 may be connected. The commands 3300 form the primary analytic software 2814 to the device location software 2802 is a command to locate 3302 a wireless device 104, as well as an identifier such as the phone number 3304 of a wireless device 104. The device location software “starts” 3306 and receives the phone number 3308 of the wireless device 104. It then checks the phone number to see if it is valid for tracking. If the number is invalid 3310, meaning the number is not valid for any traceable device, an error message is sent 3312 to the primary analytic software 2814 If the number is valid 3310, then the device location software 2802 first can query (if it is connected to) a ULD 900 for the location 3314. If the number and location is found 3316, then the latitude/longitude of the device is retrieved 3318, and then a message is sent 3320 with the latitude/longitude to the primary analytic software 2814 and then finishes 3322. Still referring to FIG. 33, if the number of the wireless device 104 was not found 3316 then it queries 3324 a similar device such as a ULDC 908. If the number of the wireless device 104 and latitude/longitude location is found 3326, then the latitude/longitude of the wireless device 104 is retrieved 3318, and then sent 3320 to the primary analytic software 2814 and then finishes 3322. If the wireless device 104 location is not found 3326, then the device location software 2802 queries the BSC 118-A for location information 3328 including timing information on the number of the wireless device 104 including all radio tower sectors in use. The device location software 2802 can then compute the latitude and longitude directly 3330 from information derived from the BSC 118-A and radio tower latitude/longitude database 2824 by using calculation techniques 3332. These calculation techniques include triangulation of round trip delay (RTD) from network timing information, triangulation from the signal strength and other commonly known locations techniques. Referred to by this patent are location techniques disclosed in the Provisional Patent, U.S. Ser. No. 60/327,327 that was filed on Oct. 4, 2001. Still referring to FIG. 33, the location of the wireless device 104 may also be retrieved from the BSC 118-A if the wireless device 104 contains a global positioning system (GPS) that may transmit the wireless device's latitude/longitude to the BSC 118-A via the “keep alive” signal or other signal from the wireless device 104. Alternatively the location of the wireless device 104 can be determined at the wireless device 104 using triangulation, or other location techniques. If the wireless device 104 is equipped with a GPS unit, this would be the preferred location technique due to the GPS's inherent accuracy. The latitude/longitude of the device is returned, and then sent to the primary analytic software 2814 and then finishes 3322. Now referring to FIG. 34 is a diagram that illustrates methods, which can be chosen to track and isolate wireless devices 104-A, 104-B, 104-C, 104-D on a radio tower network 108. These methods are used by the device location software 2802. In a generic radio tower network 108, consisting of a plurality of radio towers with base-station transceiver subsystem (BTS)('s) 110-A, 110-B, 110-C, 110-D, 110-E, there are three primary ways to track wireless devices 104-A, 104-B, 104-C, 104-D. These three ways are to specify: 1. BTS a. a single BTS (eg. 110-A, 110-B, etc) b. a plurality of BTS's 110-A, 110-B, 110-C, 110-D, 110-E c. all BTS's 2. Sector a. a sector on a BTS (eg. 3400-B or 3400-A) b. a plurality of sectors on BTS's (eg. 3400-A, 3400-B, 3402-A, 3402-B) etc.) c. All Sectors 3. Wireless device a. a specific wireless device (eg. 104-A or 104-B) b. a plurality of wireless devices (eg. 104-A, 104-B, 104-C, 104-D) c. All wireless devices Still referring to FIG. 34 , these tracking methods are initiated by the primary analytic software 2814. The primary analytic software 2814 chooses which method to use based on the user's choice which is interfaced at the user input device (BSS manager or other) 126 and consequently the fault monitoring software and other internal configurations. Again referring to FIG. 34, examples of tracking would be if the primary analytic software 2814 instructed the device location software 2802 to track wireless devices 104-A, 104-B, 104-C, 104-D on radio tower and BTS 110. The result returned would be wireless device 104-B, 104-C. If the primary analytic software 2814 instructed the device location software 2802 to track wireless devices 104-A, 104-B, 104-C, 104-D on sector 3400-B the result would be wireless device 104-A. Now referring to FIG. 35-A describes the primary analytic software 2814. The process used by the primary analytic software “starts” 3000 by initializing the primary analytic software/hardware 2814 along with the operating system 3500. The primary analytic software 2814 then brings up a main menu 3502 for a user using the display software 2832. The user can select: Active mode Inactive mode Passive mode Display case file File management Exit program Still referring to FIG. 35-A, if the user selects inactive mode 3504 then the system is placed in standby mode 3506 and then goes into an idle state 3508. The primary analytic software 2814 then waits for mouse movement or input action 3510. When this occurs (mouse or input action) the system returns to the display menu 3502. If the user selects the active mode 3512, then the system displays the active mode menu 3516. The user is then prompted with a menu selection for the following: Track a single wireless device Track a list of wireless devices Track wireless device by sector Again referring to FIG. 35-A, if the user selects ‘track a single wireless device 3518, then the user is prompted to enter an identifier for the phone such as the number for a wireless device 3520. The user is then prompted to selects a time period to track the wireless device 3522. The primary analytic software 2814 then will record the data for the given time on the wireless device 3528. The primary analytic software 2814 utilizes the device location software 2802 to perform this process. The primary analytic software 2814 then records the file to a storage medium and the user is prompted to rename file 3526. The user is then prompted if they wish to continue tracking/track 3528 another wireless device. If the answer is yes 3528, the user is brought back to the active menu 3530. If they chose no 3528, then the user is brought back to the main menu 3536. If the user is in the active mode 3512, they can also select to “track a list of wireless devices” 3536. If the user selects yes, they can enter them into a plurality phone numbers of wireless devices 104-A 104-B, 104-C, 104-D they wish to track 3538. The user then selects a time period 3522 to track the wireless devices 104. The primary analytic software 2814 then will record the data for the given time on the wireless device 3524. The primary analytic software 2814 uses the device location software 2802 to record the data on the given time of the wireless device 104. It then records the file to a storage medium and the user is prompted to rename the file 3526. The user is then prompted if they wish to continue tracking/track 3528 another wireless device 104. If the answer is yes 3528, the user is brought back to the active menu 3530. If they chose no 3528, then the user is brought back to the main menu 3532. Still referring to FIG. 35-A, the user can also select to track wireless devices by sector(s) delineation (choosing sectors track on) 3540. The user is prompted to enter/select/choose a list of sector(s) to track wireless devices on 3542. The user then selects a time period 3522 to track the wireless devices. The primary analytic software 2814 then will record the data for the given time on the wireless devices 104 with the selected sectors being tracked 3524. The primary analytic software 2814 utilizes the device location software 2802 to perform this process. The primary analytic software 2814 then records the file to a storage medium and the user is prompted to rename the file 3526. The user is the prompted if they wish to continue tracking /track 3528 another wireless device. If the answer is yes 3528, the user is brought back to the active menu 3530. If they chose no 3528, then the user is brought back to the main menu 3532. The user interface software 2826 is used to allow the user it interact with the various processes of the primary analytic software. FIG. 35-B Now referring to FIG. 35-B, the user is prompted to select the passive mode at the main menu 3544. If the user selects the passive mode then the system displays the passive mode menu 3546 using the display software 2832. The user is prompted to enter the sector/BTS (or list) to track in passive mode 3548. The primary analytic software 2814 then asks the user to enter (if any) the ‘error criteria’ and if the auto-correct mode should be enabled 3550. The software then sends the information 3552 to the fault monitoring software 2802. When a fault is detected 3554, then the system creates a case file and prompts the user for a name (if none is entered then a default is used) 3556. The primary analytic software then sends 3558 the case file to the fault diagnostics/ correction software 2806. If the user enables the ‘auto-correction mode’ then corrections are received 3560 from the fault diagnosis/correction software 2806. These corrections, contained within the case file, are then sent 3562 to the BSC via the BSC access control software 2804. The user can then select to hit the cancel key 3564 and go back to the main menu 3566, or not hit the cancel key, go back to the passive mode menu 3568. Still referring to FIG. 35-B, from the main menu, if the user selects to “display case files” 3570, the user is forwarded to FIG. 35-C, BOX 3572. If the user selects file management 3574, (via the user interface software 2826) from the main menu, then a list of case files in the user's storage medium are displayed 3576 via the display software 2832. The user can select a plurality of case files 3578 via the user interface software 2826. The user is then prompted to delete 3580 selected case files. If the user selects to delete 3582 a chosen case files, the case files are deleted and returned 3584 to a display of listed case files. If the user selects to rename 3586 chosen case files, the case files are renamed 3588 and the user is returned 3584 to the display of stored case files. If the user selects 3586 to not “rename case files”, the user is then prompted to “exit” the system 3588. If the user selects to ‘exit” the system 3588, they are returned 3566 to the main menu. If the user does not choose to “exit” the system 3588, the user is returned 3584 to the display which lists the stored case files. Again referring to FIG. 35-B, the user can at any point select to “exit program” 3589, from the main menu, shut down the primary analytic software 3590, and exit the program 3591. Now referring to FIG. 35-C, the user can select from the main menu to “display case file”. The user is then prompted to select/enter a case file name 3572 (via the user interface software 2826). Then the user is prompted to enter a list of criteria to display 3592 (via the user interface software 2826). The case file criterion is then sent to the display package 3593 which includes: Correlated mapping software 2828 Correlated lat/long information 2830 Display software 2832 Still referring to FIG. 35-C, the primary analytic software 2814 then waits until the user information is displayed 3594 and the user exits the display package 3595. When the user is done with the display package 3595, the user is asked if they want to modify the parameters displayed 3596 (via the user interface software 2826). If the user chooses to display and edit parameters 3597, then the user is returned back to enter criteria to display 3598. If the user does not chose to display and edit parameters 3599, then they are returned to the main menu (FIG. 35-A, BOX 3502). Now referring to FIG. 36 is a flow chart, which describes the monitoring software. The monitoring software begins by receiving a “start” command 3602 from the primary analytic software 2814, and a list of flagged criteria 3604 form the primary analytic software 2814. The monitoring software then “starts” 3000 by monitoring 3606 the BSCII8-A for new messages. The monitoring software does so by accessing the BSC 118-A. If no new message is received 3608, it continues to monitor the BSC for new messages unless a software interrupt is called. If a new message is received from the BSC 3608, then the new message is compared 3606 to the flagged criteria list. If the new message 3610 is not in the flagged criteria list, then the monitoring software resumes looking for new messages from the BSC 3606. Still referring to FIG. 36, if the new message was in the flagged criteria list 3608, then the monitoring software extracts 3612 the “flagged criteria” information from the new message. The monitoring software then decodes 3614 and encodes the flagged criteria data into a case file format. The monitoring software then creates 3616 a customizes case file based of the specific flagged criteria. The monitoring software then sends 3618 the case file to the primary analytic software. Following the case file formatting process, the monitoring software then resumes waiting for error messages in the flagged criteria list 3606. Now referring to FIG. 37, this diagram illustrates the case file generation process and how a case file 2820 is organized. Information included in case files, and encoded in any industry standard database format includes: Case file distinguisher (number) 3722 Individual wireless device number 3724 Individual wireless device location 3700 Error codes of device 3704 Forward receive power 3704 Forward transmit power 3706 Ec/lo 3708 Neighbor list 3710 Messaging 3712 FER 3714 Other error codes 3716 Service effecting factors 2822 Radio tower latitude/longitude locations 2824 Other user defined factors 3718 The actual case file 2820 is composed of a software database entry as shown. It would include ‘N’ number of entries for all wireless devices 104-A, 104-B, 104-C, 104-D being monitored as requested by the primary analytic software 2814. Still referring to FIG. 37, the format of the industry standard database can be determined by a software engineer, but one approach may be to use the logical format shown in case file 2820 illustrated herein. Table column labels referring to the above types of criteria are in the case file 2820 structure. Any deviation or other structure can be considered within the scope of this patent because this format is a less than critical element of the patent. Now referring to FIG. 38-A is a description of the fault diagnosis/correction software 2806. The inputs 3800 which are past from the primary analytic software 2814, and utilized by the fault diagnosis/correction software 2806 include case files 2820, request correction command 3802, and protocol command exchange 3804. The fault diagnosis/correction software 2806 then “starts” 3000 when the case file 2820 is received 3806 and the protocol commands are exchanged 3808 from the primary analytic software 2814 and the fault diagnosis/correction software 2806. The case file 2820 is then parsed 3810 to extract information from the case file 2820. The case files 2820 data is then separated and sorted into defined (by input data) categories 3812 and each error and related data is stored as database entries 3814 into the local error database 3816. The fault diagnosis/correction software 2806 then ‘starts” to examine the error 3818. The fault diagnosis/correction software 2806 accesses 3820 the stored case files 2820 (stored in the local error database 3816) and creates an additional entry based on data for 15 seconds (or a length of time determined by a network engineer for a particular configuration) prior to the error, including the following data: Case file distinguisher (number) 3722 Individual wireless device number 3724 Individual wireless device location 3700 Error codes of device 3720 Forward receive power 3704 Forward transmit power 3706 Ec/Ib 3708 Neighbor list 3710 Messaging 3712 FER 3714 Other error codes 3716 Service effecting factors 2822 Radio tower latitude/longitude locations 2824 Other user defined factors 3718 Still referring to FIG. 38-A, the fault diagnosis/correction software 2806 can now proceed to apply standard (common knowledge by engineers in the field) techniques to detect and identify errors by type 3822. The fault diagnosis/correction software 2806 determines data value trends 3824 for data leading up until the error begins. The trend analysis is then stored 3826 as a trend analysis database entry 3828. Again referring to FIG. 38-A, the fault diagnosis/correction software 2806 then examines 3830 the trend analysis database entry 3828 and compares preliminary trend analysis criteria 3832 against patterns' that indicate error types and resolutions. These patterns are unique to networks, and should be programmed by network engineers for specific networks/setups. Default patterns are suggested by the embodiment of this patent in FIG. 38-B. These can be modified or appended and stay within the scope of this patent's claims. Now referring to FIG. 38-B, the resulting patterns/error resulting from calculations (as described in FIG. 38-A, BOX 3832) are compared 3836, 3840, 3844, 3848, 3852 to defined error criteria. The resulting error code/pattern evaluation produces messages that are then sent back 3856 to the primary analytic software 2814. If the auto-correction mode was enabled by the user 3858, (correction requested) then the fault diagnosis/correction software 2806 makes corrections based on the error codes/patterns. The shown default corrections are 3860, 3862, 3864, 3866, 3868. Still referring to FIG. 38-B, corrections that are a result of the fault diagnosis/correction software's 2806 analysis are then sent 3870 to the primary analytic software 2814 where they are processed. If no correction was requested 3858 (auto-correction mode is off), or if there are no more errors 3872 in the local error database 3874, then the trend analysis data 3828, stored error data 3878, is purged 3876. If there is another error in the ‘local error database” 3872, then the fault diagnosis/correction software 2806 returns to the “start” point 3000 of the error examination process 3884. If there are more errors 3872, the system returns back to the idle “start” point 3884 were the fault diagnosis/correction software 2806 waits for new messages to be passed from the primary analytic software 2814. Now referring to FIG. 38-C is a description of the default error table 3878, message table 3886, and correction table 3888. These tables are used in FIG. 38-B as defaults for the fault diagnosis/correction software 2806. Additions and modifications can be made to these tables 3878, 3886, 3888 and stay within the scope of this patent. These tables 3878, 3886, 3888, can be customized depending on the configurations of the wireless network, hardware and software considerations, the parameters set by network engineers, or other considerations which would require customizing the configurations of these tables 3878, 3886, 3888. Now referring to FIG. 39 is a description of the correlated mapping software 2828 flow. Output 3900 methods supplied by the primary analytic software 2814 include command to display an output 3902, raw data file with network data (case file) 3904, and mapping element list 3906. The mapping element list 3906 contains all the elements (types of data) that the user wants to map. The correlated mapping software 2828 now “starts” 3000 by checking if the case file is valid 3808. If the case file is not valid 3808, the correlated mapping software 2828 sends an error message to the primary analytic software 2814 and the display software 2832. If the case file is valid 3908, the correlated mapping software 2828 reads an element from the case file 3912. The correlated mapping software 2828 then assigns a reference color code to the data element to be used later for mapping 3914. The correlated mapping software 2828 then correlates the data to latitude/longitude values where the data was recorded 3916, and stores the correlated data 3918 to a data layer 3920 in memory. If this is not the last element in the case file 3922, then the correlated mapping software 2828 returns to read a new element in the case file 3912, and continues reading new elements until all elements have been read 3922. When the last element has been processed 3922, the correlated mapping software 2828 groups data layers into one file 3924, and stores all the file data to a 3926 master data layer 3920 file as a database entry. Still referring to FIG. 39, the correlated mapping software 2828 then calculates the most extreme west/east/north/south points in the data layer 3928. The correlated mapping software 2828 then imports 3930 maps 2810, 2812, 2824, 3956 based on these extremes. The correlated mapping software 2828 then saves each of these new maps as an individual layer 3932. The correlated mapping software 2828 follows by grouping these maps to one data file containing all the layers 3934 and stores them in the master map layer 3936. Based on the requirements of the mapping element list 3906, the correlated mapping software 2828 filters the case file data and map layers 3938 so that the resulting data contains only data and map layers 3938 relevant to what needs to be mapped. The filtered data 3942 is saved to the filtered master data layer 3940 and filtered mapping layers 3946 are saved to the filtered master mapping layer 3944. Both the filtered data layer 3942 and the filtered mapping layers 3946 are combined into the primary display layer data file 3950. The correlated mapping software 2828 records time and date of data and other configurable information and saved into a secondary data file 3948. The primary display layer data file 3950 and the secondary data file 3948 are then sent to the primary display software 3952. The correlated mapping software 2828 now closes itself and purges temporary data 3954. Now referring to FIG. 40 is description of the display software's operations. The display software's inputs 4000 are the primary display layer 4002, the secondary display layer 4004, and command/info passed to the display software 2832 from the primary analytic software 2814. The display software 2832 “starts” 3000 by sending the primary display layer 4002 and secondary display layers 4004 to two sub routines. Still referring to FIG. 40, the primary display layer's 4002 subroutine begins 4006 by reading data from the primary display layer 4002 data file data file. The display software 2832 then checks if the output for the user is defined as full screen 4008. If the output is a full screen 4008, as defined in the set-up, the display software 2832 then calculates dimensions for the screen size 4012/4016/4020 for full screen operation. If the output is a “window” screen 4008, as defined in the set-up, the display software 2832 then calculates dimensions for the screen size 4010/4014/4018 for the window screen operation. The display software 2832 then sends the results 4022 to commonly used/known mapping software 2828. If this is not the last data layer 4024, the system reads the next layer in 4006 and continues as before. Again referring to FIG. 40, the secondary subroutine starts 3000 by reading data 4026 from the secondary data file. The display software 2832 checks if the output is defined as full screen 4028. The display software 2832 then calculates dimensions for the screen size 4032/4036/4040 for full screen operation. If the output is defined as window screen 4028, the display software 2832 then calculates dimensions for the window screen size 4030/4034/4038 for window screen operation. The display software 2832 sends the results 4024 to commonly used/known mapping software 2828. If this is not the last secondary data layer, the system reads the next layer in 4006 and continues as before. After both subroutines are finished, the display software 2832 outputs the graphic display to the screen 4046/4048 using commonly known techniques. Now referring to FIG. 41 is a description of the final display output format. The final display has seven or more layers. These layers are: Radio tower locations display layer 4100 Wireless device locations display layer 4110 Service affecting factors (mapped to locations) display layer 4120 Error codes (mapped to locations) display layer 4130 Criss-cross phonebook entries (i.e. landmarks such as buildings) display layer 4140 Auxiliary object locations display layer 4150 Geographic/topological street map overlay display layer 4160 The final display output is the sum of the above display layers. A plurality of auxiliary object location display layers may be added by the user via the user interface software. By doing so, the user may expand the mapping And display features of the resulting maps. Still referring to FIG. 41, layer one 4100 is the location (latitude and longitude) of all the radio towers and BTS's 110-A, 110-B, 110-C, 110-D, 110-E in the radio tower and BTS network 108. Layer two 4110 overlays the latitude/longitude of the wireless devices 104-A, 104-B, 104-C, 104-D (and the previous locations relative to time) of the wireless devices 104-A, 104-B, 104-C, 104-D. Layer three 4120 plots the service effecting factors in the case file based on the recorded latitude and longitude where the factors 4121, 4122, 4124, 4126, 4128 were recorded. Layer four 4130 plots the error codes in the case file based on the recorded latitude and longitude where the factors 4132, 4134, 4136 were recorded. Layer five 4140 plots selected entries from the criss-cross phonebook database with lat/long correlations. The displayed entries 4142, 4144 and 4146 could represent such entries as, for example, hospitals, gas stations, restaurants, or a private residence. Layer six 4150 plots auxiliary latllong correlations of user selected/inputted entities 4152, 4154, 4156. Layer seven 4160 overlays a topographic map with road locations with correlated to their actual latitude and longitude locations. Still referring to FIG. 41, the final display output 4170 is sent to the user and shows all layers above combined together. Alternative Embodiments Now referring to FIG. 28, two alternative embodiments are contained within the current invention. The first alternative embodiment provides a means for providing a display screen machine and process, which enables access to the current invention by other applications through e-mobility services 144 or other interfaces. This alternative embodiment could be used by other applications which have a need to display the geographic location of wireless devices 104-A, 104-B, 104-C, 104-D, geographic location of entries contained with the crisscross phonebook database 2812, maps of or other data contained within the geographic information database 2810, user selected auxiliary entries, or other entries contained within the current invention 2800. The primary elements required by this first alternative embodiment include: Expansion to current embodiment to allow external queries to be processed (e-mobility services 144) Alternative Embodiment Requirements a BSC access control software 2804 and/or a user location database 900 or user location database coordinator 908 Monitoring software 2802 Device location software 2808 Geographic information database 2810 Criss-cross phonebook with lat/long database 2812 Standardization/conversion hardware/software 906 Primary analytic software 2814 Internal CPU and computer 2816 Internal storage 2818 User interface software 2826 Correlated mapping software 2828 Correlated data for lat/long information 2830 Display software 2832 Inner system logical connection and other connections 132 The primary external queries will initiate from the e-mobility services 144 of a wireless network 100. This implementation greatly reduces the necessity for excessive amounts of integration to occur. E-mobility services 144 already in current wireless networks 100 have access to the internet though certain firewall, LAN routing, and data protection schemes. This can be exploited by allowing external software to query, using a secure data connection via the internet, the said first alternative embodiment. All calculations, and processing would occur at the wireless networks server. Access to this data would be limited by defined settings such as. Viewable layers in final output Topological data Roadways Location of wireless devices Criss-cross phonebook data Geographic information data Other user defined data Service affecting factors Receive strength Signal to noise ratio Other user defined data Location and or previous location of the wireless device ULD database tracking ULDC queries to track mobile Other user defined data Types of queries Individual wireless device 104 Sector of BTS BTS Network ULD 900 ULDC 908 Device location software 2802 Other user defined queries Amount of time until processing occurs Level of precision in latitude and longitude Multiple query submission Have a predefined list of criteria to be submitted at regular intervals to the system Have reports automatically generated and sent through E-mobility applications 144 back to Internet user. Ability to report System errors Internet connected user can report false information reported by the system. Internet connected user can report missing information reported by the system. Other user defined objects 2848 External Connectivity of Preferred Embodiment Now referring to FIG. 29, the physical realization of the preferred embodiment and the alternative embodiments is illustrated. These embodiments include a plurality of methods to develop case files and hence detailed information on users/conditions that exist on a wireless network 100. When these case files are generated they are stored on the server—which is located at the switch (MTX or other) 130. This allows rapid use of these case files for debugging and optimization. The wireless network 100 can however be accessed from access points other than the switch 130. These locations are the corporate LAN 2912 and the Internet 3202. Both connections offer secure connections. Examples of secure connections would be secure server language (SSL) and other similar connections. Still referring to FIG. 29, the ability to access the switch (MIX or other) 130 from an external software package is integrated into the preferred embodiments. These preferred embodiments allows a plurality of software packages to access the databases and primary analytic software 2814 contained within these embodiments. These external software packages can be assigned certain security allowances in addition to individual user privileges. These restrictions would be able to limit software packages that the wireless network 100 has not authorized to various levels of access. An example of third-party I remote internet 3202 access programs could be a program that a wireless service provider uses to integrate billing information with communications (call, page, text message, etc.) logs. The wireless service provider could set up a location information program that could be marketed to users as a way to access location information regarding communications made on their wireless devices 104 billing statement. This location information program could be accessed by users, allowing them to remotely access the preferred embodiments and initiate a continuous tacking ability on the wireless device 104, when communications are made or at any other time. A user could also retrieve location information from a web site on the Internet 3202 for any communication (call, page, text message, etc.) on his wireless device bill, for example, thereby allowing the user to access a log of the geographic location information correlated to the user's logged communications. This would allow an employer to monitor the locations of employees at the time communication are sent and received. Another example would be for a program issued to police or law enforcement agencies to track a list, of a plurality of wireless devices 104 that could be submitted over the Internet 3202. This list would get updated at the switch (MTX or other) 130 in the users account and allow case files to be generated on the list of wireless devices 104 the user submitted. There are many possible ways to use this external connectivity option, however any use of its features would be considered within the realm of this patent's legal claims. The primary elements (access of many options could be defined by access rights of user/connection type) of this external connectivity would be the following: Ability to negotiate a secure connection via the internet 3202/corporate LAN 2912 Ability to authenticate software package and user Ability to negotiate commands to create a new user account with the preferred embodiment for the said new user. This account would contain profile, preferences, and storage ability for case files generated for the user. Ability to send a list of wireless device identifications 3726 (phone #s, ESN's, etc) of mobile devices that would allow the preferred embodiment to track these items. Ability to set tracking modes for the list of identified mobiles that are submitted to the said embodiment. These modes are: Manual (one time tracking only) and automatic (track and record mobile devices for a said period of time at any given interval. These intervals can include time of day, time of call (when the mobile makes a call), and default settings (every 24 hours). The ability to submit criteria for tracking other than a unique identifier phone a said wireless device 104. This can include: Geographic criteria (track—create case files—for wireless devices in a said geographic region. Demographic criteria (track wireless devices of users of a said demographic profile Other customizable criteria The ability to simply locate a wireless device 104 and return its location ® The ability to view any saved case files in the user home directory. This includes any manually developed case files as well as case files automatically generated by the user's profile settings—per prior request of the user. The viewing of these said case files would be generated by the preferred embodiments display software 2832 and could have limitations placed n it by access rights. These access rights could limit what layers are displayed on the output. Levels such as network information, cellular tower location, etc could be removed. Ability to negotiate file maintenance on a user directory from the remote connection is another option that could have restrictions based on access levels. Maintenance commands could include: Delete file Rename file Copy file Etc. The ability to remotely submit case files manually for auto-correction (user would require high access). A specific concern that users would need to be aware of is the ability of their records to be accessed by this system. Wireless devices 104 should be able to submit preference flags that will control access to the tracking and access of their accounts by the said embodiment. The levels that could be defined for this type of preference are: 1. Open access—any party may access all information about user 2. Limited access (Default option)—information such as the users name, and other private information is masked. Demographic information and the ability to anonymously track the mobile (ex: tracking by demographic information). 3. Polling access—No information is listed under the account, however tracking can still occur but only by geographic region. Results of the track would not include any information other than a generic identifier for the phone 4. No access—under this mode the user may not be tracked, but certain features such as the ability for the user to track him/her self will be disabled. Ramifications and uses stemming from these access levels are beneficial to the wireless service providers. The wireless service provider can choose to only allow certain levels to be used by a wireless customer. To this regard, under most circumstances they could make it mandatory for most wireless devices to be tracked. This information is a very valuable commodity. Many applications stemming from this exist beyond the ability for third party applications to simply access, view case files, and setup tracking options. Two specific claimed additional uses and processes would be: Allowing marketing companies access to tracking based on their target audience (demographic/geographic location/etc) Traffic Analysis and route planning software The first process would allow marketing or interested organization/persons to use software to access information about users based on customizable criteria. These criteria could be used to: Send wireless messages to the wireless device 104 when it enters a definable geographic region. Research consumer habits based on the consumer's profile/demographic information. Allow unsolicited interaction with a customer based on a profile set-up by a marketing company with the said process. (for example, and out of town user receives a solicitation for a discounted hotel rate as they enter town). Allow a user to request solicitations for specified products or services based on the users geographic location. (For example, the user is at Broadway and Vt Ave. and wants to know which restaurants in the area have a lunch special. Receive a ‘wireless coupon” for wireless device users 102 on user selected goods and services, based on the users geographic location. This “wireless coupon” would be realized by transiting the user a coupon code, number or word, etc., By putting the user on a “wireless coupon” list comprising the user names and/ or wireless device phone numbers 3724. This “wireless coupon” list is distributed to the service provider's business. Direct the user of the wireless device 104 to the closest service such as a hospital, gas station or restaurant for example. Of concern to users would be the abuse of this technology. They would be able to block any such attempts by limiting their access rights in their profile, or by wireless providers reaching agreements with its consumers. The second process is the ability for a directional assistance network (DAN) application to be developed that could analyze traffic patterns and determine alternate travel patterns that my offer a less congested path for a consumer while driving. This DAN application would function by first querying the wireless network 100, ULD 900, ULDC 908, or other systems to track all wireless devices 104 in a traffic grid (the geographic criteria would include roadways but not accessible—drivable land). It would then determine which devices are considered to be part of the traffic on a particular roadway. Because the wireless devices 104 are being tracked by a case file, they can be monitored for movement. If a device is in motion along a roadway grid for more than an allocated (a tunable) time, then it is considered traffic. When this has been calculated, all wireless devices 104 that are not selected are considered to be non-traffic devices. The system would now look at all moving devices and calculate four attributes: Average speed of all wireless devices on a given section of a roadway Density of wireless devices on the roadway Peak/Min speed of all devices on a road way Other programmable criteria The system would access internal databases to obtain posted traffic speeds on the various road segments. If the average speed is below the posted limit by a programmable amount, then it is deemed congested. If the traffic density is also to dense for the roadway (indicating bumper to bumper) then the traffic density is defined as heavily congested. Based on these criteria a traffic flow analysis can be done on the entire wireless network 100. Using the results a program can display to a user where traffic is bad/good in a visual display. Users can enter into this software a starting location and a destination location. Commonly used software packages are capable of finding simples routes. The standard method would first be used. If the resulting route had a congested element on it, a change would need to be made for the user. The DAN application can then find the fastest route based on roadway congestion. It would tell the route finding software to recalculate a route but NOT use the congested area. The resulting route would be analyzed for congestion again and resubmitted, as before, if necessary. The resulting information could easily be sent to the user via the wireless web as a message to their wireless device 104. The additional programming need would be to interface with an e-mobility application 144 that controls wireless messaging over the wireless web (for example). The route would then be sent directly to the mobile device. The user could also select for the route to be continually checked and updates sent to the wireless device 104 until the feature is disabled (by the user reaching the destination) or the feature is timed out by the user entering a time limit. The system knows the identification of the wireless device 104 of the user 102 and then could access the primary embodiment to access the mobile location and travel direction and speed. It could then recalculate the routing information if the user of the wireless device 104 were to get off the primary route. Updates could then be sent to the phone alerting of the change. Second Alternative Embodiment; Customized Case File Generation The second alternative embodiment comprised within the machine and process of the primary embodiments is a powerful feature for a consumer point of view, which allows the user to have external access to the primary analytical software 2814. This access, as described in more detail later, can take place from the Internet 3202, corporate LAN 2912 and from a local computer at the switch (MTX or other) 130. This access to the primary analytic software 2814 is through a secure connection, and allows the user access to stored case files, the ability to generate customized case files and for use of the primary access software. A specific feature of the second alternative embodiment is its ability to allow subprograms the ability to create customized case files. These customized case files contain monitoring data on the wireless network 100 that allow a plurality of data analysis to be made on the network. This analysis takes place by the fault diagnosis and correction software 2806. Additional analysis can be done by outside, third party, software. For this reason, special provisions in the preferred embodiments have been made to allow customizable case files to be generated. These custom case files better meet the needs and demands from consumers. While in normal operation, case files are generated by subprograms as part of their activities. For example, when the user selects the system to monitor for faults and correct them (auto fault correction mode) the system generates case files and then submits them to the fault diagnosis and correction software 2806. In this instance the generation of the case file is said to be autonomous. Contrary to this method, case files can also be generated monitoring for specific activities other than faults. A second mode of generating case files is when the user chooses to have the system create customized case files for specific criteria and simply save the results to a local storage medium. This local medium is defined as part of the storage system that the primary analytic software 2814 is running on. The medium is allocated for storage and divided into user directories that can have information stored into by specific users. A user has the option of looking for wireless network 100 variables other than just errors. The system is capable of recording data on the network based on several other criteria such as: Single or plurality of said wireless devices based on phone #, ESN, etc. Specific sectors on BTS's. Plurality of sectors on one or more BTS. Time of day Geographic criteria (track—create case files—for wireless devices in a said geographic region) Demographic criteria (track wireless devices of users of a said demographic profile) Other user defined criteria The first of the customizable criterion is being able to locate devices by a unique identifier that corresponds to the wireless device 104. A user may submit a single, or plurality, of identifiers for wireless devices 104 to the preferred embodiment. The monitoring software 2826 will then begin to monitor the network for activity by these devices. Activity can be defined as active calls, active data transfers, or any other form of activity from the wireless device 104, which would allow tracking on its location to occur. The monitoring software 2802 uses the BSC access control software 2804 to acquire data on these devices and stores it to a local case file for the user's later review. The next two tracking methods (other than for errors on the network) is when the user specifies specific or a plurality of sectors to track. The primary analytic software 2814 will again use the monitoring software 2802 subprogram to monitor (using the BSC access control software 2904) the sectors that were specified. All data recorded on these sectors will be stored to a case file 2820 that allows the user to retrieve information and perform data analysis by a third party program at a later time. The next criteria can be used in conjunction with the above and below criterion for creating case files. The time parameter equals the amount of time for which monitoring should occur on any specified prerequisite criteria. If a user asked for a specific sector to be tacked, the user could then specify for how tong (if he didn't then the default time limit—as defined in the software setup—would be used. Two specialized formats that allow very precise consumer oriented potential are case files 2820 being generated based on geographic and demographic criteria. The first, geographic criteria, is specified by a user in 3 ways: latitude I longitude coordinates and boundaries; geographic criteria that can be chosen from the primary analytic software's 2814 geographic information database 2810; or from predefined segments. The primary analytic software 2814 responds by translating these inputs into actual sectors that cover these areas. The monitoring software 2802 as well as the device location software 2808 then read in data on active devices in these areas. A further filter is then applied that removes devices not in the specified geographic region by comparing their locations with the locations acquired from the device location software 2808. The result is only devices in the desired region will be recorded to the case file. It also reduces computation power by only monitoring sectors that cover the geographic region chosen by the user. All data recorded on the geographic region will be stored to a case file that allows the user to retrieve information and perform data analysis by a third party program at a later time. The demographic criterion selection is different, however, in that it can use many of the above criteria to refine its monitoring pattern. Alone, the demographic criterion allows a user to specify demographic information on the user of wireless devise 104 on the network to track. This occurs by the user entering the demographic information and the primary analytic software 2814 looking up corresponding users in its local user database. This local user database is derived from a customer profile kept on record by the telecommunication company. Only relevant demographic information can be stored here. Sensitive financial information is not copied here to prevent fraudulent misuse or abuse. The matches are then sent to the monitoring software 2802 to be tracked and recorded to a case file 2820. Refinements can be used by combining this be geographic tracking to limit the area of geographic interest. Time, sector, and other combinations can also be used. The customizable ability for creating case files 2820 is a component of the preferred embodiment that would allow internal and external programs to generate analysis's that could be beneficial to consumer needs. These needs could be to track a list of employee wireless devices 104 to prevent misuse. Another example is tracking people for targeted marketing strategies. An important use of case file generation is for non-visible file operations. In these operations, case files are generated for internal programs and used as intermediate steps. When the case file is no longer needed, it is deleted. Its classification would be as a temporary file. Subprograms that use these temporary case files are: Monitoring software 2802 Display software 2832 Fault diagnostic and correction software 2806 The monitoring software 2802 continually creates temporary case files 2820 for internal use. The reason this subprogram uses the temporary case files is so it can capture events that contain errors and send them to the fault diagnostic and correction software 2806. This software, listed above, then parses the case file and discovers corrections that can be made to the network. Once the corrections are made, the case file can be deleted. This type of internal operation is transparent to the end user, but critical to the normal operation of the primary preferred embodiment. The display software 2832 also uses temporary case files when it is required to display certain information to the screen. It parses larger case files into smaller case files so specific information can be analyzed, displayed, and outputted back to the system for further diagnostics. The temporary case files are again transparent to any user's perception. Specific examples of a case file being used by the display software 2832 is if a user looks at a larger case file 2820 and then decides to only display certain information (time frame/geographic region/etc). The new display creates a new smaller case file. If the user finds a problem, he can submit the smaller case file for manual correction by the fault diagnostic and correction software 2806. When this process is done, the temporary case file is again deleted leaving the only original file. Circumstances under which temporary case files are not deleted are when a system administrator sets the system to retain these files for debugging or for validation reasons. Modifications to the network by the fault diagnostic and correction software 2806 may need to be checked by engineers after the system makes changes. In this case, retention of the temporary case files is critical. Manual deletion, or time marked deletion (delete temp files older than a certain age) is also possible by setting customizable configuration options. These listed uses of case files are in no way limiting to the scope of this claimed patent. Derivations and extensions of these ideas are completely within the scope of this patent, and in no way exceed the spirit in which the herein claimed embodiment is expressed. Pro-Active Tuning of a Wireless Device Network Where the primary embodiment of the said patent refers to analyzing the wireless network 100 for errors and then the resulting said processes, there exists the ability for the Network Tuning System (NTS) 2800 to take a pro-active role in network tuning. To allow this possibility to occur, the network must be able to support additional overhead processing. The pro-active tuning requires that the physical hardware used to run the MTX 130 will have enough processing clock cycles and available RAM and storage stage to accommodate this addition. As processing ability various by MTX 130 design and original provisioning of resources, it is simply stated that the resources will have to be added if they cannot be repositioned from the current architecture. The NTS 2800 primary role is to monitor a plurality of sectors or clusters (group of geographically close sectors) for load bearing factors. As a wireless network increases its user load, or due to many other factors, optimum performance is often not obtained. The increased user load can often result in loss of coverage for wireless subscribers. Using the ULD 900 to locate wireless devices and then analyzing network parameters; the pro-active approach allows the NTS 2800 to compensate for various factors the influence network performance. Network engineers currently using current industry methods can only design one configuration, which runs until a problem is encountered. At that point, the NTS 2800 could make changes or the network engineer could make modifications based on the network tuning systems reported data and/or recommendations. Network Factors Factors that can cause the network to perform poorly can occur for varying reasons, and at varying times. The results are the same however, that the perceived Quality of Service, or QoS, is reduced for the user. The primary factors are: Thermal interference Active Wireless Unit Density Terrain Interference Network Equipment Performance Thermal Interference Thermal interference causes Radio Frequency (RF) interference in the RF bands used by wireless subscribers of wireless networks. The core result is that the range a wireless device 104 (cellular phone for example) on a radio tower and BTS network 108 may transmit is reduced significantly. The reduction occurs because the receiver cannot recover the signal in the presence of the thermal noise. The significance of the noise is that is causes the affective range of a radio tower and BTS network 108 coverage to be reduced. Based on the level of solar activity by the sun this can vary during the daylight hours. The amount of direct daylight is closely proportional to the level of thermal interference causing the strongest periods to be at mid-day and the weakest and sunrise and sunset. The direct daylight causes the affective area of wireless coverage to vary as the time of day does. Secondly, at nighttime when thermal interference is less; signals can be received/transmitted at much greater lengths. At nighttime the wireless coverage becomes larger than during daylight hours. The primary goal by the pro-active ability of the NTS 2800 is to reduce or eliminate coverage loss due to shrinking radio tower and BTS network 108 coverage area. A secondary goal is to reduce the cross-interference of radio tower and BTS networks 108 when thermal noise is less. Active Wireless Unit Density Another factor in network coverage is active wireless unit density. Active wireless unit density primarily concerns CMDN/CDMA2000 and other spread spectrum technologies, but has minor implications in technologies such as TDMA, GSM, and other frequency division protocols. The reason that the factor is more affecting to spread spectrum protocols is that due to the fact that users share the same bandwidth, RF activity by individual users are seen as interference to others. The wireless density causes the noise floor to rise and results in a similar situation as in the thermal noise case. Technologies such as frequency division typically use guard bands to prevent intra-cluster interference from happening to users in close geographic proximity. There can still be a problem though when frequency reuse levels allow users in relatively close geographic proximity to interfere with each other RF signals. The typical case would be to consider a sector of a CDMA network. (Note, that this is a real situation using hypothetical numbers that closely approximate actual performance) With only one user, a radio tower and BTS network 108 can send and receive signals to a wireless device 104 at a range of 10 km. When a second user in close proximity to the first user and in the coverage of the radio tower and BTS network 108 becomes active, the second user begins to interfere with the wireless device's ability to recover signals from the radio tower and BTS network 108. The Ec/lo reduces from the wireless devices perspective. As more wireless devices become active, the Echo for each device reduces until the receiver in the wireless device reaches its detection threshold. At this point the wireless device can no longer receive asignal from the tower. The wireless device must move geographically closer to the radio tower and BTS network 108 to receive the signal. The trend tends to decrease coverage for all wireless devices on the sector. Typical network planning allows for sector coverage overlap and prevents coverage gaps under ideal conditions. When highly dense areas of wireless phones are active, however, coverage may reduce to the point that the typical overlap is no longer present. The high density results in coverage gaps, and loss of wireless device service in the affected areas. Terrain Interference Terrain Interference is a factor that can be caused by either manmade or natural terrain objects. Man made objects can include: New Buildings Power Lines Artificial Manipulation of natural terrain (cement) Other man made objects Natural terrain interference can be caused by the following factors: Foliage Density New Foliage Leaf Attenuation (density of leafs on Foliage)—Seasonal Bodies of Water (water level, location, etc) Rain Snow Both natural and manmade factors tend to simply impede RE propagation and cause signal loss. The factors result in radio tower and BTS network 108 coverage that can vary in size. The affect of this is much more gradual than that of active wireless unit density with respect to time. Network Equipment Performance Network equipment performance inaccuracies are often the case for problems to go unnoticed by a network engineer. The system may be set to have a radio tower and BTS network 108 transmit at a particular power level, but in fact will not. The network equipment performance inaccuracies cause the actual field performance not to follow computer models. The performance can be seen by evaluation of the sector as it communicates to users. Using the location of users from the ULD 900 the system can determine if the appropriate sectors are communicating with the device. If the incorrect sectors are communicating the transmit level and/or orientation should be changed on the radio tower and BTS network 108 to correct for the field inaccuracies in the equipment. Network Compensation Techniques To compensate for performance factors, the system dynamically adjusts the configuration of the network. The transmit power, intensity, or other transmit measure must be able to be adjusted from the MTX 130, to make the required changes. The system then can vary the performance dynamically, thus altering RF coverage properties of the network to compensate for the less than optimal network performance. An additional adjustable factor that is not required but is useful when correcting network hardware performance issues is a variable orientation control for radio tower and BTS network 108 sectors. The variable orientation control would however require additional hardware to be installed to allow remote orientation control of radio tower and BTS network 108. Thermal Noise Thermal noise in most cases affects all sectors of a wireless device network relatively equally. The exception is when antennas and hardware on the sectors are exposed to varying amounts of sunlight due to mounting design or location (in a shadow, etc). The coverage area must be broken into sectors. Computer simulations establish the coverage zone for each sector using ideal factors. FIG. 48 describes the process for each sector. Each sector undertakes the following process. To adjust for thermal noise interference, the system must first establish the location of all active wireless devices in the predicted coverage zone for a sector 4800. When the NTS 2800 obtains the location for each device from the ULDIULDC 900/908 or other method, the NTS 2800 records all send and receive powers all devices communicating with the sector via the BSC 300, BOX 4805. The measurements are used as follows. The wireless device will transmit at a particular level and report its transmittal strength and/or Ec/lo 4810. The radio tower and BTS network 108 receives the signal from the devices and receives and calculates the normalized Ec/lo for the entire sector 4815. The network engineer establishes a typical free space loss per unit distance and establishes a minimal Ec/Lo value for the entire sector. The minimum value can be an included item in the configuration file so the free space loss per unit distance is available to the software. To establish a minimum value for loss, nighttime measurements would be ideal. The NTS 2800 compares the normalized sector base loss with the minimum loss value. The resulting number indicates the amount of noise affecting the signal 4820. To insure that the noise is mainly due to thermal conditions, the system can also mathematically remove the added noise by other devices by subtracting the power levels at the distance from the secondary device to the primary devices. The system then increases Ec/lo levels to a ratio that compensates for the reduction due to thermal noise. In other words, calculate the amount of reduction in Ec/lo due to thermal noise, and then increase the transmit power of the sector until it has increased the Ec/lo values to target levels. The increase should be such that the Ec (energy per chip) increases the ratio back to the base level. If the recorded Ec/lo value of the system is above the normal level by greater than 10dB when the above calculations are done 4825, the system should reset the transmit power level to its default value and then resample the sector to attempt to get the Ec/lo to be at a level that compensates for thermal noise 4830. If the Ec/Lo value is less than 10 dB above the minimum value 4825, the NTS 2800 repeats the process for the next sector 4850. If the Ec/lo level is less then the minimum value to maintain coverage, the system should increase the transmit power by some small unit 4835. If the Ec/lo level is 8 dB above the minimum level 4840, the NTS sends an error message to the network engineer 4845. The NTS then repeats the process for the next sector 4850. If the Ec/lo level is 8 dB below the minimum level 4840, the NTS repeats the process for the same sector 4800. Active Wireless Unit Density FIG. 49 displays the process to tune a wireless network using the active wireless unit density. To tune the wireless network by active wireless unit density, the NTS 2800 breaks up the coverage area into grids. An example of a grid layout is presented in FIG. 43. The number of zones will be determined by the size of the network and the size of each zone. Each zone should be in the range of 0.05-0.25 square-km in size. The zones are analyzed one at a time; say zone ‘n’ of “m’ total zones. To compensate for active wireless unit density, the network must first determine the location of all the mobile units in a particular area 4905. To get the location of all the wireless devices, the system can submit the coordinates of the zone to the device location software 2808 of the NTS 2800 that queues the ULD 900 for the location of the devices in the sector. It may also retrieve location results via GPS information or direct query of the BSC/MTX 118-A/130. When the location has been determined for the wireless devices, the system then determines other sectors currently communicating with the wireless devices. Because QoS is the primary goal and wireless density is a very rapidly changing factor, the Packet loss, Bit Error Rate (BER), or Frame Error Rate (FER) are good standards for measuring the QoS for users. A general practice is that above 2% on any of these parameters is unacceptable for users. A network engineer could however choose the value of this percentage at their discretion for any network configuration. The NTS 2800 checks if the average density of wireless devices is less than 10 units per 0.1 km2 4910. If the average density is less than 10 units per 0.1 km2, the NTS 2800 repeats the active wireless unit density tuning process for the next zone 4915. If the average density is greater than 10 units per 0.1 km2, the BER/FER/Packet Loss value is calculated for each wireless device in the zone 4920. The NTS 2800 determines if of the users are experiencing BER, FER, etc of over the threshold limit 4925. Commonly published studies have shown that if 50% of users with a wireless transmit density of 10 wireless units per 0.1 sq km are experiencing error rates greater than 2-20% than they are with a 75-90% likelihood interfering with each other and reducing QOS and coverage. FIG. 44 shows a typical layout in a wireless network with 3 sector BTS's. Zones B and D have greater than 50% of the active units transmitting with greater than 2-20% BER/FER. QoS is the best measure of network perceived usability and these factors (BER, etc) are used as a gauge by this embodiment to prevent coverage gaps. Next, the NTS 2800 determines which sector has the largest percentage of users in the zone 4930 and increases the transmit power of the BTS 108 by one unit 4935. A typical power increase increment would be 1-1OdBmW for the transmit strength. The system then checks the geographically adjacent sectors and makes sure that the unique users on those sectors are not affected by the change (no increase in BER and other determining factors) 4940. If adjacent sectors are interfered with, the NTS 2800 sends an error message to the network engineer 4950 and the NTS 2800 processes the next zone 4915. If adjacent sectors are not interfered with, the NTS 2800 checks if the maximum transmit power is reached 4945. The maximum level prevents ‘overshoot’, which is when a sector will project its RF inadvertently into distant sectors coverage. A typical limit could be in the range of 5 dBmW to 100 dBmW. If the transmit power has not reached the maximum level 4945, the NTS 2800 repeats the process starting with recording the BER/FER/Packet Loss 4920. The system will then continue to increase transmit power until the percentage of users failing the 2-20% criteria has either been reduced to below the designated level 50% in spot areas (or another network-engineer prescribed level) or the increase causes an increase in the BER of adjoining sectors polled. If the maximum level is reached, the system sends a report to the network engineer 4950. The NTS 2800 then analyzes the next zone 4915. The technique should be done on every zone in the network. The frequency of the polling and resulting adjustments should be fast, so as stated, adequate processing ability should exist. Terrain Interference Terrain interference has in some cases limited recoverability in network performance by the pro-active system. In most cases the obstruction cannot be overcome by parameter modifications. To begin the system should query the ULD 900 for the location all wireless devices in the ‘theoretical’ zone of coverage for a sector 5005. This ‘theoretical’ zone consists of a predefined geographic area that network engineers expect full coverage from for any giver sector on a radio tower and BTS network 108. Such geographic zones are usually determined during initial network provisioning and are updated when physical changes in RF equipment are made. A list of all the sectors that all wireless devices in the theoretical zone are communicating with are listed. Devices that are communicating with the sector being diagnosed are kept in a list (or database entry, file, etc). A list of these sectors, for naming purposes it is called list one, is made for diagnosis. The devices in list one consist of all devices that are both in the theoretical zone and communicating with the sector being diagnosed 5010. A second list, for naming purposes list two, should be created that contains all devices in the theoretical zone that are not talking to the sector being diagnosed 5015. Basic interpretation of list two will show all the devices that cannot communicate with the sector being diagnosed. With the exception of software errors, the primary reason is lack of RF coverage from the sector. Software errors can be ruled out by the network tuning system or by a qualified RF engineer using commonly known techniques in the field. The performance evaluation should be done in zones 5020. The zones can be defined by percentages of distance from the radio tower and BTS network 108 to the theoretical ending of coverage for the sector FIG. 45. Another defining range could be in units of distance, for example meter, miles, feet, etc. There can be an arbitrary number of zones in the system. Further expansion of this method that would only need additional software programming, and does not take away from the novelty of this design, would be to add additional zones in a radial pattern from the radio tower and BTS network 108 in FIG. 46. A radial pattern allows multiple zones at the same distance from the radio tower and BTS network 108. Examples of zones in a 4-zone non-radial divided system are: Zone 1- 0%-25% distance from Sector Zone 2- 25%-50% distance from Sector Zone 3- 50%-75% distance from Sector Zone 4- 75%-100% distance from Sector The zones should be scanned starting from 1 to 4. For a radial divided system, the sub zones should be examined from one radial side to the other, in a sweeping direction that repeats in the same direction for each zone. The scanning should examine list one. List two does not need to be examined because devices are not talking to the sector and would waste both time and resources. For each zone a calculation of the percentage of devices in list one versus the over all devices in list one and two for each sector should be made 5025. If less than 50-80% of the devices in a zone (or sub-grid) are communicating with the radio tower and BTS network 108 sector then an obstruction may exist 5030. Each sub-grid is flagged either bad or good depending on the communications of the devices in the zone 5035, 5040. In most cases, the problem areas will result at the extreme edges of the theoretical zone. A second calculation should then be made to calculate the overall coverage of this sector 5045. The best method is to first disregard all zones on the edges (border zones) of the theoretical coverage FIG. 47. The disregard of border zones is most appropriate in radial divided zoning displayed in FIG. 46. With the zones disregarded, the percentage of zones that failed the first criteria (less than 50-80% of the devices in a zone (or sub-zone) are communicating with the radio tower and BTS network 108 sector) should be calculated 5045. If over 1-20% failed than the system then can attempt to increase transmit power to compensate for this problem 5050. The power is increased one unit level at a time (as listed in the configuration file). The NTS 2800 checks the power against adjacent sectors as it was with the wireless density factor resolution process as described in this embodiment 5055. If the wireless density causes interference with an adjacent sector, the NTS 2800 reduces the level by one unit 5060, sends an error message to the network engineer 5075 and then moves to analyze the next sector 5080. If there is not interference with adjacent sectors 5055 and the maximum power is not reached 5065, the NTS 2800 reanalyzes the zones 5070. The power should be increased until less than 20% of zones in the fail the second calculation (over 1-20% failed) or until a threshold limit is reached on transmit power 5065. If a limit is reached an error message is sent to the network engineer 5075. The technique should be done on every sector in the network. The frequency of the polling and resulting adjustments should be fast, so as stated, adequate processing ability should exist Network Equipment Performance The network equipment performance of a network can be evaluated by comparing simulated results to actual numbers. FIG. 51 displays the process to analyze a wireless network using network equipment performance. The NTS 2800 queries the location of all devices on the theoretical coverage of a sector (say sector “n’ of “rn’ total sectors in the network) from a ULD 900 and then the received powers (relative to wireless device) are recorded 5105. The figures are compared against theoretical numbers for the antenna arrays and their power relative to the locations for wireless units communicating to the hardware. If the measured power levels (receive level) are to off by +/−20% (compared to theoretical predicted values for the current transmit power) for 80% of the devices then the network equipment is most often the cause 5110. If the receive level is to high 5115, the NTS 2800 decreases the transmit power by one unit 5125. The NTS 2800 then checks if the minimum power level has been reached 5140. If the minimum level has not been reached, the NTS 2800 checks for interference with adjacent sectors 5145. If there is no interference, the NTS 2800 repeats the process again for the same sector 5132. If the minimum power level is reached 5140, or there is interference with adjacent sectors 5145, the NTS 2800 sends an error message to the network engineer 5155, and repeats the process for the next sector 5160. If the receive level is too low, the NTS 2800 increases the transmit power by one unit 5120. The NTS 2800 then checks if the maximum power level has been reached 5135. If the maximum level has not been reached, the NTS 2800 checks for interference with adjacent sectors 5150. If there is no interference, the NTS 2800 repeats the process again for the same sector 5132. If the maximum power level is reached 5135, or there is interference with adjacent sectors 5150, the NTS 2800 decreases the transmit power by one unit 5130, sends an error message to the network engineer 5155, and repeats the process for the next sector 5160. Implementation with Network Tuning System Implementation using the Network Tuning System requires individual components to perform special functions to accommodate the added functionality of the pro-active monitoring features. The additional features add to the ability of the tuning software allowing it to both correct faults in the system reactively but also proactively monitor and optimize the network to reduce the faults from occurring in the first place. As stated, the pro-active software 4200 can access the components of the network tuning system 2800. The primary analytic software 2814 on the NTS 2800 will run the pro-active software 4200 as an additional subroutine FIG. 42 and integrate pro-active software 4200 with its native components. The proactive software 4200 can integrate into the NTS 2800 native software structure. The below components of the NTS 2800 are described in regards to their interaction with the pro-active software 4200 and any modifications necessary to allow the NTS 2800 and pro-active software 4200 to integrate seamlessly. The NTS 2800 reference numbers refer to the NTS FIG. 28. Monitoring Software (2802) The monitoring software 2802 in the NTS 2800 is responsible for monitoring the network for error codes generated that indicate irregular network problems and or other indications. The monitoring software 2802 intercepts and decodes error codes produced by the BSC 118-A and interprets their effects on the wireless device. If the error is service affecting then the fault is sent to the primary analytic software 2814. To modify the monitoring software 2802 to allow integration of the proactive system, the monitoring software 2802 should monitor for messaging other than just ‘error-codes’. The system needs to monitor for network messaging on individual sectors and clusters of sectors. The primary analytic software 2814 sends a request to the monitoring software 2802 for the network parameters of a single or plurality of sectors. The typical parameters gathered by the monitoring software 2802 and returned to the primary analytic software 2814 for these ‘new’ types of queries are: Echo Forward Link Statistics for active connections Ec/lo Reverse Link Statistics for active connections Receive Power Forward Link Statistics for active connections Receive Power Reverse Link Statistics for active connections Reverse Link Transmit Power Statistics for active connections Forward Link BER/FER Statistics for active connections Reverse Link BER/FER Statistics for active connections Reference List of Mobile Identifiers for all Mobile Devices on Sector(s) Other User Defined Variables BSC Access Control Software (2804) The base station controller (BSC) access control software 2804 is responsible for interfacing the components and processes of the current invention with the BSC 118-A of a wireless network. The BSC 118-A contains all the call information as well as all the information on network faults. It should be noted that some wireless network designs have the network fault information stored elsewhere, and that the BSC access control software 2804 could be used to access that information at any other location also. The BSC access control software 2804 interacts directly with the BSC 118-A and the primary analytic software 2814 as well as the monitoring software 2804. The monitoring software 2804 specifically uses the BSC access control software 2804 to retrieve network statistics such as Echo and Receive Powers from the BTS/Sectors(s) for pro-active queries of the pro-active software 4200. Fault Diagnosis and Correction Software (2806) The fault diagnosis and correction software 2806 is typically responsible for obtaining case files from the primary analytic software 2814 and generating a solutions and implementing changes to the network to resolve the problem. The modifications necessary to accommodate the pro-active software 4200 are a new set of protocols that are defined for pro-active network monitoring. The protocols are specifically designed to address the four issues: Thermal Interference, Active Wireless Unit Density, Terrain Interference, and Network Equipment Performance. The protocols as described in the ‘Network Compensation’ section allow the fault diagnosis and correction software 2806 to react to case files that contain the pro-active data and make appropriate changes to the network, as it would do for reactive ‘fault’ case files. Device Location Software (2808) The device location software 2808 is the package that when activated by the primary analytic software 2814 is able to retrieve information from a database such as a ULD 900, or a ULDC 908, that holds geographic information (as well as time, date of the acquired geographic information). Additionally, as an alternative embodiment this device location software 2808 can directly query the BSC 118-A and calculate the location of a wireless device 104, as instructed by the primary analytic software 2814. The device location software 2808 interacts directly with the BSC 118-A, the primary analytic software 2814, the User Location Database 900 and/or User Location Database Coordinator 1600. To modify the device location software 2808 to allow integration of the proactive software's 4200 new features only limited changes must be made. The first change is that the queries from the primary analytic software 2814 must be given a higher priority than normal queries when they regard pro-active monitoring. When the primary analytic software 2814 queries the monitoring software 2802 for the network statistics of a single of plurality of sectors, the primary analytic software 2814 receives a list of wireless identifiers. The primary analytic software 2814 then immediately queries the device location software 2808 for the location of the said devices returned from the monitoring software 2802. To allow for the location to be as synchronized to the data from the sectors, the location should be retrieved quickly. In this case, and messages queued with lower priorities should be bypassed and these queries should be processed first. In practice, the pro-active location queries should only be superceded by manual location submissions (or overrides by an administrator). User Location Database Coordinator (1600) No modifications to the User Location Database Coordinator (ULDC) 908 or similar software/hardware and necessary because it is simply used as an intermediary to resolve the location of mobile devices. User Location Database (900) No modifications to the User Location Database (ULD) 900 or similar software/hardware and necessary because it is simply used as an resource to obtain the location of mobile devices. Geographic Information Database (2810) No modifications to the geographic information database 2810 or similar software/hardware and necessary because it is simply used as an resource to obtain the mapping information that is not specifically needed for the pro-active software 4200 to operate. Case Files with Lat/Long Correlations (2820) Case files are typically created to contain-the appropriate information for reactive diagnostics for the fault diagnosis and correction software 2806. For the case of a pro-active diagnostic to be performed by the fault diagnosis and correction software 2806, a modified version of the standard case file must be submitted. The modifications to the standard case only need to include an additional database field indicating pro-active or reactive case files type. Having this field allows the fault diagnosis and correction software 2806 to determine what diagnostic protocols to use to analyze the case file. In the case of the pro-active field being marked, the system would use the new protocols listed in the ‘Network Compensation Techniques’ section. Radio Tower Lat/Long Correlations (2824) No modifications to the radio tower lat/long correlations 2824 or similar software/database entries and necessary because it is simply used as a resource to obtain the mapping and analytical iQformatiorl. Its uses are the same in the new configuration that includes the pro-active software 4200. Internal Memory Storage (2818) Additional memory should be added to allow the pro-active software 4200 to function with additional overhead and not require hard disk caching of data. The amount may vary by final software implementation and network hardware design. Software engineers using standard provisioning techniques should determine the final amount of additional memory. Internal Central Processing Unit and Computer (2816) Additional CPU processing power should be added to allow the pro-active software 4200 to function with additional overhead clock cycles and not encounter CPU maximum utilization at peak operating conditions. The amount of additional processing ability may vary by final software implementation and network hardware design. Software engineers using standard provisioning techniques should determine the final amount of additional processor ability. User Interface Software (2826) The modifications to the user interface software 2826 are simply to add additional menu systems to the software to allow integration with the pro-active software 4200. The following commands should be available for the user and be displayed by the display software for the user. The order and menu placement is suggested to be as follows: Main Menu Item: Pro-Active Features <Pro-Active Features> Thermal Interference Configure Thermal Interference Activate/Deactivate Thermal Interference Exit Thermal Interference Active Wireless Unit Density Configure Active Wireless Unit Density Activate/Deactivate Active Wireless Unit Density Exit Active Wireless Unit Density Terrain Interference Configure Terrain interference Activate/Deactivate Terrain Interference Exit Terrain Interference Network Equipment Performance Configure Network Equipment Performance Activate/Deactivate Network Equipment Performance Exit Network Equipment Performance Exit Pro-Active Menu In the manual verification mode any changes will not occur until a network engineer verifies the change. A list of suggested changes and the case file that is created will be sent to engineers as the changes are created. In auto correction mode all changes will be made immediately. To reduce any system catastrophes network wide changes are limited to certain tolerances in the diagnostic protocols to eliminate network instability issues. Correlating Mapping Software (2828) No modification to the correlated mapping software 2828 or similar software/hardware is necessary because it is not specifically needed for the proactive software to operate. Correlating Data For Lat/Long Information (2830) No modification to the correlated data for Iat'long information 2830 or similar software/database entry(s) is necessary because its uses are the same in the new configuration that includes the pro-active software 4200. Display Software (2832) The display software 2832 does not need modified because it is used in the same way when the pro-active software is integrated. Primary Analytic Software (2814) The primary analytic software 2814 is the controlling software of the NTS and integrates all the elements into a single software package for a user. From the software, a user may access all features of the system and run either active, passive, or inactive modes. The pro-active system 4200 can integrate in the primary analytic software 2814 in the active and passive modes. However, many features can only be available in the active mode due to the real-time requirements for some pro-active tuning features. Passive mode will always prompt the network engineer before making changes and therefore is unrealistic for most pro-active features. All features are available in the active mode while only the terrain and network features are available in the passive mode. The specific reason is listed below for each feature. Thermal Interference—The ability for the system to react to thermal interference requires a CASE file to be generated frequently to record network performance factors that indicate thermal interference. A typical interval will be at 10-30 minute intervals. The primary analytic software 2814 then submits the changes to the fault diagnosis and correction software 2806 where modifications for pro-active diagnostics are implemented. The frequency in manual mode is to frequent for network engineers to manually approve each time. Active mode allows case files to be sent automatically and modifications to be made also. Active Wireless Unit Density—Active mobile unit density is a rapidly changing factor that changes every second or faster. The processing ability and excess overhead internal trunking affect the time necessary to calculate density. CASE files are generated as fast as possible without affecting other vital processes. The system could not send network engineer approval requests before making changes. Specific changes to accommodate the inclusion of the pro-active features are very specific. First, all CASE files created that are for pro-active features must have a flag set that indicates that fact. The flag allows fast routing of the diagnostics to be considered by new pro-active decision algorithms. Second, the system must first allocate additional processing power and other resources for pro-active features as the active wireless unit density specifically requires additional processing power that can take away from other processes. User Interaction with the Pro-active System The user's primary interaction will be through the display software 2832 and will interact will the additional menu items. As described in the display software section, the user may access these menus to control the new features. Specific interaction and the results are listed below for all the new menu items. Also to be noted, the user may access this system using the existing tuning system's architecture that allows for remote access via intranet, Internet, and other devices. Main Menu Item: Pro-Active Features 5205: The additional menu item appears at the main menu, which is presented to a user after logging on to the system and being authenticated. Thermal Interference 5210: Selecting this feature enables the system to monitor and adapt to thermal interference. Configure Thermal Tuning 5211: The selection allows the user to edit the thermal tuning configuration file. Enable/Disable Thermal Tuning 5212: The selection toggles enable or disable thermal tuning. Exit 5213: Exits the thermal tuning menu. Active Wireless Unit Density 5215: Selecting this feature enables the system to monitor and adapt to active wireless unit density. Configure Active Wireless Unit Density Tuning 5216: The selection allows the user to edit the active wireless unit density tuning configuration file. Enable/Disable Active Wireless Unit Density Tuning 5217: The selection toggles enable or disable active wireless unit density tuning. Exit 5218: Exits the active wireless unit density tuning menu. Terrain Interference 5220: Selecting this feature enables the system to monitor and adapt to terrain interference. Configure Terrain Tuning 5221: The selection allows the user to edit the terrain tuning configuration file. Enable/Disable Terrain Tuning 5222: The selection toggles enable or disable terrain tuning. Exit 5223: Exits the terrain tuning menu. Network Equipment Performance 5225: Selecting this feature enables the system to monitor and adapt to network equipment performance. Configure Network Equipment Tuning 5226: The selection allows the user to edit the network equipment tuning configuration file. Enable/Disable Network Equipment Tuning 5227: The selection toggles enable or disable network equipment tuning. Exit 5228: Exits the network equipment tuning menu. Exit 5230: Exits the pro-active tuning menu. Location Tracking System Detailed Description of the Operations Drawings FIG. 53 FIG. 53 is a flowchart illustrating the process of a user logging into the location tracking system (LTS) 5300. The LTS 5300 may be provided by a wireless service provider, an internet website provider, an asset tracking service, an employee tracking service, a personal tracking service or other types of service providers. The user accesses the LTS 5300 thru an internet 3202 website, a wireless interface, a wireless service provider, publicly switched telephone network 138, a fax on demand service, an automated telephone system, a laptop/desktop computer 2910, a PDA, a wireless device 104, or other types of devices. To begin the login process, the LTS 5300 prompts the user to enter a username and password 5302. The LTS 5300 then waits for the user to respond with a username and password 5304. If the user responds 5304, the LTS's 5300 internal CPU and computer 2816 logs the entered username and password 5304 into its internal storage memory 5306. The LTS 5300 checks the LTS's 5300 membership database for the username and password 5304. If the LTS 5300 finds the user's record 5312, the user then enters the desired telephone number, FIG. 53, BOX 5314. FIG. 54 displays the complete entry process. If the user's records cannot be found 5312, the LTS 5300 informs the user that there is a problem with the username or password 5302, and the user is returned to FIG. 53, BOX 5302, as shown in FIG. 53, BOX 5316. The LTS 5300 then prompts the user to enter username and password 5302. If the user does not enter a username and/or password 5304, the LTS 5300 prompts the user to become a user of record 5312 by entering personal information and billing information into the LTS 5318. The LTS 5300 then waits for the user to enter personal and billing information 5320. If the user does not enter personal and billing information within a specified period of time 5320, the user is logged off 5322 the LTS 5300, sent to help menu or forwarded to a service agent or operator 5322, depending on the configuration of the LTS 5300 settings and the users choice. If the user enters personal and billing information 5320, the LTS's 5300 internal CPU and computer 2816 logs the personal information and billing information into its internal storage memory 5306. The LTS 5300 then attempts to verify the user's personal information and billing information 5326 by placing a call through a modem to the LTS's 5300 merchant credit card services account and charges to the users credit card 5326. If the user's personal and billing information can be verified 5328, and the users credit card is billed, the LTS 5300 establishes a user record 5312 by transferring the logging the personal and billing information from the internal storage memory 5306 to the LTS's membership database 5308. The user is then enters the desired telephone number, FIG. 53, BOX 5332. FIG. 54 displays the complete entry process. If the user's personal information and billing information cannot be verified 5328, the user is notified is a problem with their personal information and billing information and returned to FIG. 53, BOX 5318, as shown in FIG. 53, BOX 5330. The user login, personal information and billing information are optional features of this embodiment. The LTS 5300 may be provided at no charge, or offered as a value added feature in conjunction with other services. Whoever, if the user wishes to utilize all the features of the LTS 5300, a login is required to enable the LTS 5300 to retrieve and access the user's settings and user's entries from the LTS's 5300 memory. FIG. 54 FIG. 54 illustrates the initial entry of a phone number that the user wishes to track. Once the user has logged onto the LTS 5300, the internal computer and CPU 2816 checks the users records 5312 if the user has a phonebook saved in the membership database 5400. If the user has phonebook entries saved as part of the user's records, the LTS 5300 gives the user menu choices, 5404. This process is illustrated in FIG. 55. If the user has not previously saved an entry into the phonebook 5400, the LTS 5300 then prompts the user to enter the telephone number or identification information of the wireless device 104 the user wishes to locate and/or track 5402. The LTS 5300 then waits a specified period for the user to enter a telephone number 5406. If the user enters a telephone number for a wireless device 104 that they wish to track, the LTS 5300 logs the user's entry into the internal storage memory 5306. The LTS 5300 then queries a user location database(ULD) 900, user location database coordinator(ULDC) 908, access users case files 2820, queries the base station controller (BSC) 206 of a wireless network 100 with the LTS's device location software 2808 for the lat/long coordinates of the wireless device 104 being tracked, Global Positioning System (GPS) Information, or other means of obtaining locations of wireless devices 5406. The use of ULD 900, ULDC 908, and other location means is disclosed (offered only as an example of location means) in a Provisional Patent Application Ser. No. 60/327,327; and was files on Oct. 4, 2001. If the wireless device 104 is not located, the user is informed of the problem, and returned to FIG. 54, BOX 5402, as illustrated in FIG. 54, BOX 5416. If the wireless device 104 is located 5414, the LTS 5300 receives the lat/long coordinates and displays the lat/long coordinates to the user in their choice of formats. For example, the location may by overlaid on a display screen 2836 along with a street map overlay 5418, a map of the overlaid screens may be faxed to a user via a fax on demand service, the location may be converted to a postal address 5422 or cross-street using the LTS's postal address conversion software 5422 and displayed on a screen 2836, faxed to a user, or read to a user over the phone using the LTS's 5300 automated answering system and voice text read-up software 5426. Once the wireless device 104 has been located and displayed 5418, the LTS 5300 prompts the user to enter the specific wireless device 104 into a user phonebook by selecting “phonebook” 5428. If the user selects “phonebook” 5428 to save the entry to their Phonebook 5430, the user is forwarded to the phonebook menu section, FIG. 56, BOX 5600, as illustrated in FIG. 54, BOX 5432. If the user does not select to save the current entry to their phone book 5330, the user is forwarded to the phonebook section of the user's choice menu FIG. 55, BOX 5500, as illustrated is FIG. 54, BOX 5434. When prompted by the LTS 5406, if the user does not enter a phone number of the wireless device 104 they wish to locate and/or track, the LTS 5300 prompts the user to enter other identification information such as a persons name, company name, or other identifying information 5438. If the user does not enter identification information within a specified period of time 5438, the LTS 5300 logs off the user 5440. If the user enters identification information 5438, the LTS 5300 logs the user's entry, and the identification information is then cross referenced against the LTS's Cuss-Cross Phonebook database 2812 or other supplies sources to obtain the phone number for the desired wireless device 5442. If the LTS 5300 finds the phone number 5410, the LTS 5300 logs the phone number 5406, and the location process continues as described as if the user entered the number described above 5408. If the phone number of the wireless device 104 cannot be located in the Criss-Cross Phonebook database 2812, the LTS 5300 informs the user the number could not be found and prompts the user to enter a phone number 5412. FIG. 55 FIG. 55 illustrated the processing of the user's choice menu 5502. The user's choice menu's 5502 physical realization may be in the form of a display screen 2836 navigated by a mouse, keyboard/keypad, interactive display screen, voice recognition or other forms of selection. The user's choice menu 5502 also may be an automated answering system and could be navigated by voice recognition, a keyboard/keypad or other forms of selection. Initially, the LTS 5300 prompts the user to enter a phone number of a wireless device 104 that the user wants to locate or track by selecting ‘locate” 5500. The LTS 5300 waits a specified period for the user to select ‘locate” 5504. If the user responds by selecting ‘locate” 5504, the LTS 5300 asks the user to enter a phone number by the process described in FIG. 54, FIG. 55, BOX 5506. If the user does not respond within the specified period of time 5504, the LTS 5300 prompts the user to select a phonebook entry he wishes to locate 5508. The LTS 5300 then waits a specified period for the user to select “phonebook” 5530. If the user responds by selecting “phonebook” 5330, the user selects the building he wants to display 5510. FIG. 56 describes the process. If the user does not respond within the specified period of time 5530, the LTS 5300 prompts the user to add, delete or edit a phonebook entry(ies) to a wireless device(s)1 04 that the user wants to locate/track by selecting ‘Add, Delete or Edit” 5512. The LTS 5300 then waits a specified period for the user to select “Add, Delete, or Edit” 5514. If the user responds by selecting “Add, Delete or Edit” 5514, the LTS 5300 prompts the user to add, delete, or edit phonebook entries 5516. FIG. 57 describes the process. If the user does not respond within the specified period 5514, the LTS 5300 prompts the user to view selected businesses, government buildings, and/or homes on the display screen by selecting “buildings” 5518. The LTS 5300 then waits a specified period for the user to select “buildings” 5520. If the user responds by selecting “buildings” 5520, the LTS 5300 prompts the user to select buildings to display 5522. FIG. 58 describes the process to select buildings for display. If the user does not respond within the specified period 5520, the LTS 5300 prompts the user to view a history of call/location/tracking history of phonebook entry(ies) to a wireless device(s) 104 that the user wants to locate/track by selection “view history” 5524. The LTS 5300 then waits a specified period for the user to select “view history” 5526. If the user responds by selecting “view history” 5526, the LTS 5300 forwards the user to the view history process 5528. FIG. 67 illustrates the view history process. If the user does not respond within the specified period of time 5526, the LTS 5300 prompts the user to print a history of call/location history of phonebook entry(ies) to a wireless device(s)104 by selecting “print history” 5530. The LTS 5300 then waits a specified period for the user to select “print history” 5532. If the user responds by selecting “print history” 5532, the LTS 5300 forwards the user to the print history process 5534. FIG. 68 illustrates the print history process. If the user does not respond within the specified period of time 5530, the LTS 5300 prompts the user to add a history of call/location/tracking history to the wireless service bill by selecting “add to bill” 5536. The LTS 5300 then waits a specified period for the user to select ‘add to bill” 5538. If the user responds by selecting ‘add to bill” 5539, the LTS 5300 executes the process to add the call/location report to the wireless service bill 5540. FIG. 69 illustrates the process to add the call/location report to the wireless service bill. If the user does not respond within the specified period 5538, the LTS 5300 logs the user off 5542. FIG. 56 FIG. 56, illustrates the process of entering and selecting phonebook entries. When the user is transferred to the “phonebook” section, the LTS 5300 first queries the user records 5312 to determine if the user is currently locating/tracking the location of a wireless device 5600. If the LTS 5300 is currently locating/tracking a wireless device 5600, the LTS 5300 logs the current entry into the phonebook 5602. The LTS 5300 then displays the user's phonebook including the new entry 5604. Once the LTS 5300 displays the phonebook 5604, the LTS 5300 prompts the user to select phonebook entries that they would like to locate/track 5606. The LTS 5300 then waits a specified period for the user to respond 5608. If the user selects phonebook entries to be located/tracked 5608, the LTS 5300 logs the selected phonebook entries and retrieves the location of the wireless devices 104 requested by the user 5610. The LTS 5300 retrieves the lat/long locations of the wireless devices 104 by querying a ULD 900, a ULDC 908, by querying case files 2820 containing lat/long of wireless devices 104, by querying the wireless network's BSC 206 or by other location means. The LTS 5300 then plots the lat/long of the located wireless devices 104 and overlays the locations onto a street/topographic map 5612. If the LTS 5300 is not able to locate a selected entry, the LTS 5300 notifies the user that the entry(ies) could not be located 5614. The LTS 5300 then prompts the user to select businesses, government buildings and/or private homes to be added to the display screen by selecting “buildings” 5518. The LTS 5300 then waits a specified period for the user to select “buildings” 5520. If the user selects “buildings” 5520, the LTS 5300 prompts the user to select buildings for display 5522. FIG. 58 illustrates the process. If the user does not select “buildings” 5520, the user is forwarded to the user choice menu 5502. If the LTS 5300 is not currently locating/tracking a wireless device 104 when the user logs into the “phonebook” menu 5600, the LTS 5300 determines if the user has previously established a phonebook containing stored entries, within the user's record 5312. If the user does have a phonebook within the user's record 5312, the LTS 5300 displays the user's phonebook 5616, and the LTS 5300 permits the user to select and locate wireless devices 104 from their phonebook 5606. If the user does not have a phonebook as part of the user's records 5312, the user is informed that no phonebook records are contained in the user's record 5618, and the LTS 5300 forwards the user to the user's choice menu 5502. FIG. 57 FIG. 57 illustrates the “add, delete, and editing phonebook entries menu”. The diagram illustrates the process, which allows users to add, delete, and edit phonebook entries. The LTS 5300 prompts the user to add a new entry to the phonebook by selecting “add” 5700. The LTS 5300 then waits a specified period for the user to respond by selecting “add” 5702. If the user responds by selecting “add” 5702 a new entry, the LTS 5300 prompts the user to enter a telephone number or identification information 5704, described in FIG. 54. If the user does not respond 5702, the LTS 5300 then prompts the user to delete an existing entry in the phonebook by selecting “delete” 5706. The LTS 5300 then waits a specified period for the user to respond selecting “delete” 5708. If the user responds by selecting “delete” 5708, the LTS 5300 allows the user to delete a selected phonebook entry and the LTS 5300 logs the change 5710 to the user's record 5312. The LTS 5300 then forwards the user to the user's choice menu 5502. If the user does not respond within the specified period of time 5708, the LTS 5300 then prompts the user to edit an existing entry in the phonebook by selecting “edit” 5712. The LTS 5300 then waits a specified period for the user to respond selecting ‘edit” 5712. If the user responds by selecting ‘edit” 5714, the LTS 5300 allows the user to edit a selected phonebook entry and the LTS 5300 logs the change 5716 to the user's record 5312. The LTS 5300 forwards the user to the user's choice menu 5502. If the user does not respond within the specified period of time 5714, the LTS 5300 forwards the user to the user's choice menu 5502. FIG. 58 FIG. 58 illustrates the process of selection “buildings” that will be displayed on the display screen 2836. The LTS 5300 determines the user's current location 5800. The LTS 5300 prompts the user to enter or select a city by city name or zip code if the default city is not desired 5802. The LTS 5300 waits for the user to select a city 5804. If the user selects a different city 5804, the LTS 5300 logs the user's choice and makes it the default city 5806. After the user selects a city, the LTS 5300 checks if the user has entries in the building memory 5808. If the user does not have entries in the building memory 5808, the LTS 5300 sends the user to the building memory choice menu 5810, described in FIG. 59. If the user has entries in the building memory 5808, the LTS 5300 asks the user if he wants to select “building memory” 5812. The LTS 5300 waits for user response 5814. If the user does not select “building memory” 5814, the LTS 5300 sends the user to the building memory choice menu 5814 described in FIG. 59. If the user selects “building memory” 5814, the LTS 5300 displays the user's building memory and prompts the user to select entries 5816. The LTS 5300 waits for a user response 5818. If the user selects entries, the selected entries are display on the display screen 5820. Then the LTS 5300 sends the user to the building memory choice menu 5810 described in FIG. 59. If the user does not select any entries 5818, the LTS 5300 sends the user to the building memory choice menu 5810 described in FIG. 59. FIG. 59 The building memory user's choice menu 5902 allows the user to add, select, and delete entries to their building memory. The LTS 5300 prompts the user to select a business, government office or home by selection “Display Building” 5900. If the user selects “display building” 5902, the LTS 5300 prompts the user to enter the listing they want to display 5904. If the user does not select “display building” 5902, the LTS 5300 prompts the user to add an entry to the building memory by selecting “add” 5906. If the user selects “add” 5908, the LTS 5300 forwards the user to the add building process 5910. FIG. 60 illustrates the add building process. If the user does not select add 5914, the LTS 5300 prompts the user to delete an entry in the building memory by selecting “delete” 5912. If the user selects “delete” 5914 , the LTS 5300 logs the user's choice and displays the user's building memory 5916. The LTS 5300 prompts the user to select the entry he wants to delete 5918. If the user selects an entry 5920, the LTS 5300 logs the user's choice and deletes the entry from the building memory 5922. The LTS 5300 then prompts the user to either go to the user's choice menu or log off 5924. If the user selects to go to the user's choice menu 5926, the LTS 5300 returns the user to the user's choice menu 5502. If the user chooses to logoff 5926, the LTS 5300 logs the user off the system 5930. If the user does not select an entry to delete 5930, the LTS 5300 then prompts the user to either go to the user's choice menu or log off 5924. If the user selects to go to the user's choice menu 5926, the LTS 5300 returns the user to the user's choice menu 5502. If the user chooses to logoff 5926, the LTS 5300 logs the user off the system 5930. If the user does not select the “delete” option 5912, the LTS 5300 then prompts the user to either go to the user's choice menu or log off 5924. If the user selects to go to the user's choice menu 5926, the LTS 5300 returns the user to the user's choice menu 5502. If the user chooses to logoff 5926, the LTS 5300 logs the user off the system 5930. FIG. 60 FIG. 60 continues the building memory process and illustrates the process to add an entry to the building memory. The LTS 5300 prompts the user to add a new building by selecting “name”, “category”, ‘address“, or “phone number” 6000. If the user selects “name” 6002, the LTS 5300 adds the entry by name 6004. FIG. 63 illustrates the process to add an entry by name. If the user selects “category” 6006, the LTS 5300 adds the entry by category 6008. FIG. 64 illustrates the process to add an entry by category. If the user selects “address” 6010, the LTS 5300 adds the entry by address 6012. FIG. 65 illustrates the process to add an entry by address. If the user selects “phone number” 6014, the LTS 5300 adds the entry by phone number 6016. FIG. 66 illustrates the process to add an entry by phone number. If the user does not select any menu option 6014, the LTS 5300 returns the user to the user's choice menu 5502. FIG. 61 FIG. 61 illustrates the process for categorizing the building memory. The LTS 5300 logs the user's choice and prompts the user to enter the desired listing by name, category, address or phone number 6100. If the user enters a listing 6102, the LTS 5300 adds a “listing” 6104. FIG. 62 illustrates the add “listing” process. If the user does not enter a “listing” 6102, the LTS 5300 prompts the user to enter the name of the desired entry 6106. If the user enters a name 6108, the LTS 5300 adds the entry by name 6110. FIG. 63 illustrates the process to add an entry by name. If the user does not enter name 6108, the LTS 5300 prompts the user to enter a category 6112. If the user enters a category 6114, the LTS 5300 adds the entry by category 6116. FIG. 64 illustrates the process to add an entry by category. If the user does not enter a category 6114, the LTS 5300 prompts the user to enter an address 6118. If the user enters an address 6120, the LTS 5300 adds the entry by address 6122. FIG. 65 illustrates the process to add an entry by address. If the user does not enter an address 6120, the LTS 5300 prompts the user to enter a phone number 6124. If the user enters a phone number 6126, the LTS 5300 adds the entry by phone number 6128. FIG. 66 illustrates the process to add an entry by address. If the user does not enter a phone number 6126, the LTS 5300 returns the user to the user’ choice menu 5502. FIG. 62 FIG. 62 displays the process to enter a “listing” to the building memory. The LTS 5300 logs the user's entered listing and searches the criss-cross phonebook with the lat/long correlation 2810 or address coordinates for all matching entries 6200. If the listing is not found 1005, the LTS notifies the user the listing is not found 6202 and the user is sent to the user choices menu 5502. If the listing is found 6202, the LTS 5300 displays all the entries that contain the entered “listing” and the LTS 5300 prompts the user to select the desired entry 6206. If the user does not select a listing 6208, the user is sent to the user choices menu 5502. If the user selects an entry 6208, the LTS 5300 displays the selected listing on the display screen 2836 with the following information: name, category of listing, address, and phone number. The LTS 5300 plots and labels the listing location on a street map with the location of the wireless devices 6210. The LTS 5300 prompts the user if he wants to save the listing in the building memory 6212. If the user does not save the listing 6214, he is sent to the user choices menu 5502. If the user saves the listing, the LTS 5300 saves the listing in the building memory 6216, and the LTS 5300 returns the user to the building memory user's choice menu 6218. FIG. 63 FIG. 63 displays the process to enter a “name” to the building memory. The LTS 5300 logs the user's entered name and searches the criss-cross phonebook with the lat/long correlation 2812 or address correlation's for all matching entries 6300. If the name is not found 6302, the LTS 5300 notifies the user the listing is not found 6304 and the user is sent to the user choices menu 5502. If the listing is found 6302, the LTS 5300 displays all the entries that contain the entered “name” and the LTS 5300 prompts the user to select the desired entry 6306. If the user does not select a listing 6308, the user is sent to the user choices menu 5502. If the user selects an entry 6308, the LTS 5300 displays the selected listing on the display screen 2836 with the following information: name, category of listing, address, and phone number. The LTS 5300 plots and labels the listing location on a street map with the location of the wireless devices 6310. The LTS 5300 prompts the user if he wants to save the listing in the building memory 6212. If the user does not save the listing 6214, he is sent to the user choices menu 5502. If the user saves the listing, the LTS 5300 saves the listing in the building memory 6316, and the LTS 5300 and the LTS 5300 returns the user to the building memory user's choice menu 6218. FIG. 64 FIG. 64 displays the process to enter a “category” to the building memory. The LTS 5300 logs the user's entered listing and searches the criss-cross phonebook with the 1st/long correlations 2812 or address coordinates for all matching entries 6400. If the listing is not found 6402, the LTS 5300 notifies the user the listing is not found 6404 and the user is sent to the user choices menu 5502. If the listing is found 6204, the LTS 5300 displays all the entries that contain the entered “category” and the LTS 5300 prompts the user to select the desired entry 6406. If the user does not select a listing 6408, the user is sent to the user choices menu 5502. If the user selects an entry 6408, the LTS 5300 displays the selected listing on the display screen 2836 with the following information: name, category of listing, address, and phone number. The LTS 5300 plots and labels the listing location on a street map with the location of the wireless devices 6410. The LTS 5300 prompts the user if he wants to save the listing in the building memory 6212. If the user does not save the listing 6214, he is sent to the user choices menu 5502. If the user saves the listing, the LTS 5300 saves the listing in the building memory 6216, and the LTS 5300 and the LTS 5300 returns the user to the building memory user's choice menu 6218. FIG. 65 FIG. 65 displays the process to enter a “address” to the building memory. The LTS 5300 logs the user's entered listing and searches the criss-cross phonebook with the latllong correlations 2812 or address coordinates for all matching entries 6500. If the listing is not found 6502, the LTS 5300 notifies the user the listing is not found 6504 and the user is sent to the user choices menu 5502. If the listing is found 6502, the LTS 5300 displays all the entries that contain the entered “address” and the LTS 5300 prompts the user to select the desired entry 6506. If the user does not select a listing 6508, the user is sent to the user choices menu 5502. If the user selects an entry 6508, the LTS 5300 displays the selected listing on the display screen 2836 with the following information: name, category of listing, address, and phone number. The LTS 5300 plots and labels the listing location on a street map with the location of the wireless devices 6510. The LTS 5300 prompts the user if he wants to save the listing in the building memory 6212. If the user does not save the listing 6214, he is sent to the user choices menu 5502. If the user saves the listing, the LTS 5300 saves the listing in the building memory 6216, and the LTS 5300 and the LTS 5300 returns the user to the building memory users choice menu 6218. FIG. 66 FIG. 66 displays the process to enter a “phone number” to the building memory. The LTS 5300 logs the user's entered listing and searches the crisscross phonebook with the lat/long correlations 2812 or address coordinates for all matching entries 6600. If the listing is not found 6602, the LTS 5300 notifies the user the listing is not found 6604 and the user is sent to the user choices menu 5502. If the listing is found 6602, the LTS 5300 displays all the entries that contain the entered “phone number” and the LTS 5300 prompts the user to select the desired entry 6606. If the user does not select a listing 6608, the user is sent to the user choices menu 5502. If the user selects an entry 6608, the LTS 5300 displays the selected listing on the display screen 2836 with the following information: name, category of listing, address, and phone number. The LTS 5300 plots and labels the listing location on a street map with the location of the wireless devices 6610. The LTS 5300 prompts the user if he wants to save the listing in the building memory 6212. If the user does not save the listing 6214, he is sent to the user choices menu 5502. If the user saves the listing, the LTS 5300 saves the listing in the building memory 6216, and the LTS 5300 and the LTS 5300 returns the user to the building memory user's choice menu 6218. FIG. 67 The user's history report may be generated by building and/or retrieving case files that are generated at the time that communications are sent/received by the wireless device 104, and which contain the location of the wireless device 104 at the time of the communication. This tracking method is best for tracking wireless devices 104, which are used, on a frequent basis during the day. Alternatively, the user's history report may be generated by building and/or retrieving case files by periodically (every hour, twice a day etc.) querying a user location database 900, user location database coordinator 908, or querying the wireless networks base station controller 118-A or other network components, for the location of the wireless device 104. This alternative method of generating a user's history report would be preferred for locating/tracking wireless devices 104 that are not used frequently. If a wireless device 104 only receives one or two communications a day, a periodic report (every hour, etc.) would give a more complete report of the location of the wireless device 104 through the day. A third method of generating a user's history report is to combine the two methods mentioned above. This involves reporting case files with call/location generated when the wireless device 104 sends/receives a communication, combined with the periodic case file, which is generated periodically (every hour, etc., depending on the selected monitoring period set by the owner of the wireless device 104, the user of the LTS 5300, or the wireless service provider). FIG. 67 shows the process to display call history report. The LTS 5300 prompts the user to select a range of time the report will cover 6700. If the user does not select a time range 6702, the LTS 5300 will send the user to the user choice menu 5502. If the user selects a time range 6702, the LTS 5300 logs the time range 6704 and the LTS 5300 queries the ULD 900 or case file database that correspond with the selected phonebook entries and time range 6706. The ULD 900, GPS, or the BSC 118-A determine the lat/long of the case files 6708. The LTS 5300 correlation software converts the latitude and longitude of the case files to a postal address, cross street, business, government, house name 6710. The LTS 5300 prompts the user to select how he wants to sort the call history 6712. The user can sort the call history by: time of call, location of call, calling party, or wireless phone number 6712. If the user does not select a sort type 6714, the default sort type is used 6716. Otherwise, the LTS 5300 logs the users choice and displays the transcribed postal address in the selected order with the corresponding phone number, length of call, time of call, and calling party 6718. The LTS 5300 then prompts the user to select an individual call record that the user desires to plot on a map 6720. If the user does not select a call record 6722, the LTS 5300 asks the user if he wants to print the call history 6724. If the user selects a call record 6722, the LTS 5300 logs the choice and overlays the calls latitude and longitude location on a topographic street map 6726. The LTS 5300 then prompts the user if he wants to return to the call/location display screen 6728. If the user selects to return to the call/location display screen 6730, the LTS 5300 prompts the user to select a time range for the call history report 6732. Otherwise, the LTS 5300 returns the user to the users choice menu 5502. FIG. 68 FIG. 68 shows the process to print call history report. The LTS 5300 prompts the user to select a range of time the report will cover 6800. If the user does not select a time range 6802, the LTS 5300 will send the user to the user choice menu 5502. If the user selects a time range 6802, the LTS 5300 logs the time range 6804 and the LTS 5300 queries the ULD 900 or case file database that correspond with the selected phonebook entries and time range 6806. The ULD 900, GPS, or the BSC 206 determine the latllong of the case files 6808. The LTS 5300 correlation software converts the latitude and longitude of the case files to a postal address, cross street, business, government, house name 6810. The LTS 5300 prompts the user to select how he wants to sort the call history 6812. The user can sort the call history by: time of call, location of call, calling party, or wireless phone number. If the user does not select a sort type 6814, the default sort type is used 6816. Otherwise, the LTS 5300 logs the user's choice and displays the transcribed postal address in the selected order with the corresponding phone number, length of call, time of call, and calling party 6818. The LTS 5300 then prompts the user if he wants to print the history report 6820. If the user does not print the history report 6822, the LTS 5300 prompts the user if he wants to include the call history report on the user's phone bill 6826. If the user prints the call history report 6822, the LTS 5300 sends the report to the desired printer 6824. The LTS 5300 then prompts the user if he wants to include the call history report on the user's phone bill 6826. If the user selects to include the report with the user's phone bill 6828, the LTS 5300 includes the call history report in the user's phone bill 6832. Otherwise, the LTS 5300 returns the user to the users choice menu 5502. FIG. 69 FIG. 69 displays the process to include the call history report in the user's phone bill. The LTS asks the user if he wants the call history report included in the billing statement. If the user chooses not to add the call history report 6902, the LTS 5300 returns the user to the user's choice menu 5502. If the user chooses to add the call history 6902, the LTS 5300 logs the user's choice 6904, and prompts the user to enter authorization information to verify he is the owner of the wireless device 6906. If the user does not enter authorization information 6908, the LTS 5300 returns the user to the user's choice menu 5502. If the user enters authorization information 6908, the LTS 5300 logs the authorization information and matches the information with wireless providers records 6910. If the authorization information does not match the records 6914, the LTS 5300 notifies the user of the mismatch 6916, and returns the user to the user's choice menu 5502. If the information matches 6914, the LTS 5300 prompts the user to approve the charges added to the bill for the call history report 6918. If the user does not approve the charges 6920, the LTS 5300 returns the user to user's choice menu 5502. If the user approves the charges 6920, the LTS 5300 logs the user's choice and instructs the wireless service to include the call location history report to the bill 6922. The LTS 5300 prompts the user if he wants to return the user's choice menu 6924. If the user selects to returns to the user's choice menu 6926, the LTS 5300 returns the user to the user's choice menu 5502. Otherwise the user is logged off the LTS 6930. Location Tracking System; Summary The location tracking system 5300 is a method of determining the location and then tracking a single or plurality of wireless devices 104 on a given wireless device network(s) 100 based on a criterion provided by a user. Based on this criterion a log is created that record the location and network status of any wireless device 104 fitting the criterion. These logs are recorded to a database and then later transferred to a user database for storage on a local server database. Accessing the database can be accomplished remotely or locally. Local access is from local service terminals on the network or mainframe. Remote access can be from a TCP/IP, IPX, Dial-up, remote server SQL Queries, and other listed methods. This allows for third party vendors to have access to the said primary embodiment 2800 features and use the technology to create product support and technological spin-offs. Examples of technological spin-offs would be; a cellular phone bill that gives the user's geographic location at the time of each logged call, an internet 3202 website that would allow business owners to track the location of employees or equipment comprising a wireless device 104, or a geographical advertising system (GAS) that would allow targeted advertising based on the location of the user of a wireless device 104. Many other technological spin-offs are also possible. Tracking the wireless devices 104 can be done by utilizing a user location database (ULD) 900, GPS data from the phone, direct analysis of the network communication parameters, or by other third party methods. When a wireless device 104 is not located on a local server a user location database coordinator (ULDC) 908 or other system can be used to discover the location of a device to allow a log to be created. Logs can be created and appended as a wireless device 104 roams a local wireless device network 100 or a remote wireless device 1900 network. Using TCP/IP and ATM connections, servers for discreet wireless device networks 100 can communicate together and allow seamless network interoperability. This allows the tracking logs to record the location of wireless devices 104 on a plurality of wireless device networks 100 having had a request generated from any network connected to the deemed wide-area network. Internet 3202 Protocol 6 and 7 should allow this to become even more practical. Notification from the server to external programs, users, wireless devices 104 is a native capability of the said primary embodiment 2800. The messages can be sent alerting the said wireless device 104 of a system event. A user sets up this event when the log setup process begins by the user. The user can have the system send an alert based on a criterion such as the completion of a log. The advantage is that an alert can be sent to external programs triggering an external event. This allows third party software to use this to create a new technology and create a new product for their consumers. An example is for a wireless device user 102 to be tracked and logged. A message could be sent via SMS (simple message system) to a prescribed wireless device 104 when that wireless device 104 being tracked leaves a certain geographic region. The system would for example allow a parent to be alerted when their child is going somewhere they shouldn't. The primary embodiment 2800 also describes a method for allowing a large volume of users to access the logging and tracking database. The primary embodiment 2800 describes the method that allows a large volume of tracking to be done and logged simultaneously. By making separate database structures on separate hardware entities the load is divided into active database buffers were logs being created are stored, to a separate structure where inactive logs are saved for users. A graphical interface and display protocol database 3004 is described that allows users to interact with the system and remotely retrieve meaningful representations of the data from the logs. Tracking logs simply contain data that describes network parameters as well as geographic and timing information. Alone this data is simply text. The said graphical display allows a useful extraction of the data to be represented. Multiple logs can be shown with data overlays including maps, topological information 4160, and other network parameters. The physical structure for the wireless device network 100 is described in including the database hardware implementation, the networking implementation and the processing implementation. Examples of appropriate hardware and peripherals are given. Amounts of storage and hardware configurations are described. RAID architecture is listed and the preferred level of RAID deployment is also suggested for various deployments of the primary embodiment 2800 based on budget and performance. A major user interaction of the primary embodiment 2800 is envisioned, but not excluded to, the ability to track and record wireless devices 104 that users have administrative control over. This would allow them to monitor, record, and review were and how their wireless devices 104 are used. Uses could be to monitor the location of workers, children, demographically defined users, and other types. Monitoring wireless devices 104 by demographics has the unique ability to allow business to discover the location and moving habits of its customers. An example of this would be for a company to track all wireless devices 104 based on a set of demographic criterion that matches its target audience. The system would then track all wireless devices 104 matching those criterion and record the locations to a server database log, allowing the company to find a location to possibly build a new store that would maximize it exposure to its target customers. Another us would be for a company to search for customers (based on a local mailing list of customers phone numbers) and when the customer enters a region (geographic distance) from the store location, a log would be created. A page or message could be sent to an external program indicating the event. A subsequent push' message technology such as SMS could be used to deliver content to the wireless device 104 in the form of an advertisement. This technology would allow the company to restrict its advertising to valid customers of interest and reduce the costs of advertising. Description Of Embodiments Device Tracking and Logging The wireless device 104 tracking and logging option of the location tracking system 5300 is used to monitor and record the location (latitude/longitude/altitude) of a wireless device 104 over a period of time. The feature requires the use of the device location software 2808, location database manager904, as their associated components. For a wireless device 104 to be tracked it must be able to be recognized by the system. The device location software 2808 allows for a wireless device 104 (wireless device 104, 2 way pager, satellite phone, GPS enabled device, wireless LAN device, other) to be tracked as long as the system can access the control hardware/software for the appropriate wireless device network 100. For GPS satellite network 114 enabled devices, certain considerations must be taken into account due to the nature of multi-path in cellular environments. Multi-path is the error caused by reflected signals entering the front end of the receiver and masking the real correlation peak. In this case, signal from the GPS satellite network 114 to the wireless device 104. The effects tend to be more pronounced in a static receiver near large reflecting surfaces, where 15 m in or more in ranging error can be found in extreme cases. In this case, a wireless device 104 slightly indoor or in a city between buildings would be relevant. Monitor or reference stations (in this case the BTS 118-A of the wireless device network 100) require special care in placing (the BTS's 118-A) to avoid unacceptable errors. The first line of defense is to use the combination of antenna 2430 cut-off angle and antenna 2430 location that minimizes this problem. It however is not always possible in a wireless device network 100 and can cause undue or uneven accuracy in location ability over a wireless device network 100. A second approach is to use so-called “narrow correlatoe” receivers that tend to minimize the impact of multi-path on range tracking accuracy's. The approach does not apply to wireless device networks 100 and should not be used. Overall the effects of GPS satellite network 114 error still allow the most accurate location results. But consideration for its inaccuracies should be noted. The wireless devices 104 that can be tracked are limited to the wireless device networks 100 the device location software 2808 is attached to. A noted exception is when a ULD 900 or ULDC network 1600 (or similar) is available for the system to query. In this case the wireless device 104 will be able to retrieve the location of any wireless device 104 that exists in the database regardless of the type of network it is operating on. The design would be preferred because it creates a type of universal standard that would allow a plurality of wireless devices 100 to be tracked over a variety of networks. A further requirement for the wireless device 104 to be tracked is that the attached network or ULD 900/ULDC 908 to the location tracking system 5300 is capable of being polled (by software means) for locations of wireless devices 104 at regular intervals as short as less than one second or as long as many hours. The necessary hardware must exist on the wireless device network 100 to accommodate the required bandwidth and pipe-lining of multiple simultaneous requests for the location of a wireless device 104. When no database such as an ULD 900 or ULDC network 1600 is available, the attached networks are required to provide the following elements from internal registers pertaining to an attached wireless device 104 on the wireless device network 100, as to allow the location tracking system 5300 software to calculate a location for the wireless device 104: Base station(s) 118-A or antenna(s) 2430 location for all network equipment communicating with the wireless device 104 and; The round trip delay time for communications between the network antenna(s) 2430 and the wireless device 104 and/or; The signal receive strength from the wireless device 104 to the network antenna(s) 2430 and/or; Other location assisting information When these design requirements on the network side are available then the location tracking system 5300 is capable of tracking a plurality of wireless devices 104 and recording user records 5312 to an internal/external database that includes the location referenced to time for the said wireless devices 104. The location tracking system 5300 software first utilizes the display screen 2836 to display a menu to the user on their display screen 2836 of the wireless device 104 they are accessing the system from. The menu asks for the user to enter a single or list of wireless devices 104 to be logged. It also asks for a time frame to track these wireless devices 104 for. The time frame can be from the current system time to any given time. It can also begin at a future time and then end at any arbitrary time. Additionally, it can offer a log to be generated that includes only the location and basic other information (1 second duration or other short time). The location tracking system 5300 software would allow subsequent database queries to retrieve call location for all calls to a wireless device 104. Hence, an additional option that allows a log to be generated for all calls by a wireless device 104 for an indefinite time period is also required. The user then can specify the log entry filenames for the database entries. When the user enters this information they are prompted with alerting options. These options include the user to be sent a message in the case of a set criterion is met. The user can then enter a list of criteria. These include: Geographic boundary that wireless devices 104 cannot exceed/enter Distance wireless devices 104 may travel from any user defined location If a wireless device 104 comes with in some distance of a user defines location When these criteria are entered the user enters their contact information. The location tracking system 5300 will alert the user if any criterion are met and include a message that indicates the wireless device 104 name and database entry that may be viewed to retrieve the results. The alerting options may take any of the following forms but are not limited to: Email SMS messaging Website posting Online messaging Page Text messaging Automated voice call (synthesized voice) to a voice line Fax Other messaging protocols that can send to wireless devices 104 Once the user selects this option the system can ask the user to review the choices. The user approves them, then the system sends the criteria to the location database manager 904. The users selected wireless devices 104 will be tracked for the remainder of the selected times. The user connects and they also review a list of active logs and cancel the logging or change the parameters and resubmit them to the location database manager 904. The system will overwrite the old tracking options for any modified wireless device 104. The location database manager 904 now adds the wireless device 104 names (and corresponding wireless device identification 3724 information) into its location queue. The location queue contains the wireless device identifiers 3724 of all wireless devices 104 being logged. The location database manager 904 cycles through the list and determines the location of each wireless device 104 at the said time, and stores that information to a database record as named by the user in the setup. When a new entry is added to the queue a database entry is established and necessary disk space is allotted for the duration specified by the user. The process assures that the system will not have to slow down to a lot more space later. The database disk space reserved is equal to the data storage rate times the file size per location query times the tracking time plus overhead for the database file entry. The queue is automatically cycled though. Its size is dynamic because entries to it are constantly being made. Additionally, entries are always being removed from it. As the time(s) for entries to stop recording, as entered by a user, are met, and entry is removed from the queue. The database entry is then moved to a storage database on a different physical medium. The disk space on the primary databases physical drive is then free to be recorded to by a new record. Users may now access any records on the second database. They may also access records for location tracking(s) in progress. When this occurs the location database manager 904 overwrites the end time to the current time. The location database manager 904 then creates a new entry that starts at the current time and ends at the original end time. The result is that on the next cycle through the queue the record would be stored (up to the current time) to the secondary database so that the user could access the tracking information up to the current time. When a user retrieves the user record(s) 5312 the display software 2832 generates a map that covers the geographic boundaries of the users record(s) 5312 being opened. To display the user records 5312 the following information is needed: Geographic database 4160 Metropolitan road database Building location database Topographic information 2810 Other The information is then correlated to the user records 5312 based on the location in terms of latitude and longitude (and possible altitude). At this point the display software 2832 overlays this onto the user records 5312 and displays this information to the user. The user may zoom in and move the geographic boundaries. The resolution of the record will be limited to the time between updates and the distance traveled between those times by the wireless device 104. Mathematical extrapolations for missing data can be made by commonly known techniques to approximate the location between samples. Location Database Logs Logs created by the location tracking system 5300 software and database management software must have a consistent format that will allow universal parsing of the formatted data. The content listed in the logs must allow for a complete list of descriptive data to be saved and stored in an efficient manner. When the data is stored to the logs key elements. are required to identify the logs owner and relevant network identifiers. The requirements to establish this are the following categories: User identifier Home network for user Current network log is being generated on User's permanent storage location The next elements listed in the database log are the elements that will be tracked. These elements will be listed under categories in the log to allow rapid parsing of the log by software after it has been created and stored to a user's local directory of sectionalized portion of a home database structure. The categories are: Device ID numbers 3724 Network hardware ID numbers Event ID numbers The device ID numbers 3724 correspond to a unique identifier that is assigned to every wireless device 104 on a plurality of wireless device networks 100 that identifies itself and the wireless device network 100 it is on (ESN number, HEX ID code, wireless device 104 number, etc). The network hardware ID numbers are the identifiers of specific radio tower with BTS 110 or radio tower network 105 side equipment that communicates with users. Listed hardware elements here allow all wireless devices 104 communicating with these network components to be logged. Event ID numbers correspond to system events that would allow subsequent tracking of wireless devices 104. An example is when a wireless device network 100 fault occurs the system will monitor the wireless device 104 that the fault occurred on. The log has a start and stop time stamp field additionally that allows the date and time of the logs creation and completion to be noted and parsed quickly. Additionally there are time stamps for all recorded data. The next fields are data log fields. In this section there exists only wireless device ID numbers 3726 because only wireless devices 104 are ever tracked. The structure of this field is: Wireless device number 3726 Tracking reference ID a plurality of data measurements (taken at sequential times) Location of device (GPS data or latitude/longitude) Time of measurement Date of measurement Other Network parameters Wireless device 104 statistics Etc There can be many wireless device numbers 3726 in the log as well as many data measurements for each wireless device 104. The structure allows a plurality of wireless devices 104 to be listed and for each wireless device 104 to have independent amounts of data written to it. The tracking reference ID number allows for a link to the initial reason the wireless device 104 was tracked. An external query can just look for wireless devices 104 with respect to initial tracking criteria. For example, if a criterion was to monitor all wireless devices 104 on 2 physical radio tower network 105, then a tracking reference ID would be associated with that and affixed to every wireless device 104 log that was created for that reason. The tracking elements each have pre assigned ID numbers that are given by the database manager software and the software then also puts the same ID on each relevant wireless device 104 tracked corresponding to the tracking requirement. Cumulative Reports for Devices The idea of a cumulative report would be to allow a user to retrieve information on a plurality of database log entries made on a specific or plurality of wireless devices 104. The reports could be extended to include details on all call activity on a wireless device 104 by allowing that wireless device 104 to have a log generated each time an active call is made. The location tracking system 5300 software is designed to allow this to happen. A short duration track occurs for every call that is made from a wireless device 104 and stored a personal storage space on the secondary database used for user long-term storage. The qualifications placed on all tracking a wireless device 104 are that the wireless device 104 must verify a location and all call activity must be valid on the traffic channel. The qualification would exclude certain types of calls from being recorded. In general these calls would not show up as billable calls and would result in a user not being able to even initiate a voice channel on the phone. Their duration are typically less than one second. Examples of situations that would not record data including location of a wireless device 104 are: Network Access Failures Drop Calls before call is established on Network Poor Physical channel properties resulting in a call/network time out Hard Block Soft Block Capacity Block All calls that are successfully initiated on the wireless device network 100 will have a location database log created by the location tracking system 5300 software, and subsequently user location database manager 904. All the logs are then stored into the user directory. A possible use of this data is for it to be included in billing data. The user would receive a bill from the wireless device 104 carrier they use that could include call location information on where every call was initiated 6904. The caller ID features could allow the system to retrieve the number of the phone that was incoming or the outgoing phone dialed. This would also allow the location of that wireless device 104 to be noted. The location of the user's wireless device 104 when the call was made would be accomplished by parsing the user's database 3216 by means of SQL techniques or by other database query tools commonly known. Each call logged would be referenced to other call information including time and date. They can then be referenced to calls listed on the billable statement sent to the user. The location would be recorded as a latitude and longitude location. If a user elects the system could convert this to a landmark location or address by referring to a criss-cross latitude longitude map/database. The nearest address could be listed. An additional option would be to list a general area as opposed to an address which could often be incorrect due to location accuracy. The dialed number (for outgoing calls) or incoming caller's Id (for received calls) could also have a location listed. To accomplish this, the remote wireless device 1900 would be determined if it is a land line 142 device or a wireless device 104. If the device is a land locked device than an address for the phone number will be available through a database from the phone service provider of the number. If, however, the device is a wireless device 104 unit then this will not work. The wireless device 104 will have to be queried remotely. In this case the system can use an ATM, I based, or other method to query the main service provider of the wireless device 104 for the user location database 900 entry for that user. If authentication is allowed, and a log was made for a call at that time then a location would be available. The location could then be added to a billing cycle. If as in many cases, the remote wireless device 1900 had no call log made, then the wireless device 104 location can only be guessed upon. The system would have to resort to the users “home” NID and then supply that to the querying system. The NID could be resolved into a city, state, geographic region. The information would be included in the billing cycle as an approximation of the user's location. An appropriate consideration would be to inform on the billing cycle that is location is inaccurate and only an approximation and could be incorrect. An additional use of a cumulative report would be for an external query to be made on a plurality of logs. The logging criteria could list any data field include wireless device identifiers 3724 (ex: phone #'s), logs from geographic regions, etc. The query could be remote or from an internal memory storage 2818 system. To make this possible, the external query would have to be IP base, ATM, or another universal standard that would allow a plurality of users access to the system and provide a secure data transmission. The filter can then derive only the logs for a given user, or group of users, personal database folders. The results would then be returned and could be listed either textually or graphically to the user. A text representation would be for a list of database entries that met the specifications to be listed on the screen. A graphical representation could be to plot a map and indicate log locations on it. These options are described in the data log graphical display section. Data Log Graphical Display The user may parse a tracking log in their personal database. These logs will contain the location tracking system 5300 information for anything the user requested from the location tracking system 5300 software. The user can read this information after it is parsed in text form however a series of latitudes and longitudes will simply be repeated at the update intervals for each time a location was determined. The series of latitudes and longitudes is not very valuable to a user in general. An easy way for the user to gain valuable insight is to display this information on a graphical display unit. This could be a monitor or other display hardware attached to the querying device. It could also be a hard copy reproduced and printed on a printing device. The log can be parsed and converted to a graphical display for the user by the following method. First, the database entry must be scanned and read all the correlated data for latitude and longitude information 2830 for the tracked wireless device 104. The most extreme dimensions in for example, east, west, north and south (using Cartesian coordinates) will be noted. In this case you could also use any other dimensionally system convenient (radial, spherical). The extreme locations will be the boundaries of the displayed map. The data points will be plotted on that map, correlating data for latitude and longitude information 2832 to the correlated pixel separation as correlated to the scale of the map. The minimum resolution is the pixel separation at the monitors screen resolution. The distance will be used to disregard location points at distances less than a given amount. The plotting system can then plot the remaining points to the display screen 2836. The system will then have a map with the data points plotted to it. To increase accuracy the system may also be able to provide the described functionality that is not common knowledge. All roadways and transportation ways will be illustrated and correlating data for latitude and longitude information 2830 on the map. If a wireless device 104 is traveling in a direction for a given distance and follows a road way but is not on it exactly the software could assume the wireless device 104 is on the roadway and re-center the data points on the roadway to increase accuracy. The plotting system would allow the system to more accurately display a tracked wireless device 104 to a user. When the location of this wireless device 104 is plotted it would not show the device passing though buildings or other objects and allow the location of the data point to be shifted to the adjacent roadway or habitable area. Definable parameters would be the distance traveled along a roadway and the distance away from the road way that the software could use as criteria to assume the wireless device 104 is on the road. The distance should be conservative as to prevent obscuring real locations. An appropriate distance could be from 5 meters to 100 meters depending on the tuning of a network engineer for a particular situation. Displaying the wireless device 104 travel vector may also be useful. This Would allow the user to see the relative travel direction and speed of the wireless device 104. To accomplish this, the system would sample a defined parameter that represents how many data points to average. If the software averages 20 data points then the average direction and velocity would be represented by a vector on the display. The foot of the vector would be at the mean location of the sample range, and the vector length from foot to tip would be proportional to the average velocity over that sample time. The vectors would be plotted for every group of data points. The group size could be adjustable by the user and is accomplishable through any data interface. Another display option would be for the user to have a real-time replay of the user's location. The display could be accomplished by plotting points to the screen at the minimum pixel separation over the time interval shown. The plotting is easily done and would give the user a perspective of where the user was at various points in time. A text information box can then additionally show the time during the call while points are being plotted. The display software 2832 that gives the GUI and mapping ability can also show a plurality of log locations for a plurality of log database entries. The mapping can be accomplished by, as before, scanning logs for extreme distances. In this case though, all logs that are selected would have to be scanned for their maximum geographic dimensions. Once this is done, a map could be generated based on the dimensions. The overlay for the logs would be definable by programming, but a convenient method is to determine the initial starting location of each call and then to plot these points for each call on the map. The user may select points and then the entire route can be plotted on the map. The user who wants more detail may zoom in. The new dimensionally of the map would require the minimum pixel separation to be re-computed and would then allow more detail or less depending on if the user zoomed in or out. Alternate method that could be used if more detailed location information is available in future network configurations would be: Plotting altitude Inside building location Plotting call detail (logged speech) Inter Network Communication To make the location tracking system 5300 available to other networks outside any single entity, a database sharing system must be established. A most likely case would be for a system such as an ATM routing center or an IP (con nectionless) based system to be used. The first system is beneficial in cases where a large number of database queries may be made. ATM switching allows for a dedicated path to be established between host and user sites and allow a rapid connection once the line is established. Basic benefits to consider when choosing ATM switching are: High performance via hardware switching Dynamic bandwidth for busy traffic Class-of-service support for various traffic type Scalability in speed and network size Common LAN/WAN architecture Opportunities for simplification via VC architecture International standards compliance The benefits of IP switching as opposed to direct ATM connections between wireless device networks 100 are that the complexity is reduced. You only route packets to the next routing point and can take advantage of preexisting hardware on other networks to get your data to the destination, in our case the other wireless device 104 network. The ability to handle security on a traditional router basis is very complex and the speed at which a router switches or routs a packet is very slow and cumbersome because every packet has to be looked at as it goes through the wireless device network 100. This can reduce security and is a consideration for any wireless provider when implementing IP switching. With an IF switch (MTX or other) 130-based network, what happens is the first packet is looked at and the supplementary packets do a quick forward look-up and then everything else goes through the network very, quickly, so it's less costly and it's easier to administer. ATM systems require new and expensive hardware to be added but are often faster and more reliable. The system is also a far more secure method because all information is on a protected network at all times. IF based system here could use the internet 3202 to send requests between wireless device network 100 locations and allow for rapid development and low cost of implementation. The inter-network structure would allow wireless device networks 100 to query each other for information. Security and fire-wall precautions aside, this allows one wireless device network 100 to retrieve the location of a wireless device 104 on any other wireless device network 100. The inter-network structure would allow the tracking of the two, or more, wireless devices 104 on a call or other communication. It would also allow tracking wireless devices 104 as they moved off of a network providers system and on to a remote system. IF version 6 provides for the internet 3202 solutions to inter-network wireless device 104 movement and would allow tracking to occur over multiple wireless device networks 100. The data logs could then be generated at the remote wireless device network 100 and retrieved by the user's home wireless device network 100. This would allow tracking beyond the users own network boundaries. Security The security of this wireless device network 100 can be viewed in two subsystems. First the network must secure access to the system at a user level access, or group access scheme. Second, the system must secure user system rights. In this regard, it must secure that any user may not gain access to sensitive information of another user it does not have rights to. The access of a user to the system will be defined and can be implemented by various methods. Secure Socket Layer (SSL) can be used to guarantee that and external wireless device user 102 has a secure connection. Modern internet 3202 browsers use a SSL to encrypt the information that flows between the browser and the web server. A browser using SSL has established a secure encrypted connection with the server, meaning it is safe to send sensitive data. In the case of a local connection less line security is necessary. 128 bit or higher encryption of data across a wireless device network 100 will allow data to remain private in transit. To allow for a secure connection various protocols can be used. FTP, and telnet offer some protection, but secure connections such as used by verisign and other companies to establish “user identity” are recommended. The connection types should be connectionless service types. The secure connection ensures that packet never follow the same path across a network such as the internet 3202. The secure connection allows for less possibility of snooping and more security. On secure connections (point-to-point), connection oriented ATM links can suffice because the line is secure in a physical sense. Wireless device users 102 will be placed in categories based on access rights. All three categories are defined by a administrator and are adjustable, but generally accepted standards are: User Super user Administrator A user level access will give the entity connecting to the system the ability to access only files created and stored in it user directory. The user may only request logs be created for wireless devices 104 that have been added to its authorized list by an administrative account. A super user has access to all the user rights for itself, but may also have rights to the files and permissions of a group of wireless device users 102. This would allow the user to track wireless devices 104 listed on other wireless device users 102 accounts. An administrator has all the access of the super user but also has the ability to create and delete accounts, as well as file management. This allows the administrator unrestricted access to all files on a server. It can also alter and change system parameters that affect any or all wireless device users 102. Physical Hardware to Realize Embodiment To implement the primary embodiment 2800 there must be a hardware platform for the software to function from. The term function refers to the normal operation of the software that includes the primary embodiment 2800 as well as any other secondary software packages that would run to assist the primary embodiment 2800. The secondary processes are commonly known and would not be covered by this patent. An example would be dynamic link libraries that are commonly known and used to linking various software elements. The hardware required to implement the user location database manager 904 is inclusive of but not limited to, based on any unique hardware setup: Data storage medium Data storage controller (RAID, etc) Computer 2910 (includes motherboard, CPU, RAM, etc) Network interface card The data storage medium should consist of a hard disk or other nonvolatile storage medium that is can be accessed by a computer 2910. It can conform to either, IDE or SCSI standards. Extended standards could include ultra wide SCSI and EIDE as well as other derivations. The claimed scope is that a communications protocol database 3004 and physical layer would provide high bandwidth capacity and high efficiency. Examples of this hardware may be a western digital 10,000 RPM 80 GB deskstar hard disk drive. The data storage controller consists of one of the following generic classes: IDE/EIDE/etc SCSI/U W-SCSI/etc RAID type 1, 2, etc The controllers are required for the computer 2910 to be allowed to access the hard disk drive. To allow for this to work the computer 2910 must be compatible with the controller. The RAID controller allows a unique benefit to the database and storage architecture. Having many configurations, very high bandwidth and redundancy of data is possible. The accurate usage of RAID architecture is critical for these databases as VERY high bandwidth is required on large wireless device networks 100. Explained as follows are the recommended RAID types and the considerations in choosing each. In RAID 0, the controller will store the data across two or more disks, writing the data in blocks across the disks. For example, if you have two disks, block one will be written to disk one, block two to disk two, block three to disk one, and so on. The data will increase performance since the controller can read/write in parallel, but there is no redundancy, if one disk fails, the whole array fails, since the data is spread across the array. RAID 0 is the most efficient level in terms of cost/space/performance, as you will increase performance without sacrificing any disk space, though access times suffer slightly. RAID 0 is best used where cost/performance is critical, but data integrity is not. For this reason the type of RAID would be the least recommended for the primary embodiment 2800 and its databases. A RAID 1 array consists of two or more disks and acts as one logical disk while mirrored data 1532 is passed between the disks. If you have an array consisting of two 36 GB disks, you will end up with a logical disk of 36 GB, with data being stored on both the physical disks. Hence one of the physical disks can fail, and the array will keep working, and if the disks are hot-swappable, which is the case with most SCSI RAID setups, the failed disk can be swapped for a new disk, and the controller will synch the data between the disks, restoring the array to full functionality, with no downtime. RAID 1 also increases the read performance since both disks can be read at once, while write performance will be more or less identical to that of one single disk. RAID 1 is a way to achieve good read performance, as well as redundancy. For this reason it is recommended over RAID 0 and will allow higher bandwidth and therefore more throughput from the database to the computer 2910 Striping with parity increases performance while maintaining a handle on redundancy. RAID 3 does this by implementing a RAID 0 and then creating a separate disk to write parity information. RAID 3 helps, if you lose a disk, that disk's information can be recreated. RAID 3 works on a binary system. (i.e. 11=Oparity, 000parity, 01=1parity, 10=11parity) You can take any two bits, and recreate the lost one. The benefits of this are performance and safety, although with RAID 3 you put a large strain on the odd disk that contains parity as everything has to be calculated and written to it. For ever bit written to any other disk, one gets written there, both bottlenecking performance, and creating more strain on this disk. 50 is considered to be a much better option. A required minimum of 3 disks, and an odd number of disks. RAID 3 is very expensive in terms of CPU power when implemented in software. For this reason this configuration is recommended over RAID 0 but less than RAID 1 for the primary embodiment 2800. RAID 5 is a quite common type of RAID but it doesn't offer the performance of RAID 1+0, but is much cheaper. Three or more disks a required for a RAID 5 array. RAID 5 stores parity information (unlike RAID 1 which stores data redundantly) across the disks in the array, this information can then be used to rebuild lost data in case of disk failure. Raid 5 is not recommended at all but is explained such that RAID 50 can next be fully understood. Raid 50 is the combo of RAID 5 and RAID 0. The major benefit is speed. RAID 50s take the data to write, say 256 k, then split that among the RAID 0, so 128 k+128 k, then split that among the RAID 5s, so you could be writing 32 k+32 k+32 k+32 k+32 k+32 k+32 k+32 k all to separate disks at the same time. The same is true in reverse as well for reading. You could also lose I disk out of each array and the controller would keep running. You can stream high amounts of data to several machines at once over the network. To do it right it really should be done on two controllers, or one multi-channel controller to give the arrays as much bandwidth as possible. RAID 50 requires a minimum of 6 disks, and an even number of disks. The setup is recommended for the database controller. The system will be able to keep up with network connection bandwidth (T-1, T-3, OC-3, etc). The primary embodiment 2800 will operate at maximum efficiency using this setup. The physical hardware should consist of a processor capable of computing the necessary work load. A dual processor system would reduce the load further. An intel XEON system (dual processor) at 1 GHz or above would suffice. Additional RAM in excess of 1 G would be beneficial and allow fast access to cached data. Similar systems to this are produced by AMD and other chip manufacturers. The location tracking software 5300 may exist on any of the above said hardware but should have its own reserved storage medium. A low bandwidth connection to the computer 2910 is OK because the software will run from cache memory as it is a static program that is accessed frequently. The display software 2832 does not require a specific set of hardware, more of a class of hardware. The display hardware 2832 required is a display driver or graphics hardware controller, commonly called a graphics card. Performance of the card need not be high but should allow for an adequate resolution display for the minimum programming of the display software 2832. Display hardware 2832 that could be used as the physical display device can be CRT computer 2910 monitor displays, LCD displays of various sizes including palm-top sized displays. Example of this is a Viewsonic 19″ CRT G790, this monitor would support up to 1 600×1 200 at 80 Hz refresh which would allow proper viewing of all visual data from the preferred embodiment 2800 The network interface cards required would be a 121100 base-T or higher connection. Hardware such as a 3COM Etherfast NIC would function properly. External connectivity to the internet 3202 or other high speed data access points is also required which often requires a ATM connection or other gateway routing wireless device 104. Directional Assistance Network (DAN) The Dan Comprises: A COMPUTER SYSTEM HARDWARE/SOFTWARE AN OPERATING SYSTEM A DIRECTIONAL ASSISTANCE OPERATING PROGRAM AN AUTOMATED TELEPHONE HARDWARE/SOFTWARE A VOICE RECOGNITION HARDWARE/SORTWARE TRAFFIC MONITORING AND ROUTE PLANNING HARDWARE /SOFTWARE AND MAPPING HARDWARE/SOFTWARE A WIRELESS DEVICE USER LOCATION DATABASE AND DATABASE LOGIC CENTER HARDWARE/SOFTWARE (OPTIONAL IF LOCATION DATA IS OBTAINED FROM AN OUTSIDE DATABASE, E-MOBILITY, ETC.) A PSTN USER LOCATION DATABASE AND DATABASE LOGIC CENTER HARDWARE/SOFTWARE (OPTIONAL IF LOCATION DATA IS OBTAINED FROM AN OUTSIDE DATABASE, E-MOBILITY, ETC.) LOCATION CONVERSION HARDWARE/SOFTWARE AND DATABASE TO CONVERT STREET ADDRESSES TO LONGITUDE AND LATITUDE DATA, AND TO CONVERT LONGITUED AND LATITUDE DATA TO STREET ADDRESS DATA. A VOICE MAIL SYSTEM INTERNET ACCES SABLE INTERNET ADDRESS AND WEB SITE. ABILITY TO MAKE AND SENT MAPS TO WCD, NAVIGATIONAL SYSTEMS, FAXES, E-MAILS, ETC. A LIVE OPERATOR WHO CAN ACCESS, PROGRAM AND SERVICE ALL PARTS OF THE DAN. CONVERSION/STANDERDIZATION HARDWARE/SOFTWARE FOR INTER-FACING WITH WIRELESS NETWORKS, WIRELESS DEVICES AND PUBLICLY SWITCHED TETEPHONE NETWORKS. CONVERSION/STANDERDIZATION HARDWARE/SOFTWARE FOR SENDING AND RECEIVING MAPS, F-MAILS AND FAXES. DETAILED DESCRIPTION OF THE EMBODIMENTS FIG. 70 is a flowchart of the Directional Assistance Network (DAN) query process. To begin the query process, a person seeking directional assistance or location information begins a query for directional assistance by dialing a specified phone number, such as, for example, 411, 511, an 800 number or a dedicated button on a wireless device, navigational system or a land-based communications device 7000. The user may also process a DAN query via the Internet. The user can enter his DAN query via a keypad or keyboard, through the use of voice recognition software, a live operator or by way of an interactive display screen, such as may be found on a wireless device or a navigational system. The process begins when the DAN 8100 receives the user's call 7002. The DAN 8100 then queries a user location database (ULD) to determine the user's location and logs to user's location within the DAN 8100, BOX 7003. Still referring to FIG. 70, BOX 7003, if the DAN 8100 determines that the user is calling from a wireless communication device (WCD) 8205, such as, for example, a cellular phone, an Personal Digital Assistant (FDA), wireless navigational system, etc, then DAN 8100 queries a wireless network's ULD 900 in order to determine the user's location within the wireless network. The wireless network's ULD 900 can exist internally to the DAN 8100 and constructed by the DAN 8100 with information obtained from the wireless network through querying the wireless network's e-mobility services, switch and/or base station controller. The DAN 8100 could also find the user's location without a wireless network's ULD 900, by retrieving the user's location data from the wireless network on an as needed basis. The DAN 8100 can generate the location on an as needed basis by accessing pertinent location data, which can be obtained from the switch (MTX or other) 130, and the base station controller (BSC) 206. The pertinent information would include the round trip delay (RTD), signal strength and other factors needed for determining location of wireless device, which are disclosed in an attached document. The ability to determine the user's geographic location in the form of longitude and latitude data, when calling from a wireless device, is disclosed in an attached document entitled, ‘A machine for providing a dynamic database of geographic location information for a plurality of wireless communications devices and process for making same”. This document referenced above, is a United States Provisional Patent, U.S. Ser. No. 60/327,327, which was filed on Oct. 4, 2001, is hereby incorporated into this disclosure. Also, the wireless network's ULD 900 may be comprised of only a single service provider's network, or in may comprise a plurality of service provider's networks data regarding wireless device user location data. The DAN 8100 may use its conversion/standardization hardware/software 8160 to interface with wireless networks and wireless devices. Still referring to FIG. 70, BOX 7003, if the user's call originates from a publicly switched telephone network (PSTN) 138, the user's location can be determined by querying a PSTN phone location database 8145 which consists of listings of the names of businesses and private residences, their respective street addresses, city, state and corresponding longitude and latitude coordinates, and their telephone numbers. The PSTN phone location database 8145 could be internal or external to the DAN 8100. The database could also be comprised of a street map location system instead of a longitude and latitude based system. The DAN 8100 could also find the user's location without a PSTN's phone location database 8145, by retrieving the user's location data from the PSTN 138 on an as needed basis. The location can be generated on an as needed basis within the DAN 8100 by accessing pertinent location data, which can be obtained from the switch (MTX or other) 130, and the base station controller (BSC) 206 of the PSTN 138. The DAN 8100 may use its conversion/standardization hardware/software 8160 to interface with the PSTN 138. Regardless of whether the user is calling form a wireless device or a landline, once the user's geographic location has been determined and logged into the DAN's voice mapping software 8110, The DAN's automated telephone system prompts the user with a menu of services 7004. Still referring to FIG. 70, the DAN 8100 first asks the user “If you know the phone number of your desired destination, and would like to receive directions to that destination, please press or say 1” 7006. The automated telephone system waits for the user's response 7008. If the user selects “1”, the user is forwarded to FIG. 71, BOX 7100, the portion of the query process that retrieves the geographic coordinates of the users destination, based on the destination's area code and telephone number 7010. Again referring to FIG. 70, BOX 7008, if the user does not select “1” within a specified period of time, the automated telephone system continues to instruct the user “For the telephone number and directions to a specific business or person by name, press or say “2” 7012. The automated telephone system waits for the user's response 7014. If the user selects “2”, the user is forwarded to FIG. 72, BOX 7200, the portion of the query process that retrieves the business or residential listing by the name of the listing 7016. Still referring to FIG. 70, BOX 7014, if the user does not select “2” within a specified period of time, the automated telephone system continues to instruct the user, “For a phone number and directions to the nearest business by category, such as for example, a gas station or restaurant, press or say “3” 7018. If the user selects “3”, the user is forwarded to FIG. 73, BOX 7300, the portion of the query process that retrieves the geographic coordinates of the users destination, based on the category of the business which the user wishes to find 7022. Again referring to FIG. 70, BOX 7020, if the user does not select “3” within a specified period of time, the automated telephone system continues to instruct the user, “For a phone number and directions to as specific address, press or say “4” 7024. If the user selects “4”, the user is forwarded to FIG. 74, BOX 7400, the portion of the query process that retrieves the geographic coordinates of the specific address the user is requesting directions and the phone number 7028. Still referring to FIG. 70, BOX 7026, if the user does not select “4” within a specified period of time, the automated telephone system continues to instruct the user, “To locate or track a wireless device, press or say “5” 7030. The DAN 8100 then waits a specified period of time for the user to respond by selecting “5” 7032. If the user selects “5”, the user is forwarded to FIG. 78, BOX 7800 and the DAN 8100 continues it's query process 7034. Again referring to FIG. 70, BOX 7032, if the user does not select ‘5” within a specified period of time, the automated telephone system continues to instruct the user, “To repeat these choices, press or say “6” 7036. The DAN 8100 then waits a specified period of time for the user to respond by selecting “6” 7038. If the user selects “6”, the user is returned to FIG. 70, BOX 7006, the portion of the query process which has been described above is repeated 7032. If the user does not select “6” within a specified period of time, the automated telephone system continues to instruct the user, “To end this call, press or say “9”, or hang up” 7040. The DAN 8100 then waits a specified period of time for the user to respond by selecting “9” 7042. If the user selects “9”, the call is terminated 7044. If the user does not select ‘9” within a specified period of time, the automated telephone system continues to instruct the user, “To be connected to a DAN Operator, press or say “0”, or say on the line” 7046. The automated telephone system then forwards the user's call, to a live operator for assistance 7048. The live operator has direct access to all components of the DAN 8100 and can assist the user's how are having trouble with the automated system. Now referring to FIG. 71, the automated telephone system instructs the user, “Please dial or speak the area code and phone number of your desired destination to receive directions to that location” 7100. The automated telephone system waits for the user to dial or speak the area code and telephone number to the desired destination 7102. The automated telephone system waits for the user to respond within a specified period of time by dialing the phone number 7104. If the user dials the phone number, the number is matched against numbers within the PSTN phone location database 7110 of business and residential listings, which may be internal or external to the DAN 8100. The automated telephone system then tells the user, “We have located “X” number possible match(s)” 7114. Still referring to FIG. 71, if the user does not dial a phone number within the specified period of time, the automated telephone system waits for the user to respond by speaking the phone number 7106. If the user does not respond within a specified period of time, the user's query is forwarded to FIG. 71 BOX 7126, for further processing. If the user responds by speaking the phone number, a voice recognition program within the DAN 8100 converts the user's words into texts 7108. The DAN 8100 matches the text against telephone numbers contained within the database of business and residential listings 7112. The automated telephone system tells the user, “We have located “X” number possible match(s)” 7114. Again referring to FIG. 71, the automated telephone system then instructs the user, “For directions to “listing 1” located at “address 1” with a phone number of “phone 1”, press or say “1” 7116. The automated telephone system then waits a specified period of time for the user to press or say “1” 7118. If the user selects “1”, the user's choice is logged within the DAN 8100, and the user's query is forwarded to FIG. 75, BOX 7500, for further processing 7120. If the user does not select “1”, the automated telephone system instructs the user, “To repeat listing(s), press or say “4” 7122. The automated telephone system then waits a specified period of time for the user to respond by pressing or saying “4” 7124. If the user does select “4”, the automated telephone system returns to FIG. 71, BOX 7116 and repeats the listing. If the user does not select “4” within the specified period of time, the automated telephone system instructs the user, “To request a new listing, press or say “5” 7126. If the user selects “5”, the DAN 8100 returns the user to FIG. 70, BOX 7006, where the user can begin to search for a new listing 7130. If the user does not select “5”, the automated telephone system instructs the user, “To be connected to a Directional Assistance Operator, press or say “0”, or stay online” 7132. The automated telephone system then forwards the user, to a live directional assistance operator for assistance 7134. Now referring to FIG. 72, the automated telephone system instructs the user, “Please speak the name of the business or residents you wish to find” 7200. The automated telephone system waits for the user to speak the name of the desired business or person 7202. The voice interface software 8105 and voice mapping software 8110 within the DAN 8100 converts the user's spoken words into text 7204. The DAN 8100 matches the text against names within the PSTN phone location database 8145, which may be internal or external to the DAN 8100, BOX 7206. The automated telephone system then informs the user, “We have located “X” number of possible match(s)” 7208. Still referring to FIG. 72, the automated telephone system then instructs that user, “For directions to “listing 1” located at “address 1”, with a phone number of “phone number 1”, press or say 1” 7210. The automated telephone system then waits a specified period of time for the user to respond by selecting “1” 7212. If the user selects “1”, the user's choice is logged into the DAN 8100, and the DAN 8100 forwards the user to FIG. 75, BOX 7500, for further processing 7214. If the user does not respond by selecting “1”, the automated telephone system instructs the user, “For directions to “listing 2” located at “address 2”, with a phone number of “phone number 2”, press or say “2” 7216. The automated telephone system then waits a specified period of time for the user to respond by selecting “2” 7218. If the user selects “2”, the user's choice is logged into the DAN 8100, and the DAN 8100 forwards the user to FIG. 75, BOX 7500, for further processing 7220. If the user does not respond by selecting “2”, the automated telephone system instructs the user, “For directions to “listing 3” located at “address 3”, with a phone number of “phone number 3”, press or say “3” 7222. The automated telephone system then waits a specified period of time for the user to respond by selecting “3” 7224. If the user selects “3”, the user's choice is logged into the DAN 8100, and the DAN 8100 forwards the user to FIG. 75, BOX 7500, for further processing 7226. Again referring to FIG. 72, if the user does not respond by selecting “3”, the automated telephone system instructs the user, “To repeat the previous listing(s), press or say “4” 7228. The automated telephone system then waits a specified period of time for the user to respond by selecting “4” 7230. If the user selects “4”, the DAN 8100 returns the user to FIG. 72, BOX 7210, were listings are repeated by the DAN's automated telephone system. If the user does not select the automated telephone system instructs the user, “To request a new listing, press or say “5” 7232. The automated telephone system then waits a specified period of time for the user to respond by selecting “5” 7234. If the user selects “5”, the DAN 8100 returns the user's query to FIG. 70, BOX 7006, were a new query process can begin 7236. If the user does not select “5”, the automated telephone system instructs the user, “To be connected to a Directional Assistance Operator, Press “0”, or say on the line” 7238. The user's call is then forwarded to a live operator for assistance 7240. Now referring to FIG. 73, the automated telephone system instructs the user, “Please speak the category of business you wish to find” 7300. The automated telephone system waits for the user to speak the name of the desired business category 7302. The voice interface software 8105 and voice mapping software 8110 within the DAN 8100 converts the user's spoken words into text 7304. The DAN 8100 matches the text against categories within the PSTN phone location database 8145 that most closely correspond to the user's geographic location 7306. If the DAN 8100 does not find any listings within the user's selected category 7308, the automated telephone system informs the user, “No listings were found in this category” 7336. The automated telephone system then instructs the user, “To request a new listing, press or say 5” 7338. The DAN 8100 then waits a specified period of time for the user's response 7340. If the user selects “5”, the user is returned to FIG. 70, BOX 7006, for an opportunity to select a new listing 7342. If the user does not select “5”, the automated telephone system instructs the user, “To be connected to a Directional Assistance Operator, Press “0”, or say on the line” 7344. The user's call is then forwarded to a live operator for assistance 7346. Still referring to FIG. 73, if the DAN 8100 finds the requested category, the listings contained within that category are sorted according to distance from the user's geographic location 7310. The automated telephone system then informs the user, ‘We have located “X” number of possible match(s)” 7312. The number “found” listings that are actually available to the user can be set within the DAN 8100 so as only to provide, for example, only the three closest listings within the selected category. Still referring to FIG. 73, the automated telephone system then instructs that user, “For directions to “listing 1” located at “address 1”, with a phone number of ‘phone number 1”, press or say “1” 7314. The automated telephone system then waits a specified period of time for the user to respond 7316. If the user selects “1”, the user's choice is logged into the DAN 8100, and the DAN 8100 forwards the user to FIG. 75, BOX 7500, for further processing 7318. If the user does not respond, the automated telephone system instructs the user, “For directions to ‘listing 2” located at “address 2”, with a phone number of “phone number 2”, press or say ‘2” 7320. The automated telephone system then waits a specified period of time for the user to respond 7322. If the user selects “2”, the user's choice is logged into the DAN 8100, and the DAN 8100 forwards the user to FIG. 75, BOX 7500, for further processing 7324. If the user does not respond, the automated telephone system instructs the user, “For directions to “listing 3” located at “address 3”, with a phone number of “phone number 3”, press or say “3” 7326. The automated telephone system then waits a specified period of time for the user to respond 7328. If the user selects “3”, the user's choice is logged into the DAN 8100, and the DAN 8100 forwards the user to FIG. 75, BOX 7500, for further processing 7330. Again referring to FIG. 73, if the user does not respond, the automated telephone system instructs the user, “To repeat the previous listing(s), press or say “4” 7332. The automated telephone system then waits a specified period of time for the user to respond 7334. If the user selects “4”, the user is returned to FIG. 73, BOX 7314, were listings are repeated through the DAN's automated telephone system. If the user does not select “4”, the automated telephone system instructs the user, “To request a new listing, press or say “5” 7338. If the user selects “5”, the user's query is returned to FIG. 70, BOX 7006, were a new query process can begin 7342. If the user does not select “5”, the automated telephone system instructs the user, “To be connected to a Directional Assistance Operator, Press “0”, or say on the line” 7344. The user's call is then forwarded to a live operator for assistance 7346. Now referring to FIG. 74, the automated telephone system instructs the user, “Please speak the complete Street address including city and state, to receive phone number and directions to that address” 7400. The automated telephone system waits for the user to speak the name of the desired business or person 7402. The voice interface software 8105 and voice mapping software 8110 within the DAN 8100 converts the user's spoken words into text 7404. The DAN 8100 matches the text against addresses within the PSTN phone location database 7406. The automated telephone system then informs the user, “We have located “X” number of possible match(s)” 7408. Still referring to FIG. 74, the automated telephone system then instructs the user, “For directions to “listing 1” located at “address 1”, with a phone number of “phone number 1”, press or say 1” 7410. The automated telephone system then waits a specified period of time for the user to respond 7412. If the user selects 1”, the user's choice is logged into the DAN 8100, and the DAN 8100 forwards the user to FIG. 75, BOX 7500, for further processing 7414. If the user does not respond, the automated telephone system instructs the user, “For directions to “listing 2” located at “address 2”, with a phone number of “phone number 2”, press or say “2” 7416. The automated telephone system then waits a specified period of time for the user to respond 7418. If the user selects ‘2” the user's choice is logged into the DAN 8100, and the DAN 8100 forwards the user to FIG. 75, BOX 7500, for further processing 7420. If the user does not respond, the automated telephone system instructs the user, “For directions to “listing 3” located at “address 3”, with a phone number of “phone number 3”, press or say “3” 7422. The automated telephone system then waits a specified period of time for the user to respond 7424. If the user selects “3”, the user's choice is logged into the DAN 8100, and the DAN 8100 forwards the user to FIG. 75, BOX 7500, for further processing 7426. Again referring to FIG. 74, if the user does not respond, the automated telephone system instructs the user, “To repeat the previous listing(s), press or say “4” 7428. The automated telephone system then waits a specified period of time for the user to respond 7430. If the user selects ‘4”, the DAN 8100 returns the user to FIG. 74, BOX 7410, where listings are repeated. If the user does not select “4”, the automated telephone system instructs the user, “To request a new listing, press or say “5” 7432. If the user selects “5”, the user's query is returned to FIG. 70, BOX 7006, were a new query process can begin 7436. If the user does not select “5”, the automated telephone system instructs the user, “To be connected to a Directional Assistance Operator, Press “0”, or say on the tine” 7438. The user's call is then forwarded to a live operator for assistance 7440. Now referring to FIG. 75, the automated telephone system instructs the user, “To receive directions based on fastest travel time with current traffic conditions, press or say 1” 7500. The automated telephone system waits a specified period of time for the user to respond 7502. If the user does not respond with a specified period of time, the query process is forwarded to FIG. 76, BOX 7600, for further processing 7506. If the user does select “1”, the traffic monitoring software 8125 and routing software 8120, within the DAN 8100, plots the user's location and location of the selected destination, and determines a selected number of possible logical routes. The routes are sent to the DAN's traffic monitoring software and routing software 7504. The traffic monitoring software 8125 and routing software 8120 queries the wireless network's ULD 900 to examine the flow of traffic based on the movement and density of wireless devices, and calculates the fastest route based on available information including traffic movement, speed limits (if available) and distance 7508. Still referring to FIG. 75, upon determining the fastest route, the traffic monitoring software 8125 and routing software 8120 then calculates direction, distance, and estimated travel time 7510. The automated telephone system then informs the user, “Your destination is “X’ miles “North/South” and “Y” miles “East/West”, with an estimated driving distance of “W” miles. Current travel time is estimated at ‘1’ minutes” 7512. The automated telephone system then instructs the user, “To continue with these directions and receive the travel plans, press or say “1” 7514. The automated telephone system then waits a specified period of time for the user to select 1” 7516. If that user does not respond with within a specified period of time, the automated telephone system then instruments the user, “To repeat the previous information, press or say “2” 7528. The automated telephone system then waits a specified period of time for the user to select ‘2” 7530. If the user responds by selecting ‘2″, the DAN 8100 returns the user to FIG. 75, BOX 7512. If the user does not select “2” within a specified period of time, the automated telephone system then instruments the user, To return to the main menu, or to enter a new destination, press or say “3” 7532. The automated telephone system then waits a specified period of time for the user to select “3” 7534. If the user responds by selecting “3”, the user is returned to FIG. 70, BOX 7006 to began a new query 7536. If the user does not select “3” within a specified period of time, the automated telephone system then informs the user, “Thanking you for using the Direction Assistance Service”, and the call is terminated 7526. Again referring to FIG. 75, BOX 7516, if the user selects “1”, the automated telephone system then instructs the user, “To repeat these directions at anytime, press or say “9”. The directions are as follows, “XXXXXX” 7518. The automated telephone system then instructs the user, “To be instructed when to turn, to receive a notice when the fastest route to changes due to traffic conditions, or to receive a map of the travel plan, press or say 1” 7520. The automated telephone system then waits a specified period of time for the user to select “1” 7522. If the user responds by selecting “1”, the user is forwarded to FIG. 79, BOX 7900 for further processing 7524. If the user does not select “1” within a specified period of time, the automated telephone system then informs the user, “Thanking you for using the Direction Assistance Services”, and the call is terminated 7526. Now referring to FIG. 76, the automated telephone system instructs the user, “To receive directions based shortest travel distance, press or say “2” 7600. The automated telephone system waits a specified period of time for the user to respond 7602. If the user does not respond with a specified period of time, the DAN 8100 forwards the query process to FIG. 77, BOX 7700, for further processing 7606. If the user does select “2”, the traffic monitoring software 8125 and routing software 8120 comprised within the DAN 8100, plots the user's location, and location of the selected destination, and determines the shortest possible logical route 7604. The traffic monitoring software 8125 and routing software 8120 then determines the direction, distance, and estimated travel time 7610. The automated telephone system then informs the user, “Your destination is “X” miles “North/South” and “Y” miles “East/West”, with an estimated driving distance of “W” miles. Driving time is estimated at “Z” minutes” 7612. The automated telephone system then instructs the user, “To continue with these directions and receive the travel plans, press or say “1” 7614. The automated telephone system then waits a specified period of time for the user to select “1” 7616. If that user does not respond with within a specified period of time, the automated telephone system then instructs the user, “To repeat the previous information, press or say “2” 7628. The automated telephone system then waits a specified period of time for the user to select “2” 7630. If the user responds by selecting “2”, the user is returned to FIG. 76, BOX 7612. If the user does not select “2” within a specified period of time, the automated telephone system then instructs the user, “To return to the main menu, or to enter a new destination, press or say “3” 7632. The automated telephone system then waits a specified period of time for the user to-select “3” 7634. If the user responds by selecting “3”, the DAN 8100 returns the user to FIG. 70, BOX 7006 to began a new query 7636. If the user does not select “3” within a specified period of time, the automated telephone system then informs the user, “Thanking you for using the Directional Assistance Services”, and the call is terminated 7626. Again referring to FIG. 76, BOX 7616, if the user selects “1”, the automated telephone system then instructs the user, “To repeat these directions at anytime, press or say “9”. The directions are as follows, “XXXXXX” 7618. The automated telephone system then instructs the user, “To be instructed when to turn, or to receive a map of the travel plan, press or say “1” 7620. The automated telephone system then waits a specified period of time for the user to select “1” 7622. If the user responds by selecting “1”, the DAN 8100 forwards the user to FIG. 79, BOX 7900 for further processing 7624. If the user does not select “1” within a specified period of time, the automated telephone system then informs the user, “Thanking you for using the Directional Assistance Services”, and the call is terminated 7626. Now referring to FIG. 77, the automated telephone system instructs the user, “To be connected to your selective listing, press or say “3” 7700. The automated telephone system waits a specified period of time for the user to respond 7702. If the user does select “3”, the automated telephone system connects the user to their selected listing 7704. If the user does not respond by selecting “3” within a specified period of time, the automated telephone system instructs to user, “To repeat these choices, press or say “4” 7706. If the user does select ‘4”, the automated telephone system returns the user to FIG. 75, BOX 7500, and the query process continues 7710. If the user does not respond by selecting “4” within a specified period of time, the automated telephone system instructs to user, “To return to the main menu or to enter a new destination, press or say “5” 7712. If the user does select “5”, the automated telephone system returns the user to FIG. 70, BOX 7006, and the query process starts over 7716. If the user does not respond by selecting “5” within a specified period of time, the automated telephone system returns the user to FIG. 70, BOX 7046 and the user is connected to a live Directional Assistance Operator 7718. Now referring to FIG. 78, the automated telephone system instructs the user, “Please dial the area code and phone number of the wireless communications device you want to locate 7800. The automated telephone system then waits a specified period for time for the user to respond by dialing the wireless communications device's phone number the user wishes to find 7802. If the user does not respond within the specified period of time, the automated telephone system instructs the user, “To request a new listing, press or say 4” 7832. If the user does respond within the specified period of time, the telephone phone number is logged into the DAN 8100 and the telephone number is matched against telephone numbers within the wireless communication network's ULD 900, BOX 7804. The DAN 8100 then determines if the requested telephone number is located 7806. Still referring to FIG. 78, BOX 7806, if the phone number is not found, the automated telephone system instructs the user, “The wireless communications device (WCD) you are trying to locate cannot be found at this time. Please record and message for the wireless communications device's user, or press “4” for more options.” If the user selects “4”, the query is forwarded to FIG. 78, BOX 7832, to begin a new query 7808. If the user does not selected “4”, the DAN's voice mail system records the caller's message. The DAN 8100 searches for the wireless communications device periodically. When the wireless communications device is located, the DAN 8100 calls the wireless communications device and plays the recorded message 7810. Again referring to FIG. 78, BOX 7806, if the phone number is found, the automated telephone system tells the user, “We have located the phone number “XXX-XXX-XXXX” 7812. The automated telephone system then tells the user, “For current location of the wireless communications device, press or say “1” 7814. The automated telephone system then waits a specified period of time, for the user to respond by pressing 1” 7816. If the user does not select “1”, the automated telephone system forwards the user to FIG. 78, BOX 7832, to request a new listing. If the user does select “1”, the DAN's geographic database mapping software 8155 criss-cross lat/long geographic database 8150 and then converts the longitude and latitude coordinates provided by the wireless communication network's ULD 900 to a street address format 7818. The automated telephone system then informs the user of the Street address by saying, “The wireless device is currently located at “XXXXXXXX” 7820. The automated telephone system then instructs the user, “To repeat this location, press or say “2” 7822. The automated telephone system then waits for the user to respond by selecting “2” 7824. If the user does select “2” within a specified period of time, the users query is returned to FIG. 78, BOX 7820, in order to repeat the location information. Still referring to FIG. 78, BOX 7824, if the user does not select “2” within the specified period of time, the automated telephone system then instructs the user, “To receive a map of the wireless device's location, or to track the wireless device, press or say “3” 7826. The automated telephone system then waits for the user to respond within a selected period of time by selecting “3” 7828. If that user does select “3” within the specified period of time, the DAN 8100 logs the user's choice and forwards the user's query to FIG. 79, BOX 7900, for further processing 7830. Again referring to FIG. 78, BOX 7828, if the user does not select “3” within the specified period of time, the automated telephone system instructs the user, “To request a new listing, press or say “4” 7832. The automated telephone system then waits for the user to respond by selecting “4” 7834. If the user selects “4” within the specified period of time, the user's query is forwarded to FIG. 70 BOX 7006 to begin a new query 7836. If that user does not select “4” with them the specified period of time, the automated telephone system instructs the user, “To be connected to the Directional Assistance Operator, press “0” or stay on the line” 7838. The user is then forwarded to a live Operator for assistance 7840. Now referring to FIG. 79, the automated telephone system instructs the user, “To have a map and travel plans sent to your wireless device via a page, press or say “1” 7900. The automated telephone system then waits for the user to respond by selecting “1” 7902. If the user selects “1”, the DAN 8100 sends a map and travel plans to the standardization/conversion hardware/software 8160 to convert the map and travel plan to a format which will interface with the protocol of the user's wireless device. The map and travel plans are sent to the user's wireless device via a page and are updated if the user requests an update as traffic conditions change to as to offer a faster route. The user can also be notified when to turn if the DAN 8100 monitors the user's location and pages the user when the user is approaching a turn 7904. Again referring to FIG. 79, BOX 7902, if the user does not select 1’, the automated telephone system instructs the user, “To have a map and travel plans sent to your e-mail address, press or say ‘2” 7906. The automated telephone system then waits for the user to respond by selecting “2” 7908. If the user selects “2”, the DAN 8100 instructs the user to enter their e-mail address via keypad/keyboard, voice recognition, interactive display screen or other. The DAN 8100 then sends a map and travel plans to the standardization/conversion hardware/software 8160 to convert the map and travel plan to a format which will interface with the protocol of the user's e-mail service and navigational program. The map and travel plans are sent to the user's e-mail address and are updated if the user requests an update as traffic conditions change to as to offer a faster route. The user can also be notified when to turn if the DAN 8100 monitors the user's location and e-mails the user when the user is approaching a turn 7910. Again referring to FIG. 79, BOX 7908, if the user does not select “2”, the automated telephone system instructs the user, “To have a map and travel plans sent to your fax machine, press or say ‘3” 7912. The automated telephone system then waits for the user to respond by selecting “3” 7914. If the user selects “3”, the DAN 8100 instructs the user to enter the area code and telephone number were the faxes are to be sent. The DAN 8100 then sends a map and travel plans to the standardization/conversion hardware/software 8160 to convert the map and travel plan to a format, which will interface with the protocol of the user's Fax machine/program. The map and travel plans are sent to the user's fax machine and are updated if the user requests an update as traffic conditions change to as to offer a faster route. The user can also be notified when to turn if the DAN 8100 monitors the user's location and fax the user when the user is approaching a turn 7816. Again referring to FIG. 79, BOX 7914, if the user does not select “3”, the automated telephone system instructs the user, ‘To track a wireless device and have a map of their location sent to your wireless device, e-mail or fax, press or say “4” 7918. The automated telephone system then waits for the user to respond by selecting “4” 7920. If the user selects “4”, the DAN 8100 instructs the user to enter whether the tracking and map information should be sent to their wireless communication device, e-mail, website, navigational system, computer or fax. The users choice can be entered via a keyboard/keypad, voice recognition, interactive display screen or other. The DAN 8100 then instructs the user to input the wireless device area code and phone number, e-mail address, website address, navigational system address, computer address and/or area code and telephone number were the map and location information is to be sent regarding the wireless device being monitored. The DAN 8100 then sends a map and travel plans to the standardization/conversion hardware/software to convert the map and travel plan to a format, which will interface with the protocol of the user's wireless device, e-mail, website, navigational system, computer system or Fax machine/program. The map and location information are sent to the user's wireless device, e-mail, website, navigational system, computer system or fax machine and are updated if the user requests an update, as monitored wireless device travels from one location to another, or from time to time 7922. Again referring to FIG. 79, BOX 7920, if the user does not select “4”, the automated telephone system instructs the user, “To repeat these choices, press or say “5” 7924. The automated telephone system then waits for the user to respond by selecting “5” 7926. If the user selects “5”, the users query is returned to FIG. 79, BOX 7900, to repeat the choices 7928. Again referring to FIG. 79, BOX 7926, if the user does not select “5”, the automated telephone system instructs the user, “To return to the main menu, press or say “6” 7930. The automated telephone system then waits for the user to respond by selecting ‘6” 7932. If the user selects “6”, the users query is returned to FIG. 70, BOX 7006, to restart the query process 7934. If the user does not select “6”, the automated telephone system returns the user to FIG. 70, BOX 7046, to be connected with a Directional Assistance Operator 7936. FIG. 80 is a flowchart describing the operation of the DAN's traffic monitoring software 8125 and routing software 8120. To begin the query process, the traffic monitoring software 8125 and routing software 8120 plots the user's location. If the user is calling from a wireless device, the DAN 8100 queries the wireless network's ULD 900 to retrieve the user's longitude and latitude coordinates. The DAN 8100 then converts the longitude and latitude coordinates to a street address or location. This location is plotted into the traffic monitoring software 8125 and routing software 8120. If the user is calling from a landline within a PSTN 8138, the DAN 8100 retrieves the users location from the PSTN phone location database 8145. Then the DAN 8100 plots the street address provided by the PSTN phone location database into the traffic monitoring software 8125 and routing software 8120 BOX 8000. Still referring to FIG. 80, the DAN 8100 then plots the user's desired destination by cross-referencing and retrieving the destination information from the PSTN phone location database 8145. If the user has entered more than one destination, the DAN 8100 can plot multiple destinations for route planning purposes 8002. The traffic monitoring software 8125 and routing software 8120 them determines a selected number of possible logical driving routes and the distance in miles or meters for each possible route 8004. The traffic monitoring software 8125 and routing software 8120 then examines the movement of wireless devices that are traveling the possible logical routes to determine average speed or number of wireless devices on the possible logical routes 8006. The traffic monitoring software 8125 and routing software 8120 then calculates the estimated travel time for each route in order to determine the shortest possible travel time. Routes are considered in order of miles/meters from shortest to longest. The basic formula to obtain the travel time for a possible route is as follows: Distance(miles/meters)×Average Speed (Miles/Meters Per Hour)=Route Travel Time This is the basic formula, but other formulas may be entered into the traffic monitoring software 8125 and routing software 8120 to include such things as number of wireless devices on a route, weather conditions, posted speed limits, train schedules, road work, road closures, historical average speeds based on time of day/year, etc. 8008. The traffic monitoring software 8125 and routing software 8120 informs the user of the shortest or fastest route (as per their request) and sends the travel plan and map to the user if requested, in the form the user requested (Page to wireless device, e-mail, fax, etc.). If the user has requested to receive updates, the traffic monitoring software 8125 and routing software 8120 monitors the users location and informs them of faster routes, when to turn, and other requested items 8010. Detailed Description of the Preferred Embodiment The directional assistance network (DAN) 8100 is a machine and process that provides a dynamic location routing system and directional assistance to an entity though a variety of remote methods. One objective of the DAN 8100 is to provide a means for an entity to request mapping, voice, or other methods of directions that would give the said entity directions from entity's current geographic location to entity's target location. The routing system allows a. plurality of devices to connect to the DAN 8100 and request directional assistance to a plurality of target locations. The claimed entities could exist as a: Wireless device user Land line phone user Internet (world-wide-web) user Intranet user Non-human element such a software package Voice-over IP network user Dial-up user Other user selected entities The geographic location based technology would allow the said users to be routed along a path that would take the most direct or most timely route to the user's selected destination. For example, a user of a wireless device could query the DAN 8100 for a display of the user's current location on a street map, and the fastest driving route to the user's place of employment, based on current traffic conditions, distance, and other user defined attributes from available sources. The routing software 8120 within the DAN 8100 facilitates this process. The routing software 8120 allows a discrete computational analysis of traffic conditions based on recorded data from a plurality of sources. Current day realizable sources of this information are: data sampling from a wireless network, live national traffic alert databases, local traffic database entries, traffic cams, traffic radar gun” database, direct user input, or other available sources. The DAN 8100 also comprises traffic monitoring software 8125 that monitors traffic conditions in real time by, for example, tracking the movement of a plurality of wireless devices to determine the location of slow moving traffic. The routing software 8120 uses the traffic monitoring software 8125 to determine routing information, in order to provide directional assistance. This directional assistance is deliverable to the above listed entities. The user can select routing information based on the following: Time to destination Distance to destination Alternate routes based on ‘way points’ set by user Scenic routes (pre-programmed scenic information comprised within a criss-cross lat/long geographic database 8150) Routes bases on probability of reaching a destination within time constraints Routes to alternate locations of similar interest (Hospitals, etc) Routes based on user preferences established in a local preferences database. The first step of the routing software's 8120 is to retrieve the current geographic location of the requesting entity. The DAN 8100 retrieves the users current geographic location using the device location software 8115. The device location software 8115 allows the location of a wireless device, (and-fixed, Internet, or other user defined entity to be obtained. The device location software 8115 has the ability to query external sources for information. In the case of a wireless network, the device location software 8115 would analyze wireless network parameters and data at the base station controller (BSC) 206 or the MTX 130 for call information to determine the location of a wireless device. An additional technology that would allow rapid access to this data would be a dynamic database or system designed to store and hold information including latitude and longitude of the said wireless devices. The supporting databases required for the above claimed software to function include a criss-cross lat/long geographic database 8150. The crisscross at/long geographic database 8150 contains latitude and longitude information correlating to actual street locators, such as a directory of listings of business and residential address locations and contact information. Scenic locations, hospitals, and other ‘categorized’ locations could be extrapolated from this database. The geographic database mapping software 8155 controls the criss-cross lat/long geographic database 8150. The geographic mapping software 8155 allows multiple simultaneous requests, and is responsible for both resolving addressing information to latitude/longitude coordinates and resolving latitude/longitude coordinates to addressing information. To effective processing, the external connections to the criss-cross lat/long geographic database 8150, and primary logic software 8101, can utilize an ATM type packet routing. The ATM type pocket routing will allow very fast switching times and transfer speeds. To allow the entities to access the claimed primary embodiment, the DAN 8100 contains two similar software packages. The first software package is the voice interface software 8105. The voice interface software 8105 allows the user to access the functionality of the DAN 8100 via the human voice, To interpret the voice signal of the user, the voice interface software 8105 works with the voice mapping software 8110. The voice mapping software 8110 interprets voice signals from the user (spoken words) and converts the voice signals into data inputs for the voice interface software 8105. The voice mapping software 8110 allows the user to walk through a series of menus and input information. Menus such as “press 1 to spell or say the name of your destination” will be synthesized and presented to the human user. The user can then respond using their voice, “Hospital”. The voice mapping software 8110 would then resolve the spoken work “Hospital” into a data representation of the term. In addition, the voice mapping software 8110 allows target location information to be resolved into a data-formatted address that can be used along with the routing software to route directions, The next software component utilized by the DAN 8100 is the data interface software 8130. The data interface software 8130 receives input data in a usable format. The data interface software 8130 simply parses the supplied data and passes it to the DAN's 8100 primary logic software 8101. The external DAN query interface software 8135 allows external connectivity to the DAN 8100. The external DAN query interface software 8135 adapts and standardizes the many different physical interfaces and protocols that connects with the DAN 8100. The package is very important because it needs to be able to support many sophisticated entities that connects to the DAN 8100. The entities supply data in many different ways. These external connections to query devices 8140 can be: Physical Data connections (Ti, DCI, etc) Telephony connections Wireless network connection Direct Dial-up connection Data Formats SQL database entries Scripting Unformatted raw ascii text Formatted text WAP text entries Data Interface Protocols ftp http telnet dial-up direct-connect SMS The external DAN query interface software 8135 takes these external sources and formats the data stream that both the data interface software 8130 and the voice mapping software 8110 use to retrieve information from external sources. The DAN 8100 also includes the standardization/conversion hardware/software 8160. The standardization/conversion hardware/software 8160 is listed under the previously referenced provisional patent. The standardization/conversion hardware/software 8160 functions under a singleinput/single-output (SISO) type control structure, where a single input results in a single output. The standardization/conversion hardware/software 8160 receives a command from one protocol, and outputs the correct protocol to the receiving machine. The standardization/conversion hardware/software 8160 receives a command from an external network connection 8165 or from the primary logic software 8101. The standardization/conversion hardware/software 8160 first checks the received protocol against a pre-configured protocol, and then checks known types of protocols by querying an internal protocol database. If there is a matching protocol found within the internal protocol database, then the standardization/conversion hardware/software 8160 the appropriate protocol by checking the receive protocol list. The standardization/conversion hardware/software 8160 then determines if a conversion can be made. If the standardization/conversion hardware/software 8160 can convert the protocol command, then the command is sent to the connected device. The standardization/conversion hardware/software 8160 waits for another command. If any of the decision boxes are “no” than an error is recorded and send back to the sending source. The standardization/conversion hardware/software 8160 differs from the external DAN query interface software 8135 in that the DAN 8100 utilizes the standardization/conversion hardware/software 8160 to connect to networks or other devices and retrieve information used by various subroutines. The general example would be for the DAN 8100 to query a wireless network's MTX 130 and then BSC 206 to retrieve user information. Controlling all the software and hardware of the DAN 8101 is the primary logic software 8101. The primary logic software 8101 generates and processes the usage and pure control commands. Data storage is also part of the primary logic software 8101. The primary logic software 8101 must be able to process a large volume of external requests and processes created by entities requesting geographic routing information. The recommended physical architecture that the DAN 8100 would reside in a hardware that could supply enough bandwidth, memory, physical storage and processing ability to respond to an entities geographic routing request in a reasonable amount of time determined by a customer. The location that the DAN 8100 could exist can be any of the following: At a wireless switching office At telephony switching center/PSTN Located on the interne (with some static/dynamic range of IF addresses) In alternate embodiments where the DAN 8100 is located at locations other than a wireless network, additional equipment will need to be located at a wireless switch. The DAN linking software 8300 allows remote queries of the wireless switch. The DAN linking software 8300 connects to the e-mobility services 144 that links to the MTX 130. The DAN linking software 8300 includes the interim linking software 8515. The interim linking software 8515 negotiates and retrieves data from the MTX 130 or the BSC 206 components of a wireless switch. In addition, the DAN linking software 8300 includes packet routing software/hardware 8520 that allows packets to be passed from wireless devices (the WAP/e-mobility connections) to the DAN 8100 that is remotely located. The DAN linking software 8300 also includes the DAN data query software 8525 to manage the methods used to query the local wireless networks hardware/software. Routing Methodology to Obtain Directions for Requesting Entity When an entity connected to the DAN 8100 requests directions to an address or location, the DAN 8100 must have access to data sources that gives the location of the wireless device and the target location. The following are examples of data sources for obtaining this information: User location database (ULD)—containing mobile device location information 900 User location database coordinator (ULDC)—Containing ability to query multiple ULD's 908 Direct query of MTX 130 or BSC 206 for location of wireless devices Location information calculated by GPS at/in the wireless device Public addressing database containing addressing for location queried by wireless device. PSTN Database with a correlated latllong information for a fixed device, 8145 Location information sent from the querying device to the DAN 8100 When a wireless device requests directions to a location the following steps to carry out this process: The DAN determines the wireless devices current location in terms of latitude/longitude and converting to postal addressing relative to roadways. The DAN then determines the location of the target The DAN then calculates the route to the target through current streets and roads The DAN 8100 determines the wireless devices' location with the use of the criss-cross lat/long geographic database 8150, latitude/longitude coordinates obtained by GPS systems on the wireless device, a location retrieved though a ULD 900 or ULDC 908, or similar device that calculates the current location. The criss-cross lat/long geographic database 8150 can convert either an address to a latitude/longitude coordinate or a latitude/longitude coordinate into an address. After obtaining the location of the device in latitude/longitude coordinate form the information is processed and converted to standard addressing. Next, the DAN 8100 determines the target's location. The target location address could be resolved by querying a public addressing database for known locations. If the target location is another wireless device, the location would be retrieved though a ULD 900, or ULDC 908, or by querying the MTX 130 and/or the BSC 206 controlling the target wireless device, then converted to a standard address by the criss-cross lat/long geographic database 8150. Next, the DAN 8100 determines the most efficient route to the target address. While current commonly known software can accomplish this task, it is limited to resolving routes based on: Shortest distance (miles/Kilometers) traveled Time to arrive at destination User sensitive settings such as scenic routes What the commonly used software lacks is the ability to compensate for current road conditions (traffic jams, weather, etc). The DAN 8100 has the ability to resolve routes using information obtained from a wireless network or from other traffic databases, to determine the fastest route in units of time or distance. The routing software 8125 initially determines the route using commonly known methods, but then uses a unique and new method to check the level of traffic congestion along the route. The level of traffic congestion can be determined from either gathering information from traffic databases or from obtaining the location of devices on a wireless network. To gather the location of devices on any given segment of a road or route, data can be gathered from a MTX 130, in combination with a ULD 900 or ULDC 908, or direct query of the MTX 130 or the BSC 206. The information obtained from the ULD/ULDC/Direct Query includes the following: Number of wireless devices on the route calculated to target location Location of wireless devices on the route calculated to target location Current state (active/standby) of wireless devices along calculated route The routing software 8120 uses the route wireless device information to determine the congestion of the route. The congestion is measured by the following calculations. First, the location of the wireless devices is correlated to locations on the route. Next, the velocities of the wireless devices are calculated. The velocity is calculated by sampling the location of a device at fixed time intervals. The routing software 8120 then compares the velocities of the devices to the posted speed limits along the different segments of the route. The comparison measures the traffic flow and validates the devices that are in the traffic route and not on a sidewalk or other close area. In addition, the routing software 8120 calculates the wireless device geographic density along the route. Average and normal density would be calibrated depending on the size and attributes of the road. For example, a larger road would have a different average density than a smaller road. A multilane highway would have a different average density than a two-lane highway. The average values for wireless device density on roads would have to be adjusted for various road attributes. The routing software 8120 evaluates the current levels and compares them to the average value. After the routing software 8120 calculates the traffic density measurement, the routing software 8120 evaluates the traffic conditions along any given route. The routing software 8120 compares the calculated traffic density to a predetermined normal level. The comparison is described by the following: Dr=Dc/Dn, where Dr=density ratio, Dc=current density, and Dn=normal density. Using this formula, the density ratio for any traffic condition is calculated. For example, if a current traffic density of a geographic region is 100 units/distance, and the normal density is 50 units/distance, then the density ratio would be 2. The density ratio corresponds to 2 times or 200% more traffic than the normal traffic density for that area. The equation that determines the time it would take to cross a geographic segment is defined by the following formula: Time=α×eDr*β where α is an experimentally determined scaling factor that a network engineer can tune, and β is the normal time to cross the geographic segment. From this formula it is apparent that when is adjusted the time can be linearly scaled by the traffic engineer. It is also apparent that when the value of D changes that the Time changes exponentially. This should make since b/c as traffic increases, the time does not increases linearly For example, when Dr is 2 (2 times more or 200% the normal traffic) the time to reach the destination is not double the time, but less than that amount of time. Using the formula you can see the affects of the values of Dr and in FIGS. 86 and 87 respectively. After the time calculation is computed an adjusted travel time for the segment is sent to the routing software. Alternate routes based on normal traffic travel times are then send and run through this algorithm. When the route with least time based on actual traffic conditions is found, the DAN 8100 locks the route as the best traffic route. Each segment of the route is completed in this method. The result is a complete route from the origin of the device to the destination that allows for the quickest travel based on time. The DAN 8100 then sends the resulting route to the wireless device and the wireless device displays the route to the user. The user can then travel to the location. If the user desires, the software can continually monitor the route and alert the user to changing road conditions and report route corrections to the previous calculated directions. The user can then take additional detours to further speed the time or distance to the route. If the user requests directions to a wireless device on the wireless network, the calculated route would obviously not be a static route. The DAN 8100 would continuously update the route as required. The route could be calculated based on the route taken by the wireless device being tracked, or by simply using the method above to determining the fastest route to the target. The current state of the tracked wireless device would be taken into account. If the tracked wireless device were in an active state, then the route would update continuously. However, if the tracked wireless device is not active or if current location information is not available, then the route would not update, and the DAN 8100 can calculate the route using the last known location of the wireless device. The DAN 8100 would relay the tracked wireless device state to the requesting wireless device. Alternate Embodiment to the Directional Assistance Network The primary embodiment refers to a system that users on a plurality of devices (wireless/fixed location) may obtain directional mapping from their current locations. The DAN 8100 can also be implemented by an alternate method. The alternate method would include directional mapping databases and software integrated into its system. The method would not take into consideration traffic density and other variables that would affect directional routing. For the alternative method to work the wireless device would need to contain a map and a latitude/longitude referenced database of target locations. The databases could be cities, metropolitan areas, states, countries, or other variable sized geographic areas. The map would need to contain information on the current location of the wireless device. The wireless device could obtain the current location information from the device itself using GPS or from the wireless network. The database would need a large storage medium that could be created on a plurality of mediums including but not limited to: Hard Disk Micro Drive Optical Storage Medium (CD/DVD/etc) Flash Memory Device Memory Card EPROM EEPROM Removable Storage Medium The alternate embodiment requires the wireless device to have the ability to locate a destination based on address, company name, landmark, etc. If the wireless device cannot find the destination in the internal database, the wireless device queries the wireless network for the destination information. The wireless network server resolves the request. When the network server finds the destination information, it sends back the latitude and longitude of the destination to the requesting wireless device. The wireless device stores and appends the destination information with the latitude/longitude in the local database for subsequent path resolution. If the wireless network server does not find the destination, then the wireless device alerts the user that the device could not find the destination. Advantages of the alternative embodiment are the user will be able to: Obtain faster routing information Not inquire a connection cost Not require an active connection to the network To allow faster routing, the wireless device can query the wireless network server for traffic congestion information. To allow faster routing of the wireless device in regards to time to the destination or for multiple waypoints and then a destination, a query to the server could be requested if a network connection is available. This would allow the network to access traffic databases that contain information on traffic congestion along a route to be analyzed. Each segment of a route could be analyzed and assigned a numerical figure representing the expected amount of time to travel through the segment. The routing at the server could then send corrections to the device and make alterations to the routing information to improve the results given to the user. The connection to the network by a device would require any, but not limited to, the following connections that could be resolved and eventually routed to TCP/IP or other I routing protocols: TCP/IP Network Connection IPX/ULD PPP/SLIP Wireless Networks 2G 3G 2.5G GSM TDMA CDMA CDMA2000 Direct Connection To make the computations the wireless network the following are required: a database of a plurality of geographic locations with addressing correlated to latitude and longitudes; software to determine the time to travel on a given route; logistic software to determine a faster route; interface with the requesting software. The logistics software works by accessing traffic condition databases not claimed by this patent. The basic requirement of the databases is to return information that corresponds to the traffic density of a roadway or other geographic location. When the logistics software acquires this information, the software compares the current traffic density to a predetermihed normal level. The resulting route can then (after being calculated) be sent to the wireless device or may already exist there and will not need to be updated in this case. The route will then be graphically reproduced or printed as text and displayed to the user. The user can then travel to the location. Description of Figures FIG. 81 FIG. 81 describes the structure of the DAN 8100. The figure shows the DAN 8100 with all the components logically connected. In addition, the figure illustrates the connectivity of the DAN 8100 to external sources. The figure also illustrates other devices internal to the DAN 8100. The DAN 8100 contains two external connectivity points. The tandardization/conversion hardware/software 8160 connects to an external network connection 8165 and connects the DAN 8100 to friendly networks used to obtain additional data. The external directional assistance network query interface software 8135 connects to external connections to query devices 8140. The connection point connects to devices/entities that can remotely query the DAN 8100. Both the standardization/conversion hardware/software 8160 and the external DAN network query interface software 8140 interface with the primary logic software 8101. The primary logic software 8101 handles the primary control and processing for the DAN 8100. The primary logic software 8101 controls the interaction between the different internal components and external interfaces, and processes all requests by the different components. The data interface software 8130 and voice interface software 8105 allow interactivity to external entities accessing the DAN 8100. Both components interface with the primary logic software 8101. The voice interface software 8105 utilizes the voice mapping software 8110. The voice mapping software also interfaces with the primary logic center 8101. The routing software 8120 component interfaces directly with the primary logic software 8101. The routing software 8120 utilizes the traffic monitoring software 8125. The routing software 8120 utilizes the device location software 8115 indirectly. The device location software 8115 interfaces with the primary logic software 8101. Any access of the device location software 8115 must be done through the primary logic software 8101. The database attached to the DAN 8100 is the criss-cross latllong geographic database 8150. The geographic database mapping software 8155 controls and interfaces with the criss-cross at/long geographic database 8150. Both of these components interface with the primary logic software 8101. The primary logic software 8101 also interfaces with the PSTN phone location database 8145. FIG. 82 FIG. 82 illustrates the primary embodiment of the invention; the DAN 8100 co-located at a wireless network. FIG. 82 displays devices that interact with the DAN 8100. Wireless communication device 8205 connects to cellular towers 8235, Via Ti/other connection links 8232 from the BTS 108, the wireless communication device 8205 connects with the cellular base station controller (BSC) 206. The BSC 206 links 8227 to the MTX 130. The MTX 130 links to the e-mobility services 144. The e-mobility services 144 links to the DAN 8100. The user location database (ULD) 900 and the wireless communications device location software 8270 also connect to the MTX 130. The MTX 130 links to the packet data network (PDN) 156, and to an internet gateway, 8255 and finally to the Internet 8260. The MTX 130 also links to a publicly switched telephony network (PSTN) 138. The PSTN 138 contains the PSTN phone location database 8145. The PSTN 138 connects to fixed location phones 8220 via land lines 142. FIG. 83 FIG. 83 illustrates the primary embodiment's alternate location; the DAN 8100 located remotely via the Internet 8260 at a remote server. FIG. 83 displays devices that ultimately interact with the DAN 8100. Wireless communication devices 8205 connect to cellular towers (BTS) 108. Via Ti/other connection link 8232 from the BTS 108, the wireless communication devices connect with the base station controller (BSC) 206. The BSC 206 links 8227 to the MTX 130. The MTX 130 links to the packet data network (PDN) 156 that links to the internet gateway 8255. The internet gateway 8225 links to the Internet 8260. The DAN 8100 interfaces 8310 the wireless network through the Internet 8200. The ULD 900 and the wireless communications device location software 8270 also connects to the MTX 130. The MTX 130 links to the e-mobility services 144. The e-mobility services 144 links to the DAN linking software, 8300. The MTX 130 also links to a publicly switched telephony network (PSTN) 138. The PSTN 138 contains the PSTN phone location database 8145. The PSTN connects to fixed location phones 8220 via land lines 142. FIG. 84 FIG. 84 illustrates the DAN 8100 remotely located at the PSTN 215. FIG. 84 displays devices that ultimately interact with the DAN 8100. Wireless communication devices 8205 connect to cellular towers (BTS) 108. Via Ti/other connection link 8232 from the BTS 108, the wireless communication devices 8205 connect with the wireless base station controller (BSC) 206. The BSC 206 links 8227 to the MIX 130. The MTX 130 connects to the PSTN 138 and then to the DAN 8100. The PSTN connects to other remote PSTN switching centers also. The PSTN 138 contains the PSTN Phone Location Database 8145. The PSTN 138 connects to fixed location phones 8220 via land lines 142. The MIX 130 links to the e-mobility services 144. The e-mobility services 144 links to the DAN linking software 8300. The user location database (ULD) 900 and the wireless communications device location software 8270 also connect to the MIX 130. FIG. 85 FIG. 85 illustrates the DAN linking software 8300 used by the DAN 8100. The DAN linking software, 8300, allows the DAN 8100 to interface with wireless networks, when it is remotely located. Wireless communications devices 8205 send requests to the DAN 8100 signals via e-mobility services, 144. The interim linking software 8515 receives the signals and routes them to the packet rerouting software/hardware 8520. Packets are then routed to the remotely located DAN 8100. The DAN data query software 8525 connects to the interim linking software 8515. The DAN data query software 8525 allows the DAN 8100 to remotely pass queries to the MTX, 130, which via the e-mobility services 144. FIG. 86 FIG. 86 shows the Traffic Time Calculation Performance Based on user or network-defined variables. The figure shows the alpha, an experimentally obtained scaling factor, on the traffic density-time algorithm. The network engineer determines the value of the variables. As shown, the effects of alpha are linearly proportional to the output of the algorithm. So an increase in one variable proportionally affects the output of the equation. FIG. 87 FIG. 87 shows the traffic time calculation performance based on a variable traffic density ratio. The effects of Dr, the density ratio is shown to produce an exponential result for the expected time to travel on any given route. When the traffic density compared to the normal density level increases, as expected the time to travel along that route increases exponentially as well. Pro-Active Traffic Routing System Overview The traffic control system allows network traffic engineers to optimize traffic flow in real-time based on feedback from systems such as the DAN and the LTS. Both of these system poll on data from other resources such as the ULD/ULDC and GPS data from mobile devices. The location tracking system allows network software located (physically or virtually) at the MTX to access information on the movement of mobile devices on a cellular network. These moving devices, tracked by the LTS, can be filtered to include only devices on roadways, which is of interest and is used by programs such as the DAN to route users from one location to the next allowing them to avoid traffic congestion. This congestion is based on mobile unit density on the roadways. Of interest to the traffic control software is the density of traffic along roadway section that have various traffic control devices that can be altered remotely. Altering their parameters would allow traffic flow to be altered and ease congestion. Automating this process, the traffic control software would, in real time, allow traffic congestion reduction over many roadways that otherwise would take much longer to implement. These changes are based on various methodologies described in the following text. Additionally, basic software architecture for such a system is recommended, but does not limit the spirit of this invention. Traffic Control Devices To discuss the ability to monitor or control traffic flow, the devices that control this factor should be discussed. Not all devices that control traffic flow can be remotely controlled, and thus cannot be used by the traffic control software. The devices that can work in this system will be listed and discussed in broad terms, as to allow them to apply to many design n a generic sense. Particular devices may be extruded from these descriptions and easily adapted to any specific setup. The following generic devices are usable for the traffic control system: Intersection Traffic Control Lights Highway Inlet Traffic Control Lights Variable Speed Limit Roadway Signs Intersection traffic control lights are defined as those lighting systems that include roadway intersection of two or more roadways at a single point, with a lighting system that directs what road way should cross at any given time. Variables that are affected here are the length any roadway may go cross the intersection, and the length of a turn lane being able to direct traffic from one lane to the next during that cycle. Highway inlet traffic control lights are a simple way to moderate and control the inlet of traffic onto major roadways. These roadways are typically one directional and the inlet is also one directional. The lighting system is usually an on/off system. A red light moderates traffic by allowing one car though at a time, and then stopping the next car for a time limit, then allowing it to pass and enter the highway. The control variable is the hold time between letting cars though. Variable speed limit roadways signs are signs that can alter posted speed limits based on a remote signal. The speed limit can be controlled remotely thus allowing the posted limit to change and thus control the flow of traffic. The variable here is the posted speed limit. Detecting Traffic Congestion Traffic congestion that can be alleviated by a controllable traffic control device must exist at the geographic site of the device. In other words, a device cannot alter congestion for which its function plays no role. The congestion must be co-located at the devices location, or in its field of control. Many devices have a range of control. The specific devices must have their characteristics programmed into the software. These characteristics include range and in what direction, that the device affects flow control. Also, the flow control depends on the type of device. To detect the traffic congestion the traffic control software must know the location of each device. The system must then know the range and direction to monitor for congestion. These characteristics, as described above, will allow a profile to be sent to the LTS for each device. The LTS can return the traffic density and average velocity of the mobiles in this region. This information will show the levels of congestion. There should be limits at which the system will modify default values. It should not be necessary to modify the defaults if there is little congestion, as it would result in little or no change to the roadway traffic. More specifically, for a generic system, the traffic can be monitored in all indicated directions for the defined distance for each. Some default traffic density value should be defined for all directions. Some speed value for traffic can also be assigned. Four possible methods of congestion can be used. The first is to use the system in the DAN. The second is to look at the average velocity of the devices on a roadway. The third is to look at the density of the mobile devices against some default value. The fourth is to look at both the density and the velocity of the devices. Using the forth method, a formula such as multiplying the average speed and density together to result in a number could allow a basis for more accurate congestion detection. Again a default value could be defined as to indicate when it is exceed that traffic congestion is bad. An additional value that indicates the severity of congestion could be the percent that the roadway is congested over its default value. These methods should be chosen based on need and function on any particular design. Further in this description, it will be implied that this method results in two categories, pass and fail. Pass is that the threshold is not met and normal traffic exists. Fail indicates that the limit has been exceeded and the traffic is above tolerable limits. Described as follows are methods to control and alleviate congestion based on device type. Methodology for Alleviating Congestion Various methods are needed based on the type of traffic control device. Described for each classification of device, are the methodologies to reduce congestion. Intersection Traffic Control Lights The congestion of traffic control lights should be monitored in the direction of the lighting system along the intersecting roadways for a reasonable distance. This distance can be defined and included in software programming, but a typical value may be 50% of the distance to the next intersection controlled by a traffic control light. This value could vary from one traffic lighting system to the next. The system should start by analyzing traffic congestion along all roadways at the intersection. The roadways should then either be classified as pass or fail. All fail roadways should have a percentage calculated that indicates the amount over the default value that they are congested. To alleviate the traffic, the roadways that are above the limit should be placed in order of descending percent over-congestion. The most congested roadways should have the timing adjusted such that they are allowed additional time on the crossing direction of the intersection. This would represent a longer green light. This would also scale the turn signal direction. The time increase could be proportional to the percent over-congestion. The second, and descending congestion roadways could function in a similar manner, but give less than the same increase. The roadways with no congestion would have the time crossing decreased. One additional factor is the time to cycle between all roadways (green light offered for every roadway in intersection). This should increase by some defined amount based on the number of congested roads. There should be a limit though programmed into the software. All timings for individual directions should sum up to this time. To accomplish this, it would be necessary to decrease the total time allowed for crossing on the non congested directions, when and increase occurs in the congested directions. Note, that if no directions are congested, then no changing in timing occurs. Highway Inlet Traffic Control Lights This system is relatively simple and is based on the ability of the traffic control system to use the LTS to determine only the traffic density of the roadway that the inlet lets into. The density should examine the average density along the roadway, again using some distance defined for the inlet control device. The period that the device allows cars to pass is inversely proportional to the density of the traffic along this distance. A set of criteria should be established that would adjust the timing for various densities. Lesser densities mean more cars per unit time can safely enter the highway. The converse is similarly true. These exact timings depend on particular roadways and should be unique to every device and configured initially based on field experiments. Below is an example that demonstrates these criteria for a generic system, using generic values: Traffic Density Inlet Entrance Rate 10 cars/100 m 20 cars/minute 20 cars/100 m 15 cars/minute 30 cars/100 m 10 cars/minute 40 cars/100 m 5 cars/minute Variable Speed Limit Roadway Signs This is a method very similar to above, but is mainly a safety feature that can reduce the possibility of an accident, and thus the primary case for traffic delays, roadside accidents. The system is inversely proportional to traffic density as above. The system should poll the LTS for device density for a distance defined for the specific device. The speed then should be adjusted to levels that are safe for various traffic densities. As cars are closer together, the safe speed limit decreases. Various brackets of speed to indicate for various ranges of traffic density could be defined and integrated into the software. The traffic control software than can automatically adjust the speed values based on traffic density. Basic Software Requirements The software architecture of this system is designed so it can be collocated at the MTX or virtually hosted elsewhere but assessable to the MTX. The software should have access to the LTS and have subroutines written to allow it to submit tracking queries to the LTS to determine traffic density and other necessary factors. The system should be designed to have an administrator's option to enable and disable the system and any particular devices. The system should allow a device to be added and all its parameters added as well. As each device is added, a device ID can be associated. This device ID would allow each device to be distinguished among each other. The system could then send electronic signals to the devices though direct or indirect routes to modify parameters on each device. These routes can be custom design or pass over public or private networks that connect the two points. The devices and their modification methodology are not the focus of this patent, however these devices are commonly known technology and software can easily be integrated into this that allows remote control to occur. Call Routing System Overview The call routing system allows a user to have calls that are intended for the users mobile device, routed to alternate location, based on the current location or the device and its proximity to the said alternate locations. The user has the option to supply the phone numbers of devices that the user would like it devices to auto-route incoming calls to when the user is near those locations, and when the feature is activated. The user also submits a geographic distance from the device that when the user's device enters into, will activate the routing feature and allow the user the option of having its calls routed to the new device (user is asked if the new location, is acceptable for routing by SMS or similar 2-way message from server). When the user exits the region near the device (as listed in his preferences) the system again asks if the user wants call to be routed back to the users mobile device. If the user has no devices near them, a feature also allows nearby public devices to be offered to the user as alternate locations for routing. The call routing system also allows for outing call routing which allows a user, service provider or manufacturer to route outgoing calls to selected phone numbers based on the location of the wireless device. For example, if a user dials “911” for emergency services, the call will be routed to the closest “911” call center, based on the location of the wireless device. An other example of the outgoing call routing system would be a user accessing the internet. When the user dials to connect to the internet, her call may be routed to a local internet access number based on the location of the wireless device. This outgoing call routing system will enable a user of a wireless device to optimize the use of his wireless device by receiving better service at a lower cost. System Design and Function For the routing system to function, the system must deploy its software at the MTX of a cellular provider. An alternate location on a intranet or internet is possible, but would require the MTX to link to that service and transport method. The software would rely on a service such as the LTS to allow monitoring and tracking of mobile devices. It also requires a database of user preferences that include: routing numbers and distance from routing numbers to activate routing. Authentication and other system level information for users should also exist. A plurality of users may activate the system, and the system will function for all active users. The LTS acts as an cooperative program that helps the current embodiment in many ways, as listed below. This software requires the flowing methods and function as listed below to be carried out to function properly. Determining Location of User To allow the system to operate the user of a mobile device must have his or her devices location monitored by the network. To do this, various methods exist such as the directional assistance network (DAN). The DAN allows a device to be monitored for location and additionally allows system events to be triggered based on the location of the device. The main requirement is that the location of the device be stored in a database or other location such that an external program can queue this information. A possible way to implement this is to use a User Location Database or a User Location Database Network. Other methods would be direct querying of the MTX or BSC to determine the location of a said mobile device, or a mobile device equipped with location information such as GPS or triangulation. Determining Phones Near to User To determine the fixed phones near a mobile device the system must first obtain the location of the said mobile device. When the system, using any of the above methods as further explained in accompanying documentation (on LTS, ULD, ULDC), has acquired the devices location, it stores it to a temporary register (software variable). The system must then check the user preferences, as stored in a local or remote configuration file, to determine the routing protocols. In this case, it must check the configuration to see if the user has indicated a phone number to route calls to. If no number exists then the system can attempt to route the call to any public telephone device in the vicinity. Routing to a private phone system would also be possible, but security and privacy concerns would hamper this. But for completeness, the methodology here applies to all cases. If the system checks the configuration and no devices are listed, or no devices near the mobile device (near implies a distance parameter that is in the configuration file) exist, then the mobile devices can be sent a message alerting the user that private devices were found. If this is the case, then the user can reply with three options: Route to nearest public device Route to new private device (user must enter new device ID) Turn off Routing Determining Public Phones Near to User The user has the option to have the call routed to the nearest public device. If the user chooses this option than the system would query the PSTN and retrieve all public phones within the following parameters. The system currently would have the geographic location of the mobile device. Using the PSTN's public phone network database it would query for a list of devices within the mobile devices telecommunication sub-region. These sub-regions are determined by the telecommunications company, and having indicated a particular region, the system can then retrieve all public device phone numbers. Having done this, the phone numbers can then be submitted again to the PSTN to resolve their addresses. Using commonly known techniques the system can then calculate the distance form the user (user's device) to the public phone(s) retrieved from the PSTN. The nearest device would then be chosen. This device and its address would then be sent to the user via the messaging capability of the phone, possible using wireless internet or other e-mobility techniques. The user may accept or reject the location. If the user accepts the location then the user would have calls that were routed to his mobile devices, rerouted to the public device. If the user rejects the location, subsequent locations based on distance can be presented (closest to furthest). The user may again either at any time, add a private number, accept the public location, or turn off routing. Determining Fixed (Private) Phones Near to User If the user has entered a list of private numbers in the configuration file, or adds a private number when no device in its proximity is found, the system can apply a simpler technique than above. The system can use the features of the LTS to its advantage by setting alert modes. These alert modes will be to create a custom tracking criteria for the device. The tracking criteria would be to create circular regions with a radius found in the configuration file, and instruct the LTS to alert the program when a user enters/exists these regions. Thus two options can exist when a user activates tracking: a user turns on tracking while in a region, a user turns on tracking while not in a region. If the user is not in a region then the system will not receive a message from the LTS, it can then as above, ask the user if they wish to search for a public device. A second option should be to allow the user to disable public device searching. Thus, a user may not be near a routable location (based on locations in a configuration file) but when a user does enter a region, the system will be alerted by the LTS. When the system is alerted of a user entering a specific region near a listed private phone, then the system will route calls to this device. Conversely, when the user exists this region, the LTS will again notify the system and the users calls will not be routed. As before with the public system, the user (user's device) will be sent a message to ask if routing preferences should be changed. The user can chose to accept new routing or decline it. If routing is declined, then the system will ignore the LTS alert when the user exists the region of the private line. It should however then receive the alert when a user enters another private device region and again prompt the user. Determining Mobile Phone Near to User When in the above case a user places in his configuration, or when prompted to add a private device (via a message sent to the mobile device), a routing destination that is itself a mobile device the system must add another subroutine to handle this. The procedure above for a private fixed land phone is the same until the location for the device at the PSTN is queried. At this point, the PSTN would return a result that indicates that the device is a mobile phone. The PSTN would also indicate the service provider for the device. With this information there are 3 different ways to obtain the location of the device. The first approach is to use the ULDC network to retrieve the devices location. A second, is to query the service provider (possibly the same service provider as the active user) through a cooperative data sharing agreement and retrieve the mobile location on a ULD. The third option is to directly query a BSCIMTX for information to resolve the mobiles location. When the tracking system is activated, all number indicated to be mobile numbers will require the system to periodically refresh the location of the devices. This time between refreshing can be configured by a system configuration parameter. When the device is refreshed, a new tracking criteria will be submitted to the LTS and the old criteria deleted. Besides these alteration, the system works just as it did for the land fixed device routing. System Routing Change When the mobile device has a new forwarding location the system then forwards this new phone number to the routing ability function of the cellular network. This allows external requests from outside the MTX (incoming calls) to be forwarded to a new number supplied from the current embodiment. Methods to Alert User of Device of Routing Information Many methods in current software and hardware designs of cellular networks exists to allow 2 direction communication from a software program on a MTX/lntranet to communicative with a mobile device. Methods which exist now that can accomplish the necessary tasks are: SMS Wireless Internet WML Proprietary Software These methods would require the user to respond in some cases. The system would then receive a response from the user, which would contain the users phone ID thus allowing the system to route the response to the particular mobiles preferences and routing queues. Geographic Advertising System Summary The geographic advertising system (GAS) is a geographically based advertising system which enables the delivery of targeted advertising to and from wireless device users based on their geographic location. GAS monitors the movement of wireless users via monitoring hardware and software connected to a wireless network or user location database, and when a wireless device meets a certain criteria, the wireless device user may by targeted for an advertising solicitation. For example, a user of a wireless device who has traveled outside his home calling area, may receive a text message on his wireless device telling him of a discount on a hotel room in the area. A business initiated solicitation to a wireless device may be triggered by: Distance between wireless device and soliciting business Location of the wireless device's home calling area Demographic information (age, sex, race, etc.) Historic travel patterns If wireless device is currently geographically located at a particular location (For example, shopping at the competition's store) Other defined criteria The solicitation may be delivered by; A text message to the wireless device A phone call to a wireless device A message deposited in the users voice mail An e-mail Postal mail A user of a wireless device may also initiate a solicitation by, for example, requesting the prices of hotel rooms within a given geographic radius. For a user initiated solicitation, the user may sort by: Type of goods and services Name of business providing goods and services Price of goods and services Distance to goods and services Other defined criteria This GAS can work in conjunction with the DAN or other mapping software to provide driving directions, for example, to the hotel which is soliciting the user. BSC BASE STATION CONTROLER BSS MANAGER BASE STATION SUBSYSTEM MANAGER BTS BASESTATION TRANSCIEVER SUBSYSTEM GPS GLOBAL POSITIONING SYSTEM HLR HOME LOCATION REGISTER MTX METROPOLITAN TELEPHONY EXCHANGE PSTN PULBLIC SWITCH TELEPHONY NETWORK RF RADIO FREQUENCY RSSI RECEIVE STRENGTH SIGNAL TDOA TIME DIFFERENCE OF ARRIVAL ULD USER LOCATION DATABASE ULDC USER LOCATION DATABASE COORDINATOR ULDCN USER LOCATION DATABASE COORDINATOR NETWORK USER LOCATION DATAB SE MANAGER ULDM
<SOH> BACKGROUND OF THE INVENTION <EOH>Wireless networks 100 are becoming increasingly important worldwide. Wireless networks 100 are rapidly replacing conventional wire-based telecommunications systems in many applications. Cellular radio telephone networks (“CRT”), and specialized mobile radio and mobile data radio networks are examples. The general principles of wireless cellular telephony have been described variously, for example in U.S. Pat. No. 5,295, 180 to Vendetti, et al., which is incorporated herein by reference. There is great interest in using existing infrastructures of wireless networks 100 for locating people and/or objects in a cost effective manner. Such a capability would be invaluable in a variety of situations, especially in emergency or crime situations. Due to the substantial benefits of such a location system, several attempts have been made to design and implement such a system. Systems have been proposed that rely upon signal strength and triangulation techniques to permit location include those disclosed in U.S. Pat. Nos. 4,818,998 and 4,908,629 to Apsell et al. (“the Apsell patents”) and U.S. Pat. No. 4,891,650 to Sheffer (“the Sheffer patent”). However, these systems have drawbacks that include high expense in that special purpose electronics are required. Furthermore, the systems are generally only effective in line-of-sight conditions, such as rural settings. Radio wave multipath, refractions and ground clutter cause significant problems in determining the location of a signal source in most geographical areas that are more than sparsely populated. Moreover, these drawbacks are particularly exacerbated in dense urban canyon (city) areas, where errors and/or conflicts in location measurements can result in substantial inaccuracies. Another example of a location system using time difference of arrival (TDOA) and triangulation for location are satellite-based systems, such as the military and commercial versions of the global positioning satellite system (GPS). GPS can provide accurate position from a time-based signal received simultaneously from at least three satellites. A ground-based GPS receiver at or near the object to be located determines the difference between the time at which each satellite transmits a time signal and the time at which the signal is received and, based on the time differentials, determines the object's location. However, the GPS is impractical in many applications. The signal power levels from the satellites are low and the GPS receiver requires a clear, line-of-sight path to at least three satellites above a horizon greater than about 60 degrees for effective operation. Accordingly, inclement weather conditions, such as clouds_, terrain features, such as hills and trees, and buildings restrict the ability of the GPS receiver to determine its position. Furthermore, the initial GPS signal detection process for a GPS receiver can be relatively long (i.e., several minutes) for determining the receiver's position. Such delays are unacceptable in many applications such as, for example, emergency response and vehicle tracking. Additionally there exists no one place that this location information is stored such that a plurality of wireless devices 104 could be located on a geographic basis.
<SOH> Summary of Factors Affecting Rf Propagation <EOH>The physical radio propagation channel perturbs signal strength, causing rate changes, phase delay, low signal to noise ratios (e.g., ell for the analog case, or E b /no, RF energy per bit, over average noise density ratio for the digital case) and doppler-shift. Signal strength is usually characterized by: Free space path loss (L p ) Slow fading loss or margin (L slow ) Fast fading loss or margin (L fast ) Loss due to slow fading includes shadowing due to clutter blockage (sometimes included in 1.p). Fast fading is composed of multipath reflections which cause: 1) delay spread; 2) random phase shift or rayleigh fading, and 3) random frequency modulation due to different doppler shifts on different paths. Summing the path loss and the two fading margin loss components from the above yields a total path loss of: in-line-formulae description="In-line Formulae" end="lead"? L total =L p ±L slow +L fast in-line-formulae description="In-line Formulae" end="tail"? Referring to FIG. 3 , the figure illustrates key components of a typical cellular and PCS power budget design process. The cell designer increases the transmitted power P TX by the shadow fading margin L slow which is usually chosen to be within the 1−2 percentile of the slow fading probability density function (PDF) to minimize the probability of unsatisfactorily low received power level P RX at the receiver. The P RX level must have enough signal to noise energy level (e.g., 10 dB) to overcome the receiver's internal noise level (e.g., −118 dBm in the case of cellular 0.9 GHz), for a minimum voice quality standard. Thus in the example P Rx must never be below −108 dBm, in order to maintain the quality standard. Additionally the short term fast signal fading due to multipath propagation is taken into account by deploying fast fading margin L fast , which is typically also chosen to be a few percentiles of the fast fading distribution. The 1 to 2 percentiles compliment other network blockage guidelines. For example the cell base station traffic loading capacity and network transport facilities are usually designed for a 1−2 percentile blockage factor as well. However, in the worst-case scenario both fading margins are simultaneously exceeded, thus causing a fading margin overload.
H04W4023
20170927
20180313
20180208
67921.0
H04W402
5
PATEL, AJIT
INTERNET QUERIED DIRECTIONAL NAVIGATION SYSTEM WITH MOBILE AND FIXED ORIGINATING LOCATION DETERMINATION
UNDISCOUNTED
1
CONT-ACCEPTED
H04W
2,017
15,717,359
ACCEPTED
PROTOCOL FOR LIGHTING CONTROL VIA A WIRELESS NETWORK
A monitor lighting control device receives a state change event message that includes a payload specifying: (i) a state change event of an occupancy, audio, or daylight sensor, or a switch to turn lighting on/off, dim up/down, set scene or the like; (ii) an identifier of a member lighting control device that detected the state change event; and (iii) a lighting control group identifier of a lighting control group that includes the member lighting control device and the monitor lighting control device. The monitor lighting control device transmits an acknowledgement of receipt of the state change event message to the member lighting control device. The monitor lighting control device generates a state change multicast message that includes the state change event of the payload. Also, the monitor lighting control device transmits the generated state change multicast message to the lighting control group.
1. A lighting control system comprising: a lighting control group, including a group monitor, a member lighting control device, and a luminaire; wherein the group monitor comprises: a wireless radio communication interface system configured for wireless communication over a wireless lighting control network communication band; a processor; a memory accessible to the processor; and programming in the memory which configures the processor to: receive via the wireless radio communication interface a state change event message including: (i) a state change event of an occupancy sensor, an audio sensor, a daylight sensor, or a switch to turn lighting on/off, dim up/down, or set scene; and (ii) an identifier of the member lighting control device that detected the state change event; generate a state change message that includes the state change event; and transmit via the wireless radio communication interface the generated state change message to members of the lighting control group. 2. The lighting control system of claim 1, wherein the state change event message further includes: (iii) a lighting control group identifier of the lighting control group that includes the member lighting control device and the group monitor. 3. The lighting control system of claim 1, wherein the state change event message is received via unicast communication. 4. The lighting control system of claim 1, wherein the generated state change message is transmitted via multicast communication. 5. The lighting control system of claim 1, wherein the generated state change message is transmitted via broadcast communication. 6. The lighting control system of claim 1, wherein the programming in the memory further configures the processor to: transmit the generated state change message to the members of the lighting control group at least two times. 7. The lighting control system of claim 1, wherein the programming in the memory further configures the processor to: look up identification for a set of lighting control devices that are members of the lighting control group in a lighting control group network table; generate a check message for the identified set of lighting control devices to confirm receipt of the generated state change message; and send the check message to each of the identified set of lighting control devices. 8. The lighting control system of claim 7, wherein the check message is unicasted to each of the identified set of lighting control devices in order as specified in the lighting control group network table. 9. The lighting control system of claim 8, wherein the programming in the memory further configures the processor to: in response to unicasting the check message, receive an acknowledgement message from each of the identified set of lighting control devices indicating success or failure to execute illumination operation based on the state change event. 10. A member lighting control device comprising: a wireless radio communication interface system configured for wireless communication over a wireless lighting control network communication band; drive/sense circuitry to detect a state change of an occupancy sensor, an audio sensor, a daylight sensor, or a switch to turn lighting on/off, dim up/down, or set scene; a processor coupled to the drive/sense circuitry; a memory accessible to the processor; and programming in the memory which configures the processor to: detect a state change event of the occupancy sensor, the audio sensor, the daylight sensor, or the switch via the drive/sense circuitry; in response to the detected state change event, generate a state change event message including: (i) an identifier of the member lighting control device, (ii) the state change event, and (iii) a lighting control group identifier of a lighting control group that includes the member lighting control device; transmit via the wireless radio communication interface the state change event message to a group monitor of the lighting control group; and upon failing to receive an acknowledgement of the state change event message from the group monitor within a predetermined time period, transmit via the wireless radio communication interface the state change event message including the state change event to members of the lighting control group. 11. The member lighting control device of claim 10, wherein the state event message is transmitted to the group monitor via unicast communication. 12. The member lighting control device of claim 11, wherein the programming in the memory further configures the processor to: upon failing to receive the acknowledgement of the state change event message from the group monitor within the predetermined time period, determine the failure to receive the acknowledgement of the state change event message from the group monitor is a communication fault. 13. The member lighting control device of claim 10, wherein the state event message is transmitted to the members of the lighting control group listening on a broadcast channel or an address of the lighting control group. 14. The member lighting control device of claim 10, wherein the state event message is transmitted to the members of the lighting control group via multicast communication. 15. The member lighting control device of claim 10, wherein the programming in the memory further configures the processor to: upon failing to receive the acknowledgement of the state change event message from the group monitor, increase power of the wireless radio communication interface prior to transmitting the state change event message to the members of the lighting control group. 16. The member lighting control device of claim 10, wherein the programming in the memory further configures the processor to: after transmitting the state change event message to the members of the lighting control group, initiate a re-survey of radio frequency (RF) connectivity with the group monitor. 17. A luminaire comprising: a wireless radio communication interface system configured for wireless communication over a wireless lighting control network communication band; a processor; a light emitting diode (LED) light source; an LED driver circuit to drive the LED light source; a memory accessible to the processor; and programming in the memory which configures the processor to: receive via the wireless radio communication interface a state change message from a group monitor including: (i) a state change event of an occupancy, an audio sensor, a daylight sensor, or a switch to turn lighting on/off, dim up/down, or set scene; and (ii) a lighting control group identifier of a lighting control group; receive via the wireless radio communication interface a confirmation message from the group monitor to confirm receipt of the state change message; send an acknowledgement message of the confirmation message via the wireless radio communication to the group monitor to confirm receipt of the state change message; check the lighting control group identifier to determine whether the luminaire is a member of the lighting control group specified in the state change message; and upon determining that the luminaire is a member of the lighting control group, adjust illumination light output of the LED light source via the LED driver circuit in accordance with the state change event. 18. The luminaire of claim 17, wherein the state change message is received via multicast communication. 19. The luminaire of claim 17, wherein the confirmation message is received via unicast communication. 20. The luminaire of claim 17, wherein the programming in the memory further configures the processor to: before adjusting illumination light output of the LED light source via the LED driver circuit in accordance with the state change event, determine that the luminaire has not already acted in accordance with the state change event specified in the state change message.
CROSS-REFERENCE TO RELATED APPLICATION This application is a continuation of U.S. patent application Ser. No. 15/214,962, filed on Jul. 20, 2016, the entire disclosure of which is incorporated herein by reference. BACKGROUND Traditional luminaires can be turned ON and OFF, and in some cases may be dimmed, usually in response to user activation of a relatively simple input device. Often traditional luminaires are controlled individually or as relatively small groups at separate locations. More sophisticated lighting control systems automate the operation of the luminaires throughout a building or residence based upon preset time schedules, occupancy, and/or daylight sensing. Such lighting control systems receive sensor signals at a central lighting control panel, which responds to the received signals by deciding which, if any, relays, switching devices, and/or dimming ballasts to drive in order to turn on or off and/or adjust the light levels of one or more luminaires. More recent lighting systems are wireless; however, operating luminaires to operate over wireless communication systems using group based controls can be difficult. For example, multiple simultaneous control requests can ovewhelm a node that is tasked with managing the group. Accordingly, a system is needed to overcome these and other limitations in the art. BRIEF DESCRIPTION OF THE DRAWINGS The drawing figures depict one or more implementations in accord with the present teachings, by way of example only, not by way of limitation. In the figures, like reference numerals refer to the same or similar elements. FIG. 1A is a high-level functional block diagram of an example of a system of networks and devices that provide a variety of lighting controls, including communications in support of turning lights on/off, dimming, set scene, and sensor trip events. FIG. 1B is another high-level functional block diagram of an example of a system of networks and devices that further includes plug load controller and power pack devices and various lighting control groups. FIG. 2 is a state change event protocol procedure for the lighting control system of FIGS. 1A-B. FIGS. 3A-C are block diagrams of luminaires that communicate via the lighting control system of FIG. 1A or FIG. 1B. FIGS. 4A-C are block diagrams of different examples of a wall switch that communicates via the lighting control system of FIG. 1A or FIG. 1B. FIG. 5 is a block diagram of a plug load controller that communicates via the lighting control system of FIG. 1B. FIG. 6 is a block diagram of a power pack that communicates via the lighting control system of FIG. 1B. FIG. 7 is a flow chart presenting the states and transitions for the various lighting control devices of FIGS. 1A-B. FIG. 8 is a high-level functional block diagram of a mobile device for commissioning and maintenance of the lighting control system of FIGS. 1A-B. FIG. 9A is a media access control (MAC) layer message for communicating a state change event to a lighting control device on a lighting control network. FIG. 9B is a transport layer message for communicating a state change event to a lighting control device on a lighting control network. FIG. 9C is an application layer message for communicating a state change event to a lighting control device on a lighting control network. DETAILED DESCRIPTION In the following detailed description, numerous specific details are set forth by way of examples in order to provide a thorough understanding of the relevant teachings. However, it should be apparent to those skilled in the art that the present teachings may be practiced without such details. In other instances, well known methods, procedures, components, and/or circuitry have been described at a relatively high-level, without detail, in order to avoid unnecessarily obscuring aspects of the present teachings. Reference now is made in detail to the examples illustrated in the accompanying drawings and discussed below. FIGS. 1A-B are functional block diagrams illustrating examples, each relating to a system of networks and devices that provide a variety of lighting control capabilities, including communications in support of turning lights on/off, dimming, set scene, and sensor trip events. FIG. 1B is the same as FIG. 1A, but further includes additional lighting control devices (LCDs): a plug load controller 30 and a power pack 35; and illustrates exemplary lighting control groups. It should be understood that the term “lighting control device” means a device that includes a controller (sensor/control module or micro-control unit) as shown in FIGS. 3A-C, 4A-C, 5, and 6 that executes a lighting application for communication over a wireless lighting control network communication band, of control and systems operations information during control network operation over the lighting control network communication band. For example, a luminaire (FIGS. 3A-C) that includes a sensor/control module 315 having a micro-control unit 330 that executes lighting application 327 is a lighting control device. A wall switch or touch panel (FIGS. 4A-C) that includes a sensor/control module 415 having a micro-control unit 430 that executes lighting application 427 is a lighting control device. A plug load controller (FIG. 5) that includes a micro-control unit 530 that executes lighting application 527 is a lighting control device. A power pack (FIG. 6) that includes a micro-control unit 630 that executes lighting application 627 is a lighting control device. The lighting control system 1 may be designed for indoor commercial spaces. As shown, system 1 includes a variety of lighting control devices, such as a set of luminaires 10A-N (lighting fixtures) and a set of wall switches 20A-N. Daylight, occupancy, and audio sensors are embedded in lighting control devices, in this case luminaires 10A-N to enable controls for occupancy and dimming. Luminaires 10A-N, wall switches 20A-N, plug load controller 30, and power pack 35 communicate control over a 900MHz (sub-GHz) wireless control network 5 and accordingly each include a first radio in the sub-GHz range. A variety of controls are transmitted over wireless control network 5, including, for example, turn lights on/off, dim up/down, set scene (e.g., a predetermined light setting), and sensor trip events. Each luminaire 10A-N, wall switch 20A-N, plug load controller 30, and power pack 35, is also equipped with a second near range Bluetooth Low Energy (BLE) radio that communicate over commissioning network 7 for purposes commissioning and maintenance the wireless lighting control system 1, however no controls pass over this commissioning network 7. Plug load controller 30 plugs into existing AC wall outlets, for example, and allows existing wired lighting devices, such as table lamps or floor lamps that plug into a wall outlet, to operate in the lighting control system 1. The plug load controller 30 instantiates the table lamp or floor lamp by allowing for commissioning and maintenance operations and processes wireless lighting controls in order to the allow the lighting device to operate in the lighting control system 1. Power pack 35 retrofits with existing wired light fixtures (luminaires). The power pack 35 instantiates the wired light fixture by allowing for commissioning and maintenance operations and processes wireless lighting controls in order to allow the lighting device to operate in the lighting control system 1. Both plug load controller 30 and power pack 35 can include the same circuitry, hardware, and software as light fixtures 10A-N and wall switches 20A-N. The system 1 is provisioned with a mobile device 25 that includes a commissioning/maintenance application 22 for commissioning and maintenance functions of the lighting control system 1. For example, mobile device 25 enables mobile commissioning, configuration, and maintenance functions and can be a PDA or smartphone type of device with human interfacing mechanisms sufficient to perform clear and uncluttered user directed operations. Mobile device 25 runs mobile type applications on iOS7, Android KitKat, and windows 10 operating systems and commissioning/maintenance application 22 to support commissioning. Web enabled (cloud) services for facilitating commissioning and maintenance activities is also provided by mobile device 25. The commissioning/maintenance application 22 of mobile commissioning device 25 interfaces with the cloud services to acquire installation and configuration information for upload to luminaires 10A-N, wall switches 20A-N, plug load controller 30, and power pack 35. The installation and configuration information is received by mobile device 25 from the gateway 55. The gateway 50 engages in communication through the wide area network (WAN) 55. Lighting control system 1 can leverage existing sensor and fixture control capabilities of Acuity Brands Lighting's commercially available nLight® wired product through firmware reuse. In general, Acuity Brands Lighting's nLight® wired product provides the lighting control applications. However, the illustrated lighting control system 1 includes a communications backbone and includes model - transport, network, media access control (MAC) /physical layer (PHY) functions. The sub-GHz communications of the wireless control network 5 features are built on a near 802.15.4 MAC and PHY implantation with network and transport features architected for special purpose control and air time optimizations to limit chatter. The lighting control system 1 can be deployed in standalone or integrated environments. System 1 can be a an integrated deployment, or a deployment of standalone groups with no gateway 50. One or more groups of lighting control system 1 may operate independently of one another with no backhaul connections to other networks. Lighting control system 1 may comprise a mix and match of various indoor systems, wired lighting systems (nLight® wired), emergency, and outdoor (dark to light) products that are networked together to form a collaborative and unified lighting solution. Additional control devices and lighting fixtures, gateway(s) 50 for backhaul connection, time sync control, data collection and management capabilities, and interoperation with the Acuity Brands Lighting's commercially available SensorView product may also be provided. As shown in FIG. 1B, control, configuration, and maintenance operations of the lighting control system 1 involve networked collaboration between the luminaires 10A-N, wall switches 20A-N, plug load controller(s) 30, and power pack(s) 35 that comprise a lighting control group. An installation is comprised of one or more lighting control groups each operating independently of one another. One or more lighting control groups may exist in the wireless control network 5. Each lighting control group will have a group monitor, and this is shown in FIG. 1B where there a two groups and each group has a monitor. Groups are formed during commissioning of the lighting control system 1 where all members of the group are connected together over wireless control network 5, which in our example is a sub-GHz subnetwork defined by an RF channel and a lighting control group identifier. The lighting control devices subscribe to channels and only listen for/react to messages on the RF channel with the identifier (ID) of the subscribed channel that designates the lighting control group that the lighting control device is a member of For example, the lighting control devices subscribe to a multicast group as identified by the lighting control group identifier and only react to messages on the RF channel of the lighting control group. In general, groups do not share RF channels and thus form their own RF subnetwork, however with only 10 available channels some overlap is inevitable. Analysis and simulation have indicated that group distribution and spatial separation will mitigate the congestion and collision side effects that can occur when many lighting control devices 10A-N, 20A-N, 30, 35 share a singular RF enclave. A group can be further divided to address control to specific control zones within the group defined by a control zone identifier. Zone communications are managed as addressable features at run time. Up to 16 independent zones of control are available for each group and each group can support up to 128 addressable elements (luminaires 10A-N, wall switches 20A-N, plug load controller 30, power pack 35). The wireless control network 5 distributes control messages and events, network management messages and events, health and failover events, and group commissioning and maintenance communications, such as firmware update distributions and group membership changes. Wireless control network 5 provides a secure control network (Sub-GHz) on which to operate. Devices are manually added to the wireless control network 5 via the commissioning process via commissioning/maintenance application 22 of mobile device 25. The commissioning process includes authorization and authentication features that allow only trusted and known entities to add confirmed devices 10A-N, 20A-N, 30, 35 to the network. Requirements relating to network modification (device add/delete/modify) are allocated to the mobile device 25 and its interface (commissioning/maintenance application 22) to the lighting control system 1. Message authentication in the lighting control system 1 is provided by the 802.15.4 compliant MAC layer solution commercially available from Silicon Labs. The solution uses the AES CCM block cypher mode of operation to secure over the air frames. The mode of operation provides NIST compliant authentication, encryption, and integrity assurance to defeat replay attacks as well as device and message spoofing. Lighting control system 1 also implements an additional layer of authentication by performing checks on the message source and addressing mechanisms to reject messages from unknown sources (i.e. sources that are not authorized members of a lighting control group network). An intrusion detection scheme using the above schemes and that reports such events will be made via the gateway 50. The sub-GHz MAC/PHY (wireless control network 5) thus provides secure communication features (authentication, data integrity, and encryption assurance) based on the 802.15.4 standard. The lighting control devices over the wireless control network 5 together may engage in any-to-many (unicast and multicast) communication and can implement a non-mesh wireless network topology. In our example, wireless control network 5 is a star topology network. Although other network schemes may be utilized, a star topology may be the best fit for aligning the required control communications features with the characteristics of sub-GHz wireless radio. At the center of each lighting control group in a star topology wireless control network 5 is a singular group monitor as shown in FIG. 1B. In FIG. 1B, luminaire 10A is the group monitor for lighting control group 1 and luminaire 10B is the group monitor for lighting control group 2. Lighting control group 1 further comprises luminaire 10N, wall switch 20A, and plug load controller 30. Lighting control group 2 further comprises wall switch 20B and power pack 35. The monitor is responsible for receiving control events from their source (luminaires 10A-N, wall switches 20A-N, plug load controller 30, and power pack 35) and ensuring reliable and timely delivery of the event to the other members of the group. The monitor uses a quick best effort 0 mechanism for fast high-probability delivery. The monitor follows up the multicast with a reliable point to point communication to ensure that all destination devices received the event. Commissioning Commissioning is the process that sets the lighting control configuration and settings that drive the behavior of the lighting control system 1. One or more mobile devices 25 can be used to commission the installation of lighting control system 1. During setup, commissioning/maintenance application 22 of the mobile device 25 provides a secure method for a system installer to configure the lighting control devices (LCDs) for installation commissioning. The lighting control devices include luminaires 10A-N, wall switches 20A-N, plug load controller 30, and power pack 35. General behavioral settings and network addressing information are stored on the mobile device 25 for upload and allocation to the installation's lighting control devices via commissioning/maintenance application 22. The installation information is managed by commissioning/maintenance application 22 of mobile device 25 to ensure correctness and to eliminate common errors such as assignment of duplicate network addresses. Communication between the mobile device 25 for commissioning/maintenance and the lighting control devices is over the commissioning network 7, such as a BLE network. The lighting control devices are initially in an installation state, beaconing their advertisements when the commissioning starts. Upon connection with the mobile device 25, the commissioning/maintenance application 22 of mobile device 25 transitions the lighting control devices to a commissioning state. Further upon connection, the lighting control device authenticates the mobile device 25 and is ready to accept commands over the commissioning network 7. The wall switches 20A-N suppress sleep mode until completion of the commissioning process and transition to operational mode. Wall switches 20A-N will re-enter sleep mode if the commissioning process is interrupted—two elapsed hours with no activity. An installation is commissioned according to lighting control groups. A group is a collection of LCDs sharing the same space within an installation (e.g. a room or area). Each lighting control group in the installation has a special lighting control device called the group monitor. The group monitor keeps tabs on the overall state and health of the lighting control devices within the group and assists in the communication of lighting control events between group elements. In general, one can visualize the group network topology as a star with the group monitor as the central node and the remainder of the group's lighting control devices at points of the star. A group is commissioned by first establishing the group's lighting control network 5 and then configuring the group's control behavior. The lighting control network 5 is established over a 802.15.4 based MAC riding on top of a sub-GHz (904 MHz to 926MHz) PHY. The commissioning network 7, such as a Bluetooth Low Energy MAC/PHY, is used to as the point to point connection medium to transfer control network configuration from the commissioning/maintenance application 22 of the mobile device 25 to a lighting control device The commissioning/maintenance application 22 of mobile device 25 builds a network table of the group devices while establishing the lighting control network 5. The network table, used by the group monitor in the execution of its responsibilities, is uploaded from the mobile device 25 to the group's lighting control devices via commissioning/maintenance application 22. Each lighting control device also has a behavioral configuration. The configuration is specified by a group of settings that define control characteristics such as sensor set points, delays, modes, and ranges. The control characteristics also specify independent zones of control within the group. These characteristics and settings are customized as necessary and uploaded from the mobile device 25 to each lighting control device via commissioning/maintenance application 22. During the commissioning process, line powered lighting control devices are installed, powered, and advertising over BLE. Battery powered lighting control devices, such as wall switches 20A-N, are installed and in sleep mode to conserve power. After the mobile device 25 is setup, an installer opens the commissioning/maintenance application 22 on the mobile device 25 and walks into an area of the installation that is ready to commission as a lighting control group. Configuring a Group Network Wall switches 20A-N and luminaires 10A-N are under the command of the mobile device 25 and respond to a sequence of commands to configure a group network. The wall switches 20A-N respond to a blink request by rapidly blinking an LED. The LED pilot light brightness level is set to a maximum. The luminaires 10A-N responds to a blink request by rapidly blinking an LED light pack. At any time, the lighting control device, including luminaires 10A-N, wall switches 20A-N, plug load controller 30, plug pack 35, etc., ceases blinking upon command. The device then accepts the sub-GHz short MAC address, group number, group name, group RF channel, and personal area network (PAN) ID from the mobile device 25. The device persists this information in non-volatile memory (NVM). The device ceases blinking. The lighting control device accepts the settings from the commissioning/maintenance application 22 of mobile device 25 and persists the settings in non-volatile memory. Additionally, lighting control devices that are luminaires 10A-N also receive settings for an on-board controller (MCU) and on-board integrated sensors. The lighting control device may also receive a request to execute an RF spectrum scan to determine the group RF channel. If so, the lighting control device executes the scan and returns the results to the mobile device 25 for distribution to the other group devices. The above sequence of commands issued from the commissioning/maintenance application 22 of mobile device 25 are expected to be in order. Commands received out of order are consider to be an intrusion attempt. The lighting control device configures its media access control (MAC) layer device circuitry and its physical layer circuitry for the OSI model (PHY) with the data transferred from the mobile device 25 and remains in commissioning state. Connecting a Group Network To connect to the group network, the lighting control devices accept the group address table from the mobile device 25. The group address table identifies all of the lighting control devices in the group. The device persists this information in non-volatile memory. The device uses the lighting control network 5 (e.g., sub-GHz network) to pass the group address table to the other lighting control devices, such as luminaires 10A-N and wall switches 20A-N, in the group. The communication over the lighting control network 5 is reliable-unicast and may involve some message segmenting if the table size exceeds transport protocol data unit (PDU) size. The lighting control device returns a status to the mobile device 25 indicating success or failures encountered while distributing the table. The lighting control device accepts a command to tune the group RF transmission (TX) power levels and executes the tune according to the discussion below. The commissioning/maintenance application 22 of mobile device 25 disconnects after issuing the command to tune the group RF TX power levels. The above sequence of commands issued from the mobile device 25 are expected to be in order. As noted previously, commands received out of order are consider to be an intrusion attempt. Upon completion, the lighting control devices in the group transition to an operational state. Radio Frequency Channel Selection The group RF channel is determined at commissioning time by a line powered lighting fixture, such as luminaires 10A-N. The commissioning/maintenance application 22 of mobile device 25 requests the A spectrum scan of the available channels (10) seeking the channel with the lowest average noise level measured over a short period of time. The process is as follows. Mobile device 25 is connected to a luminaire 10A-N via the commission network 7 (e.g., BLE). The mobile device 25 requests a spectrum scan indicating the number of samples/per channel to be produced. The luminaire 10A-N executes a passive scan of the following channels (channel number, center frequency): 1 904 MHz 2 906 MHz 3 908 MHz 4 910 MHz 5 912 MHz 6 914 MHz 7 916 MHz 8 918 MHz 9 920 MHz 10 922 MHz 11 924 MHz 12 926 MHz The luminaire 10A-N returns the average energy and peak energy detected for each channel. The commissioning/maintenance application 22 of mobile device 25 determines the optimum RF channel from the average and peak energy samples giving preference (via a weighting factor) to channels 5-8. The commissioning/maintenance application 22 of mobile device 25 commands the lighting control device to configure its MAC/PHY to use the optimum RF channel. A modified method that replaces the above method with one that uses a discovery and link quality measurement to join the optimum gateway subnetwork may also be used. Whatever the method (gateway 50 or non-gateway), the RF channel selection scheme is timely to meet the user experience requirements for commissioning. Alternatively, this procedure may be decoupled from mobile device 25 so that channel selection can also execute independently by lighting control devices, such as luminaires 10A-N and wall switches 20A-N. Transmission Power Adjustment Sub-GHz RF TX power levels are managed to optimize intra-group communications in a way that limits adverse effects (collisions, retries, corrupt packets, etc.) on adjacent group subnetworks that happen to be sharing the RF channel. The group monitor executes a link test with each lighting control device in the group as follows. The group monitor sends a link test message to the lighting control device. The device returns a link test response to the group monitor indicating the received strength signal indicator (RSSI-1) of the received message in 1. The group monitor receives the response and notes the RSSI of the received message (RSSI-2). If RSSI-1 is less than the minimum RSSI-1s recorded so far, it records the new minimum RSSI. The group monitor returns a link test response acknowledgment to the device indicating RSSI-2. The device receives the acknowledgement. The device adjusts it RF TX power appropriately if the RSSI-2 does not fall within the desired range. The device returns a link test status (continue) to the group monitor. The device returns a link test status (complete) if the RSSI-2 is within the desired range. The group monitor receives the link test status. The process repeats if the status indicates continue (is within the desired range). Steps 1 through 6 are repeated until all devices in the group have been tested. The transmission (TX) power adjustment can also be invoked for a single group monitor—device link. In this case, all devices in the group do not need to be tested. Lighting Control Device Health The group monitor periodically checks the health of each lighting control device, such as luminaires 10A-N, wall switches 20A-N, plug load controller 30, and power pack 35, in the group. The group monitor runs a round robin check of each group device such that every device receives a request to report health once every hour. In an example, given a group with a maximum number of devices (128), the group monitor will issue a request for health status every ˜28.125 seconds while a group of six will result in a health request every 10 minutes. Clock drift and frequency of over the air messaging are not expected to cause undesirable side effects or performance hits to the network 5, however health requests are delayed via a back off timer of 10 seconds during bursts of network traffic to allow potential congestions to clear and make way for higher priority control operations. The group monitor records faults reported by lighting control devices for later retrieval by commissioning/maintenance application 22 of mobile device 25 for commissioning and maintenance. Communication Failures Wireless messaging failures are possible and expected, however continuous failures indicate a problem that might be rectified by adjusting the RF properties of the communications link of lighting control devices, such as luminaires 10A-N and wall switches 20A-N. Continuous failures may result if there is a change to the environment that alters RF performance or in cases where a lighting control device is experiencing internal failures. Attempts to resolve communications failures are managed by the group monitor rather than separately at each lighting control device. Reliable-unicast messaging acknowledgement is the driver for detecting communications failures. At lighting control devices, a communication failure occurs when the device transmits a reliable-unicast message and fails to receive an acknowledgement within a retry period. Upon detecting such a failure, the lighting control device increments its counters of total failures and attempts. The lighting control device reports the percentage of failures in response to a request for health status from the group monitor. The lighting control device resets its counters after successful report of health status. At a group monitor, the group monitor associates a four bit counter with each lighting control device in the group for purposes of tracking communication failures. A failure occurs when the group monitor receives no acknowledgement back after transmitting a reliable-unicast message to a group device. The group monitor will increment the counter for that lighting control device whenever a failure occurs. The counter is reset whenever a successful transmission occurs. If the counter reaches a value of 0×7 for any lighting control device, the group monitor attempts to correct the consistent communication failure by issuing a command to the lighting control device to incrementally increase its RF TX power level. If the counter reaches a value of 0×E for any lighting control device, the group monitor initiates an RF TX Power adjustment for the link. Counters that reach a max of 0×F remain there and may indicate a dead lighting control device. Power level adjustment trigger may be changed to act on percentage of failures (similar to the device health method below) rather than consecutive failure conditions. The group monitor 10A issues a command to the lighting control device to incrementally increase its RF TX power level if the device's status indicates transmission failures at or greater than 15%. The group monitor initiates an RF TX Power adjustment for any communications link where the lighting control device's status indicates transmission failures at or greater than 25%. FIG. 2 is a state change event protocol procedure for the lighting control system of FIGS. 1A-B. As noted above, a group is a collection of lighting control devices that are managed by a “monitor.” A zone is an operational collection of lighting control devices within the group and may comprise the entire group. The group/zone monitor (luminaire 10A in the example) has knowledge of the group/zone configuration (e.g., handled at the network layer level) to execute a reliable delivery check on sensor/switch state changes. Group membership and management functions may be performed by the application layer or the network layer. Luminaire 10A stores a lighting control group network table that maintains a group/zone list of the group/zone that each lighting control device is a member of. The lighting control group network table may be shared with other luminaires and/or sensors, plug load controllers or switches in the group, e.g. to enable failover to another group member upon failure of the group/zone monitor functionality at the luminaire 10A. Lighting control devices (luminaires 10A-N, wall switches 20A-N, plug load controller 30, and power pack 35) go through a series of states, transitions, and engage in communications with each other upon detecting a state change event of the lighting control system. Although luminaires 10A and 10N are shown in this example, it should be understood that the state change event protocol shown applies to all of the other lighting control devices, such as a wall switches 20A-N, plug load controller 30, power pack 35, or other types of switches/sensors. Assumptions of the state change event protocol procedure in this example may be the following. Sensor/switches of lighting control devices (luminaires 10A-N, wall switches 20A-N, plug load controller 30, and power pack 35) behave in a similar manner when communicating events at least over the lighting control network 5 (e.g., group and zone network level) and possibly beyond. Battery powered sensors and line powered switches/sensors behave in a similar manner when communicating events at least over the lighting control network 5 and possibly beyond. Lighting control devices, including sensors/switches, attempt to communicate state change of interest directly to gateway 50. A group monitor may communicate group/zone state change to the group/zone devices and the gateway 50 in addition to the sensors/switches. Battery life conservation may drive the design of the communication pattern, e.g. for communications for a battery powered wall switch, sensor or the like. There may be a 1 second maximum time for event detection to lights on/off. State change events involve a state change of an occupancy, audio, or daylight sensor (e.g., a new reading different from a previous reading), or a switch to turn lighting on/off, dim up/down, or set scene. For example, state change includes on/off for switches, occupied/unoccupied for occupancy sensors, and lighting intensity adjustments for dimmers. Groups may be subdivided into zones. Switches and sensors control a group or zones within the group. A zone may comprise an entire group (e.g., all on/off). In the example, luminaire 10N is a member lighting control device of group/zone 1 and zone 1 includes all members of group 1. Beginning in block S200, programming in a memory of the luminaire 10N, specifically lighting application 327, configures a processor of the luminaire 10N to detect a state change event and transmit a state change event message via the lighting control network communication band to a monitor lighting control device of group/zone 1 (luminaire 10A). For example, drive/sense circuitry 335 of luminaire 10N detects a state change event via detector(s) 365. Alternatively, if the lighting control device is a wall switch 20, then drive/sense circuitry 435 detects a state change event via switches 465. Situations may arise that require protection in order to maintain integrity of the lighting control system 1. For example, a rapid fire communication of multiple switch events could overwhelm the ability of the group/zone 1 monitor (luminaire 10A) to issue a state change multicast message and perform a state change check with each lighting control device in the group. Having sensor/switch de-bounce capability addresses this potential problem. The de-bounce mechanism limits the rate at which state change event messages can be initiated by a sensor/switch. Luminaire 10N checks the hardware state of detector(s) 365 and, if a state change is detected, luminaire 10N performs the following two steps. First, the luminaire 10N unicasts a state change event message to the group 1 monitor (luminaire 10A) using a reliable effort. Reliable effort means that if an acknowledgement is not received from the recipient, then a retry effort is made to resend the message to the recipient. Second, the luminaire 10N also unicasts a state change event message to the gateway 50 using a best effort (not shown). Best effort means that if an acknowledgement is not received from the recipient, then no retry effort is made to resend the message to the recipient. Luminaire 10N then delays for a regular polling period (e.g., 1 second) before re-checking the hardware state of sensors/switches again. Of note, if the group/zone 1 member lighting control device is a wall switch instead of a luminaire, then a switch change similarly results in a state change event message. However, if the member lighting control device that sent the original state change message is battery operated (e.g., a wall switch), then the regular polling period may be extended to a longer period of time (e.g., 10 seconds) or there may not be any polling at all to conserve battery life. Lighting application 327 builds application control messages, such as the state change event message. The state change event message is sent to the transport layer by the lighting application 327 for unicast transmission to luminaire 10A. Moving to block S205, luminaire 10A (monitor of group/zone 1) receives the state change event message and acknowledges receipt of the state change event message. Luminaire 10A examines the application message body, determines that the protocol relates to lighting control operation, and extracts the payload. To handle multiple concurrent group/zone state change requests, luminaire 10A determines if the received message involves a group/zone state change while a state change is in progress for the exact same group/zone. If the received message is for the same group/zone, then luminaire 10A cancels the in-progress activity and executes the new state change. Continuing in block S210, luminaire 10N determines whether an acknowledgement of the state change event message has been received from luminaire 10A acting as the group/zone monitor. If the acknowledgment message has been received, then block S215 is entered. In block S215, luminaire 10A as the group/zone monitor multicasts a state change event message to all of the lighting control group/zone devices in a respective lighting control group/zone. In the example, if the payload indicates an inter-zone group, then the luminaire 10A performs a look up in a zone table to see if any local lighting control devices are members of that group. If the local lighting control devices are members of the inter-zone group or if the payload indicates an intra-zone group, then luminaire 10A (zone monitor) broadcasts the message (e.g., 3 times), with the zone set to the zone identifier and the protocol set to lighting control operation. The multicast message may be addressed to a group/zone broadcast group address or channel. Luminaire 10A may push up the transmission (TX) power for the multicast. Proceeding now to block S220, luminaire 10A begins a unicast check with each local lighting control device participating in the group to confirm receipt of the multicast message. Luminaire 10A unicasts (reliable effort) a check to each lighting control device in the group/zone to confirm state change. The luminaire 10A may unicast in order beginning with the lighting control device with the lowest received strength signal indicator (RSSI) and then proceed in ascending order. Alternatively, luminaire 10A may unicast in order beginning with the lighting control device with the highest round-trip time (RTT) and then proceed in descending order. Moving now to block S225, the zone lighting control devices receive the broadcast message and determine whether the device itself is in the targeted lighting control group/zone. If the lighting control device is not in the targeted lighting control group/zone, then the message is discarded. The message, minus transport header, is passed to the lighting application 327. The lighting application 327 uses the payload of the message and its internal settings to determine whether or not the message is to be processed. If the message is processed, then the LED light source of the lighting control device is adjusted (e.g., turned on/off) in accordance with the state change event. Each lighting control device in the group/zone with exception of the original member lighting control device 10N that sent the original state change message, returns an acknowledgment message (MAC layer) and an application layer message (reliable effort) indicating the success or failure to execute the state change event from the state change event message, thereby enabling tracking. Further, each acknowledgement includes an indication whether the initial multicast message from block S215 was received by the respective lighting control device. The acknowledgment message is received by luminaire 10A. In an example, if a switch controls 15 light fixtures then the group monitor of the respective lighting control group would receive 15 acknowledgment messages back after communicating the state change, thereby tracking the output of the light fixtures. Continuing to block S230, luminaire 10A also sends the state change event message to gateway computer 50, for example, via unicast and using a reliable effort. However, if the member lighting control device that sent the original state change message is battery operated (e.g., a wall switch), then the monitor lighting control device sends the state change event message to gateway computer 50, for example, via unicast and using a reliable effort to conserve battery power. Moving back to step S210, if luminaire 10N determines that no acknowledgement of the state change event message has been received from luminaire 10A (group monitor), then block S235 is entered. This indicates that the group monitor received the state change event message in block S205, but the sensor/switch (luminaire 10N) did not hear an acknowledgement message back from the group monitor. Alternatively, this means that the group monitor never actually received the state change event message. In either case, luminaire 10N powers a wireless radio communication interface up to full power and multicasts a state change event message to group/zone lighting control devices listening on a respective broadcast channel or address. Next, in block S240, luminaire 10N initiates a re-survey of its RF connectivity with luminaire 10A. The group monitor tracks RF net degradation over time using aggregated stats and then initiates the RF re-scan. As shown in block S245, if a response from luminaire 10A is received, then block S250 is entered, which indicates luminaire 10A is now operating correctly. Accordingly, in block S250 the protocol branches to block S215 so that luminaire 10A proceeds to execute the steps shown as S215-S230. Any time luminaire 10A hears the multicast message of block S235 without hearing the unicast message of block S200, the group/zone monitor branches to block S220 and unicasts a check to each group/zone device to confirm state change (as shown in block S220). Blocks S225 and S230 will subsequently be entered as well. However, if a response is not received luminaire 10A in block S245, then luminaire 10N assumes that luminaire 10A has failed operating. Accordingly, in block S255, the luminaire 10N unicasts a fault message to the backup group/zone monitor, for example, the backup group/zone monitor is the second entry listed in the lighting control group network table, A table of different state change event message communication types and transmission protocols is shown below. Various message exchanges that occur upon control actions (e.g., wall switch activated), including the number and nature (source, destination, type—unicast/broadcast/multicast) is shown. Pattern Source Destination Transport Scheme Use One to one Sensor/Switch Zone monitor Redbox unicast/MAC Occupancy, reliable (all) unicast with ack/retry photo sensor state change One to one best Sensor/Switch Gateway Redbox unicast/MAC On selected effort (all) unicast state change One to many Zone monitor Selected zone Redbox unicast/MAC Occupancy, best effort devices broadcast, addressed to photo sensor zone/broadcast channel state change One to one Zone monitor Selected zone Redbox unicast/MAC Zone monitor reliable devices unicast with ack/retry checks devices to confirm state change One to one Selected zone Zone monitor Redbox unicast/MAC Application reliable devices unicast with ack/retry layer confirmation of state change One to one Zone monitor Gateway Redbox unicast/MAC On selected reliable unicast state change One to many Sensor/Switch Selected zone Redbox unicast/MAC On failure to best effort (all) devices broadcast, addressed to hear ack zone/broadcast channel from zone monitor on occupancy, photo sensor state change One to one Sensor/Switch Zone monitor Redbox unicast/MAC Request RF reliable (all) unicast survey One to one Zone monitor Sensor/Switch Redbox unicast/MAC Response to reliable (all) unicast RF survey request One to many Sensor/Switch All zone Redbox unicast/MAC Zone monitor best effort (sleepy) devices broadcast, addressed to discover zone message One to one Zone monitor Sensor/Switch With ack/retry Reply to reliable (sleepy) zone monitor discover FIGS. 3A-C are block diagrams of a luminaire 10 that communicate via the lighting control system of FIGS. 1A-B. Luminaire 10 is an integrated light fixture that generally includes a power supply 305 driven by a power source 300. Power supply 305 receives power from the power source 300, such as an AC mains, battery, solar panel, or any other AC or DC source. Power supply 305 may include a magnetic transformer, electronic transformer, switching converter, rectifier, or any other similar type of circuit to convert an input power signal into a power signal suitable for luminaire 10. Luminaire 10 furthers include an intelligent LED driver circuit 310, sensor/control module 315, and a light emitting diode (LED) light source 320. Intelligent LED driver circuit 310 is coupled to LED light source 320 and drives that LED light source 320 by regulating the power to LED light source 320 by providing a constant quantity or power to LED light source 320 as its electrical properties change with temperature, for example. The intelligent LED driver circuit 310 includes a driver circuit that provides power to LED light source 320 and a pilot LED 317. The pilot LED 317 may be included as part of the sensor/control module 315. Intelligent LED driver circuit 310 may be a constant-voltage driver, constant-current driver, or AC LED driver type circuit that provides dimming through a pulse width modulation circuit and may have many channels for separate control of different LEDs or LED arrays. An example of a commercially available intelligent LED driver circuit 310 is manufactured by EldoLED. LED driver circuit 310 can further include an AC or DC current source or voltage source, a regulator, an amplifier (such as a linear amplifier or switching amplifier), a buck, boost, or buck/boost converter, or any other similar type of circuit or component. LED driver circuit 310 outputs a variable voltage or current to the LED light source 320 that may include a DC offset, such that its average value is nonzero, and/or a AC voltage. The pilot LED 317 indicates the state of the luminaire 10, for example, during the commissioning and maintenance process. For purposes of communication and control, luminaire 10 is treated as single addressable device that can be configured to operate as a member of one or more lighting control groups or zones. The luminaire 10 is line powered and remains operational as long as power is available. Sensor/control module 315 includes power distribution circuitry 325, a micro-control unit (MCU) 330, drive/sense circuitry 335, and detector(s) 365. As shown, MCU 330 is coupled to LED driver circuit 310 and controls the light source operation of the LED light source 320. MCU 330 includes a memory 322 (volatile and non-volatile) and a central processing unit (CPU) 323. The memory 322 includes a lighting application 327 (which can be firmware) for both lighting control operations and commissioning, maintenance, and diagnostic operations. The power distribution circuitry 325 distributes power and ground voltages to the MCU 330, drive/sense circuitry 335, wireless transceivers 345 and 350, and detector(s) 365 to provide reliable operation of the various circuitry on the sensor/control module 315 chip. Luminaire 10 also includes a dual-band wireless radio communication interface system configured for two way wireless communication. It should be understood that “dual-band” means communications over two separate RF bands. The communication over the two separate RF bands can occur simultaneously (concurrently); however, it should be understood that the communication over the two separate RF bands may not actually occur simultaneously. In our example, luminaire 10 has a radio set that includes radio 345 for sub-GHz communications and another radio 350 for Bluetooth RF communications. A first transceiver 345, such as a 900 MHz wireless transceiver, issues control operations on the lighting control network. This first transceiver 345 is for any-to-many (unicast and multicast) communication, over a first of the two different wireless communication bands, of control and systems operations information, during luminaire operation and during control network operation over the first wireless communication band. Two transport methods ride on the network layer function of the first transceiver 345: unicast and multicast. The first transceiver 345 engages in multicast group communication of a one-to-many or a many-to-many distribution where group communication is addressed to a group simultaneously. A second transceiver 350, such as a 2.4 GHz BLE (Bluetooth) wireless transceiver carries out commissioning, maintenance, and diagnostics of the lighting control network. This second transceiver 350 is for point-to-point communication, over a second of the two different wireless communication bands, of information other than the control and systems operations information, concurrently with at least some communications over the first wireless communication band. As shown, the MCU 330 includes programming in the memory 322 which configures the CPU (processor) 323 to control operations of the respective luminaire 10, including the communications over the two different wireless communication bands via the dual-band wireless radio communication interface system 345, 350. The programming in the memory 322 includes a real-time operating system (RTOS) and further includes a lighting application 327 which is firmware/software that engages in communications with the commissioning/maintenance application 22 of mobile device 25 over the commissioning network 7 of FIGS. 1A-B. The lighting application 327 programming in the memory 322 carries out lighting control operations over the lighting control network 5 of FIGS. 1A-B. The RTOS supports multiple concurrent processing threads for different simultaneous control or communication operations of the luminaire 10. Three different CPU and memory architectures are shown for the sensor/control module 315 and the MCU 330 of the luminaire 10 in FIGS. 3A-C. In FIG. 3A, in addition to the memory 322 and the CPU 323 of the MCU 330 itself, the first transceiver 345 and the second transceiver 350 each include a separate memory (not shown) and a processor (not shown). Hence, in the example of FIG. 3A, the sensor/control module 15 includes a total of three processors and three sets of memory. In FIG. 3B, the MCU 330 itself does not include a separate memory 322 and a CPU 323. Instead, only the first transceiver 345 and the second transceiver 350 each include a separate memory 322 and a processor 323. For efficiency purposes, such as to save manufacturing costs and conserve power (e.g., line power or battery power), the memory 322 and CPU 323 of the first transceiver 345 is selected to perform processing because the majority of processing (normal lighting control operations) occur over the sub-GHz wireless control network 5. Hence, in the example of FIG. 3B, the sensor/control module 315 includes a total of two processors and two sets of memory. In FIG. 3C, the MCU 330 comprises a dual band system on chip (SOC) 345, 350 and the MCU 330 itself does not include a separate memory 322 and a CPU 323. Instead, the first transceiver 345 and the second transceiver 350 are integrated and combined into the chipset of the MCU 330. Hence, in the example of FIG. 3C, the sensor/control module 315 includes a total of one processor and one set of memory. Integrating the first transceiver 345 and second transceiver 350 into a dual band SOC chipset of the MCU 330, saves manufacturing costs and conserves power (e.g., line power or battery power). As shown, luminaire 10 includes detector(s) 365, such as an in-fixture daylight sensor, an occupancy sensor, an audio sensor, a temperature sensor, or other environmental sensor. Detector(s) 365 may be based on Acuity Brands Lighting's commercially available xPoint® Wireless ES7 product. Drive/sense circuitry 335, such as application firmware, drives the in-fixture occupancy, audio, and photo sensor hardware. Outlined below are lighting controls and communications in the lighting control network that occur when drive/sense circuitry 335 of luminaire 10 detects state changes in the detector(s) 365, such as occupancy, daylight, and audio sensors. Sensor State Change When an occupancy sensor, daylight sensor, or audio sensor state change occurs is detected by drive/sense circuitry 335, MCU 330 of the luminaire 10 generates a network packet(s) and a wireless message is created with a state change event as at least part of the payload. The message is sent to the group monitor via the transceiver radio 345 as reliable unicast (unless luminaire 10 is hosting the group monitor) by the lighting application 327 running on MCU. If a gateway 50 (shown in FIGS. 1A-B) is present, a wireless gateway notification is created indicating the sensor, the sensor state (occupied or unoccupied, inhibiting or not inhibiting), the group, and the zone. The message is then unicast to the gateway 50 by the lighting application 327 running on MCU 330. If the luminaire 10 misses acknowledgement of the wireless message indicating the sensor state change that luminaire 10 unicasted to group monitor within a predetermined time period, for example, then the luminaire 10 generates and issues/transmits a group multicast message indicating the sensor state change. No check message follow up is issued from the luminaire 10 following this multicast message, but such communication faults and anomalies are tallied by the luminaire 10 for health status reporting as described with reference to FIGS. 1A-B. Group Monitor The group monitor acknowledges receipt of the unicast message (MAC layer) from the luminaire 10 indicating the sensor state change. The group monitor extracts the payload of the network packet(s) from the unicast message and creates a multicast message in response using the extracted payload of the unicast message. The group monitor interrogates the extracted payload of the unicast message to determine the type of control and the zone. The payload of the multicast message indicates or specifies a lighting control event (e.g., turn on/off or dim a light source) and specifies a lighting control group, for example, using a lighting control group identifier. The created multicast message and extracted payload of the unicast message are temporarily saved. The group monitor transmits the multicast message at least two or three times, for example. The group monitor also sends the extracted payload to the applications that share the processor with the group monitor. If a gateway 50 (see FIG. 1A) is present and the type of control is occupancy, daylight, or audio sensor related or the zone to make the adjustment to is global, a gateway notification is created indicating the sensor, its state (occupied or unoccupied, inhibiting or not inhibiting), the group, and the zone. The message is then reliably unicast to the gateway 50. After interrogating the extracted payload to determine the type of control and zone, the group monitor uses the group table to look up the set of lighting control devices that are members of the zone. The group monitor forms a check message using at least part of the extracted payload of the unicast message as the payload. The group monitor sends the message reliable unicast to each device in the zone as a check to confirm the receipt of the multicast in order as specified in the lighting control group network table. This confirmation check is not made with the luminaire 10 that has the sensor that actually initiated the state change event. The group monitor service accommodates concurrent multiple occupancy, daylighting, or audio events irrespective of zone. The group monitor service cancels a confirmation check if it receives a state that obsolesces an active state in progress. In this case, the group monitor service starts a new confirmation check based on the latest state. If the group monitor misses the unicast message from the luminaire 10 but gets the multicast issued by the luminaire 10—the group monitor executes the gateway and zone check described above. Recipient Lighting Control Devices Upon receipt of a multicast message from the group monitor at a recipient lighting control device (e.g., luminaire, wall switch, plug load controller, or power pack) that was sent in response to the original message from luminaire 10, the recipient device checks the group indication and the counter. The message is discarded if the lighting control device is not a member of the identified lighting control group specified in the message. The message is also discarded if it is a duplicate (multicast switch state change events are transmitted at least two or three times, for example, by the group monitor). The payload is extracted from the multicast message and processed by the lighting application 327 running on the MCU 330. Upon receipt of the confirmation check, the message is acknowledged (MAC). The recipient lighting control device determines if it has already acted on the event. If not, then the payload is extracted from the unicast message and processed by the lighting application 327 running on the MCU 330. Applications are responsible for either processing the extracted payload or discarding it as out of zone scope. For example, upon receipt of the multicast message from the lighting control group monitor at a respective recipient lighting control device, the respective recipient lighting control device checks a lighting control group identifier to determine whether the respective recipient control device is a member of the identified lighting control group in the message. The recipient lighting control device then determines whether the recipient lighting control device has already acted on a lighting control event (e.g., turn on/off or dim a light source) for lighting control network operation that is similar or identical to the event in the multicast message. If the recipient lighting control device has not already acted in accordance with the control event for lighting control operation, the recipient lighting control device adjusts one of its own LED light source(s) in accordance with the control event. Alternatively, if the recipient lighting control device has already acted on the lighting control event specified in the multicast message, no further action is taken in response by discarding the multicast message. In an example, the scope of daylight light sensor control is that of the hosting luminaire 10 itself. Therefore events of this type may only be processed locally and not distributed over the lighting control network 5. FIGS. 4A-C are block diagrams of a wall switch 20 that communicate via the lighting control system of FIGS. 1A-B. The circuitry, hardware, and software of wall switch 20 shown is similar to the luminaire 10 of FIG. 3. However, wall switch 20 is a controller that can be a battery powered device. Wall switch 20 is similar to luminaire 10 in that they are singularly addressable devices that can be configured to operate as a member of one or more lighting control groups or zones. As shown, wall switch 20 includes a power supply 405, such as a battery or line power, to power itself. Wall switch 10 furthers include an LED driver circuit 410, and a light emitting diode(s) (LED) 420. LED driver circuit 410 is coupled to LED(s) 420 and drives that LED(s) 420 by regulating the power to LED(s) 420 by providing a constant quantity or power to LED light source 420 as its electrical properties change with temperature, for example. The LED driver circuit 410 includes a driver circuit that provides power to LED(s) 420 and a pilot LED 417. LED driver circuit 410 may be a constant-voltage driver, constant-current driver, or AC LED driver type circuit that provides dimming through a pulse width modulation circuit and may have many channels for separate control of different LEDs or LED arrays. An example of a commercially available intelligent LED driver circuit 410 is manufactured by EldoLED. LED driver circuit 410 can further include an AC or DC current source or voltage source, a regulator, an amplifier (such as a linear amplifier or switching amplifier), a buck, boost, or buck/boost converter, or any other similar type of circuit or component. LED driver circuit 410 outputs a variable voltage or current to the LED light source 420 that may include a DC offset, such that its average value is nonzero, and/or a AC voltage. The pilot LED 417 indicates the state of the wall switch 20, for example, during the commissioning and maintenance process. As shown, an MCU 430 is coupled to LED driver circuit 410 and controls the light source operation of the LED(s) 420. MCU 430 includes a memory 422 (volatile and non-volatile) and a central processing unit (CPU) 423. The memory 422 includes a lighting application 427 (which can be firmware) for both lighting control operations and commissioning/maintenance operations. The power distribution circuitry 425 distributes power and ground voltages to the LED driver circuit 410, MCU 430, drive/sense circuitry 435, wireless transceivers 445 and 450, and switches 465 to provide reliable operation of the various circuitry on the wall switch 20. Wall switch 20 also includes a dual-band wireless radio communication interface system configured for two way wireless communication. In our example, wall switch 12 has a radio set that includes radio 445 for sub-GHz communications an another radio 450 for Bluetooth RF communication. A first transceiver 445, such as a 900 MHz wireless transceiver, issues control operations on the lighting control network. This first transceiver 445 is for any-to-many (unicast and multicast) communication, over a first of the two different wireless communication bands, of control and systems operations information, during luminaire operation and during control network operation over the first wireless communication band. A second transceiver 450, such as a 2.4 GHz BLE (Bluetooth) wireless transceiver carries out commissioning and maintenance of the lighting control network. This second transceiver 450 is for point-to-point communication, over a second of the two different wireless communication bands, of information other than the control and systems operations information, concurrently with at least some communications over the first wireless communication band. As shown, the MCU 430 includes programming in the memory 422 which configures the CPU (processor) 423 to control operations of the respective wall switch 20, including the communications over the two different wireless communication bands via the dual-band wireless radio communication interface system 445, 450. The programming in the memory 422 includes a real-time operating system (RTOS) and further includes a lighting application 427 which is firmware/software that engages in communications with the commissioning/maintenance application 22 of mobile device 25 over the commissioning network 7 of FIGS. 1A-B. The lighting application 427 programming in the memory 422 carries out lighting control operations over the lighting control network 5 of FIGS. 1A-B. The RTOS supports multiple concurrent processing threads for different simultaneous control or communication operations of the wall switch 20. Three different CPU and memory architectures are shown for the MCU 430 of the wall switch 20 in FIGS. 4A-C. In FIG. 4A, in addition to the memory 422 and the CPU 423 of the MCU 430 itself, the first transceiver 445 and the second transceiver 450 each include a separate memory (not shown) and a processor (not shown). Hence, in the example of FIG. 4A, the MCU 430, first transceiver 445, and second transceiver 450 combine to include a total of three processors and three sets of memory. In FIG. 4B, the MCU 430 itself does not include a separate memory 422 and a CPU 423. Instead, only the first transceiver 445 and the second transceiver 450 each include a separate memory 422 and a processor 423. For efficiency purposes, such as to save manufacturing costs and conserve power (e.g., line power or battery power), the memory 422 and CPU 423 of the first transceiver 445 is selected to perform processing because the majority of processing (normal lighting control operations) occur over the sub-GHz wireless control network 5. Hence, in the example of FIG. 4B, the sensor/control module 415 includes a total of two processors and two sets of memory. In FIG. 4C, the MCU 430 comprises a dual band system on chip (SOC) 445, 450 and the MCU 430 itself does not include a separate memory 422 and a CPU 423. Instead, the first transceiver 445 and the second transceiver 450 are integrated and combined into the chipset of the MCU 430. Hence, in the example of FIG. 4C, the MCU 430 includes a total of one processor and one set of memory. Integrating the first transceiver 445 and second transceiver 450 into a dual band SOC chipset of the MCU 330, saves manufacturing costs and conserves power (e.g., line power or battery power). As shown, wall switch 20 includes switches 465, such as a dimmer switch, set scene switch. Switches 465 can be or include sensors, such as infrared sensors for occupancy or motion detection, an in-fixture daylight sensor, an audio sensor, a temperature sensor, or other environmental sensor. Switches 465 may be based on Acuity Brands Lighting's commercially available xPoint® Wireless ES7 product. Drive/sense circuitry 435, such as application firmware, drives the occupancy, audio, and photo sensor hardware. In our example, wall switch 20 includes a single shared button switch 465 for on/off functions that requires knowledge of state to differentiate between on and off. The wireless control network 5 communicates output device (luminaire 10, plug load controller 30, power pack 35) state to the wall switches 20 as a means of providing the differentiating state. However, the wireless control network 5 suppresses the communication of output devices to constrain network traffic. Therefore control network 5 will rely on the default mechanism (tracked on the device) for determining on/off on all of the types of wall switch. It is therefore possible for the wall switch 20 to occasionally be out of sync with the actual state of the zone particularly at installation commissioning time. Toggling the switch button 465 one or more times will clear any mismatched state. In our example, wireless control network 5 does not communicate load state via the pilot LED 417 of wall switch 20) 20; however, in other examples wireless control network 5 communicates load state via the pilot LED 417 of wall switch 20. Outlined below are lighting controls and communications in the lighting control network that occur when drive/sense circuitry 435 detects state changes in the switches 365 of wall switch 20. Wall Switch Button Pushed When the on switch 465 is pushed, the lighting application 427 running on MCU 430 generates a network packet(s) having a payload indicating the control event. A wireless message is created with the network packet(s) having the payload indicating the control event. The message is sent to the group monitor as reliable unicast. If a gateway 50 (see FIG. 1A) is present and if the message is a switch on/off control, then a gateway notification is created indicating the wall switch 20, the state of the wall switch 20, the group, and the zone. The message is unicasted to the gateway 50. If the wall switch 20 is a battery powered (sleepy) type wall switch which uses a sleep feature as a means of power conservation and thus requires a special mechanism to acquire certain communications upon wake up, the following extension is used. The wall switch 20 detects the button push and turns on the transceiver radio 445 and transmits the wireless message with the network packet(s) having the payload indicating the control event. Next, the wall switch 20 cancels its wake up timer. The timer wakes the device to check its mailbox in the case where no button push has occurred for a while. The wall switch 20 sends a request for communications to the mail box server on the group monitor. The group monitor returns the contents of the mailbox addressed to the wall switch. The wall switch 20 processes each request. Examples include a request for health status or a state change request. The wall switch sets it wake up timer and the timer period is directly related to the frequency of system health reporting. The lighting application 427 de-bounces a continual or rapid button depress sequence so as to not create a message storm at the group monitor. If the wall switch 20 doesn't receive the acknowledgment from the group monitor when the message having the payload indicating the control event is unicasted to the group monitor, then the switch will generate and issue the group multicast. In this instance, no check message follow up is issued from the wall switch 20. Communication faults and anomalies are tallied by the switch for health status reporting as described previously with reference to luminaire 10. Group Monitor The group monitor acknowledges (MAC layer) receipt of the unicast message from the wall switch 20 indicating pushing of the on switch 465. The group monitor extracts the payload of the network packet(s) from the unicast message and creates a multicast message in response using the extracted payload of the unicast message. The group monitor interrogates the extracted payload of the unicast message to determine the type of control and the zone. The payload of the multicast message indicates or specifies a lighting control event (e.g., turn on/off or dim a light source) and specifies a lighting control group, for example, using a lighting control group identifier. The created multicast message and extracted payload of the unicast message are temporarily saved. The group monitor transmits the multicast message at least two or three times, for example. The group monitor also sends the extracted payload to the applications that share the processor with the group monitor. If a gateway 50 (see FIG. 1A) is present and the type of control is a switch on/off or the zone to make the adjustment to is global, then a gateway notification is created indicating the state of the switch, the group, and the zone. The message is reliably unicast to the gateway 50. The group monitor uses the group table to look up the set of devices that are members of the zone. The group monitor forms a check message using at least part of the saved extracted payload of the unicast message as the payload. The group monitor sends the message (reliable unicast) to each lighting control device in the zone as a check to confirm the receipt of the multicast. Of note, the confirmation check is not made with the wall switch 20 that actually initiated the control event. The group monitor service accommodates concurrent multiple switch on/off events irrespective of zone. The group monitor service cancels a confirmation check if it receives a state that obsolesces an active state in progress. In this case the group monitor service starts a new confirmation check based on the latest state. If the group monitor misses the unicast message from the switch but gets the multicast issued by the switch - the group monitor executes the gateway and zone check described above. Recipient Lighting Control Devices Upon receipt of a multicast message from the group monitor at a recipient lighting control device (e.g., luminaire, wall switch, plug load controller, or power pack) that was sent in response to the original message from wall switch 20, the recipient device checks the group indication and the counter. The message is discarded if the recipient device is not a member of the identified lighting control group specified in the message. The message is also discarded if it is a duplicate (multicast switch state change events are transmitted at least two or three times, for example, by the group monitor). The payload is extracted from the multicast message and processed by the lighting application 427 running on the MCU 430. Upon receipt of the confirmation check, the message is acknowledged (MAC). The recipient lighting control device determines if it has already acted on the event. If not then the payload is extracted from the unicast message and processed by the lighting application 427. The applications are responsible for either processing the extracted payload or discarding it as out of zone scope. For example, upon receipt of the multicast message from the lighting control group monitor at a respective recipient lighting control device, the respective recipient lighting control device checks a lighting control group identifier to determine whether the respective recipient control device is a member of the identified lighting control group in the message. The recipient lighting control device then determines whether the recipient lighting control device has already acted on a lighting control event (turn on/off or dim) for lighting control network operation that is similar or identical to the event in the multicast message. If the recipient lighting control device has not already acted in accordance with the control event for lighting control operation, the recipient lighting control device adjusts one of its own LED light source(s) in accordance with the control event. Alternatively, if the recipient lighting control device has already acted on the lighting control event specified in the multicast message, no further action is taken in response by discarding the multicast message. FIG. 5 is a block diagram of a plug load controller 30 that communicates via the lighting control system of FIG. 1B. The circuitry, hardware, and software of plug load controller 30 shown is similar to the luminaire 10 of FIG. 3. However, plug load controller 30 is a retrofit device that plugs into existing AC wall outlets, for example, and allows existing wired lighting devices, such as table lamps or floor lamps that plug into a wall outlet, to operate in the lighting control system. The plug load controller 30 instantiates the table lamp or floor lamp by allowing for commissioning and maintenance operations and processes wireless lighting controls in order to the allow the lighting device to operate in the lighting control system. Plug load controller 30 is similar to luminaire 10 in that they are singularly addressable devices that can be configured to operate as a member of one or more lighting control groups or zones. As shown, plug load controller 30 includes a DC conversion circuit 505 (which may instead be a power supply) driven by a power source 500, in our example, an AC line or mains. Power source 500, however, may be a battery, solar panel, or any other AC or DC source. DC conversion circuit 505 receives power from the power source 500, and may include a magnetic transformer, electronic transformer, switching converter, rectifier, or any other similar type of circuit to convert an input power signal into a suitable power signal to power itself. Plug load controller 500 further comprises an AC power relay 560 which relays incoming AC power from power source 500 to other devices that may plug into the receptacle of plug load controller 30 thus providing an AC power outlet 570. Plug load controller 30 furthers include an LED driver circuit 510 and a light emitting diode(s) (LED) 520. LED driver circuit 510 is coupled to LED(s) 520 and drives that LED(s) 520 by regulating the power to LED(s) 520 by providing a constant quantity or power to LED(s) 520 as its electrical properties change with temperature, for example. The LED driver circuit 510 includes a driver circuit that provides power to LED(s) 520 and a pilot LED 517. LED driver circuit 510 may be a constant-voltage driver, constant-current driver, or AC LED driver type circuit that provides dimming through a pulse width modulation circuit and may have many channels for separate control of different LEDs or LED arrays. An example of a commercially available intelligent LED driver circuit 510 is manufactured by EldoLED. LED driver circuit 510 can further include an AC or DC current source or voltage source, a regulator, an amplifier (such as a linear amplifier or switching amplifier), a buck, boost, or buck/boost converter, or any other similar type of circuit or component. LED driver circuit 510 outputs a variable voltage or current to the LED(s) 520 that may include a DC offset, such that its average value is nonzero, and/or a AC voltage. The pilot LED 417 indicates the state of the plug load controller 30, for example, during the commissioning and maintenance process. For purposes of communication and control, plug load controller 30 is treated as single addressable device that can be configured to operate as a member of one or more lighting control groups or zones. The plug load controller 30 is line powered and remains operational as long as power is available. Plug load controller 30 includes power distribution circuitry 525 and a micro-control unit (MCU) 530. As shown, MCU 530 is coupled to LED driver circuit 510 and controls the light source operation of the LED(s) 520. MCU 530 includes a memory 522 (volatile and non-volatile) and a central processing unit (CPU) 523. The memory 522 includes a lighting application 527 (which can be firmware) for both lighting control operations and commissioning/maintenance operations. The power distribution circuitry 525 distributes power and ground voltages to the LED driver circuit 510, MCU 530, and wireless transceivers 545 and 550 to provide reliable operation of the various circuitry on the plug load controller 30 chip. Plug load controller 30 also includes a dual-band wireless radio communication interface system configured for two way wireless communication. In our example, plug load controller 30 has a radio set that includes radio 545 for sub-GHz communications and another radio 550 for Bluetooth RF communications. A first transceiver 545, such as a 900 MHz wireless transceiver, issues control operations on the lighting control network. This first transceiver 545 is for any-to-many (unicast and multicast) communication, over a first of the two different wireless communication bands, of control and systems operations information, during luminaire operation and during control network operation over the first wireless communication band. A second transceiver 550, such as a 2.4 GHz BLE (Bluetooth) wireless transceiver carries out commissioning and maintenance of the lighting control network. This second transceiver 550 is for point-to-point communication, over a second of the two different wireless communication bands, of information other than the control and systems operations information, concurrently with at least some communications over the first wireless communication band. As shown, the MCU 530 includes programming in the memory 522 which configures the CPU (processor) 523 to control operations of the respective plug load controller 30, including the communications over the two different wireless communication bands via the dual-band wireless radio communication interface system 545, 550. The programming in the memory 522 includes a real-time operating system (RTOS) and further includes a lighting application 527 which is firmware/software that engages in communications with the commissioning/maintenance application 22 of mobile device 25 over the commissioning network 7 of FIGS. 1A-B. The lighting application 527 programming in the memory 522 carries out lighting control operations over the lighting control network 5 of FIGS. 1A-B. The RTOS supports multiple concurrent processing threads for different simultaneous control or communication operations of the plug load controller 30. Although not shown, it should be understood that the MCU 530 of plug load controller 30 may be of the three different CPU and memory architectures depicted and described for the luminaire 10 in FIGS. 3A-C and the wall switch 20 in FIGS. 4A-C. As explained earlier, integrating the first transceiver 545 and second transceiver 550, for example, into a dual band SOC chipset of the MCU 530, saves manufacturing costs and conserves power (e.g., line power or battery power). Plug load controller 30 may include detector(s), such as a daylight sensor, an occupancy sensor, an audio sensor, a temperature sensor, or other environmental sensor (not shown). Detector(s) may be based on Acuity Brands Lighting's commercially available xPoint® Wireless ES7 product. Drive/sense circuitry (not shown), such as application firmware, can drive the occupancy and photo sensor hardware. FIG. 6 is a block diagram of a power pack 35 that communicates via the lighting control system of FIG. 1B. The circuitry, hardware, and software of power pack 35 shown is similar to the luminaire 10 of FIG. 3. However, power pack 35 is a device that retrofits with existing wired light fixtures (luminaires). The power pack 35 instantiates the wired light fixture by allowing for commissioning and maintenance operations and processes wireless lighting controls in order to allow the lighting device to operate in the lighting control system. Power pack 35 is similar to luminaire 10 in that they are singularly addressable devices that can be configured to operate as a member of one or more lighting control groups or zones. As shown, power pack 35 includes a DC conversion circuit 605 (which may instead be a power supply) driven by a power source 600, in our example, an AC line or mains. Power source 600, however, may be a battery, solar panel, or any other AC or DC source. DC conversion circuit 605 receives power from the power source 600, and may include a magnetic transformer, electronic transformer, switching converter, rectifier, or any other similar type of circuit to convert an input power signal into a suitable power signal to power itself. Power pack 35 further comprises an AC power relay 660 which relays incoming AC power from power source 600 to the existing wired luminaire. Power pack 35 furthers include an LED driver circuit 610. LED driver circuit 610 is coupled to luminaire and drives that luminaire by regulating a driving signal, in our example, a 0-10V dimming signal 620. The LED driver circuit 610 includes a driver circuit that provides power to a pilot LED 617 and a dimming signal to luminaire 620. LED driver circuit 610 may be a constant-voltage driver, constant-current driver, or AC LED driver type circuit that provides dimming through a pulse width modulation circuit and may have many channels for separate control of different LEDs or LED arrays. An example of a commercially available intelligent LED driver circuit 610 is manufactured by EldoLED. LED driver circuit 610 can further include an AC or DC current source or voltage source, a regulator, an amplifier (such as a linear amplifier or switching amplifier), a buck, boost, or buck/boost converter, or any other similar type of circuit or component. LED driver circuit 610 outputs a variable voltage or current as the dimming signal to luminaire(s) 620 that may include a DC offset, such that its average value is nonzero, and/or a AC voltage. The pilot LED 617 indicates the state of the power pack 35, for example, during the commissioning and maintenance process. For purposes of communication and control, power pack 35 is treated as single addressable device that can be configured to operate as a member of one or more lighting control groups or zones. The power pack 35 is line powered and remains operational as long as power is available. Power pack 35 includes power distribution circuitry 625 and a micro-control unit (MCU) 630. As shown, MCU 630 is coupled to LED driver circuit 610 and controls the light source operation of the luminaire via the dimming signal to luminaire 620. MCU 630 includes a memory 622 (volatile and non-volatile) and a central processing unit (CPU) 623. The memory 622 includes a lighting application 627 (which can be firmware) for both lighting control operations and commissioning/maintenance operations. The power distribution circuitry 625 distributes power and ground voltages to the LED driver circuit 610, MCU 630, and wireless transceivers 645 and 650 to provide reliable operation of the various circuitry on the power pack 35 chip. Power pack 35 also includes a dual-band wireless radio communication interface system configured for two way wireless communication. In our example, power pack 35 has a radio set that includes radio 645 for sub-GHz communications and another radio 650 for Bluetooth RF communications. A first transceiver 645, such as a 900 MHz wireless transceiver, issues control operations on the lighting control network. This first transceiver 645 is for any-to-many (unicast and multicast) communication, over a first of the two different wireless communication bands, of control and systems operations information, during luminaire operation and during control network operation over the first wireless communication band. A second transceiver 650, such as a 2.4 GHz BLE (Bluetooth) wireless transceiver carries out commissioning and maintenance of the lighting control network. This second transceiver 650 is for point-to-point communication, over a second of the two different wireless communication bands, of information other than the control and systems operations information, concurrently with at least some communications over the first wireless communication band. As shown, the MCU 630 includes programming in the memory 622 which configures the CPU (processor) 623 to control operations of the respective power pack 35, including the communications over the two different wireless communication bands via the dual-band wireless radio communication interface system 645, 650. The programming in the memory 622 includes a real-time operating system (RTOS) and further includes a lighting application 627 which is firmware/software that engages in communications with the commissioning/maintenance application 22 of mobile device 25 over the commissioning network 7 of FIGS. 1A-B. The lighting application 627 programming in the memory 622 carries out lighting control operations over the lighting control network 5 of FIGS. 1A-B. The RTOS supports multiple concurrent processing threads for different simultaneous control or communication operations of the power pack 35. Although not shown, it should be understood that the MCU 630 of power pack 35 may be of the three different CPU and memory architectures depicted and described for the luminaire 10 in FIGS. 3A-C and the wall switch 20 in FIGS. 4A-C. As explained earlier, integrating the first transceiver 645 and second transceiver 650, for example, into a dual band SOC chipset of the MCU 630, saves manufacturing costs and conserves power (e.g., line power or battery power). Power pack 35 may include detector(s), such as a daylight sensor, an occupancy sensor, an audio sensor, a temperature sensor, or other environmental sensor (not shown). Detector(s) may be based on Acuity Brands Lighting's commercially available xPoint® Wireless ES7 product. Drive/sense circuitry (not shown), such as application firmware, can drive the occupancy and photo sensor hardware. FIG. 7 is a flow chart presenting the states and transitions for the various lighting control devices of FIGS. 1A-B. As shown in FIG. 7, the various lighting control devices (luminaires 10A-N, wall switches 20A-N, plug load controller 30, and power pack 35) go through a series of states and transitions during commissioning of the lighting control system, when lighting control operations are executed, and during maintenance. Beginning in block 700, lighting control devices are not yet powered up or installed. Moving now to block 710, upon power up after installation the lighting control devices behave as autonomous devices. There is no sub-GHz subnetwork to provide collaborative control, however the lighting control devices begin BLE beaconing to identify themselves to a commissioning/maintenance application 22 executing on a mobile device 25. Upon power up, luminaries 10A-N enter an autonomous control mode that permits the integrated detector(s) (e.g., occupancy, daylight/photo, or audio sensors) to exert limited control (lights on/off, dim up/down) of the light fixture. The control behavior is defined as default settings for the device. After power up, wall switches 20A-N may turn off their beacons after a predetermined time period (e.g., one hour) after powering up in order to conserve battery life. While in an installed state, the wall switches 20A-N can be induced to restart their beacons by pushing any button offered. For example, the wall switches 20A-N switch off their beacons after a predetermined time period (e.g., one hour) after a button push. On board pilot LEDs of the luminaires 10A-N, wall switches 20A-N, and other lighting control devices visually signal the state of the lighting control device (for all states) as an aid to the system installer and maintainer that is operating the commissioning/maintenance application 22 on the mobile device 25. The pilot LED goes off when the lighting control device is in an installed state. Continuing now to block 720, the luminaires 10A-N, wall switches 20A-N, and other lighting control devices enter a commissioning state from the installed state upon connection to the commissioning/maintenance application 22 of the mobile device 25. The luminaires 10A-N, wall switches 20A-N, and other lighting control devices receive configuration information via the commissioning/maintenance application 22 and will transition to an operational state upon completing the commissioning process and connecting to the group subnetwork. The advertising beacon signals a sub-state while the luminaires 10A-N and wall switches 20A-N undergo commissioning. The luminaires 10A-N, wall switches 20A-N, and other lighting control devices advertise an un-configured sub-state until completion of MAC-PHY configuration. Afterwards and until operational, the wall switches 20A-N or luminaires 10A-N advertise a waiting-connect (sub-GHz net) sub-state. Each of the luminaires 10A-N, wall switches 20A-N, and other lighting control devices is commanded to issue a blink during its commissioning phase, otherwise the LED is off. Proceeding now to block 730, the luminaires 10A-N, wall switches 20A-N, and other lighting control devices participate in collaborative group and zone lighting control while in an operational state. For example, sensors 365 of luminaires 10A-N, wall switches 20A-N, and other lighting control devices affect zone behavior by signaling control measures to the lighting elements in the zone's fixtures. As a security measure all luminaires 10A-N, wall switches 20A-N, and other lighting control devices, with the exception of the group monitor, cease BLE beaconing during the operational state. The group monitor changes its advertisement to indicate its role as the group monitor and its state (operational). The pilot LED remains off during the operational state. Continuing now to block 740, depending on condition, luminaires 10A-N, wall switches 20A-N, and other lighting control devices experiencing faults may enter a degraded state where partial capability is available. It may be possible to correct a degraded state through the commissioning/maintenance application 22 of the mobile device 25. In this case, the degraded luminaires 10A-N, wall switches 20A-N, and other lighting control devices are commanded to switch to the maintenance state, the commissioning/maintenance application 22 of the mobile device 25 is connected, a fix is attempted, and the device transitions to either operational state or back to degraded state depending on outcome of fix. Pilot LEDs can issue a bright S-O-S indication of three rapid blinks, three off counts, and three rapid blinks while in degraded state. Upon button push, wall switches issue the same S-O-S type of signal 5 times and then cease activity to conserve battery power. Moving now to block 750, luminaires 10A-N, wall switches 20A-N, and other lighting control devices can be commanded to enter a maintenance state. The command arrives over the lighting control network (sub-GHz network) from the group monitor. The luminaires 10A-N, wall switches 20A-N, and other lighting control devices maintain full or degraded operating capability while in the maintenance state. The luminaires 10A-N, wall switches 20A-N, and other lighting control devices resume BLE advertising (state=maintenance) seeking connection with commissioning/maintenance application 22 of the mobile device 25. Luminaires 10A-N, wall switches 20A-N, and other lighting control devices can then be re-configured via the commissioning/maintenance application 22 of the mobile device 25. The luminaires 10A-N, wall switches 20A-N, and other lighting control devices transition to an operational (or degraded) state upon command to exit the maintenance state. The pilot LED executes a continuous bright blink when in the maintenance state. Upon button push, wall switches 20A-N issue the same continuous bright blink type of signal 5 times and then cease LED activity to conserve battery power. FIG. 8 is a high-level functional block diagram of a mobile device 25 for commissioning and maintenance of the lighting control system of FIGS. 1A-B. Shown are elements of a touch screen type of mobile device 25 having the commissioning/maintenance application 22 loaded, although other non-touch type mobile devices can be used in the prior token-based communications under consideration here. Examples of touch screen type mobile devices that may be used include (but are not limited to) a smart phone, a personal digital assistant (PDA), a tablet computer or other portable device. However, the structure and operation of the touch screen type devices 25 is provided by way of example; and the subject technology as described herein is not intended to be limited thereto. For purposes of this discussion, FIG. 8 therefore provides a block diagram illustration of the example of mobile device 25 having a touch screen display for displaying content and receiving user input as (or as part of) the user interface. The activities that are the focus of discussions here typically involve data communications. As shown in FIG. 8, the mobile device 25 includes a first digital transceiver (XCVR) 809a, for digital wireless communications via a wide area wireless mobile communication network and second digital XCVR 810a for digital wireless communications via a Bluetooth network, although the mobile device 25 may include additional digital or analog transceivers (not shown). The transceiver 810a (network communication interface) conforms to one or more of the various digital wireless communication standards for Bluetooth communications. As discussed previously, communications through the Bluetooth transceiver 810a and the commissioning network 7 shown in FIGS. 1A-B relate to protocols and procedures in support of commissioning and maintaining lighting control devices, including luminaires 10A-N, wall switches 20A-N, plug load controller 30, and power pack 35. In addition, communications to gateway 50 are also supported. Such communications, for example, may utilize IP packet data transport utilizing the digital wireless transceiver (XCVR) 810a and over the air communications via commissioning network 7 shown in FIGS. 1A-B. Transceiver 810a connects through radio frequency (RF) send-and-receive amplifiers (not shown) to an antenna 810b. The transceiver 809a (network communication interface) conforms to one or more of the various digital wireless communication standards utilized by modern mobile networks. Examples of such transceivers include (but are not limited to) transceivers configured to operate in accordance with Code Division Multiple Access (CDMA) and 3rd Generation Partnership Project (3GPP) network technologies including, for example and without limitation, 3GPP type 2 (or 3GPP2) and LTE, at times referred to as “4G.” For example, transceiver 809a provides two-way wireless communication of information including digitized audio signals, still image and/or video signals, web page information for display as well as web related inputs, and various types of mobile message communications to/from the mobile device 25. In one example, the transceiver 809a sends and receives a variety of signaling messages in support of various data services provided by a network of a wireless service provider, to user(s) of mobile device 25 via a mobile communication network (not shown). Transceiver 809a also connects through radio frequency (RF) send-and-receive amplifiers (not shown) to an antenna 809b. Many modern mobile device(s) 25 also support wireless local area network communications over WiFi, instead of or in addition to data communications using the wide area mobile communication network. Hence, in the example of FIG. 8, for packet data communications, mobile device 25 may also include a WiFi transceiver 811a and associated antenna 811b. Although WiFi is used here as the example, the transceiver 811a may take the form of any available two-way wireless local area network (WLAN) transceiver of a type that is compatible with one or more standard protocols of communication implemented in wireless local area networks, such as one of the WiFi standards under IEEE 802.11 and/or WiMAX. The transceiver 811a, for example, may provide two-way data transport for wireless communication with a wireless access point in a residence or enterprise that the user frequents or with any available hotspot offered in a public venue. A WiFi access point (not shown), communicates with compatible user equipment, such as the mobile device 25, over the air using the applicable WiFi protocol. The WiFi access point provides network connectivity, usually to a wide area network 55 (as shown in FIGS. 1A-B), such as the Internet. In a home or office premises, for example, the WiFi access point would connect directly or via a local area network (LAN) to a line providing internet access service. In a more public venue, an access point configured as a hotspot may offer similar connectivity for customers or others using the venue, on terms and conditions set by the venue operator. Although communicating through a different network or networks, the transceiver 811a supports various types of data communications similar to the packet data communications supported via the mobile network transceiver 809a, including communications to and from gateway 50 and the other devices shown in FIGS. 1A-B. The mobile device 25 further includes a microprocessor, sometimes referred to herein as the host controller 802. A processor 802 is a circuit having elements structured and arranged to perform one or more processing functions, typically various data processing functions. Although discrete logic components could be used, the examples utilize components forming a programmable CPU. A microprocessor 802 for example includes one or more integrated circuit (IC) chips incorporating the electronic elements to perform the functions of the CPU. The processor 802, for example, may be based on any known or available microprocessor architecture, such as a Reduced Instruction Set Computing (RISC) using an ARM architecture, as commonly used today in mobile devices and other portable electronic devices. Of course, other processor circuitry may be used to form the CPU or processor hardware in mobile device 25, other devices and server computers (e.g., gateway 50), network elements, etc. Returning more specifically to the mobile device 25 example of FIG. 8, the microprocessor 802 serves as a programmable host controller for mobile device 25 by configuring device 25 to perform various operations, for example, in accordance with instructions or programming executable by processor 802. For example, such operations may include various general operations of the mobile device 25, as well as operations related to communications with luminaires 10A-N, wall switches 20A-N and other lighting control devices during commissioning and maintenance performed by the commissioning/maintenance application 22. Although a processor may be configured by use of hardwired logic, typical processors in mobile devices are general processing circuits configured by execution of programming. The mobile device 25 includes a memory or storage system 804, for storing data and programming. In the example, the memory system 804 may include a flash memory 804a and a random access memory (RAM) 804b. The RAM 804b serves as short term storage for instructions and data being handled by the processor 802, e.g. as a working data processing memory. The flash memory 804a typically provides longer term storage. Hence, in the example of mobile device 25, the flash memory 804a is used to store programming or instructions for execution by the processor 802. Depending on the type of device, the mobile device 25 stores and runs a mobile operating system through which specific applications, including commissioning/maintenance application 22 (which may be a web browser executing a dynamic web page) or a native application, run on the mobile device 25. Examples of mobile operating systems include Google Android, Apple iOS (I-Phone or iPad devices), Windows Mobile, Amazon Fire OS, RIM BlackBerry operating system, or the like. Flash memory 804a may also be used to store mobile configuration settings for different mobile applications or services executable at device 25 using processor 802. Of course, other storage devices or configurations may be added to or substituted for those in the example. Such other storage devices may be implemented using any type of storage medium having computer or processor readable instructions or programming stored therein and may include, for example, any or all of the tangible memory of the computers, processors or the like, or associated modules. The instructions or programming may be used to implement any other device functions associated with communications for commissioning and maintenance on mobile device 25. Program aspects of the technology may be thought of as “products” or “articles of manufacture” typically in the form of executable code or process instructions and/or associated data that is stored on or embodied in a type of machine or processor readable medium (e.g., transitory or non-transitory), such as one of the memories 804a, 804b of memory system 804, or a memory of a computer used to download or otherwise install such programming into the mobile device, or a transportable storage device or a communications medium for carrying program for installation in the mobile device 25. In the example, the flash memory 804a stores applications for execution by the microprocessor-based host controller 802, typically through operation/execution of the device operating system. Of note, for purposes of the present discussion, the flash memory 804 stores a commissioning/maintenance application 22 as one of the programs for execution by the microprocessor 802. Execution of commissioning/maintenance application 22 by the microprocessor 802 configures mobile device 25 to perform a variety of functions, particularly to commission and maintain the lighting control devices over the commissioning network 7. In the example, commissioning/maintenance application 22 also engages in communications with the gateway 50. In the illustrated example, the mobile device 25 includes a secure component 800. The secure component 800 (e.g. a secure element or “SE”) may be provisioned as a section within the memory 804 or may take the form of a universal integrated circuit card (UICC) located within the device 25. A common example of a UICC implementation of the SE 800 is a subscriber identity module (SIM). As discussed above, the SE provides secure storage for various identifiers associated with mobile device 25. The SE typically has a unique identifier and is provisioned for operation of the mobile device 25 by storage of a mobile directory number (MDN) and/or mobile identification number (MIN) assigned to the device 25 by the carrier network operator. The secure component contains applications that use secure keys running inside the secure processor. Although similar to other applications, the applications for the secure processor are sometimes smaller and sometimes referred to as applets 843. In an example, commissioning/maintenance application 22 may be an applet residing in the SE 800. For example, there may be at least one applet 842 to engage in communications. The mobile device 25 may include a variety of different types of physical user interface elements to interact with the commissioning/maintenance application 22. For discussion purposes, in the mobile device 25 shown in FIG. 8, the physical user interface elements of device 20 includes a touch screen display 820 (also referred to herein as “touch screen 820” or “display 820”) to support gestures. For output purposes, the touch screen 820 includes a display screen, such as a liquid crystal display (LCD) or the like. For input purposes, touch screen display 820 includes a plurality of touch sensors 822. A keypad may be implemented in hardware as a physical keyboard of mobile device 25, and keys may correspond to hardware keys of such a keyboard. Alternatively, some or all of the keys 830 (and keyboard) of device 25 may be implemented as “soft keys” of a virtual keyboard graphically represented in an appropriate arrangement via touch screen display 820. The soft keys presented on the touch screen display 820 may allow the user of device 25 to invoke the same user interface functions as with the physical hardware keys for authentication purposes. In general, touch screen display 820 and touch sensors 822 (and one or more keys 630, if included) are used to provide a textual and graphical user interface for the mobile device 25. In an example, touch screen display 820 provides viewable content to the user at device 25. Touch screen display 820 also enables the user to interact directly with the viewable content provided in the content display area, typically by touching the surface of the screen with a finger or an implement such as a stylus. As shown in FIG. 8, the mobile device 25 also includes a sense circuit 828 coupled to touch sensors 822 for detecting the occurrence and relative location/position of each touch with respect to a content display area of touch screen display 820. In this example, sense circuit 828 is configured to provide processor 802 with touch-position information based on user input received via touch sensors 822. In some implementations, processor 802 is configured to correlate the touch position information to specific content being displayed within the content display area on touch screen display 820. The touch-position information captured by the sense circuit 828 and provided to processor 802 may include, but is not limited to, coordinates identifying the location of each detected touch with respect to the display area of touch screen display 820 and a timestamp corresponding to each detected touch position. Accordingly, the processor 802 may determine input of a phone number, a token, or menu identifiers selected during audible scripts, for example. Various packet formats are shown in FIGS. 9A-C. In FIG. 9A, a media access control (MAC) layer message for communicating a state change event to a lighting control device on a lighting control network is shown. As shown, a MAC layer message 900 includes the following fields: option(s) 905, a source identifier 910, an RSSI/tag 915, a length of message 920, and a protocol data unit (PDU) or payload. In an example, the protocol for communicating the state change event is the AT command-response protocol defined in the SiLabs SPP-Over-BLE Application Note, 15, Nov. 2013, version 1.0, section 7. Options 905 may include a namespace field that has a command identifier. Source 910 identifies the lighting control device that has detected the state change event, for example, the source is the short sub-GHz MAC address of the detecting lighting control device. Length 920 specifies the length of the message, for example, number of bytes of the whole message (header plus payload plus checksum). Payload 925 is device specific and the form of the payload 925 is interpreted and managed by the lighting application 327. The MAC layer message 900 may further include a destination address (not shown) which is the sub-GHz short MAC address of the destination lighting control device (e.g., group/zone monitor). FIG. 9B is a transport layer message for communicating a state change event to a lighting control device on a lighting control network. As shown, the transport layer message 930 includes the following fields: version 935, protocol 940, multicast identification 945, and lighting control group/zone identification 950. Version 935 specifies the firmware protocol version of the lighting application 327, for example. Protocol 940 specifies the lighting control network command communication protocol. Multicast identification 945 specifies the broadcast channel or an address of the lighting control group/zone. Lighting control group/zone 950 identifies the lighting control group or zone of the lighting control device that detected the state change event. FIG. 9C is an application layer message for communicating a state change event to a lighting control device on a lighting control network. As shown, the application layer message 960 includes the broadcast channel or address of all of the lighting control group(s)/zone(s) that should receive the message. A lighting control group/zone monitor peaks into the application layer message 960 body and extracts the payload to pass the message to local and downstream lighting control devices. It will be understood that the terms and expressions used herein have the ordinary meaning as is accorded to such terms and expressions with respect to their corresponding respective areas of inquiry and study except where specific meanings have otherwise been set forth herein. Relational terms such as first and second and the like may be used solely to distinguish one entity or action from another without necessarily requiring or implying any actual such relationship or order between such entities or actions. The terms “comprises,” “comprising,” “includes,” “including,” or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. An element preceded by “a” or “an” does not, without further constraints, preclude the existence of additional identical elements in the process, method, article, or apparatus that comprises the element. Unless otherwise stated, any and all measurements, values, ratings, positions, magnitudes, sizes, and other specifications that are set forth in this specification, including in the claims that follow, are approximate, not exact. They are intended to have a reasonable range that is consistent with the functions to which they relate and with what is customary in the art to which they pertain. While the foregoing has described what are considered to be the best mode and/or other examples, it is understood that various modifications may be made therein and that the subject matter disclosed herein may be implemented in various forms and examples, and that they may be applied in numerous applications, only some of which have been described herein. It is intended by the following claims to claim any and all modifications and variations that fall within the true scope of the present concepts.
<SOH> BACKGROUND <EOH>Traditional luminaires can be turned ON and OFF, and in some cases may be dimmed, usually in response to user activation of a relatively simple input device. Often traditional luminaires are controlled individually or as relatively small groups at separate locations. More sophisticated lighting control systems automate the operation of the luminaires throughout a building or residence based upon preset time schedules, occupancy, and/or daylight sensing. Such lighting control systems receive sensor signals at a central lighting control panel, which responds to the received signals by deciding which, if any, relays, switching devices, and/or dimming ballasts to drive in order to turn on or off and/or adjust the light levels of one or more luminaires. More recent lighting systems are wireless; however, operating luminaires to operate over wireless communication systems using group based controls can be difficult. For example, multiple simultaneous control requests can ovewhelm a node that is tasked with managing the group. Accordingly, a system is needed to overcome these and other limitations in the art.
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>The drawing figures depict one or more implementations in accord with the present teachings, by way of example only, not by way of limitation. In the figures, like reference numerals refer to the same or similar elements. FIG. 1A is a high-level functional block diagram of an example of a system of networks and devices that provide a variety of lighting controls, including communications in support of turning lights on/off, dimming, set scene, and sensor trip events. FIG. 1B is another high-level functional block diagram of an example of a system of networks and devices that further includes plug load controller and power pack devices and various lighting control groups. FIG. 2 is a state change event protocol procedure for the lighting control system of FIGS. 1A-B . FIGS. 3A-C are block diagrams of luminaires that communicate via the lighting control system of FIG. 1A or FIG. 1B . FIGS. 4A-C are block diagrams of different examples of a wall switch that communicates via the lighting control system of FIG. 1A or FIG. 1B . FIG. 5 is a block diagram of a plug load controller that communicates via the lighting control system of FIG. 1B . FIG. 6 is a block diagram of a power pack that communicates via the lighting control system of FIG. 1B . FIG. 7 is a flow chart presenting the states and transitions for the various lighting control devices of FIGS. 1A-B . FIG. 8 is a high-level functional block diagram of a mobile device for commissioning and maintenance of the lighting control system of FIGS. 1A-B . FIG. 9A is a media access control (MAC) layer message for communicating a state change event to a lighting control device on a lighting control network. FIG. 9B is a transport layer message for communicating a state change event to a lighting control device on a lighting control network. FIG. 9C is an application layer message for communicating a state change event to a lighting control device on a lighting control network. detailed-description description="Detailed Description" end="lead"?
H05B370272
20170927
20180626
20180201
57220.0
H05B3702
0
LE, TUNG X
PROTOCOL FOR LIGHTING CONTROL VIA A WIRELESS NETWORK
UNDISCOUNTED
1
CONT-ACCEPTED
H05B
2,017
15,717,502
PENDING
Novel Reagents for Directed Biomarker Signal Amplification
Described herein are methods, compositions and articles of manufacture involving neutral conjugated polymers including methods for synthesis of neutral conjugated water-soluble polymers with linkers along the polymer main chain structure and terminal end capping units. Such polymers may serve in the fabrication of novel optoelectronic devices and in the development of highly efficient biosensors. The invention further relates to the application of these polymers in assay methods.
1-40. (canceled) 41. A water soluble conjugated polymer having the structure of the formula: wherein: Ar is an aryl or heteroaryl unit substituted with a non-ionic side group capable of imparting solubility in water; MU is a polymer modifying unit or band gap modifying unit that is evenly or randomly distributed along the polymer main chain and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C1-C12 alkoxy, C2-C18 (hetero)aryloxy, C2-C18 (hetero)arylamino, a C2-C18 (hetero)aryl group and (CH2)x′(OCH2CH2)y′OCH3 where x′ is independently an integer from 0-20 and y′ is independently an integer from 0 to 50; optional linkers L1 and L2 are each independently an aryl or a heteroaryl group evenly or randomly distributed along the polymer main chain and are substituted with one or more pendant chains terminated with: i) a functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated ester, N-hydroxysuccinimidyl, hydrazine, hydrazide, hydrazone, azide, alkyne, aldehyde, thiol, and protected groups thereof for conjugation to a molecule or biomolecule; or ii) a conjugated organic dye or biomolecule; G1 and G2 are each independently selected from hydrogen, halogen, alkyne, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic ester, boronic acid, optionally substituted fluorene and aryl or heteroaryl substituted with one or more pendant chains terminated with: i) a functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazine, hydrazide, hydrazone, azide, alkyne, aldehyde, thiol, and protected groups thereof for conjugation to a molecule or biomolecule; or ii) a conjugated organic dye or biomolecule; wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated ester, N-hydroxysuccinimidyl, hydrazines, hydrazide, hydrazone, azide, alkyne, aldehyde, and thiol within G1, G2, L1 or L2, or a conjugated organic dye or biomolecule; n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. 42. The water soluble conjugated polymer according to claim 41, wherein MU is selected from optionally substituted benzothiadiazole, benzoxidazole, benzoselenadiazole, benzotellurodiazole, naphthoselenadiazole, 4,7-di(thien-2-yl)-2,1,3-benzothiadiazole, squaraine dyes, quinoxaline, perylene, perylene diimide, diketopyrrolopyrrole, thienopyrazine low bandgap commercial dyes, olefin, and cyano-substituted olefins and isomers thereof. 43. The water soluble conjugated polymer according to claim 41, wherein MU is selected from the group consisting of a′- k′ having the structure: wherein * is a site for covalent attachment to unsaturated backbone and each R is a non-ionic side group capable of imparting solubility in water. 44. The water soluble conjugated polymer according to claim 43, wherein MU is selected from one of the following: wherein * is site for covalent attachment to unsaturated backbone. 45. The water soluble conjugated polymer according to claim 41, wherein MU is a phenyl. 46. The water soluble conjugated polymer according to claim 45, wherein MU is wherein *=site for covalent attachment to unsaturated backbone. 47. The water soluble conjugated polymer according to claim 41, wherein the non-ionic side group comprises an ethylene glycol oligomer. 48. The water soluble conjugated polymer according to claim 47, wherein the non-ionic side group comprises mPEG5, mPEG8, mPEG11 or mPEG24. 49. The water soluble conjugated polymer according to claim 47, wherein Ar is substituted with one or more groups selected from (CH2)x′(OCH2CH2)y′OCH3 where x′ is independently an integer from 0-20 and y′ is independently an integer from 0 to 50, and a benzyl substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)zOCH3 where z is independently an integer from 0 to 50. 50. The water soluble conjugated polymer according to claim 47, wherein Ar is substituted with one or more (CH2)x′(OCH2CH2)y′OCH3 where x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50. 51. The water soluble conjugated polymer according to claim 47, wherein Ar is substituted with a dendrimer of PAMAM, PEA, PEHAM, PPI, tri-branched benzoate, or glycerol with a generation of 1 to 4 and optional terminal substitutions selected from (- - - - -)CH2CH2O)jCH3 and (- - - - -)OCH2CH2)jCH3 where j is an integer from 0 to 25 and the dotted lines (- - - - -) are each independently selected from any one or a combination of, C1-C12 alkyl, C1-C12 alkoxy, C2-C12 alkene, amido, amino, aryl, (CH2)r(OCH2CH2)s(CH2)r where each r is independently an integer from 0-20, s is independently an integer from 0 to 50, carbamate, carboxylate, C3-C12 cycloalkyl, imido, phenoxy and C4-C18(hetero)aryl group. 52. The water soluble conjugated polymer according to claim 41, wherein Ar is a substituted fluorene unit. 53. The water soluble conjugated polymer according to claim 41, wherein L1 and/or L2 are present. 54. The water soluble conjugated polymer according to claim 53, wherein L1 and/or L2 is conjugated to a signaling chromophore. 55. The water soluble conjugated polymer according to claim 53, wherein L1 and/or L2 have the structure: wherein: *=site for covalent attachment to backbone; each R25 is independently a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl; (CH2)x(OCH2CH2)p(CH2)x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50; aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups; and at least one R25 is terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated ester, N-hydroxysuccinimidyl, hydrazine, hydrazide, hydrazone, azide, alkyne, aldehyde and thiols, or a conjugated organic dye or biomolecule. 56. The water soluble conjugated polymer according to claim 55, wherein L1 and/or L2 have the structure: 57. The water soluble conjugated polymer according to claim 41, wherein at least one of G1 and G2 comprises a functional conjugation site. 58. The water soluble conjugated polymer according to claim 57, wherein at least one of G1 and G2 has the structure: wherein: *=site for covalent attachment to backbone; and R11 is a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl, (CH2)x(OCH2CH2)p(CH2)x wherein each x is independently an integer from 0-20 and p is an integer from 0 to 50, aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonate, sulfide, disulfide, or imido groups; and is terminated with: i) a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof, or ii) a conjugated organic dye or biomolecule. 59. The water soluble conjugated polymer according to claim 41, wherein at least one of G1 and G2 is selected from the group consisting of capping units 1-31 having the structures: wherein: *=site for covalent attachment to backbone; k is 2, 4, 8, 12 or 24; and R15 is selected from the group consisting of 1-t having the structures: 60. The water soluble conjugated polymer according to claim 59, wherein at least one of G1 and G2 is selected from one of the following structures:
CROSS-REFERENCE This application is a continuation of application Ser. No. 15/239,713, filed Aug. 17, 2016; which application is a continuation of application Ser. No. 14/821,386, filed Aug. 7, 2015 and issued as U.S. Pat. No. 9,547,008; which application is a continuation of application Ser. No. 14/018,985, filed Sep. 5, 2013 and issued as U.S. Pat. No. 9,139,869; which application is a continuation of application Ser. No. 13/009,764, filed Jan. 19, 2011 and issued as U.S. Pat. No. 8,575,303, which claims the benefit of U.S. Provisional Application Ser. No. 61/296,379, filed Jan. 19, 2010 and U.S. Provisional Application Ser. No. 61/358,406, filed Jun. 24, 2010, which applications are incorporated herein by reference in their entireties. BACKGROUND OF THE INVENTION Fluorescent hybridization probes have developed into an important tool in the sequence-specific detection of DNA and RNA. The signals generated by the appended fluorescent labels (or dyes) can be monitored in real time and provide simple, rapid, and robust methods for the detection of biological targets and events. Utility has been seen in applications ranging from microarrays and real time PCR to fluorescence in situ hybridization (FISH). Recent work in the area of multichromophores, particularly regarding conjugated polymers (CPs) has highlighted the potential these materials have in significantly improving the detection sensitivity of such methods (Liu and Bazan, Chem. Mater., 2004). The light harvesting structures of these materials can be made water soluble and adapted to amplify the fluorescent output of various probe labels (See U.S. patent application Ser. No. 10/600,286, filed Jun. 20, 2003 and Gaylord, Heeger, and Bazan, Proc. Natl. Acad. Sci., 2002, both of which are incorporated herein by reference in their entirety). Results such as these indicate CPs to be highly promising in the field of nucleic acid diagnostics, particularly where sample quantities are scarce. However, there exist methods for the amplification (or replication) of nucleic acid targets, i.e., PCR. Comparatively, in the field of protein recognition, there are no such simple methods for amplifying the targeted materials. As such, signal enhancement arising from CP application is of high consequence in this area. Dye-labeled antibodies are regularly used for the detection of protein targets in applications such as immunohistochemistry, protein arrays, ELISA tests, and flow cytometry. Integrating CP materials into such methodologies promises to provide a dramatic boost in the performance of such assays, enabling detection levels previously unattainable with conventional fluorescent reporters (e.g., dyes). Beyond addition signal, one of the other key drivers in biological detection formats is the ability to detect multiple analytes in the same test or multiplexing. This is commonly achieved by using fluorescent reporters with operate at different, decernable wavelengths. CP materials are ideally suited to provide a platform for expanded multiplexing. This can be achieved by tuning the structure of different CPs to operate at different wavelengths or by incorporating a dye within the polymer-biomolecule conjugate. The material and methods to produce higher sensitivity biological assays and increase multiplexing are highly desired in both molecular (nucleic acid) and immunoassay formats. SUMMARY OF THE INVENTION Provided herein are water soluble conjugated polymers of Formula (I): wherein: each R is independently a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL; MU is a polymer modifying unit or band gap modifying unit that is evenly or randomly distributed along the polymer main chain and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C1-C12 alkoxy, C2-C18(hetero)aryloxy, C2-C18(hetero)arylamino, (CH2)x′(OCH2CH2)y′OCH3 where each x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50, or a C2-C18(hetero)aryl group; each optional linker L1 and L2 are aryl or heteroaryl groups evenly or randomly distributed along the polymer main chain and are substituted with one or more pendant chains terminated with a functional group for conjugation to another substrate, molecule or biomolecule selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof; G1 and G2 are each independently selected from hydrogen, halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiol, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters, boronic acids, optionally substituted fluorene and aryl or heteroaryl substituted with one or more pendant chains terminated with a functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule; wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, and thiols within G1, G2, L1 or L2 that allows, for functional conjugation to another molecule, substrate or biomolecule; each dashed bond, - - - - - - , is independently a single bond, triple bond or optionally substituted vinylene (—CR5═CR5—) wherein each R5 is independently hydrogen, cyano, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group, wherein each C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, or C1-C12 haloalkyl; and n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. In one aspect, water soluble conjugated polymers of Formula (I) have the structure of Formula (Ia): wherein R, L1, L2, G1, G2, MU, a, b, c, d and n are described previously for formula (I). In some embodiments, each R is independently (CH2)x(OCH2CH2)yOCH3 where each x is independently an integer from 0-20, each y is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)zOCH3 where each z is independently an integer from 0 to 50. In some instances, each R is (CH2)3(OCH2CH2)11OCH3. In other embodiments, each R is a benzyl substituted with at least one (OCH2CH2)10OCH3 group. In some instances, the benzyl is substituted with two (OCH2CH2)10OCH3 groups. In other instances, the benzyl is substituted with three (OCH2CH2)10OCH3 groups. In some embodiments, optional linkers L1 or L2 have the structure: *=site for covalent attachment to unsaturated backbone; wherein R3 is independently hydrogen, halogen, alkoxy(C1-C12), C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group, wherein each C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, or C1-C12 haloalkyl; and q is an integer from 0 to 4. In other embodiments, optional linkers L1 or L2 have the structure: *=site for covalent attachment to unsaturated backbone wherein A is a site for conjugation, chain extension or crosslinking and is [O—CH2—CH2]q—W, or (C1-C12)alkoxy-X or C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule.; W is —OH or —COOH; X is —NH2, —NHCOOH, —NHCOOC(CH3)3, —NHCO(C3-C12)cycloalkyl(C1-C4)alkyl-N-maleimide; or —NHCO[CH2—CH2—O]tNH2; q is an integer from 1 to 20; and t is an integer from 1 to 8. In yet other embodiments, optional linkers L1 or L2 have the structure: *=site for covalent attachment to backbone wherein R25 are each independently any one of or a combination of a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl, (CH2)x(OCH2CH2)p(CH2)x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups; wherein at least one R25 is terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In further embodiments, optional linkers L1 or L2 have the structure: *=site for covalent attachment to unsaturated backbone; wherein R35 is any one of or a combination of a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl, (CH2)x(OCH2CH2)p(CH2)x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In further embodiments, optional linkers L1 or L2 are selected from the group consisting of a-h having the structures: *=site for covalent attachment to unsaturated backbone; wherein R′ is independently H, halogen, C1-C12 alkyl, (C1-C12 alkyl)NH2, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C2-C18(hetero)aryl, C2-C18(hetero)arylamino, —[CH2—CH2]r′—Z1, or (C1-C12)alkoxy-X1; and wherein Z1 is —OH or —COOH; X1 is —NH2, —NHCOOH, —NHCOOC(CH3)3, —NHCO(C3-C12)cycloalkyl(C1-C4)alkyl-N-maleimide; or —NHCO[CH2—CH2—O]s′(CH2)s′NH2; r′ is an integer from 1 to 20; and each s′ is independently an integer from 1 to 20, (CH2)3(OCH2CH2)x″OCH3 where x″ is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)y—OCH3 where each y″ is independently an integer from 0 to 50 and R′ is different from R; wherein k is 2, 4, 8, 12 or 24; wherein R15 is selected from the group consisting of 1-t having the structure: *=site for covalent attachment to backbone. In yet further embodiments, optional linkers L1 or L2 are In some embodiments, G1 and G2 are each independently selected from hydrogen, halogen, alkyne, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters, boronic acids, optionally substituted fluorine and aryl or heteroaryl substituted with one or more pendant chains terminated with a functional group, molecule or biomolecule selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In some embodiments, G1 and G2 each independently have the structure wherein R11 is any one of or a combination of a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl, (CH2)x(OCH2CH2)p(CH2)x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In other embodiments, G1 and G2 are each independently selected from the group consisting of 1-31 having the structures: *=site for covalent attachment to backbone wherein R15 is selected from the group consisting of 1-t having the structure: and k is 2, 4, 8, 12 or 24. In further embodiments, G1 and G2 are optionally substituted aryl or heteroaryl wherein the optional substituent is selected from halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiol, boronic acid, boronate radical, boronic esters and optionally substituted fluorene. In some embodiments, G1 and G2 are the same. In other embodiments, G1 and G2 are different. In further embodiments, the polymer contains a single conjugation site at only one terminus of the polymer chain G1 or G2. In yet further embodiments, G1 and G2 is In some embodiments, MU is selected from the group consisting of a′-k′ having the structure: *=site for covalent attachment to unsaturated backbone wherein R is a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL. In some embodiments, the water soluble conjugated polymer has the structure of formula: wherein at least one of G1 or G2 comprises a functional conjugation site. In some embodiments, the water soluble conjugated polymer has the structure of formula: wherein L1 comprises a functional conjugation site. In some embodiments, the water soluble conjugated polymer has the structure of formula: wherein at least one of G1 or G2 comprises a functional conjugation site. In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In some instances, a signaling chromophore is attached to the polymer via the NH2 group. In certain instances, the signaling chromophore is Cy3 or Dylight 594 dye. In certain instances, the linker, is about 10% of the entire polymer. In other instances, the polymer is conjugated to a secondary dye reporter and an antibody. In some embodiments of conjugated polymers described herein, the polymer is further conjugated to additional molecules. In some embodiments, the polymer is conjugated to a streptavidin, antibody or nucleic acid and used as a direct fluorescent reporter. In certain embodiments, the polymer is conjugated to a streptavidin. In other embodiments, the polymer is conjugated to thiol groups at the hinge region of an antibody. In yet other embodiments, the polymer is conjugated to an amine group on a protein which is modified with a heterobifuntional linker. In further embodiments, the polymer is conjugated to a nucleic acid. In yet further embodiments, the polymer is conjugated to an antibody. In certain instances, the polymer is conjugated to a monoclonal antibody, a secondary antibody or a primary antibody. In other instances, a polymer antibody conjugate is excited at about 405 nm in a flow cytometry assay where the specific signal is at least 3 fold greater than the same antibody conjugated to Pacific Blue. In some embodiments of conjugated polymers described herein, the polymer is purified by ion exchange chromatography. In other embodiments, the polymer is >95% pure. In some embodiments of conjugated polymers described herein, the polymer is used in flow cytometry assays to identify different cell markers or cell types. In other embodiments, the polymer is used to sort cells. In yet other embodiments, the polymer is used to sort cells for use in therapeutics. In some embodiments of conjugated polymers described herein, the polymer is used for intracellular staining. In certain instances, the polymer is used in flow cytometry assays to identify different cell markers or cell types. In some embodiments of conjugated polymers described herein, the polymer comprises a minimum number average molecular weight of greater than 40,000 g/mol and a water solubility of greater than 50 mg/mL in pure water or a phosphate buffered saline solution. In some embodiments of conjugated polymers described herein, the polymer comprises at least two unique conjugation linkers which can conjugated to two unique materials. Also provided herein are assay methods comprising providing a sample that is suspected of containing a target biomolecule; providing a sensor protein conjugated to at least one signaling chromophore and is capable of interacting with the target biomolecule or a target-associated biomolecule; providing a water soluble conjugated polymer described herein; contacting the sample with the sensor protein and the conjugated polymer in a solution under conditions in which the sensor protein can bind to the target biomolecule or a target-associated biomolecule if present; applying a light source to the sample that can excite the conjugated polymer; and detecting whether light is emitted from the signaling chromophore. In some embodiments, the sensor protein is an antibody. In other embodiments, the sensor protein comprises a plurality of sensor proteins conjugated to a plurality of signaling chromophores, wherein at least two of the plurality of chromophores emit different wavelengths of light upon energy transfer from the multichromophore. Also provided herein are conjugated polymer complexes comprising a polymer coupled to at least one biomolecule selected from the group consisting of a sensor biomolecule, a bioconjugate and a target biomolecule wherein the polymer is covalently bound by at least one bioconjugation site pendant thereto, and the polymer comprises a signaling chromophore or a signaling chromophore optionally is covalently bound to the polymer or the sensor biomolecule; wherein the polymer comprises the structure of formula: wherein: each R is a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL; MU is a polymer modifying unit or band gap modifying unit that is evenly or randomly distributed along the polymer main chain and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C1-C12 alkoxy, C2-C18(hetero)aryloxy, C2-C18(hetero)arylamino, (CH2)x′(OCH2CH2)y′OCH3 where each x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50, or a C2-C18(hetero)aryl group; each optional linker L1 and L2 are aryl or heteroaryl groups evenly or randomly distributed along the polymer main chain and are substituted with one or more pendant chains terminated with a functional group for conjugation to another molecule, substrate or biomolecule selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof; G1 and G2 are each independently selected from hydrogen, halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiol, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters, boronic acids, optionally substituted fluorene and aryl or heteroaryl substituted with one or more pendant chains terminated with a functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule; wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, and thiols within G1, G2, L1 or L2 that allows, for functional conjugation to another molecule, substrate or biomolecule; n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. In some embodiments, the sensor biomolecule is selected from the group consisting of an avidin, streptavidin, neutravidin, avidinDN, and avidinD. In other embodiments, the conjugated polymer complex is further configured to bind to a complex selected from the group consisting of a biotin-labeled antibody, biotin-labeled protein, and biotin-labeled target biomolecule. In further embodiments, the sensor biomolecule is an antibody. In yet further embodiments, both the signaling chromophore and the sensor biomolecule are covalently linked to the multichromophore through a plurality of linkers. In some other embodiments, both the signaling chromophore and the sensor biomolecule are covalently linked to the polymer through a central linking site that covalently binds the polymer, the signaling chromophore and the sensor biomolecule. In yet other embodiments, the signaling chromophore, when covalently bound to the polymer or the sensor biomolecule, is an organic dye. Also provided herein are water soluble conjugated polymer having the structure of Formula (Ia): wherein: each R is independently (CH2)x(OCH2CH2)yOCH3 where each x is independently an integer from 0-20, y is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)zOCH3 where each z is independently an integer from 0 to 50; each optional linker L1 or L2 is selected from the group consisting of a-i having the structure *=site for covalent attachment to unsaturated backbone wherein R′ is independently H, halogen, C1-C12 alkyl, (C1-C12 alkyl)NH2, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C2-C18(hetero)aryl, C2-C18(hetero)arylamino, —[CH2—CH2]r′—Z1, or (C1-C12)alkoxy-X1; and wherein Z1 is —OH or —COOH; X1 is —NH2, —NHCOOH, —NHCOOC(CH3)3, —NHCO(C3-C12)cycloalkyl(C1-C4)alkyl-N-maleimide; or —NHCO[CH2—CH2—O]s′(CH2)s′NH2; r′ is an integer from 1 to 20; and each s′ is independently an integer from 1 to 20, (CH2)3(OCH2CH2)x″OCH3 where x″ is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)y″OCH3 where each y″ is independently an integer from 0 to 50 and R′ is different from R; wherein R15 is selected from the group consisting of 1-t having the structure: and k is 2, 4, 8, 12 or 24; *=site for covalent attachment to backbone MU is a polymer modifying unit or band gap modifying unit that is selected from the group consisting of a′-k′ having the structure: *=site for covalent attachment to unsaturated backbone; wherein R is a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL; G1 and G2 are each independently selected from the group consisting of 1-31 having the structures: wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, and thiols within G1, G2, L1 or L2 that allows, for functional conjugation to another molecule, substrate or biomolecule; n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. Also provided herein are water soluble conjugated polymer having the structure of Formula: wherein Ar is an aryl or heteroaryl and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C1-C12 alkoxy, C2-C18(hetero)aryloxy, C2-C18(hetero)arylamino, (CH2)x′(OCH2CH2)y′OCH3 where each x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50; and dashed bonds, L1, L2, G1, G2, MU, a, b, c, d and n are described previously for formula (I). INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: FIG. 1. Schematic of binding of a conjugated polymer in one embodiment of the invention. FIG. 2. Schematic of a bioconjugated polymer of one embodiment of the invention. FIG. 3. Schematic of exemplary conjugated polymers conjugated (A) antibody; (B) an avidin; (C) nucleic acid; (D) dye, e.g., chromophore. FIG. 4. Schematic of (A) a polymer conjugated to dye-labeled antibody resulting in FRET; (B) a polymer conjugated dye-labeled strepavidin resulting in FRET; (C) nucleic acid probe sequences labeled with a quencher molecule conjugated to a conjugated polymer; (D) nucleic acid probe sequences labeled with a quencher molecule conjugated polymer-dye tandem complex. FIG. 5. Schematic of various methods of assaying for a target biomolecule or target associated biomolecule. (A) Conjugated polymer linked to a bioconjugate; (B) polymer and dye labeled antibodies recognize a common target; (C) sensor biomolecule conjugated to both a dye and a second bioconjugate; (D) second bioconjugate and the signaling chromopohre both conjugated to a nucleic acid. FIG. 6. Schematic of an addition of a second linking site within the polymer. FIG. 7. Schematic of a polymer conjugated to a dye and a biomolecule and resulting energy transfer (A) polymer is conjugated to both a bioconjugate; (B) polymer is conjugated to a strepavidin and a dye; (C) polymer is conjugated to a nucleic acid and a dye. FIG. 8. Schematic of indirect associations with a sensor biomolecule or target associated biomolecule. (A) biotinylated antibody interacting with a covalent conjugate of the conjugated polymer; (B) biotinylated antibody conjugated polymer-dye tandem complex; (C) biotinylated nucleic acid interacting with a covalent conjugate of the conjugated polymer; (D) biotinylated nucleic conjugated polymer-dye tandem complex; (E) nucleic acid with digoxygenin moiety interacting with a covalent conjugate of the conjugated polymer; (F) nucleic acid with digoxygenin moiety conjugated polymer-dye tandem complex. FIG. 9. Schematic of exemplary conjugated polymers conjugated to secondary antibodies ( ) and primary antibodies (B). FIG. 10. Schematic of a sandwich-type complex. (A) conjugated polymer complex bioconjugated to a strepavidin; (B) biotin-labeled 1° antibody e used to probe the target protein directly. FIG. 11. Schematic of appending one or two phenyl capping units to a fluorene polymer. FIG. 12. Block diagram showing a representative example logic device. FIG. 13. Block diagram showing a representative example of a kit. FIG. 14. Schematic of a streptavidin conjugation with a conjugated polymer and the resulting conjugate structure (top) and Coomassie stained agarose gel representative of the streptavidin-attached CP (below). FIG. 15. Representative acrylamide gel depiction of biotinylated polymer alone or bound to Cy5-labeled streptavidin. FIG. 16. Schematic of streptavidin-attached conjugated polymer of FIG. 14 binding to biotinylated microspheres (top) and plot of fluorescence excitation of control biotinylated microspheres and microspheres bound to streptavidin conjugated polymer. FIG. 17. Schematic of streptavidin-attached conjugated polymer of FIG. 14 selectively bound to biotinylated microspheres and energy transfer to dye acceptors on co-localized streptavidin-dye conjugates (top) and plot of energy transfer from streptavidin-attached conjugated polymer to dye acceptor (bottom). FIG. 18. Schematic of biotinylated polymer of FIG. 14 binding to streptavidin coated microspheres (top) and plot of fluorescence excitation of control streptavidin coated microspheres and microspheres bound to biotinylated polymer. FIG. 19. Schematic of biotinylated polymer of FIG. 14 binding to dye-labeled streptavidin conjugates and FRET (top); plot of energy transfer from biotinylated polymer to two different dye acceptors (bottom left) and titration plot of polymer saturation (bottom right). FIG. 20. Flow cytometry analysis of CD4 marking of Cyto-trol cells with 440 nm polymer-streptavidin-conjugates. FIG. 21. (A) Polymer structure of Example 38b conjugated to (from left to right) FITC, Cy3, DyLight 594 and DyLight633; (B) Comparison of the fluorescence of the dye (DyLight594) excited near its absorbance maximum (lower curve) and polymer-dye conjugate excited at 405 nm (upper curve); (C) Comparison of the fluorescent signal of the base polymer (no dye, peak emission near 420 nm) to that of the polymer-dye conjugate (peak emission near 620 nm). FIG. 22. Plot of flow testing of monoclonal antibody (antiCD4) conjugates on whole lysed blood samples. FIG. 23. Plot of florescence of a dye (DyLight594) and a polymer-dye conjugate by excitation of dye at 594 nm and the polymer-dye conjugate at 380 nm. FIG. 24. Plot of fluorescent immunoassay (ELISA) with streptavidin-attached conjugated polymer. FIG. 25. Plot of fluorescent intensity vs. temperature of a DNA oligomer-polymer conjugate hybridized to a target. FIG. 26. Ion exchange chromatogram for a polymer antibody conjugate to remove free polymer (left) and an SEC chromatogram showing the separation of final conjugate from free antibody. In both chromatograms absorbance was monitored at 280 nm (lower curves) and 407 nm (upper curves). FIG. 27. Sandwich immunoassay on Luminex assay (left) and corresponding results on the Luminex system using 532 nm excitation of both the conjugated polymer and PE streptavidin detection conjugates. FIG. 28. Data on left show results obtained with compensation beads while the data set on the right results from a 4 color assay on human blood samples. FIGS. 29. (A) and (B) Schematic of covalent linkage of conjugated polymer to 2° antibody. FIG. 30. Schematic of conjugated polymers in Fluorescent Immuno Assay (FIA). (A) conjugated polymer covalently linked to a detection antibody; (B) biotin binding protein covalently bound to the conjugated polymer and interacting with a biotinylated detection antibody; (C) secondary antibody covalently linked to the conjugated polymer and interacting with a detection antibody. FIG. 31. (A) Schematic of nucleic acid probe sequences labeled with a quencher molecule conjugated to a conjugated polymer; (B) nucleic acid probe sequences labeled with a quencher molecule conjugated to a conjugated polymer-dye tandem complex. FIG. 32. Schematic of modifications of the HybProbe detection technique. (A) conjugated polymer covalently linked to the donor probe and resulting energy transfer to acceptor probe; (B) “Signal off” modification of the HybProbe approach where the conjugated polymer is quenched by an acceptor probe. FIG. 33. Comparison of non-specific binding in various polymers (top) in a Jurkat cell (lymphocyte cell line) model; (bottom) plot ranking the polymers in terms of signal generated purely by non-specific binding (NSB). FIG. 34. Histograms collected from flow cytometry analysis (405 nm excitation in a BD LSR-II cytometer) using a Jurkat cell line; (left) unstained cells and a negative control, anionic P4 polymer; (middle) range of different polymer and polymer side chain combinations tested on the same cells; (right) neutral polymer P20 showed almost no off set from the untreated cells. FIG. 35. Gel electrophoresis depicting relative mobility of avidin as a function of the degree of conjugation with polymer AA1. FIG. 36. Fractionation of crude polymer-avidin conjugate mixtures on a Superdex 200 size exclusion column; (top) monitoring fractions by UV absorbance; (bottom) gel electrophoresis of selected fractions to visualize the degree to which avidin was attached to polymer. FIG. 37. Gel electrophoresis of conjugation reactions performed with polymer in varying molar excess to streptavidin; (left) UV illumination; (right) 532 nm excitation. FIG. 38. Plot depicting purification of polymer streptavidin conjugates with polymers exemplified in Example 9, denoted P30, (top) crude samples; (bottom) purified conjugates). DETAILED DESCRIPTION OF THE INVENTION Before the present invention is described in further detail, it is to be understood that this invention is not limited to the particular methodology, devices, solutions or apparatuses described, as such methods, devices, solutions or apparatuses can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention. Use of the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, reference to “an aggregation sensor” includes a plurality of aggregation sensors, reference to “a probe” includes a plurality of probes, and the like. Additionally, use of specific plural references, such as “two,” “three,” etc., read on larger numbers of the same subject less the context clearly dictates otherwise. Terms such as “connected,” “attached,” “conjugated” and “linked” are used interchangeably herein and encompass direct as well as indirect connection, attachment, linkage or conjugation unless the context clearly dictates otherwise; in one example, the phrase “conjugated polymer” is used in accordance with its ordinary meaning in the art and refers to a polymer containing an extended series of unsaturated bonds, and that context dictates that the term “conjugated” should be interpreted as something more than simply a direct or indirect connection, attachment or linkage. Where a range of values is recited, it is to be understood that each intervening integer value, and each fraction thereof, between the recited upper and lower limits of that range is also specifically disclosed, along with each subrange between such values. The upper and lower limits of any range can independently be included in or excluded from the range, and each range where either, neither or both limits are included is also encompassed within the invention. Where a value being discussed has inherent limits, for example where a component can be present at a concentration of from 0 to 100%, or where the pH of an aqueous solution can range from 1 to 14, those inherent limits are specifically disclosed. Where a value is explicitly recited, it is to be understood that values which are about the same quantity or amount as the recited value are also within the scope of the invention, as are ranges based thereon. Where a combination is disclosed, each subcombination of the elements of that combination is also specifically disclosed and is within the scope of the invention. Conversely, where different elements or groups of elements are disclosed, combinations thereof are also disclosed. Where any element of an invention is disclosed as having a plurality of alternatives, examples of that invention in which each alternative is excluded singly or in any combination with the other alternatives are also hereby disclosed; more than one element of an invention can have such exclusions, and all combinations of elements having such exclusions are hereby disclosed. Unless defined otherwise or the context clearly dictates otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are now described. All publications mentioned herein are hereby incorporated by reference for the purpose of disclosing and describing the particular materials and methodologies for which the reference was cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. Definitions In describing the present invention, the following terms will be employed, and are intended to be defined as indicated below. “Alkyl” refers to a branched, unbranched or cyclic saturated hydrocarbon group of 1 to 24 carbon atoms optionally substituted at one or more positions, and includes polycyclic compounds. Examples of alkyl groups include optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-decyl, hexyloctyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like, as well as cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and norbornyl. The term “lower alkyl” refers to an alkyl group of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Exemplary substituents on substituted alkyl groups include hydroxyl, cyano, alkoxy, ═O, ═S, —NO2, halogen, haloalkyl, heteroalkyl, carboxyalkyl, amine, amide, thioether and —SH. “Alkoxy” refers to an “—Oalkyl” group, where alkyl is as defined above. A “lower alkoxy” group intends an alkoxy group containing one to six, more preferably one to four, carbon atoms. “Alkenyl” refers to a branched, unbranched or cyclic hydrocarbon group of 2 to 24 carbon atoms containing at least one carbon-carbon double bond optionally substituted at one or more positions. Examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), 1-methylvinyl, cyclopropenyl, 1-butenyl, 2-butenyl, isobutenyl, 1,4-butadienyl, cyclobutenyl, 1-methylbut-2-enyl, 2-methylbut-2-en-4-yl, prenyl, pent-1-enyl, pent-3-enyl, 1,1-dimethylallyl, cyclopentenyl, hex-2-enyl, 1-methyl-1-ethylallyl, cyclohexenyl, heptenyl, cycloheptenyl, octenyl, cyclooctenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl and the like. Preferred alkenyl groups herein contain 2 to 12 carbon atoms. The term “lower alkenyl” intends an alkenyl group of 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. The term “cycloalkenyl” intends a cyclic alkenyl group of 3 to 8, preferably 5 or 6, carbon atoms. Exemplary substituents on substituted alkenyl groups include hydroxyl, cyano, alkoxy, ═O, ═S, —NO2, halogen, haloalkyl, heteroalkyl, amine, thioether and —SH. “Alkenyloxy” refers to an “—Oalkenyl” group, wherein alkenyl is as defined above. “Alkylaryl” refers to an alkyl group that is covalently joined to an aryl group. Preferably, the alkyl is a lower alkyl. Exemplary alkylaryl groups include benzyl, phenethyl, phenopropyl, 1-benzylethyl, phenobutyl, 2-benzylpropyl and the like. “Alkylaryloxy” refers to an “—Oalkylaryl” group, where alkylaryl is as defined above. “Alkynyl” refers to a branched or unbranched hydrocarbon group of 2 to 24 carbon atoms containing at least one —C “Amide” refers to —C(O)NR′R″, where R′ and R″ are independently selected from hydrogen, alkyl, aryl, and alkylaryl. “Amine” refers to an —N(R′)R″ group, where R′ and R″ are independently selected from hydrogen, alkyl, aryl, and alkylaryl. “Aryl” refers to an aromatic group that has at least one ring having a conjugated pi electron system and includes carbocyclic, heterocyclic, bridged and/or polycyclic aryl groups, and can be optionally substituted at one or more positions. Typical aryl groups contain 1 to 5 aromatic rings, which may be fused and/or linked. Exemplary aryl groups include phenyl, furanyl, azolyl, thiofuranyl, pyridyl, pyrimidyl, pyrazinyl, triazinyl, biphenyl, indenyl, benzofuranyl, indolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridopyridinyl, pyrrolopyridinyl, purinyl, tetralinyl and the like. Exemplary substituents on optionally substituted aryl groups include alkyl, alkoxy, alkyl carboxy, alkenyl, alkenyloxy, alkenylcarboxy, aryl, aryloxy, alkylaryl, alkylaryloxy, fused saturated or unsaturated optionally substituted rings, halogen, haloalkyl, heteroalkyl, —S(O)R, sulfonyl, —SO3R, —SR, —NO2, —NRR′, —OH, —CN, —C(O)R, —OC(O)R, —NHC(O)R, —(CH2)nCO2R or —(CH2)nCONRR′ where n is 0-4, and wherein R and R′ are independently H, alkyl, aryl or alkylaryl. “Aryloxy” refers to an “—Oaryl” group, where aryl is as defined above. “Carbocyclic” refers to an optionally substituted compound containing at least one ring and wherein all ring atoms are carbon, and can be saturated or unsaturated. “Carbocyclic aryl” refers to an optionally substituted aryl group wherein the ring atoms are carbon. “Halo” or “halogen” refers to fluoro, chloro, bromo or iodo. “Halide” refers to the anionic form of the halogens. “Haloalkyl” refers to an alkyl group substituted at one or more positions with a halogen, and includes alkyl groups substituted with only one type of halogen atom as well as alkyl groups substituted with a mixture of different types of halogen atoms. Exemplary haloalkyl groups include trihalomethyl groups, for example trifluoromemyl. “Heteroalkyl” refers to an alkyl group wherein one or more carbon atoms and associated hydrogen atom(s) are replaced by an optionally substituted heteroatom, and includes alkyl groups substituted with only one type of heteroatom as well as alkyl groups substituted with a mixture of different types of heteroatoms. Heteroatoms include oxygen, sulfur, and nitrogen. As used herein, nitrogen heteroatoms and sulfur heteroatoms include any oxidized form of nitrogen and sulfur, and any form of nitrogen having four covalent bonds including protonated forms. An optionally substituted heteroatom refers to replacement of one or more hydrogens attached to a nitrogen atom with alkyl, aryl, alkylaryl or hydroxyl. “Heterocyclic” refers to a compound containing at least one saturated or unsaturated ring having at least one heteroatom and optionally substituted at one or more positions. Typical heterocyclic groups contain 1 to 5 rings, which may be fused and/or linked, where the rings each contain five or six atoms. Examples of heterocyclic groups include piperidinyl, morpholinyl and pyrrolidinyl. Exemplary substituents for optionally substituted heterocyclic groups are as for alkyl and aryl at ring carbons and as for heteroalkyl at heteroatoms. “Heterocyclic aryl” refers to an aryl group having at least 1 heteroatom in at least one aromatic ring. Exemplary heterocyclic aryl groups include furanyl, thienyl, pyridyl, pyridazinyl, pyrrolyl, N-lower alkyl-pyrrolo, pyrimidyl, pyrazinyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl, imidazolyl, bipyridyl, tripyridyl, tetrapyridyl, phenazinyl, phenanthrolinyl, purinyl, perylene, perylene diimide, diketopyrrolopyrrole, benzothiodiazol, benzoxadiazol, thienopyrazine and the like. “Hydrocarbyl” refers to hydrocarbyl substituents containing 1 to about 20 carbon atoms, including branched, unbranched and cyclic species as well as saturated and unsaturated species, for example alkyl groups, alkylidenyl groups, alkenyl groups, alkylaryl groups, aryl groups, and the like. The term “lower hydrocarbyl” intends a hydrocarbyl group of one to six carbon atoms, preferably one to four carbon atoms. A “substituent” refers to a group that replaces one or more hydrogens attached to a carbon or nitrogen. Exemplary substituents include alkyl, alkylidenyl, alkylcarboxy, alkoxy, alkenyl, alkenylcarboxy, alkenyloxy, aryl, aryloxy, alkylaryl, alkylaryloxy, —OH, amide, carboxamide, carboxy, sulfonyl, ═O, ═S, —NO2, halogen, haloalkyl, fused saturated or unsaturated optionally substituted rings, —S(O)R, —SO3R, —SR, —NRR′, —OH, —CN, —C(O)R, —OC(O)R, —NHC(O)R, —(CH2)nCO2R or —(CH2)nCONRR′ where n is 0-4, and wherein R and R′ are independently H, alkyl, aryl or alkylaryl. Substituents also include replacement of a carbon atom and one or more associated hydrogen atoms with an optionally substituted heteroatom. “Sulfonyl” refers to —S(O)2R, where R is alkyl, aryl, —C(CN)═C-aryl, —CH2CN, alkylaryl, or amine. “Thioamide” refers to —C(S)NR′R″, where R′ and R″ are independently selected from hydrogen, alkyl, aryl, and alkylaryl. “Thioether” refers to —SR, where R is alkyl, aryl, or alkylaryl. As used herein, the term “binding pair” refers to first and second molecules that bind specifically to each other with greater affinity than to other components in the sample. The binding between the members of the binding pair is typically noncovalent. Exemplary binding pairs include immunological binding pairs (e.g. any haptenic or antigenic compound in combination with a corresponding antibody or binding portion or fragment thereof, for example digoxigenin and anti-digoxigenin, fluorescein and anti-fluorescein, dinitrophenol and anti-dinitrophenol, bromodeoxyuridine and anti-bromodeoxyuridine, mouse immunoglobulin and goat anti-mouse immunoglobulin) and nonimmunological binding pairs (e.g., biotin-avidin, biotin-streptavidin, hormone [e.g., thyroxine and cortisol]-hormone binding protein, receptor-receptor agonist or antagonist (e.g., acetylcholine receptor-acetylcholine or an analog thereof) IgG-protein A, lectin-carbohydrate, enzyme-enzyme cofactor, enzyme-enzyme-inhibitor, and complementary polynucleotide pairs capable of forming nucleic acid duplexes) and the like. One or both member of the binding pair can be conjugated to additional molecules. The terms “polynucleotide,” “oligonucleotide,” “nucleic acid” and “nucleic acid molecule” are used interchangeably herein to refer to a polymeric form of nucleotides of any length, and may comprise ribonucleotides, deoxyribonucleotides, analogs thereof, or mixtures thereof. These terms refer only to the primary structure of the molecule. Thus, the terms includes triple-, double- and single-stranded deoxyribonucleic acid (“DNA”), as well as triple-, double- and single-stranded ribonucleic acid (“RNA”). It also includes modified, for example by alkylation, and/or by capping, and unmodified forms of the polynucleotide. Additional details for these terms as well as for details of base pair formation can be found in U.S. application Ser. No. 11/344,942, filed Jan. 31, 2006, which is incorporate herein by reference in its entirety. “Complementary” or “substantially complementary” refers to the ability to hybridize or base pair between nucleotides or nucleic acids, such as, for instance, between a sensor peptide nucleic acid and a target polynucleotide. Complementary nucleotides are, generally, A and T (or A and U), or C and G. Two single-stranded polynucleotides or PNAs are said to be substantially complementary when the bases of one strand, optimally aligned and compared and with appropriate insertions or deletions, pair with at least about 80% of the bases of the other strand, usually at least about 90% to 95%, and more preferably from about 98 to 100%. Alternatively, substantial complementarity exists when a polynucleotide or PNA will hybridize under selective hybridization conditions to its complement. Typically, selective hybridization will occur when there is at least about 65% complementary over a stretch of at least 14 to 25 bases, preferably at least about 75%, more preferably at least about 90% complementary. See, M. Kanehisa Nucleic Acids Res. 12:203(1984). “Preferential binding” or “preferential hybridization” refers to the increased propensity of one polynucleotide or PNA to bind to its complement in a sample as compared to a noncomplementary polymer in the sample. Hybridization conditions for polynucleotides will typically include salt concentrations of less than about 1M, more usually less than about 500 mM and preferably less than about 200 mM. In the case of hybridization between a peptide nucleic acid and a polynucleotide, the hybridization can be done in solutions containing little or no salt. Hybridization temperatures can be as low as 5° C., but are typically greater than 22° C., more typically greater than about 30° C., and preferably in excess of about 37° C. Longer fragments may require higher hybridization temperatures for specific hybridization. Other factors may affect the stringency of hybridization, including base composition and length of the complementary strands, presence of organic solvents and extent of base mismatching, and the combination of parameters used is more important than the absolute measure of any one alone. Other hybridization conditions which may be controlled include buffer type and concentration, solution pH, presence and concentration of blocking reagents to decrease background binding such as repeat sequences or blocking protein solutions, detergent type(s) and concentrations, molecules such as polymers which increase the relative concentration of the polynucleotides, metal ion(s) and their concentration(s), chelator(s) and their concentrations, and other conditions known in the art. “Multiplexing” herein refers to an assay or other analytical method in which multiple analytes can be assayed simultaneously. “Having” is an open ended phrase like “comprising” and “including,” and includes circumstances where additional elements are included and circumstances where they are not. “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. The embodiments disclosed herein relate generally to compositions of conjugated polymer materials that contain active functional groups for conjugation (or attachment) to other molecules, substrates or the like. Certain embodiments describe methods and compositions that provide for specific control of the incorporation and subsequent conjugation of such functional sites. Linkers can be incorporated at one or both ends of a conjugated polymer chain or internally controlled by ratio of monomers used in the polymerizations. Such linkers can be the same or different to allow for more than one distinct entity to be attached to the conjugated polymer structure. Further embodiments describe conjugated polymer compositions that not only provide for active conjugation sites but also are solublized through the use of non-ionic side chains (no formal charges). Such embodiments exhibit exceptional water solubility and provide minimal interactions with biological molecules and other common biological assay components. The embodiments disclosed herein further relate generally to assays and complexes including conjugated polymers useful for the identification of target biomolecules or biomolecules associated with target molecules through enhanced signal afforded by their unique properties. In certain general embodiments the conjugated polymer serves directly as the optical reporter bound to a biomolecule, substrate or other assay component. The conjugated polymers act as extended light harvesting structures that when excited can absorb more energy than conventional organic dyes. The polymer then re-emits the light which can be detected or measured. The signals generated from such conjugated polymer complexes can be significantly greater than those obtained from other fluorescent reporters. In other embodiments one aspect includes energy transfer from conjugated polymers to dyes bound to the polymer or to a sensor which can be a biomolecule including a bioconjugate (e.g., an antibody, a streptavidin or nucleic acid sequence). In such embodiments it is common to observe amplified dye signal (relative to direct dye excitation) as a result of the conjugated polymer excitation and subsequent energy transfer. Further it is possible to use a range of dyes with varying energy to create a basis for a multicolor or multiplex detection format. In certain embodiments the neutral conjugated polymers are bound to antibodies for the identification of specific cell markers and cell types in flow cytometry and cell sorting assays. In other embodiments the conjugated polymers are further bound to a secondary dye reporter. In further embodiments the polymer and polymer-dye structures are bound to monoclonal antibodies. In other embodiments the neutral conjugated polymers are bound to antibodies for use in various sandwich immunoassays. In one embodiment, an approach modifying a format as followed in relation to nucleic acid sensor assays as described in Gaylord, Heeger, and Bazan, J. Am. Chem. Soc., 2003 can be followed. Specifically, signal amplification of conjugated polymers can be based on binding events to indicate a hybridization event. Any established conjugated polymers can be chosen as the donor, and one or more dye, preferably a dye with a history of efficient energy transfer, for example, fluorescein and Cy3, can be chosen as the acceptors. It is envisioned that the dye can be directly conjugated to a sensor molecule. As shown schematically in FIG. 1, the sensor can be a biomolecule (e.g., an antibody) in a solution or on a substrate, to which conjugated polymers can be added. In the embodiment shown in FIG. 1, a dye can be covalently linked (bioconjugated) to an antibody (Y-shaped structure), which possesses a net negative charge. Addition of conjugated polymers (shown as wavy lines) can result in interaction or binding between the conjugated polymer and the antibody, bringing the conjugated polymers and dye into close proximity. Interaction or binding can be achieved by any known method including, but not limited to, avidin/biotin labeling. Distance requirements for fluorescence resonance energy transfer (FRET) can thus be met, and excitation of the polymer with light (shown as hν) results in amplified dye emission. It is envisioned that the conjugated polymers can be excited at a wavelength where the dye does not have significant absorbance. In one embodiment the dye emission can be at a longer wavelength than the conjugated polymer emission. In use it is envisioned that an assay method can include the steps of providing a sample that is suspected of containing a target biomolecule, providing a sensor conjugated to a signaling chromophore and capable of interacting with the target biomolecule, providing a conjugated polymer that interacts with the sensor and upon excitation is capable of transferring energy to the sensor signaling chromophore and contacting the sample with the sensor and the conjugated polymer in a solution under conditions in which the sensor can bind to the target biomolecule if present. Next, the method can include applying a light source to the sample that can excite the conjugated polymer, and detecting whether light is emitted from the signaling chromophore. As disclosed herein, interaction or binding between conjugated polymers and dye-labeled antibodies can be a viable approach for increasing detection sensitivities, for example of a biomolecule target. In a further embodiment, covalently attaching the conjugated polymers to a dye, biomolecule (e.g., an antibody complex) or both offers several advantages including reduced background and/or improved energy transfer. In the case of direct linkage to a biomolecule, biorecognition events, rather than non-specific polymer interaction or binding events (such as those described above in FIG. 1), should govern conjugated polymer presence. In this manner, nonspecific binding of conjugated polymers to biomolecules can be eliminated, reducing any background emission resulting from the conjugated polymer itself. The abovementioned biomolecules include but are not limited to proteins, peptides, affinity ligands, antibodies, antibody fragments, sugars, lipids, enzymes and nucleic acids (as hybridization probes and/or aptamers). In general, in another aspect the invention includes the bioconjugation of polymers to affinity ligands (affinity ligands describing a biomolecule that has an affinity for another biomolecule). FIG. 2 illustrates a class of materials in which a conjugated polymer (shown as a wavy line) is linked to a dye, biomolecule, or biomolecule/dye complex (labeled X). Linking to the conjugated polymer can be via a first functionality linker A on the conjugated polymer that serves as a bioconjugation site capable of covalently linking with a second functionality linker A′ linked to a biomolecule and/or dye (see X). This arrangement can fix the distance between the conjugated polymer and X, thereby ensuring only specific interactions between polymer and X. It is envisioned that a biomolecule component X in this embodiment can be any of the various biomolecules disclosed herein, including but not limited to an antibody, protein, affinity ligand, enzyme or nucleic acid. Linker A can be anywhere on the conjugated polymer including terminal positions of the polymer, internally on a repeating subunit, in between repeating subunits or any combination thereof. Likewise, Linker A′ can be linked anywhere on a biomolecule and/or dye. The linking chemistry for A-A′ can include, but is not limited to, maleimide/thiol; thiol/thiol; pyridyldithiol/thiol; succinimidyl iodoacetate/thiol; N-succinimidylester (NHS ester), sulfodicholorphenol ester (SDP ester), or pentafluorophenyl-ester (PFP ester)/amine; bissuccinimidylester/amine; imidoesters/amines; hydrazine or amine/aldehyde, dialdehyde or benzaldehyde; isocyanate/hydroxyl or amine; carbohydrate-periodate/hydrazine or amine; diazirine/aryl azide chemistry; pyridyldithiol/aryl azide chemistry; alkyne/azide; carboxy-carbodiimide/amine; amine/Sulfo-SMCC (Sulfosuccinimidyl 4-[N-maleimidomethyl]cyclohexane-1-carboxylate)/thiol; and amine/BMPH (N-[β-Maleimidopropionic acid]hydrazide.TFA)/thiol. It is envisioned that the X in this context can be, but is not limited to, a dye, fluorescence protein, nanomaterial (e.g., Quantum Dot), chemluminescence-generating molecule, a conjugate between dye and chemluminescence-generating molecule, a conjugate between fluorescence protein and chemluminescence-generating molecule, a conjugate between nanomaterial (e.g., Quantum Dot) and chemluminescence-generating molecule, streptavidin, avidin, enzyme, substrate for an enzyme, substrate analog for an enzyme, receptor, ligand for a receptor, ligand analog for a receptor, DNA, RNA, modified nucleic acid, DNA aptamer, RNA aptamer, modified nucleic aptamer, peptide aptamer, antibody, antigen, phage, bacterium or conjugate of any two of the items described above. In another aspect, the invention includes the use of conjugated polymers as direct labels. FIG. 3 shows examples of labeled conjugated polymers. In one embodiment, FIG. 3A, a polymer (shown as encircled hexagons) is shown conjugated to an antibody which can be, for example, a 1° or 2° antibody. The conjugate of the polymer and the antibody can be used as a direct reporter, for example, in an assay. In additional embodiments, the signal from the polymer is not modulated by other assay components rather it is dependent on its presence in the assay at the time of detection as a function of specific biomolecule recognition. Excitation of the polymer with light (not shown) can result in polymer emission, indicating the presence of the antibody (1° or 2°) in the assay or assay solution. FIGS. 3B and 3C further exemplify the use of conjugated polymers as biomolecule labels capable of detecting specific targets and target associated biomolecules. FIG. 3B depicts a polymer avidin (streptavidin, neutraAvidin, etc.) conjugate capable of binding to biotin modified molecules, biomolecules or substrates. FIG. 3C depicts a nucleic acid (DNA, RNA, PNA, etc.) conjugate capable of hybridizing to complementary nucleic acid sequences. Linkage or conjugation of fluorescent conjugated polymer to a molecule capable of recognizing a target biomolecule or target associated molecule (such as those exemplified in FIG. 3) provides a direct means of detection. In additional embodiments, the signals generated from excitation of the conjugated polymer are not modulated by other assay components except those which are directly conjugated to the polymer. In such embodiments the polymer complex is acting directly as a fluorescent label. In another embodiment shown in FIG. 3D, the conjugated polymer is labeled with a dye, for example, a chromophore. In this case, the conjugated polymer can act as a donor and the dye can act as an acceptor in an energy transfer process. Here, the conjugated polymer can act as a light harvester, and excitation of the conjugated polymer is followed by the channeling of the excitations to the dye via an energy transfer process including, but not limited to, FRET. This results in amplified dye emission (as compared to direct excitation of the dye). The fluorescence of the donor conjugated polymer, in one embodiment, can be quenched (e.g., >90% quenching). This is exemplified in Example 38 and shown in FIG. 21, by way of example only. In some instances, the conjugated polymer in FIG. 3D (and similar drawings disclosed herein) can have multiple dye attachments which can be positioned internally or at the terminus of the polymer structure (single dye shown for illustrative purposes only). In the case of direct linkage to a dye (FIG. 3D) or biomolecule/dye complex (as exemplified in FIG. 4), donor-acceptor distances can be fixed, rather than dependent on the strength of interaction or binding, and energy transfer efficiency can be significantly increased. This has significant consequences in the context of improving dye signaling (or quenching) and reducing background fluorescence associated with donor-acceptor cross-talk. Cross-talk in this case refers to the overlap between conjugated polymer (donor) and dye (acceptor) emission peaks. Conjugated polymers which bind non-specifically at distances too great for energy transfer can contribute to the background fluorescence (or crosstalk). Shorter (fixed) distances between the donor and acceptor can not only facilitate direct dye amplification, but also can greatly quench the donor emission, as depicted in FIG. 21 by way of example only. This results in less donor emission at the acceptor emission wavelengths, which subsequently reduces or even eliminates the need for cross-talk correction. In further embodiments the localization of the conjugated polymer and a signaling chromophore are brought together by recognition event, for example by the binding of two affinity pairs or by co-recognition of the same target molecule or target associated molecule (FIG. 5). Such embodiments could be performed in solution based formats or in such configurations where one or more of elements is bound to another biomolecule (cell, tissue, protein, nucleic acid, etc.) or a substrate (bead, well plate, surface, tube, etc.). In general, another aspect the invention includes a method of assaying for a target biomolecule or target associated biomolecule. As shown in FIG. 5A, in one embodiment a conjugated polymer (shown as a wavy line) can be linked to a first bioconjugate (shown as a Y-shaped object), for example, a 2° antibody that is specific for second a dye-labeled bioconjugate, for example, a 1° antibody. Here, the recognition event between the 1° and 2° antibody will result in the reduction of distance between the donor conjugated polymer and acceptor dye. In a similar embodiment depicted in FIG. 5B, polymer and dye labeled antibodies recognize a common target. After either of these recognition events, excitation of the donor conjugated polymer with light (shown as hν) will result in energy transfer, e.g., FRET, to the acceptor dye (shown as curved arrow), and amplified dye emission (in comparison with direct excitation of the dye) will be observed. In use it is envisioned that an assay method could include providing a sample that is suspected of containing a target biomolecule by the steps of providing a first bioconjugate, for example, a 1° antibody conjugated to a signaling chromophore and capable of interacting with the target biomolecule. This is followed by providing a second bioconjugate, for example, a 2° antibody or 1° antibody, conjugated to a polymer, wherein the second bioconjugate can bind to the first bioconjugate or target and wherein upon such binding excitation of the conjugated polymer is capable of transferring energy to the signaling chromophore. Next, the method includes contacting the sample with the first bioconjugate in a solution under conditions in which the first bioconjugate can bind to the target biomolecule if present and contacting the solution with the second bioconjugate. The method then includes applying a light source to the target biomolecule or tagged target biomolecule, wherein the light source can excite the conjugated polymer and subsequently detecting whether light is emitted from the signaling chromophore. In another aspect, the invention includes a method of assaying a sample using a conjugated polymer and a sensor biomolecule complex. As shown in FIGS. 5C and D, a polymer (shown as a wavy line) can be conjugated to a first bioconjugate, for example, streptavidin (SA) which has a strong affinity for biotin. In FIG. 5C, a sensor biomolecule (e.g., an antibody which can be a 1° or 2° antibody), is conjugated to both a dye and a second bioconjugate (e.g., a biotin moiety). Similar embodiments are depicted in FIG. 5D where the second bioconjugate (e.g., a biotin moiety) and the signaling chromopohre are both conjugated to a nucleic acid. After a biorecognition event between the first and second bioconjugates (e.g. between SA and biotin), the conjugated polymer and dye will be brought into close proximity, and excitation of the donor conjugated polymer will result in energy transfer to the acceptor dye. Dye emission will indicate the presence of the first bioconjugate (e.g., the antibody or nucleic acid). In comparison with direct excitation of the dye, amplification of the dye signal intensity will be observed when excited indirectly through an energy transfer process, e.g., FRET. A method of using the embodiment shown in FIGS. 5C and D can include the steps of providing a sample that is suspected of containing a target biomolecule, providing a conjugated polymer comprising a covalently linked first bioconjugate (e.g., SA), providing a sensor biomolecule complex comprising a sensor biomolecule capable of interacting with the target molecule, a signaling chromophore, and covalently linked second bioconjugate capable of binding with the first bioconjugate, wherein upon such binding excitation of the conjugated polymer is capable of transferring energy to the signaling chromophore. The method can further include the steps of contacting the sample with the sensor biomolecule complex in a solution under conditions in which the sensor biomolecule can bind to the target biomolecule if present, contacting the solution with the conjugated polymer, applying a light source to the sample that can excite the conjugated polymer, and detecting whether light is emitted from the signaling chromophore. Further the conjugated polymer can contain additional linking site suitable for conjugation or attachment to more than one species. FIG. 6 exemplifies the addition of a second linking site within the polymer. Such linkers A and B can be the same or different to allow for orthogonal conjugation of different species. The linkers can be anywhere on the polymer including terminal and internal positions. The linking chemistry for A-A′ and B-B′ (and optionally C-C′, D-D′, etc.) can include, but is not limited to, maleimide/thiol; thiol/thiol; pyridyldithiol/thiol; succinimidyl iodoacetate/thiol; N-succinimidylester (NHS ester), sulfodicholorphenol ester (SDP ester), or pentafluorophenyl-ester (PFP ester)/amine; bissuccinimidylester/amine; imidoesters/amines; hydrazine or amine/aldehyde, dialdehyde or benzaldehyde; isocyanate/hydroxyl or amine; carbohydrate-periodate/hydrazine or amine; diazirine/aryl azide chemistry; pyridyldithiol/aryl azide chemistry; alkyne/azide; carboxy-carbodiimide/amine; amine/Sulfo-SMCC (Sulfosuccinimidyl 4[N-maleimidomethyl]cyclohexane-1-carboxylate)/thiol; and amine/BMPH (N-[β-Maleimidopropionic acid]hydrazide.TFA)/thiol. A tri-functional linker such as the commercially available Sulfo-SBED Sulfosuccinimidyl[2-6-(biotinamido)-2-(p-azidobenzamido)-hexanoamido]-ethyl-1,3′-dithiopropionate can serve well in the three way linkage among X, Y, and conjugated polymer. In the embodiment illustrated in FIG. 6, X or Y can be, but are not limited to, a dye, fluorescence protein, nanomaterial (e.g., Quantum Dot), chemluminescence-generating molecule, a conjugate between dye and chemluminescence-generating molecule, a conjugate between fluorescence protein and chemluminescence-generating molecule, a conjugate between nanomaterial (e.g., Quantum Dot) and chemluminescence-generating molecule, streptavidin, avidin, enzyme, substrate for an enzyme, substrate analog for an enzyme, receptor, ligand for a receptor, ligand analog for a receptor, DNA, RNA, modified nucleic acid, DNA aptamer, RNA aptamer, modified nucleic aptamer, peptide aptamer, antibody, antigen, phage, bacterium or conjugate of any two of the items described above. In general, in another aspect the invention provides a conjugated polymer complex including a polymer, a sensor biomolecule and a signaling chromophore for identifying a target biomolecule. As shown in FIG. 6, in one embodiment a polymer (wavy line) can be bioconjugated to a dye X via linker functionalities A-A′ and a biomolecule Y via linker functionalities B-B′. As depicted in FIG. 7, in one embodiment a polymer can be bioconjugated to both a dye and a biomolecule, for example a biorecognition molecule. Useful biomolecules can include but are not limited to antibodies (FIG. 7A), avidin derivatives (FIG. 7B) affinity ligands, nucleic acids (FIG. 7C), proteins, nanoparticles or substrates for enzymes. The benefits of covalently linking a dye in proximity to a polymer have been described above. By affixing both an acceptor dye and a biorecognition molecule to a polymer, the benefits are two fold, by both fixing donor-acceptor distances, such that an acceptor is guaranteed to be within the vicinity of a donor conjugated polymer (and vice versa), and also increasing the specificity of polymer binding to indicate a biorecognition event. These covalent complexes can be made via the monomer, polymer and linking chemistries described herein. In use, the embodiments shown in FIG. 6 can be a conjugated polymer complex for identifying a target biomolecule wherein the complex includes a conjugated polymer, a signaling chromophore covalently linked to the conjugated polymer and a sensor biomolecule covalently linked to the conjugated polymer. The signaling chromophore of the complex is capable of receiving energy from the conjugated polymer upon excitation of the conjugated polymer and the sensor biomolecule is capable of interacting with the target biomolecule. It is envisioned that the biomolecules can include but are not limited to an antibody, protein, affinity ligand, peptide, or nucleic acid. In one embodiment shown in FIG. 7A, a polymer is conjugated to both a bioconjugate, for example, an antibody (1° or 2°) and a dye. Covalent linkage between the donor conjugated polymer and acceptor dye ensures close proximity. Excitation of the donor conjugated polymer results in energy transfer, e.g., FRET, to the acceptor dye. Where the bioconjugate is an antibody, if the antibody binds to its target (e.g., antigen), this will be indicated by dye emission upon donor polymer excitation. In an alternative embodiment, as shown in FIG. 7B, a polymer can be conjugated to both a SA and a dye. Again, covalent linkage between the donor conjugated polymer and acceptor dye ensure close proximity, and excitation of the donor conjugated polymer results in energy transfer to the acceptor dye. The SA complex can be used to label or detect a biotin-labeled biomolecule such as a biotinylated antibody or nucleic acid. Polymer excitation followed by energy transfer to the dye label will result in greatly enhanced detection signals (i.e., greater sensitivity). The example exemplified in FIG. 7A is a conjugated polymer labeled with a dye acceptor and further conjugated to an antibody. This Tandem configuration can be used in similar fashion as those described for the structure in FIG. 3A but are useful in generating a secondary signal for detection, often in multiplex formats. The conjugated polymer complexes in FIG. 7 can have multiple dye attachments which can be positioned internally or at the terminus of the polymer structure (single dye shown for illustrative purposes only). In other embodiments as shown in FIGS. 3A and 7A, a sensor biomolecule for example a 1° antibody (Y shape) is conjugated covalently linked to the conjugated polymer (encircled hexagons) or conjugated polymer-dye tandem complex (hexagons with pendant encircled star). Upon conjugated polymer excitation, emission from the conjugated polymer (FIG. 3A) or dye (FIG. 7A) will indicate presence of the biocomplex and by extension with appropriate assay design that of the target recognized by the sensor molecule allowing use as a reporter, for example in an assay. FIGS. 29A and 29B represent comparable examples with covalent linkage of the conjugated polymer to a 2° antibody. As an alternative embodiment, the conjugated polymer may be associated indirectly with the sensor biomolecule or target associated biomolecule. FIGS. 8C and 8D illustrate a sequence specific oligonucleotide probe (wavy line) covalently conjugated to a biotin moiety (drop shape). Here the conjugated polymer (encircled hexagons) or conjugated polymer-dye tandem complex (hexagons with pendant encircled star) is covalently bound or conjugated to a biotin recognizing protein (for example, avidin, streptavidin or similar with high specific affinity for the ligand biotin). FIGS. 8A and 8B illustrate comparable examples with a biotinylated antibody interacting with a covalent conjugate of the conjugated polymer (FIG. 8A) and conjugated polymer-dye tandem complex (FIG. 8B) to the biotin recognizing protein. Indirect association of the target associated biomolecule with the conjugated polymer is not limited to biotin mediated interactions. FIGS. 8E and F represent sequence specific oligonucleotides (wavy line) which have been covalently labeled with a digoxygenin moiety (7 pointed star). In turn the digoxygenin moiety has been recognized by a primary antibody covalently linked to the conjugated polymer (FIG. 8E) and the conjugated polymer-dye tandem complex (FIG. 8F). Although not shown pictorially, further embodiments employing indirect detection of digoxygenin using biotinylated antibodies and biotin recognizing proteins covalently linked to conjugated polymers (or conjugated polymer-dye tandem complexes) or unlabelled primary antibodies recognizing digoxygenin and appropriate secondary antibodies covalently linked to the conjugated polymer (or conjugated polymer-dye tandem complexes) are intended. A number of further embodiments are also predicated on energy transfer (for example but not limited to FRET) between the conjugated polymer and an acceptor dye. Given the potential for multiplexing analysis, it is envisioned that the conjugated polymer can be linked to a number of dyes or signaling chromophores, including, but not limited to, fluorescein, 6-FAM, rhodamine, Texas Red, California Red, iFluor594, tetramethylrhodamine, a carboxyrhodamine, carboxyrhodamine 6G, carboxyrhodol, carboxyrhodamine 110, Cascade Blue, Cascade Yellow, coumarin, Cy2®, Cy3®, Cy3.5®, Cy5®, Cy5.5®, Cy7®, Cy-Chrome, DyLight 350, DyLight 405, DyLight 488, DyLight 549, DyLight 594, DyLight 633, DyLight 649, DyLight 680, DyLight 750, DyLight 800, phycoerythrin, PerCP (peridinin chlorophyll-a Protein), PerCP-Cy5.5, JOE (6-carboxy-4′,5′-dichloro-2′,7′-dimethoxyfluorescein), NED, ROX (5-(and-6)-carboxy-X-rhodamine), HEX, Lucifer Yellow, Marina Blue, Oregon Green 488, Oregon Green 500, Oregon Green 514, Alexa Fluor® 350, Alexa Fluor® 430, Alexa Fluor® 488, Alexa Fluor® 532, Alexa Fluor® 546, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 633, Alexa Fluor® 647, Alexa Fluor® 660, Alexa Fluor® 680, 7-amino-4-methylcoumarin-3-acetic acid, BODIPY® FL, BODIPY® FL-Br2, BODIPY® 530/550, BODIPY® 558/568, BODIPY® 564/570, BODIPY® 576/589, BODIPY® 581/591, BODIPY® 630/650, BODIPY® 650/665, BODIPY® R6G, BODIPY® TMR, BODIPY® TR, conjugates thereof, and combinations thereof. These embodiments include modifications of the above examples where the acceptor dye serves as the assay reporter (as exemplified in FIGS. 3D, 4D, 7, 8B, 8D, 8E, 29B, wherein the encircled ten pointed star represents the dye). In certain embodiments the conjugated polymer conjugates provided in FIGS. 2-10, 29 and 30 are intended for but not limited to use in flow cytometry, cell sorting, molecular diagnostics, fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), polymerase chain reaction, microscopy (fluorescent, confocal, 2 photon, etc.), blotting (e.g. northern, southern, western), cytomic bead arrays (Luminex formats, etc.), fluorescent immune assay (FIA or ELISA), nucleic acid sequencing and microarrays. Embodiments are also envisaged where conjugated polymers are used to enhance the detection and quantification of nucleic acids using sequence specific fluorescent probes combined with nucleic acid amplification techniques such as but not limited to polymerase chain reaction, transcription mediated amplification, rolling circle amplification, recombinase polymerase amplification, helicase dependent amplification and Linear-After-The-Exponential polymerase chain reaction. FIG. 32 represents modifications of the HybProbe detection technique. In FIG. 32A, the dye conventionally used as an energy transfer donor is replaced by the conjugated polymer (hexagon chain) which is covalently linked to the donor probe (wavy helical structure represented as right hand helical duplex due to association with nucleic acid target depicted a longer helical wavy line). Upon sequence specific hybridization the donor and acceptor (represented similarly to donor probe but on left hand side of nucleic acid target) probes are spatially juxtaposed on the target nucleic acid strand of interest in sufficiently close proximity to allow energy transfer to take place between the fluors. Excitation energy is transduced through the conjugated polymer and emitted as a readable signal by the dye (encircled ten pointed star) to allow nucleic acid quantification, detection and/or characterization. Presence of increased template allows increased numbers of probe co-hybridisation events and thus correlates to increased specific signal from the acceptor dye. In combination with the melt curve technique commonly employed in HybProbe experiments it is envisaged that sequence specific information corresponding to sequence variations will be collectable in appropriately designed experiments. FIG. 32B represents a “signal off” modification of the HybProbe approach where the conjugated polymer is quenched by an acceptor probe consisting of a small molecule fluorescence quencher (for example but not limited to Black Hole Quenchers™ Iowa Black® or Dabsyl). In another embodiment, conjugated polymer and conjugated polymer-dye tandem complexes similar to those described in FIGS. 4C and 4D are used in the detection, quantification and/or characterization of nucleic acid targets. Nucleic acid probe sequences labeled with a quencher molecule (black circle, for example but not limited to Black Hole Quenchers™, Iowa Black® or Dabsyl) are also conjugated to a conjugated polymer (FIGS. 4C and 31A) and a conjugated polymer-dye tandem complex (FIGS. 4D and 31B). In FIGS. 4C and D the recognition of the target sequence leads to a hybridization and separation of the quencher from the conjugated polymer or conjugated polymer-dye tandem complex and upon polymer excitation produces an increase in fluorescent signal. In FIGS. 31A and 31B the nucleic acid probe conjugate will hybridize to a complementary target sequence and by treatment with specific enzymes the probe sequence is cleaved or hydrolyzed freeing the conjugated polymer or conjugated conjugated polymer-dye tandem complex from the quencher and upon polymer excitation produces an increase in fluorescent signal. The most common example of the methods described in FIG. 31 is the use of DNA polymerase enzymes which contain nuclease activity (e.g. TaqMan PCR assays). FIG. 9 shows examples of conjugated polymer (hexagons) conjugated to secondary antibodies (FIG. 9A) and primary antibodies (FIG. 9B) (antibodies shown as Y-shaped structures). In an assay, an unlabeled 1° antibody can bind to an antigen, for example, a target protein (shown as a black triangle). Addition of the 2° antibody, which is conjugated to a polymer, can bind specifically to the 1° antibody. After washing to remove unbound 2° antibody and upon application of light of suitable excitation wavelength, observance of polymer emission is indicative of specific binding (FIG. 9A). In other assay embodiments, a polymer-labeled 1° antibody can directly bind a target protein, shown as a black triangle, and after washing to remove unbound 1° antibody and upon application of light of suitable excitation wavelength, observance of polymer emission is indicative of specific binding (FIG. 9B). Optionally, whether conjugated to the 1° or 2° antibody, the polymer may be further conjugated to a dye. In such a case, optical excitation of the conjugated polymer can result in energy transfer to the dye, and amplified dye emission, in comparison to direct dye excitation results. Observance of dye emission is indicative of specific binding. FIG. 10 shows an example of a sandwich-type complex of one embodiment of the invention. In the assay shown in FIG. 10A the conjugated polymer complex is composed of a polymer (shown as hexagons) that is bioconjugated a biomolecule, for example, streptavidin (X shape). After an unlabeled 1° antibody binds the target (e.g. protein), shown as a black triangle, a biotin-labeled 2° antibody binds specifically to the 1° antibody. In a separate step, addition of the conjugated polymer complex will result in specific binding between the biotin and streptavidin. Excitation of the conjugated polymer will result in polymer emission, indicating the presence of the target protein. Additionally in another embodiment, a biotin-labeled 1° antibody may be used to probe the target protein directly (FIG. 10B). After this binding event takes place, addition of a streptavidin-polymer complex will result in specific binding between the biotin and streptavidin, and excitation of the conjugated polymer will result in polymer emission, indicating the presence of the target protein. Optionally, the polymer may be further conjugated to a dye. In such a case, optical excitation of the polymer will result in amplified dye emission, as compared to direct excitation of the dye. Signals arising from dye emission will indicate the presence of the target protein. FIG. 30 depicts example embodiments around the use of conjugated polymers in Fluorescent Immuno Assay (FIA). In FIG. 30 panels A-C analyte antigen is immobilised on a surface which can include but is not limited to a microtitre plate well, bead particle, glass slide, plastic slide, lateral flow strip, laminar flow device, microfluidic device, virus, phage, tissue or cell surface. Analyte molecules are then detected by use of labelled detection conjugates or sensor biomolecules. In FIG. 30A, a conjugated polymer covalently linked to a detection antibody is utilized for detection. In FIG. 30B, a biotin binding protein (for example but not limited to avidin, streptavidin or other high affinity biotin specific derivatives) covalently bound to the conjugated polymer and interacting with a biotinylated detection antibody is utilized for detection. In FIG. 30C, a secondary antibody covalently linked to the conjugated polymer and interacting with a detection antibody is utilized for detection. In FIG. 5B, a homogenous, solution based example is also embodied where two separate antibodies each bind to the antigen of interest. One antibody is covalently linked to the conjugated polymer, the other to a dye. When bound to the antigen, the respective fluorophores are brought into sufficient spatial proximity for energy transfer to occur. In assays predicated on the designs in FIG. 30 and FIG. 5B, the sample is interrogated with light matched to the excitation of the conjugated polymer and signal reported at the emission wavelength of the dye. In the examples embodied in FIG. 30 A-C the use of a polymer-dye tandem complex is further disclosed. In such cases, optical excitation of the polymer will result in amplified dye emission, as compared to direct excitation of the dye. Signals arising from dye emission will indicate the presence of the target. In a further aspect, the invention provides for the multiplexing of donor energy transfer to multiple acceptors. By using a conjugated polymer as a donor in an energy transfer system, benefits also include the ability to multiplex. A single donor can transfer energy to several dyes; thus with a single excitation source, the intensity of multiple dyes can be monitored. This is useful for applications including but not limited to cell imaging (i.e. immunohistochemistry), flow cytometry and cell sorting, where the different types of cells can be monitored by protein-antibody recognition events. In one embodiment, two dye-labeled antibodies can be incubated with a biological material, for example, a cultured cell line, tissue section or blood sample. Antibodies are able to recognize cells with a target protein expressed on its surface and specifically bind only to those proteins. By labeling the two antibodies with different dyes, it is possible to monitor for the expression of two different proteins or different cell types simultaneously. Typically, this would require two scans, excitations or images, once each with the correct excitation wavelength. As a final step prior to analysis, these two images or data sets would have to be overlaid or combined. By using antibodies conjugated with both a dye and a conjugated polymer, one excitation wavelength can be used for the conjugated polymer to excite both dyes, and a single image or scan will include data sets from each of the two antibodies. This can be done with any number of antibody combinations provided there is sufficient ability to resolve the resulting signals. It is envisioned that the invention described herein can be used to increase the sensitivity of any of a number of commercially available tests including but not limited to the OraQuick Rapid HIV-1/2 Antibody Test, manufactured by OraSure Technologies, Inc. (Bethlehem, Pa.), which is a FDA-approved HIV diagnostic test for oral fluid samples. This test can provide screening results with over 99 percent accuracy in as little as 20 minutes. Conjugated Polymers Light harvesting conjugated polymer systems can efficiently transfer energy to nearby luminescent species. Mechanisms for energy transfer include, for example, resonant energy transfer (Forster (or fluorescence) resonance energy transfer, FRET), quantum charge exchange (Dexter energy transfer) and the like. Typically, however, these energy transfer mechanisms are relatively short range, and close proximity of the light harvesting conjugated polymer system to the signaling chromophore is required for efficient energy transfer. Amplification of the emission can occur when the number of individual chromophores in the light harvesting conjugated polymer system is large; emission from a fluorophore can be more intense when the incident light (the “pump light”) is at a wavelength which is absorbed by the light harvesting conjugated polymer system and transferred to the fluorophore than when the fluorophore is directly excited by the pump light. The conjugated polymers used in the present invention can be charge neutral, cationic or anionic. In some embodiments, the conjugated polymers are polycationic conjugated polymers. In other embodiments, the conjugated polymers are polyanionic conjugated polymers. In further embodiments, the conjugated polymers can include cationic, anionic, and/or neutral groups in various repeating subunits. In yet other embodiments, the conjugated polymers are neutral conjugated polymers. In some instances, conjugated polymers contain groups such as ethylene glycol oligomers, ethylene glycol polymers, co-ammonium alkoxy salts, and/or w-sulfonate alkoxy salts that impart solubility in aqueous solutions. In some instances the neutral conjugated polymers with non-ionic side chains are soluble in greater than 10 mg/mL in water or phosphate buffered saline solutions and in certains cases the solubility is greater than 50 mg/mL. In some embodiments the conjugated polymers contain either a terminal linking site (e.g., capping unit), internal linking site or both. In some embodiments, a conjugated polymer is one that comprises “low bandgap repeat units” of a type and in an amount that contribute an absorption to the polymer in the range of about 450 nm to about 1000 nm. The low bandgap repeat units may or may not exhibit such an absorption prior to polymerization, but does introduce that absorption when incorporated into the conjugated polymer. Such absorption characteristics allow the polymer to be excited at wavelengths that produce less background fluorescence in a variety of settings, including in analyzing biological samples and imaging and/or detecting molecules. Shifting the absorbance of the conjugated polymer to a lower energy and longer wavelength thus allows for more sensitive and robust methods. Additionally, many commercially available instruments incorporate imaging components that operate at such wavelengths at least in part to avoid such issues. For example, thermal cyclers that perform real-time detection during amplification reactions and microarray readers are available which operate in this region. Providing polymers that absorb in this region allows for the adaptation of detection methods to such formats, and also allows entirely new methods to be performed. Incorporation of repeat units that decrease the band gap can produce conjugated polymers with such characteristics. Exemplary optionally substituted species which result in polymers that absorb light at such wavelengths include 2,1,3-benzothiadiazole, benzoxidazole, benzoselenadiazole, benzotellurodiazole, naphthoselenadiazole, 4,7-di(thien-2-yl)-2,1,3-benzothiadiazole, squaraine dyes, quinoxalines, perylene, perylene diimides, diketopyrrolopyrrole, thienopyrazine low bandgap commercial dyes, olefins, and cyano-substituted olefins and isomers thereof. Further details relating to the composition, structure, properties and synthesis of suitable conjugated polymers can be found in U.S. patent application Ser. No. 11/329,495, filed Jan. 10, 2006, now published as US 2006-0183140 A1, which is incorporated herein by reference in the entirety. In one aspect, provided herein are conjugated polymers of Formula (I): wherein: each R is independently a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL; MU is a polymer modifying unit or band gap modifying unit that is evenly or randomly distributed along the polymer main chain and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C1-C12 alkoxy, C2-C18(hetero)aryloxy, C2-C18(hetero)arylamino, (CH2)x′(OCH2CH2)y′OCH3 where each x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50, or a C2-C18(hetero)aryl group; each optional linker L1 and L2 are aryl or heteroaryl groups evenly or randomly distributed along the polymer main chain and are substituted with one or more pendant chains terminated with a functional group for conjugation to another substrate, molecule or biomolecule selected from amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof; G1 and G2 are each independently selected from hydrogen, halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiol, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters, optionally substituted fluorine and aryl or heteroaryl substituted with one or more pendant chains terminated with a functional group, molecule or biomolecule selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule; wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, and thiols within G1, G2, L1 or L2 that allows, for functional conjugation to another molecule, substrate or biomolecule; each dashed bond, - - - - - - , is independently a single bond, triple bond or optionally substituted vinylene (—CR5═CR5—) wherein each R5 is independently hydrogen, cyano, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group, wherein each C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, or C1-C12 haloalkyl; and n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. Non-ionic side groups capable of imparting solubility in water as used herein refer to side groups which are not charged and allow the resulting polymer to be soluble in water or aqueous solutions with no visible particulates. In some embodiments, each R is independently a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL, in excess of 15 mg/mL, in excess of 20 mg/mL, in excess of 25 mg/mL, in excess of 30 mg/mL, in excess of 35 mg/mL, in excess of 40 mg/mL, in excess of 45 mg/mL, in excess of 50 mg/mL, in excess of 60 mg/mL, in excess of 70 mg/mL, in excess of 80 mg/mL, in excess of 90 mg/mL or in excess of 100 mg/mL. In some embodiments, conjugated polymers described herein comprises a minimum number average molecular weight of greater than 5,000 g/mol, greater than 10,000 g/mol, greater than 15,000 g/mol, greater than 20,000 g/mol, greater than 25,000 g/mol, greater than 30,000 g/mol, greater than 40,000 g/mol, greater than 50,000 g/mol, greater than 60,000 g/mol, greater than 70,000 g/mol, greater than 80,000 g/mol, greater than 90,000 g/mol, or greater than 100,000 g/mol. In some embodiments, each R is independently (CH2)x(OCH2CH2)yOCH3 where each x is independently an integer from 0-20, each y is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)zOCH3 where each z is independently an integer from 0 to 50. In some instances, each R is (CH2)3(OCH2CH2)11OCH3. In other embodiments, each R is independently a benzyl substituted with at least one (OCH2CH2)zOCH3 group where each z is independently an integer from 0 to 50. In some instances, each R is a benzyl substituted with at least one (OCH2CH2)10OCH3 group. In other instances, each R is a benzyl substituted with at least two (OCH2CH2)10OCH3 groups. In further instances, each R is a benzyl substituted with at least three (OCH2CH2)10OCH3 groups. In further embodiments, each R is independently where k and l are independent integers from 0 to 25; *=site for covalent attachment. In yet further embodiments, each R is independently is a dendrimer of PAMAM, PEA, PEHAM, PPI, tri-branched benzoate, or glycerol with a generation of 1 to 4 and optionally terminal substitutions, said optionally terminal substitutions are (- - - - -)CH2CH2O)jCH3 or (- - - - -)(OCH2CH2)jCH3 and j is an integer from 0 to 25 and the dotted lines (- - - - -) are each independently selected from any one or a combination of, C1-C12 alkyl, C1-C12 alkoxy, C2-C12 alkene, amido, amino, aryl, (CH2)r(OCH2CH2)s(CH2)r where each r is independently an integer from 0-20, s is independently an integer from 0 to 50, carbamate, carboxylate, C3-C12 cycloalkyl, imido, phenoxy, or C4-C18(hetero)aryl groups. In alternative embodiments, each R is independently, Where k and l are independent integers from 0 to 25 and the dotted lines (- - - - -) are each independently selected from any one or a combination of, C1-C12 alkyl, C1-C12 alkoxy, C2-C12 alkene, amido, amino, aryl, (CH2)r(OCH2CH2)s(CH2)r where each r is independently an integer from 0-20, s is independently an integer from 0 to 50, carbamate, carboxylate, C3-C12 cycloalkyl, imido, phenoxy, or C4-C18(hetero)aryl groups; *=site for covalent attachment. In alternative embodiments, each R is independently, Where k and l are independent integers from 0 to 25 and the dotted lines (- - - - -) are each independently selected from any one or a combination of, C1-C12 alkyl, C1-C12 alkoxy, C2-C12 alkene, amido, amino, aryl, (CH2)r(OCH2CH2)s(CH2)r where each r is independently an integer from 0-20, s is independently an integer from 0 to 50, carbamate, carboxylate, C3-C12 cycloalkyl, imido, phenoxy, or C4-C18(hetero)aryl groups; *=site for covalent attachment. In some embodiments, conjugated polymers described herein contain no optional linkers, L1 and/or L2. In other embodiments, conjugated polymers contain at least about 0.01 mol %, at least about 0.02 mol %, at least about 0.05 mol %, at least about 0.1 mol %, at least about 0.2 mol %, at least about 0.5 mol %, at least about 1 mol %, at least about 2 mol %, at least about 5 mol %, at least about 10 mol %, at least about 20 mol %, or about 25 mol % of optional linkers, L1 and/or L2. In some embodiments, conjugated polymers contain up to 50 mol % total of optional linkers, L1 and L2, and may contain about 40 mol % or less, about 30 mol % or less, about 25 mol % or less, about 20 mol % or less, about 15 mol % or less, about 10 mol % or less, or about 5 mol % or less. Linkers can be evenly or randomly distributed along the polymer main chain. In some embodiments, optional linkers L1 or L2 have the structure: *=site for covalent attachment to unsaturated backbone wherein R3 is independently hydrogen, halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group, wherein each C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, or C1-C12 haloalkyl; and q is an integer from 0 to 4. In some embodiments, optional linkers L1 or L2 have the structure represented by: *=site for covalent attachment to unsaturated backbone wherein A is a site for conjugation, chain extension or crosslinking and is —[O—CH2—CH2]t—W, or (C1-C12)alkoxy-X; W is —OH or —COOH; X is —NH2, —NHCOOH, —NHCOOC(CH3)3, —NHCO(C3-C12)cycloalkyl(C1-C4)alkyl-N-maleimide; or —NHCO[CH2—CH2—O]uNH2; t is an integer from 1 to 20; and u is an integer from 1 to 8. In other embodiments, optional linkers L1 or L2 are selected from the group consisting of a-h having the structure: *=site for covalent attachment to unsaturated backbone wherein R′ is independently H, halogen, C1-C12 alkyl, (C1-C12 alkyl)NH2, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C2-C18(hetero)aryl, C2-C18(hetero)arylamino, —[CH2—CH2]r′—Z1, or (C1-C12)alkoxy-X1; and wherein Z1 is —OH or —COOH; X1 is —NH2, —NHCOOH, —NHCOOC(CH3)3, —NHCO(C3-C12)cycloalkyl(C1-C4)alkyl-N-maleimide; or —NHCO[CH2—CH2—O]s′(CH2)s′NH2; r′ is an integer from 1 to 20; and each s′ is independently an integer from 1 to 20, (CH2)3(OCH2CH2)x″OCH3 where x″ is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)y″OCH3 where each y″ is independently an integer from 0 to 50 and R′ is different from R; wherein R15 is selected from the group consisting of 1-t having the structure: and k is 2, 4, 8, 12 or 24; *=site for covalent attachment to backbone. In certain embodiments, optional linkers L1 or L2 are In some embodiments, G1 and G2 are optionally substituted aryl wherein the optional substituent is selected from halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, boronic acid, boronate radical, boronic esters and optionally substituted fluorene. In other embodiments, G1 and G2 are the same. In further embodiments, G1 and G2 are different. G1 and G2 can be activated units that allow further conjugation, crosslinking, or polymer chain extension, or they may be nonactivated termination units. In some embodiments, G1 and G2 are independently selected from structures represented by: *=site for covalent attachment to backbone wherein R11 is any one of or a combination of a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl, (CH2)x(OCH2CH2)p(CH2)x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In other embodiments, G1 and G2 are independently selected from the group consisting of 1-18 having the structure: *=site for covalent attachment to backbone wherein R15 is selected from the group consisting of 1-t having the structure: and k is 2, 4, 8, 12 or 24. In further embodiments, G1 and G2 is In some embodiments, optional linkers, L1 and/or L2, G1, and/or G2 can be further conjugated to an organic dye, a biomolecule or a substrate. Covalent linkage can be introduced by any known method and can include, but is not limited to, chemistry involving maleimide/thiol; thiol/thiol; pyridyldithiol/thiol; succinimidyl iodoacetate/thiol; N-succinimidylester (NHS ester), sulfodicholorphenol ester (SDP ester), or pentafluorophenyl-ester (PFP ester)/amine; bissuccinimidylester/amine; imidoesters/amines; hydrazine or amine/aldehyde, dialdehyde or benzaldehyde; isocyanate/hydroxyl or amine; carbohydrate-periodate/hydrazine or amine; diazirine/aryl azide chemistry; pyridyldithiol/aryl azide chemistry; alkyne/azide; carboxy-carbodiimide/amine; amine/Sulfo-SMCC (Sulfosuccinimidyl 4-[N-maleimidomethyl]cyclohexane-1-carboxylate)/thiol; and amine/BMPH (N-[β-Maleimidopropionic acid]hydrazide.TFA)/thiol. In some embodiments, MU is selected from the group consisting of a′-k′ having the structure: =site for covalent attachment to unsaturated backbone wherein R is a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL. Non-ionic side groups include those previously described for polymers of Formula (I). As used herein, in some embodiments, a pendant chain is any one of or a combination of a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl, (CH2)x(OCH2CH2)p(CH2)x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups which connects a polymer with a functional group for conjugation to another substrate, molecule, or biomolecule. In some embodiments, conjugated polymers of Formula (I) have the structure of Formula (Ia): wherein R, L1, L2, G1, G2, MU, a, b, c, d and n are described previously for formula (I). In a further aspect, conjugated polymers of Formula I have the structure of Formula (Ib): wherein at least one of G1 or G2 comprises a functional conjugation cite. In a further aspect, conjugated polymers of Formula I have the structure of Formula (Ic): wherein L1 comprises a functional conjugation cite. In a further aspect, conjugated polymers of Formula I have the structure of Formula (Id): wherein at least one of G1 or G2 comprises a functional conjugation cite. In a further aspect, conjugated polymers of Formula I have the structure of Formula (II): wherein L1, G1, G2, a, c, n and dashed bonds are described previously for formula (I). In some embodiments, conjugated polymers of Formula (II) have the structure of Formula (IIa): wherein L1, G1, G2, a, c, and n are described previously for formula (I). In a further aspect, conjugated polymers of Formula I have the structure of Formula (III): wherein L1, G1, G2, a, c, n and dashed bonds are described previously for formula (I). In some embodiments, conjugated polymers of Formula (III) have the structure of Formula (IIIa): wherein L1, G1, G2, a, c, and n are described previously for formula (I). In a further aspect, conjugated polymers of Formula I have the structure of Formula (IV): wherein each R5 is independently hydrogen, cyano, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group, wherein each C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, or C1-C12 haloalkyl; and L1, G1, G2, a, c, n and dashed bonds are described previously for formula (I). In a further aspect, conjugated polymers of Formula I have the structure of Formula (V): wherein each R5 is independently hydrogen, cyano, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group, wherein each C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, or C1-C12 haloalkyl; and L1, G1, G2, a, c, n and dashed bonds are described previously for formula (I). Also provided herein are polymers having the structure of the following formula: wherein: G1 and G2 are each independently selected from hydrogen, halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, optionally substituted aryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters and optionally substituted fluorene; L is a bond or an aryl or heteroaryl group that is evenly or randomly distributed along the polymer main chain and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C1-C12 alkoxy, C2-C18(hetero)aryloxy, C2-C18(hetero)arylamino, (CH2)x(OCH2CH2)pOCH3 where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, or a C2-C18(hetero)aryl group; L1, L1′, L2 and L2′ are each independently a covalent bond, a C1-C12 alkylene, a C3-C12 cycloalkylene, a C2-C12 alkenylene, a C2-C12 alkynylene, a (C6-C18)aryl(C1-C12)alkylene, a (C6-C18)aryl(C2-C12)alkenylene, a (C6-C18)aryl(C1-C12)alkynylene, a C6-C18 arylene group, —Y1—[O—Y2]p—, —O—Y1—[O—Y2]p— wherein each C1-C12 alkylene, C3-C12 cycloalkylene, (C6-C18)aryl(C1-C12)alkylene, or C6-C18 arylene group is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, C1-C12 haloalkyl, —Y1—[O—Y2]p— or —O—Y1—[O—Y2]p—; q is 0 or an integer from 1 to 8; p is 0 or an integer from 1 to 24; Y1 and Y2 are each independently a covalent bond, or a C1-12 alkylene group, a C3-C12 cycloalkylene, a C2-C18(hetero)arylene, a (C6-C18)aryl(C1-C12)alkylene, wherein each C1-12 alkylene group, a C3-C12 cycloalkylene, a C2-C18(hetero)arylene, a (C6-C18)aryl(C1-C12)alkylene is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, or C1-C12 haloalkyl; E1 and E1′ are each independently, hydrogen, C1-C6 alkyl, —OH, —COOH, —SH, —SR, —SHR+, SR2+, —SO3−, —PO4−, Br, —NH2, —NHR, —NR2, —NH3+, —NH2R+, —NHR2+or —NR3, wherein and each R is independently a C1-C6 alkyl and —SHR+, SR2+, —SO3−, —PO4−, —NH3+, —NH2R+, —NHR2+or —NR3+each optionally has an associated counterion; and n is an integer from 1 to about 1,000. Also provided herein are polymers having the structure of the following formula: wherein each R is independently O(CHx), or (CH2)3(OCH2CH2)pOCH3 where each x is independently an integer from 0-20, each p is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)mOCH3 where each m is independently an integer from 0 to 50; G1 is selected from hydrogen, halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, optionally substituted aryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters and optionally substituted fluorene; and n is an integer from 1 to about 10,000. Additional embodiments of conjugated polymers are described in the following Examples. Preparation of Conjugated Polymers The synthesis of conjugated polymers described herein may be accomplished using means described in the chemical literature, using the methods described herein, or a combination thereof. Conjugated polymers described herein may be synthesized using standard synthetic techniques known to those of skill in the art or using methods known in the art in combination with methods described herein. In additions, solvents, temperatures and other reaction conditions presented herein may vary according to the practice and knowledge of those of skill in the art. The starting material used for the synthesis of the conjugated polymers of Formula (1) and polymers having the structures described in the prior section as described herein can be obtained from commercial sources, such as Aldrich Chemical Co. (Milwaukee, Wis.), Sigma Chemical Co. (St. Louis, Mo.), or the starting materials can be synthesized. The polymers described herein, and other related polymers having different substituents can be synthesized using techniques and materials known to those of skill in the art, such as described, for example, in March, ADVANCED ORGANIC CHEMISTRY 4th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wiley 1999) (all of which are incorporated by reference in their entirety). General methods for the preparation of polymers as disclosed herein may be derived from known reactions in the field, and the reactions may be modified by the use of appropriate reagents and conditions, as would be recognized by the skilled person, for the introduction of the various moieties found in the formulae as provided herein. As a guide the following synthetic methods may be utilized. Generally, polymerization of fluorene polymeric structures may be accomplished using polymerization techniques known to those of skill in the art or using methods known in the art in combination with methods described herein. For example, polymerization can be achieved via Suzuki coupling with a commercially available fluorene-dihalide monomer, e.g., 2,7-dibromofluorene, and its diboronic acid or ester derivative: Structures A-1 and A-2 are catalyzed by a metal catalyst to form exemplary polymer A-3 with termination points, labeled Y. Each Y is independently —H, —Br, —B(OH)2, or boronic ester, e.g., 4,4,5,5,-tetramethyl- 1,3,2-dioxaborolanyl. Synthesis of diboronic ester derivatives from a fluorene-dihalide monomer can also be accomplished via Suzuki coupling with bis(pinacolato)diboron: Substituents such as ethylene glycol oligomers or ethylene glycol polymers may be attached to monomers prior to polymerization or to the polymer itself after polymerization. An exemplary scheme of synthesizing substituted fluorene monomers with mPEGylated groups is as follows: 2,7-dibromofluorene (B-1) and 3-bromopropanol in the presence of a strong base such as sodium hydroxide, potassium hydroxide, or the like and a phase transfer catalyst, e.g. tetrabutylammonium bromide, is heated and reacted to completion to form 2,7-dibromo-9,9-di(3′-hydroxypropanyl)fluorene (B-2). —OH groups of B-2 are tosylated with tosyl chloride in the presence of pyridine and allowed to react to completion to form 2,7-dibromo-9,9-di(3′-methylbenzenesulfonatopropanyl)fluorene (B-3). B-3 is then reacted with a mPEG(x) alcohol in the presence of potassium tert-butoxide to form B-4 with attached mPEG chains. mPEG alcohols can have 1-50 mPEG chains. Typical sizes include but are not limited to mPEG5, mPEG8, mPEG11, mPEG24. In an alternative scheme, mPEG alcohols can be tosylated first via tosyl chloride and then reacted to B-2 to form B-4. Substituted monomers, such as exemplary structure B-4, can be further derivatized to diboronic esters in the schemes disclosed herein and subsequently be used for polymerization such as via Suzuki coupling. Polymeric fluorenes may also be obtained through the use of other reaction schemes involving organometallic catalysis. For example, the Yamamoto reaction uses a nickel(0)-based catalyst for the homo-coupling of aryl halide monomers like exemplary structure B-4. Additionally, conjugated polymers can be synthesized using Stille, Heck, and Sonogashira coupling reactions. See, e.g., Yamamoto et al., Macromolecules 25: 1214-1223, 1992; Kreyenschmidt et al., Macromolecules 28: 4577-4582, 1995; and Pei et al., J. Am. Chem. Soc. 118: 7416-7417, 1996 regarding Yamamoto reaction schemes. See, also, Leclerc, Polym. Sci. Part A: Polym. Chem. 39: 2867-2873, 2001 for Stille reaction schemes; Mikroyannidis et al., J. Polym. Sci. Part A: Polym. Chem. 45: 4661-4670, 2007 for Heck reaction schemes; and Sonogashira et al., Tetrahedron Lett. 16: 4467-4470, 1975 and Lee et al., Org. Lett. 3: 2005-2007, 2001 for Sonogashira reaction schemes. Linkers and capping units can be conjugated to a fluorene polymer backbone via similar mechanisms as described previously. For example, bromo- and boronic esters of capping units can be used to append one or both ends of a polymer. Utilizing both bromo- and boronic esters of capping units will append both ends of polymer. Utilizing only one form, either a bromo- or boronic ester of a capping unit, will append only those ends terminated with its repective complement and for symmetric A-A+B-B polymerizations can be used to statistically modify only one end of a polymer. For asymmetric polymers this approach is used to chemically ensure the polymers are only modified at a single chain terminus. FIG. 11 depicts appending an exemplary fluorene polymer with Y ends with one or more phenyl groups with bromobenzene, phenyl boronic acid or both using Suzuki coupling. Capping units can also be appended asymmetrically by first reacting a bromo-capping unit with a polymer with Y ends and subsequently reacting the polymer with a boronic ester capping unit. Exemplary bromo- and boronic ester capping units include but are not limited to the following structures: Further capping units can be found in structures 1-31 described herein or in the following Examples and methods for their attachment. The incorporation of optional linkers into conjugated polymer backbones further described in U.S. application Ser. No. 11/868,870, filed Oct. 8, 2007 and published as U.S. Application No. 2008/0293164, which application is herein incorporated by reference in its entirety. A desired optional linker incorporation can be achieved by varying the molar ratio of optional linker to bi-functional monomer. For example, an optional linker can be incorporated by substituting a percentage of one of the bi-functional monomers with a similar bi-functional optional linker which comprises the conjugation site of interest. The number and type of linking site included in the polymer is controlled by the feed ratio of the monomers to optional linker in the polymerization reaction. By varying the feed ratio, conjugated polymers can contain at least about 0.01 mol % of linker, L, and may contain at least about 0.02 mol %, at least about 0.05 mol %, at least about 0.1 mol %, at least about 0.2 mol %, at least about 0.5 mol %, at least about 1 mol %, at least about 2 mol %, at least about 5 mol %, at least about 10 mol %, at least about 20 mol %, or at least about 30 mol %. The conjugated polymers may contain up to 100 mol % of linker, L, and may contain about 99 mol % or less, about 90 mol % or less, about 80 mol % or less, about 70 mol % or less, about 60 mol % or less, about 50 mol % or less, or about 40 mol % or less. Linkers can be evenly or randomly distributed along the polymer main chain. In further embodiments, an optional linker can further allow covalent attachment of the resulting polymer to biomolecules, secondary reporters or other assay components. In alternative embodiments, the methods described herein to incorporate optional linkers may be used in combination with methods of introducing capping units with linking sites to produce polymers with both internal and terminal linking sites for conjugation. A non-limiting application of a polymer with both optional linkers and terminal capping units with linking sites for conjugation are polymer-dye-biomolecule tandem conjugates where the polymer is used as an energy transfer donor, such as in FRET, to a secondary dye acceptor thus shifting the emission wavelength to that of the corresponding dye. The person skilled in the art may further appreciate various syntheses and polymerization methods and embodiments of the present disclosure upon review of the following illustrative and non-limiting Examples. Antigen-Antibody Interactions The interactions between antigens and antibodies are the same as for other non-covalent protein-protein interactions. In general, four types of binding interactions exist between antigens and antibodies: (i) hydrogen bonds, (ii) dispersion forces, (iii) electrostatic forces between Lewis acids and Lewis bases, and (iv) hydrophobic interactions. Certain physical forces contribute to antigen-antibody binding, for example, the fit or complimentary of epitope shapes with different antibody binding sites. Moreover, other materials and antigens may cross-react with an antibody, thereby competing for available free antibody. Measurement of the affinity constant and specificity of binding between antigen and antibody is a pivotal element in determining the efficacy of an immunoassay, not only for assessing the best antigen and antibody preparations to use but also for maintaining quality control once the basic immunoassay design is in place. Antibodies Antibody molecules belong to a family of plasma proteins called immunoglobulins, whose basic building block, the immunoglobulin fold or domain, is used in various forms in many molecules of the immune system and other biological recognition systems. A typical immunoglobulin has four polypeptide chains, containing an antigen binding region known as a variable region and a non-varying region known as the constant region. Native antibodies and immunoglobulins are usually heterotetrameric glycoproteins of about 150,000 Daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies between the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains. Each light chain has a variable domain at one end (VL) and a constant domain at its other end. The constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain. Depending on the amino acid sequences of the constant domain of their heavy chains, immunoglobulins can be assigned to different classes. There are at least five (5) major classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, and several of these may be further divided into subclasses (isotypes), e.g. IgG-1, IgG-2, IgG-3 and IgG-4; IgA-1 and IgA-2. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known. Further details regarding antibody structure, function, use and preparation are discussed in U.S. Pat. No. 6,998,241, issued Feb. 14, 2006, the entire contents of which are incorporated herein by reference. Sandwich Assays Antibody or multiple antibody sandwich assays are well known to those skilled in the art including a disclosed in U.S. Pat. No. 4,486,530, issued Dec. 4, 1984, and references noted therein. The structures described in FIGS. 6, 7, 8, 9, 10 and 14 can be used directly as described or in various sandwich configurations including those described in Example 37. A sandwich configuration or a sandwich assay refers to the use of successive recognition events to build up layers of various biomolecules and reporting elements to signal the presence of a particular biomolecule, for example a target biomolecule or a target-associated biomolecule. A standard example of this would be the successive use of antibodies. In these assays, a primary antibody binds the target, the secondary antibody binds the primary, a third antibody can bind the secondary and so on. With each successive layer additional reporting groups can be added. Another strategy is using a repetitive addition of alternating layers of two (or more) mutually-recognizable components, or more than two components in a chain-recognition relationship, which comprise one or both of the components in a form of multimeric structure. In such a setup, one or more of the functional group(s) in each of the multimeric structure can be labeled with reporting group(s) and the unoccupied functional group(s) can serve as the recognition site for the other component(s), and this system will subsequently provide a platform for signal amplification. A typical example of this approach is the use of streptavidin-reporter conjugate and biotinylated anti-streptavidin antibody. In such assays, a biotinylated sensor molecule (nucleic acid or antibody) can be used to bind a target biomolecule, which is subsequently recognized by a detection system containing a streptavidin-reporter conjugate and biotinylated anti-streptavidin antibody. The sandwich structure in this case can be built up by successive rounds of biotinylated antibodies and labeled streptavidin complexes interaction to achieve the signal amplification. With an additional conjugation of a conjugated polymer to either the biotinylated antibody or the streptavidin-reporter complex, it is possible to further increase the signal output. In essence, the integration of a conjugated polymer in this type of signal amplification system can further amplify signals to a higher level. The bioconjugated polymer complexes described in FIGS. 6, 7, 8, 9, 10, 14, 15, 16 and 17 can be used to create optically enhanced sandwich assays by directly integrating a light harvesting conjugated polymer into commonly utilized recognition elements. The benefits of the conjugated polymer conjugated structures can also be applied directly to the primary target recognition elements without the need for successive recognition elements. For example, a primary antibody can be directly conjugated to polymer-dye complex such as shown in FIG. 14. Such a complex can be used to directly probe the presence of a target biomolecule. Polynucleotides Amplified target polynucleotides may be subjected to post amplification treatments. For example, in some cases, it may be desirable to fragment the target polynucleotide prior to hybridization in order to provide segments which are more readily accessible. Fragmentation of the nucleic acids can be carried out by any method producing fragments of a size useful in the assay being performed; suitable physical, chemical and enzymatic methods are known in the art. An amplification reaction can be performed under conditions which allow the sensor polynucleotide to hybridize to the amplification product during at least part of an amplification cycle. When the assay is performed in this manner, real-time detection of this hybridization event can take place by monitoring for light emission during amplification. Real time PCR product analysis (and related real time reverse-transcription PCR) provides a well-known technique for real time PCR monitoring that has been used in a variety of contexts, which can be adapted for use with the methods described herein (see, Laurendeau et al. (1999) “TaqMan PCR-based gene dosage assay for predictive testing in individuals from a cancer family with INK4 locus haploinsufficiency” Clin Chem 45(7):982-6; Laurendeau et al. (1999) “Quantitation of MYC gene expression in sporadic breast tumors with a real-time reverse transcription-PCR assay” Clin Chem 59(12):2759-65; and Kreuzer et al. (1999) “LightCycler technology for the quantitation of bcr/abl fusion transcripts” Cancer Research 59(13):3171-4, all of which are incorporated by reference). Samples In principle, a sample can be any material suspected of containing a target biomolecule (e.g., antibody, protein, affinity ligand, peptide, nucleic acid and the like) capable of causing excitation of a conjugated polymer complex. In some embodiments, the sample can be any source of biological material which comprises biomolecules that can be obtained from a living organism directly or indirectly, including cells, tissue or fluid, and the deposits left by that organism, including viruses, mycoplasma, and fossils. The sample may comprise a target biomolecule prepared through synthetic means, in whole or in part. Typically, the sample is obtained as or dispersed in a predominantly aqueous medium. Nonlimiting examples of the sample include blood, urine, semen, milk, sputum, mucus, a buccal swab, a vaginal swab, a rectal swab, an aspirate, a needle biopsy, a section of tissue obtained for example by surgery or autopsy, plasma, serum, spinal fluid, lymph fluid, the external secretions of the skin, respiratory, intestinal, and genitourinary tracts, tears, saliva, tumors, organs, samples of in vitro cell culture constituents (including but not limited to conditioned medium resulting from the growth of cells in cell culture medium, putatively virally infected cells, recombinant cells, and cell components), and a recombinant library comprising polynucleotide sequences. The sample can be a positive control sample which is known to contain the target biomolecule or a surrogate therefore. A negative control sample can also be used which, although not expected to contain the target biomolecule, is suspected of containing it (via contamination of one or more of the reagents) or another component capable of producing a false positive, and is tested in order to confirm the lack of contamination by the target biomolecule of the reagents used in a given assay, as well as to determine whether a given set of assay conditions produces false positives (a positive signal even in the absence of target biomolecule in the sample). The sample can be diluted, dissolved, suspended, extracted or otherwise treated to solubilize and/or purify any target polynucleotide present or to render it accessible to reagents which are used in an amplification scheme or to detection reagents. Where the sample contains cells, the cells can be lysed or permeabilized to release the polynucleotides within the cells. One step permeabilization buffers can be used to lyse cells which allow further steps to be performed directly after lysis, for example a polymerase chain reaction. Organic Dyes Organic dyes include signaling chromophores and fluorophores. In some embodiments, a signaling chromophore or fluorophore may be employed, for example to receive energy transferred from an excited state of an optically active unit, or to exchange energy with a labeled probe, or in multiple energy transfer schemes. Fluorophores useful in the inventions described herein include any substance which can absorb energy of an appropriate wavelength and emit or transfer energy. For multiplexed assays, a plurality of different fluorophores can be used with detectably different emission spectra. Typical fluorophores include fluorescent dyes, semiconductor nanocrystals, lanthanide chelates, and fluorescent proteins. Exemplary fluorescent dyes include fluorescein, 6-FAM, rhodamine, Texas Red, tetramethylrhodamine, a carboxyrhodamine, carboxyrhodamine 6G, carboxyrhodol, carboxyrhodamine 110, Cascade Blue, Cascade Yellow, coumarin, Cy2 ®, Cy3 ®, Cy3.5 ®, Cy5 ®, Cy5.5®, Cy-Chrome, DyLight 350, DyLight 405, DyLight 488, DyLight 549, DyLight 594, DyLight 633, DyLight 649, DyLight 680, DyLight 750, DyLight 800, phycoerythrin, PerCP (peridinin chlorophyll-a Protein), PerCP-Cy5.5, JOE (6-carboxy-4′,5′-dichloro-2′,7′-dime1hoxyfluorescein), NED, ROX (5-(and-6)-carboxy-X-rhodamine), HEX, Lucifer Yellow, Marina Blue, Oregon Green 488, Oregon Green 500, Oregon Green 514, Alexa Fluor® 350, Alexa Fluor® 430, Alexa Fluor® 488, Alexa Fluor® 532, Alexa Fluor® 546, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 633, Alexa Fluor® 647, Alexa Fluor® 660, Alexa Fluor® 680, 7-amino-4-methylcoumarin-3-acetic acid, BODIPY® FL, BODIPY® FL-Br2, BODIPY® 530/550, BODIPY® 558/568, BODIPY® 564/570, BODIPY® 576/589, BODIPY® 581/591, BODIPY® 630/650, BODIPY® 650/665, BODIPY® R6G, BODIPY® TMR, BODIPY® TR, conjugates thereof, and combinations thereof. Exemplary lanthanide chelates include europium chelates, terbium chelates and samarium chelates. A wide variety of fluorescent semiconductor nanocrystals (“SCNCs”) are known in the art; methods of producing and utilizing semiconductor nanocrystals are described in: PCT Publ. No. WO 99/26299 published May 27, 1999, inventors Bawendi et al.; U.S. Pat. No. 5,990,479 issued Nov. 23, 1999 to Weiss et al.; and Bruchez et al., Science 281:2013, 1998. Semiconductor nanocrystals can be obtained with very narrow emission bands with well-defined peak emission wavelengths, allowing for a large number of different SCNCs to be used as signaling chromophores in the same assay, optionally in combination with other non-SCNC types of signaling chromophores. Exemplary polynucleotide-specific dyes include acridine orange, acridine homodimer, actinomycin D, 7-aminoactmomycin D (7-AAD), 9-amino-6-chlor-2-methoxyacridine (ACMA), BOBO™-1 iodide (462/481), BOBO™-3 iodide (570/602), BO-PRO™-1 iodide (462/481), BO-PRO™-3 iodide (575/599), 4′,6-diamidino-2- phenylindole, dihydrochloride (DAPI), 4′,6-diamidino-2-phenylindole, dihydrochloride (DAPI), 4′,6-diamidino-2-phenylindole, dilactate (DAPI, dilactate), dihydroethidium (hydroethidine), dihydroethidium (hydroethidine), dihydroethidium (hydroethidine), ethidium bromide, ethidium diazide chloride, ethidium homodimer-1 (EthD-1), ethidium homodimer-2 (EthD-2), ethidium monoazide bromide (EMA), hexidium iodide, Hoechst 33258, Hoechst 33342, Hoechst 34580, Hoechst S769121, hydroxystilbamidine, methanesulfonate, JOJO™-1 iodide (529/545), JO-PRO™-1 iodide (530/546), LOLO™-1 iodide (565/579), LO-PRO™-1 iodide (567/580), NeuroTrace™ 435/455, NeuroTrace™ 500/525, NeuroTrace™ 515/535, NeuroTrace™ 530/615, NeuroTrace™ 640/660, OliGreen, PicoGreen® ssDNA, PicoGreen® dsDNA, POPO™-1 iodide (434/456), POPO™-3 iodide (534/570), PO-PRO™-1 iodide (435/455), PO-PRO™-3 iodide (539/567), propidium iodide, RiboGreen®, SlowFade®, SlowFade® Light, SYBR® Green I, SYBR® Green II, SYBR® Gold, SYBR® 101, SYBR® 102, SYBR® 103, SYBR® DX, TO-PRO®-1, TO-PRO®-3, TO-PRO®-5, TOTO®-1, TOTO®-3, YO-PRO®-1 (oxazole yellow), YO-PRO®-3, YOYO®-1, YOYO®-3, TO, SYTOX® Blue, SYTOX® Green, SYTOX® Orange, SYTO® 9, SYTO® BC, SYTO® 40, SYTO® 41, SYTO® 42, SYTO® 43, SYTO® 44, SYTO® 45, SYTO® Blue, SYTO® 11, SYTO® 12, SYTO® 13, SYTO® 14, SYTO® 15, SYTO® 16, SYTO® 20, SYTO® 21, SYTO® 22, SYTO® 23, SYTO® 24, SYTO® 25, SYTO® Green, SYTO® 80, SYTO® 81, SYTO® 82, SYTO® 83, SYTO® 84, SYTO® 85, SYTO® Orange, SYTO® 17, SYTO® 59, SYTO® 60, SYTO® 61, SYTO® 62, SYTO® 63, SYTO® 64, SYTO® Red, netropsin, distamycin, acridine orange, 3,4-benzopyrene, thiazole orange, TOMEHE, daunomycin, acridine, pentyl-TOTAB, and butyl-TOTIN. Asymmetric cyanine dyes may be used as the polynucleotide-specific dye. Other dyes of interest include those described by Geierstanger, B. H. and Wemmer, D. E., Annu. Rev. Vioshys. Biomol. Struct. 1995, 24, 463-493, by Larson, C. J. and Verdine, G. L., Bioorganic Chemistry: Nucleic Acids, Hecht, S. M., Ed., Oxford University Press: New York, 1996; pp 324-346, and by Glumoff, T. and Goldman, A. Nucleic Acids in Chemistry and Biology, 2nd ed., Blackburn, G. M. and Gait, M. J., Eds., Oxford University Press: Oxford, 1996, pp 375-441. The polynucleotide-specific dye may be an intercalating dye, and may be specific for double-stranded polynucleotides. The term “fluorescent protein” includes types of protein known to absorb and emit light. One of the more commonly used classes of such materials are phycobiliproteins. Examples include but are not limited to phycoerythrin (PE and R-PE), allophycocyanin (APC) and PerCP. Other classes include green fluorescent protein and related versions. The term “green fluorescent protein” refers to both native Aequorea green fluorescent protein and mutated versions that have been identified as exhibiting altered fluorescence characteristics, including altered excitation and emission maxima, as well as excitation and emission spectra of different shapes (Delagrave, S. et al. (1995) Bio/Technology 13:151-154; Heim, R. et al. (1994) Proc. Natl. Acad. Sci. USA 91:12501-12504; Heim, R. et al. (1995) Nature 373:663-664). Delgrave et al. isolated mutants of cloned Aequorea victoria GFP that had red-shifted excitation spectra. Bio/Technology 13:151-154 (1995). Heim, R. et al. reported a mutant (Tyr66 to His) having a blue fluorescence (Proc. Natl. Acad. Sci. (1994) USA 91:12501-12504). Substrates In some embodiments, an assay component can be located upon a substrate. The substrate can comprise a wide range of material, either biological, nonbiological, organic, inorganic, or a combination of any of these. For example, the substrate may be a polymerized Langmuir Blodgett film, functionalized glass, Si, Ge, GaAs, GaP, SiO2, SiN4, modified silicon, or any one of a wide variety of gels or polymers such as (poly)tetrafluoroethylene, (poly)vinylidenedifluoride, polystyrene, cross-linked polystyrene, polyacrylic, polylactic acid, polyglycolic acid, poly(lactide coglycolide), polyanhydrides, poly(methyl methacrylate), poly(ethylene-co-vinyl acetate), polysiloxanes, polymeric silica, latexes, dextran polymers, epoxies, polycarbonates, or combinations thereof. Conducting polymers and photoconductive materials can be used. Substrates can be planar crystalline substrates such as silica based substrates (e.g. glass, quartz, or the like), or crystalline substrates used in, e.g., the semiconductor and microprocessor industries, such as silicon, gallium arsenide, indium doped GaN and the like, and includes semiconductor nanocrystals. The substrate can take the form of a photodiode, an optoelectronic sensor such as an optoelectronic semiconductor chip or optoelectronic thin-film semiconductor, or a biochip. The location(s) of probe(s) on the substrate can be addressable; this can be done in highly dense formats, and the location(s) can be microaddressable or nanoaddressable. Silica aerogels can also be used as substrates, and can be prepared by methods known in the art. Aerogel substrates may be used as free standing substrates or as a surface coating for another substrate material. The substrate can take any form and typically is a plate, slide, bead, pellet, disk, particle, microparticle, nanoparticle, strand, precipitate, optionally porous gel, sheets, tube, sphere, container, capillary, pad, slice, film, chip, multiwell plate or dish, optical fiber, etc. The substrate can be any form that is rigid or semi-rigid. The substrate may contain raised or depressed regions on which an assay component is located. The surface of the substrate can be etched using well known techniques to provide for desired surface features, for example trenches, v-grooves, mesa structures, or the like. Surfaces on the substrate can be composed of the same material as the substrate or can be made from a different material, and can be coupled to the substrate by chemical or physical means. Such coupled surfaces may be composed of any of a wide variety of materials, for example, polymers, plastics, resins, polysaccharides, silica or silica-based materials, carbon, metals, inorganic glasses, membranes, or any of the above-listed substrate materials. The surface can be optically transparent and can have surface Si—OH functionalities, such as those found on silica surfaces. The substrate and/or its optional surface can be chosen to provide appropriate characteristics for the synthetic and/or detection methods used. The substrate and/or surface can be transparent to allow the exposure of the substrate by light applied from multiple directions. The substrate and/or surface may be provided with reflective “mirror” structures to increase the recovery of light. The substrate and/or its surface is generally resistant to, or is treated to resist, the conditions to which it is to be exposed in use, and can be optionally treated to remove any resistant material after exposure to such conditions. Polynucleotide or polypeptide probes can be fabricated on or attached to the substrate by any suitable method, for example the methods described in U.S. Pat. No. 5,143,854, PCT Publ. No. WO 92/10092, U.S. patent application Ser. No. 07/624,120, filed Dec. 6, 1990 (now abandoned), Fodor et al., Science, 251: 767-777 (1991), and PCT Publ. No. WO 90/15070). Techniques for the synthesis of these arrays using mechanical synthesis strategies are described in, e.g., PCT Publication No. WO 93/09668 and U.S. Pat. No. 5,384,261. Still further techniques include bead based techniques such as those described in PCT Appl. No. PCT/US93/04145 and pin based methods such as those described in U.S. Pat. No. 5,288,514. Additional flow channel or spotting methods applicable to attachment of sensor polynucleotides or polypeptides to the substrate are described in U.S. patent application Ser. No. 07/980,523, filed Nov. 20, 1992, and U.S. Pat. No. 5,384,261. Reagents are delivered to the substrate by either (1) flowing within a channel defined on predefined regions or (2) “spotting” on predefined regions. A protective coating such as a hydrophilic or hydrophobic coating (depending upon the nature of the solvent) can be used over portions of the substrate to be protected, sometimes in combination with materials that facilitate wetting by the reactant solution in other regions. In this manner, the flowing solutions are further prevented from passing outside of their designated flow paths. Typical dispensers include a micropipette optionally robotically controlled, an ink-jet printer, a series of tubes, a manifold, an array of pipettes, or the like so that various reagents can be delivered to the reaction regions sequentially or simultaneously. The substrate or a region thereof may be encoded so that the identity of the sensor located in the substrate or region being queried may be determined. Any suitable coding scheme can be used, for example optical codes, RFID tags, magnetic codes, physical codes, fluorescent codes, and combinations of codes. Excitation and Detection Any instrument that provides a wavelength that can excite the conjugated polymer complex and is shorter than the emission wavelength(s) to be detected can be used for excitation. Commercially available devices can provide suitable excitation wavelengths as well as suitable detection components. Exemplary excitation sources include a broadband UV light source such as a deuterium lamp with an appropriate filter, the output of a white light source such as a xenon lamp or a deuterium lamp after passing through a monochromator to extract out the desired wavelengths, a continuous wave (cw) gas laser, a solid state diode laser, or any of the pulsed lasers. Emitted light can be detected through any suitable device or technique; many suitable approaches are known in the art. For example, a fluorimeter or spectrophotometer may be used to detect whether the test sample emits light of a wavelength characteristic of the signaling chromophore upon excitation of the conjugated polymer. Compositions of Matter Also provided are compositions of matter of any of the molecules described herein in any of various forms. The conjugated polymers and complexes including conjugated polymers as described herein may be provided in purified and/or isolated form. The conjugated polymers and complexes including conjugated polymers may be provided in either crystalline or amorphous form. The conjugated polymers and complexes including conjugated polymers may be provided in solution, which may be a predominantly aqueous solution, which may comprise one or more of the additional solution components described herein, including without limitation additional solvents, buffers, biomolecules, polynucleotides, fluorophores, etc. In addition, a mixture of CPs in solution is also able to provide improved detection sensitivity as compared to that for a single CP/dye system. The conjugated polymers and complexes including conjugated polymers can be present in solution at a concentration at which a first emission from the first optically active units can be detected in the absence of biomolecule target or a biomolecule associated therewith. The solution may comprise additional components as described herein, including labeled probes such as fluorescently labeled antibodies or polynucleotides, specific for a species or a class of biomolecule target or a biomolecule associated therewith for the conjugated polymers and complexes including conjugated polymers. The conjugated polymers and complexes including conjugated polymers may be provided in the form of a film. The compositions of matter may be claimed by any property described herein, including by proposed structure, by method of synthesis, by absorption and/or emission spectrum, by elemental analysis, by NMR spectra, or by any other property or characteristic. In some embodiments expression of a gene is detected in a sample. In a further embodiment identification of a cell marker or cell type is detected in a sample either in a flow cytometer, cell sorter, microscope, plate reader or fluorescence imager. In a further embodiment the identification of cell type or marker is used in the diagnosis of lymphoma or other circulating cancers. In a further embodiment the identification of cell type or marker is used in the diagnosis and monitoring of HIV infection. In a further embodiment the identification of cell type or marker is used to sort cells for therapeutic application. In a further embodiment, a measured result of detecting a biomolecule target or a biomolecule associated therewith can be used to diagnose a disease state of a patient. In yet another embodiment the detection method of the invention can further include a method of diagnosing a disease state. In a related embodiment, the method of diagnosing a disease can include reviewing or analyzing data relating to the presence of a biomolecule target or a biomolecule associated therewith and providing a conclusion to a patient, a health care provider or a health care manager, the conclusion being based on the review or analysis of data regarding a disease diagnosis. Reviewing or analyzing such data can be facilitated using a computer or other digital device and a network as described herein. It is envisioned that information relating to such data can be transmitted over the network. In practicing the methods of the present invention, many conventional techniques in molecular biology are optionally utilized. These techniques are well known and are explained in, for example, Ausubel et al. (Eds.) Current Protocols in Molecular Biology, Volumes I, II, and III, (1997), Ausubel et al. (Eds.), Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, 5th Ed., John Wiley & Sons, Inc. (2002), Sambrook et al., Molecular Cloning: A Laboratory Manual, 3rd Ed., Cold Spring Harbor Laboratory Press (2000), Innis et al. (Eds.) PCR Protocols: A Guide to Methods and Applications, Elsevier Science & Technology Books (1990), and Greg T. Hermanson, Bioconjugate Techniques, 2nd Ed., Academic Press, Inc. (2008) all of which are incorporated herein by reference. FIG. 12 is a block diagram showing a representative example logic device through which reviewing or analyzing data relating to the present invention can be achieved. Such data can be in relation to a disease, disorder or condition in a subject. FIG. 12 shows a computer system (or digital device) 800 connected to an apparatus 820 for use with the conjugated polymers or conjugated polymers complexes 824 to, for example, produce a result. The computer system 800 may be understood as a logical apparatus that can read instructions from media 811 and/or network port 805, which can optionally be connected to server 809 having fixed media 812. The system shown in FIG. 12 includes CPU 801, disk drives 803, optional input devices such as keyboard 815 and/or mouse 816 and optional monitor 807. Data communication can be achieved through the indicated communication medium to a server 809 at a local or a remote location. The communication medium can include any means of transmitting and/or receiving data. For example, the communication medium can be a network connection, a wireless connection or an internet connection. It is envisioned that data relating to the present invention can be transmitted over such networks or connections. In one embodiment, a computer-readable medium includes a medium suitable for transmission of a result of an analysis of a biological sample. The medium can include a result regarding a disease condition or state of a subject, wherein such a result is derived using the methods described herein. Kits Kits comprising reagents useful for performing described methods are also provided. In some embodiments, a kit comprises reagents including conjugated polymers or conjugated polymers complexes, bioconjugates, for example, antibodies, nucleic acids, and other components as described herein. The kit may optionally contain one or more of the following: one or more labels that can be incorporated into conjugated polymers or conjugated polymers complexes; and one or more substrates which may or may not contain an array, etc. The components of a kit can be retained by a housing. Instructions for using the kit to perform a described method can be provided with the housing, and can be provided in any fixed medium. The instructions may be located inside the housing or outside the housing, and may be printed on the interior or exterior of any surface forming the housing that renders the instructions legible. A kit may be in multiplex form for detection of one or more different target biomolecules or biomolecules associated therewith. As described herein and shown in FIG. 13, in certain embodiments a kit 903 can include a container or housing 902 for housing various components. As shown in FIG. 13, and described herein, in one embodiment a kit 903 comprising one or more conjugated polymers or conjugated polymers complexes reagents 905, and optionally a substrate 900 is provided. As shown in FIG. 13, and described herein, the kit 903 can optionally include instructions 901. Other embodiments of the kit 903 are envisioned wherein the components include various additional features described herein. EXAMPLES The following examples provide illustrative methods for making and testing the effectiveness of the conjugated polymers described herein. These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. It will be apparent to those of skill in the art that variations may be applied to the methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the claims. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the appended claims. Example 1: Synthesis of a Polymer of Formula (I) Example 1a: Synthesis of monomers, 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (A) and 9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-2,7-di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)fluorene (B) for subsequent polymerization Step 1: 2,7-dibromo-9,9-di(3′-hydroxypropanyl)fluorene 2,7-dibromofluorene (9.72 g, 30 mmol), tetrabutylammonium bromide (300 mg, 0.93 mmol), and DMSO (100 mL) were added to a 3-neck flask under nitrogen(g), followed by the addition of 50% NaOH (15 mL, 188 mmol) via syringe. The mixture was heated to 80° C., and 3-bromopropanol (6.70 mL, 77 mmol) was added dropwise via addition funnel, and the reaction mixture was stirred at 80° C. for another 2 hours. Upon completion, the mixture was cooled to room temperature and quenched with water (250 mL). The aqueous layer was extracted with ethyl acetate (3 150 mL portions). The organic layers were combined, washed with water, then dried over MgSO4, and filtered. The solvent was removed and the residual was recrystallized in chloroform to yield pale yellow needle crystals (9.20 g, 70%). Step 2: 2,7-dibromo-9,9-di(3′-methylbenzenesulfonatopropanyl)fluorene 2,7-dibromo-9,9-di(3′-hydroxypropanyl)fluorene (500 mg, 1.14 mmol) was dissolved in dichloromethane (5 mL) at 0° C. under nitrogen(g). To the mixture, added p-toluenesulfonyl chloride (650 mg, 3.40 mmol), followed by pyridine (0.39 mL, 4.77 mmol). Allowed reaction to stir at 0° C. and naturally rise to room temperature over night. The reaction was quenched with water (15 mL). Removal of solvent by vacuo resulted solids formation. Filtered off solids to yield white solids (758 mg, 89%). Step 3: 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (A) mPEG11 alcohol (770 mg, 1.49 mmol) was dissolved in anhydrous THF (2 mL) at 0° C. under nitrogen. To the mixture, was added potassium tert-butoxide (1.63 mmol, 1.63 mL, 1M in THF). After 10 min stirring, 2,7-dibromo-9,9-di(3′-methylbenzenesulfonatopropanyl)fluorene (504 mg, 0.673 mmol) in 10 mL of THF was added via a syringe. The mixture was allowed to room temperature and stirred overnight. The reaction mixture was diluted with THF. The insoluble inorganic salt was removed by filtration. Concentration of the filtrate yielded crude product, which was purified by column chromatography (DCM-MeOH) to yield a colorless oil (605 mg, 62.5%). Step 4: 9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-2,7-di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)fluorene (B) 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (1.510 g, 1.501 mmol), bis(pinacolato)diboron (800 mg, 3.15 mmol), potassium acetate (619 mg, 6.31 mmol), Pd(dppf)Cl2 [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)] (51.5 mg, 0.063 mmol) and DMSO (30 mL) were mixed under N2. The mixture was heated at 80° C. for 5.5 hour. Upon completion, the DMF was distilled and water (50 mL) was added. The product was extracted with DCM (3×40 mL). The organic layers were combined and concentrated. The crude product was purified by column chromatography (DCM-MeOH) to give colorless oil (1.015 g, 63%). Example 1b: Polymerization of Monomers (A) and (B) 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (A) (0.084 mmol, 120 mg), 9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-2,7-di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)fluorene (B) (0.088 mmol, 135 mg), and palladium tetra(triphenylphosphine) (0.0035 mmol, 4 mg) were combined in a round bottom flask equipped with a stirbar. Next, 0.35 mL of 2M potassium carbonate (aq) and 1.9 mL of tetrahydrofuran were added and the flask is fitted with a vacuum adaptor and put on a Schlenk line. The mixture was degassed using 3 freeze-pump-thaw cycles. The degassed mixture was heated to 80° C. under nitrogen with vigorous stirring for 18 hours. The reaction mixture was then cooled and the solvent removed with rotary evaporation. The resulting semisolid was diluted with ca. 50 mL water and filtered through glass fiber filter paper. Ethanol was added to adjust the solvent to 20% ethanol in water. Preparative gel permeation chromatography was performed with G-25 desalting medium to remove excess salts from the polymer. Solvent in the fractions was removed with rotary evaporation and 100 mg of poly [2,7{9,9-bis (2, 5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene] was collected as an amber oil. Example 2: Synthesis of Asymmetric Polymers of Formula (I) Via Suzuki Coupling Example 2a: Synthesis of Asymmetric Monomer, 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene (C) for Subsequent Polymerization Step 1: 2-dibromo-7-iodofluorene 2-bromofluorene (10.01 g, 40.84 mmol), acetic acid (170 mL), water (8 mL), iodine (4.34 g, 17.20 mmol), potassium iodate (2.18 g, 10.19 mmol) and sulfuric acid (4 mL) were mixed under nitrogen. The resulting mixture was heated at 80° C. for 2 h and cooled to room temperature. The formed precipitate which is the desired product was collected after filtration and acetic acid wash (13.68 g, 90%). Step 2: 2-dibromo-9,9-di(3′hydroxypropanyl)-7-iodofluorene 2-dibromo-7-iodofluorene (2.186 g, 5.892 mmol), tetrabutylammonium bromide (60 mg, 0.186 mmol), and DMSO (25 mL) were added to a 3-neck flask under nitrogen(g), followed by the addition of 50% NaOH (4 mL, 50 mmol) via syringe. The mixture was heated to 80° C., and 3-bromopropanol (1.33 mL, 14.7 mmol) was added slowly, and the reaction was stirred at 80° C. for another 1 hour. Upon completion, the mixture was cooled to room temperature and quenched with water. The precipitate as crude product was collected after filtration. The crude product was purified by column chromatography (eluant: hexane-ethylacetate) to give pale yellow solid (2.15 g, 75%). Step 3: 2-bromo-9,9-di(3′-hydroxypropanyl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene 2-dibromo-9,9-di(3′hydroxypropanyl)-7-iodofluorene (2.454 g, 5.037 mmol), bis(pinacolato)diboron (1.407 g, 5.541 mmol), potassium acetate (1.483 g, 15.11 mmol), Pd(dppf)Cl2 (123 mg, 0.15 mmol) and DMSO (25 mL) were mixed under N2. The mixture was heated at 80° C. for 1.5 hour. Upon completion, the mixture was cooled to room temperature and quenched with water (50 mL). The product was extracted with DCM (3×40 mL). The organic layers were combined and concentrated. The crude product was purified by column chromatography (eluant: hexane-ethylacetate) to give pale solid (2.09 g, 85%). Step 4: 2-bromo-9,9-di(3′-methanesulfanotopropanyl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene 2-bromo-9,9-di(3′-hydroxypropanyl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene (2.280 g, 4.694 mmol) and p-toluenesulfonyl chloride (2.684 g, 14.08 mmol) were dissolved in dichloromethane at room temperature under N2. Triethylamine (3.95 mL, 28.2 mmol) was added slowly via syringe. The mixture was stirred at room temperature over night. The mixture was then concentrated and purified by column chromatography (Hexane-EtOAc) to yield pale solid (2.66 g, 72%). Step 5: 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorine (C) mPEG11 alcohol (3.331 g, 6.448 mmol) was dissolved in anhydrous THF (20 mL) at 0° C. under nitrogen. To the mixture, was added potassium tert-butoxide (7.74 mmol, 7.74 mL, 1M in THF). After 10 min stirring, 2-bromo-9,9-di(3′-methanesulfanotopropanyl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorine (2.052 g, 2.579 mmol) in 20 mL of anhydrous THF was added via a syringe. The mixture was allowed to room temperature and stirred overnight. After evaporation of THF, brine (50 mL) was added and crude product was extracted with dichloromethane (3×40 mL). The combined organic layers were concentrated and purified by column chromatography (DCM-isopropanol) to give colorless gel-like product (2.164 g, 57%). Example 2b: Synthesis of an Asymmetric Polymer Via Suzuki Coupling Polymerization Asymmetric polymers are synthesized using conditions similar to polymerization conditions as described in Example 1b. Example 3: Synthesis of a Linker or Capping Unit Example 3a: Synthesis of Linker or Capping Unit, Tert-Butyl 4-(3,5-Dibromophenoxy)Butylcarbamate Step 1: 4-(3,5-dibromophenoxy)butan-1-amine 1-(4′-phthalimidobutoxy)3,5-dibromobenzene (1.0 g, 2.20 mmol) was dissolved in ethanol (45 mL) for 5 minutes under nitrogen. Hydrazine monohydrate (610 mg, 12.1 mmol) was added and the reaction was refluxed at 80° C. for 2 hours. To the reaction aqueous 1M HCl (17.7 mL, 17.7 mmol) was added and refluxed at 105° C. for another 2 hours. The aqueous layer was extracted with dichloromethane (2×150 mL). The organic layers were combined, washed with saturated NaHCO3 (3×), water, and brine, then dried over MgSO4, and filtered. Removal of solvent yielded a yellow oil (560 mg, 78%). Step 2: Tert-butyl 4-(3,5-dibromophenoxy)butylcarbamate 4-(3,5-dibromophenoxy)butan-1-amine (397 mg, 1.23 mmol) was dissolved in anhydrous THF (24.6 mL) under nitrogen. Di-tert-butyl dicarbonate (423 mL, 1.84 mmol) was added to the mixture and refluxed reaction at 40° C. for 2 hours. After extraction of the reaction with dichloromethane (2×50 mL), the organic layers were combined, washed with saturated NaHCO3, water, and brine, then dried over MgSO4, and filtered. The solvent is removed and the residue is purified by column chromatography (9:1, hexanes: EtOAc) to give a white solid (306 mg, 59%). Example 3b: Synthesis of Linker or Capping Unit, Tert-butyl-4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butylcarbamate Step 1: 2,7-dibromo-9-methyl-9H-fluorene 2,7-dibromofluorene (30 g, 92.59 mmol) was dissolved in anhydrous THF (300 mL) under nitrogen and cooled to −78° C. To solution at −78° C., added n-butyllithium (40.36 mL, 100.9 mmol) over 5 minutes and allowed reaction stir for another 10 minutes. To reaction, then add methyl iodide (6.29 mL, 100.9 mmol) and allowed reaction to stir at −78° C. for 2.0 hours. The reaction was poured into a mixture of dichloromethane and water. The organic layer was collected, and the water layer was further extracted with dichloromethane. Combined all organic layers and removed solvent via vacuo. The crude material was triturated with hexanes and filtered using Buchner funnel to give white solids (22 g, 70%). 1H NMR (500 MHz, CDCl3): δ=7.62 (s, 2H), 7.56-7.58 (d, 2H), 7.48-7.50 (dd, 2H), 3.90-3.94 (q, 1H), 1.49-1.51 (d, 3H). Step 2: 2-(4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butyl)isoindoline-1,3-dione 2,7-dibromo-9-methyl-9H-fluorene (10.0 g, 29.58 mmol) was dissolved in 50 mL DMSO under nitrogen. To mixture was added KOH (2.01 g, 35.79 mmol), water (1.5 mL), N-(4-bromobutyl)phthalimide (9.93 g, 35.2 mmol), and stirred reaction at room temperature for 2.0 hours, then at 50° C. for 3.0 hours. The reaction was cooled to room temperature and diluted with dichloromethane. The organic layer was washed with brine (2λ), and water. Removal of solvent yield a solid, which was purified by column chromatography (7:3, hexanes:EtOAc) to yield white solids (3.08 g, 20%). 1H NMR (500 MHz, CDCl3): δ=7.81-7.83 (m, 2H), 7.68-7.71 (m, 2H), 7.48-7.51 (m, 4H), 7.41-7.44 (dd, 2H), 3.46-3.49 (t, 2H), 2.00-2.04 (p, 2H), 1.47-1.49 (m, 2H), 1.45 (s, 3H), 0.65-0.68 (m, 2H). Step 3: 4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butan-1-amine 2-(4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butyl)isoindoline-1,3-dione (3.08, 5.71 mmol) was dissolved in ethanol (250 mL) under nitrogen. To the mixture was added hydrazine monohydrate (2.77 mL, 57.1 mmol), and the reaction was refluxed at 80° C. for 3.0 hours. The reaction was cooled to room temperature, and added 1M HCl (˜100 mL). The mixture was stirred for 30 minutes or until all solids were dissolved. Dichloromethane was added to the solution and the organic layer was extracted with saturated NaHCO3 three times, and washed with water. The organic layers were collected and removed solvent by vacuo to give an yellow oil (2.33 g, 100%). 1H NMR (500 MHz, CD2Cl2): δ=7.57 (d, 2H), 7.52 (d, 2H), 7.46-7.48 (dd, 2H), 2.39-2.42 (t, 2H), 1.95-1.98 (t, 2H), 1.44 (s, 3H), 1.17-1.23 (m, 2H), 0.59-0.65 (m, 2H). Step 4: tert-butyl-4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butylcarbamate 4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butan-1-amine (2.39 g, 5.84 mmol) was dissolved in anhydrous THF (20 mL) under nitrogen. To solution, was added di-tert-butyl-dicarbonate (2.01 mL, 8.76 mmol), and the reaction was stirred at 40° C. for 3 hours. The reaction was cooled to room temperature and concentrated via vacuo. Crude solids were triturated with hexanes and filtered using buchner funnel to yield the desired white solids (2.34 g, 79%). 1H NMR (500 MHz, CDCl3): δ=7.53 (d, 2H), 7.45-7.47 (d, 4H), 4.30 (s, 1H), 2.88-2.90 (q, 2H), 1.93-1.96 (t, 2H), 1.43 (s, 3H), 1.41 (s, 9H), 1.25-1.28 (m, 2H), 0.59-0.66 (m, 2H). Example 4: Synthesis of a Linker or Capping Unit Example 4a: Synthesis of Tert-butyl 4-(4-bromophenoxy)butylcarbamate Step 1: N(4-(4-bromophenoxy)butyl)phthalimide Combined 4-bromophenol (4.64 g, 26.8 mmol), N-(4-bromobutylphthalimide) (6.30 g, 22.33 mmol), K2CO3 (11.09 g, 80.38 mmol), 18-crown-6 (265 mg, 1.00 mmol), and acetone (100 mL), and refluxed reaction under nitrogen at 70° C. over night. The reaction was cooled to room temperature and removed solvent by vacuum. The crude mixture was diluted with dichloromethane (200 mL) and washed with water (3×), then dried over MgSO4, and filtered. Removal of solvent, followed by trituration with hexanes, and filtered using Buchner funnel to yield a white solid (6.03 g, 71%). Step 2: 4-(4-bromophenoxy)butan-1-amine N(4-(4-bromophenoxy)butyl)phthalimide (6.01 g, 16.1 mmol) is dissolved in ethanol (200 mL) under nitrogen, followed by the addition of hydrazine monohydrate (7.8 mL, 161 mmol). The reaction was refluxed at 80° C. for 2 hours. Once reaction completed (solids formed at the top layer), cooled reaction to room temperature and neutralized with 1M HCl (50 mL). The mixture is allowed to stir until all solids are completely dissolved and diluted with dichloromethane (150 mL). The solution was extracted with two portions of saturated NaHCO3 (2×). The organic layers were combined, washed with brine and water, then dried over MgSO4, and filtered. Removal of solvent yields a yellow oil (2.93 g, 75%). Step 3: Tert-butyl 4-(4-bromophenoxy)butylcarbamate 4-(4-bromophenoxy)butan-1-amine (1.0 g, 4.09 mmol) was dissolved in anhydrous THF (20 mL) under nitrogen and stirred until solution is homogenous. Di-tert-butyl-dicarbonate (1.34 g, 6.14 mmol) was added and the reaction was stirred at 40° C. for 2 hours. The reaction was quenched with water (30 mL) and stirred at room temperature for 1.0 hour. The aqueous layer was extracted with ethyl acetate (50 mL×2). The organic layers were combined, washed with saturated NaHCO3, water, and brine, then dried over MgSO4, and filtered. Removal of solvent yield a solid, which was purified by column chromatography (9:1, hexanes:EtOAc) to yield white solids (1.0 g, 71%). Example 4b: Synthesis of tert-butyl 4-(4-bromophenyl)butanoate Allowed tert-butanol to melt and added 20 mL to round bottom flask. To the solution, added di-tert-butyl-dicarbonate (1.79 g, 8.22 mmol) and 4-(4-bromophenyl)butyric acid (1.0 g, 4.11 mmol). To reaction, then added DMAP (150.7 mg, 1.23 mmol) and stirred reaction at room temperature over night. The reaction was concentrated via vacuo, and re-diluted in ethyl acetate. The organic layer was washed with 1M HCl, brine, and water. After removal of solvent, the crude solids were purified via column chromatography (20:1, hexanes:EtOAc) to give the desired product (570 mg, 46%), which is a clear oil. 1H NMR (500 MHz, CD2Cl2): 5=7.39-7.41 (d, 2H), 7.03-7.09 (d, 2H), 2.57-2.60 (t, 2H), 2.18-2.21 (t, 2H), 1.83-1.186 (p, 2H), 1.42 (s, 9H). Example 4c: Synthesis of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butanoic acid Combined 4-(4-bromophenyl)butyric acid (10 g, 41.13 mmol), bis(pinacolato)diboron (15.67 g, 61.70 mmol), potassium acetate (12.11 g, 123.4 mmol), and DMSO (100 mL), and purged mixture with nitrogen for 10 minutes at room temperature. To reaction under nitrogen, added Pd(dppf)Cl2 and purged reaction again with nitrogen for another 20 minutes at room temperature. The reaction was then refluxed at 80° C. over night. After cooling to room temperature, the reaction was quenched with water and stirred for 1.0 hour. The solids formed were filtered using Buchner funnel. The crude solids were purified via column chromatography (8.5:1.5, hexanes:EtOAc). The desired fractions were collected and concentrated via vacuo, and triturated with hexanes and filtered to give the desired white solids (6.7 g, 56%). Example 5: Synthesis of Linker or Capping Unit, Tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butylcarbamate Combined tert-butyl 4-(4-bromophenoxy)butylcarbamate from Example 4a (500 mg, 1.45 mmmol), potassium acetate (428 mg, 4.36 mmol), bis(pinacolato)diboron (737 mg, 2.90 mmol) and DMSO (12 mL), and purged mixture with nitrogen for 10 minutes at room temperature. To mixture was added Pd(dppf)Cl2 (59.3 mg, 0.07 mmol) and continued to stir solution at room temperature under nitrogen for another 20 minutes. After refluxing at 80° C. for 3 hours, the reaction was cooled to room temperature and quenched with water (30 mL). The aqueous layer was extracted with dichloromethane (50 mL×2). The organic layers were combined, washed with brine, then dried over MgSO4, and filtered. Removal of solvent yield a dark brown oil, which was purified by column chromatography (9:1, hexanes:EtOAc) to yield a light yellow oil (539 mg, 95%). Example 6: Synthesis of Linker or Capping Unit with Long Oligoether Spacer Between Arylhalide Phenyl and FMOC Protected Primary Amine 4-(4-bromophenoxy)butan-1-amine+oligoether-FMOC+N,N′-dicyclohexylcarbodiimide (DCC) (9H-fluoren-9-yl)methyl 80-(4-bromophenoxy)-75-oxo-3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,63,66,69,72-tetracosaoxa-76-azaoctacontylcarbamate. 4-(4-bromophenoxy)butan-1-amine (21.5 mg, 0.09 mmol), 1-(9H-fluoren-9-yl)-3-oxo-2,7,10,13,16,19,22,25,28,31,34,37,40,43,46,49,52,55,58,61,64,67,70,73,76-pentacosaoxa-4-azanonaheptacontan-79-oic acid (100 mg, 0.073 mmol), and N,N′-dimethylaminopyridine (5.4 mg, 0.044 mmol) were combined in a round bottom flask flushed with nitrogen and charged with a Teflon stirbar. Next 5 mL of anhydrous dichloromethane was added via syringe. N,N-Dicyclohexylcarbodiimide (23 mg, 0.11 mmol) is transferred to a second flask flushed with nitrogen and charged with a stirbar and 5 mL of anhydrous dichloromethane is added via syringe. While stirring the first solution, add the dicyclohexylcarbodiimide solution slowly, dropwise. The reaction is then allowed to proceed overnight. The following day solids from the reaction were filtered off and the filtrate was concentrated onto silica. Column chromatography in methanol and dichloromethane gave a clear thick oil (83.3 mg, 71% yield). Example 7: Synthesis of Polymer, Poly[2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene}-co-3,5-phenylbut-V-oxy-4″-amine], with an Internal Linking Site The incorporation of internal conjugation sites into conjugated polymer backbones is described in U.S. application Ser. No. 11/868,870, filed Oct. 8, 2007 and published as U.S. Application No. 2008/0293164, which application is herein incorporated by reference in its entirety. Provided is a modified synthesis based on the protocol. 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (0.084 mmol, 120 mg), 9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-2,7-di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)fluorene (0.088 mmol, 135 mg), tert-butyl-4-(3,5-dibromophenoxy)butylcarbamate (0.0044 mmol, 2.0 mg), and palladium tetra(triphenylphosphine) (0.0035 mmol, 4 mg) are combined in a round bottom flask equipped with a stirbar. Next, 0.35 mL of 2M potassium carbonate (aq) and 1.9 mL of tetrahydrofuran are added and the flask is fitted with a vacuum adaptor and put on a Schlenk line. The mixture is degassed using 3 freeze-pump-thaw cycles. The degassed mixture is heated to 80 C under nitrogen with vigorous stirring for 18 hours. The reaction mixture is then cooled and the solvent is removed with rotary evaporation. Next, 4 mL of 4 M HCl in dioxane is added and the mixture is stirred for no less than 4 hours. The solution is neutralized with 2M potassium carbonate solution. The bulk of the solvent is again removed with rotary evaporation. The resulting semisolid is diluted with ca. 50 mL water and filtered through glass fiber filter paper. Ethanol is added to adjust the solvent to 20% ethanol in water. Preparative gel permeation chromatography is performed with G-25 desalting medium to remove excess salts from the polymer. Solvent in the fractions is removed with rotary evaporation and 100 mg of poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene}-co-3,5-tert-butyl-4-(4-bromophenoxy)amine] is collected as an amber oil. Example 8: Synthesis of Phenylene Vinylene Co-Polymer with an Internal Linking Site A modified synthesis similar to that described in Examples 7 and 15. Example 9: Synthesis of Polymer with Exclusively Terminal Amine Capping Units 2,7-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene])-diphen-4-oxybutyl-4′-amine 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (0.163 mmol, 235 mg), 9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-2,7-di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)fluorene (0.163 mmol, 250 mg), and palladium tetra(triphenylphoshine) (0.0065, 7.5 mg) are combined in a round bottom flask equipped with a stirbar. Next, 0.75 mL of 2M potassium carbonate (aq) and 3 mL of tetrahydrofuran are added and the flask is fitted with a vacuum adaptor. The reaction mixture is put on a Schenk line and is degassed with three freeze-pump-thaw cycles and then heated to 80 C under nitrogen with vigorous stirring for 18 hours. A solution of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butylcarbamate (0.064 mmol, 25 mg) in 0.5 mL tetrahydrofuran is degassed with three freeze-pump-thaw cycles and then added to the polymerization reaction via cannula under excess nitrogen pressure. The reaction is allowed to continue for an additional 4 hours at 80 C with stirring. Next, a solution of tert-butyl 4-(4-bromophenoxy)butylcarbamate (0.192 mmol, 66 mg) in 0.5 mL of THF is degassed with three freeze-pump-thaw cycles and then added to the polymerization reaction via cannula under excess nitrogen pressure. The reaction was allowed to proceed overnight. The reaction mixture was allowed to cool and solvent was removed with rotary evaporation. A 4 mL portion of 4M HCl in dioxane was added to the residue and stirred for a minimum of 4 hours. The solution was neutralized with 2 M potassium carbonate (aq) and then the solvent was removed under vacuum. The resulting residue was diluted to −30 mL with 20% ethanol in water and filtered. Preparative gel permeation chromatography is performed with G-25 desalting medium to remove excess salts from the polymer. Solvent in the fractions is removed with rotary evaporation and 337 mg of polymer is collected as an amber oil. The order of end linker addition (aryl hylide or boronic ester/acid) can be reversed. Similar processes can be used to add alternative linkers or end capping units. Example 10: Synthesis of Polymer, 2-(Poly [2,7{9,9-Bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene])-phen-4-oxybutyl-4′-amine, Statistically Enriched in Chains with a Single Terminal Amine Capping Unit 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (0.163 mmol, 235 mg), 9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-2,7-di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)fluorene (0.163 mmol, 250 mg), and palladium tetra(triphenylphoshine) (0.0065, 7.5 mg) are combined in a round bottom flask equipped with a stirbar. Next, 0.75 mL of 2M potassium carbonate (aq) and 3 mL of tetrahydrofuran are added and the flask is fitted with a vacuum adaptor. The reaction mixture is put on a Schenk line and is degassed with three freeze-pump-thaw cycles and then heated to 80 C under nitrogen with vigorous stirring for 18 hours. A solution of tert-butyl 4-(4-bromophenoxy)butylcarbamate (0.049 mmol, 17 mg) in 0.5 mL tetrahydrofuran is degassed with three freeze-pump-thaw cycles and then added to the polymerization reaction via cannula under excess nitrogen pressure. The reaction is allowed to continue for an additional 4 hours at 80 C with stirring. Next, a solution of phenylboronic acid (0.150 mmol, 18 mg) in 0.5 mL of THF is degassed with three freeze-pump-thaw cycles and then added to the polymerization reaction via cannula under excess nitrogen pressure. The reaction was allowed to proceed overnight. The reaction mixture was allowed to cool and solvent was removed with rotary evaporation. A 4 mL portion of 4M HCl in dioxane was added to the residue and stirred for a at least 4 hours. The solution was neutralized with 2 M potassium carbonate (aq) and then the solvent was removed under vacuum. The resulting residue was diluted to −30 mL with 20% ethanol in water and filtered. Preparative gel permeation chromatography is performed with G-25 desalting medium to remove excess salts from the polymer. Solvent in the fractions is removed with rotary evaporation and 315 mg of polymer is collected as an amber oil. Resulting polymers contain chains with an enriched fraction of chains with one amine linker plus chains with 2 linkers and no linkers. Example 11: Synthesis of Polymer Statistically Enriched in Chains with a Single Terminal Capping Unit with a Long Oligoether Spacer (24 Repeats) Between the Polymer Chain and the Primary Amine Linking Group 2-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene])-phen-4-oxybutyl-4′-amine. 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (0.163 mmol, 235 mg), 9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-2,7-di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)fluorene (0.163 mmol, 250 mg), and palladium tetra(triphenylphoshine) (0.0065, 7.5 mg) are combined in a round bottom flask equipped with a stirbar. Next, 0.75 mL of 2M potassium carbonate (aq) and 3 mL of tetrahydrofuran are added and the flask is fitted with a vacuum adaptor. The reaction mixture is put on a Schenk line and is degassed with three freeze-pump-thaw cycles and then heated to 80 C under nitrogen with vigorous stirring for 18 hours. A solution of tert-butyl 4-(4-bromophenoxy)butylcarbamate (0.049 mmol, 17 mg) in 0.5 mL tetrahydrofuran is degassed with three freeze-pump-thaw cycles and then added to the polymerization reaction via cannula under excess nitrogen pressure. The reaction is allowed to continue for an additional 4 hours at 80 C with stirring. Next, a solution of phenylboronic acid (0.150 mmol, 18 mg) in 0.5 mL of THF is degassed with three freeze-pump-thaw cycles and then added to the polymerization reaction via cannula under excess nitrogen pressure. The reaction was allowed to proceed overnight. The reaction mixture was allowed to cool and solvent was removed with rotary evaporation. A 4 mL portion of 4M HCl in dioxane was added to the residue and stirred for a minimum of 4 hours. The solution was neutralized with 2 M potassium carbonate (aq) and then the solvent was removed under vacuum. The resulting residue was diluted to −30 mL with 20% ethanol in water and filtered. Preparative gel permeation chromatography is performed with G-25 desalting medium to remove excess salts from the polymer. Solvent in the fractions is removed with rotary evaporation and 315 mg of polymer is collected as an amber oil. Example 12: Synthesis of an Asymmetric Polymer with a Terminal Carboxylic Capping Unit Added During Polymerization Reaction The linking monomer is added during the polymerization reaction as described in Examples 9, 10 and 11. The carboxylic acid group can later be converted to an activated ester such as N-hydroxysuccinimidyl as is described in Example 29. Example 13: Synthesis of an Asymmetric Polymer with a Terminal Carboxylic Acid Capping Unit Added Post Polymerization The linking monomer is added after the polymerization reaction is completed and polymer purified. Linker addition is done under similar reaction conditions as those described in Examples 9, 10 and 11. The carboxylic acid group can later be converted to an activated ester such as N-hydroxysuccinimidyl as is described in Example 29. Example 14: Synthesis of an Polymer with Branched PEG Groups Example 14a: Synthesis of Monomers, (D) and (E) for Subsequent Polymerization Step 1: 2,7-dibromo-9,9-bis(3,5-dimethoxybenzyl)fluorene 2,7-dibromofluorene (4.16 g, 12.8 mmol) and tetrabutylammonium bromide (362 mg, 1.12 mmol) were added to a round bottom flask charged with a Teflon stirbar. Next, 60 mL of dimethylsulfoxide was added to the flask and the mixture was stirred for 5 minutes. A portion of 50% NaOH aqueous solution (5.2 mL) was added followed immediately by 3,5-dimethoxybenzyl bromide (7.14 g, 31 mmol). Over the course of 2 hours the solution changes color from orange to blue. The reaction is stirred overnight. The resulting mixture is slowly poured into 200 mL of water and then extracted with three 100 mL portions of dichloromethane. The organic layers are combined and dried over magnesium sulfate and then filtered. The crude product is purified by column chromatography using hexanes and dichloromethane as eluent to give a pale yellow solid (6.63 g, 79% yield). Step 2: 2,7-Dibromo-9,9-Bis(3,5-Dihydroxybenzyl)-9H-Fluorene 2,7-dibromo-9,9-bis(3,5-dimethoxybenzyl)-9H-fluorene (1.3 g, 2.08 mmol) was added to a round bottom flask charged with a stirbar and equipped with a rubber septum. The flask is purged with nitrogen for 10 min. Anhydrous dichloromethane (20 mL) is transferred to the flask via cannula and the mixture is stirred until the solids are completely dissolved. The solution is then cooled with a dry ice/acetone bath for 10 minutes. BBr3 (6.1 mL, 63.3 mmol) is added dropwise via cannula with constant stirring. The bath is allowed to warm to room temperature and the mixture is stirred overnight. The reaction is quenched with the slow addition of 125 mL of water. The solution is then extracted with 3 portions of ethyl acetate (50 mL). The organic layer is dried over MgSO3, filtered, and dried onto silica. Flash chromatography of the crude using ethyl acetate in dichloromethane gives an off-white crystalline solid (800 mg, 68% yield). Step 3: 2,7-dibromo-9,9-bis(3,5-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl) benzyl)-9H-fluorene (D) 2,7-dibromo-9,9-bis(3,5-dihydroxybenzyl)-9H-fluorene (537 mg, 0.945 mmol), 2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl 4-methylbenzenesulfonate (2.788 g, 4.156 mmol), potassium carbonate (1.57 g, 11.34 mmol) and acetone (80 mL) are transferred to a round bottom flask charged with a Teflon stirbar and equipped with a reflux condenser. The mixture is refluxed with constant stirring overnight. The mixture is then allowed to cool to room temperature and the acetone is removed under vacuum. After extracting with 3 portions of dichloromethane, the organic layer is dried over MgSO4, filtered, and the filtrate is concentrated onto silica. Column chromatography using methanol and dichloromethane affords the product as a slightly colored thick oil (1.69 g, 70% yield). Step 4: 2,7- di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)-9,9-bis(3,5-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl) benzyl)-9H-fluorene (E) Monomer (E) is synthesized using conditions similar to conditions as described in Example 1. Example 14b: Polymerization of (D) and (E) Polymerization of (D) and (E) are polymerized using conditions similar to polymerization conditions as described in Example 1b. Example 15: Synthesis of a Neutral Base Phenylene Vinylene Co-Polymer 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (0.25 mmol), 1,4-divinylbenzene (32.3 mg, 0.25 mmol), palladium acetate (3 mg, 0.013 mmol), tri-ortho-tolylphosphine, (10 mg, 0.033 mmol), and potassium carbonate (162 mg, 1.2 mmol) are combined with 5 mL of DMF in a small round bottom flask charged with a Teflon coated stirbar. The flask is fitted with a needle valve and put in a Schlenk line. The solution is degassed by three cycles of freezing, pumping, and thawing. The mixture is then heated to 100° C. overnight. The polymer can be subsequently reacted with terminal linkers or capping units using similar (in situ) protocols to those provided in the previous examples (9, 10 and 11) or by modifying them post polymerization work up as a separate set of reactions. Example 16: Synthesis of a Branched Phenylene Vinylene Co-Polymer 2,7-dibromo-9,9-bis(3,5-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl) benzyl)-9H-fluorene (636 mg, 0.25 mmol), 1,4-divinylbenzene (32.3 mg, 0.25 mmol), palladium acetate (3 mg, 0.013 mmol), tri-ortho-tolylphosphine, (10 mg, 0.033 mmol), and potassium carbonate (162 mg, 1.2 mmol) were combined with 5 mL of DMF in a small round bottom flask charged with a Teflon coated stirbar. The flask was fitted with a needle valve and put in a Schlenk line. The solution was degassed by three cycles of freezing, pumping, and thawing. The mixture was then heated to 100° C. overnight. The polymer can be subsequently reacted with terminal linkers or capping units using similar (in situ) protocols to those provided in Example 5 or by modifying them post polymerization work up as a separate set of reactions. Example 17: Synthesis of a Branched Phenylene Vinylene Co-Polymer with Functional Amines for Covalent Conjugation. Poly [2,7-divinyl{9,9-bis(3,5-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl)benzyl)-9H-fluorene}-alt-1,4-benzene-co-4-phenoxybutyl-N-t-butylcarbamate] Step 1: Polymerization 2,7-dibromo-9,9-bis(3,5-(2,5, 8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl) benzyl)-9H-fluorene (636 mg, 0.25 mmol), 1,4-divinylbenzene (32.3 mg, 0.25 mmol), palladium acetate (3 mg, 0.013 mmol), tri-ortho-tolylphosphine, (10 mg, 0.033 mmol), and potassium carbonate (162 mg, 1.2 mmol) were combined with 5 mL of DMF in a small round bottom flask charged with a Teflon coated stirbar. The flask was fitted with a needle valve and put in a Schlenk line. The solution was degassed by three cycles of freezing, pumping, and thawing. The mixture was then heated to 100° C. overnight. Step 2: Linker Addition The next morning divinylbenzene (10 mg, 0.077 mmol) was transferred to a small round bottom flask with 1 mL of DMF. The flask was fitted with a needle valve and put in a Schlenk line. The solution was degassed by three cycles of freezing, pumping, and thawing. The solution was transferred via cannula through the needle valves and into the polymerization reaction. After this addition the reaction was allowed to continue at 100° C. overnight. The next day tert-butyl 4-(4-bromophenoxy)butylcarbamate (53 mg, 0.15 mmol) and 1 mL of DMF were transferred to a small round bottom flask. The flask was fitted with a needle valve and put in a Schlenk line. The solution was degassed by three cycles of freezing, pumping, and thawing. The solution was transferred via cannula through the needle valves and into the polymerization reaction. After this addition the reaction was allowed to continue at 100° C. overnight. Step 3: Work up The reaction is then cooled and diluted with 100 mL of water. The aqueous solution was filtered twice through G-6 glass fiber filter paper. The filtrate was evaporated to dryness and re-diluted with dichloromethane. The organic layer was dried over MgSO4 and filtered. The filtrate was evaporated to yield an amber colored oil (342 mg, 56% yield). A 4 mL portion of 4M HCl in dioxane was added to the polymer residue and stirred for a minimum of 4 hours. The solution was neutralized with 2 M potassium carbonate (aq) and then the solvent was removed under vacuum. The resulting residue was diluted to −30 mL with 20% ethanol in water and filtered. Preparative gel permeation chromatography is performed with G-25 desalting medium to remove excess salts from the polymer. Solvent in the fractions is removed with rotary evaporation and the polymer is collected as an amber oil. The linker or capping unit addition steps can be performed in the polymerization reaction as presented above or alternatively, in some embodiments, can be performed in a separate set of reactions after the polymerization work up. In the latter case, the polymer is reacted under the analogous conditions as those provided in the example. In other embodiments, it is also possible to react with a combination of terminal monomers to introduce polymers with bi-functionality, allowing the polymer to be conjugated to more than one entity. Example 18: Synthesis of a Fluorene Monomer with Glycerol-Based Dendrimers Step 1 Dimethyl 3,3′-(2,7-dibromo-9H-fluorene-9,9-diyl)dipropanoate. 2,7-Dibromofluorene (1 g, 3.1 mmol), methyl acrylate (861 mg, 10 mmol) tetrabutylammonium bromide (100 mg, 0.3 mmol) and toluene (5 mL) were added to a small round bottom flask with a Teflon-coated stirbar. Next 2 mL of 50% NaOH (aq) is added while stirring. The reaction is allowed to proceed overnight. The next day the toluene layer is transferred to a flask and the aqueous layer extracted with two portions of toluene. The organic layers are combined, dried with Mg2SO4, and filtered. Silica (2 g) is added to the filtrate and the solution is evaporated. The product is obtained as a white solid (1.23 g, 80% yield) after purification by column chromatography. Step 2 3,3′-(2,7-dibromo-9H-fluorene-9,9-diyl)dipropanoic acid. Dimethyl 3,3′-(2,7-dibromo-9H-fluorene-9,9-diyl)dipropanoate (1.23 g, 2.5 mmol) is transferred to a small round bottom flask equipped with a Teflon-coated stirbar. A mixture of THF:MeOH:H2O, 3:2:1, (10 mL) is added and the mixture is stirred for 1 hr. Then a 1 mL portion of 1M NaOH (aq) is added and the mixture is stirred overnight. The next day the water layer is isolated and extracted with 20 mL portions diethyl ether three times. Next the water layer is acidified to ˜pH 2. The water layer is extracted three times with 20 mL portions of dichloromethane. The organic layers are combined and dried with Mg2SO4. The organic solution is filtered and the solvent evaporated to obtain the product as an off-white solid (948 mg, 90% yield). Step 3 3,3′-(2,7-Dibromo-9H-fluorene-9,9-diyl)bis(N-(7,15-bis((2,3-dihydroxypropoxy)methyl)-1,3,19,21-tetrahydroxy-5,9,13,17-tetraoxahenicosan-11-yl)propanamide). 3,3′-(2,7-Dibromo-9H-fluorene-9,9-diyl)dipropanoic acid (500 mg, 1.1 mmol), 11-amino-7,15-bis((2,3-dihydroxypropoxy)methyl)-5,9,13,17-tetraoxahenicosane-1,3,19,21-tetraol (1.954, 3.3 mmol) (prepared as per ref. Heek, T.; Fasting, C.; Rest, C.; Zhang, X.; Wurthner, F.; Haag, R. Chem. Commun., 2010, 46, 1884-1886), and N,N′-dimethylaminopyridine (61 mg, 0.5 mmol) are combined in a round bottom flask equipped with a Teflon-coated stirbar and sealed with a rubber septum. The flask was flushed with N2 and 10 mL of anhydrous dichloromethane was added via syringe. The mixture is stirred to dissolve the solids. In another round bottom flask equipped with a Teflon-coated stirbar, dicyclohexylcarbodiimide (DCC, 910 mg 4.4 mmol) transferred and the flask is sealed with a rubber septum. Next, 5 mL of anhydrous dichloromethane is transferred to the flask via syringe. The DCC solution is transferred to the fluorene reaction mixture via a syringe dropwise. The reaction is allowed to react overnight. The next day the reaction mixture is filtered. The filtrate is purified by column chromatography to afford a clear oil (1.24 g, 70% yield). Example 19: Synthesis of a Fluorene Monomer PAMAM-Based Dendritic Side Chain Capped with methylPEG Chains Step 1: 9,9′-(3,3′-Diamido(tetramethyl PAMAM G[2])-2,7-dibromofluorene (i) Dimethyl 3,3′-(2,7-dibromo-9H-fluorene-9,9-diyl)dipropanoate (1 g, 2.0 mmol) is transferred to a round bottom flask equipped with a stirbar and sealed with a rubber septum. The flask is flushed with nitrogen and 10 mL of dry methanol is transferred to the flask via syringe and the solid is dissolved by stirring. Ethylenediamine (5.5 mL, 82 mmol) is added via syringe slowly and the mixture is allowed to stir for 2 hours. The septum is removed and the methanol and unreacted ethylenediamine is removed under vacuum. Another 10 mL portion of methanol is added and stirred and then was evaporated to remove any remaining ethylenediamine. The residue remaining in the flask was then sealed again with a septum, flushed with nitrogen, and dry methanol (10 mL) was added and stirred. Methyl acrylate (7.2 mL, 80 mmol) is added slowly via syringe and the mixture is allowed to stir for 2 hours. The septum is again removed and the methanol and methyl acrylate are removed under vacuum. A 10 mL portion of toluene is added, the mixture stirred, and the solvent removed under vacuum affording an off-white solid (1.79 g, quantitative yield). Step 2: 9,9′-(3,3′-Diamido(PAMAM G[2] tetraacid)-2,7-dibromofluorene (ii) 9,9′-(3,3′-Diamido(tetramethyl PAMAM G[2])-2,7-dibromofluorene (i) (1.79 g, 2 mmol) is transferred to a small round bottom flask equipped with a Teflon-coated stirbar. A mixture of THF:MeOH:H2O, 3:2:1, (10 mL) is added and the mixture is stirred for 1 hr. Then a 1 mL portion of 1M NaOH (aq) is added and the mixture is stirred overnight. The next day the water layer is isolated and extracted with 20 mL portions diethyl ether three times. Next the water layer is acidified to ˜pH 2. The water layer is extracted three times with 20 mL portions of dichloromethane. The organic layers are combined and dried with Mg2SO4. The organic solution is filtered and the solvent evaporated to obtain the product as an off-white solid (1.51 g, 90% yield). Step 3: 9,9′-(3,3′-Diamido(PAMAM G[2] N-(2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl)propionamidyl)-2,7-dibromofluorene (iii) 9,9′-(3,3′-Diamido(PAMAM G[2] tetraacid)-2,7-dibromofluorene (ii) (500 mg, 0.6 mmol), 2,5,8,11,14,17,20,23-octaoxapentacosan-25-amine (1.15 g, 3 mmol)), and N,N′-dimethylaminopyridine (12 mg, 0.1 mmol) are combined in a round bottom flask equipped with a Teflon-coated stirbar and sealed with a rubber septum. The flask was flushed with N2 and 10 mL of anhydrous dichloromethane was added via syringe. The mixture is stirred to dissolve the solids. In another round bottom flask equipped with a Teflon-coated stirbar, dicyclohexylcarbodiimide (DCC, 825 mg 4.0 mmol) transferred and the flask is sealed with a rubber septum. Next, 5 mL of anhydrous dichloromethane is transferred to the flask via syringe. The DCC solution is transferred to the fluorene reaction mixture via a syringe dropwise. The reaction is allowed to react overnight. The next day the reaction mixture is filtered. The filtrate is purified by column chromatography to afford a clear oil (967 g, 70% yield). Example 20: Synthesis of a Fluorene Monomer with Highly Branched PEGylated Side Chains Based on a Trihydroxybenzene Linkage Step 1: Methyl 3,4,5-tris(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yloxy)benzoate (iv) Methyl 3,4,5-trihydroxybenzoate (200 mg, 1.1 mmol), 2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl 4-methylbenzenesulfonate (2.58 g, 3.85 mmol), and 18-crown-6 (100 mg, 0.38 mmol) are transferred to a round bottom flask equipped with a Teflon-coated stirbar. Acetone (10 mL) is added and the flask is equipped with a reflux condenser. The mixture is refluxed with constant stirring overnight. The next day silica (4 g) is added and the solvent evaporated. After purification by column chromatography, a clear oil is obtained (887 mg, 48% yield). Step 2: 3,4,5-Tris(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yloxy)-N-(2-aminoethyl)benzamide (v) Methyl 3,4,5-tris(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yloxy)benzoate (iv) (887 mg, 0.52 mmol) flask is transferred to a round bottom flask equipped with a stirbar and sealed with a rubber septum. The flask is flushed with nitrogen and 10 mL of dry methanol is transferred to the flask via syringe and the solid is dissolved by stirring. Ethylenediamine (0.7 mL, 10.4 mmol) is added via syringe slowly and the mixture is allowed to stir for 2 hours. The septum is removed and the methanol and unreacted ethylenediamine is removed under vacuum. The product is obtained as an oil (886 mg, quanitative yield). Step 3:]3,3′-(2,7-Dibromo-9H-fluorene-9,9-diyl)bis(N-(2-3,4,5-tris(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yloxy)-benzamidyl-N amidoethyl)propanamide) (vi) 3,4,5-Tris(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yloxy)-N-(2-aminoethyl)benzamide (v) (886 mg, 0.52 mmol), 3,3′-(2,7-Dibromo-9H-fluorene-9,9-diyl)dipropanoic acid (112 mg, 0.24 mmol), and N,N′-dimethylaminopyridine (12 mg, 0.1 mmol) are combined in a round bottom flask equipped with a Teflon-coated stirbar and sealed with a rubber septum. The flask was flushed with N2 and 10 mL of anhydrous dichloromethane was added via syringe. The mixture is stirred to dissolve the solids. In another round bottom flask equipped with a Teflon-coated stirbar, dicyclohexylcarbodiimide (DCC, 148 mg 0.72 mmol) transferred and the flask is sealed with a rubber septum. Next, 5 mL of anhydrous dichloromethane is transferred to the flask via syringe. The DCC solution is transferred to the fluorene reaction mixture via a syringe dropwise. The reaction is allowed to react overnight. The next day the reaction mixture is filtered. The filtrate is purified by column chromatography to afford a clear oil (924 mg, 70% yield). Example 21. Dual End Capped Polymer Used to Create a Polymer-Dye Label for Biomolecule or Substrate Conjugation Step 1: Synthesis of an Asymmetric Neutral Water-Soluble Polymer with a t-BOC Protected Amine Pendant Group at One Terminus of the Polymer 2-bromo-7-(4″-phenoxybutyl-1-tert-butyl carbamate)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene (1.0 g, 0.674 mmol), 3 mL of tetrahydrofuran, and 2 mL of 2M potassium carbonate (aqueous) were transferred to a small round bottom flask charged with a Teflon stirbar. The flask was fitted with a septum and the solution is degassed by sparging with Ar for 15 minutes. Palladium tetra(triphenylphoshine) (15.6 mg, 0.013 mmol) was added through the neck of the flask and the flask was transferred to a reflux condenser equipped with a needle valve and fixed to a Schlenk line. The solution was quickly frozen solid with liquid nitrogen and was further degassed using freeze-pump-thaw technique. Once degassed the reaction was heated to 80° C. with constant stirring. The reaction was allowed to proceed overnight. The next day tert-butyl 4-(4-bromophenoxy)butylcarbamate (35 mg, 0.10 mmol) in 1 mL of THF was degassed with three freeze-pump-thaw cycles and then added to the polymerization reaction via cannula under excess nitrogen pressure. The reaction continued overnight at 80° C. The next day the reaction mixture was cooled and the bulk of the solvent was removed under vacuum. The remaining material was transferred to a small Erlenmeyer flask with a total of −50 mL of dichloromethane. The solution was stirred for 30 minutes. Approximately 1 g of MgSO4(anhydrous) was added to the solution and the mixture was filtered through a fluted paper filter. The filtrate was evaporated and 410 mg (47% yield) of an amber oil was collected. Step 2: Synthesis to Append a Terminal Linking Monomer with a t-Butyl Ester at the Terminus Opposite the Protected Amine Pendant 2-(4-(tert-butyl 1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oate))-7-(4″-phenoxybutyl-1-tert-butyl carbamate)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene 2-Bromo-7-(4″-phenoxybutyl-1-tert-butyl carbamate)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene (410 mg, 0.32 mmol of repeat unit), tert-butyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-3,6,9,12,15,18,21-heptaoxatetracosan-24-oate (33 mg, 0.048 mmol), 2 mL of tetrahydrofuran, and 1.5 mL of 2M potassium carbonate (aqueous) were transferred to a small round bottom flask charged with a Teflon stirbar. The flask was fitted with a septum and the solution is degassed by sparging with Ar for 15 minutes. Palladium tetra(triphenylphoshine) (15 mg, 0.013 mmol) was added through the neck of the flask and the flask was transferred to a reflux condenser equipped with a needle valve and fixed to a Schlenk line. The solution was quickly frozen solid with liquid nitrogen and was further degassed using freeze-pump-thaw technique. Once degassed the reaction was heated to 80° C. with constant stirring. The reaction was allowed to proceed overnight. The remaining material was transferred to a small Erlenmeyer flask with a total of −50 mL of dichloromethane. The solution was stirred for 30 minutes. Approximately 1 g of MgSO4(anhydrous) was added to the solution and the mixture was filtered through a fluted paper filter. The filtrate was evaporated and 351 mg (78% yield) of an amber oil was collected. Step 3: Synthesis of a Neutral Water-Soluble Polymer with Primary Amine at One Terminus and a t-Butyl Ester Pendant on the Other 2-(4-(tert-butyl 1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oate))-7-(4″-phenoxybutyl-1-amino)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene 2-(4-(tert-butyl 1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oate))-7-(4″-phenoxybutyl-1-tert-butyl carbamate)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene (23 mg, 0.018 mmol) and 0.5 mL of 4M HCl in dioxane were combined in a 1 dram vial with a Teflon-coated stirbar. The mixture was stirred for 4 hours. The mixture was neutralized with 2M potassium carbonate (aqueous). The solution was then diluted to 50 mL of roughly 20% ethanol in water and filtered through G-6 glass fiber filter paper. The filtrate was desalted by centrifugation in a 4 mL 10 KDa cutoff centrifuge filter. The retentate was evaporated under vacuum and two 1 mL portions of toluene were added and removed under vacuum to remove any remaining water. A thick amber liquid was recovered from the desalting (21 mg, 85% yield). Step 4 Attachment of an NHS-functionalized dye to a primary amine pendant on a neutral water-soluble polymer. 2-(4-(tert-butyl 1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oate))-7-(4″-phenoxybutyl-1-amido-DYE)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene 2-(4-(tert-butyl 1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oate))-7-(4″-phenoxybutyl-1-amino)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene (518 ug, 0.4 μM) was dissolved in 100 μL of dry dichloromethane in a glass vial. A small crystal of 4-N,N′-dimethylaminopyridine was added. In another vial 65 μg (0.06 □uM) of NHS-functionalized DyLight 594 (Pierce) was dissolved in 50 of dry dichloromethane. The two solutions were combined and allowed to stir in a sealed vial for 4 hours covered in foil. The solvent was then evaporated and the remaining material was dissolved in 95% ethanol and injected onto a Sepharose 6 column. The remaining dye was separated from the polymer. A solution of dye-labeled polymer was obtained from combining fractions (˜100 μg, 20% yield). Step 5 Hydrolysis of the t-butyl ester pendant on the dye-labeled neutral water-soluble polymer to form the carboxylic acid pendant on one of the termini. 2-(4-(1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosane-27-acid))-7-(4″-phenoxybutyl-1-amido-DYE)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene The polymer was combined with ZnBr2 in dichloromethane and stirred overnight. The next day a portion of water was added and the mixture was stirred for 1 hour. The solvent was evaporated and the residue was dissolved in 20% ethanol in water. The filtrate was then desalted by centrifugation in a 4 mL 10 KDa cutoff centrifuge filter. The retentate was evaporated under vacuum and two 1 mL portions of toluene were added and removed under vacuum to remove any remaining water. Activation (for subsequent conjugation) of the second functional group in this example (carboxylic acid) can be achieved using a number of different methods including those described in Examples 29 and other examples with carboxylic acid to amine to maleimide. One such method is given below in Step 6, by way of example only. Step 6: NHS Activation of the Carboxylic Acid Penant of a Dye-Labeled Neutral Water-Soluble Polymer 2-(4-(1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosane-27-N-hydroxysuccinimidyl ester))-7-(4″-phenoxybutyl-1-amido-DYE)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene. 2-(4-(1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosane-27-acid))-7-(4″-phenoxybutyl-1-amido-DYE)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene and O—(N-Succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate and DIPEA are combined in dry acetonitrile and allowed to react under nitrogen for 30 min. The solution is evaporated and the solid is resuspended in dry dichloromethane. Solids are filtered off and the filtrate is evaporated to afford the NHS ester. In further embodiments, various commonly used protecting groups can be used with those functional groups provided (amine and carboxylic acid). Additionally different capping monomers and protecting group combinations can be used to produce polymers with different functional groups for conjugation. Eliminating or substituting the dye labeling step for another entity will result in a polymer with two different functional groups for conjugation. The dye attachment via NHS/amine chemistry can be performed under a variety of commonly used conditions. Dye attachment can also be performed with other functional chemistries. Example 22. Asymmetric Polyfluorene Synthesis Using Non-Regulated Suzuki Conditions Step 1: Polymerization Method A: A solution of K2CO3 in water (2M, 4 mL) was added to a stirred mixture of 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene (A) (2.3 g, 1.5 mmol) and THF (6 mL) in a round bottom flask. This mixture was degassed with argon for 15 min. Palladium tetrakis(triphenylphosphine) (38.5 mg, 0.03 mmol) was added to the mixture and the flask was attached to a reflux condenser. The reaction vessel was degassed via 3 freeze-pump-thaw cycles and then heated to 80° C. for 12 h. The reaction mixture was cooled to 23° C. and solvent removed by rotary evaporation. The resulting residue was transferred to an Erlenmeyer flask and diluted with 20% EtOH/H2O (75 mL). EDTA (300 mg, 1.0 mmol) was added to the mixture and stirred at 23° C. for 1 h. The mixture was filtered through a glass fiber filter paper and the filter paper rinsed with 20% EtOH/H2O. The resulting filtrate was then filtered through a 0.45 um cup filter. The filtered reaction mixture was purified using tangential flow filtration (TFF) and was diafiltered into 20% ethanol using a 10,000 molecular weight cutoff membrane (regenerated cellulose Prep/Scale TFF cartridge system, Millipore, Billerica, Mass.) until conductivity of the filtrate measured less than 0.01 mS/cm. The solvent was then removed under vacuum to give poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene] (B) as a gel-like product (1.41 g, 71%) Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=51,000, Mw=108,000, Mp=90,000, D=2.1). The extent of end linker incorporation was determined by first converting the acid to an NHS ester (similar protocol to that provided in Example 29) then reacting with an amine functional dye. After purification of free dye the ratio of dye to polymer was determined from absorbance measurements, factoring in the difference in extinction coefficients and polymer molecular weight. Method B: A solution of K2CO3 in water (2M, 4 mL) was added to a stirred mixture of 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene (A) (2.3 g, 1.5 mmol) and DMF (6 mL) in a round bottom flask. This mixture was degassed with argon for 15 min. Palladium tetrakis(triphenylphosphine) (38.5 mg, 0.03 mmol) was added to the mixture and the flask was attached to a reflux condenser. The reaction vessel was degassed via 3 freeze-pump-thaw cycles and then heated to 80° C. for 12 h. Work-up and purification was performed in a manner similar to previously described Method A. Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=96,000, Mw=231,000, Mp=185,000, D=2.4). Method C: Cs2CO3 (2.08 g, 6.4 mmol) was added to a stirred mixture of 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene (A) (200 mg, 0.135 mmol) and DMF (7 mL) in a round bottom flask. This mixture was degassed with argon for 15 min. Palladium tetrakis(triphenylphosphine) (15.6 mg, 10 mol %) was added to the mixture and the flask was attached to a reflux condenser. The reaction vessel was degassed via 3 freeze-pump-thaw cycles and then heated to 80° C. for 12 h. Work-up and purification was performed in a manner similar to previously described Method A. Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=95,000, Mw=218,000, Mp=206,000, D=2.3). Step 2: End Capping -(4-iodophenyl)butanoic acid (227 mg, 0.783 mmol) was washed into a flask containing poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene] (B) (1.00 g, 0.783 mmol) using THF (3.5 mL). A solution of K2CO3 in water (2M, 2.3 mL) was added to the flask and this mixture was degassed with argon for 15 min. Palladium tetrakis(triphenylphosphine) (36 mg, 4 mol %) was added to the mixture and the flask was attached to a reflux condenser. The reaction vessel was degassed via 3 freeze-pump-thaw cycles and then heated to 80° C. for 12 h. The reaction mixture was cooled to 23° C. and the solvent removed with rotary evaoporation. The resulting residue was transferred to an Erlenmeyer flask and diluted with 20% EtOH/H2O (150 mL). EDTA (500 mg) was added to the mixture and stirred at 23° C. for 1 h. The mixture was filtered through a glass fiber filter paper and the filter paper rinsed with 20% EtOH/H2O. The resulting filtrate was then filtered through a 0.45 um cup filter. The filtered reaction mixture was purified using tangential flow filtration (TFF) and was diafiltered into 20% ethanol using a 10,000 molecular weight cutoff membrane (regenerated cellulose Prep/Scale TFF cartridge system, Millipore, Billerica, Mass.) until conductivity of the filtrate measured less than 0.01 mS/cm. The solvent was then removed under vacuum to give 4-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene]yl)phenyl)butanoic acid (C) as a gel-like product (388 mg, 39%) Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=89,000, Mw=196,000, Mp=124,000, D=2.2). The extent of end linker incorporation was determined by first converting the acid to an NHS ester (similar protocol to that provided in Example 29) then reacting with an amine functional dye. After purification of free dye the ratio of dye to polymer was determined from absorbance measurements, factoring in the difference in extinction coefficients and polymer molecular weight. Step 3: Amine Activation 4-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene]yl)phenyl)butanoic acid (C) (200 mg, 0.156 mmol) was dissolved in 2 mL ethanol, then added drop-wise to 23 mL of MES buffer (50 mM, pH 5) at 4° C. while stirring. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (576 mg, 3.00 mmol) was added in portions, followed by N-hydroxy succinimide (115 mg, 1.00 mmol) in one portion. The solution was stirred for 30 minutes, ethylene diamine (0.501 mL, 7.50 mmol) was added drop-wise and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then desalted over a G25 desalting column and the solvent removed via rotary evaporation to give N-(2-aminoethyl)-4-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene]yl)butanamide as a clear yellow oil (190 mg, 95%). Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=89,000, Mw=196,000, Mp=124,000, D=2.2). Extent of amine conversion was determined by reacting the amine polymer with an NHS active dye in similar fashion as that described in Example 38. Example 23. Asymmetric Polyfluorene Synthesis Using Linker Modified End Caps to Regulate the Suzuki Polymerization Step 1: Polymerization/End Capping/Work-up A solution of K2CO3 in water (2M, 4 mL) was added to a stirred mixture of 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene (A) (2.3 g, 1.55 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butanoic acid (B) (6.7 mg, 2 mol %), and DMF (6 mL) in a round bottom flask equipped with a side-arm stopcock. This mixture was degassed with argon for 25 min. Palladium tetrakis(triphenylphosphine) (38.5 mg, 2 mol %) was then added to the mixture and the flask was attached to a reflux condenser. The reaction vessel was further degassed via 3 freeze-pump-thaw cycles and then heated to 80° C. Separately, 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butanoic acid (B) (230 mg, 0.793 mmol) was dissolved in DMF (3 mL) in a found bottom flask equipped with a side arm stopcock. This solution was sparged with argon for 15 minutes, attached to a reflux condenser, and degassed via three freeze-pump thaw cycles. Upon thawing the solution was added to the reaction mixture after two hours of reaction time using an argon flushed syringe. The reaction mixture was stirred for an additional 12 h at 80° C. The reaction mixture was cooled to 23° C. and solvent removed with rotary evaporation. The resulting residue was transferred to an Erlenmeyer flask and diluted with 20% EtOH/H2O (75 mL). EDTA (300 mg, 1.00 mmol) was added to the mixture and stirred at 23° C. for 1 h. The mixture was filtered through a glass fiber filter paper and the filter paper rinsed with 20% EtOH/H2O. The resulting filtrate was then filtered through a 0.45 um cup filter. The filtered reaction mixture was purified and size fractionated using tangential flow filtration (TFF) and was diafiltered into 20% ethanol using a 30,000 molecular weight cutoff membrane (polyethersulfone Prep/Scale TFF cartridge system, Millipore, Billerica, Mass.) until conductivity of the filtrate measured less than 0.01 mS/cm and Mn of the retentate measured more than 70,000 by GPC. The solvent was then removed under vacuum to give 4-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene]yl)phenyl)butanoic acid as a gel-like product (1.41 g, 71%). Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=68,000, Mw=134,000, Mp=122,000, D=1.9). The extent of end linker incorporation was determined by first converting the acid to an NHS ester (similar protocol to that provided in Example 29) then reacting with an amine functional dye. After purification of free dye the ratio of dye to polymer was determined from absorbance measurements, factoring in the difference in extinction coefficients and polymer molecular weight. Despite having a molecular weight in excess of 50,000 g/mole the polymer is soluble in both water and phosphate buffered saline solutions at concentrations easily greater than 10 mg/mL. In many conjugation experiments the polymer provided (and other described herein with similar structure) was concentrated to 50 mg/mL or higher which is remarkable for a neutral conjugated polymer. The moderate molecular weight also provides extinction coefficients greater than 2,500,000 M−1 cm−1. The large extinction coefficient and quantum yield of 60% (PBS) provide for exceptionally bright fluorescent reporters for use in biological assays including their use in flow cytometry. Step 2: Amine Activation 4-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene]yl)phenyl)butanoic acid (C) (500 mg, 0.13 mmol) was dissolved in 2 mL ethanol, then added drop-wise to 23 mL of MES buffer (50 mM, pH 5) at 4° C. while stirring. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride was added in portions, followed by N-hydroxy succinimide (0.52 g) in one portion. The solution was stirred for 30 minutes, ethylene diamine (2.8 mL) was added drop-wise and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then desalted over a G25 desalting column and the solvent removed via rotary evaporation to give N-(2-aminoethyl)-4-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene]yl)butanamide as a yellow oil (450 mg, 90%). Extent of amine conversion was determined by reacting the amine polymer with an NHS active dye in similar fashion as that described in Example 38. Example 24. Yamamoto Polymerization of PEG Modified Polyfluorene Step 1 Yamamoto Polymerization/Work-up In a dry box, Ni(COD)2(0.387 g, 1.41 mmol), 2,2′-bipyridyl (0.220 g, 1.41 mmol), COD (0.152 g, 1.41 mmol) and anhydrous DMF (16 ml) were added to a long-neck round bottom flask. [00251] 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (A) (1.00, 0.696) was weighed into a 40 ml vial and dissolved in anhydrous DMF (8 ml). The flask was sealed with a septum and the vial was closed with a septum screw cap. The catalyst mixture and the monomer solution were transferred out of the dry box and were placed under static argon. The reaction flask was heated to 70° C. for 45 min. The monomer solution was then was quickly transferred from the vial to the catalyst mixture flask with an argon flushed syringe. The reaction mixture was then heated to 70° C. for 6 h. The reaction mixture was cooled and solvent removed by rotary evaporation. The resultant black residue was re-dissolved in 20% EtOH (80 mL) and centrifuged at 2400 rpm for 12 hours. The supernatant was then decanted and filtered through a 0.45 um cup filter. The filtered reaction mixture was purified using tangential flow filtration (TFF) and was diafiltered into 20% ethanol using a 10,000 molecular weight cutoff membrane (polyethersulfone Prep/Scale TFF cartridge system, Millipore, Billerica, Mass.) until GPC analysis of retentate indicated the absence of low molecular weight material. The solvent was then removed under vacuum to give poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene] (B) as a viscous oil (0.700 g, 79%) Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=62,000, Mw=127,000, Mp=93,000, D=2.0). Step 2 End Capping: End capping is performed in a manner similar to Example 22, Step 2. Step 3 Amine Activation: Amine activation is performed in a manner similar to Example 22, Step 3. Example 25. Synthesis of a Tandem Polymer with Two Different Linkers Step 1: Polymerization In a dry box, Ni(COD)2 (0.765 g, 2.78 mmol), 2,2′-bipyridyl (0.435 g, 2.78 mmol), COD (0.301 g, 2.78 mmol) and anhydrous DMF (20 ml) were added to a long-neck round bottom flask. 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (A) (1.80, 1.26 mmol) and tert-butyl 4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butylcarbamate (B) (0.071 g, 0.126 mmol) were added to a 40 ml vial and dissolved in anhydrous DMF (30 ml). The flask was sealed with a septum and the vial was closed with a septum screw cap. The catalyst mixture and the monomer solution were transferred out of the dry box and were placed under static argon. The reaction flask was heated to 70° C. for 45 min. The monomer solution was then was quickly transferred from the vial to the catalyst mixture flask with an argon flushed syringe. The reaction mixture was then heated to 70° C. for 6 h. The reaction mixture was cooled and solvent removed by rotary evaporation. The resultant black residue was re-dissolved in 20% EtOH (80 mL) and centrifuged at 2400 rpm for 12 hours. The supernatant was then decanted and filtered through a 0.45 um cup filter. The filtered reaction mixture was purified using tangential flow filtration (TFF) and was diafiltered into 20% ethanol using a 10,000 molecular weight cutoff membrane (polyethersulfone Prep/Scale TFF cartridge system, Millipore, Billerica, Mass.) until GPC analysis of retentate indicated the absence of low molecular weight material. The solvent was then removed under vacuum to give 2,7-dibromo-poly-[2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene-co-2,7-(9-methyl-9′-(butyl-4-t-butylcarbamate)fluorene)] (C) as a viscous oil (1.3 g, 45%) Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=72,000, Mw=156,000, Mp=138,000, D=2.1). Step 2: End Capping A solution of K2CO3 in water (2M, 4 mL) was added to a stirred mixture of 2,7-dibromo-poly-[2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene-co-2,7-(9-methyl-9′-(butyl-4-t-butylcarbamate)fluorene)] (C) (800 mg, 0.67 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butanoic acid (D) (120 mg, 0.41 mmol), and DMF (6 mL) in a round bottom flask. This mixture was degassed with argon for 15 min. Palladium tetrakis(triphenylphosphine) (50 mg, 6 mol %) was added to the mixture and the flask was attached to a reflux condenser. The reaction vessel was degassed via 3 freeze-pump-thaw cycles and then heated to 80° C. for 12 h. The reaction mixture was cooled to 23° C. and concentrated in vacuo to a volume of 2 mL. The crude reaction mixture was transferred to an Erlenmeyer flask and diluted with 20% EtOH/H2O (75 mL). EDTA (300 mg, 2.00 mmol) was added to the mixture and stirred at 23° C. for 1 h. The mixture was filtered through a glass fiber filter paper and the filter paper rinsed with 20% EtOH/H2O. The resulting filtrate was then filtered through a 0.45 um cup filter. The filtered reaction mixture was purified and size fractionated using tangential flow filtration (TFF) and was diafiltered into 20% ethanol using a 10,000 molecular weight cutoff membrane (polyethersulfone Prep/Scale TFF cartridge system, Millipore, Billerica, Mass.) until conductivity of the filtrate measured less than 0.01 mS/cm. The solvent was then removed under vacuum to give 4-(4-(2-bromo-poly-[2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene-co-2,7-(9-methyl-9′-(butyl-4-t-butylcarbamate)fluorene)])phenyl)butanoic acid (E) as a yellow oil (660 mg, 82%). Step 3: Linker Deprotection Trifluoroacetic acid (4 mL) was added dropwise to a stirred solution of 4-(4-(2-bromo-poly-[2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene-co-2,7-(9-methyl-9′-(butyl-4-t-butylcarbamate)fluorene)])phenyl)butanoic acid (E) (200 mg, 0.169 mmol) and dichloromethane (16 mL) in a round bottom flask. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was redissolved in minimal 20% EtOH and 1M HCl was added to the solution until pH=7. The neutralized solution was then desalted over G25 gel and the resultant material was concentrated to dryness to yield a clear pale yellow oil (F). Examples of dye incorporation, linker activation and bioconjugation are contained in further Example 38 and related examples. Example 26: Synthesis of a Tandem Polymer with Two Different Linkers Using End Capping Units to Regulate the Polymerization Reaction Step 1: Yamamoto Polymerization In a dry box, Ni(COD)2 (0.433 g, 8.40 mmol), 2,2′-bipyridyl (0.246 g, 8.40 mmol), COD (0.170 g, 8.40 mmol) and anhydrous DMF (15 ml) were added to a long-neck round bottom flask. 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (A) (1.00, 0.696 mmol), tert-butyl 4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butylcarbamate (B) (0.037 g, 0.069 mmol), and tert-butyl 4-(4-bromophenyl)butanoate (C) (0.004 g, 0.007 mmol) were added to a 40 ml vial and dissolved in anhydrous DMF (10 ml). The flask was sealed with a septum and the vial was closed with a septum screw cap. The catalyst mixture and the monomer solution were transferred out of the dry box and were placed under static argon. The reaction flask was heated to 70° C. for 45 min. The monomer solution was then was quickly transferred from the vial to the catalyst mixture flask with an argon flushed syringe. The reaction mixture was then heated to 70° C. for 6 h. The reaction mixture was cooled and solvent removed by rotary evaporation. The resultant black residue was re-dissolved in 20% EtOH (80 mL) and centrifuged at 2400 rpm for 12 hours. The supernatant was then decanted and filtered through a 0.45 um cup filter. The filtered reaction mixture was purified using tangential flow filtration (TFF) and was diafiltered into 20% ethanol using a 10,000 molecular weight cutoff membrane (polyethersulfone Prep/Scale TFF cartridge system, Millipore, Billerica, Mass.) until GPC analysis of retentate indicated the absence of low molecular weight material. The solvent was then removed under vacuum to give tert-butyl 4-(4-(2-bromo-poly-[2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene-co-2,7-(9-methyl-9′-(butyl-4-t-butylcarbamate)fluorene)])phenyl)butanoate (D) as a viscous oil (664 g, 80%). Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=50,000, Mw=88,000, Mp=174,000, D=1.8). Step 2: Linker Deprotection Trifluoroacetic acid (6 mL) was added dropwise to a stirred solution of Polymer (300 mg, X mmol) and dichloromethane (24 mL) in a round bottom flask. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was redissolved in minimal 20% EtOH and 1M HCl was added to the solution until pH=7. The neutralized solution was then desalted over G25 gel and the resultant material was concentrated to dryness to yield a clear pale orange oil (261 mg, 87%). Examples of dye incorporation, linker activation and bioconjugation are contained in further Example 38 and related examples. Example 27. Dual Functional Asymmetric Polymer with Both Internal and Terminal Conjugation Sites Used to Create a Polymer-Dye Label for Biomolecule or Substrate Conjugation Suzuki polymerization of 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-′7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene is performed under those conditions described in Example 23 where y % is the mol % of the end linker used to regulate the polymerization and ensure high incorporation of linker. The linker in this example is 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butanoic acid. In this example, x mol % of the internal linker is also added to the polymerization to incorporate the second linking site into the polymer. This method for incorporating the internal linker is generally described in Examples 21, 25 and 26. The internal linker must be incorporated during the polymerization as indicated, however, it is expected that it would be possible to add the terminal linker as a separate step as described in Examples 9, 10, 11 and 21. Example 28: Enrichment of Linker-Functionalized Polymers The synthesis of linker-functionalized polymers can yield a mixture of chains with and without linker functionalities. Because conjugation efficiency is expected to improve with higher purity polymers for conjugation, the methods described in this example address this by enriching for chains containing linker. For a polymer batch containing a mixture of a COOH-modified and unmodified polymer: Dissolve polymer in 95% EtOH, then dilute with water to a final EtOH concentration of 20%. Desalt the polymer using 10 kDa MWCO filter until conductance is <0.1 mS/cm. Inject onto Q-Sepharose column, ensuring that the polymer load is suitable for the column capacity. Pass 20% EtOH in water over column to wash out unbound polymer. Release bound material by changing the eluting buffer to 1M NaCl in 20% EtOH in water for two column volumes to trigger the release of the bound polymeric material. Collect enriched material. The polymer is passed over a strong anion exchanger such as a Q-Sepharose column. Polymer chains bearing a functional carboxylic acid group will bind the strong anion exchanger, and polymer that is not functionalized will not bind and instead will wash through. After the non-functionalized polymer has passed through the column, the column is washed with 1M NaCl, which triggers the release of the acid-functionalized polymer by screening the acid group from the media. By using this method, the percent functional polymer has been shown to increase from 25% of polymer chains bearing a carboxylic acid group to >80% of polymer chains bearing a carboxylic acid group. This increase in functional chains has been shown by analyzing the absorbance ratios of polymer-dye conjugates pre- and post-enrichment. This procedure is also described in Example 38. A similar process has been validated for the enrichment of amine containing polymers. In that case an anionic exchange resin, SP Sephrose (or similar), is loaded at reduced conductivity (below 0.01 mS/cm). Example 29: Preparation of Polymer-Streptavidin Conjugates Via NHS/Amine Coupling Example 29a: Polymer Modifications Polymer Modification—Carboxylic Acid to Amine Conversion 1.35 g of a carboxylic acid terminated polymer was dissolved at in 9 mL ethanol, then added dropwise to 80 mL of 4° C. 50 mM IVIES, pH 5 while stirring. 0.52 g N-hydroxy succinimide was added in one portion. Once the N-hydroxy succinimide had dissolved, 2.3 g N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride was added in portions. After stirring the solution for 30 minutes, 2.8 mL of ethylene diamine was added dropwise. The solution was stirred overnight at room temperature and purified by tangential flow filtration (MWCO=10 kDa). 1.22 g yield (90%). Polymer Modification—Amine to Carboxylic Acid Conversion 70 mg of an amine-terminated polymer was dissolved in 7 mL DMSO. 2.3 mg DIPEA was added to the polymer solution. 2.2 mg DMAP was dissolved in 220 μL DMSO and added to the resulting polymer solution. 5.5 mg succinic anhydride was dissolved in 550 μL DMSO and added to the resulting polymer solution. The solution was agitated at room temperature overnight. The reaction was then purified over Amicon Ultra centrifugal filtration units (MWCO=10 kDa) with 25 mM IVIES pH 5 buffer. 62 mg yield (89%). Polymer Modification—Carboxylic Acid to NETS-Ester Conversion 60 mg of a carboxylic acid-terminated polymer was dissolved in 600 μL acetonitrile. 1.2 μg DIPEA was added to the polymer solution. 2.8 mg N,N,N′,N′-Tetramethyl-O—(N-succinimidyl)uronium was dissolved in 370 μL acetonitrile and added to the polymer solution. The solution was agitated at room temperature for 15 minutes. After the reaction is complete, the solvent was evaporated under reduced pressure. 50 mg yield (83%). Example 29b: Protein-Polymer Conjugation Streptavidin protein is dissolved in 50 mM NaHCO3 pH 8.2 buffer to make a 1 mg/mL solution. Crude activated polymer (10-15 eq or as required) solution from Step 2 is added to the aqueous streptavidin protein solution; the protein concentration is adjust with buffer to ensure that the volume of organic solvent added is <10% of the total volume, if necessary. The solution is agitated at room temperature for 3 hr and the reaction transferred to a Amicon Ultra filter (MWCO=10 kDa) to remove DMF. The protein is recovered into the initial volume with 25 mM PO4 pH 6.5 buffer. Purification of the Protein-Polymer Conjugate A 1 mL HiTrap SP Sepharose FF column is equilibrated with 20 mM Na Citrate pH 3 buffer. 1 mL (0.3-1 mg/mL) of Streptavidin-polymer conjugate is loaded in 25 mM NaHPO4 pH 6.5. The sample is wash through column with 20 mM Na Citrate pH 3 buffer until a stable baseline is obtained. Multiple 1 mL aliquots of sample may subsequently be loaded and washed. The column is washed with a minimum of 10 column volumes of 20 mM Na Citrate pH 3 buffer. The conjugate is eluted with 10 column volumes of 20 mM Na Citrate in 0.6 M NaCl pH 7.6 buffer and the column is stripped with 10 column volumes of 20% ethanol in the elution buffer. The elution peak is concentrated with an Amicon Ultra filter (MWCO=10 kDa) to reduce the volume to ˜200 μl. A 10×300 mm Superose 12 column is equilibrated with 20 mM Na Citrate in 0.6 M NaCl pH 7.6 buffer. 200 μL of concentrated Streptavidin-polymer conjugate is loaded and eluted with 20 mM Na Citrate in 0.6 M NaCl pH 7.6 buffer. Fractions are pooled and buffer exchanged into PBS+0.05% NaN3 using Amicon Ultra Centrifugation filters (10 kD MWCO). Elutions are concentrated to desired concentration for testing; at around 2 μM Streptavidin. Characterization of a Purified Protein-Polymer Conjugate A 4-20% acrylamide Tris-HCl Ready Gel (BioRad) is prepared and the gel is loaded with the conjugate along with free streptavidin and free polymer in separate lanes. Gel electrophoresis is performed in 25 mM Tris 192 mM, Glycine pH 8.3 and stained with Coomassie to visualize the protein. The gel is stained for 30 minutes then destained with commercial destain overnight. Agarose gel conditions were also used to characterize polymer-streptavidin conjugates, an example which is shown in FIG. 29. In alternative embodiments, the above example can be adapted to allow for conjugation of the polymer to biomolecules or dyes, including but not limited to, antibodies and nucleic acids. The amine on the polymer is converted to a maleimide and a carboxylic acid (further activated to form the NHS ester) using alternative crosslinkers or modifiers. In certain embodiments, conjugation of the same polymer to other biomolecules (streptavidin, antibody fragments, nucleic acids) is facilitated using malimide-thiol chemistry (using SATA linkers to convert free amines on the biomolecule or TCEP (or DPP) reduction of an antibody to create free thiols). Example 30: Preparation of Polymer-Streptavidin Conjugates Via Hydrazide/Benzaldehyde Coupling Step 1: Streptavidin-4FB Modification Streptavidin protein is reconstituted at 1.7 mg/mL and exchange into reaction buffer, 50 mM NaHCO3, pH 8. 15 molar equivalents of bifunctional benzaldehyde/succinimidyl linker, S-4FB (Solulink, San Diego, Calif.) 20 mg/mL in anhydrous DMSO is added to streptavidin, ensuring that the organic phase is less than 10% of the total volume. Reaction is mixed on shaker for 4 hours at room temperature and unreacted linker is subsequently filtered away via Amicon Ultra filter, 10 kD MWCO with 50 mM IVIES buffer, pH 5; centrifuged at 2400 rpm and a repeated wash ×3. Streptavidin protein is recovered in its initial volume, targeting 1.7 mg/mL in conjugation buffer, 50 mM NaPO4, pH 6.5. Step 2: Polymer Modification Polymer with terminal amine group (1 molar eq) is dissolved with DMF to make a 10 mg/mL solution. 20 molar equivalents of a bifunctional hydrazine/succinimidyl linker, SHTH (Solulink, San Diego, Calif.) at 80 mg/mL in anhydrous DMSO is added to the polymer solution. 1 drop of DIPEA is added to the reaction by a syringe and 22 g needle. The solution is agitated at room temperature for 4 hr and the reaction transferred to a Amicon Ultra filter (MWCO=10 kDa) filled with 25 mM MES pH 5 buffer. The solution is then centrifuged. The filter is refilled and washed with the following wash buffers: 1x DI H2O+1 drop 1 M HCl 1x DI H2O+1 drop 1M NaOH 3x 50 mM MES, pH 5 Step 3: Protein-Polymer Conjugation 15 equivalents of modified polymer from Step 2 are added with desired amount of modified protein from Step 1. Aniline is added to the reaction for a final concentration of 10 mM and allowed to mix for 12 hours. The reaction is purified with Amicon Ultra filter (MWCO=10 kDa) to remove DMF and recovered with 25 mM PO4 pH 6.5 buffer. Step 4: Purification of the Protein-Polymer Conjugate A 1 mL HiTrap SP Sepharose FF column is equilibrated with 20 mM Na Citrate pH 3 buffer. 1 mL (0.3-1 mg/mL) of Streptavidin-polymer conjugate is loaded in 25 mM NaHPO4 pH 6.5. The sample is wash through column with 20 mM Na Citrate pH 3 buffer until a stable baseline is obtained. Multiple 1 mL aliquots of sample may subsequently be loaded and washed. The column is washed with a minimum of 10 column volumes of 20 mM Na Citrate pH 3 buffer. The conjugate is eluted with 10 column volumes of 20 mM Na Citrate in 0.6 M NaCl pH 7.6 buffer and the column is stripped with 10 column volumes of 20% ethanol in the elution buffer. The elution peak is concentrated with an Amicon Ultra filter (MWCO=10 kDa) to reduce the volume to ˜200 μl. A 10×300 mm Superose 12 column is equilibrated with 20 mM Na Citrate in 0.6 M NaCl pH 7.6 buffer. 200 μL of concentrated Streptavidin-polymer conjugate is loaded and eluted with 20 mM Na Citrate in 0.6 M NaCl pH 7.6 buffer. Fractions are pooled and buffer exchanged into PBS+0.05% NaN3 using Amicon Ultra Centrifugation filters (10 kD MWCO). Elutions are concentrated to desired concentration for testing; at around 2 μM Streptavidin. Step 5: Characterization of a Purified Protein-Polymer Conjugate A 4-20% acrylamide Tris-HCl Ready Gel (BioRad) is prepared and the gel is loaded with the conjugate along with free streptavidin and free polymer in separate lanes. Gel electrophoresis is performed in 25 mM Tris 192 mM, Glycine pH 8.3 and stained with Coomassie to visualize the protein. The gel is stained for 30 minutes then destained with commercial destain overnight. FIG. 14 top, depicts conjugation of streptavidin to a polymer of formula (Vb) in cartoon format. FIG. 14, bottom, is a Coomassie stain of acrylamide gel which depicts the mobility of the conjugate is retarded relative to the free protein indicating an increase in mass. A neutral polymer alone shows no evidence of staining and without a formal charge, the polymer is not mobile in the electrophoritic field. In alternative embodiments, the above example can be adapted to allow for conjugation of the polymer to biomolecules or dyes, including but not limited to, antibodies and nucleic acids. The amine on the polymer is converted to a maleimide and a carboxylic acid (further activated to form the NHS ester) using alternative crosslinkers or modifiers. In certain embodiments, conjugation of the same polymer to other biomolecules (streptavidin, antibody fragments, nucleic acids) is facilitated using malimide-thiol chemistry (using SATA linkers to convert free amines on the biomolecule or TCEP reduction of an antibody to create free thiols) and NETS-amine chemistry (reacting the NETS polymer directly with lysines on the protein or nucleic acid). Example 31: Preparation of Biotin-Labeled Polymers Amine functionalized polymer of formula (Vc) is dissolved at 10 mg/mL in anhydrous DMF and divided into two portions. NHS-biotin (0.9 mg in 90 μL, 88 equivalents) (Pierce, 20217) and NHS-LC-LC-biotin (Pierce, 21343) at 10 mg/mL (1.5 mg in 150 μL, 88 equivalents) are dissolved in anhydrous DMF. The NHS-biotin and NHS-LC-LC-biotin solutions are immediately added to the two portions of polymer solution and allowed to mix on a shaker overnight in the dark. Excess reactant is removed by washing the solution using Amicon Ultra-4 mL 10 kD MWCO filter cartridges in a series of wash steps: First, the cartridge is first filled approximately halfway with water, and the reaction solution (by pipet) subsequently added directly into the water. Next, the cartridge is filled with water until it is full. The solution is mixed by pipetting up and down. Then, the cartridge is centrifuged at 2400 rpm for 30 minutes, or until the volume is reduced to 250 μL. The cartridge is then refilled with water 1 drop of 1M HCl is added; the solution is mixed, and centrifuged at 2400 rpm for 30 minutes, or until the volume was reduced to 250 μL. Next, the cartridge is refilled with water, 1 drop of 1M NaOH is added; the solution is mixed, and centrifuged at 2400 rpm for 30 minutes, or until the volume is reduced to 250 μL. The cartridge is then refilled with water, mixed and centrifuged at 2400 rpm for 30 minutes, or until the volume is reduced to 250 μL. This final step is repeated for a total of 5 washes. Characterization of a Purified Biotin-Labeled Polymer Excess biotin-labeled polymer is incubated with a Cy5-labeled streptavidin in DPBS buffer plus 0.2% BSA and 0.05% NaN3. A 0.8% agarose gel is is prepared and the gel is loaded with the conjugate along with free Cy5-streptavidin and free biotinylated polymer in separate lanes. Gel electrophoresis is performed in 10 mM NaHCO3 pH10 and and visualized using a Typhoon gel imager with 457 nm and 635 nm laser excitation. FIG. 15 (bottom) depicts retardation of mobility of the polymer-streptavidin complex relative to the free protein indicating an increase in mass. The polymer alone shows little mobility on its own due to a lack of formal charge. This protocol is adapted to successfully biotin-modify a range of conjugated polymers containing both internal and terminal amine linkers. Example 32: Functional Testing of Covalent Polymer Streptavidin Conjugates by Selective Binding to Biotinylated Microspheres Materials Required: 1x TBST: 50 mM Tris-HCl, 150 mM NaCl, 0.1% Tween20, pH 7.5; Biotin microspheres (10 mg/mL in TBST); BSA (1 mg/mL); AvDN (220 μM); and Polymer-Strepavidin (SA) conjugate: (1 μM with regard to SA, provided at 5 μM). Preparation of Master Mixes: Prepare in Labelled 1.5 mL Microfuge Tubes: Experimental Negative control master mix master mix 14 μl TBST 9 μl TBST 6 μl BSA stock 6 μl BSA stock 5 μl bead stock 5 μl avidin stock 5 μl bead stock Briefly vortex both tubes and allow 20-30 minutes to pre-incubate the negative control beads with excess avidin before proceeding. A variable speed orbital mixer at 800 RPM for incubation is suggested to keep beads from settling. Bead Hybridization: Pipette 10 μL of each master mix into separate labelled 1.5 ml microfuge tubes. Add 2 μL of polymer-SA conjugate to each. Prepare additional tube containing 10 μL master mix and no polymer to be used as a blank. Briefly vortex and pulse spin all tubes. Transfer to variable speed orbital mixer and incubate for 30 mins at 800 RPM. Bead Processing/Washing: Add 0.5 ml TBST to all samples and controls and vortex briefly. Centrifuge at 1200 g for 2 min and remove 480 μl supernatant being diligent not to disturb bead pellet. Add 0.5 ml TBST to all samples and controls and vortex briefly. Centrifuge at 1200 g for 2 min and remove 500 μl supernatant being diligent not to disturb bead pellet. Repeat steps 3 and 4. Remove as much of remaining supernatant as possible using P200 pipette without disturbing bead pellet. Add 100 μL TBST and vortex briefly to re-suspend beads. Bead Measurement: Transfer 100 μL of positive, negative and blank beads to a BLACK 96 well plate. Excite wells at 430 nm and collect emission in the range 450-650 nm using required slit widths and/or sensitivity setting to achieve measurable signals above background. Compare emission of positive and negative control beads. FIG. 16 shows the polymer streptavidin conjugate was bound to a biotinylated microsphere. Excitation at 440 nm in a florometer resulted in emission from the polymer as indicated by the solid curve. The dashed curve represents the negative control where the biotin bead was first treated with excess avidin to block the biotin binding sites prior to treatment with the polymer streptavidin conjugate. Example 33: Functional Testing of Covalent Polymer Streptavidin Conjugates by Selective Binding to Biotinylated Microspheres and FRET to Dye Acceptors on Co-Localized Streptavidin-Dye Conjugates Materials Required: 1x TBST: 50 mM Tris-HCl, 150 mM NaCl, 0.1% Tween20, pH 7.5. Biotin microspheres (10 mg/mL in TBST). Cy3-SA (1 μM or 50 μg/mL). Polymer-Strepavidin (SA) conjugate: (1 μM with regard to SA, provided at 5 μM). Bead Preparation and Hybridization: Prepare in labelled 1.5 mL microfuge tubes: Blank control Cy3-SA control FRET-SA Control 16 μl TBST 14 μl TBST 14 μl TBST 4 μl bead stock 2 μl Cy3-SA stock 2 μl Cy3-SA stock 4 μl bead stock 2 μl polymer-SA stock 4 μl bead stock Briefly vortex all tubes and transfer to variable speed orbital mixer for incubation of at least 30 mins at 800 RPM. Bead Processing/Washing: Add 0.5 ml TBST to all samples and controls and vortex briefly. Centrifuge at 1200 g for 2 min and remove 480 μl supernatant being diligent not to disturb bead pellet. Add 0.5 ml TBST to all samples and controls and vortex briefly. Centrifuge at 1200 g for 2 min and remove 500 μl supernatant being diligent not to disturb bead pellet. Repeat steps 3 and 4. Remove as much of remaining supernatant as possible using P200 pipette without disturbing bead pellet. Add 100 μL TBST and vortex briefly to re-suspend beads. Bead Measurement: Transfer 100 μL of all samples to a BLACK 96 well plate. Excite wells at 430 nm and collect emission in the range 450-650 nm using required slit widths and/or sensitivity setting to achieve measurable signals above background. Detect and record polymer emission in the range of 480-500 nm and Cy3 emission at the expected 570 nm. FIG. 17 shows the polymer streptavidin conjugate was bound to a biotinylated microsphere. Excitation at 440 nm in a florometer resulted in energy transfer between the polymer and a Cy3 dye conjugated to a different streptavidin protein as indicated by the solid upper curve. The dashed curve shows beads alone and the lower solid curve direct excitation of the Cy3-streptavidin conjugate at 440 nm. Example 34: Functional Testing of Biotin-Labeled Polymers by Selective Binding to Avidin Coated Microspheres Materials Required: 1x TBST: 50 mM Tris-HCl, 150 mM NaCl, 0.1% Tween20, pH 7. SA microspheres (10 mg/mL in TBST). Biotin (1 mM). 440 nm biotin-polymer conjugate: (46 μM). Bead Preparation and Hybridization: Prepare in labelled 1.5 mL microfuge tubes: Blank control Negative control Positive Control 16 μl TBST 11 μl TBST 15 μl TBST 4 μl bead stock 4 μl biotin stock 4 μl bead stock 4 μl bead stock Briefly vortex all tubes and transfer to variable speed orbital mixer for incubation of 20-30 mins at 800 RPM to ensure biotin has blocked all SA sites on negative control beads. Add 1 uL of polymer-biotin stock to both positive and negative control tubes. Vortex briefly and transfer to variable speed orbital mixer and incubate for 30 mins at 800 RPM. Bead Processing/Washing: Add 0.5 ml TBST to all samples and controls and vortex briefly. Centrifuge at 1200 g for 2 min and remove 480 μl supernatant being diligent not to disturb bead pellet. Add 0.5 ml TBST to all samples and controls and vortex briefly. Centrifuge at 1200 g for 2 min and remove 500 μl supernatant being diligent not to disturb bead pellet. Repeat steps 3 and 4. Remove as much of remaining supernatant as possible using P200 pipette without disturbing bead pellet. Add 100 μL TBST and vortex briefly to re-suspend beads. Bead Measurement: Transfer 100 μL of all samples to a BLACK 96 well plate. Excite wells at 430 nm and collect emission in the range 450-650 nm using required slit widths and/or sensitivity setting to achieve measurable signals above background. Compare emission of positive and negative control beads. FIG. 18 shows the biotin modified polymer was bound to a streptavidin microsphere (top). In FIG. 18 (bottom), excitation at 440 nm in a florometer resulted in emission from the polymer as indicated by the solid upper curve. The lower solid curve represents the negative control where the streptavidin bead was first treated with excess biotin to block the binding sites prior to treatment with the biontinylated polymer. The lower solid curve represents beads alone. Example 35: Selective Binding of Biotin-Labeled Polymer to Dye-Labeled SA Conjugates to Validate FRET Properties and Functional Activity of the Polymer Modification Materials Required: Biotin-Polymer Conjugate: (46 μM). Cy3-SA conjugate (1 mg/mL or 18.9 μM). BLACK 96-well plate. Forming the Biotin-Streptavidin Complex: In a 1.5 mL microfuge tube, combine 9.4 μL of the biotin-polymer conjugate and 2.9 μL of the Cy3-SA. Vortex to mix, then incubate on a shaker (under foil) for 0.5 h. Longer incubation times are also suitable. Instrument Settings: Model experiments were conducted on a BioTek Synergy 4 in the Fluorescence mode with the following settings: Emission: 400-750 nm in 5 nm steps and Sensitivity level: 50. Plate Layout: Prepare solutions in a BLACK 96-well plate as in the below table. Take care to add the A+B solution last, after all other materials have been added: Material Well 1 Well 2 Well 3 Polymer-biotin 9.4 μL* 9.4 μL — Cy3-SA 2.9 μL* — 2.9 μL Buffer 100 μL 100 μL 100 μL *Pre-incubated in the first step, Forming the Biotin-Streptavidin Complex. FIG. 19 shows the biotin modified polymer was bound to a dye labeled streptavidin (Cy3 or Texas Red—top). Excitation at 440 nm in a florometer resulted in emission from the dye acceptors at their respective emission wavelength (approximately 570 nm and 620 nm respectively—bottom left) as well as some residual emission from the polymer (approximately 520 nm). A titration was also performed to saturate the binding of polymer to the streptavidin (bottom right). The solid curve indicates the emission from the Cy3 label on the streptavidin via energy transfer from the polymer at 440 nm excitation. The dotted curve represents the negative control where the streptavidin was first treated with excess biotin to block the binding sites prior to treatment with the biontinylated polymer. Example 36: Polymer-Streptavidin Conjugates for Use in Flow Cytometry Polymer bioconjugates are evaluated by Stain Index, as defined by Becton Dickinson (BD) Biosciences on a flow cytometer. See, e.g., H. Maeker and J. Trotter, BD Biosciences Application Note: “Selecting Reagents for Multicolour Flow Cytometry”, September 2009. The stain index reports a measure of the polymer's brightness, nonspecific binding and can also be related by the Resolution Index on a flow cytometer. Flow cytometry provides a method through which to measure cells of a specific phenotype or analytes of interest on specific microspheres. This can be done with direct labeling of a primary antibody or, if signal amplification is desired, through a secondary antibody or the avidin-biotin complexation with avidin-polymer conjugates. Procedure for Cell Staining Cells of interest are taken up in sufficient quantity, at least 105 per test condition. Cells are then spun down at 250 rcf for 3 minutes, washed in DPBS+0.2% BSA and 0.05% NaN3 (staining buffer), then resuspended in staining buffer at 1×107 cells/mL. For primary incubation, cells are incubated with a primary conjugate (reporter labeled antibody) specific to an antigen of interest, negative cells serve as a negative non-specific binding reference. A control population or an established commercial conjugate is used as a positive control. Primary polymer conjugates are incubated at 4° C. with 4×105 cell aliquots at concentrations with volume dilutions from 10-330 nM for 30 minutes. Following primary incubation, cells are rinsed with 5 volumes staining buffer and spun down at 250 rcf for 3 minutes; this rinse is repeated three times. Cells are resuspended for testing at 8×105 cells/mL in DPBS+0.2% BSA, 0.05% NaN3. For secondary antibody labeling, an unlabeled primary antibody to the antigen of interest is incubated at 0.4 ug/uL, or other titrated amount, at 4° C. with 4×105 cells per test condition for 30 min. Following primary incubation, cells are rinsed with 5 volumes staining buffer and spun down at 250 rcf for 3 minutes; this rinse is repeated three times. Species reactive secondary polymer conjugates are incubated at 4° C. with 4×105 cell aliquots at concentrations with volume dilutions from 10-330 nM for 30 minutes. Following secondary incubation, cells are rinsed with 5 volumes staining buffer and spun down at 250 rcf for 3 minutes; this rinse is repeated three times. Cells are resuspended for testing at 8×105 cells/mL in DPBS+0.2% BSA, 0.05% NaN3. For streptavidin-polymer conjugate labeling, cells are incubated with a biotinylated primary antibody to the marker of interest, as detailed above for the secondary antibody labeling, instead of an unlabeled primary. Following the primary washing, cells are resuspended and divided in 4×105 cell aliquots and incubated with streptavidin-polymer conjugates at 1-100 nM volume dilutions for 30 minutes at 4° C. Following secondary incubation, cells are rinsed with 5 volumes staining buffer and spun down at 250 rcf for 3 minutes; this rinse is repeated three times. Cells are resuspended for testing at 8×105 cells/mL in DPBS+0.2% BSA, 0.05% NaN3. If further signal amplification is desired, cells and be incubated with an unlabeled primary antibody and then subsequently follow with a species reactive biotinylated secondary antibody prior to incubation with streptavidin conjugates. The incubation steps, washing protocol and testing protocol should follow as previously detailed. These flow testing procedures have been developed specific to CD4 markers on Cyto-trol cells. Cell preparation and incubation protocols may vary with cell type and an optimal staining, washing and handling protocol should be developed specific to cell type. Working concentration ranges of antibodies have been identified as optimal for both CD4 (35-50% population) and CD45 (85% population) markers on Cyto-trol control lymphocytes as well as on Whole Lysed Blood (for primary antibody only). Markers which have populations significantly different than these ranges may fall outside of the suggested titration ranges. Testing was also done on a Jurkat cell line grown in culture following similar protocols. In these tests a CD45 marker was used. As there are no negative cell populations a different negative control procedure was used. In the negative control samples the primary antibody was omitted from the primary incubation step. This step and all subsequent steps were performed according to the standard protocol. Again a commercially dye-antibody or dye-strepatvidin conjugate were used as a positive control. Procedure for Flow Cytometry Analysis Flow testing was done in test tubes, at 0.5 mL volumes on a BD LSR II Flow Cytometer. Flow testing is performed using the voltage settings determined from daily calibration of the cytometer with calibration particles by flow facility staff. Lymphocyte specific gating by forward scatter vs. side scatter is performed on unstained cell samples as a background control. Standard doublet gating is performed for both forward scatter and side scatter area vs. width profiles. With only a single color, no compensation is required. Data are collected for all forward and side scatter parameters and fluorescence measurements are made using BD's standard Pacific Blue channel. Pacific Blue data utilizes excitation with the 408 nm Violet lasers and a 450/50 BP filter. Samples are collected for 30,000 events within the stated gating parameters. Representative Experiments: CD4 marking was measured on Cyto-trol cells, lyophilized human lymphocytes for analysis of polymer performance in flow. Cyto-trol cells (Beckman Coulter) were reconstituted in the provided reconstitution buffer and allowed to swell for 15 minutes at room temperature. Cells were then spun down at 250 rcf for 3 minutes, washed in DPBS+0.2% BSA and 0.05% NaN3 (staining/testing buffer), then resuspended in staining buffer at 1×107 cells/mL. Cell suspension was divided in two; half the cells were incubated with biotinylated anti-CD4 at 0.4 ug/uL, the other half of the cells were incubated with staining buffer as a negative control for 30 min. Following primary incubation, cells were rinsed with 5 volumes staining buffer and spun down at 250 rcf for 3 minutes; this rinse was repeated three times. Cells were resuspended at prior volume in staining buffer. 4×105 cells were measured per test and divided out accordingly, streptavidin-fluorophore conjugates prepared in Example 19 were incubated at 100 nM with each aliquot of cells for 30 min, allowing the avidin-biotin complex to form. Following the secondary incubation, cells were rinsed and detailed previously. Final cell suspensions were made for testing at 8×105 cells/mL. Flow analysis was performed on a BD LSR II flow cytometer at The Scripps Research Institute (TSRI), San Diego, Calif. Routine calibration with Rainbow fluorescent particles for aligning fluorescent channels on the cytometer was performed by staff at TSRI, all calibrated voltages were used, per staff recommendation. All samples were excited with a 408 nm Violet laser, the polymer conjugate was measured in the AmCyan channel with a 525/50 filter. All samples were initially referenced to unstained cells. The polymer streptavidin conjugate from FIG. 14 showed specific secondary labeling of the primary identified CD4 positive cells, with the positive cells as 44% of the population. The polymer streptavidin conjugate demonstrated a positive stain index showed low non-specific binding with reference to unstained cells and its respective negative control (FIG. 20. (A)). This provides evidence that the polymer, although its peak absorbance is a 440 nm, is a viable fluorescent material for use in flow cytometry with Violet laser excitation. Secondary Antibody Polymer Conjugate on Cyto-Trol Cells Amine-functionalized 405 polymer was conjugated to goat anti-mouse IgG κ1 purified antibody by route of maleimide-thiol conjugation and TCEP partial reduction of the antibody. The polymer and conjugation proceedure are provided specifically in Example 46. Conjugates were tested on Cyto-trol cells (Beckman Coulter), a fixed and lypholized lymphocyte cell population for control testing of specific human antigens. Cell staining followed secondary cell staining protocol. Cells were incubated with and without (negative control) unlabeled anti-CD4 (RPA-T4 clone, BD Biosciences) raised in mouse against the human antigen. After complete washing of primary antibody incubation, cells were incubated with polymer labeled goat anti-mouse conjugates for specific labeling of primary identified CD4 positive cells. Secondary labeling occurs by Fc recognition and binding of the mouse primary antibody by the secondary goat IgG, raised against murine species. A positive control was used by incubation with commercially available Pacific Blue goat anti-mouse IgG (Invitrogen) as the secondary labeling species. FIG. 20 (B) depicts the specific recognition of CD4 specific cells by the secondary fluorescent conjugates. Unstained cells show a negative control and natural autoflourescence of the cells, and incubation of polymer conjugate on cells with no primary labeling show minimal non-specific binding of the conjugate to unlabeled cells. Positive control, Pacific Blue goat anti-mouse shows the commercially available standard for CD4 labeling by secondary antibody with Violet excitation. 405 polymer-goat anti-mouse conjugate (red) shows positive identification of CD4 positive cells, a minimal shift in the negative cell population and great fluorescent signal and resolution that Pacific Blue standard. FIG. 20 (C) depicts Streptavidin polymer conjugates on Jurkat cells. Conjugates were produced with the polymer provided in Example 11 using the protocol defined in Example 29. The stain index for the polymer streptavidin conjugate was over 10 fold higher than that obtained for the commercially available Pacific Blue streptavidin control conjugate. FIG. 20 (D) depicts a primary monoclonal antibody polymer (antiCD4, RPA-T4) conjugate evaluated on Cyto-trol cells using the protocols defined above. The conjugate was prepared using the polymers and protocols defined in Example 46. Additional details on the conjugation can also be found in Example 39. Example 37: Preparation of Polymer Conjugated to —COOH Beads Via EDC Coupling Materials (per 100 μL of Beads): LodeStars —COOH functionalized magnetic beads (Varian, Inc. PL6727-0001) (100 μL of suspension at spec'd 30 mg/mL). Polymer with amine terminal ends from Example 17 (125 μL at 1.6 μM in 25 mM MES pH 5, for a 10-fold excess over theoretical bead capacity). 10 mM NaOH (2 mL). DI H2O (3 mL). 25 mM cold MES, pH 5. EDC at 50 mg/mL in 25 mM cold MES, pH 5 (100 μL). NHS at 50 mg/mL in 25 mM cold MES, pH 5 (100 μL). 100 mM Tris/HCl pH 7.4 (1 mL). Centrifuge and black flat-bottom 96-well plate. Antibody capacity was given at 10 ug/mg bead, giving an amine coupling capacity of 2 nmol polymer/mL bead (at 30 mg/mL). A 10 fold-excess of polymer over the suggested capacity was used to target the antibody concentration given in Varian's protocol. Bead Washing Beads were washed collectively as 600 μL and then split into 6×100 μL samples for coupling. Beads were washed 2× with 1 mL 10 mM NaOH, then 3× with 1 mL DI H2O; in between washes, the tube was centrifuged 1 min at 3000 rpm to recollect the beads as a pellet, supernatant was discarded and beads were resuspended in the next wash. After the final wash, beads were resuspended in 600 μL cold 25 mM MES, pH 5 and aliquoted into 6×100 μL volumes in microcentrifuge tubes. Beads were centrifuged again 1 min at 3000 rpm and supernatant was discarded. EDC Activation 100 μL of the EDC solution was added to each reaction set. 100 μL of the NHS solution was added to each reaction set. Beads were resuspended by vortexing and then allowed to mix on a rotator for 30 minutes. Beads were washed 2× in cold 25 mM MES pH 5, pelleted by centrifuging for 1 min at 3000 rpm and the supernatant was discarded. Beads were resuspended in 125 μL cold 25 mM MES, pH 5. Polymer Coupling 125 μL of polymer at 1.6 μM was added. Samples were vortexed to mix thoroughly and then reacted at RT on a mixer for 3 hours. Beads were pelleted by centrifuging for 1 min at 3000 rpm; supernatant was discarded. Beads were resuspended in 1 mL 100 mM Tris/HCl to block unreacted —COOH sites, vortexed and mixed for 1 hour. Beads were recollected by centrifugation and resuspended in 100 μL 25 mM MES. At this point, the supernatant of several tubes were yellow in color and had significant absorbance at 440 nm; the beads were washed 6 times until absorbance was at baseline. Beads sat for an additional 2 days prior to fluorescence measurement, after sitting in solution for 2 days, the supernatant was again yellow in color and had measureable absorbance. Beads were washed 3 more times with 30 minute mixes in between until no absorbance was measureable. At 2 days following fluorescence measurements, the supernatant remained clear and free of measureable absorbance. Example 38: Preparation of Polymer-Dye Conjugates Example 38a: Preparation of Polymer-Dye Conjugate at Polymer Terminal 0.5 mg amine-terminated polymer was dissolved in 15 μL DMSO. The polymer solution was then exchanged into 50 mM NaHCO3/Na2CO3, pH 8 buffer and recovered in buffer at −5 mg/mL as determined by UV-VIS absorbance. 50 μg NETS-ester dye (DyLight 594) was dissolved at 10 mg/mL in anhydrous DMSO, which was then immediately added to 120 μg of polymer. The tube was mixed on shaker (600-800 rpm) for 1 h and subsequently diluted to 100 with 20% EtOH in water. The mixture was added to a 30 cm Superdex 200 SEC column in 0.6M NaCl and 20% EtOH to separate polymer-dye conjugate from unreacted dye. The addition of dye can be used to estimate the incorporation of linker on the polymer structure by measuring an absorbance ratio based on the relative extinction coefficients of the polymer and dye. Using the molecular weight of the polymer it is possible to estimate the number of polymer chains which contain a linker. In additional embodiments, polymers with a carboxylic acid side chain are modified with amine functional dyes using standard EDC conjugation procedures or by first converting to the NETS ester using the protocol similar to that described in Example 29. Thiol dyes conjugated to maleimide terminated polymers have also been demonstrated. Any range of chemistry pairs would be expected to work in similar fashion to conjugate a polymer and dye. Example 38b: Preparation of Polymer-Dye Conjugate at Internal Position In a glovebox, 100 mg polymer with internal amine functionalities was dissolved in 10 mL anhydrous DMSO in a 20 mL amber scintillation vial. 0.32 mL DIPEA was added to the polymer solution. 24 mg of NETS-ester dye (Cy3) was dissolved in 2.4 mL in anhydrous DMSO and added to the polymer solution. The vial was tightly sealed, then removed from the glovebox and stirred at room temperature for 48 hours. The reaction was then purified over Amicon Ultra centrifugal filtration units (MWCO=30 kDa) with 20% ethanol in water until all free dye was removed. Purity was verified by running a 0.15 mg sample over a 30 cm Superdex 200 SEC column in 0.6M NaCl and 20% ethanol. 90 mg yield (90%). The addition of dye can be used to estimate the incorporation of linker monomers in the polymer structure by measuring an absorbance ratio based on the relative extinction coefficients of the polymer and dye. For polymers described above, the ratio of linker monomers (or dye attachments) per fluorene monomer in the final polymer are in general agreement with the molar feed ratio of monomers used in the polymerization reaction. Polymers with a carboxylic acid side chain can also be modified with amine functional dyes using standard EDC conjugation procedures or by first converting to the NHS ester using the protocol similar to that described in Example 29. Analogous procedures can be used to conjugate a range of dyes including Cy3, DyLight 549, DyLight 633, FAM, FITC, Alexa633, Alexa647 and several others. Polymers with a carboxylic acid side chain can also be modified with amine functional dyes using standard EDC conjugation procedures. FIG. 21 (A) shows the polymer structure above conjugated to (from left to right) FITC, Cy3, DyLight 594 and DyLight633. The polymer alone is show for reference (far left). Note in each case the amount of residual donor (polymer) emission is minimal. The data highlight the capablity of generating several diagnostic signals at different wavelenghts for multiplex applications. In this embodiment a single light source is capable of generating five distinct emission wavelengths. Example 38c: Energy Transfer Evaluation for Polymer-Dye Conjugates Based on Polymer Excitation for Use in Polymer Tandem Conjugates FIG. 21 (B) depicts a comparison of the fluorescence of the dye (DyLight594) excited near its absorbance maximum (lower curve) and polymer-dye conjugate excited at 405 nm (upper curve). Dye emission around 620 nm was over 5 fold brighter from the polymer-dye conjugate at the same molar concentration of dye versus direct dye excitation. Such embodiments highlight the signal amplification afforded by the disclosed polymer donors in energy transfer processes. The picture in the upper left corner highlights the visual color change in the emission of the complex based on dye conjugation. The polymer solution emits blue in the absence of dye and red upon dye conjugation (post purification). FIG. 21 (C) compares the fluorescent signal of the base polymer (no dye, peak emission near 420 nm) to that of the polymer-dye conjugate (peak emission near 620 nm). The DyLight594 dye quenches >98% of the polymer emission when conjugated to the polymer above (Example 38b). This is a feature of the polymer materials as any remaining donor emission could manfest as background signal in multilpex assay formats. The ability to conjugate the dye directly to the polymer structure and vary the number of attachement sites provides for efficent transfer that can be regulated by chemical design. Example 39: Flow Testing of Monoclonal Antibody (antiCD4) Conjugates on Whole Lysed Blood Samples Polymer conjugates of primary antiCD4 antibody (RPA-T4 clone) were produced using 3 different conjugation routes as provided in Examples 45, 46 and 49. 1) Amine modified polymer converted to a maleimide reactive group using SMCC (maleimide/NHS crosslinker) reacted with thiol groups on the antibody introduced by reacting SATA (thiol/NHS cross linker) with lysine (amine) groups (CJ11-2, FIG. 22). 2) Same polymer modified with SMCC (malemide) but with thiol groups introduced on antibody using TCEP to partially reduce the disulfide linkages in the antibody (CJ13-2, FIG. 22 and FIG. 20D). 3) A carboxylic acid terminated polymer activated with TSTU to form the NHS ester was reacted directly with the lysine (amine) groups on the antibody (CJ04-2 FIG. 22). All conjugates were made from the same polymer structure and batch. The polymer was synthesized using the protocol depicted in Example 12 with an amine end capping unit in place of the carboxylic acid capping unit shown. The NHS/amine conjugation was done with the protocol described in Example 45. The maleimide/thiol conjugation reactions were done in lines with those protocols described in Examples 46 and 49. FIG. 22 depicts the performance of these conjugates in flow cytometry conduced as follows. 100 μl whole human blood from a healthy volunteer was aliqoted into FACS tubes (duplicates for each sample). Antibody conjugates were diluted in wash buffer (PBS with 0.5% BSA and 0.1% Sodium Azide) and added to the blood at specified concentrations. Samples were vortexed vigorously then incubated for 15-30 mins in the dark at room temperature. 2 ml of 1x BD FACS Lyse solution was added to each sample and mixed in by vigorous vortexing prior to a further 10 mins incubation in the dark at room temperature. Samples were centrifuged for 5 min at 500 g and the supernatant tipped off and discarded. Samples were vortexed and 3 ml of wash buffer (PBS with 0.5% BSA and 0.1% Sodium Azide) added. Centrifugation was repeated at 500 g for a further 5 min. The resulting supernatant was tipped off and discarded and the remaining cell pellet vortexed. Samples were run on a BD LSRII flow cytometer acquiring all violet channels equipped with a violet laser and 450/50 nm filter that had been set up and precalibrated against BD CST beads. All polymer conjugate samples (CJ04-2, CJ11-2 and CJ13-1 lines) showed minimal non specific binding compared to unstained cells. Further, all polymer conjugates produced significantly higher positive signals than a commercially available Pacific Blue control conjugate of the same antibody clone which is commonly used for flow cytometry at compatible wavelengths. The best performing conjugates from this set provided over 6 fold high stain index than the commercially available Pacific Blue control antibody. Example 40: Preparation of Polymer-Dye Conjugate The polymer is conjugated to a dye, Dylight 594, and purified in a manner similar to the methods as described in Example 36. FIG. 23 depicts a comparison of the florescence of the dye (DyLight594) and polymer-dye conjugate. The dye was excited at 594 nm and the polymer-dye conjugate at 380 nm. Example 41: Fluorescent Immunoassay (ELISA) with Streptavidin-Conjugated Polymer An immunoassay for human IgG was developed as a demonstrative system in 96 well plate format. In further embodiments, similar functionality would be equally applicable in other formats including suspended microspheres and protein chip microarrays. Step 1: Preparation of Reagents Wash concentrate was prepared by dissolving 79.2 g Tris base pre-set crystals (pH 7.7), 225 g sodium chloride and 0.5 g Thimerosol in 1000 mL deionised water. Wash solution was prepared by adding 100 mL wash concentrate to 2400 mL deionised water. Subsequently, 10 mL 10% Triton X-100 was added. The basic assay buffer was prepared by dissolving 14.8 g Tris base pre-set crystals (pH 7.7), 18 g sodium chloride and 0.5 g Thimerosol in 2000 mL Milli-Q water (conductivity 18.2 mΩcm). Subsequently, 2 mL 10% Tween 20 and 10 g Bovine Serum Albumin Fraction V, essentially gamma globulin free were added. The solution was filtered and stored at 4° C. Step 2: Preparation of Capture Antibody Coated Plates Capture antibody was coated onto the surface of Nunc white Maxisorp 96 well plates at a concentration of approximately 1 microgramme per well. The plates were sealed and stored overnight at 4° C. Subsequently, the plates were washed once with wash solution and tapped dry on absorbent paper. Unless otherwise stated all plate washing in this example was performed on an automated microtitre plate washer. Two hundred and fifty (250) microlitres of blocking buffer (0.1M PBS containing 2% BSA) were added to each well, the plates re-sealed and stored at 4° C. until use. Step 3: Immunoassay Capture antibody-coated microtitre plates were washed twice with wash solution and tapped dry on absorbent paper. Two hundred (200) μL of either assay standard or experimental unknown sample were added in quadruplicate to appropriate wells of the coated plate. The plates were incubated on a shaker for 2 hours at 18° C. Subsequently, the plates were washed three times with wash solution, tapped dry on absorbent paper, and 200 μL of biotinylated detection antibody at a previously determined optimal concentration (diluted in assay buffer and filtered before use) were added to each well. The plates were incubated on an orbital shaker at ambient temperature for a further 60 minutes. The plates were then washed three times and tapped dry on absorbent paper. Two hundred (200) μL of 0.2 micron syringe filtered Streptavidin-polymer conjugate as prepared in Example 30 diluted to a concentration previously determined as suitable in assay buffer. The polymer was a fluorene polymer with neutral PEG11 side chains and an amine conjugation site. The plates were incubated on an orbital shaker at ambient temperature for a further 2 hours. The plates were then washed six times, tapped dry, turned around 180o, and re-washed a further six times. The plates were again tapped dry on absorbent paper. Two hundred (200) μL of filtered release reagent (0.1M sodium hydroxide, 2% Triton X-100) were added using a multi-channel pipette, the plates shaken for 60 minutes at ambient temperature and the fluorescence measured with a Victor Fluorometer. The plate was then sealed, stored overnight at 4° C. and re-read in the Victor Fluorimeter the following morning. Fluorescence counts were analysed using the Multicalc Software from Perkin Elmer to determine lower limit of assay detection and assorted similar parameters. Alternative conditions were also evaluated to release the conjugate from the well plate surface to improve the fluorescent readout. A representative data set is shown in FIG. 24. Comparisons were also made to commercially available SA-dye conjugates. The polymer conjugates demonstrated superior detection limits relative to the dye conjugates as was expected due to the collective optical properties. Example 42: Synthesis, Conjugation and Application of Para-Phenylene Vinylene Co-Polymer with Active Functional Linker for Bioconjugation Poly(1,4-(di2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl 2,5-dibromoterephthalate)-vinyl-alt-para(2-methoxy-5-2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl benzene)-vinylene) with phenylbutoxyamino termini. Di-2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl 2,5-dibromoterephthalate (2.0 g, 1.52 mmol),34-(4-methoxy-2,5-divinylphenoxy)-2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontane (1.11 g, 1.52 mmol), palladium acetate (13.6 mg, 0.061 mmol), tri-o-tolylphosphine (37 mg, 0.121 mmol), triethylamine (1 mL, 7.6 mmol) and 4 mL of DMF were combined in a small round bottom flask, equipped with a Teflon stribar, fitted with a needle valve and transferred to a Schlenk line. The solution was degassed via three freeze-pump-thaw cycles, put under nitrogen and heated to 100 C with constant stirring overnight. Next di-2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl 2,5-dibromoterephthalate (2.0 g, 1.52 mmol) (100 mg, 5 mol %), palladium acetate (5 mg), and tri-o-tolylphosphine and 0.5 mL DMF were combined in a small round bottom flask which is fitted with a needle valve and transferred to the Schlenk line. The solution was degassed via three cycles of freeze-pump-thaw and once warmed to room temperature was transferred to the polymerization reaction via cannula to exclude air and moisture. Allowed the mixture to react overnight. Next 4-(4-bromophenoxy)butan-1-amine (43 mg, 15 mol %) and 0.5 mL of DMF were combined in a small round bottom flask, equipped with a Teflon stribar, fitted with a needle valve and transferred to a Schlenk line. Once warmed to room temperature the solution was transferred to the polymerization reaction via cannula to exclude air and moisture. Allowed the mixture to react overnight. The next day the reaction was cooled to room temperature and the bulk of triethylamine was removed under vacuum. The reaction mixture was diluted with ˜30 mL of water and filtered through G 6 glass fiber filter paper. The filtrate was transferred to several Amicon filters (10 kDa cutoff) to concentrate the polymer and remove DMF. The remaining water is removed under vacuum and the residue is extracted into methylene chloride. The methylene chloride solution is dried over magnesium sulfate and filtered. The solvent is removed leaving behind a dark red thick oil, approximately 900 mg. The polymer was found to have a Mn of 20,400 g/mol as determined by GPC analysis relative to polystyrene standards. Incorporation of the amine linker was verified by conjugating a dye to the final polymer as described in Example 38. The polymer was then conjugated to streptavidin protein as follows: Amine polymer was dissolved at 50 mg/ml and desalted and buffer exchanged into 100 mM phosphate buffer pH 7.5. Polymer concentration was assessed by absorbance and 25 molar equivalents of SMCC (10 mg/ml in anhydrous DMSO) added. The reaction was mixed for 60 mins at room temperature and then desalted and buffer exchanged into PBS pH7.0+5 mM EDTA prior to repeat polymer concentration determination and confirmation of malemide functionality by SAMSA-fluorescein dye test. Streptavidin (5 mg/ml in 100 mM phosphate buffer pH7.5) was activated by addition of 20 molar equivalents of SATA (5 mg/ml in anhydrous DMSO). The reaction was mixed at room temperature for 60 mins prior to quenching (>15 mins room temp) with 10% (v/v) 50 mM EDTA, 2.5M hydroxylamine pH7.0. The activated protein was desalted and buffer exchanged into the same buffer as the activated polymer prior to an performance of an Ellman's assay to confirm and quantify thiol incorporation. Both the activated polymer and streptavidin were used as follows without delay. A greater than order of magnitude molar excess of SMCC activated polymer was added to the SATA activated streptavidin and the two mixed for 2 hours at room temperature prior to quenching with 20 molar equivalents of N-ethylmaleimide which was mixed in for 15 minutes at room temperature. Ion exchange and size exclusion chromatography were used to purify the bioconjugate of unreacted polymer and streptavidin. Appropriate fractions were pooled to maximize yield and performance and then concentrated by ultrafiltration. The conjugate was tested and its performance compared to a commercially available streptavidin-phycoerythrin (SA-PE) conjugate designed for purpose in a model Luminex xMap assay (FIG. 27, left). Donkey anti-mouse IgG antibody was covalently conjugated to xMap beads. A standard curve titration of Mouse IgG was then performed under standard Luminex xMap assay conditions (FIG. 27, right). Replicate samples were detected using either 4 μg/mL streptavidin-phycoerythrin or streptavidin conjugated polymer conjugate prepared as above (concentration not rigorously controlled). Samples were then read on a Luminex instrument. Absolute signals were found to be lower using the conjugated polymer. This is partially attributed to a non-ideal match between the polymer spectra and the excitation and emission optics in the instrument as well as the putative lower concentration of detection reagent used compared with the commercially available phycoerythrin product. However, the proportional background (non specific signal) from the polymer was also markedly lower resulting in a very comparable lower limit of detection for both detection formats (Fluorescence highest point in standard curve/fluorescence zero concentration of analyte (MFI/zero): 21.8 PE, 26.6 Polymer). Example 43: Synthesis of a Fluorene Co-Polymer with a DPP Hand Gap Modifying Unit To a 25 mL round-bottomed flask were added: PEGylated dibromo-DPP monomer (110 mmol), PEGylated fluorene diboronicester (110 mmol), THF (2.4 mL) solvent, 2M K2CO3 (1.6 mL) and tetrakis(triphenylphosphine)palladium (3.3 mmol) catalyst. The mixture was degassed by three freeze-pump-thaw cycles and then stirred under argon at 80 C over night. The resulting mixture was allowed to r.t. and diluted with water. Polymer was collected after dichloromethane extraction. The resulting polymer was found to have an absorption maxima at 520 nm and emission maxima at 590 nm with quantum yield of 6% in water. The polymer had a MW estimated at 16,000 by GPC analysis relative to polystyrene standards and was soluble in water, methanol and dichloromethane. End linker incorporation can be performed using methods similar to those described above and including methods described in Examples 9, 10 and 11. Example 44: Synthesis of a Substituted Divinylbenzene Polymer Methods used to prepare the polymer above were similar to those provided in Example 38. General methods for the preparation of divinylbenzene polymers as disclosed herein may be derived from known reactions in the field as well as methods found herein, and the reactions may be modified by the use of appropriate reagents and conditions, as would be recognized by the skilled person, for the introduction of the various moieties found in the formulae as provided herein. Example 45: Conjugation of Polymer to an Amine on a Primary Antibody Procedure for Production of NHS Ester Polymer-Antibody Conjugate Primary monoclonal antibody, anti-CD4 (RPA-T4 clone) was desalted, and exchanged into 50 mM NaHCO3 buffer, pH 8.2 at 1 mg/mL. Enriched NHS functionalized polymer was dissolved into anhydrous dimethyl sulfoxide (DMSO) at 100 mg/mL. Polymer solution was added at 30 fold molar excess of antibody into the antibody solution and allowed to mix by agitation for 3 hours at RT. Protein concentration was adjusted with buffer prior to incubation to ensure the volume of organic solvent was <10% the total volume. Following ultrafiltration over a 10 KDa MWCO filter device, ion exchange and size exclusion chromatographic techniques were then used to purify the bioconjugate of unreacted polymer and antibody, respectively. Appropriate fractions were pooled to maximize yield and buffer exchanged into PBS+0.05% NaN3 and simultaneously concentrated by ultrafiltration as above. Degree of labeling (indicated as p above) was determined via absorbance at 405 nm and a corrected 280 nm value. The polymer conjugate (CJ04-02) provided in Example 39 (FIG. 22) had an F/P (# of polymers per antibody) of approximately 2.04. This conjugate demonstrated flow performance as determined by stain index measurements which were greater than 3 fold higher than a Pacific Blue control conjugate of the same antibody. Example 46: Conjugation of Polymer to an Antibody Using Malemide/Thiol Chemistry Malemide/Thiol Conjugation of Polymers to Partially Reduced Antibodies Secondary antibody, goat anti-mouse IgG (H+L) was reconstituted in PBS+10 mM acetic acid and desalted/exchanged into 50 mM Tris-HCl buffer, pH7.4 at 1.0 mg/mL. TCEP (tris(2-carboxyethyl)phosphine) was dissolved in 50 mM Tris-HCl buffer, pH7.4, added at 6 molar excess with a final TCEP concentration of 10 mM and mixed for 30 minutes at room temperature. The modified protein was purified over a PD-10 desalting column to remove excess TCEP and exchanged into reaction buffer, 100 mM NaPO4, pH 6.5 reaction buffer with 10 mM EDTA. Amine-activated polymer was dissolved in anyhydrous DMSO at 10 mg/mL and mixed with succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) linker. The linker was added at 50 mg/mL, 20 molar excess in DMSO to the polymer solution and activated by diisopropylethylamine (DIPEA). The reaction was purified over Amicon Ultra centrifugation filters and exchanged into reaction buffer, 100 mM NaPO4, pH 6.5 reaction buffer with 10 mM EDTA. Immediately following disulfide reduction, maleimide functionalized polymer in reaction buffer at 10 mg/mL was added in 20 molar excess of antibody and allowed to mix for 4 hours. Ion exchange and size exclusion chromatographic techniques were then used to purify the bioconjugate of unreacted polymer and antibody, respectively. Degree of labeling (indicated as p above) is determined via absorbance at 405 nm and a corrected 280 nm value. The polymer conjugate provided in Example 36 (FIG. 20B) had an F/P (# of polymers per antibody) of approximately 2. This conjugate demonstrated flow performance as determined by stain index measurements which were greater than 4 fold higher than a Pacific Blue control conjugate of the same antibody. Malemide/Thiol Conjugation of Polymers to Thiol Modified Antibodies Secondary antibody, goat anti-mouse IgG (H+L) was reconstituted in PBS+10 mM acetic acid and desalted/exchanged into 100 mM phosphate pH7.5 buffer. SATA (N-succinimidyl-S-acetylthioacetate) was dissolved anhydrous DMSO, added at 15 molar excess and mixed for 60 minutes at room temperature. After quenching with a hydroxylamine solution, the modified protein was desalted over a PD-10 column to remove excess SATA and exchanged into reaction buffer, 5 mM EDTA, PBS pH 7.0 buffer. Amine-activated polymer was dissolved in anyhydrous DMSO at 10 mg/mL and mixed with succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) linker. The linker was added at 50 mg/mL, 20 molar excess in DMSO to the polymer solution and activated by diisopropylethylamine (DIPEA). The reaction was purified over Amicon Ultra centrifugation filters and exchanged into reaction buffer, 5 mM EDTA, PBS pH 7.0 buffer. Immediately following activation of the antibody, maleimide functionalized polymer in reaction buffer at 10 mg/mL was added in 20 molar excess of antibody and allowed to mix for 4 hours. Ion exchange and size exclusion chromatographic techniques were then used to purify the bioconjugate of unreacted polymer and antibody, respectively. Degree of labeling (indicated as p above) is determined by absorbance at 405 nm and a corrected 280 nm value. The resulting purified conjugates were flow tested in similar fashion as those described in Example 36 for the conjugates prepared using TCEP reduction (data not provided). The polymer structures defined in Example 39 were used to prepare primary antiCD4 (RPA-T4) antibody conjugates in similar fashion to those described in the example above. 30 eq of polymer were reacted with the SATA modified antibody (CJ11-2, FIG. 22) and TCEP reduced antibody (CJ13-1, FIG. 20D and FIG. 22) to produce polymer conjugates for testing in flow cytometry assays after purification. SMCC modified polymers from Examples 23 and 26 were also successfully conjugated to antiCD4 (RPA-T4) and antiCD8 (RPA-T8) antibodies using the TCEP reduction method. DTT reduction was also successfully performed in place of TCEP. Performance in flow cytometry of the antiCD4 and antiCD8 conjugates were evaluated in similar fashion to those described in Example 39 (FIG. 22). Example 47: Polymer Conjugation to a DNA Oligomer Azide Polymer Synthesis for Click Conjugation to Alkyne Terminated DNA Oligo A solution of azidohexanoic acid NHS ester (2.5 mg) in anhydrous DMF (100 μL) was added to a solution of the amine-functional polymer (9.9 mg) in anhydrous DMF (100 μL) under argon. Diisopropylethylamine (2 μL) was then added. The reaction was agitated at room temperature for 15 hours. Water was then added (0.8 mL) and the azide-modified polymer was purified over a NAP-10 column. The eluent was freeze dried overnight. Yield 9.4 mg, 95%. Oligo Synthesis with Pendant Alkyne (Hexyne) for Click Conjugation to Azide Polymer The 3′ propanol oligo A8885 (sequence YATTTTACCCTCTGAAGGCTCCP, where Y=hexynyl group and P=propanol group (SEQ ID NO: 1)) was synthesized using 3′ spacer SynBase™ CPG 1000 column on an Applied Biosystems 394 automated DNA/RNA synthesizer. A standard 1.0 mole phosphoramidite cycle of acid-catalyzed detritylation, coupling, capping and iodine oxidation was used. The coupling time for the standards monomers was 40 s, and the coupling time for the 5′ alkyne monomer was 10 min. The oligo was cleaved from the solid support and deprotected by exposure to concentrated aqueous ammonia for 60 min at room temperature, followed by heating in a sealed tube for 5 h at 55° C. The oligo was then purified by RP-HPLC under standard conditions. Yield 34 OD. Solution Phase Click Conjugation: Probe Synthesis A solution of degassed copper sulphate pentahydrate (0.063 mg) in aqueous sodium chloride (0.2 M, 2.5 μL) was added to a degassed solution of tris-benzo triazole ligand (0.5 mg) and sodium ascorbate (0.5 mg) in aqueous sodium chloride (0.2 M, 12.5 μL). Subsequently, a degassed solution of oligo A8885 (50 nmole) in aqueous sodium chloride (0.2 M, 30 μL) and a degassed solution of azide polymer (4.5 mg) in anhydrous DMF (50 μL) were added, respectively. The reaction was degassed once more with argon for 30 s prior to sealing the tube and incubating at 55° C. for 2 h. Water (0.9 mL) was then added and the modified oligo was purified over a NAP-10 column. The eluent was freeze-dried overnight. The conjugate was isolated as a distinct band using PAGE purification and characterized by mass spectrometry. Yield estimated at 10-20%. Fluorescence Studies The oligo-polymer conjugate was used as a probe in fluorescence studies. The probe was hybridized with the target A8090 (sequence GGAGCCTTCAGAGGGTAAAAT-Dabcyl (SEQ ID NO: 2)), which was labeled with dabcyl at the 3′ end to act as a fluorescence quencher. The target and probe were hybridized, and fluorescence monitored in a Peltier-controlled variable temperature fluorimeter. The fluorescence was scanned every 5° C. over a temperature range of 30° C. to 80° C. at a rate of 2° C./min. FIG. 25 shows increasing fluorescence intensity or emission with increasing temperature, indicating that as the probe-target pair melt, the polymer and quencher separate and fluorescence is recovered. Polymer conjugation to nucleic acids can also be performed using methods adapted from the protocols described in Examples 14, 45 and 46. Example 48: Purification of Polymer Antibody Conjugates Polymer antibody conjugates produced via the protocols described in Examples 45, 46 and 49 were purified using a two step method. First ion exchange is used to remove free, unreacted polymer. As the polymers described in this invention do not possess any formal charge they do not bind to the ion exchange media. Proteins (antibodies), however, do contain charged groups and are commonly bound to various ion exchange media for purification. In the examples provided the pH and conductivity of the conjugate solution (post reaction) was lowered to improve the binding of the free antibody and conjugate to the cationic exchange resin. After loading the conjugate, the resin is washed to baseline (measuring both 280 and 407 nm absorbance) to ensure all free polymer is removed. Bound antibody and polymer antibody conjugate are eluted by increasing the pH and ionic strength. A representative example of this separation is provided below in FIG. 26 (left) where the left peak represents the free polymer and the right peak the eluted conjugate and free protein. Removal of free polymer can also be achieved using affinity chromatograph methods in a similar fashion. Specific affinity resin can be used to bind the free protein and conjugate while removing polymer. After the polymer is removed, the conjugate solution is concentrated and loaded on a size exclusion column to separate any un-reacted or free antibody from the polymer. The polymer compositions described in Examples 43 and 44 elute much earlier than then antibodies despite having a lower molecular weight. This is expected to be a result of the rigid polymer structure. The conjugates thus elute well before any free antibody providing near base line separation of the desired conjugate. Isolating fractions near the center of the distribution also ensures no free antibody is included. A representative example of this separation is provided below in FIG. 26 (right) where the left peak represents the conjugate and the small peak on the far right the free antibody. Retention times of the individual components was verified in an independant experiment. Taken together the purification ensures that both free antibody and free polymer are removed. Purity of the resulting conjugates is reasonably estimated at >95%. Pooled samples can be concentrated and concentration measured by absorbance at 280 and 407 nm, being sure to correct for the polymer absorbance at 280 nm. Such measurements also allow for the determination of polymer to antibody labelling ratios (F/P). Example 49: Dye Labeling and Linker Activation of Tandem Polymer Tandem Dye Conjugation In a glovebox, 93 mg tandem polymer (from Example 26) was dissolved at 15 mg/mL in anhydrous DMSO in a glass vial with stir bar. 22.5 mg Cy3-NHS ester was also dissolved at 15 mg/mL in anhydrous DMSO and added to the polymer solution, followed by 0.3 mL diisopropylethylamine. After stirring for 48 h at room temperature, the solution was diluted to 90 mL with 20% EtOH in water and concentrated over Amicon Ultra-15 filters. The retentate was repeatedly diluted and concentrated over the filters until excess Cy3 was removed. 90% yield. Labeling and linker content were validated by measuring and taking the ratio of polymer and dye absorbance as described in Example 38. Amine Modification of Tandem (Aqueous Conditions) 100 mg of polymer-dye conjugate was dissolved at 150 mg/mL in ethanol. This was added dropwise to 6 mL 50 mM MES buffer (pH 5) at 4° C. 38 mg N-hydroxy succinimide was added in one portion, and the solution was stirred to dissolve the solids. After dissolution, 192 mg of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride was added in portions while stirring. After stirring the solution for 30 minutes, 33 μL of ethylene diamine was added. After stirring overnight at room temperature, the solution was diluted to 90 mL with 20% EtOH in water and concentrated over Amicon Ultra-15 filters. The retentate was repeatedly diluted and concentrated over the filters a total of four times to remove impurities. 90% yield, 60% conversion. Linker conversion was verified by conjugating a second dye to the terminal amine as described in Example 38. Tandem Conjugation to a Primary Antibody Primary monoclonal antibody, anti-CD8 (RPA-T8 clone) was desalted/exchanged into 5 mM EDTA, 50 mM phosphate 150 mM NaCl pH 7.0 buffer. TCEP (tris(2-carboxyethyl)phosphine) was dissolved water and added at 12 molar excess and mixed for 90 minutes at 30° C. The modified protein was purified over a PD-10 desalting column to remove excess TCEP and exchanged into 5 mM EDTA, 50 mM phosphate 150 mM NaCl pH 7.0 buffer. Amine-activated tandem polymer was dissolved in ethanol at 50 mg/mL and this solution was mixed with two volumes of 100 mM phosphate pH 7.5 buffer. This solution was then desalted/exchanged into 100 mM phosphate pH 7.5 buffer using a PD-10 desalting column. To this solution was added 25 molar excess of succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) linker (prepared as a 10 mg/ml solution in anhydrous DMSO). The resulting solution was rollermixed at 20° C. for 60 minutes before being desalted/exchanged into 5 mM EDTA, 50 mM phosphate 150 mM NaCl pH 7.0 buffer using a PD-10 desalting column. Immediately following disulfide reduction, the maleimide functionalized polymer was added in 25 molar excess of antibody and allowed to mix for 2 hours at 20° C. Ion exchange and size exclusion chromatographic techniques were then used to purify the bioconjugate of unreacted polymer and antibody, respectively. Degree of labeling (indicated as p below) is determined via absorbance and a corrected 280 nm value. Flow Cytometry Analysis of Polymer Tandem Conjugate in Multicolor Experiment The resulting antiCD8 Tandem conjugate was evaluated on both compensation beads and whole blood samples on a flow cytometer. Anti mouse IgG compensation beads were used to capture the antibody and quantify signal spill over into detection channels (detectors with unique emission filters) other than that intended for the conjugate. FIG. 28 (left) shows the signal measured when the tandem conjugate was excited with a violet laser with emission detected using a 610 nm filter matched to the conjugates emission (labeled QDotA). Crosstalk into the flow cytometer's other channels paired with the violet excitation laser (DAPI-A and AmCyan-A) and two channels off the 488 nm laser (FITC-A and PE-A) are also shown in this panel of the figure. The data show minimal crosstalk in the 450/50 nm filter (DAPI-A) which specifically detects residual polymer (donor) emission. The significantly higher signal from the Cy3 reporter on the Tandem (610 nm filter) relative to the other channels above illustrates that minimal compensation (maximally no more than 6% in this example and case by case often much lower) is required. The Tandem anti CD8 conjugate was subsequently evaluated in a 4 color flow assay with other labeled antibodies (anti CD3 Pacific Blue, anti CD45 Phycoerythrin and anti CD4 fluorescein) on whole human blood from a healthy volunteer using staining and analysis protocols in accord and developed from Example 39. The data in FIG. 28 (right) clearly show the compatibility of the Tandem label with common multicolour flow cytometry instrumentation, reagents and protocols. Specifically, intense and specific staining of CD8 positive lymphocytes is observed and within the CD4 positive subset ready discrimination of CD8 expressive and non expressive cells is clear Collectively the data highlight the viability of the polymer-dye Tandem conjugates in multicolor flow assays as described in the disclosed invention (See, e.g., FIG. 20 and FIG. 22). Example 50: Validation of Non-Ionic Polymer Side Chains for Water Solubility and Flow Cytometry Application A series of different polyfluorene polymers were produced to investigate the interaction of water soluble conjugated polymers with cells. This was done by first synthesizing a range of monomers substituted with different solublizing side chains (e.g., PEG-, sulfonate-, quaternary amine-, zwitterion- substituted) which were then polymerized using Suzuki coupling. The purpose was to determine what influence the side chains had on both non-specific cell binding and polymer solubility in typical buffers used in biological assays, particularly those used in flow cytometry (e.g. PBS and DPBS). The number and property diversity of polymer candidates synthesized made it impractical to produce purified conjugates of each for flow cytometry testing. Thus, a system was developed to score each candidate polymer based on its contribution to non-specific binding to cells. Such a system enabled ranking of polymers, with predictive value on whether they would perform sufficiently once conjugated. A Non-specific Binding (NSB) “Index” was developed around a Jurkat cell model (lymphocyte cell line). In this, cells were incubated with a fixed concentration of each polymer, washed, and analyzed by flow. FIG. 33 displays the outcome following such analysis, and illustrates the wide variation in signal generated by each polymer type. The polymers in FIG. 33 were evaluated with a phtalamide protecting group on the pendant amine with the exception of P9. The data ranks these polymers in terms of signal generated purely by NSB. More accurate assessment of relative NSB was enabled by adjusting further normalizing the flow signal by differences in fluorescence efficiency (crude assessment of quantum yield) of each form of polymer when assayed independently in stain buffer using 405 nm excitation on a fluorometer and monitoring emission in the range of 420-460 nm (to estimate a 440/40 nm filter in the cytometer). Representative polymers P5, P2, P9 and P12 showed increasing NSB relative to unstained cells (far left curve, intensity represented on x-axis). The data in FIG. 34 go on to highlight the difference in polymers produced with neutral, non-ionic PEG side chains (designated P20) verses those which also incorporate anionic side chains (designated P4). The data are histograms collected from flow cytometry analysis (405 nm excitation in a BD LSR-II cytometer) using a Jurkat cell line as in FIG. 33. The panel on the left shows unstained cells and a negative control (cells treated with a non-specific Pacific Blue labeled conjugate) which are the two curves on the far left. Little if any non-specific staining is observed for the Pacific Blue control. In this same panel, however, curve on the right represents cells treated with the anionic P4 polymer and has a clear off set in signal (x-axis) as shown. Conversely the neutral polymer P20 showed almost no off set from the untreated cells which is in line with the Pacific Blue control. The panel in the middle represents a range of different polymer and polymer side chain combinations tested on the same cells. The data highlighted the advantage of neutral side chains. This advantage has also translated to other assay formats including plate based immunoassays and cytometric bead arrays (data not shown). The neutral side chains also unexpectedly resulted in a significant increase in the solubility of the conjugated polymers in aqueous solutions relative to those made previously with ionic side chains. This was particularly true in buffers containing even moderate ionic strength (such as those used in basic cell protocols). The solution quantum yields were also seen to increase, possibly due to the higher aqueous solubility (and less aggregation). The poor solubility in buffers also made protein conjugation more difficult and streptavidin conjugates produced from P4 showed signs of aggregation in typical assay buffers such as phosphate buffered saline (PBS). This was not true of polymers and conjugates produced in other examples disclosed herein. Example 51: Purification and Characterization of Polymer-Avidin Conjugates Gel Analysis of Polymer-Avidin Conjugates To verify successful conjugation to avidin (AvDN), an agarose gel electrophoresis method was developed and used to assess the relative mobility of AvDN as a function of the degree of conjugation with polymer (FIG. 35). Prior to gel loading, the conjugation reaction was stained with biotinyl-fluorescein, which bound polymer-AvDN conjugate and free AvDN. Electrophoresis was performed in 0.8% agarose gels, poured and run in a buffer of 10 mM Sodium Borate, pH 11. The gel was visualized under UV illumination (to visualize the polymer) and by 532 nm excitation (to visualize fluorescein) to assess the degree of conjugation. Under UV illumination, a single band was observed for polymer. Under 532 nm excitation, bands were observed for unbound biotinyl-fluorescein, unreacted AvDN, and polymer-AvDN conjugate which coincided with the free polymer band, indicating that unreacted polymer co-eluted with polymer-AvDN conjugate (FIG. 35). Conjugation was confirmed by the intensity of the conjugate band. The key at the top of the gel images (FIG. 35) indicates which components were included in the conjugation reaction, as well as whether the samples were pre-incubated with biotinyl fluorescein prior to loading and electrophoresis. The image on left visualizes polymer by UV-excitation, whereas the image on right captures the result of fluorescein excitation. On the right image, biotinylated fluorescein can be seen associating with polymer when conjugation was performed in the presence, but not in the absence, of hetero-bifunctional NHS-ethoxy-maleimide linkers (linkers were used to functionalize the polymer amine, while protein amines were partially converted to thiols using Traut's reagent, prior to the maleimide-thiol coupling). Abbreviations: AvDN=avidin DN, AA1=polymer, Linker=hetero-bifunctional NHS-Maleimide linker included in the reaction, Biot-F=biotinyl fluorescein pre-staining before electrophoresis. Purification: Removal of Unreacted Avidin by SEC Chromatography The crude conjugate mixture was fractionated on a Superdex 200 size exclusion column, while fractions were monitored by UV absorbance (FIG. 36, top). To validate the method, fractions were analyzed by agarose gel electrophoresis. As described above, this method of electrophoresis made it possible to visualize the degree to which avidin was attached to polymer, and in this case to analyze the composition of each fraction from the column. Selected fractions were incubated with biotinyl-fluorescein (1 molar equivalent relative to avidin) prior to gel loading, with biotinyl-fluorescein loaded separately as a marker (leftmost lane, FIG. 36, bottom). Electrophoresis was performed in 0.8% agarose gels, poured and run in a buffer of 10 mM Sodium Borate, pH 11. The gel was visualized by 532 nm excitation. Retardation of fluorescein-visualized bands for fractions C2-C6 indicates purified polymer-avidin conjugate, while the two bands observed for fraction C8 indicate a mixture of polymer-avidin conjugate and free avidin. Fractions C10-D2 show only free avidin. Evaluation of Conjugation Efficiency by Gel Analysis In order to determine the best ratio of polymer to streptavidin in conjugation reactions, the molar equivalents of polymer to streptavidin were varied from 0-24 equivalents. Post conjugation, the conjugation products were incubated with biotinyl-fluorescein prior to electrophoresis. The gel was visualized by UV illumination and 532 nm excitation (FIG. 37). At 0 molar equivalents of polymer to streptavidin, free streptavidin is observed as a band with relatively high mobility. As the molar equivalents for polymer are increased from 3 equivalents to 12 equivalents, the free streptavidin band decreases in intensity while the polymer-streptavidin conjugate band increases in intensity. At 24 equivalents of polymer, only the conjugate band is observed by 532 nm excitation. Impact of Purification on Conjugate Performance on Cell Analysis by Flow Cytometry Purification of polymer streptavidin conjugates (polymer structure exemplified in Example 9, denoted P30 in FIG. 38) was performed to determine the impact on flow cytometry performance. Cation-exchange chromatography was implemented in purification to improve removal of excess free polymer. Uncharged polymer eluted in the flow-through while protonated amines on proteins were retained by the media. Thus, streptavidin, whether conjugated to polymer or unreacted, was retained. This ion exchange phase of purification was kept simple with a step gradient, which resulted in co-elution of conjugated and unreacted SA. Further fractionation was enabled by subsequent size-exclusion chromatography, which provided better resolution of conjugate from free SA. Performance benefits in flow cytometry of this new purification method were observed using Jurkat cells incubated with polymer-streptavidin conjugate which were analyzed by flow cytometry. Comparisons were made between crude samples (FIG. 38—top) and purified conjugates (FIG. 38 bottom). Commercially available Pacific Blue-streptavidin conjugates were used as a comparator for brightness, nonspecific binding, and stain index. An improvement in overall Stain Index of approximately 3-fold was shown for Jurkat cells, with similar NSB for both Polymer conjugates and PB-SA based on the histograms shown in FIG. 38. Testing in blood (data not shown) indicated a significant reduction in NSB to levels similar to PB-SA upon conjugate purification. In a separate experiment with a similar polymer (exemplified in Example 11), conjugates with varying polymer to streptavidin ratios were obtained by SEC. Those with the higher ratio provided flow performance relative to those with lower labeling. Ratios were determined based on a ratio of absorbance at 385 nm/280 nm. Relative performance to a Pacific Blue control showed an increase from 10.9 times higher stain index (385/280 ratio of 3.6) to a stain index 13.8 times that of Pacific Blue (A385/280 ratio of 4.7). While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
<SOH> BACKGROUND OF THE INVENTION <EOH>Fluorescent hybridization probes have developed into an important tool in the sequence-specific detection of DNA and RNA. The signals generated by the appended fluorescent labels (or dyes) can be monitored in real time and provide simple, rapid, and robust methods for the detection of biological targets and events. Utility has been seen in applications ranging from microarrays and real time PCR to fluorescence in situ hybridization (FISH). Recent work in the area of multichromophores, particularly regarding conjugated polymers (CPs) has highlighted the potential these materials have in significantly improving the detection sensitivity of such methods (Liu and Bazan, Chem. Mater., 2004). The light harvesting structures of these materials can be made water soluble and adapted to amplify the fluorescent output of various probe labels (See U.S. patent application Ser. No. 10/600,286, filed Jun. 20, 2003 and Gaylord, Heeger, and Bazan, Proc. Natl. Acad. Sci., 2002, both of which are incorporated herein by reference in their entirety). Results such as these indicate CPs to be highly promising in the field of nucleic acid diagnostics, particularly where sample quantities are scarce. However, there exist methods for the amplification (or replication) of nucleic acid targets, i.e., PCR. Comparatively, in the field of protein recognition, there are no such simple methods for amplifying the targeted materials. As such, signal enhancement arising from CP application is of high consequence in this area. Dye-labeled antibodies are regularly used for the detection of protein targets in applications such as immunohistochemistry, protein arrays, ELISA tests, and flow cytometry. Integrating CP materials into such methodologies promises to provide a dramatic boost in the performance of such assays, enabling detection levels previously unattainable with conventional fluorescent reporters (e.g., dyes). Beyond addition signal, one of the other key drivers in biological detection formats is the ability to detect multiple analytes in the same test or multiplexing. This is commonly achieved by using fluorescent reporters with operate at different, decernable wavelengths. CP materials are ideally suited to provide a platform for expanded multiplexing. This can be achieved by tuning the structure of different CPs to operate at different wavelengths or by incorporating a dye within the polymer-biomolecule conjugate. The material and methods to produce higher sensitivity biological assays and increase multiplexing are highly desired in both molecular (nucleic acid) and immunoassay formats.
<SOH> SUMMARY OF THE INVENTION <EOH>Provided herein are water soluble conjugated polymers of Formula (I): wherein: each R is independently a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL; MU is a polymer modifying unit or band gap modifying unit that is evenly or randomly distributed along the polymer main chain and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C 1 -C 12 alkyl, C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl, C 1 -C 12 haloalkyl, C 1 -C 12 alkoxy, C 2 -C 18 (hetero)aryloxy, C 2 -C 18 (hetero)arylamino, (CH 2 ) x′ (OCH 2 CH 2 ) y′ OCH 3 where each x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50, or a C 2 -C 18 (hetero)aryl group; each optional linker L 1 and L 2 are aryl or heteroaryl groups evenly or randomly distributed along the polymer main chain and are substituted with one or more pendant chains terminated with a functional group for conjugation to another substrate, molecule or biomolecule selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof; G 1 and G 2 are each independently selected from hydrogen, halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiol, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters, boronic acids, optionally substituted fluorene and aryl or heteroaryl substituted with one or more pendant chains terminated with a functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule; wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, and thiols within G 1 , G 2 , L 1 or L 2 that allows, for functional conjugation to another molecule, substrate or biomolecule; each dashed bond, - - - - - - , is independently a single bond, triple bond or optionally substituted vinylene (—CR 5 ═CR 5 —) wherein each R 5 is independently hydrogen, cyano, C 1 -C 12 alkyl, C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl or a C 2 -C 18 (hetero)aryl group, wherein each C 1 -C 12 alkyl, C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl or a C 2 -C 18 (hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl group, C 1 -C 12 alkoxy, or C 1 -C 12 haloalkyl; and n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. In one aspect, water soluble conjugated polymers of Formula (I) have the structure of Formula (Ia): wherein R, L 1 , L 2 , G 1 , G 2 , MU, a, b, c, d and n are described previously for formula (I). In some embodiments, each R is independently (CH 2 ) x (OCH 2 CH 2 ) y OCH 3 where each x is independently an integer from 0-20, each y is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C 1 -C 12 alkoxy, or (OCH 2 CH 2 ) z OCH 3 where each z is independently an integer from 0 to 50. In some instances, each R is (CH 2 ) 3 (OCH 2 CH 2 ) 11 OCH 3 . In other embodiments, each R is a benzyl substituted with at least one (OCH 2 CH 2 ) 10 OCH 3 group. In some instances, the benzyl is substituted with two (OCH 2 CH 2 ) 10 OCH 3 groups. In other instances, the benzyl is substituted with three (OCH 2 CH 2 ) 10 OCH 3 groups. In some embodiments, optional linkers L 1 or L 2 have the structure: *=site for covalent attachment to unsaturated backbone; wherein R 3 is independently hydrogen, halogen, alkoxy(C 1 -C 12 ), C 1 -C 12 alkyl, C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl or a C 2 -C 18 (hetero)aryl group, wherein each C 1 -C 12 alkyl, C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl or a C 2 -C 18 (hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl group, C 1 -C 12 alkoxy, or C 1 -C 12 haloalkyl; and q is an integer from 0 to 4. In other embodiments, optional linkers L 1 or L 2 have the structure: *=site for covalent attachment to unsaturated backbone wherein A is a site for conjugation, chain extension or crosslinking and is [O—CH 2 —CH 2 ] q —W, or (C 1 -C 12 )alkoxy-X or C 2 -C 18 (hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule.; W is —OH or —COOH; X is —NH 2 , —NHCOOH, —NHCOOC(CH 3 ) 3 , —NHCO(C 3 -C 12 )cycloalkyl(C 1 -C 4 )alkyl-N-maleimide; or —NHCO[CH 2 —CH 2 —O] t NH 2 ; q is an integer from 1 to 20; and t is an integer from 1 to 8. In yet other embodiments, optional linkers L 1 or L 2 have the structure: *=site for covalent attachment to backbone wherein R 25 are each independently any one of or a combination of a bond, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 2 -C 20 alkene, C 2 -C 20 alkyne, C 3 -C 20 cycloalkyl, C 1 -C 20 haloalkyl, (CH 2 ) x (OCH 2 CH 2 ) p (CH 2 ) x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C 2 -C 18 (hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups; wherein at least one R 25 is terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In further embodiments, optional linkers L 1 or L 2 have the structure: *=site for covalent attachment to unsaturated backbone; wherein R35 is any one of or a combination of a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl, (CH2)x(OCH2CH2)p(CH2)x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In further embodiments, optional linkers L 1 or L 2 are selected from the group consisting of a-h having the structures: *=site for covalent attachment to unsaturated backbone; wherein R′ is independently H, halogen, C 1 -C 12 alkyl, (C 1 -C 12 alkyl)NH 2 , C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl, C 1 -C 12 haloalkyl, C 2 -C 18 (hetero)aryl, C 2 -C 18 (hetero)arylamino, —[CH 2 —CH 2 ] r′ —Z 1 , or (C 1 -C 12 )alkoxy-X 1 ; and wherein Z 1 is —OH or —COOH; X 1 is —NH 2 , —NHCOOH, —NHCOOC(CH 3 ) 3 , —NHCO(C3-C12)cycloalkyl(C1-C4)alkyl-N-maleimide; or —NHCO[CH 2 —CH 2 —O] s′ (CH 2 ) s′ NH 2 ; r′ is an integer from 1 to 20; and each s′ is independently an integer from 1 to 20, (CH 2 ) 3 (OCH 2 CH 2 ) x″ OCH 3 where x″ is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C 1 -C 12 alkoxy, or (OCH 2 CH 2 ) y —OCH 3 where each y″ is independently an integer from 0 to 50 and R′ is different from R; wherein k is 2, 4, 8, 12 or 24; wherein R 15 is selected from the group consisting of 1-t having the structure: *=site for covalent attachment to backbone. In yet further embodiments, optional linkers L 1 or L 2 are In some embodiments, G 1 and G 2 are each independently selected from hydrogen, halogen, alkyne, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters, boronic acids, optionally substituted fluorine and aryl or heteroaryl substituted with one or more pendant chains terminated with a functional group, molecule or biomolecule selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In some embodiments, G 1 and G 2 each independently have the structure wherein R 11 is any one of or a combination of a bond, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 2 -C 20 alkene, C 2 -C 20 alkyne, C 3 -C 20 cycloalkyl, C 1 -C 20 haloalkyl, (CH 2 ) x (OCH 2 CH 2 ) p (CH 2 ) x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C 2 -C 18 (hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In other embodiments, G 1 and G 2 are each independently selected from the group consisting of 1-31 having the structures: *=site for covalent attachment to backbone wherein R 15 is selected from the group consisting of 1-t having the structure: and k is 2, 4, 8, 12 or 24. In further embodiments, G 1 and G 2 are optionally substituted aryl or heteroaryl wherein the optional substituent is selected from halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiol, boronic acid, boronate radical, boronic esters and optionally substituted fluorene. In some embodiments, G 1 and G 2 are the same. In other embodiments, G 1 and G 2 are different. In further embodiments, the polymer contains a single conjugation site at only one terminus of the polymer chain G 1 or G 2 . In yet further embodiments, G 1 and G 2 is In some embodiments, MU is selected from the group consisting of a′-k′ having the structure: *=site for covalent attachment to unsaturated backbone wherein R is a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL. In some embodiments, the water soluble conjugated polymer has the structure of formula: wherein at least one of G 1 or G 2 comprises a functional conjugation site. In some embodiments, the water soluble conjugated polymer has the structure of formula: wherein L 1 comprises a functional conjugation site. In some embodiments, the water soluble conjugated polymer has the structure of formula: wherein at least one of G 1 or G 2 comprises a functional conjugation site. In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In some instances, a signaling chromophore is attached to the polymer via the NH 2 group. In certain instances, the signaling chromophore is Cy3 or Dylight 594 dye. In certain instances, the linker, is about 10% of the entire polymer. In other instances, the polymer is conjugated to a secondary dye reporter and an antibody. In some embodiments of conjugated polymers described herein, the polymer is further conjugated to additional molecules. In some embodiments, the polymer is conjugated to a streptavidin, antibody or nucleic acid and used as a direct fluorescent reporter. In certain embodiments, the polymer is conjugated to a streptavidin. In other embodiments, the polymer is conjugated to thiol groups at the hinge region of an antibody. In yet other embodiments, the polymer is conjugated to an amine group on a protein which is modified with a heterobifuntional linker. In further embodiments, the polymer is conjugated to a nucleic acid. In yet further embodiments, the polymer is conjugated to an antibody. In certain instances, the polymer is conjugated to a monoclonal antibody, a secondary antibody or a primary antibody. In other instances, a polymer antibody conjugate is excited at about 405 nm in a flow cytometry assay where the specific signal is at least 3 fold greater than the same antibody conjugated to Pacific Blue. In some embodiments of conjugated polymers described herein, the polymer is purified by ion exchange chromatography. In other embodiments, the polymer is >95% pure. In some embodiments of conjugated polymers described herein, the polymer is used in flow cytometry assays to identify different cell markers or cell types. In other embodiments, the polymer is used to sort cells. In yet other embodiments, the polymer is used to sort cells for use in therapeutics. In some embodiments of conjugated polymers described herein, the polymer is used for intracellular staining. In certain instances, the polymer is used in flow cytometry assays to identify different cell markers or cell types. In some embodiments of conjugated polymers described herein, the polymer comprises a minimum number average molecular weight of greater than 40,000 g/mol and a water solubility of greater than 50 mg/mL in pure water or a phosphate buffered saline solution. In some embodiments of conjugated polymers described herein, the polymer comprises at least two unique conjugation linkers which can conjugated to two unique materials. Also provided herein are assay methods comprising providing a sample that is suspected of containing a target biomolecule; providing a sensor protein conjugated to at least one signaling chromophore and is capable of interacting with the target biomolecule or a target-associated biomolecule; providing a water soluble conjugated polymer described herein; contacting the sample with the sensor protein and the conjugated polymer in a solution under conditions in which the sensor protein can bind to the target biomolecule or a target-associated biomolecule if present; applying a light source to the sample that can excite the conjugated polymer; and detecting whether light is emitted from the signaling chromophore. In some embodiments, the sensor protein is an antibody. In other embodiments, the sensor protein comprises a plurality of sensor proteins conjugated to a plurality of signaling chromophores, wherein at least two of the plurality of chromophores emit different wavelengths of light upon energy transfer from the multichromophore. Also provided herein are conjugated polymer complexes comprising a polymer coupled to at least one biomolecule selected from the group consisting of a sensor biomolecule, a bioconjugate and a target biomolecule wherein the polymer is covalently bound by at least one bioconjugation site pendant thereto, and the polymer comprises a signaling chromophore or a signaling chromophore optionally is covalently bound to the polymer or the sensor biomolecule; wherein the polymer comprises the structure of formula: wherein: each R is a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL; MU is a polymer modifying unit or band gap modifying unit that is evenly or randomly distributed along the polymer main chain and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C 1 -C 12 alkyl, C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl, C 1 -C 12 haloalkyl, C 1 -C 12 alkoxy, C 2 -C 18 (hetero)aryloxy, C 2 -C 18 (hetero)arylamino, (CH 2 ) x′ (OCH 2 CH 2 ) y′ OCH 3 where each x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50, or a C 2 -C 18 (hetero)aryl group; each optional linker L 1 and L 2 are aryl or heteroaryl groups evenly or randomly distributed along the polymer main chain and are substituted with one or more pendant chains terminated with a functional group for conjugation to another molecule, substrate or biomolecule selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof; G 1 and G 2 are each independently selected from hydrogen, halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiol, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters, boronic acids, optionally substituted fluorene and aryl or heteroaryl substituted with one or more pendant chains terminated with a functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule; wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, and thiols within G 1 , G 2 , L 1 or L 2 that allows, for functional conjugation to another molecule, substrate or biomolecule; n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. In some embodiments, the sensor biomolecule is selected from the group consisting of an avidin, streptavidin, neutravidin, avidinDN, and avidinD. In other embodiments, the conjugated polymer complex is further configured to bind to a complex selected from the group consisting of a biotin-labeled antibody, biotin-labeled protein, and biotin-labeled target biomolecule. In further embodiments, the sensor biomolecule is an antibody. In yet further embodiments, both the signaling chromophore and the sensor biomolecule are covalently linked to the multichromophore through a plurality of linkers. In some other embodiments, both the signaling chromophore and the sensor biomolecule are covalently linked to the polymer through a central linking site that covalently binds the polymer, the signaling chromophore and the sensor biomolecule. In yet other embodiments, the signaling chromophore, when covalently bound to the polymer or the sensor biomolecule, is an organic dye. Also provided herein are water soluble conjugated polymer having the structure of Formula (Ia): wherein: each R is independently (CH 2 ) x (OCH 2 CH 2 ) y OCH 3 where each x is independently an integer from 0-20, y is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C 1 -C 12 alkoxy, or (OCH 2 CH 2 ) z OCH 3 where each z is independently an integer from 0 to 50; each optional linker L 1 or L 2 is selected from the group consisting of a-i having the structure *=site for covalent attachment to unsaturated backbone wherein R′ is independently H, halogen, C 1 -C 12 alkyl, (C 1 -C 12 alkyl)NH 2 , C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl, C 1 -C 12 haloalkyl, C 2 -C 18 (hetero)aryl, C 2 -C 18 (hetero)arylamino, —[CH 2 —CH 2 ] r′ —Z 1 , or (C 1 -C 12 )alkoxy-X 1 ; and wherein Z 1 is —OH or —COOH; X 1 is —NH 2 , —NHCOOH, —NHCOOC(CH 3 ) 3 , —NHCO(C3-C12)cycloalkyl(C1-C4)alkyl-N-maleimide; or —NHCO[CH 2 —CH 2 —O] s′ (CH 2 ) s′ NH 2 ; r′ is an integer from 1 to 20; and each s′ is independently an integer from 1 to 20, (CH 2 ) 3 (OCH 2 CH 2 ) x″ OCH 3 where x″ is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C 1 -C 12 alkoxy, or (OCH 2 CH 2 ) y″ OCH 3 where each y″ is independently an integer from 0 to 50 and R′ is different from R; wherein R 15 is selected from the group consisting of 1-t having the structure: and k is 2, 4, 8, 12 or 24; *=site for covalent attachment to backbone MU is a polymer modifying unit or band gap modifying unit that is selected from the group consisting of a′-k′ having the structure: *=site for covalent attachment to unsaturated backbone; wherein R is a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL; G 1 and G 2 are each independently selected from the group consisting of 1-31 having the structures: wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazids, hydrazones, azide, alkyne, aldehydes, and thiols within G 1 , G 2 , L 1 or L 2 that allows, for functional conjugation to another molecule, substrate or biomolecule; n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. Also provided herein are water soluble conjugated polymer having the structure of Formula: wherein Ar is an aryl or heteroaryl and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C 1 -C 12 alkyl, C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl, C 1 -C 12 haloalkyl, C 1 -C 12 alkoxy, C 2 -C 18 (hetero)aryloxy, C 2 -C 18 (hetero)arylamino, (CH 2 ) x′ (OCH 2 CH 2 ) y′ OCH 3 where each x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50; and dashed bonds, L 1 , L 2 , G 1 , G 2 , MU, a, b, c, d and n are described previously for formula (I).
G01N3358
20170927
20180315
86750.0
G01N3358
1
TRUONG, DUC
Novel Reagents for Directed Biomarker Signal Amplification
UNDISCOUNTED
1
CONT-ACCEPTED
G01N
2,017
15,717,580
PENDING
Novel Reagents for Directed Biomarker Signal Amplification
Described herein are methods, compositions and articles of manufacture involving neutral conjugated polymers including methods for synthesis of neutral conjugated water-soluble polymers with linkers along the polymer main chain structure and terminal end capping units. Such polymers may serve in the fabrication of novel optoelectronic devices and in the development of highly efficient biosensors. The invention further relates to the application of these polymers in assay methods.
1.-40. (canceled) 41. A method of determining whether a target is present in a sample, the method comprising: contacting the sample with a conjugated polymer complex comprising a sensor for the target conjugated to a water soluble conjugated polymer having the structure of the formula: wherein: Ar is an aryl or heteroaryl unit substituted with a non-ionic side group capable of imparting solubility in water; MU is a polymer modifying unit or band gap modifying unit that is evenly or randomly distributed along the polymer main chain and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C1-C12 alkoxy, C2-C18 (hetero)aryloxy, C2-C18 (hetero)arylamino, a C2-C18 (hetero)aryl group and (CH2)x′(OCH2CH2)y′OCH3 where x′ is independently an integer from 0-20 and y′ is independently an integer from 0 to 50; optional linkers L1 and L2 are each independently an aryl or a heteroaryl group evenly or randomly distributed along the polymer main chain and are substituted with one or more pendant chains terminated with: i) a functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated ester, N-hydroxysuccinimidyl, hydrazine, hydrazide, hydrazone, azide, alkyne, aldehyde, thiol, and protected groups thereof for conjugation to a molecule or biomolecule; or ii) a conjugated organic dye or biomolecule; G1 and G2 are each independently selected from hydrogen, halogen, alkyne, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic ester, boronic acid, optionally substituted fluorene and aryl or heteroaryl substituted with one or more pendant chains terminated with: i) a functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazine, hydrazide, hydrazone, azide, alkyne, aldehyde, thiol, and protected groups thereof for conjugation to a molecule or biomolecule; or ii) a conjugated organic dye or biomolecule; wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated ester, N-hydroxysuccinimidyl, hydrazines, hydrazide, hydrazone, azide, alkyne, aldehyde, and thiol within G1, G2, L1 or L2, or a conjugated organic dye or biomolecule; n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. 42. The method according to claim 41, wherein MU is selected from optionally substituted benzothiadiazole, benzoxidazole, benzoselenadiazole, benzotellurodiazole, naphthoselenadiazole, 4,7-di(thien-2-yl)-2,1,3-benzothiadiazole, squaraine dyes, quinoxaline, perylene, perylene diimide, diketopyrrolopyrrole, thienopyrazine low bandgap commercial dyes, olefin, and cyano-substituted olefins and isomers thereof. 43. The method according to claim 41, wherein MU is selected from the group consisting of a′-k′ having the structure: wherein * is a site for covalent attachment to unsaturated backbone and each R is a non-ionic side group capable of imparting solubility in water. 44. The method according to claim 43, wherein MU is selected from one of the following: wherein * is site for covalent attachment to unsaturated backbone. 45. The method according to claim 41, wherein MU is a phenyl. 46. The method according to claim 45, wherein MU is wherein *=site for covalent attachment to unsaturated backbone. 47. The method according to claim 41, wherein the non-ionic side group comprises an ethylene glycol oligomer. 48. The method according to claim 47, wherein Ar is substituted with one or more non-ionic side groups comprising mPEG5, mPEG8, mPEG11 or mPEG24. 49. The method according to claim 47, wherein Ar is substituted with one or more groups selected from (CH2)x′(OCH2CH2)y′OCH3 where x′ is independently an integer from 0-20 and y′ is independently an integer from 0 to 50, and a benzyl substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)zOCH3 where z is independently an integer from 0 to 50. 50. The method according to claim 47, wherein Ar is substituted with one or more (CH2)x′(OCH2CH2)y′OCH3 where x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50. 51. The method according to claim 47, wherein Ar is substituted with a dendrimer of PAMAM, PEA, PEHAM, PPI, tri-branched benzoate, or glycerol with a generation of 1 to 4 and optional terminal substitutions selected from ( - - - )CH2CH2O)jCH3 and ( - - - )(OCH2CH2)jCH3 where j is an integer from 0 to 25 and the dotted lines ( - - - ) are each independently selected from any one or a combination of, C1-C12 alkyl, C1-C12 alkoxy, C2-C12 alkene, amido, amino, aryl, (CH2)r(OCH2CH2)s(CH2)r where each r is independently an integer from 0-20, s is independently an integer from 0 to 50, carbamate, carboxylate, C3-C12 cycloalkyl, imido, phenoxy and C4-C18(hetero)aryl group. 52. The method according to claim 41, wherein Ar is a substituted fluorene unit. 53. The method according to claim 41, wherein L1 and/or L2 is conjugated to a signaling chromophore. 54. The method according to claim 41, wherein L1 and/or L2 are present and have the structure: wherein: *=site for covalent attachment to backbone; each R25 is independently a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl; (CH2)x(OCH2CH2)p(CH2)x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50; aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups; and at least one R25 is terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated ester, N-hydroxysuccinimidyl, hydrazine, hydrazide, hydrazone, azide, alkyne, aldehyde and thiols, or a conjugated organic dye or biomolecule. 55. The method according to claim 41, wherein at least one of G1 and G2 comprises a functional conjugation site. 56. The method according to claim 55, wherein at least one of G1 and G2 has the structure: wherein: *=site for covalent attachment to backbone; and R11 is a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl, (CH2)x(OCH2CH2)p(CH2)x wherein each x is independently an integer from 0-20 and p is an integer from 0 to 50, aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonate, sulfide, disulfide, or imido groups; and is terminated with: i) a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof, or ii) a conjugated organic dye or biomolecule. 57. The method according to claim 41, wherein at least one of G1 and G2 is selected from the group consisting of capping units 1-31 having the structures: wherein: *=site for covalent attachment to backbone; k is 2, 4, 8, 12 or 24; and R15 is selected from the group consisting of l-t having the structures: 58. The method according to claim 41, wherein the sensor is an antibody. 59. The method according to claim 41, wherein the method is configured for intracellular staining. 60. The method according to claim 41, wherein the method is configured for flow cytometry.
CROSS-REFERENCE This application is a continuation of application Ser. No. 15/239,713, filed Aug. 17, 2016; which application is a continuation of application Ser. No. 14/821,386, filed Aug. 7, 2015 and issued as U.S. Pat. No. 9,547,008; which application is a continuation of application Ser. No. 14/018,985, filed Sep. 5, 2013 and issued as U.S. Pat. No. 9,139,869; which application is a continuation of application Ser. No. 13/009,764, filed Jan. 19, 2011 and issued as U.S. Pat. No. 8,575,303, which claims the benefit of U.S. Provisional Application Ser. No. 61/296,379, filed Jan. 19, 2010 and U.S. Provisional Application Ser. No. 61/358,406, filed Jun. 24, 2010, which applications are incorporated herein by reference in their entireties. BACKGROUND OF THE INVENTION Fluorescent hybridization probes have developed into an important tool in the sequence-specific detection of DNA and RNA. The signals generated by the appended fluorescent labels (or dyes) can be monitored in real time and provide simple, rapid, and robust methods for the detection of biological targets and events. Utility has been seen in applications ranging from microarrays and real time PCR to fluorescence in situ hybridization (FISH). Recent work in the area of multichromophores, particularly regarding conjugated polymers (CPs) has highlighted the potential these materials have in significantly improving the detection sensitivity of such methods (Liu and Bazan, Chem. Mater., 2004). The light harvesting structures of these materials can be made water soluble and adapted to amplify the fluorescent output of various probe labels (See U.S. patent application Ser. No. 10/600,286, filed Jun. 20, 2003 and Gaylord, Heeger, and Bazan, Proc. Natl. Acad. Sci., 2002, both of which are incorporated herein by reference in their entirety). Results such as these indicate CPs to be highly promising in the field of nucleic acid diagnostics, particularly where sample quantities are scarce. However, there exist methods for the amplification (or replication) of nucleic acid targets, i.e., PCR. Comparatively, in the field of protein recognition, there are no such simple methods for amplifying the targeted materials. As such, signal enhancement arising from CP application is of high consequence in this area. Dye-labeled antibodies are regularly used for the detection of protein targets in applications such as immunohistochemistry, protein arrays, ELISA tests, and flow cytometry. Integrating CP materials into such methodologies promises to provide a dramatic boost in the performance of such assays, enabling detection levels previously unattainable with conventional fluorescent reporters (e.g., dyes). Beyond addition signal, one of the other key drivers in biological detection formats is the ability to detect multiple analytes in the same test or multiplexing. This is commonly achieved by using fluorescent reporters with operate at different, discernable wavelengths. CP materials are ideally suited to provide a platform for expanded multiplexing. This can be achieved by tuning the structure of different CPs to operate at different wavelengths or by incorporating a dye within the polymer-biomolecule conjugate. The material and methods to produce higher sensitivity biological assays and increase multiplexing are highly desired in both molecular (nucleic acid) and immunoassay formats. SUMMARY OF THE INVENTION Provided herein are water soluble conjugated polymers of Formula (I): wherein: each R is independently a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL; MU is a polymer modifying unit or band gap modifying unit that is evenly or randomly distributed along the polymer main chain and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C1-C12 alkoxy, C2-C18(hetero)aryloxy, C2-C18(hetero)arylamino, (CH2)x′(OCH2CH2)y′OCH3 where each x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50, or a C2-C18(hetero)aryl group; each optional linker L1 and L2 are aryl or heteroaryl groups evenly or randomly distributed along the polymer main chain and are substituted with one or more pendant chains terminated with a functional group for conjugation to another substrate, molecule or biomolecule selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof; G1 and G2 are each independently selected from hydrogen, halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiol, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters, boronic acids, optionally substituted fluorene and aryl or heteroaryl substituted with one or more pendant chains terminated with a functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule; wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, and thiols within G1, G2, L1 or L2 that allows, for functional conjugation to another molecule, substrate or biomolecule; each dashed bond, , is independently a single bond, triple bond or optionally substituted vinylene (—CR5═CR5—) wherein each R5 is independently hydrogen, cyano, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group, wherein each C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, or C1-C12 haloalkyl; and n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. In one aspect, water soluble conjugated polymers of Formula (I) have the structure of Formula (Ia): wherein R, L1, L2, G1, G2, MU, a, b, c, d and n are described previously for formula (I). In some embodiments, each R is independently (CH2)x(OCH2CH2)yOCH3 where each x is independently an integer from 0-20, each y is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)zOCH3 where each z is independently an integer from 0 to 50. In some instances, each R is (CH2)3(OCH2CH2)11CH3. In other embodiments, each R is a benzyl substituted with at least one (OCH2CH2)10OCH3 group. In some instances, the benzyl is substituted with two (OCH2CH2)10OCH3 groups. In other instances, the benzyl is substituted with three (OCH2CH2)10OCH3 groups. In some embodiments, optional linkers L1 or L2 have the structure: *=site for covalent attachment to unsaturated backbone; wherein R3 is independently hydrogen, halogen, alkoxy(C1-C12), C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group, wherein each C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, or C1-C12 haloalkyl; and q is an integer from 0 to 4. In other embodiments, optional linkers L1 or L2 have the structure: *=site for covalent attachment to unsaturated backbone wherein A is a site for conjugation, chain extension or crosslinking and is [O—CH2—CH2]q—W, or (C1-C12)alkoxy-X or C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule; W is —OH or —COOH; X is —NH2, —NHCOOH, —NHCOOC(CH3)3, —NHCO(C3-C12)cycloalkyl(C1-C4)alkyl-N-maleimide; or —NHCO[CH2—CH2—O]tNH2; q is an integer from 1 to 20; and t is an integer from 1 to 8. In yet other embodiments, optional linkers L1 or L2 have the structure: *=site for covalent attachment to backbone wherein R25 are each independently any one of or a combination of a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl, (CH2)x(OCH2CH2)p(CH2)x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups; wherein at least one R25 is terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In further embodiments, optional linkers L1 or L2 have the structure: *=site for covalent attachment to unsaturated backbone; wherein R35 is any one of or a combination of a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl, (CH2)x(OCH2CH2)p(CH2)x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In further embodiments, optional linkers L1 or L2 are selected from the group consisting of a-h having the structures: *=site for covalent attachment to unsaturated backbone; wherein R′ is independently H, halogen, C1-C12 alkyl, (C1-C12 alkyl)NH2, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C2-C18(hetero)aryl, C2-C18(hetero)arylamino, —[CH2—CH2]r′—Z1, or (C1-C12)alkoxy-X1; and wherein Z1 is —OH or —COOH; X1 is —NH2, —NHCOOH, —NHCOOC(CH3)3, —NHCO(C3-C12)cycloalkyl(C1-C4)alkyl-N-maleimide; or —NHCO[CH2—CH2—O]s′(CH2)s′NH2; r′ is an integer from 1 to 20; and each s′ is independently an integer from 1 to 20, (CH2)3(OCH2CH2)x″OCH3 where x″ is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)y—OCH3 where each y″ is independently an integer from 0 to 50 and R′ is different from R; wherein k is 2, 4, 8, 12 or 24; wherein R15 is selected from the group consisting of l-t having the structure: *=site for covalent attachment to backbone. In yet further embodiments, optional linkers L1 or L2 are In some embodiments, G1 and G2 are each independently selected from hydrogen, halogen, alkyne, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters, boronic acids, optionally substituted fluorine and aryl or heteroaryl substituted with one or more pendant chains terminated with a functional group, molecule or biomolecule selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In some embodiments, G1 and G2 each independently have the structure wherein R11 is any one of or a combination of a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl, (CH2)x(OCH2CH2)p(CH2)x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In other embodiments, G1 and G2 are each independently selected from the group consisting of 1-31 having the structures: *=site for covalent attachment to backbone wherein R15 is selected from the group consisting of l-t having the structure: and k is 2, 4, 8, 12 or 24. In further embodiments, G1 and G2 are optionally substituted aryl or heteroaryl wherein the optional substituent is selected from halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiol, boronic acid, boronate radical, boronic esters and optionally substituted fluorene. In some embodiments, G1 and G2 are the same. In other embodiments, G1 and G2 are different. In further embodiments, the polymer contains a single conjugation site at only one terminus of the polymer chain G1 or G2. In yet further embodiments, G1 and G2 is In some embodiments, MU is selected from the group consisting of a′-k′ having the structure: *=site for covalent attachment to unsaturated backbone wherein R is a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL. In some embodiments, the water soluble conjugated polymer has the structure of formula: wherein at least one of G1 or G2 comprises a functional conjugation site. In some embodiments, the water soluble conjugated polymer has the structure of formula: wherein L1 comprises a functional conjugation site. In some embodiments, the water soluble conjugated polymer has the structure of formula: wherein at least one of G1 or G2 comprises a functional conjugation site. In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In some instances, a signaling chromophore is attached to the polymer via the NH2 group. In certain instances, the signaling chromophore is Cy3 or Dylight 594 dye. In certain instances, the linker, is about 10% of the entire polymer. In other instances, the polymer is conjugated to a secondary dye reporter and an antibody. In some embodiments of conjugated polymers described herein, the polymer is further conjugated to additional molecules. In some embodiments, the polymer is conjugated to a streptavidin, antibody or nucleic acid and used as a direct fluorescent reporter. In certain embodiments, the polymer is conjugated to a streptavidin. In other embodiments, the polymer is conjugated to thiol groups at the hinge region of an antibody. In yet other embodiments, the polymer is conjugated to an amine group on a protein which is modified with a heterobifunctional linker. In further embodiments, the polymer is conjugated to a nucleic acid. In yet further embodiments, the polymer is conjugated to an antibody. In certain instances, the polymer is conjugated to a monoclonal antibody, a secondary antibody or a primary antibody. In other instances, a polymer antibody conjugate is excited at about 405 nm in a flow cytometry assay where the specific signal is at least 3 fold greater than the same antibody conjugated to Pacific Blue. In some embodiments of conjugated polymers described herein, the polymer is purified by ion exchange chromatography. In other embodiments, the polymer is >95% pure. In some embodiments of conjugated polymers described herein, the polymer is used in flow cytometry assays to identify different cell markers or cell types. In other embodiments, the polymer is used to sort cells. In yet other embodiments, the polymer is used to sort cells for use in therapeutics. In some embodiments of conjugated polymers described herein, the polymer is used for intracellular staining. In certain instances, the polymer is used in flow cytometry assays to identify different cell markers or cell types. In some embodiments of conjugated polymers described herein, the polymer comprises a minimum number average molecular weight of greater than 40,000 g/mol and a water solubility of greater than 50 mg/mL in pure water or a phosphate buffered saline solution. In some embodiments of conjugated polymers described herein, the polymer comprises at least two unique conjugation linkers which can conjugated to two unique materials. Also provided herein are assay methods comprising providing a sample that is suspected of containing a target biomolecule; providing a sensor protein conjugated to at least one signaling chromophore and is capable of interacting with the target biomolecule or a target-associated biomolecule; providing a water soluble conjugated polymer described herein; contacting the sample with the sensor protein and the conjugated polymer in a solution under conditions in which the sensor protein can bind to the target biomolecule or a target-associated biomolecule if present; applying a light source to the sample that can excite the conjugated polymer; and detecting whether light is emitted from the signaling chromophore. In some embodiments, the sensor protein is an antibody. In other embodiments, the sensor protein comprises a plurality of sensor proteins conjugated to a plurality of signaling chromophores, wherein at least two of the plurality of chromophores emit different wavelengths of light upon energy transfer from the multichromophore. Also provided herein are conjugated polymer complexes comprising a polymer coupled to at least one biomolecule selected from the group consisting of a sensor biomolecule, a bioconjugate and a target biomolecule wherein the polymer is covalently bound by at least one bioconjugation site pendant thereto, and the polymer comprises a signaling chromophore or a signaling chromophore optionally is covalently bound to the polymer or the sensor biomolecule; wherein the polymer comprises the structure of formula: wherein: each R is a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL; MU is a polymer modifying unit or band gap modifying unit that is evenly or randomly distributed along the polymer main chain and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C1-C12 alkoxy, C2-C18(hetero)aryloxy, C2-C18(hetero)arylamino, (CH2)x′(OCH2CH2)y′OCH3 where each x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50, or a C2-C18(hetero)aryl group; each optional linker L1 and L2 are aryl or heteroaryl groups evenly or randomly distributed along the polymer main chain and are substituted with one or more pendant chains terminated with a functional group for conjugation to another molecule, substrate or biomolecule selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof; G1 and G2 are each independently selected from hydrogen, halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiol, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters, boronic acids, optionally substituted fluorene and aryl or heteroaryl substituted with one or more pendant chains terminated with a functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule; wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, and thiols within G1, G2, L1 or L2 that allows, for functional conjugation to another molecule, substrate or biomolecule; n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. In some embodiments, the sensor biomolecule is selected from the group consisting of an avidin, streptavidin, neutravidin, avidinDN, and avidinD. In other embodiments, the conjugated polymer complex is further configured to bind to a complex selected from the group consisting of a biotin-labeled antibody, biotin-labeled protein, and biotin-labeled target biomolecule. In further embodiments, the sensor biomolecule is an antibody. In yet further embodiments, both the signaling chromophore and the sensor biomolecule are covalently linked to the multichromophore through a plurality of linkers. In some other embodiments, both the signaling chromophore and the sensor biomolecule are covalently linked to the polymer through a central linking site that covalently binds the polymer, the signaling chromophore and the sensor biomolecule. In yet other embodiments, the signaling chromophore, when covalently bound to the polymer or the sensor biomolecule, is an organic dye. Also provided herein are water soluble conjugated polymer having the structure of Formula (Ia): wherein: each R is independently (CH2)x(OCH2CH2)yOCH3 where each x is independently an integer from 0-20, y is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)zOCH3 where each z is independently an integer from 0 to 50; each optional linker L1 or L2 is selected from the group consisting of a-i having the structure *=site for covalent attachment to unsaturated backbone wherein R′ is independently H, halogen, C1-C12 alkyl, (C1-C12 alkyl)NH2, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C2-C18(hetero)aryl, C2-C18(hetero)arylamino, —[CH2—CH2]r′—Z1, or (C1-C12)alkoxy-X1; and wherein Z1 is —OH or —COOH; X1 is —NH2, —NHCOOH, —NHCOOC(CH3)3, —NHCO(C3-C12)cycloalkyl(C1-C4)alkyl-N-maleimide; or —NHCO[CH2—CH2—O]s′(CH2)s′NH2; r′ is an integer from 1 to 20; and each s′ is independently an integer from 1 to 20, (CH2)3(OCH2CH2)x″OCH3 where x″ is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)y″OCH3 where each y″ is independently an integer from 0 to 50 and R′ is different from R; wherein R15 is selected from the group consisting of l-t having the structure: and k is 2, 4, 8, 12 or 24; *=site for covalent attachment to backbone MU is a polymer modifying unit or band gap modifying unit that is selected from the group consisting of a′-k′ having the structure: *=site for covalent attachment to unsaturated backbone; wherein R is a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL; G1 and G2 are each independently selected from the group consisting of 1-31 having the structures: wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, and thiols within G1, G2, L1 or L2 that allows, for functional conjugation to another molecule, substrate or biomolecule; n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. Also provided herein are water soluble conjugated polymer having the structure of Formula: wherein Ar is an aryl or heteroaryl and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C1-C12 alkoxy, C2-C18(hetero)aryloxy, C2-C18(hetero)arylamino, (CH2)x′(OCH2CH2)y′OCH3 where each x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50; and dashed bonds, L1, L2, G1, G2, MU, a, b, c, d and n are described previously for formula (I). INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: FIG. 1. Schematic of binding of a conjugated polymer in one embodiment of the invention. FIG. 2. Schematic of a bioconjugated polymer of one embodiment of the invention. FIG. 3. Schematic of exemplary conjugated polymers conjugated (A) antibody; (B) an avidin; (C) nucleic acid; (D) dye, e.g., chromophore. FIG. 4. Schematic of (A) a polymer conjugated to dye-labeled antibody resulting in FRET; (B) a polymer conjugated dye-labeled strepavidin resulting in FRET; (C) nucleic acid probe sequences labeled with a quencher molecule conjugated to a conjugated polymer; (D) nucleic acid probe sequences labeled with a quencher molecule conjugated polymer-dye tandem complex. FIG. 5. Schematic of various methods of assaying for a target biomolecule or target associated biomolecule. (A) Conjugated polymer linked to a bioconjugate; (B) polymer and dye labeled antibodies recognize a common target; (C) sensor biomolecule conjugated to both a dye and a second bioconjugate; (D) second bioconjugate and the signaling chromophore both conjugated to a nucleic acid. FIG. 6. Schematic of an addition of a second linking site within the polymer. FIG. 7. Schematic of a polymer conjugated to a dye and a biomolecule and resulting energy transfer (A) polymer is conjugated to both a bioconjugate; (B) polymer is conjugated to a strepavidin and a dye; (C) polymer is conjugated to a nucleic acid and a dye. FIG. 8. Schematic of indirect associations with a sensor biomolecule or target associated biomolecule. (A) biotinylated antibody interacting with a covalent conjugate of the conjugated polymer; (B) biotinylated antibody conjugated polymer-dye tandem complex; (C) biotinylated nucleic acid interacting with a covalent conjugate of the conjugated polymer; (D) biotinylated nucleic conjugated polymer-dye tandem complex; (E) nucleic acid with digoxygenin moiety interacting with a covalent conjugate of the conjugated polymer; (F) nucleic acid with digoxygenin moiety conjugated polymer-dye tandem complex. FIG. 9. Schematic of exemplary conjugated polymers conjugated to secondary antibodies ( ) and primary antibodies (B). FIG. 10. Schematic of a sandwich-type complex. (A) conjugated polymer complex bioconjugated to a strepavidin; (B) biotin-labeled 1° antibody e used to probe the target protein directly. FIG. 11. Schematic of appending one or two phenyl capping units to a fluorene polymer. FIG. 12. Block diagram showing a representative example logic device. FIG. 13. Block diagram showing a representative example of a kit. FIG. 14. Schematic of a streptavidin conjugation with a conjugated polymer and the resulting conjugate structure (top) and Coomassie stained agarose gel representative of the streptavidin-attached CP (below). FIG. 15. Representative acrylamide gel depiction of biotinylated polymer alone or bound to Cy5-labeled streptavidin. FIG. 16. Schematic of streptavidin-attached conjugated polymer of FIG. 14 binding to biotinylated microspheres (top) and plot of fluorescence excitation of control biotinylated microspheres and microspheres bound to streptavidin conjugated polymer. FIG. 17. Schematic of streptavidin-attached conjugated polymer of FIG. 14 selectively bound to biotinylated microspheres and energy transfer to dye acceptors on co-localized streptavidin-dye conjugates (top) and plot of energy transfer from streptavidin-attached conjugated polymer to dye acceptor (bottom). FIG. 18. Schematic of biotinylated polymer of FIG. 14 binding to streptavidin coated microspheres (top) and plot of fluorescence excitation of control streptavidin coated microspheres and microspheres bound to biotinylated polymer. FIG. 19. Schematic of biotinylated polymer of FIG. 14 binding to dye-labeled streptavidin conjugates and FRET (top); plot of energy transfer from biotinylated polymer to two different dye acceptors (bottom left) and titration plot of polymer saturation (bottom right). FIG. 20. Flow cytometry analysis of CD4 marking of Cyto-trol cells with 440 nm polymer-streptavidin-conjugates. FIG. 21. (A) Polymer structure of Example 38b conjugated to (from left to right) FITC, Cy3, DyLight 594 and DyLight633; (B) Comparison of the fluorescence of the dye (DyLight594) excited near its absorbance maximum (lower curve) and polymer-dye conjugate excited at 405 nm (upper curve); (C) Comparison of the fluorescent signal of the base polymer (no dye, peak emission near 420 nm) to that of the polymer-dye conjugate (peak emission near 620 nm). FIG. 22. Plot of flow testing of monoclonal antibody (antiCD4) conjugates on whole lysed blood samples. FIG. 23. Plot of florescence of a dye (DyLight594) and a polymer-dye conjugate by excitation of dye at 594 nm and the polymer-dye conjugate at 380 nm. FIG. 24. Plot of fluorescent immunoassay (ELISA) with streptavidin-attached conjugated polymer. FIG. 25. Plot of fluorescent intensity vs. temperature of a DNA oligomer-polymer conjugate hybridized to a target. FIG. 26. Ion exchange chromatogram for a polymer antibody conjugate to remove free polymer (left) and an SEC chromatogram showing the separation of final conjugate from free antibody. In both chromatograms absorbance was monitored at 280 nm (lower curves) and 407 nm (upper curves). FIG. 27. Sandwich immunoassay on Luminex assay (left) and corresponding results on the Luminex system using 532 nm excitation of both the conjugated polymer and PE streptavidin detection conjugates. FIG. 28. Data on left show results obtained with compensation beads while the data set on the right results from a 4 color assay on human blood samples. FIGS. 29. (A) and (B) Schematic of covalent linkage of conjugated polymer to 2° antibody. FIG. 30. Schematic of conjugated polymers in Fluorescent Immuno Assay (FIA). (A) conjugated polymer covalently linked to a detection antibody; (B) biotin binding protein covalently bound to the conjugated polymer and interacting with a biotinylated detection antibody; (C) secondary antibody covalently linked to the conjugated polymer and interacting with a detection antibody. FIG. 31. (A) Schematic of nucleic acid probe sequences labeled with a quencher molecule conjugated to a conjugated polymer; (B) nucleic acid probe sequences labeled with a quencher molecule conjugated to a conjugated polymer-dye tandem complex. FIG. 32. Schematic of modifications of the HybProbe detection technique. (A) conjugated polymer covalently linked to the donor probe and resulting energy transfer to acceptor probe; (B) “Signal off” modification of the HybProbe approach where the conjugated polymer is quenched by an acceptor probe. FIG. 33. Comparison of non-specific binding in various polymers (top) in a Jurkat cell (lymphocyte cell line) model; (bottom) plot ranking the polymers in terms of signal generated purely by non-specific binding (NSB). FIG. 34. Histograms collected from flow cytometry analysis (405 nm excitation in a BD LSR-II cytometer) using a Jurkat cell line; (left) unstained cells and a negative control, anionic P4 polymer; (middle) range of different polymer and polymer side chain combinations tested on the same cells; (right) neutral polymer P20 showed almost no off set from the untreated cells. FIG. 35. Gel electrophoresis depicting relative mobility of avidin as a function of the degree of conjugation with polymer AA1. FIG. 36. Fractionation of crude polymer-avidin conjugate mixtures on a Superdex 200 size exclusion column; (top) monitoring fractions by UV absorbance; (bottom) gel electrophoresis of selected fractions to visualize the degree to which avidin was attached to polymer. FIG. 37. Gel electrophoresis of conjugation reactions performed with polymer in varying molar excess to streptavidin; (left) UV illumination; (right) 532 nm excitation. FIG. 38. Plot depicting purification of polymer streptavidin conjugates with polymers exemplified in Example 9, denoted P30, (top) crude samples; (bottom) purified conjugates). DETAILED DESCRIPTION OF THE INVENTION Before the present invention is described in further detail, it is to be understood that this invention is not limited to the particular methodology, devices, solutions or apparatuses described, as such methods, devices, solutions or apparatuses can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention. Use of the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, reference to “an aggregation sensor” includes a plurality of aggregation sensors, reference to “a probe” includes a plurality of probes, and the like. Additionally, use of specific plural references, such as “two,” “three,” etc., read on larger numbers of the same subject less the context clearly dictates otherwise. Terms such as “connected,” “attached,” “conjugated” and “linked” are used interchangeably herein and encompass direct as well as indirect connection, attachment, linkage or conjugation unless the context clearly dictates otherwise; in one example, the phrase “conjugated polymer” is used in accordance with its ordinary meaning in the art and refers to a polymer containing an extended series of unsaturated bonds, and that context dictates that the term “conjugated” should be interpreted as something more than simply a direct or indirect connection, attachment or linkage. Where a range of values is recited, it is to be understood that each intervening integer value, and each fraction thereof, between the recited upper and lower limits of that range is also specifically disclosed, along with each subrange between such values. The upper and lower limits of any range can independently be included in or excluded from the range, and each range where either, neither or both limits are included is also encompassed within the invention. Where a value being discussed has inherent limits, for example where a component can be present at a concentration of from 0 to 100%, or where the pH of an aqueous solution can range from 1 to 14, those inherent limits are specifically disclosed. Where a value is explicitly recited, it is to be understood that values which are about the same quantity or amount as the recited value are also within the scope of the invention, as are ranges based thereon. Where a combination is disclosed, each subcombination of the elements of that combination is also specifically disclosed and is within the scope of the invention. Conversely, where different elements or groups of elements are disclosed, combinations thereof are also disclosed. Where any element of an invention is disclosed as having a plurality of alternatives, examples of that invention in which each alternative is excluded singly or in any combination with the other alternatives are also hereby disclosed; more than one element of an invention can have such exclusions, and all combinations of elements having such exclusions are hereby disclosed. Unless defined otherwise or the context clearly dictates otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are now described. All publications mentioned herein are hereby incorporated by reference for the purpose of disclosing and describing the particular materials and methodologies for which the reference was cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. Definitions In describing the present invention, the following terms will be employed, and are intended to be defined as indicated below. “Alkyl” refers to a branched, unbranched or cyclic saturated hydrocarbon group of 1 to 24 carbon atoms optionally substituted at one or more positions, and includes polycyclic compounds. Examples of alkyl groups include optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-decyl, hexyloctyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like, as well as cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and norbornyl. The term “lower alkyl” refers to an alkyl group of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Exemplary substituents on substituted alkyl groups include hydroxyl, cyano, alkoxy, ═O, ═S, —NO2, halogen, haloalkyl, heteroalkyl, carboxyalkyl, amine, amide, thioether and —SH. “Alkoxy” refers to an “—Oalkyl” group, where alkyl is as defined above. A “lower alkoxy” group intends an alkoxy group containing one to six, more preferably one to four, carbon atoms. “Alkenyl” refers to a branched, unbranched or cyclic hydrocarbon group of 2 to 24 carbon atoms containing at least one carbon-carbon double bond optionally substituted at one or more positions. Examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), 1-methylvinyl, cyclopropenyl, 1-butenyl, 2-butenyl, isobutenyl, 1,4-butadienyl, cyclobutenyl, 1-methylbut-2-enyl, 2-methylbut-2-en-4-yl, prenyl, pent-1-enyl, pent-3-enyl, 1,1-dimethylallyl, cyclopentenyl, hex-2-enyl, 1-methyl-1-ethylallyl, cyclohexenyl, heptenyl, cycloheptenyl, octenyl, cyclooctenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl and the like. Preferred alkenyl groups herein contain 2 to 12 carbon atoms. The term “lower alkenyl” intends an alkenyl group of 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. The term “cycloalkenyl” intends a cyclic alkenyl group of 3 to 8, preferably 5 or 6, carbon atoms. Exemplary substituents on substituted alkenyl groups include hydroxyl, cyano, alkoxy, ═O, ═S, —NO2, halogen, haloalkyl, heteroalkyl, amine, thioether and —SH. “Alkenyloxy” refers to an “—Oalkenyl” group, wherein alkenyl is as defined above. “Alkylaryl” refers to an alkyl group that is covalently joined to an aryl group. Preferably, the alkyl is a lower alkyl. Exemplary alkylaryl groups include benzyl, phenethyl, phenopropyl, 1-benzylethyl, phenobutyl, 2-benzylpropyl and the like. “Alkylaryloxy” refers to an “—Oalkylaryl” group, where alkylaryl is as defined above. “Alkynyl” refers to a branched or unbranched hydrocarbon group of 2 to 24 carbon atoms containing at least one —C “Amide” refers to —C(O)NR′R″, where R′ and R″ are independently selected from hydrogen, alkyl, aryl, and alkylaryl. “Amine” refers to an —N(R′)R″ group, where R′ and R″ are independently selected from hydrogen, alkyl, aryl, and alkylaryl. “Aryl” refers to an aromatic group that has at least one ring having a conjugated pi electron system and includes carbocyclic, heterocyclic, bridged and/or polycyclic aryl groups, and can be optionally substituted at one or more positions. Typical aryl groups contain 1 to 5 aromatic rings, which may be fused and/or linked. Exemplary aryl groups include phenyl, furanyl, azolyl, thiofuranyl, pyridyl, pyrimidyl, pyrazinyl, triazinyl, biphenyl, indenyl, benzofuranyl, indolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridopyridinyl, pyrrolopyridinyl, purinyl, tetralinyl and the like. Exemplary substituents on optionally substituted aryl groups include alkyl, alkoxy, alkyl carboxy, alkenyl, alkenyloxy, alkenylcarboxy, aryl, aryloxy, alkylaryl, alkylaryloxy, fused saturated or unsaturated optionally substituted rings, halogen, haloalkyl, heteroalkyl, —S(O)R, sulfonyl, —SO3R, —SR, —NO2, —NRR′, —OH, —CN, —C(O)R, —OC(O)R, —NHC(O)R, —(CH2)n—CO2R or —(CH2)n—CONRR′ where n is 0-4, and wherein R and R′ are independently H, alkyl, aryl or alkylaryl. “Aryloxy” refers to an “—Oaryl” group, where aryl is as defined above. “Carbocyclic” refers to an optionally substituted compound containing at least one ring and wherein all ring atoms are carbon, and can be saturated or unsaturated. “Carbocyclic aryl” refers to an optionally substituted aryl group wherein the ring atoms are carbon. “Halo” or “halogen” refers to fluoro, chloro, bromo or iodo. “Halide” refers to the anionic form of the halogens. “Haloalkyl” refers to an alkyl group substituted at one or more positions with a halogen, and includes alkyl groups substituted with only one type of halogen atom as well as alkyl groups substituted with a mixture of different types of halogen atoms. Exemplary haloalkyl groups include trihalomethyl groups, for example trifluoromemyl. “Heteroalkyl” refers to an alkyl group wherein one or more carbon atoms and associated hydrogen atom(s) are replaced by an optionally substituted heteroatom, and includes alkyl groups substituted with only one type of heteroatom as well as alkyl groups substituted with a mixture of different types of heteroatoms. Heteroatoms include oxygen, sulfur, and nitrogen. As used herein, nitrogen heteroatoms and sulfur heteroatoms include any oxidized form of nitrogen and sulfur, and any form of nitrogen having four covalent bonds including protonated forms. An optionally substituted heteroatom refers to replacement of one or more hydrogens attached to a nitrogen atom with alkyl, aryl, alkylaryl or hydroxyl. “Heterocyclic” refers to a compound containing at least one saturated or unsaturated ring having at least one heteroatom and optionally substituted at one or more positions. Typical heterocyclic groups contain 1 to 5 rings, which may be fused and/or linked, where the rings each contain five or six atoms. Examples of heterocyclic groups include piperidinyl, morpholinyl and pyrrolidinyl. Exemplary substituents for optionally substituted heterocyclic groups are as for alkyl and aryl at ring carbons and as for heteroalkyl at heteroatoms. “Heterocyclic aryl” refers to an aryl group having at least 1 heteroatom in at least one aromatic ring. Exemplary heterocyclic aryl groups include furanyl, thienyl, pyridyl, pyridazinyl, pyrrolyl, N-lower alkyl-pyrrolo, pyrimidyl, pyrazinyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl, imidazolyl, bipyridyl, tripyridyl, tetrapyridyl, phenazinyl, phenanthrolinyl, purinyl, perylene, perylene diimide, diketopyrrolopyrrole, benzothiadiazol, benzoxadiazol, thienopyrazine and the like. “Hydrocarbyl” refers to hydrocarbyl substituents containing 1 to about 20 carbon atoms, including branched, unbranched and cyclic species as well as saturated and unsaturated species, for example alkyl groups, alkylidenyl groups, alkenyl groups, alkylaryl groups, aryl groups, and the like. The term “lower hydrocarbyl” intends a hydrocarbyl group of one to six carbon atoms, preferably one to four carbon atoms. A “substituent” refers to a group that replaces one or more hydrogens attached to a carbon or nitrogen. Exemplary substituents include alkyl, alkylidenyl, alkylcarboxy, alkoxy, alkenyl, alkenylcarboxy, alkenyloxy, aryl, aryloxy, alkylaryl, alkylaryloxy, —OH, amide, carboxamide, carboxy, sulfonyl, ═O, ═S, —NO2, halogen, haloalkyl, fused saturated or unsaturated optionally substituted rings, —S(O)R, —SO3R, —SR, —NRR′, —OH, —CN, —C(O)R, —OC(O)R, —NHC(O)R, —(CH2)nCO2R or —(CH2)nCONRR′ where n is 0-4, and wherein R and R′ are independently H, alkyl, aryl or alkylaryl. Substituents also include replacement of a carbon atom and one or more associated hydrogen atoms with an optionally substituted heteroatom. “Sulfonyl” refers to —S(O)2R, where R is alkyl, aryl, —C(CN)═C-aryl, —CH2CN, alkylaryl, or amine. “Thioamide” refers to —C(S)NR′R″, where R′ and R″ are independently selected from hydrogen, alkyl, aryl, and alkylaryl. “Thioether” refers to —SR, where R is alkyl, aryl, or alkylaryl. As used herein, the term “binding pair” refers to first and second molecules that bind specifically to each other with greater affinity than to other components in the sample. The binding between the members of the binding pair is typically noncovalent. Exemplary binding pairs include immunological binding pairs (e.g. any haptenic or antigenic compound in combination with a corresponding antibody or binding portion or fragment thereof, for example digoxigenin and anti-digoxigenin, fluorescein and anti-fluorescein, dinitrophenol and anti-dinitrophenol, bromodeoxyuridine and anti-bromodeoxyuridine, mouse immunoglobulin and goat anti-mouse immunoglobulin) and nonimmunological binding pairs (e.g., biotin-avidin, biotin-streptavidin, hormone [e.g., thyroxine and cortisol]-hormone binding protein, receptor-receptor agonist or antagonist (e.g., acetylcholine receptor-acetylcholine or an analog thereof) IgG-protein A, lectin-carbohydrate, enzyme-enzyme cofactor, enzyme-enzyme-inhibitor, and complementary polynucleotide pairs capable of forming nucleic acid duplexes) and the like. One or both member of the binding pair can be conjugated to additional molecules. The terms “polynucleotide,” “oligonucleotide,” “nucleic acid” and “nucleic acid molecule” are used interchangeably herein to refer to a polymeric form of nucleotides of any length, and may comprise ribonucleotides, deoxyribonucleotides, analogs thereof, or mixtures thereof. These terms refer only to the primary structure of the molecule. Thus, the terms includes triple-, double- and single-stranded deoxyribonucleic acid (“DNA”), as well as triple-, double- and single-stranded ribonucleic acid (“RNA”). It also includes modified, for example by alkylation, and/or by capping, and unmodified forms of the polynucleotide. Additional details for these terms as well as for details of base pair formation can be found in U.S. application Ser. No. 11/344,942, filed Jan. 31, 2006, which is incorporate herein by reference in its entirety. “Complementary” or “substantially complementary” refers to the ability to hybridize or base pair between nucleotides or nucleic acids, such as, for instance, between a sensor peptide nucleic acid and a target polynucleotide. Complementary nucleotides are, generally, A and T (or A and U), or C and G. Two single-stranded polynucleotides or PNAs are said to be substantially complementary when the bases of one strand, optimally aligned and compared and with appropriate insertions or deletions, pair with at least about 80% of the bases of the other strand, usually at least about 90% to 95%, and more preferably from about 98 to 100%. Alternatively, substantial complementarity exists when a polynucleotide or PNA will hybridize under selective hybridization conditions to its complement. Typically, selective hybridization will occur when there is at least about 65% complementary over a stretch of at least 14 to 25 bases, preferably at least about 75%, more preferably at least about 90% complementary. See, M. Kanehisa Nucleic Acids Res. 12:203(1984). “Preferential binding” or “preferential hybridization” refers to the increased propensity of one polynucleotide or PNA to bind to its complement in a sample as compared to a noncomplementary polymer in the sample. Hybridization conditions for polynucleotides will typically include salt concentrations of less than about 1M, more usually less than about 500 mM and preferably less than about 200 mM. In the case of hybridization between a peptide nucleic acid and a polynucleotide, the hybridization can be done in solutions containing little or no salt. Hybridization temperatures can be as low as 5° C., but are typically greater than 22° C., more typically greater than about 30° C., and preferably in excess of about 37° C. Longer fragments may require higher hybridization temperatures for specific hybridization. Other factors may affect the stringency of hybridization, including base composition and length of the complementary strands, presence of organic solvents and extent of base mismatching, and the combination of parameters used is more important than the absolute measure of any one alone. Other hybridization conditions which may be controlled include buffer type and concentration, solution pH, presence and concentration of blocking reagents to decrease background binding such as repeat sequences or blocking protein solutions, detergent type(s) and concentrations, molecules such as polymers which increase the relative concentration of the polynucleotides, metal ion(s) and their concentration(s), chelator(s) and their concentrations, and other conditions known in the art. “Multiplexing” herein refers to an assay or other analytical method in which multiple analytes can be assayed simultaneously. “Having” is an open ended phrase like “comprising” and “including,” and includes circumstances where additional elements are included and circumstances where they are not. “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. The embodiments disclosed herein relate generally to compositions of conjugated polymer materials that contain active functional groups for conjugation (or attachment) to other molecules, substrates or the like. Certain embodiments describe methods and compositions that provide for specific control of the incorporation and subsequent conjugation of such functional sites. Linkers can be incorporated at one or both ends of a conjugated polymer chain or internally controlled by ratio of monomers used in the polymerizations. Such linkers can be the same or different to allow for more than one distinct entity to be attached to the conjugated polymer structure. Further embodiments describe conjugated polymer compositions that not only provide for active conjugation sites but also are solubilized through the use of non-ionic side chains (no formal charges). Such embodiments exhibit exceptional water solubility and provide minimal interactions with biological molecules and other common biological assay components. The embodiments disclosed herein further relate generally to assays and complexes including conjugated polymers useful for the identification of target biomolecules or biomolecules associated with target molecules through enhanced signal afforded by their unique properties. In certain general embodiments the conjugated polymer serves directly as the optical reporter bound to a biomolecule, substrate or other assay component. The conjugated polymers act as extended light harvesting structures that when excited can absorb more energy than conventional organic dyes. The polymer then re-emits the light which can be detected or measured. The signals generated from such conjugated polymer complexes can be significantly greater than those obtained from other fluorescent reporters. In other embodiments one aspect includes energy transfer from conjugated polymers to dyes bound to the polymer or to a sensor which can be a biomolecule including a bioconjugate (e.g., an antibody, a streptavidin or nucleic acid sequence). In such embodiments it is common to observe amplified dye signal (relative to direct dye excitation) as a result of the conjugated polymer excitation and subsequent energy transfer. Further it is possible to use a range of dyes with varying energy to create a basis for a multicolor or multiplex detection format. In certain embodiments the neutral conjugated polymers are bound to antibodies for the identification of specific cell markers and cell types in flow cytometry and cell sorting assays. In other embodiments the conjugated polymers are further bound to a secondary dye reporter. In further embodiments the polymer and polymer-dye structures are bound to monoclonal antibodies. In other embodiments the neutral conjugated polymers are bound to antibodies for use in various sandwich immunoassays. In one embodiment, an approach modifying a format as followed in relation to nucleic acid sensor assays as described in Gaylord, Heeger, and Bazan, J. Am. Chem. Soc., 2003 can be followed. Specifically, signal amplification of conjugated polymers can be based on binding events to indicate a hybridization event. Any established conjugated polymers can be chosen as the donor, and one or more dye, preferably a dye with a history of efficient energy transfer, for example, fluorescein and Cy3, can be chosen as the acceptors. It is envisioned that the dye can be directly conjugated to a sensor molecule. As shown schematically in FIG. 1, the sensor can be a biomolecule (e.g., an antibody) in a solution or on a substrate, to which conjugated polymers can be added. In the embodiment shown in FIG. 1, a dye can be covalently linked (bioconjugated) to an antibody (Y-shaped structure), which possesses a net negative charge. Addition of conjugated polymers (shown as wavy lines) can result in interaction or binding between the conjugated polymer and the antibody, bringing the conjugated polymers and dye into close proximity. Interaction or binding can be achieved by any known method including, but not limited to, avidin/biotin labeling. Distance requirements for fluorescence resonance energy transfer (FRET) can thus be met, and excitation of the polymer with light (shown as hν) results in amplified dye emission. It is envisioned that the conjugated polymers can be excited at a wavelength where the dye does not have significant absorbance. In one embodiment the dye emission can be at a longer wavelength than the conjugated polymer emission. In use it is envisioned that an assay method can include the steps of providing a sample that is suspected of containing a target biomolecule, providing a sensor conjugated to a signaling chromophore and capable of interacting with the target biomolecule, providing a conjugated polymer that interacts with the sensor and upon excitation is capable of transferring energy to the sensor signaling chromophore and contacting the sample with the sensor and the conjugated polymer in a solution under conditions in which the sensor can bind to the target biomolecule if present. Next, the method can include applying a light source to the sample that can excite the conjugated polymer, and detecting whether light is emitted from the signaling chromophore. As disclosed herein, interaction or binding between conjugated polymers and dye-labeled antibodies can be a viable approach for increasing detection sensitivities, for example of a biomolecule target. In a further embodiment, covalently attaching the conjugated polymers to a dye, biomolecule (e.g., an antibody complex) or both offers several advantages including reduced background and/or improved energy transfer. In the case of direct linkage to a biomolecule, biorecognition events, rather than non-specific polymer interaction or binding events (such as those described above in FIG. 1), should govern conjugated polymer presence. In this manner, nonspecific binding of conjugated polymers to biomolecules can be eliminated, reducing any background emission resulting from the conjugated polymer itself. The abovementioned biomolecules include but are not limited to proteins, peptides, affinity ligands, antibodies, antibody fragments, sugars, lipids, enzymes and nucleic acids (as hybridization probes and/or aptamers). In general, in another aspect the invention includes the bioconjugation of polymers to affinity ligands (affinity ligands describing a biomolecule that has an affinity for another biomolecule). FIG. 2 illustrates a class of materials in which a conjugated polymer (shown as a wavy line) is linked to a dye, biomolecule, or biomolecule/dye complex (labeled X). Linking to the conjugated polymer can be via a first functionality linker A on the conjugated polymer that serves as a bioconjugation site capable of covalently linking with a second functionality linker A′ linked to a biomolecule and/or dye (see X). This arrangement can fix the distance between the conjugated polymer and X, thereby ensuring only specific interactions between polymer and X. It is envisioned that a biomolecule component X in this embodiment can be any of the various biomolecules disclosed herein, including but not limited to an antibody, protein, affinity ligand, enzyme or nucleic acid. Linker A can be anywhere on the conjugated polymer including terminal positions of the polymer, internally on a repeating subunit, in between repeating subunits or any combination thereof. Likewise, Linker A′ can be linked anywhere on a biomolecule and/or dye. The linking chemistry for A-A′ can include, but is not limited to, maleimide/thiol; thiol/thiol; pyridyldithiol/thiol; succinimidyl iodoacetate/thiol; N-succinimidylester (NHS ester), sulfodicholorphenol ester (SDP ester), or pentafluorophenyl-ester (PFP ester)/amine; bissuccinimidylester/amine; imidoesters/amines; hydrazine or amine/aldehyde, dialdehyde or benzaldehyde; isocyanate/hydroxyl or amine; carbohydrate-periodate/hydrazine or amine; diazirine/aryl azide chemistry; pyridyldithiol/aryl azide chemistry; alkyne/azide; carboxy-carbodiimide/amine; amine/Sulfo-SMCC (Sulfosuccinimidyl 4-[N-maleimidomethyl]cyclohexane-1-carboxylate)/thiol; and amine/BMPH (N—[B-Maleimidopropionic acid]hydrazide⋅TFA)/thiol. It is envisioned that the X in this context can be, but is not limited to, a dye, fluorescence protein, nanomaterial (e.g., Quantum Dot), chemiluminescence-generating molecule, a conjugate between dye and chemiluminescence-generating molecule, a conjugate between fluorescence protein and chemiluminescence-generating molecule, a conjugate between nanomaterial (e.g., Quantum Dot) and chemiluminescence-generating molecule, streptavidin, avidin, enzyme, substrate for an enzyme, substrate analog for an enzyme, receptor, ligand for a receptor, ligand analog for a receptor, DNA, RNA, modified nucleic acid, DNA aptamer, RNA aptamer, modified nucleic aptamer, peptide aptamer, antibody, antigen, phage, bacterium or conjugate of any two of the items described above. In another aspect, the invention includes the use of conjugated polymers as direct labels. FIG. 3 shows examples of labeled conjugated polymers. In one embodiment, FIG. 3A, a polymer (shown as encircled hexagons) is shown conjugated to an antibody which can be, for example, a 1° or 2° antibody. The conjugate of the polymer and the antibody can be used as a direct reporter, for example, in an assay. In additional embodiments, the signal from the polymer is not modulated by other assay components rather it is dependent on its presence in the assay at the time of detection as a function of specific biomolecule recognition. Excitation of the polymer with light (not shown) can result in polymer emission, indicating the presence of the antibody (1° or 2°) in the assay or assay solution. FIGS. 3B and 3C further exemplify the use of conjugated polymers as biomolecule labels capable of detecting specific targets and target associated biomolecules. FIG. 3B depicts a polymer avidin (streptavidin, neutraAvidin, etc.) conjugate capable of binding to biotin modified molecules, biomolecules or substrates. FIG. 3C depicts a nucleic acid (DNA, RNA, PNA, etc.) conjugate capable of hybridizing to complementary nucleic acid sequences. Linkage or conjugation of fluorescent conjugated polymer to a molecule capable of recognizing a target biomolecule or target associated molecule (such as those exemplified in FIG. 3) provides a direct means of detection. In additional embodiments, the signals generated from excitation of the conjugated polymer are not modulated by other assay components except those which are directly conjugated to the polymer. In such embodiments the polymer complex is acting directly as a fluorescent label. In another embodiment shown in FIG. 3D, the conjugated polymer is labeled with a dye, for example, a chromophore. In this case, the conjugated polymer can act as a donor and the dye can act as an acceptor in an energy transfer process. Here, the conjugated polymer can act as a light harvester, and excitation of the conjugated polymer is followed by the channeling of the excitations to the dye via an energy transfer process including, but not limited to, FRET. This results in amplified dye emission (as compared to direct excitation of the dye). The fluorescence of the donor conjugated polymer, in one embodiment, can be quenched (e.g., >90% quenching). This is exemplified in Example 38 and shown in FIG. 21, by way of example only. In some instances, the conjugated polymer in FIG. 3D (and similar drawings disclosed herein) can have multiple dye attachments which can be positioned internally or at the terminus of the polymer structure (single dye shown for illustrative purposes only). In the case of direct linkage to a dye (FIG. 3D) or biomolecule/dye complex (as exemplified in FIG. 4), donor-acceptor distances can be fixed, rather than dependent on the strength of interaction or binding, and energy transfer efficiency can be significantly increased. This has significant consequences in the context of improving dye signaling (or quenching) and reducing background fluorescence associated with donor-acceptor cross-talk. Cross-talk in this case refers to the overlap between conjugated polymer (donor) and dye (acceptor) emission peaks. Conjugated polymers which bind non-specifically at distances too great for energy transfer can contribute to the background fluorescence (or crosstalk). Shorter (fixed) distances between the donor and acceptor can not only facilitate direct dye amplification, but also can greatly quench the donor emission, as depicted in FIG. 21 by way of example only. This results in less donor emission at the acceptor emission wavelengths, which subsequently reduces or even eliminates the need for cross-talk correction. In further embodiments the localization of the conjugated polymer and a signaling chromophore are brought together by recognition event, for example by the binding of two affinity pairs or by co-recognition of the same target molecule or target associated molecule (FIG. 5). Such embodiments could be performed in solution based formats or in such configurations where one or more of elements is bound to another biomolecule (cell, tissue, protein, nucleic acid, etc.) or a substrate (bead, well plate, surface, tube, etc.). In general, another aspect the invention includes a method of assaying for a target biomolecule or target associated biomolecule. As shown in FIG. 5A, in one embodiment a conjugated polymer (shown as a wavy line) can be linked to a first bioconjugate (shown as a Y-shaped object), for example, a 2° antibody that is specific for second a dye-labeled bioconjugate, for example, a 1° antibody. Here, the recognition event between the 1° and 2° antibody will result in the reduction of distance between the donor conjugated polymer and acceptor dye. In a similar embodiment depicted in FIG. 5B, polymer and dye labeled antibodies recognize a common target. After either of these recognition events, excitation of the donor conjugated polymer with light (shown as hν) will result in energy transfer, e.g., FRET, to the acceptor dye (shown as curved arrow), and amplified dye emission (in comparison with direct excitation of the dye) will be observed. In use it is envisioned that an assay method could include providing a sample that is suspected of containing a target biomolecule by the steps of providing a first bioconjugate, for example, a 1° antibody conjugated to a signaling chromophore and capable of interacting with the target biomolecule. This is followed by providing a second bioconjugate, for example, a 2° antibody or 1° antibody, conjugated to a polymer, wherein the second bioconjugate can bind to the first bioconjugate or target and wherein upon such binding excitation of the conjugated polymer is capable of transferring energy to the signaling chromophore. Next, the method includes contacting the sample with the first bioconjugate in a solution under conditions in which the first bioconjugate can bind to the target biomolecule if present and contacting the solution with the second bioconjugate. The method then includes applying a light source to the target biomolecule or tagged target biomolecule, wherein the light source can excite the conjugated polymer and subsequently detecting whether light is emitted from the signaling chromophore. In another aspect, the invention includes a method of assaying a sample using a conjugated polymer and a sensor biomolecule complex. As shown in FIGS. 5C and D, a polymer (shown as a wavy line) can be conjugated to a first bioconjugate, for example, streptavidin (SA) which has a strong affinity for biotin. In FIG. 5C, a sensor biomolecule (e.g., an antibody which can be a 1° or 2° antibody), is conjugated to both a dye and a second bioconjugate (e.g., a biotin moiety). Similar embodiments are depicted in FIG. 5D where the second bioconjugate (e.g., a biotin moiety) and the signaling chromophore are both conjugated to a nucleic acid. After a biorecognition event between the first and second bioconjugates (e.g. between SA and biotin), the conjugated polymer and dye will be brought into close proximity, and excitation of the donor conjugated polymer will result in energy transfer to the acceptor dye. Dye emission will indicate the presence of the first bioconjugate (e.g., the antibody or nucleic acid). In comparison with direct excitation of the dye, amplification of the dye signal intensity will be observed when excited indirectly through an energy transfer process, e.g., FRET. A method of using the embodiment shown in FIGS. 5C and D can include the steps of providing a sample that is suspected of containing a target biomolecule, providing a conjugated polymer comprising a covalently linked first bioconjugate (e.g., SA), providing a sensor biomolecule complex comprising a sensor biomolecule capable of interacting with the target molecule, a signaling chromophore, and covalently linked second bioconjugate capable of binding with the first bioconjugate, wherein upon such binding excitation of the conjugated polymer is capable of transferring energy to the signaling chromophore. The method can further include the steps of contacting the sample with the sensor biomolecule complex in a solution under conditions in which the sensor biomolecule can bind to the target biomolecule if present, contacting the solution with the conjugated polymer, applying a light source to the sample that can excite the conjugated polymer, and detecting whether light is emitted from the signaling chromophore. Further the conjugated polymer can contain additional linking site suitable for conjugation or attachement to more than one species. FIG. 6 exemplifies the addition of a second linking site within the polymer. Such linkers A and B can be the same or different to allow for orthogonal conjugation of different species. The linkers can be anywhere on the polymer including terminal and internal positions. The linking chemistry for A-A′ and B-B′ (and optionally C-C′, D-D′, etc.) can include, but is not limited to, maleimide/thiol; thiol/thiol; pyridyldithiol/thiol; succinimidyl iodoacetate/thiol; N-succinimidylester (NHS ester), sulfodicholorphenol ester (SDP ester), or pentafluorophenyl-ester (PFP ester)/amine; bissuccinimidylester/amine; imidoesters/amines; hydrazine or amine/aldehyde, dialdehyde or benzaldehyde; isocyanate/hydroxyl or amine; carbohydrate-periodate/hydrazine or amine; diazirine/aryl azide chemistry; pyridyldithiol/aryl azide chemistry; alkyne/azide; carboxy-carbodiimide/amine; amine/Sulfo-SMCC (Sulfosuccinimidyl 4[N-maleimidomethyl]cyclohexane-1-carboxylate)/thiol; and amine/BMPH (N—[B-Maleimidopropionic acid]hydrazide⋅TFA)/thiol. A tri-functional linker such as the commercially available Sulfo-SBED Sulfosuccinimidyl[2-6-(biotinamido)-2-(p-azidobenzamido)-hexanoamido]-ethyl-1,3′-dithiopropionate can serve well in the three way linkage among X, Y, and conjugated polymer. In the embodiment illustrated in FIG. 6, X or Y can be, but are not limited to, a dye, fluorescence protein, nanomaterial (e.g., Quantum Dot), chemiluminescence-generating molecule, a conjugate between dye and chemluminescence-generating molecule, a conjugate between fluorescence protein and chemiluminescence-generating molecule, a conjugate between nanomaterial (e.g., Quantum Dot) and chemiluminescence-generating molecule, streptavidin, avidin, enzyme, substrate for an enzyme, substrate analog for an enzyme, receptor, ligand for a receptor, ligand analog for a receptor, DNA, RNA, modified nucleic acid, DNA aptamer, RNA aptamer, modified nucleic aptamer, peptide aptamer, antibody, antigen, phage, bacterium or conjugate of any two of the items described above. In general, in another aspect the invention provides a conjugated polymer complex including a polymer, a sensor biomolecule and a signaling chromophore for identifying a target biomolecule. As shown in FIG. 6, in one embodiment a polymer (wavy line) can be bioconjugated to a dye X via linker functionalities A-A′ and a biomolecule Y via linker functionalities B-B′. As depicted in FIG. 7, in one embodiment a polymer can be bioconjugated to both a dye and a biomolecule, for example a biorecognition molecule. Useful biomolecules can include but are not limited to antibodies (FIG. 7A), avidin derivatives (FIG. 7B) affinity ligands, nucleic acids (FIG. 7C), proteins, nanoparticles or substrates for enzymes. The benefits of covalently linking a dye in proximity to a polymer have been described above. By affixing both an acceptor dye and a biorecognition molecule to a polymer, the benefits are two fold, by both fixing donor-acceptor distances, such that an acceptor is guaranteed to be within the vicinity of a donor conjugated polymer (and vice versa), and also increasing the specificity of polymer binding to indicate a biorecognition event. These covalent complexes can be made via the monomer, polymer and linking chemistries described herein. In use, the embodiments shown in FIG. 6 can be a conjugated polymer complex for identifying a target biomolecule wherein the complex includes a conjugated polymer, a signaling chromophore covalently linked to the conjugated polymer and a sensor biomolecule covalently linked to the conjugated polymer. The signaling chromophore of the complex is capable of receiving energy from the conjugated polymer upon excitation of the conjugated polymer and the sensor biomolecule is capable of interacting with the target biomolecule. It is envisioned that the biomolecules can include but are not limited to an antibody, protein, affinity ligand, peptide, or nucleic acid. In one embodiment shown in FIG. 7A, a polymer is conjugated to both a bioconjugate, for example, an antibody (1° or 2°) and a dye. Covalent linkage between the donor conjugated polymer and acceptor dye ensures close proximity. Excitation of the donor conjugated polymer results in energy transfer, e.g., FRET, to the acceptor dye. Where the bioconjugate is an antibody, if the antibody binds to its target (e.g., antigen), this will be indicated by dye emission upon donor polymer excitation. In an alternative embodiment, as shown in FIG. 7B, a polymer can be conjugated to both a SA and a dye. Again, covalent linkage between the donor conjugated polymer and acceptor dye ensure close proximity, and excitation of the donor conjugated polymer results in energy transfer to the acceptor dye. The SA complex can be used to label or detect a biotin-labeled biomolecule such as a biotinylated antibody or nucleic acid. Polymer excitation followed by energy transfer to the dye label will result in greatly enhanced detection signals (i.e., greater sensitivity). The example exemplified in FIG. 7A is a conjugated polymer labeled with a dye acceptor and further conjugated to an antibody. This Tandem configuration can be used in similar fashion as those described for the structure in FIG. 3A but are useful in generating a secondary signal for detection, often in multiplex formats. The conjugated polymer complexes in FIG. 7 can have multiple dye attachments which can be positioned internally or at the terminus of the polymer structure (single dye shown for illustrative purposes only). In other embodiments as shown in FIGS. 3A and 7A, a sensor biomolecule for example a 1° antibody (Y shape) is conjugated covalently linked to the conjugated polymer (encircled hexagons) or conjugated polymer-dye tandem complex (hexagons with pendant encircled star). Upon conjugated polymer excitation, emission from the conjugated polymer (FIG. 3A) or dye (FIG. 7A) will indicate presence of the biocomplex and by extension with appropriate assay design that of the target recognized by the sensor molecule allowing use as a reporter, for example in an assay. FIGS. 29A and 29B represent comparable examples with covalent linkage of the conjugated polymer to a 2° antibody. As an alternative embodiment, the conjugated polymer may be associated indirectly with the sensor biomolecule or target associated biomolecule. FIGS. 8C and 8D illustrate a sequence specific oligonucleotide probe (wavy line) covalently conjugated to a biotin moiety (drop shape). Here the conjugated polymer (encircled hexagons) or conjugated polymer-dye tandem complex (hexagons with pendant encircled star) is covalently bound or conjugated to a biotin recognizing protein (for example, avidin, streptavidin or similar with high specific affinity for the ligand biotin). FIGS. 8A and 8B illustrate comparable examples with a biotinylated antibody interacting with a covalent conjugate of the conjugated polymer (FIG. 8A) and conjugated polymer-dye tandem complex (FIG. 8B) to the biotin recognizing protein. Indirect association of the target associated biomolecule with the conjugated polymer is not limited to biotin mediated interactions. FIGS. 8E and F represent sequence specific oligonucleotides (wavy line) which have been covalently labeled with a digoxygenin moiety (7 pointed star). In turn the digoxygenin moiety has been recognized by a primary antibody covalently linked to the conjugated polymer (FIG. 8E) and the conjugated polymer-dye tandem complex (FIG. 8F). Although not shown pictorially, further embodiments employing indirect detection of digoxygenin using biotinylated antibodies and biotin recognizing proteins covalently linked to conjugated polymers (or conjugated polymer-dye tandem complexes) or unlabelled primary antibodies recognizing digoxygenin and appropriate secondary antibodies covalently linked to the conjugated polymer (or conjugated polymer-dye tandem complexes) are intended. A number of further embodiments are also predicated on energy transfer (for example but not limited to FRET) between the conjugated polymer and an acceptor dye. Given the potential for multiplexing analysis, it is envisioned that the conjugated polymer can be linked to a number of dyes or signaling chromophores, including, but not limited to, fluorescein, 6-FAM, rhodamine, Texas Red, California Red, iFluor594, tetramethylrhodamine, a carboxyrhodamine, carboxyrhodamine 6G, carboxyrhodol, carboxyrhodamine 110, Cascade Blue, Cascade Yellow, coumarin, Cy2®, Cy3®, Cy3.5®, Cy5®, Cy5.5®, Cy7®, Cy-Chrome, DyLight 350, DyLight 405, DyLight 488, DyLight 549, DyLight 594, DyLight 633, DyLight 649, DyLight 680, DyLight 750, DyLight 800, phycoerythrin, PerCP (peridinin chlorophyll-a Protein), PerCP-Cy5.5, JOE (6-carboxy-4′,5′-dichloro-2′,7′-dime1hoxyfluorescein), NED, ROX (5-(and-6)-carboxy-X-rhodamine), HEX, Lucifer Yellow, Marina Blue, Oregon Green 488, Oregon Green 500, Oregon Green 514, Alexa Fluor® 350, Alexa Fluor® 430, Alexa Fluor® 488, Alexa Fluor® 532, Alexa Fluor® 546, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 633, Alexa Fluor® 647, Alexa Fluor® 660, Alexa Fluor® 680, 7-amino-4-methylcoumarin-3-acetic acid, BODIPY® FL, BODIPY® FL-Br2, BODIPY® 530/550, BODIPY® 558/568, BODIPY® 564/570, BODIPY® 576/589, BODIPY® 581/591, BODIPY® 630/650, BODIPY® 650/665, BODPY® R6G, BODIPY® TMR, BODIPY® TR, conjugates thereof, and combinations thereof. These embodiments include modifications of the above examples where the acceptor dye serves as the assay reporter (as exemplified in FIGS. 3D, 4D, 7, 8B, 8D, 8E, 29B, wherein the encircled ten pointed star represents the dye). In certain embodiments the conjugated polymer conjugates provided in FIGS. 2-10, 29 and 30 are intended for but not limited to use in flow cytometry, cell sorting, molecular diagnostics, fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), polymerase chain reaction, microscopy (fluorescent, confocal, 2 photon, etc.), blotting (e.g. northern, southern, western), cytomic bead arrays (Luminex formats, etc.), fluorescent immune assay (FIA or ELISA), nucleic acid sequencing and microarrays. Embodiments are also envisaged where conjugated polymers are used to enhance the detection and quantification of nucleic acids using sequence specific fluorescent probes combined with nucleic acid amplification techniques such as but not limited to polymerase chain reaction, transcription mediated amplification, rolling circle amplification, recombinase polymerase amplification, helicase dependent amplification and Linear-After-The-Exponential polymerase chain reaction. FIG. 32 represents modifications of the HybProbe detection technique. In FIG. 32A, the dye conventionally used as an energy transfer donor is replaced by the conjugated polymer (hexagon chain) which is covalently linked to the donor probe (wavey helical structure represented as right hand helical duplex due to association with nucleic acid target depicted a longer helical wavy line). Upon sequence specific hybridization the donor and acceptor (represented similarly to donor probe but on left hand side of nucleic acid target) probes are spatially juxtaposed on the target nucleic acid strand of interest in sufficiently close proximity to allow energy transfer to take place between the fluors. Excitation energy is transduced through the conjugated polymer and emitted as a readable signal by the dye (encircled ten pointed star) to allow nucleic acid quantification, detection and/or characterization. Presence of increased template allows increased numbers of probe co-hybridisation events and thus correlates to increased specific signal from the acceptor dye. In combination with the melt curve technique commonly employed in HybProbe experiments it is envisaged that sequence specific information corresponding to sequence variations will be collectable in appropriately designed experiments. FIG. 32B represents a “signal off” modification of the HybProbe approach where the conjugated polymer is quenched by an acceptor probe consisting of a small molecule fluorescence quencher (for example but not limited to Black Hole Quenchers™ Iowa Black® or Dabsyl). In another embodiment, conjugated polymer and conjugated polymer-dye tandem complexes similar to those described in FIGS. 4C and 4D are used in the detection, quantification and/or characterization of nucleic acid targets. Nucleic acid probe sequences labeled with a quencher molecule (black circle, for example but not limited to Black Hole Quenchers™, Iowa Black® or Dabsyl) are also conjugated to a conjugated polymer (FIGS. 4C and 31A) and a conjugated polymer-dye tandem complex (FIGS. 4D and 31B). In FIGS. 4C and D the recognition of the target sequence leads to a hybridization and separation of the quencher from the conjugated polymer or conjugated polymer-dye tandem complex and upon polymer excitation produces an increase in fluorescent signal. In FIGS. 31A and 31B the nucleic acid probe conjugate will hybridize to a complementary target sequence and by treatment with specific enzymes the probe sequence is cleaved or hydrolyzed freeing the conjugated polymer or conjugated polymer-dye tandem complex from the quencher and upon polymer excitation produces an increase in fluorescent signal. The most common example of the methods described in FIG. 31 is the use of DNA polymerase enzymes which contain nuclease activity (e.g. TaqMan PCR assays). FIG. 9 shows examples of conjugated polymer (hexagons) conjugated to secondary antibodies (FIG. 9A) and primary antibodies (FIG. 9B) (antibodies shown as Y-shaped structures). In an assay, an unlabeled 1° antibody can bind to an antigen, for example, a target protein (shown as a black triangle). Addition of the 2° antibody, which is conjugated to a polymer, can bind specifically to the 1° antibody. After washing to remove unbound 2° antibody and upon application of light of suitable excitation wavelength, observance of polymer emission is indicative of specific binding (FIG. 9A). In other assay embodiments, a polymer-labeled 1° antibody can directly bind a target protein, shown as a black triangle, and after washing to remove unbound 1° antibody and upon application of light of suitable excitation wavelength, observance of polymer emission is indicative of specific binding (FIG. 9B). Optionally, whether conjugated to the 1° or 2° antibody, the polymer may be further conjugated to a dye. In such a case, optical excitation of the conjugated polymer can result in energy transfer to the dye, and amplified dye emission, in comparison to direct dye excitation results. Observance of dye emission is indicative of specific binding. FIG. 10 shows an example of a sandwich-type complex of one embodiment of the invention. In the assay shown in FIG. 10A the conjugated polymer complex is composed of a polymer (shown as hexagons) that is bioconjugated a biomolecule, for example, streptavidin (X shape). After an unlabeled 1° antibody binds the target (e.g. protein), shown as a black triangle, a biotin-labeled 2° antibody binds specifically to the 1° antibody. In a separate step, addition of the conjugated polymer complex will result in specific binding between the biotin and streptavidin. Excitation of the conjugated polymer will result in polymer emission, indicating the presence of the target protein. Additionally in another embodiment, a biotin-labeled 1° antibody may be used to probe the target protein directly (FIG. 10B). After this binding event takes place, addition of a streptavidin-polymer complex will result in specific binding between the biotin and streptavidin, and excitation of the conjugated polymer will result in polymer emission, indicating the presence of the target protein. Optionally, the polymer may be further conjugated to a dye. In such a case, optical excitation of the polymer will result in amplified dye emission, as compared to direct excitation of the dye. Signals arising from dye emission will indicate the presence of the target protein. FIG. 30 depicts example embodiments around the use of conjugated polymers in Fluorescent Immuno Assay (FIA). In FIG. 30 panels A-C analyte antigen is immobilised on a surface which can include but is not limited to a microtitre plate well, bead particle, glass slide, plastic slide, lateral flow strip, laminar flow device, microfluidic device, virus, phage, tissue or cell surface. Analyte molecules are then detected by use of labelled detection conjugates or sensor biomolecules. In FIG. 30A, a conjugated polymer covalently linked to a detection antibody is utilized for detection. In FIG. 30B, a biotin binding protein (for example but not limited to avidin, streptavidin or other high affinity biotin specific derivatives) covalently bound to the conjugated polymer and interacting with a biotinylated detection antibody is utilized for detection. In FIG. 30C, a secondary antibody covalently linked to the conjugated polymer and interacting with a detection antibody is utilized for detection. In FIG. 5B, a homogenous, solution based example is also embodied where two separate antibodies each bind to the antigen of interest. One antibody is covalently linked to the conjugated polymer, the other to a dye. When bound to the antigen, the respective fluorophores are brought into sufficient spatial proximity for energy transfer to occur. In assays predicated on the designs in FIG. 30 and FIG. 5B, the sample is interrogated with light matched to the excitation of the conjugated polymer and signal reported at the emission wavelength of the dye. In the examples embodied in FIG. 30 A-C the use of a polymer-dye tandem complex is further disclosed. In such cases, optical excitation of the polymer will result in amplified dye emission, as compared to direct excitation of the dye. Signals arising from dye emission will indicate the presence of the target. In a further aspect, the invention provides for the multiplexing of donor energy transfer to multiple acceptors. By using a conjugated polymer as a donor in an energy transfer system, benefits also include the ability to multiplex. A single donor can transfer energy to several dyes; thus with a single excitation source, the intensity of multiple dyes can be monitored. This is useful for applications including but not limited to cell imaging (i.e. immunohistochemistry), flow cytometry and cell sorting, where the different types of cells can be monitored by protein-antibody recognition events. In one embodiment, two dye-labeled antibodies can be incubated with a biological material, for example, a cultured cell line, tissue section or blood sample. Antibodies are able to recognize cells with a target protein expressed on its surface and specifically bind only to those proteins. By labeling the two antibodies with different dyes, it is possible to monitor for the expression of two different proteins or different cell types simultaneously. Typically, this would require two scans, excitations or images, once each with the correct excitation wavelength. As a final step prior to analysis, these two images or data sets would have to be overlaid or combined. By using antibodies conjugated with both a dye and a conjugated polymer, one excitation wavelength can be used for the conjugated polymer to excite both dyes, and a single image or scan will include data sets from each of the two antibodies. This can be done with any number of antibody combinations provided there is sufficient ability to resolve the resulting signals. It is envisioned that the invention described herein can be used to increase the sensitivity of any of a number of commercially available tests including but not limited to the OraQuick Rapid HIV-1/2 Antibody Test, manufactured by OraSure Technologies, Inc. (Bethlehem, Pa.), which is a FDA-approved HIV diagnostic test for oral fluid samples. This test can provide screening results with over 99 percent accuracy in as little as 20 minutes. Conjugated Polymers Light harvesting conjugated polymer systems can efficiently transfer energy to nearby luminescent species. Mechanisms for energy transfer include, for example, resonant energy transfer (Forster (or fluorescence) resonance energy transfer, FRET), quantum charge exchange (Dexter energy transfer) and the like. Typically, however, these energy transfer mechanisms are relatively short range, and close proximity of the light harvesting conjugated polymer system to the signaling chromophore is required for efficient energy transfer. Amplification of the emission can occur when the number of individual chromophores in the light harvesting conjugated polymer system is large; emission from a fluorophore can be more intense when the incident light (the “pump light”) is at a wavelength which is absorbed by the light harvesting conjugated polymer system and transferred to the fluorophore than when the fluorophore is directly excited by the pump light. The conjugated polymers used in the present invention can be charge neutral, cationic or anionic. In some embodiments, the conjugated polymers are polycationic conjugated polymers. In other embodiments, the conjugated polymers are polyanionic conjugated polymers. In further embodiments, the conjugated polymers can include cationic, anionic, and/or neutral groups in various repeating subunits. In yet other embodiments, the conjugated polymers are neutral conjugated polymers. In some instances, conjugated polymers contain groups such as ethylene glycol oligomers, ethylene glycol polymers, co-ammonium alkoxy salts, and/or w-sulfonate alkoxy salts that impart solubility in aqueous solutions. In some instances the neutral conjugated polymers with non-ionic side chains are soluble in greater than 10 mg/mL in water or phosphate buffered saline solutions and in certain cases the solubility is greater than 50 mg/mL. In some embodiments the conjugated polymers contain either a terminal linking site (e.g., capping unit), internal linking site or both. In some embodiments, a conjugated polymer is one that comprises “low bandgap repeat units” of a type and in an amount that contribute an absorption to the polymer in the range of about 450 nm to about 1000 nm. The low bandgap repeat units may or may not exhibit such an absorption prior to polymerization, but does introduce that absorption when incorporated into the conjugated polymer. Such absorption characteristics allow the polymer to be excited at wavelengths that produce less background fluorescence in a variety of settings, including in analyzing biological samples and imaging and/or detecting molecules. Shifting the absorbance of the conjugated polymer to a lower energy and longer wavelength thus allows for more sensitive and robust methods. Additionally, many commercially available instruments incorporate imaging components that operate at such wavelengths at least in part to avoid such issues. For example, thermal cyclers that perform real-time detection during amplification reactions and microarray readers are available which operate in this region. Providing polymers that absorb in this region allows for the adaptation of detection methods to such formats, and also allows entirely new methods to be performed. Incorporation of repeat units that decrease the band gap can produce conjugated polymers with such characteristics. Exemplary optionally substituted species which result in polymers that absorb light at such wavelengths include 2,1,3-benzothiadiazole, benzoxidazole, benzoselenadiazole, benzotellurodiazole, naphthoselenadiazole, 4,7-di(thien-2-yl)-2,1,3-benzothiadiazole, squaraine dyes, quinoxalines, perylene, perylene diimides, diketopyrrolopyrrole, thienopyrazine low bandgap commercial dyes, olefins, and cyano-substituted olefins and isomers thereof. Further details relating to the composition, structure, properties and synthesis of suitable conjugated polymers can be found in U.S. patent application Ser. No. 11/329,495, filed Jan. 10, 2006, now published as US 2006-0183140 A1, which is incorporated herein by reference in the entirety. In one aspect, provided herein are conjugated polymers of Formula (I): wherein: each R is independently a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL; MU is a polymer modifying unit or band gap modifying unit that is evenly or randomly distributed along the polymer main chain and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C1-C12 alkoxy, C2-C18(hetero)aryloxy, C2-C18(hetero)arylamino, (CH2)x′(OCH2CH2)y′OCH3 where each x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50, or a C2-C18(hetero)aryl group; each optional linker L1 and L2 are aryl or heteroaryl groups evenly or randomly distributed along the polymer main chain and are substituted with one or more pendant chains terminated with a functional group for conjugation to another substrate, molecule or biomolecule selected from amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof; G1 and G2 are each independently selected from hydrogen, halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiol, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters, optionally substituted fluorine and aryl or heteroaryl substituted with one or more pendant chains terminated with a functional group, molecule or biomolecule selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule; wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, and thiols within G1, G2, L1 or L2 that allows, for functional conjugation to another molecule, substrate or biomolecule; each dashed bond, , is independently a single bond, triple bond or optionally substituted vinylene (—CR5═CR5—) wherein each R5 is independently hydrogen, cyano, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group, wherein each C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, or C1-C12 haloalkyl; and n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. Non-ionic side groups capable of imparting solubility in water as used herein refer to side groups which are not charged and allow the resulting polymer to be soluble in water or aqueous solutions with no visible particulates. In some embodiments, each R is independently a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL, in excess of 15 mg/mL, in excess of 20 mg/mL, in excess of 25 mg/mL, in excess of 30 mg/mL, in excess of 35 mg/mL, in excess of 40 mg/mL, in excess of 45 mg/mL, in excess of 50 mg/mL, in excess of 60 mg/mL, in excess of 70 mg/mL, in excess of 80 mg/mL, in excess of 90 mg/mL or in excess of 100 mg/mL. In some embodiments, conjugated polymers described herein comprises a minimum number average molecular weight of greater than 5,000 g/mol, greater than 10,000 g/mol, greater than 15,000 g/mol, greater than 20,000 g/mol, greater than 25,000 g/mol, greater than 30,000 g/mol, greater than 40,000 g/mol, greater than 50,000 g/mol, greater than 60,000 g/mol, greater than 70,000 g/mol, greater than 80,000 g/mol, greater than 90,000 g/mol, or greater than 100,000 g/mol. In some embodiments, each R is independently (CH2)x(OCH2CH2)yOCH3 where each x is independently an integer from 0-20, each y is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)zOCH3 where each z is independently an integer from 0 to 50. In some instances, each R is (CH2)3(OCH2CH2)11OCH3. In other embodiments, each R is independently a benzyl substituted with at least one (OCH2CH2)zOCH3 group where each z is independently an integer from 0 to 50. In some instances, each R is a benzyl substituted with at least one (OCH2CH2)10OCH3 group. In other instances, each R is a benzyl substituted with at least two (OCH2CH2)10OCH3 groups. In further instances, each R is a benzyl substituted with at least three (OCH2CH2)10OCH3 groups. In further embodiments, each R is independently where k and l are independent integers from 0 to 25; *=site for covalent attachment. In yet further embodiments, each R is independently is a dendrimer of PAMAM, PEA, PEHAM, PPI, tri-branched benzoate, or glycerol with a generation of 1 to 4 and optionally terminal substitutions, said optionally terminal substitutions are ( - - - )CH2CH2O)jCH3 or ( - - - )(OCH2CH2)jCH3 and j is an integer from 0 to 25 and the dotted lines ( - - - ) are each independently selected from any one or a combination of, C1-C12 alkyl, C1-C12 alkoxy, C2-C12 alkene, amido, amino, aryl, (CH2)r(OCH2CH2)s(CH2)r where each r is independently an integer from 0-20, s is independently an integer from 0 to 50, carbamate, carboxylate, C3-C12 cycloalkyl, imido, phenoxy, or C4-C18(hetero)aryl groups. In alternative embodiments, each R is independently, Where k and l are independent integers from 0 to 25 and the dotted lines () are each independently selected from any one or a combination of, C1-C12 alkyl, C1-C12 alkoxy, C2-C12 alkene, amido, amino, aryl, (CH2)r(OCH2CH2)s(CH2)r where each r is independently an integer from 0-20, s is independently an integer from 0 to 50, carbamate, carboxylate, C3-C12 cycloalkyl, imido, phenoxy, or C4-C18(hetero)aryl groups; *=site for covalent attachment. In alternative embodiments, each R is independently, Where k and l are independent integers from 0 to 25 and the dotted lines ( - - - ) are each independently selected from any one or a combination of, C1-C12 alkyl, C1-C12 alkoxy, C2-C12 alkene, amido, amino, aryl, (CH2)r(OCH2CH2)s(CH2)r where each r is independently an integer from 0-20, s is independently an integer from 0 to 50, carbamate, carboxylate, C3-C12 cycloalkyl, imido, phenoxy, or C4-C18(hetero)aryl groups; *=site for covalent attachment. In some embodiments, conjugated polymers described herein contain no optional linkers, L1 and/or L2. In other embodiments, conjugated polymers contain at least about 0.01 mol %, at least about 0.02 mol %, at least about 0.05 mol %, at least about 0.1 mol %, at least about 0.2 mol %, at least about 0.5 mol %, at least about 1 mol %, at least about 2 mol %, at least about 5 mol %, at least about 10 mol %, at least about 20 mol %, or about 25 mol % of optional linkers, L1 and/or L2. In some embodiments, conjugated polymers contain up to 50 mol % total of optional linkers, L1 and L2, and may contain about 40 mol % or less, about 30 mol % or less, about 25 mol % or less, about 20 mol % or less, about 15 mol % or less, about 10 mol % or less, or about 5 mol % or less. Linkers can be evenly or randomly distributed along the polymer main chain. In some embodiments, optional linkers L1 or L2 have the structure: *=site for covalent attachment to unsaturated backbone wherein R3 is independently hydrogen, halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group, wherein each C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, or C1-C12 haloalkyl; and q is an integer from 0 to 4. In some embodiments, optional linkers L1 or L2 have the structure represented by: *=site for covalent attachment to unsaturated backbone wherein A is a site for conjugation, chain extension or crosslinking and is —[O—CH2—CH2]t—W, or (C1-C12)alkoxy-X; W is —OH or —COOH; X is —NH2, —NHCOOH, —NHCOOC(CH3)3, —NHCO(C3-C12)cycloalkyl(C1-C4)alkyl-N-maleimide; or —NHCO[CH2—CH2—O]uNH2; t is an integer from 1 to 20; and u is an integer from 1 to 8. In other embodiments, optional linkers L1 or L2 are selected from the group consisting of a-h having the structure: *=site for covalent attachment to unsaturated backbone wherein R′ is independently H, halogen, C1-C12 alkyl, (C1-C12 alkyl)NH2, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C2-C18(hetero)aryl, C2-C18(hetero)arylamino, —[CH2—CH2]r′—Z1, or (C1-C12)alkoxy-X1; and wherein Z1 is —OH or —COOH; X1 is —NH2, —NHCOOH, —NHCOOC(CH3)3, —NHCO(C3-C12)cycloalkyl(C1-C4)alkyl-N-maleimide; or —NHCO[CH2—CH2—O]s′(CH2)s′NH2; r′ is an integer from 1 to 20; and each s′ is independently an integer from 1 to 20, (CH2)3(OCH2CH2)x″OCH3 where x″ is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)y″OCH3 where each y″ is independently an integer from 0 to 50 and R′ is different from R; wherein R15 is selected from the group consisting of l-t having the structure: and k is 2, 4, 8, 12 or 24; *=site for covalent attachment to backbone. In certain embodiments, optional linkers L1 or L2 are In some embodiments, G1 and G2 are optionally substituted aryl wherein the optional substituent is selected from halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, boronic acid, boronate radical, boronic esters and optionally substituted fluorene. In other embodiments, G1 and G2 are the same. In further embodiments, G1 and G2 are different. G1 and G2 can be activated units that allow further conjugation, crosslinking, or polymer chain extension, or they may be nonactivated termination units. In some embodiments, G1 and G2 are independently selected from structures represented by: *=site for covalent attachment to backbone wherein R11 is any one of or a combination of a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl, (CH2)x(OCH2CH2)p(CH2)x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In other embodiments, G1 and G2 are independently selected from the group consisting of 1-18 having the structure: *=site for covalent attachment to backbone wherein R15 is selected from the group consisting of l-t having the structure: and k is 2, 4, 8, 12 or 24. In further embodiments, G1 and G2 is In some embodiments, optional linkers, L1 and/or L2, G1, and/or G2 can be further conjugated to an organic dye, a biomolecule or a substrate. Covalent linkage can be introduced by any known method and can include, but is not limited to, chemistry involving maleimide/thiol; thiol/thiol; pyridyldithiol/thiol; succinimidyl iodoacetate/thiol; N-succinimidylester (NHS ester), sulfodicholorphenol ester (SDP ester), or pentafluorophenyl-ester (PFP ester)/amine; bissuccinimidylester/amine; imidoesters/amines; hydrazine or amine/aldehyde, dialdehyde or benzaldehyde; isocyanate/hydroxyl or amine; carbohydrate-periodate/hydrazine or amine; diazirine/aryl azide chemistry; pyridyldithiol/aryl azide chemistry; alkyne/azide; carboxy-carbodiimide/amine; amine/Sulfo-SMCC (Sulfosuccinimidyl 4-[N-maleimidomethyl]cyclohexane-1-carboxylate)/thiol; and amine/BMPH (N-[β-Maleimidopropionic acid]hydrazide⋅TFA)/thiol. In some embodiments, MU is selected from the group consisting of a′-k′ having the structure: =site for covalent attachment to unsaturated backbone wherein R is a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL. Non-ionic side groups include those previously described for polymers of Formula (I). As used herein, in some embodiments, a pendant chain is any one of or a combination of a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl, (CH2)x(OCH2CH2)p(CH2)x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups which connects a polymer with a functional group for conjugation to another substrate, molecule, or biomolecule. In some embodiments, conjugated polymers of Formula (I) have the structure of Formula (Ia): wherein R, L1, L2, G1, G2, MU, a, b, c, d and n are described previously for formula (I). In a further aspect, conjugated polymers of Formula I have the structure of Formula (Ib): wherein at least one of G1 or G2 comprises a functional conjugation cite. In a further aspect, conjugated polymers of Formula I have the structure of Formula (Ic): wherein L1 comprises a functional conjugation cite. In a further aspect, conjugated polymers of Formula I have the structure of Formula (Id): wherein at least one of G1 or G2 comprises a functional conjugation cite. In a further aspect, conjugated polymers of Formula I have the structure of Formula (II): wherein L1, G1, G2, a, c, n and dashed bonds are described previously for formula (I). In some embodiments, conjugated polymers of Formula (II) have the structure of Formula (IIa): wherein L1, G1, G2, a, c, and n are described previously for formula (I). In a further aspect, conjugated polymers of Formula I have the structure of Formula (III): wherein L1, G1, G2, a, c, n and dashed bonds are described previously for formula (I). In some embodiments, conjugated polymers of Formula (III) have the structure of Formula (IIIa): wherein L1, G1, G2, a, c, and n are described previously for formula (I). In a further aspect, conjugated polymers of Formula I have the structure of Formula (IV): wherein each R5 is independently hydrogen, cyano, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group, wherein each C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, or C1-C12 haloalkyl; and L1, G1, G2, a, c, n and dashed bonds are described previously for formula (I). In a further aspect, conjugated polymers of Formula I have the structure of Formula (V): wherein each R5 is independently hydrogen, cyano, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group, wherein each C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl or a C2-C18(hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, or C1-C12 haloalkyl; and L1, G1, G2, a, c, n and dashed bonds are described previously for formula (I). Also provided herein are polymers having the structure of the following formula: wherein: G1 and G2 are each independently selected from hydrogen, halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, optionally substituted aryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters and optionally substituted fluorene; L is a bond or an aryl or heteroaryl group that is evenly or randomly distributed along the polymer main chain and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkene, C2-C12 alkyne, C3-C12 cycloalkyl, C1-C12 haloalkyl, C1-C12 alkoxy, C2-C18(hetero)aryloxy, C2-C18(hetero)arylamino, (CH2)x(OCH2CH2)pOCH3 where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, or a C2-C18(hetero)aryl group; L1, L1′, L2 and L2′ are each independently a covalent bond, a C1-C12 alkylene, a C3-C12 cycloalkylene, a C2-C12 alkenylene, a C2-C12 alkynylene, a (C6-C18)aryl(C1-C12)alkylene, a (C6-C18)aryl(C2-C12)alkenylene, a (C6-C18)aryl(C1-C12)alkynylene, a C6-C18 arylene group, —Y1—[O—Y2]p—, —O—Y1—[O—Y2]p— wherein each C1-C12 alkylene, C3-C12 cycloalkylene, (C6-C18)aryl(C1-C12)alkylene, or C6-C18 arylene group is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, C1-C12 haloalkyl, —Y1—[O—Y2]p— or —O—Y1—[O—Y2]p—; q is 0 or an integer from 1 to 8; p is 0 or an integer from 1 to 24; Y1 and Y2 are each independently a covalent bond, or a C1-12 alkylene group, a C3-C12 cycloalkylene, a C2-C18(hetero)arylene, a (C6-C18)aryl(C1-C12)alkylene, wherein each C1-12 alkylene group, a C3-C12 cycloalkylene, a C2-C18(hetero)arylene, a (C6-C18)aryl(C1-C12)alkylene is optionally substituted with one or more halogen, hydroxyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl group, C1-C12 alkoxy, or C1-C12 haloalkyl; E1 and E1′ are each independently, hydrogen, C1-C6 alkyl, —OH, —COOH, —SH, —SR, —SHR+, SR2+, —SO3−, —PO4−, Br, —NH2, —NHR, —NR2, —NH3+, —NH2R+, —NHR2+or —NR3, wherein and each R is independently a C1-C6 alkyl and —SHR+, SR2+, —SO3−, —PO4−, —NH3+, —NH2R+, —NHR2+or —NR3+ each optionally has an associated counterion; and n is an integer from 1 to about 1,000. Also provided herein are polymers having the structure of the following formula: wherein each R is independently O(CHx), or (CH2)3(OCH2CH2)pOCH3 where each x is independently an integer from 0-20, each p is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C1-C12 alkoxy, or (OCH2CH2)mOCH3 where each m is independently an integer from 0 to 50; G1 is selected from hydrogen, halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, optionally substituted aryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters and optionally substituted fluorene; and n is an integer from 1 to about 10,000. Additional embodiments of conjugated polymers are described in the following Examples. Preparation of Conjugated Polymers The synthesis of conjugated polymers described herein may be accomplished using means described in the chemical literature, using the methods described herein, or a combination thereof. Conjugated polymers described herein may be synthesized using standard synthetic techniques known to those of skill in the art or using methods known in the art in combination with methods described herein. In additions, solvents, temperatures and other reaction conditions presented herein may vary according to the practice and knowledge of those of skill in the art. The starting material used for the synthesis of the conjugated polymers of Formula (1) and polymers having the structures described in the prior section as described herein can be obtained from commercial sources, such as Aldrich Chemical Co. (Milwaukee, Wis.), Sigma Chemical Co. (St. Louis, Mo.), or the starting materials can be synthesized. The polymers described herein, and other related polymers having different substituents can be synthesized using techniques and materials known to those of skill in the art, such as described, for example, in March, ADVANCED ORGANIC CHEMISTRY 4th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wiley 1999) (all of which are incorporated by reference in their entirety). General methods for the preparation of polymers as disclosed herein may be derived from known reactions in the field, and the reactions may be modified by the use of appropriate reagents and conditions, as would be recognized by the skilled person, for the introduction of the various moieties found in the formulae as provided herein. As a guide the following synthetic methods may be utilized. Generally, polymerization of fluorene polymeric structures may be accomplished using polymerization techniques known to those of skill in the art or using methods known in the art in combination with methods described herein. For example, polymerization can be achieved via Suzuki coupling with a commercially available fluorene-dihalide monomer, e.g., 2,7-dibromofluorene, and its diboronic acid or ester derivative: Structures A-1 and A-2 are catalyzed by a metal catalyst to form exemplary polymer A-3 with termination points, labeled Y. Each Y is independently —H, —Br, —B(OH)2, or boronic ester, e.g., 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl. Synthesis of diboronic ester derivatives from a fluorene-dihalide monomer can also be accomplished via Suzuki coupling with bis(pinacolato)diboron: Substituents such as ethylene glycol oligomers or ethylene glycol polymers may be attached to monomers prior to polymerization or to the polymer itself after polymerization. An exemplary scheme of synthesizing substituted fluorene monomers with mPEGylated groups is as follows: 2,7-dibromofluorene (B-1) and 3-bromopropanol in the presence of a strong base such as sodium hydroxide, potassium hydroxide, or the like and a phase transfer catalyst, e.g. tetrabutylammonium bromide, is heated and reacted to completion to form 2,7-dibromo-9,9-di(3′-hydroxypropanyl)fluorene (B-2). —OH groups of B-2 are tosylated with tosyl chloride in the presence of pyridine and allowed to react to completion to form 2,7-dibromo-9,9-di(3′-methylbenzenesulfonatopropanyl)fluorene (B-3). B-3 is then reacted with a mPEG(x) alcohol in the presence of potassium tert-butoxide to form B-4 with attached mPEG chains. mPEG alcohols can have 1-50 mPEG chains. Typical sizes include but are not limited to mPEG5, mPEG8, mPEG11, mPEG24. In an alternative scheme, mPEG alcohols can be tosylated first via tosyl chloride and then reacted to B-2 to form B-4. Substituted monomers, such as exemplary structure B-4, can be further derivatized to diboronic esters in the schemes disclosed herein and subsequently be used for polymerization such as via Suzuki coupling. Polymeric fluorenes may also be obtained through the use of other reaction schemes involving organometallic catalysis. For example, the Yamamoto reaction uses a nickel(0)-based catalyst for the homo-coupling of aryl halide monomers like exemplary structure B-4. Additionally, conjugated polymers can be synthesized using Stille, Heck, and Sonogashira coupling reactions. See, e.g., Yamamoto et al., Macromolecules 25: 1214-1223, 1992; Kreyenschmidt et al., Macromolecules 28: 4577-4582, 1995; and Pei et al., J. Am. Chem. Soc. 118: 7416-7417, 1996 regarding Yamamoto reaction schemes. See, also, Leclerc, Polym. Sci. Part A: Polym. Chem. 39: 2867-2873, 2001 for Stille reaction schemes; Mikroyannidis et al., J. Polym. Sci. Part A: Polym. Chem. 45: 4661-4670, 2007 for Heck reaction schemes; and Sonogashira et al., Tetrahedron Lett. 16: 4467-4470, 1975 and Lee et al., Org. Lett. 3: 2005-2007, 2001 for Sonogashira reaction schemes. Linkers and capping units can be conjugated to a fluorene polymer backbone via similar mechanisms as described previously. For example, bromo- and boronic esters of capping units can be used to append one or both ends of a polymer. Utilizing both bromo- and boronic esters of capping units will append both ends of polymer. Utilizing only one form, either a bromo- or boronic ester of a capping unit, will append only those ends terminated with its respective complement and for symmetric A-A+B-B polymerizations can be used to statistically modify only one end of a polymer. For asymmetric polymers this approach is used to chemically ensure the polymers are only modified at a single chain terminus. FIG. 11 depicts appending an exemplary fluorene polymer with Y ends with one or more phenyl groups with bromobenzene, phenyl boronic acid or both using Suzuki coupling. Capping units can also be appended asymmetrically by first reacting a bromo-capping unit with a polymer with Y ends and subsequently reacting the polymer with a boronic ester capping unit. Exemplary bromo- and boronic ester capping units include but are not limited to the following structures: Further capping units can be found in structures 1-31 described herein or in the following Examples and methods for their attachment. The incorporation of optional linkers into conjugated polymer backbones further described in U.S. application Ser. No. 11/868,870, filed Oct. 8, 2007 and published as U.S. Application No. 2008/0293164, which application is herein incorporated by reference in its entirety. A desired optional linker incorporation can be achieved by varying the molar ratio of optional linker to bi-functional monomer. For example, an optional linker can be incorporated by substituting a percentage of one of the bi-functional monomers with a similar bi-functional optional linker which comprises the conjugation site of interest. The number and type of linking site included in the polymer is controlled by the feed ratio of the monomers to optional linker in the polymerization reaction. By varying the feed ratio, conjugated polymers can contain at least about 0.01 mol % of linker, L, and may contain at least about 0.02 mol %, at least about 0.05 mol %, at least about 0.1 mol %, at least about 0.2 mol %, at least about 0.5 mol %, at least about 1 mol %, at least about 2 mol %, at least about 5 mol %, at least about 10 mol %, at least about 20 mol %, or at least about 30 mol %. The conjugated polymers may contain up to 100 mol % of linker, L, and may contain about 99 mol % or less, about 90 mol % or less, about 80 mol % or less, about 70 mol % or less, about 60 mol % or less, about 50 mol % or less, or about 40 mol % or less. Linkers can be evenly or randomly distributed along the polymer main chain. In further embodiments, an optional linker can further allow covalent attachment of the resulting polymer to biomolecules, secondary reporters or other assay components. In alternative embodiments, the methods described herein to incorporate optional linkers may be used in combination with methods of introducing capping units with linking sites to produce polymers with both internal and terminal linking sites for conjugation. A non-limiting application of a polymer with both optional linkers and terminal capping units with linking sites for conjugation are polymer-dye-biomolecule tandem conjugates where the polymer is used as an energy transfer donor, such as in FRET, to a secondary dye acceptor thus shifting the emission wavelength to that of the corresponding dye. The person skilled in the art may further appreciate various syntheses and polymerization methods and embodiments of the present disclosure upon review of the following illustrative and non-limiting Examples. Antigen-Antibody Interactions The interactions between antigens and antibodies are the same as for other noncovalent protein-protein interactions. In general, four types of binding interactions exist between antigens and antibodies: (i) hydrogen bonds, (ii) dispersion forces, (iii) electrostatic forces between Lewis acids and Lewis bases, and (iv) hydrophobic interactions. Certain physical forces contribute to antigen-antibody binding, for example, the fit or complimentary of epitope shapes with different antibody binding sites. Moreover, other materials and antigens may cross-react with an antibody, thereby competing for available free antibody. Measurement of the affinity constant and specificity of binding between antigen and antibody is a pivotal element in determining the efficacy of an immunoassay, not only for assessing the best antigen and antibody preparations to use but also for maintaining quality control once the basic immunoassay design is in place. Antibodies Antibody molecules belong to a family of plasma proteins called immunoglobulins, whose basic building block, the immunoglobulin fold or domain, is used in various forms in many molecules of the immune system and other biological recognition systems. A typical immunoglobulin has four polypeptide chains, containing an antigen binding region known as a variable region and a non-varying region known as the constant region. Native antibodies and immunoglobulins are usually heterotetrameric glycoproteins of about 150,000 Daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies between the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains. Each light chain has a variable domain at one end (VL) and a constant domain at its other end. The constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain. Depending on the amino acid sequences of the constant domain of their heavy chains, immunoglobulins can be assigned to different classes. There are at least five (5) major classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, and several of these may be further divided into subclasses (isotypes), e.g. IgG-1, IgG-2, IgG-3 and IgG-4; IgA-1 and IgA-2. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known. Further details regarding antibody structure, function, use and preparation are discussed in U.S. Pat. No. 6,998,241, issued Feb. 14, 2006, the entire contents of which are incorporated herein by reference. Sandwich Assays Antibody or multiple antibody sandwich assays are well known to those skilled in the art including a disclosed in U.S. Pat. No. 4,486,530, issued Dec. 4, 1984, and references noted therein. The structures described in FIGS. 6, 7, 8, 9, 10 and 14 can be used directly as described or in various sandwich configurations including those described in Example 37. A sandwich configuration or a sandwich assay refers to the use of successive recognition events to build up layers of various biomolecules and reporting elements to signal the presence of a particular biomolecule, for example a target biomolecule or a target-associated biomolecule. A standard example of this would be the successive use of antibodies. In these assays, a primary antibody binds the target, the secondary antibody binds the primary, a third antibody can bind the secondary and so on. With each successive layer additional reporting groups can be added. Another strategy is using a repetitive addition of alternating layers of two (or more) mutually-recognizable components, or more than two components in a chain-recognition relationship, which comprise one or both of the components in a form of multimeric structure. In such a setup, one or more of the functional group(s) in each of the multimeric structure can be labeled with reporting group(s) and the unoccupied functional group(s) can serve as the recognition site for the other component(s), and this system will subsequently provide a platform for signal amplification. A typical example of this approach is the use of streptavidin-reporter conjugate and biotinylated anti-streptavidin antibody. In such assays, a biotinylated sensor molecule (nucleic acid or antibody) can be used to bind a target biomolecule, which is subsequently recognized by a detection system containing a streptavidin-reporter conjugate and biotinylated anti-streptavidin antibody. The sandwich structure in this case can be built up by successive rounds of biotinylated antibodies and labeled streptavidin complexes interaction to achieve the signal amplification. With an additional conjugation of a conjugated polymer to either the biotinylated antibody or the streptavidin-reporter complex, it is possible to further increase the signal output. In essence, the integration of a conjugated polymer in this type of signal amplification system can further amplify signals to a higher level. The bioconjugated polymer complexes described in FIGS. 6, 7, 8, 9, 10, 14, 15, 16 and 17 can be used to create optically enhanced sandwich assays by directly integrating a light harvesting conjugated polymer into commonly utilized recognition elements. The benefits of the conjugated polymer conjugated structures can also be applied directly to the primary target recognition elements without the need for successive recognition elements. For example, a primary antibody can be directly conjugated to polymer-dye complex such as shown in FIG. 14. Such a complex can be used to directly probe the presence of a target biomolecule. Polynucleotides Amplified target polynucleotides may be subjected to post amplification treatments. For example, in some cases, it may be desirable to fragment the target polynucleotide prior to hybridization in order to provide segments which are more readily accessible. Fragmentation of the nucleic acids can be carried out by any method producing fragments of a size useful in the assay being performed; suitable physical, chemical and enzymatic methods are known in the art. An amplification reaction can be performed under conditions which allow the sensor polynucleotide to hybridize to the amplification product during at least part of an amplification cycle. When the assay is performed in this manner, real-time detection of this hybridization event can take place by monitoring for light emission during amplification. Real time PCR product analysis (and related real time reverse-transcription PCR) provides a well-known technique for real time PCR monitoring that has been used in a variety of contexts, which can be adapted for use with the methods described herein (see, Laurendeau et al. (1999) “TaqMan PCR-based gene dosage assay for predictive testing in individuals from a cancer family with INK4 locus haploinsufficiency” Clin Chem 45(7):982-6; Laurendeau et al. (1999) “Quantitation of MYC gene expression in sporadic breast tumors with a real-time reverse transcription-PCR assay” Clin Chem 59(12):2759-65; and Kreuzer et al. (1999) “LightCycler technology for the quantitation of bcr/abl fusion transcripts” Cancer Research 59(13):3171-4, all of which are incorporated by reference). Samples In principle, a sample can be any material suspected of containing a target biomolecule (e.g., antibody, protein, affinity ligand, peptide, nucleic acid and the like) capable of causing excitation of a conjugated polymer complex. In some embodiments, the sample can be any source of biological material which comprises biomolecules that can be obtained from a living organism directly or indirectly, including cells, tissue or fluid, and the deposits left by that organism, including viruses, mycoplasma, and fossils. The sample may comprise a target biomolecule prepared through synthetic means, in whole or in part. Typically, the sample is obtained as or dispersed in a predominantly aqueous medium. Nonlimiting examples of the sample include blood, urine, semen, milk, sputum, mucus, a buccal swab, a vaginal swab, a rectal swab, an aspirate, a needle biopsy, a section of tissue obtained for example by surgery or autopsy, plasma, serum, spinal fluid, lymph fluid, the external secretions of the skin, respiratory, intestinal, and genitourinary tracts, tears, saliva, tumors, organs, samples of in vitro cell culture constituents (including but not limited to conditioned medium resulting from the growth of cells in cell culture medium, putatively virally infected cells, recombinant cells, and cell components), and a recombinant library comprising polynucleotide sequences. The sample can be a positive control sample which is known to contain the target biomolecule or a surrogate therefore. A negative control sample can also be used which, although not expected to contain the target biomolecule, is suspected of containing it (via contamination of one or more of the reagents) or another component capable of producing a false positive, and is tested in order to confirm the lack of contamination by the target biomolecule of the reagents used in a given assay, as well as to determine whether a given set of assay conditions produces false positives (a positive signal even in the absence of target biomolecule in the sample). The sample can be diluted, dissolved, suspended, extracted or otherwise treated to solubilize and/or purify any target polynucleotide present or to render it accessible to reagents which are used in an amplification scheme or to detection reagents. Where the sample contains cells, the cells can be lysed or permeabilized to release the polynucleotides within the cells. One step permeabilization buffers can be used to lyse cells which allow further steps to be performed directly after lysis, for example a polymerase chain reaction. Organic Dyes Organic dyes include signaling chromophores and fluorophores. In some embodiments, a signaling chromophore or fluorophore may be employed, for example to receive energy transferred from an excited state of an optically active unit, or to exchange energy with a labeled probe, or in multiple energy transfer schemes. Fluorophores useful in the inventions described herein include any substance which can absorb energy of an appropriate wavelength and emit or transfer energy. For multiplexed assays, a plurality of different fluorophores can be used with detectably different emission spectra. Typical fluorophores include fluorescent dyes, semiconductor nanocrystals, lanthanide chelates, and fluorescent proteins. Exemplary fluorescent dyes include fluorescein, 6-FAM, rhodamine, Texas Red, tetramethylrhodamine, a carboxyrhodamine, carboxyrhodamine 6G, carboxyrhodol, carboxyrhodamine 110, Cascade Blue, Cascade Yellow, coumarin, Cy2 ®, Cy3 ®, Cy3.5®, Cy5®, Cy5.5®, Cy-Chrome, DyLight 350, DyLight 405, DyLight 488, DyLight 549, DyLight 594, DyLight 633, DyLight 649, DyLight 680, DyLight 750, DyLight 800, phycoerythrin, PerCP (peridinin chlorophyll-a Protein), PerCP-Cy5.5, JOE (6-carboxy-4′,5′-dichloro-2′,7′-dimelhoxyfluorescein), NED, ROX (5-(and-6)-carboxy-X-rhodamine), HEX, Lucifer Yellow, Marina Blue, Oregon Green 488, Oregon Green 500, Oregon Green 514, Alexa Fluor® 350, Alexa Fluor® 430, Alexa Fluor® 488, Alexa Fluor® 532, Alexa Fluor® 546, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 633, Alexa Fluor® 647, Alexa Fluor® 660, Alexa Fluor® 680, 7-amino-4-methylcoumarin-3-acetic acid, BODIPY® FL, BODIPY® FL-Br2, BODIPY® 530/550, BODIPY® 558/568, BODIPY® 564/570, BODIPY® 576/589, BODIPY® 581/591, BODIPY® 630/650, BODIPY® 650/665, BODIPY® R6G, BODIPY® TMR, BODIPY® TR, conjugates thereof, and combinations thereof. Exemplary lanthanide chelates include europium chelates, terbium chelates and samarium chelates. A wide variety of fluorescent semiconductor nanocrystals (“SCNCs”) are known in the art; methods of producing and utilizing semiconductor nanocrystals are described in: PCT Publ. No. WO 99/26299 published May 27, 1999, inventors Bawendi et al.; U.S. Pat. No. 5,990,479 issued Nov. 23, 1999 to Weiss et al.; and Bruchez et al., Science 281:2013, 1998. Semiconductor nanocrystals can be obtained with very narrow emission bands with well-defined peak emission wavelengths, allowing for a large number of different SCNCs to be used as signaling chromophores in the same assay, optionally in combination with other non-SCNC types of signaling chromophores. Exemplary polynucleotide-specific dyes include acridine orange, acridine homodimer, actinomycin D, 7-aminoactmomycin D (7-AAD), 9-amino-6-chlor-2-methoxyacridine (ACMA), BOBO™-1 iodide (462/481), BOBO™-3 iodide (570/602), BOPRO™-1 iodide (462/481), BOPRO™-3 iodide (575/599), 4′,6-diamidino-2-phenylindole, dihydrochloride (DAPI), 4′,6-diamidino-2-phenylindole, dihydrochloride (DAPI), 4′,6-diamidino-2-phenylindole, dilactate (DAPI, dilactate), dihydroethidium (hydroethidine), dihydroethidium (hydroethidine), dihydroethidium (hydroethidine), ethidium bromide, ethidium diazide chloride, ethidium homodimer-1 (EthD-1), ethidium homodimer-2 (EthD-2), ethidium monoazide bromide (EMA), hexidium iodide, Hoechst 33258, Hoechst 33342, Hoechst 34580, Hoechst S769121, hydroxystilbamidine, methanesulfonate, JOJO™-1 iodide (529/545), JO-PRO™-1 iodide (530/546), LOLO™-1 iodide (565/579), LO-PRO™-1 iodide (567/580), NeuroTrace™ 435/455, NeuroTrace™ 500/525, NeuroTrace™ 515/535, NeuroTrace™ 530/615, NeuroTrace™ 640/660, OliGreen, PicoGreen® ssDNA, PicoGreen® dsDNA, POPO™-1 iodide (434/456), POPO™-3 iodide (534/570), PO-PRO™-1 iodide (435/455), POPRO™-3 iodide (539/567), propidium iodide, RiboGreen®, SlowFade®, SlowFade® Light, SYBR® Green I, SYBR® Green II, SYBR® Gold, SYBR® 101, SYBR® 102, SYBR® 103, SYBR® DX, TO-PRO®-1, TO-PRO®-3, TO-PRO®-5, TOT™-1, TOTO®-3, YO-PRO®-1 (oxazole yellow), YO-PRO®-3, YOYO®-1, YOYO®-3, TO, SYTOX® Blue, SYTOX® Green, SYTOX® Orange, SYTO® 9, SYTO® BC, SYTO® 40, SYTO® 41, SYTO® 42, SYTO® 43, SYTO® 44, SYTO® 45, SYTO® Blue, SYTO® 11, SYTO® 12, SYTO® 13, SYTO® 14, SYTO® 15, SYTO® 16, SYTO® 20, SYTO® 21, SYTO® 22, SYTO® 23, SYTO® 24, SYTO® 25, SYTO® Green, SYTO® 80, SYTO® 81, SYTO® 82, SYTO® 83, SYTO® 84, SYTO® 85, SYTO® Orange, SYTO® 17, SYTO® 59, SYTO® 60, SYTO® 61, SYTO® 62, SYTO® 63, SYTO® 64, SYTO® Red, netropsin, distamycin, acridine orange, 3,4-benzopyrene, thiazole orange, TOMEHE, daunomycin, acridine, pentyl-TOTAB, and butyl-TOTIN. Asymmetric cyanine dyes may be used as the polynucleotide-specific dye. Other dyes of interest include those described by Geierstanger, B. H. and Wemmer, D. E., Annu. Rev. Vioshys. Biomol. Struct. 1995, 24, 463-493, by Larson, C. J. and Verdine, G. L., Bioorganic Chemistry: Nucleic Acids, Hecht, S. M., Ed., Oxford University Press: New York, 1996; pp 324-346, and by Glumoff, T. and Goldman, A. Nucleic Acids in Chemistry and Biology, 2nd ed., Blackburn, G. M. and Gait, M. J., Eds., Oxford University Press: Oxford, 1996, pp 375-441. The polynucleotide-specific dye may be an intercalating dye, and may be specific for double-stranded polynucleotides. The term “fluorescent protein” includes types of protein known to absorb and emit light. One of the more commonly used classes of such materials are phycobiliproteins. Examples include but are not limited to phycoerythrin (PE and R-PE), allophycocyanin (APC) and PerCP. Other classes include green fluorescent protein and related versions. The term “green fluorescent protein” refers to both native Aequorea green fluorescent protein and mutated versions that have been identified as exhibiting altered fluorescence characteristics, including altered excitation and emission maxima, as well as excitation and emission spectra of different shapes (Delagrave, S. et al. (1995) Bio/Technology 13:151-154; Heim, R. et al. (1994) Proc. Natl. Acad. Sci. USA 91:12501-12504; Heim, R. et al. (1995) Nature 373:663-664). Delgrave et al. isolated mutants of cloned Aequorea victoria GFP that had red-shifted excitation spectra. Bio/Technology 13:151-154 (1995). Heim, R. et al. reported a mutant (Tyr66 to His) having a blue fluorescence (Proc. Natl. Acad. Sci. (1994) USA 91:12501-12504). Substrates In some embodiments, an assay component can be located upon a substrate. The substrate can comprise a wide range of material, either biological, nonbiological, organic, inorganic, or a combination of any of these. For example, the substrate may be a polymerized Langmuir Blodgett film, functionalized glass, Si, Ge, GaAs, GaP, SiO2, SiN4, modified silicon, or any one of a wide variety of gels or polymers such as (poly)tetrafluoroethylene, (poly)vinylidenedifluoride, polystyrene, cross-linked polystyrene, polyacrylic, polylactic acid, polyglycolic acid, poly(lactide coglycolide), polyanhydrides, poly(methyl methacrylate), poly(ethylene-co-vinyl acetate), polysiloxanes, polymeric silica, latexes, dextran polymers, epoxies, polycarbonates, or combinations thereof. Conducting polymers and photoconductive materials can be used. Substrates can be planar crystalline substrates such as silica based substrates (e.g. glass, quartz, or the like), or crystalline substrates used in, e.g., the semiconductor and microprocessor industries, such as silicon, gallium arsenide, indium doped GaN and the like, and includes semiconductor nanocrystals. The substrate can take the form of a photodiode, an optoelectronic sensor such as an optoelectronic semiconductor chip or optoelectronic thin-film semiconductor, or a biochip. The location(s) of probe(s) on the substrate can be addressable; this can be done in highly dense formats, and the location(s) can be microaddressable or nanoaddressable. Silica aerogels can also be used as substrates, and can be prepared by methods known in the art. Aerogel substrates may be used as free standing substrates or as a surface coating for another substrate material. The substrate can take any form and typically is a plate, slide, bead, pellet, disk, particle, microparticle, nanoparticle, strand, precipitate, optionally porous gel, sheets, tube, sphere, container, capillary, pad, slice, film, chip, multiwell plate or dish, optical fiber, etc. The substrate can be any form that is rigid or semi-rigid. The substrate may contain raised or depressed regions on which an assay component is located. The surface of the substrate can be etched using well known techniques to provide for desired surface features, for example trenches, v-grooves, mesa structures, or the like. Surfaces on the substrate can be composed of the same material as the substrate or can be made from a different material, and can be coupled to the substrate by chemical or physical means. Such coupled surfaces may be composed of any of a wide variety of materials, for example, polymers, plastics, resins, polysaccharides, silica or silica-based materials, carbon, metals, inorganic glasses, membranes, or any of the above-listed substrate materials. The surface can be optically transparent and can have surface Si—OH functionalities, such as those found on silica surfaces. The substrate and/or its optional surface can be chosen to provide appropriate characteristics for the synthetic and/or detection methods used. The substrate and/or surface can be transparent to allow the exposure of the substrate by light applied from multiple directions. The substrate and/or surface may be provided with reflective “mirror” structures to increase the recovery of light. The substrate and/or its surface is generally resistant to, or is treated to resist, the conditions to which it is to be exposed in use, and can be optionally treated to remove any resistant material after exposure to such conditions. Polynucleotide or polypeptide probes can be fabricated on or attached to the substrate by any suitable method, for example the methods described in U.S. Pat. No. 5,143,854, PCT Publ. No. WO 92/10092, U.S. patent application Ser. No. 07/624,120, filed Dec. 6, 1990 (now abandoned), Fodor et al., Science, 251: 767-777 (1991), and PCT Publ. No. WO 90/15070). Techniques for the synthesis of these arrays using mechanical synthesis strategies are described in, e.g., PCT Publication No. WO 93/09668 and U.S. Pat. No. 5,384,261. Still further techniques include bead based techniques such as those described in PCT Appl. No. PCT/US93/04145 and pin based methods such as those described in U.S. Pat. No. 5,288,514. Additional flow channel or spotting methods applicable to attachment of sensor polynucleotides or polypeptides to the substrate are described in U.S. patent application Ser. No. 07/980,523, filed Nov. 20, 1992, and U.S. Pat. No. 5,384,261. Reagents are delivered to the substrate by either (1) flowing within a channel defined on predefined regions or (2) “spotting” on predefined regions. A protective coating such as a hydrophilic or hydrophobic coating (depending upon the nature of the solvent) can be used over portions of the substrate to be protected, sometimes in combination with materials that facilitate wetting by the reactant solution in other regions. In this manner, the flowing solutions are further prevented from passing outside of their designated flow paths. Typical dispensers include a micropipette optionally robotically controlled, an ink-jet printer, a series of tubes, a manifold, an array of pipettes, or the like so that various reagents can be delivered to the reaction regions sequentially or simultaneously. The substrate or a region thereof may be encoded so that the identity of the sensor located in the substrate or region being queried may be determined. Any suitable coding scheme can be used, for example optical codes, RFID tags, magnetic codes, physical codes, fluorescent codes, and combinations of codes. Excitation and Detection Any instrument that provides a wavelength that can excite the conjugated polymer complex and is shorter than the emission wavelength(s) to be detected can be used for excitation. Commercially available devices can provide suitable excitation wavelengths as well as suitable detection components. Exemplary excitation sources include a broadband UV light source such as a deuterium lamp with an appropriate filter, the output of a white light source such as a xenon lamp or a deuterium lamp after passing through a monochromator to extract out the desired wavelengths, a continuous wave (cw) gas laser, a solid state diode laser, or any of the pulsed lasers. Emitted light can be detected through any suitable device or technique; many suitable approaches are known in the art. For example, a fluorimeter or spectrophotometer may be used to detect whether the test sample emits light of a wavelength characteristic of the signaling chromophore upon excitation of the conjugated polymer. Compositions of Matter Also provided are compositions of matter of any of the molecules described herein in any of various forms. The conjugated polymers and complexes including conjugated polymers as described herein may be provided in purified and/or isolated form. The conjugated polymers and complexes including conjugated polymers may be provided in either crystalline or amorphous form. The conjugated polymers and complexes including conjugated polymers may be provided in solution, which may be a predominantly aqueous solution, which may comprise one or more of the additional solution components described herein, including without limitation additional solvents, buffers, biomolecules, polynucleotides, fluorophores, etc. In addition, a mixture of CPs in solution is also able to provide improved detection sensitivity as compared to that for a single CP/dye system. The conjugated polymers and complexes including conjugated polymers can be present in solution at a concentration at which a first emission from the first optically active units can be detected in the absence of biomolecule target or a biomolecule associated therewith. The solution may comprise additional components as described herein, including labeled probes such as fluorescently labeled antibodies or polynucleotides, specific for a species or a class of biomolecule target or a biomolecule associated therewith for the conjugated polymers and complexes including conjugated polymers. The conjugated polymers and complexes including conjugated polymers may be provided in the form of a film. The compositions of matter may be claimed by any property described herein, including by proposed structure, by method of synthesis, by absorption and/or emission spectrum, by elemental analysis, by NMR spectra, or by any other property or characteristic. In some embodiments expression of a gene is detected in a sample. In a further embodiment identification of a cell marker or cell type is detected in a sample either in a flow cytometer, cell sorter, microscope, plate reader or fluorescence imager. In a further embodiment the identification of cell type or marker is used in the diagnosis of lymphoma or other circulating cancers. In a further embodiment the identification of cell type or marker is used in the diagnosis and monitoring of HIV infection. In a further embodiment the identification of cell type or marker is used to sort cells for therapeutic application. In a further embodiment, a measured result of detecting a biomolecule target or a biomolecule associated therewith can be used to diagnose a disease state of a patient. In yet another embodiment the detection method of the invention can further include a method of diagnosing a disease state. In a related embodiment, the method of diagnosing a disease can include reviewing or analyzing data relating to the presence of a biomolecule target or a biomolecule associated therewith and providing a conclusion to a patient, a health care provider or a health care manager, the conclusion being based on the review or analysis of data regarding a disease diagnosis. Reviewing or analyzing such data can be facilitated using a computer or other digital device and a network as described herein. It is envisioned that information relating to such data can be transmitted over the network. In practicing the methods of the present invention, many conventional techniques in molecular biology are optionally utilized. These techniques are well known and are explained in, for example, Ausubel et al. (Eds.) Current Protocols in Molecular Biology, Volumes I, II, and III, (1997), Ausubel et al. (Eds.), Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, 5th Ed., John Wiley & Sons, Inc. (2002), Sambrook et al., Molecular Cloning: A Laboratory Manual, 3rd Ed., Cold Spring Harbor Laboratory Press (2000), Innis et al. (Eds.) PCR Protocols: A Guide to Methods and Applications, Elsevier Science & Technology Books (1990), and Greg T. Hermanson, Bioconjugate Techniques, 2nd Ed., Academic Press, Inc. (2008) all of which are incorporated herein by reference. FIG. 12 is a block diagram showing a representative example logic device through which reviewing or analyzing data relating to the present invention can be achieved. Such data can be in relation to a disease, disorder or condition in a subject. FIG. 12 shows a computer system (or digital device) 800 connected to an apparatus 820 for use with the conjugated polymers or conjugated polymers complexes 824 to, for example, produce a result. The computer system 800 may be understood as a logical apparatus that can read instructions from media 811 and/or network port 805, which can optionally be connected to server 809 having fixed media 812. The system shown in FIG. 12 includes CPU 801, disk drives 803, optional input devices such as keyboard 815 and/or mouse 816 and optional monitor 807. Data communication can be achieved through the indicated communication medium to a server 809 at a local or a remote location. The communication medium can include any means of transmitting and/or receiving data. For example, the communication medium can be a network connection, a wireless connection or an internet connection. It is envisioned that data relating to the present invention can be transmitted over such networks or connections. In one embodiment, a computer-readable medium includes a medium suitable for transmission of a result of an analysis of a biological sample. The medium can include a result regarding a disease condition or state of a subject, wherein such a result is derived using the methods described herein. Kits Kits comprising reagents useful for performing described methods are also provided. In some embodiments, a kit comprises reagents including conjugated polymers or conjugated polymers complexes, bioconjugates, for example, antibodies, nucleic acids, and other components as described herein. The kit may optionally contain one or more of the following: one or more labels that can be incorporated into conjugated polymers or conjugated polymers complexes; and one or more substrates which may or may not contain an array, etc. The components of a kit can be retained by a housing. Instructions for using the kit to perform a described method can be provided with the housing, and can be provided in any fixed medium. The instructions may be located inside the housing or outside the housing, and may be printed on the interior or exterior of any surface forming the housing that renders the instructions legible. A kit may be in multiplex form for detection of one or more different target biomolecules or biomolecules associated therewith. As described herein and shown in FIG. 13, in certain embodiments a kit 903 can include a container or housing 902 for housing various components. As shown in FIG. 13, and described herein, in one embodiment a kit 903 comprising one or more conjugated polymers or conjugated polymers complexes reagents 905, and optionally a substrate 900 is provided. As shown in FIG. 13, and described herein, the kit 903 can optionally include instructions 901. Other embodiments of the kit 903 are envisioned wherein the components include various additional features described herein. EXAMPLES The following examples provide illustrative methods for making and testing the effectiveness of the conjugated polymers described herein. These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. It will be apparent to those of skill in the art that variations may be applied to the methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the claims. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the appended claims. Example 1: Synthesis of a Polymer of Formula (I) Example 1a: Synthesis of Monomers, 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (A) and 9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-2,7-di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)fluorene (B) for Subsequent Polymerization Step 1: 2,7-dibromo-9,9-di(3′-hydroxypropanyl)fluorene 2,7-dibromofluorene (9.72 g, 30 mmol), tetrabutylammonium bromide (300 mg, 0.93 mmol), and DMSO (100 mL) were added to a 3-neck flask under nitrogen(g), followed by the addition of 50% NaOH (15 mL, 188 mmol) via syringe. The mixture was heated to 80° C., and 3-bromopropanol (6.70 mL, 77 mmol) was added dropwise via addition funnel, and the reaction mixture was stirred at 80° C. for another 2 hours. Upon completion, the mixture was cooled to room temperature and quenched with water (250 mL). The aqueous layer was extracted with ethyl acetate (3 150 mL portions). The organic layers were combined, washed with water, then dried over MgSO4, and filtered. The solvent was removed and the residual was recrystallized in chloroform to yield pale yellow needle crystals (9.20 g, 70%). Step 2: 2,7-dibromo-9,9-di(3′-methylbenzenesulfonatopropanyl)fluorene 2,7-dibromo-9,9-di(3′-hydroxypropanyl)fluorene (500 mg, 1.14 mmol) was dissolved in dichloromethane (5 mL) at 0° C. under nitrogen(g). To the mixture, added p-toluenesulfonyl chloride (650 mg, 3.40 mmol), followed by pyridine (0.39 mL, 4.77 mmol). Allowed reaction to stir at 0° C. and naturally rise to room temperature over night. The reaction was quenched with water (15 mL). Removal of solvent by vacuo resulted solids formation. Filtered off solids to yield white solids (758 mg, 89%). Step 3: 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (A) mPEG11 alcohol (770 mg, 1.49 mmol) was dissolved in anhydrous THF (2 mL) at 0° C. under nitrogen. To the mixture, was added potassium tert-butoxide (1.63 mmol, 1.63 mL, 1M in THF). After 10 min stirring, 2,7-dibromo-9,9-di(3′-methylbenzenesulfonatopropanyl)fluorene (504 mg, 0.673 mmol) in 10 mL of THF was added via a syringe. The mixture was allowed to room temperature and stirred overnight. The reaction mixture was diluted with THF. The insoluble inorganic salt was removed by filtration. Concentration of the filtrate yielded crude product, which was purified by column chromatography (DCM-MeOH) to yield a colorless oil (605 mg, 62.5%). Step 4: 9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-2,7-di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)fluorene (B) 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (1.510 g, 1.501 mmol), bis(pinacolato)diboron (800 mg, 3.15 mmol), potassium acetate (619 mg, 6.31 mmol), Pd(dppf)Cl2 [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)] (51.5 mg, 0.063 mmol) and DMSO (30 mL) were mixed under N2. The mixture was heated at 80° C. for 5.5 hour. Upon completion, the DMF was distilled and water (50 mL) was added. The product was extracted with DCM (3×40 mL). The organic layers were combined and concentrated. The crude product was purified by column chromatography (DCM-MeOH) to give colorless oil (1.015 g, 63%). Example 1b: Polymerization of Monomers (A) and (B) 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (A) (0.084 mmol, 120 mg), 9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-2,7-di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)fluorene (B) (0.088 mmol, 135 mg), and palladium tetra(triphenylphosphine) (0.0035 mmol, 4 mg) were combined in a round bottom flask equipped with a stirbar. Next, 0.35 mL of 2M potassium carbonate (aq) and 1.9 mL of tetrahydrofuran were added and the flask is fitted with a vacuum adaptor and put on a Schlenk line. The mixture was degassed using 3 freeze-pump-thaw cycles. The degassed mixture was heated to 80° C. under nitrogen with vigorous stirring for 18 hours. The reaction mixture was then cooled and the solvent removed with rotary evaporation. The resulting semisolid was diluted with ca. 50 mL water and filtered through glass fiber filter paper. Ethanol was added to adjust the solvent to 20% ethanol in water. Preparative gel permeation chromatography was performed with G-25 desalting medium to remove excess salts from the polymer. Solvent in the fractions was removed with rotary evaporation and 100 mg of poly [2,7{9,9-bis (2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene] was collected as an amber oil. Example 2: Synthesis of Asymmetric Polymers of Formula (I) Via Suzuki Coupling Example 2a: Synthesis of Asymmetric Monomer, 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene (C) for Subsequent Polymerization Step 1: 2-dibromo-7-iodofluorene 2-bromofluorene (10.01 g, 40.84 mmol), acetic acid (170 mL), water (8 mL), iodine (4.34 g, 17.20 mmol), potassium iodate (2.18 g, 10.19 mmol) and sulfuric acid (4 mL) were mixed under nitrogen. The resulting mixture was heated at 80° C. for 2h and cooled to room temperature. The formed precipitate which is the desired product was collected after filtration and acetic acid wash (13.68 g, 90%). Step 2: 2-dibromo-9,9-di(3′hydroxypropanyl)-7-iodofluorene 2-dibromo-7-iodofluorene (2.186 g, 5.892 mmol), tetrabutylammonium bromide (60 mg, 0.186 mmol), and DMSO (25 mL) were added to a 3-neck flask under nitrogen(g), followed by the addition of 50% NaOH (4 mL, 50 mmol) via syringe. The mixture was heated to 80° C., and 3-bromopropanol (1.33 mL, 14.7 mmol) was added slowly, and the reaction was stirred at 80° C. for another 1 hour. Upon completion, the mixture was cooled to room temperature and quenched with water. The precipitate as crude product was collected after filtration. The crude product was purified by column chromatography (eluant: hexane-ethylacetate) to give pale yellow solid (2.15 g, 75%). Step 3: 2-bromo-9,9-di(3′-hydroxypropanyl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene 2-dibromo-9,9-di(3′hydroxypropanyl)-7-iodofluorene (2.454 g, 5.037 mmol), bis(pinacolato)diboron (1.407 g, 5.541 mmol), potassium acetate (1.483 g, 15.11 mmol), Pd(dppf)Cl2 (123 mg, 0.15 mmol) and DMSO (25 mL) were mixed under N2. The mixture was heated at 80° C. for 1.5 hour. Upon completion, the mixture was cooled to room temperature and quenched with water (50 mL). The product was extracted with DCM (3×40 mL). The organic layers were combined and concentrated. The crude product was purified by column chromatography (eluant: hexane-ethylacetate) to give pale solid (2.09 g, 85%). Step 4: 2-bromo-9,9-di(3′-methanesulfanotopropanyl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene 2-bromo-9,9-di(3′-hydroxypropanyl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene (2.280 g, 4.694 mmol) and p-toluenesulfonyl chloride (2.684 g, 14.08 mmol) were dissolved in dichloromethane at room temperature under N2. Triethylamine (3.95 mL, 28.2 mmol) was added slowly via syringe. The mixture was stirred at room temperature over night. The mixture was then concentrated and purified by column chromatography (Hexane-EtOAc) to yield pale solid (2.66 g, 72%). Step 5: 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorine (C) mPEG11 alcohol (3.331 g, 6.448 mmol) was dissolved in anhydrous THF (20 mL) at 0° C. under nitrogen. To the mixture, was added potassium tert-butoxide (7.74 mmol, 7.74 mL, 1M in THF). After 10 min stirring, 2-bromo-9,9-di(3′-methanesulfanotopropanyl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorine (2.052 g, 2.579 mmol) in 20 mL of anhydrous THF was added via a syringe. The mixture was allowed to room temperature and stirred overnight. After evaporation of THF, brine (50 mL) was added and crude product was extracted with dichloromethane (3×40 mL). The combined organic layers were concentrated and purified by column chromatography (DCM-isopropanol) to give colorless gel-like product (2.164 g, 57%). Example 2b: Synthesis of an Asymmetric Polymer Via Suzuki Coupling Polymerization Asymmetric polymers are synthesized using conditions similar to polymerization conditions as described in Example 1b. Example 3: Synthesis of a Linker or Capping Unit Example 3a: Synthesis of Linker or Capping Unit, Tert-butyl 4-(3,5-dibromophenoxy)butylcarbamate Step 1: 4-(3,5-dibromophenoxy)butan-1-amine 1-(4′-phthalimidobutoxy)3,5-dibromobenzene (1.0 g, 2.20 mmol) was dissolved in ethanol (45 mL) for 5 minutes under nitrogen. Hydrazine monohydrate (610 mg, 12.1 mmol) was added and the reaction was refluxed at 80° C. for 2 hours. To the reaction aqueous 1M HCl (17.7 mL, 17.7 mmol) was added and refluxed at 105° C. for another 2 hours. The aqueous layer was extracted with dichloromethane (2×150 mL). The organic layers were combined, washed with saturated NaHCO3 (3×), water, and brine, then dried over MgSO4, and filtered. Removal of solvent yielded a yellow oil (560 mg, 78%). Step 2: Tert-butyl 4-(3,5-dibromophenoxy)butylcarbamate 4-(3,5-dibromophenoxy)butan-1-amine (397 mg, 1.23 mmol) was dissolved in anhydrous THF (24.6 mL) under nitrogen. Di-tert-butyl dicarbonate (423 mL, 1.84 mmol) was added to the mixture and refluxed reaction at 40° C. for 2 hours. After extraction of the reaction with dichloromethane (2×50 mL), the organic layers were combined, washed with saturated NaHCO3, water, and brine, then dried over MgSO4, and filtered. The solvent is removed and the residue is purified by column chromatography (9:1, hexanes: EtOAc) to give a white solid (306 mg, 59%). Example 3b: Synthesis of Linker or Capping Unit, Tert-butyl-4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butylcarbamate Step 1: 2,7-dibromo-9-methyl-9H-fluorene 2,7-dibromofluorene (30 g, 92.59 mmol) was dissolved in anhydrous THF (300 mL) under nitrogen and cooled to −78° C. To solution at −78° C., added n-butyllithium (40.36 mL, 100.9 mmol) over 5 minutes and allowed reaction stir for another 10 minutes. To reaction, then add methyl iodide (6.29 mL, 100.9 mmol) and allowed reaction to stir at −78° C. for 2.0 hours. The reaction was poured into a mixture of dichloromethane and water. The organic layer was collected, and the water layer was further extracted with dichloromethane. Combined all organic layers and removed solvent via vacuo. The crude material was triturated with hexanes and filtered using Buchner funnel to give white solids (22 g, 70%). 1H NMR (500 MHz, CDCl3): δ=7.62 (s, 2H), 7.56-7.58 (d, 2H), 7.48-7.50 (dd, 2H), 3.90-3.94 (q, 1H), 1.49-1.51 (d, 3H). Step 2: 2-(4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butyl)isoindoline-1,3-dione 2,7-dibromo-9-methyl-9H-fluorene (10.0 g, 29.58 mmol) was dissolved in 50 mL DMSO under nitrogen. To mixture was added KOH (2.01 g, 35.79 mmol), water (1.5 mL), N-(4-bromobutyl)phthalimide (9.93 g, 35.2 mmol), and stirred reaction at room temperature for 2.0 hours, then at 50° C. for 3.0 hours. The reaction was cooled to room temperature and diluted with dichloromethane. The organic layer was washed with brine (2×), and water. Removal of solvent yield a solid, which was purified by column chromatography (7:3, hexanes:EtOAc) to yield white solids (3.08 g, 20%). 1H NMR (500 MHz, CDCl3): δ=7.81-7.83 (m, 2H), 7.68-7.71 (m, 2H), 7.48-7.51 (m, 4H), 7.41-7.44 (dd, 2H), 3.46-3.49 (t, 2H), 2.00-2.04 (p, 2H), 1.47-1.49 (m, 2H), 1.45 (s, 3H), 0.65-0.68 (m, 2H). Step 3: 4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butan-1-amine 2-(4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butyl)isoindoline-1,3-dione (3.08, 5.71 mmol) was dissolved in ethanol (250 mL) under nitrogen. To the mixture was added hydrazine monohydrate (2.77 mL, 57.1 mmol), and the reaction was refluxed at 80° C. for 3.0 hours. The reaction was cooled to room temperature, and added 1M HCl (˜100 mL). The mixture was stirred for 30 minutes or until all solids were dissolved. Dichloromethane was added to the solution and the organic layer was extracted with saturated NaHCO3 three times, and washed with water. The organic layers were collected and removed solvent by vacuo to give an yellow oil (2.33 g, 100%). 1H NMR (500 MHz, CD2Cl2): δ=7.57 (d, 2H), 7.52 (d, 2H), 7.46-7.48 (dd, 2H), 2.39-2.42 (t, 2H), 1.95-1.98 (t, 2H), 1.44 (s, 3H), 1.17-1.23 (m, 2H), 0.59-0.65 (m, 2H). Step 4: tert-butyl-4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butylcarbamate 4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butan-1-amine (2.39 g, 5.84 mmol) was dissolved in anhydrous THF (20 mL) under nitrogen. To solution, was added di-tert-butyl-dicarbonate (2.01 mL, 8.76 mmol), and the reaction was stirred at 40° C. for 3 hours. The reaction was cooled to room temperature and concentrated via vacuo. Crude solids were triturated with hexanes and filtered using buchner funnel to yield the desired white solids (2.34 g, 79%). 1H NMR (500 MHz, CDCl3): δ=7.53 (d, 2H), 7.45-7.47 (d, 4H), 4.30 (s, 1H), 2.88-2.90 (q, 2H), 1.93-1.96 (t, 2H), 1.43 (s, 3H), 1.41 (s, 9H), 1.25-1.28 (m, 2H), 0.59-0.66 (m, 2H). Example 4: Synthesis of a Linker or Capping Unit Example 4a: Synthesis of Tert-butyl 4-(4-bromophenoxy)butylcarbamate Step 1: N(4-(4-bromophenoxy)butyl)phthalimide Combined 4-bromophenol (4.64 g, 26.8 mmol), N-(4-bromobutylphthalimide) (6.30 g, 22.33 mmol), K2CO3 (11.09 g, 80.38 mmol), 18-crown-6 (265 mg, 1.00 mmol), and acetone (100 mL), and refluxed reaction under nitrogen at 70° C. over night. The reaction was cooled to room temperature and removed solvent by vacuum. The crude mixture was diluted with dichloromethane (200 mL) and washed with water (3×), then dried over MgSO4, and filtered. Removal of solvent, followed by trituration with hexanes, and filtered using Buchner funnel to yield a white solid (6.03 g, 71%). Step 2: 4-(4-bromophenoxy)butan-1-amine N(4-(4-bromophenoxy)butyl)phthalimide (6.01 g, 16.1 mmol) is dissolved in ethanol (200 mL) under nitrogen, followed by the addition of hydrazine monohydrate (7. 8 mL, 161 mmol). The reaction was refluxed at 80° C. for 2 hours. Once reaction completed (solids formed at the top layer), cooled reaction to room temperature and neutralized with 1M HCl (50 mL). The mixture is allowed to stir until all solids are completely dissolved and diluted with dichloromethane (150 mL). The solution was extracted with two portions of saturated NaHCO3 (2×). The organic layers were combined, washed with brine and water, then dried over MgSO4, and filtered. Removal of solvent yields a yellow oil (2.93 g, 75%). Step 3: Tert-butyl 4-(4-bromophenoxy)butylcarbamate 4-(4-bromophenoxy)butan-1-amine (1.0 g, 4.09 mmol) was dissolved in anhydrous THF (20 mL) under nitrogen and stirred until solution is homogenous. Di-tert-butyl-dicarbonate (1.34 g, 6.14 mmol) was added and the reaction was stirred at 40° C. for 2 hours. The reaction was quenched with water (30 mL) and stirred at room temperature for 1.0 hour. The aqueous layer was extracted with ethyl acetate (50 mL×2). The organic layers were combined, washed with saturated NaHCO3, water, and brine, then dried over MgSO4, and filtered. Removal of solvent yield a solid, which was purified by column chromatography (9:1, hexanes:EtOAc) to yield white solids (1.0 g, 71%). Example 4b: Synthesis of tert-butyl 4-(4-bromophenyl)butanoate Allowed tert-butanol to melt and added 20 mL to round bottom flask. To the solution, added di-tert-butyl-dicarbonate (1.79 g, 8.22 mmol) and 4-(4-bromophenyl)butyric acid (1.0 g, 4.11 mmol). To reaction, then added DMAP (150.7 mg, 1.23 mmol) and stirred reaction at room temperature over night. The reaction was concentrated via vacuo, and re-diluted in ethyl acetate. The organic layer was washed with 1M HCl, brine, and water. After removal of solvent, the crude solids were purified via column chromatography (20:1, hexanes:EtOAc) to give the desired product (570 mg, 46%), which is a clear oil. 1H NMR (500 MHz, CD2Cl2): δ=7.39-7.41 (d, 2H), 7.03-7.09 (d, 2H), 2.57-2.60 (t, 2H), 2.18-2.21 (t, 2H), 1.83-1.186 (p, 2H), 1.42 (s, 9H). Example 4c: Synthesis of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butanoic acid Combined 4-(4-bromophenyl)butyric acid (10 g, 41.13 mmol), bis(pinacolato)diboron (15.67 g, 61.70 mmol), potassium acetate (12.11 g, 123.4 mmol), and DMSO (100 mL), and purged mixture with nitrogen for 10 minutes at room temperature. To reaction under nitrogen, added Pd(dppf)Cl2 and purged reaction again with nitrogen for another 20 minutes at room temperature. The reaction was then refluxed at 80° C. over night. After cooling to room temperature, the reaction was quenched with water and stirred for 1.0 hour. The solids formed were filtered using Buchner funnel. The crude solids were purified via column chromatography (8.5:1.5, hexanes:EtOAc). The desired fractions were collected and concentrated via vacuo, and triturated with hexanes and filtered to give the desired white solids (6.7 g, 56%). Example 5: Synthesis of Linker or Capping Unit, Tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butylcarbamate Combined tert-butyl 4-(4-bromophenoxy)butylcarbamate from Example 4a (500 mg, 1.45 mmmol), potassium acetate (428 mg, 4.36 mmol), bis(pinacolato)diboron (737 mg, 2.90 mmol) and DMSO (12 mL), and purged mixture with nitrogen for 10 minutes at room temperature. To mixture was added Pd(dppf)Cl2 (59.3 mg, 0.07 mmol) and continued to stir solution at room temperature under nitrogen for another 20 minutes. After refluxing at 80° C. for 3 hours, the reaction was cooled to room temperature and quenched with water (30 mL). The aqueous layer was extracted with dichloromethane (50 mL×2). The organic layers were combined, washed with brine, then dried over MgSO4, and filtered. Removal of solvent yield a dark brown oil, which was purified by column chromatography (9:1, hexanes:EtOAc) to yield a light yellow oil (539 mg, 95%). Example 6: Synthesis of Linker or Capping Unit with Long Oligoether Spacer Between Arylhalide Phenyl and FMOC Protected Primary Amine 4-(4-bromophenoxy)butan-1-amine+oligoether-FMOC+N,N′-dicyclohexylcarbodiimide (DCC) (9H-fluoren-9-yl)methyl 80-(4-bromophenoxy)-75-oxo-3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,63,66,69,72-tetracosaoxa-76-azaoctacontylcarbamate. 4-(4-bromophenoxy)butan-1-amine (21.5 mg, 0.09 mmol), 1-(9H-fluoren-9-yl)-3-oxo-2,7,10,13,16,19,22,25,28,31,34,37,40,43,46,49,52,55,58,61,64,67,70,73,76-pentacosaoxa-4-azanonaheptacontan-79-oic acid (100 mg, 0.073 mmol), and N,N′-dimethylaminopyridine (5.4 mg, 0.044 mmol) were combined in a round bottom flask flushed with nitrogen and charged with a Teflon stirbar. Next 5 mL of anhydrous dichloromethane was added via syringe. N,N-Dicyclohexylcarbodiimide (23 mg, 0.11 mmol) is transferred to a second flask flushed with nitrogen and charged with a stirbar and 5 mL of anhydrous dichloromethane is added via syringe. While stirring the first solution, add the dicyclohexylcarbodiimide solution slowly, dropwise. The reaction is then allowed to proceed overnight. The following day solids from the reaction were filtered off and the filtrate was concentrated onto silica. Column chromatography in methanol and dichloromethane gave a clear thick oil (83.3 mg, 71% yield). Example 7: Synthesis of Polymer, Poly[2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene}-co-3,5-phenylbut-V-oxy-4″-amine], with an Internal Linking Site The incorporation of internal conjugation sites into conjugated polymer backbones is described in U.S. application Ser. No. 11/868,870, filed Oct. 8, 2007 and published as U.S. Application No. 2008/0293164, which application is herein incorporated by reference in its entirety. Provided is a modified synthesis based on the protocol. 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (0.084 mmol, 120 mg), 9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-2,7-di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)fluorene (0.088 mmol, 135 mg), tert-butyl-4-(3,5-dibromophenoxy)butylcarbamate (0.0044 mmol, 2.0 mg), and palladium tetra(triphenylphosphine) (0.0035 mmol, 4 mg) are combined in a round bottom flask equipped with a stirbar. Next, 0.35 mL of 2M potassium carbonate (aq) and 1.9 mL of tetrahydrofuran are added and the flask is fitted with a vacuum adaptor and put on a Schlenk line. The mixture is degassed using 3 freeze-pump-thaw cycles. The degassed mixture is heated to 80 C under nitrogen with vigorous stirring for 18 hours. The reaction mixture is then cooled and the solvent is removed with rotary evaporation. Next, 4 mL of 4 M HCl in dioxane is added and the mixture is stirred for no less than 4 hours. The solution is neutralized with 2M potassium carbonate solution. The bulk of the solvent is again removed with rotary evaporation. The resulting semisolid is diluted with ca. 50 mL water and filtered through glass fiber filter paper. Ethanol is added to adjust the solvent to 20% ethanol in water. Preparative gel permeation chromatography is performed with G-25 desalting medium to remove excess salts from the polymer. Solvent in the fractions is removed with rotary evaporation and 100 mg of poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene}-co-3,5-tert-butyl-4-(4-bromophenoxy)amine] is collected as an amber oil. Example 8: Synthesis of Phenylene Vinylene Co-Polymer with an Internal Linking Site A modified synthesis similar to that described in Examples 7 and 15. Example 9: Synthesis of Polymer with Exclusively Terminal Amine Capping Units 2,7-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene])-diphen-4-oxybutyl-4′-amine. 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (0.163 mmol, 235 mg), 9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-2,7-di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)fluorene (0.163 mmol, 250 mg), and palladium tetra(triphenylphoshine) (0.0065, 7.5 mg) are combined in a round bottom flask equipped with a stirbar. Next, 0.75 mL of 2M potassium carbonate (aq) and 3 mL of tetrahydrofuran are added and the flask is fitted with a vacuum adaptor. The reaction mixture is put on a Schenk line and is degassed with three freeze-pump-thaw cycles and then heated to 80 C under nitrogen with vigorous stirring for 18 hours. A solution of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butylcarbamate (0.064 mmol, 25 mg) in 0.5 mL tetrahydrofuran is degassed with three freeze-pump-thaw cycles and then added to the polymerization reaction via cannula under excess nitrogen pressure. The reaction is allowed to continue for an additional 4 hours at 80 C with stirring. Next, a solution of tert-butyl 4-(4-bromophenoxy)butylcarbamate (0.192 mmol, 66 mg) in 0.5 mL of THF is degassed with three freeze-pump-thaw cycles and then added to the polymerization reaction via cannula under excess nitrogen pressure. The reaction was allowed to proceed overnight. The reaction mixture was allowed to cool and solvent was removed with rotary evaporation. A 4 mL portion of 4M HCl in dioxane was added to the residue and stirred for a minimum of 4 hours. The solution was neutralized with 2 M potassium carbonate (aq) and then the solvent was removed under vacuum. The resulting residue was diluted to ˜30 mL with 20% ethanol in water and filtered. Preparative gel permeation chromatography is performed with G-25 desalting medium to remove excess salts from the polymer. Solvent in the fractions is removed with rotary evaporation and 337 mg of polymer is collected as an amber oil. The order of end linker addition (aryl hylide or boronic ester/acid) can be reversed. Similar processes can be used to add alternative linkers or end capping units. Example 10: Synthesis of Polymer, 2-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene])-phen-4-oxybutyl-4′-amine, Statistically Enriched in Chains with a Single Terminal Amine Capping Unit 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (0.163 mmol, 235 mg), 9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-2,7-di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)fluorene (0.163 mmol, 250 mg), and palladium tetra(triphenylphoshine) (0.0065, 7.5 mg) are combined in a round bottom flask equipped with a stirbar. Next, 0.75 mL of 2M potassium carbonate (aq) and 3 mL of tetrahydrofuran are added and the flask is fitted with a vacuum adaptor. The reaction mixture is put on a Schenk line and is degassed with three freeze-pump-thaw cycles and then heated to 80 C under nitrogen with vigorous stirring for 18 hours. A solution of tert-butyl 4-(4-bromophenoxy)butylcarbamate (0.049 mmol, 17 mg) in 0.5 mL tetrahydrofuran is degassed with three freeze-pump-thaw cycles and then added to the polymerization reaction via cannula under excess nitrogen pressure. The reaction is allowed to continue for an additional 4 hours at 80 C with stirring. Next, a solution of phenylboronic acid (0.150 mmol, 18 mg) in 0.5 mL of THF is degassed with three freeze-pump-thaw cycles and then added to the polymerization reaction via cannula under excess nitrogen pressure. The reaction was allowed to proceed overnight. The reaction mixture was allowed to cool and solvent was removed with rotary evaporation. A 4 mL portion of 4M HCl in dioxane was added to the residue and stirred for a at least 4 hours. The solution was neutralized with 2 M potassium carbonate (aq) and then the solvent was removed under vacuum. The resulting residue was diluted to ˜30 mL with 20% ethanol in water and filtered. Preparative gel permeation chromatography is performed with G-25 desalting medium to remove excess salts from the polymer. Solvent in the fractions is removed with rotary evaporation and 315 mg of polymer is collected as an amber oil. Resulting polymers contain chains with an enriched fraction of chains with one amine linker plus chains with 2 linkers and no linkers. Example 11: Synthesis of Polymer Statistically Enriched in Chains with a Single Terminal Capping Unit with a Long Oligoether Spacer (24 Repeats) Between the Polymer Chain and the Primary Amine Linking Group 2-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene])-phen-4-oxybutyl-4′-amine. 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (0.163 mmol, 235 mg), 9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-2,7-di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)fluorene (0.163 mmol, 250 mg), and palladium tetra(triphenylphoshine) (0.0065, 7.5 mg) are combined in a round bottom flask equipped with a stirbar. Next, 0.75 mL of 2M potassium carbonate (aq) and 3 mL of tetrahydrofuran are added and the flask is fitted with a vacuum adaptor. The reaction mixture is put on a Schenk line and is degassed with three freeze-pump-thaw cycles and then heated to 80 C under nitrogen with vigorous stirring for 18 hours. A solution of tert-butyl 4-(4-bromophenoxy)butylcarbamate (0.049 mmol, 17 mg) in 0.5 mL tetrahydrofuran is degassed with three freeze-pump-thaw cycles and then added to the polymerization reaction via cannula under excess nitrogen pressure. The reaction is allowed to continue for an additional 4 hours at 80 C with stirring. Next, a solution of phenylboronic acid (0.150 mmol, 18 mg) in 0.5 mL of THF is degassed with three freeze-pump-thaw cycles and then added to the polymerization reaction via cannula under excess nitrogen pressure. The reaction was allowed to proceed overnight. The reaction mixture was allowed to cool and solvent was removed with rotary evaporation. A 4 mL portion of 4M HCl in dioxane was added to the residue and stirred for a minimum of 4 hours. The solution was neutralized with 2 M potassium carbonate (aq) and then the solvent was removed under vacuum. The resulting residue was diluted to ˜30 mL with 20% ethanol in water and filtered. Preparative gel permeation chromatography is performed with G-25 desalting medium to remove excess salts from the polymer. Solvent in the fractions is removed with rotary evaporation and 315 mg of polymer is collected as an amber oil. Example 12: Synthesis of an Asymmetric Polymer with a Terminal Carboxylic Capping Unit Added During Polymerization Reaction The linking monomer is added during the polymerization reaction as described in Examples 9, 10 and 11. The carboxylic acid group can later be converted to an activated ester such as N-hydroxysuccinimidyl as is described in Example 29. Example 13: Synthesis of an Asymmetric Polymer with a Terminal Carboxylic Acid Capping Unit Added Post Polymerization The linking monomer is added after the polymerization reaction is completed and polymer purified. Linker addition is done under similar reaction conditions as those described in Examples 9, 10 and 11. The carboxylic acid group can later be converted to an activated ester such as N-hydroxysuccinimidyl as is described in Example 29. Example 14: Synthesis of an Polymer with Branched PEG Groups Example 14a: Synthesis of Monomers, (D) and (E) for Subsequent Polymerization Step 1: 2,7-dibromo-9,9-bis(3,5-dimethoxybenzyl)fluorene 2,7-dibromofluorene (4.16 g, 12.8 mmol) and tetrabutylammonium bromide (362 mg, 1.12 mmol) were added to a round bottom flask charged with a Teflon stirbar. Next, 60 mL of dimethylsulfoxide was added to the flask and the mixture was stirred for 5 minutes. A portion of 50% NaOH aqueous solution (5.2 mL) was added followed immediately by 3,5-dimethoxybenzyl bromide (7.14 g, 31 mmol). Over the course of 2 hours the solution changes color from orange to blue. The reaction is stirred overnight. The resulting mixture is slowly poured into 200 mL of water and then extracted with three 100 mL portions of dichloromethane. The organic layers are combined and dried over magnesium sulfate and then filtered. The crude product is purified by column chromatography using hexanes and dichloromethane as eluent to give a pale yellow solid (6.63 g, 79% yield). Step 2: 2,7-dibromo-9,9-bis(3,5-dihydroxybenzyl)-9H-fluorene 2,7-dibromo-9,9-bis(3,5-dimethoxybenzyl)-9H-fluorene (1.3 g, 2.08 mmol) was added to a round bottom flask charged with a stirbar and equipped with a rubber septum. The flask is purged with nitrogen for 10 min. Anhydrous dichloromethane (20 mL) is transferred to the flask via cannula and the mixture is stirred until the solids are completely dissolved. The solution is then cooled with a dry ice/acetone bath for 10 minutes. BBr3 (6.1 mL, 63.3 mmol) is added dropwise via cannula with constant stirring. The bath is allowed to warm to room temperature and the mixture is stirred overnight. The reaction is quenched with the slow addition of 125 mL of water. The solution is then extracted with 3 portions of ethyl acetate (50 mL). The organic layer is dried over MgSO3, filtered, and dried onto silica. Flash chromatography of the crude using ethyl acetate in dichloromethane gives an off-white crystalline solid (800 mg, 68% yield). Step 3: 2,7-dibromo-9,9-bis(3,5-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl) benzyl)-9H-fluorene (D) 2,7-dibromo-9,9-bis(3,5-dihydroxybenzyl)-9H-fluorene (537 mg, 0.945 mmol), 2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl 4-methylbenzenesulfonate (2.788 g, 4.156 mmol), potassium carbonate (1.57 g, 11.34 mmol) and acetone (80 mL) are transferred to a round bottom flask charged with a Teflon stirbar and equipped with a reflux condenser. The mixture is refluxed with constant stirring overnight. The mixture is then allowed to cool to room temperature and the acetone is removed under vacuum. After extracting with 3 portions of dichloromethane, the organic layer is dried over MgSO4, filtered, and the filtrate is concentrated onto silica. Column chromatography using methanol and dichloromethane affords the product as a slightly colored thick oil (1.69 g, 70% yield). Step 4: 2,7- di(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolanyl)-9,9-bis(3,5-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl) benzyl)-9H-fluorene (E) Monomer (E) is synthesized using conditions similar to conditions as described in Example 1. Example 14b: Polymerization of (D) and (E) Polymerization of (D) and (E) are polymerized using conditions similar to polymerization conditions as described in Example 1b. Example 15: Synthesis of a neutral base phenylene vinylene co-polymer 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (0.25 mmol), 1,4-divinylbenzene (32.3 mg, 0.25 mmol), palladium acetate (3 mg, 0.013 mmol), tri-ortho-tolylphosphine, (10 mg, 0.033 mmol), and potassium carbonate (162 mg, 1.2 mmol) are combined with 5 mL of DMF in a small round bottom flask charged with a Teflon coated stirbar. The flask is fitted with a needle valve and put in a Schlenk line. The solution is degassed by three cycles of freezing, pumping, and thawing. The mixture is then heated to 100° C. overnight. The polymer can be subsequently reacted with terminal linkers or capping units using similar (in situ) protocols to those provided in the previous examples (9, 10 and 11) or by modifying them post polymerization work up as a separate set of reactions. Example 16: Synthesis of a Branched Phenylene Vinylene Co-Polymer 2,7-dibromo-9,9-bis(3,5-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl) benzyl)-9H-fluorene (636 mg, 0.25 mmol), 1,4-divinylbenzene (32.3 mg, 0.25 mmol), palladium acetate (3 mg, 0.013 mmol), tri-ortho-tolylphosphine, (10 mg, 0.033 mmol), and potassium carbonate (162 mg, 1.2 mmol) were combined with 5 mL of DMF in a small round bottom flask charged with a Teflon coated stirbar. The flask was fitted with a needle valve and put in a Schlenk line. The solution was degassed by three cycles of freezing, pumping, and thawing. The mixture was then heated to 100° C. overnight. The polymer can be subsequently reacted with terminal linkers or capping units using similar (in situ) protocols to those provided in Example 5 or by modifying them post polymerization work up as a separate set of reactions. Example 17: Synthesis of a branched phenylene vinylene co-polymer with functional amines for covalent conjugation. Poly [2,7-divinyl{9,9-bis(3,5-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl)benzyl)-9H-fluorene}-alt-1,4-benzene-co-4-phenoxybutyl-N-t-butylcarbamate] Step 1: Polymerization 2,7-dibromo-9,9-bi s(3,5-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl) benzyl)-9H-fluorene (636 mg, 0.25 mmol), 1,4-divinylbenzene (32.3 mg, 0.25 mmol), palladium acetate (3 mg, 0.013 mmol), tri-ortho-tolylphosphine, (10 mg, 0.033 mmol), and potassium carbonate (162 mg, 1.2 mmol) were combined with 5 mL of DMF in a small round bottom flask charged with a Teflon coated stirbar. The flask was fitted with a needle valve and put in a Schlenk line. The solution was degassed by three cycles of freezing, pumping, and thawing. The mixture was then heated to 100° C. overnight. Step 2: Linker Addition The next morning divinylbenzene (10 mg, 0.077 mmol) was transferred to a small round bottom flask with 1 mL of DMF. The flask was fitted with a needle valve and put in a Schlenk line. The solution was degassed by three cycles of freezing, pumping, and thawing. The solution was transferred via cannula through the needle valves and into the polymerization reaction. After this addition the reaction was allowed to continue at 100° C. overnight. The next day tert-butyl 4-(4-bromophenoxy)butylcarbamate (53 mg, 0.15 mmol) and 1 mL of DMF were transferred to a small round bottom flask. The flask was fitted with a needle valve and put in a Schlenk line. The solution was degassed by three cycles of freezing, pumping, and thawing. The solution was transferred via cannula through the needle valves and into the polymerization reaction. After this addition the reaction was allowed to continue at 100° C. overnight. Step 3: Work Up The reaction is then cooled and diluted with 100 mL of water. The aqueous solution was filtered twice through G-6 glass fiber filter paper. The filtrate was evaporated to dryness and re-diluted with dichloromethane. The organic layer was dried over MgSO4 and filtered. The filtrate was evaporated to yield an amber colored oil (342 mg, 56% yield). A 4 mL portion of 4M HCl in dioxane was added to the polymer residue and stirred for a minimum of 4 hours. The solution was neutralized with 2 M potassium carbonate (aq) and then the solvent was removed under vacuum. The resulting residue was diluted to ˜30 mL with 20% ethanol in water and filtered. Preparative gel permeation chromatography is performed with G-25 desalting medium to remove excess salts from the polymer. Solvent in the fractions is removed with rotary evaporation and the polymer is collected as an amber oil. The linker or capping unit addition steps can be performed in the polymerization reaction as presented above or alternatively, in some embodiments, can be performed in a separate set of reactions after the polymerization work up. In the latter case, the polymer is reacted under the analogous conditions as those provided in the example. In other embodiments, it is also possible to react with a combination of terminal monomers to introduce polymers with bi-functionality, allowing the polymer to be conjugated to more than one entity. Example 18: Synthesis of a Fluorene Monomer with Glycerol-Based Dendrimers Step 1: Dimethyl 3,3′-(2,7-dibromo-9H-fluorene-9,9-diyl)dipropanoate 2,7-Dibromofluorene (1 g, 3.1 mmol), methyl acrylate (861 mg, 10 mmol) tetrabutylammonium bromide (100 mg, 0.3 mmol) and toluene (5 mL) were added to a small round bottom flask with a Teflon-coated stirbar. Next 2 mL of 50% NaOH (aq) is added while stirring. The reaction is allowed to proceed overnight. The next day the toluene layer is transferred to a flask and the aqueous layer extracted with two portions of toluene. The organic layers are combined, dried with Mg2SO4, and filtered. Silica (2 g) is added to the filtrate and the solution is evaporated. The product is obtained as a white solid (1.23 g, 80% yield) after purification by column chromatography. Step 2: 3,3′-(2,7-dibromo-9H-fluorene-9,9-diyl)dipropanoic acid Dimethyl 3,3′-(2,7-dibromo-9H-fluorene-9,9-diyl)dipropanoate (1.23 g, 2.5 mmol) is transferred to a small round bottom flask equipped with a Teflon-coated stirbar. A mixture of THF:MeOH:H2O, 3:2:1, (10 mL) is added and the mixture is stirred for 1 hr. Then a 1 mL portion of 1M NaOH (aq) is added and the mixture is stirred overnight. The next day the water layer is isolated and extracted with 20 mL portions diethyl ether three times. Next the water layer is acidified to ˜pH 2. The water layer is extracted three times with 20 mL portions of dichloromethane. The organic layers are combined and dried with Mg2SO4. The organic solution is filtered and the solvent evaporated to obtain the product as an off-white solid (948 mg, 90% yield). Step 3: 3,3′-(2,7-Dibromo-9H-fluorene-9,9-diyl)bis(N-(7,15-bis((2,3-dihydroxypropoxy)methyl)-1,3,19,21-tetrahydroxy-5,9,13,17-tetraoxahenicosan-11-yl)propanamide) 3,3′-(2,7-Dibromo-9H-fluorene-9,9-diyl)dipropanoic acid (500 mg, 1.1 mmol), 11-amino-7,15-bis((2,3-dihydroxypropoxy)methyl)-5,9,13,17-tetraoxahenicosane-1,3,19,21-tetraol (1.954, 3.3 mmol) (prepared as per ref. Heek, T.; Fasting, C.; Rest, C.; Zhang, X.; Wurthner, F.; Haag, R. Chem. Commun., 2010, 46, 1884-1886), and N,N′-dimethylaminopyridine (61 mg, 0.5 mmol) are combined in a round bottom flask equipped with a Teflon-coated stirbar and sealed with a rubber septum. The flask was flushed with N2 and 10 mL of anhydrous dichloromethane was added via syringe. The mixture is stirred to dissolve the solids. In another round bottom flask equipped with a Teflon-coated stirbar, dicyclohexylcarbodiimide (DCC, 910 mg 4.4 mmol) transferred and the flask is sealed with a rubber septum. Next, 5 mL of anhydrous dichloromethane is transferred to the flask via syringe. The DCC solution is transferred to the fluorene reaction mixture via a syringe dropwise. The reaction is allowed to react overnight. The next day the reaction mixture is filtered. The filtrate is purified by column chromatography to afford a clear oil (1.24 g, 70% yield). Example 19: Synthesis of a Fluorene Monomer PAMAM-Based Dendritic Side Chain Capped with methylPEG Chains Step 1: 9,9′-(3,3′-Diamido(tetramethyl PAMAM G[2])-2,7-dibromofluorene (i) Dimethyl 3,3′-(2,7-dibromo-9H-fluorene-9,9-diyl)dipropanoate (1 g, 2.0 mmol) is transferred to a round bottom flask equipped with a stirbar and sealed with a rubber septum. The flask is flushed with nitrogen and 10 mL of dry methanol is transferred to the flask via syringe and the solid is dissolved by stirring. Ethylenediamine (5.5 mL, 82 mmol) is added via syringe slowly and the mixture is allowed to stir for 2 hours. The septum is removed and the methanol and unreacted ethylenediamine is removed under vacuum. Another 10 mL portion of methanol is added and stirred and then was evaporated to remove any remaining ethylenediamine. The residue remaining in the flask was then sealed again with a septum, flushed with nitrogen, and dry methanol (10 mL) was added and stirred. Methyl acrylate (7.2 mL, 80 mmol) is added slowly via syringe and the mixture is allowed to stir for 2 hours. The septum is again removed and the methanol and methyl acrylate are removed under vacuum. A 10 mL portion of toluene is added, the mixture stirred, and the solvent removed under vacuum affording an off-white solid (1.79 g, quantitative yield). Step 2: 9,9′-(3,3′-Diamido(PAMAM G[2] tetraacid)-2,7-dibromofluorene (ii) 9,9′-(3,3′-Diamido(tetramethyl PAMAM G[2])-2,7-dibromofluorene (i) (1.79 g, 2 mmol) is transferred to a small round bottom flask equipped with a Teflon-coated stirbar. A mixture of THF:MeOH:H2O, 3:2:1, (10 mL) is added and the mixture is stirred for 1 hr. Then a 1 mL portion of 1M NaOH (aq) is added and the mixture is stirred overnight. The next day the water layer is isolated and extracted with 20 mL portions diethyl ether three times. Next the water layer is acidified to ˜pH 2. The water layer is extracted three times with 20 mL portions of dichloromethane. The organic layers are combined and dried with Mg2SO4. The organic solution is filtered and the solvent evaporated to obtain the product as an off-white solid (1.51 g, 90% yield). Step 3: 9,9′-(3,3′-Diamido(PAMAM G[2] N-(2,5,8,11,14,17,20,23-octaoxapentacosane-25-yl)propionamidyl)-2,7-dibromofluorene (iii). 9,9′-(3,3′-Diamido(PAMAM G[2] tetraacid)-2,7-dibromofluorene (ii) (500 mg, 0.6 mmol), 2,5,8,11,14,17,20,23-octaoxapentacosan-25-amine (1.15 g, 3 mmol)), and N,N′-dimethylaminopyridine (12 mg, 0.1 mmol) are combined in a round bottom flask equipped with a Teflon-coated stirbar and sealed with a rubber septum. The flask was flushed with N2 and 10 mL of anhydrous dichloromethane was added via syringe. The mixture is stirred to dissolve the solids. In another round bottom flask equipped with a Teflon-coated stirbar, dicyclohexylcarbodiimide (DCC, 825 mg 4.0 mmol) transferred and the flask is sealed with a rubber septum. Next, 5 mL of anhydrous dichloromethane is transferred to the flask via syringe. The DCC solution is transferred to the fluorene reaction mixture via a syringe dropwise. The reaction is allowed to react overnight. The next day the reaction mixture is filtered. The filtrate is purified by column chromatography to afford a clear oil (967 g, 70% yield). Example 20: Synthesis of a Fluorene Monomer with Highly Branched PEGylated Side Chains Based on a Trihydroxybenzene Linkage Step 1: Methyl 3,4,5-tris(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yloxy)benzoate (iv) Methyl 3,4,5-trihydroxybenzoate (200 mg, 1.1 mmol), 2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl 4-methylbenzenesulfonate (2.58 g, 3.85 mmol), and 18-crown-6 (100 mg, 0.38 mmol) are transferred to a round bottom flask equipped with a Teflon-coated stirbar. Acetone (10 mL) is added and the flask is equipped with a reflux condenser. The mixture is refluxed with constant stirring overnight. The next day silica (4 g) is added and the solvent evaporated. After purification by column chromatography, a clear oil is obtained (887 mg, 48% yield). Step 2: 3,4,5-Tris(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yloxy)-N-(2-aminoethyl)benzamide (v) Methyl 3,4,5-tris(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yloxy)benzoate (iv) (887 mg, 0.52 mmol) flask is transferred to a round bottom flask equipped with a stirbar and sealed with a rubber septum. The flask is flushed with nitrogen and 10 mL of dry methanol is transferred to the flask via syringe and the solid is dissolved by stirring. Ethylenediamine (0.7 mL, 10.4 mmol) is added via syringe slowly and the mixture is allowed to stir for 2 hours. The septum is removed and the methanol and unreacted ethylenediamine is removed under vacuum. The product is obtained as an oil (886 mg, quantitative yield). Step 3:] 3,3′-(2,7-Dibromo-9H-fluorene-9,9-diyl)bis(N-(2-3,4,5-tris(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yloxy)-benzamidyl-N amidoethyl)propanamide) (vi) 3,4,5-Tris(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yloxy)-N-(2-aminoethyl)benzamide (v) (886 mg, 0.52 mmol), 3,3′-(2,7-Dibromo-9H-fluorene-9,9-diyl)dipropanoic acid (112 mg, 0.24 mmol), and N,N′-dimethylaminopyridine (12 mg, 0.1 mmol) are combined in a round bottom flask equipped with a Teflon-coated stirbar and sealed with a rubber septum. The flask was flushed with N2 and 10 mL of anhydrous dichloromethane was added via syringe. The mixture is stirred to dissolve the solids. In another round bottom flask equipped with a Teflon-coated stirbar, dicyclohexylcarbodiimide (DCC, 148 mg 0.72 mmol) transferred and the flask is sealed with a rubber septum. Next, 5 mL of anhydrous dichloromethane is transferred to the flask via syringe. The DCC solution is transferred to the fluorene reaction mixture via a syringe dropwise. The reaction is allowed to react overnight. The next day the reaction mixture is filtered. The filtrate is purified by column chromatography to afford a clear oil (924 mg, 70% yield). Example 21. Dual End Capped Polymer Used to Create a Polymer-Dye Label for Biomolecule or Substrate Conjugation Step 1: Synthesis of an Asymmetric Neutral Water-Soluble Polymer with a t-BOC Protected Amine Pendant Group at One Terminus of the Polymer 2-bromo-7-(4″-phenoxybutyl-1-tert-butyl carbamate)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene. 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene (1.0 g, 0.674 mmol), 3 mL of tetrahydrofuran, and 2 mL of 2M potassium carbonate (aqueous) were transferred to a small round bottom flask charged with a Teflon stirbar. The flask was fitted with a septum and the solution is degassed by sparging with Ar for 15 minutes. Palladium tetra(triphenylphoshine) (15.6 mg, 0.013 mmol) was added through the neck of the flask and the flask was transferred to a reflux condenser equipped with a needle valve and fixed to a Schlenk line. The solution was quickly frozen solid with liquid nitrogen and was further degassed using freeze-pump-thaw technique. Once degassed the reaction was heated to 80° C. with constant stirring. The reaction was allowed to proceed overnight. The next day tert-butyl 4-(4-bromophenoxy)butylcarbamate (35 mg, 0.10 mmol) in 1 mL of THF was degassed with three freeze-pump-thaw cycles and then added to the polymerization reaction via cannula under excess nitrogen pressure. The reaction continued overnight at 80° C. The next day the reaction mixture was cooled and the bulk of the solvent was removed under vacuum. The remaining material was transferred to a small Erlenmeyer flask with a total of ˜50 mL of dichloromethane. The solution was stirred for 30 minutes. Approximately 1 g of MgSO4(anhydrous) was added to the solution and the mixture was filtered through a fluted paper filter. The filtrate was evaporated and 410 mg (47% yield) of an amber oil was collected. Step 2: Synthesis to Append a Terminal Linking Monomer with a t-Butyl Ester at the Terminus Opposite the Protected Amine Pendant 2-(4-(tert-butyl 1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oate))-7-(4″-phenoxybutyl-1-tert-butyl carbamate)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene. 2-Bromo-7-(4″-phenoxybutyl-1-tert-butyl carbamate)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene (410 mg, 0.32 mmol of repeat unit), tert-butyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-3,6,9,12,15,18,21-heptaoxatetracosan-24-oate (33 mg, 0.048 mmol), 2 mL of tetrahydrofuran, and 1.5 mL of 2M potassium carbonate (aqueous) were transferred to a small round bottom flask charged with a Teflon stirbar. The flask was fitted with a septum and the solution is degassed by sparging with Ar for 15 minutes. Palladium tetra(triphenylphoshine) (15 mg, 0.013 mmol) was added through the neck of the flask and the flask was transferred to a reflux condenser equipped with a needle valve and fixed to a Schlenk line. The solution was quickly frozen solid with liquid nitrogen and was further degassed using freeze-pump-thaw technique. Once degassed the reaction was heated to 80° C. with constant stirring. The reaction was allowed to proceed overnight. The remaining material was transferred to a small Erlenmeyer flask with a total of ˜50 mL of dichloromethane. The solution was stirred for 30 minutes. Approximately 1 g of MgSO4(anhydrous) was added to the solution and the mixture was filtered through a fluted paper filter. The filtrate was evaporated and 351 mg (78% yield) of an amber oil was collected. Step 3: Synthesis of a Neutral Water-Soluble Polymer with Primary Amine at One Terminus and a t-Butyl Ester Pendant on the Other 2-(4-(tert-butyl 1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oate))-7-(4″-phenoxybutyl-1-amino)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene. 2-(4-(tert-butyl 1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oate))-7-(4″-phenoxybutyl-1-tert-butyl carbamate)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene (23 mg, 0.018 mmol) and 0.5 mL of 4M HCl in dioxane were combined in a 1 dram vial with a Teflon-coated stirbar. The mixture was stirred for 4 hours. The mixture was neutralized with 2M potassium carbonate (aqueous). The solution was then diluted to 50 mL of roughly 20% ethanol in water and filtered through G-6glass fiber filter paper. The filtrate was desalted by centrifugation in a 4 mL 10 KDa cutoff centrifuge filter. The retentate was evaporated under vacuum and two 1 mL portions of toluene were added and removed under vacuum to remove any remaining water. A thick amber liquid was recovered from the desalting (21 mg, 85% yield). Step 4: Attachment of an NHS-Functionalized Dye to a Primary Amine Pendant on a Neutral Water-Soluble Polymer 2-(4-(tert-butyl 1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oate))-7-(4″-phenoxybutyl-1-amido-DYE)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene. 2-(4-(tert-butyl 1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oate))-7-(4″-phenoxybutyl-1-amino)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene (518 ug, 0.4 μM) was dissolved in 100 μL of dry dichloromethane in a glass vial. A small crystal of 4-N,N′-dimethylaminopyridine was added. In another vial 65 μg (0.06 □uM) of NHS-functionalized DyLight 594 (Pierce) was dissolved in 50 of dry dichloromethane. The two solutions were combined and allowed to stir in a sealed vial for 4 hours covered in foil. The solvent was then evaporated and the remaining material was dissolved in 95% ethanol and injected onto a Sepharose 6 column. The remaining dye was separated from the polymer. A solution of dye-labeled polymer was obtained from combining fractions (100 μg, 20% yield). Step 5: Hydrolysis of the t-Butyl Ester Pendant on the Dye-Labeled Neutral Water-Soluble Polymer to Form the Carboxylic Acid Pendant on One of the Termini 2-(4-(1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosane-27-acid))-7-(4″-phenoxybutyl-1-amido-DYE)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene. The polymer was combined with ZnBr2 in dichloromethane and stirred overnight. The next day a portion of water was added and the mixture was stirred for 1 hour. The solvent was evaporated and the residue was dissolved in 20% ethanol in water. The filtrate was then desalted by centrifugation in a 4 mL 10 KDa cutoff centrifuge filter. The retentate was evaporated under vacuum and two 1 mL portions of toluene were added and removed under vacuum to remove any remaining water. Activation (for subsequent conjugation) of the second functional group in this example (carboxylic acid) can be achieved using a number of different methods including those described in Examples 29 and other examples with carboxylic acid to amine to maleimide. One such method is given below in Step 6, by way of example only. Step 6: NHS Activation of the Carboxylic Acid Penant of a Dye-Labeled Neutral Water-Soluble Polymer 2-(4-(1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosane-27-N-hydroxysuccinimidyl ester))-7-(4″-phenoxybutyl-1-amido-DYE)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene. 2-(4-(1-phenoxy-3,6,9,12,15,18,21,24-octaoxaheptacosane-27-acid))-7-(4″-phenoxybutyl-1-amido-DYE)-poly-2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene and O—(N-Succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate and DIPEA are combined in dry acetonitrile and allowed to react under nitrogen for 30 min. The solution is evaporated and the solid is resuspended in dry dichloromethane. Solids are filtered off and the filtrate is evaporated to afford the NHS ester. In further embodiments, various commonly used protecting groups can be used with those functional groups provided (amine and carboxylic acid). Additionally different capping monomers and protecting group combinations can be used to produce polymers with different functional groups for conjugation. Eliminating or substituting the dye labeling step for another entity will result in a polymer with two different functional groups for conjugation. The dye attachment via NHS/amine chemistry can be performed under a variety of commonly used conditions. Dye attachment can also be performed with other functional chemistries. Example 22. Asymmetric Polyfluorene Synthesis Using Non-Regulated Suzuki Conditions Step 1: Polymerization Method A: A solution of K2CO3 in water (2M, 4 mL) was added to a stirred mixture of 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene (A) (2.3 g, 1.5 mmol) and THF (6 mL) in a round bottom flask. This mixture was degassed with argon for 15 min. Palladium tetrakis(triphenylphosphine) (38.5 mg, 0.03 mmol) was added to the mixture and the flask was attached to a reflux condenser. The reaction vessel was degassed via 3 freeze-pump-thaw cycles and then heated to 80° C. for 12 h. The reaction mixture was cooled to 23° C. and solvent removed by rotary evaporation. The resulting residue was transferred to an Erlenmeyer flask and diluted with 20% EtOH/H2O (75 mL). EDTA (300 mg, 1.0 mmol) was added to the mixture and stirred at 23° C. for 1 h. The mixture was filtered through a glass fiber filter paper and the filter paper rinsed with 20% EtOH/H2O. The resulting filtrate was then filtered through a 0.45 um cup filter. The filtered reaction mixture was purified using tangential flow filtration (TFF) and was diafiltered into 20% ethanol using a 10,000 molecular weight cutoff membrane (regenerated cellulose Prep/Scale TFF cartridge system, Millipore, Billerica, Mass.) until conductivity of the filtrate measured less than 0.01 mS/cm. The solvent was then removed under vacuum to give poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene] (B) as a gel-like product (1.41 g, 71%) Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=51,000, Mw=108,000, Mp=90,000, D=2.1). The extent of end linker incorporation was determined by first converting the acid to an NHS ester (similar protocol to that provided in Example 29) then reacting with an amine functional dye. After purification of free dye the ratio of dye to polymer was determined from absorbance measurements, factoring in the difference in extinction coefficients and polymer molecular weight. Method B: A solution of K2CO3 in water (2M, 4 mL) was added to a stirred mixture of 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene (A) (2.3 g, 1.5 mmol) and DMF (6 mL) in a round bottom flask. This mixture was degassed with argon for 15 min. Palladium tetrakis(triphenylphosphine) (38.5 mg, 0.03 mmol) was added to the mixture and the flask was attached to a reflux condenser. The reaction vessel was degassed via 3 freeze-pump-thaw cycles and then heated to 80° C. for 12 h. Work-up and purification was performed in a manner similar to previously described Method A. Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=96,000, Mw=231,000, Mp=185,000, D=2.4). Method C: Cs2CO3 (2.08 g, 6.4 mmol) was added to a stirred mixture of 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene (A) (200 mg, 0.135 mmol) and DMF (7 mL) in a round bottom flask. This mixture was degassed with argon for 15 min. Palladium tetrakis(triphenylphosphine) (15.6 mg, 10 mol %) was added to the mixture and the flask was attached to a reflux condenser. The reaction vessel was degassed via 3 freeze-pump-thaw cycles and then heated to 80° C. for 12 h. Work-up and purification was performed in a manner similar to previously described Method A. Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=95,000, Mw=218,000, Mp=206,000, D=2.3). Step 2: End Capping -(4-iodophenyl)butanoic acid (227 mg, 0.783 mmol) was washed into a flask containing poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene] (B) (1.00 g, 0.783 mmol) using THF (3.5 mL). A solution of K2CO3 in water (2M, 2.3 mL) was added to the flask and this mixture was degassed with argon for 15 min. Palladium tetrakis(triphenylphosphine) (36 mg, 4 mol %) was added to the mixture and the flask was attached to a reflux condenser. The reaction vessel was degassed via 3 freeze-pump-thaw cycles and then heated to 80° C. for 12 h. The reaction mixture was cooled to 23° C. and the solvent removed with rotary evaporation. The resulting residue was transferred to an Erlenmeyer flask and diluted with 20% EtOH/H2O (150 mL). EDTA (500 mg) was added to the mixture and stirred at 23° C. for 1 h. The mixture was filtered through a glass fiber filter paper and the filter paper rinsed with 20% EtOH/H2O. The resulting filtrate was then filtered through a 0.45 um cup filter. The filtered reaction mixture was purified using tangential flow filtration (TFF) and was diafiltered into 20% ethanol using a 10,000 molecular weight cutoff membrane (regenerated cellulose Prep/Scale TFF cartridge system, Millipore, Billerica, Mass.) until conductivity of the filtrate measured less than 0.01 mS/cm. The solvent was then removed under vacuum to give 4-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene]yl)phenyl)butanoic acid (C) as a gel-like product (388 mg, 39%) Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=89,000, Mw=196,000, Mp=124,000, D=2.2). The extent of end linker incorporation was determined by first converting the acid to an NHS ester (similar protocol to that provided in Example 29) then reacting with an amine functional dye. After purification of free dye the ratio of dye to polymer was determined from absorbance measurements, factoring in the difference in extinction coefficients and polymer molecular weight. Step 3: Amine Activation 4-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene]yl)phenyl)butanoic acid (C) (200 mg, 0.156 mmol) was dissolved in 2 mL ethanol, then added drop-wise to 23 mL of MES buffer (50 mM, pH 5) at 4° C. while stirring. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (576 mg, 3.00 mmol) was added in portions, followed by N-hydroxy succinimide (115 mg, 1.00 mmol) in one portion. The solution was stirred for 30 minutes, ethylene diamine (0.501 mL, 7.50 mmol) was added drop-wise and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then desalted over a G25 desalting column and the solvent removed via rotary evaporation to give N-(2-aminoethyl)-4-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene]yl)butanamide as a clear yellow oil (190 mg, 95%). Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=89,000, Mw=196,000, Mp=124,000, D=2.2). Extent of amine conversion was determined by reacting the amine polymer with an NHS active dye in similar fashion as that described in Example 38. Example 23. Asymmetric Polyfluorene Synthesis Using Linker Modified End Caps to Regulate the Suzuki Polymerization Step 1: Polymerization/End Capping/Work-Up A solution of K2CO3 in water (2M, 4 mL) was added to a stirred mixture of 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene (A) (2.3 g, 1.55 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butanoic acid (B) (6.7 mg, 2 mol %), and DMF (6 mL) in a round bottom flask equipped with a side-arm stopcock. This mixture was degassed with argon for 25 min. Palladium tetrakis(triphenylphosphine) (38.5 mg, 2 mol %) was then added to the mixture and the flask was attached to a reflux condenser. The reaction vessel was further degassed via 3 freeze-pump-thaw cycles and then heated to 80° C. Separately, 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butanoic acid (B) (230 mg, 0.793 mmol) was dissolved in DMF (3 mL) in a found bottom flask equipped with a side arm stopcock. This solution was sparged with argon for 15 minutes, attached to a reflux condenser, and degassed via three freeze-pump thaw cycles. Upon thawing the solution was added to the reaction mixture after two hours of reaction time using an argon flushed syringe. The reaction mixture was stirred for an additional 12 h at 80° C. The reaction mixture was cooled to 23° C. and solvent removed with rotary evaporation. The resulting residue was transferred to an Erlenmeyer flask and diluted with 20% EtOH/H2O (75 mL). EDTA (300 mg, 1.00 mmol) was added to the mixture and stirred at 23° C. for 1 h. The mixture was filtered through a glass fiber filter paper and the filter paper rinsed with 20% EtOH/H2O. The resulting filtrate was then filtered through a 0.45 um cup filter. The filtered reaction mixture was purified and size fractionated using tangential flow filtration (TFF) and was diafiltered into 20% ethanol using a 30,000 molecular weight cutoff membrane (polyethersulfone Prep/Scale TFF cartridge system, Millipore, Billerica, Mass.) until conductivity of the filtrate measured less than 0.01 mS/cm and Mn of the retentate measured more than 70,000 by GPC. The solvent was then removed under vacuum to give 4-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene]yl)phenyl)butanoic acid as a gel-like product (1.41 g, 71%). Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=68,000, Mw=134,000, Mp=122,000, D=1.9). The extent of end linker incorporation was determined by first converting the acid to an NHS ester (similar protocol to that provided in Example 29) then reacting with an amine functional dye. After purification of free dye the ratio of dye to polymer was determined from absorbance measurements, factoring in the difference in extinction coefficients and polymer molecular weight. Despite having a molecular weight in excess of 50,000 g/mole the polymer is soluble in both water and phosphate buffered saline solutions at concentrations easily greater than 10 mg/mL. In many conjugation experiments the polymer provided (and other described herein with similar structure) was concentrated to 50 mg/mL or higher which is remarkable for a neutral conjugated polymer. The moderate molecular weight also provides extinction coefficients greater than 2,500,000 M−1cm−1. The large extinction coefficient and quantum yield of 60% (PBS) provide for exceptionally bright fluorescent reporters for use in biological assays including their use in flow cytometry. Step 2: Amine Activation 4-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene]yl)phenyl)butanoic acid (C) (500 mg, 0.13 mmol) was dissolved in 2 mL ethanol, then added drop-wise to 23 mL of MES buffer (50 mM, pH 5) at 4° C. while stirring. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride was added in portions, followed by N-hydroxy succinimide (0.52 g) in one portion. The solution was stirred for 30 minutes, ethylene diamine (2.8 mL) was added drop-wise and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then desalted over a G25 desalting column and the solvent removed via rotary evaporation to give N-(2-aminoethyl)-4-(Poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene]yl)butanamide as a yellow oil (450 mg, 90%). Extent of amine conversion was determined by reacting the amine polymer with an NHS active dye in similar fashion as that described in Example 38. Example 24. Yamamoto polymerization of PEG modified polyfluorene Step 1: Yamamoto Polymerization/Work-Up In a dry box, Ni(COD)2(0.387 g, 1.41 mmol), 2,2′-bipyridyl (0.220 g, 1.41 mmol), COD (0.152 g, 1.41 mmol) and anhydrous DMF (16 ml) were added to a long-neck round bottom flask. [00251] 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (A) (1.00, 0.696) was weighed into a 40 ml vial and dissolved in anhydrous DMF (8 ml). The flask was sealed with a septum and the vial was closed with a septum screw cap. The catalyst mixture and the monomer solution were transferred out of the dry box and were placed under static argon. The reaction flask was heated to 70° C. for 45 min. The monomer solution was then was quickly transferred from the vial to the catalyst mixture flask with an argon flushed syringe. The reaction mixture was then heated to 70° C. for 6 h. The reaction mixture was cooled and solvent removed by rotary evaporation. The resultant black residue was re-dissolved in 20% EtOH (80 mL) and centrifuged at 2400 rpm for 12 hours. The supernatant was then decanted and filtered through a 0.45 um cup filter. The filtered reaction mixture was purified using tangential flow filtration (TFF) and was diafiltered into 20% ethanol using a 10,000 molecular weight cutoff membrane (polyethersulfone Prep/Scale TFF cartridge system, Millipore, Billerica, Mass.) until GPC analysis of retentate indicated the absence of low molecular weight material. The solvent was then removed under vacuum to give poly [2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene] (B) as a viscous oil (0.700 g, 79%) Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=62,000, Mw=127,000, Mp=93,000, D=2.0). Step 2: End Capping: End Capping is Performed in a Manner Similar to Example 22, Step 2 Step 3: Amine Activation: Amine Activation is Performed in a Manner Similar to Example 22, Step 3 Example 25. Synthesis of a Tandem Polymer with Two Different Linkers Step 1: Polymerization In a dry box, Ni(COD)2 (0.765 g, 2.78 mmol), 2,2′-bipyridyl (0.435 g, 2.78 mmol), COD (0.301 g, 2.78 mmol) and anhydrous DMF (20 ml) were added to a long-neck round bottom flask. 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (A) (1.80, 1.26 mmol) and tert-butyl 4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butylcarbamate (B) (0.071 g, 0.126 mmol) were added to a 40 ml vial and dissolved in anhydrous DMF (30 ml). The flask was sealed with a septum and the vial was closed with a septum screw cap. The catalyst mixture and the monomer solution were transferred out of the dry box and were placed under static argon. The reaction flask was heated to 70° C. for 45 min. The monomer solution was then was quickly transferred from the vial to the catalyst mixture flask with an argon flushed syringe. The reaction mixture was then heated to 70° C. for 6 h. The reaction mixture was cooled and solvent removed by rotary evaporation. The resultant black residue was re-dissolved in 20% EtOH (80 mL) and centrifuged at 2400 rpm for 12 hours. The supernatant was then decanted and filtered through a 0.45 um cup filter. The filtered reaction mixture was purified using tangential flow filtration (TFF) and was diafiltered into 20% ethanol using a 10,000 molecular weight cutoff membrane (polyethersulfone Prep/Scale TFF cartridge system, Millipore, Billerica, Mass.) until GPC analysis of retentate indicated the absence of low molecular weight material. The solvent was then removed under vacuum to give 2,7-dibromo-poly-[2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene-co-2,7-(9-methyl-9′-(butyl-4-t-butylcarbamate)fluorene)] (C) as a viscous oil (1.3 g, 45%) Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=72,000, Mw=156,000, Mp=138,000, D=2.1). Step 2: End Capping A solution of K2CO3 in water (2M, 4 mL) was added to a stirred mixture of 2,7-dibromo-poly-[2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene-co-2,7-(9-methyl-9′-(butyl-4-t-butylcarbamate)fluorene)] (C) (800 mg, 0.67 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butanoic acid (D) (120 mg, 0.41 mmol), and DMF (6 mL) in a round bottom flask. This mixture was degassed with argon for 15 min. Palladium tetrakis(triphenylphosphine) (50 mg, 6 mol %) was added to the mixture and the flask was attached to a reflux condenser. The reaction vessel was degassed via 3 freeze-pump-thaw cycles and then heated to 80° C. for 12 h. The reaction mixture was cooled to 23° C. and concentrated in vacuo to a volume of 2 mL. The crude reaction mixture was transferred to an Erlenmeyer flask and diluted with 20% EtOH/H2O (75 mL). EDTA (300 mg, 2.00 mmol) was added to the mixture and stirred at 23° C. for 1 h. The mixture was filtered through a glass fiber filter paper and the filter paper rinsed with 20% EtOH/H2O. The resulting filtrate was then filtered through a 0.45 um cup filter. The filtered reaction mixture was purified and size fractionated using tangential flow filtration (TFF) and was diafiltered into 20% ethanol using a 10,000 molecular weight cutoff membrane (polyethersulfone Prep/Scale TFF cartridge system, Millipore, Billerica, Mass.) until conductivity of the filtrate measured less than 0.01 mS/cm. The solvent was then removed under vacuum to give 4-(4-(2-bromo-poly-[2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene-co-2,7-(9-methyl-9′-(butyl-4-t-butylcarbamate)fluorene)])phenyl)butanoic acid (E) as a yellow oil (660 mg, 82%). Step 3: Linker Deprotection Trifluoroacetic acid (4 mL) was added dropwise to a stirred solution of 4-(4-(2-bromo-poly-[2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene-co-2,7-(9-methyl-9′-(butyl-4-t-butylcarbamate)fluorene)])phenyl)butanoic acid (E) (200 mg, 0.169 mmol) and dichloromethane (16 mL) in a round bottom flask. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was redissolved in minimal 20% EtOH and 1M HCl was added to the solution until pH=7. The neutralized solution was then desalted over G25 gel and the resultant material was concentrated to dryness to yield a clear pale yellow oil (F). Examples of dye incorporation, linker activation and bioconjugation are contained in further Example 38 and related examples. Example 26: Synthesis of a Tandem Polymer with Two Different Linkers Using End Capping Units to Regulate the Polymerization Reaction Step 1: Yamamoto Polymerization In a dry box, Ni(COD)2 (0.433 g, 8.40 mmol), 2,2′-bipyridyl (0.246 g, 8.40 mmol), COD (0.170 g, 8.40 mmol) and anhydrous DMF (15 ml) were added to a long-neck round bottom flask. 2,7-dibromo-9,9-di(2′,5′,8′,11′,14′,17′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)fluorene (A) (1.00, 0.696 mmol), tert-butyl 4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butylcarbamate (B) (0.037 g, 0.069 mmol), and tert-butyl 4-(4-bromophenyl)butanoate (C) (0.004 g, 0.007 mmol) were added to a 40 ml vial and dissolved in anhydrous DMF (10 ml). The flask was sealed with a septum and the vial was closed with a septum screw cap. The catalyst mixture and the monomer solution were transferred out of the dry box and were placed under static argon. The reaction flask was heated to 70° C. for 45 min. The monomer solution was then was quickly transferred from the vial to the catalyst mixture flask with an argon flushed syringe. The reaction mixture was then heated to 70° C. for 6 h. The reaction mixture was cooled and solvent removed by rotary evaporation. The resultant black residue was re-dissolved in 20% EtOH (80 mL) and centrifuged at 2400 rpm for 12 hours. The supernatant was then decanted and filtered through a 0.45 um cup filter. The filtered reaction mixture was purified using tangential flow filtration (TFF) and was diafiltered into 20% ethanol using a 10,000 molecular weight cutoff membrane (polyethersulfone Prep/Scale TFF cartridge system, Millipore, Billerica, Mass.) until GPC analysis of retentate indicated the absence of low molecular weight material. The solvent was then removed under vacuum to give tert-butyl 4-(4-(2-bromo-poly-[2,7{9,9-bis(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontane)fluorene-co-2,7-(9-methyl-9′-(butyl-4-t-butylcarbamate)fluorene)])phenyl)butanoate (D) as a viscous oil (664 g, 80%). Molecular weight determined by GPC analysis relative to polystyrene standards (Mn=50,000, Mw=88,000, Mp=174,000, D=1.8). Step 2: Linker Deprotection Trifluoroacetic acid (6 mL) was added dropwise to a stirred solution of Polymer (300 mg, X mmol) and dichloromethane (24 mL) in a round bottom flask. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was redissolved in minimal 20% EtOH and 1M HCl was added to the solution until pH=7. The neutralized solution was then desalted over G25 gel and the resultant material was concentrated to dryness to yield a clear pale orange oil (261 mg, 87%). Examples of dye incorporation, linker activation and bioconjugation are contained in further Example 38 and related examples. Example 27. Dual Functional Asymmetric Polymer with Both Internal and Terminal Conjugation Sites Used to Create a Polymer-Dye Label for Biomolecule or Substrate Conjugation Suzuki polymerization of 2-bromo-9,9-di(2′,5′,8′,11′,14′,17′,20′,23′,26′,29′,32′,35′-dodecaoxaoctatriacontan-38′-yl)-′7-(4″,4″,5″,5″-tetramethyl-1″,3″,2″-dioxaborolan-2-yl)fluorene is performed under those conditions described in Example 23 where y % is the mol % of the end linker used to regulate the polymerization and ensure high incorporation of linker. The linker in this example is 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butanoic acid. In this example, x mol % of the internal linker is also added to the polymerization to incorporate the second linking site into the polymer. This method for incorporating the internal linker is generally described in Examples 21, 25 and 26. The internal linker must be incorporated during the polymerization as indicated, however, it is expected that it would be possible to add the terminal linker as a separate step as described in Examples 9, 10, 11 and 21. Example 28: Enrichment of Linker-Functionalized Polymers The synthesis of linker-functionalized polymers can yield a mixture of chains with and without linker functionalities. Because conjugation efficiency is expected to improve with higher purity polymers for conjugation, the methods described in this example address this by enriching for chains containing linker. For a polymer batch containing a mixture of a COOH-modified and unmodified polymer: Dissolve polymer in 95% EtOH, then dilute with water to a final EtOH concentration of 20%. Desalt the polymer using 10 kDa MWCO filter until conductance is <0.1 mS/cm. Inject onto Q-Sepharose column, ensuring that the polymer load is suitable for the column capacity. Pass 20% EtOH in water over column to wash out unbound polymer. Release bound material by changing the eluting buffer to 1M NaCl in 20% EtOH in water for two column volumes to trigger the release of the bound polymeric material. Collect enriched material. The polymer is passed over a strong anion exchanger such as a Q-Sepharose column. Polymer chains bearing a functional carboxylic acid group will bind the strong anion exchanger, and polymer that is not functionalized will not bind and instead will wash through. After the non-functionalized polymer has passed through the column, the column is washed with 1M NaCl, which triggers the release of the acid-functionalized polymer by screening the acid group from the media. By using this method, the percent functional polymer has been shown to increase from 25% of polymer chains bearing a carboxylic acid group to >80% of polymer chains bearing a carboxylic acid group. This increase in functional chains has been shown by analyzing the absorbance ratios of polymer-dye conjugates pre- and post-enrichment. This procedure is also described in Example 38. A similar process has been validated for the enrichment of amine containing polymers. In that case an anionic exchange resin, SP Sephrose (or similar), is loaded at reduced conductivity (below 0.01 mS/cm). Example 29: Preparation of Polymer-Streptavidin Conjugates Via NHS/Amine Coupling Example 29a: Polymer Modifications Polymer Modification—Carboxylic Acid to Amine Conversion 1.35 g of a carboxylic acid terminated polymer was dissolved at in 9 mL ethanol, then added dropwise to 80 mL of 4° C. 50 mM MES, pH 5 while stirring. 0.52 g N-hydroxy succinimide was added in one portion. Once the N-hydroxy succinimide had dissolved, 2.3 g N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride was added in portions. After stirring the solution for 30 minutes, 2.8 mL of ethylene diamine was added dropwise. The solution was stirred overnight at room temperature and purified by tangential flow filtration (MWCO=10 kDa). 1.22 g yield (90%). Polymer Modification—Amine to Carboxylic Acid Conversion 70 mg of an amine-terminated polymer was dissolved in 7 mL DMSO. 2.3 mg DIPEA was added to the polymer solution. 2.2 mg DMAP was dissolved in 220 μL DMSO and added to the resulting polymer solution. 5.5 mg succinic anhydride was dissolved in 550 μL DMSO and added to the resulting polymer solution. The solution was agitated at room temperature overnight. The reaction was then purified over Amicon Ultra centrifugal filtration units (MWCO=10 kDa) with 25 mM MES pH 5 buffer. 62 mg yield (89%). Polymer Modification—Carboxylic Acid to NETS-Ester Conversion 60 mg of a carboxylic acid-terminated polymer was dissolved in 600 μL acetonitrile. 1.2 μg DIPEA was added to the polymer solution. 2.8 mg N,N,N′,N′-Tetramethyl-O—(N-succinimidyl)uronium was dissolved in 370 μL acetonitrile and added to the polymer solution. The solution was agitated at room temperature for 15 minutes. After the reaction is complete, the solvent was evaporated under reduced pressure. 50 mg yield (83%). Example 29b: Protein-Polymer Conjugation Streptavidin protein is dissolved in 50 mM NaHCO3 pH 8.2 buffer to make a 1 mg/mL solution. Crude activated polymer (10-15 eq or as required) solution from Step 2 is added to the aqueous streptavidin protein solution; the protein concentration is adjust with buffer to ensure that the volume of organic solvent added is <10% of the total volume, if necessary. The solution is agitated at room temperature for 3 hr and the reaction transferred to a Amicon Ultra filter (MWCO=10 kDa) to remove DMF. The protein is recovered into the initial volume with 25 mM PO4 pH 6.5 buffer. Purification of the Protein-Polymer Conjugate A 1 mL HiTrap SP Sepharose FF column is equilibrated with 20 mM Na Citrate pH 3 buffer. 1 mL (0.3-1 mg/mL) of Streptavidin-polymer conjugate is loaded in 25 mM NaHPO4 pH 6.5. The sample is wash through column with 20 mM Na Citrate pH 3 buffer until a stable baseline is obtained. Multiple 1 mL aliquots of sample may subsequently be loaded and washed. The column is washed with a minimum of 10 column volumes of 20 mM Na Citrate pH 3 buffer. The conjugate is eluted with 10 column volumes of 20 mM Na Citrate in 0.6 M NaCl pH 7.6 buffer and the column is stripped with 10 column volumes of 20% ethanol in the elution buffer. The elution peak is concentrated with an Amicon Ultra filter (MWCO=10 kDa) to reduce the volume to ˜200 μl. A 10×300 mm Superose 12 column is equilibrated with 20 mM Na Citrate in 0.6 M NaCl pH 7.6 buffer. 200 μL of concentrated Streptavidin-polymer conjugate is loaded and eluted with 20 mM Na Citrate in 0.6 M NaCl pH 7.6 buffer. Fractions are pooled and buffer exchanged into PBS+0.05% NaN3 using Amicon Ultra Centrifugation filters (10 kD MWCO). Elutions are concentrated to desired concentration for testing; at around 2 μM Streptavidin. Characterization of a Purified Protein-Polymer Conjugate A 4-20% acrylamide Tris-HCl Ready Gel (BioRad) is prepared and the gel is loaded with the conjugate along with free streptavidin and free polymer in separate lanes. Gel electrophoresis is performed in 25 mM Tris 192 mM, Glycine pH 8.3 and stained with Coomassie to visualize the protein. The gel is stained for 30 minutes then destained with commercial destain overnight. Agarose gel conditions were also used to characterize polymer-streptavidin conjugates, an example which is shown in FIG. 29. In alternative embodiments, the above example can be adapted to allow for conjugation of the polymer to biomolecules or dyes, including but not limited to, antibodies and nucleic acids. The amine on the polymer is converted to a maleimide and a carboxylic acid (further activated to form the NHS ester) using alternative crosslinkers or modifiers. In certain embodiments, conjugation of the same polymer to other biomolecules (streptavidin, antibody fragments, nucleic acids) is facilitated using maleimide-thiol chemistry (using SATA linkers to convert free amines on the biomolecule or TCEP (or DPP) reduction of an antibody to create free thiols). Example 30: Preparation of Polymer-Streptavidin Conjugates Via Hydrazide/Benzaldehyde Coupling Step 1: Streptavidin-4FB Modification Streptavidin protein is reconstituted at 1.7 mg/mL and exchange into reaction buffer, 50 mM NaHCO3, pH 8. 15 molar equivalents of bifunctional benzaldehyde/succinimidyl linker, S-4FB (Solulink, San Diego, Calif.) 20 mg/mL in anhydrous DMSO is added to streptavidin, ensuring that the organic phase is less than 10% of the total volume. Reaction is mixed on shaker for 4 hours at room temperature and unreacted linker is subsequently filtered away via Amicon Ultra filter, 10 kD MWCO with 50 mM MES buffer, pH 5; centrifuged at 2400 rpm and a repeated wash ×3. Streptavidin protein is recovered in its initial volume, targeting 1.7 mg/mL in conjugation buffer, 50 mM NaPO4, pH 6.5. Step 2: Polymer Modification Polymer with terminal amine group (1 molar eq) is dissolved with DMF to make a 10 mg/mL solution. 20 molar equivalents of a bifunctional hydrazine/succinimidyl linker, SHTH (Solulink, San Diego, Calif.) at 80 mg/mL in anhydrous DMSO is added to the polymer solution. 1 drop of DIPEA is added to the reaction by a syringe and 22 g needle. The solution is agitated at room temperature for 4 hr and the reaction transferred to a Amicon Ultra filter (MWCO=10 kDa) filled with 25 mM MES pH 5 buffer. The solution is then centrifuged. The filter is refilled and washed with the following wash buffers: 1×DI H2O+1 drop 1 M HCl 1×DI H2O+1 drop 1M NaOH 3×50 mM MES, pH 5 Step 3: Protein-Polymer Conjugation 15 equivalents of modified polymer from Step 2 are added with desired amount of modified protein from Step 1. Aniline is added to the reaction for a final concentration of 10 mM and allowed to mix for 12 hours. The reaction is purified with Amicon Ultra filter (MWCO=10 kDa) to remove DMF and recovered with 25 mM PO4 pH 6.5 buffer. Step 4: Purification of the Protein-Polymer Conjugate A 1 mL HiTrap SP Sepharose FF column is equilibrated with 20 mM Na Citrate pH 3 buffer. 1 mL (0.3-1 mg/mL) of Streptavidin-polymer conjugate is loaded in 25 mM NaHPO4 pH 6.5. The sample is wash through column with 20 mM Na Citrate pH 3 buffer until a stable baseline is obtained. Multiple 1 mL aliquots of sample may subsequently be loaded and washed. The column is washed with a minimum of 10 column volumes of 20 mM Na Citrate pH 3 buffer. The conjugate is eluted with 10 column volumes of 20 mM Na Citrate in 0.6 M NaCl pH 7.6 buffer and the column is stripped with 10 column volumes of 20% ethanol in the elution buffer. The elution peak is concentrated with an Amicon Ultra filter (MWCO=10 kDa) to reduce the volume to ˜200 μl. A 10×300 mm Superose 12 column is equilibrated with 20 mM Na Citrate in 0.6 M NaCl pH 7.6 buffer. 200 μL of concentrated Streptavidin-polymer conjugate is loaded and eluted with 20 mM Na Citrate in 0.6 M NaCl pH 7.6 buffer. Fractions are pooled and buffer exchanged into PBS+0.05% NaN3 using Amicon Ultra Centrifugation filters (10 kD MWCO). Elutions are concentrated to desired concentration for testing; at around 2 μM Streptavidin. Step 5: Characterization of a Purified Protein-Polymer Conjugate A 4-20% acrylamide Tris-HCl Ready Gel (BioRad) is prepared and the gel is loaded with the conjugate along with free streptavidin and free polymer in separate lanes. Gel electrophoresis is performed in 25 mM Tris 192 mM, Glycine pH 8.3 and stained with Coomassie to visualize the protein. The gel is stained for 30 minutes then destained with commercial destain overnight. FIG. 14 top, depicts conjugation of streptavidin to a polymer of formula (Vb) in cartoon format. FIG. 14, bottom, is a Coomassie stain of acrylamide gel which depicts the mobility of the conjugate is retarded relative to the free protein indicating an increase in mass. A neutral polymer alone shows no evidence of staining and without a formal charge, the polymer is not mobile in the electrophoretic field. In alternative embodiments, the above example can be adapted to allow for conjugation of the polymer to biomolecules or dyes, including but not limited to, antibodies and nucleic acids. The amine on the polymer is converted to a maleimide and a carboxylic acid (further activated to form the NHS ester) using alternative crosslinkers or modifiers. In certain embodiments, conjugation of the same polymer to other biomolecules (streptavidin, antibody fragments, nucleic acids) is facilitated using maleimide-thiol chemistry (using SATA linkers to convert free amines on the biomolecule or TCEP reduction of an antibody to create free thiols) and NETS-amine chemistry (reacting the NETS polymer directly with lysines on the protein or nucleic acid). Example 31: Preparation of Biotin-Labeled Polymers Amine functionalized polymer of formula (Vc) is dissolved at 10 mg/mL in anhydrous DMF and divided into two portions. NHS-biotin (0.9 mg in 90 μL, 88 equivalents) (Pierce, 20217) and NHS-LC-LC-biotin (Pierce, 21343) at 10 mg/mL (1.5 mg in 150 μL, 88 equivalents) are dissolved in anhydrous DMF. The NHS-biotin and NHS-LC-LC-biotin solutions are immediately added to the two portions of polymer solution and allowed to mix on a shaker overnight in the dark. Excess reactant is removed by washing the solution using Amicon Ultra-4 mL 10 kD MWCO filter cartridges in a series of wash steps: First, the cartridge is first filled approximately halfway with water, and the reaction solution (by pipet) subsequently added directly into the water. Next, the cartridge is filled with water until it is full. The solution is mixed by pipetting up and down. Then, the cartridge is centrifuged at 2400 rpm for 30 minutes, or until the volume is reduced to 250 μL. The cartridge is then refilled with water 1 drop of 1M HCl is added; the solution is mixed, and centrifuged at 2400 rpm for 30 minutes, or until the volume was reduced to 250 μL. Next, the cartridge is refilled with water, 1 drop of 1M NaOH is added; the solution is mixed, and centrifuged at 2400 rpm for 30 minutes, or until the volume is reduced to 250 μL. The cartridge is then refilled with water, mixed and centrifuged at 2400 rpm for 30 minutes, or until the volume is reduced to 250 μL. This final step is repeated for a total of 5 washes. Characterization of a Purified Biotin-Labeled Polymer Excess biotin-labeled polymer is incubated with a Cy5-labeled streptavidin in DPBS buffer plus 0.2% BSA and 0.05% NaN3. A 0.8% agarose gel is prepared and the gel is loaded with the conjugate along with free Cy5-streptavidin and free biotinylated polymer in separate lanes. Gel electrophoresis is performed in 10 mM NaHCO3 pH10 and visualized using a Typhoon gel imager with 457 nm and 635 nm laser excitation. FIG. 15 (bottom) depicts retardation of mobility of the polymer-streptavidin complex relative to the free protein indicating an increase in mass. The polymer alone shows little mobility on its own due to a lack of formal charge. This protocol is adapted to successfully biotin-modify a range of conjugated polymers containing both internal and terminal amine linkers. Example 32: Functional Testing of Covalent Polymer Streptavidin Conjugates by Selective Binding to Biotinylated Microspheres Materials Required: 1×TBST: 50 mM Tris-HCl, 150 mM NaCl, 0.1% Tween20, pH 7.5; Biotin microspheres (10 mg/mL in TBST); BSA (1 mg/mL); AvDN (220 μM); and Polymer-Strepavidin (SA) conjugate: (1 μM with regard to SA, provided at 5 μM). Preparation of Master Mixes: Prepare in labelled 1.5 mL microfuge tubes: Experimental Negative control master mix master mix 14 μl TBST 9 μl TBST 6 μl BSA stock 6 μl BSA stock 5 μl bead stock 5 μl avidin stock 5 μl bead stock Briefly vortex both tubes and allow 20-30 minutes to pre-incubate the negative control beads with excess avidin before proceeding. A variable speed orbital mixer at 800 RPM for incubation is suggested to keep beads from settling. Bead Hybridization: Pipette 10 μL of each master mix into separate labelled 1.5 ml microfuge tubes. Add 2 μL of polymer-SA conjugate to each. Prepare additional tube containing 10 μL master mix and no polymer to be used as a blank. Briefly vortex and pulse spin all tubes. Transfer to variable speed orbital mixer and incubate for 30 mins at 800 RPM. Bead Processing/Washing: Add 0.5 ml TBST to all samples and controls and vortex briefly. Centrifuge at 1200 g for 2 min and remove 480 μl supernatant being diligent not to disturb bead pellet. Add 0.5 ml TBST to all samples and controls and vortex briefly. Centrifuge at 1200 g for 2 min and remove 500 μl supernatant being diligent not to disturb bead pellet. Repeat steps 3 and 4. Remove as much of remaining supernatant as possible using P200 pipette without disturbing bead pellet. Add 100 μL TBST and vortex briefly to re-suspend beads. Bead Measurement: Transfer 100 μL of positive, negative and blank beads to a BLACK 96 well plate. Excite wells at 430 nm and collect emission in the range 450-650 nm using required slit widths and/or sensitivity setting to achieve measurable signals above background. Compare emission of positive and negative control beads. FIG. 16 shows the polymer streptavidin conjugate was bound to a biotinylated microsphere. Excitation at 440 nm in a fluorometer resulted in emission from the polymer as indicated by the solid curve. The dashed curve represents the negative control where the biotin bead was first treated with excess avidin to block the biotin binding sites prior to treatment with the polymer streptavidin conjugate. Example 33: Functional Testing of Covalent Polymer Streptavidin Conjugates by Selective Binding to Biotinylated Microspheres and FRET to Dye Acceptors on Co-Localized Streptavidin-Dye Conjugates Materials Required: 1×TBST: 50 mM Tris-HCl, 150 mM NaCl, 0.1% Tween20, pH 7.5. Biotin microspheres (10 mg/mL in TBST). Cy3-SA (1 μM or 50 μg/mL). Polymer-Strepavidin (SA) conjugate: (1 μM with regard to SA, provided at 5 μM).. Bead Preparation and Hybridization: Prepare in labelled 1.5 mL microfuge tubes: Blank control Cy3-SA control FRET-SA Control 16 μl TBST 14 μl TBST 14 μl TBST 4 μl bead stock 2 μl Cy3-SA stock 2 μl Cy3-SA stock 4 μl bead stock 2 μl polymer-SA stock 4 μl bead stock Briefly vortex all tubes and transfer to variable speed orbital mixer for incubation of at least 30 mins at 800 RPM. Bead Processing/Washing: Add 0.5 ml TBST to all samples and controls and vortex briefly. Centrifuge at 1200 g for 2 min and remove 48 μl supernatant being diligent not to disturb bead pellet. Add 0.5 ml TBST to all samples and controls and vortex briefly. Centrifuge at 1200 g for 2 min and remove 500 μL supernatant being diligent not to disturb bead pellet. Repeat steps 3 and 4. Remove as much of remaining supernatant as possible using P200 pipette without disturbing bead pellet. Add 100 TBST and vortex briefly to re-suspend beads. Bead Measurement: Transfer 100 μL of all samples to a BLACK 96 well plate. Excite wells at 430 nm and collect emission in the range 450-650 nm using required slit widths and/or sensitivity setting to achieve measurable signals above background. Detect and record polymer emission in the range of 480-500 nm and Cy3 emission at the expected 570 nm. FIG. 17 shows the polymer streptavidin conjugate was bound to a biotinylated microsphere. Excitation at 440 nm in a fluorometer resulted in energy transfer between the polymer and a Cy3 dye conjugated to a different streptavidin protein as indicated by the solid upper curve. The dashed curve shows beads alone and the lower solid curve direct excitation of the Cy3-streptavidin conjugate at 440 nm. Example 34: Functional Testing of Biotin-Labeled Polymers by Selective Binding to Avidin Coated Microspheres Materials Required: 1×TBST: 50 mM Tris-HCl, 150 mM NaCl, 0.1% Tween20, pH 7. SA microspheres (10 mg/mL in TBST). Biotin (1 mM). 440 nm biotin-polymer conjugate: (46 μM). Bead Preparation and Hybridization: Prepare in labelled 1.5 mL microfuge tubes: Blank control Negative control Positive Control 16 μl TBST 11 μl TBST 15 μl TBST 4 μl bead stock 4 μl biotin stock 4 μl bead stock 4 μl bead stock Briefly vortex all tubes and transfer to variable speed orbital mixer for incubation of 20-30 mins at 800 RPM to ensure biotin has blocked all SA sites on negative control beads. Add 1 uL of polymer-biotin stock to both positive and negative control tubes. Vortex briefly and transfer to variable speed orbital mixer and incubate for 30 mins at 800 RPM. Bead Processing/Washing: Add 0.5 ml TBST to all samples and controls and vortex briefly. Centrifuge at 1200 g for 2 min and remove 480 μL supernatant being diligent not to disturb bead pellet. Add 0.5 ml TBST to all samples and controls and vortex briefly. Centrifuge at 1200 g for 2 min and remove 500 μl supernatant being diligent not to disturb bead pellet. Repeat steps 3 and 4. Remove as much of remaining supernatant as possible using P200 pipette without disturbing bead pellet. Add 100 μL TBST and vortex briefly to re-suspend beads. Bead Measurement: Transfer 100 μL of all samples to a BLACK 96 well plate. Excite wells at 430 nm and collect emission in the range 450-650 nm using required slit widths and/or sensitivity setting to achieve measurable signals above background. Compare emission of positive and negative control beads. FIG. 18 shows the biotin modified polymer was bound to a streptavidin microsphere (top). In FIG. 18 (bottom), excitation at 440 nm in a fluorometer resulted in emission from the polymer as indicated by the solid upper curve. The lower solid curve represents the negative control where the streptavidin bead was first treated with excess biotin to block the binding sites prior to treatment with the biotinylated polymer. The lower solid curve represents beads alone. Example 35: Selective Binding of Biotin-Labeled Polymer to Dye-Labeled SA Conjugates to Validate FRET Properties and Functional Activity of the Polymer Modification Materials Required: Biotin-Polymer Conjugate: (46 Cy3-SA conjugate (1 mg/mL or 18.9 μM). BLACK 96-well plate. Forming the Biotin-Streptavidin Complex: In a 1.5 mL microfuge tube, combine 9.4 μL of the biotin-polymer conjugate and 2.9 μL of the Cy3-SA. Vortex to mix, then incubate on a shaker (under foil) for 0.5 h. Longer incubation times are also suitable. Instrument Settings: Model experiments were conducted on a BioTek Synergy 4 in the Fluorescence mode with the following settings: Emission: 400-750 nm in 5 nm steps and Sensitivity level: 50. Plate Layout: Prepare solutions in a BLACK 96-well plate as in the below table. Take care to add the A+B solution last, after all other materials have been added: Material Well 1 Well 2 Well 3 Polymer-biotin 9.4 μL* 9.4 μL — Cy3-SA 2.9 μL* — 2.9 μL Buffer 100 μL 100 μL 100 μL *Pre-incubated in the first step, Forming the Biotin-Streptavidin Complex. FIG. 19 shows the biotin modified polymer was bound to a dye labeled streptavidin (Cy3 or Texas Red—top). Excitation at 440 nm in a fluorometer resulted in emission from the dye acceptors at their respective emission wavelength (approximately 570 nm and 620 nm respectively—bottom left) as well as some residual emission from the polymer (approximately 520 nm). A titration was also performed to saturate the binding of polymer to the streptavidin (bottom right). The solid curve indicates the emission from the Cy3 label on the streptavidin via energy transfer from the polymer at 440 nm excitation. The dotted curve represents the negative control where the streptavidin was first treated with excess biotin to block the binding sites prior to treatment with the biotinylated polymer. Example 36: Polymer-Streptavidin Conjugates for Use in Flow Cytometry Polymer bioconjugates are evaluated by Stain Index, as defined by Becton Dickinson (BD) Biosciences on a flow cytometer. See, e.g., H. Maeker and J. Trotter, BD Biosciences Application Note: “Selecting Reagents for Multicolour Flow Cytometry”, September 2009. The stain index reports a measure of the polymer's brightness, nonspecific binding and can also be related by the Resolution Index on a flow cytometer. Flow cytometry provides a method through which to measure cells of a specific phenotype or analytes of interest on specific microspheres. This can be done with direct labeling of a primary antibody or, if signal amplification is desired, through a secondary antibody or the avidin-biotin complexation with avidin-polymer conjugates. Procedure for Cell Staining Cells of interest are taken up in sufficient quantity, at least 105 per test condition. Cells are then spun down at 250 rcf for 3 minutes, washed in DPBS+0.2% BSA and 0.05% NaN3 (staining buffer), then resuspended in staining buffer at 1×107 cells/mL. For primary incubation, cells are incubated with a primary conjugate (reporter labeled antibody) specific to an antigen of interest, negative cells serve as a negative non-specific binding reference. A control population or an established commercial conjugate is used as a positive control. Primary polymer conjugates are incubated at 4° C. with 4×105 cell aliquots at concentrations with volume dilutions from 10-330 nM for 30 minutes. Following primary incubation, cells are rinsed with 5 volumes staining buffer and spun down at 250 rcf for 3 minutes; this rinse is repeated three times. Cells are resuspended for testing at 8×105 cells/mL in DPBS+0.2% BSA, 0.05% NaN3. For secondary antibody labeling, an unlabeled primary antibody to the antigen of interest is incubated at 0.4 ug/uL, or other titrated amount, at 4° C. with 4×105 cells per test condition for 30 min. Following primary incubation, cells are rinsed with 5 volumes staining buffer and spun down at 250 rcf for 3 minutes; this rinse is repeated three times. Species reactive secondary polymer conjugates are incubated at 4° C. with 4×105 cell aliquots at concentrations with volume dilutions from 10-330 nM for 30 minutes. Following secondary incubation, cells are rinsed with 5 volumes staining buffer and spun down at 250 rcf for 3 minutes; this rinse is repeated three times. Cells are resuspended for testing at 8×105 cells/mL in DPBS+0.2% BSA, 0.05% NaN3. For streptavidin-polymer conjugate labeling, cells are incubated with a biotinylated primary antibody to the marker of interest, as detailed above for the secondary antibody labeling, instead of an unlabeled primary. Following the primary washing, cells are resuspended and divided in 4×105 cell aliquots and incubated with streptavidin-polymer conjugates at 1-100 nM volume dilutions for 30 minutes at 4° C. Following secondary incubation, cells are rinsed with 5 volumes staining buffer and spun down at 250 rcf for 3 minutes; this rinse is repeated three times. Cells are resuspended for testing at 8×105 cells/mL in DPBS+0.2% BSA, 0.05% NaN3. If further signal amplification is desired, cells and be incubated with an unlabeled primary antibody and then subsequently follow with a species reactive biotinylated secondary antibody prior to incubation with streptavidin conjugates. The incubation steps, washing protocol and testing protocol should follow as previously detailed. These flow testing procedures have been developed specific to CD4 markers on Cyto-trol cells. Cell preparation and incubation protocols may vary with cell type and an optimal staining, washing and handling protocol should be developed specific to cell type. Working concentration ranges of antibodies have been identified as optimal for both CD4 (35-50% population) and CD45 (85% population) markers on Cyto-trol control lymphocytes as well as on Whole Lysed Blood (for primary antibody only). Markers which have populations significantly different than these ranges may fall outside of the suggested titration ranges. Testing was also done on a Jurkat cell line grown in culture following similar protocols. In these tests a CD45 marker was used. As there are no negative cell populations a different negative control procedure was used. In the negative control samples the primary antibody was omitted from the primary incubation step. This step and all subsequent steps were performed according to the standard protocol. Again a commercially dye-antibody or dye-strepatvidin conjugate were used as a positive control. Procedure for Flow Cytometry Analysis Flow testing was done in test tubes, at 0.5 mL volumes on a BD LSR II Flow Cytometer. Flow testing is performed using the voltage settings determined from daily calibration of the cytometer with calibration particles by flow facility staff. Lymphocyte specific gating by forward scatter vs. side scatter is performed on unstained cell samples as a background control. Standard doublet gating is performed for both forward scatter and side scatter area vs. width profiles. With only a single color, no compensation is required. Data are collected for all forward and side scatter parameters and fluorescence measurements are made using BD's standard Pacific Blue channel. Pacific Blue data utilizes excitation with the 408 nm Violet lasers and a 450/50 BP filter. Samples are collected for 30,000 events within the stated gating parameters. Representative Experiments: CD4 marking was measured on Cyto-trol cells, lyophilized human lymphocytes for analysis of polymer performance in flow. Cyto-trol cells (Beckman Coulter) were reconstituted in the provided reconstitution buffer and allowed to swell for 15 minutes at room temperature. Cells were then spun down at 250 rcf for 3 minutes, washed in DPBS+0.2% BSA and 0.05% NaN3 (staining/testing buffer), then resuspended in staining buffer at 1×107 cells/mL. Cell suspension was divided in two; half the cells were incubated with biotinylated anti-CD4 at 0.4 ug/uL, the other half of the cells were incubated with staining buffer as a negative control for 30 min. Following primary incubation, cells were rinsed with 5 volumes staining buffer and spun down at 250 rcf for 3 minutes; this rinse was repeated three times. Cells were resuspended at prior volume in staining buffer. 4×105 cells were measured per test and divided out accordingly, streptavidin-fluorophore conjugates prepared in Example 19 were incubated at 100 nM with each aliquot of cells for 30 min, allowing the avidin-biotin complex to form. Following the secondary incubation, cells were rinsed and detailed previously. Final cell suspensions were made for testing at 8×105 cells/mL. Flow analysis was performed on a BD LSR II flow cytometer at The Scripps Research Institute (TSRI), San Diego, Calif. Routine calibration with Rainbow fluorescent particles for aligning fluorescent channels on the cytometer was performed by staff at TSRI, all calibrated voltages were used, per staff recommendation. All samples were excited with a 408 nm Violet laser, the polymer conjugate was measured in the AmCyan channel with a 525/50 filter. All samples were initially referenced to unstained cells. The polymer streptavidin conjugate from FIG. 14 showed specific secondary labeling of the primary identified CD4 positive cells, with the positive cells as 44% of the population. The polymer streptavidin conjugate demonstrated a positive stain index showed low non-specific binding with reference to unstained cells and its respective negative control (FIG. 20. (A)). This provides evidence that the polymer, although its peak absorbance is a 440 nm, is a viable fluorescent material for use in flow cytometry with Violet laser excitation. Secondary Antibody polymer conjugate on Cyto-trol cells Amine-functionalized 405 polymer was conjugated to goat anti-mouse IgG κ1 purified antibody by route of maleimide-thiol conjugation and TCEP partial reduction of the antibody. The polymer and conjugation procedure are provided specifically in Example 46. Conjugates were tested on Cyto-trol cells (Beckman Coulter), a fixed and lyophilized lymphocyte cell population for control testing of specific human antigens. Cell staining followed secondary cell staining protocol. Cells were incubated with and without (negative control) unlabeled anti-CD4 (RPA-T4 clone, BD Biosciences) raised in mouse against the human antigen. After complete washing of primary antibody incubation, cells were incubated with polymer labeled goat anti-mouse conjugates for specific labeling of primary identified CD4 positive cells. Secondary labeling occurs by Fc recognition and binding of the mouse primary antibody by the secondary goat IgG, raised against murine species. A positive control was used by incubation with commercially available Pacific Blue goat anti-mouse IgG (Invitrogen) as the secondary labeling species. FIG. 20 (B) depicts the specific recognition of CD4 specific cells by the secondary fluorescent conjugates. Unstained cells show a negative control and natural autofluorescence of the cells, and incubation of polymer conjugate on cells with no primary labeling show minimal non-specific binding of the conjugate to unlabeled cells. Positive control, Pacific Blue goat anti-mouse shows the commercially available standard for CD4 labeling by secondary antibody with Violet excitation. 405 polymer-goat anti-mouse conjugate (red) shows positive identification of CD4 positive cells, a minimal shift in the negative cell population and great fluorescent signal and resolution that Pacific Blue standard. FIG. 20 (C) depicts Streptavidin polymer conjugates on Jurkat cells. Conjugates were produced with the polymer provided in Example 11 using the protocol defined in Example 29. The stain index for the polymer streptavidin conjugate was over 10 fold higher than that obtained for the commercially available Pacific Blue streptavidin control conjugate. FIG. 20 (D) depicts a primary monoclonal antibody polymer (antiCD4, RPA-T4) conjugate evaluated on Cyto-trol cells using the protocols defined above. The conjugate was prepared using the polymers and protocols defined in Example 46. Additional details on the conjugation can also be found in Example 39. Example 37: Preparation of Polymer Conjugated to —COOH Beads Via EDC Coupling Materials (Per 100 μL of Beads) LodeStars —COOH functionalized magnetic beads (Varian, Inc. PL6727-0001) (100 μL of suspension at spec′ d 30 mg/mL). Polymer with amine terminal ends from Example 17 (125 μL at 1.6 μM in 25 mM MES pH 5, for a 10-fold excess over theoretical bead capacity). 10 mM NaOH (2 mL). DI H2O (3 mL). 25 mM cold MES, pH 5. EDC at 50 mg/mL in 25 mM cold MES, pH 5 (100 μL). NHS at 50 mg/mL in 25 mM cold MES, pH 5 (100 μL). 100 mM Tris/HCl pH 7.4 (1 mL). Centrifuge and black flat-bottom 96-well plate. Antibody capacity was given at 10 ug/mg bead, giving an amine coupling capacity of 2 nmol polymer/mL bead (at 30 mg/mL). A 10 fold-excess of polymer over the suggested capacity was used to target the antibody concentration given in Varian's protocol. Bead Washing Beads were washed collectively as 600 μL and then split into 6×100 μL samples for coupling. Beads were washed 2× with 1 mL 10 mM NaOH, then 3x with 1 mL DI H2O; in between washes, the tube was centrifuged 1 min at 3000 rpm to recollect the beads as a pellet, supernatant was discarded and beads were resuspended in the next wash. After the final wash, beads were resuspended in 600 μL cold 25 mM MES, pH 5 and aliquoted into 6×100 μL volumes in microcentrifuge tubes. Beads were centrifuged again 1 min at 3000 rpm and supernatant was discarded. EDC Activation 100 μL of the EDC solution was added to each reaction set. 100 μL of the NHS solution was added to each reaction set. Beads were resuspended by vortexing and then allowed to mix on a rotator for 30 minutes. Beads were washed 2x in cold 25 mM MES pH 5, pelleted by centrifuging for 1 min at 3000 rpm and the supernatant was discarded. Beads were resuspended in 125 μL cold 25 mM MES, pH 5. Polymer Coupling 125 μL of polymer at 1.6 μM was added. Samples were vortexed to mix thoroughly and then reacted at RT on a mixer for 3 hours. Beads were pelleted by centrifuging for 1 min at 3000 rpm; supernatant was discarded. Beads were resuspended in 1 mL 100 mM Tris/HCl to block unreacted —COOH sites, vortexed and mixed for 1 hour. Beads were recollected by centrifugation and resuspended in 100 μL 25 mM MES. At this point, the supernatant of several tubes were yellow in color and had significant absorbance at 440 nm; the beads were washed 6 times until absorbance was at baseline. Beads sat for an additional 2 days prior to fluorescence measurement, after sitting in solution for 2 days, the supernatant was again yellow in color and had measurable absorbance. Beads were washed 3 more times with 30 minute mixes in between until no absorbance was measurable. At 2 days following fluorescence measurements, the supernatant remained clear and free of measurable absorbance. Example 38: Preparation of Polymer-Dye Conjugates Example 38a: Preparation of Polymer-Dye Conjugate at Polymer Terminal 0.5 mg amine-terminated polymer was dissolved in 15 μL DMSO. The polymer solution was then exchanged into 50 mM NaHCO3/Na2CO3, pH 8 buffer and recovered in buffer at ˜5 mg/mL as determined by UV-VIS absorbance. 50 μg NETS-ester dye (DyLight 594) was dissolved at 10 mg/mL in anhydrous DMSO, which was then immediately added to 120 μg of polymer. The tube was mixed on shaker (600-800 rpm) for 1 h and subsequently diluted to 100 μL with 20% EtOH in water. The mixture was added to a 30 cm Superdex 200 SEC column in 0.6M NaCl and 20% EtOH to separate polymer-dye conjugate from unreacted dye. The addition of dye can be used to estimate the incorporation of linker on the polymer structure by measuring an absorbance ratio based on the relative extinction coefficients of the polymer and dye. Using the molecular weight of the polymer it is possible to estimate the number of polymer chains which contain a linker. In additional embodiments, polymers with a carboxylic acid side chain are modified with amine functional dyes using standard EDC conjugation procedures or by first converting to the NETS ester using the protocol similar to that described in Example 29. Thiol dyes conjugated to maleimide terminated polymers have also been demonstrated. Any range of chemistry pairs would be expected to work in similar fashion to conjugate a polymer and dye. Example 38b: Preparation of Polymer-Dye Conjugate at Internal Position In a glovebox, 100 mg polymer with internal amine functionalities was dissolved in 10 mL anhydrous DMSO in a 20 mL amber scintillation vial. 0.32 mL DIPEA was added to the polymer solution. 24 mg of NETS-ester dye (Cy3) was dissolved in 2.4 mL in anhydrous DMSO and added to the polymer solution. The vial was tightly sealed, then removed from the glovebox and stirred at room temperature for 48 hours. The reaction was then purified over Amicon Ultra centrifugal filtration units (MWCO=30 kDa) with 20% ethanol in water until all free dye was removed. Purity was verified by running a 0.15 mg sample over a 30 cm Superdex 200 SEC column in 0.6M NaCl and 20% ethanol. 90 mg yield (90%). The addition of dye can be used to estimate the incorporation of linker monomers in the polymer structure by measuring an absorbance ratio based on the relative extinction coefficients of the polymer and dye. For polymers described above, the ratio of linker monomers (or dye attachments) per fluorene monomer in the final polymer are in general agreement with the molar feed ratio of monomers used in the polymerization reaction. Polymers with a carboxylic acid side chain can also be modified with amine functional dyes using standard EDC conjugation procedures or by first converting to the NHS ester using the protocol similar to that described in Example 29. Analogous procedures can be used to conjugate a range of dyes including Cy3, DyLight 549, DyLight 633, FAM, FITC, Alexa633, Alexa647 and several others. Polymers with a carboxylic acid side chain can also be modified with amine functional dyes using standard EDC conjugation procedures. FIG. 21 (A) shows the polymer structure above conjugated to (from left to right) FITC, Cy3, DyLight 594 and DyLight633. The polymer alone is show for reference (far left). Note in each case the amount of residual donor (polymer) emission is minimal. The data highlight the capability of generating several diagnostic signals at different wavelengths for multiplex applications. In this embodiment a single light source is capable of generating five distinct emission wavelengths. Example 38c: Energy Transfer Evaluation for Polymer-Dye Conjugates Based on Polymer Excitation for Use in Polymer Tandem Conjugates FIG. 21 (B) depicts a comparison of the fluorescence of the dye (DyLight594) excited near its absorbance maximum (lower curve) and polymer-dye conjugate excited at 405 nm (upper curve). Dye emission around 620 nm was over 5 fold brighter from the polymer-dye conjugate at the same molar concentration of dye versus direct dye excitation. Such embodiments highlight the signal amplification afforded by the disclosed polymer donors in energy transfer processes. The picture in the upper left corner highlights the visual color change in the emission of the complex based on dye conjugation. The polymer solution emits blue in the absence of dye and red upon dye conjugation (post purification). FIG. 21 (C) compares the fluorescent signal of the base polymer (no dye, peak emission near 420 nm) to that of the polymer-dye conjugate (peak emission near 620 nm). The DyLight594 dye quenches >98% of the polymer emission when conjugated to the polymer above (Example 38b). This is a feature of the polymer materials as any remaining donor emission could manifest as background signal in multiplex assay formats. The ability to conjugate the dye directly to the polymer structure and vary the number of attachement sites provides for efficent transfer that can be regulated by chemical design. Example 39: Flow Testing of Monoclonal Antibody (antiCD4) Conjugates on Whole Lysed Blood Samples Polymer conjugates of primary antiCD4 antibody (RPA-T4 clone) were produced using 3 different conjugation routes as provided in Examples 45, 46 and 49. 1) Amine modified polymer converted to a maleimide reactive group using SMCC (maleimide/NHS crosslinker) reacted with thiol groups on the antibody introduced by reacting SATA (thiol/NHS cross linker) with lysine (amine) groups (CJ11-2, FIG. 22). 2) Same polymer modified with SMCC (malemide) but with thiol groups introduced on antibody using TCEP to partially reduce the disulfide linkages in the antibody (CJ13-2, FIG. 22 and FIG. 20D). 3) A carboxylic acid terminated polymer activated with TSTU to form the NHS ester was reacted directly with the lysine (amine) groups on the antibody (CJ04-2 FIG. 22). All conjugates were made from the same polymer structure and batch. The polymer was synthesized using the protocol depicted in Example 12 with an amine end capping unit in place of the carboxylic acid capping unit shown. The NHS/amine conjugation was done with the protocol described in Example 45. The maleimide/thiol conjugation reactions were done in lines with those protocols described in Examples 46 and 49. FIG. 22 depicts the performance of these conjugates in flow cytometry conduced as follows. 100 μl whole human blood from a healthy volunteer was aliquoted into FACS tubes (duplicates for each sample). Antibody conjugates were diluted in wash buffer (PBS with 0.5% BSA and 0.1% Sodium Azide) and added to the blood at specified concentrations. Samples were vortexed vigorously then incubated for 15-30 mins in the dark at room temperature. 2 ml of 1×BD FACS Lyse solution was added to each sample and mixed in by vigorous vortexing prior to a further 10 mins incubation in the dark at room temperature. Samples were centrifuged for 5 min at 500 g and the supernatant tipped off and discarded. Samples were vortexed and 3 ml of wash buffer (PBS with 0.5% BSA and 0.1% Sodium Azide) added. Centrifugation was repeated at 500 g for a further 5 min. The resulting supernatant was tipped off and discarded and the remaining cell pellet vortexed. Samples were run on a BD LSRII flow cytometer acquiring all violet channels equipped with a violet laser and 450/50 nm filter that had been set up and precalibrated against BD CST beads. All polymer conjugate samples (CJ04-2, CJ11-2 and CJ13-1 lines) showed minimal non specific binding compared to unstained cells. Further, all polymer conjugates produced significantly higher positive signals than a commercially available Pacific Blue control conjugate of the same antibody clone which is commonly used for flow cytometry at compatible wavelengths. The best performing conjugates from this set provided over 6 fold high stain index than the commercially available Pacific Blue control antibody. Example 40: Preparation of Polymer-Dye Conjugate The polymer is conjugated to a dye, Dylight 594, and purified in a manner similar to the methods as described in Example 36. FIG. 23 depicts a comparison of the florescence of the dye (DyLight594) and polymer-dye conjugate. The dye was excited at 594 nm and the polymer-dye conjugate at 380 nm. Example 41: Fluorescent Immunoassay (ELISA) with Streptavidin-Conjugated Polymer An immunoassay for human IgG was developed as a demonstrative system in 96 well plate format. In further embodiments, similar functionality would be equally applicable in other formats including suspended microspheres and protein chip microarrays. Step 1: Preparation of Reagents Wash concentrate was prepared by dissolving 79.2 g Tris base pre-set crystals (pH 7.7), 225 g sodium chloride and 0.5 g Thimerosol in 1000 mL deionised water. Wash solution was prepared by adding 100 mL wash concentrate to 2400 mL deionised water. Subsequently, 10 mL 10% Triton X-100 was added. The basic assay buffer was prepared by dissolving 14.8 g Tris base pre-set crystals (pH 7.7), 18 g sodium chloride and 0.5 g Thimerosol in 2000 mL Milli-Q water (conductivity 18.2 mΩcm). Subsequently, 2 mL 10% Tween 20 and 10 g Bovine Serum Albumin Fraction V, essentially gamma globulin free were added. The solution was filtered and stored at 4° C. Step 2: Preparation of Capture Antibody Coated Plates Capture antibody was coated onto the surface of Nunc white Maxisorp 96 well plates at a concentration of approximately 1 microgramme per well. The plates were sealed and stored overnight at 4° C. Subsequently, the plates were washed once with wash solution and tapped dry on absorbent paper. Unless otherwise stated all plate washing in this example was performed on an automated microtitre plate washer. Two hundred and fifty (250) microlitres of blocking buffer (0.1M PBS containing 2% BSA) were added to each well, the plates re-sealed and stored at 4° C. until use. Step 3: Immunoassay Capture antibody-coated microtitre plates were washed twice with wash solution and tapped dry on absorbent paper. Two hundred (200) μL of either assay standard or experimental unknown sample were added in quadruplicate to appropriate wells of the coated plate. The plates were incubated on a shaker for 2 hours at 18° C. Subsequently, the plates were washed three times with wash solution, tapped dry on absorbent paper, and 200 μL of biotinylated detection antibody at a previously determined optimal concentration (diluted in assay buffer and filtered before use) were added to each well. The plates were incubated on an orbital shaker at ambient temperature for a further 60 minutes. The plates were then washed three times and tapped dry on absorbent paper. Two hundred (200) μL of 0.2 micron syringe filtered Streptavidin-polymer conjugate as prepared in Example 30 diluted to a concentration previously determined as suitable in assay buffer. The polymer was a fluorene polymer with neutral PEG11 side chains and an amine conjugation site. The plates were incubated on an orbital shaker at ambient temperature for a further 2 hours. The plates were then washed six times, tapped dry, turned around 180o, and re-washed a further six times. The plates were again tapped dry on absorbent paper. Two hundred (200) μL of filtered release reagent (0.1M sodium hydroxide, 2% Triton X-100) were added using a multi-channel pipette, the plates shaken for 60 minutes at ambient temperature and the fluorescence measured with a Victor Fluorometer. The plate was then sealed, stored overnight at 4° C. and re-read in the Victor Fluorimeter the following morning. Fluorescence counts were analysed using the Multicalc Software from Perkin Elmer to determine lower limit of assay detection and assorted similar parameters. Alternative conditions were also evaluated to release the conjugate from the well plate surface to improve the fluorescent readout. A representative data set is shown in FIG. 24. Comparisons were also made to commercially available SA-dye conjugates. The polymer conjugates demonstrated superior detection limits relative to the dye conjugates as was expected due to the collective optical properties. Example 42: Synthesis, Conjugation and Application of Para-Phenylene Vinylene Co-Polymer with Active Functional Linker for Bioconjugation Poly(1,4-(di2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl 2,5-dibromoterephthalate)-vinyl-alt-para(2-methoxy-5-2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl benzene)-vinylene) with phenylbutoxyamino termini. Di-2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl 2,5-dibromoterephthalate (2.0 g, 1.52 mmol), 34-(4-methoxy-2,5-divinylphenoxy)-2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontane (1.11 g, 1.52 mmol), palladium acetate (13.6 mg, 0.061 mmol), tri-o-tolylphosphine (37 mg, 0.121 mmol), triethylamine (1 mL, 7.6 mmol) and 4 mL of DMF were combined in a small round bottom flask, equipped with a Teflon stribar, fitted with a needle valve and transferred to a Schlenk line. The solution was degassed via three freeze-pump-thaw cycles, put under nitrogen and heated to 100 C with constant stirring overnight. Next di-2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl 2,5-dibromoterephthalate (2.0 g, 1.52 mmol) (100 mg, 5 mol %), palladium acetate (5 mg), and tri-o-tolylphosphine and 0.5 mL DMF were combined in a small round bottom flask which is fitted with a needle valve and transferred to the Schlenk line. The solution was degassed via three cycles of freeze-pump-thaw and once warmed to room temperature was transferred to the polymerization reaction via cannula to exclude air and moisture. Allowed the mixture to react overnight. Next 4-(4-bromophenoxy)butan-1-amine (43 mg, 15 mol %) and 0.5 mL of DMF were combined in a small round bottom flask, equipped with a Teflon stribar, fitted with a needle valve and transferred to a Schlenk line. Once warmed to room temperature the solution was transferred to the polymerization reaction via cannula to exclude air and moisture. Allowed the mixture to react overnight. The next day the reaction was cooled to room temperature and the bulk of triethylamine was removed under vacuum. The reaction mixture was diluted with ˜30 mL of water and filtered through G 6 glass fiber filter paper. The filtrate was transferred to several Amicon filters (10 kDa cutoff) to concentrate the polymer and remove DMF. The remaining water is removed under vacuum and the residue is extracted into methylene chloride. The methylene chloride solution is dried over magnesium sulfate and filtered. The solvent is removed leaving behind a dark red thick oil, approximately 900 mg. The polymer was found to have a Mn of 20,400 g/mol as determined by GPC analysis relative to polystyrene standards. Incorporation of the amine linker was verified by conjugating a dye to the final polymer as described in Example 38. The polymer was then conjugated to streptavidin protein as follows: Amine polymer was dissolved at 50 mg/ml and desalted and buffer exchanged into 100 mM phosphate buffer pH 7.5. Polymer concentration was assessed by absorbance and 25 molar equivalents of SMCC (10 mg/ml in anhydrous DMSO) added. The reaction was mixed for 60 mins at room temperature and then desalted and buffer exchanged into PBS pH7.0+5 mM EDTA prior to repeat polymer concentration determination and confirmation of malemide functionality by SAMSA-fluorescein dye test. Streptavidin (5 mg/ml in 100 mM phosphate buffer pH7.5) was activated by addition of 20 molar equivalents of SATA (5 mg/ml in anhydrous DMSO). The reaction was mixed at room temperature for 60 mins prior to quenching (>15 mins room temp) with 10% (v/v) 50 mM EDTA, 2.5M hydroxylamine pH7.0. The activated protein was desalted and buffer exchanged into the same buffer as the activated polymer prior to an performance of an Ellman's assay to confirm and quantify thiol incorporation. Both the activated polymer and streptavidin were used as follows without delay. A greater than order of magnitude molar excess of SMCC activated polymer was added to the SATA activated streptavidin and the two mixed for 2 hours at room temperature prior to quenching with 20 molar equivalents of N-ethylmaleimide which was mixed in for 15 minutes at room temperature. Ion exchange and size exclusion chromatography were used to purify the bioconjugate of unreacted polymer and streptavidin. Appropriate fractions were pooled to maximize yield and performance and then concentrated by ultrafiltration. The conjugate was tested and its performance compared to a commercially available streptavidin-phycoerythrin (SA-PE) conjugate designed for purpose in a model Luminex xMap assay (FIG. 27, left). Donkey anti-mouse IgG antibody was covalently conjugated to xMap beads. A standard curve titration of Mouse IgG was then performed under standard Luminex xMap assay conditions (FIG. 27, right). Replicate samples were detected using either 4 μg/mL streptavidin-phycoerythrin or streptavidin conjugated polymer conjugate prepared as above (concentration not rigorously controlled). Samples were then read on a Luminex instrument. Absolute signals were found to be lower using the conjugated polymer. This is partially attributed to a non-ideal match between the polymer spectra and the excitation and emission optics in the instrument as well as the putative lower concentration of detection reagent used compared with the commercially available phycoerythrin product. However, the proportional background (non specific signal) from the polymer was also markedly lower resulting in a very comparable lower limit of detection for both detection formats (Fluorescence highest point in standard curve/fluorescence zero concentration of analyte (MFI/zero): 21.8 PE, 26.6 Polymer). Example 43: Synthesis of a Fluorene Co-Polymer with a DPP Band Gap Modifying Unit To a 25 mL round-bottomed flask were added: PEGylated dibromo-DPP monomer (110 mmol), PEGylated fluorene diboronicester (110 mmol), THF (2.4 mL) solvent, 2M K2CO3 (1.6 mL) and tetrakis(triphenylphosphine)palladium (3.3 mmol) catalyst. The mixture was degassed by three freeze-pump-thaw cycles and then stirred under argon at 80 C over night. The resulting mixture was allowed to r.t. and diluted with water. Polymer was collected after dichloromethane extraction. The resulting polymer was found to have an absorption maxima at 520 nm and emission maxima at 590 nm with quantum yield of 6% in water. The polymer had a MW estimated at 16,000 by GPC analysis relative to polystyrene standards and was soluble in water, methanol and dichloromethane. End linker incorporation can be performed using methods similar to those described above and including methods described in Examples 9, 10 and 11. Example 44: Synthesis of a Substituted Divinylbenzene Polymer Methods used to prepare the polymer above were similar to those provided in Example 38. General methods for the preparation of divinylbenzene polymers as disclosed herein may be derived from known reactions in the field as well as methods found herein, and the reactions may be modified by the use of appropriate reagents and conditions, as would be recognized by the skilled person, for the introduction of the various moieties found in the formulae as provided herein. Example 45: Conjugation of Polymer to an Amine on a Primary Antibody Procedure for Production of NHS Ester Polymer-Antibody Conjugate Primary monoclonal antibody, anti-CD4 (RPA-T4 clone) was desalted, and exchanged into 50 mM NaHCO3 buffer, pH 8.2 at 1 mg/mL. Enriched NHS functionalized polymer was dissolved into anhydrous dimethyl sulfoxide (DMSO) at 100 mg/mL. Polymer solution was added at 30 fold molar excess of antibody into the antibody solution and allowed to mix by agitation for 3 hours at RT. Protein concentration was adjusted with buffer prior to incubation to ensure the volume of organic solvent was <10% the total volume. Following ultrafiltration over a 10 KDa MWCO filter device, ion exchange and size exclusion chromatographic techniques were then used to purify the bioconjugate of unreacted polymer and antibody, respectively. Appropriate fractions were pooled to maximize yield and buffer exchanged into PBS+0.05% NaN3 and simultaneously concentrated by ultrafiltration as above. Degree of labeling (indicated as p above) was determined via absorbance at 405 nm and a corrected 280 nm value. The polymer conjugate (CJ04-02) provided in Example 39 (FIG. 22) had an F/P (# of polymers per antibody) of approximately 2.04. This conjugate demonstrated flow performance as determined by stain index measurements which were greater than 3 fold higher than a Pacific Blue control conjugate of the same antibody. Example 46: Conjugation of Polymer to an Antibody Using Malemide/Thiol Chemistry Malemide/Thiol Conjugation of Polymers to Partially Reduced Antibodies Secondary antibody, goat anti-mouse IgG (H+L) was reconstituted in PBS+10 mM acetic acid and desalted/exchanged into 50 mM Tris-HCl buffer, pH7.4 at 1.0 mg/mL. TCEP (tris(2-carboxyethyl)phosphine) was dissolved in 50 mM Tris-HCl buffer, pH7.4, added at 6 molar excess with a final TCEP concentration of 10 mM and mixed for 30 minutes at room temperature. The modified protein was purified over a PD-10 desalting column to remove excess TCEP and exchanged into reaction buffer, 100 mM NaPO4, pH 6.5 reaction buffer with 10 mM EDTA. Amine-activated polymer was dissolved in anhydrous DMSO at 10 mg/mL and mixed with succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) linker. The linker was added at 50 mg/mL, 20 molar excess in DMSO to the polymer solution and activated by diisopropylethylamine (DIPEA). The reaction was purified over Amicon Ultra centrifugation filters and exchanged into reaction buffer, 100 mM NaPO4, pH 6.5 reaction buffer with 10 mM EDTA. Immediately following disulfide reduction, maleimide functionalized polymer in reaction buffer at 10 mg/mL was added in 20 molar excess of antibody and allowed to mix for 4 hours. Ion exchange and size exclusion chromatographic techniques were then used to purify the bioconjugate of unreacted polymer and antibody, respectively. Degree of labeling (indicated as p above) is determined via absorbance at 405 nm and a corrected 280 nm value. The polymer conjugate provided in Example 36 (FIG. 20B) had an F/P (# of polymers per antibody) of approximately 2. This conjugate demonstrated flow performance as determined by stain index measurements which were greater than 4 fold higher than a Pacific Blue control conjugate of the same antibody. Malemide/Thiol Conjugation of Polymers to Thiol Modified Antibodies Secondary antibody, goat anti-mouse IgG (H+L) was reconstituted in PBS+10 mM acetic acid and desalted/exchanged into 100 mM phosphate pH7.5 buffer. SATA (N-succinimidyl-S-acetylthioacetate) was dissolved anhydrous DMSO, added at 15 molar excess and mixed for 60 minutes at room temperature. After quenching with a hydroxylamine solution, the modified protein was desalted over a PD-10 column to remove excess SATA and exchanged into reaction buffer, 5 mM EDTA, PBS pH 7.0 buffer. Amine-activated polymer was dissolved in anhydrous DMSO at 10 mg/mL and mixed with succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) linker. The linker was added at 50 mg/mL, 20 molar excess in DMSO to the polymer solution and activated by diisopropylethylamine (DIPEA). The reaction was purified over Amicon Ultra centrifugation filters and exchanged into reaction buffer, 5 mM EDTA, PBS pH 7.0 buffer. Immediately following activation of the antibody, maleimide functionalized polymer in reaction buffer at 10 mg/mL was added in 20 molar excess of antibody and allowed to mix for 4 hours. Ion exchange and size exclusion chromatographic techniques were then used to purify the bioconjugate of unreacted polymer and antibody, respectively. Degree of labeling (indicated as p above) is determined by absorbance at 405 nm and a corrected 280 nm value. The resulting purified conjugates were flow tested in similar fashion as those described in Example 36 for the conjugates prepared using TCEP reduction (data not provided). The polymer structures defined in Example 39 were used to prepare primary antiCD4 (RPA-T4) antibody conjugates in similar fashion to those described in the example above. 30 eq of polymer were reacted with the SATA modified antibody (CJ11-2, FIG. 22) and TCEP reduced antibody (CJ13-1, FIG. 20D and FIG. 22) to produce polymer conjugates for testing in flow cytometry assays after purification. SMCC modified polymers from Examples 23 and 26 were also successfully conjugated to antiCD4 (RPA-T4) and antiCD8 (RPA-T8) antibodies using the TCEP reduction method. DTT reduction was also successfully performed in place of TCEP. Performance in flow cytometry of the antiCD4 and antiCD8 conjugates were evaluated in similar fashion to those described in Example 39 (FIG. 22). Example 47: Polymer Conjugation to a DNA Oligomer Azide Polymer Synthesis for Click Conjugation to Alkyne Terminated DNA Oligo A solution of azidohexanoic acid NHS ester (2.5 mg) in anhydrous DMF (100 μL) was added to a solution of the amine-functional polymer (9.9 mg) in anhydrous DMF (100 μL) under argon. Diisopropylethylamine (2 μL) was then added. The reaction was agitated at room temperature for 15 hours. Water was then added (0.8 mL) and the azide-modified polymer was purified over a NAP-10 column. The eluent was freeze dried overnight. Yield 9.4 mg, 95%. Oligo Synthesis with Pendant Alkyne (Hexyne) for Click Conjugation to Azide Polymer The 3′ propanol oligo A8885 (sequence YATTTTACCCTCTGAAGGCTCCP, where Y=hexynyl group and P=propanol group (SEQ ID NO: 1)) was synthesized using 3′ spacer SynBase™ CPG 1000 column on an Applied Biosystems 394 automated DNA/RNA synthesizer. A standard 1.0 mole phosphoramidite cycle of acid-catalyzed detritylation, coupling, capping and iodine oxidation was used. The coupling time for the standards monomers was 40 s, and the coupling time for the 5′ alkyne monomer was 10 min. The oligo was cleaved from the solid support and deprotected by exposure to concentrated aqueous ammonia for 60 min at room temperature, followed by heating in a sealed tube for 5 h at 55° C. The oligo was then purified by RP-HPLC under standard conditions. Yield 34 OD. Solution Phase Click Conjugation: Probe Synthesis A solution of degassed copper sulphate pentahydrate (0.063 mg) in aqueous sodium chloride (0.2 M, 2.5 μL) was added to a degassed solution of tris-benzo triazole ligand (0.5 mg) and sodium ascorbate (0.5 mg) in aqueous sodium chloride (0.2 M, 12.5 μL). Subsequently, a degassed solution of oligo A8885 (50 nmole) in aqueous sodium chloride (0.2 M, 30 μL) and a degassed solution of azide polymer (4.5 mg) in anhydrous DMF (50 μL) were added, respectively. The reaction was degassed once more with argon for 30s prior to sealing the tube and incubating at 55° C. for 2 h. Water (0.9 mL) was then added and the modified oligo was purified over a NAP-10 column. The eluent was freeze-dried overnight. The conjugate was isolated as a distinct band using PAGE purification and characterized by mass spectrometry. Yield estimated at 10-20%. Fluorescence Studies The oligo-polymer conjugate was used as a probe in fluorescence studies. The probe was hybridized with the target A8090 (sequence GGAGCCTTCAGAGGGTAAAAT-Dabcyl (SEQ ID NO: 2)), which was labeled with dabcyl at the 3′ end to act as a fluorescence quencher. The target and probe were hybridized, and fluorescence monitored in a Peltier-controlled variable temperature fluorimeter. The fluorescence was scanned every 5° C. over a temperature range of 30° C. to 80° C. at a rate of 2° C./min. FIG. 25 shows increasing fluorescence intensity or emission with increasing temperature, indicating that as the probe-target pair melt, the polymer and quencher separate and fluorescence is recovered. Polymer conjugation to nucleic acids can also be performed using methods adapted from the protocols described in Examples 14, 45 and 46. Example 48: Purification of Polymer Antibody Conjugates Polymer antibody conjugates produced via the protocols described in Examples 45, 46 and 49 were purified using a two step method. First ion exchange is used to remove free, unreacted polymer. As the polymers described in this invention do not possess any formal charge they do not bind to the ion exchange media. Proteins (antibodies), however, do contain charged groups and are commonly bound to various ion exchange media for purification. In the examples provided the pH and conductivity of the conjugate solution (post reaction) was lowered to improve the binding of the free antibody and conjugate to the cationic exchange resin. After loading the conjugate, the resin is washed to baseline (measuring both 280 and 407 nm absorbance) to ensure all free polymer is removed. Bound antibody and polymer antibody conjugate are eluted by increasing the pH and ionic strength. A representative example of this separation is provided below in FIG. 26 (left) where the left peak represents the free polymer and the right peak the eluted conjugate and free protein. Removal of free polymer can also be achieved using affinity chromatograph methods in a similar fashion. Specific affinity resin can be used to bind the free protein and conjugate while removing polymer. After the polymer is removed, the conjugate solution is concentrated and loaded on a size exclusion column to separate any un-reacted or free antibody from the polymer. The polymer compositions described in Examples 43 and 44 elute much earlier than then antibodies despite having a lower molecular weight. This is expected to be a result of the rigid polymer structure. The conjugates thus elute well before any free antibody providing near base line separation of the desired conjugate. Isolating fractions near the center of the distribution also ensures no free antibody is included. A representative example of this separation is provided below in FIG. 26 (right) where the left peak represents the conjugate and the small peak on the far right the free antibody. Retention times of the individual components was verified in an independent experiment. Taken together the purification ensures that both free antibody and free polymer are removed. Purity of the resulting conjugates is reasonably estimated at >95%. Pooled samples can be concentrated and concentration measured by absorbance at 280 and 407 nm, being sure to correct for the polymer absorbance at 280 nm. Such measurements also allow for the determination of polymer to antibody labelling ratios (F/P). Example 49: Dye Labeling and Linker Activation of Tandem Polymer Tandem Dye Conjugation In a glovebox, 93 mg tandem polymer (from Example 26) was dissolved at 15 mg/mL in anhydrous DMSO in a glass vial with stir bar. 22.5 mg Cy3-NHS ester was also dissolved at 15 mg/mL in anhydrous DMSO and added to the polymer solution, followed by 0.3 mL diisopropylethylamine. After stirring for 48 h at room temperature, the solution was diluted to 90 mL with 20% EtOH in water and concentrated over Amicon Ultra-15 filters. The retentate was repeatedly diluted and concentrated over the filters until excess Cy3 was removed. 90% yield. Labeling and linker content were validated by measuring and taking the ratio of polymer and dye absorbance as described in Example 38. Amine Modification of Tandem (Aqueous Conditions) 100 mg of polymer-dye conjugate was dissolved at 150 mg/mL in ethanol. This was added dropwise to 6 mL 50 mM MES buffer (pH 5) at 4° C. 38 mg N-hydroxy succinimide was added in one portion, and the solution was stirred to dissolve the solids. After dissolution, 192 mg of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride was added in portions while stirring. After stirring the solution for 30 minutes, 33 μL of ethylene diamine was added. After stirring overnight at room temperature, the solution was diluted to 90 mL with 20% EtOH in water and concentrated over Amicon Ultra-15 filters. The retentate was repeatedly diluted and concentrated over the filters a total of four times to remove impurities. 90% yield, 60% conversion. Linker conversion was verified by conjugating a second dye to the terminal amine as described in Example 38. Tandem Conjugation to a Primary Antibody Primary monoclonal antibody, anti-CD8 (RPA-T8 clone) was desalted/exchanged into 5 mM EDTA, 50 mM phosphate 150 mM NaCl pH 7.0 buffer. TCEP (tris(2-carboxyethyl)phosphine) was dissolved water and added at 12 molar excess and mixed for 90 minutes at 30° C. The modified protein was purified over a PD-10 desalting column to remove excess TCEP and exchanged into 5 mM EDTA, 50 mM phosphate 150 mM NaCl pH 7.0 buffer. Amine-activated tandem polymer was dissolved in ethanol at 50 mg/mL and this solution was mixed with two volumes of 100 mM phosphate pH 7.5 buffer. This solution was then desalted/exchanged into 100 mM phosphate pH 7.5 buffer using a PD-10 desalting column. To this solution was added 25 molar excess of succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) linker (prepared as a 10 mg/ml solution in anhydrous DMSO). The resulting solution was roller mixed at 20° C. for 60 minutes before being desalted/exchanged into 5 mM EDTA, 50 mM phosphate 150 mM NaCl pH 7.0 buffer using a PD-10 desalting column. Immediately following disulfide reduction, the maleimide functionalized polymer was added in 25 molar excess of antibody and allowed to mix for 2 hours at 20° C. Ion exchange and size exclusion chromatographic techniques were then used to purify the bioconjugate of unreacted polymer and antibody, respectively. Degree of labeling (indicated as p below) is determined via absorbance and a corrected 280 nm value. Flow Cytometry Analysis of Polymer Tandem Conjugate in Multicolor Experiment The resulting antiCD8 Tandem conjugate was evaluated on both compensation beads and whole blood samples on a flow cytometer. Anti mouse IgG compensation beads were used to capture the antibody and quantify signal spill over into detection channels (detectors with unique emission filters) other than that intended for the conjugate. FIG. 28 (left) shows the signal measured when the tandem conjugate was excited with a violet laser with emission detected using a 610 nm filter matched to the conjugates emission (labeled QDotA). Crosstalk into the flow cytometer's other channels paired with the violet excitation laser (DAPI-A and AmCyan-A) and two channels off the 488 nm laser (FITC-A and PE-A) are also shown in this panel of the figure. The data show minimal crosstalk in the 450/50 nm filter (DAPI-A) which specifically detects residual polymer (donor) emission. The significantly higher signal from the Cy3 reporter on the Tandem (610 nm filter) relative to the other channels above illustrates that minimal compensation (maximally no more than 6% in this example and case by case often much lower) is required. The Tandem anti CD8 conjugate was subsequently evaluated in a 4 color flow assay with other labeled antibodies (anti CD3 Pacific Blue, anti CD45 Phycoerythrin and anti CD4 fluorescein) on whole human blood from a healthy volunteer using staining and analysis protocols in accord and developed from Example 39. The data in FIG. 28 (right) clearly show the compatibility of the Tandem label with common multicolour flow cytometry instrumentation, reagents and protocols. Specifically, intense and specific staining of CD8 positive lymphocytes is observed and within the CD4 positive subset ready discrimination of CD8 expressive and non expressive cells is clear Collectively the data highlight the viability of the polymer-dye Tandem conjugates in multicolor flow assays as described in the disclosed invention (See, e.g., FIG. 20 and FIG. 22). Example 50: Validation of Non-Ionic Polymer Side Chains for Water Solubility and Flow Cytometry Application A series of different polyfluorene polymers were produced to investigate the interaction of water soluble conjugated polymers with cells. This was done by first synthesizing a range of monomers substituted with different solubilizing side chains (e.g., PEG-, sulfonate-, quaternary amine-, zwitterion- substituted) which were then polymerized using Suzuki coupling. The purpose was to determine what influence the side chains had on both non-specific cell binding and polymer solubility in typical buffers used in biological assays, particularly those used in flow cytometry (e.g. PBS and DPBS). The number and property diversity of polymer candidates synthesized made it impractical to produce purified conjugates of each for flow cytometry testing. Thus, a system was developed to score each candidate polymer based on its contribution to non-specific binding to cells. Such a system enabled ranking of polymers, with predictive value on whether they would perform sufficiently once conjugated. A Non-specific Binding (NSB) “Index” was developed around a Jurkat cell model (lymphocyte cell line). In this, cells were incubated with a fixed concentration of each polymer, washed, and analyzed by flow. FIG. 33 displays the outcome following such analysis, and illustrates the wide variation in signal generated by each polymer type. The polymers in FIG. 33 were evaluated with a phthalamide protecting group on the pendant amine with the exception of P9. The data ranks these polymers in terms of signal generated purely by NSB. More accurate assessment of relative NSB was enabled by adjusting further normalizing the flow signal by differences in fluorescence efficiency (crude assessment of quantum yield) of each form of polymer when assayed independently in stain buffer using 405 nm excitation on a fluorometer and monitoring emission in the range of 420-460 nm (to estimate a 440/40 nm filter in the cytometer). Representative polymers P5, P2, P9 and P12 showed increasing NSB relative to unstained cells (far left curve, intensity represented on x-axis). The data in FIG. 34 go on to highlight the difference in polymers produced with neutral, non-ionic PEG side chains (designated P20) verses those which also incorporate anionic side chains (designated P4). The data are histograms collected from flow cytometry analysis (405 nm excitation in a BD LSR-II cytometer) using a Jurkat cell line as in FIG. 33. The panel on the left shows unstained cells and a negative control (cells treated with a non-specific Pacific Blue labeled conjugate) which are the two curves on the far left. Little if any non-specific staining is observed for the Pacific Blue control. In this same panel, however, curve on the right represents cells treated with the anionic P4 polymer and has a clear off set in signal (x-axis) as shown. Conversely the neutral polymer P20 showed almost no off set from the untreated cells which is in line with the Pacific Blue control. The panel in the middle represents a range of different polymer and polymer side chain combinations tested on the same cells. The data highlighted the advantage of neutral side chains. This advantage has also translated to other assay formats including plate based immunoassays and cytometric bead arrays (data not shown). The neutral side chains also unexpectedly resulted in a significant increase in the solubility of the conjugated polymers in aqueous solutions relative to those made previously with ionic side chains. This was particularly true in buffers containing even moderate ionic strength (such as those used in basic cell protocols). The solution quantum yields were also seen to increase, possibly due to the higher aqueous solubility (and less aggregation). The poor solubility in buffers also made protein conjugation more difficult and streptavidin conjugates produced from P4 showed signs of aggregation in typical assay buffers such as phosphate buffered saline (PBS). This was not true of polymers and conjugates produced in other examples disclosed herein. Example 51: Purification and Characterization of Polymer-Avidin Conjugates Gel Analysis of Polymer-Avidin Conjugates To verify successful conjugation to avidin (AvDN), an agarose gel electrophoresis method was developed and used to assess the relative mobility of AvDN as a function of the degree of conjugation with polymer (FIG. 35). Prior to gel loading, the conjugation reaction was stained with biotinyl-fluorescein, which bound polymer-AvDN conjugate and free AvDN. Electrophoresis was performed in 0.8% agarose gels, poured and run in a buffer of 10 mM Sodium Borate, pH 11. The gel was visualized under UV illumination (to visualize the polymer) and by 532 nm excitation (to visualize fluorescein) to assess the degree of conjugation. Under UV illumination, a single band was observed for polymer. Under 532 nm excitation, bands were observed for unbound biotinyl-fluorescein, unreacted AvDN, and polymer-AvDN conjugate which coincided with the free polymer band, indicating that unreacted polymer co-eluted with polymer-AvDN conjugate (FIG. 35). Conjugation was confirmed by the intensity of the conjugate band. The key at the top of the gel images (FIG. 35) indicates which components were included in the conjugation reaction, as well as whether the samples were pre-incubated with biotinyl fluorescein prior to loading and electrophoresis. The image on left visualizes polymer by UV-excitation, whereas the image on right captures the result of fluorescein excitation. On the right image, biotinylated fluorescein can be seen associating with polymer when conjugation was performed in the presence, but not in the absence, of hetero-bifunctional NHS-ethoxy-maleimide linkers (linkers were used to functionalize the polymer amine, while protein amines were partially converted to thiols using Traut's reagent, prior to the maleimide-thiol coupling). Abbreviations: AvDN=avidin DN, AA1=polymer, Linker=hetero-bifunctional NHS-Maleimide linker included in the reaction, Biot-F=biotinyl fluorescein pre-staining before electrophoresis. Purification: Removal of Unreacted Avidin by SEC Chromatography The crude conjugate mixture was fractionated on a Superdex 200 size exclusion column, while fractions were monitored by UV absorbance (FIG. 36, top). To validate the method, fractions were analyzed by agarose gel electrophoresis. As described above, this method of electrophoresis made it possible to visualize the degree to which avidin was attached to polymer, and in this case to analyze the composition of each fraction from the column. Selected fractions were incubated with biotinyl-fluorescein (1 molar equivalent relative to avidin) prior to gel loading, with biotinyl-fluorescein loaded separately as a marker (leftmost lane, FIG. 36, bottom). Electrophoresis was performed in 0.8% agarose gels, poured and run in a buffer of 10 mM Sodium Borate, pH 11. The gel was visualized by 532 nm excitation. Retardation of fluorescein-visualized bands for fractions C2-C6 indicates purified polymer-avidin conjugate, while the two bands observed for fraction C8 indicate a mixture of polymer-avidin conjugate and free avidin. Fractions C10-D2 show only free avidin. Evaluation of Conjugation Efficiency by Gel Analysis In order to determine the best ratio of polymer to streptavidin in conjugation reactions, the molar equivalents of polymer to streptavidin were varied from 0-24 equivalents. Post conjugation, the conjugation products were incubated with biotinyl-fluorescein prior to electrophoresis. The gel was visualized by UV illumination and 532 nm excitation (FIG. 37). At 0 molar equivalents of polymer to streptavidin, free streptavidin is observed as a band with relatively high mobility. As the molar equivalents for polymer are increased from 3 equivalents to 12 equivalents, the free streptavidin band decreases in intensity while the polymer-streptavidin conjugate band increases in intensity. At 24 equivalents of polymer, only the conjugate band is observed by 532 nm excitation. Impact of Purification on Conjugate Performance on Cell Analysis by Flow Cytometry Purification of polymer streptavidin conjugates (polymer structure exemplified in Example 9, denoted P30 in FIG. 38) was performed to determine the impact on flow cytometry performance. Cation-exchange chromatography was implemented in purification to improve removal of excess free polymer. Uncharged polymer eluted in the flow-through while protonated amines on proteins were retained by the media. Thus, streptavidin, whether conjugated to polymer or unreacted, was retained. This ion exchange phase of purification was kept simple with a step gradient, which resulted in co-elution of conjugated and unreacted SA. Further fractionation was enabled by subsequent size-exclusion chromatography, which provided better resolution of conjugate from free SA. Performance benefits in flow cytometry of this new purification method were observed using Jurkat cells incubated with polymer-streptavidin conjugate which were analyzed by flow cytometry. Comparisons were made between crude samples (FIG. 38—top) and purified conjugates (FIG. 38 bottom). Commercially available Pacific Blue-streptavidin conjugates were used as a comparator for brightness, nonspecific binding, and stain index. An improvement in overall Stain Index of approximately 3-fold was shown for Jurkat cells, with similar NSB for both Polymer conjugates and PB-SA based on the histograms shown in FIG. 38. Testing in blood (data not shown) indicated a significant reduction in NSB to levels similar to PB-SA upon conjugate purification. In a separate experiment with a similar polymer (exemplified in Example 11), conjugates with varying polymer to streptavidin ratios were obtained by SEC. Those with the higher ratio provided flow performance relative to those with lower labeling. Ratios were determined based on a ratio of absorbance at 385 nm/280 nm. Relative performance to a Pacific Blue control showed an increase from 10.9 times higher stain index (385/280 ratio of 3.6) to a stain index 13.8 times that of Pacific Blue (A385/280 ratio of 4.7). While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
<SOH> BACKGROUND OF THE INVENTION <EOH>Fluorescent hybridization probes have developed into an important tool in the sequence-specific detection of DNA and RNA. The signals generated by the appended fluorescent labels (or dyes) can be monitored in real time and provide simple, rapid, and robust methods for the detection of biological targets and events. Utility has been seen in applications ranging from microarrays and real time PCR to fluorescence in situ hybridization (FISH). Recent work in the area of multichromophores, particularly regarding conjugated polymers (CPs) has highlighted the potential these materials have in significantly improving the detection sensitivity of such methods (Liu and Bazan, Chem. Mater., 2004). The light harvesting structures of these materials can be made water soluble and adapted to amplify the fluorescent output of various probe labels (See U.S. patent application Ser. No. 10/600,286, filed Jun. 20, 2003 and Gaylord, Heeger, and Bazan, Proc. Natl. Acad. Sci., 2002, both of which are incorporated herein by reference in their entirety). Results such as these indicate CPs to be highly promising in the field of nucleic acid diagnostics, particularly where sample quantities are scarce. However, there exist methods for the amplification (or replication) of nucleic acid targets, i.e., PCR. Comparatively, in the field of protein recognition, there are no such simple methods for amplifying the targeted materials. As such, signal enhancement arising from CP application is of high consequence in this area. Dye-labeled antibodies are regularly used for the detection of protein targets in applications such as immunohistochemistry, protein arrays, ELISA tests, and flow cytometry. Integrating CP materials into such methodologies promises to provide a dramatic boost in the performance of such assays, enabling detection levels previously unattainable with conventional fluorescent reporters (e.g., dyes). Beyond addition signal, one of the other key drivers in biological detection formats is the ability to detect multiple analytes in the same test or multiplexing. This is commonly achieved by using fluorescent reporters with operate at different, discernable wavelengths. CP materials are ideally suited to provide a platform for expanded multiplexing. This can be achieved by tuning the structure of different CPs to operate at different wavelengths or by incorporating a dye within the polymer-biomolecule conjugate. The material and methods to produce higher sensitivity biological assays and increase multiplexing are highly desired in both molecular (nucleic acid) and immunoassay formats.
<SOH> SUMMARY OF THE INVENTION <EOH>Provided herein are water soluble conjugated polymers of Formula (I): wherein: each R is independently a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL; MU is a polymer modifying unit or band gap modifying unit that is evenly or randomly distributed along the polymer main chain and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C 1 -C 12 alkyl, C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl, C 1 -C 12 haloalkyl, C 1 -C 12 alkoxy, C 2 -C 18 (hetero)aryloxy, C 2 -C 18 (hetero)arylamino, (CH 2 ) x′ (OCH 2 CH 2 ) y′ OCH 3 where each x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50, or a C 2 -C 18 (hetero)aryl group; each optional linker L 1 and L 2 are aryl or heteroaryl groups evenly or randomly distributed along the polymer main chain and are substituted with one or more pendant chains terminated with a functional group for conjugation to another substrate, molecule or biomolecule selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof; G 1 and G 2 are each independently selected from hydrogen, halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiol, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters, boronic acids, optionally substituted fluorene and aryl or heteroaryl substituted with one or more pendant chains terminated with a functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule; wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, and thiols within G 1 , G 2 , L 1 or L 2 that allows, for functional conjugation to another molecule, substrate or biomolecule; each dashed bond, , is independently a single bond, triple bond or optionally substituted vinylene (—CR 5 ═CR 5 —) wherein each R 5 is independently hydrogen, cyano, C 1 -C 12 alkyl, C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl or a C 2 -C 18 (hetero)aryl group, wherein each C 1 -C 12 alkyl, C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl or a C 2 -C 18 (hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl group, C 1 -C 12 alkoxy, or C 1 -C 12 haloalkyl; and n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. In one aspect, water soluble conjugated polymers of Formula (I) have the structure of Formula (Ia): wherein R, L 1 , L 2 , G 1 , G 2 , MU, a, b, c, d and n are described previously for formula (I). In some embodiments, each R is independently (CH 2 ) x (OCH 2 CH 2 ) y OCH 3 where each x is independently an integer from 0-20, each y is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C 1 -C 12 alkoxy, or (OCH 2 CH 2 ) z OCH 3 where each z is independently an integer from 0 to 50. In some instances, each R is (CH 2 ) 3 (OCH 2 CH 2 ) 11 CH 3 . In other embodiments, each R is a benzyl substituted with at least one (OCH 2 CH 2 ) 10 OCH 3 group. In some instances, the benzyl is substituted with two (OCH 2 CH 2 ) 10 OCH 3 groups. In other instances, the benzyl is substituted with three (OCH 2 CH 2 ) 10 OCH 3 groups. In some embodiments, optional linkers L 1 or L 2 have the structure: *=site for covalent attachment to unsaturated backbone; wherein R 3 is independently hydrogen, halogen, alkoxy(C 1 -C 12 ), C 1 -C 12 alkyl, C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl or a C 2 -C 18 (hetero)aryl group, wherein each C 1 -C 12 alkyl, C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl or a C 2 -C 18 (hetero)aryl group is optionally substituted with one or more halogen, hydroxyl, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl group, C 1 -C 12 alkoxy, or C 1 -C 12 haloalkyl; and q is an integer from 0 to 4. In other embodiments, optional linkers L 1 or L 2 have the structure: *=site for covalent attachment to unsaturated backbone wherein A is a site for conjugation, chain extension or crosslinking and is [O—CH 2 —CH 2 ] q —W, or (C 1 -C 12 )alkoxy-X or C 2 -C 18 (hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule; W is —OH or —COOH; X is —NH 2 , —NHCOOH, —NHCOOC(CH 3 ) 3 , —NHCO(C 3 -C 12 )cycloalkyl(C 1 -C 4 )alkyl-N-maleimide; or —NHCO[CH 2 —CH 2 —O] t NH 2 ; q is an integer from 1 to 20; and t is an integer from 1 to 8. In yet other embodiments, optional linkers L 1 or L 2 have the structure: *=site for covalent attachment to backbone wherein R 25 are each independently any one of or a combination of a bond, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 2 -C 20 alkene, C 2 -C 20 alkyne, C 3 -C 20 cycloalkyl, C 1 -C 20 haloalkyl, (CH 2 ) x (OCH 2 CH 2 ) p (CH 2 ) x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C 2 -C 18 (hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups; wherein at least one R 25 is terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In further embodiments, optional linkers L 1 or L 2 have the structure: *=site for covalent attachment to unsaturated backbone; wherein R35 is any one of or a combination of a bond, C1-C20 alkyl, C1-C20 alkoxy, C2-C20 alkene, C2-C20 alkyne, C3-C20 cycloalkyl, C1-C20 haloalkyl, (CH2)x(OCH2CH2)p(CH2)x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C2-C18(hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In further embodiments, optional linkers L 1 or L 2 are selected from the group consisting of a-h having the structures: *=site for covalent attachment to unsaturated backbone; wherein R′ is independently H, halogen, C 1 -C 12 alkyl, (C 1 -C 12 alkyl)NH 2 , C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl, C 1 -C 12 haloalkyl, C 2 -C 18 (hetero)aryl, C 2 -C 18 (hetero)arylamino, —[CH 2 —CH 2 ] r′ —Z 1 , or (C 1 -C 12 )alkoxy-X 1 ; and wherein Z 1 is —OH or —COOH; X 1 is —NH 2 , —NHCOOH, —NHCOOC(CH 3 ) 3 , —NHCO(C3-C12)cycloalkyl(C1-C4)alkyl-N-maleimide; or —NHCO[CH 2 —CH 2 —O] s′ (CH 2 ) s′ NH 2 ; r′ is an integer from 1 to 20; and each s′ is independently an integer from 1 to 20, (CH 2 ) 3 (OCH 2 CH 2 ) x″ OCH 3 where x″ is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C 1 -C 12 alkoxy, or (OCH 2 CH 2 ) y —OCH 3 where each y″ is independently an integer from 0 to 50 and R′ is different from R; wherein k is 2, 4, 8, 12 or 24; wherein R 15 is selected from the group consisting of l-t having the structure: *=site for covalent attachment to backbone. In yet further embodiments, optional linkers L 1 or L 2 are In some embodiments, G 1 and G 2 are each independently selected from hydrogen, halogen, alkyne, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters, boronic acids, optionally substituted fluorine and aryl or heteroaryl substituted with one or more pendant chains terminated with a functional group, molecule or biomolecule selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In some embodiments, G 1 and G 2 each independently have the structure wherein R 11 is any one of or a combination of a bond, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 2 -C 20 alkene, C 2 -C 20 alkyne, C 3 -C 20 cycloalkyl, C 1 -C 20 haloalkyl, (CH 2 ) x (OCH 2 CH 2 ) p (CH 2 ) x where each x is independently an integer from 0-20, p is independently an integer from 0 to 50, aryl, C 2 -C 18 (hetero)aryl, phenoxy, amido, amino, carbamate, carboxylate, carbonates, sulfide, disulfide, or imido groups terminated with a functional group selected from amine, carbamate, carboxylate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule. In other embodiments, G 1 and G 2 are each independently selected from the group consisting of 1-31 having the structures: *=site for covalent attachment to backbone wherein R 15 is selected from the group consisting of l-t having the structure: and k is 2, 4, 8, 12 or 24. In further embodiments, G 1 and G 2 are optionally substituted aryl or heteroaryl wherein the optional substituent is selected from halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiol, boronic acid, boronate radical, boronic esters and optionally substituted fluorene. In some embodiments, G 1 and G 2 are the same. In other embodiments, G 1 and G 2 are different. In further embodiments, the polymer contains a single conjugation site at only one terminus of the polymer chain G 1 or G 2 . In yet further embodiments, G 1 and G 2 is In some embodiments, MU is selected from the group consisting of a′-k′ having the structure: *=site for covalent attachment to unsaturated backbone wherein R is a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL. In some embodiments, the water soluble conjugated polymer has the structure of formula: wherein at least one of G 1 or G 2 comprises a functional conjugation site. In some embodiments, the water soluble conjugated polymer has the structure of formula: wherein L 1 comprises a functional conjugation site. In some embodiments, the water soluble conjugated polymer has the structure of formula: wherein at least one of G 1 or G 2 comprises a functional conjugation site. In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In other embodiments, the polymer has the structure of formula: In some instances, a signaling chromophore is attached to the polymer via the NH 2 group. In certain instances, the signaling chromophore is Cy3 or Dylight 594 dye. In certain instances, the linker, is about 10% of the entire polymer. In other instances, the polymer is conjugated to a secondary dye reporter and an antibody. In some embodiments of conjugated polymers described herein, the polymer is further conjugated to additional molecules. In some embodiments, the polymer is conjugated to a streptavidin, antibody or nucleic acid and used as a direct fluorescent reporter. In certain embodiments, the polymer is conjugated to a streptavidin. In other embodiments, the polymer is conjugated to thiol groups at the hinge region of an antibody. In yet other embodiments, the polymer is conjugated to an amine group on a protein which is modified with a heterobifunctional linker. In further embodiments, the polymer is conjugated to a nucleic acid. In yet further embodiments, the polymer is conjugated to an antibody. In certain instances, the polymer is conjugated to a monoclonal antibody, a secondary antibody or a primary antibody. In other instances, a polymer antibody conjugate is excited at about 405 nm in a flow cytometry assay where the specific signal is at least 3 fold greater than the same antibody conjugated to Pacific Blue. In some embodiments of conjugated polymers described herein, the polymer is purified by ion exchange chromatography. In other embodiments, the polymer is >95% pure. In some embodiments of conjugated polymers described herein, the polymer is used in flow cytometry assays to identify different cell markers or cell types. In other embodiments, the polymer is used to sort cells. In yet other embodiments, the polymer is used to sort cells for use in therapeutics. In some embodiments of conjugated polymers described herein, the polymer is used for intracellular staining. In certain instances, the polymer is used in flow cytometry assays to identify different cell markers or cell types. In some embodiments of conjugated polymers described herein, the polymer comprises a minimum number average molecular weight of greater than 40,000 g/mol and a water solubility of greater than 50 mg/mL in pure water or a phosphate buffered saline solution. In some embodiments of conjugated polymers described herein, the polymer comprises at least two unique conjugation linkers which can conjugated to two unique materials. Also provided herein are assay methods comprising providing a sample that is suspected of containing a target biomolecule; providing a sensor protein conjugated to at least one signaling chromophore and is capable of interacting with the target biomolecule or a target-associated biomolecule; providing a water soluble conjugated polymer described herein; contacting the sample with the sensor protein and the conjugated polymer in a solution under conditions in which the sensor protein can bind to the target biomolecule or a target-associated biomolecule if present; applying a light source to the sample that can excite the conjugated polymer; and detecting whether light is emitted from the signaling chromophore. In some embodiments, the sensor protein is an antibody. In other embodiments, the sensor protein comprises a plurality of sensor proteins conjugated to a plurality of signaling chromophores, wherein at least two of the plurality of chromophores emit different wavelengths of light upon energy transfer from the multichromophore. Also provided herein are conjugated polymer complexes comprising a polymer coupled to at least one biomolecule selected from the group consisting of a sensor biomolecule, a bioconjugate and a target biomolecule wherein the polymer is covalently bound by at least one bioconjugation site pendant thereto, and the polymer comprises a signaling chromophore or a signaling chromophore optionally is covalently bound to the polymer or the sensor biomolecule; wherein the polymer comprises the structure of formula: wherein: each R is a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL; MU is a polymer modifying unit or band gap modifying unit that is evenly or randomly distributed along the polymer main chain and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C 1 -C 12 alkyl, C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl, C 1 -C 12 haloalkyl, C 1 -C 12 alkoxy, C 2 -C 18 (hetero)aryloxy, C 2 -C 18 (hetero)arylamino, (CH 2 ) x′ (OCH 2 CH 2 ) y′ OCH 3 where each x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50, or a C 2 -C 18 (hetero)aryl group; each optional linker L 1 and L 2 are aryl or heteroaryl groups evenly or randomly distributed along the polymer main chain and are substituted with one or more pendant chains terminated with a functional group for conjugation to another molecule, substrate or biomolecule selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof; G 1 and G 2 are each independently selected from hydrogen, halogen, amine, carbamate, carboxylic acid, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiol, optionally substituted aryl, optionally substituted heteroaryl, halogen substituted aryl, boronic acid substituted aryl, boronic ester substituted aryl, boronic esters, boronic acids, optionally substituted fluorene and aryl or heteroaryl substituted with one or more pendant chains terminated with a functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, thiols, and protected groups thereof for conjugation to another substrate, molecule or biomolecule; wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, and thiols within G 1 , G 2 , L 1 or L 2 that allows, for functional conjugation to another molecule, substrate or biomolecule; n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. In some embodiments, the sensor biomolecule is selected from the group consisting of an avidin, streptavidin, neutravidin, avidinDN, and avidinD. In other embodiments, the conjugated polymer complex is further configured to bind to a complex selected from the group consisting of a biotin-labeled antibody, biotin-labeled protein, and biotin-labeled target biomolecule. In further embodiments, the sensor biomolecule is an antibody. In yet further embodiments, both the signaling chromophore and the sensor biomolecule are covalently linked to the multichromophore through a plurality of linkers. In some other embodiments, both the signaling chromophore and the sensor biomolecule are covalently linked to the polymer through a central linking site that covalently binds the polymer, the signaling chromophore and the sensor biomolecule. In yet other embodiments, the signaling chromophore, when covalently bound to the polymer or the sensor biomolecule, is an organic dye. Also provided herein are water soluble conjugated polymer having the structure of Formula (Ia): wherein: each R is independently (CH 2 ) x (OCH 2 CH 2 ) y OCH 3 where each x is independently an integer from 0-20, y is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C 1 -C 12 alkoxy, or (OCH 2 CH 2 ) z OCH 3 where each z is independently an integer from 0 to 50; each optional linker L 1 or L 2 is selected from the group consisting of a-i having the structure *=site for covalent attachment to unsaturated backbone wherein R′ is independently H, halogen, C 1 -C 12 alkyl, (C 1 -C 12 alkyl)NH 2 , C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl, C 1 -C 12 haloalkyl, C 2 -C 18 (hetero)aryl, C 2 -C 18 (hetero)arylamino, —[CH 2 —CH 2 ] r′ —Z 1 , or (C 1 -C 12 )alkoxy-X 1 ; and wherein Z 1 is —OH or —COOH; X 1 is —NH 2 , —NHCOOH, —NHCOOC(CH 3 ) 3 , —NHCO(C3-C12)cycloalkyl(C1-C4)alkyl-N-maleimide; or —NHCO[CH 2 —CH 2 —O] s′ (CH 2 ) s′ NH 2 ; r′ is an integer from 1 to 20; and each s′ is independently an integer from 1 to 20, (CH 2 ) 3 (OCH 2 CH 2 ) x″ OCH 3 where x″ is independently an integer from 0 to 50, or a benzyl optionally substituted with one or more halogen, hydroxyl, C 1 -C 12 alkoxy, or (OCH 2 CH 2 ) y″ OCH 3 where each y″ is independently an integer from 0 to 50 and R′ is different from R; wherein R 15 is selected from the group consisting of l-t having the structure: and k is 2, 4, 8, 12 or 24; *=site for covalent attachment to backbone MU is a polymer modifying unit or band gap modifying unit that is selected from the group consisting of a′-k′ having the structure: *=site for covalent attachment to unsaturated backbone; wherein R is a non-ionic side group capable of imparting solubility in water in excess of 10 mg/mL; G 1 and G 2 are each independently selected from the group consisting of 1-31 having the structures: wherein the polymer comprises at least 1 functional group selected from amine, carbamate, carboxylic acid, carboxylate, maleimide, activated esters, N-hydroxysuccinimidyl, hydrazines, hydrazides, hydrazones, azide, alkyne, aldehydes, and thiols within G 1 , G 2 , L 1 or L 2 that allows, for functional conjugation to another molecule, substrate or biomolecule; n is an integer from 1 to about 10,000; and a, b, c and d define the mol % of each unit within the structure which each can be evenly or randomly repeated and where a is a mol % from 10 to 100%, b is a mol % from 0 to 90%, and each c and d are mol % from 0 to 25%. Also provided herein are water soluble conjugated polymer having the structure of Formula: wherein Ar is an aryl or heteroaryl and is optionally substituted with one or more optionally substituted substituents selected from halogen, hydroxyl, C 1 -C 12 alkyl, C 2 -C 12 alkene, C 2 -C 12 alkyne, C 3 -C 12 cycloalkyl, C 1 -C 12 haloalkyl, C 1 -C 12 alkoxy, C 2 -C 18 (hetero)aryloxy, C 2 -C 18 (hetero)arylamino, (CH 2 ) x′ (OCH 2 CH 2 ) y′ OCH 3 where each x′ is independently an integer from 0-20, y′ is independently an integer from 0 to 50; and dashed bonds, L 1 , L 2 , G 1 , G 2 , MU, a, b, c, d and n are described previously for formula (I).
G01N3358
20170927
20180315
86750.0
G01N3358
1
TRUONG, DUC
NOVEL REAGENTS FOR DIRECTED BIOMARKER SIGNAL AMPLIFICATION
UNDISCOUNTED
1
CONT-ACCEPTED
G01N
2,017
15,719,560
ACCEPTED
FLOOR DRAIN FOR SAME FLOOR DRAINAGE WITHOUT DESCENDING FLOOR OF BUILDING
A floor drain for same floor drainage of a building consists of a floor drain body and a floor drain cover The floor drain body consists of a lower accumulated water collection tank, a lateral accumulated water collection tank and an accumulated water discharge port. A bottom of the lower accumulated water collection tank is sealed, and has an angle of 70° to 120° with the lateral accumulated water collection tank. The floor drain cover is a plate with holes, and is divided into a lower upstream face and a lateral upstream face. The lower upstream face of the floor drain cover is located above the lower accumulated water collection tank, and the lateral upstream face of the floor drain cover is located outside the lateral accumulated water collection tank.
1. A floor drain for same floor drainage without descending floor of a building, consisting of a floor drain body (1) and a floor drain cover (2), wherein the floor drain cover (2) and the floor drain body (1) are separable; the floor drain body (1) consists of a lower accumulated water collection tank (3), a lateral accumulated water collection tank (4) and an accumulated water discharge port (5); a bottom of the lower accumulated water collection tank (3) is closed, and the lower accumulated water collection tank (3) has an angle of 70° to 120° with the lateral accumulated water collection tank (4); the accumulated water discharge port (5) is located at the rear of the lateral accumulated water collection tank (4); the floor drain cover (2) is a plate with holes, and is divided into a lower upstream face (6) and a lateral upstream face (7); an angle between the lower upstream face (6) and the lateral upstream face (7) is 70° to 120°; the lower upstream face (6) of the floor drain cover (2) is located above the lower accumulated water collection tank (3); and the lateral upstream face (7) of the floor drain cover (2) is located outside the lateral accumulated water collection tank (4). 2. The floor drain for same floor drainage without descending floor of a building according to claim 1, wherein an inner wall of the bottom of the lower accumulated water collection tank (3) of the floor drain body (1) is higher than or level with an inner wall of a bottom of the accumulated water discharge port (5), and an area of a drainage section of the accumulated water discharge port (5) level with a horizontal section of a top surface of the lower accumulated water collection tank (3) of the floor drain body (1) is greater than or equal to 450 mm2 and less than 3500 mm2. 3. The floor drain for same floor drainage without descending floor of a building according to claim 2, wherein a support (8) protruding from an outer wall is arranged at the bottom of the lower accumulated water collection tank (3), and when the accumulated water discharge port (5) is horizontal, a bottom of the support (8) is above 5 mm lower than a bottom of the accumulated water discharge port (5), and a distance from the bottom of the support (8) to a top surface of the lower upstream face of the floor drain cover (2) is greater than 10 mm and less than 70 mm. 4. The floor drain for same floor drainage without descending floor of a building according to claim 3, wherein a distance from the closed bottom of the lower accumulated water collection tank (3) of the floor drain body (1) to a top surface of the lower upstream face (6) of the floor drain cover (2) is greater than 10 mm and less than 60 mm. 5. The floor drain for same floor drainage without descending floor of a building according to claim 4, wherein when the inner wall of the closed bottom of the lower accumulated water collection tank (3) centers on the accumulated water discharge port (5), a middle is lower and two sides are high. 6. The floor drain for same floor drainage without descending floor of a building according to claim 1, wherein more than one slot (9) is arranged on the lower accumulated water collection tank (3); more than one clamping groove (10) is arranged on the lateral accumulated water collection tank (4); more than one convex point (11) corresponding to the slot (9) is arranged on the lower upstream face (6) of the floor drain cover; or more than one slot (9) is arranged on the lateral accumulated water collection tank (4); more than one clamping groove (10) is arranged on the lower accumulated water collection tank (3); and a convex point (11) corresponding to the slot (9) is formed on the lateral upstream face (7) of the floor drain cover. 7. The floor drain for same floor drainage without descending floor of a building according to claim 2, wherein more than one slot (9) is arranged on the lower accumulated water collection tank (3); more than one clamping groove (10) is arranged on the lateral accumulated water collection tank (4); more than one convex point (11) corresponding to the slot (9) is arranged on the lower upstream face (6) of the floor drain cover; or more than one slot (9) is arranged on the lateral accumulated water collection tank (4); more than one clamping groove (10) is arranged on the lower accumulated water collection tank (3); and a convex point (11) corresponding to the slot (9) is formed on the lateral upstream face (7) of the floor drain cover. 8. The floor drain for same floor drainage without descending floor of a building according to claim 3, wherein more than one slot (9) is arranged on the lower accumulated water collection tank (3); more than one clamping groove (10) is arranged on the lateral accumulated water collection tank (4); more than one convex point (11) corresponding to the slot (9) is arranged on the lower upstream face (6) of the floor drain cover; or more than one slot (9) is arranged on the lateral accumulated water collection tank (4); more than one clamping groove (10) is arranged on the lower accumulated water collection tank (3); and a convex point (11) corresponding to the slot (9) is formed on the lateral upstream face (7) of the floor drain cover. 9. The floor drain for same floor drainage without descending floor of a building according to claim 4, wherein more than one slot (9) is arranged on the lower accumulated water collection tank (3); more than one clamping groove (10) is arranged on the lateral accumulated water collection tank (4); more than one convex point (11) corresponding to the slot (9) is arranged on the lower upstream face (6) of the floor drain cover; or more than one slot (9) is arranged on the lateral accumulated water collection tank (4); more than one clamping groove (10) is arranged on the lower accumulated water collection tank (3); and a convex point (11) corresponding to the slot (9) is formed on the lateral upstream face (7) of the floor drain cover. 10. The floor drain for same floor drainage without descending floor of a building according to claim 5, wherein more than one slot (9) is arranged on the lower accumulated water collection tank (3); more than one clamping groove (10) is arranged on the lateral accumulated water collection tank (4); more than one convex point (11) corresponding to the slot (9) is arranged on the lower upstream face (6) of the floor drain cover; or more than one slot (9) is arranged on the lateral accumulated water collection tank (4); more than one clamping groove (10) is arranged on the lower accumulated water collection tank (3); and a convex point (11) corresponding to the slot (9) is formed on the lateral upstream face (7) of the floor drain cover. 11. The floor drain for same floor drainage without descending floor of a building according to claim 6, wherein a plane greater than 50 mm is formed at the bottom of the support (8). 12. The floor drain for same floor drainage without descending floor of a building according to claim 7, wherein a plane greater than 50 mm is formed at the bottom of the support (8). 13. The floor drain for same floor drainage without descending floor of a building according to claim 8, wherein a plane greater than 50 mm is formed at the bottom of the support (8). 14. The floor drain for same floor drainage without descending floor of a building according to claim 9, wherein a plane greater than 50 mm is formed at the bottom of the support (8). 15. The floor drain for same floor drainage without descending floor of a building according to claim 10, wherein a plane greater than 50 mm is formed at the bottom of the support (8).
TECHNICAL FIELD The present invention relates to a floor drain for same floor drainage, and more specifically, to a floor drain for same floor drainage without descending floor of a building. BACKGROUND Currently, if same floor drainage needs to be realized in a building toilet, a floor of the toilet is required to be descended entirely or locally. To reduce the height of descending the floor, the width of a flow path of a floor drain and an area of a drainage section are also reduced, thereby easily causing blockage or impeded drainage of the floor drain and a drainage pipeline. SUMMARY The purpose of the present invention is to overcome existing technical defects, so as to provide a floor drain for same floor drainage used in the same floor drainage without descending floor of a building, thereby improving the unobstruction and difficult blocking of the drainage, being easy to maintain, and improving human life and sanitary environments. A floor drain for same floor drainage without descending floor of a building in the present invention comprises a floor drain body and a floor drain cover. The floor drain cover and the floor drain body are separable. The floor drain body comprises a lower accumulated water collection tank, a lateral accumulated water collection tank and an accumulated water discharge port. A bottom of the lower accumulated water collection tank is closed, and the lower accumulated water collection tank has an angle of 70° to 120° with the lateral accumulated water collection tank. The accumulated water discharge port is located at the rear of the lateral accumulated water collection tank. The floor drain cover is a plate with holes, and is divided into a lower upstream face and a lateral upstream face. An angle between the lower upstream face and the lateral upstream face is 70° to 120°. The lower upstream face of the floor drain cover is located above the lower accumulated water collection tank. The lateral upstream face of the floor drain cover is located outside the lateral accumulated water collection tank. The floor drain can drain surface water from the lower upstream face and the lateral upstream face simultaneously, thereby increasing the area of a water inlet section and accelerating the drainage of the surface water. According to the floor drain for same floor drainage without descending floor of the building in the present invention, an inner wall of the bottom of the lower accumulated water collection tank of the floor drain body is higher than or level with an inner wall of a bottom of the accumulated water discharge port, so that when surface water enters the accumulated water discharge port, a certain level difference can be formed, and the surface water can directly flow into a drainage concentrator having a water sealing function and a maintenance function without passing through a water seal, thereby greatly improving the unobstruction of drainage. An area of a drainage section of the accumulated water discharge port level with a horizontal section of a top surface of the lower accumulated water collection tank of the floor drain body is greater than or equal to 450 mm2 and less than 3500 mm2, thereby guaranteeing that the floor drain has relatively large drainage discharge. According to the floor drain for same floor drainage without descending floor of the building in the present invention, a support protruding from an outer wall is arranged at the bottom of the lower accumulated water collection tank, and when the accumulated water discharge port is horizontal, a bottom of the support is above 5 mm lower than a bottom of the accumulated water discharge port, thereby guaranteeing that a certain slope is formed by the accumulated water discharge port and a pipeline connecting the accumulated water discharge port so that accumulated water is not retained in the pipeline, and guaranteeing that a water flow has a certain speed. A distance from the bottom of the support to a top surface of the lower upstream face of the floor drain cover is greater than 10 mm and less than 70 mm, so that the floor drain for same floor drainage can be directly embedded in a cushion, a leveling layer and a decorative layer of the building, thereby achieving a using effect of not descending the floor. According to the floor drain for same floor drainage without descending floor of the building in the present invention, a distance from the closed bottom of the lower accumulated water collection tank of the floor drain body to a top surface of the lower attaining surface of the floor drain cover is greater than 10 mm and less than 60 mm, and thus, the area of a flowing section of the accumulated water discharge port can be increased on the premise of applying to a condition of not descending the floor. According to the floor drain for same floor drainage without descending floor of the building in the present invention, when the inner wall of the closed bottom of the lower accumulated water collection tank centers on the accumulated water discharge port, a middle is lower and two sides are higher, so that a water flow having certain kinetic energy can be rapidly formed when only a little quantity of accumulated water enters the lower accumulated water collection tank on the ground, so that the lower accumulated water collection tank is not deposited, thereby improving a drainage effect. According to the floor drain for same floor drainage without descending floor of the building in the present invention, more than one slot is arranged on the lower accumulated water collection tank; more than one clamping groove is arranged on the lateral accumulated water collection tank; more than one convex point corresponding to the slot is formed on the lower attaining surface of the floor drain cover; or more than one slot is arranged on the lateral accumulated water collection tank; more than one clamping groove is arranged on the lower accumulated water collection tank; and a convex point corresponding to the slot is formed on the lateral attaining surface of the floor drain cover. Therefore, when the convex point is inserted into the slot, the floor drain cover can be fixed to the floor drain body or separated from the floor drain body for blockage removal and maintenance by applying a certain force to the floor drain cover in a position of the clamping groove. According to floor drain for same floor drainage without descending floor of the building in the present invention, a plane greater than 50 mm is formed at the bottom of the support, and when the floor drain for same floor drainage is installed, the floor drain for same floor drainage placed on the ground can be guaranteed not to fall toward one side when the lower accumulated water collection tank has a lower middle and two higher sides. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a top view of the present invention; FIG. 2 is a sectional view of a section A-A of FIG. 1; FIG. 3 is a side view of FIG. 1; FIG. 4 is a front view of FIG. 1; FIG. 5 is a rear view of FIG. 1; FIG. 6 is a sectional view of a section B-B of FIG. 1; and FIG. 7 is a diagram of separation of a floor drain body and a floor drain cover of the present invention. DETAILED DESCRIPTION The present invention is further described below in combination with drawings, but is not limited to embodiments. Embodiment 1 As shown in FIGS. 1, 2 and 7, a floor drain for same floor drainage without descending floor of a building in the present invention consists of a floor drain body 1 and a floor drain cover 2. The floor drain body 1 and the floor drain cover 2 are separable. The floor drain body 1 consists of a lower accumulated water collection tank 3, a lateral accumulated water collection tank 4 and an accumulated water discharge port 5. A bottom of the lower accumulated water collection tank 3 is closed, and the lower accumulated water collection tank 3 has an angle of 90° with the lateral accumulated water collection tank 4. The accumulated water discharge port 5 is located at the rear of the lateral accumulated water collection tank 4. The floor drain cover 2 is a plate with holes, and is divided into a lower upstream face 6 and a lateral upstream face 7. An angle between the lower upstream face 6 and the lateral upstream face 7 is 90°. The lower upstream face 6 of the floor drain cover 2 is located above the lower accumulated water collection tank 3 of the floor drain body 1. The lateral upstream face 7 of the floor drain cover 2 is located outside the lateral accumulated water collection tank 4 of the floor drain body 1. Embodiment 2 As shown in FIGS. 2 and 5, an inner wall of the bottom of the lower accumulated water collection tank 3 of the floor drain body 1 of the floor drain for same floor drainage without descending floor of the building in the present invention is higher than or level with an inner wall of a bottom of the accumulated water discharge port 5. An area of a drainage section of the accumulated water discharge port 5 level with a horizontal section of a top surface of the lower accumulated water collection tank of the floor drain body 1 is greater than or equal to 450 mm2 and less than 3500 mm2, preferably 1080 mm2. Others are the same as those of Embodiment 1. Embodiment 3 As shown in FIGS. 2, 3 and 4, a distance from the inner wall of the closed bottom of the lower accumulated water collection tank 3 of the floor drain body 1 of the floor drain for same floor drainage without descending floor of the building in the present invention to the lower attaining surface of the floor drain cover 2 is 20 mm. A support 8 protruding from an outer wall is arranged at the bottom of the lower accumulated water collection tank 3, and when the accumulated water discharge port 5 is horizontal, a bottom of the support 8 is 8 mm lower than a bottom of the accumulated water discharge port 5, and a distance from the bottom of the support 8 to a top surface of the lower upstream face of the floor drain cover 2 is 35 mm. Others are the same as those of Embodiment 2. Embodiment 4 As shown in FIGS. 5 and 6, when the inner wall of the closed bottom of the lower accumulated water collection tank 3 of the floor drain for same floor drainage without descending floor of the building in the present invention centers on the accumulated water discharge port 5, a middle is lower and two sides are higher. Others are the same as those of Embodiment 3. Embodiment 5 As shown in FIGS. 1 and 4, two slots 9 are formed on the lower accumulated water collection tank 3 of the floor drain for same floor drainage without descending floor of the building in the present invention. One clamping groove 10 is formed in a lateral accumulated water collection tank 4. Two convex points 11 corresponding to the slot 9 are formed on the lower upstream face 6 of the floor drain cover. Others are the same as those of Embodiment 4. Embodiment 6 As shown in FIGS. 2, 3, 4 and 5, the bottom of the support 8 of the floor drain for same floor drainage without descending floor of the building in the present invention is a rectangular plane, and a long side is 90 mm. The above only describes preferred embodiments of the present invention, and is only used for describing the technical solution of the present invention, rather than liming the present invention. Although the present invention is described in detail by referring to better embodiments, those ordinary skilled in the art should understand that any amendment, equivalent replacement, improvement and the like made within spirits and principles of the present invention should be included in a protection scope of the present invention.
<SOH> BACKGROUND <EOH>Currently, if same floor drainage needs to be realized in a building toilet, a floor of the toilet is required to be descended entirely or locally. To reduce the height of descending the floor, the width of a flow path of a floor drain and an area of a drainage section are also reduced, thereby easily causing blockage or impeded drainage of the floor drain and a drainage pipeline.
<SOH> SUMMARY <EOH>The purpose of the present invention is to overcome existing technical defects, so as to provide a floor drain for same floor drainage used in the same floor drainage without descending floor of a building, thereby improving the unobstruction and difficult blocking of the drainage, being easy to maintain, and improving human life and sanitary environments. A floor drain for same floor drainage without descending floor of a building in the present invention comprises a floor drain body and a floor drain cover. The floor drain cover and the floor drain body are separable. The floor drain body comprises a lower accumulated water collection tank, a lateral accumulated water collection tank and an accumulated water discharge port. A bottom of the lower accumulated water collection tank is closed, and the lower accumulated water collection tank has an angle of 70° to 120° with the lateral accumulated water collection tank. The accumulated water discharge port is located at the rear of the lateral accumulated water collection tank. The floor drain cover is a plate with holes, and is divided into a lower upstream face and a lateral upstream face. An angle between the lower upstream face and the lateral upstream face is 70° to 120°. The lower upstream face of the floor drain cover is located above the lower accumulated water collection tank. The lateral upstream face of the floor drain cover is located outside the lateral accumulated water collection tank. The floor drain can drain surface water from the lower upstream face and the lateral upstream face simultaneously, thereby increasing the area of a water inlet section and accelerating the drainage of the surface water. According to the floor drain for same floor drainage without descending floor of the building in the present invention, an inner wall of the bottom of the lower accumulated water collection tank of the floor drain body is higher than or level with an inner wall of a bottom of the accumulated water discharge port, so that when surface water enters the accumulated water discharge port, a certain level difference can be formed, and the surface water can directly flow into a drainage concentrator having a water sealing function and a maintenance function without passing through a water seal, thereby greatly improving the unobstruction of drainage. An area of a drainage section of the accumulated water discharge port level with a horizontal section of a top surface of the lower accumulated water collection tank of the floor drain body is greater than or equal to 450 mm 2 and less than 3500 mm 2 , thereby guaranteeing that the floor drain has relatively large drainage discharge. According to the floor drain for same floor drainage without descending floor of the building in the present invention, a support protruding from an outer wall is arranged at the bottom of the lower accumulated water collection tank, and when the accumulated water discharge port is horizontal, a bottom of the support is above 5 mm lower than a bottom of the accumulated water discharge port, thereby guaranteeing that a certain slope is formed by the accumulated water discharge port and a pipeline connecting the accumulated water discharge port so that accumulated water is not retained in the pipeline, and guaranteeing that a water flow has a certain speed. A distance from the bottom of the support to a top surface of the lower upstream face of the floor drain cover is greater than 10 mm and less than 70 mm, so that the floor drain for same floor drainage can be directly embedded in a cushion, a leveling layer and a decorative layer of the building, thereby achieving a using effect of not descending the floor. According to the floor drain for same floor drainage without descending floor of the building in the present invention, a distance from the closed bottom of the lower accumulated water collection tank of the floor drain body to a top surface of the lower attaining surface of the floor drain cover is greater than 10 mm and less than 60 mm, and thus, the area of a flowing section of the accumulated water discharge port can be increased on the premise of applying to a condition of not descending the floor. According to the floor drain for same floor drainage without descending floor of the building in the present invention, when the inner wall of the closed bottom of the lower accumulated water collection tank centers on the accumulated water discharge port, a middle is lower and two sides are higher, so that a water flow having certain kinetic energy can be rapidly formed when only a little quantity of accumulated water enters the lower accumulated water collection tank on the ground, so that the lower accumulated water collection tank is not deposited, thereby improving a drainage effect. According to the floor drain for same floor drainage without descending floor of the building in the present invention, more than one slot is arranged on the lower accumulated water collection tank; more than one clamping groove is arranged on the lateral accumulated water collection tank; more than one convex point corresponding to the slot is formed on the lower attaining surface of the floor drain cover; or more than one slot is arranged on the lateral accumulated water collection tank; more than one clamping groove is arranged on the lower accumulated water collection tank; and a convex point corresponding to the slot is formed on the lateral attaining surface of the floor drain cover. Therefore, when the convex point is inserted into the slot, the floor drain cover can be fixed to the floor drain body or separated from the floor drain body for blockage removal and maintenance by applying a certain force to the floor drain cover in a position of the clamping groove. According to floor drain for same floor drainage without descending floor of the building in the present invention, a plane greater than 50 mm is formed at the bottom of the support, and when the floor drain for same floor drainage is installed, the floor drain for same floor drainage placed on the ground can be guaranteed not to fall toward one side when the lower accumulated water collection tank has a lower middle and two higher sides.
E03F50407
20170929
20180605
20180125
80742.0
E03F504
0
SCHNEIDER, CRAIG M
FLOOR DRAIN FOR SAME FLOOR DRAINAGE WITHOUT DESCENDING FLOOR OF BUILDING
SMALL
1
CONT-ACCEPTED
E03F
2,017
15,721,589
PENDING
OUTLET BOX
A utility box for mounting at least in part within a wall for use with a fluid carrying supply pipe, the box comprising, a housing including a top wall, a bottom wall, a first side wall and a second side wall, a back wall and a front opening providing access into an interior of the housing defined by the top, bottom, first side, second side and back walls, a bottom wall aperture in the bottom wall sized for extending the pipe through the bottom wall aperture with the pipe terminating in a free end portion positioned within the interior of the housing at a location above the bottom wall, a valve attachable to the free end portion of the pipe, the junction of the valve and the pipe being within the interior of the housing above the bottom wall, and a first seal positioned to provide a fluid-tight seal between the bottom wall and the pipe to prevent fluid within the interior of the housing from passing out of the interior of the housing through the bottom wall aperture.
1. A utility box for mounting at least in part within a wall for use with a fluid carrying supply pipe, the box comprising: a housing including a top wall, a bottom wall, a first side wall and a second side wall, a back wall and a front opening providing access into an interior of the housing defined by the top, bottom, first side, second side and back walls; a bottom wall aperture in the bottom wall sized for extending the pipe through the bottom wall aperture with the pipe terminating in a free end portion positioned within the interior of the housing at a location above the bottom wall; a valve attachable to the free end portion of the pipe, the junction of the valve and the pipe being within the interior of the housing above the bottom wall; and a first seal positioned to provide a fluid-tight seal between the bottom wall and the pipe to prevent fluid within the interior of the housing from passing out of the interior of the housing through the bottom wall aperture. 2. A utility box mounted at least in part within a wall, the box comprising: a housing including a top wall, a bottom wall, a first side wall and a second side wall, a back wall and a front opening providing access into an interior of the housing defined by the top, bottom, first side, second side and back walls; a bottom wall aperture in the bottom wall; a fluid carrying supply pipe extending through the bottom wall aperture and terminating in a free end portion within the interior of the housing at a location above the bottom wall; a valve attached to the free end portion of the pipe, the junction of the valve and the pipe being within the interior of the housing above the bottom wall; a first seal providing a fluid-tight seal between the bottom wall and the pipe to prevent fluid within the interior of the housing from passing out of the interior of the housing through the bottom wall aperture; and a second seal providing a fluid-tight seal between the free end portion of the pipe and the valve. 3. The utility box of claim 2, further comprising: a manifold positioned to provide a fluid path between the free end portion of the pipe and the valve, the manifold having a lower connecting portion, an upper connecting portion and a side connecting portion positioned between the lower and upper connecting portions, with the lower connecting portion being connected in a fluid-tight arrangement to the free end portion of the pipe and one of the upper and side connecting portions being connected in a fluid-tight arrangement to the valve. 4. The utility box of claim 3 for use with a fitting having a push-fit connector, wherein one of the upper and side connecting portions is a tube sized for having the push-fit connector pressed thereon. 5. The utility box of claim 4, wherein the lower connecting portion comprises a push-fit connector sized for being pressed onto the free end portion of the pipe. 6. The utility box of claim 3 for use with an arrestor assembly, wherein valve is connected to the side connecting portion and the upper connection portion is configured for connection to the arrestor assembly. 7. The utility box of claim 2, further comprising: a manifold positioned to provide a fluid path between the free end portion of the pipe and the valve, the manifold having a lower connecting portion and an upper connecting portion, with the lower connecting portion being connected in a fluid-tight arrangement to the free end portion of the pipe and the upper connecting portions being connected in a fluid-tight arrangement to the valve. 8. A utility box for mounting at least in part within a wall for use with an in-wall drain pipe and a drain-fluid source conduit transporting a drain fluid for entry into the drain pipe, the box comprising: a housing including a top wall, a bottom wall, a first side wall and a second side wall, a back wall and a front opening providing access into an interior of the housing defined by the top, bottom, first side, second side and back walls; a bottom wall aperture in the bottom wall sized to be placed in fluid communication with the drain pipe; a drain including a drain base positioned within the bottom wall aperture and in fluid-tight communication with the drain pipe, and a retaining member for removable attachment to the drain base for retaining the drain-fluid source conduit in place relative to the drain base for communication of the drain fluid into the drain base. 9. A method of mounting a utility box at least in part within a wall, the method comprising: providing a housing including a top wall, a bottom wall, a first side wall and a second side wall, a back wall and a front opening providing access into an interior of the housing defined by the top, bottom, first side, second side and back walls, the bottom wall having a bottom wall aperture; extending a fluid carrying supply pipe through the bottom wall aperture and an positioning a free end portion of the pipe within the interior of the housing at a location above the bottom wall; attaching a valve to the free end portion of the pipe with the junction of the valve and the pipe being within the interior of the housing above the bottom wall; positioning a first seal between the bottom wall and the pipe to provide a fluid-tight seal prevent fluid therebetween to prevent fluid within the interior of the housing from passing out of the interior of the housing through the bottom wall aperture; and positioning a second seal between the free end portion of the pipe and the valve to provide a fluid-tight seal therebetween.
RELATED APPLICATIONS This application claims benefit of U.S. Provisional Application No. 62/402,896, filed on Sep. 30, 2016, the entire disclosures and content of which are hereby incorporated by reference in their entirety. FIELD OF INVENTION The invention relates to outlet boxes for mounting in a wall, and more particularly, to outlet boxes having a housing with one or more apertures for installing fixtures for utilities, such as water. BACKGROUND Utility outlet boxes may be installed in building walls to provide access and/or disposal points for utilities, such as water. In one application, outlet boxes may be installed within building walls during the construction or renovation, and pipes and/or fixtures may be connected to the outlet boxes. Leaks that develop in the outlet box, such as in the connected pipes and/or fixtures connected thereto, may be difficult to discover because water drains out of the outlet box. Water leaking in the outlet box may drain or otherwise intrude into interior portions of the surrounding wall potentially causing mold or water damage. Additionally, even if the leak is discovered, removal of a portion of the wall or removal of the outlet box from the wall or may be required to repair or discover the offending leak. Accordingly, there is a need for an outlet box that prevents water leaks from intruding into the surrounding building walls, that increases detectability of leaks, and that improves ease of repair of leaky fixtures and/or pipes connected to the outlet box. Previously-implemented outlet boxes may also be difficult to mount to building walls and may not be securely attached when mounted thereto. For example, some currently existing methods for attachment of outlet boxes include securing the outlet boxes using straps. However, straps may require access to the rear of the outlet box during installation, and not provide adequate structural support for the outlet box alone. There is therefore the need for an apparatus that facilitates an easier and more secure means of mounting the outlet boxes within building walls. Previously-implemented outlet boxes are also configured for use in a single application, such as installing a water fixture for supplying water to an appliance. Installation of additional boxes may be necessary to provide additional drains, an air admittance valve, or additional water supply valves, for example. Therefore, currently existing outlet boxes do not provide sufficient versatility for installing different combinations of fixtures. Further, previously-implemented outlet boxes do not easily accommodate attachment of differently sized pipes or different fixtures, and do not allow for pipes and/or fixtures to be connected to the outlet boxes at different positions. For example, a pipe above an outlet box may need to be routed to the underside of the utility box because the top of the utility box does not include an appropriate receptacle for receiving the pipe. Even when the previously-implemented outlet box installed in the building wall has an appropriately located receptacle for receiving a pipe (e.g., at the bottom), the receptacle may not be appropriately sized for connecting the pipe. The previously-implemented may not allow for installation of fixtures having differently sized attachment portions. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 illustrates a perspective view of a utility box according to a first embodiment. FIG. 2 illustrates a first exploded view of the utility box of FIG. 1. FIG. 3 illustrates a second exploded view of the utility box of FIG. 1. FIG. 4 illustrates a third exploded view of the utility box of FIG. 1. FIG. 5 illustrates a front view of a box main housing of the utility box of FIG. 1. FIG. 6 illustrates a top plan view of the box main housing of FIG. 5. FIG. 7 illustrates a bottom plan view of the box main housing of FIG. 5. FIG. 8A illustrates an enlarged cross-sectional view substantially along line 1A-1A of the box main housing of FIG. 5. FIG. 8B illustrates an enlarged cross-sectional view substantially along line 1B-1B of the box main housing of FIG. 5. FIG. 9 illustrates an enlarged cross-sectional view substantially along line 1A-1A of a support receptacle of the box main housing of FIG. 5. FIG. 10 illustrates a right side view of the box main housing of FIG. 5. FIG. 11 illustrates a rear view of the box main housing of FIG. 5. FIG. 12 illustrates an enlarged cross-sectional view substantially along line 1A-1A of a second upper receptacle of the box main housing of FIG. 5. FIG. 13A illustrates a bottom perspective view of a box main housing according to a second embodiment. FIG. 13B illustrates a front view of a box main housing according to a third embodiment. FIG. 13C illustrates a bottom perspective view of the box main housing of FIG. 13B. FIG. 14A illustrates a bottom perspective view of the box main housing of FIG. 5 positioned against an interior side of a building wall and having a pipe inserted into a second lower receptacle thereof. FIG. 14B illustrates a cross-sectional view of a lower wall of the box main housing of FIG. 14A taken along line 1-1 of FIG. 5. FIG. 15 illustrates a front perspective view of the lower wall of the box main housing of FIG. 5. FIG. 16A illustrates a front view of a first manifold body of a valve assembly. FIG. 16B illustrates a left side view of the first manifold body of FIG. 16A. FIG. 17 illustrates a cross-sectional view of the first manifold body of FIG. 16A substantially along line 2-2. FIG. 18 illustrates a bottom view of a manifold spacer. FIG. 19 illustrates a cross-sectional view of the manifold spacer of FIG. 18 substantially along line 3-3. FIG. 20A illustrates a front view of a second manifold body of the valve assembly. FIG. 20B illustrates a left side view of the second manifold body of FIG. 20A. FIG. 21 illustrates a cross-sectional view of the second manifold body of FIG. 20A substantially along line 4-4. FIG. 22 illustrates a cross-sectional view of a liquid flow switch and a bushing assembly installed in the second manifold body of FIG. 20A substantially along line 4-4, and having a port interface and a C-clip attached to the second manifold body. FIG. 23 illustrates a bottom plan view of an end bushing of the bushing assembly of FIG. 22. FIG. 24 illustrates a side view of the end bushing of FIG. 23. FIG. 25 illustrates a cross-sectional view of the end bushing of FIG. 23 along the line 5-5. FIG. 26 illustrates a side view of a port of the second manifold body of FIG. 20A. FIG. 27 illustrates a side view of the port interface of FIG. 22. FIG. 28 illustrates a cross-sectional view of the port interface of FIG. 27. FIG. 29 illustrates a plan view of the C-clip of FIG. 22. FIG. 30A illustrates a top plan view of a manifold support ferrule. FIG. 30B illustrates a cross-sectional view of the manifold support ferrule of FIG. 30B along the line 6-6. FIG. 31 illustrates the utility box of FIG. 1 equipped with a pair of valve assemblies and a drain assembly. FIG. 32 illustrates a front view of a drain base of the drain assembly of FIG. 31. FIG. 33 illustrates a right side view of the drain base. FIG. 34 illustrates a cross-sectional view of the drain base of FIG. 32 substantially along line 7-7. FIG. 35 illustrates a top perspective view of a retaining member of the drain assembly of FIG. 31. FIG. 36 illustrates a top rear perspective view of a mounting bracket and a pipe supportably attaching the utility box of FIG. 1 to wall studs and an adjacent second utility box. FIG. 37 illustrates a top rear perspective view of the mounting bracket and the pipe of FIG. 36 supportably attaching a utility box according to a second embodiment to wall studs. FIG. 38 illustrates a perspective view of the mounting bracket of FIG. 36. FIG. 39 illustrates a front view of the mounting bracket of FIG. 36. FIG. 40 illustrates a side view of the mounting bracket of FIG. 36. FIG. 41 illustrates a perspective view of a pipe support bracket attached to a pipe according to a first embodiment. FIG. 42 illustrates a perspective view of a collar of the pipe support bracket of FIG. 41. FIG. 43 illustrates a rear perspective view of a brace of the pipe support bracket of FIG. 41. FIG. 44 illustrates a front perspective view of a brace of the pipe support bracket of FIG. 41. FIG. 45 illustrates a perspective view of a second collar of a pipe support bracket according to a second embodiment of the pipe support bracket. FIG. 46 illustrates a cross-sectional view of the pipe support bracket of FIG. 45. FIG. 47 illustrates a perspective view of the pipe support bracket of FIG. 45. FIG. 48 illustrates a front view of a utility box having a plurality of valve assemblies installed therein, and provided with partially transparent and partial sectional views of some of the valve assemblies. FIG. 49 illustrates a cross-sectional view of the utility box of FIG. 48 taken substantially along line 8-8. FIG. 50 illustrates an enlarged cross-sectional view of a water valve assembly installed in the utility box of FIG. 48 taken substantially along line 8-8. FIGS. 51-93 illustrate additional embodiment of the utility box and its component parts similar to those shown in FIGS. 1-50. DETAILED DESCRIPTION A utility box 10 according to a first embodiment is shown in FIG. 1. The utility box 10 is configured to be installed in the wall of a residential or commercial building to provide one or more access and/or disposal points for utilities. The utility box 10 may be comprised of a rigid waterproof material, such as plastics, polymers, or polyvinyl chloride (PVC); however, other similar materials are contemplated. In this first embodiment, the utility box 10 is configured to provide water access and disposal points for appliances, such as washing machines, dishwashers and ice makers; however, those of ordinary skill in the art will recognize that the configuration of the utility box may be suitable for other applications. The utility box 10 includes a box main housing 12 having a generally three-dimensional square or rectangular outer shape, as shown in FIGS. 5, 6, 7, 8A, 10 and 11. A forwardly opening cavity portion 14 is defined by housing walls 16 extending rearwardly from an opening 18 and terminating at a rear wall 20. The housing walls 16 are comprised of a lower wall 22, an upper wall 24 opposite to the lower wall, and opposing left and right sidewalls 26L and 26R, as shown in FIG. 5. The opening 18 is sized to allow a user's hand to reach into the cavity portion 14 for operation, installation and removal of water valves and drains therein, as described below. The utility box 10 includes one or more receptacles for connecting a water pipe to the utility box, and for installation of a water supply valve or drain, such as a valve assembly 28 shown in FIGS. 1, 2, 3, and 4. A pair of laterally offset first lower receptacles 30 is disposed on the lower wall 22, as shown in FIGS. 5, 7, 8B, and 11. The lower receptacles 30 each include an annular wall 32 circumferentially extending around a removable circular knockout portion 34, as shown in FIGS. 7 and 8B. The knockout portion 34 is at least partially joined or connected to the lower wall 22 by two narrow bridge portions 36 extending radially inward from the annular ring to the knockout portion, as shown in FIGS. 3 and 9. The bridge portions 36 are located at 180° from one another around the knockout portion 34. The knockout portion 34 may include an outer portion 37 having a thickness less than the annular wall 32, the outer portion extending around the circumference of the knockout portion 34 between the bridge portions 36 and connecting the knockout portion to the annular wall 32. The outer portion 37 may have a tapered or angular cross-sectional shape that tapers radially inward from an upper surface to a lower surface of the knockout portion 34. The knockout portion 34 may be removed by cutting through all or most of the outer portion 37, using a utility knife or blade for example, without severing the bridge portions 36. The remaining bridge portions 36 may be broken after severing the outer portion to prevent unintentional loss of the knockout portion within the wall or a pipe. The bridge portions 36 may act as pivot points about which the knockout portion 34 may be rotated to increase strain in, and thereby weaken, the bridge portions. After rotating the knockout portion 34 about the bridge portions 36, the user may grip the knockout portion and sever the bridge portions 36 to remove the knockout portion from the utility box 10 without the dropping it into a wall or pipe below. Removal of the knockout portion 34 creates an aperture 33 defined by the surrounding annular wall 32, the aperture being sized and shaped to receive a corresponding part, such as a pipe, having a known size and shape. In other embodiments, an air gap may space the annular wall 32 apart from the knockout portion 34 instead of having the outer portion 37 therebetween. A pilot guide 38 is provided to guide a drill bit through a center the bottom side of the knockout portion to create an aperture of a desired size therein for receiving a pipe or hose, as shown in FIG. 8B. The pilot guide 38 may be a hole or divot extending partially or completely through the center of the knockout portion 34. The lower receptacles 30 include a cylindrical sidewall portion 40 extending downwardly from a lower surface 42 of the lower wall 22 around the annular wall 32 and defining a cavity 44 therein. The design of the receptacles (e.g., lower receptacles 30) and associated components prevents water from leaking therethrough and into the wall containing the utility box 10. Installation of the pipe and associated components are now described with reference to FIGS. 48, 49, and 50. First, an upper end of a pipe 35 is inserted through the aperture 33 of the lower receptacle 30 to extend between the cavity portion 14 and a lower side of the lower wall 22. An O-ring 46 may be positioned around the pipe 35 below the lower wall 22 and against or abutting the annular wall 32. The O-ring 46 is sized and shaped to resiliently and radially compress between the outer diameter of the pipe 35 and the inner diameter of the cylindrical sidewall portion 40, thereby forming a fluid-tight seal around the pipe 35 at the lower surface of the annular wall 32. A metallic gripper ring 48 having circumferentially spaced axially and radially inwardly protruding teeth (described in U.S. Pat. No. 6,464,266, which is incorporated herein in its entirety by reference) may be installed around the pipe 35 beneath the O-ring 46 to help retain the O-ring within the cavity 44. When the pipe 35 is inserted through the gripper ring 48, the inwardly protruding teeth of the gripper ring 48 bend in the direction of insertion, and dig into or press inwardly against the outer diameter of the pipe 35. For instance, the teeth of the gripper ring 48 may bend downwardly when the pipe 35 is inserted downwardly through the aperture 33. The pipe 35 may be rotated in a first direction (e.g., clockwise) relative to the gripper ring 48 to score the outer diameter of the pipe 35 and prevent further movement of the pipe 35 through the gripper ring 48. The gripper ring 48 may have a larger diameter than the inner diameter of the sidewall portion 40 so as to abut a lower side of the sidewall portion 40. In some embodiments, the gripper ring 48 may be fixed to the bottom of the sidewall portion 40 using adhesives or sonic welding, by way of non-limiting example. When the pipe 35 is inserted through the aperture 33, the O-ring 46, and the gripper ring 48, as described above, the pipe 35 is maintained in fluid-tight attachment to the box main housing 12. Thereafter, a valve assembly 28 or other assembly may be installed over the upper end of the pipe 35 within the cavity portion 14, as described below. If the valve assembly 28 leaks or breaks, or water otherwise accumulates within the cavity portion 14, the O-ring 46 sealed around the pipe 35 prevents liquid from leaking through the aperture 33 and into the wall. The inside of the building walls is thereby protected from leaks within or around the utility box 10, and leaking water will pool within the cavity portion 14 providing a visual indication of a leak. Moreover, a leaky valve assembly 28 may be removed and replaced without removal of the building wall or the box main housing 12 from the wall. Thus, the valve assembly 28 may be easily removed or replaced without extensive cost or effort. The utility box 10 may be provided with the pipe 35 installed in the fluid-tight configuration. Alternatively, the pipe 35 may be installed in the fluid-tight configuration on site. In some embodiments, one or more second lower receptacle 52 having a different configuration than the first lower receptacles 30 may also be disposed on the lower wall 22, as shown in FIGS. 7 and 8A. The second lower receptacle 52 may have a larger outer diameter than the first lower receptacles 30 to allow for attachment of a pipe 67 having a larger diameter than the pipe 35. A second sidewall 54 having a cylindrical shape with a larger diameter than the sidewall 40 extends downwardly from the lower wall 22 to define a downwardly opening cavity 56. The second sidewall 54 may have a length extending downwardly farther than the sidewall 40. The second lower receptacle 52 may include one or more removable knockout portions for installing a pipe and/or a water supply or drain. For example, an annular first knockout portion 58 of the second lower receptacle 52 is located radially inward of the second sidewall 54. The first knockout portion 58 may be connected to the lower surface 22 by an outer portion 59 and a plurality of the bridge portions 61 substantially similar to those described above, except that there may be a different number of bridge portions than two. For example, the second lower receptacle 52 may have four bridge portions 61 spaced apart at 90° from one another around the perimeter of the first knockout portion 58. The first knockout portion 58, including all portions of the second lower receptacle 52 located radially inward thereof, by severing the bridge portions 61 and the outer portion 59. The second lower receptacle 52 may include a second knockout portion 60 located radially inward from the first knockout portion 58. The second knockout portion 60 may include a circular plate 62 having a radial wall thickness greater than the first knockout portion. The second knockout portion 60 may be connected to the first knockout portion 58 by a plurality of the bridge portions 63 and/or the outer portion in the manner described above. The circular plate 62 is removable from the second lower receptacle 52 without also removing the first knockout portion 58. In particular, a pipe 67 having a similar inner diameter to the first knockout portion 58 may be inserted upward into the cavity 56 and abutting against a lower surface of the first knockout portion 58, as shown in FIGS. 14A and 14B. The first knockout portion 58 is sized such that it is too large to fall into the pipe 67 when the knockout portion 58 is severed or removed from the box main housing 12. The outer portion 37 between the second knockout portion 60 and the first knockout portion 58 may be broken or severed to remove the second knockout portion 60. A blade or other tool may be used to cut along at least some of the outer portion 37, and a user may push or pull the second knockout portion 60 to further separate the second knockout portion 60 and the first knockout portion 58 along the outer portion 37. The bridge portion(s) 36 is thicker than the outer portion 37, and designed so that it may not be broken when the outer portion 37 is severed so as to prevent the second knockout portion 60 from falling into the pipe below the receptacle. After breaking the outer portion 37, the user may then grip the second knockout portion 60 and break the remaining bridge portion 36 to separate the second knockout portion 60 from the second lower receptacle 52 without removing the first knockout portion 58. Thereafter, a drain assembly may be installed in the second lower receptacle 52 through the cavity portion 14 of the utility box 10. The box main housing 12 may include a feature providing a guide or outline 69 indicating where to cut to remove a knockout portion, as shown in FIG. 15. The guide 69 may be an annular recess disposed on an upper surface of the lower wall 22 in the cavity portion 14, and coaxially located with the knockout portions of the second lower receptacle 52 (or other receptacles). The guide 69 in the present embodiment is circumferentially located along the outer diameter of the first knockout portion 58. A user may insert the tip of a blade in and cut along the guide 69 to remove the knockout portion 58 and the portions radially inward therefrom. Therefore, the knockout portion 58 may be removed after the utility box 10 is installed in a building wall or without requiring access to the lower surface of the lower wall 22. In some embodiments, the guide 69 may include an outline or indication provided on the upper surface of the lower wall 22. There may be a plurality of concentrically-located guides 69 on each receptacle for which the guides are provided. For example, there may be another guide 69 located between the first knockout portion 58 and the second knockout portion 60 (i.e. located along the outer portion 59) for removing the second knockout portion 60 while leaving the first knockout portion 58 installed. One or more of the other receptacles (e.g., first lower receptacle 30) may be provided with one or more of the guides 69 for removing knockout portions. Referring to FIG. 8A, the second lower receptacle 52 may also include a pilot guide 64 similar to the pilot guide 38 described above extending partially or completely through the center of the plate section 62, providing a pilot hole or divot to guide a drill bit to drill upwardly through the bottom side of the knockout portion to create an aperture of a desired size therein. The second lower receptacle 52 may further include a third lower receptacle 66 disposed at the center of the plate section 62. The third lower receptacle 66 may be substantially similar in structure and/or size to the first lower receptacle 30. That is, the third lower receptacle 66 may include an annular wall surrounding a removable circular knockout portion, and a cylindrical sidewall portion extending downwardly from a lower surface of the plate section 62 in a structure substantially similar to the lower receptacles 30. The second lower receptacle 52 may have more knockout portions 65 disposed radially inward of the first knockout portion 58 and the second knockout portion 60, as shown in FIG. 14B. The differently sized knockout portions of the second lower receptacle allow for connection of differently sized pipes or hoses to the utility box 10. A pair of laterally offset first upper receptacles 68 may be disposed on the upper wall 24, as shown in FIG. 6. The first upper receptacles 68 may allow for pipes and valves to be connected to an upper side of the utility box 10. The first upper receptacles 68 may have a similar configuration to the first lower receptacles 30. In particular, each of the first upper receptacles 68 may include a knockout portion 70 substantially similar to the knockout portions 34 described above and two narrow bridge portions 72 extending radially inward from the upper wall 24 to the knockout portion 70. The knockout portion 70 may include an outer portion 71 having a thickness less than the upper wall 24 and extending around the circumference of the knockout portion 70 between the bridge portions 72 and connecting the knockout portion to the upper wall 24. The outer portion 71 may have a tapered or angular shape tapering radially inward toward an upper surface of the knockout portion 70. In other embodiments, the outer portion 71 may be omitted and an air gap may separate the knockout portion 70 from the upper wall 24. The center of the knockout portion 70 may include a pilot guide substantially similar to the pilot guide 38. In some embodiments, the first upper receptacles may each include a cylindrical sidewall portion extending upwardly from the upper wall 24 around the connecting ring (or air gap) in a manner similar to the sidewall portion 40. A second upper receptacle 74 may be disposed on a central portion of the upper wall 24. The second upper receptacle 74 may have a plurality of concentrically arranged knockout portions arranged in a “bullseye” configuration for connecting pipes and/or fixtures having different sizes at the upper wall 24, as shown in FIGS. 6, 8A, and 12. For example, the second upper receptacle 74 may include a first knockout portion 76 having a largest outer diameter, a second knockout portion 78 having an outer diameter positioned radially inward of an inner diameter of the first knockout portion, and a third knockout portion 80 having an outer diameter positioned radially inward of an the second knockout portion. The upper wall 24 is connected to the first knockout portion 76 by an outer portion 81 and a pair of narrow radially extending first bridge portions 82, which are similar to the bridge portions 36 and located at 180° from one another around the outer circumference of the first knockout portion. The outer portion 81 has a thickness less than the first knockout portion 76 and extends circumferentially around the first knockout portion. The outer portion 81 may have a tapered or angular cross-sectional shape that tapers radially inward from lower surface to an upper surface of the knockout portion 76. Each of the plurality of concentrically arranged knockout portions may be connected by circumferentially offset bridge portions. The first knockout portion 76 is connected to the second knockout portion 78 by an outer portion 83 and a pair of second bridge portions 84 similar to the bridge portions 36, but each of which are circumferentially offset relative to one of the first bridge portions 82 around at 120° (and conversely −60° to the other of the first bridge portions). The second knockout portion 78 is connected to the third knockout portion 80 by an outer portion 85 and a pair of third bridge portions 86 similar to the bridge portions 36, but each of which are circumferentially offset relative to one of the second bridge portions 84 at 120°. The outer portions 83 and 85 have a structure similar to the outer portion 81 describe above, as shown in FIG. 12. Circumferentially offsetting the bridge portions 82, 84, 86 from one another allows a user to remove an inner knockout portion without removal of an adjacent outer knockout portion, thereby adjusting the circumference of an aperture of the second upper receptacle 74 for installation a pipe or fixture having approximately the same outer circumference. To remove the third knockout portion 80, a user may sever the outer portion 85, then grip the third knockout portion and sever or forcibly break the bridge portions 86. A pipe or fixture having an outer circumference similar to the inner circumference of the second knockout portion 78 may be inserted through the aperture left by the removed third knockout portion 80. An upper surface of the third knockout portion 80 may include a pilot guide substantially similar to the pilot guide 36 described above for drilling an aperture of a desired size in the second upper receptacle 74. The configuration of the lower and/or upper receptacles of the utility box 10 allow for attachment of different fixtures, valves and drains thereto, and to facilitate simple and secure connection of pipes and/or hoses to the different fixtures, valves and drains. Although three receptacles for attaching fixtures are provided on each of the upper wall 24 and lower wall 22 of the box main housing 12, a different number of receptacles may be provided in other embodiments. For example, a box main housing 13A may be provided having four second lower receptacles 52, as shown in FIG. 13A. Accordingly, two separate drain assemblies and two separate water valve assemblies, described below, may be attached to the box main housing, allowing for greater variation in uses and configurations. For example, a dishwasher and ice maker, each using a single water supply assembly and a single drain assembly, may be attached at the same outlet box instead of having two separate outlet boxes. A different number of receptacles may be provided in other embodiments. For instance, a box main housing 13B is shown in FIGS. 13B and 13C having three lower receptacles 52. Each of the lower receptacles 52 may include one of the third lower receptacles 66 (see FIG. 13C) for installing a pipe and/or a valve, as described below. Different configurations of drains and/or valves may be installed in the box main housing 13B. A drain assembly may be installed in each of the leftmost one and center one of the receptacles 52 shown in FIG. 13C, and a water supply valve may be installed in the rightmost one of the receptacles 52, by way of non-limiting example. Therefore, a user may configure the box main housings 13A and 13B according to the application, or the most convenient access to the supply or drain pipe. In one aspect, water supply valves 28 may be installed in the first lower receptacles 30, as shown in FIGS. 1, 31, 48, 49 and 50. During installation of the utility box 10 in a building wall, the knockout portions 34 are removed leaving an aperture through which the pipe 35 may be inserted. Referring to FIGS. 2 and 50, an upper end of the pipe 35 may be inserted through a metallic gripper ring 48 having circumferentially spaced axially and radially inwardly protruding teeth described in U.S. Pat. No. 6,464,266, which is incorporated herein in its entirety by reference. The upper end of the pipe 35 may then be inserted through the O-ring 46 and through the aperture of the lower first receptacle, positioning the upper end of the pipe 35 above the lower wall 22 within the cavity portion 14 of the housing main box 12. The O-ring 46 is positioned within the cylindrical sidewall 40 near or against the lower surface 42 of the lower wall 22. Thereafter, the valve assembly 28 may be installed over the upper end of the pipe 35 in the cavity portion 14. The valve assemblies may be installed in the upper receptacles of the box main housing 12, as shown in FIG. 48, for example. The valve assembly 28 is a “push-fit” assembly comprising components that lock into place when a male component is pushed or inserted into a female component without threaded attachment. The valve assembly 28 includes a substantially L-shaped hollow outlet 90 with a rearwardly extending receiving tube 90T for sealably connecting with a push-fit tube 88T of a manifold 88, as shown in FIG. 2, 3, or 31, or sealably connecting with a pipe 35, as shown in FIGS. 48, 49, and 50. The manifold 88 may be a component of the valve assembly 28 comprising a substantially T-shaped or L-shaped hollow body having a lower connecting portion 88L, as shown in FIGS. 16A, 16B, 17. The manifold 88 and/or outlet 90 may be push-fit components that are monolithically formed by an injection molding process using a polymer material, such as chlorinated polyvinyl chloride (CPVC) or PVC. An upper end of the manifold 88 may include an upper connecting portion 88U for threadably attaching a water arrestor assembly, as described below. The tube 88T extends outwardly from a side of the manifold 88 providing a push-fit connection point for attaching the outlet 90. The single-piece injection-molded manifold 88 eliminates joints or seams that may leak or fail in other devices, and provides a monolithic attachment point for connecting different outlets in a push-fit manner. A manifold spacer 92 may be installed within the cavity portion 14 between the lower wall 22 and the lower connecting portion 88L to space them apart at an appropriate distance according to the length of the end of the pipe 35. As shown in FIGS. 18 and 19, the manifold spacer 92 has an annular upper portion 92U having an outer circumference sized to snuggly fit into the lower end of the lower connecting portion 88L, and a cylindrical lower portion 92L having a circumference larger than the upper portion 92U and sized equal to or larger than the bottom of the lower connecting portion 88L. An upwardly facing ledge 92L of the manifold spacer 92 abuts a lower surface of the lower connecting portion 88L of the manifold 88 when the upper portion 92U is inserted therein. The cylindrical lower portion 92L has a plurality of axially offset and radially inwardly extending guide ribs or ridges 92R for guiding the end of the pipe 35 through the manifold spacer and into the manifold 88. A length of the tube 88T of the manifold 88 may be inserted into a cavity 90A of the receiving tube 90T of the outlet 90 to connect the manifold 88 and the outlet 90. A bushing assembly 93 may be nested or installed at least partially within the cavity 90A of the receiving tube 90T to facilitate water-tight fluid communication between the manifold 88 and the outlet 90, as shown in FIG. 22. The bushing assembly 93 allows for a push-fit assembly of the outlet 90 (or other similar outlet) to the manifold 88 (or the pipe 35). The bushing assembly 93 may include one or more O-rings, one or more gripper rings, and an end bushing 94. The end bushing 94 has a body portion 94B sized and shaped to fit against inner surfaces within the cavity 90A, an inner cavity extending axially through the end bushing 94, and a rear flange portion 90F that abuts a rearward surface of the receiving tube 90T, as shown in FIGS. 23, 24 and 25. The flange portion 94F may include a plurality of recesses 94R axially offset and radially positioned along a rearward surface of the flange portion 90F. One or more of the recesses 94F may engage with a thin fin portion 88F projecting forwardly from and extending vertically along a forward surface of the manifold 88 (see FIGS. 16B and 17) to allow secure rotational movement between the manifold 88 and the outlet 90 without failure of the fluid-tight seal therebetween. The end bushing 94 may further include a plurality of axially offset ridges or ribs 94T projecting radially inward in the inner cavity 94C to guide the tube 88T within the cavity 90A. The outlet 90 has an elongated downwardly extending port 96 extending downwardly from the receiving tube 90T, as shown in FIGS. 20A, 20B, and 21, for sealably connecting and supplying water to a hose of an appliance. The port 96 has a substantially cylindrical shape extending in an axial direction, and an inner conduit portion in fluid communication with the receiving tube 90T and terminating at the lower end, as shown in FIG. 26. An upper portion 96U of the port 96 may have a flared portion 96F flaring outward circumferentially and upwardly. An exterior surface of the cylindrical shape of the port 96 may have one or more circumferentially extending grooves 96G positioned axially along the length of the port 96 for receiving and retaining one or more O-rings. The grooves 96G may have a square cross-sectional shape for securely retaining the O-ring. A lower end portion 96L of the port 96 may include a tapered portion 97 narrowing or tapering inwardly toward the lower end of the port 96. A lower groove or annular recess 96R having a rounded concave cross-sectional shape is provided axially below the grooves 96G for receiving a C-shaped ring described below. The port 96 includes a center portion 96C between the grooves 96G and the recess 96R, which narrows or tapers downwardly toward the lower end portion 96L. In other embodiments, the exterior surface of the port 96 may include a threaded portion to facilitate direct connection of the hose of the appliance to the valve assembly 28. In one aspect, a port interface 98 may be provided for attaching to the hose of an appliance to the port 96, as shown in FIGS. 22 and 27. The port interface 98 may be positioned over the port 96 and attached thereto, allowing for attachment of the hose of the appliance to the valve assembly 28. The port interface 98 has an inner conduit 98C defined by downwardly extending sidewalls 98S extending axially therethrough from an upper end 98U to a lower end 98L of the port interface, a threaded attachment portion 98T for threadably attaching to the hose, and one or more rings 98R projecting circumferentially from an exterior surface of the sidewalls 98S at an axial position above the threaded portion 98T. The inner conduit 98C has a section with an inner contour sized and shaped to snuggly engage with the exterior surface shape of the port 96. Specifically, the inner conduit 98C includes an inwardly projecting annular portion 98A projecting radially inwardly from the inner surfaces of the sidewall 98S. The annular portion 98A may have an angled or tapered upwardly facing surface configured to engage with a downwardly facing surface of the tapered portion 97 of the port 96 when inserted into the inner conduit 98C. The bottom side of the annular portion 98A may have a curved or flat shaped lower portion 99 for retaining a retaining ring, as described below. A resiliently compressible C-shaped clip or retaining ring 101 (see FIG. 29) may be installed in the recess 96R to supportably attach the port interface 98 the port 96, as shown in FIG. 22. Different port interfaces 98 having different outer sidewall diameters may be provided to allow for hoses of different sizes to the valve assembly 28. Moreover, the port interface 98 helps to prevent over-torqueing and/or cracking of the outlet 90 of the valve assembly 28. To attach the port 96 to the port interface 98, the lower end of the port 96 is first inserted into the upper end of the inner conduit 98C of the port interface. The port interface 98 is moved axially upward over the exterior surface of the sidewalls 98S of the port 96 until the annular portion 98A of the port interface 98 is positioned snuggly against a downwardly facing surface of the center portion 96C. O-rings positioned in the grooves 96G axially above center portion 96C may compress against the inner surface of the sidewalls 98S to seal the inner conduit 98C against the outer diameter of the port 96 in a fluid-tight manner. The flared portion 96F of the port fits snuggly against an outwardly opening portion 98W at an upper end 98U, thereby preventing further downward movement of the port 96 within the port interface 98. The c-shaped ring 101 may then be inserted upwardly into the inner conduit 98C of the port interface 98 and installed within the recess 96R. The c-shaped retaining ring 101 installed within the recess 96R abuts the lower portion 99 of the annular portion 98A, preventing separation of the port interface 98 from the port 96. After the port interface 98 is attached to the port 96 in the manner described above, water supplied from a water source attached to the pipe 35 may flow through the valve assembly 28, out of the lower end of the port 96, and through a hose attached to the lower end 98L of the port interface 98. The valve assembly 28 may include other features, such as an arrestor assembly 102 at the upper connecting portion 88U of the manifold 88, and a push-pull liquid flow valve stem 104 at a front of the outlet 90. The flow valve stem 104 may be user-actuated to a first position (e.g., rearward “on” position) that allows fluid flow through the second manifold body 88, and a second position blocking fluid flow through the second manifold body 88 (e.g., forward “off” position). The arrestor assembly 102 is a dampening mechanism that absorbs kinetic energy of fluid flowing into the valve assembly 28 when the flow valve stem 104 is transitioned from the first position to the second position. Specifically, when the flow valve stem 104 is transitioned from the first position to the second position, a sudden pressure change of fluid flowing through the valve assembly may cause vibration in the valve assembly 28 or the pipes in the wall leading to the valve assembly due to overshoot in the system (i.e., “water hammer”). The arrestor assembly 102 has a sliding piston mechanism for absorbing the kinetic energy of the fluid during the transition between positions, thereby reducing or preventing vibration in the system. A cylindrical arrestor lower portion 102L of the arrestor assembly 102 threadably engages with the upper connecting portion 88U to allow fluid communication between the piston of the arrestor assembly 102 and the tube 88T of the manifold 88. According to one aspect, the valve assembly 28 may further include a metallic manifold support ferrule 106 configured to fit over an outer cylindrical portion of the upper connecting portion 88U of the manifold 88 to reduce hoop stresses on the manifold 88 and prevent over-torqueing of the arrestor lower portion 102L against the manifold 88, as shown in FIGS. 2, 3, and 4. The support ferrule 106 includes a cylindrical portion 106C extending in an axial direction, and an upper annular portion 106R extending radially inward from an upper end of the cylindrical portion 106C, as shown in FIGS. 30A and 30B. The cylindrical portion 106C has an outer cylindrical portion 106C with an inner diameter slightly larger (˜1.10″) than an outer diameter of the upper connecting portion 88U (˜1.06″). The plastic or polymer material (e.g., PVC) of the manifold 88 may experience significant hoop or cylinder stresses induced by fluctuations of water pressure flowing therethrough to and from the arrestor assembly 102, which may cause the manifold 88 to crack and/or fail over time. The metallic material (e.g., aluminum, copper, steel) of the support ferrule 106 has significantly higher tensile strength than the plastic or polymer material of the manifold 88. The cylindrical portion 106C absorbs at least some of the hoop or cylindrical stresses induced on the manifold 88 by pressure differentials of water flowing therethrough, thereby reducing cracks and/or failures in the manifold 88 and improving its longevity. When the support ferrule 106 is assembled with the manifold 88, the cylindrical portion 106C of the support ferrule 106 is positioned over the cylindrical outer body of the upper connecting portion 88U and the annular portion 106R is positioned against the upper surface of the manifold 88. The lower portion 102L of the arrestor assembly 102 may then be inserted through the annular portion 106R and threadably engaged with the upper connecting portion 88U of the manifold 88. The annular portion 106R has an inner diameter approximately equal to or slightly larger than the diameter of an uppermost opening of the inner tube 88T at the upper connecting portion 88U. The arrestor assembly 102 may abut an upper surface of the annular portion 106R when the lower portion 102L is threadably engaged with the upper connecting portion 88U of the manifold 88. In some embodiments, an O-ring may be positioned between and abutting the upper surface of the annular portion 106R and the arrestor assembly 102 to help create a fluid-tight seal for fluid communication between the manifold 88 and the arrestor assembly 102. Fixtures other than the valve assembly 28 may be installed in the utility box 10. In one embodiment, a drain assembly 108 is provided that may be installed in the utility box 10, as shown in FIG. 31. The drain assembly 108 includes a drain base 110 that may be installed in the second lower receptacle 52 of the box main housing 12 and a retaining member 112 for retaining a hose and/or funneling liquid into the drain base 110. The drain base 110 includes a hollow cylindrical base portion 114 defining a drain channel, a curved rear wall portion 116 extending upwardly from the base portion 114, and a pair of laterally offset attachment apertures 118 for removably attaching the retaining member 112 to the drain base 110, as shown in FIGS. 32, 33, and 34. A drain tube or hose, such as a condensation hose from an air conditioning unit, may be inserted through the first upper receptacle 68 or the second upper receptacle 74 and into the cavity portion 14, where the drain tube may be attached to the retaining member 112 or inserted into the drain base 110. Additionally, a drain tube from an appliance, such as a dishwasher or washing machine, may be inserted through the opening 18 of the box main housing 12 and into the drain base 110. The cylindrical base portion 114 is sized and shaped for insertion into the first knockout portion 58 of the second lower receptacle 52 after the second knockout portion 60 is removed, as described above. Specifically, a recess 120 extends upwardly from a bottom of the base portion 114 along a front side and a rear side thereof. The front and rear recesses 120 create laterally offset curved sidewalls 122 that may flex laterally or radially inward when the cylindrical base portion 114 is inserted into the second lower receptacle 52 to frictionally retain the drain base 110 therein. The cylindrical base portion 114 may have a tapered shape tapering radially inward from an upper end to a lower end thereof. The cylindrical base portion 114 has a diameter sufficient to allow for insertion of one or more drain tubes. A rim portion 124 may protrude radially outward from the outer circumference of the cylindrical base portion 114 and have an outer dimension or radius larger than the inner diameter of the first knockout portion 58. The rim portion 124 may abut with an upper surface of the lower wall 22 when the cylindrical base portion 114 is inserted into the second lower receptacle 52, preventing further insertion of the drain base 110 therein. One or more hoses or tubes may be inserted into the cylindrical base portion 114 for draining fluid into a pipe attached to a lower side of the second lower receptacle 52. Referring to FIG. 35, the retaining member 112 is configured to retain a hose or tube thereto and drain fluids downwardly into the drain base 110 to which the retaining member is attached. The retaining member 112 includes a bracket portion 126 having bracket sidewalls 126S extending forwardly from a bracket rear wall 126R, a drain conduit 128 having a major surface extending downwardly at an angle from the bracket portion 126, and a hose retention post 130 projecting upwardly from the drain conduit 128 for retaining a drain hose or tube to the retaining member 112. A pair of laterally offset attachment members 132 each project from a rearward facing side of the bracket rear wall 126R. The attachment members 132 may be inserted into corresponding ones of the attachment apertures 118 to removably attach the retaining member 112 to the rear wall portion 116 of the drain base 110. The vertical position of the retention post 130 may be adjusted by moving the retaining member vertically along the rear wall portion 116 according to the length of the hose or tube extending downwardly into the cavity portion 14 from the upper wall 24 of the box main housing 12. Specifically, the attachment apertures 118 may have an elongated shape extending downwardly along the rear wall portion 116 of the drain base 110. The position of the attachment members 132 within the elongated attachment apertures 118 may be adjusted to select the vertical position of the retaining member 112 along the rear wall portion 116 and thereby select the vertical position of the retention post 130. The attachment members 132 may each have a curved shape curving laterally outward toward left and right lateral sides of the retaining member 112. The outwardly curved attachment members 132 press against the lateral outward sides of the attachment apertures 118 when the attachment members 132 are inserted therein to frictionally retain the vertical position of the retaining member 112 within the rear wall portion 116. The end of a drain hose or tube may be positioned around and snuggly fitted over the retention post 130 to attach the drain tube to the retaining member 112. After the drain tube is attached to the retaining member 112 of the drain assembly 108, liquid draining from the drain hose flows rearward along and drips from the drain conduit 128 onto the rear wall portion 116 and/or into the base portion 114 to drain from a drain pipe attached to the second lower receptacle 52. The retention post 130 has a conical or tapered shape tapering inwardly and upwardly from the drain conduit 128 to allow for snug attachment of drain hoses having different inner diameters. The retention post 130 comprises a plurality of fin members 130F (e.g., four) extending radially outward from a central portion 130C of the retention post 130, which allows liquid to flow freely from the attached drain hose onto the drain conduit 128. The bracket sidewalls 126S may extend downwardly along laterally sides of the drain conduit 128 to help guide liquid flow onto the rear wall portion 116 and/or into the base portion 114 and prevent liquid from spilling into the cavity portion 14. The utility box 10 may include several features for securely attaching the box main housing 12 within a building wall. For example, a support receptacle 134 on a rear side of the box main housing 12 is provided for supportably attaching the box main housing 12 to a pipe or tube 136, as shown in FIGS. 8, 9, 10, 11, 36, and 37. The support receptacle 134 in the current embodiment is a rearwardly-opening channel or groove extending horizontally along the entire rear side of the box main housing 12. The cross-sectional shape of the support receptacle 134 channel or groove may include opposing parallel upper and lower receptacle walls 134U and 134L leading to a semi-circular front wall portion 134W centered about an axis 134A, as shown in FIGS. 8A and 9. The cross-sectional shape of the support receptacle 134 is sized to receive a pipe 136 having an outer diameter equal to or less than a standard diameter, such as 0.675″ (⅜″) or less. A protuberance 134P may protrude downwardly from the upper receptacle wall 134U and/or protrude upwardly from the lower receptacle wall 134L to help retain the pipe 136 inserted in the support receptacle 134. The pipe 136 to which the box main housing 12 attaches may be a pre-existing or previously installed pipe in the building wall. However, it is unlikely that a previously installed pipe in the building will be optimally positioned for attachment of the box main housing 12 thereto. A pair of mounting brackets 138 are therefore provided for optimally positioning and installing a length of pipe 136 between opposing wall studs 139 or other opposing surfaces of the building wall, as shown in FIGS. 36 and 37. After the mounting brackets 138 are attached to opposing studs with the length of pipe 136 extending therebetween, the box main housing 12 may be mounted in the wall studs by pressing the housing inward to insert the length of pipe 136 within the support receptacle 134. The mounting brackets 138 have a substantially flat bracket main body 140 having a first section 142 at a first end 144 of the bracket main body 140, a second section 146 extending from a side of the first section 142 opposite to the first end 144 and terminating at a second end 148, and a pipe retaining member 150 for mounting the pipe 136 to the mounting bracket 138, as shown in FIGS. 38, 39, and 40. The first section 142 is a rectangular portion extending in a width direction of the main body 140 and the second section 146 is a rectangular portion extending in a length direction of the bracket main body 140 from a central portion of the side of the first section 142. The first end 144 of the bracket main body 140 has a substantially flat edge with a width wider than a substantially flat edge of the second end 148 opposite to the first end 144. Holes 149 extend through the thickness of the bracket main body 140 for receiving screws or nails therein to supportably mount the bracket main body 140 to a stud. In the present embodiment, there is a pair of holes 149 positioned on lateral sides of the first section 142; however, the position and/or number of holes 149 may vary in other embodiments, such as an additional hole positioned along the second section 146 or at the second end 148. The retaining member 150 is sized and shaped to be inserted into the open end of the length of pipe 136. The length of pipe 136 extends between the pair of mounting brackets attached to the opposing faces of the two opposing wall studs 136 for supportably mounting the support receptacle 134 of the box main housing 12, as shown in FIG. 40. The retaining member 150 is a support projecting outward orthogonally from a first surface 140F of the flat bracket main body 140. The retaining member 150 in the present embodiment has a plurality of fin members 150F (e.g., four) extending radially outward from a central portion 150C. The cross-sectional area of the retaining member 150 is sized to snuggly fit a pipe 136 having a known inner diameter, such as 0.49 inches. The fin members 150F may each have a tapered or angular shape tapering or angled inwardly from the first surface 140F of the bracket main body 140 to a tip 150T of the retaining member 150. The tapered or angular shape may allow attachment of different sized pipes 136 to the mounting bracket 138. In some embodiments, the retaining member 150 may instead have a cylindrical or conical shape without fin members 150F. The mounting brackets 138 are configured to allow the user to position the pipe 136 such that the front 21 of the box main housing 12 will be flush with the forward edge of the wall stud 139. Specifically, affixing the mounting brackets 138 to the wall stud 139 in a certain orientation depending on the standard size of the wall stud will ensure that the front of the box main housing 12 will be flush with the forward edge of the wall stud 139, without measuring the position of the mounting brackets 138 or box main housing 12. According to construction industry standards, the dimensions of wall studs 139 dimensions are typically either approximately 1.5 inches thick by 3.5 inches wide (i.e., “2×4 size”) or approximately 1.5 inches thick by 5.5 inches wide (i.e., “2×6 size”). A central axis C of the retaining member 150 is offset along a length of the mounting bracket 138 at a first distance D1 from the first end 144 of the mounting bracket and at a second distance D2 from the second end 148 of the mounting bracket, as shown in FIGS. 39 and 40. In the current embodiment, for example, the first distance D1 is approximately 0.315 inches and the second distance D2 is approximately 2.315 inches (for a 0.63 inch outer diameter pipe). The mounting brackets 138 should be installed on the wall studs 139 in a first orientation if the wall stud 139 is of the 2×4 size and in a second orientation if the wall stud 139 is of the 2×6 size. In the first orientation, the first end 144 is positioned flush with the rearward side 139R of the 2×4 size wall studs 139 and the second and 148 oriented facing forward toward the forward side 139F of the wall studs 139 opposite to the rearward side 139R, as shown in FIGS. 36 and 37. In the second orientation, the second end 148 is positioned flush with the rearward side 139R of the 2×6 size wall studs 139 and the first end 144 is oriented facing forward toward the forward side of the wall studs 139 opposite to the rearward side 139R. In either case, the central axis C of the pipe 136 extending between the opposing wall studs 139 will be offset from the forward side of the wall studs 139 at approximately the same distance L. In this instance, the distance L is the distance between the front 21 of the box main housing 12 and the center axis 134A of the support receptacle 134 (see FIGS. 8A and 9). The distance L in the current embodiment may be approximately 3.2 inches, for example. The box main housing 12 may include flanges 151 projecting outwardly from lateral sides 26L, 26R of the box main housing, as shown in FIGS. 6, 7, and 11. A front surface of the flanges 151 may be flush with the front 21 of the main box 12 for abutting inwardly facing surfaces of the building walls. The flanges 151 may have screw or nail holes extending therethrough for affixing the box main housing to the building walls. In some embodiments, the flanges 151 may be spaced at the distance L from the center axis 134A of the support receptacle 134 and rearwardly offset from the front 21 of the box main housing 12. Accordingly, when the box main housing 12 is installed and mounted using the mounting brackets 138 described above, the front 21 of the box main housing 12 may project through a hole in the building wall with the flanges 151 positioned flush against the inwardly facing surfaces of the building walls. Mounting tabs 152 are disposed on box lateral sides 26L and 26R near or at the rear wall 20 for affixing the box main housing 12 to the wall studs 139, as shown in FIGS. 6, 11, and 36. The mounting tabs 152 are thin, flat portions having a mounting aperture 154 extending therethrough for receiving a fastener, such as a screw or a nail. The mounting apertures 154 in some embodiments may be elongated slots leading to a rearwardly opening mouth portion at a rear edge of the mounting tabs 152 for slideably receiving the shank of a fastener driven into the wall stud 139. If desired, the box main housing 12 may be affixed to the wall studs by driving a fastener through the mounting apertures 154 and into the wall studs 139, or by sliding the shank of a fastener into the rearwardly opening mouth portion of the elongated slot mounting apertures 154. The rearward edge of the mounting tabs 152 may be flush with or may not extend beyond the back surface of the rear wall 20, thereby reducing the amount of space required to affix the box main housing 12 to wall studs 139 within the building wall. A mounting recess 158 may be disposed in the rear wall 20 on an inwardly facing side of the mounting tab 152 for receiving the head and/or the shank of a fastener. The mounting tabs 152 are disposed at corners of the rear wall 20 in the present embodiment, although the mounting tabs may be disposed between corners on lateral sides of the rear wall 20 in other embodiments. The mounting recesses 156 may include a mouth portion opening upwardly along the upper wall 24 or downwardly along the lower wall 22 to facilitate insertion of a fastener therein. Pipe support brackets are provided for supportably attaching one pipe to another pipe. A pipe support bracket 160 includes a first collar 162 attachable to a first pipe 164, and a brace 166 for attaching a second pipe 168 to the first collar 162, as shown in FIG. 41. The first collar 162 has a C-shaped or semi-circular collar body 170 with opposing ends 170A and 170B spaced apart by an opening 172, as shown in FIG. 42. The first collar 162 has first attachment portions 174A and 174B projecting in parallel away from the ends 170A and 170B, then inwardly toward each other. Each first attachment portion has a latch element 176 protruding from an outwardly facing surface thereof. The collar body 170 is comprised of a resilient material, such as metal, PVC or polymer, that is flexible to space the ends 170A and 170B further apart for inserting the first pipe 164 into the collar body though the opening 172. The brace 166 has an elongated U-shape comprising a pair of brackets 178 extending in parallel with each other outwardly from a base portion 180, as shown in FIGS. 43 and 44. Each of the brackets 178 has a semi-circular or C-shaped pipe receptacle 182 having an opening 184 for receiving the second pipe 168 therein. Both of the pipe receptacles 182 are aligned with each other along a first direction (e.g., length) of the base portion 180 to supportably and firmly retain a length of the second pipe 168 in an orientation along the first direction. The base portion has a pair of collar receptacles 186 each sized and shaped for receiving a corresponding one of the first attachment portions 174A and 174B therein. The collar receptacles 186 may be apertures or recesses disposed on sidewall portions 180S of the base portion 180. A catch 188 located outwardly adjacent to each of the collar receptacles 184 is provided for retaining the attachment portions 174A and 1746 inserted in the adjacent collar receptacle. Specifically, the catch 188 is a resiliently flexible member configured to be flexed or bent outwardly by the latch element 176 when the first attachment portion 174A and 174B is inserted into the collar receptacle 186. The catch 188 is configured to then rebound inwardly back to its original position when the latch element 176 is inserted beyond an inward edge of the catch 188, thereby helping to block or prevent removal of the attachment portion 174A and 1746 from the collar receptacle 186 when inserted therein. In another embodiment, a second collar 190 having a different configuration than the first collar 162 is provided for attaching to the brace 166, as shown in FIGS. 45, 46, and 47. The second collar 190 is sized and shaped for attaching, in conjunction with the brace 166, to a pipe 194 having a smaller diameter than the pipe 164. The second collar 190 has a concave or U-shaped collar body 192 extending in an axial direction. The second collar body 192 has a curved or round rear wall 192R, and may have sidewall portions 192S extending in parallel with each other in a direction orthogonal to the axial direction. End portions 192A and 192B at ends of the second collar body 192 each flare outwardly away from each other. Attachment portions 196A and 1966 project in parallel from the end portions 192A and 1926, then inwardly toward each other. The attachment portions 196A and 1966 are spaced apart by an opening 198 for receiving the pipe 194 within the second collar body 192. The second collar 190 is attachable to the brace 166 by engaging the attachment portions 196A and 1966 with the openings 184 of the brace 166 in a manner substantially identical to the attachment portions 174A and 174B described above. The base portion 180 of the brace 166 attached to the second collar 192 opposes the rear wall 192R and may abut a side of the second pipe 194 to help prevent or reduce movement or vibration of the second pipe therein. FIGS. 51-93 illustrate additional embodiment of the utility box and its component parts similar to those shown in FIGS. 1-50 and described above. Embodiments of the present disclosure can be described in view of the following clauses: 1. A utility box for mounting at least in part within a wall for use with a fluid carrying supply pipe, the box comprising: a housing including a top wall, a bottom wall, a first side wall and a second side wall, a back wall and a front opening providing access into an interior of the housing defined by the top, bottom, first side, second side and back walls; a bottom wall aperture in the bottom wall sized for extending the pipe through the bottom wall aperture with the pipe terminating in a free end portion positioned within the interior of the housing at a location above the bottom wall; a valve attachable to the free end portion of the pipe, the junction of the valve and the pipe being within the interior of the housing above the bottom wall; and a first seal positioned to provide a fluid-tight seal between the bottom wall and the pipe to prevent fluid within the interior of the housing from passing out of the interior of the housing through the bottom wall aperture. 2. A utility box mounted at least in part within a wall, the box comprising: a housing including a top wall, a bottom wall, a first side wall and a second side wall, a back wall and a front opening providing access into an interior of the housing defined by the top, bottom, first side, second side and back walls; a bottom wall aperture in the bottom wall; a fluid carrying supply pipe extending through the bottom wall aperture and terminating in a free end portion within the interior of the housing at a location above the bottom wall; a valve attached to the free end portion of the pipe, the junction of the valve and the pipe being within the interior of the housing above the bottom wall; a first seal providing a fluid-tight seal between the bottom wall and the pipe to prevent fluid within the interior of the housing from passing out of the interior of the housing through the bottom wall aperture; and a second seal providing a fluid-tight seal between the free end portion of the pipe and the valve. 3. The utility box of clauses 1 or 2, further comprising: a manifold positioned to provide a fluid path between the free end portion of the pipe and the valve, the manifold having a lower connecting portion, an upper connecting portion and a side connecting portion positioned between the lower and upper connecting portions, with the lower connecting portion being connected in a fluid-tight arrangement to the free end portion of the pipe and one of the upper and side connecting portions being connected in a fluid-tight arrangement to the valve. 4. The utility box of any of clauses 1-3 for use with a fitting having a push-fit connector, wherein one of the upper and side connecting portions is a tube sized for having the push-fit connector pressed thereon. 5. The utility box of any of clauses 1-4, wherein the lower connecting portion comprises a push-fit connector sized for being pressed onto the free end portion of the pipe. 6. The utility box of any of clauses 1-5 for use with an arrestor assembly, wherein valve is connected to the side connecting portion and the upper connection portion is configured for connection to the arrestor assembly. 7. The utility box of any of clauses 1-6, further comprising: a manifold positioned to provide a fluid path between the free end portion of the pipe and the valve, the manifold having a lower connecting portion and an upper connecting portion, with the lower connecting portion being connected in a fluid-tight arrangement to the free end portion of the pipe and the upper connecting portions being connected in a fluid-tight arrangement to the valve. 8. A utility box for mounting at least in part within a wall for use with an in-wall drain pipe and a drain-fluid source conduit transporting a drain fluid for entry into the drain pipe, the box comprising: a housing including a top wall, a bottom wall, a first side wall and a second side wall, a back wall and a front opening providing access into an interior of the housing defined by the top, bottom, first side, second side and back walls; a bottom wall aperture in the bottom wall sized to be placed in fluid communication with the drain pipe; a drain including a drain base positioned within the bottom wall aperture and in fluid-tight communication with the drain pipe, and a retaining member for removable attachment to the drain base for retaining the drain-fluid source conduit in place relative to the drain base for communication of the drain fluid into the drain base. 9. A method of mounting a utility box at least in part within a wall, the method comprising: providing a housing including a top wall, a bottom wall, a first side wall and a second side wall, a back wall and a front opening providing access into an interior of the housing defined by the top, bottom, first side, second side and back walls, the bottom wall having a bottom wall aperture; extending a fluid carrying supply pipe through the bottom wall aperture and an positioning a free end portion of the pipe within the interior of the housing at a location above the bottom wall; attaching a valve to the free end portion of the pipe with the junction of the valve and the pipe being within the interior of the housing above the bottom wall; positioning a first seal between the bottom wall and the pipe to provide a fluid-tight seal prevent fluid therebetween to prevent fluid within the interior of the housing from passing out of the interior of the housing through the bottom wall aperture; and positioning a second seal between the free end portion of the pipe and the valve to provide a fluid-tight seal therebetween. The foregoing described embodiments depict different components contained within, or connected with, different other components. It is to be understood that such depicted architectures are merely exemplary, and that in fact many other architectures can be implemented which achieve the same functionality. In a conceptual sense, any arrangement of components to achieve the same functionality is effectively “associated” such that the desired functionality is achieved. Likewise, any two components so associated can also be viewed as being “operably connected,” or “operably coupled,” to each other to achieve the desired functionality. While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that, based upon the teachings herein, changes and modifications may be made without departing from this invention and its broader aspects and, therefore, the appended claims are to encompass within their scope all such changes and modifications as are within the true spirit and scope of this invention. Furthermore, it is to be understood that the invention is solely defined by the appended claims. It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.).
<SOH> BACKGROUND <EOH>Utility outlet boxes may be installed in building walls to provide access and/or disposal points for utilities, such as water. In one application, outlet boxes may be installed within building walls during the construction or renovation, and pipes and/or fixtures may be connected to the outlet boxes. Leaks that develop in the outlet box, such as in the connected pipes and/or fixtures connected thereto, may be difficult to discover because water drains out of the outlet box. Water leaking in the outlet box may drain or otherwise intrude into interior portions of the surrounding wall potentially causing mold or water damage. Additionally, even if the leak is discovered, removal of a portion of the wall or removal of the outlet box from the wall or may be required to repair or discover the offending leak. Accordingly, there is a need for an outlet box that prevents water leaks from intruding into the surrounding building walls, that increases detectability of leaks, and that improves ease of repair of leaky fixtures and/or pipes connected to the outlet box. Previously-implemented outlet boxes may also be difficult to mount to building walls and may not be securely attached when mounted thereto. For example, some currently existing methods for attachment of outlet boxes include securing the outlet boxes using straps. However, straps may require access to the rear of the outlet box during installation, and not provide adequate structural support for the outlet box alone. There is therefore the need for an apparatus that facilitates an easier and more secure means of mounting the outlet boxes within building walls. Previously-implemented outlet boxes are also configured for use in a single application, such as installing a water fixture for supplying water to an appliance. Installation of additional boxes may be necessary to provide additional drains, an air admittance valve, or additional water supply valves, for example. Therefore, currently existing outlet boxes do not provide sufficient versatility for installing different combinations of fixtures. Further, previously-implemented outlet boxes do not easily accommodate attachment of differently sized pipes or different fixtures, and do not allow for pipes and/or fixtures to be connected to the outlet boxes at different positions. For example, a pipe above an outlet box may need to be routed to the underside of the utility box because the top of the utility box does not include an appropriate receptacle for receiving the pipe. Even when the previously-implemented outlet box installed in the building wall has an appropriately located receptacle for receiving a pipe (e.g., at the bottom), the receptacle may not be appropriately sized for connecting the pipe. The previously-implemented may not allow for installation of fixtures having differently sized attachment portions.
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 illustrates a perspective view of a utility box according to a first embodiment. FIG. 2 illustrates a first exploded view of the utility box of FIG. 1 . FIG. 3 illustrates a second exploded view of the utility box of FIG. 1 . FIG. 4 illustrates a third exploded view of the utility box of FIG. 1 . FIG. 5 illustrates a front view of a box main housing of the utility box of FIG. 1 . FIG. 6 illustrates a top plan view of the box main housing of FIG. 5 . FIG. 7 illustrates a bottom plan view of the box main housing of FIG. 5 . FIG. 8A illustrates an enlarged cross-sectional view substantially along line 1 A- 1 A of the box main housing of FIG. 5 . FIG. 8B illustrates an enlarged cross-sectional view substantially along line 1 B- 1 B of the box main housing of FIG. 5 . FIG. 9 illustrates an enlarged cross-sectional view substantially along line 1 A- 1 A of a support receptacle of the box main housing of FIG. 5 . FIG. 10 illustrates a right side view of the box main housing of FIG. 5 . FIG. 11 illustrates a rear view of the box main housing of FIG. 5 . FIG. 12 illustrates an enlarged cross-sectional view substantially along line 1 A- 1 A of a second upper receptacle of the box main housing of FIG. 5 . FIG. 13A illustrates a bottom perspective view of a box main housing according to a second embodiment. FIG. 13B illustrates a front view of a box main housing according to a third embodiment. FIG. 13C illustrates a bottom perspective view of the box main housing of FIG. 13B . FIG. 14A illustrates a bottom perspective view of the box main housing of FIG. 5 positioned against an interior side of a building wall and having a pipe inserted into a second lower receptacle thereof. FIG. 14B illustrates a cross-sectional view of a lower wall of the box main housing of FIG. 14A taken along line 1 - 1 of FIG. 5 . FIG. 15 illustrates a front perspective view of the lower wall of the box main housing of FIG. 5 . FIG. 16A illustrates a front view of a first manifold body of a valve assembly. FIG. 16B illustrates a left side view of the first manifold body of FIG. 16A . FIG. 17 illustrates a cross-sectional view of the first manifold body of FIG. 16A substantially along line 2 - 2 . FIG. 18 illustrates a bottom view of a manifold spacer. FIG. 19 illustrates a cross-sectional view of the manifold spacer of FIG. 18 substantially along line 3 - 3 . FIG. 20A illustrates a front view of a second manifold body of the valve assembly. FIG. 20B illustrates a left side view of the second manifold body of FIG. 20A . FIG. 21 illustrates a cross-sectional view of the second manifold body of FIG. 20A substantially along line 4 - 4 . FIG. 22 illustrates a cross-sectional view of a liquid flow switch and a bushing assembly installed in the second manifold body of FIG. 20A substantially along line 4 - 4 , and having a port interface and a C-clip attached to the second manifold body. FIG. 23 illustrates a bottom plan view of an end bushing of the bushing assembly of FIG. 22 . FIG. 24 illustrates a side view of the end bushing of FIG. 23 . FIG. 25 illustrates a cross-sectional view of the end bushing of FIG. 23 along the line 5 - 5 . FIG. 26 illustrates a side view of a port of the second manifold body of FIG. 20A . FIG. 27 illustrates a side view of the port interface of FIG. 22 . FIG. 28 illustrates a cross-sectional view of the port interface of FIG. 27 . FIG. 29 illustrates a plan view of the C-clip of FIG. 22 . FIG. 30A illustrates a top plan view of a manifold support ferrule. FIG. 30B illustrates a cross-sectional view of the manifold support ferrule of FIG. 30B along the line 6 - 6 . FIG. 31 illustrates the utility box of FIG. 1 equipped with a pair of valve assemblies and a drain assembly. FIG. 32 illustrates a front view of a drain base of the drain assembly of FIG. 31 . FIG. 33 illustrates a right side view of the drain base. FIG. 34 illustrates a cross-sectional view of the drain base of FIG. 32 substantially along line 7 - 7 . FIG. 35 illustrates a top perspective view of a retaining member of the drain assembly of FIG. 31 . FIG. 36 illustrates a top rear perspective view of a mounting bracket and a pipe supportably attaching the utility box of FIG. 1 to wall studs and an adjacent second utility box. FIG. 37 illustrates a top rear perspective view of the mounting bracket and the pipe of FIG. 36 supportably attaching a utility box according to a second embodiment to wall studs. FIG. 38 illustrates a perspective view of the mounting bracket of FIG. 36 . FIG. 39 illustrates a front view of the mounting bracket of FIG. 36 . FIG. 40 illustrates a side view of the mounting bracket of FIG. 36 . FIG. 41 illustrates a perspective view of a pipe support bracket attached to a pipe according to a first embodiment. FIG. 42 illustrates a perspective view of a collar of the pipe support bracket of FIG. 41 . FIG. 43 illustrates a rear perspective view of a brace of the pipe support bracket of FIG. 41 . FIG. 44 illustrates a front perspective view of a brace of the pipe support bracket of FIG. 41 . FIG. 45 illustrates a perspective view of a second collar of a pipe support bracket according to a second embodiment of the pipe support bracket. FIG. 46 illustrates a cross-sectional view of the pipe support bracket of FIG. 45 . FIG. 47 illustrates a perspective view of the pipe support bracket of FIG. 45 . FIG. 48 illustrates a front view of a utility box having a plurality of valve assemblies installed therein, and provided with partially transparent and partial sectional views of some of the valve assemblies. FIG. 49 illustrates a cross-sectional view of the utility box of FIG. 48 taken substantially along line 8 - 8 . FIG. 50 illustrates an enlarged cross-sectional view of a water valve assembly installed in the utility box of FIG. 48 taken substantially along line 8 - 8 . FIGS. 51-93 illustrate additional embodiment of the utility box and its component parts similar to those shown in FIGS. 1-50 . detailed-description description="Detailed Description" end="lead"?
E03C1021
20170929
20180405
97595.0
E03C102
0
MURPHY, KEVIN F
OUTLET BOX
SMALL
0
ACCEPTED
E03C
2,017
15,722,239
PENDING
INFORMATION PROCESSING APPARATUS CAPABLE OF ACHIEVING IMPROVED USABILITY, METHOD OF CONTROLLING INFORMATION PROCESSING APPARATUS, NON-TRANSITORY STORAGE MEDIUM ENCODED WITH PROGRAM READABLE BY COMPUTER OF INFORMATION PROCESSING APPARATUS, AND INFORMATION PROCESSING SYSTEM
An information processing system includes an operation apparatus and a main body apparatus which is capable of communicating with the operation apparatus. The operation apparatus includes a first transceiver which transmits operation data to the main body apparatus. The main body apparatus includes a memory in which an operation scheme of the operation apparatus is registered, a second transceiver which receives the operation data, and a controller. The controller registers the operation scheme of the operation apparatus in the memory as a first operation scheme when the operation data received by the second transceiver indicates a first operation and registers the operation scheme of the operation apparatus in the memory as a second operation scheme when the operation data received by the second transceiver indicates a second operation, and performs processing based on the operation scheme registered in the memory onto the operation data received by the second transceiver.
1. An information processing system comprising: an operation apparatus; and a main body apparatus which is capable of communicating with the operation apparatus, the operation apparatus including a first transceiver which transmits operation data representing an operation by a user to the main body apparatus, the main body apparatus including a memory in which an operation scheme of the operation apparatus is registered, a second transceiver which receives the operation data transmitted from the first transceiver, and a controller, the controller registering the operation scheme of the operation apparatus in the memory as a first operation scheme when the operation data received by the second transceiver indicates a first operation and registering the operation scheme of the operation apparatus in the memory as a second operation scheme when the operation data received by the second transceiver indicates a second operation, and performing processing based on the operation scheme registered in the memory onto the operation data received by the second transceiver. 2. The information processing system according to claim 1, wherein the operation apparatus further includes a first operation portion and a second operation portion, and the controller registers the operation scheme of the operation apparatus in the memory as the first operation scheme when the operation data received by the second transceiver indicates the first operation of the first operation portion and registers the operation scheme of the operation apparatus in the memory as the second operation scheme when the operation data received by the second transceiver indicates the second operation of the second operation portion. 3. The information processing system according to claim 2, wherein the first operation portion and the second operation portion are disposed on different surfaces of a housing of the operation apparatus, respectively. 4. The information processing system according to claim 2, wherein the operation apparatus further includes a third operation portion, and the controller performs processing on operation data of the third operation portion received by the second transceiver differently between the first operation scheme and the second operation scheme registered in the memory. 5. The information processing system according to claim 4, wherein the controller performs prescribed processing on the operation data of the third operation portion received by the second transceiver when the first operation scheme is registered in the memory, and converts the operation data of the third operation portion received by the second transceiver into converted operation data when the second operation scheme is registered in the memory and performs the prescribed processing based on the converted operation data. 6. The information processing system according to claim 5, wherein the operation data of the third operation portion includes direction data representing a direction of input, and the controller performs the prescribed processing on the direction data of the third operation portion received by the second transceiver when the first operation scheme is registered in the memory, and converts the direction data of the third operation portion received by the second transceiver into converted direction data different in direction of input from the direction data when the second operation scheme is registered in the memory and performs the prescribed processing based on the converted direction data. 7. The information processing system according to claim 2, wherein the first and second operation portions are disposed on identical sides of prescribed operation surfaces of a housing of the operation apparatus, respectively when the user performs an operation in any of the first and second operation schemes. 8. The information processing system according to claim 1, wherein a plurality of operation apparatuses are provided, and when a plurality of pieces of the operation data received by the second transceiver indicate the first operation, the controller sets a plurality of operation apparatuses as one set and registers an operation scheme of the set of the operation apparatuses in the memory as the first operation scheme. 9. The information processing system according to claim 8, wherein two operation apparatuses of the plurality of operation apparatuses are set as one set, and the two operation apparatuses constituting the set are designated in advance. 10. The information processing system according to claim 8, wherein the controller registers the operation scheme of the set of the operation apparatuses in the memory as the first operation scheme when the plurality of pieces of operation data received by the second transceiver simultaneously indicate the first operation. 11. An information processing apparatus which is capable of communicating with an operation apparatus comprising: a memory in which an operation scheme of the operation apparatus is registered; a transceiver which receives operation data transmitted from the operation apparatus; and a controller, the controller registering the operation scheme of the operation apparatus in the memory as a first operation scheme when the operation data received by the transceiver indicates a first operation and registering the operation scheme of the operation apparatus in the memory as a second operation scheme when the operation data received by the transceiver indicates a second operation, and performing processing based on the operation scheme registered in the memory onto the operation data received by the transceiver. 12. A method of controlling an information processing apparatus which is capable of communicating with an operation apparatus, the method comprising: receiving operation data transmitted from the operation apparatus; registering an operation scheme of the operation apparatus in a storage unit as a first operation scheme when the received operation data indicates a first operation; registering the operation scheme of the operation apparatus in the storage unit as a second operation scheme when the received operation data indicates a second operation; and performing processing based on the operation scheme registered in the storage unit onto the received operation data. 13. An information processing system comprising: a first operation apparatus; a second operation apparatus; and a main body apparatus which is capable of communicating with the first operation apparatus and the second operation apparatus, the first operation apparatus and the second operation apparatus each including a first transceiver which transmits operation data representing an operation by a user to the main body apparatus, the main body apparatus including a memory in which operation schemes of the first operation apparatus and the second operation apparatus are registered, a second transceiver which receives the operation data transmitted from the first transceiver, and a controller, the controller setting, when a plurality of pieces of operation data received from the first operation apparatus and the second operation apparatus by the second transceiver indicate a first operation, the first operation apparatus and the second operation apparatus as one set and registering an operation scheme of the set in the memory as a first operation scheme, and registering, when the operation data received from any one of the first operation apparatus and the second operation apparatus by the second transceiver indicates a second operation, the operation scheme of any of the first operation apparatus and the second operation apparatus in the memory as a second operation scheme. 14. The information processing system according to claim 13, wherein each of the first operation apparatus and the second operation apparatus further includes a first operation portion, a second operation portion, and a third operation portion, and the controller registers the operation scheme in the memory as the first operation scheme when the plurality of pieces of operation data received from the first operation apparatus and the second operation apparatus by the second transceiver indicate the first operation of the first operation portion and registers the operation scheme in the memory as the second operation scheme when the operation data received from any one of the first operation apparatus and the second operation apparatus by the second transceiver indicates the second operation of the second operation portion and the third operation portion.
Information Processing Apparatus Capable of Achieving Improved Usability, Method of Controlling Information Processing Apparatus, Non-Transitory Storage Medium Encoded With Program Readable by Computer of Information Processing Apparatus, and Information Processing System This nonprovisional application is based on Japanese Patent Application No. 2016-217073 filed with the Japan Patent Office on Nov. 7, 2016, the entire contents of which are hereby incorporated by reference. FIELD The present disclosure relates to an information processing apparatus, a method of controlling an information processing apparatus, a non-transitory storage medium encoded with a program readable by a computer of an information processing apparatus, and an information processing system, and particularly to operation processing by an information processing apparatus. BACKGROUND AND SUMMARY In a game system representing one example of a conventional information processing system, when a game controller representing an operation apparatus is registered in correspondence with a player number, the game controller may be registered by successively performing the same prescribed operation onto each game controller. Selection from among a plurality of operation schemes can be made for an operation apparatus in some cases. In such a case, though an operation scheme should also be registered, successive registration complicates a procedure for registration and there is a room for improvement in usability. The present disclosure is provided to solve the above-described problems and an object thereof is to provide an information processing system which can achieve improved usability, an information processing apparatus, a method of controlling an information processing apparatus, and an information processing program. An information processing system according to one aspect includes an operation apparatus and a main body apparatus which is capable of communicating with the operation apparatus. The operation apparatus includes a first transceiver which transmits operation data representing an operation by a user to the main body apparatus. The main body apparatus includes a memory in which an operation scheme of the operation apparatus is registered, a second transceiver which receives the operation data transmitted from the first transceiver, and a controller. The controller registers the operation scheme of the operation apparatus in the memory as a first operation scheme when the operation data received by the second transceiver indicates a first operation and registers the operation scheme of the operation apparatus in the memory as a second operation scheme when the operation data received by the second transceiver indicates a second operation, and performs processing based on the operation scheme registered in the memory onto the operation data received by the second transceiver. The controller can register the operation scheme of the operation apparatus in the memory as the first operation scheme or the second operation scheme based on the operation data transmitted from the operation apparatus. Therefore, processing for registering the operation scheme of the operation apparatus can readily be performed and usability can be improved. In the exemplary embodiment, the operation apparatus further includes a first operation portion and a second operation portion. The controller may register the operation scheme of the operation apparatus in the memory as the first operation scheme when the operation data received by the second transceiver indicates the first operation of the first operation portion and register the operation scheme of the operation apparatus in the memory as the second operation scheme when the operation data received by the second transceiver indicates the second operation of the second operation portion. The controller can register the operation scheme of the operation apparatus in the memory as the first operation scheme based on the operation data transmitted from the first operation portion and register the operation scheme of the operation apparatus in the memory as the second operation scheme based on the operation data transmitted from the second operation portion. Therefore, since the operation scheme of the operation apparatus is registered based on the operation data from different operation portions, registration processing can readily be performed and usability can be improved. In the exemplary embodiment, the first operation portion and the second operation portion may be disposed on different surfaces of a housing of the operation apparatus, respectively. Since the first operation portion and the second operation portion are provided on different surfaces of the housing, respectively, registration processing can readily be performed without confusion and usability can be improved. In the exemplary embodiment, the operation apparatus further includes a third operation portion. The controller may perform processing on operation data of the third operation portion received by the second transceiver differently between the first operation scheme and the second operation scheme registered in the memory. The controller can perform appropriate processing in accordance with the operation scheme by performing processing on the operation data of the third operation portion differently between the first operation scheme and the second operation scheme. In the exemplary embodiment, the controller may perform prescribed processing on the operation data of the third operation portion received by the second transceiver when the first operation scheme is registered in the memory, and convert the operation data of the third operation portion received by the second transceiver into converted operation data when the second operation scheme is registered in the memory and perform the prescribed processing based on the converted operation data. When the second operation scheme is registered, the controller converts the operation data into converted operation data and performs prescribed processing based on the converted operation data. Therefore, even when the second operation scheme is registered, it is not necessary to change prescribed processing in accordance with the operation scheme by conversion to converted operation data corresponding to the operation data under the first operation scheme and processing can readily be realized. In the exemplary embodiment, the operation data of the third operation portion includes direction data representing a direction of input. The controller may perform the prescribed processing on the direction data of the third operation portion received by the second transceiver when the first operation scheme is registered in the memory and convert the direction data of the third operation portion received by the second transceiver into converted direction data different in direction of input from the direction data when the second operation scheme is registered in the memory and perform the prescribed processing based on the converted direction data. In the exemplary embodiment, the first and second operation portions may be disposed on identical sides of prescribed operation surfaces of a housing of the operation apparatus, respectively when the user performs an operation under any of the first and second operation schemes. The first and second operation portions are provided on the side of the prescribed operation surface of the housing of the operation apparatus when the user performs an operation under each of the first operation scheme and the second operation scheme so that an intuitive operation in selection of the operation scheme can be performed and usability can be improved. In the exemplary embodiment, a plurality of operation apparatuses are provided, and when a plurality of pieces of the operation data received by the second transceiver indicate the first operation, the controller may set a plurality of operation apparatuses as one set and register an operation scheme of the set of the operation apparatuses in the memory as the first operation scheme. Since the controller can make registration of one set of operation apparatuses in the memory based on a plurality of pieces of operation data transmitted from a plurality of operation apparatuses, registration processing can readily be performed and usability can be improved. In the exemplary embodiment, two operation apparatuses of the plurality of operation apparatuses are set as one set. The two operation apparatuses constituting the set may be designated in advance. By designating in advance two operation apparatuses to constitute a set, management of the operation apparatuses is facilitated and processing can be accelerated. In the exemplary embodiment, the controller registers the operation scheme of the set of the operation apparatuses in the memory as the first operation scheme when the plurality of pieces of operation data received by the second transceiver simultaneously indicate the first operation. Since the controller can make registration of one set of operation apparatuses in the memory when a plurality of pieces of operation data transmitted from a plurality of operation apparatuses simultaneously indicate the first operation, one set of operation apparatuses can easily be distinguished and registration processing can readily be performed. An information processing apparatus which is capable of communicating with an operation apparatus according to one aspect includes a memory in which an operation scheme of the operation apparatus is registered, a transceiver which receives operation data transmitted from the operation apparatus, and a controller. The controller registers the operation scheme of the operation apparatus in the memory as a first operation scheme when the operation data received by the transceiver indicates a first operation and registers the operation scheme of the operation apparatus in the memory as a second operation scheme when the operation data received by the transceiver indicates a second operation, and performs processing based on the operation scheme registered in the memory onto the operation data received by the transceiver. The controller can register the operation scheme of the operation apparatus in the memory as the first operation scheme or the second operation scheme based on the operation data transmitted from the operation apparatus. Therefore, processing for registering the operation scheme of the operation apparatus can readily be performed and usability can be improved. A method of controlling an information processing apparatus which is capable of communicating with an operation apparatus according to one aspect includes receiving operation data transmitted from the operation apparatus, registering an operation scheme of the operation apparatus in a storage unit as a first operation scheme when the received operation data indicates a first operation, registering the operation scheme of the operation apparatus in the storage unit as a second operation scheme when the received operation data indicates a second operation, and performing processing based on the operation scheme registered in the storage unit onto the received operation data. In the registering an operation scheme, the operation scheme of the operation apparatus can be registered in the storage unit as the first operation scheme or the second operation scheme based on the operation data transmitted from the operation apparatus. Therefore, processing for registering the operation scheme of the operation apparatus can readily be performed and usability can be improved. A non-transitory storage medium encoded with a program readable by a computer of an information processing apparatus which is capable of communicating with an operation apparatus according to one aspect is provided. The program causes the computer to perform receiving operation data transmitted from the operation apparatus, registering an operation scheme of the operation apparatus in a memory as a first operation scheme when the received operation data indicates a first operation, registering the operation scheme of the operation apparatus in the memory as a second operation scheme when the received operation data indicates a second operation, and performing processing based on the operation scheme registered in the memory onto the received operation data. The computer can register the operation scheme of the operation apparatus in the memory as the first operation scheme or the second operation scheme based on the operation data transmitted from the operation apparatus. Therefore, processing for registering the operation scheme of the operation apparatus can readily be performed and usability can be improved. An information processing system according to one aspect includes a first operation apparatus, a second operation apparatus, and a main body apparatus which is capable of communicating with the first operation apparatus and the second operation apparatus. The first operation apparatus and the second operation apparatus each include a first transceiver which transmits operation data representing an operation by a user to the main body apparatus. The main body apparatus includes a memory in which operation schemes of the first operation apparatus and the second operation apparatus are registered, a second transceiver which receives the operation data transmitted from the first transceiver, and a controller. The controller sets, when a plurality of pieces of operation data received from the first operation apparatus and the second operation apparatus by the second transceiver indicate a first operation, the first operation apparatus and the second operation apparatus as one set and registers an operation scheme of the set in the memory as a first operation scheme, and registers, when the operation data received from any one of the first operation apparatus and the second operation apparatus by the second transceiver indicates a second operation, the operation scheme of any of the first operation apparatus and the second operation apparatus in the memory as a second operation scheme. The controller can register the operation scheme of the operation apparatus in the memory as the first operation scheme or the second operation scheme based on the operation data transmitted from the operation apparatus. Therefore, processing for registering the operation scheme of the operation apparatus can readily be performed and usability can be improved. In the exemplary embodiment, each of the first operation apparatus and the second operation apparatus further includes a first operation portion, a second operation portion, and a third operation portion. The controller registers the operation scheme in the memory as the first operation scheme when the plurality of pieces of operation data received from the first operation apparatus and the second operation apparatus by the second transceiver indicate the first operation of the first operation portion and registers the operation scheme in the memory as the second operation scheme when the operation data received from any one of the first operation apparatus and the second operation apparatus by the second transceiver indicates the second operation of the second operation portion and the third operation portion. The controller can register the operation scheme of the operation apparatus in the memory as the first operation scheme or the second operation scheme based on the operation data transmitted from the operation apparatus. Therefore, processing for registering the operation scheme of the operation apparatus can readily be performed and usability can be improved. The foregoing and other objects, features, aspects and advantages of the exemplary embodiments will become more apparent from the following detailed description of the exemplary embodiments when taken in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic diagram showing appearance of a game device 1 according to the present embodiment. FIG. 2 is a schematic diagram showing appearance of another manner of game device 1 according to the present embodiment. FIG. 3 is a diagram of a main body apparatus 2 according to the present embodiment when viewed from six sides. FIG. 4 is a diagram of a left controller 3 according to the present embodiment when viewed from six sides. FIG. 5 is a diagram of a right controller 4 according to the present embodiment when viewed from six sides. FIG. 6 is a schematic diagram showing appearance when game device 1 according to the present embodiment is used together with a cradle. FIG. 7 is a block diagram showing an internal configuration of main body apparatus 2 according to the present embodiment. FIG. 8 is a block diagram showing an internal configuration of left controller 3 and right controller 4 according to the present embodiment. FIG. 9 is a diagram showing one example of a manner of use of game device 1 with left controller 3 and right controller 4 being attached to main body apparatus 2. FIG. 10 is a diagram showing one example of a manner of use of game device 1 with left controller 3 and right controller 4 being detached from main body apparatus 2. FIG. 11 is a diagram showing one example of a manner of use of game device 1 with two users each holding one controller in a detached state. FIG. 12 is a diagram showing one example of a manner of use of game device 1 with main body apparatus 2 being attached to a cradle 5. FIGS. 13A and 13B are diagrams showing examples of a manner of use of three or more controllers. FIG. 14 is a diagram showing appearance of an accessory controller 401 based on an embodiment. FIGS. 15A and 15B are diagrams showing examples illustrating a controller registration screen displayed by game device 1 based on the embodiment. FIG. 16 is a diagram illustrating one example of registration information based on the embodiment. FIG. 17 is a diagram illustrating a functional block configuration of main body apparatus 2 based on the embodiment. FIG. 18 is a flowchart illustrating one example of a flow of processing for registration of a controller performed in main body apparatus 2 based on the embodiment. FIGS. 19A to 19C are diagrams illustrating operation data transmitted from the controller based on the embodiment to main body apparatus 2. FIG. 20 is a diagram showing one example of game processing performed by game device 1 based on the embodiment. FIG. 21 is a flowchart illustrating a processing procedure involved with game processing based on the embodiment. DETAILED DESCRIPTION OF NON-LIMITING EXAMPLE EMBODIMENTS This embodiment will be described in detail with reference to the drawings. The same or corresponding elements in the drawings have the same reference characters allotted and description thereof will not be repeated. [A. Information Processing System] An apparatus configuration relating to an information processing system according to the present embodiment will be described. The information processing system according to the present embodiment is configured at least with an information processing apparatus described below. For example, an information processing apparatus may be a portable (also referred to as mobile) device such as a portable game device, a portable telephone, or a smartphone, a stationary apparatus such as a personal computer or a home game console, or a large apparatus such as an arcade game machine. In the present example, a game device representing one example of an information processing apparatus will be described by way of example. Though a game controller provided for a game device will be described in the present example by way of example of an operation apparatus, limitation in particular to a game controller is not intended and any operation apparatus may be applicable so long as it functions as an input device capable of transmitting operation data to an information processing apparatus. (a1: Overall Configuration of Game Device) FIG. 1 is a schematic diagram showing appearance of a game device 1 according to the present embodiment. As shown in FIG. 1, game device 1 includes a main body apparatus 2, a left controller 3, and a right controller 4. Main body apparatus 2 includes a display 12 representing one example of a display portion and performs various types of processing including game processing in game device 1. FIG. 2 is a schematic diagram showing appearance of another manner of game device 1 according to the present embodiment. As shown in FIG. 2, left controller 3 and right controller 4 may be constructed as being detachable from main body apparatus 2. Left controller 3 and right controller 4 may integrally be constructed or left controller 3 and right controller 4 may be constructed as separate apparatuses. Thus, left controller 3 and right controller 4 corresponding to an operation portion may be constructed separately from main body apparatus 2. Left controller 3 can be attached to a left side (a side of a positive direction of an x axis shown in FIG. 1) of main body apparatus 2. Right controller 4 can be attached to a right side (a side of a negative direction of the x axis shown in FIG. 1) of main body apparatus 2. In the description below, left controller 3 and right controller 4 may collectively be referred to as a “controller”. A more specific configuration example of main body apparatus 2, left controller 3, and right controller 4 will be described below. (a2: Structure of Main Body Apparatus) FIG. 3 is a diagram of main body apparatus 2 according to the present embodiment when viewed from six sides. Referring to FIG. 3, main body apparatus 2 has a housing 11 substantially in a form of a plate. A main surface of housing 11 (that is, a front surface or a surface where display 12 is provided) is substantially in a rectangular shape. In the description below, housing 11 is in a horizontally long shape and a longitudinal direction of the main surface (that is, the direction of the x axis shown in FIG. 1) is referred to as a lateral direction (or a left-right direction) and a direction of a short side of the main surface (that is, a direction of a y axis shown in FIG. 1) is referred to as a vertical direction (or an up-down direction). A direction perpendicular to the main surface of housing 11 (that is, a direction of a z axis shown in FIG. 1) is referred to as a direction of depth (or a front-rear direction). Main body apparatus 2 can be used with its main surface being laterally oriented or with its surface being vertically oriented when a user holds the main body apparatus. Therefore, denotation as the lateral direction and the vertical direction is given for the sake of convenience of description. A shape and a size of housing 11 can arbitrarily be designed. For example, in another embodiment, a protrusion portion or a grip portion for facilitating holding by a user may be added to housing 11. (1) Member Provided on Main Surface of Housing 11 As shown in FIGS. 1 to 3, display 12 is provided on the main surface of housing 11 of main body apparatus 2. Display 12 shows an image obtained or generated by main body apparatus 2 (which may be a still image or moving images). When game processing is performed, display 12 shows a virtual space and an object in the virtual space. Though display 12 is typically implemented by a liquid crystal display (LCD), a display apparatus of any type can be adopted. A touch panel 13 is provided on a screen of display 12. Typically, a device of a type accepting a multi-touch input (for example, a capacitance type) is adopted as touch panel 13. For example, a device of any type such as a device of a type accepting a single-touch input (for example, a resistive film type) can be adopted as touch panel 13. Speaker holes 11a and 11b are provided in the main surface of housing 11 of main body apparatus 2 and sound generated from a speaker (a speaker 88 shown in FIG. 7) arranged in housing 11 is output through speaker holes 11a and 11b. Two speakers are provided in main body apparatus 2 and speaker holes 11a and 11b are provided in correspondence with respective positions of a left speaker and a right speaker. Speaker hole 11a is provided on a left side of display 12 in correspondence with the left speaker and speaker hole 11b is provided on a right side of display 12 in correspondence with the right speaker. A position, a shape, and the number of speaker holes 11a and 11b can arbitrarily be designed. For example, in another embodiment, speaker holes 11a and 11b may be provided in a side surface or a rear surface of housing 11. (2) Member Provided on Left Side Surface of Housing 11 A left rail member 15 for removably attaching left controller 3 to main body apparatus 2 is provided in a left side surface of housing 11. Left rail member 15 extends along the up-down direction in the left side surface of housing 11. Left rail member 15 is in a shape allowing engagement thereof with a slider (a slider 40 shown in FIG. 4) for left controller 3. A slide mechanism is formed by left rail member 15 and slider 40. With such a slide mechanism, left controller 3 can slidably and removably be attached to main body apparatus 2. A left terminal 17 is provided in the left side surface of housing 11. Left terminal 17 is a terminal for wired communication between main body apparatus 2 and left controller 3. Left terminal 17 is provided at a position where it comes in contact with a terminal (a terminal 42 shown in FIG. 4) of left controller 3 when left controller 3 is attached to main body apparatus 2. Left terminal 17 should be arranged at any position where the left terminal of main body apparatus 2 and the terminal of left controller 3 are in contact with each other while left controller 3 is attached to main body apparatus 2. By way of example, as shown in FIG. 3, left terminal 17 is provided around a lower end portion of left rail member 15. (3) Member Provided in Right Side Surface of Housing 11 As shown in FIG. 3, a feature similar to the feature provided in the left side surface is provided in a right side surface of housing 11. A right rail member 19 for removably attaching right controller 4 to main body apparatus 2 is provided in the right side surface of housing 11. Right rail member 19 extends along the up-down direction in the right side surface of housing 11. Right rail member 19 is in a shape allowing engagement thereof with a slider (a slider 62 shown in FIG. 5) for right controller 4. A slide mechanism is formed by right rail member 19 and slider 62. With such a slide mechanism, right controller 4 can slidably and removably be attached to main body apparatus 2. Right rail member 19 is in a shape similar to left rail member 15. Right rail member 19 is in a grooved shape similar in cross-sectional shape to left rail member 15. Right rail member 19 does not have to be exactly the same in shape as left rail member 15. For example, another embodiment may be constructed such that slider 62 for right controller 4 cannot be engaged with left rail member 15 and/or slider 40 for left controller 3 cannot be engaged with right rail member 19 by making a size and/or a shape of the groove different between left rail member 15 and right rail member 19. A right terminal 21 is provided in the right side surface of housing 11. Right terminal 21 is a terminal for wired communication between main body apparatus 2 and right controller 4. Right terminal 21 is provided at a position where it comes in contact with a terminal (a terminal 64 shown in FIG. 5) of right controller 4 when right controller 4 is attached to main body apparatus 2. Right terminal 21 should be arranged at any position where the right terminal of main body apparatus 2 and the terminal of right controller 4 are in contact with each other while right controller 4 is attached to main body apparatus 2. By way of example, as shown in FIG. 3, right terminal 21 is provided around a lower end portion of right rail member 19. As described above, housing 11 of main body apparatus 2 according to the present embodiment is provided with left rail member 15 and right rail member 19 for attaching the controllers. A position, a shape, and a size of left rail member 15 and right rail member 19 can arbitrarily be designed. For example, in another embodiment, left rail member 15 and right rail member 19 may be provided at left and right end portions in a main surface and/or a rear surface of housing 11, respectively. Any feature can be adopted for a mechanism for removably attaching main body apparatus 2 and the controllers to each other, and a slider mechanism different from the slider mechanism shown in FIGS. 1 to 3 may be adopted and a mechanism different from the slider mechanism may be adopted. For example, a construction may be such that a projection provided on a side of the main body apparatus may be fitted and attached to a recess provided on a side of the controller, or a construction may be such that a magnet is provided on the side of the main body apparatus or the side of the controller and a portion made of a magnetic element is provided in the other for attachment of the main body apparatus and the controller to each other by attraction. (4) Member Provided on Upper Side Surface of Housing 11 As shown in FIG. 3, a first slot 23 for attaching a storage medium of a first type is provided in an upper side surface of housing 11. A lid portion which can be opened and closed is provided in an opening in first slot 23 as a typical feature, and a storage medium of the first type can be inserted in first slot 23 while the lid portion is open. The storage medium of the first type is, for example, a storage medium exclusively designed for game device 1 and a game device of the same type (for example, a dedicated memory card). The storage medium of the first type is used, for example, for storing data used in main body apparatus 2 (for example, data saved for an application) and/or a program executed in main body apparatus 2 (for example, a program for an application). A power button 28 for switching on and off main body apparatus 2 is provided on the upper side surface of housing 11. In the present embodiment, power button 28 is used also for switching between an ON mode and a sleep mode. The ON mode refers, for example, to a mode in which representation on a screen of display 12 is provided and the sleep mode refers, for example, to a mode in which representation on the screen of display 12 is not provided. In the sleep mode, representation on the screen of display 12 is not provided, and additionally or instead, processing in an application being executed (for example, game processing in a game application) may be suspended. When power button 28 is pressed and held (for example, power button 28 is continuously pressed for a prescribed time period or longer), processing for switching on and off main body apparatus 2 is performed. When power button 28 is pressed for a short period of time (for example, power button 28 is pressed for a time period shorter than the prescribed time period above), processing for switching between the ON mode and the sleep mode is performed. As described above, power button 28 of main body apparatus 2 according to the present embodiment is used for switching on and off and/or switching between the ON mode and the sleep mode. In another embodiment, power button 28 may be used only for any one type of switching. In this case, another button for the other type of switching may be provided in main body apparatus 2. An audio input and output terminal 25 (specifically an earphone jack) is provided in the upper side surface of housing 11. A microphone or an earphone can be attached to audio input and output terminal 25. (5) Member Provided on Lower Side Surface of Housing 11 As shown in FIG. 3, a lower terminal 27 for wired communication between main body apparatus 2 and a cradle 5 which will be described later is provided in a lower side surface of housing 11. Lower terminal 27 is provided at a position where it comes in contact with a terminal of cradle 5 when main body apparatus 2 is attached to cradle 5. Typically, a universal serial bus (USB) connector (more specifically, a female connector) can be adopted as lower terminal 27. A second slot 24 for attaching a storage medium of a second type different from the first type is provided in the lower side surface of housing 11. Second slot 24 may be provided in the surface where first slot 23 is provided. A lid portion which can be opened and closed is provided in an opening in second slot 24 as a typical feature, and a storage medium of the second type can be inserted in second slot 24 while the lid portion is open. The storage medium of the second type may be, for example, a general-purpose storage medium (for example, an SD card). The storage medium of the second type is used, for example, for storing data used in main body apparatus 2 (for example, data saved for an application) and/or a program executed in main body apparatus 2 (for example, a program for an application), similarly to the storage medium of the first type. A position, a shape, and the number of components (specifically, a button, a slot, and a terminal) provided in housing 11 described above can arbitrarily be designed. For example, in another embodiment, some of power button 28, first slot 23, and second slot 24 may be provided in another side surface or the rear surface of housing 11. Some of the components do not have to be provided. (a3: Structure of Left Controller) FIG. 4 is a diagram of left controller 3 according to the present embodiment when viewed from six sides. Referring to FIG. 4, left controller 3 has a housing 31 substantially in a form of a plate. A main surface of housing 31 (that is, a front surface or a surface on a side of a negative direction of the z axis shown in FIG. 1) is substantially in a rectangular shape. Housing 31 is in a vertically long shape, that is, long in the up-down direction (that is, the direction of the y axis shown in FIG. 1). Left controller 3 can be used with its main surface being vertically oriented or with its surface being horizontally oriented when a user holds the left controller while the left controller is detached from main body apparatus 2. A shape and a size of housing 31 can arbitrarily be designed. In another embodiment, housing 31 may be constructed into a shape other than a shape substantially in a form of a plate. Housing 31 does not have to be rectangular either, and for example, a semicircular shape may be adopted. Housing 31 does not have to vertically be long. A length of housing 31 in the up-down direction is preferably substantially the same as a length in the up-down direction of housing 11 of main body apparatus 2. A thickness of housing 31 (that is, a length in a front-rear direction or a length in the direction of the z axis shown in FIG. 1) is preferably substantially the same as a thickness of housing 11 of main body apparatus 2. Therefore, when left controller 3 is attached to main body apparatus 2 (see FIG. 1), a user can hold main body apparatus 2 and left controller 3 as if they were an integrated apparatus. A left corner portion of the main surface of housing 31 is rounded more than a right corner portion. A portion of connection between an upper side surface and a left side surface of housing 31 and a portion of connection between a lower side surface and the left side surface of housing 31 are rounded more than a portion of connection between the upper side surface and a right side surface and a portion of connection between the lower side surface and the right side surface (that is, a curve of beveling is great). Therefore, when left controller 3 is attached to main body apparatus 2 (see FIG. 1), the left side of game device 1 is rounded and hence such a shape facilitates holding by a user. An analog stick 32 is provided in left controller 3. As shown in FIG. 4, analog stick 32 is provided on the main surface of housing 31. Analog stick 32 represents one example of a direction instruction portion with which a direction can be input. Analog stick 32 includes a stick member which can be tilted in all directions (that is, a 360° direction including up, down, left, right, and diagonal directions) in parallel to the main surface of housing 31. Analog stick 32 is an analog input device with which a user can input a direction in accordance with a direction of tilt by titling the stick member. Analog stick 32 may further be constructed to be able to give an input of magnitude in accordance with an angle of tilt in addition to input of a direction in accordance with a direction of tilt when the stick member is tilted. Alternatively, a slide stick may implement the direction instruction portion. The slide stick is an input portion having a stick member slidable in all directions in parallel to the main surface of housing 31, and the user can give an input in accordance with a direction of slide by sliding the stick member. The slide stick may further be constructed also to give an input of magnitude in accordance with an amount of slide. Alternatively, the direction instruction portion may be implemented as an input portion indicating a direction through an operation to press a button. For example, the direction instruction portion may be implemented as an input portion indicating a direction with a cross-shaped key or four buttons corresponding to up, down, left, and right directions, respectively. In the present embodiment, an input can be given by pressing the stick member (in the direction perpendicular to housing 31). Analog stick 32 in the present embodiment is an input portion with which an input of a direction and magnitude in accordance with a direction of tilt and an amount of tilt of the stick member can be given and an input resulting from pressing of the stick member can be given. Left controller 3 includes four operation buttons 33 to 36 (specifically, a right direction button 33, a down direction button 34, an up direction button 35, and a left direction button 36). As shown in FIG. 4, these four buttons 33 to 36 are provided under analog stick 32 on the main surface of housing 31. Though four operation buttons are provided on the main surface of left controller 3 in the present embodiment, any number of operation buttons may be provided. These operation buttons 33 to 36 are used for giving an instruction in accordance with various programs (for example, an OS program or an application program) executed in main body apparatus 2. Since operation buttons 33 to 36 may be used for giving an input of a direction in the present embodiment, operation buttons 33 to 36 are also referred to as right direction button 33, down direction button 34, up direction button 35, and left direction button 36 for the sake of convenience of description. Operation buttons 33 to 36 may be used for giving an instruction other than an input of a direction. An operation portion (specifically, analog stick 32 and operation buttons 33 to 36) provided on the main surface of left controller 3 is operated, for example, with the left thumb of a user who holds game device 1 when left controller 3 is attached to main body apparatus 2 (see FIG. 9). When left controller 3 is used as being detached from main body apparatus 2, the operation portion is operated, for example, with the left thumb of the user who holds left controller 3 (see FIG. 10). A first L button 38 and a ZL button 39 are provided in left controller 3. These operation buttons 38 and 39 are used for giving an instruction in accordance with various programs executed in main body apparatus 2, similarly to operation buttons 33 to 36 described above. As shown in FIG. 4, first L button 38 is provided in an upper left portion on the side surface of housing 31. ZL button 39 is provided in an upper left portion as extending from the side surface to the rear surface of housing 31 (strictly speaking, the upper left portion when housing 31 is viewed from the front). ZL button 39 is provided in the rear of first L button 38 (a side of a positive direction of the z axis shown in FIG. 1). Since the upper left portion of housing 31 is rounded in the present embodiment, first L button 38 and ZL button 39 are in a rounded shape in conformity with rounding of the upper left portion of housing 31. When left controller 3 is attached to main body apparatus 2, first L button 38 and ZL button 39 are arranged in the upper left portion of game device 1 (see FIG. 1). Therefore, a user who holds game device 1 can operate first L button 38 and ZL button 39 with his/her left forefinger or long finger. Left controller 3 has slider 40 described above. As shown in FIG. 4, slider 40 extends along the up-down direction in the right side surface of housing 31. Slider 40 is in a shape allowing engagement with left rail member 15 (more specifically, a groove in left rail member 15) of main body apparatus 2. Specifically, slider 40 has a projecting cross-section (specifically, a cross-section perpendicular to the up-down direction). More specifically, slider 40 has a cross-section in a T shape in conformity with a shape of a cross-section of left rail member 15. Therefore, slider 40 engaged with left rail member 15 is fixed and does not come off in a direction perpendicular to a direction of slide (that is, a direction of extension of left rail member 15). Left controller 3 includes a second L button 43 and a second R button 44. These buttons 43 and 44 are used for giving an instruction in accordance with various programs executed in main body apparatus 2 similarly to other operation buttons 33 to 36. As shown in FIG. 4, second L button 43 and second R button 44 are provided in the surface where slider 40 is attached. Second L button 43 is provided above the center in terms of the up-down direction (the direction of they axis shown in FIG. 1) on the surface where slider 40 is attached. Second R button 44 is provided under the center in terms of the up-down direction on the surface where slider 40 is attached. Second L button 43 and second R button 44 are arranged at positions where they cannot be pressed while left controller 3 is attached to main body apparatus 2. Second L button 43 and second R button 44 are used while left controller 3 is detached from main body apparatus 2. Second L button 43 and second R button 44 are operated, for example, with a forefinger or a long finger of left and right hands of a user who holds left controller 3 detached from main body apparatus 2. Left controller 3 includes a notification LED 45. Notification LED 45 is a notification unit for notifying a user of prescribed information. Information given by notification LED 45 is any information. In the present embodiment, when main body apparatus 2 communicates with a plurality of controllers, notification LED 45 indicates information for identifying each controller to a user. Specifically, left controller 3 includes as notification LED 45, LEDs as many as left controllers (four here) with which main body apparatus 2 can simultaneously communicate. An LED among four LEDs in accordance with a number provided to a controller is turned on. Thus, the user can be notified of the number through notification LED 45. In another embodiment, notification LED 45 may notify the user of a state of communication between left controller 3 and main body apparatus 2. For example, notification LED 45 may be turned on when communication with main body apparatus 2 has been established. Though the number of LEDs (in other words, light emission portions) functioning as notification LED 45 is set to four in the present embodiment, the number of LEDs is set to any number. In the present embodiment, notification LED 45 is provided on the surface where slider 40 is attached as shown in the figure. Therefore, notification LED 45 is arranged at a position hidden while left controller 3 is attached to main body apparatus 2. Notification LED 45 is used when left controller 3 is detached from main body apparatus 2. In the present embodiment, a button (specifically, second L button 43 and second R button 44) provided on the surface where slider 40 is attached is provided not to protrude from that surface. An upper surface of the button (in other words, a surface which is pressed) is arranged flush with the surface where slider 40 is attached or at a position lower than such a surface. Thus, while slider 40 is attached to left rail member 15 of main body apparatus 2, slider 40 can smoothly be slid with respect to left rail member 15. (a4: Structure of Right Controller) FIG. 5 is a diagram of right controller 4 according to the present embodiment when viewed from six sides. Referring to FIG. 5, right controller 4 has a housing 51 substantially in a form of a plate. A main surface of housing 51 (that is, a front surface or a surface on the side of the negative direction of the z axis shown in FIG. 1) is substantially in a rectangular shape. Housing 51 is in a vertically long shape, that is, long in the up-down direction. Right controller 4 can be used with its main surface being vertically oriented or with its surface being horizontally oriented when a user holds the right controller while the right controller is detached from main body apparatus 2. Similarly to housing 31 of left controller 3, a length of housing 51 of right controller 4 in the up-down direction is preferably substantially the same as the length in the up-down direction of housing 11 of main body apparatus 2 and a thickness thereof is preferably substantially the same as the thickness of housing 11 of main body apparatus 2. Therefore, when right controller 4 is attached to main body apparatus 2 (see FIG. 1), a user can hold main body apparatus 2 and right controller 4 as if they were an integrated apparatus. A right corner portion of the main surface of housing 51 is rounded more than a left corner portion. A portion of connection between an upper side surface and a right side surface of housing 51 and a portion of connection between a lower side surface and the right side surface of housing 51 are rounded more than a portion of connection between the upper side surface and a left side surface and a portion of connection between the lower side surface and the left side surface (that is, a curve of beveling is great). Therefore, when right controller 4 is attached to main body apparatus 2 (see FIG. 1), the right side of game device 1 is rounded and hence such a shape facilitates holding by a user. An analog stick 52 is provided in right controller 4 as a direction instruction portion as in left controller 3. Analog stick 52 is constructed substantially similarly to analog stick 32 in left controller 3. Right controller 4 includes four operation buttons 53 to 56 (specifically, an A button 53, a B button 54, an X button 55, and a Y button 56) similarly to left controller 3. These four operation buttons 53 to 56 are substantially the same in mechanism as four operation buttons 33 to 36 in left controller 3. As shown in FIG. 5, analog stick 52 and operation buttons 53 to 56 are provided on the main surface of housing 51. Though four operation buttons are provided on the main surface of right controller 4 in the present embodiment, any number of operation buttons may be provided. Positional relation between two types of operation portions (analog stick 52 and the operation buttons) in right controller 4 is opposite to positional relation of these two types of operation portions in left controller 3. In right controller 4, analog stick 52 is arranged under operation buttons 53 to 56, whereas in left controller 3, analog stick 32 is arranged above operation buttons 33 to 36. With such arrangement, when two controllers are used as being detached from main body apparatus 2, both of the controllers can be used with similar operational feeling. When right controller 4 is attached to main body apparatus 2, the operation portion (specifically analog stick 52 and operation buttons 53 to 56) provided on the main surface of right controller 4 is operated, for example, with the right thumb of a user who holds game device 1 (see FIG. 9). When right controller 4 is used as being detached from main body apparatus 2, the operation portion is operated, for example, with the right thumb of a user who holds right controller 4. A first R button 60 and a ZR button 61 are provided in right controller 4. As shown in FIG. 5, first R button 60 is provided in an upper right portion on the side surface of housing 51. ZR button 61 is provided in an upper right portion as extending from the side surface to the rear surface of housing 51 (strictly speaking, the upper right portion when housing 51 is viewed from the front). ZR button 61 is provided in the rear of first R button 60 (the side of the positive direction of the z axis shown in FIG. 1). Since the upper right portion of housing 51 is rounded in the present embodiment, first R button 60 and ZR button 61 are in a rounded shape in conformity with rounding of the upper right portion of housing 51. When right controller 4 is attached to main body apparatus 2, first R button 60 and ZR button 61 are arranged in the upper right portion of game device 1 (see FIG. 1). Therefore, a user who holds game device 1 can operate first R button 60 and ZR button 61 with his/her right forefinger or long finger. In the present embodiment, first L button 38 and first R button 60 are not symmetric to each other in shape, and ZL button 39 and ZR button 61 are not symmetric to each other in shape. In another embodiment, first L button 38 and first R button 60 may be symmetric to each other in shape, and ZL button 39 and ZR button 61 may be symmetric to each other in shape. Right controller 4 has terminal 64 for wired communication between right controller 4 and main body apparatus 2. Terminal 64 is provided at a position where it comes in contact with right terminal 21 (FIG. 3) of main body apparatus 2 when right controller 4 is attached to main body apparatus 2. Terminal 64 should be arranged at any position where main body apparatus 2 and right controller 4 are in contact with each other while right controller 4 is attached to main body apparatus 2. By way of example, as shown in FIG. 5, terminal 64 is provided around a lower end portion of a surface where slider 62 is attached. A position, a shape, and the number of components (specifically, a slider, a stick, a button, and an LED) provided in housing 31 of left controller 3 and/or housing 51 of right controller 4 can arbitrarily be designed. For example, in another embodiment, the controller may include a direction instruction portion of a type different from the analog stick. Slider 40 or 62 may be arranged at a position in accordance with a position of left rail member 15 and right rail member 19 provided in main body apparatus 2, and for example, may be arranged in the main surface or the rear surface of housing 31 or 51. Some of the components do not have to be provided. Right controller 4 includes a second L button 65 and a second R button 66 as in left controller 3. These buttons 65 and 66 are used for giving an instruction in accordance with various programs executed in main body apparatus 2 similarly to other operation buttons 53 to 56. As shown in FIG. 5, second L button 65 and second R button 66 are provided on the surface where slider 62 is attached. Second L button 65 is provided under the center in terms of the up-down direction (the direction of the y axis shown in FIG. 1) on the surface where slider 62 is attached. Second R button 66 is provided above the center in terms of the up-down direction on the surface where slider 62 is attached. Second L button 65 and second R button 66 are arranged at positions where they cannot be pressed while right controller 4 is attached to main body apparatus 2. Second L button 65 and second R button 66 are used while right controller 4 is detached from main body apparatus 2. Second L button 65 and second R button 66 are operated, for example, with a forefinger or a long finger of left and right hands of a user who holds right controller 4 detached from main body apparatus 2. Right controller 4 includes a notification LED 67. Notification LED 67 is a notification unit for notifying a user of prescribed information similarly to notification LED 45 of left controller 3. Right controller 4 includes four LEDs as notification LEDs 67, as in left controller 3. An LED among four LEDs in accordance with a number provided to a controller is turned on. Thus, the user can be notified of the number through notification LED 67. In the present embodiment, similarly to notification LED 45, notification LED 67 is provided on the surface where slider 62 is attached as shown in the figure. Therefore, notification LED 67 is arranged at a position hidden while right controller 4 is attached to main body apparatus 2. Notification LED 67 is used when right controller 4 is detached from main body apparatus 2. In the present embodiment, also in right controller 4 as in left controller 3, a button (specifically, second L button 65 and second R button 66) provided on the surface where slider 62 is attached is provided not to protrude from that surface. An upper surface of the button (in other words, a surface which is pressed) is arranged flush with the surface where slider 62 is attached or at a position lower than such a surface. Thus, while slider 62 is attached to right rail member 19 of main body apparatus 2, slider 62 can smoothly be slid with respect to right rail member 19. (a5: Use of Cradle) FIG. 6 is a schematic diagram showing appearance when game device 1 according to the present embodiment is used together with a cradle. The game system shown in FIG. 6 includes game device 1 and cradle 5. Cradle 5 is constructed to be able to carry game device 1 and constructed to be able to communicate with a television 6 representing one example of an external display apparatus separate from display 12 of game device 1. When game device 1 is carried on cradle 5, an image obtained or generated by game device 1 can be shown on television 6. Communication between cradle 5 and television 6 may be wired communication or wireless communication. Cradle 5 may have a function to charge placed game device 1 and a function as a communication hub apparatus (for example, a USB hub). [B. Internal Configuration of Each Apparatus] An internal configuration of each apparatus associated with the information processing system according to the present embodiment will initially be described. (b1: Internal Configuration of Main Body Apparatus) FIG. 7 is a block diagram showing an internal configuration of main body apparatus 2 according to the present embodiment. Main body apparatus 2 includes components shown in FIG. 7. The components shown in FIG. 7 are accommodated in housing 11, for example, as being mounted on an electronic circuit substrate as electronic components. Main body apparatus 2 includes a central processing unit (CPU) 81 corresponding to an information processing unit (or a processor) performing various types of processing including game processing. CPU 81 reads and executes a program stored in an accessible storage unit (specifically, an internal storage medium such as a flash memory 84 or an external storage medium attached to first slot 23 or second slot 24). Main body apparatus 2 includes flash memory 84 and a dynamic random access memory (DRAM) 85 by way of example of an embedded internal storage medium. Flash memory 84 is a non-volatile memory mainly storing various types of data (which may be a program) saved in main body apparatus 2. DRAM 85 is a volatile memory temporarily storing various types of data used in information processing. Main body apparatus 2 includes a first slot interface (I/F) 91 and a second slot interface 92. The first slot interface is connected to first slot 23 and reads and writes data from and into a storage medium of the first type (for example, an SD card) attached to first slot 23, in response to an instruction from CPU 81. Second slot interface 92 is connected to second slot 24 and reads and writes data from and into a storage medium of the second type (for example, a dedicated memory card) attached to second slot 24, in response to an instruction from CPU 81. Main body apparatus 2 includes a network communication unit 82 for communication (specifically, wireless communication) with an external apparatus through a network. For example, a communication module authorized for Wi-Fi is employed for network communication unit 82 and network communication unit 82 communicates with an external apparatus through wireless LAN. In another embodiment, main body apparatus 2 may have a function for connection and communication with a mobile communication network (that is, a portable telephone communication network) in addition to (or instead of) a function for connection and communication with wireless LAN. Main body apparatus 2 includes a controller communication unit 83 for wireless communication with left controller 3 and/or right controller 4. Though any scheme is applicable for communication between main body apparatus 2 and each controller, for example, a communication scheme under the Bluetooth® specifications can be adopted. CPU 81 is connected to left terminal 17, right terminal 21, and lower terminal 27. CPU 81 transmits and receives data to and from left controller 3 through left terminal 17 when wired communication with left controller 3 is established. CPU 81 transmits and receives data to and from right controller 4 through right terminal 21 when wired communication with right controller 4 is established. Data transmitted from CPU 81 to left controller 3 or right controller 4 is, for example, data for controlling a vibration generation portion of left controller 3 or right controller 4. Data received by CPU 81 from left controller 3 or right controller 4 is, for example, operation data output in response to an operation by a user of the operation portion in left controller 3 or right controller 4. CPU 81 transmits data to cradle 5 through lower terminal 27 when it communicates with cradle 5. In the present embodiment, main body apparatus 2 can establish both of wired communication and wireless communication with left controller 3 and right controller 4. Main body apparatus 2 includes a touch panel controller 86 for control of touch panel 13. Touch panel controller 86 generates data indicating a position of a touch input in response to a signal from touch panel 13, and outputs the data to CPU 81. Display 12 shows an image generated by execution of various types of processing by CPU 81 and/or an image obtained from the outside. Main body apparatus 2 includes a codec circuit 87 and speaker 88 (specifically, the left speaker and the right speaker). Codec circuit 87 controls input and output of audio data to and from speaker 88 and audio input and output terminal 25. More specifically, when codec circuit 87 receives audio data from CPU 81, it outputs an audio signal resulting from D/A conversion of the audio data to speaker 88 or audio input and output terminal 25. Thus, sound is output from speaker 88 or an audio output portion (for example, an earphone) connected to audio input and output terminal 25. When codec circuit 87 receives an audio signal from audio input and output terminal 25, it subjects the audio signal to A/D conversion and outputs audio data in a prescribed format to CPU 81. Main body apparatus 2 has an acceleration sensor 89 and an angular speed sensor 90. Acceleration sensor 89 detects magnitude of a linear acceleration along directions of prescribed three axes (for example, the xyz axes shown in FIG. 1). Acceleration sensor 89 may detect an acceleration in a direction of one axis or accelerations in directions of two axes. Angular speed sensor 90 detects angular speeds around prescribed three axes (for example, the xyz axes shown in FIG. 1). Angular speed sensor 90 may detect an angular speed around one axis or angular speeds around two axes. A result of detection by acceleration sensor 89 and angular speed sensor 90 is output to CPU 81. CPU 81 can calculate information on a motion and/or an attitude of main body apparatus 2 based on the result of detection by acceleration sensor 89 and angular speed sensor 90. Main body apparatus 2 includes an electric power control unit 97 and a battery 98. Electric power control unit 97 controls supply of electric power from battery 98 to each component based on a command from CPU 81. Electric power control unit 97 controls supply of electric power in accordance with an input onto power button 28. When an operation to turn off power supply is performed on power button 28, electric power control unit 97 stops supply of electric power totally or in part, and when an operation to turn on power supply is performed on power button 28, it starts full supply of electric power. When an instruction to switch to the sleep mode is given to power button 28, electric power control unit 97 stops supply of electric power to some components including display 12, and when an instruction to switch to the ON mode is given to power button 28, it starts supply of electric power. When an external charging apparatus (for example, cradle 5) is connected to lower terminal 27 and electric power is supplied to main body apparatus 2 through lower terminal 27, battery 98 is charged with supplied electric power. Battery 98 of main body apparatus 2 is preferably higher in charging capacity than a battery of left controller 3 and right controller 4. (b2: Internal Configuration of Controller) FIG. 8 is a block diagram showing an internal configuration of left controller 3 and right controller 4 according to the present embodiment. FIG. 8 also depicts components of main body apparatus 2 associated with left controller 3 and right controller 4. Left controller 3 includes a communication control unit 101 for communication with main body apparatus 2. Communication control unit 101 can communicate with main body apparatus 2 through both of wired communication through terminal 42 and wireless communication not through terminal 42. Communication control unit 101 selects wired communication or wireless communication depending on whether or not left controller 3 is attached to main body apparatus 2, and establishes communication under a selected communication method. While left controller 3 is attached to main body apparatus 2, communication control unit 101 establishes communication with main body apparatus 2 through terminal 42. While left controller 3 is detached from main body apparatus 2, communication control unit 101 establishes wireless communication with main body apparatus 2 (specifically, controller communication unit 83). The communication control unit should only be able to establish communication with the main body apparatus, and for example, it may be configured to establish only either wired communication or wireless communication. While left controller 3 is detached from main body apparatus 2, wireless communication is established by way of example, however, wired communication may be established, for example, through a cable. Left controller 3 includes, for example, a memory 102 such as a flash memory. Communication control unit 101 is implemented, for example, by a microprocessor and performs various types of processing by executing firmware stored in memory 102. Left controller 3 includes an operation button group 103 (specifically operation buttons 33 to 36, 38, and 39) and analog stick 32. Information on an operation onto operation button group 103 and analog stick 32 is repeatedly output to communication control unit 101 with a prescribed period. Left controller 3 has an acceleration sensor 104 and an angular speed sensor 105. Acceleration sensor 104 detects magnitude of a linear acceleration along directions of prescribed three axes (for example, the xyz axes shown in FIG. 1). Acceleration sensor 104 may detect an acceleration in a direction of one axis or accelerations in directions of two axes. Angular speed sensor 105 detects angular speeds around prescribed three axes (for example, the xyz axes shown in FIG. 1). Angular speed sensor 105 may detect an angular speed around one axis or angular speeds around two axes. A result of detection by acceleration sensor 104 and angular speed sensor 105 is repeatedly output to communication control unit 101 with a prescribed period. Communication control unit 101 obtains information on an input from each of operation button group 103, analog stick 32, acceleration sensor 104, and angular speed sensor 105 (for example, information on an operation by a user or a result of detection by the sensor). Communication control unit 101 transmits data including obtained information (or information obtained by subjecting obtained information to prescribed processing) to main body apparatus 2. Data is transmitted to main body apparatus 2 repeatedly with a prescribed period. A period of transmission of information on an input to main body apparatus 2 may or may not be identical among input devices. Main body apparatus 2 can know an input given to left controller 3 based on transmitted data. More specifically, main body apparatus 2 can discriminate an operation onto operation button group 103 and analog stick 32. Main body apparatus 2 can calculate information on a motion and/or an attitude of left controller 3. Left controller 3 includes an electric power supply unit 109 including a battery and an electric power control circuit. Electric power supply unit 109 controls supply of electric power to each component of left controller 3. When left controller 3 is attached to main body apparatus 2, the battery is charged by power feed from main body apparatus 2 through terminal 42. Electric power supply unit 109 gives battery warning information to main body apparatus 2 when the battery runs out of electric power. Right controller 4 is configured basically similarly to left controller 3 described above. Right controller 4 includes a communication control unit 111, an operation button group 113 (specifically operation buttons 53 to 56, 60, and 61), analog stick 52, an acceleration sensor 114, an angular speed sensor 115, and an electric power supply unit 119. When the battery runs out of electric power, electric power supply unit 119 gives battery warning information to main body apparatus 2. Since other components of right controller 4 have features and functions the same as those of corresponding components described in connection with left controller 3, detailed description will not be repeated. Thus, game device 1 according to the present embodiment includes left controller 3 held in the left hand of the user (one hand) (a portion held in the left hand of the user) and right controller 4 held in the right hand (the other hand) of the user (a portion held in the right hand of the user). The “operation portion” herein may mean a function or a feature accepting an operation by a user and encompass any component such as a button, an analog stick, and various sensors arranged in main body apparatus 2, left controller 3, and right controller 4, so long as it can sense an operation by a user. The operation portion may be configured to be able to sense an operation by the user based on combination of a button, an analog stick, and various sensors as being distributed in main body apparatus 2, left controller 3, and right controller 4. [C. Manner of Use of Game System] As described above, game device 1 according to the present embodiment is constructed such that left controller 3 and right controller 4 are removable. Game device 1 can output an image and sound to television 6 by being attached to cradle 5. Therefore, game device 1 can be used in various manners of use as will be described below. A main manner of use of game device 1 will be exemplified below. (c1: Manner of Use With Controller Being Attached to Main Body Apparatus) FIG. 9 is a diagram showing one example of a manner of use of game device 1 with left controller 3 and right controller 4 being attached to main body apparatus 2 (hereinafter also referred to as an “attached state”). As shown in FIG. 9, in the attached state, game device 1 can be used as a portable device. In the attached state, basically, communication between main body apparatus 2, and left controller 3 and right controller 4 is established through wired communication. In another embodiment, communication between main body apparatus 2, and left controller 3 and right controller 4 may be established through wireless communication also in the attached state. In the attached state, four operation buttons 33 to 36 of left controller 3 may be used for inputting a direction (that is, an instruction for a direction). A user can input a direction with analog stick 32 or operation buttons 33 to 36. Since the user can input a direction with his/her preferred operation means, operability can be improved. For which instruction operation buttons 33 to 36 are used may arbitrarily be determined depending on a program executed in main body apparatus 2. In the present embodiment, arrangement of the analog stick and four operation buttons (that is, A, B, X, and Y buttons) is reverse between left controller 3 and right controller 4. In the attached state, analog stick 32 is arranged above four operation buttons 33 to 36 in left controller 3, whereas four operation buttons 53 to 56 are arranged above analog stick 52 in right controller 4. Therefore, when a user holds game device 1 with his/her both hands being located at the same height (that is, at positions the same in the up-down direction) as shown in FIG. 9, the analog stick is located at a position readily operable with one hand and the four operation buttons are located at positions readily operable with the other hand. Game device 1 according to the present embodiment thus provides a feature facilitating an operation of the analog stick and four operation buttons. (c2: Manner of Use With One Set of Controllers Being Detached From Main Body Apparatus) FIG. 10 is a diagram showing one example of a manner of use of game device 1 with left controller 3 and right controller 4 being detached from main body apparatus 2 (hereinafter also referred to as a “detached state”). As shown in FIG. 10, in the detached state, the user can operate left controller 3 and right controller 4 in his/her left and right hands, respectively. In this case, analog stick 32 and four operation buttons 33 to 36 of left controller 3 are operated as being arranged vertically in the left hand in which the controller is held. Similarly, analog stick 52 and four operation buttons 53 to 56 of right controller 4 are operated as being arranged vertically in the right hand in which the controller is held. The controller is used such that the main surface thereof is vertically oriented when the user holds the controller (also referred to as an operation in vertical holding). In the detached state, basically, communication between main body apparatus 2, and left controller 3 and right controller 4 is established through wireless communication. Main body apparatus 2 receives data from the controller with which it has established wireless communication (typically pairing has been done) and performs game processing based on the received data. In the present embodiment, in wireless communication, main body apparatus 2 distinguishes between left controller 3 and right controller 4 which are communication counterparts. Main body apparatus 2 identifies whether the data received from the controller is from left controller 3 or from right controller 4. Though FIG. 10 shows a manner of use by one user of one set of controllers (the left controller and the right controller), such a manner of use that two users use the respective controllers is also applicable. In this case, two users can simultaneously participate in a game with one set of controllers (the left controller and the right controller). Though FIG. 10 shows a state that both of left controller 3 and right controller 4 are detached from main body apparatus 2, limitation thereto is not intended and any one of left controller 3 and right controller 4 can be detached from main body apparatus 2 and game device 1 can be used with the other being attached to main body apparatus 2. (c3: Manner of Use of Respective Controllers by Two Users) FIG. 11 is a diagram showing one example of a manner of use of game device 1 with two users each holding one controller in the detached state. As shown in FIG. 11, two users can perform operations in the detached state. Specifically, one user (called a “first user”) uses left controller 3 to perform an operation and the other user (called a “second user”) can use right controller 4 to perform an operation. Game device 1 performs, for example, information processing for controlling an operation of a first object (for example, a player character) in a virtual space based on an operation onto left controller 3 and for controlling an operation of a second object in the virtual space based on an operation onto right controller 4. In the manner shown in FIG. 11 as well, as in the manner shown in FIG. 10, the user can perform an operation onto the operation portion included in the controller and/or an operation to move the controller itself. In this case, analog stick 32 and four operation buttons 33 to 36 in left controller 3 used by the first user are operated as being arranged laterally between the left and right hands in which the controller is held. Similarly, analog stick 52 and four operation buttons 53 to 56 in right controller 4 used by the second user are operated as being arranged laterally between the left and right hands in which the controller is held. The controller is used such that the main surface thereof is laterally oriented when the user holds the controller (also referred to as an operation in lateral holding). Though description will be given later, under an operation scheme in lateral holding of left controller 3 and right controller 4, functions of the operation portions in left controller 3 and right controller 4 are changed from those in an operation scheme in vertical holding. In the present embodiment, positional relation between analog stick 52 and operation buttons 53 to 56 in right controller 4 is opposite to positional relation between these two types of operation portions in left controller 3. Therefore, when two users hold left controller 3 and right controller 4 in the same orientation, for example, as shown in FIG. 11, positional relation between the two types of operation portions is the same between the two controllers. In the present embodiment, the user can use the two types of operation portions in left controller 3 and right controller 4 detached from main body apparatus 2 with similar operation feeling. Operability of the controller can thus be improved. In the detached state, four operation buttons 33 to 36 of left controller 3 may be used to perform functions the same as those of four operation buttons 53 to 56 in right controller 4 (in other words, may be used for giving the same instruction). Specifically, right direction button 33 may be used to perform a function the same as that of Y button 56, down direction button 34 may be used to perform a function the same as that of X button 55, up direction button 35 may be used to perform a function the same as that of B button 54, and left direction button 36 may be used to perform a function the same as that of A button 53. Thus, in the present embodiment, functions of operation buttons 33 to 36 may be changed between the attached state and the detached state. For which instruction each operation button is used may freely be determined depending on a program executed in main body apparatus 2. In FIG. 11, in game device 1, a display area of display 12 of main body apparatus 2 is divided into two sections, and game device 1 shows an image for the first user (for example, an image including the first object) in one divided display area and shows an image for the second user (for example, an image including the second object) in the other divided display area. Depending on an application executed in game device 1, however, game device 1 may show an image for two users (for example, an image including both of the first object and the second object) without the display area of display 12 being divided. In the manner shown in FIG. 11 as well, as in the manner shown in FIG. 10, communication between main body apparatus 2, and left controller 3 and right controller 4 is established through wireless communication. Main body apparatus 2 distinguishes between controllers to be communication counterparts. (c4: Manner of Use of Television) FIG. 12 is a diagram showing one example of a manner of use of game device 1 with main body apparatus 2 being attached to cradle 5. As shown in FIG. 12, by attaching main body apparatus 2 to cradle 5, an image obtained or generated by game device 1 can be shown on television 6. A user operates left controller 3 and/or right controller 4 while the user watches an image shown on television 6 (and an image shown on the display of main body apparatus 2 as necessary). (c5: Manner of Use of Three or More Controllers) As described above, in the present embodiment, main body apparatus 2 can communicate with a plurality of left controllers. Main body apparatus 2 can communicate with a plurality of right controllers. Therefore, in the present embodiment, three or more controllers can simultaneously be used. FIGS. 13A and 13B are diagrams showing examples of a manner of use of three or more controllers. FIGS. 13A and 13B show examples in which four controllers in total of two left controllers 3a and 3b and two right controllers 4a and 4b are used. Each controller is detached from main body apparatus 2. Thus, when the four controllers are used, at least a manner of use of one controller by each of four users (FIG. 13A) and a manner of use of two controllers by each of two users (specifically, one set of controllers on each of a left side and a right side) (FIG. 13B) are possible. (Manner of Use of One Controller by One User) In FIG. 13A, four controllers 3a, 3b, 4a, and 4b are used by respective users. In the present embodiment, when four controllers are prepared, four users of a user A to a user D can use the controllers to perform operations. Game device 1 performs, for example, information processing controlling an operation of an object corresponding to each controller based on an operation onto the controller. In FIG. 13A, main body apparatus 2 establishes wireless communication with each of four controllers 3a, 3b, 4a, and 4b. In the present embodiment, main body apparatus 2 distinguishes among four controllers 3a, 3b, 4a, and 4b. Main body apparatus 2 identifies from which of the four controllers received operation data has come. In FIG. 13A, main body apparatus 2 distinguishes between left controller 3a and left controller 3b and distinguishes between right controller 4a and right controller 4b. (Manner of Use of One Set of Controllers by One User) In FIG. 13B, one user uses one set of controllers. User A uses one set of left controller 3a and right controller 4a, and user B uses one set of left controller 3b and right controller 4b. Thus, in the present embodiment, when four controllers are prepared, each of two users can operate one set of controllers. Game device 1 performs information processing with two pieces of operation data received from one set of controllers being defined as one set. For example, game device 1 performs information processing controlling an operation of an object corresponding to one set of controllers based on an operation onto that one set of controllers. Specifically, an operation of the first object is controlled based on an operation onto left controller 3a and right controller 4a, and an operation of the second object is controlled based on an operation onto left controller 3b and right controller 4b. In the present embodiment, in the manner of use shown in FIG. 13B, main body apparatus 2 sets a set of a left controller and a right controller to be used by one user. Main body apparatus 2 performs information processing by using two pieces of operation data from the two controllers included in the set as one set (for example, using the data as operation data for controlling one operation target). Any method may be adopted as a method of setting a set of controllers, and in the present embodiment, a set is set by attaching left and right controllers to main body apparatus 2. Main body apparatus 2 sets simultaneously attached left controller and right controller as one set of controllers. For example, when a set of controllers shown in FIG. 13B is set, the user initially attaches left controller 3a and right controller 4a to main body apparatus 2, detaches left controller 3a and right controller 4a from main body apparatus 2, and thereafter attaches left controller 3b and right controller 4b to main body apparatus 2. Thus, a set of left controller 3a and right controller 4a and a set of left controller 3b and right controller 4b can be set (or registered) in main body apparatus 2. When three or more controllers are used, other than manners of use shown in FIGS. 13A and 13B, the information processing system can be used in various manners. For example, the information processing system can be used in such a manner that one user uses a set of controllers consisting of left and right controllers and another user uses one controller. Alternatively, for example, one user can use a controller attached to main body apparatus 2 and another user can use a controller detached from main body apparatus 2. (c6: Other Manners) In addition to the manners of use as described above, a head mounted display (HMD) type display can also be used. (c7: Advantages in Terms of Operation) In the present embodiment, information on a motion and/or an attitude of each controller can be calculated based on a result of detection by the acceleration sensor and/or the angular speed sensor in the left controller and the right controller. Game device 1 can accept an operation by a user to move the controller itself as an input. The user can perform not only an operation onto the operation portion (the operation buttons and the analog stick) in each controller but also an operation to move the controller itself. In the present embodiment, game device 1 can provide a user with an operation to move a controller (without moving a display) while it is a portable device. Game device 1 can also provide a game device allowing a user to perform an operation at a location distant from display 12 while it is a portable device. Game device 1 can calculate information on a motion and/or an attitude of game device 1 based on a result of detection by the acceleration sensor and/or the angular speed sensor in the left controller and the right controller not only in the detached state but also in the attached state. Game device 1 can also calculate information on a motion and/or an attitude of game device 1 based on a result of detection by acceleration sensor 89 and/or angular speed sensor 90 in main body apparatus 2 in the attached state. [D. Accessory Controller] An accessory controller 401 will now be described. Separately from left controller 3 and right controller 4, accessory controller 401 which can communicate with main body apparatus 2 of game device 1 can also be provided. FIG. 14 is a diagram showing appearance of accessory controller 401 based on an embodiment. As shown in FIG. 14, accessory controller 401 is mainly constituted of a housing 402 including grip portions 400L and 400R on the left and right (which may hereinafter collectively also be called a grip portion 400) and an operation portion including two analog sticks protruding through openings provided in a surface of housing 402 and a plurality of operation buttons (which will be described later). Housing 402 is substantially in a smooth trapezoidal shape with a longitudinal direction thereof being defined as a lateral direction when viewed from the front. The housing may be in such a shape that an upper side is slightly recessed and a lower side is more recessed than the upper side, in other words, grip portions 400L and 400R extend toward a bottom surface (forward when viewed from a player while the controller is held). A front surface side may be constructed substantially planar except for a position where the analog stick is provided. A position where the analog stick is located is slightly raised and grip portions 400L and 400R may be in a shape gently curved rearward from the front. Housing 402 in the present example may be formed, for example, through plastic molding. A first analog stick 411 (hereinafter a left stick) is provided around an upper surface side at a left end on a front surface of housing 402 and a second analog stick 412 (hereinafter a right stick) is provided around a lower surface side at a right end on the front surface of housing 402. More specifically, left stick 411 is arranged at a position operable with the thumb of the left hand with which grip portion 400L is held (more suitably, a position where the thumb of the left hand with which grip portion 400L is held is naturally located), and right stick 412 is arranged at a position operable with the thumb of the right hand with which grip portion 400R is held. Left stick 411 and right stick 412 are sticks which can be tilted in any direction around 360 degrees and used for indicating any direction. Left stick 411 and right stick 412 can be pressed rearward and also play a role as a push button. Left stick 411 and right stick 412 function in accordance with a program executed by main body apparatus 2 to which the controller is connected. Since a distance between left stick 411 and right stick 412 is thus great, a distance between the thumbs is not small even in an operation to tilt both of them inward and hence operability is good. A cross-shaped key (which may also be called a direction key) 421 is provided at a position on the left of a substantially central position on the front surface of housing 402 and on an inner side of left stick 411, where the cross-shaped key is operable with the thumb of the left hand with which grip portion 400L is held. More specifically, cross-shaped key 421 is provided at a position on the lower right of left stick 411. Cross-shaped key 421 is such a four-directional cross-shaped push switch that operation portions corresponding to four respective directions (front, rear, left, and right) are arranged at an interval of 90° on respective projecting parts of the cross. As a player presses any operation portion of cross-shaped key 421, any of the front, rear, left, and right directions is selected. Cross-shaped key 421 functions in accordance with a program executed by main body apparatus 2 to which the controller is connected. Cross-shaped key 421 is not limited to the shape as illustrated and any shape is applicable so long as a shape allows input of four directions. For example, such a shape that a cross-shaped raised portion is provided in a circular base is acceptable and four separate keys may be acceptable. Operation buttons 422A to 422D (which may hereinafter also be called a first operation button group) are arranged at upper, lower, left, and right positions of a cross pattern on the right of substantially the center on the front surface of housing 402 in an area above right stick 412, where the buttons are operable with the thumb of the right hand with which grip portion 400R is held. More specifically, operation buttons 422A to 422D are arranged at upper, lower, left, and right positions of the cross-pattern in an area located on the upper right of right stick 412. For example, operation buttons 422A to 422D are used for indicating enter or cancel. By arranging cross-shaped key 421 at a position on the lower right of left stick 411, the thumb pad can be moved to the position of cross-shaped key 421 by moving the thumb with the root of the left thumb being set as the fulcrum. In other words, the thumb pad can be moved to the position of cross-shaped key 421 simply by moving the thumb to the right with the root of the thumb being set as the fulcrum without particularly changing an attitude to hold grip portion 400L and the thumb can also be returned to the position of left stick 411 by moving the thumb to the left. Skip between left stick 411 and cross-shaped key 421 is facilitated and operability can be improved. In other words, there is no lowering in operability caused by the stick constituting the obstacle as being located between the tip end of the thumb (the position of the cross-shaped key) and the root of the thumb in operation of cross-shaped key 421. Similarly, by arranging right stick 412 at the position on the lower left of the first operation button group (operation buttons 422A to 422D), the thumb can be moved between right stick 412 and the first operation button group simply by moving the thumb with the root of the right thumb being set as the fulcrum. Skip between right stick 412 and the first operation button group is thus facilitated and operability can be improved. An L button 425L is provided on a front side in a left end portion of the upper surface of housing 402 and a ZL button is provided under the same (on a rear side). An R button 425R is arranged on the front side in a right end portion of the upper surface of housing 402 and a ZR button is arranged under the same (on the rear side). L button 425L is arranged at a position where the L button can be reached by the forefinger of the left hand with which grip portion 400L is held and the ZL button is arranged at a position where the ZL button can be reached by the left long finger or ring finger. R button 425R is arranged at a position where the R button can be reached by the forefinger of the right hand with which grip portion 400R is held and the ZR button is arranged at a position where the ZR button can be reached by the right long finger or ring finger. Functions in accordance with a program executed by the information processing apparatus are allocated as appropriate to L button 425L, R button 425R, the ZL button, and the ZR button. Operation buttons similar to the operation buttons provided in left controller 3 and right controller 4 described above are also provided in accessory controller 401. A plurality of indicators are provided on a bottom surface side of the front surface of housing 402. Specifically, a notification LED 431 is provided. Notification LED 431 serves as a notification unit for notifying a user of prescribed information, similarly to the notification LED of the left controller. Notification LED 431 includes four LEDs. Among the four LEDs, an LED in accordance with a player number allocated to a controller is turned on. Thus, the user can be notified of the player number by notification LED 431. Since accessory controller 401 is basically similar in internal configuration to left controller 3 or right controller 4 described with reference to FIG. 8, detailed description thereof will not be repeated. Identification information represented by a value (for example, an ID) specifically provided to accessory controller 401 is stored in a memory of accessory controller 401. Main body apparatus 2 can identify a controller as the accessory controller, not as left controller 3 or right controller 4, based on the identification information. Unlike left controller 3 and right controller 4, selection from among a plurality of operation schemes is not allowed for accessory controller 401 in the present example. In another embodiment, selection from among a plurality of operation schemes may be allowed. [E: Controller Registration Processing] FIGS. 15A and 15B are diagrams showing examples illustrating a controller registration screen displayed by game device 1 based on the embodiment. As shown in FIGS. 15A and 15B, controllers held by users PA to PD representing four players are registered in a controller registration screen shown on television 6. The controller registration screen represents one example of a screen shown when controller registration is indicated in a home menu. The home menu is provided to allow launch of a game application together with various types of setting (controller registration). For example, an icon for launching a game application is provided, and a game application is launched by selecting the icon. An icon for registering a controller is also provided. An application for controller registration processing is launched by selecting the icon and the controller registration screen is shown. An instruction for registration of a controller can be given also from each game application, and in that case, a manner of an available controller is shown depending on a game application. For example in an example of a game application in which only left and right controllers are used but the accessory controller is not used, the accessory controller is not shown. Since an instruction for registration of a controller can also be given from each game application, it is not necessary to perform a bothersome procedure for performing setting processing by returning to the home menu, and hence usability can be improved. Television 6 in the present example in FIG. 15A shows a message that “press ‘L’ and ‘R’ of controller to be used.” In the present example, each user is invited to press the L button and the R button in registration of a controller held by each user. Through a series of processes in response to pressing, a player number is registered for a controller of each user. One operation scheme is set in a controller adapted to a plurality of operation schemes. In the present example, any of an operation scheme in vertical holding of two controllers and an operation scheme in lateral holding of one controller representing a plurality of operation schemes is set. For example, in specifying an operation scheme, an operation scheme may be specified based on whether two controllers or one controller are/is held, or an operation scheme can also be specified based on whether the controller is held vertically or laterally. A controller can be registered in accordance with such a message. A state that a controller has not been registered is shown. A player number is allocated as a controller is registered. Then, a manner of a registered controller corresponding to the allocated player number is schematically shown in areas from P1 to P4 corresponding to player numbers. A manner of a controller which can be registered is shown in an upper area of the controller registration screen. Registration of two controllers of left controller 3 and right controller 4, registration of accessory controller 401, and registration of one controller, that is, left controller 3 or right controller 4, are shown. When two controllers are registered, in order to show a position of a button to be selected, together with an image of two controllers, the position is shown as being emphasized with a circular image being added. When accessory controller 401 is registered, in order to show a position of a button to be selected, together with an image of accessory controller 401, the position is shown as being emphasized with a circular image being added. Possibility of use of two controllers by two persons is also shown. In registration of one controller, in order to show a position of a button to be selected, together with an image of one controller, the position is shown as being emphasized with a circular image being added. A user can register a controller in a more simplified manner by checking on the controller registration screen, a position of the button emphasized by the circular image, together with the image of the controller. By way of example, user PA holds left controller 3a and right controller 4a. User PB holds accessory controller 401. User PC holds left controller 3b. User PD holds right controller 4b. When user PA registers two controllers, the user presses first L button 38 provided in left controller 3a and first R button 60 provided in right controller 4a. When user PB registers accessory controller 401, the user presses L button 425L and R button 425R in accessory controller 401. When user PC registers one controller with left controller 3b, the user presses second L button 43 and second R button 44 provided in left controller 3b. When user PD registers one controller with right controller 4b, the user presses second L button 65 and second R button 66 provided in right controller 4b. Game device 1 receives operation data transmitted from each controller, allocates a player number to each controller based on the received operation data, and registers an operation scheme in registration information as necessary. FIG. 15B shows an example in which a controller is registered in accordance with operation data. Specifically, an image of two controllers held by user PA is shown as the controller to which a player number P1 is allocated. An image of the accessory controller held by user PB is shown as the controller to which a player number P2 is allocated. An image of one controller held by user PC is shown as the controller to which a player number P3 is allocated. A state that a player number P4 has not yet been registered (an area shown with a dotted line) is shown. In the present example, a check image is shown in an area for player number P4 which has not yet been registered. In the check image, an image of a controller representing an operation scheme in lateral holding and an image of a controller representing an operation scheme in vertical holding are alternately shown. By showing the image of two controllers for which the operation scheme in vertical holding has been registered and an image of one controller for which the operation scheme in lateral holding has been registered, difference in manner of a method of operation of the controller is clearly shown and hence usability is improved. By further showing a name and a function of a button of the controller for which the operation scheme in vertical holding has been registered together with the image, information on the method of operation may be presented. By further showing a name and a function of a button of the controller for which the operation scheme in lateral holding has been registered together with the image, information on the method of operation may be presented. FIG. 16 is a diagram illustrating one example of registration information based on the embodiment. As shown in FIG. 16, registration information includes number information, identification information, information associated with wireless communication information, a player number, and information on an operation scheme. The number information is represented by a number provided to a registered controller. The identification information is information representing a value (for example, an ID) specifically provided to a controller. A controller can uniquely be identified based on the identification information. In the present embodiment, the identification information includes information indicating whether a controller is the left controller or the right controller. Main body apparatus 2 can determine based on the identification information provided to the controller whether the controller is the left controller or the right controller. In another embodiment, the identification information does not have to include information indicating whether the controller is the left controller or the right controller. The registration information may include (separately from the identification information) information indicating whether a controller is the left controller or the right controller. The wireless communication information indicates whether connection setting (that is, pairing) in connection with wireless communication with main body apparatus 2 has been made. When pairing between main body apparatus 2 and a controller has been completed, information indicating “set” is stored as wireless communication information associated with the controller. When pairing between main body apparatus 2 and a controller has not been completed, information indicating “not set” is stored as wireless communication information associated with the controller. Main body apparatus 2 may store information on connection setting for wireless communication (separately from the registration information), and does not have to carry out pairing again with the controller with which pairing has once been done. A player number represents identification information specifying a player operated in an application. The notification LED described above in the controller is controlled to indicate a value based on this number. The player number may be allocated in the order of registration of players or randomly by way of example. Information on the operation scheme represents information indicating a selected operation scheme when selection from among a plurality of operation schemes can be made for a controller. For left controller 3 and right controller 4 in the present example, an operation in vertical holding and an operation in lateral holding representing a plurality of operation schemes can be selected as described with reference to FIGS. 10 and 11. Some of registration information may be deleted or changed in accordance with an instruction from a user. For example, main body apparatus 2 may delete information on a designated controller and change information on a number provided to the controller, a player number, and an operation scheme in accordance with an instruction from a user. A functional block configuration of main body apparatus 2 based on the embodiment will now be described. FIG. 17 is a diagram illustrating a functional block configuration of main body apparatus 2 based on the embodiment. Referring to FIG. 17, a game execution processing module 302, a registration processing module 304, and a communication control module 310 are implemented by execution of a program by CPU 81 of main body apparatus 2. A program implementing the functional block is read, for example, from flash memory 84 of main body apparatus 2 or a memory card attached to the first slot, saved in DRAM 85, and executed. Communication control module 310 performs processing for communication with the controller as necessary. Game execution processing module 302 is a module controlling game processing and successively updates contents of representation on display 12 in accordance with contents of an operation by a user. Registration processing module 304 performs processing for pairing with a controller in wireless communication in wireless setting processing, obtains identification information of the controller, and updates registration information. Registration processing module 304 performs controller registration processing to have a player number registered and updated in the registration information in the flash memory. Registration processing module 304 registers an operation scheme of the controller as necessary. FIG. 18 is a flowchart illustrating one example of a flow of processing for registration of a controller performed in main body apparatus 2 based on the embodiment. Processing in each step in the flowchart shown in FIG. 18 is merely by way of example. So long as similar results can be obtained, an order of processing in the steps may be changed or another processing may be performed in addition to (or instead of) processing in each step. Though processing in each step in the flowchart is described as being performed by CPU 81 of main body apparatus 2 in the present embodiment, processing in some steps in the flowchart may be performed by a processor or a dedicated circuit other than CPU 81. A part of processing performed in main body apparatus 2 may be performed by another information processing apparatus which can communicate with main body apparatus 2 (for example, a server which can communicate with main body apparatus 2 through a network). Each processing shown in FIG. 18 may be performed by cooperation of a plurality of information processing apparatuses including main body apparatus 2. Referring to FIG. 18, CPU 81 makes setting (also called pairing) for establishing wireless communication between main body apparatus 2 and a controller (step S2). In the present embodiment, main body apparatus 2 performs wireless setting processing for making setting for wireless communication with a controller. CPU 81 determines whether or not pairing has been completed through wireless communication with the controller. When pairing has been completed, the process proceeds to a next step. When CPU 81 determines that pairing has not been completed through wireless communication with the controller, it has necessary registration information registered in the storage unit. Specifically, registration information stored in the storage unit is updated to add number information, identification information, and wireless communication information of the controller to registration information in association with one another. For example, information representing a number which has not been set for other registered controllers is set as number information. Identification information provided to the controller is set. As pairing is completed, information representing “set” is set. A player number and an operation scheme are set in subsequent processing. CPU 81 determines whether or not an instruction to register the controller has been given (step S4). In the present embodiment, an instruction to register the controller is given in response to transmission of a prescribed command from the controller to main body apparatus 2. By way of example, main body apparatus 2 performs processing for registering the controller by selecting an item for controller registration processing in a not-shown menu screen through the controller. Initially, when CPU 81 determines that an instruction to register the controller has been given (YES in step S4), it has a controller registration screen shown (step S20). CPU 81 maintains a state in step S4 until an instruction to register the controller is given. When an instruction to register the controller is given, registration processing module 304 has the controller registration screen as described with reference to FIG. 15 (A) shown. CPU 81 determines whether or not it has received operation data (step S22). Specifically, registration processing module 304 determines whether or not it has received operation data from the controller through communication control module 310. When CPU 81 does not receive operation data in step S22 (NO in step S22), it stands by until it receives operation data, and when it determines that it has received operation data (YES in step S22), it determines whether or not the operation data is operation data of the accessory controller (step S24). Specifically, registration processing module 304 determines whether or not the controller is the accessory controller based on the identification information in the received operation data. When CPU 81 determines in step S24 that the operation data is not operation data of the accessory controller (NO in step S24), it determines whether or not the operation data has second L button operation data and second R button operation data (step S26). Specifically, registration processing module 304 determines whether or not the received operation data includes second L button operation data and second R button operation data. When CPU 81 determines in step S26 that the operation data has second L button operation data and second R button operation data (YES in step S26), it has a player number for one controller registered (step S28). Specifically, registration processing module 304 has a player number registered in the registration information. The player number is registered in accordance with the order of registration of players. A player number P1 is registered for the first player, a player number P2 is registered for the second player, and so on. CPU 81 has the operation scheme in lateral holding registered in the registration information (step S30). Specifically, registration processing module 304 has information representing the operation scheme in lateral holding registered in a field of the operation scheme in the registration information. FIGS. 19A to 19C are diagrams illustrating operation data transmitted from the controller based on the embodiment to main body apparatus 2. FIG. 19A shows operation data 500 transmitted from controller 3b by way of example. Operation data 500 includes identification information data 501, second L button operation data 502, and second R button operation data 503. By way of example, second L button operation data 502 and second R button operation data 503 are operation data resulting when user PC presses both of second L button 43 and second R button 44 provided in left controller 3b. Though operation data of controller 3b is described, operation data of controller 4b is basically also similar. In the case of operation data of controller 4b, second L button operation data 502 and second R button operation data 503 are operation data resulting when user PD presses both of second L button 65 and second R button 66 provided in right controller 4b. Main body apparatus 2 can identify a type of a controller based on identification information data 501 included in operation data 500. In this case, when it is determined that the controller is not the accessory controller in accordance with identification information data 501, CPU 81 determines whether or not operation data 500 includes second L button operation data and second R button operation data. In this case, one controller is registered in operation data 500 based on second L button operation data 502 and second R button operation data 503. A player number is allocated to one controller. Main body apparatus 2 has the operation in lateral holding registered as the operation scheme in the registration information. Referring again to FIG. 18, CPU 81 updates the controller registration screen (step S32). Specifically, registration processing module 304 has an image of the controller set in accordance with the order of registration of players shown. For example, when a third player number is registered, a left controller operated as being laterally held is shown in a region third from the left in the controller registration screen. An indicator image showing that the third player number is set is shown as an indicator image. A corresponding notification LED in the left controller may be turned on in correspondence with the player number. CPU 81 determines whether or not controller registration processing has ended (step S34). Specifically, when the “A” button is selected in the controller registration screen described with reference to FIG. 15, registration processing module 304 determines that the controller registration processing has ended. When CPU 81 determines in step S34 that controller registration processing has ended (YES in step S34), the process ends (end). When CPU 81 determines that controller registration processing has not ended (NO in step S34), the process returns to step S22 and the process is repeated. When CPU 81 determines in step S26 that the operation data is not second L button operation data and second R button operation data (NO in step S26), it has a check image shown (step S35). Registration processing module 304 has the controller registration screen as described with reference to FIG. 15B shown. Specifically, by way of example, a check image shown in a region for player number P4 is shown. An image of the controller showing the operation scheme in lateral holding and an image of the controller showing the operation scheme in vertical holding are alternately shown. In this case, the image of the controller is shown in a region of a player number which has not yet been registered. CPU 81 determines whether or not it has received operation data (step S36). Specifically, registration processing module 304 determines whether or not it has further received operation data from the controller through communication control module 310. CPU 81 maintains a state in step S36 until it receives operation data. When CPU 81 determines in step S36 that it has received operation data (YES in step S36), the process proceeds to a next step S37. CPU 81 determines in step S37 whether or not first L button operation data and first R button operation data have simultaneously been received as the operation data. Specifically, registration processing module 304 determines whether or not one piece of a plurality of simultaneously received pieces of operation data includes the first L button operation data and the other piece of them includes the first R button operation data. When CPU 81 determines in step S37 that the first L button operation data and the first R button operation data have simultaneously been received as the operation data (YES in step S37), it has a player number for two controllers constituting a set registered (step S40). Specifically, registration processing module 304 has a player number registered in the registration information. The player number for two controllers is registered in accordance with the order of registration of players. A player number P1 is registered for the first player, a player number P2 is registered for the second player, and so on. Left controller 3 and right controller 4 constitute a set in the present example. Therefore, two left controllers or two right controllers do not constitute a set. Simultaneous reception of operation data is not limited to exactly the same timing of reception, and it is a concept encompassing also an example in which a period from reception of first operation data until reception of subsequent operation data is extremely short. CPU 81 has the operation scheme in vertical holding registered in the registration information (step S42). Specifically, registration processing module 304 has information representing the operation scheme in vertical holding registered in a field of the operation scheme in the registration information. FIG. 19B shows operation data 510 and 520 transmitted from controllers 3a and 4a, respectively, by way of example. Operation data 510 includes identification information data 512 and first L button operation data 514. Operation data 520 includes identification information data 522 and first R button operation data 524. By way of example, first L button operation data 514 is operation data resulting when user PA presses first L button 38 provided in left controller 3a. First R button operation data 524 is operation data resulting when user PA presses first R button 60 provided in right controller 4a. Main body apparatus 2 can identify a left controller based on identification information data 512 included in operation data 510. Main body apparatus 2 can identify a right controller based on identification information data 522 included in operation data 520. Main body apparatus 2 determines whether or not it has received the first L button operation data and the first R button operation data from the left controller and the right controller, respectively, and when it determines that the main body apparatus has received both of them, it has two controllers registered. A player number is allocated to the two controllers. Main body apparatus 2 has the operation in vertical holding registered as the operation scheme. Referring again to FIG. 18, CPU 81 updates the controller registration screen (step S32). Specifically, registration processing module 304 has an image of the controller set in accordance with the order of registration of players shown. For example, when the first player number is registered, a left controller and a right controller operated as being vertically held are shown in a region first from the left in the controller registration screen. An indicator image showing that the first player number is set is shown as an indicator image. Notification LEDs in the left controller and the right controller corresponding to the player number may be turned on. Since subsequent processing is similar, detailed description thereof will not be repeated. When CPU 81 determines in step S37 that the operation data does not have the first L button operation data or the first R button operation data (NO in step S37), CPU 81 determines whether or not the operation data has second L button operation data and second R button operation data (step S45). When CPU 81 determines that the operation data has second L button operation data and second R button operation data (YES in step S45), the process proceeds to “A”. A player number for one controller is registered (step S28). Specifically, registration processing module 304 has a player number registered in the registration information. The player number is registered in accordance with the order of registration of players. A player number P1 is registered for the first player, a player number P2 is registered for the second player, and so on. CPU 81 has the operation scheme in lateral holding registered in the registration information (step S30). Specifically, registration processing module 304 has information representing the operation scheme in lateral holding registered in a field of the operation scheme in the registration information. CPU 81 updates the controller registration screen (step S32). Specifically, registration processing module 304 has an image of the controller set in accordance with the order of registration of players shown. For example, when the third player number is registered, a left controller operated as being laterally held is shown in a region third from the left in the controller registration screen. An indicator image showing that the third player number is set is shown as an indicator image. A notification LED in the corresponding left controller may be turned on in correspondence with the player number. When CPU 81 determines in step S45 that the operation data does not have second L button operation data and second R button operation data (NO in step S45), the process proceeds to step S34 as determining that no operation scheme has been set. When CPU 81 determines in step S24 that the operation data is operation data of the accessory controller (YES in step S24), it determines whether or not the operation data has L button operation data and R button operation data (step S44. Specifically, registration processing module 304 determines whether or not the received operation data includes L button operation data and R button operation data. When CPU 81 determines in step S44 that the operation data has L button operation data and R button operation data (YES in step S44), it has a player number for the accessory controller registered (step S46). Specifically, registration processing module 304 has a player number registered in the registration information. The player number is registered in accordance with the order of registration of players. A player number P1 is registered for the first player, a player number P2 is registered for the second player, and so on. FIG. 19C shows operation data 530 transmitted from accessory controller 401 by way of example. Operation data 530 includes identification information data 532, L button operation data 534, and R button operation data 536. By way of example, L button operation data 534 and R button operation data 536 are operation data resulting when user PB presses both of L button 425L and R button 425R provided in accessory controller 401. Main body apparatus 2 can identify the accessory controller based on identification information data 532 included in operation data 530. Main body apparatus 2 has the accessory controller registered based on L button operation data 534 and R button operation data 536 included in operation data 530. A player number is allocated to the accessory controller. Since the accessory controller is not provided with a plurality of operation schemes, no operation scheme is registered therefor. Though description will be given later, whether or not operation data is converted is determined based on contents of registration of the operation scheme (whether or not the operation scheme is the operation scheme in vertical holding or the operation scheme in lateral holding), and therefore data on conversion may be registered also for the accessory controller. Specifically, no conversion may be registered as a conversion scheme. Referring again to FIG. 18, CPU 81 updates the controller registration screen (step S32). Specifically, registration processing module 304 has an image of the controller set in accordance with the order of registration of players shown. For example, when the second player number is registered, the accessory controller is shown in a region second from the left in the controller registration screen. An indicator image showing that the second player number is set is shown as an indicator image. A notification LED in the accessory controller corresponding to the player number may be turned on. Since subsequent processing is similar, detailed description thereof will not be repeated. When CPU 81 determines in step S44 that the operation data does not have L button operation data and R button operation data (NO in step S44), the process proceeds to step S34 as determining that no operation scheme has been set. Through the processing, controller registration processing can be performed based on operation data transmitted from each controller. In the controller registration processing, one operation scheme can be registered for a controller for which selection from among a plurality of operation schemes can be made based on operation contents of the operation data. Controller registration processing in connection with the operation scheme can thus be performed in a simplified manner and usability can be improved. In the controller registration processing, the operation scheme once registered can also be changed. For example, after the operation scheme in vertical holding using two controllers is registered, change to the operation scheme in lateral holding using one controller can also be made. Specifically, both of the second L button and the second R button are pressed in left controller 3 of two controllers registered as player number P1. Through the processing, operation data is transmitted from the left controller to main body apparatus 2. Main body apparatus 2 receives the operation data and performs processing for registering again the player and processing for registering lateral holding. The operation scheme of left controller 3 registered as player number P1 is changed to the operation scheme in lateral holding while the player number in the registration information is maintained. Information on allocation of the player number and the operation scheme in the registration information for right controller 4 registered as player number P1 is deleted. Though description is given for left controller 3, description is also the same for right controller 4, and processing for registering again the player and processing for registering lateral holding can similarly be performed. After the operation scheme in lateral holding using one controller is registered, change to the operation scheme in vertical holding using two controllers can also be made. Specifically, both of the first L button and the first R button in both of left controller 3 registered as player number P3 and right controller 4 registered as player number P4 are pressed. Through the processing, operation data is transmitted from left controller 3 and right controller 4 to main body apparatus 2. Main body apparatus 2 receives the operation data and performs processing for registering again the player and processing for registering vertical holding in accordance with the scheme described above. Left controller 3 registered as player number P3 and right controller 4 registered as player number P4 are determined as controllers constituting a set. In the registration information, the operation scheme of left controller 3 registered as player number P3 is changed to the operation scheme in vertical holding while the player number is maintained. The player number of right controller 4 registered as player number P4 is changed to player number P3 and the operation scheme thereof is changed to the operation scheme in vertical holding. [F. Game Processing] FIG. 20 is a diagram of one example illustrating game processing performed by game device 1 based on the embodiment. In FIG. 20, an image generated by game device 1 is shown on television 6. In the present example, four players are shown. User PA operates a corresponding object with two controllers 3a and 4a. User PB operates a corresponding object with accessory controller 401. User PC operates a corresponding object with one controller 3b. User PD operates a corresponding object with one controller 4b. In the present example, game device 1 divides a display area of television 6 into four sections, and shows an image for user PA (for example, an image including the first object) in a divided display area 6A and an image for user PB (for example, an image including the second object) in a divided display area 6B. Similarly, game device 1 shows an image for user PC (for example, an image including a third object) in a divided display area 6C and an image for user PD (for example, an image including a fourth object) in a divided display area 6D. Each controller controls a notification LED based on a player number from game device 1. In the present example, users PA to PD representing four players operate corresponding objects with the controllers, respectively. This is also applicable to an example in which there is one player. [G. Processing Procedure] A processing procedure involved with game processing in game device 1 based on the embodiment will now be described. FIG. 21 is a flowchart showing a processing procedure involved with the game processing based on the embodiment. Each step shown in FIG. 21 is typically performed by execution of a program by CPU 81 of main body apparatus 2. Referring to FIG. 21, CPU 81 determines whether or not start of game processing has been indicated (step S50). Game execution processing module 302 determines whether or not start of game processing has been indicated. When CPU 81 determines that start of game processing has been indicated (YES in step S50), it generates a game image in which an object is arranged in a game space (step S51). Game execution processing module 302 generates a game image in which an object is arranged in a game space based on a program saved and executed in DRAM 85. Then, CPU 81 determines whether or not it has obtained operation data (step S52). Specifically, game execution processing module 302 determines whether or not operation data has been obtained through communication control module 310. When CPU 81 determines in step S52 that it has obtained operation data (YES in step S52), it determines whether or not the operation data is operation data of the accessory controller (step S53). Specifically, game execution processing module 302 determines whether or not the controller is the accessory controller based on identification information in the received operation data described with reference to FIG. 20. When CPU 81 determines in step S53 that the operation data is not the operation data of the accessory controller (NO in step S53), it determines whether or not an operation in lateral holding has been registered (step S54). Specifically, game execution processing module 302 determines whether or not the operation scheme in lateral holding has been registered in the information on the operation scheme in the registration information for a controller corresponding to the obtained operation data, by referring to the registration information stored in flash memory 84. When CPU 81 determines in step S54 that the operation in lateral holding has not been registered (NO in step S54), it performs processing based on the operation data (step S56). Specifically, when game execution processing module 302 determines that the operation scheme in lateral holding has not been registered in the information on the operation scheme in the registration information for the controller corresponding to the obtained operation data by referring to the registration information stored in flash memory 84, it performs game processing based on the obtained operation data. Then, CPU 81 updates the game image (step S58). Specifically, game execution processing module 302 generates a game image in accordance with the operation data in accordance with an obtained operation by a user. Then, updated output is given to television 6 in accordance with the generated game image. Then, CPU 81 determines whether or not end of game processing has been indicated (step S60). When CPU 81 determines in step S60 that end of game processing has been indicated (YES in step S60), the process ends (end). When CPU 81 determines in step S60 that end of game processing has not been indicated (NO in step S60), the process returns to step S52 and the process is repeated. When CPU 81 determines in step S53 that the operation data is the operation data of the accessory controller (YES in step S53), it performs processing based on the operation data (step S56). Specifically, when game execution processing module 302 determines that the operation data is the operation data of the accessory controller, it performs game processing based on the obtained operation data. Then, CPU 81 updates the game image (step S58). Specifically, game execution processing module 302 generates a game image in accordance with the operation data in accordance with an obtained operation by a user. Then, updated output is given to television 6 in accordance with the generated game image. Since subsequent processing is similar, detailed description thereof will not be repeated. When CPU 81 determines in step S54 that the operation in lateral holding has been registered (YES in step S54), it performs processing for converting operation data into converted operation data (step S62). Specifically, when game execution processing module 302 determines that the operation scheme in lateral holding has been registered in the information on the operation scheme in the registration information for the controller corresponding to the obtained operation data by referring to the registration information stored in flash memory 84, it performs processing for converting the operation data into converted operation data. Specifically, in the case of left controller 3, conversion to such converted operation data that a direction instruction from analog stick 32 is rotated counterclockwise by 90° is made. Thus, an instruction from left controller 3 operated as being laterally held onto an object can be the same in direction as a direction instruction from analog stick 32 of left controller 3 operated as being vertically held. Functions of four operation buttons 33 to 36 are allocated to the X button, the A button, the Y button, and the B button, respectively. Thus, the operation buttons in left controller 3 operated as being laterally held for an object can be the same in function as four operation buttons 33 to 36 under the operation scheme in vertical holding. In the case of right controller 4, conversion to such converted operation data that a direction instruction from analog stick 52 is rotated clockwise by 90° is made. Thus, an instruction from right controller 4 operated as being laterally held onto an object can be the same in direction as a direction instruction from analog stick 52 of right controller 4 operated as being vertically held. Functions of four operation buttons 53 to 56 are allocated to the B button, the Y button, the A button, and the X button, respectively. Thus, the operation buttons in right controller 4 operated as being laterally held for an object can be the same in function as four operation buttons 53 to 56 under the operation scheme in vertical holding. Then, CPU 81 performs processing based on the converted operation data (step S64). Specifically, game execution processing module 302 generates a game image in accordance with the converted operation data. Then, updated output is given to television 6 in accordance with the generated game image. Since subsequent processing is similar, detailed description thereof will not be repeated. Then, CPU 81 updates the game image (step S58). Specifically, game execution processing module 302 generates a game image in accordance with operation data in accordance with an obtained operation by a user. Then, updated output is given to television 6 in accordance with the generated game image. Since subsequent processing is similar, detailed description thereof will not be repeated. An application executable on a personal computer may be provided as a program in the present embodiment. The program according to the present embodiment may be incorporated as some functions of various application programs executed on the personal computer. Though embodiments of the present invention have been described, it should be understood that the embodiments disclosed herein are illustrative and non-restrictive in every respect. The scope of the present invention is defined by the terms of the claims and is intended to include any modifications within the scope and meaning equivalent to the terms of the claims. While certain example systems, methods, devices, and apparatuses have been described herein, it is to be understood that the appended claims are not to be limited to the systems, methods, devices, and apparatuses disclosed, but on the contrary, are intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.
<SOH> BACKGROUND AND SUMMARY <EOH>In a game system representing one example of a conventional information processing system, when a game controller representing an operation apparatus is registered in correspondence with a player number, the game controller may be registered by successively performing the same prescribed operation onto each game controller. Selection from among a plurality of operation schemes can be made for an operation apparatus in some cases. In such a case, though an operation scheme should also be registered, successive registration complicates a procedure for registration and there is a room for improvement in usability. The present disclosure is provided to solve the above-described problems and an object thereof is to provide an information processing system which can achieve improved usability, an information processing apparatus, a method of controlling an information processing apparatus, and an information processing program. An information processing system according to one aspect includes an operation apparatus and a main body apparatus which is capable of communicating with the operation apparatus. The operation apparatus includes a first transceiver which transmits operation data representing an operation by a user to the main body apparatus. The main body apparatus includes a memory in which an operation scheme of the operation apparatus is registered, a second transceiver which receives the operation data transmitted from the first transceiver, and a controller. The controller registers the operation scheme of the operation apparatus in the memory as a first operation scheme when the operation data received by the second transceiver indicates a first operation and registers the operation scheme of the operation apparatus in the memory as a second operation scheme when the operation data received by the second transceiver indicates a second operation, and performs processing based on the operation scheme registered in the memory onto the operation data received by the second transceiver. The controller can register the operation scheme of the operation apparatus in the memory as the first operation scheme or the second operation scheme based on the operation data transmitted from the operation apparatus. Therefore, processing for registering the operation scheme of the operation apparatus can readily be performed and usability can be improved. In the exemplary embodiment, the operation apparatus further includes a first operation portion and a second operation portion. The controller may register the operation scheme of the operation apparatus in the memory as the first operation scheme when the operation data received by the second transceiver indicates the first operation of the first operation portion and register the operation scheme of the operation apparatus in the memory as the second operation scheme when the operation data received by the second transceiver indicates the second operation of the second operation portion. The controller can register the operation scheme of the operation apparatus in the memory as the first operation scheme based on the operation data transmitted from the first operation portion and register the operation scheme of the operation apparatus in the memory as the second operation scheme based on the operation data transmitted from the second operation portion. Therefore, since the operation scheme of the operation apparatus is registered based on the operation data from different operation portions, registration processing can readily be performed and usability can be improved. In the exemplary embodiment, the first operation portion and the second operation portion may be disposed on different surfaces of a housing of the operation apparatus, respectively. Since the first operation portion and the second operation portion are provided on different surfaces of the housing, respectively, registration processing can readily be performed without confusion and usability can be improved. In the exemplary embodiment, the operation apparatus further includes a third operation portion. The controller may perform processing on operation data of the third operation portion received by the second transceiver differently between the first operation scheme and the second operation scheme registered in the memory. The controller can perform appropriate processing in accordance with the operation scheme by performing processing on the operation data of the third operation portion differently between the first operation scheme and the second operation scheme. In the exemplary embodiment, the controller may perform prescribed processing on the operation data of the third operation portion received by the second transceiver when the first operation scheme is registered in the memory, and convert the operation data of the third operation portion received by the second transceiver into converted operation data when the second operation scheme is registered in the memory and perform the prescribed processing based on the converted operation data. When the second operation scheme is registered, the controller converts the operation data into converted operation data and performs prescribed processing based on the converted operation data. Therefore, even when the second operation scheme is registered, it is not necessary to change prescribed processing in accordance with the operation scheme by conversion to converted operation data corresponding to the operation data under the first operation scheme and processing can readily be realized. In the exemplary embodiment, the operation data of the third operation portion includes direction data representing a direction of input. The controller may perform the prescribed processing on the direction data of the third operation portion received by the second transceiver when the first operation scheme is registered in the memory and convert the direction data of the third operation portion received by the second transceiver into converted direction data different in direction of input from the direction data when the second operation scheme is registered in the memory and perform the prescribed processing based on the converted direction data. In the exemplary embodiment, the first and second operation portions may be disposed on identical sides of prescribed operation surfaces of a housing of the operation apparatus, respectively when the user performs an operation under any of the first and second operation schemes. The first and second operation portions are provided on the side of the prescribed operation surface of the housing of the operation apparatus when the user performs an operation under each of the first operation scheme and the second operation scheme so that an intuitive operation in selection of the operation scheme can be performed and usability can be improved. In the exemplary embodiment, a plurality of operation apparatuses are provided, and when a plurality of pieces of the operation data received by the second transceiver indicate the first operation, the controller may set a plurality of operation apparatuses as one set and register an operation scheme of the set of the operation apparatuses in the memory as the first operation scheme. Since the controller can make registration of one set of operation apparatuses in the memory based on a plurality of pieces of operation data transmitted from a plurality of operation apparatuses, registration processing can readily be performed and usability can be improved. In the exemplary embodiment, two operation apparatuses of the plurality of operation apparatuses are set as one set. The two operation apparatuses constituting the set may be designated in advance. By designating in advance two operation apparatuses to constitute a set, management of the operation apparatuses is facilitated and processing can be accelerated. In the exemplary embodiment, the controller registers the operation scheme of the set of the operation apparatuses in the memory as the first operation scheme when the plurality of pieces of operation data received by the second transceiver simultaneously indicate the first operation. Since the controller can make registration of one set of operation apparatuses in the memory when a plurality of pieces of operation data transmitted from a plurality of operation apparatuses simultaneously indicate the first operation, one set of operation apparatuses can easily be distinguished and registration processing can readily be performed. An information processing apparatus which is capable of communicating with an operation apparatus according to one aspect includes a memory in which an operation scheme of the operation apparatus is registered, a transceiver which receives operation data transmitted from the operation apparatus, and a controller. The controller registers the operation scheme of the operation apparatus in the memory as a first operation scheme when the operation data received by the transceiver indicates a first operation and registers the operation scheme of the operation apparatus in the memory as a second operation scheme when the operation data received by the transceiver indicates a second operation, and performs processing based on the operation scheme registered in the memory onto the operation data received by the transceiver. The controller can register the operation scheme of the operation apparatus in the memory as the first operation scheme or the second operation scheme based on the operation data transmitted from the operation apparatus. Therefore, processing for registering the operation scheme of the operation apparatus can readily be performed and usability can be improved. A method of controlling an information processing apparatus which is capable of communicating with an operation apparatus according to one aspect includes receiving operation data transmitted from the operation apparatus, registering an operation scheme of the operation apparatus in a storage unit as a first operation scheme when the received operation data indicates a first operation, registering the operation scheme of the operation apparatus in the storage unit as a second operation scheme when the received operation data indicates a second operation, and performing processing based on the operation scheme registered in the storage unit onto the received operation data. In the registering an operation scheme, the operation scheme of the operation apparatus can be registered in the storage unit as the first operation scheme or the second operation scheme based on the operation data transmitted from the operation apparatus. Therefore, processing for registering the operation scheme of the operation apparatus can readily be performed and usability can be improved. A non-transitory storage medium encoded with a program readable by a computer of an information processing apparatus which is capable of communicating with an operation apparatus according to one aspect is provided. The program causes the computer to perform receiving operation data transmitted from the operation apparatus, registering an operation scheme of the operation apparatus in a memory as a first operation scheme when the received operation data indicates a first operation, registering the operation scheme of the operation apparatus in the memory as a second operation scheme when the received operation data indicates a second operation, and performing processing based on the operation scheme registered in the memory onto the received operation data. The computer can register the operation scheme of the operation apparatus in the memory as the first operation scheme or the second operation scheme based on the operation data transmitted from the operation apparatus. Therefore, processing for registering the operation scheme of the operation apparatus can readily be performed and usability can be improved. An information processing system according to one aspect includes a first operation apparatus, a second operation apparatus, and a main body apparatus which is capable of communicating with the first operation apparatus and the second operation apparatus. The first operation apparatus and the second operation apparatus each include a first transceiver which transmits operation data representing an operation by a user to the main body apparatus. The main body apparatus includes a memory in which operation schemes of the first operation apparatus and the second operation apparatus are registered, a second transceiver which receives the operation data transmitted from the first transceiver, and a controller. The controller sets, when a plurality of pieces of operation data received from the first operation apparatus and the second operation apparatus by the second transceiver indicate a first operation, the first operation apparatus and the second operation apparatus as one set and registers an operation scheme of the set in the memory as a first operation scheme, and registers, when the operation data received from any one of the first operation apparatus and the second operation apparatus by the second transceiver indicates a second operation, the operation scheme of any of the first operation apparatus and the second operation apparatus in the memory as a second operation scheme. The controller can register the operation scheme of the operation apparatus in the memory as the first operation scheme or the second operation scheme based on the operation data transmitted from the operation apparatus. Therefore, processing for registering the operation scheme of the operation apparatus can readily be performed and usability can be improved. In the exemplary embodiment, each of the first operation apparatus and the second operation apparatus further includes a first operation portion, a second operation portion, and a third operation portion. The controller registers the operation scheme in the memory as the first operation scheme when the plurality of pieces of operation data received from the first operation apparatus and the second operation apparatus by the second transceiver indicate the first operation of the first operation portion and registers the operation scheme in the memory as the second operation scheme when the operation data received from any one of the first operation apparatus and the second operation apparatus by the second transceiver indicates the second operation of the second operation portion and the third operation portion. The controller can register the operation scheme of the operation apparatus in the memory as the first operation scheme or the second operation scheme based on the operation data transmitted from the operation apparatus. Therefore, processing for registering the operation scheme of the operation apparatus can readily be performed and usability can be improved. The foregoing and other objects, features, aspects and advantages of the exemplary embodiments will become more apparent from the following detailed description of the exemplary embodiments when taken in conjunction with the accompanying drawings.
<SOH> BACKGROUND AND SUMMARY <EOH>In a game system representing one example of a conventional information processing system, when a game controller representing an operation apparatus is registered in correspondence with a player number, the game controller may be registered by successively performing the same prescribed operation onto each game controller. Selection from among a plurality of operation schemes can be made for an operation apparatus in some cases. In such a case, though an operation scheme should also be registered, successive registration complicates a procedure for registration and there is a room for improvement in usability. The present disclosure is provided to solve the above-described problems and an object thereof is to provide an information processing system which can achieve improved usability, an information processing apparatus, a method of controlling an information processing apparatus, and an information processing program. An information processing system according to one aspect includes an operation apparatus and a main body apparatus which is capable of communicating with the operation apparatus. The operation apparatus includes a first transceiver which transmits operation data representing an operation by a user to the main body apparatus. The main body apparatus includes a memory in which an operation scheme of the operation apparatus is registered, a second transceiver which receives the operation data transmitted from the first transceiver, and a controller. The controller registers the operation scheme of the operation apparatus in the memory as a first operation scheme when the operation data received by the second transceiver indicates a first operation and registers the operation scheme of the operation apparatus in the memory as a second operation scheme when the operation data received by the second transceiver indicates a second operation, and performs processing based on the operation scheme registered in the memory onto the operation data received by the second transceiver. The controller can register the operation scheme of the operation apparatus in the memory as the first operation scheme or the second operation scheme based on the operation data transmitted from the operation apparatus. Therefore, processing for registering the operation scheme of the operation apparatus can readily be performed and usability can be improved. In the exemplary embodiment, the operation apparatus further includes a first operation portion and a second operation portion. The controller may register the operation scheme of the operation apparatus in the memory as the first operation scheme when the operation data received by the second transceiver indicates the first operation of the first operation portion and register the operation scheme of the operation apparatus in the memory as the second operation scheme when the operation data received by the second transceiver indicates the second operation of the second operation portion. The controller can register the operation scheme of the operation apparatus in the memory as the first operation scheme based on the operation data transmitted from the first operation portion and register the operation scheme of the operation apparatus in the memory as the second operation scheme based on the operation data transmitted from the second operation portion. Therefore, since the operation scheme of the operation apparatus is registered based on the operation data from different operation portions, registration processing can readily be performed and usability can be improved. In the exemplary embodiment, the first operation portion and the second operation portion may be disposed on different surfaces of a housing of the operation apparatus, respectively. Since the first operation portion and the second operation portion are provided on different surfaces of the housing, respectively, registration processing can readily be performed without confusion and usability can be improved. In the exemplary embodiment, the operation apparatus further includes a third operation portion. The controller may perform processing on operation data of the third operation portion received by the second transceiver differently between the first operation scheme and the second operation scheme registered in the memory. The controller can perform appropriate processing in accordance with the operation scheme by performing processing on the operation data of the third operation portion differently between the first operation scheme and the second operation scheme. In the exemplary embodiment, the controller may perform prescribed processing on the operation data of the third operation portion received by the second transceiver when the first operation scheme is registered in the memory, and convert the operation data of the third operation portion received by the second transceiver into converted operation data when the second operation scheme is registered in the memory and perform the prescribed processing based on the converted operation data. When the second operation scheme is registered, the controller converts the operation data into converted operation data and performs prescribed processing based on the converted operation data. Therefore, even when the second operation scheme is registered, it is not necessary to change prescribed processing in accordance with the operation scheme by conversion to converted operation data corresponding to the operation data under the first operation scheme and processing can readily be realized. In the exemplary embodiment, the operation data of the third operation portion includes direction data representing a direction of input. The controller may perform the prescribed processing on the direction data of the third operation portion received by the second transceiver when the first operation scheme is registered in the memory and convert the direction data of the third operation portion received by the second transceiver into converted direction data different in direction of input from the direction data when the second operation scheme is registered in the memory and perform the prescribed processing based on the converted direction data. In the exemplary embodiment, the first and second operation portions may be disposed on identical sides of prescribed operation surfaces of a housing of the operation apparatus, respectively when the user performs an operation under any of the first and second operation schemes. The first and second operation portions are provided on the side of the prescribed operation surface of the housing of the operation apparatus when the user performs an operation under each of the first operation scheme and the second operation scheme so that an intuitive operation in selection of the operation scheme can be performed and usability can be improved. In the exemplary embodiment, a plurality of operation apparatuses are provided, and when a plurality of pieces of the operation data received by the second transceiver indicate the first operation, the controller may set a plurality of operation apparatuses as one set and register an operation scheme of the set of the operation apparatuses in the memory as the first operation scheme. Since the controller can make registration of one set of operation apparatuses in the memory based on a plurality of pieces of operation data transmitted from a plurality of operation apparatuses, registration processing can readily be performed and usability can be improved. In the exemplary embodiment, two operation apparatuses of the plurality of operation apparatuses are set as one set. The two operation apparatuses constituting the set may be designated in advance. By designating in advance two operation apparatuses to constitute a set, management of the operation apparatuses is facilitated and processing can be accelerated. In the exemplary embodiment, the controller registers the operation scheme of the set of the operation apparatuses in the memory as the first operation scheme when the plurality of pieces of operation data received by the second transceiver simultaneously indicate the first operation. Since the controller can make registration of one set of operation apparatuses in the memory when a plurality of pieces of operation data transmitted from a plurality of operation apparatuses simultaneously indicate the first operation, one set of operation apparatuses can easily be distinguished and registration processing can readily be performed. An information processing apparatus which is capable of communicating with an operation apparatus according to one aspect includes a memory in which an operation scheme of the operation apparatus is registered, a transceiver which receives operation data transmitted from the operation apparatus, and a controller. The controller registers the operation scheme of the operation apparatus in the memory as a first operation scheme when the operation data received by the transceiver indicates a first operation and registers the operation scheme of the operation apparatus in the memory as a second operation scheme when the operation data received by the transceiver indicates a second operation, and performs processing based on the operation scheme registered in the memory onto the operation data received by the transceiver. The controller can register the operation scheme of the operation apparatus in the memory as the first operation scheme or the second operation scheme based on the operation data transmitted from the operation apparatus. Therefore, processing for registering the operation scheme of the operation apparatus can readily be performed and usability can be improved. A method of controlling an information processing apparatus which is capable of communicating with an operation apparatus according to one aspect includes receiving operation data transmitted from the operation apparatus, registering an operation scheme of the operation apparatus in a storage unit as a first operation scheme when the received operation data indicates a first operation, registering the operation scheme of the operation apparatus in the storage unit as a second operation scheme when the received operation data indicates a second operation, and performing processing based on the operation scheme registered in the storage unit onto the received operation data. In the registering an operation scheme, the operation scheme of the operation apparatus can be registered in the storage unit as the first operation scheme or the second operation scheme based on the operation data transmitted from the operation apparatus. Therefore, processing for registering the operation scheme of the operation apparatus can readily be performed and usability can be improved. A non-transitory storage medium encoded with a program readable by a computer of an information processing apparatus which is capable of communicating with an operation apparatus according to one aspect is provided. The program causes the computer to perform receiving operation data transmitted from the operation apparatus, registering an operation scheme of the operation apparatus in a memory as a first operation scheme when the received operation data indicates a first operation, registering the operation scheme of the operation apparatus in the memory as a second operation scheme when the received operation data indicates a second operation, and performing processing based on the operation scheme registered in the memory onto the received operation data. The computer can register the operation scheme of the operation apparatus in the memory as the first operation scheme or the second operation scheme based on the operation data transmitted from the operation apparatus. Therefore, processing for registering the operation scheme of the operation apparatus can readily be performed and usability can be improved. An information processing system according to one aspect includes a first operation apparatus, a second operation apparatus, and a main body apparatus which is capable of communicating with the first operation apparatus and the second operation apparatus. The first operation apparatus and the second operation apparatus each include a first transceiver which transmits operation data representing an operation by a user to the main body apparatus. The main body apparatus includes a memory in which operation schemes of the first operation apparatus and the second operation apparatus are registered, a second transceiver which receives the operation data transmitted from the first transceiver, and a controller. The controller sets, when a plurality of pieces of operation data received from the first operation apparatus and the second operation apparatus by the second transceiver indicate a first operation, the first operation apparatus and the second operation apparatus as one set and registers an operation scheme of the set in the memory as a first operation scheme, and registers, when the operation data received from any one of the first operation apparatus and the second operation apparatus by the second transceiver indicates a second operation, the operation scheme of any of the first operation apparatus and the second operation apparatus in the memory as a second operation scheme. The controller can register the operation scheme of the operation apparatus in the memory as the first operation scheme or the second operation scheme based on the operation data transmitted from the operation apparatus. Therefore, processing for registering the operation scheme of the operation apparatus can readily be performed and usability can be improved. In the exemplary embodiment, each of the first operation apparatus and the second operation apparatus further includes a first operation portion, a second operation portion, and a third operation portion. The controller registers the operation scheme in the memory as the first operation scheme when the plurality of pieces of operation data received from the first operation apparatus and the second operation apparatus by the second transceiver indicate the first operation of the first operation portion and registers the operation scheme in the memory as the second operation scheme when the operation data received from any one of the first operation apparatus and the second operation apparatus by the second transceiver indicates the second operation of the second operation portion and the third operation portion. The controller can register the operation scheme of the operation apparatus in the memory as the first operation scheme or the second operation scheme based on the operation data transmitted from the operation apparatus. Therefore, processing for registering the operation scheme of the operation apparatus can readily be performed and usability can be improved. The foregoing and other objects, features, aspects and advantages of the exemplary embodiments will become more apparent from the following detailed description of the exemplary embodiments when taken in conjunction with the accompanying drawings.
A63F1322
20171002
20180510
65883.0
A63F1322
0
WILLIAMS, ROSS A
INFORMATION PROCESSING APPARATUS CAPABLE OF ACHIEVING IMPROVED USABILITY, METHOD OF CONTROLLING INFORMATION PROCESSING APPARATUS, NON-TRANSITORY STORAGE MEDIUM ENCODED WITH PROGRAM READABLE BY COMPUTER OF INFORMATION PROCESSING APPARATUS, AND INFORMATION PROCESSING SYSTEM
UNDISCOUNTED
0
ACCEPTED
A63F
2,017
15,724,732
ACCEPTED
MASK SYSTEM WITH SNAP-FIT SHROUD
A shroud (1020) for a mask system includes a retaining portion structured to retain a frame (1040), a pair of upper headgear connectors (1024) each including an elongated arm (1026) and a slot (1027) at the free end of the arm adapted to receive a headgear strap, and a pair of lower headgear connectors (1025) each adapted to attach to a headgear strap. The retaining portion, the upper headgear connectors, and the lower headgear connectors are integrally formed as a one piece structure.
1. A mask system, comprising: a frame defining a breathing chamber; a cushion provided to the frame and adapted to form a seal with the patient's face; and a shroud provided to the frame, wherein the shroud and the frame are co-molded with one another, the frame being constructed of a first, relatively soft, elastomeric material and the shroud being constructed of a second material that is more rigid than the frame, and at least a portion of the frame includes a concertina section having a plurality of folds, each of the folds having a side wall with the side walls of the folds becoming progressively longer away from the patient's face. 2. A mask system according to claim 1, wherein the frame is constructed of silicone. 3. A mask system according to claim 1, wherein the shroud is constructed of polycarbonate. 4. A mask system according to claim 1, wherein the concertina section is provided to a nasal bridge region of the frame. 5. A mask system according to claim 1, wherein the cushion is a full-face cushion. 6. A mask system according to claim 1, wherein the flexibility of the concertina section is variable. 7. A mask system according to claim 6, wherein the flexibility of the concertina section is variable by varying at least one of a number of folds, a wall thickness of each fold, and a depth of each fold. 8. A cushion module, comprising: a frame defining a breathing chamber; and a cushion adapted to form a seal with the patient's face, wherein the frame and the cushion are co-molded with one another, the cushion being constructed of a first, relatively soft, elastomeric material and the frame being constructed of a second material that is more rigid than the cushion, and at least a portion of the frame includes a concertina section. 9. A cushion module according to claim 8, wherein the concertina section includes a bellows structure with one or more folds. 10. A cushion module according to claim 9, wherein the flexibility of the concertina section is variable. 11. A cushion module according to claim 10, wherein the flexibility of the concertina section is variable by varying at least one of a number of folds, a wall thickness of each fold, and a depth of each fold. 12. A cushion module according to claim 8, wherein the concertina section is provided to a nasal bridge region of the frame. 13. A cushion module according to claim 8, wherein the cushion is a full-face cushion. 14. A mask system, comprising: a shroud; and a cushion module according to claim 8 provided to the shroud. 15. A mask system according to claim 14, wherein the shroud includes headgear connectors adapted to removably attach to respective headgear straps of headgear. 16. A mask system according to claim 15, wherein the shroud includes upper and lower headgear connectors on each side of the shroud. 17. A mask system according to claim 16, wherein each upper headgear connector includes an elongated arm and a slot at the free end of the arm adapted to receive a respective headgear strap in use. 18. A mask system according to claim 16, wherein each lower headgear connector includes a clip receptacle adapted to be removably interlocked with a headgear clip associated with a respective headgear strap. 19. A mask system according to claim 14, wherein the shroud includes an open construction that provides an annular retaining portion structured to retain the frame. 20. A mask system according to claim 14, further comprising an elbow adapted to be connected to an air delivery tube that delivers breathable gas to the patient.
CROSS-REFERENCE TO APPLICATION This application is a continuation of U.S. patent application Ser. No. 15/682,117, filed Aug. 21, 2017, pending, which is a continuation of U.S. patent application Ser. No. 15/440,972, filed Feb. 23, 2017, now U.S. Pat. No. 9,770,568, which is a continuation of U.S. patent application Ser. No. 13/964,280, filed Aug. 12, 2013, now U.S. Pat. No. 9,757,533, which is a continuation of U.S. application Ser. No. 13/745,077, now U.S. Pat. No. 8,528,561, filed on Jan. 18, 2013, which is a continuation of U.S. application Ser. No. 12/736,024, now U.S. Pat. No. 8,550,084, filed on Sep. 2, 2010, which is the U.S. National Stage of PCT/AU2009/000241, filed Feb. 27, 2009, which claims benefit to U.S. Provisional Application Nos. 61/064,406, filed Mar. 4, 2008, 61/071,893, filed May 23, 2008, and 61/136,617, filed Sep. 19, 2008, each of which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION The present invention relates to a mask system used for treatment, e.g., of Sleep Disordered Breathing (SDB) with Continuous Positive Airway Pressure (CPAP) or Non-Invasive Positive Pressure Ventilation (NIPPV). BACKGROUND OF THE INVENTION Patient interfaces, such as a full-face or nasal mask systems, for use with blowers and flow generators in the treatment of sleep disordered breathing (SDB), typically include a soft face-contacting portion, such as a cushion, and a rigid or semi-rigid shell or frame. In use, the interface is held in a sealing position by headgear so as to enable a supply of air at positive pressure (e.g., 2-30 cm H2O) to be delivered to the patient's airways. One factor in the efficacy of therapy and compliance of patients with therapy is the comfort and fit of the patient interface. The present invention provides alternative arrangements of mask systems to enhance the efficacy of therapy and compliance of patients with therapy. SUMMARY OF THE INVENTION One aspect of the invention relates to a mask system provided without a forehead support adapted to engage the patient's forehead. Another aspect of the invention relates to a mask system including a frame and a shroud removably connected to the frame and adapted to attach headgear. Another aspect of the invention relates to a mask system including a frame defining a breathing chamber, a cushion provided to the frame and adapted to form a seal with the patient's face, and a shroud provided to the frame. The shroud and the frame are co-molded with one another. The frame is constructed of a first, relatively soft, elastomeric material and the shroud is constructed of a second material that is more rigid than the frame. At least a portion of the frame includes a concertina section having a plurality of folds. Each of the folds has a side wall with the side walls of the folds becoming progressively longer away from the patient's face. Another aspect of the invention relates to a cushion module including a frame defining a breathing chamber and a cushion adapted to form a seal with the patient's face. The frame and the cushion are co-molded with one another. The cushion is constructed of a first, relatively soft, elastomeric material and the frame is constructed of a second material that is more rigid than the cushion. At least a portion of the frame includes a concertina section. Another aspect of the invention relates to a method for constructing a cushion module. The method includes molding a first part of the cushion module with a first, relatively soft, elastomeric material, co-molding a second part of the cushion module to the first part with a second material that is more rigid than the first material, and molding at least a portion of the second part to include a concertina section. Another aspect of the invention relates to a shroud for a mask system including a retaining portion structured to retain a frame, a pair of upper headgear connectors each including an elongated arm and a slot at the free end of the arm adapted to receive a headgear strap, and a pair of lower headgear connectors each adapted to attach to a headgear strap, wherein the retaining portion, the upper headgear connectors, and the lower headgear connectors are integrally formed as a one piece structure. Another aspect of the invention relates to a mask system including a frame defining a breathing chamber, a cushion provided to the frame and adapted to form a seal with the patient's face, a shroud provided to the frame and adapted to attach headgear, and an elbow provided to the frame and adapted to be connected to an air delivery tube that delivers breathable gas to the patient. The shroud includes a retaining mechanism structured to establish a positive connection between the shroud and the frame. Another aspect of the invention relates to a mask system including a frame defining a breathing chamber and a cushion provided to the frame. The cushion includes a main body and a cushion, wherein the cushion is adapted to engage at least a portion of the patient's face. The cushion includes a base wall connected to an undercushion layer and a membrane, wherein the membrane extends around the perimeter of the cushion and contacts the patient's face. The undercushion layer is positioned underneath the membrane and supports the membrane. The under cushion layer provides differential support to the membrane at predetermined regions of the face. Another aspect of the invention relates to a mask assembly for use in medical applications having a top and bottom ends defined by its position relative to a patient's face, wherein the mask assembly is connected to a plurality of flexible straps, which are adapted to engage the patient's head. The flexible straps engage at least two elongated rigid arms integrally molded to a portion of the mask assembly, and wherein the elongated arms are molded to the mask assembly proximal to the top end of the mask assembly. Another aspect of the invention relates to a mask assembly for use in medical applications including a main body connected to a cushion adapted to cover nose and/or mouth and wherein the mask assembly is attached by a force substantially perpendicular towards the face and wherein the force is approximately constant along the length of the mask and is balanced by a portion of the cushion engaging the patient's cheeks. Another aspect of the invention relates to a cushion for use with a medical mask including an outer membrane layer adapted to sealably engage a face and an undercushion layer adapted to support the membrane layer. The membrane or undercushion layer includes a surface positioned between the two layers adapted to allow the layers to slide against the respective surface. Another aspect of the invention relates to a mask system including a frame defining a breathing chamber, a cushion provided to the frame and adapted to form a seal with the patient's face, and a releasable shroud adapted to engage a portion of the outer surface of the frame, wherein the shroud is connected to straps to position the mask system. Another aspect of the invention relates to a mask assembly for use in medical applications including an upper end and a lower end wherein the upper end is adapted to cover the nose and the lower end is adapted to cover the mouth of a patient. The mask assembly includes no forehead support and includes two stiffened members attached to the upper end on opposed sides of the mask assembly, and wherein the stiffened members include a general curved shape and adapted to avoid covering the patient's field of vision. Another aspect of the invention relates to a cushion for attaching to a medical mask, wherein the cushion is flexible and includes a membrane attached to the circumference of the cushion adapted to seal against the face of a patient, and at least one undercushion adapted to support the membrane and positioned underneath the membrane to prevent collapse of the membrane, in use. The membrane is softer than the undercushion. The undercushion in the regions of nasal bridge or chin is between 0 mm and 30 mm in height as measured between the base and the tip of the undercushion. Another aspect of the invention relates to a mask assembly for use in medical applications including an upper end and a lower end wherein the upper end is adapted to cover the nose and the lower end is adapted to cover the mouth of a patient. The mask assembly includes no forehead support and includes two stiffened members attached to the upper end on opposed sides of the mask assembly, and wherein the stiffened members include a general curved shape and adapted to avoid covering the patient's field of vision. In an alternative embodiment, the mask system may include a headgear connector or rigidizer structured to attach to the frame with a snap-fit, mechanical interlock, friction fit, and/or grommet arrangement (e.g., constructed of rubber). In an alternative embodiment, the mask system may include headgear having an arrangement of straps constructed of silicone and/or Breath-O-Prene™ material. Other aspects, features, and advantages of this invention will become apparent from the following detailed description when taken in conjunction with the accompanying drawings, which are a part of this disclosure and which illustrate, by way of example, principles of this invention. BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings facilitate an understanding of the various embodiments of this invention. In such drawings: FIG. 1 is a front perspective view of a mask system according to an embodiment of the present invention: FIG. 1B is a perspective view showing the mask system of FIG. 1 with headgear positioned on a patient's head; FIG. 1C is a cross-sectional view through the mask system of FIG. 1; FIG. 1D is another cross-sectional view through the mask system of FIG. 1; FIG. 1E is a side view of the mask system of FIG. 1; FIG. 2 is a front perspective view showing the frame and cushion of the mask system of FIG. 1; FIG. 3 is an exploded perspective view of the mask system of FIG. 1 showing the frame, cushion, shroud, and elbow; FIG. 4 is another exploded perspective view of the mask system of FIG. 1 showing the frame, cushion, and shroud; FIG. 5 is an exploded perspective view of the mask system of FIG. 1 showing the shroud and assembled frame/cushion: FIG. 6 is a front perspective view showing the shroud of the mask system of FIG. 1; FIG. 7 is a front perspective view showing the cushion of the mask system of FIG. 1; FIG. 8 is a cross-sectional view showing a portion of the cushion of FIG. 7: FIG. 8B is a cross-sectional view through nasal bridge and chin regions of the cushion of FIG. 7; FIG. 9 is a plan view of headgear laid out flat according to an embodiment of the present invention; FIG. 10 is a front perspective view of a mask system according to another embodiment of the present invention; FIG. 11 is a front perspective view showing the frame of the mask system of FIG. 10; FIG. 12 is a front view showing the frame of the mask system of FIG. 10: FIG. 13 is a side view showing the frame of the mask system of FIG. 10; FIG. 14 is a front perspective view showing the shroud of the mask system of FIG. 10: FIG. 15 is a front view showing the shroud of the mask system of FIG. 10; FIG. 16 is a side view showing the shroud of the mask system of FIG. 10: FIG. 17 is a rear perspective view showing the shroud of the mask system of FIG. 10; FIGS. 18-1 to 18-2 are cross-sectional views showing in sequential relation attachment of the shroud to the frame of the mask system of FIG. 10; FIGS. 19-1 to 19-4 are cross-sectional views showing in sequential relation attachment of the shroud to the frame of the mask system of FIG. 10: FIG. 20 is a perspective view showing an alternative arrangement for attaching the shroud to the frame; FIG. 21 is a rear perspective view showing the shroud of the mask system of FIG. 10: FIG. 22 is a cross-sectional view showing attachment of the shroud to the frame of the mask system of FIG. 10; FIG. 23 is a cross-sectional view showing attachment of the shroud, frame, and elbow of the mask system of FIG. 10; FIG. 24 is a cross-sectional view showing an alternative arrangement for attaching the shroud to the frame; FIG. 25 is a front perspective view of a mask system according to another embodiment of the present invention; FIG. 26 is a rear perspective view of the mask system of FIG. 25: FIG. 27 is a front perspective view of a mask system according to another embodiment of the present invention; FIG. 28 is an exploded view of the mask system shown in FIG. 27; FIG. 29 is an enlarged front perspective view of the mask system shown in FIG. 17; FIG. 30 is a side view of the mask system shown in FIG. 27: FIGS. 31-1 is a rear view of a cushion according to an embodiment of the present invention; FIG. 31-2 is a front view of the cushion shown in FIG. 31-1 with a partial cut-away: FIG. 31-3 is a cross-section view through line 31-3-31-3 in FIG. 31-1: FIG. 31-4 is a cross-section view through line 31-4-31-4 in FIG. 31-1: FIG. 31-5 is a cross-section view through line 31-5-31-5 in FIG. 31-1; FIGS. 32-1 to 32-3 illustrate top, front, and side views respectively of a concertina section according to an embodiment of the present invention; FIG. 33 is a side view of a mask system according to a variation of the present invention; FIG. 34 illustrates a cushion including a concertina section according to an embodiment of the present invention: FIGS. 35-1 to 35-3 are front, side, and rear views of a mask system according to another embodiment of the present invention; FIG. 36 is a perspective view of a shroud for a mask system according to an embodiment of the present invention: FIGS. 37-1 to 37-3 are perspective, front, and side views of a mask system according to another embodiment of the present invention; FIGS. 38-1 to 38-5 are perspective, front, top, side, and bottom views of a shroud of the mask system shown in FIGS. 37-1 to 37-3: FIGS. 39-1 to 39-6 are perspective, front, side, bottom, and top views of a mask system according to another embodiment of the present invention: FIGS. 40-1 and 40-2 are perspective and side views of a mask system according to another embodiment of the present invention: FIG. 40-3 is a perspective view of the frame of the mask system shown in FIGS. 40-1 and 40-2; FIGS. 40-4 and 40-5 illustrate a retaining member of the frame shown in FIG. 40-3; FIGS. 40-6 and 40-7 illustrate a clip-on upper headgear connector of the mask system shown in FIGS. 40-1 and 40-2; FIGS. 41-1 and 41-2 are rear and front perspective views of a mask system according to another embodiment of the present invention; FIGS. 41-3 and 41-4 are exploded views of the mask system shown in FIGS. 41-1 and 41-2; FIGS. 41-5 to 41-12 are various views of a clip-on upper headgear connector of the mask system shown in FIGS. 41-1 and 41-2; FIG. 42-1 is a rear perspective view of a mask system according to another embodiment of the present invention; FIG. 42-2 is an exploded view of the mask system shown in FIG. 42-1; FIGS. 42-3 to 42-7 are various views of a clip-on upper headgear connector of the mask system shown in FIG. 42-1; FIGS. 43-1 to 43-4 are perspective, side, front, and rear views of a mask system according to another embodiment of the present invention; FIG. 44 illustrates a mask system according to another embodiment of the present invention; and FIG. 45 illustrates a mask system according to another embodiment of the present invention. DETAILED DESCRIPTION OF ILLUSTRATED EMBODIMENTS The following description is provided in relation to several embodiments or examples which may share common characteristics and features. It is to be understood that one or more features of any one embodiment or example may be combinable with one or more features of the other embodiments or examples. In addition, any single feature or combination of features in any of the embodiments or examples may constitute additional embodiments or examples. In this specification, the word “comprising” is to be understood in its “open” sense, that is, in the sense of “including”, and thus not limited to its “closed” sense, that is the sense of “consisting only of”. A corresponding meaning is to be attributed to the corresponding words “comprise”, “comprised” and “comprises” where they appear. The term “air” will be taken to include breathable gases, for example air with supplemental oxygen. The term “shroud” will be taken to include components that partially or fully cover a second component within the illustrated embodiments. In an embodiment, the shroud may include the component that partially covers or is mounted on the frame components of the illustrated embodiments. The term “positive connection” will be taken to include connections between components of the illustrated embodiments wherein connectors mounted on respective components are adapted to engage each other respectively. 1. Mask System Embodiments of the invention are directed towards a mask system provided without a forehead support adapted to engage the patient's forehead. Such arrangement provides the mask system with a less obtrusive arrangement which does not significantly affect the patient's field of view. Although the system is designed such that a forehead support is not required, such a forehead support can be added if desired. As described in greater detail below, the mask system includes a frame, a cushion provided to the frame and adapted to form a seal with the patient's face, a shroud provided to the frame and adapted to attach headgear, and an elbow provided to the frame and adapted to be connected to an air delivery tube that delivers breathable gas to the patient. Headgear may be removably attached to the shroud to maintain the mask system in a desired adjusted position on the patient's face. The mask system is intended for use in positive pressure therapy for users with Obstructive Sleep Apnea (OSA) or another respiratory disorder. While each embodiment below is described as including a full-face or oro-nasal interface type, each embodiment may be adapted for use with other suitable interface types. That is, the interface type is merely exemplary, and each embodiment may be adapted to include other interface types, e.g., nasal interface, nasal mask, nasal prongs, etc. 2. Stabilizing Mechanisms The stabilizing mechanisms (e.g., frame, shroud, headgear with associated headgear vectors) of a mask system according to embodiments of the invention are structured to accommodate the elimination of a forehead support from a full-face type interface. For example, a forehead support typically eliminates rotation of the mask system in the sagittal and coronal planes, so the mask system and headgear according to embodiments of the invention are structured to take on these functions since there is no forehead support. The headgear is connected to the top and bottom of the frame either directly or via the shroud, which shroud provides headgear connection points for headgear positioned and arranged to stably maintain the mask system in position on the patient's face. 2.1 Frame As shown in FIGS. 1, 1B-1E, and 2-5, the frame 1040 of the mask system 1010 is structured to maintain the cushion 1060, shroud 1020, and elbow 1070 in an operative position with respect to the patient's face. The frame 1040 is constructed (e.g., injection molded) from a more rigid material (e.g., polyurethane) than the cushion 1060 (made of, e.g., silicone), however other materials may function likely as well (e.g., polycarbonate). In an embodiment, the frame has a general wall thickness of about 1-2 mm. e.g., 1.5 mm. The frame 1040 defines a breathing chamber or cavity adapted to receive the patient's nose and mouth and provide air communication to the patient. One or the lower portion of the frame 1040 includes an opening 1046 adapted to receive or otherwise communicate with the elbow 1070 (e.g., swivel elbow) and another or upper portion of the frame 1040 includes a vent arrangement 1076 for gas washout. In addition, the upper portion of the frame 1040 includes an interfacing structure 1048 adapted to interface or otherwise removably connect to the shroud 1020. FIGS. 27-30 shows a mask system 10 including a frame 40 with a cushion 44 that provides a sealing portion or sealing ring adapted to form a seal with the patient's nose and/or mouth. Also, the frame 40 includes an opening 46 that is adapted to communicate with the elbow 70. 2.2 Shroud As shown in FIGS. 1 and 3-6, the shroud 1020 is connected to the frame 1040 and is structured to attach headgear to the mask system. In an embodiment, the shroud 1020 is constructed (e.g., injection molded) of a resilient material including but not limited to plastic or nylon (e.g., Nylon 12). However, the shroud may be constructed of other suitable materials, e.g., polycarbonate, polypropylene, thermoplastic elastomer (TPE), Pocan®, etc. In an embodiment, the shroud has a general wall thickness of about 1-2 mm, e.g., 1.3 mm. The top end of the shroud 1020 is adapted to be positioned proximal to the nasal bridge region or nose of the patient and the bottom end is adapted to be positioned proximal to the mouth or chin of the patient. The top end includes an opening or vent receiving hole 1021 to accommodate the vent arrangement 1076 that protrudes from the frame 1040, and the bottom end includes an opening or elbow hole 1032 to accommodate the elbow 1070 and elbow opening into the frame 1040 (e.g., shroud provides no contact with elbow when assembled). Upper headgear connectors 1024 extend from each side of the top end, and lower headgear connectors 1025 extend from each side of the lower end. The headgear connectors 1024, 1025 may be integrally molded or otherwise attached to the shroud. 2.2.1 Upper Headgear Connectors Each upper headgear connector 1024 includes an elongated arm 1026 and a slot or receiving hole 1027 at the free end of the arm 1026 adapted to receive a respective headgear strap. In use, the arms 1026 extend around the face of the patient in a generally concave angle below the eyes of the patient so as to avoid the patient's field of view, i.e., direct headgear away from the patient's eyes. For example, as shown in FIG. 1E, each arm 1026 may extend at an angle α between about 10-25° (e.g., 170) with respect to horizontal. That is, each arm 1026 is suitably formed, shaped, or contoured to follow the contours of the patient's face and avoid line of sight in use. In an embodiment, the shape of the arms may be generally arcuate and adapted to extend in a direction across the cheek of the patient, % while avoiding the eyes or limiting the field of vision. In an embodiment, the arms may be integrally molded to the shroud of the mask system. One possible advantage of molding the arms onto the shroud is that it greatly increases manufacturability and also the shroud may be easily replaced in the case of accidental breakage of the arms rather than replacing the complete mask system. Additionally, molding of the arms onto the shroud may greatly increase the strength of the connection and reduce or limit the actual likelihood of breakage of the arms. In an embodiment, the arms 1026 are at least semi-rigid (e.g., relatively rigid) so as to prevent up and down movement or bending of the arms relative to the face of the patient. Thus, the arms 1026 may act as rigidizers to effectively act as a level arrangement and generate a mechanical advantage wherein the pressure or force applied to top end of the mask system is readjusted to a fulcrum point being about the center of balance between the top and bottom ends of the mask system. In an embodiment, the arms are attached to the highest possible point relative to the mask system to additionally stabilize the configuration. In an embodiment, the fulcrum point or moment of pivoting is positioned between the upper and lower connection points of the straps, and wherein the design, angle, length and/or configuration of the arms 1026 may effectively adjust the fulcrum point. In the illustrated embodiment, the fulcrum point is shown to be between the vent arrangement and elbow of the mask system. Additionally, when positioned on the face, the mask system may have a fulcrum point around or about the region between the bottom of the patient's nose and lip area. This feature effectively stabilizes the mask system on the patient's face without the traditional need for a forehead support. The net result of the arms 1026 mounted in a position extending from the top end of the mask system around the face of the patient is that the mask system is more stable and reduces the net torsional forces experiences about the x-axis 1001 (see FIG. 1) for the mask system in use. Please note that the arms 1026 may be rigidly connected to the mask system in other suitable positions to generate a similar result. In an embodiment, the arms 1026 may be used to stabilize the mask system by contacting the patient's face at the cheeks. A cheek pad may be provided to the inner surface of the arm to support the arm on the patient's cheek in use. Also, the arms 1026 may be enveloped in a soft fabric sleeve to act as additional padding against the cheeks of the patient. The soft fabric sleeve may be in the configuration of an elastic tube covering a portion of the arms 1026. 2.2.2 Lower Headgear Connectors Each lower headgear connector 1025 includes an abbreviated arm and a clip receptacle 1031 at the free end of the arm adapted to be removably interlocked with a headgear clip associated with a respective headgear strap. The clips allow for easier positioning or donning/removal of the mask system. In an embodiment, the abbreviated arms and clips are also relatively rigid so as to prevent lateral movement of the arms along the y-axis 1002, relative to the mask system in use. FIGS. 27-30 illustrate an exemplary headgear clip 33 adapted to be removably interlocked with a clip receptacle 31. As best shown in FIG. 28, each clip 33 includes two spring arms 35 adapted to interlock with the respective clip receptacle 31 with a snap-fit and a slot 37 adapted to receive a respective headgear strap in use. 2.2.3 Alternative Headgear Connectors As shown in FIGS. 27-30, the arm 26 may be removably coupled to the shroud, e.g., arm 26 includes clip structure adapted to removably interlock with a clip receptacle provided to the shroud. This arrangement allows different styles of upper and lower headgear connectors to be used with the shroud, e.g., arms for both upper and lower headgear connectors, clips for both upper and lower headgear connectors, different length arms for upper and lower headgear connectors, etc. However, the shroud may provide other suitable arrangements for attaching headgear straps of headgear. Also, the shroud may include one or more additional components, e.g., forehead support. 2.2.4 Headgear Connector Positioning In the embodiment of FIGS. 1-6, the upper and lower headgear connectors 1024, 1025 provide headgear connection points that are as far from each other as possible (i.e., top and bottom of frame) to allow for greater adjustability (e.g., allows adjustment at the top and bottom of the mask system) and stability (e.g., anchor points spread out around the mask system so more secure on the patient's face). Also, the upper headgear connectors are positioned as close to the top of the mask system as possible without obstructing the patient's eyes in use. 2.2.5 Separate Shroud In the embodiment of FIGS. 1-6, the shroud 1020 is formed separately (e.g., molded) and attached to the frame 1040. Such arrangement facilitates molding of the shroud, allows different materials to be used for the frame and shroud (e.g., frame can be semi-rigid or rigid for stability and shroud with headgear rigidizers can be flexible for adjustment, allows the shroud to hide elbow retention features around elbow/frame opening for retaining elbow to frame (e.g., provides visual shroud for aesthetics), allows frame to be free of lower clip receptacles, allows shroud to be used with different size frames, and allows the shroud to be designed or stylized to minimize obtrusiveness of the mask system. The separate shroud may also allow the headgear, frame, cushion, and/or elbow to be replaced or washed independently. 2.2.6 Sleeves In an embodiment, soft fabric sleeves may be mounted on the upper and/or lower headgear connectors. For example, the sleeves may be elastic and adapted to slide over the arms of the headgear connectors to form a tight fit. In an embodiment, the sleeves form elastic tubes. The sleeves may be padded to increase the comfort of the mask system in use. The sleeves may be particularly useful where the arms of the headgear connectors contact the patient's skin, e.g., to protect the patient's skin from irritation. 2.2.7 Arm Extends Over the Patient's Ear FIGS. 35-1 to 35-3 and 36 illustrate a shroud 220 for mask system 210 according to another embodiment of the present invention. The shroud 220 includes an annular retaining portion 222 structured to retain the frame 240 and upper and lower headgear connectors 224, 225 on each side of the retaining portion 222. In the illustrated embodiment, the shroud 220 is integrally formed in one piece (e.g., see FIG. 36). In the illustrated embodiment, each upper headgear connector 224 includes an elongated arm 226 and a slot 227 at the free end of the arm 226 adapted to receive a respective rear strap 298 in use. As illustrated, the arm 226 is suitably contoured to extend along the cheeks and over the patient's ear just anterior of the patient's temple and retain the respective rear strap 298 in spaced relation over the patient's ear, e.g., to avoid the strap rubbing or irritating the patient's ear in use. Also, each arm 226 is structured to extend along and engage an upper strap 292 of the headgear in use. As illustrated, each arm 226 is secured to the upper strap 292 to add rigidity to the strap and stabilize the mask system on the patient's face in use. In addition, the strap 292 provides padding to the arm 226 on the patient's face in use. In an embodiment, the upper strap 292 may be fixed to the arm 226 by gluing or stitching for example. Alternatively, the arms 226 may be encapsulated by or inserted into respective straps 292 so that the arms 226 are substantially not visible. Each lower headgear connector 225 includes an abbreviated arm 228 with a slot 229 at the free end of the arm 229 adapted to receive a respective lower strap 294 in use. As illustrated, the arm 228 is suitably oriented to retain the respective lower strap 294 in spaced relation under the patient's ear, e.g., to avoid the strap rubbing or irritating the patient's ear in use. In an embodiment, each arm may be attached to the upper end of the mask system and curves below the patient's field of vision or eyes and curves upwards at an angle between about 10 to 20 degrees away from the horizontal axis. In an alternative embodiment, as shown in FIG. 36, each lower headgear connector 225 may include a clip receptacle 231 adapted to be removably interlocked with a headgear clip (not shown) associated with a respective lower strap 294. In an embodiment, the headgear clip receptacle and clip may be similar to that on ResMed's Mirage Liberty™ mask. Exemplary clip arrangements are disclosed in U.S. Patent Publication Nos. 2007/0144525 and 2006/0283461, each of which is incorporated herein by reference in its entirety. 2.2.8 Shroud without Upper Headgear Connector FIGS. 37-1 to 37-3 illustrate a mask system 310 according to another embodiment of the present invention. As illustrated, the mask system 310 includes a shroud 320, a frame 340, a cushion 344, and an elbow 370. As best shown in FIGS. 38-1 to 38-5, the shroud 320 includes an opening 322 structured to receive the elbow 370 and a headgear connector 325 on each side thereof. In the illustrated embodiment, each headgear connector 325 includes a clip receptacle 331 adapted to be removably interlocked with a headgear clip (not shown) associated with a respective lower headgear strap. The frame 340 is removably attached to the shroud 320, e.g., fingers and tabs 345 extending from opening 322 adapted to engage collar of frame 340. The frame 340 includes an upper headgear connector 324 on each upper side thereof. Each headgear connector 324 includes a clip retainer 333 adapted to be removably interlocked with a headgear clip (not shown) associated with a respective upper headgear strap. FIGS. 39-1 to 39-6 illustrate an alternative version of the mask system 310, which is indicated with similar reference numerals. As illustrated, the frame 340 is provided without upper headgear connectors, and the each clip receptacle 331 includes an alternative configuration (e.g., holes for snap-fit tabs on the clip). Also, the shroud 320 in FIGS. 39-1 to 39-6 includes support bars 329 structured to wrap around respective auxiliary ports 343, while the shroud 320 in FIGS. 37-1 to 38-5 includes support bars 329 that extend in front of respective auxiliary ports 343. 2.3 Headgear Headgear may be removably attached to the headgear connectors 1024, 1025 of the shroud 1020 to maintain the mask system 1010 in a desired position on the patient's face, e.g., see FIG. 1B. As shown in FIG. 9, the headgear 1090 includes a pair of upper and lower straps 1092, 1094 with the upper straps 1092 removably attached to respective upper headgear connectors 1024 and the lower straps 1094 removably attached to respective lower headgear connectors 1025. The free end of each strap may include a Velcro® tab structured to engage the remainder of the strap to secure the strap in place. Such Velcro® attachment also allows adjustment of the length of the straps. However, the upper and lower headgear straps may be secured to the shroud in any other suitable manners, e.g., adjustable ladder-lock arrangement, etc. The upper straps 1092 split at the crown of the patient's head to top straps 1096 (e.g., connected to one another by a buckle) adapted to pass over the top of the patient's head in use and rear straps 1098 adapted to pass behind the patient's head in use. In an embodiment, the headgear 1090 is structured to be self-supporting. In FIG. 9, the top straps 1096 are adapted to be connected to one another by a buckle. In an alternative embodiment, as shown in FIG. 27-30, headgear 90 may include upper and lower straps 92, 94, top strap 96, and rear strap 98, with the top straps 96 integral with one another. The upper straps 1092 are designed to adjust the position of the mask in a similar way that an adjustable forehead support would alter the position of the mask system, i.e., move the top of the mask system closer or further away from the patient's nasal bridge. Without the forehead support, the headgear is connected at the top and bottom of the mask frame 1040 via the shroud 1020, and in order to avoid the eyes and ears, the arm 1026 of the upper headgear connector extends at an angle. In doing so, the headgear vectors V1 and V2 (see FIGS. 1 and 1B) are aligned such that the mask system may have a tendency to ride up the patient's face (i.e., upper headgear connectors position upper headgear vectors upwardly from horizontal and lower headgear connectors position lower headgear vectors generally horizontal). By splitting the upper headgear strap 1092 at the crown of the patient's head (i.e., top and rear straps 1096, 1098), the upper headgear vectors are realigned to prevent the mask system from sliding up the patient's face. 2.3.1 Headgear Adjustment FIGS. 35-1 to 35-3 illustrate headgear 290 attached to the headgear connectors 224, 225 of the shroud 220 to maintain the mask system in a desired position on the patient's face. In the illustrated embodiment, the headgear 290 includes a pair of upper or top straps 292, a pair of lower or bottom straps 294, and a pair of rear straps 298. In use, the upper straps 292 are secured to respective upper connectors or arms 226, the lower straps 294 are removably attached to respective lower connectors via slots 229/clip arrangement 231, and the rear straps 298 are removably attached to respective upper connectors via slots 227. The upper straps 292 may include upper strap portions adapted to pass over the top of the patient's head and couple to one another, e.g., via a headgear buckle or adjustable ladder-lock arrangement 299. In the illustrated embodiment, the lower straps 294 and rear straps 298 are formed in one piece. This headgear arrangement allows adjustment to occur at three positions, i.e., upper straps 292 at the headgear buckle 299, lower straps 294 at the slot 229/clip 231 connection, and rear straps 298 at the slot 227 connection. As illustrated, the free end of each strap may include a hook and loop tab 295 (e.g., Velcro®) structured to engage the remainder of the strap to removably secure the strap in place. Such hook and loop attachment also facilitates adjustment of the length of the straps. In the illustrated embodiment, the lower straps 294 and rear straps 298 are adapted to join and pass behind the patient's head in use (e.g., see FIG. 35-3). As illustrated, the lower straps 294 join at an angle α (e.g., similar to the bottom strap in ResMed's Mirage Liberty mask) to prevent the strap from irritating the patient's neck and/or prevent movement of the strap due to movement of the patient's neck in use. In an embodiment, the headgear may be similar to that for ResMed's Mirage Liberty mask, however the top straps have been modified and there is an added rigidizer system. The top straps may be similar to ResMed's Swift style headgear, with the rigidizers extending along the sides. 2.3.2 Alternative Headgear Material FIGS. 43-1 to 43-4 illustrate a mask system 610 including a mask 615 and headgear 690 according to another embodiment of the present invention. In the illustrated embodiment, the headgear 690 includes an arrangement of straps wherein some of the straps are constructed of silicone and some of the straps are constructed of Breath-O-Prene™ material. However, the headgear may be constructed such that the straps are completely constructed of silicone or completely constructed of Breath-O-Prene™. As illustrated, the lower strap portion 692 of the headgear is constructed of Breath-O-Prene™ and extends along the cheeks and around the back of the patient's head. The upper strap portion 694 of the headgear is constructed of silicone and includes side straps 694(1) that extend along the upper cheek and over the patient's ear, a top strap 694(2) that extends over the top of the patient's head, rear straps 694(3) that extend behind the patient's head and connects to the lower strap portion 692 (see FIG. 43-4), and connecting portions 694(4) that extend from respective side straps 694(1) in front of the patient's ear and connect to the lower strap portion 692. The headgear straps may be connected to the mask in any suitable manner. For example, in the illustrated embodiment, the lower strap portion 692 is connected to the mask by a headgear clip arrangement and the upper strap portion 694 is connected to the mask using an elongated buckle 695 with buckle portions on each end thereof. In an embodiment, the headgear straps are arranged such that the force vectors applied by the headgear to the mask are substantially perpendicular to the mask and substantially parallel to one another (e.g., as shown by the arrows in FIG. 43-2). This arrangement enhances the mask seal as the headgear forces the mask directly into the patient's face. 3. Seal The seal (i.e., cushion) of the mask system is structured to accommodate the elimination of a forehead support from a full-face type interface. 3.1 Cushion As shown in FIGS. 1-5 and 7-8, the cushion 1060 is structured to interface with the frame 1040 and form a seal with the patient's nose and mouth in use. In the illustrated embodiment, the cushion is a full-face cushion adapted to engage the patient's face generally along nasal bridge, cheek, and lower lip/chin regions of the patient's face. However, other cushion interfaces are possible, e.g., nasal. The cushion 1060 is structured be more compliant or flexible (e.g., particularly in the nasal bridge region) to accommodate more movement due to loss of some stability without a forehead support. The cushion 1060 is constructed of a soft and flexible biocompatible material, e.g., such as silicone. In the illustrated embodiment, the cushion 1060 includes a dual wall configuration wherein the cushion comprises an undercushion or support wall 1062 underneath a membrane 1064 as shown in FIG. 8. The membrane 1064 is generally softer and less stiff than the undercushion 1062 and provides a seal against the patient's face in use. The membrane may be relatively thin to allow for wider fit range and better conformance to the patient's face in view of less mask stability with a forehead support. The undercushion is structured to generally support the membrane and prevents collapse of the membrane when the mask system is attached and tightened using the headgear. The membrane 1064 is generally concave and curves inwards towards the breathing chamber. The undercushion 1062 may also curve inwardly but is generally shorter, thicker, and more rigid than the membrane. In an embodiment, the undercushion 1062 at the regions of the nasal bridge and/or chin of the patient is shorter in height or completely absent and the height from the tip to base of the undercushion 1062 may be between about 0 mm and 30 mm. The membrane is generally longer than the undercushion 1062 at any given cross-section and may be between about 1 mm and 40 mm. For example, FIG. 8B illustrates a cross-section through nasal bridge and chin regions of the cushion to illustrate the membrane 1064 without an undercushion in these regions. In an embodiment, the undercushion 1062 may only be provided in selected regions of the mask system, e.g., where the mask system is to be pushed away from the patient's face. Certain pre-determined regions of the patient's face may be preferably avoided for applying pressure by the tightening of the headgear. In the illustrated embodiment, the nasal bridge and chin regions of the patient do not include an undercushion 1062. In these regions, the undercushion is only provided along lateral sides of the cushion (e.g., see FIG. 7) which press against the cheeks of a patient so as to more evenly distribute the force vectors applied by the mask system in use. In an embodiment, the undercushion may be relatively stiff along the cheek regions because these points of contact are acting as anchor points, i.e., holds mask system in position to provide effective seal. This configuration of avoiding the nasal bridge and chin of the patient may increase the comfort of the mask system for patients by reducing the pressure or force applied to sensitive areas or to protruding regions of the patient's face that experience relatively higher contact pressures. Additionally, this arrangement avoids the cushion pinching the nasal bridge of the patient when the mask system is adjusted. Additionally, the cushion of this embodiment may be noticeably softer in the regions of the nasal bridge and chin because of the absence of the undercushion. In an embodiment, the undercushion may include a variable height, stiffness, and/or thickness to generate a variable softness in the aforementioned predetermined regions of the face that require lighter support. In the illustrated embodiment, the cushion may be structured to seal lower down on the patient's nasal bridge and the eye sockets so that the cushion is less obtrusive. In an embodiment, the cushion may be generally frosted except at patient contacting surfaces where it is polished. In an embodiment, the frosting of the cushion may reduce restriction between the face and membrane and/or the membrane and undercushion. The frosting allows the surface of the membrane and undercushion to slide against each other's respective surface without the same restriction of unfrosted silicone. This feature may also prevent or limit sticking of the membrane to the undercushion components and also may generally improve the overall comfort and sealing properties of the cushion. Additionally, the frosting of the cushion may be easier to manufacture and may lead to a reduction of costs of manufacturing. The cushion may be constructed of frosted silicone or other suitable materials. 3.2 Cushion Lower on Nasal Bridge FIGS. 31-1 to 31-5 illustrate various views of a cushion 44 (e.g., constructed of silicone) according to an embodiment of the present invention. As illustrated, the cushion 44 includes a base wall 44(1) provided to the frame, an undercushion layer (UCL) 44(2) extending away from the base wall 44(1), and a membrane 44(3) provided to substantially cover the UCL 44(2) and provide a sealing structure. In the illustrated embodiment, the cushion 44 is structured to sit lower on the nasal bridge to reduce mask obtrusiveness and improve “line of sight” in use. Also, as best shown in FIGS. 31-3 and 31-5, the UCL 44(2) design in the nasal bridge region is structured to provide improved stability across the nasal bridge in use. As shown in FIGS. 31-1 and 31-3, the UCL is not provided in the lower lip/chin region. However, other arrangements of the UCL are possible, e.g., UCL around entire perimeter. In an embodiment of the cushion shown in FIGS. 31-1 to 31-5, D1 may be about 15-20 mm, e.g., 18.2 mm, D2 may be about 53-59 mm, e.g., 55.8 mm, D3 may be about 88-93 mm, e.g., 90 mm, D4 may be about 78-83 mm, e.g., 81.1, D5 may be about 58-63 mm, e.g., 60 mm, D6 may be about 95-100 mm, e.g., 98.1 mm, D7 may be about 57-62 mm. e.g., 59.7 mm, D8 may be about 77-82 mm, e.g., 79 mm, D9 may be about 88-93 mm, e.g., 90.7 mm, D10 may be about 30-35 mm, e.g., 33.1 mm, D11 may be about 14-19 mm. e.g., 16.4 mm, D12 may be about 8-13 mm, e.g., 9.6 mm. D13 may be about 0.3-0.5 mm, e.g., 0.35 mm, D14 may be about 0.4-0.6 mm, e.g., 0.5 mm, and D15 may be about 0.3-0.5 mm. e.g., 0.4 mm. Although specific dimensions and ranges are indicated, it is to be understood that these dimensions and ranges are merely exemplary and other dimensions and ranges are possible depending on application. For example, the exemplary dimensions may vary by 10-20% or more or less depending on application. 3.3 Cushion Higher on Nasal Bridge FIGS. 35-1 and 35-2 illustrate a full-face cushion 244 adapted to engage the patient's face generally along nasal bridge, cheek, and lower lip/chin regions of the patient's face. In this embodiment, the cushion 244 is structured such that it is positioned higher on the bridge of the nose for sealing and comfort (e.g., with respect to the cushion 44 described above). The cushion 244 may also be better for anthropometrics, i.e., the cushion will fit more people. In an embodiment, the cushion 244 may include a concertina section as described below (e.g., in the nasal bridge region) to enhance the flexibility of the cushion in use. 3.4 Concertina Section As best shown in FIGS. 30 and 33, a concertina section 50 may be provided in a nasal bridge region of the cushion and/or frame. As illustrated, the concertina section 50 includes a bellows structure with one or more folds 52 that provide a higher degree of flexibility or increased movement. That is, the concertina section 50 provides a higher level of adaptability or flexibility to the nasal bridge region of the cushion/frame which is a more sensitive region of the patient's face in use. Moreover, the concertina section 50 provides increased movement without compromising seal. FIGS. 32-1 to 32-3 illustrate various views of a concertina section 50 (isolated from the remainder of the cushion/frame) with one or more folds 52 according to an embodiment of the present invention. As best shown in FIG. 32-3, the folds may have different lengths, depths, and/or contours with respect to one another to optimize the concertina effect, e.g., provide sufficient degree of movement without compromising seal. For example, as shown in FIG. 32-3, each fold 52 includes a first side wall 52(1) and a second side wall 52(2) that interconnects adjacent side walls 52(1). In the illustrated embodiment, the first side walls 52(1) and/or the second side walls 52(2) may become progressively longer away from the patient's face. For example, the first side wall 52(1) and/or the second side wall 52(2) adjacent patient's face, or the combination of side walls 52(1) and 52(2), may have a length that is longer than and in some cases significantly longer than the adjacent side wall 52(1) and/or 52(2) (e.g., one side wall at least 25% greater than and up to 5× as long as the other side wall, e.g., 1×, 2×, 3×, or 4×). The folds may be constructed and arranged to provide a predetermined order of movement or folding, e.g., folds structured to fold in a sequential or progressive manner wherein one fold collapses before an adjacent fold collapses. For example, upon application of force, the folds closest to the patient's face may fold or collapse before the folds furthest from the patient's face. Also, the folds may be constructed and arranged to provide various degrees of fold or collapse, e.g., folds may fold or collapse more than others. In an embodiment of the concertina section shown in FIGS. 32-1 to 32-3, D1 may be about 50-60 mm, e.g., 55.7 mm, D2 may be about 5-15 mm, e.g., 9.7 mm, and D3 may be about 0.3-0.5 mm, e.g., 0.4 mm. Although specific dimensions and ranges are indicated, it is to be understood that these dimensions and ranges are merely exemplary and other dimensions and ranges are possible depending on application. For example, the exemplary dimensions may vary by 10-20% or more or less depending on application. It should be appreciated that a concertina section 50 may be provided in other regions of the cushion and/or frame, e.g., depending on patient comfort. For example, the concertina section 50 may be provided around the entire perimeter of the cushion and/or frame or may be provided in selected regions of the cushion and/or frame. Also, the flexibility of the concertina section 50 may be varied and may be varied in different regions of the cushion and/or frame, e.g., depending on patient comfort. For example, the cushion and/or frame may include a concertina section in the nasal bridge region with a relatively high degree of flexibility and a concertina section in the lower lip/chin region with a relatively low degree of flexibility. The flexibility of the concertina section 50 may be varied by varying the number of folds 52 (e.g., 1-5 folds), the wall lengths, the wall thickness of the folds 52, the depth of the folds 52, etc. As noted above, the cushion and frame may be co-molded of two parts with different materials/rigidities or may be integrally formed of the same material. In both embodiments, the concertina section may be provided in the frame and/or the cushion. In FIGS. 27-30, the cushion 44 and frame 40 are co-molded of two parts with the concertina section 50 provided in the frame 40. The frame 40 and cushion 44 include different rigidities in order to optimize the function of each part. For example, one part (i.e., cushion 44) may be constructed of a relatively soft, supple material to optimize the sealing effect and the other part (i.e., frame 40) may be constructed of a more rigid material to provide adequate support for the cushion while at the same time allowing a sufficient degree of movement to optimize the concertina effect. While the frame is more rigid than the cushion, the frame may be constructed of a flexible material to allow the concertina effect. In FIG. 33, the frame 40 and cushion 44 are integrally formed in one piece with the concertina section 50 provided in the frame 40. The material properties and/or dimensions may be selectively modified to optimize sealing and concertina effects. For both embodiments of FIGS. 27-30 and 33, it should be appreciated that the concertina section may be alternatively provided in the cushion 44 or in both the frame 40 and cushion 44. For example, FIG. 34 illustrates a concertina section 50 integrally formed with the cushion 44 in the nasal bridge region. 4. Elbow As shown in FIG. 3, the elbow 1070 (e.g., constructed of a relatively hard material such as polycarbonate or polypropylene) includes a first end portion 1074(1) and a second end portion 1074(2). The first end portion 1074(1) provides an interfacing structure structured to interface or otherwise attach to the frame 1040. The second end portion 1074(2) is adapted to be connected to an air delivery tube. 4.1 Elbow Connection to Frame The frame 1040 is structured to maintain the elbow 1070 in an operative position with respect to the patient's face. That is, the frame acts as a carrier and bearing surface for the elbow. The frame and elbow may connect with a friction fit, snap-fit, mechanical interlock, or other suitable attachment mechanism. However, other suitable arrangements for attaching the elbow to the frame are possible. In the illustrated embodiment, the elbow 1070 includes a series of tangs 1075 adapted to releasably engage within the opening 1032 of the frame 1040, e.g., with a snap-fit. The tangs 1075 hold the elbow in place (e.g., preferably a relatively airtight connection) and permit rotation or swiveling of the elbow with respect to the frame. That is, the elbow is rotatably attached to the frame so that the elbow may be rotated relative to the frame in use, e.g., 360° rotation. This arrangement allows the elbow to assume different orientations in use, e.g., depending on patient preference. For example, the elbow may assume a first orientation so that the elbow extends generally downwardly from the mask to direct the air delivery tube under the patient's head in use. Alternatively, the elbow may be rotated and assume a second orientation so that the elbow extends upwardly from the mask to direct the air delivery tube over the patient's head in use. In an embodiment, the frame and elbow may be constructed of dissimilar materials to prevent or at least reduce squeak between the components in use. The second end portion of the elbow may be provided to a swivel joint adapted to be connected to the air delivery tube. For example, FIGS. 27-30 illustrate a swivel joint 80 provided to the second end portion 74(2) of elbow 70. In the illustrated embodiment, the swivel joint 80 is provided to a short tube 82 (e.g., extendable and retractable tube) that interconnects the elbow with the air delivery tube. In an embodiment, the swivel joint 80 may be integrally formed in one piece with the short tube 82. 4.2 AAV The elbow 1070 includes a slot 1081 to receive an anti-asphyxia valve (AAV), a port 1079 that is selectively closed by a flap portion of the AAV (depending on the presence of pressurized gas), and structure for attaching the AAV, e.g., with a snap-fit. FIGS. 27-30 illustrate an exemplary AAV 85 including a flap portion 86 to selectively close port 79 in elbow 70. In this embodiment, a clip portion 88 is provided to the flap portion 86 for attaching the AAV 85 to the elbow 70. In the illustrated embodiment, the flap portion 86 and the clip portion 88 are co-molded with one another to form a one-piece, integrated component. However, the flap portion 86 and clip portion 88 may be secured to one another in other suitable manners, e.g., mechanical interlock. In an embodiment, the flap portion 86 may be constructed of a relatively soft elastomeric material (e.g., silicone) and the clip portion 88 may be constructed of a more rigid material (e.g., rigid plastic) for interfacing with the elbow 70. The clip portion 88 of the AAV 85 includes structure for removably interlocking with the elbow 70, e.g., with a snap-fit. For example, the clip portion 88 may include tabs structured to interlock with respective recesses/protrusions provided to the elbow. FIGS. 35-1 and 35-2 illustrate an elbow 270 including a port 279 that is selectively closed by a flap portion 286 of the AAV 285 (depending on the presence of pressurized gas). Also, FIGS. 37-1 to 37-3 illustrate elbow 370 including a port 379 and a slot 381 to retain the AAV. Alternative embodiments of the AAV are disclosed in PCT Application No. PCT/AU2006/000031, which is incorporated herein by reference in its entirety. 4.3 Large Diameter End Portion As shown in FIGS. 27-30, the first end portion 74(1) of the elbow 70 may provide a relatively large diameter which allows the potential for cleaner/smoother lines thereby contributing to the overall mask aesthetic and reduced obtrusiveness. In addition, the relatively large diameter elbow offers the potential for the patient's nose to protrude into the elbow cavity thereby permitting the mask to be brought closer to the patient's face (i.e., reduced obtrusiveness), less moment since center of gravity of mask is closer to the patient's face, and/or improved line of sight. 5. Modular Design The mask system provides a modular design that allows different styles and/or sizes of the frame (also referred to as a frame module), shroud (also referred to as a shroud module), cushion (also referred to as a cushion module), and/or elbow (also referred to as an elbow module) to be interchanged or mixed and matched with one another to provide a more customized mask system for the patient. In addition, such design allows selected modules to be easily replaced, e.g., treatment requirements change, worn out or damaged, etc. In an embodiment, the mask system may be provided with a number of different cushions, e.g., each having cushions of different styles and/or sizes (e.g., depending on patient preference and/or fit). For example, the non-face contacting side of each cushion may include a common or universal configuration for interfacing with the frame, and the face-contacting side of the cushion may include different styles and/or sizes. This provides a modular arrangement that allows the frame to be selectively (e.g., and removably) coupled to one of multiple cushion. For example, the different cushions may include different size cushions (e.g., small, medium, and large) and may include a different cushion structures. In an embodiment, the mask system may be provided with different shrouds, e.g., each shroud having a different style and/or size (e.g., shroud with different arrangement/style of headgear connectors, shroud with forehead support, different headgear vectors, etc). In an embodiment, the mask system may be provided with different frames, e.g., each frame having a different style and/or size (e.g., frame with different vent arrangement, small, medium, and large size frame, etc). In an embodiment, the mask system may be provided with a number of different elbows, e.g., each having a vent arrangement, AAV (in the case of an oro-nasal mask), and/or elbow of different styles and/or sizes. In the illustrated embodiment of FIGS. 27-30, the vent arrangement 76 and AAV 85 are structured to be removably attachable to the elbow 70. This provides a modular arrangement that allows the elbow to be selectively and removably coupled to one of multiple vent arrangements and/or AAVs. This also allows the vent arrangement and AAV to be easily replaced, e.g., if damaged. 5.1 Shroud to Frame Connection The shroud is mounted on the outer surface of the frame, e.g., preferably with a tight, conforming fit on the frame. 5.1.1 Upper Retaining Mechanism In the illustrated embodiment of FIGS. 1-5, the shroud 1020 is connected to the frame 1040 by an upper retaining mechanism or interfacing structure 1048 located on the top end of the frame and shroud. As shown in FIGS. 2 to 5, the upper retaining mechanism 1048 is in the form of two taper locks structured to secure the shroud 1020 on the frame 1040 and prevent unintentional disassembly particularly due to headgear forces. In this embodiment, opposing sides of the frame include a female slot 1055 adapted to receive a respective tang protrusion (which tapers along its length) on the underside of the shroud 1020. The tapered protrusion engages within a respective female slot, e.g., with a friction fit. FIGS. 10 to 19-4 show another embodiment of a mask system 1110 which more clearly illustrates an embodiment of the taper lock. FIGS. 10 to 17 show various views of the frame 1140, shroud 1120, and elbow 1170 of the mask system 1110. As best shown in FIGS. 11 to 13, opposing sides of the top end of the frame 1140 include a platform 1154 which provides a first female slot 1155(1). In addition, the space between the platform 1154 and the outer surface of the frame 1140 defines a second female slot 1155(2). As best shown in FIG. 17, opposing sides of the top end of the shroud 1120 include a tang protrusion 1156 on the underside of the shroud 1120. The tang protrusion 1156 includes a first tang 1156(1) and a second tang 1156(2) that extends generally transverse to the first tang 1156(1). As shown in FIGS. 18-1 and 18-2, each tang may taper along its length, i.e., thinner towards its free end. FIGS. 18-1 and 18-2 and 19-1 to 19-4 sequentially illustrate attachment of the shroud 1120 to the frame 1140. As illustrated, the tangs 115((1), 1156(2) of each tang protrusion 1156 are structured to engage with respective slots 1155(1). 1155(2), e.g., with a friction fit. As best shown in FIGS. 19-1 to 19-4, each slot 1155(2) includes lead-ins or guides 1157 that curve along their length (i.e., extend in vertical and horizontal direction) so as to guide the tang 1156(2) into the slot 1155(2) and aid assembly. FIGS. 18-2 and 19-4 show the tangs 1156(1), 1156(2) when fully inserted with respective slots 1155(1), 1155(2). In an alternative embodiment, as shown in FIG. 20, the upper retaining mechanism may include a clip-type arrangement. As illustrated, opposing sides of the top end of the frame 1240 provide a shoulder 1255(1) and a tapered protrusion 1255(2). Opposing sides of the top end of the shroud 1220 include a first tang 1256(1) and a second tang 1256(2) on the underside of the shroud 1220. In use, each first tang 1256(1) is engaged with the respective shoulder 1255(1) and the second tang 1256(2) is engaged or clipped onto the tapered protrusion 1255(2), e.g., with a snap-fit. 5.1.2 Lower Retaining Mechanism In an embodiment, the shroud may also be connected to the frame by a lower retaining mechanism located on the bottom end of the frame and shroud. For example, a retaining mechanism may be provided to the opening of the shroud which is structured to interlock or otherwise engage with the opening of the frame. For example, as shown in FIGS. 14, 15, 17, and 21, the opening 1132 of the shroud 1120 may include structure adapted to engage the collar 1149 surrounding the frame opening 1146 with a snap-fit. As illustrated, the shroud 1120 includes snap fingers 1145(1) (e.g., three snap fingers) and sandwich tabs 1145(2) (e.g., three sandwich tabs) that extend from the opening 1132. The snap fingers and sandwich tabs are alternatively spaced about the opening. In use, the snap fingers 1145(1) resiliently deflect (e.g., 0.5 mm deflection) and engage respective part-annular protrusions 1149(1) provided to the collar 1149 (e.g., see FIGS. 22 and 23) to provide an initial retention of the shroud 1120 to the frame 1140 (e.g., with allowable stresses), e.g., to facilitate assembly and disassembly. In addition, as the snap fingers 1145(1) engage respective protrusions 1149(1), the sandwich tabs 1145(2) are received in respective recesses 1149(2) provided to the end of the collar 1149 (e.g., see FIGS. 22 and 23). When the elbow 1170 is engaged with the frame 1140 (e.g., see FIG. 23), an annular protrusion 1171 on the elbow 1170 is positioned on an opposing side of the sandwich tabs 1145(2) so that the sandwich tabs 1145(2) are sandwiched between the collar 1149 and the elbow 1170. Thus, the sandwich tabs utilize elbow retention forces to retain the shroud on the frame during use. The elbow 1170 has a distal shoulder 1173 adapted to extend under the edge of the frame 1140 to retain the elbow to the frame. The snap fingers 1145(1) allow the shroud to connect to the frame independent of the elbow. In an alternative embodiment, as shown in FIG. 24, the shroud's lower section may be structured to clip to a single point below the collar. As illustrated, the lower end of the shroud 1320 includes a snap finger 1345 that is engaged or clipped onto a protrusion 1349(1) spaced below the collar 1349 of the frame 1340, e.g., with a snap-fit. In this embodiment, the protrusion 1349 extends from the cover enclosing auxiliary ports. This arrangement may facilitate molding of the collar on the frame, e.g., uniform thickness of the collar prevents molding distortions. In addition, removal of the protrusions 1149(1)/recesses 1449(2) from the collar may reduce the risk of leak. 5.1.3 Finger Grip In an embodiment, the outer surface of the frame 1040 may include finger grips or recessed portions 1097, which are positioned to be exposed under the shroud 1020. The finger grips are adapted to allow the patient an improved ability to grip the frame and/or shroud which is particularly useful when disengaging the shroud from the frame. 5.1.4 Alternative Interfacing Structure In an alternative embodiment, as shown in FIG. 27-30, the shroud 20 includes an open construction that provides an annular or part annular retaining portion 22 structured to retain the frame 40 and the elbow 70. As illustrated, the annular retaining portion 22 includes an interfacing structure 23 along an inner edge that is adapted to interface with or otherwise removably connect to an interfacing structure 48 along the outer perimeter of the frame 40 (e.g., see FIG. 28). In the illustrated embodiment, the interfacing structure 23 is in the form of opposed flanges 23(1) that are adapted to interlock with respective locking structures 48(1) provided on opposing sides of the frame 40. However, other suitable arrangements for attaching the frame 40 to the shroud 20 are possible, e.g., friction fit, snap-fit, mechanical interlock, or other suitable attachment mechanism. For example, the frame 40 may be coupled to the shroud 20 in a manner that allows the frame 40 to be locked in different angular positions with respect to the shroud 20, e.g., pivotally mounted. 5.1.5 Alternative Upper Headgear Connector FIGS. 40-1 to 40-7 illustrate a frame and a clip-on upper headgear connector or rigidizer according to another embodiment of the present invention. The frame 442 includes an opening 449 adapted to engage a frame shroud and/or elbow. Around and under the opening 449 is the u-shaped slot 402 for gas washout and auxiliary ports 443 on each side thereof. In this embodiment, each upper side of the frame 442 includes a retaining member 433 and an upper intermediate portion of the frame 442 includes retaining grooves 435, which are structured and arranged to retain an upper headgear connector or rigidizer 424. As best shown in FIGS. 40-6 and 40-7, the upper headgear connector 424 includes a pair of elongated arms or rigidizers 426 coupled by a pair of wire members 428. Each rigidizer 426 includes a slot 427 at its free end adapted to receive a respective headgear strap in use. In use, the upper headgear connector 424 is adapted to clip onto the frame 442 (e.g., see FIGS. 40-1 and 40-2). Specifically, intermediate portions of the wire members 428 are received in respective grooves 435 of the frame 442, and end portions of the wire members 428 extend through respective retaining members 433 with the rigidizers 426 providing a shoulder to interlock with respective retaining members 433. FIGS. 40-4 and 40-5 show an upper portion of a retaining member 433 to illustrate the groove 433(1) adapted to receive a respective wire. As illustrated, the end of the groove 433(1) includes tapered side walls 433(2) and drops off towards a rear side 433(3) to position the rigidizers 426 into interlocking engagement with the retaining member 433. FIGS. 41-1 to 41-12 illustrate an upper portion of a frame and a clip-on upper headgear connector or rigidizer according to another embodiment of the present invention. As illustrated, the upper portion of the frame 542 includes a retaining member 533 on each side thereof and a retaining groove 535 along an intermediate portion thereof, which are structured and arranged to retain an upper headgear connector or rigidizer 524. As best shown in FIGS. 41-5 and 41-12, the upper headgear connector 524 includes a pair of elongated arms or rigidizers 526 coupled by a connecting portion 528. Each rigidizer 526 includes a slot 527 at its free end adapted to receive a respective headgear strap in use. In addition, the upper headgear connector 524 includes a clip structure 525 on each side of the connecting portion 528. In use, the upper headgear connector 524 is adapted to clip onto the frame 542 (e.g., see FIGS. 41-1 and 41-2). Specifically, the connecting portion 528 is received in the groove 535 of the frame 542, and the clip structures 525 releasably interlock with respective retaining members 533. As best shown in FIGS. 41-3 and 41-4, each retaining member 533 provides a cross-bar, and each clip structure 525 provides a v-shaped configuration that is adapted to resiliently deflect through the cross-bar and provide a shoulder to releasably interlock with the cross-bar. FIGS. 42-1 to 42-7 illustrate an alternative embodiment for engaging the upper headgear connector with the frame. As illustrated, each retaining member 533 provides an open-ended cross-bar, and each clip structure 525 provides an elongated arm. In this embodiment, the cross-bar is structured to resiliently deflect to allow the clip structure 525 to extend through the cross-bar and releasably engage the cross-bar, e.g., with a friction fit. In addition, the upper headgear connector 524 of FIGS. 42-1 to 42-7 includes a c-shaped clip structure 529 adapted to interlock with a tab 549 provided to the frame 542 (see FIGS. 42-1 and 42-2). 5.1.6 Grommet Attachment FIGS. 44 and 45 illustrate an alternative mask arrangement in which the shroud is attached to the frame via a grommet. For example, as shown in FIG. 44, the frame 740 includes a grommet 745 (e.g., constructed of a rubber) and the shroud 720 includes an opening 725 adapted to receive the grommet 745 to secure the shroud 720 to the frame 740. As illustrated, the shroud 720 includes elongated upper and lower arms 724, 726 each with a slot 727 at its free end adapted to receive a respective headgear strap in use. FIG. 45 illustrates an alternative shroud 820 which includes a single arm with a slot 827 at each end adapted to receive a respective headgear strap in use. In addition, the shroud 820 provides an elongated inner slot 825 adapted to receive the grommet 745 of the frame 740. The elongated slot 825 allows the grommet 745 to be fixed in one of multiple positions along the length of the slot 825, in contrast to the shroud 720 which provides a single fixed position. In an embodiment, the shroud 820 may be slidable with respect to the grommet 745 to allow an infinite number of positions with respect to the frame 740. In each embodiment, the grommet 745 (e.g., constructed of a rubber) fixes the shroud in position but the inherent flexibility of the grommet provides a flexible connection to decouple the shroud from the frame and allow a range of movement between the two components, e.g., like a ball joint or gimbal. Such arrangement helps with fitting and sealing of the mask to the patient's face. That is, the flexible connection allows the mask to selectively adjust and/or self-fit with the patient's face. 5.2 Cushion to Frame Connection In FIGS. 1-8, the non-face contacting side of the cushion 1060 is connected to frame 1040 in a tongue and groove relationship. The tongue 1066 (see FIGS. 1C, 1D, and 8) of the cushion 1060 is inserted within a groove 1041 (see FIGS. 1C and 1D) provided along the perimeter of the frame 1040. The tongue and groove relationship may also include a locking lip or sealing lip 1068 (see FIGS. 1C, 1D, and 8) on the cushion that is adapted to interlock with an undercut bead 1042 (see FIGS. 1C and 1D) within the frame groove to fixably retain the cushion to the frame. In the illustrated embodiment, the cushion 1060 also includes one or more positioning features located around its circumference to assist with proper alignment of the cushion with the frame 1040. As shown in FIG. 7, the cushion 1060 includes notches and/or protrusions (e.g., two notches 1067 and one protrusion 1069) adapted to engage with complementary features in the frame, e.g., interlocking relationship. 5.2.1 Co-Molding Frame and Cushion In an embodiment, as shown in FIGS. 27-30, the frame 40 and cushion 44 may be co-molded with one another to form a one-piece, integrated component. For example, the frame 40 may be molded of a first material adapted to interface with the shroud 20 and the cushion 44 may be co-molded onto the frame 40 of a second material adapted to interface with patient's face. In such embodiment, the cushion 44 may be constructed of a relatively soft elastomeric material (e.g., silicone) for sealing and the frame 40 may be constructed of a more rigid material than the cushion 44 (e.g., polycarbonate, polypropylene) for interfacing with the frame. Co-molding the frame 40 to the cushion 44 provides a chemical bond without necessarily forming a mechanical interlock. As a result, the connection includes no cracks, a gas tight seal, and clean interface. Moreover, such co-molded connection relaxes tolerances as the mold materials are sufficiently flexible to fill in any gaps at the interface between the frame 40 and the cushion 44. Also, the co-molded frame/cushion provides a reduced part count (reduced cost) and facilitates assembly/disassembly to the shroud 20. In an alternative embodiment, as shown in FIG. 33, the frame 40 and cushion 44 may be integrally formed in one piece, e.g., of a silicone material. That is, the frame 40 may have the same shape and structure as described above, but be integrally molded of the same material, e.g., silicone. In an embodiment, the integrally formed frame 40/cushion 44 may be co-molded to the shroud 20, e.g., constructed of polycarbonate or polypropylene. For example, the shroud 20 may be constructed of a relatively rigid material (e.g., polycarbonate or polypropylene) and the frame 40/cushion 44 may be co-molded onto the shroud 20 of a relatively soft elastomeric material (e.g., silicone). 5.3 Vent Arrangement In FIGS. 1, 1B, IC, 1D, and 2-5, the vent arrangement 1076 is provided to the frame and includes a plurality of holes 1077 (e.g., 5-100 holes, e.g., 20-50 holes, or about 35 holes) oriented at an angle (e.g., 45°) on the outer surface of the frame so as ensure the exhausted air is directed away from the patient and preferably their bed partner when the patient is sleeping. As shown in FIGS. 1C and 1D, each hole 1077 may include a contour or taper along its length. However, it should be appreciated that the vent arrangement may include other suitable arrangements, e.g., different number of holes, hole arrangement, positioning on frame, vent provides part pf interlocking structure with shroud, etc. FIG. 35-1 illustrates a vent arrangement 276 provided to the frame 240 for gas washout. In the illustrated embodiment, the vent arrangement 276 is in the form of a vent insert (e.g., elastomeric vent insert) that is adapted to be removably supported within an outlet opening in the frame 240. The vent insert may be similar those described in U.S. Pat. Nos. 6,561,190, 6,561,191, and 7,207,335, each of which is incorporated herein by reference in its entirety. However, it should be appreciated that the vent arrangement may have other suitable forms (e.g., vent holes in main body, etc.). FIGS. 37-3, 39-2, and 39-4 illustrate a frame 340 that includes a u-shaped slot 302 that receives a u-shaped plug-type vent 305 for gas washout. As illustrated, the plug-type vent 305 wraps around and under the opening in the frame 340 for the elbow 370. The plug-type vent 305 includes a plurality of tracks or grooves 307 on each side thereof. In use, the grooved plug-type vent 305 forms a seal with the slot 302 so that exhausted air can exit between the slot walls and the grooves 307 on the plug-type vent 305. In an embodiment, the port caps 347 may be integrated or incorporated into the plug-type vent 305 (e.g., integrally formed in one piece). Further details of such a plug-type vent arrangement are provided in U.S. patent application Ser. No. 12/230,120, filed Aug. 22, 2008, which is incorporated herein by reference in its entirety. FIGS. 39-2 to 39-6 show the frame 340 with the grooved plug-type vent 305 removed so as to more clearly illustrate the u-shaped slot 302 and auxiliary ports 343 on each side thereof. Also, it should be appreciated that the vent arrangement may be provided to the elbow. For example, a shown in FIGS. 27-30, the vent arrangement 76 is in the form of a vent insert that is adapted to be removably supported within an outlet opening in the elbow 70. In an embodiment, the vent arrangement 76 includes a base adapted to be supported within the outlet opening, one or more grill components or media (e.g., filter, membrane, or other porous material) provided to the base and structured to diffuse vent flow, and a cover to maintain the grill components/media within the base. Only the cover 77 of the vent arrangement 76 is visible in FIGS. 27-30. Exemplary embodiments of such a vent arrangement are disclosed in U.S. patent application Ser. No. 12/230,120, filed Aug. 22, 2008, which is incorporated herein by reference in its entirety. However, it should be appreciated that the vent arrangement may include other suitable arrangements, e.g., vent insert with one or more vent holes. Also, the elbow may provide an alternative venting arrangement to the vent insert. For example, as indicated in dashed lines in FIG. 30, the first end portion 74(1) of the elbow 70 (e.g., along the interfacing structure 75) may include one or more vent holes 276 for gas washout. The one or more holes 276 may be provided to a soft part (e.g., silicone seal as described below) and/or a hard part (e.g., polycarbonate, polypropylene) of the elbow. The holes 276 may extend around the entire perimeter of the first end portion 74(1) or may extend along one or more portions of the first end portion 74(1). It is noted that providing vent holes along the entire perimeter of the elbow may help to disperse the vent flow in use. However, other suitable hole arrangements, hole numbers, and/or hole shapes along the first end portion 74(1) and/or other portions of the elbow are possible. 5.4 Ports In FIGS. 1-5, the base of the frame 1040 includes two ports 1043 positioned so that in use, oxygen or other breathable gas can be delivered close to the patient's nares or pressure monitoring equipment can be attached. The ports 1043 may also be used to attach additional medical equipment such as pressure or flow sensors. The ports may be selectively closable or sealable by a ports cap. In an alternative embodiment, as shown in FIGS. 25 and 26, the frame 1040 may include a side port 1043.1, e.g., in addition to or as an alternative to the ports 1043. FIGS. 35-1 and 35-2 show a frame 240 that includes an auxiliary port or spigot 243 on an upper portion of the frame, e.g., for supplemental oxygen, measurement device, etc. In FIGS. 37-1 to 37-3 and 39-1 to 39-6, the frame 340 includes an auxiliary port or spigot 343 on each side thereof, e.g., for supplemental oxygen, measurement device, etc. Port caps 347 are provided to seal respective ports 343. 6. Interface Seal In an embodiment, a seal may be provided at the interface between the elbow and the shroud, at the interface between the frame and the shroud, and/or at the interface between the elbow and the frame. For example, a seal (e.g., elastomeric, ring-shaped seal) may be formed separately from the modules and attached at the interface (e.g., sandwiched between modules, adhesive, etc.). Alternatively, a seal may be co-molded with one or more of the modules. In an embodiment, a silicone lip seal may be provided to the frame to seal against the elbow, thereby reducing leak. In another embodiment, as shown in FIG. 27-30, the interfacing structure 75 of the elbow 70 may be constructed of a relatively soft, sealing material (e.g., silicone, which may be co-molded to the harder material of the elbow) that is structured to provide a seal at the interface between the elbow 70 and the shroud 20. Also, the relatively soft interfacing structure 75 (e.g., silicone) provides a “soft” attachment to the relatively hard shroud 20 (e.g., polycarbonate, polypropylene) which may allow an interference type fit. As noted above, one or more vent holes may be provided to the softer interfacing structure and/or the harder elbow. While the invention has been described in connection with what are presently considered to be the most practical and preferred embodiments, it is to be understood that the invention is not to be limited to the disclosed embodiments, but on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the invention. Also, the various embodiments described above may be implemented in conjunction with other embodiments, e.g., aspects of one embodiment may be combined with aspects of another embodiment to realize yet other embodiments. Further, each independent feature or component of any given assembly may constitute an additional embodiment. Furthermore, each individual component of any given assembly, one or more portions of an individual component of any given assembly, and various combinations of components from one or more embodiments may include one or more ornamental design features. In addition, while the invention has particular application to patients who suffer from OSA, it is to be appreciated that patients who suffer from other illnesses (e.g., congestive heart failure, diabetes, morbid obesity, stroke, bariatric surgery, etc.) can derive benefit from the above teachings. Moreover, the above teachings have applicability with patients and non-patients alike in non-medical applications.
<SOH> BACKGROUND OF THE INVENTION <EOH>Patient interfaces, such as a full-face or nasal mask systems, for use with blowers and flow generators in the treatment of sleep disordered breathing (SDB), typically include a soft face-contacting portion, such as a cushion, and a rigid or semi-rigid shell or frame. In use, the interface is held in a sealing position by headgear so as to enable a supply of air at positive pressure (e.g., 2-30 cm H 2 O) to be delivered to the patient's airways. One factor in the efficacy of therapy and compliance of patients with therapy is the comfort and fit of the patient interface. The present invention provides alternative arrangements of mask systems to enhance the efficacy of therapy and compliance of patients with therapy.
<SOH> SUMMARY OF THE INVENTION <EOH>One aspect of the invention relates to a mask system provided without a forehead support adapted to engage the patient's forehead. Another aspect of the invention relates to a mask system including a frame and a shroud removably connected to the frame and adapted to attach headgear. Another aspect of the invention relates to a mask system including a frame defining a breathing chamber, a cushion provided to the frame and adapted to form a seal with the patient's face, and a shroud provided to the frame. The shroud and the frame are co-molded with one another. The frame is constructed of a first, relatively soft, elastomeric material and the shroud is constructed of a second material that is more rigid than the frame. At least a portion of the frame includes a concertina section having a plurality of folds. Each of the folds has a side wall with the side walls of the folds becoming progressively longer away from the patient's face. Another aspect of the invention relates to a cushion module including a frame defining a breathing chamber and a cushion adapted to form a seal with the patient's face. The frame and the cushion are co-molded with one another. The cushion is constructed of a first, relatively soft, elastomeric material and the frame is constructed of a second material that is more rigid than the cushion. At least a portion of the frame includes a concertina section. Another aspect of the invention relates to a method for constructing a cushion module. The method includes molding a first part of the cushion module with a first, relatively soft, elastomeric material, co-molding a second part of the cushion module to the first part with a second material that is more rigid than the first material, and molding at least a portion of the second part to include a concertina section. Another aspect of the invention relates to a shroud for a mask system including a retaining portion structured to retain a frame, a pair of upper headgear connectors each including an elongated arm and a slot at the free end of the arm adapted to receive a headgear strap, and a pair of lower headgear connectors each adapted to attach to a headgear strap, wherein the retaining portion, the upper headgear connectors, and the lower headgear connectors are integrally formed as a one piece structure. Another aspect of the invention relates to a mask system including a frame defining a breathing chamber, a cushion provided to the frame and adapted to form a seal with the patient's face, a shroud provided to the frame and adapted to attach headgear, and an elbow provided to the frame and adapted to be connected to an air delivery tube that delivers breathable gas to the patient. The shroud includes a retaining mechanism structured to establish a positive connection between the shroud and the frame. Another aspect of the invention relates to a mask system including a frame defining a breathing chamber and a cushion provided to the frame. The cushion includes a main body and a cushion, wherein the cushion is adapted to engage at least a portion of the patient's face. The cushion includes a base wall connected to an undercushion layer and a membrane, wherein the membrane extends around the perimeter of the cushion and contacts the patient's face. The undercushion layer is positioned underneath the membrane and supports the membrane. The under cushion layer provides differential support to the membrane at predetermined regions of the face. Another aspect of the invention relates to a mask assembly for use in medical applications having a top and bottom ends defined by its position relative to a patient's face, wherein the mask assembly is connected to a plurality of flexible straps, which are adapted to engage the patient's head. The flexible straps engage at least two elongated rigid arms integrally molded to a portion of the mask assembly, and wherein the elongated arms are molded to the mask assembly proximal to the top end of the mask assembly. Another aspect of the invention relates to a mask assembly for use in medical applications including a main body connected to a cushion adapted to cover nose and/or mouth and wherein the mask assembly is attached by a force substantially perpendicular towards the face and wherein the force is approximately constant along the length of the mask and is balanced by a portion of the cushion engaging the patient's cheeks. Another aspect of the invention relates to a cushion for use with a medical mask including an outer membrane layer adapted to sealably engage a face and an undercushion layer adapted to support the membrane layer. The membrane or undercushion layer includes a surface positioned between the two layers adapted to allow the layers to slide against the respective surface. Another aspect of the invention relates to a mask system including a frame defining a breathing chamber, a cushion provided to the frame and adapted to form a seal with the patient's face, and a releasable shroud adapted to engage a portion of the outer surface of the frame, wherein the shroud is connected to straps to position the mask system. Another aspect of the invention relates to a mask assembly for use in medical applications including an upper end and a lower end wherein the upper end is adapted to cover the nose and the lower end is adapted to cover the mouth of a patient. The mask assembly includes no forehead support and includes two stiffened members attached to the upper end on opposed sides of the mask assembly, and wherein the stiffened members include a general curved shape and adapted to avoid covering the patient's field of vision. Another aspect of the invention relates to a cushion for attaching to a medical mask, wherein the cushion is flexible and includes a membrane attached to the circumference of the cushion adapted to seal against the face of a patient, and at least one undercushion adapted to support the membrane and positioned underneath the membrane to prevent collapse of the membrane, in use. The membrane is softer than the undercushion. The undercushion in the regions of nasal bridge or chin is between 0 mm and 30 mm in height as measured between the base and the tip of the undercushion. Another aspect of the invention relates to a mask assembly for use in medical applications including an upper end and a lower end wherein the upper end is adapted to cover the nose and the lower end is adapted to cover the mouth of a patient. The mask assembly includes no forehead support and includes two stiffened members attached to the upper end on opposed sides of the mask assembly, and wherein the stiffened members include a general curved shape and adapted to avoid covering the patient's field of vision. In an alternative embodiment, the mask system may include a headgear connector or rigidizer structured to attach to the frame with a snap-fit, mechanical interlock, friction fit, and/or grommet arrangement (e.g., constructed of rubber). In an alternative embodiment, the mask system may include headgear having an arrangement of straps constructed of silicone and/or Breath-O-Prene™ material. Other aspects, features, and advantages of this invention will become apparent from the following detailed description when taken in conjunction with the accompanying drawings, which are a part of this disclosure and which illustrate, by way of example, principles of this invention.
A61M160622
20171004
20180508
20180125
65185.0
A61M1606
1
DITMER, KATHRYN ELIZABETH
MASK SYSTEM WITH SNAP-FIT SHROUD
UNDISCOUNTED
1
CONT-ACCEPTED
A61M
2,017
15,725,437
PENDING
MACHINE LEARNING DEVICE AND MACHINE LEARNING METHOD FOR LEARNING CORRELATION BETWEEN SHIPMENT INSPECTION INFORMATION AND OPERATION ALARM INFORMATION FOR OBJECT
A machine learning device which learns a correlation between shipment inspection information obtained by inspecting an object in shipment thereof and operation alarm information issued during operation of the object, includes a state observation unit which observes the shipment inspection information and the operation alarm information; and a learning unit which generates a learning model based on the shipment inspection information and the operation alarm information observed by the state observation unit.
1. A machine learning device which learns a correlation between shipment inspection information obtained by inspecting an object in shipment thereof and operation alarm information issued during operation of the object, comprising: a state observation unit which observes the shipment inspection information and the operation alarm information; and a learning unit which generates a learning model based on the shipment inspection information and the operation alarm information observed by the state observation unit. 2. The machine learning device according to claim 1, wherein the learning unit generates a distribution correlation between the shipment inspection information and the operation alarm information as the learning model. 3. The machine learning device according to claim 1, further comprising: an output utilization unit which outputs an inspection item in shipping the object, which influences an alarm issued during the operation of the object, based on the learning model generated by the learning unit. 4. The machine learning device according to claim 1, wherein the learning unit generates the learning model by clustering the shipment inspection information and the operation alarm information. 5. The machine learning device according to claim 4, wherein the learning unit generates the learning model by hierarchical clustering in which the shipment inspection information and the operation alarm information are arithmetically processed in a hierarchical structure, and nonhierarchical clustering in which the shipment inspection information and the operation alarm information are arithmetically processed until a predetermined number is reached based on a distance between nodes. 6. The machine learning device according to claim 1, wherein the machine learning device further comprises a neural network. 7. The machine learning device according to claim 1, wherein the machine learning device is connectable to at least one different machine learning device and exchanges or shares the learning model generated by the learning unit of the machine learning device with the at least one different machine learning device. 8. The machine learning device according to claim 7, wherein the machine learning device is located on a first cloud server, and the different machine learning device is located on a second cloud server different from the first cloud server. 9. The machine learning device according to claim 1, wherein the object comprises a motor, and the shipment inspection information comprises inspection results of inspection items associated with a model of the motor and an inspection date of the motor. 10. The machine learning device according to claim 1, wherein the object comprises a servo amplifier which performs servo driving of a motor, and the shipment inspection information comprises inspection results of inspection items associated with a model of the servo amplifier and an inspection date of the servo amplifier. 11. The machine learning device according to claim 1, wherein the shipment inspection information comprises at least one of an insulation resistance value, an earth resistance value, a current value, and a switching surge voltage for the object, and the operation alarm information comprises at least one of an overcurrent alarm, a noise alarm, and an overload alarm for the object. 12. A machine learning method for learning a correlation between shipment inspection information obtained by inspecting an object in shipment thereof and operation alarm information issued during operation of the object, comprising: observing the shipment inspection information and the operation alarm information; and generating a learning model based on the observed shipment inspection information and operation alarm information. 13. The machine learning method according to claim 12, wherein the generating the learning model comprises generating a distribution correlation between the shipment inspection information and the operation alarm information as the learning model. 14. The machine learning method according to claim 12, further comprising: outputting an inspection item in shipping the object, which influences an alarm issued during the operation of the object, based on the generated learning model. 15. The machine learning method according to claim 12, wherein the generating the learning model comprises generation by clustering the shipment inspection information and the operation alarm information.
BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a machine learning device and a machine learning method for learning the correlation between shipment inspection information and operation alarm information for an object. 2. Description of the Related Art Conventionally, electric motors (motors: objects) have been used for a variety of electrical machines and devices including, e.g., machine tools and robots controlled by computer numerical control (CNC) devices. Such motors normally undergo shipment inspection in shipping products such as machine tools or robots, which are then delivered to users. This shipment inspection is conducted in shipping not only products which use motors but also, e.g., the motors themselves, both of which are then delivered to users. In this specification, information obtained by inspecting a motor or a product which uses the motor in shipment will be referred to as shipment inspection information hereinafter. After being delivered to users, products (motors) such as machine tools or robots are used (operated) in, e.g., actual fields, but alarms may be issued during the operation of the machine tools or the like. The alarms are issued during the operation due to various factors including, e.g., electrical problems based on, e.g., motor insulation failure or servo amplifier failure or mechanical (structural) problems based on, e.g., bearing failure or metal fatigue. In this specification, information concerning an alarm issued during the operation of a motor or a product which uses the motor will be referred to as operation alarm information hereinafter. In this specification, a motor (a product which uses the motor) will be mainly taken as an example of an object targeted for learning the correlation between shipment inspection information and operation alarm information by machine learning, but the object is not limited to a motor, and various objects whose shipment inspection information and operation alarm information may be acquired, including, e.g., a servo amplifier which performs servo driving of a motor, may be applicable. The correlation between shipment inspection information and operation alarm information for an object (motor), as described above, has conventionally attracted little attention, and even if the shipment inspection information and the operation alarm information for the motor have a certain correlation, persons may expend enormous efforts to analyze (organize) this correlation. In addition, since, for example, the use conditions (e.g., the ambient temperature or humidity, the running time, and the magnitude of the load in use) of each individual motor (including motors used for a variety of electrical machines and devices) significantly vary for each field of actual use, it is difficult for persons to comprehend the actual use conditions and elucidate the correlation between shipment inspection information and operation alarm information for this motor. Incidentally, hitherto, for example, Japanese Laid-Open Patent Publication No. H07-174616 discloses an inspection device which inspects an object such as a compact motor for abnormalities on the basis of vibration of the object or a sound emitted by the object. The inspection device detects vibration of the object or a sound emitted by the object using a sensor, performs envelope detection and Fourier transformation, calculates a certainty factor for the presence of an abnormality of the object using an arithmetic unit, further calculates a certainty factor for the presence of an abnormality of the object by inputting a feature vector signal representing the features of Fourier transform signals to a neural network, performs fuzzy computation based on the certainty factors calculated by both the arithmetic unit and the neural network, and determines the presence or absence of an abnormality of the object. Further, Japanese National Publication of International Patent Application No. 2007-528985, for example, discloses a technique for optically measuring a structure formed on a semiconductor wafer, using a machine learning system. In other words, in a method for inspecting a structure formed on a semiconductor wafer, a first diffraction signal measured using a measurement device is obtained, and at least one parameter which features the profile of the structure is received as input to obtain a second diffraction signal generated using the machine learning system. The first diffraction signal and the second diffraction signal are compared with each other, and when they match each other within the range of matching criteria, the shape of the structure is obtained on the basis of the profile or the at least one parameter used by the machine learning system to generate the second diffraction signal. In addition, Japanese Laid-Open Patent Publication No. 2004-354250, for example, discloses as a defect inspection device capable of processing an image obtained by capturing an object to efficiently, accurately classify defects, a defect inspection device which uses a neural network provided in correspondence with each specific defect to be classified occurring in the process of manufacturing an object, allows learning of each neural network for each defect to be classified, and detects the presence or absence of a defect in the object for each defect to be classified by each learned neural network. The neural network includes a neural network for shot defocus defects for classifying defocus defects occurring shot by shot in the process of exposing the object, and the image size is converted in correspondence with the input layer size as preprocessing input to the neural network. Some patent literatures of the related art conventionally disclose techniques for calculating a certainty factor for the presence of an abnormality of a motor using a neural network, or techniques for inspecting a semiconductor wafer or the like on the basis of a machine learning model, as described above. However, no particular attention has been focused on the correlation between shipment inspection information and operation alarm information for a motor, and even though the shipment inspection information and the operation alarm information for the motor have a certain correlation, it is difficult for persons to analyze this correlation because they may expend enormous efforts, as described earlier. In addition, since the use conditions of each individual motor significantly vary for each field of actual use, it may be very difficult for persons to comprehend the actual use conditions and elucidate the correlation between shipment inspection information and operation alarm information for this motor, and the correlation between shipment inspection information and operation alarm information for a motor, taking such actual use conditions into consideration, is evaluated on the basis of only experiences or intuitions of skilled engineers or users who have used the motor in the field for a long period of time. In consideration of the above-described conventional problems, it is an object of the present invention to obtain a correlation between shipment inspection information and operation alarm information for an object. Obtaining a correlation between shipment inspection information and operation alarm information for an object in this manner leads to solutions to various problems such as improvements in shipment inspection items, and structural upgrading, life determination, and an improvement in quality of the object. SUMMARY OF INVENTION According to a first aspect of the present invention, there is provided a machine learning device which learns a correlation between shipment inspection information obtained by inspecting an object in shipment thereof and operation alarm information issued during operation of the object, including a state observation unit which observes the shipment inspection information and the operation alarm information; and a learning unit which generates a learning model based on the shipment inspection information and the operation alarm information observed by the state observation unit. The learning unit may generate a distribution correlation between the shipment inspection information and the operation alarm information as the learning model. The machine learning device may further include an output utilization unit which outputs an inspection item in shipping the object, which influences an alarm issued during the operation of the object, based on the learning model generated by the learning unit. The learning unit may generate the learning model by clustering the shipment inspection information and the operation alarm information. The learning unit may generate the learning model by hierarchical clustering in which the shipment inspection information and the operation alarm information are arithmetically processed in a hierarchical structure, and nonhierarchical clustering in which the shipment inspection information and the operation alarm information are arithmetically processed until a predetermined number is reached based on a distance between nodes. The machine learning device may further include a neural network. The machine learning device may be connectable to at least one different machine learning device and exchange or share the learning model generated by the learning unit of the machine learning device with the at least one different machine learning device. The machine learning device may be located on a first cloud server, and the different machine learning device may be located on a second cloud server different from the first cloud server. The object may include a motor, and the shipment inspection information may include inspection results of inspection items associated with a model of the motor and an inspection date of the motor. The object may include a servo amplifier which performs servo driving of a motor, and the shipment inspection information may include inspection results of inspection items associated with a model of the servo amplifier and an inspection date of the servo amplifier. The shipment inspection information may include at least one of an insulation resistance value, an earth resistance value, a current value, and a switching surge voltage for the object, and the operation alarm information may include at least one of an overcurrent alarm, a noise alarm, and an overload alarm for the object. According to a second aspect of the present invention, there is provided a machine learning method for learning a correlation between shipment inspection information obtained by inspecting an object in shipment thereof and operation alarm information issued during operation of the object, including observing the shipment inspection information and the operation alarm information; and generating a learning model based on the observed shipment inspection information and operation alarm information. The generating the learning model may include generating a distribution correlation between the shipment inspection information and the operation alarm information as the learning model. The machine learning method may further include outputting an inspection item in shipping the object, which influences an alarm issued during the operation of the object, based on the generated learning model. The generating the learning model may include generation by clustering the shipment inspection information and the operation alarm information. BRIEF DESCRIPTION OF THE DRAWINGS The present invention will be understood more clearly by referring to the following accompanying drawings. FIG. 1 is a block diagram schematically illustrating an embodiment of a machine learning device according to the present invention; FIG. 2 is a plot for explaining exemplary arithmetic processing applied to the machine learning device illustrated in FIG. 1; and FIG. 3 is a diagram for explaining another exemplary arithmetic processing applied to the machine learning device illustrated in FIG. 1. DETAILED DESCRIPTION Hereinafter, embodiments of a machine learning device and a machine learning method according to the present invention will be described in detail below with reference to the accompanying drawings. A motor will be mainly taken hereinafter as an example of an object targeted for learning the correlation between shipment inspection information and operation alarm information by machine learning, but the object is not limited to a motor, and various objects whose shipment inspection information and operation alarm information may be acquired, including, e.g., a servo amplifier which performs servo driving of a motor, may be applicable. FIG. 1 is a block diagram schematically illustrating an embodiment of a machine learning device according to the present invention. A machine learning device 2 according to this embodiment includes a state observation unit 21, a learning unit 22, and an output utilization unit 23, as illustrated in FIG. 1. The state observation unit 21 observes, e.g., shipment inspection information (X1n) obtained by inspection in shipping a motor (object) and operation alarm information (X2n) issued during the operation of the motor, as data input from an environment 1. The environment 1 includes, e.g., a motor inspection device 11 which inspects a motor in its shipment and outputs shipment inspection information (X1n), and a motor controller 12 which issues an alarm during the operation of the motor and outputs operation alarm information (X2n). The shipment inspection information (X1n) and the operation alarm information (X2n) observed by the state observation unit 21 are input to the learning unit 22, which generates a distribution correlation between the shipment inspection information (X1n) and the operation alarm information (X2n) as a learning model. The output utilization unit 23 outputs, for example, an inspection item in shipping a motor, which influences an alarm issued during the operation of the motor, based on the learning model generated by the learning unit 22. The output utilization unit 23 may be located outside the machine learning device 2, and even the output of the output utilization unit 23 based on the learning model generated by the learning unit 22 is not limited to the above-mentioned inspection item in shipping a motor, which influences an alarm issued during the operation of the motor. The learning unit 22 applies “unsupervised learning” to the shipment inspection information (X1n) and the operation alarm information (X2n) to generate a learning model by, e.g., clustering. In other words, the learning unit 22 generates a learning model by hierarchical clustering in which the shipment inspection information (X1n) and the operation alarm information (X2n) are arithmetically processed in a hierarchical structure, or nonhierarchical clustering in which the shipment inspection information (X1n) and the operation alarm information (X2n) are arithmetically processed until a predetermined number is reached based on the distance between nodes. FIG. 2 is a plot for explaining exemplary arithmetic processing applied to the machine learning device illustrated in FIG. 1, i.e., explaining nonhierarchical clustering (clustering based on the k-means method). FIG. 3 is a diagram for explaining another exemplary arithmetic processing applied to the machine learning device illustrated in FIG. 1, and illustrates an exemplary neural network applied to an auto-encoder for dimensional compression in hierarchical clustering. The machine learning device (machine learning method) according to this embodiment employs “unsupervised learning” to perform clustering, and thus extracts, e.g., a useful rule, a knowledge representation, and a determination criterion by analysis from input data of shipment inspection information (X1n) and operation alarm information (X2n), outputs the determination results, and learns knowledge (machine learning). The machine learning device 2 uses, e.g., a neural network, but in actually implementing the machine learning device 2, a general-purpose computer or processor may be used, while the use of general-purpose computing on graphics processing units (GPGPU) or large-scale PC clusters allows higher-speed processing. In unsupervised learning, only input data are fed into the machine learning device 2 in large amounts to learn the distribution of the input data to, e.g., compress, classify, and shape the input data without corresponding teacher output data, unlike “supervised learning.” This allows, e.g., clustering of features seen in sets of input data into similar features, and on the basis of the obtained result, any norm may be defined and outputs are allocated to optimize it, thus predicting output. “Unsupervised learning” in this specification refers to broadly-defined “unsupervised learning” including, e.g., an intermediate between “supervised learning” and “unsupervised learning,” called “semi-supervised learning.” More specifically, as illustrated in FIG. 2, the machine learning device 2 (learning unit 22) may receive shipment inspection information (X1n) and operation alarm information (X2n) and perform, e.g., clustering until a predetermined number (e.g., k=3) is reached based on the distance between nodes (the distance between dots in FIG. 2) to obtain clusters A, B, and C. In other words, clusters A, B, and C based on the correlation between shipment inspection information (X1n) and operation alarm information (X2n) for a motor (object) may be obtained. As illustrated in FIG. 3, when, for example, input shipment inspection information (X1n) and operation alarm information (X2n) for a motor are hierarchized and clustered, a neural network 3 is applicable as an auto-encoder for dimensional compression. Shipment inspection information (X1n) and operation alarm information (X2n) for a motor, for example, are used as input X (input data Xn) of the neural network (auto-encoder) 3, and hierarchically clustered output data Yn is output as output Y. The nonhierarchical clustering represented in FIG. 2 and the hierarchical clustering represented in FIG. 3 are merely examples, and various known “unsupervised learning” methods are naturally applicable to the machine learning device 2 according to this embodiment. The machine learning device 2 according to this embodiment may be located on, e.g., a server of a manufacturer, as will be described in detail later, but the machine learning device 2 is connectable to at least one different machine learning device and may exchange or share a learning model generated by the learning unit (22) of each machine learning device (2) with the at least one different machine learning device. The servers equipped with these machine learning devices 2 may be implemented as, e.g., different cloud servers accessible via a communication line such as the internet. In this manner, with the machine learning device (machine learning method) according to this embodiment, a correlation (e.g., clusters A, B, and C in FIG. 2) between shipment inspection information and operation alarm information for an object (motor) may be obtained. Examples of the obtained correlation may include various correlations such as that between the surge voltage in the shipment inspection information and a noise alarm (an alarm for a communication error) in the operation alarm information, and that between the earth resistance in the shipment inspection information and an alarm for a communication error in the operation alarm information. Obtaining a correlation between shipment inspection information and operation alarm information for an object may result in solutions to various problems such as improvements in shipment inspection items, and structural upgrading, life determination, and an improvement in quality of the object. An application example of the machine learning device (machine learning method) according to this embodiment will be described below. First, the motor inspection device 11 conducts shipment inspection of a motor in its shipment to obtain information (X1n) concerning the inspection conducted in shipment. Examples of the shipment inspection information (X1n) of each motor may include the type (model), the inspection date, the insulation resistance value, the winding resistance value, the back electromotive force value, and the current value and the shaft friction torque value during driving for this motor, and the shipment inspection information (X1n) is recorded in a storage device (e.g., a nonvolatile storage device such as a hard disk drive or a flash memory). After the motors are shipped, operation alarm information (X2n) during the operation of each motor is acquired. Examples of the operation alarm information (X2n) of each motor may include the details of an alarm, the time until the occurrence of the alarm, and the velocity, the torque, the current, and the temperature upon the occurrence of the alarm, and the operation alarm information (X2n) is recorded in a storage device. Examples of the types of alarms may include an overcurrent alarm, a noise alarm (an alarm issued when noise is present at a predetermined level or more or an alarm issued upon the occurrence of a communication error), an overload alarm (an alarm issued upon motor overheating), and an excessive error upon movement. The shipment inspection information (X1n) of each individual motor is stored in, e.g., a server (server storage device) of a manufacturer of a motor or a product which uses the motor. The operation alarm information (X2n) of each individual motor is temporarily stored in, e.g., a storage device of the controller 12 that controls the motor, and is copied from the controller 12 to the server of the manufacturer by the service engineer of the manufacturer and stored. Alternatively, the operation alarm information (X2n) of each individual motor may be configured to be, e.g., directly uploaded from the motor controller 12 to the server of the manufacturer via a communication line such as the internet. Hence, the machine learning device 2 located on the server of the manufacturer, for example, may perform learning (processing) using the shipment inspection information (X1n) and the operation alarm information (X2n) of each individual motor as input. Processing by the machine learning device according to this embodiment located on the server of the manufacturer, for example, will be described below. First, from shipment inspection information (X1n) and operation alarm information (X2n) for a motor, a correlation between (X1n) and (X2n) is generated as a learning model, and shipment inspection items (a1, a2, a3, a4, . . . ) belonging to the shipment inspection information (X1n) for the motor that influences the operation alarm information (X2n) are output from the learning model. For faults involving specific alarms (e.g., a ground fault of a motor involving an overcurrent alarm, and demagnetization of the motor involving an overheat alarm), the rate of occurrence of faults may be predicted on the basis of, e.g., information (shipment inspection information) concerning the shipment inspection items of motors still operating without any problem from shipment inspection information (X1n) for the motor which influences an alarm. In other words, the rate of occurrence of faults of a certain motor in operation may be predicted on the basis of, e.g., the shipment inspection information of the certain motor from the correlation between shipment inspection information (X1n) and operation alarm information (X2n) for the motor. The effects obtained from the correlation between shipment inspection information and operation alarm information for a motor (object) are not limited to such prediction of the rate of occurrence of faults of the motor, and various effects may be obtained, as a matter of course. Regarding, e.g., demagnetization of a motor involving an overheat alarm, its cause may be estimated and a prompt measure may be taken as follows: when the back electromotive force in the shipment inspection information (shipment inspection) is concerned, magnet selection in design or magnet magnetization, for example, may be estimated to be responsible; when the winding resistance in the shipment inspection information is concerned, winding in the manufacture, for example, may be estimated to be responsible; or when the shaft friction resistance value in the shipment inspection information is concerned, an increase in friction resistance because of damage inflicted on the bearing in the manufacture, for example, may be estimated to be responsible. When the rate of occurrence of a specific alarm increases after a certain shipment date, a point of change in a component used, a manufacturing facility, or the like, for example, may be estimated to be responsible. When the rate of occurrence of alarms increases for a specific model, factors unique to the model in design, for example, may be estimated to be responsible. In any case, confirming the correlation between shipment inspection information and operation alarm information allows prediction of the rate of occurrence of faults for each individual motor operating in the field, and even allows effective limitation or the like of a target for a measure against the faults when such a measure is taken. Although a motor has been taken as an example of the object in the foregoing description, a servo amplifier which performs servo driving of a motor will be exemplified as the object below. In this case, the shipment inspection information (X1n) of the servo amplifier includes the model of the servo amplifier, and the inspection results of inspection items associated with the inspection date of the servo amplifier. More specifically, the shipment inspection information (X1n) of the servo amplifier includes, e.g., the insulation resistance value, the earth resistance value, the current value, and the switching surge voltage for the servo amplifier, and the operation alarm information (X2n) of the servo amplifier includes, e.g., an overcurrent alarm, a noise alarm, and an overload alarm (overheating amplifier) for the servo amplifier. Examples of the correlation obtained by the machine learning device (machine learning method) according to this embodiment may include various correlations such as that between the surge voltage in the shipment inspection information and an alarm for a communication error (noise alarm) in the operation alarm information, and that between the earth resistance in the shipment inspection information and an alarm for a communication error in the operation alarm information, as in the case where a motor is assumed as the object. Obtaining a correlation between shipment inspection information and operation alarm information for an object leads to solutions to various problems such as improvements in shipment inspection items, and structural upgrading, life determination, and an improvement in quality of the object, as described earlier. The machine learning device and the machine learning method according to the present invention have the effect of obtaining a correlation between shipment inspection information and operation alarm information for an object. All examples and conditional language provided herein are intended for the pedagogical purposes of aiding the reader in understanding the invention and the concepts contributed by the inventor to further the art, and are not to be construed as limitations to such specifically recited examples and conditions, nor does the organization of such examples in the specification relate to a showing of the superiority and inferiority of the invention. Although one or more embodiments of the present invention have been described in detail, it should be understood that various changes, substitutions, and alterations could be made hereto without departing from the spirit and scope of the invention.
<SOH> BACKGROUND OF THE INVENTION <EOH>
<SOH> SUMMARY OF INVENTION <EOH>According to a first aspect of the present invention, there is provided a machine learning device which learns a correlation between shipment inspection information obtained by inspecting an object in shipment thereof and operation alarm information issued during operation of the object, including a state observation unit which observes the shipment inspection information and the operation alarm information; and a learning unit which generates a learning model based on the shipment inspection information and the operation alarm information observed by the state observation unit. The learning unit may generate a distribution correlation between the shipment inspection information and the operation alarm information as the learning model. The machine learning device may further include an output utilization unit which outputs an inspection item in shipping the object, which influences an alarm issued during the operation of the object, based on the learning model generated by the learning unit. The learning unit may generate the learning model by clustering the shipment inspection information and the operation alarm information. The learning unit may generate the learning model by hierarchical clustering in which the shipment inspection information and the operation alarm information are arithmetically processed in a hierarchical structure, and nonhierarchical clustering in which the shipment inspection information and the operation alarm information are arithmetically processed until a predetermined number is reached based on a distance between nodes. The machine learning device may further include a neural network. The machine learning device may be connectable to at least one different machine learning device and exchange or share the learning model generated by the learning unit of the machine learning device with the at least one different machine learning device. The machine learning device may be located on a first cloud server, and the different machine learning device may be located on a second cloud server different from the first cloud server. The object may include a motor, and the shipment inspection information may include inspection results of inspection items associated with a model of the motor and an inspection date of the motor. The object may include a servo amplifier which performs servo driving of a motor, and the shipment inspection information may include inspection results of inspection items associated with a model of the servo amplifier and an inspection date of the servo amplifier. The shipment inspection information may include at least one of an insulation resistance value, an earth resistance value, a current value, and a switching surge voltage for the object, and the operation alarm information may include at least one of an overcurrent alarm, a noise alarm, and an overload alarm for the object. According to a second aspect of the present invention, there is provided a machine learning method for learning a correlation between shipment inspection information obtained by inspecting an object in shipment thereof and operation alarm information issued during operation of the object, including observing the shipment inspection information and the operation alarm information; and generating a learning model based on the observed shipment inspection information and operation alarm information. The generating the learning model may include generating a distribution correlation between the shipment inspection information and the operation alarm information as the learning model. The machine learning method may further include outputting an inspection item in shipping the object, which influences an alarm issued during the operation of the object, based on the generated learning model. The generating the learning model may include generation by clustering the shipment inspection information and the operation alarm information.
G06Q5028
20171005
20180412
58717.0
G06Q5028
0
SECK, ABABACAR
MACHINE LEARNING DEVICE AND MACHINE LEARNING METHOD FOR LEARNING CORRELATION BETWEEN SHIPMENT INSPECTION INFORMATION AND OPERATION ALARM INFORMATION FOR OBJECT
UNDISCOUNTED
0
PENDING
G06Q
2,017
15,725,505
PENDING
CONSIGNMENT BOOKING APPARATUSES, METHODS, AND SYSTEMS
Implementations for consignment booking include actions of providing a user interface including a plurality of consignment data entry fields that include a pickup location entry field configured to receive data identifying a pickup location for a consignment, a delivery destination entry field configured to receive data identifying a delivery destination for the consignment, and a content entry field configured to receive data identifying a content of the consignment to be delivered, retrieving the data identifying the pickup location, the delivery destination and the content, transmitting a call signal to be transmitted to a mobile computing device of each agent in a plurality of agents, determining a respective location of each agent in the plurality of agents based on a response to each call signal, and selecting an agent from the plurality of agents based at least in part on the respective agent locations with respect to the pickup location.
1. A computing system for consignment booking, the system comprising: a user interface module configured to cause a display of a plurality of consignment data entry fields on a computer display, the consignment data entry fields comprising: a pickup location entry field configured to receive data identifying a pickup location for a consignment, a delivery destination entry field configured to receive data identifying a delivery destination for the consignment, and a content entry field configured to receive data identifying a content of the consignment to be delivered; and an agent selection module configured to determine respective agent locations for each agent in a plurality of agents and to select an agent from the plurality of agents based at least in part on the respective agent locations, the pickup location, the delivery destination, and the content of the consignment. 2. The system of claim 1, wherein the agent selection module is configured to select the agent having a closest proximity to the pickup location. 3. The system of claim 1, wherein the agent selection module is configured to determine an estimated time to travel to the pickup location of each agent in the plurality of agents and to select the agent having a shortest estimated time to travel to the pickup location. 4. The system of claim 1, wherein the agent selection module is configured to determine an estimated time of pickup for each agent in the plurality of agent s and to select the agent with the earliest estimated pickup time. 5. The system of claim 4, wherein the estimated time of pickup is determined based on an estimate of the time to travel from the agent location to the pickup location with a traffic delay estimate. 6. The system of claim 4, wherein the estimated time of pickup is determined based on an estimate of an average speed of the agent along a route from the agent location to the pickup location. 7. The system of claim 1, wherein the agent location is determined by receiving a location signal from a global positioning system of a mobile electronic device in response to a positioning call to each agent in the plurality of agent s. 8. The system of claim 1, further comprising an agent location module is configured to identify an un-located agent position as a last known agent position in response to the mobile electronic device failing to respond to the positioning call. 9. The system of claim 1, wherein the agent selection module is configured to determine an estimated time of drop off at the delivery destination. 10. The system of claim 9, wherein the estimated time of drop off is determined based on at least one subsequent consignment pickup that the selected agent is scheduled to make after picking up the consignment. 11. The system of claim 1, wherein the agent selection module is configured to select the agent having a closest proximity to the pickup location and a highest a rating. 12. The system of claim 1, wherein the agent selection module is configured to generate an alert communication for transmission to the agent based on the agent selection. 13. The system of claim 12, wherein the agent selection module is configured to track the agent based on transmission of the alert communication. 14. The system of claim 1, further comprising a classification module configured to retrieve one or more of the pickup location, the deliver destination and the content based on data entered into the consignment data entry fields and to identify a classification of the consignment based on a comparison of the data with a classification database. 15. A computer-implemented method executed by one or more processors of an electronic computing device, the method comprising: providing a computer display to display a user interface comprising a plurality of consignment data entry fields, the consignment data entry fields comprising: a pickup location entry field configured to receive data identifying a pickup location for a consignment, a delivery destination entry field configured to receive data identifying a delivery destination for the consignment, and a content entry field configured to receive data identifying a content of the consignment to be delivered; retrieving the data identifying the pickup location, the delivery destination and the content; transmitting a call signal to be transmitted to a mobile computing device of each agent in a plurality of agents; determining a respective location of each agent in the plurality of agents based on a response to each call signal; and selecting an agent from the plurality of agents based at least in part on the respective agent locations with respect to the pickup location. 16. The method of claim 15, further comprising selecting an agent based at least in part on the delivery destination. 17. The method of claim 15, further comprising selecting an agent based at least in part on the content of the consignment. 18. The method of claim 15, further comprising determining an estimated time to travel to the pickup location of each agent in the plurality of agent s and selecting the agent having a shortest estimated time to travel to the pickup location. 19. The method of claim 14, further comprising classifying the content of the consignment based on the data entered into the consignment data entry fields. 20. A non-transitory computer-readable storage medium coupled to one or more processors and having instructions stored thereon which, when executed by the one or more processors, cause the one or more processors to: cause a computer display to display a user interface comprising a plurality of consignment data entry fields, the consignment data entry fields comprising: a pickup location entry field configured to receive data identifying a pickup location for a consignment a delivery destination entry field configured to receive data identifying a delivery destination for the consignment and a content entry field configured to receive data identifying a content of the consignment to be delivered; retrieve the data identifying the pickup location, the delivery destination and the content; cause a call signal to be transmitted to a mobile computing device of each agent in a plurality of agents; determine a respective location of each agent in the plurality of agents based on a response to each call signal; select an agent from the plurality of agents based at least in part on the respective agent locations with respect to the pickup location.
CROSS-REFERENCE TO RELATED APPLICATION This application claims priority to Indian Patent Application No. 201641034044, filed on Oct. 5, 2016, entitled “Consignment Booking Apparatuses, Methods, And Systems,” the entirety of which is hereby incorporated by reference. TECHNICAL FIELD The present application is related to consignment bookings in particular to computer systems configured to facilitate consignment bookings. BACKGROUND Present systems for booking consignments involve customers traveling to consignment agency locations to book the consignment. The customer fills out a hand written form at the booking agency location and provides it to an agency associate to book the consignment. The agency associate uses written information to book an agent for picking up the consignment. Once the consignment is booked a delivery agent picks up the consignment and delivers the consignment to the delivery address. Because the consignment request is commonly provided via a hand written form and because the handwriting of a customer and a driver varies widely from person to person and region to region, the details of the consignment request such as the pickup location, the delivery location, the contents, and any other related information are not conducive to an automated approach such as scanning. Additionally, determining the status and location of a consignment during interim periods can be difficult and time consuming, if not indeterminable. SUMMARY The inventors have appreciated that computer implemented systems and methods can improve the accuracy and efficiency of booking and delivering consignments. Accordingly, various implementations of the present disclosure are directed to methods, systems, and apparatuses, for booking and delivering consignments. Certain implementations provide a computing system for consignment booking. The system includes a user interface module configured to cause a display of a plurality of consignment data entry fields. The consignment data entry fields include a pickup location entry field configured to receive data identifying a pickup location for a consignment, a delivery destination entry field configured to receive data identifying a delivery destination for the consignment and a content entry field configured to receive data identifying a content of the consignment to be delivered. The system includes an agent selection module configured to determine respective agent locations for each agent in a plurality of agents and to select an agent from the plurality of agents based at least in part on the respective agent locations, the pickup location, the delivery destination, and the content of the consignment. In some implementations, the agent selection module is configured to select the agent having a closest proximity to the pickup location. In some implementations, the agent selection module is configured to determine an estimated time to travel to the pickup location of each agent in the plurality of agents and to select the agent having a shortest estimated time to travel to the pickup location. In some implementations, the agent selection module is configured to determine an estimated time of pickup for each agent in the plurality of agent s and to select the agent with the earliest estimated pickup time. In some implementations, the estimated time of pickup is determined based on an estimate of the time to travel from the agent location to the pickup location with a traffic delay estimate. In some implementations, the estimated time of pickup is determined based on an estimate of an average speed of the agent along a route from the agent location to the pickup location. In some implementations, the agent location is determined by receiving a location signal from a global positioning system of a mobile electronic device in response to a positioning call to each agent in the plurality of agents. In some implementations, the system includes an agent location module is configured to identify an un-located agent position as a last known agent position in response to the mobile electronic device failing to respond to the positioning call. In some implementations, the agent selection module is configured to determine an estimated time of drop off at the delivery destination. In some implementations, the estimated time of drop off is determined based on at least one subsequent consignment pickup that the selected agent is scheduled to make after picking up the consignment. In some implementations, the agent selection module is configured to select the agent having a closest proximity to the pickup location and a highest a rating. In some implementations, the agent selection module is configured to generate an alert communication for transmission to the agent based on the agent selection. In some implementations, the agent selection module is configured to track the agent based on transmission of the alert communication. In some implementations, the system includes a classification module configured to retrieve one or more of the pickup location, the deliver destination and the content based on data entered into the consignment data entry fields and configured to identify a classification of the consignment based on a comparison of the data with a classification database. Certain implementations provide a computer-implemented method executed by one or more processors of an electronic computing device for booking and delivering consignments. The computer implemented method includes causing a computer display to display a user interface comprising a plurality of consignment data entry fields. The consignment data entry fields displayed include a pickup location entry field configured to receive data identifying a pickup location for a consignment, a delivery destination entry field configured to receive data identifying a delivery destination for the consignment, and a content entry field configured to receive data identifying a content of the consignment to be delivered. The method includes retrieving the data identifying the pickup location, the delivery destination and the content. The method includes causing a call signal to be transmitted to a mobile computing device of each agent in a plurality of agents. The method includes determining a respective location of each agent in the plurality of agents based on a response to each call signal. The method includes selecting an agent from the plurality of agents based at least in part on the respective agent locations with respect to the pickup location. In some implementations, the method includes selecting an agent based at least in part on the delivery destination. In some implementations, the method includes selecting an agent based at least in part on the content of the consignment. In some implementations, the method includes determining an estimated time to travel to the pickup location of each agent in the plurality of agents and selecting the agent having a shortest estimated time to travel to the pickup location. In some implementations, the method includes classifying the content of the consignment based on the data entered into the consignment data entry fields. Certain implementations provide a non-transitory computer-readable storage medium coupled to one or more processors and having instructions stored thereon for booking and delivering consignments. When the instructions are executed by the one or more processors, the instructions cause the one or more processors to cause a computer display to display a user interface comprising a plurality of consignment data entry fields. The consignment data entry fields displayed include a pickup location entry field configured to receive data identifying a pickup location for a consignment, a delivery destination entry field configured to receive data identifying a delivery destination for the consignment and a content entry field configured to receive data identifying a content of the consignment to be delivered. The instructions cause the one or more processors to retrieve the data identifying the pickup location, the delivery destination and the content. The instructions cause the one or more processors to cause a call signal to be transmitted to a mobile computing device of each agent in a plurality of agents. The instructions cause the one or more processors to determine a respective location of each agent in the plurality of agents based on a response to each call signal. The instructions cause the one or more processors to select an agent from the plurality of agents based at least in part on the respective agent locations with respect to the pickup location. Implementations disclosed herein advantageously facilitate easy and reliable tracking of a consignment, provides customers with more certainty on pickup expectations, and allow efficient management of agent resources by administration systems. It is appreciated that such implementations in accordance with the present disclosure can include any combination of the aspects and features described herein. That is, implementations in accordance with the present disclosure are not limited to the combinations of aspects and features specifically described herein, but also include any combination of the aspects and features provided. The details of one or more implementations of the present disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure will be apparent from the description and drawings, and from the claims. BRIEF DESCRIPTION OF DRAWINGS The drawings primarily are for illustrative purposes and are not intended to limit the scope of the inventive subject matter described herein. The drawings are not necessarily to scale; in some instances, various aspects of the inventive subjection matter disclosed herein may be shown enlarged in the drawings to facilitate an understanding of different features. In the drawings, like reference characters generally refer to like features (e.g. functionally similar and/or structurally similar elements). FIG. 1 is a flow diagram of operations of a customer system for booking a consignment pickup. FIG. 2 shows an information architecture of customer system application for booking a consignment pickup. FIG. 3 illustrates a user interface of a customer system application for booking a consignment pickup. FIG. 4 is a flow diagram of operations of an administration system for accepting a consignment pickup request. FIG. 5 shows an information architecture of an administration system application for accepting a consignment pickup request. FIG. 6 illustrates a user interface of an administration application for accepting a consignment pickup request. FIG. 7 is a flow diagram of operations of an agent system for coordinating consignment pickup requests from customers with agents. FIG. 8 shows an information architecture of an agent system application for coordinating consignment pickup requests from customers with agents. FIG. 9 illustrates a user interface of an agent application for coordinating consignment pickup requests from customers with agents. FIG. 10 is a flow diagram illustrating the interoperations of a customer system, an administration system, and an agent system for consignment booking and delivery. The features and advantages of implementations of the inventive subject matter disclosed herein will become more apparent from the detailed description set forth below when taken in conjunction with the drawings. DETAILED DESCRIPTION Implementations of the present disclosure are generally directed to computing systems and methods for booking consignment pickups and deliveries. As described in further detail herein, the systems and methods provide a system architecture configured to determine location information related to a consignment requests in order to accurately and efficiently book the consignment and track the delivery of the consignment. FIG. 1 is a flow diagram of operations of a customer system 100 for booking a consignment pickup. At 101, a customer wanting to request a consignment pickup signs into a consignment booking application. The consignment booking application can include an application programming interface operating a computing device, such as a mobile electronic computing device. The customer can enter a user name and a password to log into the application programming interface. The user name and password may automatically populate information related to the customer such as a common pickup location(s), common content shipped, and/or common destination(s). At 102, the application requests the pickup location from the customer. The pickup location can be entered for a new customer or changed, for example for a returning customer, if a pickup location is not stored or a new pickup location is desired. At 103, the application requests a delivery destination, for example by displaying a destination field. At 104, the application can request a pickup date and a pickup time. At 105, the application requests that the user enter a description of the contents of the consignment. The application can also request a quantity, weight, volume, etc. in connection with requesting the description. As discussed in further detail herein, the content information can be used by a classification module to identify a specific classification identification and/or to guide particular handling instructions or determine fees associated with moving the goods. These instructions may be facilitated in part by the destination of the consignment. The description of the contents can also be factored into the agent selection. For example, certain consignment contents may require a certain amount of room or a particular type of vehicle. If a delivery agent has already picked up one or more other consignments he or she may not have the cargo room to pick up another consignment depending on the volume required. The application can automatically determine the capacity of an agent based on tracked consignments of the agent and based on profile information maintained about the agent in a central database. FIG. 2 shows an information architecture of a customer system application for booking a consignment pickup. The customer system includes customer system application 200. The customer application 200 allows a customer 202 to either sign in, if they have an existing account, or to sign-up, if they are a new user, via selector 204. Based upon the selection of the customer 202, the user interface of the application 200 takes the customer to either the sign-in interface 206 or the sign-up interface 208. Once the customer 202 has logged in, the system 200 presents a homepage interface 210. From the homepage interface 210, the customer 202 can search for a consignment that has already been booked by entering a unique shipment identification number for the consignment. From the homepage interface 210, the customer 202 can also create a new consignment. In response to selecting an option to create a new consignment from the homepage interface 210, the application 200 launches a consignment creation window 212 where the customer 202 can enter information to request the consignment. The information entered into the consignment creation window 212 includes the pickup location, the destination, and the contents. The window 212 can be a separate window or may include a modified version of the homepage interface 210. The information can also include a date or time of pickup, information such as weight or size, and/or any special handling instructions. After the consignment is requested, the customer 202 can schedule the pickup via scheduling window 226. The scheduling window 226 will access an administrator module and an agent module to select an agent for pickup, as discussed in further detail herein. The agent selection can be optimized based on the preferences of the customer 202 and/or based on the information provided in the consignment request. At window 214, the customer 202 can proceed to check-out to complete the transaction, and at window 216, the customer 202 can select and/or enter payment information for the consignment request. Consummation of the payment process can be facilitated via an online payment 220 or via a payment gateway 224, which can link to a 3rd party payment application. Alternatively, the user can designate a cash payment 218. Once the payment information is complete, the application 200 will provide a confirmation 222, which can include the unique shipment identification information for the customer 202 to retrieve and check the status of their consignment. A navigation window 232 permits the customer 202 to browse their account to check on a myriad of functions. For example, the navigation window 232 includes an option that allows the customer 202 to open a profile window 234. The profile window 234 permits the customer 202 to update account information, such as their address or pickup location, to review their payment history, to update their account username or password, to update their contact information, such as their e-mail address or telephone number, and to review any feedback or ratings provided on their account. The navigation window 232 also permits the customer 202 to review any consignments that they have booked via a consignment window 236. Through the consignment window 236, the customer 202 can view both active consignments that are in transit as well as archived consignments that have already been picked up and delivered. The customer 202 can provide feedback on an agent based on consignments that have been delivered or picked up and that are viewable in the consignment window 236. The customer 202 can also access active consignments via the consignment window 236 to track and trace the consignments that are in progress. In response to the customer checking in on the tracking status of an active consignment, a tracking window 228 is opened. The tracking window 228 receives updates from the agent either directly or indirectly via the administrator to determine where the package is or has been and/or to provide an expected time of arrival. The updates may be provided via a global positioning system (GPS) associated with a mobile computing device of the agent. The customer 202 may be permitted to change certain aspects of the delivery via a delivery option adjustment window 230 depending on where the consignment is located at in transit, as indicated by the tracking window 228. The updates can be sent to the agent to redirect the agent, for example by modifying the navigation system on the mobile computing device of the agent automatically. In some implementations, the agent can be provided with the option to accept or reject the modifications. The navigation window 232 also permits the customer to access information such as the transit rates and estimated timing via a rates window 238 and facility location information via a location window 240. The facility location information can be based on a location of the customer 202 as indicated by the customer, by the customer's profile, and/or by a location of the device upon which the application 200 is running. The navigation window 232 also provides access to a customer support module 242, an account settings module 244, and a sign out module 246. FIG. 3 illustrates an application programming interface 301 of the customer system application 200 for booking a consignment pickup. The customer system application 200 operates on a computing device 300 and includes a search field 302 in the user interface 301 for searching for a consignment based on the shipment ID. A new consignment icon 304 can be selected to generate a new consignment. A schedule pickup icon 306 can be selected to schedule a pickup of a new consignment. As discussed in connection with window 226 of FIG. 2, selecting to schedule a pickup causes the application 200 to initiate a protocol that gets real-time or near real-time information about the status and location of one or more agents or couriers that are available or that are signed on and are within a certain proximity to the pickup location. For example, this protocol can cause an administration application, to initiate transmission of a call sequence to determine the location of agents by requesting a GPS or location signal from the mobile computing device of the agent. If, for example, there are no agents within a first proximity a larger second proximity may be queried automatically. The administration application can then optimize the agent selection based, at least in part on the location of the agent with respect to the pickup location. The customer 202 can in certain implementations be permitted to select a particular agent identified, for example based on agent reviews. Consignment status bars 308a and 308b are provided in the user interface 301 of the customer system application 200. As demonstrated, the status bars 308a and 308 provide information regarding what action has taken place, a current status 310a, 310b, graphically illustrated by a progress bar 311a, 311b, a pickup date 312a, 312b, an expected delivery date 313a, 313b, a consignment content or description 314a, 314b (provided by the customer 202), and a shipment identification number 315a, 315b. In particular embodiments, a customer can request a consignment through the implementation of an image capture device of a mobile computing device and through an image recognition system operating on the data obtained through the image capture device. Consignment creation through an image capture device can be implemented via a portal to a customer system opening, for example, through an agent interface discussed in greater detail in FIG. 9. For example, if a customer requests a consignment from a remote location by calling into a shipping administrator via telephone, the shipping administrator can dispatch a particular agent to a pick-up location (for example via using an agent system as shown in FIGS. 7-9). At the pick-up location, the agent can obtain a handwritten consignment request directly from the customer. The agent can then use a camera of the mobile computing device, such as a mobile telephone, to capture an image of the handwritten consignment. The captured image of the handwritten consignment can be uploaded to the consignment booking application. The consignment booking application can be used to scan the image of the handwritten consignment in order to obtain information such as the drop-off location, the contents of the consignment, the customer information, the classification information, and other delivery parameters. The information can be obtained by text recognition software configured to translate the handwritten request into typed text. The text recognition software can be configured based on the layout of the handwritten request forms, such that the text recognition software identifies information in certain locations of the image as corresponding to certain data fields. For example, the software can be configured to identify information in uppermost right corner of the image as the delivery location. The handwritten request forms can be laid out in the same format as the data entry fields on the mobile application, in certain implementation, to efficiently mange correlating the translated text into the appropriate data entry fields. The text recognition software can be running directly on the mobile computing device or the image can be transmitted over the internet to a remote server where a remote computing device operating the text recognition software analyzes the image, obtains the shipping information, and then automatically uploads the shipping information into the consignment request of the consignment booking application on the mobile computing device. If the agent needs to pick up the consignment from another location different than the location of the image scanning, the scan of the image of the handwritten information can also obtain the pick-up location from the handwritten form. In certain embodiments, if the agent indicates, by selection or by default, that the consignment pick-up location corresponds to the location of the image capture, the mobile computing device can obtain location information of the mobile computing device at the time of image capture, for example via a global positioning system, and automatically upload the pick-up information into the consignment request. If the agent obtaining the consignment request via the image capture device is picking-up the consignment at the time of the image capture, the agent's information will be obtained from the mobile computing device and will be automatically entered into the consignment request of the consignment booking application. Once the information for the consignment request is entered into the appropriate data fields, the consignment is booked and location information obtained from the mobile computing device is used to track the status of the package as the agent leaves the pick-up location and heads to the delivery location, just as at 109. The tracking information can include a predictive analysis of the arrival time of the consignment at the delivery location. The mobile computing device can engage a mapping or navigation application operating on the device to determine the fastest route to the delivery location and this information can be provided to the administrator and/or to the customer to provide real-time status information on the tracking and progress of the package once the agent leaves the pick-up location. FIG. 4 is a flow diagram of operations of an administration system for accepting a consignment pickup request. At 401, the administration system receives a consignment request. The consignment request is received in response to a customer 202 scheduling an assignment request at 105, for example via window 220. In response to receiving the consignment request, the administration system automatically transmits call signals to a group of agents, for example to agents who are generally located within a particular region, at 402. The call signal requests a GPS response from the agents so that the administration system can determine where each agent in the group of agents are currently located with respect to the pickup area identified by the customer 202 in the consignment request 212. At 403, the administration system determines the proximity of each responding agent with respect to the pickup location. The response can come from a mobile device such as a mobile telephone, a smart watch, a tablet, or another computing device carried by the agent. The response can be automatically provided by the computing device if the agent is currently running the agent application or logged into the application (discussed in more detail in connection with FIGS. 7-9). The administration system can produce a graphical display of the agents' locations and/or provide a listing of the agents with respect to the pickup location sorted, for example listed in ascending order by proximity to the pickup location. At 404, the administration system selects an agent for an assignment to the consignment request. In some implementations, the administration system may automatically select the agent closest to the pickup location or the agent projected to be closest to the pickup location at the appropriate time of pickup. In other embodiments, the administration system can factor in other aspects before assigning an agent, which can include, but are not limited to, a rating of an agent by prior customers, the agents availability in view of other scheduled consignment assignments, the agents capacity based on the size of their transportation and other assignments, the estimated time of travel based on the traffic (actual or projected) from an agent location (actual or projected) to the pickup location, and type of transportation. This information can be provided in the agent's profile and updated as the agent accepts consignment assignments, as discussed in further detail herein. At 405, the administration system sends a request to the computing device of the selected agent. If the agent accepts the consignment assignment, the administration system receives a confirmation at 406. If the first agent automatically selected does not accept the consignment assignment, the administration system can automatically send a request to the next agent in the queue until an agent accepts the consignment assignment. At 407, the administration system sends the confirmation to the customer system, providing the customer with tracking information and estimated time of pickup. At 408, the administration system adds the tracking information to a composite tracking system where all of the agent assignments are collectively tracked. This composite tracking system can be provided in an active map format illustrating the package locations in real-time or near real-time. At 409, the administration system transmits updates to the customer 202 based on updates received on the status of the package from the agent device. For example, the agent device, such as a mobile phone can provide location information via a global positioning system of the device as the agent is in route to the customer 202 to provide the customer with an estimated time of arrival. The agent can provide an indication of pickup upon arrival at the pickup location and the device can continue to provide location information via the global positioning system once the agent leaves the pickup location and is in route to the delivery location for tracking the progress of the package. The agent can confirm pickup by obtaining an image of the consignment, which image can be uploaded to the administration system for verification. The agent can confirm pickup by scanning a label or a barcode on a pre-printed label to be affixed to the consignment upon pick-up. FIG. 5 shows an information architecture of an administration system application for accepting a consignment pickup request. The administration system includes an administration application 500. The administration application 500 allows an administrator 502 to sign in to the system via selector 504. The administration application 500 provides a sign-in portal 506 for the administrator to enter his or her credentials. After the administrator 502 has successfully entered his or her administrator credentials, the administration application 500 opens a dashboard 508 that allows the administrator 502 to search for consignments, request new consignments assignments (in response to customer requests), view new request, and view scheduled consignments. If a new request has been received, the administrator 502 can open the request and facilitate an assignment of the request via request portal 510. The request portal sends the call request to the agents (as discussed in connection with phase 402 in FIG. 4. The call request can send a text or short messaging service communication, an e-mail communication or other notification to the agents to obtain information about their existing location (GPS) or planned location within a time period of the pickup request. The administration dashboard 508 can include a link to the account setting 512 of the system or a sign-out link 514. The administration dashboard 508 can also provide a portal a consignment tracking and update window 516, where the administrator can view the status of a particular consignment assignment. The administration dashboard 508 allow the administrator to manage the administration system users via management window 518 or to generate reports via report window 520. The report window can provide statistics on efficiency by comparing the requested and estimated pickup and delivery times to the actual times as reflected by the tracking information. The efficiency statics can confirm that an agent was at a location at the time that a pickup or delivery is confirmed via the agent application. The management window 518 can allow the administrator to view information about the customers via customer window 522 and allow the administrator to add new agents via the new agent window 524. The new agent window 524 can have a Tillable form that receives the agent's mobile telephone number so that when a call request is transmitted the agent's information is automatically pulled up. FIG. 6 illustrates an application programming interface 601 of the administration application 500 for accepting a consignment pickup request. The application programming interface 601 is presented on a computing device 600 and provides access to the administration dashboard, reports, consignment assignment management, settings, alerts, etc. via the associated icons including dashboard icon 631, report icon 632, consignment assignment management icon 633, settings icon 634, and alert icon 635 displayed in the application interface. The interface 601 includes a new consignment creation tool 602 for creating new consignment assignments. The consignments are created based on the consignment request 604a, 604b, and 604c that are in the request queue. The interface 601 shows the active consignment 608a, 608b, and 608c that have been scheduled including an active and updating status of those active consignments. A new consignment window 640 shows the agent selection process for agent assignment, in response to the administrator assigning the assignment request 604a. The new consignment window indicates the consignment request delivery tune 610, contents 612 of the consignment, a pickup location 614, and a delivery location 615. A geographic map 616 shows the pickup location, the delivery location, the projected route and the location of the potential agents 618b-618g. The administration system has automatically selected a potential agent 618a, based at least in part on the location of the agent 618a. Upon approval of the agent via approval icon 622, a confirmation a request will be sent to the agent for acceptance. If the agent accepts, the consignment will be assigned and schedule accordingly. If the agent does not accept, the assignment the administrator can send a request to another agent on the list. The administration system, can also be configured to generate alerts, for example if an agent is scheduled to make a pickup at a certain time, but the location of the agent indicates an estimated arrival time that is a predetermined time beyond the requested pickup time. In response to generating such an alert, for example indicated via the alert icon 635, the administrator can re-assign attempt to re-assign the request to a new agent. Such a re-assignment can be facilitated in a similar manner as the original assignment (e.g. locating real-time position of agents) and selected the optimal agent based on proximity to the pickup location and/or estimated time to arrive at the pickup location. In certain embodiments, the administration system includes a classification module configured to classify the contents of the consignment based on the description provided by the customer. The classification can be based on one or more of the pickup location, the delivery location, and the transit route. This information can be used and compared against information in a classification database to automatically determine a classification of the consignment, which may vary for region to region and may dictate any additional fees or transit instructions that may be warranted. FIG. 7 is a flow diagram of operations of an agent system for coordinating consignment pickup requests from customers with agents. At 701, the agent system receives a consignment assignment request on the mobile electronic device of the agent. The consignment assignment request is received in response to an administrator 502 sending a call request at 402. In response to receiving the call request, the agent mobile computing device sends a location signal (actual or projected based on itinerary) at 702. At 703, the agent system receives an assignment request, if in response to the location signal sent at 702 the administration system selects the agent for the assignment. At 704, the agent transmits an acceptance of the request to the administration system. At 705, a calendar or itinerary of the agent can be updated to reflect the assignment in conjunction with any other assignments. At 706, the agent's location information is used to determine the status of the consignment. This information can be requested for a period of time before the pickup time. At 707, the agent confirms the pickup. Confirmation of the pickup can be facilitated, at least in part, by arrival of the agent at the pickup site (automatically based on GPS or manually by confirmation that is verified by GPS). At 708, the agent's itinerary for any further pickup s or delivery of the package is updated for the customer and the administration to track the status of the consignment. FIG. 8 shows an information architecture of agent system application for coordinating consignment pickup requests from customers with agents. The agent system includes an agent application 800. The agent application 800 facilitates an agent 802 signing into the application via selector 804 and sign-in portion 806 so that the agent can send location information, accept consignments, and send transit updates. An agent home page 808 allows an agent to view consignment requests and active consignments. For a selected consignment, the agent can open a consignment detail window 810 to view customer information, to confirm pickup, to confirm delivery, to obtain directions through a navigation system, to contact the customer, and to confirm the consignment contents. A status update window 812 may be selected in response to the user updating the status information for a specific consignment. The status update window 812 allows the agent to confirm specific actions, which will update the tracking information in the customer system and the administration system. A delivery and pickup confirmation window 814 can be provided. A navigation window 816 allows the agent to move through various areas in the agent application. An agent can access his or her profile information via a profile window 818. The profile window 818 can indicate the rating of the agent, can include specific feedback provided to the agent, can list the agent's history, can allow the agent to update login information or account or contact information. The navigation window 816 provides access to the agent's consignments including active consignment assignments and completed consignment assignments. The navigation window 816 also provides access to the agent's calendar, which is automatically populated in response to the agent accepting a consignment assignment and updated based on the estimated time of travel and based on the progress of the agent. The navigation window 816 also provides access to the account settings of the agent via icon 524 and allows the agent to sign out via sign out icon 526, which will prevent further tracking of the agent, for example if the agent is off and/or on break. If an agent signs out during transport of an active consignment or loses reception during transport of an active consignment, the last known location of the agent can be transported to the administration system and an update request can be repeatedly transmitted to the agent until a new location signal is received. The agent system can also be updated with information such as the agent transport vehicle or available cargo volume, which can account for any active consignments. FIG. 9 illustrates an application programming interface 901 of the agent application 800 for coordinating consignment pickup requests from customers with agents. The agent interface 901 is running on a computing device, such as a mobile phone 900. The agent interface 901 provides information of daily scheduled deliveries 902 and pickups 903. Status bars 904a and 904b provide information regarding particular consignments and include information such as, a current status 905a 905b an estimated delivery time 906a, 906b, a consignment content or description 907a, 907b and a shipment identification number 908a, 908b. FIG. 10 is a flow diagram illustrating the interoperations of a customer system, an administration system, and an agent system for consignment booking and delivery. The present disclosure describes an agent system, administration system, and an agent system. The operation of these systems depends on inputs derived or received from their counterparts. A customer system 1002 analyzes a request at 1011 and creates a new requests entry at 1012, which request is transmitted at 1013 to the administration system 1004. The requests that are determined to be old request at 1014 are archived at 1015 and can be viewed in the customer system as desired by the customer for status information. In response to receipt of the request at 1020, the administration module analyzes the request and for valid requests assigns them to an agent by transmitting the request to an agent system 1008. If there is a problem with the request analyzed at 1020, the administration system 1004 sends a notification to the customer system 1002 so that the request can be corrected. The agent system 1008, provides updates once the agent picks up packages for valid requests. The agent updates verified at 1031 are transmitted to the administration system 1004 at 1023, which notification can be sent to the customer system 1002. The administration system 1004 can further track the progress of the consignment. For example, the administration system 104 is updated at 1024 as the consignment is transmitted by the agent to the closest delivery location. In some implementations, the delivery system can be an interim between the final destination and the administration system can assign a new agent to deliver the consignment to its final location at 1025. The system of the new agent will track the delivery of the consignment to the shipment address at 1032. At 1033, if the document has been delivered a verification will be produced at 1034 and sent to the customer system 1002, via the administration system 1004. If the consignment has not been delivered, tracking information of the agent system 1008 will be sent to the administration system 1004 and to the customer system 1002 until the package is delivered at 1036. A number of implementations have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the disclosure. For example, various forms of the flows shown above may be used, with steps re-ordered, added, or removed. Accordingly, other implementations are within the scope of the following claims. Implementations and all of the functional operations described in this specification may be realized in digital electronic circuitry, or in computer software, firmware, or hardware, including the structures disclosed in this specification and their structural equivalents, or in combinations of one or more of them. Implementations may be realized as one or more computer program products, i.e., one or more modules of computer program instructions encoded on a computer readable medium for execution by, or to control the operation of, data processing apparatus. The computer readable medium may be a machine-readable storage device, a machine-readable storage substrate, a memory device, a composition of matter effecting a machine-readable propagated signal, or a combination of one or more of them. The term “computing system” encompasses all apparatus, devices, and machines for processing data, including by way of example a programmable processor, a computer, or multiple processors or computers. The apparatus may include, in addition to hardware, code that creates an execution environment for the computer program in question, e.g., code that constitutes processor firmware, a protocol stack, a database management system, an operating system, or a combination of one or more of them. A propagated signal is an artificially generated signal, e.g., a machine-generated electrical, optical, or electromagnetic signal that is generated to encode information for transmission to suitable receiver apparatus. A computer program (also known as a program, software, software application, script, or code) may be written in any appropriate form of programming language, including compiled or interpreted languages, and it may be deployed in any appropriate form, including as a stand-alone program or as a module, component, subroutine, or other unit suitable for use in a computing environment. A computer program does not necessarily correspond to a file in a file system. A program may be stored in a portion of a file that holds other programs or data (e.g., one or more scripts stored in a markup language document), in a single file dedicated to the program in question, or in multiple coordinated files (e.g., files that store one or more modules, sub programs, or portions of code). A computer program may be deployed to be executed on one computer or on multiple computers that are located at one site or distributed across multiple sites and interconnected by a communication network. The processes and logic flows described in this specification may be performed by one or more programmable processors executing one or more computer programs to perform functions by operating on input data and generating output. The processes and logic flows may also be performed by, and apparatus may also be implemented as, special purpose logic circuitry, e.g., an FPGA (field programmable gate array) or an ASIC (application specific integrated circuit). Processors suitable for the execution of a computer program include, by way of example, both general and special purpose microprocessors, and any one or more processors of any appropriate kind of digital computer. Generally, a processor will receive instructions and data from a read only memory or a random access memory or both. Elements of a computer can include a processor for performing instructions and one or more memory devices for storing instructions and data. Generally, a computer will also include, or be operatively coupled to receive data from or transfer data to, or both, one or more mass storage devices for storing data, e.g., magnetic, magneto optical disks, or optical disks. However, a computer need not have such devices. Moreover, a computer may be embedded in another device, e.g., a mobile telephone, a personal digital assistant (PDA), a mobile audio player, a Global Positioning System (GPS) receiver, to name just a few. Computer readable media suitable for storing computer program instructions and data include all forms of non-volatile memory, media and memory devices, including by way of example semiconductor memory devices, e.g., EPROM, EEPROM, and flash memory devices; magnetic disks, e.g., internal hard disks or removable disks; magneto optical disks; and CD ROM and DVD-ROM disks. The processor and the memory may be supplemented by, or incorporated in, special purpose logic circuitry. To provide for interaction with a user, implementations may be realized on a computer having a display device, e.g., a CRT (cathode ray tube) or LCD (liquid crystal display) monitor, for displaying information to the user and a keyboard and a pointing device, e.g., a mouse or a trackball, by which the user may provide input to the computer. Other kinds of devices may be used to provide for interaction with a user as well; for example, feedback provided to the user may be any appropriate form of sensory feedback, e.g., visual feedback, auditory feedback, or tactile feedback; and input from the user may be received in any appropriate form, including acoustic, speech, or tactile input. Implementations may be realized in a computing system that includes a back end component, e.g., as a data server, or that includes a middleware component, e.g., an application server, or that includes a front end component, e.g., a client computer having a graphical user interface or a Web browser through which a user may interact with an implementation, or any appropriate combination of one or more such back end, middleware, or front end components. The components of the system may be interconnected by any appropriate form or medium of digital data communication, e.g., a communication network. Examples of communication networks include a local area network (“LAN”) and a wide area network (“WAN”), e.g., the Internet. The computing system may include clients and servers. A client and server are generally remote from each other and typically interact through a communication network. The relationship of client and server arises by virtue of computer programs running on the respective computers and having a client-server relationship to each other. While this specification contains many specifics, these should not be construed as limitations on the scope of the disclosure or of what may be claimed, but rather as descriptions of features specific to particular implementations. Certain features that are described in this specification in the context of separate implementations may also be implemented in combination in a single implementation. Conversely, various features that are described in the context of a single implementation may also be implemented in multiple implementations separately or in any suitable sub-combination. Moreover, although features may be described above as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination may in some cases be excised from the combination, and the claimed combination may be directed to a sub-combination or variation of a sub-combination. Similarly, while operations are depicted in the drawings in a particular order, this should not be understood as requiring that such operations be performed in the particular order shown or in sequential order, or that all illustrated operations be performed, to achieve desirable results. In certain circumstances, multitasking and parallel processing may be advantageous. Moreover, the separation of various system components in the implementations described above should not be understood as requiring such separation in all implementations, and it should be understood that the described program components and systems may generally be integrated together in a single software product or packaged into multiple software products. Thus, particular implementations have been described. Other implementations are within the scope of the following claims. For example, the actions recited in the claims may be performed in a different order and still achieve desirable result.
<SOH> BACKGROUND <EOH>Present systems for booking consignments involve customers traveling to consignment agency locations to book the consignment. The customer fills out a hand written form at the booking agency location and provides it to an agency associate to book the consignment. The agency associate uses written information to book an agent for picking up the consignment. Once the consignment is booked a delivery agent picks up the consignment and delivers the consignment to the delivery address. Because the consignment request is commonly provided via a hand written form and because the handwriting of a customer and a driver varies widely from person to person and region to region, the details of the consignment request such as the pickup location, the delivery location, the contents, and any other related information are not conducive to an automated approach such as scanning. Additionally, determining the status and location of a consignment during interim periods can be difficult and time consuming, if not indeterminable.
<SOH> SUMMARY <EOH>The inventors have appreciated that computer implemented systems and methods can improve the accuracy and efficiency of booking and delivering consignments. Accordingly, various implementations of the present disclosure are directed to methods, systems, and apparatuses, for booking and delivering consignments. Certain implementations provide a computing system for consignment booking. The system includes a user interface module configured to cause a display of a plurality of consignment data entry fields. The consignment data entry fields include a pickup location entry field configured to receive data identifying a pickup location for a consignment, a delivery destination entry field configured to receive data identifying a delivery destination for the consignment and a content entry field configured to receive data identifying a content of the consignment to be delivered. The system includes an agent selection module configured to determine respective agent locations for each agent in a plurality of agents and to select an agent from the plurality of agents based at least in part on the respective agent locations, the pickup location, the delivery destination, and the content of the consignment. In some implementations, the agent selection module is configured to select the agent having a closest proximity to the pickup location. In some implementations, the agent selection module is configured to determine an estimated time to travel to the pickup location of each agent in the plurality of agents and to select the agent having a shortest estimated time to travel to the pickup location. In some implementations, the agent selection module is configured to determine an estimated time of pickup for each agent in the plurality of agent s and to select the agent with the earliest estimated pickup time. In some implementations, the estimated time of pickup is determined based on an estimate of the time to travel from the agent location to the pickup location with a traffic delay estimate. In some implementations, the estimated time of pickup is determined based on an estimate of an average speed of the agent along a route from the agent location to the pickup location. In some implementations, the agent location is determined by receiving a location signal from a global positioning system of a mobile electronic device in response to a positioning call to each agent in the plurality of agents. In some implementations, the system includes an agent location module is configured to identify an un-located agent position as a last known agent position in response to the mobile electronic device failing to respond to the positioning call. In some implementations, the agent selection module is configured to determine an estimated time of drop off at the delivery destination. In some implementations, the estimated time of drop off is determined based on at least one subsequent consignment pickup that the selected agent is scheduled to make after picking up the consignment. In some implementations, the agent selection module is configured to select the agent having a closest proximity to the pickup location and a highest a rating. In some implementations, the agent selection module is configured to generate an alert communication for transmission to the agent based on the agent selection. In some implementations, the agent selection module is configured to track the agent based on transmission of the alert communication. In some implementations, the system includes a classification module configured to retrieve one or more of the pickup location, the deliver destination and the content based on data entered into the consignment data entry fields and configured to identify a classification of the consignment based on a comparison of the data with a classification database. Certain implementations provide a computer-implemented method executed by one or more processors of an electronic computing device for booking and delivering consignments. The computer implemented method includes causing a computer display to display a user interface comprising a plurality of consignment data entry fields. The consignment data entry fields displayed include a pickup location entry field configured to receive data identifying a pickup location for a consignment, a delivery destination entry field configured to receive data identifying a delivery destination for the consignment, and a content entry field configured to receive data identifying a content of the consignment to be delivered. The method includes retrieving the data identifying the pickup location, the delivery destination and the content. The method includes causing a call signal to be transmitted to a mobile computing device of each agent in a plurality of agents. The method includes determining a respective location of each agent in the plurality of agents based on a response to each call signal. The method includes selecting an agent from the plurality of agents based at least in part on the respective agent locations with respect to the pickup location. In some implementations, the method includes selecting an agent based at least in part on the delivery destination. In some implementations, the method includes selecting an agent based at least in part on the content of the consignment. In some implementations, the method includes determining an estimated time to travel to the pickup location of each agent in the plurality of agents and selecting the agent having a shortest estimated time to travel to the pickup location. In some implementations, the method includes classifying the content of the consignment based on the data entered into the consignment data entry fields. Certain implementations provide a non-transitory computer-readable storage medium coupled to one or more processors and having instructions stored thereon for booking and delivering consignments. When the instructions are executed by the one or more processors, the instructions cause the one or more processors to cause a computer display to display a user interface comprising a plurality of consignment data entry fields. The consignment data entry fields displayed include a pickup location entry field configured to receive data identifying a pickup location for a consignment, a delivery destination entry field configured to receive data identifying a delivery destination for the consignment and a content entry field configured to receive data identifying a content of the consignment to be delivered. The instructions cause the one or more processors to retrieve the data identifying the pickup location, the delivery destination and the content. The instructions cause the one or more processors to cause a call signal to be transmitted to a mobile computing device of each agent in a plurality of agents. The instructions cause the one or more processors to determine a respective location of each agent in the plurality of agents based on a response to each call signal. The instructions cause the one or more processors to select an agent from the plurality of agents based at least in part on the respective agent locations with respect to the pickup location. Implementations disclosed herein advantageously facilitate easy and reliable tracking of a consignment, provides customers with more certainty on pickup expectations, and allow efficient management of agent resources by administration systems. It is appreciated that such implementations in accordance with the present disclosure can include any combination of the aspects and features described herein. That is, implementations in accordance with the present disclosure are not limited to the combinations of aspects and features specifically described herein, but also include any combination of the aspects and features provided. The details of one or more implementations of the present disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure will be apparent from the description and drawings, and from the claims.
G06Q100835
20171005
20180405
63528.0
G06Q1008
0
WALSH, EMMETT K
CONSIGNMENT BOOKING APPARATUSES, METHODS, AND SYSTEMS
UNDISCOUNTED
0
PENDING
G06Q
2,017
15,726,165
PENDING
Stable Aqueous Formulations of Adalimumab
The invention provides aqueous pharmaceutical adalimumab compositions suitable for long-term storage of adalimumab, methods of manufacture of these compositions, methods of administration, and kits containing same.
1. A stable aqueous pharmaceutical composition comprising: i) adalimumab; ii) a buffer; and iii) a stabilizer; wherein the composition is free of polyol and has a pH of about 5 to about 6. 2. The composition of claim 1, wherein the composition is free of citrate buffer. 3. The composition of claim 1, wherein the composition further comprises a surfactant. 4. The composition of claim 1, wherein the composition has osmolality of about 180 to 420 mOsM; the composition is suitable for administration to a subject as a single dose; and the dose contains about 40 mg of adalimumab. 5. The composition of claim 1, wherein the composition is free of sodium chloride. 6. The composition of claim 5, wherein the composition further comprises a surfactant. 7. The composition of claim 6, wherein the composition has osmolality of about 180 to 420 mOsM; the composition is suitable for administration to a subject as a single dose; and the dose contains about 40 mg of adalimumab. 8. A stable aqueous pharmaceutical composition comprising adalimumab and a citrate-free buffer, wherein the composition is free of polyol and has a pH of about 5 to about 6. 9. The composition of claim 8, wherein the composition further comprises a surfactant. 10. The composition of claim 8, wherein the composition has osmolality of about 180 to 420 mOsM; the composition is suitable for administration to a subject as a single dose; and the dose contains about 40 mg of adalimumab. 11. The composition of claim 8, wherein the composition is free of sodium chloride. 12. The composition of claim 11, wherein the composition further comprises a surfactant. 13. The composition of claim 12, wherein the composition has osmolality of about 180 to 420 mOsM; the composition is suitable for administration to a subject as a single dose; and the dose contains about 40 mg of adalimumab.
FIELD OF THE INVENTION The present invention relates to aqueous pharmaceutical compositions suitable for long-term storage of adalimumab (including antibody proteins considered or intended as “biosimilar” or “bio-better” variants of commercially available adalimumab), methods of manufacture of the compositions, methods of their administration, and kits containing the same. BACKGROUND OF THE INVENTION Tumor necrosis factor alpha (TNFα) is a naturally occurring mammalian cytokine produced by various cell types, including monocytes and macrophages in response to endotoxin or other stimuli. TNFα is a major mediator of inflammatory, immunological, and pathophysiological reactions (Grell, M., et al. (1995) Cell, 83: 793-802). Soluble TNFα is formed by the cleavage of a precursor transmembrane protein (Kriegler, et al. (1988) Cell 53: 45-53), and the secreted 17 kDa polypeptides assemble to soluble homotrimer complexes (Smith, et al. (1987), J. Biol. Chem. 262: 6951-6954; for reviews of TNF, see Butler, et al. (1986), Nature 320:584; Old (1986), Science 230: 630). These complexes then bind to receptors found on a variety of cells. Binding produces an array of pro-inflammatory effects, including (i) release of other pro-inflammatory cytokines such as interleukin (IL)-6, IL-8, and IL-1, (ii) release of matrix metalloproteinases and (iii) up-regulation of the expression of endothelial adhesion molecules, further amplifying the inflammatory and immune cascade by attracting leukocytes into extravascular tissues. There are many disorders associated with elevated levels of TNFα. For example, TNFα has been shown to be up-regulated in a number of human diseases, including chronic diseases such as rheumatoid arthritis (RA), inflammatory bowel disorders, including Crohn's disease and ulcerative colitis, sepsis, congestive heart failure, asthma bronchiale and multiple sclerosis. TNFα is also referred to as a pro-inflammatory cytokine. Physiologically, TNFα is also associated with protection from particular infections (Cerami. et al. (1988), Immunol. Today 9:28). TNFα is released by macrophages that have been activated by lipopolysaccharides of Gram-negative bacteria. As such, TNFα appears to be an endogenous mediator of central importance involved in the development and pathogenesis of endotoxic shock associated with bacterial sepsis. Adalimumab (Humira®, AbbVie, Inc.) is a recombinant human IgG1 monoclonal antibody specific for human TNF. This antibody is also known as D2E7. Adalimumab consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons. Adalimumab has been described and claimed in U.S. Pat. No. 6,090,382, the disclosure of which is hereby incorporated by reference in its entirety. Adalimumab is usually produced by recombinant DNA technology in a mammalian cell expression system, such as, for example, Chinese Hamster Ovary cells. Adalimumab binds specifically to TNFα and neutralizes the biological function of TNF by blocking its interaction with the p55 and p75 cell surface TNF receptors. Various formulations of adalimumab are known in the art. See, for example, U.S. Pat. Nos. 8,216,583 and 8,420,081. There is still need for stable liquid formulations of adalimumab that allow its long term storage without substantial loss in efficacy. SUMMARY OF THE INVENTION The invention provides stable aqueous formulations comprising adalimumab that allow its long term storage. In a first embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab; a stabilizer comprising at least one member selected from the group consisting of a polyol and a surfactant; and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 4 to about 8 and preferably about 5 to about 6, and wherein said buffer does not comprise a combination of citrate and phosphate, and preferably does not comprise any citrate buffer. In this embodiment, the stabilizer preferably comprises both polyol and surfactant. In a second embodiment, utilizing a single buffer system, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a polyol, a surfactant, and a buffer system comprising a single buffering agent, said single buffering agent being selected from citrate, phosphate, succinate, histidine, tartrate or maleate, but not including combinations of the foregoing; wherein the formulation has a pH of about 4 to 8, and preferably about 5 to about 6. Histidine and succinate are particularly preferred for use as single buffering agents. As used herein the term buffer, buffer system, or buffering agent, and like terminology, is intended to denoted buffer components that introduce buffer capacity in the formulation in addition to any buffering capacity offered by the protein itself, hence the term “buffer”, etc, is not intended to include the protein itself as a self buffering entity. In a third embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a stabilizer comprising at least one member selected from a polyol and a surfactant, wherein said composition has a pH of about 4 to about 8, and preferably about 5 to about 6, and wherein said composition is substantially free of a buffer. In a fourth embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a polyol, and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 4 to about 8 and preferably about 5 to about 6, and wherein said composition is free or substantially free of a surfactant. Preferably, the composition (i) does not contain the buffer combination of citrate and phosphate; and (ii) the buffer is at least one member selected from the group consisting of histidine and succinate; and (iii) the polyol is selected from the group consisting of mannitol, sorbitol and trehalose. In a fifth embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a surfactant, and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 4 to 8 and preferably about 5 to about 6, and wherein said composition is substantially free of polyol. Preferably, the composition (i) does not contain the buffer combination of citrate and phosphate; and (ii) the buffer is at least one member selected from the group consisting of histidine and succinate, including combinations thereof. In each of the five embodiments discussed above, the composition may optionally further comprise a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. The amino acid stabilizer may be selected from the group consisting of glycine, alanine, glutamate, arginine and methionine. The salt stabilizer may be selected from the group consisting of sodium chloride and sodium sulfate. The metal ion stabilizer may be selected from the group consisting of zinc, magnesium and calcium. Preferably, adalimumab formulations containing the stabilizers mentioned above also do not contain buffer systems in which phosphate buffer and citrate buffer are present in combination, and, most preferably contains buffer systems free or substantially free of citrate buffer. In particularly preferred embodiments, (i) the optional additional stabilizer present in this embodiment is not sodium chloride, or comprises sodium chloride present in amounts not to exceed about 100 mM, and comprises at least one of arginine and glycine, including combinations of the two amino acids; (ii) the buffer, when present, contains no citrate, or at least no citrate and phosphate combination, but is instead at least one of histidine and succinate, including combinations thereof; and (iii) the stabilizer when it includes a polyol is preferably mannitol in amounts exceeding about 150 mM. In further embodiments the invention is directed to an aqueous, buffered pharmaceutical composition comprising adalimumab and a buffer, wherein (i) the composition is free or substantially free of a buffer combination that comprises both a citrate buffer and a phosphate buffer; and (ii) the composition exhibits long term stability. Another embodiment of the invention concerns an aqueous, buffered pharmaceutical composition exhibiting long term stability, said composition comprising: (i) adalimumab; (ii) a buffer selected from the group consisting of histidine buffer, succinate buffer, and combinations thereof; (iii) a polysorbate or poloxamer surfactant, or combinations thereof; and (iv) one or both of the following: (a) a stabilizer selected from the group consisting of glycine, alanine, glutamate, arginine, methionine, EDTA, sodium chloride, sodium sulfate, metal ions, and combinations thereof; and (b) a polyol selected from sorbitol, mannitol, and trehalose, or combinations thereof. Optionally, the formulation may also include a sugar, such as sucrose. In a further embodiment the invention is an aqueous, buffered pharmaceutical composition comprising adalimumab and a buffer, wherein (i) the composition is free or substantially free of a polyol; and (ii) the composition exhibits long term stability. In still a further embodiment the invention is directed to an aqueous, buffered pharmaceutical composition comprising adalimumab and a buffer, wherein (i) the composition is free or substantially free of surfactant; and (ii) the composition exhibits long term stability. Another embodiment of the inventions concerns an aqueous pharmaceutical composition comprising adalimumab wherein: (i) the composition is free or substantially free of buffer; and (ii) the composition exhibits long term stability. In another embodiment, the adalimumab formulation of the present invention comprises, consists of, or consists essentially of, adalimumab, histidine buffer as the sole buffer in the formulation, glycine (or arginine, or combinations thereof) as the sole stabilizer among the non-surfactant stabilizers referenced earlier, and polysorbate 80. In this formulation, the amount of adalimumab is 20 to 150 mg/ml, the amount of histidine buffer is up to about 50 mM; the amount of glycine is up to about 300 mM; and the amount of polysorbate 80 is in the range of about 0.01 to about 0.2 wt %. Optionally, this formulation may include up to about 100 mM NaCl. The present invention also contemplates modification of this formulation to combine the histidine buffer with one or more of citrate, acetate, phosphate, maleate, tartrate buffers. In yet another embodiment, the adalimumab formulation of the present invention comprises, consists of, or consists essentially of, adalimumab, histidine buffer as the sole buffer, mannitol (or sorbitol or trehelose), and polysorbate 80, and further being free or substantially free of the non-surfactant stabilizers (e.g. glycine, arginine, etc.) referenced above. In this formulation, the amount of adalimumab is 20 to 150 mg/ml; the amount of histidine buffer is up to about 50 mM; the amount of polyol is up to about 300 mM; and the amount of polysorbate 80 is in the range of about 0.01 to about 0.2 wt %. Optionally, this formulation may include up to about 100 mM NaCl. The present invention also contemplates modification of this formulation to combine the histidine buffer with one or more of citrate, acetate, phosphate, maleate, tartrate buffers. In a method aspect, the invention is directed to a method for enhancing long term stability in an aqueous, buffered adalimumab formulation, comprising one or more of the steps of: (a) incorporating histidine buffer, succinate buffer, or a combination thereof, in the formulation based on empirical data indicating that such buffers contribute to the stability of the formulation to a greater extent than other buffers or buffer combinations; or (b) incorporating glycine, arginine or a combination thereof as stabilizers in the formulation, based upon empirical data indicating that such stabilizer contribute to the stability of the formulation to a greater extent than other stabilizers; or (c) substantially excluding the presence of buffer or buffer combinations comprising citrate buffer (especially buffer combinations comprising both citrate and phosphate) based upon empirical data indicating that such buffer or buffer combinations perform poorly in terms of stabilizing the formulation in comparison to other buffers. The method may further comprise the selection of PS 80 as a surfactant based on empirical data indicating that PS 80 imparts better thermal stability to the adalimumab formulation than other surfactants, including PS 20. The method is useful to obtain a formulation of adalimumab that exhibits long term stability comparable to or better than commercially available adalimumab formulations marketed under the trademark Humira®. In a further method aspect, the invention is directed to a method for treating an inflammatory condition in a subject which comprises administering to such subject any of the adalimumab formulation embodiments as described herein. In the foregoing embodiments, where the above referenced stabilizers may be included in the formulations, it is further discovered that satisfactory stabilization can be attained when such stabilizers are used in place of both polyol and surfactant and hence stabilized formulations of the present invention can be free or substantially free of both polyol and surfactant. Accordingly, in a sixth embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, optionally a buffer, a stabilizer selected from the group consisting of an amino acid, a salt, EDTA, and a metal ion, and wherein said composition has a pH of about 4 to about 8, and preferably 5 to about 6, and wherein said composition is either substantially free of both polyol and surfactant. When buffer is present in this embodiment, it is especially preferred that (i) the buffer not include the combination of citrate and phosphate; (ii) the buffer is selected from the group consisting of histidine and succinate; and (iii) the stabilizer does not comprise sodium chloride, but instead is at least one member selected from the group consisting of arginine and glycine. Important aspects of the present invention in certain embodiments include (i) that sorbitol and trehalose are discovered to be significantly better stabilizers of adalimumab formulations than mannitol, unless mannitol is used at concentrations in excess of about 200-300 mM in which case the three are generally equivalent; (ii) arginine and glycine (and combinations) are discovered to be significantly better stabilizers of adalimumab formulations than sodium chloride; and; (iii) when buffers are used in the formulation, it is discovered that the combination of citrate and phosphate is surprisingly significantly poorer in stabilizing adalimumab than other buffers such as succinate, histidine, phosphate and tartrate. The relatively poor performance of the buffer combination of citrate and phosphate is rather unexpected considering the apparent importance attributed to the use of a citrate/phosphate combined buffer in U.S. Pat. No. 8,216,583. To the contrary, we have now found that a phosphate/citrate buffer combination is not an optimal choice for obtaining a stabilized adalimumab formulation, and in fact, an element of our invention is the discovery that this combination should be avoided altogether in favor of other buffer systems. Preferably, a polyol is a sugar alcohol; and even more preferably, the sugar alcohol is selected from the group consisting of mannitol, sorbitol and trehalose. However, as between mannitol and sorbitol, the invention has discovered, as noted above, a distinct stabilization advantage in using sorbitol or trehalose instead of mannitol, unless mannitol is used at concentrations in excess of about 200 mM, in which case mannitol, sorbitol and trehalose are generally equivalent. At concentrations below about 200 mM, mannitol has been found to be a poorer stabilizer than sorbitol or trehalose in an adalimumab formulation. Preferably, a surfactant is a polysorbate or poloxamer; and even more preferably PS 80, PS 40, PS20, Pluronic F-68 and combinations. We have discovered a distinct and surprising thermal stabilization advantage in selecting PS 80 instead of PS-20. These and other aspects will become apparent from the following description of the various embodiments, although variations and modifications therein may be affected without departing from the spirit and scope of the novel concepts of the disclosure. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. Further representative embodiments are set forth in the numerous formulation studies reported in the detailed description, as well as the various embodiments listed in Appendices A, B and C attached hereto and made a part hereof. BRIEF DESCRIPTION OF THE DRAWINGS The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. FIG. 1 is a bar chart of stability of various adalimumab formulations as determined by size exclusion chromatography (SEC). FIG. 2 is a bar chart of stability of various adalimumab formulations as determined by reversed phase (RP) high performance liquid chromatography (HPLC). FIG. 3 is a graph of a partial least squares (PLS) model 1 demonstrating effect of citrate/phosphate on stability. FIG. 4 is a graph of a PLS model 2 demonstrating effect of citrate/phosphate on stability. FIG. 5 is a graph of a PLS model 1 demonstrating effect of histidine/glycine on stability. FIG. 6 is a graph of a PLS model 1 demonstrating effect of arginine/sorbitol on stability. FIG. 7 is a graph of a PLS model 1 demonstrating effect of pH/histidine on stability. FIG. 8 is a graph of a PLS model 2 demonstrating effect of pH/histidine on stability. FIG. 9 is a graph of a PLS model 2 demonstrating effect of trehalose/PS80 on stability. FIG. 10 is a graph of a PLS model 2 demonstrating effect of mannitol/PS80 on stability. FIG. 11 is a graph of a PLS model 1 demonstrating effect of mannitol/NaCl on stability. FIG. 12 is a graph of a PLS model 1 demonstrating effect of EDTA/methionine on stability. FIG. 13 is a graph of a PLS model A demonstrating effect of citrate and phosphate on stability. FIG. 14 is a graph of a PLS model A demonstrating effect of pH and histidine buffer on stability. FIG. 15 is a graph of a PLS model A demonstrating effect of glycine and arginine on stability. FIG. 16 is a graph of a PLS model A demonstrating effect of NaCl and polysorbate 80 (PS 80) on stability. FIG. 17 is a graph of a PLS model B demonstrating effect of citrate and phosphate on stability. FIG. 18 is a graph of a PLS model B demonstrating effect of pH and histidine buffer on stability. FIG. 19 is a graph of a PLS model B demonstrating effect arginine and glycine on stability. FIG. 20 is a graph of a PLS model B demonstrating effect of PS80 and mannitol on stability. FIG. 21 is a graph of a PLS model B demonstrating effect of EDTA and NaCl on stability. FIG. 22 is a graph of a PLS model B demonstrating effect of succinate buffer and histidine buffer on stability. FIG. 23 is a graph of a PLS model C demonstrating effect of citrate and phosphate on stability. FIG. 24 is a graph of a PLS model C demonstrating effect of pH and histidine buffer on stability. FIG. 25 is a graph of a PLS model C demonstrating effect of arginine and glycine on stability. FIG. 26 is a graph of a PLS model C demonstrating effect of mannitol and PS 80 on stability. FIG. 27 is a graph of a PLS model C demonstrating effect of PS 80 and NaCl on stability. FIG. 28 is a graph of a PLS model C demonstrating effect of pH and protein concentration on stability. DETAILED DESCRIPTION OF THE INVENTION Various embodiments of the invention are now described in detail. As used in the description and throughout the claims, the meaning of “a”, “an”, and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description and throughout the claims, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise. Additionally, some terms used in this specification are more specifically defined below. Definitions The terms used in this specification generally have their ordinary meanings in the art, within the context of the invention, and in the specific context where each term is used. Certain terms that are used to describe the invention are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the invention. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and in no way limits the scope and meaning of the invention or of any exemplified term. The invention is not limited to the various embodiments given in this specification. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In the case of conflict, the present document, including definitions will control. “Around,” “about” or “approximately” shall generally mean within 20 percent, within 10 percent, within 5, 4, 3, 2 or 1 percent of a given value or range. Numerical quantities given are approximate, meaning that the term “around,” “about” or “approximately” can be inferred if not expressly stated. The term “adalimumab” is synonymous with the active pharmaceutical ingredient in Humira® as well as protein considered or intended as biosimilar or bio-better variants thereof. Adalimumab is a recombinant human IgG1 monoclonal antibody specific for human TNF. Adalimumab is also known as D2E7. Adalimumab has two light chains, each with a molecular weight of approximately 24 kilodaltons (kDa) and two IgG1 heavy chains each with a molecular weight of approximately 49 kDa. Each light chain consists of 214 amino acid residues and each heavy chain consists of 451 amino acid residues. Thus, adalimumab consists of 1330 amino acids and has a total molecular weight of approximately 148 kDa. The term adalimumab is also intended to encompass so-called bio-similar or bio-better variants of the adalimumab protein used in commercially available Humira®. For example, a variant of commercial Humira® may be acceptable to the FDA when it has essentially the same pharmacological effects as commercially available Humira®, even though it may exhibit certain physical properties, such as glycosylation profile, that may be similar if not identical to Humira®. For the purposes of the present application, the term “adalimumab” also encompasses adalimumab with minor modifications in the amino acid structure (including deletions, additions, and/or substitutions of amino acids) or in the glycosylation properties, which do not significantly affect the function of the polypeptide. The term “adalimumab” encompasses all forms and formulations of Humira®, including but not limited to concentrated formulations, injectable ready-to-use formulations; formulations reconstituted with water, alcohol, and/or other ingredients, and others. The term “human TNFα” (which may be abbreviated as hTNFα, or simply hTNF), as used herein, is intended to refer to a human cytokine that exists as a 17 kD secreted form and a 26 kD membrane associated form, the biologically active form of which is composed of a trimer of noncovalently bound 17 kD molecules. The structure of hTNFα is described further in, for example, Pennica, D., et al. (1984) Nature 312:724-729; Davis, J. M., et al. (1987) Biochemistry 26:1322-1326; and Jones, E. Y., et al. (1989) Nature 338:225-228. The term human TNFα is intended to include recombinant human TNFα (rhTNFα), which can be prepared by standard recombinant expression methods or purchased commercially (R & D Systems, Catalog No. 210-TA, Minneapolis, Minn.). The term “antibody”, as used herein, refers to immunoglobulin molecules comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In one embodiment of the invention, the formulation contains an antibody with CDR1, CDR2, and CDR3 sequences like those described in U.S. Pat. Nos. 6,090,382; 6,258,562, and 8,216,583. An antibody or antigen-binding portion thereof may be part of a larger immunoadhesion molecule, formed by covalent or noncovalent association of the antibody or antibody portion with one or more other proteins or peptides. Examples of such immunoadhesion molecules include use of the streptavidin core region to make a tetrameric scFv molecule (Kipriyanov, S. M., et al. (1995) Human Antibodies and Hybridomas 6:93-101) and use of a cysteine residue, a marker peptide and a C-terminal polyhistidine tag to make bivalent and biotinylated scFv molecules (Kipriyanov, S. M., et al. (1994) Mol. Immunol. 31:1047-1058). Antibody portions, such as Fab and F(ab′)2 fragments, can be prepared from whole antibodies using conventional techniques, such as papain or pepsin digestion, respectively, of whole antibodies. Moreover, antibodies, antibody portions and immunoadhesion molecules can be obtained using standard recombinant DNA techniques, as described herein. The term “isolated antibody”, as used herein, refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds hTNFα is substantially free of antibodies that specifically bind antigens other than hTNFα). An isolated antibody that specifically binds hTNFα may, however, have cross-reactivity to other antigens, such as TNFα molecules from other species. Moreover, an isolated antibody may be substantially free of other cellular material and/or chemicals. The term “glycine” refers to an amino acid whose codons are GGT, GGC, GGA, and GGG. The term “arginine” refers to an α-amino acid whose codons are CCU, CCC, CCA, and CCG. The term “alanine” refers to an amino acid whose codons are GCT, GCC, GCA, and GCG. The term “methionine” refers to an amino acid whose codon is ATG. The term “glutamate” refers to an amino acid whose codons are GAA and GAG. The term “sugar” refers to monosaccharides, disachharides, and polysaccharides. Examples of sugars include, but are not limited to, sucrose, glucose, dextrose, and others. The term “polyol” refers to an alcohol containing multiple hydroxyl groups. Examples of polyols include, but are not limited to, mannitol, sorbitol, and others. The term “metal ion” refers to a metal atom with a net positive or negative electric charge. For the purposes of the present application, the term “metal ion” also includes sources of metal ions, including but not limited to metal salts. The term “long-term storage” or “long term stability” is understood to mean that the pharmaceutical composition can be stored for three months or more, for six months or more, and preferably for one year or more, most preferably a minimum stable shelf life of at least two years. Generally speaking, the terms “long term storage” and “long term stability” further include stable storage durations that are at least comparable to or better that the stable shelf typically required for currently available commercial formulations of adalimumab, without losses in stability that would render the formulation unsuitable for its intended pharmaceutical application. Long-term storage is also understood to mean that the pharmaceutical composition is stored either as a liquid at 2-8° C., or is frozen, e.g., at −20° C., or colder. It is also contemplated that the composition can be frozen and thawed more than once. The term “stable” with respect to long-term storage is understood to mean that adalimumab contained in the pharmaceutical compositions does not lose more than 20%, or more preferably 15%, or even more preferably 10%, and most preferably 5% of its activity relative to activity of the composition at the beginning of storage. The term “substantially free” means that either no substance is present or only minimal, trace amounts of the substance are present which do not have any substantial impact on the properties of the composition. If reference is made to no amount of a substance, it should be understood as “no detectable amount”. The term “mammal” includes, but is not limited to, a human. The term “pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material, formulation auxiliary, or excipient of any conventional type. A pharmaceutically acceptable carrier is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation. The term “composition” refers to a mixture that usually contains a carrier, such as a pharmaceutically acceptable carrier or excipient that is conventional in the art and which is suitable for administration into a subject for therapeutic, diagnostic, or prophylactic purposes. It may include a cell culture in which the polypeptide or polynucleotide is present in the cells or in the culture medium. For example, compositions for oral administration can form solutions, suspensions, tablets, pills, capsules, sustained release formulations, oral rinses or powders. The terms “pharmaceutical composition” and “formulation” are used interchangeably. The term “treatment” refers to any administration or application of remedies for disease in a mammal and includes inhibiting the disease, arresting its development, relieving the disease, for example, by causing regression, or restoring or repairing a lost, missing, or defective function; or stimulating an inefficient process. The term includes obtaining a desired pharmacologic and/or physiologic effect, covering any treatment of a pathological condition or disorder in a mammal. The effect may be prophylactic in terms of completely or partially preventing a disorder or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disorder and/or adverse affect attributable to the disorder. It includes (1) preventing the disorder from occurring or recurring in a subject who may be predisposed to the disorder but is not yet symptomatic, (2) inhibiting the disorder, such as arresting its development, (3) stopping or terminating the disorder or at least its associated symptoms, so that the host no longer suffers from the disorder or its symptoms, such as causing regression of the disorder or its symptoms, for example, by restoring or repairing a lost, missing or defective function, or stimulating an inefficient process, or (4) relieving, alleviating or ameliorating the disorder, or symptoms associated therewith, where ameliorating is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, such as inflammation, pain and/or tumor size. The term “disease” refers to any condition, infection, disorder or syndrome that requires medical intervention or for which medical intervention is desirable. Such medical intervention can include treatment, diagnosis and/or prevention. The term “therapeutically effective amount” refers to an amount which, when administered to a living subject, achieves a desired effect on the living subject. For example, an effective amount of the polypeptide of the invention for administration to the living subject is an amount that prevents and/or treats an integrin αvβ3-mediated disease. The exact amount will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques. As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by those skilled in the art. Embodiments of the Invention When pharmaceutical compositions containing adalimumab (Humira®), including aqueous and lyophilized formulations of adalimumab are stored on a long-term basis, the activity of adalimumab can be lost or decreased due to aggregation and/or degradation. Thus, the present invention provides aqueous formulations of adalimumab that allow stable long-term storage of adalimumab, so that adalimumab is stable over the course of storage either in liquid or frozen states. The provided formulations do not require any extra steps such as rehydrating. Numerous embodiments of the present invention are explained in a greater detail below. Adalimumab All of the compositions of the present invention comprise adalimumab. As explained in the Background section of this application, adalimumab is a recombinant human IgG1 monoclonal antibody specific for human tumor necrosis factor (TNF). This antibody is also known as D2E7. Adalimumab consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons. Adalimumab has been described and claimed in U.S. Pat. No. 6,090,382. The term “adalimumab” is also intended to mean so-called “bio-similar” and “bio-better” versions of the active adalimumab protein present in commercially available Humira®. Adalimumab suitable for storage in the present pharmaceutical composition can be produced by standard methods known in the art. For example, U.S. Pat. Nos. 6,090,382 and 8,216,583 describe various methods that a skilled artisan could use to prepare adalimumab protein for use in the formulations of the present invention. These methods are incorporated by reference herein. For example, adalimumab can be prepared by recombinant expression of immunoglobulin light and heavy chain genes in a host cell. Purification of the expressed adalimumab can be performed by any standard method. When adalimumab is produced intracellularly, the particulate debris is removed, for example, by centrifugation or ultrafiltration. When adalimumab is secreted into the medium, supernatants from such expression systems can be first concentrated using standard polypeptide concentration filters. Protease inhibitors can also be added to inhibit proteolysis and antibiotics can be included to prevent the growth of microorganisms. Adalimumab can be purified using, for example, hydroxyapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography, and any combination of known or yet to be discovered purification techniques, including but not limited to Protein A chromatography, fractionation on an ion-exchange column, ethanol precipitation, reverse phase HPLC, chromatography on silica, chromatography on heparin SEPHAROSET®, an anion or cation exchange resin chromatography (such as a polyaspartic acid column), chromatofocusing, SDS-PAGE, and ammonium sulfate precipitation. I Formulations of Adalimumab with a Polyol and/or Surfactant, but without a Citrate/Phosphate Buffer In a first embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab; a stabilizer comprising at least one member selected from the group consisting of a polyol and a surfactant; and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 4 to about 8, and preferably about 5 to about 6, and wherein said buffer does not comprise a combination of citrate and phosphate. In this embodiment, the stabilizer preferably comprises both polyol and surfactant. The pharmaceutical composition can comprise one, or any combination of two or more buffers, as long as it does not comprise both citrate and phosphate. The surfactant may be any pharmaceutically acceptable surfactant, preferably polysorbates (e.g., polysorbate 80) or poloxamers (e.g., Pluronic F-68). II Formulations of Adalimumab Using a Single Buffer System In a second embodiment, utilizing a single buffer system, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a polyol, a surfactant, and a buffer system comprising a single buffering agent, said single buffering agent being selected from citrate, phosphate, succinate, histidine, tartrate or maleate, but not including combinations of the foregoing; wherein the formulation has a pH of about 4 to 8, and preferably about 5 to about 6. Histidine and succinate are particularly preferred for use as single buffering agents. It was surprisingly discovered that adalimumab compositions which comprise only one buffer (as opposed to two or more buffers) are more stable than adalimumab compositions comprising both a citrate buffer and a phosphate buffer. In the single buffer embodiment, adalimumab can be present at a concentration from about 20 to about 150 mg/ml, more preferably from about 20 to about 100 mg/ml, and even more preferably from about 30 to about 50 mg/ml. The buffer is present at a concentration from about 5 mM to about 50 mM. The pH of the compositions is between about 5 and about 6. The single buffer compositions of the invention may further comprise a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. The amino acid is selected from the group consisting of glycine, alanine, glutamate, arginine and methionine, most preferably glycine, arginine and methionine. The salt is selected from the group consisting of sodium chloride and sodium sulfate. The metal ion is selected from the group consisting of zinc, magnesium and calcium. The compositions of the invention may further comprise a surfactant. The surfactant is a polysorbate surfactant or a poloxamer surfactant. Polysorbate surfactants include polysorbate 80, polysorbate 40 and polysorbate 20. A preferred polysorbate surfactant is polysorbate 80. Poloxamer surfactants include poloxamer 188 (also available commercially as Pluronic F-68). Most preferably, the surfactant is polysorbate 80. The single buffer composition may further comprise a polyol. Preferably, the polyol is a sugar alcohol; and even more preferably, the sugar alcohol is mannitol, sorbitol or trehalose. The single buffer adalimumab composition may also comprise a sugar, preferably sucrose, glucose or dextrose. In one embodiment of a single buffer adalimumab formulation, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to 50 μM, and succinate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of any other buffers. In another embodiment of a single buffer adalimumab formulation, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to 50 μM, and histidine at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of any other buffers. In a further embodiment of a single buffer adalimumab formulation, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to 50 μM, and either tartrate, maleate or acetate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of any other buffers. III Formulations of Adalimumab which Exclude Buffer In a third embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a stabilizer comprising at least one member selected from a polyol and a surfactant, wherein said composition has a pH of about 4 to about 8 and preferably about 5 to about 6, and wherein said composition is substantially free of a buffer. The term “free of buffer” should be understood to allow inclusion of the inherent buffering effect of the protein itself. In a buffer free formulation, the stabilizers referenced above may also be present (e.g. glycine, arginine and combinations thereof). IV Formulations of Adalimumab which Exclude Surfactant In a fourth embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a polyol, and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 4 to about 8 and preferably about 5 to about 6, and wherein said composition is free or substantially free of a surfactant. Preferably, the composition (i) does not contain the buffer combination of citrate and phosphate; and (ii) the buffer is at least one member selected from the group consisting of histidine and succinate; and (iii) the polyol is not mannitol at concentrations less than about 150 mM, but instead is selected from the group consisting of mannitol at concentrations exceeding about 150 mM, sorbitol and trehalose. V Formulations of Adalimumab which Exclude Polyol In a fifth embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a surfactant, and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 4 to about 8, and preferably about 5 to about 6, and wherein said composition is substantially free of polyol. Preferably, the composition (i) does not contain the buffer combination of citrate and phosphate; and (ii) the buffer is at least one member selected from the group consisting of histidine and succinate. Additional Stabilizers Useful in Embodiments I Through V. Optionally, in each of the five embodiments summarized above, the composition may further comprise a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. The amino acid stabilizer may be selected from the group consisting of glycine, alanine, glutamate, arginine and methionine. The salt stabilizer may be selected from the group consisting of sodium chloride and sodium sulfate. The metal ion stabilizer may be selected from the group consisting of zinc, magnesium and calcium. Preferably, adalimumab formulations containing the stabilizers mentioned above also do not contain buffer systems in which phosphate buffer and citrate buffer are present in combination. Most preferably (i) the optional additional stabilizer present in this embodiment is not sodium chloride, and comprises at least one or both of arginine and glycine; (ii) the buffer, when present, contains no citrate and phosphate combination but is instead at least one of histidine and succinate; and (iii) the stabilizer when it includes a polyol is not mannitol unless in amounts greater than about 150 mM, and may also include trehalose and sorbitol. Preferably the amount of mannitol is greater than about 150 mM, and most preferably greater than about 200 mM. VI Formulations of Adalimumab Replacing Both Surfactant and Polyol with Other Stabilizers It has been further discovered that satisfactory stabilization can be attained when the stabilizers mentioned above are used in place of both polyol and surfactant, accordingly, in a sixth embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, optionally a buffer, a stabilizer selected from the group consisting of an amino acid, a salt, EDTA, and a metal ion, and wherein said composition has a pH of about 4 to about 8, and preferably about 5 to about 6, and wherein said composition is free or substantially free of a polyol and surfactant. When buffer is present in this embodiment, it is especially preferred that (i) the buffer not include the combination of citrate and phosphate; (ii) the buffer is selected from the group consisting of histidine and succinate; and (iii) the stabilizer does not comprise sodium chloride, but instead is at least one member selected from the group consisting of arginine and glycine. It is also preferred that the buffer is free or substantially free of citrate buffer, as we have discovered that it is generally poorer in terms of stability contribution than other buffers, such as histidine and succinate. In each of the embodiments above at least one of the following advantageous conditions can be optionally present (unless stated as being required): (i) the buffer preferably does not contain a combination of citrate and phosphate, or is free or substantially free of citrate buffer (ii) the buffer preferably is at least one member selected from the group consisting of histidine and succinate; and (iii) the stabilizer preferably does not include sodium chloride, or if present is controlled to levels less than about 100 mM; (iv) the stabilizer is at least one member selected from the group consisting of arginine and glycine, including combinations thereof; and (v) the polyol is preferably not mannitol (unless mannitol is present in amounts greater than about 150 mM and preferably greater than about 200 mM) but may include sorbitol and trehalose. When using polyols for stabilization, mannitol is discovered herein to be destabilizing in comparison to sorbitol and trehalose unless the mannitol is present in amounts generally above about 150 to 200 mM. When using other stabilizers, it is discovered herein that sodium chloride is destabilizing compared to arginine or glycine, but we observe some stabilization when the levels of sodium chloride are controlled to less than about 100 mM and preferably less than about 75 mM. Preferably, adalimumab is present in the composition of the present invention at a concentration from about 20 to about 150 mg/ml, more preferably from about 20 to about 100 mg/ml, and even more preferably from about 30 to about 50 mg/ml. Buffer, if present, is present at a concentration from about 5 mM to about 50 mM. Surfactant, if present, is preferably a polysorbate (PS). In an even more preferred embodiment, the polysorbate is polysorbate 80 (PS 80). Poloxamer surfactants are also suitable (e.g., Pluronic® F-68). The polyol, if present, is a sugar alcohol. In an even more preferred embodiment, the sugar alcohol is selected from the group consisting of mannitol, sorbitol and trehalose, and most preferably sorbitol and trehalose. Preferably, the polyol is at a concentration from about 1 to about 10%, more preferably, from about 2 to about 6%, and even more preferably from about 3 to 5%, wherein said values are weight by volume (w/v) of the total composition. A stabilizer, when present, can be selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. The amino acid can be selected from the group consisting of glycine, alanine, glutamate, arginine and methionine. The salt may be selected from the group consisting of sodium chloride and sodium sulfate. The metal ion may be selected from the group consisting of zinc, magnesium and calcium. Glycine and arginine are particularly preferred stabilizers. Zinc, magnesium and calcium, when present for stabilization, may be at a concentration from about 1 mM to about 100 mM, and more preferably from about 1 to about 10 mM. Glycine, or arginine, or combinations thereof, if present for stabilization, is at a total concentration of up to about 300 mM, and preferably about 150 to 300 mM. Methionine, if present for stabilization, is present at a concentration from about 1 to about 10 mg/ml, more preferably from about 1 mg/ml to about 5 mg/ml. Sodium chloride, if present for stabilization, is at a concentration from about 5 to about 150 mM, more preferably, from about 20 to about 140 mM, and even more preferably less than about 100 mM. Sodium sulfate, if present if present for stabilization, is at a concentration from about 5 to about 150 mM, more preferably, from about 20 to about 120 mM, and even more preferably from about 60 to about 100 mM. EDTA, if present for stabilization, is present at a concentration from about 0.01% to about 0.05%, more preferably from about 0.05% to about 0.25%, and even more preferably from about 0.08% to about 0.2%. Preferably, the pH of the composition is from about 5 to about 5.5; and even more preferably is about 5.2 to 5.4. In an example of Embodiment I and II, above, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, sorbitol or trehalose at a concentration from about 1 to 10% weight by volume, polysorbate 80 at a concentration from about 1 to 50 μM, and at least one of succinate, histidine, phosphate, tartrate, maleate or citrate buffer, at a concentration from about 5 mM to about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and provided said composition is free or substantially free of citrate/phosphate buffer combination. Further, we rank citrate as the poorest of buffers, and preferably avoid it although it is still within the scope of the invention to formulate stable formulations of adalimumab that include citrate buffer, if not the combination thereof with phosphate. In an example of Embodiment IV, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, sorbitol or trehalose at a concentration from about 1 to 10% weight by volume, and at least one of succinate, histidine, phosphate, tartrate, maleate or citrate buffer, at a concentration from about 5 mM to about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of a surfactant and, optionally, and preferably, free or substantially free of citrate/phosphate buffer combination. In an example of Embodiment VI, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, glycine at a concentration from about 20 to about 200 mM, and at least one of succinate, histidine, phosphate, tartrate, maleate or citrate buffer, at a concentration from about 5 mM to about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is free or substantially free polyol; surfactant (e.g. PS8) is preferably, but optionally present; and the composition is, optionally, and preferably, free or substantially free of citrate/phosphate buffer combination. In a further example of Embodiment VI, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, arginine or glycine at a concentration from about 1 to about 250 mM, and at least one of succinate, histidine, phosphate, tartrate, maleate or citrate buffer, at a concentration from about 5 mM and about 50 mM wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of polyol. Surfactant (e.g. PS80) is preferably but optionally present, and the composition is, optionally, and preferably, free or substantially free of citrate/phosphate buffer combination. In a further example of Embodiment VI, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, sodium chloride at a concentration from about 5 to about 150 mM, and at least one of succinate, histidine, phosphate, tartrate, maleate or citrate buffer, at a concentration from about 5 mM and about 50 mM wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is free or substantially free of a polyol. Surfactant (e.g. PS80) is preferably but optionally present; and the composition is, optionally, and preferably, free or substantially free of citrate/phosphate buffer combination. In an example of Embodiment V, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, sodium chloride at a concentration from about 5 to about 150 mM, polysorbate 80 at a concentration from about 1 to 50 μM, and at least one of succinate, histidine, phosphate, tartrate, maleate or citrate buffer, at a concentration from about 5 mM and about 50 mM wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is free or substantially free of a polyol and, optionally, and preferably, free or substantially free of citrate/phosphate buffer. In an example of Embodiments I and II, with additional stabilization, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to about 50 μM, sorbitol or trehalose at a concentration from about 1 to about 10% weight by volume, EDTA at a concentration from about 0.01% to about 0.5%, and at least one of succinate, histidine, phosphate, tartrate, maleate or citrate, as a sole buffer, at a concentration from about 5 mM and about 50 mM wherein said composition has a pH of about 5 to about 5.5, and wherein the composition is free, or substantially free of citrate/phosphate buffer combination. In a further example of Embodiments I and II, with additional stabilization, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to about 50 μM, sorbitol or trehalose at a concentration from about 1 to about 10% weight by volume, methionine at a concentration from about 1 to about 10 mg/ml, %, and at least one of succinate, histidine, phosphate, tartrate, maleate or citrate at a concentration from about 5 mM and about 50 mM wherein said composition has a pH of about 5 to about 5.5, wherein the composition is free or substantially free of any citrate/phosphate buffer combination. In a further example of Embodiments I and II, with additional amino acid stabilization, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to about 50 μM, mannitol, sorbitol or trehalose (preferably sorbitol) at a concentration from about 1 to about 10% weight by volume, and amino acid that is preferably one and not both of (a) arginine at a concentration from about 1 to about 250 mg/ml, and (b) glycine at a concentration of about 20 to 200 mg/ml, and histidine buffer or succinate buffer at a concentration from about 5 mM and about 50 mM, and wherein said composition has a pH of about 5 to about 5.5; and wherein the composition is free or substantially free of any citrate/phosphate buffer combination. In a further example of Embodiment IV, with additional amino acid stabilization, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to about 50 μM, arginine at a concentration from about 1 to about 250 mg/ml, glycine at a concentration of about 20 to 200 mg/ml, and histidine buffer or succinate buffer at a concentration from about 5 mM to about 50 mM, and wherein said composition has a pH of about 5 to about 5.5 and is free or substantially free of polyol; and, optionally, wherein the composition is preferably free of any citrate/phosphate buffer combination. Numerous embodiments of the adalimumab formulations of the present invention were prepared in eight separate blocks of experiments, referred to herein as “Block A” through “Block H.” Each block had 12 to 16 different formulations that were exposed to accelerated storage conditions, 1 week at 40° C. and 2 weeks at 25° C. For each time point the chemical and physical stability of the adalimumab protein was measured by SEC, RP, UV, pH, CE-IEF and CE-SDS. Materials and Methods 1. Equipment Used in the Formulation Studies Equipment Manufacture Model Serial Number Balance Sartorius CPA124S 23350022 pH meter Denver Model 250 E25006B100 Instrument UV Cary Bio 100 EL07103025 HPLC Dionex 3 Ultimate 3000 8047439 UPLC HPLC Dionex 2 Ultimate 3000, 8036991 UPLC Beckman Beckman P/ACE 455436 CE Agilent CE Agilent 3DCE 1600A 3546G00736 Rocker Labnet Orbit P4 8091840 Plate 2. Chemicals and Materials Used in the Formulation Studies Chemical/Materials Producer Purity Lot Number: Citrate Mallinckrodt ACS H28475 Phosphate Fisher FCC 103372 Fisher ACS 113670 Succinate Spectrum Reagent ZM0462 Histidine Spectrum USP XV0239 Spectrum USP ZG0216 Tartrate Spectrum FCC 1BC0152 Maleate TCI >99% 206-738-1 Mannitol BDH USP 57910 Glycine Spectrum FCC YM3312 Spectrum FCC 1BJ0243 Fisher Tissue Grade 070082 Arginine Spectrum USP 2AK0238 Spectrum USP 1CB0771 Sodium Chloride Mallinckrodt ACS J52619 Macron USP 26434 Polysorbate 80 Sigma-Aldrich Low Peroxide 028K5309 Sorbitol Spectrum NF 1AH0521 Trehalose Spectrum N/A 1AE0739 Acetate Mallinckrodt FCC H31613 EDTA Sigma 98.5% 057K00071 Methionine Spectrum USP ZF0377 F-68 Sigma Cell Culture 057K00331 Polysorbate 20 Spectrum NF 1AE0882 Sodium dodecyl Fluka ACS 1344034 sulfate Tris base Fisher ACS S61374 2-mercaptoethanol Fisher Electrophoresis 107667 Material/Reagents Part Number Supplier Slide-A-Lyzers 7K cutoff 66373 Thermo Mini Dialysis Units 69550 Thermo Millex ®-GV 0.22 μM, SLGV004SL Millipore Filter 1 mL Vials 4500050375 SCHOTT cIEF Gel Polymer Solution 477497 Beckman Coulter pI Marker Kit A58481 Beckman Coulter Pharmalyte 3-10 ampholyte 17-0456-01 GE Healthcare Fused silica capillary TSP050375 Polymicro (50 μm i.d.) SDS-MW gel buffer A10663 Beckman 10 kD internal standard A26487 Beckman 3. HPLC Columns Used in the Formulation Studies Column Company Part # Lot Poroshell 300SB- Agilent 660750-906 USZW003083 C8, 2.1 × 75 mm, 5 um Poroshell 300SB- Agilent 660750-906 USZW003073 C8, 2.1 × 75 mm, 5 um ACQUITY UPLC Waters 186005225 138123331 BEH200 SEC, 1.7 um Column, 4.6 × 150 mm ACQUITY UPLC Waters 186005225 01471130951 BEH200 SEC, 1.7 um Column, 4.6 × 150 mm Processing of Humira®. Block A experiments used adalimumab present in commercially available Humira®. Humira® material was dialyzed as follows: 100 μL of Humira® was placed into Mini Dialysis units with a 3.5 MWCO and dialyzed in 1 L of formulation buffer for 24 hours at 4 to 8° C. A few samples did experience a small increase in volume due to the dialysis, but never to extent that the concentration of the polysorbate 80 dropped below the CMC (critical micelle concentration). The protein concentration for each formulation was measured by UV absorbance spectroscopy, using an calculated experimental molar absorptivity based on reported concentration of Humira®, 50 mg/mL. For a number of the formulations the protein concentration was adjusted by using a spin concentrator. The sample was placed in the spin concentrator and rotated at 14,000 RPM for 30 to 60 secs. The protein concentration was then checked with UV. After the targeted protein concentration around 50 mg/mL was reached the samples were filtered through a 0.22 μM sterile filter into sterile vials in a biosafety hood. The samples were then placed on stability at 40° C. for one and two weeks. Processing of a Proprietary Adalimumab Protein. The formulation studies described herein used a proprietary adalimumab biosimilar protein which did not contain polysorbate 80. The material was dialyzed using 7,000 MWCO Slide-A-Lyzers in different formulation buffers for 24 hours at a temperature range between 4 to 8° C. After dialysis the protein concentration was measured by UV and sample pH was measured. The target concentration of samples was 50±2.5 mg/mL, which was adjusted if the sample concentration fell out of the above range. Some of the samples did experience an increase in sample volume do to dilution, requiring the concentration of the protein to increase. For these samples the protein concentration was increased by using spin concentrators, usually at 14,000 rpm for 30 to 60 secs. The pH of a number of samples were adjusted using 1M NaOH or 1M HCl to reach the target pH of 5.2. After the targeted protein concentration and pH of the samples were determined to be within experimental parameters, the samples were filtered through a 0.22 μM sterile filter into sterile vials in a biosafety hood. The samples were then placed on stability at 40° C. for one week and 25° C. for two weeks. Freeze-Thaw Conditions: The freeze thaw samples were prepared on the day of analysis to match with t=0. The samples were frozen at −80° C. between 3 to 7 minutes. The frozen sample was then thawed at room temperature until all the ice had thawed. The freeze and thaw cycle was repeated 5 times for each sample. Agitation Studies. The samples were aggregated at 150 rpm for 24 hours at 4° C. on a rockerplate. A control was prepared and placed next to the rocker plate for each sample that underwent agitation. pH Measurements. The pH each sample was measured using a micro-pH probe. Before the start of analysis the pH probe was calibrated with three pH standards ordered from fisher. The pH values of the stability samples were measured by transferring 604 of each stability sample to 100 μL PCR tube. The micro-pH probe was then submerged into the sample and after the value stabilized it was recorded. UV Absorbance Spectroscopy. UV spectroscopy was used to measure the protein concentration in the samples. The mole extinction coefficient at 280 nm for bulk substance was 1.6355 mg/mL, which was determined experiential. The protein concentrations of the all formulations for LB-140 were measured using a cell path length of 0.0096 cm. Below is the analysis parameters used for LB-140. Scan Range: 400 to 200 nm Average Time (min): 0.1 Date Interval (nm): 1 Scan Rate (nm/min): 600 Cycle Count: 5 Size Exclusion Chromatography (SEC) Method. The SEC method used to analyze the LB-140 stability samples was developed at Legacy BioDesign. Below is a brief summary of the SEC method parameter used for the analysis of the LB-140 samples. Method Parameters Column Information: ACQUITY UPLC BEH200 SEC, 1.7 um Column, 4.6×150 mm Analysis Buffer: 50 mM Phosphate, 250 mM NaCl, pH 6.8 Flow rate: 0.3 mL/min Column temperature: 30° C. Detection: 280 nm Injection volume: 2 μL Sample temperature: Approx. 5° C. RP HPLC Method. The RP HPLC method was found to be stability indicating and was used to analyze LB-140 stability samples. Below is a summary of the RP method parameter used for the analysis of the LB-140. Method Parameters Column Information: Poroshell 300SB-C8, 2.1×75 mm, 5 um Mobile Phase A: 98% (v/v) H2O/2% (v/v) IPA/0.1% (v/v) TFA Mobile Phase B: 10% (v/v) H2O/70% (v/v) IPA/20% (v/v) ACN/0.1% (v/v) TFA Flow rate: 0.25 mL/min Column temperature: 80° C. Detection: 225 nm Injection volume: 1 μL Sample temperature: Approx. 5° C. Run time: 15 minutes Gradient: Time % A % B 0 100 0 10 50 50 10.1 100 0 15 100 0 CE-IEF Analysis. Capillary isoelectric focusing (cIEF) was conducted as described in the PA 800 plus Application Guide published by Beckman Coulter. A more detailed description can be found in a research article published by Mack et al1. All analyses were conducted using a Beckman Coulter P/ACE MDQ system (Beckman Coulter, Inc.; Brea, Calif.) operated at ambient temperature with a 30 cm total length (20 cm effective) neutral capillary. The neutral capillary was prepared by immobilizing poly(acrylamide) to the capillary wall using a method described by Gao et al.2 cIEF samples were prepared by mixing the protein of interest at 0.25 mg/mL with a mixture of 3M urea-cIEF gel containing ampholyte, cathodic stabilizer, anodic stabilizer, and pI markers. Sample was pressure injected at 9.5 psi into the capillary for 4.1 min, after which time it was focused by applying a voltage of 25 kV for 15 min between analyte and catholyte. This step was followed by chemical mobilization at 30 kV for 30 min between analyte and chemical mobilizer. The pI markers and the protein of interest were detected with absorbance at 280 nm during the mobilization step. The pI of the protein was calculated from the resultant regression equation of pI vs. first peak moment obtained from the pI standards. CE-SDS Analysis. Analysis by CE-SDS was conducted under reducing conditions utilizing a method adapted from the SOP published by Beckman-Coulter for determining IgG purity/heterogeneity. Briefly, the antibody was diluted with DDI water to 6 mg/mL, denatured by adding sample buffer (0.1 M Tris/1.0% SDS, pH 8.0), and reduced via addition of 2-mercaptoethanol; the final antibody concentration was 1.2 mg/mL. Denaturing and reduction was facilitated by heating the sample at 70° C. for 10 min. The sample was cooled for 10 min at room temperature prior to analysis. A centrifuge step (300 g, 5 min) was employed prior to heating the sample and directly after the cooling it. CE analysis was conducted using a Beckman Coulter P/ACE MDQ system operated at ambient temperature with a 30 cm total length (20 cm effective, 50 μm i.d.) capillary. Prior to sample introduction, the capillary was sequentially rinsed with 0.1 M NaOH, 0.1M HCL, DDI water, and SDS-gel buffer solution. Sample was injected electrokinetically at 5 kV for 30 s followed by separation at 30 kV for 30 min. For both injection and separation, the instrument was operated in reverse polarity mode. Antibody fragments were detected using absorbance at 214 nm (4 Hz acquisition) and time-normalized areas reported for measured peaks. Block A Formulation Studies The Block A studies examined different buffer systems and used a commercially available adalimumab material which was reprocessed for these studies. We note that U.S. Pat. No. 8,216,583 references stability of an adalimumab formulation in relation to use of a citrate/phosphate buffer system at pH 5.2, and in fact the patent required the use of such a buffer combination. The work we have done, reflected here, indicates that citrate/phosphate is in fact a rather poor buffer choice in comparison to others such as histidine and succinate. In the Block A studies below, pH was kept constant at 5.2. The concentrations of mannitol and polysorbate 80 were also held constant. Samples were kept at 40° C. for two weeks. The study design is summarized in the Table below. TABLE A BLOCK A STUDY DESIGN PS Form Citrate Phosphate Succinate Histidine Tartrate Maleate Mannitol 80 No. API (mM) (mM) (mM) (mM) (mM) (mM) (mM) (%) 1 Humira ® 8 18 0 0 0 0 12 0.1 2 Humira ® 10 0 0 0 0 0 12 0.1 3 Humira ® 0 10 0 0 0 0 12 0.1 4 Humira ® 0 0 10 0 0 0 12 0.1 5 Humira ® 0 0 0 10 0 0 12 0.1 6 Humira ® 0 0 0 0 10 0 12 0.1 7 Humira ® 0 0 0 0 0 10 12 0.1 Analysis by SEC showed that the formulation with citrate alone performed more poorly than the buffer combination (Table A), indicating that the phosphate was the primary stabilizer in that combination. This was surprising and unexpected, as this pH is outside of the nominal buffering capacity range of phosphate, but well within the buffering range for citrate. Furthermore, succinate, histidine, and tartrate did as well or better than the citrate/phosphate combination, indicating that other buffer systems would provide equal or superior stability for adalimumab. Accordingly, the present invention in one of its embodiments is directed to adalimumab formulations exhibiting long term stability, wherein a buffer combination of citrate and phosphate is avoided in favor of at least one buffer selected from the group consisting of histidine, phosphate, succinate and tartrate. Acetate is also a suitable replacement for the citrate phosphate buffer combination. The purity of these stored samples was checked using RP HPLC (FIG. 2). As with SEC, the citrate formulation exhibited the poorest stability, while all of the other buffers did as well or better than the buffer combination found in commercially available adalimumab (Humira®). These results demonstrate our discovery that changing the buffer (i.e. avoiding the citrate/phosphate buffer combination of the commercial adalimumab) could improve the stability profile of adalimumab. Block B Formulation Studies A second study (“BLOCK B”) was conducted examining just changes in the buffer species, where the pH (5.2) was not changed, as outlined in the table below labeled “BLOCK B Study Design. In this case, the commercially available formulation for Humira® was used as a control, while all of the other formulations employed a proprietary adalimumab biosimilar protein. Table B-1, below summarizes the percent monomer for the Block B formulations (as well the percentage amount of an impurity determined to be a fragment of the adalimumab protein). TABLE B BLOCK B STUDY DESIGN PS Form Citrate Phosphate Succinate Histidine Tartrate Maleate Mannitol 80 No. API (mM) (mM) (mM) (mM) (mM) (mM) (mM) (%) 1 Humira ® 8 18 0 0 0 0 12 0.1 2 Adalimumab 10 0 0 0 0 0 12 0.1 biosimilar 3 Adalimumab 0 10 0 0 0 0 12 0.1 biosimilar 4 Adalimumab 0 0 10 0 0 0 12 0.1 biosimilar 5 Adalimumab 0 0 0 10 0 0 12 0.1 biosimilar 6 Adalimumab 0 0 0 0 10 0 12 0.1 biosimilar 7 Adalimumab 0 0 0 0 0 10 12 0.1 biosimilar TABLE B-1 Percent monomer for Block B formulations at t0 and after two weeks at 40 C. (t2) Form Monomer Monomer Fragment Fragment No. API Buffer (t0) (t2) (t0) (t2) 1 Humira ® Citrate/phosphate 99.34 0.26 2 Adalimumab citrate 98.71 97.92 0.62 0.40 biosimilar 3 Adalimumab phosphate 99.21 98.07 0.05 0.30 biosimilar 4 Adalimumab succinate 99.19 98.04 0.04 0.31 biosimilar 5 Adalimumab histidine 99.19 98.41 0.07 0.23 biosimilar 6 Adalimumab tartrate 99.13 98.10 0.04 0.29 biosimilar 7 Adalimumab maleate 98.91 97.90 0.36 0.76 biosimilar As can be seen from Table B-1 above, upon storage for two weeks at 40 C, the monomer content decreases by more than 1% for all of the samples in Block B, except for the one containing histidine (His) buffer (Table B-1). From this study we discovered the likelihood that His would be a superior buffer system for adalimumab. (We note that the fragment level measured by SEC reported for Formulation 2 appears to be incorrect as all of the other initial fragment s levels are less than 0.1%.) Block C Formulation Studies A large-scale formulation screening study was carried out in the studies conducted in Block C (See Table C, below). Samples were stored for one week at 40 C (hereinafter referenced as “t1”) or two weeks at 25 C (hereinafter referenced as “t2”). These conditions were used throughout the remainder of our studies, so this terminology will be employed throughout the present detailed discussion. Block C was designed to expand on the buffer assessment conducted in Block B. In addition, it examined glycine (Gly) and/or arginine (Arg) as possible stabilizers in place of mannitol and/or NaCl (Table C). Note that the buffer system used in the Humira® product employs the 8 mM citrate/18 mM phosphate buffer, which is the composition of Formulation 1 of Block C. In this case, a proprietary adalimumab biosimilar protein was used for formulation 1 of Block C, instead of adalimumab protein obtained from commercially available Humira®. TABLE C BLOCK C STUDY DESIGN Form No. API citrate phosphate succinate histidine glycine arginine mannitol NaCl 1 Adalimumab 8 18 0 0 0 0 65 100 biosimilar 2 Adalimumab 18 8 0 0 0 0 65 100 biosimilar 3 Adalimumab 20 0 0 0 0 0 65 100 biosimilar 4 Adalimumab 20 0 0 0 65 0 0 100 biosimilar 5 Adalimumab 0 20 0 0 65 0 0 100 biosimilar 6 Adalimumab 20 0 0 0 0 65 0 100 biosimilar 7 Adalimumab 0 20 0 0 0 65 0 100 biosimilar 8 Adalimumab 0 0 20 0 65 0 0 100 biosimilar 9 Adalimumab 0 0 20 0 0 65 0 100 biosimilar 10 Adalimumab 0 0 0 20 65 0 0 100 biosimilar 11 Adalimumab 0 0 0 20 0 65 0 100 biosimilar 12 Adalimumab 0 20 0 0 0 130 0 35 biosimilar 13 Adalimumab 0 0 20 0 0 130 0 35 biosimilar 14 Adalimumab 0 0 0 20 0 130 0 35 biosimilar 15 Adalimumab 0 20 0 0 130 0 0 60 biosimilar 16 Adalimumab 0 20 0 20 130 0 0 60 biosimilar TABLE C-1 Measured pH for Block C formulations at t0 and t1 (one week, 40° C.) Form pH pH No. citrate phosphate succinate histidine glycine arginine mannitol NaCl t0 t2 1 8 18 0 0 0 0 65 100 5.51 5.57 2 18 8 0 0 0 0 65 100 5.46 5.43 3 20 0 0 0 0 0 65 100 5.28 5.27 4 20 0 0 0 65 0 0 100 5.27 5.24 5 0 20 0 0 65 0 0 100 5.43 5.44 6 20 0 0 0 0 65 0 100 5.29 5.29 7 0 20 0 0 0 65 0 100 5.28 5.32 8 0 0 20 0 65 0 0 100 5.22 5.17 9 0 0 20 0 0 65 0 100 5.19 5.16 10 0 0 0 20 65 0 0 100 5.28 5.30 11 0 0 0 20 0 65 0 100 5.26 5.29 12 0 20 0 0 0 130 0 35 5.24 5.24 13 0 0 20 0 0 130 0 35 5.18 5.16 14 0 0 0 20 0 130 0 35 5.28 5.35 15 0 20 0 0 130 0 0 60 5.31 5.31 16 0 20 0 20 130 0 0 60 5.36 5.40 TABLE C-2 Monomer content by SEC for formulations in Block C at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. citrate phosphate succinate His Gly Arg mannitol NaCl t0 t1 t2 1 8 18 0 0 0 0 65 100 98.75 97.90 98.06 2 18 8 0 0 0 0 65 100 99.26 98.22 98.80 3 20 0 0 0 0 0 65 100 99.28 98.32 98.78 4 20 0 0 0 65 0 0 100 99.36 98.45 99.03 5 0 20 0 0 65 0 0 100 99.25 98.20 98.77 6 20 0 0 0 0 65 0 100 99.42 98.68 99.10 7 0 20 0 0 0 65 0 100 99.39 98.59 99.13 8 0 0 20 0 65 0 0 100 99.41 98.51 99.04 9 0 0 20 0 0 65 0 100 99.36 98.52 98.96 10 0 0 0 20 65 0 0 100 99.41 98.66 99.15 11 0 0 0 20 0 65 0 100 99.37 98.70 99.15 12 0 20 0 0 0 130 0 35 99.41 98.66 99.14 13 0 0 20 0 0 130 0 35 99.42 98.71 99.17 14 0 0 0 20 0 130 0 35 99.40 98.75 99.26 15 0 20 0 0 130 0 0 60 99.32 98.53 99.05 16 0 20 0 20 130 0 0 60 99.40 98.66 99.19 TABLE C-3 Percent purity by RP HPLC for formulations in Block C at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. citrate phosphate succinate His Gly Arg mannitol NaCl t0 t1 t2 1 8 18 0 0 0 0 65 100 98.04 97.92 98.10 2 18 8 0 0 0 0 65 100 97.94 97.83 98.03 3 20 0 0 0 0 0 65 100 98.03 97.92 98.00 4 20 0 0 0 65 0 0 100 97.94 97.75 97.98 5 0 20 0 0 65 0 0 100 97.98 97.69 97.95 6 20 0 0 0 0 65 0 100 97.89 97.72 97.92 7 0 20 0 0 0 65 0 100 97.80 97.70 97.91 8 0 0 20 0 65 0 0 100 97.98 97.77 98.01 9 0 0 20 0 0 65 0 100 97.98 97.73 97.94 10 0 0 0 20 65 0 0 100 97.98 97.76 98.00 11 0 0 0 20 0 65 0 100 97.87 97.78 97.97 12 0 20 0 0 0 130 0 35 97.88 97.71 97.95 13 0 0 20 0 0 130 0 35 97.95 97.62 97.93 14 0 0 0 20 0 130 0 35 97.98 97.72 98.04 15 0 20 0 0 130 0 0 60 97.91 97.72 97.96 16 0 20 0 20 130 0 0 60 98.00 97.79 97.78 TABLE C-4 Percentage of main bands seen in the cIEF profile of formulations in Block C at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. pH t0 t1 t2 1 8.59 1.94 1.97 1.82 8.43 11.76 11.30 12.49 8.27 58.29 49.88 51.54 8.20 7.18 7.59 8.05 21.49 22.38 19.79 7.86 6.53 5.35 4.66 2 8.60 1.96 1.84 8.44 12.08 10.89 8.29 51.70 47.63 8.22 9.74 12.32 8.09 16.29 18.25 7.91 3.50 3.64 3 8.60 1.83 1.82 1.12 8.43 11.58 9.67 10.40 8.27 45.80 32.99 44.04 8.20 12.44 22.27 18.68 8.01 17.57 16.21 14.40 7.86 4.39 3.61 4 8.57 2.31 2.04 2.13 8.41 12.94 11.51 12.62 8.25 33.37 59.98 61.97 8.20 23.03 8.02 15.21 18.33 16.07 7.88 3.45 5.32 3.70 5 8.58 2.40 2.00 2.30 8.41 13.01 11.02 12.34 8.25 42.09 46.32 37.30 8.21 15.58 10.65 15.80 8.03 18.48 20.58 16.80 7.86 3.74 6.13 4.83 6 8.57 2.83 8.38 13.17 13.23 8.23 32.66 31.18 8.18 17.52 18.54 8.02 17.48 13.82 7.91 5.30 5.83 7 8.58 2.08 2.41 2.64 8.44 13.42 12.64 12.63 8.27 56.79 52.48 54.76 8.16 5.36 6.16 6.38 8.04 16.91 20.09 18.45 7.94 5.44 4.12 5.15 8 8.57 1.76 2.37 1.55 8.44 14.41 12.13 11.61 8.29 60.01 48.87 52.94 8.19 7.07 10.66 8.10 16.22 16.55 17.10 7.95 7.61 5.02 4.55 9 8.58 2.19 2.06 0.99 8.41 11.69 10.64 12.73 8.26 50.07 44.21 60.33 8.19 10.66 10.39 8.01 15.62 21.51 17.79 7.87 4.67 5.37 8.16 10 8.57 1.78 2.64 1.62 8.41 10.55 10.95 8.11 8.25 43.82 42.93 36.11 8.21 15.96 15.24 17.66 8.02 14.63 14.58 14.22 7.88 3.82 4.21 3.95 11 8.58 1.59 1.81 1.89 8.41 12.98 11.58 12.86 8.23 62.74 29.63 12.00 8.19 22.86 34.77 8.02 17.15 19.52 17.06 7.87 5.54 5.56 4.77 12 8.61 0.35 1.57 1.47 8.35 13.24 13.41 8.83 8.19 43.18 60.12 26.52 8.15 15.43 20.46 25.60 7.98 16.74 17.38 7.88 4.96 4.44 4.99 13 8.58 1.71 1.67 8.41 11.63 10.01 8.26 49.19 42.65 8.20 14.25 16.64 8.03 17.35 18.12 7.86 4.28 4.18 14 8.56 1.64 1.79 1.73 8.39 13.17 10.45 10.96 8.25 58.68 46.06 45.60 8.21 11.03 13.34 8.07 14.10 20.24 14.50 7.92 2.10 5.13 4.28 15 8.57 1.74 1.22 1.60 8.41 10.49 15.21 10.78 8.25 46.06 55.05 44.98 8.20 14.46 13.79 8.02 13.90 20.31 10.79 7.89 4.23 4.90 3.43 16 8.56 1.96 1.08 8.40 9.25 12.23 12.58 8.24 38.08 31.03 58.61 8.20 19.02 22.08 21.50 8.03 12.00 13.24 7.31 7.89 4.73 4.82 TABLE C-5 Percentage of bands for light chain (LC), heavy chain (HC), non- glycosylated HC, and other species for formulations in Block C at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. Time LC HC ngHC Other 1 t0 35.87 63.20 0.51 0.42 t1 29.71 63.08 0.37 6.84 t2 31.01 67.83 0.54 0.61 2 t0 29.50 69.57 0.56 0.37 t1 30.51 67.28 0.56 1.65 t2 32.32 65.51 0.56 1.61 3 t0 32.53 66.45 0.54 0.47 t1 33.04 65.34 0.55 1.07 t2 31.94 66.60 0.57 0.90 4 t0 33.40 64.90 0.46 1.24 t1 30.96 67.16 0.52 1.36 t2 32.08 65.84 0.56 1.52 5 t0 34.17 63.89 0.49 1.45 t1 33.60 64.27 0.56 1.57 t2 32.15 66.20 0.48 1.17 6 t0 37.91 60.35 0.54 1.19 t1 34.80 62.88 0.73 1.59 t2 32.90 65.62 0.50 0.99 7 t0 32.17 66.80 0.55 0.49 t1 29.83 68.33 0.59 1.25 t2 33.32 65.97 0.55 0.15 8 t0 33.83 65.51 0.49 0.17 t1 30.37 68.48 0.58 0.57 t2 32.86 66.40 0.55 0.19 9 t0 30.69 69.31 0.00 0.00 t1 34.30 64.24 0.52 0.94 t2 29.08 69.87 0.62 0.43 10 t0 38.68 59.95 0.57 0.80 t1 36.52 58.65 0.00 4.83 t2 43.68 54.39 1.92 0.00 11 t0 35.25 59.00 1.75 4.00 t1 30.71 67.58 0.66 1.05 t2 30.18 67.14 0.47 2.21 13 t0 44.58 55.42 0.00 0.00 t1 37.73 60.75 0.25 1.28 t2 38.05 61.44 0.52 0.00 14 t0 32.50 66.66 0.60 0.24 t1 30.91 67.77 0.61 0.70 t2 29.14 70.32 0.23 0.31 15 t0 30.07 68.95 0.63 0.35 t1 30.14 68.49 0.62 0.75 t2 31.57 67.55 0.62 0.26 16 t0 30.54 68.61 0.63 0.22 t1 29.81 68.81 0.63 0.75 t2 29.46 69.14 0.59 0.81 Discussion of Block C Results Referring to Table C-1 above, the pH was measured and found to be relatively stable for all of the formulations. However, the initial pH values were slightly higher for the citrate/phosphate formulations. The least stable formulation by SEC analysis appears to be Formulation 1, the one using the Humira® buffer system. By comparison we discovered that formulations using His as the buffer and/or formulations containing Gly or Arg exhibited the greatest stability (See Table C-2). Similar trends are seen when the purity by RP HPLC is considered (See Table C-3). It appears that SEC may be a better stability-indicating method than RP HPLC, although, when taken as a whole, the RP HPLC method does appear to be stability-indicating. Based on the Block C data summarized above, we have discovered that Histidine is suitable as a preferred buffer in terms of formulation stability, and that glycine or arginine, or combinations thereof, are also stability enhancing components for inclusion in an adalimumab formulation. The stored samples were further analyzed by cIEF at t1 and t2 (Table C-4 above). A proprietary adalimumab material exhibit four to five peaks with integrated intensities above 1% or so. In general, there are some small decreases in the intensity of the main peak upon storage. These losses are usually greater at t1 than at t2. Still, no significant new peaks are observed, suggesting that there is minimal chemical degradation occurring that would lead to changes in the overall charge on the protein. The variance in the data indicates that this method, while useful for characterization, does not appear to be stability-indicating. The final analytical method used to evaluate the stability of adalimumab formulation is CE-SDS, which is essentially the CE version of SDS-PAGE slab gels. This method indicates that the relative areas of the LC peak do decrease when stored at elevated temperatures (Table C-5), while the amount of new peaks (cumulatively called ‘Other’) increases. Altogether, these changes are usually less than 2% for any of the formulations. There are some samples where the percentage of ‘Other’ is in the 4-6% range, but these are likely artifacts. Block D Formulation Studies Another set of formulations were evaluated as “Block D.” Sixteen formulations were designed to evaluate other stabilizers as alternatives to mannitol, such as sorbitol and trehalose (See Table D). Block D also examined using mannitol or NaCl as the sole tonicity agent, instead of using a mixture of the two excipients. The pH stability of the formulations was quite good, although the actual initial pH values were slightly lower than the target values for some formulations (Table D-1). TABLE D BLOCK D STUDY DESIGN Form PS No. API citrate phosphate sorbitol trehalose mannitol NaCl 80 1 Adalimumab 8 18 0 0 65 100 0.1 biosimilar 2 Adalimumab 8 18 0 0 65 100 0 biosimilar 3 Adalimumab 20 0 0 0 65 100 0.1 biosimilar 4 Adalimumab 20 0 0 0 65 100 0 biosimilar 5 Adalimumab 0 20 0 0 65 100 0.1 biosimilar 6 Adalimumab 0 20 0 0 65 100 0 biosimilar 7 Adalimumab 8 18 65 0 0 100 0.1 biosimilar 8 Adalimumab 8 18 0 65 0 100 0.1 biosimilar 9 Adalimumab 0 20 65 0 0 100 0.1 biosimilar 10 Adalimumab 0 10 0 0 240 0 0.1 biosimilar 11 Adalimumab 0 10 240 0 0 0 0.1 biosimilar 12 Adalimumab 0 10 0 240 0 0 0.1 biosimilar 13 Adalimumab 10 0 0 0 0 150 0.1 biosimilar 14 Adalimumab 10 0 0 0 0 150 0 biosimilar 15 Adalimumab 0 10 0 0 0 150 0.1 biosimilar 16 Adalimumab 0 10 0 0 0 150 0 biosimilar TABLE D-1 Measured pH for Block D formulations at t0 and t1 (one week, 40° C.) Form PS No. API citrate phosphate sorbitol trehalose mannitol NaCl 80 t0 t1 t2 1 Adalimumab 8 18 0 0 65 100 0.1 5.09 5.17 5.12 biosimilar 2 Adalimumab 8 18 0 0 65 100 0 5.12 5.16 5.16 biosimilar 3 Adalimumab 20 0 0 0 65 100 0.1 5.11 5.16 5.14 biosimilar 4 Adalimumab 20 0 0 0 65 100 0 5.13 5.17 5.18 biosimilar 5 Adalimumab 0 20 0 0 65 100 0.1 5.19 5.25 5.24 biosimilar 6 Adalimumab 0 20 0 0 65 100 0 5.16 5.24 5.17 biosimilar 7 Adalimumab 8 18 65 0 0 100 0.1 5.14 5.17 5.18 biosimilar 8 Adalimumab 8 18 0 65 0 100 0.1 5.15 5.21 5.16 biosimilar 9 Adalimumab 0 20 65 0 0 100 0.1 5.19 5.29 5.28 biosimilar 10 Adalimumab 0 10 0 0 240 0 0.1 5.23 5.28 5.27 biosimilar 11 Adalimumab 0 10 240 0 0 0 0.1 5.45 5.35 5.33 biosimilar 12 Adalimumab 0 10 0 240 0 0 0.1 5.44 5.32 5.31 biosimilar 13 Adalimumab 10 0 0 0 0 150 0.1 5.30 5.25 5.23 biosimilar 14 Adalimumab 10 0 0 0 0 150 0 5.39 5.20 5.18 biosimilar 15 Adalimumab 0 10 0 0 0 150 0.1 5.35 5.30 5.22 biosimilar 16 Adalimumab 0 10 0 0 0 150 0 5.41 5.33 5.28 biosimilar TABLE D-2 Monomer content by SEC for formulations in Block D at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form PS No. API citrate phosphate sorbitol trehalose mannitol NaCl 80 t0 t1 t2 1 Adalimumab 8 18 0 0 65 100 0.1 99.28 98.21 98.96 biosimilar 2 Adalimumab 8 18 0 0 65 100 0 99.25 98.11 98.85 biosimilar 3 Adalimumab 20 0 0 0 65 100 0.1 99.25 98.16 98.86 biosimilar 4 Adalimumab 20 0 0 0 65 100 0 99.27 98.26 98.92 biosimilar 5 Adalimumab 0 20 0 0 65 100 0.1 99.24 98.16 98.84 biosimilar 6 Adalimumab 0 20 0 0 65 100 0 99.21 98.23 98.82 biosimilar 7 Adalimumab 8 18 65 0 0 100 0.1 99.30 98.19 98.94 biosimilar 8 Adalimumab 8 18 0 65 0 100 0.1 99.28 98.14 98.85 biosimilar 9 Adalimumab 0 20 65 0 0 100 0.1 99.29 98.23 98.90 biosimilar 10 Adalimumab 0 10 0 0 240 0 0.1 97.93 98.54 biosimilar 11 Adalimumab 0 10 240 0 0 0 0.1 99.32 98.65 99.00 biosimilar 12 Adalimumab 0 10 0 240 0 0 0.1 99.32 98.53 98.96 biosimilar 13 Adalimumab 10 0 0 0 0 150 0.1 99.29 98.12 98.84 biosimilar 14 Adalimumab 10 0 0 0 0 150 0 99.28 98.28 98.90 biosimilar 15 Adalimumab 0 10 0 0 0 150 0.1 99.26 97.99 98.83 biosimilar 16 Adalimumab 0 10 0 0 0 150 0 99.20 97.76 98.62 biosimilar TABLE D-3 Percent purity by RP HPLC for formulations in Block D at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form PS No. API citrate phosphate sorbitol trehalose mannitol NaCl 80 t0 t1 t2 1 Adalimumab 8 18 0 0 65 100 0.1 98.17 97.75 98.02 biosimilar 2 Adalimumab 8 18 0 0 65 100 0 98.09 97.84 98.08 biosimilar 3 Adalimumab 20 0 0 0 65 100 0.1 98.03 97.81 98.19 biosimilar 4 Adalimumab 20 0 0 0 65 100 0 98.17 97.85 98.06 biosimilar 5 Adalimumab 0 20 0 0 65 100 0.1 98.11 97.88 98.18 biosimilar 6 Adalimumab 0 20 0 0 65 100 0 98.21 97.77 98.10 biosimilar 7 Adalimumab 8 18 65 0 0 100 0.1 98.11 97.80 98.14 biosimilar 8 Adalimumab 8 18 0 65 0 100 0.1 98.06 97.73 98.03 biosimilar 9 Adalimumab 0 20 65 0 0 100 0.1 98.09 97.80 98.07 biosimilar 10 Adalimumab 0 10 0 0 240 0 0.1 98.13 97.82 98.08 biosimilar 11 Adalimumab 0 10 240 0 0 0 0.1 98.10 97.90 98.06 biosimilar 12 Adalimumab 0 10 0 240 0 0 0.1 98.13 97.95 98.14 biosimilar 13 Adalimumab 10 0 0 0 0 150 0.1 98.07 97.79 98.02 biosimilar 14 Adalimumab 10 0 0 0 0 150 0 98.13 97.78 98.14 biosimilar 15 Adalimumab 0 10 0 0 0 150 0.1 98.17 97.80 98.10 biosimilar 16 Adalimumab 0 10 0 0 0 150 0 98.14 97.79 98.06 biosimilar TABLE D-4 Percentage of main bands seen in the cIEF profile of formulations in Block D at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. pH t0 t1 t2 1 8.56 2.26 1.81 8.41 13.84 12.88 11.73 8.25 62.27 59.80 56.15 8.14 6.48 8.04 15.71 22.93 13.73 7.99 5.92 4.39 4.13 2 8.55 2.08 1.58 8.40 12.89 12.58 8.24 60.15 53.24 8.14 5.98 6.69 8.03 11.92 9.72 7.98 3.65 5.67 3 8.57 1.58 2.10 1.89 8.41 11.87 11.83 11.99 8.26 54.93 54.45 54.51 8.16 9.10 6.31 8.24 8.05 9.21 11.16 10.22 7.91 7.60 4.16 5.26 4 8.57 3.57 1.82 1.05 8.40 11.12 10.66 10.83 8.24 49.37 47.85 42.34 8.14 3.01 1.83 3.68 8.03 10.11 10.06 17.12 7.90 2.78 4.72 3.84 5 8.55 2.30 2.18 2.13 8.40 7.63 8.86 8.63 8.25 33.90 14.41 16.64 8.20 23.41 33.90 33.75 8.03 10.14 20.39 19.42 7.99 6.76 5.42 4.63 6 8.59 1.87 1.39 8.42 11.25 11.18 11.89 8.27 50.07 61.72 64.17 8.20 12.43 22.08 19.18 8.03 10.20 7.91 2.70 5.01 3.38 7 8.55 8.40 8.25 8.20 8.03 7.99 8 8.59 1.46 2.64 1.16 8.39 13.52 13.62 7.37 8.22 60.79 50.83 55.40 8.08 5.21 11.28 9.78 8.02 15.24 8.55 11.94 7.91 3.79 3.02 5.18 9 8.53 2.64 3.25 1.94 8.38 13.83 12.72 11.67 8.25 64.97 51.32 54.14 8.17 8.33 11.21 8.61 8.06 11.75 9.98 9.03 8.01 5.79 4.80 7.31 10 8.54 1.78 3.26 8.38 13.04 11.19 8.21 60.53 44.83 8.15 19.60 10.95 7.99 9.41 7.90 5.05 4.27 11 8.52 1.95 2.11 1.89 8.36 11.24 12.43 12.43 8.21 48.64 54.10 59.90 8.13 11.69 6.31 8.00 10.30 21.14 11.14 8.01 5.27 5.64 8.32 12 8.51 1.85 8.29 11.31 11.38 8.18 63.11 45.14 8.14 2.54 8.05 16.16 22.03 7.94 5.03 6.88 13 8.62 3.51 3.05 8.44 12.44 12.30 8.29 65.10 51.44 8.21 12.18 8.06 15.37 17.25 7.91 3.58 3.77 14 8.61 2.74 1.73 8.43 10.60 12.19 8.27 46.23 41.11 8.21 13.97 10.49 8.05 18.56 17.52 7.91 5.15 15 8.62 8.35 12.40 10.91 8.34 8.21 31.87 30.32 36.39 8.20 41.14 25.57 30.62 8.02 12.42 13.72 18.26 7.89 2.18 5.44 3.86 16 8.61 8.48 12.96 12.86 13.19 8.34 34.40 31.45 39.25 8.31 27.74 20.29 18.81 8.05 22.76 19.35 7.89 8.17 7.69 4.83 TABLE D-5 Percentage of bands for light chain (LC), heavy chain (HC), non- glycosylated HC, and other species for formulations in Block D at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. Time LC HC ngHC Other 1 t0 t1 34.11 62.58 0.58 2.73 t2 33.19 64.28 0.60 1.92 2 t0 30.25 66.81 0.64 2.31 t1 30.61 65.79 0.54 3.07 t2 29.22 67.04 0.64 3.10 3 t0 27.48 68.51 0.59 3.42 t1 30.84 67.27 0.54 1.35 t2 30.30 68.13 0.58 0.99 4 t0 30.88 68.33 0.60 0.19 t1 29.76 68.32 0.57 1.34 t2 31.49 66.95 0.55 1.01 5 t0 33.77 64.50 0.56 1.17 t1 31.59 66.54 0.52 1.34 t2 29.19 69.16 0.59 1.06 6 t0 30.90 68.08 0.56 0.47 t1 29.32 69.88 0.54 0.26 t2 31.08 67.58 0.54 0.79 7 t0 30.41 68.60 0.56 0.43 t1 30.87 66.95 0.55 1.63 t2 30.14 68.28 0.55 1.03 8 t0 31.68 67.41 0.60 0.31 t1 t2 9 t0 29.62 68.12 0.51 1.75 t1 t2 29.46 68.10 0.61 1.83 10 t0 29.80 67.99 0.58 1.64 t1 30.04 65.53 0.45 3.98 t2 30.41 66.27 0.53 2.80 11 t0 29.85 67.63 0.61 1.91 t1 29.02 68.18 0.60 2.20 t2 30.44 67.14 0.58 1.84 12 t0 29.38 68.11 0.55 1.96 t1 30.16 65.55 0.49 3.80 t2 28.20 69.19 0.59 2.02 13 t0 31.38 66.28 0.55 1.79 t1 33.67 64.10 0.56 1.67 t2 29.72 67.99 0.58 1.71 14 t0 37.34 60.53 0.52 1.62 t1 33.03 63.46 0.53 2.97 t2 34.39 63.62 0.54 1.45 15 t0 30.20 68.42 0.59 0.79 t1 28.67 69.42 0.58 1.33 t2 29.96 68.24 0.56 1.24 16 t0 31.62 66.95 0.58 0.85 t1 30.48 66.36 0.55 2.61 t2 27.94 70.17 0.60 1.29 Results of Block D The pH stability was quite good for these formulations (Table D-1). Once again, the commercial adalimumab (Humira®) formulation was used as a control (but using a proprietary adalimumab biosimilar protein as the API). The commercial formulation again showed poorer stability by SEC than those using single buffers like phosphate and His (See Table D-2). Of the two buffers used in Humira®, we have now discovered that phosphate is the better stabilizer. This is surprising, as phosphate has virtually no buffer capacity at pH 5.2, while citrate buffers well at this pH. This suggests that the differences in stability profile may be due to direct interaction of the buffer with the protein, a phenomenon that, in the case of the commercial Humira® formulation, we believe was not previously understood or appreciated. Accordingly, the comparative benefit of selecting phosphate as a buffer in an adalimumab formulation, due to superior stability in the formulation versus the selection of a citrate/phosphate combination constitutes one of the important aspects of our invention. Both sorbitol and trehalose display better stability profiles than mannitol when used as the sole tonicity agent in these formulations. It also appears that removal of the polysorbate 80 (PS 80) decreases stability somewhat. The best stability profile by SEC appears to be for Formulations 10 and 11, which contain high concentrations of sorbitol or trehalose in place of mannitol/NaCl (Table D-2). These results indicate to us that removing NaCl from the formulation, or limiting its concentration below certain targeted levels (for example less than about 100 mM), will be beneficial for stability. (We note that mannitol does appear to be a stabilizing ingredient, but at levels preferably above 150.) The RP data indicates that either citrate or phosphate provides better stability than the combination used in Humira® (Table D-3). Again, the avoidance of the citrate/phosphate combination represents an important feature of our invention. It could not have been known or predicted that citrate alone, or phosphate alone would provide better formulation stability than the commercial buffer system comprising a combination of citrate and phosphate. The cIEF analyses were run for Block D samples (Table D-4 above). As before, there is some decrease in the intensity of the main peak, but no new peaks are observed. In some cases, there is some small increase in the intensity of the more acidic peaks. The decreases in the main peak appear to be greater at t1 than at t2, suggesting that degradation at 5° C. would be almost imperceptible. Still, overall it looks like less than 5% (and probably much less than 5%) is degrading as measured by cIEF (Table D-4). Likewise, little degradation is seen by CE-SDS (Table D-5). At most 2 to 4% degradation is seen, but the variability in the method makes it difficult to determine if these are real changes. There does appear to be higher impurity levels (Other) for Formulations 1 and 2 and 10 through 14. Block E Formulation Studies This block of formulations was designed to evaluate the stability of formulations at different pH levels. If a buffer is not specified, acetate buffer (10 mM) was employed (Table E). A secondary objective was to evaluate Gly and Arg at higher concentrations and in combination as alternative stabilizers to mannitol and NaCl. TABLE E BLOCK E STUDY DESIGN Form PS No. API pH citrate phosphate sorbitol Gly Arg mannitol NaCl 80 1 Adalimumab 5.2 8 18 0 0 0 65 100 0.1 biosimilar 2 Adalimumab 3.5 8 18 0 0 0 65 100 0.1 biosimilar 3 Adalimumab 5.2 0 0 0 0 0 65 100 0.1 biosimilar 4 Adalimumab 3.5 0 0 0 0 0 65 100 0.1 biosimilar 5 Adalimumab 3.5 0 0 65 0 0 0 100 0.1 biosimilar 6 Adalimumab 3.5 0 0 0 0 130 0 0 0.1 biosimilar 7 Adalimumab 3.5 0 0 0 0 130 0 0 0 biosimilar 8 Adalimumab 3.5 0 0 0 240 0 0 0 0 biosimilar 9 Adalimumab 5.2 0 0 0 240 0 0 0 0 biosimilar 10 Adalimumab 3.5 0 0 0 100 100 0 0 0 biosimilar 11 Adalimumab 5.2 0 0 0 100 100 0 0 0 biosimilar 12 Adalimumab 3.5 0 0 0 150 50 0 0 0 biosimilar TABLE E-1 Measured pH for Block E formulations at t0 and t1 (one week, 40° C.) Form PS No. pH citrate phosphate sorbitol Gly Arg mannitol NaCl 80 t0 t1 t2 1 5.2 8 18 0 0 0 65 100 0.1 5.15 5.11 5.21 2 3.5 8 18 0 0 0 65 100 0.1 3.36 3.49 3.50 3 5.2 0 0 0 0 0 65 100 0.1 5.13 5.24 5.24 4 3.5 0 0 0 0 0 65 100 0.1 3.31 3.43 3.45 5 3.5 0 0 65 0 0 0 100 0.1 3.30 3.48 3.42 6 3.5 0 0 0 0 130 0 0 0.1 3.24 3.52 3.42 7 3.5 0 0 0 0 130 0 0 0 3.27 3.59 3.48 8 3.5 0 0 0 240 0 0 0 0 3.27 3.33 3.39 9 5.2 0 0 0 240 0 0 0 0 5.05 5.25 5.20 10 3.5 0 0 0 100 100 0 0 0 3.30 3.45 3.41 11 5.2 0 0 0 100 100 0 0 0 5.20 5.38 5.39 12 3.5 0 0 0 150 50 0 0 0 3.24 3.38 3.37 TABLE E-2 Monomer content by SEC for formulations in Block E at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form PS No. pH citrate phosphate sorbitol Gly Arg mannitol NaCl 80 t0 t1 t2 1 5.2 8 18 0 0 0 65 100 0.1 99.23 98.20 98.85 2 3.5 8 18 0 0 0 65 100 0.1 98.82 44.15 86.37 3 5.2 0 0 0 0 0 65 100 0.1 99.30 98.37 99.02 4 3.5 0 0 0 0 0 65 100 0.1 95.85 33.51 76.21 5 3.5 0 0 65 0 0 0 100 0.1 97.37 26.21 77.80 6 3.5 0 0 0 0 130 0 0 0.1 97.79 35.67 65.83 7 3.5 0 0 0 0 130 0 0 0 99.00 55.51 90.60 8 3.5 0 0 0 240 0 0 0 0 99.24 75.60 98.24 9 5.2 0 0 0 240 0 0 0 0 99.08 98.63 99.18 10 3.5 0 0 0 100 100 0 0 0 99.28 51.03 91.66 11 5.2 0 0 0 100 100 0 0 0 99.32 98.54 99.09 12 3.5 0 0 0 150 50 0 0 0 99.29 45.86 93.06 TABLE E-3 Percent purity by RP HPLC for formulations in Block E at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form PS No. pH citrate phosphate sorbitol Gly Arg mannitol NaCl 80 t0 t1 t2 1 5.2 8 18 0 0 0 65 100 0.1 98.58 96.88 96.91 2 3.5 8 18 0 0 0 65 100 0.1 98.51 90.29 95.99 3 5.2 0 0 0 0 0 65 100 0.1 98.50 96.90 96.83 4 3.5 0 0 0 0 0 65 100 0.1 98.56 91.18 95.55 5 3.5 0 0 65 0 0 0 100 0.1 98.45 90.96 95.71 6 3.5 0 0 0 0 130 0 0 0.1 98.71 93.28 95.38 7 3.5 0 0 0 0 130 0 0 0 98.40 90.65 96.54 8 3.5 0 0 0 240 0 0 0 0 98.03 93.94 96.82 9 5.2 0 0 0 240 0 0 0 0 98.23 97.19 97.12 10 3.5 0 0 0 100 100 0 0 0 98.13 91.10 96.67 11 5.2 0 0 0 100 100 0 0 0 98.13 97.17 97.12 12 3.5 0 0 0 150 50 0 0 0 98.07 93.40 96.48 TABLE E-4 Percentage of bands for light chain (LC), heavy chain (HC), non- glycosylated HC, and other species for formulations in Block E at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. Time LC HC ngHC Other 1 t0 29.97 68.80 0.59 0.64 t1 28.49 70.07 0.60 0.81 t2 28.21 70.29 0.59 0.90 2 t0 28.50 68.67 0.52 2.31 t1 29.69 50.92 0.30 19.09 t2 28.76 69.64 0.60 1.00 3 t0 24.30 74.01 0.60 1.09 t1 28.27 69.63 0.60 1.51 t2 28.17 69.89 0.54 1.40 4 t0 29.45 68.73 0.56 1.26 t1 29.52 51.33 0.30 18.86 t2 27.92 65.73 0.52 5.83 5 t0 35.59 63.85 0.56 0.00 t1 32.47 48.72 0.30 18.52 t2 34.98 60.88 0.46 3.68 6 t0 34.33 63.39 0.51 1.77 t1 t2 35.32 61.31 0.45 2.92 7 t0 30.13 68.87 0.60 0.40 t1 28.13 54.79 0.59 16.49 t2 34.39 63.32 0.53 1.76 8 t0 33.27 64.97 0.55 1.21 t1 33.20 52.62 0.33 13.85 t2 33.25 65.26 0.58 0.92 9 t0 32.28 66.34 0.57 0.81 t1 31.81 65.76 0.57 1.86 t2 31.23 66.81 0.57 1.39 10 t0 35.66 63.36 0.43 0.56 t1 24.96 58.61 0.33 16.10 t2 33.44 66.03 0.53 0.00 11 t0 29.75 69.08 0.60 0.57 t1 27.67 70.83 0.61 0.89 t2 28.81 69.86 0.59 0.73 12 t0 30.23 49.07 0.26 20.44 t1 28.14 70.11 0.58 1.18 t2 29.75 69.08 0.60 0.57 TABLE E-5 Percentage of main bands seen in the cIEF profile of formulations in Block E at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C. Form No. pH t0 t1 t2 1 8.56 8.37 12.52 12.65 8.23 51.77 50.04 8.14 8.03 21.54 12.40 7.93 14.17 16.26 2 1.88 1.49 8.37 10.07 17.66 14.15 8.21 37.52 32.26 33.88 8.13 19.03 9.96 8.01 16.57 28.70 7.93 4.12 7.45 4 8.54 1.04 2.67 8.38 10.50 9.32 8.21 68.34 31.91 8.13 28.52 8.02 16.55 10.05 7.88 3.57 8.67 5 6 7 8 9 8.60 1.40 2.60 3.26 8.43 10.04 12.33 12.03 8.26 62.39 63.19 63.89 8.14 8.03 15.00 16.95 16.57 7.88 7.08 4.93 4.25 Results of Block E Studies The pH stability was modest, with increases in pH occurring at t1 for many of the formulations, especially those buffered with acetate at low pH (Table E-1 above). Two of the samples (Formulations 6 and 12) gelled at t1. There were sizable losses in monomer content for the pH3.5 samples (Table E-3), whereas the pH 5.2 samples displayed stability comparable to what was seen in the preceding Blocks. It was also clear that the degradation was much more pronounced at 40 C than at 25, despite being stored for twice the length of time. In fact, Formulation 8 lost less than 1% monomer at t2 (Table E-2). The Gly and Arg formulations all displayed good stability, provided the pH was held 5.2. The data in this block of studies confirm our discovery that glycine or arginine, or a mixture thereof are good stabilizers in an adalimumab formulation. The RP HPLC data shows large decreases in purity, although not nearly as great as for monomer loss by SEC (Table E-3). This suggests that chemical instability is less than physical instability. As with the SEC results, the loss of stability is more pronounced at t1 than at t2. The CE-SDS results show large increases in new peaks, with the Other category increasing to 15-20% for low pH samples at t1 (Table E-4). The most stable formulation by CE-SDS appears to be Formulation 11, which contains both Gly and Arg as the tonicity modifiers/stabilizers. We encountered difficulties running the cIEF for many of the Block E samples. However, given the clearly inferior stability at pH 3.5, it is unlikely that cIEF would provide any new information on those stability profiles. For example, Formulation 4 (pH 3.5) shows a splitting of the main peak at t1. Block F Formulation Studies The Block F studies were intended to investigate the stability for His-containing formulation using either mannitol, Gly or Arg as the sole tonicity modifier (Table F below). It also served as an opportunity to evaluate additives such as EDTA and methionine (Met), which can be effective at slowing oxidation. In addition, one high citrate concentration and one high phosphate concentration formulation were examined. TABLE F BLOCK F STUDY DESIGN Form PS No. API pH citrate phosphate His Gly Arg mannitol NaCl 80 EDTA Met 1 Adalimumab 5.2 8 18 0 0 0 65 100 0.1 0 0 biosimilar 2 Adalimumab 5.2 8 18 0 0 0 65 100 0.1 0.5 0 biosimilar 3 Adalimumab 5.2 0 0 10 0 150 0 0 0 0.1 0 biosimilar 4 Adalimumab 5.2 0 0 10 0 150 0 0 0 0.5 0 biosimilar 5 Adalimumab 5.2 0 0 10 0 0 240 0 0 0 0 biosimilar 6 Adalimumab 5.2 0 0 10 0 0 240 0 0 0 10 biosimilar 7 Adalimumab 5.2 0 0 10 0 0 240 0 0 0 50 biosimilar 8 Adalimumab 5.2 30 0 0 240 0 0 0 0 0 0 biosimilar 9 Adalimumab 5.2 0 30 0 240 0 0 0 0 0 0 biosimilar 10 Adalimumab 5.2 0 0 30 240 0 0 0 0 0 0 biosimilar 11 Adalimumab 5.2 0 0 20 0 25 120 0 0.1 0 0 biosimilar 12 Adalimumab 5.2 0 0 20 0 25 120 0 0.1 0 0 biosimilar TABLE F-1 Measured pH for Block F formulations at t0 and t1 (one week, 40° C.) Form PS No. citrate phosphate His Gly Arg mannitol NaCl 80 EDTA Met t0 t1 t2 1 8 18 0 0 0 65 100 0.1 0 0 4.67 4.88 4.77 2 8 18 0 0 0 65 100 0.1 0.5 0 5.05 5.15 5.20 3 0 0 10 0 150 0 0 0 0.1 0 5.11 5.22 5.27 4 0 0 10 0 150 0 0 0 0.5 0 4.95 5.06 5.15 5 0 0 10 0 0 240 0 0 0 0 5.12 5.25 5.29 6 0 0 10 0 0 240 0 0 0 10 4.45 4.74 4.67 7 0 0 10 0 0 240 0 0 0 50 5.03 5.24 5.24 8 30 0 0 240 0 0 0 0 0 0 5.09 5.18 5.22 9 0 30 0 240 0 0 0 0 0 0 5.13 5.25 5.32 10 0 0 30 240 0 0 0 0 0 0 5.08 5.24 5.24 11 0 0 20 0 25 120 0 0.1 0 0 5.01 5.17 5.18 12 0 0 20 0 25 120 0 0.1 0 0 5.06 5.20 5.19 TABLE F-2 Monomer content by SEC for formulations in Block F at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form PS No. citrate phosphate His Gly Arg mannitol NaCl 80 EDTA Met t0 t1 t2 1 8 18 0 0 0 65 100 0.1 0 0 97.69 94.75 96.06 2 8 18 0 0 0 65 100 0.1 0.5 0 99.25 98.14 98.92 3 0 0 10 0 150 0 0 0 0.1 0 99.30 98.54 99.16 4 0 0 10 0 150 0 0 0 0.5 0 99.28 98.31 99.14 5 0 0 10 0 0 240 0 0 0 0 99.17 98.64 99.14 6 0 0 10 0 0 240 0 0 0 10 99.07 98.50 99.07 7 0 0 10 0 0 240 0 0 0 50 99.29 98.92 99.24 8 30 0 0 240 0 0 0 0 0 0 99.28 98.40 99.04 9 0 30 0 240 0 0 0 0 0 0 99.30 98.50 99.08 10 0 0 30 240 0 0 0 0 0 0 99.31 98.60 99.23 11 0 0 20 0 25 120 0 0.1 0 0 99.27 98.64 99.16 12 0 0 20 0 25 120 0 0.1 0 0 99.29 98.51 99.17 TABLE F-3 Percent purity by RP HPLC for formulations in Block F at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form PS No. citrate phosphate His Gly Arg mannitol NaCl 80 EDTA Met t0 t1 t2 1 8 18 0 0 0 65 100 0.1 0 0 97.47 96.89 97.98 2 8 18 0 0 0 65 100 0.1 0.5 0 97.33 97.02 97.99 3 0 0 10 0 150 0 0 0 0.1 0 97.64 97.14 98.04 4 0 0 10 0 150 0 0 0 0.5 0 97.59 97.00 97.97 5 0 0 10 0 0 240 0 0 0 0 97.11 97.30 98.03 6 0 0 10 0 0 240 0 0 0 10 97.61 97.27 98.03 7 0 0 10 0 0 240 0 0 0 50 97.55 97.37 98.08 8 30 0 0 240 0 0 0 0 0 0 97.48 97.51 98.05 9 0 30 0 240 0 0 0 0 0 0 97.64 97.58 98.03 10 0 0 30 240 0 0 0 0 0 0 97.68 97.41 98.06 11 0 0 20 0 25 120 0 0.1 0 0 97.67 97.18 98.03 12 0 0 20 0 25 120 0 0.1 0 0 97.68 97.33 98.02 TABLE F-4 Percentage of bands for light chain (LC), heavy chain (HC), non- glycosylated HC, and other species for formulations in Block F at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. Time LC HC ngHC Other 1 t0 27.36 71.86 0.60 0.17 t1 t2 25.34 73.18 0.63 0.86 2 t0 27.80 71.07 0.60 0.53 t1 28.29 71.08 0.63 0.00 t2 27.53 70.97 0.64 0.86 3 t0 27.78 70.62 0.65 0.95 t1 28.26 70.85 0.66 0.23 t2 28.26 70.50 0.63 0.61 4 t0 28.20 70.24 0.60 0.96 t1 29.17 69.30 0.74 0.80 t2 29.17 70.27 0.56 0.00 5 t0 27.50 70.74 0.59 1.17 t1 29.56 65.79 0.41 4.24 t2 28.24 69.90 0.58 1.28 6 t0 29.10 68.84 0.54 1.52 t1 28.58 69.18 0.54 1.70 t2 27.47 70.39 0.54 1.60 7 t0 27.87 70.28 0.55 1.30 t1 t2 8 t0 34.72 64.87 0.41 0.00 t1 34.94 64.53 0.53 0.00 t2 33.21 65.76 0.50 0.52 9 t0 31.96 68.04 0 0 t1 48.51 51.49 0 0 t2 33.15 65.82 0.57 0.46 10 t0 27.81 71.27 0.51 0.40 t1 29.59 68.46 0.53 1.43 t2 31.25 67.89 0.50 0.36 11 t0 27.33 70.80 0.61 1.26 t1 26.54 71.00 0.64 1.82 t2 29.46 69.85 0.69 0.00 12 t0 24.18 71.21 0 4.61 t1 t2 28.95 68.98 0.59 1.46 TABLE F-5 Percentage of main bands seen in the cIEF profile of formulations in Block F at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C. Form No. pH t0 t1 t2 1 8.65 2.11 8.31 13.07 11.43 34.17 8.24 64.66 67.99 28.67 8.14 2.29 8.08 16.13 17.73 15.98 7.95 6.14 4.80 2 8.60 1.56 1.93 1.12 8.48 12.95 11.26 11.12 8.24 58.99 55.85 60.37 8.13 20.98 22.43 18.77 7.93 3.56 6.41 6.09 8.60 1.56 1.93 1.12 3 8.56 1.56 1.69 8.34 10.88 12.85 10.83 8.18 66.93 55.35 62.00 8.02 17.28 19.04 20.13 7.89 4.91 11.21 5.35 4 8.58 1.86 1.68 8.45 13.79 10.61 12.84 8.27 65.06 51.89 61.94 8.06 19.29 18.85 25.22 7.96 6.28 4.91 5 8.60 1.35 1.78 1.45 8.45 12.35 13.63 8.59 8.27 60.12 55.07 64.28 8.07 20.50 20.35 19.73 7.94 5.69 9.17 5.95 6 8.55 1.30 1.30 1.08 8.43 13.29 13.26 13.23 8.24 54.83 56.88 61.67 8.08 20.76 19.79 17.19 7.96 9.82 8.76 6.84 7 8.57 1.28 1.41 2.40 8.44 12.08 12.63 13.05 8.27 61.50 55.33 60.70 8.08 17.55 19.48 17.43 7.94 5.93 8.92 4.25 8 8.55 1.32 0.90 8.43 11.51 12.47 10.09 8.24 62.99 54.09 63.81 8.05 15.43 22.71 20.91 7.90 8.75 9.83 5.19 9 8.59 1.35 1.63 8.45 11.59 13.67 11.40 8.28 63.60 52.70 63.11 8.06 17.98 24.08 18.57 7.94 2.28 7.05 5.29 10 8.57 1.56 2.50 2.08 8.45 13.22 11.93 12.90 8.28 61.86 55.12 61.87 8.08 17.87 20.99 18.74 7.97 5.50 4.71 4.41 11 8.59 1.43 1.19 8.45 12.25 11.42 9.85 8.28 58.83 59.88 64.13 8.08 18.18 22.06 17.46 7.97 9.61 5.45 6.97 12 8.56 1.64 1.39 0.94 8.39 15.30 13.07 15.71 8.21 63.76 59.71 62.92 8.02 16.72 20.51 16.60 7.97 2.58 4.21 3.85 Results of Block F In this block of formulations, the pH values were all slightly lower than the target value of pH 5.2 (Table F-1). In addition, the pH does change by about 0.1 units for most of the formulations when measured at t1. These differences were considered when constructing mathematical models of the data, as discussed below. The addition of EDTA does appear to improve stability for the worst formulation (Formulation 1). Whether it increases stability in general was less clear, based on the SEC data (Table F-2). The formulations containing high concentrations of Arg or Gly all performed quite well upon storage (Table F-2). The initial purities by RP HPLC were universally lower than expected for these formulations (Table F-3). Upon storage at t1 and t2, there are some slight differences, with Gly- and Arg-based formulations showing the greatest stability. Based upon the RP HPLC data, EDTA does not appear to be a significant stabilizer (Table F-3). Likewise, the effect of Met appears to be minimal on stability as measured by RP HPLC or SEC, with the exception of the monomer content for the highest Met concentration (Table F-2, Formulation 7). Analysis by CE-SDS indicates that very little degradation occurs upon storage (usually less than 1% increase in ‘Other’) (Table F-4). However, there are some formulations that begin with higher ‘Other’ contents (Formulations 4 through 7, for example). These are all formulations using a high concentration of mannitol (240 mM). The same seems to be true for formulations containing 120 mM mannitol. As for analysis by cIEF, there is little change in the relative intensities of the main peak, at least in a systematic fashion that would allow one to discern stability trends (Table F-5). In general, the changes are smaller at t2 than at t1. Block G Formulation Studies The Block G formulation studies examined a variety of formulations with combinations of Gly and Arg as the primary stabilizers (Table XXXIV). In addition, two other surfactants (Pluronic F-68 and polysorbate 20, PS 20) were evaluated in addition to PS 80. Finally, a range of PS 80 concentrations was evaluated. TABLE G BLOCK G STUDY DESIGN Form No. API citrate phosphate succinate HIS Gly Arg mannitol NaCl F68 PS20 PS80 1 Adalimumab 8 18 0 0 0 0 65 100 0 0 0.1 biosimilar 2 Adalimumab 8 18 0 0 0 0 65 100 0 0.1 0 biosimilar 3 Adalimumab 8 18 0 0 0 0 65 100 0.1 0 0 biosimilar 4 Adalimumab 0 0 0 10 120 120 0 0 0 0 0.1 biosimilar 5 Adalimumab 0 0 0 10 120 120 0 0 0 0 0.05 biosimilar 6 Adalimumab 0 0 0 10 120 120 0 0 0 0 0.01 biosimilar 7 Adalimumab 0 0 0 10 120 120 0 0 0 0.05 0 biosimilar 8 Adalimumab 0 0 0 10 120 120 0 0 0.1 0 0 biosimilar 9 Adalimumab 0 0 10 0 120 120 0 0 0 0 0.05 biosimilar 10 Adalimumab 0 0 20 0 150 100 0 0 0 0.05 0 biosimilar 11 Adalimumab 0 0 0 20 150 100 0 0 0 0 0.01 biosimilar 12 Adalimumab 0 0 0 20 120 120 0 0 0 0.01 0 biosimilar TABLE G-1 Measured pH for Block G formulations at t0, t1 (one week, 40° C.), and t2 (two weeks, 40° C.) Form No. citrate phosphate succinate His Gly Arg mannitol NaCl F68 PS20 PS80 t0 t1 t2 1 8 18 0 0 0 0 65 100 0 0 0.1 5.19 5.38 5.25 2 8 18 0 0 0 0 65 100 0 0.1 0 5.23 5.28 5.24 3 8 18 0 0 0 0 65 100 0.1 0 0 5.22 5.26 5.20 4 0 0 0 10 120 120 0 0 0 0 0.1 5.20 5.33 5.29 5 0 0 0 10 120 120 0 0 0 0 0.05 5.23 5.34 5.29 6 0 0 0 10 120 120 0 0 0 0 0.01 5.19 5.40 5.27 7 0 0 0 10 120 120 0 0 0 0.05 0 5.23 5.39 5.42 8 0 0 0 10 120 120 0 0 0.1 0 0 5.19 5.38 5.41 9 0 0 10 0 120 120 0 0 0 0 0.05 5.19 5.27 5.24 10 0 0 20 0 150 100 0 0 0 0.05 0 5.23 5.28 5.24 11 0 0 0 20 150 100 0 0 0 0 0.01 5.23 5.33 5.27 12 0 0 0 20 120 120 0 0 0 0.01 0 5.22 5.29 5.29 TABLE G-2 Monomer content by SEC for formulations in Block G at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. citrate phosphate succinate His Gly Arg mannitol NaCl F68 PS20 PS80 t0 t1 t2 1 8 18 0 0 0 0 65 100 0 0 0.1 99.17 97.45 98.09 2 8 18 0 0 0 0 65 100 0 0.1 0 99.11 97.78 98.09 3 8 18 0 0 0 0 65 100 0.1 0 0 98.99 97.74 97.92 4 0 0 0 10 120 120 0 0 0 0 0.1 99.12 98.67 98.68 5 0 0 0 10 120 120 0 0 0 0 0.05 99.05 98.57 98.53 6 0 0 0 10 120 120 0 0 0 0 0.01 99.05 98.66 98.70 7 0 0 0 10 120 120 0 0 0 0.05 0 99.04 98.63 98.50 8 0 0 0 10 120 120 0 0 0.1 0 0 99.11 98.64 98.55 9 0 0 10 0 120 120 0 0 0 0 0.05 99.12 98.56 98.98 10 0 0 20 0 150 100 0 0 0 0.05 0 99.10 98.49 98.88 11 0 0 0 20 150 100 0 0 0 0 0.01 99.07 98.76 98.45 12 0 0 0 20 120 120 0 0 0 0.01 0 99.11 98.48 TABLE G-3 Percent purity by RP HPLC for formulations in Block G at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C. Form No. citrate phosphate succinate HIS Gly Arg mannitol NaCl F68 PS20 PS80 t0 t1 t2 1 8 18 0 0 0 0 65 100 0 0 0.1 99.74 99.66 98.93 2 8 18 0 0 0 0 65 100 0 0.1 0 99.59 99.66 98.97 3 8 18 0 0 0 0 65 100 0.1 0 0 99.58 99.60 99.22 4 0 0 0 10 120 120 0 0 0 0 0.1 99.62 99.62 98.99 5 0 0 0 10 120 120 0 0 0 0 0.05 99.70 99.61 99.01 6 0 0 0 10 120 120 0 0 0 0 0.01 99.60 99.66 99.00 7 0 0 0 10 120 120 0 0 0 0.05 0 99.71 99.65 98.99 8 0 0 0 10 120 120 0 0 0.1 0 0 99.70 99.61 99.03 9 0 0 10 0 120 120 0 0 0 0 0.05 99.71 99.60 99.03 10 0 0 20 0 150 100 0 0 0 0.05 0 99.72 99.60 99.02 11 0 0 0 20 150 100 0 0 0 0 0.01 99.72 99.61 99.05 12 0 0 0 20 120 120 0 0 0 0.01 0 99.61 99.04 TABLE G-4 Percentage of bands for light chain (LC), heavy chain (HC), non- glycosylated HC, and other species for formulations in Block G at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. Time LC HC ngHC Other 1 t0 28.55 70.77 0.50 0.17 t1 29.71 69.42 0.57 0.30 t2 30.32 68.80 0.53 0.35 2 t0 37.14 62.38 0.49 0.00 t1 30.31 69.38 0.28 0.03 t2 31.60 67.87 0.53 0.00 3 t0 28.95 70.40 0.65 0.00 t1 28.17 70.26 0.58 0.99 t2 27.32 71.52 0.56 0.59 4 t0 29.56 69.02 0.65 0.77 t1 32.19 66.09 0.53 1.19 t2 31.58 66.03 0.57 1.81 5 t0 36.54 62.48 0.56 0.42 t1 28.77 69.28 0.62 1.33 t2 23.76 74.49 0.60 1.16 6 t0 29.60 68.61 0.58 1.21 t1 30.37 67.42 0.59 1.61 t2 32.27 66.08 0.59 1.06 7 t0 31.90 65.50 0.63 1.97 t1 31.26 66.66 0.56 1.51 t2 31.37 66.64 0.67 1.31 8 t0 31.04 67.38 0.54 1.04 t1 30.34 67.99 0.62 1.05 t2 30.21 67.63 0.68 1.48 9 t0 33.12 65.34 0.61 0.94 t1 34.01 63.97 0.56 1.46 t2 34.47 63.77 0.57 1.19 10 t0 36.78 61.61 0.54 1.07 t1 39.25 58.66 0.53 1.56 t2 32.83 65.42 0.55 1.21 11 t0 36.37 61.97 0.54 1.11 t1 t2 34.97 63.14 0.54 1.36 12 t0 34.26 64.16 0.52 1.05 t1 t2 34.90 63.35 0.56 1.19 TABLE G-5 Percentage of main bands seen in the cIEF profile of formulations in Block G at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C. Form No. pH t0 t1 t2 1 8.53 1.24 1.21 8.36 14.30 12.69 13.67 8.24 64.03 53.50 60.30 8.14 8.01 15.77 9.32 19.12 7.86 3.73 3.35 4.48 2 8.52 1.06 1.37 0.88 8.35 13.10 13.30 12.53 8.16 66.28 59.68 57.99 7.97 17.14 19.60 21.55 7.83 2.42 4.78 4.92 3 8.51 0.65 0.65 1.03 8.34 13.31 14.00 15.31 8.16 65.13 59.04 60.70 8.14 7.98 17.26 18.90 17.56 7.82 2.89 5.68 4.16 4 8.36 1.87 2.43 1.00 8.19 7.74 10.89 11.69 7.99 61.91 54.27 59.10 7.82 20.94 22.72 19.81 7.66 6.35 7.98 6.92 5 8.44 1.79 0.95 071 8.26 13.33 12.85 10.43 8.06 61.67 59.94 60.12 7.88 17.49 21.08 20.82 7.69 4.02 4.50 6.50 6 8.36 1.71 4.76 8.21 12.37 12.93 10.95 8.04 62.53 54.16 56.48 7.87 19.24 26.08 17.97 7.64 4.15 2.07 6.50 7 8.54 0.77 1.19 0.79 8.34 7.15 12.32 13.15 8.17 54.73 42.64 60.58 8.02 22.18 29.90 17.28 7.83 7.12 11.47 4.77 7.69 1.41 2.48 2.11 8 8.55 1.04 2.11 8.39 7.28 10.69 14.82 8.23 64.01 57.42 55.68 8.05 20.81 23.86 23.76 7.96 6.79 5.37 5.74 9 8.54 8.48 10.99 7.91 8.31 53.85 61.43 8.17 31.58 23.83 7.99 8.82 7.85 3.58 3.27 10 8.50 0.95 2.16 8.36 9.10 10.65 15.79 8.18 59.02 55.35 58.56 8.02 23.76 24.79 25.66 7.87 5.63 7.05 11 8.58 2.08 1.68 8.40 9.74 10.05 9.67 8.21 62.70 56.96 57.36 8.05 21.39 24.14 25.18 7.99 5.24 6.77 6.11 12 8.54 1.67 8.37 15.99 8.22 63.18 8.02 15.41 7.82 3.75 TABLE G-6 Block G study design for F/T and agitation studies Form No. API citrate phosphate succinate HIS Gly Arg mannitol NaCl F68 PS20 PS80 1 Adalimumab 8 18 0 0 0 0 65 100 0 0 0.1 biolsimilar 2 Adalimumab 8 18 0 0 0 0 65 100 0 0.1 0 biolsimilar 3 Adalimumab 8 18 0 0 0 0 65 100 0.1 0 0 biolsimilar 4 Adalimumab 0 0 0 10 120 120 0 0 0 0 0.1 biolsimilar 5 Adalimumab 0 0 0 10 120 120 0 0 0 0 0.05 biolsimilar 6 Adalimumab 0 0 0 10 120 120 0 0 0 0 0.01 biolsimilar 7 Adalimumab 0 0 0 10 120 120 0 0 0 0.05 0 biolsimilar 8 Adalimumab 0 0 0 10 120 120 0 0 0.1 0 0 biolsimilar 9 Adalimumab 0 0 10 0 120 120 0 0 0 0 0.05 biolsimilar 10 Adalimumab 0 0 20 0 150 100 0 0 0 0.05 0 biolsimilar 11 Adalimumab 0 0 0 20 150 100 0 0 0 0 0.01 biolsimilar 12 Adalimumab 0 0 0 20 120 120 0 0 0 0.01 0 biolsimilar TABLE G-7 Monomer content by SEC for select formulations in Block G that were untreated (Q, quiescent), underwent 5 F/T cycles or subjected to agitation for 24 hours Form No. citrate phosphate succinate HIS Gly Arg mannitol NaCl F68 PS20 PS80 Q F/T agit 1 8 18 0 0 0 0 65 100 0 0 0.1 99.15 99.03 99.14 4 0 0 0 10 120 120 0 0 0 0 0.1 99.21 99.11 99.18 8 0 0 0 10 120 120 0 0 0.1 0 0 99.18 99.14 99.17 11 0 0 0 20 150 100 0 0 0 0 0.01 99.16 99.09 99.13 12 0 0 0 20 120 120 0 0 0 0.01 0 99.10 TABLE G-8 Percent purity by RP HPLC for select formulations in Block G that were untreated (Q, quiescent), underwent 5 F/T cycles or subjected to agitation for 24 hours Form No. citrate phosphate succinate HIS Gly Arg mannitol NaCl F68 PS20 PS80 Q F/T agit 1 8 18 0 0 0 0 65 100 0 0 0.1 99.60 99.72 99.76 4 0 0 0 10 120 120 0 0 0 0 0.1 99.56 99.70 99.59 8 0 0 0 10 120 120 0 0 0.1 0 0 99.58 99.57 99.73 11 0 0 0 20 150 100 0 0 0 0 0.01 99.72 99.59 99.65 12 0 0 0 20 120 120 0 0 0 0.01 0 99.75 99.56 Results of Block G All of the pH values were close to the target values (Table G-1), with relatively small changes occurring upon storage. There appears to be some preference in terms of polysorbates over F-68 in terms of stability, as measured by SEC (Table G-2). However, the differences are relatively small. It does appear that succinate formulations (Formulations 9 and 10) fared reasonably well as far as monomer content retained. The RP HPLC data are all very close, making any determination of stability differences virtually impossible (Table G-3). These data will only be interpretable when examined in the larger context of all of the blocks of screening studies. The CE-SDS results suggest that PS 20 is the best stabilizer at 0.1% concentration for the Humira® formulation (Formulations 1 through 3) (Table G-4). Otherwise, the differences appear to be too small and variable to make any general conclusions. As seen before, the results for cIEF data are variable enough to make interpretation difficult (Table G-5). It does appear that the changes are smaller in the Gly/Arg formulations than for formulations using other stabilizers, like mannitol. Still, overall, the stability by cIEF looks to be quite good for many of the formulations in this study. Block G (F/T and Agitation) Studies. For a liquid formulation, it is important to evaluate the sensitivity to interfacial stress. Two kinds of stress studies were selected. The first is agitation at 150 rpm on an orbital shaker for 24 hours at 2-8° C. The second is five successive cycles of freezing and thawing (F/T), where this cycle should generate increasing amounts of damage protein, if the protein is sensitive to interfacial damage. Four formulations from Block G were selected for assessment, and they are highlighted in blue bold text Table G-6. Upon repeated F/T cycling, there is a very small decrease in monomer content for all of the formulations tested (Table G-7). Thus, it seems like there is little interfacial sensitivity form this stress and that the presence of PS 80 is not critical for protection. As for agitated samples, the losses are even smaller. The trends in the RP HPLC data are essentially the same (Table G-8). There are little, if any, losses in purity upon exposure to interfacial stress. Block H Formulation Studies The Block H formulations focused on three aspects of the adalimumab formulation: (1) higher protein concentrations, (2) formulations with no buffers present (other than the protein), and (3) the use of various buffer combinations beside citrate-phosphate (See Table H). TABLE H BLOCK H STUDY DESIGN Form No. API protein citrate phosphate succinate HIS ACETATE Gly Arg mannitol NaCl PS80 1 *** 100 8 18 0 0 0 0 0 65 100 0.1 2 *** 100 0 0 0 10 0 120 120 0 0 0.1 3 *** 50 0 0 0 0 0 0 0 65 100 0.1 4 *** 50 0 0 0 0 0 120 120 0 0 0.1 5 *** 50 0 0 0 0 0 120 120 0 0 0 6 *** 50 0 0 0 10 10 0 0 65 100 0.1 7 *** 50 0 0 10 10 0 0 0 65 100 0.1 8 *** 50 0 10 0 10 0 0 0 65 100 0.1 9 *** 50 0 0 10 0 10 0 0 65 100 0.1 10 *** 50 10 0 10 0 0 0 0 65 100 0.1 11 *** 50 10 0 0 10 0 0 0 65 100 0.1 12 *** 50 0 0 10 10 0 120 100 0 0 0.1 *** denotes proprietary adalimumab biosimilar TABLE H-1 Measured pH for Block H formulations at t0, t1 (one week, 40° C.), and t2 (two weeks, 40° C.) Form No. protein Citrate Phosphate Succinate Histidine acetate Gly Arg Mannitol NaCl PS80 t0 t1 t2 1 100 8 18 0 0 0 0 0 65 100 0.1 5.19 5.30 5.29 2 100 0 0 0 10 0 120 120 0 0 0.1 5.20 5.19 5.15 3 50 0 0 0 0 0 0 0 65 100 0.1 5.21 5.23 5.21 4 50 0 0 0 0 0 120 120 0 0 0.1 5.21 5.41 5.46 5 50 0 0 0 0 0 120 120 0 0 0 5.21 5.30 5.39 6 50 0 0 0 10 10 0 0 65 100 0.1 5.20 5.28 5.28 7 50 0 0 10 10 0 0 0 65 100 0.1 5.21 5.24 5.24 8 50 0 10 0 10 0 0 0 65 100 0.1 5.20 5.17 5.16 9 50 0 0 10 0 10 0 0 65 100 0.1 5.21 5.24 5.29 10 50 10 0 10 0 0 0 0 65 100 0.1 5.20 5.24 5.26 11 50 10 0 0 10 0 0 0 65 100 0.1 5.21 5.24 5.26 12 50 0 0 10 10 0 120 100 0 0 0.1 5.21 5.26 5.29 TABLE H-2 Monomer content by SEC for formulations in Block H at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. protein Citrate Phosphate Succinate Histidine acetate Gly Arg mannitol NaCl PS80 t0 t1 t2 1 100 8 18 0 0 0 0 0 65 100 0.1 99.25 98.36 98.42 2 100 0 0 0 10 0 120 120 0 0 0.1 99.19 98.88 98.47 3 50 0 0 0 0 0 0 0 65 100 0.1 99.06 98.81 98.74 4 50 0 0 0 0 0 120 120 0 0 0.1 99.19 99.06 98.99 5 50 0 0 0 0 0 120 120 0 0 0 99.26 99.03 98.96 6 50 0 0 0 10 10 0 0 65 100 0.1 99.26 98.92 98.86 7 50 0 0 10 10 0 0 0 65 100 0.1 99.14 98.98 98.93 8 50 0 10 0 10 0 0 0 65 100 0.1 99.11 98.93 98.66 9 50 0 0 10 0 10 0 0 65 100 0.1 99.16 98.79 98.63 10 50 10 0 10 0 0 0 0 65 100 0.1 99.10 98.79 98.49 11 50 10 0 0 10 0 0 0 65 100 0.1 99.21 98.93 98.18 12 50 0 0 10 10 0 120 100 0 0 0.1 99.30 99.22 98.65 TABLE H-3 Percent purity by RP HPLC for formulations in Block F at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. protein citrate phosphate succinate histidine acetate Gly Arg mannitol NaCl PS80 t0 t1 t2 1 100 8 18 0 0 0 0 0 65 100 0.1 99.36 99.64 99.64 2 100 0 0 0 10 0 120 120 0 0 0.1 99.37 99.68 99.74 3 50 0 0 0 0 0 0 0 65 100 0.1 99.45 99.47 99.70 4 50 0 0 0 0 0 120 120 0 0 0.1 99.50 99.69 99.59 5 50 0 0 0 0 0 120 120 0 0 0 99.47 99.71 99.56 6 50 0 0 0 10 10 0 0 65 100 0.1 99.48 99.56 99.72 7 50 0 0 10 10 0 0 0 65 100 0.1 99.43 99.45 99.72 8 50 0 10 0 10 0 0 0 65 100 0.1 99.43 99.51 99.72 9 50 0 0 10 0 10 0 0 65 100 0.1 99.47 99.55 99.72 10 50 10 0 10 0 0 0 0 65 100 0.1 99.48 99.53 99.67 11 50 10 0 0 10 0 0 0 65 100 0.1 99.45 99.69 99.60 12 50 0 0 10 10 0 120 100 0 0 0.1 99.44 99.54 99.72 TABLE H-4 Percentage of bands for light chain (LC), heavy chain (HC), non- glycosylated HC, and other species for formulations in Block H at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. Time LC HC ngHC Other 1 t0 32.87 65.48 0.54 1.11 t1 28.08 70.09 0.58 1.25 t2 52.57 47.43 0.00 0.00 2 t0 36.20 62.40 0.55 0.86 t1 29.64 68.68 0.57 1.11 t2 43.09 55.23 0.57 1.10 3 t0 34.70 63.55 0.57 1.18 t1 28.24 69.72 0.61 1.57 t2 34.25 63.97 0.67 1.11 4 t0 41.04 57.61 0.51 0.84 t1 27.58 70.65 0.62 1.15 t2 34.14 64.01 0.60 1.26 5 t0 37.64 60.77 0.50 1.09 t1 28.07 70.02 0.61 1.30 t2 37.67 60.76 0.55 1.02 6 t0 31.64 66.46 0.55 1.34 t1 27.67 70.19 0.50 1.64 t2 34.07 63.49 0.62 1.81 7 t0 30.38 69.10 0.53 0.00 t1 27.14 70.55 0.62 1.69 t2 46.41 51.21 0.00 2.38 8 t0 28.46 71.19 0.35 0.00 t1 30.05 68.71 0.55 0.69 t2 34.14 63.97 0.63 1.25 9 t0 27.74 70.63 0.60 1.03 t1 27.48 70.48 0.61 1.43 t2 36.56 61.59 0.49 1.36 10 t0 t1 27.69 70.46 0.60 1.24 t2 11 t0 27.64 70.83 0.57 1.13 t1 31.85 66.08 0.61 1.46 t2 38.58 59.26 0.52 1.64 12 t0 29.48 68.55 0.58 1.40 t1 29.53 68.68 0.58 1.40 t2 30.64 68.20 0.70 0.46 TABLE H-5 Percentage of main bands seen in the cIEF profile of formulations in Block H at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. pH t0 t1 t2 1 8.55 1.20 1.17 1.21 8.39 9.57 5.57 8.23 8.23 46.84 38.18 39.78 7.99 13.67 12.64 11.62 7.81 6.93 4.61 3.70 2 8.43 1.17 1.06 1.38 8.26 8.97 8.15 8.38 8.09 45.46 40.27 39.95 7.87 13.37 16.45 6.77 7.72 5.47 5.39 9.55 7.56 1.64 1.52 3.33 3 8.36 0.80 0.74 0.61 8.16 6.02 6.03 7.30 7.98 35.60 35.58 37.24 7.83 11.75 14.10 13.15 7.64 2.17 4.78 2.00 7.51 1.23 1.81 4 8.40 0.82 0.74 0.30 8.22 7.87 7.38 6.29 8.04 42.46 34.42 35.89 7.89 14.44 13.71 11.34 7.71 3.18 3.31 2.69 7.56 0.98 0.95 5 8.42 0.82 1.02 8.25 7.22 5.09 8.07 34.68 28.99 7.91 2.67 3.63 7.86 10.63 7.83 7.72 2.52 2.05 6 8.42 1.17 1.28 1.22 8.23 9.88 8.56 7.90 8.09 45.26 40.45 40.80 7.94 13.23 16.50 13.28 7 8.59 1.79 1.45 1.90 8.45 11.74 11.32 11.51 8.28 59.90 61.63 56.22 8.05 20.34 19.49 22.98 7.92 6.24 6.11 7.39 8 8.58 1.59 2.94 1.38 8.44 11.86 12.83 12.12 8.26 61.08 60.20 63.05 8.05 20.21 24.03 23.45 7.88 5.25 6.55 9 8.61 1.22 1.42 1.21 8.48 12.47 12.36 11.00 8.33 56.64 54.59 55.34 8.10 23.37 23.81 25.31 7.94 6.30 7.83 Results of Block H The pH stability of these formulations was acceptable (<0.1 units), except for Formulations 4 and 5. These are the buffer-free formulations using Gly and Arg as the stabilizers (Table H-1). There was also a slight rise in pH for Formulation 1 (the Humira® formulation at 100 mg/ml protein concentration). Stability of Block H formulations was monitored using SEC and RP HPLC. There is little loss in monomer content, with Formulation 1 appearing to be the least stable by SEC (Table H-2). At 100 mg/ml of adalimumab biosimilar API the histidine-buffered formulation containing Gly and Arg appears to be quite stable. In general, the best buffer combination appears to be His-succinate (Formulations 7 and 12). Buffer-free formulations with Gly and Arg show acceptable stability as well (Table H-2). The RP HPLC data indicate that the buffer-free formulations (4 and 5) may not do quite as well as shown by SEC (Table H-3), with measurable decreases in purity, but are believed to be satisfactory for obtaining a formulation having long term stability. The CE-SDS data detect the least change in Formulation 12, which is a His-succinate formulation (Table H-4). The largest change at t1 occurs with Formulation 7, which is also a His-succinate formulation, but using mannitol and NaCl as the tonicity modifiers. PLS Modeling PLS Method The data for the adalimumab formulations in Blocks A through H were analyzed together using a chemometric method termed partial least squares (PLS). Detailed descriptions of PLS modeling have been published. See, for example, Katz, M. H. Multivariate Analysis: A Practice Guide for Clinicians. Cambridge University Press, New York, pp. 158-162 (1999); Stahle, L., Wold, K., Multivariate data analysis and experimental design in biomedical research. Prog. Med. Chem. 1988, 25: 291-338; Wold S. PLS-regression: a basic tool of chemometrics. Chemom. Intell. Lab. Syst. 2001, 58: 109-130; and Martens, H.; Martens, M. Multivariate Analysis of Quality: An Introduction, Wiley and Sons, Chichester, UK (2001). For any large matrix of values, where there are a reasonable number of samples (together forming the so-called X-matrix), mathematical models can be constructed that explain the largest amount of variance in the dependent variable(s) of interest (the Y-matrix). The best single description of the relationship between the variation in the X-matrix and the endpoint (the Y matrix) is called the first principal component, PC1. The next important (in terms of describing the variance in the Y-matrix) component is called the second principal component, PC2, and so on. Quite often, only one or two PCs are required to explain most of the variance in the Y-matrix. Each of these PCs contains some contribution from each of the variables in the X-matrix. If a variable within the X-matrix contributes heavily to the construction of a given PC, then it is ranked as being significant. In fact, regression coefficients can be calculated for each variable in the X-matrix for a given model, where a model is the composite of a certain number of PCs in order to provide an adequate description of the Y-matrix. In summary, PLS takes information from the X-matrix, calculates the desired number of PCs, and constructs a suitable model. The model that includes all of the samples is termed a calibration model [1,2]. The overall coefficient of determination (r2) indicates the quality of the model. All PLS calculations were conducted using Unscrambler® software (CAMO, Corvallis, Oreg.). A PLS analysis done with a single variable in the Y-matrix is termed PLS1 analysis. Building a model that fits multiple variables in the Y-matrix is called PLS2 analysis. A full cross validation was performed on all calibration models using standard techniques. Briefly, one sample is removed at a time, the data set is recalibrated, and a new model is constructed. This process is repeated until all of the calibration samples are removed once and quantified as a validation model. Therefore, the first set, containing all samples is referred to as the calibration set and the one after cross-validation as the validation set. The jack-knife algorithm (See, Martens et al) was used to determine statistical significance for any factor used in constructing the PLS models described above. PLS Modeling of Adalimumab Formulations (Blocks B, C and D) See FIGS. 3 Through 12 Note: The PLS surface graphs depicted in FIGS. 3 through 12 are based on the data obtained from Blocks B, C and D. The following is a discussion of the findings reflected in the PLS surface plots shown in FIGS. 3 through 12. PLS Model 1—FIG. 3. FIG. 3 contains a depiction of the monomer content at t1 (model 1) as a function of citrate and phosphate concentrations. The pH has been fixed at 5.2. The model indicated that phosphate and citrate by themselves were weak destabilizers (not to statistical significance), along with tartrate and maleate. By comparison, succinate, which is structurally similar to citrate, tartrate and maleate, was a weak stabilizer. The only buffer found to be a significant stabilizer was histidine. None of these findings could have been predicted based on the literature or examination of the chemical structure of each buffer. The model also indicated that when citrate and phosphate buffer are used together, the formulation is least stable. If one only uses a single buffer, especially phosphate, stability improves. This is surprising, as phosphate has little or no buffer capacity at pH 5.2, while citrate buffer does. None of this behavior could have been predicted based on what was known in the art. PLS Model 2—FIG. 4. FIG. 4 contains a depiction of the monomer content at t2 (model 2). Likewise, a model was constructed using the monomer content by SEC at t2 as the endpoint. This model also demonstrated that the stability is lowest when citrate and phosphate are used together. The lowest stability was shown when citrate is above 10 mM and phosphate is between 5 and 15 mM. Stability improves when the citrate concentration is lowered and/or phosphate concentration is lowered or raised. These findings suggest that a single buffer composition is preferred. The same trend in buffer stabilization is seen as with PLS Model 1, with citrate and phosphate being weak stabilizers (not statistically significant), while histidine is a strong stabilizer (statistically significant). PLS Model 1—FIG. 5. FIG. 5 is a PLS model 1 showing the effect of histidine and glycine on the stability of formulations. It contains a depiction of the monomer content at t1 (model 1). This model indicated that the combination of histidine and glycine yielded very good stability results. Both histidine (His) and glycine (Gly) were determined to be stabilizers. The lowest stability on the response surface (shown in blue) is when there is the lowest concentration of His and Gly. The effect of His on stability is greater, with 20 mM His providing comparable stabilization to 120 mM Gly (note the opposite corners of the graph). The model indicates that there will be an additive benefit to stability by using both excipients, with the highest stability occurring when the His concentration is 20 mM and the Gly concentration is 120 mM. PLS Model 1—FIG. 6. FIG. 6 is a PLS model 1 showing the effect of arginine and sorbitol on the stability of formulations. It contains a depiction of the monomer content at t1 (model 1). This model indicated that arginine was a good stabilizer, while sorbitol was a poor stabilizer. Likewise, arginine (Arg) provides a degree of stabilization that is similar to that found for Gly. The poorest stability as indicated by this model is when the Arg concentration is low and the sorbitol concentration is low (the blue area of the graph). As the concentrations of each excipient are increased, the monomer content at t1 is increased. The effect of sorbitol is roughly linear with concentration, while the effect of Arg appears to be increasing more rapidly once the concentration exceeds 60 mM. Even though sorbitol is predicted to increase the stability of adalimumab in terms of retained monomer content, its ability to increase stability is less than that found for Gly and Arg (on a molar basis). PLS Model 1—FIG. 7. FIG. 7 is a PLS model 1 showing the effect of pH and histidine on the stability of formulations. It contains a depiction of the monomer content at t1 (model 1). This model indicated that histidine appears to be the best buffer, while pH should preferably be at 5 or higher for best stability. PLS Model 2—FIG. 8. FIG. 8 is a PLS model 2 showing the effect of pH and histidine on the stability of formulations. It contains a depiction of the monomer content at t2 (model 2). This model indicated that histidine appears to be the best buffer, while pH should preferably be at 5 or higher for best stability. The results indicate that the optimal pH is near 5.2. Of all of the buffers that were examined, histidine provides the greatest degree of stabilization. This response surface illustrates two important points. First, the stability appears to be maximal near pH 5.2, falling off at a higher and lower pH. Second, histidine is shown to provide a significant increase in stability. When histidine is used at 20 mM, it provides a marked increase in stability over lower buffer concentrations. In fact, the effect appears to be non-linear, with more stabilization occurring from 10 to 20 mM than from 0 to 10 mM. Further, the loss in stability is more abrupt at higher pH than at lower pH. PLS Model 2—FIG. 9. FIG. 9 is a PLS model 2 showing the effect of trehalose and PS80 on the stability of formulations. It contains a depiction of the monomer content at t2. This model indicated that trehalose appears to be a weak stabilizer, while PS80 improves thermal stability. The response surface shown in FIG. 9 indicates that PS 80 is a potent stabilizer for protecting adalimumab against thermal stress, with a concentration of 0.1% providing maximal stability. The concentration of PS 80 has not been varied other than at 0 and 0.1%. By comparison, this model shows that the stabilization effect of trehalose is quite small, certainly less than what was seen with sorbitol. PLS Model 2—FIG. 10. FIG. 10 is a PLS model 2 showing the effect of mannitol and PS80 on the stability of formulations. It contains a depiction of the monomer content at t2 (model 2). This model indicated that mannitol appears to be a destabilizer, while PS80 improves thermal stability. The PLS model using monomer content by SEC at t2 allows one to examine the relative effects of any of the factors included in the model. As the mannitol concentration increases, the overall stability decreases. By comparison, the impact of PS80 on the stability is rather small. PLS Model 1—FIG. 11. FIG. 11 is a PLS model 1 showing the effect of mannitol and NaCl on the stability of formulations. It contains a depiction of the monomer content at t1 (model 1). This model indicated that mannitol and NaCl both appear to be destabilizers. The stability, as indicated by the monomer content at t1, is lowest when the mannitol concentration is anywhere below 150 mM. Likewise, addition of NaCl also diminishes the stability of adalimumab. PLS Model 1—FIG. 12. FIG. 12 is a PLS model 1 showing the effect of EDTA and methionine on the stability of formulations. It contains a depiction of the monomer content at t1. In the case of EDTA, the stability decreases slightly as the concentration of this additive increases. In contrast, addition, of Met appears to improve stability. PLS Modeling of Adalimumab Formulations for Blocks B through G See FIGS. 13 Through 28 The First PLS Model (“PLS Model A) The first PLS model (PLS Model A) used difference in monomer content at t1 as the endpoint. The model employed three PCs and had a correlation coefficient for the calibration set of 0.83 and a r-value of 0.67 for the validation set. It was a quadratic model including pH-buffer and buffer-buffer interaction terms. TABLE J PLS “MODEL A” COEFFICIENTS Factor r-value pH t0 0.041 protein −0.025 citrate +0.123 phos +0.267 succinate −0.089 histidine −0.174 acetate −0.053 glycine −0.190 arginine −0.128 sorbitol −0.003 trehalose +0.020 mannitol −0.104 NaCl +0.250 F68 +0.018 PS 20 +0.021 PS 80 −0.152 EDTA +0.112 Met −0.062 Note: Overall correlation coefficients for each linear factor includes in the first PLS model (PLS Model A) using the difference in monomer content by SEC at t1 as the endpoint. Factors deemed to be statistically significant are highlighted in bold text. The model quality is acceptable, considering the correlation coefficients of the calibration and validation sets. The overall correlation coefficients for the various factors included in the model are summarized in Table J. Note that the quadratic and interaction terms are not listed here. As the endpoint is the difference in monomer content, one wishes to minimize this value. Thus, stabilizers exhibit negative correlation coefficients, while destabilizers have positive r-values. Of the stabilizers, His, Gly, Arg, and PS 80 are the most potent, although mannitol and succinate also have a stabilizing effect (Table J). Meanwhile, there are some significant destabilizers, such as NaCl, citrate, and phosphate. Keep in mind that these models are a composite of all of the stability data gathered across the various blocks of formulations, A through H, and individual formulations could vary from the model. While the table of correlation coefficients is helpful to gauge the effects of various factors, they do not capture the non-linear and interaction effects, so it is helpful to view response surfaces to examine the effects of various parameters in greater detail, as shown in the response surfaces that are reproduced in FIGS. 13 through 28. Discussion of PLS Model A—FIGS. 13 and 14. The Krause '583 patent describes the citrate-phosphate buffer system as being integral to product stability. Our studies show this not to be the case. The poorest stability would occur when these two buffers were used in combination and the effect would get worse as the buffer concentrations increase, according to this model (FIG. 13[1]). The response surface indicates that the phosphate and citrate are equally destabilizing, contrary to some earlier observations, but the quantitative nature of these surfaces must be considered with some care as they include data from all of the formulations from Blocks B through H. The effect of pH and His is shown in FIG. 14. It shows that His is destabilizing at low pH, where it is clearly outside of the buffer capacity of His. Again, this result is a function of all pH observations in this study, not just those involving His (although this could be done). According to this response surface, the optimal pH may be nearer to 5.4 than 5.2, although the surface is relatively flat through this region, indicating a shallow response surface from pH 5 to 5.4 (FIG. 14). Discussion of PLS Model A—FIG. 15 The response surface for Gly and Arg is shown in FIG. 15. The studies repeatedly show that these two amino acids can be potent stabilizers of adalimumab. Note that the minimum difference in monomer content (i.e., the blue part of the surface) is reached at 100 mM Arg, but at 200 mM Gly, suggesting that Arg may be the better stabilizer for adalimumab at pH 5.2. Discussion of PLS Model A—FIG. 16 The final response surface shown for PLS Model A is for the effect of NaCl and PS 80 (FIG. 16). It shows that the stability of adalimumab decreases upon addition of NaCl, especially above 100 mM. Meanwhile, PS 20 provides significant stability when used above 0.04%. The Second PLS Model (PLS Model B) The second PLS model (PLS Model B) used the monomer content at t1 and at t2 as the endpoints. The model employed four PCs and had a correlation coefficient for the calibration set of 0.82 and a r-value of 0.67 for the validation set. It was a quadratic model including pH-buffer and buffer-buffer interaction terms. In terms of model quality, this is comparable to the first PLS Model A described above. TABLE K (L) PLS “MODEL B” CORRELATION COEFFICIENTS Factor r-value pH −0.086 protein +0.030 citrate −0.079 phos −0.157 succinate +0.060 histidine +0.185 acetate +0.063 glycine +0.126 arginine +0.150 sorbitol +0.025 trehalose +0.006 mannitol +0.014 NaCl −0.215 F68 −0.044 PS 20 −0.028 PS 80 +0.227 EDTA −0.097 Met +0.096 The endpoints for PLS Model B are the total monomer contents at both t1 and t2. Therefore, one will wish to maximize these values. This means that stabilizers with have positive correlation coefficients and destabilizers will display negative r-values (Table K). As with the previous model, citrate, phosphate, and NaCl are significant destabilizers. On the other hand, His, Gly Arg, and PS 20 are potent stabilizers. In this model, trehalose, sorbitol and mannitol have very little effect. The primary differences are that pH is now a significant factor and that EDTA is a significant destabilizer, while Met appears to be a stabilizer as well. Discussion of PLS Model B—FIG. 17 This model suggests that addition of citrate has little effect on stability if phosphate is absent (view the back edge of the response surface of FIG. 5). On the other hand, added phosphate does decrease monomer content (view the right hand edge) and the combination is even more destabilizing (FIG. 5). Thus, the citrate-phosphate buffer combination is not effective at stabilizing adalimumab, contrary to what is taught by the '583 patent. The destabilizing effect of phosphate is about three-fold greater than for citrate according to this model. Discussion of PLS Model B—FIG. 18 The use of His at low pH has little or detrimental effects (FIG. 18[6\). However, when employed at pH 5.2 or above, the His provides a significant increase in stability (as measured by monomer content by SEC). Discussion of PLS Model B—FIG. 19 The response surface for Gly and Arg is shown in FIG. 19. Including both stabilizers at high concentrations would be beneficial for stability, but impractical for tonicity reasons. It does appear that Arg is the more potent stabilizer in this model compared to Gly, where a 75 mM concentration of Arg has the same effect as ˜120 mM Gly. The model indicates either one alone would work well, or that a combination would be effective as well. Discussion of PLS Model B—FIG. 20 The PLS model B shows a modest effect of mannitol on stability, whereas PS 80 is an effective stabilizer above concentrations near 0.05% (FIG. 20). Thus, one could conclude from this data that a stable formulation could be comprised of 240 mM mannitol and 0.1% PS 80 at pH 5.2. Discussion of PLS Model B—FIG. 21 Throughout the project, it appears that NaCl is a destabilizer of adalimumab, especially when the concentration reach 100 mM or above, as shown in this response surface (FIG. 21). While only a few formulations were tested that included EDTA, it appears that this excipient is destabilizing, unless the concentration were ˜0.1%. We also note that the effect of Met was favorable with respect to stability, but it did not prove to be a significant effect, probably because relatively few examples were evaluated. Discussion of PLS Model B—FIG. 22 The final response surface from the PLS Model B to be considered is the effect of succinate and His (FIG. 22). The model did include all relevant buffer-buffer interactions. This surface shows that succinate has little or even deleterious effects on its own (see the front edge of the plot). However, in conjunction with His it proves to increase the overall stability (e.g., note that back edge of the surface). Therefore, a His-succinate buffer system appear to be the most favorable of all of the buffer combinations tested to date. The Third PLS Model (PLS Model C) The third PLS model C used the difference in percent purity by RP HPLC at t1 as the endpoint. The model employed two PCs and had a correlation coefficient for the calibration set of 0.86 and a r-value of 0.67 for the validation set. It was a quadratic model including pH-buffer and buffer-buffer interaction terms. In terms of model quality, this is very similar to the previous model. TABLE L PLS “MODEL C” CORRELATION COEFFICIENTS Factor r-value pH −0.115 protein −0.139 citrate +0.014 phosphate +0.084 succinate −0.051 histidine −0.075 acetate +0.159 glycine −0.096 arginine −0.045 sorbitol +0.029 trehalose +0.020 mannitol −0.060 NaCl +0.068 F68 −0.047 PS 20 −0.067 PS 80 −0.028 EDTA +0.099 Met −0.015 PLS Model C demonstrates that RP HPLC is stability-indicating, even though the sensitivity may be less than for SEC. The model finds that both phosphate and citrate are destabilizing, with the effect of phosphate being statistically significant (Table LI). Likewise, acetate is a strong destabilizer as is EDTA. Both Gly and Arg are shown to be stabilizers, but the effects are not deemed to be statistically significant. Only His was found to be a significant stabilizer (along with protein concentration). Discussion of PLS Model C—FIG. 23 The response surface for citrate and phosphate at pH 5.2 is shown in FIG. 23[11]. Both buffers are destabilizing (follow the front and left-hand edges of the plot). Above concentrations of ˜10 mM, the combination becomes quite destabilizing. Overall, phosphate is predicted to be more destabilizing according to this model (FIG. 11). Discussion of PLS Model C—FIG. 24 As seen in previous models, the stability of adalimumab decreases as the pH is reduced to less than 5.0 (FIG. 12). In this model the stabilizing effect of His is seen across all pH values, but is most pronounced when the pH is lower. Discussion of PLS Model C—FIG. 25 The effects of Gly and Arg are seen in FIG. 25. Both excipients decrease loss of purity as the concentration increases and they are predicted to be roughly equipotent, as judged by the slopes along the edges of the response surface. Otherwise, it appears that it takes less Arg (75 mM) to achieve optimal loss of purity (the blue region of the graph) than for Gly (˜200 mM). Discussion of PLS Model C—FIG. 26 The effect of mannitol and PS 80 is seen in the response surface in FIG. 26[14]. It is clear that chemical stability is greatly improved by adding PS 80, especially at concentrations above 0.04%. Meanwhile, mannitol is also stabilizing, but even 240 mM mannitol has less effect than a small about of the surfactant. Discussion of PLS Model C—FIG. 27 While mannitol is believed to be a stabilizer in the Humira® formulation, NaCl is clearly a destabilizer, both in this model (See FIG. 27[15]), and in previous PLS models. The effect is substantial when the NaCl concentration exceeds 75 mM or so. Discussion of PLS Model C—FIG. 28 The final response surface from PLS Model C is seen in FIG. 28[16] describing the effects of pH and protein concentration. As seen before, the stability is best when the pH is above 4.8 or 5.0. As for the protein effect, this model predicts that the stability, based on RP HPLC, is better at higher protein concentrations. A similar trend, albeit a fairly weak one, was seen for the SEC data (monomer content at t1 and t2). Therefore, it may be possible to achieve similar stability profiles at concentrations at 100 mg/ml as one could obtain at 50 mg/ml. Summary of Findings for Blocks A Through H The formulation studies in Blocks A through H evaluated adalimumab formulations stored at elevated temperature and held for either one week at 40° C. or for two weeks at 25° C. The stability was monitored using SEC, RP HPLC, cIEF and CE-SDS. The optimal pH appears to be 5.2±0.2. Of all of the buffer compositions tested, the citrate-phosphate combination is inferior to nearly any other buffer system evaluated, hence an important aspect of the present invention is the avoidance of this combined buffer system altogether. The best single buffer appears to be His, while a His-succinate buffer also offers very good stability. Even buffer-free systems, which rely on the ability of the protein to buffer the formulation, appear to have acceptable stability profiles under accelerated stress conditions. Of all of the stabilizers/tonicity modifiers evaluated, both Arg and Gly elicit very good stabilization of adalimumab. They both work better than mannitol. Mannitol does appear to be a stabilizer, however we have discovered that if used it should be at the highest possible concentrations, but in any event exceeding about 150 mM, ad most preferably at or exceeding about 200 mM. By comparison, NaCl is clearly a destabilizer, especially when the concentrations exceed 75-100 mM; hence, NaCl, if present should be controlled to levels below about 75 mM. Other polyols, such as sorbitol and trehalose, appear to work about as well as mannitol and therefore may be substituted for mannitol if desired. Surprisingly, polysorbate 80 (PS 80) provides significant protection against thermal stress. While the mechanism of stabilization is not known, it appears that other surfactants tested (PS 20 and F-68), do not appear to be nearly as effective as PS 80. Hence the selection of PS80 versus PS 20 is a preferred feature of the present invention. Formulations according to the present invention preferably contain at least 0.04% (w/v) PS 80. Based on the findings in the formulation studies of Blocks A through H, the following are particularly preferred adalimumab formulations according to the present invention. TABLE M SELECTED FORMULATIONS NaCl PS 80 Form No pH His (mM) succinate (mM) Gly (mM) Arg (mM) mannitol (mM) (mM) (wt %) A 5.2 30 0 240 0 0 0 0.1 B 5.2 30 0 240 0 0 0 0.02 C 5.2 30 0 0 0 240 0 0.1 D 5.2 30 15 0 0 220 0 0.1 E 5.2 30 0 90 0 150 0 0.1 F 5.2 30 0 240 0 0 0 0 G 5.2 20 0 0 0 240 0 0 H 5.4 30 0 240 0 0 0 0.02 I 5.2 30 0 120 80 0 0 0.1 J 5.2 30 15 90 80 0 0 0.1 K 5.2 30 0 0 0 240 0 0.1 L 5.2 30 0 0 50 160 0 0.1 M 5.2 30 0 90 100 0 0 0.1 N 5.2 20 0 120 90 0 0 0.1 O 5.4 30 0 120 80 0 0 0.1 P 5.2 30 0 120 0 0 50 0.01 Q 5.2 30 0 0 0 240 0 0.02 Additional Components of the Provided Pharmaceutical Compositions The formulations of the invention may also include other buffers (unless they are specifically excluded in the description of the specific embodiments of the invention), tonicity modifiers, excipients, pharmaceutically acceptable carriers and other commonly used inactive ingredients of the pharmaceutical compositions. A tonicity modifier is a molecule that contributes to the osmolality of a solution. The osmolality of a pharmaceutical composition is preferably adjusted to maximize the active ingredient's stability and/or to minimize discomfort to the patient upon administration. It is generally preferred that a pharmaceutical composition be isotonic with serum, i.e., having the same or similar osmolality, which is achieved by addition of a tonicity modifier. In a preferred embodiment, the osmolality of the provided formulations is from about 180 to about 420 mOsM. However, it is to be understood that the osmolality can be either higher or lower as specific conditions require. Examples of tonicity modifiers suitable for modifying osmolality include, but are not limited to amino acids (not including arginine) (e.g., cysteine, histidine and glycine), salts (e.g., sodium chloride or potassium chloride) and/or sugars/polyols (e.g., sucrose, sorbitol, maltose, and lactose). In a preferred embodiment, the concentration of the tonicity modifier in the formulation is preferably between about 1 mM to about 1 M, more preferably about 10 mM to about 200 mM. Tonicity modifiers are well known in the art and are manufactured by known methods and available from commercial suppliers. Suitable tonicity modifiers may be present in the compositions of the invention unless they are specifically excluded in the description of the specific embodiments of the invention. Excipients, also referred to as chemical additives, co-solutes, or co-solvents, that stabilize the polypeptide while in solution (also in dried or frozen forms) can also be added to a pharmaceutical composition. Excipients are well known in the art and are manufactured by known methods and available from commercial suppliers. Examples of suitable excipients include but are not limited to sugars/polyols such as: sucrose, lactose, glycerol, xylitol, sorbitol, mannitol, maltose, inositol, trehalose, glucose; polymers such as: serum albumin (bovine serum albumin (BSA), human SA or recombinant HA), dextran, PVA, hydroxypropyl methylcellulose (HPMC), polyethyleneimine, gelatin, polyvinylpyrrolidone (PVP), hydroxyethylcellulose (HEC); non-aqueous solvents such as: polyhydric alcohols, (e.g., PEG, ethylene glycol and glycerol) dimethysulfoxide (DMSO) and dimethylformamide (DMF); amino acids such as: proline, L-serine, sodium glutamic acid, alanine, glycine, lysine hydrochloride, sarcosine and gamma-aminobutyric acid; surfactants such as: Tween®-80 (polysorbate 80), Tween®-20 (polysorbate 20), SDS, polysorbates, poloxamers; and miscellaneous excipients such as: potassium phosphate, sodium acetate, ammonium sulfate, magnesium sulfate, sodium sulfate, trimethylamine N-oxide, betaine, CHAPS, monolaurate, 2-O-beta-mannoglycerate or any combination of the above. Suitable excipients may be present in the compositions of the invention unless they are specifically excluded in the description of the specific embodiments of the invention. The concentration of one or more excipients in a formulation of the invention is/are preferably between about 0.001 to 5 weight percent, more preferably about 0.1 to 2 weight percent. Methods of Treatment In another embodiment, the invention provides a method of treating a mammal comprising administering a therapeutically effective amount of the pharmaceutical compositions of the invention to a mammal, wherein the mammal has a disease or disorder that can be beneficially treated with adalimumab. In a preferred embodiment, the mammal is a human. Diseases or disorders that can be treated with the provided compositions include but are not limited to rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Wegener's disease (granulomatosis), Crohn's disease (or inflammatory bowel disease), chronic obstructive pulmonary disease (COPD), Hepatitis C, endometriosis, asthma, cachexia, psoriasis, and atopic dermatitis. Additional diseases or disorders that can be treated with the compositions of the present invention include those described in U.S. Pat. Nos. 6,090,382 and 8,216,583 the relevant portions of which are incorporated herein by reference. The provided pharmaceutical compositions may be administered to a subject in need of treatment by injection systemically, such as by intravenous injection; or by injection or application to the relevant site, such as by direct injection, or direct application to the site when the site is exposed in surgery; or by topical application. In one embodiment, the invention provides a method of treatment and/or prevention of rheumatoid arthritis comprises administering to a mammal in need thereof a therapeutically effective amount of one of the provided adalimumab compositions. The therapeutically effective amount of the adalimumab in the provided compositions will depend on the condition to be treated, the severity of the condition, prior therapy, and the patient's clinical history and response to the therapeutic agent. The proper dose can be adjusted according to the judgment of the attending physician such that it can be administered to the patient one time or over a series of administrations. In one embodiment, the effective adalimumab amount per adult dose is from about 1-500 mg/m2, or from about 1-200 mg/m2, or from about 1-40 mg/m2 or about 5-25 mg/m2. Alternatively, a flat dose may be administered, whose amount may range from 2-500 mg/dose, 2-100 mg/dose or from about 10-80 mg/dose. If the dose is to be administered more than one time per week, an exemplary dose range is the same as the foregoing described dose ranges or lower and preferably administered two or more times per week at a per dose range of 25-100 mg/dose. In another embodiment, an acceptable dose for administration by injection contains 80-100 mg/dose, or alternatively, containing 80 mg per dose. The dose can be administered weekly, biweekly, or separated by several weeks (for example 2 to 8). In one embodiment, adalimumab is administered at 40 mg by a single subcutaneous (SC) injection. In some instances, an improvement in a patient's condition will be obtained by administering a dose of up to about 100 mg of the pharmaceutical composition one to three times per week over a period of at least three weeks. Treatment for longer periods may be necessary to induce the desired degree of improvement. For incurable chronic conditions the regimen may be continued indefinitely. For pediatric patients (ages 4-17), a suitable regimen may involve administering a dose of 0.4 mg/kg to 5 mg/kg of adalimumab, one or more times per week. In another embodiment, the pharmaceutical formulations of the invention may be prepared in a bulk formulation, and as such, the components of the pharmaceutical composition are adjusted to be higher than would be required for administration and diluted appropriately prior to administration. The pharmaceutical compositions can be administered as a sole therapeutic or in combination with additional therapies as needed. Thus, in one embodiment, the provided methods of treatment and/or prevention are used in combination with administering a therapeutically effective amount of another active agent. The other active agent may be administered before, during, or after administering the pharmaceutical compositions of the present invention. Another active agent may be administered either as a part of the provided compositions, or alternatively, as a separate formulation. Administration of the provided pharmaceutical compositions can be achieved in various ways, including parenteral, oral, buccal, nasal, rectal, intraperitoneal, intradermal, transdermal, subcutaneous, intravenous, intra-arterial, intracardiac, intraventricular, intracranial, intratracheal, intrathecal administration, intramuscular injection, intravitreous injection, and topical application. The pharmaceutical compositions of this invention are particularly useful for parenteral administration, i.e., subcutaneously, intramuscularly, intravenously, intraperitoneal, intracerebrospinal, intra-articular, intrasynovial, and/or intrathecal. Parenteral administration can be by bolus injection or continuous infusion. Pharmaceutical compositions for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. In addition, a number of recent drug delivery approaches have been developed and the pharmaceutical compositions of the present invention are suitable for administration using these new methods, e.g., Inject-Ease®, Genject®, injector pens such as GenPen®, and needleless devices such as MediJector® and BioJector®. The present pharmaceutical composition can also be adapted for yet to be discovered administration methods. See also Langer, 1990, Science, 249:1527-1533. The provided pharmaceutical compositions can also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the formulations may be modified with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. The pharmaceutical compositions may, if desired, be presented in a vial, pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. In one embodiment the dispenser device can comprise a syringe having a single dose of the liquid formulation ready for injection. The syringe can be accompanied by instructions for administration. In another embodiment, the present invention is directed to a kit or container, which contains an aqueous pharmaceutical composition of the invention. The concentration of the polypeptide in the aqueous pharmaceutical composition can vary over a wide range, but is generally within the range of from about 0.05 to about 20,000 micrograms per milliliter (μg/ml) of aqueous formulation. The kit can also be accompanied by instructions for use. In addition to the formulations referenced in the formulation studies of Blocks A through H, the following additional examples are provided as further embodiments of the invention, as are the representative embodiments which are included in Appendices A through C which are to be understood as part of this specification. Example 1 Stabilized Adalimumab Formulation (Simile Buffer) Containing Polyol; without Surfactant A stable aqueous pharmaceutical composition containing adalimumab, using a single buffer, and substantially free of a surfactant may be prepared as follows: Each solid formulation component may be weighed to the amount required for a given volume of formulation buffer. These components may then be combined into a beaker or vessel capable of carrying and measuring the given volume of formulation buffer. A volume of deionized water equal to approximately ¾ of the target given formulation buffer may be added to the beaker, and the components may be solubilized through use of a magnetic stir bar. The pH of the buffer may be adjusted to the target formulation pH using 1 molar sodium hydroxide and/or 1 molar hydrogen chloride. The final formulation buffer volume may then be raised to the target volume through the addition of deionized water. The solution may then be mixed with a magnetic stir bar after final water addition. Adalimumab solution may then be placed in dialysis material housing (such as Thermo Scientific Slide-A-Lyzer MINI Dialysis Unit 10,000 MWCO), which may then be placed in contact with the desired formulation buffer for 12 hours at 4° C. Formulation buffer volume to protein solution volume ratio should be no less than 1000:1. The dialysis housing and protein solution it contains may then be placed in a second, equal volume of formulation buffer for an additional 12 hours at 4° C. Resulting adalimumab solution may then be removed from the dialysis material housing, and the concentration of adalimumab may then be determined using ultraviolet spectroscopy. Adalimumab concentration may then be adjusted to the desired level using centrifugation (such as Amicon Ultra 10,000 MWCO Centrifugal Concentrators) and/or dilution with formulation buffer. A sample composition of the invention is represented in Table 1 below: TABLE 1 Ingredient concentration Adalimumab (active ingredient) 50 mg/ml Mannitol (inactive ingredient) 4% Citrate (pH 5.2) (single buffer) 15 mM The composition disclosed in Table 1 does not contain a combination of citrate and phosphate buffer. It also does not require the presence of a surfactant. Example 2 Stabilized Adalimumab Formulation (Single Buffer) without Polyol or Surfactant Ingredient concentration Adalimumab (active ingredient) 50 mg/ml Citrate (pH 5.2) 15 mM Glycine (inactive ingredient) 100 mM Example 3 Stabilized Adalimumab Formulation (Single Buffer) Containing Polyol without Surfactant Ingredient concentration Adalimumab (active ingredient) 50 mg/ml Mannitol (inactive ingredient) 4% Citrate (pH 5.2) 15 mM The compositions of examples 2 and 3 have long term stability and do not contain a combination of citrate and phosphate buffer, and do not require the presence of a surfactant. Example 4 Stabilized Adalimumab Formulation (Simile Buffer) Containing Surfactant; without Polyol 4A Ingredient concentration Adalimumab (active ingredient) 50 mg/ml (No polyol ingredient) — Histidine Buffer (pH 5.2) (sole buffer) 20 mM Glycine (stabilizer) 50 mM Arginine (stabilizer) 130 mM Polysorbate 80 0.1 (wt %) (w/v) 4B Ingredient concentration Adalimumab (active ingredient) 50 mg/ml (No polyol ingredient) — Histidine Buffer (pH 5.2) (sole buffer) 20 mM Glycine (stabilizer) 120 mM Arginine (stabilizer) 100 mM Polysorbate 80 0.1 (wt %) (w/v) 4C Ingredient concentration Adalimumab (active ingredient) 50 mg/ml (No polyol ingredient) — Histidine Buffer (pH 5.2) (sole buffer) 10 mM Glycine (stabilizer) 50 mM Arginine (stabilizer) 130 mM Polysorbate 80 0.1 (wt %) (w/v) 4D Ingredient concentration Adalimumab (active ingredient) 50 mg/ml (No polyol ingredient) — Succinate Buffer (pH 5.2) (sole buffer) 20 mM Glycine (stabilizer) 50 mM Arginine (stabilizer) 130 mM Polysorbate 80 0.1 (wt %) (w/v) 4E Ingredient concentration Adalimumab (active ingredient) 50 mg/ml (No polyol ingredient) — Succinate Buffer (pH 5.2) (sole buffer) 20 mM Glycine (stabilizer) 120 mM Arginine (stabilizer) 100 mM Polysorbate 80 0.1 (wt %) (w/v) 4F Ingredient concentration Adalimumab (active ingredient) 50 mg/ml (No polyol ingredient) — Succinate Buffer (pH 5.2) (sole buffer) 10 mM Glycine (stabilizer) 50 mM Arginine (stabilizer) 130 mM Polysorbate 80 0.1 (wt %) (w/v) The compositions disclosed in Examples 4(a) through 4(f) above will afford stability without need for polyol and without need for a combined buffer system. Insofar as the present invention has discovered that the citrate/phosphate buffer combination required in U.S. Pat. No. 8,216,583 is not required for stabilization of adalimumab formulations according to the present invention, persons skilled in the art may appreciate, in practicing examples 4(a) through 4(f), that additional buffers may be employed in combination with the histidine and succinate buffers disclosed herein (e.g, acetate, citrate, maleate, tartrate, and phosphate buffers); provided the formulation does not use a buffer combination of citrate and phosphate. Example 5 Stabilized Adalimumab Formulation (Simile Buffer) Containing Surfactant; and Polyol 5A Ingredient Concentration Adalimumab (active ingredient) 50 mg/ml Sorbitol 65 mM Histidine Buffer (pH 5.2) (sole buffer) 20 mM Arginine (stabilizer) 130 mM Polysorbate 80 0.1 (wt %) (w/v) 5B Ingredient Concentration Adalimumab (active ingredient) 50 mg/ml Sorbitol 65 mM Succinate Buffer (pH 5.2) (sole buffer) 20 mM Arginine (stabilizer) 130 mM Polysorbate 80 0.1 (wt %) (w/v) The foregoing description of the exemplary embodiments of the invention in the block studies A through H, in the examples above, and in the Appendices A through C, are presented only for the purposes of illustration and description and is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in light of the above teaching. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims. Appendix A Further Representative Embodiments Disclosed in Priority Application U.S. Ser. No. 61/698,138 A. A stable aqueous pharmaceutical composition comprising adalimumab, a polyol, a surfactant, and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 5 to about 6, and wherein said buffer does not comprise both of citrate and phosphate. B. A stable aqueous pharmaceutical composition comprising adalimumab, a polyol, and a surfactant, wherein said composition has a pH of about 5 to about 6, and wherein said composition is substantially free of a buffer. C. The composition of any of embodiments A-B, wherein said adalimumab is at a concentration from about 20 to about 150 mg/ml. D. The composition of any of embodiments A-C, wherein said adalimumab is at a concentration from about 20 to about 100 mg/ml. E. The composition of any of embodiments A-D, wherein said adalimumab is at a concentration from about 30 to about 50 mg/ml. F. The composition of any of embodiments A-E, wherein said buffer is at a concentration from about 5 mM to about 50 mM. G. The composition of any of embodiments A-F, wherein said buffer is at a concentration from about 5 mM to about 20 mM. H. The composition of any of embodiments A-G, wherein said buffer is at a concentration from about 10 mM to about 20 mM. I. The composition of any of embodiments A-G, wherein said surfactant is a polysorbate. J. The composition of embodiment I, wherein said polysorbate is polysorbate 80. K. The composition of any of embodiments A-J, wherein said polyol is a sugar alcohol. L. The composition of embodiment K, wherein said sugar alcohol is selected from the group consisting of mannitol, sorbitol and trehalose. M. The composition of embodiment L, wherein said mannitol is at a concentration from about 1 to 10% weight by volume of the total composition. N. The composition of any of embodiments L-M, wherein said mannitol is at a concentration from about 2 to 6% weight by volume of the total composition. O. The composition of any of embodiments L-N, wherein said mannitol is at a concentration from about 3 to 5% weight by volume of the total composition. P. The composition of any of embodiments A-O further comprising a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. Q. The composition of embodiment P, wherein said amino acid is selected from the group consisting of glycine, alanine, glutamate, arginine and methionine. R. The composition of embodiment P, wherein said salt is selected from the group consisting of sodium chloride and sodium sulfate. S. The composition of embodiment P, wherein said metal ion is selected from zinc, magnesium and calcium. T. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, mannitol at a concentration from about 1 to 10% weight by volume, polysorbate 80 at a concentration from about 1 to 50 μM, and citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of phosphate. U. A stable aqueous pharmaceutical composition comprising adalimumab, a polyol, and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 5 to about 6, and wherein said composition is substantially free of a surfactant. V. The composition of embodiment U, wherein said adalimumab is at a concentration from about 20 and about 150 mg/ml. W. The composition of any of embodiments U-V, wherein said adalimumab is at a concentration from about 20 and about 100 mg/ml. X. The composition of any of embodiments U-V, wherein said adalimumab is at a concentration from about 20 and about 40 mg/ml. Y. The composition of any of embodiments U-Y, wherein said buffer is at a concentration from about 5 mM and about 50 mM. Z. The composition of any of embodiments U-Y, wherein said buffer is at a concentration from about 5 mM and about 20 mM. AA. The composition of any of embodiments U-Z, wherein said buffer is at a concentration from about 10 mM and about 20 mM. BB. The composition of any of embodiments U-AA, wherein said polyol is a sugar alcohol. CC. The composition of embodiment BB, wherein said sugar alcohol is selected from the group consisting of mannitol, sorbitol and trehalose. DD. The composition of embodiment CC, wherein said mannitol is at a concentration from about 1 to 10% weight by volume of the total composition. EE. The composition of any of embodiments CC-DD, wherein said mannitol is at a concentration from about 2 to 6% weight by volume of the total composition. FF. The composition of any of embodiments CC-EE, wherein said mannitol is at a concentration from about 3 to 5% weight by volume of the total composition. GG. The composition of any of embodiments CC-FF further comprising a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. HH. The composition of embodiment GG, wherein said amino acid is selected from the group consisting of glycine, alanine, glutamate, arginine and methionine. II. The composition of embodiment GG, wherein said salt is selected from the group consisting of sodium chloride and sodium sulfate. JJ. The composition of embodiment GG, wherein said metal ion is selected from zinc, magnesium and calcium. KK. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, mannitol at a concentration from about 1 to 10% weight by volume, and citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of a surfactant. LL. A stable aqueous pharmaceutical composition comprising adalimumab, a buffer, a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion, and wherein said composition has a pH of about 5 to about 6, and wherein said composition is substantially free of a polyol. MM. The composition of embodiment LL, wherein said adalimumab is at a concentration from about 20 and about 150 mg/ml. NN. The composition of any of embodiments LL-MM, wherein said adalimumab is at a concentration from about 20 and about 100 mg/ml. OO. The composition of any of embodiments LL-NN, wherein said adalimumab is at a concentration from about 20 and about 40 mg/ml. PP. The composition of any of embodiments LL-00, wherein said buffer is at a concentration from about 5 mM and about 50 mM. QQ. The composition of any of embodiments LL-PP, wherein said buffer is at a concentration from about 5 mM and about 20 mM. RR. The composition of any of embodiments LL-QQ, wherein said buffer is at a concentration from about 10 mM and about 20 mM. SS. The composition of embodiment LL, wherein said stabilizer is selected from the group consisting of an amino acid, a salt, EDTA and a metal ion. TT. The composition of embodiment SS, wherein said amino acid is selected from the group consisting of glycine, alanine and arginine. UU. The composition of embodiment SS wherein said salt is selected from the group consisting of sodium chloride and sodium sulfate. VV. The composition of embodiment TT, wherein said glycine is at a concentration from about 20 to about 200 mM. WW. The composition of embodiment W, wherein said glycine is at a concentration from about 50 to about 200 mM. XX. The composition of embodiment SS, wherein said arginine is at a concentration from about 1 to about 250 mM. YY. The composition of embodiment XX, wherein said arginine is at a concentration from about 20 to about 200 mM. ZZ. The composition of embodiment YY, wherein said arginine is at a concentration from about 20 to about 100 mM. AAA. The composition of embodiment UU, wherein said sodium chloride is at a concentration from about 5 to about 150 mM. BBB. The composition of embodiment AAA, wherein said sodium chloride is at a concentration from about 20 to about 140 mM. CCC. The composition of embodiment BBB, wherein said sodium chloride is at a concentration from about 75 to about 125 mM. DDD. The composition of embodiment UU, wherein said sodium sulfate is at a concentration from about 5 to about 150 mM. EEE. The composition of embodiment UU, wherein said sodium chloride is at a concentration from about 20 to about 120 mM. FFF. The composition of embodiment EEE, wherein said sodium chloride is at a concentration from about 60 to about 100 mM. GGG. The composition of any of embodiments LL-FF further comprising a surfactant. HHH. The composition of embodiment GGG, wherein said surfactant is a polysorbate. III. The composition of embodiment HHH, wherein said polysorbate is polysorbate 80. JJJ. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, glycine at a concentration from about 20 to about 200 mM, citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of a polyol. KKK. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, arginine at a concentration from about 1 to about 250 mM, citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH from about 5 to about 5.5, and wherein said composition is substantially free of a polyol. LLL. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, sodium chloride at a concentration from about 5 to about 150 mM, citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of a polyol. MMM. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, sodium chloride at a concentration from about 5 to about 150 mM, polysorbate 80 at a concentration from about 1 to 50 μM, citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of a polyol. NNN. A stable aqueous pharmaceutical composition comprising adalimumab, a polyol, a surfactant, a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion, and a buffer selected from the group consisting of citrate, phosphate, succinate, tartrate and maleate, wherein said composition has a pH from about 5 to about 6. OOO. The composition of embodiment NNN, wherein the buffer does not comprise a combination of citrate and phosphate. PPP. The composition of embodiment NNN, wherein said adalimumab is at a concentration from about 20 and about 150 mg/ml. QQQ. The composition of any of embodiments NNN-PPP, wherein said adalimumab is at a concentration from about 20 and about 100 mg/ml. RRR. The composition of any of embodiments NNN-QQQ, wherein said adalimumab is at a concentration from about 20 and about 40 mg/ml. SSS. The composition of any of embodiments NNN-RRR, wherein said buffer is at a concentration from about 5 mM and about 50 mM. TTT. The composition of any of embodiments NNN-SSS, wherein said buffer is at a concentration from about 5 mM and about 20 mM. UUU. The composition of any of embodiments NNN-TTT, wherein said buffer is at a concentration from about 10 mM and about 20 mM. VVV. The composition of any of embodiments NNN-UUU, wherein said surfactant is a polysorbate. WWW. The composition of embodiment VVV, wherein said polysorbate is polysorbate 80. XXX. The composition of any of embodiments NNN-WWW, wherein said polyol is a sugar alcohol. YYY. The composition of embodiment XXX, wherein said sugar alcohol is selected from the group consisting of mannitol, sorbitol and trehalose. ZZZ. The composition of embodiment XXX, wherein said mannitol is at a concentration from about 1 to 10% weight by volume of the total composition. AAAA. The composition of any of embodiments XXX-ZZZ, wherein said mannitol is at a concentration from about 2 to 6% weight by volume of the total composition. BBBB. The composition of any of embodiments YYY-AAAA, wherein said mannitol is at a concentration from about 3 to 5% weight by volume of the total composition. CCCC. The composition of any of embodiments NNN-BBBB, wherein said stabilizer is EDTA. DDDD. The composition of embodiment CCCC, wherein said EDTA is at a concentration from about 0.01% to about 0.5%. EEEE. The composition of embodiment DDDD, wherein said EDTA is at a concentration from about 0.05% to about 0.25%. FFFF. The composition of embodiment EEEE, wherein said EDTA is at a concentration from about 0.08% to about 0.2%. GGGG. The composition of any of embodiments NNN-BBBB, wherein said stabilizer is methionine. HHHH. The composition of embodiment GGGG, wherein said methionine is at a concentration from about 1 to about 10 mg/ml. IIII. The composition of embodiment GGGG, wherein said methionine is at a concentration from about 1 to about 5 mg/ml. JJJJ. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to about 50 μM, mannitol at a concentration from about 1 to 10% weight by volume, EDTA at a concentration from about 0.01% to about 0.5%, citrate at a concentration from about 5 mM and about 50 mM, and wherein said composition has a pH of about 5 to about 5.5. KKKK. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to about 50 μM, mannitol at a concentration from about 1 to 10% weight by volume, methionine at a concentration from about 1 to about 10 mg/ml, citrate at a concentration from about 5 mM and about 50 mM, and wherein said composition has a pH of about 5 to about 5.5. LLLL. A stable aqueous pharmaceutical composition comprising adalimumab, a polyol, and a buffer selected from the group consisting of citrate, phosphate, succinate, tartrate and maleate, wherein said composition has a pH of about 3.5. MMMM. The composition of embodiment LLLL, wherein said adalimumab is at a concentration from about 20 and about 150 mg/ml. NNNN. The composition of any of embodiments LLLL-MMMM, wherein said adalimumab is at a concentration from about 20 and about 100 mg/ml. OOOO. The composition of any of embodiments LLLL-NNNN, wherein said adalimumab is at a concentration from about 20 and about 40 mg/ml. PPPP. The composition of any of embodiments LLLL-0000, wherein said buffer is at a concentration from about 5 mM and about 50 mM. QQQQ. The composition of any of embodiments LLLL-PPPP, wherein said buffer is at a concentration from about 5 mM and about 20 mM. RRRR. The composition of any of embodiments LLLL-QQQQ, wherein said buffer is at a concentration from about 10 mM and about 20 mM. SSSS. The composition of any of embodiments LLLL-RRRR, wherein said polyol is a sugar alcohol. TTTT. The composition of embodiment SSSS, wherein said sugar alcohol is selected from the group consisting of mannitol, sorbitol and trehalose. UUUU. The composition of embodiment TTTT, wherein said mannitol is at a concentration from about 1 to about 10% weight by volume of the total composition. VVVV. The composition of any of embodiments TTTT-UUUU, wherein said mannitol is at a concentration from about 2 to about 6% weight by volume of the total composition. WWWW. The composition of any of embodiments TTTT-VVVV, wherein said mannitol is at a concentration from about 3 to about 5% weight by volume of the total composition. XXXX. The composition of any of embodiments LLLL-WWWW further comprising a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. YYYY. The composition of embodiment XXXX, wherein said amino acid is selected from the group consisting of glycine, alanine, glutamate, arginine and methionine. ZZZZ. The composition of embodiment XXXX, wherein said salt is selected from the group consisting of sodium chloride and sodium sulfate. AAAAA. The composition of embodiment XXXX, wherein said metal ion is selected from zinc, magnesium and calcium. BBBBB. The composition of any of embodiments TTTT-AAAAA further comprising a surfactant. CCCCC. The composition of embodiment BBBBB, wherein said surfactant is a polysorbate. DDDDD. The composition of embodiment CCCCC, wherein said polysorbate is polysorbate 80. Appendix B Further Representative Embodiments Disclosed in Priority Application U.S. Ser. No. 61/770,421 A. A stable aqueous pharmaceutical composition comprising adalimumab, a polyol, a surfactant, and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 5 to about 6, and wherein said buffer does not comprise both of citrate and phosphate. B. A stable aqueous pharmaceutical composition comprising adalimumab, a polyol, and a surfactant, wherein said composition has a pH of about 5 to about 6, and wherein said composition is substantially free of a buffer. C. The composition of any of embodiments A-B, wherein said adalimumab is at a concentration from about 20 to about 150 mg/ml. D. The composition of any of embodiments A-C, wherein said adalimumab is at a concentration from about 20 to about 100 mg/ml. E. The composition of any of embodiments A-D, wherein said adalimumab is at a concentration from about 30 to about 50 mg/ml. F. The composition of any of embodiments A-E, wherein said buffer is at a concentration from about 5 mM to about 50 mM. G. The composition of any of embodiments A-F, wherein said buffer is at a concentration from about 5 mM to about 20 mM. H. The composition of any of embodiments A-G, wherein said buffer is at a concentration from about 10 mM to about 20 mM. I. The composition of any of embodiments A-H, wherein said surfactant is a polysorbate. J. The composition of embodiment I, wherein said polysorbate is polysorbate 80. K. The composition of any of embodiments A-J, wherein said polyol is a sugar alcohol. L. The composition of embodiment K, wherein said sugar alcohol is selected from the group consisting of mannitol, sorbitol and trehalose. M. The composition of embodiment L, wherein said mannitol is at a concentration from about 1 to 10% weight by volume of the total composition. N. The composition of any of embodiments L-M, wherein said mannitol is at a concentration from about 2 to 6% weight by volume of the total composition. O. The composition of any of embodiments L-N, wherein said mannitol is at a concentration from about 3 to 5% weight by volume of the total composition. P. The composition of any of embodiments A-O further comprising a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. Q. The composition of embodiment P, wherein said amino acid is selected from the group consisting of glycine, alanine, glutamate, arginine and methionine. R. The composition of embodiment P, wherein said salt is selected from the group consisting of sodium chloride and sodium sulfate. S. The composition of embodiment P, wherein said metal ion is selected from zinc, magnesium and calcium. T. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, mannitol at a concentration from about 1 to 10% weight by volume, polysorbate 80 at a concentration from about 1 to 50 μM, and citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of phosphate. U A stable aqueous pharmaceutical composition comprising adalimumab, a polyol, and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 5 to about 6, and wherein said composition is substantially free of a surfactant. V. The composition of embodiment U, wherein said adalimumab is at a concentration from about 20 and about 150 mg/ml. W. The composition of any of embodiments U-V, wherein said adalimumab is at a concentration from about 20 and about 100 mg/ml. X. The composition of any of embodiments U-W, wherein said adalimumab is at a concentration from about 20 and about 40 mg/ml. Y. The composition of any of embodiments U-X, wherein said buffer is at a concentration from about 5 mM and about 50 mM. Z. The composition of any of embodiments U-Y, wherein said buffer is at a concentration from about 5 mM and about 20 mM. AA. The composition of any of embodiments U-Z, wherein said buffer is at a concentration from about 10 mM and about 20 mM. BB. The composition of any of embodiments U-AA, wherein said polyol is a sugar alcohol. CC. The composition of embodiment BB, wherein said sugar alcohol is selected from the group consisting of mannitol, sorbitol and trehalose. DD. The composition of embodiment CC, wherein said mannitol is at a concentration from about 1 to 10% weight by volume of the total composition. EE. The composition of any of embodiments CC-DD, wherein said mannitol is at a concentration from about 2 to 6% weight by volume of the total composition. FF. The composition of any of embodiments CC-EE, wherein said mannitol is at a concentration from about 3 to 5% weight by volume of the total composition. GG. The composition of any of embodiments U-FF further comprising a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. HH. The composition of embodiment GG, wherein said amino acid is selected from the group consisting of glycine, alanine, glutamate, arginine and methionine. II. The composition of embodiment GG, wherein said salt is selected from the group consisting of sodium chloride and sodium sulfate. JJ. The composition of embodiment GG, wherein said metal ion is selected from zinc, magnesium and calcium. KK. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, mannitol at a concentration from about 1 to 10% weight by volume, and citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of a surfactant. LL. A stable aqueous pharmaceutical composition comprising adalimumab, a buffer, a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion, and wherein said composition has a pH of about 5 to about 6, and wherein said composition is substantially free of a polyol. MM. The composition of embodiment LL, wherein said adalimumab is at a concentration from about 20 and about 150 mg/ml. NN. The composition of any of embodiments LL-MM, wherein said adalimumab is at a concentration from about 20 and about 100 mg/ml. OO. The composition of any of embodiments LL-NN, wherein said adalimumab is at a concentration from about 20 and about 40 mg/ml. PP. The composition of any of embodiments LL-00, wherein said buffer is at a concentration from about 5 mM and about 50 mM. QQ. The composition of any of embodiments LL-PP, wherein said buffer is at a concentration from about 5 mM and about 20 mM. RR. The composition of any of embodiments LL-QQ, wherein said buffer is at a concentration from about 10 mM and about 20 mM. SS. The composition of embodiment LL, wherein said stabilizer is selected from the group consisting of an amino acid, a salt, EDTA and a metal ion. TT. The composition of embodiment TT, wherein said amino acid is selected from the group consisting of glycine, alanine and arginine. UU. The composition of embodiment TT, wherein said salt is selected from the group consisting of sodium chloride and sodium sulfate. VV. The composition of embodiment TT, wherein said glycine is at a concentration from about 20 to about 200 mM. WW. The composition of embodiment W, wherein said glycine is at a concentration from about 50 to about 200 mM. XX. The composition of embodiment TT, wherein said arginine is at a concentration from about 1 to about 250 mM. YY. The composition of embodiment XX, wherein said arginine is at a concentration from about 20 to about 200 mM. ZZ. The composition of embodiment YY, wherein said arginine is at a concentration from about 20 to about 100 mM. AAA. The composition of embodiment UU, wherein said sodium chloride is at a concentration from about 5 to about 150 mM. BBB. The composition of embodiment AAA, wherein said sodium chloride is at a concentration from about 20 to about 140 mM. CCC. The composition of embodiment AAA, wherein said sodium chloride is at a concentration from about 75 to about 125 mM. DDD. The composition of embodiment UU, wherein said sodium sulfate is at a concentration from about 5 to about 150 mM. EEE. The composition of embodiment UU, wherein said sodium chloride is at a concentration from about 20 to about 120 mM. FFF. The composition of embodiment EEE, wherein said sodium chloride is at a concentration from about 60 to about 100 mM. GGG. The composition of any of embodiments LL-FF further comprising a surfactant. HHH. The composition of embodiment GGG, wherein said surfactant is a polysorbate. III. The composition of embodiment HHH, wherein said polysorbate is polysorbate 80. JJJ. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, glycine at a concentration from about 20 to about 200 mM, citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of a polyol. KKK. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, arginine at a concentration from about 1 to about 250 mM, citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH from about 5 to about 5.5, and wherein said composition is substantially free of a polyol. LLL. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, sodium chloride at a concentration from about 5 to about 150 mM, citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of a polyol. MMM. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, sodium chloride at a concentration from about 5 to about 150 mM, polysorbate 80 at a concentration from about 1 to 50 μM, citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of a polyol. NNN. A stable aqueous pharmaceutical composition comprising adalimumab, a polyol, a surfactant, a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion, and a buffer selected from the group consisting of citrate, phosphate, succinate, tartrate and maleate, wherein said composition has a pH from about 5 to about 6. OOO. The composition of embodiment NNN, wherein the buffer does not comprise a combination of citrate and phosphate. PPP. The composition of embodiment NNN, wherein said adalimumab is at a concentration from about 20 and about 150 mg/ml. QQQ. The composition of any of embodiments NNN-PPP, wherein said adalimumab is at a concentration from about 20 and about 100 mg/ml. RRR. The composition of any of embodiments NNN-QQQ, wherein said adalimumab is at a concentration from about 20 and about 40 mg/ml. SSS. The composition of any of embodiments NNN-RRR, wherein said buffer is at a concentration from about 5 mM and about 50 mM. TTT. The composition of any of embodiments NNN-SSS, wherein said buffer is at a concentration from about 5 mM and about 20 mM. UUU. The composition of any of embodiments NNN-TTT, wherein said buffer is at a concentration from about 10 mM and about 20 mM. VVV. The composition of any of embodiments NNN-UUU, wherein said surfactant is a polysorbate. WWW. The composition of embodiment VVV, wherein said polysorbate is polysorbate 80. XXX. The composition of any of embodiments NNN-WWW, wherein said polyol is a sugar alcohol. YYY. The composition of embodiment XXX, wherein said sugar alcohol is selected from the group consisting of mannitol, sorbitol and trehalose. ZZZ. The composition of embodiment YYY, wherein said mannitol is at a concentration from about 1 to 10% weight by volume of the total composition. AAAA. The composition of any of embodiments YYY-ZZZ, wherein said mannitol is at a concentration from about 2 to 6% weight by volume of the total composition. BBBB. The composition of any of embodiments YYY-AAAA, wherein said mannitol is at a concentration from about 3 to 5% weight by volume of the total composition. CCCC. The composition of any of embodiments NNN-BBBB, wherein said stabilizer is EDTA. DDDD. The composition of embodiment CCCC, wherein said EDTA is at a concentration from about 0.01% to about 0.5%. EEEE. The composition of embodiment DDDD, wherein said EDTA is at a concentration from about 0.05% to about 0.25%. FFFF. The composition of embodiment EEEE, wherein said EDTA is at a concentration from about 0.08% to about 0.2%. GGGG. The composition of any of embodiments NNN-BBBB, wherein said stabilizer is methionine. HHHH. The composition of embodiment GGGG, wherein said methionine is at a concentration from about 1 to about 10 mg/ml. IIII. The composition of embodiment GGGG, wherein said methionine is at a concentration from about 1 to about 5 mg/ml. JJJJ. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to about 50 μM, mannitol at a concentration from about 1 to 10% weight by volume, EDTA at a concentration from about 0.01% to about 0.5%, citrate at a concentration from about 5 mM and about 50 mM, and wherein said composition has a pH of about 5 to about 5.5. KKKK. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to about 50 μM, mannitol at a concentration from about 1 to 10% weight by volume, methionine at a concentration from about 1 to about 10 mg/ml, citrate at a concentration from about 5 mM and about 50 mM, and wherein said composition has a pH of about 5 to about 5.5. LLLL. A stable aqueous pharmaceutical composition comprising adalimumab, a polyol, and a buffer selected from the group consisting of citrate, phosphate, succinate, tartrate and maleate, wherein said composition has a pH of about 3.5. MMMM. The composition of embodiment LLLL, wherein said adalimumab is at a concentration from about 20 and about 150 mg/ml. NNNN. The composition of any of embodiments LLLL-MMMM, wherein said adalimumab is at a concentration from about 20 and about 100 mg/ml. OOOO. The composition of any of embodiments LLLL-NNNN, wherein said adalimumab is at a concentration from about 20 and about 40 mg/ml. PPPP. The composition of any of embodiments LLLL-0000, wherein said buffer is at a concentration from about 5 mM and about 50 mM. QQQQ. The composition of any of embodiments LLLL-PPPP, wherein said buffer is at a concentration from about 5 mM and about 20 mM. RRRR. The composition of any of embodiments LLLL-QQQQ, wherein said buffer is at a concentration from about 10 mM and about 20 mM. SSSS. The composition of any of embodiments LLLL-RRRR, wherein said polyol is a sugar alcohol. TTTT. The composition of embodiment SSSS, wherein said sugar alcohol is selected from the group consisting of mannitol, sorbitol and trehalose. UUUU. The composition of embodiment TTTT, wherein said mannitol is at a concentration from about 1 to about 10% weight by volume of the total composition. VVVV. The composition of any of embodiments TTTT-UUUU, wherein said mannitol is at a concentration from about 2 to about 6% weight by volume of the total composition. WWWW. The composition of any of embodiments TTTT-VVVV, wherein said mannitol is at a concentration from about 3 to about 5% weight by volume of the total composition. XXXX. The composition of any of embodiments LLLL-WWWW further comprising a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. YYYY. The composition of embodiment XXXX, wherein said amino acid is selected from the group consisting of glycine, alanine, glutamate, arginine and methionine. ZZZZ. The composition of embodiment XXXX, wherein said salt is selected from the group consisting of sodium chloride and sodium sulfate. AAAAA. The composition of embodiment XXXX, wherein said metal ion is selected from zinc, magnesium and calcium. BBBBB. The composition of any of embodiments LLLL-AAAAA further comprising a surfactant. CCCCC. The composition of embodiment BBBBB, wherein said surfactant is a polysorbate. DDDDD. The composition of embodiment CCCCC, wherein said polysorbate is polysorbate 80. EEEEE. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to about 50 μM; polyol selected from sorbitol, mannitol or trehalose at a concentration from about 1 to about 10% weight by volume, and at least one amino acid stabilizer selected from the group consisting of (a) arginine at a concentration from about 1 to about 250 mg/ml and (b) glycine at a concentration of about 20 to 200 mg/ml, and histidine buffer or succinate buffer at a concentration from about 5 mM and about 50 mM, and wherein said composition has a pH of about 5 to about 5.5. FFFFF. The composition of embodiment EEEEE wherein the polyol is sorbitol, and the composition is free or substantially free of any citrate/phosphate buffer combination, and the formulation comprises arginine or glycine, but not both. GGGGG. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to about 50 μM, arginine at a concentration from about 1 to about 250 mg/ml, glycine at a concentration of about 20 to 200 mg/ml, and histidine buffer or succinate buffer at a concentration from about 5 mM and about 50 mM, and wherein said composition has a pH of about 5 to about 5.5 and said composition is free or substantially free of polyol. HHHHH. The composition of embodiment GGGGG wherein the composition is free or substantially free of any citrate/phosphate buffer combination. Appendix C Further Representative Embodiments Disclosed in Priority Application U.S. Ser. No. 61/769,581 A. A stable aqueous pharmaceutical composition comprising adalimumab and a single buffer. B. The composition of embodiment A, wherein said single buffer is selected from the group consisting of succinate, histidine, citrate, phosphate, tartrate and maleate. C. The composition of any of the preceding embodiments, wherein said composition has a pH of about 5 to about 6. D. The composition of any of the preceding embodiments, wherein said adalimumab contained in said pharmaceutical compositions does not lose more than 20% of its activity relative to activity of the composition at the beginning of storage. E. The composition of any of the preceding embodiments, further comprising a surfactant. F. The composition of embodiment E, wherein said surfactant is a polysorbate. G. The composition of embodiment F wherein said polysorbate is polysorbate 80. H. The composition of any of the preceding embodiments, further comprising a polyol. I. The composition of embodiment H, wherein said polyol is a sugar alcohol. J. The composition of embodiment I, wherein said sugar alcohol is sorbitol. K. The composition of any of the preceding embodiments, further comprising a sugar. L. The composition of embodiment K, wherein said sugar is selected from the group consisting of sucrose and trehalose. M. The composition of any of the preceding embodiments, wherein said adalimumab is at a concentration from about 20 to about 150 mg/ml. N. The composition of any of the preceding embodiments, wherein said buffer is at a concentration from about 5 mM to about 50 mM. O. The composition of any of embodiments A-N further comprising a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. P. The composition of embodiment O, wherein said amino acid is selected from the group consisting of glycine, alanine, glutamate, arginine and methionine. Q. The composition of embodiment 0, wherein said metal ion is selected from zinc, magnesium and calcium. R. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 0.01% w/v to 0.5% w/v by weight of the total formulation, and succinate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of any other buffers. S. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 0.01% w/v to 0.5% w/v by weight of the total formulation, and histidine at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of any other buffers. T. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 0.01% w/v to 0.5% w/v by weight of the total formulation, and tartrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of any other buffers. U. A method of treating a mammal comprising administering to said mammal a therapeutically effective amount of the composition of any of preceding embodiments, wherein said mammal has a disease or disorder that can be beneficially treated with adalimumab. V. The method of embodiment U, wherein said disease or disorder is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Wegener's disease (granulomatosis), Crohn's disease (or inflammatory bowel disease), chronic obstructive pulmonary disease (COPD), Hepatitis C, endometriosis, asthma, cachexia, psoriasis, and atopic dermatitis.
<SOH> BACKGROUND OF THE INVENTION <EOH>Tumor necrosis factor alpha (TNFα) is a naturally occurring mammalian cytokine produced by various cell types, including monocytes and macrophages in response to endotoxin or other stimuli. TNFα is a major mediator of inflammatory, immunological, and pathophysiological reactions (Grell, M., et al. (1995) Cell, 83: 793-802). Soluble TNFα is formed by the cleavage of a precursor transmembrane protein (Kriegler, et al. (1988) Cell 53: 45-53), and the secreted 17 kDa polypeptides assemble to soluble homotrimer complexes (Smith, et al. (1987), J. Biol. Chem. 262: 6951-6954; for reviews of TNF, see Butler, et al. (1986), Nature 320:584; Old (1986), Science 230: 630). These complexes then bind to receptors found on a variety of cells. Binding produces an array of pro-inflammatory effects, including (i) release of other pro-inflammatory cytokines such as interleukin (IL)-6, IL-8, and IL-1, (ii) release of matrix metalloproteinases and (iii) up-regulation of the expression of endothelial adhesion molecules, further amplifying the inflammatory and immune cascade by attracting leukocytes into extravascular tissues. There are many disorders associated with elevated levels of TNFα. For example, TNFα has been shown to be up-regulated in a number of human diseases, including chronic diseases such as rheumatoid arthritis (RA), inflammatory bowel disorders, including Crohn's disease and ulcerative colitis, sepsis, congestive heart failure, asthma bronchiale and multiple sclerosis. TNFα is also referred to as a pro-inflammatory cytokine. Physiologically, TNFα is also associated with protection from particular infections (Cerami. et al. (1988), Immunol. Today 9:28). TNFα is released by macrophages that have been activated by lipopolysaccharides of Gram-negative bacteria. As such, TNFα appears to be an endogenous mediator of central importance involved in the development and pathogenesis of endotoxic shock associated with bacterial sepsis. Adalimumab (Humira®, AbbVie, Inc.) is a recombinant human IgG1 monoclonal antibody specific for human TNF. This antibody is also known as D2E7. Adalimumab consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons. Adalimumab has been described and claimed in U.S. Pat. No. 6,090,382, the disclosure of which is hereby incorporated by reference in its entirety. Adalimumab is usually produced by recombinant DNA technology in a mammalian cell expression system, such as, for example, Chinese Hamster Ovary cells. Adalimumab binds specifically to TNFα and neutralizes the biological function of TNF by blocking its interaction with the p55 and p75 cell surface TNF receptors. Various formulations of adalimumab are known in the art. See, for example, U.S. Pat. Nos. 8,216,583 and 8,420,081. There is still need for stable liquid formulations of adalimumab that allow its long term storage without substantial loss in efficacy.
<SOH> SUMMARY OF THE INVENTION <EOH>The invention provides stable aqueous formulations comprising adalimumab that allow its long term storage. In a first embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab; a stabilizer comprising at least one member selected from the group consisting of a polyol and a surfactant; and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 4 to about 8 and preferably about 5 to about 6, and wherein said buffer does not comprise a combination of citrate and phosphate, and preferably does not comprise any citrate buffer. In this embodiment, the stabilizer preferably comprises both polyol and surfactant. In a second embodiment, utilizing a single buffer system, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a polyol, a surfactant, and a buffer system comprising a single buffering agent, said single buffering agent being selected from citrate, phosphate, succinate, histidine, tartrate or maleate, but not including combinations of the foregoing; wherein the formulation has a pH of about 4 to 8, and preferably about 5 to about 6. Histidine and succinate are particularly preferred for use as single buffering agents. As used herein the term buffer, buffer system, or buffering agent, and like terminology, is intended to denoted buffer components that introduce buffer capacity in the formulation in addition to any buffering capacity offered by the protein itself, hence the term “buffer”, etc, is not intended to include the protein itself as a self buffering entity. In a third embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a stabilizer comprising at least one member selected from a polyol and a surfactant, wherein said composition has a pH of about 4 to about 8, and preferably about 5 to about 6, and wherein said composition is substantially free of a buffer. In a fourth embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a polyol, and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 4 to about 8 and preferably about 5 to about 6, and wherein said composition is free or substantially free of a surfactant. Preferably, the composition (i) does not contain the buffer combination of citrate and phosphate; and (ii) the buffer is at least one member selected from the group consisting of histidine and succinate; and (iii) the polyol is selected from the group consisting of mannitol, sorbitol and trehalose. In a fifth embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a surfactant, and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 4 to 8 and preferably about 5 to about 6, and wherein said composition is substantially free of polyol. Preferably, the composition (i) does not contain the buffer combination of citrate and phosphate; and (ii) the buffer is at least one member selected from the group consisting of histidine and succinate, including combinations thereof. In each of the five embodiments discussed above, the composition may optionally further comprise a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. The amino acid stabilizer may be selected from the group consisting of glycine, alanine, glutamate, arginine and methionine. The salt stabilizer may be selected from the group consisting of sodium chloride and sodium sulfate. The metal ion stabilizer may be selected from the group consisting of zinc, magnesium and calcium. Preferably, adalimumab formulations containing the stabilizers mentioned above also do not contain buffer systems in which phosphate buffer and citrate buffer are present in combination, and, most preferably contains buffer systems free or substantially free of citrate buffer. In particularly preferred embodiments, (i) the optional additional stabilizer present in this embodiment is not sodium chloride, or comprises sodium chloride present in amounts not to exceed about 100 mM, and comprises at least one of arginine and glycine, including combinations of the two amino acids; (ii) the buffer, when present, contains no citrate, or at least no citrate and phosphate combination, but is instead at least one of histidine and succinate, including combinations thereof; and (iii) the stabilizer when it includes a polyol is preferably mannitol in amounts exceeding about 150 mM. In further embodiments the invention is directed to an aqueous, buffered pharmaceutical composition comprising adalimumab and a buffer, wherein (i) the composition is free or substantially free of a buffer combination that comprises both a citrate buffer and a phosphate buffer; and (ii) the composition exhibits long term stability. Another embodiment of the invention concerns an aqueous, buffered pharmaceutical composition exhibiting long term stability, said composition comprising: (i) adalimumab; (ii) a buffer selected from the group consisting of histidine buffer, succinate buffer, and combinations thereof; (iii) a polysorbate or poloxamer surfactant, or combinations thereof; and (iv) one or both of the following: (a) a stabilizer selected from the group consisting of glycine, alanine, glutamate, arginine, methionine, EDTA, sodium chloride, sodium sulfate, metal ions, and combinations thereof; and (b) a polyol selected from sorbitol, mannitol, and trehalose, or combinations thereof. Optionally, the formulation may also include a sugar, such as sucrose. In a further embodiment the invention is an aqueous, buffered pharmaceutical composition comprising adalimumab and a buffer, wherein (i) the composition is free or substantially free of a polyol; and (ii) the composition exhibits long term stability. In still a further embodiment the invention is directed to an aqueous, buffered pharmaceutical composition comprising adalimumab and a buffer, wherein (i) the composition is free or substantially free of surfactant; and (ii) the composition exhibits long term stability. Another embodiment of the inventions concerns an aqueous pharmaceutical composition comprising adalimumab wherein: (i) the composition is free or substantially free of buffer; and (ii) the composition exhibits long term stability. In another embodiment, the adalimumab formulation of the present invention comprises, consists of, or consists essentially of, adalimumab, histidine buffer as the sole buffer in the formulation, glycine (or arginine, or combinations thereof) as the sole stabilizer among the non-surfactant stabilizers referenced earlier, and polysorbate 80. In this formulation, the amount of adalimumab is 20 to 150 mg/ml, the amount of histidine buffer is up to about 50 mM; the amount of glycine is up to about 300 mM; and the amount of polysorbate 80 is in the range of about 0.01 to about 0.2 wt %. Optionally, this formulation may include up to about 100 mM NaCl. The present invention also contemplates modification of this formulation to combine the histidine buffer with one or more of citrate, acetate, phosphate, maleate, tartrate buffers. In yet another embodiment, the adalimumab formulation of the present invention comprises, consists of, or consists essentially of, adalimumab, histidine buffer as the sole buffer, mannitol (or sorbitol or trehelose), and polysorbate 80, and further being free or substantially free of the non-surfactant stabilizers (e.g. glycine, arginine, etc.) referenced above. In this formulation, the amount of adalimumab is 20 to 150 mg/ml; the amount of histidine buffer is up to about 50 mM; the amount of polyol is up to about 300 mM; and the amount of polysorbate 80 is in the range of about 0.01 to about 0.2 wt %. Optionally, this formulation may include up to about 100 mM NaCl. The present invention also contemplates modification of this formulation to combine the histidine buffer with one or more of citrate, acetate, phosphate, maleate, tartrate buffers. In a method aspect, the invention is directed to a method for enhancing long term stability in an aqueous, buffered adalimumab formulation, comprising one or more of the steps of: (a) incorporating histidine buffer, succinate buffer, or a combination thereof, in the formulation based on empirical data indicating that such buffers contribute to the stability of the formulation to a greater extent than other buffers or buffer combinations; or (b) incorporating glycine, arginine or a combination thereof as stabilizers in the formulation, based upon empirical data indicating that such stabilizer contribute to the stability of the formulation to a greater extent than other stabilizers; or (c) substantially excluding the presence of buffer or buffer combinations comprising citrate buffer (especially buffer combinations comprising both citrate and phosphate) based upon empirical data indicating that such buffer or buffer combinations perform poorly in terms of stabilizing the formulation in comparison to other buffers. The method may further comprise the selection of PS 80 as a surfactant based on empirical data indicating that PS 80 imparts better thermal stability to the adalimumab formulation than other surfactants, including PS 20. The method is useful to obtain a formulation of adalimumab that exhibits long term stability comparable to or better than commercially available adalimumab formulations marketed under the trademark Humira®. In a further method aspect, the invention is directed to a method for treating an inflammatory condition in a subject which comprises administering to such subject any of the adalimumab formulation embodiments as described herein. In the foregoing embodiments, where the above referenced stabilizers may be included in the formulations, it is further discovered that satisfactory stabilization can be attained when such stabilizers are used in place of both polyol and surfactant and hence stabilized formulations of the present invention can be free or substantially free of both polyol and surfactant. Accordingly, in a sixth embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, optionally a buffer, a stabilizer selected from the group consisting of an amino acid, a salt, EDTA, and a metal ion, and wherein said composition has a pH of about 4 to about 8, and preferably 5 to about 6, and wherein said composition is either substantially free of both polyol and surfactant. When buffer is present in this embodiment, it is especially preferred that (i) the buffer not include the combination of citrate and phosphate; (ii) the buffer is selected from the group consisting of histidine and succinate; and (iii) the stabilizer does not comprise sodium chloride, but instead is at least one member selected from the group consisting of arginine and glycine. Important aspects of the present invention in certain embodiments include (i) that sorbitol and trehalose are discovered to be significantly better stabilizers of adalimumab formulations than mannitol, unless mannitol is used at concentrations in excess of about 200-300 mM in which case the three are generally equivalent; (ii) arginine and glycine (and combinations) are discovered to be significantly better stabilizers of adalimumab formulations than sodium chloride; and; (iii) when buffers are used in the formulation, it is discovered that the combination of citrate and phosphate is surprisingly significantly poorer in stabilizing adalimumab than other buffers such as succinate, histidine, phosphate and tartrate. The relatively poor performance of the buffer combination of citrate and phosphate is rather unexpected considering the apparent importance attributed to the use of a citrate/phosphate combined buffer in U.S. Pat. No. 8,216,583. To the contrary, we have now found that a phosphate/citrate buffer combination is not an optimal choice for obtaining a stabilized adalimumab formulation, and in fact, an element of our invention is the discovery that this combination should be avoided altogether in favor of other buffer systems. Preferably, a polyol is a sugar alcohol; and even more preferably, the sugar alcohol is selected from the group consisting of mannitol, sorbitol and trehalose. However, as between mannitol and sorbitol, the invention has discovered, as noted above, a distinct stabilization advantage in using sorbitol or trehalose instead of mannitol, unless mannitol is used at concentrations in excess of about 200 mM, in which case mannitol, sorbitol and trehalose are generally equivalent. At concentrations below about 200 mM, mannitol has been found to be a poorer stabilizer than sorbitol or trehalose in an adalimumab formulation. Preferably, a surfactant is a polysorbate or poloxamer; and even more preferably PS 80, PS 40, PS20, Pluronic F-68 and combinations. We have discovered a distinct and surprising thermal stabilization advantage in selecting PS 80 instead of PS-20. These and other aspects will become apparent from the following description of the various embodiments, although variations and modifications therein may be affected without departing from the spirit and scope of the novel concepts of the disclosure. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. Further representative embodiments are set forth in the numerous formulation studies reported in the detailed description, as well as the various embodiments listed in Appendices A, B and C attached hereto and made a part hereof.
A61K3939591
20171005
20180215
72243.0
A61K39395
1
KIM, YUNSOO
Stable Aqueous Formulations of Adalimumab
UNDISCOUNTED
1
CONT-ACCEPTED
A61K
2,017
15,726,215
PENDING
Stable Aqueous Formulations of Adalimumab
The invention provides aqueous pharmaceutical adalimumab compositions suitable for long-term storage of adalimumab, methods of manufacture of these compositions, methods of administration, and kits containing same.
1. A stable aqueous pharmaceutical composition comprising: i) adalimumab; ii) a single buffer; iii) a surfactant; and iv) a sugar, wherein the composition is free of polyol and has a pH of about 5 to about 6. 2. The composition of claim 1, wherein the composition is free of citrate buffer. 3. The composition of claim 2, wherein the single buffer is acetate. 4. The composition of claim 1, wherein the surfactant is polysorbate 80. 5. The composition of claim 1, wherein the sugar is sucrose. 6. The composition of claim 5, wherein the single buffer is acetate and the surfactant is polysorbate 80. 7. The composition of claim 6, wherein the composition is free of sodium chloride. 8. The composition of claim 1, wherein the composition has osmolality of about 180 to 420 mOsM; the composition is suitable for administration to a subject as a single dose; and the dose contains about 40 mg of adalimumab. 9. The composition of claim 8, wherein the single buffer is acetate, the surfactant is polysorbate 80, and the sugar is sucrose.
FIELD OF THE INVENTION The present invention relates to aqueous pharmaceutical compositions suitable for long-term storage of adalimumab (including antibody proteins considered or intended as “biosimilar” or “bio-better” variants of commercially available adalimumab), methods of manufacture of the compositions, methods of their administration, and kits containing the same. BACKGROUND OF THE INVENTION Tumor necrosis factor alpha (TNFα) is a naturally occurring mammalian cytokine produced by various cell types, including monocytes and macrophages in response to endotoxin or other stimuli. TNFα is a major mediator of inflammatory, immunological, and pathophysiological reactions (Grell, M., et al. (1995) Cell, 83: 793-802). Soluble TNFα is formed by the cleavage of a precursor transmembrane protein (Kriegler, et al. (1988) Cell 53: 45-53), and the secreted 17 kDa polypeptides assemble to soluble homotrimer complexes (Smith, et al. (1987), J. Biol. Chem. 262: 6951-6954; for reviews of TNF, see Butler, et al. (1986), Nature 320:584; Old (1986), Science 230: 630). These complexes then bind to receptors found on a variety of cells. Binding produces an array of pro-inflammatory effects, including (i) release of other pro-inflammatory cytokines such as interleukin (IL)-6, IL-8, and IL-1, (ii) release of matrix metalloproteinases and (iii) up-regulation of the expression of endothelial adhesion molecules, further amplifying the inflammatory and immune cascade by attracting leukocytes into extravascular tissues. There are many disorders associated with elevated levels of TNFα. For example, TNFα has been shown to be up-regulated in a number of human diseases, including chronic diseases such as rheumatoid arthritis (RA), inflammatory bowel disorders, including Crohn's disease and ulcerative colitis, sepsis, congestive heart failure, asthma bronchiale and multiple sclerosis. TNFα is also referred to as a pro-inflammatory cytokine. Physiologically, TNFα is also associated with protection from particular infections (Cerami. et al. (1988), Immunol. Today 9:28). TNFα is released by macrophages that have been activated by lipopolysaccharides of Gram-negative bacteria. As such, TNFα appears to be an endogenous mediator of central importance involved in the development and pathogenesis of endotoxic shock associated with bacterial sepsis. Adalimumab (Humira®, AbbVie, Inc.) is a recombinant human IgG1 monoclonal antibody specific for human TNF. This antibody is also known as D2E7. Adalimumab consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons. Adalimumab has been described and claimed in U.S. Pat. No. 6,090,382, the disclosure of which is hereby incorporated by reference in its entirety. Adalimumab is usually produced by recombinant DNA technology in a mammalian cell expression system, such as, for example, Chinese Hamster Ovary cells. Adalimumab binds specifically to TNFα and neutralizes the biological function of TNF by blocking its interaction with the p55 and p75 cell surface TNF receptors. Various formulations of adalimumab are known in the art. See, for example, U.S. Pat. Nos. 8,216,583 and 8,420,081. There is still need for stable liquid formulations of adalimumab that allow its long term storage without substantial loss in efficacy. SUMMARY OF THE INVENTION The invention provides stable aqueous formulations comprising adalimumab that allow its long term storage. In a first embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab; a stabilizer comprising at least one member selected from the group consisting of a polyol and a surfactant; and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 4 to about 8 and preferably about 5 to about 6, and wherein said buffer does not comprise a combination of citrate and phosphate, and preferably does not comprise any citrate buffer. In this embodiment, the stabilizer preferably comprises both polyol and surfactant. In a second embodiment, utilizing a single buffer system, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a polyol, a surfactant, and a buffer system comprising a single buffering agent, said single buffering agent being selected from citrate, phosphate, succinate, histidine, tartrate or maleate, but not including combinations of the foregoing; wherein the formulation has a pH of about 4 to 8, and preferably about 5 to about 6. Histidine and succinate are particularly preferred for use as single buffering agents. As used herein the term buffer, buffer system, or buffering agent, and like terminology, is intended to denoted buffer components that introduce buffer capacity in the formulation in addition to any buffering capacity offered by the protein itself, hence the term “buffer”, etc, is not intended to include the protein itself as a self buffering entity. In a third embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a stabilizer comprising at least one member selected from a polyol and a surfactant, wherein said composition has a pH of about 4 to about 8, and preferably about 5 to about 6, and wherein said composition is substantially free of a buffer. In a fourth embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a polyol, and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 4 to about 8 and preferably about 5 to about 6, and wherein said composition is free or substantially free of a surfactant. Preferably, the composition (i) does not contain the buffer combination of citrate and phosphate; and (ii) the buffer is at least one member selected from the group consisting of histidine and succinate; and (iii) the polyol is selected from the group consisting of mannitol, sorbitol and trehalose. In a fifth embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a surfactant, and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 4 to 8 and preferably about 5 to about 6, and wherein said composition is substantially free of polyol. Preferably, the composition (i) does not contain the buffer combination of citrate and phosphate; and (ii) the buffer is at least one member selected from the group consisting of histidine and succinate, including combinations thereof. In each of the five embodiments discussed above, the composition may optionally further comprise a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. The amino acid stabilizer may be selected from the group consisting of glycine, alanine, glutamate, arginine and methionine. The salt stabilizer may be selected from the group consisting of sodium chloride and sodium sulfate. The metal ion stabilizer may be selected from the group consisting of zinc, magnesium and calcium. Preferably, adalimumab formulations containing the stabilizers mentioned above also do not contain buffer systems in which phosphate buffer and citrate buffer are present in combination, and, most preferably contains buffer systems free or substantially free of citrate buffer. In particularly preferred embodiments, (i) the optional additional stabilizer present in this embodiment is not sodium chloride, or comprises sodium chloride present in amounts not to exceed about 100 mM, and comprises at least one of arginine and glycine, including combinations of the two amino acids; (ii) the buffer, when present, contains no citrate, or at least no citrate and phosphate combination, but is instead at least one of histidine and succinate, including combinations thereof; and (iii) the stabilizer when it includes a polyol is preferably mannitol in amounts exceeding about 150 mM. In further embodiments the invention is directed to an aqueous, buffered pharmaceutical composition comprising adalimumab and a buffer, wherein (i) the composition is free or substantially free of a buffer combination that comprises both a citrate buffer and a phosphate buffer; and (ii) the composition exhibits long term stability. Another embodiment of the invention concerns an aqueous, buffered pharmaceutical composition exhibiting long term stability, said composition comprising: (i) adalimumab; (ii) a buffer selected from the group consisting of histidine buffer, succinate buffer, and combinations thereof; (iii) a polysorbate or poloxamer surfactant, or combinations thereof; and (iv) one or both of the following: (a) a stabilizer selected from the group consisting of glycine, alanine, glutamate, arginine, methionine, EDTA, sodium chloride, sodium sulfate, metal ions, and combinations thereof; and (b) a polyol selected from sorbitol, mannitol, and trehalose, or combinations thereof. Optionally, the formulation may also include a sugar, such as sucrose. In a further embodiment the invention is an aqueous, buffered pharmaceutical composition comprising adalimumab and a buffer, wherein (i) the composition is free or substantially free of a polyol; and (ii) the composition exhibits long term stability. In still a further embodiment the invention is directed to an aqueous, buffered pharmaceutical composition comprising adalimumab and a buffer, wherein (i) the composition is free or substantially free of surfactant; and (ii) the composition exhibits long term stability. Another embodiment of the inventions concerns an aqueous pharmaceutical composition comprising adalimumab wherein: (i) the composition is free or substantially free of buffer; and (ii) the composition exhibits long term stability. In another embodiment, the adalimumab formulation of the present invention comprises, consists of, or consists essentially of, adalimumab, histidine buffer as the sole buffer in the formulation, glycine (or arginine, or combinations thereof) as the sole stabilizer among the non-surfactant stabilizers referenced earlier, and polysorbate 80. In this formulation, the amount of adalimumab is 20 to 150 mg/ml; the amount of histidine buffer is up to about 50 mM; the amount of glycine is up to about 300 mM; and the amount of polysorbate 80 is in the range of about 0.01 to about 0.2 wt %. Optionally, this formulation may include up to about 100 mM NaCl. The present invention also contemplates modification of this formulation to combine the histidine buffer with one or more of citrate, acetate, phosphate, maleate, tartrate buffers. In yet another embodiment, the adalimumab formulation of the present invention comprises, consists of, or consists essentially of, adalimumab, histidine buffer as the sole buffer, mannitol (or sorbitol or trehelose), and polysorbate 80, and further being free or substantially free of the non-surfactant stabilizers (e.g. glycine, arginine, etc.) referenced above. In this formulation, the amount of adalimumab is 20 to 150 mg/ml; the amount of histidine buffer is up to about 50 mM; the amount of polyol is up to about 300 mM; and the amount of polysorbate 80 is in the range of about 0.01 to about 0.2 wt %. Optionally, this formulation may include up to about 100 mM NaCl. The present invention also contemplates modification of this formulation to combine the histidine buffer with one or more of citrate, acetate, phosphate, maleate, tartrate buffers. In a method aspect, the invention is directed to a method for enhancing long term stability in an aqueous, buffered adalimumab formulation, comprising one or more of the steps of: (a) incorporating histidine buffer, succinate buffer, or a combination thereof, in the formulation based on empirical data indicating that such buffers contribute to the stability of the formulation to a greater extent than other buffers or buffer combinations; or (b) incorporating glycine, arginine or a combination thereof as stabilizers in the formulation, based upon empirical data indicating that such stabilizer contribute to the stability of the formulation to a greater extent than other stabilizers; or (c) substantially excluding the presence of buffer or buffer combinations comprising citrate buffer (especially buffer combinations comprising both citrate and phosphate) based upon empirical data indicating that such buffer or buffer combinations perform poorly in terms of stabilizing the formulation in comparison to other buffers. The method may further comprise the selection of PS 80 as a surfactant based on empirical data indicating that PS 80 imparts better thermal stability to the adalimumab formulation than other surfactants, including PS 20. The method is useful to obtain a formulation of adalimumab that exhibits long term stability comparable to or better than commercially available adalimumab formulations marketed under the trademark Humira®. In a further method aspect, the invention is directed to a method for treating an inflammatory condition in a subject which comprises administering to such subject any of the adalimumab formulation embodiments as described herein. In the foregoing embodiments, where the above referenced stabilizers may be included in the formulations, it is further discovered that satisfactory stabilization can be attained when such stabilizers are used in place of both polyol and surfactant and hence stabilized formulations of the present invention can be free or substantially free of both polyol and surfactant. Accordingly, in a sixth embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, optionally a buffer, a stabilizer selected from the group consisting of an amino acid, a salt, EDTA, and a metal ion, and wherein said composition has a pH of about 4 to about 8, and preferably 5 to about 6, and wherein said composition is either substantially free of both polyol and surfactant. When buffer is present in this embodiment, it is especially preferred that (i) the buffer not include the combination of citrate and phosphate; (ii) the buffer is selected from the group consisting of histidine and succinate; and (iii) the stabilizer does not comprise sodium chloride, but instead is at least one member selected from the group consisting of arginine and glycine. Important aspects of the present invention in certain embodiments include (i) that sorbitol and trehalose are discovered to be significantly better stabilizers of adalimumab formulations than mannitol, unless mannitol is used at concentrations in excess of about 200-300 mM in which case the three are generally equivalent; (ii) arginine and glycine (and combinations) are discovered to be significantly better stabilizers of adalimumab formulations than sodium chloride; and; (iii) when buffers are used in the formulation, it is discovered that the combination of citrate and phosphate is surprisingly significantly poorer in stabilizing adalimumab than other buffers such as succinate, histidine, phosphate and tartrate. The relatively poor performance of the buffer combination of citrate and phosphate is rather unexpected considering the apparent importance attributed to the use of a citrate/phosphate combined buffer in U.S. Pat. No. 8,216,583. To the contrary, we have now found that a phosphate/citrate buffer combination is not an optimal choice for obtaining a stabilized adalimumab formulation, and in fact, an element of our invention is the discovery that this combination should be avoided altogether in favor of other buffer systems. Preferably, a polyol is a sugar alcohol; and even more preferably, the sugar alcohol is selected from the group consisting of mannitol, sorbitol and trehalose. However, as between mannitol and sorbitol, the invention has discovered, as noted above, a distinct stabilization advantage in using sorbitol or trehalose instead of mannitol, unless mannitol is used at concentrations in excess of about 200 mM, in which case mannitol, sorbitol and trehalose are generally equivalent. At concentrations below about 200 mM, mannitol has been found to be a poorer stabilizer than sorbitol or trehalose in an adalimumab formulation. Preferably, a surfactant is a polysorbate or poloxamer; and even more preferably PS 80, PS 40, PS20, Pluronic F-68 and combinations. We have discovered a distinct and surprising thermal stabilization advantage in selecting PS 80 instead of PS-20. These and other aspects will become apparent from the following description of the various embodiments, although variations and modifications therein may be affected without departing from the spirit and scope of the novel concepts of the disclosure. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. Further representative embodiments are set forth in the numerous formulation studies reported in the detailed description, as well as the various embodiments listed in Appendices A, B and C attached hereto and made a part hereof. BRIEF DESCRIPTION OF THE DRAWINGS The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. FIG. 1 is a bar chart of stability of various adalimumab formulations as determined by size exclusion chromatography (SEC). FIG. 2 is a bar chart of stability of various adalimumab formulations as determined by reversed phase (RP) high performance liquid chromatography (HPLC). FIG. 3 is a graph of a partial least squares (PLS) model 1 demonstrating effect of citrate/phosphate on stability. FIG. 4 is a graph of a PLS model 2 demonstrating effect of citrate/phosphate on stability. FIG. 5 is a graph of a PLS model 1 demonstrating effect of histidine/glycine on stability. FIG. 6 is a graph of a PLS model 1 demonstrating effect of arginine/sorbitol on stability. FIG. 7 is a graph of a PLS model 1 demonstrating effect of pH/histidine on stability. FIG. 8 is a graph of a PLS model 2 demonstrating effect of pH/histidine on stability. FIG. 9 is a graph of a PLS model 2 demonstrating effect of trehalose/PS80 on stability. FIG. 10 is a graph of a PLS model 2 demonstrating effect of mannitol/PS80 on stability. FIG. 11 is a graph of a PLS model 1 demonstrating effect of mannitol/NaCl on stability. FIG. 12 is a graph of a PLS model 1 demonstrating effect of EDTA/methionine on stability. FIG. 13 is a graph of a PLS model A demonstrating effect of citrate and phosphate on stability. FIG. 14 is a graph of a PLS model A demonstrating effect of pH and histidine buffer on stability. FIG. 15 is a graph of a PLS model A demonstrating effect of glycine and arginine on stability. FIG. 16 is a graph of a PLS model A demonstrating effect of NaCl and polysorbate 80 (PS 80) on stability. FIG. 17 is a graph of a PLS model B demonstrating effect of citrate and phosphate on stability. FIG. 18 is a graph of a PLS model B demonstrating effect of pH and histidine buffer on stability. FIG. 19 is a graph of a PLS model B demonstrating effect arginine and glycine on stability. FIG. 20 is a graph of a PLS model B demonstrating effect of PS80 and mannitol on stability. FIG. 21 is a graph of a PLS model B demonstrating effect of EDTA and NaCl on stability. FIG. 22 is a graph of a PLS model B demonstrating effect of succinate buffer and histidine buffer on stability. FIG. 23 is a graph of a PLS model C demonstrating effect of citrate and phosphate on stability. FIG. 24 is a graph of a PLS model C demonstrating effect of pH and histidine buffer on stability. FIG. 25 is a graph of a PLS model C demonstrating effect of arginine and glycine on stability. FIG. 26 is a graph of a PLS model C demonstrating effect of mannitol and PS 80 on stability. FIG. 27 is a graph of a PLS model C demonstrating effect of PS 80 and NaCl on stability. FIG. 28 is a graph of a PLS model C demonstrating effect of pH and protein concentration on stability. DETAILED DESCRIPTION OF THE INVENTION Various embodiments of the invention are now described in detail. As used in the description and throughout the claims, the meaning of “a”, “an”, and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description and throughout the claims, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise. Additionally, some terms used in this specification are more specifically defined below. Definitions The terms used in this specification generally have their ordinary meanings in the art, within the context of the invention, and in the specific context where each term is used. Certain terms that are used to describe the invention are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the invention. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and in no way limits the scope and meaning of the invention or of any exemplified term. The invention is not limited to the various embodiments given in this specification. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In the case of conflict, the present document, including definitions will control. “Around,” “about” or “approximately” shall generally mean within 20 percent, within 10 percent, within 5, 4, 3, 2 or 1 percent of a given value or range. Numerical quantities given are approximate, meaning that the term “around,” “about” or “approximately” can be inferred if not expressly stated. The term “adalimumab” is synonymous with the active pharmaceutical ingredient in Humira® as well as protein considered or intended as biosimilar or bio-better variants thereof. Adalimumab is a recombinant human IgG1 monoclonal antibody specific for human TNF. Adalimumab is also known as D2E7. Adalimumab has two light chains, each with a molecular weight of approximately 24 kilodaltons (kDa) and two IgG1 heavy chains each with a molecular weight of approximately 49 kDa. Each light chain consists of 214 amino acid residues and each heavy chain consists of 451 amino acid residues. Thus, adalimumab consists of 1330 amino acids and has a total molecular weight of approximately 148 kDa. The term adalimumab is also intended to encompass so-called bio-similar or bio-better variants of the adalimumab protein used in commercially available Humira®. For example, a variant of commercial Humira® may be acceptable to the FDA when it has essentially the same pharmacological effects as commercially available Humira®, even though it may exhibit certain physical properties, such as glycosylation profile, that may be similar if not identical to Humira®. For the purposes of the present application, the term “adalimumab” also encompasses adalimumab with minor modifications in the amino acid structure (including deletions, additions, and/or substitutions of amino acids) or in the glycosylation properties, which do not significantly affect the function of the polypeptide. The term “adalimumab” encompasses all forms and formulations of Humira®, including but not limited to concentrated formulations, injectable ready-to-use formulations; formulations reconstituted with water, alcohol, and/or other ingredients, and others. The term “human TNFα” (which may be abbreviated as hTNFα, or simply hTNF), as used herein, is intended to refer to a human cytokine that exists as a 17 kD secreted form and a 26 kD membrane associated form, the biologically active form of which is composed of a trimer of noncovalently bound 17 kD molecules. The structure of hTNFα is described further in, for example, Pennica, D., et al. (1984) Nature 312:724-729; Davis, J. M., et al. (1987) Biochemistry 26:1322-1326; and Jones, E. Y., et al. (1989) Nature 338:225-228. The term human TNFα is intended to include recombinant human TNFα (rhTNFα), which can be prepared by standard recombinant expression methods or purchased commercially (R & D Systems, Catalog No. 210-TA, Minneapolis, Minn.). The term “antibody”, as used herein, refers to immunoglobulin molecules comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In one embodiment of the invention, the formulation contains an antibody with CDR1, CDR2, and CDR3 sequences like those described in U.S. Pat. Nos. 6,090,382; 6,258,562, and 8,216,583. An antibody or antigen-binding portion thereof may be part of a larger immunoadhesion molecule, formed by covalent or noncovalent association of the antibody or antibody portion with one or more other proteins or peptides. Examples of such immunoadhesion molecules include use of the streptavidin core region to make a tetrameric scFv molecule (Kipriyanov, S. M., et al. (1995) Human Antibodies and Hybridomas 6:93-101) and use of a cysteine residue, a marker peptide and a C-terminal polyhistidine tag to make bivalent and biotinylated scFv molecules (Kipriyanov, S. M., et al. (1994) Mol. Immunol. 31:1047-1058). Antibody portions, such as Fab and F(ab′)2 fragments, can be prepared from whole antibodies using conventional techniques, such as papain or pepsin digestion, respectively, of whole antibodies. Moreover, antibodies, antibody portions and immunoadhesion molecules can be obtained using standard recombinant DNA techniques, as described herein. The term “isolated antibody”, as used herein, refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds hTNFα is substantially free of antibodies that specifically bind antigens other than hTNFα). An isolated antibody that specifically binds hTNFα may, however, have cross-reactivity to other antigens, such as TNFα molecules from other species. Moreover, an isolated antibody may be substantially free of other cellular material and/or chemicals. The term “glycine” refers to an amino acid whose codons are GGT, GGC, GGA, and GGG. The term “arginine” refers to an α-amino acid whose codons are CCU, CCC, CCA, and CCG. The term “alanine” refers to an amino acid whose codons are GCT, GCC, GCA, and GCG. The term “methionine” refers to an amino acid whose codon is ATG. The term “glutamate” refers to an amino acid whose codons are GAA and GAG. The term “sugar” refers to monosaccharides, disachharides, and polysaccharides. Examples of sugars include, but are not limited to, sucrose, glucose, dextrose, and others. The term “polyol” refers to an alcohol containing multiple hydroxyl groups. Examples of polyols include, but are not limited to, mannitol, sorbitol, and others. The term “metal ion” refers to a metal atom with a net positive or negative electric charge. For the purposes of the present application, the term “metal ion” also includes sources of metal ions, including but not limited to metal salts. The term “long-term storage” or “long term stability” is understood to mean that the pharmaceutical composition can be stored for three months or more, for six months or more, and preferably for one year or more, most preferably a minimum stable shelf life of at least two years. Generally speaking, the terms “long term storage” and “long term stability” further include stable storage durations that are at least comparable to or better that the stable shelf typically required for currently available commercial formulations of adalimumab, without losses in stability that would render the formulation unsuitable for its intended pharmaceutical application. Long-term storage is also understood to mean that the pharmaceutical composition is stored either as a liquid at 2-8° C., or is frozen, e.g., at −20° C., or colder. It is also contemplated that the composition can be frozen and thawed more than once. The term “stable” with respect to long-term storage is understood to mean that adalimumab contained in the pharmaceutical compositions does not lose more than 20%, or more preferably 15%, or even more preferably 10%, and most preferably 5% of its activity relative to activity of the composition at the beginning of storage. The term “substantially free” means that either no substance is present or only minimal, trace amounts of the substance are present which do not have any substantial impact on the properties of the composition. If reference is made to no amount of a substance, it should be understood as “no detectable amount”. The term “mammal” includes, but is not limited to, a human. The term “pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material, formulation auxiliary, or excipient of any conventional type. A pharmaceutically acceptable carrier is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation. The term “composition” refers to a mixture that usually contains a carrier, such as a pharmaceutically acceptable carrier or excipient that is conventional in the art and which is suitable for administration into a subject for therapeutic, diagnostic, or prophylactic purposes. It may include a cell culture in which the polypeptide or polynucleotide is present in the cells or in the culture medium. For example, compositions for oral administration can form solutions, suspensions, tablets, pills, capsules, sustained release formulations, oral rinses or powders. The terms “pharmaceutical composition” and “formulation” are used interchangeably. The term “treatment” refers to any administration or application of remedies for disease in a mammal and includes inhibiting the disease, arresting its development, relieving the disease, for example, by causing regression, or restoring or repairing a lost, missing, or defective function; or stimulating an inefficient process. The term includes obtaining a desired pharmacologic and/or physiologic effect, covering any treatment of a pathological condition or disorder in a mammal. The effect may be prophylactic in terms of completely or partially preventing a disorder or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disorder and/or adverse affect attributable to the disorder. It includes (1) preventing the disorder from occurring or recurring in a subject who may be predisposed to the disorder but is not yet symptomatic, (2) inhibiting the disorder, such as arresting its development, (3) stopping or terminating the disorder or at least its associated symptoms, so that the host no longer suffers from the disorder or its symptoms, such as causing regression of the disorder or its symptoms, for example, by restoring or repairing a lost, missing or defective function, or stimulating an inefficient process, or (4) relieving, alleviating or ameliorating the disorder, or symptoms associated therewith, where ameliorating is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, such as inflammation, pain and/or tumor size. The term “disease” refers to any condition, infection, disorder or syndrome that requires medical intervention or for which medical intervention is desirable. Such medical intervention can include treatment, diagnosis and/or prevention. The term “therapeutically effective amount” refers to an amount which, when administered to a living subject, achieves a desired effect on the living subject. For example, an effective amount of the polypeptide of the invention for administration to the living subject is an amount that prevents and/or treats an integrin αvβ3-mediated disease. The exact amount will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques. As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by those skilled in the art. EMBODIMENTS OF THE INVENTION When pharmaceutical compositions containing adalimumab (Humira®), including aqueous and lyophilized formulations of adalimumab are stored on a long-term basis, the activity of adalimumab can be lost or decreased due to aggregation and/or degradation. Thus, the present invention provides aqueous formulations of adalimumab that allow stable long-term storage of adalimumab, so that adalimumab is stable over the course of storage either in liquid or frozen states. The provided formulations do not require any extra steps such as rehydrating. Numerous embodiments of the present invention are explained in a greater detail below. Adalimumab All of the compositions of the present invention comprise adalimumab. As explained in the Background section of this application, adalimumab is a recombinant human IgG1 monoclonal antibody specific for human tumor necrosis factor (TNF). This antibody is also known as D2E7. Adalimumab consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons. Adalimumab has been described and claimed in U.S. Pat. No. 6,090,382. The term “adalimumab” is also intended to mean so-called “bio-similar” and “bio-better” versions of the active adalimumab protein present in commercially available Humira®. Adalimumab suitable for storage in the present pharmaceutical composition can be produced by standard methods known in the art. For example, U.S. Pat. Nos. 6,090,382 and 8,216,583 describe various methods that a skilled artisan could use to prepare adalimumab protein for use in the formulations of the present invention. These methods are incorporated by reference herein. For example, adalimumab can be prepared by recombinant expression of immunoglobulin light and heavy chain genes in a host cell. Purification of the expressed adalimumab can be performed by any standard method. When adalimumab is produced intracellularly, the particulate debris is removed, for example, by centrifugation or ultrafiltration. When adalimumab is secreted into the medium, supernatants from such expression systems can be first concentrated using standard polypeptide concentration filters. Protease inhibitors can also be added to inhibit proteolysis and antibiotics can be included to prevent the growth of microorganisms. Adalimumab can be purified using, for example, hydroxyapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography, and any combination of known or yet to be discovered purification techniques, including but not limited to Protein A chromatography, fractionation on an ion-exchange column, ethanol precipitation, reverse phase HPLC, chromatography on silica, chromatography on heparin SEPHAROSET®, an anion or cation exchange resin chromatography (such as a polyaspartic acid column), chromatofocusing, SDS-PAGE, and ammonium sulfate precipitation. I Formulations of Adalimumab with a Polyol and/or Surfactant, but without a Citrate/Phosphate Buffer In a first embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab; a stabilizer comprising at least one member selected from the group consisting of a polyol and a surfactant; and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 4 to about 8, and preferably about 5 to about 6, and wherein said buffer does not comprise a combination of citrate and phosphate. In this embodiment, the stabilizer preferably comprises both polyol and surfactant. The pharmaceutical composition can comprise one, or any combination of two or more buffers, as long as it does not comprise both citrate and phosphate. The surfactant may be any pharmaceutically acceptable surfactant, preferably polysorbates (e.g., polysorbate 80) or poloxamers (e.g., Pluronic F-68). II Formulations of Adalimumab Using a Single Buffer System In a second embodiment, utilizing a single buffer system, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a polyol, a surfactant, and a buffer system comprising a single buffering agent, said single buffering agent being selected from citrate, phosphate, succinate, histidine, tartrate or maleate, but not including combinations of the foregoing; wherein the formulation has a pH of about 4 to 8, and preferably about 5 to about 6. Histidine and succinate are particularly preferred for use as single buffering agents. It was surprisingly discovered that adalimumab compositions which comprise only one buffer (as opposed to two or more buffers) are more stable than adalimumab compositions comprising both a citrate buffer and a phosphate buffer. In the single buffer embodiment, adalimumab can be present at a concentration from about 20 to about 150 mg/ml, more preferably from about 20 to about 100 mg/ml, and even more preferably from about 30 to about 50 mg/ml. The buffer is present at a concentration from about 5 mM to about 50 mM. The pH of the compositions is between about 5 and about 6. The single buffer compositions of the invention may further comprise a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. The amino acid is selected from the group consisting of glycine, alanine, glutamate, arginine and methionine, most preferably glycine, arginine and methionine. The salt is selected from the group consisting of sodium chloride and sodium sulfate. The metal ion is selected from the group consisting of zinc, magnesium and calcium. The compositions of the invention may further comprise a surfactant. The surfactant is a polysorbate surfactant or a poloxamer surfactant. Polysorbate surfactants include polysorbate 80, polysorbate 40 and polysorbate 20. A preferred polysorbate surfactant is polysorbate 80. Poloxamer surfactants include poloxamer 188 (also available commercially as Pluronic F-68). Most preferably, the surfactant is polysorbate 80. The single buffer composition may further comprise a polyol. Preferably, the polyol is a sugar alcohol; and even more preferably, the sugar alcohol is mannitol, sorbitol or trehalose. The single buffer adalimumab composition may also comprise a sugar, preferably sucrose, glucose or dextrose. In one embodiment of a single buffer adalimumab formulation, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to 50 μM, and succinate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of any other buffers. In another embodiment of a single buffer adalimumab formulation, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to 50 μM, and histidine at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of any other buffers. In a further embodiment of a single buffer adalimumab formulation, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to 50 μM, and either tartrate, maleate or acetate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of any other buffers. III Formulations of Adalimumab which Exclude Buffer In a third embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a stabilizer comprising at least one member selected from a polyol and a surfactant, wherein said composition has a pH of about 4 to about 8 and preferably about 5 to about 6, and wherein said composition is substantially free of a buffer. The term “free of buffer” should be understood to allow inclusion of the inherent buffering effect of the protein itself. In a buffer free formulation, the stabilizers referenced above may also be present (e.g. glycine, arginine and combinations thereof). IV Formulations of Adalimumab which Exclude Surfactant In a fourth embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a polyol, and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 4 to about 8 and preferably about 5 to about 6, and wherein said composition is free or substantially free of a surfactant. Preferably, the composition (i) does not contain the buffer combination of citrate and phosphate; and (ii) the buffer is at least one member selected from the group consisting of histidine and succinate; and (iii) the polyol is not mannitol at concentrations less than about 150 mM, but instead is selected from the group consisting of mannitol at concentrations exceeding about 150 mM, sorbitol and trehalose. V Formulations of Adalimumab which Exclude Polyol In a fifth embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a surfactant, and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 4 to about 8, and preferably about 5 to about 6, and wherein said composition is substantially free of polyol. Preferably, the composition (i) does not contain the buffer combination of citrate and phosphate; and (ii) the buffer is at least one member selected from the group consisting of histidine and succinate. Additional Stabilizers Useful in Embodiments I Through V. Optionally, in each of the five embodiments summarized above, the composition may further comprise a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. The amino acid stabilizer may be selected from the group consisting of glycine, alanine, glutamate, arginine and methionine. The salt stabilizer may be selected from the group consisting of sodium chloride and sodium sulfate. The metal ion stabilizer may be selected from the group consisting of zinc, magnesium and calcium. Preferably, adalimumab formulations containing the stabilizers mentioned above also do not contain buffer systems in which phosphate buffer and citrate buffer are present in combination. Most preferably (i) the optional additional stabilizer present in this embodiment is not sodium chloride, and comprises at least one or both of arginine and glycine; (ii) the buffer, when present, contains no citrate and phosphate combination but is instead at least one of histidine and succinate; and (iii) the stabilizer when it includes a polyol is not mannitol unless in amounts greater than about 150 mM, and may also include trehalose and sorbitol. Preferably the amount of mannitol is greater than about 150 mM, and most preferably greater than about 200 mM. VI Formulations of Adalimumab Replacing Both Surfactant and Polyol with Other Stabilizers It has been further discovered that satisfactory stabilization can be attained when the stabilizers mentioned above are used in place of both polyol and surfactant, accordingly, in a sixth embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, optionally a buffer, a stabilizer selected from the group consisting of an amino acid, a salt, EDTA, and a metal ion, and wherein said composition has a pH of about 4 to about 8, and preferably about 5 to about 6, and wherein said composition is free or substantially free of a polyol and surfactant. When buffer is present in this embodiment, it is especially preferred that (i) the buffer not include the combination of citrate and phosphate; (ii) the buffer is selected from the group consisting of histidine and succinate; and (iii) the stabilizer does not comprise sodium chloride, but instead is at least one member selected from the group consisting of arginine and glycine. It is also preferred that the buffer is free or substantially free of citrate buffer, as we have discovered that it is generally poorer in terms of stability contribution than other buffers, such as histidine and succinate. In each of the embodiments above at least one of the following advantageous conditions can be optionally present (unless stated as being required): (i) the buffer preferably does not contain a combination of citrate and phosphate, or is free or substantially free of citrate buffer (ii) the buffer preferably is at least one member selected from the group consisting of histidine and succinate; and (iii) the stabilizer preferably does not include sodium chloride, or if present is controlled to levels less than about 100 mM; (iv) the stabilizer is at least one member selected from the group consisting of arginine and glycine, including combinations thereof; and (v) the polyol is preferably not mannitol (unless mannitol is present in amounts greater than about 150 mM and preferably greater than about 200 mM) but may include sorbitol and trehalose. When using polyols for stabilization, mannitol is discovered herein to be destabilizing in comparison to sorbitol and trehalose unless the mannitol is present in amounts generally above about 150 to 200 mM. When using other stabilizers, it is discovered herein that sodium chloride is destabilizing compared to arginine or glycine, but we observe some stabilization when the levels of sodium chloride are controlled to less than about 100 mM and preferably less than about 75 mM. Preferably, adalimumab is present in the composition of the present invention at a concentration from about 20 to about 150 mg/ml, more preferably from about 20 to about 100 mg/ml, and even more preferably from about 30 to about 50 mg/ml. Buffer, if present, is present at a concentration from about 5 mM to about 50 mM. Surfactant, if present, is preferably a polysorbate (PS). In an even more preferred embodiment, the polysorbate is polysorbate 80 (PS 80). Poloxamer surfactants are also suitable (e.g., Pluronic® F-68). The polyol, if present, is a sugar alcohol. In an even more preferred embodiment, the sugar alcohol is selected from the group consisting of mannitol, sorbitol and trehalose, and most preferably sorbitol and trehalose. Preferably, the polyol is at a concentration from about 1 to about 10%, more preferably, from about 2 to about 6%, and even more preferably from about 3 to 5%, wherein said values are weight by volume (w/v) of the total composition. A stabilizer, when present, can be selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. The amino acid can be selected from the group consisting of glycine, alanine, glutamate, arginine and methionine. The salt may be selected from the group consisting of sodium chloride and sodium sulfate. The metal ion may be selected from the group consisting of zinc, magnesium and calcium. Glycine and arginine are particularly preferred stabilizers. Zinc, magnesium and calcium, when present for stabilization, may be at a concentration from about 1 mM to about 100 mM, and more preferably from about 1 to about 10 mM. Glycine, or arginine, or combinations thereof, if present for stabilization, is at a total concentration of up to about 300 mM, and preferably about 150 to 300 mM. Methionine, if present for stabilization, is present at a concentration from about 1 to about 10 mg/ml, more preferably from about 1 mg/ml to about 5 mg/ml. Sodium chloride, if present for stabilization, is at a concentration from about 5 to about 150 mM, more preferably, from about 20 to about 140 mM, and even more preferably less than about 100 mM. Sodium sulfate, if present if present for stabilization, is at a concentration from about 5 to about 150 mM, more preferably, from about 20 to about 120 mM, and even more preferably from about 60 to about 100 mM. EDTA, if present for stabilization, is present at a concentration from about 0.01% to about 0.05%, more preferably from about 0.05% to about 0.25%, and even more preferably from about 0.08% to about 0.2%. Preferably, the pH of the composition is from about 5 to about 5.5; and even more preferably is about 5.2 to 5.4. In an example of Embodiment I and II, above, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, sorbitol or trehalose at a concentration from about 1 to 10% weight by volume, polysorbate 80 at a concentration from about 1 to 50 μM, and at least one of succinate, histidine, phosphate, tartrate, maleate or citrate buffer, at a concentration from about 5 mM to about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and provided said composition is free or substantially free of citrate/phosphate buffer combination. Further, we rank citrate as the poorest of buffers, and preferably avoid it although it is still within the scope of the invention to formulate stable formulations of adalimumab that include citrate buffer, if not the combination thereof with phosphate. In an example of Embodiment IV, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, sorbitol or trehalose at a concentration from about 1 to 10% weight by volume, and at least one of succinate, histidine, phosphate, tartrate, maleate or citrate buffer, at a concentration from about 5 mM to about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of a surfactant and, optionally, and preferably, free or substantially free of citrate/phosphate buffer combination. In an example of Embodiment VI, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, glycine at a concentration from about 20 to about 200 mM, and at least one of succinate, histidine, phosphate, tartrate, maleate or citrate buffer, at a concentration from about 5 mM to about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is free or substantially free polyol; surfactant (e.g. PS8) is preferably, but optionally present; and the composition is, optionally, and preferably, free or substantially free of citrate/phosphate buffer combination. In a further example of Embodiment VI, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, arginine or glycine at a concentration from about 1 to about 250 mM, and at least one of succinate, histidine, phosphate, tartrate, maleate or citrate buffer, at a concentration from about 5 mM and about 50 mM wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of polyol. Surfactant (e.g. PS80) is preferably but optionally present, and the composition is, optionally, and preferably, free or substantially free of citrate/phosphate buffer combination. In a further example of Embodiment VI, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, sodium chloride at a concentration from about 5 to about 150 mM, and at least one of succinate, histidine, phosphate, tartrate, maleate or citrate buffer, at a concentration from about 5 mM and about 50 mM wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is free or substantially free of a polyol. Surfactant (e.g. PS80) is preferably but optionally present; and the composition is, optionally, and preferably, free or substantially free of citrate/phosphate buffer combination. In an example of Embodiment V, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, sodium chloride at a concentration from about 5 to about 150 mM, polysorbate 80 at a concentration from about 1 to 50 μM, and at least one of succinate, histidine, phosphate, tartrate, maleate or citrate buffer, at a concentration from about 5 mM and about 50 mM wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is free or substantially free of a polyol and, optionally, and preferably, free or substantially free of citrate/phosphate buffer. In an example of Embodiments I and II, with additional stabilization, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to about 50 μM, sorbitol or trehalose at a concentration from about 1 to about 10% weight by volume, EDTA at a concentration from about 0.01% to about 0.5%, and at least one of succinate, histidine, phosphate, tartrate, maleate or citrate, as a sole buffer, at a concentration from about 5 mM and about 50 mM wherein said composition has a pH of about 5 to about 5.5, and wherein the composition is free, or substantially free of citrate/phosphate buffer combination. In a further example of Embodiments I and II, with additional stabilization, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to about 50 μM, sorbitol or trehalose at a concentration from about 1 to about 10% weight by volume, methionine at a concentration from about 1 to about 10 mg/ml, %, and at least one of succinate, histidine, phosphate, tartrate, maleate or citrate at a concentration from about 5 mM and about 50 mM wherein said composition has a pH of about 5 to about 5.5, wherein the composition is free or substantially free of any citrate/phosphate buffer combination. In a further example of Embodiments I and II, with additional amino acid stabilization, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to about 50 μM, mannitol, sorbitol or trehalose (preferably sorbitol) at a concentration from about 1 to about 10% weight by volume, and amino acid that is preferably one and not both of (a) arginine at a concentration from about 1 to about 250 mg/ml, and (b) glycine at a concentration of about 20 to 200 mg/ml, and histidine buffer or succinate buffer at a concentration from about 5 mM and about 50 mM, and wherein said composition has a pH of about 5 to about 5.5; and wherein the composition is free or substantially free of any citrate/phosphate buffer combination. In a further example of Embodiment IV, with additional amino acid stabilization, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to about 50 μM, arginine at a concentration from about 1 to about 250 mg/ml, glycine at a concentration of about 20 to 200 mg/ml, and histidine buffer or succinate buffer at a concentration from about 5 mM to about 50 mM, and wherein said composition has a pH of about 5 to about 5.5 and is free or substantially free of polyol; and, optionally, wherein the composition is preferably free of any citrate/phosphate buffer combination. Numerous embodiments of the adalimumab formulations of the present invention were prepared in eight separate blocks of experiments, referred to herein as “Block A” through “Block H.” Each block had 12 to 16 different formulations that were exposed to accelerated storage conditions, 1 week at 40′C and 2 weeks at 25′C. For each time point the chemical and physical stability of the adalimumab protein was measured by SEC, RP, UV, pH, CE-IEF and CE-SDS. Materials and Methods 1. Equipment Used in the Formulation Studies Equipment Manufacture Model Serial Number Balance Sartorius CPA124S 23350022 pH meter Denver Model 250 E25006B100 Instrument UV Cary Bio 100 EL07103025 HPLC Dionex 3 Ultimate 3000 UPLC 8047439 HPLC Dionex 2 Ultimate 3000, 8036991 UPLC Beckman Beckman P/ACE 455436 CE Agilent CE Agilent 3DCE 1600A 3546G00736 Rocker Labnet Orbit P4 8091840 Plate 2. Chemicals and Materials Used in the Formulation Studies Chemical/Materials Producer Purity Lot Number: Citrate Mallinckrodt ACS H28475 Phosphate Fisher FCC 103372 Fisher ACS 113670 Succinate Spectrum Reagent ZM0462 Histidine Spectrum USP XV0239 Spectrum USP ZG0216 Tartrate Spectrum FCC 1BC0152 Maleate TCI >99% 206-738-1 Mannitol BDH USP 57910 Glycine Spectrum FCC YM3312 Spectrum FCC 1BJ0243 Fisher Tissue 070082 Grade Arginine Spectrum USP 2AK0238 Spectrum USP 1CB0771 Sodium Chloride Mallinckrodt ACS J52619 Macron USP 26434 Polysorbate 80 Sigma-Aldrich Low 028K5309 Peroxide Sorbitol Spectrum NF 1AH0521 Trehalose Spectrum N/A 1AE0739 Acetate Mallinckrodt FCC H31613 EDTA Sigma 98.5% 057K00071 Methionine Spectrum USP ZF0377 F-68 Sigma Cell Culture 057K00331 Polysorbate 20 Spectrum NF 1AE0882 Sodium dodecyl sulfate Fluka ACS 1344034 Tris base Fisher ACS S61374 2-mercaptoethanol Fisher Electrophoresis 107667 Part Material/Reagents Number Supplier Slide-A-Lyzers 7K cutoff 66373 Thermo Mini Dialysis Units 69550 Thermo Millex ®-GV 0.22 μM, Filter SLGV004SL Millipore 1 mL Vials 4500050375 SCHOTT cIEF Gel Polymer Solution 477497 Beckman Coulter pI Marker Kit A58481 Beckman Coulter Pharmalyte 3-10 ampholyte 17-0456-01 GE Healthcare Fused silica capillary (50 μm TSP050375 Polymicro i.d.) SDS-MW gel buffer A10663 Beckman 10 kD internal standard A26487 Beckman 3. HPLC Columns Used in the Formulation Studies Column Company Part # Lot Poroshell 300SB- Agilent 660750-906 USZW003083 C8, 2.1 × 75 mm, 5um Poroshell 300SB- Agilent 660750-906 USZW003073 C8, 2.1 × 75 mm, 5um ACQUITY UPLC BEH200 Waters 186005225 138123331 SEC, 1.7 um Column, 4.6 × 150 mm ACQUITY UPLC BEH200 Waters 186005225 01471130951 SEC, 1.7 um Column, 4.6 × 150 mm Processing of Humira®. Block A experiments used adalimumab present in commercially available Humira®. Humira® material was dialyzed as follows: 100 μL of Humira® was placed into Mini Dialysis units with a 3.5 MWCO and dialyzed in 1 L of formulation buffer for 24 hours at 4 to 8° C. A few samples did experience a small increase in volume due to the dialysis, but never to extent that the concentration of the polysorbate 80 dropped below the CMC (critical micelle concentration). The protein concentration for each formulation was measured by UV absorbance spectroscopy, using an calculated experimental molar absorptivity based on reported concentration of Humira®, 50 mg/mL. For a number of the formulations the protein concentration was adjusted by using a spin concentrator. The sample was placed in the spin concentrator and rotated at 14,000 RPM for 30 to 60 secs. The protein concentration was then checked with UV. After the targeted protein concentration around 50 mg/mL was reached the samples were filtered through a 0.22 μM sterile filter into sterile vials in a biosafety hood. The samples were then placed on stability at 40° C. for one and two weeks. Processing of a Proprietary Adalimumab Protein. The formulation studies described herein used a proprietary adalimumab biosimilar protein which did not contain polysorbate 80. The material was dialyzed using 7,000 MWCO Slide-A-Lyzers in different formulation buffers for 24 hours at a temperature range between 4 to 8° C. After dialysis the protein concentration was measured by UV and sample pH was measured. The target concentration of samples was 50±2.5 mg/mL, which was adjusted if the sample concentration fell out of the above range. Some of the samples did experience an increase in sample volume do to dilution, requiring the concentration of the protein to increase. For these samples the protein concentration was increased by using spin concentrators, usually at 14,000 rpm for 30 to 60 secs. The pH of a number of samples were adjusted using 1M NaOH or 1M HCl to reach the target pH of 5.2. After the targeted protein concentration and pH of the samples were determined to be within experimental parameters, the samples were filtered through a 0.22 μM sterile filter into sterile vials in a biosafety hood. The samples were then placed on stability at 40° C. for one week and 25° C. for two weeks. Freeze-Thaw Conditions: The freeze thaw samples were prepared on the day of analysis to match with t=0. The samples were frozen at −80° C. between 3 to 7 minutes. The frozen sample was then thawed at room temperature until all the ice had thawed. The freeze and thaw cycle was repeated 5 times for each sample. Agitation Studies. The samples were aggregated at 150 rpm for 24 hours at 4° C. on a rockerplate. A control was prepared and placed next to the rocker plate for each sample that underwent agitation. pH Measurements. The pH each sample was measured using a micro-pH probe. Before the start of analysis the pH probe was calibrated with three pH standards ordered from fisher. The pH values of the stability samples were measured by transferring 60 μL of each stability sample to 100 μL PCR tube. The micro-pH probe was then submerged into the sample and after the value stabilized it was recorded. UV Absorbance Spectroscopy. UV spectroscopy was used to measure the protein concentration in the samples. The mole extinction coefficient at 280 nm for bulk substance was 1.6355 mg/mL, which was determined experiential. The protein concentrations of the all formulations for LB-140 were measured using a cell path length of 0.0096 cm. Below is the analysis parameters used for LB-140. Scan Range: 400 to 200 nm Average Time (min): 0.1 Date Interval (nm): 1 Scan Rate (nm/min): 600 Cycle Count: 5 Size Exclusion Chromatography (SEC) Method. The SEC method used to analyze the LB-140 stability samples was developed at Legacy BioDesign. Below is a brief summary of the SEC method parameter used for the analysis of the LB-140 samples. Method Parameters Column Information: ACQUITY UPLC BEH200 SEC, 1.7 urn Column, 4.6×150 mm Analysis Buffer: 50 mM Phosphate, 250 mM NaCl, pH 6.8 Flow rate: 0.3 mL/min Column temperature: 30° C. Detection: 280 nm Injection volume: 2 μL Sample temperature: Approx. 5° C. RP HPLC Method. The RP HPLC method was found to be stability indicating and was used to analyze LB-140 stability samples. Below is a summary of the RP method parameter used for the analysis of the LB-140. Method Parameters Column Information: Poroshell 300SB-C8, 2.1×75 mm, 5 um Mobile Phase A: 98% (v/v) H2O/2% (v/v) IPA/0.1% (v/v) TFA Mobile Phase B: 10% (v/v) H2O/70% (v/v) IPA/20% (v/v) ACN/0.1% (v/v) TFA Flow rate: 0.25 mL/min Column temperature: 80° C. Detection: 225 nm Injection volume: 1 μL Sample temperature: Approx. 5° C. Run time: 15 minutes Gradient: Time % A % B 0 100 0 10 50 50 10.1 100 0 15 100 0 CE-IEF Analysis. Capillary isoelectric focusing (cIEF) was conducted as described in the PA 800 plus Application Guide published by Beckman Coulter. A more detailed description can be found in a research article published by Mack et al1. All analyses were conducted using a Beckman Coulter P/ACE MDQ system (Beckman Coulter, Inc.; Brea, Calif.) operated at ambient temperature with a 30 cm total length (20 cm effective) neutral capillary. The neutral capillary was prepared by immobilizing poly(acrylamide) to the capillary wall using a method described by Gao et al.2 cIEF samples were prepared by mixing the protein of interest at 0.25 mg/mL with a mixture of 3M urea-cIEF gel containing ampholyte, cathodic stabilizer, anodic stabilizer, and pl markers. Sample was pressure injected at 9.5 psi into the capillary for 4.1 min, after which time it was focused by applying a voltage of 25 kV for 15 min between analyte and catholyte. This step was followed by chemical mobilization at 30 kV for 30 min between analyte and chemical mobilizer. The pl markers and the protein of interest were detected with absorbance at 280 nm during the mobilization step. The pl of the protein was calculated from the resultant regression equation of pl vs. first peak moment obtained from the pl standards. CE-SDS Analysis. Analysis by CE-SDS was conducted under reducing conditions utilizing a method adapted from the SOP published by Beckman-Coulter for determining IgG purity/heterogeneity. Briefly, the antibody was diluted with DDI water to 6 mg/mL, denatured by adding sample buffer (0.1 M Tris/1.0% SDS, pH 8.0), and reduced via addition of 2-mercaptoethanol; the final antibody concentration was 1.2 mg/mL. Denaturing and reduction was facilitated by heating the sample at 70° C. for 10 min. The sample was cooled for 10 min at room temperature prior to analysis. A centrifuge step (300 g, 5 min) was employed prior to heating the sample and directly after the cooling it. CE analysis was conducted using a Beckman Coulter P/ACE MDQ system operated at ambient temperature with a 30 cm total length (20 cm effective, 50 μm i.d.) capillary. Prior to sample introduction, the capillary was sequentially rinsed with 0.1 M NaOH, 0.1M HCL, DDI water, and SDS-gel buffer solution. Sample was injected electrokinetically at 5 kV for 30 s followed by separation at 30 kV for 30 min. For both injection and separation, the instrument was operated in reverse polarity mode. Antibody fragments were detected using absorbance at 214 nm (4 Hz acquisition) and time-normalized areas reported for measured peaks. Block a Formulation Studies The Block A studies examined different buffer systems and used a commercially available adalimumab material which was reprocessed for these studies. We note that U.S. Pat. No. 8,216,583 references stability of an adalimumab formulation in relation to use of a citrate/phosphate buffer system at pH 5.2, and in fact the patent required the use of such a buffer combination. The work we have done, reflected here, indicates that citrate/phosphate is in fact a rather poor buffer choice in comparison to others such as histidine and succinate. In the Block A studies below, pH was kept constant at 5.2. The concentrations of mannitol and polysorbate 80 were also held constant. Samples were kept at 40° C. for two weeks. The study design is summarized in the Table below. TABLE A BLOCK A STUDY DESIGN PS Form Citrate Phosphate Succinate Histidine Tartrate Maleate Mannitol 80 No. API (mM) (mM) (mM) (mM) (mM) (mM) (mM) (%) 1 Humira ® 8 18 0 0 0 0 12 0.1 2 Humira ® 10 0 0 0 0 0 12 0.1 3 Humira ® 0 10 0 0 0 0 12 0.1 4 Humira ® 0 0 10 0 0 0 12 0.1 5 Humira ® 0 0 0 10 0 0 12 0.1 6 Humira ® 0 0 0 0 10 0 12 0.1 7 Humira ® 0 0 0 0 0 10 12 0.1 Analysis by SEC showed that the formulation with citrate alone performed more poorly than the buffer combination (Table A), indicating that the phosphate was the primary stabilizer in that combination. This was surprising and unexpected, as this pH is outside of the nominal buffering capacity range of phosphate, but well within the buffering range for citrate. Furthermore, succinate, histidine, and tartrate did as well or better than the citrate/phosphate combination, indicating that other buffer systems would provide equal or superior stability for adalimumab. Accordingly, the present invention in one of its embodiments is directed to adalimumab formulations exhibiting long term stability, wherein a buffer combination of citrate and phosphate is avoided in favor of at least one buffer selected from the group consisting of histidine, phosphate, succinate and tartrate. Acetate is also a suitable replacement for the citrate phosphate buffer combination. The purity of these stored samples was checked using RP HPLC (FIG. 2). As with SEC, the citrate formulation exhibited the poorest stability, while all of the other buffers did as well or better than the buffer combination found in commercially available adalimumab (Humira®). These results demonstrate our discovery that changing the buffer (i.e. avoiding the citrate/phosphate buffer combination of the commercial adalimumab) could improve the stability profile of adalimumab. Block B Formulation Studies A second study (“BLOCK B”) was conducted examining just changes in the buffer species, where the pH (5.2) was not changed, as outlined in the table below labeled “BLOCK B Study Design. In this case, the commercially available formulation for Humira® was used as a control, while all of the other formulations employed a proprietary adalimumab biosimilar protein. Table B-1, below summarizes the percent monomer for the Block B formulations (as well the percentage amount of an impurity determined to be a fragment of the adalimumab protein). TABLE B BLOCK B STUDY DESIGN PS Form Citrate Phosphate Succinate Histidine Tartrate Maleate Mannitol 80 No. API (mM) (mM) (mM) (mM) (mM) (mM) (mM) (%) 1 Humira ® 8 18 0 0 0 0 12 0.1 2 Adalimumab 10 0 0 0 0 0 12 0.1 biosimilar 3 Adalimumab 0 10 0 0 0 0 12 0.1 biosimilar 4 Adalimumab 0 0 10 0 0 0 12 0.1 biosimilar 5 Adalimumab 0 0 0 10 0 0 12 0.1 biosimilar 6 Adalimumab 0 0 0 0 10 0 12 0.1 biosimilar 7 Adalimumab 0 0 0 0 0 10 12 0.1 biosimilar TABLE B-1 Percent monomer for Block B formulations at t0 and after two weeks at 40 C. (t2) Form Monomer Monomer Fragment Fragment No. API Buffer (t0) (t2) (t0) (t2) 1 Humira ® Citrate/phosphate 99.34 0.26 2 Adalimumab citrate 98.71 97.92 0.62 0.40 biosimilar 3 Adalimumab phosphate 99.21 98.07 0.05 0.30 biosimilar 4 Adalimumab succinate 99.19 98.04 0.04 0.31 biosimilar 5 Adalimumab histidine 99.19 98.41 0.07 0.23 biosimilar 6 Adalimumab tartrate 99.13 98.10 0.04 0.29 biosimilar 7 Adalimumab maleate 98.91 97.90 0.36 0.76 biosimilar As can be seen from Table B-1 above, upon storage for two weeks at 40 C, the monomer content decreases by more than 1% for all of the samples in Block B, except for the one containing histidine (His) buffer (Table B-1). From this study we discovered the likelihood that His would be a superior buffer system for adalimumab. (We note that the fragment level measured by SEC reported for Formulation 2 appears to be incorrect as all of the other initial fragment s levels are less than 0.1%.) Block C Formulation Studies A large-scale formulation screening study was carried out in the studies conducted in Block C (See Table C, below). Samples were stored for one week at 40 C (hereinafter referenced as “t1”) or two weeks at 25 C (hereinafter referenced as “t2”). These conditions were used throughout the remainder of our studies, so this terminology will be employed throughout the present detailed discussion. Block C was designed to expand on the buffer assessment conducted in Block B. In addition, it examined glycine (Gly) and/or arginine (Arg) as possible stabilizers in place of mannitol and/or NaCl (Table C). Note that the buffer system used in the Humira® product employs the 8 mM citrate/18 mM phosphate buffer, which is the composition of Formulation 1 of Block C. In this case, a proprietary adalimumab biosimilar protein was used for formulation 1 of Block C, instead of adalimumab protein obtained from commercially available Humira®. TABLE C BLOCK C STUDY DESIGN Form No. API citrate phosphate succinate histidine glycine arginine mannitol NaCl 1 Adalimurnab 8 18 0 0 0 0 65 100 biosimilar 2 Adalimumab 18 8 0 0 0 0 65 100 biosimilar 3 Adalimumab 20 0 0 0 0 0 65 100 biosimilar 4 Adalimumab 20 0 0 0 65 0 0 100 biosimilar 5 Adalimumab 0 20 0 0 65 0 0 100 biosimilar 6 Adalimumab 20 0 0 0 0 65 0 100 biosimilar 7 Adalimurnab 0 20 0 0 0 65 0 100 biosimilar 8 Adalimurnab 0 0 20 0 65 0 0 100 biosimilar 9 Adalimumab 0 0 20 0 0 65 0 100 biosimilar 10 Adalimumab 0 0 0 20 65 0 0 100 biosimilar 11 Adalimurnab 0 0 0 20 0 65 0 100 biosimilar 12 Adalimumab 0 20 0 0 0 130 0 35 biosimilar 13 Adalimumab 0 0 20 0 0 130 0 35 biosimilar 14 Adalimurnab 0 0 0 20 0 130 0 35 biosimilar 15 Adalimumab 0 20 0 0 130 0 0 60 biosimilar 16 Adalimumab 0 20 0 20 130 0 0 60 biosimilar TABLE C-1 Measured pH for Block C formulations at t0 and t1 (one week, 40° C.) Form pH pH No. citrate phosphate succinate histidine glycine arginine mannitol NaCl t0 t2 1 8 18 0 0 0 0 65 100 5.51 5.57 2 18 8 0 0 0 0 65 100 5.46 5.43 3 20 0 0 0 0 0 65 100 5.28 5.27 4 20 0 0 0 65 0 0 100 5.27 5.24 5 0 20 0 0 65 0 0 100 5.43 5.44 6 20 0 0 0 0 65 0 100 5.29 5.29 7 0 20 0 0 0 65 0 100 5.28 5.32 8 0 0 20 0 65 0 0 100 5.22 5.17 9 0 0 20 0 0 65 0 100 5.19 5.16 10 0 0 0 20 65 0 0 100 5.28 5.30 11 0 0 0 20 0 65 0 100 5.26 5.29 12 0 20 0 0 0 130 0 35 5.24 5.24 13 0 0 20 0 0 130 0 35 5.18 5.16 14 0 0 0 20 0 130 0 35 5.28 5.35 15 0 20 0 0 130 0 0 60 5.31 5.31 16 0 20 0 20 130 0 0 60 5.36 5.40 TABLE C-2 Monomer content by SEC for formulations in Block C at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. citrate phosphate succinate His Gly Arg mannitol NaCl t0 t1 t2 1 8 18 0 0 0 0 65 100 98.75 97.90 98.06 2 18 8 0 0 0 0 65 100 99.26 98.22 98.80 3 20 0 0 0 0 0 65 100 99.28 98.32 98.78 4 20 0 0 0 65 0 0 100 99.36 98.45 99.03 5 0 20 0 0 65 0 0 100 99.25 98.20 98.77 6 20 0 0 0 0 65 0 100 99.42 98.68 99.10 7 0 20 0 0 0 65 0 100 99.39 98.59 99.13 8 0 0 20 0 65 0 0 100 99.41 98.51 99.04 9 0 0 20 0 0 65 0 100 99.36 98.52 98.96 10 0 0 0 20 65 0 0 100 99.41 98.66 99.15 11 0 0 0 20 0 65 0 100 99.37 98.70 99.15 12 0 20 0 0 0 130 0 35 99.41 98.66 99.14 13 0 0 20 0 0 130 0 35 99.42 98.71 99.17 14 0 0 0 20 0 130 0 35 99.40 98.75 99.26 15 0 20 0 0 130 0 0 60 99.32 98.53 99.05 16 0 20 0 20 130 0 0 60 99.40 98.66 99.19 TABLE C-3 Percent purity by RP HPLC for formulations in Block C at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. citrate phosphate succinate His Gly Arg mannitol NaCl t0 t1 t2 1 8 18 0 0 0 0 65 100 98.04 97.92 98.10 2 18 8 0 0 0 0 65 100 97.94 97.83 98.03 3 20 0 0 0 0 0 65 100 98.03 97.92 98.00 4 20 0 0 0 65 0 0 100 97.94 97.75 97.98 5 0 20 0 0 65 0 0 100 97.98 97.69 97.95 6 20 0 0 0 0 65 0 100 97.89 97.72 97.92 7 0 20 0 0 0 65 0 100 97.80 97.70 97.91 8 0 0 20 0 65 0 0 100 97.98 97.77 98.01 9 0 0 20 0 0 65 0 100 97.98 97.73 97.94 10 0 0 0 20 65 0 0 100 97.98 97.76 98.00 11 0 0 0 20 0 65 0 100 97.87 97.78 97.97 12 0 20 0 0 0 130 0 35 97.88 97.71 97.95 13 0 0 20 0 0 130 0 35 97.95 97.62 97.93 14 0 0 0 20 0 130 0 35 97.98 97.72 98.04 15 0 20 0 0 130 0 0 60 97.91 97.72 97.96 16 0 20 0 20 130 0 0 60 98.00 97.79 97.78 TABLE C-4 Percentage of main bands seen in the cIEF profile of formulations in Block C at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. pH t0 t1 t2 1 8.59 1.94 1.97 1.82 8.43 11.76 11.30 12.49 8.27 58.29 49.88 51.54 8.20 7.18 7.59 8.05 21.49 22.38 19.79 7.86 6.53 5.35 4.66 2 8.60 1.96 1.84 8.44 12.08 10.89 8.29 51.70 47.63 8.22 9.74 12.32 8.09 16.29 18.25 7.91 3.50 3.64 3 8.60 1.83 1.82 1.12 8.43 11.58 9.67 10.40 8.27 45.80 32.99 44.04 8.20 12.44 22.27 18.68 8.01 17.57 16.21 14.40 7.86 4.39 3.61 4 8.57 2.31 2.04 2.13 8.41 12.94 11.51 12.62 8.25 33.37 59.98 61.97 8.20 23.03 8.02 15.21 18.33 16.07 7.88 3.45 5.32 3.70 5 8.58 2.40 2.00 2.30 8.41 13.01 11.02 12.34 8.25 42.09 46.32 37.30 8.21 15.58 10.65 15.80 8.03 18.48 20.58 16.80 7.86 3.74 6.13 4.83 6 8.57 2.83 8.38 13.17 13.23 8.23 32.66 31.18 8.18 17.52 18.54 8.02 17.48 13.82 7.91 5.30 5.83 7 8.58 2.08 2.41 2.64 8.44 13.42 12.64 12.63 8.27 56.79 52.48 54.76 8.16 5.36 6.16 6.38 8.04 16.91 20.09 18.45 7.94 5.44 4.12 5.15 8 8.57 1.76 2.37 1.55 8.44 14.41 12.13 11.61 8.29 60.01 48.87 52.94 8.19 7.07 10.66 8.10 16.22 16.55 17.10 7.95 7.61 5.02 4.55 9 8.58 2.19 2.06 0.99 8.41 11.69 10.64 12.73 8.26 50.07 44.21 60.33 8.19 10.66 10.39 8.01 15.62 21.51 17.79 7.87 4.67 5.37 8.16 10 8.57 1.78 2.64 1.62 8.41 10.55 10.95 8.11 8.25 43.82 42.93 36.11 8.21 15.96 15.24 17.66 8.02 14.63 14.58 14.22 7.88 3.82 4.21 3.95 11 8.58 1.59 1.81 1.89 8.41 12.98 11.58 12.86 8.23 62.74 29.63 12.00 8.19 22.86 34.77 8.02 17.15 19.52 17.06 7.87 5.54 5.56 4.77 12 8.61 0.35 1.57 1.47 8.35 13.24 13.41 8.83 8.19 43.18 60.12 26.52 8.15 15.43 20.46 25.60 7.98 16.74 17.38 7.88 4.96 4.44 4.99 13 8.58 1.71 1.67 8.41 11.63 10.01 8.26 49.19 42.65 8.20 14.25 16.64 8.03 17.35 18.12 7.86 4.28 4.18 14 8.56 1.64 1.79 1.73 8.39 13.17 10.45 10.96 8.25 58.68 46.06 45.60 8.21 11.03 13.34 8.07 14.10 20.24 14.50 7.92 2.10 5.13 4.28 15 8.57 1.74 1.22 1.60 8.41 10.49 15.21 10.78 8.25 46.06 55.05 44.98 8.20 14.46 13.79 8.02 13.90 20.31 10.79 7.89 4.23 4.90 3.43 16 8.56 1.96 1.08 8.40 9.25 12.23 12.58 8.24 38.08 31.03 58.61 8.20 19.02 22.08 21.50 8.03 12.00 13.24 7.31 7.89 4.73 4.82 TABLE C-5 Percentage of bands for light chain (LC), heavy chain (HC), non-glycosylated HC, and other species for formulations in Block C at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. Time LC HC ngHC Other 1 t0 35.87 63.20 0.51 0.42 t1 29.71 63.08 0.37 6.84 t2 31.01 67.83 0.54 0.61 2 t0 29.50 69.57 0.56 0.37 t1 30.51 67.28 0.56 1.65 t2 32.32 65.51 0.56 1.61 3 t0 32.53 66.45 0.54 0.47 t1 33.04 65.34 0.55 1.07 t2 31.94 66.60 0.57 0.90 4 t0 33.40 64.90 0.46 1.24 t1 30.96 67.16 0.52 1.36 t2 32.08 65.84 0.56 1.52 5 t0 34.17 63.89 0.49 1.45 t1 33.60 64.27 0.56 1.57 t2 32.15 66.20 0.48 1.17 6 t0 37.91 60.35 0.54 1.19 t1 34.80 62.88 0.73 1.59 t2 32.90 65.62 0.50 0.99 7 t0 32.17 66.80 0.55 0.49 t1 29.83 68.33 0.59 1.25 t2 33.32 65.97 0.55 0.15 8 t0 33.83 65.51 0.49 0.17 t1 30.37 68.48 0.58 0.57 t2 32.86 66.40 0.55 0.19 9 t0 30.69 69.31 0.00 0.00 t1 34.30 64.24 0.52 0.94 t2 29.08 69.87 0.62 0.43 10 t0 38.68 59.95 0.57 0.80 t1 36.52 58.65 0.00 4.83 t2 43.68 54.39 1.92 0.00 11 t0 35.25 59.00 1.75 4.00 t1 30.71 67.58 0.66 1.05 t2 30.18 67.14 0.47 2.21 13 t0 44.58 55.42 0.00 0.00 t1 37.73 60.75 0.25 1.28 t2 38.05 61.44 0.52 0.00 14 t0 32.50 66.66 0.60 0.24 t1 30.91 67.77 0.61 0.70 t2 29.14 70.32 0.23 0.31 15 t0 30.07 68.95 0.63 0.35 t1 30.14 68.49 0.62 0.75 t2 31.57 67.55 0.62 0.26 16 t0 30.54 68.61 0.63 0.22 t1 29.81 68.81 0.63 0.75 t2 29.46 69.14 0.59 0.81 Discussion of Block C Results Referring to Table C-1 above, the pH was measured and found to be relatively stable for all of the formulations. However, the initial pH values were slightly higher for the citrate/phosphate formulations. The least stable formulation by SEC analysis appears to be Formulation 1, the one using the Humira® buffer system. By comparison we discovered that formulations using His as the buffer and/or formulations containing Gly or Arg exhibited the greatest stability (See Table C-2). Similar trends are seen when the purity by RP HPLC is considered (See Table C-3). It appears that SEC may be a better stability-indicating method than RP HPLC, although, when taken as a whole, the RP HPLC method does appear to be stability-indicating. Based on the Block C data summarized above, we have discovered that Histidine is suitable as a preferred buffer in terms of formulation stability, and that glycine or arginine, or combinations thereof, are also stability enhancing components for inclusion in an adalimumab formulation. The stored samples were further analyzed by cIEF at t1 and t2 (Table C-4 above). A proprietary adalimumab material exhibit four to five peaks with integrated intensities above 1% or so. In general, there are some small decreases in the intensity of the main peak upon storage. These losses are usually greater at t1 than at t2. Still, no significant new peaks are observed, suggesting that there is minimal chemical degradation occurring that would lead to changes in the overall charge on the protein. The variance in the data indicates that this method, while useful for characterization, does not appear to be stability-indicating. The final analytical method used to evaluate the stability of adalimumab formulation is CE-SDS, which is essentially the CE version of SDS-PAGE slab gels. This method indicates that the relative areas of the LC peak do decrease when stored at elevated temperatures (Table C-5), while the amount of new peaks (cumulatively called ‘Other’) increases. Altogether, these changes are usually less than 2% for any of the formulations. There are some samples where the percentage of ‘Other’ is in the 4-6% range, but these are likely artifacts. Block D Formulation Studies Another set of formulations were evaluated as “Block D.” Sixteen formulations were designed to evaluate other stabilizers as alternatives to mannitol, such as sorbitol and trehalose (See Table D). Block D also examined using mannitol or NaCl as the sole tonicity agent, instead of using a mixture of the two excipients. The pH stability of the formulations was quite good, although the actual initial pH values were slightly lower than the target values for some formulations (Table D-1). TABLE D BLOCK D STUDY DESIGN Form No. API citrate phosphate sorbitol trehalose mannitol NaCl PS 80 1 Adalimumab 8 18 0 0 65 100 0.1 biosimilar 2 Adalimumab 8 18 0 0 65 100 0 biosimilar 3 Adalimumab 20 0 0 0 65 100 0.1 biosimilar 4 Adalimumab 20 0 0 0 65 100 0 biosimilar 5 Adalimumab 0 20 0 0 65 100 0.1 biosimilar 6 Adalimumab 0 20 0 0 65 100 0 biosimilar 7 Adalimumab 8 18 65 0 0 100 0.1 biosimilar 8 Adalimumab 8 18 0 65 0 100 0.1 biosimilar 9 Adalimumab 0 20 65 0 0 100 0.1 biosimilar 10 Adalimumab 0 10 0 0 240 0 0.1 biosimilar 11 Adalimumab 0 10 240 0 0 0 0.1 biosimilar 12 Adalimumab 0 10 0 240 0 0 0.1 biosimilar 13 Adalimumab 10 0 0 0 0 150 0.1 biosimilar 14 Adalimumab 10 0 0 0 0 150 0 biosimilar 15 Adalimumab 0 10 0 0 0 150 0.1 biosimilar 16 Adalimumab 0 10 0 0 0 150 0 biosimilar TABLE D-1 Measured pH for Block D formulations at t0 and t1 (one week, 40° C.) Form PS No. API citrate phosphate sorbitol trehalose mannitol NaCl 80 t0 t1 t2 1 Adalimumab 8 18 0 0 65 100 0.1 5.09 5.17 5.12 biosimilar 2 Adalimumab 8 18 0 0 65 100 0 5.12 5.16 5.16 biosimilar 3 Adalimumab 20 0 0 0 65 100 0.1 5.11 5.16 5.14 biosimilar 4 Adalimumab 20 0 0 0 65 100 0 5.13 5.17 5.18 biosimilar 5 Adalimumab 0 20 0 0 65 100 0.1 5.19 5.25 5.24 biosimilar 6 Adalimumab 0 20 0 0 65 100 0 5.16 5.24 5.17 biosimilar 7 Adalimumab 8 18 65 0 0 100 0.1 5.14 5.17 5.18 biosimilar 8 Adalimumab 8 18 0 65 0 100 0.1 5.15 5.21 5.16 biosimilar 9 Adalimumab 0 20 65 0 0 100 0.1 5.19 5.29 5.28 biosimilar 10 Adalimumab 0 10 0 0 240 0 0.1 5.23 5.28 5.27 biosimilar 11 Adalimumab 0 10 240 0 0 0 0.1 5.45 5.35 5.33 biosimilar 12 Adalimumab 0 10 0 240 0 0 0.1 5.44 5.32 5.31 biosimilar 13 Adalimumab 10 0 0 0 0 150 0.1 5.30 5.25 5.23 biosimilar 14 Adalimumab 10 0 0 0 0 150 0 5.39 5.20 5.18 biosimilar 15 Adalimumab 0 10 0 0 0 150 0.1 5.35 5.30 5.22 biosimilar 16 Adalimumab 0 10 0 0 0 150 0 5.41 5.33 5.28 biosimilar TABLE D-2 Monomer content by SEC for formulations in Block D at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form PS No. API citrate phosphate sorbitol trehalose mannitol NaCl 80 t0 t1 t2 1 Adalimumab 8 18 0 0 65 100 0.1 99.28 98.21 98.96 biosimilar 2 Adalimumab 8 18 0 0 65 100 0 99.25 98.11 98.85 biosimilar 3 Adalimumab 20 0 0 0 65 100 0.1 99.25 98.16 98.86 biosimilar 4 Adalimumab 20 0 0 0 65 100 0 99.27 98.26 98.92 biosimilar 5 Adalimumab 0 20 0 0 65 100 0.1 99.24 98.16 98.84 biosimilar 6 Adalimumab 0 20 0 0 65 100 0 99.21 98.23 98.82 biosimilar 7 Adalimumab 8 18 65 0 0 100 0.1 99.30 98.19 98.94 biosimilar 8 Adalimumab 8 18 0 65 0 100 0.1 99.28 98.14 98.85 biosimilar 9 Adalimumab 0 20 65 0 0 100 0.1 99.29 98.23 98.90 biosimilar 10 Adalimumab 0 10 0 0 240 0 0.1 97.93 98.54 biosimilar 11 Adalimumab 0 10 240 0 0 0 0.1 99.32 98.65 99.00 biosimilar 12 Adalimumab 0 10 0 240 0 0 0.1 99.32 98.53 98.96 biosimilar 13 Adalimumab 10 0 0 0 0 150 0.1 99.29 98.12 98.84 biosimilar 14 Adalimumab 10 0 0 0 0 150 0 99.28 98.28 98.90 biosimilar 15 Adalimumab 0 10 0 0 0 150 0.1 99.26 97.99 98.83 biosimilar 16 Adalimumab 0 10 0 0 0 150 0 99.20 97.76 98.62 biosimilar TABLE D-3 Percent purity by RP HPLC for formulations in Block D at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form PS No. API citrate phosphate sorbitol trehalose mannitol NaCl 80 t0 t1 t2 1 Adalimumab 8 18 0 0 65 100 0.1 98.17 97.75 98.02 biosimilar 2 Adalimumab 8 18 0 0 65 100 0 98.09 97.84 98.08 biosimilar 3 Adalimumab 20 0 0 0 65 100 0.1 98.03 97.81 98.19 biosimilar 4 Adalimumab 20 0 0 0 65 100 0 98.17 97.85 98.06 biosimilar 5 Adalimumab 0 20 0 0 65 100 0.1 98.11 97.88 98.18 biosimilar 6 Adalimumab 0 20 0 0 65 100 0 98.21 97.77 98.10 biosimilar 7 Adalimumab 8 18 65 0 0 100 0.1 98.11 97.80 98.14 biosimilar 8 Adalimumab 8 18 0 65 0 100 0.1 98.06 97.73 98.03 biosimilar 9 Adalimumab 0 20 65 0 0 100 0.1 98.09 97.80 98.07 biosimilar 10 Adalimumab 0 10 0 0 240 0 0.1 98.13 97.82 98.08 biosimilar 11 Adalimumab 0 10 240 0 0 0 0.1 98.10 97.90 98.06 biosimilar 12 Adalimumab 0 10 0 240 0 0 0.1 98.13 97.95 98.14 biosimilar 13 Adalimumab 10 0 0 0 0 150 0.1 98.07 97.79 98.02 biosimilar 14 Adalimumab 10 0 0 0 0 150 0 98.13 97.78 98.14 biosimilar 15 Adalimumab 0 10 0 0 0 150 0.1 98.17 97.80 98.10 biosimilar 16 Adalimumab 0 10 0 0 0 150 0 98.14 97.79 98.06 biosimilar TABLE D-4 Percentage of main bands seen in the cIEF profile of formulations in Block D at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. pH t0 t1 t2 1 8.56 2.26 1.81 8.41 13.84 12.88 11.73 8.25 62.27 59.80 56.15 8.14 6.48 8.04 15.71 22.93 13.73 7.99 5.92 4.39 4.13 2 8.55 2.08 1.58 8.40 12.89 12.58 8.24 60.15 53.24 8.14 5.98 6.69 8.03 11.92 9.72 7.98 3.65 5.67 3 8.57 1.58 2.10 1.89 8.41 11.87 11.83 11.99 8.26 54.93 54.45 54.51 8.16 9.10 6.31 8.24 8.05 9.21 11.16 10.22 7.91 7.60 4.16 5.26 4 8.57 3.57 1.82 1.05 8.40 11.12 10.66 10.83 8.24 49.37 47.85 42.34 8.14 3.01 1.83 3.68 8.03 10.11 10.06 17.12 7.90 2.78 4.72 3.84 5 8.55 2.30 2.18 2.13 8.40 7.63 8.86 8.63 8.25 33.90 14.41 16.64 8.20 23.41 33.90 33.75 8.03 10.14 20.39 19.42 7.99 6.76 5.42 4.63 6 8.59 1.87 1.39 8.42 11.25 11.18 11.89 8.27 50.07 61.72 64.17 8.20 12.43 22.08 19.18 8.03 10.20 7.91 2.70 5.01 3.38 7 8.55 8.40 8.25 8.20 8.03 7.99 8 8.59 1.46 2.64 1.16 8.39 13.52 13.62 7.37 8.22 60.79 50.83 55.40 8.08 5.21 11.28 9.78 8.02 15.24 8.55 11.94 7.91 3.79 3.02 5.18 9 8.53 2.64 3.25 1.94 8.38 13.83 12.72 11.67 8.25 64.97 51.32 54.14 8.17 8.33 11.21 8.61 8.06 11.75 9.98 9.03 8.01 5.79 4.80 7.31 10 8.54 1.78 3.26 8.38 13.04 11.19 8.21 60.53 44.83 8.15 19.60 10.95 7.99 9.41 7.90 5.05 4.27 11 8.52 1.95 2.11 1.89 8.36 11.24 12.43 12.43 8.21 48.64 54.10 59.90 8.13 11.69 6.31 8.00 10.30 21.14 11.14 8.01 5.27 5.64 8.32 12 8.51 1.85 8.29 11.31 11.38 8.18 63.11 45.14 8.14 2.54 8.05 16.16 22.03 7.94 5.03 6.88 13 8.62 3.51 3.05 8.44 12.44 12.30 8.29 65.10 51.44 8.21 12.18 8.06 15.37 17.25 7.91 3.58 3.77 14 8.61 2.74 1.73 8.43 10.60 12.19 8.27 46.23 41.11 8.21 13.97 10.49 8.05 18.56 17.52 7.91 5.15 15 8.62 8.35 12.40 10.91 8.34 8.21 31.87 30.32 36.39 8.20 41.14 25.57 30.62 8.02 12.42 13.72 18.26 7.89 2.18 5.44 3.86 16 8.61 8.48 12.96 12.86 13.19 8.34 34.40 31.45 39.25 8.31 27.74 20.29 18.81 8.05 22.76 19.35 7.89 8.17 7.69 4.83 TABLE D-5 Percentage of bands for light chain (LC), heavy chain (HC), non-glycosylated HC, and other species for formulations in Block D at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. Time LC HC ngHC Other 1 t0 t1 34.11 62.58 0.58 2.73 t2 33.19 64.28 0.60 1.92 2 t0 30.25 66.81 0.64 2.31 t1 30.61 65.79 0.54 3.07 t2 29.22 67.04 0.64 3.10 3 t0 27.48 68.51 0.59 3.42 t1 30.84 67.27 0.54 1.35 t2 30.30 68.13 0.58 0.99 4 t0 30.88 68.33 0.60 0.19 t1 29.76 68.32 0.57 1.34 t2 31.49 66.95 0.55 1.01 5 t0 33.77 64.50 0.56 1.17 t1 31.59 66.54 0.52 1.34 t2 29.19 69.16 0.59 1.06 6 t0 30.90 68.08 0.56 0.47 t1 29.32 69.88 0.54 0.26 t2 31.08 67.58 0.54 0.79 7 t0 30.41 68.60 0.56 0.43 t1 30.87 66.95 0.55 1.63 t2 30.14 68.28 0.55 1.03 8 t0 31.68 67.41 0.60 0.31 t1 t2 9 t0 29.62 68.12 0.51 1.75 t1 t2 29.46 68.10 0.61 1.83 10 t0 29.80 67.99 0.58 1.64 t1 30.04 65.53 0.45 3.98 t2 30.41 66.27 0.53 2.80 11 t0 29.85 67.63 0.61 1.91 t1 29.02 68.18 0.60 2.20 t2 30.44 67.14 0.58 1.84 12 t0 29.38 68.11 0.55 1.96 t1 30.16 65.55 0.49 3.80 t2 28.20 69.19 0.59 2.02 13 t0 31.38 66.28 0.55 1.79 t1 33.67 64.10 0.56 1.67 t2 29.72 67.99 0.58 1.71 14 t0 37.34 60.53 0.52 1.62 t1 33.03 63.46 0.53 2.97 t2 34.39 63.62 0.54 1.45 15 t0 30.20 68.42 0.59 0.79 t1 28.67 69.42 0.58 1.33 t2 29.96 68.24 0.56 1.24 16 t0 31.62 66.95 0.58 0.85 t1 30.48 66.36 0.55 2.61 t2 27.94 70.17 0.60 1.29 Results of Block D The pH stability was quite good for these formulations (Table D-1). Once again, the commercial adalimumab (Humira®) formulation was used as a control (but using a proprietary adalimumab biosimilar protein as the API). The commercial formulation again showed poorer stability by SEC than those using single buffers like phosphate and His (See Table D-2). Of the two buffers used in Humira®, we have now discovered that phosphate is the better stabilizer. This is surprising, as phosphate has virtually no buffer capacity at pH 5.2, while citrate buffers well at this pH. This suggests that the differences in stability profile may be due to direct interaction of the buffer with the protein, a phenomenon that, in the case of the commercial Humira® formulation, we believe was not previously understood or appreciated. Accordingly, the comparative benefit of selecting phosphate as a buffer in an adalimumab formulation, due to superior stability in the formulation versus the selection of a citrate/phosphate combination constitutes one of the important aspects of our invention. Both sorbitol and trehalose display better stability profiles than mannitol when used as the sole tonicity agent in these formulations. It also appears that removal of the polysorbate 80 (PS 80) decreases stability somewhat. The best stability profile by SEC appears to be for Formulations 10 and 11, which contain high concentrations of sorbitol or trehalose in place of mannitol/NaCl (Table D-2). These results indicate to us that removing NaCl from the formulation, or limiting its concentration below certain targeted levels (for example less than about 100 mM), will be beneficial for stability. (We note that mannitol does appear to be a stabilizing ingredient, but at levels preferably above 150.) The RP data indicates that either citrate or phosphate provides better stability than the combination used in Humira® (Table D-3). Again, the avoidance of the citrate/phosphate combination represents an important feature of our invention. It could not have been known or predicted that citrate alone, or phosphate alone would provide better formulation stability than the commercial buffer system comprising a combination of citrate and phosphate. The cIEF analyses were run for Block D samples (Table D-4 above). As before, there is some decrease in the intensity of the main peak, but no new peaks are observed. In some cases, there is some small increase in the intensity of the more acidic peaks. The decreases in the main peak appear to be greater at t1 than at t2, suggesting that degradation at 5° C. would be almost imperceptible. Still, overall it looks like less than 5% (and probably much less than 5%) is degrading as measured by cIEF (Table D-4). Likewise, little degradation is seen by CE-SDS (Table D-5). At most 2 to 4% degradation is seen, but the variability in the method makes it difficult to determine if these are real changes. There does appear to be higher impurity levels (Other) for Formulations 1 and 2 and 10 through 14. Block E Formulation Studies This block of formulations was designed to evaluate the stability of formulations at different pH levels. If a buffer is not specified, acetate buffer (10 mM) was employed (Table E). A secondary objective was to evaluate Gly and Arg at higher concentrations and in combination as alternative stabilizers to mannitol and NaCl. TABLE E BLOCK E STUDY DESIGN Form PS No. API pH citrate phosphate sorbitol Gly Arg mannitol NaCl 80 1 Adalimumab 5.2 8 18 0 0 0 65 100 0.1 biosimilar 2 Adalimumab 3.5 8 18 0 0 0 65 100 0.1 biosimilar 3 Adalimumab 5.2 0 0 0 0 0 65 100 0.1 biosimilar 4 Adalimumab 3.5 0 0 0 0 0 65 100 0.1 biosimilar 5 Adalimumab 3.5 0 0 65 0 0 0 100 0.1 biosimilar 6 Adalimumab 3.5 0 0 0 0 130 0 0 0.1 biosimilar 7 Adalimumab 3.5 0 0 0 0 130 0 0 0 biosimilar 8 Adalimumab 3.5 0 0 0 240 0 0 0 0 biosimilar 9 Adalimumab 5.2 0 0 0 240 0 0 0 0 biosimilar 10 Adalimumab 3.5 0 0 0 100 100 0 0 0 biosimilar 11 Adalimumab 5.2 0 0 0 100 100 0 0 0 biosimilar 12 Adalimumab 3.5 0 0 0 150 50 0 0 0 biosimilar TABLE E-1 Measured pH for Block E formulations at t0 and t1 (one week, 40° C.) Form PS No. pH citrate phosphate sorbitol Gly Arg mannitol NaCl 80 t0 t1 t2 1 5.2 8 18 0 0 0 65 100 0.1 5.15 5.11 5.21 2 3.5 8 18 0 0 0 65 100 0.1 3.36 3.49 3.50 3 5.2 0 0 0 0 0 65 100 0.1 5.13 5.24 5.24 4 3.5 0 0 0 0 0 65 100 0.1 3.31 3.43 3.45 5 3.5 0 0 65 0 0 0 100 0.1 3.30 3.48 3.42 6 3.5 0 0 0 0 130 0 0 0.1 3.24 3.52 3.42 7 3.5 0 0 0 0 130 0 0 0 3.27 3.59 3.48 8 3.5 0 0 0 240 0 0 0 0 3.27 3.33 3.39 9 5.2 0 0 0 240 0 0 0 0 5.05 5.25 5.20 10 3.5 0 0 0 100 100 0 0 0 3.30 3.45 3.41 11 5.2 0 0 0 100 100 0 0 0 5.20 5.38 5.39 12 3.5 0 0 0 150 50 0 0 0 3.24 3.38 3.37 TABLE E-2 Monomer content by SEC for formulations in Block E at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form PS No. pH citrate phosphate sorbitol Gly Arg mannitol NaCl 80 t0 t1 t2 1 5.2 8 18 0 0 0 65 100 0.1 99.23 98.20 98.85 2 3.5 8 18 0 0 0 65 100 0.1 98.82 44.15 86.37 3 5.2 0 0 0 0 0 65 100 0.1 99.30 98.37 99.02 4 3.5 0 0 0 0 0 65 100 0.1 95.85 33.51 76.21 5 3.5 0 0 65 0 0 0 100 0.1 97.37 26.21 77.80 6 3.5 0 0 0 0 130 0 0 0.1 97.79 35.67 65.83 7 3.5 0 0 0 0 130 0 0 0 99.00 55.51 90.60 8 3.5 0 0 0 240 0 0 0 0 99.24 75.60 98.24 9 5.2 0 0 0 240 0 0 0 0 99.08 98.63 99.18 10 3.5 0 0 0 100 100 0 0 0 99.28 51.03 91.66 11 5.2 0 0 0 100 100 0 0 0 99.32 98.54 99.09 12 3.5 0 0 0 150 50 0 0 0 99.29 45.86 93.06 TABLE E-3 Percent purity by RP HPLC for formulations in Block E at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form PS No. pH citrate phosphate sorbitol Gly Arg mannitol NaCl 80 t0 t1 t2 1 5.2 8 18 0 0 0 65 100 0.1 98.58 96.88 96.91 2 3.5 8 18 0 0 0 65 100 0.1 98.51 90.29 95.99 3 5.2 0 0 0 0 0 65 100 0.1 98.50 96.90 96.83 4 3.5 0 0 0 0 0 65 100 0.1 98.56 91.18 95.55 5 3.5 0 0 65 0 0 0 100 0.1 98.45 90.96 95.71 6 3.5 0 0 0 0 130 0 0 0.1 98.71 93.28 95.38 7 3.5 0 0 0 0 130 0 0 0 98.40 90.65 96.54 8 3.5 0 0 0 240 0 0 0 0 98.03 93.94 96.82 9 5.2 0 0 0 240 0 0 0 0 98.23 97.19 97.12 10 3.5 0 0 0 100 100 0 0 0 98.13 91.10 96.67 11 5.2 0 0 0 100 100 0 0 0 98.13 97.17 97.12 12 3.5 0 0 0 150 50 0 0 0 98.07 93.40 96.48 TABLE E-4 Percentage of bands for light chain (LC), heavy chain (HC), non-glycosylated HC, and other species for formulations in Block E at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. Time LC HC ngHC Other 1 t0 29.97 68.80 0.59 0.64 t1 28.49 70.07 0.60 0.81 t2 28.21 70.29 0.59 0.90 2 t0 28.50 68.67 0.52 2.31 t1 29.69 50.92 0.30 19.09 t2 28.76 69.64 0.60 1.00 3 t0 24.30 74.01 0.60 1.09 t1 28.27 69.63 0.60 1.51 t2 28.17 69.89 0.54 1.40 4 t0 29.45 68.73 0.56 1.26 t1 29.52 51.33 0.30 18.86 t2 27.92 65.73 0.52 5.83 5 t0 35.59 63.85 0.56 0.00 t1 32.47 48.72 0.30 18.52 t2 34.98 60.88 0.46 3.68 6 t0 34.33 63.39 0.51 1.77 t1 t2 35.32 61.31 0.45 2.92 7 t0 30.13 68.87 0.60 0.40 t1 28.13 54.79 0.59 16.49 t2 34.39 63.32 0.53 1.76 8 t0 33.27 64.97 0.55 1.21 t1 33.20 52.62 0.33 13.85 t2 33.25 65.26 0.58 0.92 9 t0 32.28 66.34 0.57 0.81 t1 31.81 65.76 0.57 1.86 t2 31.23 66.81 0.57 1.39 10 t0 35.66 63.36 0.43 0.56 t1 24.96 58.61 0.33 16.10 t2 33.44 66.03 0.53 0.00 11 t0 29.75 69.08 0.60 0.57 t1 27.67 70.83 0.61 0.89 t2 28.81 69.86 0.59 0.73 12 t0 30.23 49.07 0.26 20.44 t1 28.14 70.11 0.58 1.18 t2 29.75 69.08 0.60 0.57 TABLE E-5 Percentage of main bands seen in the cIEF profile of formulations in Block E at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C. Form No. pH t0 t1 t2 1 8.56 8.37 12.52 12.65 8.23 51.77 50.04 8.14 8.03 21.54 12.40 7.93 14.17 16.26 2 1.88 1.49 8.37 10.07 17.66 14.15 8.21 37.52 32.26 33.88 8.13 19.03 9.96 8.01 16.57 28.70 7.93 4.12 7.45 4 8.54 1.04 2.67 8.38 10.50 9.32 8.21 68.34 31.91 8.13 28.52 8.02 16.55 10.05 7.88 3.57 8.67 5 6 7 8 9 8.60 1.40 2.60 3.26 8.43 10.04 12.33 12.03 8.26 62.39 63.19 63.89 8.14 8.03 15.00 16.95 16.57 7.88 7.08 4.93 4.25 Results of Block E Studies The pH stability was modest, with increases in pH occurring at t1 for many of the formulations, especially those buffered with acetate at low pH (Table E-1 above). Two of the samples (Formulations 6 and 12) gelled at t1. There were sizable losses in monomer content for the pH3.5 samples (Table E-3), whereas the pH 5.2 samples displayed stability comparable to what was seen in the preceding Blocks. It was also clear that the degradation was much more pronounced at 40 C than at 25, despite being stored for twice the length of time. In fact, Formulation 8 lost less than 1% monomer at t2 (Table E-2). The Gly and Arg formulations all displayed good stability, provided the pH was held 5.2. The data in this block of studies confirm our discovery that glycine or arginine, or a mixture thereof are good stabilizers in an adalimumab formulation. The RP HPLC data shows large decreases in purity, although not nearly as great as for monomer loss by SEC (Table E-3). This suggests that chemical instability is less than physical instability. As with the SEC results, the loss of stability is more pronounced at t1 than at t2. The CE-SDS results show large increases in new peaks, with the Other category increasing to 15-20% for low pH samples at t1 (Table E-4). The most stable formulation by CE-SDS appears to be Formulation 11, which contains both Gly and Arg as the tonicity modifiers/stabilizers. We encountered difficulties running the cIEF for many of the Block E samples. However, given the clearly inferior stability at pH 3.5, it is unlikely that cIEF would provide any new information on those stability profiles. For example, Formulation 4 (pH 3.5) shows a splitting of the main peak at t1. Block F Formulation Studies The Block F studies were intended to investigate the stability for His-containing formulation using either mannitol, Gly or Arg as the sole tonicity modifier (Table F below). It also served as an opportunity to evaluate additives such as EDTA and methionine (Met), which can be effective at slowing oxidation. In addition, one high citrate concentration and one high phosphate concentration formulation were examined. TABLE F BLOCK F STUDY DESIGN Form PS No. API pH citrate phosphate His Gly Arg mannitol NaCl 80 EDTA Met 1 Adalimurnab 5.2 8 18 0 0 0 65 100 0.1 0 0 biosimilar 2 Adalimumab 5.2 8 18 0 0 0 65 100 0.1 0.5 0 biosimilar 3 Adalimumab 5.2 0 0 10 0 150 0 0 0 0.1 0 biosimilar 4 Adalimumab 5.2 0 0 10 0 150 0 0 0 0.5 0 biosimilar 5 Adalimumab 5.2 0 0 10 0 0 240 0 0 0 0 biosimilar 6 Adalimumab 5.2 0 0 10 0 0 240 0 0 0 10 biosimilar 7 Adalimurnab 5.2 0 0 10 0 0 240 0 0 0 50 biosimilar 8 Adalimurnab 5.2 30 0 0 240 0 0 0 0 0 0 biosimilar 9 Adalimumab 5.2 0 30 0 240 0 0 0 0 0 0 biosimilar 10 Adalimumab 5.2 0 0 30 240 0 0 0 0 0 0 biosimilar 11 Adalimurnab 5.2 0 0 20 0 25 120 0 0.1 0 0 biosimilar 12 Adalimumab 5.2 0 0 20 0 25 120 0 0.1 0 0 biosimilar TABLE F-1 Measured pH for Block F formulations at t0 and t1 (one week, 40° C.) Form PS No. citrate phosphate His Gly Arg mannitol NaCl 80 EDTA Met t0 t1 t2 1 8 18 0 0 0 65 100 0.1 0 0 4.67 4.88 4.77 2 8 18 0 0 0 65 100 0.1 0.5 0 5.05 5.15 5.20 3 0 0 10 0 150 0 0 0 0.1 0 5.11 5.22 5.27 4 0 0 10 0 150 0 0 0 0.5 0 4.95 5.06 5.15 5 0 0 10 0 0 240 0 0 0 0 5.12 5.25 5.29 6 0 0 10 0 0 240 0 0 0 10 4.45 4.74 4.67 7 0 0 10 0 0 240 0 0 0 50 5.03 5.24 5.24 8 30 0 0 240 0 0 0 0 0 0 5.09 5.18 5.22 9 0 30 0 240 0 0 0 0 0 0 5.13 5.25 5.32 10 0 0 30 240 0 0 0 0 0 0 5.08 5.24 5.24 11 0 0 20 0 25 120 0 0.1 0 0 5.01 5.17 5.18 12 0 0 20 0 25 120 0 0.1 0 0 5.06 5.20 5.19 TABLE F-2 Monomer content by SEC for formulations in Block F at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form PS No. citrate phosphate His Gly Arg mannitol NaCl 80 EDTA Met t0 t1 t2 1 8 18 0 0 0 65 100 0.1 0 0 97.69 94.75 96.06 2 8 18 0 0 0 65 100 0.1 0.5 0 99.25 98.14 98.92 3 0 0 10 0 150 0 0 0 0.1 0 99.30 98.54 99.16 4 0 0 10 0 150 0 0 0 0.5 0 99.28 98.31 99.14 5 0 0 10 0 0 240 0 0 0 0 99.17 98.64 99.14 6 0 0 10 0 0 240 0 0 0 10 99.07 98.50 99.07 7 0 0 10 0 0 240 0 0 0 50 99.29 98.92 99.24 8 30 0 0 240 0 0 0 0 0 0 99.28 98.40 99.04 9 0 30 0 240 0 0 0 0 0 0 99.30 98.50 99.08 10 0 0 30 240 0 0 0 0 0 0 99.31 98.60 99.23 11 0 0 20 0 25 120 0 0.1 0 0 99.27 98.64 99.16 12 0 0 20 0 25 120 0 0.1 0 0 99.29 98.51 99.17 TABLE F-3 Percent purity by RP HPLC for formulations in Block F at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form PS No. citrate phosphate His Gly Arg mannitol NaCl 80 EDTA Met t0 t1 t2 1 8 18 0 0 0 65 100 0.1 0 0 97.47 96.89 97.98 2 8 18 0 0 0 65 100 0.1 0.5 0 97.33 97.02 97.99 3 0 0 10 0 150 0 0 0 0.1 0 97.64 97.14 98.04 4 0 0 10 0 150 0 0 0 0.5 0 97.59 97.00 97.97 5 0 0 10 0 0 240 0 0 0 0 97.11 97.30 98.03 6 0 0 10 0 0 240 0 0 0 10 97.61 97.27 98.03 7 0 0 10 0 0 240 0 0 0 50 97.55 97.37 98.08 8 30 0 0 240 0 0 0 0 0 0 97.48 97.51 98.05 9 0 30 0 240 0 0 0 0 0 0 97.64 97.58 98.03 10 0 0 30 240 0 0 0 0 0 0 97.68 97.41 98.06 11 0 0 20 0 25 120 0 0.1 0 0 97.67 97.18 98.03 12 0 0 20 0 25 120 0 0.1 0 0 97.68 97.33 98.02 TABLE F-4 Percentage of bands for light chain (LC), heavy chain (HC), non-glycosylated HC, and other species for formulations in Block F at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. Time LC HC ngHC Other 1 t0 27.36 71.86 0.60 0.17 t1 t2 25.34 73.18 0.63 0.86 2 t0 27.80 71.07 0.60 0.53 t1 28.29 71.08 0.63 0.00 t2 27.53 70.97 0.64 0.86 3 t0 27.78 70.62 0.65 0.95 t1 28.26 70.85 0.66 0.23 t2 28.26 70.50 0.63 0.61 4 t0 28.20 70.24 0.60 0.96 t1 29.17 69.30 0.74 0.80 t2 29.17 70.27 0.56 0.00 5 t0 27.50 70.74 0.59 1.17 t1 29.56 65.79 0.41 4.24 t2 28.24 69.90 0.58 1.28 6 t0 29.10 68.84 0.54 1.52 t1 28.58 69.18 0.54 1.70 t2 27.47 70.39 0.54 1.60 7 t0 27.87 70.28 0.55 1.30 t1 t2 8 t0 34.72 64.87 0.41 0.00 t1 34.94 64.53 0.53 0.00 t2 33.21 65.76 0.50 0.52 9 t0 31.96 68.04 0 0 t1 48.51 51.49 0 0 t2 33.15 65.82 0.57 0.46 10 t0 27.81 71.27 0.51 0.40 t1 29.59 68.46 0.53 1.43 t2 31.25 67.89 0.50 0.36 11 t0 27.33 70.80 0.61 1.26 t1 26.54 71.00 0.64 1.82 t2 29.46 69.85 0.69 0.00 12 t0 24.18 71.21 0 4.61 t1 t2 28.95 68.98 0.59 1.46 TABLE F-5 Percentage of main bands seen in the cIEF profile of formulations in Block F at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C. Form No. pH t0 t1 t2 1 8.65 2.11 8.31 13.07 11.43 34.17 8.24 64.66 67.99 28.67 8.14 2.29 8.08 16.13 17.73 15.98 7.95 6.14 4.80 2 8.60 1.56 1.93 1.12 8.48 12.95 11.26 11.12 8.24 58.99 55.85 60.37 8.13 20.98 22.43 18.77 7.93 3.56 6.41 6.09 8.60 1.56 1.93 1.12 3 8.56 1.56 1.69 8.34 10.88 12.85 10.83 8.18 66.93 55.35 62.00 8.02 17.28 19.04 20.13 7.89 4.91 11.21 5.35 4 8.58 1.86 1.68 8.45 13.79 10.61 12.84 8.27 65.06 51.89 61.94 8.06 19.29 18.85 25.22 7.96 6.28 4.91 5 8.60 1.35 1.78 1.45 8.45 12.35 13.63 8.59 8.27 60.12 55.07 64.28 8.07 20.50 20.35 19.73 7.94 5.69 9.17 5.95 6 8.55 1.30 1.30 1.08 8.43 13.29 13.26 13.23 8.24 54.83 56.88 61.67 8.08 20.76 19.79 17.19 7.96 9.82 8.76 6.84 7 8.57 1.28 1.41 2.40 8.44 12.08 12.63 13.05 8.27 61.50 55.33 60.70 8.08 17.55 19.48 17.43 7.94 5.93 8.92 4.25 8 8.55 1.32 0.90 8.43 11.51 12.47 10.09 8.24 62.99 54.09 63.81 8.05 15.43 22.71 20.91 7.90 8.75 9.83 5.19 9 8.59 1.35 1.63 8.45 11.59 13.67 11.40 8.28 63.60 52.70 63.11 8.06 17.98 24.08 18.57 7.94 2.28 7.05 5.29 10 8.57 1.56 2.50 2.08 8.45 13.22 11.93 12.90 8.28 61.86 55.12 61.87 8.08 17.87 20.99 18.74 7.97 5.50 4.71 4.41 11 8.59 1.43 1.19 8.45 12.25 11.42 9.85 8.28 58.83 59.88 64.13 8.08 18.18 22.06 17.46 7.97 9.61 5.45 6.97 12 8.56 1.64 1.39 0.94 8.39 15.30 13.07 15.71 8.21 63.76 59.71 62.92 8.02 16.72 20.51 16.60 7.97 2.58 4.21 3.85 Results of Block F In this block of formulations, the pH values were all slightly lower than the target value of pH 5.2 (Table F-1). In addition, the pH does change by about 0.1 units for most of the formulations when measured at t1. These differences were considered when constructing mathematical models of the data, as discussed below. The addition of EDTA does appear to improve stability for the worst formulation (Formulation 1). Whether it increases stability in general was less clear, based on the SEC data (Table F-2). The formulations containing high concentrations of Arg or Gly all performed quite well upon storage (Table F-2). The initial purities by RP HPLC were universally lower than expected for these formulations (Table F-3). Upon storage at t1 and t2, there are some slight differences, with Gly- and Arg-based formulations showing the greatest stability. Based upon the RP HPLC data, EDTA does not appear to be a significant stabilizer (Table F-3). Likewise, the effect of Met appears to be minimal on stability as measured by RP HPLC or SEC, with the exception of the monomer content for the highest Met concentration (Table F-2, Formulation 7). Analysis by CE-SDS indicates that very little degradation occurs upon storage (usually less than 1% increase in ‘Other’) (Table F-4). However, there are some formulations that begin with higher ‘Other’ contents (Formulations 4 through 7, for example). These are all formulations using a high concentration of mannitol (240 mM). The same seems to be true for formulations containing 120 mM mannitol. As for analysis by cIEF, there is little change in the relative intensities of the main peak, at least in a systematic fashion that would allow one to discern stability trends (Table F-5). In general, the changes are smaller at t2 than at t1. Block G Formulation Studies The Block G formulation studies examined a variety of formulations with combinations of Gly and Arg as the primary stabilizers (Table XXXIV). In addition, two other surfactants (Pluronic F-68 and polysorbate 20, PS 20) were evaluated in addition to PS 80. Finally, a range of PS 80 concentrations was evaluated. TABLE G BLOCK G STUDY DESIGN Form No. API citrate phosphate succinate HIS Gly Arg mannitol NaCl F68 PS20 PS80 1 Adalimumab 8 18 0 0 0 0 65 100 0 0 0.1 biosimilar 2 Adalimumab 8 18 0 0 0 0 65 100 0 0.1 0 biosimilar 3 Adalimumab 8 18 0 0 0 0 65 100 0.1 0 0 biosimilar 4 Adalimumab 0 0 0 10 120 120 0 0 0 0 0.1 biosimilar 5 Adalimumab 0 0 0 10 120 120 0 0 0 0 0.05 biosimilar 6 Adalimumab 0 0 0 10 120 120 0 0 0 0 0.01 biosimilar 7 Adalimumab 0 0 0 10 120 120 0 0 0 0.05 0 biosimilar 8 Adalimumab 0 0 0 10 120 120 0 0 0.1 0 0 biosimilar 9 Adalimumab 0 0 10 0 120 120 0 0 0 0 0.05 biosimilar 10 Adalimumab 0 0 20 0 150 100 0 0 0 0.05 0 biosimilar 11 Adalimumab 0 0 0 20 150 100 0 0 0 0 0.01 biosimilar 12 Adalimumab 0 0 0 20 120 120 0 0 0 0.01 0 biosimilar TABLE G-1 Measured pH for Block G formulations at t0, t1 (one week, 40° C.), and t2 (two weeks, 40° C.) Form No. citrate phosphate succinate His Gly Arg mannitol NaCl F68 PS20 PS80 t0 t1 t2 1 8 18 0 0 0 0 65 100 0 0 0.1 5.19 5.38 5.25 2 8 18 0 0 0 0 65 100 0 0.1 0 5.23 5.28 5.24 3 8 18 0 0 0 0 65 100 0.1 0 0 5.22 5.26 5.20 4 0 0 0 10 120 120 0 0 0 0 0.1 5.20 5.33 5.29 5 0 0 0 10 120 120 0 0 0 0 0.05 5.23 5.34 5.29 6 0 0 0 10 120 120 0 0 0 0 0.01 5.19 5.40 5.27 7 0 0 0 10 120 120 0 0 0 0.05 0 5.23 5.39 5.42 8 0 0 0 10 120 120 0 0 0.1 0 0 5.19 5.38 5.41 9 0 0 10 0 120 120 0 0 0 0 0.05 5.19 5.27 5.24 10 0 0 20 0 150 100 0 0 0 0.05 0 5.23 5.28 5.24 11 0 0 0 20 150 100 0 0 0 0 0.01 5.23 5.33 5.27 12 0 0 0 20 120 120 0 0 0 0.01 0 5.22 5.29 5.29 TABLE G-2 Monomer content by SEC for formulations in Block G at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. citrate phosphate succinate His Gly Arg mannitol NaCl F68 PS20 PS80 t0 t1 t2 1 8 18 0 0 0 0 65 100 0 0 0.1 99.17 97.45 98.09 2 8 18 0 0 0 0 65 100 0 0.1 0 99.11 97.78 98.09 3 8 18 0 0 0 0 65 100 0.1 0 0 98.99 97.74 97.92 4 0 0 0 10 120 120 0 0 0 0 0.1 99.12 98.67 98.68 5 0 0 0 10 120 120 0 0 0 0 0.05 99.05 98.57 98.53 6 0 0 0 10 120 120 0 0 0 0 0.01 99.05 98.66 98.70 7 0 0 0 10 120 120 0 0 0 0.05 0 99.04 98.63 98.50 8 0 0 0 10 120 120 0 0 0.1 0 0 99.11 98.64 98.55 9 0 0 10 0 120 120 0 0 0 0 0.05 99.12 98.56 98.98 10 0 0 20 0 150 100 0 0 0 0.05 0 99.10 98.49 98.88 11 0 0 0 20 150 100 0 0 0 0 0.01 99.07 98.76 98.45 12 0 0 0 20 120 120 0 0 0 0.01 0 99.11 98.48 TABLE G-3 Percent purity by RP HPLC for formulations in Block G at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C. Form No. citrate phosphate succinate HIS Gly Arg mannitol NaCl F68 PS20 PS80 t0 t1 t2 1 8 18 0 0 0 0 65 100 0 0 0.1 99.74 99.66 98.93 2 8 18 0 0 0 0 65 100 0 0.1 0 99.59 99.66 98.97 3 8 18 0 0 0 0 65 100 0.1 0 0 99.58 99.60 99.22 4 0 0 0 10 120 120 0 0 0 0 0.1 99.62 99.62 98.99 5 0 0 0 10 120 120 0 0 0 0 0.05 99.70 99.61 99.01 6 0 0 0 10 120 120 0 0 0 0 0.01 99.60 99.66 99.00 7 0 0 0 10 120 120 0 0 0 0.05 0 99.71 99.65 98.99 8 0 0 0 10 120 120 0 0 0.1 0 0 99.70 99.61 99.03 9 0 0 10 0 120 120 0 0 0 0 0.05 99.71 99.60 99.03 10 0 0 20 0 150 100 0 0 0 0.05 0 99.72 99.60 99.02 11 0 0 0 20 150 100 0 0 0 0 0.01 99.72 99.61 99.05 12 0 0 0 20 120 120 0 0 0 0.01 0 99.61 99.04 TABLE G-4 Percentage of bands for light chain (LC), heavy chain (HC), non-glycosylated HC, and other species for formulations in Block G at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. Time LC HC ngHC Other 1 t0 28.55 70.77 0.50 0.17 t1 29.71 69.42 0.57 0.30 t2 30.32 68.80 0.53 0.35 2 t0 37.14 62.38 0.49 0.00 t1 30.31 69.38 0.28 0.03 t2 31.60 67.87 0.53 0.00 3 t0 28.95 70.40 0.65 0.00 t1 28.17 70.26 0.58 0.99 t2 27.32 71.52 0.56 0.59 4 t0 29.56 69.02 0.65 0.77 t1 32.19 66.09 0.53 1.19 t2 31.58 66.03 0.57 1.81 5 t0 36.54 62.48 0.56 0.42 t1 28.77 69.28 0.62 1.33 t2 23.76 74.49 0.60 1.16 6 t0 29.60 68.61 0.58 1.21 t1 30.37 67.42 0.59 1.61 t2 32.27 66.08 0.59 1.06 7 t0 31.90 65.50 0.63 1.97 t1 31.26 66.66 0.56 1.51 t2 31.37 66.64 0.67 1.31 8 t0 31.04 67.38 0.54 1.04 t1 30.34 67.99 0.62 1.05 t2 30.21 67.63 0.68 1.48 9 t0 33.12 65.34 0.61 0.94 t1 34.01 63.97 0.56 1.46 t2 34.47 63.77 0.57 1.19 10 t0 36.78 61.61 0.54 1.07 t1 39.25 58.66 0.53 1.56 t2 32.83 65.42 0.55 1.21 11 t0 36.37 61.97 0.54 1.11 t1 t2 34.97 63.14 0.54 1.36 12 t0 34.26 64.16 0.52 1.05 t1 t2 34.90 63.35 0.56 1.19 TABLE G-5 Percentage of main bands seen in the cIEF profile of formulations in Block G at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C. Form No. pH t0 t1 t2 1 8.53 1.24 1.21 8.36 14.30 12.69 13.67 8.24 64.03 53.50 60.30 8.14 8.01 15.77 9.32 19.12 7.86 3.73 3.35 4.48 2 8.52 1.06 1.37 0.88 8.35 13.10 13.30 12.53 8.16 66.28 59.68 57.99 7.97 17.14 19.60 21.55 7.83 2.42 4.78 4.92 3 8.51 0.65 0.65 1.03 8.34 13.31 14.00 15.31 8.16 65.13 59.04 60.70 8.14 7.98 17.26 18.90 17.56 7.82 2.89 5.68 4.16 4 8.36 1.87 2.43 1.00 8.19 7.74 10.89 11.69 7.99 61.91 54.27 59.10 7.82 20.94 22.72 19.81 7.66 6.35 7.98 6.92 5 8.44 1.79 0.95 071 8.26 13.33 12.85 10.43 8.06 61.67 59.94 60.12 7.88 17.49 21.08 20.82 7.69 4.02 4.50 6.50 6 8.36 1.71 4.76 8.21 12.37 12.93 10.95 8.04 62.53 54.16 56.48 7.87 19.24 26.08 17.97 7.64 4.15 2.07 6.50 7 8.54 0.77 1.19 0.79 8.34 7.15 12.32 13.15 8.17 54.73 42.64 60.58 8.02 22.18 29.90 17.28 7.83 7.12 11.47 4.77 7.69 1.41 2.48 2.11 8 8.55 1.04 2.11 8.39 7.28 10.69 14.82 8.23 64.01 57.42 55.68 8.05 20.81 23.86 23.76 7.96 6.79 5.37 5.74 9 8.54 8.48 10.99 7.91 8.31 53.85 61.43 8.17 31.58 23.83 7.99 8.82 7.85 3.58 3.27 10 8.50 0.95 2.16 8.36 9.10 10.65 15.79 8.18 59.02 55.35 58.56 8.02 23.76 24.79 25.66 7.87 5.63 7.05 11 8.58 2.08 1.68 8.40 9.74 10.05 9.67 8.21 62.70 56.96 57.36 8.05 21.39 24.14 25.18 7.99 5.24 6.77 6.11 12 8.54 1.67 8.37 15.99 8.22 63.18 8.02 15.41 7.82 3.75 TABLE G-6 Block G study design for F/T and agitation studies Form No. API citrate phosphate succinate HIS Gly Arg mannitol NaCl F68 PS20 PS80 1 Adalimumab 8 18 0 0 0 0 65 100 0 0 0.1 biolsimilar 2 Adalimumab 8 18 0 0 0 0 65 100 0 0.1 0 biolsimilar 3 Adalimumab 8 18 0 0 0 0 65 100 0.1 0 0 biolsimilar 4 Adalimumab 0 0 0 10 120 120 0 0 0 0 0.1 biolsimilar 5 Adalimumab 0 0 0 10 120 120 0 0 0 0 0.05 biolsimilar 6 Adalimumab 0 0 0 10 120 120 0 0 0 0 0.01 biolsimilar 7 Adalimumab 0 0 0 10 120 120 0 0 0 0.05 0 biolsimilar 8 Adalimumab 0 0 0 10 120 120 0 0 0.1 0 0 biolsimilar 9 Adalimumab 0 0 10 0 120 120 0 0 0 0 0.05 biolsimilar 10 Adalimumab 0 0 20 0 150 100 0 0 0 0.05 0 biolsimilar 11 Adalimumab 0 0 0 20 150 100 0 0 0 0 0.01 biolsimilar 12 Adalimumab 0 0 0 20 120 120 0 0 0 0.01 0 biolsimilar TABLE G-7 Monomer content by SEC for select formulations in Block G that were untreated (Q, quiescent), underwent 5 F/T cycles or subjected to agitation for 24 hours Form No. citrate phosphate succinate HIS Gly Arg mannitol NaCl F68 PS20 PS80 Q F/T agit 1 8 18 0 0 0 0 65 100 0 0 0.1 99.15 99.03 99.14 4 0 0 0 10 120 120 0 0 0 0 0.1 99.21 99.11 99.18 8 0 0 0 10 120 120 0 0 0.1 0 0 99.18 99.14 99.17 11 0 0 0 20 150 100 0 0 0 0 0.01 99.16 99.09 99.13 12 0 0 0 20 120 120 0 0 0 0.01 0 99.10 TABLE G-8 Percent purity by RP HPLC for select formulations in Block G that were untreated (Q, quiescent), underwent 5 F/T cycles or subjected to agitation for 24 hours Form No. citrate phosphate succinate HIS Gly Arg mannitol NaCl F68 PS20 PS80 Q F/T agit 1 8 18 0 0 0 0 65 100 0 0 0.1 99.60 99.72 99.76 4 0 0 0 10 120 120 0 0 0 0 0.1 99.56 99.70 99.59 8 0 0 0 10 120 120 0 0 0.1 0 0 99.58 99.57 99.73 11 0 0 0 20 150 100 0 0 0 0 0.01 99.72 99.59 99.65 12 0 0 0 20 120 120 0 0 0 0.01 0 99.75 99.56 Results of Block G All of the pH values were close to the target values (Table G-1), with relatively small changes occurring upon storage. There appears to be some preference in terms of polysorbates over F-68 in terms of stability, as measured by SEC (Table G-2). However, the differences are relatively small. It does appear that succinate formulations (Formulations 9 and 10) fared reasonably well as far as monomer content retained. The RP HPLC data are all very close, making any determination of stability differences virtually impossible (Table G-3). These data will only be interpretable when examined in the larger context of all of the blocks of screening studies. The CE-SDS results suggest that PS 20 is the best stabilizer at 0.1% concentration for the Humira® formulation (Formulations 1 through 3) (Table G-4). Otherwise, the differences appear to be too small and variable to make any general conclusions. As seen before, the results for cIEF data are variable enough to make interpretation difficult (Table G-5). It does appear that the changes are smaller in the Gly/Arg formulations than for formulations using other stabilizers, like mannitol. Still, overall, the stability by cIEF looks to be quite good for many of the formulations in this study. Block G (F/T and Agitation) Studies. For a liquid formulation, it is important to evaluate the sensitivity to interfacial stress. Two kinds of stress studies were selected. The first is agitation at 150 rpm on an orbital shaker for 24 hours at 2-8° C. The second is five successive cycles of freezing and thawing (F/T), where this cycle should generate increasing amounts of damage protein, if the protein is sensitive to interfacial damage. Four formulations from Block G were selected for assessment, and they are highlighted in blue bold text Table G-6. Upon repeated F/T cycling, there is a very small decrease in monomer content for all of the formulations tested (Table G-7). Thus, it seems like there is little interfacial sensitivity form this stress and that the presence of PS 80 is not critical for protection. As for agitated samples, the losses are even smaller. The trends in the RP HPLC data are essentially the same (Table G-8). There are little, if any, losses in purity upon exposure to interfacial stress. Block H Formulation Studies The Block H formulations focused on three aspects of the adalimumab formulation: (1) higher protein concentrations, (2) formulations with no buffers present (other than the protein), and (3) the use of various buffer combinations beside citrate-phosphate (See Table H). TABLE H BLOCK H STUDY DESIGN Form No. API protein citrate phosphate succinate HIS ACETATE Gly Arg mannitol NaCl PS80 1 *** 100 8 18 0 0 0 0 0 65 100 0.1 2 *** 100 0 0 0 10 0 120 120 0 0 0.1 3 *** 50 0 0 0 0 0 0 0 65 100 0.1 4 *** 50 0 0 0 0 0 120 120 0 0 0.1 5 *** 50 0 0 0 0 0 120 120 0 0 0 6 *** 50 0 0 0 10 10 0 0 65 100 0.1 7 *** 50 0 0 10 10 0 0 0 65 100 0.1 8 *** 50 0 10 0 10 0 0 0 65 100 0.1 9 *** 50 0 0 10 0 10 0 0 65 100 0.1 10 *** 50 10 0 10 0 0 0 0 65 100 0.1 11 *** 50 10 0 0 10 0 0 0 65 100 0.1 12 *** 50 0 0 10 10 0 120 100 0 0 0.1 *** denotes proprietary adalimumab biosimilar TABLE H-1 Measured pH for Block H formulations at t0, t1 (one week, 40° C.), and t2 (two weeks, 40° C.) Form No. protein Citrate Phosphate Succinate Histidine acetate Gly Arg Mannitol NaCl PS80 t0 t1 t2 1 100 8 18 0 0 0 0 0 65 100 0.1 5.19 5.30 5.29 2 100 0 0 0 10 0 120 120 0 0 0.1 5.20 5.19 5.15 3 50 0 0 0 0 0 0 0 65 100 0.1 5.21 5.23 5.21 4 50 0 0 0 0 0 120 120 0 0 0.1 5.21 5.41 5.46 5 50 0 0 0 0 0 120 120 0 0 0 5.21 5.30 5.39 6 50 0 0 0 10 10 0 0 65 100 0.1 5.20 5.28 5.28 7 50 0 0 10 10 0 0 0 65 100 0.1 5.21 5.24 5.24 8 50 0 10 0 10 0 0 0 65 100 0.1 5.20 5.17 5.16 9 50 0 0 10 0 10 0 0 65 100 0.1 5.21 5.24 5.29 10 50 10 0 10 0 0 0 0 65 100 0.1 5.20 5.24 5.26 11 50 10 0 0 10 0 0 0 65 100 0.1 5.21 5.24 5.26 12 50 0 0 10 10 0 120 100 0 0 0.1 5.21 5.26 5.29 TABLE H-2 Monomer content by SEC for formulations in Block H at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. protein Citrate Phosphate Succinate Histidine acetate Gly Arg mannitol NaCl PS80 t0 t1 t2 1 100 8 18 0 0 0 0 0 65 100 0.1 99.25 98.36 98.42 2 100 0 0 0 10 0 120 120 0 0 0.1 99.19 98.88 98.47 3 50 0 0 0 0 0 0 0 65 100 0.1 99.06 98.81 98.74 4 50 0 0 0 0 0 120 120 0 0 0.1 99.19 99.06 98.99 5 50 0 0 0 0 0 120 120 0 0 0 99.26 99.03 98.96 6 50 0 0 0 10 10 0 0 65 100 0.1 99.26 98.92 98.86 7 50 0 0 10 10 0 0 0 65 100 0.1 99.14 98.98 98.93 8 50 0 10 0 10 0 0 0 65 100 0.1 99.11 98.93 98.66 9 50 0 0 10 0 10 0 0 65 100 0.1 99.16 98.79 98.63 10 50 10 0 10 0 0 0 0 65 100 0.1 99.10 98.79 98.49 11 50 10 0 0 10 0 0 0 65 100 0.1 99.21 98.93 98.18 12 50 0 0 10 10 0 120 100 0 0 0.1 99.30 99.22 98.65 TABLE H-3 Percent purity by RP HPLC for formulations in Block F at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. protein citrate phosphate succinate histidine acetate Gly Arg mannitol NaCl PS80 t0 t1 t2 1 100 8 18 0 0 0 0 0 65 100 0.1 99.36 99.64 99.64 2 100 0 0 0 10 0 120 120 0 0 0.1 99.37 99.68 99.74 3 50 0 0 0 0 0 0 0 65 100 0.1 99.45 99.47 99.70 4 50 0 0 0 0 0 120 120 0 0 0.1 99.50 99.69 99.59 5 50 0 0 0 0 0 120 120 0 0 0 99.47 99.71 99.56 6 50 0 0 0 10 10 0 0 65 100 0.1 99.48 99.56 99.72 7 50 0 0 10 10 0 0 0 65 100 0.1 99.43 99.45 99.72 8 50 0 10 0 10 0 0 0 65 100 0.1 99.43 99.51 99.72 9 50 0 0 10 0 10 0 0 65 100 0.1 99.47 99.55 99.72 10 50 10 0 10 0 0 0 0 65 100 0.1 99.48 99.53 99.67 11 50 10 0 0 10 0 0 0 65 100 0.1 99.45 99.69 99.60 12 50 0 0 10 10 0 120 100 0 0 0.1 99.44 99.54 99.72 TABLE H-4 Percentage of bands for light chain (LC), heavy chain (HC), non-glycosylated HC, and other species for formulations in Block H at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. Time LC HC ngHC Other 1 t0 32.87 65.48 0.54 1.11 t1 28.08 70.09 0.58 1.25 t2 52.57 47.43 0.00 0.00 2 t0 36.20 62.40 0.55 0.86 t1 29.64 68.68 0.57 1.11 t2 43.09 55.23 0.57 1.10 3 t0 34.70 63.55 0.57 1.18 t1 28.24 69.72 0.61 1.57 t2 34.25 63.97 0.67 1.11 4 t0 41.04 57.61 0.51 0.84 t1 27.58 70.65 0.62 1.15 t2 34.14 64.01 0.60 1.26 5 t0 37.64 60.77 0.50 1.09 t1 28.07 70.02 0.61 1.30 t2 37.67 60.76 0.55 1.02 6 t0 31.64 66.46 0.55 1.34 t1 27.67 70.19 0.50 1.64 t2 34.07 63.49 0.62 1.81 7 t0 30.38 69.10 0.53 0.00 t1 27.14 70.55 0.62 1.69 t2 46.41 51.21 0.00 2.38 8 t0 28.46 71.19 0.35 0.00 t1 30.05 68.71 0.55 0.69 t2 34.14 63.97 0.63 1.25 9 t0 27.74 70.63 0.60 1.03 t1 27.48 70.48 0.61 1.43 t2 36.56 61.59 0.49 1.36 10 t0 t1 27.69 70.46 0.60 1.24 t2 11 t0 27.64 70.83 0.57 1.13 t1 31.85 66.08 0.61 1.46 t2 38.58 59.26 0.52 1.64 12 t0 29.48 68.55 0.58 1.40 t1 29.53 68.68 0.58 1.40 t2 30.64 68.20 0.70 0.46 TABLE H-5 Percentage of main bands seen in the cIEF profile of formulations in Block H at t0, t1 (one week at 40° C.), and t2 (two weeks at 25° C.) Form No. pH t0 t1 t2 1 8.55 1.20 1.17 1.21 8.39 9.57 5.57 8.23 8.23 46.84 38.18 39.78 7.99 13.67 12.64 11.62 7.81 6.93 4.61 3.70 2 8.43 1.17 1.06 1.38 8.26 8.97 8.15 8.38 8.09 45.46 40.27 39.95 7.87 13.37 16.45 6.77 7.72 5.47 5.39 9.55 7.56 1.64 1.52 3.33 3 8.36 0.80 0.74 0.61 8.16 6.02 6.03 7.30 7.98 35.60 35.58 37.24 7.83 11.75 14.10 13.15 7.64 2.17 4.78 2.00 7.51 1.23 1.81 4 8.40 0.82 0.74 0.30 8.22 7.87 7.38 6.29 8.04 42.46 34.42 35.89 7.89 14.44 13.71 11.34 7.71 3.18 3.31 2.69 7.56 0.98 0.95 5 8.42 0.82 1.02 8.25 7.22 5.09 8.07 34.68 28.99 7.91 2.67 3.63 7.86 10.63 7.83 7.72 2.52 2.05 6 8.42 1.17 1.28 1.22 8.23 9.88 8.56 7.90 8.09 45.26 40.45 40.80 7.94 13.23 16.50 13.28 7 8.59 1.79 1.45 1.90 8.45 11.74 11.32 11.51 8.28 59.90 61.63 56.22 8.05 20.34 19.49 22.98 7.92 6.24 6.11 7.39 8 8.58 1.59 2.94 1.38 8.44 11.86 12.83 12.12 8.26 61.08 60.20 63.05 8.05 20.21 24.03 23.45 7.88 5.25 6.55 9 8.61 1.22 1.42 1.21 8.48 12.47 12.36 11.00 8.33 56.64 54.59 55.34 8.10 23.37 23.81 25.31 7.94 6.30 7.83 Results of Block H The pH stability of these formulations was acceptable (<0.1 units), except for Formulations 4 and 5. These are the buffer-free formulations using Gly and Arg as the stabilizers (Table H-1). There was also a slight rise in pH for Formulation 1 (the Humira® formulation at 100 mg/ml protein concentration). Stability of Block H formulations was monitored using SEC and RP HPLC. There is little loss in monomer content, with Formulation 1 appearing to be the least stable by SEC (Table H-2). At 100 mg/ml of adalimumab biosimilar API the histidine-buffered formulation containing Gly and Arg appears to be quite stable. In general, the best buffer combination appears to be His-succinate (Formulations 7 and 12). Buffer-free formulations with Gly and Arg show acceptable stability as well (Table H-2). The RP HPLC data indicate that the buffer-free formulations (4 and 5) may not do quite as well as shown by SEC (Table H-3), with measurable decreases in purity, but are believed to be satisfactory for obtaining a formulation having long term stability. The CE-SDS data detect the least change in Formulation 12, which is a His-succinate formulation (Table H-4). The largest change at t1 occurs with Formulation 7, which is also a His-succinate formulation, but using mannitol and NaCl as the tonicity modifiers. PLS Modeling PLS Method The data for the adalimumab formulations in Blocks A through H were analyzed together using a chemometric method termed partial least squares (PLS). Detailed descriptions of PLS modeling have been published. See, for example, Katz, M. H. Multivariate Analysis: A Practice Guide for Clinicians. Cambridge University Press, New York, pp. 158-162 (1999); Stahle, L., Wold, K., Multivariate data analysis and experimental design in biomedical research. Prog. Med. Chem. 1988, 25: 291-338; Wold S. PLS-regression: a basic tool of chemometrics. Chemom. Intell. Lab. Syst. 2001, 58: 109-130; and Martens, H.; Martens, M. Multivariate Analysis of Quality: An Introduction, Wiley and Sons, Chichester, UK (2001). For any large matrix of values, where there are a reasonable number of samples (together forming the so-called X-matrix), mathematical models can be constructed that explain the largest amount of variance in the dependent variable(s) of interest (the Y-matrix). The best single description of the relationship between the variation in the X-matrix and the endpoint (the Y matrix) is called the first principal component, PC1. The next important (in terms of describing the variance in the Y-matrix) component is called the second principal component, PC2, and so on. Quite often, only one or two PCs are required to explain most of the variance in the Y-matrix. Each of these PCs contains some contribution from each of the variables in the X-matrix. If a variable within the X-matrix contributes heavily to the construction of a given PC, then it is ranked as being significant. In fact, regression coefficients can be calculated for each variable in the X-matrix for a given model, where a model is the composite of a certain number of PCs in order to provide an adequate description of the Y-matrix. In summary, PLS takes information from the X-matrix, calculates the desired number of PCs, and constructs a suitable model. The model that includes all of the samples is termed a calibration model [1,2]. The overall coefficient of determination (r2) indicates the quality of the model. All PLS calculations were conducted using Unscrambler® software (CAMO, Corvallis, Oreg.). A PLS analysis done with a single variable in the Y-matrix is termed PLS1 analysis. Building a model that fits multiple variables in the Y-matrix is called PLS2 analysis. A full cross validation was performed on all calibration models using standard techniques. Briefly, one sample is removed at a time, the data set is recalibrated, and a new model is constructed. This process is repeated until all of the calibration samples are removed once and quantified as a validation model. Therefore, the first set, containing all samples is referred to as the calibration set and the one after cross-validation as the validation set. The jack-knife algorithm (See, Martens et al) was used to determine statistical significance for any factor used in constructing the PLS models described above. PLS Modeling of Adalimumab Formulations Blocks B, C and D See FIGS. 3 Through 12 Note: The PLS surface graphs depicted in FIGS. 3 through 12 are based on the data obtained from Blocks B, C and D. The following is a discussion of the findings reflected in the PLS surface plots shown in FIGS. 3 through 12. PLS Model 1—FIG. 3. FIG. 3 contains a depiction of the monomer content at t1 (model 1) as a function of citrate and phosphate concentrations. The pH has been fixed at 5.2. The model indicated that phosphate and citrate by themselves were weak destabilizers (not to statistical significance), along with tartrate and maleate. By comparison, succinate, which is structurally similar to citrate, tartrate and maleate, was a weak stabilizer. The only buffer found to be a significant stabilizer was histidine. None of these findings could have been predicted based on the literature or examination of the chemical structure of each buffer. The model also indicated that when citrate and phosphate buffer are used together, the formulation is least stable. If one only uses a single buffer, especially phosphate, stability improves. This is surprising, as phosphate has little or no buffer capacity at pH 5.2, while citrate buffer does. None of this behavior could have been predicted based on what was known in the art. PLS Model 2—FIG. 4. FIG. 4 contains a depiction of the monomer content at t2 (model 2). Likewise, a model was constructed using the monomer content by SEC at t2 as the endpoint. This model also demonstrated that the stability is lowest when citrate and phosphate are used together. The lowest stability was shown when citrate is above 10 mM and phosphate is between 5 and 15 mM. Stability improves when the citrate concentration is lowered and/or phosphate concentration is lowered or raised. These findings suggest that a single buffer composition is preferred. The same trend in buffer stabilization is seen as with PLS Model 1, with citrate and phosphate being weak stabilizers (not statistically significant), while histidine is a strong stabilizer (statistically significant). PLS Model 1—FIG. 5. FIG. 5 is a PLS model 1 showing the effect of histidine and glycine on the stability of formulations. It contains a depiction of the monomer content at t1 (model 1). This model indicated that the combination of histidine and glycine yielded very good stability results. Both histidine (His) and glycine (Gly) were determined to be stabilizers. The lowest stability on the response surface (shown in blue) is when there is the lowest concentration of His and Gly. The effect of His on stability is greater, with 20 mM His providing comparable stabilization to 120 mM Gly (note the opposite corners of the graph). The model indicates that there will be an additive benefit to stability by using both excipients, with the highest stability occurring when the His concentration is 20 mM and the Gly concentration is 120 mM. PLS Model 1—FIG. 6. FIG. 6 is a PLS model 1 showing the effect of arginine and sorbitol on the stability of formulations. It contains a depiction of the monomer content at t1 (model 1). This model indicated that arginine was a good stabilizer, while sorbitol was a poor stabilizer. Likewise, arginine (Arg) provides a degree of stabilization that is similar to that found for Gly. The poorest stability as indicated by this model is when the Arg concentration is low and the sorbitol concentration is low (the blue area of the graph). As the concentrations of each excipient are increased, the monomer content at t1 is increased. The effect of sorbitol is roughly linear with concentration, while the effect of Arg appears to be increasing more rapidly once the concentration exceeds 60 mM. Even though sorbitol is predicted to increase the stability of adalimumab in terms of retained monomer content, its ability to increase stability is less than that found for Gly and Arg (on a molar basis). PLS Model 1—FIG. 7. FIG. 7 is a PLS model 1 showing the effect of pH and histidine on the stability of formulations. It contains a depiction of the monomer content at t1 (model 1). This model indicated that histidine appears to be the best buffer, while pH should preferably be at 5 or higher for best stability. PLS Model 2—FIG. 8. FIG. 8 is a PLS model 2 showing the effect of pH and histidine on the stability of formulations. It contains a depiction of the monomer content at t2 (model 2). This model indicated that histidine appears to be the best buffer, while pH should preferably be at 5 or higher for best stability. The results indicate that the optimal pH is near 5.2. Of all of the buffers that were examined, histidine provides the greatest degree of stabilization. This response surface illustrates two important points. First, the stability appears to be maximal near pH 5.2, falling off at a higher and lower pH. Second, histidine is shown to provide a significant increase in stability. When histidine is used at 20 mM, it provides a marked increase in stability over lower buffer concentrations. In fact, the effect appears to be non-linear, with more stabilization occurring from 10 to 20 mM than from 0 to 10 mM. Further, the loss in stability is more abrupt at higher pH than at lower pH. PLS Model 2—FIG. 9. FIG. 9 is a PLS model 2 showing the effect of trehalose and PS80 on the stability of formulations. It contains a depiction of the monomer content at t2. This model indicated that trehalose appears to be a weak stabilizer, while PS80 improves thermal stability. The response surface shown in FIG. 9 indicates that PS 80 is a potent stabilizer for protecting adalimumab against thermal stress, with a concentration of 0.1% providing maximal stability. The concentration of PS 80 has not been varied other than at 0 and 0.1%. By comparison, this model shows that the stabilization effect of trehalose is quite small, certainly less than what was seen with sorbitol. PLS Model 2—FIG. 10. FIG. 10 is a PLS model 2 showing the effect of mannitol and PS80 on the stability of formulations. It contains a depiction of the monomer content at t2 (model 2). This model indicated that mannitol appears to be a destabilizer, while PS80 improves thermal stability. The PLS model using monomer content by SEC at t2 allows one to examine the relative effects of any of the factors included in the model. As the mannitol concentration increases, the overall stability decreases. By comparison, the impact of PS80 on the stability is rather small. PLS Model 1—FIG. 11. FIG. 11 is a PLS model 1 showing the effect of mannitol and NaCl on the stability of formulations. It contains a depiction of the monomer content at t1 (model 1). This model indicated that mannitol and NaCl both appear to be destabilizers. The stability, as indicated by the monomer content at t1, is lowest when the mannitol concentration is anywhere below 150 mM. Likewise, addition of NaCl also diminishes the stability of adalimumab. PLS Model 1—FIG. 12. FIG. 12 is a PLS model 1 showing the effect of EDTA and methionine on the stability of formulations. It contains a depiction of the monomer content at t1. In the case of EDTA, the stability decreases slightly as the concentration of this additive increases. In contrast, addition, of Met appears to improve stability. PLS Modeling of Adalimumab Formulations for Blocks B Through G See FIGS. 13 Through 28 The First PLS Model (“PLS Model A) The first PLS model (PLS Model A) used difference in monomer content at t1 as the endpoint. The model employed three PCs and had a correlation coefficient for the calibration set of 0.83 and a r-value of 0.67 for the validation set. It was a quadratic model including pH-buffer and buffer-buffer interaction terms. TABLE J PLS “MODEL A” COEFFICIENTS Factor r-value pH t0 0.041 protein −0.025 citrate +0.123 phos +0.267 succinate −0.089 histidine −0.174 acetate −0.053 glycine −0.190 arginine −0.128 sorbitol −0.003 trehalose +0.020 mannitol −0.104 NaCl +0.250 F68 +0.018 PS 20 +0.021 PS 80 −0.152 EDTA +0.112 Met −0.062 Note: Overall correlation coefficients for each linear factor includes in the first PLS model (PLS Model A) using the difference in monomer content by SEC at t1 as the endpoint. Factors deemed to be statistically significant are highlighted in bold text. The model quality is acceptable, considering the correlation coefficients of the calibration and validation sets. The overall correlation coefficients for the various factors included in the model are summarized in Table J. Note that the quadratic and interaction terms are not listed here. As the endpoint is the difference in monomer content, one wishes to minimize this value. Thus, stabilizers exhibit negative correlation coefficients, while destabilizers have positive r-values. Of the stabilizers, His, Gly, Arg, and PS 80 are the most potent, although mannitol and succinate also have a stabilizing effect (Table J). Meanwhile, there are some significant destabilizers, such as NaCl, citrate, and phosphate. Keep in mind that these models are a composite of all of the stability data gathered across the various blocks of formulations, A through H, and individual formulations could vary from the model. While the table of correlation coefficients is helpful to gauge the effects of various factors, they do not capture the non-linear and interaction effects, so it is helpful to view response surfaces to examine the effects of various parameters in greater detail, as shown in the response surfaces that are reproduced in FIGS. 13 through 28. Discussion of PLS Model A—FIGS. 13 and 14. The Krause '583 patent describes the citrate-phosphate buffer system as being integral to product stability. Our studies show this not to be the case. The poorest stability would occur when these two buffers were used in combination and the effect would get worse as the buffer concentrations increase, according to this model (FIG. 13[1]). The response surface indicates that the phosphate and citrate are equally destabilizing, contrary to some earlier observations, but the quantitative nature of these surfaces must be considered with some care as they include data from all of the formulations from Blocks B through H. The effect of pH and His is shown in FIG. 14. It shows that His is destabilizing at low pH, where it is clearly outside of the buffer capacity of His. Again, this result is a function of all pH observations in this study, not just those involving His (although this could be done). According to this response surface, the optimal pH may be nearer to 5.4 than 5.2, although the surface is relatively flat through this region, indicating a shallow response surface from pH 5 to 5.4 (FIG. 14). Discussion of PLS Model A—FIG. 15 The response surface for Gly and Arg is shown in FIG. 15. The studies repeatedly show that these two amino acids can be potent stabilizers of adalimumab. Note that the minimum difference in monomer content (i.e., the blue part of the surface) is reached at 100 mM Arg, but at 200 mM Gly, suggesting that Arg may be the better stabilizer for adalimumab at pH 5.2. Discussion of PLS Model A—FIG. 16 The final response surface shown for PLS Model A is for the effect of NaCl and PS 80 (FIG. 16). It shows that the stability of adalimumab decreases upon addition of NaCl, especially above 100 mM. Meanwhile, PS 20 provides significant stability when used above 0.04%. The Second PLS Model (PLS Model B) The second PLS model (PLS Model B) used the monomer content at t1 and at t2 as the endpoints. The model employed four PCs and had a correlation coefficient for the calibration set of 0.82 and a r-value of 0.67 for the validation set. It was a quadratic model including pH-buffer and buffer-buffer interaction terms. In terms of model quality, this is comparable to the first PLS Model A described above. TABLE K (L) PLS “MODEL B” CORRELATION COEFFICIENTS Factor r-value pH −0.086 protein +0.030 citrate −0.079 phos −0.157 succinate +0.060 histidine +0.185 acetate +0.063 glycine +0.126 arginine +0.150 sorbitol +0.025 trehalose +0.006 mannitol +0.014 NaCl −0.215 F68 −0.044 PS 20 −0.028 PS 80 +0.227 EDTA −0.097 Met +0.096 The endpoints for PLS Model B are the total monomer contents at both t1 and t2. Therefore, one will wish to maximize these values. This means that stabilizers with have positive correlation coefficients and destabilizers will display negative r-values (Table K). As with the previous model, citrate, phosphate, and NaCl are significant destabilizers. On the other hand, His, Gly Arg, and PS 20 are potent stabilizers. In this model, trehalose, sorbitol and mannitol have very little effect. The primary differences are that pH is now a significant factor and that EDTA is a significant destabilizer, while Met appears to be a stabilizer as well. Discussion of PLS Model B—FIG. 17 This model suggests that addition of citrate has little effect on stability if phosphate is absent (view the back edge of the response surface of FIG. 5). On the other hand, added phosphate does decrease monomer content (view the right hand edge) and the combination is even more destabilizing (FIG. 5). Thus, the citrate-phosphate buffer combination is not effective at stabilizing adalimumab, contrary to what is taught by the '583 patent. The destabilizing effect of phosphate is about three-fold greater than for citrate according to this model. Discussion of PLS Model 6—FIG. 18 The use of His at low pH has little or detrimental effects (FIG. 18[6\). However, when employed at pH 5.2 or above, the His provides a significant increase in stability (as measured by monomer content by SEC). Discussion of PLS Model B—FIG. 19 The response surface for Gly and Arg is shown in FIG. 19. Including both stabilizers at high concentrations would be beneficial for stability, but impractical for tonicity reasons. It does appear that Arg is the more potent stabilizer in this model compared to Gly, where a 75 mM concentration of Arg has the same effect as ˜120 mM Gly. The model indicates either one alone would work well, or that a combination would be effective as well. Discussion of PLS Model 6—FIG. 20 The PLS model B shows a modest effect of mannitol on stability, whereas PS 80 is an effective stabilizer above concentrations near 0.05% (FIG. 20). Thus, one could conclude from this data that a stable formulation could be comprised of 240 mM mannitol and 0.1% PS 80 at pH 5.2. Discussion of PLS Model B—FIG. 21 Throughout the project, it appears that NaCl is a destabilizer of adalimumab, especially when the concentration reach 100 mM or above, as shown in this response surface (FIG. 21). While only a few formulations were tested that included EDTA, it appears that this excipient is destabilizing, unless the concentration were ˜0.1%. We also note that the effect of Met was favorable with respect to stability, but it did not prove to be a significant effect, probably because relatively few examples were evaluated. Discussion of PLS Model B—FIG. 22 The final response surface from the PLS Model B to be considered is the effect of succinate and His (FIG. 22). The model did include all relevant buffer-buffer interactions. This surface shows that succinate has little or even deleterious effects on its own (see the front edge of the plot). However, in conjunction with His it proves to increase the overall stability (e.g., note that back edge of the surface). Therefore, a His-succinate buffer system appear to be the most favorable of all of the buffer combinations tested to date. The Third PLS Model (PLS Model C) The third PLS model C used the difference in percent purity by RP HPLC at t1 as the endpoint. The model employed two PCs and had a correlation coefficient for the calibration set of 0.86 and a r-value of 0.67 for the validation set. It was a quadratic model including pH-buffer and buffer-buffer interaction terms. In terms of model quality, this is very similar to the previous model. TABLE L PLS “MODEL C” CORRELATION COEFFICIENTS Factor r-value pH −0.115 protein −0.139 citrate +0.014 phosphate +0.084 succinate −0.051 histidine −0.075 acetate +0.159 glycine −0.096 arginine −0.045 sorbitol +0.029 trehalose +0.020 mannitol −0.060 NaCl +0.068 F68 −0.047 PS 20 −0.067 PS 80 −0.028 EDTA +0.099 Met −0.015 PLS Model C demonstrates that RP HPLC is stability-indicating, even though the sensitivity may be less than for SEC. The model finds that both phosphate and citrate are destabilizing, with the effect of phosphate being statistically significant (Table LI). Likewise, acetate is a strong destabilizer as is EDTA. Both Gly and Arg are shown to be stabilizers, but the effects are not deemed to be statistically significant. Only His was found to be a significant stabilizer (along with protein concentration). Discussion of PLS Model C—FIG. 23 The response surface for citrate and phosphate at pH 5.2 is shown in FIG. 23[11]. Both buffers are destabilizing (follow the front and left-hand edges of the plot). Above concentrations of ˜10 mM, the combination becomes quite destabilizing. Overall, phosphate is predicted to be more destabilizing according to this model (FIG. 11). Discussion of PLS Model C—FIG. 24 As seen in previous models, the stability of adalimumab decreases as the pH is reduced to less than 5.0 (FIG. 12). In this model the stabilizing effect of His is seen across all pH values, but is most pronounced when the pH is lower. Discussion of PLS Model C—FIG. 25 The effects of Gly and Arg are seen in FIG. 25. Both excipients decrease loss of purity as the concentration increases and they are predicted to be roughly equipotent, as judged by the slopes along the edges of the response surface. Otherwise, it appears that it takes less Arg (75 mM) to achieve optimal loss of purity (the blue region of the graph) than for Gly (˜200 mM). Discussion of PLS Model C—FIG. 26 The effect of mannitol and PS 80 is seen in the response surface in FIG. 26[14]. It is clear that chemical stability is greatly improved by adding PS 80, especially at concentrations above 0.04%. Meanwhile, mannitol is also stabilizing, but even 240 mM mannitol has less effect than a small about of the surfactant. Discussion of PLS Model C—FIG. 27 While mannitol is believed to be a stabilizer in the Humira® formulation, NaCl is clearly a destabilizer, both in this model (See FIG. 27[15]), and in previous PLS models. The effect is substantial when the NaCl concentration exceeds 75 mM or so. Discussion of PLS Model C—FIG. 28 The final response surface from PLS Model C is seen in FIG. 28[16] describing the effects of pH and protein concentration. As seen before, the stability is best when the pH is above 4.8 or 5.0. As for the protein effect, this model predicts that the stability, based on RP HPLC, is better at higher protein concentrations. A similar trend, albeit a fairly weak one, was seen for the SEC data (monomer content at t1 and t2). Therefore, it may be possible to achieve similar stability profiles at concentrations at 100 mg/ml as one could obtain at 50 mg/ml. Summary of Findings for Blocks a Through H The formulation studies in Blocks A through H evaluated adalimumab formulations stored at elevated temperature and held for either one week at 40° C. or for two weeks at 25° C. The stability was monitored using SEC, RP HPLC, cIEF and CE-SDS. The optimal pH appears to be 5.2±0.2. Of all of the buffer compositions tested, the citrate-phosphate combination is inferior to nearly any other buffer system evaluated, hence an important aspect of the present invention is the avoidance of this combined buffer system altogether. The best single buffer appears to be His, while a His-succinate buffer also offers very good stability. Even buffer-free systems, which rely on the ability of the protein to buffer the formulation, appear to have acceptable stability profiles under accelerated stress conditions. Of all of the stabilizers/tonicity modifiers evaluated, both Arg and Gly elicit very good stabilization of adalimumab. They both work better than mannitol. Mannitol does appear to be a stabilizer, however we have discovered that if used it should be at the highest possible concentrations, but in any event exceeding about 150 mM, ad most preferably at or exceeding about 200 mM. By comparison, NaCl is clearly a destabilizer, especially when the concentrations exceed 75-100 mM; hence, NaCl, if present should be controlled to levels below about 75 mM. Other polyols, such as sorbitol and trehalose, appear to work about as well as mannitol and therefore may be substituted for mannitol if desired. Surprisingly, polysorbate 80 (PS 80) provides significant protection against thermal stress. While the mechanism of stabilization is not known, it appears that other surfactants tested (PS 20 and F-68), do not appear to be nearly as effective as PS 80. Hence the selection of PS80 versus PS 20 is a preferred feature of the present invention. Formulations according to the present invention preferably contain at least 0.04% (w/v) PS 80. Based on the findings in the formulation studies of Blocks A through H, the following are particularly preferred adalimumab formulations according to the present invention. TABLE M SELECTED FORMULATIONS NaCl PS 80 Form No pH His (mM) succinate (mM) Gly (mM) Arg (mM) mannitol (mM) (mM) (wt %) A 5.2 30 0 240 0 0 0 0.1 B 5.2 30 0 240 0 0 0 0.02 C 5.2 30 0 0 0 240 0 0.1 D 5.2 30 15 0 0 220 0 0.1 E 5.2 30 0 90 0 150 0 0.1 F 5.2 30 0 240 0 0 0 0 G 5.2 20 0 0 0 240 0 0 H 5.4 30 0 240 0 0 0 0.02 I 5.2 30 0 120 80 0 0 0.1 J 5.2 30 15 90 80 0 0 0.1 K 5.2 30 0 0 0 240 0 0.1 L 5.2 30 0 0 50 160 0 0.1 M 5.2 30 0 90 100 0 0 0.1 N 5.2 20 0 120 90 0 0 0.1 O 5.4 30 0 120 80 0 0 0.1 P 5.2 30 0 120 0 0 50 0.01 Q 5.2 30 0 0 0 240 0 0.02 Additional Components of the Provided Pharmaceutical Compositions The formulations of the invention may also include other buffers (unless they are specifically excluded in the description of the specific embodiments of the invention), tonicity modifiers, excipients, pharmaceutically acceptable carriers and other commonly used inactive ingredients of the pharmaceutical compositions. A tonicity modifier is a molecule that contributes to the osmolality of a solution. The osmolality of a pharmaceutical composition is preferably adjusted to maximize the active ingredient's stability and/or to minimize discomfort to the patient upon administration. It is generally preferred that a pharmaceutical composition be isotonic with serum, i.e., having the same or similar osmolality, which is achieved by addition of a tonicity modifier. In a preferred embodiment, the osmolality of the provided formulations is from about 180 to about 420 mOsM. However, it is to be understood that the osmolality can be either higher or lower as specific conditions require. Examples of tonicity modifiers suitable for modifying osmolality include, but are not limited to amino acids (not including arginine) (e.g., cysteine, histidine and glycine), salts (e.g., sodium chloride or potassium chloride) and/or sugars/polyols (e.g., sucrose, sorbitol, maltose, and lactose). In a preferred embodiment, the concentration of the tonicity modifier in the formulation is preferably between about 1 mM to about 1 M, more preferably about 10 mM to about 200 mM. Tonicity modifiers are well known in the art and are manufactured by known methods and available from commercial suppliers. Suitable tonicity modifiers may be present in the compositions of the invention unless they are specifically excluded in the description of the specific embodiments of the invention. Excipients, also referred to as chemical additives, co-solutes, or co-solvents, that stabilize the polypeptide while in solution (also in dried or frozen forms) can also be added to a pharmaceutical composition. Excipients are well known in the art and are manufactured by known methods and available from commercial suppliers. Examples of suitable excipients include but are not limited to sugars/polyols such as: sucrose, lactose, glycerol, xylitol, sorbitol, mannitol, maltose, inositol, trehalose, glucose; polymers such as: serum albumin (bovine serum albumin (BSA), human SA or recombinant HA), dextran, PVA, hydroxypropyl methylcellulose (HPMC), polyethyleneimine, gelatin, polyvinylpyrrolidone (PVP), hydroxyethylcellulose (HEC); non-aqueous solvents such as: polyhydric alcohols, (e.g., PEG, ethylene glycol and glycerol) dimethysulfoxide (DMSO) and dimethylformamide (DMF); amino acids such as: proline, L-serine, sodium glutamic acid, alanine, glycine, lysine hydrochloride, sarcosine and gamma-aminobutyric acid; surfactants such as: Tween®-80 (polysorbate 80), Tween®-20 (polysorbate 20), SDS, polysorbates, poloxamers; and miscellaneous excipients such as: potassium phosphate, sodium acetate, ammonium sulfate, magnesium sulfate, sodium sulfate, trimethylamine N-oxide, betaine, CHAPS, monolaurate, 2-O-beta-mannoglycerate or any combination of the above. Suitable excipients may be present in the compositions of the invention unless they are specifically excluded in the description of the specific embodiments of the invention. The concentration of one or more excipients in a formulation of the invention is/are preferably between about 0.001 to 5 weight percent, more preferably about 0.1 to 2 weight percent. Methods of Treatment In another embodiment, the invention provides a method of treating a mammal comprising administering a therapeutically effective amount of the pharmaceutical compositions of the invention to a mammal, wherein the mammal has a disease or disorder that can be beneficially treated with adalimumab. In a preferred embodiment, the mammal is a human. Diseases or disorders that can be treated with the provided compositions include but are not limited to rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Wegener's disease (granulomatosis), Crohn's disease (or inflammatory bowel disease), chronic obstructive pulmonary disease (COPD), Hepatitis C, endometriosis, asthma, cachexia, psoriasis, and atopic dermatitis. Additional diseases or disorders that can be treated with the compositions of the present invention include those described in U.S. Pat. Nos. 6,090,382 and 8,216,583 the relevant portions of which are incorporated herein by reference. The provided pharmaceutical compositions may be administered to a subject in need of treatment by injection systemically, such as by intravenous injection; or by injection or application to the relevant site, such as by direct injection, or direct application to the site when the site is exposed in surgery; or by topical application. In one embodiment, the invention provides a method of treatment and/or prevention of rheumatoid arthritis comprises administering to a mammal in need thereof a therapeutically effective amount of one of the provided adalimumab compositions. The therapeutically effective amount of the adalimumab in the provided compositions will depend on the condition to be treated, the severity of the condition, prior therapy, and the patient's clinical history and response to the therapeutic agent. The proper dose can be adjusted according to the judgment of the attending physician such that it can be administered to the patient one time or over a series of administrations. In one embodiment, the effective adalimumab amount per adult dose is from about 1-500 mg/m2, or from about 1-200 mg/m2, or from about 1-40 mg/m2 or about 5-25 mg/m2. Alternatively, a flat dose may be administered, whose amount may range from 2-500 mg/dose, 2-100 mg/dose or from about 10-80 mg/dose. If the dose is to be administered more than one time per week, an exemplary dose range is the same as the foregoing described dose ranges or lower and preferably administered two or more times per week at a per dose range of 25-100 mg/dose. In another embodiment, an acceptable dose for administration by injection contains 80-100 mg/dose, or alternatively, containing 80 mg per dose. The dose can be administered weekly, biweekly, or separated by several weeks (for example 2 to 8). In one embodiment, adalimumab is administered at 40 mg by a single subcutaneous (SC) injection. In some instances, an improvement in a patient's condition will be obtained by administering a dose of up to about 100 mg of the pharmaceutical composition one to three times per week over a period of at least three weeks. Treatment for longer periods may be necessary to induce the desired degree of improvement. For incurable chronic conditions the regimen may be continued indefinitely. For pediatric patients (ages 4-17), a suitable regimen may involve administering a dose of 0.4 mg/kg to 5 mg/kg of adalimumab, one or more times per week. In another embodiment, the pharmaceutical formulations of the invention may be prepared in a bulk formulation, and as such, the components of the pharmaceutical composition are adjusted to be higher than would be required for administration and diluted appropriately prior to administration. The pharmaceutical compositions can be administered as a sole therapeutic or in combination with additional therapies as needed. Thus, in one embodiment, the provided methods of treatment and/or prevention are used in combination with administering a therapeutically effective amount of another active agent. The other active agent may be administered before, during, or after administering the pharmaceutical compositions of the present invention. Another active agent may be administered either as a part of the provided compositions, or alternatively, as a separate formulation. Administration of the provided pharmaceutical compositions can be achieved in various ways, including parenteral, oral, buccal, nasal, rectal, intraperitoneal, intradermal, transdermal, subcutaneous, intravenous, intra-arterial, intracardiac, intraventricular, intracranial, intratracheal, intrathecal administration, intramuscular injection, intravitreous injection, and topical application. The pharmaceutical compositions of this invention are particularly useful for parenteral administration, i.e., subcutaneously, intramuscularly, intravenously, intraperitoneal, intracerebrospinal, intra-articular, intrasynovial, and/or intrathecal. Parenteral administration can be by bolus injection or continuous infusion. Pharmaceutical compositions for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. In addition, a number of recent drug delivery approaches have been developed and the pharmaceutical compositions of the present invention are suitable for administration using these new methods, e.g., Inject-Ease®, Genject®, injector pens such as GenPen®, and needleless devices such as MediJector® and BioJector®. The present pharmaceutical composition can also be adapted for yet to be discovered administration methods. See also Langer, 1990, Science, 249:1527-1533. The provided pharmaceutical compositions can also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the formulations may be modified with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. The pharmaceutical compositions may, if desired, be presented in a vial, pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. In one embodiment the dispenser device can comprise a syringe having a single dose of the liquid formulation ready for injection. The syringe can be accompanied by instructions for administration. In another embodiment, the present invention is directed to a kit or container, which contains an aqueous pharmaceutical composition of the invention. The concentration of the polypeptide in the aqueous pharmaceutical composition can vary over a wide range, but is generally within the range of from about 0.05 to about 20,000 micrograms per milliliter (μg/ml) of aqueous formulation. The kit can also be accompanied by instructions for use. In addition to the formulations referenced in the formulation studies of Blocks A through H, the following additional examples are provided as further embodiments of the invention, as are the representative embodiments which are included in Appendices A through C which are to be understood as part of this specification. Example 1 Stabilized Adalimumab Formulation (Simile Buffer) Containing Polyol; without Surfactant A stable aqueous pharmaceutical composition containing adalimumab, using a single buffer, and substantially free of a surfactant may be prepared as follows: Each solid formulation component may be weighed to the amount required for a given volume of formulation buffer. These components may then be combined into a beaker or vessel capable of carrying and measuring the given volume of formulation buffer. A volume of deionized water equal to approximately ¾ of the target given formulation buffer may be added to the beaker, and the components may be solubilized through use of a magnetic stir bar. The pH of the buffer may be adjusted to the target formulation pH using 1 molar sodium hydroxide and/or 1 molar hydrogen chloride. The final formulation buffer volume may then be raised to the target volume through the addition of deionized water. The solution may then be mixed with a magnetic stir bar after final water addition. Adalimumab solution may then be placed in dialysis material housing (such as Thermo Scientific Slide-A-Lyzer MINI Dialysis Unit 10,000 MWCO), which may then be placed in contact with the desired formulation buffer for 12 hours at 4° C. Formulation buffer volume to protein solution volume ratio should be no less than 1000:1. The dialysis housing and protein solution it contains may then be placed in a second, equal volume of formulation buffer for an additional 12 hours at 4° C. Resulting adalimumab solution may then be removed from the dialysis material housing, and the concentration of adalimumab may then be determined using ultraviolet spectroscopy. Adalimumab concentration may then be adjusted to the desired level using centrifugation (such as Amicon Ultra 10,000 MWCO Centrifugal Concentrators) and/or dilution with formulation buffer. A sample composition of the invention is represented in Table 1 below: TABLE 1 Ingredient concentration Adalimumab (active ingredient) 50 mg/ml Mannitol (inactive ingredient) 4% Citrate (pH 5.2) (single buffer) 15 mM The composition disclosed in Table 1 does not contain a combination of citrate and phosphate buffer. It also does not require the presence of a surfactant. Example 2 Stabilized Adalimumab Formulation (Single Buffer) without Polyol or Surfactant Ingredient concentration Adalimumab (active ingredient) 50 mg/ml Citrate (pH 5.2) 15 mM Glycine (inactive ingredient) 100 mM Example 3 Stabilized Adalimumab Formulation (Single Buffer) Containing Polyol without Surfactant Ingredient concentration Adalimumab (active ingredient) 50 mg/ml Mannitol (inactive ingredient) 4% Citrate (pH 5.2) 15 mM The compositions of examples 2 and 3 have long term stability and do not contain a combination of citrate and phosphate buffer, and do not require the presence of a surfactant. Example 4 Stabilized Adalimumab Formulation (Simile Buffer) Containing Surfactant; without Polyol Ingredient concentration 4A Adalimumab (active ingredient) 50 mg/ml (No polyol ingredient) — Histidine Buffer (pH 5.2) (sole buffer) 20 mM Glycine (stabilizer) 50 mM Arginine (stabilizer) 130 mM Polysorbate 80 0.1 (wt %) (w/v) 4B Adalimumab (active ingredient) 50 mg/ml (No polyol ingredient) — Histidine Buffer (pH 5.2) (sole buffer) 20 mM Glycine (stabilizer) 120 mM Arginine (stabilizer) 100 mM Polysorbate 80 0.1 (wt %) (w/v) 4C Adalimumab (active ingredient) 50 mg/ml (No polyol ingredient) — Histidine Buffer (pH 5.2) (sole buffer) 10 mM Glycine (stabilizer) 50 mM Arginine (stabilizer) 130 mM Polysorbate 80 0.1 (wt %) (w/v) 4D Adalimumab (active ingredient) 50 mg/ml (No polyol ingredient) — Succinate Buffer (pH 5.2) (sole buffer) 20 mM Glycine (stabilizer) 50 mM Arginine (stabilizer) 130 mM Polysorbate 80 0.1 (wt %) (w/v) 4E Adalimumab (active ingredient) 50 mg/ml (No polyol ingredient) — Succinate Buffer (pH 5.2) (sole buffer) 20 mM Glycine (stabilizer) 120 mM Arginine (stabilizer) 100 mM Polysorbate 80 0.1 (wt %) (w/v) 4F Adalimumab (active ingredient) 50 mg/ml (No polyol ingredient) — Succinate Buffer (pH 5.2) (sole buffer) 10 mM Glycine (stabilizer) 50 mM Arginine (stabilizer) 130 mM Polysorbate 80 0.1 (wt %) (w/v) The compositions disclosed in Examples 4(a) through 4(f) above will afford stability without need for polyol and without need for a combined buffer system. Insofar as the present invention has discovered that the citrate/phosphate buffer combination required in U.S. Pat. No. 8,216,583 is not required for stabilization of adalimumab formulations according to the present invention, persons skilled in the art may appreciate, in practicing examples 4(a) through 4(f), that additional buffers may be employed in combination with the histidine and succinate buffers disclosed herein (e.g, acetate, citrate, maleate, tartrate, and phosphate buffers); provided the formulation does not use a buffer combination of citrate and phosphate. Example 5 Stabilized Adalimumab Formulation (Simile Buffer) Containing Surfactant; and Polyol Ingredient Concentration 5A Adalimumab (active ingredient) 50 mg/ml Sorbitol 65 mM Histidine Buffer (pH 5.2) (sole buffer) 20 mM Arginine (stabilizer) 130 mM Polysorbate 80 0.1 (wt %) (w/v) 5B Adalimumab (active ingredient) 50 mg/ml Sorbitol 65 mM Succinate Buffer (pH 5.2) (sole buffer) 20 mM Arginine (stabilizer) 130 mM Polysorbate 80 0.1 (wt %) (w/v) The foregoing description of the exemplary embodiments of the invention in the block studies A through H, in the examples above, and in the Appendices A through C, are presented only for the purposes of illustration and description and is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in light of the above teaching. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims. APPENDIX A Further Representative Embodiments Disclosed in Priority Application U.S. Ser. No. 61/698,138 A. A stable aqueous pharmaceutical composition comprising adalimumab, a polyol, a surfactant, and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 5 to about 6, and wherein said buffer does not comprise both of citrate and phosphate. B. A stable aqueous pharmaceutical composition comprising adalimumab, a polyol, and a surfactant, wherein said composition has a pH of about 5 to about 6, and wherein said composition is substantially free of a buffer. C. The composition of any of embodiments A-B, wherein said adalimumab is at a concentration from about 20 to about 150 mg/ml. D. The composition of any of embodiments A-C, wherein said adalimumab is at a concentration from about 20 to about 100 mg/ml. E. The composition of any of embodiments A-D, wherein said adalimumab is at a concentration from about 30 to about 50 mg/ml. F. The composition of any of embodiments A-E, wherein said buffer is at a concentration from about 5 mM to about 50 mM. G. The composition of any of embodiments A-F, wherein said buffer is at a concentration from about 5 mM to about 20 mM. H. The composition of any of embodiments A-G, wherein said buffer is at a concentration from about 10 mM to about 20 mM. I. The composition of any of embodiments A-G, wherein said surfactant is a polysorbate. J. The composition of embodiment I, wherein said polysorbate is polysorbate 80. K. The composition of any of embodiments A-J, wherein said polyol is a sugar alcohol. L. The composition of embodiment K, wherein said sugar alcohol is selected from the group consisting of mannitol, sorbitol and trehalose. M. The composition of embodiment L, wherein said mannitol is at a concentration from about 1 to 10% weight by volume of the total composition. N. The composition of any of embodiments L-M, wherein said mannitol is at a concentration from about 2 to 6% weight by volume of the total composition. O. The composition of any of embodiments L-N, wherein said mannitol is at a concentration from about 3 to 5% weight by volume of the total composition. P. The composition of any of embodiments A-O further comprising a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. Q. The composition of embodiment P, wherein said amino acid is selected from the group consisting of glycine, alanine, glutamate, arginine and methionine. R. The composition of embodiment P, wherein said salt is selected from the group consisting of sodium chloride and sodium sulfate. S. The composition of embodiment P, wherein said metal ion is selected from zinc, magnesium and calcium. T. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, mannitol at a concentration from about 1 to 10% weight by volume, polysorbate 80 at a concentration from about 1 to 50 μM, and citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of phosphate. U. A stable aqueous pharmaceutical composition comprising adalimumab, a polyol, and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 5 to about 6, and wherein said composition is substantially free of a surfactant. V. The composition of embodiment U, wherein said adalimumab is at a concentration from about 20 and about 150 mg/ml. W. The composition of any of embodiments U-V, wherein said adalimumab is at a concentration from about 20 and about 100 mg/ml. X. The composition of any of embodiments U-V, wherein said adalimumab is at a concentration from about 20 and about 40 mg/ml. Y. The composition of any of embodiments U-Y, wherein said buffer is at a concentration from about 5 mM and about 50 mM. Z. The composition of any of embodiments U-Y, wherein said buffer is at a concentration from about 5 mM and about 20 mM. AA. The composition of any of embodiments U-Z, wherein said buffer is at a concentration from about 10 mM and about 20 mM. BB. The composition of any of embodiments U-AA, wherein said polyol is a sugar alcohol. CC. The composition of embodiment BB, wherein said sugar alcohol is selected from the group consisting of mannitol, sorbitol and trehalose. DD. The composition of embodiment CC, wherein said mannitol is at a concentration from about 1 to 10% weight by volume of the total composition. EE. The composition of any of embodiments CC-DD, wherein said mannitol is at a concentration from about 2 to 6% weight by volume of the total composition. FF. The composition of any of embodiments CC-EE, wherein said mannitol is at a concentration from about 3 to 5% weight by volume of the total composition. GG. The composition of any of embodiments CC-FF further comprising a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. HH. The composition of embodiment GG, wherein said amino acid is selected from the group consisting of glycine, alanine, glutamate, arginine and methionine. II. The composition of embodiment GG, wherein said salt is selected from the group consisting of sodium chloride and sodium sulfate. JJ. The composition of embodiment GG, wherein said metal ion is selected from zinc, magnesium and calcium. KK. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, mannitol at a concentration from about 1 to 10% weight by volume, and citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of a surfactant. LL. A stable aqueous pharmaceutical composition comprising adalimumab, a buffer, a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion, and wherein said composition has a pH of about 5 to about 6, and wherein said composition is substantially free of a polyol. MM. The composition of embodiment LL, wherein said adalimumab is at a concentration from about 20 and about 150 mg/ml. NN. The composition of any of embodiments LL-MM, wherein said adalimumab is at a concentration from about 20 and about 100 mg/ml. OO. The composition of any of embodiments LL-NN, wherein said adalimumab is at a concentration from about 20 and about 40 mg/ml. PP. The composition of any of embodiments LL-OO, wherein said buffer is at a concentration from about 5 mM and about 50 mM. QQ. The composition of any of embodiments LL-PP, wherein said buffer is at a concentration from about 5 mM and about 20 mM. RR. The composition of any of embodiments LL-QQ, wherein said buffer is at a concentration from about 10 mM and about 20 mM. SS. The composition of embodiment LL, wherein said stabilizer is selected from the group consisting of an amino acid, a salt, EDTA and a metal ion. TT. The composition of embodiment SS, wherein said amino acid is selected from the group consisting of glycine, alanine and arginine. UU. The composition of embodiment SS wherein said salt is selected from the group consisting of sodium chloride and sodium sulfate. VV. The composition of embodiment TT, wherein said glycine is at a concentration from about 20 to about 200 mM. WW. The composition of embodiment W, wherein said glycine is at a concentration from about 50 to about 200 mM. XX. The composition of embodiment SS, wherein said arginine is at a concentration from about 1 to about 250 mM. YY. The composition of embodiment XX, wherein said arginine is at a concentration from about 20 to about 200 mM. ZZ. The composition of embodiment YY, wherein said arginine is at a concentration from about 20 to about 100 mM. AAA. The composition of embodiment UU, wherein said sodium chloride is at a concentration from about 5 to about 150 mM. BBB. The composition of embodiment AAA, wherein said sodium chloride is at a concentration from about 20 to about 140 mM. CCC. The composition of embodiment BBB, wherein said sodium chloride is at a concentration from about 75 to about 125 mM. DDD. The composition of embodiment UU, wherein said sodium sulfate is at a concentration from about 5 to about 150 mM. EEE. The composition of embodiment UU, wherein said sodium chloride is at a concentration from about 20 to about 120 mM. FFF. The composition of embodiment EEE, wherein said sodium chloride is at a concentration from about 60 to about 100 mM. GGG. The composition of any of embodiments LL-FF further comprising a surfactant. HHH. The composition of embodiment GGG, wherein said surfactant is a polysorbate. III. The composition of embodiment HHH, wherein said polysorbate is polysorbate 80. JJJ. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, glycine at a concentration from about 20 to about 200 mM, citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of a polyol. KKK. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, arginine at a concentration from about 1 to about 250 mM, citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH from about 5 to about 5.5, and wherein said composition is substantially free of a polyol. LLL. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, sodium chloride at a concentration from about 5 to about 150 mM, citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of a polyol. MMM. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, sodium chloride at a concentration from about 5 to about 150 mM, polysorbate 80 at a concentration from about 1 to 50 μM, citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of a polyol. NNN. A stable aqueous pharmaceutical composition comprising adalimumab, a polyol, a surfactant, a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion, and a buffer selected from the group consisting of citrate, phosphate, succinate, tartrate and maleate, wherein said composition has a pH from about 5 to about 6. OOO. The composition of embodiment NNN, wherein the buffer does not comprise a combination of citrate and phosphate. PPP. The composition of embodiment NNN, wherein said adalimumab is at a concentration from about 20 and about 150 mg/ml. QQQ. The composition of any of embodiments NNN-PPP, wherein said adalimumab is at a concentration from about 20 and about 100 mg/ml. RRR. The composition of any of embodiments NNN-QQQ, wherein said adalimumab is at a concentration from about 20 and about 40 mg/ml. SSS. The composition of any of embodiments NNN-RRR, wherein said buffer is at a concentration from about 5 mM and about 50 mM. TTT. The composition of any of embodiments NNN-SSS, wherein said buffer is at a concentration from about 5 mM and about 20 mM. UUU. The composition of any of embodiments NNN-TTT, wherein said buffer is at a concentration from about 10 mM and about 20 mM. VVV. The composition of any of embodiments NNN-UUU, wherein said surfactant is a polysorbate. WWW. The composition of embodiment VVV, wherein said polysorbate is polysorbate 80. XXX. The composition of any of embodiments NNN-WWW, wherein said polyol is a sugar alcohol. YYY. The composition of embodiment XXX, wherein said sugar alcohol is selected from the group consisting of mannitol, sorbitol and trehalose. ZZZ. The composition of embodiment XXX, wherein said mannitol is at a concentration from about 1 to 10% weight by volume of the total composition. AAAA. The composition of any of embodiments XXX-ZZZ, wherein said mannitol is at a concentration from about 2 to 6% weight by volume of the total composition. BBBB. The composition of any of embodiments YYY-AAAA, wherein said mannitol is at a concentration from about 3 to 5% weight by volume of the total composition. CCCC. The composition of any of embodiments NNN-BBBB, wherein said stabilizer is EDTA. DDDD. The composition of embodiment CCCC, wherein said EDTA is at a concentration from about 0.01% to about 0.5%. EEEE. The composition of embodiment DDDD, wherein said EDTA is at a concentration from about 0.05% to about 0.25%. FFFF. The composition of embodiment EEEE, wherein said EDTA is at a concentration from about 0.08% to about 0.2%. GGGG. The composition of any of embodiments NNN-BBBB, wherein said stabilizer is methionine. HHHH. The composition of embodiment GGGG, wherein said methionine is at a concentration from about 1 to about 10 mg/ml. IIII. The composition of embodiment GGGG, wherein said methionine is at a concentration from about 1 to about 5 mg/ml. JJJJ. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to about 50 μM, mannitol at a concentration from about 1 to 10% weight by volume, EDTA at a concentration from about 0.01% to about 0.5%, citrate at a concentration from about 5 mM and about 50 mM, and wherein said composition has a pH of about 5 to about 5.5. KKKK. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to about 50 μM, mannitol at a concentration from about 1 to 10% weight by volume, methionine at a concentration from about 1 to about 10 mg/ml, citrate at a concentration from about 5 mM and about 50 mM, and wherein said composition has a pH of about 5 to about 5.5. LLLL. A stable aqueous pharmaceutical composition comprising adalimumab, a polyol, and a buffer selected from the group consisting of citrate, phosphate, succinate, tartrate and maleate, wherein said composition has a pH of about 3.5. MMMM. The composition of embodiment LLLL, wherein said adalimumab is at a concentration from about 20 and about 150 mg/ml. NNNN. The composition of any of embodiments LLLL-MMMM, wherein said adalimumab is at a concentration from about 20 and about 100 mg/ml. OOOO. The composition of any of embodiments LLLL-NNNN, wherein said adalimumab is at a concentration from about 20 and about 40 mg/ml. PPPP. The composition of any of embodiments LLLL-OOOO, wherein said buffer is at a concentration from about 5 mM and about 50 mM. QQQQ. The composition of any of embodiments LLLL-PPPP, wherein said buffer is at a concentration from about 5 mM and about 20 mM. RRRR. The composition of any of embodiments LLLL-QQQQ, wherein said buffer is at a concentration from about 10 mM and about 20 mM. SSSS. The composition of any of embodiments LLLL-RRRR, wherein said polyol is a sugar alcohol. TTTT. The composition of embodiment SSSS, wherein said sugar alcohol is selected from the group consisting of mannitol, sorbitol and trehalose. UUUU. The composition of embodiment TTTT, wherein said mannitol is at a concentration from about 1 to about 10% weight by volume of the total composition. VVVV. The composition of any of embodiments TTTT-UUUU, wherein said mannitol is at a concentration from about 2 to about 6% weight by volume of the total composition. WWWW. The composition of any of embodiments TTTT-VVVV, wherein said mannitol is at a concentration from about 3 to about 5% weight by volume of the total composition. XXXX. The composition of any of embodiments LLLL-WWWW further comprising a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. YYYY. The composition of embodiment XXXX, wherein said amino acid is selected from the group consisting of glycine, alanine, glutamate, arginine and methionine. ZZZZ. The composition of embodiment XXXX, wherein said salt is selected from the group consisting of sodium chloride and sodium sulfate. AAAAA. The composition of embodiment XXXX, wherein said metal ion is selected from zinc, magnesium and calcium. BBBBB. The composition of any of embodiments TTTT-AAAAA further comprising a surfactant. CCCCC. The composition of embodiment BBBBB, wherein said surfactant is a polysorbate. DDDDD. The composition of embodiment CCCCC, wherein said polysorbate is polysorbate 80. APPENDIX B Further Representative Embodiments Disclosed in Priority Application U.S. Ser. No. 61/770,421 A. A stable aqueous pharmaceutical composition comprising adalimumab, a polyol, a surfactant, and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 5 to about 6, and wherein said buffer does not comprise both of citrate and phosphate. B. A stable aqueous pharmaceutical composition comprising adalimumab, a polyol, and a surfactant, wherein said composition has a pH of about 5 to about 6, and wherein said composition is substantially free of a buffer. C. The composition of any of embodiments A-B, wherein said adalimumab is at a concentration from about 20 to about 150 mg/ml. D. The composition of any of embodiments A-C, wherein said adalimumab is at a concentration from about 20 to about 100 mg/ml. E. The composition of any of embodiments A-D, wherein said adalimumab is at a concentration from about 30 to about 50 mg/ml. F. The composition of any of embodiments A-E, wherein said buffer is at a concentration from about 5 mM to about 50 mM. G. The composition of any of embodiments A-F, wherein said buffer is at a concentration from about 5 mM to about 20 mM. H. The composition of any of embodiments A-G, wherein said buffer is at a concentration from about 10 mM to about 20 mM. I. The composition of any of embodiments A-H, wherein said surfactant is a polysorbate. J. The composition of embodiment I, wherein said polysorbate is polysorbate 80. K. The composition of any of embodiments A-J, wherein said polyol is a sugar alcohol. L. The composition of embodiment K, wherein said sugar alcohol is selected from the group consisting of mannitol, sorbitol and trehalose. M. The composition of embodiment L, wherein said mannitol is at a concentration from about 1 to 10% weight by volume of the total composition. N. The composition of any of embodiments L-M, wherein said mannitol is at a concentration from about 2 to 6% weight by volume of the total composition. O. The composition of any of embodiments L-N, wherein said mannitol is at a concentration from about 3 to 5% weight by volume of the total composition. P. The composition of any of embodiments A-O further comprising a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. Q. The composition of embodiment P, wherein said amino acid is selected from the group consisting of glycine, alanine, glutamate, arginine and methionine. R. The composition of embodiment P, wherein said salt is selected from the group consisting of sodium chloride and sodium sulfate. S. The composition of embodiment P, wherein said metal ion is selected from zinc, magnesium and calcium. T. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, mannitol at a concentration from about 1 to 10% weight by volume, polysorbate 80 at a concentration from about 1 to 50 μM, and citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of phosphate. UA stable aqueous pharmaceutical composition comprising adalimumab, a polyol, and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 5 to about 6, and wherein said composition is substantially free of a surfactant. V. The composition of embodiment U, wherein said adalimumab is at a concentration from about 20 and about 150 mg/ml. W. The composition of any of embodiments U-V, wherein said adalimumab is at a concentration from about 20 and about 100 mg/ml. X. The composition of any of embodiments U-W, wherein said adalimumab is at a concentration from about 20 and about 40 mg/ml. Y. The composition of any of embodiments U-X, wherein said buffer is at a concentration from about 5 mM and about 50 mM. Z. The composition of any of embodiments U-Y, wherein said buffer is at a concentration from about 5 mM and about 20 mM. AA. The composition of any of embodiments U-Z, wherein said buffer is at a concentration from about 10 mM and about 20 mM. BB. The composition of any of embodiments U-AA, wherein said polyol is a sugar alcohol. CC. The composition of embodiment BB, wherein said sugar alcohol is selected from the group consisting of mannitol, sorbitol and trehalose. DD. The composition of embodiment CC, wherein said mannitol is at a concentration from about 1 to 10% weight by volume of the total composition. EE. The composition of any of embodiments CC-DD, wherein said mannitol is at a concentration from about 2 to 6% weight by volume of the total composition. FF. The composition of any of embodiments CC-EE, wherein said mannitol is at a concentration from about 3 to 5% weight by volume of the total composition. GG. The composition of any of embodiments U-FF further comprising a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. HH. The composition of embodiment GG, wherein said amino acid is selected from the group consisting of glycine, alanine, glutamate, arginine and methionine. II. The composition of embodiment GG, wherein said salt is selected from the group consisting of sodium chloride and sodium sulfate. JJ. The composition of embodiment GG, wherein said metal ion is selected from zinc, magnesium and calcium. KK. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, mannitol at a concentration from about 1 to 10% weight by volume, and citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of a surfactant. LL. A stable aqueous pharmaceutical composition comprising adalimumab, a buffer, a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion, and wherein said composition has a pH of about 5 to about 6, and wherein said composition is substantially free of a polyol. MM. The composition of embodiment LL, wherein said adalimumab is at a concentration from about 20 and about 150 mg/ml. NN. The composition of any of embodiments LL-MM, wherein said adalimumab is at a concentration from about 20 and about 100 mg/ml. OO. The composition of any of embodiments LL-NN, wherein said adalimumab is at a concentration from about 20 and about 40 mg/ml. PP. The composition of any of embodiments LL-OO, wherein said buffer is at a concentration from about 5 mM and about 50 mM. QQ. The composition of any of embodiments LL-PP, wherein said buffer is at a concentration from about 5 mM and about 20 mM. RR. The composition of any of embodiments LL-QQ, wherein said buffer is at a concentration from about 10 mM and about 20 mM. SS. The composition of embodiment LL, wherein said stabilizer is selected from the group consisting of an amino acid, a salt, EDTA and a metal ion. TT. The composition of embodiment TT, wherein said amino acid is selected from the group consisting of glycine, alanine and arginine. UU. The composition of embodiment TT, wherein said salt is selected from the group consisting of sodium chloride and sodium sulfate. VV. The composition of embodiment TT, wherein said glycine is at a concentration from about 20 to about 200 mM. WW. The composition of embodiment VV, wherein said glycine is at a concentration from about 50 to about 200 mM. XX. The composition of embodiment TT, wherein said arginine is at a concentration from about 1 to about 250 mM. YY. The composition of embodiment XX, wherein said arginine is at a concentration from about 20 to about 200 mM. ZZ. The composition of embodiment YY, wherein said arginine is at a concentration from about 20 to about 100 mM. AAA. The composition of embodiment UU, wherein said sodium chloride is at a concentration from about 5 to about 150 mM. BBB. The composition of embodiment AAA, wherein said sodium chloride is at a concentration from about 20 to about 140 mM. CCC. The composition of embodiment AAA, wherein said sodium chloride is at a concentration from about 75 to about 125 mM. DDD. The composition of embodiment UU, wherein said sodium sulfate is at a concentration from about 5 to about 150 mM. EEE. The composition of embodiment UU, wherein said sodium chloride is at a concentration from about 20 to about 120 mM. FFF. The composition of embodiment EEE, wherein said sodium chloride is at a concentration from about 60 to about 100 mM. GGG. The composition of any of embodiments LL-FF further comprising a surfactant. HHH. The composition of embodiment GGG, wherein said surfactant is a polysorbate. III. The composition of embodiment HHH, wherein said polysorbate is polysorbate 80. JJJ. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, glycine at a concentration from about 20 to about 200 mM, citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of a polyol. KKK. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, arginine at a concentration from about 1 to about 250 mM, citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH from about 5 to about 5.5, and wherein said composition is substantially free of a polyol. LLL. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, sodium chloride at a concentration from about 5 to about 150 mM, citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of a polyol. MMM. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, sodium chloride at a concentration from about 5 to about 150 mM, polysorbate 80 at a concentration from about 1 to 50 μM, citrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of a polyol. NNN. A stable aqueous pharmaceutical composition comprising adalimumab, a polyol, a surfactant, a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion, and a buffer selected from the group consisting of citrate, phosphate, succinate, tartrate and maleate, wherein said composition has a pH from about 5 to about 6. OOO. The composition of embodiment NNN, wherein the buffer does not comprise a combination of citrate and phosphate. PPP. The composition of embodiment NNN, wherein said adalimumab is at a concentration from about 20 and about 150 mg/ml. QQQ. The composition of any of embodiments NNN-PPP, wherein said adalimumab is at a concentration from about 20 and about 100 mg/ml. RRR. The composition of any of embodiments NNN-QQQ, wherein said adalimumab is at a concentration from about 20 and about 40 mg/ml. SSS. The composition of any of embodiments NNN-RRR, wherein said buffer is at a concentration from about 5 mM and about 50 mM. TTT. The composition of any of embodiments NNN-SSS, wherein said buffer is at a concentration from about 5 mM and about 20 mM. UUU. The composition of any of embodiments NNN-TTT, wherein said buffer is at a concentration from about 10 mM and about 20 mM. VVV. The composition of any of embodiments NNN-UUU, wherein said surfactant is a polysorbate. WWW. The composition of embodiment VVV, wherein said polysorbate is polysorbate 80. XXX. The composition of any of embodiments NNN-WWW, wherein said polyol is a sugar alcohol. YYY. The composition of embodiment XXX, wherein said sugar alcohol is selected from the group consisting of mannitol, sorbitol and trehalose. ZZZ. The composition of embodiment YYY, wherein said mannitol is at a concentration from about 1 to 10% weight by volume of the total composition. AAAA. The composition of any of embodiments YYY-ZZZ, wherein said mannitol is at a concentration from about 2 to 6% weight by volume of the total composition. BBBB. he composition of any of embodiments YYY-AAAA, wherein said mannitol is at a concentration from about 3 to 5% weight by volume of the total composition. CCCC. The composition of any of embodiments NNN-BBBB, wherein said stabilizer is EDTA. DDDD. The composition of embodiment CCCC, wherein said EDTA is at a concentration from about 0.01% to about 0.5%. EEEE. The composition of embodiment DDDD, wherein said EDTA is at a concentration from about 0.05% to about 0.25%. FFFF. The composition of embodiment EEEE, wherein said EDTA is at a concentration from about 0.08% to about 0.2%. GGGG. The composition of any of embodiments NNN-BBBB, wherein said stabilizer is methionine. HHHH. The composition of embodiment GGGG, wherein said methionine is at a concentration from about 1 to about 10 mg/ml. IIII. The composition of embodiment GGGG, wherein said methionine is at a concentration from about 1 to about 5 mg/ml. JJJJ. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to about 50 μM, mannitol at a concentration from about 1 to 10% weight by volume, EDTA at a concentration from about 0.01% to about 0.5%, citrate at a concentration from about 5 mM and about 50 mM, and wherein said composition has a pH of about 5 to about 5.5. KKKK. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to about 50 μM, mannitol at a concentration from about 1 to 10% weight by volume, methionine at a concentration from about 1 to about 10 mg/ml, citrate at a concentration from about 5 mM and about 50 mM, and wherein said composition has a pH of about 5 to about 5.5. LLLL. A stable aqueous pharmaceutical composition comprising adalimumab, a polyol, and a buffer selected from the group consisting of citrate, phosphate, succinate, tartrate and maleate, wherein said composition has a pH of about 3.5. MMMM. The composition of embodiment LLLL, wherein said adalimumab is at a concentration from about 20 and about 150 mg/ml. NNNN. The composition of any of embodiments LLLL-MMMM, wherein said adalimumab is at a concentration from about 20 and about 100 mg/ml. OOOO. The composition of any of embodiments LLLL-NNNN, wherein said adalimumab is at a concentration from about 20 and about 40 mg/ml. PPPP. The composition of any of embodiments LLLL-OOOO, wherein said buffer is at a concentration from about 5 mM and about 50 mM. QQQQ. The composition of any of embodiments LLLL-PPPP, wherein said buffer is at a concentration from about 5 mM and about 20 mM. RRRR. The composition of any of embodiments LLLL-QQQQ, wherein said buffer is at a concentration from about 10 mM and about 20 mM. SSSS. The composition of any of embodiments LLLL-RRRR, wherein said polyol is a sugar alcohol. TTTT. The composition of embodiment SSSS, wherein said sugar alcohol is selected from the group consisting of mannitol, sorbitol and trehalose. UUUU. The composition of embodiment TTTT, wherein said mannitol is at a concentration from about 1 to about 10% weight by volume of the total composition. VVVV. The composition of any of embodiments TTTT-UUUU, wherein said mannitol is at a concentration from about 2 to about 6% weight by volume of the total composition. WWWW. The composition of any of embodiments TTTT-VVVV, wherein said mannitol is at a concentration from about 3 to about 5% weight by volume of the total composition. XXXX. The composition of any of embodiments LLLL-WWWW further comprising a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. YYYY. The composition of embodiment XXXX, wherein said amino acid is selected from the group consisting of glycine, alanine, glutamate, arginine and methionine. ZZZZ. The composition of embodiment XXXX, wherein said salt is selected from the group consisting of sodium chloride and sodium sulfate. AAAAA. The composition of embodiment XXXX, wherein said metal ion is selected from zinc, magnesium and calcium. BBBBB. The composition of any of embodiments LLLL-AAAAA further comprising a surfactant. CCCCC. The composition of embodiment BBBBB, wherein said surfactant is a polysorbate. DDDDD. The composition of embodiment CCCCC, wherein said polysorbate is polysorbate 80. EEEEE. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to about 50 μM; polyol selected from sorbitol, mannitol or trehalose at a concentration from about 1 to about 10% weight by volume, and at least one amino acid stabilizer selected from the group consisting of (a) arginine at a concentration from about 1 to about 250 mg/ml and (b) glycine at a concentration of about 20 to 200 mg/ml, and histidine buffer or succinate buffer at a concentration from about 5 mM and about 50 mM, and wherein said composition has a pH of about 5 to about 5.5. FFFFF. The composition of embodiment EEEEE wherein the polyol is sorbitol, and the composition is free or substantially free of any citrate/phosphate buffer combination, and the formulation comprises arginine or glycine, but not both. GGGGG. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 1 to about 50 μM, arginine at a concentration from about 1 to about 250 mg/ml, glycine at a concentration of about 20 to 200 mg/ml, and histidine buffer or succinate buffer at a concentration from about 5 mM and about 50 mM, and wherein said composition has a pH of about 5 to about 5.5 and said composition is free or substantially free of polyol. HHHHH. The composition of embodiment GGGGG wherein the composition is free or substantially free of any citrate/phosphate buffer combination. APPENDIX C Further Representative Embodiments Disclosed in Priority Application U.S. Ser. No. 61/769,581 A. A stable aqueous pharmaceutical composition comprising adalimumab and a single buffer. B. The composition of embodiment A, wherein said single buffer is selected from the group consisting of succinate, histidine, citrate, phosphate, tartrate and maleate. C. The composition of any of the preceding embodiments, wherein said composition has a pH of about 5 to about 6. D. The composition of any of the preceding embodiments, wherein said adalimumab contained in said pharmaceutical compositions does not lose more than 20% of its activity relative to activity of the composition at the beginning of storage. E. The composition of any of the preceding embodiments, further comprising a surfactant. F. The composition of embodiment E, wherein said surfactant is a polysorbate. G. The composition of embodiment F wherein said polysorbate is polysorbate 80. H. The composition of any of the preceding embodiments, further comprising a polyol. I. The composition of embodiment H, wherein said polyol is a sugar alcohol. J. The composition of embodiment I, wherein said sugar alcohol is sorbitol. K. The composition of any of the preceding embodiments, further comprising a sugar. L. The composition of embodiment K, wherein said sugar is selected from the group consisting of sucrose and trehalose. M. The composition of any of the preceding embodiments, wherein said adalimumab is at a concentration from about 20 to about 150 mg/ml. N. The composition of any of the preceding embodiments, wherein said buffer is at a concentration from about 5 mM to about 50 mM. O. The composition of any of embodiments A-N further comprising a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. P. The composition of embodiment O, wherein said amino acid is selected from the group consisting of glycine, alanine, glutamate, arginine and methionine. Q. The composition of embodiment O, wherein said metal ion is selected from zinc, magnesium and calcium. R. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 0.01% w/v to 0.5% w/v by weight of the total formulation, and succinate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of any other buffers. S. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 0.01% w/v to 0.5% w/v by weight of the total formulation, and histidine at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of any other buffers. T. A stable aqueous pharmaceutical composition comprising adalimumab at a concentration from about 20 and about 150 mg/ml, polysorbate 80 at a concentration from about 0.01% w/v to 0.5% w/v by weight of the total formulation, and tartrate at a concentration from about 5 mM and about 50 mM, wherein said composition has a pH of about 5 to about 5.5, and wherein said composition is substantially free of any other buffers. U. A method of treating a mammal comprising administering to said mammal a therapeutically effective amount of the composition of any of preceding embodiments, wherein said mammal has a disease or disorder that can be beneficially treated with adalimumab. V. The method of embodiment U, wherein said disease or disorder is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Wegener's disease (granulomatosis), Crohn's disease (or inflammatory bowel disease), chronic obstructive pulmonary disease (COPD), Hepatitis C, endometriosis, asthma, cachexia, psoriasis, and atopic dermatitis.
<SOH> BACKGROUND OF THE INVENTION <EOH>Tumor necrosis factor alpha (TNFα) is a naturally occurring mammalian cytokine produced by various cell types, including monocytes and macrophages in response to endotoxin or other stimuli. TNFα is a major mediator of inflammatory, immunological, and pathophysiological reactions (Grell, M., et al. (1995) Cell, 83: 793-802). Soluble TNFα is formed by the cleavage of a precursor transmembrane protein (Kriegler, et al. (1988) Cell 53: 45-53), and the secreted 17 kDa polypeptides assemble to soluble homotrimer complexes (Smith, et al. (1987), J. Biol. Chem. 262: 6951-6954; for reviews of TNF, see Butler, et al. (1986), Nature 320:584; Old (1986), Science 230: 630). These complexes then bind to receptors found on a variety of cells. Binding produces an array of pro-inflammatory effects, including (i) release of other pro-inflammatory cytokines such as interleukin (IL)-6, IL-8, and IL-1, (ii) release of matrix metalloproteinases and (iii) up-regulation of the expression of endothelial adhesion molecules, further amplifying the inflammatory and immune cascade by attracting leukocytes into extravascular tissues. There are many disorders associated with elevated levels of TNFα. For example, TNFα has been shown to be up-regulated in a number of human diseases, including chronic diseases such as rheumatoid arthritis (RA), inflammatory bowel disorders, including Crohn's disease and ulcerative colitis, sepsis, congestive heart failure, asthma bronchiale and multiple sclerosis. TNFα is also referred to as a pro-inflammatory cytokine. Physiologically, TNFα is also associated with protection from particular infections (Cerami. et al. (1988), Immunol. Today 9:28). TNFα is released by macrophages that have been activated by lipopolysaccharides of Gram-negative bacteria. As such, TNFα appears to be an endogenous mediator of central importance involved in the development and pathogenesis of endotoxic shock associated with bacterial sepsis. Adalimumab (Humira®, AbbVie, Inc.) is a recombinant human IgG1 monoclonal antibody specific for human TNF. This antibody is also known as D2E7. Adalimumab consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons. Adalimumab has been described and claimed in U.S. Pat. No. 6,090,382, the disclosure of which is hereby incorporated by reference in its entirety. Adalimumab is usually produced by recombinant DNA technology in a mammalian cell expression system, such as, for example, Chinese Hamster Ovary cells. Adalimumab binds specifically to TNFα and neutralizes the biological function of TNF by blocking its interaction with the p55 and p75 cell surface TNF receptors. Various formulations of adalimumab are known in the art. See, for example, U.S. Pat. Nos. 8,216,583 and 8,420,081. There is still need for stable liquid formulations of adalimumab that allow its long term storage without substantial loss in efficacy.
<SOH> SUMMARY OF THE INVENTION <EOH>The invention provides stable aqueous formulations comprising adalimumab that allow its long term storage. In a first embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab; a stabilizer comprising at least one member selected from the group consisting of a polyol and a surfactant; and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 4 to about 8 and preferably about 5 to about 6, and wherein said buffer does not comprise a combination of citrate and phosphate, and preferably does not comprise any citrate buffer. In this embodiment, the stabilizer preferably comprises both polyol and surfactant. In a second embodiment, utilizing a single buffer system, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a polyol, a surfactant, and a buffer system comprising a single buffering agent, said single buffering agent being selected from citrate, phosphate, succinate, histidine, tartrate or maleate, but not including combinations of the foregoing; wherein the formulation has a pH of about 4 to 8, and preferably about 5 to about 6. Histidine and succinate are particularly preferred for use as single buffering agents. As used herein the term buffer, buffer system, or buffering agent, and like terminology, is intended to denoted buffer components that introduce buffer capacity in the formulation in addition to any buffering capacity offered by the protein itself, hence the term “buffer”, etc, is not intended to include the protein itself as a self buffering entity. In a third embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a stabilizer comprising at least one member selected from a polyol and a surfactant, wherein said composition has a pH of about 4 to about 8, and preferably about 5 to about 6, and wherein said composition is substantially free of a buffer. In a fourth embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a polyol, and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 4 to about 8 and preferably about 5 to about 6, and wherein said composition is free or substantially free of a surfactant. Preferably, the composition (i) does not contain the buffer combination of citrate and phosphate; and (ii) the buffer is at least one member selected from the group consisting of histidine and succinate; and (iii) the polyol is selected from the group consisting of mannitol, sorbitol and trehalose. In a fifth embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, a surfactant, and a buffer selected from the group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate, wherein said composition has a pH of about 4 to 8 and preferably about 5 to about 6, and wherein said composition is substantially free of polyol. Preferably, the composition (i) does not contain the buffer combination of citrate and phosphate; and (ii) the buffer is at least one member selected from the group consisting of histidine and succinate, including combinations thereof. In each of the five embodiments discussed above, the composition may optionally further comprise a stabilizer selected from the group consisting of an amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. The amino acid stabilizer may be selected from the group consisting of glycine, alanine, glutamate, arginine and methionine. The salt stabilizer may be selected from the group consisting of sodium chloride and sodium sulfate. The metal ion stabilizer may be selected from the group consisting of zinc, magnesium and calcium. Preferably, adalimumab formulations containing the stabilizers mentioned above also do not contain buffer systems in which phosphate buffer and citrate buffer are present in combination, and, most preferably contains buffer systems free or substantially free of citrate buffer. In particularly preferred embodiments, (i) the optional additional stabilizer present in this embodiment is not sodium chloride, or comprises sodium chloride present in amounts not to exceed about 100 mM, and comprises at least one of arginine and glycine, including combinations of the two amino acids; (ii) the buffer, when present, contains no citrate, or at least no citrate and phosphate combination, but is instead at least one of histidine and succinate, including combinations thereof; and (iii) the stabilizer when it includes a polyol is preferably mannitol in amounts exceeding about 150 mM. In further embodiments the invention is directed to an aqueous, buffered pharmaceutical composition comprising adalimumab and a buffer, wherein (i) the composition is free or substantially free of a buffer combination that comprises both a citrate buffer and a phosphate buffer; and (ii) the composition exhibits long term stability. Another embodiment of the invention concerns an aqueous, buffered pharmaceutical composition exhibiting long term stability, said composition comprising: (i) adalimumab; (ii) a buffer selected from the group consisting of histidine buffer, succinate buffer, and combinations thereof; (iii) a polysorbate or poloxamer surfactant, or combinations thereof; and (iv) one or both of the following: (a) a stabilizer selected from the group consisting of glycine, alanine, glutamate, arginine, methionine, EDTA, sodium chloride, sodium sulfate, metal ions, and combinations thereof; and (b) a polyol selected from sorbitol, mannitol, and trehalose, or combinations thereof. Optionally, the formulation may also include a sugar, such as sucrose. In a further embodiment the invention is an aqueous, buffered pharmaceutical composition comprising adalimumab and a buffer, wherein (i) the composition is free or substantially free of a polyol; and (ii) the composition exhibits long term stability. In still a further embodiment the invention is directed to an aqueous, buffered pharmaceutical composition comprising adalimumab and a buffer, wherein (i) the composition is free or substantially free of surfactant; and (ii) the composition exhibits long term stability. Another embodiment of the inventions concerns an aqueous pharmaceutical composition comprising adalimumab wherein: (i) the composition is free or substantially free of buffer; and (ii) the composition exhibits long term stability. In another embodiment, the adalimumab formulation of the present invention comprises, consists of, or consists essentially of, adalimumab, histidine buffer as the sole buffer in the formulation, glycine (or arginine, or combinations thereof) as the sole stabilizer among the non-surfactant stabilizers referenced earlier, and polysorbate 80. In this formulation, the amount of adalimumab is 20 to 150 mg/ml; the amount of histidine buffer is up to about 50 mM; the amount of glycine is up to about 300 mM; and the amount of polysorbate 80 is in the range of about 0.01 to about 0.2 wt %. Optionally, this formulation may include up to about 100 mM NaCl. The present invention also contemplates modification of this formulation to combine the histidine buffer with one or more of citrate, acetate, phosphate, maleate, tartrate buffers. In yet another embodiment, the adalimumab formulation of the present invention comprises, consists of, or consists essentially of, adalimumab, histidine buffer as the sole buffer, mannitol (or sorbitol or trehelose), and polysorbate 80, and further being free or substantially free of the non-surfactant stabilizers (e.g. glycine, arginine, etc.) referenced above. In this formulation, the amount of adalimumab is 20 to 150 mg/ml; the amount of histidine buffer is up to about 50 mM; the amount of polyol is up to about 300 mM; and the amount of polysorbate 80 is in the range of about 0.01 to about 0.2 wt %. Optionally, this formulation may include up to about 100 mM NaCl. The present invention also contemplates modification of this formulation to combine the histidine buffer with one or more of citrate, acetate, phosphate, maleate, tartrate buffers. In a method aspect, the invention is directed to a method for enhancing long term stability in an aqueous, buffered adalimumab formulation, comprising one or more of the steps of: (a) incorporating histidine buffer, succinate buffer, or a combination thereof, in the formulation based on empirical data indicating that such buffers contribute to the stability of the formulation to a greater extent than other buffers or buffer combinations; or (b) incorporating glycine, arginine or a combination thereof as stabilizers in the formulation, based upon empirical data indicating that such stabilizer contribute to the stability of the formulation to a greater extent than other stabilizers; or (c) substantially excluding the presence of buffer or buffer combinations comprising citrate buffer (especially buffer combinations comprising both citrate and phosphate) based upon empirical data indicating that such buffer or buffer combinations perform poorly in terms of stabilizing the formulation in comparison to other buffers. The method may further comprise the selection of PS 80 as a surfactant based on empirical data indicating that PS 80 imparts better thermal stability to the adalimumab formulation than other surfactants, including PS 20. The method is useful to obtain a formulation of adalimumab that exhibits long term stability comparable to or better than commercially available adalimumab formulations marketed under the trademark Humira®. In a further method aspect, the invention is directed to a method for treating an inflammatory condition in a subject which comprises administering to such subject any of the adalimumab formulation embodiments as described herein. In the foregoing embodiments, where the above referenced stabilizers may be included in the formulations, it is further discovered that satisfactory stabilization can be attained when such stabilizers are used in place of both polyol and surfactant and hence stabilized formulations of the present invention can be free or substantially free of both polyol and surfactant. Accordingly, in a sixth embodiment, the invention provides a stable aqueous pharmaceutical composition comprising adalimumab, optionally a buffer, a stabilizer selected from the group consisting of an amino acid, a salt, EDTA, and a metal ion, and wherein said composition has a pH of about 4 to about 8, and preferably 5 to about 6, and wherein said composition is either substantially free of both polyol and surfactant. When buffer is present in this embodiment, it is especially preferred that (i) the buffer not include the combination of citrate and phosphate; (ii) the buffer is selected from the group consisting of histidine and succinate; and (iii) the stabilizer does not comprise sodium chloride, but instead is at least one member selected from the group consisting of arginine and glycine. Important aspects of the present invention in certain embodiments include (i) that sorbitol and trehalose are discovered to be significantly better stabilizers of adalimumab formulations than mannitol, unless mannitol is used at concentrations in excess of about 200-300 mM in which case the three are generally equivalent; (ii) arginine and glycine (and combinations) are discovered to be significantly better stabilizers of adalimumab formulations than sodium chloride; and; (iii) when buffers are used in the formulation, it is discovered that the combination of citrate and phosphate is surprisingly significantly poorer in stabilizing adalimumab than other buffers such as succinate, histidine, phosphate and tartrate. The relatively poor performance of the buffer combination of citrate and phosphate is rather unexpected considering the apparent importance attributed to the use of a citrate/phosphate combined buffer in U.S. Pat. No. 8,216,583. To the contrary, we have now found that a phosphate/citrate buffer combination is not an optimal choice for obtaining a stabilized adalimumab formulation, and in fact, an element of our invention is the discovery that this combination should be avoided altogether in favor of other buffer systems. Preferably, a polyol is a sugar alcohol; and even more preferably, the sugar alcohol is selected from the group consisting of mannitol, sorbitol and trehalose. However, as between mannitol and sorbitol, the invention has discovered, as noted above, a distinct stabilization advantage in using sorbitol or trehalose instead of mannitol, unless mannitol is used at concentrations in excess of about 200 mM, in which case mannitol, sorbitol and trehalose are generally equivalent. At concentrations below about 200 mM, mannitol has been found to be a poorer stabilizer than sorbitol or trehalose in an adalimumab formulation. Preferably, a surfactant is a polysorbate or poloxamer; and even more preferably PS 80, PS 40, PS20, Pluronic F-68 and combinations. We have discovered a distinct and surprising thermal stabilization advantage in selecting PS 80 instead of PS-20. These and other aspects will become apparent from the following description of the various embodiments, although variations and modifications therein may be affected without departing from the spirit and scope of the novel concepts of the disclosure. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. Further representative embodiments are set forth in the numerous formulation studies reported in the detailed description, as well as the various embodiments listed in Appendices A, B and C attached hereto and made a part hereof.
A61K3939591
20171005
20180215
72243.0
A61K39395
1
KIM, YUNSOO
Stable Aqueous Formulations of Adalimumab
UNDISCOUNTED
1
CONT-ACCEPTED
A61K
2,017
15,726,899
PENDING
WIRELESS PRINTING DEVICES THAT PROVIDE PRINTING SERVICES OVER A NETWORK WITHOUT A PRINTER SPECIFIC PRINTER DRIVER AFTER HAVING REGISTERED THE PRINTING DEVICE WITH A SERVICE OVER THE NETWORK
Wireless printing devices that are configured to register with a service over a network (e.g., Internet) for providing printing services for one or more client devices without printer drivers are herein disclosed and enabled. The printing device may include a touch sensitive screen interface to receive security information for connecting to a wireless local area network (LAN). While connected to the wireless LAN, the printing device accesses the service for registering the printing device, and transmits device information related the printing device to the service. Subsequent to registration, one or more client devices using the service over the network may select the registered printing device for printing, and the printing device is configured to receive output data either from the service or via a computing device within the wireless LAN, and wherein output data is related to the device information transmitted to the service.
1. A printing device that is a wireless printing device for wirelessly providing printing services to one or more client devices over a network without the need for the one or more client devices to install a device specific printer driver that is device specific to the printing device, the printing device includes: an interface for interacting with a user; wireless communication circuitry for establishing a connection to a wireless local area network; memory or storage component storing software for connecting to one or more computing devices over the network; and wherein the printing device: (1) receives, via the interface of the printing device from the user, security information for establishing the connection to a wireless local area network; (2) establishes, via the wireless communication circuitry of the printing device, the connection to a wireless local area network using, at least in part, the security information received in (1); (3) wirelessly accesses, via the wireless communication circuitry of the printing device and using the connection to a wireless local area network established in (2), the network; (4) wirelessly connects, via the wireless communication circuitry of the printing device and using the software stored in the memory or storage component of the printing device, to the one or more computing devices over the network accessed in (3); (5) wirelessly transmits, via the wireless communication circuitry, device information from the printing device to the one or more computing devices over the network connected in (4), the device information includes at least one of identification information, capability information, address information, status information, or attribute information, individually or in any combination, related to the printing device, and the transmitting of the device information is for registering the printing device; and (6) wirelessly receives, via the wireless communication circuitry of the printing device, output data from the one or more computing devices subsequent to having registered the printing device in (5), the output data is related to digital content for rendering at the printing device; and wherein the output data received in (6) is further related, at least in part, to the device information transmitted in (5) from the printing device to the one or more computing devices over the network. 2. The printing device of claim 1, wherein the wireless communication circuitry includes one or more chips or chipsets, the one or more chips or chipsets are compatible, at least in part, with at least part of a protocol within IEEE 802.11 standards for wirelessly connecting to the wireless local area network in (1). 3. The printing device of claim 2, wherein the device information transmitted from the printing device to the one or more computing devices in (5) includes identification information of the printing device, the identification information includes one or more of a name, a model, a brand, an identifier, a registration, a URL, a security key, a PIN, or an IP address, individually or in any combination, and the identification information is to facilitate identification of the printing device for service. 4. The printing device of claim 3, wherein the device information transmitted from the printing device to the one or more computing devices in (5) includes capability information related to one or more languages or formats supported by the printing device, and wherein the output data received at the printing device is in accordance, at least in part, to the one or more languages or formats supported by the printing device and specified in the device information. 5. The printing device of claim 4, wherein the printing device further includes a display screen with a touch sensitive screen interface for interacting with a user, and wherein the receiving of the security information in (1) for establishing the connection to a wireless local area network is received via the touch sensitive screen interface. 6. The printing device claim 5, wherein the network in (3) includes the Internet, and the one or more computing devices over the network being one or more servers over the Internet, and wherein the one or more servers are operated, at least in part, by a service provided over the Internet, and wherein the wireless transmitting of the device information in (5) is from the printing device to the one or more servers for registering the printing device with the service. 7. The printing device claim 5, wherein the network in (3) includes the wireless local area network, and the one or more computing devices includes an information apparatus that is in the wireless local area network, and wherein the information apparatus includes a client application for communicating with the printing device over the established wireless local area network, and wherein the client application: obtains security information or authentication information for connecting to one or more servers over the Internet, the one or more servers operated, at least in part, by a service provided over the Internet; receives, via the wireless local area network, the device information from the printing device; transmits the received device information over the Internet from the computing device to the one or more servers, the transmitting of the device information is for registering the printing device with the service or for selecting the printing device for the service. 8. The printing device of claim 5, wherein the software includes an application programming interface (API) and the printing device uses the application programming interface (API) to register the printing device with the service; and wherein the output data received from the one or more computing devices over the network includes an encryption scheme that is device specific for rendering at the printing device. 9. The printing device of claim 4, wherein the interface of the printing device is a wireless interface that wirelessly communicates with a portable wireless communication device over a local or a short range wireless communication link, and wherein the receiving of the security information for establishing the connection to a wireless area network in (1) is received using the wireless interface of the printing device and from the portable wireless communication device.
CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 10/053,765 filed Jan. 18, 2002, which claims priority to U.S. Provisional Patent Application Ser. No. 60/262,764, filed Jan. 19, 2001. Additionally, this application is a continuation-in-part of U.S. patent application Ser. No. 09/992,413 filed Nov. 18, 2001, which claims benefit of U.S. Provisional Patent Application Ser. No. 60/252,682 filed Nov. 20, 2000. Moreover, this application is a continuation-in-part of U.S. patent application Ser. No. 13/710,299 filed Dec. 10, 2012, which is a continuation of U.S. patent application Ser. No. 12/903,048 filed Oct. 12, 2010 and now issued as U.S. Pat. No. 8,332,521, which is a continuation of U.S. patent application Ser. No. 10/016,223 filed Nov. 1, 2001 and now issued as U.S. Pat. No. 7,941,541, and which claims benefit of U.S. Provisional Patent Application Ser. No. 60/245,101, filed Nov. 1, 2000. The complete disclosures of the above patent applications are hereby incorporated by reference for all purposes. TECHNICAL FIELD OF THE INVENTION Present invention relates to providing content to an output device and, in particular, to providing universal output in which an information apparatus can pervasively output content to an output device without the need to install a dedicated device dependent driver or applications for each output device. BACKGROUND OF THE DISCLOSURE The present invention relates to universal data output and, in particular, to providing a new data output method and a new raster image process for information apparatuses and output devices. As described herein, information apparatuses refer generally to computing devices, which include both stationary computers and mobile computing devices (pervasive devices). Examples of such information apparatuses include, without limitation, desktop computers, laptop computers, networked computers, palmtop computers (hand-held computers), personal digital assistants (PDAs), Internet enabled mobile phones, smart phones, pagers, digital capturing devices (e.g., digital cameras and video cameras), Internet appliances, e-books, information pads, and digital or web pads. Output devices may include, without limitation, fax machines, printers, copiers, image and/or video display devices (e.g., televisions, monitors and projectors), and audio output devices. For simplicity and convenience, hereafter, the following descriptions may refer to an output device as a printer and an output process as printing. However, it should be understood that the term printer and printing used in the discussion of present invention refer to one embodiment used as a specific example to simplify the description of the invention. The references to printer and printing used here are intended to be applied or extended to the larger scope and definition of output devices and should not be construed as restricting the scope and practice of present invention. Fueled by an ever-increasing bandwidth, processing power, wireless mobile devices, and wireless software applications, millions of users are or will be creating, downloading, and transmitting content and information using their pervasive or mobile computing devices. As a result, there is a need to allow users to conveniently output content and information from their pervasive computing devices to any output device. As an example, people need to directly and conveniently output from their pervasive information apparatus, without depending on synchronizing with a stationary computer (e.g., desktop personal computer) for printing. To illustrate, a mobile worker at an airport receiving e-mail in his hand-held computer may want to walk up to a nearby printer or fax machine to have his e-mail printed. In addition, the mobile worker may also want to print a copy of his to-do list, appointment book, business card, and his flight schedule from his mobile device. As another example, a user visiting an e-commerce site using his mobile device may want to print out transaction confirmation. In still another example, a user who takes a picture with a digital camera may want to easily print it out to a nearby printer. In any of the above cases, the mobile user may want to simply walk up to a printer and conveniently print a file (word processing document, PDF, HTML etc) that is stored on the mobile device or downloaded from a network (e.g., Internet, corporate network). Conventionally, an output device (e.g., a printer) is connected to an information apparatus via a wired connection such as a cable line. A wireless connection is also possible by using, for example, radio communication or infrared communication. Regardless of wired or wireless connection, a user must first install in the information apparatus an output device driver (e.g., printer driver in the case the output device is a printer) corresponding to a particular output device model and make. Using a device-dependent or specific driver, the information apparatus may process output content or digital document into a specific output device's input requirements (e.g., printer input requirements). The output device's input requirements correspond to the type of input that the output device (e.g., a printer) understands. For example, a printer's input requirement may include printer specific input format (e.g., one or more of an image, graphics or text format or language). Therefore, an output data (or print data in the case the output device is a printer) herein refers to data that is acceptable for input to an associated output device. Examples of input requirements may include, without limitation, audio format, video format, file format, data format, encoding, language (e.g., page description language, markup language etc), instructions, protocols or data that can be understood or used by a particular output device make and model. Input requirements may be based on proprietary or published standards or a combination of the two. An output device's input requirements are, therefore, in general, device dependent. Different output device models may have their own input requirements specified, designed or adopted by the output device manufacturer (e.g., the printer manufacturer) according to a specification for optimal operation. Consequently, different output devices usually require use of specific output device drivers (e.g., printer drivers) for accurate output (e.g., printing). Sometimes, instead of using a device driver (e.g., printer driver), the device driving feature may be included as part of an application software. Installation of a device driver (e.g., printer driver) or application may be accomplished by, for example, manual installation using a CD or floppy disk supplied by the printer manufacturer. Or alternatively, a user may be able to download a particular driver or application from a network. For a home or office user, this installation process may take anywhere from several minutes to several hours depending on the type of driver and user's sophistication level with computing devices and networks. Even with plug-and-play driver installation, the user is still required to execute a multi-step process for each printer or output device. This installation and configuration process adds a degree of complexity and work to end-users who may otherwise spend their time doing other productive or enjoyable work. Moreover, many unsophisticated users may be discouraged from adding new peripherals (e.g., printers, scanners, etc.) to their home computers or networks to avoid the inconvenience of installation and configuration. It is therefore desirable that an information apparatus can output to more than one output device without the inconvenience of installing multiple dedicated device dependent drivers. In addition, conventional output or printing methods may pose significantly higher challenges and difficulties for mobile device users than for home and office users. The requirement for pre-installation of a device-dependent driver diminishes the benefit and concept of mobile (pervasive) computing and output. For example, a mobile user may want to print or output e-mail, PowerPoint® presentation documents, web pages, or other documents at an airport, gas station, convenience store, kiosk, hotel, conference room, office, home, etc. It is highly unlikely that the user would find at any of these locations a printer of the same make and model as is at the user's base station. As a consequence, under the conventional printing method, the user would have to install and configure a printer driver each time at each such remote location before printing. It is usually not a viable option given the hundreds, or even thousands of printer models in use, and the limited storage, memory space, and processing power of the information apparatus. Moreover, the user may not want to be bothered with looking for a driver or downloading it and installing it just to print out or display one page of email at the airport. This is certainly an undesirable and discouraging process to promote pervasive or mobile computing. Therefore, a more convenient printing method is needed in support of the pervasive computing paradigm where a user can simply walk up to an output device (e.g., printer or display device) and easily output a digital document without having to install or pre-install a particular output device driver (e.g., printer driver). Another challenge for mobile users is that many mobile information apparatuses have limited memory space, processing capacity and power. These limitations are more apparent for small and low-cost mobile devices including, for example, PDAs, mobile phones, screen phones, pagers, e-books, Internet Pads, Internet appliances etc. Limited memory space poses difficulties in installing and running large or complex printer or device drivers, not to mention multiple drivers for a variety of printers and output devices. Slow processing speed and limited power supply create difficulties driving an output device. For example, processing or converting a digital document into output data by a small mobile information apparatus may be so slow that it is not suitable for productive output. Intensive processing may also drain or consume power or battery resources. Therefore, a method is needed so that a small mobile device, with limited processing capabilities, can still reasonably output content to various output devices. To output or render content (e.g. digital document) to an output device, a raster image processing (RIP) operation on the content is usually required. RIP operation can be computationally intensive and may include (1) a rasterization operation, (2) a color space conversion, and (3) a halftoning operation. RIP may also include other operations such as scaling, segmentation, color matching, color correction, GCR (Grey component replacement), Black generation, image enhancement compression/decompression, encoding/decoding, encryption/decryption GCR, image enhancement among others. Rasterization operation in RIP involves converting objects and descriptions (e.g. graphics, text etc) included in the content into an image form suitable for output. Rasterization may include additional operations such as scaling and interpolation operations for matching a specific output size and resolution. Color space conversion in RIP includes converting an input color space description into a suitable color space required for rendering at an output device (e.g. RGB to CMYK conversion). Digital halftoning is an imaging technique for rendering continuous tone images using fewer luminance and chrominance levels. Halftoning operations such as error diffusion can be computationally intensive and are included when the output device's bit depth (e.g. bits per pixel) is smaller than the input raster image bit depth. Conventionally, RIP operations are included either in an information apparatus, or as part of an output device or output system (e.g. in a printer controller). FIG. 1A illustrates a flow diagram of a conventional data output method 102 in which RIP 110 is implemented in the information apparatus. Output devices that do not include a printer controller to perform complex RIP operations, such as a lower-cost, lower speed inkjet printer, normally employ data output method 102. In data output method 102, an information apparatus obtains content (e.g. a digital document) in step 100 for rendering or output at an output device. The information apparatus may includes an application (e.g. device driver), which implements RIP operation 110. The information apparatus generates an output data in step 120 and transmits the output data to the output device in step 130 for rendering. The output data relating to the content is in an acceptable form (e.g. in an appropriate output size and resolution) to the output engine (e.g. display engine, printer engine etc.) included in the output device. The output data in a conventional output method 102 is usually device dependent. One drawback for the data output method 102 of FIG. 1A is that the information apparatus performs most if not the entire raster image processing operations 110 required for output. The RIP operations may require intensive computation. Many information apparatus such as mobile information device might have insufficient computing power and/or memory to carry out at an acceptable speed the RIP operations 110 required in an output process. Another drawback for the conventional data output method 102 of FIG. 1A is that the generated output data is device dependent and therefore is typically not very portable to other output devices. As a result, the information apparatus may need to install multiple applications or device drivers for multiple output devices, which may further complicate its feasibility for use in information apparatuses with limited memory, storage and processing power. FIG. 1B illustrates a flow diagram of another conventional data output method 104 in which the RIP is implemented in an output device. An example of an output device that implements process 104 is a high-speed laser printer which includes a printer controller for performing RIP operations and an output engine (e.g. printer engine) for rendering content. Printer controller may be internally installed or externally connected to an output device (printer in this example). In data output method 104, an information apparatus obtains content for output in step 100 and generates in step 160 an output data or print data for transmitting to the output device in step 170. Print data includes information related to the content and is usually encoded in a page description language (PDL) such as PostScript and PCL etc. In step 180, the printer receives the output data or print data (in a PDL). In step 190, a printer controller included in the printer interprets the PDL, performs RIP operations, and generates a printer-engine print data that is in a form acceptable to the printer engine (e.g. a raster image in an appropriate output size, bit depth, color space and resolution). In step 150 the printer engine renders the content with the printer-engine print data. It will be understood that a reference to print data or output data including a language, such as PDL, should be interpreted as meaning that the print data or output data is encoded using that language. Correspondingly, a reference to a data output process generating a language, such as PDL, should be interpreted as meaning that the data output process encodes data using that language. There are many drawbacks in the conventional data output method 104 shown in FIG. 1B. These drawbacks are especially apparent for mobile computing devices with limited processing power and memory. One such drawback is that the output data or print data, which include a page description language (PDL) such as PostScript or PCL, can be very complex. Generating complex PDL may increase memory and processing requirements for an information apparatus. Furthermore, interpreting, decoding and then raster image processing complex PDL can increase computation, decrease printing speed, and increase the cost of the output device or its printer controller. Another drawback is that the output data that includes PDL can creates a very large file size that would increase memory and storage requirements for the information apparatus, the output device and/or the printer controller etc. Large file size may also increase the bandwidth required in the communication link between the information apparatus and the output device. Finally, to rasterize text in an output device, a printer controller may need to include multiple fonts. When a special font or international characters is not included or missing in the printer controller, the rendering or output can potentially become inaccurate or inconsistent. SUMMARY OF THE INVENTION Accordingly, this invention provides a convenient universal data output method in which an information apparatus and an output device or system share the raster image processing operations. Moreover, the new data output method eliminates the need to install a plurality of device-dependent dedicated drivers or applications in the information apparatus in order to output to a plurality of output devices. In accordance with present invention, an electronic system and method of pervasive and universal output allow an information apparatus to output content conveniently to virtually any output device. The information apparatus may be equipped with a central processing unit, input/output control unit, storage unit, memory unit, and wired or wireless communication unit or adapters. The information apparatus preferably includes a client application that may be implemented as a software application, a helper application, or a device driver (a printer driver in case of a printer). The client application may include management and control capabilities with hardware and software components including, for example, one or more communication chipsets residing in its host information apparatus. The client application in the information apparatus may be capable of communicating with, managing and synchronizing data or software components with an output device equipped with an output controller of present invention. Rendering content in an output device refers to printing an image of the content onto an substrate in the case of a printing device; displaying an image of the content in the case of a displaying device; playing an audio representation of the content in a voice or sound output device or system. An output controller may be a circuit board, card or software components residing in an output device. Alternatively, the output controller may be connected externally to an output device as an external component or “box.” The output controller may be implemented with one or more combinations of embedded processor, software, firmware, ASIC, DSP, FPGA, system on a chip, special chipsets, among others. In another embodiment, the functionality of the output controller may be provided by application software running on a PC, workstation or server connected externally to an output device. In conventional data output method 102 as described with reference to FIG. 1A, an information apparatus transmits output data to an output device for rendering. Output data corresponds to content intended for output and is mostly raster image processed (RIPed) and therefore is device dependent because raster image processing is a typical device dependent operation. Output data may be encoded or compressed with one or more compression or encoding techniques. In present invention, an information apparatus generates an intermediate output data for transmitting to an output device. The intermediate output data includes a rasterized image corresponding to the content; however, device dependent image processing operations of a RIP (e.g. color matching and halftoning) have not been performed. As a result, an intermediate output data is more device independent and is more portable than the output data generated by output method with reference to FIG. 1A. In one implementation of this invention, the intermediate output data includes MRC (Mixed raster content) format, encoding and compression techniques, which further provides improved image quality and compression ratio compared to conventional image encoding and compression techniques. In an example of raster image process and data output method of the present invention, a client application such as a printer driver is included in an information apparatus and performs part of raster image processing operation such as rasterization on the content. The information apparatus generates an intermediate output data that includes an output image corresponding to the content and sends the intermediate output data to an output device or an output system for rendering. An output controller application or component included in the output device or output system implements the remaining part of the raster image processing operations such as digital halftoning, color correction among others. Unlike conventional raster image processing methods, this invention provides a more balanced distribution of the raster image processing computational load between the Information apparatus and the output device or the output system. Computational intensive image processing operations such as digital halftoning and color space conversions can be implemented in the output device or output system. Consequently, this new raster image processing method reduces the processing and memory requirements for the information apparatus when compared to conventional data output methods described with reference to FIG. 1A in which the entire raster image process is implemented in the information apparatus. Additionally, in this invention, a client application or device driver included in the information apparatus, which performs part of the raster image processing operation, can have a smaller size compared to a conventional output application included in the information apparatus, which performs raster image processing operation. In another implementation, the present invention provides an information apparatus with output capability that is more universally accepted by a plurality of output devices. The information apparatus, which includes a client application, generates an intermediate output data that may include device independent attributes. An output controller includes components to interpret and process the intermediate output data. The information apparatus can output content to different output devices or output systems that include the output controller even when those output devices are of different brand, make, model and with different output engine and input data requirements. Unlike conventional output methods, a user does not need to preinstall in the information apparatus multiple dedicated device dependent drivers or applications for each output device. The combination of a smaller-sized client application, a reduced computational requirement in the information apparatus, and a more universal data output method acceptable for rendering at a plurality of output devices enable mobile devices with less memory space and processing capabilities to implement data output functions which otherwise would be difficulty to implement with conventional output methods. In addition, this invention can reduce the cost of an output device or an output system compared to conventional output methods 104 that include a page description language (PDL) printer controller. In the present invention, an information apparatus generates and sends an intermediate output data to an output device or system. The intermediate output data in one preferred embodiment includes a rasterized output image corresponding to the content intended for output. An output controller included in an output device or an output system decodes and processes the intermediate output data for output, without performing complex interpretation and rasterization compared to conventional methods described in process 104. In comparison, the conventional data output process 104 generates complex PDL and sends this PDL from an information apparatus to an output device that includes a printer controller (e.g. a PostScript controller or a PCL5 controller among others). Interpretation and raster image processing of a PDL have much higher computational requirements compared to decoding and processing the intermediate output data of this invention that include rasterized output image or images. Implementing a conventional printer controller with, for example, PDL increases component cost (e.g. memories, storages, ICs, software and processors etc.) when compared to using the output controller included in the data output method of this present invention. Furthermore, an output data that includes PDL can create a large file size compared to an intermediate output data that includes rasterized output image. The data output method for this invention comparatively transmits a smaller output data from an information apparatus to an output device. Smaller output data size can speed up transmission, lower communication bandwidth, and reduce memory requirements. Finally, this invention can provide a convenient method to render content at an output device with or without connection to a static network. In conventional network printing, both information apparatus and output device must be connected to a static network. In this invention, through local communication and synchronization between an information apparatus and an output device, installation of hardware and software to maintain static network connectivity may not be necessary to enable the rendering of content to an output device. According to the several aspects of the present invention there is provided the subject matter defined in the appended independent claims. Additional objects and advantages of the present invention will be apparent from the detailed description of the preferred embodiment thereof, which proceeds with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1A is a flow diagram of a conventional data output method and its corresponding raster image process in accordance with prior art. FIG. 1B is a flow diagram of a second conventional data output method and its corresponding raster image process for an output device that includes a conventional printer controller in accordance with prior art. FIGS. 2A and 2B are block diagrams illustrating components of an operating environment that can implement the process and apparatus of the present invention. FIG. 3A is a schematic block diagram illustrating hardware/software components of an information apparatus implementation in accordance with the present invention. The information apparatus includes an operating system. FIG. 3B is a second schematic block diagram illustrating hardware/software components of an information apparatus implementation in accordance with the present invention. FIG. 4A is a block diagram of a conventional printing system or printer with a conventional printer controller. FIG. 4B is a block diagram of a second conventional output system or output device. FIG. 5A is a schematic block diagram of a printing system or printer with a conventional printer controller and an output controller in accordance with present invention. FIG. 5B is a schematic block diagram of a second output system or output device that includes an output controller in accordance with present invention. FIG. 6A is a schematic block diagram illustrating hardware/software components of an output controller in accordance with present invention. The output controller includes an operating system. FIG. 6B is a second schematic block diagram illustrating hardware/software components of an output controller in accordance with present invention. The output controller does not include an operating system. FIG. 6C is a third schematic block diagram illustrating hardware/software components of an output controller in accordance with present invention. The output controller combines the functionality of a printer controller and an output controller of present invention. FIGS. 7A-7F illustrate various configurations and implementations of output controller with respect to an output device such as a printer. FIG. 8A is a block diagram illustrating an exemplary implementation of hardware/software components of wireless communication unit. FIG. 8B is block diagram illustrating a second exemplary implementation of hardware/software components of wireless communication unit. FIG. 9 is a flow diagram of a universal data output method and its corresponding raster imaging process of the present invention. FIG. 10 is a block diagram of a universal data output method of the present invention with respect to the components, system and apparatus described with reference to FIG. 2. FIG. 11 is a flow diagram illustrating one way of implementing a discovery process optionally included in the output process of FIG. 10. FIGS. 12A and 12B are flow diagrams of exemplary client application process included in the output process of FIG. 10. FIGS. 13A and 13B are flow diagrams of exemplary output device or output system process included in the output process of FIG. 10. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Sets forth below are definitions of terms that are used in describing implementations of the present invention. These definitions are provided to facilitate understanding and illustration of implementations of the present invention and should in no way be construed as limiting the scope of the invention to a particular example, class, or category. Output Device Profile (or Object) An output device profile (or object) includes software and data entity, which encapsulates within itself both data and attributes describing an output device and instructions for operating that data and attributes. An output device profile may reside in different hardware environments or platforms or applications, and may be transported in the form of a file, a message, a software object or component among other forms and techniques. For simplicity of discussion, a profile or object may also include, for example, the concept of software components that may have varying granularity and can consist of one class, a composite of classes, or an entire application. The term profile or object used herein is not limited to software or data as its media. Any entity containing information, descriptions, attributes, data, instructions etc. in any computer-readable form or medium such as hardware, software, files based on or including voice, text, graphics, image, or video information, etc., are all valid forms of profile and object definition. A profile or object may also contain in one of its fields or attributes a reference or pointer to another profile or object, or a reference or pointer to data and or content. A reference to a profile or object may include one or more, or a combination of pointers, identifiers, names, paths, addresses or any descriptions relating to a location where an object, profile, data, or content can be found. An output device profile may contain one or more attributes that may identify and describe, for example, the capabilities and functionalities of a particular output device such as a printer. An output device profile may be stored in the memory component of an output device, an information apparatus or in a network node. A network node includes any device, server or storage location that is connected to the network. As described below in greater detail, an information apparatus requesting output service may communicate with an output device. During such local service negotiation, at least a partial output device profile may be uploaded to the information apparatus from the output device. By obtaining the output device profile (or printer profile in the case of a printer), the information apparatus may learn about the capability, compatibility, identification, and service provided by the output device. As an example, an output device profile may contain one or more of the following fields and or attribute descriptions. Each of following fields may be optional, and furthermore, each of the following fields or attributes may or may not exist in a particular implementation (e.g., may be empty or NULL): Identification of an output device (e.g., brand, model, registration, IP address etc.) Services and feature sets provided by an output device (e.g., color or grayscale output, laser or inkjet, duplex, output quality, price per page, quality of service, etc.) Type of input languages, formats, output data and/or input requirements (e.g., PostScript, PCL, XML, RTL, etc.) supported by an output device. Device specific or dependent parameters and information (e.g., communication protocols, color space, color management methods and rendering intents, resolution, halftoning methods, dpi (dots-per-inch), bit depth, page size, printing speed, number of independent colors channels or ink etc.) Data and tables needed for image processing such as color table, halftone table, scale factor, encoding/decoding parameters and methods, compression and decompression parameters and method etc. Another profile which contain parameters and information about the output device and its service (e.g. color profiles, halftoning profiles, communication profiles, rasterization profiles, quality of service etc.). Payment information on a plurality of services provided by an output device. Information or security requirements and type of authentication an output device supports. Date and version of the output device profile, history of its modification and updates. Software components containing algorithms or instructions or data, which may be uploaded to run in an information apparatus. For example, a graphical user interface (GUI) software component may be uploaded to an information apparatus. The software component may be incorporated into or launched in the information apparatus by a client application of present invention to capture a user's preferences (e.g., print quality, page layout, number of copies, number of cards per page, etc.). In another example, software components may include methods, instructions or executables for compression/decompression, encoding/decoding, color matching or correction, segmentation, scaling, halftoning, encryption/decryption among others. Pointer or reference to one or more output device parameters, including one or more of the above described output device profile or object fields and or attribute descriptions. For example, a more up-to-date or original version of output device parameters may sometimes be stored in a network node (any device, server or storage location that is connected to the network), or within the information apparatus where it can be obtained by the client application. An output device profile may include pointer or pointers to these output device parameters. Content (or Data Content, Digital Content, Output Content) Content (or data content, digital content, output content) is the data intended for output, which may include texts, graphics, images, forms, videos, audio among other content types. Content may include the data itself or a reference to that data. Content may be in any format, language, encoding or combination, and it can be in a format, language or encoding that is partially or totally proprietary. A digital document is an example of content that may include attributes and fields that describe the digital document itself and or reference or references to the digital document or documents. Examples of a digital document may be any one or combination of file types: HTML, VHTML, PostScript, PCL, XML, PDF, MS Word, PowerPoint, JPEG, MPEG, GIF, PNG, WML, VWML, CHTML, HDML, ASCII, 2-byte international coded characters, etc. Content may be used interchangeably with the term data content, output content or digital content in the descriptions of present invention. Intermediate Output Data Output data (or print data in case of a printer) is the electronic data sent from an information apparatus to an output device. Output data is related to the content intended for output and may be encoded in a variety of formats and languages (e.g. postscript, PCL, XML), which may include compressed or encrypted data. Some output device manufacturers may also include in the output data (or print data) a combination of proprietary or non-proprietary languages, formats, encoding, compression, encryption etc. Intermediate output data is the output data of the present invention, and it includes the broader definition of an output file or data generated by an information apparatus, or a client application or device driver included in the information apparatus. An intermediate output data may contain text, vector graphics, images, video, audio, symbols, forms or combination and can be encoded with one or more of a page description language, a markup language, a graphics format, an imaging format, a metafile among others. An intermediate output data may also contain instructions (e.g. output preferences) and descriptions (e.g. data layout) among others. Part or all of an intermediate output data may be compressed, encrypted or tagged. In a preferred embodiment of this invention, intermediate output data contains rasterized image data. For example, vector graphics and text information or objects that are not in image form included in content can be rasterized or conformed into image data in an information apparatus and included in an intermediate output data. Device dependent image processing operations of a RIP such as digital halftoning and color space conversions can be implemented at an output device or an output system. The intermediate output data can be device dependent or device independent. In one implementation, the rasterized output image is device dependent if the rasterization parameters used, such as resolution, scale factor, bit depth, output size and or color space are device dependent. In another implementation of this invention, the rasterized image may be device independent if the rasterization parameters used are device independent. Rasterization parameter can become device independent when those parameters include a set of predetermined or predefined rasterization parameters based on a standard or a specification. With predefined or device independent rasterization parameters, a client application of present invention can rasterize at least a portion of the content and generate a device independent image or images included in the intermediate output data. By doing so, the intermediate output data may become device independent and therefore, become universally acceptable with output devices that have been pre-configured to accept the intermediate output data. One advantage of rasterizing or converting text and graphics information into image data at the information apparatus is that the output device or printer controller no longer needs to perform complex rasterization operation nor do they need to include multiple fonts. Therefore, employing the intermediate output data and the data output method described herein could potentially reduce the cost and complexity of an output controller, printer controller and or output device. One form of image data encoding is known as mixed raster content, or MRC. Typically, an image stored in MRC includes more than one image or bitmap layers. In MRC, an image can be segmented in different layers based on segmentation criteria such as background and foreground, luminance and chrominance among others. For example, an MRC may include three layers with a background layer, a foreground layer and a toggle or selector layer. The three layers are coextensive and may include different resolution, encoding and compression. The foreground and background layers may each contain additional layers, depending on the manner in which the respective part of the image is segmented based on the segmentation criteria, component or channels of a color model, image encoding representation (HLS, RGB, CMYK, YCC, LAB etc) among others. The toggle layer may designate, for each point, whether the foreground or background layer is effective. Each layer in a MRC can have different bit depths, resolution, color space, which allow, for example, the foreground layer to be compressed differently from the background layer. The MRC form of image data has previously been used to minimize storage requirements. Further, an MRC format has been proposed for use in color image fax transmission. In one embodiment of present invention, the intermediate output data includes one or more rasterized output images that employ MRC format, encoding and or related compression method. In this implementation, different layers in the output image can have different resolutions and may include different compression techniques. Different information such as chrominance and luminance and or foreground and background information in the original content (e.g. digital document) can be segmented and compressed with different compression or encoding techniques. Segmented elements or object information in the original content can also be stored in different image layers and with different resolution. Therefore, with MRC, there is opportunity to reduce output data file size, retain greater image information, increase compression ratio, and improve image quality when compared to other conventional image encoding and compression techniques. Implementations of rasterization, raster image processing and intermediate output data that include MRC encoding in the present invention are described in more detail below. Rasterization Rasterization is an operation by which graphics and text in a digital document are converted to image data. For image data included in the digital document, rasterization may include scaling and interpolation. The rasterization operation is characterized by rasterization parameters including, among others bit depth and resolution. A given rasterization operation may be characterized by several more rasterization parameters, including output size, color space, color channels etc. Values of one or more of the rasterization parameters employed in a rasterization operation may be specified by default; values of one or more of the rasterization parameters may be supplied to the information apparatus as components of a rasterization vector. In a given application, the rasterization vector may specify a value of only one rasterization parameter, default values being employed for other rasterization parameters used in the rasterization operation. In another application the rasterization vector may specify values of more than one, but less than all, rasterization parameters, default values being employed for at least one other rasterization parameter used in the rasterization operation. And in yet another application the rasterization vector may specify values of all the rasterization parameters used in the rasterization operation. FIGS. 2A and 2B are block diagrams illustrating components of an operating environment that can implement the process and apparatus of present invention. FIG. 2A shows an electronic system which includes an information apparatus 200 and an output device 220. The output device 220 includes an output controller 230. FIG. 2B illustrates a second implementation of an electronic system that includes an information apparatus 200 and an output system 250. The output system 250 includes an output device 220 and an output controller 230 which may be externally connected to, or otherwise associated with, the output device 220 in the output system 250. Information apparatus 200 is a computing device with processing capability. In one embodiment, information apparatus 200 may be a mobile computing device such as palmtop computer, handheld device, laptop computer, personal digital assistant (PDA), smart phone, screen phone, e-book, Internet pad, communication pad, Internet appliance, pager, digital camera, etc. It is possible that information apparatus 200 may also include a static computing device such as a desktop computer, workstation, server, etc. FIGS. 3A and 3B are block diagrams illustrating examples of hardware/software components included in an information apparatus 200 of present invention. Information apparatus 200 may contain components such as a processing unit 380, a memory unit 370, an optional storage unit 360 and an input/output control unit (e.g. communication manager 330). Information apparatus 200 may include an interface (not shown) for interaction with users. The interface may be implemented with software or hardware or a combination. Examples of such interfaces include, without limitation, one or more of a mouse, a keyboard, a touch-sensitive or non-touch-sensitive screen, push buttons, soft keys, a stylus, a speaker, a microphone, etc. Information apparatus 200 typically contains one or more network communication unit 350 that interfaces with other electronic devices such as network node (not shown), output device 220, and output system 230. The network communication unit may be implemented with hardware (e.g., silicon chipsets, antenna), software (e.g., protocol stacks, applications) or a combination. In one embodiment of the present invention, communication interface 240 between information apparatus 200 and output device 220 or output system 250 is a wireless communication interface such as a short-range radio interface including those implemented according to the Bluetooth or IEEE 802.11 standard. The communication interface may also be realized by other standards and/or means of wireless communication that may include radio, infrared, cellular, ultrasonic, hydrophonic among others for accessing one or more network node and/or devices. Wired line connections such as serial or parallel interface, USB interface and fire wire (IEEE 1394) interface, among others, may also be included. Connection to a local network such as an Ethernet or a token Ring network, among others, may also be implemented in the present invention for local communication between information apparatus 200 and output device 220. Examples of hardware/software components of communication units 350 that may be used to implement wireless interface between the information apparatus 200 and the output device 220 are described in more detail with reference to FIGS. 8A and 8B below. For simplicity, FIG. 3 illustrates one implementation where an information apparatus 200 includes one communication unit 350. However, it should be noted that an information apparatus 200 may contain more than one communication unit 350 in order to support different interfaces, protocols, and/or communication standards with different devices and/or network nodes. For example, information apparatus 200 may communicate with one output device 220 through a Bluetooth standard interface or through an IEEE 802.11 standard interface while communicating with another output device 220 through a parallel cable interface. The information apparatus 200 may also be coupled to a wired or wireless network (e.g. the Internet or corporate network) to send, receive and/or download information. Information apparatus 200 may be a dedicated device (e.g., email terminal, web terminal, digital camera, e-book, web pads, Internet appliances etc.) with functionalities that are pre-configured by manufacturers. Alternatively, information apparatus 200 may allow users to install additional hardware components and or application software 205 to expand its functionality. Information apparatus 200 may contain a plurality of applications 205 to implement its feature sets and functionalities. As an example, a document browsing or editing application may be implemented to help user view and perhaps edit, partially or entirely, digital documents written in certain format or language (e.g., page description language, markup language, etc.). Digital documents may be stored locally in the information apparatus 200 or in a network node (e.g., in content server). An example of a document browsing application is an Internet browser such as Internet Explorer, Netscape Navigator, or a WAP browser. Such browsers may retrieve and display content (e.g. digital content) written in mark-up languages such as HTML, WML, XML, CHTML, HDML, among others. Other examples of software applications in the information apparatus 200 may include a document editing software such as Microsoft Word™ which also allows users to view and or edit digital documents that have various file extensions (e.g., doc, rtf, html, XML etc.) whether stored locally in the information apparatus 200 or in a network node. Still, other example of software applications 205 may include image acquisition and editing software. As illustrated previously with reference to FIG. 1, there are many difficulties in providing output capability to an information apparatus 200 that has limited memory and processing capability. To address theses difficulties, information apparatus 200 includes a client application 210 that helps provide the universal data output capability of the present invention. Client application 210 may include software and data that can be executed by the processing unit 380 of information apparatus 200. Client application 210 may be implemented as a stand-alone software application or as a part of or feature of another software application, or in the form of a device driver, which may be invoked, shared and used by other application software 205 in the information apparatus 200. Client application 210 may also include components to invoke other applications 205 (e.g., a document browsing application, editing application, data and/or image acquisition application, a communication manager, a output manager etc.) to provide certain feature sets, as described below. FIG. 3 illustrates a configuration where the client application 210 is a separate application from the other application 205 such as the case when the client application is a device driver; however, it should be noted that the client application 210 can be combined or being part of the other application not shown in FIG. 3. Client application 210 may be variously implemented in an information apparatus 200 and may run on different operating systems or platforms. The client application 210 may also run in an environment with no operating system. For example, FIG. 3A illustrates an implementation where the information apparatus 200A includes an operating system 340A; while FIG. 3B illustrates an implementation where the information apparatus 200B does not include an operating system. Client application 210 includes a rasterization component 310 to conform content into one or more raster output images according to one or more rasterization parameters; an intermediate output data generator component 320 that generates and/or encodes intermediate output data that includes the one or more output images; and a communications manager 330 that manages the communication and interaction with an output device 220 or system 250 or output controller 230. Communications manager can be implemented as part of the client application 210 (shown in FIG. 3) or as a separate application (not shown). Components in a client application can be implemented in software, hardware or combination. As an example, client application 210 may include or utilize one or more of the following: Components or operations to obtain content (e.g. digital document) for output. The client application 210 may obtain a digital document from other applications 205 (e.g. document browsing application, content creation and editing application, etc.), or the client application 210 may provide its own capability for user to browse, edit and or select a digital document. Components or operations to rasterize content that includes text, graphics and images among others objects or elements into one or more raster images according to a set of rasterization parameters such as scale factor, output size, bit depth, color space and resolution. The rasterization parameters may be obtained in various ways, for example, from an output device profile uploaded from an output device 220, or stored locally in information apparatus 200, or manually inputted by a user. Alternatively, rasterization parameters may be based on a predefined standard or specification stored in the information apparatus 200 as a set of defaults, or hard-coded in the client application 210, or calculated by the client application 210 after communicating with an output device 220, output controller 230, and/or a user. Components or operations to generate intermediate output data that includes at least one rasterized output image corresponding to the content (e.g. digital document). This process may further include one or combination of compression, encoding, encryption and color correction among others. The intermediate output data may include, for example, images, instructions, documents and or format descriptions, color profiles among others. Components or operations to transmit the intermediate output data to an output device 220 or system 250 through wired or wireless communication link 240. The client application 210 may also optionally include or utilize one or more of the following components or operations: Components or operations to communicate with one or more output devices 220 to upload an output device profile. Components or operations to communicate directly or indirectly (such as through an operating system or component or object model, messages, file transfer etc.) with other applications 205 residing in the same information apparatus 200 to obtain objects, data, and or content needed, or related to the pervasive output process of present invention (e.g. obtain a digital document for printing). Components or operations to manage and utilize directly or indirectly functionalities provided by hardware components (e.g. communication unit 350) residing in its host information apparatus 200. Components or operations to provide a graphical user interface (GUI) in host information apparatus to interact with user. Components or operations to obtain user preferences. For example, a user may directly input his or her preferences through a GUI. A set of default values may also be employed. Default values may be pre-set or may be obtained by information apparatus 200 as result of communicating and negotiating with an output device 220 or output controller 230. The above functionalities and process of client application 210 of present invention are described in further detail in the client application process with reference to FIG. 12. Output device 220 is an electronic system capable of outputting digital content regardless of whether the output medium is substrate (e.g., paper), display, projection, or sound. A typical example of output device 220 is a printer, which outputs digital documents containing text, graphics, image or any combination onto a substrate. Output device 220 may also be a display device capable of displaying still images or video, such as, without limitation, televisions, monitors, and projectors. Output device 220 can also be a device capable of outputting sound. Any device capable of playing or reading digital content in audio (e.g., music) or data (e.g., text or document) formats is also a possible output device 220. A printer is frequently referred to herein as an example of an output device to simplify discussion or as the primary output device 220 in a particular implementation. However, it should be recognized that present invention applies also to other output devices 220 such as fax machines, digital copiers, display screens, monitors, televisions, projectors, voice output devices, among others. Rendering content with an output device 220 refers to outputting the content on a specific output medium (e.g., papers, display screens etc). For example, rendering content with a printer generates an image on a substrate; rendering content with a display device generates an image on a screen; and rendering content with an audio output device generates sound. A conventional printing system in general includes a raster image processor and a printer engine. A printer engine includes memory buffer, marking engine among other components. The raster image processor converts content into an image form suitable for printing; the memory buffer holds the rasterized image ready for printing; and the marking engine transfers colorant to substrate (e.g., paper). The raster image processor may be located within an output device (e.g. included in a printer controller 410) or externally implemented (in an information apparatus 200, external controller, servers etc). Raster image processor can be implemented as hardware, software, or a combination (not shown). As an example, raster image processor may be implemented in a software application or device driver in the information apparatus 200. Examples of raster image processing operations include image and graphics interpretation, rasterization, scaling, segmentation, color space transformation, image enhancement, color correction, halftoning, compression etc. FIG. 4A illustrates a block diagram of one conventional printing system or printer 400A that includes a printer controller 410 and a printer engine 420A. The printer controller 410 includes an interpreter 402 and a raster image processor 406, and the printer engine 420 includes memory buffer 424A and a marking engine 426A. Marking engine may use any of a variety of different technologies to transfer a rasterized image to paper or other media or, in other words, to transfer colorant to a substrate. The different marking or printing technologies that may be used include both impact and non-impact printing. Examples of impact printing may include dot matrix, teletype, daisywheel, etc. Non-impact printing technologies may include inkjet, laser, electrostatic, thermal, dye sublimation, etc. The marking engine 426 and memory buffer 424 of a printer form its printer engine 420, which may also include additional circuitry and components, such as firmware, software or chips or chipsets for decoding and signal conversion, etc. Input to a printer engine 420 is usually a final rasterized printer-engine print data generated by a raster image processor 406. Such input is usually device dependent and printer or printer engine specific. The printer engine 420 may take this device dependent input and generate or render output pages (e.g. with ink on a substrate). When a raster image processor is located inside an output device 220, it is usually included in a printer controller 410 (as shown in FIG. 4A). A printer controller 410 may interpret, rasterize, and convert input print data in the form of a page description language (e.g., PostScript, PCL), markup language (e.g., XML, HTML) or other special document format or language (e.g. PDF, EMF) into printer-engine print data which is a final format, language or instruction that printer engine 420A can understand. Print data sent to a printer with printer controller 410 is usually in a form (e.g. postscript) that requires further interpretation, processing or conversion. A printer controller 410 receives the print data, interprets, process, and converts the print data into a form that can be understood by the printer engine 420A. Regardless of the type of print data, conventionally, a user may need a device-specific driver in his or her information apparatus 200 in order to output the proper language, format, or file that can be accepted by a specific printer or output device 220. FIG. 4B illustrates another conventional output device 400B. Output device 400B may be a printing device, a display device, a projection device, or a sound device. In the case that the output device is a printing device or a printer, the printer with reference to FIG. 4B does not include a printer controller 410. As an example, printer 400B may be a low-cost printer such as a desktop inkjet printer. RIP operations in this example may be implemented in a software application or in a device driver included in an information apparatus 200. The information apparatus 200 generates device dependent output data (or print data in case of a printer) by rasterizing and converting a digital document into output data (e.g. into a compressed CMKY data with one or more bits per pixel) that can be understood by an output engine (or printer engine in case of a printer) 420B. Regardless of type or sophistication level, different output device 220 conventionally needs different printer drivers or output management applications in an information apparatus 200 to provide output capability. Some mobile devices with limited memory and processing power may have difficulty storing multiple device drivers or perform computational intensive RIP operations. It may also be infeasible to install a new device dependent or specific printer driver each time there is a need to print to a new printer. To overcome these difficulties, present invention provides several improvements to output device 220 or output system 250 as described in detail next. In present invention, output device 220 may include an output controller 230 to help managing communication and negotiation processes with an information apparatus 200 and to process output data. Output controller 230 may include dedicated hardware or software or combination of both for at least one output device 220. Output controller 230 may be internally installed, or externally connected to one or more output devices 220. The output controller 230 is sometimes referred to as a print server or output server. FIGS. 5A and 5B illustrate two exemplary internal implementations of the output controller 230 of present invention. FIG. 5A illustrates the implementation of an output controller 230 inside a conventional printer with reference to FIG. 4A, which includes a conventional printer controller 410(5A). The output controller 230(5A) includes an interpreter 510A component for decoding the intermediate output data of present invention; and a converter component 530A for converting one or more decoded output images into a printer-controller print data that is suitable for input to the printer controller 410(5A). An optional image processing component 520A may be included in the output controller 230(5A). FIG. 5B illustrates the implementation of an output controller 230 included internally in a conventional output device 220 with reference to FIG. 4B, which does not include a printer controller. The output controller 230(5B) includes an interpreter 510B component for decoding the intermediate output data of present invention; an image processor 520B component for performing one or more image processing operations such as color space conversion, color matching and digital halftoning; and an optional encoder 530B component to conform the processed output images into an output-engine output data that is suitable for input to the output engine 420B if the result of the image processing is not already in required form suitable for the output engine 420B. In one implementation, output device 220 may include a communication unit 550 or adapter to interface with information apparatus 200. Output device 220 may sometimes include more than one communication unit 550 in order to support different interfaces, protocols, or communication standards with different devices. For example, output device 220 may communicate with a first information apparatus 200 through a Bluetooth interface while communicating with a second information apparatus 200 through a parallel interface. Examples of hardware components of a wireless communication unit are described in greater detail below with reference to FIGS. 8A and 8B. In one embodiment, output controller 230 does not include a communication unit, but rather utilizes or manages a communication unit residing in the associated output device 220 such as the illustration in FIG. 5. In another embodiment, output controller 230 may include or provide a communication unit to output device 220 as shown in FIG. 6. For example, an output controller 230 with a wireless communication unit may be installed internally or connected externally to a legacy printer to provide it with wireless communication capability that was previously lacking. FIG. 6 includes three functional block diagrams illustrating the hardware/software components of output controller 230 in three different implementations. Each components of an output controller 230 may include software, hardware, or combination. For example, an output controller 230 may include components using one or more or combinations of an application-specific integrated circuit (ASIC), a digital signal processor (DSP), a field programmable gate array (FPGA), firmware, system on a chip, and various communication chip sets. Output controller 230 may also contain embedded processors 670 A with software components or embedded application software to implement its feature sets and functionalities. Output controller 230 may contain an embedded operating system 680. With an operating system, some or all functionalities and feature sets of the output controller 230 may be provided by application software managed by the operating system. Additional application software may be installed or upgraded to newer versions in order to, for example, provide additional functionalities or bug fixes. FIG. 6A and FIG. 6C illustrates examples of implementation with an operating system 680 while FIG. 6B illustrates an example without the operating system 680 or the optional embedded processor 670. Output controller 230 typically includes a memory unit 640, or may share a memory unit with, for example, printer controller 410. The memory unit and storage unit, such as ROM, RAM, flash memory and disk drive among others, may provide persistent or volatile storage. The memory unit or storage unit may store output device profiles, objects, codes, instructions or data (collectively referred to as software components) that implement the functionalities of the output controller 230. Part of the software components (e.g., output device profile) may be uploaded to information apparatus 200 during or before a data output operation. An output controller 230 may include a processor component 670A and 670C, a memory component 650, an optional storage component 640, and an optional operating system component 680. FIG. 6 shows one architecture or implementation where the memory 650, storage 640, processor 670, and operating system 680 components, if exist, can be share or accessed by other operational components in the output controller 230 such as the interpreter 610 and image processor 650. FIG. 6 shows two communication units 660A and 660B included in the output controller 230; however, the output controller 230 of present invention may include any number of communication units 660. It is also possible that the output controller does not contain any communication unit but rather utilizes the communication unit of an output device. The output controller 230 may be connected externally to an output device 220 or integrated internally into the output device 220. FIGS. 5A and 5B illustrate implementations of output controller 230 inside an output device 220. The output controller 230, however, may also be implemented as an external box or station that is wired or wirelessly connected to an output device 220. An output controller 230 implemented as an external box or station to an output device 220 may contain its own user interface. One example of such an implementation is a print server connected to an output device 220 in an output system 250. Another configuration and implementation is to integrate or combine the functionalities of an output controller 230 with an existing printer controller 410 (referred to as “combined controller”) if the output device 220 is a printer as shown with reference to FIG. 7C or 7F. A combined controller can also be internally integrated or externally connected to output device 220, and include functionalities of both printer controller 410 (e.g., input interpretation and or raster image processing) and output controller 230 of present invention. One advantage of this configuration is that the functionalities or components of output controller 230 and printer controller 410 may share the same resources, such as processing unit, memory unit, etc. FIG. 6C illustrates an example of a combined controller implementation or output controller 230 where the printer controller 410C, interpreter 610C and converter 630C shares the use of the processor 670C, memory 650C and storage 640C, managed by an operating system 680C. Various exemplary implementations and configurations of an output controller 230 with respect to an output device 220 or output system 250 are illustrated in further detail with reference to FIG. 7. Other possible implementations of output controller 230 may include, for example, a conventional personal computer (PC), a workstation, and an output server or print server. In these cases, the functionalities of output controller 230 may be implemented using application software installed in a computer (e.g., PC, server, or workstation), with the computer connected with a wired or wireless connection to an output device 220. Using a PC, server, workstation, or other computer to implement the feature sets of output controller 230 with application software is just another possible embodiment of the output controller 230 and in no way departs from the spirit, scope and process of the present invention. The difference between output controller 230 and printer controller 410 should be noted. Printer controller 410 and output controller 230 are both controllers and are both dedicated hardware and or software for at least one output device 220. Output controller 230 refers to a controller with feature sets, capabilities, and functionalities of the present invention. A printer controller 410 may contain functions such as interpreting an input page description language, raster image processing, and queuing, among others. An output controller 230 may include part or all of the features of a printer controller 410 in addition to the feature sets, functionalities, capabilities, and processes of present invention. Functionalities and components of output controller 230 for the purpose of providing universal data output may include or utilize: Components and operations to receive output data from a plurality of information apparatus 200; the output data may include an intermediate output data containing at least one rasterized image related to the data content intended for output. Components and operations to interpret and/or decode the intermediate output data. Components and operations to process the intermediate output data. Such components and operations may include image processing functions such as scaling, segmentation, color correction, color management, GCR, image enhancement, decompression, decryption, and or halftoning among others. Components and operations to generate an output-engine output data, the output-engine output data being in an output data format acceptable for input to an output engine. Components and operations to send the output-engine output data to the output engine. When associated with an output device 220 that includes a printer controller 410, the output controller of present invention may further include or utilize: Components and operations to convert the intermediate output data into a printer-controller print data (e.g. a PDL such as PostScript and PCL), the printer-controller print data being in a format acceptable to a printer controller. Components and operations to send printer-controller print data to one or more printer controllers. In addition to the above components and functionalities, output controller 230 may further include one or more of the following: Components and operations to communicate with one or more information apparatus 200 through a wired or wireless interface. Components and operations to communicate and or manage a communication unit included in the output controller 230 or output device 220. Components and operations to store at least part of an output device profile (a printer profile in case of a printer) in a memory component. Components and operations to respond to service request from an information apparatus 200 by transmitting at least part of an output device profile to the information apparatus requesting service. The output controller 230 may transmit the output device profiles or object in one or multiple sessions. Components and operations to broadcast or advertise the services provided by a host output device 220 to one or more information apparatus 200 that may request such services. Components and operations to implement payment processing and management functions by, for example, calculating and processing payments according to the services requested or rendered to a client (information apparatus 200). Components and operations to provide a user interface such as display screen, touch button, soft key, etc. Components and operations to implement job management functions such as queuing and spooling among others. Components and operations to implement security or authentication procedures. For example, the output controller 230 may store in its memory component (or shared memory component) an access control list, which specifies what device or user may obtain service from its host (or connected) output device 220. Therefore, an authorized information apparatus 200 may gain access after confirming with the control list. When output controller 230 is implemented as firmware, or an embedded application, the configuration and management of the functionalities of output controller 230 may be optionally accomplished by, for example, using controller management software in a host computer. A host computer may be a desktop personal computer (PC), workstation, or server. The host computer may be connected locally or through a network to the output device 220 or the controller 230. Communication between the host computer and the output controller 230 can be accomplished through wired or wireless communication. The management application software in the host computer can manage the settings, configurations, and feature sets of the output controller 230. Furthermore, host computer's configuration application may download and or install application software, software components and or data to the output controller 230 for the purpose of upgrading, updating, and or modifying the features and capabilities of the output controller 230. Output device 220 in one implementation includes or is connected to output controller 230 described above. Therefore, functionalities and feature sets provided by output controller 230 are automatically included in the functionalities of output device 220. The output device 220 may, however, implement or include other controllers and/or applications that provide at least partially the features and functionalities of the output controller 230. Therefore, the output device 220 may include some or all of the following functionalities: Components and operations to receive multiple service requests or queries (e.g., a service request, a data query, an object or component query etc.) from a plurality of information apparatus 200 and properly respond to them by returning components, which may contain data, software, instructions and/or objects. Components and operations to receive output data from a plurality of information apparatus 200; the output data may include an intermediate output data containing one or more rasterized image related to the content intended for output. Components and operations to interpret and/or decoding the intermediate output data. Components and operations to process and/or convert the intermediate output data into a form (e.g. output-engine print data) suitable for rendering at an output engine associated with the output device. Components and operations to render a representation or an image related to the content onto an output medium (e.g. substrate or a display screen). An output device 220 may further comprise optionally one or more of the following functionalities: Components and operations for establishing and managing a communication link with an information apparatus 200 requesting service; the communication link may include wired or wireless communication. Components and operations for storing at least part of an output device profile (e.g. printer profile) in a memory component. Components and operations to provide at least part of an output device profile (e.g., printer profile in case of a printer) to one or more information apparatus 200 requesting service. The output device 220 may transmit the output device profile in one or multiple sessions. Components and operations to advertise or broadcast services provided or available to one or more information apparatus 200. Components and operations to implement payment processing and management functions by, for example, calculating and processing payments according to the services requested by or rendered to a client (information apparatus 200). Components and operations to implement job management functionalities such as queuing and spooling among others. Components and operations to provide a user interface such as display screen touch button, soft key, power switch, etc. Components and operations to implement security or authentication procedures. For example, the output device 220 may store in its memory component (or a shared memory component) an access control list, which specifies what device or user may obtain service from it. Therefore, an authorized information apparatus 200 may gain access after confirming with the control list. FIGS. 7A-7F illustrate various alternative configurations and implementations of output controller 230 with respect to an output device 230. Printer is sometimes used as an exemplary output device 230 to demonstrate the various configurations. It should be understood, however, the output device 230 of present invention is not limited to printers. As described with reference to FIG. 4, a printer may or may not contain a printer controller 410. Printer 400A that includes a printer controller 410 typically has higher speed and is more expensive than printer 400B which does not include a printer controller 410. FIG. 7A shows that output controller 230 may be cascaded externally to one or more printers (only one shown). Information apparatus 200 communicates with output controller 230A, which then communicates with output device 220 such as a printer 220A. The communication link between the output controller 230A and the printer 220A may be a wired link or a wireless link, as described above. FIGS. 6A and 6B illustrates two examples of functional component design of the output controller that can implement the configuration illustrated in FIG. 7A. The Image processor 620 in this implementation is optional. FIG. 7B shows another implementation in which output controller 230B is installed as one or more circuit boards or cards internally inside printer 220B. The output controller 230B may co-exist with printer controller 410 and other components of the printer 220B. One example of this implementation is to connect output controller 230B sequentially with the printer controller 310. FIG. 5A shows as an example of an implementation. FIG. 7C shows another implementation in which the functionalities of output controller 230 and printer controller 410 are combined into a single controller (referred to as “combined controller”) 230C. In this implementation, it is possible to reduce the cost of material when compared to implementing two separate controllers as shown in FIG. 7B. As an example, the combined controller 230C may share the same processors, memories, and storages to run the applications and functionalities of the two types of controllers and therefore, may have lower component costs when compared to providing two separate controllers. FIG. 6C illustrates an example of a combined controller functional component implementation. Some printers do not include a raster image processor or printer controller 410, as illustrated in FIG. 4B. An example of this type of printer is a lower cost desktop inkjet printer. Input to an inkjet printer may consist of a compressed CMYK data (proprietary or published) with one or more bits per pixel input. To output to a printer that does not include a printer controller, a device specific software application or a printer driver is typically required in an information apparatus 200 to perform raster image processing operations. Accordingly, output controller 230 can be implemented into a variety of output devices 220 and/or output systems 250 including printers that do not have printer controllers for performing raster image processing operations. FIG. 7D and FIG. 7E illustrate two implementations of output controller 230 in an output device 220 or system 250. The output device 230 or system 250 may include a display device, a projection device, an audio output device or a printing device. In the case when the output device 220D or 220E is a printer, it does not include a printer controller. FIG. 7D illustrates an implementation of an output controller 230D installed as an external component or “box” to output device 220D. For example, the output controller 230 may be implemented as an application in a print server or as a standalone box or station. In this configuration, some or all of raster image processing operations may be implemented in the output controller 230D. Output controller 230D receives intermediate output data from an information apparatus 200 and generates output-engine output data that is acceptable to the output engine included in the output device 220D. The output controller 230D may send the output data to the output device 220D through a wired or wireless communication link or connection. FIGS. 6A and 6B illustrates two example of functional component design of the output controller that can implement the configurations for both FIGS. 7D and 7E. FIG. 7E shows a fifth implementation of output controller 230E in which the output controller 230E is incorporated within output device 220E as one or more circuit boards or cards and may contain software and applications running on an embedded processor. As with output device 220D (FIG. 7D), output device 220E does not include a printer controller 410. Accordingly, the output controller 230E implements the functionalities and capabilities of present invention that may include part of or complete raster imaging processing operation. FIG. 7F shows a sixth implementation, an external combined controller 230F that integrates the functionalities of a printer controller 310 and an output controller into a single external combined controller component or “box” 230F. The two controller functions may share a common processor as well as a common memory space to run applications of the two types of controllers. Under this configuration, either information apparatus 200 or the combined controller 230F could perform or share at least part of raster image processing functionality. FIG. 6C shows an example of functional components of a combined controller 230F. Another implementation of the combined controller 230F shown in FIG. 7F is to use an external computing device (PC, workstation, or server) running one or more applications that include the functionality of output controller 230 and printer controller 410. The above are examples of different implementations and configurations of output controller 230. Other implementations are also possible. For example, partial functionalities of output controller 230 may be implemented in an external box or station while the remaining functionalities may reside inside an output device 220 as a separate board or integrated with a printer controller 410. As another example, the functionalities of output controller 230 may be implemented into a plurality of external boxes or stations connected to the same output device 220. As a further example, the same output controller 230 may be connected to service a plurality of output devices 220 FIGS. 8A and 8B are block diagrams illustrating two possible configurations of hardware/software components of wireless communication units. These wireless communication units can be implemented and included in information apparatus 200, in output controller 230 and in output device 220. Referring to FIG. 8A, a radio adapter 800 may be implemented to enable data/voice transmission among devices (e.g., information apparatus 200 and output device 220) through radio links. An RF transceiver 814 coupled with antenna 816 is used to receive and transmit radio frequency signals. The RF transceiver 814 also converts radio signals into and from electronic signals. The RF transceiver 814 is connected to an RF link controller 810 by an interface 812. The interface 812 may perform functions such as analog-to-digital conversion, digital-to-analog conversion, modulation, demodulation, compression, decompression, encoding, decoding, and other data or format conversion functions. RF link controller 810 implements real-time lower layer (e.g., physical layer) protocol processing that enables the hosts (e.g., information apparatus 200, output controller 230, output device 220, etc.) to communicate over a radio link. Functions performed by the link controller 810 may include, without limitation, error detection/correction, power control, data packet processing, data encryption/decryption and other data processing functions. A variety of radio links may be utilized. A group of competing technologies operating in the 2.4 GHz unlicensed frequency band is of particular interest. This group currently includes Bluetooth, Home radio frequency (Home RF) and implementations based on IEEE 802.11 standard. Each of these technologies has a different set of protocols and they all provide solutions for wireless local area networks (LANs). Interference among these technologies could limit deployment of these protocols simultaneously. It is anticipated that new local area wireless technologies may emerge or that the existing ones may converge. Nevertheless, all these existing and future wireless technologies may be implemented in the present invention without limitation, and therefore, in no way depart from the scope of present invention. Among the currently available wireless technologies, Bluetooth may be advantageous because it requires relatively lower power consumption and Bluetooth-enabled devices operate in piconets, in which several devices are connected in a point-to-multipoint system. Referring to FIG. 8B, one or more infrared (IR) adapters 820 may be implemented to enable data transmission among devices through infrared transmission. The IR adapters 820 may be conveniently implemented in accordance with the Infrared Data Association (IrDA) standards and specifications. In general, the IrDA standard is used to provide wireless connectivity technologies for devices that would normally use cables for connection. The IrDA standard is a point-to-point (vs. point-to-multipoint as in Bluetooth), narrow angle, ad-hoc data transmission standard. Configuration of infrared adapters 820 may vary depending on the intended rate of data transfer. FIG. 8B illustrates one embodiment of infrared adapter 820. Transceiver 826 receives/emits IR signals and converts IR signals to/from electrical signals. A UART (universal asynchronous receiver/transmitter) 822 performs the function of serialization/deserialization, converting serial data stream to/from data bytes. The UART 822 is connected to the IR transceiver 826 by encoder/decoder (ENDEC) 824. This configuration is generally suitable for transferring data at relatively low rate. Other components (e.g., packet framer, phase-locked loop) may be needed for higher data transfer rates. FIGS. 8A and 8B illustrate exemplary hardware configurations of wireless communication units. Such hardware components may be included in devices (e.g., information apparatus 200, output controller 230, output device 220, etc.) to support various wireless communications standards. Wired links, however, such as parallel interface, USB, Firewire interface, Ethernet and token ring networks may also be implemented in the present invention by using appropriate adapters and configurations. FIG. 9 is a logic flow diagram of an exemplary raster imaging process (RIP) 902 that can implement the universal output method of present invention. Content (e.g. digital document) 900 may be obtained and/or generated by an application running in an information apparatus 200. For example, a document browsing application may allow a user to download and or open digital document 900 stored locally or in a network node. As another example, a document creating or editing application may allow a user to create or edit digital documents in his/her information apparatus 200. A client application 210 in the information apparatus may be in the form of a device driver, invoked by other applications residing in the information apparatus 200 to provide output service. Alternatively, the client application 210 of present invention may be an application that includes data output and management component, in addition of other functionalities such as content acquisitions, viewing, browsing, and or editing etc. For example, a client application 210 in an information apparatus 200 may itself include components and functions for a user to download, view and or edit digital document 900 in addition of the output management function described herein. Raster image process method 902 allows an information apparatus 200 such as a mobile device to pervasively and conveniently output content (e.g. a digital document) to an output device 220 or system 250 that includes an output controller 230. A client application 210 in an information apparatus 200 may perform part of raster image processing operations (e.g. rasterization operation). Other operations of raster image processing such as halftoning can be completed by the output device 220 or by the output controller 230. In conventional data output methods, raster image processing is either implemented entirely in an information apparatus (e.g. a printer that does not include a printer controller with reference to FIG. 1A) or in an output device (e.g. a printer that includes a printer controller with reference to FIG. 1B). Present invention provides a more balanced approach where raster image process operations are shared between an information apparatus 200 and an output device 220 or system 250. For example, content 600 may be processed (e.g. raster image processed) by different components or parts of an overall output system from a client application 210 to an output controller 230 before being sent to an output engine or a printer engine for final output in step 960. Because the raster image processing operations are not completely implemented in the information apparatus 200, there is less processing demand on the information apparatus 200. Therefore, present RIP process may enable additional mobile devices with less memory and processing capability to have data output capability. In step 910, rasterization operation, a content (e.g. digital document), which may include text, graphics, and image objects, is conformed or rasterized to image form according to one or more rasterization parameters such as output size, bit depth, color space, resolution, number of color channels etc. During the rasterization operation, text and vector graphics information in the content are rasterized or converted into image or bitmap information according to a given set of rasterization parameters. Image information in the content or digital document may be scaled and or interpolated to fit a particular output size, resolution and bit depth etc. The rasterization parameters are in general device dependent, and therefore may vary according to different requirements and attributes of an output device 220 and its output engine. There are many ways to obtain device dependent rasterization parameters, as described in more detail below with reference to FIG. 12A. Device dependent rasterization parameters, in one example, may be obtained from an output device profile stored in an information apparatus 200, an output device 220 or an output controller 230. In an alternative implementation, rasterization parameters may be predetermined by a standard or specification. In this implementation, in step 910 the content 900 is rasterized to fit or match this predefined or standard rasterization parameters. Therefore, the rasterized output image becomes device independent. One advantage of being device independent is that the rasterized output image is acceptable with controllers, devices and/or output devices implemented or created with the knowledge of such standard or specification. A rasterized image with predefined or standardized attributes is usually more portable. For example, both the client application 210 and output device 220 or its output controller 230 may be preprogrammed to receive, interpret, and or output raster images based on a predefined standard and/or specification. Occasionally, a predefined standard or specification for rasterization parameters may require change or update. One possible implementation for providing an easy update or upgrade is to store information and related rasterization parameters in a file or a profile instead of hard coding these parameters into programs, components or applications. Client application 210, output controller 230, and/or the output device 220 can read a file or a profile to obtain information related to rasterization parameters. To upgrade or update the standard specification or defaults requires only replacing or editing the file or the profile instead of replacing a software application or component such as the client application 210. In step 920 the rasterized content in image form is encoded into an intermediate output data. The intermediate output data, which describes the output content, may include image information, instructions, descriptions, and data (e.g. color profile). The rasterized output image may require further processing including one or more of compression, encoding, encryption, smoothing, image enhancement, segmentation, color correction among others before being stored into the intermediate output data. The output image in the intermediate output data may be encoded in any image format and with any compression technique such as JPEG, BMP, TIFF, JBIG etc. In one preferred embodiment, a mixed raster content (MRC) format and its related encoding and/or compression methods are used to generate the output image. The advantages of using MRC over other image formats and techniques may include, for example, better compression ratio, better data information retention, smaller file size, and or relatively better image quality among others. In step 930, the intermediate output data is transmitted to the output device 220 or output system 250 for further processing and final output. The transmission of the intermediate output data may be accomplished through wireless or wired communication links between the information apparatus 200 and the output device 220 and can be accomplished through one or multiple sessions. In step 940, the output device 220 or output system 250 receives the transmitted intermediate output data. The output device 220 or output system 250 may include an output controller 230 to assist communicating with the information apparatus 200 and/or processing the intermediate output data. Output controller 230 may have a variety of configurations and implementations with respect to output device 220 as shown in FIG. 7A-7F. Interpretation process 940 may include one or more of parsing, decoding, decompression, decryption, image space conversion among other operations if the received intermediate output data requires such processing. An output image is decoded or retrieved from the intermediate output data and may be temporarily stored in a buffer or memory included in the output device/output system (220/250) or output controller 230 for further processing. If the intermediate output data includes components with MRC format or encoding techniques, it may contain additional segmented information (e.g. foreground and background), which can be used to enhance image quality. For example, different techniques or algorithms in scaling, color correction, color matching, image enhancement, anti-aliasing and or digital halftoning among others may be applied to different segments or layers of the image information to improve output quality or maximize retention or recovery of image information. Multiple layers may later be combined or mapped into a single layer. These image processing and conversion components and/or operations can be included in the output controller 230 of present invention. In step 950, the decoded or retrieved output image from the intermediate output data may require further processing or conversion. This may include one or more of scaling, segmentation, interpolation, color correction, GCR, black generation, color matching, color space transformation, anti-aliasing, image enhancement, image smoothing and or digital halftoning operations among others. In an embodiment where the output device 220 does not include a printer controller, an output controller 230 or an output device 220 that includes output controller, after performing the remaining portion of RIP operations (e.g. color space conversion and halftoning) on the output image, may further convert the output data in step 950 into a form that is acceptable for input to a printer engine for rendering. In an alternative embodiment where the output device 220 or the output system 250 includes a conventional printer controller, the output controller may simply decodes and or converts the intermediate output data (print data in this example) into format or language acceptable to the printer controller. For example, a printer controller may require as input a page description language (e.g. PostScript, PCL, PDF, etc.), a markup language (HTML, XML etc) or other graphics or document format. In these cases, the output controller 230 may interpret, decompress and convert the intermediate print data into an output image that has optimal output resolution, bit depth, color space, and output size related to the printer controller input requirements. The output image is then encoded or embedded into a printer-controller print data (e.g. a page description language) and sent to the printer controller. A printer-controller print data is a print data that is acceptable or compatible for input to the printer controller. After the printer controller receives the printer-controller print data, the printer controller may further perform operations such as parsing, rasterization, scaling, color correction, image enhancement, halftoning etc on the output image and generate an appropriate printer-engine print data suitable for input to the printer engine. In step 960, the output-engine output data or printer-engine print data generated by the output controller 230 or the printer controller in step 950 is sent to the output engine or printer engine of the output device for final output. FIG. 10 illustrates a flow diagram of a universal data output process of the present invention that includes the raster image processing illustrated with reference to FIG. 9. A universal data output process allows an information apparatus 200 to pervasively output content or digital document to an output device. The data output process may include or utilize: A user interface component and operation where a user initiates an output process and provides an indication of the selected output content (e.g. digital document) for output. A client application component or operation that processes the content indicated for output, and generates an intermediate output data. The intermediate output data may include at least partly a raster output image description related to the content. An information apparatus component or operation that transmits the intermediate output data to one or more selected output device 220. An output device component (e.g. output controller) or operation that interprets the intermediate output data and may further process or convert the output data into a form more acceptable to an output engine for rendering of the content. With reference to FIG. 10, a user in step 1000 may initiate the universal output method or process 1002. Typically, a user initiates the output process by invoking a client application 210 in his/her information apparatus 200. The client application 210 may be launched as an independent application or it may be launched from other applications 205 (such as from a document browsing, creating or editing application) or as part of or component of or a feature of another application 205 residing in the same information apparatus 200. When launched from another application 205, such as the case when the client application is a device driver or helper application, the client application 210 may obtain information, such as the content (e.g. digital document) from that other application 205. This can be accomplished, for example, by one or combinations of messages or facilitated through an operating system or a particular object or component model etc. During output process 1002, a user may need to select one or more output devices 220 for output service. An optional discovery process step 1020 may be implemented to help the user select an output device 220. During the discovery process step 1020, a user's information apparatus 200 may (1) search for available output devices 220; (2) provide the user with a list of available output devices 220; and (3) provide means for the user to choose one or more output devices 220 to take the output job. An example of a discovery process 1020 is described below in greater detail with reference to FIG. 11. The optional discovery process 1020 may sometimes be unnecessary. For example, a user may skip the discovery process 1020 if he or she already knows the output device (e.g., printer) 220 to which the output is to be directed. In this case, the user may simply connect the information apparatus 200 to that output device 220 by wired connections or directly point to that output device 220 in a close proximity such as in the case of infrared connectivity. As another example, a user may pre-select or set the output device or devices 220 that are used frequently as preferred defaults. As a result, the discovery process 1020 may be partially or completely skipped if the default output device 220 or printer is found to be available. In stage 1030, the client application may interact with output device 220, the user, and/or other applications 205 residing in the same information apparatus 200 to (1) obtain necessary output device profile and/or user preferences, (2) perform functions or part of raster image processing operations such as rasterization, scaling and color correction, and/or (3) convert or encode at least partially the rasterized content (e.g. digital document) into an intermediate output data. The processing and generation of the intermediate output data may reflect in part a relationship to an output device profile and/or user preferences obtained, if any. The intermediate output data generated by the client application 210 is then transmitted through wired or wireless local communication link(s) 240 to the output controller 230 included or associated with the selected output device 220 or output system 250. An exemplary client application process is described in greater detail with reference to FIG. 12. In step 1040, the output controller 230 of present invention receives the intermediate output data. In the case where the selected output device 230 does not include a printer controller, the output controller 230 of present invention may further perform processing functions such as parsing, interpreting, decompressing, decoding, color correction, image enhancement, GCR, black generation and halftoning among others. In addition, the output controller 230 may further convert or conform the intermediate output data into a form or format suitable for the output engine (e.g. printer engine in the case of a printer). The generated output-engine output data from the output controller is therefore, in general, device dependent and acceptable for final output with the output engine (or the printer engine in case of a printer) included in the selected output device 220 or output system 250. In the case where the selected output device 220 is a printer, and when the printer includes or is connected to a printer controller, the output controller 230 may generate the proper language or input format required to interface with the printer controller (referred to as printer-controller print data). The printer controller may for example require a specific input such as a page description language (PDL), markup language, or a special image or graphics format. In these cases, the output controller 230 in step 1040 may interpret and decode the intermediate output data, and then convert the intermediate output data into the required printer-controller print data (e.g. PDL such as PostScript or PCL). The printer-controller print data generated by the output controller is then sent to the printer controller for further processing. The printer controller may perform interpretation and raster image processing operations among other operations. After processing, the printer controller generates a printer-engine print data suitable for rendering at the printer engine. In either case, the output controller 230 or printer controller generates an output-engine output data that is suitable for sending to or interfacing with the output engine or the printer engine included in the output device for rendering. The output data may be temporarily buffered in components of the output device 220. An implementation of the output device process 1040 is described in greater detail with reference to FIG. 13. The steps included in the universal pervasive output process 1002 may proceed automatically when a user requests output service. Alternatively, a user may be provided with options to proceed, cancel, or input information at each and every step. For example, a user may cancel the output service at any time by, for example, indicating a cancellation signal or command or by terminating the client application 210 or by shutting down the information apparatus 200 etc FIG. 11 is a flow diagram of an example of a discovery process 720, which may be an optional step to help a user locate one or more output devices 220 for an output job. The discovery process 1020 may, however, be skipped partially or entirely. Implementation of discovery process 1020 may require compatible hardware and software components residing in both the information apparatus 200 and the output device 220. The information apparatus 200 may utilize the client application 210 or other application 205 in this process. The discovery process 1020 may include: An information apparatus 200 communicating with available output devices 220 to obtain information and attributes relating to the output device 220 and or its services such as output device capability, feature sets, service availability, quality of service, condition. An Information apparatus 200 provides the user information on each available and or compatible output devices 220. A user selects or the client application 210 (automatically or not) selects one or more output devices 220 for the output service from the available or compatible output devices 220. Various protocols and or standards may be used during discovery process 1020. Wireless communication protocols are preferred. Wired communication, on the other hand, may also be implemented. Examples of applicable protocols or standards may include, without limitation, Bluetooth, HAVi, Jini, Salutation, Service Location Protocol, and Universal Plug-and-play among others. Both standard and proprietary protocols or combination may be implemented in the discovery process 1020. However, these different protocols, standards, or combination shall not depart from the spirit and scope of present invention. In one implementation an application (referred here for simplicity of discussion as a “communication manager,” not shown) residing in the information apparatus 200 helps communicate with output device 220 and manages service requests and the discovery process 1020. The communication manager may be a part of or a feature of the client application 210. Alternatively or in combination, the communication manager may also be a separate application. When the communication manager is a separate application, the client application 210 may have the ability to communicate, manage or access functionalities of the communication manager. The discovery process 1020 may be initiated manually by a user or automatically by a communication manager when the user requests an output service with information apparatus 200. In the optional step 1100, a user may specify searching or matching criteria. For example, a user may indicate to search for color printers and or printers that provide free service. The user may manually specify such criteria each time for the discovery process 1020. Alternatively or in combination, a user may set default preferences that can be applied to a plurality of discovery processes 1020. Sometimes, however, no searching criteria are required: the information apparatus 200 may simply search for all available output devices 220 that can provide output service. In step 1101, information apparatus 200 searches for available output devices 220. The searching process may be implemented by, for example, an information apparatus 200 (e.g. with the assistance of a communication manager) multi-casting or broadcasting or advertising its service requests and waiting for available output devices 220 to respond. Alternatively or in combination, an information apparatus 200 may “listen to” service broadcasts from one or more output devices 220 and then identify the one or more output devices 220 that are needed or acceptable. It is also possible that multiple output devices 220 of the same network (e.g., LAN) register their services with a control point (not shown). A control point is a computing system (e.g., a server) that maintains records on all service devices within the same network. An information apparatus 200 may contact the control point and search or query for the needed service In step 1102, if no available output device 220 is found, the communication manager or the client application 210 may provide the user with alternatives 1104. Such alternatives may include, for example, aborting the discovery process 1020, trying discovery process 1020 again, temporarily halting the discovery process 1020, or being notified when an available output device 220 is found. As an example, the discovery process 1020 may not detect any available output device 220 in the current wired/wireless network. The specified searching criteria (if any) are then saved or registered in the communication manager. When the user enters a new network having available output devices 220, or when new compatible output devices 220 are added to the current network, or when an output device 220 becomes available for any reason, the communication manager may notify the user of such availability. In step 1106, if available output devices 220 are discovered, the communication manager may obtain some basic information, or part of or the entire output device profile, from each discovered output device 220. Examples of such information may include, but not limited to, device identity, service charge, subscription, service feature, device capability, operating instructions, etc. Such information is preferably provided to the user through the user interface (e.g., display screen, speaker, etc.) of information apparatus 200. In step 1108, the user may select one or more output devices 220 based on information provided, if any, to take the output job. If the user is not satisfied with any of the available output device 220, the user may decline the service. In this case, the user may be provided with alternatives such as to try again in step 1110 with some changes made to the searching criteria. The user may choose to terminate the service request at any time. In step 1112, with one or more output devices 220 selected or determined, the communication link between information apparatus 200 and the selected output device or devices 220 may be “locked”. Other output devices 220 that are not selected may be dropped. The output process 1020 may then proceed to the client application process of step 1030 of FIG. 10. FIG. 12A is a flow diagram of an exemplary client application process with reference to step 1030 of FIG. 10. A client application process 1202 for universal output may include or utilize: A client application 210 that obtains content (e.g. digital document) intended for output. A client application 210 that obtains output device parameters (e.g. rasterization parameters, output job parameters). One example of implementation is to obtain the output device parameters from an output device profile (e.g. printer profile), which includes device dependent parameters. Such profile may be stored in an output controller 230, output device 220 or information apparatus 200. A client application 210 that may optionally obtain user preferences through (1) user's input (automatic or manual) or selections or (2) based on preset preference or pre-defined defaults or (3) combination of the above. A client application 210 that rasterizes at least part of the content intended for output (e.g. a digital document) according to one or more rasterization parameters obtained from previous steps such as through output device profile, user selection, predefined user preferences, predefined default or standard etc. A client application 210 that generates an intermediate output data containing at least part of the rasterized image related at least partly to the content intended for output. A client application that transmits the intermediate output data to an output device 220 or output controller 230 for further processing and or final output. A client application 210 may obtain content (e.g. digital document) 900 or a pointer or reference to the content in many ways. In a preferred embodiment, the client application 210 is in the form of a device driver or an independent application, and the content or its reference can be obtained by the client application 210 from other applications 205 in the same information apparatus 200. To illustrate an example, a user may first view or download or create a digital document by using a document browsing, viewing and or editing application 205 in his/her information apparatus 200, and then request output service by launching the client application 210 as a device driver or helper application. The client application 210 communicates with the document browsing or editing application to obtain the digital document or reference to the digital document. As another example, the client application 210 is an independent application and it launches another application to help locate and obtain the digital document for output. In this case, a user may first launch the client application 210, and then invoke another application 205 (e.g. document editing and or browsing application) residing in the same information apparatus 200 to view or download a digital document. The client application 210 then communicates with the document browsing or editing application to obtain the digital document for output. In another embodiment, the client application 210 itself provides multiple functionalities or feature sets including the ability for a user to select the content (e.g. digital document) for output. For example, the client application 210 of present invention may provide a GUI where a user can directly input or select the reference or path of a digital document that the user wants to output. In order to perform rasterization operation on content (e.g. digital document) 900, the client application 210 in step 1210 needs to obtain device dependent parameters of an output device 220 such as the rasterization parameters. Device dependent parameters may be included in an output device profile. A client application 210 may obtain an output device profile or rasterization parameters in various ways. As an example, an output device profile or rasterization parameters can be obtained with one or combination of the following: The client application communicates with an output device 220 to upload output device profile or information related to one or more rasterization parameters. The client application 210 obtains the output device profile from a network node (e.g. server). A user selects an output device profile stored in the user's information apparatus 200. The client application 210 automatically retrieves or uses a default profile, predefined standard values or default values among others. The client application 210 obtains output device parameters by calculating, which may include approximation, based at least partly on the information it has obtained from one or combination of an output device 220, a user, default values, and a network node. It is important to note that step 1210 is an optional step. In some instance, part of or the entire output device profile or related device dependent information may have been already obtained by the client application 210 during the prior optional discovery process (step 1020 in FIG. 10). In this case, step 1210 may be partially or entirely skipped. In one implementation, the client application 210 communicates with one or more output devices 220 to upload output device profiles stored in the memory or storage components of those one or more output devices 220 or their associated one or more output controllers 230. In some instance, the uploaded output device profile may contain partially or entirely references or pointers to device parameters instead of the device parameters themselves. The actual output device parameters may be stored in a network node or in the information apparatus 200, where they can be retrieved by the client application 210 or by other applications 205 using the references or pointers. It should be noted that a plurality of information apparatuses 200 may request to obtain output device profile or profiles from the same output device 220 at the same time or at least during overlapping periods. The output device 220 or its associated output controller 230 may have components or systems to manage multiple communication links and provide the output device profile or profiles concurrently or in an alternating manner to multiple information apparatuses 200. Alternatively, an output device 220 may provide components or systems to queue the requests from different information apparatuses 200 and serve them in a sequential fashion according to a scheme such as first come first served, quality of service, etc. Multi-user communication and service management capability with or without queuing or spooling functions may be implemented by, for example, the output controller 230 as optional feature sets. In another implementation, one or more output device profiles may be stored locally in the information apparatus 200. The client application 210 may provide a GUI where a user can select a profile from a list of pre-stored profiles. As an example, the GUI may provide the user with a list of output device names (e.g. makes and models), each corresponding to an output device profile stored locally. When the user selects an output device 220, the client application 210 can then retrieve the output device profile corresponding to the name selected by the user. In certain cases, during a discovery or communication process described earlier, the client application 210 may have already obtained the output device ID, name, or reference or other information in a variety of ways described previously. In this case, the client application 210 may automatically activate or retrieve an output device profile stored in the information apparatus 200 based on the output device ID, name, or reference obtained without user intervention. In yet another implementation, the client application 210 may use a set of pre-defined default values stored locally in a user's information apparatus 200. Such defaults can be stored in one or more files or tables. The client application 210 may access a file or table to obtain these default values. The client application 210 may also create or calculate certain default values based on the information it has obtained during previous steps (e.g. in optional discovery process, based on partial or incomplete printer profile information obtained, etc). A user may or may not have an opportunity to change or overwrite some or all defaults. Finally, if, for any reason, no device dependent information is available, the client application 210 may use standard output and rasterization parameters or pre-defined default parameters. The above illustrates many examples and variations of implementation, these and other possible variations in implementation do not depart from the scope of the present invention. In step 1220, the client application 210 may optionally obtain user preferences. In one exemplary implementation, the client application 210 may obtain user preferences with a GUI (graphical user interface). For simplicity, a standard GUI form can be presented to the user independent of the make and model of the output device 220 involved in the output process. Through such an interface, the user may specify some device independent output parameters such as page range, number of cards per page, number of copies, etc. Alternatively or in combination, the client application 210 may also incorporate output device-dependent features and preferences into the GUI presented to the user. The device-dependent portion of the GUI may be supported partly or entirely by information contained in the output device profile obtained through components and processes described in previous steps. To illustrate, device dependent features and capabilities may include print quality, color or grayscale, duplex or single sided, output page size among others. It is preferred that some or all components, attributes or fields of user preferences have default values. Part or all default values may be hard-coded in software program in client application 210 or in hardware components. Alternatively, the client application 210 may also access a file to obtain default values, or it may calculate certain default values based on the information it has obtained during previous steps or components (e.g. from an output device profile). A user may or may not have the ability to pre-configure, or change or overwrite some or all defaults. The client application 210 may obtain and use some or all defaults with or without user intervention or knowledge. In step 1230, the client application 210 of present invention performs rasterization operation to conform a content (e.g. a digital document), which may includes objects and information in vector graphics, text, and images, into one or more output images in accordance with the rasterization parameters obtained in previous steps. During rasterization process, text and vector graphics object or information in the content is rasterized or converted into image or bitmap form according to the given set of rasterization parameters. Image information in the content may require scaling and interpolation operations to conform the rasterization parameters. Rasterization process may further include operations such as scaling, interpolation, segmentation, image transformation, image encoding, color space transformation etc. to fit or conform the one or more output images to the given set of rasterization parameters such as target output size, resolution, bit depth, color space and image format etc. In step 1240, the client application 210 generates an intermediate output data that includes the rasterized one or more output images. The intermediate output data of the present invention may contain image information, instructions, descriptions, and data such as color profile among others. Creating and generating intermediate output data may further include operations such as compression, encoding, encryption, smoothing, segmentation, scaling and or color correction, among others. The image or images contained in an intermediate output data may be variously encoded and/or implemented with different image formats and/or compression methods (e.g. JPEG, BMP, TIFF, JBIG etc or combination). One preferred implementation is to generate or encode the output image in the intermediate output data with mixed raster content (MRC) description. The use of MRC in the data output process of present invention provides opportunities to improve the compression ratio by applying different compression techniques to segmented elements in the content. In addition, MRC provides opportunities to maintain more original content information during the encoding process of the output image and, therefore, potentially improve output quality. In step 1250, the client application 210 transmits intermediate output data to an output device 220 through local communication link 240. The communication link may be implemented with wired or wireless technologies and the transmission may include one or multiple sessions. It should be recognized that FIG. 12A illustrates one example of a client application process 1030 in the data output method 1002 of present invention. Other implementations with more or less steps are possible, and several additional optional processes not shown in FIG. 12 may also be included in the client application process 1030. Use of these different variations, however, does not result in a departure from the scope of the present invention. As an example, an optional authentication step may be included when the selected output device 220 provides service to a restricted group of users. Various authentication procedures may be added in step 1210 when client application 210 obtains output device profile by communicating with an output device or an output controller. As another example, authentication procedures may also be implemented in step 1250 when the client application transmits intermediate output data to one or more output devices 220 or output controllers 230. A simple authentication may be implemented by, for example, comparing the identity of an information apparatus 200 with an approved control list of identities stored in the output device 220 or output controller 230. Other more complex authentication and encryption schemes may also be used. Information such as user name, password, ID number, signatures, security keys (physical or digital), biometrics, fingerprints, voice among others, may be used separately or in combination as authentication means. Such identification and or authentication information may be manually provided by user or automatically detected by the selected output device or devices 220 or output controller 230. With successful authentication, a user may gain access to all or part of the services provided by the output device 220. The output device profile that the client application 210 obtains may vary according to the type or quality of service requested or determined. If authentication fails, it is possible that a user may be denied partially or completely access to the service. In this case, the user may be provided with alternatives such as selecting another output device 220 or alternative services. Another optional process is that a user may be asked to provide payment or deposit or escrow before, during or after output service such as step 1210 or 1250 with reference to FIG. 12. Examples of payment or deposit may include cash, credit card, bankcard, charge card, smart card, electronic cash, among others. The output controller 220 may provide payment calculation or transaction processing as optional feature sets of present invention. FIG. 12B illustrates another exemplary client application output process 1030 with which an information apparatus 200 can pervasively and universally output content to one or more output devices 220 associated with or equipped with an output controller 230 of present invention. The process illustrated in FIG. 12B is similar to the process described in FIG. 12A except that step 1210, obtaining output device profile, is skipped. In this embodiment, the client application 210 utilizes a set of hard-coded, standard or predefined output device parameters including rasterization parameters with which the client application 210 can perform rasterization operation and other required image processing functions. Users may be provided with the option of changing these parameters or inputting alternative parameters. Rasterization parameters include output size, output resolution, bit depth, color space, color channels, scale factors etc. These pre-defined parameters typically comply with a specification or a standard. The same specification and standard may also defined or describe at least partly the intermediate output data. Predefined standard parameters can be stored in a file or profile in an information apparatus 200, an output controller 230, and/or in an output device 220 for easy update or upgrade. In client output process 1204, since the rasterization parameters are predefined, the client application 210 may not need to upload printer profiles from the selected output device 230. Consequently, no two-way communication between the information apparatus 200 and the output device or devices 220 is necessary in this process 1204 when compared with process 1202 illustrated in FIG. 12A. The client application 210 performs rasterization operation 1225 based on standard and/or predefined parameters and generates a rasterized output image with predefined or standard properties of those rasterization parameters. The resulting intermediate output data, which includes at least one rasterized output image, is transmitted from the information apparatus 200 to an output device 220 in step 1250 or to its associated output controller 230 for rendering or output. The intermediate output data generated in process 1202 in general is less device dependent compared to the intermediate output data generated in the process 1202 shown in FIG. 12A. The output controller 230 included or associated with the output device 220 may be preprogrammed to interpret the raster output image, which includes properties or attributes that correspond to those standard or predefined parameters. The standard or predefined rasterization parameters may be hard coded or programmed into the client application 210 and/or the output controller 230. However, instead of hard coding those parameters, one technique to facilitate updates or changes is to store those standard parameters in a default file or profile. The standard or predefined parameters contained in the file or profile can be retrieved and utilized by applications in an information apparatus 200 (e.g. client application 210) and/or by applications or components in an output device 220 or the output controller 230. In this way, any necessary updates, upgrades or required changes to those predefined or standard parameters can be easily accomplished by replacing or modifying the file or profile instead of modifying or updating the program, application or components in the information apparatus 200, output device 220 and/or output controller 230. A client application process 1204 providing universal output capability to information apparatus 200 may include or utilize: A client application 210 that obtains content (e.g. digital document) intended for output. A client application 210 that optionally obtains user preferences (in step 1220) through (1) user's input (automatic or manual) or selections or (2) based on preset preference or predefined defaults or (3) combination of the above. A client application 210 that rasterizes content (in step 1230 or 1225) according to pre-defined or standard rasterization parameters. A client application 210 that generates intermediate output data (in step 1240) for rendering or output at an output device 220; the intermediate output data containing at least partially a rasterized image related to the content intended for output. A client application 210 that transmits the intermediate output data to an output device 220 (in step 1250) for further processing and final output. One advantage of the client output process 1204 of FIG. 12B compared to the process 1202 illustrated in FIG. 12A is that the generated intermediate output data is in general less device dependent. The device independent attribute allows the intermediate output data to be more portable and acceptable to more output devices equipped or associated with output controllers. Both data output processes (1202 and 1204) enable universal output; allowing a user to install a single client application 210 or components in an information apparatus 200 to provide output capability to more than one output device 220. FIG. 13A illustrates one example of an output device process 1302 and its associated raster imaging method of present invention. In this output device process 1302, an output device 220 is capable of receiving an intermediate output data from an information apparatus 200. The output device process 1302 and its operations may include or utilize: An output device/system or output controller that receives intermediate output data (in step 1300). The intermediate output data includes at least partially a raster output image describing at least part of the content for rendering at the output device 220 or system 250. An output device/system or output controller that interprets (in step 1310) the intermediate output data; in one preferred embodiment, the intermediate output data includes an output image utilizing one or more MRC formats or components. An output device/system or output controller that performs image processing operation (in step 1320) on the raster image. The image processing operation may include but not limited to image decompression, scaling, halftoning, color matching, among others. An output device/system or output controller that converts and or generates (in step 1330) output-engine output data that is in a format or description suitable for input to an output engine (e.g. printer engine in case of a printer) included in an output device 220. An output engine in an output device 220 that renders or generates a final output (e.g. the output-engine output data) in step 1370. The output device 220 or output system 250 may include an output controller 230 internally or externally to assist the management and operation of the output process 1302. As shown in FIG. 7, there are many possible configurations and implementations of an output controller 230 associated to an output device 220 Herein and after, output controller 230 is regarded as an integral part of the output device to which it is attached. Hence, the following described output device operations may be partially or completely performed by the output controller associated with it. In step 1300, output device process 1302 is initiated by client application 210 transmitting an intermediate output data to output device 220 or output system 250. In step 1310, the output device 220 reads and interprets the intermediate output data, containing at least one raster output image relating to the content intended for output. During the reading and interpretation process 1310, the output device 220 may include components that parse the intermediate output data and perform operations such as decompression, decoding, and decryption among others. The output image may be variously encoded and may include one or more compression methods. In the event that the method of image encoding includes MRC format, then, in one example implementation, during decoding and mapping of the output image in step 1310, the lower resolution layer and information in an image that includes MRC may be mapped, scaled or interpolated to a higher-resolution output image to produce a better image quality. Therefore, step 1310, in the event that the intermediate output data includes MRC component, each layer in an MRC image can be decompressed, processed, mapped and combined into a single combined output image layer. Step 1310 may also include scaling, color space transformation, and/or interpolation among others. In addition to the possibility of mapping methods using different scaling and interpolation ratio with different layers, another advantage of using MRC is that segmentation information contained in MRC can be utilized to apply different image processing and enhancement techniques to data in different layers of an MRC image in step 1320. In step 1320, the output device 220 may further perform image processing operations on the decoded output image. These image processing operations may include, for example, color correction, color matching, image segmentation, image enhancement, anti-aliasing, image smoothing, digital watermarking, scaling, interpolation, and halftoning among others. The image processing operations 1320 may be combined or operated concurrently with step 1310. For example, while each row, pixel, or portion of the image is being decoded and or decompressed, image processing operations 1320 is applied. In another implementation, the image processing 1320 may occur after the entire output image or a large portion of the image has been decoded or decompressed. If the intermediate output data includes MRC component, then in step 1320, there are additional opportunities to improve image quality. An image encoded in MRC contains segmented information that a traditional single layer image format does not usually have. As an example, foreground can be in one layer, and background in another. As another example, chrominance information may be in one layer and luminance may be in another. This segmented information in MRC may be used to apply different or selective image processing methods and algorithms to different layers or segments to enhance image quality or retain or recover image information. Different image processing techniques or algorithms may include color matching, color correction, black generation, halftoning, scaling, interpolation, anti-aliasing, smoothing, digital watermarking etc. For example, one can apply calorimetric color matching to foreground information and perceptual color matching to background information or vice versa. As another example, error diffusion halftoning can be applied to foreground and stochastic halftoning can be applied to background or vice versa. As yet another example, bi-cubic interpolation can be applied to a layer and bi-linear or minimum distance interpolation can be applied to a different layer. In step 1330, the output device 220 or the output controller 230 may convert the processed image (e.g. halftoned) into a form acceptable to the output engine of output device 220. This conversion step is optional, depending on the type, format and input requirement of a particular output device engine (e.g. printer engine in case of a printer). Different output engines may have different input raster image input requirements. As an example different output engines may require different input image formats, number of bits or bytes per pixel, compression or uncompressed form, or different color spaces (e.g. such as RGB, CMY, CMYK, or any combination of Hi-Fi color such as green, orange, purple, red etc). Incoming raster image data can be encoded in a row, in a column, in multiple rows, in multiple columns, in a chunk, in a segment, or a combination at a time for sending the raster data to the output engine. In some cases, step 1330 may be skipped if the result of step 1320 is already in a form acceptable to the output device engine. In other cases, however, further conversion and or processing may be required to satisfy the specific input requirement of a particular output device engine. It is important to note that the above described processing from step 1310 to step 1330 may require one or more memory buffers to temporarily store processed results. The memory buffer can store or hold a row, a column, a portion, or a chunk, of the output image in any of the steps described above. Storing and retrieving information into and from the memory buffer may be done sequentially, in an alternating fashion, or in an interlaced or interleaved fashion among other possible combinations. Step 1310 to step 1330 operations can be partially or completely implemented with the output controller 230. In step 1370, the output device engine included in the output device 220 or output system 250 receives the output-engine output data generated in step 1330 or step 1320. The output-engine output data is in a form that satisfies the input requirements and attributes of the output engine, such as color space, color channel, bit depth, output size, resolution, etc. The output engine then takes this output-engine output data and outputs or renders the data content through its marking engine or display engine. One advantage of data output method 1002 that includes output device process 1302 is that it has less processing requirements on an information apparatus 200 compared to conventional process with reference to FIG. 1A, and therefore, enables more information apparatus 200 with relatively lower processing power and memory space to have output capability. For example, some image processing functions, such as halftoning (e.g. error diffusion) may require substantial processing and computing power. In data output process 1002 that includes output device process 1302, halftoning is performed in step 1320 by an output device component (e.g. the output controller 230) included in the output device 220 or the output system 250, not in the information apparatus 200; therefore reducing the computational requirements for the information apparatus 200. Another advantage of data output 1302 is that the intermediate output data is less device dependent than the output data generated by conventional output method 102 with reference to FIG. 1A. The device independence provides opportunity to allow a single driver or application in an information apparatus 200 to output intermediate output data to a plurality of output devices 220 that include output controllers 230. Some output devices 220 may contain a printer controller 410. An example of this type of output device or printer is a PostScript printer or PCL printer among others. FIG. 13B illustrates an example of an output device process 1304 with a printer that includes a printer controller 410. As discussed in FIG. 1, a printer with a printer controller requires input such as page description language (e.g. PostScript, PCL etc.), markup language (HTML, XML etc), special image format, special graphics format, or a combination, depending on the type of the printer controller. There are many printing system configurations for providing the data output capability and process to a printer or a printing system that includes a printer controller. In one example, the existing printer controller in the output device 220 may incorporate the feature sets provided by the output controller to form a “combined controller” as described previously with reference to FIGS. 7C and 7F. In another example, the output controller 230 of present invention may be connected sequentially or cascaded to an existing printer controller; the output controller 230 can be internally installed (with reference to FIG. 7B) or externally connected (with reference to FIG. 7A) to the output device 220. For output device 220 that includes a printer controller, the output controller 230 may simply decode the intermediate output data in step 1310 and then convert it into a form acceptable for input to the printer controller in step 1350. An output device process 1304 and operations for an output device 220 or system 250 that includes a printer controller 410 may include or utilize: An output controller 230 or components in an output device 220 or system 250 that receives an intermediate print data or output data (with reference to step 1300), the intermediate print data includes at least a raster image related at least in part to the content for rendering at the output device 220. An output controller 230 or components in an output device 220 or system 250 that interprets the intermediate output data (with reference to step 1310); in one preferred embodiment, the intermediate output data includes an output image utilizing one or more MRC format or components. An output controller 230 or components in an output device 220 or system 250 that converts the intermediate output data into a printer-controller print data (with reference to step 1350); the printer-controller print data includes a format or language (e.g. PDL, PDF, HTML, XML etc.) that is acceptable or compatible to the input requirement of a printer controller. A printer controller or components in an output device 220 or system 250 that receives a printer controller print data; the printer controller may parse, interpret and further process (e.g. rasterization, scaling, image enhancement, color correction, color matching, halftoning etc.) and convert the printer-controller print data into a printer-engine print data (with reference to step 1360); the printer-engine print data comprising of a format or description acceptable for input to a printer engine in the output device 220 or the output system 250. A printer engine or components in an output device 220 or system 250 that renders or generates a final output (with reference to step 1370) with the input printer engine print data. In output device process 1304, step 1300 (receiving intermediate output data) and step 1310 (interpret intermediate output data) are identical to step 1300 and step 1310 in output device process 1302, which have been described in previous sections with reference to FIG. 13A. In step 1350, the output controller 230 converts the intermediate print data into a printer-controller print data that is in a form compatible or acceptable for input to a printer controller. For example, a printer controller may require as input a specific page description language (PDL) such as PostScript. The output controller 230 then creates a PostScript file and embeds the output image generated or retrieved in step 1310 into the PostScript file. The output controller 230 can also create and embed the output image from step 1310 into other printer controller print data formats, instructions or languages. In step 1360, the printer controller receives printer-controller print data generated in step 1350 that includes an acceptable input language or format to the printer controller. The printer controller may parse, interpret, and decode the input printer-controller print data. The printer controller may further perform raster image processing operations such as rasterization, color correction, black generation, GCR, anti-aliasing, scaling, image enhancement, and halftoning among others on the output image. The printer controller may then generate a printer-engine print data that is suitable for input to the printer engine. The type and or format of printer-engine print data may vary according to the requirement of a particular printer engine. It is important to note that the above described process from step 1310 to step 1360 may require one or more memory buffer to temporarily store processed results. The memory buffer can store or hold a row, a column, a portion, or a chunk, of the output image in any of the steps described above. Storing and retrieving information into and from the memory buffer may be done sequentially, alternated, or in an interlaced or interleaved fashion among other possible combinations. Process and operations of step 1310 to step 1360 can be implemented with output controller 230. In step 1370, the printer engine included in the output device 220 or output system 250 generates or renders the final output based on the printer-engine print data generated in step 1360. For example, the printer-engine print data may be in CMY, CMYK, and RGB etc, and this may be in one or more bits per pixel format, satisfying the size and resolution requirement of the printer engine. The printer engine included the output device 220 may take this print data and generate or render an output page through its marking engine. Having described and illustrated the principles of our invention with reference to an illustrated embodiment, it will be recognized that the illustrated embodiment can be modified in arrangement and detail without departing from such principles. In view of the many possible embodiments to which the principles of our invention may be applied, it should be recognized that the detailed embodiments are illustrative only and should not be taken as limiting the scope of our invention. Rather, I claim as my invention all such embodiments as may come within the scope of the following claims and equivalents thereto. Unless the context indicates otherwise, a reference in a claim to the number of instances of an element, be it a reference to one instance or more than one instance, requires at least the stated number of instances of the element but is not intended to exclude from the scope of the claim a structure or method having more instances of that element than stated. Specifically, but without limitation, a reference in a claim to an or one output device or system, to an or one image, or to a or one rasterization parameter is not intended to exclude from the scope of the claim a structure or method having, including, employing or supplying two or more output devices or system, images or rasterization parameters.
<SOH> BACKGROUND OF THE DISCLOSURE <EOH>The present invention relates to universal data output and, in particular, to providing a new data output method and a new raster image process for information apparatuses and output devices. As described herein, information apparatuses refer generally to computing devices, which include both stationary computers and mobile computing devices (pervasive devices). Examples of such information apparatuses include, without limitation, desktop computers, laptop computers, networked computers, palmtop computers (hand-held computers), personal digital assistants (PDAs), Internet enabled mobile phones, smart phones, pagers, digital capturing devices (e.g., digital cameras and video cameras), Internet appliances, e-books, information pads, and digital or web pads. Output devices may include, without limitation, fax machines, printers, copiers, image and/or video display devices (e.g., televisions, monitors and projectors), and audio output devices. For simplicity and convenience, hereafter, the following descriptions may refer to an output device as a printer and an output process as printing. However, it should be understood that the term printer and printing used in the discussion of present invention refer to one embodiment used as a specific example to simplify the description of the invention. The references to printer and printing used here are intended to be applied or extended to the larger scope and definition of output devices and should not be construed as restricting the scope and practice of present invention. Fueled by an ever-increasing bandwidth, processing power, wireless mobile devices, and wireless software applications, millions of users are or will be creating, downloading, and transmitting content and information using their pervasive or mobile computing devices. As a result, there is a need to allow users to conveniently output content and information from their pervasive computing devices to any output device. As an example, people need to directly and conveniently output from their pervasive information apparatus, without depending on synchronizing with a stationary computer (e.g., desktop personal computer) for printing. To illustrate, a mobile worker at an airport receiving e-mail in his hand-held computer may want to walk up to a nearby printer or fax machine to have his e-mail printed. In addition, the mobile worker may also want to print a copy of his to-do list, appointment book, business card, and his flight schedule from his mobile device. As another example, a user visiting an e-commerce site using his mobile device may want to print out transaction confirmation. In still another example, a user who takes a picture with a digital camera may want to easily print it out to a nearby printer. In any of the above cases, the mobile user may want to simply walk up to a printer and conveniently print a file (word processing document, PDF, HTML etc) that is stored on the mobile device or downloaded from a network (e.g., Internet, corporate network). Conventionally, an output device (e.g., a printer) is connected to an information apparatus via a wired connection such as a cable line. A wireless connection is also possible by using, for example, radio communication or infrared communication. Regardless of wired or wireless connection, a user must first install in the information apparatus an output device driver (e.g., printer driver in the case the output device is a printer) corresponding to a particular output device model and make. Using a device-dependent or specific driver, the information apparatus may process output content or digital document into a specific output device's input requirements (e.g., printer input requirements). The output device's input requirements correspond to the type of input that the output device (e.g., a printer) understands. For example, a printer's input requirement may include printer specific input format (e.g., one or more of an image, graphics or text format or language). Therefore, an output data (or print data in the case the output device is a printer) herein refers to data that is acceptable for input to an associated output device. Examples of input requirements may include, without limitation, audio format, video format, file format, data format, encoding, language (e.g., page description language, markup language etc), instructions, protocols or data that can be understood or used by a particular output device make and model. Input requirements may be based on proprietary or published standards or a combination of the two. An output device's input requirements are, therefore, in general, device dependent. Different output device models may have their own input requirements specified, designed or adopted by the output device manufacturer (e.g., the printer manufacturer) according to a specification for optimal operation. Consequently, different output devices usually require use of specific output device drivers (e.g., printer drivers) for accurate output (e.g., printing). Sometimes, instead of using a device driver (e.g., printer driver), the device driving feature may be included as part of an application software. Installation of a device driver (e.g., printer driver) or application may be accomplished by, for example, manual installation using a CD or floppy disk supplied by the printer manufacturer. Or alternatively, a user may be able to download a particular driver or application from a network. For a home or office user, this installation process may take anywhere from several minutes to several hours depending on the type of driver and user's sophistication level with computing devices and networks. Even with plug-and-play driver installation, the user is still required to execute a multi-step process for each printer or output device. This installation and configuration process adds a degree of complexity and work to end-users who may otherwise spend their time doing other productive or enjoyable work. Moreover, many unsophisticated users may be discouraged from adding new peripherals (e.g., printers, scanners, etc.) to their home computers or networks to avoid the inconvenience of installation and configuration. It is therefore desirable that an information apparatus can output to more than one output device without the inconvenience of installing multiple dedicated device dependent drivers. In addition, conventional output or printing methods may pose significantly higher challenges and difficulties for mobile device users than for home and office users. The requirement for pre-installation of a device-dependent driver diminishes the benefit and concept of mobile (pervasive) computing and output. For example, a mobile user may want to print or output e-mail, PowerPoint® presentation documents, web pages, or other documents at an airport, gas station, convenience store, kiosk, hotel, conference room, office, home, etc. It is highly unlikely that the user would find at any of these locations a printer of the same make and model as is at the user's base station. As a consequence, under the conventional printing method, the user would have to install and configure a printer driver each time at each such remote location before printing. It is usually not a viable option given the hundreds, or even thousands of printer models in use, and the limited storage, memory space, and processing power of the information apparatus. Moreover, the user may not want to be bothered with looking for a driver or downloading it and installing it just to print out or display one page of email at the airport. This is certainly an undesirable and discouraging process to promote pervasive or mobile computing. Therefore, a more convenient printing method is needed in support of the pervasive computing paradigm where a user can simply walk up to an output device (e.g., printer or display device) and easily output a digital document without having to install or pre-install a particular output device driver (e.g., printer driver). Another challenge for mobile users is that many mobile information apparatuses have limited memory space, processing capacity and power. These limitations are more apparent for small and low-cost mobile devices including, for example, PDAs, mobile phones, screen phones, pagers, e-books, Internet Pads, Internet appliances etc. Limited memory space poses difficulties in installing and running large or complex printer or device drivers, not to mention multiple drivers for a variety of printers and output devices. Slow processing speed and limited power supply create difficulties driving an output device. For example, processing or converting a digital document into output data by a small mobile information apparatus may be so slow that it is not suitable for productive output. Intensive processing may also drain or consume power or battery resources. Therefore, a method is needed so that a small mobile device, with limited processing capabilities, can still reasonably output content to various output devices. To output or render content (e.g. digital document) to an output device, a raster image processing (RIP) operation on the content is usually required. RIP operation can be computationally intensive and may include (1) a rasterization operation, (2) a color space conversion, and (3) a halftoning operation. RIP may also include other operations such as scaling, segmentation, color matching, color correction, GCR (Grey component replacement), Black generation, image enhancement compression/decompression, encoding/decoding, encryption/decryption GCR, image enhancement among others. Rasterization operation in RIP involves converting objects and descriptions (e.g. graphics, text etc) included in the content into an image form suitable for output. Rasterization may include additional operations such as scaling and interpolation operations for matching a specific output size and resolution. Color space conversion in RIP includes converting an input color space description into a suitable color space required for rendering at an output device (e.g. RGB to CMYK conversion). Digital halftoning is an imaging technique for rendering continuous tone images using fewer luminance and chrominance levels. Halftoning operations such as error diffusion can be computationally intensive and are included when the output device's bit depth (e.g. bits per pixel) is smaller than the input raster image bit depth. Conventionally, RIP operations are included either in an information apparatus, or as part of an output device or output system (e.g. in a printer controller). FIG. 1A illustrates a flow diagram of a conventional data output method 102 in which RIP 110 is implemented in the information apparatus. Output devices that do not include a printer controller to perform complex RIP operations, such as a lower-cost, lower speed inkjet printer, normally employ data output method 102 . In data output method 102 , an information apparatus obtains content (e.g. a digital document) in step 100 for rendering or output at an output device. The information apparatus may includes an application (e.g. device driver), which implements RIP operation 110 . The information apparatus generates an output data in step 120 and transmits the output data to the output device in step 130 for rendering. The output data relating to the content is in an acceptable form (e.g. in an appropriate output size and resolution) to the output engine (e.g. display engine, printer engine etc.) included in the output device. The output data in a conventional output method 102 is usually device dependent. One drawback for the data output method 102 of FIG. 1A is that the information apparatus performs most if not the entire raster image processing operations 110 required for output. The RIP operations may require intensive computation. Many information apparatus such as mobile information device might have insufficient computing power and/or memory to carry out at an acceptable speed the RIP operations 110 required in an output process. Another drawback for the conventional data output method 102 of FIG. 1A is that the generated output data is device dependent and therefore is typically not very portable to other output devices. As a result, the information apparatus may need to install multiple applications or device drivers for multiple output devices, which may further complicate its feasibility for use in information apparatuses with limited memory, storage and processing power. FIG. 1B illustrates a flow diagram of another conventional data output method 104 in which the RIP is implemented in an output device. An example of an output device that implements process 104 is a high-speed laser printer which includes a printer controller for performing RIP operations and an output engine (e.g. printer engine) for rendering content. Printer controller may be internally installed or externally connected to an output device (printer in this example). In data output method 104 , an information apparatus obtains content for output in step 100 and generates in step 160 an output data or print data for transmitting to the output device in step 170 . Print data includes information related to the content and is usually encoded in a page description language (PDL) such as PostScript and PCL etc. In step 180 , the printer receives the output data or print data (in a PDL). In step 190 , a printer controller included in the printer interprets the PDL, performs RIP operations, and generates a printer-engine print data that is in a form acceptable to the printer engine (e.g. a raster image in an appropriate output size, bit depth, color space and resolution). In step 150 the printer engine renders the content with the printer-engine print data. It will be understood that a reference to print data or output data including a language, such as PDL, should be interpreted as meaning that the print data or output data is encoded using that language. Correspondingly, a reference to a data output process generating a language, such as PDL, should be interpreted as meaning that the data output process encodes data using that language. There are many drawbacks in the conventional data output method 104 shown in FIG. 1B . These drawbacks are especially apparent for mobile computing devices with limited processing power and memory. One such drawback is that the output data or print data, which include a page description language (PDL) such as PostScript or PCL, can be very complex. Generating complex PDL may increase memory and processing requirements for an information apparatus. Furthermore, interpreting, decoding and then raster image processing complex PDL can increase computation, decrease printing speed, and increase the cost of the output device or its printer controller. Another drawback is that the output data that includes PDL can creates a very large file size that would increase memory and storage requirements for the information apparatus, the output device and/or the printer controller etc. Large file size may also increase the bandwidth required in the communication link between the information apparatus and the output device. Finally, to rasterize text in an output device, a printer controller may need to include multiple fonts. When a special font or international characters is not included or missing in the printer controller, the rendering or output can potentially become inaccurate or inconsistent.
<SOH> SUMMARY OF THE INVENTION <EOH>Accordingly, this invention provides a convenient universal data output method in which an information apparatus and an output device or system share the raster image processing operations. Moreover, the new data output method eliminates the need to install a plurality of device-dependent dedicated drivers or applications in the information apparatus in order to output to a plurality of output devices. In accordance with present invention, an electronic system and method of pervasive and universal output allow an information apparatus to output content conveniently to virtually any output device. The information apparatus may be equipped with a central processing unit, input/output control unit, storage unit, memory unit, and wired or wireless communication unit or adapters. The information apparatus preferably includes a client application that may be implemented as a software application, a helper application, or a device driver (a printer driver in case of a printer). The client application may include management and control capabilities with hardware and software components including, for example, one or more communication chipsets residing in its host information apparatus. The client application in the information apparatus may be capable of communicating with, managing and synchronizing data or software components with an output device equipped with an output controller of present invention. Rendering content in an output device refers to printing an image of the content onto an substrate in the case of a printing device; displaying an image of the content in the case of a displaying device; playing an audio representation of the content in a voice or sound output device or system. An output controller may be a circuit board, card or software components residing in an output device. Alternatively, the output controller may be connected externally to an output device as an external component or “box.” The output controller may be implemented with one or more combinations of embedded processor, software, firmware, ASIC, DSP, FPGA, system on a chip, special chipsets, among others. In another embodiment, the functionality of the output controller may be provided by application software running on a PC, workstation or server connected externally to an output device. In conventional data output method 102 as described with reference to FIG. 1A , an information apparatus transmits output data to an output device for rendering. Output data corresponds to content intended for output and is mostly raster image processed (RIPed) and therefore is device dependent because raster image processing is a typical device dependent operation. Output data may be encoded or compressed with one or more compression or encoding techniques. In present invention, an information apparatus generates an intermediate output data for transmitting to an output device. The intermediate output data includes a rasterized image corresponding to the content; however, device dependent image processing operations of a RIP (e.g. color matching and halftoning) have not been performed. As a result, an intermediate output data is more device independent and is more portable than the output data generated by output method with reference to FIG. 1A . In one implementation of this invention, the intermediate output data includes MRC (Mixed raster content) format, encoding and compression techniques, which further provides improved image quality and compression ratio compared to conventional image encoding and compression techniques. In an example of raster image process and data output method of the present invention, a client application such as a printer driver is included in an information apparatus and performs part of raster image processing operation such as rasterization on the content. The information apparatus generates an intermediate output data that includes an output image corresponding to the content and sends the intermediate output data to an output device or an output system for rendering. An output controller application or component included in the output device or output system implements the remaining part of the raster image processing operations such as digital halftoning, color correction among others. Unlike conventional raster image processing methods, this invention provides a more balanced distribution of the raster image processing computational load between the Information apparatus and the output device or the output system. Computational intensive image processing operations such as digital halftoning and color space conversions can be implemented in the output device or output system. Consequently, this new raster image processing method reduces the processing and memory requirements for the information apparatus when compared to conventional data output methods described with reference to FIG. 1A in which the entire raster image process is implemented in the information apparatus. Additionally, in this invention, a client application or device driver included in the information apparatus, which performs part of the raster image processing operation, can have a smaller size compared to a conventional output application included in the information apparatus, which performs raster image processing operation. In another implementation, the present invention provides an information apparatus with output capability that is more universally accepted by a plurality of output devices. The information apparatus, which includes a client application, generates an intermediate output data that may include device independent attributes. An output controller includes components to interpret and process the intermediate output data. The information apparatus can output content to different output devices or output systems that include the output controller even when those output devices are of different brand, make, model and with different output engine and input data requirements. Unlike conventional output methods, a user does not need to preinstall in the information apparatus multiple dedicated device dependent drivers or applications for each output device. The combination of a smaller-sized client application, a reduced computational requirement in the information apparatus, and a more universal data output method acceptable for rendering at a plurality of output devices enable mobile devices with less memory space and processing capabilities to implement data output functions which otherwise would be difficulty to implement with conventional output methods. In addition, this invention can reduce the cost of an output device or an output system compared to conventional output methods 104 that include a page description language (PDL) printer controller. In the present invention, an information apparatus generates and sends an intermediate output data to an output device or system. The intermediate output data in one preferred embodiment includes a rasterized output image corresponding to the content intended for output. An output controller included in an output device or an output system decodes and processes the intermediate output data for output, without performing complex interpretation and rasterization compared to conventional methods described in process 104 . In comparison, the conventional data output process 104 generates complex PDL and sends this PDL from an information apparatus to an output device that includes a printer controller (e.g. a PostScript controller or a PCL5 controller among others). Interpretation and raster image processing of a PDL have much higher computational requirements compared to decoding and processing the intermediate output data of this invention that include rasterized output image or images. Implementing a conventional printer controller with, for example, PDL increases component cost (e.g. memories, storages, ICs, software and processors etc.) when compared to using the output controller included in the data output method of this present invention. Furthermore, an output data that includes PDL can create a large file size compared to an intermediate output data that includes rasterized output image. The data output method for this invention comparatively transmits a smaller output data from an information apparatus to an output device. Smaller output data size can speed up transmission, lower communication bandwidth, and reduce memory requirements. Finally, this invention can provide a convenient method to render content at an output device with or without connection to a static network. In conventional network printing, both information apparatus and output device must be connected to a static network. In this invention, through local communication and synchronization between an information apparatus and an output device, installation of hardware and software to maintain static network connectivity may not be necessary to enable the rendering of content to an output device. According to the several aspects of the present invention there is provided the subject matter defined in the appended independent claims. Additional objects and advantages of the present invention will be apparent from the detailed description of the preferred embodiment thereof, which proceeds with reference to the accompanying drawings.
G06F31236
20171006
20180208
66411.0
G06F312
6
RILEY, MARCUS T
WIRELESS PRINTING DEVICES THAT PROVIDE PRINTING SERVICES OVER A NETWORK WITHOUT A NEED FOR A CLIENT DEVICE OF THE PRINTING DEVICE TO USE, AT THE CLIENT DEVICE, A PRINTER SPECIFIC PRINTER DRIVER
UNDISCOUNTED
1
CONT-ACCEPTED
G06F
2,017
15,726,901
PENDING
AMLODIPINE FORMULATIONS
Provided herein are stable amlodipine oral liquid formulations. Also provided herein are methods of using amlodipine oral liquid formulations for the treatment of certain diseases including hypertension and Coronary Artery Disease (CAD).
1. An oral liquid formulation, comprising: (i) amlodipine benzoate in an amount corresponding to 1.0 mg/ml amlodipine freebase; (ii) about 3 mM of a citrate buffer; (iii) about 0.2 mg/ml to about 10 mg/ml of sodium benzoate; (iv) about 0.5 mg/ml of silicon dioxide; (v) about 7.5 mg/ml of hydroxypropyl methylcellulose; (vi) about 0.15 mg/ml simethicone; (vii) about 1.0 mg/ml of polysorbate 80; and (viii) water; wherein the formulation is stable between about 5±5° C. and about 25±5° C. for at least 12 months. 2. The formulation of claim 1, wherein the amlodipine benzoate is formed in situ. 3. The formulation of claim 2, wherein the amlodipine benzoate is formed by a reaction of a pharmaceutically acceptable salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate with a molar excess of sodium benzoate. 4. The formulation of claim 3, wherein the salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate is selected from amlodipine besylate, amlodipine tosylate, amlodipine mesylate, amlodipine succinate, amlodipine salicylate, amlodipine maleate, amlodipine acetate, and amlodipine hydrochloride. 5. The formulation of claim 2, wherein the amlodipine benzoate is formed by the reaction of amlodipine besylate with a molar excess of sodium benzoate. 6. The formulation of claim 1, wherein the formulation further comprises a flavoring agent. 7. The formulation of claim 1, wherein the formulation further comprises a sweetener. 8. The formulation of claim 7, wherein the sweetener is sucralose. 9. The formulation of claim 1, wherein the formulation is in the form of a suspension. 10. The formulation of claim 1, wherein the pH of the formulation is between about 3 and about 8. 11. The formulation of claim 10, wherein the pH is between about 4 and about 5. 12. The formulation of claim 10, wherein the pH is between about 5 and about 6. 13. The formulation of claim 1, wherein the formulation is stable at about 25±5° C. for at least 12 months. 14. The formulation of claim 1, wherein the formulation is stable at about 5±5° C. for at least 12 months. 15. The formulation of claim 1, wherein the formulation is stable at about 25±5° C. for at least 24 months. 16. The formulation of claim 1, wherein the formulation is stable at about 5±5° C. for at least 24 months.
CROSS-REFERENCE This application claims the benefit of U.S. Application Ser. No. 62/405,455 filed Oct. 7, 2016, which is hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION Hypertension, or high blood pressure, is a serious health issue in many countries. According to the National Heart Blood and Lung Institute, it is thought that about 1 in 3 adults in the United States alone have hypertension. Left unchecked, hypertension is considered a substantial risk factor for cardiovascular and other diseases including coronary heart disease, myocardial infarction, congestive heart failure, stroke and kidney failure. Hypertension is classified as primary (essential) hypertension or secondary hypertension. Primary hypertension has no known cause and may be related to a number of environmental, lifestyle and genetic factors such as stress, obesity, smoking, inactivity and sodium intake. Secondary hypertension can be caused by drug or surgical interventions or by abnormalities in the renal, cardiovascular or endocrine system. A number of antihypertensive drugs are available for treating hypertension. Various therapeutic classes of antihypertensive drugs include alpha-adrenergic blockers, beta-adrenergic blockers, calcium-channel blockers, hypotensives, mineralcorticoid antagonists, central alpha-agonists, diuretics and rennin-angiotensin-aldosterone inhibitors which include angiotensin II receptor antagonists (ARB) and angiotensin-converting enzyme (ACE) inhibitors. Angiotensin-converting enzyme (ACE) inhibitors inhibit angiotensin-converting enzyme (ACE), a peptidyl dipeptidase that catalyzes angiotension I to angiotension II, a potent vasoconstrictor involved in regulating blood pressure. Amlodipine is a calcium channel blocker. It affects the movement of calcium into the cells of the heart and blood vessels. As a result, amlodipine relaxes blood vessels and increases the supply of blood and oxygen to the heart while reducing its workload. The structural formula of amlodipine is as follows: Amlodipine is currently administered in the form of oral tablets, (e.g., Norvasc) or in the form of a refrigerated liquid formulation. In addition to the treatment of hypertension, amlodipine tablets have been used for coronary artery disease (CAD) such as chronic stable angina, vasospastic angina, or angiographically documented coronary artery disease in patients without heart failure or an ejection fraction <40%. SUMMARY OF THE INVENTION Disclosed herein is an oral liquid formulation, comprising: (i) amlodipine benzoate in an amount corresponding to 1.0 mg/ml amlodipine freebase; (ii) about 3 mM of a citrate buffer; (iii) about 0.2 mg/ml to about 10 mg/ml of sodium benzoate; (iv) about 0.5 mg/ml of silicon dioxide; (v) about 7.5 mg/ml of hydroxypropyl methylcellulose; (vi) about 0.15 mg/ml simethicone; (vii) about 1.0 mg/ml of polysorbate 80; and (viii) water; wherein the formulation is stable between about 5±5° C. and about 25±5° C. for at least 12 months. In some embodiments of an oral liquid formulation, the amlodipine benzoate is formed in situ. In some embodiments of an oral liquid formulation, the amlodipine benzoate is formed by the reaction of a pharmaceutically acceptable salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate with a molar excess of sodium benzoate. In some embodiments of an oral liquid formulation, the salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate is selected from amlodipine besylate, amlodipine tosylate, amlodipine mesylate, amlodipine succinate, amlodipine salicylate, amlodipine maleate, amlodipine acetate, and amlodipine hydrochloride. In some embodiments of an oral liquid formulation, the amlodipine benzoate is formed by the reaction of amlodipine besylate with a molar excess of sodium benzoate. In some embodiments of an oral liquid formulation, the formulation further comprises a flavoring agent. In some embodiments of an oral liquid formulation, the formulation further comprises a sweetener. In some embodiments of an oral liquid formulation, the sweetener is sucralose. In some embodiments of an oral liquid formulation, the formulation is in the form of a suspension. In some embodiments of an oral liquid formulation, the pH of the formulation is between about 3 and about 8. In some embodiments of an oral liquid formulation, the pH is between about 4 and about 5. In some embodiments of an oral liquid formulation, the pH is between about 5 and about 6. In some embodiments of an oral liquid formulation, the formulation is stable at about 25±5° C. for at least 12 months. In some embodiments of an oral liquid formulation, the formulation is stable at about 5±5° C. for at least 12 months. In some embodiments of an oral liquid formulation, the formulation is stable at about 25±5° C. for at least 24 months. In some embodiments of an oral liquid formulation, the formulation is stable at about 5±5° C. for at least 24 months. Also disclosed herein is a method of treating hypertension in a subject comprising administering to that subject an oral liquid formulation, comprising: (i) amlodipine benzoate in an amount corresponding to 1.0 mg/ml amlodipine freebase; (ii) about 3 mM of a citrate buffer; (iii) about 0.2 mg/ml to about 10 mg/ml of sodium benzoate; (iv) about 0.5 mg/ml of silicon dioxide; (v) about 7.5 mg/ml of hydroxypropyl methylcellulose; (vi) about 0.15 mg/ml simethicone; (vii) about 1.0 mg/ml of polysorbate 80; and (viii) water; wherein the formulation is stable between about 5±5° C. and about 25±5° C. for at least 12 months. In some embodiments of a method of treating hypertension, the amlodipine benzoate is formed in situ. In some embodiments of a method of treating hypertension, the amlodipine benzoate is formed by the reaction of a pharmaceutically acceptable salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate with a molar excess of sodium benzoate. In some embodiments of a method of treating hypertension, the salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate is selected from amlodipine besylate, amlodipine tosylate, amlodipine mesylate, amlodipine succinate, amlodipine salicylate, amlodipine maleate, amlodipine acetate, and amlodipine hydrochloride. In some embodiments of a method of treating hypertension, the amlodipine benzoate is formed by the reaction of amlodipine besylate with a molar excess of sodium benzoate. In some embodiments of a method of treating hypertension, the formulation further comprises a flavoring agent. In some embodiments of a method of treating hypertension, the formulation further comprises a sweetener. In some embodiments of an oral liquid formulation, the sweetener is sucralose. In some embodiments of a method of treating hypertension, the formulation is in the form of a suspension. In some embodiments of a method of treating hypertension, the pH of the formulation is between about 3 and about 8. In some embodiments of a method of treating hypertension, the pH is between about 4 and about 5. In some embodiments of a method of treating hypertension, the pH is between about 5 and about 6. In some embodiments of a method of treating hypertension, the formulation is stable at about 25±5° C. for at least 12 months. In some embodiments of a method of treating hypertension, the formulation is stable at about 5±5° C. for at least 12 months. In some embodiments of a method of treating hypertension, the formulation is stable at about 25±5° C. for at least 24 months. In some embodiments of a method of treating hypertension, the formulation is stable at about 5±5° C. for at least 24 months. In some embodiments of a method of treating hypertension, the hypertension is primary (essential) hypertension. In some embodiments of a method of treating hypertension, the hypertension is secondary hypertension. In some embodiments of a method of treating hypertension, the subject has blood pressure values greater than or equal to 140/90 mmm Hg. In some embodiments of a method of treating hypertension, the subject is an adult. In some embodiments of a method of treating hypertension, the subject is elderly. In some embodiments of a method of treating hypertension, the subject is a child. In some embodiments of a method of treating hypertension, the formulation is administered to the subject in a fasted state. In some embodiments of a method of treating hypertension, the formulation is administered to the subject in a fed state. In some embodiments of a method of treating hypertension, the formulation is further administered in combination with an agent selected from the group consisting of diuretics, beta blockers, alpha blockers, mixed alpha and beta blockers, calcium channel blockers, angiotensin II receptor antagonists, ACE inhibitors, aldosterone antagonists, and alpha-2 agonists. Also disclosed herein is a method of treating Coronary Artery Disease (CAD) in a subject comprising administering to that subject an oral liquid formulation, comprising: (i) amlodipine benzoate in an amount corresponding to 1.0 mg/ml amlodipine freebase; (ii) about 3 mM of a citrate buffer; (iii) about 0.2 mg/ml to about 10 mg/ml of sodium benzoate; (iv) about 0.5 mg/ml of silicon dioxide; (v) about 7.5 mg/ml of hydroxypropyl methylcellulose; (vi) about 0.15 mg/ml simethicone; (vii) about 1.0 mg/ml of polysorbate 80; and (viii) water; wherein the formulation is stable between about 5±5° C. and about 25±5° C. for at least 12 months. In some embodiments of a method of treating Coronary Artery Disease (CAD), the amlodipine benzoate is formed in situ. In some embodiments of a method of treating Coronary Artery Disease (CAD), the amlodipine benzoate is formed by the reaction of a pharmaceutically acceptable salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate with a molar excess of sodium benzoate. In some embodiments of a method of treating Coronary Artery Disease (CAD), the salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate is selected from amlodipine besylate, amlodipine tosylate, amlodipine mesylate, amlodipine succinate, amlodipine salicylate, amlodipine maleate, amlodipine acetate, and amlodipine hydrochloride. In some embodiments of a method of treating Coronary Artery Disease (CAD), the amlodipine benzoate is formed by the reaction of amlodipine besylate with a molar excess of sodium benzoate. In some embodiments of a method of treating Coronary Artery Disease (CAD), the formulation further comprises a flavoring agent. In some embodiments of a method of treating Coronary Artery Disease (CAD), the formulation further comprises a sweetener. In some embodiments of an oral liquid formulation, the sweetener is sucralose. In some embodiments of a method of treating Coronary Artery Disease (CAD), the formulation is in the form of a suspension. In some embodiments of a method of treating Coronary Artery Disease (CAD), the pH of the formulation is between about 3 and about 8. In some embodiments of a method of treating Coronary Artery Disease (CAD), the pH is between about 4 and about 5. In some embodiments of a method of treating Coronary Artery Disease (CAD), the pH is between about 5 and about 6. In some embodiments of a method of treating Coronary Artery Disease (CAD), the formulation is stable at about 25±5° C. for at least 12 months. In some embodiments of a method of treating Coronary Artery Disease (CAD), the formulation is stable at about 5±5° C. for at least 12 months. In some embodiments of a method of treating Coronary Artery Disease (CAD), the formulation is stable at about 25±5° C. for at least 24 months. In some embodiments of a method of treating Coronary Artery Disease (CAD), the formulation is stable at about 5±5° C. for at least 24 months. In some embodiments of a method of treating Coronary Artery Disease (CAD), the Coronary Artery Disease (CAD) is chronic stable angina, vasospastic angina, or angiographically documented coronary artery disease. In some embodiments of a method of treating Coronary Artery Disease (CAD), the angiographically documented coronary artery disease is in patients without heart failure or an ejection fraction <40%. In some embodiments of a method of treating Coronary Artery Disease (CAD), the formulation is further administered in combination with an additional anti-anginal agent. Disclosed herein is an oral liquid formulation, comprising: (i) a pharmaceutically acceptable salt of amlodipine; (ii) a buffer; (iii) water; and (iv) optionally one or more agents selected from the group consisting of preservatives, flavoring agents, sweetening agents, surfactants, suspensions aids, and antifoaming agents; wherein the formulation is stable between about 5±5° C. and about 25±5° C. for at least 12 months. In some embodiments of an oral liquid formulation, the pharmaceutically acceptable salt of amlodipine is amlodipine benzoate or amlodipine naphthalene sulfonate. In some embodiments of an oral liquid formulation, the amlodipine benzoate or amlodipine naphthalene sulfonate are formed in situ. In some embodiments of an oral liquid formulation, the amlodipine benzoate or amlodipine naphthalene sulfonate are formed by the reaction of a pharmaceutically acceptable salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate or amlodipine naphthalene sulfonate with a molar excess of a salt forming agent. In some embodiments of an oral liquid formulation, the pharmaceutically acceptable salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate or amlodipine naphthalene sulfonate is amlodipine besylate. In some embodiments of an oral liquid formulation, the salt forming agent is sodium benzoate. In some embodiments of an oral liquid formulation, the amount of sodium benzoate as the salt forming agent is about 1.0 mg/ml to about 10.0 mg/ml. In some embodiments of an oral liquid formulation, the salt forming agent is sodium naphthalene-2-sulfonate. In some embodiments of an oral liquid formulation, the amount of sodium naphthalene-2-sulfonate as the salt forming agent is about 0.5 mg/ml to about 2.5 mg/ml. In some embodiments of an oral liquid formulation, the oral liquid formulation comprises a surfactant. In some embodiments of an oral liquid formulation, the surfactant is polysorbate 80. In some embodiments of an oral liquid formulation, the amount of the surfactant is about 0.1 mg/ml to about 2.5 mg/ml. In some embodiments of an oral liquid formulation, the oral liquid formulation comprises a preservative. In some embodiments of an oral liquid formulation, the preservative is selected from the group consisting of sodium benzoate, a paraben or paraben salt, and combinations thereof. In some embodiments of an oral liquid formulation, the amount of preservative is about 0.1 mg/ml to about 2.0 mg/ml. In some embodiments of an oral liquid formulation, the buffer comprises a citrate buffer. In some embodiments of an oral liquid formulation, the citrate buffer concentration is about 3 mM. In some embodiments of an oral liquid formulation, the buffer comprises a phosphate buffer. In some embodiments of an oral liquid formulation, the phosphate buffer concentration is about 3 mM. In some embodiments of an oral liquid formulation, the oral liquid formulation comprises a suspension aid. In some embodiments of an oral liquid formulation, the suspension aid comprises silicon dioxide, hydroxypropyl methylcellulose, methylcellulose, microcrystalline cellulose, carboxymethylcellulose sodium, polyvinylpyrrolidone, or combinations thereof. In some embodiments of an oral liquid formulation, the suspension aid is silicon dioxide. In some embodiments of an oral liquid formulation, the amount of silicon dioxide is about 0.1 mg/ml to about 1.0 mg/ml. In some embodiments of an oral liquid formulation, the suspension aid is hydroxypropyl methylcellulose. In some embodiments of an oral liquid formulation, the amount of hydroxypropyl methylcellulose is about 3 mg/ml to about 10 mg/ml. In some embodiments of an oral liquid formulation, the suspension aid is a combination of silicon dioxide and hydroxypropyl methylcellulose. In some embodiments of an oral liquid formulation, the amount of silicon dioxide is about 0.1 mg/ml to about 1.0 mg/ml and the amount of hydroxypropyl methylcellulose is about 3 mg/ml to about 10 mg/ml. In some embodiments of an oral liquid formulation, the oral liquid formulation comprises an antifoaming agent. In some embodiments of an oral liquid formulation, the antifoaming agent is simethicone. In some embodiments of an oral liquid formulation, the amount of the antifoaming agent is about 0.05 mg/ml to about 1.0 mg/ml. In some embodiments of an oral liquid formulation, the formulation comprises a flavoring agent. In some embodiments of an oral liquid formulation, the oral liquid formulation comprises a sweetener. In some embodiments of an oral liquid formulation, the sweetener is sucralose. In some embodiments of an oral liquid formulation, the oral liquid formulation further comprises unreacted salt forming agent. In some embodiments of an oral liquid formulation, the oral liquid formulation is in the form of a suspension. In some embodiments of an oral liquid formulation, the pH of the oral liquid formulation is between about 3 and about 8. In some embodiments of an oral liquid formulation, the pH is between about 4 and about 5. In some embodiments of an oral liquid formulation, the pH is between about 5 and about 6. In some embodiments of an oral liquid formulation, the amount of the pharmaceutically acceptable salt of amlodipine corresponds to about 0.8 mg/ml to about 1.2 mg/ml of amlodipine free base. In some embodiments of an oral liquid formulation, the formulation is stable at about 25±5° C. for at least 12 months. In some embodiments of an oral liquid formulation, the formulation is stable at about 5±5° C. for at least 12 months. In some embodiments of an oral liquid formulation, the formulation is stable at about 25±5° C. for at least 24 months. In some embodiments of an oral liquid formulation, the formulation is stable at about 5±5° C. for at least 24 months. Also disclosed herein is an oral liquid formulation, comprising: (i) a pharmaceutically acceptable salt of amlodipine in an amount corresponding to 1.0 mg/ml amlodipine freebase; (ii) about 3 mM of a citrate buffer; (iii) about 0.2 mg/ml to about 10 mg/ml of sodium benzoate; (iv) about 0.5 mg/ml of silicon dioxide; (v) about 7.5 mg/ml of hydroxypropyl methylcellulose; (vi) about 0.15 mg/ml simethicone; (vii) optionally about 1.0 mg/ml of polysorbate 80; and (viii) water; wherein the formulation is stable between about 5±5° C. and about 25±5° C. for at least 12 months. In some embodiments of an oral liquid formulation, the pharmaceutically acceptable salt of amlodipine is amlodipine benzoate or amlodipine naphthalene sulfonate. In some embodiments of an oral liquid formulation, the amlodipine benzoate or amlodipine naphthalene sulfonate are formed in situ. In some embodiments of an oral liquid formulation, the amlodipine benzoate or amlodipine naphthalene sulfonate are formed by the reaction of amlodipine besylate with a molar excess of a salt forming agent. In some embodiments of an oral liquid formulation, the salt forming agent is sodium benzoate. In some embodiments of an oral liquid formulation, the amount of sodium benzoate as the salt forming agent is about 1.0 mg/ml to about 10.0 mg/ml. In some embodiments of an oral liquid formulation, the salt forming agent is sodium naphthalene-2-sulfonate. In some embodiments of an oral liquid formulation, the amount of sodium naphthalene-2-sulfonate as the salt forming agent is about 0.5 mg/ml to about 2.5 mg/ml. In some embodiments of an oral liquid formulation, the formulation further comprises a flavoring agent. In some embodiments of an oral liquid formulation, the formulation further comprises a sweetener. In some embodiments of an oral liquid formulation, the sweetener is sucralose. In some embodiments of an oral liquid formulation, the oral liquid formulation further comprises unreacted salt forming agent. In some embodiments of an oral liquid formulation, the formulation is in the form of a suspension. In some embodiments of an oral liquid formulation, the pH of the formulation is between about 3 and about 8. In some embodiments of an oral liquid formulation, the pH is between about 4 and about 5. In some embodiments of an oral liquid formulation, the pH is between about 5 and about 6. In some embodiments of an oral liquid formulation, the formulation is stable at about 25±5° C. for at least 12 months. In some embodiments of an oral liquid formulation, the formulation is stable at about 5±5° C. for at least 12 months. In some embodiments of an oral liquid formulation, the formulation is stable at about 25±5° C. for at least 24 months. In some embodiments of an oral liquid formulation, the formulation is stable at about 5±5° C. for at least 24 months. Also disclosed herein is a process for preparing a stable amlodipine oral liquid formulation, the process comprising mixing a first mixture with a second mixture; the first mixture comprising: (i) amlodipine benzoate; (ii) sodium benzoate; (iii) optionally polysorbate 80; and (iv) water; and the second mixture comprising: (i) citric acid; (ii) sodium citrate; (iii) sucralose; (iv) optionally a flavoring agent; (v) hydroxypropyl methylcellulose; (vi) simethicone; (vii) silicon dioxide; and (viii) water. In some embodiments of a process for preparing a stable amlodipine oral liquid formulation, the first mixture is obtained by a process comprising: (i) adding water to a first container which is not stainless steel; (ii) adding amlodipine besylate to the first container; (iii) adding sodium benzoate to the first container; (iv) optionally adding polysorbate 80 to the first container; and (v) stirring until amlodipine benzoate substantially precipitates. In some embodiments of a process for preparing a stable amlodipine oral liquid formulation, the second mixture is obtained by a process comprising: (i) adding water to a second container; (ii) adding citric acid to the second container; (iii) adding sodium citrate to the second container; (iv) adding sucralose to the second container; (v) optionally adding the flavoring agent to the second container; (vi) adding hydroxypropyl methylcellulose to the second container; (vii) adding simethicone to the second container; (viii) adding silicon dioxide to the second container; and (ix) stirring. Also disclosed herein is a process for preparing a stable amlodipine oral liquid formulation, the process comprising mixing a first mixture with a second mixture; the first mixture comprising: (i) amlodipine naphthalene sulfonate; (ii) optionally sodium benzoate; (iii) optionally polysorbate 80; and (iv) water; and the second mixture comprising: (i) citric acid; (ii) sodium citrate; (iii) sucralose; (iv) optionally a flavoring agent; (v) hydroxypropyl methylcellulose; (vi) simethicone; (vii) silicon dioxide; and (viii) water. In some embodiments of a process for preparing a stable amlodipine oral liquid formulation, the first mixture is obtained by a process comprising: (i) adding water to a first container which is not stainless steel; (ii) adding amlodipine besylate to the first container; (iii) adding sodium naphthalene-2-sulfonate to the first container; (iv) adding sodium benzoate to the first container; (v) optionally adding polysorbate 80 to the first container; and (vi) stirring until amlodipine naphthalene sulfonate substantially precipitates. In some embodiments of a process for preparing a stable amlodipine oral liquid formulation, the second mixture is obtained by a process comprising: (i) adding water to a second container; (ii) adding citric acid to the second container; (iii) adding sodium citrate to the second container; (iv) adding sucralose to the second container; (v) optionally adding the flavoring agent to the second container; (vi) adding hydroxypropyl methylcellulose to the second container; (vii) adding simethicone to the second container; (viii) adding silicon dioxide to the second container; and (ix) stirring. In some embodiments of a process for preparing a stable amlodipine oral liquid formulation, the first mixture does not comprise sodium benzoate and the second mixture further comprises a paraben. Also disclosed herein is a method of treating hypertension in a subject comprising administering to that subject a therapeutically effective amount of an amlodipine oral liquid formulation comprising: (i) a pharmaceutically acceptable salt of amlodipine in an amount corresponding to 1.0 mg/ml amlodipine freebase; (ii) about 3 mM of a citrate buffer; (iii) about 0.2 mg/ml to about 10 mg/ml of sodium benzoate; (iv) about 0.5 mg/ml of silicon dioxide; (v) about 7.5 mg/ml of hydroxypropyl methylcellulose; (vi) about 0.15 mg/ml simethicone; (vii) optionally about 1.0 mg/ml of polysorbate 80; and (viii) water; wherein the formulation is stable between about 5±5° C. and about 25±5° C. for at least 12 months. In some embodiments of a method of treating hypertension, the pharmaceutically acceptable salt of amlodipine is amlodipine benzoate or amlodipine naphthalene sulfonate. In some embodiments of a method of treating hypertension, the amlodipine benzoate or amlodipine naphthalene sulfonate are formed in situ. In some embodiments of a method of treating hypertension, the oral liquid formulation further comprises unreacted salt forming agent. In some embodiments of a method of treating hypertension, the salt forming agent is sodium benzoate. In some embodiments of a method of treating hypertension, the salt forming agent is sodium naphthalene-2-sulfonate. In some embodiments of a method of treating hypertension, the hypertension is primary (essential) hypertension. In some embodiments of a method of treating hypertension, the hypertension is secondary hypertension. In some embodiments of a method of treating hypertension, the subject has blood pressure values greater than or equal to 140/90 mmm Hg. In some embodiments of a method of treating hypertension, the subject is an adult. In some embodiments of a method of treating hypertension, the subject is elderly. In some embodiments of a method of treating hypertension, the subject is a child. In some embodiments of a method of treating hypertension, the formulation is administered to the subject in a fasted state. In some embodiments of a method of treating hypertension, the formulation is administered to the subject in a fed state. In some embodiments of a method of treating hypertension, the formulation is further administered in combination with an agent selected from the group consisting of diuretics, beta blockers, alpha blockers, mixed alpha and beta blockers, calcium channel blockers, angiotensin II receptor antagonists, ACE inhibitors, aldosterone antagonists, and alpha-2 agonists. Also disclosed herein is a method of treating Coronary Artery Disease (CAD) in a subject comprising administering to that subject a therapeutically effective amount of an amlodipine oral liquid formulation comprising: (i) a pharmaceutically acceptable salt of amlodipine in an amount corresponding to 1.0 mg/ml amlodipine freebase; (ii) about 3 mM of a citrate buffer; (iii) about 0.2 mg/ml to about 10 mg/ml of sodium benzoate; (iv) about 0.5 mg/ml of silicon dioxide; (v) about 7.5 mg/ml of hydroxypropyl methylcellulose; (vi) about 0.15 mg/ml simethicone; (vii) optionally about 1.0 mg/ml of polysorbate 80; and (viii) water; wherein the formulation is stable between about 5±5° C. and about 25±5° C. for at least 12 months. In some embodiments of a method of treating Coronary Artery Disease (CAD), the pharmaceutically acceptable salt of amlodipine is amlodipine benzoate or amlodipine naphthalene sulfonate. In some embodiments of a method of treating Coronary Artery Disease (CAD), the amlodipine benzoate or amlodipine naphthalene sulfonate are formed in situ. In some embodiments of a method of treating Coronary Artery Disease (CAD), the oral liquid formulation further comprises unreacted salt forming agent. In some embodiments of a method of treating Coronary Artery Disease (CAD), the salt forming agent is sodium benzoate. In some embodiments of a method of treating Coronary Artery Disease (CAD), the salt forming agent is sodium naphthalene-2-sulfonate. In some embodiments of a method of treating Coronary Artery Disease (CAD), the Coronary Artery Disease (CAD) is chronic stable angina, vasospastic angina, or angiographically documented coronary artery disease. In some embodiments of a method of treating Coronary Artery Disease (CAD), the angiographically documented coronary artery disease is in patients without heart failure or an ejection fraction <40%. In some embodiments of a method of treating Coronary Artery Disease (CAD), the formulation is further administered in combination with an additional anti-anginal agent. INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: FIG. 1 shows the amount of amlodipine remaining in solution over time. FIG. 2 shows the amount of amlodipine in solution for (x) amlodipine besylate and (∘) amlodipine benzoate in the presence of added sodium benzoate. DETAILED DESCRIPTION OF THE INVENTION Provided herein are stable amlodipine oral liquid formulations. These amlodipine formulations described herein are useful for the treatment of hypertension and coronary artery disease. The formulations are advantageous over conventional solid dosage administration of amlodipine ranging from ease of administration, accuracy of dosing, accessibility to additional patient populations such as to children and the elderly, and an increased patient compliance to medication. It is generally known that certain segments of the population have difficulty ingesting and swallowing solid oral dosage forms such as tablets and capsules. As many as a quarter of the total population has this difficulty. Often, this leads to non-compliance with the recommended medical therapy with the solid dosage forms, thereby resulting in rending the therapy ineffective. Further, solid dosage forms are not recommended for children or elderly due to increased risk in choking. Furthermore, the dose of amlodipine to be given to children is calculated according to the child's weight. When the calculated dose is something other than the amount present in one or more intact solid dosage forms, the solid dosage form must be divided to provide the correct dose. This leads to inaccurate dosing when solid dosages forms, such as tablets, are compounded to prepare other formulations for children. For amlodipine, one solution to overcoming the use of the tablet form is for a compounding pharmacist to pulverize and crush the amlodipine tablet(s) into a powder via mortar and pestle and reconstitute the powder in some liquid form. However, forming a amlodipine oral liquid in this fashion has significant drawbacks including large variability in the actual dosage, incomplete solubilizing of the amlodipine tablet in the liquid, rapid instability, inconsistent formulation methods per compounding pharmacy, and a number of other potential issues. The crushed tablet liquid formulation may also be potentially unsafe due to contamination with residual drugs and other substances from the mortar and pestle or other crushing agent. The present embodiments described herein provide a safe and effective oral administration of amlodipine for the treatment of hypertension and other disorders. In particular, the embodiments provide stable amlodipine oral liquid formulations. As used herein, “amlodipine” refers to amlodipine base, its salt, or solvate or derivative or isomer or polymorph thereof. Suitable compounds include the free base, the organic and inorganic salts, isomers, isomer salts, solvates, polymorphs, complexes etc. U.S. Pat. No. 4,572,909, U.S. Pat. No. 4,879,303, U.S. Pat. No. 6,846,931 and WO2002/053134 disclose amlodipine and exemplary amlodipine salt forms. In some embodiments, the amlodipine used in the formulations described herein is a pharmaceutically acceptable amlodipine salt. In some instances, the amlodipine salt is amlodipine benzoate. In other instances, the amlodipine salt is in the form of amlodipine naphthalene sulfonate. Amlodipine Oral Liquid Formulations Oral liquids include, but are not limited to, solutions (both aqueous and nonaqueous), suspensions, emulsions, syrups, slurries, juices, elixirs, dispersions, and the like. It is envisioned that solution/suspensions are also included where certain components described herein are in a solution while other components are in a suspension. In some embodiments, the oral liquid formulation is a suspension. In one aspect, the amlodipine liquid formulations described herein comprise a pharmaceutically acceptable salt of amlodipine, a buffer, water, and optionally one or more agents selected from the group consisting of preservatives, flavoring agents, sweetening agents, surfactants, suspension aids, and antifoaming agents. In one embodiment, the buffer is a citrate buffer. In one embodiment, the buffer comprises citric acid. In some embodiments, the buffer further comprises sodium citrate. In one embodiment, the buffer is a phosphate buffer. In one embodiment, the optional sweetening agent is sucralose. In one embodiment, the optional sweetening agent is a combination of sucralose and maltodextrin. In one embodiment, the optional sweetening agent is not maltitol. In another embodiment, the optional sweetening agent is not sucrose. In another embodiment, the optional preservative is sodium benzoate. In some embodiments, the optional preservative is a paraben. In some embodiments, the optional preservative is a mixture of parabens. In one embodiment, the optional surfactant is a polysorbate. In some embodiments, the optional surfactant is polysorbate 80. In one embodiment, the optional suspension aid is silicon dioxide. In some embodiments, the silicon dioxide is colloidal silicon dioxide. In some embodiments, the optional suspension aid is hydroxypropyl methylcellulose. In some embodiments, the optional suspension aid is a combination of hydroxypropyl methylcellulose and silicon dioxide. In some embodiments, the optional suspension aid is polyvinylpyrrolidone. In some embodiments, the optional suspension aid is methyl cellulose. In one embodiment, the optional antifoaming agent is simethicone. Pharmaceutically Acceptable Salt of Amlodipine in the Oral Liquid Formulations Disclosed herein is a stable amlodipine oral liquid formulation. In some embodiments, the stable amlodipine oral liquid formulation is in the form of a suspension. In some embodiments, the stable amlodipine oral liquid formulation comprises a pharmaceutically acceptable salt of amlodipine which is not soluble in an aqueous media. In some embodiments, the pharmaceutically acceptable salt of amlodipine is amlodipine benzoate or amlodipine naphthalene sulfonate. In some embodiments, amlodipine benzoate or amlodipine naphthalene sulfonate are formed in situ. In some embodiments, amlodipine benzoate or amlodipine naphthalene sulfonate are formed by the reaction of a pharmaceutically acceptable salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate or amlodipine naphthalene sulfonate with a molar excess of a salt forming agent. In some embodiments, the pharmaceutically acceptable salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate or amlodipine naphthalene sulfonate is selected from the group consisting of amlodipine besylate, amlodipine tosylate, amlodipine mesylate, amlodipine succinate, amlodipine salicylate, amlodipine maleate, amlodipine acetate, and amlodipine hydrochloride. In some embodiments, the pharmaceutically acceptable salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate or amlodipine naphthalene sulfonate is amlodipine besylate. In some embodiments, the pharmaceutically acceptable salt of amlodipine is amlodipine benzoate and is formed in situ by the reaction of a pharmaceutically acceptable salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate with a benzoate salt forming agent. In some embodiments, the benzoate salt forming agent is benzoic acid, sodium benzoate, calcium benzoate, or potassium benzoate. In some embodiments, an excess of the benzoate salt forming agent is used to form the benzoate salt in situ. In some embodiments, the benzoate salt forming agent is sodium benzoate. In some embodiments, an excess of sodium benzoate is used to form the benzoate salt in situ. In some embodiments, the amount of sodium benzoate used as the salt forming agent is about 1.0 mg/ml to about 10.0 mg/ml. In some embodiments, the amount of sodium benzoate used as the salt forming agent is about 1.0 mg/ml, about 1.1 mg/ml, about 1.2 mg/ml, about 1.3 mg/ml, about 1.4 mg/ml, about 1.5 mg/ml, about 1.6 mg/ml, about 1.7 mg/ml, about 1.8 mg/ml, about 1.9 mg/ml, about 2.0 mg/ml, about 2.1 mg/ml, about 2.2 mg/ml, about 2.3 mg/ml, about 2.4 mg/ml, about 2.5 mg/ml, about 2.6 mg/ml, about 2.7 mg/ml, about 2.8 mg/ml, about 2.9 mg/ml, about 3.0 mg/ml, about 3.1 mg/ml, about 3.2 mg/ml, about 3.3 mg/ml, about 3.4 mg/ml, about 3.5 mg/ml, about 3.6 mg/ml, about 3.7 mg/ml, about 3.8 mg/ml, about 3.9 mg/ml, about 4.0 mg/ml, about 4.1 mg/ml, about 4.2 mg/ml, about 4.3 mg/ml, about 4.4 mg/ml, about 4.5 mg/ml, about 4.6 mg/ml, about 4.7 mg/ml, about 4.8 mg/ml, about 4.9 mg/ml, about 5.0 mg/ml, about 5.1 mg/ml, about 5.2 mg/ml, about 5.3 mg/ml, about 5.4 mg/ml, about 5.5 mg/ml, about 5.6 mg/ml, about 5.7 mg/ml, about 5.8 mg/ml, about 5.9 mg/ml, about 6.0 mg/ml, about 6.1 mg/ml, about 6.2 mg/ml, about 6.3 mg/ml, about 6.4 mg/ml, about 6.5 mg/ml, about 6.6 mg/ml, about 6.7 mg/ml, about 6.8 mg/ml, about 6.9 mg/ml, about 7.0 mg/ml, about 7.1 mg/ml, about 7.2 mg/ml, about 7.3 mg/ml, about 7.4 mg/ml, about 7.5 mg/ml, about 7.6 mg/ml, about 7.7 mg/ml, about 7.8 mg/ml, about 7.9 mg/ml, about 8.0 mg/ml, about 8.1 mg/ml, about 8.2 mg/ml, about 8.3 mg/ml, about 8.4 mg/ml, about 8.5 mg/ml, about 8.6 mg/ml, about 8.7 mg/ml, about 8.8 mg/ml, about 8.9 mg/ml, about 9.0 mg/ml, about 9.1 mg/ml, about 9.2 mg/ml, about 9.3 mg/ml, about 9.4 mg/ml, about 9.5 mg/ml, about 9.6 mg/ml, about 9.7 mg/ml, about 9.8 mg/ml, about 9.9 mg/ml, or about 10.0 mg/ml. In some embodiments, the pharmaceutically acceptable salt of amlodipine is amlodipine naphthalene sulfonate and is formed in situ by the reaction of a pharmaceutically acceptable salt of amlodipine that is more soluble in aqueous media than amlodipine naphthalene sulfonate with a naphthalene sulfonate salt forming agent. In some embodiments, the naphthalene sulfonate salt forming agent is 1-naphthalene sulfonic acid, 2-naphthalene sulfonic acid, sodium naphthalene-1-sulfonate, sodium naphthalene-2-sulfonate, or potassium naphthalene-2-sulfonate. In some embodiments, an excess of the naphthalene sulfonate salt forming agent is used to form the naphthalene sulfonate salt in situ. In some embodiments, the naphthalene sulfonate salt forming agent is sodium naphthalene-2-sulfonate. In some embodiments, an excess of sodium naphthalene-2-sulfonate is used to form the naphthalene sulfonate salt in situ. In some embodiments, the amount of sodium naphthalene-2-sulfonate used as the salt forming agent is about 0.5 mg/ml to about 2.5 mg/ml. In some embodiments, the amount of sodium naphthalene-2-sulfonate used as the salt forming agent is about 0.5 mg/ml, about 0.6 mg/ml, about 0.7 mg/ml, about 0.8 mg/ml, about 0.9 mg/ml, about 1.0 mg/ml, about 1.1 mg/ml, about 1.2 mg/ml, about 1.3 mg/ml, about 1.4 mg/ml, about 1.5 mg/ml, about 1.6 mg/ml, about 1.7 mg/ml, about 1.8 mg/ml, about 1.9 mg/ml, about 2.0 mg/ml, about 2.1 mg/ml, about 2.2 mg/ml, about 2.3 mg/ml, about 2.4 mg/ml, or about 2.5 mg/ml. In some embodiments, the amount of the pharmaceutically acceptable salt of amlodipine in the oral liquid formulation corresponds to about 0.8 mg/ml to about 1.2 mg/ml of amlodipine free base. In other embodiments, the amount of the pharmaceutically acceptable salt of amlodipine in the oral liquid formulation correspond to about 0.8 mg/ml, about 0.81 mg/ml, about 0.82 mg/ml, about 0.83 mg/ml, about 0.84 mg/ml, about 0.85 mg/ml, about 0.86 mg/ml, about 0.87 mg/ml, about 0.88 mg/ml, about 0.89 mg/ml, about 0.9 mg/ml, about 0.91 mg/ml, about 0.92 mg/ml, about 0.93 mg/ml, about 0.94 mg/ml, about 0.95 mg/ml, about 0.96 mg/ml, about 0.97 mg/ml, about 0.98 mg/ml, about 0.99 mg/ml, about 1.0 mg/ml, about 1.01 mg/ml, about 1.02, mg/ml, about 1.03 mg/ml, about 1.04 mg/ml, about 1.05 mg/ml, about 1.06 mg/ml, about 1.07 mg/ml, about 1.08 mg/ml, about 1.09 mg/ml, about 1.1 mg/ml, about 1.11 mg/ml, about 1.12, mg/ml, about 1.13 mg/ml, about 1.14 mg/ml, about 1.15 mg/ml, about 1.16 mg/ml, about 1.17 mg/ml, about 1.18 mg/ml, about 1.19 mg/ml, or about 1.2 mg/ml of amlodipine free base. In some embodiments, the amount of the pharmaceutically acceptable salt of amlodipine in the oral liquid formulation corresponds to about 0.9 mg/ml to about 1.1 mg/ml of amlodipine free base. In some embodiments, the amount of the pharmaceutically acceptable salt of amlodipine in the oral liquid formulation corresponds to about 1.0 mg/ml of amlodipine free base. In some embodiments, the pharmaceutically acceptable salt of amlodipine is amlodipine benzoate. In some embodiments, the amount of amlodipine benzoate in the oral liquid formulation corresponds to about 1.0 mg/ml of amlodipine free base. In some embodiments, the pharmaceutically acceptable salt of amlodipine is amlodipine naphthalene sulfonate. In some embodiments, the amount of amlodipine naphthalene sulfonate in the oral liquid formulation corresponds to about 1.0 mg/ml of amlodipine free base. In some embodiments, the amount of the pharmaceutically acceptable salt of amlodipine corresponds to about 1% w/w to about 16% w/w of the solids in the oral liquid formulation. In other embodiments, the amount of the pharmaceutically acceptable salt of amlodipine correspond to about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, about 6% w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w, about 6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, about 6.9% w/w, about 7% w/w, about 7.1% w/w, about 7.2% w/w, about 7.3% w/w, about 7.4% w/w, about 7.5% w/w, about 7.6% w/w, about 7.7% w/w, about 7.8% w/w, about 7.9% w/w, about 8% w/w, about 8.1% w/w, about 8.2% w/w, about 8.3% w/w, about 8.4% w/w, about 8.5% w/w, about 8.6% w/w, about 8.7% w/w, about 8.8% w/w, about 8.9% w/w, about 9% w/w, about 9.1% w/w, about 9.2% w/w, about 9.3% w/w, about 9.4% w/w, about 9.5% w/w, about 9.6% w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, about 10% w/w, about 10.1% w/w, about 10.2% w/w, about 10.3% w/w, about 10.4% w/w, about 10.5% w/w, about 10.6% w/w, about 10.7% w/w, about 10.8% w/w, about 10.9% w/w, about 11% w/w, about 11.1% w/w, about 11.2% w/w, about 11.3% w/w, about 11.4% w/w, about 11.5% w/w, about 11.6% w/w, about 11.7% w/w, about 11.8% w/w, about 11.9% w/w, about 12% w/w, about 12.1% w/w, about 12.2% w/w, about 12.3% w/w, about 12.4% w/w, about 12.5% w/w, about 12.6% w/w, about 12.7% w/w, about 12.8% w/w, about 12.9% w/w, about 13% w/w, about 13.1% w/w, about 13.2% w/w, about 13.3% w/w, about 13.4% w/w, about 13.5% w/w, about 13.6% w/w, about 13.7% w/w, about 13.8% w/w, about 13.9% w/w, about 14% w/w, about 14.1% w/w, about 14.2% w/w, about 14.3% w/w, about 14.4% w/w, about 14.5% w/w, about 14.6% w/w, about 14.7% w/w, about 14.8% w/w, about 14.9% w/w, about 15% w/w, about 15.1% w/w, about 15.2% w/w, about 15.3% w/w, about 15.4% w/w, about 15.5% w/w, about 15.6% w/w, about 15.7% w/w, about 15.8% w/w, about 15.9% w/w, or about 16% w/w of the solids in the oral liquid formulation. Sweetener in the Amlodipine Oral Liquid Formulations Sweeteners or sweetening agents include any compounds that provide a sweet taste. This includes natural and synthetic sugars, natural and artificial sweeteners, natural extracts and any material that initiates a sweet sensation in a subject. In some embodiments, a solid/powder sweetener is used in the oral liquid formulation described herein. In other embodiments, a liquid sweetening agent is used in the oral liquid formulation described herein. Sweetening agents illustratively include glucose, fructose, sucrose, xylitol, tagatose, sucralose, maltitol, isomaltulose, Isomalt™ (hydrogenated isomaltulose), lactitol, sorbitol, erythritol, trehalose, maltodextrin, polydextrose, and the like. Other sweetening agents illustratively include glycerin, inulin, maltol, acesulfame and salts thereof, e.g., acesulfame potassium, alitame, aspartame, neotame, sodium cyclamate, saccharin and salts thereof, e.g., saccharin sodium or saccharin calcium, neohesperidin dihydrochalcone, stevioside, thaumatin, and the like. Sweetening agents can be used in the form of crude or refined products such as hydrogenated starch hydrolysates, maltitol syrup, high fructose corn syrup, etc., and as branded products, e.g., Sweet Am™ liquid (propylene glycol, ethyl alcohol, and proprietary artificial flavor combination, Flavors of North America), Sweet Am™ powder (Product Code 918.005—maltodextrin, sorbitol, and fructose combination and Product Code 918.010—water, propylene glycol, sorbitol, fructose, and proprietary natural and artificial flavor combination, Flavors of North America), ProSweet™ (1-10% proprietary plant/vegetable extract and 90-99% dextrose combination, Virginia Dare), Maltisweet™ (maltitol solution, Ingredion), Sorbo™ (sorbitol and sorbitol/xylitol solution, SPI Polyols), Invertose™ (high fructose corn syrup, Ingredion), Rebalance M60 and X60 (sucralose and maltodextrin, Tate and Lyle), and Ora-Sweet® and Ora-Sweet-SF®, sugar containing and sugar-free, respectively flavored syrups (Paddock Laboratories, Inc.). Sweetening agents can be used singly or in combinations of two or more. Suitable concentrations of different sweetening agents can be selected based on published information, manufacturers' data sheets and by routine testing. In some embodiments, the amlodipine oral liquid formulation described herein comprises a sweetening agent. In some embodiments, the sweetening agent is sucralose. In some embodiments, the sweetening agent is a combination of sucralose and maltodextrin. In some embodiments, the sweetener is not maltitol. In some embodiments, the sweetener is not sucrose. In some embodiments, the sweetening agent is present in about 0.5 mg/ml to about 0.9 mg/ml in the oral liquid formulation. In other embodiments, the sweetening agent is present in about 0.51 mg/ml, about 0.52 mg/ml, about 0.53 mg/ml, about 0.54 mg/ml, about 0.55 mg/ml, about 0.56 mg/ml, about 0.57 mg/ml, about 0.58 mg/ml, about 0.59 mg/ml, about 0.60 mg/ml, about 0.61 mg/ml, about 0.62 mg/ml, about 0.63 mg/ml, about 0.64 mg/ml, about 0.65 mg/ml, about 0.66 mg/ml, about 0.67 mg/ml, about 0.68 mg/ml, about 0.69 mg/ml, about 0.70 mg/ml, about 0.71 mg/ml, about 0.72 mg/ml, about 0.73 mg/ml, about 0.74 mg/ml, about 0.75 mg/ml, about 0.76 mg/ml, about 0.77 mg/ml, about 0.78 mg/ml, about 0.79 mg/ml, about 0.80 mg/ml, about 0.81 mg/ml, about 0.82 mg/ml, about 0.83 mg/ml, about 0.84 mg/ml, about 0.85 mg/ml, about 0.86 mg/ml, about 0.87 mg/ml, about 0.88 mg/ml, about 0.89 mg/ml, or about 0.90 mg/ml in the oral liquid formulation. In some embodiments, the sweetening agent is present in about 0.6 mg/ml to about 0.8 mg/ml in the oral liquid formulation. In some embodiments, the sweetening agent is sucralose and is present in about 0.7 mg/ml in the oral liquid formulation. In some embodiments, the sweetening agent is present in about 1% w/w to about 10% w/w of the solids in the oral liquid formulation. In some embodiments, the sweetening agent is present in about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, about 6% w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w, about 6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, about 6.9% w/w, about 7% w/w, about 7.1% w/w, about 7.2% w/w, about 7.3% w/w, about 7.4% w/w, about 7.5% w/w, about 7.6% w/w, about 7.7% w/w, about 7.8% w/w, about 7.9% w/w, about 8% w/w, about 8.1% w/w, about 8.2% w/w, about 8.3% w/w, about 8.4% w/w, about 8.5% w/w, about 8.6% w/w, about 8.7% w/w, about 8.8% w/w, about 8.9% w/w, about 9% w/w, about 9.1% w/w, about 9.2% w/w, about 9.3% w/w, about 9.4% w/w, about 9.5% w/w, about 9.6% w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, or about 10% w/w of the solids in the oral liquid formulation. Preservative in the Amlodipine Oral Liquid Formulations Preservatives include anti-microbials, anti-oxidants, and agents that enhance sterility. Exemplary preservatives include ascorbic acid, ascorbyl palmitate, BHA, BHT, citric acid, EDTA and its salts, erythorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite, parabens (such as methylparaben, ethylparaben, propylparaben, butylparaben and their salts), benzoic acid, sodium benzoate, potassium sorbate, vanillin, and the like. In some embodiments, the amlodipine oral liquid formulation described herein comprises a preservative. In some embodiments, the preservative is a paraben, or a mixture of parabens and the sweetener is a sugar (such as, but not limited to glucose, fructose, sucrose, lactose, maltose) or a sugar alcohol (such as, but not limited to xylitol, mannitol, lactitol, maltitol, sorbitol). In some embodiments, the preservative is a paraben, or a mixture of parabens and the sweetener is not a sugar or a sugar alcohol. In some embodiments, the preservative is present in an amount sufficient to provide antimicrobial effectiveness to the amlodipine oral liquid formulation described herein. In some embodiments, the amount of preservative sufficient to provide antimicrobial effectiveness is between about 0.1 mg/ml and about 2.0 mg/ml. In other embodiments, the amount of preservative sufficient to provide antimicrobial effectiveness is about 0.1 mg/ml, about 0.11 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml, about 0.14 mg/ml, about 0.15 mg/ml, about 0.16 mg/ml, about 0.17 mg/ml, about 0.18 mg/ml, about 0.19 mg/ml, about 0.2 mg/ml, about 0.21 mg/ml, about 0.22 mg/ml, about 0.23 mg/ml, about 0.24 mg/ml, about 0.25 mg/ml, about 0.26 mg/ml, about 0.27 mg/ml, about 0.28 mg/ml, about 0.29 mg/ml, about 0.3 mg/ml, about 0.31 mg/ml, about 0.32 mg/ml, about 0.33 mg/ml, about 0.34 mg/ml, about 0.35 mg/ml, about 0.36 mg/ml, about 0.37 mg/ml, about 0.38 mg/ml, about 0.39 mg/ml, about 0.4 mg/ml, about 0.41 mg/ml, about 0.42 mg/ml, about 0.43 mg/ml, about 0.44 mg/ml, about 0.45 mg/ml, about 0.46 mg/ml, about 0.47 mg/ml, about 0.48 mg/ml, about 0.49 mg/ml, about 0.5 mg/ml, about 0.51 mg/ml, about 0.52 mg/ml, about 0.53 mg/ml, about 0.54 mg/ml, about 0.55 mg/ml, about 0.56 mg/ml, about 0.57 mg/ml, about 0.58 mg/ml, about 0.59 mg/ml, about 0.6 mg/ml, about 0.61 mg/ml, about 0.62 mg/ml, about 0.63 mg/ml, about 0.64 mg/ml, about 0.65 mg/ml, about 0.66 mg/ml, about 0.67 mg/ml, about 0.68 mg/ml, about 0.69 mg/ml, about 0.7 mg/ml, about 0.71 mg/ml, about 0.72 mg/ml, about 0.73 mg/ml, about 0.74 mg/ml, about 0.75 mg/ml, about 0.76 mg/ml, about 0.77 mg/ml, about 0.78 mg/ml, about 0.79 mg/ml, about 0.8 mg/ml, about 0.81 mg/ml, about 0.82 mg/ml, about 0.83 mg/ml, about 0.84 mg/ml, about 0.85 mg/ml, about 0.86 mg/ml, about 0.87 mg/ml, about 0.88 mg/ml, about 0.89 mg/ml, about 0.9 mg/ml, about 0.91 mg/ml, about 0.92 mg/ml, about 0.93 mg/ml, about 0.94 mg/ml, about 0.95 mg/ml, about 0.96 mg/ml, about 0.97 mg/ml, about 0.98 mg/ml, about 0.99 mg/ml, about 1.0 mg/ml, about 1.1 mg/ml, about 1.2 mg/ml, about 1.3 mg/ml, about 1.4 mg/ml, about 1.5 mg/ml, about 1.6 mg/ml, about 1.7 mg/ml, about 1.8 mg/ml, about 1.9 mg/ml, or about 2.0 mg/ml. In some embodiments, the preservative is sodium benzoate and the amount of sodium benzoate sufficient to provide antimicrobial effectiveness is between about 0.2 mg/ml and about 1.0 mg/ml. In some embodiments, the preservative is methyl paraben and the amount of methyl paraben sufficient to provide antimicrobial effectiveness is between about 1.0 mg/ml and about 2.0 mg/ml. In some embodiments, the preservative is propyl paraben and the amount of propyl paraben sufficient to provide antimicrobial effectiveness is between about 0.1 mg/ml and about 0.2 mg/ml. In some embodiments, the preservative is present in about 0.5% w/w to about 15% w/w of the solids in the oral liquid formulation. In other embodiments, the preservative is present in about 0.5% w/w, about 1% w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, about 5% w/w, about 5.5% w/w, about 6% w/w, about 6.5% w/w, about 7% w/w, about 7.5% w/w, about 8% w/w, about 8.5% w/w, about 9% w/w, about 9.5% w/w, about 10% w/w, about 11% w/w, about 11.5% w/w, about 12% w/w, about 12.5% w/w, about 13% w/w, about 13.5% w/w, about 14% w/w, about 14.5% w/w, or about 15% w/w of the solids in the oral liquid formulation. Sweetener and Preservative Incompatibility Paraben preservatives (especially methylparaben) can react with selected sugars (glucose, fructose, sucrose, lactose, maltose) and sugar alcohols (xylitol, mannitol, lactitol, maltitol, sorbitol) to form transesterification reaction products. This can be undesirable from a formulation and stability standpoint as the transesterification creates additional degradants. In some embodiments, the amlodipine oral liquid formulation described herein does not comprise a paraben preservative. In further embodiments, the amlodipine oral liquid formulation described herein does not comprise a paraben preservative when the formulation also comprises a sugar or sugar alcohol. Buffers in the Amlodipine Oral Liquid Formulations Buffering agents maintain the pH of the liquid amlodipine formulation. Non-limiting examples of buffering agents include, but are not limited to sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminum hydroxide/sodium bicarbonate co-precipitate, mixture of an amino acid and a buffer, a mixture of aluminum glycinate and a buffer, a mixture of an acid salt of an amino acid and a buffer, and a mixture of an alkali salt of an amino acid and a buffer. Additional buffering agents include citric acid, sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, phosphoric acid, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts. In some embodiments, the oral liquid formulation comprises a buffer. In some embodiments, the oral liquid formulation comprises a citrate buffer. In some embodiments, the buffer in the amlodipine oral liquid formulation described herein comprises citric acid. In some embodiments, the buffer in the amlodipine oral liquid formulation described herein comprises citric acid and sodium citrate. In some embodiments, the sodium citrate is monosodium citrate. In some embodiments, the sodium citrate is disodium citrate. In some embodiments, the sodium citrate is trisodium citrate. In some embodiments, the oral liquid formulation comprises a phosphate buffer. In some embodiments, the buffer in the amlodipine oral liquid formulation described herein comprises phosphoric acid. In some embodiments, the buffer in the amlodipine oral liquid formulation described herein comprises phosphoric acid and sodium phosphate. In some embodiments, the buffer in the amlodipine oral liquid formulation described herein comprises sodium phosphate. In some embodiments, the sodium phosphate is sodium dihydrogen phosphate. In some embodiments, the sodium phosphate is sodium hydrogenphosphate. In some embodiments, the sodium phosphate is trisodium phosphate. In some embodiments, the pH of the amlodipine oral liquid formulation described herein is between about 3 and about 8. In some embodiments, the pH of the amlodipine oral liquid formulation described herein is between about 4 and about 5. In some embodiments, the pH of the amlodipine oral liquid formulation described herein is between about 5 and about 6. In some embodiments, the pH of the amlodipine oral liquid formulation described herein is less than about 4, less than about 4.5, less than about 5, less than about 5.5, less than about 6, less than about 6.5, less than about 7, less than about 7.5, or less than about 8. In some embodiments, the pH of the amlodipine oral liquid formulation described herein is about 3, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, or about 8. In some embodiments, the buffer concentration is between about 1 mM and about 60 mM. In some embodiments, the buffer concentration is about 1 mM, about 1.5 mM, about 2 mM, about 2.5 mM, about 3 mM, about 3.5 mM, about 4 mM, about 4.5 mM, about 5 mM, about 5.5 mM, about 6 mM, about 6.5 mM, about 7 mM, about 7.5 mM, about 8 mM, about 8.5 mM, about 9 mM, about 9.5 mM, about 10 mM, about 10.5 mM, about 11 mM, about 11.5 mM, about 12 mM, about 12.5 mM, about 13 mM, about 13.5 mM, about 14 mM, about 14.5 mM, about 15 mM, about 15.5 mM, about 16 mM, about 16.5 mM, about 17 mM, about 17.5 mM, about 18 mM, about 18.5 mM, about 19 mM, about 19.5 mM, about 20 mM, about 20.5 mM, about 21 mM, about 21.5 mM, about 22 mM, about 22.5 mM, about 23 mM, about 23.5 mM, about 24 mM, about 24.5 mM, about 25 mM, about 25.5 mM, about 26 mM, about 26.5 mM, about 27 mM, about 27.5 mM, about 28 mM, about 28.5 mM, about 29 mM, about 29.5 mM, about 30 mM, about 30.5 mM, about 31 mM, about 31.5 mM, about 32 mM, about 32.5 mM, about 33 mM, about 33.5 mM, about 34 mM, about 34.5 mM, about 35 mM, about 35.5 mM, about 36 mM, about 36.5 mM, about 37 mM, about 37.5 mM, about 38 mM, about 38.5 mM, about 39 mM, about 39.5 mM, about 40 mM, about 40.5 mM, about 41 mM, about 41.5 mM, about 42 mM, about 42.5 mM, about 43 mM, about 43.5 mM, about 44 mM, about 44.5 mM, about 45 mM, about 45.5 mM, about 46 mM, about 46.5 mM, about 47 mM, about 47.5 mM, about 48 mM, about 48.5 mM, about 49 mM, about 49.5 mM, about 50 mM, about 50.5 mM, about 51 mM, about 51.5 mM, about 52 mM, about 52.5 mM, about 53 mM, about 53.5 mM, about 54 mM, about 54.5 mM, about 55 mM, about 55.5 mM, about 56 mM, about 56.5 mM, about 57 mM, about 57.5 mM, about 58 mM, about 58.5 mM, about 59 mM, about 59.5 mM, or about 60 mM. In some embodiments, the buffer concentration is between about 1 mM and about 5 mM, or about 2 mM and about 4 mM. In some embodiments, the buffer concentration is about 3 mM. In some embodiments, the buffer in the amlodipine oral liquid formulation described herein comprises citric acid. In some embodiments, citric acid is present in about 0.1 mg/ml to about 1.0 mg/ml in the oral liquid formulation. In other embodiments, citric acid is present in about 0.1 mg/ml, about 0.11 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml, about 0.14 mg/ml, about 0.15 mg/ml, about 0.16 mg/ml, about 0.17 mg/ml, about 0.18 mg/ml, about 0.19 mg/ml, about 0.2 mg/ml, about 0.21 mg/ml, about 0.22 mg/ml, about 0.23 mg/ml, about 0.24 mg/ml, about 0.25 mg/ml, about 0.26 mg/ml, about 0.27 mg/ml, about 0.28 mg/ml, about 0.29 mg/ml, about 0.3 mg/ml, about 0.31 mg/ml, about 0.32 mg/ml, about 0.33 mg/ml, about 0.34 mg/ml, about 0.35 mg/ml, about 0.36 mg/ml, about 0.37 mg/ml, about 0.38 mg/ml, about 0.39 mg/ml, about 0.4 mg/ml, about 0.41 mg/ml, about 0.42 mg/ml, about 0.43 mg/ml, about 0.44 mg/ml, about 0.45 mg/ml, about 0.46 mg/ml, about 0.47 mg/ml, about 0.48 mg/ml, about 0.49 mg/ml, about 0.5 mg/ml, about 0.51 mg/ml, about 0.52 mg/ml, about 0.53 mg/ml, about 0.54 mg/ml, about 0.55 mg/ml, about 0.56 mg/ml, about 0.57 mg/ml, about 0.58 mg/ml, about 0.59 mg/ml, about 0.6 mg/ml, about 0.61 mg/ml, about 0.62 mg/ml, about 0.63 mg/ml, about 0.64 mg/ml, about 0.65 mg/ml, about 0.66 mg/ml, about 0.67 mg/ml, about 0.68 mg/ml, about 0.69 mg/ml, about 0.7 mg/ml, about 0.71 mg/ml, about 0.72 mg/ml, about 0.73 mg/ml, about 0.74 mg/ml, about 0.75 mg/ml, about 0.76 mg/ml, about 0.77 mg/ml, about 0.78 mg/ml, about 0.79 mg/ml, about 0.8 mg/ml, about 0.81 mg/ml, about 0.82 mg/ml, about 0.83 mg/ml, about 0.84 mg/ml, about 0.85 mg/ml, about 0.86 mg/ml, about 0.87 mg/ml, about 0.88 mg/ml, about 0.89 mg/ml, about 0.9 mg/ml, about 0.91 mg/ml, about 0.92 mg/ml, about 0.93 mg/ml, about 0.94 mg/ml, about 0.95 mg/ml, about 0.96 mg/ml, about 0.97 mg/ml, about 0.98 mg/ml, about 0.99 mg/ml, or about 1.0 mg/ml in the oral liquid formulation. In one embodiment, citric acid is present in about 0.31 mg/ml in the oral liquid formulation. In some embodiments, citric acid is present in about 5.0 mg/ml to about 15 mg/ml in the oral liquid formulation. In other embodiments, citric acid is present in about 5.0 mg/ml, about 5.5 mg/ml, about 6.0 mg/ml, about 6.5 mg/ml, about 7.0 mg/ml, about 7.5 mg/ml, about 8.0 mg/ml, about 8.5 mg/ml, about 9.0 mg/ml, about 9.5 mg/ml, about 10.0 mg/ml, about 10.5 mg/ml, about 11.0 mg/ml, about 11.5 mg/ml, about 12.0 mg/ml, about 12.5 mg/ml, about 13.0 mg/ml, about 13.5 mg/ml, about 14.0 mg/ml, about 14.5 mg/ml, or about 15.0 mg/ml in the oral liquid formulation. In some embodiments, citric acid is present in about 1% w/w to about 45% w/w of the solids in the oral liquid formulation. In other embodiments, citric acid is present in about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, about 15% w/w, about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, about 20% w/w, about 21% w/w, about 22% w/w, about 23% w/w, about 24% w/w, about 25% w/w, about 26% w/w, about 27% w/w, about 28% w/w, about 29% w/w, about 30% w/w, about 31% w/w, about 32% w/w, about 33% w/w, about 34% w/w, about 35% w/w, about 36% w/w, about 37% w/w, about 38% w/w, about 39% w/w, about 40% w/w, about 41% w/w, about 42% w/w, about 43% w/w, about 44% w/w, or about 45% w/w of the solids in the oral liquid formulation. In some embodiments, citric acid is present in about 1% w/w to about 20% w/w of the solids in the oral liquid formulation. In some embodiments, citric acid is present in about 1% w/w to about 1.5% w/w of the solids in the oral liquid formulation. In some embodiments, the amlodipine oral liquid formulation further comprises sodium citrate. In some embodiments, sodium citrate is present in about 0.1 mg/ml to about 1.0 mg/ml in the oral liquid formulation. In other embodiments, sodium citrate is present in the oral liquid formulation is about 0.1 mg/ml, about 0.11 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml, about 0.14 mg/ml, about 0.15 mg/ml, about 0.16 mg/ml, about 0.17 mg/ml, about 0.18 mg/ml, about 0.19 mg/ml, about 0.2 mg/ml, about 0.21 mg/ml, about 0.22 mg/ml, about 0.23 mg/ml, about 0.24 mg/ml, about 0.25 mg/ml, about 0.26 mg/ml, about 0.27 mg/ml, about 0.28 mg/ml, about 0.29 mg/ml, about 0.3 mg/ml, about 0.31 mg/ml, about 0.32 mg/ml, about 0.33 mg/ml, about 0.34 mg/ml, about 0.35 mg/ml, about 0.36 mg/ml, about 0.37 mg/ml, about 0.38 mg/ml, about 0.39 mg/ml, about 0.4 mg/ml, about 0.41 mg/ml, about 0.42 mg/ml, about 0.43 mg/ml, about 0.44 mg/ml, about 0.45 mg/ml, about 0.46 mg/ml, about 0.47 mg/ml, about 0.48 mg/ml, about 0.49 mg/ml, about 0.5 mg/ml, about 0.51 mg/ml, about 0.52 mg/ml, about 0.53 mg/ml, about 0.54 mg/ml, about 0.55 mg/ml, about 0.56 mg/ml, about 0.57 mg/ml, about 0.58 mg/ml, about 0.59 mg/ml, about 0.6 mg/ml, about 0.61 mg/ml, about 0.62 mg/ml, about 0.63 mg/ml, about 0.64 mg/ml, about 0.65 mg/ml, about 0.66 mg/ml, about 0.67 mg/ml, about 0.68 mg/ml, about 0.69 mg/ml, about 0.7 mg/ml, about 0.71 mg/ml, about 0.72 mg/ml, about 0.73 mg/ml, about 0.74 mg/ml, about 0.75 mg/ml, about 0.76 mg/ml, about 0.77 mg/ml, about 0.78 mg/ml, about 0.79 mg/ml, about 0.8 mg/ml, about 0.81 mg/ml, about 0.82 mg/ml, about 0.83 mg/ml, about 0.84 mg/ml, about 0.85 mg/ml, about 0.86 mg/ml, about 0.87 mg/ml, about 0.88 mg/ml, about 0.89 mg/ml, about 0.9 mg/ml, about 0.91 mg/ml, about 0.92 mg/ml, about 0.93 mg/ml, about 0.94 mg/ml, about 0.95 mg/ml, about 0.96 mg/ml, about 0.97 mg/ml, about 0.98 mg/ml, about 0.99 mg/ml, or about 1.0 mg/ml in the oral liquid formulation. In one embodiment, sodium citrate is present in about 0.36 mg/ml in the oral liquid formulation. In some embodiments, sodium citrate is present in about 1% w/w to about 20% w/w of the solids in the oral liquid formulation. In other embodiments, sodium citrate is present in about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, about 15% w/w, about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, or about 20% w/w of the solids in the oral liquid formulation. In some embodiments, sodium citrate is present in about 1% w/w to about 2% w/w of the solids in the oral liquid formulation. In other embodiments, sodium citrate is not added to the formulation. In some embodiments, the buffer in the amlodipine oral liquid formulation described herein comprises phosphoric acid. In some embodiments, phosphoric acid is present in about 0.1 mg/ml to about 2.0 mg/ml in the oral liquid formulation. In other embodiments, phosphoric acid is present in about 0.1 mg/ml, about 0.15 mg/ml, about 0.2 mg/ml, about 0.25 mg/ml, about 0.3 mg/ml, about 0.35 mg/ml, 0.4 mg/ml, about 0.45 mg/ml, about 0.5 mg/ml, about 0.55 mg/ml, about 0.6 mg/ml, about 0.65 mg/ml, about 0.7 mg/ml, about 0.75 mg/ml, about 0.8 mg/ml, about 0.85 mg/ml, about 0.9 mg/ml, about 0.95 mg/ml, about 1.0 mg/ml, about 1.1 mg/ml, about 1.15 mg/ml, about 1.2 mg/ml, about 1.25 mg/ml, about 1.3 mg/ml, about 1.35 mg/ml, about 1.4 mg/ml, about 1.45 mg/ml, about 1.5 mg/ml, about 1.55 mg/ml, about 1.6 mg/mL, about 1.65 mg/mL, about 1.7 mg/ml, about 1.75 mg/ml, about 1.8 mg/ml, about 1.85 mg/ml, about 1.9 mg/ml, about 1.95 mg/ml, or about 2.0 mg/ml in the oral liquid formulation. In some embodiments, phosphoric acid is present in about 1% w/w to about 10% w/w of the solids in the oral liquid formulation. In other embodiments, citric acid is present in about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, about 6% w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w, about 6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, about 6.9% w/w, about 7% w/w, about 7.1% w/w, about 7.2% w/w, about 7.3% w/w, about 7.4% w/w, about 7.5% w/w, about 7.6% w/w, about 7.7% w/w, about 7.8% w/w, about 7.9% w/w, about 8% w/w, about 8.1% w/w, about 8.2% w/w, about 8.3% w/w, about 8.4% w/w, about 8.5% w/w, about 8.6% w/w, about 8.7% w/w, about 8.8% w/w, about 8.9% w/w, about 9% w/w, about 9.1% w/w, about 9.2% w/w, about 9.3% w/w, about 9.4% w/w, about 9.5% w/w, about 9.6% w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, or about 10% w/w of the solids in the oral liquid formulation. In some embodiments, the buffer in the amlodipine oral liquid formulation described herein comprises sodium hydrogenphosphate. In some embodiments, sodium hydrogenphosphate is present in about 0.1 mg/ml to about 1.0 mg/ml in the oral liquid formulation. In other embodiments, sodium hydrogenphosphate is present in the oral liquid formulation is about 0.1 mg/mL, about 0.11 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml, about 0.14 mg/ml, about 0.15 mg/ml, about 0.16 mg/ml, about 0.17 mg/ml, about 0.18 mg/ml, about 0.19 mg/ml, about 0.2 mg/ml, about 0.21 mg/ml, about 0.22 mg/ml, about 0.23 mg/ml, about 0.24 mg/ml, about 0.25 mg/ml, about 0.26 mg/ml, about 0.27 mg/ml, about 0.28 mg/ml, about 0.29 mg/ml, about 0.3 mg/ml, about 0.31 mg/ml, about 0.32 mg/ml, about 0.33 mg/ml, about 0.34 mg/ml, about 0.35 mg/ml, about 0.36 mg/ml, about 0.37 mg/ml, about 0.38 mg/ml, about 0.39 mg/ml, about 0.4 mg/ml, about 0.41 mg/ml, about 0.42 mg/ml, about 0.43 mg/ml, about 0.44 mg/ml, about 0.45 mg/ml, about 0.46 mg/ml, about 0.47 mg/ml, about 0.48 mg/ml, about 0.49 mg/ml, about 0.5 mg/ml, about 0.51 mg/ml, about 0.52 mg/ml, about 0.53 mg/ml, about 0.54 mg/ml, about 0.55 mg/ml, about 0.56 mg/ml, about 0.57 mg/ml, about 0.58 mg/ml, about 0.59 mg/ml, about 0.6 mg/ml, about 0.61 mg/ml, about 0.62 mg/ml, about 0.63 mg/ml, about 0.64 mg/ml, about 0.65 mg/ml, about 0.66 mg/ml, about 0.67 mg/ml, about 0.68 mg/ml, about 0.69 mg/ml, about 0.7 mg/ml, about 0.71 mg/ml, about 0.72 mg/ml, about 0.73 mg/ml, about 0.74 mg/ml, about 0.75 mg/ml, about 0.76 mg/ml, about 0.77 mg/ml, about 0.78 mg/ml, about 0.79 mg/ml, about 0.8 mg/ml, about 0.81 mg/ml, about 0.82 mg/ml, about 0.83 mg/ml, about 0.84 mg/ml, about 0.85 mg/ml, about 0.86 mg/ml, about 0.87 mg/ml, about 0.88 mg/ml, about 0.89 mg/ml, about 0.9 mg/ml, about 0.91 mg/ml, about 0.92 mg/ml, about 0.93 mg/ml, about 0.94 mg/ml, about 0.95 mg/ml, about 0.96 mg/ml, about 0.97 mg/ml, about 0.98 mg/ml, about 0.99 mg/ml, or about 1.0 mg/ml in the oral liquid formulation. In some embodiments, sodium hydrogenphosphate is present in about 0.5% w/w to about 5% w/w of the solids in the oral liquid formulation. In other embodiments, sodium hydrogenphosphate is present in about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, or about 5% w/w of the solids in the oral liquid formulation. Suspension Aid in the Amlodipine Oral Liquid Formulations A suspension aid or dispersion aid is used to prevent the settling of the pharmaceutically acceptable salt of amlodipine in the oral liquid formulation. Suitable suspension aids include but not limited to polymers such as 3-butoxy-2-hydroxypropylhydroxyethylcellulose, acrylamide homo- and copolymers, acrylic acid homo- and copolymer, alginates, carboxymethylcellulose (sodium and other salts), carboxymethylhydroxyethylcellulose, carboxy-vinyl copolymers, cellulose, such as microcrystalline cellulose, combinations of microcrystalline cellulose with carboxymethylcellulose sodium (such as Avicel RC-501, RC-581, RC-591, and CL-611), hydrophobically modified hydroxyethylcellulose, hydroxyethylcellulose, hydroxypropyl guar, hydroxypropyl methylcellulose (such as Benecel K750 ® or Benecel K1500®), hydroxypropylcellulose, methyl cellulose, natural gums and their derivatives, xanthan gum, guar gum, gum Arabic, partially and fully hydrolyzed polyvinyl alcohols, partially neutralized polyacrylic acid, polyalkylene glycol, polysaccharide gums, polyvinylpyrrolidone and derivatives thereof, starch and its derivatives, vinylpyrrolidone homo- and copolymers, water-soluble cellulose ethers, and the mixtures thereof. Other suitable suspension aids include silicon dioxide, silica powder prepared by precipitating water glass (sodium silicate) with sulfuric acid, which is then dried and sold as a fine powder, fumed alumina (made of primary particles which sinter together to form aggregates), clays such as bentonite, laponites, kaolinite, dickite, and nacrite, pyrophylite, talc, vermiculite, sauconite, saponte, nontronite, and montmorillonite, and organically modified montmorillonite clays. In some embodiments, the suspension aid comprises silicon dioxide. In some embodiment, the silicon dioxide is colloidal silicon dioxide. In some embodiments, the amlodipine oral liquid formulation described herein comprises a suspension aid. In some embodiments, the suspension aid comprises silicon dioxide, hydroxypropyl methylcellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, or combinations thereof. In some embodiments, the suspension aid is silicon dioxide. In some embodiments, the suspension aid is hydroxypropyl methylcellulose. In some embodiments, the suspension aid is a combination of silicon dioxide and hydroxypropyl methylcellulose. In some embodiments, the suspension aid is polyvinylpyrrolidone. In some embodiments, the suspension aid is present in about 0.1 mg/ml to about 1.0 mg/ml in the oral liquid formulation. In other embodiments, the suspension aid is present in about 0.1 mg/ml, about 0.15 mg/ml, about 0.2 mg/ml, about 0.25 mg/ml, about 0.3 mg/ml, about 0.35 mg/ml, about 0.4 mg/ml, about 0.45 mg/ml, about 0.5 mg/ml, about 0.55 mg/ml, about 0.6 mg/ml, about 0.65 mg/ml, about 0.7 mg/ml, about 0.75 mg/ml, about 0.8 mg/ml, about 0.85 mg/ml, about 0.9 mg/ml, about 0.95 mg/ml, or about 1.0 mg/ml in the oral liquid formulation. In some embodiments, the suspension aid is present in about 0.3 mg/ml to about 0.7 mg/ml in the oral liquid formulation. In some embodiments, the suspension aid is present in about 0.4 mg/ml to about 0.6 mg/ml in the oral liquid formulation. In some embodiments, the suspension aid is silicon dioxide and is present in about 0.5 mg/ml in the oral liquid formulation. In some embodiments, the suspension aid is present in about 3.0 mg/ml to about 10.0 mg/ml in the oral liquid formulation. In other embodiments, the suspension aid is present in about 3.0 mg/ml, about 3.1 mg/ml, about 3.2 mg/ml, about 3.3 mg/ml, about 3.4 mg/ml, about 3.5 mg/ml, about 3.6 mg/ml, about 3.7 mg/ml, about 3.8 mg/ml, about 3.9 mg/ml, about 4.0 mg/ml, about 4.1 mg/ml, about 4.2 mg/ml, about 4.3 mg/ml, about 4.4 mg/ml, about 4.5 mg/ml, about 4.6 mg/ml, about 4.7 mg/ml, about 4.8 mg/ml, about 4.9 mg/ml, about 5.0 mg/ml, about 5.1 mg/ml, about 5.2 mg/ml, about 5.3 mg/ml, about 5.4 mg/ml, about 5.5 mg/ml, about 5.6 mg/ml, about 5.7 mg/ml, about 5.8 mg/ml, about 5.9 mg/ml, about 6.0 mg/ml, about 6.1 mg/ml, about 6.2 mg/ml, about 6.3 mg/ml, about 6.4 mg/ml, about 6.5 mg/ml, about 6.6 mg/ml, about 6.7 mg/ml, about 6.8 mg/ml, about 6.9 mg/ml, about 7.0 mg/ml, about 7.1 mg/ml, about 7.2 mg/ml, about 7.3 mg/ml, about 7.4 mg/ml, about 7.5 mg/ml, about 7.6 mg/ml, about 7.7 mg/ml, about 7.8 mg/ml, about 7.9 mg/ml, about 8.0 mg/ml, about 8.1 mg/ml, about 8.2 mg/ml, about 8.3 mg/ml, about 8.4 mg/ml, about 8.5 mg/ml, about 8.6 mg/ml, about 8.7 mg/ml, about 8.8 mg/ml, about 8.9 mg/ml, about 9.0 mg/ml, about 9.1 mg/ml, about 9.2 mg/ml, about 9.3 mg/ml, about 9.4 mg/ml, about 9.5 mg/ml, about 9.6 mg/ml, about 9.7 mg/ml, about 9.8 mg/ml, about 9.9 mg/ml, or about 10.0 mg/ml in the oral liquid formulation. In some embodiments, the suspension aid is present in about 4.0 mg/ml to about 6.0 mg/ml in the oral liquid formulation. In some embodiments, the suspension aid is present in about 6.0 mg/ml to about 8.0 mg/ml in the oral liquid formulation. In some embodiments, the suspension aid is hydroxypropyl methyl cellulose and is present in about 5.0 mg/ml in the oral liquid formulation. In some embodiments, the suspension aid is hydroxypropyl methyl cellulose and is present in about 7.5 mg/ml in the oral liquid formulation. In some embodiments, the suspension aid is hydroxypropyl methyl cellulose and is present in about 10 mg/ml in the oral liquid formulation. In some embodiments, the suspension aid is present in about 10 mg/ml to about 30 mg/ml in the oral liquid formulation. In other embodiments, the suspension aid is present in about 10 mg/ml, about 11 mg/ml, about 12 mg/ml, about 13 mg/ml, about 14 mg/ml, about 15 mg/ml, about 16 mg/ml, about 17 mg/ml, about 18 mg/ml, about 19 mg/ml, about 20 mg/ml, about 21 mg/ml, about 22 mg/ml, about 23 mg/ml, about 24 mg/ml, about 25 mg/ml, about 26 mg/ml, about 27 mg/ml, about 28 mg/ml, about 29 mg/ml, or about 30 mg/ml in the oral liquid formulation. In some embodiments, the suspension aid is polyvinylpyrrolidone and is present in about 10 mg/ml in the oral liquid formulation. In some embodiments, the suspension aid is polyvinylpyrrolidone and is present in about 20 mg/ml in the oral liquid formulation. In some embodiments, the suspension aid is polyvinylpyrrolidone and is present in about 30 mg/ml in the oral liquid formulation. In some embodiments, the suspension aid is present in about 5 mg/ml to about 15 mg/ml in the oral liquid formulation. In other embodiments, the suspension aid is present in about 5.0 mg/ml, about 5.5 mg/ml, about 6.0 mg/ml, about 6.5 mg/ml, about 7.0 mg/ml, about 7.5 mg/ml, about 8 mg/ml, about 8.5 mg/ml, about 9 mg/ml, about 9.5 mg/ml, about 10 mg/ml, about 10.5 mg/ml, about 11 mg/ml, about 11.5 mg/ml, about 12 mg/ml, about 12.5 mg/ml, about 13 mg/ml, about 13.5 mg/ml, about 14 mg/ml, about 14.5 mg/ml, or about 15 mg/ml in the oral liquid formulation. In some embodiments, the suspension aid is Avicel® RC-591 and is present in about 5 mg/ml in the oral liquid formulation. In some embodiments, the suspension aid is Avicel® RC-591 and is present in about 7.5 mg/ml in the oral liquid formulation. In some embodiments, the suspension aid is Avicel RC-591 and is present in about 10 mg/ml in the oral liquid formulation. In some embodiments, the suspension aid is Avicel® RC-591 and is present in about 15 mg/ml in the oral liquid formulation. In some embodiments, the suspension aid is present in about 0.4% w/w to about 6% w/w of the solids in the oral liquid formulation. In other embodiments, the suspension aid is present in about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, or about 6% w/w of the solids in the oral liquid formulation. In some embodiments, the suspension aid is present in about 20% w/w to about 50% w/w of the solids in the oral liquid formulation. In other embodiments, the suspension aid is present in about 20% w/w, about 20.5% w/w, about 21% w/w, about 21.5% w/w, about 22% w/w, about 22.5% w/w, about 23% w/w, about 23.5% w/w, about 24% w/w, about 24.5% w/w, about 25% w/w, about 25.5% w/w, about 26% w/w, about 26.5% w/w, about 27% w/w, about 27.5% w/w, about 28% w/w, about 28.5% w/w, about 29% w/w, about 29.5% w/w, about 30% w/w, about 30.5% w/w, about 31% w/w, about 31.5% w/w, about 32% w/w, about 32.5% w/w, about 33% w/w, about 33.5% w/w, about 34% w/w, about 34.5% w/w, about 35% w/w, about 35.5% w/w, about 36% w/w, about 36.5% w/w, about 37% w/w, about 37.5% w/w, about 38% w/w, about 38.5% w/w, about 39% w/w, about 39.5% w/w, about 40% w/w, about 41% w/w, about 41.5% w/w, about 42% w/w, about 42.5% w/w, about 43% w/w, about 43.5% w/w, about 44% w/w, about 44.5% w/w, about 45% w/w, about 45.5% w/w, about 46% w/w, about 46.5% w/w, about 47% w/w, about 47.5% w/w, about 48% w/w, about 48.5% w/w, about 49% w/w, about 39.5% w/w, or about 50% w/w of the solids in the oral liquid formulation. In some embodiments, the suspension aid is present in about 40% w/w to about 85% w/w of the solids in the oral liquid formulation. In other embodiments, the suspension aid is present in about 40% w/w, about 41% w/w, about 42% w/w, about 43% w/w, about 44% w/w, about 45% w/w, about 46% w/w, about 47% w/w, about 48% w/w, about 49% w/w, about 50% w/w, about 51% w/w, about 52% w/w, about 53% w/w, about 54% w/w, about 55% w/w, about 56% w/w, about 57% w/w, about 58% w/w, about 59% w/w, about 60% w/w, about 61% w/w, about 62% w/w, about 63% w/w, about 64% w/w, about 65% w/w, about 66% w/w, about 67% w/w, about 68% w/w, about 69% w/w, about 70% w/w, about 71% w/w, about 72% w/w, about 73% w/w, about 74% w/w, about 75% w/w, about 76% w/w, about 77% w/w, about 78% w/w, about 79% w/w, about 80% w/w, about 81% w/w, about 82% w/w, about 83% w/w, about 84% w/w, or about 85% w/w of the solids in the oral liquid formulation. In some embodiments, the suspension aid is present in about 35% w/w to about 55% w/w of the solids in the oral liquid formulation. In other embodiments, the suspension aid is present in about 35% w/w, about 36% w/w, about 37% w/w, about 38% w/w, about 39% w/w, about 40% w/w, about 41% w/w, about 42% w/w, about 43% w/w, about 44% w/w, about 45% w/w, about 46% w/w, about 47% w/w, about 48% w/w, about 49% w/w, about 50% w/w, about 51% w/w, about 52% w/w, about 53% w/w, about 54% w/w, or about 55% w/w of the solids in the oral liquid formulation. Antifoaming Agent in the Amlodipine Oral Liquid Formulations Antifoaming agents are chemical additives that reduce and hinder the formation of foam in the preparation of an oral liquid formulation. The terms antifoaming agent and defoamer are often used interchangeably. Commonly used agents are insoluble oils, polydimethylsiloxanes (e.g., simethicone) and other silicones, certain alcohols, stearates and glycols. Simethicone is available as a pure material (100%) and in combination with other excipients to facilitate dispersion and handling. Common simethicone containing products include NuSil MED-342 (30% w/w simethicone, solid), NuSil Med-340, Med-346, and Med-347 (100% silicone, liquid), Dow Corning® Q7-2587, 7-9245, and Medical Antifoam C (30% Simethicone Emulsion). The additive is used to prevent formation of foam or is added to break foam already formed. Antifoaming agents reduce foaming in the preparation of an oral liquid formulation which can result in coagulation of aqueous dispersions. In some embodiments, the amlodipine oral liquid formulation described herein comprises an antifoaming agent. In some embodiments, the antifoaming agent is simethicone. In some embodiments, the antifoaming agent is present in about 0.05 mg/ml to about 1.0 mg/ml in the oral liquid formulation. In other embodiments, the antifoaming agent is present in about 0.05 mg/ml, about 0.1 mg/ml, about 0.15 mg/ml, about 0.2 mg/ml, about 0.25 mg/ml, about 0.3 mg/ml, about 0.35 mg/ml, about 0.4 mg/ml, about 0.45 mg/ml, about 0.5 mg/ml, about 0.55 mg/ml, about 0.6 mg/ml, about 0.65 mg/ml, about 0.7 mg/ml, about 0.75 mg/ml, about 0.8 mg/ml, about 0.85 mg/ml, about 0.9 mg/ml, about 0.95 mg/ml, or about 1.0 mg/ml in the oral liquid formulation. In some embodiments, the antifoaming agent is present in about 0.05 mg/ml to about 0.3 mg/ml in the oral liquid formulation. In some embodiments, the antifoaming agent is present in about 0.1 mg/ml to about 0.2 mg/ml in the oral liquid formulation. In some embodiments, the antifoaming agent is simethicone and is present in about 0.15 mg/ml in the oral liquid formulation. In some embodiments, the antifoaming agent is present in about 0.1% w/w to about 7% w/w of the solids in the oral liquid formulation. In other embodiments, the antifoaming agent is present in about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, about 6% w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w, about 6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, about 6.9% w/w, or about 7% w/w of the solids in the oral liquid formulation. Surfactants in the Amlodipine Oral Liquid Formulations Surfactants are compounds that lower the surface tension (or interfacial tension) between two liquids or between a liquid and a solid. Most commonly, surfactants are classified according to polar head group. A non-ionic surfactant has no charged groups in its head. The head of an ionic surfactant carries a net positive, or negative charge. If the charge is negative, the surfactant is more specifically called anionic; if the charge is positive, it is called cationic. If a surfactant contains a head with two oppositely charged groups, it is termed zwitterionic. Anionic surfactants contain anionic functional groups at their head, such as sulfate, sulfonate, phosphate, and carboxylates. Prominent alkyl sulfates include ammonium lauryl sulfate, sodium lauryl sulfate (sodium dodecyl sulfate, SLS, or SDS), and the related alkyl-ether sulfates sodium laureth sulfate (sodium lauryl ether sulfate or SLES), and sodium myreth sulfate. Others include: docusate (dioctyl sodium sulfosuccinate), perfluorooctanesulfonate (PFOS), perfluorobutanesulfonate, alkyl-aryl ether phosphates, alkyl ether phosphates. Cationic surfactant include pH-dependent primary, secondary, or tertiary amines such as octenidine dihydrochloride; and permanently charged quaternary ammonium salts such as cetrimonium bromide (CTAB), cetylpyridinium chloride (CPC), benzalkonium chloride (BAC), benzethonium chloride (BZT), dimethyldioctadecylammonium chloride, and dioctadecyldimethylammonium bromide (DODAB). Zwitterionic (amphoteric) surfactants have both cationic and anionic centers attached to the same molecule. The cationic part is based on primary, secondary, or tertiary amines or quaternary ammonium cations. The anionic part can be more variable and include sulfonates, as in the sultaines CHAPS (3[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate) and cocamidopropyl hydroxysultaine. Betaines such as cocamidopropyl betaine have a carboxylate with the ammonium. The most common biological zwitterionic surfactants have a phosphate anion with an amine or ammonium, such as the phospholipids phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, and sphingomyelins. Nonionic surfactants include fatty alcohols, cetyl alcohol, stearyl alcohol, and cetostearyl alcohol, and oleyl alcohol. Also used as nonionic surfactants are polyethylene glycol alkyl ethers (such as octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether), polypropylene glycol alkyl ethers, glucoside alkyl ethers (such as decyl glucoside, lauryl glucoside, octyl glucoside), polyethylene glycol octylphenyl ethers (such as Triton X-100), polyethylene glycol alkylphenyl ethers (such as nonoxynol-9), glycerol alkyl esters (such as glyceryl laurate), polyoxyethylene glycol sorbitan alkyl esters (such as polysorbate), sorbitan alkyl esters (such as Spans), cocamide MEA, cocamide DEA, dodecyldimethylamine oxide, block copolymers of polyethylene glycol and polypropylene glycol (such as poloxamers), and polyethoxylated tallow amine (POEA). The most commonly used surfactants are fatty acid esters of sorbitan polyethoxylates, i.e. polysorbate 20 and polysorbate 80. The two differ only in the length of the aliphatic chain that imparts hydrophobic character to the molecules, C-12 and C-18, respectively. Polysorbate 80 is more surface-active and has a lower critical micellar concentration than polysorbate 20. In some embodiments, the amlodipine oral liquid formulation described herein comprises a surfactant. In some embodiments, the surfactant is polysorbate 80. In some embodiments, the amlodipine oral liquid formulation described herein does not comprise a surfactant. In some embodiments, the surfactant, when present, is present in about 0.1 mg/ml to about 3.0 mg/ml in the oral liquid formulation. In other embodiments, the surfactant, when present, is present in about 0.1 mg/ml, about 0.15 mg/ml, about 0.2 mg/ml, about 0.25 mg/ml, about 0.3 mg/ml, about 0.35 mg/ml, about 0.4 mg/ml, about 0.45 mg/ml, about 0.5 mg/ml, about 0.55 mg/ml, about 0.6 mg/ml, about 0.65 mg/ml, about 0.7 mg/ml, about 0.75 mg/ml, about 0.8 mg/ml, about 0.85 mg/ml, about 0.9 mg/ml, about 0.95 mg/ml, about 1.0 mg/ml, about 1.1 mg/ml, about 1.15 mg/ml, about 1.2 mg/ml, about 1.25 mg/ml, about 1.3 mg/ml, about 1.35 mg/ml, about 1.4 mg/ml, about 1.45 mg/ml, about 1.5 mg/ml, about 1.55 mg/ml, about 1.6 mg/ml, about 1.65 mg/ml, about 1.7 mg/ml, about 1.75 mg/ml, about 1.8 mg/ml, about 1.85 mg/ml, about 1.9 mg/ml, about 1.95 mg/ml, about 2.0 mg/ml, about 2.1 mg/ml, about 2.15 mg/ml, about 2.2 mg/ml, about 2.25 mg/ml, about 2.3 mg/ml, about 2.35 mg/ml, about 2.4 mg/ml, about 2.45 mg/ml, about 2.5 mg/ml, about 2.55 mg/ml, about 2.6 mg/ml, about 2.65 mg/ml, about 2.7 mg/ml, about 2.75 mg/ml, about 2.8 mg/ml, about 2.85 mg/ml, about 2.9 mg/ml, about 2.95 mg/ml, or about 3.0 mg/ml in the oral liquid formulation. In some embodiments, the surfactant, when present, is polysorbate 80 and is present in about 0.5 mg/ml in the oral liquid formulation. In some embodiments, the surfactant, when present, is polysorbate 80 and is present in about 1.0 mg/ml in the oral liquid formulation. In some embodiments, the surfactant, when present, is polysorbate 80 and is present in about 2.0 mg/ml in the oral liquid formulation. In some embodiments, the surfactant, when present is present in about 1% w/w to about 15% w/w of the solids in the oral liquid formulation. In other embodiments, the surfactant, when present is present in about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 10.5%, about 11%, about 11.5%, about 12%, about 12.5%, about 13%, about 13.5%, about 14%, about 14.5%, or about 15% of the solids in the oral liquid formulation. In some embodiments, the surfactant, when present is present in about 1% w/w to about 5% w/w of the solids in the oral liquid formulation. In other embodiments, the surfactant, when present is present in about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, or about 5% of the solids in the oral liquid formulation. Additional Excipients In further embodiments, the amlodipine oral liquid formulation described herein comprises additional excipients including, but not limited to flavoring agents, coloring agents and thickeners. Additional excipients such as bulking agents, tonicity agents and chelating agents are within the scope of the embodiments. In another embodiment, the amlodipine oral liquid formulation comprises a flavoring agent or flavorant to enhance the taste or aroma of the formulation in liquid form. Suitable natural or synthetic flavoring agents can be selected from standard reference books, for example Fenaroli's Handbook of Flavor Ingredients, 3rd edition (1995). Non-limiting examples of suitable natural flavors, some of which can readily be simulated with synthetic agents or combinations thereof, include almond, anise, apple, apricot, bergamot, blackberry, blackcurrant, blueberry, cacao, caramel, cherry, cinnamon, clove, coffee, coriander, cranberry, cumin, dill, eucalyptus, fennel, fig, ginger, grape, grapefruit, guava, hop, lemon, licorice, lime, malt, mandarin, molasses, nutmeg, mixed berry, orange, peach, pear, peppermint, pineapple, raspberry, rose, spearmint, strawberry, tangerine, tea, vanilla, wintergreen, etc. Also useful, particularly where the formulation is intended primarily for pediatric use, is tutti-frutti or bubblegum flavor, a compounded flavoring agent based on fruit flavors. Presently preferred flavoring agents include anise, cinnamon, cacao, orange, peppermint, cherry (in particular wild cherry), grape, bubblegum, vanilla, and mixed berry. Flavoring agents can be used singly or in combinations of two or more. In certain embodiments, the amlodipine oral liquid formulation comprises a flavoring agent. In further embodiments, the amlodipine oral liquid formulation comprises a coloring agent for identity and/or aesthetic purposes. Suitable coloring agents illustratively include FD&C Red No. 3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, FD&C Green No. 5, FD&C Orange No. 5, caramel, ferric oxide and mixtures thereof. Thickeners impart viscosity or weight to the resultant liquid forms from the amlodipine formulation described herein. Exemplary thickeners include dextrin, cellulose derivatives (carboxymethylcellulose and its salts, ethylcellulose, hydroxyethyl cellulose, methylcellulose, hypromellose, and the like) starches, pectin, polyethylene glycol, polyethylene oxide, trehalose, certain silicates (magnesium aluminum silicate, aluminum silicate, etc. such as Veegum, Bentonite, and Kaolin) and certain gums (xanthan gum, locust bean gum, etc.). In certain embodiments, the amlodipine oral liquid formulation comprises a thickener. In further embodiments, the amlodipine liquid formulation does not comprise glycerol which may cause headache, stomach upset, and diarrhea. Additional excipients are contemplated in the amlodipine oral liquid formulation embodiments. These additional excipients are selected based on function and compatibility with the amlodipine liquid formulations described herein and may be found, for example in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, (Easton, Pa.: Mack Publishing Co 1975); Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms (New York, N.Y.: Marcel Decker 1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed (Lippincott Williams & Wilkins 1999), herein incorporated by reference in their entirety. Stability The amlodipine oral liquid formulations described herein are stable in various storage conditions including refrigerated, ambient and accelerated conditions. Stable as used herein refers to amlodipine oral liquid formulations having about 95% or greater of the initial amlodipine amount and/or about 5% w/w or less total impurities or related substances at the end of a given storage period. In some embodiment, the impurity is amlodipine USP impurity A (A.K.A EP impurity D): The percentage of impurities is calculated from the amount of impurities relative to the amount of amlodipine. Stability is assessed by HPLC or any other known testing method. In some embodiments, the stable amlodipine oral liquid formulations have about 5% w/w, about 4% w/w, about 3% w/w, about 2.5% w/w, about 2% w/w, about 1.5% w/w, about 1% w/w, or about 0.5% w/w total impurities or related substances. In other embodiments, the stable amlodipine oral liquid formulations have about 5% w/w total impurities or related substances. In yet other embodiments, the stable amlodipine oral liquid formulations have about 4% w/w total impurities or related substances. In yet other embodiments, the stable amlodipine oral liquid formulations have about 3% w/w total impurities or related substances. In yet other embodiments, the stable amlodipine oral liquid formulations have about 2% w/w total impurities or related substances. In yet other embodiments, the stable amlodipine oral liquid formulations have about 1% w/w total impurities or related substances. At refrigerated condition, the amlodipine oral liquid formulations described herein are stable for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months and at least 36 months. In some embodiments, refrigerated condition is 5±5° C. In some embodiments, refrigerated condition is about 0° C., about 0.1° C., about 0.2° C., about 0.3° C., about 0.4° C., about 0.5° C., about 0.6° C., about 0.7° C., about 0.8° C., about 0.9° C., about 1° C., about 1.1° C., about 1.2° C., about 1.3° C., about 1.4° C., about 1.5° C., about 1.6° C., about 1.7° C., about 1.8° C., about 1.9° C., about 2° C., about 2.1° C., about 2.2° C., about 2.3° C., about 2.4° C., about 2.5° C., about 2.6° C., about 2.7° C., about 2.8° C., about 2.9° C., about 3° C., about 3.1° C., about 3.2° C., about 3.3° C., about 3.4° C., about 3.5° C., about 3.6° C., about 3.7° C., about 3.8° C., about 3.9° C., about 4° C., about 4.1° C., about 4.2° C., about 4.3° C., about 4.4° C., about 4.5° C., about 4.6° C., about 4.7° C., about 4.8° C., about 4.9° C., about 5° C., about 5.1° C., about 5.2° C., about 5.3° C., about 5.4° C., about 5.5° C., about 5.6° C., about 5.7° C., about 5.8° C., about 5.9° C., about 6° C., about 6.1° C., about 6.2° C., about 6.3° C., about 6.4° C., about 6.5° C., about 6.6° C., about 6.7° C., about 6.8° C., about 6.9° C., about 7° C., about 7.1° C., about 7.2° C., about 7.3° C., about 7.4° C., about 7.5° C., about 7.6° C., about 7.7° C., about 7.8° C., about 7.9° C., about 8° C., about 8.1° C., about 8.2° C., about 8.3° C., about 8.4° C., about 8.5° C., about 8.6° C., about 8.7° C., about 8.8° C., about 8.9° C., about 9° C., about 9.1° C., about 9.2° C., about 9.3° C., about 9.4° C., about 9.5° C., about 9.6° C., about 9.7° C., about 9.8° C., about 9.9° C., or about 10° C. At accelerated conditions, the amlodipine oral liquid formulations described herein are stable for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, or at least 24 months. Accelerated conditions for the amlodipine oral liquid formulations described herein include temperatures that are at or above ambient levels (25±5° C.). In some instances, an accelerated condition is at about 25° C., about 30° C., about 35° C., about 40° C., about 45° C., about 50° C., about 55° C., or about 60° C. Accelerated conditions for the amlodipine oral liquid formulations described herein also include relative humidity (RH) that are at or above ambient levels (55±10% RH). In other instances, an accelerated condition is above 55% RH, about 65% RH, about 70% RH, about 75% RH, or about 80% RH. In further instances, an accelerated condition is about 40° C. or 60° C. at ambient humidity. In yet further instances, an accelerated condition is about 40° C. at 75±5% RH humidity. In some embodiments, the amlodipine oral liquid formulation is stable between about 5±5° C. and about 25±5° C. for at least 12 months. In one embodiment, the amlodipine oral liquid formulation is stable at about 5±5° C. for at least 12 months. In one embodiment, the amlodipine oral liquid formulation is stable at about 25±5° C. for at least 12 months. In one embodiment, the amlodipine oral liquid formulation is stable at about 5±5° C. for at least 24 months. In one embodiment, the amlodipine oral liquid formulation is stable at about 25±5° C. for at least 24 months. Kits and Articles of Manufacture For the amlodipine liquid formulations described herein, kits and articles of manufacture are also described. Such kits can comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein including an amlodipine liquid formulation. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers can be formed from a variety of materials such as glass or plastic. A kit will typically comprise one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for an amlodipine liquid formulation described herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use associated with an amlodipine liquid formulation. A set of instructions will also typically be included. A label can be on or associated with the container. A label can be on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. A label can be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate directions for use of the contents, such as in the methods described herein. Method of Manufacturing Disclosed herein is a process for preparing a stable amlodipine oral liquid formulation. In some embodiments, the stable amlodipine oral liquid formulation is in the form of a suspension. In some embodiments, the stable amlodipine oral liquid formulation comprises a pharmaceutically acceptable salt of amlodipine which is very slightly soluble in an aqueous media. In some embodiments, the stable amlodipine oral liquid formulation comprises a pharmaceutically acceptable salt of amlodipine which is practically insoluble in an aqueous media. Disclosed herein is a process for preparing a stable amlodipine oral liquid formulation, the process comprising mixing a first mixture with a second mixture; the first mixture comprising: a pharmaceutically acceptable salt of amlodipine; optionally a salt comprising the counter ions from a water soluble salt of amlodipine and a salt forming agent; one or more agent selected from the group consisting of preservatives and surfactants; and water; and the second mixture comprising: a buffer; optionally one or more agents selected from the group consisting of flavoring agents, sweetening agents, suspensions aids, and antifoaming agents; and water. In some embodiments, the first mixture comprises a pharmaceutically acceptable salt of amlodipine; a preservative; a surfactant; and water. In some embodiments, the first mixture comprises a pharmaceutically acceptable amlodipine salt; a preservative; and water. In some embodiments, the first mixture is obtained by a process comprising adding water to a first container; adding a water soluble salt of amlodipine to the first container; adding a salt forming agent to the first container; adding a preservative; optionally adding a surfactant to the first container; and stirring until a new pharmaceutically acceptable salt of amlodipine substantially precipitates. In some embodiments, the second mixture comprises a buffer; optionally a flavoring agent; a sweetening agent; suspensions aids; an antifoaming agent; and water. In some embodiments, the second mixture is obtained by a process comprising adding water to a second container; adding a buffer to a second container; adding a sweetening agent to a second container; optionally adding a flavoring agent to a second container; adding an antifoaming agent to a second container; adding suspension aids to a second container; and stirring. In some embodiments, the preservative is sodium benzoate and the buffer is a citrate buffer. In some embodiments, the preservative is a paraben or a mixture of parabens and the buffer is a phosphate buffer. Disclosed herein is a process for preparing a stable amlodipine oral liquid formulation, the process comprising mixing a first mixture with a second mixture; the first mixture comprising: amlodipine benzoate; sodium benzoate; optionally sodium besylate; optionally polysorbate 80; and water; and the second mixture comprising: citric acid; sodium citrate; sucralose; optionally a flavoring agent; hydroxypropyl methylcellulose; simethicone; silicon dioxide; and water. In some embodiments, the first mixture is obtained by a process comprising adding water to a first container which is not stainless steel; adding amlodipine besylate to the first container; adding sodium benzoate to the first container; optionally adding polysorbate 80 to the first container; and stirring until amlodipine benzoate substantially precipitates. In some embodiments, the second mixture is obtained by a process comprising adding water to a second container; adding citric acid to the second container; adding sodium citrate to the second container; adding sucralose to the second container; optionally adding a flavoring agent to the second container; adding hydroxypropyl methylcellulose to the second container; adding simethicone to the second container; adding silicon dioxide to the second container; and stirring. Disclosed herein is a process for preparing a stable amlodipine oral liquid formulation, the process comprising mixing a first mixture with a second mixture; the first mixture comprising: amlodipine benzoate; sodium benzoate; polysorbate 80; optionally sodium besylate; and water; and the second mixture comprising: citric acid; sodium citrate; sucralose; optionally a flavoring agent; hydroxypropyl methylcellulose; simethicone; silicon dioxide; and water. In some embodiments, the first mixture is obtained by a process comprising adding water to a first container which is not stainless steel; adding amlodipine besylate to the first container; adding sodium benzoate to the first container; adding polysorbate 80 to the first container; and stirring until amlodipine benzoate substantially precipitates. In some embodiments, the second mixture is obtained by a process comprising adding water to a second container; adding citric acid to the second container; adding sodium citrate to the second container; adding sucralose to the second container; optionally adding the flavoring agent to the second container; adding hydroxypropyl methylcellulose to the second container; adding simethicone to the second container; adding silicon dioxide to the second container; and stirring. Disclosed herein is a process for preparing a stable amlodipine oral liquid formulation, the process comprising mixing a first mixture with a second mixture; the first mixture comprising: amlodipine naphthalene sulfonate; sodium benzoate; optionally sodium besylate; optionally polysorbate 80; and water; and the second mixture comprising: citric acid; sodium citrate; sucralose; optionally a flavoring agent; hydroxypropyl methylcellulose; simethicone; silicon dioxide; and water. In some embodiments, the first mixture is obtained by a process comprising adding water to a first container which is not stainless steel; adding amlodipine besylate to the first container; adding sodium naphthalene-2-sulfonate to the first container; adding sodium benzoate to the first container; optionally adding polysorbate 80 to the first container; and stirring until amlodipine naphthalene sulfonate substantially precipitates. In some embodiments, the second mixture is obtained by a process comprising adding water to a second container; adding citric acid to the second container; adding sodium citrate to the second container; adding sucralose to the second container; optionally adding the flavoring agent to the second container; adding hydroxypropyl methylcellulose to the second container; adding simethicone to the second container; adding silicon dioxide to the second container; and stirring. In some embodiments, the first mixture is obtained by a process comprising adding water to a first container which is not stainless steel; adding amlodipine besylate to the first container; adding sodium naphthalene-2-sulfonate to the first container; adding sodium benzoate to the first container; and stirring until amlodipine naphthalene sulfonate substantially precipitates. In some embodiments, the second mixture is obtained by a process comprising adding water to a second container; adding citric acid to the second container; adding sodium citrate to the second container; adding sucralose to the second container; optionally adding the flavoring agent to the second container; adding hydroxypropyl methylcellulose to the second container; adding simethicone to the second container; adding silicon dioxide to the second container; and stirring. In some embodiments, the sodium benzoate is added to the second container. In some embodiments sodium benzoate is not added to the first container. Disclosed herein is a process for preparing a stable amlodipine oral liquid formulation in a single container. In some embodiments, the process for preparing a stable amlodipine oral liquid formulation in a single container comprises the formation of a pharmaceutically acceptable salt of amlodipine; followed by addition of one or more agents selected from the group consisting of preservatives, surfactants, flavoring agents, sweetening agents, suspensions aids, and antifoaming agents. In some embodiments, the pharmaceutically acceptable salt of amlodipine is obtained by a process comprising adding water to a container, adding a buffer to the container; adding a water soluble salt of amlodipine to the container; adding a salt forming agent to the container; and stirring until a new pharmaceutically acceptable salt of amlodipine substantially precipitates. The process further comprises cooling the suspension of the new pharmaceutically acceptable salt of amlodipine. The process further comprises adding optional components selected from preservatives, surfactants, flavoring agents, sweetening agents, suspensions aids, and antifoaming agents. In some embodiments, the container is not stainless steel. In some embodiments, high shear mixing is used. In some embodiments, sonication is used. In some embodiments, the process for preparing a stable amlodipine oral liquid formulation in a single container comprises the formation of a pharmaceutically acceptable salt of amlodipine following the addition of one or more agent selected from the group consisting of buffers, preservatives, surfactants, flavoring agents, sweetening agents, suspensions aids, and antifoaming agents. In some embodiments, process comprises adding water to a container; adding a salt forming agent to the container; optionally adding one or more agent selected from the group consisting of buffers, preservatives, surfactants, flavoring agents, sweetening agents, suspensions aids, and antifoaming agents to the container; adding a water soluble salt of amlodipine to the container; and stirring until a new pharmaceutically acceptable salt of amlodipine substantially precipitates. In some embodiments, the container is not stainless steel. Methods of Treatment Provided herein, in one aspect, are methods of treatment comprising administration of the amlodipine oral liquid formulations described herein to a subject. In some embodiments, the amlodipine oral liquid formulations described herein treat hypertension in a subject. Hypertension as used herein includes both primary (essential) hypertension and secondary hypertension. In certain instances, hypertension is classified in cases when blood pressure values are greater than or equal to 140/90 (systolic/diastolic) mm Hg in a subject. In certain instances, the amlodipine oral liquid formulations described herein treat a subject having a blood pressure values are greater than or equal to 140/90 mm Hg. In certain instances, the amlodipine oral liquid formulations described herein treat primary (essential) hypertension in a subject. In other instances, the amlodipine oral liquid formulations described herein treat secondary hypertension in a subject. In other embodiments, the amlodipine oral liquid formulations described herein treat prehypertension in a subject. Prehypertension as used herein refers to cases where a subject's blood pressure is elevated above normal but not to the level considered to be hypertension. In some instances, prehypertension is classified in cases when blood pressure values are 120-139/80-89 mm Hg. In certain instances, the amlodipine oral liquid formulations described herein treat a subject having blood pressure values of 120-139/80-89 mm Hg. In yet other embodiments, the amlodipine oral liquid formulations described herein are prophylactically administered to subjects suspected of having, predisposed to, or at risk of developing hypertension. In some embodiments, the administration of amlodipine oral liquid formulations described herein allow for early intervention prior to onset of hypertension. In certain embodiments, upon detection of a biomarker, environmental, genetic factor, or other marker, the amlodipine oral liquid formulations described herein are prophylactically administered to subjects. In further embodiments, the amlodipine oral liquid formulations described herein treat Coronary Artery Disease (CAD). In some embodiments, the amlodipine oral liquid formulations described herein treat chronic stable angina. In some embodiments, the amlodipine oral liquid formulations described herein treat vasospastic angina (Prinzmetal's or Variant angina). In some embodiments, the amlodipine oral liquid formulations described herein treat angiographically documented coronary artery disease in patients without heart failure or an ejection fraction <40%. Dosing In one aspect, the amlodipine oral liquid formulations are used for the treatment of diseases and conditions described herein. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of amlodipine oral liquid formulations in therapeutically effective amounts to said subject. Dosages of amlodipine oral liquid formulations described can be determined by any suitable method. Maximum tolerated doses (MTD) and maximum response doses (MRD) for amlodipine can be determined via established animal and human experimental protocols as well as in the examples described herein. For example, toxicity and therapeutic efficacy of amlodipine can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Amlodipine dosages exhibiting high therapeutic indices are of interest. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Additional relative dosages, represented as a percent of maximal response or of maximum tolerated dose, are readily obtained via the protocols. In some embodiments, the amount of a given amlodipine oral liquid formulation that corresponds to such an amount varies depending upon factors such as the particular amlodipine salt or form, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but can nevertheless be determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the liquid composition type, the condition being treated, and the subject or host being treated. In some embodiments, the amlodipine oral liquid formulations described herein are provided in a dose per day from about 0.01 mg to 100 mg, from about 0.1 mg to about 80 mg, from about 1 to about 60, from about 2 mg to about 40 mg of amlodipine. In certain embodiments, the amlodipine oral liquid formulations described herein are provided in a daily dose of about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.4 mg, about 0.6 mg, about 0.8 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 76, mg, about 80 mg, about 85 mg, about 90 mg or about 100 mg, or any range derivable therein. In certain instances, the amlodipine oral liquid formulations described herein are provided in a dose per day of about 1 mg. In certain instances, the amlodipine oral liquid formulations described herein are provided in a dose per day of about 2 mg. In certain instances, the amlodipine oral liquid formulations described herein are provided in a dose per day of about 3 mg. In certain instances, the amlodipine oral liquid formulations described herein are provided in a dose per day of about 4 mg. In certain instances, the amlodipine oral liquid formulations described herein are provided in a dose per day of about 5 mg. In certain instances, the amlodipine oral liquid formulations described herein are provided in a dose per day of about 6 mg. In certain instances, the amlodipine oral liquid formulations described herein are provided in a dose per day of about 7 mg. In certain instances, the amlodipine oral liquid formulations described herein are provided in a dose per day of about 8 mg. In certain instances, the amlodipine oral liquid formulations described herein are provided in a dose per day of about 9 mg. In certain instances, the amlodipine oral liquid formulations described herein are provided in a dose per day of about 10 mg. In certain instances, the amlodipine oral liquid formulations described herein are provided in a dose per day of about 11 mg. In certain instances, the amlodipine oral liquid formulations described herein are provided in a dose per day of about 12 mg. The dose per day described herein can be given once per day or multiple times per day in the form of sub-doses given b.i.d., t.i.d., q.i.d., or the like where the number of sub-doses equal the dose per day. In further embodiments, the daily dosages appropriate for the amlodipine oral liquid formulations described herein are from about 0.01 to about 1.0 mg/kg per body weight. In one embodiment, the daily dosages appropriate for the amlodipine oral liquid formulations are from about 0.02 to about 0.8 mg/kg amlodipine per body weight. In another embodiment, the daily dosage appropriate for the amlodipine oral liquid formulations are from about 0.05 to about 0.6 mg/kg per body weight. In another embodiment, the daily dosage appropriate for the amlodipine oral liquid formulations is about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.10 mg/kg, about 0.15 mg/kg, about 0.20 mg/kg, about 0.25 mg/kg, about 0.30 mg/kg, about 0.40 mg/kg, about 0.50 mg/kg, or about 0.60 mg/kg. In other embodiments, the amlodipine oral liquid formulations are provided at the maximum tolerated dose (MTD) for amlodipine. In other embodiments, the amount of the amlodipine oral liquid formulations administered is from about 10% to about 90% of the maximum tolerated dose (MTD), from about 25% to about 75% of the MTD, or about 50% of the MTD. In particular embodiments, the amount of the amlodipine oral liquid formulations administered is from about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or higher, or any range derivable therein, of the MTD for amlodipine. In further embodiments, the amlodipine oral liquid formulations are provided in a dosage that is similar, comparable or equivalent to a dosage of a known amlodipine tablet formulation. In other embodiments, the amlodipine oral liquid formulations are provided in a dosage that provides similar, comparable or equivalent pharmacokinetic parameters (e.g., AUC, Cmax, Tmax, Cmin, T1/2) as a dosage of a known amlodipine tablet formulation. Similar, comparable or equivalent pharmacokinetic parameters, in some instances, refer to within 80% to 125%, 80% to 120%, 85% to 125%, 90% to 110%, or increments therein, of the given values. It should be recognized that the ranges can, but need not be symmetrical, e.g., 85% to 105%. Administration Administration of an amlodipine oral liquid formulation is at a dosage described herein or at other dose levels and formulations determined and contemplated by a medical practitioner. In certain embodiments, the amlodipine oral liquid formulations described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the amlodipine oral liquid formulations are administered to a patient already suffering from a disease, e.g., hypertension, in an amount sufficient to cure the disease or at least partially arrest or ameliorate the symptoms, e.g., lower blood pressure. Amounts effective for this use depend on the severity of the disease, previous therapy, the patient's health status, weight, and response to the amlodipine formulations, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial. In prophylactic applications, the amlodipine oral liquid formulations described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, e.g., hypertension. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the risk or susceptibility of developing the particular disease, previous therapy, the patient's health status and response to the amlodipine formulations, and the judgment of the treating physician. In certain embodiments wherein the patient's condition does not improve, upon the doctor's discretion the administration of an amlodipine oral liquid formulations described herein are administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease. In other embodiments, administration of an amlodipine oral liquid formulation continues until complete or partial response of a disease. In certain embodiments wherein a patient's status does improve, the dose of an amlodipine oral liquid formulation being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days. The dose reduction during a drug holiday is, by way of example only, by 10%400%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. In some embodiments, amlodipine oral liquid formulations described herein are administered chronically. For example, in some embodiments, an amlodipine oral liquid formulation is administered as a continuous dose, i.e., administered daily to a subject. In some other embodiments, amlodipine oral liquid formulations described herein are administered intermittently (e.g. drug holiday that includes a period of time in which the formulation is not administered or is administered in a reduced amount). In some embodiments, the amlodipine oral liquid formulation is administered to a subject who is in a fasted state. A fasted state refers to a subject who has gone without food or fasted for a certain period of time. General fasting periods include at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours and at least 16 hours without food. In some embodiments, an amlodipine oral liquid formulation is administered orally to a subject who is in a fasted state for at least 8 hours. In other embodiments, an amlodipine oral liquid formulation is administered to a subject who is in a fasted state for at least 10 hours. In yet other embodiments, an amlodipine oral liquid formulation is administered to a subject who is in a fasted state for at least 12 hours. In other embodiments, an amlodipine oral liquid formulation is administered to a subject who has fasted overnight. In other embodiments, the amlodipine oral liquid formulation is administered to a subject who is in a fed state. A fed state refers to a subject who has taken food or has had a meal. In certain embodiments, an amlodipine oral liquid formulation is administered to a subject in a fed state 5 minutes post-meal, 10 minutes post-meal, 15 minutes post-meal, 20 minutes post-meal, 30 minutes post-meal, 40 minutes post-meal, 50 minutes post-meal, 1 hour post-meal, or 2 hours post-meal. In certain instances, an amlodipine oral liquid formulation is administered to a subject in a fed state 30 minutes post-meal. In other instances, an amlodipine oral liquid formulation is administered to a subject in a fed state 1 hour post-meal. In yet further embodiments, an amlodipine oral liquid formulation is administered to a subject with food. In further embodiments described herein, an amlodipine oral liquid formulation is administered at a certain time of day for the entire administration period. For example, an amlodipine oral liquid formulation can be administered at a certain time in the morning, in the evening, or prior to bed. In certain instances, an amlodipine oral liquid formulation is administered in the morning. In other embodiments, an amlodipine oral liquid formulation can be administered at different times of the day for the entire administration period. For example, an amlodipine oral liquid formulation can be administered on 8:00 am in the morning for the first day, 12 pm noon for the next day or administration, 4 pm in the afternoon for the third day or administration, and so on. Combinations The treatment of certain diseases or conditions (e.g., hypertension, heart failure, myocardial infarction and the like) in a subject with an amlodipine oral liquid formulation described herein encompass additional therapies and treatment regimens with other agents in some embodiments. Such additional therapies and treatment regimens can include another therapy, e.g., additional anti-hypertensives, for treatment of the particular disease or condition in some embodiments. Alternatively, in other embodiments, additional therapies and treatment regimens include other agents used to treat adjunct conditions associated with the disease or condition or a side effect from the amlodipine oral liquid formulation in the therapy. Additional agents for use in combination with an amlodipine oral liquid formulation described herein include, but are not limited to, diuretics (loop, thiazide, potassium-sparing, and the like), beta blockers (metoprolol, propanolol, pronethalol, and the like), alpha blockers (phentolamine, phenoxybenzamine, tamsulosin, prazosin, and the like), mixed alpha and beta blockers (bucindolol, carvedilol, labetalol), calcium channel blockers (dihydropyridines such as nifedipine, etc., diltiazem, verapamil and the like), angiotensin II receptor antagonists (saralasin, losartan, eprosartin, irbesartan, valsartan, and the like), other ACE inhibitors (enalapril, captopril, quinapril, ramipril, lisinopril, zofenopril, and the like), aldosterone antagonists (eplerenone, spironolactone and the like), vasodilators (hydralazine and the like) and alpha-2 agonists (clonidine, moxonidine, guanabenz and the like). Certain Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments described herein, certain preferred methods, devices, and materials are now described. As used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to “an excipient” is a reference to one or more excipients and equivalents thereof known to those skilled in the art, and so forth. The term “about” is used to indicate that a value includes the standard level of error for the device or method being employed to determine the value. The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and to “and/or.” The terms “comprise,” “have” and “include” are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as “comprises,” “comprising,” “has,” “having,” “includes” and “including,” are also open-ended. For example, any method that “comprises,” “has” or “includes” one or more steps is not limited to possessing only those one or more steps and also covers other unlisted steps. “Optional” or “optionally” may be taken to mean that the subsequently described structure, event or circumstance may or may not occur, and that the description includes instances where the events occurs and instances where it does not. As used herein, the term “therapeutic” means an agent utilized to treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a patient. In some embodiments, a therapeutic agent such as amlodipine is directed to the treatment and/or the amelioration of, reversal of, or stabilization of the symptoms of hypertension described herein. “Administering” when used in conjunction with a therapeutic means to administer a therapeutic systemically or locally, as directly into or onto a target tissue, or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted. Thus, as used herein, the term “administering”, when used in conjunction with an amlodipine formulation, can include, but is not limited to, providing an amlodipine formulation into or onto the target tissue; providing an amlodipine formulation systemically to a patient by, e.g., oral administration whereby the therapeutic reaches the target tissue or cells. “Administering” a formulation may be accomplished by injection, topical administration, and oral administration or by other methods alone or in combination with other known techniques. The term “animal” as used herein includes, but is not limited to, humans and non-human vertebrates such as wild, domestic and farm animals. As used herein, the terms “patient,” “subject” and “individual” are intended to include living organisms in which certain conditions as described herein can occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. In a preferred embodiment, the patient is a primate. In certain embodiments, the primate or subject is a human. In certain instances, the human is an adult. In certain instances, the human is child. In further instances, the human is 12 years of age or younger. In certain instances, the human is elderly. In other instances, the human is 60 years of age or older. Other examples of subjects include experimental animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows. The experimental animal can be an animal model for a disorder, e.g., a transgenic mouse with hypertensive pathology. A patient can be a human suffering from hypertension, or its variants or etiological forms. By “pharmaceutically acceptable”, it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The term “pharmaceutical composition” shall mean a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan. A “therapeutically effective amount” or “effective amount” as used herein refers to the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology). As such, a non-limiting example of a “therapeutically effective amount” or “effective amount” of a formulation of the present disclosure may be used to inhibit, block, or reverse the activation, migration, or proliferation of cells or to effectively treat hypertension or ameliorate the symptoms of hypertension. The terms “treat,” “treated,” “treatment,” or “treating” as used herein refers to both therapeutic treatment in some embodiments and prophylactic or preventative measures in other embodiments, wherein the object is to prevent or slow (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results. For the purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. A prophylactic benefit of treatment includes prevention of a condition, retarding the progress of a condition, stabilization of a condition, or decreasing the likelihood of occurrence of a condition. As used herein, “treat,” “treated,” “treatment,” or “treating” includes prophylaxis in some embodiments. The terms “precipitate,” “precipitates,” or “precipitation” as used herein, refers to the creation of a new solid phase comprising one or more chemical entities from solution. Those of ordinary skill in the art will understand and appreciate that the solid phase may exist in crystalline and/or amorphous forms and that crystalline forms may include, but are not limited to, polymorphs, cocrystals, ionic cocrystals, ionic cocrystal solvates, salts, solvated salts and solvates. The terms “substantially precipitate,” “substantially precipitates” or “substantial precipitation” as used herein, refers to an amount of precipitation that is detectable, directly or indirectly, by techniques known to a person of ordinary skill in the art. Examples of techniques may include, but are not limited to, visual inspection of solutions to determine changes in solution opaqueness/transparency, Focused Beam Reflectance Measurement (FBRM) technology, Infrared Spectroscopy, Raman Spectroscopy, UV spectroscopy and turbidity analysis. The terms “very slightly soluble” or “practically insoluble” as used herein, refers to a concentration of less than about 0.6 mg/mL, preferably of less than about 0.2 mg/mL, and most preferably of less than about 0.05 mg/mL. EXAMPLES Example 1. Formation of Amlodipine Salt Crystals in the Absence or Presence of a Magnetic Stir Bar (1A) Purified water (200 ml) was added to a 400 ml glass container fitted with overhead rotational stirring using a PTFE (polytetrafluoroethylene) coated 2″ diameter impeller and shaft. Stirring was initiated at 250 rpm and anhydrous citric acid (110 mg) was added and dissolved. Amlodipine besylate (278 mg) was then added followed by 1000 mg sodium benzoate. After 25 minutes, the stirring speed was increased to 450 rpm for 45 additional minutes. Results: No precipitate of amlodipine benzoate salt appeared until after 1 hour of stirring. The particles were large, >100 microns in length. (1B) The procedure in example (1A) was repeated with the exception that a magnetic stir bar was placed in the glass container in addition to the overhead stirrer. No external magnetic stirring apparatus was present, only the stir bar. The stirring speed was maintained at 250 rpm. Results: Amlodipine benzoate salt precipitated after 3 minutes of stirring. The particles were small, at <50 microns in length. (1C) Purified water (100 ml) was added to a 250 ml glass container fitted with overhead rotational stirring using a PTFE (polytetrafluoroethylene) coated 2″ diameter impeller and shaft. Stirring was initiated at 275 rpm and polysorbate 80 (1.0 grams) was added and dissolved. Amlodipine besylate (1.39 grams) was added and allowed to disperse, then sodium benzoate (5.0 grams) was added. The suspension was stirred for 30 minutes after the sodium benzoate addition then the stirring was stopped and a sample taken for microscopic evaluation. Results: A precipitate appeared in the suspension that was primarily large rod-shaped crystals, >100 microns in length. (1D) The procedure in example (1C) was repeated with the exception that a magnetic stir bar was placed in the glass container in addition to the overhead stirrer. No external magnetic stirring apparatus was present, only the stir bar. The overhead stirring speed was maintained at 275 rpm. Results: Amlodipine benzoate salt precipitated after ˜3 minutes of stirring. The particles were small and needle-shaped, at <50 microns in length. Example 2. Concentration Effect on Amlodipine Salt Crystal Formation with Non-Magnetic Stirring (2A) Purified water (50 ml) was added to a glass container fitted with overhead rotational stirring using a PTFE coated 2″ diameter impeller and shaft. Stirring was initiated at 250 rpm and 2500 mg sodium benzoate were added and dissolved. Amlodipine besylate (695 mg) was then added followed by 275 mg anhydrous citric acid. This solution is equivalent to preparing the crystals using a water amount of 10% of a final formulation weight. Results: Amlodipine benzoate salt began precipitating immediately as particles <˜50 micron. (2B) Purified water (150 ml) was added to a glass container fitted with overhead rotational stirring using a PTFE coated impeller and shaft. Stirring was initiated at 250 rpm and 2500 mg sodium benzoate were added and dissolved. Amlodipine besylate (695 mg) was then added followed by 275 mg anhydrous citric acid. This solution is equivalent to preparing the crystals using a water amount of 30% of a final formulation weight. Results: Amlodipine benzoate salt began precipitating immediately as particles <˜50 micron. (2C) Purified water (250 ml) was added to a glass container fitted with overhead rotational stirring using a PTFE coated impeller and shaft. Stirring was initiated at 250 rpm and 2500 mg sodium benzoate were added and dissolved. Amlodipine besylate (695 mg) was then added followed by 275 mg anhydrous citric acid. This solution is equivalent to preparing the crystals using a water amount of 50% of a final formulation weight. Results: Amlodipine benzoate salt began precipitating, then dissolved, and finally re-precipitated as large particles (>50 microns) after ˜1 hour. (2D) Purified water (45 ml) was added to a 250 ml glass container fitted with overhead rotational stirring using a PTFE coated 2″ diameter impeller and shaft. Stirring was initiated at 250 rpm and 500 mg of a 30% w/w simethicone powder were added and dissolved. Sodium benzoate (5000 mg) was added and dissolved and then amlodipine besylate (1390 mg in 5 ml water) was added. This solution is equivalent to preparing the crystals using a water amount of 5% of a final formulation weight. Results: Amlodipine benzoate salt precipitated immediately as very fine particles that caked on the stirrer and did not disperse easily. (2E) Purified water (90 ml) was added to a 250 mL HDPE container fitted with overhead rotational stirring using a PTFE coated 2″ diameter impeller and shaft. Stirring was initiated at 250 rpm and 500 mg of a 30% w/w simethicone powder were added and dissolved. Sodium benzoate (5000 mg) was added and dissolved and then amlodipine besylate (1390 mg in 10 ml water) was added. This solution is equivalent to preparing the crystals using a water amount of 10% of a final formulation weight. Results: Amlodipine benzoate salt precipitated rapidly as small particles that dispersed easily. (2F) Purified water (95 ml) was added to a 250 ml glass container fitted with overhead rotational stirring using a PTFE coated 2″ diameter impeller and shaft. Stirring was initiated at 250 rpm and 250 mg of a 30% w/w simethicone powder were added and dissolved. Sodium benzoate (2500 mg) was added and dissolved and then amlodipine besylate (695 mg in 5 mL water) was added. This solution is equivalent to preparing the crystals using a water amount of 20% of a final formulation weight. Results: Amlodipine benzoate salt precipitated rapidly as small particles with some agglomeration. Example 3 Amlodipine compositions were prepared using a process in which the preferred amlodipine salt is formed in one container, another part of the formulation was prepared in a second container, and the contents of the first container and the second container were combined. (3A) Purified water (approximately 10% of the final formulation weight) was added to a polyethylene first vessel (e.g., LLPD) fitted with magnetic stirring. Stirring was initiated and polysorbate 80 was added and dispersed in the solution. Amlodipine was then added with stirring until it was well dispersed, followed by the addition of the salt forming agent (e.g., sodium benzoate or sodium naphthalene-2-sulfonate). Stirring was continued for approximately 30 minutes after the addition of the salt forming agent. Purified water (approximately 80% of the final formulation weight) was added to a stainless steel second vessel fitted with overhead rotational stirring using a shaft and impeller. Stirring was initiated and the following components were added individually with sufficient stirring after each addition, to ensure each component was dissolved (citric acid, sodium citrate, sucralose, flavoring agent, hypromellose) or well dispersed (simethicone, silicon dioxide). High shear mixing was used during and after the addition of the hypromellose to facilitate dispersion and solubilization of this component. The contents of the first vessel were then transferred to the second vessel with stirring. Additional water was added to the second vessel to bring its weight to approximately 98% of the final formulation weight. The pH of the solution was measured and if required, adjusted to the desired pH, then the solution was brought to the final weight with purified water. (3B) Purified water (approximately 10% of the final formulation weight) was added to a glass vessel fitted with magnetic stirring. Stirring was initiated and simethicone was added and dispersed in the solution. The salt forming agent was then added and dissolved. Amlodipine was dispersed in purified water (approximately 1% of the final formulation weight) and the resulting liquid slowly added to the first vessel with stirring. Stirring was continued for approximately 30 minutes after the addition of the amlodipine. Purified water (approximately 22% of the final formulation weight) was added to a second glass vessel fitted with magnetic stirring. The water was heated to approximately 70° C. and silicone dioxide and hypromellose were added with stirring. The heating was discontinued and an equal portion of cold water was added to the second vessel. Stirring was continued and sucralose and flavor were added and dissolved. Purified water (approximately 6% of the final formulation weight) was then added. The solutions from the two vessels were combined with stirring. The vessels were rinsed with purified water (approximately 20% of the final formulation weight) and the rinses added to the formulation. The pH was checked, and as needed adjusted to pH 4.9 with a solution of citric acid (1.1 g anhydrous citric acid in 50 ml purified water). The solution was brought to final weight with purified water and mixed with high shear mixing. (3C) Purified water (approximately 10% of the final formulation weight) was added to a first glass vessel fitted with magnetic stirring. Stirring was initiated and one-half of the simethicone and nine-tenths of the salt forming agent were added. Amlodipine was then added over about 5 minutes. Stirring was continued for approximately 30 minutes after the addition of the amlodipine was completed. Purified water (approximately 70% of the final formulation weight) was added to a second glass vessel fitted with magnetic stirring. The remaining one-half of the simethicone, the remaining one-tenth of the salt forming agent, sucralose, silicon dioxide, flavor, and hypromellose were added to the vessel with stirring. High shear mixing was used after the addition of the hypromellose to facilitate dispersion and solubilization of this component. The contents of the first vessel were then transferred to the second vessel with stirring. Additional water was added to the second vessel to bring its weight to approximately 90% of the final formulation weight. The formulation was again subjected to high shear mixing, and then allowed to deaerate. The preparation was brought to final weight with purified water and mixed. The pH of the solution was measured and as required, adjusted to the desired pH with anhydrous citric acid. Example 4 Amlodipine compositions were prepared using a process in which the preferred amlodipine salt is formed in one container, and then transferred to a second container for the remaining process. Purified water (approximately 10% of the final formulation weight) was added to a HDPE vessel fitted with a magnetic stirrer. Stirring was initiated and simethicone was added and dispersed in the solution. The salt forming agent was then added with stirring followed by the addition of amlodipine dispersed in purified water (approximately 1% of the final formulation weight). Stirring was continued for approximately 30 minutes after the addition of the amlodipine. The preparation was transferred to a stainless steel vessel and additional purified water (approximately 45% of the final formulation weight) was added to the vessel. Stirring was initiated and the following components were added individually with stirring; citric acid, sucralose, silicon dioxide, flavor, and hypromellose. High shear mixing was used after the addition of the hypromellose to facilitate dispersion and solubilization. Purified water (30% of the final formulation weight) was added with stirring and the preparation was allowed to deaerate. The preparation was brought to final weight with purified water and mixed. The pH was measured. Example 5 Amlodipine compositions were prepared using processes in which the preferred amlodipine salt is formed in a small portion of the final volume in one container, and then additional components are added to the same container to complete the process. (5A) Purified water (approximately 10% of the final formulation weight) was added to a glass vessel fitted with magnetic stirring. Stirring was initiated and simethicone was added and dispersed in the solution. The salt forming agent was then added with stirring followed by the addition of amlodipine. Stirring was continued for approximately 30 minutes after the addition of the amlodipine. Additional purified water (approximately 85% of the final formulation weight) was added to the vessel. Stirring was initiated and the following components were added individually with stirring; citric acid, sodium citrate, sucralose, silicon dioxide, flavor, and hypromellose. High shear mixing was used after the addition of the hypromellose to facilitate dispersion and solubilization, then the preparation was allowed to deaerate. The pH was checked and adjusted if necessary, and the preparation was brought to final weight with purified water. (5B) Polysorbate 80 was added to a glass vessel fitted with magnetic stirring. Purified water (approximately 10% of the final formulation weight) was added and stirring was initiated to ensure dispersion of the polysorbate in the solution. Amlodipine was then added with stirring until it was well dispersed, followed by the addition of the salt forming agent. Stirring was continued for approximately 30 minutes after the addition of the salt forming agent. Additional purified water (approximately 85% of the final formulation weight) was added to the vessel. Stirring was initiated and the following components were added individually with stirring; citric acid, sodium citrate, sucralose, silicon dioxide, flavor, simethicone and hypromellose. High shear mixing was used after the addition of the hypromellose to facilitate dispersion and solubilization, then the preparation was allowed to deaerate. The pH was checked and adjusted if necessary, and the preparation was brought to final weight with purified water. Example 6 Amlodipine compositions were prepared using processes in which the preferred amlodipine salt is formed in one container in a volume greater than one-half of the final volume, and then additional components were added to the same container to complete the process. (6A) Purified water (approximately 90% of the final formulation weight) was added to a glass vessel fitted with magnetic stirring. Stirring was initiated and citric acid was added and dissolved in the solution, followed by amlodipine, followed by the salt forming agent. The solution was stirred for approximately 30 minutes to allow formation of the amlodipine salt. The solution was then cooled to 2-8° C. for 1 hour with continued stirring. Sucralose, silicon dioxide, simethicone, povidone for some formulations, and hypromellose were added with stirring. High shear mixing was applied to the formulation after the hypromellose addition. The formulation was then stirred for 30 minutes, brought to final weight with purified water, and stirred for another 30 minutes. (6B) Purified water (approximately 90% of the final formulation weight) was added to a glass vessel fitted with magnetic stirring. Stirring was initiated and citric acid was added and dissolved in the solution, followed by sodium citrate, amlodipine, then the salt forming agent. The solution was stirred for approximately 30 minutes to allow formation of the amlodipine salt. Sodium benzoate, sucralose, silicon dioxide, simethicone, (flavor and color in some formulations) and hypromellose were added with stirring. High shear mixing was applied to the formulation after the hypromellose addition. The formulation was then stirred for 30 minutes, brought to final weight with purified water, and stirred for another 30 minutes. (6C) Purified water (approximately 90% of the final formulation weight) was added to a glass vessel fitted with magnetic stirring. Stirring was initiated and citric acid was added and dissolved in the solution, followed by amlodipine, then the salt forming agent. The solution was stirred for approximately 30 minutes to allow formation of the amlodipine salt. The solution was then cooled to 2-8° C. for 1 hour with continued stirring. Sucralose, silicon dioxide, simethicone and povidone were added with stirring. The formulation was then stirred for 30 minutes, brought to final weight with purified water, and stirred for another 30 minutes. (6D) Purified water (approximately 90% of the final formulation weight) was added to a glass vessel fitted with magnetic stirring. Stirring was initiated and hypromellose was added and dissolved in the water with high shear mixing. Citric acid, salt forming agent, sucralose, simethicone, flavoring agent and color in some preparations, were then added with stirring. The solution was brought to its final weight with purified water, and the amlodipine was added with stirring. The solution was stirred for approximately 30 minutes to allow formation of the amlodipine salt. (6E) Purified water (approximately 90% of the final formulation weight) was added to a glass vessel fitted with magnetic stirring. Stirring was initiated and mannitol was added and dissolved in the solution, followed by hypromellose, citric acid, salt forming agent, sucralose, simethicone, silicon dioxide, and in some formulations, a flavor. The solution was brought to its final weight with purified water, and the amlodipine was added with stirring. In some preparations, the formulation was subjected to ultrasonic energy (sonication) and in some preparations the formulation was mixed with high shear mixing. The solution was then stirred for approximately 30 minutes to allow formation of the amlodipine salt. Example A: Effect of pH on the Formation of Degradants in Amlodipine Formulations Formulations were prepared containing Amlodipine according to Table A-1. Each formulation was dispensed into screw-capped high density polyethylene (HDPE) bottles and stored at both 5° C. and ambient temperature. Samples were removed periodically and analyzed by a stability indicating high performance liquid chromatography (HPLC) method for content of amlodipine and any degradants. The HPLC method provided separation of amlodipine, amlodipine degradants and formulation components on a C18 column with a gradient program using mobile phases containing 0.1% trifluoroacetic acid (TFA) in water, and 0.1% TFA in acetonitrile flowing at 1 mL/min. Detection was by UV absorbance at 237 nm for amlodipine and its degradants. Any unknown impurities were reported by their relative retention time (RRT) to amlodipine. TABLE A-1 Composition (in mg/ml) of Amlodipine Formulations at Varying pH Levels Formulation Component A1 A2 A3 A4 A5 A6 A7 A8 Amlodipine besylatea 1.39 1.39 1.39 1.39 1.39 1.39 1.39 1.39 Mannitol 90.00 — — — — — — — Hypromellose K750 5.00 — — — — — — — Citric acid, anhydrous 3.42 1.35 0.84 0.53 0.36 0.31 0.23 0.17 Sodium citrate, dihydrate — — — — — 0.36 0.47 0.55 Sodium benzoate 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 Sucralose/maltodextrin 4.00 — — — — — — — Sucralose — 0.70 0.70 0.70 0.70 0.70 0.70 0.70 Simethicone 0.15 0.15 0.15 0.15 0.15 0.15 0.15 0.15 Silicon dioxide 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 Artificial cherry flavor — 0.50 0.50 0.50 0.50 0.50 0.50 0.50 Hypromellose K1500 — 5.00 5.00 5.00 5.00 5.00 5.00 5.00 Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. pH 3.98 4.51 4.71 4.90 5.09 5.31 5.54 5.75 a= equivalent to 1 mg/ml Amlodipine The results of the HPLC analysis for amlodipine and the main degradants in the samples stored at 5° C. are provided in Table A-2. The results show a decrease in total impurities as pH is increased from 4.0 to 5.7. TABLE A-2 Assay and Primary Degradants Present in the Formulations Formulation Weeks A1 A2 A3 A4 A5 A6 A7 A8 Amlodipine (% initial) Initial 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 4 97.77 96.61 99.30 99.99 100.96 99.20 101.11 96.49 8 97.47 97.32 104.37 100.07 101.33 100.58 98.10 97.04 12 97.88 97.41 102.28 102.09 101.88 100.59 100.74 96.38 26 95.14 97.02 100.80 99.69 105.89 102.46 102.01 98.37 52 96.02 97.16 100.08 101.26 101.94 100.40 99.96 97.34 78 98.24 98.37 101.86 100.40 101.93 107.40 99.59 99.08 104 97.32 98.02 99.66 109.83 102.00 101.79 100.25 97.37 USP Impurity A/EP Impurity D (wt % of Amlodipine) Initial 0.06 0.02 0.03 0.00 0.03 0.00 0.00 0.00 4 0.08 0.05 0.03 0.04 0.04 0.00 0.02 0.04 8 0.12 0.01 0.01 0.01 0.01 0.04 0.01 0.03 12 0.13 0.17 0.02 0.02 0.03 0.05 0.02 0.04 26 0.15 0.04 0.04 0.04 0.05 0.05 0.04 0.04 52 0.15 0.07 0.06 0.06 0.06 0.07 0.06 0.06 78 0.27 0.08 0.07 0.07 0.06 0.10 0.06 0.07 104 0.33 0.06 0.05 0.04 0.04 0.05 0.04 0.04 Impurity RRT 0.97 (wt % of Amlodipine) Initial 0.02 0.00 0.00 0.00 0.00 0.00 0.00 0.00 4 0.02 0.00 0.01 0.00 0.00 0.01 0.00 0.00 8 0.06 0.02 0.02 0.01 0.01 0.00 0.00 0.00 12 0.04 0.04 0.03 0.02 0.02 0.01 0.01 0.01 26 0.07 0.08 0.07 0.05 0.04 0.04 0.03 0.02 52 0.11 0.13 0.13 0.12 0.10 0.09 0.06 0.04 78 0.16 0.21 0.20 0.18 0.15 0.14 0.10 0.06 104 0.22 0.26 0.25 0.24 0.20 0.18 0.13 0.08 Total Impurities (wt % of Amlodipine) Initial 0.23 0.07 0.06 0.03 0.08 0.06 0.06 0.08 4 0.28 0.11 0.09 0.09 0.08 0.04 0.06 0.14 8 0.66 0.09 0.09 0.07 0.09 0.07 0.06 0.10 12 0.35 0.34 0.12 0.08 0.09 0.10 0.07 0.09 26 0.42 0.25 0.21 0.18 0.17 0.15 0.12 0.10 52 0.64 0.41 0.35 0.31 0.33 0.33 0.26 0.24 78 0.84 0.53 0.46 0.38 0.33 0.40 0.27 0.25 104 1.07 0.65 0.61 0.51 0.44 0.36 0.31 0.28 The results of the HPLC analysis for amlodipine and the main degradants in the samples stored at ambient temperature are provided in Table A-3. The results show a decrease in total impurities as pH is increased from 4.0 to 5.7. TABLE A-3 Assay and Primary Degradants Present in the Formulations Formulation Weeks A1 A2 A3 A4 A5 A6 A7 A8 Amlodipine (% initial) Initial 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 32 89.38 98.81 102.36 99.31 102.33 102.05 101.23 101.34 4 90.71 97.05 99.80 100.54 105.81 101.27 99.14 98.06 6 85.22 95.86 102.42 101.22 100.86 102.45 100.42 97.03 8 83.75 97.13 99.80 101.38 103.48 101.81 100.14 101.44 12 79.33 96.28 100.33 100.61 103.18 101.61 100.90 97.50 26 — 91.68 96.97 98.87 101.72 101.53 100.27 99.20 USP Impurity A/EP Impurity D (wt % of Amlodipine) Initial 0.06 0.02 0.03 0.00 0.03 0.00 0.00 0.00 2 0.30 0.05 0.05 0.05 0.04 0.03 0.01 0.04 4 0.43 0.08 0.08 0.07 0.07 0.06 0.06 0.06 6 0.65 0.05 0.05 0.03 0.04 0.10 0.05 0.05 8 0.79 0.05 0.04 0.03 0.04 0.10 0.17 0.09 12 1.03 0.06 0.05 0.05 0.04 0.14 0.12 0.13 26 — 0.27 0.21 0.20 0.18 0.26 0.23 0.24 Impurity RRT 0.97 (wt % of Amlodipine) Initial 0.02 0.00 0.00 0.00 0.00 0.00 0.00 0.00 2 0.29 0.12 0.10 0.07 0.05 0.03 0.03 0.01 4 0.43 0.25 0.20 0.15 0.11 0.07 0.05 0.04 6 0.58 0.33 0.28 0.22 0.16 0.13 0.10 0.06 8 0.67 0.40 0.35 0.29 0.22 0.18 0.11 0.07 12 0.73 0.47 0.43 0.38 0.32 0.25 0.17 0.10 26 — 0.51 0.48 0.45 0.41 0.37 0.30 0.21 Total Impurities (wt % of Amlodipine) Initial 0.23 0.07 0.06 0.03 0.08 0.06 0.06 0.08 2 1.19 0.32 0.29 0.23 0.17 0.15 0.09 0.13 4 1.78 0.60 0.49 0.39 0.37 0.24 0.24 0.30 6 2.41 0.75 0.62 0.50 0.39 0.47 0.37 0.30 8 2.43 0.94 0.75 0.60 0.53 0.50 0.49 0.36 12 3.77 1.29 0.94 0.76 0.73 0.72 0.58 0.49 26 — 1.85 1.47 1.23 1.18 1.21 1.05 0.95 Example B. Effect of Benzoate Concentration on the Stability of Amlodipine Formulations Formulations were prepared containing Amlodipine according to Table B-1. Each formulation was dispensed into screw-capped HDPE bottles and stored at ambient temperature. Formulations B6, B7, and B8 were also stored at 5° C. Samples were removed periodically and analyzed using the HPLC method in Example A. TABLE B-1 Composition (in mg/ml) of Amlodipine Formulations at Varying Benzoate Levels Formulation Component B1 B2 B3 B4 B5 B6 B7 B8 Amlodipine besylatea 1.39 1.39 1.39 1.39 1.39 1.39 1.39 1.39 Hypromellose K750 — — — — — 5.00 5.00 5.00 Citric acid, anhydrous b b b b b 0.55 0.90 1.15 Sodium benzoate 1.00 2.00 3.00 4.00 5.00 5.00 7.50 10.00 Sucralose 0.70 0.70 0.70 0.70 0.70 0.70 0.70 0.70 Simethicone 0.15 0.15 0.15 0.15 0.15 0.15 0.15 0.15 Silicon dioxide 0.50 0.50 0.50 0.50 0.50 — — — Artificial cherry flavor 0.50 0.50 0.50 0.50 0.50 — — 0.50 Hypromellose K1500 5.00 5.00 5.00 5.00 5.00 — — — Red 40 Al lake color — — — — — — — 90.015 Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. pH 4.85 4.89 4.89 4.89 4.89 4.88 4.84 4.87 a= equivalent to 1 mg/ml Amlodipine b adjusted pH to 4.9 with a solution containing 1.1 g citric acid in 50 ml purified water before final dilution. The results of the HPLC analysis for amlodipine and the main degradants in the samples stored at 5° C. are provided in Table B-2. TABLE B-2 Assay and Primary Degradants Present in the Formulations Formulation Weeks B6 B7 B8 Amlodipine (% initial) Initial 100.00 100.00 100.00 2 97.56 99.22 98.15 4 97.18 98.00 98.18 6 99.13 99.04 97.28 8 98.81 98.44 98.17 12 99.17 98.80 98.80 26 99.89 97.03 97.42 52 96.34 98.04 97.19 78 98.10 99.20 99.07 104 97.33 98.59 97.56 USP Impurity A/EP Impurity D (wt % of Amlodipine) Initial 0.03 0.00 0.04 2 0.03 0.02 0.02 4 0.02 0.03 0.03 6 0.03 0.02 0.02 8 0.03 0.04 0.03 12 0.04 0.03 0.02 26 0.05 0.03 0.04 52 0.04 0.03 0.03 78 0.11 0.09 0.09 104 0.13 0.10 0.10 Impurity RRT 0.97 (wt % of Amlodipine) Initial 0.00 0.00 0.00 2 0.00 0.00 0.00 4 0.01 0.01 0.01 6 0.02 0.01 0.01 8 0.02 0.02 0.01 12 0.05 0.04 0.03 26 0.10 0.08 0.07 52 0.19 0.15 0.12 78 0.28 0.25 0.21 104 0.35 0.32 0.27 Total Impurities (wt % of Amlodipine) Initial 0.10 0.09 0.15 2 0.08 0.08 0.07 4 0.07 0.07 0.07 6 0.10 0.07 0.09 8 0.10 0.09 0.08 12 0.13 0.11 0.10 26 0.22 0.17 0.17 52 0.37 0.30 0.24 78 0.54 0.44 0.39 104 0.73 0.58 0.52 The results of the HPLC analysis for amlodipine and the main degradants in the samples stored at ambient temperature are provided in Table B-3. TABLE B-3 Assay and Primary Degradants Present in the Formulations Formulation Weeks B1 B2 B3 B4 B5 B6 B7 B8 Amlodipine (% initial) Initial 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 2 98.98 105.36 100.82 97.67 100.22 98.62 98.70 99.05 4 97.06 104.08 99.24 95.90 97.91 96.01 98.44 97.90 6 96.31 103.13 99.36 97.32 97.01 97.10 97.89 97.37 8 96.51 103.91 99.54 96.90 96.84 97.04 97.26 97.39 12 96.38 95.78 95.40 26 92.69 95.34 94.49 USP Impurity A/EP Impurity D (wt % of Amlodipine) Initial 0.05 0.04 0.03 0.03 0.03 0.03 0.00 0.04 2 0.17 0.10 0.08 0.07 0.07 0.05 0.04 0.05 4 0.22 0.12 0.10 0.08 0.07 0.09 0.07 0.08 6 0.28 0.15 0.11 0.10 0.08 0.12 0.09 0.09 8 0.32 0.16 0.13 0.11 0.12 0.12 0.11 0.11 12 0.16 0.14 0.13 26 0.24 0.23 0.22 Impurity RRT 0.97 (wt % of Amlodipine) Initial 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 2 0.07 0.08 0.09 0.09 0.08 0.09 0.13 0.12 4 0.19 0.19 0.19 0.18 0.19 0.22 0.28 0.25 6 0.28 0.28 0.28 0.26 0.26 0.33 0.38 0.36 8 0.34 0.33 0.34 0.34 0.33 0.40 0.47 0.44 12 0.51 0.55 0.55 26 0.60 0.63 0.63 Total Impurities (wt % of Amlodipine) Initial 0.22 0.08 0.06 0.07 0.09 0.10 0.09 0.15 2 0.59 0.40 0.43 0.39 0.35 0.26 0.27 0.29 4 0.80 0.59 0.56 0.55 0.45 0.48 0.52 0.48 6 0.99 0.70 0.63 0.60 0.57 0.69 0.70 0.65 8 1.11 0.83 0.72 0.70 0.72 0.81 0.89 0.80 12 1.06 1.05 1.07 26 1.45 1.54 1.50 Example C. Effect of Hypromellose on the Formation of Degradants in Amlodipine Formulations Formulations were prepared containing Amlodipine according to Table C-1. Each formulation was dispensed into screw-capped HDPE bottles and stored at both 5° C. and ambient temperature. Samples were removed periodically and analyzed using the HPLC method in Example A. TABLE C-1 Composition (in mg/ml) of Amlodipine Formulations with Varying Hypromellose Content Formulation Component C1 C2 C3 C4 C5 C6 C7 C8 Amlodipine besylate a 1.39 1.39 1.39 1.39 1.39 1.39 1.39 1.39 Hypromellose K750 3.00 5.00 7.50 7.50 — — — — Citric acid, anhydrous 0.55 0.55 0.55 0.55 0.55 0.55 0.55 0.55 Sodium benzoate 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 Sucralose 0.70 0.70 0.70 0.70 0.70 0.70 0.70 0.70 Simethicone 0.15 0.15 0.15 0.15 0.15 0.15 0.15 0.15 Silicon dioxide 0.50 0.50 0.50 0.50 0.50 0.50 0.50 Artificial cherry flavor — — — 0.50 — 0.50 — 0.50 Hypromellose K1500 — — — — 3.00 5.00 7.50 7.50 Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. pH 4.88 4.88 4.86 4.89 4.88 4.88 4.87 4.91 a = equivalent to 1 mg/ml Amlodipine The results of the HPLC analysis for amlodipine and the main degradants in the samples stored at 5° C. are provided in Table C-2. TABLE C-2 Assay and Primary Degradants Present in the Formulations Formulation Weeks C1 C2 C3 C4 C5 C6 C7 C8 Amlodipine (% initial) Initial 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 4 100.00 97.18 99.17 98.39 97.30 98.96 97.08 98.08 8 100.49 98.81 99.23 98.67 96.88 98.32 96.76 98.17 12 99.72 99.17 100.27 99.57 95.76 98.49 97.42 98.95 26 99.46 99.89 98.00 98.64 92.35 97.30 96.94 97.96 52 95.73 96.34 98.91 99.67 96.59 100.29 97.44 96.27 78 98.78 98.10 98.74 99.14 99.39 97.91 97.48 95.92 104 97.56 97.33 98.54 97.56 95.74 96.98 97.94 99.09 USP Impurity A/EP Impurity D (wt % of Amlodipine) Initial 0.01 0.03 0.01 0.16 0.02 0.10 0.02 0.11 4 0.01 0.02 0.03 0.17 0.02 0.11 0.03 0.10 8 0.03 0.03 0.03 0.21 0.02 0.11 0.04 0.12 12 0.03 0.04 0.04 0.21 0.03 0.10 0.04 0.11 26 0.02 0.05 0.05 0.26 0.03 0.11 0.06 0.15 52 0.06 0.04 0.07 0.35 0.06 0.14 0.07 0.20 78 0.06 0.11 0.11 0.41 0.07 0.18 0.10 0.24 104 0.09 0.13 0.11 0.32 0.09 0.13 0.13 0.19 Impurity RRT 0.97 (wt % of Amlodipine) Initial 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 4 0.00 0.01 0.01 0.00 0.00 0.00 0.01 0.00 8 0.01 0.02 0.02 0.02 0.01 0.02 0.02 0.01 12 0.03 0.05 0.03 0.02 0.03 0.02 0.04 0.02 26 0.06 0.10 0.06 0.07 0.06 0.06 0.08 0.06 52 0.11 0.19 0.13 0.15 0.09 0.12 0.14 0.15 78 0.18 0.28 0.25 0.26 0.14 0.19 0.23 0.24 104 0.21 0.35 0.35 0.34 0.18 0.23 0.32 0.31 Total Impurities (wt % of Amlodipine) Initial 0.05 0.10 0.14 0.27 0.06 0.18 0.22 0.21 4 0.07 0.07 0.08 0.28 0.08 0.16 0.10 0.16 8 0.08 0.10 0.10 0.34 0.06 0.20 0.10 0.22 12 0.10 0.13 0.12 0.35 0.10 0.21 0.14 0.23 26 0.16 0.22 0.18 0.51 0.16 0.29 0.25 0.34 52 0.25 0.37 0.31 0.74 0.24 0.42 0.33 0.55 78 0.44 0.54 0.49 1.00 0.37 0.58 0.51 0.76 104 0.46 0.73 0.61 1.02 0.44 0.65 0.63 0.80 The results of the HPLC analysis for amlodipine and the main degradants in the samples stored at ambient temperature are provided in Table C-3. TABLE C-3 Assay and Primary Degradants Present in the Formulations Formulation Weeks C1 C2 C3 C4 C5 C6 C7 C8 Amlodipine (% initial) Initial 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 2 100.27 98.62 100.25 103.21 97.02 100.83 97.57 102.18 4 96.72 96.01 99.88 99.64 96.57 97.86 97.00 98.33 6 100.45 97.10 — 100.18 96.32 98.48 — 98.24 8 99.82 97.04 99.93 99.68 96.12 97.16 95.71 97.90 12 98.33 96.38 98.93 96.31 95.40 97.05 96.84 96.80 26 96.35 92.69 96.55 94.46 92.50 94.29 94.39 93.84 USP Impurity A/EP Impurity D (wt % of Amlodipine) Initial 0.01 0.03 0.01 0.16 0.02 0.10 0.02 0.11 2 0.03 0.05 0.08 0.27 0.03 0.12 0.07 0.16 4 0.05 0.09 0.10 0.35 0.04 0.14 0.09 0.20 6 0.06 0.12 — 0.47 0.05 0.19 — 0.24 8 0.09 0.12 0.13 0.56 0.06 0.21 0.12 0.32 12 0.08 0.16 0.17 0.73 0.08 0.29 0.16 0.40 26 0.16 0.24 0.26 1.30 0.16 0.50 0.25 0.70 Impurity RRT 0.97 (wt % of Amlodipine) Initial 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 2 0.05 0.09 0.10 0.08 0.05 0.07 0.09 0.08 4 0.13 0.22 0.20 0.19 0.12 0.17 0.17 0.19 6 0.20 0.33 — 0.30 0.17 0.24 — 0.29 8 0.24 0.40 0.40 0.41 0.21 0.30 0.33 0.37 12 0.32 0.51 0.58 0.58 0.26 0.38 0.49 0.50 26 0.38 0.60 0.89 0.91 0.30 0.47 0.69 0.69 Total Impurities (wt % of Amlodipine) Initial 0.05 0.10 0.14 0.27 0.06 0.18 0.22 0.21 2 0.16 0.26 0.26 0.50 0.16 0.36 0.23 0.44 4 0.34 0.48 0.43 0.80 0.31 0.52 0.37 0.60 6 0.41 0.69 — 1.10 0.42 0.69 — 0.79 8 0.54 0.81 0.72 1.44 0.53 0.87 0.64 1.06 12 0.70 1.06 1.02 1.90 0.66 1.15 0.94 1.40 26 1.02 1.45 1.64 3.40 1.00 1.97 1.44 2.45 Example D. Effect of Povidone on the Formation of Degradants in Amlodipine Formulations Formulations were prepared containing Amlodipine according to Table D-1. Each formulation was dispensed into screw-capped HDPE bottles and stored at both 5° C. and ambient temperature. Samples were removed periodically and analyzed using the HPLC method in Example A. TABLE D-1 Composition (in mg/ml) of Amlodipine Formulations with Varying Povidone Content Formulation Component D1 D2 D3 D4 D5 D6 Amlodipine besylate a 1.39 1.39 1.39 1.39 1.39 1.39 Hypromellose K750 — — — — — 3.00 Citric acid, anhydrous 0.90 0.90 0.90 0.55 0.43 0.55 Sodium benzoate 7.50 7.50 7.50 5.00 3.00 5.00 Sucralose 0.70 0.70 0.70 0.70 0.70 0.70 Simethicone — — — — — 0.15 Silicon dioxide 0.50 0.50 0.50 0.50 0.50 0.50 K-90 Povidone 10.00 20.00 30.00 30.00 30.00 10.00 Water q.s. q.s. q.s. q.s. q.s. q.s. pH 4.87 4.89 4.92 4.96 4.83 4.91 a = equivalent to 1 mg/ml Amlodipine The results of the HPLC analysis for amlodipine and the main degradants in the samples stored at 5° C. are provided in Table D-2. TABLE D-2 Assay and Primary Degradants Present in the Formulations Formulation Weeks D1 D2 D3 D4 D5 D6 Amlodipine (% initial) Initial 100.00 100.00 100.00 100.00 100.00 100.00 4 95.19 99.46 99.87 99.23 101.99 97.83 8 96.51 98.13 99.21 96.18 102.95 99.57 12 96.40 96.19 97.81 91.38 101.78 97.16 26 97.22 98.13 100.19 100.70 97.51 100.40 52 94.66 96.70 99.27 89.30 93.84 99.65 78 96.81 98.79 99.53 98.55 89.66 100.84 104 94.89 99.34 99.50 98.92 94.48 97.93 USP Impurity A/EP Impurity D (wt % of Amlodipine) Initial 0.03 0.06 0.05 0.06 0.03 0.02 4 0.07 0.04 0.06 0.06 0.05 0.04 8 0.04 0.07 0.06 0.07 0.07 0.05 12 0.05 0.06 0.05 0.06 0.06 0.08 26 0.04 0.03 0.07 0.08 0.09 0.05 52 0.04 0.04 0.06 0.08 0.07 0.07 78 0.05 0.06 0.07 0.09 0.11 0.08 104 0.07 0.07 0.08 0.11 0.12 0.09 Impurity RRT 0.97 (wt % of Amlodipine) Initial 0.00 0.00 0.00 0.00 0.00 0.00 4 0.00 0.00 0.00 0.00 0.00 0.00 8 0.00 0.00 0.00 0.00 0.00 0.01 12 0.00 0.00 0.00 0.00 0.00 0.01 26 0.00 0.00 0.01 0.01 0.02 0.05 52 0.01 0.01 0.02 0.02 0.03 0.10 78 0.01 0.02 0.03 0.04 0.05 0.14 104 0.02 0.03 0.04 0.05 0.07 0.21 Total Impurities (wt % of Amlodipine) Initial 0.09 0.11 0.10 0.09 0.07 0.07 4 0.11 0.08 0.10 0.12 0.10 0.08 8 0.10 0.14 0.10 0.12 0.12 0.10 12 0.18 0.17 0.21 0.12 0.13 0.14 26 0.11 0.16 0.18 0.16 0.19 0.16 52 0.17 0.15 0.24 0.16 0.20 0.21 78 0.14 0.16 0.20 0.20 0.28 0.31 104 0.18 0.20 0.23 0.31 0.33 0.43 The results of the HPLC analysis for amlodipine and the main degradants in the samples stored at ambient temperature are provided in Table D-3. TABLE D-3 Assay and Primary Degradants Present in the Formulations Formulation Weeks D1 D2 D3 D4 D5 D6 Amlodipine (% initial) Initial 100.00 100.00 100.00 100.00 100.00 100.00 2 94.21 97.15 98.15 91.04 99.93 99.36 4 95.69 97.67 99.15 99.49 99.87 97.93 6 95.18 97.15 97.20 97.49 101.11 98.11 8 94.74 96.16 96.17 98.99 98.59 99.38 12 91.38 95.07 95.50 97.35 96.85 96.51 26 93.65 92.14 93.58 96.84 92.72 96.77 USP Impurity A/EP Impurity D (wt % of Amlodipine) Initial 0.03 0.06 0.05 0.06 0.03 0.02 2 0.06 0.07 0.08 0.12 0.10 0.10 4 0.07 0.08 0.08 0.12 0.13 0.10 6 0.08 0.11 0.10 0.16 — 0.12 8 0.08 0.10 0.12 0.17 0.17 0.15 12 0.10 0.15 0.13 0.21 0.25 0.18 26 0.16 0.21 0.26 0.34 0.44 0.31 Impurity RRT 0.97 (wt % of Amlodipine) Initial 0.00 0.00 0.00 0.00 0.00 0.00 2 0.00 0.01 0.02 0.01 0.01 0.05 4 0.02 0.03 0.05 0.04 0.05 0.13 6 0.03 0.04 0.06 0.06 — 0.20 8 0.04 0.06 0.08 0.08 0.08 0.25 12 0.04 0.07 0.09 0.09 0.10 0.32 26 0.05 0.10 0.13 0.13 0.14 0.41 Total Impurities (wt % of Amlodipine) Initial 0.09 0.11 0.10 0.09 0.07 0.07 2 0.17 0.19 0.20 0.25 0.26 0.24 4 0.27 0.26 0.31 0.37 0.44 0.38 6 0.30 0.36 0.38 0.48 — 0.50 8 0.25 0.47 0.49 0.51 0.64 0.61 12 0.48 0.60 0.60 0.60 0.74 0.70 26 0.59 0.82 1.07 1.29 1.83 1.47 Example E. Formulations Containing 2-Naphthalene Sulfonate Salt Form of Amlodipine Formulations were prepared containing Amlodipine according to Table E-1. Each formulation was dispensed into screw-capped HDPE bottles and stored at both ambient temperature and 40° C. Samples were removed periodically and analyzed using the HPLC method in Example A. TABLE E-1 Composition (in mg/ml) of Amlodipine Formulations Formulation Component E1 E2 E3 Amlodipine besylatea 1.39 1.39 1.39 Sodium 2-naphthalene sulfonate 1.13 1.13 2.26 Citric acid, anhydrous 0.31 0.31 0.31 Sodium citrate 0.42 0.42 0.42 Sodium benzoate 1.00 1.00 1.00 Sucralose 0.70 0.70 0.70 Simethicone 0.15 0.15 0.15 Silicon dioxide 0.50 0.50 0.50 Artificial cherry flavor — 0.50 — Red 40 Al lake color — 0.015 — Hypromellose K750 5.00 5.00 5.00 Water q.s. q.s. q.s. pH 5.09 5.10 5.08 a= equivalent to 1 mg/ml Amlodipine The results of the HPLC analysis for amlodipine and the main degradants in the samples stored at ambient temperature are provided in Table E-2. TABLE E-2 Assay and Primary Degradants Present in the Formulations Formulation Weeks E1 E2 E3 Amlodipine (% initial) Initial 100.00 100.00 100.00 4 98.82 99.90 100.13 8 98.02 99.22 99.78 12 98.62 99.66 99.76 26 97.56 98.86 99.99 52 98.80 100.17 99.51 78 98.46 100.15 100.21 104 98.36 100.38 102.36 USP Impurity A/EP Impurity D (wt % of Amlodipine) Initial 0.06 0.03 0.02 4 0.04 0.04 0.04 8 0.04 0.04 0.04 12 0.05 0.05 0.06 26 0.09 0.07 0.08 52 0.14 0.12 0.14 78 0.21 0.17 0.16 104 0.26 0.22 0.22 Impurity RRT 0.97 (wt % of Amlodipine) Initial 0.00 0.00 0.00 4 0.01 0.01 0.00 8 0.02 0.02 0.00 12 0.03 0.03 0.01 26 0.06 0.07 0.03 52 0.13 0.13 0.05 78 0.18 0.19 0.07 104 0.23 0.24 0.09 Total Impurities (wt % of Amlodipine) Initial 0.31 0.51 0.45 4 0.10 0.10 0.08 8 0.10 0.09 0.13 12 0.12 0.12 0.12 26 0.23 0.26 0.17 52 0.42 0.36 0.36 78 0.50 0.48 0.31 104 0.69 0.60 0.54 The results of the HPLC analysis for amlodipine and the main degradants in the samples stored at 40° C. are provided in Table E-3. TABLE E-3 Assay and Primary Degradants Present in the Formulations Formulation Weeks E1 E2 E3 Amlodipine (% initial) Initial 100.00 100.00 100.00 2 98.23 98.65 98.59 4 98.20 98.67 99.41 8 95.28 97.08 97.82 12 94.44 95.59 97.12 26 87.62 90.88 91.30 USP Impurity A/EP Impurity D (wt % of Amlodipine) Initial 0.06 0.03 0.02 2 0.13 0.12 0.12 4 0.20 0.19 0.19 8 0.42 0.33 0.44 12 0.67 0.47 0.87 26 1.95 1.06 5.18 Impurity RRT 0.97 (wt % of Amlodipine) Initial 0.00 0.00 0.00 2 0.11 0.12 0.05 4 0.19 0.20 0.09 8 0.32 0.33 0.15 12 0.38 0.39 0.20 26 0.41 0.41 0.20 Total Impurities (wt % of Amlodipine) Initial 0.31 0.51 0.45 2 0.40 0.41 0.32 4 0.63 0.66 0.53 8 1.20 1.10 1.06 12 1.80 1.78 1.83 26 4.07 3.21 8.22 Example F. Stability of Amlodipine Formulations Prepared by Two-Container, One-Container, and Pharmacy Compounding Processes Formulation F6 was prepared by crushing 50 commercially available 5 mg amlodipine besylate tablets (Norvasc®, Pfizer Labs) with a mortar and pestle. A small amount of Ora-Blend (Paddock Laboratories, Inc.) was triturated with the resulting powder, and then more Ora-Blend was added geometrically with mixing. The suspension was transferred to a graduated cylinder and the mortar was rinsed with Ora-Blend. The rinse was added to the cylinder then additional Ora-Blend was added to reach a final volume of 250 ml and the suspension was mixed. Formulations F1, F2, and F3 were prepared according to example 5B (one-container) and formulations F4 and F5 were prepared according to example 3A (two-container). Each formulation was dispensed into screw-capped HDPE bottles and stored at both 5° C. and ambient temperature. Samples were removed periodically and analyzed using the HPLC method in Example A. TABLE F-1 Composition (in mg/mL) of Amlodipine Formulations Formulation Component F1 F2 F3 F4 F5 F6 Amlodipine besylate a 1.39 1.39 1.39 1.39 1.39 50 tablets Citric acid, anhydrous 0.31 0.31 0.31 0.31 0.31 — Sodium citrate, anhydrous 0.36 0.36 0.36 0.36 0.36 — Sodium benzoate 5.00 5.00 5.00 5.00 5.00 — Sucralose 0.70 0.70 0.70 0.70 0.70 — Simethicone 0.15 0.15 0.15 0.15 0.15 — Silicon dioxide 0.50 0.50 0.50 0.50 0.50 — Artificial cherry flavor 0.50 0.50 0.50 0.50 — — Polysorbate 80 0.50 1.00 2.00 1.00 1.00 — 0Hypromellose K1500 5.00 5.00 5.00 7.50 7.50 — Water q.s. q.s. q.s. q.s. q.s. — Ora-Blend ™ — — — — — q.s. to 250 ml pH 5.31 5.33 5.35 5.35 5.36 4.64 a = equivalent to 1 mg/ml Amlodipine The results of the HPLC analysis for amlodipine and the main degradants in the samples stored at 5° C. are provided in Table F-2. TABLE F-2 Assay and Primary Degradants Present in the Formulations Formulation Weeks F1 F2 F3 F4 F5 F6 Amlodipine (% initial) Initial 100.00 100.00 100.00 100.00 100.00 100.0 2 99.23 100.74 99.17 — 101.85 — 4 — — — 100.37 101.69 100.3 6 98.98 101.53 99.72 — 101.09 — 8 99.70 100.86 99.06 101.12 101.40 97.2 12 98.98 100.49 98.91 100.35 101.12 26 101.14 100.91 100.20 100.26 52 99.69 100.87 99.85 101.52 78 97.82 99.94 98.94 101.72 104 99.74 99.90 98.19 USP Impurity A/EP Impurity D (wt % of Amlodipine) Initial 0.04 0.06 0.04 0.01 0.00 1.34 2 0.00 0.00 0.01 — 0.02 — 4 — — — 0.01 0.03 0.71 6 0.04 0.02 0.02 — 0.03 — 8 0.01 0.02 0.02 0.03 0.05 1.24 12 0.03 0.02 0.02 0.10 0.04 26 0.05 0.06 0.06 0.05 52 0.04 0.04 0.05 0.07 78 0.06 0.05 0.06 0.04 104 0.04 0.04 0.06 Impurity RRT 0.97 (wt % of Amlodipine) Initial 0.00 0.00 0.00 0.00 0.00 0.00 2 0.00 0.00 0.00 — 0.00 — 4 — — — 0.00 0.00 0.00 6 0.00 0.00 0.00 — 0.01 — 8 0.00 0.00 0.00 0.01 0.01 0.00 12 0.01 0.00 0.01 0.02 0.03 26 0.04 0.04 0.04 0.05 52 0.09 0.09 0.11 0.11 78 0.14 0.15 0.16 0.20 104 0.19 0.20 0.22 Total Impurities (wt % of Amlodipine) Initial 0.09 0.14 0.11 0.04 0.00 1.76 2 0.04 0.03 0.06 — 0.06 — 4 — — — 0.04 0.08 1.00 6 0.07 0.05 0.06 — 0.09 — 8 0.05 0.06 0.07 0.06 0.08 1.52 12 0.08 0.05 0.06 0.19 0.09 26 0.12 0.13 0.14 0.13 52 0.23 0.22 0.29 0.31 78 0.42 0.40 0.45 0.43 104 0.41 0.44 0.53 The results of the HPLC analysis for amlodipine and the main degradants in the samples stored at ambient temperature are provided in Table F-3. TABLE F-3 Assay and Primary Degradants Present in the Formulations Formulation Weeks F1 F2 F3 F4 F5 F6 Amlodipine (% initial) Initial 100.00 100.00 100.00 100.00 100.00 100.0 2 100.65 100.52 99.57 101.16 100.89 97.7 4 — — — 99.99 100.41 102.1 6 100.23 100.42 98.78 100.38 100.47 94.3 8 99.16 100.28 98.99 102.38 100.68 90.6 12 99.71 99.46 98.52 100.53 99.44 26 98.13 98.53 97.24 97.27 USP Impurity A/EP Impurity D (wt % of Amlodipine) Initial 0.04 0.06 0.04 0.01 0.00 1.34 2 0.05 0.04 0.05 0.04 0.05 1.62 4 — — — 0.05 0.06 2.24 6 0.06 0.06 0.07 0.09 0.08 2.78 8 0.07 0.06 0.08 0.10 0.11 3.24 12 0.10 0.09 0.10 0.15 0.13 26 0.18 0.17 0.18 0.24 Impurity RRT 0.97 (wt % of Amlodipine) Initial 0.00 0.00 0.00 0.00 0.00 0.00 2 0.03 0.03 0.04 0.03 0.04 0.03 4 — — — 0.06 0.10 0.05 6 0.12 0.13 0.13 0.11 0.13 0.09 8 0.17 0.17 0.17 0.17 0.18 0.11 12 0.23 0.23 0.24 0.28 0.30 26 0.36 0.35 0.36 0.49 Total Impurities (wt % of Amlodipine) Initial 0.09 0.14 0.11 0.04 0.00 1.76 2 0.16 0.16 0.17 0.10 0.18 2.09 4 — — — 0.24 0.37 3.09 6 0.39 0.38 0.43 0.38 0.50 4.20 8 0.46 0.48 0.52 0.51 0.64 5.05 12 0.69 0.68 0.76 0.85 1.02 26 1.26 1.38 1.47 1.65 Example G. Effect of pH, Preservatives, and Hypromellose on Stability of Amlodipine Benzoate Formulations at Accelerated Temperatures Formulations were prepared containing Amlodipine according to Table G-1. Each formulation was dispensed into screw-capped HDPE bottles and stored at 60° C. Samples were removed periodically and analyzed using the HPLC method in Example A. TABLE G-1 Composition (in mg/mL) of Amlodipine Formulations Formulation Component G1 G2 G3 G4 G5 G6 G7 G8 Amlodipine besylate a 1.39 1.39 1.39 1.39 1.39 1.39 1.39 1.39 Citric acid, anhydrous 11.66 0.33 0.71 — — — 0.31 0.31 Sodium citrate, anhydrous — 0.35 — — — — 0.36 0.36 Phosphoric acid — — — 0.96 0.67 0.39 — — Sodium benzoate 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 Sucralose 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 Methylparaben sodium — — 1.72 1.72 1.72 1.72 — — Propylparaben sodium — — 0.17 0.17 0.17 0.17 — — Simethicone 0.15 0.15 0.15 0.15 0.15 0.15 0.15 0.15 Silicon dioxide 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Artificial cherry flavor 0.5 0.5 0.5 0.5 0.5 0.5 — — Polysorbate 80 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Hypromellose K1500 5.0 5.0 5.0 5.0 5.0 5.0 7.5 10.0 Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s pH 3.0 5.3 6.4 6.4 7.2 8.0 5.4 5.4 a = equivalent to 1 mg/ml Amlodipine The results of the HPLC analysis for amlodipine and the main degradants in the samples are provided in Table G-2. TABLE G-2 Assay and Primary Degradants Present in the Formulations Formulation Hours G1 G2 G3 G4 G5 G6 G7 G8 Amlodipine (% initial) 0 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 16 79.51 94.37 93.87 92.75 91.50 85.26 — — 17 — — — — — — 93.42 96.47 36 — — — — — — 90.28 — 40 66.39 91.31 91.68 92.04 85.87 75.43 — — 52 — — — — — — 87.31 89.50 USP Impurity A/EP Impurity D (wt % of Amlodipine) 0 0.20 0.03 0.03 0.03 0.06 0.03 0.03 0.01 16 2.39 0.16 0.14 0.24 0.24 0.21 — — 17 — — — — — — 0.18 0.18 36 — — — — — — 0.29 — 40 4.24 0.29 0.21 0.35 0.34 0.35 — — 52 — — — — — — 0.58 0.50 Impurity RRT 0.97 (wt % of Amlodipine) 0 0.00 0.00 0.00 0.00 0.00 0.00 0.04 0.00 16 0.37 0.16 0.07 0.03 0.04 0.05 — — 17 — — — — — — 0.21 0.20 36 — — — — — — 0.44 — 40 0.52 0.30 0.15 0.08 0.08 0.13 — — 52 0.54 0.62 Total Impurities (wt % of Amlodipine) 0 0.48 0.08 0.19 0.23 0.43 0.72 0.10 0.08 16 7.86 1.36 1.38 1.18 2.06 3.22 — — 17 — — — — — — 1.43 1.41 36 — — — — — — 3.12 — 40 14.22 2.79 2.53 2.41 3.88 5.94 — — 52 — — — — — — 4.82 4.65 Example H. Effect of pH and Preservatives on Stability of Amlodipine Naphthalene Sulfonate Formulations at Accelerated Temperatures Formulations were prepared containing Amlodipine according to Table H-1. Each formulation was dispensed into screw-capped HDPE bottles and stored at 60° C. Samples were removed periodically and analyzed using the HPLC method in Example A. TABLE H-1 Composition (in mg/mL) of Amlodipine Formulations Formulation Component H1 H2 H3 H4 H5 H6 Amlodipine besylate a 1.39 1.39 1.39 1.39 1.39 1.39 Citric acid, anhydrous 2.92 0.73 0.28 — — — Sodium citrate, anhydrous — — 0.41 — — — Phosphoric acid — — — 1.28 0.85 0.30 Dibasic sodium phosphate, — — — 0.31 — 0.18 heptahydrate Sodium benzoate 1.0 1.0 1.0 — — — Sodium 2-naphthalene sulfonate 1.13 1.13 1.13 1.13 1.13 1.13 Sucralose 0.7 0.7 0.7 0.7 0.7 0.7 Methylparaben sodium — — — 1.72 1.72 1.72 Propylparaben sodium — — — 0.17 0.17 0.17 Simethicone 0.15 0.15 0.15 0.15 0.15 0.15 Silicon dioxide 0.5 0.5 0.5 0.5 0.5 0.5 Artificial cherry flavor 0.5 0.5 0.5 0.5 0.5 0.5 Polysorbate 80 1.0 1.0 1.0 1.0 1.0 1.0 Hypromellose K1500 5.0 5.0 5.0 5.0 5.0 5.0 Water q.s. q.s. q.s. q.s. q.s. q.s. pH 3.0 4.0 5.0 5.9 6.9 7.9 The results of the HPLC analysis for amlodipine and the main degradants in the samples are provided in Table H-2. TABLE H-2 Assay and Primary Degradants Present in the Formulations Formulation Hours H1 H2 H3 H4 H5 H6 Amlodipine (% initial) 0 100.00 100.00 100.00 100.00 100.00 100.00 16 90.01 96.31 97.94 99.10 99.76 92.65 40 69.77 85.46 90.42 95.03 91.15 65.16 USP Impurity A/EP Impurity D (wt % of Amlodipine) 0 0.07 0.03 0.04 0.08 0.06 0.23 16 1.44 0.33 0.14 0.37 0.42 0.40 40 4.98 2.65 1.01 0.88 0.75 1.14 Impurity RRT 0.97 (wt % of Amlodipine) 0 0.00 0.00 0.00 0.00 0.00 0.00 16 0.15 0.20 0.11 0.00 0.02 0.05 40 0.38 0.52 0.31 0.02 0.07 0.05 Total Impurities (wt % of Amlodipine) 0 0.13 0.09 0.25 1.09 2.92 5.57 16 3.44 1.17 0.81 1.76 3.04 13.64 40 10.82 5.76 3.39 3.21 6.92 35.53 Example I. Effect of Crystallization Time on the Formation of Amlodipine Salts A formulation was prepared in a polyethylene vessel with magnetic stirring. Purified water (33.5 kg) was added to the vessel and stirring was initiated. Polysorbate 80 (350 g) was added to the vessel along with a 500 g aliquot of purified water used to rinse the polysorbate container. The solution was stirred for 10 minutes. Amlodipine Besylate (485.5 g) was then added to the vessel along with a 500 g aliquot of purified water used to rinse the amlodipine container. The solution was stirred for 5 minutes then 1750 g of sodium benzoate were added to the container. Samples were taken from the formulation every five minutes for an hour, filtered through 0.2 micron filters to isolate only the soluble amlodipine, and analyzed by HPLC for amlodipine content. The results of the HPLC analysis for the free amlodipine fraction are provided in FIG. 1. Example J. Stability of Formulations Using Avicel RC-591 as the Suspending Agent Formulations were prepared containing Amlodipine according to Table J-1. Each formulation was dispensed into screw-capped HDPE bottles and stored at both 5° C. and 25° C. Samples were removed periodically and analyzed using the HPLC method in Example A. TABLE J-1 Composition (in mg/ml) of Amlodipine Formulations Formulation Component J1 J2 J3 Amlodipine besylatea 1.39 1.39 1.39 Citric acid, anhydrous 0.31 0.31 0.31 Sodium citrate 0.36 0.36 0.36 Sodium benzoate 5.00 5.00 5.00 Sucralose 0.70 0.70 0.70 Simethicone 0.15 0.15 0.15 Artificial cherry flavor 0.50 0.50 0.50 Polysorbate 80 0.50 0.50 0.50 Avicel ® RC-591 7.5 10.00 15.00 Water q.s. q.s. q.s. pH 5.36 5.33 5.34 a= equivalent to 1 mg/ml Amlodipine The results of the HPLC analysis for amlodipine and the main degradants in the samples stored at 5° C. are provided in Table J-2. TABLE J-2 Assay and Primary Degradants Present in the Formulations Formulation Weeks J1 J2 J3 Amlodipine (% initial) Initial 100.00 100.00 100.00 2 98.80 96.18 96.45 4 99.03 96.35 96.89 6 100.53 99.32 98.52 8 98.71 96.96 96.77 12 97.58 96.75 96.00 26 99.24 98.27 97.90 USP Impurity A/EP Impurity D (wt % of Amlodipine) Initial 0.02 0.02 0.04 2 0.03 0.03 0.02 4 0.04 0.04 0.06 6 0.02 0.02 0.04 8 0.03 0.03 0.05 12 0.02 0.03 0.03 26 0.04 0.06 0.07 Impurity RRT 0.97 (wt % of Amlodipine) Initial 0.00 0.00 0.00 2 0.00 0.00 0.00 4 0.00 0.00 0.00 6 0.00 0.00 0.00 8 0.00 0.00 0.00 12 0.00 0.00 0.00 26 0.01 0.01 0.01 Total Impurities (wt % of Amlodipine) Initial 0.09 0.09 0.14 2 0.14 0.16 0.10 4 0.12 0.14 0.14 6 0.09 0.10 0.09 8 0.16 0.13 0.18 12 0.16 0.18 0.18 26 0.18 0.22 0.18 The results of the HPLC analysis for amlodipine and the main degradants in the samples stored at 25° C. are provided in Table J-3. TABLE J-3 Assay and Primary Degradants Present in the Formulations Formulation Weeks J1 J2 J3 Amlodipine (% initial) Initial 100.00 100.00 100.00 2 99.27 97.16 96.52 4 98.94 97.73 96.89 6 99.61 98.81 98.20 8 97.34 96.91 95.85 12 95.57 95.48 93.25 26 95.39 93.67 92.65 USP Impurity A/EP Impurity D (wt % of Amlodipine) Initial 0.02 0.02 0.04 2 0.05 0.04 0.06 4 0.06 0.04 0.06 6 0.08 0.05 0.06 8 0.05 0.06 0.08 12 0.06 0.07 0.09 26 0.09 0.09 0.13 Impurity RRT 0.97 (wt % of Amlodipine) Initial 0.00 0.00 0.00 2 0.01 0.01 0.01 4 0.02 0.02 0.03 6 0.03 0.03 0.03 8 0.03 0.03 0.04 12 0.03 0.03 0.04 26 0.03 0.03 0.04 Total Impurities (wt % of Amlodipine) Initial 0.09 0.09 0.14 2 0.20 0.27 0.28 4 0.38 0.39 0.42 6 0.52 0.55 0.59 8 0.69 0.73 0.83 12 0.96 1.11 1.15 26 1.64 1.37 1.98 Example K. Clinical Trial: Bioavailability Study of 5 mg Amlodipine Oral Suspension Vs. Norvasc® 5 mg Tablets Under Fasted Conditions The objective of this single dose open-label, randomized, two-period, two-treatment crossover study was to compare the relative oral bioavailability of a test formulation of 5 mL of amlodipine oral suspension, 1 mg/mL (formulation F4), to an equivalent oral dose of the commercially available comparator product, Norvasc® (amlodipine besylate) 5 mg tablet, when administered under fasted conditions in healthy adults. Study design: Ten healthy adult subjects received a single 5 mL dose of amlodipine oral suspension, 1 mg/mL, formulation F4 (Treatment A), in one period and a separate single dose of Norvasc® (amlodipine besylate) 5 mg tablet (Treatment B) in another period. Each treatment was administered after an overnight fast of at least 10 hours, followed by a 4-hour fast postdose. During each period, blood samples were obtained prior to and following each dose at selected times through 168 hours postdose. Pharmacokinetic parameters were calculated for each formulation using non-compartmental methods. Statistical Methods: The concentration-time data were analyzed using noncompartmental methods in Phoenix™ WinNonlin® (Version 6.3, Pharsight Corporation). Concentration-time data that were below the limit of quantitation (BLQ) were treated as zero in the data summarization and descriptive statistics. In the pharmacokinetic analysis, BLQ concentrations were treated as zero from time-zero up to the time at which the first quantifiable concentration was observed; embedded and/or terminal BLQ concentrations were treated as “missing”. Actual sample times were used for all pharmacokinetic and statistical analyses. Analysis of variance (ANOVA) and the Schuirmann's two one-sided t-test procedures at the 5% significance level were applied to the log-transformed pharmacokinetic exposure parameters, Cmax, AUClast, and AUCinf. The 90% confidence interval for the ratio of the geometric means (Test/Reference) was calculated. Bioequivalence was declared if the lower and upper confidence intervals (CIs) of the log-transformed parameters were within 80% to 125%. Results: A total of 10 subjects participated in the study and 8 of these subjects completed both study periods. Based on the geometric mean ratios of amlodipine AUCs (AUClast and AUCinf), the bioavailability of the amlodipine oral suspension (formulation F4) relative to the Norvasc® tablet was approximately 103% to 104%. The geometric mean ratio of amlodipine Cmax was approximately 100%. The 90% CI for comparing the maximum exposure to amlodipine, based on ln (Cmax), was within the accepted 80% to 125% limits. The 90% CIs for comparing total systemic exposure to amlodipine, based on ln (AUClast) and ln (AUCinf), was within the accepted 80% to 125% limits. Therefore, the 5 mL test formulation of amlodipine oral suspension, 1 mg/mL, is bioequivalent to the reference product, Norvasc® (amlodipine besylate) tablet, 5 mg, under fasted conditions. Example L. Characterization of Amlodipine Benzoate A suspension was prepared by adding 0.50 g of NuSil Med-342 simethicone (30% simethicone) to 90 mL water in a glass beaker with stirring. Sodium benzoate (5.00 g) was added to the suspension and dissolved. Amlodipine besylate (1.40 g) was added to 10 mL water, then the amlodipine suspension was added to the benzoate suspension over 2-4 minutes. The resulting suspension was mixed for 30 minutes at ambient temperature. The solids were collected on filter paper and washed with ˜150 mL cold water in 15 mL portions. The solid was dried under vacuum for 1 hour, then dried in a desiccator for 18 hours. A portion of the solids were weighed and dissolved in water/HPLC diluent and the resulting solution was analyzed by a validated HPLC procedure for the presence of amlodipine and benzoic acid. The resulting molar ratio of benzoic acid:amlodipine in the solid was calculated as 1.00:1.05 demonstrating the formation of amlodipine benzoate. Example M. Solubility of Amlodipine Besylate and Amlodipine Benzoate in the Presence of Added Sodium Benzoate Amlodipine benzoate was prepared by adding 1.39 g amlodipine besylate to 100 ml purified water in a glass container. Five grams of sodium benzoate were then added and the solution was stirred for 30 minutes at ambient temperature. The resulting suspension was vacuum filtered through #1 Whatman filter paper to collect the insoluble fraction. The collected solids were rinsed with ten separate 15 mL increments (150 mL total) of 1-5° C. degree water. The solids were dried on the vacuum filtration apparatus for 1 hour then dried overnight in a desiccator. Fifteen milliliter polypropylene centrifuge tubes were set up in duplicate as shown in Table M-1. Amlodipine besylate or amlodipine benzoate was added to each tube in amounts in excess of the anticipated solubility. Ten milliliter aliquots of water, or water with varying amounts of sodium benzoate were added to each tube. The pH of each tube was adjusted to 5.3 with the addition of citric acid. The tubes were capped and mixed by inversion for 5 days to allow the suspensions to equilibrate. After the equilibration time, the tubes were opened and immediately filtered through 0.45 micron nylon filters. The clear filtrates were analyzed according to the method in Example A. The results of the HPLC analysis for the amounts of amlodipine in solution are presented in FIG. 2. TABLE M-1 Composition of Solubility Study Tubes Duplicate Tube Set Component J1 J2 J3 J4 J5 J6 Amlodipine besylate (mg) 50 — — — — — Amlodipine benzoate (mg) — 50 50 50 50 50 Citric acid, anhydrous (mg) Amount as needed to achieve pH 5.3 Sodium benzoate (mg) 0 0 2 10 30 50 Water (mL) 10 10 10 10 10 10 Measured pH 5.3 5.3 5.3 5.3 5.3 5.3 While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
<SOH> BACKGROUND OF THE INVENTION <EOH>Hypertension, or high blood pressure, is a serious health issue in many countries. According to the National Heart Blood and Lung Institute, it is thought that about 1 in 3 adults in the United States alone have hypertension. Left unchecked, hypertension is considered a substantial risk factor for cardiovascular and other diseases including coronary heart disease, myocardial infarction, congestive heart failure, stroke and kidney failure. Hypertension is classified as primary (essential) hypertension or secondary hypertension. Primary hypertension has no known cause and may be related to a number of environmental, lifestyle and genetic factors such as stress, obesity, smoking, inactivity and sodium intake. Secondary hypertension can be caused by drug or surgical interventions or by abnormalities in the renal, cardiovascular or endocrine system. A number of antihypertensive drugs are available for treating hypertension. Various therapeutic classes of antihypertensive drugs include alpha-adrenergic blockers, beta-adrenergic blockers, calcium-channel blockers, hypotensives, mineralcorticoid antagonists, central alpha-agonists, diuretics and rennin-angiotensin-aldosterone inhibitors which include angiotensin II receptor antagonists (ARB) and angiotensin-converting enzyme (ACE) inhibitors. Angiotensin-converting enzyme (ACE) inhibitors inhibit angiotensin-converting enzyme (ACE), a peptidyl dipeptidase that catalyzes angiotension I to angiotension II, a potent vasoconstrictor involved in regulating blood pressure. Amlodipine is a calcium channel blocker. It affects the movement of calcium into the cells of the heart and blood vessels. As a result, amlodipine relaxes blood vessels and increases the supply of blood and oxygen to the heart while reducing its workload. The structural formula of amlodipine is as follows: Amlodipine is currently administered in the form of oral tablets, (e.g., Norvasc) or in the form of a refrigerated liquid formulation. In addition to the treatment of hypertension, amlodipine tablets have been used for coronary artery disease (CAD) such as chronic stable angina, vasospastic angina, or angiographically documented coronary artery disease in patients without heart failure or an ejection fraction <40%.
<SOH> SUMMARY OF THE INVENTION <EOH>Disclosed herein is an oral liquid formulation, comprising: (i) amlodipine benzoate in an amount corresponding to 1.0 mg/ml amlodipine freebase; (ii) about 3 mM of a citrate buffer; (iii) about 0.2 mg/ml to about 10 mg/ml of sodium benzoate; (iv) about 0.5 mg/ml of silicon dioxide; (v) about 7.5 mg/ml of hydroxypropyl methylcellulose; (vi) about 0.15 mg/ml simethicone; (vii) about 1.0 mg/ml of polysorbate 80; and (viii) water; wherein the formulation is stable between about 5±5° C. and about 25±5° C. for at least 12 months. In some embodiments of an oral liquid formulation, the amlodipine benzoate is formed in situ. In some embodiments of an oral liquid formulation, the amlodipine benzoate is formed by the reaction of a pharmaceutically acceptable salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate with a molar excess of sodium benzoate. In some embodiments of an oral liquid formulation, the salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate is selected from amlodipine besylate, amlodipine tosylate, amlodipine mesylate, amlodipine succinate, amlodipine salicylate, amlodipine maleate, amlodipine acetate, and amlodipine hydrochloride. In some embodiments of an oral liquid formulation, the amlodipine benzoate is formed by the reaction of amlodipine besylate with a molar excess of sodium benzoate. In some embodiments of an oral liquid formulation, the formulation further comprises a flavoring agent. In some embodiments of an oral liquid formulation, the formulation further comprises a sweetener. In some embodiments of an oral liquid formulation, the sweetener is sucralose. In some embodiments of an oral liquid formulation, the formulation is in the form of a suspension. In some embodiments of an oral liquid formulation, the pH of the formulation is between about 3 and about 8. In some embodiments of an oral liquid formulation, the pH is between about 4 and about 5. In some embodiments of an oral liquid formulation, the pH is between about 5 and about 6. In some embodiments of an oral liquid formulation, the formulation is stable at about 25±5° C. for at least 12 months. In some embodiments of an oral liquid formulation, the formulation is stable at about 5±5° C. for at least 12 months. In some embodiments of an oral liquid formulation, the formulation is stable at about 25±5° C. for at least 24 months. In some embodiments of an oral liquid formulation, the formulation is stable at about 5±5° C. for at least 24 months. Also disclosed herein is a method of treating hypertension in a subject comprising administering to that subject an oral liquid formulation, comprising: (i) amlodipine benzoate in an amount corresponding to 1.0 mg/ml amlodipine freebase; (ii) about 3 mM of a citrate buffer; (iii) about 0.2 mg/ml to about 10 mg/ml of sodium benzoate; (iv) about 0.5 mg/ml of silicon dioxide; (v) about 7.5 mg/ml of hydroxypropyl methylcellulose; (vi) about 0.15 mg/ml simethicone; (vii) about 1.0 mg/ml of polysorbate 80; and (viii) water; wherein the formulation is stable between about 5±5° C. and about 25±5° C. for at least 12 months. In some embodiments of a method of treating hypertension, the amlodipine benzoate is formed in situ. In some embodiments of a method of treating hypertension, the amlodipine benzoate is formed by the reaction of a pharmaceutically acceptable salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate with a molar excess of sodium benzoate. In some embodiments of a method of treating hypertension, the salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate is selected from amlodipine besylate, amlodipine tosylate, amlodipine mesylate, amlodipine succinate, amlodipine salicylate, amlodipine maleate, amlodipine acetate, and amlodipine hydrochloride. In some embodiments of a method of treating hypertension, the amlodipine benzoate is formed by the reaction of amlodipine besylate with a molar excess of sodium benzoate. In some embodiments of a method of treating hypertension, the formulation further comprises a flavoring agent. In some embodiments of a method of treating hypertension, the formulation further comprises a sweetener. In some embodiments of an oral liquid formulation, the sweetener is sucralose. In some embodiments of a method of treating hypertension, the formulation is in the form of a suspension. In some embodiments of a method of treating hypertension, the pH of the formulation is between about 3 and about 8. In some embodiments of a method of treating hypertension, the pH is between about 4 and about 5. In some embodiments of a method of treating hypertension, the pH is between about 5 and about 6. In some embodiments of a method of treating hypertension, the formulation is stable at about 25±5° C. for at least 12 months. In some embodiments of a method of treating hypertension, the formulation is stable at about 5±5° C. for at least 12 months. In some embodiments of a method of treating hypertension, the formulation is stable at about 25±5° C. for at least 24 months. In some embodiments of a method of treating hypertension, the formulation is stable at about 5±5° C. for at least 24 months. In some embodiments of a method of treating hypertension, the hypertension is primary (essential) hypertension. In some embodiments of a method of treating hypertension, the hypertension is secondary hypertension. In some embodiments of a method of treating hypertension, the subject has blood pressure values greater than or equal to 140/90 mmm Hg. In some embodiments of a method of treating hypertension, the subject is an adult. In some embodiments of a method of treating hypertension, the subject is elderly. In some embodiments of a method of treating hypertension, the subject is a child. In some embodiments of a method of treating hypertension, the formulation is administered to the subject in a fasted state. In some embodiments of a method of treating hypertension, the formulation is administered to the subject in a fed state. In some embodiments of a method of treating hypertension, the formulation is further administered in combination with an agent selected from the group consisting of diuretics, beta blockers, alpha blockers, mixed alpha and beta blockers, calcium channel blockers, angiotensin II receptor antagonists, ACE inhibitors, aldosterone antagonists, and alpha-2 agonists. Also disclosed herein is a method of treating Coronary Artery Disease (CAD) in a subject comprising administering to that subject an oral liquid formulation, comprising: (i) amlodipine benzoate in an amount corresponding to 1.0 mg/ml amlodipine freebase; (ii) about 3 mM of a citrate buffer; (iii) about 0.2 mg/ml to about 10 mg/ml of sodium benzoate; (iv) about 0.5 mg/ml of silicon dioxide; (v) about 7.5 mg/ml of hydroxypropyl methylcellulose; (vi) about 0.15 mg/ml simethicone; (vii) about 1.0 mg/ml of polysorbate 80; and (viii) water; wherein the formulation is stable between about 5±5° C. and about 25±5° C. for at least 12 months. In some embodiments of a method of treating Coronary Artery Disease (CAD), the amlodipine benzoate is formed in situ. In some embodiments of a method of treating Coronary Artery Disease (CAD), the amlodipine benzoate is formed by the reaction of a pharmaceutically acceptable salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate with a molar excess of sodium benzoate. In some embodiments of a method of treating Coronary Artery Disease (CAD), the salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate is selected from amlodipine besylate, amlodipine tosylate, amlodipine mesylate, amlodipine succinate, amlodipine salicylate, amlodipine maleate, amlodipine acetate, and amlodipine hydrochloride. In some embodiments of a method of treating Coronary Artery Disease (CAD), the amlodipine benzoate is formed by the reaction of amlodipine besylate with a molar excess of sodium benzoate. In some embodiments of a method of treating Coronary Artery Disease (CAD), the formulation further comprises a flavoring agent. In some embodiments of a method of treating Coronary Artery Disease (CAD), the formulation further comprises a sweetener. In some embodiments of an oral liquid formulation, the sweetener is sucralose. In some embodiments of a method of treating Coronary Artery Disease (CAD), the formulation is in the form of a suspension. In some embodiments of a method of treating Coronary Artery Disease (CAD), the pH of the formulation is between about 3 and about 8. In some embodiments of a method of treating Coronary Artery Disease (CAD), the pH is between about 4 and about 5. In some embodiments of a method of treating Coronary Artery Disease (CAD), the pH is between about 5 and about 6. In some embodiments of a method of treating Coronary Artery Disease (CAD), the formulation is stable at about 25±5° C. for at least 12 months. In some embodiments of a method of treating Coronary Artery Disease (CAD), the formulation is stable at about 5±5° C. for at least 12 months. In some embodiments of a method of treating Coronary Artery Disease (CAD), the formulation is stable at about 25±5° C. for at least 24 months. In some embodiments of a method of treating Coronary Artery Disease (CAD), the formulation is stable at about 5±5° C. for at least 24 months. In some embodiments of a method of treating Coronary Artery Disease (CAD), the Coronary Artery Disease (CAD) is chronic stable angina, vasospastic angina, or angiographically documented coronary artery disease. In some embodiments of a method of treating Coronary Artery Disease (CAD), the angiographically documented coronary artery disease is in patients without heart failure or an ejection fraction <40%. In some embodiments of a method of treating Coronary Artery Disease (CAD), the formulation is further administered in combination with an additional anti-anginal agent. Disclosed herein is an oral liquid formulation, comprising: (i) a pharmaceutically acceptable salt of amlodipine; (ii) a buffer; (iii) water; and (iv) optionally one or more agents selected from the group consisting of preservatives, flavoring agents, sweetening agents, surfactants, suspensions aids, and antifoaming agents; wherein the formulation is stable between about 5±5° C. and about 25±5° C. for at least 12 months. In some embodiments of an oral liquid formulation, the pharmaceutically acceptable salt of amlodipine is amlodipine benzoate or amlodipine naphthalene sulfonate. In some embodiments of an oral liquid formulation, the amlodipine benzoate or amlodipine naphthalene sulfonate are formed in situ. In some embodiments of an oral liquid formulation, the amlodipine benzoate or amlodipine naphthalene sulfonate are formed by the reaction of a pharmaceutically acceptable salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate or amlodipine naphthalene sulfonate with a molar excess of a salt forming agent. In some embodiments of an oral liquid formulation, the pharmaceutically acceptable salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate or amlodipine naphthalene sulfonate is amlodipine besylate. In some embodiments of an oral liquid formulation, the salt forming agent is sodium benzoate. In some embodiments of an oral liquid formulation, the amount of sodium benzoate as the salt forming agent is about 1.0 mg/ml to about 10.0 mg/ml. In some embodiments of an oral liquid formulation, the salt forming agent is sodium naphthalene-2-sulfonate. In some embodiments of an oral liquid formulation, the amount of sodium naphthalene-2-sulfonate as the salt forming agent is about 0.5 mg/ml to about 2.5 mg/ml. In some embodiments of an oral liquid formulation, the oral liquid formulation comprises a surfactant. In some embodiments of an oral liquid formulation, the surfactant is polysorbate 80. In some embodiments of an oral liquid formulation, the amount of the surfactant is about 0.1 mg/ml to about 2.5 mg/ml. In some embodiments of an oral liquid formulation, the oral liquid formulation comprises a preservative. In some embodiments of an oral liquid formulation, the preservative is selected from the group consisting of sodium benzoate, a paraben or paraben salt, and combinations thereof. In some embodiments of an oral liquid formulation, the amount of preservative is about 0.1 mg/ml to about 2.0 mg/ml. In some embodiments of an oral liquid formulation, the buffer comprises a citrate buffer. In some embodiments of an oral liquid formulation, the citrate buffer concentration is about 3 mM. In some embodiments of an oral liquid formulation, the buffer comprises a phosphate buffer. In some embodiments of an oral liquid formulation, the phosphate buffer concentration is about 3 mM. In some embodiments of an oral liquid formulation, the oral liquid formulation comprises a suspension aid. In some embodiments of an oral liquid formulation, the suspension aid comprises silicon dioxide, hydroxypropyl methylcellulose, methylcellulose, microcrystalline cellulose, carboxymethylcellulose sodium, polyvinylpyrrolidone, or combinations thereof. In some embodiments of an oral liquid formulation, the suspension aid is silicon dioxide. In some embodiments of an oral liquid formulation, the amount of silicon dioxide is about 0.1 mg/ml to about 1.0 mg/ml. In some embodiments of an oral liquid formulation, the suspension aid is hydroxypropyl methylcellulose. In some embodiments of an oral liquid formulation, the amount of hydroxypropyl methylcellulose is about 3 mg/ml to about 10 mg/ml. In some embodiments of an oral liquid formulation, the suspension aid is a combination of silicon dioxide and hydroxypropyl methylcellulose. In some embodiments of an oral liquid formulation, the amount of silicon dioxide is about 0.1 mg/ml to about 1.0 mg/ml and the amount of hydroxypropyl methylcellulose is about 3 mg/ml to about 10 mg/ml. In some embodiments of an oral liquid formulation, the oral liquid formulation comprises an antifoaming agent. In some embodiments of an oral liquid formulation, the antifoaming agent is simethicone. In some embodiments of an oral liquid formulation, the amount of the antifoaming agent is about 0.05 mg/ml to about 1.0 mg/ml. In some embodiments of an oral liquid formulation, the formulation comprises a flavoring agent. In some embodiments of an oral liquid formulation, the oral liquid formulation comprises a sweetener. In some embodiments of an oral liquid formulation, the sweetener is sucralose. In some embodiments of an oral liquid formulation, the oral liquid formulation further comprises unreacted salt forming agent. In some embodiments of an oral liquid formulation, the oral liquid formulation is in the form of a suspension. In some embodiments of an oral liquid formulation, the pH of the oral liquid formulation is between about 3 and about 8. In some embodiments of an oral liquid formulation, the pH is between about 4 and about 5. In some embodiments of an oral liquid formulation, the pH is between about 5 and about 6. In some embodiments of an oral liquid formulation, the amount of the pharmaceutically acceptable salt of amlodipine corresponds to about 0.8 mg/ml to about 1.2 mg/ml of amlodipine free base. In some embodiments of an oral liquid formulation, the formulation is stable at about 25±5° C. for at least 12 months. In some embodiments of an oral liquid formulation, the formulation is stable at about 5±5° C. for at least 12 months. In some embodiments of an oral liquid formulation, the formulation is stable at about 25±5° C. for at least 24 months. In some embodiments of an oral liquid formulation, the formulation is stable at about 5±5° C. for at least 24 months. Also disclosed herein is an oral liquid formulation, comprising: (i) a pharmaceutically acceptable salt of amlodipine in an amount corresponding to 1.0 mg/ml amlodipine freebase; (ii) about 3 mM of a citrate buffer; (iii) about 0.2 mg/ml to about 10 mg/ml of sodium benzoate; (iv) about 0.5 mg/ml of silicon dioxide; (v) about 7.5 mg/ml of hydroxypropyl methylcellulose; (vi) about 0.15 mg/ml simethicone; (vii) optionally about 1.0 mg/ml of polysorbate 80; and (viii) water; wherein the formulation is stable between about 5±5° C. and about 25±5° C. for at least 12 months. In some embodiments of an oral liquid formulation, the pharmaceutically acceptable salt of amlodipine is amlodipine benzoate or amlodipine naphthalene sulfonate. In some embodiments of an oral liquid formulation, the amlodipine benzoate or amlodipine naphthalene sulfonate are formed in situ. In some embodiments of an oral liquid formulation, the amlodipine benzoate or amlodipine naphthalene sulfonate are formed by the reaction of amlodipine besylate with a molar excess of a salt forming agent. In some embodiments of an oral liquid formulation, the salt forming agent is sodium benzoate. In some embodiments of an oral liquid formulation, the amount of sodium benzoate as the salt forming agent is about 1.0 mg/ml to about 10.0 mg/ml. In some embodiments of an oral liquid formulation, the salt forming agent is sodium naphthalene-2-sulfonate. In some embodiments of an oral liquid formulation, the amount of sodium naphthalene-2-sulfonate as the salt forming agent is about 0.5 mg/ml to about 2.5 mg/ml. In some embodiments of an oral liquid formulation, the formulation further comprises a flavoring agent. In some embodiments of an oral liquid formulation, the formulation further comprises a sweetener. In some embodiments of an oral liquid formulation, the sweetener is sucralose. In some embodiments of an oral liquid formulation, the oral liquid formulation further comprises unreacted salt forming agent. In some embodiments of an oral liquid formulation, the formulation is in the form of a suspension. In some embodiments of an oral liquid formulation, the pH of the formulation is between about 3 and about 8. In some embodiments of an oral liquid formulation, the pH is between about 4 and about 5. In some embodiments of an oral liquid formulation, the pH is between about 5 and about 6. In some embodiments of an oral liquid formulation, the formulation is stable at about 25±5° C. for at least 12 months. In some embodiments of an oral liquid formulation, the formulation is stable at about 5±5° C. for at least 12 months. In some embodiments of an oral liquid formulation, the formulation is stable at about 25±5° C. for at least 24 months. In some embodiments of an oral liquid formulation, the formulation is stable at about 5±5° C. for at least 24 months. Also disclosed herein is a process for preparing a stable amlodipine oral liquid formulation, the process comprising mixing a first mixture with a second mixture; the first mixture comprising: (i) amlodipine benzoate; (ii) sodium benzoate; (iii) optionally polysorbate 80; and (iv) water; and the second mixture comprising: (i) citric acid; (ii) sodium citrate; (iii) sucralose; (iv) optionally a flavoring agent; (v) hydroxypropyl methylcellulose; (vi) simethicone; (vii) silicon dioxide; and (viii) water. In some embodiments of a process for preparing a stable amlodipine oral liquid formulation, the first mixture is obtained by a process comprising: (i) adding water to a first container which is not stainless steel; (ii) adding amlodipine besylate to the first container; (iii) adding sodium benzoate to the first container; (iv) optionally adding polysorbate 80 to the first container; and (v) stirring until amlodipine benzoate substantially precipitates. In some embodiments of a process for preparing a stable amlodipine oral liquid formulation, the second mixture is obtained by a process comprising: (i) adding water to a second container; (ii) adding citric acid to the second container; (iii) adding sodium citrate to the second container; (iv) adding sucralose to the second container; (v) optionally adding the flavoring agent to the second container; (vi) adding hydroxypropyl methylcellulose to the second container; (vii) adding simethicone to the second container; (viii) adding silicon dioxide to the second container; and (ix) stirring. Also disclosed herein is a process for preparing a stable amlodipine oral liquid formulation, the process comprising mixing a first mixture with a second mixture; the first mixture comprising: (i) amlodipine naphthalene sulfonate; (ii) optionally sodium benzoate; (iii) optionally polysorbate 80; and (iv) water; and the second mixture comprising: (i) citric acid; (ii) sodium citrate; (iii) sucralose; (iv) optionally a flavoring agent; (v) hydroxypropyl methylcellulose; (vi) simethicone; (vii) silicon dioxide; and (viii) water. In some embodiments of a process for preparing a stable amlodipine oral liquid formulation, the first mixture is obtained by a process comprising: (i) adding water to a first container which is not stainless steel; (ii) adding amlodipine besylate to the first container; (iii) adding sodium naphthalene-2-sulfonate to the first container; (iv) adding sodium benzoate to the first container; (v) optionally adding polysorbate 80 to the first container; and (vi) stirring until amlodipine naphthalene sulfonate substantially precipitates. In some embodiments of a process for preparing a stable amlodipine oral liquid formulation, the second mixture is obtained by a process comprising: (i) adding water to a second container; (ii) adding citric acid to the second container; (iii) adding sodium citrate to the second container; (iv) adding sucralose to the second container; (v) optionally adding the flavoring agent to the second container; (vi) adding hydroxypropyl methylcellulose to the second container; (vii) adding simethicone to the second container; (viii) adding silicon dioxide to the second container; and (ix) stirring. In some embodiments of a process for preparing a stable amlodipine oral liquid formulation, the first mixture does not comprise sodium benzoate and the second mixture further comprises a paraben. Also disclosed herein is a method of treating hypertension in a subject comprising administering to that subject a therapeutically effective amount of an amlodipine oral liquid formulation comprising: (i) a pharmaceutically acceptable salt of amlodipine in an amount corresponding to 1.0 mg/ml amlodipine freebase; (ii) about 3 mM of a citrate buffer; (iii) about 0.2 mg/ml to about 10 mg/ml of sodium benzoate; (iv) about 0.5 mg/ml of silicon dioxide; (v) about 7.5 mg/ml of hydroxypropyl methylcellulose; (vi) about 0.15 mg/ml simethicone; (vii) optionally about 1.0 mg/ml of polysorbate 80; and (viii) water; wherein the formulation is stable between about 5±5° C. and about 25±5° C. for at least 12 months. In some embodiments of a method of treating hypertension, the pharmaceutically acceptable salt of amlodipine is amlodipine benzoate or amlodipine naphthalene sulfonate. In some embodiments of a method of treating hypertension, the amlodipine benzoate or amlodipine naphthalene sulfonate are formed in situ. In some embodiments of a method of treating hypertension, the oral liquid formulation further comprises unreacted salt forming agent. In some embodiments of a method of treating hypertension, the salt forming agent is sodium benzoate. In some embodiments of a method of treating hypertension, the salt forming agent is sodium naphthalene-2-sulfonate. In some embodiments of a method of treating hypertension, the hypertension is primary (essential) hypertension. In some embodiments of a method of treating hypertension, the hypertension is secondary hypertension. In some embodiments of a method of treating hypertension, the subject has blood pressure values greater than or equal to 140/90 mmm Hg. In some embodiments of a method of treating hypertension, the subject is an adult. In some embodiments of a method of treating hypertension, the subject is elderly. In some embodiments of a method of treating hypertension, the subject is a child. In some embodiments of a method of treating hypertension, the formulation is administered to the subject in a fasted state. In some embodiments of a method of treating hypertension, the formulation is administered to the subject in a fed state. In some embodiments of a method of treating hypertension, the formulation is further administered in combination with an agent selected from the group consisting of diuretics, beta blockers, alpha blockers, mixed alpha and beta blockers, calcium channel blockers, angiotensin II receptor antagonists, ACE inhibitors, aldosterone antagonists, and alpha-2 agonists. Also disclosed herein is a method of treating Coronary Artery Disease (CAD) in a subject comprising administering to that subject a therapeutically effective amount of an amlodipine oral liquid formulation comprising: (i) a pharmaceutically acceptable salt of amlodipine in an amount corresponding to 1.0 mg/ml amlodipine freebase; (ii) about 3 mM of a citrate buffer; (iii) about 0.2 mg/ml to about 10 mg/ml of sodium benzoate; (iv) about 0.5 mg/ml of silicon dioxide; (v) about 7.5 mg/ml of hydroxypropyl methylcellulose; (vi) about 0.15 mg/ml simethicone; (vii) optionally about 1.0 mg/ml of polysorbate 80; and (viii) water; wherein the formulation is stable between about 5±5° C. and about 25±5° C. for at least 12 months. In some embodiments of a method of treating Coronary Artery Disease (CAD), the pharmaceutically acceptable salt of amlodipine is amlodipine benzoate or amlodipine naphthalene sulfonate. In some embodiments of a method of treating Coronary Artery Disease (CAD), the amlodipine benzoate or amlodipine naphthalene sulfonate are formed in situ. In some embodiments of a method of treating Coronary Artery Disease (CAD), the oral liquid formulation further comprises unreacted salt forming agent. In some embodiments of a method of treating Coronary Artery Disease (CAD), the salt forming agent is sodium benzoate. In some embodiments of a method of treating Coronary Artery Disease (CAD), the salt forming agent is sodium naphthalene-2-sulfonate. In some embodiments of a method of treating Coronary Artery Disease (CAD), the Coronary Artery Disease (CAD) is chronic stable angina, vasospastic angina, or angiographically documented coronary artery disease. In some embodiments of a method of treating Coronary Artery Disease (CAD), the angiographically documented coronary artery disease is in patients without heart failure or an ejection fraction <40%. In some embodiments of a method of treating Coronary Artery Disease (CAD), the formulation is further administered in combination with an additional anti-anginal agent.
A61K314422
20171006
20180412
96348.0
A61K314422
1
SOROUSH, LAYLA
AMLODIPINE FORMULATIONS
UNDISCOUNTED
0
ACCEPTED
A61K
2,017